THE ALKALOIDS Chemistry and Physiology
VOLUME XI1
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THE ALKALOIDS Chemistry and Physiology Edited by
R. H. F. MANSKE UniRoyal Limited Research Laboratory Cuelph, Ontario, Canada
VOLUME XI1
1970 ACADEMIC PRESS NEW YORK LONDON
COPYRIGHT0 1970, BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED, N O PART OF THIS BOOK MAY B E REPRODUCED IN A N Y FORM, B Y PHOTOSTAT, MICROFILM, RETRIEVAL SYSTEM, OR A N Y OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM T H E PUBLISHERS.
ACADEMIC PRESS, INC. 111 Fifth Avenue, New York, New York 10003
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PRINTED IN T H E U N I T E D STATES OF AMERICA
LIST OF CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin.
E. G. C. CLARKE,The Royal Veterinary College, University of London, London, England (513)
L. H. KEITH, Department of Chemistry, The University of Georgia, Athens, Georgia (xv, 1, 135)
R. H. F. MANSKE,UniRoyal Limited Research Laboratory, Guelph, Ontario and the University of Waterloo, Waterloo, Ontario, Canada (455)
S. W. PELLETIER, Department of Chemistry, The University of Georgia, Athens, Georgia (xv, 1, 135)
F.
~ A N T A V + ’ , Institute of Chemistry, Medical Faculty, Palack$ University, Olomouc, Czechoslovakia (333)
J. E. SAXTON, The University, Leeds, England (207) FRANKL. WARREN, C.S.I.R. Natural Products Research Unit, University of Cape Town, Rondebosch, Cape Province, South Africa (245)
V
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PREFACE The proliferation of alkaloid literature which has been so marked for several decades has continued. The discovery of new sources of known alkaloids and the discovery of new alkaloids in new and already examined sources together with new structural and synthetic studies call for periodic reviews. This volume is an attempt to bring some of the alkaloid chemistry up-to-date. As in the more recent volumes we have chosen a number of subjects which seem appropriate at this time. Entries in the Subject Index are restricted to topics which are basic to the substances or groups under discussion; incidental mention does not necessarily merit inclusion. The abbreviations used for journals in literature references are those found in Chemical Abstracts List of Periodicals. Once more the editor, on behalf of the publisher and himself, takes this opportunity to express his indebtedness to the conscientious and competent authors who have made the publication of this volume possible.
R. H. F. MANSKE Guelph, Ontario December, 1969
vii
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CONTENTS LISTOF CONTRIBUTORS ................................................... PREFACE ...............................................................
CONTENTSOFPREVIOUSVOLUMES ..........................................
V
vii xi
The Diterpene Alkaloids: General Introduction S. W . PELLETIER AND L . H . KEITH Text
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xv
Chapter 1. Diterperie Alkaloids from Aconitum. Delphinium. and Garryn Species: The (219-Diterpene Alkaloids S. W . PELLETIER AND L H . KEITH
.
I. I1. I11. IV . V.
Introduction .................................................... Lycoctonine-Type Alkaloids ....................................... Aconitine-Type Alkaloids ......................................... Lactone-Type Diterpene Alkaloids ................................. Uncharacterized Alkaloids ........................................ References ......................................................
2 10 40 109 118 129
Chapter 2 . Diterpene Alkaloids from Aconitum. Delphinium. and Garrya Species: The (220-DiterpeneAlkaloids S. W . PELLETIER AND L . H . KEITH
I. Introduction .................................................... I1. The Garrya Alkaloids ............................................. I11. The Atisine Alkaloids ............................................. IV . Correlations and Absolute Stereochemistry of Atisine and Garrya Alkaloids V. The Ternary Iminium Salts of the Atisine and Gtarrya Alkaloids ......... VI . The Chemistry of Alkaloids with a Modified Atisine Skeleton ........... VII . Synthesis of Diterpene Alkaloids ................................... References ......................................................
136 136 143 155 166 174 188 202
Chapter 3 . Alkaloids of Alstoriin Species J . E . SAXTON
I. I1. I11. IV . V.
Occurrence ...................................................... Venenatine. Isovenenatine. and Venoxidine .......................... Tetrahydroalstonine. Alstoniline. and Echitamine .................... Villalstonine .................................................... Alstophylline .................................................... ix
207 209 211 213 223
CONTENTS
X
VI . Macralstonine ................................................... VII . Macrosalhine .................................................... VIII . Macralstonidine ................................................. References ......................................................
228 235 238 243
Chapter 4 . Senecio Alkaloids FRANK L . WARREN I. I1 . I11. IV .
1’. VI . VII . VIII .
Occurrence and Constitution (37-46) ................................ Structure of the Necines (49-68) .................................... Structures of the Neck Acids (68-109) ............................... Structure of the Alkaloids (109-116) ................................ Biosynthesis ( 1 1 7 ) ............................................... Pharmacology ( 1 17) .............................................. AnalyticalProcedures ............................................ Other Pyrrolizidine Alkaloids ...................................... References ......................................................
246 246 274 299 316 319 321 322 324
Chapter 5 . Papaveraceae Alkaloids F . SANTAVP 333 I . Introduction .................................................... 344 I1. Occurrence ...................................................... I11. Structures. Chemical and Physicochemical Properties. and Biosynthesis 347 of the Papaveraceae Alkaloids ..................................... 429 IV . Biosynthetic and Chemotaxonomic Conclusions ...................... 435 V. Addendum : The Alkaloids of Fumariaceous Plants .................... 438 References ...................................................... Chapter 6 . Alkaloids Unclassified and of Unknown Structure R . H . F . MANSKE I . Introduction .................................................... I1. Plants and Their Contained Alkaloids ............................... References ......................................................
455 455 506
Chapter 7 . The Forensic Chemistry of Alkaloids E . G . C. CLARKE I . Introduction .................................................... I1. Poisoning by Alkaloids ........................................... I11. Alkaloids as Drugs of Addiction .................................... 11’. Control of Alkaloids .............................................. V . Toxicological Analysis-General Considerations ...................... T’I . Extraction Methods .............................................. VII . Identificationhlethods ............................................ VIII . Tables of Analytical Data ......................................... Refcrences ......................................................
514 515 536 540 543 545 554 560 579
A U T H O R I ~ D.......................................................... ~X SUBJECTINDEX .........................................................
591 623
CONTENTS OF PREVIOUS VOLUMES
Contents of Volume I CHAPTER 1. 2. 3. 4. 5. 6. 7.
Sources of Alkaloids and Their Isolation BY R . H . F . MANSKE Alkaloids in the Plant BY W . 0 . JAMES . . . . . . . The Pyrrolidine Alkaloids BY LEOMARION . . . . . . Senecio Alkaloids BY NELSONJ . LEONARD. . . . . . The Pyridine Alkaloids BY LEOMARION . . . . . . The Chemistry of the Tropane Alkaloids BY H . L . HOLMES . The Strychnos Alkaloids BY H . L . HOLMES . . . . . .
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1 15 91 107 165 271 375
Contents of Volume I I 1 8.1 . The Morphine Alkaloids I BY H . L . HOLMES . . . . . . . . 8.11 . TheMorphine A l k a l o i d s I I ~H~. L.HOLMESAND (INPART) GILBERT~TORK 161 9 . Sinomenine BY H . L . HOLMES . . . . . . . . . . . . 219 10. Colchicine BY J . W . COOKAND J . D . LOUDON. . . . . . . . 261 11. Alkaloids of the Amaryllidaceae BY J . W . COOKAND J . D . LOUDON. . 33 1 12. Acridine Alkaloids BY J . R . PRICE . . . . . . . . . . . 353 13. The Indole Alkaloids BY LEOMARION . . . . . . . . . . 369 14. The Erythrina Alkaloids BY LEOMARION . . . . . . . . . 499 15. The Strychnos Alkaloids . Part I1 BY H . L . HOLMES . . . . . . 513 Contents of Volume I I l B . TURNER AND 16. The Chemistry of the Cinchona Alkaloids BY RICHARD R . B . WOODWARD. . . . . . . . . . . . . . . 17 . Quinoline Alkaloids. Other than Those of Cinchona BY H . T . OPENSHAW 18. The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . 19. Lupin Alkaloids BY NELSONJ . LEONARD . . . . . . . . . 20 . The Imidazole Alkaloids BY A . R BATTERSBY AND H . T . OPENSHAW . 21 . The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOC AND 0 . JEGER . . . . . . . . . . . . . . . . . . 22 . j3-Phenethylamines BY L . RETI . . . . . . . . . . . . 23 . Ephreda Bases BY L . RETI . . . . . . . . . . . . . 24 . The Ipecac A l k a l o i d s ~MAURICE-MARIE ~ JANOT . . . . . . .
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1 65 101 119 201 247 313 339 363
Contents of Volume I V 25 . The Biosynthesis of Isoquinolines BY R . H . F. MANSKE 26 . Simple Isoquinoline Alkaloids BY L . RETI . . . . xi
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1 7
xii
CONTENTS OF PREVIOUS VOLUMES
CHAPTER 27 . Cactus Alkaloids BY L . RETI . . . . . . . . . . . . . 28. The Benzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . 29. The Protoberberine Alkaloids BY R . H. F . & f A N s K E AND WALTER R . ASHFORD
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30 . The Aporphine Alkaloids BY R . H . F . MANSKE. . . . . . . . 31. The Protopine Alkaloids BY R . H . F . MANSKE . . . . . . . . STAN?& AND R . H . F . 32 . Phthalideisoquinoline Alkaloids BY JAROSLAV MANSKE . . . . . . . . . . . . . . . . . . 33. Bisbenzylisoquinoline Alkaloids BY MARSHALLKULKA . . . . . 34 . The Cularine Alkaloids BY R . H . F . MANSKE . . . . . . . . 35. m-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . 36. The Erythrophleium Alkaloids BY G. DALMA . . . . . . . . 37 . The Aconitum and Delphinium Alkaloids BY E . S. STERN . . . .
23 29 77 119 147 167 199 249 253 265 275
Contents of Volume V 38. 39. 40 . 41. 42 . 43 . 44 . 45. 46 . 47 . 48.
Narcotics and Analgesics BY HUGOKRUEGER. . . . . Cardioactive Alkaloids BY E . L . MCCAWLEY . . . . . Respiratory Stimulants BY MARCELJ . 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. MANSKE . . . . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE
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1
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79 109 141 163 211 229 243 265 295 301
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1 31 35 123 145 179 219 247 289
Contents of Volume V I 1. 2. 3. 4. 5. 6. 7. 8. 9.
Alkaloids in the Plant BY K . MOTHES . . . . . . The Pyrrolidine Alkaloids BY LEOMARION . . . . . Senecio Alkaloids BY NELSON J . LEONARD. . . . . The Pyridine Alkaloids BY LEOM ~ R I O N . . . . . The Tropane Alkaloids BY G. FODOR . . . . . . The Strychnos Alkaloids BY J . B . HENDRIORSON . . . The Morphine Alkaloids BY GILBERTSTORK . . . . Colchicine and Related Compounds BY W . C. WILDMAN. Alkaloids of the Amaryllidaceae BY W . C. WILDMAN. .
Contents of Volume V I I 10. 11. 12. 13. 14. 15. 16.
The Indole Alkaloids BY J . E . SAXTON. . . . . . . . . . 1 The Erythrina Alkaloids BY V . BOEKELHEIDE . . . . . . . . 201 Quinoline Alkaloids Other Than Those of Cinchona BY H . T . OPENSHAW229 The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . 247 Lupin Alkaloids BY NELSON J . LEONARD . . . . . . . . . 253 Steroid Alkaloids: The Holarrhena Group BY 0 . JEGER AND V . PRELOC . 319 Steroid Alkaloids: The Solanum Group BY T'. PRELOG AND 0. JECER. 343
...
CONTENTS O F PREVIOUS VOLUMES
XI11
CHAPTER . 17. Steroid Alkaloids: Veratrum Group BY 0 . JEGER AND V. PRELOG. 18. The Ipecac Alkaloids BY R . H . F . MANSKE . . . . . . . . . 19. Isoquinoline Alkaloids BY R . H . F. MANSKE . . . . . . . . 20 . Phthalideisoquinoline Alkaloids BY JAROSLAV STANBK . . . . . 21. Bisbenzylisoquinoline Alkaloids BY MARSHALLKULKA . . . . . 22 . The Diterpenoid Alkaloids from Aconitum, Qelphinium. and Garrya Species BY E . S. STERN. . . . . . . . . . . . . . 23. The Lycopodium Alkaloids BY R . H . F . MANSKE . . . . . . . 24 . Minor Alkaloids of Unknown Structure BY R . H . F . MANSKE. . . .
363 419 423 433 439 473 505 509
Contents of Volume V I I I 1 The Simple Bases BY J . E . SAXTON. . . . . . . . . . . 27 Alkaloids of the Calabar Bean BY E . COXWORTH 47 The Carboline Alkaloids BY R . H . F. MANSEE 55 The Quinazolinocarbolines BY R . H . F. MANSKE . . . . . . . 59 Alkaloids of Mitragyna and Ourouparia Species BY J E . SAXTON . . 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 . .[. TAYLOR. . . . . . 203 The Chemistry of the 2,2 '.Indolylquinuclidine Alkaloids BY W . I . TAYLOR 238 The Pentaceras and the Eburnamine (Hunte.ria)-Vicamine Alkaloids BY W . I . TAYLOR . . . . . . . . . . . . . . . 250 12. The Vinca Alkaloids BY W . I . TAYLOR . . . . . . . . . . 272 13. Rouwolfia Alkaloids with Special Reference to the Chemistry of Reserpine BY E . SCHLITTLER. . . . . . . . . . . . . . . 287 14. The Alkaloids of Aspidosperma, Diplorrhyncus, Kopsia, Ochrosiu, Pleiocarpa, and Related Genera BY B . GILBERT. . . . . . . 336 15. Alkaloids of Calabash Curare and Strychnos Species BY A . R . BATTERSBY AND H . F . HODSON. . . . . . . . . . . . . . . 515 16. The Alkaloids of Calycanthaceae BY R . H . F . MANSKE . . . . . 581 17. St.rychnosAlkaloids BY G . F. SMITH . . . . . . . . . . . 592 18. Alkaloids of Haplophyton cimicidum BY J . E . SAXTON . . . . . 673 19. The Alkaloids of Geissospermum Species BY R . H . F. MANSKE AND W . ASHLEYHARRISON. . . . . . . . . . . . . . . 679 694 20. Alkaloids of Pseudocinchona and Yohimbe BY R . H . F. MANSKE 21. The Ergot Alkaloids BY A . STOLLAND A . HOFMANN. . . . . . 726 22 . The Ajmaline-Sarpagine Alkaloids BY W . I. TAYLOR . . . . . . 789 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11
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Contents of Volume I X 1 . The Aporphine Alkaloids
BY MAURICESHAMMA . . . . . . . 1 2 The Protoberberine Alkaloids BY P . W . JEFFS . . . . . . . . 41 STANBK . . . . . 117 3. Phthalideisoquinoline Alkaloids BY JAROSLAV 4. Bisbenzylisoquinoline and Related Alkaloids BY M . CURCUMELLIRODOSTAMO AND MARSHALLKULKA . . . . . . . . . . 133 5. Lupine Alkaloids BY FERDINAND BOHLMANN AND DIETERSCHUMANN . 175 6. Quinoline Alkaloids Other Than Those of Cinchona BY H . T . OPENSHAW223 7 . The Tropane Alkaloids BY G. FODOR . . . . . . . . . . 269
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xiv
CONTENTS O F PREVIOUS VOLUMES
CHAPTER 8. Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V . C E R N ~ a n d F . SORM. . . . . . . . . . . . . . . . . 305 9 . The Steroid Alkaloids: The Salamandra Group BY GERHARD HABERMEHL 427 10. Nuphar Alkaloids BY J . T. WROBEL. . . . . . . . . . . 441 467 11 . The Mesembrine Alkaloids BY A . POPELAK AND G. LETTENBAUER. 12. The Erythrina Alkaloids BY RICHARDK . HILL . . . . . . . . 483 . . . . . . . . 517 13. Tylophora Alkaloids BY T R GOVINDACHARI 14. The Galbulimima Alkaloids BY E . RITCHIEAND . c. TAYLOR. . . 529 15. The Stemona Alkaloids BY 0. E . EDWARDS. . . . . . . . . 545
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Contents of Volume X 1 1. Steroid Alkaloids: The Solanum Group BY KLAUSSCHRIEBER . . . 2. The Steroid Alkaloids: The Veratrurn Group BY S . MORRISKUPCHAN AND ARNOLD W . BY . . . . . . . . . . . . . . . . 193 B . MORIN . . . . . . . 287 3 . Erythrophleum Alkaloids BY ROBERT 4 . The Lycopodium Alkaloids BY D . 13. MACLEAN . . . . . . . . 306 5. Alkaloids of the Calabar Bean BY B . ROBINSON . . . . . . . 383 6 . The Benzylisoquinoline Alkaloids BY VENANCIODEULOFEU,JORGE COMIN.AND MARCELOJ . VERNENGO 402 7. The Cularine Alkaloids BY R . H . F MANSKE . . . . . . . . 463 8 . Papaveraceae Alkaloids BY R H . F. MANSKE . . . . . . . . 467 9 . a-Naphthaphenanthridine Alkaloids BY R . H F. MANSKE . . . . 485 491 10. The Simple Indole Bases BY J . E . SAXTON 11 . Alkaloids of PicraZima Nitida BY J . E . SAXTON . . . . . . . 601 12. Alkaloids of Mitragyna and Ourouparia Species BY J . E . SAXTON . . 521 13. Alkaloids Unclassified and of Unknown Structure BY R . H . F . MANSKE. 545 14. The T a m s Alkaloids BY B . LYTHGOE . . . . . . . . . . 597
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Contents of Volume X
I
1 . The Distribution of Indole Alkaloids in Plants BY V . SNIECKUS. . . 2 . The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR 3 . The 2,2 '.Indolylquinuclidine Alkaloids BY W . I. TAYLOR. . . . . 4 . The Iboga and Voacanga Alkaloids BY W I . TAYLOR 5 . The Vinca Alkaloids BY W I . TAYLOR . . . . . . . . . . 6 . The Eburnamine-Vincamine Alkaloids BY W . I TAYLOR. . . . . 7. Yohimbine and Related Alkaloids BY H . J MONTEIRO . . . . . 8 . Alkaloids of Calabash Curare and Strychnos Species BY A . R . BATTERSBY
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1 41 73 79 99 125 145
AND H . F . HODSON . . . . . . . . . . . . . . . 189 9 . The Alkaloids of Aspidospewnu, Ochrosia, Pleiocarpa, Melodinus, and Related Genera BY B . GILBERT . . . . . . . . . . . 205 10. The Amaryllidaceae Alkaloids BY W . C. WILDMAN . . . . . . . 307 11. Colchicine and Related Compounds BY W .C.WILDMAN AND B .A .PURSEY 407 12. The Pyridine Alkaloids BY W. A . AYERAND T E HABGOOD 459
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THE DITERPENE ALKALOIDS: GENERAL INTRODUCTION S. W. PELLETIERAND L. H. KEITH Department of Chemistry, The University of Georgia, Athens, Georgia
The diterpene alkaloids are derived from tetracyclic or pentacyclic diterpenes in which carbon atoms 19 and 20 are linked with the nitrogen of a molecule of 8-aminoethanol, methylamine, or ethylamine to form a heterocyclic ring. These alkaloids may be divided into two broad categories. The first group comprises the highly toxic ester bases (aconitines and lycoctonines) which are heavily substituted by methoxyl and hydroxyl groups. Hydrolysis of these esters furnishes the relatively nontoxic amino alcohols (alkamines) which are modeled on a hexacyclic (319-skeleton. This class of alkaloids is considered in Chapter 1. The second group includes a series of comparatively simple and relatively nontoxic alkamines which are modeled on a Czo-skeleton and are treated in Chapter 2. These compounds (sometimes loosely referred to as the " atisines ") are not extensively oxygenated and contain at most one methoxyl group. One of the distinguishing chemical features of this group is the formation of phenanthrenes when subjected to selenium or palladium dehydrogenation. A few compounds of this class occur in the plant as monoesters of acetic or benzoic acid. Thus far four different types of skeletons* have been encountered among the diterpene alkaloids. They are the veatchine, atisine, lycoctonine, and heteratisine types (see chart of skeletons). The veatchine skeleton which occurs in the Garrya alkaloids, e.g., veatchine, cuauchichicine, and songorine, incorporates a kaurane skeleton and obeys the isoprene rule. The atisine skeleton is modeled on an atisane nucleus and differs from the veatchine type in that ring D is six-memberedrather than five-membered ; it does not obey the isoprene rule. The atisine skeleton appears in such alkaloids as atisine, atidine, hetisine, ignavine, and kobusine. The lycoctonine skeleton, modeled on the aconane framework, is found in one
*
The nomenclature of these alkaloids is based upon the standard skeletons atisane, kaurane, and aconane with the numbering and stereoohemistry illustrated. These skeletons have been incorporated into a proposal for the Common and Systematic Nomenclature of Cyclic Diterpenes which will be submitted to the IUPAC Commission on the Nomenclature of Organic Chemistry in 1969 and published in M. Fetizon and Le-VanThoi's forthcoming book on the cyclic diterpenes.
xvi
S . W . PELLETlER AND L. H . KEITH
form or other in most of the aconitines and lycoctonines, e.g., aconitine, hypaconitine, delphinine, lycoctonine, and ajacine. It may be derived formally from the atisine skeleton by cleavage of the C-8-C-9 bond,
Kaurane
Veatchine skeleton 17
8
12 *.
1
---__
'
.?7
18
15
] O H
5
3 4
0 '\
7
-----
6
H
19 18
19 18
Atisine skeleton
Atisene 16
15
19
18
19
Lycoctonine skeleton
18
Aconane
-
16
Heteratisine skeleton
formation of new bonds between C-7 and C-20 and C-9 and C-15 and loss of the C-17 exocyclic methylene group. The heteratisine skeleton differs from the lycoctonine type in that expansion of ring C by insertion of oxygen has occurred to give a lactone. All the diterpene alkaloids encountered to date in nature are constructed on these four skeletal types.
THE DITERPENE ALKALOIDS : GENERAL INTRODUCTION
xvii
In certain alkaloids, however, one or more additional ring fusions are present. Thus, songorine has a bond between C-7 and C-20 of the veatchine skeleton and kobusine has bonds between C-14 and C-20 and between C-6 and the nitrogen of the atisine skeleton. The chemistry of the diterpene alkaloids was last reviewed in a detailed manner in 1960, with coverage of the literature through the early part of 1957. These chapters survey the literature as listed in Chemical Abstracts through July 1, 1968.
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-CHAPTER
1-
DITERPENE ALKALOIDS FROM ACONITUM. DELPHlNlUM. AND GARRYA SPECIES: THE C... DITERPENE AJXALOIDS S. W . PELLETIER A N D L . H . KEITH Department of Chemistry. The Uiiiversity of Georgin. A the iis. Georgin
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I Introduction ...................................................... I1 Lycoctonine-Type Alkaloids .......................................... A. Lycoctonine(Roy1ine) ............................................ B . Elatine, Anthranoyllycoctonine (Inuline), Ajacine, Methyllycaconitine, Delsemine, Avadharidine, and Lycaconitine .......................... C . Delpheline, Deltaline (Eldeline, Delphelatine), and Deltamine (Eldelidine) D . Delcosine (Delphamine, Lucaconine, Takao Base I, Alkaloid C), Monoacetyldelcosine (Monoacetyllucaconine, Alkaloid B), and 14-Dehydrodelcosine (Shimoburo Base 11)........................................ E Delsoline ........................................................ F. Browniine and Dehydrobrowniine .................................. I11. Aconitine-Type Alkaloids ............................................ A . Aconitine ...................................................... B Jesaconitine .................................................... C Mesaconitine, Hypaconitine, and Deoxyaconitine ...................... D . Delphinine ...................................................... E . Indaconitine and Pseudaconitine .................................... F. Bikhaconitine ................................................... G Chasmaconitine and Chasmanthinine ................................ H . Chasmanine (Toroko Base 11)....................................... I . Homochasmanine ................................................ J Neoline and Neopelline ............................................ K . Condelphine, Talatizidine, and Isotalatizidine ......................... IV . Lactone-Type Diterpene Alkaloids .................................... A . Heteratisine ..................................................... B Heterophyllisine, Heterophylline, and Heterophyllidine . . . . . . . . . . . . . . . . V. Uncharacterized Alkaloids ........................................... A. Lappaconitine, Talatisine, and Talatisamine .......................... B Newly Isolated Alkaloids .......................................... References .........................................................
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2 10 10 16
19
26 35 36 40 40 58 60 64 12 78
83 86 93 95 99 109 109 115 118 118 120 129
2
S. W. PELLETIER AND L. H. KEITH
I. Introduction The structures of the more complicated diterpene alkaloids may be subdivided into two general types of skeletons which are closely related. TABLE I ALKALOIDS OF KNOWN STRUCTURE Alkaloid
Correlated with or by-
References
By X-ray crystallography Lycoctonine Lycoctonine Lycoctonine Lycoctonine Lycoctonine Lycoctonine Lycoctonine Delpheline Delpheline Deltaline By X-ray crystallography
4-6 19 19 19 19 19 19 19 31 31 36,19 64
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. a
Lycoctonine (royline) Elatine Anthranoyllycoctonine (inuline) Ajacine Lycaconitine Methyllycaconitine Delsemine Avadharidine Deltaline Deltaline (eldeline, delphelatine) Deltamine (eldelidine) Delcosine (delphamine, lucaconine, Takao base I, alkaloid C) Monoacetyldelcosine (alkaloid B, monoacetyllucaconine) 14-Dehydrodelcosine De1so1ine Browniine Dehydrobrowniine Aconitine Jesaconitine Deoxyaconitine Mesaconitine Hypaconitine Delphinine Pseudaconitine ( a-pseudaconitine) Indaconitine Bikhaconitine Chasmaconitine Chasmanthinine Chasmanine (Toroko base 11) Homochasmanine Neolinea Neopellinea Condelphine Isotalatisidine Talatisidine Probable structures.
Delcosine
46
Delcosine Delcosine Lycoctonine Browniine By X-ray crystallography Aconitine Aconit ine Aconitine Mesaconitine Aconitine Aconitine Pseudaconitine and delphinine Pseudaconitine Bikhaconitine and delphinine Bikhaconitine Browniine Chasmanine Delphinine (only by ORD) Neoline
-
54,55 60 69
70 75, 76 100 113 1 112,113 116 123 127 129 131 131 135 137 64e 140 -
-
1.
THE
CIS-DITERPENEALKALOIDS
3
TABLE I1 ALKALOID STRUCTURESa Lycoctonine-type
I
OH
OCH3
Lycoctonine
Elatine
Anthranoyllycoctonine : R = NH2 Ajacine: R
//O
= CH&-NH-
9\ Lycaconitine: R = -N
3
Methyllycaconitine: R = -N
VCH3
0 0 Avadharidine : Et
11
= -NH-C-CHz-CHz-C-NHz
0 CH3 Dekemine : R
II I
= -NH-C-CH-CH2-C-NH2
0
or
/O
CH3
It 1 -NH-C-CH2-CH-C-NH2
/O
R0
4
S. W. PELLETIER AND L. H. KEITH
TABLE 11-continued Lycoctonine-type-continued
I
-
OR
OH Delpheline
____----OH
Deltaline : R = Ac (eldeline) Deltamine : R = H (eldelidine)
.--
OH OCH3
-
Browniine
Dehydrobrowniine
OCH, Delsoline: R = CH3 Delcosine: R = H Monoacetyldelcosine:R = Ao
Dehydrodelcosine
1. THE C
I
S
- ALKALOIDS ~ ~ ~
~
~
~5
TABLE 11-continued
Aconitine: R = Et, R’ = Bz Jesaconitine: R = Et, R’ = As Mesaconitine: R = Me, R’ = Bz
Pseudaconitine: R = Vr Indaconitine: R = Bz
OH
’.OR‘
‘‘OH OCH3 Delphinine: Bikhaconitine: Chasmaconitine: Chasmanthinine:
OCH,
R
= Me,
R
= Et,
R’ = Bz R’ = Vr R = E t , R’ = Bz R = Et, R’ = Cn
Hypaconitine : R = Me Deoxyaconitine: R = E t
OCH3
____----bCH3 OCH3 Chasmanine : R = H Homochasmanine: R = Me
OCH3 Condelphine: R = Ac Isotalatizidine: R = H
~
~
6
S . W. PELLETIER AND L. H. KEITH
TABLE IIL-continued
Aconitine-type-continued
Talatizidine
bNeoline: R = R’= H Neopelline: R = Bz, R’ = Ac
a
Abbreviations. These are used in structures throughout Chapter 1.
AS = CH30a
- c o -
Vr = CH30e
o
-
* Probable structure. The first is the lycoctonine-type, which is based on the parent alkaloid lycoctonine, and the second is the aconitine-type based on the parent alkaloid of the same name. Derivatives of both lycoctonine and aconitine have been subjected to X-ray crystallographic analysis and their absolute configurations have been established from these studies. The other alkaloids of these two groups have either been directly correlated with one of these two alkaloids or with other alkaloids which, in turn, have been correlated with one of them whenever possible. A list of the alkaloids indicating those whose structures are known, or tentatively proposed, is included in Table I along with the alkaloid or alkaloids with which each has been correlated. Table I1 shows the structures of these corresponding alkaloids. The earlier chemistry of most of these alkaloids was covered in Volumes IV and VII of this treatise ( 1 , 2 ) .It is interesting to note that a t
1.
THE
CIS-DITERPENE ALKALOIDS
7
the time of the earlier review none of the structures were known. At the time of the second review the key breakthrough of the skeletal elucidation of lycoctonine had been accomplished by X-ray crystallography and tentative structures had been proposed for delpheline and delcosine. The intervening 7 years have seen the greatest advances yet, as evidenced by Tables I and 11. There are several features which are common t o both subgroups, the most obvious being the hexacyclic skeleton system which is comprised of one seven-membered, three six-membered, and two five-membered rings. Figure 1 illustrates the lettering of the rings as well as the numbering of 13
3
1-48
16
17
19
I
7
15
FIG. 1. The numbering system used for the aconitine-type and lycoctonine-type skeletons.
the positions which will be used throughout this discussion. This skeleton has been incorporated into a proposal for the Common and Systematic Nomenclature of Cyclic Diterpenes which was submitted t o the IUPAC Commission on the Nomenclature of Organic Chemistry in 1969. There are some positions where ambiguity exists when the configuration of a functional group is referred to as equatorial or axial. This may result from more than one conformation of a ring or from nearly 55" angles of the substituents from the plane of the ring. Hence, it is often more definitive to refer to a particular functional group as being alpha (a)or beta @), where the former is defined as being cis to the nitrogen bridge and the latter as being trans to the same. All of the lycoctonine- and aconitine-type skeletons possess a tertiary nitroken substituted with either an ethyl or methyl group. I n addition, they all possess C-1 and C-8 oxygen functional groups as well as a C-14 a-oxygen functional group. This substitution pattern may not prevail in
8
S . W. PELLETIER AND 1,.H. KEITH
all future alkaloids of this type but certainly should occur in the majority of them, thereby affording important clues for structural elucidation. All but three alkaloids (delpheline, deltaline, and deltamine) possess a C-18 oxygen functional group and these three possess a C-18 methyl group instead. Finally, it is to be noted that each contains a methoxyl a t C-16 in the P-configuration. The most important difference between an aconitine-type and a lycoctonine-type skeleton is that the latt'er contains an oxygenated functional group a t C-7 whereas the former does not. The presence or absence of a ditertiary a-glycol system-either as its free hydroxyl or in its methylenated form-is thus the determining factor in the classification, as well as much of the chemistry, of the lycoctonine- and aconitinetype alkaloids, respectively. Two further trends are to be noted. All of the known lycoctonine-type alkaloids have had a P-methoxyl a t C-6 while in all of the aconitine-type alkaloids which contain a C-6 methoxyl, it is in the a-configuration. Also, whereas many of the aconitine-type alkaloids possess a bridgehead hydroxyl a t C-13, none of the lycoctonine-type alkaloids have yet been isolated with a substituent of any kind a t this position. Recent work (3) has demonstrated a chemical method of ascertaining the configuration of the C-6 methoxyl, previously obtainable only by X-ray crystallography or correlation with an alkaloid which, in turn, had had its absolute configuration determined by X-ray crystallography. Brief treatment of the diterpene alkaloids containing an a-C-6 methoxyl with neutral' potassium permanganate in aqueous acetone gave the N-dealkylated derivatives as the predominant products. The presence of a C-3 hydroxyl in ring A of some of the alkaloids had no effect on the course of the oxidation or on the yield of the N-dealkyl base produced, but a double bond in ring A lowered the yield of the latter. On the other hand, similar treatment of those alkaloids bearing a P-C-6 methoxyl gave almost exclusively the lactam derivative, except in the case of delcosine, which has a C-1 a-hydroxyl instead of a C-1 methoxyl. I n the latter the carbinolamine ether was formed instead by condensation of the C-1 hydroxyl with the initially produced carbinolamine hydroxyl and thus may be thought of as being equivalent to the formation of alactam, except that the reaction is stopped halfway by the formation of the stable inner ether. These results may be explained by the steric hindrance offered by a C-6 a-methoxyl to the vulnerable C-19 methylene, thus preventing oxidation of the latter and thereby favoring attack on the iminoethyl group instead. The P-oriented C-6 methoxyl of the lycoctonine-type alkaloids, however, offers no interferences with the C-19 methylene so
L
3
J
O
O
-
L
1. THE
3
O
CIS-DITERPENEALKALOIDS
L
9
FIG.2. Proposed mechanism for the neutral permanganate oxidation of alkaloids (a)with an a-C-6 methoxyl and (b)with a 8-C-6. methoxyl. eD
10
S. W. PELLETIER AND L. H. KEITH
that normal oxidation occurs at this position. A suggested mechanism ( 3 )is shown in Fig. 2. 11. Lycoctonine-TypeAlkaloids A. LYCOCTONINE (ROYLINE) The alkaloid lycoctonine is the parent amino alcohol of a number of ester derivatives which are found in plants of both the Aconitum and the Delphinium genera. Although a great deal of effort was put forth, the skeleton of lycoctonine completely eluded determination by chemical means, a fact well understood when elucidation was finally achieved in 1956 by X-ray crystallography ( 4 ) .The structure of des(oxymethy1ene)lycoctonine hydroiodide monohydrate (I) was determined and the
4
-
f
O
C
H
3
OH OCH3 OCH3 T
T1
1
11
I
01
OH IV
OCH3 V
1.
THE
C
1
9
- ALKALOIDS ~ ~ ~
~
~
~1 1 ~
structure for lycoctonine (11) followed unambiguously (5). Much of the previously known chemistry of lycoctonine was then quickly fitted together (5)and has been covered in the previous review of this treatise (2).Shortly before publication of the previous review, however, a further study of the X-ray crystallographic data ( 6 ) showed that the absolute configuration of des(oxymethy1ene)lycoctonine hydroiodide monohydrate was the mirror image of I. Thus, the correct representation of lycoctonine is I11 and it should be borne in mind that the structures of all of these compounds mentioned in the previous review are in reality the mirror images of those shown. Oxidation of lycoctonine with silver oxide (7-9) or lead tetraacetate (10) gives hydroxylycoctonine, a compound first formulated (5) as IV even though it was known t o form anhydronium salts (lo),the structure
-f
OCH3
OH
OH VI
VII
VIII
IX
I
I
XI
X
~
~
S. W. PELLETIER AND L. H. KEITH
12
of which (V) clearly would produce great strain from the bridgehead double bond. Other inconsistencies with structure I V are shown by the following observations: (a) the related alkaloid delphinine, in which the C-7 and C-8 oxygen functional groups are ether linkages instead of hydroxyls, does not give the corresponding hydroxydelphinine ; (b) although structure I V contains a vicinal trio1 system, glycol cleavage reagents cleaved only one vicinal diol(5); and (c) methyllycoctonamate hydrolyzed much faster than methylhydroxylycoctonamate. These inconsistencies led Valenta (11,lZ)and Edwards et al. (13)to conclude independently that
--
.
OCH3
V I ; R = CHzOH XV; R = C H i
XIV
XVIII
X I I ; R=CHzOH XVI; R=CH3
XIII; R = CHzOH XVII; R=CHa
XIX
1.
THE C
1
g
- ALKALOIDS ~ ~
~
~
~
~13
hydroxylycoctonine must be represented by structure VI and its anhydronium salts by VII. Reduction of hydroxylycoctonine with sodium borohydride produced the trio1 VIII, explained as occurring by the reduction of VII after loss of water (12). Oxidation of VIII with periodic acid gave the hemiacetal ketone IX which was then converted to the unsaturated acetate X. While there is no rigorous proof of the configuration of the C-7 hydroxyl
VI; R = H 2
XXI
xx: R = O
xxv
~
~
~
14
S . W . PELLETIER AND L. H. KEITH
in VIII, it is most likely trans to the C-6 methoxyl since the diacetate X I was observed to lose acetic acid slowly when sublimed. Edwards et al. (13)deduced the correct structure of hydroxylycoctonine from a study of isolycoctonine (XII). The latter is formed by hydrogenation of hydroxylycoctonine over platinum and contains a seven-membered ketone. Permanganate oxidation of isolycoctonine gives the neutral compound isolycoctonam (XIII) which, when further oxidized with lead tetraacetate, produces a keto acid that spontaneously cyclizes and then loses methanol when heated in acid to give the a$unsaturated keto-8-lactone7 XIV. 17-Desoxyhydroxylycoctonine(XV) gives an exactly parallel series of reactions (13)except that, of course, no lactone is formed (XV + XVIII). Zinc and refluxing acetic anhydride removed the tertiary hydroxyl in XIII. Hydrolysis followed by sodium amalgam/alcohol reduction removed the C-6 methoxyl and reduced the ketone t o produce XIX.
XXVIb
XXVId
XXVIr
TABLE I11 NEWLYDESCRIBED DERIVATIVES O F LYCOCTONINE Compound Dihydroisolycoctonine (VIII) Dihydroketosecoisolycoctonine hemiacetal ( I X ) Desmethanolacetyldihydroketosecoisolycoctonine hemiacetal ( X ) Isolycoctonam (XIII) Acetate Hydroxyisolycoctonam Desmethanolsecoisolycoctonam hemiacetal (XIV) 18-Desoxyhydroxylycoctonine(XV) Perchlorate 18-Desoxyisolycoctonine (XVI) 18-Desoxyisolycoctonam (XVII) 18-Desoxyisolycoctonamdesmethanolsecoketoacid (XVIII) 8-Deoxyisolycoctonam 8-Deoxy-6-desmethoxydihydroisolycoctonam (XIX) Desmethanolsecoketohydroxylycoctonamlactone (XXIII) Desmethanoldes(oxymethy1ene)secolycoctimideketomonocarboxylic acid (XXIVa) Desmethanolsecolycoctimide ketocarboxylic acid (XXIVb) Desmethanolsecolycoctimide ketolactone (XXV) Lycoctonine Monoacetate Anhydrolycoctonine Monoacetate Apo-anhydrolycoctonamic acid 0-Methylanhydrooxolycoctonine(CIII) 0-Methyl-6-desmethoxyanhydrooxolycoctonine (CV)
Formula Cz5H43N07
MP ("C) 176-179 173-175
Oil 182-184 180-181 185-188 255-258 Froth 203-207 162-164 147-149 248-252 110-125 197-199 235-242 203-205 dec 222-223 dec 236-240 dec 80-83 222-225 160-162 232-234 183-1 84 126-128 161-163
[ oL]D
References
- 21 -
13 12 12 12 13 13
+ 45.2 -
- 18 - 104 -
+41.7
-29.1
-
- 7.5 -6 - 102 40.8
+
-
+ 37
+9.2 + 3.4
14 13 13 13 13 13
13 13 13 13 14 14 14 158 I58 158 158 I58 63 63
w
-$
c2
W
; EM
K z]
Y
16
S. W. PELLETIER AND L.
H. KEITH
If structure VI for hydroxylycoctonine is correct the product of lead tetraacetate cleavage of hydroxylycoctonam (XX) should be XXI. This was confirmed by alkaline hydrolysis of X X I I t o the corresponding acid, which spontaneously cyclized to the lactone XXIII. Yamada ( 1 4 ) has studied the oxidation of hydroxylycoctonam (XX) with chromic acid and found that it is similar to the lead tetraacetate oxidation of hydroxylycoctonam ( 5 )and isolycoctonam (13)in that the a-ketol bond is cleaved, followed by elimination of a molecule of methanol. Two acid products (XXIVa and XXIVb) and a neutral one (XXV)were isolated from this reaction. Both oxylycoctonine (XXVIk) and its pinacolic dehydration product (XXVIb) gave lycoctamone (XXVIc), an a,p-unsaturated aldehyde, upon vigorous t,reatment with acid (15))Support for structure XXVIc is presentedfrom the followingobservations: CH2=C, 74.79 and 4.86 (2H), 3100 and 910 cm-1; CH=C-C=0,73.38 (1H);C=C-CHO, 70.2 ( l H ) , 1660 cm-1; lactam, 1610 cm-1. Furthermore, the formation of analogues of lycoctamone from demethyleneoxodelpheline (XXVId),oxodelcosine (LXXVI), and oxobrowniine (CXII) coupled with the fact that the elements of water instead of methanol were eliminated in the last two cases implicated the two oxygen functional groups on rings C and D. I n support of this hypothesis is the observation that oxodesoxybrowniine (XXVIe) gave a saturated aldehyde on treatment with acid. Finally, degradative sequences established that the aldehyde function is on a five-membered ring, that the unreactive double bond is a terminal methylene, and that a tertiary hydroxyl is allylic to it. The richest known source of lycoctonine is the root of Inula royleana DC., a plant found in the lower reaches of the Himalayas. Previously, two alkaloids named royline and inuline had been isolated from these roots (16, 16a), but reexamination showed that royline and inuline are identical with lycoctonine and anthranoyllycoctonine, respectively ( 1 7 ) . A recent report (18)describes the isolation of lycoctonine from the flowers of Consolida ragalis S. F. Gay (Delphinium consolida L.). I n Table I11 are collected data on the recently reported lycoctonine derivatives. ANTHRANOYLLYCOCTONINE (INULINE), AJACINE, B. ELATINE, METHYLLYCACONITINE, DELSEMINE, AVADHARIDINE, AND LYCACONITINE Although the structure of lycoctonine has been known since 1956, the structures of the monoester derivatives were not deduced until 3 years
&N$CH3 I
XXIX8; R = CHa XXIXb; R = H
XXVIII
0
I
69-
NHZ
xxx XXXI; R
1
= CHsC-NH-
XXXII; R = -N
3cH3 0
O \
YH3
XXXIII;n = -NH-C-CH-CH~-C-NH~
&
0
I
or
\\
-NH--C-CHz-CH--C-NH2
P
I
CH3
XXXIV; R = -N
3
0
0
XXXVI; R
XXXV; R’ OT
\
f
= -NH--C-CH~CHz--C--NHz
= CHs, Rz = H R’=H, RZ=CHs
18
S. W. PELLETIER AND L. H . KEITH
later, primarily because of the difficulty in locating which of the three hydroxyls of lycoctonine bore the ester acid moiety. This problem was overcome by Kuzovkov and Platonova, who were able to determine the structures of these seven ester derivatives with a minimum of experimental work (19). Hydrolysis of elatine gives the amino alcohol elatidine (XXVIII) and the acid XXIXa. Cleavage of the methylenedioxy group of elatidine produced lycoctonine (111).Thus, elatidiiie differs from lycoctonine only in the presence of a methylenedioxy group in place of the C-7-C-8 glycol group and the ester elatiiie must have structure XXVII. By heating elatine with phloroglucinol in acid, the alkaloid anthranoylIycoctonine (XXX)was produced. The anthranoyllycoctonine obtained from this reaction was found to be identical with the cleavage products of ajacine (XXXI), methyllycaconitine (XXXII), delsemine (XXXIII), and lycaconitine (XXXIV). Therefore, each of these four alkaloids has the primary hydroxyl group of lycoctonine esterified with antliranilic acid and each differs only in the nature of the radical acetylating the amino group of the anthranilic acid. It was known for many years ( 1 )that ajacine is N-acetylanthranoyllycoctonine. Hence, it is represented by structure XXXI. It has been known since 1954 (20)that the esterifying acid of methyllycaconitine was XXIXa. Thus, methyllycaconitine is represented by structure XXXII. The alkaloid delsemine is formed from methyllycaconitine by the cleavage of the methylsuccinimdo group with ammonia, which converts it into a methylsuccinamido group. The structure of the esterifying acid (XXXV) of delsemine had previously been established (21-23) so the structure of delsemine is represented by XXXIII. The alkaloid avadharidine differs from delsemine only in that it is a succinic acid derivative, whereas XXXIII is a methylsuccinic acid derivative. Acid cleavage of avadharidine produces anthranoyllycoctonine (XXX); thus, the structure of avadharidine is XXXVI. It is probable that avadharidine is formed from lycaconitiiie by reacting with ammonia during the extraction of the alkaloids from the plant in the same way that delsemine is formed from methyllycaconitine. The esterifying acid of lycaconitine is XXIXb, and therefore the structure of lycaconitine is XXXIV. Recent reports describe the isolation of ajacine from the seeds of Delphinium orientale F. Gay (24)and methyl1yc;tconitine from the seeds and aerial portion of Delphinium araraticurn Busch (25).
1.
THE
CIS-DITERPENEALKALOIDS
19
C. DELPHELINE, DELTALINE (ELEDELINE, DELPHELATINE), AND DELTAMINE (ELDELIDINE) The alkaloid delpheline (XLV) was isolated from Delphinium elatum L. in 1943 (26, 27). The definitive work on this alkaloid was done by Cookson and Trevett (28, 29) and reviewed by Stern ( 2 ) .Correlation of delpheline with lycoctonine was achieved independently and simultaneously in two different laboratories; one method involved the conversion of lycoctonine to a delpheline derivative (30) and the other employed the reverse interrelation (31).
XXXVII; R' = CHO, R2 = Hz XXXVIII; R' = CH3, R2 = Hz XXXIX; R1= CH3, RZ = 0
XL; R = O C H 3 XLI: R = H
{OCH3
XLII
The conversion of lycoctonine (111)to a delpheline derivative (30) began with the oxidation of the former to lycoctonal (XXXVII) which was, in turn, reduced t o desoxylycoctonine (XXXVIII)and followed by permanganate oxidation to desoxylycoctonam (XXXIX). The rearrangement of XXXIX to anhydrodesoxylycoctonam (XL) was achieved with good yields and reduction of XL with sodium amalgam in ethanol produced the keto lactam XLI. Selenium dioxide oxidation of XLI provided the final step of the sequence, giving the desired known diketone XLII (dehydrodemethyleneoxodelpheline pinacone). The secocd method involved the interconversion of the alkaloid deltaline into delpheline and then the latter into desoxylycoctonine (31). Deltaline was first isolated in 1936 from D . occidentale S. Wats (32)and later from D . barbeyi Huth (31).An alkaloid named eldeline was isolated
20
S. W. PELLETIER AND L. H. KEITH
from D . elatum (33),a plant native to the Altai Mountains in the USSR, in 1952. Two years later an alkaloid named delphelatine was isolated from the same plant (34).It was then found that delphelatine was identical with eldeline (35),the latter name being retained by the Soviet workers. Several years later it was discovered that eldeline and deltaline are identical (19).The definitive work on the structural elucidation of this alkaloid was done by Soviet researchers on the alkaloid from D.elatum, retaining the name eldeline. However, since the compound first named deltaline was isolated many years before the same alkaloid called eldeline, it seems proper that the former name be retained and the latter be deleted from the literature. Treatment of deltaline (XLIII, eldeline) with thionyl chloride yielded chloroacetyldelpheline (XLIV) and removal of the chlorine and acetate with lithium aluminum hydride produced delpheline (XLV).The secondary hydroxyl of XLV (corresponding to the acetoxyl of XLIII) was methylated with sodium hydride and methyl iodide to give O-methyldelpheline (XLVI)which, when hydrolyzed under acidic conditions, gave desoxylycoctonine (XLVII) ( 3 1 ) .Since the structure of delpheline was established the only thing necessary to complete the structural elucidation of deltaline was to determine the position of the hydroxyl that had been replaced by hydrogen in the conversion of deltaline (31)to delphe-
(
------_____ OCH3 OCH3 ,_ C_- _ - NH
G
_i _ _ _ - - - - -
; ,
__f
cH@-5-
, _ _--N’ _
____-----
‘ 0) OR XLIV; R = Ac, R’ = C1 XLV; R = R ’ = H XLVI; R = CHs, R’ = H LIX; R = A c , R ’ = H
b,
OR XLIII; R = A c , R ’ = H XLVIII; R = R’ = H LVII; R = R’ = Ac
I L; R = A c LI; R = H
XLVII; R = CHz, R’ = H XLIX; R = H , R’= OH
1.
THE
C
I
S
- ALKALOIDS ~ ~ ~
~
~
~21
LIII; R=CHO LIV; R=COOH
LII
1 LVI; R
0 LV; R
= CHO
= CHO,
R’ = COOH
OAc LVIII
line. The unreactivity of this hydroxyl group is demonstrated by the fact that treatment with chromium trioxide in acetic acid for 6 days leads to recovery of part of the alkaloid unchanged, and boiling deltaline with acetyl chloride for 4 hours leaves the bulk of the alkaloid unchanged, indicating that it is a tertiary hydroxyl(19). The stability of deltaline to reduction by lithium aluminum hydride and to catalytic hydrogenation with platinum further showed that the tertiary hydroxyl is not in the same position as in hydroxylycoctonine. Deltaline is the acetyl ester of the amino alcohol deltamine (XLVIII, eldelidine) and treatment of the latter with acid produced demethylenedeltamine (XLIX) (19, 36). It was first believed that in the periodate oxidation of XLIII, 3 moles of NaI03 was consumed and this led to the conclusion that XLIII contains four adjacent hydroxyls (19),an assumption later shown to be incorrect by the same authors (37). Apparently,
~
~
22
S. W. PELLETIER AND L. H. KEITH
due to the high alkalinity of solutions of XLIII, other groups in addition to the glycol were oxidized. A subsequent oxidation under neutral conditions led to consumption of only 2 moles of periodate, giving amphoteric uncrystallizable products. However, the periodate oxidation of the corresponding lactam (LII), prepared by permanganate oxidation of deltaline followed by hydrolysis and then cleavage of the methylenedioxy group (L + LII), gave crystalline products. The major product of this oxidation wits the neutral y-lactone (LIII), which also contained an aldehyde group capable of being further oxidized to a carboxylic acid (LIV). Treatment of LIII with alkali opened the lactone ring and, after acidification, the hydroxy acid LV was obtained. The latter could be lactonized again by heating in sulfuric acid but the product (LVI)lost one methoxyl group, giving an a,P-unsaturated ketone in the process. The formation ofa y-lactone in the periodate oxidation of demethyleneoxodeltamine (LII) and the fact that deltamine (XLVIII) is stable t o periodate oxidation unequivocally determines the position of the hydroxyl a t C-10. Since this hydroxyl was eliminated in the conversion of deltaline to delpheline, it seemed possible to represent the structure of deltaline as XLIII with some assurance. However, further experimentation by Carmack (36)cast doubt on the skeletons of deltaline, deltamine, and delpheline. Pyrolysis of acetyldeltaline (LVII) and dehydrohalogenation of chlorodeltaline (XLIV) both gave dehydrodesoxydeltaline (LVIII)which, in turn, was catalytically hydrogenated to give acetyldelpheline (LIX). Also, chlorodeltaline was found to react nearly instantly with ethanolic silver nitrate arid to undergo rapid solvolysis in aqueous methanol. Thus, it seemed that the lycoctonine skeleton was unsatisfactory for two reasons: (a) in the formation of dehydrodesoxydeltaline the introduction of a double bond placed a t a bridgehead position would appear t o violate Bredt’s rule, and (b) the halogen atom which should have been inert t o nucleophilic substitutions, since it was a t the bridgehead of a bicyclo[4.3.l]decane system, was instead quite reactive. It was suggested that deltaline and delpheline both have a perhydrophenanthrene system and should be represented by structures LX and LXI, respectively. It was then postulated (36)that a Wagner-Meerwein type of rearrangement had occurred during the acid hydrolysis of XLVI to desoxylycoctonine (XLVII) (31). Due to these discrepancies, the Russians followed up with a more detailed study of the reactions of chlorodeltaline (XLIV) (38). They found that heating XLIV in aqueous alcohol produced the hydrochloride (LXII) of a base isomeric with eldeline (deltaline) and called isoeldeline (isodeltaline). The free base LXIII could be obtained by treatment of
1.
THE
CI~-DITERPENE ALKALOIDS
28
LXII with silver oxide but when LXII was made alkaline with ammonium hydroxide it underwent rearrangement to a ketone (LXIV) and lost its acetyl group. This same ketone (LXIV) could be obtained by treatment of XLIV with silver nitrate and by then making the resulting isodeltaline nitrate (LXV) basic with ammonium hydroxide. Reduction
OR) LX; R = O H , R ’ = A c LXI: R - R ’ = H Chlorodeltaline
+
XLIV
I Isodeltaline LXIII
+-
Isodeltalille hydrochloride LXII
-
nitrate LXV
Eearranged ketone LXIV
Base isomeric with t Desoxyisodeltoline
delpheline LXVI
LXVII
of isodeltaline with lithium aluminum hydride gave a base (LXVI), C25H39N06, isomeric but not identical with delpheline (XLV).This same base (LXVI)was obtained by catalytic reduction of isodeltaline hydrochloride (LXII), which took up 1 mole of hydrogen to give desoxyisoeldeline (LXVII) upon hydrolysis. Although the structures of compounds LXII-LXVII could not be deduced from this information, the Soviet workers concluded that isodeltaline (LXIII)is not only the product of the solvolysis of chlorodeltaline, but also is the reaction product of the rearrangement. Thus, it was reasoned, the ease with which the hydrogen halide is cleaved when heated in alcohol or when treated with
24
S. W. PELLETIER AND L. H. KEITH
LXIX
LXX
silver nitrate cannot refute the theory that the halogen is a t the bridgehead (in a lycoctonine-type skeleton) since the cleavage of hydrogen chloride could take place after the rearrangement. I n refuting the argument of the violation of Bredt's rule in the formation of dehydrodesoxyeldeline, it was pointed out (38) that : (a) Prelog (39) had shown that in the case of 1.3-bicyclic systems the limit of use of the Bredt rule lies between 4.3.1- and 5.3.1-bicyclic systems, and (b) that it had been shown (40, 41) that pyrodelphinine derivatives contain a double bond a t the bridgehead of a 4.4.1-bicyclic system in the partial structure LXVIII. It was then concluded that the proposed structures of eldeline and delpheline as LX and L X I (36)were incorrect and that these two alkaloids possessed a lycoctonine-type skeleton after all (38). The unsaturated compound dehydrodesoxydeltaline would then be represented by structure LVIII. Further study 01, the chloroeldeline transformation products was promised. TABLE I V NEWLYDESCRIBED DERIVATIVES OF DELPHELINE Compound
Formula
Mp ("C)
[alD
Chloroacetyldelpheline (XLIV) (chlorodeltaline) O-Methyldelpheline (XLVI)
References
C27H40ClN07
173.3-173.5
-40.7
31
C26H41NOe
102.5-103
-6.3
31
TABLE V NEWLYDESCRIBED DERIVATIVES OF DELTALINE AND DELTAMINE Compound Chlorodeltaline (XLIV) (chloroacetyldelpheline) Demethylenedeltamine (XLIX) Oxodeltaline (L) Oxodeltamine (LI) Demethyleneoxodeltamine (LII) Secodemethyleneoxo-y-lactonodeltamine monoaldehyde (LIII) Secodemethyleneoxo-y-lactonodeltamine monoca+boxylic acid (LIV) Secodemethyleneoxo- 17-carboxydeltamine monoaldehyde (LV) Secodemethylenedesmethanoloxo-y-lactonodeltamine monoaldehyde (LVI) Acetyldeltaline (LVII) Dehydrodesoxydeltaline (LVIII) Isodeltaline hydrochloride (LXII) Isodeltaline (LXIII) “Rearranged unknown ketone” (LXIV) Isodeltaline nitrate (LXV) “Unknown base isomeric with delpheline ” (LXVI) Desoxyisodeltaline (LXVII)
Formula
[ a ] ~ 170-171.5 188-190 95-97 dec 271 -272 228-230 278-280 263-265 240 dec 229 dec 208 dec 306-307 155-156 149-150 186-188 Amorphous 2 13-2 14 161-165 dec 2 14-2 15 181-1 82
-k 27
-
-
-
-31 - 136
-
References
38 19 36 37 37 37 37 37 37 37 37 31 36 38 38 38 38 38 38
w
Ex
26
S . W. PELLETIER AND L. H. KEITH
The problem was finally solved by the use of NMR spectroscopy (42). Comparing the NNR spectra of 24 model compounds, it was demonstrated that the geminal coupling constant of the methylenedioxy protons was between 0 and 2 Hz in five-membered rings and was about 6 Hz in six-membered rings. The small coupling constants for delpheline (0 Hz), oxodelpheline (0 Hz), and dehydrooxodelpheline (1.4 Hz) clearly demonstrate that the structure of delpheline is XLV rather than LXI and hence that deltaline is XLIII instead of LX. Acid isomerizes oxodelpheline (LXIX) to isooxodelpheline (LXX), which contains a tertiary liydroxyl in place of the secondary one in LXIX. The larger coupling constant (4.3Hz) in LXX indicates a six-membered methylenedioxy ring, which is consistent with the tentative structure previously proposed for this compound (29). The biosynthetic incorporation of mevalonic acid into a natural product is frequently used to test whether the substance is of terpenoid origin. Accordingly, young plants of D.elatum were fed with dl-(14C-2)mevalonic acid and, surprisingly, the delpheline isolated had no detectable radioactivity. It was assumed this precursor is converted into the nonbasic plant terpenoids before it reaches the stage of alkaloid synthesis. However, l-(methyl-14C)-methionine was incorporated into delpheline under the same conditions (43). Tables IV and V list the newly described derivatives of delpheline, deltaline, and deltamine.
D. DELCOSINE (DELPHAMINE, LUCACONINE, TAKAO BASEI, ALKALOID C), MONOACETYLDELCOSINE (MONOACETYLLUCACONINE, ALKALOID B), AND 14-DEHYDRODELCOSINE(SHIMOBURO BASE11) The alkaloid delcosine was first isolated by Goodson (44)from the roots of D.ajacis L. and tentatively named ‘‘alkaloid C.” Marion and Edwards isolated delcosine from D . consolida (45)and it was later found that the two materials were identical (46). Another of the bases isolated by Goodson (44) was an acetylated alkaloid tentatively named “ alkaloid B,” which gave rise to “alkaloid C” on hydrolysis. Thus “alkaloid B ” is monoacetyldelcosine (46). The alkaloids lucaconine and monoacetyllucaconine, isolated from the roots of A . lucidusculum Nakai (47-51)) have also been shown t o be identical with delcosine and monoacetyldelcosine, respectively (51).Likewise, the identities of “Takao base 1,” from A . japwnicum Decne. ( s 2 )and delphamine (53)have been found to be identical with delcosine (54, 55).The alkaloid prcviously reported as Shimoburo base 11,from A . japonicum (56)is identical with 14-dehydro-
1.
THE
C
I
S
-ALKALOIDS ~ ~
~
~
~
27~
delcosine (54, 55). The widespread occurrence of delcosine is further attested to by the recent reports of its isolation from Consolida regalis ( 5 7 , l S )and from the seeds of D. orientale (58,59). The first tentative structure put forth for delcosine (46)was LXXI, and it appeared to accommodate the experimental findings a t the time of the previous review ( 2 )in this series. However, i t must be borne in mind that this and all other structures in earlier works are, in fact, the mirror images of those proposed. I n addition, further experimentation has shown that the arrangement of functional groups in LXXI is not quite correct (55,60).The empirical formula had been establishedasC24H3gNO7 and a lycoctonine-type skeleton was assumed. Of lycoctonine’s seven oxygens, three were known to be present as methoxyl groups and four as hydroxyls. Evidence for the N-ethyl was the fact that oxidation of delcosine with silver oxide gave, as one of two products, N-desethyldelcosine, which could be N-acetylated or reconverted to the original alkaloid with ethyl iodide (61).As none of the oxidations produced an acid or aldehyde, it was clear that the analogous C- 18 oxygen functional group of the lycoctonine-type skeleton must be a methoxyl. Carbinolamine ether linkages were rapidly formed with a variety of reagents, leading to the assumption (later shown to be erroneous) (55,60)that C-6 was substituted with a hydroxyl. One of the products of alkaline permanganate oxidation was a carbinolamine ether containing a five-membered cyclic ketone, lending support to the positioning of a second secondary hydroxyl a t C-14 where lycoctonine is analogously substituted with a methoxyl. Since only two of the hydroxyls are easily acetylated, the remaining two were assumed to be at the tertiary positions of C-7 and C-8 as in the alkaloid lycoctonine. Two further analogous assumptions, one of which has been proved wrong, was that the two remaining methoxyl groups are a t C-1 and C-16 as in lycoctonine. Oxidation of delcosine (LXXII) with chromic acid in acetic acid gives the five-membered ketone LXXIII. Oxidation of diacetyldelcosine (LXXIV) with Sarett reagent gives the lactam LXXV. Diacetyloxodelcosine when saponified gives oxodelcosine (LXXVI) and further oxidation of LXXVI with dichromate gives the diketo lactam LXXVII, which can also be obtained by direct oxidation of delcosine with Sarett’s reagent. The significant point is that instead of two five-membered ring ketones being produced-as would be expected from structure LXXIone five-membered and one six-membered cyclic ketone resulted! Clearly, the C-6 hydroxyl and the C-1 methoxyl of structure LXXI are switched. In addition, the facile carbinolamine ether linkages indicate that the secondary hydroxyl is a t C-1 (where it can form a six-membered ring as
~
~
28
S . W . PELLETIER AND L . H . KEITH
shown in partial structure LXXVIII) and defines the configuration of the C-1 hydroxyl as a. Another alkaloid occurring with delcosine is monoacetyldelcosine (LXXIX) which, on hydrolysis, gives delcosine. Acetylation of delcosine
I
OH OCH3
LXXI
LXXII; R = H LXXIV; R = A o
LXXV: R = A c LXXVI; R = H
\
\
OCH3 LXXIII
LXXVII
with acetic acid, catalyzed by trichloroacetic acid, gave a monoacetyl derivative which was identical with the naturally occurring monoacetyldelcosine (46). Oxidation of LXXIX with Sarett reagent gave monoacetyldehydrooxodelcosine (LXXX), a cyclic six-membered ketone. This confirmed the placement of the hydroxyl in ring A and showed that the acetate of monoacetyldelcosine is in the five-membered ring.
1. THE
CIS-DITERPENEALKALOIDS
29
LXXVIII
1
0CH3 OCH3 LXXIX
LXXX
OCHs LXXXI
Previous evidence for the two vicinal tertiary hydroxyls, as well as the C-16 methoxyl, was obtained from periodate oxidation of the carbinolamine ether derivative of delcosine (62). The secodiketone produced was formulated as LXXXI but in light of the revised structure, it must be LXXXII. On treatment with acid, the acetate LXXXIII lost
30
S. W. PELLETIER AND L. H. KEITH
one molecule of methanol, as in the analogous reactions with lycoctonine, giving the +unsaturated ketone LXXXIV. Lead tetraacetate oxidation (63) of oxodelcosine (LXXXV) gave LXXXVII, presumably arising from the expected diketone LXXXVI. Evidence favoring structure LXXXVII was the further oxidation of one of the two hydroxyls to a five-membered ketone (LXXXVIII) with Sarett's reagent. Thus, the unreacted hydroxyl of LXXXVII must be tertiary; this can be explained if the C-1 hydroxyl reacted with the (3-8 ketone to form a hemiketal. Furthermore, the hemiketal formation as
LXXXV
LXXXVI
J LXXXVII; R = H, OH LXXXVIII; R = 0
L XXXI X; R = 0 XC; R = O H
XCI; R = O XCII; R = O H
1. THE CIS-DITERPENEALKALOIDS
31
described above limits the hydroxyl to C-1 since this appears to be the only position where formation of a cyclic hemiketal is geometrically possible. As further support of this interpretation, lead tetraacetate oxidation of 1,14-didehydrooxodelcosine (LXXXIX) and 1-dehydrooxodelcosine (XC),neither of which contain the C-1 secondary hydroxyl
xcv
XCIII
XCIV
J on
omI XCVII; R = O XCVIII; R = p-on
XCIXa; R = H XCIXb; R = C H a
OH
oms XCVI
XCIXC
necessary for hemiketal formation, gave the expected secodiketones which may be formulated as XCI and XCII, respectively. An attempt to correlate delcosine with lycoctonine proved to be a failure (63),but it did show that the C-6 position of delcosine is substituted with a methoxyl group, a fact previously unestablished and assumed only by analogy with lycoctonine. The initial reactions involved an epimerization a t C-1 since lycoctonine has a P-methoxyl at C-1. This was accomplished by first oxidizing N-desethyldelcosine (XCIII) with Sarett's reagent, giving a mixture of the azomethine XCIV and the diketo lactam XCV. Ethylation of the azomethine (XCIV)was followed
32
S. W. PELLETIER AND L. H. KEITH
by epimerization with base to give what was believed t o be 14-dehydro0x0-1-epidelcosine. Sodium borohydride reduction of the latter followed by reduction with lithium aluminum hydride supposedly yielded 1-epidelcosine. Actually, the epimerization reaction gave back the original C- 1 epimer (64) 14-dehydrooxodelcosine (XCVII). Sodium borohydride reduction of the latter surprisingly gave oxoepi-14-delcosine (XCVIII)! This is the first reported instance of such an epimerization at this position. I n all other known borohydride reductions of a C-14 ketone the reaction has been almost completly stereospecific in producing the original epimer -the equatorial (a)alcohol. This stereospecificity has been attributed to the presence of ring D, which blocks the approach of the attacking reagent from the side cis to the nitrogen bridge. Direct methylation of lycoctonine produces a dimethylated product in which one of the tertiary hydroxyls, as well as the desired primary hydroxyl, is methylated. To alleviate this complication, advantage was taken of the facile pinacol rearrangement which these compounds undergo (63).Oxoepidelcosine (XCVIII)was, therefore, converted to the corresponding pinacone (XCIXa)by heating in acid and then methylated to 0,O-dimethylanhydrooxoepidelcosine(XCIXb). By a similar acidcatalyzed pinacol rearrangement, oxolycoctonine (lycoctonam) (C) was converted to anhydrooxolycoctonine (CIa) and methylated t o 0-methylanhydrooxolycoctonine (CIb). The two derivatives, XCIXb and CIb, were different. The three points of uncertainty in XCIXb were the methoxyls a t C-6, C-'14, and C-16. Both XCIXb and CIb were demethoxylated a t C-6 by treatment with sodium amalgam to yield XCIXc and CIc, respectively, thereby establishing the presence of a methoxyl a t C-6 in delcosine. At this point an X-ray crystallographic investigation of delcosine hydrobromide was initiated by Mair and Przybylska (64a).The preliminary study has shown that the skeleton of delcosine is the same as that oflycoctonine and that all of the substituents, with the exception of the C-1 hydroxyl, are oriented as in lycoctonine. I n addition, it was learned that ring A of delcosine exists in the boat conformation, in contrast to lycoctonine, which exists in the chair conformation. The difference is accounted for by the fact that intramolecular hydrogen bonding exists between the C-1 hydroxyl and the nitrogen. I n a recent paper Amiya and Shima (64b) have further described the pinacol rearrangement of delcosine and also a novel hydrogenation reaction with its product. Treatment of delcosine (LXXII) with acetyl chloride effected the rearrangement giving anhydrodiacetyldelcosine (CII). Similar treatment with oxodelcosine (LXXVI), followed by hydrolysis, produces anhydrooxodelcosine (CIII), a compound also obtainable from CII by oxidation with chromium trioxide-pyridine
1.
THE
CIS-DITERPENEALKALOIDS
33
CIe; R1= H, R2 = OCH3 CIb; R1= CH3, R2 = OCH3 CIC; R1= CH3, R2 = H
I
~CHI
OCH3
OCH3 CII
CIII
.--
OCH3 CVb
TABLE V I OF DELCOSINE NEWLYDESCRIBED DERIVATIVES Compound Diacetyldelcosine (LXXIV) Mono(trichloroacety1)delcosine Tetraacetyldelcosine Dipropionyldelcosine Diacetyloxodelcosine (LXXV) Oxodelcosine (LXXVI) Didehydrooxodelcosine (LXXVII) Monoacetyldelcosine (LXXIX) 14-Monoacetyl-1-dehydrooxodelcosine (LXXX) Seco-7-ketooxodelcosine-( 1, 8)-hemiketal (LXXXVII) 14-Dehydroseco-7-ketooxodelcosine-( 1, 8)-hemiacetal(LXXXVIII) 1-Dehydrooxodelcosine (XC) 1,14-Didehydrosecooxodelcosine(XCI) 1-Dehydrosecooxodelcosine(XCII) AT-Desethyldidehydrodelcosineazomethine (XCIV) ethiodide (XCV) N-Desethyl-1,14-didehydrooxodelcosine(XCV) 14-Dehydrooxodelcosine (XCVII) Oxoepi-14-delcosine (XCVIII) Epi-14-delcosine perchlorate Anhydrooxo-14-epidelcosine (XCIXa) 0,O-Dimethylanhydrooxo-14-epidelcosine (XCIXb) 14-0-Methyldelcosine (delsoline) (CVII)
1,14-Di-0-rnethyldelcosine Anhydrodiacetyldelcosine (CII) Anhydrooxodelcosine (CIII) Anhydro-1,14-didehydrooxodelcosine(CIV) Dihydroanhydrodiacetyldelcosine(CVb)
Formula
w
IP
MP ("C) 127-128 172.5-173.5 268.5-269.5 119-120 103-105 245-246.5 21 1-212 191-193 107-110 191-193 209-210 228-229 175-1 77 181-1 83 219-220 168-171 274-275.5 Amorphous 128-130 177-178 199-201 227-231 178-1 80 215-216 203-206
260 270 175
[a]D
References
-
46 46 46 46 55 55 55 46 55
-
+24.6 +44.3 135 32 94.5 1.5 13.7 120 + 77.4 +57.1 257.5 132.4 139 10.4 19.8 38.9 +26.8 -23.8 - 56.3 53.4 +48.6
+ + + + + + + + + + + +
+
-
-
+ 12.7
55 55 55 55 55 63 63 63 63 63 63 63 63 63 55 55 64b 64b 64b 64b
F
.r cd
M
t3 t3 M
8
0 P
Z
U
r
wx
8x
1.
THE
CIS-DITERPENE ALKALOIDS
35
complex followed by hydrolysis. Treatment of 1-dehydrooxodelcosine (XC) with acetyl chloride, followed by hydrolysis and further oxidation with Sarett’s reagent, gives anhydro- 1,14-didehydrooxodelcosine (CIV), a triketo lactam also obtained by further oxidation of CIII or of the hydrolysis product of CII. Catalytic hydrogenation of CII over platinum yielded dihydroanhydrodiacetyldelcosine (CVb) presumably going through the intermediate CVa. However, CIII was recovered unchanged after being subjected t o the same conditions of hydrogenation. Probably the unavailability of the lactam nitrogen atom’s free electron pair prevented the formation of the intermediate (CVa). Some interesting I R - and UV-spectral features were also observed. The C-7 carbonyl of CII absorbs a t 5.81 p while in the lactam derivatives, CIII and CIV, this carbonyl absorption occurred a t 5.78 p. However, in the less-strained dihydro derivative, CVb, the C-7 ketone absorption moved to 5.93 p. The UVspectrum of anhydrodiacetyldelcosine (CII) was abnormal; in methanol a maximum was observed a t 237 mp (log E 3.20). However, amide formation removes the . anomaly and absorption maxima appear near 300 mp and are ascribed t o ketone chrbonyl groups. A similar phenomenon was first observed with some pyroneoline and pyrodelphinine derivatives (64c) and is discussed in more detail in the neoline section. Recently, spectral studies of a new type of chromophore have been described (64d ). According t o this study anhydrodiacetyldelcosine is a 8-amino ketone which is set up for a 6-coupled transition. The unusual UV absorption of pyrocondelphine derivatives was taken as evidence for an aconitine-type skeleton being present in that alkaloid (64e)and it is suggested that this phenomenon, in conjunction with the pyro-isopyro rearrangement, holds promise as an indication of such a skeleton lacking a C-15 hydroxyl. Similarly, the unusual UV-absorptions of the anhydro derivatives, in conjunction with the facile pinacol rearrangement, may prove to be an indication of a lycoctonine-type skeleton in newly isolated alkaloids. Table VI lists the recently reported derivatives of delcosine.
E. DELSOLINE Delsoline is another alkaloid present in Delphinium consolida and was first reported in 1924 by Markwood (65)and later in 1941 by Cionga and Iliescu (66).The assignment of an empirical formula (67)and finally some chemical investigations followed (68).The reactions of delsoline are quite similar to those of delcosine. Thus, the formation of a carbinolamine
36
S. W. PELLETIER AND
L. H.
KEITH
ether showed the presence of a secondary hydroxyl in ring A which was assumed to be a t C-1. Oxidation with mercuric acetate produced anhydrohydroxy-N-desethyldelsolinewhich could be realkylated with ethyl iodide, showing the presence of an N-ethyl group. And O-acetyloxodelsoline is cleaved by lead tetraacetate to a secodiketone that loses methanol on recrystallization, demonstrating the presence of two vicinal tertiary hydroxyls, one of which is CL to a methoxyl group. On the other hand, dehydrooxodelsoline, after cleavage with lead tetraacetate, undergoes an internal aldol rearrangement. It was assumed that the .structure of delsoline was closely related to that of lycoctonine and structure CVI was proposed (68).
OH e
OH OOCHs OCHs C
H
3 I
OCHs CVI
CVII
After the structure of delcosine was revised (60) it became apparent that delsoline was an O-methyldelcosine. To ascertain this, delcosine was methylated with sodium hydride and methyl iodide in dioxane at room temperature. This methylation is remarkably stereospecific in that only the secondary hydroxyl of the five-membered ring was methylated while the ring A hydroxyl was left untouched; when heated, the selectivity is lost and the dimethyl derivative is obtained. The 14-0-methyldelcosine thus produced was identical with delsoline and this constitutes a correlation between the two alkaloids so that the complete structure of delsoline can now be represented as CVII. The occurrence of delsoline is also apparently fairly widespread, as recent reports show that it is found in Consolida regalis ( 1 8 , 5 7 )and also in the seeds of Delphinium orientale (58, 59), where it occurs with delcosine.
F. BROWNIINE AND DEHYDROBROWNIINE The alkaloid browniine has recently been isolated from D . brownii Rydb., a plant native t o Canada (69). The empirical formula is C~sH41N07,and thus it was assumed t o be an isomer of lycoctonine, an
1.
THE &-DITERPENE
37
ALKALOIDS
assumption well founded considering the natural source and the fact that its I R spectrum was similar to that of lycoctonine. Oxidation of browniine (CVIII) with Sarett’s reagent gave dehydrooxobrowniine (CIX),which was a cyclic five-membered monoketo lactam.
/
CVIII; R = H CX; R = A c
J OCH3 CXI; R = A c CXII; R = H
CIX; .R = 0 CXX; R = H , H
I
\ OCH3 CXV; R = H CXVl; R = C H 3
Reaction with acetic anhydridelpyridine yielded the monoacetate (CX), confirming the presence of only one secondary hydroxyl group in browniine. Permanganate oxidation of CX produced the lactam CXI which when hydrolyzed yielded oxobrowniine (CXII). Reduction of dehydrooxobrowniine with sodium borohydride gave predominantly
38
S. W. PELLETIER AND L. H. KEITH
oxobrowniine, showing a largely selective reduction. Both CIX and CXII rapidly consumed 1 mole of lead tetraacetate giving a secodiketone and a secotriketone (CXIII)as the initial products and demonstrating the presence of two vicinal tertiary hydroxyl groups. Heating CXIII caused elimination of methanol and a corresponding conversion to the unsaturated ketone (CXIV), thus showing the presence of a C-16 methoxyl group. The fact that CXIII and CXIV were colorless excluded C-6 as a possible position for the secondary hydroxyl of browniine;
CXIII
-
I R
/
OCH3 CIV
/
0
OCH3 CXVII; R = COOH CXVIII; R = H
CXIX
therefore, it had to be in ring C. The two remaining oxygen functional groups, which occur a t C-1 and C-18 in lycoctonine, must then be methoxyl groups in browniine and, as a working hypothesis, they were assumed to be a t the same positions. Thus, the probable structure of browniine was reduced to CVIII. Correlation with a lycoctonine derivative would require 0-methylation of the C-18 hydroxyl of lycoctonine and 0-methylation of the C-14 hydroxyl of browniine. To remove all of the other hydroxyls, and eliminate the problem of tertiary hydroxyl methylation, oxobrowniine (CXII) was subjected to conditions under which the pinacol rearrangement takes place and the resultant anhydrooxobrowniine (CXV) was then methylated with sodium hydride and methyl iodide in dioxane. The 0-methyl derivative CXVI was identical with the methyl ether of
TABLE VII OF BROWNIINE DERIVATIVES
Compound Browniine (CVIII) perchlorate Dehydrooxobrowniine (CIX) Monoacetylbrowniine (CX) Oxobrowniine (CXII) Seco-7,s-diketo-14-dehydrooxobrowniine (CXIII) Desmethanolseco-7,8-diketo14-dehydrooxobrowniine (CXIV) Anhydrooxobrowniine (CXV) 0-Methylanhydrooxobrowniine(CXVI) (0-methylanhydrobrowiine lycoctonam) Rearranged keto acid (CXVII) Decarboxylated rearranged ketone (CXVIII) 14-Dehydrobrowniine (CXX) Hydroxybrowniine (CCCXXV) Isobrowniine (CCCXXVII) Oxoisobrowniine (CCCXXVIII) 8-Deoxyoxoisobrowniine (CCCXXIX) 8-Deoxy-7-dihydrooxoisobrowniine (CCCXXX) 8-Deoxy-7-dihydroisobrowniine (CCCXXXI) 14-Dehydro-8-deoxyisobrowniine (CCCXXIV) (epi-7,17-secodehydro-7,14-diketochasmanine)
a
Anhydrous crystals.
Amorphous 212 169.5-171 123-124 90-93 170-171.5a 194-197 172-175 195-197 120-124 185-188 dec Amorphous 161-163 115-1 18 Amorphous Amorphous 152-154 161-166 Amorphous 156-158
-
+ 25 + 32 +40 + 62
69 69 69 69 69
+ 10
69 69 69 69
+ 124 + 150
69 69
-
+ 19 -
-
+ 12.5
YO
135 135 135 135 135 135 135
w
eD
40
S. W. PELLETIER AND L. H. KEITH
anhydrolycoctonam. Thus, the position and configuration of the substituents of browniine were proved to be as shown in CVIII. An unusual reaction was observed when CXIII was treated with hot sulfuric acid; a mixture of acids was produced. The structure of one, CXVII, containing only three methoxyl groups, was deduced from its spectra and empirical formula. Since CXIV also produced CXVII the eliminated methoxyl was shown to be the one a t C-16. Decarboxylation occurred upon melting to give the p,y-unsaturated ketone (CXVIII), which seemed to rearrange to the corresponding a,p-unsaturated ketone (CXIX),although none could be isolated. A recent report (70) describes the isolation of a new alkaloid, 14-dehydrobrowniine (CXX), along with browniine from the aerial portions of D . cardinale Hook, a large species native to southern and Baja California. Sodium borohydride reduction of 14-dehydrobrowniine proceeded stereospecifically to give browniine as the only product. Also, oxidation of browniine with sodium dichromate in acetic acid gave low yields of a basic ketonic material from which 14-dehydrooxobrowniine was separated and found to be identical with the naturally occurring alkaloid. Browniine derivatives are listed in Table VII.
111. Aconitine-Type Alkaloids
A. ACONITINE The alkaloid aconitine has been known since 1833 (71)and is one of the most accessible and most complicated representatives of the aconitum alkaloids. It has been found together with the alkaloid mesaconitine in Aconitum napellus L., A. fauriei Leveille and Vaniot, A . grossedentatum Nakai, A. hakusanense Nakai, A . mokchangense Nakai, and A. zuccarini Nakai ( 1 ) .More recently, aconitine has been isolated from the Chinese drugs Hye-shang-yi-zhi-hao ( A . bullatifolium LBveillB var homotrichum) (72) and Chuan-wu and Fu-tzu (A. carmichaeli Debaux= A . Jischeri Reichb.) (73). The early work done on aconitine is characterized by confusion and, indeed, all but the most recent studies accomplished little more than clarification of the functional groups present in the polycyclic molecule. It was shown that aconitine contains a tertiary nitrogen with an N-ethyl, one acetoxy, one benzoyloxy group, four methoxyls, and three hydroxyls. The results of studies by three laboratories led to the almost complete structure of the alkaloid in 1959. Collaboration of Professor Buchi’s laboratory a t M.I.T. and Professor Wiesner’s laboratory at the University of New Brunswick, Canada, led to a structure for
1.
THE
CIS-DITERPENE ALKALOIDS
41
aconitine by chemical means in which the methoxyl and hydroxyl were located either at C-1 and C-3 (CXXIa) or C-3 and C-1 (CXXIb), respectively (74).Within months, the results of an X-ray crystallographic analysis of demethanolaconinone hydriodide trihydrate by Marion and Przybylska were published (75).The structure a t first obtained from this study (CXXII)was later shown by the same authors (76)to be CXXIII, the enantiomer of CXXII. This independent study not only substantiated the previous structural elucidation by chemical means but also eliminated
&T-‘&y; OH
OAc
RO OCH3 OCH3
CXXIa; R = H, R’ = CH3 CXXIb; R = CH3, R’ = H
;
OCH3
OCH3 CXXII
the ambiguity of the methoxyl and hydroxyl positions in ring A, as well as providing the absolute and relative configurations of 13 out of the 15 asymmetric centers present in aconitine. A large part of the initial chemical elucidation of the structure of aconitine was based on oxonitine, a permanganate oxidation product of aconitine. Oxonitine was first formulated by Jacobs et al. (77) as C33H43N012 and later (78) as C34H45N012. The uncertainty regarding the formulation of oxonitine has centered mainly on whether the compound contains an N-acetyl or an N-formyl group. The later microanalysis data suggested that the oxidation proceeded without loss of a carbon atom, thus yielding an N-acetyl compound. However, oxonitine has also been reported as an oxidation product of mesaconitine (79, 80)
42
S. W. PELLETIER AND L. H. KEITH
which possesses an N-methyl instead of an N-ethyl. Decisive evidence was obtained by oxidation of aconitine in the presence of methanol, which caused a threefold increase in the yield of oxonitine (81),and by a degradation involving the removal of the N-ethyl group and its replacement by a formyl group (81a).Vigorous treatment of aconitine (partial structure CXXIV) with nitrous acid (81a)resulted in the cleavage of the N-ethyl and formation of the nitroso derivative CXXV. Acetylation of
cxxv
CXXIV
*
CHaCHz-N
5 OAc
5 OAc
H CXXXI
CXXXII
CXXV with acetyl chloride gave a mixture of CXXVI and its acetolysis product CXXVII in 14% and 57% yields, respectively. Treatment of CXXVI with phosgene produced CXXVIII, which was then converted to the N-formyl derivative CXXIX, a compound identical with an authentic sample of triacetyloxonitine prepared by permanganate oxidation of triacetylaconitine (CXXX). Permanganate oxidation of pentaacetylaconine (CXXXI), containing an N-ethyl group labeled a t the carbon adjacent to the nitrogen, produced pentaacetyloxonine (CXXXII) with a residual radioactivity of only 6% of that of CXXXI,
1.
THE
C
I
S
- ALKALOIDS ~ ~
~
~
~
~43
clearly indicating that the N-formyl group of oxonitine does not arise from the N-ethyl of aconitine. The original degradative work on oxonitine used in the chemical elucidation of the structure of aconitine ( 7 4 )assumed an N-acetyl group instead of an N-formyl group but a later paper (82)has summarized this work and corrected the structures. Pyrolysis of oxonitine (CXXXIII) results in the formation of pyrooxonitine (CXXXIV) with the loss of 1 mole of acetic acid. This elimination is typical of aconitine-type alkaloids with an acetoxy group a t C-8. It had previously been shown (83,84)that the CD ring system of delpheline is represented by CXXXV and undergoes pyrolytic elimination of acetic acid to give pyrodelphinine (CXXXVI).It was therefore plausible
OCH3 CXXXIVb; R = Bz CXXXVII; R = H
cxxxv
CXXXVI
~
~
44
S. W. PELLETIER AND L. H. KEITH
to assume that the loss of acetic acid from oxonitine is analogous to the corresponding reaction of delphinine, except that the product derived from oxonitine is an enol (CXXXIVa) which tautomerizes to the keto form (CXXXIVb).This evidence suggested that the C-8 acetoxy group and the (2-15hydroxyl of aconitine may be trans. The ketonic nature of pyrooxonitine was spectroscopically shown by the presence of a carbonyl
cxxxvIII
CXLIX
CXXXIX
CXL
absorption band characteristic of a cyclic six-membered ketone (1718 cm-1) in pyrooxonine (CXXXVII), the hydrolysis product of pyrooxonitine (CXXXIVb), and also by the peak typical for ketones a t 343 mp ([a]- 1020°) in the ORD curve of pyrooxonitine. Another reaction which indicated that the CD ring structure of aconitine is similar to that of delphinine was the oxidation of oxonine (CXXXVIII), the hydrolysis product of oxonitine (CXXXIII), with Sarett's reagent to obtain the rearranged diketone CXL. The latter is assumed to arise from a base-catalyzed acyloin rearrangement of the original oxidation product (CXXXIX) which was not isolated.
1.
THE
CIS-DITERPENE ALKALOIDS
45
Chemical evidence for the ketonic nature of pyroaconitine (CXLI), formed by pyrolysis of aconitine, was demonstrated by subjecting it to Wolff-Kishner reduction (85).The product of this reaction contained no carbonyl absorption in its I R spectrum, showing that not only had the ketone been reduced but also that the benzoyloxy group had been saponified. Further, one of the methoxyl groups had been eliminated. The Wolff-Kishner product was thus assumed t o possess structure CXLIII since it resisted catalytic hydrogenation. A later correlation involving OH
CXLI
OH I
UXLII
OH QH
CXLIII
CL
the conversion of pseudaconitiiie to the Wolff-Kishner reduction product of pyroaconitine showed that the latter was not CXLIII but the unsaturated derivative CXLII instead (86). Pyroaconitine undergoes hydrolysis as well as reduction of the carbonyl t o a hydroxyl on treatment with sodium borohydride. The rearrangement of CXXXVIII t o CXL is analogous t o the basecatalyzed rearrangement of a-oxodelphonine (CXLIV) (87,88).Chromic acid oxidation of CXLIV produced the ketone CXLV which rearranged with base t o the isomerized product CXLVI. Periodate cleavage of CXLVI gave CXLVIII, probably going through the intermediate CXLVII which spontaneously loses a molecule of water.
46
S. W. PELLETIER AND L. H. KEITH
Cleavage of the aconitine diketone CXL with lead tetraacetate gave the keto acid CXLIX, which is exactly analogous to its delphinine counterpart CXLVIII. If, on the other hand, oxonitine (CXXXIII) is oxidized under the same conditions as oxonine (CXXXVIII), a high yield of oxoaconitine (CL), another product from permanganate oxidation of aconitine (77, 78, 89),is obtained. This clearly demonstrates that
CXLIV
CXLV
CXLVII
CXLVI
CXLVIII
the benzoyloxy group is located a t C-14 as postulated and also that oxoaconitine is simply a C-3 ketone derived from oxonitine (82). It is perhaps significant t o note that the secondary hydroxyl a t C- 15was never observed t o undergo oxidation even though models show the hydrogen of C- 15 is quite exposed. A possible explanation lies in the steric inhibition of the chromate ester formation. This same hydroxyl is also impervious t o mesylation, even though the tertiary C-13 hydroxyl undergoes this reaction smoothly (90). A final demonstration that aconitine possessed the CD ring system as shown was the periodic acid cleavage of oxonine t o the secoketoaldehyde
1.
THE
CIS-DITERPENEALKALOIDS
47
CLI followed by an extensive rearrangement to the phenol CLVI when heated in dilute aqueous base with air passing through the solution. The postulated mechanism (74, 82, 91) begins with a retroaldol cleavage of CLIa. Then aldol condensation and dehydration with one aldehyde group occurs (CLIa + CLII) followed by dehydration to the dienonal CLIII which, by a base-catalyzed double-bond shift, could give the phenolic aldehyde CLIV. From CLIV to CLVI there appear t o be at least two
CXXXVIII
CLIb OCH3
OH
OH
CLII
i,, 4'
H
P
CHO CLVII
CLV
48
S . W. PELLETIER AND L. H. KEITH
feasible paths (82, 91),with the first seeming to be the most likely, considering the catalytic effect of bubbling air through the solution. By path ( I ) , air oxidation of CLIV would give the peroxide CLV which, when cleaved by hydroxide, would give the phenol CLVI. Path (2) envisions a tautomerization of CLIV to give CLVII followed by hydroxyl attack at OH
_____---OCHs CLIX
-
CLX
CLXI
I
OCHa CLVIII
the position geminal to the aldehyde and spontaneous elimination of the aldehyde group, producing the ketone CLVI. Compound CLVI is an amorphous solid whose spectroscopic characteristics are close t o those of acetophenone of the same substitution; the methyl ether (CLVIII) is a crfstalline compound. The existence of the secoketoaldehyde (CLI)in the cyclic acetal form (CLIb) is invoked to explain the otherwise anomalous facts that (a) sharp uptake of only 1 mole of periodate occurs and (b)the cleavage product shows no carbonyl group in its I R spectrum.
1. THE C
I
S
- ALKALOIDS ~ ~
~
~
~
49 ~
The corresponding aromatization reaction sequence was then repeated with ceoxoisopyrodelphinine (CLIX)since the structure and substitution of the CD ring system of this compound was already known. Compound OH
OCH3
OCH3
CXXI
CLXV
T OH
r
OH
CLXVII
1
CLXVI
I
OCH3 OCH3 CLXVIII
C L X I X ; R = CH3 C L X X ; R=CzHtj
CLIX takes up 1 mole of periodic acid to give the secoaldehyde CLX which, on warming with dilute alkali in the presence of oxygen, gives the phenol CLXI in complete analogy t o the sequence CXXXVIII + CLVI. Compound CLVIII was further characterized by oxidation with Sarett reagent and the resulting C-3 ketone (CLXII)was refluxed in methanolic
~
~
50
S. W. PELLETIER AND L. H. KEITH
hydrochloric acid causing hydrolysis of the formyl group and /?-elimination of the C-1 methoxyl. Acetylation then gave the crystalline derivative CLXIII. The UV spectrum of CLXIII was in agreement with that obtained by superposition of the spectra of CLVIII and demethanolaconitone (CLXIV). Aconitine N-oxide (CLXV), prepared by oxidation of aconitine with peracetic acid and reconvertible to the latter by reduction with zinc and
O I
,
OCH3 CTAXXI
CLXXII
I OH
acetic acid, eliminates ethylene and acetic acid on pyrolysis to give the pentacyclic compound CLXVII. If it is assumed that CLXVII originated from the intermediate hydroxylamine (CLXVI) a concerted reaction can be rationalized as shown ( 7 4 ) .This reaction demonstrates (a)the presence of the N-ethyl group and (b) the planar relationship described by the N-C-17-C-7-C-8 moiety. Contrary t o the pyrolysis of aconitine itself, no ketone was produced. To demonstrate that no rearrangements had occurred during pyrolysis, CLXVII was reduced with zinc i n acetic acid t o give a mixture of secondary amines which, on ethylation, gave aconitine in a 28% yield. The reformation of aconitine from CLXVII is explained by an attack a t one end of the system by the solvent molecule with cyclization to the hydroxylamine which, in turn, is reduced to the secondary amine. This is further supported by the analogous cyclization
1.
THE
CIS-DITERPENE ALKALOIDS
51
of the desbenzoylnitrone CLXVIII in methanolic or ethanolic perchloric acid. The formation of two different perchlorate salts (CLXIX and CLXX),depending on the choice of solvent, lends validity to the postu-
T
OH
I OCHg OCH3 CLXXV lated mechanism. A direct consequence of this postulationis the prediction that pyroaconitine N-oxide (CLXXI), lacking the crucial C-8 acetoxy group, should produce a hexacyclic hydroxylamine instead of a pentacyclic one ('74).The pyrolytic product (CLXXII) was, indeed, a hexacyclic hydroxylamine and was further oxidized t o CLXXIII employing aerial oxidation in ammonium hydroxide in the presence of cupric ion.
52
S. W. PELLETIER AND L. H. KEITH
Similarly, the perchlorate of CLXVII (CLXXIV) and the perchlorate CLXIX were oxidized as above to yield the nitrones CLXXVI and CLXXVII, respectively. Saponification of CLXXVI led to CLXXVII. The relationship of CLXXVII to CLXIX was established by sodium borohydride reduction of the former to the free base of the latter. Hot aqueous periodic acid oxidation of CLXXVI gave a neutral blue compound (CLXXVIII) rather than the expected carboxylic acid. Similar treatment of the nitrone CLXXIII gave the analogous nitroso derivative CLXXIX (92).Spectral evidence indicated small amounts of 8-lactones in both oxidations, but the products could not be isolated in pure form. Both of these compounds contained one methoxyl less than their precursors and the formation of CLXXIX precludes the involvement of the C-8 methoxyl. Two significant facts are gained from this transformation : ( 1) the internal ether formation is sterically feasible only if the hydroxyl in ring A is a t C-3 and a-oriented and (2) the facile lactonization across the peri positions between the generated C-4 carboxylic acid group and the C-6 methoxyl uniquely fixes both the location and configuration of the ring F methoxyl. This reaction is analogous to similar ring closures across the same positions in delphinine derivatives (84,93, 94). Reduction of dihydrodemethanolaconitinone (CLXXX) with sodium borohydride gave a mixture of C-3-epimeric alcohols which, after pyrolysis, was separated into compounds CLXXXI and CLXXXII. 1-Desmethoxypyroa.conitine (CLXXXI) was oxidized to its amorphous N-oxide and pyrolyzed to the hydroxylamine which, in turn, was oxidized with potassium ferricyanide t o the nitrone CLXXXIII. 3-Epi-1-desmethoxypyroaconitine (CLXXXII)by an identical series of transformations gave the nitrone CLXXXIV. The periodate oxidation of these two C-3 epimers demonstrated conclusively the a-configuration of this hydroxyl in aconitine and indicated the probable configuration of the C-1 methoxyl. Oxidation of CLXXXIII yielded approximately equal amount: of the blue nitrosolactone CLXXXV and the unusual oximino 8-lactone CLXXXVI. On the other hand, oxidation of CLXXXIV gave neither a P-lactone nor a nitroso-y-lactone but gave instead a crystalline oximino y-lactone (CLXXXVII). I n an eloquent argument (92)it was pointed out that since the oxidation of CLXXVI and CLXXIII gave essentially only y-lactones whereas, under identical conditions the desmethoxy derivative CLXXXIII gave both the /3-lactone and y-lactone in nearly equivalent amounts, the C-1 methoxyl prevents 8-lactone formation. Then, if it is assumed that the fused 8-lactone ring forces ring A into a pseudo-chair conformation, the bulky methoxylmethyl substituent a t C-4 is quasi-axial (CLXXXVIII)
1. THE
CIS-DITERPENE ALKALOIDS
53
and will destabilize a p-lactone by nonbonded interaction with the methoxyl at C-1 if it is axially oriented. On this basis the C-1 methoxyl was tentatively assigned the p-configuration. Up to this point in the discussion the position of the benzoyloxy group has been less rigorously demonstrated than the rest of the structure ; its assignment to C-14 rested solely on the reactions CXXXVIII + CXL
OCH3 CLXXX
OCH3 CLXXXI; C.3 a-OH CLXXXll; U - 3 P-OH I
c 0H
OUH3 ('LSXXV
CLXXXIII; C-3 a-OH CLXXXIV; C - 3 8-OH
I
OH
1
CI,SXXVI
CLXXXVII
54
S. W. PELLETIER AND L. H. KEITH
versus CXXXIII --f CL. Tsuda and Marion (95) have provided excellent spectroscopic evidence which is in agreement not only with the C- 14 assignment but also with the a-orientation a t this position, as shown in the X-ray crystallographic analysis (76) of CXXIII. The alkaloids aconitine, indaconitine, pseudaconitine, delphinine, and bikhaconitine all contain an aromatic ester functional group. It was observed that a doublet of one-proton intensity occurs a t about 75.1 in the NMR spectra of all of these compounds and it is absent in the spectra of the corresponding alkamines. Since the acetoxy group of aconitine is located on the quaternary carbon C-8 the signal must be due to the proton geminal to the benzoyloxy group and the splitting is caused by one neighboring
proton. This condition is met if the aromatic ester is a t C-14 but not if it is a t the quaternary C-13 position, the only other possible structure on the basis of the foregoing evidence. In addition, the acetoxy protons of these alkaloids all show signals a t unusually high field (about 78.7) which cannot be attributed to their tertiary nature. The explanation appears to be that the upfield shift is caused by the diamagnetic anisotropy of the aromatic ring which can easily come in close proximity to the acetoxy protons. This condition is satisfied with the C-8 acetoxy protons if the benzoyloxy group is a t C-14 but not if it is a t C-13. Dreiding models show that for an a-benzoyloxy group the C-9-C-14 H-H dihedral angle is about 40' while the dihedral angle for the /3-configuration is about 80" ; the Karplus values for dihedral angles of 40" and 80" are about 4 Hz and 0 Hz, respectively. The observed coupling constant of 4.5 Hz is thus in excellent agreement with the theoretical value for a C- 14 a-benzoyloxy group. Recently Wiesner and Santroch (97) have described an elegant synthesis of compound CLXXXIX, possessing a structure closely related to CXC so that feasible modification of the functionality of both products should lead to a common intermediate. The latter compound, along with CLVIII, is formed from the aromatization reaction sequence previously described when carried out on pyrooxonitine (CXXXIV) (82). Such a
1.
THE
C
I
S
- ALKALOIDS ~ ~
~
~
~
~55 ~
correlation of CXC with a totally synthetic product derived from CLXXXIX would constitute a rigorous chemical proof of structure of rings A, B, E, and F of aconitine (as well as of delphinine whose similar
CSC'Vn: H
=
C'SCVb; R =
H
4'
C'SCI\'II: R ('SCIVt): R
= CH&H=CHz = CH2CHO
OCH3 I
aromatization product has been correlated with that derived from aconitine). Alkylation of methoxytetralone (CXCI)with CXCII gave CXCIII and the latter, when treated with ally1 bromide and sodium hydride, afforded CXCIVa in good yield. Catalytic oxidation of CXCIVa with osmium tetroxide and sodium clzlorate produced the aldehyde CXClVb in 97% yield and treatment of the latter with sodium hydroxide effected an
~
56
S. W. PELLETIER AND L. H . KEITH
86 yo conversion to the aldol CXCVa. The tetrahydropyranyl derivative
CXCVb in methanol was saturated with ammonia and hydrogenated with Raney nickel at high temperature and pressure. The crude product
CXCVI
QJ0
t
1
Ho
,
I OCH3
CXCIX
OCH3 CLXXXIX
CXC; R = H CLVIII; R = OCH3
(CXCVI)was converted to the diacetate CXCVII. Saponification of the 0-acetate was followed by removal of the benzyl group by hydrogenolysis over palladium. Oxidation with Jones reagent gave the epimeric diketones CXCVIIIa and CXCVIIIb in a 4 : 1 ratio. Compound CXCVIIIa was then converted to CXCIX in one step (50% yield) by refluxing it in
TABLE VIII
NEWLY DESCRIBED DERIVATIVES OF ACONITINE
Compound
[.ID
- 77
N-Nitrosodesethylaconitine (CXXV) N-Nitrosodesethylaconitine triacetate (CXXVI) N-Acetyldesethylaconitine triacetate (CXXVII) N-Chlorocarbonyldesethylaconitine triacetate (CXXVIII) Rearranged diketone (CXL) Rearranged oxonine methoxylphenol (CLVIII) Aconitine d 17-nitrone (CLXVII) Desacetoxy-8-methoxyaconitineperchlorate (CLXIX) Desacetoxy- 8-ethoxyaconitine perchlorate (CLXX) Pyroaconitine N-oxide (CLXXI) Pyroaconitine dig-nitrone (CLXXIII) Desacetoxy-8-methoxyaconitinedlg-nitrone (CLXXVI) Desacetoxy-8-methoxyaconitine nitrosolactone (CLXXVIII) Pyroaconitine nitrosolactone (CLXXIX) 1-Desmethoxypyroaeonitine (CLXXXI) 1-Desmethoxypyroaconitine dig-nitrone (CLXXXIII) 3-Epi-1-desmethoxypyroaconitine d'g-nitrone (CLXXXIV) 1-Desmethoxypyroaconitinenitrosolactone (CLXXXV) I-Desmethoxypyroaconitine oximino-P-lactone (CLXXXVI) 1-Desmethoxypyroaconitineoximino-y-lactone (CLXXXVII) Anhydroaconitine perchlorate (CCVII)
287-289 262-263 186-188 195-197 238 138-140 255 2.50 dec 250 dec 159-164 230-232 210-212 233-234 237-238 131-132 243-244 231-232 179-180 235-236 244-246 200-204
Deoxyaconitine (CCVIII) Deoxyaconitine perchlorate Pyrodeoxyaconitine (CCIX) Pyrodeoxyaconine perchlorate (CCXI) N-Methyl-N-desethyldeoxyaconitine (hypaconitine)(CCVI) N-Methyl-N-desethylaconitine (mesaconitine) (CCV) Deoxyaconitine methanesulfonate
173-156 180 Amorphous 250-260 dec 172-178 dec 196-198 194-195
- 70
dec
- 55.4 -
- 155 -
-
dec
-
+ 13 dec dec
-
-
- 96 - 109 - 191 -
- 150
+ 12.1 -
-11.7 - 82 - 86 18 25.2
+
+
-
References 8lr1 61rc
81a Sla 82 82 74 71 74 7.1 74 92 92 92 92 92 92 92 92 92 112 112 112 112 112 112 113 90
58
S . W. PELLETIER AND L.
H. KEITH
an aqueous ethanol solution with an excess of potassium cyanide. The reaction proceeds via an aldol condensation to an a,@-unsaturated ketone ; then addition of cyanide t o the latter is followed by hydrolysis of the resulting nitrile to a primary amide; and lastly the hemiketal-like compound is formed. Conversion of the latter into CLXXXIX was then effected by refluxing it in a concentrated methanolic hydrochloric acid solution. Another stereospecific synthesis of pentacyclic compounds with a bridge in ring B has recently appeared (97a).An outline is given by structures CCa-CCIc. Table VIII lists the newly described derivatives of aconitine.
CH3OOC@
-
0
CCa
ccc
CCb
n t
t
0
CCIC
CCIb
CCIa
B. JESACONITINE Jesaconitine was first isolated from a variety of the tuber Aconitum Jischeri Reichb., a plant native to Hokkaido, one of the northernmost members of the Japanese archipelago (98).It has also since been found in
1.
THE
CIS-DITERPENE ALKALOIDS
59
other East Asian species, e.g., A . subcuneatum Nakai (99, loo), A . sachalinense I?. Schmidt (99, loo),and A . mitakense Nakai (101). Jesaconitine differs from aconitine (CXXI) by only one ester functional group. Whereas, aconitine is hydrolyzed to acetic acid, benzoic acid, and the parent amino alcohol aconine (CCII), jesaconitine is hydrolyzed to acetic acid, anisic acid (4-methoxybenzoic acid), and aconine (100).Pyrolysis of jesaconitine gave pyrojesaconitine but there was no mention of whether acetic acid or anisic acid was eliminated OH
OCH3
OR
’OH
OCH3 C X X I ; R = Ac, R’ = Bz CCII; R = R’= H CCIII; R = Ac,R’ = As OH
during the pyrolysis (100).Since the structure of aconine is known with certainty, it remained only to locate the acetoxy and p-methoxybenzoyloxy moieties on the aconine skeleton. Although there are five hydroxyl groups in aconine, the number of possible combinations was considerably simplified since one of the ester groups had to be a t C-8 in order to produce pyrojesaconitine. An examination of the 100-MHz NMR spectrum of jesaconitine revealed that the (3-14position was also substituted since the signal of the C-14 proton appeared a t 75.38 (doublet, J = 4.5 Hz) (102,102a).When not esterified this proton appears at about 75.8, while when esterified with a benzoyloxy or acetoxy group it usually appears a t about 75.1 and 5.2, respectively. Further proof of a C-8-C-14 substitution was the highly
60
S. W. PELLETIER AND L.
H. KEITH
shielded signal of the acetoxy protons (78.64). This has been observed with all of the aconitine-type alkaloids examined which contain a C-14 benzoyloxy-C-8 acetoxy substitution pattern. By analogy, therefore, it was expected that the same situation exists in jesaconitine. However, to eliminate any possibility that the acetoxy and benzoyloxy groups might be interchanged, the pyrolysis was carried out on a few milligrams of jesaconitine dissolved in glycerol and the progress of the reaction was ) . highly shielded continuously monitored by NMR spectra ( 1 0 2 ~ The signal of the acetoxy protons was observed to slowly disappear while a new signal, due to acetic acid, appeared and grew t o about the same intensity as the original shielded acetoxy signal. The signals due t o the aromatic protons, however, remained completely unchanged. This pyrolysis was also repeated with aconitine and mesaconitine and the same results were observed. Thus, jesaconitine is represented by structure CCIII and pyrojesaconitine by CCIV. AND DEOXYACONITINE C. MESACONITINE,HYPACONITINE,
Mesaconitine was first isolated (103) in 1929 and occurs in a large number of Aconitum species ( 1 ) . Recent reports describe its isolation from A . japonicum ( l 0 4 ) ,A . mitakense (101),A . altaicum Steinb. (105)) and A . carmichalei (the Chinese drug Chuan-wu) (7'3).It has long been known that mesaconitine differs from aconitine only in that the former has an N-methyl whereas the latter has an N-ethyl ( 1 ) .Both alkaloids produce oxonitine (CXXXIII) from permanganate oxidation. Hence, since the structure of aconitine has been established as CXXI, mesaconitine follows as CCV. Hypaconitine was also first isolated (106)in 1929 and is often found to occur with mesaconitine and aconitine. Recent reports describe its isolation from A . sanyoense Nakai var. sanyoense ( l o r ) ,A . carmichaeli (7'3, 108),A . bullatifohm var. homotrichum (the Chinese drug Hye-shang-yizhi-hao) ( l o g ) ,and A . koreanum (Auth. '1) (the Chinese drug Guan-bai-futsu) (110).Hypaconitine is clearly related to aconitine and mesaconitine in many ofits reactions; an exception, however, is its resistance to chromic acid oxidation, indicating the absence of the ring A hydroxyl that is present in the latter two alkaloids. It has long been established that, like mesaconitine, hypaconitine contains an N-methyl group (111).Thus, Gilman and Marion (112) assumed, as a working hypothesis, that hypaconitine possessed structure CCVI. To prove or disprove this hypothesis they set about t o convert aconitine into hypaconitine. The first step was the removal of the ring A hydroxyl, accomplished by
1.
THE
C
1
~ ALKALOIDS ~
~
~ 61
refluxing aconitine (CXXI) with thionyl chloride. The product, anhydro aconitine (CCVII), was hydrogenated to give deoxyaconitine (CCVIII). To assure that the ring A hydroxyl rather than the ring D hydroxyl had been removed, deoxyaconitine was pyrolyzed to pyrodeoxyaconitine (CCIX), and transesterification of the latter gave pyrodeoxyaconine (CCX),isolated as its perchlorate (CCXI). Since the IR spectrum of CCX OH
6CH3 dCH3 CCVII
CXXI
I CCVI; R CCXII; R
J
= CH3 =H
OCH3 CCIX; R = B z CCX; R = H C C X I ; perchlorate of CCX
CCVIII
~
~
62
S. W. P E L L E T I E R AND L. H. K E I T H
contained a carbonyl absorption like pyroaconine, it was concluded that the ring D hydroxyl of deoxyaconitine was still present. If the C-15 hydroxyl had been removed pyrodeoxyaconine would have been an
cq3-----r3 _ _’0 _13 _7-.- - - -
CCXXI
+
R--- --N .
HO’
‘OH
*
;. 6CH3 OCH3
/
CCXIII; R = H CCV; R = C H 3
J
CH3-
CCXIV
CCXV
t-
CCVI
dCHOSCH3 CCXVI
olefin like the other aconitine-type pyro derivatives which lack a hydroxyl a t this position. Removal of the N-ethyl group was accomplished by oxidation with mercuric acetate and the N-desethyldeoxyaconitine (CCXII) was then treated with methyl iodide. The N-methylN-desethyldeoxyaconitine thus produced was nearly identical with
1.
THE
C
I
S
- ALKALOIDS ~ ~
~
~
~
63 ~
authentic hypaconitine, although there were differences in both the IR spectra and X-ray powder patterns so it was assumed that they were not really identical. Two years later, however, Marion and his research group showed that structure CCVI was, indeed, the correct one for hypaconitine (113); thus, the differences in spectra and X-ray patterns must have been caused by impurities. As the preceding reaction sequence was inconclusive the investigators tried another approach. Starting with aconitine (CXXI), the first step again was dealkylation with permanganate to give N-desethylaconitine (CCXIII). Methylation of the latter produced mesaconitine (CCV)
TABLE I X
NEWLY DESCRIBED DERIVATIVES OF MESACONITINE AND HYPACONITINE~ Compound Pentaacetylrnesaconitine (CCXIV) Deoxymesaconitine (CCVI) (hypaconitine) Tetraacetyldeoxymesaconine (CCXVII) (tetraacetylhypaconine) a
Mp ("C)
[aID
References
C34H49N014
221-224
-
113
C33H~,N010
184-1 86
-
113
-
113
Formula
C ~ ~ H ~ ~ N O ~ Z . H Z150 O
See also Table VIII under deoxyaconitine derivatives.
(N-desethyl-N-methylaconitine). Saponification of CCV followed by acetylation gave pentaacetylmesaconine (CCXIV). Refluxing CCV with thionyl chloride produced the amorphous anhydromesaconitine (CCXV) which, after hydrogenation, gave deoxymesaconitine (CCVI), identical with hypaconitine. Furthermore, saponification of CCVI followed by acetylation gave tetraacetyldeoxymesaconine (CCXVI) (tetraacetylhypaconine), demonstrating the loss of only one hydroxyl group from
ccv.
Recrystallization of the commercial aconitine used in the above reaction sequence revealed that it was contaminated with about 20/, of an alkaloid which was shown by its IR spectrum and X-ray powder pattern to be identical with deoxyaconitine (CCVIII) (113). The recent derivatives of mesaconitine and hypaconitine are listed in Table IX.
~
~
64
S. W. PELLETIER AKD L. H. KEITH
D. DELPHININE Delphonine (CCXVII) is the parent amino alcohol of the diester delphinine (CCXVIII). The latter is the main alkaloid of Delphinium staphisagria L. which was first isolated in 1819 and became the subject of OH
CCXVII ; R CCXVIII; R
= R' = H
= Ac,
R'
=
RZ
OH
"OBz
CXXXVI
CH3@ Y O OAc -
R2
H *c3
OBz
R2
OCH3 OCH3 CCXXIa; R1= OCH3,R2 = H CCXXIb; R1= H, R2 = OCH3
OCH3 OCH3 CCXXIIS,; RI = OCH3, R2 = H CCXXIIh; I t 1 = H , Rz= OCH3
intensive experimentation (83, 9 4 , 1 1 4 ) .It was shown t o possess a hexacyclic skeleton with four methoxyls, one acetoxy, one benzoyloxy group, one tertiary hydroxyl, and an N-methyl. The structure of the CD ring system (CXXXV)was elucidated by Wiesner's research group (115). It has been rigorously demonstrated that the acid-catalyzed pyroisopyro change in delphinine (CXXXVI 4 CCXIX) is an allylic rearrangement of a methoxyl group which leaves the skeletal system un-
65
1. THE Cig-DITERPENE ALKALOIDS
changed ( 8 4 ) .This was proved in two ways and is important because it is a key factor in the structural elucidation of related alkaloids. First, by isomerizing the pyrodelphinine derivative in radioactive methanol, it was demonstrated that radioactivity corresponding to 1 mole of methanol was incorporated into the resulting isopyrodelphinine derivative. CCXXII
CCXXI
I
CH
,N,
OCH3OCHS
CH3 CH3 CICX XI1 I
CCXXIV
CCXXVI
CCXXV
Second, it was not possible to prepare CCXIX in any medium other than methanol. Thus, when CXXXVI was treated with p-toluenesulfonic acid in glacial acetic acid, the methoxyl was exchanged quantitatively for an acetoxy group (CCXX). By reevaluation of the previous chemical data in the literature Wiesner’s group was able to extend the probable structure of delphinine to one of four possible isomers represented by structures CCXXI or CCXXII (87,93).A decision between the two skeletons was achieved by
66
S. W. PELLETIER AND L. H. KEITH
clarification of the products resulting from the Hofmann degradation of delphonine (80).The methohydroxide CCXXIII when heated in strong base was postulated to undergo initial cleavage to give CCXXIV, which can be converted to the isolated product CCXXV by a reverse aldol, P-elimination of a methoxyl, and vinylogous P-ketoaldehyde cleavage (although not necessarily in that order). The decision between CCXXI and CCXXII was made possible by a study of the NMR spectrum of the Hofmann degradation product (CCXXV), since CCXXII by a similar degradation would form CCXXVI. The NMR spectrum of the product showed two sets of doublets, each of one-proton intensity, in the olefinic region. Clearly, the product of the Hofmann degradation cannot be CCXXVI, which would have only one olefinic hydrogen. a-Oxoisopyrodelphinine (CCXXVII) was converted into the secoacid CCXXVIII, in which it was assumed that the methoxyl eliminated was the same one that exchanges in the pyro-isopyro rearrangements ( 8 4 ) . This was later shown t o be correct by conversion of a-oxopyrodelphinine (CCXXIX) into the identical secoacid (CCXXVIII) (93). The similar rearrangement of a-oxodelphonine (CXLIV) to the secoacid CXLVIII was discussed earlier (87, 88). Treatment of a-oxoisopyrodelphinine (CCXXVII) with methanolic hydrochloric acid results in the replacement of two methoxyls by chlorine (87)and the product (CCXXX)can bereconvertedwith methanol into a-oxoisopyrodelphinine. The chlorines can also be replaced by hydroxyls, giving the trio1 CCXXXI, which, in turn, can be oxidized t o the hydroxy acid CCXXXII, demonstrating that one of the replaced methoxyls was substituted on a primary carbon and the other on a tertiary carbon ( 9 3 ) . The same dichloride (CCXXX) is also produced from a-oxopyrodelphinine, thereby making it decisively clear that the tertiary methoxyl which is replaced is the same one involved in the pyroisopyro rearrangement. Earlier experiments (94) had shown that octahydro-a-oxoisopyrodelphinine (CCXXXIII), produced by catalylic hydrogenation of CCXXVII, gives a dimethoxy ether (CCXXXIV) with a corresponding loss of two methoxyls when treated with aqueous zinc chloride. It had been assumed that internal ether formation took place between the same two methoxyls that were so easily displaced by chlorine. There was good proof that the primary methoxyl was involved but none concerning the second methoxyl. Wiesner (93) has shown with a simple, yet elegant, labeling experiment that only one of the two methoxyls displaced by chlorine is involved in the internal ether forniation. The dichloride CCXXX was converted, by refluxing in CD30H, into the labeled a-oxoisopyrodelphinine (CCXXVII*), and this labeled derivative was then
1.
THE
CCXXXIII; R = CH3 CCXXXIII*: R = C D ~
C
I
S
- ALKALOIDS ~ ~
~
~
~
CCXXXIV; R = CH3 CCXXXIV*: 12 = CD3
~ 67
~
~
68
S.
W. PELLETIER
AND L. H. KEITH
converted into the cyclic ether CCXXXIV*. The latter was found to have retained one of its deuterated methoxyls. Wiesner et al. achieved the first correlation of delphinine with aconitine (116).It was found that cr-oxoisopyrodelphonine (CCXXVII) undergoes the same periodate cleavage as does oxonine (CXXXVIII) (74). The secoaldehyde (CCXXXV) thus obtained was treated under identical conditions as the aconitine secoaldehyde (CLI) and the product of the rearrangement was the phenol CCXXXVI, which may be considered to arise by the same mechanism by which the methoxyphenol CLVI was produced from CLI. The phenol CCXXXVI was methylated with diazomethane and the N-formyl group hydrolyzed to give CCXXXVII, a crystalline base also characterized as its oxalate (CCXXXVIII). Borohydride reduction of pyrooxonitine (CXXXIV) followed by saponification gave an amorphous dihydropyrooxonine (CCXXXIX) which was treated with periodic acid and then immediately aromatized to yield CCXL. Treatment of the latter with diazomethane produced the methyl ether (CCXLI) which was then treated with dichlorophenylphosphine oxide, giving the chloro derivative (CCXLII). The final step of the correlation was reduction of the halogen with zinc and acetic acid followed by hydrolysis to give CCXXXVII. The latter and its oxalate (CCXXXVIII) were identical with the corresponding derivatives prepared from delphinine (116).The important point to note is that the ring A methoxyl of delphinine is shown to have the same position and configuration as that of aconitine. The C-6 methoxyl is the other defined point of the correlation since the above reaction sequence also leaves it untouched. Previously, the ring A methoxyl of delphinine had been placed at C-1 and /3 merely by analogy with aconitine. Now, the derivative chosen for the X-ray crystallographic study of aconitine (CXXIII) lacked the C-1 methoxyl and the tentative /3-configuration was therefore deduced by stereochemical considerations of the C-1 methoxyl’s influence on ,&lactone formation (92). Wiesner’s laboratory shortly thereafter rigorously proved that the C- 1 methoxyl of delphinine is trans to the nitrogen bridge (117),thus corroborating Buchi’s earlier conformational argument (92). Hydrogenation of CCXLIII gave CCXLIV which, when saponified, gave a mixture of the des-N-formyl (CCXLV) and N-formyl (CCXLVI) derivatives. The easy hydrolysis of the formamide is explained by anchiomeric assistance from the C-1 equatorial (cr) hydroxyl. Oxidation of CCXLIII gave the corresponding ketone CCXLVII obtained by earlier workers (94). Sodium borohydride reduction of CCXLVII gave CCXLVIII, a compound also produced by saponification of CCXLIII. Since the formation of an equatorial C-1 alcohol is favored by both thermodynamic and kinetic
1.
THE CIS-DITERPENEALKALOIDS
CXXXIV
CCXXXVI; R' = CHO, R2 = H CCXXXVII; R1= H, R2= CH3 CCXXXVIII; oxalate of CCXXXVII
1
CCXXXIX
CCXL; R1 = H, R2 = OH CCXLI; I%' = CH3, R2 = OH CCXLII; R1= CH3, R2 = CI
69
70
S. W. PELLETIER AND L. H. KEITH
considerations, it appears certain that CCXLIII does indeed possess a C-1 hydroxyl cis t o the nitrogen bridge. Complete methylation of CCXLVI gave CCXLIX which, when reduced with lithium aluminum ?H
OH I
CCXLVII
OH
CCXLIV
CCXLVIII
I CCXLV; R = H CCXLVI; R = CHO
CCXLIX; R = CHO CCL; R - C H 3
hydride, produced the pentamethyl derivative CCL. After saponification of CCXXXIV, complete methylation gave CCLI which, in turn, was also reduced with lithium aluminum hydride to give the pentamethyl derivative CCLII, a compound epimeric with CCL at C-1. Since CCXLIII was shown to contain an equatorial ( a )hydroxyl, CCXXXIV, which has
TABLE X
NEWLY DESCRIBED DERIVATIVES OF DELPRININE~ Compound
a-Oxoisopyrodelphoninesecoaldehyde(CLX) Rearranged phenol (CLXI) methyl ether Acetoxyisopyprooxodelphinine(CCXX) Delphonine methiodide Hofmann degradation product (CCXXV) Bis(2,4-dinitrophenylhydrazone)of CCXXV Demethoxyl-a-oxodelphoninesecoacid (CCXXVIII) Dichloro- a-oxoisopyrodelphinine (CCXXX) Hexadeut.ero-a-oxoisopyrodelphinine (CCXXVII*) Octahydrohexadeutero-a-oxoisopyrodelphinine (CCXXXIII*) Desmethoxyoctahydrotrideutero-a-oxoisopyrodelphinine cyclic ether (CCXXXIV*) Tridesmethoxyoctahydro- a-oxoisopyrodelphinine cyclic ether (CCXLIV) Des-N-formyltridesmethoxydihydroisopyrodelphonine cyclic ether (CCXLV) a-Oxotridesmethoxydihydroisopyrodelphonine cyclic ether (CCXLVI) a-Oxotridesmethoxyisopyrodelphonine cyclic ether (CCXLVIII) 8,13,14-Trimethoxy-16-desmethoxyepi-1-delphonine cyclic ether (CCL) a-Ox0-8,13,14-trimethoxy16-desmethoxydelphonine cyclic ether (CCLI) 8,13,14-Trimethoxy- 16-desmethoxydelphonine cyclic ether (CCLII) a
There are no [ a ]values ~ reported for these compounds.
Formula
MP ("C)
References
158 123 144 305 208-2 11 153 157 138 270dec 285 204-209 266
82 82 82 93 93 93 93
241 265 164 310 156 203 185
117 11Y 11Y 117 117 117 117
84 87 87 87 87
w
c-1
?I
cz
I-
'9
z M
E
; w k
k$ 5U m
72
S. W. PELLETIER AND L . H . KEITH
the undisturbed original C-1 methoxyl of delphinine, has this substituent in an axial (p) configuration. And, since the C - 1 as well as the C - 6 functional groups of delphinine have been correlated with those of aconitine (116),the C-1 methoxyl in aconitine must also be axial, a configuration left uncertain in the X-ray studies of aconitine (75, 76). The alkaloid delphonine (CCXVII) was also claimed to have been isolated from both the roots and aerial portions of Delphinium rotundifoliam Afan. (118).Although it was not compared with an authentic sample, the physical constants, character of the functional groups, and analytical data for the newly isolated alkaloid were close enough to those reported for delphonine that they were assumed to be identical. However, when the N-dealkylated derivative was realkylated with methyl iodide 0CH3
@-0J-m . - '@ .,,,. ------_____
0
CH30
\c-- ---"
H'
,'
-----______
,,
,I.
'"
_ _ _ -----
'b.,
, s '
0CH3
*,'
CCXXXIV
'\
R--- - - y
:.
.OCHs]
--------OCH3
CCLI; R = CHO CCLII; R = C H 3
and with ethyl iodide the latter product was found to be identical with the isolated base. Since delphonine has an N-methyl instead of an N-ethyl, this proves that the base from D . rotun,difolium cannot be delphonine. No further clarification has been presented by the Russian authors. The recently described derivatives of delphinine are listed in Table X.
E. INDACONITINE AND PSEUDACONITINE The alkaloid pseudaconitine (CCLIII) was first isolated in 1877 from the roots of A . ferox Wall., a plant indigenous to the Himalayas and called " bish" by the natives (119).It was soon observed that saponification gave acetic and dimethylprotocatechuic acid (veratric acid) and a base named pseudaconine (CCLIV) (120).Later researchers found that the hydrolysis of pseudaconitine can occur in two steps (121).Thus, heating an aqueous neutral solution of pseudaconitine sulfate in a sealed tube produced veratrylpseudaconine (CCLV) and acetic acid. Saponification of CCLV then gave pseudaconine and veratric acid. The observation
1. THE CI~-DITERPENE ALKALOIDS
73
(later to become indicative of a C-S acetoxy) was also made that pseudaconitine, when heated slightly above its melting point, lost acetic acid, and the base produced was named pyropseudaconitine (CCLVI). The latter furnishes pyropseudaconine (CCLVII) and veratric acid when saponified. Pseudaconitine and pseudaconine were reported to be dextrorotntory in alcohol but the ordinary salts of pseudaconitine in water as well as veratrylpseudaconine in alcohol were levorotatory (121). Much later, Marion and Edwards (122) isolated an alkaloid from A . napellus (one of the best sources of aconitine) which, when saponified, gave acetic acid, veratric acid, and an alkaloid of the same formula, melting point, and optical rotation as previously reported for pseudaconine from A .ferox (121).However, partial hydrolysis gave dextror9tatory veratroylpseudaconine and hence the new base and its partial hydrolysis product were named a-pseudaconitine and a-veratroylpseudaconine. Recently, an alkaloid identical with the reported u-pseudaconitine was isolated from the roots of A . spictatum Stapf. (123).Comparison of this alkaloid with an authentic sample of pseudaconitine also showed they were identical. Thus, the original report of veratroylpseudaconine as being levorotatory (121)must be in error and a-pseudaconitine is identical with pseudaconitine, the latter name being retained. Indaconitine (CCLVIII) was the first alkaloid isolated from A . chasmanthum Stapf in 1905 (124).It was found that acid hydrolysis produces acetic acid and benzoylpseudaconine(CCLIX)while saponification produces acetic acid, benzoic acid, and pseudaconine (CCLIV). Hence, it is clear that pseudaconitine and indaconitine differ from one another only by one ester functional group, the former derived from 3,4-dimethoxybenzoic (veratric) acid and the latter from benzoic acid. Indaconitine, like pseudaconitine, loses 1 mole of acetic acid when heated above its melting point, to give pyroindaconitine (CCLX).It has been established that indaconitine contains an N-ethyl group (125); therefore pseudaconitine must also contain one N-ethyl group. Pseudaconitine, like aconitine, is oxidized by chromic acid to an a,P-unsaturated ketone (CCLXI) containing one methoxyl less than the original alkaloid (126)and it was therefore assumed that pseudaconitine and indaconitine possessed a C-1 methoxyl and a C-3 hydroxyl as in aconitine. Since all three alkaloids lose acetic acid on pyrolysis indaconitine and pseudaconitine were assumed to have an acetoxy at C-8 also. As a working hypothesis it was assumed that by analogy with aconitine, indaconitine had structure CCLVIII. TOprove this hypothesis it was' decided to convert indaconitine to delphinine (CCXVIII) by removal of the C-3 hydroxyl and replacement of the N-ethyl with an N-methyl group (127). Accordingly, indaconitine was refluxed with
74
S. W. PELLETIER AND L. H. KEITH
thionyl chloride,which converted it into anhydroindaconitine (CCLXII), characterized as its crystalline perchlorate (CCLXIII). Catalytic hydrogenation of CCLXII gave deoxyindaconitine (CCLXIV), which was treated, in turn, with mercuric acetate to produce an amorphous N-desethyldeoxyindaconitine (CCLXV), reconvertible to CCLXIV by reaction with ethyl iodide. Reaction of CCLXV with methyl iodide gave OH
OCH3 CCLIII; CCLIV; CCLV; CCLVIII; CCLIX;
OCH3
R = Ac, R' = V r R = R' = H It=H,R'=Vr R = Ac, R' = 132 H=H,R'=Bz
CCLVI; R = Vr CCLVII; R = H CCLX; R = H s
OH
nu
I
6CH3 OCH3 CCLXII C C L X I I I perchlorate
CCLXI
OH
OCH3
CCLXIV; R = C ~ H S CCLXV: R = H
OCH3
CCXVIII
1.
THE
C
I
S
- ALKALOIDS ~ ~ ~
~
~
75 ~
N-methyl-N-desethyldeoxyindaconitine (CCXVIII),identical with delphinine. Since the undisturbed rings A, B, E, and F of delphinine have been correlated with those of aconitine, this conversion proved the stereochemistry of this portion of the structures of both indaconitine and pseudaconitine, with the exception of the ring A hydroxyl which had been removed. The formation of pyro derivatives of indaconitine and pseudaconitine with the elimination of acetic acid constitutes definite proof that the acetoxy is a t C-8. Further proof of the latter is interwoven with spectroscopic evidence for the location of the aromatic ester moieties a t C-14 and in the equatorial (a)configuration. Both indaconitine and pseudaconitine exhibit a one-proton doublet (J = 4.5 Hz) a t about 75.1. This same signal is also observed in the NMR spectra of aconitine and delphinine, both of which contain an equatorial C-14 aromatic ester. The signal then must arise from the geminal axial (/3) C-14 proton coupling with one neighboring proton. The other adjacent carbon must therefore be substituted with the tertiary hydroxyl which, by analogy, is placed a t C-13. Also, the acetoxy signal of indaconitine and pseudaconitine appears a t about 78.7. The same signal in delphinine and aconitine is seen a t 78.72 and 8.61, respectively (95), and the high-field shift is due to the diamagnetic anisotropy of the aromatic nucleus, as discussed previously. The configuration of the C-14 benzoyloxy group is assigned on the basis of the coupling constant, which is in excellent agreement with the dihedral angle between the C-9 proton and an axial C-14 proton (approx. 40'). In the previously mentioned transformation of indaconitine to delphinine the C-3 hydroxyl of the former was removed, so there was no rigorous proof of its location and configuration. This anomaly has been removed by the correlation of pseudaconitine with aconitine (86). Pyrolysis of pseudaconitine (CCLIII) in vacuo produced pyropseudaconitine (CCLVI),which was amorphous in character (86,l Z Z ) , contrary to its description by early workers (126), and hydrolysis gave pyropseudaconine (CCLVII).The NMR spectra of both derivatives showed a doublet of one-proton intensity ( J = 6 Hz) a t 74.43 and 4.45, respectively, thus proving that the adjacent c-16 position is substituted with a methoxyl (since all other functional groups have been accounted for) and further indicating that the methoxyl is /3 since a /3-proton a t C-16 would have a very small predicted coupling constant ( < 1 Hz) based on the dihedral angles involved. Reaction of CCLVI with lithium aluminum hydride produced demethoxyisopyropseudaconine (CXLII), characterized as its crystalline perchlorate (CCLXVI). The NMR spectrum of CXLII confirmed this structure by showing signals for only three methoxyl groups plus a two-proton multiplet of the olefinic hydrogens.
~
~
76
S. W. PELLETIER AND L. H. KEITH
Catalytic hydrogenation of CXLII gave a colorless gum (CXLIII) which formed a crystalline perchlorate (CCLXVII) and which should have been identical with the Wolff-Kishner reduction product of pyroaconitine (85),but instead it was different. Reexamination of the latter compound revealed that it was not saturated but contained one double bond, being, in fact, identical with demethoxyisopyropseudaconine (CXLII). The important points to note are (a)that the position and configuration of the
CCLXVI
CCLXVII
C-3 hydroxyl of indaconitine and pseudaconitine is rigorously proved and (b) that it has now been demonstrated that the stereochemistry of the CD ring system of delphinine is the same as that of aconitine, a point very reasonably assumed but unproved in previous discussions since the rearrangement involved in the correlation of aconitine and delphinine destroyed the existing CD ring systems. The latter point follows from the previous conversion of indaconitiiie to delphinine (127),which demonstrates that all three alkaloids (indaconitine, pseudaconitine, and delphinine) possess the same stereochemistry in their BCDEF ring systems. The newly described derivatives of indaconitine and pseudaconitine are reported in Tables X I and XII. TABLE X I NEWLYDESCRIBED DERIVATIVES OF INDACONITINE Compound Anhydroindaconitine perchlorate (CCLXIII) Deoxyindaconitine (CCLXIV) N-Methyl-N-desethyldeoxyindaconitine (CCXVIII) (delphinine)
Formula
Mp ("C)
[o(]D
References
C34H46ClN013
190-200 dec
+ 31
127
C34H47NOg C33H45NOg
175-180 dec 185-191 dec
+ 14 + 26
127 127
TABLE XI1 DERIVATIVES OF PSEUDACONITINE NEWLYDESCRIBED r
Compound Pyropseudaconitine (CCLVI) Monoacetylpseudaconitine perchlorate Diacetylpseudaconitine Demethoxyisopyropseudaconine (CXLII) perchlorate (CCLXVI) Dihydrodemethoxyisopyropseudaconine(CXLIII) perchlorate (CCLXVII) Anhydropseudaconitine (CCLXXIX) perchlorate Demethoxydeoxypseudaconitine(CCLXXX) (demethoxybikhaconitine) perchlorate
Formula
MP ("C) Amorphous 143-147 247-248 22 7-229 Amorphous 256-258 dec Amorphous 229-231 dec Amorphous 235-236 dec 175-182 170-175
[a]o
References
-
86 86
-
86 86 86 86 86 86 129 129 129
-
129
+ 17 -
+21 -
- 24.8 -
+16.1
c3
B M
M
78
S. W. PELLETIER AND L. H. KEITH
F. BIKHACONITINE Bikhaconitine (CCLXVIII) was first isolated in 1905 from the roots of Aconitum spictatum, a plant used extensively as a poison by the Indian population and simply denoted by most of the languages of India as (‘bikh” or bish” meaningpoison (128).It was found that bikhaconitine undergoes a two-step hydrolysis analogous to pseudaconitine and indaconitine, the first step being the formation of acetic acid and veratroylbikhaconine (CCLXIX) and the second step being the saponification t o veratric acid and bikhaconine (CCLXX). Bikhaconitine also eliminated acetic acid t o produce pyrobikhaconitine (CCLXXI) when heated above its melting point. The alkaloid had an analysis corresponding t o C36H51NOll-H20and six methoxyl groups. Later research (129) verified these findings and in addition showed (by NMR) that two of the methoxyls were aromatic (veratroyl group) and four were aliphatic. In addition, there were signals characteristic of an N-ethyl, an acetoxy group, three aromatic protons, and a one-proton doublet ( J = 4.5 Hz) a t 75.13. The acetoxy signal was a t high field and this, coupled with the oneproton doublet, was indicative that the two ester groups of bikhaconitine are located and oriented as in pseudaconitine (95,129). Treatment of bikhaconitine with acetic anhydride containing p-toluenesulfonic acid gave acetylbikhaconitine (CCLXXII) while treatment of bikhaconine (CCLXX) under the same conditions gave triacetylbikhaconine (CCLXXIII). Thus, bikhaconitine contains only one hydroxyl and since the (3-14 proton was a doublet it was assumed, as a working hypothesis, that this hydroxyl was located at (3-13 as in pseudaconitine, indaconitine, delphinine, and aconitine. Examination of the NMR spectrum of pyrobikhaconitine (129) showed only one olefinic proton signal (doublet, J = 6 Hz). This is analogous t o the NMR spectra of the pyrolysis derivatives of delphinine, indaconitine, and pseudaconitine where the doublet was used to show the presence of a C-16 methoxyl. The coupling constant is indicative of an wC-16 proton, hence ap-C-16 methoxyl. This was shown to be the case by subjecting the hydrolysis product, pryobikhaconine (CCLXXIV),to the acidic conditions conducive to the characteristic allylic rearrangement. The rearranged product, isopyrobikhaconine (CCLXXV), still showed signals for four methoxyls but also had a two-proton multiplet in the olefinic region of the spectrum. I n addition, lithium aluminum hydride caused reductive cleavage of a methoxyl and rearrangement of CCLXXI to give demethoxyisopyrobikhaconine (CCLXXVI). Formation of diacetyldemethoxyisopyrobikhaconine (CCLXXVII) showed the presence of two hydroxyls in CCLXXVI and catalytic hydrogenation of the ((
1.
79
THE CIS-DITERPENE ALKALOIDS
former confirmed the presence of the double bond by producing dihydrodiacetyldemethoxyisopyrobikhaconine(CCLXXVIII). It was reasonable to assume, from the preceding information, that bikhaconitine probably is represented by structure CCLXVIII, which differs from pseudaconitine only in that the latter has a C-3 hydroxyl. Accordingly, to prove or disprove this hypothesis, pseudaconitine (CCLIII)was dehydrated with thionyl chloride (129)in the same manner
OCH3 CCLXXIV
1 P"
S. W. PELLETIER AND L. H. KEITH
80
as previously described for indaconitine (127).The resulting anhydropseudaconitine (CCLXXIX) exhibited a two-proton olefinic multiplet in its NMR spectrum which was similar to that observed with anhydroindaconitine (CCLXII).Catalytic hydrogenation of CCLXXIX gave deoxypseudaconitine (CCLXVIII), isolated as its crystalline perchlorate. This
OCH3
OCH3
CCLXXIX
CCLXXX
------_____
[email protected] H @ Z T 3
,,,
____-----
,--_ --N ,
,__ -_ -N
+
OAc ; ,
*:
OCH3 OCH3
OCH3
UULXXXI
f
OCH3
/
CCLXXXII
OUH3
[email protected]
------_____ ____-----
, _ _- _ -N
,,
c*Hq3:::f
OCH3
,___ --N
L,
*:
OCH3 OCH3 CCLXXXV
OCH3 OCH3 CCLXXXIII: R C'CLXSXIV; R
= =
Vr H
material did not depress the melting point of bikhaconitine but it was not completely pure either, being contaminated by a demethoxydeoxypseudaconitine formulated as CCLXXX. Some of the crude product was saponified and the major component, deoxypseudaconine, had the same mobility on thin-layer chromatography as bikhaconine. Complete acetylation gave crystalline triacetyldeoxypseudaconine which was identical with triacetylbikhaconine (129). Since pseudaconitine has
1.
81
THE CIS-DITERPENE ALKALOIDS
previously been directly correlated with aconitine (123) as well as indirectly through an indaconitine-delphinine-aconitine relationship, the correlation of pseudaconitine with bikhaconitine completely establishes the structure and stereochemistry of the latter. An attempt to remove the C-13 hydroxyl of bikhaconitine by mesylation followed by high-pressure hydrogenation failed (90).Hydrogenation of bikhaconitine mesylate (CCLXXXI) gave instead the desacetyldihydro mesylate (CCLXXXII) in good yield plus a small amount of what is indicated by its NMR spectrum t o be the desired product
r
OH
OH
I
bCH3 OCH3
(XLXX; R CCXC; R
:=
CCLXXXVIII; R CCLXXXIX; R
R' = H
= CH3,
CCLXXXVII
R' = Vr
J
= CH3, R' = Vr
CCLXXXVI
ti
OH
OCH3 CCLXXI
= R' = H
CCLXVIII
TABLE XI11 OF BIKHACONITINE NEWLYDESCRIBED DERIVATIVES
Compound Acetylbikhaconitine (CCLXXII) Triacetylbikhaconine (CCLXXIII) Pyrobikhaconitine (CCLXXI) Pyrobikhaconine (CCLXXIV) Isopyrobikhaconine (CCLXXV) Demethoxyisopyrobikhaconine(CCLXXVI) Diacetyldemethoxyisopyrobikhaconine (CCLXXVII) Monoacetyldemethoxyisopyrobikhaconine Dihydrodiacetyldemethoxyisopyrobikhaconine(CCLXXVIII) Demethoxybikhaconitine (CCLXXX) (demethoxydeoxypseudaconitine) perchlorate Bikhaconitine methanesulfonate (CCLXXXI) Desacetyldihydrobikhaconitine methanesulfonate (CCLXXXII) Dihydropyrobikhaconitine(CCLXXXV) Demethylanhydroisopyrobikhaconine
Formula
MP ("C)
[,x]D
197-199 149-150 155-157
t21.6 - 8.1 198.4
Amorphous 189-192 147-150 161-163 94-97 172-174 175-182 170-175 188-190 190-1 93 181-183 942-243
+ + 33.8 + 66.7 i-31.9 +66.1
- 57.8 -
References
129 129 129 129 129 129 129 129 129 129 129 90 90 90 90
1. THE CIS-DITERPENE ALKALOIDS
83
(CCLXXXIII).The latter was hydrolyzed to CCLXXXIV but attempts to obtain a crystalline salt failed. The structure of CCLXXXII was confirmed by an alternate synthesis. Pyrobikhaconitine (CCLXXI) was converted to dihydropyrobikhaconitine (CCLXXXV) by cat'alytic hydrogenation followed by reaction with methanesulfonyl chloride. The resulting dihydropyrobikhaconitine mesylate was identical with CCLXXXII produced by the high-pressure hydrogenation. Recently Edwards (130) has used bikhaconitine to show that the pyrolytic loss of acetic acid from aconitine-type diterpene alkaloids is not the simple cis-1,2-elimination previously assumed. Instead, the elimination proceeds through the intermediate CCLXXXVI which, in turn, is attacked by the resulting acetate ion, giving rise t o the isolated pyro derivatives (CCLXXI). Evidence of the reactive intermediate CCLXXXVI was obtained by reductively trapping it with lithium tritert-butoxyaluminum hydride. The olefin obtained (CCLXXXVII) was inert to lithium aluminum hydride in contrast t o pyrobikhaconitine, but it could be oxidized with mercuric acetate and when this reaction was followed by heating in aqueous dioxane, bikhaconine was regenerated through the intermediate CCLXXXVIII. This type of oxidative cyclization is suggested to be the final step in the biosynthesis of the skeleton of these alkaloids. Also, the long-known replacement of the C-8 acetoxy group by a methoxy group when the corresponding alkaloid is heated with methanol in a sealed tube is explained as attack of methanol on C-8 of the intermediate CCLXXXIX. The pyro compounds are inert to methanol under these conditions so the mechanism must be CCLXVIII-CCLXXXIXCCXC rather than CCLXVIII-CCLXXXVI-CCLXXI-CCXC. Table XI11 lists the newly described derivatives of bikhaconitine.
G. CHASMACONITINE AND CHASMANTHININE A reexamination of the roots of Aconitum chasmanthum revealed the chasmanthinine, presence of four new alkaloids-chasmaconitine, chasmanine, and homochasmanine-in addition to indaconitine which was originally described in 1905 (124).Chasmanine and homochasmanine will be discussed in the following section. Chasmaconitine (CCXCI) (C34H47N09)exhibited signals in its NMR spectrum characteristic of four methoxyls, one acetoxy group, one benzoyloxy group, and N-ethyl (131).The I R spectrum confirmed the acetate and benzoate ester groups and in addition showed the presence
84
S. W. PELLETIER AND L. H. KEITH
of a free hydroxyl, thus accounting for all of the oxygen atoms. The acetoxy signal was shielded (78.73) as in the previously studied alkaloids where the shielding of the C-8 acetoxy protons was caused by a (2-14 aromatic ester. No mention was made of the characteristic signal due to the geminalc-14 proton. Saponification of chasmaconitine gave acetic acid, benzoic acid, and bikhaconine (CCLXX), which was characterized as its triacetyl derivative. The latter was identical with an authentic sample of triacetylbikhaconine (CCLXXIII). Hence, chasmaconitine should be identical with deoxyindaconitine (CCLXIV) ; i.e., N-ethyl-N-desmethyldelphinine. A comparison of chasmaconitine with an authentic sample of OCH3
CCLXX; IV = ~2 = ~3 = H CCLXXIII; H I = R2= R3 = AC CCXCI; H' = Ac, H 2 = Rz,R3 = H CCXCIII; R1= Ac, R2= Cn, R3 = H
OCH3 CCXVIII; R CC"XCI1; R
= CH3 =
H
deoxyindaconitine (127) showed them to be almost identical. Thus, to prove rigorously the identity of chasmaconitine it was converted to delphinine (CCXVIII) by first removing the N-ethyl group followed by methylation of the N-desethylchasmaconitine (CCXCII). The product was identical with delphinine. This correlation, as well as the one with deoxyindaconitine, completely establishes the structure and stereochemistry of chasmaconitine (131).The slight differences in properties of deoxyindaconitine are probably due to the presence of some demethoxydeoxyindaconitine arising as a side reaction from the catalytic hydrogenation of anhydroindaconitine (CCLXII + CCLXIV) in the analogous manner observed with the catalytic hydrogenation of anhydropseudaconitine (129) (CCLXXIX + CCLXVIII + CCLXXX). Chasmanthinine (CCXCIII) (C36H49N09) contains C2Hz more than chasmaconitine (131).Its NMR spectrum contains signals characteristic of four methoxyls, one acetoxy, one benzoyloxy, and an N-ethyl. The I R spectrum confirmed the two ester groups and further showed the presence of a free hydroxyl, thus accounting for all of the oxygen functional groups. I n addition, there were absorption peaks characteristic of
1. THE
CIS-DITERPENE ALKALOIDS
85
a trans-isolated double bond, the presence of which was confirmed by a two-proton AB-type quartet in the olefinic region of the NMR spectrum. Saponification of chasmanthinine gave acetic acid, trans-cinnamic acid, and bikhaconine (CCLXX), characterized as its triacetyl derivative. The latter was identical with an authentic sample of triacetylbikhaconine (CCLXXIII). The isolation of trans-cinnamic acid accounts for the additional CzHz and consequently the structure of chasmanthinine is the same as that of chasmaconitine except that the benzoyloxy group of the latter is replaced by a trans-cinnamoyl group. Proof that the aromatic ester occupies the same position as in chasmaconitine was derived from the one-proton doublet a t 75.20 (J = 4.5 Hz) characteristic of the proton geminal to the ester group. Since, of the three possible positions (C-8, TABLE XIV
CHASMACONITINE AND CHASMANTHININE Compounds
Formula
MP ("C)
Chasmaconitine (CCXCI)
C34H47N09
N-Desethylchasmaconitine (CCXCII) Chasmanthinine (CCXCIII)
C32H43NOg
181-182 dec (hexane) 165-167 (ether) 161-164.5
C36H4gNOg
160-1 6 1
[oL]D
References
+10.3
131
+25.7
131
+9.6
131
C-13, and C-14)) C-14 is the only one with a geminal proton, it was reasoned that the cinnamoyl group must be located a t this position (131). However, although this is the most probable structure, it will later be shown that the alkaloid condelphine, which contains a C-14 equatorial acetoxy group and hydrogens on the adjacent positions, likewise exhibits a one-proton signal at 75.20 (triplet, J = 4.5 Hz) attributed to this same proton geminal to the acetoxy group (64e, 131a).Thus, it has not been rigorously proved that the cinnamoyl and acetoxy groups are not switched from the expected positions shown in structure CCXCIII. The structure as shown could be conclusively demonstrated by pyrolyzing chasmanthinine and monitoring the elimination of acetic acid with NMR (102). The signal of the acetoxy group of chasmanthinine is slightly shielded (78.23) but is a t much lower field than the same signal in aconitine, jesaconitine, delphinine, indaconitine, pseudaconitine, bikhaconitine, and chasmaconitine. Models show that the C-8 acetoxy protons of chasmanthinine are too far from the aromatic ring to be shielded by it
86
S. W. PELLETIER. AND L. H. KElTH
but are close enough t o the double bond to be subject to the influence of its diamagnetic anisotropy, which is less than that of an aromatic ring. Chasmanthinine is the first diterpene alkaloid of this family that has been found t o be esterified with cinnamic acid. Since chasmanthinine has been correlated with bikhaconine, whose absolute configuration is known, the absolute configuration of chasmanthinine is also known. Properties of these compounds are given in Table XIV.
H. CHASMANINE(TOROKO BASE11) Chasmanine (CCXCIV) is the fourth diterpene alkaloid isolated from the roots of Aconitum chasmanthum and has the empirical formula spectrum revealed four methoxyls and an C~SH~~N The O ~NMR . N-ethyl group while the I R spectrum indicated two hydroxyls and showed no carbonyl absorption, thus accounting for all six oxygens (132). Acetylatiori with acetic anhydride and p-toluenesulfonic acid gave the diacetate (CCXCV), while oxidation with chromium trioxide/acetone gave a gummy five-membered ketone (CCXCVI) characterized as its monoacetate (CCXCVII). The latter reaction thus showed that chasmanine possessed a secondary hydroxyl in a five-membered ring and tertiary hydroxyl. Both CCXCVI and CCXCVII were converted to CCXCIV by reduction with sodium borohydride and lithium aluminum hydride, respectively. Oxidation with Sarett’s reagent gave two products : (1)the azomethine CCXCVIII which formed the ethiodide CCXCIX, convertible to chasmanine by reduction with sodium borohydride, and ( 2 )the neutral N-acetylN-desethyl- 14-dehydrochasmanine (CCC). The stereospecific course of the reduction of the five-membered ketone is indicative of the ketone carbonyl being a t C-14 rather than (3-12 and is consistent with the stereochemistry of these skeletons which have free access t o the C-12 position, whereas the C-14 position is hindered by ring D, leaving only one side open for attack. Pyrolysis of diacetylchasmanine (CCXCV)gave, after saponification, three products : pyrochasmanine (CCCI), isopyrochasmanine (CCCII), and demethylisopyrochasmanine (CCCIII). Pyrochasmanine shows absorption in the UV region at 244 mp which disappears on acidification. This behavior is characteristic of the aconitine-type skeleton. When heated with methanolic perchloric acid, CCCI was converted quantitatively to CCCII. The NMR spectra of CCCI (doublet in the olefinic region of one-proton intensity) and CCCII (multiplet in the olefinic region of two-proton intensity) were in accord with the assigned structures and in
I.
THE
CIS-DITERPENE ALKALOIDS
87
addition, the doublet of CCCI with its coupling constant of 6 Hz is indicative of a C-16 methoxyl in the P-configuration. The NMR spectrum of CCCIII showed signals for olefinic protons (multiplet of two-proton intensity), demonstrating that the allylic shift had occurred, but there OCH3
bCH3 CCCII; It = CH3 CCCIII; R = H
CCCI
OCH3
OCH3 CCXCIV; R = R‘ = H CCXCV; H. = I%’ = Ac
OCH3
OCH3 CCXCVI; R = CzHs, R’ = H CCXCVII; R = C2H5, R’ = AC CCC; R = CH3C0, R‘ = H OCH3
_____---OH
f--
OCHy CCXCIX
CCXCVIII
were only three methoxyl signals. Catalytic hydrogenation gave the dihydro derivative CCCIV, confirming the double bond of CCCIII. The low mobility of CCCIII on alumina suggested the introduction of ill1 additional hydroxyl and this was confirmed by preparation of the diacetyl derivative CCCV. Hydrogenation of CCCV gave the dihydrodiacetyl derivative CCCVI, also obtainable by acetylation of CCCIV. Pyrolysis of CCCVI gave a single product (CCCVII) which had signals for
88
S. W . PELLETIER AND L. H. KEITH
one olefiiiic proton (multiplet) and only one acetate in its NMR spectrum and could not be crystallized, but after hydrolysis it was characterized as its crystalline perchlorate (CCCVIII). Catalytic hydrogenation of
OCH3 CCCXI CCCXII; perchlorate
OCH3 CCCIX CCCX ; perchlorate
T OCH3 CCCIV
OCH3 CCCVII; R = AC CCCVIII ; R H, perchlorate L
1
OCH3 OCH3
cccv
CCCVI
CCCVIII gave the dihydro derivative CCCIX, also characterized as its perchlorate (CCCX). These reactions show that the acetate of CCCVI, and hence the new hydroxyl of CCCIII, is a t C-8. Pyrochasmanine (CCCI) treated with lithium aluminum hydride in tetrahydrofuran undergoes both the allylic shift and demeth0x;ylation to give CCCXI. Catalytic hydrogenation of demethoxyisopyrochasmanine perchlorate
1. THE C 1 ~ - D l T E R P E N EALKALOIDS
89
(CCCXII) gave the corresponding dihydro derivative CCCIX, isolated as the perchlorate CCCX. The unusual feature of the diacetylchasmanine pyrolysis is the production of the isopyro and demethylisopyro derivatives (CCCII and CCCIII) as direct products of the pyrolysis. Previously, only the pyro derivativcs had been isolated from the analogous reaction with other aconitine-type alkaloids and t h o corresponding isopyro derivative was then made by heating the former in perchloric acid solutions. In addition, it was observed that short-term heating (less than 5 min) favored production of CCCI while heating a t a slightly higher temperature for a longer time (1O min) produced mainly CCCII. When the crude pyrolyzed product of CCXCV was worked up by treatment with lithium aluminum hydride in tetrahydrofuran, CCCII, CCCIII, and CCCXI were obtained. Treatment of CCCII under the above conditions gave CCCIII in 30% yield and explains the higher yield of CCCIII obtained by this workup than by the hydrolysis workup. Treatment of chasmanine with benzoyl chloride/pyridine gave CCCXIII, which was characterized as its hydrochloride (CCCXIV). Acetylation of the remaining hydroxyl gave CCCXV. The NMR spectrum of this compound possessed two significant features: (1) the acetate signal appeared a t unusually high field due to shielding by the diamagnetic anisotropy of the aromatic ring and (2) the proton geminal to the benzoyloxy group was a triplet. The latter signal shows that there is no hydroxyl a t the C-13 bridgehead and confirms the fact that the ring C functional group is a t either C- 14 or C- 12. The former signal proves that the benzoyloxy group is a t C-14 rather than C-12 by virtue of the close proximity required to strongly shield the acetoxy protons. Thus, the position and configuration of all the substituents in the CD ring system have been established (132). Heating isopyrochasmanine (CCCII) with sulfuric acid for less than 1 hr gave CCCIII and CCCXVI plus an uncharacterized compound possessing only two methoxyls. With longer treatment (2 8 hr) only demethylisopyrochasmanine (CCCIII) and tridemethylanhydroisopyrochasmanine (CCCXVl) were isolated. The formation of such an internal ether accompanied by double demethylation is a characteristic of delphinine (133)and neoline (134)derivatives which contain C-6 and C-ls methoxyls and consequently these two positions in chasmanine were assumed to be substituted in like manner (132).The a-configuration of the C-6 methoxyl was established by oxidation of chasmanine with permanganate under neutral conditions ( 3 ) t o N-desethylchasmanine (CCCXVII) in about 50% yield. Treatment of CCCXVII with ethyl iodide converted it back to chasmanine, while treatment with methyl
90
S. W. PELLETIER A N D L. H. KEITH
iodide gave N-methyl-N-desethylchasmanine (CCCXVIII), a base not yet reported to occur in nature. The ring A methoxyl was assumed to be a t C-1 and by analogy with bikhaconitine and pseudaconitine. If true, then the structure suggested
r
-------____OCH3
--+
,/---
__
_____----
c-
cccxx
CCCXXI
for chasmanine would differ from that suggested for neoline only in that neoline contains an a-C-1 hydroxyl in place of the p-C-1 methoxyl of chasmanine. A correlation of the two would thus involve a demethylation of the C-1 methoxyl of chasmanine (132). However, demethylation attempts led only to the tridemethyl cyclic ether CCCXVI.
1. THE CIS-DITERPENEALKALOIDS
91
A second correlation attempt was made using bikhaconitine (CCLXVIII). This reaction sequence is covered in detail under the bikhaconitine discussion (Section II1,F) (90). A small amount of an amorphous material was obtained from the bikhaconitine reaction series
OCH3 CCCXXIV
CCCXXII; R = H, OH CCCXXIII; R = 0
T
--_ CH.0
("OH
CCCXXIX; R = 0 CCCXXX; R = H, OH
CCCXXV CCCXXVI; perchlorate
\
I
cccxxxI
CCCXXVII; R = H2 CCCXXVIII; R = 0
which was believed t o be identical with CCCXIX obtained by catalytic hydrogenation of pyrochasmanine. However, all attempts t o crystallize the two products or their salts failed. A correlation of chasmanine with browniine was finally achieved (135). The latter differs from chasmanine only in that it has a /3-oriented C-6 methoxyl and a lycoctonine-type skeleton (thereby containing a C-7
TABLE XV W E3
DERIVATIVES OF CHASMANINE Compound Chasmanine (CCXCIV) Diacetylohasmanine (CCXCV) 14-Dehydroacetylchasmanine (CCXCVII) N-Desethyl- 14-dehydroohasmanineazomethine(CCXCVIII) ethiodide (CCXCIX) N-Desethyl-N-acetyl-14-dehydrochasmanine (CCC) Pyrochasmanine (CCCI) Isopyrochasmanine (CCCII) Demethylisopyrochasmanine (CCCIII) Dihydrodemethylisopyrochasmanine(CCCIV) Diacetyldernethylisopyrochaamanine(CCCV) Diacetyldihydrodemethylisopyrochasmanine (CCCVI) Demethoxypyrochasmanine (CCCVII) perchlorate (CCCVIII) Dihydrodemethoxypyroohasmanine (CCCIX) (dihydrodemethoxyisopyrochasmanine) perchlorate (CCCX) Demethoxyisopyrochasmanine (CCCXI) perchlorate (CCCXII) Benzoylohasmanine (CCCXIII) hydrochloride (CCCXIV) Acetylbenzoylchasmanine (CCCXV) perchlorate Tridemethylanhydroisopyrochasmanine(CCCXVI) N-Desethylchasmanine (CCCXVII) N-Methyl-N-desethylohasmanine (CCCXVIII) 7 , 1 7 - S e c o d e h y d r o c h a i n e (CCCXX) 7,17-Secodehydro-7-hydroxychasmanine (CCCXXI) 7,17-Seoodehydro-7-ketochasmanine (CCCXXII) 7,17-Secodehydro-7,14-diketochasmanine (CCCXXIII) Epi-7,17-secodehydro-7,14-diketochasmanine (CCCXXIV) (14-dehydro-8-deoxyisobrowniine)
Formula
MP (“C)
[ a ] ~
0-9 1 139-141 158-1 60 196 250-251 dec 206-207 126-129 177-179 163-165 124-127 121-123 123-125 Amorphous 198-202 Amorphous
+ 23.6 -
173-174 84-88 207-210 Amorphous 248-249 148-156 231-234 245-248 dec 232-234 90-92 104-105 179-181 142-146 Froth 158-160
-
-
-
-
-
-
-
+ 12.9
References
132 132 132 I32 132 132 132 132 132 132 132 132 I32 I32 132 I32 132 132 132 138 132 132 132 138 132 135 135 135 135 135
1.
THE
CI~-DITERPENE ALKALOIDS
93
hydroxyl) and it has been correlated with lycoctonine so that its structure is known with certainty. It was reasoned that the C-6 cc-methoxyl of chasmanine, being crowded by the C-4 substituents, probably could be epimerized if a 7,17-seco-7-keto derivative of chasmanine could be prepared. Accordingly diacetylchasmanine (CCXCV) was converted t o the 7,17-seco-olefin CCCXX by treatment with lithium tri-tert-butoxyaluminum hydride in diglyme. Hydration of CCCXX with diborane gave CCCXXI which, in turn, gave a mixture of CCCXXII and CCCXXIII when oxidized with chromic oxide in acetone. After separation on alumina, CCCXXIII was refluxed in basic solution to epimerize the C-6 methoxyl and a small amount of the diketo epimer CCCXXIV was obtained. Oxidation of browniine (CVIII) with lead tetraacetate (135) gave a nearly quantitative yield of hydroxybrowniine (CCCXXV) and hydrogenation of hydroxybrowniine perchlorate (CCCXXVI) gave isobrowniine (CCCXXVII). The products of this series of reactions (CVIII + CCCXXVII) are exactly analogous with those of lycoctonine treated under similar conditions. A 3-minute oxidation of isobrowniine with permanganate in acetone produced oxoisobrowniine (CCCXXVIII) which, when reduced with zinc in acetic acid, gave a mixture of 8-deoxyoxoisobrowniine (CCCXXIX) and 8-deoxy-7-dihydrooxoisobrowniine (CCCXXX). The latter could also be produced by borohydride reduction of the former. Reduction of either CCCXXIX or CCCXXX with lithium aluminum hydride gave 8-deoxy-7-dihydroisobrowniine(CCCXXXI) which, when oxidized with chromic oxide in acetone, produced 14dehydro-8-deoxyisobrowniine(CCCXXIV). This diketone was identical with the corresponding diketone obtained from chasmanine. Toroko base I1 isolated from Aconitum subcuneatum and A . yesoenis Nakai (48)has been compared with chasmanine and found to be identical with it. The tentative name Toroko base I1 is abandoned in favor of chasmanine, which is derived from the specific name of one of the plants in which this alkaloid occurs. Chasmanine and its derivatives are listed in Table XV.
I. HOMOCHASMANINE Homochasmanine (CCCXXXII) is the fifth alkaloid characterized from Aconitum chasmanthum and has the empirical formula C ~ G H ~ ~ N O ~ , which contains one CHz more than chasmanine (137).The alkaloid is unstable and decomposes slowly on standing. The NMR spectrum shows the triplet characteristics of an N-ethyl group and also five methoxyl
94
S. W. PELLETIER AND L. H. KEITH
signals. Since only an amorphous monoacetate (CCCXXXIII) could be prepared, the compound can contain but one hydroxyl, thus accounting for all of the oxygens in the molecule. As a working hypothesis it was assumed that homochasmanine was an 0-methylchasmanine. From the structure of chasmanine (CCXCIV)it is seen that the additional methoxyl
OCH3 CCCXXXII; R = H CCCXXXIII; R = AC
must be a t either (2-8 or C-14. Some insight as to which of the two positions was correct was provided by the NMR spectrum of acetylhomochasmanine (CCCXXXIII), which contained a poorly resolved triplet a t 75.23. This signal was attributed to the proton geminal to the acetoxy group and is consistent with a C-14 acetoxy group but not with a C-8 ester since the latter would not even have a geminal proton. Confirmation of this hypothesis was achieved using a reaction whereby the C-8 acetoxy group in aconitine (138),delphinine (139),or bikhaconitine (130) is replaced by a methoxyl group by heating under pressure in methanol. Heating diacetylchasmanine (CCXCV) in methanol under pressure gave an ainorphous product (CCCXXXIII) which was saponified to give a product identical with homochasmanine. Since the structure of chasmanine is known with certainty the complete structure of homochasmanine thereby is also known. Properties of these compounds are given in Table XVI.
TABLE XVI DERIVATIVES OF HOMOCHASMANINE Compound ~__-
Formula
Hornochasmanine Acetylhomochasmanine
C26H43hTO6
~
CzsHd07
MP ("C) 105-107 Gum
[X]D
References
+19.2
137 137
-
1.
THE
CIS-DITERPENE ALKALOIDS
95
J. NEOLINE AND NEOPELLINE Neopelline is an alkaloid which was isolated as an impurity in crude aconitine from A . napellus in 1924. A few salts were prepared, an N calculated, O~ and saponification gave empirical formula of C ~ ~ H ~ Swas the amino alcohol neoline, acetic acid, and benzoic acid (140). Later, neoline was isolated as an impurity in commercial aconitine from the same plant (141).However, since it was extracted from a solution made
I ,---
OCH3 OCH3 CCCXLII
OCH3 OCH3 CCCXLIII; R = CH3 CCCXLIV; R = CD3
96
S. W. PELLETIER AND L. H. KEITH
basic with 0.1 N sodium hydroxide, it is quite possibly the artifact of neopelline. No further work appears to have been done on neopelline but a tentative structure (CCCXXXIV) has been proposed for neoline. A new empirical formula for neoline, C Z ~ H ~ ~ necessitates NO~, that the empirical formula of neopelline be C33H45N08.
--Y
OCH3
OCH3
OCH3 OCH3 CCCXLVII
OCH3 CCCXLVIII
Acetic anhydridelpyridine produced diacetylneoline (CCCXXXV), while glacial acetic acid with p-toluenesulfonic acid gave triacetylneoline (CCCXXXVI),thereby indicating the presence of one tertiary and two secondary hydroxyls. Oxidation with chromium trioxide gave 1,14diketoneoline (CCCXXXVII) which, when reduced with sodium borohydride, yielded 1-ketoneoline (CCCXXXVIII),a compound which will
1.
THE
C
I
S
-ALKALOIDS ~ ~
~
~
~ 97~
~
~
incorporate two deuterium atoms on C-2 when allowed to equilibrate with sodium methoxide in CH30D. The assignment of the ketone to C-1 was made on the basis of the similarity of the ORD-curves of CCCXXXVIII with those of a l-ketodelphinine derivative (64c). Oxidation of diacetylneoline (CCCXXXV) with permanganate followed by alkaline hydrolysis produced N-desethylneoline (CCCXXXIX), believed to arise as a result of participation of the hydrolyzed C-1
C&--
I
OCH3 OCHs CCCXL
,<,---
&= = =I
-------____
--N
:.
-
(-yJ-
,,,’--- --?+2 ,
:-
I
OCH3 CCCL
hydroxyl with the N-acetyl. This is used as evidencethat the C- 1hydroxyl is in the a-configuration. Methylation then gave N-desethyl-N-methylneoline (CCCXL),a base not yet found in nature. Hofmann degradation of CCCXL proceeded in a manner analogous to that of delphonine (93), giving a small yield of a product formulated as CCCXLI. Pyrolysis of triacetylneoline (CCCXXXVI)gave pyrodiacetylneoline (CCCXLII). The characteristic olefinic doublet in the NMR spectrum indicates a /3-methoxyl at C-16 and, of course, the pyrolysis itself is indicative of a C-8 acetoxy group in CCCXXXVI. Isopyrodiacetylneoline (CCCXLIII) was produced by warming CCCXLII in methanolic perchloric acid, a deuterated methoxyl (CCCXLIV) being incorporated when CD30H was used as the solvent. Hydrolysis of CCCXLII and CCCXLIII followed by catalylic hydrogenation gave the nonidentical
98
S. W. PELLETIER AND L. H. KEITH
products dihydropyroneoline (CCCXLV) and dihydroisopyroneoline (CCCXLVI), respectively (64c). Acetylation of N-desethylneoline (CCCXXXIX)gave N-acetylneoline triacetate (CCCXLVII) which, upon pyrolysis, produced N-acetylpyroneoline diacetate (CCCXLVIII). Reduction of CCCXLVIII with lithium aluminum hydride effected the isopyro rearrangement with removal of the C- 16 methoxyl as well as hydrolysis and reduction of the N-acetoxy group. The product, desmethoxyisopyroneoline (CCCXLIX), also results from treatment of isopyrodiacetylneoline (CCCXLIII) or its hydrolysis product with lithium aluminum hydride. The configuration of the C-16 methoxyl was reasoned to be fi since it is eliminated so easily in the allylic rearrangements. One of the most important results of this work was the discovery of the unusual spectroscopic property of these pyro derivatives in the ultraviolet region. The pyro derivatives containing an N-alkyl group exhibit an absorption maximum between 235 and 245 mp with an extinction coefficient of about 6000 when the free base is used. This absorption disappears on acidification and reappears again on neutralization. However, if the nitrogen is substituted with an acetyl or formyl group, which removes the basic properties of the nitrogen, this characteristic absorption is not observed. Nor is it observed once the rearrangement t o the corresponding isopyro derivative is accomplished. This phenomenon appears to hold promise as a specific indication of an aconitine-type skeleton, particularly when correlation with an alkaloid of known absolute configuration is not readily amenable. The bridgehead double bond in structure CCCL is highly strained so that it was suggested the structure may be represented, to a small extent, by CCCLI. If such a mesomerism is possible, it could give rise t o the observed UV absorption and models show that there is an overlap of orbitals between the C-7-C-8 or C-8-C-15 double bond and the N-C-17 double bond (64c). The placement of the remaining two methoxyls a t C-18 and C-6, as well as the configuration of the latter, is based on the formation of certain derivatives of neoline with an internal ether between C-18 and (2-6. The configuration of the C-14 hydroxyl has not yet been established, although by analogy with all of the other aconitine-type alkaloids it would be expected to be equatorial ( a ) .A full publication of the neoline work was promised. With the preceding knowledge gained from neoline and the NMR spectrum of the alkaloid, the structure of neopelline should be quite evident. The predicted structure is one having a C-8 acetoxy and a C-14 a-benzoyloxy group. If this is the case, pyrolysis with elimination of acetic
1.
THE
Clg-DITERPENE ALKALOIDS
99
acid will define the C-8 acetoxy group (102, 102a). A highly shielded acetate signal (approx. 78.6) and a triplet of one-proton intensity about 75.1 with a coupling constant of 4.5 Hz would then define the C-14 equatorial benzoyloxy group. Should any of the substituents be switched, the structure should be as easily discerned for there are but three TABLE XVII OF NEOLINE~ DERIVATIVES
Compound
Formula
Neoline (CCCXXXIV) Diacetylneoline (CCCXXXV) Triacetylneoline (CCCXXXVI) 1,14-Diketoneoline (CCCXXXVII) 1-Ketoneoline (CCCXXXVIII) N-Desethylneoline (CCCXXXIX) N-Desethyl-N-methylneoline (CCCXL) Hofmann degradation product of CCCXL (CCCXLI) Pyrodiacetylneoline (CCCXLII) Isopyrodiacetylneoline (CCCXLIII) perchlorate Pyroneoline Isopyroneoline Dihydropyroneoline (CCCXLV) Dihydroisopyroneoline (CCCXLVI) N-Acetylneoline triacetate (CCCXLVII) N-Acetylpyroneoline diacetate (CCCXLVIII) CzgH3gNOs Desmethoxyisopyroneoline (CCCXLIX) Cz3H35N04 a
Mp ("C)
References
162 Oil 161 175 176 205 210 241
64c 64c 64c 64c 64c 64c 64c 64c 64c 64c 64c 64c 64c 64c 64c
Amorphous 191
64c 64c 64c
There are no [ a ]values ~ reported for these compounds.
hydroxyls and the NMR spectra, of model compounds with the appropriate substitution and configuration a t C-1 and (2-14 are described in the literature (64e). Neoline and its derivatives are listed in Table XVII.
K. CONDELPHINE, TALATIZIDINE, AND ISOTALATIZIDINE The alkaloid condelphine (CCCLII) was first isolated in 1942 from Delphinium confusum Popov and was found to be an 0-acetate derivative of isotalatizidine (CCCLIII) (142). The latter alkaloid, along with its C-1 epimer talatizidine (CCCLIV),had been isolated 2 years earlier from Aconitum talassicum Popov, a rare species native to the mountainous
100
S. W . PELLETIER AND L. H. KEITH
regions of Talass-Alataou in Central Asia (143). Further research by Russian workers allowed the postulation of partial structures for these three closely related compounds (144) and recent work by American researchers has established the complete structures of all three (64e, 131a). The latter work was done with condelphine and isotalatizidine isolated from Delphinium denudatum Wall., a plant native t o the lower reaches of the Himalayas. Condelphine contains one ethyl, two methoxyl, one acetoxy, and two hydroxyl groups. Isotalatizidine and talatizidine are unesterified. Acetylation of isotalatizidine or condelphine with acetic anhydride/ pyridine produces the same diacetate (CCCLV)(64e,131a, 144).Likewise, vigorous treatment of either alkaloid with acetyl chloride gives the fully acetylated derivative CCCLVI. Saponification of CCCLII, CCCLV, or CCCLVI gives back the amino alcohol CCCLIII. Oxidation of isotalatizidine with Kiliani reagent was found to give didehydroisotalatizidine (CCCLVII), while oxidation with Sarett’s reagent led to didehydrooxoisotalatizidine (CCCLVIII) (144). On the other hand, oxidation of condelphine with Kiliani reagent gives dehydrohydroxycondelphine (CCCLIX)( l 4 4 ) ,while oxidation with Sarett’s reagent under under varying conditions led to mixtures of dehydrooxocondelphine (CCCLX) and dehydrocondelphine (CCCLXI) or N-desethyldidehydrocondelphine(CCCLXII) (64e,131a).The important facts derived from the above transformations are ( 1 ) that whereas isotalatizidine can give rise to cyclic five- and six-membered diketone derivatives, condelphine gives only cyclic six-membered ketones and ( 2 ) that no aldehydes are produced from the oxidations. Thus, two of the hydroxyls of isotalatizidine must be secondary and the third is tertiary. Also, the acetoxy group of condelphine must be in a five-membered ring and the C-18 position must be substituted with a methoxyl rather than a primary hydroxyl group. Borohydride reductiop of CCCLVII or CCCLXI gave a mixture of isotalatizidine and talatizidine (64e,131a, 144)while reduction of CCCLVIII with Raney nickel produced dehydroisotalatizidine (CCCLXIII) (144). Evidence of an N-ethyl group was indicated from the paramagnetic shift of the methyl triplet in the NMR spectra of condelphine salts (64e, 131a) and by the fact that the acetylated derivatives are still basic. Proof of this substitution was the dealkylation of isotalatizidine to give N-desethylisotalatizidine (CCCLXIV) plus anhydroxy-N-desethylisotalatizidine (CCCLXV) (144).Reaction of the former with ethyl iodide gives back isotalatizidine while reaction with acetic anhydridelpyridine produces N-acetyl-N-desethylisotalatizidine(CCCLXVI). Reduction of CCCLXII with borohydride followed by alkylation with ethyl iodide
1.
THE
CIS-DITERPENE ALKALOIDS
101
likewise produces isotalatizidine as well as its C-1 epimer, talatizidine (64e, 1 3 1 ~ ) . Oxidation of isotalatizidine with permanganate ip acidic acetone produces N-acetyl-N-desethyldehydroisotalatizidine(CCCLXVII) plus N acetyl-N-desethyldehydroanhydrohydroxyisotalatizidine (CCCLXVIII) (144). Formation of the latter does not preclude substitution of the ring
OCH3 CCCLIV
OCH3
OCH3 CCCLVII; R CCCLVIII; R
= H, =0
H
CCCLIX; CCCLX; CCCLXI; CCCLXIII;
R' = H, O H ; R2 = AC R' = 0; R2 = AC R' = H, H; Ra = AC R1= H , H ; RZ = H
"OAc
OH OCH3 CCCLXIV; R = H
0
CCCLXVI;
1I R = CH3C-
CCCLXII
102
S. W. PELLETIER AND L. H. KEITH
A hydroxyl a t C-2 but it does mean that this hydroxyl must be in the uconfiguration. Additional evidence for the a-configuration of the C-1 hydroxyl is the intramolecular hydrogen bonding observed in the IR spectrum of condelphine (64e, 131a). Reduction of CCCLXVIII with
I
OCH3
CCCLXV
OCH3 CCCLXVII
I
0
OCHs II CCCLXIX; R = CH&CCCLXX; R = H
OCH3 CCCLXXII
lithium aluminum hydride regenerates isotalatizidine, while reduction with borohydride, Raney nickel, or catalytic hydrogenation produces N-acetyl-N-desethylanhydrohydroxyisotalatizidine (CCCLXIX) (114). Acidic hydrolysis of the latter removes the N-acetyl group to give N-desethylanhydrohydroxyisotalatizidine(CCCLXX), also prepared by first hydrolyzing CCCLXVIII, followed by reduction of the resulting N-desethyldehydroanhydrohydroxyisotalatizidine (CCCLXXI) with
1. THE
CIS-DITERPENEALKALOIDS
103
Raney nickel. Reduction of CCCLXXI with borohydride gives CCCLXIV Reduction of CCCLXVII with borhydride produces CCCLXVI, while mild oxidation of the former yields N-acetyl-N-desethyldidehydroisotalatizidine (CCCLXXII).
I
OCH3 CCCLXXIII
OCH3 CCCLIII
cccL xxIv
cccxxv
CCCLXXVl
Dehydrogenation of isotalatizidine with selenium formed 1,3-dimethylphenanthrene (CCCLXXVI)and the proposed mechanism (144) involves two retropinacol rearrangements-the first one enlarging ring C and the second leading to the migration of an angular group from C-11 to C-1 (CCCLIII + CCCLXXIV). The migration of the C-4 methyl of CCCLXXV is justified as giving relief from the spatially strained 4-position of the phenanthrene nucleus. Proof of the C-1 position of the ring A hydroxyl was shown rigorously by both spectroscopic and chemical evidence (64e, 131a). Both the mesgrlate (CCCLXXVII) and tosylate (CCCLXXVIII) derivatives of
104
S. W. PELLETIER AND L. H. KEITH
condelphine undergo elimination to give the same product, the olefin CCCLXXIX. Had the substitution been a t C-2, two olefinic products should have been produced. Further, the proton geminal to the aromatic ester in benzoylcondelphine (CCCLXXX) is a quartet ( X proton of an ABX system) and such a signal is explicable only if the substitution were a t C-1 or C-3. Substitution a t the latter position is precluded by the formation of the inner carbinolamine ether derivatives (144)and also on the basis of the paramagnetic shifts of the NMR signals due to the C-18 methylene and methoxyl groups in CCCLX (64e, 131a). The absence of such shifts in the corresponding signals of CCCLXI shows that they are due entirely to the paramagnetic anisotropy of the lactam carbonyl of CCCLX since Dreiding models show that C-3 and C-19 are equidistant from C-19. I n addition, these shifts support the previous conclusion (based on the oxidation products) of a (C-18)Hz-OCH3 moiety. The 100-MHz spectrum of condelphine resolves the C-18 methylene signal into two one-proton doublets a t 77.02 and 6.85 ( J = 9 Hz). The large coupling constant is in accord with geminal coupling and its independence of temperature demonstrates that it arises from the inherent nonequivalence of these protons. The location of the tertiary hydroxyl at C-8 follows from the pyrolysis of triacetylisotalatizidine (144) [diacetylcondelphine (64e, 131a)l (CCCLVI) t o give the corresponding pyro derivative (CCCLXXXI). Saponification of CCCLXXXI yields pyroisotalatizidine (CCCLXXXII) as a crystalline compound (144). Isopyroacetylisotalatizidine (CCCLXXXIII) is produced by refluxing CCCLXXXI in acidic methanol (64e, 131a). The site of the partial hydrolysis was shown by oxidizing CCCLXXXIII t o dehydrooxoacetylisopyroisotalatizidine (CCCLXXXIV) followed by saponification to dehydrooxoisopyroisotalatizidine (CCCLXXXV). The latter derivative contained only infrared carbonyl absorption characteristic of a cyclic five-membered ketone and a lactam, Acetylation of CCCLXXXIII gave isopyroacetylcondelphine (CCCLXXXVI), a crystalline derivative. The UV spectrum of pyroacetylcondelphine (CCCLXXXI) contains the characteristic absorption of 240 mp, which disappears when the solution is made acidic, reappears when it is neutralized, and which is absent in the isopyro derivatives, thus demonstrating the presence of an aconitine-type skeleton. The (2-15 olefinic proton of pyroacetylcondelphine is a doublet and thereby shows that (3-16 is substituted (64e,131a).Since only a methoxyl and acetoxy group remained to be located, and the latter had been shown to be in a five-membered ring, the remaining methoxyl was assumed to be the C-16 substituent. In addition, the coupling constant ( J = 6 Hz)
1. THE
CIS-DITERPENEALKALOIDS
105
indicated that it was /3-oriented (a /3-proton would have been almost a t right angles to the olefinic proton and a coupling constant of about 1 Hz would have been expected). Both the foregoing position and configura-
I
OCH3 CCCLXXXI; R = AC CCCLXXXII; R = H
OCH3 CCCLXXIX
____-----
t
CCCLXXXIV; R = AC CCCLXXXV; R = H
CCCLX; HI = Ac, H2 = H CCCLXXXVII; R’ = R2 = H CCCLXXXVIII ; R’ = Bz, Ft2 = H CCCLXXXIX; R’= Bz,R’ = AC
OCH3 CCCLXXXIII; R = H CCCLXXXVI; R = AC
CCCXC; R = Ac CCCXCI; R = H CCCXCII; R = Bz
tion of this methoxyl group was shown t o be correct by the isopyro rearrangement. The remaining hydroxyl group of isotalatizidine was assigned to C-14 by the Soviet workers merely because acetylation of this hydroxyl (the alkaloid condelphine) does not result in a substantial lowering of basicity. They thus concluded that this hydroxyl is not spatially close to the
TABLE XVIII NEWLY.DESCRIBED OR CORRECTEDDERIVATIVES OF CONDELPHINE AND ISOTALATIZIDINE
Compound Condelphine (CCCLII) perchlorate picrate Isotalatizidine (CCCLIII) Monoacetylcondelphine (CCCLV) (diacetylisotalatizidine) perchlorate picrate hydrochloride Diacetylcondelphine (CCCLVI) (triacetylisotalatizidine) hydrochloride Didehydroisotalatizidine (CCCLVII) Didehydrooxoisotalatizidine (CCCLVIII) Dehydrohydroxycondelphine (CCCLIX) Dehydrochlorocondelphine Dehydrooxocondelphine (CCCLX) Dehydrocondelphine (CCCLXI) picrate N-Desethyldidehydrocondelphine(CCCLXII) Dehydroisotalatizidine (CCCLXIII) hydrochloride
[a]~
158-159 224-225 195.5-196.5 114-117 114.5-117 112-117 226-228 99-101 Hygroscopic 129-132 131-1 35 146-148 (159-164) 128-130 182-1 83.5 124-126 Amorphous 162-1 63 120.5-122.5 105.5-107.5 213-2 16 Amorphous 202.5-203
References
+21.3 64e, - 64e, 64e, +20.9 64e, 64e, -
-
-24.1
64e, 64e, 64e, 64e,
-
64e,
-
-
-
-
-
64e, 64e, 64e, 64e,
131a, 144 131a 131a 131a, 144 13Ia 144 131a 131a 131a 131a 144 131a 144 144 144 144 131a 131a 131a 131a 144 144
N-Desethylisotalatizidine (CCCLXIV)
Anhydroxy-N-desethylisotalatizidine(CCCLXV) N-Acetyl-N-desethylisotalatizidine (CCCLXVI) N-Acetyl-N-desethyldehydroisotalatizidine (CCCLXVII) N-Acetyl-N-desethyldehydroanhydrohydroxyisotalatizidine
(CCCLXVIII) N -Acetyl-N-desethylanhydrohydroxyisotalatizidine (CCCLXIX) N-Desethylanhydrohydroxyisotalatizidine(CCCLXX) N-Desethyldehydroanhydrohydroxyisotalatizidine (CCCLXXI) N-Acetyl-N-desethyldidehydroisotalatizidine (CCCLXXII) d1-Condelphine(CCCLXXIX) picrate Benzoylcondelphine(CCCLXXX) picrate Pyroacetylcondelphine (CCCLXXXI) (pyrodiacetylisotalatizidine) Pyroisotalatizidine (CCCLXXXII) Isopyroacetylisotalatizidine (CCCLXXXIII) Dehydrooxoisopyroacetylisotalatizidine (CCCLXXXIV) Dehydrooxoisopyrotalatizidine (CCCLXXXV) Isopyroacetylcondelphine(CCCLXXXVI) (isopyrodiacetylisotalatizidine) Dehydrooxoisotalatizidine (CCCLXXXVII) 14-Benzoyldehydrooxoisotalatizidine(CCCLXXXVIII) 8-Acetyl14-benzoyldehydrooxoisotalatizidine(CCCLXXXIX) Didehydrodeoxycondelphine (CCCXC) Didehydrodeoxyisotalatizidine (CCCXCI) Didehydrodeoxybenzoylisotalatizidine (CCCXCII)
229-230 201-202 196-198 234-236 217-219
-
163-165 167-169 196-198 234-236 202-204 Amorphous 95-98 Amorphous 1 10-1 1 1.5 Amorphous 102-104 Amorphous Amorphous Amorphous 106-107
-
198-199 183-1 85 168-170 167.5-170.5 Gum Gum
144 144 144 144 144
-
-
-
-
-
-
-
-
144 144 1-24 144 144 64e, 131a 64e, 131a 64e, 131a 64e, 13Ia 64e, 131a 64e, 144 64e, 131a 64e, 1 3 I a 64e, 13Ia 64e, 131a
64e, +54.0 64e, 64e, - 64e, 64e, -
131a 131a 131a 131a 1310, 64e, 1310
c3
c3
E
0
r
'9
i M M
3
kb str
rJ)
108
S. W. PELLETIER AND L. H. KEITH
nitrogen (which it would be a t C-6 or C-12, the other two possible positions) (144).Rigorous exclusion of C-6 and C-12 was achieved as shown in the reaction sequence CCCLXXXVII + CCCXCII (64e, 131a).Saponification of CCCLX to dehydrooxoisotalatizidine (CCCLXXXVII) was followed successively by first benzoylation (CCCLXXXVIII) and then acetylation (CCCLXXXIX). The NMR spectrum of CCCLXXXIX showed a highly shielded acetoxy signal due to the diamagnetic anisotropy of the aromatic nucleus in close proximity. Models show that a benzoyloxy group a t C-6 or C-14 can come close enough to exert such an effect but that substitution a t C-12 is far too remote to shield a C-8
\ CCCXCIII
L
CCCXCIV
acetoxy group. However, if the benzoate ester were a t C-6, the C-18 methoxyl should have been shielded also. To eliminate the conceivable possibility that the effect of the diamagnetic anisotropy of the aromatic ring is offset by the paramagnetic anisotropy of the lactam carbonyl in the aforementioned situation, dl-condelphine (CCCLXXIX) was hydrogenated and the resulting didehydrodeoxycondelphine (CCCXC) was saponified (CCCXCI) and then benzoylated (CCCXCII). A comparison of the NMR spectra of didehydrodeoxybenzoylisotalatizidine (CCCXCII) and didehydrodeoxyisotalatizidine (CCCXCI) showed that there was absolutely no shielding of either methoxyl signal of CCCXCII. The NMR spectrum of condelphine furthermore contains a triplet of one-proton intensity a t 75.20 ( J = 4.5 Hz) which is due to the proton geminal to the acetoxy group. The configuration of the ester moiety is based on ( I ) the close agreement between the observed and theoretical coupling constants and (2) the fact that reductions of the (2-14 keto derivatives regenerate exclusively the hydroxyl with the same stereochemistry as in isotalatizidine and talatizidine. Insight into the conformations of ring A in condelphine and its C-1 esters was gained from the NMR spectra of these compounds (64e,1 3 1 ~ ) . The large coupling constants of the geminal proton of the C-1 esters can only be explained by a chair conformation. Condelphine and isotalatizidine, however, must exist in the boat conformation an appreciable amount of their time, as indicated by the intramolecular hydrogen
1. THE C
I
S
- ALKALOIDS ~ ~
~
~
~ 109~
bonding between the C-1 hydroxyl and the nitrogen. Actually, they most likely exist in a rapid equilibrium between the boat (CCCXCIII) and chair (CCCXCIV)conformations as evidenced by the fact that the NMR spectra always show the C-1 proton as a multiplet when the C-1 hydroxyl is not esterified. Heating the sample resolves the multiplet into a triplet whose coupling constant ( J = 3 Hz) is in accord with that expected from this proton when ring A is in the boat conformation and the dihedral angles involved are nearly equal. Thus, a t higher temperatures the more highly energetic boat form tends t o predominate. Data for derivatives of condelphine and isotalatizidine are given in Table XVIII.
IV. Lactone-Type Diterpene Alkaloids There is a small group of diterpene alkaloids occurring in the mother liquors of Aconitum heterophyllumWall., which are modeled on a modified lycoctonine-type skeleton and contain a lactone ring. Since the most prevalent of these compounds, heteratisine, is related in a simple fashion t o the other members of the series, its chemistry will be consideredin some detail.
A. HETERATISINE Heteratisine (145, 146) occurs in the weak-base fraction of A . heterophyllum to the extent of 0.03y0. It may be an artifact obtained during isolation by hydrolysis of its benzoyl ester. The molecular formula (145, l 4 6 ) , C22H33N05, has been confirmed by crystallographic studies (147).The usual chemical tests revealed the presence of the following functional groups : two hydroxyls, one methoxyl, one N-ethyl, and a %lactone (1739 em-1). These groups account for all the hetero atoms and leave a 6-ring 19-carbon skeleton. The high level of oxygenation and failure t o yield phenanthrenes on dehydrogenation* suggested that heteratisine consists of a modified lycoctonine-type skeleton. The structure (CCCXCV)shown for heteratisine has been deduced independently by X-ray analysis of heteratisine hydrobromide monohydrate (150)and by chemical and spectral studies (151,152). The presence of methoxyl (145,146,153) and N-ethyl (153)groups is confirmed by NMR signals at 76.75 (3H singlet) and 78.98 (3H triplet,
* Alkaloids of the atisine and hypognavine types yield phenanthrenes on dehydrogenation (148, 149).
~
~
110
S. W . PELLETIER AND L. H. KEITH
J = 7.5 Hz). Other structural features clearly recognizable are a quaternary C-CH3 (79.03, 3H singlet), H-&OH (75.5, 1H multiplet), H-C-OCO (approx. 75.26, l H ) , and OH (74.97, 1H singlet) (151).One of the two hydroxyls is tertiary (resistant to acetylation and oxidation) and the other secondary. Heteratisine forms a basic monoacetate (CCCXCVI)and monobenzoate (CCCXCVII).The latter is identical with the naturally occurring benzoyl ester (145,146).The monoacetate with
.:1 5
CCCXCV; R = H2, R’ = OH CCCXCVI; R = Hz, R‘ = OAC CCCXCVII; R = H2, R’ = OBz CCCXCVIII; R = 0, R’ = OAC CCCXCIX; R = 0, R’ = OH CD; R = R’= 0 CDII; R = Hz, R’ = 0
OAC CDI
H- -
CDIIIa; R = A c CDIIIb; R = H
chromium trioxide-pyridine complex gives as the major neutral product, oxoheteratisine acetate (CCCXCVIII) (151, 154). The hydrolysis product, oxoheteratisine* (CCCXCIX),on further oxidation yields dehydrooxoheteratisine (oxoheteratisinone)* (CD) [A, 310 (e 30), 1733 cm-1 (cyclopentanone), 1748 cm-1 (blactone), 1626 cm-1 (&lactam)]. I R and NMR spectra show that these derivatives contain the N-ethyl lactam group. A basic by-product of the chromium trioxide-pyridine oxidation of heteratisine acetate is N-desethyldehydroheteratisineacetate (CDI) [1642 cm-1 (>C=N-), 72.68 (1H multiplet, HC=N), no NMR signal for N-C~HS]. Oxidation of heteratisine with chromium trioxide in acetic acid gives a basic ketone, dehydroheteratisine (heteratisinone) (CDII). Oxidation with permanganate in acetone convert’sheteratisine acetate t o
* Also
obtained directly by oxidation of heteratisine with CrOs-pyridine complex
(151, 154).
1. THE C
I
S
- ALKALOIDS ~ ~
~
~
~
1 1~1
an N-desethyl lactam acetate (probably CDIIIa)" and oxoheteratisine acetate (CCCXCVIII) (154). The location of the cyclopentanone carbonyl at C-6 in dehydroheteratisine (CDII) and dehydrooxoheteratisine (CD) was assigned on the basis of biogenetic analogy and molecular rotation changes (151).The d[M], is -370" for oxidation of heteratisine to dehydroheteratisine and -325" for the corresponding lactam derivatives. These values compare well with the value of -202' for oxidation of delpheline (CDIV) to dehydrodelpheline (CDV) and -470" for oxodelpheline (CDVI) to dehydro-
CDIV; CDV; CDVI; CDVII;
CDVIII; R = H z CDIX; R = 0
R = Hz, R' = OH R=Hs,R'=O R = 0, R'= OH R = R' = 0
1 I R
0 CDX; R = H z CDXI; R = O
oxodelpheline (CDVII) (151). Moreover, dehydroheteratisine shows a negative maximum (A, 320 mp, [a] -1290°), in agreement with the sign predicted by application of the octant rule to the 6-keto structure. Analysis of the NMR spectra of heteratisine and its derivatives a t lower field than the methoxyl resonance, in conjunction with biogenetic analogies, permits location of the lactone, the tertiary hydroxyl, and, with some reservations, the methoxyl group (151).The splitting of the H-C acetoxyl signal in heteratisine acetate (CCCXCVI) and oxoheteratisine acetate (CCCXCVIII)into a doublet of doublets is consistent with its location a t C-6 and spin coupling to H(C-7)and H(C-5). * A minute amount of its deacetyated derivative (CDIIIb) was isolated from chromium trioxide-pyridine oxidation of heteratisine monoacetate (155).
~
~
112
S. W. PELLETIER AND L. H. KEITH
The action of hot aqueous alkali on heteratisine or oxoheteratisine causes only hydrolytic opening of the lactone ring. With the corresponding ketones, however, profound degradation occurs under. these conditions. The products lack lactone or carboxyl groups (no I R absorption for 6-lactone; insoluble in alkali) and may be formed by decarboxylation of the 8-keto acids CDX and CDXI, respectively, which are formed by retroaldol cleavage of the corresponding /I-hydroxy ketone system (CDVIII, CDIX). CD
-+
--f
,--
0 CDXII
0 CDXV
CDXIII
CDXVI
CDXIV
CDXVII; R = H
CDXVIII; R
= AC
Treatment of dehydrooxoheteratisine (CD) with potassium tertbutoxide in tert-butanol leads to the y-lactone carboxylic acid, characterized as its methyl ester (CDXIV) [1787 cm-1, (y-lactone), 1748 cm-1 (cyclopentanone), 1728 cm-1 (COZMe, 1648 em-1 (6-lactam)]. Its formation by cleavage of the initial retroaldol product (CDXII) to a 6-lactone carboxylic acid (CDXIII) and subsequent isomerization to the y-lactone provides decisive proof for location of the tertiary hydroxyl a t a position /I to both the cyclopentanone and S-lactone carbonyls and four carbons removed from the 6-lactone ether oxygen. The location of a methoxyl a t C-1 follows from the fact that methoxyl elimination did not occur when dehydrooxoheteratisine (CD) was treated with butoxide (precludes C-16 as site for methoxyl) and from the observed deshielding of the H-C-1 proton which is nearly coplanar with
1.
THE
CIS-DITERPENEALKALOIDS
113
both the trigonal C-6 and C-19 and is about 5 A distant from each carbonyl. Heteratisine esters undergo a facile thermally induced ring cleavage which has unusual features (154). Thus, pyrolysis of the acetate (CCCXCVI)or the benzoate (CCCXCVII) proceeds with elimination of 1mole of the respective carboxylic acid to give pyroheteratisine (CDXV) ,A[ 235 mp ( e 10,600)] in about 90% yield and isopyroheteratisine CDXV
P
@
,--
t
?
H
Me
CDXXII
CDXXI
(CDXVI) in about 1yoyield. Hydrogenation of pyroheteratisine gives a dihydro derivative and hydroxylation with osmium tetroxide gives a cis-diol (CDXVII) which forms a basic monoacetate (CDXVIII). The signal a t H-C-OH signal a t 76.18 in the diol and the H-C-OAc 75.30 in the monoacetate both appear as sharp singlets. Brief treatment of pyroheteratisine with NaOCD3 in CD30D effects exchange of H-C-9 by deuterium ;the H-C-9 signal vanishes and the vinylic proton doublet degenerates to a singlet. This facile deuterium exchange and the accompanying loss of allylic coupling supports the structure shown. Decisive proof for structure CDXV by decarboxylation of the derived vinylogous /3-ketocarboxylate looks facile, but it is not since generation of the A8-double bond is sterically impossible. On extended boiling with aqueous alkali a t pH 9, pyroheteratisine (CDXV)suffers decarboxylative
114
S. W. PELLETIER AND L. H. KEITH
degradation and the reaction appears to follow the path CDXV-t CDXIX + CDXX -+ CDXXI + CDXXII since the spectral properties of the product permit its formulation as CDXXII [h,,254 mp ( e 8100); vlllaX 3390, 2747, 1667, 1592 cm-l; 78.93 (3H singlet), 9.03 (3H triplet), 7.90 (3H singlet), 6.60 (3H singlet), no vinyl proton signal].
+
,,-.
CDXXIV
CDXXV
1 CDXV
CDXXVI
CDXXVII
T
CCCXCVI
Isopyroheteratisine isomerizes to pyroheteratisine (CDXV) when treated with acid, or when heated, and gives a dihydro derivative identical with dihydropyroheteratisine. It therefore has structure CDXVI. Additional facts relating to the pyrolysis reaction are the following: 8-OD-des-8-OH-benzoylheteratisine yields benzoic acid-dl. Dehydroheteratisine (CDII) and oxoheteratisine acetate (CCCXCVIII) fail to undergo a parallel reaction, the latter even on admixture with heteratisine acetate. The extreme facility and high yields of the pyrolysis reaction, in conjunction with the aforementioned facts, suggest the reaction may proceed by a concerted process involving intramolecular participation of the basic nitrogen (152)(CDXXIII + CDXXIV + CDXXV +-CDXV). An alternative mechanism suggests isomerization of heteratisine monoacetate (CCCXCVI)to the 8-acetate (CDXXVI), fission to the ion pair
1.
THE
C
I
S
- ALKALOIDS ~ ~
~
~
~ 115 ~
~
(CDXXVII), and hydride transfer from C-6 to C-17 to give pyroheteratisine (CDXV) (156). The absolute configuration of heteratisine has been determined by study of the ORD curves of pyroheteratisine (CDXV)and dihydropyroheteratisine (152)and by comparison of the AM,, values for heteratisine derivatives with those of the corresponding delpheline derivatives (154). The biogenesis of heteratisine probably involves a Baeyer-Villiger type oxidation of a precursor containing a C-14 carbonyl group on the lycoctonine skeleton (154). B. HETEROPHYLLISINE, HETEROPHYLLINE, AND HETEROPHYLLIDINE These alkaloids were isolated in small quantities from the mother liquors of heteratisine (157).All contain a a-lactone ring since (a)they are
OH Heteratisine (CCCXCV) M+ 391 [6]
376 191 -17,374 [lo] -ls,373 [9] -31,360 [loo] -16J
6H Heterophyllidine (CDXXVIII)
M i 377 1351 -15,362 [35] -17c 360 [loo1
1
2
-3344 [12]
,
342 [13]
a 3 5 9 [20]
'Y
344 [lo] 342 [22]
Heterophyllisine (CDXXX)
M+ 375 [5] -15,360 [5] -17,358 [2.5] -ls, 367 [l] -31, 344 [loo] -18,328 [6]
Heterophylline (CDXXXIX)
M + 361 [25] - a 3 4 6 [30] [loo] 2 , 3 2 8 [37] -344 - a 3 4 3 [l9] Note: Numbers in [ ] represent relative peek heights.
~
TABLE X I X
HETERATISINE-TYPE ALKALOIDS AND DERIVATIVES
Compound
Heteratisine (CCCXCV) hydrochloride monoacetate (CCCXCVI) monobenzoate (CCCXCVII) monobenzoate hydrochloride Oxoheteratisine (CCCXCIX) acetate (CCCXCVIII) Dehydrooxoheteratisine (CD) (oxoheteratisinone) N-Desethyldehydroheteratisineacetate (CDI) N-Desethyldehydroheteratisineacetate hydrochloride
Formuia
References
267-26 8 265-270 175-177 161.5-167 2 13-2 14 218-22 1 345-347 280-282 270-274 313-3 17 294-298 325-330
+29(Chf.); +40(MeOH)
+ 16(Chf.)
-
+ 73(EtOH) + 50(MeOH) - 31(MeOH)
+ 125(MeOH)
-
145, 146,154 145,146 151, 154 145, 146 145,146 151 151 151, 154 151 151
Dehydroheteratisine (CDII) (heteratisinone) Dehydroheteratisine perchlorate N-Desethyl lactam acetate (CDIIIa) N-Desethyl lactam (CDIIIb) y-Lactone carboxylic acid methyl ester (CDXIV) Pyroheteratisine (CDXV) Dihydropyroheteratisine Pyroheteratisine diol (CDXVII) Pyroheteratisine diol monoacetate (CDXVIII) Isopyroheteratisine (CDXVI) CDXXII.hydrochloride Heterophyllisine (CDXXIX) Heterophylline (CDXXVIII) Heterophylline acetate Heterophyllidine (CDXXVII) Heteratisine hydrobromide hemimethanolate Heteratisine hydrobromide Heteratisine hydroiodide Heteratisine hydrobromide monohydrate Heteratisine perchlorate
124-125 130-135 266-269.5 272-273 266-269 90-92 191-192 179-1 80 215-217 251-252 154-155 200-201 178-179 221.5-223 174-176 269-272 280-2 83 272-274 274-276
252-256
- 66(Chf.);
- 56 (MeOH) -
-
+ PO(Me0H) +47(MeOH)
-
+ 15.5(MeOH) + 10.5(MeOH)
-
+42.3(MeOH) 24
+ + 26 + 19
-
151,154 154 154 154 151 152 152 152 152 152 152 157 157 157 157 147 147 147 150 154
118
S . W. PELLETIER AND L. H. KEITH
soluble in hot, aqueous sodium hydroxide solution and can be recovered from such solution after acidification and (b)they show strong absorption in the infrared a t 1727-1748 em-1. A close structural similarity to heteratisine was therefore suspected. The structures shown were derived mainly by comparison of the mass spectra of these alkaloids with that of heteratisine (157).The most abundant ions in the high-mass region are listed under the structures (CCCXCV, CDXXVIII-CDXXX).
1 . Heterophyllidine ( C D X X V I I I ) The mass spectrum in the m/e 98-300 region is identical with the spectrum of heteratisine. The molecular ion (M+) a t m/e 377, the absence of a peak a t (M+-31) and the presence of the most abundant peak a t (Mf - 17) suggest the 1-0-norheteratisine structure CDXXVIII for heterophyllidine. All other peaks expected from CDXXVIII by analogy with the mass spectrum of heteratisine (CCCXCV) are present. The NMR spectrum of heterophyllidine is very similar t o that of heteratisine except that absorption due t o -0CH3 is absent.
2. Heterophylline ( C D X X I X )and Heterophyllisine ( C D X X X ) Analysis of the mass spectra showed these alkaloids to be desoxyheterophyllidine (CDXXIX) and desoxyheteratisine (CDXXX),respectively. Absence of peaks a t m/e (334 - 18),corresponding to loss of water from the most abundant ion, suggests that oxygen is missing from either the C-8 or C-6 hydroxyl group. The latter alternative is confirmed by the NMR spectrum and chemical data. Thus, heterophylline contains a tertiary hydroxyl (resists acetylation). If this tertiary hydroxyl is a t C-8, then the other hydroxyl (acetylated, secondary) cannot be a t C-6 since pyrolysis of heterophylline acetate does not yield an enone corresponding to pyroheteratisine (152).The NMR spectra of the pairs heterophyllineheterophyllidine and heterophyllisine-heteratisine are remarkably similar, but there are two notable differences. I n the desoxy compounds, signals assignable to H-C-6-OH are absent and the 3H singlet for CH3-C- occurs a t T O . 16 higher field, presumably because the deshielding effect of the neighboring hydroxyl a t C-6 is absent. Data for heterotisine and its derivatives are given in Table XIX. V. Uncharacterized Alkaloids A. LAPPACONITINE, TALATISINE, AND TALATISAMINE I n spite of the recent advances described in the foregoing text, there still remain a few “old” alkaloids whose structures have not yet been
1. THE C
I
S
- ALKALOIDS ~ ~
~
~
~ 119 ~
completely elucidated. Lappaconitine, talatisine and talatisamine, are three examples of such alkaloids which have been known for quite a while and have appeared in recent literature. Lappaconitine has been found to occur in Aconitum septentrionale Koelle(159),A . orientale ( 1 6 4 , and A . excelsum Popov (161).Saponification of lappaconitine (CaH44N08) gives lappaconine ( C ~ H W N Oand ~) acetylanthranilic acid. The molecular formula of lappaconine has been
9lo, ------___
CDXXXI; R
=
CDXXXII; R = H
tDNHAC
bCH8 CDXXXIII
confirmed by its mass spectrum (162).Lappaconine contains an N-ethyl, three methoxyl, and three hydroxyl groups (one of which is tertiary and two of which are secondary). Strangely, acetylation with acetic anhydridelpyridine produces only the monoacetyl derivative of lappaconine and lappaconitine is not even acetylated under these conditions. Prolonged reaction with acetyl chloride, however, yields diacetyllappaconitine and triacetyllappaconine from the parent ester and ihs amino alcohol, respectively. Attempts to pyrolyze triacetyllappaconine failed and on this basis it was assumed that the tertiary hydroxyl cannot be at C-8. On the basis of further information obtained from oxidation reactions, it appeared that the partial structure of lappaconitine may be represented by CDXXXI and that of lappaconine by CDXXXII. If this is indeed the case, then lappaconitine would be the first known member of
~
~
120
S. W. PELLETIER AND
L. H. KEITH
this group of alkaloids to be devoid of an oxygen functional group a t C-8 as well as the first member to bear an esterified C-15 hydroxyl group. Talatisine and talatisamine were first isolated in 1940 along with isotalatizidine (CCCLIII) and talatizidine (CCCLIV) from the roots of A . talassicum (143).Talatisine (CzoH2gN03)has since been isolated from the stems and leaves of this same plant (163,164).Talatisamine, however, is more widely spread, as evidenced by its isolation from A . nemwum Popov (165) and A . carmichaeli (73).The molecular formula of talatisamine is C24H39N05 and not, as previously suggested (143),C22H35N04. It forms a monoacetyl derivative with acetic anhydride and a diacetyl derivative with acetyl chloride. Saponification gives back the original amine. Thus, one can conclude it contains one tertiary and one primary or secondary hydroxyl and is not esterified. It has also been determined (163)that the alkaloid possesses an N-ethyl and three methoxyl groups, so that its molecular formula may be represented as C I ~ H ~ ~ ( N C ~ H ~ ) (OH)2(OCH3)3.Absorption of 1 mole of hydrogen over platinum indicated the presence of one double bond. If this is true, then talatisamine would be the first alkaloid of this type t o possess a carbon-carbon double bond (excluding chasmanthinine, which bears a trans-cinnamyl esterifying group). Most recently talatisamine has been isolated from the above-ground . on spectral studies of some portion of A . variegatum L. ( 1 6 5 ~ )Based talatisamine derivatires a partial structure of talatisamine (CDXXXIII) has been proposed (165a). As might be expected, the two hydroxyls are located a t C-8 and C-14. It is significant t o note that the proposed structure contains no carbon-carbon double bond, contrary t o previous results. I n a recent publication Yunusov and Yu (165b) have assigned the remaining two methoxyl groups to C-1 and C-16. There was no indication of the stereochemistry involved but the C-16 methoxyl can be predicted to be beta. Talatizamine is the fourth alkaloid of the aconitine-type which lacks a C-6 methoxyl (condelphine, isotalatizidine, and talatizidine being the other three) and is the methyl homolog of either isotalatizidine or talatizidine. It should therefore be easily correlated with one of these two alkaloids. This correlation would then define the configurations of both the C-1 and the C-16 methoxyls in talatizamine.
B. NEWLYISOLATED ALKALOIDS Monoacetyltalatisamine has also been obtained with the previously described talatisamine from the forest aconite, A . nemorum (165). The
1.
THE
CIS-DITERPENE ALKALOIDS
121
same paper also describes the isolation of two unnamed alkaloids with molecular formulas of C27H31N06 and C26H34N202 from the aerial portions of the round-leaved aconite A . rotundifolium Kar. et Kir. ( A . napellus L.). The tall aconite A. excelsum contains, in addition to lappaconitine, two new alkaloids for which the names acsine and acsinatine have been proposed (161).Acsine (C21H29N05)contains one acetoxy and two hydroxyl groups plus an ether linkage. Acsinatine (C21H27N04)contains only one hydroxyl group, one acetoxy group, and one ketone group. Saponification of acsine and acsinatine gives the amino alcohols acsinidine (ClgH27N04) and acsinatidine (ClgH25N03),respectively. The alkaloid oreoline (C26H43N07)has been isolated from the roots of a central Asiatic larkspur closely related to a known species of mountain larkspur, D. aerophilum, but differing from it in morphological character (166). The base contains an N-methyl, a methylenedioxy group, one hydroxyl, and four methoxyl groups. The IR spectrum of oreoline is reportedly quite similar to that of lycoctonine, although, as an ester group is lacking, it does not contain the carbonyl absorption present in the IR spectrum of the latter. The presence of a previously unreported alkaloid contaminating samples of deltaline from D. occidentale S. Wats. is briefly mentioned (31).The name given to this contamination is delphoccine. From the roots of the Chinese drug Tzu-tsao-wu, Aconitum a new alkaloid called delavaconitine has been isolated (167). The molecular formula is C30H41NO6 and saponification gives benzoic acid and the alkylamine, delavaconine. A triacetyl derivative of the latter was prepared as well as a monoacetyl derivative of delavaconitine. It is proposed that the base contains an N-ethyl, a benzoyloxy group, two hydroxyl groups, and two methoxyl groups. Brief mention of a new alkaloid from the seeds of D . orientale is made (24). The new base is named delorine and has a molecular formula of C22H29N05. The isolation of two new alkaloids, sachaconitine and isodelphinine (tentatively reported at first as “base D”), from the roots of A . miyabei Nakai is described by Japanese researchers. Sachaconitine (168,169)has a molecular formula of C23H37N04 and, being stable to alkali, is considered to have no ester functional groups. It contains an N-ethyl, two methoxyl groups, and two hydroxyl groups (both of which are resistant to acetylation with acetic anhydride but give a diacetyl derivative with acetyl chloride). Permanganate oxidation of sachaconitine gives a mixture of the basic N-desethylsachaconitine and a neutral derivative, oxosachaconitine while chromic anhydridelpyridine oxidation of the
122
S. W. PELLETIER AND L. H . KEITH
same produces a mixture of a keto lactam, oxosachaconitone, and a diketone, N-desethyldehydrosachaconitinone.Reduction of the latter with sodium borohydride produces N-desethylsachaconitine and it can also be obtained by oxidation of N-desethylsachaconitine with chromic acid in acetone. The I R and UV spectra of N-desethyldehydrosachaconitine indicate that the two hydroxyl groups of sachaconitine were oxidized t o ketone groups but both were cyclic five-membered ketones! I n oxosachaconitinone only one of the two hydroxyls is oxidized to a cyclic five-membered ketone. Isodelphinine (170) has the same empirical formula (C33H45N09) as delphinine but differs distinctly from the latter in both melting point and I R spectrum. It forms only a *monoacetateand saponification gives the amino alcohol plus benzoic and acetic acids. It thus possesses one acetoxy and one benzoyloxy group and only one hydroxyl. I n addition, analyses indicate four methoxyl groups and an N-methyl. Isoaconitine (171) (C34H47NOll) has the same empirical formula as aconitine. However, whereas the former is represented by the partial ~)(CH~~C~ formula C ~ ~ H ~ ~ ( N C ~ H ~ ) ( O H ) ~ ( O C H ~ ) ~ ( O C O C Haconitine has all four of its methoxyl groups attached directly to its skeleton. The new alkaloid is reported to occur in the Aconitum species known as the Chinese drug Tzu-tsao-wu. The alkaloid anhweiaconitine (C30H41N09)has also been isolated from the roots of the Chinese drug Tzu-tsao-wu (172). These plants were collected in the region known as Anhwei, however, whereas the plant specimens in which isoaconitine was isolated were collected from the region called Yunnan (171). The partial formula of anhweiaconitine is given as CI~H~~(NCH~)(OH)~(OCH~)~(OCOC~H~). Seven new alkaloids have recently been isolated from A. bullatifoliurn, the Chinese drug Hye-shang-yi-zhi-hao, and provisionally named bullatine A, B, C, D, E, F, and G (72,173).BullatineA (C21H31N02)isan unsaturated base with an ethylimino group and two hydroxyls. Bullatine B (C24H39N06) contains an ethylimino, three hydroxyl, and three methoxyl groups. Bullatine C (C26H41N07) is identical with the monoacetyl derivative prepared from bullatine B. Bullatine D (C23H37N09) was obtained only in a very small amount. The same plant collected in a different district of Yunnan yielded aconitine, hypaconitine, and bullatine B, E, and F. Bullatine E (C24H39N06) has the partial formula C~~HZZ(NCZH~)(OH)~(OCH~)~ and bullatine F (C24H39N07) has the Bullatine G (C21H31N03) partial formula C~~HZI(NCZH~)(OH)~(OCH~)~. was isolated from the mother liquor after the separation of bullatine A and after standing several months. It appears to be a ketone and its partial formula was found to be C ~ ~ H Z ~ ( N C Z H ~ ):(0). OH)Z(
1.
THE
CIS-DITERPENEALKALOIDS
123
The Chinese drugs Chuan-wu and Fu-tzu ( A . carmichaeli) are rich in alkaloids. I n addition to aconitine, mesaconitine, hypaconitine, and talatisamine, two new alkaloids, provisionally named Chuan-wu bases A and B, have recently been reported (73).Chuan-wu base A (C23H37N06) is a tertiary base containing an N-ethyl, two hydroxyl, and two methoxyl groups (thus leaving two oxygen functional groups still unaccounted for). Only the empirical formula (C32H35N04) and physical properties were reported for Chuan-wu base B. An alkaloid named bishaconitine has recently been isolated, along with bishatisine, from the roots of A. falconeri (174).Saponification of bishaconitine gives benzoic and veratric acids and the amino alcohol (C25H41N09)named bishaconine. A new alkaloid named carmichaeline has been isolated from the tubers of A. carmichaeli (108).No structural information was reported in this paper. The Chinese drug Guan-bai-fu-tzu, A . koreanum, is another species rich in alkaloid content. A recent report (110)describes the isolation of five new alkaloids which are provisionally named guan-fu bases A, B, C, D, and E, respectively. Guan-fu base A (C24H31N06)is a diester which, when saponified, yields two equivalents of acetic acid and the amino alcohol CzoH27N04.It is easily reduced catalytically to a dihydro derivative and also undergoes oxidation with permanganate, the partial formula being expressed as C19H20( :N)(CH3)(OH)z(OCOCH3)2.Guan-fu base B (CzzHzgN05) is a monoacetyl ester of the C ~ O H Z ~ amino NO~ alcohol mentioned above. The monoacetyl derivative of base B is, in fact, identical with base A and its partial formula is thus C19Hzo( :N)(CH3)(OH)3(OCOCH3).Guan-fu base C has the partial formula C19H23(NC2H5)(CH3)(OH)z.Guan-fu bases D and E appear t o be amorphous and their molecular formulas are reported as C23H35N03 and C29H43N07, respectively. Two new amorphous alkaloids, as yet unnamed, are reported to have been isolated from D. rugulosum Boiss. (175, 176). Their empirical formulas are ClgH2gN04 and Cz1H31N04 and both contain hydroxyl and keto groups. Surprisingly, neither is supposed to contain any methoxyl groups. Another unnamed alkaloid was isolated from D. araraticurn (176). Three other unnamed bases of Russian origin have also recently appeared in the literature (177);a new base, C35H41N010, from A . koreanum and two new bases, CzoHz5N03 and c~3HzgNO6,from A . nemorosum Bieb. ( A . anthora L.). Extracts of the above-ground portion of A . variegatum, a common plant of Bulgaria, has yielded a new alkaloid, cammaconine, in addition to talatisamine ( 1 6 5 ~ )Cammaconine . (C23H37N05) contains three
124
S. W. PELLETIER AND L. H. KEITH
hydroxyl groups and two methoxyl groups in addition to N-ethyl and is represented by the partial formula C ~ ~ H ~ ~ ( N C Z H ~OCH3)z. )(OH)~( A recent reinvestigation of the alkaloids in A . septentrionale Koelle collected in Sweden (1'78)confirmed the presence of lappaconitine as the major alkaloid, but no trace of the earlier described (17'9) alkaloids, septentrionaline and cynoctonine, was found. Instead, six other minor alkaloids were isolated and described as follows : Alkaloid A (C43H59N3012)contains an N-ethyl, six methoxyl groups, an aromatic ring and one or more hydroxyls. Saponification yields succinoylanthranilic acid and an amorphous basic substance (C31H4sN208)still possessing the N-ethyl and five methoxyl groups. Thus, the alkamine must be esterified with either N-succinoylmethylanthranilate or the methyl succinate amide of anthranilic acid. Alkaloid B (C17H25N02)contains a quaternary methyl, an exocyclic double bond, and one or more hydroxyls but no methoxyl groups. Alkaloid C (ClgH27N03)also contains a quaternary methyl, an exocyclic double bond and one or more hydroxyls. Like deltaline (C19H25N03)alkaloid C contains neither an imino alkyl group nor methoxyls and the two are felt to be closely related. Alkaloid D (C30H42N207) is deacetyllappaconitine and is easily converted t o lappaconitine by acetylatiorl. Alkaloid E (C37H54N207) contains an N-ethyl, two methoxyl groups, and one or more hydroxyls, but lacks carbonyl band absorptions in its I R spectrum. Alkaloid F (C19H2gNOe) contains an N-ethyl, three methoxyl groups, one or more hydroxyl groups, and a cyclopentanone ring but apparently no ester linkages. Six new alkaloids have been isolated from five species of Delphinicm in Russia (180). From D. freynii Conrath was isolated delfrenine (CZ~H~~N anOunsaturated ~), benzoat; ester containing no methoxy or methylenedioxy groups. Saponification gives benzoic acid and an amino acid characterized as its methyl ester (C21H31N06). Catalytic hydrogenation of delfrenine over Adams catalyst gives C27H41N06. Extraction of D. pyramidatum Albov. gave a noncrystalline alkaloid (C49H82N2017) named delpyrine. This alkaloid contains two hydroxyls and saponifies to an uncharacterized acid and an amorphous base (C46H74N205) which likewise gave no crystalline salts. D.Jlexuosum M.B. was reported to contain a new alkaloid named delflexine (C24H3gNO6). D. semibarbaturn Bienert contained two unnamed new alkaloids : base A (C15H23N04)and base B (C~oH25N07).D . iliense Huth likewise contained an unnamed new alkaloid : base C (C45H72N2014). Another study of the bases from five Delphinium species in Armenia produced a t least five new alkaloids (181).From D.Jlexuosum was isolated methyllycaconitine, two unnamed crystalline compounds, base A (C35H54N20~)and base B ( C I S H ~ ~ N Oand ~ ) , base C, mp 113°-1150
1.
125
THE CIS-DITERPENE ALKALOIDS
(uncharacterized). There was no mention of delflexine (180)(C24H39N06, mp 191"-192"). From D . foetidum were obtained three more unnamed O~E ) , (C15H23N04, mp 153"-154"), alkaloids: base D ( C ~ ~ H ~ O Nbase which is probably identical with base A ( C I ~ H Z ~ Nmp O ~157"-158") , isolated from D . semibarbatuw by Brutko andMassagetov (180),and an amorphous base F (C27H43N206). From D. ZineariZobum, methyllycaconitine and an uncharacterized base were isolated. Methyllycaconitine was also mentioned as occurring in good yield in D. freynii although it was not mentioned by Brutko and Massagetov (180) who isolated delfrenine from this species. D . cyphoplectrum was extracted but no report of the results was made. The alkaloid content of the aerial parts of four Delphinium species growing in the Tran Shan region of the USSR was studied and found t o vary markedly depending on the location and the year of harvest (182). The results are summarized in the following tabulation : Alkaloid Condelphine Lycoctonine Methyllyceconitine Delpyrine Anthranoyllycoctonine
D. confusum D. oreophilum 0.7% 0.3% 0.3% -
-
0.5-2.6y0 0-trace 0-trace 0.03-0.5% 0.1-0.4%
D. iliense
D. poltoratzkii
0.3-0.9 yo 0-0.2% 0-trace 0.03-0.2% O.Ol-O.l%
0.54 0.004 0 0.06 0.01
TABLE XX NEWLYISOLATED UNCHARACTERIZED ALKALOIDS AND THEIR DERIVATIVES Compound Unnamed hydrochloride Unnamed Acsine sulfate Acsinidine Acsinatine Acsinatidine Oreoline hydrochloride perchlorate Delphoccine
Formula
MP ("C)
[alD
References
251.5-252 306 173-1 74 182-185a 192-195" 220 dec 248-249.5 246-247 225-227 2 1 1-2 13c 186-188 139-142
-
165 165 165 161
-
+ 4.2 -
-
- 28 -
161 161 161 161 166 166 166 31
126
S. W. PELLETIER AND L. H. KEITH TABLE XX-continued NEWLYISOLATED UNCHARACTERIZED ALKALOIDS AND THEIRDERIVATIVES Compound
Delavaconitine nitrate perchlorate Monoacetyldelavaconitine Delavaconine perchlorate aurichloride Triacetyldelavaconine Delorine hydrochloride Sachaconitine perchlorate aurichloride oxalate hydrochloride Diacetylsachaconitine Oxosachaconitine N-Desethylsachaconitine Diacetyloxosachaconitine Oxosachaconitinone N-Desethyldehydrosachaconitinone Isodelphinine perchlorate aurichloride Monoacetylisodelphinine Isoaconitine nitrate hydrochloride hydrobromide hydroiodide perchlorate thiocyanate methiodide Triacetylisoaconitine Isoaconine hydrobromide Tetraacetylisoaconine Anhweiaconitine nitrate perchlorate aurichloride rnethiodide Tetraacetylanhweiaconitine Bullatine A hydrochloride
Formula
MP ("C)
[.ID
-
-
References
154 241 106-110 150 215 184 160 - 53 + 54.7 227-229 227-229 - 13.08 129-130 188-189 -23.72 197-198dec 182-183 -29.71 203-204 - 30.43 114-116 - 10.87 194-196 - 37.8 230-231 17.1 149-151 237-239 35.7 275-277 107
167 167 167 167 167 167 167 167 24 24 168 168 168 168 168 168 160 169 169 169 169
167-168 171-1 72 228-229 188-190 144-146 139 157-162 181 220 231 196-198 199 155-160 118-123 244 151-153 199 188-1 89 226 222 210-213 181-183 251-253 265
170 170 170 170 171 171 171 171 171 171 171 171 171 171 171 171 172 172 172 172 172 172 173 173
+ + +
+20.1 - 2.38
28 - 12.5
- 18 -
-
25.2
-
- 55 -
1. THE CIS-DITERPENEALKALOIDS
127
TABLE XX-continued NEWLYISOLATED UNCHARACTERIZED ALKALOIDSAND THEIRDERIVATIVES Compound
Formula
MP ("C)
[aID
References
26 3-2 64 237 231-232 221 145-147 158-159 211 2 16-2 17 201-202 220-221 150-1 51 200 222-224 226 197-198 231-232 150
-
173 173 173 173 173 173 173 173 173 173 173 173 173 173 173 173 173
~
Bullatine A--cont. hydrobromide nitrate perchlorate picrate Diacetylbullatine A Bullatine B hydrochloride hydrobromide nitrate perchlorate Triacetylbullatine B Bullatine C hydrochloride hydrobromide nitrate perchlorate Diacetylbullatine C (monoacetylbullatine B) Bullatiue D hydrobromide Bullatine E Bullatine F Bullatine G Chuan-wu base A Chuan-wu base B Bishaconitine aurichloride reineckate Bishaconine Carmichaeline hydrobromide Diacetylcarmichaeline Guan-fu base A nitrate hydrochloride hydrobromide perchlorate inethiodide Diacetyl-guan-fu base A amino alcohol dihydro derivative oxidation product I perchlorate of oxidation product I1
211 224 182-183 186 200-201 111 185 118-119
+21.8
-
-7
-
79.6 23 -168 0
0 -
173 173 72 72 72 73 73 174 174 174 174 108 108 108 110 110 110 110 110 110 110 I I0 110 110 I I0
128
S. W. PELLETIER AND L. H. KEITH
TABLE XX-continued NEWLYISOLATED UNCHARACTERIZED ALKALOIDS AND THEIRDERIVATIVES Compound ~
~
~
~~~
Guan-fu base B hydrobromide perchlorate methiodide Triacetyl-gum-fu base B Guan-fu base C nitrate hydrobromide Diacetyl-gum-fu base C hydrochloride Guan-fu base D nitrate Guan-fu base E perchlorate Unnamed Unnamed Unnamed Unnamed hydrobromide Unnamed Unnamed hydrochloride Cammaconine Alkaloid A saponification product Alkaloid B Alkaloid C Deacetyllappaconitine (alkaloid D) Alkaloid E Alkaloid F Delfrenine Saponification product hydrochloride saponification product methyl ester hydrochloride catalytic hydrogenation product Delpyrine reineckate saponification product Delflexine Base A
MP ("C) ~~
References _____
204 257-258 255-256 317-318 154-155 150 222 235 222.5-224
110 110 110 110 110 110 110 110 110
-
110 110 110 110 175, 176 175, 176 176 177 177 177 177 177 165a 178 178 178 178 178
210-211
272
-
210 244-246
270-272 135-137 123-129 Amorphous 164-168 130-132 209-214 204-208 204-2 14 246-247 250-251
178 178 180 180
272.5-273 Amorphous
180
107-108
180
76 Amorphous 179-180 Amorphous 191-192 157-158
180 180 180 180 180
1.
THE
CI~-DITERPENE ALKALOIDS
129
TABLE XX-continued
NEWLY ISOLATED UNCHARACTERIZED ALKALOIDS AND THEIRDERIVATIVES Formula
Compound
References ~
163-154 192.5-193 166 201-202 113-1 15 110 153-154 Amorphous
Base B Base C Base A Base B Base C Base D Base E Base F a
When heated slowly.
b
When heated rapidly.
180 180 181 181 181 181 181 181 c
Under vaccum.
The basic extract of various organs of Illia larkspur and Dzhugar larkspur were studied in the budding and flowering seasons (183).The bulk of the alkaloids was contained in the flowers of Illia larkspur during the flowering season, and in the roots and leaves during the budding period. Conversely, in Dzhugar larkspur the maximum alkaloid content was in the leaves during the flowering stage. The extracts showed five spots by paper chromatography and two alkaloids, condelphine and elatine, were identified by comparison of retention times. Finally, a cursory study of three species of larkspur from the North Caucasus region of the USSR has been reported (184).Chromatography of the bases from D. dasycarpum revealed five spots, from D. schmalhausenii revealed six spots, and from D. JEexuosum revealed four spots. Methyllycaconitine was isolated from the latter two species and may be one of the bases described by Zolotnikskaya et al. (181)in their extraction of D.Jlexuosum. Table XX summarizes the data on these new alkaloids. Thus, there is an ever-increasing number of these diterpene alkaloids being found which should keep the natural products chemists busy for some time. Unfortunately, a substantial portion of these alkaloids are found in regions which, a t present, are unaccessible t o most of the world, but in time, perhaps, even these regions may be opened, thus providing a rich and abundant source of new alkaloids.
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1.
THE
C
I
S
- ALKALOIDS ~ ~
~
~
~
131 ~
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~
~
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1. THE C19-DITERPENE ALKALOIDS
133
115. K. Wiesner, F. Bickelhaupt, and Z. Valenta, Tetrahedron 4, 418 (1958). 116. K. Wiesner, D. L. Simmons, and L. R. Fowler, Tetrahedron Letters No. 18, 1 (1959). 117. K. Wiesner, D. L. Simmons, and R. H. Wightman, Tetrahedron Letters No. 15, 23 (1960). 118. N. K. Abubakurov and S. Y. Yunusov, J. Gen. USSR (English Transl.) 26, 2011 (1956). 119. C. R. A. Wright and A. P. Luff, J. Chem. SOC.31, 143 (1877). 120. C. R. A. Wright and A. P. Luff, J . Chem. SOC.33, 151 (1878). 121. W. R. Dunstan and F. H. Carr, J. Chem. SOC.71,350 (1897). 68, 2565 (1946). 122. L. Marion and 0.E. Edwards, J . Am. Chem. SOC. 123. Y. Tsuda and L. Marion, Can. J. Chem. 41, 1485 (1963). 124. W. R. Dunstan and A. E. Andrews, J. Chem. SOC.87, 1620 (1905). 125. R. Konowalowa and A. P. Orekhov, Bull. SOC.Chim. Prance 7, 95 (1940). 126. T. A. Henry and T. M. Sharp, J. Chem. SOC.1105 (1928). 127. R. E. Gilman and L. Marion, Tetrahedron Letters NO. 20,923 (1962). 128. W. R. Dunstan and A. E. Andrews, J . Chem. SOC.87, 1636 (1905). 129. Y. Tsuda and L. Marion, Can. J. Chem. 41, 3055 (1963). 130. 0. E. Edwards, Chew Commun. 14, 318 (1965). 131. 0. Achmatowicz and L. Marion, Can. J. Chem. 42, 154 (1964). 131a. S. W. Pelletier, L. H. Keith, and P. C. Parthasarathy, Tetrahedron Letters No. 35, 4217 (1966). 132. 0. Achmatowicz, Y. Tsuda, L. Marion, T. Okamoto, M. Natsume, H. H. Chang, and K. Kajima, Can. J. Chem. 43, 825 (1965). 133. W. A. Jacobs and Y. Sato, J . Biol. Chem. 180, 133 (1949). 134. W. A. Jacobs and C. F. Huebner, J . B i d . Chem. 170, 209 (1947). 135. 0. E. Edwards, L. Fonzes, and L. Marion, Can. J. Chem. 44, 583 (1966). Japan 75, 550 (1955). 136. E. Ochiai, T. Okamoto, and S. Sakai, J. P h r m . SOC. 137. 0. Achmatowicz and L. Marion, Can.J. Chem. 43, 1093 (1965). 138. H. Schulze, Arch. P h r m . 244, 165 (1906). 139. W. A. Jacobs and L. C. Craig, J. Biol. Chem. 128,431 (1939). 140. H. Schulze and G. Berger, Arch. P h r m . 262, 553 (1924). 141. W. Freudenberg and E. F. Rogers, J. A m . Chem. SOC.59,2572 (1937). 142. M. S. Rabinovich and R. A. Konovalova, Zh. Obshch.Khim. 12,329 (1942). 143. R. A. Konovalova and A. P. Orekhov, Bull. SOC.Chim. 7, 95 (1940); CA 34, 5450 (1940). 144. A. D. Kuzovkov andT. F. Platonova,J. Gen. Chem. USSR (EnglishTransl.)31,1286 (1961). 145. W. A. Jacobs and L. C. Craig, J . B i d . Chem. 143,605 (1942). 146. W. A. Jacobs and L. C. Craig, J . Biol.Chem. 147, 571 (1943). 147. R. Aneja and S. W. Pelletier, Acta Cryst. 17, 457 (1964). 148. S. W. Pelletier, Tetrahedron 14, 76 (1961). 149. L. Marion, Pure AppZ. Chem. 6, 621 (1963). 150. M. Przybylska, Can. J. Chem. 41, 2911 (1963). 151. R. Aneja and S. W. Pelletier, Tetrahedron Letter8 No. 12, 669 (1964). 152. R. Aneja and S. W. Pelletier, Tetrahedron Letters No. 3, 215 (1965). 153. C. F. Huebner and W. A. Jacobs,J. B i d . Chem. 170,515 (1947). 154. 0. E. Edwards and C. Ferrari, Can. J. Chem. 42, 172 (1964). 155. R. Aneja and S. W. Pelletier, unpublished work (1966). 156. 0. E. Edwards. Chem. Commun. 318 (1965). 157. S. W. Pelletier and R. Aneja, Tetrahedron Letters No. 6, 557 (1967).
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158. H. Suginome, S. Imato, S. Yamada, and N. Katsui, Bull. Chem. SOC. J a p a n 32, 819 (1959). 159. H. Schulze and F. Ulfert, Arch. Pharm. 260, 230 (1922). 160. A. D. Kuzovkov and P. S. Massagetov, J . Gen. Chem. U S S R (EnglishTransl.)25,161 (1955). 161. T. F. Platonova, A. D. Kuzovkov, and P. S. Massagetov, J . Gen. Chem. U S S R (English Transl.) 28, 259 (1958). 162. M. Khaimova, N. Mollov, and P. Cerneva, Tetrahedron Letters No. 38, 2711 (1964). 163. S. Y. Yunusov, E. V. Sichkova, and G . F. Potemkin, Zh. Obschch. Khim. 24, 2237 (1954); C A 50, 379 (1956). 164. S. Y. Yunusov, E. V. Sichkova, and G . F. Potemkin, Dokl. Akad. N a u k Uzb. SSR No. 2, 21 (1954); C A 50, 5240 (1956). 165. T. F. Platonova, A. D. Kuzovkov, and P. S. Massagetov, J . Gen. Chem. , U S S R (English Transl.) 28, 3157 (1958). 165a. M. A. Khaimova, M. D. Palamareva, L. G. Grozdanova, N. M. Mollov, and P. P. Panov, Compt. Rend. Acad. BulgureSci. 20, 193 (1967); C A 67, 54296 (1967). 165b. M. S. Yunusov and S. Y. Yunosov, K h i m . Prirodn. Soedin., Akad. N a u k U S S R 4, NO. 3, 198 (1968); C A 69, 77562s (1968). 166. A. V. Bocharnikova and E. I. Andreeva, J . Qen. Chem. U S S R (English Transl.) 28, 2918 (1958). 167. J. H. Chu, Y. L. Chou, P. C. Yang, and W. Y. Huang, H u a Hsueh HsuehPao 25,321 (1959); C A 54, 17440 (1960). 168. H. Suginome, N. Katsui, and G. Hasegawa, Bull. Chem.Soc.Japan 32,604 (1959). 169. N. Katsui and G. Hasegawa, Bull. Chem. SOC. J a p a n 33, 1037 (1960). 170. N. Katsui, Bull. Chem. SOC. J a p a n 32, 774 (1959). 171. J. H. Chu, S. H. Hung, andY. L. Chou, H u a HsuehHsuehPao 23, No. 4, 130 (1957); C A 52, 14632 (1958). 172. J. H. Chu and S. I. Lo, H u a Hsueh HsuehPao 25,214 (1959); C A 54,4642 (1960). 173. J. H. Chu, S. T. Fang, and W.-K. Huang, H u a Hsueh Hsueh Pao 30, 139 (1964); C A 61, 8128 (1964). 174. N. Singh, G. S. Bajiva, and M. G . Singh, Indian J . Chem. 4, 39 (1966); C A 65, 2625 (1966). 175. G. M. Mamedov,Ser. Khim. N a u k No. 2,95 (1964); C A 63,11922 (1965). 176. G. M. Mamedov, Aptechn. DeZo 14, 26 (1965); C A 64, 1007 (1966). 177. T.E.Monakhova, T. F. Platonova, A. D. Kuzovkov, and A. I. Shreter, Khim.Prirodn. S o e d k , Akad. Nauk USSR No. 2,113 (1965); C A 63,7347 (1965). 178. L. Marion, L. Fonzes, C. K. Wilkins, Jr., J. P. Boca, F. Sandburg, R . Thorsen, and E. Linden, Can. J . Chem. 45, 965 (1967). 179. H. V. Rosendahl, Thesis, Karolinska Institute Stockholm, Sweden (1894); Arb. Pharmakol. Inst. Dorpat 11, 1 (1895);L. Marion et al., Can. J . Chem. 45, 969 (1967). 180. L. I. Brutko and P. S. Massagetov, Chem. Nat. Compds. 3, No. 7, 16 (1968); Translated from K h i m . Prirodn. Soedin., Akad. N a u k U S S R 3, No. 1, 21 (1967). 181. S. Ya Zolotnikskaya, G . 0. Akopyran, I. S. Melkumyan, and L. V. Revazova, Biol. Zh. Arm. 20, 11 (1967); C A 68, 107866t (1968). 182. L. I. Brutko and P. S. Massagetov, Rust. Resursy 4,46 (1968);C A 69,30133n (1968). 183. T. K. Nikishchenko, T r . Alma-Atinsk. N e d . Inst. 23, 524 (1966); C A 68, 19585v (1968). 184. Ya S. Savchenko, Iiarmatsiya (Sofia)16,30 (1967); C A 68,57368j (1968).
-CHAPTER
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DITERPENE ALKALOIDS FROM ACONITUM. DELPHINIUM. AND GARRYA SPECIES: THE C.. DITERPENE ALKALOIDS S. W . PELLETIER AND L . H . KEITH Department of Chemistry. The University of Georgia. Athens. Georgia Page
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I Introduction ....................................................... I1 The Garrya Alkaloids ................................................ A . Garryfoline-Cuauchichicine Rearrangement ........................ B Napelline. Songorine (Napellonine or Shimoburo Base 1) and Luciculine . . I11 The Atisine Alkaloids ............................................... A . Atisine and Isoatisine ............................................ B Stereochemistry of Atisine ........................................ C. Chemistry of Atidine ............................................. D ChemistryofAjaconine .......................................... E . Denudatine ..................................................... IV Correlations and Absolute Stereochemistry of Atisine and Garrya Alkaloids . . A . Correlation of Atisine and Garrya Alkaloids .......................... B . Reactions of the Imine Group; Removal of the Nitrogen from Diterpene Alkaloids ....................................................... C Correlation of Garryfoline with Kaurene and Stevane-B................ D . Correlation of Atisine with the Resin Acids........................... E Absolute Configuration of the Atisine and Garrya Alkaloids ............ V The Ternary Iminium Salts of the Atisine and Garrya Alkaloids ............ A . Normal + Is0 Base Isomerization .................................. B . Isomerization of Tricyclic Oxazolidine Models ........................ C. Stability of Normal and Iso-Type Bases .............................. VI . The Chemistry of Alkaloids with a Modified Atisane Skeleton .............. A. Hetisine (Delatine)............................................... B . Ignavine and Anhydroignavinol ................................... C. Hypognavine andHypognavino1 ................................... D . Kobusine ...................................................... E . Pseudokobusine ................................................. F Correlation of Kobusine and Pseudokobusine ......................... G Isohypognavine ................................................. H . Diterpene Alkaloids from Spiraeajaponica L . (Rosaceae)................ V I I . Synthesis of Diterpene Alkaloids ...................................... A Partial Synthesis of Atisine ....................................... B Total Syntheses of Atisine ........................................ C. Total Syntheses of Garryine and Veatchine .......................... D . Other Syntheses of Diterpene Alkaloids ............................. References .........................................................
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136 136 136 137 143 143 146 149 150 153 155 155 155 160 161 163 166 166 169 170 174 174 177 178 181 182 184 185 187 188 188 190 191 194 202
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L. H. KEITH
I. Introduction Several reviews covering various aspects of the chemistry of the CZOditerpene alkaloids have been published over the course of the past 10 years (1-7). The chemistry of this group was last reviewed in a detailed manner in 1960, with coverage of the literature through the early part of 1957 ( 6 ) .Since that time many important developments have taken place. These include rigorous evidence for the presence of a bicyclo[2.2.2]octane system in atisine, the correlation of ajaconine, atidine, and the Garrya alkaloids (veatchine and garryfoline) with atisine, the correlation of garryfoline with kaurene and stevane-B, the correlation of atisine with the resin acids, and the determination of the stereochemistry and absolute configuration of the diterpene alkaloids. New structural work has been reported for alkaloids containing a'modified atisane skeleton, such as hetisine, kobusine, and ignavine. Finally, several total syntheses of diterpene alkaloids have been reported as well as several novel synthetic approaches to this class of compounds. These developments will now be surveyed.
11. The Garrya Allraloids A. GARRYFOLINE-CUAUCHICHICINE REARRANGEMENT This rearrangement has been discussed in a previous review ( 6 ) . Recently the mechanism of the rearrangement has been investigated using the epimeric (-)-kau-16-en-15-01~as models (7a). The 15s-01
Garryfoline: R1= OH, R2 = H Veatchine: R1= H , I t 2 = OH
Cuauchichicine
2.
THE
C
Z
,
,
- ALKALOIDS ~ ~ ~
~
~
~
~ 137 ~ ~
rearranges rapidly in mineral acid a t room temperature to 16R-( -)kaur-15-one by a 15,16-hydride shift. The 16,-01, like veatchine, is stable under these conditions. Presumably, garryfoline and the other allylic alcohols such as nepelline, kobusine, and atisine rearrange to ketones by the same mechanism.
NAPELLINE, SONGORINE (NAPELLONINE OR SHIMOBURO BASEl), AND LUCICULINE
B.
After a series of careful investigations, Wiesner assigned structure I to napelline (R = OH) and napellonine (R = 0) (8). Subsequently, Kuzovkov showed the identity of napellonine and songorine and that selenium dehydrogenation of this compound gave a trisubstituted phenanthrene which was identified by synthesis as 1,lO-dirnethyl-’Iethylphenanthrene (11)( 9 ) .He pointed out that this result confirmed the presence of a substituent a t the C-4 position and the joining of the fivemembered ring a t C-13, but made improbable a bond between C-20 and C-14. Instead, bonding from C-20 to C-6 was suggested and structure IV
-
CH2 2 3
14 is I
CHs R z 11; R’ = H, R2= CH3 111; R1= CH3, R2 = H
proposed for songorine ( 9 , l O ) .Wiesner pointed out the incompatibility of this structure with formation of a carbinolamine ether from dihydronapelline by oxidation with silver oxide (7, 11). Thus it is clear that a
138
S. W. PELLETIER AND L. H. KEITH
C-20-C-6 bond in the salt form of the carbinolamine ether (V) is impossible. Subsequently, Wiesner et al. showed that formation of glyoxal by oxidation with lead tetraacetate is not a specific reaction for the N-CHzCHzOH group and that napelline contains instead an N-ethyl group ( 7 , l l ) .The carbinolamine ether was then formulated by Wiesner as VI and its salt as VII, with a C-20-C-6 bond. Other sites for the location of the ether oxygen are of course possible a t C-1 or C-3. In
*cH3
3 Hc & ; (0
6
i)H
f
6
V
7
OH
VI
OH
VII
considering an alternative and biogenetically more plausible structure for songorine Wiesner made the attractive hypothesis that rearrangement of the 10-methyl group into the less-hindered 9-position had occurred in the last step of Kuzovkov’s synthesis of 1,10-dimethyl-7ethylphenanthrene. The “natural ” phenanthrene should then he 1,9-dimethy1-7-ethylphenanthrene (111)and songorine would possess a C-20-C-7 bond instead of a C-20-C-6 bond (7, 11).This perceptive suggestion has been shown to be correct by Ochiai et al., who have demonstrated that the songorine hydrocarbon is in fact I11 by an unambiguous synthesis (12).It is interesting to note that 111,as well as a are also small amount of 1,3,9-trimethyl-7-isopropylphenanthrene, obtained by the dehydrogenation of isodesoxysongorine (XIV) hydrochloride (13). Recently Sugasawa has questioned the assignment of a hydroxyl a t C-2 in songorine and in fact has accumulated rather compelling evidence for location of a hydroxyl a t C-1 ( 1 4 ) .This evidence will now be outlined. Isosongorine (VIII) (1736, 1695 cm-I), available from the allylic rearrangement of songorine with palladium/charcoal, gave on Huang-
2.
139
THE CZO-DITERPENEA L K A I ~ O l D S
Minlon reduction dideoxyisosoiigorine (IX)and a small yield of the glycol X (3310-3600 cm-l). Oxidation of I X with an excess of chromium trioxidc/pyridinc gave a neutral product which was formulated as a kcto %lactam (XI) (1707, 1635 cm-1). The latter gave a compound containing 1.82 atoms of deuterium when equilibrated in the presence of NaOI), MeOD, and I)& and an amorphous monobenzylidine derivative (XII), as judged by ultraviolet absorption (300 mp, log E 4.73") (14) (XI1 in contrast to X I gave a negative Zimmerman reaction). These results indicate the presence of one methylene group adjacent to the kcto function and consequently limit the site of the hydroxyl in songorine to either C-1 or C-3.
IX
VIII
e
C
d
H
XI
3
X
H
e
0
c
H
3
XI1
lsodcoxysongorine (XIV), prepared by isomerization of deoxysongorine (XIII), on oxidation with chromium trioxidelpyridine gave the dikcto lactam XV (1733, 1713, 1633 cm-1). Treatment of the latter with methyl iodide and potassium tert-butoxide in tert-butanol afforded a gem-dimcthyl derivative (XVI) (1733, 1698, 163%cm-1) which, unlike XV, did not form a benzylidine derivative. Bromination of XV in glacial acetic acid gave a pair of epimeric ketones [XVIIa, 317 mp (log E 2.81); (XVIIb, 299 mp (log E 2.11)]. Both bromides showed absorption a t 1720 cm-1. Dehydrohalogenation of the mixed bromides with lithium chloride in boiling dimethylformamide gave a product (XVIII) with spectral properties characteristic of an a,P-unsaturated ketone in a sixmembered or larger ring (1738, 1668, 1638 cm-1). Evidence that bromination had occurred in ring A and not ring D was provided by oxidation of X l I I t o a neutral product (XIX) containing the conjugated enone in the five-membered D ring [1710, 1726, 1640 cm-1; 233 mp (log E 4.17); 295 mp (log E 2.06)].
* The (E
monobenzylidine derivative of cyclohexanone shows absorption a t 290 mtL 4.05) while the dibenzylidine derivative shows absorption a t 330 mp ( E 4.40).
140
S.
W. PELLETIER AND
L. H . KEITH
It appears that dehydrohalogenation of XVII in the presence of lithium chloride is accompanied by partial epimerization of the methyl group a t C-16, for reduction of the product XVIII over palladium gave a
mixture of products [XX ( 1 733,1635,17 13 cm-11, which was not identical with XV. However, treatment of both XV and XX in methanolic sodium hydroxide gave the same equilibrium mixture of epimers, XXI, as judged by the usual criteria. To determine whether the hydroxyl in ring A is situated at C-1 or C-3, the diketo lactam XV was treated with isoamyl nitrite to give the isonitroso derivative XXII and the latter was cleaved with benzene-
id
+
CH3
HON
@ N
0
XXIV
+
L
0
0
0 &cH3
M Z M
xxv
u)
XXVI
142
S. W. PELLETIER AND L. H. KEITH
sulfonyl chloride and alkali to the nitrile X X I I I [2260 ( C r N ) , 25002700 (COzH), 1730 (CO in 5-ring and COzH), 1612, 1630 \
LN-C-O---
I
---HO-C=O
\
and ,N-C=O]. Since the latter was stable up to its melting point (185") and did not decarboxylate when boiled in ethanolic hydrogen chloride, it is probable that the keto function in X X I I is a t C-1. Had it been a t C-3, as represented in XXIV and XXV, the product of the reactions would be the malonamide XXVI, a type of compound which is known in the ignavine series to decarboxylate easily either when heated t o 140"-170" or when boiled in acid. The above transformations led Sugasawa ( 1 4 )to assign the hydroxyl in ring A t o C-1 and therefore songorine may be represented by XXVII." Since reduction of songorine with LiAlH4 affords napelline (a),the latter is the ring C equatorial alcohol XXVIII." I n order t o be able t o form a carbinolamine ether by oxidation of the C-1 hydroxyl, models show that
R1
OH
XXVIII; R = H XXIX; R = A c
this hydroxyl must be equatorial and that ether formation is accompanied by an inversion of ring A from the chair to the boat form. Japanese workers report that the reduction of songorine with LiAlH4 gives luciculine, the alkamine of lucidusculine (XXIX) (15). Since Wiesner has reported that reduction of songorine with LiAlH4 affords napelline, it is almost certain that napelline and luciculine are identical, though a direct comparison has not been made. The structure and absolute configuration of lucidusculine hydroiodide has been determined by X-ray analysis (15, 16). This determination, assuming the identity of napelline and luciculine, thereby establishes the absolute configuration of songorine and napelline, as well.
* The ahsolute configuration given here for songorine and napelline anticipates the X-ray results on lucidusculinehydroiodide cited in the next paragraph.
2.
THE
CZO-DITERPENE ALKALOIDS
143
111. The Atisine Alkaloids A. ATISINEAND ISOATISINE At the time of the 1960 review ( 6 )the structures for atisine and isoatisine were considered to be X X X and XXXI, respectively. However, aside from the suggestive nature of certain dehydrogenation data, all the chemical evidence for atisine could be accommodated as well by structure XXXII, in which the positions of the allylic hydroxyl and exocyclic methylene groups are reversed.
xxx
XXXII
Definitive evidence on this point has been provided by Dvornik and Edwards ( 1 7 ) , who have shown that hydration of the Czo-azomethine alcohol XXX.111 derived from atisine (18, 19) gave the diol XXXIV, which on reduction, acetylation, selective hydrolysis, and oxidation gave a 7,8-secomethylketo acid (XXXV). Treatment of the latter with trifluoroacetyl peroxide followed by hydrolysis and dichromate oxidation gave the bis norketo acid XXXVI (1712, 1602 cm-1). Dibromination of XXXVI followed by dehydrohalogenation gave a crystalline phenol XXXVII (828, 1586, 1638 cm-1, A,,, 282 mp shifting t o 300 mp in alkali), and a keto y-lactone (1796, 1734, 1639 cm-1). Formation of the latter, involving displacement of bromine cr to the keto group by carboxylate anion demonstrates a l,.i-relationship of the ketone and carboxyl groups in XXXVI. Thus these results, when taken with Jacobs dehydrogenation evidence for substitution a t C-12 (20, 21), show clearly that a bicyclo[2.2.2]octane system is present in atisine and that the terminal
144
S. W. PELLETIER AND L. H. KEITH
methylene group is located a t C-16 (or C-13)1and the secondary hydroxyl a t C-15 (or C-14)*, respectively ( 1 7 ) . Additional evidence on this point is provided by the following sequence of reactions (22, 23). Isomerization of isoatisine (XXXI) with ethanolic hydrochloric acid gave a mixture of epimeric methyl ketones (XXXVIII, 1712 em-1). That skeletal rearrangement had not occurred during the isomerization was shown by borohydride reduction of XXXVIII to give
6;
XXXIII
COzH
xxxv
XXXIV
Ac&13
Ac
XXXVI
XXXVII
a mixture from which the known a-tetrahydroatisine (XXXIX) ( 2 3 , 2 4 ) was isolated. Removal of the keto group to give XL was accomplished by Barton’s procedure for sterically hindered ketones. Dehydrogenation of XL with selenium gave the epimeric azomethines XLI and also I-methyl6-isopropylphenanthrene (XLII) (22, 23). Had the methylene group in isoatisine been located a t C-14 or C-15 one would have expected t o obtain either 196-dimethylphenanthreneor 1-methyl-6-n-propylphenanthrene. The formation of the isopropyl derivative is again clear evidence for assigning the methylene group to C-16 (or C-13).* Aside from stereochemical features, which are discussed in Section 111, B, atisine is thus shown to have structure XXX. Another product isolated from the dehydrogenation mixture from XL is the lactam XLIII (23) [v,, (Nujol) 3215, 1650, 1631 em-1; 78.98, 3H doublet, J = 7 cps (-CHCH3), 73.70, 1H broad (-NHCO-), 78.88, 3H singlet (C-CH3)I.
*
Since the bicyclooctane system is symmetrical, the allylic alcohol system could be located on either the cis or trans branch.
2.
THE
C
Z
~ALKALOIDS ~
~
145 ~
The Sarett oxidation of atisine and isoatisine affords the conjugated enones atisinone (XLIV) and isoatisinone (XLV), respectively (23). Refluxing XLIV in methanol or ethanol effects a smooth isomerization t o XLV, a reaction which parallels the facile atisine + isoatisine isomerization (see Section V, A). The Sarett oxidation of atisine and isoatisine also gave rise to neutral by-products of interest (23). From atisine was obtained a compound assigned structure XVLI on the basis of spectroscopic evidence [vmax (Nujol) 3289, 3195, 3077, 1704, 1629, 1658 em-1; h sh (EtOH) 228 mp (c 7800) ; ~ 9 . 0 5 , 3 H singlet (C-CH3), 74.12 and 4.84, 2H doublets ( J = 2 cps, C = C H z ) , 73.95, 1H multiplet (-NHCO-)I and by
~
146
S . W. PELLETIER AND L. H. KEITH
Atisine
Isoatisine XXXII
xxx
I hydride reduction t o the known compound XLVII. From isoatisine under similar conditions was obtained lactam XLVIII [3390, 3086, 901, 1616, 1701 cm-1; h sh (EtOH) 227 mp (c 8500); 78.83, 3 H singlet, 73.98 and 4.70,2H pair of doublets (J = 2 cps)] which could also be prepared by oxidation of oxoisoatisine (XLIX)with the Sarett reagent (23).
Atisine
__f
xxx
0
XLVII
Po Ho6
HO I
Isoetisine XXXII
XLVI
-
dCH2
+
0
XLVIII
B. STEREOCHEMISTRY OF ATISINE Conformational arguments relative t o the structure of ajaconine have shown that A/B-trans stereochemistry is present in atisine (25).Differentiation between isomers L and L I in which a trans-anti backbone is present, involves the choice of locating the allylic alcohol group on the trans (with respect to nitrogen) (isomer L) or cis branch (isomer LI) of the
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 147 ~
~
bicyclo[2.2.2]octane system. Reduction of ketones LIV and LVI with sodium borohydride gave in each case a pair of epimeric alcohols (LVa,b and LVIIa,b) each of which readily formed an 0-acetate. This relatively unhindered character of the hydroxyl group supports location of the H
L; A/B-Trans-anti
I;" LII ; ABC-Trans-syn-trans
H
LI; A/B-Trans-anti
I ; " LIII; ABC-Trans-syn-trans
allylic alcohol group on the trans bridge (isomer L) of the bicyclooctane system, for if the group were on the cis bridge (isomer LI) only one epimer would be expected on reduction due to the severe crowding a t C-14. Moreover, this view was confirmed by a study of the pK,'s of the epimeric N-ethyl compounds (LVIIIa,b) and their acetates. Clearly if the allylic alcohol system were on the cis bridge (LI) there would be more interaction between a hydroxyl (or acetoxyl) and the nitrogen atom in one epimer than in the other. I n the trans isomer (L)the interaction should be small for either epimer. The pK,' values for the epimeric alcohols (LVIIIa, b) are 9.25 and 9.13 and for the corresponding acetates 8.30 and 8.1 1. The fact that the interaction with the nitrogen is small and that the magnitude of the drop in pK,' in going from the hydroxyl derivative t o the acetate is the same for each epimer supports location of the allylic alcohol system on an unhindered bridge such as C-15-(2-16 in L but not on the C-13-C-14 bridge as in LI (17,22,23).
~
148
S. W. PELLETIER AND L. H. KEITH 13
LIV
LVe, b
OH
__f
R - --N
H
1 ' H LVI
LVIIa, b ; R = AC LVIIIe, b; R = Et
The choice between isomers L I I and L I I I of the trans-syn-perhydrophenanthrene system was made by noting that the condition of relatively unhindered hydroxyl in compounds LV, LVII, and LVIII is satisfied only in isomer L I I I but not LII. Thus the above arguments limit the stereochemistry of atisine to either L or LIII. Since anti-coupling of rings A and C is demanded by the known chemistry of ajaconine (26)the complete relative stereochemistry of atisine is expressed by structure L (3, 25). The assignment of configuration of the secondary hydroxyl in atisine is made difficult by the high degree of symmetry of the bicyclo[2.2.2]octane system. A tentative assignment of the /3-configuration as in LIX has been made on the basis of the difference in the absorption of the epimeric alcohols (LVIIa, b) on alumina (3,23).The absolute configuration shown in formulas L-LIX anticipates the results which will be discussed in Section IV.
18
--H 16
CHe
2.
THE
Czo-DITERPENE ALKALOIDS
149
C. CHEMISTRY OF ATIDINE Atidine (27, 28), C22H33N03, another constituent of A . heterophyllum Wall., is a tertiary base possessing two hydroxyl groups (3544,3454cm-I), a ketone function (oxime) in a six-membered or larger ring (1695 cm-I), an exocyclic methylene group (3086, 1658,900 cm-I), a C-methyl group (1376 cm-I), and an N-CH~CHZOH group. The presence of an exocyclic methylene and a C-methyl group indicated by infrared absorption bands in atidine and its derivatives were confirmed by NMR data. The hydroxyl groups in atidine were shown to be of primary or secondary character by formation of an amorphous diacetate [vmax (film) 1742, 1235 cm-11 which showed the absence of hydroxyl absorption in the infrared. Reduction of atidine with sodium borohydride afforded an amorphous (‘dihydroatidine ” whose IR spectrum showed the absence of carbonyl absorption. Reduction with Adams catalyst gave a tetrahydro derivative which on oxidation with lead tetraacetate in acetic acid furnished a mixture from which glyoxal was isolated as the bis-p-nitrophenylhydrazone. Initially this fact was accepted as evidence for the presence of a @-hydroxyethylaminesystem in the tetrahydro derivative. Subsequent work, however, has shown that this reaction has no diagnostic value for the presence of the /3-hydroxyethylamine group since several alkaloids bearing an N-ethyl group also furnish glyoxal when oxidized with lead tetraacetate (11).The NMR spectrum ofatidine, however, does confirm the presence of the /3-hydroxylethyl side chain: 76.42, 6.32, 6.22 (2H triplet, J = 6 cps). These results suggested that atidine is a pentacyclic tertiary base of the dihydroatisine type and contains a carbonyl group in a six-membered ring. Atidine was proved to be a ketodihydroatisine (LX) by HuangMinlon reduction to dihydroatisine (LXI). Subsequent work has shown that “dihydroatidine ” is a mixture which after acetylation is separable by chromatography (27).One of the components is a triacetate which is identical with the triacetate of the borohydride reduction product of ajaconine, viz., dihydroajaconine triacetate (LXIIIa) (26,29).Moreover, saponification of the triacetate furnished a crystalline hydrate which is identical with dihydroajaconine hydrate (LXIIIb) (28).This correlation demonstrated that the site of the exocyclic methylene and the site and stereochemistry of the 15-hydroxylare identical in atidine and ajaconine. It also showed that the carbonyl oxygen of atidine and the then unlocated hydroxyl of ajaconine are on the same carbon. Since this oxygen function has subsequently been located a t C-7 in ajaconine (26),the corresponding keto function in atidine is also located at C-7. The complete structure of atidine is thus represented by LX (28). The absolute stereochemistry
150
S . W. PELLETIER A N D L. H. KEITH
shown for LX follows from the absolute stereochemistry assigned to atisine (Section IV).
LX
LXII
LXI
\
LXIIIa: R = A c LXIIIb; R = H
D. CHEMISTRYOF AJACONINE* Ajaconine, C 2 2 H 3 3 N 0 3 , an alkaloid of Delphinium ajacis L. and D. consolida L., is of especial interest since it is the first reported example of an atisine derivative occurring in a Delphinium species (30).Ajaconine was shown to have the same carbocyclic skeleton as atisine by conversion to the oxygen-freeazomethine base (LXII),obtained earlier from atisine (29).Thus thediacetoxyazomethine (LXIVa)from ajaconine was oxidized with osmium tetroxide/periodate to the ketol diacetate (LXIVb). Wolff-Kishner reduction of LXIVb gave a mixture of the azomethine diol LXV and the monohydroxy compound LXVI. Hydrogenation of the mixture over palladium on charcoal converted LXVI to LXVII. When the mixture of LXV and LXVII from the hydrogenation was oxidized with chromic acid and then subjected to Wolff-Kishner reduction, substantially pure LXVII resulted. Oxidation of LXVII with sodium dichromate in acetic acid gave the ketone LXVIII which was converted by reduction to LXII, identical with the corresponding degradation product from atisine. That the allylic alcohol system of ajaconine has the same position and stereochemistry as in atisine was shown by reduction of atidine (LX) (previously correlated with dihydroatisine) to
* Evidence for the absolute stereochemistry shown for these structures is discussed in Section IV.
2.
THE
C
2
0
- ALKALOIDS ~ ~ ~
~
~
151 ~ ~
a mixture of epimers, one of which is dihydroajaconine (LXXIIlb) (27, 28). The work of Dvornik and Edwards (26)has shown that ajaconine contains a carbinolamine-ether system involving an oxygen atom a t C-7. Thus the alkaloid forms immonium salts (v,,, 1683 cm-1) and is reduced
LXIVe
LXIVb
LXV LXII
T
LXVI
LXIX; R = or-OH LXX; R = O
LXVII
LXXI
LXVIII
LXXII
by borohydride to a dihydro base without loss of oxygen. The position and configuration of the hydroxyl resulting on cleavage of the ether ring was established as follows : The azomethine alcohol LXVII was reduced with sodium borohydride to the secondary amino alcohol which was acetylated and selectively hydrolyzed to LXIX. Oxidation of the latter gave the ketone LXX which could be cleanly brominated t o the monobromo derivative LXXI. Dehydrobromination of L X X I gave the
~
~
152
S. W. PELLETIER AND L. H. KEITH
a,p-unsaturated ketone LXXII [v,, 1644 em-1, A,, 250 mp ( e 9300) and 329 mp ( e 96)l. This sequence locates the hydroxyl of LXIX and hence the ether oxygen of ajaconine a t C-7. The complete structure of ajaconine is represented by LXXIII. The N-methyl carbinolamine (LXXIV) derived from ajaconine was transformed by methanolic alkali into a mixture of the is0 derivative (LXXV) and a hydroxy lactam (LXXVI) (vmax 3380, 1054, 1620 em-1).
__f
LXXIII
H
LXXIV
LXXV
CHs--
LXXVI; R=-OH LXXVII; R = ---OH
LXXVIII
LXXXI
LXXIX
LXXX
The latter results from an unusual intramolecular Cannizzaro-type reaction involving a transannular hydride transfer from C-20 to C-7. Oxidation of LXXVI followed by reduction gave the epimeric hydroxyl 1082 em-1) in the original conlactam LXXVII with the hydroxyl (v,,, figuration of ajaconine. The hydroxyl in LXXVI is thus trans to the N-bridge and in LXXVII is cis thereto. Further evidence on this point is provided by the behavior of the methiodide (LXXVIII) of the azomethine alcohol (LXVII). The product liberated from this salt by hot, methanolic alkali is a hydroxyl-free base (LXXIX, pK,' 10) and hence
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 153 ~
must be an internal cyclization product derived from the 7-hydroxyl and (3-19 or C-20. Oxidation with potassium permanganate converted this base to a lactam (vmax 1655 cm-1) still containing the carbinolamineether bridge. Since in no case has it been possible to oxidize C-20 to a carbonyl with external reagents, the lactam function must be at C-19 as in LXXX and therefore the ether oxygen links C-7 and C-20. It is to be noted that treatment of LXXIX with H I will reconvert the carbinolamine ether to the ternary iminium iodide LXXVIII. This conversion is reminiscent of the oxazolidine --f ternary imminium salt transformation observed in the case of atisine, veatchine, garryfoline, etc. (seeSection V). An interesting by-product of the dehydrobromination of LXXI with LiCl in DMF has been assigned structure LXXXI (26).The compound shows no evidence of conjugation in the ultraviolet and has ,v 1696 cm-1. Reduction of the a-amino-ketone system with zinc and acetic anhydride gave the N-acetyl ketone LXX. The absolute configuration indicated for ajaconine (LXXIII) and its derivatives follows from its correlation with atisine and atidine (26-29).
E. DENUDATINE Denudatine, C21H33N02, has been reported in Delphinium denudatum Wall (31-33).* It was reported to contain two hydroxyls, an N-methyl, a C-methyl, and an exocyclic methylene group (1650,902cm-1). Selenium dehydrogenation of denudatine gave 1-methyl-6-ethylphenanthrene and l-methyl-6-ethyl-3-azaphenanthrene, characteristic products of the dehydrogenation of atisine. The provisional structure (LXXXII), which was assigned to denudatine on the basis of limited structural work, is now known to be incorrect (34). Oxidation of denudatine with CrOs/pyridine is reported to give two products, a base formulated as LXXXIII (no -OH or C=O absorption in the infrared) and a keto lactam (LXXXIV) (v,, 2941, 1712, 1666, 1631,905 cm-1) (31-33).No evidence of formation of a conjugated enone on oxidation was noted. Oxidation of denudatine with silver oxide gave a base which the authors formulated as a carbinolamine ether (LXXXV). Treatment of denudatine with HBr in methanol gave an isomeric ketone formulated as LXXXVI (v,, 2941,1709,1653,893 cm-1). Later spectroscopic evidence shows these structures are incorrect (34),but as yet no new work has been reported on this alkaloid.
*
There is considerable doubt about the identification of the plant since it was obtained in the Amritsar crude drug market under the name “Nirbasi” or “Judwar.” The crude material may consist of a number of related species.
~
~
154
N
x"
0
S. W . PELLETIER AND L . H . KEITH
+
U H
3
x
51
q$ "T
8 U
2 x
3
U
R x 3
2.
THE
CZO-DITERPENE ALKALOIDS
155
IV. Correlations and Absolute Stereochemistry of Atisine and Garrya Alkaloids A. CORRELATION OF ATISINEAND Garrya ALKALOIDS The atisine and Garrya (35,36)alkaloids have been interrelated by converting both atisine (XXX) and veatchine, by a parallel sequence of degradations, to the same N-acetyl ester (XCV) (35, 36). The respective azomethine acetates (LXXXVII, LXXXVIII) derived from atisine (12,16-bond)and veatchine (13,lS-bond)were converted to the N-acetyl derivatives (LXXXIX, XC) by reduction, acetylation, and saponification. Oxidation of LXXXIX and CX with permanganatelperiodate under controlled conditions gave the respective carboxylic acids (XCIa, b). Saponification of the dimethyl esters XCIIa, b gave XCIIIa, b, which were transformed to the corresponding monobromides XCIVa, b by the Hunsdiecker method. Reductive debromination of XCIVa and XCIVb with zinc dust in acetic acid gave the same acetyl ester, XCV. Compound XCV was also obtained from atisine by desulfurization of the thioketal (XCVII) derived from XCVI. This correlation demonstrates that the Garrya alkaloids have the same stereochemistry of ring fusions as in atisine.
B. REACTIONS OF THE IMINE GROUP;REMOVAL OF THE NITROGEN FROM THE DITERPENE ALKALOIDS Of significance relative t o the problem of degrading the Czo-diterpene alkaloids to diterpenes of established stereochemistry is the difficulty in removing the nitrogen atom. Since both positions p to the nitrogen are quaternary, Hofmann-type degradations are ineffective. What might appear to be a particularly susceptible group for an attack on the nitrogen is the azomethine linkage. This masked aldehyde manifests a remarkable stability to both acids and bases. Thus it survives boiling with 10% hydrochloric acid ( 3 ) and also conditions of the Wolff-Kishner reaction (19,29).The remarkable stability of this function is owing to the peculiar geometry of the system. Steric compression between the nitrogen and C-20 maintains the linkage in a closed position, thus effectively prohibiting reactions which would normally occur via the aldehyde. Recently success in removing the nitrogen from XCVIII has been achieved through a mild reaction with nitrous acid in aqueous dioxane containing sodium acetate (37, 38). The major product is the hemiacetal XCIX ( Y , , , , ~3350, 1050 cm-I), which was oxidized with bromine water to
17
COzR
OH
LXXXVII; 12-16 bond LXXXVIII : 13-1 6 bond
R
=(a
XCVI; R = O XCVII; R
LXXXIX; 12-16 XC; 13-16
bond bond
n xcv
XCIa,b; R = R ’ = H XCIIa, b ; R = R’ = CH3 XCIIIa, b; R = H, R’ = CH3
1
XCIVa, b
.Br
2.
THE
CZO-DITERPENE ALKALOIDS
157
a a-lactone (C) (1725 cm-1). Wolff-Kishner reduction converted the hemiacetal t o the primary alcohol (CI). This could be oxidized with sodium dichromate to an aldehyde (CII) (vmax 1696 em-1) and the latter 1690 em-I), which had a very converted to a carboxylic acid (CIII) (v,,,, low acidity: pK,' in 70% ethanol, 9.6; pK,' in 80% methyl Cellosolve, 9.2. The structure of the carboxylic acid was confirmed by comparison of
+
-
,
HO" "H XCVIII
XCIX
O
C
+ CI
CII
CIII
CH~OH
CIV
cv
its NMR spectrum with those of model diterpene carboxylic acids. It is interesting t o note that this acid could not be extracted from ether by dilute sodium hydroxide solution. All the unusual properties of this acid must be associated with shielding of the carboxyl by the angular methyl group and one branch of the bicyclooctane system. The very low acidity of CIII may be attributed to steric hindrance of solvation of the anion derived from it. Reduction of the hemiacetal (XCIX)with LiAlH4 gave a diol (CIV), which on oxidation with dichromate afforded two isomeric lactones (C and CV). Reduction of lactone C with limited amounts of
S. W. PELLETIER AND L. H. KEITH
158
LiAIH4 regenerated the corresponding hemiacetal (XCIX) in good yield but a similar reduction of lactone CV gave a mixture of unchanged lactone, the diol CIV, and the hemiacetal XCIX.
XCVIII
CVI
CVII
cx
CIX
CVIII
CVII
,H
Hot,
Q/] ?
H
4
$f] ?
CXI
d
H
(-94
+
Q/]
11,
I*
H
,*7\I’
H
HO’ H
cx
CXI
CXII
XCIX
Since the structures of these products are now secure, the question of the mechanism of the deamination reaction is of interest. The expected pathway (XCVIII --f --f CX) via the N-nitrosocarbinol arnine (CVI) would lead to a hemiacetal (CX) derived from a C-20 aldehyde. Since no
2.
THE C20-DITERPENE ALKALOIDS
159
appreciable amount of aldehyde acetate could be isolated from the reaction mixture it is clear that the aldehyde oxygen participates in the deamination to provide a cyclic oxonium ion (CXI) as the primary product. Several arguments led the Canadian workers to believe that dismutation occurs between the hemiacetals, with CX going to XCIX via oxonium ions CXI and CXII (38). A parallel series of deamination reactions has been carried out on the Garrya alkaloid series and leads to a hemiacetal analogous to XCIX (see Section IV, C).
0 XCVIII; R' = R2 = Hz CXIV; R1= CH2, R2 = OH, H CXVII; R1= CHz, R2 = OAC,H
CXVIII
CXIII; R' CXV; R' CXVI; R'
= R2 = Hz = CH2, R2 = OAc, H = CHz, R2 = OH, H
CXIX; R = A c CXX; R = H
Another unusual reaction of the imine group was encountered during attempts to open the hetero ring of compound XCVIII. Prolonged refluxing of XCVIII with acetic anhydride/acetic acid mixture gave a neutral product to which an aziridine structure (CXIII) has been assigned on the basis of the analysis and NMR spectrum (39). An analogous compound (CXV)has been prepared in the atisine series by refluxing imine CXIV with acetic anhydride for 30 hours (28).The IR spectrum of CXV showed well-defined bands for OAc (1730 cm-I), amide carbonyl (1612 and 1637 cm-I), and exocyclic methylene (907 cm-1) groups. Mild
160
S. W. PELLETIER AND L. H. KEITH
saponification of CXV afforded the aziridine alcohol (CXVI)with appropriate bands in the infrared. Treatment of CXVI with acetic anhydride/ pyridine regenerated CXV. That the allylic alcohol grouping in CXIV did not participate in the reaction leading to CXV was demonstrated by the fact that the imino acetate CXVII also afforded CXV on prolonged re fluxing with acetic anhydride. The azomethine (CXIV) derived from atisine undergoes a reaction of further interest when refluxed with zinc dust in acetic anhydride (28). The major product is the 0,N-diacetate (CXVIII) together with 5-10% of a bimolecular product to which structure CXIX is assigned. Saponification of CXIX affords the corresponding alcohol (CXX). The linkage between the halves of CXIX is believed to be a t C-19, because of the severely hindered environment about C-20.
WITH KAURENE AND STEVANE-B C. CORRELATIONOF GARRYFOLINE
The acetate iminium chloride (CXXI) derived from garryfoline was degraded by the internal Hofmann procedure (19)to the imine CXXII. Elimination of the nitrogen was effected in nearly quantitative yield by treatment of the imine CXXII with nitrous acid. The resulting hemiacetal (CXXIII)was subjected to Wolff-Kishnerreduction, which accomplished simultaneous reduction of the 15-ketoand masked 19-aldehydofunctions. Oxidation of the resulting primary alcohol (CXXIV) with the chromium trioxide/pyridine reagent gave the aldehyde CXXV which was transformed by very vigorous Wolff-Kishner conditions t o the hydrocarbon CXXVI. This compound was not identical with the two known 16epimeric dihydrophyllocladenes (CXXVIII), thus eliminating for the known to exist in diterpene alkaloids the 5a,9a,lOP-~tereochemistry phyllocladene (CXXIX). Hydrocarbon CXXVI was identical with ( - )-“P”-dihydrokaurene, the minor hydrogenation product of ( - )kaurene (CXXX) and with “ stevane-B,” a degradation product of steviol (CXXXI) (40-42). Evidence for the structure (CXXIII) of the hemiacetal is based on the extremely hindered nature of the derived aldehyde (CXXV) and carboxylic acid (CXXVII).Thus, the aldehyde exhibited a negative Cotton effect in methanol, which remained unchanged upon the addition of hydrochloric acid, indicating great resistance toward acetal formation. Attempts to prepare carbonyl derivatives of this aldehyde were unsuccessful. The acid CXXVII was prepared by oxidation of alcohol CXXIV with chromium trioxide in acetic acid. Comparison of the apparent dissociation constant of this acid (pK& 9.45) with that for
2.
THE
C20-DITERPENE ALKALOIDS
CXXI; R = CHzCHzOAo CXXII; no R subst.
CH3 CXXVIII; R = {.,-.= CXXIX; R=CHz
161
OH CXXIII
CXXIV; R = CHzOH cxxv; R = CHO CXXVI; R = CH3 CXXVII; R = COzH
deoxypodocarpic acid (pKgcs 8.45) and dehydroabietic acid (pK& 7.92) eliminates C-4 as the site of the carboxyl group and supports the (2-10 location. (MCS refers to Methyl Cellosolve.) This carboxylic acid and aldehyde are analogous to the ones prepared from an atisine derivative (37, 38) and have comparable properties. (See Section IV, B).
D. CORRELATION OF ATISINEWITH
THE
RESINACIDS
The aldehyde CXXXII, prepared by degradation of atisine, has been converted by Wolff-Kishner reduction to the hydrocarbon CXXXIII, which was identical in melting point, I R spectrum, and mass spectrum with a hydrocarbon (CXXXIV)prepared by a long degradative sequence from abieta-6,8-diene (CXXXV). The hydrocarbon from atisine
162
S. W. PELLETIER AND L. H. KEITH
(CXXXIII) showed a plain negative rotatory dispersion curve, enantiomorphic with that obtained from hydrocarbon CXXXIV. This work represents the first correlation of the tetracarbocyclic ring system of atisine with a resin acid and confirms the mirror-image relationship at C-5, C-9, and C-10 (43). Hydrocarbon CXXXIV was prepared from abieta-6,s-diene (CXXXV) by the following route. Reaction with maleic anhydride gave the adduct CXXXVI, whose dimethyl ester was ozonized to give CXXXVII in 35% yield. Oxidation of the latter with HzOz-BFs gave the keto diester CXXXVIII in 50% yield. The diacid of CXXXVIII was subjected to oxidative bis decarboxylation with lead tetraacetate in pyridine to afford the keto olefin CXXXIX. Hydrogenation of CXXXIX over palladium/
CXXXII ; R = CHO CXXXIII; R = CH:,
CXXXVIII; R = COzCHs CXXXIX; R = H, A21(22) CXL; R = H
CXXXIV
cxxxvII
cxxxv
CXXXVI
'C02CHs
k02H CXLI
CXLII
CXLIII
2. THE CZO-DITERPENE ALKALOIDS
163
charcoal gave the saturated ketone CXL. Wolff-Kishner reduction of the latter under forcing conditions gave the hydrocarbon CXXXIV. Hydrocarbon CXXXIV has also been synthesized by a similar sequence of reactions from abietic acid via maleopimaric acid (CXLI) by Zalkow and Girotra ( 4 4 , 4 5 ) .These authors have also converted CXLII, an intermediate obtained en route to hydrocarbon CXXXIV, to CXLIII, which possesses the complete carbocyclic skeleton of atisine in its correct relative configuration. Bell and Ireland had reported previously the synthesis of racemic CXLIII (46).
E. ABSOLUTE CONFIGURATION OF THE ATISINEAND Garrya ALKALOIDS The rotation of phenol CLV led Dvornik and Edwards to first suggest “that if the structure of atisine is based on an unrearranged diterpenoid skeleton, its A/B ring system bears a mirror image relation to that of the common diterpenes” ( 1 7 ) . Furthermore, the rotational arguments based on ajaconine chemistry reinforced this perceptive suggestion (17). The absolute configuration of the atisine and Garrya alkaloids has been derived by an elegant series of reactions reported by Vorbrueggen and Djerassi (40).Garryfoline was reduced with LiAIH4 and acetylated to give F-dihydrogarryfoline diacetate (CXLIV). Lemieux-Johnson oxidation of CXLIV led in excellent yield to the ketol acetate CXLV, which was reduced with calcium in liquid ammonia to 17-nor-16-0x015-deoxy-F-dihydrogarryfoline acetate (CXLVI). Similarly, veatchine was converted to the diacetate chloride CXLVII ( 3 5 ) , thence by an internal Hofmann elimination to the imine acetate CXLVIII, and then by LiAlH4 reduction and acetylation to the acetoxy amide CXLIX. Lemieux-Johnson oxidation of CXLIX gave the ketol acetate amide CL, which was reduced with calcium in liquid ammonia to the 17-nor-16ketone CLI. The 17-nor-16-ketones CXLVI and CLI exhibited a positive Cotton effect of very similar amplitude to that observed for the 17-nor-16-ketone CLII from phyllocladene (CLIII). Since the absolute configuration of phyllocladene has been established and since the configuration of C-9 in the alkaloid derivatives should not effect the sign of the Cotton effect, the absolute configuration a t C-8 and (2-13 of the Garrya alkaloids (and hence of C-8 and (3-12 of atisine) is established. These results, together with the correlation of garryfoline with ( - )-“/3”-dihydrokaurene (CXXVI) which has already been described in Section IV, C lead to the complete absolute configuration shown for garryfoline and veatchine. I n
Garryfoline R
=
yOH
CXLIV
CXLV; R =
H
~ O A C if
CXLVI; R = H z
Veatchine R = rH OH
H
H
OAC
6Ac
CXLVII; R = CHzCHzOAc CXLVIII; no R subst.
CXLIX
CL; R = r-H 6H CLI; R = H z
CLII; R = O CLIII; R = CH2
?
s
2.
THE
C
2
0
- ALKALOIDS ~ ~
~
~
~
165 ~
view of the correlation of atisine and veatchine (35,36), this absolute configurational assignment also applies to atisine (LIX) and its chemical relatives such as atidine (LX) and ajaconine (LXXIII). ApSimon and Edwards (47) have provided independent evidence for. the absolute configuration of atisine by a synthesis from podocarpic acid (CLIV) of the antipode of the phenol (CLV) (17) originally obtained by degradation of atisine. The synthesis involved photolysis of the azide (CLVI)derived from the methyl ether of podocarpic acid. Irradiation of CLVI in hexane using a Hanovia UV lamp gave a 50% yield of the isocyanate CLVII, a 5% yield of a y-lactam (structure not assigned), and a 20% yield of the &lactam CLVIII (vmax 3300, 1655, 1600, 1560 cm-1). Hydrolysis of CLVIII in refluxing 48% hydrobromic acid gave the phenolic lactam CLIX which was reduced with LiAlH4 to the secondary aminophenol CLX. This compound was acetylated and partially hydrolyzed to the N-acetyl phenol (CLXI), which had an IR spectrum identical with the N-acetyl phenol (CLV)from atisine and a rotation of + 112O, compared with - 105"for the atisine-derived phenol.
HOzC
R
CLV
CLIV
CLVI; R=C-N3 CLVII; R = N=C=O
CLX; R CLXI; R
=H = Ac
CLVIII; R = CHa CLIX; R = H
With the absolute configuration of the atisine and Garrya alkaloids established, it is interesting to note that these compounds join the ranks of terpenes with antipodal stereochemistry of the A/B ring fusion as compared with that of the steroids, e.g., andrographolide, atisirene, cafestol,
~
~
166
S. W. PELLETIER AND L. H. KEITH
copolic acid, daniellic acid, darutigenol, eperuic acid, farnesiferol-A, hautriwaic acid, iresin, ( - )-kaurene, polyalthic acid, steviol, and trachylobane.
V. The Ternary Iminium Salts of the Atisine and Garrya Alkaloids
A. NORMAL + Is0 BASEISOMERIZATION Early in their studies on the structure of atisine, Jacobs and Craig observed that brief treatment with warm alkali was sufficient to isomerize atisine t o another base named isoatisine (48).Subsequent work has shown that the related alkaloids veatchine (as),garryfoline (50),and
Atisine
Veatchine Gerryfoline
[@ ',CH3 I
'
#,I
Isoatisine
R1= OH, R2 = H R1= H, R2 = OH
H
l ' H
Garryine Isogarryfoline
-
R1= OH, R2 = H R1 = H, R2 = OH
& -+'
,,__ .*,
2
a:
H
H
'0' Cuauchiohicine
Isocuauchichicine
cuauchichicine (50) are similarly isomerized t o garryine (49),isogarryfoline (50),and isocuauchichicine (50),respectively. The isomerization is a very facile one and proceeds a t room temperature in alcohol without external base, the alkaloid itself promoting the change (50).For example,
2.
THE
CSO-DITERPENE ALKALOIDS
167
in the case of atisine, monitoring the isomerization by the change in optical rotation shows that the reaction is essentially complete after 80 minutes refluxing in methanol or after 10 days a t room temperature without external base ( 2 ) .Another feature worthy of note is that the members of these pairs of isomers manifest a remarkable difference in basic strengths. Thus atisine in 50% methanol shows a pK,’ of 12.8 while isoatisine gives a value of 10.35 (51).Similar differences prevail for the veatchine-garryine, garryfoline-isogarryfoline,and cuauchichicine-isocuauchichicine pairs (49, 50). The greater basicity of the “normal ” compounds compared with the “iso” series finds explanation in terms of the equilibria presented below. The salts of these alkaloids show bands in the infrared characteristic of the \ @
/
N=C
/
\
group and therefore exist in the ternary iminium form (51, 52). I n hydroxylic solvents atisine and the other normal type bases (CLXII) exist almost completely as the ternary iminium hydroxide (CLXIII)since parallel titrations show that in 50% methanol atisine is about as strong a base as sodium hydroxide. The question arises as t o why the is0 bases are not as strong bases as the normal bases since they might also be expected to exist in the ternary iminium form. It is obvious that the difference in position of the double bond in the ternary iminium hydroxide forms of the normal (CLXIII)and the is0 bases (CLXVI),by itself, cannot account for the large difference in the basic strengths. Rather one must assume that in the case of the normal bases a higher proportion of the ternary iminium form CLXIII is present in an equilibrium between the oxazolidine (CLXII), ternary iminium (CLXIII), and pseudo base (CLXIV) forms, whereas in the is0 bases a high proportion of the oxazolidine (CLXV)or pseudo base forms (CLXVII)is present. The fundamental reason for the preponderance of the ternary iminium hydroxide in the normal base equilibrium has been recognized as the steric interference with substituents on the tetragonal C-BOin the oxazolidine form ( 3 , 7 , 1 7 , 5 0 , 5 1 , 5 3 ) .Thus serious repulsive interactions of the hydrogens on (2-20, C-13, and C-14 occur when C-20 is tetrahedral. However, the strain is relieved in the ternary iminium form when C-20 is trigonal. Consequently, in solution atisine and the other normal bases will exist almost completely as ternary iminium hydroxides and show high pK,’s, whereas the is0 type bases, in which the steric factor does not operate to the same extent, will exist mostly in the oxazolidine form and show lower pK,’s The same explanation accounts for the isomerization of the normal to the is0 bases. In solution the isomerization proceeds through the ternary
168
0 . ' '
S. W. PELLETIER AND L. H. KEITH
TI
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 169 ~
iminium forms CLXIII and CLXVI by prototropy. Since steric factors are responsible for the is0 basee having a lower free energy than the normal bases (the reasons for this will be discussed subsequently), the equilibrium is shifted toward the sterically more favored is0 forms.
B. ISOMERIZATION OF TRICYCLIC OXAZOLIDINE MODELS The interpretation, outlined above, involving steric factors as the driving force for the isomerizations described, is given support by Leonard's study of the isomerization of a tricyclic oxazolidine model of the AEF ring system of the diterpene alkaloids (54).The mechanism (53) which has been postulated for the isomerization involves abstraction of a proton from the methylene carbon a t C-19 with concomitant addition of a proton a t trigonal carbon C-20. The catalyzing base may be either added alkali, solvent, or the alkoxide produced by heterolytic fisssion of the oxazolidine itself. Since the isomerization is accompanied by the loss and gain of a proton it is subject to study by deuterium exchange (see CLXVIII + CLXXI). It is to be noted that no steric driving force to rearrangement of the oxazolidine ring is present in the model oxazolidine CLXVIII.
cLxvIII
CLXIX
CLXX
CLXXI
When CLXVIII was heated under reflux with methanol-d for 24 hours, conditions sufficient to isomerize atisine, no deuterium was incorporated in the product, which was identical with starting material. Refluxing with added NaOD for 3 hours resulted in less than 5% incorporation. Refluxing in a mixture of dioxane and deuterium oxide a t 85" for 24 hours resulted in <30% incorporation of one deuterium atom per molecule. Thus it is evident that without the steric driving force which is present in the alkaloid system, strenuous conditions are required t o effect isomerization ( 5 4 ) .I n another model system of the arylaralkyl oxazolidine type (CLXXII and CLXXIII), in which there was no steric differentiation between the two a-N-carbons, but in which the protons on these particular carbons were relatively more acidic than in the diterpene
~
~
170
S. W. PELLETIER AND L. H. KEITH
alkaloids, isomerization did not occur under conditions which lead to formation of the is0 alkaloids. However, when either compound was heated a t 193" in diethylene glycol monomethyl ether for 24 hours, isomerization occurred to give a mixture of the two products in about equal amounts. Though isomerization can be induced, the rate is far lower than that observed for the diterpene alkaloids. These results provide clear evidence that prototropic isomerization of ternary iminium compounds is not a general phenomenon but is highly dependent upon both the steric environment and the reaction conditions (54).
C. STABILITY OF NORMAL AND ISO-TYPE BASES Since both atisine and isoatisine have tetragonal C-20 groups it is necessary to invoke factors in addition t o the above equilibria to explain the greater stability of isoatisine over atisine. The following two interactions may be observed in Dreiding models of the atisine molecule: (1) (3-20 oxygen with the C-11 hydrogen and (2) C-20 hydrogen with the C-13 and C-14 hydrogens. The C-20 oxygen: C-11 hydrogen interaction is of course absent in isoatisine. However, it must be emphasized that while it is present and causes steric strain in rotamer CLXXIV" of atisine, it is entirely absent in rotamer CLXXV. The latter therefore would be expected to be the more stable and preferred conformation. It is therefore difficult to accept the suggestion (55) that the C-20 oxygen :C-11 hydrogen interaction provides the driving force for the isomerization. If rotamer CLXXV can be shown to be less stable than CLXXIV, this interaction may be a contributing factor but by itself it is not sufficient to explain the energy difference between atisine and isoatisine (56). The great importance of the steric compression between the C-20 hydrogen and the C- 13 and C-14 hydrogens may not be immediately obvious since
* The absolute configuration is the mirror image of that represented in these conformational structures.
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 171 ~
this interaction is also present in isoatisine. However, in models of isoatisine (CLXXVI)the resulting strain can be relieved by a distortion of the ring system involving the bending of the C-10-C-20 bond and rotation of the C-20 hydrogen away from ring C. Since in atisine C-20 is a part of the oxazolidine ring and is not free to rotate, the repulsive interactions cannot be relieved by rotation and bending of the C-20 group. Thus, it seems clear that the driving force of the atisine-isoatisine isomerization is due largely to the increased steric hindrance in atisine which results from the restriction which ring E imposes upon the rotation of the C-20 group (56). Recently it has been suggested that the rearrangement of compounds CLXXVII and CLXXVIII to the 19-hydroxy compounds (CLXXIX and CLXXX) invalidates this explanation of the driving force for the rearrangement of the normal to the iso-type compounds ( 2 6 ) .It is
6H CLXXIV
OH CLXXV
to be noted that the oxygen of the 20-hydroxyl compounds CLXXVII and CLXXVIII occupies a position analogous to that of the oxygen in the oxazolidine ring in atisine, veatchine, garryfoline, and cuauchichicine. I n this case the C-20 oxygen :C-11 hydrogen interaction probably is responsible for the driving force for the isomerization since the oxazolidine ring is not present. However, the conditions reported (boiling in 0.6 N KOH in methanol for 3 hours) for the isomerization of CLXXVII and CLXXVIII are much more drastic than the mild ones required to isomerize atisine and the other normal-type bases. A reinvestigation (57) of the isomerization of CLXXVIII under the reported conditions gave a mixture of about 35% of CLXXX and 65% of the dihydro derivative CLXXXI. Reduction of CLXXVIII to CLXXXI has an analogy in the reduction of isoatisine to dihydroatisine by treatment with CH30Na in a sealed tube (48).However, the reduction of CLXXVIII is much more facile since conditions as mild as treatment with 0.01 N methanolic alkali for 5 hours a t 64" give 20% of the dihydro
~
~
172
S. W . PELLETIER AND L. H. KEITH
derivative. It has been suggested that hydride ion, formed from the decomposition of methoxide, is the reducing agent in this reaction (57). Conducting the isomerization in systems which cannot generate hydride ions (aqueous dioxane or aqueous tert-butanol) does not furnish any reduced product. A comparison of the rate of isomerization of atisine and CLXXVIII in refluxing methanol and ethanol has been reported ( 5 7 ) .The pseudo-firstorder rate constant for atisine in methanol a t 64" is 4.1 x 10-4 sec-1 and in
6H CLXXVI
CLXXVII; R = O CLXXVIII; R = H2
H CLXXIX; R = O CLXXX; R = Hz
CLXXXI
ethanol a t 78" is 12.6 x 10-4 sec-1. I n the case of CLXXVIII no isomerization could be detected after heating in methanol a t 64" for 17 hours or in ethanol a t 78" for 20 hours. It is thus obvious that in the atisine case a factor in addition t o the C-20 oxygen: 11-hydrogen interaction must be present to explain the far greater ease of isomerization. This additional factor which causes the normal-type alkaloids to undergo isomerization with such great ease is the steric hindrance resulting from the restriction which the oxazolidine ring imposes upon the rotation of the C-20 group. While the C-20 oxygen :C-11 hydrogen interaction of Edwards may furnish part of the driving force for the normal to iso-type conversion, the greater part of the driving force must be due to the steric interaction resulting from the rigidity imposed on the system by the oxazolidine ring.
2.
THE
CZO-DITERPENE ALKALOIDS
173
I n the case of the salts of the normal and is0 bases, the reverse of the situation described for the bases would be expected to obtain. The normal salts have a less bulky trigonal carbon atom in the hindered 20-position and therefore should be more stable than the is0 salts, which have the more bulky tetragonal carbon a t C-20. This reasoning has been substantiated by the demonstration that refluxing isoatisine diacetate chloride (CLXXXII) in acetic anhydride gives the atisine salt (CLXXXIII) (58).The isomerization probably proceeds by a mechanism involving a concerted abstraction and readdition of a proton by acetate ion and acetic acid, respectively, as shown in CLXXXII + CLXXXIII (51).A similar reaction in the Garrya series, resulting in the transformation of garryine diacetate chloride to veatchine diacetate chloride, has AcO
CLXXXII
CLXXXIVa; 12-16 CLXXXIVb; 13-16
CLXXXIII
bond bond
CLXXXVa; 12-16 CLXXXVb; 13-16
bond bond
also been effected (59). Moreover, recently isoatisinium chloride (CLXXXIVa) has been converted directly t o atisinium chloride (CLXXXVa) by simple refluxing in dimethyl formamide, diethyl formamide, phenol, ethylene glycol, or dimethyl sulfoxide (59, 60).A similar isomerization of garryinium chloride (CLXXXIVb) to veatchinium chloride (CLXXXVb) has also been effected in boiling DMSO or DMF. These isomerizations follow first-order kinetics and the rate is greater in proton-donor type solvents than in the nondonor type. The effect of temperature on the rate of isomerization in several solvents is shown by Arrhenius plots (60).These results clearly demonstrate that the operation of steric factors makes for the greater stability of the normal type salt which possesses sp2-type bonding at the (2-20 atom. The yields for this isomerization are on the order of 80-85%. Since the normal salts can be
174
S. W. PELLETIER AND
L. H. KEITH
readily converted, without isomerization, to the corresponding bases by treatment with cold aqueous base, this thermal isomerization of the salts provides a convenient practical method of reversing the facile normal + is0 base isomerization. Detailed rate studies on this reaction in several organic solvents have been carried out (60).
VI. The Chemistry of Alkaloids with a Modified Atisane Skeleton I n recent years a wide range of Aconitum species native to Japan and India have been examined for alkaloids. Among those encountered are several which are modeled on an atisane skeleton but possess additional ring fusions. This section will .survey the chemistry of these interesting alkaloids. A. HETISINE(DELATINE) Hetisine, C ~ O H ~ ~aNminor O ~ ,constituent of Aconitum heterophyllum (61, 62) and Delphinium cardinale Hook (62a)represents an interesting variant of the atisane skeleton. The alkaloid has one hydrogenatable double bond, three active hydrogens, and a tertiary nitrogen. N-Alkyl and methoxyl determinations are negative. The presence of an exocyclic methylene group is indicated by the IR spectra (3003, 1659, 899 cm-1) and NMR spectra (75.28, 5.46) and confirmed by the isolation of formaldehyde upon ozonolysis. C-Methyl determinations and I R absorption (1379 cm-1) show the presence of one C-methyl in hetisine and two in dihydrohetisine. This is confirmed by the appropriate NMR spectra. Since dihydrohetisine shows no adsorption in the near ultraviolet, it is clear that hetisine must have a heptacyclic skeleton (63, 6 4 ) . The nature of the oxygen functions is indicated by formation of a crystalline diacetate (3247, 1742, 1252, 1225 cm-1) and an amorphous triacetate, each of which regenerates hetisine on saponification. Furthermore, the alkaloid is inert to both periodate and lead tetraacetate and does not form an acetonide. It therefore possesses three acylatable hydroxyls which are nonvicinal and are not in a 1,3-cis-diaxial relationship (63, 64). Dehydrogenation of hetisine yields a complex mixture of hydrocarbons from which pimanthrene has been isolated. The fact that hetisine lacks a free N-alkyl group and compares in basicity (pK,' 9.85) with yuinuclidine ( 10.3) suggested a quinuclidine-type structure (CLXXXVIa) with bonding from the nitrogen to either C-1, C-2, C-3,
2.
THE
CZO-DITERPENE ALKALOIDS
175
C-6, or C-7. One additional ring and three hydroxyls are necessary to complete the structure. Possible sites for the third N-C bond and distribution of the hydroxyl groups were suggested in structures proposed for hetisine by Wiesner and Valenta (CLXXXVIb) (7) and Solo and Pelletier (CLXXXVIc) (63).The correct structure (CLXXXVII) and relative stereochemistry* have been established by an X-ray diffraction study (65, 66).
CH20H CLXXXVIa
CLXXXVII
CLXXXVIb
cLxxxvIo
HO
HO
CLXXXVIII
CLXXXIXa; CLXXXIXb;
42.3
Oxidation of hetisine diacetate affords a dehydrohetisine, named hetisinone ( 3 ) ,which proved to be identical with a dehydrohetisine later isolated from Delphinium cardinale (62a) and from Delphinium denudatum ( M a ) . The structure originally suggested for hetisinone (CLXXXVIII) ( 3 )has been confirmed by dehydration with phosphorus
* The absolute configuration of hetisine shown is based on analogy to that of the other atisine and Qarrycc alkaloids. The correlation of hetisine with a compound of known absolute configuration has not been reported.
176
S. W. PELLETIER AND L. H. KEITH
oxychloride and pyridine, followed by saponification to a crystalline mixture of olefins (CLXXXIXa and b) which showed appropriate NMR absorption (66b). Furthermore, when heated in D20-MeOD with NaOD, hetisinone gave a mixture of deuterated hetisinones which contained, by mass spectroscopic analysis: 14% d, 53% &, 24% &, and 6% d4 species. Under these conditions only CLXXXVIII, of the likely structures, should incorporate up t o four atoms of deuterium (66b). HO CHI
cxc
CXCI
CXCII
Structure CLXXXVII permits the interpretation of an unusual rearrangement which hetisine methiodide undergoes. Jacobs and Huebner (62)had described a hetisine methiodide, mp 325OC, formed in a sealed tube a t 100°C, which on Hofmann degradation gave a desmethylhetisine, C21H29N03. The latter showed .the presence of only one double bond by $cHs
Q-*-cH;:*.
CXCIII
*.
*.
,t---
p---.. ,*I
-< '
-$
'-2, CXCIV
hydrogenation and no carbonyl group. Wiesner et al. (67)have shown that under milder conditions of quaternization (refluxing methanol) an isomeric methiodide (CXC) is obtained which undergoes a Hofmann degradation t o give a normal desmethylhetisine. The latter possesses an exocyclic methylene group and a new double bond, both of which can be hydrogenated. Clearly, during quaternization Jacobs' methiodide rearranged with participation of the original exocyclic methylene group. Wiesner et al. have interpreted this rearrangement as proceeding via the ketone CXCI to the hemiketal structure CXCII (67). Dihydrodes-N-methylhetisine(CXCIII)is oxidized by permanganate to a carbinolamine ether (CXCIV). Reduction of the latter with sodium
2.
THE
C20-DITERPENE ALKALOIDS
177
borohydride regenerates CXCIII (63).This oxidation is analogous t o the cyclization of des-N-methylhypognavinol effected by oxidation with silver oxide or alkaline ferricyanide (see Section VI, C).
B. IGNAVINS AND ANHYDROIGNAVINOL These alkaloids occur in the roots of Aconitum sanyoense Nakai, A . tasiromontanum Nakai, and A . japonicum Decne (68-70). Early studies showed that ignavine, C27H31N06, lacks methoxyl, methylenedioxy, or N-methyl groups and is unreactive toward the usual carbonyl reagents. Saponification of ignavine gives 1 mole of benzoic acid and anhydroignavinol, CzoH25N04. Methiodide formation is also accompanied by the loss of water. Of the six oxygens in ignavine, two occur in the benzoyloxy group and four in hydroxyls. One of these hydroxyls is adjacent t o the benzoyloxy group since the hydrolysis product is susceptible t o periodate cleavage while ignavine is not. Diacyl derivatives are formed which contain 1 mole of water less than calculated on the basis of ignavine and are therefore anhydroignavinol derivatives. Saponification of these derivatives does indeed afford anhydroignavinol. Clearly ignavine contains an unusual hydroxyl which is eliminated during methiodide formation or acylation (71). The presence of an exocyclic methylene group in ignavine is indicated by the IR spectrum (1645 and 892 cm-1) and by formation of formaldehyde on ozonization. That the exocyclic methylene is involved in a secondary allylic alcohol system as in atisine was demonstrated by catalytic isomerization to a methyl ketone (1692 cm-1) and by oxidation to a conjugated enone (1615, 1687 cm-1) (72). Dehydrogenation of anhydroignavinol yields a complex mixture of hydrocarbons from which 1,7-dimethy1-6-n-propylphenanthrene (CXCV),1,8-dimethyl-3-ethylphenanthrene (CXCVI),and 1,%dimethyl3-isopropylphenanthrene (CXCVII) have been isolated (73-75). These products account for 19 of the 20 carbon atoms of anhydroignavinol. I n view of the diterpene nature of the Aconitum alkaloids and the demonstrated presence of an allylic alcohol system in ignavine, it is reasonable to assume the alkaloid contains a bicyclo[2.2.2]octane-allyl alcohol system as in atisine. This assumption is given credence by oxidation of des-N-methyloxoanhydroignavinolt o a dicarboxylic acid (CXCVIII) in which one of the carboxyls is tertiary. Furthermore, the three phenanthrene dehydrogenation products suggest a bond between C- 14 and C-20 and a methyl group a t C-1 (structure CXCIX). Numerous degradations
178
S. W. PELLETIER AND
L. € KEITH I.
have established the position of the nitrogen and shown the presence of hydroxyls a t C-2 and C-3 in anhydroignavinol(72,76).Since ignavine has no N-alkyl group, a third bond must extend from nitrogen t o one of the rings. The Japanese workers selected C-6 as the most likely site.
q$f \
cxcv COzH
CXCVIII
CXVI
/
CXCVII
I?
CXCIX
cc
The published data clarify the nature of four of the six oxygens of ignavine and three of the four of anhydroignavinol. The fourth oxygen in anhydroignavinol is thought to exist as an ether since no hydroxyl band is observable in the I R spectra of tribenzoyl anhydroignavinol and certain other anhydro derivatives. It is therefore likely that loss of water accompanying many of the reactions of ignavine involves ether rather than double-bond formation. Possible positions for the hydroxyls involved in the elimination assuming a /3-glycol moiety are C-11-C-13, C-7-C-14, C-7-C-9, and C-5-C-9. Since ignavine has a normal pK,' value (7.7) for a tertiary amine, it is unlikely that a hydroxyl is a t C-19 or C-20. I n view of the above anhydroignavinol and ignavine have been provisionally represented by partial structures CXCIX and CC, respectively.*
C. HYPOGNAVINE AND HYPOGNAVINOL Certain varieties of A . sanyoense contain an ester alkaloid which has one less oxygen atom than ignavine and is in many respects similar to it.
* The absolute configuration shown is based on analogy to that of the other diterpene alkaloids.
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 179 ~
This alkaloid, hypognavine, C27H31N05, is a benzoyl ester, has no methoxyl or N-methyl groups, does not react with the usual carbonyl-test reagents, and contains one hydrogenatable double bond. Like ignavine, it has two acylatable hydroxyls and an exocyclic methylene group (1666, 895 cm-1; ozonization gives formaldehyde). I n contrast t o ignavine, hypognavine may be saponified to an alkamine (hypognavinol, C20H27N04) without loss of 1 mole of water. Acylation reactions and methiodide formation are also straightforward in the case of hypognavinol (77, 78). The exocyclic methylene in hypognavine manifests the same characteristics as in ignavine and songorine, viz., partial rearrangement to a methyl ketone by hydrogenation over palladium-charcoal or by treatment with acid, Hypognavine may be oxidized t o a conjugated enone [1705,1630cm-1; A,, 231 (6 22,400)] which on reduction over palladium/ charcoal gives dihydrohypognavinone, the methyl ketone referred t o earlier. These reactions afford clear evidence for the existence of a secondary ally1 alcohol system such as occurs in atisine, ignavine, and songorine. Selenium dehydrogenation of hypognavinol furnishes 1,8-dimethylphenanthrene, 1,7-dimethy1-6-n-propylphenanthrene (CXCV), and 13dimethyl-3-ethylphenanthrene(CXCVI), the latter two being characteristic products of anhydroignavinol. This suggests that hypognavine has the same skeleton as derived for ignavine. Formula CCI will be used as a basis for interpreting the chemistry of hypognavinol (74, 78, 7 9 ) .
Hofmann degradation of hypognavinol methiodide gave the des base CCII and the isomerization product CCIII. The resistance of des-Nmethylhypognavinol toward a second Hofmann degradation is well accommodated by structure CCII, for the ,%positions to the nitrogen at C-4 and C-10 bear no hydrogen and formation of a double bond between C-14 and C-20 would violate Bredt's rule. The size of the heterocyclic ring in CCI was indicated by oxidation of three hypognavinol derivatives to a-lactams (79-84.
~
~
180
S. W. PELLETIER AND L. H. KEITH
The three remaining oxygens of hypognavinol exist as hydroxyls, of which two are acylatable. The nonacylatable hydroxyl was shown to be tertiary by oxidation experiments. Detailed transformations have shown that the a-glycol system in hypognavinol is masked by a benzoyloxy group in hypognavine. The location of the u-glycol system in ring A of hypognavinol is fixed by oxidation of des-N-methylhypognavinol (CCIV) with silver oxide or alkaline ferrocyanide to a carbinolamine ether (CCV) from which CCIV may be regenerated by reduction with NaBH4. Salts (CCVI) of the carbinolamine ether show I R absorption typical of the group (1686-1679 cm-1) and regenerate the parent base on treatment with alkali. Models show that an axial hydroxyl a t C-2 is most favorable for ether formation. It should be noted that oxidation a t C-20 is unlikely since the salt of the corresponding carbinolamine ether (CCVII) would violate Bredt’s rule. These transformations parallel the formation of a carbinolamine ether on oxidation of dihydrodes-N-methylhetisine (CXCIII + CXCIV).
QH3 OH
CCIV
5
ccv
The assignment of the second hydroxyl of the glycol system a t C-1 or C-3 is not yet settled. Periodate cleavage experiments indicate a transglycol system is present. The benzoyloxy group in hypognavine is accordingly assigned a 1/3- or 3/3-configuration.The site of the tertiary
2.
THE
C%O-DITERPENE ALKALOIDS
181
hydroxyl is unknown. Hypognavinol is thus represented by structure CCVIIIa or CCIXa and hypognavine by CCVIIIb or CCIXb (81).
CCIXa; R = H CCIXb; R = COCeHs
CCVIIIa; R = H CCVIIIb; R = COCeH5
D. KOBUSINE This alkaloid, C ~ O H ~ ~ Nhas O Zbeen , isolated from A . kamtschaticum Pall (Jischeri),A . sachalinense Fr. Schmidt, A . lucidusculum Nakai, and
IBF. EtBH
H O g c H 3
~i
Q
"O Q 'CH3
0--OH
t
\ CCXVII
'
\
CCXVI
I
\ CCXIII
I
1. OSOI/HIO~
LiAlH4
2. CrOs/Pyr.
CCXVIII
SEt
ccxv
CCXIV
182
S. W. PELLETIER AND L. H . KEITH
A . yesoensis Nakai (82-85). It possesses two secondary hydroxyl groups located in six-membered rings, one of which is involved in an allyl alcohol group such as is common to atisine, ignavine, and hypognavine. Selenium dehydrogenation furnished 1,7 - dimethyl - 6 - n - propylphenanthrene (CXCV), a characteristic product obtained also from ignavine and hypognavine. These results suggest that kobusine has the same skeleton as ignavine and hypognavine. The chemistry of kobusine will be discussed in terms of the structure (CCX) assigned by the Japanese workers (86-88). When kobusine (CCX) is warmed with dilute HCl, compounds CCXI, CCXII, and CCXIII are formed. Compounds CCXII and CCXIII are reducible to the same glycol CCXIV. Oxidation of CCXIV with CrOa/ pyridine gave a y-lactone (CCXV) showing the proximity of the two hydroxyls. Treatment of kobusine with sodium in propanol gave the deshydroxyl derivative CCXVII which was related to the methyl ketone CCXI via CCXVI. Oxidation of CCXVII with Os04/HI04 followed by CrO3/pyridine gave a y-lactone 6CXVII1, thus establishing the relationship between the two hydroxyl groups. It should be noted that none of the published data preclude the assignment of a hydroxyl group a t C-13ratherthanat C-11. The correlation of kobusine and pseudokobusine is discussed in Section VI, F. E. PSEUDOKOBUSINE Isolated from A . yesoense and A . lucidusculum, this alkaloid, C20H27N03,is closely related to kobusine (85,89).It is a tertiary base containing three acylatable hydroxyls (tribenzoate),an exocyclic methylene group (900 em-I), a C-methyl group, and no methoxyl. Oxidation reactions and palladium-catalyzed rearrangement, such as were used in the case of ignavine, demonstrate that one of the hydroxyls is involved in an allyl alcohol grouping. Oxidation experiments show the allylic hydroxyl and one other are in six-membered rings and the third hydroxyl is tertiary since it is inert to Kiliani reagent. Selenium dehydrogenation of pseudokobusine gave 1,7-dimethyl-Bn-propylphenanthrene (CXCV), a result which suggests that pseudokobusine has fundamentally the same structure as kobusine, with the addition of one tertiary hydroxyl. The chemistry of pseudokobusine will be discussed in terms of structure CCXIX, assigned by the Japanese investigators (88, 90, 91). Acetylation of pseudokobusine gave besides the normal 0-acetate, an N-acetyl-seco derivative (CCXX) 11596, 1700 em-1; vlllilX20!) ( C 3 3 ) ;
2.
THE
C
Z
O
ALKALOIDS ~ ~
~
~
~ 183~
77.87 singlet]. An analogous N-cyano-seco derivative (CCXXI) (2218, 1697 em-1) was prepared by treatment of CCXIX with cyanogen bromide. Both seco compounds (CCXX and CCXXI) regenerated pseudokobusine when hydrolyzed with 20% potassium hydroxide. Pseudokobusine methiodide (CCXXII) gave with ammonium hydroxide the N-methyl ketone CCXXIII (1675 em-I), which regenerated the methiodide (CCXXII) when treated with hydriodic acid. Absorption of the keto group in CCXXIII at longer wavelength than in CCXX or CCXXI is attributed to transannular interaction between the nitrogen and the
8
,,--C - \’ H
z
, a
N---
. ’.
’
\OH
$
2
=--
,‘I
- 4 <‘
OH
20% NaOH
CH
aR - - --N
f
-
--p+--I
OH CCXIX
\
I . Hs/l’d+
&2.I $CrOaIArOH
<-- - A \ I
OH CCXXIV
R-- --N
,,:----is ‘
zi,*
OH
8 %,
0 CCXX; R = AC CCXXI; R = C = N CCXXIII; R = CH3 &CHa
,’
N----..
,,:i
I
OH CCXXII
0
0 CCXXV; R = AC CCXXVI; R = C N CCXXVII ; R = CH3
carbonyl group. These transformations suggest the presence in pseudowhich can react kobusine of a masked amino ketone group (-N-C-OH) in the tautomeric form (HN-; C=O). To establish that the tertiary hydroxyl of pseudokobusine is part of the masked amino ketone group, ketodihydropseudokobusinone (CCXXIV) was converted to the N-acetyl triketone (CCXXV, 1632 em-I), N-cyano triketone (CCXXVI, 2221 cm-l), and N-methyl triketone (CCXXVII, 1714, 1708, 1683 em-1) by reactions parallel to those already described. Hydrolysis of CCXXV regenerated CCXXIV. The shift of the C-methyl absorption a t 78.64 (singlet) in CCXXIV to 78.94 in the corresponding 0-acetate is in accord with the formulation shown (90). The location of the third hydroxyl was determined by the following sequence. Oxidation of N-acetylsecopseudokobusine (CCXX) with
~
~
184
S . W . PELLETIER AND L. H. KEITH
Os04/NaI04 gave a hemiacetal monocarboxylic acid CCXXVIII (1720, 1650 cm-I), the methyl ester of which was oxidized with CrOs/pyridine to the y-lactone CCXXIX (1778, 1728, 1699, 1630 cm-1). The same y-lactone was obtained by another route. Oxidation of CCXX with manganese dioxide gave the enone CCXXX (3420, 1699, 1692, 1630 cm-1). Oxidation of CCXXX with Os04/NaI04, followed by esterification with diazomethane gave CCXXIX. The transformations limit the position of the third hydroxyl group in pseudokobusine to position C-11 or (3-13. The Japanese workers assign the hydroxyl to C-11, though, as in the case of kobusine, evidence for this assignment is lacking. ??
ccxx
0 CCXXVIII
COzCHa
0
ccxxx
0 CCXXIX
F. CORRELATIONOF KOBUSINE AND PSEUDOKOBUSINE Ketodihydropseudokobusinone (CCXXIV) with mesyl chloride in pyridine gave a mixture of N-mesyl and O-mesyl derivatives (CCXXXI and CCXXXII), respectively. Reduction of the latter over Raney nickel gave the alcohol CCXXXIII which was oxidized with CrOs/pyridine to ketodihydrokobusinone (CCXXXIV). The latter has been obtained from kobusine by palladium-catalyzed isomerization followed by oxidation. Furthermore, NaBH4 reduction of a sample of CCXXXIV derived from kobusine gave the alcohol identical with compound CCXXXIII from pseudokobusine (88, 91).
2. THE CZO-DITERPENE ALKALOIDS
185
The correlation of kobusine and pseudokobusine has been effected by still other routes. Dihydropseudokobusine (CCXXXV)on reduction with sodium in propanol gave dihydrokobusine (CCXXXVI).Also, reduction of either kobusine or pseudokobusine with sodium in propanol gave the same alcohol (CCXVII). @
CCXXIV
,*a
Ni
+
N--#
OSOzCHs CCXXXII
0 CCXXXI
.--_ -I .‘,
’
OH
CCXXXIII NaHH~\ICrOs/Pyr.
ccx
CCXXXVI
CCXXXIV
Kobusine
t 8
c-C -A* 8
I‘
N---
I
Na/PrOH
Nu/PrOH
.
H
‘
3
Hz
c-- -4,
I* I
I
OH N.--8
*
*. ‘3.
OH
ccxxxv
CCXVII
OH CCXIX Pseudokobusine
G. ISOHYPOGNAVINE* Isohypognavine, C Z ~ H ~ ~(CCXXXVIIb) N O ~ occurs in the roots of A . rnajirnai Nakai and A . japonicurn and is a benzoate of the alkamine, isohypognavinol (CCXXXVIIa)(70,92).The latter has three acylatable
* The name “isohypogiiavine” is unfortunate, since the compound is not isomeric with hypognavine. A inisinterpretat ion of ewly analytical data led t o assignrnent of an inrorrert molecular formula.
S. W. PELLETIER AND L. H. KEITH
186
hydroxyls, one of which is involved in the typical ally1 alcohol system as shown by oxidation with manganese dioxide to the conjugated enone, isohypognavinolone [CCXXXVIII, 1630, 1703 em-1; A,, 227 (6730)l and by isomerization of CCXXXVIIb over palladium/charcoal to the epimeric methyl ketones (CCXXXIXa).Isohypognavine (CCXXXVIIb) has been correlated with kobusine (CCX) by the following route: Oxidation of a-dihydroisohypognavinone (CCXXXIXa) with CrOz/
CCXXXVIIa; R = H CCXXXVIIb; R = Bz I
CCXXXIXa; R = Bz, R' = OH CCXXXIXb; R = Bz, R' = 0 CCXXXIXC; R = H, R' = 0 CCXXXIXd; R = SQ~CHI, R' = 0
CCXL I
lPnoa
1
Ha'Pd
HO
CCXXXIV
CCXLII
79.10 d
HO..
Br H f
75.99 8.
CCXLI
CCXLIII
78'69
''
CCXLIV
AcOH gave CCXXXIXb which was hydrolyzed t o CCXXXIXc. Conversion of the latter t o the mesylate CCXXXIXd followed by refluxing in pyridine gave CCXL (74.2-4.5, 2H multiplet). Hydrogenation of CCXL gave ketodihydrokobusinone (CCXXXIV) previously prepared from kobusine. Reduction of isohypognavinol (CCXXXVIIa) with sodium in propanol gave a desoxy derivative (CCXLI), the ethiodide of which afforded on Hofmann degradation a tertiary base (CCXLII). The
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 187 ~
very low field signal a t 7 1 . 7 7 (lH, doublet, J = 12.6 cps) disappears in the presence of acetic acid and is decoupled when a hydrogen adjacent t o a secondary hydroxyl group is irradiated. Therefore this signal was assigned to an -OH on ring A which is intramolecularly bonded to the nitrogen. If ring A is a chair the hydroxyl must be a t C-2 and axial in order to be strongly hydrogen-bonded to the nitrogen. The position of this. hydroxyl was confirmed as follows. Catalytic hydrogenation of CCXLI followed by oxidation gave the diketone CCXLIII which afforded a monobromo derivative CCXLIV. Existence of a single proton adjacent to the bromine (75.99 singlet) again restricts the position of the hydroxyl in CCXLI to C-2. The deshielding of the C-methyl in going from CCXLIII to CCXLIV also supports introduction of the bromine a t C-3 in a position / ? t othe methyl (93).
H. DITERPENE ALKALOIDS FROM Xpiraea japonica L. (ROSACEAE) Alkaloids were first isolated from this plant in 1964 by Molodozhnikov et al. ( 9 4 ) .Subsequent studies by Goto et al, (95) led t o the isolation of 10 new alkaloids. The structures of three of these, spiradine A (CCXLV), spiradine B (CCXLVI),and spiradine C (CCXLVII) have been reported.
8 18 CCXLV; R = H CCXLVIII ; R = Ac
,*--
, I
CCXLVI; R = OH CCXLVII; R = OAc
;:--
- 4*
-4<
2
CCXLIX
$CH2 ,y-
-J,<
61 **
C&--
--N---. I
%*
OH CCL
CH,-- --N
CH3--- -N
/ 0 CCIJ
OMe CCLII
Reduction of spiradine A with sodium borohydride in methanol gave spiradine B and oxidation of the latter with CrOs/pyridine regenerated spiradine A. Treatment of spiradine C with KOH in 80% ethanol gave
~
~
188
S. W. PELLETIER AND L. H. KEITH
spiradine B. When treated with acetic anhydride in pyridine, spiradine A afforded an O-acetate (CCXLVIII) [vmaX (KBr) 1735, 1250 (OAc), 1705 (C=O), 1635 (C=CHz), no -OH absorption] and an N-acetate (CCXLIX) [v,,,, (KBr) 1710 (C=O), 1690 (C=O), 1630 (N-Ac and C=C), no -OH absorption] formed by rupture of the N-C-6 bridge. Catalytic hydrogenation of spiradine A gave a dihydro derivative with an appropriate NMR spectrum. Treatment of spiradine A with methyl iodide in methanol (KBr) 3190, 1710, 1640 cm-11 which was gave a methiodide (CCL) [v,,, shaken with silver oxide in 50% methanol to give the N-methyl diketone (CCLI) [vmax 2800, 1710, 1690, 1650 cm-11. The latter was heated with methyl iodide a t 100" followed by Hofmann degradation to give CCLII [qnax1700, 1655 cm-1 (strong)]. These transformations afford evidence for the
I
-N-C-CH2-C-C
I OH
I
I
C
group in spiradine A. An X-ray analysis of spiradine A methiodide (CCL) gave the structure and absolute configuration as shown.
VII. Synthesis of Diterpene Alkaloids There has been such great activity in this area within the past few years that only the most significant developments will be summarized.
A. PARTIAL SYNTHESIS OF ATISINE The N-acetyl ester (CCLIII), a key intermediate in the correlation of the atisine and Garrya alkaloids (see Section IV, A), has been converted t o atisine by a 12-step sequence (96). Conversion of CCLIII via the acyl chloride to the corresponding diazoketone, and rearrangement of the latter with silver benzoate/triethylamine in methanol gave the homologous acid (CCLIV). Dieckmann cyclization of the dimethyl ester (CCLV)afforded a mixture of the epimeric keto esters (CCLVI).Hydrolysis of CCLVI followed by sublimation gave the ketone CCLVII. The structure of the latter was confirmed by an alternate preparation from CCLVIII. The acetate of CCLVIII (22) was oxidized with osmium tetroxide/periodate, to the keto acetate CCLIX, which on Wolff-Kishner reduction gave a mixture of basic and neutral components. Acetylation of this mixture and subsequent saponification led to a separable mixture
2. THE Czo-DITERPENE ALKALOIDS
189
of CCLX and CCLXI. Mild oxidation of the former with CrOslpyridine led in good yield to a ketone which was identical with CCLVII. Methylation of CCLVII proceeded smoothly with methyl iodide and sodium hydride in dimethyl sulfoxide t o give a mixture of epimeric
0
CCLIII
CCLVI; R = COzCHa CCLVII; R = H z
CCLIV; R = H CCLV; R = C H 3
#'
;
OR2
Ac-- --N
CCLVIII; R' = CH2, R2 =H CCLIX; R 1 = 0,R2 = Ac CCLX; R 1 = H2, R2 = H
Ac-- &--N R
CCLXI
0
0 1 ' H CCLXIV
CCLXII; R = -CHs CCLXIII; R = ---CH3
CCLXVI; R = r - - H OH CCLXVII; R = ,---OH
H
CCLXV
CCLXVIII
190
S. W. PELLETIER AND
L. H. KEITH
ketones (CCLXII and CCLXIII). Subsequent bromination of this mixture in acetic acid and hydrogen bromide gave a mixture of bromo ketones (CCLXIV) which was dehydrohalogenated to afford the known enone CCLXV ( 2 2 ) .In a parallel experiment, the alcohol CCLXVI was isomerized with boiling 10% hydrochloric acid t o a mixture of ketones (CCLXII and CCLXIII) which was separated by crystallization. Bromination of either ketone led to a mixture of bromo ketones (CCLXIV) which could be dehydrohalogenated t o furnish the enone CCLXV in 50% overall yield. Previously the reduction of enone CCLXV to the epimeric alcohols CCLXVI and CCLXVII had been reported. For the present synthesis the alcohol with the natural configuration (CCLXVI) (i.e., trans to the nitrogen bridge) was hydrolyzed with potassium hydroxide and a trace of hydrazine in boiling diethylene glycol to afford the secondary amino alcohol CCLXVIII. This product was identical with the amino alcohol derived earlier from the degradation of atisine (18, 96). Since this alcohol had already been converted to natural atisine by a fivestep sequence (18), this work represents a synthesis of atisine from CCLIII. It should be noted that this synthesis provides direct evidence for the bicyclo[2.2.2]octane system and for the location of the allylic alcohol group in atisine. B. TOTALSYNTHESES OF ATISINE The first complete stereospecific synthesis of dl-atisine was reported by Nagata et al. ( 9 7 , 9 8 )starting from ketone CCLXIX, which by a 23-step process was also converted into the previously described ketone CCLXV. Hydrocyanation of CCLXIX gave the trans-cyano ketone CCLXX which by a Wittig reaction followed by acid hydrolysis and methylation afforded CCLXXI. The latter was converted to the tetracyclic derivative CCLXXII by a three-step sequence via the lactamol. By Birch reduction, mesylation, and hydrolysis, CCLXXII was converted t o the enone CCLXXIII. To construct the D ring the latter was hydrocyanated t o the trans-cyano ketone CCLXXIV which was converted into the cyclic ketol CCLXXV via the 15~-acetylcompound. The mesylate (CCLXXVI) derived from CCLXXV on treatment with alkali gave CCLXXVII which yielded via CCLXXVIII the pentacyclic ketone CCLXXIX. After conversion of CCLXXIX into the exo olefin the protecting mesyl group was removed by Birch reduction and the desired acetyl group was then introduced (CCLXXX). Finally, introduction of the 8-hydroxyl a t C-15 was effected by a three-step process : treatment of CCLXXX with N-bromosuccinimide afforded a rearranged allylic bromide, which after epoxida-
2.
THE
C
2
0
- ALKALOIDS ~ ~ ~
~
~
191 ~ ~
tion was treated with zinc to give the desired alcohol C C L X X X I and its epimer C C L X X X I I . Compounds C C L X X X I , C C L X X X I I , and the enone CCLXV proved to be the racemic forms of the corresponding naturally derived materials. Since CCLXV and C C L X X X I had already been converted to atisine (96),this sequence represents a stereospecific total synthesis of dl-atisine. The overall yield from CCLXIX to C C L X X X I is about 1.7%.
CCLXIX
CCLXX: R
=
0
CCLXXII
CCLXXI; (‘CHO CH1
t
t
R‘ CCLXXVII
CCLXXV; H
= H,
R’= 0
CCLXXIV
CCLXXIII
/H CCLXXVI; R = Ac, R’=-..OMs
CCLXXVIII
ccLxxIx
CCLXXX; R = H z
CCLXXXI; R CCLXXXII; R
=
C. TOTAL SYNTHESES OF GARRYINEAND VEATCHINE A synthesis of dl-garryine and dl-veatchine has also been reported by Nagata et al. (99, 100). The dimesyl derivative CCLXXVI was refluxed
~
~
192
S. W. PELLETIER AND I;. H. KEITH
with collidine to give olefin CCLXXXIII. Sterically controlled hydroboration of the latter with bis (3-methyl-2-butyl) borane followed by oxidation and hydrolysis yielded the 1,Z-diol CCLXXXIV. Rearrangement of brosylate CCLXXXV to the bridged ketone CCLXXXVI folOAC!
CCLXXVI
CCLXXXIII
CCLXXXIV; R = H CCLXXXV; R = Bs
CCLXXXVI
I "OH
t
CCLXXXIX; R = COzEt CCXC; R = H CCXCI; R = CHzCHzOH
CCLXXXVII; R = MS CCLXXXVIII; R = COzEt
lowed by Wittig condensation afforded the exomethylene derivative CCLXXXVII. The secondary amine from CCLXXXVII was converted to the N-carbethoxy derivative CCLXXXVIII. Introduction of the hydroxyl at C-15 was effected as in the atisine synthesis by successive bromination, epoxidation, and debromination. The products were CCLXXXIX and its (2-15 epimer. Removal of the carbethoxy group followed by alkylation of the resulting amine (CCXC) gave dl-dihydroveatchine (CCXCI). Since dihydroveatchine has been converted to
2.
193
THE C20-DITERPENE ALKALOIDS
ccxcv
CCXCII; R = 0, R' = O H CCXCIII; R = 0, R ' = CHzBr CCXCnT; R = OTHP, R' = CHzBr
I 0D '
O
R
CCXCVI; R = THP CCXCVII; R = B z
R' CCXCVIII; R = R' = H, R" = BZ CCXCIX; R = COZMe, R' = H, R" = Bz
I ccc CCCI; R CCCTI; R
= OCH3, = OH,
R'
R'
= R" = 0
= Hz,
R"
=<'I 0
CCCIII; R = OH, R' = Hz, R" = 0
194
S . W. PELLETIER AND L. H. KEITH
garryine (101)and garryine t o veatchine (59,60)this work constitutes a total synthesis of the racemic forms of these alkaloids. D. OTHERSYNTHESES OF DITERPENE ALKALOIDS A totally different synthesis of the diterpene alkaloids has been reported by Masamune (102-104). The carboxylic acid CCXCII was converted via the bromo ketone CCXCIII to the tetrahydropyranyl ethers CCXCIV. Hydrogenolysis of the latter gave the corresponding phenols CCXCV. Base treatment of CCXCV effected cyclization of only one isomer to furnish a dienone ether (CCXCVI).Catalytic hydrogenation of the benzoate (CCXCVII) gave the tetrahydro cis-fused derivative
CCCIII
CCCIV
cccvm; R = ~
9 ~ R’ 5 =, H CCCIX; R = C2H5, R’ = AC CCCX; R = C N , R ’ = A c CCCXI; R = R ’ = H
CCCV; R = O CCCVI; R = CH2
CCCVII
CCXCVIII. Carbomethoxylation of CCXCVIII with triphenylmethylsodium and carbon dioxide followed by methylation afforded the /3-keto ester CCXCIX. Annelation of CCXCIX with ethyl vinyl ketone followed by exhaustive methylation, removal of the protective group, and oxidation gave the diketone CCC. Catalytic hydrogenation of the diketone gave a single saturated compound (CCCI). Wolff-Kishner reduction of the monoketal of CCCI gave an acid CCCII which afforded the intermediate CCCIII. Since veatchine azomethine acetate (15-OAc)has been converted to the levorotatory enantiomers of CCCII and CCCIII the stereochemistry indicated for all intermediates is correct.
2.
THE
C
2
0
-ALKALOIDS ~ ~
~
~
~ 195 ~
Intermediate CCCIII was converted by several steps via photolysis of the azide CCCIV to a ketoamide (CCCV) which was identical with the compound previously prepared by Vorbrueggen and Djerassi (40) from veatchine azomethine acetate. Introduction of a inethylene group (CCCVI) followed by isomerization gave CCCVII. Photosensitized oxygenation of CCCVII and hydride reduction of the resulting hydroperoxide gave the alcohol CCCVIII, which was converted t o the secondary amine CCCXI via CCCIX and CCCX. Since CCCXI had been previously transformed to garryine (101) this work completes a total synthesis of garryine. Masamune (104)has also converted compound CCCXII, obtained from veatchine azomethine acetate, by a multistep procedure t o the monoester carboxylic acid CCLIII. Since the latter has already been converted to atisine by Pelletier and Parthasarathy (96)this work completes in a formal sense the synthesis of atisine also. COzH
CCCXII
CCLIII
Still a third synthesis of the Garrya alkaloids has been reported by Valenta, Wiesner, and Wong (105, 106). This synthesis starts with 5-methoxy-2-tetralone and proceeds through the key intermediates CCCXIII-CCCXVIII (107).The dl-amine CCCXVIII was converted t o CCCV by a series of steps involving intermediates CCCXIX-CCCXXI. The synthesis of CCCV constitutes a total synthesis of the Garrya alkaloids since the conversion of CCCV t o the amine CCCXI has been reported by Masamune (103)and the transformation of CCCXI to garryine (101)and of garryine to veatchine (59,60)have been reported by Wiesner et al. and Pelletier et al., respectively. A recent paper (108)describes two new synthetic sequences which can be used to elaborate both atisine and Garrya-type structures. The dl-acid CCCXIVa was converted to the acyl azide CCCXXIIa by treatment with N,N‘-dicyclohexylcarbodiimideand sodium azide. Refluxing CCCXXIIa in anhydrous benzene afforded an isocyanate (CCCXXIIIa) which was cyclized with p-toluenesulfonic acid to give the keto lactam CCCXXIVa (3400, 1725, 1670 cm-1; 78.65, methyl singlet) in a yield of 26%. The latter was converted via the dithioketal CCCXXVa and lactam
~
~
HO~C-CHZ
8 OMe
0
+
OMe
+
o& 1 ’ H
H CCCXIII
OMe
CH3 CCCXIV
cccxv
t
CCCXVIII
CCCXVII
CCCXVI
cccv
CCCXIX
cccxx
CCCXXI
0
II
COzH
Ns-C
I
CCCXIVa; R = OMe, R’ = H CCCXIVb; R = H , R’ = OMe
O=C=N
I
CCCXXIIa; R = OMe, R’ = H CCCXXIIb; R = H, R’ = OMe
I
Q
CCCXXIIIa; R = OMe, R’ = H CCCXXIIIb; R = H , R’ = OMe
9
I
EM
N
M
3
b
<
R R“
CCCXXVa; R = OMe, R’ = H , R” = CCCXXVb; R = H , R’ = OMe, R”
k m
0 CCCXVIIIa; R = OMe, R’ = H
s
“7
“
=’y
CCCXXIVa; R = OMe, R’ = H CCCXXIVb; R = H , R’ = OMe
S ‘
CCCXXVIa; R = OMe, R’ = H , R” = Hz CCCXXVIb; R = H , R’ = OMe, R” = Hz CI
CD -3
198
S. W. PELLETIER AND L. H. KEITH
CCCXXVIa to the amine CCCXVIIIa which has already been converted t o the Garrya alkaloids. A similar sequence (109)has been used for an atisine synthesis starting with the dl-acid CCCXIVb. Conversion to the acyl azide CCCXXIIb was effected by treatment with ethyl chloroformate and triethylamiiie followed by sodium azide. Conversion of the acyl azide CCCXXIIb to the lactam CCCXXIIIb was effected via intermediates CCCXXIIIbCCCXXVb as in the previously described Garrya sequence. This sequence constitutes a simple high-yield construction of the basic tetracyclic atisine skeleton (109).
CCCXXVII
CCCXXVIII
CCCXXIX; R = 0 CCCXXX; R =
<:I
I CCCXXXIV
CCCXXXIII
CCCXXXI; R = 0 CCCXXXII; R = /H ‘OH
A simple route for the elaboration of the CD ring system of atisine is illustrated with the model tetracyclic dl-olefin CCCXXVII which can be prepared from 2,6-dimethoxynaphthalene (108).Catalytic reduction of CCCXXVII followed by Birch reduction gave the ketone CCCXXVIII. Irradiation of the latter in an excess of allene results in cis addition t o the less-hindered side of the molecule to give compound CCCXXIX. The corresponding ketal (CCCXXX) was oxidized with Os04/NaI04 to afford ketone CCCXXXI. Hydride reduction of CCCXXXI gave the hydroxyketal CCCXXXII which was treated with dilute sulfuric acid in THF. The product consisted of a mixture of epimeric alcohols (CCCXXXIV) formed via the ketoaldehyde CCCXXXIII. Since con-
2.
THE
Czo-DITERPENE ALKALOIDS
199
version of a ketal comparable to CCCXXXIV t o a compound containing the CD ring system of atisine has been reported by Bell and Ireland (46), this procedure promised a useful synthetic approach t o atisine (108).
0
0 CCCXXVIb
cccxxxv
CCCXXXVI; R CCCXXXVII; R
CCCXLII
CCCXLI
=0
=<:I
CCCXXXVIII; R = CHz CCCXXXIX; R = 0 CCCXL; R = OH, H
f
CCCXLIII
CCCXLIV
I CCCXLVI
CCCXLV
t t
Atisine
I n a recent paper (109)this promise has borne fruit by conversion of lactam CCCXXVIb to a compound which has previously been converted to atisine. Thus reduction of CCCXXVIb with lithium in liquid ammonia,
200
S. W. PELLETIER AND L. H. KEITH
THF, and tert-butanol, followed by hydrolysis gave a 74% yield of lactone CCCXXXV. Irradiation of the latter in the presence of a large excess of allene gave the photoadduct CCCXXXVI. Reduction of the corresponding dioxalane derivative CCCXXXVII with LiAlH4 in dioxane followed by acetylation afforded the N-acyl derivative CCCXXXVIII. Oxidation of the latter with Os04/NaI04 gave the cyclobutanone CCCXXXIX,
CCCXLVII; R' = OH, R2= CHz CCCXLVIII; R 1 = Hz, RZ = 0
CCCLI
CCCXLIX
CCCL
CCCLII
which ori subsequent reduction with NaBH4 in methanol gave the alcohol CCCXL. Hydrolysis of the latter proceeded via the aldehyde CCCXLI to give a pair of epimeric hydroxy ketones (CCCXLII). This mixture was mesylated and dehydrated to give the olefin CCCXLIII. Reduction of this olefin over Pd/charcoal gave the dl-ketone CCCXLIV in 20% overall yield from ketal CCCXXXVII. The corresponding optically active ketone was prepared from the ketol acetate CCCXLV [previously reported as a degradation product of atisine by Pelletier and Parthasarathy (SS)] by reduction with calcium in liquid ammonia. The optically active ketone CCCXLV was subjected to a Wittig reaction to give the methylene derivative CCCXLVI. Since the conversion of CCCXLVI to
2.
201
THE Czo-DITERPENE ALKALOIDS
atisine already has been described (96) the preparation of dl-ketone CCCXLIV represents a synthesis of dl-atisine. An interesting conversion of the diterpene trichokaurin (CCCXLVII) into atisine, garryine, and veatchine has been described (110).The keto acetate CCCXLVIII, derived from trichokaurin, when treated with calcium in liquid ammonia afforded the alcohol CCCX-LIXand the trio1 CCCL. Wolff-Kishner reduction of the latter followed by catalytic hydrogenation gave the diol CCCLI. Oxidation of the latter with Jones reagent gave the ketocarboxylic acid CCCLII. This compound has already been converted into atisine ( l 0 4 ) ,garryine (103),and veatchine (59).
cccLIII
CCCLIV
CCCLV
\
T CCCLVIII
\
CCCLVII
CCCLVI
A synthesis of garryine, veatchine, and atisine from ( - )-abietic acid also has been described (111). The diterpene alkaloid songorine (XXVIIa),despite its close relationship to veatchine, requires the development of synthetic methods unlike those used for the synthesis of veatchine. A synthesis of keto ester CCCLIII would permit elaboration of ring A and the nitrogen ring after which the CD ring system could be constructed from the substituted benzene ring by methods similar to those used in the veatchine synthesis (106). A four-step stereospecific synthesis of CCCLIII (R1= H, R2= -SO&&) has been reported (112).Cyclopentadiene carboxylic ester (CCCLIV)was allowed to react with the benzyne precursor CCCLV. The product (CCCLVI) (yield 30 yo)was treated with benzenesulfonyl azide to give the aziridine (CCCLVII) in a yield of 83%. Hydrolysis of the aziridine gave the hydroxy ester (CCCLVIII)in a yield of 97 %. Oxidation of CCCLVIII with Jones reagent gave CCCLIII (R1= H, R2= -SO&&s) in a yield of 87%. The hydroxy ester CCCLVIII may also be obtained by
202
S . W . PELLETIER AND L. H. KEITH
acetolysis of CCCLVII followed by hydrolysis of the acetoxy group with methanolic hydrochloric acid. Several other interesting approaches to the Czo-diterpene alkaloids have been reported (46, 113-138)-some involving total synthesis and others partial synthesis from natural products. Very brief surveys of diterpene alkaloid chemistry have also been published (139-141). ACKNOWLEDGMENTS The authors’ work reviewed in this chapter was supported by grants from the National Institutes of Health, U. S. Public Health Service. Appreciation is expressed to the Pergamon Press (London),to the Chemical Society (London),and to Experientia (Basel) for permission to use certain sections of review articles published in Tetrahedron 14, 76-1 12 (1961); Qucrrterly Rewiew.us ( L o n d o n ) 21, 525-548 (1967), and Ezperietiticr 20, 1-10 (1964), respectively.
REFERENCES 1. S. W. Pelletier, Quart. Rev. ( L o d o n ) 21, 525-548 (1967). 2. S. W. Pelletier, Ezperieritin 20, 1-10 (1964). 3. S. W. Pelletier, Tetrahedron 14, 76-112 (1961). 4 . H.-G. Boit, “Ergebnisse der Alkaloid-Chemie bis 1960,” pp. 851-905 and 1009-1010. Akademie Verlag, Berlin, 1961. 5. A. R. Pinder, in “Chemistry of Carbon Compounds” (E. R. Rodd, ed.), Vol. IVc, pp. 2019-2033. Elsevier, Amsterdam, 1960. 6. E . S. Stern, im “The Alkaloids” (It.H. F. Manske, ed.), vol. 7, pp. 473-503. Academic Press, New York, 1960. 7. K. Wiesner and Z. Valenta, Progr. Chem. Org. N u t . Prod. 16,26-63 (1958). 7a. M. F. Barnes and J. MacMillan, J . C‘hem.Soc., C 361 (1967). 8. K. Wiesner, Z. Valenta, J. F. King, R. K. Maudgal, L. G. Humber, and S. It6, Chem. & Znd. (London) 173 (1957). 9. A. D. Kuzovkov, J . Gen. Chem. 1JSSR (Ev:rLglishTrnnsl.) 28, 2320 (1958). 10. A. D. Kuzovkov, J . Gen. Chem. CSSR (Etaglish Troaxl.)29, 1706 (1959). 11. K. Wiesner, 8. ItB, and Z. Valenta, Equerieritirc 14, 167 (1958). 12. E. Ochiai, T. Okamoto, S. Sakai, T. Sugasawa, and T. Onouchi, Chem. &Pharm. Bull. (Tokyo) 7 , 542 (1959). 13. T. Sugasawa, Chevn. & l’harm. Bull. ( T o k y o )9, 889 (1961). 14. T. Sugasawa, C h e m & l’hririn. Bull. ( T o k y o ) 9, 897 (1961). 15. T. Okamoto, M. Natsume, Y. Iitake, A. Yoshino, and T. Amiya, Chem. & Phnrm. Bull. (Tokyo) 13, 1270 (1965). 16. A . Yoshino and Y. Iitaki, Actrc Cryst. 21, 57 (1966). 17. D. Dvornik and 0. E. Edwards, C’hein. & Znd. (London) 623 (1958); Cali. J. Chem. 42, 137 (1964). 18. 8. W. Pelletier and W. A. Jacobs,J. Am. Chein. Soc. 78, 4139 and 4144 (1956). 19. D. Ovornik and 0. E. Edwarda, Chem. & I d . (Londoti)248 ( 1 9 5 6 ) ;6‘wi.J.Chem. 35, 860 (1957). 20. C. F. Hucbner and W. A. Jacobs, J . B i d . Chem. 170, 203 (1047). 21. W. A. Jacohs,J. Or(]. Cl~ewi.16, 1593 (1951).
2 . THE C 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
2
0
- ALKALOIDS ~ ~ ~
~
~
203 ~ ~
S. W. Pelletier, Chem. & Ind. (London) 1116 (1958). S. W. Pelletier and P. C. Parthasarathy, J . Am. Chem. SOC.87, 777 (1965). W. A. Jacobs and L. C. Craig, J. Biol. Chem. 143, 589 (1942). A. J. Solo and S. W. Pelletier, Chem. & Ind. (London) 1108 (1960). D. Dvornik and 0. E. Edwards, Tetrahedron 14, 54 (1961). S. W. Pelletier, Chem. & Ind. (London) 1016 (1956); 1670 (1957). S. W. Pelletier, J . Am. Chem. SOC.87, 799 (1965). D. Dvornik and 0. E. Edwards, Chem. & Ind. (London)952 (1957). J. A. Goodson, J. Chem. SOC.245 (1945). N. Singh,J. Sci. I n d . Res. (Indin)20B, 39 (1961). N. Singh, A. Singh, and M. S. Malik, Chem. & Ind. (London) 1909 (1961). N. Singh and K. L. Chopra, J. Plucrm. Pharmacol. 14,288 (1962). S. W. Pelletier and L. Wright, unpublished work (1969). S. W. Pelletior, J . Am. Chem. SOC.82, 2398 (1960). S. W. Pelletier and D. M. Locke, J . Am. Chem. SOC.87, 761 (1965). 0. E. Edwards and R. Howe, Proc. Chem. SOC.62 (1959). J. W. ApSimon, 0. E. Edwards, and R. Howe, Can. J. Chem. 40, 630 (1962). 0. E. Edwards, Chem. Can. 1 3 , 4 2 (1961). H. Vorbrueggen and C. Djerassi, Tetrahedron Letters 119 (1961); J. Am. Chem. Soc.
84, 2990 (1962). 41. E. Mosettig, P. Quitt, U. Beglinger, J. A. Waters, H. Vorbrueggen, and C . Djerassi, J. Am. Chem. SOC.83, 3163 (1961). 42. C. Djerassi, P. Quitt, E. Mosettig, R. C. Cambie, P. S. Rutledge, and L. H. Briggs, J . Am. C'hem. SOC.83, 3720 (1961). 43. W. A. Ayer, C. E. McDonald, and G . G. Iverach, Tetrahedron Letters No. 17, 1095 (1963). 44. L. H. Zalkow and N. N. Girotra, J. Org. Chem. 28, 2037 (1963). 45. L. H. Zalkow and N. N. Girotra, J. Org. Chem. 29, 1299 (1964). 46. R. A. Bell and R. E. Ireland, Tetrahedron Letters No. 4, 269 (1963). 47. J. W. ApSimon and 0. E. Edwards, Cart. J. Chem. 40, 896 (1962). 48. W. A. Jacobs and L. C. Craig, J. Biol. Chem. 147,567 (1943). 49. K. Wiesner, S. K. Figdor, M. F. Bartlett, and D. R. Henderson, Can.J. Chem. 30,608 (1952). 50. C. Djerassi, C. R. Smith, A. E. Lippman, S. K. Figdor, and J. Herran, J . Am. Chern. SOC.7 7 , 4801 (1955). 51. 8. W. Pelletier and W. A. Jacobs, Chem. & Ind. (London) 1385 (1955). 52. 0 . E. Edwards and T. Singh, Curi. J . Chem. 32, 465 (1954). 53. I<. Wiesner and J. A. Edwards, Experientiu 11, 255 (1955). 80,5185 (1958). 54. N. J. Leonard, I(.Conrow, and R. R. Sauers, J . Am. Chem.SOC. 55. D. Dvornik and 0. E. Edwards, Proc. C'hem. Soc. 305 (1958). 56. A. J. Solo and S. W. Pelletier, Proc. Chem. Soe. 14 (1961). 57. S. W. Pelletier, K. W. Gopinath, and K. Kawazu, Chem. & Ind. (Loiidort) 28 (19GG). 58. 0. E. Edwards and T. Singh, Con. J . Chern. 33, 448 (1955). 59. S. W. Pelletier and K. Kawazu, ( J ~ L ~ W L& . I d . ( L o r ~ d o r 1879 ~ ) (1983). 60. S. W. Pelletier, K. Kawazu, and K. W. Gopinath, J . Am. CILem. Soc. 87, 5229 (1965). 61. W. A. Jacobs and L. C. Craig, J . Biol.C'ltem. 143, 605 (1942). 62. W. A. Jacobs and C. F. Huebner, J. Biol. (!hem. 170, 189 (1947). 62a. M. 11. Benn, Ctan. J . Chem. 44, 1 (1966). 63. A. J. Solo and S. W. Pelletier, J . Am. (,!hem. SOC. 81, 4439 (1959), 64. A. J. Solo and 8. W. Pelletier, J. Org. ('hem. 27, 2702 (1962).
~
~
204
S. W. PELLETIER A N D L. H. KEITH
65. M. Przybylska, Cun. J . Chem. 40, 566 (1962). 66. M. Przybylska, Acta Cryst. 16, 871 (1962). 66a. S . W. Pelletier, L. H. Keith, and P. C. Parthasarathy, J . Am. Chem. SOC.89, 4146 (1967). 66b. R. T. Aplin, M. H. Benn, S. W. Pelletier, A. J. Solo, 8. A. Telang, and H. Wright, Can. J. Chem. 46, 2635 (1968). 67. K. Wiesner, Z. Valenta, and L. G . Humber, Tetrahedron Letters No. 14, 621 (1962). 68. E. Ochiai, T. Okamoto, T. Sugasawa, and H. Tani, J . Phurm. SOC. Japan 27, 1605 (1952). Japan 69. E. Ochiai, T. Okamoto, T. Sugasawa, H. Tani, and H. S. Hai, J . Phurm. SOC. 27, 816 (1952). 70. E. Ochiai, T. Okamoto, S. Sakai, M. Kaneko, K. Fujisawa, U. Nagai, and H. Tani, J . Pharm. SOC. J a p a n 76,550 (1956). 71. E. Ochiai, T. Okamoto, T. Sugasawa, H. Tani, S. Sakai, H. S. Hai, and H. Endo, Pharm. Bull (Tokyo) 1, 60 (1953). 72. E. Ochiai and T. Okamoto, Chem. & Pharm. Bull. (Tokyo)7 , 550 (1959). 73. E. Ochiai, T. Okamoto, T. Sugasawa, and S . Sakai, Pharm. Bull. (Tokyo) 2, 388 (1954). 74. E. Ochiai, T. Okamoto, S. Hara, S . Sakai, ahd M. Natsume, Chem. & Pharm. Bull. (Tokyo)6, 327 (1958). 75. S . Hara and Y. Tokoushige, Chem. & Pharm. Bull. (Tokyo)8, 976 (1960). 76. E. Ochiai and T. Okamoto, Chem. & Pharm. Bull. (Tokyo)7, 556 (1959). 77. E. Ochiai, T. Okamoto, T. Sugasawa, H. Tani, and S. Saksi, Pharm. Bull. (Tokyo) 1, 152 (1953). 78. S. Sakai, J. Pharm. SOC. J a p a n 76, 1054 (1956). 79. S. Sakai, Chem. & Pharm. Bull. (Tokyo)6,448 (1958). 80. S. Sakai, Chem. & Pharm. Bull. (Tokyo)7, 50 (1959). 81. S. Sakai, Chem. & Phurm. Bull. (Tokyo)7, 55 (1959). 82. H. Suginome and F. Shimanouchi, Ann. 545,220 (1940). 83. H. Suginome and S. Imato, J . Fac. Sci., Hokkaido Uniw., Ser. I Z I 4, 33 (1950). 84. H. Suginome and S. Umezawa, J . Fuc. Sci., Hokktaido (Jniw., Ser. Z Z Z 4, 14 (1950). 85. H. Suginome, S. Kakimoto, and J. Sonoda, J . Fac, Sci., Hokkaido Uniw., Ser. ZZI 4, 25 (1950). 86. M. Natsume, Chem. & Pharm. Bull. (Tokyo)7 , 539 (1959). 87. T. Okamoto, C'hem. & Phurm. Bull. (Tokyo) 7, 44 (1959). 88. T. Okamoto, M. Natsume, H. Zenda, S. Kamata, and A. Yoshino, Abstr. Pupsrs, I.U.P.A.C.Symp. Chem. Nut. Prod., Kyoto, Japan, 1964, 115 (1964). 89. H. Suginome, T. Koyama, and Y. Kunimatsu, J . Fac. Sic., Hokkrtido Uniw., Ser. IZI 4, 16 (1950). 90. M. Natsume, Chem. & Pharm. Bull. (Tokyo) 10, 879 (1962). 91. M. Natsume, Chem. & Pharm. Bull. (Tokyo) 10, 883 (1962). 92. E.-Ochiai, T. Okamoto, S. Sakai, and S . Inoue, J . Pharm. SOC.J a p a n 75, 638 (1955). 93. T. Okamoto, ilz. Natsume, and S. Kamata, C'hem. & Phurm. Bull. (Tokyo) 12, 1124 (1964). 94. V. I. Frolova, A. I. Ban'kovskii, A . D. Kuzovkov, and M. M. Molodozhnikov, Med. Prom. SSSR 18, 19 (1964). 95. G. Goto, K. Sasaki, N. Sakabe, and Y. Hirata, Tetrahedron Letters No. 11, 1369 (1968). 96. S. W. Pelletier and P. C. Parthasarathy, Tetrnhedron Letters No. 4,208 (1963).
2.
THE
CZO-DITERPENE ALKALOIDS
205
97. W. Nagata, T. Sugasawa, M. Narisuda, T. Wakabayashi, and Y. Hayase, J. Am. Chem. SOC.85, 2342 (1963). 98. W. Nagata, T. Sugasawa, M. Narisuda, T. Wakabayashi, and Y. Hayase, J . A m . Chem. SOC.89, 1483 (1967). 99. W. Nagata, M. Narisuda, T. Wakabayashi, and T. Sugasawa,J. Am. Chem. SOC.86, 929 (1964). 100. W. Nagata, M. Narisuda, T. Wakabayashi, and T. Sugasawa, J . A m . Chem. SOC.89, 1499 (1967). 101. K. Wiesner, W. I. Taylor, S. F. Figdor, M. F. Bartlett, J. R. Armstrong, and J. A. Edwards, Ber. 86, 800 (1953). 102. S. Masamune,J. Am. Chem. SOC.86, 288 (1964). 103. S. Masamune, J. Am. Chem. SOC.86, 290 (1964). 104. S. Masamune,J. Am. Chem. SOC.86, 291 (1964). 105. Z. Valenta, K. Wiesner, and C. M. Wong, Tetrahedron Letters No. 36, 2437 (1964). 106. R . W. Guthrie, W. A. Henry, H. Immer, C. M. Wong, Z. Valenta, and K. Wiesner, Collection Czech. Chem. Commun. 31, 602 (1966). 107. J. A. Findlay, W. A. Henry, T. C. Jain, Z. Valenta, K. Wiesner, and C. M. Wong, Tetrahedron Letters No. 19, 869 (1962). 108. R. W. Guthrie, A. Philipp, Z. Valenta, and K. Wiesner, Tetrahedron Letters No. 34, 2945 (1965). 109. R. W. Guthrie, Z. Valenta, and K. Wiesner, Tetrahedron Letters No. 38, 4645 (1966). 110. E. Fujita, T. Fujita, and M. Shibuya, Chem. Commun. 468 (1967). 111. A Tahara and K. Hirao, Tetrahedron Letters No. 14, 1453 (1966). 112. K. Wiesner and A. Philipp, Tetrahedron Letters No. 14, 1467 (1966). 113. I. Iwai, A. Ogiso, and B. Shimizu, Chem. & Ind. (London) 1288 (1962). 114. I. Iwai and A. Ogiso, Chem. & Ind. (London) 1084 (1963). 115. B. Shimizu, A. Ogiso, and I. Iwai, Chem. & Pharm. Bull. (Tokyo) 11, 333 (1963). 116. B. Shimizu, A. Ogiso, and I. Iwai, Chem. & Phurm. Bull. (Tokyo) 11, 766 (1963). 117. A. Ogiso, B. Shimizu, and I. Iwai, Chem. & Pharm. Bull. (Tokyo) 11, 770 (1963). 118. A. Ogiso, B. Shimizu, and I. Iwai, Chem. & Pharrn. Bull. (Tokyo) 11, 774 (1963). 119. A. Ogiso and I. Iwai, Chem. & Pharm. Bull. (Tokyo) 12, 820 (1964). 120. A. A. Othman and N. A. J. Rogers, Tetrahedrow Letters No. 20, 1339 (1963). 121. W. L. Meyer and A. S. Levinson, Proc. Chem. SOC.15 (1963). 122. W. L. Meyer and A. S. Levinson, J . Org. Chem. 28, 2859 (1963). 123. T. Matsumoto and A. Suzuki, Bull. Chem. SOC.Japan 34, 274 (1961). 124. T. Matsumoto, M. Yanagiya, E. Kawakami, T. Okuno, M. Kakizawa, S. Yasuda, Y. Gama, J. Omi, and M. Matsunaga, Tetrahedron Letters No. 9, 1127 (1968). 125. L. H. Zalkow and N. N. Girotra, J. Org. Chem. 28, 2037 (1963). 126. L. H. Zalkow and N. N. Girotra, J . Org. Chem. 29, 1299 (1964). 127. L. H. Zalkow and N. N. Girotra, Chem. & Ind. (London) 704 (1964). 128. N. N. Girotra and L. H. Zalkow, Tetrahedron 21, 101 (1965). 129. L. H. Zalkow, N. N. Girotra, and V. B. Zalkow, J . Org. Chem. 32, 806 (1967). 130. L. H. Zalkow, B. Kumar, D. H. Miles, and J . Nabors, Tetrahedron Letters No. 16, 1965 (1968). 131. D. H. R. Barton and J. R. Hanson, C'hem. Commun. 117 (1965). 132. R. A. Finnegan and P. L. Bachman, J. Org. Chern. 30, 4145 (1965). 133. A. Tahara, K. Hirao, and Y. Hamazaki, Chem. & Ind. (London)850 (1965). 134. A. Tahara, K. Hirao, and Y. Hamazaki, Tetrahedron 21, 2133 (1965). 135. A. Tahara, K. Hirao, and Y. Hamazaki, Chem. & Phorm. Bull. (Tokyo)15,1785 (1967).
206
S. W. PELLETIER AND L. H. KEITH
136. 137. 138. 139. 140. 141.
A. A. Othmann, M. A. Qasseem, and N. A. J. Rogers, Tetrahedron 23, 87 (1967). K. Wiesner, A. Philipp, and P . Ho, TetrahedronLettem No. 10, 1209 (1968). J. R. Hanson, Tetrahedron 22, 1701 (1966). E. Fujita, Bull. Znst. Chem. Res., Kyoto Univ. 43, 278 (1965). E. Fujita, Bull. h s t . Chem. Res., Kyoto Univ. 44, 239 (1966). E. Fujita, Bull. Znst. Chem. Res., Kyoto 1Jniv. 45, 252 (1967).
-CHAPTER
3-
ALKALOIDS OF ALSTONIA SPECIES J. E. SAXTON The Uiaiversity, Leeds, England
I. Occurrence . . . . . . . . . . . . . . . . . . . 11. Venenatine, Isovenenatine 111. Tetrahydroalstonine, Alsto
............................ ............
207 209
..........................
V. VI. VII. VIII.
Alstophylline. . . . . . . . . . . . ..................... Macralstonine ....................... Macrosalhine . . . . . . . . . . . . Macralstonidine . . . . . . . . . ................... References . . . . . . . . . . . . . . ...................
I. Occurrence
In the period that has elapsed since the preparation of Volume VIII in this series, some notable investigations on the Alstonia alkaloids have been reported and several new alkaloids have been isolated; the occurrence of Alstonia alkaloids in other genera has also been observed. The
G:k aT@ H
H
HO
\
CHOHMe
COOMe
Me
H
I
I1
Echitamine
Echitamidine
H,,COOMe
I11 Picrinine
die
208
J. E. SAXTON
presence of alstonine ( 1 ) and tetrahydroalstonine (2-4) in the roots of Vinca rosea L. (Catharanthus roseus G. Don) has again been noted; alstonine also occurs in the root bark of RauwolJa vomitoria Afzel ( 5 ) , while the leaves of the same species contain tetrahydroalstonine ( 6 , 7). The bark of Alstonia scholaris R. Br. has long been known to contain echitamine (I) and echitamidine (19-hydroxy-19,20-dihydroakuammicine) (11); a recent investigation of the leaves of this species has revealed the presence of picrinine (deacetyldeformopicraline) (111) (8).
IV
v
Kopsinine
Venalstonine
VI; Echitovenine, R = COMe VII; Echitovenidine, R = COCH=CMeZ VIII; (+)-Minovincinine, R = H
VIIIa Venoterpine
The bark of A . macrophylla Wall. contains, in addition to the five known alkaloids (villalstonine, macralstonine, macralstonidine, macrophylline, and Alkaloid M), a new tertiary base, alstophylline, CzzHz~Nz03 (mp 155"-158"; [a],)- 151" (MeOH)) (9, lo),and a quaternary alkaloid, macrosalhine (10a).The roots of this species contain different alkaloids from the stem bark, and the principal base appears to be Alkaloid 1, C44H54N405 (mp 270"-272'), a diacidic base about which little is known a t present (11).The only other Alstonia species t o have been examined recently is A . venenata R. Br. Brief comment was made on the first of these investigations in Volume V I I I ; in the intervening period intensive investigation has shown that this species is moderately rich in alkaloids, only one of which has been encountered in other Alstonia species. The bark of A . venenata contains reserpine, venenatine (12),3-isovenenatine (alstovenine) (12, 13), venoxidine (venenatine N,,-oxide) ( 1 4 ) ,kopsinine
3.
ALKALOIDS OF
Alstonia SPECIES
209
(IV) (14,15),venalstonine (V),venalstonidine (venalstonine 6,7-epoxide), and echitovenine (VI) (16).The fruits of the same plant contain echitovenidine (VII), ( + )-minovincinine* (VIII) ( 1 7 ) )and the monoterpenoid alkaloid, venoterpine (probably VIIla) (17a); the co-occurrence of venoterpine with typical indole alkaloids in this plant is of considerable interest biogenetically. Venalstonine and venalstonidine also occur in the bark of Melodinus australis (F.Muell.) Pierre (18). 11. Venenatine, Isovenenatine, and Venoxidine
Venenatine, C22HzsN204 [mp 123'-126" dec; [a]?' - 76.1'; pK, 7.2 (in methyl Cellosolve)] is a tertiary base which contains two methoxyl groups and two active hydrogen atoms but no C-methyl or N-methyl groups (12, 15, 19). I t s UV spectrum ,,,A,(, 226, 271, and 293 mp) resembles that of an ar-methoxy-2,3-disubstituted indole, the methoxyl group probably being attached to position 4; this is confirmed by the NMR spectrum which, in the aromatic region, closely resembles that of mitragynine. This position of the methoxyl group is also supported by the result of demethylation of venenatine with boiling hydrochloric acid, which yields a phenolic acid, norvenenatic acid; this gives a positive Gibbs' test, indicating the presence of an unsubstituted position para t o the phenolic hydroxyl group. The I R spectrum of venenatine discloses the presence of a hydroxyl group, an imino group, and an ester function. That this is a methyl ester function is shown by the NMR spectrum, by saponification, which afFords venenatic acid, C2lH2sN204.2H20, and by lithium aluminum hydride reduction, which gives venenatyl alcohol, CzlHzsNz03. Esterification of venenatic acid with methanol and hydrogen chloride regenerates venenatine. Oppenauer oxidation of venenatine gives a ketone, C Z O H Z ~ N ~by O Zoxidation , of a secondary hydroxyl group and concomitant loss of the ester function. The presence of a secondary hydroxyl group in venenatine is also shown by the NMR multiplet a t 4.2 ppm (CHOH), which is shifted t o 5.37 ppm on acetylation (12, 15, 19). These reactions are characteristic of a methoxyyohimbine, a conclusion which is amply supported by the striking similarity between the mass spectra of venenatine and 3-epi-a-yohimbine, if appropriate allowance is made for the presence of an additional (aromatic) methoxyl group in venenatine ( 1 2 ) . The position of this aromatic methoxyl group was rigorously established by selenium dehydrogenation of venenatic acid,
* These last six alkaloids are discussed in greater detail in the chapter on alkaloids of Aspidosperma and related genera in Vol. XI of this series.
210
J. E. SAXTON
which gave 5-methoxyyobyrine (IX) (15)) identical with authentic material prepared by an unambiguous synthesis (20). Venenatine is thus a 9-methoxyyohimbine and may be formulated as X (stereochemistry so far not defined).The stereochemistry of venenatine was unequivocally deduced as follows. Reaction of venenatine with tertbutyl hypochlorite gave the corresponding 7-chloroindolenine derivative, which was converted by methanolic hydrogen chloride into As-dehydrovenenatine. Reduction of the latter with sodium borohydride yielded OMe
OMe
OMe
TsOe
I
bH IX
X
XI
Venenatine
3-epivenenatine) mp 169'-1 70', identical with naturally occurring isovenenatine (12).The reverse process can also be achieved by oxidation of isovenenatine (alstovenine) with mercuric acetate followed by reduction of the A3-dehydroisovenenatine thus produced with zinc dust and acetic acid. This yields a mixture of venenatine and isovenenatine, which are therefore C-3 epimers (12,19).I n contrast t o isovenenatine, venenatine is not readily oxidized by mercuric acetate ; this suggests the presence in venenatine of equatorial hydrogen at CI3 ( 1 2 , 1 9 ) ,a conclusion which is further supported by the downfield position (4.45 ppm) of the C-3 proton signal in the NMR spectrum (19).This confirms the presence of a cisquinolizidine system with equatorial hydrogen at C-3 (21).To complete the evidence, isovenenatine shows "trans" bands, i.e., fine structure on the long-wavelength side of the 2800-cm-1 band in the I R spectrum, consistent with the presence of a trans-quinolizidine system and axial hydrogen a t C-3 (12). The reaction of venenatyl alcohol with toluene-p-sulfonyl chloride in pyridine yields a quaternary tosylate (XI), which is presumably formed by intramolecular nucleophilic displacement of an initially formed primary tosylate by N , ; hence the D/E ring junction must be cis and the hydrogen a t C-16 must also be cis with respect to the hydrogen atoms a t C-15 and C-20. I n contrast, venenatine itself reacts with toluene-p-
3.
ALKALOIDS OF
Alstonia
SPECIES
21 1
sulfonyl chloride in pyridine to give a C-17 0-tosylate, hence the tosyloxy group must be unfavorably oriented to allow internal attack by N , . Consequently the tosyloxy group in the derivative, and the original hydroxyl group in venenatine, must be oriented /3, i.e., axial. The complete structure and stereochemistry of venenatine are therefore as given in X and isovenenatine differs by the configuration at C-3 (12,15). Venoxidine, CzzHzsN205 [mp 218O-219O dec; [a]gO- 58.2' (HzO); pK, 4.6 (in HzO)] is a weak base, soluble in water, but insoluble in most organic solvents, which was proved to be simply venenatine N,-oxide (14).Hydrogenation of venoxidine over a platinum catalyst, reduction with zinc and acetic acid, or reduction with ferrous sulfate afforded venenatine, and the latter could be reconverted into ven oxidine by oxidation with peracetic acid. Interestingly, the mass spectrum of venoxidine exhibited a " molecular ion " peak a t m/e 384 (calculated : 400) and showed a fragmentation pattern identical with that of venenatine. This was evidently the result of loss of an oxygen atom by thermal decomposition at the vaporization temperature used in the mass spectrometer (14).
111. Tetrahydroalstonine,* Alstoniline, and Echitamine By the end of 1962the stereochemistry shown in XI1 had been deduced for tetrahydroalstonine and the evidence on which this conclusion was based was briefly outlined in Volume VIII. This evidence included the chemical correlation of tetrahydroalstonine with transformation products of corynantheine and corynantheidine, which firmly established the presence of a cis D/E ring junction. This was consistent with the weakly basic character of tetrahydroalstonine and with its low rate of reaction with methyl iodide. The methyl group attached to C-19 was placed cis with respect to the hydrogen atoms a t C-15 and C-20 on the basis of the NMR spectral data. The conformation XI1 for tetrahydroalstonine has been further consolidated in a detailed discussion of the stereochemistry of 12 heteroyohimbine alkaloids (22).The general validity in this series of alkaloids of the evidence derived from the dissociation constants, the rate of methiodide formation, and the NMR spectrum has been firmly established, and some new evidence has been added. Thus, the I R spectrum of tetrahydroalstonine exhibits " trans" bands in the 2800-cm-1 region as expected; this confirms that it belongs to the allo series and not the
* For a recent total synthesis of tetrahydroalstonine see Winterfeldt et al. (21a).
212
J. E. SAXTOW
epiallo series. I n the NMR spectrum the exact position of the doublet owing to the methyl group attached to C-19 (1.38 ppm) allows the alkaloids to be assigned to their stereochemical series ; tetrahydroalstonine belongs to a group which includes aricine, reserpinine, and isoreserpiline, in which the C/D ring junction is trans and the C-18 methyl group is CL and equatorial to ring E. The C/D ring fusion is also trans in tetrahydroalsto\@
nine methiodide; in general the protons of the TNMe group in quinolizidinium salts absorb a t lower fields in the cis series than in the trans series ( 2 3 ) .I n the series of alkaloids studied it was apparent that tetrahydroalstonine methiodide belongs to a group which possess a trans C/D ring fusion ( 2 2 ) .
F=. O=C
O=;: OMe XI1 Tetrahydroalstonine
I
OMe
XIIIb
XIIIa
The optical rotatory dispersion of tetrahydroalstonine and 11 other heteroyohimbine alkaloids has also been investigated (24).All these bases show two Cotton effects, one in the region of 300 mp and the other a t 235-255 mp. However, there appears t o be no obvious relation between the sign of the Cotton effect near 300 mp and the absolute stereochemistry of the molecule. The Cotton effect a t 235-255 mp is ascribed to the C L , ~ unsaturated ester system adjacent t o C-15, which exhibits a UV absorption maximum a t 248 mp. Tetrahydroalstonine and five other bases which possess &-hydrogena t C-3 and C-20 show a negative Cotton effect a t 235-255 mp; all the other bases studied show positive Cotton effects in this region. It is tentatively suggested that the sign of the Cotton effect in these compounds is related to the chirality of ring E. I n tetrahydroCL ring E is shaped as shown in XIIIa alstonine and the other ~ C L , ~ Obases, and these compounds give rise to negative Cotton effects ;in all the other bases examined ring E has the opposite chirality (XIIIb) and positive Cotton effects are obtained (24). I n the alstoniline series full details of the total synthesis of alstoniline chloride by Ban and Seo have been published (25).
3.
ALKALOIDS OF
Abtonia
SPECIES
213
The structure of echitamine (I),as deduced from the X-ray crystal structure of echitamine iodide, has again been discussed (26, 27); the contribution by Manohar and Ramaseshan (27) gives full details of this particular application of the Bijvoet technique for the elucidation of absolute configuration.
IV. Villalstonine The structure of villalstonine (XIV),the principal alkaloid of Alstonia macrophylla, has recently been elucidated (28-32), mainly owing to the brilliant investigations of Hesse, Schmid, Taylor, and their collaborators (29, 30); their conclusions have been triumphantly confirmed by an independent X-ray crystal structure determination (31).Alkaloid B, one of the constituent bases of A . muelleriana Domin. (33),has been shown t o be identical with villalstonine (31),the early work on which (see Volume VIII) may be briefly summarized as follows. Villalstonine is a dimeric, diacidic base, which contains one methoxycarbonyl group, two methylimino groups, and an ethylidene group. I t s UV spectrum is consistent with the presence of indole and dihydroindole chromophores containing no substituents in the benzene rings. Alkali fusion yields 2-methylindole, indole 2-carboxylic acid, and a 8-carboline derivative ;selenium dehydrogenation also affords a /3-carboline derivative, so far unidentified. Acid hydrolysis of villalstonine yields pleiocarpamine (XV), one of the alkaloids of Pleiocarpa mutica Benth. The molecular formula of villalstonine, earlier presumed to be C40H~oN404,was subsequently corrected to C41H48N404 on the basis of the molecular weight (660) determined by mass spectrometry (28). The lithium aluminum hydride reduction of villalstonine gives villalstoninol, C40H48N403 (XIV ; COOMe -+ CH20H) by normal reduction of the methoxycarbonyl group ; the other two oxygen atoms remain unaffected. Since villalstonine, in contrast t o earlier reports, cannot be acetylated and shows no hydroxyl absorption in its I R spectrum, the remaining two oxygen atoms are probably contained in ether linkages. The UV spectra of villalstonine and villalstoninol are almost identical and are closely similar to the summation spectrum of 2,T-dihydropleiocarpamine and voachalotine, a derivative of N,-methyltetrahydro/3-carboline; hence, villalstonine almost certainly contains indole and indoline chromophores. The presence of an indoline grouping is also indicated by the absorption a t 1660 cm-1 in the I R spectra of villalstonine and villalstoninol, similar to that observed in the spectra of
214
J. E. SAXTON
2,7-dihydropleiocarpamine and 2,7-dihydropleiocarpaminol (2,7-dihydro-XVI). This band is absent from the spectra of indole derivatives (29, 30). The isolation of pleiocarpamine from the fission of villalstonine with 70% perchloric acid constituted an enormous advance toward the
H
XIV
Villelstonine
XV; Pleiocarpamine, R = COOMe XVI; Pleiocarpaminol, R = CHzOH
elucidation of its structure and efforts were then made to isolate the second cleavage product. Unfortunately, only unidentifiable decomposition products were obtained. Villalstoninol behaved similarly toward perchloric acid and only pleiocarpaminol (XVI) could be isolated. The same situation was encountered in the acid fission of 19,20-dihydrovillalstonine ; the only product that could be isolated was 19,20-dihydropleiocarpamine. Similarly, treatment of villalstonine with hydrochloric acid in the presence of tin, zinc, or stannous chloride gave only the pleio-
3.
ALKALOIDS OF
Alstonia
SPECIES
215
carpamine unit of the molecule as 2,7-dihydropleiocarpamine(29,30). These attempts at isolation of the second half of the molecule having been frustrated, other possible modes of degradation of villalstonine were explored. The reaction of villalstonine with a mixture of trifluoroacetic acid and trifluoroacetic anhydride afforded a mixture of two isomers of villalstonine, villoine and villamine (XVII). Villoine proved to be unstable toward acids and bases and was not further investigated. Villamine shows the same UV spectrum as villalstonine and also exhibits I R abscjrption owing to the ester group and the indoline ring. In contrast to its progenitor, however, it exhibits bands owing to an enol ether and a hydroxyl group; the presence of the latter was established by formation of an O-acetyl derivative. The mass spectrum of villamine (M 660) discloses an interesting fragmentation ; cleavage clearly occurs to give two units, of m/e 322 and 338, which together account for all the atoms of villamine. The peak at m/e 322 is due to pleiocarpamine and the one at 338 to the hitherto unknown second half of the molecule, designated macroline (XVIII). Macroline itself was prepared by pyrolysis of villamine a t 250°/0.01 mm, which gave a mixture of pleiocarpamine and macroline. The separation of these two tertiary bases was achieved by brief reaction with methyl iodide, which resulted in the preferential quaternization of pleiocarpamine, and thus allowed a convenient and efficient purification of macroline. The two components of the molecule thus being available, it was readily shown that subtraction of the mass spectrum of pleiocarpamine from that of villamine gave a spectrum essentially identical with that of macroline (29,30). Macroline, C21H26N202 (mp 21 lo-213O) is an indole derivative (UV spectrum) which contains a hydroxyl group and an a,p-unsaturated ketone function (IR spectrum). Its NMR spectrum discloses the presence of four aromatic protons, two vinyl protons (one of which shows fine splitting owing to coupling with an allylically situated proton), an N,-methyl group, an N,-methyl group, and a methyl ketone. These data indicate the presence in macroline of the part-structure X I X ; this conclusion was verified by a consideration of the spectra of its hydrogenation product, 20,21-dihydromacroline and its lithium aluminum hydride \ reduction product, macrolinol (XVIII, ,C=O + CHOH). Macroline did not give a homogeneous product on acetylation ; hence O-acetylmacroline was prepared by pyrolysis of O-acetylvillamine and separation of the mixture of products by the partial quaternization method described above. The I R and NMR spectra of O-acetylmacroline also exhibited the characteristics expected of the part-structure XIX. The presence of two hydroxyl groups in macrolinol was established by the normal acetylation procedure, which gave 0,O-diacetylmacrolinol (29, 30).
216
J. E. SAXTON
On the basis of this evidence the structure XVIII was proposed as a working hypothesis for the structure of macroline; this proved t o be capable of providing a rational expIanation ofthe mass spectra ofrnacroline and its derivatives and was ultimately shown t o be correct. The mass spectrum of macroline indicates that two prominent fragmentation processes occur. The first of these leads to the p-carbolinium ion XXb a t
CHzOH
H XVII
Villamine
.3rz XIX 18
Me XVIII
Macroline
m/e 197, apparently by two alternative pathways, via XXa or XXc. The intermediacy of XXa a t m/e 320 agrees with the appearance of peaks a t m/e 322 in the mass spectra of macrolinol and dihydromacroline, the peak a t m/e 197 remaining unaffected. An alternative pathway to XXb was invoked to account for the formation of this fragment under conditions where the peak a t m/e 320 was not observed. This involves fission
3.
ALKALOIDS O F
Al8tOnia SPECIES
217
of the 3,14-bond in macroline to give a radical ion (XXc, m/e 338) which can break down t o the /3-carbolinium ion, XXb, via a cyclic transition state. The fragment responsible for the base peak a t m/e 197was assigned the /3-carbolinium ion structure (XXb) by analogy with the compound X X I which gave a base peak a t m/e 215 in its mass spectrum owing to the fragment XXII. However, XXb contains two fewer hydrogen atoms in ring C than does XXII, a fact which indicates that the precursor of XXb, i.e., macroline, possesses one additional substituent attached t o either C-5 or (2-6. The second fragmentation undergone by macroline begins with a retro Diels-Alder reaction in ring C t o give an ion (XXd) in which the 14,15-bond is allylic to both the 2,3- and 20,21-bonds. Fission of the 14,15-bond thus gives the ion XXe (m/e 170); alternatively, hydrogen migration and fission of the 15,16-bond gives the important fragment XXf, a t m/e 251. From XXf arise the radical ions XXg, a t m/e 208; XXi, a t m/e 181, and XXj, a t m/e 182. These last two fragments presumably originate from cyclization of XXf followed by further fragmentation. I n support of these assignments the mass spectrum of O-acetylmacroline contains the same important peaks and the mass spectra of 20,2 1-dihydromacroline and macrolinol also contain peaks owing to XXb, XXe, XXi, and XXj. However, in the mass spectrum of 20,21-dihydromacroline the peaks corresponding t o XXf and XXg are observed a t m/e 253 and 210, respectively, and in the mass spectrum of macrolinol they appear a t m/e 253 and 208. Additional evidence for the presence of the Nb-methyl group in the fragments which give rise t o the peaks a t m/e 320 and 197 was provided by the mass spectrum of an (approximately) equimolecular mixture of macroline and Nb-da-macroline, prepared by pyrolysis of N,-trideuteromethylmacroline iodide ; here the peaks a t m/e 338, 320, and 197 were each twinned with equally intense peaks a t m/e 341, 323, and 200, respectively, the peaks having half the intensity of the corresponding ones in the spectrum of macroline (29). Perhaps the most convincing evidence in support of structure XVIII for macroline was provided by the mass spectra of the two epimeric degradation products of ajmaline, XXIIIa and XXIIIb. These compounds give almost identical spectra, the only differences occurring in the relative intensities of the corresponding peaks. In these spectra the most prominent peaks are a t m/e 326 (M+), 197 (owing to XXb), 329 (XXIVa, cf. XXfin the spectrum ofmacroline), 210 (XXIVb, cf. XXg), 182 (XXj), 181 (XXi),and 170 (XXe).Hence a completely analogous fragmentation to that postulated for macroline occurs with the two compounds XXIIIa and XXIIIb of known structure (89).
218
m
t
J . E. SAXTON
m n
cr)
. ..
E
A x
3. ALKALOIDS OF
?ZS
x
8 z
SPECIES
i!
Y
x
0;1
Alstonia
;
B x
#’
?Z.J
$j \ /
219
220
J. E. SAXTON
The structures of pleiocarpamine and macroline having been elucidated, the constitution of villamine can now be considered. Villamine contains a methoxycarbonyl group and one hydroxyl group, the latter corresponding to the primary hydroxyl group in macroline, since pyrolysis of 0-acetylvillamine (which shows no hydroxyl absorption in its I R spectrum) affords 0-acetylmacroline. The fourth oxygen atom in villamine is not present in a hydroxyl group and is very probably contained in an ether linkage. One of the indole rings in the fission products is present in villamine as a dihydroindole ring system (UV spectrum) while the a$-unsaturated ketone grouping, present in macroline, must be
XXIIIa; R = H, R’ = Et XXIIIb; R = Et, R’= H
XXIVa; m/e 239
XXIVb; m/e 210
contained in some other form in villamine since this chromophore is not present (IR and NMR spectra). The complex NMR spectrum of villamine contains several absorptions that can also be discerned in the These include a quartet with spectrum of 2,7-dihydropleiocarpamine. fine structure centered on 5.37 ppm (C-19H), a doublet a t 4.44 ppm (probably C-16H), and a doublet a t 1.55 pprn (C-19methyl group), in addition to the methyl of the methoxycarbonyl group. I n the lOO-Mc/sec spectrum the protons a t C-21give rise t o a doublet a t 4.30ppm. Hence in villamine the pleiocarpamine unit can not be attached via C-16,C-15,or the C-18to C-21system to the macroline unit, neither can a union involving the aromatic positions be entertained, since villamine contains eight aromatic protons (NMR spectrum). I n villamine, therefore, positions 2 and 7 of pleiocarpamine must be attached to the a,P-unsaturated ketone grouping of macroline; of the various possibilities XVII was proposed since this accounts for the chemistry and spectra of villamine in an entirely satisfactory way and its biogenetic origin can also be most easily rationalized. I n this structure the fourth oxygen atom appears in an enol ether function while the C-18’methyl group is evidently the one responsible for a singlet a t 1.31 ppm in the NMR spectrum. The pyrolysis of villamine is thus seen to be a retro Diels-Alder reaction which results in cleavage of the dihydropyran ring. The structure XVII for villamine thus leads to the constitution XIV for villalstonine; this is in complete accord with the UV, I R , and
3.
ALKALOIDS O F
AktOlzia
SPECIES
22 1
NMR spectra of villalstonine, which show a marked overall similarity t o the corresponding spectra of villamine. The most significant differences concern the bands owing to the hydroxyl group and the enol ether function in the IR spectrum of villamine ;these are absent from the spectrum of villalstonine. The C-18' methyl group, which is now attached t o a ketal carbon atom, gives rise t o a singlet a t 1.22 ppm in the NMR spectrum. I n accordance with the structures XVII and XIV, villamine can be reconverted into villalstonine by treatment with methanolic hydrochloric acid (29, 30). The mass spectrum of villalstonine indicates that in addition t o cleavage to pleiocarpamine (m/e 322) and a unit (m/e 338) related to macroline, a second important fragmentation process occurs which gives rise t o a peak at m/e 352 ; its partner is presumably the minor peak at m/e 308. The base peak in the spectrum (at m/e 121) is one which is not by any means prominent in the spectrum of villamine and is considered t o be related to that a t m/e 352. This second fragmentation is postulated
QJ-m N
I
0 MeO
I
J
XXV; m/e352
\
XXVIa; m/e 121
XXVIb; m/e 135
222
J. E. SAXTON
to involve the fission of the tetrahydropyran ring in villalstonine in an alternative sense to give, as one of the products, the ion XXV. This suffers further degradation to give the radical ions responsible for the peaks a t m/e 121 (XXVIa),135 (XXVIb),and 107 (XXVIc);these occur in the spectrum of villalstonine in addition to the characteristic peaks derived from the macroline and pleiocarpamine units of the molecule. The cleavage of villalstonine to give XXV is of particular importance as the latter contains one carbon atom and one oxygen atom more than does pleiocarpamine. It thus provides strong support for the proposal that the union between the two halves in the villalstonine molecule involves one carbon-carbon and one carbon-oxygen bond. A priori, there are two structures that can be written for villalstonine in which the 2,7-double bond of pleiocarpamine is attached to the a$-unsaturated ketone function of the macroline molecule. However, it is reasonable to suppose that the biosynthesis of villalstonine actually involves a coupling of this kind, and the most acceptable rationalization of this process leads only to the structure XIV for villalstonine as shown in the following part-formulas :
6'
XIV
The structure XIV for villalstonine receives convincing support from the prolonged reduction with lithium aluminum hydride which affords villalstonine triol (XXVII) and isovillalstonine triol, two stereoisomers which presumably differ by the configuration a t C-19'. The mass spectra of villalstonine triol and its triacetate are completely in accord with the structures proposed, and demonstrate that in these molecules the attachment of the two halves is by means of one single carbon-carbon bond. Consequently, the carbon-oxygen bond must have been severed during
3.
ALKALOIDS OF
Alstorzia
SPECIES
223
the course of the reduction; this, and the fact that a triol is formed, are best explained by the presence in villalstonine of an aminoketal function, which can suffer hydrogenolysis to an amino diol, the third alcohol function in the product originating from the methoxycarbonyl group (30).
XXVII
Villalstonine triol
As was mentioned above these conclusions were strikingly confirmed by a definitive X-ray crystallographic study of the structure of villalstonine ; this investigation also established that the relative stereochemistry is as shown in XIV (31).If the assumption is made that villalstonine possesses the same absolute configuration at C-15 and C-15’ as all the yohimbine and heteroyohimbine alkaloids, then XIV also represents the absolute configuration of the molecule.
V. Alstophylline Alstophylline, C22H26N203, the tertiary base recently isolated from the bark of A . macrophylla, is a “monomeric” alkaloid of structure XXVIII (9).The presence in themolecule of the/l-alkoxy-a,B-unsaturated ketone grouping was deduced from the I R spectrum, which exhibits maxima at 1616 and 1640 cm-1 similar to those exhibited by dimedone methyl ether (XXIX). This deduction is also cornsistent with the UV spectrum of alstophylline which closely resembles the summation spectrum of XXIX and 7-methoxy-9-methyl-l,2,3,4-tetrahydrocarbazole (XXX). The NMR spectrum of alstophylline confirms this orientation of the methoxyl group. I n the aromatic region (6.60-7.52ppm) the integrated signals disclose the presence of four protons, i.e., three aromatic ones and the olefinic proton /3 to the carbonyl group. If the
224
J. E. SAXTON
signal owing to this olefinic proton is ignored the aromatic proton multiplets are very similar t o those exhibited by XXX and quite different from the pattern of absorption shown by its methoxyl isomers. Other signals evident in the NMR spectrum of alstophylline are those owing to the N,-methyl and N,-methyl groups and the methyl ketone function; there are no absorptions in the normal olefinic proton region (9).
XXVIII Alstophylline
8 Me
OMe
Me XXIX
xxx
Chemical confirmation of the presence in alstophylline of the unsaturated ketone grouping was provided by reduction and by acid hydrolysis. Alstophylline is resistant to hydrogenation under ordinary conditions but the ketone function can be reduced by sodium borohydride. The product, alstophyllinol, exhibits the spectral characteristics expected of the related secondary alcohol. I t s UV spectrum is identical with that of XXX and its IR spectrum lacks the carbonyl band a t 1618 cm-1; instead, it contains a hydroxyl band a t 3630 cm-1. Two bands, at 1622 and 1653 cm-1, correspond, respectively, t o the aromatic and olefinic stretching frequencies. The NMR spectrum contains a doublet a t 1.06 ppm (3H, CH3CH:) instead of the methyl ketone singlet, and the olefinic proton now appears at 6.45 ppm as a singlet with fine (allylic) splitting (9). The acid hydrolysis of alstophylline affords formic acid and the methyl ketone XXXI, a hydroxyketone which gives rise to an 0-acetate. The IR, NMR, and UV spectra are in complete accord with the structure XXXI. An interesting feature of the NMR spectrum is the presence of signals a t 2.03 ppm ( 2H) and 1.37 ppm ( IH) which indicates that in deuterochloroform solution this ketone exists as the tetracyclic ketone (XXXI)in equilibrium with the pentacyclic hemiketal form (XXXIa). The structure of the methyl ketone (XXXI)was established by a study of the mass spectra of XXXI and its derivatives and by a comparison with the mass spectrum of the closely related base, macroline (XVIII).
-
-
3.
ALKALOIDS OF
Alstonia
225
SPECIES
The mass spectra of the ketone (XXXI) and macroline show considerable similarity, indicating that the two bases suffer analogous fragmentation processes on electron impact. Thus, fragmentation of XXXI by a route analogous to the sequence XVIII + XXc + XXb leads to the formation of the l l-methoxy derivative of XXb at m/e 227, which is the base
COMe XXXI; M 356
r Me
i
l@
OH Me
Me
XXXIa XXXII; m/e 269
i
Fission of 19.20-bond
CH2
XXXIII; m/e 226
XXXIV; m/e 338
R\
Me0
I
I
COCD,
XXVIILa
COCD,
X X X I b ; R=OMe X X X I c ; R=D
226
J. E. SAXTON
peak in the spectrum. By routes entirely analogous to those described for macroline the appropriate methoxy derivatives of XXe (m/e ZOO), XXi (m/e21 I), and XXj (m/e 212) are formed. The intermediate cleavage product in this sequence is X X X I I (m/e 269); this can itself break down to an ion, XXXIII, a t m/e 226, which contains one carbon atom fewer in its unbranched chain (i.e., the one originating from C-21) than the corresponding fragment (XXg) from macroline (9). An interesting result is obtained if the acid hydrolysis of alstophylline is carried out with deuterium chloride in DzO. The product is an octadeutero derivative (XXXIb)of the ketone XXXI, in which, as expected, all five hydrogen atoms cc to the carbonyl function (i.e., those attached to C-18 and C-20) have been replaced by deuterium; the remaining three deuterium atoms are situated a t the three available aromatic positions (9, 10, and 12). This pattern of deuterium substitution is very firmly established by the NMR spectrum of the octadeutero ketone, which exhibits practically no absorption ( < 0.5H) in the aromatic region, and by its mass spectrum. The latter exhibits a molecular ion peak a t m/e 364 and fragmentation occurs in exactly the same way as happens with XXXI with appropriate displacement of the ions t o higher mass numbers, depending on the number of deuterium atoms present. For example, the ion corresponding t o X X X I I appears at m/e 277 and that corresponding to XXXIII at m/e 231 ;the 11-methoxy-trideutero derivative of XXe is observed a t m/e 203. A further point of interest concerns the loss of water from the molecular ion of X X X I to give a peak a t m/e 338. I n the mass spectrum of the octadeutero derivative (XXXIb) this ion appears a t m/e 345, which corresponds to the loss of HDO, not HzO. The only deuterated positions in the molecule, abide from the aromatic positions, are a t C-18 and C-20, hence one of these must be involved in the dehydration. It is therefore clear that the loss of water occurs with the cyclic form (XXXIa) and the fragment produced, of m/e 338, has the constitution XXXIV ‘(9). The structure XXXI for the acid hydrolysis product leads unequivocally t o the constitution XXVIII for alstophylline itself; this is in complete accord with the UV, I R , and NMR data, mentioned briefly above, and with the mass spectra of alstophylline and its derivatives. As with the ketone X X X I fragmentation of alstophylline gives the 1l-methoxy derivatives of XXb, XXe, XXi, and XXj. Retro Diels-Alder cleavage of ring C affords an ion of similar mass number (XXXV)which by opening of ring E and loss of (7-17,C-16, and its attached substituent leads to the ion XXXVIa (m/e 297) or its hydrogen-migration isomer, XXXVIb. This last ion can give the ll-methoxy derivatives of XXi or X X j by a combined cyclization and degradation or it can suffer loss of either the methyl
3.
ALKALOIDS OF
Alstonia
/
XXVIII; M 386
227
SPECIES
Fission at 14,15 bond
xxxv
/
i
Ir 11-OMe-XXe; m/e 200
11-OMe-XXb; m/e 227
Me0
Me
H+HO XXXVIb
bOMe
COMe
11-OMe-XXi; m/e 211
\
11-OMe-XXj; m/e 212 B
Me
1
\
XXXVIa; m/e 297
\I
Me
H&CHO
XXXVII; m/e 264 H-{ COMe XXXVIII; m/e 268
ketone or the aldehyde group to give the ions XXXVII (m/e 254) and XXXVIII (m/e 268). This view of the fragmentation of alstophylline is confirmed in all respects by the mass spectra of alstophyllinol (XXVIII ; CO + CHOH), hexadeuteroalstophylline (XXVIIIa) obtained by the cleavage of macralstonine (P.v.)with deuterium chloride in D20, and the ajmaline-derived base XXXIX of known structure.
228
J. E. SAXTON
The st,ereochemistry of alstophylline has not yet been elucidated; however, its structure bears a close and obvious relationship t o that of Alkaloid C (XL), the oxindole alkaloid of A . muelleriana, and it seems probable that these two alkaloids are also related stereochemically ( 9 ) .
CH2CH3
XXXIX
H XL Alkaloid C
VI. Macralstonine Macralstonine was first isolated in 1934 from the bark of A . macrophylla by Sharp (36),who attributed to it the molecular formula C44H54N405. Very little information was obtained concerning its structure but analysis by Sharp and later investigators indicated that the molecule contained one methoxyl group, a t least two G-methyl groups, and three or possibly four N-methyl groups. The UV spectrum of macralstonine resembles that of a bz-unsubstituted tetrahydro-P carboline derivative (e.g., yohimbine) and the I R spectrum discloses the presence of an imino or hydroxyl group, possibly a /&alkoxyacrylic ester chromophore, and an o-disubstituted benzene nucleus. The formation of a dinitrophenylhydrazone demonstrates the presence of a potential carbonyl group in the molecule. More recently Chatterjee et al. (28)have revised the molecular formula of macralstonine and proposed C4~H46N405on the basis of a mass spectrometrically determined molecular weight of 686 and a proton count of 46 f 2 from the NMR spectrum. The results of ozonolysis experiments excluded the presence of an ethylidene or methylene group in the molecule but the formation of 3-ethylpyridine on zinc dust distillation was reported. Some preliminary deductions from the NMR spectrum and mass spectrum were also noted. I n another remarkable contribution on the Alstonia alkaloids Hesse, Schmid, Taylor, and their collaborators have very recently discussed in detail the chemistry of macralstonine, for which the structure XLI is proposed (10). The molecular formula C43H52N405, mol. wt. 704,
3.
ALKALOIDS O F
AlstOnia SPECIES
229
required by the structure, was established by elementary analysis, by high-resolution mass spectrometric determination of the elementary composition of the molecular ion, and by the total proton count in the NMR spectrum.
XLIa
XLI b Macralstonine
The first insight into the structure of macralstonine came from the fission with 7 0 % perchloric acid a t room temperature which afforded a good yield of alstophylline (XXVIII) ; in addition, a trace of a second product was obtained, which was suspected t o be 0- or N,-demethylalstophylline. Hence the alstophylline molecule represents one-half of the structure of macralstonine, a conclusion that is supported by the IR and UV spectra. For it is evident that the ring E chromophore in the alstophylline molecule is responsible for the bands a t 1 6 4 5 and 1 6 2 0 cm-1 in the IR spectrum of macralstonine. It is also apparent that the two hydroxyl bands and the unconjugated carbonyl band a t 1 7 0 6 cm-1 in the same spectrum in chloroform solution must represent chromophores in the second component of the macralstonine molecule. However, the 1 7 0 6 cm-1 band is only moderately intense and is hardly to be observed in the
230
J. E. SAXTON
spectrum in mineral oil suspension; correspondingly, only one hydroxyl band is observed. This behavior is best explained by the presence in the macralstonine molecule of a y- or 6-hydroxyketone part-structure which can participate in ring-chain tautomerism (cf. XXXI). This is confirmed
by the formation from macralstonine of an 0-acetyl derivative of indefinite melting point which exhibits two carbonyl bands in its IR spectrum ; this is probably a mixture of either the a and /3 cyclic acetates or the keto acetate and a cyclic acetate. Methanolic hydrogen chloride furnishes a methyl ether devoid of unconjugated carbonyl groups which is presumably a mixture of the cyclic methyl ketals. High-vacuum distillation or treatment of macralstonine with hydrogen chloride in chloroform yields anhydromacralstonine (XLII), which is also a cyclic derivative (IR spectrum) (10).
Me0
XLII Anhydromecralstonine
The se.cond component of the macralstonine molecule, which contains the tautomeric hydroxyketone grouping, possesses a simple indole chromophore ;this was readily deduced from the UV spectrum of macralstonine which, after substraction of the spectrum of alstophylline, gave a curve identical with that expected for a simple indole derivative. Evidently the chromophores present in macralstonine are not conjugated. A further substantial advance toward elucidation of the structure of macralstonine was provided by its 3-hour reaction with boiling dilute hydrochloric acid, which gave alstophylline (XXVIII), the methoxy ketone XXXI, itself an acid hydrolysis product of alstophylline under these same conditions so its presence was of no further assistance in the
3.
ALKALOIDS OF
Alstonia
SPECIES
23 1
present context, the ketone XLIII, and formaldehyde. This last base (XLIII) is clearly derived from the second component of the macralstonine molecule; this is supported by the observation that summation of the UV-spectra of XLIII and alstophylline (XXVIII) gave a spectrum superposable on that of macralstonine. The structure of the fission product XLIII was firmly established by comparison of its spectra with those of its 11-methoxy analogue (XXXI). I n particular the nonaromatic regions of the NMR spectra of XXXI and XLIII were virtually identical while the aromatic region in the spectrum of XLIII closely resembled that exhibited by macroline (XVIII). The presence in the spectrum of XLIII of singlets a t 2.03 ppm (2H), 1.34 (0.7H), and 1.24 ppm (0.3H)indicated clearly that in solution this ketone existed as the tetracyclic ketone XLIII in equilibrium with the two stereoisomeric pentacyclic hemiketal forms. Further impressive evidence concerning the structure of XLIII was derived from its mass spectrum which, when appropriate allowance was made for the absence of an aromatic methoxyl group, was identical with the mass spectrum of the methoxyketone XXXI (10).
Me
XLIII
A0 XLIV
I n later experiments the acid hydrolysis of macralstonine was carried out using shorter reaction times (0.5 hour) and the monomeric products were separated from the dimeric and polymeric material by highvacuum distillation. The products thus obtained were alstophylline (XXVIII),macroline (XVIII),the ketone XLIII, and its cyclic anhydro derivative, XLIV. No trace of the methoxyketone (XXXI) could be found. The presence of XLIV was perhaps not surprising since this ketone also arises by distillation of XLIII under the same conditions. However, a comparison of the results of these two hydrolyses is instructive. After brief reaction times alstophylline is produced but not the methoxyketone X X X I ; the latter must therefore arise by subsequent hydrolysis of alstophylline. I n contrast the ketone XLIII is not generated by further reaction of macroline (XVIII) with hydrochloric acid since under these reaction conditions macroline gives only resinous products. Hence both macroline and the ketone XLIII must be obtained directly
232
J. E. SAXTON
from macralstonine by, presumably, alternative modes of reaction with hydrochloric acid. Consequently the essential components of the structure of macralstonine (C43H~zN405) are alstophylline (CzzHzsN~03)and macroline (C21Hz6N,O2).The bond between these two component molecules does not result in increased conjugation between any of the existing chromophores, since the UV spectrum of macralstonine is simply the summation of the spectrum of alstophylline together with that of a bz-unsubstituted indole derivative. The 20,21-double bond of macroline must, however, be involved in the union since macralstonine exhibits IR carbonyl absorption at 1706 crn-l, close t o that observed for 20,21dihydromacroline (1708 cm-l) ; macroline itself absorbs a t 1681 cm-1. This conclusion is in accord with the NMR evidence since the signals at 6.18 ppm (1H)and 5.96 pprn (1H)in the spectrum of macroline, owing to the protons of the C-21 methylene group, are not present in the spectrum of macralstonine. Since macralstonine does not contain any additional C-methyl groups compared with alstophylline and macroline (NMR spectrum) C-21, and not C-SO, in the macroline component must be the point of attachment of the alstophylline molecule (10). The point of attachment of C-21 of the macroline component to the alstophylline molecule may be deduced from the NMR spectrum of macralstonine, from which it is evident that there are only six aromatic hydrogen atoms in the molecule. The NMR spectrum of macralstonine itself is complicated by the fact that it is a mixture of hydroxyketone (XLIb)and hemiketal (XLIa)forms; this results not only in a splitting of the signal owing to the C-18 methyl group but also in splitting of the signals owing to the C-9' and C-12' protons. No such complication occurs with anhydromacralstonine (XLII),which exhibits singlets a t 6.09 pprn and 6.31 ppm (100-Mc/secNMR spectrum in carbon tetrachloride) owing to the C-9' and C-12' protons, respectively. The two aromatic protons in the alstophylline component of the molecule are consequently not coupled with protons in the ortho and meta positions and must accordingly be situated para to each other, in positions 9' and 12'. The macroline component must therefore be attached a t C-lo', from which it follows that the structure of macralstonine is XLI, a or b (1 0 ). Limited support for this structure is provided by the fission of macralstonine with deuterium chloride in DzO, which affords hexadeuteroalstophylline (XXVIIIa), the octadeutero methoxyketone (XXXIb), and the nonadeutero ketone (XXXIc); the structures of these products were established by comparison of their mass spectra with those of the undeuterated analogues. Although the isolation of these products does not permit the unequivocal deduction of the structure of macralstonine it does a t least limit the points of attachment of the two halves of the
3.
ALKALOIDS O F
Ak'tO'tZiGZ SPECIES
233
molecule to those positions that are deuterated in the products and the results are entirely consistent with the constitution XLI. Similarly, the complicated mass spectra of macralstonine and its derivatives are in complete accord with, but do not rigorously prove, the structure XLI. The mass spectra of macralstonine and anhydromacralstonine show a close resemblance although the spectrum of macralstonine exhibits a few characteristic peaks absent from the spectrum of its anhydro derivative. The molecular ion peak in the macralstonine spectrum is much less intense than the peak a t m/e 686, owing to anhydromacralstonine ; it seems probable that dehydration of macralstonine precedes electron impact a t the temperature used. It is convenient, therefore, to discuss the somewhat simpler spectrum of anhydromacralstonine. I n the higher mass region are peaks a t m/e 671 (M+-CH3), 655 (M+-OCH3), and 617, owing to a fragment of composition C39H43N304. This last fragment is probably formed by a reverse DielsAlder cleavage of rings C and E. Two fragments are possible (XLVa and XLVb), depending on which of the two component ring systems suffers fragmentation ; both ions are probably formed. In the region mje 300-400 are two important peaks, a t mje 307 and 379, which are probably due to the fragments XLVIa and XLVIb; together these account for all the atoms of anhydromacralstonine. The peak a t m/e 379 is the more intense of the two, presumably because the ion XLVIb is benzylic in character and is stabilized to a greater extent than the ion XLVIa. Cleavage of macralstonine a t the 20,21-bond, to give XLVIa and XLVIb, would be expected on energetic grounds but the formation of XLVIb, i.e., an alstophylline molecule with an additional carbon atom a t C-lo', is also in accord with the notable absence of typical alstophylline-derived peaks, e.g., a t m/e 200 (1I-methoxy-XXe) and m/e 227 (1I-methoxy-XXb),in the mass spectrum of anhydromacralstonine. I n the lower mass regions of this spectrum the typical fragments derived from the macroline half of the molecule are evident, e.g., XXb, XXe, XXf, XXi, and X X j (10). In contrast the mass spectrum of macralstonine itself exhibits ions a t m/e 661 and 073; these are presumably the result of loss of an acetyl group and a hydroxymethyl group, respectively, from the hydroxy ketone form (XLIb),since neither of these peaks has its analogue in the spectrum of anhydromacralstonine (10). One quite important peak in the mass spectra of macralstonine and its anhydro derivative is one a t mje 486, whose origin is a t present obscure, a t least on the basis of the presently proposed structures XLI and XLII. This brings into discussion the possibility of an alternative constitution, XLVII, for macralstonine, which, aside from the NMR spectrum, is
234
8
I
J. E. SAXTON
0
i
3.
ALKALOIDS OF
AktOnkX
SPECIES
235
capable of explaining the chemistry of the alkaloid and its derivatives. The peak a t rn/e 486 would then be due to the fragment XLVIII, formed by a well-accepted route, i.e., retro Diels-Alder cleavage of ring C. However, this fragment should be accompanied by one a t m/e 200; i.e., the appropriate methoxy derivative of XXe, and, as mentioned earlier, this is not observed in the spectrum. Further, the analogous cleavage of ring C in the macroline half of the molecule would be expected to generate ions of m/e 170 and 51 6 ;the former (XXe)is a moderately intense peak but there is no sign of the latter in the mass spectra of either XLI or XLII (10).
XLVII
Me
Me
XLVIII; m/e 480
The evidence described above thus indicates that the structure of macralstonine is almost certainly XLIa zb, and it is presumably formed in the plant by a Michael reaction between alstophylline and macroline, or alternatively, by a Mannich reaction involving alstophylline, the hydroxyketone XLIII, and a formaldehyde equivalent. The acid fission of macralstonine to alstophylline and macroline or t o alstophylline, XLIII, and formaldehyde is thus seen to be the reverse of these reactions (10).
VII. Macrosalhine Macrosalhine, CzlH27N202+ (XLIX),is a quaternary alkaloid belonging to a new structural type which has recently been isolated from the
236
J . E. SAXTON
stem bark of A . macrophylla (IOa). Macrosalhine chloride has m p + 27" (MeOH),an d exhibits the ultraviolet spectrum of a n N,-methyl-l,2,3,4-tetrahydro-P-carboliniumchromophore. I t s lOO-Mc/sec NMR spectrum (in DzO) exhibits signals owing t o four aromatic hydrogen atoms (6.7-7.7 pprn), a n acetal hydrogen at C-21 (5.37 pprn), a hydrogen at C-3 (doublet at 4.83 ppm), two N-methyl groups (singlets at 3.58an d 2.87 ppm), and two hydrogen atoms attached t o C-17(two doublets at 3.8 and 3.4 ppm). The methyl group attached t o C- 19 appears a s a doublet centered a t 1.64 ppm. and the signal owing to the hydrogen a t C-19 as a multiplet centered a t 4.2 p p m; the downfield position of this last signal is a consequence of its proximity t o N , . Rlacrosalhine thus contains the partial structure 284"-286" dec,
e
-NMe-CHMe
I I Pyrolysis of macrosalhine chloride at 24O0-33O0 in high vacuum results in Hofmann degradation and dehydration, th e product being the ZO, amorphous anhydromacrosalhinc methine (L), C Z ~ H ~ ~ Ntogether with a dimer of the methine of unknown constitution. The I R spectrum of L exhibits a n enol ether band a t 1637 cm-1; this accords with the presence of a hemiacetal grouping in macrosalhine, which in turn accounts for the absence of carbonyl absorption in the KBr spectrum of the latter. The NMR spectrum of anhydromacrosalhine rnethiiie is in all respects consistent with this postulated structure. Thus, the hydrogen atom 011 (3-21 gives rise t o a singlet a t 6.46 ppm an d the hydrogen on C-19 to a quartet centered a t 5.88 ppm which is coupled with doublets at 4.63 and 4.36 ppm owing t o the olefinic hydrogens on C-18. The C-17 hydrogen atoms appear as triplets centered a t 4.95 and 4.02 pprn and the C-3 hydrogen as a broad signal a t 1 . 7 0 ppm. The N-methyl groups are responsible for signals a t 3.70 and 2.7!) ppm. These data strongly suggest the presence i n anhydromacrosalhinc methine of a vinyl group and the part-structure in L encornpassing C-16 to C-20. The reduction of macrosalhine thiocyanate with sodium and methanol gives a n amorphous tertiary base which contains no carbonyl groups, hemiacetal groups, or olefinic double bonds. The propcrties of this 1n-oduct, including its mass spectrum, are in accord with the constitution LI. The structure X L I X for rnacrosalhine and L for anhydromacrosalhine methine are strongly supported by their behavior on electron impact. When introduced into the mass spectrometer macrosalhine chloride undergoes thermal Hofmann degradation and the mass spectrum observed is t ha t of the methine base LII, CzlHesN202, JI :338, which is an isomer of macroline (XVIII). As expected, several of the l'eaks in the
3.
ALKALOIDS OF
Alstonia
237
SPECIES
Me
OH
Me
CHzOH
XLIX Macrosalhine
LI
Me CH=CHz LII
Me LIIIb
LIIIa r-
14
L
J LIVa; m/e 251
LIVb; m/e 250
[Q-L]iqy-L /
Me LIVc; rn/e 223
/
/
/
Me LIVd: in/e 222
spectrum of LII are also observed in the spectrum of macroline (see above), e.g., the peaks a t m/e 1!)7 (base peak, owing to the /harbolinium ionXXb), 182 (owing to W - X X i , LIIIa, and LIIIb), 181 (XXi),and 170 (XXe).The " molecular ion "in the spectrum of macrosalhine chloride is thus observed a t m/e 338 ; dehydration gives an ion a t m/e 320, owing to a radical ion derived from aiihydromacrosalhine methine (L); indeed, the
238
J . E. SAXTON
mass spectra of L and LII are virtually identical below m/e 320. Fragmentation of the ion from L by two retro Diels-Alder processes in rings C and E generates the radical ion LIVa (m/e 251) (cf. macroline) which can lose a hydrogen atom to give LIVb (m/e 2 5 0 ) . Further fragmentation of LIVa occurs by loss of carbon monoxide to give LIVc (m/e 223) followed by loss of a hydrogen atom to give LIVd (m/e 2 2 2 ) (10a). The evidence thus available is consistent with the structure XLIX for macrosalhine; the relative stereochemistry a t carbon atoms 3, 4, 5, 15, 16, and 20 follows from the particular nature of the ring system involved and the only centers of uncertain configuration are (2-19 and C-21. The structure XLIX for macrosalhine has been confirmed by the X-ray crystal structure analysis of macrosalhine bromide ; this work has also defined the relative stereochemistry a t C-19 and (2-21, as shown in XLIX ( 3 4 ) .
VIII. Macralstonidine Macralstonidine [mp 295"-300" dec; c c ~ z o+ 166" (CHC13)], the third dimeric alkaloid of Alstonia macrophylla, has the constitution LV ( 3 5 ) .Its molecular formula, as determined by mass spectroscopy, is C41H48N403 ; this differs by only two hydrogen atoms from the molecular formula originally proposed b y Sharp (36).The UV spectrum of macralstonidine system and is in fact resembles that of an N-alkyltetrahydro-P-carboline identical with the summation spectrum of a typical N-methyltetrahydro-P-carboline derivative and 6-methoxy-N-methyltetrahydrocarbazole. I n the I R region macralstonidine exhibits bands owing to a hydroxyl group, a C-methyl group, and a ketal or acetal function (four bands in the region 1040-1 170 cm-1) ; the spectrum contains no absorptions owing to a free carbonyl group or an enol ether grouping. The lOO-Mc/sec NMR spectrum provides evidence for the presence of an ethylidene grouping (one-proton quartet a t 5.39 ppm coupled with a three-proton doublet a t 1.65 ppm; J = 7.5 cps), two N,-methyl groups (singlets a t 3.55 and 3.43 pprn), an N,-methyl group (singlet a t 2.27 ppm), and six aromatic protons, of which two are situated ortho to each other in a tetrasubstituted benzene ring (doublets a t 7.12 and 6.70 ppm; J = 8 . 5 cps). Other signals in the spectrum are attributed t o a proton attached to an ethereal carbon atom and coupled with two other protons (triplet a t 4.60 ppm; J = 12 cps) and a methyl group attached to a ketal carbon atom (singlet a t 1.36 ppm) ( 3 5 ) . The hydroxyl group in macralstonidine is contained in a primary alcohol function since Oppenauer oxidation gives an aldehyde, macral-
3.
ALKALOIDS O F
AktOfLiU.SPECIES
239
stonidinal (vCr0 1 7 1 5 cm-l), and acetylation gives an 0-acetate (vCE0 1 7 3 9 cm-1) ; both these products exhibit UV spectra practically identical with that of macralstonidine.
LV
Macralstonidine
I
LVI N,-Methylsarpagine
18’
I
Reaction of macralstonidine with concentrated hydrochloric acid a t 120’ gives rise to the tetracyclic aminoketone XLIII, the related primary
chloride (XLIII ; CHzOH + CHzCl), N,-methylsarpagine (LVI), and formaldehyde. The base XLIII was identified by direct comparison with material obtained from macralstonine by thin-layer chromatography in eight different plate/solvent combinations and by its mass spectrum. N,-Methylsarpagine was similarly identified with material obtained by pyrolysis of ( + )-N,,N,-dimethylsarpagine chloride isolated from Pleiocarpa mutica. This last sarpagine derivative was known to have the same absolute configuration as ( )-sarpagine ; unfortunately, the lack of available material prevented the absolute configuration of either of the fission products from macralstonidine from being rigorously established. Nevertheless, it seems reasonable to presume that both C-15 and C - 1 5 ’ in the macralstonidine molecule have the same absolute configuration as the other Alstonia bases, as shown in LV. Macralstonidine does not contain a phenolic hydroxyl group since its UV spectrum does not show a bathochromic shift in alkaline solution and 0-acetylmacralstonidine does not exhibit the I R spectrum of a phenolic acetate. Hence it is clear that in macralstonidine the phenolic group of N,-methylsarpagine must be involved in the attachment of the remainder
+
240
J. E. SAXTON
of the molecule, presumably in an ether linkage. A priori it also seems probable that the formaldehyde obtained on acid fission arises from a carbon atom attached to C-20 of the second component, i.e., the amino ketone XLIII. Hence the actual units from which macralstonidine is constructed may be N,-methylsarpagine and macroline (XVIII). If this is so, macralstonidine (LV) can be imagined to arise by nucleophilic attack a t C-20 in a macroline molecule by the electron-rich C-9 in an N,-methylsarpagine molecule followed by closure of the ketal rings. HOCHz
q
J7-
HOCHz
LV
LVII
The acid-catalyzed fission of macralstonidine can then be explained by the reversal of these processes, i.e., as a combination of retro Michael and retro aldol cleavages on the phenolic hydroxyketone LVII (35). I n accordance with the constitution LV, the mild (70") treatment of macralstonidine with deuterium chloride in deuterium oxide gives a mixture of the nonadeutero ketone (XXXIc), 9 , l l ,12-trideutero-N,methylsarpagine, and 9,10,11,12,18,18,18,20,ll', 12'-decadeuteromacralstonidine (LV-dlo). The first of these products was unequivocally identified with the fission product obtained from macralstonine under similar reaction conditions (see above). The deuterium substitution pattern in the trideutero-N:,-methylsarpagine becomes clear from its mass spectrum since all fragment ions which contain the intact benzene ring (e.g., LVIII) are observed three mass units higher than in the undeuterated compound.
LVIII
The introduction of 10 deuterium atoms into the macralstonidine molecule in the reaction with deuterium chloride is consistent with the structure LV. Further, the positions occupied by these deuterium atoms
3.
ALKALOIDS OF
24 1
AZstonia SPECIES
Fission of riny C
I
Fission of I1,lB-I~ond
XXe; rn/e 170
242
J . E. SAXTON
are fully confirmed by a comparison of the mass spectra of LV and LV-dlo ; these, together with the mass spectra of 0-acetylmacralstonidine and macralstonidinal, provide convincing confirmation of the structure of LV. One of the most intense ions in the mass spectrum of macralstonidine is, interestingly, the molecular ion. Numerous fragmentations occur on electron impact, however, as might be expected of so complex a molecule ; these include fission of either the macroline or the sarpagine part of the molecule, and the “halving” of the molecule into two fragments of similar mass. Fragmentation of the macroline part of the molecule is exemplified by the formation of the ions XXe (m/e 170) and L X I (m/e 574) ; these are presumed to be formed by retro Diels-Alder cleavage of ring C in the molecular ion, which gives the isomeric ion LIX. Fission a t
LXIII; m/e 211
LXII; m/e519
the allylic 14,15-bond in LIX then gives XXe; alternatively, a proton transfer (arrows in LIX) affords the radical ion LX which, by fragmentation as shown, gives the important ion LXI. Fragmentation of the N,-methylsarpagine unit in macralstonidine occurs, as in sarpagine itself, by loss of CH20H (31 mass units) to give an ion a t m/e 613 ; alternatively, loss of CgH130 from the molecular ion gives the /3-carbolinium ion LXII (m/e 519). Loss of the macroline unit from LXII, as shown by the arrows, then gives the fragment LXIII (m/e 21 1 ) . The fission of the macralstonidine molecular ion into two fragments of similar mass occurs by reverse Diels-Alder cleavage of ring F, which affords the two ions LXIV (m/e 308) and LXV (m/e 336). Further loss of the hydroxymethyl group from LXV then gives a fragment responsible
3.
ALKALOIDS OF
Alstonia
SPECIES
243
for a peak a t m/e 305. As expected from this interpretation of the mass spectrum decadeuteromacralstonidine (LV-dlo)gives an octadeutero ion (LXIV-ds) a t m/e 316 (35).
Me LXIV; m/e308 J
LXV; m/e336
REFERENCES 1. I. Ciulei, E. Tarpo, 0. Contz, M. Gheorgiu, G. H. Mateesku, and N. Paslarascu, Pharmazie 20, 522 (1965); C A 63, 16775 (1965);Farmacia (Bucharest) 13,321 (1965); C A 64, 2412 (1966). 2. G. H. Svoboda, N. Neuss, and M. Gorman, J. Am. Pharm. Assoc. 48, 659 (1959). 3. B. K. Moza and J. Trojanek, Collection Czech. Chem. Comrnun.28, 1419 (1963). 4. N. J. Cone, R. Miller, and N. Neuss, J. Pharm. Sci. 52,688 (1963). 5. S. Siddiqni and M. Manzur-i-Khuda,Pakistan J.Sci. Ind. Res. 4 , 1 (1961). 6. M. B. Patel, J. Poisson, J. L. Pousset, and J. M. Rowson, J . Pharm. Pharmacol. 16, Suppl. 163 (1964). 7. J. L. Pousset and J. Poisson, Compt. Rend. 259, 597 (1964). 8. A. Chatterjee, B. Mukherjee, A. B. Ray, and B. Das, Tetrahedron Letters 3633 (1965). 9. T. Kishi, M. Hesse, C. W. Gemenden, W. I. Taylor, and H. Schmid, Helv. Chim. Acta 48, 1349 (1965). 10. T. Kishi, M. Hesse, W. Vetter, C. W. Gemenden, W. I. Taylor, and H. Schmid, Helv. Chim. Acta 49,946 (1966). 10a. Z. M. Khan, M. Hesse, and H. Schmid, Helv. Chim. Acta 50, 1002 (1967). 11. R. C. Elderfield and G. D. Manalo,J.Philippine P h r m . Assoc. 50,91 (1964). 12. T. R. Govindachari, N. Viswanathan, B. R. Pai, and T. S. Savitri, Tetrahedron Letters 901 (1964). 13. A. B. Ray and A. Chatterjee, J. Indian Chem. Soc. 40, 1043 (1963). 14. A. Chatterjee, P. L. Majumder, and A. B. Ray, Tetrahedron Letters 159 (1965). 15. T. R. Govindachari, N. Viswanathan, B. R. Pai, and T. S. Savitri, Tetrahedron 21,2951 (1965). 16. B. Das, K. Bismann, A. Chatterjee, A. B. Ray, and P. L. Majumder, Tetrahedron Letters 2239 (1965). 17. B. Das, K. Biemann, A. Chatterjee, A. B. Ray, and P. L. Majumder, Tetrahedron Letters 2483 (1966). 17a. A. B. Ray and A. Chatterjee, Tetrahedron Letters 2763 (1968). 18. H. H. A. Linde, Helv. Chim. Acta 48, 1822 (1965). 19. A. B. Ray and A. Chatterjee, J. Indian Chem. Soc. 41, 638 (1964). 20. T. R. Govindachari, P. M. Pillai, K. Nagarajan, and N. Viswanathan, Tetrahedron 21, 2957 (1965).
244
J . E. SAXTON
21. M. UskokoviO, H. Bruderer, C. von Planta, T. Williams, and A. Brossi, J . Am. Chem. SOC.86, 3364 (1964). 21a. E. Winterfeldt, H. Radunz, and T. Korth, Chem. Ber. 101,3172 (1968). 22. M. Shamma and J. M. Richey, J . Am. Chem. SOC. 85,2507 (1963). 23. T. M. Moynehan, K. Schofield, R. A. Y. Jones, and A. R. Katritzky, J. Chem.Soc. 2637 (1962). 24. N. Finch, W. I. Taylor, T. R. Emerson, W. Klyne, and R. J. Swan, Tetrahedron 22, 1327 (1966). 25. Y. Ban and M. Seo, Chem. & Pharm. Bull. (Tokyo) 12,1296 (1964). 26. H. Manohar and S. Ramaseshan, Proc. Indian Acad. Sci. A58, 109 (1963). 27. B. D. Sharma, R. E. Marsh, and J. Donohue, 2. Krist. 119, 252 (1963). 28. A. Chatterjee and G. Ganguli, J . Sci. Ind. Res. (India)23, 178 (1964). 29. M. Hesse, H. Hurzeler, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, Helv. Chim. Acta 48, 689 (1965). 30. M. Hesse, F. Bodmer, C: W. Gemenden, B. S. Joshi, W. I.-Taylor, and H. Schmid, Helv. Chim. Acta 49, 1173 (1966). 31. C. E. Nordman and S. K. Kumra, J . Am. Chem. SOC.87,2059 (1965). 32. S. K. Talapatra and A. Chatterjee, Sci. Cult. (Calcutta) 31, 368 (1965); C A 64, 11268 (1966). 33. R. E. Gilman, Dissertation Abstr. 20, 1578 (1959). 34. H. Wulf and A. Niggli, Helv. Chim. Acta 50, 1011 (1967). 35. E. E. Waldner, M. Hesse, W. I. Taylor, and I€. Schmid, Helv. Chim. Acta 50, 1926 (1967). 36. T. M. Sharp, J . Chem. Soc. 1227 (1934).
-CHAPTER
4 -
SENECIO ALKALOIDS PRANKL. WARREN* C.S.I.R. Natural Products Research Unit. University of Cape Town. Rondeboach. Cape Province
. .
I Occurrence and Constitution (37-46)t ................................ I1 Structure oftheNecines(49-68) ..................................... A . AbsoluteConfiguration .......................................... B NewNecines .................................................. C. Syntheses of Hydroxylated Methylpyrrolizidines .................... D Otonecine(67-68) .............................................. E . Crotanecine .................................................... I11. Structures of the Necic Acids (68-109) ................................ A . CgAcids(68) ................................................... B. CeAcids(69) ................................................... C. C'IAcids(74) ................................................... D CsAcids(79) ................................................... E . Clo Glutaric Acids (86) .......................................... F Clo Adipic Acids ................................................ G Summary of the Structures of the Acids ........................... IV Structure of the Alkaloids (109-116) .................................. A . General ....................................................... B Monoesters .................................................... C Noncyclic Diesters .............................................. D . Cyclic Diesters of the Glutaric Acids ............................... E Cyclic Esters of the Clo Adipic Acids .............................. F. Alkaloids Containing Aromatic Acids .............................. V . Biosynthesis(117) ................................................. A . Bases ......................................................... B Acids ......................................................... C TotalAlkaloids ................................................. ................................... VI . Phirmacology ( 117) . . . . . . . . . VII . AnalyticalProcedures .............................................. VIII Other Pyrrolizidine Alkaloids ....................................... A . Festucine ...................................................... B Loline, Lolinine, and Norloline .................................... C . Cassipourine ................................................... References ........................................................
. .
.
. . .
. . . . .
.
.
246 246 246 262 270 273 274 274 275 276 276 282 283 285 299 299 299 300 303 306 309 315 316 316 317 318 319 321 322 322 322 323 324
* The Author acknowledges the invaluable assistance of Miss Jill Zoutendyk in the completion of references and the assembly of the manuscript
.
7 Numbers in parentheses following headings and subheadings in the contents and text refer to pages in Volume VI. Chapter 3. to which this material is supplementary
.
246
FRANK L. WARREN
I. Occurrence and Constitution (37-46) Only 8 years have elapsed since Leonard’s excellent chapter ( 1 )on the Senecio alkaloids was published in this series, and Boit’s concise account (2) appeared. This chapter must be considered as an extension of Leonard’s to include studies to November, 1968. The author, who has recently reviewed the pyrrolizidine alkaloids ( 3 ) )has confined attention to the accepted concept of “Senecio alkaloids ’) as those alkaloids which contain a hydroxylated pyrrolizidine esterified with one or more acids, which were originally designated “necine” bases and “necic” acids by Manske. Table I lists all the Senecio alkaloids with their melting points and specific rotation, togebher. with information on the plant origin additional to that previously reported (1, 4). The occurrence of the free bases in the plants of the Crotalaria species, reported by Culvenor and his collaboratqrs, is of interest and is fully reported. The alkaloids which do not fall within this general category but contain the pyrrolizidine ring are only briefly referred to here. Considerable advances have been made in the isolation of new alkaloids, the determination of structures including absolute configurations, and the stereospecificsynthesis of both bases and acids. It is now possible to get a glimpse at the overall picture and to write some general structures for acids and alkaloids. Structural studies have been considerably facilitated by NMR spectra, mass spectra, and X-ray analysis, particularly where the hydrolysis of the alkaloid has resulted in extensive fragmentation. Furthermore the beginning of chemotaxonomical studies are seen in the summary of the “necine” bases and “necic” acids in the families Fabaceae, Boraginaceae, and Asteraceae. Biosynthetic studies have given a tentative overall picture of the mode of formation of the acids of different structures, and pharmacological studies have indicated at least some of the degradation products found in the liver and urine in Senecio hepatitis.
II. Structure of the Necines (49-68) A. ABSOLUTE CONFIGURATION The absolute configuration of ( - )-heliotridane (I) established previously (101)has been confirmed by Adams and his collaborators (102, 103). ( - )-Rehonecanone had been synthesized from ( - )-3-methyl5-aminovaleric acid (11)the structure of which has been correlated with that of (-)-methylsuccinic acid which has an S-configuration, so that
TABLE I
Senecio ALKALOIDS~
Alkaloid
Source (References)
[alDb
MP ("C)
~~
Ambaline Ci5Hz5N04 Anacrotine CisHz5N06 7 - Angelylheliotridine
Ci3HigN03 Angelylheliotridine trachelanthate Angelylheliotridine viridiflorate 7-Angelylretronecine Ci3HigN03 Angularine CieHd06 [Aquaticine] Axillarin CisHz7N07 Base 4 Brachyglottine c15H23N05 [Brasilinecine] Campestrine Ci3HigN03 [Carthamoidine] Clivorine CziHzsNOs
Cynoglossum amabile Stopt & Drummond (5)
Oil
-7.1 d
Crotalaria anagyroides H. B. C K. (6) C. i m a n a L. ( 7 ) C. laburnijolia L. ( 8 ) Heliotropium supinum L. ( 9 ) Senecio rivularis Remy ( 1 0 )
191-192
$30 d
116-1 17
- 18 a
-
-
76-77
f49 d
S. angulatus L. (12, 13)
200-201
-98 d
(4
220 205 dec
- 83
176-178 98-99
-
Brachyglottis repanda J.E. and G. Frost (15)
(1) (4)
171 dec 93
- 68.2 a -
(1) Ligularia clivorum (10)
-
-
147-149
79 a 49 b
Heliotropium supinum ( 9 ) H . m p i n u m (9) Cynoglossum latijolium R.Br. (11)
Crotalaria axillaris Dryand. ( 1 4 )
(4
tP 19 d
3
2
3. 0
II52
s
E
+65.1 e
+88 d
Is lP -J
TABLE I--continued Alkaloid
Source (References)
MP (“C)
[alDb
~~
Crispat ine CisHz3NOj Crosemperine CigH3iNOs Crotalaburnine ( ? ) Cruent ine A CisH~sNos Cruentine B CisHzsNOs Cynaustine CisHzsN04 Cynaustraline Ci5Hz7N04 Cynoglossophine CZOH~~NOS Dicrotaline C14H19N05 [Douglasiine] Echimidiiie CzoH3iN07 Echinatine CisHznNOs
Echinatine N-oxide CisHzsNOs
Crotnlaria crispata F. Muell. ex Benth. ( 1 6 ) C. semperfiorens Vent. (17)
137-138
+41 d
117-118
45 a 2.2 d
C. laburnifolia ( 1 8 ) S. cruentus DC.(?) (19)
185-186 dec 218-220
-
S. cruentus DC. ( 1 9 )
200-202
- 63.4 a
Cynoglossum australe R.Br. ( 5 )
135-136 (picrate) Gum 149-150 (picrolonate) Deliques.
+ 13.2 d
C. australe ( 5 )
C. oficinale L. (20)
170 dec
-94.1 a
-
+ 48.0 d O0
13.4 d
(1) C . antabile ( 5 ) Lindelofia stylosa A. Brand ( 2 1 ) Solenanthus coronatus Regel ( 2 1 ) Lindelofia stylosa (21)
-
(1)
[Eremophiline] Europine Ci6Hz7NO6 Europine A'-oxide CieHz7N07 Floricaline Cz3H33NOio.#%He Floridanine CziH3iN09 Florosenine CziHzsNOs Franchetine Fuchsisenecionhe C12H21N03 Fulvine Ci6Hz3N05
Graminifoline CisHz3N05 Grantianine CigHz3N07 Hastacine CisHz7N05
99-100
Amsinckia hispida I. M . Johnston ( 2 2 ) A . intermedia Fisch. & Mey. ( 2 2 ) A . lycopsioides Lehm. ( 2 2 ) (1)
14.4 d
10.9 d
(4 (1)
171
25.3 d
CaculiafloridunaA. Gray ( 2 3 ) (S. floridanus Sch. Bip.) C . $oridam ( 2 3 )
177-178 120-122 195-196
+ 74.3 a +66.5 a ip
C . fEoridana ( 2 3 )
100-1 0 3
S. francheti C . Winkl. ( 2 4 ) S.fuchsii C . C . Gmel. ( 4 , 2 5 )
124-125 225-227 (HCl salt) 167.5-168.5 (Au salt) 2 12-213
Crota,laria crispata F. Muell. ex Benth. ( 1 6 ) C. fulwa Roxb. ( 2 6 ) C. paniculata Willd. ( 2 7 ) (4)
236
(4)
204-205 dec
50.6 a
(4) Caealia robusta Tolmatch. ( 2 8 )
170-171
- 72.3
67-68
- 12.0 d
C. hastuta L. ( 2 3 ) (1)
10
u1 0
TABLE I-continued Alkaloid Heliosupine CZOH31N07 Heliosupine N-oxide CzoHsiNOs Heliotridine viridiflorate N-oxide Heliotrine Ci6Hz7N05
Heliotrine N-oxide Ci6HwN06 [Hieracifoline] 7p-Hydroxy-l-methylene88-pyrrolizidine Hygrophylline CisHwNOa Incanine CisHzsN05 Incanine N-oxide CisHzsNOs Indicine Ci5Hz5N05 Indicine (monoacetyl) Ci7Hz7NOs Indicinine CisHzsNOs ( ? )
Source (References)
MP ("C)
[.IDb
(1)
-
-4.3 d
Cynoglossum oflcinale ( 2 9 )
-
-
179-180
-
128
63.8 a 17.6 d
171-172
26.6 d
-
-
33-35
+36 d
S. hygrophyllus Dyer and Sm. (32, 33)
176
- 67.3 d
Trichodesma incanum Bunge (34, 35)
96-97
-
T . incanum ( 3 4 )
168-169
-
Heliotropium indicum L. ( 3 6 )
97-98
+ 23.3 d
H . indicum ( 3 7 )
Gum
- 14.8 d
H . indicum (37)
Gum
+9.4 d
C. offkinale (29) (4) (1) Heliotropium dasycarpum Ledob. ( 3 0 ) H . olgae Bunge ( 2 1 ) (1)
(1) C. goreensis Guill. et Perr. ( 3 1 )
Integerrimine (Squalidine) CisHzsNOs
Isatidine (Retrorsine N-oxide) ‘ I Isoheliotrine ” (Heliotrine) Jacobine CisHzsNOa Jacodine (Seneciphylline) Jacoline ClSH27N07 Jaconine CzoH3zClN07 Jacozine CisHz3N06
Junceine CisHz7N07 Kumokirine CszH48NOs *HzO-CsHzN307 Kuramerine CzsH44NOs-CsHzN307
(1,4) S. alpinus (L.) Scop. ( 3 8 ) S. brasiliensis Legs. ( 3 9 ) S. incanus L. subsp. carniolicus (Willd.) Br-Bl(38) S. kleinia Sch. Bip. (40-42) S. magnijcus F. Muell ( 4 3 ) S. subalpinus Koch ( 3 8 ) 8.viscosus L.( 4 4 ) Crotalaria brevifolia ( 8 , 45) C. usaramoensis ( 4 6 ) Amsinckia hispida ( 2 2 ) A. intermedia ( 2 2 ) A. lycopsioides ( 2 2 )
172-172.5
4.3 a
171-172
-22.1 a
$4.7 d b P
-
-
229-230
- 28
-
-
(1)
221
48 a
(1)
146-147
(1) S. alpinus ( 3 8 ) S. incanus L. subsp. carnwlicus (Willd.) Br-Bl. (38) S. subalpinus ( 3 8 ) (1) Crotalaria rubiginosa Willd. var. wightina ( 4 7 ) Liparis kumokiri F. Maekwa ( 4 8 )
228
28 a 30 d - 140 a
191-192
-3e
100-102 (picrate)
Liparis kurameri Franch. et Sav. ( 4 8 )
105-107 (picrate)
-23.4 b (HC1salt) - 19.7 b (HClsalt)
(1) (1) (1)
(4
-
b m-
$
3. 0
E1 5
EI
t~
2
E3
TABLE I-continued Alkaloid Laburnine CsHi5NO Laburnine benzoate
Source (References)
Planchonella anteridifera White & Francis ( 4 9 ) P . thyrsoidea C. T. White ( 4 9 ) Laburnine-trans-3-methylthiopropenate Planchonella anteridifera ( 4 9 ) Laburnine tiglate Planchonella anteridifera ( 4 9 ) P . thyrsoidea ( 4 9 ) Lanigerosine (1) CisHz7NOs Lasiocarpine CziH33N07 Lasiocarpine N-oxide CziH33NOs Cynoglossum latifolium Latifoline CzoHz7N07 (14 Lindelofamine (1) CzoH33NOs Lindelofine (1) LindeloJia macrostyla Bunge ( 5 0 ) C15H27N04 Lindelojia macrostyla ( 5 0 ) Lindelofine N-oxide C1.5H27No.5 a-Longilobine(Seneciphylline) (1) p-Longilobine (Retrorsine) (1) Lycopsamine Amsinckia hispida ( 2 2 ) A . intemedia ( 2 2 ) Ci5Hz5N05 A . lycopsioides ( 2 2 ) Macrophylline (1) Cl3HZlNO3
01
N
MP ("C)
-
[alDb
15.5 d
-
184
-
96.5-97
-3.5 d
133 dec
13.1 d
102-103
+57.0 d
88
-
106-107
50 d
195-196.5
20.6
-
-
-
-
+3.3 d
42-44
34.5 d
3r $
k
Ez
Macrotomine Ci5Hz7N05 Madurensine CisHz5NOe Methoxymethyl- 1,2-epoxypyrrolizidine 1- Methylene 8a-pyrrolizidine ~
1-Methyl-1,2-epoxypyrrolizidine Mikanoidine (Sarracine) CisH23N04 Monocrotaline Ci6Hz3N06 [Mucronatine] (trans-Retrorsine) Neoplatyphylline CisHmN05 Nervosine C36H53NOiz*HzO-CsH3N307 Onetine CisHzgNOs Otosenine (Tomentosine) CigHmNO7 Planchonelline CizHisNOzS Platyphylline CisH27N05 Platyphylline N-oxide CisHz7NOs [Pterophine]
(1)
95-97
Crotalaria agatifolia Schweinf. ( 6 ) C. m d u r e n s i s Wight ( 6 ) C. aridicola Domin. (51-53) C. trifoliastrum Willd. (51-53) C. anagyroides H.B. and K. (54, 55) C. damrensis Engl. (55) C. goreensis Guill. et Perr. ( 3 2 ) (194) (5657) (4) C. grakmiana Wight e t Am. (58) C. retusa L. ( 5 9 ) C. mucronata Desv. (8, 6 0 ) S. platyphyllus D.C. ( 6 1 )
-
-
Liparis nervosa Lindl. ( 6 2 )
130-1 3 1
+ 12.8 b
S. othonnae Bieb. (63, 6 4 )
192-193
(HCl salt) 73.0
(1) S. erraticus Bert. spp. barharaeifoliolius Krock ( 6 5 ) Cacalia fioridana ( 2 3 ) Planchonella thyrsoidea ( 4 9 ) P. anteridijera ( 4 9 ) (194) S. grandifolia ( 6 6 ) S. platyphylldirtes Somm. e t Levier ( 6 7 ) (1)
218-219 dec
20.8 a
-6.9 d
175-176 bp 53'/0.1 mm
-63 d
98-100
-7 d
bp 112-114/3 mm
+9.3 d
19f-198
- 54.7 a
-
ip
131-133
+9 a 129
-56 a
180-181
- 44.6 8
5m
TABLE I-continued
M
cn I+
Alkaloid Renardine (Senkirkine) CisHz5N05
( - )-Isoretronecanyl tiglate ( - )-Isoretronecanyl-tram-
Source (References)
(1) S. kleinia ( 4 2 ) S. kirkii Ho0k.f. ( 6 8 ) S. renardi C. Winkl. (68-70) Planchonella spp. ( 7 1 ) Planchonella spp. ( 7 1 )
MP ("C)
[.IDb
193-195
-2.2 a
111-1 13
- 57.2 d
207-208 or 216-216.5(?)
-48.6 a or -62.4 ( 5 )
0-2
3-methylthiopropenate (?)
Retrorsine CisHzsNOs
Retrorsine AT-oxide(Isatidie) Ci8Hz5N07 Retusamine CigHz5N07
Retusine C16H25N05 Riddelliine CisHdOs Rivularine Cl3Hl9N03 (Compestrine has a similar formula)
Mimusops elengi L. ( 7 1 ) (194)
S. brasiliensis Less. (39, 7 2 ) S. discolor D. C. (73, 7 4 ) S. grisebachii Baker (72) Crotalaria spartioides D. C. ( 7 5 ) C. usaramoensis E. G. Baker ( 4 6 ) (1) C. crassipes Auth? ( 7 6 ) C. rnitchellii Benth. ( 7 6 ) C. novae-hollandiaeDC. ( 7 6 ) C . retusa L. ( 6 4 , 77) C. retusa (77)
S. riwularis D. C. ( 4 4 )
w F
i! 145
-8.2 c
174.5 174-17 5
+ 13.0 d
195-196
-109 a
115-117
-19a
-F 16.0 d
f4
4
(134) S. angulatus L.( 13 ) S. halirnifolius L.( 7 8 ) Rosmarinine N-oxide CisH27N07 Ruwenine ~i8H27N06 Ruzorine C18H27NO8 Sarracine (Mikanoidine) Ci8Hd05 Sarracine N-oxide CisH27NOs Alkaloid SC C18H23NO6 Sceleratine C18HmN07 Alkaloid SD (Integerrimhe) Senecifolidine Ci8Hz5N07 Senecifoline CisHmNOs Senecine Senecionine Ci8H25N05
(1)
209
- 120 a
175.5-179 dec
(1)
161-163 dec
(1) S. platyphyllus D. C. (roots and rhizomes ( 7 9 ) 9. rhombifoliolius Bolle ( 6 7 ) (1) S. mikanioides (Walp.) Otto ( 5 7 ) . S. francheti C. Winkl. ( 2 4 ) S. erucifolius L. ( 8 0 )
51-52
- 129.7 d
123-124 125-126 193
-81.6 d -94d -73 c -100 k 2 d
(1)
178
54 d
8.erraticus Bert. spp. barbaraeifolius Krock ( 4 4 )
-
(4)
166-168 212
(4)
194-195
28.1 d
- 13.9 d
bF-
3 %
9. 0
Ek
8 rn
(1, 4) 236 dec (1, 4) C . avagyroides ( 6 ) C . usararnoensis ( 4 6 ) S. brasiliensis (39, 7 2 ) S. discolor D. C. ( 7 3 ) S. erucifolius L.( 8 0 ) S. erraticus Bert. spp. barbaraeifo1iu.s Krock (65, 81, 8 2 ) S. kleinia Sch. Bip. ( 4 0 )
-56 d
t 9
cn cn
f.3
rn
TABLE I-continued Alkaloid
a
Source (References)
Senecionine CisHzsNOs
Senecionine N-oxide CisHzsNOs Seneciphylline Ci~Hz3Nos
Seneciphylline N-oxide CisHzsNOs
S. magnificus F. Meull. ( 8 3 ) S. pampeanus Cabrera ( 8 4 ) S. subalpinus Koch (38) S. triangularis Hook.f.(85) s.viscosus L. ( 4 4 ) S. triangularis Hook.f.(85) (194) S. alpinus ( 3 8 ) S . borysthenicus Andrz. ex D. C. ( 8 6 ) S. cineraria D. C. ( 8 7 ) S. crysanthemoides D. C. (88) S. erraticus Bert. spp barbaraeifolius Krock ( 6 5 ) S . grandifolia ( 6 6 ) S. incanus subsp. carniolicus (38) S. othonnae Bieb. ( 6 3 ) S. palmatus ( 8 9 ) S. paludosus L. ( 9 0 , 9 1 ) S. platyphylloides ( 6 7 ) S. platyphyllus D. C. ( 6 1 ) S. racernosus D. C. ( 9 2 ) S. rhombifolius ( 6 7 ) S. subalpinus ( 3 8 ) Ukranian and Sakhalin ragweed ( 9 3 ) (1)
244
-57.7 a
-
-
217-218 dec
- 134 a
120
Senkirkine (Renardine) CisHzsNO6 0-Acetylsenkirkine Alkaloid SF Ci5HziN03 Silvasenecine C12H21N04 Sincamidine
C16H27N05 Spartioidine clSH23No5 Spectabiline CisHztiN07 Squalidine (Integerrimhe) CisHesN05 Strigosine Ci4Hd04 SupLine CisHz5NOs Supinine N-oxide CisHz5NOs Thesine C34H42N206 Thesinecine CioHiiNOz Thesinine C17HZlN03 Tomentosine (Otoeenine) Trachelanthamine CI~HZ~NO~
-
(1) Brachyglottis repanda J. E. and G. Frost ( 1 5 ) 8.kirkii Ho0k.f. (68) 8.ViSCOSUS L. ( 4 4 )
197-198
-6.2 a
195-196 228-230
- 148 a
(4)
-
-
Anwinckia interrnediu (22)
-
-
(4
178
- 83.7 d
Crotalaria spectabilis Roth. ( 9 4 )
186
+121 a
(4)
169
- 26.9 a
Heliotropium strigosurn Willd. (95)
Gum
- 19.3 d
$’
(1)
148-149
- 12 d
L
(4
-
-
-34 b
+P
5 $ c,
i 8
u1
Thesium minkwitzianum B. Fedtsch. (96-98)
254-256
+ 33.4
Thesium minkwitzianum (96)
124-125
-
Thesium minkwitzianum (96)
38-40
-
(4
232 92-93
14 a - 18.1 c
(194)
Trachelanthushissarkus Lipsky ( 2 4 ) T . kwolkovii Lipsky ( 2 4 )
I9
w
4
cn 00
TABLE 1-ontinued Alkaloid Trachelanthamine N-oxide C15H27N05 Trachelanthine (TrachelanthamineN-oxide) Trichodesmine CisHz7NOa Turneforcine Ci3HziN03 [Usaramine] (trans-Retrorsine)
[Usaramoensine] Viridiflorine Ci5Hz7N04
Source (References)
MP ("C)
[Ebb
(4)
166-167
-22.5 c
(1) Trachelanthus hissarkus ( 2 4 ) T . korolkovii ( 2 4 ) (1,4) T r i c h o d e m incanum Bunge (34) Crotalaria rubiginosa Willd. var. wightina ( 4 7 ) (1)
160-161
38 d
Crotularia mucronata ( 8 ) C. brevifolia ( 8 ) C. usaramoensis ( 4 6 ) (1, 99)
(4 Lindelojia stylosa ( 2 1 ) Trachelanthus hissarkus ( 2 4 ) Lindelojia stylosa A. Brand ( 2 1 ) Trachelanthus hissarkus ( 2 4 ) (4) (4) (4) (1)
(4 (4)
154-155
182.5-183.5
+7.1 d
221 dec 102.5-103.5
-25 a -11.7 d
8
b
158-159 dec
-
2
Lindelofia*mcrostylaBunge (50) (4) (4) (4) (1) (4)
Crotalaria laburnifolia ( 1 0 0 )
149-151 222 169 175-176
20-25 b
-
- 62.4 b
-
-
237 dec 197-199
-
kP
$
ca
3. 0 k+
+29.7 d,-19 a
L
This table is a supplement to those in Leonard ( 1 , 4 ) .Where References (I)and/or ( 4 )arecitedonly, the source material in those chapters may be considered complete. Other entries are additions and corrections. Alkaloids marked in brackets [ ] are mixtures. b Solvents: a, Chloroform; b, methanol; c, water; d, ethanol; e, pyridine. Where no reference is made in the text, the solvent is ethanol. a
2
E
260
FRANK L. WARREN
I
I1
I11
( - )-retronecanone has structure 111.The configuration a t C-8 was confirmed by the ozonization of isoheliotridene (IV) to the keto acid, V, and esterification and reaction with methylmagnesium iodide to the ditertiary alcohol VI, which was identical with that from S-proline. Furthermore X-ray studies on jacobine bromhydrin (104)and retusamine (64) have given support for the relative configurations in retronecine (CXLIV in 1 ) .
The interrelationships between the 1-hydroxymethylpyrrolizidines have been established by Labenskii et al. (105)and Likhosherstov et al. (106)in a series of oxidation studies. It was shown that when the CHzOH group was cis to the C-S hydrogen only one acid was formed, but in the trans arrangement partial inversion resulted in the formation of two acids.
&a/& R
CHzOH
t
COOH
__f
t
N
IXa; R=COzH IXb; R = CHzOH
VII (-)-Isoretronecanol
VIII (-)-Isoretroneoanolic acid
& & & CHzOH
t
XIIe; R=COzH XIIb; R = CHzOH
COOH
+
X (+)-Isoretroneoanol
XI
4. Xenecio ALKALOIDS
261
Thus ( - )-isoretronecanol (VII) on oxidation gave ( - )-isoretronecanolic acid (VIII), [mp 228"-229"; [a]D - 71.4' (ethanol); picrate, mp 220"-221'1 and ( - )-trachelanthamidinic acid (IXa) [mp 215"-216"; [aID - 32.5"(ethanol); picrate, mp 178"-179'1. Lindelofidine (X)yielded two isomeric acids one of which had properties comparable with isoretronecanolic acid (XI) but with [aID + 71.5" and ( + )-trachelanthami+ 32.5" (ethanol). Heating of the mixture of acids dinic acid (XIIa)DI.[ from ( - )-isoretronecanol (VII) with ethanol and hydrochloric acid gave ethyl trachelanthamidate ([a]D - 33" (benzene);picrate, mp 180"-181") which was reduced with lithium aluminum hydride to trachelanthamidine (IXb)([a]D - 22";picrate, mp 172"-174").Thus the heliotridane series is converted to the pseudoheliotridane series. A similar conversion permits the formation of laburnine (XIIb). The establishment of the absolute configuration of ( - )-heliotridane (I)together with the several interconversions, now permits the absolute structures to be given to the mono-, di-, and trihydroxylated l-methylpyrrolizidines (Table 11)and to the mono- and dihydroxylated l-methyl1,2-dehydropyrrolizidines(Table 111).It is of interest for structural studies that weak intramolecular hydrogen-bonding has been observed in trans-2,8-H-2-hydroxypyrrolizidine (107). TABLE I1 THEABSOLUTE CONFIGURATION OF HYDROXYLATED 1-METHYLPYRROLIZIDINES
Compound
C-7-X
Heliotridane Pseudoheliotridane ( - )-Trachelanthamidine ( + )-Trachelanthamidine(Laburnine) ( - )-Isoretronecanol ( )-Isoretronecanol (Lindelofidine) Oxyheliotridane Retronecanol Dihydroxyheliotridane Platynecine (Mikanecine) Macronecine Hastanecine and/or turniforcidine
+
Rosmarinecine
H H H H H
C-8-H U
a U
P U
H uOH POH uOH POH uOH POH
P
POH
U
U U
U U U U
c-1-Y
Z
H H H H H H H H H H H H OH
262
FRANK L. WARREN
TABLE I11 THEABSOLUTE CONFIGURATION OF HYDROXYLATED 1-METHYL-1,%DEHYDROPYRROIJZIDINES
Compound Heliotridine Retronecine Supinidine Desoxyretronecine Crotanecine
C-7-X
C-8-H
Y
Z
aOH BOH H BOH BOH
U
OH OH OH H OH
H H H H OH
U
a U U
The “necine” bases, which have noC been previously reported, and those for which further information has become available since (1) (see Table I1 in Volume VI, Chapter 3) are shown in Table IV together with their structures, and with the parent alkaloids.
B. NEWNECINES 1. Miscellaneous Hastanecine N-ethochloride (XIII), CloH2oClNO2 (mp 21 8.5’-220”) has been found esterified with trachelanthic acid in the second alkaloid, C17HSzClN05, from LindeZoJia macrostyla (50) [mp 149’-151’; [a]= 20.25’ (methanol)]. H?
VHzOH
!
CZH5
XI11
XIV
Several pyrrolizidine bases have now been .found free in the plant.
(
+ )-Isoretronecanol has been found free in the roots, and as the esters
thesine and thesinine in the aerial portion of Thesium minkwitzianum (96).Retronecine N-oxide has been isolated from Crotalaria retusa. It is of interest that 1-methyl-2,3,8,1-didehydropyrrolizid-7-one (XIV) has been isolated from the exocrine secretion of danaid butterflies (108).
TABLE IV
NECINESG Necine
Chemical (and stereochemical)name
-
(
+ )-Supinidine
( - )-Supinidbe
CsHi3NO2 Heliotridine
Retronecine
CsH13N03 Crotanecine
1-Methylene-8u-pyrrolizidine 7b-Hydroxy-1-methylene8fi-pyrrolizidine 7p-Hydroxy-1-methylene8u-pyrrolizidine 1-Hydroxymethyl-1,2-dehydro8b-pyrrolizidine 1-Hydroxymethyl-1,2-dehydro8u-pyrrolizidine 7u-Hydroxy-1-hydroxymethyl1,2-dehydr0-8u-pyrrolizidine
7b-Hydroxy-1-hydroxymethyl1,2-dehydro-Sa-pyrrolizidine
MP ("C)
Parent alkaloid
[ulDb
Fuchsisenecionine Occurs free as the base Occurs free as the base
155.5 bp 120°/170mm 34-35
-
Occurs free as the base
35-36
- 150 d
Cynaustine
-
-
Ambaline
-
-
7-Angelylheliotridine Angelyl heliotridine trachelanthate Angelyl heliotridine viridiflorate 7-Angelylretronecine Chlorodesoxysceleratine Crispatine Fulvine Incanine Indicine Latifoline Alkaloid SC Spectabiline
-
6~,7~-Dihydroxy-l-hydroxymethyl- Anacrotine 1,2-dehydr0-8u-pyrrolizidine
-43.1 d +36.1 d
-
-
-
TABLE IV-continued Necine CsHisNO ( )-Isoretronecanol (Lindelofidine)
+
( - )-Isoretronecanol
Chemical (and stereochemical) name
1a-Hydroxymethyl-S,&pyrrolizidine
18-Hydroxy-8a-pyrrolizidine
Laburnine 1fl-Hydroxymethyl-B/%pyrrolizidine ( )-Trachelanthamidine
+
( - )-Trachelanthamidine la-Hydroxymethyl-8a-pyrrolizidine CsHisNOz Hastanecine 1~-Hydroxymethyl-7/3-hydroxy8a-pyrrolizidine Macronecine 1a-Hydroxymethyl-7a-hydroxy8a-pyrrolizidine Platynecine 1/3-Hydroxymethyl-7fi-hydroxy8a-pyrrolizidine Trachelanthidine Trachelanthamidine N-oxide CsHisN03 Rosmarinecine 1/3-Hydroxymethyl-2/3,7B-dihydroxy 8a-pyrrolizidine Isomer of rosmminecine -
CgHi5NO Supinidine methyl ether
1-Met,hyoxymethyl-1,2-dehydro8a-pyrrolizidine
Parent alkaloid
Cynaustraline Nervosine Thesine Thesinine ( - )-Isoretronecanyl tiglate ( - )-Isoretronecanyl truns3-methylthiopropenate Laburnine benzoate Laburnine tiglate Planchonelline (Laburnine truns3-methylthiopropenate) Strigosine
MP ("C)
[.IDb
40-4 1
+79 d
-
-
bp 80°-90"/0.01 IIM
+ 15.15 d
-
-
126-128
+ 49.29 d
Hygrophylline Neoplat yphylline
-
-
-
-
-
Angularine
-
-
Brachyglottine
-
-
Occurs free as the base
bp 100°/10mm
-24 d
Retusine
Retronecine methyl
CgHisNO+ CioHzoNOzCl Hastanecine N-ethochloride Formula unknown Cynoglossophidine
1 -Methoxymethyl- 1,2-dehydro8a-pyrrolizidine Methoxymethyl- 1 ,I-epoxypyrrolizidine l-Methoxymethyl-7/3-hydroxy1,2-dehydro-8a-pyrrolizidine 1 -Methoxymethyl-7-hydroxy1,2-dehydro-8a-pyrrolizidine
bp 100°/10mm
- 24
Occurs free as the base
bp 53'/0.1 mm
-63 d
Occurs free as the base
35-40
+38 d
35-40
+ 38
-
7&8a-Dihydroxy- 1 -hydroxymethyl0-Acetylsenkirkine 1,2-dehydropyrrolizidineN-methosalt Clivorine Crosemperine Floricaline Floridamine Florosenine Onetine Retusamine N-Methyl-( )-trachelanthamidine Kumokirine
+
1 a-Hydroxymethyl-7/3-hydroxy8a-pyrrolizidine N-ethochloride
-
This table is a supplement to Table I1 in Volume VI, Chapter 3. BReference to solvents as in Table I.
a
-
143 ip
-
C17H3zN05Cl from L. macrostyla
218.5-220
Cynoglossophine
-
-
266
FRANK L. WARREN
2. 1-Methylene-8a-pyrrolizidine Crotalaria anagyroides (54) and C. damarensis (55)respectively, gave the partially racemized and ( - )-1-methylene-8a-pyrrolizidine(XV) [bp 115°/150mm; [a]= - 100" (ethanol);tartrate, mp 98"-100°, ["ID - 7" (ethanol); picrate, mp 217"-218"; picrolonate, mp 171.5"-172.5'1. The 3-bromo-8-sulfonate [mp 178"-179"; [a]= - 49" (ethanol)] was used t o resolve the (&)-form.The base on oxidation gave formaldehyde and 1-ketopyrrolizidine, and on catalytic reduction yielded a mixture of 26% heliotridane (XVI) and 74% pseudoheliotridane (XVII),from which the latter was obtained pure and identified as its picrolonate (mp 172"173.5"; ["ID 3.2 f 1.0").XVisdifferentfrompureXVIIIa (isoheliotridene,
t
__t
N
XVII
xv
XVI
XVIIIe; X = Y = H XVIIIb; X = H,Y = OH XVIIIo; X = OH,Y = H
l-methyl-l,2-dehydro-8cr-pyrrolizidine) ([a]= - 42.8" ; picrolonate, mp 186"-187"), prepared pure from 7p-hydroxy-1-methy1-l72-dehydro-8apyrrolizidine (desoxyretronecine, XVIIIb) (31,109,110)and in doubtful purity from supinidine (XVIIIc) (31, 54). The two compounds XV and XVIIIa show no melting point depression on admixture and their I R spectra are very similar. Culvenor ( 5 4 ) draws attention t o the unreliability of the picrates for identification and warns concerning the sign of rotation when two measurements are not made. Reliable figures seem now t o be as follows : heliotridene, [a]= - 159 & 5" ; 7-chlororetronecane, [a]= - 30"; and ( - )-pseudoheliotridane, [a]b - 2.5". The value for ( + )-pseudoheliotridane, [.ID 17.1", -is considered incorrect. The diagnostic difference between the two heliotridanes is given as heliotridane picrolonate, vmax 995 and 1020 cm-l, and pseudoheliotridane picrolonate, ,v 1115 cm-1. A partially racemized form of 1-methylenepyrrolizidine (XV)has been prepared by the Wittig reaction on pyrrolizid-l-one and resolved as its (+)-tartrateto the ( - )-form, [.ID - 43.1" (111).
+
3. 7~-Hydroxy-l-methylene-8~-pyrrolizidine The structure of 7p-hydroxy- 1-methylene-8/?-pyrrolizidine(XIX) (bp 62"/0.03 mm; mp 33"-35'; [a]= +36'; picrate, mp 173.5"-174.5'; picrolonate, mp 234"-234.5"; phenylurethane, mp 135.5"-136", [aID
4 . Senecio ALKALOIDS
267
-20.5") from C. goreemis (31) was established by oxidation to give formaldehyde and by catalytic reduction to yield ( + )-7&hydroxyheliotridane (XX) (mp 63"-64'; [aID +20.5'; picrate, mp 201.5'-202.5"; phenylurethane, mp 125.5'-126.5', [a]= - 12.6"). Compound X X was enantiomeric with ( - )-7a-hydroxyheliotridane (XXI) (mp 61.5"-62.5' ; [aID - 20.8'; picrate, mp 202"-203"; phenylurethane, mp 125'-126",
-
HO
H
7
5
xx
XIX
H?
X
3
&
HO
t
CHzOCOR
t
N
N
N
XXI
XXIIIa; X = O H XXIIIb; X = C1
XXII
["ID + 16') obtained by the hydrogenolysis over Raney nickel of heliotrine (XXII) (109).Hydrogenation of heliotrine (XXII) on palladium/ charcoal yielded 7a-hydroxy-1-methyl-l,2-dehydro-8a-pyrrolizidine (XXIIIa) (mp 67'-68'; [.ID +31.1'; picrate, mp 150'-151", [aID 0'; picrolonate, mp 218'-218.5') which on further hydrogenation gave XXI and with thionyl chlorideyielded the chloro compound, XXIIIb (picrate, mp 230"-231", [aID - 31.4').
4. 7u-Hydroxy-1-methylene-8a-pyrrolizidine In an elegant series of reactions Culvenor and Smith (31) synthesized the enantiomorph of XIX. Heliotridine (XXIV) with thionyl chloride
xxv
XXVI
XXIV __f
XXVII
XXVIII
268
FRANK L. WARREN
under mild conditions gave 7a-hydroxy- 1-chloromethyl-l,2-dehydro8a-pyrrolizidine (XXV) (hydrochloride, mp 166.5"-167') which on reduction gave 7a-hydroxy- 1-methylene-8~-pyrrolizidine(XXVI) ([.ID - 37.2'; picrate, mp 174'-175', [aID - 22.0'; picrolonate, mp 232"-233", mixed with picrolonate of XXIIIa, mp 202"-205"). Heliotridine was treated with thionyl chloride at higher temperatures t o yield the 7-chloroI-chloromethyl-1,2-dehydro-8a-pyrrolizidine(XXVII) (picrate, mp 168.5'-169") which on reduction with zinc gave 7-chloro-1-methylene8a-pyrrolizidine (XXVIII) (picrate, mp 234.5'-235.5", ["ID - 68.4').
5 . 7/3-Hydroxy-l-methylene-8a-pyrrolizidine The second compound from C. goreensis (31)was the 8a-isomer XXIX [a]= -150'; picrate, mp 203.5'-204", (bp 41'/0.1 mm; mp 35'-36'; [.IU - 47.5'; picrolonate, mp 209"-209.5") which on oxidation gave formaldehyde and on reduction, retronecanol (XXX), and was synthesized from retronecine (XXXIa) by way of its chloroderivative, XXXIb (112),which on reduction gave 80% of X X I X and 20% ofdesoxyretronecine (XXXIc) previously obtained by Adams and Rogers (109).
xxx
XXXIIa; X = H , Y=OCHs XXXIIb; X = H, Y = Br XXXIIC; X = H , Y = O H XXXIId; X = OH, Y = OCHs XXXIIe; X = C1, Y = OCHs
XXIX
XXXIIIO; X = H, Y = OCHs XXXIIIb; X = H , Y = B r XXXIIIC; X = Y = H XXXIIId; X = OH, Y = OCHs
XXXIa; X = O H XXXIb; X=C1 XXXIc; X = H
XXXIV
6. l-Methoxymethyl-l,2-dehydro-8cr-pyrrolizidine and its 7-Hydroxy Derivative Two other nonesterified pyrrolizidine bases were obtained from C. trifoliastrum and C. aridicola (52). The base (bp lO O ' /lO mm; [.IU - 24';
4. Senecio
ALKALOIDS
269
picrate, mp 155"-156", [a]D - 12.4")was identified as 1-methoxymethyl1,2-dehydro-8a-pyrrolizidine (XXXIIa) which on hydrogenation gave l~-methoxymethyl-8a-pyrrolizidine(XXXIIIa) (bp 40°/1 mm ; [a]D - 77"; picrate, mp 17Oo-17l0,[a]D - 18.7").The latter with hydrobromic acid yielded the bromo hydrobromide, XXXIIIb (mp 153"-154" ;picrate, mp 180"-181") which with Raney nickel gave heliotridane (XXXIIIc). The action of hydrobromic acid on the base itself, XXXIIa, gave the corresponding bromide, XXXIIb (picrate, mp 179"-180") identical with the compound formed from supinidine (XXXIIc). The second base, the 7-hydroxy derivative, XXXIId, was obtained as an hygroscopic solid (bp 77'/0.4 mm; mp 35"-40"; [.ID +38"; picrate, mp 185"-186", [.ID - 9.0°; HCl, mp 159"-160", ["ID - 19.2'). Hydrogenation gave the dihydro derivative, XXXIIId (picrate, mp 202"-203") which with hydrobromic acid gave anhydroplatynecine. The treatment of XXXIId with thionyl chloride gave the chloro compound XXXIIe (picrate, mp 126"-127"), which was reduced with chromous chloride to XXXIIa, and which on distillation gave anhydroretronecine (XXXIV), (bp 60"/100 mm; [trID + 358"; picrate, mp 236"-238"; picrolonate, mp 204"-206"), giving on reduction anhydroplatynecine.
7. 1-Methyl- and l-Methoxymethyl-l,2-epoxypyrrolizidine The third nonesterified base from C. goreensis (31) (bp 112"-114"/3 mm; [a],, + 9.3"; picrate, mp 173"-174"), showed 0.55 CH3 groups, and on
XXXVe; X = H XXXVb; X = OCHa
catalytic reduction absorbed 1 mole of hydrogen to give an oil characterized as its picrate (mp 194"-195"; [a]D 0"; picrolonate, mp 249"-249.5'). This compound was envisaged as 1-methylpyrrolizidine-1,Z-epoxide (XXXVa). The third base, C9H15N02 [bp 53"/0.1 mm; [a]D -63" (ethanol); picrate, mp 166'-168"; picrolonate, mp 164"-165"; HCl, mp 232"-234", [.ID -40.4" (ethanol)] from C. trifoliastrum and C. aridicola (52) was identified (51)by its mass spectra and NMR spectra as 1-methoxymethyl1,2-epoxypyrrolizidine, XXXVb. Catalytic reduction gave the dihydro derivative, CgH17N02 (picrate, mp 126"-127") which with acetic anhydride yielded the methyl ether of supinidine.
270
FRANK L. WARREN
C. SYNTHESES OF HYDROXYLATED METHYLPYRROLIZIDINES Several syntheses have been reported for pyrrolizidine (113-121), 1 -methylpyrrolizidine (118, 122-124) and 3-methyl- and 3-hydroxy-
methylpyrrolizidine (125-129). Only those syntheses will be outlined here which are stereoselective.
1. ( f )-Pseudoheliotridune ( f )-Pseudoheliotridane (XXXVIa) has been prepared by cervinka (130)in a novel manner from 1 -methyl-2-ethyl-d2-pyrroline (XXXVII) by reaction with ethyl bromoacetate and heating of the resulting product with potassium formate and sulfuric acid to give “erythr0”-(& )-3(N-methyl-2-pyrrolidy1)butyrate(XXXVIII). Reduction with lithium aluminum hydride and ring closure with hydrobromic acid yielded XXXVIa. CHI ac2H5
I
CH3 XXXVII
+~
~ H c H z c o o c z H+ 5
I
CHa XXXVIII qHzX
COOEt
&-c?-) XXXVIa; X = H XXXVIb; X = O H
CHzBr
CHzBr
XXXIX
2. ( f )-Truchelunthamidine(49) ( f )-Trachelanthamidine (XXXVIb) has been synthesized by Kotchetkov and his collaborators (131, 132) by ring closure of the tribromide, XXXIX, with ammonia and reduction with lithium aluminum hydride.
3. 1-Hydroxymethylpyrroldzidine 1-Hydroxymethylpyrrolizidinehas been synthesized by cervinka, Pi 12, and Jirkovskf (133)by a novel ring closure of dimethyl N-benzylpyr *ol-2-yl-succinate(XL) which on reduction gave 1-carbomethoxy-
271
4. Senecio ALKALOIDS
3-oxopyrrolizidine (XLI) which with lithium aluminum hydride gave a mixture (9 :1) of ( f )-trachelanthamidine (IXb + XIIb) and ( f )-isoretronecanol (VII + X). The former was resolved by its dibenzoyltartrate (mp 157'-158"; [t~]~) -72"), to give (+)-laburnine (XII) ( [ a ] I )+13.6"). COzCH3
qAF&
0
CHaCaHs XL
XLI
XLII
XLIII
A similar mixture in which the ( f )-isoretronecanol predominated resulted from the Dieckmann ring closure of methyl 3-(2'-carbomethoxyN-pyrrolidy1)propionate (XLII) to XLIII followed by the cyanhydrin synthesis. COzCzHs
CHzCOzCzHs
COzCzHs
-c+ +c+ 0 XLV
XLIV
0 XLVI
J
VII f
X
t
(xiCzH5 N
0 XLVII
The stereospecificsynthesis of ( f )-retronecanolhas been accomplished by Nair and Adams (134).Ethyl pyrrolidylacetate (XLIV) condensed with ethyl oxalate to give ethyl 2,3-dioxopyrrolizidine-1-carboxylate (XLV) which was catalytically reduced to the 2-hydroxy derivative, XLVI, which dehydrated to ethyl 3-oxopyrrolizid-1,2-ene-1-carboxylate
272
FRANK L. WARREN
(XLVII). Lithium aluminum hydride reduction yielded ( 2 )-isoretronecanol (VII + X ) (picrate, mp 188"-189" ; benzoate picrate, mp 130"131").
4. 1-Hydroxymethyl-2-hydroxypyrrolizidine. Adams et al. (135)have synthesized the 1-hydroxymethyl-2-hydroxypyrrolizidine from 2,3-dioxopyrrolizidine-1 -carboxylate (XLV) the keto group of which was reduced with a rhodium catalyst at 20 psi to the 2-hydroxy-3-0x0 compound, XLVI, which with lithium aluminum hydride yielded 1-hydroxymethyl-2-hydroxypyrrolizidine(XLVIII) (mp 123"-124"). The action of thionyl chloride did not form a cyclic sulfite ester but a l-chloromethyl-2-chloropyrrolizidine,from which it was assumed that the groups were trans oriented. COzCzHs
O H
I
CHz ___f
-k
'CO
XLV
I
COzCzHs
(0
CHzOH
@
-
XLVI
I CHzOH
CzH5
a $ O H L
0 XLIX
XLVIII
Goldschmidt (136)condensed pyrroline and ethyl oxosuccinate to give the dioxo compound XLV, which was reduced catalytically and dehydrated by way of the tosylate to 3-0xo-l,8-dehydropyrrolizidine1-carboxylate (XLIX) which yielded isosupinidine (L) with lithium aluminum hydride, and gave ( f )-isoretronecanol on further reduction.
5 . Retronecine (63) Geissman and Waiss (137)have effected the first stereospecific synthesis of retronecine (CXLIV in 1 ) by a series of reactions which is shown in (LI) was added to Chart I. Ethyl N-carbethoxy-3-aminopropionate diethyl fumarate and the product ring-closed to the pyrrolidone, LII, which on hydrolysis and reduction yielded the required 3-hydroxypyrrolidine-%acetic acid lactone (LIII). Reaction of this lactone with ethyl bromoacetate gave the N-acetic ester, LIV which by ring closure
4. Senecio ALKALOIDS
273
and reduction yielded ethyl 2,7-dihydroxy-pyrrolizidine1 -carboxylate (LV). Hydrolysis and dehydration of the ester and reduction of the resulting acid gave ( )-retronecine which was resolved as its ( )camphorate to ( + )-retronecine (LVI). ROzCCH=CHCOzR i-
1-
ROzCCHaCHzNHCOzR LI J
ROzCCHCHzCOzR
I
RO2CCHzCHzNCOzR
I /,NCO~R
LIII
LII
J LIV
LV
LVI
CHARTI. Stereospecific synthesis of retronecine (R = CzH5).
D. OTONECINE(67-68) Otonecine hydrochloride, CgHl~N03mHC1, obtained originally from otosenine, has now been obtained (70) together with anhydrootonecine hydrochloride, CgH13N02 * HC1 (mp 203"-205" ; [.In O " ) , by the hydrolysis of renardine, while only the anhydro form was obtained from onetine (63). The base was envisaged as the necine moiety of retusamine (77) although no basic hydrolysis product could be isolated. Tetrahydrootonecine, CgH17N02 (bp 72"-74"/8 mm; [a]D -18.2"; HC1 salt, mp 240"-242", [aID - 30.4";bitartrate, mp 171"-173",[a]D 0"-2") has been obtained by catalytic hydrogenolysis of both renardine (70)and onetine (63). Structure LVII follows from that of retusamine (see Section IV, D, 4) determined by Wunderlich (64).The alkaloid exists as the salt as LVII and as the free base as LVIII so that otonecine may be regarded as
274
FRANK L. WARREN
8-hydroxy-N-methylretronecine. The structure of tetrahydrootonecine (LIX),which has been studied by Koretskaya, Danilova, and Utkin (138), follows logically and explains the formation from it of two oximes (mp 181.5"-183'; [aID68.8'; picrolonate, mp 133"-135"; and mp 131.5'-133"; [.ID 90.8') which did not precipitate a picrolonate (70).
I CHs LVII
CHI LVIII
CHI LIX
E. CROTANECINE
+
Crotanecine, C~H13N03(mp 202"-203.5"; [.IU 39.2' ; picrate, mp 131') was the necine (LX) found by Atal and Kapur (139)in anacrotine and madurensine, the structures of which followed from a study of their
NMR spectra. This structure, LX, receives confirmation (140)from the catalytic reduction t o crotanecanol (LXI) (mp 132').
HO LX
LXI
111. Structures of the Necic Acids (68-109) The chemical structures of almost all the known necic acids have been elucidated, and the absolute configurations have been determined in the C ~ adipic O acids : senecic, integerrinecic, hydrophyllinecic, jaconecic, and isojaconecic acids, all of which have the same configuration R a t C-2. cervinka et u1. (141)have applied optical rotatory dispersion successfully to show that for five and six-membered lactone rings (LXITa and b) with the carboxyl group vicinal to the heterocyclic oxygen and with Sconfiguration a t this carboii atom exhibits positive Cotton effects. On this basis clivoiiecic acid has the S-, and monocrotalic acid the R-configuration. (See Section 111,F. 5 and D, 1.)
4. Senecio ALKALOIDS
275
It is of interest that 3-methylthiopropenic acid, CH3SCH=CHCOzH, has been isolated from two alkaloids, esters of this acid with laburnine and isoretronecanol, by Hart et al. (49, 71).
0 LXIIb
The LLnecic”acids, which have not been previously reported, and those for which further information has become available since (1)(see Table I11 in Volume VI, Chapter 3) are shown in Table V with their structure and the new parent alkaloids.
A.
C5
ACIDS(68)
1. Sarracinic Acid (68) Culvenor and Geissman (56, 57) have criticized the reported structure of mikanecic acid (141a) (A,,,;,, 216 mp, ~11,000)and reexamined S. mikanoides to find the alkaloid sarracine and its N-oxide only. Hydrolysis of sarracine with alkali gave sarracinic acid, C5Hs03 (mp 57’48’) and mikanecic acid (see next section). The NMR spectrum showed (77.83, 7.96 as a doublet, and 3.60, single proton showing 1 : 3 : 3 :1 splitting, indicative of CH&H=C, and 75.74 due to CH2, which is compatible with LXIII and not LXIV. Hydrogenation of the acid gave a-methylbutyric acid. CH3CH(OH)C(=CH2)COOH LXIV
CH&H=C( CHz0H)COOH LXIII
ROCH2CCOzR’ CH~CO~CH~COCO~C~HS +
II
HCCH3
+
ROCH2CC02R’
II
CH3CH
LXVa; R = CHBCO, R’ = CzH5
LXVIa; R = CH3C0, R’ = CzH5
LXVb; R = R ’ = H
LXVIb; R = R ’ = H
The assignment of the trans’arrangement in sarracinic acid was derived from a study of chemical shift in NMR spectra. Edwards et al. (142)have now synthesized both forms and confirm the structures assigned. Acetoxypyruvic acid was allowed to react with ethylidenetriphenylphosphorane to give a mixture of the cis and trans forms, LXVa and LXVIa, which on hydrolysis yielded sarracinic acid (LXVb) and its cis
276
FRANK L. WARREN
isomer, LXVIb. Isomerism from LXVIb to LXVb was effected by UVirradiation, and both forms gave mikanecic acid on prolonged treatment with alkali.
2. Mikanecic Acid (86) This acid has been shown by Culvenor and Geissman (56)to be l-vinyl3-cyclohexene-l,4-dicarboxylicacid (LXVII). It results from a DielsAlder dimerization of butadiene-2-carboxylic acid from sarracinic acid. cH2=CH*OH
HOzC LXVII
B.
c(3ACIDS(69)
1. Acid from Strigosine The acid, C(3H1204, obtained by Mattocks (95) as an oil [.ID - 17.6" (ethanol); in 1 N HC1, [aID -2.1' (water); brucine salt, mp 215' dec, [.In - 28.8" (water); quinine salt, mp 204"-205") [a]=- 137" (methanol) resulted from the barium hydroxide hydrolysis of strigosine. Oxidation with periodate gave butanone and carbon dioxide. The structure as 2,3-dihydroxy-3-methylpentanoicacid (LXVIII) was confirmed by synthesis (143). CHaCHzC(OH)(CHa)CH(0H)COzH LXVIII COzHCHzC(OH)(CHa)CH2C02H LXIX
2. Dicrotalic Acid (69) Dicrotalic acid (LXIX)is the only other acid having six carbon atoms. C. C7 ACIDS(74)
1. Trachelanthic and Viridijoric Acids (74) A new procedure of resolution of trachelanthic acid has been demonstrated by Kulakov et al. (144) by using the salt (mp 156"-158"; [.], - 9.4") of ( + )-trachelanthic acid and ( - )-benzylmethylamine. The previous structures advanced for trachelanthic and viridifloric acids have been confirmed by Likhosherstov et al. (145).
TABLE V NECK ACIDS~ Necic acid
Tiglic CSH1204 C7H602 C7HlO05 Latifolic
Chemical (and stereochemical) name
Parent alkaloid
MP (“C)
“Y-lDb
trans-3-Thiomethoxyacrylic
Planchonelline
-
truns-2,3-Dimethylacrylicacid
45-4&
cis-2,3-Dimethylacrylicacid
7 -Angelylheliotridine Angelylheliotridine trachelanthate Angelylheliotridine viridiflorate 7-Angelylretronecine Brachyglottine Cynoglossophine Latifoline Laburnine tiglate
64
-
2,3-Dihydroxy-3-methylvaleric acid Benzoic acid
Strigosine Laburnine benzoate
Oil
- 17.6 d
-
-
165-166
+ 94.0 d
3,4-Dihydroxy-pentan-2,3-dicarboxylicLatifoline acid lactone
C7H1202 a-Dihydroanhydromonocrotalic
4-Hydroxy-2,3-dimethylpentanoic acid lactone
C7H1404 Trachelanthic
(
+ )-threo-3,4-Dihydroxy-2-methyl3-pentanecarboxylic acid
Retusine
rp
E
s z!
-
Angelylheliotridine 93-94 trachelanthate, C I ~ H ~ ~ N O ~ C I ex L. macrostyla.
2.4 c 3.7 d p.3
-3 -3
TABLE V-continued Necic acid
Chemical (and stereochemical) name
Parent alkaloid
E.3 4 00
MP ("C)
[alDb
-
( - )-Trachelanthic
( - )-thre0-3,4-Dihydroxy-2-methyl-
Viridifloric
3-pentanecarboxylic acid ( +)- or (- )-erythro-3,4-Dihydroxy2-methyl-3-pentane-carboxylic acid
CSH1405 Crispatic Fulvinic CgH803 C9H1406 Retusaminecic
Echiumine Indicine Ambaline Angelylheliotridine viridiflorate Cynaustine Cynaustraline
3-Methylpentan-2,4-dicarboxylicacid 3-Methylpentan-2,4-dicarboxylic acid p-Hydroxycinnamic acid
Crispatine Fulvine Thesinine
2-Hydroxy-3-methylhexan-2,4dicarboxylic acid
Retusamine
142
- 1.3 a
133-134 113-1 14
0 0
-
C10H1204
Clivonecic C10H1405 Sceleranecic CioHi3C104 Sceleratinic dilactone
2R-Hydroxy-3-methyl-cis,cis-3,5-dieneClivorine 2,5-dicarboxylic mid
142-1 44
156
- 9.3
1-chloro-2,5-dihydroxy-3-methylheptanChlorodesoxysceleratine 2,5-dicarboxylic acid dilactone
207
-
2R,3R,4R-2,4-Dihydroxy-3-methyl- Hygrophylline hept-trans-5-ene-2,5-dicarboxylic
180-1 81
- 18.7 b
1,2,5-Trihydroxy-3-methylheptan2,5-dicarboxylic acid dilactone
Sceleratine
c1OH 1 4 05 Hygrophyllinecic
acid monolactone
2 kw
Seneciphyllic ClOH1406 0-Acetylmonocrotalic ClOHl605 Senecic Integerrinecic Isomers of senecic ClOHl804 Incanic Isoincanic
2R-Hydroxy-3-methylene-hept-cis- Angularine 5-ene-2,5-dicarboxylicacid Spectabiline
2R,3R-2-Hydroxy-3-methylhept$runs-5-ene-2,5-dicarboxylic acid
Anacrotine Renardine Madurensine Neoplatyphylline
151
15.9 b
-
-
Incanine
161-163
+ 25
Incanine Crosemperine
122-123
cis-form
5,6-Dihydroxy-2,4-dimethylhexan3,5-dicarboxylic acid Same as above
-
2,4-Di-p-hydroxyphenylcyclobutan1,3-dicarboxylic acid
to Table I11 in Volume VI, Chapter 3. Reference to solvents as in Table I.
a This table is a supplement b
- 13.2 c
2-Hydroxy-3-acetoxy-3-methylpentan-2,4-dicarboxylic acid lactone
ClZHlsO6 0-Acetyl senecic C18H1606' Thesinic
115
152
0-acetylsenkirkine ( -renardine) Thesine
>300
11.8 d
b P
280
FRANK L. WARREN
2 . Hellotrinic Acid (84) The synthesis of ( & )-heliotramide has been reported by Adams et al. ( 1 4 6 ) .2-Methoxypropionitrile (LXX) reacted with isopropylmagiiesium chloride and the product was treated with hydrocyanic acid. The cyanoCH3CH(OCH3)CN
__f
CHsCH(OCHa)COCH(CH3)z
LXX
J CHaCH(OCH3)C(OH)(CONHz)CH(CHa)g (threo form) LXXI
hydrin on hydrolysis gave ( f )-threo-2-methoxy-4-methylpentan-2carboxylic amide (LXXI) (mp 81"-82"), showing an I R spectrum similar t o ( + )-heliotramide, and the ( f )-erythro amide (LXXI) (mp 145"146").
3. Lasiocarpic Acid ( 8 5 ) The structure of lasiocarpic acid (LXXIIa) was tentatively assigned as the threo form since alkaline hydrolysis gave the 5-hydroxy-3-methoxybutyric acid (LXXIIIa)so that it would correspond to that of heliotrinic acid (LXXIVa) and trachelanthic acid (LXXIVb). Petrova et al. (147) have shown that, the free acid reacts with alkali 200 times slower than the methyl ester to give a compound, C ~ H 1 0 0 4(LXXIIla) (quinine salt, mp 158"-15!)", [ a ] , )- 58.5"). Crowley and Culvenor (148)have made a thorough study of the degradat,ions with hydrochloric acid. Concentrated hydrochloric acid at 100" yielded acetaldehyde, dimetliylpyruvic acid (LXXV),and ( )-2-keto-:%hydroxy-3 , :-d ~ i methy 1pentanoic acid lactone (LXXVI) and a compound A, C~H1202(2>4-IINP,m p 146"-147"). The reaction steps were envisaged as by way of the carbonium ion, LXXVII, to LXXV and LXXVI. With 8N hydrochloric acid there were obtained acetone, acetaldehyde, dimethylpyruvic acid, and ( + )-2-methoxy4-methylpentan-%one (LXXVIII) (bp 140°-142"; 2,4-DNP, mp 123"124', [ a ] , ) + 236"), ( )-2-methylpent-l-en-3-one (LXXIX) (2,4-DNP, mp 149"), and compound A. The isolation of LXXVIII also from heliotrinic acid showed the identity of the asymmetry with lasiocarpic acid a t C-3.
4 . Senecio ALKALOIDS
28 1
COzH
I I
+
(CHs)&H-C-OH
CHsC--CO
I1
CHz
RO-C-H
I
CH3
CH3 LXXVIII
CH3
I I
CHz
LXXIX
LXXIVa; R = CH3 LXXIVb; R = H
COzH
COzH
I
(CHs)zC(OH)--C-OH
I I
__f
RO-C-H
+ I I CH30-C-H I
(CH3)zC-C-OH
CH3
CH3
LXXVII
LXXIIa; R = CH3 LXXIIb; R = H I
I
CHaCHO
COzH
+
I
H-C-OH
I
RO4-H
I
+ (CHs)zCO
CH3
(CH~)ZCHCOCO~H
CH3CH-0
+
I
(CH3)zCHC-CO-CO
I
LXXVI
LXXV
LXXIIIa; R = CH3 LXXIIIb; R = H
4 . Echimidinic Acid (Macrotomic)(78) That these two acids are identical has not been established. Macrotomine gives trachelanthamidine and 2,3-dihydroxybutyric acid (quinine salt, mp 173"-174", [.IU - 104.4') with sodium hydroxide a t 100°C. The same acid forms less readily from heliosupine ( l a g ) , and a similar structure has been assigned t o the acid in the optically inactive cynoglossophine (150).
282
FRANK L. WARREN
5 . Latifolic Acid Latifolic acid, C7H1005 [mp 165°-1660, [all, + 94.0' (ethanol)], obtained from latifoline by catalytic hydrogenation by Crowley and Culvenor ( I I ) , showed two C-methyl groups and the NMR spectrum was in agreement with the lactone formulation LXXX. CH(CH3)COO
\
/
HOOCC(0H)CHCHa LXXX
6 . Summary The C7 acids of this group, shown in Chart 11, are essentially oxygenated derivatives of 2,3-dihydroxy-2-isopropylbutyricacid, while latifolic acid has one of the methyl groups replaced by a carboxyl group. The configuration of lasiocarpic acid a t *C is the same as in trachelanthic and heliotrinic acids. CH3
CH3
I HO-C-H I HO-C-CH(CH3)2 I
*I RO-C-H I
(CH3)2CH-C-OH
I
COOH Trachelanthic R Heliotririic R
= =
COOH
H CH3
Viridifloric
CH3
CH3
I
I
CH-0,
*CH(OR)
I I COOH
C(OH)C(OH)(CH3)z
Echirnidinic R Macrotomic R Lasiocarpic R
=
H
I
,co
v(OH)CH(CH3) I COOH Latifolic
=H =
CH3
CHART11. The structural relation of the C, necic acids.
1 . Fulvinic and Crispatic Acids
Fulvinic acid, CsH1405 (mp 114'), was obtained by Schoental by the alkaline hydrolysis of fulvine (26).The NMR spectrum showed bands a t 79.5 cps (doublet, J = 7 . 2 cps) and 177 cps (quartet, 1 :3:3:1 , J = 7 . 2 cps) attributed to CH3CH, and a t 85 cps (singlet) due to CH3C .,' A similar TH3 /OH CH39-C-FCH3 H" 'COzH H ' 'COzH
Ho>,s,CH3
'\
LXXXI
CHqF,-C-
FCH3
H CO2H
& 'C02H
LXXXII
acid, crispatic acid (mp 133"-134") has been obtained by Culvenor and Smith ( 1 6 )from crispatine. Neither acid showed optical activity and they are assigned structures LXXXI and LXXXII. Edwards and Matsumoto (151) have synthesized these acids by the Reformatsky reaction using ethyl a-methylacetoacetate and ethyl 2-bromopropionate. Cram's asymmetric induction rule predicts the yields should be, in order, racemate, (S)-mesoand (R)-meso. On the basis of this and the published NMR spectrum (methyl signals for fulvinic acid a t lower field because of steric interaction) crispatic acid is assigned the S-configuration and fulvinic the (R)-mesostructure.
2. Acids from Retusine Culvenor and Smith (77) hydrolyzed retusine to obtain two lactone acids, CsH1204, which were identified as epimeric dihydroanhydromonocrotalic acids (LXXXIIIa) the a-acid (mp 130"-131"; [u] +3.3"), which was the form present in the alkaloid, and the /%acid (mp 1 1 8 " ; ["]I) - S O " ) .
4 . Summary
All the acids of this group may accordingly be represented by the general formula LXXXIII. The R configuration a t C-2 of monocrotalic acids has been determined by Cervinka et al. (141). CH~CH(CO~H)CX(CH~)CY(COZH)CH~ LXXXIII LXXXIII LXXXIII LXXXIII
a, Crispatic and fulvinic acids b, Acids from retusine (lactone form) c, Monorrotalic acid (lactone form) d, Acetylmonocrotalic acid (lactone form)
X=OH, Y = H X=H, Y=OH X=Y,=OH (140) X =CHsCOO, Y = OH (94)
E. C ~ GLUTARIC O ACIDS(86) 1. Trichodesmic Acid (100)
A neat synthesis of trichodesmic acid has been effected by Edwards and Matsumoto (152) starting with ( & )-2,3-dimethy1-4-isopropyl2-cyclopentanone (LXXXIV),which was cis-hydroxylated with osmium tetroxide to the glycol racemate. This glycol, after protection as the orthoformate ester (LXXXV),was converted to the benzylidene derivative, LXXXVI, ozonized, and decomposed with alkaline peroxide to yield ( k )-trichodesmic acid (LXXXVII) (mp 194"-195"; methyl ester,
284
FRAR'K L. WARREN
mp 116"-119"). Resolution by way of the cinchinodine salt (mp 247"248"), gave the (+)-acid (mp 209"-211"; [aID +2.96"; methyl ester, mp 6!)"-70", [ a ] , )- 6.83").Since senecic, integerrinecic, hygrophyllinecic, jaconecic, and "retusaminecic" acids all have the same absolute configuration a t the grouping -C(OH)(C02H)CH3, trichodesmic acid is considered as LXXXVII (2R, 3R, 4R).
LXXXIV
LXXXV
(C CsHsCH H3)&H-qcf!HCzHs t
'CHI 0 LXXXVI
LXXXVII
2. Incanic and Isoincanic Acids Incanic acid, C10H1604 (mp 163"; [.In 25"; methyl ester, bp 140°, + 10.6") was obtained by alcoholic potassium hydroxide hydrolysis of incanine, while alcoholic sodium hydroxide gave an insoluble salt, [a],) - 29", which yielded isoincanic acid (mp 122"-123.5"; [.ID - 25"; methyl ester, mp 11"-48",[ a l l , - 31 .so)which on heating with potassium hydroxide regenerated sodium isoincanate (34, 35, 153, 154). Oxidation with chromic acid gave acetone and acetic acid (2.3 moles). Reduction of methyl isoincanic acid with lithium aluminum hydride gave a triol, C ~ O H ~ ~ ( (nil) O H 66"; ) ~ [ a l l , - l0.8"), and methyl incanate gave a noncrystalline isomer ( [ a ] , ,- 6.So), which with periodic acid gave formaldehyde. The acids have been assigned structure LXXXVIIIb which recalls trichodesmic (LXXXVIIIa) and junceic (LXXXVIIIc)acids. [a],,
(CHa)zCHCHCY(CHa)C(COOH)CH2X
I co-
I
0
LXXXVIIIa; Trichodesmic acid
X
= OH, Y = H
LXXXVIIIb; Incanic and isoincanic acids
X
= H,
Y =H
LXXXVIIIc; Junceic acid
X
= OH.
Y = OH
4. Senecio ALKALOIDS
285
Y. Gruntianic Acid (94). The structure LXXXIX proposed previously (154a)would place this acid in this group as containing the same carbon skeleton with a carboxyl group in place of a methyl group, a relationship observed between latifolic acid and viridifloric and trachelanthic acids (see Chart 11).Wunderlich ( 6 4 ) has proposed an alternative structure (XCa) indicative of a relationship with the acid in retusamirie (CXb) (64).
co 0 I I CHsCHCH(COzH)C(CH3)C(OH) (C02H)CHa LXXXIX CHsCHzC(COzH)CX(CHs)C( COzH)CH:,
I
co
I
0
XCe; X = O H XCb; X = H
F. Clo ADIPICACIDS 1. Integerrinecic Acid and Senecic Acid and Their Diastereoisomers (95,97)
a. Integerrinecic and senecic acids. An elegant synthesis of integerriiiecic and senecic acids has been effected by Culvenor and Geissman (15,5). Methyl 2-methylene-3-acetoxybutanoate(XCI), prepared from 3-acetoxy- 1-butyne and nickel carbonyl, was condensed with ethyl acetopropanate, hydrolyzed, and decarboxylated to give ( k )-&methylhept-L'-en-6-one-:3-carljoxylicacid (XCII)in both the trans ( m p 4 7 O - 5 l o ) , and cis forms (2,4-DNP,mp 19Oo-191"), identical with the corresponding acid from the oxidation of senecic acid. The ( f )-trans acid was converted to the cyaiihydrin and hydrolyzed to ( f )-integerrinecic acid lactone (XCIII), which was resolved by way of its brucine salt to yield the two eiiantiomers. Irradiation of the lactone gave the cis-lactone (XCIII)
286
FRANK L. WARREN
which gave senecic acid on hydrolysis. The cis-lactone had not previously been prepared since lactonization methods used had effected geometrical isomerism ; this cis-lactone was shown to result from partial retention of the configuration of the double bond by 60% sulfuric acid at room temperature. The physical constants for the acids are shown in Chart 111. CH3 H H,
;c==c'
CH3
,CH2AC(
,,C02H 'C'
'COzH
HO'
'CH3
2R, 3R Integerrinecic acid
2R, 3R Senecic acid
)-acid (+)-acid(2R, 3R) (-)-acid (2S, 3 s ) (
bIp ("c) 163-165 146-148 146
"XlD -
( f )-acid
(+)-acid (2R, 3R) (-))-acid (25, 35) ( )-lactone
-
-9.9"
+ ( + )-lactone ( - )-lactone
2R, 35; 28, 3R Diastereoisomeric senecic acid Ilp ( f )-acid ( )-itrid ( - )-acid
+
("c)
1.X-160
-
148 142 141 1.55-156 153 153.5 153
[&ID
- 6" -
+ 40" - 30.4'
- 40'
2R, 35; 2S, 3R Diastereoisomeric integerrinecic acid
[a]D
+
lRirP("c) 178-180
-
I I $)- I20 46.0' 11!)-1%0 -42.6"
)-acid ( )-acid (-)-acid ( f )-lactone ( +)-lactone ( - )-lactone (
+
Mp ("C) 159-162 132-133 132-133 154-156 134-136 134-136
[&ID
+26" -24'
-
+ 10.8" - 10.0"
CHART111. The structure and physical properties of senecic acid, integerrinecic acid and their diastereoisomers (155, 159-ZfiZ).
6. ( f )-Integerrinecic acid. The synthesis of ( f )-integerrinecic acid is also reported by Kochetkov et al. (156). The Michael condensation of diethyl malonate with 2-methylbut-1-en-3-one (XCIV) to give the keto ester, XCVa, the ethylene ketal of which was converted to the sodio derivative and reacted with chlorethyl ethyl ether to give diethyl 3methyl-6-ethoxy-2,2-ethylenedioxyheptane-5,~-dicarboxylate(XCVI).
4. Serbecio ALKALOIDS
287
Hydrolysis and the elimination of ethanol gave the unsaturated keto acid, XCII, which by way of its cyanhydrin yielded a ( k )-trans-acid identical with ( f )-integerrinecic acid (see Chart 111). CHR(CO~CZHS)~ + CHz=C(CH3)COCHs XCIV
-
XCVs; R = H XCVb; R = CzHs
J
XCII f
CR(COZC~H~)~CH~CH(CH~)COCH~
CH~CII(OC~H~)C(COZC~H~)~CHZCH(CH~)C(O~C~H*)C
XCIII XCVI
c. ( k )-Dihydrosenecic acid. Kochetkov and Vasil’ev (157, 158) have reported tJlie synthesis of ( & )-dihydrosenecic acid by the Michael condensation of diethyl ethylmalonate with %methylbut- 1-en-%one (XCIV) to give the keto ester, XCVb, which by cyanhydrin formation and hydrolysis gave a 8-lactone (bp 167°-1690),reported as identical with the lactone formed from the natural acid. d. Senecic acid, all isomers. Careful experimental studies carried out by Edwards et al. (159,160)has led t o the isolation of all the isomeric forms of senecic acid. The lactone ester XCVII was treated with morpholine borane to reduce the keto group and then exposed to Adams catalyst to yield XCVIII, which mixture of stereoisomers was dehydrated t o give in small yield the cis and trans forms of the lactone ester XCIX. Separations CHaCOCHCH&(=CH2)C( C02CH3)CH3
I co
I
0 XCVII
1 CHsCH(OH)CHCH&H(CHs)C(C02CHs)CH3
I co
I
0 XCVIII
CH&H=CCH&H( CH3)C(CO&H3)CH3
I
I
co
0 XCIX
288
FRANK L. WARREN
then effectedthe isolation of ( k )-senecic acid, which was resolved by way of its cinchonidine salt to senecic acid, ( & )-integerrinecic acid, and the diastereoisomeric ( k )-integerrinecic acid, the lactone acid of which was resolved by using the brucine salt. The ( + )- and ( - )-diastereoisomeric forms of senecic dicarboxylic acid were obtained from the corresponding diastereoisomeric integerrinecic acids. The acids and their derivatives are shown on Chart I11 and do not correspond to the reported values for platynecic acid (160a) or usaramoensinecic acid (160b); accordingly, these acids must be deleted from the literature. The ( - )-senecic acid was also obtained by Mattocks and Warren (161) from the hydrolysis of isosenecionine obtained from retrosine by oxidation with sodium metaperiodate and reaction of the resulting keto compound with methylmagnesium iodide. The ( - )-senecic acid was converted t o ( - )-integerrinecic acid lactone. The oxidation of this ( - )senecic acid with lead tetraacetate gave a keto acid (2,4-DNP,mp 183", - 11.6') enantiomeric with that from ( +)-sene& acid (see Chart 111).
2. Acids from Jacobine, Jaconine, and Jacoline (105) a. Structure studies. The structures of the several alkaloids of this group have resulted from the careful experiments of Bradbury and his co-workers (162-168), and these have been interpreted by Bradbury and Masamune (169)and Geissman (170). The proposed new structures for jacobine (C) and jaconine (CIa) readily explain the conversion of jacobine to jaconine with hydrochloric acid and the reverse change with alkali (164)and the conversion of jacobine on heating with sulfuric acid t o give jacoline. The hydrolysis with alkali of either jacobine or jaconine to give jaconecic acid (CII) and isojaconecic acid (CIII) is envisaged as the opening of the epoxide ring to form a furan and pyran ring, respectively. The intermediate neutral product which is formed by the hydrolysis of both alkaloids is then considered as arising as a chloro-di-6-lactone, CIVa, from jacobine by way of jaconine, and it may be regarded as the dilactone of the acid which occurs in jaconine and could be designated "jaconinecic" acid dilactone. This reaction has been confirmed by Koretskaya et al. (171).The disparity between the observed band a t 1781 cm-1 and that normally associated with 6-lactones ( - 1745 cm-1) is attributed to the rigidity of the dilactone structure (see sceleranecic acid, Section 111,F, 6). Hydrolysis of jacoline with 6 N sulfuric acid and acetylation of the acid product gave acetyljacolinecic lactone (CV) (mp 159"-160") (163, 170). The new structure for jaconecic acid (CII)permits an explanation of its oxidation: (i) with lead tetraacetate (163,168,169)to give acetaldehyde
4. Xenecio
289
ALKALOIDS
and carbon dioxide, 8-methyllevulinic acid, C~H1003(CVI) [bp 112"113'; [.IU + 43" (water) ; p-bromophenacyl ester, mp 90"; p-phenylphenacyl ester, mp 59"; semicarbazone, mp 186"-187", [L%]D+ 62"; 2,4-dinitrophenylhydrazone,mp 152'1, and P-methyl-y-carboxy-yvalerolactone (CVII) {[a],) + 13.0" (water); p-bromophenacyl ester,
F
CHaCHX (OH)CHzCH(CH3)C(OH)CH3 I
Y
K+
Retronecine
CH3
Cia; Jaconine, X = C1 CIb; Jacoline, X = OH
H
cv
Acetyljacolinecic anhydride
0 CH&H--C-CH&H(CH3)C(OH)CH3
I
I coo
coo
I
""\
+ CH&HXCCHZCH(CH~)CCH~
co-0 I
/
LRetronecinel C Jacobine
CIVa; X=C1 CIVb; X = OH
I 0 1 I01 CH3CHC(OH)CHzCH(CHs)CCH:, I I I I
CHsCH(OH)CCHzCH(CH3)CCHa COzH
CII Jaconecic acid
COzH
CO2H
COzH
CIII Isojaconecic acid
mp 83"-84" and lOS"}; (ii) with nitric acid to give dimethylmalic acid (CVIII) (165, 169); and (iii) by vigorous acetylation (168) to yield an acetate of an anhydride, CIX, which gave on mild hydrolysis the acetate of jaconecic acid. Dimethyl jaconecate (CXa), with lithium aluminum hydride gave an oil, CXb, which formed a bis (p-toluenesulfonate) and a triacetate (169)and which did not react with periodic acid. Isojaconecic acid (CIII) [mp 119°-120"; ["ID + 116.5" (water)], was shown (169)to be an a-hydroxy acid which gave monoacetylisojaconecic
290
FEANK L. WARREN
acid (mp 195'). Dimethyl isojaconecate (CXIa)was reduced with lithium aluminum hydride to give an oil, CXIb { [ c L ] ~+58.6'; bis(p-toluenesulfonate), C24H320852, mp 116'-117' ; triacetate, C16H2607, bp 148'/ 0.6 mm, [.ID + 47.8'). Oxidation of the oil with periodic acid gave an oil, CH&H(CH3)C(C02H)CHa+ C 0 2
HO&CH&H(CH3)COCH3
I co-
CVI
CH3CHO +
I
0
CH(CHs)C(OH)CH3 !i.-2CH(CH3)C(OHFH3 COzH CO2H I
COzH
I
COzH CVIII
- 0 1 T O 1 CH&H(OH)CRCH2CH(CH3)CRCH3 + CHaCH(O&H8)CCH&H(CH3)CCHs I I co-oCO CXa; R = C02CH3 CXb; R = CHzOH CIX
CXIIb ([a]D + 8.0'), which gave a bis (2,4-dinitrophenylhydrazone), C21H24N8010 (CXIIIb) (mp 192'-193'). Oxidation (169) of isojaconecic acid itself gave carbon dioxide, acetaldehyde, and. an oil + 48.2'; p-bromophenacyl ester, C17H1905Br, mp 107°-1080; (['z]D 2,4-dinitrophenylhydrazone,C21H22N8011, mp 240'; semicarbazone, The dinitrophenylhydrazone is envisaged CloH17N304, mp 165'-166'). by Geissman as an osazone, CXIIIa.
1 ° 1
~HSCHC(OH)RCH~CH(CH~)CRCH~ CXIa; R = COzCHs CXIb; R = CHzOH
1 ° 1
CH&HCOCHZCH(CH~)CICH~ CXIIa; R = CO2H CXIIb; R = CHzOH
CH~C(=NNHA~)C(=NNHA~)CHZCH(CH~)C( OH)RCH3 CXIII a, R = COzH (2x111 b ; R=CHzOH
4. Senecio
291
ALKALOIDS
cxv
CXIV
b. Absolute configuration in jacobine. The absolute configuration of the necic acid in jacobine (C) was determined by Masamune (172) in an elegant series of reactions which established the geometry of 2-methylbutan-3-01-1,3-dicarboxylic acid lactone (CVII). The methyl ester of ( - )-/3-methyllevulinic acid, CXIV, under conditions of the BaeyerVilliger reaction gave ( - )-3-hydroxybutyric acid hydrazide (mp 127”, HOOCCHzCH(CH3)COCH3 CVI CH3 H COOH CHz-
CH3
\c,/
I
I
co
0 CXVI
CH3 H
CH3 P O O H
\&
\ . CHzC‘ I
+ (C,H~)ZC=CH-CH(CH~)C(OH) (CH3)COOH
I 0
co
CXVIII
CXVII
HOzC-CH(CH3)C(OH) (CH3)COOH CXIX
/
CHzOH
,
‘CHzOII
cxx
CXXI
t 4
CHzOH
CHzOH
CXXIII
CHzOH CHzOH CXXII
292
FRANK L. WARREN
[&ID -25.1"), of known configuration (CXV)which establishes the configuration a t C-3 of jacobine (C). The absolute configuration at C-2 of C was elucidated by identifying (CVII)with one of the two the ( + )-/3-methyl-y-carboxy-y-valerolactone possible forms (threo or erythro). The cyanhydrin of ( & )-B-methyllevulinic acid (CXVI)gave on hydrolysis two lactones : ( f )-lactone A, CXVI (mp 151'-152"; p-bromophenacyl ester, mp 86"-88") and lactone B, CXVII (mp 65"-67" ; p-bromophenacyl ester, mp 105"-106"). Lactone B
CXXIV a; R CXXIVb; R
= CH3, = CH3,
R' = COCOCBHS R'= H
was resolved by way of its cinchonidine salt (mp 201") (169),to give the ( + )-acidUI.[( + 14.5";~-bromophenacyl ester, mp 105"-106")and hence identified with the oxidation product CVII. The ( f )-lactone B, CVII, treated with phenylmagnesium bromide and dilute acid, gave the compound CXVIII which on ozonolysis gave a,/zI-dimethylmalic acid (CXIX)which was reduced to the 2,3-dimethylbutan-l,2,4-triol (CXX) [bis(p-nitrobenzoate), mp 156"-157"]. This triol must have the structure assigned since it was different from the triol CXXI [bis(p-nitrobenzoate), mp 162"-163.5'1 synthesized from dimethylmaleic anhydride by way of its glycol CXXII and the epoxide CXXIII.Accordingly the configuration of two methyl groups must be cis in the lactone CXVII. Since acetyljaconecic anhydride was readily formed the two carboxyl groups must be cis in CXXIV.
-
H
H3C/
I c j )c-
,XOOR
0'
H3C
H3C\
=
XOOR
C,'
I
cxxv
R-R
HO-'?
H3C\,,*H CH2-
OH
Retronecine
?dH3 dOzH
'C02H
bH3 CXXVI
CXXVII
4 . Senecio ALKALOIDS
293
The phenyl glyoxalate ester (CXXIVa), of dimethyl jaconecate (CXXIVb) ([a],, + 28.5'), gave ( + )-atrolactic acid ([a],, + 4.31'), and hence the configuration a t C-6. This establishes the stereochemistry of the necic acid in jacobine, CXXV, jaconecic acid, CXXVI, and isojaconecic acid, CXXVII, based on inversion on cleavage of the epoxide ring on hydrolysis. c . Senecic and epoxyjaconecic acid structures. Structural interrelation of senecic and epoxyjaconecic acid was demonstrated by Koretskaya, Danilova, and Utkin (173) by the treatment of otosenine (CXXVIII), with hydrobromic acid to give a monobromide (mp 116°-116.50, [all) - 30'), which was epimeric with a similar substance from senecic acid lactone (mp 113'-113.5', [a],, - 56.2'). Both bromides on reduction gave the dilactone, C10H14O4 (mp 50.5"-51.0", [.IU - 53.7"), which gave the acid CXXIX (mp 139"-139.5', [.ID 9.6').
'
CH3CH-
0 I 'C(CO2R)CH2CH(CH,)C(OH) (C0zR)CHs CXXVIII R-R = Otonecine
Br
I
CH&HC(OH)(CO&)---
_ _ f
Dilectone
\ CH&H=
FcoCH~CH(CHS)C(COZH)CH~ I 0
__f
CH,CHC(OH)(COO-)---
I
Br
XCIII CH&H&(OH) (COzH)CHzCH(CH3)C( OH) (C02H)CHs
/
CXXIX
3. Hygrophyllinecic Acid Hygrophyllinecic acid was obtained by Schlosser and Warren (33)by the acid hydrolysis of hygrophylline as its monolactone, C1oH1405 (mp 180'-181'; [a],) - 187.9'; A,,, 220, 64830) which on distillation gave a dilactone, C10H1204 (mp 103"-105"; [aID - 97.6'). The NMR spectrum of the dilactone [ d . O (doublet), 8.5 (singlet), and 7 . 7 (doublet)] can be accommodated in the groups /
CHaCH,
/
CH3C-
\
and
CH&H=
294
FRANK L. WARREN
respectively. The NMR spectrum is further indicative of CH3CH=C
/ \
(73.3, single proton showing 1: 3 : 3 : 1 splitting), and suggests
I
-C-CH(
O-)CH(CHa)-
I (75.05,doublet with each peak showing fine splitting, and 77.2-7.8 complex splitting). Ozonization of the monolactone gave acetaldehyde and carbon dioxide, which could arise from the system CH&H=C(COzH)-, while lithium aluminum hydride reduction of the alkaloid and peroxide oxidation of the neutral fraction gave formaldehyde and hence the glycol grouping \
-C(OH)CHzOH /
from an cc-hydroxyacid. These several groupings could be accommodated in the general structure of the necic acids (174)as CXXX for the monolactone. The hydrogenolysis of the monolactone with Adams catalyst activated with perchloric acid gave dihydrosenecic acid, identified as its CH&H=C(COOH)CHCH( CHs)C(OH)CHa
I -co cxxx
J?
I
CH3
-0 CXXXI
monolactone (mp 122"-124O). This reduction was interpreted as placing the reducible hydroxyl groups in an allylic position and confirmed the structure for the monolactone. Since the absolute structure of senecic acid is known (see Chart 111) the absolute structure of hygrophyllinecic acid dilactone can be represented as CXXXI, i.e., 2L,3R,4R-2,4dihydroxy-3-methylhept-trans-5-ene-2,5-dicarboxylic acid dilactone. It is not possible to make a model of the dilactone if the 4-hydroxyl group has the opposite configuration, and the trans geometry is assigned on the basis that the absorption peak a t 220 mp has €4800 (174).
4. Senecio
295
ALKALOIDS
4. Seneciphyllic and Isoseneciphyllic Acid (89-92), and “Spartiodinecic ” and Riddellic Acid (92-94) Masamune (175) has drawn attention to the incompatibility of the previously proposed structure for isoseneciphyllic acid with the reported A,,,, 2 14 mp ( € 8130) and has advanced structures for isoseneciphyllic acid (CXXXIIa), and seneciphyllic acid (CXXXIIb). The oxidation of seneciphyllic acid with permanganatelperiodate gave formaldehyde, and the reduction of the dimethyl ester with lithium aluminum hydride yielded a trihydroxy derivative, which with periodic acid yielded formaldehyde. The NMR spectrum of the methyl ester gave confirmation of one hydroxyl group (123 cps, singlet) ; ethylidene (15.4 cps, quadruplet, CH3CH= and 177.5 cps, doublet, CH&H=); and methyl groups (193 cps, singlet). Masamune suggested that the structures of riddellic (CXXXIIc) and spartiodinecic acid should be similarly revised to CXXXIId. 6
5
4
2
3
1
CH~CH=C(CO~IE)CHZC(=CHZ)C( OH)(C02H)CH2X CXXXII a ; Isoseneciphyllic acid CXXXII b ; Seneciphyllic acid CXXXII c ; Riddellic aoid CXXXII d ; “Spartiodinecic ” acid
X =H X=H X=OH X =H
trans 2R cis 2R
-
-
trans 25
The total synthesis of the seneciphyllic acids has been effected by Edwards et al. (176). The cyanhydrin of 3-methylbut-3-en-2-one (CXXXIII) was converted by way of the orthomethyl ester to methyl CH&(=CH2)COCH3 CXXXIII
+ XCH&(=CHz)C(OH) (COzCH3)CHs CXXXIVe; X = H CXXXIVb; X = Br
CXXXVI
296
FRANK L. WARltEN
2-hydroxy-2,3-dimethylbut-3-enoate (CXXXIVa). This ester with N-bromosuccinimide gave the ally1 bromide (CXXXIVb), which was condensed with methyl acetoacetate to yield the 8-lactone) CXXXV. Reduction, dehydration, and hydrolysis gave cis-( & )- and trans( f )seneciphyllic acid (CXXXVI) (mi) !17"-!)8" and 161 "-1 ( i d o , respectively). Resolution using the cinchonidine salt gave cis-(+ )- and cis-( - )-seneciphyllic acid (mp 114"-1 l A o and I l B " - l 14') and trans-( + ) - and trans(-)-seneciphyllic acid (mp 144"-14(j0 and 144"-145").
5 . Clivonecic Acid Clivonecicacid, C10H12O4 [mp 149"-144"; [a],, - 2,08"(cthanol), - ! ) I " (water)], obtained by Klasek (10)from clivorine by alkaline hydrolysis has been assigned the absolute structure by cervinka (141) with an Sconfiguration a t C-2 and hence may be regarded as dehydrohygrophyllinecic acid.
6. Sceleranecic Acid ( 8 7 ) This acid has been degraded by a new route by de Waal, Wiechers, and Warren (177).Lithium aluminum hydride reduction of sceleranecic acid gave a glycol, which with periodic acid yielded formaldehyde and 2,3dimethyllevulinic acid (CXXXVII), which with sodium hypobromite gave butarie-d,:l-diaarboxylic acid (CXXXVIII) [bis(p-bromophenacyl) ester, mi) I 8 S 0 ] . Oxidation of disodiurn sceleranecate with lead tetraacid lactone (CXXXIX) acetate gave %hydroxy-d,:%,4-triinethylglutaric and CXXXVII. The formation of the glycol and CXXXIX invalidates the previous structures proposed by several authors (154a, 178-180) and permits the reformulation of sceleranecic acid as CXLa and its reduction product as CXLI. The structure CXL leads directly to a reinterpretation of previously reported reactions : Dipotassium sceleranecate with thionyl chloride yielded sceleratinic acid (CXLb),C10H13C104 (mp 208"), which with alkali yielded a hydroxydicarboxylic acid CXLIIa, c8H&(oH)(C02H)z (mp 1!)2"), which in turn yielded the chloro acid CXLIIb, C8€€13ClO(C02H)z (mp 131"),and the nitric acid oxidation product CXLc, C S H ~ I O ~ C Owhich ~ H , gave with chromic acid the monolactone monocarboxylic acid CXXXIX, CsH 11(-COz-)C02H (mp 1 O O O ) . The increased carbonyl frequency gives support for the new formula CXLa (see Section 111, F, 2 ) , and the different rates of opening of the two lactone rings are attributed to the monolactone having the more stable chain conformation.
4. Senecio ALKALOIDS
297
HOZCCH(CH~)CH(CH~)COZH CXXXVIII
CHaCOCH(CH3)CH(CH3)COzH CXXXVII
COzH I CH3hCH(CHs)CH(CH3)
I
-0
I co
CHzOH
I
CHSC(OH)CH(CH~)CH(CH~) CXLI
COzH
CO2H
I CH&CH(CH3)CH(CHs)
I
0
i,, Y
CXLIIa; Y = OH CXLIIb; Y = C1
CXLa; Sceleranecic acid, R = CHzOH CXLb; Sceleratinic acid, R = CHzCl CXLc; R=COzH
295
FUANK L. WARREN
7. General Structure The general structure CXLIII of the C ~ necic O acids envisaged as two units advanced originally by Kropman and Warren (174) has been found in 12 acids shown in Chart IV. The structures of sceleranecic acid (CXLa) CHsCH=C( COzH)CHX---CH(CH3)C( OH)(COzH)CHzY Acid
X
Y
H H H H OH
H H OH OH H
___.
Senecic Integerrinecic Isatinecic Retronecic Hygrophyllinecic
CiS
trans CiS
trans cis
CH3CH=C(COzH)CI ---C(=CHZ)C(OH)(COZH)CH: Y
Acid
H H H OH
Isoseneciphyllic Seneciphyllic Spartionecic Riddellic
CiS
trans CiS -
CH~CH=C(COZH)CH==C(CH~)C(OH)(C02H)CHs Clivonecic acid I
0
\
CH~CH-C(COZH)CHZ--CH(CH~)C(OH)(COzH)CH3 Acid in jacobine
CH&H(OH)C(OH)(COZH)-CH(CH~)C(OH)(COZH)CH~ Acid in jacoline
CH3CHC(OH)(COzH)
-1
CH(CH3)C(OH)(COzH)CHzX
I Sceleranecic acid, X =OH Sceleratinic acid, X=CI
CH~CH~C(CO~H)Z---CH(CH~)C(OH)(C~ZH)CH~ Retusanecic acid CHARTIV. The necic acids having the structure of Clo adipic acids.
4. Berrwio
299
ALKALOIDS
and sceleratinic acid (CXLb)are shown as these two same units differently joined, while two similar units are found separated as angelic and sarracinic acid in the alkaloid sarracine. C-C-C(
COzH)--C-C(C)--C(COzH)-C CXLIII General structure
CH3CH=C(COzH)CH3 Angelic acid
CH(CHs)=C(COzH)CH20H Sarracinic acid
G. SUMMARY OF THE STRUCTURES OF THE ACIDS The several structures which show repeating carbon units and different positions of hydroxylation are summarized in Chart V. Adipic acids
Tc-c-c-c-c-c * * * CI
FF**
* * I
I
CO2H
c-9-c-c-c-c
I COzH
COzH
CO2H
Glutaric acids C
I * * * c-c-c-c-c-c
I
I
C C-C
bOzH COzH
b0zH COzH
I c-c-c--c-c * * * '-1
I
CO2H CO2H
Succinic acids
* * I
c-c-c-c-c I
CO2H CO2H
Monocarboxylic acids
c-c
*
c-c-
CO2H I
-c 102H
CHARTV. The carbon skeletons of the acids in the pyrrolizitlirie alkaloids showing repeating units aid position of hydroxylatiori (*).
IV. Structure of the Alkaloids (109-1 16) A. GENERAL The Senecio alkaloids fall naturally into two classes, the noncyclic mono- and diesters and the cyclic diegters. Carbonyl stretching frequencies studied by Culvenor and Dal Bon (181)permit some indication
300
FRANK L. WARREN
of two carbonyl groups from integrated intensities and molecular extinction coefficients. The structures of the many alkaloids follow from those of the bases and acids. The orientation of the acid moiety has been elucidated by the rate of hydrolysis, as in CXLIV in which the acid RCOzH is more readily hydrolyzed, or by hydrogenolysis when CXLV gives CXLVI. Where the acid can exist in isomeric forms the study of the reactions and spectra of the alkaloid itself has been informative. The few conversions of one alkaloid to another, the isomerizations, and syntheses have given confirmation to the assigned structures. R'C02 bv5202CR
R ' C M z O Z C R -
R
'
C
M
s
+ RCOzH CXLIV
CXLV
CXLVI
The alkaloids have been assembled in a series of general formulas based on the type of acid present and show an interesting structural correlation.
B. MONOESTERS 1. Esters of Angelic, Tiglic, and Acrylic Acids There are three esters of angelic acid, namely, 7-angelylheliotridine (9), 7-angelylretronecine (ll),and macrophylline. a. Macrophylline ( 1 16). This alkaloid, C13H21N03, which hydrolyzed to macronecine and angelic acid (182, 183), has been studied further by Danilova and Utkin (182).Reduction of macrophylline (CXLVII) and treatment with thionyl chloride and sodium hydroxide gave deoxychlorohydromacrophylline (CXLVIII), C13H~&lN02 ([.In - 2.9"; picrate, mp 155"-156"). Reduction yielded laburnine ([.II, 19.8") and hence the structure of macrophylline is CXLVII. H?
-
~HZOCOC(CH~)=CHCH~
CXLVII
G 2 0 C 0 C 4 H 9
CXLVIII
b. Tiglic acid. Tiglic acid has been found in two alkaloids : as the ester of laburnine from Planchonella spp. (as),and as the ester of either laburnine or isoretronecanol in Mimusops elengi (71).
4. Senecio
30 1
ALKALOIDS
c. trans-3-Methylthioacrylic acid. Methylthioacrylic acid (mp 137"131)') has been found by Hart et al. ( 4 9 , 7 l )esterified with laburnine in the alkaloid planchonelline, ClzH19NOzS ( [ a J , , !jO;picrate, m p 127°-1280)
+
from Planchonella anteridifera and P. thyrsoidea, and from Mimusops d e n g i in an alkaloid (mp 1 1 1"-113"; [ a ] , )- 57.2") containing either laburnine or isoretronecanol.
2. Esters of 2-isopropylbutanoic Acids The structures of the 12 alkaloids are summarized in Table VI. Only TABLE VI
ALKALOIDSW H I C H ARE ~ ~ O N O E S T E ROSF H Y D R O X Y L A T E D 2-ISOPRoPYLI3UTANOlC ACIDS (CH3)zCXC(OH)(COOB)CHYCHs
(
Base Ba
Acid
X
Y
+ )-Trachelanthic
H H H H
OH OH 0-Angelyl OH OH
T L L S Hel-Ethi-salt
OH OAc OH OH OH OH
R
H ( - )-Trachelanthic
H Monoacetyl-(- )-trarhelanthic H H Trarhelanthir ( ? ) H Viridifloric
Heliotrinic Lasiocarp ic Macrotomic
H H H H H OH OH
OH OCH3 OCH3 OCH3 OH
R
R S iR T Hel He1
s He1
T
Alkaloid Trachelanthamine Lindelofine Lindelofainine Supinine Alkaloid ex L . m acrostyla Indicine Acetylindicine Indicine Cynaust ine Cynaustraline Viridiflorine Echinatine Heliotrine Heleurine Europine Macrotomine
0 (Hel= Heliot,ridine, L =lindelofidine, R=retroiiecine, S =supinidine, T = trwvhelanthamidine), iR = ( + )-isoretroneoanol.
two new alkaloids have been found in this group: Indicine is of interest in containing ( - )-trachelanthic acid, and the alkaloid from L. rnacrostyla has hastanecine as its quaternary etho salt. The syntheses have been reported for supinine, heliotrine, and trachelanthamine. a. Indicine, acetylindicine, and indicinine. These alkaloids were isolated by !Mattocks (37)in the ratio 81 : 12 : 7 from Heliotropiurn indicurn.
302
FRANK L. WARREN
Indicine, C15H25N05 [mp 97"-98"; [aID + 22.3" (ethanol); HCl salt, nip 131'-132', [a]= + 11.5' (ethanol); reineckate, mp 141"-142"; picrate.CGH6, mp 88'-90'; picrate-HzO, mp 66"-68"; CH31, mp 159"-l6Oo, [ a ] ] , + 12.5" (ethanol); N-oxide, C15H25NOtj*CH30H,mp 130"-131°, [a],, + 34.0'1 was isolated and the structure determined by Mattocks et al. (36).On hydrolysis it gave retronecine and ( - )-trachelanthic acid while hydrogenolysis yielded retronecanol. Acetylindicine ([all) - 14.8") was not obtained crystalline. Mild hydrolysis gave indicine, and gentle acetylation yielded diacetylindicine which on hydrogenolysis gave acetylretronecanol and monoacetyltxachelanthic acid, which in turn was shown to be an a-hydroxy acid. S
z
C
l
N
CXLIXa; X = H CXLIXb; X = O H
s z O z C C ( O H CH(CH3)z )I C H ( O R ) C H 3
N
CLe; X = H , R = H CLb; X = OH, R = CH3
Indicinine ([aID + 9.4") was a gum and failed to give crystalline derivatives. It gave on hydrolysis retronecine and a noncrystalline acid giving a crystalline brucine salt, while hydrogenolysis gave retronecanol. 6 . Supinine and heliotrine. The synthesis of these two alkaloids has been effected by Culvenor, Dann, and Smith (184).Chlorodesoxy supinidine (CXLIXa) and monochlorodesoxy heliotridine (CXLIXb) with the sodium trachelanthate and heliotrinate gave, respectively, supinine (CLa) and heliotrine (CLb). c. Trachelanthamine and Viridi$orine. Trachelanthamine has been synthesized by Kulakov et al. (144) by reacting methyl 2,3-0-dibenzyl( + )-trachelanthate with ( - )-trachelanthamidine in the presence of sodium methoxide to give the trans esterification product which was directly hydrogenated to trachelanthamine (mp 91"-92'; [.In - 17.2"). A similar synthesis has also been devised for viridiflorine (145). (1. Cynaustine, cynaustraline, and ambaline. These alkaloids were isolated by Culvenor and Smith ( 5 ) . Cynaustine, C15H27N04, a pale yellow gum ([c(]D + 13.2'; picrate, m p 135'-136'), hydrolyzed to ( - )-viridifloric acid and ( + )-supinidine. This is the first isolation of an ester of a (+)-enantiomer of an allylic *.necine * ' base. Cynaustraline, C15H27N04, a colorless gum ([x]D + 48.0" ; picrolonate, nip 11!1"-150') gave on hydrolysis ( + )-retronecanol (lindelofidine) and ( - )-viridifloric acid. Ambaline, C15H25N04, reported by Culvenor and Smith ( 5 ) ,was not obtained crystalline. Its structure was deduced from its alkaline hydroly-
4. Senecio
303
ALKALOIDS
sis products, ( - )-supinidineandviridifloric acid, while its NMR spectrum was virtually identical with that of cynaustine.
3. Ester of 2,3-Dihydroxy-3-methylpentanoic acid Extraction of H . strigosum gave strigosine (95) as a gum (["ID - 19.3"; picrate, mp 141"; HCl, mp 137.5"; CH31, mp 135"-136", ["ID - 15.5"). Hydrolysis with alkali gave trachelanthamidine ([.ID - 12.0°), and the oily acid, C~H1204,so the alkaloid is CLI.
a' $!H20COCH( O H )
I
C(OH)CH3 CHzCH3
CLI
C. NONCYCLIC DIESTERS 1. Esters of Angelic and 8-isopropylbutanoic Acids Three new alkaloids have been reported in this group. a. Cynoglossophine. The alkaloid C~oH35N08([.In 0"; picrate, mp 105"; picrolonate, mp 102"-104"), obtained from Cynoglossurn ojicinale TABLE VII ALKALOIDS CONTAINING ANGELIC ACIDAND 8-ISOPROPYLBUTYRIC ACIDSAND LATIFOLINE
/CH3
(CH3)2CXC(OH)CHYCH3
I
H>c=c CH3 'CO
Acid Trachelanthic Trachelanthic Viridifloric Echimidinic Isoechimidinic Lasiocarpic Acetic "Cynoglossophinic"
a
X
Y
H H H OH OH OH OH
OH OH OH OH OH OC& OH
H = Heliotridine, 7 u ;R = retronecine, 7p.
Basea
Alkaloid Echiumine Alkaloid Alkaloid Echimidine Heliosupine Lasiocarpine Brachyglottine Cynoglossophine
304
FRANK L. WARREN
(20),was hydrolyzed in alkali to acetone, angelic acid, and an amino acid cynoglossophidine (picrate, mp 99"-99.5') so that the alkaloid probably contained the acid (CH&C(OH)C(oH)(COzH)CH(OH)CH3. b. Echimidine (111).This alkaloid, C20H31N07 (picrate, mp 132"-133" N-oxide, mp 165') isolated by Culvenor (185)from Echium plantagineum gave on hydrolysis angelic acid and retronecine together with acetone. Hydrogenolysis yielded 7-(2'-methylbutyryl)retronecanol and echimidinic acid. c. Echiumine (112). CzoHslNOs [mp 99"-100'; [alU + 14.4' (ethanol); picrate, mp 131"-132'] isolated by Culvenor from Echium plantagineum (185)gave on hydrolysis retronecine, angelic acid, and trachelanthic acid. Hydrogenolysis gave trachelanthic acid and 7-(2'-methylbutyryl)retronecanol. 2. Other Diesters Containing Angelic Acid
+
a. Brachyglottine. The alkaloid C15H23N05 [mp 98"-99"; [a]= 88" (ethanol); A,, 218 mp, €12,150; HC1 salt, mp 146'1 isolated by White (15,186)contained an hydroxyl group and gave on hydrolysis angelic and acetic acids. The necine base (HCl salt, mp 200") was not identical with rosmarinecine and the alkaloid may be represented as CLII. /CH3
"c=c-c00 HsC
~ c H 2 0 A c OH )
CLII
b. Latifoline. The alkaloid CzoH27N07 [mp 102"-103"; [aID + 57" (ethanol)]was isolated by Crowley and Culvenor (11).Alkaline hydrolysis only permitted the identification of retronecine and angelic acid, while catalytic hydrogenation gave latifolic acid, C7H1005, and retronecanyl 2-methylbutyrate, so that latifoline is CLIII, and may be included in this group as it contains one methyl group replaced by a carboxyl group (see also Section 111, E, 3, grantianine).
CLIII
4. Senecio ALKALOIDS
305
c . Sarracine (112). This alkaloid, C18H27N05 (57, 187) (mp 51"-52"; [a],, - 129"; picrate, mp 141'; bitartrate, mp 182'-183", [aID -71" in
water) and sarracine N-oxide hydrate, C18H27NO6.HzO (mp 125"-126"; -94"; picrate, mp 108"; chloraurate, mp 153'-155"), have been shown to have structure CLIV. The sarracinic acid esterifies the primary H\
/CHI
CH3
'coo
,c=c
HOCH2\ CH20-CO'
c=c ,H
'CH3
I B I
CLIV
hydroxyl of platynecine since it is hydrolyzed preferentially (57).The possibility of sarracinic acid having the alternative tautomeric formula in the alkaloid CLIV is dismissed on the basis of NMR spectra and the geometrical configurations are assigned on chemical shift of r-values. Sarracine and sarracine N-oxide on catalytic hydrogenation gave tetrahydrosarracine, C18H31N05 (picrate, mp 70"-71" ; N-oxide picrate, mp 127")which on hydrolysisgave angelic acid and 2-methylbutyric acid.
D. CYCLICDIESTERSOF
THE
GLUTARIC ACIDS
Seven new alkaloids related t o monocrotaline and one having a structure resembling trichodesmine have been isolated. These alkaloids now constitute an interesting group which may be conveniently divided into three according to the carbon skeleton of the acid moiety, namely, the alkaloids which are esters of 2,3,4-trimethylglutaric acid, 2,3-dimethyl4-isopropylglutaric, and 2-ethyl-4-isopropyl glutaric acids (see Table VIII) ; and the other alkaloids : monocrotaline (CLV), grantianine (CLVI),and retusamine (CLX),which are esters of differently substituted glutaric acids.
co-0
CHzC(0H)(CH3)CHt
I
C 0 2 -R-OzC
I
I
1
CHzCH HC(CHI)C(OH)(CH3)
CLV
9C02-R-02CI CLVI
1. Esters of 2,3,4-Trimethylglutaric Acids
a. Fulvine. Fulvine (CLVIIa) C ~ ~ H Z [mp ~ N 212"-213"; O ~ [aID - 50.8" (CHC13);picrate, dec 250" ;HCl salt, mp 285'; N-oxide, C16HzsNO6 H20,
306
FRANK L. WARREN
mp 198'; picrate, mp 185'1 was isolated by Schoental (26)from C .fulva Roxb., and by Culvenor and Smith (16)from C. crispata. Hydrolysis gave fulvinic acid and retronecine. Hydrogenolysis over platinum oxide gave an amino acid, CLVIII, C16H25N05 (mp 227'), and then CLIX C16H27N05 (HC1salt, mp 178"-179"). TABLE V I I I ALKALOIDS CONTAINING 2,3,4-TRIMETHYLGLUTARICACIDSAND 2,3-DIMETHYL-4-ISOPROPYLGLUTARICACIDS X-CHCY
I
(CHs)CZ(CHa)
CO2-B-02C
x
Acid
Y
Fulvinic Crispatic Monocrotalic Acetylmonocrotalic or-"Retusanecic"
CH3 CH3 CH3 CH3 CH3
OH OH OH OAc
Trichodesmic Incanic Incanic Junceic Grantianic
(CH3)zCH (CH3)zCH (CH3)2CH (CH3)2CH HOzCCH(CH3)
OH H
(1
I
Z
H H OH OH OH
H
H OH OH OH OH
H OH OH
Basea B R R
R R Has R R 0 R
R
Alkaloid Fulvine Crispatine Monocrotaline (114) Spectabiline Retusine Trichodesmine ( 116) Incanine Crosemperine Junceine Grantianine
R = Retronecine, Has= hastanecine, 0 = otonecine.
R\ ,/R' CH(CHs)-C-CH(CHs)
I co
\O
&
I co I
CHzO
CeHi3COzH
I
C
O
H
N
N
CLVIIa; R = OH, R' = CH3 CLVIIb; R = CH3, R' = H
CLVIII
CsHi3C02H 3
I c o y 5 3 ?r'
CLIX
b. Crispatine. Crispatine, C16H23N05 (CLVIIb) (mp 137"-138'; [aID was obtained (16) together with fulvine from C . crispata, and gave on hydrolsyis crispatic acid and retronecine. c. Spectabiline. The alkaloid C18H25N07 [mp 185"-186'; [aID + 143' (ethanol)],obtained by Culvenor and Smith (94),gave on hydrogenation
+ 40.7')
4. Senecio
ALKALOIDS
307
over Raney nickel acetylmonocrotalic acid and was synthesized from monocrotaline with ketene. The acetyl group is placed on the /?-hydroxyl group since hydrogenolysis to the amino acid and gentle hydrolysis gave acetyl monocrotalic acid. d . Retusine. The alkaloid, C16H25N05 (mp 174"-175'; ["Iu + 16")) isolated by Culvenor and Smith (77) from C. retusa, gave on alkaline hydrolysis the two epimeric dihydroanhydromonocrotalic acids (188)and on acid hydrolysis only the a-form.
2. Esters of 2,3-Dimethyl-4-isopropylglutaric acid a. Incanine and crosemperine. Incanine, C18HzgN05 [mp 96"-97'; picrate, mp 246";HBr, mp 206"-208") [a],, - 65.4"(water) ;HI, mp 206"207", ["I1) - 58.4' (water);CH31, mp 227"-228"; N-oxide, mp 168"-169" ( 3 4 ) ;HN03, mp 182"; HCl, mp 199"; chloroplatinate, mp 154' (154)] gave on alkaline hydrolysis retronecine and incanic and isoincanic acids. Hydrogenation gave a product (mp 156') which with sulfuric acid gave retronecanol and incanic acid. Acetylation of incanine gave a crude acetyl derivative which catalytically reduced t o hydroacetoincanine, CzoH33NO6 (mp 194"). The structure (Table VIII) shows the relation to monocrotaline, trichodesmine, and junceine (153).the arrangement of the ester groups being assigned to correspond t o the orientation of the acid moiety of retrorsine (189). Crosemperine, C19H31N06 [mp 117°-1180; [all) 45" (CHC13)) 2.2" (EtOH); HC1, mp 180"; MeI, mp 208"-209"; reineckate, mp 151"-152"], was isolated by Atal et al. ( 1 7 ) . The structure as the cyclic ester of incanic acid with otonecine was established by NMR spectra, mass spectrometry, and hydrolysis to incanic acid and hydrogenolysis t o dihydrodeoxyotonecine. b. Trichodesmine (116).The suggestion that the two tertiary hydroxyl groups are cis (erythro) in monocrotaline and trans in trichodesmine was based on the difference in their rates of oxidation and on formation under similar conditions of a cyclic sulfite hydrochloride from monocrotaline, and an acid sulfite ester hydrochloride, C ~ ~ H Z ~ .HCl N O (mp ~ S 172"))from trichodesmine. Leonard (1)suggested that the rate difference could result from a more hindered cis-glycol in trichodesmine and draws attention to the striking similarity of the I R spectra suggestive of a similar relative configuration. Support for this concept comes from the ready conversion (154,190) of the trichodesmine acid sulfite (mp 170"; [.Iu 11.8") t o a cyclic sulfite, C18H25N07S (mp 151"-152"), which on hydrogenation gave trichodesmine and trichodesmic acid, arfd from the synthesis of trichodesmic acid.
308
FRANK L. WARREN
3. Ester of 2-Ethyl-4-isopropylglutaric acid Axillarin, C18H27N07 (mp 205" dec; [a]= +65.l; HC1, mp 228"; picrate, 214"-216" dec) was isolated and its structure established by Crout (14)from NMR spectra and mass spectra. It is of interest in that it (CHB)ZCHCHCH(OH)
I
C02-R-02
contains a new and fifth type of C ~acid O esterified with retronecine. Crout extrapolates from his elegant biosynthetic studies (191)to suggest that it is derived in vivo from valine and isoleucine.
4. Esters of 4-Methylhexun-5-ol-3,3,5-tricarboxylic Acid
Retusarnine, ClgHz~N07(mp 174.5"; [a]D + 13O), isolated by Culvenor and Smith (77),was shown by Wunderlich (64)from X-ray diffraction of a single crystal of its a-bromo-(+ )-camphor-trans-r-sulfonate monohydrate to have structure CLX. The free base, however, is best
CO-R-CO
I
kHs CLX
CHs CLXI
CO-R-CO2H I
drHs CLXII
represented as a trans annular formulation CLXI of Leonard and his collaborators (192,193).Catalytic reduction took up two molecules of hydrogen to yield a saltlike tetrahydro derivative CLXII which on hydrolysis gave the same acid as that obtained by direct hydrolysis of the unreduced alkaloid. Accordingly the four hydrogens had been taken up in the basic moiety to give the ester of 8-hydroxy-N-methylretronecanol (CLXII). The necine base could not be isolated, but its identity with otonecine was established by Culvenor et al. (76)since hydrogenolysis of retusamine gave ( - )-dihydrodeoxyotonecine.
4. Senecio
E. CYCLICESTERS OF
309
ALKALOIDS
THE
Clo ADIPICACIDS
1. AbsoluteStructure of Jacobine, Jaconine,Jacoline, ( 116) andsenecionine (115)
The X-ray analysis of the bromohydrin of jacobine, Cl8Hz6BrNO6 * CZHSOH, made by Fridrichsons et al. (104) has revealed the atomic CH3 OH
T
:
X-C-F-CH2-y-C
A mho H
QH3 O H
:
\
: H
I ,CO
CH3
CLXIIIa; X = Br CLXIIIb; X = C1 CLXIIIC; X = O H
distribution which is given as the absolute orientation in CLXIIIa, in confirmation of the findings of Masamune (172)(see Section 111,F, 2). This gives jaconine (CLXIIIb)and jacoline (CLXIIIc)while the structure of senecionine follows from the demonstration of Koretskaya et al. (173) that senecic acid had the same asymmetric centers as the acid in jacobine. This has received confirmation by Culvenor (194), who has converted jacobine to senecionine by treatment with potassium selenocyanide.
2. New and Modijied Structures
+
a. Anacrotine. The alkaloid ClsHz5NO6 (mp 191"-192"; [aID 30"), isolated by Atal et al. (6) and Mattocks (7), was hydrolyzed to senecic acid and crotanecine. The structure was determined from the NMR spectrum (see Table IX). b. Madurensine. The base C18H25N06 (mp 175"-176") (6) gave on hydrolysis integerrinecic acid and crotanecine, and the structure (Table IX) was confirmed from its NMR spectrum. c. Anguhrine. The alkaloid C ~ ~ H Z ~ [mp N 200"-201"; O~ [aID - 98.0" (ethanol)],obtained by Porter and Geissman (13)from S. anguhtus, was hydrolyzed to give rosmarinecine and a mixture of senecic acid and seneciphyllic acid; and it would seem to be the seneciphyllic ester of rosmarinecine with some rosmarinine. d . Jacozine (1 16). This alkaloid, C ~ ~ H Z ~was N Oshown ~ , by Bradbury and Willis (163)to hydrolyze to retronecine and jacozinecic acid. Culvenor
310
FRANK L. WARREN
TABLE IX
THESTRUCTURES OF THE PYRROLIZIDINE ALKALOIDS CONTAININQ THE
C ~ ADIPIC O ACIDS
CH3 Baaes: Platynecine (P), R Rosmarinecine (Ros), R Acid
=H = OH
Retrorsine (R), R Crotanecine (C), R
X
Y
Base
Otonecine (0)
=H = OH
Alkaloid
Acid : CH~CH=C(COZH)CHXCH(CH~)C(OH)(COZH)CHZY cis H H R Senecionine Anacrotine cis H H C Renardine cis H H O Platyphylline cis H H P cis H H Ros Rosmarinine H H R Integerrimine Integerrinecic trans H H C Madurensine trans Ci8 H OH R Retrorsine Isatinecic H OH R trans-Retrorsine Retronecic trans Hygrophyllinecic cis OH H P Hygrophylline Senecic
]
I
Acid : CH~CHX-CY(CO~H)CH~CH(CH~)C(OH)(C~ZH)CH~
-0-0C1 OH OH OH OH OH
“Jacobinecic ” “Jaconecic ” “Jacolinecic ”
R 0 R R 0
Jacobine Otosenine Jaconine Jacoline Onetine
Acid : CH~CH=C(CO~H)CHzC(=CHz)C(OH)(COzH)CHzY Isoseneciphyllic Seneciphyllic epoxide Spartiodinecic Riddellic
-
-
H H H H OH
R Ros R R R
Seneciphylline Angularine Jacozine Spartioidine Riddelline
Acid : CH~C(OH)(CO~H)CH(CH~)CH(CH~)C(OH)(COZH)CHZX Sceleranecic Sceleratinic
OH c1
-
R R
Sceleratine Chlorodesoxysceleratine
4. Senecio ALKALOIDS
311
(194)by a comparative study of the UV, IR, andNMR spectra of jacozine with those of jacobine formulated jacozine as seneciphylline epoxide. This was confirmed by the conversion ,of jacozine to seneciphylline by treatment with potassium selenocyanate. e. trans-Retrorsine. Mattocks (195) has shown that when retrorsine was brominated and then directly debrominated it gave trans-retrorsine (mp 145'; [aID + 6.6"; Cl8H25NO6.HC1, mp 246"; picrate, C24H28N4013.CH30H, mp 237"), which hydrolyzed to retronecine and retronecic acid. trans-Retrorsine is identified with usaramine (46). f. Neoplatyphylline. Neoplatyphylline, C18H27N05 (mp 131'-133' ; [aID 1.95'; picrate, mp 164"-165'), has been isolated by Danilova et al. (61)from S. platyphyllus. It hydrolyzed to platynecine and senecic acid, but was different from platyphylline. Reduction with lithium aluminum hydride gave a trihydroxy compound as a viscous oil whose bis(p-nitrobenzoate) was optically inactive. Platyphylline treated similarly gave a bis(p-nitrobenzoate) (mp 136'-137'; ["ID 19.4'). Dimethyl senecate gave a p-nitrobenzoate [a]D - 5.47'). The three trihydroxy compounds were not identical. g. Seneciphylline (115), spartioidine (116), and riddelline (1 14). The structures of seneciphylline (CLXIVa), spartioidine (CLXIVc), and riddelline (CLXIVb) have been reformulated on the basis of the new structures of isoseneciphyllic acid and riddellic acid. Seneciphylline (CLXIVa) has been further studied by Danilova and Koretskaya (196). Reduction with lithium aluminum hydride gave a trio1 (p-nitrobenzoate, mp 128"-129", [a]D - 6.35") identical with that formed similarly from dimethyl cis-seneciphyllate. The dimethyl trans-seneciphyllate ([.ID -6.73") on reduction failed to give a solid derivative, indicative that the acid in seneciphylline is the cis form. Seneciphylline on catalytic reduction gave a dihydro derivative (mp 168"-169") (which hydrolyzed to seneciphyllic acid and desoxyretronecine), and a tetrahydro derivative (mp 194"-195"; [.IU 87.9'). Reduction over platinum in hydrochloric acid gave an octahydro derivative which hydrolyzed to tetrahydroseneciphyllic acid (methyl ester, [a]D - 13.5'; lactone, [a]= - 28.2") and retronecanol. h. Clivorine. Clivorine, CzlH29NOs [mp 147"-149'; [aID 79" (CHCls), 49" (MeOH); picrate, mp 173'-175"], containing an NMe and an acetyl group, was isolated from Ligularia clivorum by Klasek et al. (10).Alkaline hydrolysis gave clivonecic acid, and acid hydrolysis followed by hydrogenation yielded dihydrodeoxyotonecine. The acetate group was probably on the tertiary carbon atom and eliminated during hydrolysis (see structure below). i. Hygrophylline. Hygrophylline, C18H27N06 (mp 173"-174"; ["Iu N
312
FRANK L. WARREN
CLXIVa; Seneciphylline, X = H CLXIVb; Riddelline, X = O H
CLXIVc ; Spartioidine
-67'), isolated by Richardson and Warren (32), has been studied by Schlosser and Warren (33).Hydrolysis gave platynecine and hygrophyllinecic acid monolactone. Performic acid oxidation of the alkaloid gave dihydroxydihydrohygrophylline (mp 85"-87"), which with periodic acid yielded acetone and a basic moiety which hydrolyzed to give oxalic acid. (See structure above.) 0
CHz
I I
I
CH3CCH(CH3)CH(CH3)C(OH)
I coo
CLXVa; X = O H CLXVb; X = C 1
CHzOOC
CLXVI
j. Sceleratine ( 1 15) and chlorodesoxysceleratine.The structure, CLXVa, of sceleratine has been redrawn (177)to accommodate the new structure for sceleranecic acid. Chlorodesoxysceleratine, C18H26ClNO6 (CLXVb) (mp 196'; ["ID +32.4'; picrate, mp 213'-215'), has also been isolated from S. sceleratus by Gordon-Gray (197).Catalytic hydrogenolysis gave directly sceleratinic acid and retronecanol, while alkaline hydrolysis yielded the acid CXLIIb (mp 192'). Trea.tment of the alkaloid with sodium hydroxide a t room temperature gave an amorphous alkaloid,
4. Senecio
313
ALKALOIDS
CLXVI, C18H25N06 (mp 149"-150"; picrate, mp 179'-181"); which on catalytic hydrogenation followed by hydrolysis gave retronecanol and CXLIIb. k. Mucronatinine. Mucronatinine, C18H25N06 (mp 161°-163"C; picrate, mp 228"-229"C ; methiodide, mp 229.5"-230.5"C) was isolated as the major alkaloid from Crotolaria mucronata Desv. by Bhacca and Sharma (261). The structure has been assigned as a diasteriomer of retrorsine.
3. Structures Containing Otonecine The structures of these alkaloids followed from the elucidation of the structure of retusamine. a. Onetine. The alkaloid, C1gH2gNOs (mp 192"-193"; ["ID 73"; flavinate, mp 238"-240°), was isolated by Danilova, Koretskaya, and Utkin (63)as the third alkaloid from S. othonnae. Catalytic hydrogenation gave tetrahydrootonecine and an acid, C10H1807 (mp 142"-143"; ["ID 10'; diamide, CloHzoNz05, mp 168"-169", ["ID 48". The alkaloid, hydrolyzed with sulfuric acid and acetylated, gave an acetoxydilactone, C12H1606 (mp 157"-158"; [a],-, 4.6"), identified as the derivative of jacolinecic acid. b. Otosenine (tmnentosine)(116). This alkaloid, C19H27N07 (mp 221"; [.ID 20.8"),hydrolyzed with sulfuric acid, gave an acid, characterized as its diamide and acetoxy derivatives, as the same as that from onetine (63). c. Floricaline, Jloridanine, and Jlorosenine. These three alkaloids have been isolated from CaEaliaJloridana together with otosenine by Weisbach et al. (23). Florosenine, C21H29N08 (mp 100°-1030; ["ID 31.9"), was monoacetylotosenine. Floridanine, C21H~gN08(mp 195"-196' ; [all) + 66.5"), is considered from spectroscopic data as florosenine with the epoxide ring opened, so OR
/9 I CH~C-C-CHZCH(CH~) CH3
y $
'coo
'i
CH3 Otosenine ; R = H Florosenine : R = Ac
OH
I ?
PR
R'
CH3 Onetine; R = H Floridenine ; R = Ac Floriceline: R = Ac
R' = H R' = H R' = Ac
314
FRANK L. WARREN
that florosenine and floridanine are related bases like otosenine and onetine. Floricaline, C23H33N010--&&H6(mp 177'-178'; [aID 74.3'; 1 C6H6, m p 120O-122") is shown to be acetylfloridanine. Mass spectral data and actual interconversion establish these structures. d . Renardine (senkirkine).This alkaloid, C19H27N06 (mp 197'-197.5' ; [a],) - 13'; picrate, mp 219'-220'; bitartrate, mp 193"-194", ["ID - 13'; CH31, mp 194"-196' dec; picrolonate, mp 138'; aurichloride, mp 182.5"183.5"; chloroplatinate, nip 196"-197"), was isolated from Nardosmia Zaevigata by Massagetov and Kuzovkov (198) and later identified with senkirkine which Briggs et al. (68) isolated from S. kirkii. Its structure was determined by Danilova, Koretskaya, and Utkin (70).It gave on hydrolysis otonecine and anh ydrootonecine as hydrochlorides and senecic acid, while catalytic hydrogenation ('70) gave tetrahydrootonecine, CgH17N02, so that renardine (senkirkine) had the structure CLXVII.
+
CHg CLXVII
This structure received confirmation fro,m the NMR spectrum made by Briggs and his co-workers (68). e . 0-Acetylrenardine. The alkaloid C21HZgN07.3Hzo [mp 195'-196'; [ a ] , ) - 3 4 f 1' (methanol);A,,, 218 mp(1og E 3.81), vlllaX 1761 and 1421 (CH3COO) 1739 (ester CO), 1727 (conjugate ester CO), 1689 (C=C) 1639 (C=-0 8-), 1241 em-1; picrate, mp 208'-209'; picrolonate, mp 222'; aurichloride, mp 108'-109'1, was isolated and its structure determined by Briggs and his co-workers (68). 4. General Structures
The alkaloids of this group all contain the necine bases with the C-7 hydroxyl trans to the C-8 hydrogen, that is, with the hydroxyl group in the fold of the molecule as if the macrocyclic diester necessitated this arrangement. The structures are coordinated according to the acid present and fall naturally into four groups (see Table IX). I n this group also occurs the quaternary base otonecine.
4. Senecio ALKALOIDS
315
F. ALKALOIDS CONTAINING AROMATIC ACIDS 1. Benzoate of Laburnine The benzoate of laburnins has been isolated from Planchonella spp. (49). 2. Thesine and Thesinine Both thesine and thesinine were isolated by Arendaruk, Proskurnina, and Konovalova (96) from Thesium minkwitzianurn and the structures determined by Arendaruk and Skoldinov (97,98).
CLXIX
CLXVIII
Thesine, C34H42N206 (CLXVIII) (96) (mp 254'-256" ; sulfate tetrahydrate, mp 244"-246", [ a ] , )33.4"; dipicrate, 224"-226'; dimethiodide, mp 140"-150", [a]D 33.24') hydrolyzed to (D)-isoretronecanoland thesinic acid (mp 130";dimethyl dimethoxythesinate, mp 125"-126" ;dimethoxythesinic acid, mp 250"-251") which was identified as p,p'-dihydroxy-atruxillic acid. Thesinine, C17H21N03 (CLXIX) (mp 38"-40") hydrolyzed to ( + )-isoretronecanol and p-hydroxycinnamic acid.
3. Kuramerine, Kumokirine, and Nervosine Three new alkaloids occurring as esters have been isolated by Nishikawa et al. (48,62)from Liparis spp. of Orcidaceae. Nervosine, ~ 3 6 ~ ~ (picrate, 3 ~ 0 1mp~ 13Oo-13l0; HCl salt, [ a ] D + 12.80) (CLXXa) gave on alkaline hydrolysis lindelofidine and nervosinic acid - 14'), which gave a (CLXXd), C28H400129H20 (mp 168'-169"; UI.[ tetrahydro derivative (mp 187'-189'), bhich with acid gave a dibasic acid, C17H2603 (mp 138"-139"), D-glucose, and L-arabinose. Nervosinic acid on mild acid hydrolysis afforded nervogenic acid, C17H2203 (mp
316
FRANK L. WARREN
96'-97') (CLXXe). The structures are assigned on the basis of these reactions and NMR spectra. Kuramerine, CZgH44NOg' (picrate, mp 105'-107'; HC1 salt, [a]= - 19.7") (CLXXb), on alkaline hydrolysis gave choline and kurameric acid, C23H3208. H20 (mp 103"-105") (CLXXf),which gave a tetrahydro derivative, and which on acid hydrolysis yielded CLXXe. Kumokirine, C32H4gN0gt' (picrate, mp 100°-1020; HCl salt, [a]= - 23.4') (CLXXc) on hydrolysis gave kumokiridine, CgH18NO+ (picrate, mp 248"; [a]= + 12"), identified as N-methyl-(+ )-trachelanthamidine (N-methyllaburnine), and kurameric acid (CLXXf). YOOR'
CLXX
R
R'
CLXXa; Nervosine
Glucose-arabinose Lindelofidine
CLXXb; Kuramerine
Glucose
Choline
CLXXc ; Kumokirine
Glucose
N-Methyl-(+)-trachelanthamidine
CLXXd; Nervosinic acid
Glucose
H
CLXXe; Nervogenic acid
H
H
CLXXf: Kurameric acid
Glucose
H
V. Biosynthesis (117) Studies of the alkaloid content of S. platyphyllus has shown that the alkaloid concentrates in the roots in the reduced form in the autumn while the highest yield is in the aerial parts as the N-oxide during flowering (199, 200).
A. BASES Byerrum (201) and Hughes et al. (202) have confirmed Robinson's prediction (203)that ornithine is the precursor of the necines by feeding 2-14C-ornithine. Bottomlcy and Geissman (204) have fed 1,4-14C-putricine, 2-14C- and 5-14C-ornithine to 8. douglasii and found 25% of the
4. Senecio
317
ALKALOIDS
activity in the hydroxymethyl group of retronecine, indicative of a symmetrical intermediate for one of the two molecules involved. B. ACIDS Crout et al. (205)using S . douglasii have demonstrated the high specific incorporation of universally labeled L-threonine (CLXXI) and L-isoleucine into seneciphyllic acid (CLXXIII). Experiments with uniformly labeled L-isoleucine (CLXXII)showed that the activity of the ethylidine group C-6-C-7 of seneciphyllic acid was twice that, of C-10, while studies with 1-14C-~-isoleucineindicated that C- 1 was not incorporated. Finally 0
.
0
CH&H(OH)CH(NHz)COOH
-
0 A 0 CH&HzCHCH(NHz)COOH
0
I
(CHsCO)
A A
CH3 A
CLXXI
CLXXII
CHz 7
6
5 4
I(
2‘
8
CHsCH=CCHzC--C( OH)CH3
I
10 COzH
I
YOzH
CLXXIIIa
CHz A 0 11 CH&H-CHCHz-C--C( OH)CH3
0
0
I
COzH A
I
COzH
CLXXIIIb
uniformly labeled L-threonine was incorporated into the C - 6 4 - 7 unit more than four times better than into C-10, which gives support for the scheme shown below. The exact nature of the C-1-C-2-C-3-C-9 unit is obscure. Threonine can supply the C-1-C-2 unit, and the C-9 comes from formate or methionine. Crout (206) has fed 4-14C-~~-valine to Cynoglossum oficinale to give 0.25% incorporation into heliosupine (CLXXVII).The alkaloid had 85% of its activity in the echimidinic acid moiety, which had 93% in the gemdimethyl group. The incorporation of 2-14C-acetatewas by contrast only 0.2%. The conclusion was reached that the biosynthetic route was by way of a two-carbon insertion into 2-oxo-3-hydroxy-3-methylbutyric acid (CLXXIV). Taken in conjunction with the established biosynthesis of valine (CLXXV) from pyruvic acid by way of acetyllactic acid (CLXXVI)and the ketol rearrangement to CLXXIV the biosynthesis of echimidinic acid may be formulated as in Chart VI. The occurrence of trichodesmic acid (CLXXVIII) in trichodesmine in T. incanum and echimidinic acid in helibsupine in C. oficinale, two plants of the same tribe (Cynoglosseae)of the family Boraginaceae, suggested t o
318
FRANK L. WARREN
Crout (206)a biosynthetic correlation between trichodesmic and echimidinic acids and hence the Cg unit in monocrotalic and the Clo adipic acids. He envisaged the C g unit common to both acids as being developed from pyruvate, threonine, and methionine or formate. (COCHB)
+
COCH3
I
COzH
-
COCHs
C(OH) (CH3)Z
I
CH(CH3)
I I
I I
C(OH)CH3
I
CH(NHz) COzH
COzH
COzH CLXXVI
CLXXIV
C H ~ C H Z C HCH3)CH(NHz)COzH ( CLXXII
I
CLXXV
CH3 CH3 \ / C ( 0 H ) CH3
I
I I
C(0H)-CH(0H)
C&CH=C(CH3)COO
CHz-COz
# H I
Tiglic acid-heliotridine--echimidinicacid
CLXXVII Heliosupine
II
CH&H==CCHzCC(OH)CH3
I
‘e
CH3 CH3 9H3
CHz
I
CH-C(OH)C(OH)CH3
I
COzH
COzH COzH
I
COzH
CXXXII
CLXXVIII
Seneciphyllic acid
Trichodesmic acid
CHARTVI. The biosynthesis of tiglic, echimidinic, and trichodesmic acids, and the Cs unit common to the Clo adipic acids and monocrotalic acid according to Crout.
I n another experiment Crout (207) fed U-l4C-~-isoleucine(CLXXII) and sodium 2-14C-acetate to Cynoglossuin ofiicinale and found tenfold incorporation of isoleucine relative to acetate, and 98% activity located in the angeloyl moiety of heliosupine. C. TOTALALKALOIDS Labeled integerrinecic acid has been synthesized in our laboratories (208) from senecic acid (CLXXIX) by oxidation to the keto acid,
4 . Senecio
319
ALKALOIDS
CLXXX, treatment with 14C-hydrocyanic acid, and hydrolysis to integerrinecic acid, CLXXXI. This acid was fed to 8. adnatus and the resulting rosmarinine was shown to have 89% of the activity in the carboxyl group of the senecic acid indicative of the acid being incorporated after synthesis into the alkaloid. RC(OH)(COzH)CH3+ RCOCH3 + RC(OH)(14COzH)CH3 CLXXIX
CLXXX
CLXXXI
R = CH&H=C(COzH)CH2CH(CHa)
The chemotaxonomy elaborated by Santavy (209) for this group of alkaloids should have greater significance as the biosynthetic pathways are elaborated. CH&H=CCHzCH(CHa)CO
CH&H=CCHzCH( CHs)C(0H)CHzX
I
"9
I co
I co I
I
co I
HI04 ___f
c--''CHsMgI
CLXXXIIa; X = H CLXXXIIb; X = OH
CLXXXIII
The synthesis by Mattocks and Warren (161)of senecionine (CLXXXa) from retrorsine (CLXXXb)by oxidation with periodate to the keto ester, CLXXXIII, and reaction with the Grignard reagent has permitted the preparation of CH&W-senecionine for studies of the role of the total alkaloid in the plant and animal.
VI. Pharmacology ( 1 17) Active interest in the toxic nature of the Senecio alkaloids continues to be t'aken by R. Schoental and her collaborators in Britain and by L. B. Bull and A. T. Dick and their co-workers in Australia. The different effects might be summarized as follows : (i) Chronic liver lesions have been produced by single doses while sublethal doses given over a period have effected malignant tumors (210,211). (ii) The susceptibility to liver damage was more pronounced during low-protein diet (212),in males more than in females, and in the young more than in the adult (213). (iii) The alkaloid and its N-oxide do not differ in toxicity (211, 214).
320
FRANK L. WARREN
(iv) The cyclic esters of the Clo adipic acids are highly toxic (215). (v) The noncyclic diester, lasiocarpine, was more toxic than the monoester, heliotrine (215). (vi) Synthetic esters of retronecine with branched-chain monocarboxylic acids caused liver lesions and cytological effects similar to the natural alkaloids (216). (vii) Lasiocarpine given to lactating rats caused death due to liver lesions in the young (217).Newberne (262) has reported the influence of a low lipotropic diet on response to maternal and fetal rats to lasiocarpine. (viii) Monocrotaline and fulvine produce an effect on the lungs as well as on the liver (218, 219). It may be significant that these two alkaloids are glutaric esters as distinct from the C ~ adipic O esters and noncyclic diesters. (ix) Senecionine and its N-oxide are reported to inhibit Walker carcinosarcoma 256 tumor growth in vivo (85,220). (x) Pathochemical shifts have been studied in experimental heliotrineinduced liver dysfunction (221-225) and the effects of prednisolone and methandrotenolone recorded (226). (xi) Hypotensive activity is reported from extracts of Crotalaria agatijlora (227),and pyrrolizidine-carboxylic amides (228). (xii) Mercaptoethylamine and cysteine give protection against monocrotaline intoxication (229). Additional studies have included the nature of the pathological changes (15, 230-236). Several theories have been advanced with regard to the mechanism of both the hepatotoxic action in animals and the sterility in Drosophila which, once started, seem to be irreversible. Schoental (213)suggests a disorientation of the steroid hormone synthesis, possibly due to the disturbance of the cocarboxylase activity. Clark’s observation on mutagenic activity using Drosophila (237)links with the concept of mitotic poisoning developed by Schoental and Magee (238). Barnes and Schoental (233) have drawn attention to the similarity of the large cells in the liver in Senecio poisoning and of kwashiorkor victims. Culvenor, Dick, and their collaborators (239, 240) have observed that heliotrine in the rumen of sheep is converted to 7a-hydroxy-1 -methylene-8a-pyrrolizidineand suggest an alkyl oxygen fission of the ester group and alkylation as the mechanism by which the hepatotoxic alkaloids act on the cell nuclei. A very significant contribution to toxicity studies has been made by Mattocks (241, 242). The reaction of retrorsine N-oxide with acetic anhydride has given pyrrole derivatives (CLXXXIV a, b, c), which were
4. Senecio
32 1
ALKALOIDS
themselves toxic, with CLXXXIVa probably the most toxic. Color reactions with Ehrlich’s reagent, characteristic of pyrrole derivatives, were demonstrated in the urine and liver tissue of rats given a single dose of retrorsine. The saturated pyrrolizidine bases, which are nontoxic even when esterified as in the natural alkaloids, have been used by Kuzovkov et al. (243, 244) to synthesize diquaternary ammonium salts with curare-like properties. ,R,
coo
CHzOOC
COO
CHzOOC
OR’
CHzOR2
@ - & -M 0
Retrorsine
Pyrrole derivative
CLXXXIVa; R1= CHI, R2 = CHaCO OT R2 = CH3, R1 = CHsCO CLXXXIVb; R1= CH3, R a = H Or R Z= CH3, R1= H CLXXXIVC; R1= R2 = CHI
VII. Analytical Procedures Microcrystalloscopic methods for detection have been devised by Egorova (245)for platyphylline, sarracine, and seneciphylline. The Polonovsky reaction (246) whereby a 3-pyrroline ring system is oxidized to the N-oxide and treated with acetic anhydride to give the pyrrole, has been employed by Dann (247) to detect pyrrolizidine alkaloid N-oxides on paper chromatograms, the fluorescence of the pyrrole being observed. The method has been developed by Mattocks (248) as a spectrophotometric procedure, applicable also to biological material (248), and for detecting these alkaloids on thin-layer chromatograms (249).The chromatographic plates are sprayed with hydrogen peroxide to give the N-oxide, and then sprayed with acetic anhydride and heated to produce the pyrrole derivative, which is developed by Ehrlich’s reagent (see Section VI). The method has been studied further by Bingley (250). The same conversion of the N-oxide to pyrroles has been shown by Mattocks (242) to be brought about by ferrous, but not ferric, salts, although ferric salts were effective in the presence of reducing agents. The reaction rate is increased by fluoride and sodium salicylate, which form
322
BRANK L. WARREN
complexes with Fe(II1) but not with Fe(I1). This enhancement is explained by the removal of Fe(II1) which can chelate with 3 moles of retrorsine N-oxide which cannot then react so readily with Fe(I1). The method is useful for preparing pure pyrrole derivatives.
VIII. Other Pyrrolizidine Alkaloids The Senecio alkaloids discussed above are esters of mono-, di-, and trihydroxy- 1-methylpyrrolizidines, and a few of these necine bases or their derivatives have been found free in the plant. The pyrrolizidine structure has more recent,ly been found in a number of other alkaloids.
A. FESTUCINE The base Festucine, C18H14N20 (diHC1salt, mp 237"-242", [a]D + 4.6" (water); N-acetyl, mp 202"-203", ["ID + 5.4'; N-nitroso, mp 64"-65.5') from Pestucia arundinaceae was isolated by Yates and Tookey (251,252)
CLXXXV
and the structure CLXXXV established by McMillan and Dickerson (253) from X-ray diffraction studies. The structure is in conformity with the reaction with hydrochloric acid to give an hydroxychloro derivative which yielded an N-acetyl and an N,O-diacetyl derivative.
B. LOLINE,LOLININE,AND NORLOLINE Loline, lolinine, and norloline were isolated from the seeds of Lolium cuneatum, and their structures determined by Yunusov and Akramov (254-258). Loline, C7HloNO(NHCH3) (["ID 18.9"; diHCl salt, mp 256"257", [aID 6.2") on acetylation gave lolinine, C7HloNON(CH3) (COCH3) (mp 73"; [aID 36.9') and with potassium permanganate norloline, C7HloNO(NH2)(bp 94"-95"; [.ID + 15.1"). The structures for loline (CLXXXVIa), lolinine (CLXXXVIb), and norloline (CLXXXVIc) follow from reactions which are shown in Chart VII. The ether bridge in loline was established by treating the alkaloid
4. Senecio ALKALOIDS
323
with hydrogen chloride to give hydroxychlorololine dihydrochloride, CsH15ClN20 2HC1, which with potassium hydroxide gave loline. Reduction of the hydroxychlorololine gave dihydrololine, C8HleN20, which with thionyl chloride gave hydrodeoxychlorololine, C8H15ClNz which gave on reduction hydrodcsoxyloline, C8H16N2 (CLXXXVIIa) and Hydroxychlorololine CgHi.QN2.HC1
TI
Dihydrololine
QHlsN2O
+--
I
m
N
R
R
f
N CLXXXVIa; R = CH3, R’ = H CLXXXVIb; R = CHa, R’ =COCH3 CLXXXVI C ; R = R’ = H
Hydrodeoxy chlorloline
C~HIOCIN~
CLXXXVIIe; R” =NHCHs CLXXXVIIb; R” = H CHARTVII. Reactions of loline, lolinine, end norloline.
pyrrolizidine (CLXXXVIIb). The position of the oxygen bridge in lolinine was assigned on the evidence that loline underwent only two Hofmann reactions, indicative that hydrogen was absent from one of the carbon atoms p with respect t o the tertiary nitrogen atom. C. CASSIPOURINE This alkaloid, C14H22N2S4 [mp 212’; [“ID - 11.8’ (chloroform)] was isolated by Wright and Warren (259)from Cassipourea gummijlua and its structure established by CookF, Warren, and Williams (260). Raney nickel desulfurization yielded pyrrolizidine, and zinc dust distillation gave pyrrolo[ 1,Z-a]pyrrolidine. Oxidation with nitric acid gave pyrrolizidinedisulfonic acid N-oxide. The formation of a single product from zinc distillation and only one disulfonic acid by oxidation would follow if cassipourine were a bis(disulfide) with the two halves symmetrically substituted, and a 1,2structure was envisaged as the most rational. The X-ray analysis of a
324
FRANK L. WARREN
single crystal showed cassipourine as 1~,2/3,1’cr,2’/3-bis(dithio)di-8apyrrolizidine (CLXXXVIII).
CLXXXVIII
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198. R. S. Massagetov and A. D. Kuzovkov, Zh. Obshch. Khim. 23, 158 (1953). 199. L. Ya. Areshkina, Dokl. Akad. Nnuk SSSR 61, 483 (1948). 200. V. S. Alekseev, T. G. Bilyuga, 0.E. Taldykin, A. M. Oleksandruk, A. G. Timoshenko, N. N. Malukha, A. F. Minko, V. S. Shabel’nyuk, P. P. Girenko, and V. V. Mazenko, Nuuchn. Dokl. VyssheiShkoly, Biol. NnukiNo. 2,152 (1962); C A 57, 10224 (1962). 201. E. Nowacki and R. U. Byerrum, LifeSci. 5, 157 (1962). 202. C. A. Hughes, R. Letcher, and F. L. Warren, J . Chem. SOC.4974 (1964); of. C. A. Hughes, Ph.D. thesis, University of Natal, South Africa. 203. Sir R. Robinson, “The Structural Relations of Natural Products,” p. 72. Oxford Univ. Press, London and New York, 1955. 204. W. Bottomley and T. A. Geissman, Phytochemistry 3, 357 (1964). 205. D. H. G. Crout, M. H. Benn, H. Imaseki, and T. A. Geissman, Phytochemistry 5 , 1 (1966). 206. D. H. G. Crout, J. Chem. Soc. 1968 (1966). 207. D. H. G. Crout, J. Chem. SOC.,C 1233 (1967). 208. C. A. Hughes, C. G. Gordon-Gray, F. D. Schlosser, and F. L. Warren, J . Chem. SOC. 2370 (1965). 209. F. Santavjr, Abhandl. Deut. Akad. Wiss.Berlin, K l . Chem., Geol. Biol.No. 3,43 (1966); C A 66, 10484 (1967). 210. R. Schoental and P. N. Magee,J.Pathol. Bacteriol. 74,305 (1957);C A 52,2270 (1958). 211. R. Schoental, Nature 179, 361 (1957). 212. R. Schoental, Voedirig 16, 268 (1955). 213. R. Schoental, Proc. Roy.Soc. Med. 284 (1960). 214. L. B. Bull, A. T. Dick, and J. S. McKenzie, J. Pathol. Bacteriol. 75, 17 (1958). 215. R. Schoental and M. Head, Brit. J. Cancer 9,229 (1955). 216. R. Schoental and A. R. Mattocks, Nature 185, 842 (1960). 217. R. Schoental, J. Pathol. Bacteriol. 77, 485 (1959). 218. R. Schoental, Biochem. J. 88, 57P (1963). 219. J. J. Lalich and L. A. Ehrhart, J. Atherosclerosis Res. 2, 482 (1962); C A 59, 5611 (1963). 220. C. C. J. Culvenor, J. Pharm. Sci. 57, 1112 (1968). 221. S. M. Prigozhina, Eksperim. Khirurg. i Anesteziol. 11, 41 (1966); C A 66, 1061 (1967). 222. N. Kh. Abdullaev, Vopr. Pituniyn 25,69 (1966);C A 66,9585 (1967). 223. C. H. Gallagher, Biochem. Pharmocol. 17,533 (1968); C A 68, 113165 (1968). 224. J. Reddy, C. Harris, and D. Svoboda, Nature 217, 659 (1968). 225. C. H. Gallagher and J. D. Judah, Biochem. Phurmucol. 16,883 (1967); C A 67, 10019 (1967). 226. N. Kh. Abdullaev, Probl. Endokrinol. i Gormonoterap. 2, 71 (1966); C A 66, 44083 (1967). 227. F. Sadritdinov, Fnrmctkol. Formukoter. Alkaloidov Glikozidov, Akad. Nauk Uzb. SSR,Khim.-Tekhnol. Biol. Otd. 60 (1966); C A 67,42230 (1967). 228. M. L. Sharma, G. B. Singh, and B. J. Ray, IndionJ. Exptl. Biol. 5 , 149 (1967); C A 67, 115625 (1967). 229. Y. Hayashi and J. J. Lalich. Toxicol. A p p l . Pharmacol. 12, 36 (1968); C A 69, 1485 (1968). 230. J. R. Allen, J. J. Lalich, and S. C. Schmittle, Lab. Invest. 12,512 (1963); C A 59,4310 (1963). 231. L. M. Markson, Proc. Roy. Soc. Med. 283 (1960). 232. E. Ch. Pukhalskaya, M. F. Petrova, and I. W. Man’ko, Bull. Exptl. Biol. Med. ( ( I S S R ) (English Transl.)48, 91 (1959); C A 58, 2753 (1963).
4. Senecio ALKALOIDS
331
233. J. M. Barnes and It. Schoental, Brit. Med. Bull. 14, No. 2,165 (1958). 234. R. Schoental and J. P. M. Bensted, Brit. J. Cancer 17,242 (1963). 235. J. S. McKenzie, Australian J . Ezptl. Biol. Med. Sci. 36, 11 (1958); C A 52, 11265 (1958). 236. R. Schoental, Bull. World Hecclth Organ. 29, 823 (1963). 237. A. M. Clark, Nnture 183, 731 (1959). 238. R. Schoental and P. N. Magee, Actn CInio Intern. Contra Cancrum 15 (1959). 239. C. C. J. Culvenor, A. T. Dann, and A. T. Dick, Nature 195, 570 (1962). 240. A. T. Dick, A. T. Dann, L. B. Bull, and C. C. J. Culvenor, Nuture 197,207 (1963). 241. A. R. Mattocks, Nature 217, 723 (1968). 242. A. R. Mattocks, Nature 219, 480 (1968). 243. A. D. Kuzovkov and G. P. Men'shikov, Zh. Obshch. Khim. 21, 2245 (1951). 244. A. D. Kuzovkov, M. D. Mashkovskii, A. V. Danilova, and G. P. Men'shikov, Dokl. Akad. Nnuk SSSR 103, 251 (1955). 245. E . I. Egorova, Sudebno-Med. Ekspertiza, M i n . Zdravookhr. SSSR 10, 36 (1967); CIA 67, 62722 (1967). 246. M. Polonovsky and M. Polonovsky, Bull. SOC.Chim. de Franc [iv] 41, 1190 (1927). 247. A. T. Dann, Nnture 186, 1051 (1960). 248. A. R. Mattocks, A n d . Chem. 39, 443 (1967). 249. A. R. Mattocks, J. Chromatog. 27, 505 (1967). 250. J. B. Bingley, A n d . Chem. 40, 1166 (1968). 251. S. G. Yates,J. C'hromtrtog. 12, 423 (1963). 252. S. G. Yates and H. L. Tookey, Australian J . Chem. 18, 53 (1965); C A 62, 11865 (1965). 253. J. A. McMillan and R. E. Dickerson, unpublished data. 254. S. Yu. Junusov (Yunusov) and S. T. Akramov, Zh. Obshch. Khirn. 25, 1813 (1955); C A 50, 7117 (1956). 255. S. Yu. Junusov (Yunusov)and S. T. Akramov, Dokl. Akad. Nauk. Uz. S S R No. 4,28 (1959); CA 54, 11028 (1960). 256. S. Yu. Junusov (Yunusov) and S. T. Akramov, Zh. Obshch. Khim. 30, 677 (1960); C A 54,24831 (1960). 257. S. Yu. Junusov (Yupusov) and S. T. Akramov, Zh. Obshch. Khim. 30, 683 (1960); C A 54, 24831 (1960). 258. S. Yu. Junusov (Yunusov) and S. T. Akramov, Zh. Obshch. Khirn. 30, 3132 (1960); CIA 55, 19981 (1961). 259. W. G. Wright and F. L. Warren, J . Chem. SOC.283 (1967). 260. R. G. Cooks, F. L. Warren and D. H. Williams, J . Chem. SOC.286 (1967). 261. N. S. Bhacca and R. K. Sharma, Tetrahedron 24, 6319 (1968). 262. P. M. Newberne, Cancer Res. 28, 2327 (1968).
This Page Intentionally Left Blank
-CHAPTER
5-
PAPAVERACEAE ALKALOIDS F. SANTAVP Imtitute of Chemistry. Medical Faculty. Palack$ University. Olomouc. Czechoslovakia
I . Introduction ....................................................... I1. Occurrence ......................................................... I11. Structures. Chemical and Physicochemical Properties. and Biosynthesis of the Papaveraceae Alkaloids .............................................. A . Benzylisoquinoline Group ......................................... B . ProaporphineGroup ............................................. C. Aporphine Group ................................................ D . Promorphinane Group ............................................ E Morphinane Group ............................................... F. Cularine Group .................................................. G. PavineGroup .................................................... H Isopavine Group ................................................. I Tetrahydroprotoberberineand Protoberberine Groups ................ J . Protopine Group ................................................. K . Phthalideisoquinoline Group ....................................... L . Narceine Group .................................................. M Rhoeadine Group ................................................ N . Benzophenanthridine (a-Naphthaphenanthridine) Group ............... 0. Ochotensimine Group ............................................. P . Alkaloids of Unknown Structure ................................... IV . Biosynthetic and Chemotaxonomic Conclusions.......................... V . Addendum : The Alkaloids of Fumariaceous Plants ...................... References ......................................................... Note inproof .......................................................
.
. .
.
333 344 347 347 349 361 362 364 368 370 380 383 390 397 397 398 417 420 429 429 436 438 464
.
I Introduction I n view of the tremendous progress in the investigation of the alkaloids of the plant family Papaveraceae. it seemed desirable to bring up t o date the chapters dealing with this problem which were published earlier in this series . I n this connection. mention should be made that sufficient data have been accumulated to make it profitable to undertake biogenetic and chemotaxonomic studies . According to Engler’s book (345). the European Papaveraceae are subdivided into the tribes and genera given in Table I. which indicates where. in the future. related alkaloids might be expected .
S U R V E Y O F THE
TABLE I GENERAO F THE P L A N T FAMILY PAPAVERACEAE ACCORDING TO ENQLER
AND THE
GROUPSOF ALKALOIDS FOUND^
w w b P
Types of known alkaloids
I. Eypecoideae
ReferencIe ( 3 4 5 ) . The grnera marked hy an asterisk %-ereincluded in this tahle according to de Dalla Torre and Harm ( 1 2 4 ) ' the number of sperieswas not given. The chemotaxo. nrrrriiraIly imDurtant groups of alkaloids of thc individual t.rihes or genera have h e n marked by m, 0 . 4 . @, '+, x ,
*.
TABLE I1
PLANTS OF Plant
Argemone aenea G . B. Ownb. A. alba Lestib. A. hispida Gray A . mexicana L. (seeds) A . munita Dur. C Hilg., subsp. rotundata (Rydb.) A. plntyceras Link & Otto
Rocconiu cordnta (Macleya cordata)
B. latisepnln Wats. B. fruteseens B. pearcei Hutsch.
Chelidonium majua L.
Corydalis aurea Willd. C . bulbosa D.C. C . caseam A. Gray C. cauu Schweigg. C Korte
(syn. C . tuberosa DC)
THE
PAPAVERACEAE AND THEIR ALKALOIDS
Alkaloid
Genera other than Papaver Allocryptopine, berberine, protopine Allocryptopine, berberine, coptisine, chelerythrine, protopine, sanguinarine, Alkaloid A ( - )-Argemonine, ( - )-bisnorargemonine, ( - )-norargemonine, ( )-reticuline Dihydrosanguinarine, sanguinarine ( - )-Bisnorargemonine, cryptopine, ( - )-munitagine, muramine, ( + )-reticuline Allocryptopine, argemonine, berberine, coptisine, norargemonine, platycerine, protopine, sanguinarine Allocryptopine, bocconine, chelerythrine, oxysanguinarine, protopine, sanguinarine, alkaloids A, B, and C Allocryptopine, chelerythrine, oxysanguinarine, protopine, sanguinarine Allocryptopine, chelerythrine, protopine, sanguinarine, and unknown base (mp 268") Allocryptopine, berberine, chelerythrine, chelirubine, coptisine, protopine, sanguinarine Allocryptopine, chelamidine, chelamine, chelidamine[( - )-stylopine], chelidonine, chelerythrine, chelilutine, chelirubine, coptisine, corysamine, oxysanguinarine, protopine, sanguinarine, sparteine Capaurine +sendaverine (Alkaloid F-28)= Corpaverine Columbamine, coptisine, dehydrocorydalline, ( - )-tetrahydrocolumbamine Caseamine (Alkaloid F-33),caseadine (Alkaloid F-35) Corydaline and nonphenolic base (mp 226')
+
References
130 491 518
436 51 8 85,195,480 363a, 5233 I32 523a 279 195, 233, 402, 443, 446, 455, 456, 473, 482 241,242,244,297, 316 228a, 228b 107 536
w w
or
TABLE 11-continued
W
W
oa
Plant
C. claviculata L. C. incisa (Thunb.) Pers. C. nnknii Ishidoya
C. sewertzoiuii Riegel Dicentrn cucullaria (L.) Bernh. D . spectnbilis Lam.
Dicranostigma franchetianurn (Prain.) Fedde D . lnctucoides H0ck.f. & Thoms
Eschscholtzia californicn Cham.
E . douglasii (Hook. & Am.) Walp.
E . glnucn Greene
E. lobbii Greene E. oregnna Greene ( ? )
Alkaloid
References
+
+ )-cularidine, ( )-cularine 245, 297,318, 319 Bicuculine, coptisine, corynoline, corypalmine, corysamine, protopine, 522, 524 sanguinarine 251a Corydine, corysamine, ( + )-isocorydine, ( )-norisocorydine, ( - )-reticdine, (- )-scoulerine, ( - )-tetrahydrocolumbamine,and unknown bases A and H Allocryptopine, ( - )-bicuculine, corlumine, cryptopine, sanguinarine 418a, 554 Cularidine, ( - )-cularine, ochotensine (F-17) 245,297, 319 Chelerythrine, chelilutine, chelirubine, coptisine, protopine, 457 sanguinarine Allocryptopine, berberine, chelerythrine, chelirubine, coptisine, 195,488 isocorydine, protopine, sanguinarine Allocryptopine, berberine, chelerythrine, chelirubine, coptisine, 195, 479 corytuberine, isocorydine, oxysanguinarine, protopine, sanguinarine, base (mp. 178') Allocryptopine, bisnorargemonine, californidine, coptisine, 175, 177, 195, 326, 327, chelerythrine, chelirubine, chelilutine, escholine, eschscholtzidine, 474 eschscholtzine (californine), glaucine, lauroscholtzine, N-methyllaurotetanine, protopine, sanguinarine Allocryptopine, berberine, californidine, chelilutine, chelirubine, 484 coptisine, eschscholtzidine, eschscholtzine (californine), macarpine, protopine Allocryptopine, berberine, californidine, chelerythrine, chelirubine, 484, 490 coptisine, eschscholtzidine (?), eschscholtzine, macarpine, protopine, sanguinarine Berberine, chelerythrine, coptisine, protopine, sanguinarine 195,490 Allocryptopine, berberine, chelerythrine, chelilutine, chelirubine, 490 escholamine, protopine, sanguinarine
( + )-Cularicine, (
+
Fumaria micrantha Lag. F. parviflora Lam. F . Vaillantii Loisl. Glnucium corniculatum Curt.
G. elegans Fisch. & Mey
G.flavurn Cranz.
G.Jlavum ssp. fulvum (Smith) Fedde G. leiocarpum Boiss. G. oxylobum Boiss. & Buhse
G. squamigerum Kar. et Kir.
(G. elegans Fisch. & Mey). Hunnmnannirc. fumuriaefolia Sweet
Hylomecon vernalis Maxim.
Hypecoum leptoca,rpum Hook. f . & Thoms. H . procumbens L. H . trilobum Trautv. Platystemon calqornicua Benth.
Fumaramine, protopine ( - )-Adlumine, ( + )-bicuculine, cryptopine, fumaramine, fumaridine, a-hydrastine Fumaramine, fumaridine, u-hydrastine, protopine Allocryptopine, berberine, chelerythrine, ( - )-chelidonine, chelirubine, coptisine, ( )-corydine, ( )-isocorydine, protopine, sanguinarine Allocryptopine, chelerythrine, ( f )-chelidonine (diphylline), chelirubine, coptisine, corydine, glaucine, isoboldine (?), isocorydine (?), protopine, sanguinarine Allocryptopine, chelerythrine, 1-chelidonine, chelirubine, corydine, glaucine, glauflavine, ( )- and ( f )-isoboldine (aurotensine), isocorydine, magnoflorine, 1-norchelidonine, protopine, sanguinarine ( +)- and ( f )-Isoboldine (“aurotensine”) Aurotensine, glaucine, protopine, base (mp 194”),base (mp 247”) Allocryptopine, berberine, chelerythrine, chelilutine, chelirubine, coptisine, corydine, domesticine, ( )- and ( )-isoboldine (aurotensine), protopine, sanguinarine, and others Allocryptopine, berberine, chelerythrine, coptisine, corydine, protopine, sanguinarine, and others Allocryptopine, berberine, chelerythrine, chelilutine, chelirubine, coptisine, .corysamine, hunnemannine, protopine, sanguinarine, alkaloid HF 1, (scoulerine (?)), and others Allocryptopine, berberine, chelerythrine, chelidonine, chelilutine, chelirubine, coptisine, protopine, sanguinarine, stylopine, tetrahydroberberine Chelerythrine, chelirubine, coptisine, protopine, sanguinarine
195, 402 227b
Allocryptopine, chelerythrine, chelirubine, coptisine, protopine, sanguinarine, and others Chelerythrine, protopine, sanguinarine Berberine, chelerythrine, chelirubine, coptisine, protopine, saneuinarine
478
+
+
+
+
D
227b 177,195, 402, 475
487
176,195, 402, 456, 458, 466, 467,477 458,466 228 466,481
402,486 489
465
478
547 461
w
W 00
TABLE 11-continued Plant
Roerneria refracta (Stev.) DC.
Romneya coulteri var. trichocalyx (Eastwood) Jepson Sanguinaria canadensis L.(Leaves)
Stylomecon heterophylla (Benth.) G . Tayl. (Meconopsis heterophyllu Benth.) Stylophorum diphyllum (Michx.) Nutt. Fumnria o~cicinulisL.
Alkaloid
References
+
Anonaine, coptisine, liriodenine, ( )-mecambrine, ( - )-mecambroline, 483, 549, 550 protopine, reframidine, reframine, reframoline, remrehe, roemeramine, ( - )-roemerine, roemeroline, roemeronine Coulteropine, protopine, ( + )-reticdine, ( )-romneine 513, 514
+
Allocryptopine, berberine, chelerythrine, chelilutine, chelirubine, coptisine, oxysanguinarine, protopine, sanguilutine, sanguinarine, sanguirubine, stylopine, tetrahydroberberine Allocryptopine, berberine, chelerythrine, coptisine, cryptopine, protopine, sanguinarine, stylophylline [( - )- -hydrastinel
+ )-Chelidonine, (
)-chelidonine (diphylline), chelirubine, coptisine, macarpine, protopine, sanguinarine, stylopine Fumarophycine (mp. log", [ a ] ~ 67" (CHCkd),protopine, sinactine
(
465
465
195, 459 350
Genus Papaver a. Section Orthorhoeades Papawer arenuriuna Marsch.-Bieb. P. californicum A. Gray
P . commutatum Fisch. C Mey.
1 ' . dubium L.
Isorhoeadine, papaverrubine A (Alkaloid R-S),rhoeadine, rhoeagenine Cryptopine, latericine, papaverrubines, protopine, rhoeadine, rhoeagenine, base (mp. 169") Coptisine, corytuberine, isocorydine, isorhoeadine, isorhoeagenine, isorhoeagenine-glycoside,papaverine, rhoeadine, rhoeagenine, sanguinarine, base R-D Berberine, coptisine, mecambrine (aporheidine), oxysanguinarine, papaverrubine A, B, and E, protopine, rhoeadine, rhoeagenine, ( )-roemerine (aporheine), alkaloids Rd-B, Rd-C, Rd-F
+
410 361, 433 195, 348, 361, 469
84, 187, 195, 359, 361, 386, 460
P. dubium, ssp. albijlorum (Boiss.) Dost. P. dubium, ssp. lecoquii (Lamotte) Fedde P. intermedium Bedker 0. Ktze. P. litwinoui Fedde P. rhoeas L.
P. rhoeas, var. decaisnei Hochst. & Stend. P. rhoeas, var. $ore albo P. rhoeas, var. flore pleno
P. strigosum Schur.
P. apulum Ten. P . nrgemone L.
P. hispidum Lam. ( =syn. P. hybriduw?) P. hybridum L. P: pnconinum Fisch. & Mey. (P.pnvoninum Schrenk)
Allocryptopine,berberine, coptisine, others
462
Allocryptopine, berberine, coptisine, isorhoeadine, rhoeadine, base (mp 230°),base (mp 297" dec), oxysanguinarine Rhoeadine, thebaine ( ?), oxysanguinarine Oxysanguinarine,base (mp 241"; [a]D +78"); base (mp 273'; [.ID +29") Allocryptopine, berberine (R-F),coptisine (R-U),cryptopine, glaucamine (R-L),glaudine, isorhoeadine (R-A),isorhoeagenine, isorhoeagenine-glycoside(R-C),oxysanguinarine,papaverrubine A (R-S),B, C, D, and E, protopine, rhoeadine, rhoeagenine, sanguinarine, sinactine, stylopine, thebaine, base R-B, base R-D, R-E,R-K,R-0,R-2 Coptisine, isorhoeadine, isorhoeagenine-glycoside,oxysanguinarine, protopine, rhoeadine, rhoeagenine, stylopine Isorhoeadine (R-A),oxysanguinarine, papaverrubine A, rhoeadine, base (mp 246') Coptisine, isorhoeadine, oxysanguinarine, papaverrubine A, protopine, rhoeadine, rhoeagenine, stylopine Coptisine, papaverrubine A, B, D, E, protopine, rhoeadine, rhoeagenine, thebaine ( ? )
135, 410, 462
b. Section Argemonorhoeades Coptisine and others Coptisine, isorhoeadine, oxysanguinarine, papaverrubine D, E, protopine, rhoeadine, rhoeagenine, Alkaloid PA-1, and base (mp 283' dec) Berberine, coptisine, cryptopine, 13-oxoprotopine,protopine, rhoeadine, rhoeagenine, oxysanguinarine Berberine, coptisine, pahybrine, papaverrubine A, D, E, sanguinarine Allocryptopine, coptisine, papaverrubine D, E, protopine, rhoeadine, roemeridine, sanguinarine
433 410 13, 135, 187, 195, 212, 233a, 357, 359, 361, 372, 381, 386, 387, 389, 410, 434, 435, 457, 462, 544 409a, 410 410 409a, 410 386,433,468
468 386,410,433
339 195,386,402,468 195,386, 402, 433, 468
0
TABLE II-continued
I+
0
Plant c.
P. macrostomum Boiss. & Huet..
References
Alkaloid
Section Carinatae
Papaverrubine A, B, D, E, protopine, rhoeadine, base (mp 197')
386, 410
d. .Section Meconee
P. glaucum Boiss. & Hauskn. P. gracile Auch. P. paeonijorum P. setigerum DC.
P. somniferum L.a.0
Coptisine, glaucamine, glaudine, glaupavine, papaverrubine B, C, D, rhoeadine, sanguinarine, base (mp 179") Oxysanguinarine, rhoeadine, and others Codeine, narcotine, papaverine, papaverrubine D, rhoeadine, thebaine Codeine, coptisine, cryptopine, laudanine, laudanosine, morphine, narceine, narcotine, narcotoline, papaverine, papaverrubine A, B, D, E, protopine, sanguinarine, thebaine Codamine, codeine, codeinone, coptisine, corytuberine, cryptopine, glaudinc, gnoscopine, N-methyl-14-O-desmethylepiporphyroxine, hydrocotarnine, 10-hydroxycodeine, ( )-isoboldine, ( - )-isocorypalmine, lenthopine, laudanidine, laudanine, laudanosine, magnoflorine, morphine, narceine, narcotoline, narcotine, neopine, nornarceine, papaveraldine, papaveramine, papaverine, papaverrubine C, porphyroxine (papaverrubine D), protopine, pseudomorphine, ( f )-reticuline, mlutaridine, salutaridinol-I, sanguinarine, ( - )-scoulerine, thebaine, base X, allocryptopine, berberine, palaudine
+
P. arrneniacum L. (DC)
e. Section Miltantha Armepavine, coptisine, mecambrine, palmatine, protopine, sanguinarine
84, 156, 195,379,380, 386,393,433,468 409a, 410 82,386
r
m. 8, 139, 156,195, 261, 262, 273,386 36, 50, 51, 62, 80a, 86, 87, 88, 88a, 89, 90, 134,177a,182,195,226, 270, 273, 363, 368a, 381, 384, 386, 398, 411, 457, 492, 520, 520b, 520d, 526a
269,277,391a, 468
z
k= 4
''
P. caucasicum Marsch.-Bieb.
P. jloribundum Desf. P. f u g a x Poir.
P. persicurn Lindl.
P. polychuetum Schott & Kotschy P. triniaefolium Boiss.
Armepavine, coptisine, N-methylcrotonosine, glaziovine, mecambrine, mecambroline, nuciferine, nuciferoline, palmatine, papaverrubine A, B, C, D, E, ( - )-pronuciferine (miltanthin), protopine, roemerine (isoroemerine), salutaridine, sanguinarine, base (mp 248") Armepavine, floribundine, floripavidine, salutaridine (floripavine), base (mp 206") Armepavine, chelerythrine, coptisine, mecambrine, nuciferine, palmatine, papaverrubine C, D, E, protopine, pronuciferine, ( + )-roemerine, (d-isoroemerine),salutaridine, sanguinarine Armepavine, coptisine, ( - )-mecambrine, mecambroline, L-( + )-nuciferine, 0-demethylnuciferine, palmatine, papaverrubine B, D, ( - )-pronuciferine, protopine, ( - )-roemerine, sanguinarine Armepavine, mecambrine, nuciferine, palmatine, papaverrubine B, D, E (?), pronuciferine, roemerina, sanguinarine Armepavine, coptisine, mecambrine, nuciferine, oxysanguinarine, palmatine, papaverrubine B, D, pronuciferine, protopine, reomerine, sanguinarine, base (mp 238O), base (mp 244O), base (mp 268")
226, 276, 277, 386, 390, 391a, 404, 552, 553
269,391~ 273, 386, 409a, 543, 552, 553 274, 277, 386, 391, 391a, 404,468 274,277,3910 1 9 5 , 2 7 4 , 2 7 7 , 3 9 1 ~409a, , 468
f . Section Pilosa
P. atlanticum Ball.
P . feddei Schwz. P. heldreichii Boiss. P. latericium C. Koch. P. monanthum Trautv.
Coptisine, cryptopine, muramine, 13-oxoprotopine, oxysanguinarine, papaverrubine A, B, C, D, E, protopine, rhoeadine, rhoeagenine, sanguinarine, 13-0xocryptopine, ( - )-stylopine Amurine, glaucine, papaverrubine B, D, E, roemerine Papaverrubine A, B, D, E, sanguinarine Latericine, papaverrubine A, B, D, E, protopine, rhoeadine, rhoeagenine, base (mp 240') Coptisine, latericine, oxysanguinarine, protopine, rhoeadine, sanguinarine
195, 339, 386, 399, 410, 433,468
386,393 195,386 386,433,442 l95,395,409a, 410
TABLE 11-continued
w ip
tc Plant P . oreophilum Rupr.
P. pannosum Schw. P . pilosum Sibth. & Smith P. rupifrugum Boiss. & Reut.
References
Alkaloid 1-Methoxy-13-oxoallocryptopine, isocorydine, isorhoeadine, mecambridine, nuciferine, oreodine, oreogenine oridine (oreoline), N-methyloridine, papaverrubine A, B, D, E, F, protopine, rhoeadine, rhoeagenine, sanguinarine, thebaine, oxysanguinarine Alkaloid R-K (PO-5), Amurine, glaucine, roemerine Coptisine, latericine, muramine, papaverrubine A, B, D, E, protopine, rhoeadine, rhoeagenine, sanguinarine, and others Papaverrubine A, B, D, E, others
287, 288, 337, 339, 386, 392, 394, 395a, 431
395 1 9 5 , 3 8 6 , 4 0 9 ~410 , 386,543
r g . Section Macmntha
P. bracteaturn Lindl.
P . orienlale L.
+
Alpinigenine (Alkaloid E), bractamine, bracteine [( )-orientalinone], 87, 193, 218, 219, 220, bracteoline, coptisine, isothebaine, mecambridine (oreophiline), 256,386,397,405,409a nuciferine, orientalidine (bractavine), oripavine, oxysanguinarine, papaverrubine B, D, E, protopine, salutaridine, thebaine, and others Alkaloid PO-3, Alkaloid PO-4, Alkaloid PO-5 (alborine, Alkaloid 48, 156, 195, 264, 362, R-K),coptisine, glaucidine, isothebaine, mecambridine, nuciferine, 386, 409 orientalidine, orientaline (?), orientalinone (?), oripavine, oxysanguinarine, dihydroorientalinone (?), papaverrubine B, D, E, protopine, salutaridine, sanguinarine, thebaine, base (mp 239")
h. Section ScupiJora P . alboroseum Hulten P . alpinum L. ssp. burseri (Crantz) Fedde ssp. kerneri (Hayek) Fedde ssp. totricum Nyar
Alkaloid PO-5(alborine, Alkaloid R-K), mecambridine, papaverrubine C, D Alborine, alpinigenine, alpinine, alpinone ( 13-oxomuramine), amurensine, amurensinine, amurine, coptisine, cryptopine, mecambridine, muramine, papaverrubine B, D, E, G, protopine, sanguinarine, epialpinine, oxysanguinarine, others
400 336,337,386, 388a
if
2c
*.
P. anomulum FeddeC
P. nudicaule L. P. nudicaule L.,
336,337,401 Amurensine, amurensinine, coptisine, cryptopine, glaucamine, mecambridine, oxysanguinarine, papaverrubine C, D, G, pavanoline, prbtopine, rhoeadine, sanguinarine, and others 386 Papaverrubine B, D Amurensine, amurine, amuroline, amuronine, muramine 83,84
var. amurense N. Busch. Amurine, nudaurine 84 var. nurantiacum Loisel Amurine, muramine, 13-oxomuramine,protopine, amuronine 84,133,143 P. nudicaule L., var. croceum Ledeb 337 Amurensine, amurensinine, cryptopine, glaucamine, mecambridine P. nudicaule L., var. leiocarpum (oreophiline),oxysanguinarine, papaverrubine, protopine, rhoeadine (Turcz.) Fedde 336,337 P. nudicaule L., ssp. rubroaurantiacum Amurensine, amurensinine, amurine, amuronine, muramine, nudicaulinole, oxysanguinarine, papaverrubine, protopine, rhoeadine, (DC) Fedde rhoeagenine, sanguinarine, others 336,337 Amurensine, amurensinine, amurine, coptisine, cryptopine, P. nudicaule L., ssp. mnthopetalum mecambridine, muramine, oxysanguinarine, papaverrubine, (Trautv.) Fedde protopine, rhoeadine, sanguinarine, others Allocryptopine, amurensinine, coptisine, muramine, oxysanguinarine, 336, 337 P. pyrenaicum (L.) Kerner papaverrubine, sanguinarine, amurensine, others Amurensinine, coptisine, oxysanguinarine, papaverrubine, protopine, 337 P. suaveolens Lap. sanguinarine
P. nudicaule L.,
cn
i. Section Horrida P. aculeatum Thunb.
Aculeatine, coptisine, oxysanguinarine, papaverrubine, sanguinarine, others
195,337
The history of opium has been reviewed (270). Bognar et al. (80a)described the modified method of Kabay for the isolation of minor alkaloidscontained in the dry plant P. somniferum. c Plant probably identical with P. nudicaule L., ssp. xanthopetullum (Trautv.) Fedde, var. Zeiocarpum (Turc.), containing except for pavanoline ( $ 0 1 )the same alkaloids (337),which gives rise t o the question whether these two plants are not identical. a b
w
6
0
344
F.
~ANTAVP
De Dalla Torre and Harms (124)undertook a systematic classification of all the genera of the Papaveraceae. Fedde (140) [see Hegi (210)]subdivided the genus Papaver into the following sections : (a)Orthorhoeades, (b) Argemonorhoeades, (c) Carinatae, (d) Mecones, (e) Miltantha, ( f ) Pilosa, (g) Macrantha, (h) Scapiflora, and (i) Horrida. The plant family Papaveraceae consists of about 700 species which are classified in approximately 50 genera. 11. Occurrence
Table I1 is supplementary to the tables of plants and their alkaloids (see The Alkaloids, Vol. IV, p. 79; Vol. IX, p. 44; and Vol. X, p. 467). Table I1 lists all the recently investigated plants, the reinvestigated plants, and those where the already isolated alkaloids have now been examined for structure elucidation. The alkaloids listed in Table I1 can be grouped on the basis of their skeletons as follows : (A) benzylisoquinoline ( 1-benzylisoquinoline, 1-benzyltetrahydroisoquinoline,and N-benzyltetrahydroisoquinoline), (B) proaporphine, (C) aporphine, (D) promorphinane, (E) morphinane, (F)cularine, (G) pavine, (H)isopavine, (I)tetrahydroprotoberberine and protoberberine, (J) protopine (protopine, 13-oxoprotopine, and 13methylprotopine),(K)phthalideisoquinoline, (L)narceine, (M)rhoeadine (and papaverrubine), (N) benzphenanthridine (chelidonine, sanguinarine, oxysanguinarine, chelirubine, and corynoline), (0) ochotensimine, and (P) alkaloids of unknown structure. In addition to these groups of alkaloids, the plant Chelidonium majus contains (233, 443) sparteine, belonging to the group of quinolizidine alkaloids. The N benzyltetrahydroisoquinoline, proaporphine, promorphinane, pavine, isopavine, rhoeadine, corynoline, and the ochotensimine groups of alkaloids could be differentiated only recently. The importance of many of these groups of alkaloids contained in the plant family Papaveraceae has increased steadily because of their widespread distribution and great variety. Many alkaloids could not be isolated on account of their low basicity and high polarity. It was only by means of modern analytical and separation methods that they could even be detected in a large number of plant species, genera, and sections. Tables 111-IX, XI, XIV, XV, XVII, XVIII, XXI, XXII, and XXIV give the thus far isolated alkaloids of the plant family Papaveraceae. Pfeifer et al. (273, 385) have recently published a summary on the alkaloids of the genus Papaver. The separation by paper or thin-layer chromatography has been dealt with (87,382,425).A suitable method for
TABLE I11
BENZYLTETRAHYDROISOQUINOLINE ALKALOIDS ~~
Substituents at C or N Atoms Compound
2
( - )-Armepavine
CH3
( - )-Norarmepavinec ( - )-0-Methylarmepavined (
H CH3
6
7
8
OCH3 OCH3 H
OCH3 OCH3 H OCH3 OCH3 H
3’
H
H H
4’ OH
OH OCH3
+ )-7-Demethyl-O-methyl-
armepavined ( - )-7-Demethyl-O-methylJ armepavine ( f )-Coclaurine ( )-N-Methylcoclaurined (Aglycone of latericine) ( )-Codamine (-)-Corpaverine (Alkaloid F 24) ( )-Latericine ( )-0-Methyllatericined ( - )-Laudanidine (Tritopine) ( f )-Laudanine ( )-Laudanosine ( f )-Laudanosolined ( )-Norlaudanosolined ( )-Norlaudanosolined ( )-Orientalined
+ + + +
149
153 63 Amorphous
[@IDa
Absolute configurationb
- 119 (C)
R
-23 (C) - 78 (C) +81 (M)
S
120, 122,138, 142, 180, 267, 532, 551 120,278 406 406
-88(M)
R
528
-
153a, 268 272,406,528
OCH3 Amorphous
H CH3
0
+ 60 (C) + 120 (M) -
- 154 (C) +93 (E)
] CH3
-94 (C)
1
CH3 CH3
R
S S -
S S
OCH3 om3 H OH OH H
om3 OH
OH OH
OH
H
OH
OCH3 OH
H
OCH3 OH
OH CH3
S
.kl
s
Y P
0
OCH3 OH
CH3 CH3 CH3 CH3
+ + +
CH3
Melting point (“C)
References (constitution and absolute configuration)
89 194 282HCl 293HC1
0 52 (C) 0 +17e 0
130c
-53 (W)f
+
R S -
(R) -
(S)
115, 499 92, 241a, 316 406 406 115,120,142, 511 496 115, 120, 414 441 51 412 38, 49
2b &w &
8 m
W
bF. v1
TABLE III--continued
Substituents a t C or N Atoms Compound
+
( ) -Pseudocodamined ( -)-Retidine ( )-Reticuline(Coclanoline)
+ +
( )-Romneine ( )-Pseudolaudanined Sendaverineg
2 CH3
1
6
om3
7
8
OCH3 H
H CH3 0-CH2-0 H CH3 OH OCH3 H H Benzyl OCH3 OH CH3
OCH3 OH
3'
4'
Melting point ("C)
Amorphous 90 OCH3 87
[UID'I
OCH3 OH
+25(C)
OH
-55 (E) 0
OCH3 OCH3 OCH3 OCH3 H 0CH3
Oil 116 135
+37 E) +76 ((E) -
References (constitution and absolute configuration)
Absolute configurationb
R S (S) -
155 50,513
87
277a, 513,514 98 241,242,244
C, chloroform; E , ethanol; M, methanol; W, water. I n parentheses has been given the absolute configuration derived in this review based on the direction of the optical rotation. c Perchlorate. Alkaloid prepared only synthetically or not yet isolated from the Papaveraceae. e Hydrochloride in acetone-water 1 : 1. f Hydrochloride. 9 N-Benzyltetrahydroisoquinolinealkaloid. a
b
rr
2c
*\
5.
347
PAPAVERACEAE ALKALOIDS
preparative separation of the alkaloids of the Papaveraceae was reported by Slav& (479, 480). The countercurrent distribution of the alkaloids found in Chelidonium majus has been described (233).
III. Structures, Chemical and Physicochemical Properties, and Biosynthesis of the Papaveraceae Alkaloids A. BENZYLISOQUINOLINE GROUP* The finding that the majority of the Papaveraceae alkaloids arise from the benzylisoquinoline precursors reticuline, orientaline, and probably norlaudanosoline, by phenolic oxidation (30,40,137,148,353),has
I Papaverine type
I1 Armepavine (3' = H ; 4' = OH or OCH3)-Laudanosine (3', 4' or OCHa) type
I11 Sendaverine type = OH
aroused considerable interest in this field of relatively simple alkaloids. It was found that the N-benzyltetrahydroisoquinoline structure (111) has to be assigned (241)to the alkaloid sendaverine which consequently repxesents another type of benzylisoquinolinealkaloids besides the thus far known alkaloids of the papaverine (I)and armepavine-laudanosine (11) types. The absolute configuration of ( + )-norlaudanosine was elucidated by adopting a degradative method (isolation of N-a-carboxyethyl-L-aspartic acid) (115),which in turn permitted the establishment of the absolute configuration of the proaporphine, aporphine, promorphinane, morphinane, and tetrahydroprotoberberine alkaloids (Scheme 20). The optical rotatory data (63),the ORD-curves (2,41,120, 122), and the CD-curves (73) have led to an accumulation of sufficient information for the determination of the absolute configuration even of
* This material is supplementary to The Alkaloids, Val. IV, Chapter 28 and Vol. VII, Chapter 20. For the armepavine type of alkaloids see also Vol. IV, Chapter 33; Vol. VII, Chapter 21; Vol. IX, Chapter 4; Vol. X, Chapter 6.
348
F.
BANTAVP
those alkaloids of this series which, because of insufficient material, could not be determined by degradative methods. The recently isolated alkaloids are ( - )-, ( + )-, ( f )-reticuline, ( + )romneine, orientaline (?), and ( + )-latericine. The latter alkaloid was found to be (1S)-7cr-~-xylosido-7-demethylarmepavine (Table 111). The relative of papaverine having two methylenedioxy groups was also isolated and designated as escholamine (Table IV). Mass spectrometry (190, 364, 529) of the majority of tetrahydroisoquinoline alkaloids did not reveal a molecular peak. The main peak in the spectrum was that of the 3,4-dihydroisoquinolinium ion which corresponded to the rings A and B of the alkaloid under investigation. A similar TABLE IV OF THE PAPAVERACEAE BENZYLISOQUINOLINE ALKALOIDS
Substituents at C atoms Compound Papaverine Papaveraldine (xanthaline) Escholamine Palaudine
6
7
9
3'
Melting point
4'
("C)
Reference (constitution)
OCH3 OCH3 Hz OCH3 OCH3 0
OCH3 OCH3 OCH3 OCH3
210
185 186
0-CH2-0 Hz OCHs OCH3 H Z
0-CH-0 OH OCHa
Iodide266 176
490 88
148
phenomenon was observed (364) in the case of phthalideisoquinoline alkaloids (see Section 111,K). On the basis of NMR spectroscopic data (32, 76, 77, 87, 146, 271, 403, 406, 421, 514, 534, 535), the signals were assigned to the corresponding aromatic, aliphatic, NCH3, methylenedioxy, and methoxyl groups of reticuline, armepavine, laudanosine, romneine, corpaverine, and latericine. UV Spectroscopy showed (223)the effect of methoxyl and methylenedioxy groups on the position and extinction of the maxima at 240 and 280 nm ; the presence of a methylenedioxy group instead of two methoxyl groups brings about a decrease in the extinction of the maxima at 240 nm and an increase in the extinction of the maxima at 280 nm. A similar phenomenon is exhibited by all the alkaloids having one or two aromatic rings. The polarography of papaverine and its derivatives (341)and of the photolysis of papaverine (516) has been reported. The total synthesis of ( & )-N-norarmepavine,( f )-armepavine (420a), and ( )-romneine(514)was accomplished by standard reactions. N
N
N
5.
349
PAPAVERACEAE ALKALOIDS
B. PROAPORPHINE GROUP Shortly after Barton and Cohen (30,31,35)and Erdtman and Wachtmeister (137) put forward the hypothesis that the cyclohexadienone compounds, which are formed by phenolic oxidation* (26, 38, 40,154, 275,353, 445) from the corresponding benzylisoquinoline bases, are the precursors of the aporphine alkaloids, these structures were recognized in some known alkaloids (mecambrine)or they were isolated. At present we know a large number of proaporphines? (100) (Tables Va-Vc). Many of Proaporphine Types of Alkaloids Listed in Tables Va-Vc
-R3
R4 R6
Va
Vb
vo
R1, Ra, R3 = H or CH3 or R 1 + R2 = C& R4 + Ra = 0 or H + OH Re = H or OCH3
them were isolated from the plant genera Croton (Euphorbiaceae), Nelumbo (Nymphaeaceae), Stephania (Menispermaceae), Ocotea, and Neolitsea (Lauraceae) which do not belong to the family Papaveraceae. Since the proaporphine alkaloids have not yet been summarized systematically, we have included in Tables Va-Vc (and VII) all the known cyclohexadienone alkaloids of the proaporphine (and promorphinane) type. The general structures of these alkaloids are given on pp. 354 and 355. The above-mentioned families yield, beside the proper cyclohexadienone alkaloids (types I V and XIV, Schemes 1 and 2), their partially reduced derivatives (types V, VII, VIII, IX, and XII). The reduction involves either the ketonic group, which gives rise to two dienol isomers (VI and VII or XVIII), or it involves only one or both of the double bonds of the cyclohexadienone ring and the ketonic group doeslor does not remain intact (V and VIII). Provided that the cyclohexadienone ring
* The phenolic oxidation of tetrahydroisoquinolinebases has been reported by Franok et al. (148-150).
t Slavik ( 4 6 3 ) suggested the designation “mecambrane” for the skeleton of proaporphine alkaloids. Proaporphine alkaloids reviewed (70b, 5 1 9 ~ ) .
TABLE Va W
PROAPORPHINE ALKALOIDS DIHYDROPRO APORPHINES
Substituents a t C or N atoms Compound
1
Mecambrine (Fugapavine)
0-CH2-0
Crotsparine Glaziovine N-Methylcrotsparine Stepharine (
+ )-Pronuciferin (Base A)
(Milthanthine) ( - )-Pronuciferine
2
I
6 CH3
9
10
H
=O
179
H
=O
195,278b 237 225 182
H
=O
OCH3 OCH3 H
H
=O
OCH3 OCH3 CH3
H
=O
129
om3
Crotonosine Homolinear isine (L-( - )-N-Methylcrotonosine) D-( )-N-Methylcrotonosine ( - )-Orientalinone ( )-Orientalinone (Bracteine ?) Orientalinol-Id Orientalinol-IId
OCH3 OH
H
H
=O
OCH3 OH
CHI
H
=O
+
a
I
]
OH
OCH3 CH3
OCH3 CH3
0
Absolute configuration
[UlD"
- 116 (C)
S
- 30 (C)
S R (S) R
+7 (C) -113 (C) 143 (C) 155 ( E ) 991 (C) 106 ( E ) - 109 ( E )
+ + + +
R
References (constitution and absolute configuration)
76, 460, 463, 464, 493,552 75 181,530 75 70a, 100, 493
S
65-69,7Oa, 205, 208, 493 391
?
R
69
202 220
180 (M) -116 (M)
R S
206, 207,209, 493 205,207,208,493
218 186c 230 190 dec Amorphous
+'122 (M) -62 (C) 120 (E)
R
207,208,493 48,49,219,231 256 48,49 48,49
128
Pronuciferinol
+
Melting point ("C)
cn
?
+
+
C, Chloroform; M, methanol; E, ethanol.
* Hydrochloride.
CMp racemate 203Odec ( 4 9 ) ;orientalinone isolated fromP. bracteaturn (219),mp 232", d The compound has not been isolated from plant material yet.
[OL]D-76'
(C).
S R
r p'
3
5id.
TABLE Vb
PROAPORPHINE ALKALOIDS DIHYDROAND TETRAHYDROPROAPORPHINE ALKALOIDS
Substituents a t C or N atoms -
Compound Amuronine
1
2
6
9
H
Amuroline
10
=O /H \OH
8,9- (or 11,12-)-Dihydro-
170
193C
H =O H =O OCH3 =o H =O
Epiroemeramine
C, Chloroform; M, methanol. The compound has not been isolated from plant material yet. c 0,O-Diacetate. d 8,9-Dihydro-L-( - )-N-methylcrotonosine. C Dihydro derivative. b
132
145
Epiamurolineb N-methylisocrotonosinol Jacularine Linearisined Dihydroorientalinone Roemeronine Roemeramine
Melting point ("C)
/H \OH
174e 222 ?
131 67
211
[KID"
+ 124 (C) + 106 (C)
Absolute configuration
References (constitution and absolute configuration)
6aS, 7aR
70a,145, 493
6aS, 7aR, 10s
70a, 133,145, 493
+37 (C) 6aS, 7aR, 10R
133,145, 493
- 18 (M)'
203
-
- 122 (M)e 116 (M) 6aS, 7aR 50 (C) -167 (M) 6aR -93 (M) 6aR
+
+
-43(M)
6aR
520c 207-209, 493 48 483 483
483
TABLE Vc
PROAPORPHINE ALKALOIDS TETRAHYDROAND HEXAHYDROPROAPORPHINE ALKALOIDS
Substituents at C or N atoms Compound
2
1
6
10
O-CHZ-O
Litsericine
0-CHz-0
H
/H \OH
0-CHz-0
CH3
CH3
/H \OH
[a]Da
References (constitution and absolute configuration)
r
269 185
-38 (C) +53(E)
6aS 6aR
349 355
*
; c
Deoxo-N-methyllitsericinone Tetrahydroglaziovine
O-cHz--o 0-CH-0 OH OCH3
CH3 CH3 CH3
=O /H ,OH Hz -0
Oridine (Oreoline)
OH
H
\OH /H
I
("C)
Absolute configuration
ux
Tetrahydromecambrinole-b (L-( - )-cis-Hexahydrofugapavine) N-Methyllitsericine
N-Methyllitsericinone L-Tetrahydrofugapavine N-Methyllitsericinol I N-Methyllitsericinol I1
Melting point
OCH3
156 148 156 Amorphousb 258b 80 116 241
++
+ 67 (E)
6aR
355,356,530
+91 (E)
6aR
-
-
356,530 356 356 356 530 181
-88 (M)
6aS
288,431
-
-
+47 ( ? )
6aR
-
N-Methyloridine (N-Methyloreoline)
OH
0-Methyloridinec
OCH3
Dihydroamuronine
OCH3
Tetrahydropronuciferine Hexahydropronuciferine I N,O-Dimethyloridined Hexahydropronuciferine I I C Dihydroamurolined L-( )-Dihydrolinearisine D-( + )-N-Methyltetrahydrocrotonosine Tetrahydrostepharine Deoxotetrahydrostepharinec N,O-Dimet,hyldeoxohexahydrocrotonosine
]
+
/H \OH
/H \OH -0
OCH3
=O
OCH3
\OH
/H
OCHs
=O
OCH3 OCH3
=O Hz
OCH3
Hz
193
-
-
288, 3950, 431
132
-
-
3950, 431
-40 (C) - 23 (M)' +52 ( 9 )
6aS
126 244e 126 254 (HC1) 184 208 ( H a ) Amorphous 227 228 122
235e
-49 (C)
- 15 (C) -61 (M) 59 (M) 105 ( ? )
+
+
-
+ 2 , 3 (M)
-
6aR 6aR 6aS 6aR 6aS 6aS
145 145 530 69,133 431 69
133 209
-
209
6aR -
530 530
6aR
203
C, Chloroform; M, methanol; E, ethanol. N-Methyllitsericinol I acetate, mp 152' ; N-Methyllitsericinol I1 acetate, mp 149'. The compound has not been isolated from plant material as yet. d N,O-Dimethyloridine and dihydroamuroline show that the position of the hydroxyl group at the (2-10 atom is reversed (N,O-dimethyloridine-axial, dihydroamuroline-equatorial). e Methiodide. Q
rn
b
w Ql w
R20 /
-R3
R
1
O
p -R3
@
HO
0
V Dihydroamuronine type
IV Mecambrane type
VI
VII Pronuciferinol type
5. PAPAVERACEAE ALKALOIDS
XI1 Ammline type
SCHEME 1. Formation, rearrangement, and reduction of proaporphine bases. R1, R2, R3=H or CH3.
355
XI Epiamuroline type
356
F.
~ANTAVP
carries a methoxyl group (type XIV), the correspondingstructure in fact represents two diastereomers, one having the methoxyl group of ring C below the general plane of rings A, B, and D and another having ring C reversed so that its methoxyl group lies above this plane. Reduction of the double bond of ring C also results in hydrogenolytic cleavage of the methoxyl group of the ring C. Consequently we may add other groups of substances to the proper proaporphine alkaloids which were listed in Tables Vb and Vc. When the keto group of the compounds listed in these Tables is also reduced, the corresponding hydroxyl group may be located either in the axial or the equatorial position (IX and X ; X I and XII). Bernauer (69)carried out a detailed analysis of similar compounds on the basis of the NMR spectra. The compoundshaving one intact double bond (type VIII) (Table Vb) may form two pairs of derivatives of different relative configuration (Scheme 1 ) . Snatzke and Wollenberg (493)deduced from the signs and the position of the circular dichroism bands of various proaporphine alkaloids the absolute configuration of those substances having one double bond in ring C. The signs of the Cotton effects of the aromatic bands are not only dependent on the configuration but also on the type of substitution. From the circular dichroism data the configuration of linearisine at the spiro atom C-7a is shown to be (7aR). By the same method the conformation of the enone and dienone chromophores of these alkaloids were deduced. On reductive cleavage (100)with sodium in liquid ammonia the proaporphine alkaloids with dienone structure are converted into benzylisoquinoline bases (IV -+ I; XIV -+ XIII). By treatment with N-hydrochloric acid the dienone alkaloids are transformed (69, 349) into the aporphine alkaloids (Schemes 1 and 2 ) by dienone-phenol rearrangement (IV -+ 11; XIV + XV, XVI, and XVII). Substitution of the proaporphine base at C-9 by a methoxyl function involves rearrangement which gives rise to two isomers, i.e., XV and XVI. On the other hand, by reduction of dienone with sodium borohydride (formation of two dienols) and following treatment with hydrochloric acid these dienols are converted (65,66,68,69,349)into the aporphine alkaloids with formation of a new aromatic ring (VI and V I I --f I11; XVIII + XIX and XX). The reduction with borohydride and the acid-catalyzed dienonephenol/dienol-benzene rearrangements leave the center of chirality at C-6a intact. Consequently, the absolute configuration of this center can be intercorrelated with that of the benzylisoquinoline, proaporphine, and aporphine alkaloids (Schemes 1 , 2 , and 20). Oxidation of a number of benzylisoquinoline bases followed by the dienone-phenol or dienol-benzene (after reduction with borohydride) rearrangement has afforded several aporphine bases (27, 28, 49, 96, 229,
H3CO / H
HO
xv
O
\ OCH3 XVI
H&O
-cH3
P 4H3
H3C
\ OH XVII
SCHEME 2. Formation and rearrangement of 9-methoxyproaporphines.
H
/ O
P 4H3
OCH3 XIX
358
F.
~ANTAVP
231, 250, 451). The oxidizing agents (353) are usually ferricyanide in alkaline medium (49,148)or ferric chloride in aqueous ammonium acetate (neutral or acidic solution) at room temperature. Franck and Tietze (150) obtained high yields (50-60%) of aporphine from laudanosoline or norlaudanosoline by using high concentration of Fe(II1) chloride as oxidizing agent and a chelating agent to hinder the formation of o-quinone
Hop 4q OCHs
HsCO
** H
3
(7aS)
(4
(0)
FIG.1. Octant projections and predicted signs of the Cotton effects of the two possible pairs of conformations of (7aR)-and (7aS)-linearisine;(a)correspondsto natural linemisine [according to Snatzke and Wollenberg (493)l.
as intermediate. Thus the authors draw attention to the simplest synthesis of glaucine. Mass spectrometry (22, 96,181, 530,531) and NMR spectroscopy (65, 69,181,209,431)have been recorded. The UV spectra of the dienone alkaloids differ in the extinction maxima (proaporphine alkaloids at 220 nm (c 24800) and 285 nm (c 3000); promorphinane alkaloids 230 nm ( e 24,000) and 285 nm (c 7500)). IR Spectroscopy reveals characteristic frequencies of the cross-conjugated dienone at 1655, 1630, and 1613 cm-1. On polarography the proaporphine and the promorphinane dienone compounds are reduced (335)at a half-wave potential similar to that of aromatic aldehydes.
-
N
-
-
N
-
TABLE V I APORPHINE ALKALOIDS
Substituents at C or N atoms Compound
1
2
6
Anonaine ,4porheine (roemerine) Bracteoline Bulbocapnine Corydine (glaucentrine)
0-CHz-0 0-CHz-0 OH OCH3 0-CH-0 OH OCHI
Corytuberine Dicentrine (eximine) Domesticine
OH ocH3 CH3 0-CHz-0 CH3 OH OCH3 CH3
Domestine (nantenine) Glaucine Isoboldine Isocorydine (artabotrine, luteanine) Isothebaine ( )-Mecambroline (isofugapavine, isofungipavine) ( - )-Mecambroline Nuciferine
+
Nuciferoline
H H OCH3 H H
10
H OCHs O H OCH3 OCH3 H 0-CHz-0 H
240 169 117
+282 (?) + 6 2 (C) +60(?)
s
(S)
23,27 460 220 168 231, 452, 497 497 497 200 259
CH3 OCH3 OCH3 CH3
0-CHz-0 H OCH3 OCH3 H
139 120
+ l o 1 (?) +114 (E)
(S) S
259 161,229, 451,497
OH OCH3 CH3 OCH3 OCH3 CHz
OH H
OCH3 H OCH3 O H
128 186
- 114 (E)
(R) S (S)
184, 229,451 229,527 497
OH
H
H
OcH3
(S) (S)
47, 64,260 463
CH3
H
OH
H
(R)
OCH3 CH3
H
H
H
OCH3 OCH3 CH3
H
OH
H
204 + 2 8 5 (E) 145 + 7 6 (C) (253) 234 -77 (C) 167 + I 6 5 ( E ) -157 (E) 214 - 1 5 4 ( E )
70 391 6,121 390
0-CHz-0
OC&
H H H OH OCH3
[OL]D~
Refemnces (constitution and absolute configuration)
-52(C) + S O (E) +35(C) +237 (C) +205(C) - 205 (C)
OCH3 CH3
H H OH OCH3
11
Absolute configuration*
123 103 221 199 149
I
H CH3 CHI CHI CHI
9
Melting point ("C)
+ 6 5 (C) +195(C)
-
(S) (S)
S
(S) (R) (S)
(S)
R (R)
P Cd
ti P c
8 kM
k
k El
w 01 CD
W Q)
0
TABLE VI-continued
Substituents at C or N atoms Compound
1
2
0-Demethylnuciferine (1-hydroxy-OH OCH3 2-methoxyaporphine) 0-CHz-0 Roemerine Roemeroline 0-CHz-0 Rogersine (N-methyllauroOCH3 OCH3 tetanine) Magnoflorine OH om3 H H Apomorphine HCle
6
9
10
11
or]^"
Absolute configurationb
215
-
-
404
-80 ( E )
(R)
23,27 483 370
CH3
H
H
CH3 CH3 CH3
H OH OH
H H H H OCH3 H
103 231 224c
OCH3 O H OH OH
249d -214(M)d
-
-
R
(CH3)2 H CH3 H
H
References (constitution and absolute configuration)
Melting point ("C)
?
+73 (E)c
-
R -
354 121
C, Chloroform; E , ethanol; M, methanol. The absolute configuration, derived in this review on the basis of the direction of the optical rotation, has been given in parentheses. c Hydrobromide. d Hydroiodide. e The compound has not been isolated from plant material yet.
a b
5.
36 1
PAPAVERACEAE ALKALOIDS
C. APORPHINE GROUP The aporphine alkaloids have been previously reviewed in this series* and there has also been published a summarizing report (450).Therefore, only a tabulation (Table VI) of those bases which were isolated from the Papaveraceae and their photochemical synthesis, the characteristic Pellagri reaction, the physicochemical data, and the biosynthesis are given.
Oxidation product of Pellagri reaction
Liriodenine
H
H
-
-CH3
0
OH-
t
H+
H&O
0/
Alkaloid PO-3
The dehydroaporphane compounds arise easily from the corresponding 1 -benzyl-3,4-dihydroisoquinolineor 1 -benzylidene-1,2,3,4tetrahydroisoquinoline compounds by photochemical synthesis (99,546). Toward the end of the last century Pellagri (373)reported the color reaction of morphine alkaloids. He observed that this reaction proceeds via the resultant aporphine. Later on the results showed that this reaction is also characteristic for some other aporphine (407) alkaloids. Thus, for example, isothebaine oxidized by air-oxygen affords the green alkaloid PO-3. The reaction is often utilized in connection with paper and thin-layer chromatography. Recently, a study of the oxidative character (136, 160, 191, 211, 252, 260, 284a, 371, 407, 417a) of the Pellagri reaction and of the reaction mechanism leading to products of
* This material is supplementary to The Alkaloids, Vol. IV, p. 119 and Vol. IX, p. 2.
362
B.
BANTAVP
the quinone type was carried out. The first step of the carefully controlled oxidation affords the 6,7-didehydroaporphine derivative (dehydroaporphane) and it is only in the second step that all these alkaloids having a phenolic group at C-1 or C-11, and at C-10 and C-11 produce the quinoid compound of green color. Only these compounds are able on oxidation to produce a derivative which can form the zwitterion accounting for the green coloration. The compounds having the phenolic groups a t C-1 and C-2, or at C-1 and C-9 also tend to produce a quinoid structure but the product does not develop a green coloration. Oxidation of the aporphine alkaloids with chromium trioxide in pyridine results in demethylation of the tertiary nitrogen, aromatization of the heterocyclic ring, and formation of the keto group at C-7 ; there also arise compounds of the liriodenine type of alkaloids (526)which have not yet been found in plants of the Papaveraceae. The mass spectrometric data have been adequately dealt with (96,181, 230,364,452,530),as have the NMR spectroscopic data (17,18,77,106, 181, 205, 208, 231, 370, 451, 537), the UV spectroscopic data (223, 422, 448, 450), the absolute configuration (loo),and the ORD-curves ( 2 , 63, 115, 121, 125, 448, 449). The biosynthesis of aporphine alkaloids takes the course-laudanosoline, norlaudanosoline, reticuline, or orientaline-by means of phenolic oxidation via the cyclohexadienone proaporphine (27,28,3 9 , 4 0 , 4 7 , 4 9 , 65, 66, 68, 69,147, 148,150, 229, 231, 240, 250, 275, 349, 445, 451, 512) after dienone-phenol or dienol-benzene rearrangement, as described in more detail in the preceding section. The foregoing results, considered as a whole (39,49),provide good evidence that isothebaine is biosynthesized in P . orientale along the following pathway : (+)-Orientdine -+ (-))-Orientalinone --f (9)-Orientalinol + + (+)-Isothebaine
D. PROMORPHINANE GROUP* Similar to proaporphine bases which are intermediates in the biosynthesis. of the aporphine alkaloids, the promorphinanes, having a cyclohexadienone ring D, form an intermediate in the biosynthesis of the morphinane alkaloids. They also arise from benzyltetrahydroisoquinoline bases by phenolic oxidation. The first known alkaloid of this group was salutaridine (36)(first isolated from Croton salutaris) (see Scheme 3 ) which in all probability is identical with the already known floripavine
* In this review, the term promorphinane compounds has been used for those bases which have no ether bridge between the rings A and D of the morphinane skeleton. These compounds were found to occur both in the Papaveraceae and the Menispermacem.
TABLE VII
PROMORPHINANE ALKALOIDS
Substituents a t C or N atoms Compound
2
3
4
6
7
13
Melting point ("C)
Salutaridine (floripavine)
+111 ( E ) 9R 104 (AA) -112 ( E ) 9s
+
Sinoacutine (enantiomer of salutaridine) Norsinoacutine Salutaridinol-I
-107 ( E ) +42 (AA)
Salutaridinol-IIb 8,14-Dihydrosalutaridine 8,14-Dihydronorsalutaridine 8,14-Dihydrosalutaridinolb 5,6; 8,14-Tetrahydrosalutaridinolb Amurine Nudaurine (amurinol-I) Flavinine Flavinantine Isosalutaridine
[Or]D"
Absolute configuration
+29 (AA) -76(M) -69(M)
-
0-CH2-0
H
O m 3 OH H OCH3 OH H OH OCH3 H
OC&
a
C, Chloroform; E , ethanol; M, methanol; AA, acetic acid.
c
0-acetyl derivative.
* Alkaloid prepared only synthetically.
36,409 34,114,224
9s 104,520 7R, 9R 2 9 , 3 3 , 3 6
7S, 9R -
-20(M) + 9 (C)
9R
-
29, 33,36 204,205 204 204 204 83, 133a, 144, 234b,
CH3
202
-52 (C)
335,493 7R, 9R 33, 83, 84, 133a, 493
H CH3 CH3
132 132 203c
-6 (E) -l4(E)
9R 9R
OCH3 =O OCH3 =O OCH3 =O
References (constitution and absolute configuration)
-
-
520 104" 149
? w
k
% 8 hM L
kE
2 ? I. _
364
F.
SANTAVP
(269).I t s enantiomer is sinoacutine (34, 114, 224) which was isolated from Sinomenium acutum Rehd. e t Wils. whence sinomenine had been isolated and identified (188).The promorphinane structure of amurine (144) (from genus Papaver) and flavinine (520)(from Croton Jlavens L.) was also recognized. Salutaridine has the oxygen substituents in ring A located a t C-3 and C-4 whereas amurine and flavinine have them a t C-2 and C-3. I n addition t o these alkaloids, the above-mentioned plant material yielded in ring D partially hydrogenated products (salutaridinolI and amurinol-I) and the secondary bases (Table VII and Scheme 3). The promorphinane compound (isosalutaridine) had already been prepared (149) by oxidative coupling from reticuline. Mass spectrometry (542)and NMR spectroscopy (133a, 204, 520) have been recorded. The UV spectra show two maxima a t 230 nm ( E 24,000) and 285 nm ( e 7500) (see also p. 358). The dienone alkaloids of the promorphinane type exhibit characteristic frequencies (cross-conjugated dienones) at 1670, 1640, and 1625 cm-1 in the I R spectrum and they are polarographically readily reducible (335).The absolute configuration (52) of these promorphinane derivatives has been established (29).It was shown that, on reductive cleavage with sodium in liquid ammonia and following methylation, O-methylsalutaridine afforded laudanosine. From the CDcurves (493) of ( - )-sinoacutine, ( + )-amwine, and ( - )-nudaurine, the absolute configuration of the recently isolated alkaloids of this series could be derived. On the basis of the absolute configuration of salutaridinol-I (29),the absolute configuration of amurinol-I (nudaurine) and amurinol-I1 could also be determined (33). Reticuline labeled with tritium was used in experiments to show (29) that thebaine (and consequently also codeine and morphine) arises from ( - )-reticuline, which is in agreement with the known absolute configuration of these morphinane bases. I t s intermediate is salutaridinol-I (not its epimer 11)where the absolute configuration of the hydroxyl group was determined by isolation of L-glyceric acid (after degradation).
-
-
-
E. MORPHINANEGROUP The group of morphinane alkaloids has already been discussed in detail in previous Volumes of The Alkaloids (Vol. 11,Chapter 8-1; Vol. 11, Chapter 8-11; Vol. VI, Chapter 7). Furthermore, there appeared a monograph (62) and two reviews (134, 182) on this problem, and the chemistry of the stereoisomeric sinomenine was dealt with in a book (188). Therefore, in this chapter only a tabulation (Table VIII) of the known bases and the biosynthesis of the morphinane alkaloids in the genus Papaver are given.
365
5. PAPAVERACEAE ALKALOIDS
Morphine Codeine 10-Hydroxyoodeine Codeinone
R1= R1= R1= R1=
OH, R 2 = OH, R3 = H OCH3, R2 = OH, R3 = H OCH3, R 2 and R3 = OH OCH3, + H = 0, R3 = H
Oripavine Thebaine
R R
Neopine
=H = CH3
TABLE V I I I
MORPHINANEALKALOIDS OF
Compound Codeine 10-Hydroxycodeine Codeinone Morphine Neopine (8-codeine) Oripavine Pseudomorphine Thebaine (paramorphine)
THE
FAMILY PAPAVERACEAE~
Melting point ("C) 167 207
[alDb
- 137 ( E ) - 132 ( E )
186
- 205 ( E )
254 127 201 237 193
- 131 (M) -28 -212 -115 -219
(C) (C) (HC1) (E)
a The papers dealing with the elucidation of the constitution and the relative and absolute configuration constitute Vol. VI, Chapter 7 of this series. The absolute stereochemical relationship between morphine, benzyltetrahydroisoquinoline, aporphine, and tetrahydroprotoberberine alkaloids has been determined (63). b C, Chloroform; E, ethanol; M, methanol.
366
F. QANTAV+
The mass spectrometry of morphinane alkaloids (including sinomenine and salutaridine) ( 9 , 285, 525, 542)) the NMR spectroscopy (37))the ORD-analysis (116),and the polarography (423)have been recorded. Labeled compounds were used in order t o study the biosynthesis of morphinane alkaloids (29,36,38,39,44,45,46,51,52,56,58,80,91,204, 255, 263, 265, 275, 280, 416, 417, 512, 517). These experiments showed that ( + )-isothebainearises from ( + )-orientaline [via ( - )-orientalinone] in P. orientale, whereas thebaine comes from ( - )-reticuline (39,52): Two sets of P . orientale plants were fed separately, one with doubly labeled orientaline and the other with 3-14C-reticuline. The former batch of plants afforded radioactive isothebaine (1.6% incorporation) and negligibly active thebaine ( < 5 x 10-4y0 incorporation) whereas the latter batch gave a reverse result. From these, the thebaine was active (0.2% incorporation) and the isothebaine was virtually inactive ( < 7 x lO-4% incorporation).Clearly both alkaloids are being biosynthesized at the time of these experiments and the results show that no significant conversion of isothebaine into thebaine occurs. These experiments also demonstrate that biosynthesis in the oriental poppy is directed to different final skeletons at least in part by 0-methylation (39).
Experiments carried out with labeled compounds did not prove conclusively that orientaline and norlaudanosoline (51)were the precursors of morphinane bases. A special problem is the conversion of thebaine to codeine and thence t o morphine or the reverse. The N - and 0-methyl groups of these compounds originate from methionine (351)whereas formate has proved t o be less effective. It may be assumed that in the first step of biosynthesis morphine is formed from reticuline which is further methylated into codeine and thebaine. Experiments with radioactively labeled codeine and morphine have shown, however, (255,332,351)that codeine can be demethylated to morphine in poppy leaves but that morphine under these conditions cannot be methylated to codeine (263, 265, 517). Investigation of the degree of incorporation of 1% carbon dioxide (417) and 2-14C-tyrosine(416)into morphine (46),codeine (280),and thebaine (44)has shown that in the beginning thebaine had the highest degree of labeling, followed by codeine and morphine. After a few days, the situation was reversed, i.e., morphine was labeled more than codeine and thebaine. From this it can be concluded that thebaine is formed first and is then transformed into codeinone (80, 91))codeine, and morphine, as had already been shown to be true for the codeine-morphine pair (44). Finally, P . somniferum was shown to be capable of transforming radioactively labeled thebaine into labeled codeine and morphine, whereas radiocativity from codeine and morphine could not be transferred to thebaine (517).These results indicate that thebaine (44)is formed first on the biosynthetic pathway to morphine (46) and that thebaine is then demethylated to codeine (280)and morphine.
T
x 0''
I
\ /"'
0 u, x
0'
I
X
(14a
8-
d
6
#
5. PAPAVERACEAE ALKALOIDS
I
x"
u
367
368
F.
~ANTAVB
The stereochemical relationship between ( - )-reticuline and morphine during biosynthesis has already been dealt with in connection with the promorphinane bases (52). The intermediates of the biosynthesis of morphine have the same R-configuration on the tertiary C-9 atom to which nitrogen is attached. Consequently, the biosynthesis of morphine proceeds along the following pathway (see Scheme 3) : Tyrosine + (+)-Norlaudanosoline (?) + (-))-Reticdine + (+)-Salutaridinol-I+ Thebaine + Codeinone --f Codeine + Morphine
Thus far, the role played by 10-hydroxycodeine (isolated from P. smniferum) in this biosynthetic pathway is still obscure. I n P. smnniferum the biosynthesis of morphine can also proceed from ( + )-reticuline provided that this compound is first transformed into ( - )-reticuline. The biosynthesis is, however, impossible (via thebaine) from ( f )-reticuline methochloride (52). I n the plant family Papaveraceae, morphinane alkaloids were found only in some sections and species of the genus Papaver. The occurrence of thebaine was observed in the sections Orthorlpeades, Mecones, Pilosa, and Macrantha whereas morphine and codeine were found only in P. smniferum and P. setigerum (Section Mecones). It follows that not all Papaver species are capable of demethylating and hydrogenating thebaine to codeine and morphine.
F. CULARINE GROUP* Another of the known alkaloids of this group (cularine, cularidine, and cularimine) is cularicine, whose isolation and constitution have been recorded (318).Table I X summarizes some properties of these alkaloids. The center of chirality of the cularine alkaloids is located at C-1 (73). The ORD- and CD-curves of these compounds indicate that, contrary t o benzyltetrahydroisoquinoline alkaloids, the cularine alkaloids having a positive optical rotation a t the D-line possess the R-configuration. Due t o inhibition of rotation of ring C, the Cotton effect a t 290 nm has a reversed maximum contrary to the short-wavelength Cotton effect which does not show any changes in comparison with that of the benzyltetrahydroisoquinoline alkaloids (120).A similar effect is encountered (73)in the case of I (Scheme 4) and the 1-(4’,5’-dimethoxy-2’-hydroxybenzy1)-7methoxy-N-methyltetrahydroisoquinolinewhere the rotation of the corresponding ring C is hindered by the phenolic or methoxyl group in position C-8 or C-2’. The cularine alkaloids may be assigned three different conformational formulas; on the basis of the NMR data the spatial *This material is supplementary to The Alkaloids, Vol. IV, Chapter 34; Vol. X, Chapter 7.
TABLE I X CULARINE ALKALOIDS AND SOME OF THEIRPROPERTIES
Substituents at C or N atoms Compound ( ( ( (
+ )-Cularine + )-Cularicine + )-Cularidine + )-Cularimine
2 CH3 CH3 CH3 H
7 OCH3 OH OH
ocH3
4'
5'
OCH3 OCH3 0-CH2-0 OCH3 OCH3 OCH3 OCH3
Melting point ("C) 114 185 156
102 (142)
[UID"
+ 285 (M) + 295 (C) + 295 (C) +259 (M)
Absolute configuration
R
R R R
References (constitution and absolute configuration)
73,239a, 245,247 318 318,319 234, 245-249,305,313
b
49
b M
k sU m
a
C, Chloroform; M, methanol.
370
F.
SANTAVP
arrangement of cularine may be formulated as I V (73). The mass spectrometric fragmentation of cularine has been described (96).
OH
OH
R1oYRz HO
0
~
4
0
IV
I11
SCHEME 4. Biosynthesis of cularine alkaloids. R' = R 2 = H or Me; R3, R4=H, CH3 or R3f R4= CH2.
The biosynthesis of cularine alkaloids (239)by phenolic oxidation also proceeds via the dienone compound (Scheme 4) similar t o the aporphine or morphinane alkaloids. The cularine alkaloids appear to occur only in the genera Corydalis and Dicentra.
G. PAVINE GROUP* After a short period (253,437,449,494),during which argemonine was ascribed the aporphine structure, i t was recognized (330, 515) on the basis of NMR-analyses (Table XI), that this alkaloid has a symmetrical molecule and consequently the skeletal structure which was reported earlier for pavine by Schopf (439)and then by Battersby (42).By degra-
* This material is supplementary to The Alkaloids, Vol. IV, p. 34 and Vol. X, p. 477.
TABLE X
PAVINE ALKALOIDS Substituents at C or N atoms Compound
2
3
7
8
9
Argemonine OCH3 OCH3 H OCH3 OCH3 (N-met,hylpavine) OH OCH3 H OCH3 OCH3 Norargemonine Isonorargemonineb OCH3 OH H OCH3 OCH3 Bisnorargemoninec OH OH H OCH3 OCH3 Rotundined 2 OH and 2 OCH3 Eschscholtzine 0-CHz-0 H 0-CHz-0 (crychine, californine) 0-CHz-0 H 0-CH2-0 Californidine
Eschscholtzidine Caryachinec Munitagine Platycerine 0-Methylplatycerine (identical with 0,Odimethylmunitagine)
0-CHZ-0 H OCH3 0-CHz-0 H OCH3 OCH3 O H OH OCH3 3 OCH3 and 1 O H OCH3 OCH3 OCH3 OCH3
OCH3 OH H
H H
13
Melting point (“C) 155 238 177 254 245 128 286 326 Oil 175 169 132 125
[alDu
- 188 (C) - 214 ( E ) - I54 (C) - 266 (M) - 266 (M) - 202 (M) -212 (iodide) -217 (perchlorate) - 194 (M) - 270 - 239 (C) - 267 (C) - 292 (C) -202 (C)
C, Chloroform; M, methanol; E, ethanol. The compound has not been isolated from plant material. c The position of the phenolic and methoxyl groups on rings A and B can be reversed. d On methylation with diazomethane this alkaloid yields argemonine. a 0
Absolute configuration
References (constitution and absolute configuration)
6s. 125 2 4 , 4 2 , 1 0 5 , 330, 333, 334 6S, 1 2 s 24, 105,519 519 6S, 1 2 s 2 4 ,1 0 5,495 253 6S, 125 2 4 ,1 0 5,175, 328 484
6S, 1 2 s 24, 105, 327 6S, 1 2 s 24, 284 6S, 125 2 4 ,1 8 3,518 480 183, 518 480
1
\
P
\ XI11
XI1
SCHEME 5. The structural elucidation of alkaloids of the argemonine (R1,R z ; R3, R4=OH, OCH3, or OCH20; R5=H) and the munitagine (R1, R3; R4, R5=OH, ocH3, or OCHzO; R3=H) type.
W 4 W
TABLE X I OF SOME PAVINE ALKALOIDS~ NUCLEAR MAGNETIC RESONANCE SPECTRA
Compound (References) ( - )-Argemonine (328, 518) (I)
( - )-Norargemonine (518) (11) ( ) -1sonorargemonine ( 5 1 8 ) (111) ( - )-Bisnorargemonine (518)b(IV) Esohscholtzine (328) (V)
Aromatic protons a t positions ~ _ _ _ 1 4 7 10
3.34 (3.30)
3.51 (3.52)
3.34 (3.30)
3.51 (3.52)
3.38 3.58 3.38 3.58 (3.44) (3.55) (3.27) (3.50) 3.53 3.53 3.41 3.41 (3.30) (3.64) (3.29) (3.49) 3.60 3.58 3.37 3.43 (3.47) (3.55) (3.32) (3.67) 3.42 and 3.60 Two singlets
Other protons _ ~~
Ha
Hb
5.92 Jab=6.0 Jac=O Doublet
6.47 6.58 Apeir of doublets
Hc
7.38 17
-OH -
Jcb=
Jac=O
Doublet
6.07 6.51 7.52 J c b = 17 6.78 Jab=6.0 Jac =0 TWO pairs of J a c = 0 Doublet Doublet doublets
-
-0CHa
-0CHzO-
-NCHs
6.08 6.16 Two singlets
-
7.43 Singlet
-
-
-
-
4.19 4.23 A pair of doublets
7.51 Singlet
r
r 3
5*\
5.66 Jab = 6 Jac=O Doublet 5.99 Jde = 6 Jdf=0 Doublet, part hidden 5.62 ( - )-Munitagine (518) (VII) 3.40 3.59 3.38 3.52 (3.47) (3.54) Jab = 6 J=8 Jac = O Pair of doublets Doublet (3.31) (3.61) 6.07 Jde = 6 Jdf=O Doublet
0,O-Dimethylmunitagine (518)(VI)
a b
3.39 3.54 3.29 (3.35) (3.49) (3.28)
3.29 (3.28) Singlet
6.45 6.73 Jde= Jbc = 6 Jbc= Jef = 17 Pair of doublets
6.49 6.77 Jab = Jde = 6 Jbc= Jef = 17 Pair of doublets
7.37 Jbc=17 Doublet
-
6.06 6.15 6.20 6.23 Four singlets
-
7.44 Singlet
-4.0 Broad singlet
6.18 6.24 Two singlets
-
7.47 Singlet
7.37 Jet= 17 Doublet
7.31 Jbc=17 Doublet (Pad under NCH3) 7.44 Jet= 17 Doublet
Chemical shifts are quoted in r units. Values are given in deuteriochloroform, those in dimethyl sulfoxide are in parentheses. A few drops of dimethyl sulfoxide-de was added to the deuteriochloroform solution to increase solubility. W
4
cn
376
F.
GANTAVP
dation (1,328,331,449,484,495)(Scheme 5) and UV spectroscopy, the pavine structure of argemonine and those of the alkaloids eschscholtzine, eschscholtzidine, and californidine (Table X ) were confirmed. A specific product of pavine alkaloids is 3,4 ; 7,8-dibenzocyclooctatetraene (VII, Scheme 5) which arises in the second step of a Hofmann degradation. This compound shows characteristic UV spectra (42,328,429,484,518).The UV spectra of the pavine alkaloids resemble (222)those of benzyltetrahydroisoquinoline alkaloids. Independently Soine et al. ( I ) and Slavik (484) reported that on Hofmann exhaustive methylation procedure (Scheme 5) the generated compound VI is easily rearranged with halogen acids t o provide dibenzocycloheptatriene derivatives VIII and I X , which on dehydrohalogenation yield the l-methylene-2,3;6,7-dibenzoheptatriene derivative XI ;the latter is also obtained on Hofmann degradation of isopavine alkaloids (61,429)(Tables XI1 and XIII). Isolation of argemonine (437)in the absence of mineral acids showed that this compound is no artifact arising from treatment during isolation, from which it follows that argemonine does not result from N-methyl1,2-dihydropapaverine. I n addition to the completely symmetrical pavine alkaloids, Stermitz et al. (518) found other pavine alkaloids of munitagine type (Tables X and XI) in Argemone munita, spp. rotundata. The location of the substituents of the two aromatic rings was determined on the one hand by the classic chemical method, i.e., isolation of hemipinic (IIb) and metahemipinic (IIa)acids after alkaline oxidation of 0,O-dimethylmunitagine and, on the other, by NMR analysis; oxidative degradation of argemonine resulted only in metahemipinic acid (IIa)and its methylimide (111), respectively. The mass spectrometry of pavine alkaloids has been recorded (127, 311,328,330,484,518,533).The absolute configuration of ( - )-argemonine (SS, l2S), ( - )-eschscholtzine, and of related alkaloids was elucidated by correlating ORD- and CD-curves (103,105,333, 334) and then particularly by exhaustive ozonization of desargemonine (IV) and isolation of L-aspartic acid (24). The synthesis of pavine alkaloids proceeds by acid-catalyzed rearrangement of N-methyl- 1,2-dihydropapaverine compounds. Under suitable conditions, 1,2-dihydropapaverine gives rise to pavine. However, some 70 years elapsed before N-methylpavine was proved t o be a racemate corresponding t o argemonine. Satisfactory methods were developed for degradation and synthesis of these bases by Soine and Kier ( I ,253,331), Soine et al. (272a),Battersby et al. (24, 42, 328), and Stermitz and Sieber (519).The biosynthesis of ( - )-argemonine is assumed (32) to proceed via ( + )-reticuline.
TABLE XI1
ISOPAVINE ALKALOIDS Substituents at C or N atoms Compound
2
6
7
3'
4'
Melting point ("C)
[alDa
References
ur Amurensine Amurensinine
CH3 CH3
~ H Z -
Isopavinec
H
CH3
cH3
Remreflne
(cH3)2
CHS
CH3
-CHz-
Reframine
CH3
CRs
CH3
-CH2-
Reframidine
CH3
-CH2-
-cH2-
Reframoline
cH3
H, CH3
-CHz-
4H2-
C, Chloroform; M, methanol; W, water. See Pfeifer and Thomas (401). c The compound has not been isolated from plant material. d Chloride. e Iodide. f Methiodide. a
b
H , CH3 CH3 CHs CH3
CH3
215 164 146b 151 (175) 242d 244e Amorphous 266f Amorphous 225f Amo~hous
- 178 (M) - 162 (C)
429 429
Racemic
61
- 147 (W)
129, 550
- 146 (M)
129,483
- 123 (M)
129, 483
- 140 (M)
129,483
d
Em c
M
TABLE XI11 CHEMICAL SHIFT DATAF O R THE PROTON RESONANCES OR AMURENSINE, AMURENSININE, AND RELATED C0MPOUNDSa.b
H Compound
H
\c=c / "\ CHZ =CHZ / \ /
Aromatic H
Amurensine (1)C.a
3.30 3.42 3.47
Amurensinine (1I)Csa
3.27 3.37s 3.47
I
(IIIa) 3.23 3.24 N-Methylamurensininemethinec (IIIb) 3.26 3.29 Dihydro-N-methyl-(Va) amurensinine 3.2 1-3.4Oh methinec (Vb)
H
3.32i 3.35
I
AH
OCH3 OCH3 -CHz-CHz-
N(CH3)e C C H z - N
CH3
O
4.07e.f 4.10 4.15 4.17 4.07e.f 4.10 4.15 4.17 4.09e.f 4.10 4.14 4.15 3.92 and 4.12
-
6.12s 6.19 6.26
6.17
-
6.86h (6.37-7.31)
-
-
-
-
5.98g 6.07 6.16
6.14
6.22
6.861
-
-
-
-
5.85g 5.93 6.01
6.10
6.17
-
7.85
8.73
-
-
6.10
6.17
7.71
-
-
-
c. 6.09 6.15
6.19
7.77'c
-
-
-
c. 6.09 6.09
6.15
7.88i
-
8.76
4.11 4.18
6.97j
Amurensininebis- (IV) 3.17 3.39 methinel,'
3.321 3.35
Dihydroamuren-
4.09
4.84
-
6.10
6.15
-
-
-
-
3.98 and 4.12
4.60f 4.71
-
6.10
6.15
6.90t 6.98
-
-
-
-
c. 6.00
6.05
6.10
-
-
-
8.72
-
6.06 6.09 6.12
6.13m
6.17m
7.77
8.35
-
-
6.12m
6.16m
6.82~ 6.91 7.00 7.12 6.95
-
-
3.35 3.26 3.38
-
-
4,5-Dihydroisopavine- 3.12 3.38 bismethinec (42)
-
-
4,5-Dihydro-Nmethylisopavine methinec (42)
4.65
-
Chemical shifts are quoted in T units (deuteriochloroform) downfield from the tetramethylsilane internal reference. All resonances are singlets unless stated otherwise. c Data recorded for operation at 60 Mcps. 6 NMR-value for NCH3 = 7.50. e Quartet. f A similar quartet also observed in eschscholtzine (328). 8 Triplet. * Multiplet. Doublet. Multiplet 7.07-7.41 for Ar-CH-CH2-Ar. a
b
I
N Ratio of the peaks 2 : 1;in the compound V a a superimposition of the peaks N(CH3)zand C C H z N cannot be excluded. 1 Data recorded for operation at 100 Mcps. m Two methoxyl groups (6 protons).
380
F.
~ANTAVP
H. ISOPAVINE GROUP* From the plants Papaver nudicaule, P . pyrenaicum, P. alpinum, P . tatricum, and P. suaveolens two related alkaloids amurensine C1gH1gN04 (I,Scheme 6) and amurensinine CzoHzlN04 (11)of different polarity were isolated. The less polar substance (429) possessed two methoxyl groups, one methylenedioxy group, one tertiary NCH3 group, and four rings (two of them aromatic) in its skeleton. On methylation with diazomethane, amurensine (I)was converted into amurensinine (11). It was assumed that the following two types of ring arrangement-the pavine type A and the isopavine type Bt-could be taken into consideration for these two alkaloids.
\ A
B
The UV spectrum of amurensinine is similar t o those of the benzyltetrahydroisoquinoline alkaloids having two aromatic rings (223). The NMR spectra (Table X I I I ) of amurensinine show signals for four aromatic protons in addition to a singlet for one NCH3 group, a quartet €or the methylenedioxy group, and signals corresponding to six aliphatic protons which have not yet been assigned. Hofmann’s exhaustive methylation of amurensinine and the spectroscopic data of its degradation products confirm the presence of the isopavine structure B. The f i s t step of this degradation (Scheme 6) affords N-methylamurensininemethine (111)whose UV spectrum is practically identical (Table XIV) with that of the previously (61) described N methylisopavinemethine (VIII) and similar to that of the spectrum of cis-stilbene. The NMR spectroscopic data (Table X I I I ) have shown, however, that this degradation gives rise to the isomer I I I a and, in addition, to varying amounts (0-30%) of the isomer IIIb. The compounds IIIa, I I I b and Va, Vb are optically active. By repeated Hofmann exhaustive methylation they afford the optically inactive amurensininebismethine IV and a mixture of its dihydroderivatives VIa, VIb, respectively. These substances are assumed to be derivatives of l-methylenedibenzo[2,3 ; 6,7]cycloheptatriene which is a degradation product of
* This material is supplementary to The Alkaloids, Vol. X, p. 479. t Some time ago the racemic compound VII was prepared and the isopavine structure assigned to it by Battersby and Yeowell (61). Hofmann’s exhaustive methylation of this compound takes a parallel route to that in amurensinine (11).Schopf (430) assumed this structure to be one of those which might be assigned to pavine.
TABLE XIV OF
AND OF THE PRODUCTS ULTRAVIOLET SPECTRAL DATAOF AMURENSININE HOFMANN’S METHYLATION OF SOME PAVINE AND ISOPAVINE DERIVATIVES (IN ETHANOL)
cd
Compound Amurensinine ( 4 2 9 ) N-Methylamurensininemethine(IIIa and IIIb) ( 4 2 9 ) Dihydro-N-methylamurensininemethine(Va and Vb) ( 4 2 9 ) Amurensininebismethine(IV) ( 4 2 9 ) Dihydroamurensininebismethine (VIa and VIb) ( 4 2 9 ) N-Methylpavinemethine( 4 2 ) Dihydropavinebismethine ( 4 2 ) N-Methylisopavinemethine(VIII) ( 6 1 ) 4,5-Dihydro-N-methylisopavinemethine (42, 6 1 ) 4,5-Dihydroisopavinebismethine( 4 2 , 61)
Maxima, nm (log E ) 230(4.07), 250(3.67)sh, 294(3.95) 224(4.48), 240(4.51), 319(4.16) 234(4.43), 291(4.15), 312(3.99)sh 247(4.56), 270(4.16)sh, 328(4.01) 220(4.43)sh, 253(4.00), 295(3.93) 290.5(3.97) 296(4.04) 239(4.54), 314(4.15) 227(4.24), 286(3.89) 220(4.55), 261(4.06), Zgl(3.93)
Minima, nm (log E ) 263(3.29) 227(4.47), 268(3.79) 223(4.40), 261(3.67) 223(4.22), 294(3.78) 248(3.99), 281(3.85) 272(3.88) 2 6 7 4 3.85) 272(3.83) 257(3.29) 246(3.96), 281(3.89)
kP 4w
%M
b
r
?i
8
v)
382
F.
SANTAVB
IV
I: R = H
CHz
VII
VIII
SCHEME 6. The structural elucidation of alkaloids of the isopavine type.
5 . PAPAVERACEAE ALKALOIDS
383
isopavine compounds (43, 61). The UV spectrum of the nitrogen-free degradation product IV closely resembles that of this hydrocarbon (222); it differs, however, from that of dibenzocyclooctatetraene (42). The oxidation of amurensine (I) with potassium permanganate in alkaline medium gave 4,5-methylenedioxyphthalicacid. Consequently the methylenedioxy group may be located on ring A and the methoxyl and phenolic group on ring B. A comparison of the NMR spectra (Table XIII) of the substances III-VI with those of 4,5-dihydro-N-methylisopavinemethine and 4,5-dihydroisopavinebismethine indicates unambiguously that the two methoxyl groups of amurensinine (11)are in the positions 4’and 5’ as in isopavine (VII). Analogy with the thus far known alkaloids of the genus Papaver suggests that the free hydroxyl group of amurensine is in position 5’. Immediately after publication of the paper (429)on the constitution of amurensine and amurensinine, Yunusov et al. (550) reported the isopavine structure for the alkaloid remrefine which was previously isolated by him. A short time later, Slavik et al. (483) isolated three other compounds (Table XII), reframine, reframidine, and reframoline, whose constitution was determined by correlation of the UV and I R spectra of the products of Hofmann degradation. From the optical rotatory data it appears that all the alkaloids isolated thus far have the same configuration a t the C-1 and the C-4 atoms. The isopavine structure of the isolated alkaloids (except for the alkaloid remrefine) (Table X I I ) was also derived from mass spectrometric d a t a (127, 129). The mass spectrum of isopavine alkaloids differs considerably from that of pavine compounds. I n the latter type of bases the ion (M - 43)+ is not cleaved due to the presence of two tertiary carbon atoms in the a-position t o the nitrogen atom.
I. TETRAHYDROPROTOBERBERINE AND PROTOBERBERINE GROUPS* On the basis of mass spectrometric and NMR-spectroscopic data, the structure of the alkaloids caseamine (alkaloid F-33)(VII, Scheme 7) and caseadine (alkaloid F-35)(VIII) isolated from Corydalis caseana A. Gray, could be determined (107).It is interesting to note the position of the oxygen substituents on the two aromatic rings. The absolute configuration of these two alkaloids was derived from infrared spectroscopy (Bohlmann’s frequency--“ trans-band ”) and optical rotation. The recently isolated alkaloids orientalidine (IX) and mecambridine (X) on
* This material is supplementary to The Alkaloids, Vol. IV, Chapter 29 and Vol. IX, Chapter 2. The nomenclature of these alkaloids (9a, 81) has been reviewed by Thomas and Pfeifer ( 5 2 6 b ) .
TABLE XV w
TETRAHYDROPROTOBERBERINE ALKALOIDS
00 I+
Substituents at C and N atoms Compound Alkaloid HF-1 Aurotensine
"-I-+-(
1
2
3
9
10
H H
OH+OCH3 OH+OCH3 OH OCH3 OH ocH3
H
0-CH-0
11
[m]~a
H H
H H
202 128
-356 ( ? ) - 70
H
H
133
H H H H H H
164 208 212 145 257 252 262
298 (C) -298 (C) -271 (C)
CHs CH3 H H
242 136 239 236
+ 303 (C) + 300 (C) + 337 (C) + 280 (C)
H
H
184
- 280 (C) -311 (M)
180 241
+ 300 (C) + 303 (C)
241
- 303 (C)
Absolute configurationb
References (constitution and absolute configuration)
489 299
f 1-
scoulerine] ( + )-Canadine
ocH3
OCH3
( - )-Capaurine ( f )-Capauridine ( - )-Capaurimine (-))-Caseadine (F 35) (-)-Caseamine (F 33) ( - )-Coramine ( - )-Coreximine (Alkaloid F-29) ( )-Corybulbine ( )-Corydaline ( )-Corydalmine ( )-Corypalmine
+ + + +
( - )-Cheilanthifoline (Alkaloid F-13) (+)-Isocorybulbine ( )-Isocorypalmine (-)-Isocorypalmine (casealutine, Tetrahydrocolumbamine )
+
13
Melting point ("C)
H
OH
OCH3 0-CH2-0
H
OH
OCH3 OCH3
Om3
H
cH3
H
OH
OCHs OCH3
OCH3
H
H
+
538 115 115, 237b, 323 238,242-244,323 115, 234a, 237b, 312 107 107 548 59,115,235,315
-287 (C) - 393 (C) -406 (C) - 391
232, 498 12,166 227 115, 504 109 306
R R
232,498 115,506 325
4
3 %%
( - )-Mecambridine (oreophiline) (- )-Ophiocarpine ( - )-Orientalidine (bractavine) ( )-Scoulerine ( - )-Sinactine ( k )-Sinactine ( )-Stylopine (Tetrahydrocoptisine) ( )-Stylopine ( f )-Tetrahydroberberine [( k )-Canadinel ( )-Tetrahydropalmatine (Caseanine) ( f )-Tetrahydropalmatine Alkaloid F-51? ( )-Thalictricavine (Base 11) (. .)-Thalictrifoline Tetrahydrocorysamine
*
CHzOHc OCH3
OCH3 H
178
-254 (C)
(S)
H
OCH3 OCH3 CH2-0-CH2-0'
H OH OCHad H
188
-284 (C) -259 (C)
S S
H
H
204
H
H
176 170 203
ow3
+
+
OCH3 0-C€Iz-0
IH
O-CH2--0 0-CH2-0
0-CH2-0
0-CH-0
H
+
+318(M) -318 (M) -312(C) 0
+310 (C) -310 (C)
300,366, 367 218,358,405,408a, 454 59,115, 169, 236 I89 I15 501 I15 rd
H
H
22 1 171
0 0
508 197, 413, 538
E
4
M
EM
u
+
+
198
397 408a, 454
).
142
H
+292 (E)
- 292 (E)
148
0
171 149
0
H
H H
H H
H H
155 203
115, 236,507 115, 505 505
H
+292 (C) $218 (M) ?
304a 232,317,521
k k
8m
232, 310 523,524
C, Chloroform; E, ethanol; M, methanol. The absolute configuration,derived in this review on the basis of the direction of the optical rotation, is given in parentheses. c The substituent is at c-12. d The group OCHa is at C-10, and the group CH2-0-CH2-0 at C-12, C-11. b
0 00
Ln
F. ~ A N T A V P
386
dehydrogenation yield the alkaloids PO-4 and PO-5 which were also found present in the plants. Orientalidine (Bractavine)2 Alkaloid P O - 4 Mecambridine (Oreophiline)2 Alkaloid PO-5 (Alborine)
By catalytic reduction the compounds PO-4 and PO-5 afford the racemates of orientalidine and mecambridine, respectively. The constitution of orientalidine was established (218,358,408a)by degradation experiments (Hofmann's exhaustive methylation), UV, IR,NMR spectroscopy, and mass spectrometry. Similarly to tetrahydroprotoberberine (I), the second step of Hofmann methylation of orientalidine affords bis methine (type 111) having a trans configuration. The structure of mecambridine (X) (397)could be established by mass spectrometry and NMR spectroscopy. The degradation products I1 and I11 (Scheme 7)
IV
4
;"1--
V
__t
R1 = H or OCH3
I1
\
I11
SCHEME 7. Degradation of protoberberine alkaloids. Type a : R1=H; R2, R3, R4, R5= H or CH3 or R2+R3; R4+R5= CH2. Type b : R1= OH or OCH3; R2, R3, R4, R6 = H or CH3; R2+R3 R ~ ; + R ~ = C H Z .
387
5. PAPAVERACEAE ALKALOIDS
which arise from degradation (exhaustive methylation) of tetrahydroberberine bases exhibit (420,454)very characteristic UV spectra. Oxidation of tetrahydroprotoberberinecompounds (havingoxygensubstituents a t C-9 and C-lo) gives rise to compounds of the l-oxotetrahydroisoquinoline type (IV) (169)and to bases of protoberberine type (V) (162)which on hydrogenation afford the initial compounds which, however, are racemic. The compounds which carry a methoxyl group at C- 11 (pseudotetrahydroprotoberberine compounds) differ in their behavior from those of other tetrahydroprotoberberines. On oxidation they do not yield derivatives of the 1-oxotetrahydroisoquinoline type (IV) and the UV
0
VI
X
XI
~
3
TABLE X V I PROTOBERBERINE ALKALOIDS Substituents at C and N atoms Compound Alkaloid PO-4a Alkaloid PO-5 (a1borine)a Berberine Coptisine Corysamine (worenine) Dehydrocorybulbine Dehydrocorydaline Dehydrocorydalmine Dehydrothalictricavine Dehydrothalictrifoline Palmatine a
1
2
3
9
10
11
13
H H H H CH3 H CH3 H CH3 m3
H
Melting point ("C) >300 >300 234 (picrate) 280 (iodide) 300 (iodide) 237 (nitrate) 240 (iodide) 282 (iodide) 271 (chloride) 241 (iodide)
The location of the substituents in ring D is the same as in mecambridine and orientalidine (Table XV).
[oL]D
0 0 0 0 0 0 0 0 0 0 0
References
408 400, 408 159, 375 257 258,524 521 166 133b, 227 521 310 141
r
r
2c
++
5.
389
PAPAVERACEAE ALKALOIDS
spectra of their dehydrogenation products are different (445a,4453,454). On this basis, the pseudoprotoberberine structure could be assigned t o the alkaloids PO-4 and PO-5 (alborine) (400,408a,454).The compounds of berberine type can be very easily differentiated from the tetrahydroprotoberberine compounds and the totally dehydrogenated products of the deoxythalidastine (VI) or coralyne (XII) type by UV spectroscopy (221, 449a). The alkaloid “corpaverine” (238,243,297,316)was shown t o be (242, 244) a mixture of capaurine and sendaverine (Table 111).
% :’“k.. /
\
__f
\
SCHEME 8. Two types of photosynthesis of the protoberberine alkaloids (131, 282).
Kametani and Ihara (237, 237c) observed that treatment of optically active protoberberine alkaloids, namely ( - )-coreximine, ( - )-tetrahydropalmatine, and ( - )-norcoralydine with hydrogen in the presence of platinum oxide afforded the corresponding racemic tetrahydroprotoberberines. Kametani et al. (237b) found on the basis of X-ray analysis and NMR and mass spectral data that the skeleton of capaurimine and capaurine would be cis-quinolizidine. Although the quaternary structure is assigned to the alkaloids of protoberberine type, it is of interest to note that during isolation they are frequently extracted into chloroform from either the basic or the acidic media. This phenomenon has been explained (97, 438) by the formation of a labile complex X I between the alkaloid and chloroform. The NMR spectroscopy, mass spectrometry, and the biosynthesis (Scheme 2 ) of the tetrahydroprotoberberine alkaloids were described in detail in The Alkaloids, Vol. I X , Chapter 2 and in various publications
390
F.
SANTAVP
(106a, 133b). The UV spectra of tetrahydroprotoberberine alkaloids are similarly influenced by the methoxyl and methylenedioxy groups as those observed in the other benzyltetrahydroisoquinoline alkaloids (223). The UV and I R spectroscopy of some protoberberine and pseudoprotoberberine alkaloids (173, 221, 408a, 445a, 4453) and their polarography (423)have been reviewed. The isolation of the alkaloids of the protoberberine type (lO2j and the synthesis of columbamine from berberine (101)have been reported. The synthesis of coreximine, scoulerine, and tetrahydropalmatine have been described (59, 235, 236). The synthesis of alkaloids having a protoberberine skeleton has been reviewed (374). Recently, attention has been paid to the photosynthesis of tetrahydroprotoberberine alkaloids (131, 282) from N-acetyl- 1-benzylidenetetrahydroisoquinolines (a) and from bases of protopine type (b) which proceeds along the two pathways shown in Scheme 8.
J. PROTOPINE GROUP* New alkaloids have been added to the known alkaloids of the protopine type and the constitution of many of them could be elucidated. The constitution of muramine (83, 117, 336) was originally based on UV, I R , and NMR spectroscopy and mass spectrometry and then confirmed by
)qp-qql& /
/
H3C
\
/
\
I
I1
Protopine type
13-Oxoprotopine type
I11 13-Methylprotopine type
partial synthesis from allocryptopine (321)and by total synthesis (178)so that even the location of the substituents in ring C could be established. Recently the constitution of hunnemannine was confirmed by partial synthesis (179)from berberine. Stermitz et al. (514 isolated coulteropine, which by UV, I R , and NMR spectroscopy as well as by mass spectrometry was identified as 1-methoxyprotopine. UV and IR spectroscopy (3, 5 , 352), polarography (423, 485), and NMR analysis (514a) showed that in acidic media the structure A and
* This material is supplementary to The Alkaloids, Vol. IV, Chapter 31 and Vol. X, Chapter 8.
TABLE XVII PROTOPINE ALKALOIDS Substituents at C atoms Compound
1
2
3
9
10
Melting point l3
("c)
[EID
References on constitution UI
Protopine (macleyine, fumarine) u-and fi-Allocryptopine (fi- and y homochelidonine, a-fagmine) Cryptopine (cryptocavine) Muramine Hunnemannine Coulteropine Ochrobirine ( ? ) 13-Oxoprotopine 13-Oxoallocryptopine 13- Oxocryptopine 13-Oxomuramine (alpinone) 1-Methoxy-13-oxoallocryptopine ( )-Corycavamine ( f )-Corycavamine (corycavine) ( )-Corycavidine ( )-Corycavidine
+ +
a
]
Hydrate.
H H
0-CH2-0 0-cH2-0
H H H
ocH3 H
207 160
0 0
124,128,201,376 128,163, 198
H H
221 177 209 168 198 230 124a 186 212 213 149 219 213 194
0 0
3 , 1 2 8 , 307a, 376 83, 117, 178, 321, 336
H H OH =O =O =O -0 =O CH3
OCH3 H H H H H
l H
H H
0-CH-0
0 128, 179 0 514 +36 (C) 290 0 196, 283 0 196 0 196 0 143,196,339 0 339 +167 (C) 292 0 292 +203 (C) 292 0 292
'd
5 -4
M
d
M
k L
P
F
s F1
392
F.
SANTAVP
in alkaline media the structure B are assignable to the alkaloids of the protopine type, which indicates a transannular interaction between the ketonic group and the tertiary nitrogen atom.
A
B
From the plants of the genus Papaver, the alkaloids of the protopine series and their derivatives having a ketonic group on C-13 could be isolated, namely 13-oxoprotopine" (339, 410), 13-0xocryptopine+ (339, 410), 13-oxomuramine (143,337,339),and 1-methoxy-l3-oxoallocryptopine (oreonone) (339). Their.IR spectra in the region between 1700 and 1600 cm-1 resemble those of the protopine alkaloids or of the compounds having a cross-conjugated dienone system (339). They can be easily recognized by NMR spectroscopy (Table XVIII) ( 4 ) and mass spectrometry, for the mode of fragmentation of the protopine series (117,128)differs from that of the 13-oxoprotopine series (196).A comparison (339)of the ionization constants of the bases of 13-oxoprotopine type with the pK value of the corresponding protopine alkaloids (221) revealed lower ionization constants for 13-oxoprotopine alkaloids. The low basicity might explain why they escaped attention during isolation. The UV spectroscopy of protopine alkaloids has been described (221, 223). The alkaloids of the protopine series may be converted (131)into the alkaloids of the berberine type by the action of light (Scheme 8). Brown and Dyke (93,93a)(Scheme 9) have elucidated the structure of anhydrocryptopine (IV), epicryptopirubine (V), epicryptopine A (VI), epicryptopine B and C (VII), and +-cryptopine (VIII) i.e., the degradation products of cryptopine which were found by Perkin (376)during his classical studies of the constitution of cryptopine. This problem was also studied by Onda et al. (363b, 363c) who obtained dihydrosanguinarine by photocyclization of anhydrocryptopine. The biosynthesis of protopine was studied (32)in the plants Dicentra spectabilis, Argemone hispida, and A . mexicana. The results showed that in these three plants the biosynthesis proceeds along the same pathway
* Gadamer and Kollmar ( 1 6 7 ) were the first who studied the oxidation of protopine, cryptopine, and allocryptopine by using mercury(I1) acetate; the final constitution of 13-oxoprotopine was then determined by Leonard and Sauers (283).
TABLE X V I I I
NMR DATAO F PROTOPINE ALKALOIDS AND THEIR DERIVATIVES=
Protones
Protopine Allocryptopine (4,74,514) (117) 8.08
-
8.15 6.21; 6.16
ArCHzCHzN ArCHzCHzN ArCHzN
7.45 7.12 6.42
7.14 (m) 7.40 (m) 6.50-6.00 (m)
ArCHzCO 0-CHZ-0 para-Arom. protones
6.22 4.08; 4.04 3.10 (C-1) 3.35 (C-4) 3.31
6.50-6.00 (m) 4.08 3.05 (C-1) 3.36 (C-4) 3.13 (9) J = 8 . 5 CPS
ortho-Arom. protones
b
Muramine (117)
Coulteropine ( 1-methoxyprotopine)
(514)
8.15 6.20 (3 H ) ; 6.15 (9H) 7.05 (m) 7.40 (m) 6.50-5.90 (m)
7.93 6.00
6.50-5.90 (m)
6.50-6.20 (m) 4.15
2.93 (C-1) 3.31 (C-4) 3-11 (9) J = 9 cps
-
?
7.60 6.50-6.20 (m)
-
3.78 (C-4) A weak AB quartet above 3.46
Oreonone Alpinoneb ( 1-methoxy-13-0x0(13-oxomuramine) allocryptopine) (339) 8.14 6.20; 6.13; 6.10; 6.06 7.26
8.07 6.19; 6.10; 6.00
?
?
7.20-7.45
6.10 (hidden under A poorly formed multiplet centered OCH3) above 6.30
2.54 ((2-1) 3.30 (C-4) 3.16; 3.02; 2.42; 2.27 J = 8.5-9 CPS
-
4.05 -
3.57 (C-4) 3.20; 3.04; 2.75; 2.60 J=-8.5 CPS
Values expressed in 7 ; m=multiplet; q=quartet. Spectrum obtained from Prof. W. Dopke. w (0 w
394
F.
SANTAVP
Anhydrocryptopine IV Hf
red salt
N-Acetate
AcrO t-
Epicryptopine C VII
Epicryptopirubine C1-
V
SCHEME 9. Formation of epicryptopirubine (V) and epicryptopines (VI and VII) from anhydrocryptopine (IV) (according to Brown and Dyke, 93).
t
5. PAPAVERACEAE ALKALOIDS
H H
\
m
.f ru
395
TABLE X I X
W
co oa
PHTHALIDEISOQUINOLINE ALKALOIDS Substituents at C atoms Compound ~~
6
7
8
3'
4'
Melting point ("C)
Configurat,ion [ a ] ~ pKaa Relative Absolute
References (constitution and configuration)
~
Bicuculine Adlumidine Capnoidine Corlumine Adlumine Corlumidine 8-Hydrastineb a-Hydrastine (stylophylline) or-Narcotine
I
1
177
H
0-cH2-0
OCH3 OCH3 H
0-CH2-0
OCH3 H
0-CHz-0
O-CHFO
OH
I
0-CH2-0
H
OCH3 OCH3
8-Narcotine
+130 (C) -llO(C) +116(C) -Il6(C) +77 (C) +42(C) +80 (C) -68 (C)
4.85
195 239 239 159 180 236 132 162
-163(C)
-
176c
-2OO(C)
4.85
176
-
202 196d 156e 119
- 189 (C)
4.72
Erythro
-
-
-
-
-
-
4.20 4.16 5.13 4.18 5.25 4.93
88 (C) 4.70
Erythro Erythro Threo Threo Erythro Threo Erythro Erythro Threo
78, 79,290, 419 554 78, 79,297,314 78,79,314 78, 7 9 , 1 9 2 , 4 1 9 , 541 78, 79,297, 419 78, 79, 294 78, 79, 153, 347, 365, 366, 368,419 IR, 9R 78, 7 9 , 3 6 6 , 4 6 5
Erythro
lR, 9 s
Threo
lS, 9R lR, 9 s lS, 9 s lR, 9R lS, 9R 1%9 s IS, 9R lR, 9s
60, 78, 79, 367, 377, 419, 540 l R , 9R 78, 7 9 , 3 2 9 , 3 6 5 , 3 6 7 , 368, 540 lR, 9 s 60, 78, 7 9 , 5 4 5 202
~
I n 80% methyl Cellosolve. Not found in the plant family Papaveraceae. c ( )-Gnoscopine, mp 232". d Natural product. e Racemate. a
b
202,294, 297
4
p
3
5*\
5.
PAPAVERACEAE ALKALOIDS
397
and that in the majority of cases the initial compound is ( + )-reticuline (Scheme 1 1 ) .
K. PHTHALIDEISOQUINOLINE GROUP* From the plant Stylomecon heterophylla, a new alkaloid stylophylline was isolated. Since it is the enantiomer of the already known (-)-/3hydrastine, it represents ( - )-m-hydrastine. Recently, the isolation of ( - )-bicuculline from Corydalis severtzovii was reported. The elucidation of the relative and absolute configuration of phthalideisoquinoline alkaloids was independently and simultaneously achieved by several groups of workers (60, 78, 79, 365-368, 419, 540). Although different methods were applied [model compounds, IR, and NMR spectroscopy, pKso~,oMcs, optical rotation, preparation of corresponding diols (type 11),1-benzyltetrahydroisoquinoline (VII),and tetrahydroprotoberberine compounds 111-VI (Scheme lo), ORD- and CD-analyses], the results obtained were concordant (Table XIX). The UV and IR spectroscopy of the phthalideisoquinoline alkaloids (221)and mass spectrometry (364)have been studied. The biosynthesis of these alkaloids was also solved (53, 57, 57a). It is again based on reticuline (VIII) and the lactone carbonyl group is derived from the N-methyl group of this benzylisoquinoliiie alkaloid by a process not involving significant fission of the N-methyl bond until after the bond to ring B has been established. The formation of a protoberberine (Schemes 11 and 20), probably scoulerine, as a precursor of phthalideisoquinoline alkaloids, is an attractive step. I n analogy with hydrastine, the methyl group of the methoxyls, the methylenedioxy groups, and the N-methyl group were derivable from methionine (174, 194).
L. NARCEINEGROUP Narceine and nornarceine have already been described in The Alkaloids, Vol. IV, p. 179. These two substances are easily reduced (423)by polarography, which can be used to advantage for their quantitative determination. The UV and IR spectroscopy of narceine and nornarceine have been reported (221).Their properties are as follows :narceine, C Z ~ H Z ~ N O ~ , mp 145"; trihydrate, mp 170°C (151, 152); nornarceine (oxynarcotine), C22H25NO8, mp 147" or 229" C(415).(For formula of narceine see Scheme 20, structure XI.)
* This material is supplementary to The Alkaloids, Vol. IV, Chapter 32, Vol. VII, Chapter 20, and Vol. IX, Chapter 3.
398
F.
BANTAVP
VIII
XVI
XIV
XI11
SCHEME1 1. The biosynthetic and stereochemical relationship between reticuline (VIII), narcotine (XI),protopine (XII), and chelidonine (XVI) (according to Battersby et al., 53); W, A indicate 14C label.
M. RHOEADINE GROUP* In 1837 E. Merck (346)discovered the presence of a substance in opium which turned deep red when treated with mineral acids. He named the substance porphyroxine and Berzelius (72) renamed it opine. In 1865 Hesse (212,213)reported the isolation of rhoeadine from Papaver rheas which he thought was identical with Merck’s porphyroxine. However, 3 years later he recognized (214)that he was mistaken; he assigned the name meconidine (215)to the substance which when treated with mineral acids was responsible for the red coloration. These findings showed that a
* This material is supplementary to The Alkaloids, Vol. X, p. 474. Rhoeadine and papaverrubinealkaloids have been reviewed by Pfeifer et al. (397a).
5.
PAPAVERACEAE ALKALOIDS
399
substance of analogous properties occurs both in P. somniferum and in
P.rhoeas. Hesse’s error finds its explanation in the fact that rhoeadine is tenaciously accompanied (13, 15) by substances which structurally are very similar to porphyroxine and which Awe and Winkler (15) call rhoearubines. The substances which give a red coloration when treated with mineral acids have been extensively studied by Pfeifer and coworkers. He named (378, 386) this new group of substances papaverrubines.* The history of the discovery of these “porphyroxine-meconidines” was studied by Fulton (157, 158). However, before going into more detail regarding the constitution of substances of the papaverrubine group, we shall discuss rhoeadine, the representative of the rhoeadineisorhoeadine type of bases [there was also isolated (359, 435, -544) an isomer called isorhoeadine (see below)]. During the past 10 years numerous compounds of similar structure have been isolated beside rhoeadineisorhoeadine from the genus Papaver. Table XX lists these compounds and the corresponding papaverrubines. At present these substances are easily detected on the basis of their characteristic reaction with conc. sulfuric acid (red + brown + green).
1. The Rhoeadine-Isorhoeadine Alkaloids Hesse (214)found that by treatment of rhoeadine, C21H21NO6, with diluted mineral acids it is converted into rhoeagenine, CzoHlgNOs. Slavik (457) reported that such hydrolysis resulted in liberation of a molecule of methanol. Both rhoeadine and rhoeagenine possess two methylenedioxy groups, one tertiary NCH3 group, and two aromatic nuclei (10,11,510).Dehydrogenation of rhoeagenine with zinc dust (11, 510)affordsisoquinoline and oxidation with nitric acid hydrastinine (IX) (13,15,543a).Nitrogen can be eliminated from the molecule of rhoeadine or rhoeagenine in two steps of Hofmann’s exhaustive methylation (14, 432, 510). During that reaction rhoeagenine (510) gave amorphous substances which could not be characterized. The first step of degradation of rhoeadine gave a product having a vinyl group (111, Scheme 12), the second step gave a trans-stilbene derivative (V). Alkaline oxidation of rhoeagenine yielded hydrastic (XI) and isohydrastic (XII) acids along with the methylimide of hydrastic acid (16, 432, 510). Since acid hydrolysis of rhoeadine affords rhoeagenine, it is assumed (432)that the fifth oxygen atoms of rhoeadine and rhoeagenine are of acetal and half-
* The alkaloids of this group can be easily detected. They produce red spots on thinlayer chromatography, e.g., on silica gel after exposure t o vapors of hydrochloric acid (318, 382, 386).
IP 0 0
TABLE XX THE KNOWN ALKALOIDS OF
THE
RHOEADINE AND PAPAVERRUBINE TYPES
Substituents at C and N atoms Compound Alpinigenine (Alkaloid E ) Glaucamine (Alkaloid R-L)
10
11
OCH3 OCH3 H 0-CHz-0
Oreogenine N-Methyl-14-0-desmethylepiporphyroxine Isorhoeagenine Rhoeagenine Alpinine Glaudine Epiglaudine Oreodine
]
14
Melting point ("C)
Erythro Erythro
195 224
Threo Erythro
175a 218
Erythro Threo Erythro Erythro Erythro Threo
215 234 105 105 Amorphous 186
H
0-CHz-0
H
0-CHz-0
H
OCH3 OCH3 CH3 0-CHz-0
Relative configuration at c-1,c-2.
CH3
[ a ]in ~ chloroform
References (constitution and configuration)
193,286,337,338 119,380,393,397, 428,471 118,392,396 340e 88a
+286 +300
+ + 153b + 134C + 280 +455 +224
428, 430 428, 430 193,286,337, 338 380,393,397 226,453 118,383,392,396
r vl<
b
3
%*\
Isorhoeadine (Alkaloid Epiisorhoeadine R - A ) ] CH3 Rhoeadine Isorhoeagenine-glycoside CH3 (Alkaloid R-C) Papaverrubine G H Papaverrubine D (porphyroxine) H Papaverrubine C (epiporphyroxine) Papaverrubine B H Papaverrubine F Papaverrubine A H (Alkaloid R-S) Papaverrubine E
I
Methiodide. Methanol-chloroform ( 1 + 1). c Pyridine. d Picrate. 8 Methanol. a b
0-CH2-0
0-CH2-0
0-CH2-0
0-CH2-0
Erythro 161 Erythro Amorphous Threo 253 glucose Erythro 242 CHI
OCH3 OCH3 OCH3 OCH3 CH3
+314 +248 +235 255c
+
Erythro
1660
-
+
428,430 426 428,430 357 388a
0-CHa-0
CH3
Erythro Erythro
244d 188
391 +283
OCH3 OCH3
O-CHz--O
CH3
Erythro Threo
204 225
+ 398 -
225, 379, 388 287
0-CH-0
0-CH2-0
CH3
Erythro
223
+410
387,388,434
Threo
231
+ 331
286,387,388
OCHp
OH
88,388,398 225,226
TABLE X X I UV-ABSORPTION MAXIMAAND MINIXA OF RHOEADINE AND ITSDERIVATIVEP Compound Rhoeadine (IIa) Desrhoeadine (111) Dihydrodesdesrhoeadine (VI) Desdesrhoeadine (V) Rhoeageninediol (VII) Desrhoeageninediol (XIII) Desdesrhoeageninediol (XIV) Oxyrhoeagenine (VIII) 4,5-Methylenedioxyphthalide( X ) a
b
Reference (430). Shoulder.
Maxima, Anlax, nm (log E)
205 (4.91),240 (3.96),292 (3.94) 207 (4.76),222b (4.30),269 (4.00),294 (3.92) 204 (4.69),292 (4.25),327 (4.19) 204 (4.49),224b (4.41),266 (4.21),325 (4.25) 204 (4.87),241 (3.87),292 (3.93) 204 (4.77),2370 (4.00),289 (3.79),312b (3.26) 206 (4.46),267 (4.03),284b (3.79),301b (3.71) 223 (4.36),242b (4.04),292 (3.84),325 (3.64) 200 (4.63),2046 (4.61),224 (4.74),270 (4.05),294 (3.97)
Minima, Amin, nm (log E )
229 (3.90),263 (3.28) 256 (3.94),286 (3.88) 254 (3.84) 250 (4.10),289 (4.15) 230 (3.81),262 (2.95) 256 (3.53) 251 (3.89) 265 (3.23),307 (3.45) 210 (4.45),240 (3.53),286 (3.95)
r
r
? 4
6
5. PAPAVERACEAE ALKALOIDS
403
acetal nature," respectively. The preparation of 2,4-dinitrophenylhydrazone (5204 and oxime (80c), demonstrated the presence of the aldehyde group of rhoeadine and rhoeagenine. On the basis of these experiments (in connection with physiochemical methods), formula I was suggested (16,432)for rhoeadine-rhoeagenine.
Rhoeadine, R = CHI ( previous formulae) Rhoeagenine, R = H ') I
The structure of rhoeagenine (I)suggested that oxidation might give rise t o bicuculline or adlumidine (phthalideisoquinoline alkaloids) and that by subsequent correlation the absolute configuration of the rhoeadine and the isorhoeadine series, respectively, could be determined. Reduction would then afford the corresponding diols. However, oxidation and reduction afforded products (430) which did not correspond t o phthalideisoquinoline derivatives (see Section 111, K). Rhoeadine cannot be reduced by lithium aluminum hydride, or by hydrogen over Adam's catalyst. Rhoeagenine, however, can be reduced by both these methods to rhoeageninediol (VII, Scheme 12). Oxidation of rhoeagenine and of the diol VII by means of chromium trioxide or manganese dioxide affords oxyrhoeagenine (VIII). More drastic oxidation of rhoeageninediol (VII)gave hydrastinine (IX) and 4,5-methylenedioxyphthalide (X). An attempt to cyclize and to convert rhoeageninediol into X X I I I (Scheme 17), yielded ( 2 5 9 ~ )(under simultaneous rearrangement) coptisine. However, when rhoeageninediol is treated with mineral acids it easily cyclizes to lose 1 mole of water (formation of 14-demethoxyrhoeadine) (426). Hofmann exhaustive methylation of diol VII gave first the nonstyrenoid product XI11 in contrast to similar degradation of rhoeadine.
* According to the applied alcohol, the etherification of the genines (half-acetals)can be carried out (360) in acid medium. Therefore, on investigating plants containing rhoeadine and papaverrubine alkaloids, the extraction must not be carried out with acidified ethanol, for this might result in a n exchange of the ether group. On the other hand, this reaction was utilized (338, 388, 472) for the preparation of a series of methyl ethers from the corresponding genines of the other rhoeadine type of alkaloids.
404 F.
~ANTAVP
t
1
I
x
I
I
T
405
B. ~ A N T A V P
406
W N - C H . A
C
B
A second step of exhaustive methylation yielded an optically active styrene derivative (XIV) without any trans double bond. The IR spectra of oxyrhoeagenine (VIII) showed that the compound contains a six-memberedlactone ring in contrast to phthalideisoquinoline alkaloids. A substantial difference in pK values for these two lactone types was also noticed (430).It followed that the suggested tetrahydroisoquinoline constitution of the rhoeadine alkaloids had to be revised (430).
I11
H
,CHz
”(N-CHa I
\(+)
__f
o H c x
-
o$;
0
I
HzC-0
HzC-O(+)
HzC-0
SCHEME 13. Mass spectrometric fragmentationof desrhoeadine.
5. P A P A V E R A C E A E ALKALOIDS
407
All the mass spectrometric findings (430)showed (Fig. 2 and Schemes 13-16) that the partial structures A, B, and C can be ascribed to rhoeadine. The NMR data demonstrate the presence of the ArCHN, ArCHO, and ArCHOz groups in rhoeadine and lead to the probable skeleton of rhoeadine C when the presence of two methylenedioxy groups and of a methyl group from the acetal grouping is taken into consideration. The NMR spectral data for rhoeadine and several derivatives (Table XXII) indicate two aromatic protons in the para position and two in the ortho
RBO
-R5
R20
b i
OR^
OHCQ ~ 3 \ 0
"'"rnLR5
OR4 e
R20
C
R1O RZO%
,
~
3
\ 0 OR^ d
+ Re-9-CH
\
-
ROO ~
3
0
~ 0
~
4
3
0 \
RsO-CH
OR^ OR^
f SCHEME 14. Two different types of mass spectrometric fragmentation of alkaloids of rhoeadine and papaverrubine type (according to Doleji and HanuL, 126).
TABLE XXIT
NMR SPECTRA OF RHOEADINE-ISORHOEADINE, CLAUDINE-OREODINE, AND SOME OF THEIRDERIVATIVES~,~
Compound
-NCH3
14-OCH3 14-H
Rhoeadine (IIa)
7.69
6.45
4.28
Rhoeageninediol (VII)
7.75
-
-
Oxyrhoeagenine (VIII)
7.68
Isorhoeadine
C
C
1.17
RingA 1 4 - H ~-0CHzO-
~
5.32
4.05 4.10
RingD -0CH203.90C J =1.1 4.05
6-H
9-H
3.33
3.23
3.18
3.35
3.40
3.08 4.88 3.28 3.42 A B quartet J=8.2 3.13 3.27 3.22 3.35 AB quartet J=8 2.87 3.02 3.11 3.25
-
-
-
4.03
4.03
3.19
3.32
6.32
4.05
-
4.05
3.93 J=-1
3.33
2.68
10-H
11-H
2-H
1-H
6.39 4.9s J=2.5 J=2.5 5.98c 5.01c 6.01c 5.05c J=2.0 J = 1 . 9
r
3 5*\
5.95 4.8% J=9.1 J=9.3
& II
3
W 1-
r:
2%
II
5 . PAPAVERACEAE ALKALOIDS
0
*“1%
W
%
c9
W 3
z m
2 011
Y m
*Y
‘9
m
2
m
I
w
2
22%
& & II
m
x
W
x t-
Q!
m
L9
2
2 4
u3
I
2
m
I I-
=? t-
409
410
F.
GANTAVP (+)
O=CH
I
H2cQ CI HzC-0
HzC-O
XIV SCHEME 15. Mass spectrometric fragmentation of desrhoeageninediol (XIII)(according to Santavf et al., 430).
position; this finding showed, in connection with the isolation of the hydrastic (XI), isohydrastic acid (XII), hydrastinine (IX), and 4,5methylenedioxyplithalide (X),the position of the methylenedioxy groups as given in the formulas I I a and IIb.
100
Ib
50
c e
LAd&LtkIl.i.u dLf
*
0
FIG.2. Mass spectra of rhoeadine (a) and papaverrubine A (b) (according to Dolejg and HanuB, 126).
3H
0C
0
i
..
R3 bR4 9
\ \.*
FR5
PAPAVERACEAE ALKALOIDS
+OR4
OR4
5.
t O~
OR4 j SCHEME 16. Mass spectrometric fragmentation of alkaloids of the rhoeagenine type (accordingto Dolejli and HanuB, 126).
41 1
412
F.
~ANTAVP
Mass spectrometric fragmentation of rhoeadine (126, 430) takes the same course in isorhoeadine as in the other alkaloids of these two series (88a, 193, 338, 396, 430, 471, 472). The spectra exhibit the fragments a t o f (Fig. 2, Scheme 14) whose masses shift in dependence on the substituents attached to the rings A and C. The mass spectra of rhoeagenine and of some other semiacetal alkaloids (Scheme 16) of this group exhibit (126)the fragments g t o j . These data are also in agreement with the structure of the rhoeadine (X1X)isorhoeadine (XX) alkaloids bearing a seven-membered ring B attached to the six-membered acetal ring D.
HzfJq) 3
HsCO
HzC-0 XIX Rhoeadine
H2C 4
xx Isorhoeadine
The revised structure offers a satisfactory explanation for the chemistry of these alkaloids. The formation of hydrastinine (IX) with a sixmembered ring B by dilute nitric acid oxidation of either rhoeagenine (IIb)or rhoeageninediol (VII)can be explained on the basis of the Criegee and Malaprade cleavage. Similar conclusions were drawn from the NMR analysis (Table XXII) of glaucamine (119), glaudine (118), oreodine (118), isorhoeagenineglycoside (357), alpinine, and alpinigenine (193, 338), and papaverrubine C (226).
2. Papaverrubines The known papaverrubines (Table X X ) are N-demethylated compounds of the rhoeadine or isorhoeadine type. Similar t o the rhoeadine alkaloids, the papaverrubines occur exclusively in the genus Papaver. The constitution of these compounds was elucidated (388)by correlation of the mass spectra with those of the corresponding rhoeadineisxhoeadine compounds (126, 430). By methylation of the secondary nitrogen the individual papaverrubines are converted (287, 387, 434) into the rhoeadine or isorhoeadine alkaloids. As already mentioned above, the papaverrubines (type XXI, Scheme 17) give an intense red coloration when treated with diluted mineral acids.
5. PAPAVERACEAE ALKALOIDS
413
/
0
H&\
0
d
HlC Ho XXI Papaverrubine A
XXII
XXIII
/
OCH3
xxv SCHEME 17. Determinationof the constitution of the red products of the papaverrubines (according to Welterova and Santavf, 239).
414
F.
GANTAVP
The red substance possesses the structure of Schiff’sbase XXII (393,457, 539)which on hydrogenation affords the compound XXIII. Oxidation of this compound with mercury(I1) acetate yields an unsaturated lactam, XXIV, which exhibits a characteristic UV spectrum. A similar lactam is afforded by “Schopf’s base V I ” (XXV) (440).
3. Relative and Absolute ConJiguraticm The alkaloids of the rhoeadine-isorhoeadine type possess three centers of chirality and therefore the spatial arrangement of the substituents at each of them has to be determined. The NMR spectroscopy (88,88a,118, 119,193, 226, 338, 357, 430, 453) of isorhoeadine compounds revealed the trans configurationofthe protons at the C-1 and the C-2 atom and the cis configuration of those in rhoeadine. The alkaloids of the isorhoeadine series have a lower melting point, a higher rotation, and they migrate more rapidly when subjected to paper or thin-layer chromatography than the alkaloids of the rhoeadine series. Correlation (428)of the ORD-curves of isorhoeadine-rhoeadie and isorhoeageninediol-rhoeageninediol with those of the alkaloids of the phthalideisoquinoline series showed that the isorhoeadine series must be assigned the erythro configuration at the C-1 and C-2 atoms and the threo configurationat those of the rhoeadine series. This is also consistent with the results obtained from the NMR analysis (seeabove). A further confirmation of this finding is provided by the easy conversion of the isorhoeagenine series into the rhoeagenine series when treated with mineral acids (226,286,383,385,434).By correlation of the ORD-curves, the isorhoeadine (XX) series was assigned the absolute configuration 1S,2R at the above-mentioned carbon atoms and the rhoeadine (XIX) series the 1R,2R configuration (see p. 412). Shamma et al. (453)and Pfeifer and Mann (395a)assign the reverse configuration 1S,2S to the alkaloids of the rhoeadine type on the basis of the mechanism of epimerization of the C-2 atom of the alkaloids of the isorhoeadine typeFurther support for the configuration assigned to the rhoeadine series was also provided by a comparison (426)ofthe rotatory properties (ORDand CD-curves)of tetrahydrorhoeageninemethine (XVIII)with those of 1,2-diphenylaminoethanol. The third center of chirality at C-14 remains to be discussed. By O-methylation of rhoeagenine, rhoeadine is recovered (360).However, by acid-catalyzed methylation of isorhoeagenine it is the epiisorhoeadine and not the naturally occurring isorhoeadine which is recovered (453).A similar derivative was also obtained by epimerization of the papaverrubine A or of similar compounds of the erythro aeries on treatment with
5. PAPAVERACEAE ALKALOIDS
415
hydrochloric acid in methanol (225,226,286).Hughes et al. (226)assume that epimerization takes place at the C-14 atom and the interconversion can be depicted in the manner shown in Scheme 18. Oreodine
(Methylation)
t Oreogenine (Hydrolysis)
/
~LYSiS
(Methylation)
Porphyroxine
CHaNa ___i,
H+ (catalysis)
I
Papaverrubine C (Epiporphyroxine)
Papaverrubine
Me1
d
(catalysis) CHaNa
Epipapaverrubine B
Glaudine
Me1
H+ (hvdrolvsls)
Glaucamine
Epiglaudine (O-Methylglaucamine) (N-MethylepipapaverrubineB)
SCHEME 18. Mutual transformation of the erythro and threo series of rhoeadinepapaverrubine alkaloids by H+ catalysis and methylation(226,453).
Shamma et al. (453) deduced from the NMR analysis (Table XXII) and on the basis of the rate of the methiodide formation, the spatial arrangement (relative configuration) of the protons at C-1 and C-14 of glaudine (cis),epiglaudine (trans),and oreodine (trans).A similar relative configuration at these two carbon atoms can also be assigned to the other alkaloids of the isorhoeadine and rhoeadine series. The compounds of the epiisorhoeadinetype exhibit the same ORD- and CD-curves; their rotation in chloroform is, however, lower by about 30% than that of the corresponding isorhoeadine compounds, and the R, value is by about 13% higher (426).On the basis of these analytical data, rhoeadine (XIX) can be assigned the absolute configuration 1R,2R,14s; isorhoeadine (XX), lS,2R,14S; and epiisorhoeadine, 1S,2R,14R (or vice versa). Similarly, porphyroxine was independently (87) assigned the absolute configuration lS,2R,14S (see p. 412). 4 . Biogenetical Considerations
The structures of rhoeadine-isorhoeadine represent a new type of skeleton in alkaloids. The occurrence of rhoeadine-papaverrubine alkaloids was observed in all of the thus far examined sections of the genus Papaver. Their common occurrence leads to the assumption that a biogenetical relationship to the other alkaloids of the Papaveraceae exists. They greatly resemble the phthalideisoquinoline alkaloids. With this in
416
F.
E~ANTAV~~
view, it is possible to draw a simple scheme (Scheme 19) which indicates the possible biogenetic relation between these two types of alkaloids.
Phthelideisoquinoline type
Hydrastimethine type
I Neroeine type
N-CHs
0 Rhoedine type
0
SCHEME 19. Probable pathway of the biosynthesis of the rhoeadine alkaloids.
Another possibility might be that the rhoeadine alkaloids arise from protopine alkaloids (see Scheme 20) which are always found present in the plants of the genus Papaver.
5.
417
PAPAVERACEAE ALKALOIDS
N. BENZOPHENANTHRIDINE (WNAPHTHAPHENANTHRIDINE) GROUP*
e0\
The investigations carried out during the past 15 years have shown that the benzophenanthridine bases of the sanguinarine type are the most widely distributed (195)alkaloids (Tables I, 11, and XXV) of the plant family Papaveraceae. More recently, the group of the known alkaloids was augmented by the alkaloids norchelidonine, chelirubine, chelilutine,
RIO
/I
lI\
4\
~>N+-cH~
o'CHa
5/
l " C
H
2
N-CHs 0 ' 1 H2C-0 X Dihydrosenguinarinetype ( X = Hz Oxysenguinarine type ( X = 0 )
OH-
R20 Sanguinerinetype ( R = H ) Sanguilutine type (R = OCHs)
P
f / l
o
>
C
H0
a
N-R3
R1O R20
X
Chelidonine type (R4= H, X = Hz) Corynoline type (R4 = CHI, X = Hz) R1+ R2= CH:, or R1= R2= CH3, R3 = H or CHI X = H:, or 0
sanguirubine, sanguilutine, macarpine, and corynoline whose constitution has also been elucidated. In addition, the alkaloid ( - )-chelidonine (Scheme 20, formula XIV) was isolated (Table XXIII). On studying the relative configuration of the chelidonine alkaloids it was found (71,356a,427,447)that rings B and C form a cis juncture and that the hydroxyl group at the C-10 atom forms a hydrogen bridge with a free electron pair at the nitrogen. It has been reported (427)that the optical rotation of ( + )-chelidoninein dependence on solvents behaves in the same manner as in ( - )-phenylethylamine and that consequently ( + )-chelidonine probably has the lOS,l2S configuration. This assumption could be confirmed ( 5 3 , 5 5 )on the basis of biosynthetic experiments carried out by Battersby et al. (Scheme 11) who showed that ( + ) chelidonine arises biosynthetically from ( + )-retidine. In this case the *This material is supplementary to The Alkaloids, Vol. IV, Chapter 35; Vol. X, Chapter 9.
TABLE XXIII THEBENZOPHENANTHRIDINE ALKALOIDS Substituents at C and N atoms Compound
2
Sanguinarine H Chelerythrine H Dihydrosanguinarine H Oxysanguinarine H Chelirubine H Chelilutine H Sanguirubine H Sanguilutine H Macarpine Chelidonine (
)-Chelidonine (diphylline)
i"
3
4
6
I
9
10
11
13
H
0-CH2-0 0CH.q OCH3
H
0-m2-0
Hz
0-cH2-0
=O H H H
0-CH2-0 OCH3 OCH3 0-CHz-0 OCH3 OCH3 0-CH2-0
0-CHZ-0
H H
0-CHz-0
Hz
OH
H
Hz
14
CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3
Melting point ("C)
[alDa
References (constitution and configuration)
213b 0 2140 0 192 0 360 0 283b 0 198b 0 276b 0 1640 0 285b 0 136 +115(E)
170, 502 19, 20, 165, 418, 503
136 216
476 482
CH3
-113(E)
-
436 509 470 470 470 470 484
55, 71, 94, 95, 164, 266, 356a, 427, 444, 447, 500, 502
r
z% ++
Norchelidonine Methoxychelidonine Oxychelidonine or-Homochelidonine Chelamidine (Alkaloid XV) Chelamine Corynoline Nitidinec Oxynitidinec Avicinec Oxyavicinec
H H H H H
0-CH-0 0-CH2-0 0-CHZ-0 OCH3 OCH3 2 OCHs,
H 2 OCH3, H 0-CH-0 OCH3 OCH3 H OCH3 OCH3 H H O-CH2-0 0-CH2-0 H
0-CH-0 0-CHz-0 0-CH-0 0-CH-0
0-CHz-0 0-CHz-0 0-CH2-0 0-CH-0 0-CHz-0
Hz
OH H OCH3 H H2 OH H Hz OH H 0-CHz-0, 2 OH H2
0-CH2-0,l H H H H H H H H H H
C, chloroform; E, ethanol Hydrochloride. c Isolated from t h e plant genera Toddalia and Zanthoxylum.
OH CH3
-
-
Hz Hz =O H2
H2
H =O H =O
H CH3 CH3 CHs CH3
199 22 1 >285 182 226
CH3 CH3 CH3 CH3 CH3 CH3
204 217 286” 285 ?
277
- 112 (E)
+ 116 (C) + 103 ( C + E ) + 128 (E) + 123 (C) + 107 (C) ?
0 0 0 0
427, 458,477 94,172 171 165,427,503 482
or +d
E P 4
482 356a, 522 7 7 7 7,158
d
M
ti
a 0
u,
420
F.
~ANTAVP
precursors are the tetrahydroprotoberberine bases (53, 55, 281) where oxidation at the C-6 atom results in the formation of a-carbinolamine (or its tautomeric aldehyde form) which attack the C-13 atom (numeration of the protoberberine skeleton) with formation of the benzophenanthridine ring system of chelidone. Dehydration and dehydrogenation then give rise to other groups of benzophenanthridine bases. Takao (522)determined the structure and the relative configuration of corynoline. This alkaloid can be derived from the alkaloids of the corydaline type (Table XV). These two groups of bases-corydaline and corynoline-have also been isolated from the plant genus Corydalis. It has not yet been decided whether one of the initial compounds which arise during the biosynfhesis of alkaloids of the corydaline type is a tropic acid derivative. The NMR spectroscopy of chelidonine and corynoline has been described (356a, 447) in connection with its relative configuration. The UV and IR spectroscopy of many of thk known benzophenanthridine alkaloids has been recorded (221).The polarography of the alkaloids of the sanguinarine type has been described (25,423). Besides the benzophenanthridine bases having oxygen constituents at the C-3 and C-4 atoms, some bases having oxygen substituents in the positions C-2 and C-3 (alkaloids nitidine, oxynitidine, and avicine) could be isolated from the plant genera Toddalia and Zanthoxylum (Rutaceae). Sanguinarine and similar bases have recently been synthesized by Dyke et al. ( 1 3 4 ~ - c ) .
0. OCHOTENSIMINE GROUP From the plants Corydalis ochotensis and Dicentra cucullaria, the alkaloids ochotensine and ochotensimine (methyl ether of ochotensine) were isolated. Hofmann degradation (342, 344) in connection with UV, IR, and NMR spectroscopy and mass spectrometry, and X-ray analysis
I; R = H 11; R=CH3
TABLE XXIV OCHOTENSIMMEALKALOIDS Substituents at C atoms Compound
2
3
Ochotensine (Alkaloid F-17) Ochotensimine (Alkaloid F-48)
CH3 CH3
H CH3
0-CH2-0 0-CH2-0
Alkaloid F-37
CH3
CH3
H
H
0-CH2-0
10
11
12
13
14
H H
H H
=CH2
=CH2
Alkaloid
H CH3
H
H
0-CH2-0
,OH /H /H \OH
Fumariline
-CHz-
H
H
0-CH2-0
=O
C, Chloroform; M, methanol. Hydrochloride. c Methiodide. a
b
+
Melting point ("C)
[a]~a
References
252 19Ob
+52 (C) 342,343,344 +49c (M) 342,344
177
-31 (C)
157
?
138
299,436~1 436a
+138 (C) 436a
@
TABLE XXV
IQ
m
ALKALOIDS OF UNKNOWN CONSTITUTION
Compound Arqemone crlbn Lestib Alkaloid A B o c c o ~ i kcrrborea Substance A Substance B Substance C Chelidonium nurjus Chelidamine
Corydrclis awtbigua Alkaloid K Alkaloid I
Alkaloid J Alkaloid K Alkaloid L Alkaloid M Corydalis X Corydalis Y Base V Base 1'1 (sina,ctine ?) Gorydalis aureu Alkaloid F 27 Alkaloid F 28
Empirical formula
Melting point ("C)
[ulna
Other properties
References
Amorphous
-
CzoHi7N04 CzaHi5N04 C31H33N05
302 191 332
Nonphenolic, 1 or 2 OCH3 Nonphenolic. Nonphenolic
311 311 311
C19H19N04
204
Hydrochloride, mp 256"; iodomethylate, mp 275"
402
r if
-
Hydrobromide, mp 23B0,[Or]D 0' Hydrochloride, mp 236'; hydrobromide, mp 241O; oxalate, mp 1 W ; nonphenolic Hydrochloride, mp 235"
108 100. 512
Ic.
104
118
225 236 161
401
Nonphenolic Nonphenolic with allocryptopine
200 229
-
195 172
-
148
135
-
With 4 OCH3 Phenolic with 2 OCHs
I10 110, 111 111 I l l , 112 I13 113 521 521 297 297
z%
Corydalis msearul Alkaloid F 34 Corydalis mvu
Alkaloid Corydalis claviculata Alkaloid F 52 Corydalis incisu Alkaloid F 62 Base I Base I11 Base V Base VII Corydalis rnicrantha Alkaloid F 41 Alkaloid F 42 Alkaloid F 43
218
Phenolic with 3 OCH3, HzS04 yellow 325
226
Nonphenolic
536
Amorphous 196 217 240 210 Amorphous 177 239 230
305
Nonphenolic -
Methiodide, mp 163'
314 523 523 523 523
Phenolic, HzS04 colorleas Phenolic, HzS04 colorless Phenolic with 3 OCH3, HzS04 colorless
301 301 301
Corydalis rnontam (aurm)
Alkaloid F 56 Corydalis nobilis Alkaloid P 53 Alkaloid F 54
207
Phenolic ( P ) with 4 om3
308
I83 143
307 307
Alkaloid F 55 Corydalis ochotensis Alkaloid F 49 Corydalis ochroleuca Alkaloid F 45 Alkaloid F 46 Corydalis plutycarpa Alkaloid
209
Nonphenolic, HzS04 lilac Phenolic with 2 OCH3, greenish blue Phenolic, HzS04 colorless
228
Phenolic with 1 ocH3
304
268 227
Phenolic With 1 O&Hz
302 302
172
Nonphenolic
309
307
rp
IP E.l
IP
TABLE XXV-continued
Compound Corydalis pseudoadunca Alkaloid Alkaloid
Alkaloid Coramine (Coreximine?) Corydalis sempervirens Alkaloid F 20 Corydalis sewertzowii Rgl. Corydalis sibiricn Alkaloid F 14 Alkaloid F 15 Alkaloid F 16 Corydalis stricta Alkaloid [( )-hydrasthe ?)] Corydalis thnlictrifolia Alkaloid F 59
+
Alkaloid F 60 Dicentra canademis Alkaloid F 22
Empirical formula
Melting point ("C)
195 132
203 252 221 202 198 212 236 129
[UlD"
+ 112
+ 63
Other properties
-
These bases gave oxidation products characteristic of phthalideisoquinolines
-
Methylenedioxy group With 1OzCHz(?),HzS04 violet Nonphenolic with 2 OCH3, HzSO4 brown-pink Nonphenolio with 2 OCH3 -
References
548 548
548 548 297 554 295 295 295 21
176 200 92 123
Nonphenolic with 1 OCH3, HzS04 colorless, emerald green Nonphenolic with 1 OCH3
238
Orange quaternary base with 3 OCH3; 289, 297 chloride, mp 286'
310 310
Dicentra chrysantha Alkaloid F 25 Dicentra eximia Alkaloid F 21 Alkaloid F 30 Dicentra oregona Alkaloid e Dicranostigm lactwoides Alkaloid Fumaria micrantha (densifloa) Fumaramine Fumaria o&inalis Alkaloid F 37 Alkaloid F 38 Fumaroplycine Alkaloid Alkaloid (fumaritine P ) Fumaria schleicheri Fumarimine Fumaritine
CzoHziNOs
Fumaria vaillnntii Fumvaillin
CzoHigNOe
Eschscholtziu cnlifornica Escholine
CigHzzN03.OH
230
-
Phenolic with 1 NCH3
296
80 102
-
-
With 4 OCH3, HzS04 orange With 3 OCH3
291 297
230
-
Phenolic with probably 2 OCH3
293
178
+148 (C)
233
-
Yellow base with 1 CO-group
177 256 109 138 157
-
Nonphenolic with 2 OCHa, HzSO.4 blue 299 Phenolic with 1 OCH3 299 350 322 322
190
-
159
-
191
-
181
-44 (C)
-
0
-
-
479 402
Light yellow, with 1 NCH3; hydro402 chloride, mp 257"; oxalate, mp 213' With NCH3; hydrochloride, mp 224'; 402 hydrobromide, mp 219" Yellow with 1 CO and 2 OCH3; 402 dichloride, mp 214";dipicrate, mp 205'; tartrate, mp 217"; iodomethylate, mp 248" Phenolic with 2 OCH3; hydrochloride, 402 mp 212'
NCH3,1-OH, 2OCH3
175
+P
le
TABLE XXV-continued
Compound
Glauciumjlavum Alkaloid F 47 Glauflavine Hunnemnnnia fumarinefolia Alkaloid F 58 Papaver anomalum Pavanoline Alkaloid Alkaloid Alkaloid Alkaloid Papaver alpinum Alkaloid Alkaloid Alkaloid Papaver argemone Alkaloid PA- 1 Alkaloid Papaver bracteatum Bracteoline
Papaver californnicurn Alkaloid
Empirical formula
Melting point ("C)
[UID"
Q,
Other properties
Iodide, mp 217";ol.[ 174
-
244 - 226 (C) 230 dec 250 250 (Pavenoline ?) 300 dec 118 215 258
-
143 300
-
221
+35 (C)
169
(Muramine?)
-
-
+45"
References
303 176
Nonphenolic with 2 OCH3, HzS04 orange
324
NCH3,l OH, 2 oCH3,l OCOCH3 HzSO4 green HzSO4 yellow-brown HzS04 red
401 336 336 336
HzS04 green-yellow
336
HzSO4 red-brown-green HzS04 red HzSO4 red
336 336 336
&SO4 yellow &SO4 yellow
410 433
Aporphine alkaloid with two methoxyl-, two phenolic, and one N-CHs group
220
-
433
Papaver caucasicum Alkaloid Papaver c m m u t a t u m , Alkaloid R-D Alkaloid PC-1 Papaver dubium Alkaloid Rd-B Alkaloid Rd-C
-
+ 340 (C+M) -
Alkaloid Rd-F Papaver jloribundurn Base V Papaver glaucum Alkaloid Papaver laterieium Alkaloid
Papaver aculeatum Aculeatine Papaver Litwinowii Alkaloid Alkaloid Papaver macrostomum Alkaloid Papaver ndiCaUk Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid
-
248
-
-
160
-
178
-
264
-
-
206
-
-
179
-
-
240
+ 118 (C+M)
HzS04 red-brown-green
404
HzS04 colorless-violet HzS04 colorless
359 361
HzSO4 yellow; with NCH3, no OCH3 361 HzS04 colorless-green (aporphine 361 skeleton) HzSO4 violet-pink 361 -
HzS04 red-brown
+
155 HzSO4 violet (10% ac. Acid)
269 433 433
234
+ 335 (C)
HzS04 colorless-pink
337
-
241 273
+ 7 8 (C) +29 (C)
HzS04 orange HzS04 brown-violet
410 410
-
197
-
&SO4 yellow
410
-
84 204 210 230 247
-
HzSO4 red-violet HzS04 red H2S04 red-violet HzSO4 yellow HzSO4 green-yellow
336 336 340 336 337
M 307
-
-
__ -
-
P v
F4 w
P
d M
P
M
k 3
k
8rn
4
TABLE XXV--continued
Compound
Empirical formula
Melting point (“C)
-
247 (white needles) 254 260 dec 262 261 (red needles) 266 dec
[mlDa
Other properties
References
~~
Papaver nwlicciule Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid
-
Alkaloid
-
a
-
-
C, chloroform; E, ethanol; M, methanol.
-
HzS04 colorless
336
-
-
HzS04 pink HzS04 red HzS04 red-yellow HzS04 orange
336 336 336 336
-
HzS04 blue-violet
336
-
5.
PAPAVERACEAE ALKALOIDS
429
(343)revealed the unusual structures I and I1 of these alkaloids, which were described in detail in Vol. X , p. 479 of this series. Recently three other alkaloids were isolated (436a) from the plant Fumaria officinalis. They also have the basic ochotensimine skeleton. For the whole group of these alkaloids (Table XXIV), the location of the mefhylenedioxy group in the ring D could be more firmly established on the basis of the nuclear Overhauser effect. The total synthesis of ( f )-ochotensine, ( f.)-ochotensimine, and their analogues has been reported (6lu, 227a, 249a, 344a). P. ALKALOIDS OF UNKNOWN STRUCTURE On studying the plant family Papaveraceae for the presence of alkaloids, there were isolated numerous bases whose constitution has not been elucidated and whose classification has not been carried out. It is also difficult to look for these compounds in the pertinent literature because frequently even reference journals do not record them. Boit (81) was the first to summarize them systematically in his monograph. Since then many bases have been identified and others added. I n Table XXV an attempt has been made to list the thus far undetermined bases of the plant family Papaveraceae. Their identification is often difficult because especially in older literature neither the optical rotation, the I R spectra, nor the color reactions with concentrated sulfuric acid or other reagents are mentioned.
IV. Biosynthetic and Chemotaxonomic Conclusions The systematic investigation of alkaloids of the plant family Papaveraceae has led to an accumulation of considerable knowledge which a t present can be used for a t least a preliminary chemotaxonomic classification of the genera and sections and elimination of those alkaloids which are unsuitable for chemotaxonomic studies. Manske (298)was the first t o carry out the classification of the plants of this family on the basis of the contained alkaloids followed by Santavf (424).The difference observed in the occurrence of the individual groups of alkaloids in the genera and sections might be used for a chemotaxonomic revision of the present morphological system since the chemical data indicate the presence/ absence of the enzymic systems which are responsible for the corresponding chemical reaction in the alkaloid series. I n this connection it should be noted that it is well known that in the
430
\ /
1
m
I
2
3
U
U
&\ d
0
4;
4;I
7 z H Y
F. ~ANTAVP
X
xv
I I
XI11
XI
SCHEME 20. The interrelationshipof some alkaloids of the papaveraceae (the C atoms of reticuline, I, marked by dots and arrows, show the possible linkage during the formation of the derivatives 11-XV). a = Oxidative coupling; b = reductive cleavage; R = H or CH3.
rp
w
432
F.
SANTAV~.
majority of the groups of alkaloids of the family Papaveraceae the common precursors are the benzylisoquiiioline alkaloids (Scheme 20, type I) which, on phenolic oxidative coupling (40,353),give rise to the different skeletons II-XV. The tetrahydroprotoberberine (VIII) and the protopine (XII) skeletons arise due to the formation of the so-called berberine bridge (31, 32, 39, 54). The alkaloids of the benzophenanthridine type (XIV) arise from the tetrahydroprotoberberine structure (VIII) (39, 512). Thus far, experimental confirmation of the biosynthesis of the rhoeadine (XIII) alkaloids has not been given and no hypothesis has been put forward regarding the biosynthesis of the sendaverine and 13-methyltetrahydroprotoberberinealkaloids and their natural derivatives. As already mentioned in the section on the benzophenanthridine bases (Section 1II.N) the author of this review assumes that dihydroxyphenylalanine and the liydroxy derivatives of tropic acid are the biosyntlietic precursors of the 13-methyltetrahydroprotoberberinebases and of their derivatives ( 13-methylprotopine bases, corynoline, and ochotensimine). A classification of the known alkaloids based on the individual tribes, genera, and sections (Table I) shows that all the investigated genera contain protoberberine, protopine, aiid benzophenanthridine alkaloids of the sanguinarine and chelerythrine type (195).There was also observed a frequent occurrence of the aporphine alkaloids. I n the plant family Papaveraceae, the aporphine alkaloids having oxygen substituents in position C-8 are absent. None of these groups of alkaloids can be used for chemotaxonomic purposes. The enzymes which synthesize them are therefore ubiquitous for the whole family Papaveraceae. The pavine alkaloids (VI) were detected in the plant genera Eschscholtzia and Argemone, the isopavine alkaloids (VII) in the tribe Papavereae (genus Roemeria and Papaver), the cularine alkaloids (Section 111,F) in the genera Dicentra and Corydalis (tribe Corydaleae), and the phthalideisoquinoline alkaloids (X) in the plant genera Stylophorum, Hylomecon, Papaver (only in the section Mecones), Adlumia, Corydalis, and Dicentra (Table I).The genera Corydalis, Dicentra and Fumaria were found to contain ocliotensimine (Section II1,O) alkaloids. The alkaloids of the armepavine type were detected in the genus Papaver (section Miltantha) aiid in the form of a glycoside (latericine) in the sections Orthorhoeades and Pilosa. From this it follows that only these sections elaborate enzymes which are able to cleave the phenol group from the C-3' atom or to use tyrosine for the biosynthesis of armepavine alkaloids. It is of interest that all the sections of the genus Papaver (Table XXVI) contain alkaloids of the rhoeadine type (XIII) which could not be found
TABLE XXVI TYPESOF ALKALOIDS FOUNDIN DIFFERENT SECTIONS OF
THE
PLANTGENUSPupaver"
Types of alkaloids
Sections of the genus Pupaver -
Orthorhoeades Argemonorhoeades Carinahe Mecones Miltantha Pilosa Macrantha Scapiflora Horrida
+ + + + + +
-
-
Reference (240). Benzylisoquinoline alkaloids of the armepavine type. c Presence of codeine and morphine. d In these sections rhoeadine was absent. e Papaverrubines detected only by paper chromatography.
b
+ + + + + + + -
+ + + + + + + +
-
+ + + + + +
+d
+d
+t-d'e
+ + + + + + + + +
434
F.
~ANTAVP
in any other genera; rhoeadine was not found in the sections Miltantha, Macrantha, Scapiflora, and Horrida. The sections Macrantha and Scapiflora were found to contain alkaloids of the alpinine type (related to rhoeadine-see Table XVIII). The alkaloids of the glaudine type (also related to rhoeadine) were detected in the plant sections Mecones and Pilosa (in the plant P. oreophilum). On account of this finding, P. oreophilum differs from the other plants of the section Pilosa and it should therefore be relegated to the section Mecones. Since rhoeadine is also present in P . oreophilum, it might be that it represents a transitory form between the plants of the sections Pilosa and Mecones. It is noticeable that all the plants which produce alkaloids of rhoeadine type (threo compounds) are able to produce alkaloids of the isorhoeadine type (erythro compounds).All the thus far detectedalkaloids having the rhoeadine-isorhoeadine structure have the R-configuration at the C-2 atom. The investigated sections of the genus Papaver elaborate the erythro and the threo series also in the papaverrubine alkaloids (N-demethylated rhoeadine-isorhoeadine compounds). The promorphinane alkaloids were found in the sections Miltantha, Pilosa, Macrantha, and Scapiflora, and thebaine in some plants of the sections Orthorhoeades, Mecones, Pilosa, and Macrantha (genus Papaver). Codeine and morphine could be detected only in the plants P. somniferum and P . setigerum in spite of thorough searches in other species. It appears that only these two plants have enzymic systems which are able to carry out demethylation at C-6. Consequently these two plants ought to be excluded from the section Mecones and a new section should be suggested for them. Even the closure of the oxygen ring between the C-4 and C-5 atoms probably is not a common reaction in the sections and genera of the family Papaveraceae (see p. 366). The genus Papaver differs substantially from other members of the Papaveraceae by the presence of rhoeadine-papaverrubine alkaloids and the genera Corydalis, Dicentra and probably Fumaria which, in addition to the common benzylisoquinoline alkaloids contained in this family, are also able to synthesize some alkaloids having an additional CHQ group (13-methyltetrahydroprotoberberine and its natural derivativessee p. 384, and 13-methylprotopine-see p. 391). The alkaloid sparteine was isolated only from the plant Chelidonium majus. It differs in its constitution from the already mentioned groups of alkaloids which were derived from 1-benzylisoquinoline precursors. Schutte (443)studied the biosynthesis of sparteine in Chelidonium majus by means of radioactive cadaverine. He arrived at the conclusion that in this plant the biosynthesis takes the same pathway as in Lupinus luteus L.
V. Addendum: The Alkaloids of Fumariaceous Plants THEALKALOIDS OF FUMARIACEOUS PLANTS
No.
Name or designation
Mp°C
Formula
Functional groups
Reaction with HzS04
Referencesa ~
F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 F 10 F 11 F i2 F 13 F 14 F 15 F 16 F 17 F 18 F 19 F 20 F 21 F 22 F 23 F 24 F 25 F 26 F 27 F 28
Bicuculline (ct) d-Adlumine Adlumidine Capnoidine Glaucentrine (6) Capaurine Capauridine Corypalline Cu 1arine Cularidine Corlumine Corlumidine Cheilanthifoline tc-Cheilanthifoline A-Cheilanthifoline p -Cheilanthifoliqe Ochotensine ( 1 ) Aurotensine Cordrastine
2 OzCHz Greenish yellow OzCHz; 2 OMe 2 OzCHz (?) 2 OzCHz ( ? ) 3 OMe; O H 4 OMe; O H Colorless 4 OMe; O H OMe; O H 3 OMe 2 OMe; O H OzCHz; 2 OMe OzCHz; OMe; O H OzCHz; OMe; O H Violet OzCHz ( ? ) Brown-pink OzCHz( ?) ; 2 OMe OzCHz(9); 2 OMe OzCHz(?); OMe; O H 2 OMe; 2 O H 4 OMe
-
-
-
1-Adlumine (7) Corpaverine
Cryptocavine
-
238 180 138 230 223 148 135
C37H40010Nz CziHziO6N CigHz304N CigH1706N CzzHzsOsN CziHz604N C17Hig03N
4 OMe 3 OMe OzCHz ; 2 OMe 3 OMe; O H OzCHz(?);NMe OzCHz; 2 OMe 4 OMe 2 OMe; O H
-
Orange
Violet
-
2-4, 6 , 8, 12, 13, 15 4, 5 4
6, I & 7, 9, I 0 8
8 I4 17 17 11-13 11, 12, 14 12,13 13 \ 13 13 17 17 17 C q d a l i s sempervirens 17 Dicentra eximia 1 Dicentra canadensis 12 17 15 Dicentra chrysantha 15 :F)~orydalisclurea
I+
w
01
V. Addendum-continued
No. F 29 F 30 F 31 F 32 F 33 F 34 F 35 F 36
F 37 F 38 F 39 F 40 F 41 F 42 F 43 F 44 F 45 F 46 F 47 F 48 F 49 F 50 F 51 F 52 F 53 F 54 F 55 F 56 F 57
Name or designation Coreximine
Isocorypalmine Caseamine
Caseadine ( + ) -Tetrahydropalmatine caseanine Ochotensimine derivative
-
Mp "C
Formula
Functional groups 2 OMe; 2 OH 3 OMe OzCHz ( ? ) 3 OMe; OH 2 OMe 3 OMe 3 OMe OMe 2 OMe OMe
-
3 OMe
-
-
-
-
Yellow Colorless
-
-
-
-
-
-
._
-
-
-
-
2 OMe
-
4 OMe
Capaurimine ( ) -Tetrahydropalmatine
-
17 17 Dicentra eximia
15 18 18 18 Gorydalis cuseana 18 19
20
20 Corydalis micrantha 20 )20a Corydalis ochroleuca 20h Glauciumpavum 21a Corydalis ochotensis
Colorless
-
-
Lilac Greenish blue Colorless -
-
Q,
-
Colorless Colorless Colorless
20CH3 1 OMe 3 OMe 3 OMe
Ochotensimine
References=
-
-
OzCHz
-
-
-
Blua
-
+ w
Reaction with HzS04
-
21 21 22 Corydalis chvicuhta
23 23a Corydalis montana
c
6
F 58 F 59 F 58 F 59
Hunnemanine Thalictrifoline
F 60 F 61 F 62
-
-
174 CzzHzi05N 209 CzoHziOsN 155 CziHz304N 176 CzoHz304N 192-200
OMe OMe; OH
Orange
OMe
Lilac Emeraldgreen
251
"
Colorless-emerald 25 corydalis t~lictr.l,foolia green
-
-
196 CigH1705N
References. 1. R. H. F. Manske, Can. J. Res. 7, 258 (1932). 2. R. H. F. Manske, Can.J. Res. 7, 265 (1932). 3. R. H. F. Manske, Can. J. Res. 8 , 142 (1933). 4. R. H. F. Manske, Can.J. Res. 8 , 210 (1933). 5. R. H. F. Manske, Can. J. Res. 8, 404 (1933). 6. R. H. F. Manske, Can.J. Res. 8, 407 (1933). 7. R. H. F. Manske, Can. J. Res. 8, 592 (1933). 8. R. H. F. Manske, Can.J. Res. 9,436 (1933). 9. R. H. F. Manske, Can.J. Res. 10, 521 (1934). 10. R. H. F. Manske, Cun.J. Res. 10, 765 (1934). 11. R. H. F. Manske, Can. J. Res. B14, 325 (1936). 12. R. H. F. Manske, Gun.J. Res. B14, 347 (1936). 13. R. H. F. Manske, Can.J. Res. B14, 354 (1936). 14. R. H. F. Manske, Can.J.Res. B15, 159 (1937). 15. R. H. F. Manske, Can.J. Res. B15, 274 (1937). 16. H. Eppson, J. Am. Pharrn. Assoc. 24, 113 (1935).
-
-
26 Corydalis incisa
Q
17. R. H. F. Manske, Can.J. Res. B16, 81 (1938). 18. R. H. F. Manske and M. R. Miller, Can. J. Res. B16, 153 (1938). 19. R. H. F. Manske, Can.J. Res. B16, 438 (1938). 20. R. H. F. Manske, Can. J. Res. B17,57 (1939). 20a. R. H. F. Manske, Can.J. Res. B17,96 (1939). 20b. R. H. F. Manske, Can.J. Res. B17, 399 (1939). 21. R. H. F. Manske, Can.J. Res. Bl8,80 (1940). 21a. R. H. F. Manske, Can.J. Res. Bl8, 75 (1940). 22. R. H. F. Manske, Can.J.Res. B18,97 (1940). 23. R. H. F. Manske, Can. J. Res. B20,288 (1940). 23a. R. H. F. Manske, Can. J. Res. B20, 49 (1942). 24. R. H. F. Manske, L. Marion, and A. E. Ledingham, J. Am. Chem. SOC.64, 1659 (1942). 25. R. H. F. Manske, Can.J. Res. B21, 111 (1943). 26. R. H. F. Manske, J. Am. Chem. SOC.72, 3207 (1950). b Hydrochloride.
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349. V. A. Mnatsakanyan and S. Yu. Yunusov, Dokl. Akad. Nauk Uz.SSR No. 12, 36 (1961); C A 58, 1503 (1963). 350. N. M. Mollov, G. I. Yakimov, and P. P. Panov, Compt. Rend. Acad. BulgareSci. 20, 557 (1967). 351. K. Mothes and H. R. Schiitte, Angew. Chem. Intern. Ed. Engl. 2,341 and 441 (1963). 352. E. H. Mottus, H. Schwarz, and L. Marion, Can.J. Chem. 31, 1114 (1953). 353. H. Musso, i n “Organic Substances of Natural Origin” (A. R. Battersby and W. I. Taylor, eds.), Vol. 1, p. 1. Marcel Dekker, New York, 1967. 354. T. Nakano, Pharm. Bull. 2,329 (1954). 355. T. Nakasato and S. Asada, Yakugaku Zasshi 86, 134 (1966); C A 64, 19696a (1966). 356. T. Nakasato and S. Asada, Yakugaku Zasshi 86, 1205 (1966); C A 66,65671b (1967). 356a. S. Naruto, S. Arakawa, and H. Kaneko, Tetrahedron Letters 1705 (1968). 357. A. NBmeEkov&,A. D. Cross, and F. Santavf, Natumuiss. 54,45 (1967). 358. A. NBmeEkovB, V. Preininger, and F. Santavf, Abhandl. Deut. Akad. Wiss. Berlin, K l . Chem., Geol. Biol. 319 (1966). 359. A. NBmeEkovB and F. Bantavf, Collection Czech. Chem. Commun. 27, 1210 (1962). 360. A. NGmeEkova and F. Santavf; Collection Czech. Chem. Commun. 30, 912 (1965). 361. A. NBmeEkovB and F. Bantavf, Collection Czech. Chem. Commun. (in press). 362. D. Neubauer and K. Mothes, Planta Med. 9, 466 (1961). 363. M. M. Nijland, Pharm. Weekblad 100, 88 (1965). 363a. M. Onda, K. Takiguchi, M. Hirakura, H. Fukushima, M. Akagawa, and F. Naoi, Nippon Nogeikagaku Kaishi 39, 168 (1965). 363b. M. Onda, K. Abe, and K. Yonezawa, Chem. Pharm. Bull. (Tokyo) 16, 2005 (1968). 363c. M. Onda, K. Yonezawa, and K. Abe, Chem. Pharm. Bull. (Tokyo) 17, 404 (1969). 364. M. Ohashi, J. M. Wilson, H. Budzikiewicz, M. Shamma, W. A. Slusarohyk, and C. Djerassi, J. Am. Chem. SOC.85,2807 (1963). 365. M. Ohta, H. Tani, and S. Morozumi, Tetrahedron Letters 859 (1963). 366. M. Ohta, H. Tani, and S. Morozumi, Chem. & Pharm. Bull. (Tokyo) 12, 1072 (1964). 367. M. Ohta, H. Tani, S. Morozumi, and S. Kodaira, Chem. & Pharm. Bull. (Tokyo) 12, 1080 (1964). 368. M. Ohta, H. Tani, S. Morozumi, S. Kodaira, and K. Kuriyama, Tetrahedron Letters 1857 (1963); 693 (1964). 368a. S. Ose, H. Kaneko, and K. Namba, Jap. Pat. 15364 (1960); C.C. 55, 3933 (1961). 369. G. B. Ownbey, Torrey Botan. Club Mem. 21, 1 (1958); Brittonia 13, 91 (1961). 370. K. G. R. Pachler, R. R. Arndt, and W. H. Baarschers, Tetrahedron 21, 2159 (1965). 371. V. Parrak, 0. MohelskB, and F. MachovicovQ,Pharmazie 14,685 (1959). 372. V. Pavesi, Reale Zst. LombardoSci. Lettere Rend. [2] 38, 117 (1905); Chem. Zentr. I, 826 (1905). 373. G. Pellagri, Gazz. Chim. Ital. 7 , 297 (1877). 374. K. Pelz, Chem. Listy 57, 1107 (1963). 375. W. €3.. Perkin, Jr., J. Chem. SOC.55, 63 (1889); 57, 992 (1890). 376. W. €3.. Perkin,J. Chem.Soc. 109, 315, 815 (1916); 115, 713 (1919). 377. W. H. Perkin and R. Robinson, J . Chem. SOC.99, 775 (1911). 378. S. Pfeifer, Pharmazie 17, 298 (1962). 379. S. Pfeifer, Pharmazie 19, 678 (1964). 380. S. Pfeifer, Pharmazie 19, 724 (1964); C A 62, 6803 (1965). 381. S. Pfeifer, Pharmazie 20, 240 (1965). 382. S. Pfeifer, J. Chromatog. 24, 364 (1966). 383. S. Pfeifer, J. Pharm. Pharmacol. 18, 133 (1966); C A 64, 12744 (1966). 384. S. Pfeifer, Pharnzrczie 21, 492 (1966).
5. PAPAVERACEAE ALKALOIDS
449
385. S. Pfeifer, Pharm. Ztg. 111, 463 (1966). 386. S.Pfeifer and S. K. Banerjee, Pharmzie 19,286 (1964). 387. S. Pfeifer and S. K. Banerjee, Arch. Pharm. 298,385 (1965). 388. S. Pfeifer, S. K . Banerjee, L. Dolejg, and V. Hanu&,P h a m z i e 20,45(1965);C A 62, 14990 (1965). 388a. S. Pfeifer and H. Dohnert, Pharmazb 22,343 (1967). 389. S. Pfeifer and V. HanuF;,Pharmazie 20,394 (1965). 390. S.Pfeifer and L. Kuhn, Pharmazie 20,394 (1965). 391. S.Pfeifer and L. Kuhn, Pharmazie 22,221 (1967). 391a. S. Pfeifer and L. Kuhn, Pharmazie 28, 199 and 267 (1968). 392. S. Pfeifer and I. Mann, Pharmazie 19,786 (1964). 393. S. Pfeifer and I. Mann, Pharmzie 20,643 (1965). 394. S.Pfeifer and I. Mann, Pharmazie 21,251 (1966). 395. S.Pfeifer and I. Mann, Rbhandl. Deut. Akad. Wiss. Berlin, K l . Chem., Geol. Biol. 315 ( 1966). 395a. S.Pfeifer and I. Mann, Pharmuzie 23,82 (1968). 396. S:Pfeifer,I.Mann,L.Dolej&,andV. Hanu&,Pharmazie20,585(1965). 397. S. Pfeifer, I. Mann, L. Dolejli, V. H a n d , and A. D. Cross, Tetrahedron Letters 83 (1967). 397a. S.Pfeifer, I.Mann, and L. Kiihn, Pharm. Zentralhalle 107, 1 (1968). 398. S. Pfeifer and J. Teige, Pharmazie 17,692 (1962). 399. S. Pfeifer and D. Thomas, Pharmzie 21,378(1966). 400. S. Pfeifer and D. Thomas, Pharmazie 21,701 (1966). 401. S. Pfeifer and D. Thomas, Pharmzie 22,454(1967). 402. T.F. Platonova, P. S. Massagetov, A. D. Kuzovkov, and L. M. Utkin, Zh. Obshch. Khim. 26,173 (1956);CA 50, 13960 (1956). 403. L. Pohl and W. Wiegrebe, Z . Naturforsch. 20b,1032 (1965). 404. V. Preininger, J.Appelt, L. SlavikovB,and J. Slavik, CollectionCzech.Chem. Commun. 32,2682(1967). 405. V. Preininger, A. D. Cross, J. W. Murphy, F. Santavjr, and T. Toube, Collection Czech. Chem. Cornrnun. 34, 875 (1969). 406. V. Preininger, A. D. Cross, and F. Santavjr, Collection Czech. Chem. Conzmun. 31, 3345 (1966). 407. V. Preininger, J. Hrbek, Jr., Z. Samek, and F. Santavjr, Acta Univ. Palackianae Olomucensis, Pac. Med. (1969)(in press); Arch. Phcrm. (in press). 408. V.Preininger, J.Hrbek, Jr.,andF.Santavjr,privateobservation(1967). 40%. V. Preininger, L. Hruban, V. SimAnek, and F. Bantavjr, Collection Czech. Chem. Commun. (1969)(in press). 409. V. Preininger and F. Santavjr, Acta Univ. Palackianae Olomucensis, Fuc. Med. 43,5 (1966). 409a. V. Preininger and F. Santavjr, Pharmazie (in press). 410. V. Preininger, P. VBcha, B. Sula, and F. Santavjr, Planta Med. 10, 124 (1962); C A 58,5988 (1963). 411. V. Preininger, P. Vrublovskjr, and V. Stastnjr, Pharnuzzie 20,439(1965). 412. F.L. Pyman,J. Chem. SOC.95,1619 (1909). 413. F. L.Pyman,J. Chem. Soc. 103,817 (1913). 414. F.L. Pyman,J. Chem. Soc. 107, 176 (1915). 415. P. Rabe and A. McMillian, Ann. 377, 223 (1910). 416. H. Rapoport, N.Levy, and F. R. Stermitz,J. Am. Chem. SOC.83,4298(1961). 417. H. Rapoport, F. R. Stermitz, and D. R. Baker, J . Am. Chem. Soc. 82,2765 (1960).
450
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BANTAVJ
417a. K. Rehse, Naturwiss. 55, 390 (1968). 418. R. Robinson, A. S. Bailey, and R. S. Staunton, Nature 165,235 (1950);J. Chem.Soc. 2277 (1950). 418a. B. K. Rostockii and J. L. Lvova, Med. Proin. SSSR, No. 2,17 (1964). 419. S. Safe and R. Y. Moir, Can. J . Chem. 42, 160 (1964). 420. I. Sallay and R. H. Ayers, Tetrahedron 19, 1397 (1963). 420a. J. Sam and A. J. Bej, J . Phtrrm. Sci. 56, 906 (1967). 421. E. Sanchez and J. Comin, Tetrahedron 23, 1139 (1967). 422. A. W. Sangster and K. L. Stuart, Chem. Rev. 65, 69 (1965). 423. F. Santavf, Abhandl. Deut. Akud. Wiss. Berlin, K l . Chem., Geol. Biol. 1 and 85 (1964);Pharmazie 15, 676 (1960). 424. F. Santavf, Collection Czech. Chem. Commun. 27, 1717 (1962). 425. F. Santavf, Alkaloide i n “ Dunnschicht-Chromatographie” (E. Stahl, ed.), 2nd ed., pp. 405-449. Springer, Berlin, 1967. 426. F. Santavj., personal observation (1967). 427. F. Santavf, M. HorBk, M. MaturovB, and J. Brabenec, Collection Czech. Chem. Commun. 25, 1344 (1960). 428. F. h n t a v f , J. Hrbek, Jr., and K. Blitha, Collection Czech. Chem. Commun. 32, 4452 (1967). 429. F. Bantavf, L. Hruban, and M. Maturova, Collection Czech. Chem. Commun. 31,4286 (1966). 430. F. Santavf, J. L. Kaul, L. Hruban, L. DolejB, V. H a n d , K. Blitha, and A. D. Cross, Collection Czech. Chem. Commun. 30, 335 and 3479 (1965); C A 64, 14230 (1966). 431. F. Santavf andM. MaturovB,Planta &fed. 15, 311 (1967). 432. F. Santavf, M. MaturovB, A. NBmeEkovB, and M. Hortik, Collection Czech. Chem. Commun. 24, 3493 (1959); 25, 1901 (1960). 433. F. santavp, M. Maturovh, A. NBmeEkova, H. B. Schroter, H. PotBHilovB, and V. Preininger, Planta Med. 8, 167 (1960); C A 54, 18884 (1960). 434. F. Santavf and A. NBmeEkova, Collection Czech. Chem. Commun. 32, 461 (1967). 435. F. h n t a v f , H. PotBBiloviL, and A. NBmeEkovB, Actn Chim. Acnd. Sci.Hung. 18,457 (1959). 436. S . N. Sarkar, Nnture 162, 265 (1948); C A 43,361 (1949). 436a. J. K. Saunders, R. A. Bell, C . - Y . Chen, D. B. MacLean, and R. H. F. Manske, Can. J. Chern. 46, 2873, 2876 (1968). 437. J. W. Schermerhorn and T. 0. Soine, J . A m . Pharm. Assoc., Sci.Ed. 40, 19 (1951). 438. E. Schmidt, Arch. Pharm. 237, 625 (1899). 439. C. Schopf, Angew. Chem. 62,453 (1950). 440. C. Schopf and M. Schweickert, Ber. 98, 2566 (1965). 441. C. Schopf and K. Thierfelder, Ann. 497, 22 (1932). 442. H. B. Schroter, M. Maturova, and F. Santavf, Plantn Med. 7, 329 (1959). 443. H. R. Schutte and H. Hindorf, Nnturzuisa. 51, 463 (1964). 444. Schwarz; Dissertation, Marburg (1928), acc. to “Chemistry of Carbon Compounds” (E. H. Rodd, ed.), Vol. IV C, p. 1965. Elsevier, Amsterdam, 1960. 445. A. I. Scott, Quart. Rev. (London) 19, 1 (1965). 445a. E. Sebe, S. Abe, N. Murase, and H. Sugaya, J. C‘hin. Chem. Soc. (Taipei) 15, 146 (1968). 445b. E. Sebe, S. Abe, N. Murase, and Y. Shibata, J. Chin. Chem. 8oc. (Taipei) 14, 135 (1967). 446. E. Seoane, Anales RenlSoc. Espan. Pis. Quim. ( M e d r i d )B61, 747 (1965). 447. E. Seoane, Anriles RealSoc. Espan. Fis.Quim. ( M a d r i d )B61,755 (1965).
5. PAPAVERACEAE ALKALOIDS
45 1
448. M. Shamma, Experientia 16, 484 (1960). 449. M. Shamma, Ezperientia 18, 64 (1962). 449a. M. Shamma and B. S. Dudock, Tetrahedron Letters 3825 (1965). 450. M. Shamma and W. A. Slusarchyk, Chem. Rev. 64, 59 (1964). 4.51. M. Shamma and W. A. Slusarchyk, Chem. Commun. 528 (1965). 452. M. Shamma and W. A. Slusarchyk, Tetrahedron Letters 1509 (1965). 453. M. Shamma, J. A. Weiss, S. Pfeifer, and H. Dohnert, Chem. Commun. 212 (1968). 454. V. Simanek, V. Preininger, and P.Santavf, Tetrahedron Letters 2106 (1969). 455. J. Slavik, Cesk. Furm. 4, 15 (1955). 456. J. Slavik, Collection Czech. Chem. Contmun. 20, 198 (1955); C A 49, 11673 (1955). 457. J. Slavik, Chem. Listy 52, 1957 (1958); C A 53, 1640 (1959); Collection Czech. Chem. Commun. 24, 2506 (1959). 458. J. Slavik, Collectiori Czech. Chef?,.Commun. 24, 3601 (1959); C A 54, 6777 (1960). 459. J. Slavik, Collectiou Czech. Chem. Commun. 26,2933 (1961); C A 56, 7426 (1962). 460. J. Slavik, Collection Czech. Chem. Commun. 28, 1738 (1963); C A 59, 11886 (1963). 461. J. Slavik, Collection Czech. Chem. Commun. 28, 1917 (1963); C A 59, 11886 (1963). 462. J. Slavik, Collection Czech. Chem. Commun. 29, 1314 (1964). 463. J. Slavik, C'ollection Czech. Chem. Commun. 30, 914 (1965). 464. J. Slavik, Collection Czech. Chem. Commun. 31, 4184 (1966). 465. J. Slavik, Collection Czech. Chem. Commun. 32, 4431 (1967). 466. J. Slavik, Collection Czech. Chem. Commun. 33, 323 (1968). 467. J. Slavik, personal communication (1967). 468. J. Slavik and J. Appelt, Collection Czech. Chem. Commun. 30, 3687 (1965). 469. J. Slavik, J. Appelt, and L. Slavikova, Collection Czech. Chem. Chmmun. 30, 3961 (1965). 470. J. Slavik, L. DolejB, V. HanG, and A. D. Cross,Collection Czech. Chem. Commun. 33, 1619 (1968). 471. J . Slavik, L. DolejB, K. VokaE, and V. HanuG. Collection Czech. Chem. Cornmun. 30. 2864 (1965); CA 63,8423 (1965). 472. J . Slavik, V. HanuB, K. Voka6, and L. DolejB, Collection Czech. Chem. Commun. 30, 2464 (1965). 473. J. Slavik and L. SlavikovB, Chem. Listy 48, 1382 (1954); Collection Czech. Chem. Commun. 20,21 (1955). 474. J . Slavik and L. Slavikovii, Collection Czech. Chem. Commun. 20, 27 (1955); CA 49, 10987 (1955). 475. J. Slavik and L. SlavikovB, Chem. Listy 50, 969 (1956). 476. J. Slavik and L. SlavikovQ, Collection Czech. Chem. Commun. 22, 279 (1957). 477. J. Slavik and L. Slavikova, Collection Czech. Chem. Commun. 24, 3141 (1959); C A 54, 2390 (1960). 478. J. Slavik and L. SlavikovL, Collection Czech. Chem. Commun. 26, 1472 (1961); C A 55, 27782 (1961). 479. J. Slavik and L. Slavikova, Collection Czech. Chem. Commun. 26, 1839 (1961); C A 55,27782 (1961). 480. J. Slavik and L. SlavikovB, Collection Czech. Chem. Commun. 28, 1728 (i963). 481. J. Slavik and L. Slavikovh, Collection Czech. Chem. C'ommun. 28, 2530 (1963); C A 59, 15331 (1963). 482. J. Slavik, L. SlavikovQ,and J. Brabenec, Collection Czech. Chem. Commun. 30, 3697 (1965). 483. J. Slavik, L. Slavikova, and L. DolejB, Collection Czech. Chem. L'ommun. 33, 4066 (1968).
452
F.
BANTAVP
484. J. Slavik, L. SlavikovB, and K. HaisovB, Collection Czech. Chem. Commun. 32, 4420 (1967). 485. J. Slavik, L. SlavikovB, V. Freininger, and F. Santavf, Collection Czech. Chem. Commun. 21, 1058 (1956). 486. L. SlavikovQ,Collection Czech. Chem. Commun. 31, 4181 (1966). 487. L. SlavikovB, Collection Czech. Chem. Commun. 33, 635 (1968). 488. L. SlavikovQand J. Slavik, Chem. Listy 51, 1923 (1957); CA 52, 2344 (1958). 489. L. SlavikovB and J. Slavik, Collection Czech. Chem. Commun. 31, 1355 (1966); CA 64, 17653 (1966). 490. L. SlavikovB and J. Slavik, Collection Czech. Chem. Commun. 31, 3362 (1966). 491. L. Slavikovii,T. Shun, and J. Slavik, CollectionCzech. Chem. Commun. 25,756 (1960). 492. L. F. Small, cit. acc. to B. Witkop and S. Goodwin,J. Am. Chem.SOC.75,3371 (1953). 493. G. Snatzke and G. Wollenberg, J. Chem. SOC.,C 1681 (1966). 494. T. 0. Soine and L. B. Kier, J. Am. Pharm. Assoc., Sci. Ed. 51, 1196 (1962). 495. T. 0. Soine and L. B. Kier, J . Pharm. Sci. 52, 1013 (1963). 496. E. Spiith, Molzntsh. 41, 297 (1920). 497. E. Spiith and F. Berger, Ber. 64, 2038 (1931). 498. E. Spiith and A. Dobrowsky, Ber. 58, 1274 (1925). 499. E. Spiith and H. Epstein, Ber. 59, 2791 (1926). 500. E. Spiith and H. Holter, Ber. 60, 1897 (1927). 501. E. Spiith and P. L. Julian, Ber. 64, 1131 (1931). 502. E. Spiith and F. Kuffner, Ber. 64, 370 (1931). 503. E. Spiith and F. Kuffner, Ber. 64, 1123 (1931). 504. E. Spiith and E. Mosettig, Ber. 58, 2133 (1925). 505. E. Spiith and E. Mosettig, Ber. 59, 1496 (1926). 506. E. Spiith and E. Mosettig, Ber. 60, 383 (1927). 507. E. Sphth, E. Mosettig, and 0.Trothandl, Ber. 56, 875 (1923). 508. E. Spiith and R. Posega, Ber. 62, 1029 (1929). 509. E. Spiith, F. Schlemmer, G. Schenck, and A. Gempp, Ber. 70, 1677 (1937). 510. E. Spiith, L. Schmid, and H. Sternberg, Monatsh. 68, 33 (1936). 511. E. Spiith andR. Seka, Ber. 58, 1272 (1925). 512. I. D. Spenser, Llvydia 29, 71 (1966). 513. F. R. Stermitz and L. Chen Teng, TetrahedronLelters 1601 (1967). 514. F. R. Stsrmitz, L. Chen, and J. I. White, Tetrahedron 22, 1095 (1966). 514% F. R. Stermitz, R. M. Coomes, and D. R. Harris, Tetrahedron Letters 3915 (1968). 515. F. R. Stermitz, S.-Y. Lwo, and G. Kallos, J. Am. Chem. SOC.85, 1551 (1963). 516. F. R. Stermitz, R. Pua, and H. Vyas, Chem. Commun. 326 (1967). 517. F. R. Stermitz and H. Rapoport, Nature 189,310 (1961);J . Am. Chem. SOC.83,4045 (1961). 518. F. R. Stermitz and J. N. Seiber, J . Org. Chem. 31,2925 (1966). 519. F. R. Stermitz and J. N. Seiber, Tetrahedron Letters 1177 (1966), and references therein. 519a. K. L. Stuart and M. P. Cava, Chem. Rev.68, 321 (1968). 520. K. L. Stuart and C. Chambers, Tetrahedron Letters 2879 (1967). 520a. J. Suszko and M. D. Rozwadowska, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 12, 767 (1964). 520b. K. L. Stuart and M. P. Cava, Chem. Rev. 68,321 (1968). 520c. K. L. Stuart, L. J. Haynes, M. Barrett, and G. E. M. Husbands, Tetrahedron Letters 4473 (1968). 520d. K. Szendrei, Bull. Narcotics, U.N., Dept. Social Affairs 20, No. 1, p. 51 (1968).
5 . PAPAVERACEAE ALKALOIDS
453
521. H. Tagurhi and I. Imaseki, J . Phurm. SOC.Japa?i 83, 578 (1963); 84, 773 and 955 (1964). 522. N. Tskao, C'hem. & PIicmn. Bull. (Tokyo) 11, 1306 and 1312 (1963). 523. Ch. Twni, S. Titkizo, N. Takao, and K. Tagahara, Yakugccku Zasshi 82, 748 and 7.51 (1962). 523a. Ch. Tani and S. Takao, Yakugaku Zasshi 87,699 (1967). 523b. Ch. Tani and N. Takao, Yakugaku Zasshi 82, 755 (1962). 524. Ch. Tani, N. Takao, and S. Takao, Yukugaku Zasshi 82,594 and 598 (1962); C'A 57, 4758 (1962). 525. A. Tatematsu, T. Goto, T. Nakamura, and S. Yamaguchi, Ynkugaku Zrtsshi 86, 195 (1966). 526. W. I. Taylor, Tetrahedron 14, 42 (1961). 52th. P. TBtBnyi and D. V&gu,jfalvi,Plant. Med. Phytothk. 2, 97 (1968). 52613. D. Thomas and S. Pfeifer, Phnrm. Zentralhulle 107, 173 (1968). 527. M. Tomita and M. Fujita, J. Pharm. SOC. Japan 82, 1457 (1962). 528. M. Tomita and M. Furukawa, TetrtchedronLetters 2637 (1964). 529. M. Tomita, H. Furukawa, T. Kikuchi, A. Kato, and T. Ibuka, Chem. & Pharm. Bull. (Tokyo) 14, 232 (1966). 530. M. Tomita, A. Kato, T. Ibuka, H. Furukawa, S. Asada, and M. Kozuka, Shitsuryo Bunseki 15, 104 (1967). 531. M. Tomita, A. Kato, T. Ibuka, H. Furukawa, and M. Kozuka, Tetrahedron Letters 2825 (1965). 532. M. Tomita and J. Kunitomo, YakugakuZasshi 82,734 (1962); CA 58,4613 (1963). 533. M. Tomita, S.-T. Lu, and T. Ibuka, J . Pharm. SOC. Japan 86,414 (1966). 534. M. Tomita, T. Shingu, K. Fujitani, and H. Furukawa, Chem. & Phtrrm. Bull. (Tokyo) 13, 921 (1965). 535. M. Tomita, T. Shingu, and H. Furukawa, Yakuguku Znsshi 86, 373 (1966). 536. H. Trabert and U. Schneidewind, Pharm. Zentrulhalle 98, 447 (1959); C A 54, 819 (1960). 537. R. Tschesche, P. Welzel, and G. Legler, Tetrahedron Letters 445 (1965). 538. A. Voss and J. Gadamer, Arch. Pharm. 248,44 (1910). 539. D. Walterovh and F. Santavj., Collection Czech. Chem. Comnaun. 33, 1623 (1968). 540. W.-K. Huang, C . 4 . Chang, and K . 3 . Lin, Actu, Chim. Sinicn 31, 470 (1965); CA 64, 15936e (1966). 541. W. M. Whaley and M. Meadow, J . Chem. SOC.1067 (1953). 542. D. M. S. Wheeler, T. H. Kinstle, and K. L. Rinehart, Jr., J . Am.'Chem. SOC. 89, 4494 .( 1967). 543. E. Wiechens, Inaugural dissertation, Munster (1960). 543a. W. Winkler, Arch. Pharm. 292, 293 (1959). 544. W. Winkler and W. Awe, Arch. Pharm. 294, 301 (1961). 545. F. Wrede, Forsch. Portschr. 14, 173 (1938). 546. N. C. Yang, G. R. Lenz, and A. Shani, Tetroltedron Letter.? 2941 (1966). 547. S. Yu. Yunusov, S. T. Akramov, and G. P. Sidyakin, Dokl. A k a d . Ntruk U z . SSR No. 7 , 2 3 (1957); C A 53, 3606 (1959). 548. S. M. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Dokl. Akod. Nciuk SSSR 162, 607 (1965); C A 63, 5695 (1965). 549. S. M. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Dokl. Aknd. Nriuk CJz. SSR No. 23, 38 (1966). 550. S. M. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Khim. Prirodu. Soedin. 1, 68 (1967).
454
F.
GANTAVP
551. S.Yunusov, R. A. Konovalova, and A. P. Orechov, Zh. Obshch.Khim. 10,641 (1940); Chem. Zentr. I, 2530 (1941). 552. S. Yu. Yunusov, V. A. Mnatsakanyan, and S. T. Akramov, Dokl. Akad. Nauk Uz. SSR No. 8, 43 (1961); C A 57, 9900 (1962). 553. S . Yu. Yunusov, V. A. Mnatsakanyan, and S. T. Akramov, Izv. Akad. Nauk SSSR, Ser. Khim. 502 (1965); G A 63,642 (1965). 554. S . M. Yunusov and S. Yu. Yunusov, Khim. Prirodn. Soedin. 4 , 6 1 (1968). Note added in proof. The plant Chelidonium majus L. also gave the alkaloids berberine and methoxychelidonine [R. Lavenir and R. R. Paris, Ann. Pharm. Franc. 23,307 (1965)l. From the plant Corydalis govaniana (Wall. Tent.) there were isolated the alkaloids protopine, corlumine, bicuculine, and isocorydine [O. E. Edwards and K. L. Hands, Can. J . Chem. 39, 1801 (196l)l. The alkaloid corydine which was isolated earlier from the plant Corydalis stewartii was identified as protopine [G. A. Miana, Ikram Mohamed, and S. A. Warsi, Pakistan J. Sci. I d . Res. 11, 337 (1968)J
-CHAPTER
6-
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE R. H. F. MANSKE Uniroyul Limited Research Laboratory, Guelph, Onturio and the University of Wuterloo, Waterloo, Ontario
I. Int,roduction ........................................................ 11. Plants and Their Contained Alkaloids.. ................................. References ..........................................................
455 455 506
I. Introduction This chapter is the inevitable miscellany devoted primarily t o records of new alkaloids obtained mostly from plants not hitherto examined. Where known their structures and other pertinent data are included. Many of the data have been retrieved from Chemical Abstracts and the descriptions are consequently rather brief. The author's personal bias is perhaps evident in a number of instances where new knowledge of well known alkaloids is reported. Where a plant or an alkaloid has been discussed in previous volumes of The Alkaloids the volume number and page are given in parentheses following the subject heading.
II. Plants and Their Contained Alkaloids 1 . Acacia berlandieri Benth. (Leguminosae)
Tyramine, N-methyltyramine, and hordenine ( I ) . 2. Acacia complanata A. Cunn.
N,-Methyltetrahydroharman (mp 109"; [aID f 0) (2). 3 . Acacia longifolia Willd. (Acacia phlebophylla P. Muell.)
N,N,,-Dimethyltryptamine was the only alkaloid found in this plant (3).
456
R. H. F. MANSKE
4. Acronychia haplophylla Eng. ( A . tetrandra F. Muell.) (Rutaceae) Acrophylline, C17H1703N (mp 120') (I)and acrophyllidine, C17H1904N (mp 177') (11).The structures were determined largely by spectroscopic
methods but the hexahydro derivative of I was shown to have structure I11 by a synthesis. For this purpose N-acetyl-m-anisidine was alkylated with isoamyl bromide in the presence of sodium hydride in DMF. Hydrolysis gave N-isoamyl-m-anisidine which on heating to reflux temperature with diethyl malonate in diphenyl ether gave I11 (mp 174') ( 3 a ) . 5 . Acutumine (Vol. VII, p. 435)
This base was shown to have a chlorine atom in its molecule and the empirical formula was corrected to C19H2406NC1 (mp 238"-240' ; [a]: - 206'). The halogen is not present as chloride nor is i t removed by reaction with silver oxide, with lithium aluminum hydride, nor by catalytic reduction. There are present'three methoxyls and a second hydroxyl which can be oxidized to the corresponding carbonyl by manganese dioxide (oxime, mp 213") ( 4 ) . Acutumine is accompanied by its lower homologue, acutumidine, ClsH~206NC1(mp 238'-241'; [0r.lD - 211") (5) and their structures have been shown to be I I I a and IIIb, respectively. The evidence was largely obtained from X-ray spectra but other spectral data and chemical studies served to confirm the structure and to assign the partial absolute configuration (6, 7').
6. Alangium lawmrckii Thw. (Alanginaceae) (Vol. X , p. 546)
The leaves of this plant have yielded two new alkaloids : alangimarckine, CZgH3703N3 (mp 186"; [a]$ - 67.7")whose structure was shown t o be IIIc; amkorine, C19H2904N (mp 176'; [a]: -02') which had previously been isolated (8) but whose structure (IV) had not been determined. The assigned structures were arrived a t largely by the modern physical methods (9). A stereoisomer of tubulosine, C~gH3703N3(mp 178'; [ a ] g - 84") (3'-epitubulosine)has also been isolated from this plant (10). 7 . Alangiurn lamarckii
Two new alkaloids have been isolated from the root bark of this plant ; alangicine, C2&@5N2 (mp 14%";["ID +641'), was shown to have structure V as the result of exhaustive spectral data; and desmethylpsychotrine, C27H3404N2 (mp 168'; [aID + 67.8") which was obtainable
6. NEW
457
ALKALOIDS
from psychotrine by partial demethylation and convert,ible into psychotrine 0-methyl ether by means of diazomethane. Spectral data show that it is either V I or V I I (12). 0
MeO
OH
0
&
M
e
O
h
0
Me0
clc
%
OH I11
I1
I
M +fo )e0
0 OMe
OH
1118; R = M e 1IIb; R = H
IV
1110
Me0 "Et
OH V
VI; R ' = M e , R = H VII; R'= H, R =Me
8 . Alangium lamarckii
Two new alkaloids, marcine (mp 281"; [ c x ] ' ~ -68') and marckidine were present but their empirical formulas were not reported. Functional groups were recognized by IR spectra and the melting points of some derivatives were reported (12). 9. Alangium salviifolium Wangerin (Alanginaceae)
There still seems to be some confusion regarding the status of this plant. An earlier name is Grewia salviifolia L.f. family Tiliaceae and indeed the
458
R. H. F. MANSKE
genus Alangium has for long been regarded as in the family Cornaceae. Cephaeline was present in the specimen examined (13). 10. Alseodaphne archeboldiana (Allen) Kostermans (Lauraceae) ( - )-N-Norarmepavine, ( + )-reticuline, and ( + )- and ( & )-coclaurine (14). 11.
Alstonia venenatu R.Br. (Apocynaceae)
The new monoterpenoid alkaloid, venoterpine, CgH11ON (mp 128"130") was isolated in very small yield (0.0008%) from the fruit of this plant. Its structure (VIIa) was determined almost exclusively by NMR studies (15). 12. Anisotes sessiliflorus C.B.Q. (Acanthaceae)
Five new 4-quinazolinealkaloids were isolated from this plant and their structures were elucidated by the use of exhaustive spectral data followed in a few cases by chemical reactions. (The main alkaloid was dlvasicine, mp 21 lo.)The new alkaloids were anisotine, CzoH1gOzN3 (mp 189") (VIII); anisessine, CzoH1903N3 (mp 170") (IX); aniflorine, CzoHz103N3 (mp 197') (X); deoxyaniflorine, CzoHz10zN3 (mp 168"172') (XI); and sessiflorine, C19H190zN3 (mp 195"-197") (XII) (16). 13. Antirrhoea putaminosa F. Muell. (Rubiaceae) There is considerable confusion in the older literature regarding the naming of this plant. It has been placed a t various times in the genera Antirrhoeu, Timonius, and Guatturella. The major alkaloid is antirhine, C19Hz40Nz (mp 112"-114"; ["ID -2") whose structure is XIII. Its dihydro derivative melts a t 106°-108" (["ID + 23") ( 1 7 ) .
VII a
14. Amurine and Nudaurine(Vo1. X, p. 471)
Previously suggested structures of these alkaloids were shown to be inconsistent with spectral data. Exhaustive NMR investigations pointed to structures XIIIa and XIIIb, respectively, for amurine and nudaurine.
6.
459
NEW ALKALOIDS
VIII; H’
=
H” = H, I
NHMe XI; R’ = H, R” = OMe,
X; R’= OH, H”= OMe,
XII; H’= H, R” = OMe,
I
I
CH(CHzOH)CH=CHz
XI11
Limited, though crucial, chemical transformations confirmed these structures. Hofmann degradation of amurine gave rise to 2-hydroxy3-tnethoxyphenanthrene, and rearrangement under acidic conditioils generated the phenanthrene XIIIc. Reduction of amurine with LiAlH in THE’ gave a mixture of nudaurine and epinudaurine, the latter of which on oxidatmion with manganese dioxide regenerated amurine (18). 15. Annbusis ccphylln L. (Chenopodiaceae)(Vol. I, p. 2 2 8 )
Anabasamine, C ~ G H I ~on N ~the , basis of spectral data was b’ riven structure XIIId (19).
460
R. H. F. MANSKE
16. Anthotroche pannosa Endl. (Solanaceae)
Among a t least seven bases evidenced on a chromatogram, the major constituent proved to be ( - )-hyoscyamine (20). 17. Aquilegia karelini Baker ( A . vulgaris) (Ranunculaceae)
An alkaloid (hydriodide, mp 249"; [a]:: + 1 0 0 " ; diacetyl, mp 634", + 115') regarded as a dihydroxydimethoxyaporphine (21).
'Me
Me0
OH XIIIa
XIIIb
XIIIC
Me
XIIId
18. Aristolochia argentina Griseb. (Aristolochiaceae)
Base 1 , C19H2102N (oxalate, m p 176'; picrate, mp 235") whose structure was shown to be XIV by a synthesis of the corresponding 0-ethyl ether (22). 19. Aristolochia indica L. (Aristolochiaceae)
The alkaloid aristolochine (23)was shown to be identical with 1-curine (24). 20. Arundo donax L. (Vol. 11, p. 373) (Gramineae)
A more exhaustive examination of this plant disclosed the presence of N,N-dimethyltryptamine, bufotenine, and 5-methoxy-N-methyltryptamine as well as gramine and its N-oxide (25).
6.
461
NEW ALKALOIDS
2 1 . Astragalus tibetcsnus Benth. (Leguminosae) Smirnovine (26). 2%.Avicine and Nitidine (Vol. X, p. 487).
Among other syntheses, that of oxyavicine (XVI), is typical. Several routes were explored but the one chosen involved the combination of the amino aeetal (XVII)with glyoxylie acid in hydrochloric acid to generate XVIII. Condensation of the latter with (i-nitropi~)eronaland reduction HO MeC
\ XIV XV CH(0Me)g
I
XVI
XVII
XVIII
XIX
xx
462
R. H. F. MANSKE
of the product with ammoniacal ferrous sulfate gave XIX. Ring closure of XIX by the known procedure (27)gave XX, which upon decarboxylation, N-methylation, and oxidation generated XVI (28).
6' 0 OMe OMe
Me XXI
XXIa
23. Azima tetracantha Lam. (Salvadoraceae)
I n addition to the known carpaine this plant yielded two alkaloids: azimine (XV; n = m = 5 ) , C24H4204N2 (mp 112'-113'; [a]!$' k 0 ) and azcarpine (n= 5, m = 7), C26H4604N2 (amorphous). Exhaustive spectral data, and particularly the mass spectra, indicated that azimine was closely related to carpaine. Alkaline hydrolysis yielded only one product, azimic acid, and reduction with LiAlH gave only azimidiol, thus proving the symmetrical nature of the lactone ring system. The structure of azcarpine was similarly elucidated and the hydrolysis products, carpamic and azinic acids, confirmed it (29).
0
XXII
XXIII COzH I
XXIV
24. Balfourodendron riedellianum Engl. (Vol. IX, p. 236)
A phenolic tertiary base, ribalinidine, C15H1704N (mp 257'; [a]!$'= 15') of structure XXI has been obtained. The structure was arrived a t by
6. NEW ALKALOIDS
463
exhaustive spectral examination without recourse to chemical degradation (30). 25. Berberis laurina Billb. (Berberidaceae)
The leaves of this shrub gave berberine, ( - )-tetrahydropalmatine, and protopine. The bark gave berberine, obaberine, and two new bisbenzylisoquinoline alkaloids : 0-methylisothalicberine, C38H4206N2 (mp 208"; ["ID - 195")and lauberine, C37H4006N2 (hydrobromide, mp 250"-255"; ["]I) -335") (31). 26. Berberis lycium Royle ( 2 ) (Berberidaceae)
Berbenine, C19H2103N (mp 152"; [a]: + 98"),berbericine, C20H1704N (mp 162"; ["ID f 0), and berbericidine hydriodide, CzlH2104N.HI (mp 205"; ["ID f o ) (32). 27. Bocconia cordata Willd. (Papaveraceae) (Vol. IV, p. 79)
Sanguinarine, heleritrine, protopine, allocryptopine, and two bases, mp 180" and mp 286" (33). 28. Boehmeria platyphylla D. Don (Urticaceae) (Vol. X, p. 577)
The major alkaloid proved to be 3,4-dimethoxy-w-(2-piperidyl)acetophenone, C1bH2103N (mp 82"; [.ID 0) (XXIa) identical with a specimen obtained by the 0-methylation of pleurospermine (34).Reduction with sodium borohyrdide gave the dihydro derivative (mp 143"). 29. Brevicolline (Vol. X, p. 550)
Spectral evidence points to structure XXII for brevicolline. Some confirmation of this structure was obtained by oxidizing the alkaloid with' chromic-sulfuric acid. In addition to N-methylsuccinimide there were obtained the two compounds XXIII (mp 284") and XXIV (mp 205"). The decarboxylation of XXIV gave harman (mp 237') (35). 30. Bruguiera sexangula (Lour.) Prir. (Rhizophoraceae)
Brugine, C12H902NS2 (resin) (XXV). Hydrolysis gave tropine and 1,2-ditholane-3-carboxylicacid (mp SO0). Desulfurization with Raney nickel gave tropine n-butyrate (36).
464
R. H. F. MANSKE
31. Buphthalmum speciosum. Schreb. (Telekia speciosa Baum.) (Compo-
sitae) Telekine, C22H2307N (mp 170'; picrate, mp 150") (37). 3 2. Camptotheca accurninata Decne. (Nyssaceae)
Camptothecine, C20H1604N2 (mp 264'-267"; [a]$ + 31.3") was shown to have inhibitor activity against both lukemia and tumors. Exhaustive spectral analysis, finally by X-ray methods, showed that it had structure XXVI. The formation of several crystalline derivatives by the known chemical reactions was consistent with this structure (38). 33. Capaurimine (Vol. I X , p. 102)
A compound, which was assumed t o have the structure originally assigned to capaurimine, was.synthesized by a series of well-known reactions. The penultimate condensation with formaldehyde on a bromobenzylisoquinoline gave a product, which on reduction with zinc in alkaline solution, was not identical with capaurimine. The authors therefore question the correctness of the assigned structure (39) although the synthesis does not appear to be entirely unambiguous ( 4 0 ) . 34. Carnegia gigantea (Engelm.) Britton and Rose (Cactaceae) (Vol. IV, P. 15)
I n addition to the previously known carnegine this plant yielded gigantine, C13H1903N (mp 152"; [ a ] g + 27") which was shown, mostly by exhaustive spectral methods, to have structure XXVII (27). This alkaloid and macromerine along with berberastine are a group of bases having a benzylic hydroxyl reminiscent of that in adrenaline and ephedrine (41). 35. Cassipourea gurvwnijlua Tul. var . verticillata Lewis (Rhizophoraceae)
Cassipourine, C14H22N2S4 (mp 212"; [a]g- 11.8"; dimethiodide, mp 260'). C. gerrardii Alston gave gerrardine, CllH19N02S4 [mp 90" and 178"; hydrochloride, mp 267'; [a]% - 172" (HzO)] and two amorphous bases, gerrardamine (CgH15NOSZ) and gerrardoline (CgH15NOzSz) (42). NMR-data and other spectral data point to XXVIII as the structure of gerrardine. Disulfurization with Raney nickel gave a compound, CloH 2 0 0 2 (mp 33') which is probably decane-2,R-diol. X-Ray studies confirmed the above structure (43).
6.
465
NEW ALKALOIDS
Chemical degradation of cassipourine gave, among other and intractable products, pyrrolizidine (Raney nickel disulfurization). X-Ray analysis as well as exhaustive spectral data show that this alkaloid has structure XXIX (44).
s-s
p - p . c o u .
xxv
o
XXVI
?H
MeoQN,M
MeO- \
I
I OH
Me
Me XXVII
XXIX
I OH
XXVIII
:::p Me0
\OH
xxx
MeO-
\
0 L
XXXI
\ O
XXXII
36. Cassytha melantha R.Br. and C. glabella R.Br. ( 2 ) (Lauraceae)
(Vol. IX, p. 8) The major alkaloid of these plants is cassythicine (XXX). The N desmethyl derivative was also present in trace amounts. It is identical with actinodaphnine (45).
466
R. H. F. MANSKE
37. Cassytha racemosa Nees (Lauraceae) (Vd. I X , p. 8)
This plant yielded nantenine, isoboldine, laurotetanine, N-methyllaurotetanine, ( + )-coclaurine, as well as the new alkaloids, nornantenine (XXXI) which on N-methylation gave nantenine and 1,2-dimethoxy9,10-methylenedioxy-7-oxodibenzo(de,g)quinoline (XXXII) the structure of which follows from its preparation by the oxidation of nantenine (46). 38. Caulophyllum thalictroides Michx. (Berberidaceae)
The roots and rhizomes of this plant yielded methylcytisine, baptifoline, anagyrine, and magnoflorine ( 4 7 ) . 39. Ceanothus americanus L. (Rhamnaceae) (Vol. X, p. 551) A mixture of americine, C31H3904N5 (mp 136" and 142"-182"; [a12 - 198")and its homologue, homoamericine, was difficult to separate
but served for the purpose of structure investigations. I n addition to UV, IR, and NMR spectroscopy which identified many structural features, the use of mass spectroscopy and complete hydrolysis of americine and its dihydro derivative resulted in the elucidation of its structure as XXXIIa (48).Further study of ceanothamine-B has resulted in a revised structure XXXIIb, based on exhaustive physical methods and upon ozonolysis and hydrolysis (49, 50). It is identical with adouetine-X and ceanothamine-A is identical with frangulanine (49, 50). 40. Ceanothus integerrimus Hook. and Am. (Rhamnaceae) (Vol. X , p. 551)
Mass spectral examination was almost exclusively the means of determining the structures of integerrisine, C33H3804N4 (mp 285' ; [.]% - 164')
Ph
I
Me
XXXIIa
XXXIIb
6. NEW
467
ALKALOIDS
(XXXIII) and integerrenine, C31H4204N4 (mp 278'; [a]% - 228') (XXIV) but confirmation was achieved by hydrolysis and identification of the expected amino acids (51). A later report described the isolation of still a third polypeptide alkaloid, integerrine, C35H3904N5(mp 2 5 8 O ) , which on the basis of its mass spectrum was assigned structure XXXV (52). 42. Clausena heptaphylla Wt. & Am. (Rutaceae)
The weakly basic alkaloid, heptaphylline, C18H1702N (mp 170") is optically inactive. Exhaustive spectral analysis indicated a carbazole nucleus with hydroxyl and formyl substituents and an isoprenoid side chain. Treatment with polyphosphoric acid generated the isomeric chroman, cycloheptaphylline (mp 250') so that, ofthe possible structures, the most likely is XXXVII (54).
Ph
XXXIII
xxxv
XXXIV
XXXVI
0 XXXVII
XXXVIII
468
R. H. F. MANSKE
41. Chelidonine (Vol. X , p. 488) Though the chemical evidence had been satisfactory but not quite unambiguous for the structure of chelidonine, it was still desirable t o obtain confirmation and to reaffirm its stereochemistry. An exhaustive NMR spectral study has confirmed not only the general structure but has indicated that the most likely stereo structure which accounts for the strong hydrogen bonding is that shown (XXXVI) (53). 43. Cocculus trilobus DC. (Menisoermaceae) (Vol. VI, p. 443) Cocculolidine, C15H1903N (mp 146"; [a]$'+ 273"). This new alkaloid is toxic to a number of insects. It gave a remarkable series of products under a variety of conditions and these together with exhaustive spectral data point to its structure as XXXVIII (55). 44. Corydalis stewartii Fedde (Papaveraceae) Corycidine (mp 290"-291"; [a12 - 32"))corydinine(mp 199"-200"), and corydicine (mp 181"-184"). No analyses are given but the melting points of some salts and I R spectra are recorded (56). 45. Corydalis stricta Steph. OGN this , plant was shown to be The alkaloid, Base 2, C ~ ~ H ~ ~ from identical with a,P-hydrastine (mp 127"-129"; [a]? + 72"; picrate, mp 142"; methiodide, mp 189'-191") (57). 46. Corynoline (Vol. X , p. 487) The structure of this alkaloid had already been announced but the stereochemistry remained uncertain. An independent study has confirmed the earlier work and the stereostructure XXXIX is now given on the basis of exhaustive spectral data and a comparison of these with those of chelidonine :Alkaloid-V, also isolated from Corydalis incisa Pers. and obtainable from corynoline, is given structure XL (58). 47. Coryphantha runyonii Britton and Rose (Cactaceae) Macromerine was present. Its spectral data are consonant with structure XLa. It is also present in C. macromeris Lem. (59).
6. NEW ALKALOIDS
469
48. Crotalaria laburnifolia L. (Leguminosae)
An alkaloid [mp 197'-199"; [a]: + 29.7"(EtOH), - 19" (CHC13)Igave a picrate (mp 220"-222") and a methiodide (mp 220"-222"). Hydrolysis yielded an unidentified necine and senecic acid (60).
XXXIX
XL
49. Croton j-lavescens L.(Euphorbiaceae)
Norsinoactine, C18H1904N (mp 114"-115°; [a]',"- 107")(XLI) which had been isolated previously from Croton balsamifera Jacq. ( 4 4 )was isolated from the above species along with a new base, flavinine, C18Hlg04N (mp 130"-132'; [a]'," - 6"). Exhaustive spectral data indicate not only the structural features but the absolute stereochemistry as XLII ( R + R ' = H+Me) (45) similar t o that already ascribed to amurine (XLII; R+R'=CHz) (61,62). OH
I
eCH-CH2-NMez
50. Croton linearis Jacq. (Vol. X, p. 405
Two new alkaloids have been isolated from this plant: 8,14-dihydrosalutaridine, C19H2304N (mp 198"-203"; [ a ] g - 76.1)(XLIIa; R=Me, R' = H) and 8,14-dihydronorsalutaridine,C18H2104N (mp 208"-212" ; [a]? - 69.1") (XLIIa ; R = R' = H). These structures were arrived at largely by spectroscopic methods but they were confirmed by chemical reactions, particularly by hydrogenation to known compounds (63).
470
R. H. F. MANSKE
XLII
XLI
51. Croton wilsonii Griseb.
Five phenolic aporphines were isolated : wilsonirine, ClgHz104N (mp 211"-214") gave a neutral diacetate (mp 229"; [ a ] g +56") and on Nmethylation it gave a base (mp 188")shown to be identical with O-methylisoboldine, so that wilsonirine is XLIII ; hernovine ;N-methylhernovine,
I; XLIIe
(hydrochloride, mp 244"; [a13 + 209") (XLIV; R =Me; R'= R"=H ) ; 10-O-methylhernovine,C10H2104N (mp 157"; [a]:: + 188") (XLIV ; R = R' = H, R" =Me) ; N,Olo-dimethylhernovine,C~oH2304N (hydrochloride, mp 218"; [a13 + 139") (XLIV;R = R"= Me, R'= H).The structures were assigned on the basis of spectral analysis and on conversions to bases of known structure (64). C19H2104N
Me0
Me0
'
R"O
XLV
I OMe XLIII
XLIV
6.
NEW ALKALOIDS
471
52. Cryptocarya konishii Hyata and Machilus acuminatissimus (Hyata) Kahehira (Lauraceae) Crykonisine, C18H1703N (rnp 235"),on reduction with zinc and hydrochloric acid generated dl-N-norarmepavine (the L-form was present in the root of M. acuminatissimusalong with dl-coclaurine)and therefore it has structure XLV (65). 53. Cryptostylisfulva Schltr. (Orchidaceae)
This plant yielded the first 1-phenyltetrahydroisoquinoline alkaloid to be found in nature. Spectral data indicated that it was 1-(3,4methylenedioxyphenyl)-2-methyl-6,7-dimethoxy-l,2,3,4-tetrahydroiso quinoline, C19H2904N (mp 101'; [a]= +54') and a synthesis of the dlform confirmed this structure (XLVI). The amide resulting from the reaction of piperonoyl chloride with 3,4-dimethoxyphenethylaminewas cyclized by means of phosphorus oxychloride. The resulting dihydroisoquinoline was converted to methiodide and the latter reduced with sodium borohydride. The resulting dl-base (mp 117') was identical in spectral properties with the natural alkaloid (66). 54. Cuscuta monogyna Vahn ( 2 ) (Convolvulaceae)(Vol. VI, p. 10) Of the seeds of six species belonging to the same family, only the above yielded alkaloids. Agroclavine was isolated in 0.015% from the abovenamed plant (67).The named genus represents parasitic plants. 55. Cynoglossum australe R.Br. & C. amabile Stapf and Drummond (Borraginaceae) C. australe gave two new pyrrolizidene alkaloids : cynaustraline, C15H2704N (amorph.; picrolonate, mp 149') and cynaustine, C15H2504N (amorph.; picrate, mp 135'). Hydrolysis of these bases gave viridifloric acid in both cases and ( + )-isoretronecanol and ( + )-supinidine, respectively. C. amabile yielded echinatine and a new base, amabiline, which differs from cynaustine only in that the basic hydrolytic fragment is ( - )-supinidine (68). 56. Daphniphylline and Codaphniphylline The structure of daphniphylline (XLVIa) was determined by X-ray diffraction studies and is in accord with other spectral data. Codaphniphylline has structure XLVIa except that the OAc group is replaced by
472
R. H. F. MANSKE
hydrogen. Hydrolysis of daphniphylline to the corresponding carbinol followed by reaction with methanesulfonyl chloride and reduction of the resulting methanesulfonate (mp 162'-164") with zinc in methanol generated codaphniphylline (69).
M e 0e
o
q
I
m
e
57. Daphniphyllum macropodium Miq. (Euphorbiaceae) (Vol. X, p. 556)
Hirata and co-workers (70) have reported the isolation of two more alkaloids from this plant. Codaphniphylline, C30H4703N (amorph. ; hydrochloride, mp 266") showed spectrg which indicated that it was desacetoxydaphniphylline and the conversion of daphniphylline into the former was achieved. For this purpose it was hydrolyzed to the correspon-
XLVIa
ding carbinol and this converted into its methanesulfonate (mp 162")by reaction with methanesulfonyl chloride in pyridine. Reduction of the methanesulfonate with active zinc powder in methanol gave desacetoxydaphniphylline identical with codaphniphylline (71). Neoyuzurimine (picrate, mp 195"-198O) was not further characterized (70). Some transformations of the daphniphylline molecule were studied in detail. Desacetylisodaphniphylline was generated when the parent base was digested for 45 minutes a t 80"with 6 N hydrochloric acid and when it was treated with zinc powder in acetic anhydride saturated with
6. NEW
473
ALKALOIDS
hydrogen chloride the methyl ketone was reduced t o form desoxyisodaphniphylline(hydrochloride,mp 212') (72). The structure of yuzurimine (XLVII)had already been shown t o be of a different type from that of daphniphylline and the isolation of two more alkaloids was reported (73). Yuzurimine A, C25H3505N (hydrochloride, mp 249"-252"), was shown to be desacetoxyyuzurimine (XLVIII) by
R
XLVII; R = OAc, R' = OH XLVIII; R = H, R' = OH XLIX; R = H , R ' = H
HO
LI
OMe LII
OH
OMe
L I11
OMe LIV
47 4
R. H. F. MANSKE
means of exhaustive spectral analyses. Yuzurimine B, C23H3303N (hydrochloride, mp 282"-284'), on similar analyses, was regarded as the carbinol obtainable by hydrolysis of XLIX ( 7 4 ) . An independent research disclosed the following alkaloids with the assigned structures as shown ( 7 5 ) .The same plant and the contained alkaloids were also exhaustively examined by a group from another Japanese laboratory and a summary of their findings follows. The structures which they assign are either similar to or identical with those already given. Macrodaphnine (XLIX) is apparently identical with yuzurimine and macrodaphniphyllidine (XLVIII) appears to be the acetyl derivative of yuzurimine B (75). Daphnimacropine, C27H4104N (mp 75"-84") (L). Daphniphyllamine, C32H4905N (identical with daphniphylline). Daphmacrine, C32H4904N (hydrobromide, mp > 300"; [aID + 30.1'). Macrodaphniphyllidine, C25H3504N (hydrobromide, mp 305"-306' ; [a]D +3.9') (XLIX). Macrodaphnine, C27H3907N (mp 180'; hydrobromide, mp 249"-252'; [a]D - 18.4') (XLVII). Daphmacropodine, C32H5104N (mp 214'-215"; [a]D 4.9'; hydrobromide, mp 215'-218"). Macrodaphniphyllamine, C23H3304N (mp 152'; ["ID - 51.7'; hydrobromide, mp 229"-230") (LI). 8.3'; hydroMacrodaphnidine, C27H3707N (mp 150"-152"; [a]D bromide, mp 240'-242").
+
+
58. Decodon vertidlatus (L.) E l l . (Lythraceae) (Vol. X , p. 556)
NMR data and mass spectral data show that decaline (LII) and vertaline (LIII) have the same skeleton and differ only in their stereochemistry. The given assignments are based on these and ORD-data ( 7 6 ) . Desmethylvertaline and desmethyldecaline were isolated and on methylation were converted into their nonphenolic congeners ( 7 7 ) .The alkaloid sinine, C26H3206N, was shown to be identical with lythridine and by means of'exhaustive spectral examination was shown to have structure LIV though its stereochemistry was not elucidated. It is to be noted that it is a diphenyl derivative rather than a diphenyl ether ( 7 8 ) . 59. Dsndrobiurn anosmum Lindl. & D . parishii Roxb. f. (Orchidaceae)
These plants yield a quaternary base isolated as its bromide, whose structure (LV)was determined largely by spectroscopic methods. Upon reduction with lithium aluminum hydride CllH17N2Br (mp 164'),
6.
475
NEW ALKALOIDS
it generated LVI, which was also prepared from the reaction product (LVII) of 2-bromoethylpyridine and 2-bromopyridine by catalytic reduction (79). 60. Dendrobium nobile Lindl. (Vol. X , p. 558). Dendramine, as the result of further study by largely spectroscopic methods, has been given structure LVIII (80,81).Its 6-hydroxy deriva-
o(----Q & LV
LVII
LVI
B
Me
LVIII
LIX
LIXa
tive as well as the new alkaloid dendroxine, C17H2303N (mp 114’; [“ID -30.1), were also isolated from D. nobile. The functional groups shown in structure LIX for dendroxine were recognized by chemical and spectroscopic methods. Catalytic reduction severed the C-O-ether linkage t o generate a compound identical with that obtained by reacting nordendrobine with ethylene oxide (82). 61. Duboisia Zeichhardtii F. Muell. (Solanaceae)
Tetramethylputrescine was present in the root-wood and when infiltrated into detached shoots of this plant it was almost completely metabolized t o unknown products (83). 62. Echinops ritro L. and E . sphaerocephalus L. (Compositae) (Vol. 111, P- 66)
A reexamination of the bases in these species has disclosed that echinopsine and its congeners were artefacts. The quaternary alkaloid echinorin, was isolated as its perchlorate, C11H1102N-HC104(mp 251’),
476
R. H. F. MANSKE
and its structure shown to be LIXa. Upon treatment with alkali it is converted into echinopsine and methanol (84). 63. Elaeocarpinine
This alkaloid, C ~ ~ H Z(mp I N 229"-230°; ~ [aID & 0), isolated from Elaeocarpus archboldianus A. C. Sm. (Tiliaceae), was shown t o have structure LIXb on the basis of exhaustive spectral analysis. Chemical confirmation was obtained when it was observed that selenium dehydrogenation generated 1-ethyl-P-carboline. Furthermore hydrogenation severed the labile N-CH-N system and the resulting dihydro base (mp 123"-125") (LIXc) on exhaustive Hofmann degradation gave N-methylpyrrolidine (85).
LIXb
LIXC
64. Elaeocurpus polydactylus Schl. (Elaeocarpaceae)
Elaeocarpine, C ~ ~ H ~ ~(mp O Z N [.ID + 0.1") and isoelaeocarpine 81'; (mp 51"; [aIn +O.4") are two new indolizidine alkaloids of a new structural type. The complete structure and stereochemistry of elaeocarpine were determined by X-ray crystal structure analysis of its hydrobromide as LX. Its isomer, LXI, is obtained from LX by treatment with methanolic potassium hydroxide a t room temperature. Spectral data are in accord with these structures (86). 65. Erythrophleum guineense G. Don (Leguminosae) (Vol. IV, p. 265)
Erythrophleguine, C25H3906Nr was given structure LXII on the basis of exhaustive spectral evidence and because the acid formed upon its hydrolysis on hydrogenation gives dihydrocassamic acid (87). 66. Erythroxylurn uustrule F. Muell. (Erythroxylaceae)
Meteloidine and small amounts of other bases which appear to beesters, largely of tiglic acid (88).
6.
477
NEW ALKALOIDS
67. Eschscholtzia Spp. (Vol. X , p. 477)
Escholamine (iodide, mp 266') recently isolated from Eschscholtzia oreyana Greene was shown to have structure LXIII. Reduction with zinc and hydrochloric acid generated the corresponding tetrahydro base (mp 97'). E . glauca Greene and E. lobii Greene contain protopine, sanguinarine, coptisine, and other bases in trace amounts (89).
LX
LXI
LXII
LXIII
68. Euxylophora paraensis Hub. (Rutaceae)
Euxylophorine, C21H1903N3 (mp 227"-2:30") (LXIIIa); euxylophoricine A, C20H1703N3 (nip 295"-298') (LXIIIb); euxylophorine B, C20H1503N3 (mp 310°-312") (LXIIIc). These alkaloids are relatives of the rutaecarpine type. Their structures were largely determined by spectroscopic tnethods and confirmed by degradation and syntheses. Hydrolysis of LXIIIa with refluxing amyl alcoholic potash affolcled 1 -ketotetrahydroharman and 6-methylaminovcratric acid. Recombination of these fragments regenerated LXIIIa. Similar hydrolysis of LXIIIb afforded the same keto compound and 6-aminoveratric acid and a recombination of these fragments regeneratcd the starting material. When LXIIIb was dehydrogenated by heating with seleniutn, LXIIIc was fortned (90).
478
R . H. F. MANSKE
60. Evodia alata F. Muell. (Vol. VII, p. 240)
The new alkaloid, evoprenine, C20H2104N (mp 143') was shown to have structure LXIV by spectral methods and by a synthesis from evoxanthine (91).
OMe
OMe LXIIIa
LXIIIb
OMe LXIIIC
70. Evodia Oelahe Baill. (Rutaceae)
Dictamine, evolitrine, and kukusaginine (92).
moMe 0
OH
OCH&H=CMeZ
I
lile
LXIV
71. Fagara leprieurii Eng. ( = Zanthoxylum leprieurii Guill. and Perr.)
(Rutaceae) The O-acridanone (LXIVa),present in this plant, was converted to the known O-methyl derivative (mp 168') (93).
6.
NEW ALKALOIDS
479
72. Furnaria oflicinalis L. (Papaveraceae) (Vol. X, p. 469)
Fumarophycine, CzzH2306N (mp 107"-109'; [ a ] g - 67.5') which on alkaline hydrolysis gave fumarophycinal (mp 128'-130") and on methylation with diazomethane gave the 0-methyl ether (mp 124'-126'). Spectral examination indicated the presence of NMe, phenolic OH, OMe, OzCH2, and acetyl groups. Protopine and sinactine were also isolated (94). 0
I::-&
OH
I Me
LXIVE
73. Gardneria angustifolia Wall. ( = G . nutans Sieb. & ZUCC.)
(Loganiaceae) Four new alkaloids were isolated from this plant : gardneramine, C23H2s05N2(mp 133'; [a]: - 287'); gardnutine, CzoHzzOzNz (mp 319'; [a]% - 30.3') ; gardnerine, C2oH2402Nz (mp 243'; [aID - 29.4'); and hydroxygardnutine, CzoH2403Nz (mp 31 1'; [ a ] D 362') (95).
74. Genista hystrix Lge. (Leguminosae)
The new alkaloid hystrine, CloH16Nz (liquid; dihydrochloride, mp ["ID 0') and ammodendrine, but none of quinolizidine type (96). The former (LXV) was prepared from the latter by first reacting with hypo,chlorite to generate the N-chloro compound LXVI, treatment of which with alkali eliminated the elements of hydrogen chloride and hydrolyzed the acetyl group. The crude product was conveniently purified by conversion to the N-nitroso derivative followed by reduction of the latter with cuprous chloride (97). 209';
75. Glycosrnispentaphylla (Retz.)Correa (Rutaceae) (Vol. V, p. 310)
The root bark of this shrub yielded noracronycine, C19H1703N (mp 200') des-N-methylacronycine (mp 270")) and des-N-methynoracronycine (mp 246') along with skimmianine (98).
480
R. H.F. MANSKE
76. Gymnacranthera paniculata (A.DC.) Warb. (Myristicaceae)
This plant yielded an ind-N-methoxy derivative, namely 1,5-dimethoxygramine, C13H1802N2 (liquid; picrate, mp 154") (LXVII) and N,,-methyltetrahydro-/3-carboline(mp 21 6") (99).
cy'3 f l N
M e O ~ - c H z N M e z
'
N
I
H LXV
COMe LXVI
I
OMe LXVII
77. Gynotroches axillaris B1. (Rhizophoraceae) Trace quantities of ( + )-hygroline were obtained from the bark (100). 78. Haloxylon salicornicurn Bunge (Chenqpodiaceae) (Vol. X , p. 565)
Exhaustive chromatographic procedures were employed t o separate the following alkaloids : piperidine, betaine, aldotripiperideine, haloxine, base C15H2703N (mp 105"-107°), halosaline (alsoprepared synthetically), and base C15H2703N (mp 135"-136") (101).
LXVIIa
79. Haplophyllum tuberculatum Juss. (Ruta tuberculata Porsk. )
(Rutaceae) Flindersine and a new quinolone alkaloid, 3-dimethylallyl-4-dimethylallyloxy-%quinolone, C19H2302N (mp 114"-115") were isolated. Mass and NMR spectroscopy indicated structure LXVIIa for this base. Minor chemical reactions served t o confirm this structure, particularly catalytic hydrogenation, which induced rapid hydrogenolysis of the ether linkage (102).
6.
481
NEW ALKALOIDS
80. Harmine (Vol. VIII, 11. 49)
Harmine was shown to be present in the aerial parts of Calycunthus occidentalis Hook and Am. and tetrahydroharman and harman were isolated from the leaves of Elaeagnus a n g u s t i f o h L. (103). 81. Heliotropiurn olgae Bunge (H. chorassanicum Bunge)
(Boraginaceae) The major alkaloid was heliotrine but others were evidenced on chromatograms. Xolenanthus coronutus Regel yielded a mixture consisting Me
Me
LXVIII
LXIX
largely of echinatine. Lindelojia stylosa A. Brand gave echinatine, its N-oxide, viridiflorine, and its N-oxide (104). 82. Himgaline (Vol. X, p. 531)
The stereochemistry of this alkaloid has been determined and is represented by LXVIII (105). 83. Hodgkinsine (Vol. VIII, p. 588)
An X-ray analysis of the tris(methiodide) showed this alkaloid to be a trimeric indole derivative (C33H38N6)with the structure LXIX (106). 84. Homalium ufricanu Benth. (Flacourtiaceae ; formerly Symadaceae)
The structure of homaline, C30H4202N4 (mp 134'; [&ID - 34') is still in question although extensive spectral data have been recorded. Acid
482
R. H. F. MANSKE
hydrolysis gives trans-cinnamic acid and reduction with lithium aluminum hydride generates a base, C30H46N4. The base yields a monomethiodide and a bis(methiodide), both of which gave the expected methines on Hofmann degradation (107). 85. Hunnemanine, Synthesis (Vol. IV, p. 160)
Berberrubine was converted to hunnemanine by the procedure used by Perkin to convert tetrahydroberberines into protopines. The free hydroxyl was protected as its benzyl derivative (108). 86. Hymenocardia acida Tul. (Euphorbiaceae)
Hymenocardine (mp 261"; [a]= - 124") from this.plant was shown to have structure LXX largely because of its acid and alkaline hydrolysis to tryptophan, N-dimethylisoleucylvaline, and p-hydroxy-w-aminoacetophenone. Exhaustive spectral analyses confirmed this structure and aided in the identification of the hydrolytic fragments (109).
LXX;
Q = EtCHMe.CH(NMe2)CO.NHCH(CHMeZ)CO.NH
87. Hystrine
This alkaloid, CloHlsNz, from Genista hystrix Lange was assigned structure LXXa on the basis, mostly, of physical methods (110).
LXXa
88. Ipecoside
This neutral glycoside, C27H35012N (mp 175"; [mID - 185"; hexacetyl, mp 128") had already been isolated from Psychotria ipecacuanha Stokes
6.
NEW ALKALOIDS
483
(111).Its structure has now been elucidated (UZ),almost exclusively by exhaustive spectral data. Hydrolysis by acid generated glucose and acetic acid. Hydrogenation gave a dihydro derivative (mp 161'). The glucoside linkage is /I, on the basis of hydrolysis with /I-glucosidase.It was possible to convert the aglycone to ( - )-dihydroprotoemetine and consequently the absolute stereochemistry is as depicted in structure LXXI.
LXXI
89. Jasminum Species (Oleaceae)
The alkaloid jasminine, CllH1203N2(mp 174'-176'; - 37.5') from several Jasminum species has also been obtained from Ligustrum novoguineense Lingelsh. It is a monoterpenoid base whose structure is given as LXXIa (113).
LXXIa
90. Kreysigine (Vol. X, p. 269)
The structure of this base and some of its congeners was proved by exhaustive spectral data as well as by a synthesis. The diphenol LXXII (R = OMe) prepared by standard procedures was oxidized by alkaline ferricyanide to LXXIII (R = OMe) which is thus a ring homologue of the proaporphines. This product rearranged in concentrated sulfuric acid to yield LXXIV (R = R2= R4 = H, R = OMe, R3 = Me), methylation of which with diazomethane gave a mixture of ( f )Lkreysigine (LXXIV; R = R4 = H, R1= OMe, R2 = R3 = Me) and its 0-methyl ether. Deacetylcolchicine was also found in the plant from which these alkaloids were isolated (114).Shortly after the above was reported there appeared a
484
R. H. F. MANSKE
report of an unsuccessful attempt to obtain androcymbine and melanthioidine (Vol. IX, p. 169) by the phenolic oxidative coupling of 1phenethylisoquinolines. A number of these were subjected to oxidation with potassium ferricyanide and with ferric chloride and a dienone, identical with one of Battersby's compounds, was obtained from the same precursors (115).
;p,M ::y
Me0
Me0
/
Ho \
R20 \
R
0
R4 ~
3
R
LXXII
LXXIII
OMe
LXXV
LXXVI
LXXIV
OMe
LXXVII
A still later examination of this plant yielded the dienone LXXIII ( R = H ) which had been prepared by the ferricyanide oxidation of LXXII (R = H).Furthermore the dihydro derivative of LXXII (LXXV), CzoH2504N (mp 2 17'-222') was also isolated. Ferricyanide oxidation of LXXVI which is the biological precursor of colchicine (116) gave by direct coupling the homoaporphine LXXVII (117). 91. Kreysiginine (Alkaloid CC-21)
This alkaloid was shown to be structurally identical with alkaloid CC-2, from Colchicum cornigerum (Schweinf.)Tackh. et Drar. (Liliaceae)
(118,119)but enantiomeric. Exhaustive spectroscopic analysis followed by chemical transformation to O-methylandrocymbine (120)proved its structure to be LXXVIa (121).Its absolute molecular structure has been elucidated by an X-ray analysis of its methiodide (122).Mass and NMR-
6.
NEW ALKALOIDS
485
spectroscopy also are in agreement with structure LXXVIa (123).It is to be noted that the skeleton is that of the morphine alkaloids except for an enlargement of one of the rings. The congeners of kreysiginine are known t o be homoaporphines. ?Me
LXXVIa
92. Laurelia novae-zelandiae A. Cunn. (Lauraceae)
I n addition to the alkaloids previously isolated from this plant the following were obtained: ( - )-pukateine 0-methyl ether, ( - )-roemerine, ( - )-mecambroline, ( + )-boldine, ( + )-isoboldine, ( + )-laurolitsine, and ( + )-stepharine. Laureline and laurepukine, previously reported from this plant, were not obtained. Fractional crystallization followed by chromatography were the procedures used t o effect the separations (124).
93. Lamprolobium fruticosum Benth. (Leguminosae) ([a]= Z N+Z29";picrate, mp 153")is a colorless Lamprolobine, C ~ & ~ ~ ~ O oil which on hydrolysis affords glutaric acid and ( + )- 1-aminomethyl-
LXXVIII
quinolizidine, whose stereochemistry was established by showing that its acetyl derivative (mp 144"; [aJD +46") was identical with a specimen already obtained from epilupinine (125).The structure of the new alkaloid is therefore LXXVIII. Cytisine was also obtained from this plant (126).
486
R . H. F. MANSKE
94. Leontice alberti Regel (Berberidaceae) (Vol. X, p. 570)
In addition to thaspine and N-methylcytisine there were isolated the following : leontalbine (perchlorate, [a]$ - 131.2"; hydrochloride, mp 277'), albertine, C15HzzOzNz (mp 161'; [a13 - 101.5"; perchlorate, mp 288'), and leontalbinine, C15HzzONz (mp 107"; [a13 - 135.5'; perchlorate, mp 245O) whose structure (LXXIX) was determined by
&g
Me0
moco.~
~
~
z
I
~
~
NH
Me0
LXXIX
~
LXXX
IXXXI
conversion to allomatrine (127).In a slightly later publication there was reported the isolation of thaspine, N-methylcytisine, and d-sophoridine (mp 108'; [.ID +59.3") (128). 95. Leonurine (Vol. X, p. 570)
Two syntheses of this base (LXXXI) were achieved and therefore possible alternatives have been eliminated. The most direct involved the condensation of 4-carbethoxysyringoyl chloride with N-nitro-"(6-hydroxybuty1)guanidineto LXXX and catalytic reduction of the latter (129). 96. Linaria Species (Vol. X, p. 571)
Most of the 15 species examined contained peganine or Dragendorffpositive compounds (130). 97. Liparis kurameri Franch. et Sav. and L. kurnokiri F. Maekwa (Orchidaceae)
The former gave kuramerine, CzsH440sN+ (picrate, mp 105"-102"; [a]$ - 19.7"as hydrochloride) which on hydrolysis generated choline and
~
z
6.
487
NEW ALKALOIDS
an acid which was shown to be the glucoside of an acid already obtained from nervosine. Hence kuramerine is LXXII. L. kumokiri gave kumokirine, C32H4808Nf (picrate, mp 100"-102"; [a]? - 23.4" as hydrochloride) which on hydrolysis generated N-methyltrachelanthamidine and the same acid that was obtained from kuramerine. Hence, the structure of kumokirine is LXXXIII (131).
Me
LXXXIII
LXXXIV
98. Liparis nervosa Lindl.
A glycoalkaloid, nervosine, C36H53012N, wa isolated as its picrat : (mp 131' ; [a]? + 12.8"as hydrochloride). Alkaline hydrolysis generated lindelofidine (d-isoretronecanol) and an acid which on hydrolysis with acid generated D-glucose and L-arabinose. The disaccharide obtained on mild hydrolysis was reduced with sodium borohydride and then hydrolyzed further. There was obtained arabinose, indicating that the aldehyde function of the glucose is coupled with the phenolic hydroxyl of the acid moiety. Exhaustive spectral analysis of the latter as well as of its tetrahydro derivative show that nervosine is LXXXIV (132). 99. Litsericine (Vol. IX, p. 37)
This alkaloid was shown to be a hexahydroproaporphine of structure LXXXIVa. It was converted into its N-methyl derivatve and this was
H LXXXIVa
488
R. H.F. MANSKE
oxidized to the corresponding ketone (mp 148") (133).It had been isolated from Neolitsia sericea (Blume) Koidz. (Lauraceae) along with a number of alkaloids, mostly of the aporphine type. 100. Lobelia portoricensis Urb. (Lobeliaceae)
The new alkaloid, C21H2303N (mp 115"; hydrochloride, mp 187'; perchlorate, mp 156";picrate, mp 175") has carbonyl and NH groups but lacks methyl and hydroxyl (134). 101. Lophophora williamsii (Lemaire) Coulter (Cactaceae)
A new alkaloid, peyonine, C16H1905N (mp 131"-133") was shown to have structure LXXXIVb, largely by means of spectroscopic data (135). MeO-
/
M e O q N y c o 2 H LXXXIVb
102. Lunasia quercifolia K.Schum. & Lauterb. (Androcephaliumquercifolium Warb.) Euphorbiaceae (Vol. IX, p. 225).
5-Hydroxy- l-methyl-2-phenyl-4-quinolone was obtained as a minor constituent (136). 103. Lythrum anceps Makino (Vol. X, p. 566)
This plant has yielded three new alkaloids : lythranine, C28H3705N (0,O-diacety1,-hydrochloride, mp 180°-218"; [m]? - 33") (LXXXV);
LXXXV
LXXXVI
6. NEW ALKALOIDS
489
lythranidine ( = deacetyllythranine) ; and lythramine, C29H3705N (LXXXVI). Only the last was obtained crystalline and then with 0.5 mole of acetone of crystallization. Though there are minor points still to be clarified, the structure shown rests largely upon mass and NMR spectroscopy. Sufficient chemical degradation was carried out where feasible and in most instances crystalline products of the anticipated properties were obtained (137). 104. Machilus macrantha Nees (Lauraceae)
Macranthine, C13H1703N (hydrochloride, mp 242-"; picrate, mp 136") has phenolic hydroxyl and a methoxyl group (138). 105. Magnolia grandi$ora
L.(Magnoliaceae)
Minute quantities of anolobine, anonaine, and N-nornuciferine were isolated from the wood of this plant (139). 106. Malaxis congesta comb. nov. (Reichb. f.) (Orchidaceae)
is a glucoside of Malaxine, C26H3708N (mp 151"-159O; [a]: --'31°) the 4-hydroxy-3-(3-methyl-2-butenyl)benzoic ester .of laburnine (LXXXVII). This was confirmed by hydrolysis to laburnine, glucose, and the above-mentioned acid (mp 99'-102O) (140).
& LXXXVII
107. Marckine (Vol. X,p. 577)
This was shown to be identical with tubulosine (141). 108. Melochia corchorifolia Wall. ( = Waltheria indica L.) (Vol. X, p. 587) (Sterculeaceae)
This plant yielded the three peptide alkaloids :frangufoline, franginine, and adouetine Y', the last of which was obtained in a pure form,
490
R . H. F. MANSKE
C~lH4204N4(mp 289"; [a]:' -305"), and whose structure was shown t o be LXXXVIIa (142).Adouetine Y is identical with ceanothine-A (50).
i
+
H
4
MezPh-B-Hyleu-Ileu-NH-CH=CH
LXXXVIIa
109. Mesembrine (Vol. I X , p. 467)
A new synthesis of this alkaloid has been reported. The cyclopropane derivative (LXXXVIIb)was prepared by reacting 3,4-dimethoxyphenylacetonitrile with 1,2-dibromopropane in alkaline dimethyl sulfoxide. This was converted into the aldehyde (LXXXVIIc) by reduction with diisobutylaluminum hydride and this in turn converted to the imine LXXXVIId. The isomerization of LXXXVl Id t o LXXXVIIe was achieved by heating to 160" in the presence of ammonium chloride and the condensation of the latter with methyl vinyl ketone in refluxing 1,2diethoxyethane generated ( f )-mesembrine (LXXXVIIf) (143). Further syntheses have been reported and depend largely upon the synthesis of LXXXVIIe (144,145).
M
e
O
a
M
e
O
q
Ma ,
,
R i
MH
0 LXXXVIIb; R = C N LXXXVIIc; R = CHO LXXXVIId; R = C H : N M e
LXXXVIIe
N Me LXXXVIIf
ocHoy% Me-aL2& \
LXXXVIIg
LXXXVIIh
LXXXVIIi
6.
NEW ALKALOIDS
49 1
110. Murraya koenigii Spreng. (Vol. X, p. 573)
A new optically inactive compound, murrayacine, C18H1502N (mp 244") has been isolated. Spectral examination suggested that this substance is a 3-formylcarbazoleand zinc dust distillation gave carbazole. Its dihydro derivative on reduction with lithium aluminum hydride furnished a compound C&1@N (mp 176") which was identical with dihydrogirinimbine LXXXVIIh. Murrayacine is therefore LXXXVIIg (146). 111. Nicotiana tabacum L. (Solanaceae) (Vol. I, p. 230) The roots of this much investigated plant have yielded a new alkaloid, anatalline, C15H17N3 (perchlorate, mp 244"-252" ; picrate, mp 258") whose structure LXXXVIIi was determined by spectrographic analyses and confirmed by dehydrogenation to nicotelline (147). 112. Nothaphoebe konishii Hayata (Machilus konishii Hayata) (Lauraceae) Several unknown bases and L- and (mp 180") (148).
DL-( - )-N-norarmepavine
and
L-( +)-laudanidine
113. Ochrosia borbonica J. F. Gmel. (Apocynaceae) This plant yielded 9-methoxyellipticine (LXXXVIII) (mp 295') which was identical with a synthetic specimen (149). Me
Me
LXXXVIII
114. Ochotensimine,A Synthesis (Vol.X, p. 479) The condensation of the diketone LXXXVIIIa with the amine LXXXVIIIb in hydrochloric acid generated LXXXVIIIc (R = H ; mp 104°-1070), which on treatment with diazomethane yielded LXXXVIIIc (R=Me; mp 176'179"). N-Methylation of the latter and a subsequent Wittig reaction generated racemic ochotensimine (LXXXVIIId) (250).
492
R. H. F. MANSKE
115. Ocotea macropoda Mez. (Persea macropodn H. B. & K. and Ocotea species (Lauraceae)
The former yielded dicentrine, dehydrodicentrine (mp 2 18') (LXXXVIIIe), and ocopodine, C21H2305N (mp 166' ; [a]: + 87') (LXXXVIIIf). The second, not entirely identified, species yielded isocorydine and two new aporphines : ocokryptine, CzoHz105N (mp 160'; [ a ] g + 164") (LXXXVIIIg) (R = H) and oconovine, C Z ~ H Z ~ O ~ N 0
LXXXVIIIa,
(amorph. ; [a]: + 156")(LXXXVIIIh). These st'ructures were elucidated largely by spectral methods, but ocopodine in the racemic form had already been synthesized (151) and spectral comparison proved the identity of the two products (152). 1 16. Ophiorrhiza japonica Blume (Rubiaceae)
Harman (mp 234'-238') was isolated in small yield (153). 1 1 7 . Oxotuberostemonine (Vol. I X , p. 545)
The ambiguity regarding the structure of this oxidation product of tuberostemonine, which also occurs naturally, has been resolved by an X-ray study without the aid ofa heavy atom derivative. The structure is LXXXVIIIi (154). 1 18. Palmeria fengeriana Perkins (Monimiaceac)
Laurotetanine and its N-methyl derivative ( 1 5 5 ) . 1 1 9. Palaudine
This is a new alkaloid, C I ~ H ~ ~ isolated O ~ N , froin opium and the structure (LXXXVIIIj) was confirmed by a synthesis (256).
6.
RO
NEW ALKALOIDS
/
493
Meo
Me0
- 0
Meo%
0
LXXXVIIIb
LXXXVIIId
LXXXVIIIC
\Me
OMe LXXXVIIIe
LXX X VII Ig
LXXXVIIIf
OMe
Me0 Meo@N,\ Me
LX X X VI I I i
LXXXVIIIh
OH
COzH
OMe LXXXVIIIj
LXXXVIIIk
494
R. H. F. MANSKE
120. Palustrine (Vol. X, p. 559) Hofmann degradation of dihydropalustrine followed by hydrolysis generated as-N-dimethylputrescine and dihydropalustraminic acid whose structure was shown to be LXXXVIIIk, largely by carefully controlled oxidation experiments confirmed by spectral data. It is argued that the double bond in palustrine is as shown on the basis of spectral data and the new structure of the alkaloid (LXXXVIIII) is that of a piperidine derivative (157).
I LXXXVIII 1
121. Pavine Group (Vol. X, p. 477)
ORD-Studies show that argemonine has the absolute structure LXXXIX (157a) and this structure has been confirmed by its degradation to a derivative of L-aspartic acid (157b).Later optical methods confirmed this (158). Finally, ORD- and CD-measurements show that, except for ( + )-O-methylcaryachine, the known alkaloids which have the
LXXXIX
pavine skeleton differ only in the nature of the substituents on the oxygens (159).These structures (1s.58) are in agreement with the proposed biosyntheses from X-( + )-reticuline (160). 122. Phoebe clemensii C. K. Allen (Lauraceae) The alkaloids in the leaves of this plant consisted largely of isocrydine and two new aporphines, namely, lO-hydroxy-l,2-(rnethylenedioxy)aporphine and 2,l l-dihydroxy-1 ,1O-dimethoxyaporphine. The bark yielded predominantly laurolitsine ( 1 6 0 ~ ) .
6.
495
NEW ALKALOIDS
123. Picrasma ailanthoides Planch. ( P . qisnssioides Benn.) (Simarubaceae) The yellow heartwood of this Idant yielded nigakinone, C15H1003N2 (mp 224') (LXXXIXa) and its 0-methyl ether, namely 4,5-dimethoxycanthin-&one, C16H1203N2 ( m p 146") (LXXXIXb). Oxidation of the former with permanganate generated methyl /3-carboline-1-carboxylate (mp 168') (161). Me(CHZ),-CH-(
I
CH&-CO
I
OR LXXXIXO
LXXXIXa; R = H LXXXIXb; R = Me
124. Pithecolobine (Vol. X, p. 570)
A further examination of this alkaloid, or mixture of alkaloids, has shown that there is present only one oxygen and it is present in the form of an amide linkage. A general formula for the alkaloids has been shown to be LXXXIXc in which n and m are equal t o 9, 10, or 11 and there is a considerable proportion in which m = 1. However, one of the alkaloids was shown to be LXXXIXc where n = 6 and m = 3. Hofmann degradation was the essential chemical t'ool and exhaustive spectral data were used throughout though mass spectra were of only minor aid (162).The plant source has recently been renamed Sarnanea saman Merr. 125. Piper peepuloides Roxb. (Piperaceae) Peepuloidin, C14H1905N (mp 149') was shown to be an amide of pyrrolidine and a highly substituted cinnamic acid. Spectral data indicated structure XC and this was confirmed by permanganate oxidation t o 2,3-dimethoxy-4,5-methylenedioxybenzoic acid (mp 148') (163). 0
(OlV2"= 0
\OMe OMr
xc!
496
R. H. F. MANSKE
126. Pogostemonpatchouli Pellet ( =P.heyneanus Benth.) (Labiatae)
Two new alkaloids were found in trace amounts in the essential oil obtained from this plant, patchoulipyridine, C15H21N (mp 24"-26" ; [a]? - 31.3"; perchlorate, mp 276"-279") (XCI) and epiguaipyridine, C15H21N (oil; perchlorate, mp 105"; [a12 - 17") (XCII),whose structures were elucidated by a combination of spectroscopy and chemical degradation, and ultimately by the synthesis of dihydroepiguaipyridine from
XCI
XC'III
XCII
Q; N XCIV
guaiol of known absolute configuration. Similarly patchoulipyridine was synthesized from /I-patchoulene by reaction with hydrazoic acid in the presence of sulfuric acid, dehydrogenating the resulting mixture of amines, and finally separating the mixture of bases by chromatography (164). 127. Polygala tenuifolia ( 2 ) Polygalaceae)
Tenuidine, C21H3105N3 (mp 256"; indicates indole-quinoline nuclei (165). 128. Prangosine (vol.
[a]g5+ 1200");
IR-spectrum
x, p. 578)
Largely on the basis of spectral evidence structure XCIII (R = CMe2NH2) was advanced for this alkaloid. Oxidation with chromic
6.
NEW ALKALOIDS
497
anhydride gave acetone and heating with acetic anhydride eliminated ammonia, forming XCIII (R = CMe=CH2) (mp 184'). The same product was formed when the methiodide of XCIII ( R = CMezNHe2) (mp 160"; methiodide, mp 180') was heated with alkali. Oxidation with strong nitric acid generated 2,4,6-trinitroresorcinol(166). 129. Protoemetine (vol. X, p. 579)
The reference given for the synthesis of this base is erroneous and should be to Szkiitay and co-workers (167). 130. Protopine (Vol. X, p. 423)
Recent work has shown the route by which protopine and chelidonine are biosynthesized not only from reticuline but also from scoulerine (168). 131. Protopine Alkaloids-Photochemical
Reactions
Protopine, nllocryptopine, and cryptopine when irradiated in ethanol or chloroform under a nitrogen atmosphere gave yields of 23% to 76% of coptisine, berberine, and epiberberine. The reaction rate in chloroform was greater than in ethanol (or methanol) and the yields were better (169). 132. Rauwolfia verticillata (Lour.) Baill. (Vol. VIII, p. 289)
A monoterpenoid alkaloid RW 47, CSH11ON (mp 130'; [a].. +27") isolated from this plant was assigned structure XCIV, largely on the basis of spectral evidence (170). 133. Rhamnus frangula L. (Rhamnaceae)
Column chromatography of the alkaloids revealed the presence of six, one of which, frangulanine, C28H4404N4 (mp 275'; [a],, - 288") (XCV) was shown t o be closely related t o integerrisine and integerrinine isolated from Ceanothus integerrimus. The structure was determined almost exclusively by mass spectroscopy but total hydrolysis generated the expected amino acids (171). A subsequent publication reported the isolation of franganine, C28H4404N4 (mp 248'; "1% - 302") (XCVa) and frangufoline, C~lH4204N4(mp 244"; [a]: - 299') (XCVb), the latter from the leaves. Exhaustive spectral data, supplemented by hydrolysis to known amino acids, indicated the given structures (172).
498
R. H. F. MANSKE
134. Ruta graveolens L. (Rutaceae) The base from this plant was assigned structure XCVII on the basis of spectral data and this structure was confirmed by a synthesis. 3,4Methylenedioxycinnamaldehyde was condensed with 2-methyl-4-quinoline in the presence of acetic anhydride. The intermediate butadiene
NMez
XCVe; R = MezCH4H2XCVb; R = PhCHz
derivative (XCVI) on hydrogenation gave a base, 2-[4-(3,4-methylenedioxyphenyl)butyl]-4-quinolone (XCVII) identical with the natural product (173). The same plant yielded another alkaloid, ruacridone, C ~ ~ N I ~(mp O ~161" N - 43" which on the basis of spectral evidence was assigned structure XCVIII (174). 135. Samandarone (Vol. IX, p. 432) A total synthesis of this base from 1-formvl-A-nor-5B-androst-1 -en17p-01 (XCiX) in over a dozen stages has bien reported. Though the 0
8
u XCVI
XCVIII
XCVII
XCIX
6. NEW ALKALOIDS
499
yields in many stages were excellent and though some of the intermediates were not isolated and characterized the final product was obtained in only 1.5mg quantity. Nevertheless, enough characterization was reported to leave no doubt as to the authenticity of the various steps (175). 136. Sanguinarine A new synthesis of this alkaloid has been reported. The reductive condensation of 2,3-methylenedioxybenzaldehydewith aminodimethylacetone and its subsequent reactionwith glyoxylic acid in the presence of 6 N hydrochloric acid generated XCIXa in about 40% overall yield.
XCIXa
XCIXb; R = OH XCIXC; R = H
XCIXd
Condensation of the latter with 6-nitropiperonal, followed by reduction, diazotization, heating in the presence of copper powder, and finally decarboxylation in quinoline gave an overall yield of 4% of the sanguinarine (176). 137. Schelhammera pedunculata F.Muell. (Liliaceae) Three alkaloids: schelhammerine, C19H2304N (mp 173'; [a]= + 186"; 0-acetyl-, mp 143') (XCIXb),schelhammeridine, C1gH2103N (mp11 8") (XCIXc), and schelhammericine, ClgH2103N (mp 76'; [.ID 122') (XCIXd). Their structures were determined by the combined spectral methods, including X-ray analysis, and by several chemical reactions and interconversions. These alkaloids are the first representatives of a " homoerythrina" group (17'7).
+
138. Scutia buxifolia Reiss. (Rhamnaceae) This plant gave a new cyclic peptide type of alkaloid, scutianine (mp 187'; [aID - 399'). I t s dihydro derivative (mp 240'; [aID - 158') was
500
R . H. F. MANSKE
prepared by catalytic reduction. Hydrolysis generated N,N-dimethylphenylalanine, proline, phenylalanine, and p-hydroxyleucine. Mass spectral studies permitted structure C to be assigned (178).
C
139. Senecio Alkaloids
The cinnabar moth (Callimorphajacobaea L.) is unacceptable to a wide variety of vertebrate predators. The larvae feed on Senecio vulgaris L. and S. jacobaea L. and the pupae in general have a higher concentration of total alkaloids than the plants upon which they have been reared. In both pupae and imagos there was detected a metabolite, C15H2505N, which was not present in the plants. Whether or not these alkaloids and the metabolites confer security from predators is not yet certain (179).
140. Severinia buxifolia (Poir) Ten. ( = Atalantia buxifolia Oliver) (Rutaceae)
A compound was present in small amounts which on mild hydrolysis generated palmitic acid and a neutral N-benzoyltyramine derivative of structure CI (180). MeZC(OH)CH(OH)CHzCHZC(Me)=FH
\=/ CI
141. Sickingia klugei. Standley (Calderonia klugei Standley) (Rubiaceae)
Harman (mp 243") was isolated (181).
6.
NEW ALKALOIDS
50 1
142. Slaframine (Vol. X, p. 579)
A revision of the earlier structure to CIa was achieved on the basis of an exhaustive NMR spectral analysis confirmed by mass spectra (182). OAc
CIa
143. Solanum tripartitum Dunal (Solanaceae) O ~mass N , spectroSolapartine, a liquid alkaline fraction ( C Z ~ H ~ ~by metry) which on hydrolysis generated solamine, C12H29N3, and a mixture of and c18 acids. Hydrolysis of reduced solapartine gave solamine and an 80 : 20 mixture of palmitic and stearic acids. Hofmann degradation of M-acetylsolamine showed that it had the structure [Me2N(CH2)4I2NH. Solapalmine and solapalmitine were ultimately separated as pure bases from solapartine and were shown t o be identical with the palmitoyl and trans-hexadec-2-enoyl derivatives, respectively, of solamine. Solopartine was significantly cytotoxic against human carcinoma of the nasopharynx in cell cultures a t 0.21 mg/ml(183). 144. Sphacelia sorghi McRae
This fungus is probably related t o the genus Claviceps and the sclerotia collected from Sorghum vulgare Pers. gave a mixture of ergotlike alkaloids the major constituent of which was shown t o be identical with a synthetic specimen of dihydroergosine. The same alkaloid was obtained from surface and submerged cultures of the fungus (184). 145. Spiraeajaponica L.f. (Rosaceae) (Vol. X, p. 581)
A reexamination of this plant established the presence of no less than 10 alkaloids and of these the structures of three were determined. Details of the isolation were not recorded but the data leading t o the structures are largely documented. The three alkaloids are spirodane-A, CzoN250zN (mp 281"; methiodide, mp 330"); spirodane-B, CzoH2702N (mp 259"); and spirodane-C, C22H2903N (mp 248"). Spirodane-A upon sodium borohydride reduction generates spirodane-B, which can be reconverted to the former by means of chromic anhydride in pyridine. Hydrolysis of
502
R. H. F. MANSKE
spirodane-C gives spirodane-B and acetic acid. The structures assigned are CII, CIII, and CIV, respectively, for spirodanes-A, -B, and -C (185).
N.-
___.
<--
Me
H
CII; R = 0 CIII; R = H CIV; R = H
CV; R = I I
+ OH
+ 0.CO.Me
CVI; R =
140. Stemona tuberosa Lour. (Vol. I X , p. 545)
A new alkaloid, stenine, C17H2702N (mp 65"-67'; [a]D -30.2") was isolated from the roots of this plant. Reduction with lithium aluminum hydride gave a diol which was identical with a diol obtained by the reduction of a lactone of known structure already obtained from the degradation of stemonine. Stenine is therefore CV and this is confirmed in detail by NMR, I R , and mass spectral data (186) and a later examination (187)disclosed its absolute configuration as well as that of tuberostemonine (CVI). 147. Stephania dinklaqei Diels (Menispermaceae) ( + )-Corydine, ( + )-isocorydine, and ( - )-roemerine were isolated in crystalline condition and a number of others were detected on chromatograms (188). 148. Stephania qlabra Miers (Vol. X, p. 582)
+
Two proaporphines, ( + )-stepharine and ( )-nuciferine, as well as ( - )-tetrahydropalmatine, ( - )-corydalmine, and the new base ( - )stepholidine, C19H2104N [mp 158" (hydrate); [a]D - 31 lo]. On methylation with diazomethane the last gave ( - )-tetrahydropalmatine. I t s di-O-ethyl ether on appropriate oxidation gave 6-methoxy-7-ethoxy1-keto-1,2,3,4-tetrahydroisoquinolinebut the ultimate oxidation products did not yield a 3,4-disubstituted phthalic acid. Nevertheless, only two structures for stepholidine are therefore possible. One of these is that
6.
NEW ALKALOIDS
503
of scoulerine and since the spectra of the two bases exclude possible identity the structure of stepholidine is CVIa (189).
CVIa
149. Stephania rotunda Lour. (S.glabra Miers) (Menispermaceae) (Vol. X, p. 582)
The tubers of this plant yielded six quaternary alkaloids (190),four of which were shown to be palmatine, jatrorrhizine, columbamine, and the ubiquitous magnoflorine. One of the remaining ones (A) was shown t o be dehydrocorydalmine and the other (B), shown t o be new, was named stepharanine (hydrochloride, mp 274"), and was shown t o be CVII. This was accomplished by partially methylating the alkaloid to a mixture of palmatine, columbamine, and dehydrocorydalmine (191).Tetrahydropalmatine and stepharine were also reported t o be present. 150. Strychnos jobertiana Baill. andS. rondeletioides Spruce (Loganiaceae)
The former plant yielded O-acetyldiaboline-B, also termed jobertine (mp 87"), while the latter gave a mixture of tertiary bases consisting largely of diaboline (192). 151 . Strychnos mittscherlichii Schomb. (S.smilacina Berth.) & S. gardneri A.Dc. (Loganiaceae)
The bark of these plants was shown to contain diaboline and the former contained deacetyldiaboline. Separation and identification were affected by chromatographic methods (193). 152. Teclea natalensis (Sond.) Engl. (Rutaceae)
The bark of this plant of South African origin yielded less than 0.01 yo of a new alkaloid, tecleanine, C28H3604N2 (mp 204"-205"; [.ID - 245'). Both nitrogens are basic and the four oxygens are nonphenolic but
504
R. H. F. MANSKE
acylatable, and therefore there are no methoxyl or methylenedioxy groups. Two N-methyl groups are present (194). 153. Thalictrumdasycarpum Fisch. & Lall. (Ranunculaceae)
Among other alkaloids, whose isolation had been described in part (195),there was obtained dehydrothalicarpine C31N3608N2 (mp 186";
2 %
/
\
OMe
-OH
Me-EF2 /
/
\
OM0
0Me0
Me
CVII
CVIII
Mc
cx
CIX
CXI
MeCOz
MeCOz M e
C
O
g
CXII
[a]= + 55") (CVIII) whose structure was determined by the fragments obtained on hydrogenolysis by sodium/liquid ammonia (196).
154. Thalictrum minus L. (Ranunculaceae) (Vol. IX, p. 144)
The alkaloid thalictrimine was shown t o be allocryptopine, its first recorded presence in a Thalictrum species (197).
6.
NEW ALKALOIDS
505
155. Thelocactus macromeris (Engelm.) L. Benson (Goryphanthu macromeris Engelm.) Lem. (Cactaceae)
The main alkaloid was macromerine, C12H1903N [mp 66"; [aID - 147" (CHCl,); [a],, - 42.6"(EtOH)]whose structure (CIX) was confirmed by two syntheses : (1)chloracetoveratrone was reacted with excess trimethylamine and the product reduced with sodium borohydride; (2) a Hoesch condensation of veratrole with dimethylaminoacetonitrile followed by sodium borohydride reduction. Macromerine has halucinogenic properties and shows antiadrenaline reactions in the turtle heart (198).Macromerine is similar to gigantine (CX) and berberastine in having a benzylic hydroxyl that resembles the hydroxyl in adrenaline and ephedrine (41). 156. Thermopsis dolichocarpa V. Nikitin (Leguminosae)
Pachycarpine and cytisine (199). 157. Toddalia aculeata Pers. (Vol. VII, p. 431)
I n addition to the known chelerythrine and its dihydro derivative the root bark of this plant was found t o contain 7,8-dimethoxy-2,3-methylenedioxy benzo [c ]-phenanthridine (mp 2 20") (200). 158. Tuberostemonine (Vol. IX, p. 546)
The structure, based upon a combination of chemical reactions but mostly on NMR spectra, has been confirmed by chemical degradation to recognizable fragments. The action of an excess of phenylmagnesium bromide generated a crystalline substance, C40H5104N, containing three phenyl groups. I t s NMR spectrum was consistent with that of a product that could be expected though there were two possibilities. However, oxidation with chromium trioxide in pyridine gave, among other suband this served to confirm stances, y,y-diphenyl-p-methylbutyrolactone not only the mooted structure of the Grignard reaction product but a number of other transformations, which could only be explained on the basis of the accepted structure of tuberostemonine (201).Furthermore, the indole derivative (CXI)which had previously been obtained from the alkaloid was prepared synthetically (202). 159. Xylopia papuana Diels (Annonaceae)
Coclaurine (203, 204).
506
R . H. F. MANSKE
160. Yuzuramine (ex Daphniphyllum macropodum Miquel) (Vol. X , p. 556) X-Ray determination of the structure of the hydrobromide (CXII) (mp 251"-253") (205). 161. Zanthoxylum ailanthoides Sieb. & Zucc. (Rutaceae) Nitidine, dictamnine, skimianine, and laurofoline (206). 162. Zanthoxylum caribaeum Lam. (2. elephantiasis Macfad.)
6-Canthinone, 5-methoxy-6-canthinone, and laurifoline (207). The bark of a specimen collected in Venezuela yielded 5-methoxy-6-canthinone and the N-methylisocorydinium cation (208). 163. Zanthoxylum martinicense DC. The bark of this West Indian tree yielded lupeol and d-sesamine in addition to five quaternary alkaloids, namely, chelerythrine, 1-canadine methochloride, candicine, and d-tambetarine, all isolated as chlorides as well as alkaloid-A (mp 266'-268"), which is not to be confused with alkaloid-A from Stephania rotunda (209).The plant has also been referred t o as 2.follis oblongo-ovatis Browne, 2. clavaherculis SW., Z. caribaeum Hitchc., and Fagara martinicense Lam. REFERENCES 1. H. R. Adams and B. J. Camp, Tozicon 4 , 8 5 (1966); C A 65, 12562 (1966). 2. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustralianJ. Chem. 19,1539 (1966). 3. B. Rovelli and G. N. Vaughan, Australian J . Chem. 20, 1299 (1967). 3a. F. N. Lahey and M. McCamish, Tetrahedron Letters 1525 (1968). 4. K. Goto, M. Tomita, Y. Okamoto, Y. Sasaki, and K. Matoba, Proc. Japan Acad. 42, 1181 (1966). Japan 4 , 2 2 0 (1929). 5. K. Goto and H. Sudzuki, Bull. Chem. SOC. 6. M. Tomita, Y. Okamoto, T. Kikuchi, K. Osaki, M. Nishikawa, K. Kamiya, Y. Sasaki, K. Matoba, and K. Goto, Tetrahedron Letters 2421 (1967). 7. M. Tomita, Y. Okamoto, T. Kikuchi, K. Osaki,M. Nishikawa, K. Kamiya, Y. Sasaki, K. Matoba, and K. Goto, Tetrahedron Letters 2425 (1967). 8. A. Fiirst and P. A. Plattner, Helw. Chim. Acta 32, 275 (1949). 9. A. R. Battersby, R. S. Kapil, D. S. Bakuni, S. P. Popli, J. R. Merchant, and S. S. Salgar, Tetrnhedron Letters 4965 (1966). 10. A. Popelak, E. Hsack, and H. Spingler, Tetrahedron Letters 5077 (1966). 11. S. C. Pakrashi and E. Ali, Tetrahedron Letters 2143 (1967). 12. S. Siddiqui, M. A. Ali, and V. U. Ahmad, PalcistanJ. Sci. Ind. Res. 8, 161 (1965); C A 68, 899d (1968).
6. NEW ALKALOIDS
507
P. D. Desai, IndianJ. Chem. 4,457 (1966); C A 66, 44253b (1967). S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustralianJ. Chem. 20,1729 (1967). A. B. Ray and A. Chatterjee, Tetrahedron Letters 2763 (1968). R. R. Arndt, S. H. Eggers, and A. Jordan, Tetrahedron 23,3521 (1967). S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Australian J . Chem. 20, 1463 (1967). 18. W. Dopke, H. Flentje, and P. W . Jeffs, Tetrahedron 24, 4459 (1968). 19. A. S. Sadykov, S. Z. Mukhamedzhanov, and K. A. Aslanov, Dokl. Akad. Nauk Uz. SSR 24, 34 (1967); C A 68, 78473e (1968). 20. J. B. Bremner and J. R. Cannon, Australian J . Chem. 21, 1369 (1968). 21. S. Abdizhabbarov, Z. F. Ismailov, and S. Y. Yunusov, Khim. Prirodn. Soedin. 3,344 (1967); C A 68 47002w (1968). 22. H. A. Priestap, E. A. Ruveda, S. M. Abonico, and V. Deulofeu, Chem. Commun. 754 (1967). 23. P. R. Krishnaswamy, B. L. Manjunath, and S. V. Rao, J. Indian Chem. SOC.12,476 (1935); C A 30, 233 (1936). 24. T. R. Govindachari and N. Viswanathan, Indian J . Chem. 5 , 655 (1967); C A 69, 36314u (1968). 25. S . K. Dutta and S. Ghosal, Chem. & Ind. (London) 2046 (1967); C A 68, 112149r (1968). 26. L. I. Brutko, P. S. Massagetov, and L. M. Utkin, Khim.Prirodn.Soedin. 2,441 (1966); CA 66, 10247011 (1967). 27. R. A. Abramovitch and G. Tertzakian, Can. J . Chem. 41, 2265 (1963). 28. S. F. Dyke, M. Sainsbury, and B. J. Moon, Tetrahedron 24, 1467 (1968). 29. G. J. H. Rall, H. L. de Waal, and R. R. Arndt, Tetrahedron Letters 3465 (1967). 30. R. A. Corral, 0.0. Orazi, and I. A. Benages, Tetrahedron Letters 545 (1968). 31. M. R. Falco, J. X. deVries, A. G. de Brovetto, Z. Maccio, S. Rebuffo, and J. R. Bick, Tetrahedron Letters 1953 (1968). 32. M. Ikram, M. E. Huq, and S. A. Warsi,PakistanJ.Sci.Ind. Res. 9,343 (1966); C A 68, 13233g (1968). 33. N. G. Kiryakov, M. S. Kitova, and A. V. Georgieva, Compt. Rend. Acad. Bulgare Sci. 20, 189 (1967); C A 67, 32849h (1967). 34. N. K. Hart, S. R. Johns, and J. A. Lamberton, Australian J . Chem. 21,1397 (1968). 35. P. A. Vember, I. V. Terent'eva, and G. V. Lazur'evskii, Khim. Prirodn. Soedin. 3,249 (1967); C A 67, 108816t (1967). 36. J. W. Loder and C. B. Russell, Tetrahedron Letters 6327 (1966). 37. L. I. Brutko and P. S. Massagetov, Khim. Prirodn. Soedin. 4, 57 (1968); C A 68, 112175~ (1968). 38. 'M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail, and G. A. Sim, J. Am. Chem. SOC.88, 3888 (1966). 39. T. Kametani, K. Fukumoto, H. Yagi, H. Iida, and T. Kikuchi,J. Chem.Soc., C 1178 (1968). 40. T. Kametani, M. Ihara, K. Fukumoto, H. Yagi, II. Shimanouchi, and Y.Sasada, Tetrahedron Letters 4251 (1968). 41. J. E. Hodgkins, S. D. Brown, and J. L. Massingill, TetrahedronLetters 1321 (1967). C 283 (1967). 42. W. G. Wright and F. L. Warren,J. Chem. SOC., C 284 (1967). 43. W. G. Wright and F. L. Warren, J . Chem. SOC., 44. R. G. Cooks, F. L. Warren, and D. H. Williams,J. Chem. SOC.,C 286 (1967). 45. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustralianJ. Chem. 19,2339 (1966). 46. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustraZianJ. Chem. 20,1457 (1967). 13. 14. 15. 16. 17.
508
R. H. F. MANSKE
47. M. S. Flom, R. W. Doskotch, and J. L. Beal, J. Pharm. Sci. 56, 1515 (1967); CA 69, 3048g (1968). 48. F. K. Klein and H. Rapoport, J. Am. Chem. Soc. 90, 2398 (1968). 49. F. K. Klein and H. Rapoport, J. Am. Chem. SOC.90, 3576 (1968). 50. R. E. Servis and A. I. Kosak, J. Am. Chem. Soc. 90, 4179 and 6895 (1968). 51. R. Tschesche, J. Rheingans, H. W. Fehlhaber, and G. Legler, Ber. 100,3924 (1967). 52. R. Tschesche, E. Froberg, and H. W. Fehlhaber, TetrahedronLetters 1311 (1968). 53. C. Y. Chen and D. B. MacLean, Can. J . Chem. 45,3001 (1967). 54. B. S. Joshi, V. N. Kamat, A. K. Saksena, and T. R. Govindachari, TetrahedronLetters 4019 (1967). 55. K. Wada, S. Marumo, and K. Munakata, TetrahedronLetters 5179 (1966). 56. M. Ikram, M. H. Hug, and S. A. Warsi, Pnkistan J.Sci. Ind. Res. 9, 34 (1966); CA 67, 117031k (1967). 57. K. S. Baisheva and B. K. Rostotskii, Dokl. Akrtd. Nauk Tadzh. SSR 10, 30 (1967); CA 68, 877v (1968). 58. S. Naruto, S. Arakawa, and H. Kaneko, Tetrfhedron Letters 1705 (1968). 59. L. E. Below, A. Y. Leung, J. L. McLaughlin, and A. G:Paul, J. Pharm. Sci. 57,516 (1968); CA 69, 19338n (1968). 60. R. N. Gandhi, T. R. Rajagopalan, and T. R. Seshadri, Current Sci. (India)36, 363 (1967); C.4 67, 88295s (1967). 61. G. Snat,zke and G. Wollenberg, J . Chem. SOC.,C' 1681 (1966). 62. A. Flentje, W. Dopke, and P. W. Jeffs, Nuturwiss. 52,259 (1965). 63. L. J. Haynes, G. E. M. Husbands, and K. L. Stuart, J. Chem.Soc., C' 951 (1968). 64. K. L. Stuart and C. Chambers, Tetrahedron Letters 4135 (1967). 65. S.-T. Lu, Yakugaku Znsshi 87, 1278 (1967); CA 68,59777r (1968). 66. K. Leander and B. Liining, TetrahedronLetters 1393 (1968). 67. R. Ikan, E. Rapoport, and E. D. Bergmann, Israel J . Chem. 6, 65 (1968); CA 69, 678b (1968). 68. C. C. J. Culvenor and L. W. Smith, AustrrilictnJ. Chem. 20,2499 (1967). 69. H. Irikawa, N. Sakabe, S. Yamamura, and Y. Hirata, Tetrahedron 5691 (1968). 70. H. Irikawa, S. Yamamura, N. Sakabe, and Y. Hirata, TetrahedronLetters 553 (1967). 71. H. Irikawa, H. Sakurai, N. Sakabe, and Y. Hirata, Tetrahedron Letters 5363 (1966). 72. S. Yamamura, H. Irikawa, and Y. Hirata, TetrahedronLetters 3361 (1967). 73. H. Sakurai, N. Sakabe, and Y. Hirata, Tetrahedron Letters 6309 (1966). 74. H. Sakurai, H. Irikawa, S. Yamamura, and Y. Hirata, Tetrahedron Letters 2883 (1967). 75. T. Nakano and Y. Saeki, TetrahedronLetters 4791 (1967). 76. R. C. Briner, C. B. Boyce, N. H. Ferris, and J. P. Ferris, Am. Chem. Soc., Div. Org. Chem. (1967). 77. J. P. Ferris, R. C. Briner, C. B. Boyce, andM. J. Wolf, TetrahedronLetters 5123 (1966). 78. H. Appel and H. Achenbach, TetrahedronLetters 5789 (1966). 79. K. Leander and B. Liining, TetrahedronLetters 905 (1968). 80. Y. Inubushi, Y. Tsuda, and E. Katarao, C'hem. & Pharm. Bull. (Tokyo)14,668 (1966); CA 65, 10632 (1966). 81. T. Okamoto, M. Natsume, T. Onaka, F. Uchimaru, and M. Shimizu, Chem. & P h r m . Bull. (Tokyo) 14, 670 (1966); CA 65, 10633 (1966). 82. T. Okamoto, M. Natsume, T. Onaka, F. Uchimaru, and M. Shimizu, Chem. & Pharm. Bull. (Tokyo) 14, 672 (1966); CA 65, 10633 (1966). 83. W. J . Griffin, Audmlian J. P h r m . [N.S.] 48, 520 (1967). 84. P. Bchriider and M. Luckner, Arch. PArcmz. 301, 39 (1968).
6.
NEW ALKALOIDS
509
85. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Chem. Commun. 410 (1968). 86. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and J. A. Wunderlich, Chern. Cornmun. 290 (1968). 87. F. Sandberg, T. Norin, 0. Lindwall, and R. Thorsen, Herb. Hung. 5,61(1966); C A 68, 597711 (1968). 88. S. R. Johns and J. A. Lamberton, Australian J. Chem. 20, 1301 (1967). 89. L. Slavikova and J. Slavik, CoZCection Czech. Chem. Commun. 31,3362 (1966); C A 65, 15437 (1966).
90. L. Canonica, B. Danieli, P. Menitto, G. Russo, and G. Ferrari, Tetrahedron Letters 4865 (1968). 91. J. A. Diment, E. Ritchie, and W. C. Taylor, Australian J. Chem. 20,1719 (1967). 92. J. Rondest, B. C. Das, M. N. Ricroch, C. Kan-Fan, P. Potier, and J. Polonsky, Phytochemistry 7 , 1019 (1968); CA 69, 16818h (1968). 93. L. Fonzes and F. Winternitz, Compt. Rend. C 266,930 (1968); C A 69,36303q (1968). 94. N. M. Mollov, G. I. Yakimov, and P. P. Panov, C m p t . Rend. Acad. BulgareSci. 20, 557 (1967); C A 67, 117013f (1967). 95. J. Haginiwa, S. Sakai, A. Kubo, and T. Hamamoto, Yakugaku Zasshi 87,1484 (1968) ; C A 69, 19365u (1968). 96. E. Steinegger and C. Moser, P h a m . Acta HeZw. 42, 177 (1967). 97. E. Steinegger and P. Weber, Helw. Chim. Acta 51, 206 (1968). 98. T. R. Govindachari, B. R. Pai, end P. S. Subramanian, Tetrahedron 22,3245 (1966). 99. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Australian J. Chem. 20, 1737 (1967). 100. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, BustraZianJ. Chern. 20,1303 (1967). 101. K. H. Michel, F. Sandberg, F. Haglid, and T. Norin, ActaPharm. Suecica 4,97 (1967); C A 67, 40992q (1967). 102. D. Lavie, N. Danieli, R. Weitman, and E. Glotter, Tetrahedron 24, 3011 (1968). 103. J. Lutomski, 2. Kowalewski, end K. Drost, Herba Polon. 13, 103 (1967); C A 68, 112163r (1968). 104. F. Kiyamitdinova, S. T. Akramov, and S. Y. Yunusov, Khim. Prirodn. Soedin. 3,411 (1967); C A 68, 75730a (1968). 105. L. N. Mander, R. H. Prager, M. Rasmussen, E. Ritchie, and W. C. Taylor, Australian J . Chem. 20, 1705 (1967). 106. J. Fridrichsons, M. F. MacKay. and A. Mel-Mathieson, Tetrahedron Letters 3521 (1967). 107. M. Pais, G. Rattle, R. Sarfati, and F. X. Jarreau, C o q t . Rend. C266, 37 (1968); C A 68, 87443x (1968). 108. D. Giacopello and V. Deulofeu, Tetrahedron 23, 3265 (1967). 109. M. Pais, J. Mrtrchand, X. Monseur, F. X. Jarreau, and R. Goutarel, Compt. Rend. C264, 1409 (1967); C A 67, 117008h (1967). 110. E. Steinegger, C. Moser, and P. Weber, Phytochemistry 7,849 (1968); C A 69, 19342j (1968). 111. P. Bellet, Ann. Pharm. Franc. 10, 81 (1952). 112. A. R. Battersby, B. Gregory, H. Spencer, and J. C. Turner, Chem. Commun. 219 (1967). 113. N. K. Hart, S. R. Johns, and J. A. Lamberton, AustraZianJ. Chem. 21, 1321 (1968); C A 6 9 , 4 4 0 8 8 ~(1968). 114. A. R. Battersby, R. B. Bradbury, R. B. Herbert, M. H. G. Munro, and R. Ramage, Chem. Commun. 450 (1967). 115. T. Kametan], K. Fukumoto, H. Yagi, and F. Sato, Chern. Commun. 878 (1967).
5 10
R. H. F. MANSKE
116. A. R. Battersby, R. B. Herbert, E. McDonald, R. Ramage, and J. H. Clements, Chem. Commun. 603 (1966). 117. A. R. Battersby, E. McDonald, M. H. G. Munro, and R. Ramage, Chem. Commun. 934 (1967). 118. &I.Saleh, S. El-Gangihi, A. El-Homidi, and F. Santavf, Collection Czech. Chem. Commun. 28, 3413 (1963). 119. H. PotBSilova, J. Hrbek, ,Jr., and F. Santavl, Collectiorb Czech. Chem. Commun. 32, 141 (1967). 120. A. C. Barker, A. R. Battersby, E. McDonald, R. Ramage, and J. H. Clements, Chem. Commun. 390 (1967). 121. A. R. Battersby, M. H. G . Munro, R. B. Rradbury, and F. santavf, Chem. Commun. 695 (1968). 122. J. Fridrichsons, M. F. MacKay, and A. McL. Mathieson, Tetrahedron Letters 2887 (1968). 123. N. K. Hart, S. R. Johns, J. A. Lamberton, and J. K. Saunders, Tetrahedron Letters 2891 (1968). 124. K. Bernauer, Helv. Chim. Acto 50, 1583 (1967). 125. S. Okuda, H. Kataoka, and K. Tsuda, Chem. & Pharm. Bull (Tokyo)13,491 (1965). 126. N. K. Hart, S. R. Johns, and J. A. Lamberton, Chem. Commun. 302 (1968). 127. S. Iskandarov, R. N. Nuriddinov, and S. Y. Yunusov, Khim. Prirodn. Soedin. 3, 26 (1967); C A 67, 100294a (1967). 128. D. Kamalitdinov, S. Iskandarov, and S. Y. Yunusov, Khim. Prirodn. Soedin. 3,352 (1967); CA 68, 29927x (1968). 129. Y. Kishi, S. Sugiura, S. Inoue, and Y. Hayashi, Tetrahedron Letters 637 (1968). 130. S. Johne and D. Groeger,Phamizie 23, 35 (1968); C A 68,93504j (1968). 131. K. Nishikawa, M. Miyamura, and Y. Hirata, Tetrohedroa Letters 2597 (1967). 132. K. Nishikawa and Y. Hirata, Tetrahedron Letters 2591 (1967). 133. T. Nakasato and S. Asada, YakugalPu Zasshi 86, 1205 (1966); C A 66,65671b (1967). 134. N. Melendez, L. Carreras, and J. R. Gigon, J . Pharm. Sci. 56, 1677 (1967); CA 68, 27513k (1968). 135. G. J. Kapadia and R. .J. Highet, J . Pharm. Sci. 57, 191 (1968); CA 69, 10593j (1968). 136. N. K. Hart, S. R. Johns, J. A. Lamberton, and J. A. Price, AustrctlicrnJ. Chem. 21, 1389 (1968). 137. E. Fujita, K. Fuji, K. Bessho, A. Sumi, and S. Nakamura, Tetrahedron Letters 4595 (1967). 138. S . K. Bavega, M. L. Garg, and M. P. Joneja, IndianJ. Pharm. 30, 11 (1968); CA 68, 75725c (1968). 139. M. Tomita and M. Kozuka, Yakugaku Zrtsshi 87,1134 (1967);CA 68, 10233w (1968). 140. K. Leander and B. Luning, TetrahedronLetters 3477 (1967). 141. V. U. Ahmad, M. A. Ali, and S. Siddiqui, Pakistan J . Sci. Ind. Res. 8, 166 (1965); CA 68, 2 9 9 3 1 ~ (1968). 142. R. Tschesche and I. Reutel, Tetrcrhedroi~ Letters 3817 (1968). 143. S. L. Keely, Jr. and F. C. Tahk, Chem. C’ommun.441 (1968);J . Am. Chem. Soc. 90, 5584 (1968). 144. T. J. Curphey and K. L. Kim, Tetrahedron Letters 1441 (1968). 145. R. V. Stevens and M. P. Wentland, J . Am. Chem. Soc. 90,5580 (1968). 146. D. P. Chakraborty and K. C. Das, Chem. Commun. 967 (1968). 147. T. Kisaki, 8 . Mizusaki, and E. Tamaki, I’hytoehemistry 7, 326 (1968); C-4 69, 30510 (1968). 118. S-T. Lu, YrtkuyrXu Zicrishi 87, 1282 (1!167); C’A 68, 47025f(1968).
6. NEW
ALKALOIDS
51 1
J. Poisson and C. Miet, Aim.Ph~trm. Frunc. 25, 523 (1967);C’A 68, 10180b (1968). S. McLean, M-S. Lin, and J . Whelan, Tetruhedron Letters 2425 (1968). M. Tomita and K. Hirai, Yrtkugrrku Ztrsshi 80, 608 (1960). M. P. Cava, Y. Watanabe, K. Bessho, & J. I. Mitchell, A. I. daRocha, B. Hwang, B. Douglas, and J. A. Weisbach, Tetrahedron Letter8 2437 (1968). 153. E. Fujitaand A. Sumi, Ynkugmku Zusshi 87, 1153 (1967); C A 68, 10235y (1968). 154. C. P. Huber, S. R. Hall, and E. N. Maulen, Tetrdedron Letters 4081 (1968). 165. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Austrdiuit J . Chem. 20, 1787 (1967). 136. E. Brochmann-Hanssen and K. Hirai, J . Phnr?n.Sci. 57,940 (1968); C A 69, 36305s (1968). 157. C. Meyer, W. Trueb, J. Wilson, and C. H. Eugster, Helv. C’liim. Acta 51, 661 (1968). 157a. 0. Cervinka, A. Flbryova, and V. Novlk, Tetruhedroia Letters 5375 (1966). 157b. A.C.BakerandA.R.Battersby,J. Chem.Soc. 1317 (1967). 158. S. F. Mason, K. Schofield, R. J. Wells, J. S. Whitehurst, and G. W. Vane, Tetrnhedroia Letters 137 (1967). 159. R. P. K. Chan, J. C. Craig, R. H. F. Manske, and T. 0. Soine, Tetrnhedron 23, 4209 (1967). 160. D. H. R. Barton, R. H. Hesse, and G. W. Kirby, J. Chem. SOC.6379 (1965). 16Oa. S.R. Johnsand J. A.Lamberton, AustrcLZianJ.Chem. 20,1277 (1967);C A W , 40996u (1967). 161. Y . Kimura, M. Takido, and S. Koizumi, Y a k u p k u Zasshi 87, 1371 (1967); C‘A 68, 87441~ (1968). 162. K. Wiesner, D. M. MacDonald, C. Bankiewicz, and D. E. Orr, Can. J . Chem. 46,1881 (1968). 163. C. K. Atal, P. N. Moza, and A. Pelter, Tetrahedron Letters 1397 (1968). 88,3109 (1966). 164. G. Buchi, I. M. Goldman, and D. W. Mayo, J. A m . Chem. SOC. 165. J. H. Kim, Yakhak Hoeji 8,59 (1964); C A 65, 12248 (1966). 166. K. S. Mukhamedova, 8. T. Akramov, a n d S . Y. Yunusov, Khim.Prirorln.Soedin. 3, 117 and 287 (1967); C A 6 7 , 5 4 2 8 4 ~and 11699811 (1967). 167. C. SzAntay, L. Toke, and P. Kolonitz, Tetrahedron Letters 247 (1963);J. Org. Chem. 31, 1447 (1966). 168. A. R. Battersby, R. J. Francis, M. Hirst, R. Southgate, and J. Staunton, Chem. Commun. 602 (1967). 169. X. A. Dominguez, J. G. Delgado, W. P. Reeves, and P. D. Gardner, Tetrahedron Letters 2493 (1967). 170. H. R. Arthur, S. R. Johns, J. A. Lamberton, and S. N. Loo, AustrcdictnJ. Chem. 20, 2505 (1967); C A 68, 39865q (1968). 171. R. Tschesche, H. Last, and H. W. Fehlhaber, Ber. 100, 3937 (1967). 172. R . Tschesche and H. Last, Tetrahedron Letters 2993 (1968). 173. J. Reisch, I. Novak, K . Szendrei, and E. Minker, Naturwiss. 54, 517 (1967); C A 6 8 , 39860j (1968). 174. J. Reisch, K. Szendrei, E. Minker, and I. Novak, ActnPharm. Suecicn 4, 265 (1967); C A 68,39861k (1968). 175. S. Hara and K. Oka, J. A m . Chem. SOC.89, 1041 (1967). 176. S. F. Dyke, B. J. Moon, and M. Sainabury, Tetruhedron Letters 3933 (1968). 177. S. R. Johns, C. Kowala, J. A. Lamberton, A. A. Sioumis, and J. A. Wunderlich, Chem. Commun. 1102 (1968). 178. R. Tschesche, R. Welters, and H. W. Fehlhaber, Ber. 100, 323 (1967). 179. R. T. Aplin, M. H . Benn, and M.Rothschild, Nrrture 219, 747 (1968). 180. D. L. Dreyer, 153rd Meeti)tq Am. (‘he7n. Soc., Miumi Bench (1967).
149. 150. 151. 152.
512
R. H. F. MANSKE
181. T. Nakano and E. Corothie, Phytochemistry 7, 891 (1968); C A 69, 4979612 (1968). 182. R. A. Gardiner, K. L. Rinehart, Jr., J. J. Snyder, and H. P. Broquist, J . Am. Chem. SOC.90, 6639 (1968). 183. S. M. Kupchan, A. P. Davies, J. J. Barboutis, H. K. Schnoes, and A. L. Burlingame, J . Am. Chern. SOC.89, 5718 (1967). 184. P. G. Mantle and E. S. Waight, Nature 218, 581 (1968). 185. G. Goto, K. Sasaki, and N. Sakabe, Tetrrrhedron Letters 1369 (1968). 186. S. Uyeo, H. h i e , and H. Harada, Chem.& Pharwa. Bull (Tokyo) 15, 768 (1967); CA 67, 90981f (1967). 187. H. Harada, H. Irie, N. Masaki, K. Osaki, and S. Uyeo, L'hena. Commun. 460 (1967). 188. M. Debray, M. Plat, and J. Le Men, Ann. Phtrrm. Franc. 25, 237 (1967); C A 67, 97607x (1967). 189. M. P. Cava, K. Nomura, S. K. Talapatra, M. J. Mitchell, R. H. Schlessinger, I(. T. Buck, J. L. Beal, B. Douglas, R. F. Raffauf, and J. A. Weisbach, J . Org. C'hem. 33, 2785 (1968). 190. M. T. Wa, J. L. Beal, and R. W. Doskotch, LZoydur 30,245 (1967). 191. R. W. Doskotch, M. Y. Malik, and J. L. Beal, LZoydirr 32,53 (1967). 192. F. D. Monache, E. Corio, and G. B. Marini-Bettolo, Ann. 1st. Super. Sanitu 3, 564 (1967); CA 68, 7 7 4 4 0 ~(1968). 193. F. D. Monache, E. Corio, and G. B. Marini-Bettolo, Ann. 1st. Super. Srmittr 3, 190 (1967); C A 67, 88277n (1967). 194. W. G. Wright, K. H. Pegel, and R. T. Brown, J. Chem. Soc. 2262 (1967). 195. S. M. Kupchan, K. K. Chakravarti, and N. Yokoyama,J.Phorm. Sci. 52,985 (1963). 196. S. M. Kupchan, T. Y. Yang, M. L. King, and R. T. Borchardt,J. Org. Chem. 33,1052 (1968). 197. K. I. Kuchkora and G. V. Lazur'evskii, Izv. Akod. Nriuk MoZdovsk. SSR, Ser. Khim. Biol. 11, 43 (1965); C A 66, 95252h (1967). 198. J. E. Hodgkins, S. D. Brown, and J. L. Massingill, Tetrahedron Letters 1321 (1967). 199. T. T. Shakirov, K. A. Sabirov, and R. I. Shamsutdinov, Khim. Prirodn. Soedin. 4, 61 (1968); CA 69, 6832 (1968). 200. T. R. Govindachari and N. Viswanathan, Iridirrn J . C'hem. 5, 280 (1967); CA 68, 3037g (1968). 201. M. Gotz, T. Bogri, A. H. Gray, and G. M . Strunz, Tetrrthcdron 24, 2631 (1968). 202. G. M. Strunz, Tetrahedron 24,2645 (1968). 203. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustrrtZirrnJ.d'hem. 20, 1729 (1967). 204. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, AustrttZitrnJ. Chem. 21, 1383(1968). 206: H. Sakurai, N. Sakabe, and Y. Hirata, Tetrtrhedron Letters 6309 (1966). 206. H. Ishiiand T. Komaki, Ynkugoku Zu.~shi86,631 (1966); ( ' 4 65, 12564 (1966). 207. A. T. Awad, J. L. Beal, S. K . Talapatra, and W.P. Cava,J.~'/i(rr?~~.Sci. 56,279 (1967). 208. D. D. Casa and M. Sojo, J . C'hem. ~Soc.,C 2155 (1967). 209. J. Tomko, A. T. Awad, J. L. Beal, and It. W. Doskotch, Lloydirr 30,231 (1967).
-CHAPTER
7-
THE FORENSIC CHEMISTRY OF ALKALOIDS E . G. C. CLARKE The Royal Veterinary College. University of London London. England
I. Introduction ...................................................... I1 Poisoning by Alkaloids ............................................. A Introduction ................................................... B Pyrrolizidine Alkaloids .......................................... C Pyridine Alkaloids .............................................. D . Tropane Alkaloids .............................................. E Strychnos Alkaloids ............................................. F. Morphine Alkaloids ............................................. G. Colchicine ..................................................... H . Alkaloids of the Amaryllidaceae .................................. I. Indole Alkaloids ................................................ J Cinchona Alkaloids .............................................. K . Lupin Alkaloids L . Solanum and Veratrum Alkaloids .................................. M p-Phenethylamine and Ephedra Bases ............................. N . or-NaphthaphenanthridineAlkaloids ............................... 0. Erythrophleum Alkaloids ......................................... P. Aconitum and Delphinium Alkaloids ............................... Q . AlkaloidsoftheBuxaceae ........................................ R . Alkaloids of the Taxaceae .... ................................... S. Xanthine Derivatives ........................................... I11. Alkaloids as Drugs of Addiction ...................................... A Introduction ................................................... B . The Narcotic Analgesics ......................................... C. Stimulants or Psychoenergetics ................................... D Hallucinogens .................................................. IV ControlofAlkaloids ................................................ A . InternationalControl ............................................ B NationalControl ................................................ V Toxicological Analysis-General Considerations ........................ VI Extractionmethods ................................................ A . Introduction ................................................... B . Typesofsample ................................................ C Classification of Poisons ......................................... VII Identification Methods ............................................. A Introduction .................................................... B . Analytical Techniques ...........................................
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614 516 615 518 621 623 624 626 626 626 627 629 629 630 632 632 633 633 634 634 636 636 636 636 638 639 640 640 642 643 646 646 646 548 664 664 667
514
E. G. C. CLARKE
VIII. Tables of Analytical D a t a . . ......................................... Iiitroduction ...................................................... Table I. Solubility of Alkaloids ...................................... Table 11. Paper chromatography data. ............................... Table 111. Thin-layer chromatography data. ........................... Table IV. Ultraviolet spectrophotometry data ......................... Table V. Color Tests ............................................... StructuresofSynthetics ............................................ References ........................................................
560 560 561 561 566 570 573 576 579
I. Introduction Although the forensic chemistry of alkaloids has a long history, dating back t o the judicial murder of Socrates in B.C. 399’ or even before, it is only within comparatively recent times that the Law has seen fit to control and limit their use. As long as they were used solely for medicinal purposes, the Law had little interest in them. The isolation of the pure compounds from the original plant material during the 19th century, however, served to highlight their toxic and addictive properties, and it was these attributes that brought them into conflict with authority. Once a subject becomes of interest t o the Law, the question of detinition becomes of paramount importance. To confine the meaning of the word “alkaloid” to the original definition of “ a nitrogenous vegetable base” is to oversimplify the problem. Morphine is undoubtedly an alkaloid; so is codeine (although 90% of the codeine used is semisynthetic). Heroin is a simple derivative of morphine and levorphanol [( -)-3hydroxy-N-methylmorphinan] is a more distant one ; but pethidine and methadone cannot be regarded as derivatives of any vegetable base. Yet to the pharmacologist, the toxicologist, and the lawyer these are all members of the same group. They have a similar pharmacological action, they are isolated by the same analytical procedures, and controlled by the same laws. It is difficult t o draw a line of demarcation among them. The number of synthetic bases used in medicine increases almost dailynearly 1000 are mentioned in the current volume of the Extra Pharmacopoeia (1)-while plant alkaloids are falling into disuse as they are replaced by the cheaper and safer synthetics. Were one t o base one’s definition on therapeutic or toxicological importance, few vegetable bases would be included. I n order t o keep the subject within reasonable bounds, however, it has been decided to limit this chapter to the consideration of the plant alkaloids and their derivatives, purely synthetic substances being dealt with only if they illustrate some point of unusual forensic or analytical importance,
7.
THE FORENSIC CHEMISTRY O F ALKALOIDS
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11. Poisoning by Alkaloids
A. INTRODUCTION 1. Poisoning in Man Poisoning in man falls under one of the three headings: accident, suicide, or murder. Of these, accidents and suicides are distressingly common, and murder comparatively rare. I n England and Wales during the years 1958-61 there were a total of 1633 cases of accidental poisoning and 3955 suicides by poisoning, but only 6 cases of murder by this means ( 2 ) .At least, only 6 cases that were recognized as murder; there is, of course, no record of the number of cases of homicidal poisoning that were buried under the convenient epitaph of “death by natural causes.’’ Nowadays alkaloidal substances do not constitute a very important source of poisoning in man. During the years 1948-61 (2)a total of 15,045 people died of poisoning in England and Wales, deaths from carbon monoxide being excluded. Of this total, over half (8483) were due to barbiturates. Only 562 (3.7%) were due t o basic drugs; 429 of these were plant alkaloids (nicotine 123, morphine 94, strychnine 92, codeine 44, aconitine 26, atropine 18, quinine 10, ephedrine 8, heroin 5, cocaine 4, and ergotoxin,” hyoscine, quinidine, coniine, and theophylline 1 each), the remaining 133 being synthetic drugs such as analgesics, tranquillizers, and antihistamines. The number of deaths from alkaloidal poisoning has been decreasing for over a century. Taking the figures for England and Wales during 1837-38, 42% of all cases of poisoning were due to alkaloids, 37 % being due to morphine, which is here taken as including opium and laudanum (3).I n the years 1863-67 the figures were very similar, 42% due t o alkaloids, 39% due to morphine. By 1881 the totals had dropped t o 30% and 26%, respectively (4), while for the 10 years 1895-1904 out of a total of 8701 cases of poisoning, 1794 (21%) were due t o alkaloids, 1477 (17%) being caused by morphine ( 5 ) .I n America the same trend is noticed. I n the county of New York in the years 1841-43 75% of all poisoning was caused by alkaloids, 60% by morphine. Between 1866 and 1880 the figures had dropped to 28% and 20%, respectively, and in 1889 t o 1892 t o 14% and 12% (4).This steady decrease in the number of cases of poisoning caused by alkaloids is not entirely due to the increasing use of barbiturates, which did not become really popular until the period of World War 11. Other poisons have from time to time been fashionable. Paris green was the most popular poison in New York in the 1870’s, phenol (carbolic acid) in Great Britain a t the beginning of this century. ((
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The situation is rather different in the East. I n the Indian state of Uttar Pradesh for the years 1963 to 1965, out of 1355 cases in which poison was found, no fewer than 450 (33%) were due to alkaloids or substances containing them. This total included opium or morphine 248, datura or atropine 180, aconitine 12, and strychnine or nux vomica 10. Barbiturates only accounted for 73 cases (5.4%) (6).
2. Poisoning in Animals I n man poisoning is usually due to the ingestion of the pure alkaloid, or of some pharmaceutical preparation containing it ; it is seldom nowadays that the plant itself is involved, although such cases do occur from time to time. With animals, on the other hand, except in the case of strychnine, it is more frequently the plant that is eaten. Poisoning is nearly always accidental ; malicious poisoning is rare in spite of frequent accusations. It is difficult t o acquire any relevant figures, as authority is not interested in the deaths of animals unless they reach epidemic proportions or are caused by deliberate intent, and a full investigation is rarely made unless particular economic or sentimental factors are involved. Otherwise there is no inquest, seldom a postmortem, and rarely a toxicological analysis. But it is only from those cases in which an analysis is made that we can get any figures a t all, although for the reasons given above these may not form a representative sample. Out of 360 consecutive cases sent for analysis to a toxicologist in the south of England (7), 83 were found to be due to alkaloids or alkaloidcontaining material. Strychnine (76 cases) was by far the most common, the others comprising taxine (5 cases), solanine (2 cases), nicotine and theobromine (1 of each). Of cases submitted to the Royal (Dick) School of Veterinary Studies in Edinburgh from 1959-61, 10% were due t o strychnine (8).A similar figure was found in the cases submitted to the Wallaceville Animal Research Station in New Zealand in the years 1951-60 (9).These figures, however, do not present a true picture, as they deal only with cases arising from man-made conditions such as the use of strychnine as a rodenticide and take no account of the deaths of farm stock from the ingestion of such plants as ragwort (Senecio spp.),larkspur (Delphinium spp.), and Crotalaria spp. Such poisoning is most likely t o occur in remote rural areas where facilities for toxicological analysis are lacking, and therefore any diagnosis of poisoning always subject t o suspicion. There is often a tendency to argue post hoc, ergo propter hoc. A cow is found dead in a patch of hemlock, therefore it died of hemlock poisoning. Plants are frequently identified incorrectly ; and even if the plant contains an alkaloid it is not necessarily the cause of death. An
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animal which has died after consuming seed of the castor oil plant (Ricinuscommunis)has been poisoned by the phytotoxin ricin not by the alkaloid ricinine. I n spite of this, however, it must be realized that plants containing alkaloids are responsible for many hundreds of deaths in farm stock every year, and probably in a much larger number of cases for ill health and loss of condition due t o the ingestion of such plants in quantities insufficient t o cause death or even definite clinical symptoms.
3. Doping There is one example of animal poisoning which requires special mention-the doping or illicit medication of racing animals (10-13). By definition, doping is the administration of a drug t o an animal in order to affect its speed, stamina, courage, or conduct in a race. Horses are the animals most frequently subjected to this practice, but greyhounds, racing pigeons, and (possibly) bulls are sometimes doped, while athletes may dope themselves. Doping usually consists either of the administration of a stimulant to make an animal go faster (doping t o win) or of a sedative t o make it go more slowly (doping to lose or "nobbling"), but other procedures such as the use of local anesthetics to mask lameness, of tranquillizers t o control a highly spirited animal, and of sex hormones for a female in estrus are also employed. It is as stimulants that alkaloids most frequently find employment. Possibly caffeine has been used more frequently than any other drug. It is cheap, easy to obtain, and reasonably effective. A horse is more alert, gets away t o a better start, and responds more quickly t o its rider. Strychnine has also been used extensively for this purpose, but its act,ion seems less reliable. Both morphine and heroin, which act as stimulants in the horse, have also been widely used in the past. If the dose and the timing are both correct a horse doped with morphine will run far above its normal form. As these substances are alkaloids, the idea has arisen in certain circles that any alkaloid will do, and so such unlikely compounds as atropine, ephedrine, yohimbine, and quinine have been employed. Cocaine has also been used with limited success. The modern tendency however is to use synthetic drugs such as amphetamine," Alkaloids are not used as sedative drugs in the horse-barbiturates or chloral are usually employed-but codeine and quinine, the latter in contradistinction to its use as a potential stimulant in the horse, have
* The structures of the alkaloids mentioned in this chapter are given in other volumes of this series. The stri-cturesof the synthetic drugs discussed in this chapter are given at the end of Section VIII (p. 576).
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been used for this purpose in greyhounds, which are nearly always doped to lose. Racing pigeons are sometimes given amphetamine to delay the onset of fatigue. Bulls are reported to have been quietened with tranquillizers. The doping of athletes consists of self-medication with drugs of the amphetamine type. The proof of doping lies in the demonstration of the presence of the drug in the body fluids of the animal. Sweat, blood, saliva, and urine are available. The first is undesirable owing to likelihood of contamination, the second involves the risk, remote but theoretically possible, of damage to the animal while it is taken. Saliva is sometimes useful, as a drug may be present in unaltered form, although in small quantities and for a limited time only. It is also easy to obtain. Urine is more difficult to collect and usually contains a much larger quantity of the drug, but our knowledge of the metabolic processes of a horse is so limited that one seldom knows in what form it is likely to be encountered. B. PYRROLIZIDINE ALKALOIDS Pyrrolizidine alkaloids (14, 15) occur in a large number of plants including the genera Senecio and Erechtites (Compositae), Echium, Heliotropium, Trachelanthus and Trichodesma (Boraginaceae), and Crotalaria (Leguminoseae). Many of them are hepatotoxic, and give rise both in man and beast to the condition known as seneciosis, which has a worldwide distribution (16). I n man, poisoning may arise from eating bread made from flour contaminated with fragments of the leaves and stems of various species of Senecio, par‘ticularly 8. burchelli and 8. ilicifolius (the so-called “bread poisoning” of South Africa) (17,18), or from drinking “bush tea,” a concoction made in the West Indies from a number of plants including Crotalaria retusa (19)and C. fulva (20).This gives rise; particularly in children, to a partial or complete occlusion of the centrilobular veins of the liver causing a condition known as venoocclusive disease. The causative agent is monocrotaline (21). Poisoning in animals is usually due to eating plants belonging to the genera Crotalaria, Heliotropeum, or Senecio. This gives rise to a condition knowrLin different parts of the world as “walking disease,” “Winton disease,” ‘(Pictou disease,” (‘Molten0 disease,” or dunsiekte.” All species of farm stock are susceptible and, as in man, the chief pathological lesion seen is centrilobular necrosis of the liver. The condition has been produced experimentally on a number of occasions (22,23).Stock normally refuse to eat the growing plants as they seem to be unpalatable, but will consume them readily if they are made into hay, as when dried they ((
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lose their unpleasant taste, but not their toxicity. There is a considerable lapse of time between ingestion of the plant and the onset of clinical symptoms, which may not be seen until weeks or months after the animals have eaten the contaminated hay or been removed from the ragwortinfested pasture. It has been said that ragwort causes more poisoning among stock in Great Britain than all other poisonous plants put together (24). Members of the Senecio genus are not the only plants containing pyrrolizidine alkaloids to cause poisoning. Severe losses among stock have occurred in Australia due to eating Heliotropeum europeum, which contained heliotrine, lasiocarpine, and their N-oxides. Sheep are the animals most commonly affected. Cattle dislike the plant, and will only eat it if no other food is available, although, as with many other poisonous plants, animals introduced from another locality will eat it more readily than “resident ’) beasts (25).The effect is cumulative, and animals will often survive one year to succumb the next. The alkaloids cause typical liver lesions, the essential pathology being an atrophic hepatosis with megalocytosis of the parenchymal cells (26-28). The liver damage is apparently responsible for some malfunctioning of the copper storage mechanism, which leads to an accumulation of copper in the liver, very high values (over 1000 ppm) being found a t postmortem. Similar high copper values have been found in sheep poisoned by Echium plantagineum which contains echimidine and echiumidine (29).It is not certain what part copper plays in the syndrome, although death may be associated with an acute hemolytic crisis similar to that which occurs in chronic copper poisoning. It is noteworthy that pyrrolizidine alkaloids in which the ester chain has two or more hydroxyl groups on adjacent carbon atoms, e.g., monocrotaline, lasiocarpine, form complexes with copper, but there is as yet no evidence that this has any connection with the high copper content of the liver (30). Considerable losses have also been caused by various species of Crotalaria, which has already been mentioned in connection with “bush tea.” I n America, C . spectabilis, grown as a cover crop on sandy soils in the southern states, is the most toxic species. All parts of the plant are poisonous, but the highest concentration of the alkaloid (monocrotaline) is found in the seeds. Horses, cattle, pigs, and poultry have all been affected, the last named being particularly susceptible. Poisoning may arise from animals eating the green plant (31-33) or from contamination of grain by the seed ( 3 4 ) .As in cases of poisoning by Senecio or Heliotropeum spp., the fundamental lesion is damage to the liver, but ascites and gastric hemorrhage are also common findings a t postmortem (33-35). There may be an interval of weeks or months between removal from the
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plant and death (31).C. Sagittarius has caused poisoning in horses (36). C. giantstriata, although poisonous, is much less toxic than C. spectabilis. I n South Africa C. dura and C. globifera may give rise t o the condition known as “jaagsiekte” in horses ( 1 8 ) )while in Australia it has been shown that “Kimberley horse disease’’ is caused by C. retusa (37) or C. crispata (38). Trichodesma incanum which grows in central Asia is responsible for suiljuk,” a condition in cattle and horses which appears t o be similar t o seneciosis. Certain Cynoglossum spp. have also been shown to contain pyrrolizidine alkaloids. Poisoning of cattle by C. oflcinale has been reported (39))but it is not clear whether the alkaloids are implicated. An interesting point about the hepatotoxicity of the pyrrolizidine alkaloids is that male animals are considerably more susceptible to poisoning by them than female. It was found that the LD50 of retrorsine was 60 mg/kg for male rats and 180 mg/kg for females (40).Out of a herd of young cattle that had eaten silage containing ragwort, 40% of the bullocks died but only 27.5% of the heifers (41).I n an outbreak of poisoning by Heliotropeum europeum in Australia, 50% of the bullocks died, the heifers remaining clinically unaffected (15).Injection of testosterone into a spayed female rat gives it the susceptibility of the male, while injecting an estrogen into a castrated male gives it the resistance of the female (40). The pyrrolizidine alkaloids are not all poisonous. Schoental (42) has postulated that for an alkaloid to be toxic it must have a double bond between C-1 and C-2. The cyclic diesters are twice as toxic as the open diesters, and four times as toxic as the open monoesters. Esters of branched-chain acids are toxic while esters of straight-chain acids are not (43). The mechanism by which the alkaloids exert their hepatotoxic effect is still not clear. It is considered that the essential action is an alkylation, brought about by an alkyl-oxygen fission. and it has been shown that heliotrine appears to undergo a transformation of this kind in the sheep (44).The alkaloids interfere with a number of enzyme systems. I n vitro, lasiocarpine and heliotrine inhibit enzyme systems that need pyridine nucleotides for electron transfer ( 4 5 ) .The nicotinamide-adenine dinucleotide pyrophosphorylase activity of nuclei from rat liver that has been treated with heliotrine is reduced significantly below that of controls (46).It has recently been shown that in rats lasiocarpine inhibits RNA synthesis, causes a substantial reduction in tryptophan pyrrolase activity, and decreases the activity of RNA polymerase ( 4 7 ) . It is suggested that the alkaloids themselves are not hepatotoxic, but are converted in the liver to pyrrolelike derivatives which react with
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tissue constituents to form “bound pyrroles ” which either remain in the tissues or are excreted in the urine (48). It has been shown (49)that if heliotrine is incubated in rumen fluid in the presence of vitamin BIZit is converted to the nontoxic I-methylene derivative. This suggests that cobalt pellets might be used to protect sheep and cattle from chronic intoxication ; but so far this suggestion has not been confirmed (50).Treatment of poisoning is usually unrewarding, although some success has been claimed in the use of crystalline methionine for treating horses poisoned by Xenecio (51). A number of other toxic manifestations of the pyrrolizidine alkaloids have been recorded. Ingestion of C. spectabilis leads to alopecia of the dark-colored areas of skin in pigs (34).Young rats, suckled by mothers treated with lasiocarpine or retrorsine, may die with acute liver lesions even if the alkaloids have produced no apparent symptoms in the mother. This finding gives rise to the suggestion that liver disorders in children may result from drinking the milk of cows that have eaten plants containing these compounds in their fodder (52).Clark (53)has found that heliotrine is mutagenic in Drosophila. Schoental and Head ( 5 4 )have shown that it produces liver tumors in rats. Poisoning by the pyrrolizidine alkaloids has recently been reviewed by Bull ( 5 5 ) )who suggests that the condition should be called pyrrolizidine alkaloidosis. C. PYRIDINE ALKALOIDS The areca or betel nut, the fruit of Areca catechou, contains arecoline and other bases (56).It is cut into slices and chewed by the people of many races in India and Eastern Asia, usuaily after being mixed with lime and wrapped in leaves. Poisoning is rare, although it may be caused by the use of unripe nuts, the symptoms being flushing, perspiration, bronchial spasms, contraction of the pupils, diarrhea, dyspnea, and collapse. Some people are hypersensitive to betel nuts, and fatal cases have occurred after taking even small fragments of a nut (57).Arecoline in the form of the hydrobromide was formerly used ia human medicine as a cholinergic, and gave rise to occasional cases of poisoning through overdosage. It is seldom met with nowadays, though it is still used in veterinary medicine as an anthelmintic, either alone or in combination with acetarsol. Numerous cases of poisoning in dogs and cats have followed its use in inexpert hands, the combination with acetarsol being particularly dangerous. Lobeline, the chief alkaloid of Lobelia inJlata and other Lobelia spp. has a nicotinelike action and has had limited use as a respiratory stimulant
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and a smoking deterrent. Overdosage may cause nausea and vomiting, followed by convulsions and collapse. It has proved fatal when used as an abortifacient, a dram of the powderedleaves having caused death (57). I n addition to the classic case of Socrates, coniine from Conium maculatum (spotted hemlock or poison hemlock) has caused poisoning on many occasions. It has been used as a homicidal agent and has caused death accidentally through having been mistaken for parsley. Symptoms of poisoning have also followed inhalation of the vapor. Poisoning among animals is still fairly common as the young green shoots of hemlock come up in water meadows in the spring before the grass starts to grow. Ducks, sheep, cattle, and horses have all been poisoned (58, 59), but with large animals it is rarely fatal (60). Coniine is also said to occur in Aethusa cynapeum (fool’s parsley) which is recorded as having caused poisoning inpigs (61). Nicotine, the common alkaloid of Nicotiana tabacum is an extremely poisonous substance, the fatal dose for man being between 40 and 60 mg. It is the most common cause of poisoning by alkaloids in Great Britain a t the present time, probably because it is readily available. It is sometimes used as a suicidal agent, but most cases of poisoning arise accidentally through careless handling when employed as a horticultural insecticide. Poisoning may occur by absorption through the intact skin, the lungs, or the gastrointestinal tract. With large doses of poison death may occur in a few minutes. Nicotine has also been used as a homicidal agent on a number of occasions, the best known of these being the murder of Count Bocarmh by his brother-in-law, Gustav Fougnies, in 1850, an incident of great toxicological interest, as its investigation gave rise to the classic Stas-Otto process which was to hold the field for nearly a century (62). Smugglers carrying tobacco next to the skin have been poisoned by the nicotine absorbed. Children have been poisoned through being allowed to play with old tobacco pipes, and a,5-month-old baby by milk into which tobacco had been dropped by accident (63). Pigs have been poisoned after breaking into a field and eating a large quantity of tobacco plants (24) and poisoning from eating tobacco has also been recorded in the cat (64)and in the dog (65),but the most common cause of poisoning in animals is the use of solutions of nicotine as an insecticide. The poison may be absorbed through the intact skin or through wounds, or by animals licking themselves. The use of nicotine sulfate in the treatment of warble fly has resulted in the poisoning of cattle on numerous occasions (SS-SS), the nicotine being absorbed through the warble fly holes. Dosing with nicotine sulfate has also proved fatal in lambs (69).
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I n spite of its extreme toxicity, nicotine remains one of the safest horticultural insecticides, prcvided correct precautions are taken. As it is volatile it has no persistent effect and cannot give rise to lethal chain reactions such as those which may occur with the chlorinated hydrocarbons. It is reported that rabbits can consume 500 gm of fresh tobacco leaves in a week without ill effect (70).
D. TROPANE ALKALOIDS Poisoning by alkaloids of the atropine group (71,72)is fairly common, though rarely lethal. As d-hyoscyamine is almost completely inert, poisoning by atropine can be considered as being due to the 1-isomer. Atropine is usually considered to have a lethal dose in man of about 100 mg, although recovery has taken place after much larger quantities. Idiosyncracy to atropine, however, is fairly common, and cases are on record where administration of a therapeutic dose of atropine (e.g., for ophthalmic examination) has caused acute symptoms of poisoning (73). I n cases of sensitivity, fatal poisoning has been caused by less than 1 mg. Apart from this, poisoning may arise from overdosage (74, 75) and from the use of belladonna plasters on abraded skin (76, 7 7 ) . The usual symptoms are dilatation of the pupil and delirium. Hyoscine appears to be rather more toxic than hyoscyamine. The classic instance of poiqoning by hyoscine is, of course, the Crippen case : 25 mg were recovered from Mrs. Crippen’s body (78). There is a long history of poisoning associated with plants containing these alkaloids, during the middle ages particular interest having been centered on mandrake (probably Mandragoro oficinalis). Deadly nightshade (Atropa belladonna) also found considerable use by witches and professional poisoners. I n spite of the reputation which the plant had acquired, a case is on record in which deadly nightshade berries were sold in the streets of London in the last century as “edible nettleberries.” Two people died, and the man who sold the berries was convicted of manslaughter (79).Children are most frequently the victims of nightshade poisoning (80). Poisoning has been recorded on a number of occasions, particularly in South Africa, of children eating the seeds of Datura stramonium (81).Various species of Datura have been used as ordeal poisons. I n animals, poisoning arises from eating plants containing the alkaloids. Atropa belladonna poisoning has been recorded in pigs (82, 83), goats (84),and cattle (85).It is well known that rabbits can flourish on a
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diet of nothing but A . belladonna (86) and that the meat of such animals can be poisonous to man (87).A case is also recorded of atropine poisoning in a woman who had eaten an extract made from the livers of cattle which had apparently been grazing on deadly nightshade (88). Animals usually avoid Hyoscyarnus niger (henbane) owing to its unpleasant smell and taste, but they may eat it occasionally, particularly if it is fed in forage (89). Poisoning by Datura stramonium is also known (90,91),Pigs can tolerate small daily doses of datura seeds for long periods (92),while poultry have a very high resistance to it and can tolerate up t o 15 gm per day (93). Members of the genus Cestrum which are South American in origin, but are now cultivated as ornamental shrubs in various parts of the world, are reputed to contain alkaloids of the atropine type. They are known to have caused poisoning in stock (94) and their toxicity has been confirmed by experiment (95,96). Poisoning by cocaine is rare, and the chief forensic interest in this compound is as a drug of addiction. At one time, however, it was a fairly common suicidal agent. As ti local anesthetic it has now been almost completely replaced by synthetic compounds such as procaine and lignocaine which are without addictive properties, and whose toxicity, though by no means negligible, is considerably less than that of cocaine (97). Cocaine is not particularly stable as the ester linkage is easily hydrolyzed. Coca leaves kept for 40 years under museum conditions were found to contain no trace of the alkaloid. Rising and Lynn (98) mixed cocaine with the stomach contents of a sheep and found none remaining after 7 months.
E. Strychnos ALKALOIDS Strychnine (99, 100) has been used as a rodenticide in Europe since the 16th century. For almost as long it has found widespread use in medicine owing to its reputation, probably mistaken, as a tonic. As mentioned earlier, its ready availability and extreme toxicity led to its becoming one of the most common causes of suicidal and accidental poisoning, the latter being particularly common in children. I n spite of its intensely bitter taste i t has been used as a homicidal agent on numerous occasions. The lethal dose in man is usually given as 30 mg, but half this quantity could prove fatal. Death usually occurs within a few hours and has been known to take place in as little as 15 minutes after a massive dose (101). The longer the patient survives the greater the chance of recovery. About 7 0 % of the strychnine ingested is destroyed in the liver, most of the remainder being eliminated, mainly in the urine, within 24 hours. Strych-
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nine is very stable, and has been found in bodies exhumed years after death. Allergy to strychnine has been recorded (102). Owing to its widespread use as a vermin killer, strychnine has been and still is responsible for many deaths among domestic animals, especially dogs and cats, which appear to be particularly susceptible. Although the retail sale of strychnine, except under license for the destruction of moles, is now prohibited in Great Britain, such deaths still occur. This is prohably due t o the fact that during World War I1 the regulations governing the sale of strychnine were suspended in order to enable farmers t o deal with the plague of foxes brought about by the suspension of hunting. Many farmers laid in a stock of strychnine which they still possess. Brucine has only one-tenth of the toxicity of strychnine and poisoning by it is very rare. If it is met with in addition to strychnine in a toxicological analysis, it suggests that poisoning has been due to some preparation of nux vomica and not t o the pure alkaloid.
F. MORPHINE ALKALOIDS I n spite of the fact referred t o previously that morphine (103,104)and substances such as opium and laudanum which contain it were by far the most common cause of poisoning in man during the last century, strict control of the drug because of its addictive properties has greatly reduced the incidence of morphine poisoning, such cases as occur nowadays being usually associated with doct.ors, nurses, and midwives who have legitimate access to it. I n the East, however, opium still remains one of the chief causes of poisoning (57). Children are particularly susceptible t o poisoning by morphine, the fatal dose being in the order of 1 mg; and many cases have been caused by the use of “soothing syrups” containing opium t o quieten fractious infants. Such cases may still occur (105) although preparations of this kind are restricted by law to a morphine content of less than 0.02%. I n veterinary toxicology interest in morphine is limited to its use as a “dope” in racehorses. It is noteworthy that in the horse and the cat morphine acts as a stimulant. The forensic importance of the morphine alkaloids is centered on their use as drugs of addiction, and is discussed subsequently. Codeine, which has only one-quarter of the toxicity of morphine, is sometimes used as a suicidal agent ( Z ) , probably because it is easy to obtain, but as the majority of such suicides are caused by tablets in which the codeine is compounded with other substances such as aspirin or phenacetin, it is difficult to say if it is really the cause of death.
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G. COLCHICINE During the last century, poisoning by Colchicum autumnale (autumn crocus, meadow saffron) (106,107)was comparatively frequent. Witthaus ( 4 )collated references to 132 cases of human poisoning. Of these 1 18 were accidental, 6 suicidal, and 5 homicidal, the accidents being due to such diverse causes as inclusion of the leaves in salad, use of the drug as an abortifacient and gross errorsindispensing. Of these cases, 75% were fatal. The usual symptoms are nausea, vomiting, and hemorrhagic diarrhea. There is a latent period of about 4 hours between ingestion of the poison and onset of the symptoms. Death may be caused by as little as 5 mg of colchicine, and usually ensues within 24 to 36 hours, being due to asphyxia and circulatory collapse (97). Poisoning in livestock has been recorded on many occasions, and is due to animals grazing in meadows where C. autumnale grows. It is most likely to occur in spring and autumn. Cases due to inclusion of the plant in hay are also known. Horses and cattle are the animals most commonly affected (108-110). Colchicine is also found in various Gloriosa spp., G . superba being the best known. Decoctions of the plant have found considerable use in native medicine, particularly as abortifacients, and numerous fatalities are on record (81).Poisoning has occurred also through the tubers being mistaken for those of the yam (111).Alopecia is a prominent symptom.
H. ALKALOIDS OF THE AMARYLLIDACEAE Although a number of the Amaryllidaceae are poisonous, the agent responsible is not always an alkaloid. Agave lecheguilla, for example, which has caused heavy losses among sheep and goats in Texas and neighboring states, contains a photosensitizing agent and an abortifacient, both of which appear to be saponins (112,113). A number of both wild and cultivated species, however, contain alkaloids, of which lycorine is the most common (114,115).Of the cultivated species, various types of narcissus have been responsible for poisoning in both man and animals. Human poisoning has occurred through daffodil bulbs being mistaken for onions. Pigs have been poisoned by bulbs rooted up in a, park, and cattle when fed with bulbs owing to shortages of other foodstuffs in Holland during World War I1 (116). Some species belonging to the genera Amaryllis, Crinum, Haemanthus, and Nerine, which grow wild in South Africa, have been responsible for losses among sheep and goats (18, 81). The bulbs of Buphane disticha
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which contain buphanine and other bases have been used as a source of arrow poison. They have caused poisoning on a number of occasions when used as native medicine (81).
I. INUOLE ALKALOIDS 1. Xiinple Bases Tryptamine and its simple derivatives (117) are of interest mainly as hallucinogens, although the Australian grass Phalaris tuberosa, the cause of Phalaris staggers in sheep, contains N,N-dimethyltryptamine and its 5-hydroxy and 5-methoxy derivatives. The last named, given subcutaneously in a dose of 1-2 mg/kg, is lethal to sheep, producing symptoms similar to those of acute staggers (118-120).
2. Ergot Alkaloids Poisoning by ergot (121-123) is comparatively rare nowadays, but during the middle ages the mysterious scourge known as St. Anthony's Fire was responsible for many thousands of deaths, particularly in Eastern Europe where rye was a staple cereal. Poisoning arises from contamination of the grain-usually rye, but occasionally other cerealswith the sclerotia of Claviceps purpurea, and is most common in wet seasons. I n a heavy infestation as much as a quarter of the weight of the grain may be due to ergot, whereas grain containing as little as 1 % of ergot ma,ybe toxic. Since it became known that the condition was caused by ergot, outbreaks of chronic ergotism have become far less frequent, but they still occur from time to time. There was one in the south of France in 1952 (124) due to heavily contaminated bread. About 200 people were affected, several cases being fatal. The last outbreak in Great Britain appears t o have been in Manchester in 1988 (125).I n Russia during the years 192687 no fewer than 100,000 people are said to have been affected (126). It is usual to divide chronic ergotism into two types-gangrenous and convulsive-but there seems to be no clear line of demarcation between them as the symptoms, which include vomiting, diarrhea, peripheral pain, delirium, and hallucinations, vary from case to case, depending on the age and health of the individual and, it has been suggested, on the proportion of the various alkaloids present in the ergot (126). Acute poisoning is rare and is usually associated with gross overdosage with some ergot preparation taken in an attempt to procure abort' u1011.
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Ergot poisoning in animals is usually due to infestation of the growing grasses :perennial rye grass (Loliumperenne), cocksfoot (Dactylisglomerata),timothy (Phleumpratense),crested dogs tail (Cynosuruscristatus),oat grass (Avena pubescens), and Yorkshire fog (Holcus lanatus) are among British grasses susceptible to attack (127); while in America wheat grasses (Agropyron spp.), redtop (Agrostis alba), smooth bromegrass (Bromus inermis),reed grasses (Calamagrostis spp.), wild rye (Elymus spp.), reed canarygrass (Phalaris arundinacea),and bluegrasses (Poaspp.) have been implicated (128).The animals most frequently affected are cattle, but poisoning in sheep, horses, and pigs has also been recorded. Both the convulsive type of poisoning (129,130)and the gangrenous (131,132)occur; in some cases the symptoms recorded would fit either category (133). Although abortion in cattle grazing on ergotized pastures has been noted, there seems to be considerable doubt as to whether the quantity of alkaloid likely to be ingested is sufficient to cause i t (134))and it has not been possible to produce the condition experimentally (135). Sows fed on ergotiaed barley show a complete retardation of udder development and inhibition of milk secretion, but no other symptoms (136).
3. Alkaloids of Perganum harmala African rue (Perganum harmala )which contains harmine and similar bases (137, 138) has been suspected of poisoning cattle in New Mexico and its toxicity has been confirmed by experiment (139). Recent toxicological interest in the P-carboline bases depends not so much on their being a possible cause of plant poisoning, but because some of them (e.g., harman and norharman) may be met with in the most unlikely places, such as tobacco smoke (140))homemade wine (141))and postmortem material (142). It seems probable that they are artifacts formed by ring closure from tryptophan.
4 . G . Alkaloids of Gelsemiurn spp. I n the 19th century when tincture of gelsemium made from the root of Gelsemiurn sempervirens (143-145) was widely used in the treatment of neuralgia and similar conditions, cases of poisoning in man were fairly common (146,147).Death has been caused by 5 ml of the fluid extract. The preparation is still mentioned in the Extra Pharmacopoeia ( 1 ) . Poisoning is also said to have been caused by honey made from the flowers. A number of cases of poisoning in farm stock have occurred, the usual symptoms being weakness, incoordination, and convulsions. Morphine is said to be a specific antidote (148).Heavy mortality has been reported among turkeys, the birds becoming lethargic and incoordinate
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(149).Gelsemine also occurs in the Indian creeper Gelsemium elegans ; decoctions of this plant are frequently used for criminal purposes (52’).
5. Alkaloids of the Calabar bean Physostigmine (15U-152) is found in the seeds of Physostigma venenosum, the Calabar beau or ordeal bean of West Africa, where it has been used for centuries as a test for witchcraft. Poisoning has arisen from accident, as when the sweepings from a ship’s hold were dumped on a rubbish heap in Liverpool and eaten by children, one of whom succumbed after eating six seeds (73),or by overdosage (153),but such cases are rare and seldom fatal, although death has been caused by as little as 1.2 mg (154). Poisoning by synthetic substitutes for physostigmine, such as neostigniine, is rather more common (97).Physostigmine is an inhibitor of cholinesterase, so atropine or PAM (‘2 -pyridinealdoxime) may be used as antidotes. Animal poisoning seems to be unknown.
J. Cinchona ALKALOIDS Quinine is one of the least toxic alkaloids, but there is wide variation in . cases of poisontolerance to it, and allergy is not unknown ( 6 3 ) Nonfatal ing may be caused from its use as an antimalarial (155),but fatalities are usually due to its use as an abortifacient (156, 157). The toxic dose is difficult t o assess and may be anywhere in the region from 2 t o 20 gm. Deafness and blindness, which may be permanent, are symptoms commonly seen. Quinine was the most common cause of suicide in Bulgaria in the 1930’s (158). Poisoning in animals by quinine does not appear to have been recorded. It has, however, been used in doping : as a stimulant in the horse and as a sedative in the greyhound. Poisoning by quinidine is very rare and is associated with its clinical use (159).
K. LUPINALKALOIDS Since classical times lupins have been used as green manure, as a fodder crop, and as a source of meal for both man and beast. No cases of poisoning appear to have been recorded before the 19th century, although i t was realized that the seeds had harmful i)roperties, and special methods were used in preparing them for food (160). From 1860 onwards, however, numerous outbreaks of poisoning occurred in northern Europe, losses in
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sheep running into many thousands (161,162),but it seems that the condition, known as lupinosis and characterized by extensive liver damage, was not due to the alkaloidal content of the plant, but was probably fungal in origin. A similar condition has been noted in Western Australia during the last two decades (163-169). Poisoning in America, which has caused heavy mortality (270),is undoubtedly due to the alkaloids contained in the plant, which is particularly dangerous a t the seeding stage. Sheep are the animals most frequenkly affected. The symptoms are somewhat variable, but among those usually noted are nervousness, dyspnea, and ataxia, followed by convulsions, coma, and death. Unlike that of the hepatotoxin which gives rise to lupinosis, the effect is not cumulative and an animal may eat comparatively large quantities provided it does not consume a lethal dose a t any one time (171).Not all lupins are harmful. The most poisonous species are said t o be Lupinus sericeus, L. leucophyllus, L. argenteus, L. caudatus, and L. perennis, while certain European strains known as “sweet” lupins are practically nontoxic (162).During recent years, strains entirely free from alkaloids have been produced by selective breeding. Of the numerous alkaloids present in the lupin (172, 173),d-lupanine is the most widely distributed and is usually regarded as the most toxic (174).The alkaloids are excreted in the urine, Poisoning by cytisine (172,173)from Cytisus laburnum (syn. Laburnum anagyroides Medic.) is comparatively common. The alkaloid is found in all parts of the tree and children have been poisoned from eating the seeds or even from chewing twigs, but such cases are rarely fatal. I n spite of this, a decoction of laburnum bark has been used for homicidal purposes (78). Poisoning in animals is also well known and has been recorded in cattle ( 175,176),in pigs ( 17 7 ) ,and in horses (?a).Symptoms are usually excitement, sweating, and incoordination, occasionally followed by convulsions and death. Cytisine is excreted in the milk, and children may be poisoned by milk from a cow which itself shows no clinical symptoms. Cattle may be poisoned-by picking up laburnum seed in the grass (178). Cytisine is also found in Sophora secundiJlora (mountain laurel or mescal bean), which is found in the western United States, and has given rise to poisoning in cattle, sheep, and goats. Although the seeds contain the highest proportion of alkaloids, they pass through the digestive tract intact, and are thus harmless. Poisoning is usually caused by foliage or broken seeds (179).
L. Solanum AND Veratrum ALKALOIDS I n dealing with poisoning by Solanurn spp. it is convenient, in spite of the elaborate work which has been done in elucidating the structure of
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these compounds (180, 181), to consider “solanine” as a single entity. There is as yet no evidence as to whether the different solanine alkaloids vary in toxicity, although i t is suggested that the glycoalkaloid causes the irritant symptoms, the alkamine the nervous ones. The whole question is complicated by the fact that many of the Solanum spp. (including the potato) contain an active cholinesterase (182),but the part, if any, that this plays in the syndrome is as yet unexplained, although it has been shown to be present in an amount roughly proportional to the solanine content (183). Solanine poisoning is usually caused by potatoes. Normally, the inside of the tuber is comparatively harmless, containing from 5 t o 2 0 mg/100 gm of solanine, but the level is higher in the peel, in green or unripe potatoes, and particularly in the sprouts, where it may reach 500 mg yo. Poisoning in man has usually arisen when a population is living mainly on potatoes of doubtful quality under conditions of near starvation, or when the potatoes for some reason, climatic or otherwise, contain a much higher proportion of solanine than usual (184).The usual symptoms are vomiting, abdominal pain, diarrhea, and general malaise. The toxic dose in man is about 25 mg and although numerous outbreaks have been recorded, fatal poisoning is almost unknown. I n farm stock, on the other hand, many fatalities have been recorded, in cattle (185), horses (186), pigs (187-189), and sheep (190).Poisoning usually arises from green or sprouting potatoes ; the former have also caused poisoning in a dog (191), but seem to be harmless to poultry (192).Potato haulm has been known to cause poisoning in man (193)and cattle (194). Other Solanurn spp. are also harmful. Cattle (195, 196), horses (197), and sheep (198)have been poisoned by woody nightshade (S.dulcamara), while the berries of this plant have poisoned children (199, ZOO). S. elaeagnifolium (silver-leaved nightshade) has caused cattle losses in Western Texas (201).S. nigrum (black nightshade) has also proved toxic on a number of occasions (202-204) ; the plants are most toxic when the berries are green, although there is a cultivated variety which is completely nontoxic (128).Solanurn rostratum (buffaloburr)has caused losses in pigs, although they normally refuse t o eat it (205).S. carolinense may cause convulsions and death in sheep (204). Although a number of cases of poisoning by the veratrum alkaloids (180,181)in both man (206,207)and animals (208,209),usually due t o ingestion of the root or misuse of crude preparations of the drug, are on record, recent interest has centered on the teratogenic effects of Veratrum californicum in sheep (210-212). If ewes eat this plant on or about the 14th day of pregnancy the lambs are born with a cyclopean-type malformation (213).The exact agent has not yet been determined, as although
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veratramine has a teratogenic effect (214) the malformation caused is different from that caused by the growing plant. The Death Camas (Zygadenus spp.) which contain zygadenine, zygacine, and other bases (180, 181) are among the most dangerous plants growing in Western Canada and the United States, and are responsible for heavy losses every year among sheep on the spring ranges. The usual sequence of symptoms is salivation, nausea, vomition, ataxia, dyspnea, prostration, coma, and death. The different species of Zygudenus vary considerably in toxicity, Z . gramineus and Z . nuttalli being the most dangerous (128).
M. /3-PHENETHYLAMINE AND EPHEDRA BASES /3-Phenethylamine (215)is found in postmortem material where it has usually been formed by the deamination of phenylalanine. It also occurs in a number of plants, including the mistletoe (Viscum album), but the toxicity of the latter (39)is due to a polypeptide (216).Tyramine produced from tyrosine is also found in postmortem material, but its chief interest in toxicology lies in the fact that it may give rise to serious or even fatal poisoning if substances which contain it such as cheese (217-219), broad beans (220),or chianti (221)are consumed after taking one of the monoamine oxidase-inhibiting drugs such as phenelzine or tranylcypromine. Acacia berlandieri, a shrub growing in Texas and North Mexico, gives rise to a paralysis of the hindquarters known as “limberleg” or “guajillo wobbles,” in sheep and goats, particularly in times of drought when the condition may reach epidemic proportions. The plant contains tyramine, N-methyltyramine, and N-methyl-/3-phenethylamine (222,223).Hordenine has been suspected of playing some part in barley poisoning in stock. Mescaline is of interest only as an hallucinogen. Ephedrine is used in the treatment of asthmatic conditions. It is of low toxicity, but its prolonged use may lead to toxic psychosis with auditory and visual hallucinations (224).
N. a-NAPHTHAPHENANTHRIDINE ALKALOIDS
Chelidonium majus, the greater celandine, contains the a-naphthaphenanthridine alkaloids chelidonine, homchelidonine, chelerythrine, and sanguinarine together with other bases (225).The plant has been known to poison cattle (226),but cases are rare; as the leaves and stems
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contain an acrid vesicant juice which causes intense conjunctivitis (24)it is not certain to what extent such poisonings are due t o the alkaloids present. Sanguinarine is also found in numerous other members of the Papaveraceae (227), among them Argemone mexicana (Mexican prickly poppy), the seeds of which, present as contaminants in wheat, have proved toxic t o poultry (228, 229). As sanguinarine is excreted in milk and is known t o increase intraocular tension, it has been suggested that milk from cattle grazing on fumitory type weeds may be responsible for endemic primary glaucoma in man (230). Papaver nudicale (Iceland poppy) has caused poisoning in sheep and cattle, which show nervous symptoms. The toxicity of the plant has been confirmed by experiment. Prostigmine may be used as an antidote (231, 232).
0. Erythrophleum ALKALOIDS Most of the members of the genus Erythrophleum contain alkaloids (233),and many have proved t.oxic to animals. I n particular, ironwood (E.chlorostachys)has caused poisoning in horses, cattle, sheep, and goats in tropical Australia, a few ounces of the leaves being sufficient t o cause death (234).
P. Aconitum AND Delphinium ALKALOIDS Aconite (235,236)has a long history and is reputed t o have been one of the ingredients of the euthanasic agent used by the inhabitants of the island of Ceos to get rid of their more elderly citizens. I n spite of its extreme toxicity-it is one of the most poisonous alkaloids known-poisoning by aconite has never been really common in Europe or America, although i t is met with more frequently in India where the roots of Aconitum chasmanthum are widely used in native medicine (57).Poisoning may arise from injudicious use of the Dincture, 5 ml of which may be fatal, or ingestion of the plant, the roots having been mistaken for horseradishand the leavesincluded in salad. Symptoms set in almost immediately, the most constant feature being a tingling of the tongue, mouth, and stomach, which spreads to all parts of the body and is accompanied by a burning sensation followed by numbness. These symptoms are almost diagnostic. The lethal dose is said to be as little as 2 mg of the pure alkaloid, but two medical students who took between
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5 and 10 mg in mistake for vitamin C recovered within a few hours with-
out treatment after experiencing the usual symptoms (Zl?7). Aconite is sometimes added to liquors in India to increase their intoxicating effect, and this has been known to lead to fatal poisoning. Numerous species of Aconitum occur in various parts of the world, varying considerably in their toxicity and alkaloidal content. Poisoning in livestock is not common, though horses have been known to crop the plant (238, 239) and cattle have been poisoned by plants thrown out of the garden in autumn ( 2 4 ) . Although the seeds of various species of larkspur (Delphinium spp.) (235, 236) have been used for medicinal purposes since classical times, there do not appear to be any cases of human poisoning on record. I n animals, however, the larkspurs are regarded as one of the most common causes of poisoning in the United States where they occur abundantly in the western ranges (240, 241). They are divided empirically into “tall” and “ low ” larkspurs, D. burbeyi being regarded as the most toxic of the former and D . nelsonii and D . tricorne of the latter. Poisoning is most common among cattle, as they eat the plant readily and appear to be particularly susceptible. Cases among sheep and horses sometimes occur. The symptoms shown include staggering and falling, with nausea, excessive salivation and frequent swallowing, death being due to paralysis of the respiratory centers; bloat is commonly seen (171).I n Britain the cultivated D. consolidum, thrown into a field with garden refuse, has been known to poison sheep (242).
Q. ALKALOIDS OF THE BUXACEAE I n spite of the extreme toxicity of the common box (Buxus sempervirens),an understanding of the alkaloids it contains is of comparatively recent date (243). Fatal cases have 6een recorded in most species of domestic animal, pigs being particularly susceptible (24, 244, 245). The chief symptom of poisoning is hemorrhagic enteritis.
R. ALKALOIDS OF THE TAXACEAE The yew (Tuxusspp.) contains the alkaloids taxine (246)and ephedrine, the former being responsible for the toxic properties of the tree. All species of yew, and all parts of the tree except the flesh of the berry, are
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poisonous. Toxicity is not reduced by drying, although taxine is thermolabile, being completely destroyed by heating a t fiOo for 1 hour (247),a fact to be remembered during toxicological analysis. Human poisoning is rare and is usually associated with decoctions of the leaves used as abortifacients. I n animals, however, it is comparatively common and the tree is considered the most dangerous in Great Britain ( 2 4 ) .All species of animal are susceptible and cases have been recorded in cattle (248,249),horses (250,251),pigs (251),and dogs (252).Cases usually occur through branches cut from trees being thrown where animals can find them, though they sometimes arise through branches being weighted down with snow, thus bringing them within reach of stock which cannot find alternative food, Animals fed on small quantities of yew can acquire a high degree of tolerance which may account for the fact that animals newly introduced into a locality where yew trees grow seem much more susceptible than animals living among them. Death occurs from heart failure accompanied by respiratory paralysis and is usually very rapid (247).The animal may be found lying dead under a tree with twigs of yew still in its mouth or falling down suddenly as if shot if attempts are made to drive it (253).
S. XANTHINEDERIVATIVES The toxicologist usually classes the xanthine derivatives caffeine, theobromine, and theophylline as alkaloids owing to similarity in methods of isolation and identification. There appear to be no fatal cases of poisoning in man by caffeine on record, but doses over 1 gm may produce alarming symptoms, including tachycardia and sensory disturbances. Theobromine and theophylline seem to be even less harmful, although the theophylline derivative, aminophylline, has caused poisoning in children on a number of occasions, some cases ending fatally (254,255). I n animals, several cases of poisoning have been reported. Dogs have been fatally poisoned from accidental ingestion of caffeine (256,257'),and there is an old record (258)of a horse being poisoned owing to the inclusion of 10 lb of dry tea on its corn. Poisoning due to theobromine has been noted on many occasions. During times of shortage, cacao meal containing up to 5% of theobromine has been used as food for pigs and poultry and has proved to be definitely harmful (259,260).Dogs have been poisoned by a proprietary food containing 15 grains of theobromine per pound (26'1).Aminophylline, dispensed in error, has proved very toxic t o pigs (262).
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111. Alkaloids as Drugs of Addiction A. INTRODUCTION Addiction may be defined as a state of intoxication, harmful t o the individual and to society, produced by repeated administration of a drug and leading to a compulsion to continue taking it in increasing dosage and to a state of physical or psychic dependence on its effects. Nowadays the term “drug dependence ” is frequently used instead of “addiction.” The causes of addiction are many and complex, but a t least two factors must be present-a personality defect in the addict and availability of the drug. I n addition to these there is frequently some precipitating factor such as an emotional crisis ; this is usually something that would be considered trivial by a normal person. Addiction to drugs may be associated with any or all of three phenomena: (i) tolerance; in order to obtain the same effect the dose must be continually increased: (ii) physical dependence on the drug, due to the physiological changes which are produced by its continued administration, and which are responsible for the unpleasant withdrawal symptoms when it is withheld; (iii) habituation or psychological dependence on the drug, a condition probably arising from the euphoria which it produces (263, 264). New drugs are tested for their addictive action by investigation of their ability (i)to cause addiction, (ii)to prevent the onset ofwithdrawal symptoms in a subject habituated to morphine, and (iii) to give rise to such symptoms when suddenly stopped or challenged by a dose of a narcotic antagonist (265). Drugs of addiction may be divided into three classes: the narcotic analgesics (e.g., morphine and heroin) ; the stimulants or psychoenergetics (e.g., cocaine and amphetamine) ; and the hallucinogens (e.g., mescaline and LSD25).
B. THENARCOTIC ANALGESICS The morphine-type analgesics constitute the largest and probably the most important class of drugs of addiction (263, 266). Although opium has been in use as a sedative and soporific for over 6000 years, addiction to i t does not appear t o have been a serious problem in classical or medieval times. The isolation of morphine in 1805 led to a steady increase in “ morphinism,” during the nineteenth century. Heroin (267)was first isolated in 1874, hut it was not until some 20 years later that i t came into
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widespread clinical use for the treatment of respiratory diseases. At first thought to be nonaddictive, and even used t o treat cases of “morphinism,” it was only slowly realized that it was a drug of addiction far more dangerous than morphine, or, in fact, than any drug discovered since. I t s use was forbidden in the U.S.A. in 1924, and is now prohibited in most countries, one of the few exceptions being Great Britain, where it is argued that its value in the treatment of terminal cancer outweighs its danger as a drug of addiction. It is debatable whether there is any real point in prohibiting heroin so long as morphine is available, as the latter may be converted into the former with the greatest of ease, using the simplest of equipment installed in kitchen, bathroom, or garage and reagents which are free from any control. Morphine used for the clandestine manufacture of heroin is usually derived from opium, though it can also be prepared from codeine (268),which has only one-tenth of the addictive action of morphine and is therefore not so strictly controlled. The enormous profits to be made from the illicit sale of heroin make its manufacture an extremely lucrative proceeding, and in order t o put a stop to it the authorities have made every effort t o stamp out the traffic in opium. For this purpose i t is essential to know where a contraband cargo of opium originated, and much work has been done on methods of differentiating between consignments of opium from different sources. It has, for example, been shown that the percentage of codeine is highest in opium grown in the Far East and lowest in that from Yugoslavia and Greece (269).Similarly, Russian opium has a higher narcotiiie content than that from India, while Indian opium contains more narcotine than Yugoslavian or Turkish (270). During the last 60 years repeated efforts have been made to modify tlie morphine molecule to give a compound which shall have the analgesic effect of morphine but without its addiction-forming properties ; but all such attempts have been unsuccessful, as the two attributes seem to be inseparably linked. A number of interesting compounds have, however, been prepared, and passing mention must be made of certain substaiices sometimes referred to as derivatives of oripavine (271-274) in which an ethylenic bridge has been added between positions 6 and 14 of the morphine molecule, and a new center created a t position 7 . Some of these co~npounds have unprecedented analgesic potency ranging up to 10,000 times that of morphine. The best known of them is etorphine ( h 1 . ~ ; 7,8 - dihydro - 7 ~ r- [l(R)- hydroxy - 1 - methylbutyl] - 06 - methyl - f i , I l endoethenomorphine), which has found considerable application in the control of large wild animals, an elephant or a rhinoceros being completely sedated and rendered immobile by the injection of as little as 2 ing of the compound when administered in a syringe fired as a dart (275).
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Acetorphine (M.183), its O-acetyl derivative, is more potent but less stable. Cyprenorphine (M.285), N-cyclopropylmethyl-7,8-dihydro-7cr'(1-hydroxy-l-methylethyl)-O~-methyl-6,14-endoethenonormorphine, is a narcotic antagonist resembling nalorphine in its action. Compounds with such potency as these pose quite a new problem for the forensic toxicologist, as the levels likely to be found in body tissues are far below anything that can be detected by existing techniques. I n addition to modifications of the morphine molecule, many purely synthetic analgesics have been produced, the first of these, pethidine (meperidine), having been synthesized in 1939 in an attempt t o make a substitute for atropine (276).As in the case of heroin, pethidine was a t first thought to be nonaddictive. It has been followed by a hundred or so other compounds of several different types, but, as with the morphine derivatives, none, with the possible exception of pentazocine, has been found to have analgesic without addictive properties. However, it seems that the two effects may not be entirely inseparable, as diphenoxylate, which has come into use as an antidiarrheal drug, has been found to possess the power to cause addiction but no analgesic action a t all (277). C. STIMULANTS OR PSYCHOENERGETICS 1. Cocaine Coca leaves (Erythroxylum coca) have been used in South America since the time of the Incas, if not longer. Although the habit of coca chewing is usually attributed to the extremes of altitude and climate, other causes, such as malnutrition and adverse social, educational, and economic factors, are probably of more importance (278).As with opium, use of the crude plant material does not produce so dramatic a syndrome as does the use of the pure alkaloid (279).Nevertheless, in spite of the often-repeated statement that the use of coca increases resistance to fatigue and is harmless and possibly beneficial in its natural environment, the fact remains that it undermines the physical and mental health of the population and thus leads to a deterioration of the very living conditions that caused it (280). Cocaine (281)when sniffed or injected gives rise to a state of euphoria often followed by paranoid delusions. Although there are no withdrawal symptoms, as it does not cause physical dependence, it probably does more harm to brain and body than any other drug (282).There is a good case for its total prohibition, as it no longer serves any essential medical purpose, and, unlike heroin, there is no readily available natural source from which it may be manufactured. Cocaine is frequently injected in conjunction with heroin.
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2. Amphetamine Both chemically and historically most drugs of the amphetamine type are related to ephedrine (215).The latter, the main active ingredient of the plant Ma Huang (Ephedrrc spp.), was used in China for some 5000 years before being introduced into clinical use in the West shortly after World War I, when it quickly found considerable application in the treatment of asthma and similar conditions. I t s success led to a search for a synthetic substitute, and a number were produced, amphetamine becoming the most widely used. I n addition to its original employment as a vasoconstrictor, amphetamine (particularly the d-isomer) was found t o be a powerful stimulator of the central nervous system, and became used for the treatment of depression, as an anorectic agent, and to delay the onset of fatigue, particularly under war conditions. It pr6duces a sensation of elation and excitability, leading to truculence and aggression, and has become highly popular among the lunatic fringe of teen-age society. Its harmful effects on young people were first noticed in Japan during the period of social confusion during the immediate postwar years (283), but have since become apparent in most “civilized” countries. There are numerous drugs of the amphetamine type on the market, very similar in structure and action. Analytical differentiation between them may sometimes present a problem (284). Before leaving the subject of the stimulant drugs, brief mention must be made of Khat (Cathu edulis), a plant grown in Ethiopia, and used by people of many races over a wide area of North Africa. Chewing it gives rise to a feeling of euphoria and depresses the appetite, and although it is not regarded officially as a drug of addiction, it nonetheless constitutes a definite social evil in that its consumption costs what is relatively a considerable proportion of the daily wage, and so leads to a lowered standard of living with consequent lowering of resistance to disease (285).The active principle is usually regarded as being d-norpseudoephedrine, but there is almost certainly some other factor involved, as the fresh plant is considerably more toxic than the total alkaloids which it contains (286).
I).
HALLUCINOGENS
From earliest times men have sought for a means to attain a transcendental state which will enable them to appear t o rise above their everyday earthbound existence and bring them closer to some ultimate reality beyond. I n certain primitive cultures, notably in Central and South America, this has been attempted through religious rites in which
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the participants eat or inhale substances obtained from certain plants which contain the drugs now called hallucinogens. Such plants include the cactus peyotl (Anhulonium lewinii) which contains mescaline (287), the Mexican sacred mushroom (Psilocybe mexicunu), which contains psilocin and its phosphate ester psilocybin (117,288),various Piptudeniu spp. which contain dimethyltryptamine and its 5-methoxy derivative bufotenine (289), and certain kinds of morning glory (Ipomoeu spp.) which contain lysergic acid alkaloids similar to, but apparently not identical with, lysergic acid diethylamide (290).It was the accidental discovery by Hofmann (291, 292) of the properties of the latter substance that initiated modern interest in hallucinogenic drugs. These may be divided into three groups (i)the mescaline group, (ii) the dimethyltryptamine group, and (iii) the lysergic acid amide group. These compounds vary greatly in activity, the effective dose of mescaline being 500010,000 pglkg, of psilocybin 100-200 pg/kg, and of lysergic acid diethylamide (lysergide, LSD25) only 1-2 pg/kg (293).It is mainly on the last of these substances that forensic interest is centered. It finds some legitimate application in the treatment of certain psychiatric states, but during the last few years it has come t o be used illicitly by numerous unbalanced people seeking for new sensations. The effects it produces can probably only be appreciated by those who have experienced them (294).Although it does not give rise t o physical dependence or tolerance, it is capable of causing profound and possibly irreversible mental disorders when used in inexpert hands. Owing to its extreme potency, only a minute dose (100-200 pg) is necessary. This makes its recognition in body fluids extremely difficult. Thin-layer chromatography (295,296)or gas chromatography (297)may be employed. The latter is the more sensitive.
IV. Control of Alkaloids Control of drugs may be national or international. The only substances under international control are, with the exception of Capnabis, basic nitrogenous compounds.
A. INTERNATIONALCONTROL By the beginning of the present century, the question of drug addiction had changed from a minor domestic issue to a major world problem. This change had come about from a number of causes, notably the marked
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improvement in transportation during the 19th century, which had made the conveyance of drugs from one part of the world t o another a simple matter; the pace of living inherent in an industrial society, which created an environment in which people tended t o turn more and more t o drugs for relief from the stresses of life ; and the ready availability of the active alkaloids extracted from the relatively inert opium and coca leaves (298). The first attempt a t international collaboration was the meeting in Shanghai in 1909 of the International Opium Commission, which had no executive powers, but which adopted resolutions recommending the suppression of opium smoking, and recognizing the dangers of manufactured drugs. This was followed by the International Opium Convention signed at The Hague in 1912 which formulated the basic principles for international control, and raised the level of the obligation to cooperate in the campaign against drugs from a purely moral one t o a duty under international law. After World War I, the control of drugs passed into the hands of the League ofNations which, under the Convention of 1925, set up the Permanent Central Opium Board, introduced a system of licensing and recording transactions in narcotic drugs, and required governments to furnish the necessary statistical information. This principle was carried further by the Convention of 1931 under which, in an effort to limit the manufacture of narcotic drugs, each country was required t o make in advance an annual estimation of the amount of each drug needed for medical and scientific purposes. The Convention of 1936 attempted t o suppress the illicit traffic in drugs by requiring member states to enact legislation imposing severe penalties on those who instigated, organized, or directed such traffic; but this attempt was only partially successful, as a number of states refused t o ratify the Convention (299). After World War 11, control of narcotic drugs passed to the United Nations, and in 1946 the Economic and Social Council set up the Commission on Narcotic Drugs to fulfill this function. When the Commission took over, there were 20 drugs, all (except Cannabis) derivatives of opium or coca; 20 years later, mainly owing t o the advent of the synthetic drugs, this number has been increased to nearly 100. One of the Commission’s first acts was to draft the Protocol of 1946, which amended the conventions of 1921, 1925, 1931, and 1936. This was followed by the Protocol of 1948 which gave it power to control synthetic drugs outside the scope of the earlier conventions. A further Protocol, aimed a t limiting the cultivation of the opium poppy, was signed in 1953, but owing to delay in ratification by the member states, did not come into force until 10 years later.
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Long before this time, however, it had become obvious that regulations based on a series of conventions, agreements, and protocols drawn up on an ad hoc basis over a period of half a century had become quite unworkable, and the increasing urgency of the question of drug addiction made it imperative that this collection of treaties should be replaced by a single instrument. This led t o the drafting of the Single Convention on Narcotic Drugs, 1961, which came into force in 1964. Stated in the briefest possible way, this convention (300)requires member states to control the legitimate trade in narcotic drugs by the licensing of imports and exports, and by the regulation of manufacture, distribution, and consumption, and to attempt to stamp out the illicit trade by such measures as the registration of addicts, and the prosecution of traffickers (301).
B. NATIONAL CONTROL As stated above, the Single Convention requires each signatory state to enact legislation to fulfill its obligations under the act. I n addition, most countries had additional laws for controlling the sale and use of drugs, including alkaloids. These vary greatly from country to country, and it is impracticable to consider them here except in the most general terms. The regulations imposed may include (1) total prohibition of possession or use, (2) restriction of possession or use to certain classes of individual, (3) limitation of sale to medical prescription only, (4) limitation of sale to those known to the pharmacist, and (5) regulations as t o labeling and packaging. It should be noted that alkaloids form only a very small fraction of the total number of drugs controlled. I n forming laws for the control of drugs, great care has to be taken t o word the regulations in such a way that not only are the proscribed compounds included and harmless compounds excluded, but that it is impossible to circumvent the rules by producing substances which, although pharmacologically active, are technically outside the scope of the regulations (302).As long as drugs are defined explicitly, using either chemical names, national approved names, or international nonproprietary names (INN), little or no difficulty arises; words such as “morphine” and cocaine’’ have an exact meaning. When, however, one comes t o the synthetic drugs, progress is so rapid that it is possible for a drug to get into circulation and do considerable harm before authority can catch up with it, give it a name, and bring it under control. Hence it is sometimes desirable t o attempt to control all possible compounds of a certain category by using such general phrases as “ derivatives of,’’ “ homologues of,” or “having the essential structure of.” It is when attempts are made t o (6
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cover a whole group of compounds, using such generic terms, that difficulty begins. The meanings of such words as “derivative” or “homologue,” although well known to chemists, are difficult to establish in law without further qualification. This was seen in a recent case in the English courts where there was considerable argument as to whether lysergide (lysergic acid diethylamide) was or was not covered by the reference in the poisons list to “ergot, alkaloids of; their homologues.” On the first occasion the jury disagreed. On the second the case was dismissed, the jury apparently having been completely bewildered by the learned arguments produced (302).An illustration of the type of situation which may arise is afforded by the British Drugs (Prevention of Misuse) Act (303)brought into use to control the amphetamine-type drugs. This prohibits the unauthorized possession or use of “P-aminopropylbenzene ; p-aminoisopropylbenzene ; any synthetic substance derived from either of the substances aforesaid by substitution in the side chain or by ring closure therein (or by both such substitution and such closure) except ephedrine, etc., etc.” Now, as will be seen, the act implicitly includes derivatives of amphetamine (P-aminopropylbenzene), such as methylamphetamine, which are substituted in the side chain ; but its wording excludes derivatives formed by substitution in the aromatic ring. Hence p-methoxyamphetamine, a potent hallucinogen (304)is not covered by the act, nor are the two extremely dangerous compounds TMA and STP (trimethoxyamphetamine and 4-methyl-2,5-dimethoxyamphetamine) (305).To control these would require special legislation.
V. Toxicological Analysis-General
Considerations
Toxicological analysis is one of the most highly specialized branches of analytical chemistry ; its difficulties are really only appreciated by those who practice it. The work of the toxicologist bears little relation to that of the clinical biochemist or of the analyst employed by the pharmaceutical manufacturers who work in a considerably more restricted field. If the toxicologist is looking for one particular named drug his task presents no particular difficulties. He has only to look up the subject in the literature and apply the relevant techniques. Should none be available, a t least he can obtain some of the compound in question and work out procedures for himself. All too often, however, he is faced with the task of searching in a mass of decomposing viscera for a few micrograms of any one of a thousand or more compounds, with no clue a t all as t o its identity ; he has to work with the urgency that is inseparable from all forensic invest,igations and with the knowledge that on the results of his analysis a man’s life,
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liberty, or reputation may depend. There is no room for error, nor opportunity for repetition, as his material once used can never be replaced. Not only is he unaware of the identity of the compound he is seeking, but also of the form in which he is likely to encounter it. I n common with many other compounds, the majority of alkaloids undergo metabolic changes in the body and are excreted in a form different from that in which they were ingested (306).These changes are brought about by enzymes, mainly in the liver, and in general may be regarded as taking place in two stages; firstly, a presynthetic stage, in which the compound undergoes oxidation, reduction, or hydrolysis ; secondly, a synthetic or conjugation reaction in which the metabolite thus formed combines with some substance present in the body. The most common conjugation mechanism is the formation of a glucuronide, but conjugation with sulfate, with glycine, or with g!utamine, as well as acetylation and methylation, also take place. If the original compound possesses a suitable group such as hydroxyl or amino in its molecule, it may be conjugated directly without undergoing the presynthetic stage. Frequently the drug follows a number of different pathways through the body and is excreted in several different forms. Taking codeine as an example, it may (i) be excreted unchanged, (ii) be conjugated with glucuronic acid to give “bound ” codeine, (iii) undergo 0-demethylation t o morphine, which may be excreted as such or as its glucuronide, and (iv) undergo N demethylation t o norcodeine, which may be excreted in the free or “bound” form. The different pathways are not all followed t o anything like the same extent; only traces of free morphine and free norcodeine are found in the urine, whereas “bound ” codeine may account for up to 50% of the dose (307). The fact that such a large proportion of the alkaloid may be present in the “bound” form, most frequently as glucuronide, has a practical bearing on the extraction techniques which must be employed. Conjugates of this type are water-soluble, and will remain in the aqueous phase during extraction with an immiscible solvent unless they are first hydrolyzed. This may be carried out by treatment with the appropriate enzyme, which, although it has the advantage of giving a cleaner product, has also the inherent drawback of specificity and is thus useless unless the type of conjugation is known, or by acid hydrolysis, which is nonspecific, but gives a very “dirty” extract and involves a risk of hydrolyzing ester linkages in the alkaloid molecule. I n toxicology, there is no such problem as a search for an unknown alkaloid, as there is nothing to differentiate poisoning by an “alkaloid” from poisoning by any other type of drug. The search for an alkaloid is simply part of the search for an unknown organic poison. It is now pro-
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posed to consider this problem with special reference to compounds containing basic nitrogen. This will, of course, include the techniques which would be employed in testing for a “known” poison; but i t must be emphasized that no drug is “known” until its presence has been established by analysis. A corpse clutching a labeled bottle provides presunil)tive evidence only. Before considering the question of analytical techniques, however, one further point must be made clear. The forensic chemist must be prepared to identify any unusual compound which he isolates from body tissues, not merely those of known and proved toxicity. Until the identity of such a compound is established beyond doubt it cannot be decided whether its presence is significant or not. To give a concrete example, some years ago the body of a man was taken fi-om a river where it had been immersed for several weeks. The pathologist was unable to decide on the cause of death and asked for a toxicological examination to be made. This disclosed the presence of a basic compound which when submitted to paper chromatography (citrate-butanol syst,em)gave an absorbing spot, weakly positive with iodoplatinate, a t Rf0.90. Elution of this spot,gave a substance which had a UV-maximum a t 264 mp, and gave a purple color with the Marquis reagent. Reference to the card index followed by comparison with a known sample identified the substance as bisacodyl, a harmless laxative, which could have played no part as the cause of death ; but until it was identified with certainty, it might have been some unusual toxic alkaloid, or else the metabolite of one.
VI.
Extraction methods
A. INTRODUCTION Before a compound can be identified it must be extracted and purified ; in the case of a “general unknown” this poses a problem of considerable difficulty. The analyst cannot choose a suitable extraction method until he knows the identity of the compound with which he is dealing, and yet at the same time he cannot begin to identify it until he has extracted it. The answer to this apparent paradox is to use a compromise method which will extract a t any rate some of any compound likely to be present,. It must be emphasized that such an extraction cannot be more than qualitative. Once the identity of the compound is known, a suitable extraction method for it can be chosen, and carried out on a further aliquot of material.
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The choice of the extraction method to be used depends on a number of factors, the most important of these being the facilities available, the urgency of the problem, and the nature of the sample.
B. TYPESOF SAMPLE The sample may consist of (i) a pure chemical substance, (ii) a pharmaceut>icalpreparation (tablet,capsule, or mixture), (iii)blood, urine, vomit, or stomach washings, or (iv) body tissues-liver, kidney, or brain, together with stomach and intestines and their contents.
1. Pure Chemical Substances These are rarely encountered in forensic toxicology. Dealing with them calls for no particular expertise; they afford almost the only case where classic procedures, such as preparation of a derivative and determination of the melting point, may be used.
2. Pharmaceutical Preparations There may sometimes be a particular urgency about these, as in the case when a child is brought into hospital unconscious, and identification of the tablets he may have taken must be made as quickly as possible so that correct therapy may be instituted. I n such a case much time may be saved by the use of some tablet identification scheme. A number of these are available (308-310), but they all suffer from the same drawbacks in that they are difficult to apply to the vast number of white tablets now available; they can never be up to date, as new drugs are continually coming onto the market, and old ones appearing in different form; and it is impossible to make them comprehensive, particularly with regard to tablets originating in another country. Nevertheless, they have great potential value as time savers, particularly as they can be used by office staff without technical training. Any tentative identification must, of course, be confirmed by chemical tJestsfollowing some simple extraction process.
3. Blood, Urine, Vomit, and Stomach Washings The reason for differentiating between these and other biological materials is that they may come from a living rather than a dead subject, and hence call for speed rather than detailed analysis. Fewer than 20
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drugs account for over ‘30% of hospital poisoning emergencies, so elaborate identification schemes are not necessary. The usual procedures in these cases are (i) to apply a series of spot tests to the urine to test for such compounds as aspirin, barbiturates, carbon monoxide, hydrocyanic acid, etc., which are the usual cause of hospital emergencies; (ii) to carry out simple extractions with immiscible solvents to isolate more complex compounds. The material is made acid with a few drops of concentrated hydrochloric acid, extracted with an equal volume of ether, then made alkaline with ammonium hydroxide and extracted with an equal volume of chloroform. The first extract (acid-ether) will contain the acidic drugs (aspirin, barbiturates, glutethimide) and the neutrals (meprobamate, carbromal), but is unlikely to contain any alkaloids. The alkaline chloroform fraction will contain any basic compounds present, the substances most likely to be met with under these conditions being the phenothiazine tranquillizers (promazine, chlorpromazine), imipramine, chlordiazepoxide, amphetamine, codeine, quinine, and the ergot alkaloids. The last named group include lysergic acid diethylamide (LSD); they are unlikely to be present in sufficient quantity to be found in blood or urine, but might be detected in stomach washings or vomit. The chloroform is evaporated, the residue taken up in a drop or two of dilute acetic acid and spotted on filter paper. The spots are examined under UV-light (preferably 2537 b)and tested with (1) iodoplatinate solution, ( 2 )p-dimethylaminobenzaldehyde solution, and (3) the Marquis reagent. Quinine and the ergot alkaloids show a bright blue fluorescence, but care must be used in interpreting this, as blue fluorescence is commonly found in crude extracts from body fluids. The iodoplatinate reagent gives a dark blueblack spot with most of the bases likely t o be met with here. p-Dimethylaminobenzaldehyde gives a blue color with the ergot alkaloids, and a bright yellow with compounds containing a primary aromatic amino group. The Marquis reagent gives a bluish purple with codeine (and morphine), a red-purple with most of the phenothiazine derivatives, and an orange color with amphetamine and several other synthetic sympathomimetic drugs. The residue may now be submitted to thin-layer chromatography and UV-spectrophotometry in order t o confirm any provisional identification made at this point, or to obtain further data on which such an identification may be based.
4 . Body tissues and visceral contents Analyses of these provide by far the largest part of the toxicologist’s work and must be considered in rather more detail in the following sections.
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C. CLASSIFICATION OF POISONS It is usual to divide poisons, from the analytical point of view, into five groups : ( 1 ) Volatile poisons (e.g., hydrocyanic acid, phosphorus)
( 2 ) Toxic anions (e.g., oxalate, fluoride) (3) Toxic metals (e.g., arsenic, barium)
(4) Solvent-extractable nonvolatile organic poisons (phenobarbitone, strychnine) (5) Miscellaneous poisons (conjugates ; quaternary ammonium compounds)
The vast majorit,y of alkaloids occur in group (4),although some may be found in groups ( 1) and ( 5 ) . The choice of the sample ta be analyzed will depend 011 what is available. Assuming it to be the whole cadaver, there is much to be said in the case of an acute poison in favor of stomach contents, as it will contain the drug in unaltered form and possibly in high concentration. When death has been delayed, intestinal contents may be more useful, while the liver, as the chief detoxicating organ of the body, has the power of concentrating many drugs. Analysis of blood, urine, and bile will also often furnish useful information. The decision as to whether a single sample should be analyzed first, or analysis of a number of samples carried out concurrently, will depend on the urgency of the case and the facilities available. 1. I’olntile Popisons
These may be isolated by steam distillation. It is usual to make two such distillations, the first from acid solut,ion, the second from alkaline. About 50-1 00 gm of tissue is homogenized, mixed with an equal quantity of water, acidified with tartaric acid and steam-distilled until a volume equal to the original sample taken has been collected. This distillate will contain neutral and acidic compounds such as hydrocyanic acid, phenol, and phosphorus. The tissue slurry is now made alkaline with sodium hydroxide solution and again subjected t o steam distillation. This second distillate will contain basic compounds. The tip of the condenser should be immersed in dilute hydrochloric acid to trap the more volatile bases. The plant alkaloids most likely to be present are nicotine, coniine, arecoline, ephedrine, and sparteine, but a number of synthetic drugs, notably amphetamine and other sympathomimetic bases, also occur in this fraction. Pethidine may also be isolated by steam distillation. The
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distillate is made alkaline with sodium hydroxide, and extracted with ether or chloroform. The extract is dried with sodium sulfate, and examined in a way similar to that described for the extracts of section 3.
2. Toxic Anions and Metals These groups do not contain any alkaloidal substances, and need not be further considered.
3. Solvent-Extractable Nonvolatile Organic Poisons This group is the most important from the point of view of basic nitrogenous compounds, as the vast majority, over 90% of them, occur here, and much work has been done in devising methods for their isolation, but it must be admitted that no really satisfactory answer has yet been discovered to what is commonly agreed to be the biggest problem in analytical toxicology. Most extraction procedures depend for their success on the fact that alkaloidal bases are usually soluble in ether or chloroform, but insoluble in water, while their salts are soluble in ethanol or water, but not in the fat solvents. Such processes, then, consist essentially of two stages, the first being the preparat,ion of a protein-free aqueous extract, and the second the extraction of this solution a t alkaline pH with an immiscible solvent. Most of these methods, however, are modifications of the classic Stas-Otto process (62,311),which is still in use after over a century. By general consent it is long and tedious, yields a somewhat impure product, and gives rather poor recoveries, yet with some modification it still remains the method of choice under certain circumstances. A version of it is described below. I n an attempt to overcome the inherent drawbacks of the Stas-Otto process, numerous other methods have been described. One of the most popular of these is that of Daubney and Nicko1:s (312-314) which removes proteins by precipitation with ammonium sulfate. Abernethy et al. (315) extract buffered homogenized tissue with acetonitrile and ether. Alha and Lindfors (316)extract with acetone instead of ethanol. Berman and Wright (317)and Valov (318)use tungstic acid as a protein precipitant, while Stewart et al. (319) use trichloracetic acid. A promising method recently described by Stevens (320)uses aluminum chloride. Gettler and Sunshine (321) and Feldstein and Klendshoj (322)extract the filtrate from the residue left after steam distillation, relying on the heat t o have denatured most of the protein. Tompsett (323) also boils the minced tissue with dilute hydrochloric acid, subsequently absorbing any alkaloids present in a cation exchange column.
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Once the clear protein-free extract has been obtained, it is extracted with an immiscible solvent. This is usually done in several stages. The most common practice is to extract the acid aqueous phase with ether to remove the acidic and neutral drugs, then to make it alkaline and extract with chloroform or ether to remove the bases. These two extracts are commonly called the acid-ether and the alkaline-chloroform extracts, and may be further subdivided as follows. The acid-ether extract is shaken with a solution of sodium bicarbonate to remove the " strong" acids such as aspirin, then with sodium hydroxide solution to remove the "weak" acids, such as the barbiturates, neutral drugs such as the carbamates, and a few weak bases such as caffeine, remaining in the ether layer. The alkaline chloroform extract may be subdivided by adding a few drops of hydrochloric acid to it and evaporating to dryness. The residue is dissolved in water, and extracted with chloroform, which removes the drugs whose hydrochlorides are soluble in chloroform. (Fraction D1; this includes aconite, cocaine, papaverine, hydrastine and many synthetic drugs, notably the phenothiazines and most of the antihistamines and narcotics.) The aqueous phase is now made alkaline with sodium hydroxide solution, and again extracted with chloroform. This gives Fraction Dz, which contains most of the organic bases. The aqueous phase is now acidified, made alkaline with either ammonium hydroxide or sodium bicarbonate, and extracted with ethyl acetate or a chloroformpropanol ( 5 :1) mixture. This gives Fraction Ds, which contains the amphoteric drugs, notably those such as morphine which contain phenolic groups. Although the fractionation of the acid-ether extract is essential, as it divides the drugs which it includes into different classes which are investigated by quite different methods, e.g., by different schemes of chromatography, in the case ofthe bases it is doubtful whether any useful purpose is served by such subdivision, unless it is particularly required to separate, say, phenothiazines from other alkaloidal compounds. There are methods of paper and thin-layer chromatography that can be used for screening all nitrogenous bases, and preliminary subdivision is of little help. The more complicated a system becomes, the more time is wasted and the more material lost. A few practical details are worth mentioning in connection with solvent extraction. Quite apart from the question of separating compounds on the basis of the solubility of their hydrochlorides, chloroform is the solvent of choice for bases, as the majority of alkaloids are much more soluble in chloroform than they are in ether (see Table I).It is certainly more prone to form emulsions, but these may usually be avoided by using a relatively large volume, 5 or 10 times as great as that of the aqueous
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phase, by the use of a rolling extractor (324)or by the addition of a little ethanol. Finally, when several extractions are being made, a solvent that is heavier than water is more convenient to use than one that is lighter. A number of authors have advised the use of continuous extraction. For the extraction of the aqueous phase when obtaining the acid-ether and alkaline-chloroform fractions this is of doubtful value, as, although it may extract marginally more of the drug, it is certain to extract considerably more impurities. Mention should be made, however, of a scheme for the continous extraction of minced tissues with ethanol described by Curry and Phang (325);this has proved most useful in extracting difficult compounds. During recent years there has been a growing tendency for toxicologists to abandon the two-stage extraction process, and to extract biological material directly with immiscible solvents. This is particularly convenient with fluids which would have to be evaporated to dryness before processes such as the Stas-Otto could be applied. Urine may be extracted without preliminary treatment (326), but blood is best deproteinated with tungstate before extraction (327). With tissue homogenates direct extraction is less satisfactory; drugs tend to be occluded in the tissue particles, and emulsions which are difficult to break frequently form. Some authors, however, use direct extraction for stomach contents (328). As it is obviously impracticable to give experimental details for all the various methods referred to above, it is proposed to limit detailed instructions to a modified Stas-Otto extraction for tissues and visceral content, a direct extraction for use with urine, and a tungstate precipitation method for use with blood. It is again emphasized that these procedures are designed for use when there is no clue at all as to the nature of the drug present. Should there be any evidence pointing to its identity, they may be simplified accordingly. The Stas-Otto type extraction is carried out as follows: 100 gm of tissue is homogenized with 200 ml of ethanol made acid with a little acetic acid. The resulting homogenate is heated on the water bath for at least 1 hour a t a temperature not exceeding 60°, cooled, and filtered. A further 100 ml of ethanol is added to the residue, the process repeated, and the two filtrates combined. The ethanol is removed a t low temperature by vacuum distillation or by heating in an open dish in a current of warm air. Hot ethanol, 50-100 ml, is added little by little to the syrupy residue, each portion being stirred and decanted before the next is added. The process is continued until the residue appears dry and granular. The extract is filtered and evaporated as before. If the residue appears dark and greasy, the extraction with hot ethanol should be repeated. The final residue is now extracted with 25 ml of 0.01N sulfuric acid; the choice of
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acid is important here if one wishes t o extract as few basic drugs as possible into the acid-ether fraction. Great care must be taken a t this stage, as it is here that most of the losses occur. Continuous stirring by hand with a glass rod is probably more efficient than mechanical shaking or stirring. Heating is not advisable for fear of hydrolysis. After filtration, the aqueous extract is ready for the next stage, which consists of shaking or rolling it with two 50 ml portions of ether. If there is any tendency to form emulsions, the volume of ether can be increased, and a little ethanol added ; but as a rule emulsions are unlikely here. The two extracts are combined, washed with 10 ml of saturated sodium chloride solution [water might remove hydroxybarbiturates (329)],and extracted with 20 ml of 5% sodium bicarbonate solution saturated with sodium chloride to remove ‘‘strung” acids, then with 20 ml of 1N sodium hydroxide solution to remove “weak ” acids, and finally dried with anhydrous sodium sulfate and evaporated to give the “neutral” Fraction C. The sodium bicarbonate extract and the sodium hydroxide extract are both acidified with a few drops of HCI and extracted with equal volumes of ether, which is dried with anhydrous sodium sulfate and evaporated to give Fractions A and B, respectively. As has been stated previously, extract A will contain the salicylates, B will contain the barbiturates, and C the neutral drugs and the weak bases such as caffeine and benzocsine. The original aqueous phase remaining after the extraction with ether is made alkaline with concentrated ammonium hydroxide solution added drop by drop and extracted twice with 100 ml of chloroform to which 10 ml of ethanol has been added. The two extracts are combined and extracted with 50 ml of 0.1N sulfuric acid. The aqueous phase is separated, made alkaline with ammonium hydroxide, and reextracted with two 50 ml volumes of chloroform. The chloroform is dried with sodium sulfate, and carefully evaporated t o dryness afher addition of one or two drops of dilute hydrochloric acid to prevent the loss of volatile compounds. This gives Fraction D. It will be noted that no attempt has been made to subdivide this fraction. As has been said before, there is little advantage t o be gained from doing so, and every unnecessary manipulation leads t o delay and loss of material. It is admitted that this process is tedious and time consuming, but it is based on a method that has been in use for many years, and about which much information is available. It does not pretend to be quantitative, but should be capable of isolating a t least some of any alkalkoid likely to be present. If one were looking for a single known substance many steps could be omitted. Similarly, if one were only concerned with acidic drugs such as barbiturates one would not use this method. The tungstate precipitation method (318,327)is much better for this purpose.
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Direct extraction of urine or blood is of particular value to the hospital biochemist when the subject is stil1,alive and every minute counts; it is also useful as a rapid screening method in routine toxicological analysis. A measured volume of urine is acidified with hydrochloric acid and added to 5 volumes of ether. The extraction may be made by shaking or rolling; the latter is essential for horse urine which forms emulsions extremely easily. Hensel(326) uses large centrifuge tubes ;simple inversion 100-200 times produces adequate partition. The layers are rapidly separated by centrifuging and may be transferred by means of bulb pipettes. After the ether layer has been separated, the aqueous phase is made alkaline with ammonia and extracted with 5 times its volume of chloroform to remove basic drugs. Blood may be treated in the same way, but the result is less satisfactory. It is more usual to remove the protein first. This may be done with sodium tungstate (318, 327) as follows: To 10 ml of blood add 2 ml of 10% w/v sodium hydroxide solution, 50 ml of water, and 20 ml of 10% wjv sodium tungstate. Then acidify by adding 2 N sulfuric acid slowly with continuous stirring or shaking. Immerse the vessel in boiling water for 10 minutes, filter, cool, and make up to 100 ml with water. Extract with 200 ml of ether. Then make the aqueous layer alkaline with ammonium hydroxide, and extract it with 5 times its volume of chloroform. The acid ether extract may be subdivided to give the strong acid, weak acid, and neutral fractions as described previously. The method is not particularly satisfactory for bases, but will often given an indication as t o what is present. 4. Miscellaneous Poisons
a. Conjugates. As has been stated above, many alkaloids undergo conjugation in the liver to form water-soluble complexes such as glucuronides which cannot be extracted by immiscible solvents. Thus, except in the case of stomach and intestinal contents, the free drug obtained by the ordinary extraction processes is only a small fraction of the total drug present. To increase the yield it is necessary t o break down the conjugate. This may be done by either acid hydrolysis or by enzyme action. The former may be carried out by mixing the material (urine or tissue homogenate) with half its volume of concentrated hydrochloric acid, and heating on a boiling water bath for 1 hour. It is then cooled, extracted with ether, made alkaline with ammonia, and extracted with chloroform (or chloroform: propanol 5: 1 if morphine is suspected). This method would almost certainly destroy any alkaloids containing ester groups. As an alternative, therefore, the sample may be hydrolyzed a t 37" a t
E. G. C. CLARKE
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pH 4.5 for 20 hours with P-glucuronidase. This will serve to break down glucuronides and will yield a cleaner extract, but would have no effect on sulfate conjugates. h . Quaternary ammonium compounds. These are invariably watersoluble, and remain in the aqueous phase. No really satisfactory method for their extraction has been described, although several have been suggested. I n one of these urine, acidified with HCI, is allowed to percolate down a column containing Dowex 500 x 12 (200-400 mesh). The alkaloids are eluted with more concentrated HCl(323). I n another, which is suitable for combining with the modified Stas-Otto process described above, the aqueous phase after extraction of the D fraction is acidified with dilute acetic acid, evaporated t o dryness under reduced pressure, and the residue extracted with methanol. The methanol extract is evaporated and submitted t o paper chromatography (330).
VII. Identification Methods
A. INTRODUCTION Once the alkaloid has been isolated, it must be identified. The methods available are ( 1 ) the classic color and crystal tests, ( 2 ) chromatography, and (3) spectrophotometry. 1. The Classic Methods Until about 20 years ago the only way in which an alkaloid isolated from cadaveric material could be identified was by means of color and crystal tests. Both of these date back for well over a century, the color test being the older of the two. It has the great advantage of speed and simplicity and is ideally suited to rapid screening procedures. It has recently secured a new lease on life owing to the way in which it may be used for locating compounds on paper and thin-layer chromatograms. Few color tests are specific, but many have the advantage that they will work satisfactorily in the presence of a high proportion of impurity. Color tests for many alkaloids have been described (331-334). Crystal tests are more specific than color tests, but need purer material, and call for more skill and experience on the part of the operator. They are extremely delicate, having sensitivities well down in the microgram range, and can thus be used on the material eluted from paper or thinlayer chromatograms. Although largely outmoded, they are still of considerable value in confirming a final identification, as a great deal of
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information about them is available (332,335,336).They are of particular value in differentiating between microgram quantities of optical isomers (337,338).This is a point which may be of considerable forensic importance as, for example, in the case of the N-methylmorphinan analgesics, where the Z-isomers have addictive properties, and are under international control as narcotic drugs, while the d-isomers, which are useful antitussives, are nonaddictive, and thus free from control.
2. Chromatography a. Paper chromatography. The introduction of paper chromatography (333,339-342)was one of the greatest single advances in analytical toxicology. Coming as it did in the 1950’swhen the post-war “pharmaceutical explosion ” was beginning to swamp the facilities then available, it provided not only a simple method of provisional identification, but in addition a means of obtaining material pure enough for subsequent spectrophotometric analysis. Although now very largely replaced by thin-layer chromatography, it still remains a most valuable tool for the forensic chemist. It is extremely simple, requiring neither expensive equipment nor skilled personnel, and is thus within the reach of any laboratory in the world. I n addition to the R, value, the appearance in UV light, and the behavior with the conventional spray reagents, paper chromatography can furnish much additional information of analytical value owing to the ease with which a variety of chemical reactions such as diazotization can be carried out directly on the paper, b. Thin-layer chromatography. Thin-layer chromatography (343-346) has come to the fore during the last 5 years or so. Compared with paper chromatography it has the great advantages of increased speed and sensitivity ; in addition most materials used will stand high temperatures and corrosive acids. On the other hand it is not quite so simple, the plates are fragile and cannot be filed for reference, and silica gel (the medium most commonly used) is strongly absorbent in UV light and hence masks absorbing spots. Ready-made plates and films can be purchased, but are expensive if used in any quantity. Even plates produced in the laboratory with a commercial spreading device tend t o make thin-layer chromatography more expensive than paper, but quite satisfactory results can be obtained with homemade equipment using microscope slides or old 3 x 3-inch projector plates. The speed with which a result can be obtained makes the technique of great value to the hospital biochemist. As with paper chromatography many simple reactions may be carried out directly on the plate. c. Gas-liquid chromatography. Gas-liquid chromatography is the latest chromatographic technique to have found application in toxicology (347,
556
E. G . C. CLARKE
348).Originally introduced for the identification of volatile compoundsa field in which it, remains unsurpassed-it has now found much wider application (349, 350). Numerous systems, varying in support material, liquid phase, and type of detector, are in use. It differs from paper and thin-layer chromatography in that the apparatus is costly and cannot be improvised. On the other hand it is in many instances considerably more sensitive. Fractions can be trapped and submitted to other analytical techniques, but the only direct information afforded is a retention time. 3 . Spectrophotometry a. Ultraviolet. During the last 15 years UV spectrophotometry (351354) has become a standard analytical technique. Earlier attempts to use it (355)were disappointing as extracts obtained directly by the Stas-Otto process were too impure to give satisfactory results, and it was not until the advent of paper chromatography that it became possible t o obtain samples sufficiently free from interfering substances t o be of any use for spectrophotometric purposes. The technique is of particular value in helping to identify substances which show a definite shift of peak with change of pH, but considerably less so when one has a whole group of related compounds (such as the amphetamines) which have a weak uncharacteristic absorption; but even in such cases the UV curves can be of some use when considered in relation to other analytical data. Tables of maxima arranged in sequential order are of considerable help in making a provisional identification, but actual comparison of the spectrum with that obtained from an authentic sample is of much more value. The apparatus is fairly expensive, but it is now (at any rate in the manually operated form) to be found in most laboratories. b. Infrared. IR spectrophotometry (354,356,357)came into use some years later than UV. Although it calls for more expensive equipment, rather more material, and a very high degree ofpurity, it is probably the most satisfactory method of final identification, as the spectra are far more characteristic than those given in the UV. The very complexity of the spectra itself poses a problem, as although various methods of coding have been described none is really satisfactory, and at the best can only allow a very tentative identification t o be made. For anything more than this a facsimile of the spectrum of the authentic compound, or better still the actual curve run on the same instrument as the unknown, is needed ; but even in the absence of such a curve a great deal can be learned about the structure of a compound from an examination of its IR spectrum.
7.
THE FORENSIC CHEMISTRY O F ALKALOIDS
557
B. ANALYTICAL TECHNIQUES Under ideal conditions the identification of an unknown alkaloid may be carried out by submitting the extracted material to gas chromatography, trapping the emerging fractions, and finding their IR, spectra, then programming the latter and feeding them to a computer. I n a few laborakories such a scheme is actually in operation. Although a computer cannot yet be considered as a normal part of laboratory equipment, most of the toxicological laboratories in Europe and North America are fully equipped for instrumental work. Many hospital laboratories on the other hand do not possess anything more sophisticated than a UV spectrophotometer, while in Asia and Africa, where the majority of cases of poisoning by alkaloids occur, only the simplest equipment is available. I n order to be of the widest use, the scheme given below is based on paper and bhin-layer chromatography with the help of UV spectrophotometry if it is available.
I . Paper chromatography Paper chromatography is carried out by the citrate-butanol system (341,358).This system has been chosen because it has proved itself over the years to be the most satisfactory for general screening purposes, and data for several hundred bases, both natural and synthetic, are available (332, 336). Sheets of Whatman No. 1 paper are dipped in a 5% solution of sodium dihydrogen citrate, roughly blotted, and hung up to dry a t room temperature. They may be stored indefinitely. The solvent is made by dissolving 4.8 gm of citric acid in a mixture of 130 ml of water and 870 ml of n-butanol. It may be used over a period o f a month or more provided that water is added from time t o time t o keep the specific gravity a t 0.843-0.844. This monophasic solution replaces the diphasic solution originally described (341)as it gives more reproducible results, but as the system is not equilibrated, reproducibility is also affected by such factors as temperature, size of tank, number of sheets of paper, and time of running (358).The Rfvalues given in Table I1 were obtained running four sheets 14 x 6 inches a t a time for 5 hours in a tank 8 x 11 x 155 inches deep and containing 500 ml of solvent, but any size paper and tank may be used provided suitable corrections are applied. After evaporation to dryness (in the presence o f a drop of dilute HCl t o avoid loss of volatile bases) the residues from the C (neutral) and D (alkaline-chloroform) extracts as well as that from the alkaline distillate fraction are dissolved in a few drops of 2N acetic acid and spotted on the paper. The amount of alkaloid needed for each spot is 10-25 pg. If only a trace of material is available, it may be dissolved in ethanol and spotted
558
E. G . C. CLARKE
in several aliquots, allowing each to dry before the next is added. For very dilute solutions a continuous flow spotting device may be employed (359). Four papers should be spotted, or four spots run on the same paper, together with adequate controls. The paper is allowed t o develop for a t least 5 hours by the ascending method. At the end of this time it is removed, dried, and examined under UV light (2537 A), absorbing or fluorescent spots being marked; in this connection i t should be noted that a certain amount of material showing blue fluorescence is nearly always extracted from body tissues. The first paper (or spot) is sprayed with iodoplatinate solution, the second with bromocresol green, the third and fourth being kept in reserve. The Rf value is measured, and compared with those given in Table 11. If a tentative identification is possible, the remaining spots may be eluted for confirmatory tests such as UV spectrophotometry, or, alternatively, color reactions such as the Marquis test may be carried out directly on the paper. If it is necessary to elute a spot which has been sprayed with iodoplatinate, it should be cut out, and moistened with successive drops of 10% sodium sulphite solution, 10% barium chloride solution, and 0.880 ammonium hydroxide solution, drying between each addition and finally eluted with chloroform (360).The barium chloride is added to convert the citrate to its insoluble barium salt and thus prevent its elution. The citrate-butanol system can be run as a thin layer system, using plates spread with a slurry made from cellulose powder and a 5 yosolution of sodium dihydrogen citrate and the same solvent as given above. Results are reasonably comparable with those obtained by paper chromatography (361).
2. Thin-Layer Chromatography A further aliquot of the same extracts is submitted t o thin-layer chromatography, using the method described by Sunshine (362).Glass plates 20 x 20 cm are coated with a slurry made by mixing 30 gm of silica gel G with 60 ml of water, to give a layer 250 p thick, and dried in the oven a t 110" for 1 hour. The figures given in Table I11 were obtained using tanks 21 x 21 x 10 cm, the ends of which are covered with paper t o assist evaporation; 100mlof methanoland 1.5mlof 0.880ammoniumhydroxide are placed in the tank which is allowed to stand for 1 hour before use in order to equilibrate. After two runs the solvent should be changed and the tank reequilibrated. The test material is dissolved in 2N acetic acid and 1 p1 spotted on the plate, which is allowed to develop for 4 hour, by which time the solvent front will have risen about 10 cm. After drying,
7.
THE FORENSIC CHEMISTRY OF ALKALOIDS
559
the plates are sprayed, the most satisfactory reagents being acidified iodoplatinate solution and a 1yoaqueous solution of potassium permanganate. The results obtained should be compared with those given in Table 111. 3. U V Spectrophotornetry
One of the spots on the paper or thin-layer chromatograms is eluted, the eluate dissolved in 0.1N sulfuric acid, and its UV spectrum determined. The wavelength of the principal peak is compared with those given in Table IV, which gives these figures arranged in descending order. No practical details are given here, as these will, Qf course, depend on the type of instrument available.
4 . Color Tests Only two color tests, those ascribed t o Marquis (363)and Vitali (364), need be used as part of a routine screening procedure, although any suitable test may be employed for confirmatory purposes. The Marquis test is carried out by placing a drop of the test solution on a white tile, allowing it to dry and moistening it with the reagent, which is made by adding a drop of 40% formaldehyde solution to 1 ml of concentrated sulfuric acid. The colors obtained with a number of alkaloids are given in Table V. It must be remembered, however, that many synthetic drugs not included in this table also give colors with this reagent ; for example, most of the phenothiazine tranquillizers give a reddish purple, while the benzhydryl ether antihistamine drugs give a bright yellow. The test may be carried out directly on the residue from the alkalinechloroform extract, or on the spot on a paper or thin-layer chromatogram, or on the material eluted from such a spot. Colors from crude extracts always tend to be duller than those obtained from pure materials owing to the charring of the impurities by the sulfuric acid, I n the case of chromatograms it is convenient to pour the reagent over the sheet resting on a sheet of white opal glass; paper chromatograms must be absolutely dry. For spots eluted from chromatograms a microtechnique (365) may be employed. Glass rods about 20 cm long and 0.5 cm in diameter are heated in the middle and pulled out until the diameter a t the thinnest point is about 0.1 cm. They are broken a t this point and the ends ground flat. When the narrow end of such a rod is allowed t o touch the surface of a liquid it brings away a small pendant “microdrop.” This is transferred to a piece of opal glass, allowed t o dry, and a microdrop of the Marquis reagent added. This technique may be used for a wide
560
E. G.
C. CLARKE
variety of color and microcrystal tests (332,336).As thevolumeof a microdrop is about 0.1 p1i t follows that 500 different tests can be carried out on one conventional drop (0.05 ml) of solution. Vitali’s test is carried out by placing a microdrop of the test solution 011 a piece of opal glass, allowing it to evaporate, adding a microdrop of fuming nitric acid, and evaporating to dryness on a boiling water bath. After cooling, the residue is moistened with a microdrop of a 5% w/v solution of potassium hydroxide in ethanol. The colors obtained after adding the fuming nitric acid and after adding the ethanolic potassium hydroxide are given in Table VI. It will be noted that many compounds give indeterminate shades of yellow, orange, or brown which have little diagnostic value. Among distinctive colors given on addition of the fuming nitric acid by synthetic drugs not included in the table may be mentioned the green color given by imipramine and its cogeners, the red color given by antazoline, and the purple flash turning to yellow given by most of the phenothiazine tranquillizers. On the addition of ethanolic potassium hydroxide, diphemanil, aminocrine, cyclopentolate, and adiphenine give a purple color not unlike that given by the atropine alkaloids. Vitali’s test cannot be carried out satisfactorily on paper or thin-layer chromatograms.
VIII. Tables of Analytical Data INTRODUCTION Table I shows the solubility of various alkaloids in ether and chloroform. Table I1 gives data for the paper chromatography of a number of alkaloids on the citrate-butanol system. The first column shows the R, value, the second the name of the alkaloid, the third the appearance under UV light (2540A), while the fourth and fifth columns indicate the most satisfactory location reagents. Table 111gives data for thin-layer chromatography with the methanolammonia system. The first column gives the R, value, the second the name of the compound, the third the most satisfactory location reagent, while the last column gives references to literature where additional chromatographic information on the substance in question may be found. Table IV gives UV spectrophotometric data, the first column giving wavelength of the principal peak, the second the name of the compound,
7.
56 1
THE FORENSIC CHEMISTRY OF ALKALOIDS TABLE I SOLUBILITY OF ALKALOIDS Base
Chloroforms
Etheru
2 5 110 0.7 0.5 1.5 1 1220 5 1.6 1.2 5
50 187 500 3.5 18 100 245 6250 250 56 250 5500
Aconitine Brncine Cinchonine Cocaine Codeine Heroin Hydrastine Morphine Narcotine Quinidine Quinine Strychnine a
Milliliters of solvent to dissolve 1 gm of base.
the third the solvent used, and the fourth the wavelengths of secondary peaks. Table V gives colors obtained with the Marquis reagent and with Vitali’s test. I n the latter case the first column shows the color formed on the addition of fuming nitric acid, the second the color shown when a solution of potassium hydroxide in ethanol is added to the residue left after evaporation of the acid. Table VI gives details of the various location and color reagents employed. TABLE I1
PAPER CHROMATOGRAPHY DATA Location reagents
Rf
Compound
0.00 0.00
Agmatine Histamine
0.00 0.02 0.02 0.03 0.03
Pethidine Pseudomorphine Trigonelline Cytisine Ecgonine
UV light
1
Iodoplatinate Iodoplatinate (white) Dragendorff Bright blue Iodoplatinate Absorbs (strongly) Iodoplatinate Blue Iodoplatinate Iodoplatinate -
-
2 Broincresol green -
Marquis Marquis Dragendorff Dragendorff -
562
E. G . C . CLARKE TABLE 11-continued ~
Location reagents
Rf
Compound
UV light
1
__ 0.03 0.04 0.05 0.0.5 0.05 0.06 0.07 0.07 0.08 0.08 0.08 0.10 0.11 0.11
Ergothionine Tubocurarine Choline Oxycanthine Tropine Ariabesine Connessiiie Nicot,ine Berbamine Hydroxylupanine Tomat ine Pilocarpine Cephaeline Dehydroemetine
Iodoplat inate Iodoplatinate Iodoplatinate Absorbs (strongly) Iodoplatinate Iodoplatinate Absorbs (strongly) Iodoplatinate Iodoplatinate Absorbs (strongly) Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplat,inate Blue Iodoplatinate
0.11
L ysergamide
Blue
0.12 0.12 0.12 0.12 0.12
Chelerythrine Cycleanine Demissine Normorphine Serotonin
0.13 0.14 0.14
Sparteine Hydrastinine Monocrotaline
0.14 0.14 0.15 0.15 0.16
Morphine Morphine N-oxide Arecoline Solanine Bufotenine
Iodoplatinate Iodoplatinate Iodoplatinate Absorbs (strongly) Iodoplatinate Iodoplatinate White (white) Iodoplatinate Bright blue Iodoplatinate Iodoplatinate (white) Absorbs (strongly) Iodoplatinate Absorbs Iodoplatinate Iodoplatinate Absorbs Iodoplatinate Iodoplatinate White
0.16 0.16 0.17 0.18 0.18 0.18 0.18 0.19 0.19 0.19 0.19 0.19
Codeine or-Isolupanine Brucine Apocodeine Lycorine Neopine Norcodeine Canadine Codeine N-oxide Cotarnine Emetine Lupanine
Absorbs (strongly) Iodoplatinate Iodoplatinate Absorbs (strongly) Iodoplatinate Blue Iodoplatinate Pale green Iodoplatinate Absorbs (strongly) Iodoplatinate Absorbs Iodoplatinate Yellow Marquis Absorbs Iodoplatinate Pale green Iodoplatinate Iodoplatinate Iodoplatinate
Absorbs Absorbs
Iodoplatinate
Orange Dark blue
2 -
Dragendorff Dragendorff Bromcresol green Bromcresol green Bromcresol green Brorncresol green Bromcresol green Dragendorff Bromcresol green Marquis Bromcresol green Dragendorff Potassium permanganate p-Dimethylaminobenzaldehyde Visible orange spot Dragendorff Bromcresol green Marquis Potassium permanganate Bromcresol green Bromcresol green Potassium permanganate Marquis Marauis Dragendorff Marquis p-Dimethylaminobenzaldehyde Marquis Bromcresol green Bromcresol green Marquis Bromcresol green Marquis Marquis -
Marquis Marquis Bromoresol green Bromcresol green
7.
563
THE FORENSIC CHEMISTRY O F ALKALOIDS
TABLE 11-continued Location reagents
Rf
Compound
UV light
1
Absorbs (strongly) Iodoplatinate Absorbs Iodoplatinate
0.20 0.20
Dihydrocodeine Homatropine, ,\T-methyl Hyoxcine, N-methyl Perloline
Bright yellow
Iodoplatinate Iodoplatinate
0.21 0.22
Bulbocapnine Anileridine
Blue Pale green
Iodoplatinate Iodoplatinate
0.22 0.23 0.23 0.23 0.25 0.25 0.25
Isolupinine /3-Colubrine Hordenine Hyoscine Atropine, N-methyl Berberine Ergometrine
Absorbs Absorbs Absorbs Absorbs Faint yellow Bright blue
0.25 0.26
Iodoplatinate Iodoplatinate
0.26 0.27 0.27 0.27 0.27 0.28
Absorbs (strongly) Mescaline 5-Methoxydimethyl. White tryptamine Absorbs (strongly) Sinomenine Blue Boldine Pale green Harmalol a-Isosparteine Blue Scoulerine 5-Methoxytryptamine White
0.29 0.30 0.30 0.30 0.30 0.30 0.30 0.31 0.31
Demecolcine Harmol Homatropine Nalorphine Staphysine Strychnine Strychnine N-oxide Procaine Psilocin
Pale yellow Bright blue Absorbs Absorbs Dark blue Absorbs (strongly) Absorbs (strongly) Blue Absorbs (strongly)
Marquis Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
0.32 0.33 0.33 0.33 0.33 0.34 0.35 0.35
Thebaine Apomorphine Bicuculline Heroin Norharman j-Phenethylamine Ethylmorphine Theobromine
0.20 0.20
-
-
-
Iodoplatinate Iodoplatinate Iodoplatinrtte Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
2
Marquis
Dragendorff Potassium permanganate Marquis p-Dimethylaminobenzaldehyde Bromcresol green Dragendorff Marquis Dragendorff Dragendorff Marquis p-Dimethylaminobenzaldehyde Nitrogen dioxide p-Dimethylaminobenzaldeh yde Marquis Marquis Bromcresol green Bromcresol green Dragendorff p-Dimethylaminobenzaldehyde -
Marquis
-
Marquis Marquis Dragendorff Dragendorff Bromcresol green p-Dimethylaminobenzaldehyde Marquis Absorbs (strongly) Iodoplatinate Iodoplatinate Marquis Blue Iodoplatinate Marquis Blue Iodoplatinate Marquis Absorbs Iodoplatinate Bromcresol green Bright blue Iodoplatinate Bromcresol green Absorbs Iodoplatinate Marquis Dark blue Brominelammonia Blue
E. G . C. CLARKE
564
TABLE 11-continued Location reagents Compound
UV light
2
1
-~
0.36 0.36 0.37 0.37 0.37 0.37 0.37 0.38 0.38 0.38
Tryptamine
Blue
Iodoplatinate (white?) Aquaticine Iodoplatinate Absorbs Atropine Iodoplatinate Dark blue Gelseminine Iodoplatinate Norpseudoephedrine Absorbs Bromcresol green Bright blue Harmine Iodoplatinate Absorbs Hyoscyamine Iodoplatinate Absorbs (strongly) Iodoplatinate Cocaine Dark blue Iodoplatinate Cryptopjne Dimethyltryptamine Blue Iodoplatinate Blue Blue
Marquis
Dragendorff Dragendorff Bromcresol green Ninhydrin Marquis Dragendorff Dragendorff Marquis p-Dimethylaminobenzaldehyde Iodoplatinate Dragendorff Iodoplatinate p-Dimethylaminobenzaldeh yde Bromcresol green Ninhydrin Iodoplatinate Bromcresol green Iodoplatinate Marquis Iodoplatinate Marquis Iodoplatinate Iodoplatinate Bromcresol green Iodoplatinate Marquis Iodoplatinate Marquis Iodoplatinate Bromcresol green p -Dimethylamino benzaldehyde
0.39 0.39 0.39 0.40 0.40 0.40 0.40 0.40 0.40 0.40
Hydrastine Tryptamine, N-methyl Norephedrine Pseudoephedrine Harmaline a-Allocryptopine Atropine N-oxide Benzoylecgonine Benzylmorphine Chelidonine Gelsemine Methylergometrine
0.40 0.41 0.42 0.43 0.45 0.45
Narcotine Cinchonidine Harman Physostigmine Ephedrine Methysergide
Bright blue Blue Bright blue Dark blue Absorbs Blue
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
0.46 0.46 0.46 0.47 0.47 0.47
Ephedrine, N-methyl Narceine Quinine Cinchonine Delphinine Lysergide
Absorbs Absorbs (strongly) Bright blue Bright blue Pale yellow Blue
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Marquis Iodoplatinate
0.48 0.48 0.49 0.51
Hydroquinine Quinidine Papaverine Amphetamine
Bright blue Bright blue Pale green
Iodoplatinate Iodoplatinate Iodoplatinate Bromcresol green Marquis
0.38 0.38
Absorbs Absorbs Green Dark blue Absorbs Absorbs Dark blue Absorbs Bright blue
-
~
Marquis Bromcresol green Marquis Dragendorff Bromcresol green p-Dimethylaminobenzaldehyde Bromcresol green Marquis Bromcresol green Bromcresol green
p-Dimethylaminobenzaldehyde Bromcresol green Bromcresol green
565
7. THE FORENSIC CHEMISTRY O F ALKALOIDS TABLE 11-coritinued Location reagents Compound
UV lighb Absorbs Absorbs (strongly) Absorbs (strongly) Bright blue Pale blue Pale blue Bright blue Absorbs
0.56 0.56 0.58 0.58 0.58 0.60 0.60 0.60 0.61 0.62 0.63 0.63 0.63
Apoatropine Cassaine Tropacocaine Hydroquinidine Pseudoyohimbine Yohimbine E thylhydrocupreine Physostigmine N-oxide Coniine Methylamphetamine Corynanthine Theophylline Thiocolchicoside Ethylnarceine Levomethorphan Levorphanol Taxine Aconitine Cyprenorphine Etorphine Dihydroergotamine
Absorbs Absorbs Absorbs Absorbs Pale blue
0.64 0.64 0.65 0.65
Ibogaine Sempervirine Caffeine Ergosine
Blue Dark blue Blue
0.65
Ergotamine
Blue
0.68 0.68 0.68 0.72 0.72 0.73 0.74 0.78 0.78 0.79 0.80
Acetorphine Veratridine Veratrine Deserpidine Rescinnamine Methoserpidine Methadone Ethylpapaverine Reserpine Aimaline " Dihydroergotoxin "
Absorbs Pale green Blue Pale Blue Blue White Absorbs Yellow Pale green Blde Green
0.82 0.83
Lobeline Colchicine
Absorbs Yellow
Rf 0.51 0.51 0.51 0.53 0.53 0.54 0.55 0.55
-
Absorbs Blue Blue Brown Absorbs (strongly)
-
-
1 Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Dragendorff
2
Bromcresol green Bromcresol green Marquis
Bromcresol green Iodoplatinate
Bromcresol green Iodoplatinate Iodoplatinate Bromcresol green Marquis Iodoplatinate Bromine/ammonia Marquis Iodoplatinate Marquis Iodoplatinate Bromcresol green Iodoplatinate Bromcresol green Iodoplatinate Marquis Iodoplatinate Iodoplatinate Marquis Iodoplatinate Marquis p-Dimethylaminobenzaldehyde Iodoplatinate Marquis Marquis Bromine/ammonia p-Dimethylaminobenzaldehyde p-Dimethylaminobenzaldehyde Iodoplatinate Dragendorff Marquis Marquis Iodoplatinate Marquis Iodoplatinate Marquis Iodoplatinate Marquis Iodoplatinate Iodoplatinate Marquis Iodoplatinate Marquis Iodoplatinate Dragendorff p-Dimethylaminobenzaldehyde Iodoplatinate Marquis Marquis
566
E. G . C . CLARKE TABLE 11-continued Location reagents
Rf
UV light
Compound
0.83 0.84 0.84
Ketoyobyrine Cinnamylephedrine “Ergotoxin”
0.87 0.90 0.92 0.95
Jervine Solanidine Colchiceine Piperine
2
1
Marquis Marquis p-Dimethylaminobenzaldehyde Marquis Marquis
Bright blue Iodoplatinate Absorbs (strongly) Iodoplatinate Blue Iodoplatinate -
Brown Absorbs
Iodoplatinate Iodoplatinate Marquis Marquis
-
TABLE I11 THIN-LAYER CHROMATOGRAPHY DATA
Rf
Location reagent
Compound
References for additional information
~~
339,366 367 368
Berberine SparZeine Ergothionine Brucine Histamine Pseudomorphine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate Iodoplatinate Iodoplatinate p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate Iodoplatinate, very acid Iodoplatinate Iodoplatinate Iodoplatinate
Connessine Homatropine
Iodoplatinate Iodoplatinate
339 366, 370, 371
N-Methyltryptamine Ecgonine Normorphine
Iodoplatinate Iodoplatinate Potassium permanganate
296 373
0.00 0.00 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.04 0.04 0.05
Hydrastinine Tubocurarine Agmatine Atropine, N-methyl Choline Cotarnine Homatropine, N-methyl Hyoscine, N-methyl Sempervirine Trigonelline Psilocybin Isosparteine Colchiceine
0.07 0.08 0.1 1 0.12 0.13 0.13 streak 0.14 0.15 streak 0.16 0.17 0.17
-
339 339,366,369
339
-
339,366 296, 339,369, 370
339,366, 367,371, 372
366
7.
567
THE FORENSIC CHEMISTRY O F ALKALOIDS
TABLE III-continued
Rf
Compound
Location reagent
0.18 0.18 0.18 0.20 0.21 0.21 0.21 0.22 0.23 0.23 0.23 0.23 0.24 0.24 0.24 0.25 0.25 0.25 0.26 0.27 0.27 0.28
Apoatropine Atropine Hyosc yamine fi-colubrine Atropine N-oxide Benzoylecgonine Norcodeine Strychnine Codeine N-oxide Mescaline Morphine N-oxide Strychnine N-oxide Levomethorphan Levorphanol Sinomenine Dihydrocodeine 5-Methoxytryptamine Serotonin Coniine Staphysine Tryptamine Ephedrine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate lodoplatinate lodoplatinate lodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate
0.28 0.30 0.31 0.32 0.32 0.32 0.32 0.32
Methylamphetamine Pseudoephedrine Physostigmine N-oxide Apocodeine Bufotenine Cytisine Hordenine 5-Methoxydimethyltryptamine N-Methylephedrine Neopine Narceine /3-Phenethylamine
Iodoplatinate Potassium permanganate Potassium permanganate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
0.32 0.32 0.33 0.33 streak 0.34 Dimethyltryptamine 0.34 Hydroxylupanine 0.34 Morphine 0.34 0.35 0.35
Psilocin Berbamine Codeine
lodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
References for additional information
371 339,346,366, 370 366,370,371 367 373 339, 346, 366, 367,370 -
296 296
-
296 339, 346, 366, 368, 371, 3 74 284,295,374 -
339 296,375
366,376 368 296 -
295, 339, 346, 369, 370-372, 376,377 296 295, 339, 346, 366, 369, 370.376. 377
568
E. G . C. CLARKE
TABLE 111-continued
Rf
Compound
0.35 0.35 0.36 0.36 0.36 0.37 0.37 0.38 0.38 0.39 0.39 0.40 0.40 0.40 0.40 0.41
Harmalol Tropacocaine Dehydroemetine Ethylmorphine Monocrotaline Benzylmorphine Methadone a-Allocryptopine Harmaline Isolupinine Oxycanthine Anabasine Bulbocapnine Cycleanine Tropine Thebaine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
0.42 0.44 0.44 0.44 0.45 0.45 0.45 0.46 0.48 0.48 0.48 0.48 0.48 0.49 0.50 0.50 streak 0.50 0.51 0.51 0.52 0.52 0.52 0.52 0.53 0.53 0.54
Hydroquinine Aquaticine Hydroquinidine Pseudoyohimbine E thylnarceine Heroin Lupanine Cryptopine Amphetamine Cinchonine Norpseudoephedrine Perloline Pethidine Gelsemine Norephedrine Ethylhydrocupreine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Potassium permanganate Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate
Gelseminine Cephaeline Cinchonidine Emetine Harmol Quinine Solanine Arecoline Cassaine Demissine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate Iodine Potassium permanganate Iodoplatinate Iodoplatinate
Location reagent
References for additional information
366,372,373 366 346,370
-
371 295, 339, 366, 369, 376,377
295, 346,366,370 339,366,376 284,374 339,346,366 370 339 -
339,366 366
339,366
-
7. THE FORENSIC CHEMISTRY OF ALKALOIDS
569
TABLE 111-continued
Rf
Compound
Location reagent
0.54 0.55 0.55 0.55 0.55 0.55 0.56
Hyoscine a-Isolupanine Lobeline Physostigmine Quinidine Yohimbine Demecolcine
0.57 0.57 0.58 0.59 0.59 0.60
Apomorphine Nicotine Lycorine Bicuculline Veratridine Cocaine
0.60
Lysergamide
0.60 0.60 0.61 0.61 0.61 0.62 0.62
Pilocarpine Scoulerine Hydrastine Procaine Veratrine Ajmaline Colchicine
0.62 0.62 0.62
Nalorphine Narcotine Thiocolchicoside
0.62 0.63 0.63 0.64 0.65 0.66
Tomatine Caffeine Dihydroergotamine Condelphine Ibogaine Lysergide
0.66 0.66
Methysergide Papaverine
p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodine Potassium permanganate p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate Iodoplatinat,e Iodoplatinate Iodoplatinate p-Dimethylaminobenzaldehyde Iodoplatinate Iodoplatinate
0.67 0.67 0.67 0.68 0.68 0.68
Chelerythrine Cinnamylephedrine Ergometrine Canadine Ergotamine Harmine
Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate
Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate Iodoplatinate p-Dimethylaminobenz aldehyde Iodoplatinate Iodoplatinate Potassium permanganate Iodoplatinate Iodine Iodoplatinate
References for additional information
346,366,370, 371 366 366,370 339,370 339, 346,366,370
-
~
366, 370 339, 346,370 -
346, 366, 370, 372, 373, 378
339, 366, 370 -
346,366 339
366
295,339,366,369, 376 -
339,346,374 295,296 295,296,297 296 295, 339, 346, 366, 369, 370,376,377 295,296 295, 296 -
570
E.
a. C.
CLARKE
TABLE 111-continued
Rf
References for additional information
Location reagent
Compound
0.68 0.68 0.68 0.70 0.70 0.70 0.70 0.71 0.71
Jervine Norharman Solanidine Corynanthine Harman Methylergometrine Taxine Aconitine “Dihydroergotoxin ”
0.72 0.72 0.72 0.72 0.72 0.73 0.73 0.75 0.75 0.77 0.77 0.77 0.78
Acetorphine Chelidonine Ergosine E thylpapaverine Etorphine Anileridine “Ergotoxin ” Cyprenorphine Deserpidine Methoserpidine Rescinnamine Reserpine Piperine
Iodoplatinate Iodoplatinate Iodine Iodoplatinate Iodoplatinate Iodoplatinate Iodine Iodoplatinate p-Dimethylaminobenzaldehyde Gdoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Iodoplatinate Potassium permanganate Potassium permanganate Potassium permanganate
339
296
366, 370 295, 296
339 296
-
339,366
TABLE IV
UV SPECTROPHOTOMETRYDATA Maximum peak 284 234 245 237 258 258 272 214 258 255 258 234
Compound Acetorphine Aconitine Ajmaline or-Allocryp topine Amphetamine Anilderidine Apomorphine Arecoline Atropine Atropine, N-methyl Atropine N-oxide Benzoylecgonine
Solvent 0.1N Hydrochloric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid
Secondary peaks
275 290 288 252, 264 252,264 252, 264 251,263 252,264 275,281
7.
571
THE FORENSIC CHEMISTRY OF ALKALOIDS
TABLE IV-continued Maximum peak
284 228 292 282 265 277 268 272 270 235 236 234 284 280 284 268 332 236 288 303 230 220 283 281 257 256 257 312 315 251 285 277 252 210 253 246 247 247 279 269 258 274 295 249 250
Compound Benzylmorphine Berberine Bicuculline Boldine Brucine Bufotenine Bulbocapnine Caffeine Chelerythrine Cinchonidme Cinchonine Cocaine Codeine Apocodeine Codeine N-oxide Coniine Cotarnine Cryptopine Cyprenorphine Cytisine Dehydroemetine Deserpidine Dihydrocodeine Emetine Ephedrine Norpseudoephedrine Pseudoephedrine Ergometrine Ergotamine Ethylhydrocupreine Ethyl morphine Ethyl narceine Ethyl papaverine Gelsemine Gelseminine Harman Norharman Harmine Heroin Histamine Homatropine Hordenine Hydrastine Hydrastinine Hy droquinidine
Solvent
0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Hydrochloric acid 0.1N Sulfuric acid 0.1N Hydrochloric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Hydrochloric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid
Secondary peaks
264, 343 327 302 300 296 306 322 316 316 275 -
253 283
232 282 272
251,263 250,262 251,263 317,347 31 0 252,280 299,366 300 320 252, 264 306, 363 317,345
572
E. G . C. CLARKE TABLE IV-continued
Maximum peak 250 257 257 258 277 278 279 249 288 269 259 269 257 257 226 284 285 23 1 285 276 312 284 260 257 247 241 215 343 227 222 267 251 250 268 264 214 254 280 284 271 260 279 280 262 220
Compound Hydroquinine Hyoscine Hyoscine, N-methyl Hyoscyamine Ibogaine Levomethorphan Levorphanol Lobeline Lycorine Mescaline Methadone Methoserpidine Methylamphetamine N-Methylephedrine Methylergometrine Morphine Normorphine Pseudomorphine Nalorphine Narceine Narcotine Neopine Nicotine Pethidine Physostigmine Physostigmine N-oxide Pilocarpine Piperine Procaine Psilocin Psilocybin Quinidine Quinine Reserpine Sinomenine Sparteine Strychnine Taxine Thebaine Theophylline Thiocolchicoside Tryptamine Tubocurarine Veratrine Yohimbine
Secondary peaks
Solvent 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.01N Hydrochloric acid Methanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid Ethanol 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid 0.1N Sulfuric acid
316, 345 251, 263 251, 263 252, 264 -
-
238 -
253, 265, 292 252, 263 251, 263 313 -
260 -
291 -
251,263 303 301 -
312 274, 279 -
317,346 317, 346, -
370 273,287 293 272,277, 288
7.
573
THE FORENSIC CHEMISTRY OF ALKALOIDS
TABLE V COLOR TESTS~ Vitali 2
1
Marquis
Compound ~
Acetorphine Ajmaline a-Allocryptopine Amphetamine Anabasine Anileridine Apoatropine Apocodeine Apomorphine Atropine Atropine, N-methyl Atropine N-oxide Benzylmorphine Berbamine Berberine Bicuculline Boldine Brucine Bufotenine Bulbocapnine Canadine Cephaijline Chelerythriie Chelidonine Cinnamylephedrine Codeine Codeine, N-oxide
Bluish gray + yellowbrown Purple Purple Orange + brown
Red Yellow
Slowly orange
-
-
Purple Purple
4
black
Yellow-brown Red-brown
-
-
-
Red-purple
(Yellow) yellow-green Orange (Green) purple 3 green
Greenish brown Brown Faint orange
(Orange) orange Green Red-brown Purple Purple
Norcodeine Colchiceine Colchicine B-Colubrine
Purple Pale yellow Yellow
Conessine Corynanthine Cotarnine Cryptopine Cycleanine Cyprenorphine
Yellow + orange Slowly brown, gray rim
Dehydroemetine Delphinine Demecolcine
Faint orange
-
Blue
4
green -
Bluish gray + yellowbrown Faint orange Faint yellow Yellow
Faint yellow Faint yellow Brown Yellow Brown Orange Greenish brown Deep brown Pale yellow Yellow (Orange) orange Yellow
-
Yellow Yellow Pale yellow Dull purple Deep purple Dull purple 4 yellow
Yellow Brown Faint yellow Faint orange Faint brown Purple Brown Gray-brown Purple Purple Purple Orange Orange Dark brown Brown Dark brown Red Brown Dark brown Brown Brown Brown Brown
Orange Purple + dark brown Pale orange Brown Red Orange
Yellow Yellow Yellow Brown
Faint yellow
Yellow
4
purple
-
Red-purple Brown Yellow Brown Faint orange Brown
Red-purple
574
E. G . C. CLARKE TABLE V-continued Vitali
Demissine Deserpidine Dihydrocodeine Dihydroergotamine Dimethyltryptamine Emetine “Ergotoxin” Ergometrine Ergosine Ergotamine Ethylmorphine Ethylnarceine Ethylpapaverine Gelsemine Gelseminine Harmaline Harmalol Harman Norharman Harmine Harmol Heroin Hordenine Hydrastine Hyoscine Hyoscine, N-methyl Hyoscyamine Ibogaine Jervine Ketoyobyrine Levorphanol Lobeline Lycorine Lysergamide Lysergide Mescaline Methoserpidine 5-Methoxydimethyltryptamine .5-Methoxytryptamine
I
Marquis
Compound
Faint yellow Gray-green Purple Gray-brown Dull orange Pale yellow Gray-brown Gray-brown Gray-brown Gray-brown Yellow + purple + black Brown + green + blue Blue + brown
-
Brown Faint yellow Dull orange Yellow Yellow Dull orange Dull orange Dull orange Dull orange Yellow Yellow -
-
-
(Yellow) brown-green (Yellow) Green Green Orange Orange Violet Brown(+ green
-
Purple + yellow
Yellow Green Yellow Faint yellow Yellow Yellow
-
-
-
-
-
Gray + pale orange Red-brown Faint gray
-
Yellow
Brown Gray Orange Gray Brown Greenish brown brown
--f
deep
Red-purple Orange Brown Red-brown Yellow Dull purple Brown-purple Dull purple Brown-purple Brown Orange Brown Bright yellow Bright yellow Brown Purple-brown Red Red Red Orange Orange Bright orange Brown Purple Purple Purple Red-brown -
Red-orange Orange -
Red-purple
Methylamphetamine Orange Methylergometrine Gray-brown N-Methyltryptamine Dull orange
-
Yellow Yellow
2
-
Yellow Brown Orange-brown Dull purple Brown Yellow
Brown Purple-brown Purple-brown Brown Purple-brown Brown
Yellow
Red-brown
Yellow-brown Yellow
Brown-purple Red-brown
-
7.
575
THE FORENSIC CHEMISTRY O F ALKALOIDS
TABLE V-continued Vitali Compound Met hysergide BIorphine Morphine A-oxide Normorphine Pseudoinorphinc Nalorphine Narceine Nnrcot ine Neopine Oxycanthine Papaverine Perloline Pethidine P-Phenet hylainine Physostigmine Physostiginine ,V-oxide Piperine I’roraine Psilocin Psilocybin Rescinnarnine Reserpine Scoulerine Seinpervirine Serotonin Sinomenine Solanidine Solanine Staphysine Strychnine Strychnine N-oxide Taxine Thebaine Thiocolchicoside Toinatine Tryptainine Tubocurarine Veratridine Veratrine Yohimbine Pseudoyohimbine
Marquis Faint gra,v Violet Purple Purple Green Purple BIWWII+ deep brown + green Bluish violet, fading Blue - v iolet
(Yellow) pale yellow Dull orange Orange
Yellow Yellow Yellow Yellow Orange Yellow Yellow
Dull purple Orange Orange Orange Brown Orange Orange
Red + yellow Pale yellow Brown Faint yellow (Yellow) pa.le yellow
Yellow Orange Orange Brown Colorless
Yellow Yellow
Greenish brown Dull orange Gray-green Gray-green + brown
Gray-green Brown, slowly Orange + green + blue (Yellow) purple Yellow + purple Orange-brown
-
Purple Yellow
Red-brown -+ green-brown Yellow -
2
1
Green-brown Yellow Red-brown Purple flash + orange Yellow Pale orange Gray-green Yellow
Faint yellow
-
-
-
-
Dull purple Orange Red-brown Red-brown Brown Brown Brown Dull orange Brown Red-purple
-
Faint yellow Bright orange Bright orange Faint brown Orange Purple brown
Yellow-brown Red + orange Yellow (Pale yellow) bright yellow Brown Faint orange Dull orange Yellow Red-brown Pale purple-brown Orange - brown Red-orange + brown Faint orange Bright purple Greenish gray Yellow Red-purple Greenish gray Yellow Red-purple
A color shown in parentheses indicates the color of the residue before the addition of the reagent. Q
576
E. G. C. CLARKE
TABLE VI REAGENTS Bromcresol green spray. 0.5% in ethanol. Bromine/ummonin. Expose the chromatogram to bromine vapor for 2 minutes, hold it in the steam from a boiling water bath for 1 minute, then heat in the oven a t 110°-120" for 5 minut,es. With caffeine, theobromine, theophylline and other xanthine derivatives a rose pink spot develops which becomes reddish purple when exposed to ammonia. p-Dii?~ethylomii~obentrrldehyde spray. 1 gm of p-dimethylaminobenzaldehydeis dissolved in 100 ml of ethanol and 10 ml of concentrated hydrochloric acid added. Drrrgendorff rengent. (a)Dissolve 0.86 gin of bismuth subnitrate in 40 ml of water and add 10 ml of glacial acetic acid. (b) Dissolve 8 gm potassium iodide in 20 ml of water. Mix 1 volume of (a),1 volume of (b), 4 volumes of glacial acetic acid, and 20 volumes of water. Zodine. 1yo in carbon tetrachloride. (Alternatively, chromatograms may be exposed to iodine vapor.) Zodoplatinnte sprny (for paper chromatograms). Add 10 ml of 5 q ! platinum chloride solution to 240 ml of 2y0 potassium iodide solution, and dilute with an equal volume of water. Iodoplatinrrte sprtry (acid; for thin-layer chromatograms). Add 10 ml of 50,: platinum chloride solution and 5 ml of concentrated hydrochloric acid to 240 ml of 2:4 potassium iodide solution. lodoplntinnte qmtcy (strongly acid, for weak bases). Mix 1 ml of 5Yb platinum chloride solution, 9 ml of 10% sodium iodide solution, 2 ml of water, and 3 ml of concentrated hydrochloric acid. Mtrrquis recigent. 1 ml of formalin solution in 10 ml of concentrated sulfuric acid. The reagent is poured over the chromatogram (which must be thoroughly dry) supported on a sheet of white opal glass. Ninhydrin spruy. 0.5% in acetone. Heat papers a t 100" for 5 minutes after spraying. Pota,ssiumpermnnganute. 1 in water.
STRUCTURES OF SYNTHETICS Acetorphine
HO-C-CH~
I
CH2CHzCH3
7.
THE FORENSIC CHEMISTRY OF ALKALOIDS Amphetamine CHz-CH-NH2
6
AH3
Cyprenorphine
HO-C-CH3
I
CHI
Diphenoxylate
Etorphine HO
0@ b C H 3
CH30
HO-C-CH~
I
C3H7
577
578
E. G . C. CLARKE
Methadone
p-Methoxyaniphetamine CHz-CH-NHz
0
AH3
OCH3
Nalorphitie
Pentazocine
~
N
~
C
H
~
-
C
H/CH3= ‘CH3
OH
Pethidine OCzH6
I
C
7.
THE FORENSIC CHEMISTRY O F ALKALOIDS
579
STP CHZ-CH-NHZ
1
i
CH3
CH3
TMA
OCH3
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E.
a. C.
CLARKE
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E. G. C. CLARKE
336. E. G. C. Clarke, ed., “The Isolation and Identification of Drugs.” Pharm. Press, London, 1969. 337. E. G. C. Clarke, J. Pharm. Pharmacol. 10, 642 (1958). 338. E. G. C. Clarke, J. Phurm. PhzrmcoZ. 15, 624 (1963). 339. R. Munier and M. Macheboeuf, Bull. SOC.Chim. Biol. 31, 1144 (1949). 340. R. Consden, in “Toxicology: Mechanisms, and Analytical Methods” (C. P. Stewart and A. Stolman, eds.), Vol. 1, p. 303. Academic Press, New York, 1961. 341. A. S. Curry and H. Powell, NcLture 173, 1143 (1954). 342. A. S. Curry, Methods Biochem. Anal. 7, 39 (1959). 343. G. Maohata, Methods Forensic Sci. 4, 229 (1965). 344. A. Stolman, Progr. Chem. Toxicol. 2,321 (1965). 345. I. Sunshine, Am. J . CZin. Pathol. 40,576 (1963). 346. I. Sunshine, W. W. Fike, and H. Landesman, J . Forensic Sci. 11,428 (1966). 347. W. J. Cadman, MethodsPorensicSci. 2, 127 (1963). 348. L. R. Goldbaum, E . L. Schoegel, and A. M. Dominguez, Progr. Chem. Toxicol. 1, I1 (1963). 349. A. H. Beckett and G. R. Wilkinson, J . Pharm. Pharmucol. 17, 1045 (1965). 350. A. H. Beckett, G. T. Tucker, and A. C. Moffat, J . Phurm. Pharmacol. 19,273 (1967). 351. P. R. Oestreicher, C. G. Farmilo, and L. Levi, Bull. Narcotics, U.N., Dept. Social AJairs 6,Nos. 3-4, 42 (1954). 352. L. W. Bradford and J. W. Brackett, Mikrochim. Acta 427 (1958). 353. M. Feldstein, in “Toxicology: Mechanisms and Analytical Methods” (C. P. Stewart and A. Stolman, eds.), Vol. 1, p. 464. Academic Press, New York, 1960. 354. I. Sunshine and R. F. Gerber, “Spectrophotometric Analysis of Drugs.” Thomas, Springfield, Illinois, 1963. 355. A. I. Biggs, J . Pharm. Pharmcol. 4, 547 (1952). 356. A. Alha and V. Tamminen, Methods Forensic Sci. 4, 265 (1965). 357. E. Hubley and L. Levi, in “Toxicology: Mechanisms and Analytical Methods” (C. P. Stewart and A. Stolman, eds.), Vol. 1, p. 513. Academic Press, New York, 1960. 358. E. G. C. Clarke and A. E. Hawkins, J.Pharm. Pharmucol. 15,390 (1963). 359. E. G. C. Clarke and S. Sowter, Nature 202,795 (1964). 360. E. G. C. Clarke, Nature 188, 411 (1960). 361. P. E. Haywood and M. S. Moss, Analyst 93, 737 (1969). 362. I. Sunshine, Am. J. Clin. Pathol. 40, 576 (1963). 363. E. Marquis, Pharm. 2. Russland 35,549 (1896). 364. D. Vitali, Arch. Pharm. 218, 307 (1881). 365. E. G. C. Clarke and M. Williams, J . Pharm. Pharmacol. 7, 255 (1955). 366. J. Reichelt, Pharmazie 13, 24 (1958). 367. A. Denoel, F. Jaminet, E. Philipott, and M. J. Dallemagne, Arch, Intern.Physiol.59, 341 (1951). 368. I. Smith, ‘‘ Chromatographic and Electrophoretic Techniques.” p. 82. Heinemann, London, 1962. 369. G. Nadeau, G. Sobolewski, L. Fiset, and C. G. Farmilo, J . Chromutog. 1, 337 (1958). 370. J. V. Jackson and M. S. Moss, in “Chromatographic and Electrophoretic Techniques” (I. Smith, ed.), p. 394. Heinemann, London, 1962. 371. J. Buchi and H. Schumacher, Pharm. Acta Helv. 32, 75 (1957). 372. J. Buchi and H. Schumacher, Pharm. Acta Helw. 32, 194 (1957). 373. W. Klementschitz and P. Mathes, Sci. Pharm. 20, 65 (1952). 374. R. Pohlondek-Fabini and K. Konig, Phurmazie 13, 131 (1958).
7.
THE FORENSIC CHEMISTRY O F ALKALOIDS
589
375. J. B. Jepson, i n “Chromatographic and Electrophoretic Techniques” (I. Smith, ed.), p. 183. Heinemann, London, 1962. 376. J. Buchi, R. Huber, and.H. Schumacher, Bull. Narcotics, U.N., Dept. Social Affairs 12, No. 2, 25 (1960). 377. K. Genest and C. Farmilo, J. Am. Pharm. Assoc., Sci. E d . 48,286 (1959). 378. G. Wagner, Arch. Phann. 286,232 (1953).
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AUTHOR INDEX Numbers in parentheses are reference numbers and indicate that an author’s work is referred to although his name is not cited in the text. Numbers in italics show the page on which the complete reference is listed. Alekseev, V. S., 256(86, 87,89,90, 91, 93), A Aadahl, G., 366(91), 440 249(28), 316(200), 325, 326, 330 Aaron, H. S . , 261 (107), 327 Alekseeva, L. D., 20(34), 130 Abbott, D. C . , 531 (183), 584 Alexander, R. F., 531 (199), 584 Abdel-Monem, M. M., 376(1), 435(1), 438 Allen, D. R., 530(175), 583 Abdizhabbarov, S., 460(21), 507 Allen, J. R., 320(230), 330 Abdullaev, N. Kh., 320(222, 226), 330 Allen, T. J., 531 (201), 584 Abe, K., 389(445a, 445b), 390(445a, 445b), Ali, E., 456(10, 12), 506 392(363b, 363c), 448, 450 Ali, M. A., 489(141), 506, 510 Abernethy, R. J., 549, 587 Alha, A. R., 549(316), 556(35b), 571(316), Abonico, S. M., 460(22), 507 572(316), 587, 588 Abramovitch, R. A., 463(27), 464(27), 507 Amiya, T., 26(50,51), 32,34(64b), 131,142 A’Brook, M. F., 532(224), 585 (15), 202 Abubakirov, N. K., 18(21, 22, 23), 46(90), Anderson, W. A., 531(211), 584 72(118), 130, 133 Andreeva, E. I., 121(166), 125(166), 134 Achenbach, H., 474(78), 508 Andrews, A. E., 73(124), 78(128), 83(124), Achmatowicz, O., 2(113, 131, 137),8(3), 10 133 (3), 57(90, 113), 81(90), 82(90), 83 Aneja, R., 107(147, 151, 152), 108(151, (131), 84(131), 85(131), 86(132), 89(3, 155), 109(151), 114(152), 115(152, 132), 90(132), 91(90), 92(132), 93 157),116(152,157),118(151),119(151, (137), 94(137), 130, 132, 133 152, 147), 133 Adams, H. R., 455(1), 506 Anet, F. A. L., 390(3, 5), 391 (3), 392(4), Adams, R., 246(102, 103), 266(109, IlO), 435(3, 4), 438 267(109),268,270(115), 271,272,280, Anet, R., 27(61), 29(62), 131 285(154a), 286(160b), 288(160b), 296 Aplin, R. T., 176(66b), 600(179), 204, 511 (154a), 307(188), 311, 327, 328, 329, Appel, H., 474(78), 508 532(222), 585 Appelt, J., 338(469), 339(468), 340(2?7, Adelaar, J. F., 533(232), 585 468), 341 (277, 404, 468), 360(404), Adelberg, E. A., 276(143), 328 427(404), 446, 449, 451 Addis-Smith, L. F., 517(10), 579 ApSimon, J. W., 155(38),159(38),161(38), Adler, T. K., 544(307), 587 165(47), 203 Ahmad, V. U., 456(12), 489(141), 506, 510 Arakawa, S., 417(356a), 418(356a), 419 Aikman, M. L., 537(273), 572(273), 586 (356a), 420(356a), 468(58), 448, 508 Akagawa, M., 335(363a), 448 Arendaruk, A. P., 257(96,97,98), 262(96), Akramov, S. T., 248(21), 249(24), 250(21, 315, 327 30), 255(24), 257(24), 258(21,24), 322, Areshkina, L. Ya., 316(199), 330 324, 325, 331 Armendariz, L. G . , 335(132), 442 Akopyran, G . O., 124(181), 129(181), 134 Armstrong, J. R., 194(101), 195(101),205 Albonico, S. M., 347(27), 362(2), 435(2), Arndt, R. R., 360(370), 362(17, 370), 435 438 (17), 436(17), 438, 448, 458(1b), 642 Alcala, A., 335(132), 442 (29), 507 591
592
AUTHOR INDEX
Arthur, H. R., 359(6), 435(6, 7), 438, 497 (170), 511 Asada, S., 350(530), 352(355,356,530), 353 (530), 358(530), 362(530), 448, 453, 488(133), 510 Asahina, H., 340(8), 435(8), 438 Asatoor, A. M., 532(217), 584 Ashby, H. T., 527(125), 582 Aslanov, K. A., 459(19), 507 Atal, C. K., 247(6, 8), 248(17), 251(8, 45, 47), 253(6, 59), 255(6), 258(6), 258(8, 47), 274, 307, 309, 324, 325, 328, 495 (163), 511 Auchterlonie, L., 530(177), 584 Audier, H., 366(9), 435(9), 438 Auld, W. C., 535(252), 570(252), 572(252), 585 Awad, A. T., 506(207, 209), 512 Awe, W., 339(13, 544), 383(9a), 384(12), 399(10, 11, 13, 14, 15, 16, 544), 403 (16), 435(10, 11, 12, 13, 14, 15), 436 (15), 438, 453 Ayers, R. H., 386(420), 450 Ayer, W. A., 162(43), 203
B Bearschers, W. H., 360(370), 362(17, 18, 370), 435(17), 436(17, 18), 438, 448 Babin, D. R., 2(64c), 24(40), 35(64c), 43 (84), 45(87), 52(84,93), 65(84, 87, 93), 66(84, 87,93), 71(84, 87, 93), 97(64c), 99(64c), 130, 131,132 Bachelor, F. W., 41(74), 43(74), 47(74), 50 (74), 51(74), 52(92), 57(74, 92), 68(74, 92), 131, 132 Bachman, P. L., 202(132), 205 Bailey, A. S., 390(3), 391(3), 418(19, 20, 418), 435(3), 436(19, 20), 438, 450 Baillie, M. J., 520(46), 580 Baisheva, K. S., 424(21), 436(21), 438, 468(57), 508 Bajiva, G. S . , 123(174), 127(174), 134 Bak, T., 531 (188), 584 Baker, A. C., 494(157b), 511 Baker, D. R., 366(417), 449 Bakuni, D. S . , 456(9), 506 Baldwin, &358(22), I., 436(22), 438
Bamford, F., 554(331), 587 Ban, Y., 212(25), 244 Banerjee, S. K., 338(386), 339(386, 387), 340(386), 341 (386), 342(386), 343 (386), 399 (386), 401 (387, 388), 403 (388), 412(387, 388), 449 Bankiewicz, C., 495(162), 511 Ban’Kovskaya, A. N., 255(79), 326 Bm’Kovskii, A. I., 187(94), 204, 255(79), 326 Barboutis, J. J., 501(183), 512 Barden, P. J., 516(8), 579 Barger, G., 359(23), 360(23), 436(23), 438 Barker, A. C., 371 (24), 376(24), 437(24), 438, 484(120), 510 Barmon, P., 24(39);130 Barnes, J. M., 320, 331 Barnes, M. F., 136(7a), 202 Barney, G. H., 524(91), 581 Barr, A. G., 522(61), 580 Barragan, V., 335(130), 442 Barrett, M., 351 (520c), 452 Barron, N. S., 528(132), 535(260), 572 (260), 582, 586 Bartar, M., 270(118), 327 Bartek, J., 420(25), 437(25), 438 Bartlett, M. F., 166(49), 167(49), 194(101), 195(101), 203, 205 Barton, D. H. R., 202(131), 205, 340(36), 347(30), 348(32), 349(26, 31, 35), 350 (206,207,208,209), 351 (207,208,209), 353(209,356(27,28), 359(27), 360(27), 362 (27,28,36,208), 363 (29,33,34,36), 364(29, 33, 34), 366(29, 36), 376(32), 392(32), 432(31,32), 437(26),438,439, 444, 494(160), 511 Batterham, T. J., 366(37), 439 Battersby, A. R., 340(36, 50, 51), 343(48), 345 (38,49, 51), 346 (50), 347 (40,41), 349(38, 40), 350(48, 49), 351(48), 356 (49), 358(49), 359(47), 362(36, 39, 40, 47, 49), 363(36), 364(52), 366(36, 38, 39, 44, 45, 46, 51, 52, 56, 5 8 ) , 368(52), 370(42), 371(24, 42, 328), 376(24, 42, 61, 328), 377(61), 379(328), 380(61), 383(42, 43, 61), 384(59), 385(59), 390 (59), 396(60), 397(53,57,57a, 60), 398, 417(53, 55), 418(55), 420(53, 55), 432 (39, 40, 54), 437(24), 438, 439, 456(9), 483(112, 114), 484(116,117,120, 121), 494(157b),497(168),506,509,510,511
AUTHOR INDEX
Bavega, S. K., 489(138), 510 Baxter, J. N., 534(246), 585 Beal, J. L., 388(133b), 390(102, 133b), 441, 442, 466(47), 503(189, 190), 506 (207, 209), 508, 512 Beckett, A. H., 556(349, 350), 588 Beckett, B. A., 429(61a), 439 Beglinger, U., 160(41), 203 Behrens, H., 527(92), 581 Bej, A. J., 348(420a), 450 Bell, K. H., 366(37), 439 Bell, R. A., 163(46), 199(46), 203, 421 (436a), 429(436a), 450 Bellet, P., 483(111), 509 Below, L. E., 468(59), 508 Benages, I. A., 463(30), 507 Bendisch, R., 346(155), 442 Benington, F., 543(305), 587 Benlzen, M., 531 (208), 584 Benn, M. H., 2(69, 70), 16(15), 36(69), 39 (69,70),40(70),130,131,174(62a),175 (62a), 176(66b), 203, 204, 308(191), 317(205), 329, 330, 500(179), 511 Bensted, J. P. M., 320(234), 331 Bentley, J. R., 524(87), 581 Bentley, K. W., 340(62), 347(63), 359(64), 362(63), 364(62), 365(63), 439, 537 (271, 272, 273), 571(272), 572(272, 273), 586 Berger, F., 359(497), 452 Berger, G., 2(140), 95(140), 133 Bergmann, E. D., 471 (67), 508 Berman, E., 549, 571(317), 572(317), 587 Rernauer, K., 350(65, 66, 67, 68, 69, 70a), 351(70a), 353(69), 356(65, 66, 68), 358(65, 66, 68), 358(65, 69), 359(70), 362(65, 66, 68, 69), 440, 485(124), 510 Bersch, H. W., 417(71), 418(71, 94, 95), 419(94), 440, 441 Berzelius, J. J., 398, 440 Bessho, K., 489(137), 492(152), 510, 51 1 Bhacca, N. S . , 313, 331, 347(73), 368(73), 369(73), 370(73), 440 Bhakuni, D. S., 350 (75, 206), 356(27, 28), 359(27), 360(27,28), 363(29), 364(29), 366(29), 438, 440, 444 Bick,I.R.C., 348(76,77),350(76),362(77), 440 Bick, J. R., 463(31), 507
593
Bickelhaupt, F., 2(64c), 24(40), 35(64c), 43(83, 84), 45(87), 52(84, 93), 64(83, 115), 65(84, 87, 93), 66(84, 87, 93), 71(84, 87, 93), 97(64c, 93), 98(64c), 99(64c), 130, 131, 132, 133 Biemann, K., 209(16), 243 Biggs, A. I . , 556(355), 588 Bilyuga, T. G., 256(87), 316(200), 326, 330 Bingley, J. B., 321, 331 Binns, W., 531(210, 211, 212, 213), 532(214), 584 Binks, R., 340(51), 345(51), 347(41), 366(44, 45, 46, 51), 370(42), 371(42), 376(42), 383(42, 43, 61), 439 Black, D. J. G., 535(260), 572(260), 586 BlBha, K., 396(78, 79), 397(78, 79), 400 (428, 430), 401 (428), 402(430), 406 (430), 407(430), 409(430), 412(430), 414(430), 440, 450 Blaschke, G., 347 (148), 349(148), 358 (148), 362(147, 148), 366(80),440, 442 Bligh, J., 537 (275), 570(275), 571 (275), 586 Blount, B. K., 531(191), 534(246), 585 Blount, W. P., 531(191), 584 Boaz, H., 308(193), 329 Boca, J. P., 124(178), 128(178), 134 Bocharnikova, A. V . , 121 (166), 125(166), 134 Bodmer, F., 213(30), 214(30), 215(30), 221 (30), 244 BognBr, R., 340(80a), 440, 443 Bogri, T., 2(64c), 35(64c), 97(64c), 98(64c), 99(64c), 131, 505(201), 512 Bohm, H., 342(193), 400(193), 403(80c), 412(193), 414(193), 440, 443 Boit, H.-G., 136(4), 202, 246(2), 324, 335 ( 8 5 ) ,338(84), 340(81, 82), 343(83, 84), 363(83,84), 383(81), 390(83),391(83), 429,440 Bokor, A., 520(38), 580 Bolin, F. M., 531 (190), 584 Borchardt, R. T., 504(196), 512 Borisyuk, G. Yu., 248(20), 324 Bottomley, W., 316, 330 Boura, A. L. A., 537(273), 572(273), 586 Bouvier, G., 523(70), 581 Boyadzhieva, M., 27(59), 36(59), 131 Boyce, C. B., 474(76, 77), 508 Brabenec, J.,.335(482), 417(427), 418(427, 482), 419(427, 482), 450, 451
594
AUTHOR INDEX
Brackett, J. W., 556(352), 588 Bradbury, R. B., 288(162, 163, 164, 165, 167, 168, 169), 289(165, 169), 290 (169), 309, 329, 483(114), 484(121) 509, 510 Brader, J., 308(193), 329 Bradford, L. W., 356(352), 588 Bradley, R. J., 543(305), 587 Bras, G., 518(19, 20), 579, 580 Braude, R., 535(259), 586 Bremmer, J. B., 460(20), 507 Brend, W. B., 515(5), 579 Brewer, H. W., 2(64c), 35(64c), 97(64c), 98(64c), 99(64c), 131 Breyer-Brandwijk, 523(81), 526(81), 527 (81), 581 Briggs, L. H., 160(42), 203, 254(68), 257(68), 314, 326 Briner, R. C., 474(76, 77), 508 Brochmann-Hanssen, E., 340(86, 87, 88, 88a, 89, go), 342(87), 344(87), 346(87), 348(87), 361(252), 366(58, 91), 400(88a), 401(88), 409(88), 412 (Ma), 414(88), 88a), 415(87), 439, 440, 445, 492(156), 511 Broquist, H. P., 501 (182), 512 Brossi, A., 210(21), 244, 345(92), 440, 443 Brown, D. W., 392(93, 93a), 394, 440 Brown, M. A., 392(4), 435(4), 438 Brown, R. F. C., 41 (74), 43(74), 47(74), 50(74), 51(74), 52(92), 57(74, 92), 68(74, 92), 131, 132 Brown, R. H., 529(149), 583 Brown, R. T., 504(194), 512 Brown, S. D., 464(41), 505(41, 198), 507, 512 Brown, T. H., 343 (48), 345 (49), 350 (48, 49), 351(48), 356(49), 358(49), 359 (47), 362(47, 49), 439 Bruderer, H., 210(21), 244 Brutko, L. I., 124(180),125(180, 182), 128 (180), 129(180),134, 461 (26), 464(37), 507 Brummerhof, B. W. D., 254(75), 326 Buchi, G., 41(74), 43(74), 50(74), 51(74), 52(92), 52(74,92), 68(74,92), 132,496 (164), 511 Buchi, J.,566(371,372),567(371,372,376), 568(371,372, 376), 569(371, 376), 588, 589
Buck, K. T., 349 (loo), 350 (loo), 356 (loo), 362(100), 441, 503(189), 512 Buck, W. B., 531 (201), 584 Buckingham, H., 526(110), 582 Budovskii, E. I., 327, 328 Budzikiewicz, H., 348(364), 356(96), 358 (96), 362(96), 364, 370(96), 397(364), 441, 448 Buehler, H., 270(119), 327 Bull, L. B., 319(214), 320(240), 330, 331, 519 (25, 28), 521 (49, 55), 580 Bunnell, S., 543(304), 587 Burlingame, A. L., 501 (183), 512 Buxton, J. B., 523(75), 581 Buzas, A., 389(97), 441 Byernun, R. U., 316, 330
C Cadman, W. J., 555(347), 571(347), 588 Calero, A., 251 (40, 41), 255(40), 325 Cambie, R. C., 160(42), 203, 254(68), 257(68), 314(68), 326 Cameron, M. A. M., 2(69), 36(69), 39(69), 131 Camp, B. J., 455(1), 526(113), 532(222, 223), 506, 582, 585 Campbell, D., 522(68), 581 Candy, B. J., 254(68), 257(68), 314(68), 326 Cannon, J. R., 460(20), 507 Canonica, L., 477(90), 509 Cardwell, H . M. E., 347(63), 362(63), 365(63), 439 Carey, J. C., 531 (202), 584 Carmack, M., 2(31, 36), 19(31), 20(31), 21(36), 22(31), 24(31, 36), 25(31, 36), 121(31), 125(31), 130 Carney, T. P., 538(281), 570(281), 586 Carpenter, R. D., 528(140), 583 Carr, F. H., 72(121), 73(121), 133 Cameras, L., 488(134), 510 Casa, D. D., 506(208), 512 Casselberry, N. H., 531 (203), 584 Cassels, B. K., 346(98), 441 Cava, M. P., 249(23), 253(23), 313(23), 324, 340(520b), 348(146), 349(100, 519a), 350(100), 356(100), 361 (99), 362(100), 390(101, 102), 441, 442, 452, 492(152), 503(109), 511, 512
AUTHOR INDEX
Cerneva, P., 117(162), 134 Cernjr, V., 534(243), 585 Cervinka, O’., 270, 274, 327, 328, 376(103), 441, 494(157a), 511 Chakraborty, D. P., 491 (l46), 510 Chakravarti, K. K., 504 (195), 512 Chamberlain, J. P., 541 (299), 571 (299), 587 Chambers, C., 340(520), 363 (104, 104a, 520), 364(520), 441, 452, 470(64), 508 Chan, R. P. K., 371(105), 376(105), 441, 494(159), 511 Chang, C.-C., 396(540), 397(540), 453 Chang, H. H., 86(132), 89(132), 90(132), 92(132), 133 Chapman, G. M., 356(27, 28), 358(27), 360(27, 28), 438 Chatterjee, A., 16(16a), 130, 20S(S, 13, 14), 209(14, 16, 17, 17a, 19), 210(19), 211(14), 213(28, 32), 228, 243, 244, 362(106), 441, 458(15), 507 Chatterji, S. K., 549(319), 587 Chen, C. Y., 468(53), 508 Chen, C.-Y., 335(107), 383(107), 384(107), 390(106a), 421(436a), 429(436a), 441,450 Chen, L., 338(514), 346(514), 348(514), 390(514), 391(514), 452 Ch’en, Y., 40(73), 60(73), 120(73), 123 (73), 127(73), 131, 422(113), 441 Chen-Teng, L., 338(513), 346(513), 452 Chernyaeva, 0. M., 249(28), 325 Chesnut, V. K., 530(170), 534(241), 583, 585 Cheung, H. T., 359(6), 435(6), 438 Chiavarelli, S., 308 (192), 329 Chopra, I. C., 16(16), 130 Chopra, K. L., 153(33), 203 Chou, T. Q., 384(109), 422(108, 109, 110, 111, 112), 441 Chou, Y. L., 121(167), 122(171), 126(167, 171), 134, 363(114), 364(114), 441 Christie, G. S., 520(46), 580 Christison, R., 515(3), 579 Chu, J. H.,40(72,73), 60(73,109,110), 120 (73), 121(167), 122(72, 171, 172, 173), 123(73, 110), 126(167, 171, 172, 173), 127(72, 73, 110, 173), 128(110), 131, 132, 134, 248(19), 253(60), 324, 325, 363( 114,224), 364(114,224), 422( 113), 441, 444
595
Chu, Y. L., 40(73), 60(73), 120(73), 123(73), 127(73), 131, 248(19), 253 (60), 324, 325 Cionga, E., 35, 131 Ciulei, I., 208(1), 243 Clark, A. M., 320(237), 331, 521(53), 580 Clark, L. C., 543(305), 587 Clark, R. T., 528(136), 582 Clarke, E. G. C., 517(11), 528(141), 535 (253), 539(284), 540(296), 551 (324), 554(330, 332), 555(332, 337, 338), 556 (332, 358), 558(359, 360), 559(365), 560(332), 567(296,284), 568(284),569 (296), 570(296), 571(253, 296), 572 (253), 579, 583, 585, 586, 587 Clarke, M. L., 535(253), 585 Clawson, A. B., 528(139), 534(240), 583, 585 Clayton D. W., 27 (61), 131 Clegg, F. G., 528(130), 582 Clements, J. H., 345(49), 350(49), 356(49), 358(49), 362(49), 439, 484(116, 120), 510 Clemo, G. R., 270(113, 114), 311(114), 327 Clough, G . W., 535(261), 586 Cohen, S., 540(294), 586 Cohen, T., 347(30), 349, 438 Comin, J., 347(2), 348(421),362(2), 435(2), 438, 450 Cone, N. J., 208(4), 243 Conisbee, E. G., 535(249), 585 Connolly, F., 530(176), 584 Connolly, J. D., 16(15), 130 Conrow, K., 169(54), 170(54), 203 Consden, R., 555(340), 588 Contz, O., 208(1), 243 Cook, A., 551 (328), 587 Cook, C. E., 464(38), 507 Cook, J. W., 526(106, 114), 582 Cooke, W. E., 529(154), 583 Cooks, R. G., 323, 331, 465(44), 507 Cookson, R. C., 11(10), 18(20), 19, 26(29, 42), 35(64d), 130,131 Coomes, R. M . , 390(514a), 452 Corcilius, F., 249(25), 324 Corio, E., 503(192, 193), 512 Cornevin, J., 530(161), 583 Corrodi, H., 345(115), 347(115), 362(115), 384(115), . . 385(115), 441 Corothie, E., 500(181), 511
596
AUTHOR INDEX
Corral, R. A., 463(30), 507 Couch, J. F., 19(32), 130, 528(139), 530 (174), 583 Cox, S. A., 519(31), 520(31), 580 Coxworth, E., 529 (152), 583 Crabb, T. A., 26(42), 131 Crabbe, P., 366(116), 441 Craig, J. C., 494(159), 511 Craig, L. C., 41(77), 46(77), 94(139), 107 (145, 146), 108(145, 146), 118(145, 146), 132, 133, 144(24), 166(48), 171 (48), 174(61), 203 Crawshaw, A. J., 522(69), 581 Cross, A. D., 342(397, 405), 345(406), 348 (406), 385(397, 405), 386(397), 390 (117), 391 (117), 392 (117), 400( 118, 119,338,397,430),402(430),403(388), 406(430), 407(430), 409(118,430), 412 (118, 119, 338, 43 0 ) ,4 1 4 ( 1 1 8 ,1 1 9 ,3 3 8 , 430), 418(470), 441, 447, 449, 450, 451 Crous, A., 296(178), 329 Crout, D. H. G., 247(14), 308(191), 317, 318, 324, 329, 330 Crowley, H. C., 247(9), 250(36), 252(11), 282, 300(9, ll), 302(36), 304, 324, 325, 328 Ctvtnik, J., 348(341), 447 Culvenor,C. C. J., 247(5, 6, 8,9, l l ) , 248(5, 16,17), 249(16,22),250(31,36),251(8, 22, 46, 47), 252 (11, 22), 253 (6, 51, 52, 53, 54, 55, 56, 57), 254(46, 76, 77), 255 (6,46,57), 256(83), 257(22,94), 258(8, 46, 47), 266(31, 54, 55), 267(31), 268 (52), 269(31,51,52), 273(77), 275,276, 280(146),282,283,285(155), 286(155), 288(167),299,300(9, l l ) ,302,304,305 (57), 306, 307(17), 308, 309,(6) 311 (46), 320(220), 324, 325, 326, 327, 328, 329, 330, 331, 471(68), 508, 520(44), 521 (49), 580 Curphey, T. J., 490(144), 510 Curry, A. S., 551(325, 327), 552(327), 553(327), 555(341, 342), 556(341), 571 (327), 587, 588 Cuthill, J. M., 532(218), 585 Cymerman, Craig, J., 345(120, 122), 347 (73, 120,122), 359(121), 360(121), 362 (121), 368(73, 120), 369(73), 370(73), 371(105), 376(105), 441
D Dahim, P. A., 531 (182), 584 DalBon, R., 299, 329 Dallemagne, M. J., 566(367), 567(367), 588 Dalma, G., 533(233), 585 Dalton, D. R., 348(146), 442 Danokwortt, P. W., 441 Danieli, B., 477(90), 509 Danieli, N., 480(102), 509 Danilova, A. V., 353 (61, 63), 254(69, 70), 256(61, 63), 273(63, 70), 274(70), 286 (160a), 288(160a, 171), 293, 300(182, 183),305(187),309(173),311,313,314, 326, 328, 329, 331 Dann, A. I., 302, 320(239, 240), 321, 329, 331, 520(44), 521(49), 580 da Rocha, A. I., 492(152), 511 Das, B. C., 208 (8), 209 (16), 243, 478 (92), 509 Das, K. C., 491 (146), 510 Dasgupta, B., 345(278), 446 Daubney, C. G., 549, 572(312, 313), 587 Davidyants, S. B., 424(21), 436(21), 438 Davies, A. P., 501 (183), 512 Davies, C. S . , 522(61), 580 Davis, P. R., 531 (200), 584 Davis, W . R., 534(244), 535(250), 571 (250), 585 Debray, M., 582(188), 512 d e Brovetto, A. G., 463(31), 507 de Dalla Torre, C. G., 334(124), 344, 390 (124), 441 Dedek, V., 270(118), 327 Delgado, J. G., 335(132), 389(131), 390 (131), 392(131), 442, 497(169), 511 D e Mayo, P., 45(88), 47(91), 48(91), 66 (88), 132 Denisova, S . I., 280(147), 328 Denoel, A., 566(367), 567 (367), 588 DeOliveira, M. M., 350(181), 352(181), 358(181), 362(181), 443 Desai, P. D., 458(13), 507 Deulofeu, V., 345(142), 346(155), 390(178, 179), 391(178, 179), 4 4 2 , 4 4 3 , 4 6 0 ( 2 2 ) , 482(108), 507, 509 de Vries, J. X., 463(31), 507 d e Waal, H. L., 254(75), 296(178, 179, 180), 312(177), 326, 329, 462(29), 507
AUTHOR INDEX
Dhar, M. M., 350(75), 440 Dick, A. T., 319(214), 320, 330, 331, 519(25, 28), 520(44), 521(49), 580 Dickenson, W. A., 531 (186), 584 Dickerson, R. E., 322, 331 Dillon, B. E., 528(129), 582 Diment, J. A,, 478(91), 509 Discombe, G., 529 (157), 583 Djerassi, C., 160(40, 41, 42), 163(40), 166(50), 167(50), 195, 203, 348(364), 356(96), 358(96), 362(96), 364, 370 (96), 397(364), 441, 448 DjokiB, S., 270(127), 327 Dobrowsky, A., 384(498), 452 Dobson, T. A., 340(36), 362(36), 363(36), 366(36), 439 Dohnert, H., 342(388a), 400(286, 453), 401 (286, 388a), 409(453), 414(286, 453), 415(286, 453), 446, 449, 451 Dolejs, L., 338(483), 342(397), 351 (483), 360 (483), 376 (127), 377 (129), 383 (127, 129, 483), 385(397), 386(397), 390 (117), 391(117, 128, 196), 392(117, 128, 196), 400(338,396,397,430,471), 401(3SS),402(430),403(338,388,472), 406(430), 407 (430),409 (430), 410,411, 412(126, 338, 388, 396, 430, 471, 472, 414(338,430), 418(470), 441, 442, 443, 447, 449, 450, 451 Dollahite, J. W., 526(113), 531(201), 532(222), 582, 584, 585 Dominguez, A. M., 556(348), 588 Dominguez,X.A., 335(130,132), 389(131), 390(131), 392(131), 442,497(169), 511 Donald, L. G., 520(41), 580 Donohue, J., 213(27), 244 Dopke, W., 351(133, 145), 353(133, 145), 363(33,133a, 144), 364(33,133&, 144), 391 (143,196), 392( 143,196), 438,442, 443,459(18), 469(62), 507, 508 Dorosh, T. P., 256(91), 326 Doskotch, R. W., 388(133b), 390(133b), 442, 466(47), 503(190, 191), 506(209), 508, 512 Douglas, B., 249(23), 253(23), 313(23), 324, 349(100), 350(100), 356(100), 362(100), 435(17), 436(17), 438, 441, 492(152), 503(189), 511, 512 Doyle, J., 530(178), 584 Dreyer, D. L., 500(180), 511 Drost, K., 481 (103), 509
597
Drummond, R. B., 524(96), 581 Duck, F., 535(258) 586 Dudoot B. S., 389(449a), 451 Duncan, W. H., 528(148), 583 Dunkelmann, G., 349(149), 363(149). 364 (149), 442 Dunstan, W. B., 72(121), 73(121, 124), 78 (128), 83 (124), 133 Durr, E. H., 519(31), 520(31), 580 Dutta, S. K., 460(25), 507 Dvornik,D., 143(17,19), 144(17), 147(17), 148(26), 149(26,29), 150(29), 151(26), 153(26, 29), 155(19, 29), l60(19), 163 (17), 167(17), 170(55), 171 (26), 202, 203 Dyke, S. F., 340(134), 359(64), 364(134), 392(93, 93a), 394, 420, 439, 440, 442, 462(28), 499(176), 507, 511
Edwards, C. M., 528(127), 582 Edwards, E. P., 534(239), 585 Edwards, J.A., 167(53), 169(53), 194(101), 195(101), 203, 205 Edwards, J. D. Jr., 275,283,286(159,160), 287, 295, 328, 329 Edwards, 0. E., 2(5, 69, 135), 11 (5, 8, 9), 12(5), 14, 15(13), 16(5, 13, 15, 17), 19 (30), 26, 35(67), 36(69), 39(69, 135), 73, 74(122), 83, 91(135), 92(135), 93( 135), 94( 130), 108(154), 109(154), 113(154), 115(154, 156), 118(154), 119 (154), 130, 131, 133, 143(17, 19), 144 (17), 147(17), 148(26), 149(26,29), 150 (29), 151(26), 153(26, 29), 155(19, 29, 37, 38), 159(38, 39), l60(19), 161(37, 38), 163(17), 165(47), 167(17, 52), 170 (55), 171(26), 173(58), 202, 203, 454 Egels, W., 339(135), 442 Eggers, S. H., 458(16), 507 Egnell, C., 389 (97), 441 Egorova, E. I., 321, 331 Ehmke, H., 340(82), 440 Ehrhart, L. A., 320(219), 330 Ekkert, E., 361 (136), 442 Elderfield, R. C., 41(77), 46(77, 89), 132, 208 (1l), 243 El-Gangihi, S., 484(118), 510 El-Homidi, A., 484(118), 510 Elphick, E. E., 534(242), 585
598
AUTHOR INDEX
Emerson, G. W., 532(220), 585 Emerson, T. R., 212(24), 244 Emmel, M. H., 519(33, 34), 580 Endo, H., 177(71), 204 Engelman, K., 532(221), 585 Everett, G., 531 (212), 584 Epstein, H., 345(499), 452 Erdtman, H., 346(137), 347(137), 349, 442 Eugster, C. H., 494(157), 511 Evans, G. W., 340(50), 346(50), 439
Filshie, I., 518(21), 580 Fike, W. W., 555(346), 567(346), 568(346), 569(346), 572(346), 588 Finch, N., 212(24), 244 Findlay, J. A., 195(107), 205 Finnegan, R. A., 202(132), 205 Firth, D., 524(87), 581 Fiset, L., 566(369), 567(369), 568(369), 569(369),588 Fitzgerald, A. E., 537 (273), 572 (273),
586 Fiyisowa, K., 60(104), 132 Flentje, A., 469 (62), 508 Flentje, H., 335(85), 338(84), 340(84), 343 F (83, 84), 351(.133, 145), 353(133, 145), FBbryovB, A., 376(103), 441, 494(157a), 363(33, 83, 84, 133a, 144), 364(33, 511 133a, 144), 390(83), 391 (83, 143), 392 Falco, M. R., 463(31), 507 (143), 438, 440, 442, 459(18), 507 Farber, D. G . , 345(138), 442 FleS,D.,246(102,103), 270(115),311(115), Fang, S. T . , 40(72), 60(109), 122(72, 173), 327 126(173), 127(72, 173), 131, 132, 134 Flitsch, W., 270(129), 327 Fangauf, R., 524(93), 581 Flom, M. S., 466(47), 508 Farmilo, C. G., 340(8), 356(351),401 (225), Fodor, G., 523(72), 581 4 1 5 ( 2 2 5 ) , 4 4 2 , 4 4 4 , 5 4 0 ( 2 9 5 ) , 5 5 4 ( 3 3 3 ) , Folkers, K., 276(143), 328 555(333),566(369), 567(295,369,377), Forbes, G. B., 631 (199), 584 568(295, 369,377), 569(295, 369), 570 Forsyth, A. A., 519(24), 522(24), 530(24), (295), 586, 587, 588, 589 533(24), 534(24), 535(24), 580 Farrington, K. J., 519(30), 580 Fonzes, L., 2(135), 39(135), 91(135), Fedde, F., 344, 433(140), 442 92(135), 93 (135), 124(178), 128(178). Fehlhaber, H. W., 467(51, 52), 497(171), 133, 134, 478(93), 509 600(178), 508, 511 Foulkes, D. M., 340(51), 345(51), 364(52), Feldstein, M., 549, 556(353), 571 (322), 366(45, 51, 52), 368(52), 439 587, 588 Fowler, L. R., 2(116), 41(74), 43(74, 82), Feist, K., 388(141), 442 46(82), 47(74, 82), 48(82), 50(74), 51 Feofilaktov, V. V., 20(34), 130 (74), 54(82),57(74,82), 68(74, 116), 71 Ferrari, C., 108(154), 109(154), 113(154), (82), 72(116), 1 3 1 , 1 3 2 , 1 3 3 115(154), 118(154), 119(154), 133, Fox, R. C., 308(192), 329 345(142), 442 Fraenkel, G., 348 (146), 442 Ferrari, G.,-477(90), 509 Francis, R. J., 366(45), 397(53), 398(53), Ferreira, P. C . , 251 (39), 254(39, 72), 417(53, 55), 418(55), 420(53, 55), 432 255(39, 72), 325, 326 (54), 439, 497(168), 511 Ferris, J. P., 2(31, 36), 19(3), 20(31), Franok, B., 347(148), 349, 358(148), 362 21(36), 22(31, 36), 24(31, 36), 25(31, (147, 148, 150), 363(149), 364(149), 36), 121(31), 125(31), 130, 474(76, 442 77), 508 Frankforter, G. B., 397 (151), 442 Ferris, N. H., 474(76), 508 Fraser, H. F., 536(265), 538(277), 572(265, Fetizon, M., 366(9), 435(9), 438 277), 586 Fiddes, F. S., 534(237), 585 Frenkiel, L., 24(39), 130 Field, K., 531 (183), 584 Freudenberg, W., 95(141), 133 Figdor, S. K., 166(49, 50), 167(49, 50), Freund, M., 396(153), 397(151, 152). 194(101), 195(101), 203, 205 442
AUTHOR INDEX
Fridrichsons, J., 260(104), 309, 327, 345 (153a), 442, 481 (106), 484(122), 509, 510 Froberg, E., 467(52), 508 Frolova, V. I., 187(94), 204 Fromming, K.-H., 349(154), 442 Frydman, B., 346(155), 442 Fuji, K., 489(137), 510 Fujisawa, K., 26(52), 131, 177(70), 185 (70), 204 Fujita, E., 201 (110), 202 (139, 140, 141), 205, 206, 345 (278), 446, 489 (137), 492(153), 510, 511 Fujita, M., 359(527), 453 Fujita, S., 340(8), 348(271), 435(8), 438 Fujita, T., 201(110), 205 Fujitani, K., 346(277a), 348(534), 446, 453 Fukumoto, K., 363(234b), 369(234, 239a, 248, 249), 370(239), 384(234a, 237b), 389(237b), 444, 445, 464(39, 40), 484(115), 507, 509 Fukushima, H., 335(363a), 448 Fulton, C. C . , 340(156), 343(156), 399, 419 (158), 442, 555(335), 587 Furst, A., 456(S), 506 Furukawa, H., 345(528), 348(529, 534, 535), 350(530), 352(530), 353(530), 358(530, 531), 362(530), 453 Furusawa, S., 26(48, 49), 93(48), 131 Furuya, T., 340(86, 87), 342(87), 344(87), 346(87), 348(87), 415(87), 440
G Gabbai, A., 527 (124), 582 Gadamer, J., 359(161, 168), 361(160). 384(166,538), 385(169,538), 386(162, 169), 388(159, 166), 391(163), 392 (167), 418(164, 165, 170), 419(165, 171, 172), 442, 443, 453 GB1, Gy., 340(80a), 440 Gallagher, C. H., 320(223, 225), 330, 519(30), 526(45), 527(118, 119), 580, 582 Gama, Y., 202(124), 205 Gandhi, R. N., 253(58), 259(100), 325, 327, 469(60), 508 Ganguli, G., 213(28), 228(28), 244 Garbers, C. F., 296(179), 329
599
Gardiner, M. R., 520(38), 530(164, 165, 166, 167, 168, 169), 580, 583 Gardiner, R. A., 501 (182), 512 Gardner, P. D., 497(169), 511 Garg, M. L., 489 (138), 510 Garing, M., 305(187), 329 Gasparec, Z., 390(173), 443 Gear, J. R., 397(174), 443 Geiger, P. L., 40(71), 131 Geissman, T. A., 247(13), 253(56, 57), 255 (13, 57), 272(137), 275, 276, 285(155), 286(155), 288, 305(57), 308(191), 309, 316, 317(205), 324, 325, 328, 329, 330 Gellert, E., 251 (43), 325 Gemenden, C. W., 208(9, lo), 213(29, 30), 214(29, 30), 215(29, 30), 217(29), 221 (29,30), 223(9), 224(9), 226(9), 228(9, lo), 230(10), 231(10), 232(10), 233 (lo), 235(10), 243, 244 Gempp, A., 418(509), 452 Genest, K., 540(295), 554(333), 555(333), 567(295, 309, 377), 568(296, 377), 569 (295, 377), 570(295), 586, 587, 589 Georgieva, A. V., 463(33), 507 Gerber, R. F., 556(354), 588 Gertig, H., 336(175), 337(176), 371(175), 425(175), 426(176), 443 Gettler, A. O., 549, 587 Gheorghia, A., 336(177), 377(177), 443 Gheorgiu, M., 208 (l),243 Ghosal, S., 460(25), 507 Ghosh, M. N., 248 (18), 249 (27), 324, 325 Giaoomazi, A., 345(138), 442 Giaoopello, D., 335(279), 390(178, 179), 391 (178, 179), 443, 446, 482(108), 509 Gianturco, M., 285(154a),296(154a), 328 Gibbons, W. J., 519(31), 520(31, 36), 521 (34), 580 Gibson, H. W., 345(180), 443 Gibson, M. S., 42(81a), 57(81a), 132 Gignon, J. R., 488(134), 510 Gilbert, B., 350(181), 352(181), 358(181), 362(181), 443 Gilbert, M. E. A., 350(181), 352(181), 358(181), 362(181), 443 Gillam,W.G.,522(58), 531(198), 535(251), 570(251), 571 (251), 572(251), 580, 584, 585 Gilman, R. E., 2(112, 127), 57(112), 60(112), 63(113), 73(127), 76(127), 80(127), 84(127), 133, 213(33), 244
600
AUTHOR INDEX
Ginsburg, D., 340(182),364(182), 366(9, 285),435(9), 438, 443, 446 Giral, F., 371 (183),443 Girenko, P. P., 316(200),330 Girota, R. N., 247(8), 251(8), 253(8), 258(8),324 Girotra, N. N., 163(44,45),202(125,126, 127,128,129),203, 205 Glick, L., 529(156), 583 Glonti, Sh. I., 253(66),256(66), 326 Glotter, E., 480(102),509 Go, J.,359(184),443 Goldbaum, L.R., 556(348),588 Goldman, I.M., 496(164),511 Goldschmidt, B. M., 272,328 Goldschmiedt, G., 348(185,186);443 Golkiewicz, W., 338(187),339(187), 443 Gonzales, A. G., 251(40,41,42),254(42), 255(40),325 Goodson, J. A., 19(26, 27), 26, 130, 150(30), 203 Gooneratne, B. W. M., 526(111),582 Gopinath, K. W., 171(57), 172(57), 173(60), 174(60), 194(60), 195(60), 203 Gordon-Gray, C. G., 312, 318(208), 329, 330 Gorecki, P., 340(80a), 440, 443 Gorman, M., 208(2), 243 Gorman, R.C . , 530(168), 583 Gotink, W. M., 534(245),h85 Goto, G., 502(185), 512 Goto, K., 364(188), 385(189), 443, 456(4, 5,6),506 Goto, T., 366(525),453 Gotz,M.,41(74),43(74,82),45(87),46(82),
47(74), 47(82),48(82),50(74),51(74), 52(93),54(82), 57(74,82),65(87,93), 66(87,93), 71(82,87,93),68(74), 97 (93),131, 132, 505(201), 512 Goutarel, R,,482(109), 509 Govindachari, T. R., 208(12),209(12,15), 210(12, 15,20),211(12, 15),243, 460 (24),467(54),479(98), 505(200),507, 508, 509,512 Grabarczyk, H., 337(176),426(176),443 Granier-Doyeux, M., 540(289), 586 Gray, A. H., 505(201), 512 Greatorex, J. C., 520(39), 580 Greenhalgh, R.,35(68),36(68), 131 Greer, F. G., 531(197),584 Gregory, B., 483(112), 509
Gresswell', J. B., 531(209),584 Grethe, G., 443 Gries, H., 361 (191),443 Griffin, W. J., 475(83)508 Griffiths, A. B., 532(218),585 Groeger, D., 486(130),510 Groenwound, P. W., 396(192),443 Gross, A. D., 339(357),401(357),412(357), 414(357), 448 Grozdanova, L. G., 120(165a),123(165a), 128(165a),134 Guercio, V.,524(94),581 Guggisberg, A., 342(193), 400(193), 412(193), 414(193),443 Gunner, D., 528(134),582 Gupta, R.N., 397(194), 443 Guthrie, R. W., 195(106, 108), 198(108, log), 199(108,109),201(106),205 Gyorgy, P., 518(20), 580
H Haack, E., 456(10),506 Hackbarth, J., 530(162), 583 Hadeck, J.,35(64d),131 Haginiwa, J., 479(95),509 Haglid, F., 480(101),509 Hai, H. S., 177(69, 71),204 Haisova, K., 336(484), 371 (484),376(484), 418(484),752 Hakim, S. A. E., 335(195),336(195),337
(195),338(195), 339(195), 340(195), 341(195), 342(195), 343(195), 417 (195), 432(195), 443, 533(227, 230), 585 Haley, T. J., 554(334),587 Hall, S.R., 492(154),511 Hall, W. T. K., 533(234),585 Hall Masheter, J. W., 535(248),585 Halmos, P. B., 529(159), 583 Hamamoto, T., 479(95),509 Hamazaki, Y . , 202(133,134,135),205 Hamilton, M., 523(74),581 Handa, K. L., 16(16), 130, 256(8S), 326 Hands, K.L., 454 Hansen, A. A., 524(90),531(204),581,584 Hanson, J. R., 202(131,138),205, 206 Hanus, V., 339(389), 342(397), 376(127),
385(397), 386(397), 390(117), 391
AUTHOR INDEX
(117, 128, 196), 392(117, 128, 196), 400 (338,396, 397,430,471), 401 (388), 402 (430), 403(338, 388, 472), 406(430), 407(430), 409(430), 410,411,412(126, 338, 388, 396,430, 471, 472), 414(338, 430),418(470),441,442,447,449,450, 451 Hara, S., 177(74, 75), 179(74), 204, 499(175), 511 Harada, H., 186, 187, 502(10), 512 Hardegger, E., 345(115), 347(115), 362 (115), 384(115), 385(115), 441 Harley-Mason, J., 348(77), 362(77), 440 Harms, H., 334(124), 344, 390(124), 441 Hanhs, R. H., 519(35), 580 Harper, B. J. T., 366(56), 439 Harris, C., 320(227), 330, 520(47), 580 Harris, D. R., 390(514a), 452 Harrison, A. J., 551 (328), 587 Hardy, D. G . , 537(271, 273), 572(273), 586 Hart, H. R. L., 340(8), 442 Hart, L., 533(228), 585 Hart,N.K., 252(49),253(49),254(71),275, 300(49,71), 301,325,326,463(34), 483 (113), 485(123, 126), 488(136), 507, 509, 510 Harthoorn, A. M., 537(275), 570(275), 571 (275), 586 Harvey, J., 2(31), 19(31), 20(31), 22(31), 24(31), 25(31), 121(31), 125(31), 130 Hase, T., 275(142), 286(159), 287(159), 295(176), 328, 329 Hasegawa, G., 121 (168, 169), 126(168, 169), 134 Hauserman, F. B., 367 (188), 329 Havlisek, S. C., 361 (99), 441 Hawkins, A. E., 558(358), 588 Hawkins, E. S., 531 (199), 584 Haworth, R. D., 359(200), 385(197), 391 (198, 201), 396(202), 443 Haywood, P. E., 558 (361), 588 Haxby, D. L., 535(262), 571 (262), 586 Hayase, Y., 190(97, 98), 205 Hayashi, Y . , 320(229), 330, 486(129), 510 Haynes, L. J., 360(205,206,207,208,209), 351(203, 207,208, 209, 520), 353(203, 209), 356(28), 358(22), 362(28, 205, 208), 363(10?, 204,205), 364(204),366
601
(20$), 436(22), 438, 441, 443, 444, 452, 469 (63), 508 Head, M. A., 320(215), 330, 521(54), 580 Hefferren, J. J., 546(309), 587 Hegi, G., 344, 444 Hencock, R. A., 540(290), 570(290), 586 Henderson, D. R., 166(49), 167(49), 203 Hendrickson, J. B., 524(100), 581 Henley, W. W., 519(34), 580 Hennig, A. J., 524(73), 255(73), 326 Henry, T. A., 73(126), 74(126), 133 Henry, W. A., 195(106,107),201(106), 205 Hensel, E. B., 551 (326), 553, 587 Hensiak, J. F., 361 (211), 444 Henstock, J., 35(64d), 131 Herbert, E. J., 26(43), 131 Herbert, R. B., 483(114), 484(116), 509, 510 Herran, J., 166(50), 167(50), 203 Herridge, C. F., 532(224), 585 Hesse, M., 208(9, lo), 213(29, 30), 214(29, 30), 215(29, 30), 217(29), 221(29, 30), 223(9), 224(9), 226(9), 228(9, lo), 230 (lo), 231(10), 232(10), 233(10), 235 (lo), 236(10a), 238(10a, 35), 240(35), 243(35), 243, 244, 342(193), 400(193), 412(193), 414(193), 443 Hesse, O., 339(212), 398(214, 215), 399, 444 Hesse, R. H., 348(32), 349(31), 376(32), 392(32), 432(31, 32), 438, 494(160), 511 Hewetson, W. T., 531 (194), 584 Heydenreich, K., 372(218, 219, 220), 350 (219), 359(220), 385(218), 386(218), 444 Hibino, S., 429(249a), 445 Highet, R. J., 488(135), 510 Hignite, C., 286(159), 287(159), 328 Hill, K. R., 518(16, 21, 22), 579, 580 Hindorf, H., 335(443), 344(443), 450 Hirai, K., 340(88, 88a), 400(88a), 401(88), 409(88), 412(88a), 414(88, 88a), 440, 492(151, 156), 511 Hirao, K., 201(111), 202(133, 134, 135), 205 Hirakura, M., 335(363a), 448 Hirata, Y., 187(95),204, 251(48), 253(62), 315(48, 62), 325, 326, 472(69, 70, 71), 473(72, 73), 474(74), 487(131, 132), 508, 510, 512
602
AUTHOR INDEX
Hirst, M., 364(52), 366(52), 368(52), 384 (59), 385(59), 390(59), 397(53, 57, 57a), 398(53), 417(53), 420(53), 432 (54), 439, 497(168), 511 Ho, L. H., 422(113), 441 Ho, P., 202(137), 206 Hodge, J. V., 532(220), 585 Hodgkins, J. E., 464(41), 505(41, 198), 507, 512 Hoffman, H., 527(119), 582 Hofheinz, W., 440 Hofmann, A., 527(123), 540(288), 570 (288), 572(288), 582, 586 Hokanson, J. F., 520(36), 580 Hollstein, U., 350(181), 352(181), 358 (181), 362(181), 443 Holmes, H. L., 384(323), 447, 523(71), 524(99), 525(103), 581, 582 Holter, H., 418(500), 452 Holubek, J., 389(221), 390(221), 392(221), 397(221), 420(221), 444 HorBk, M., 399(432), 403(432), 417 (427), 418(427), 419(427), 450 Horn, M., 524(92), 581 Horn, P., 345(267), 445 Horowitz, D., 532(221), 585 Howe, R., 155(37, 38), 159(38), 161(37, 38), 203 Hrbek, J. Jr., 361(407), 388(408), 396(78, 79), 397(78, 79), 400(428), 401 (428), 440, 449, 450, 484(119), 510 Hruban, L.,348(223), 358(335), 362(223), 363(335), 364(335), 376(429), 377 (429), 380(223, 429), 383(222, 429), 385(408a), 389(408e), 390(223, 408a), 392(223), 400(430), 402(430), 406 (430), 407(430), 409(430), 412(430), 414(430), 444, 447, 449, 450 Hsu, J. S., 363(224), 364(224), 444 Huang, W.-K., 122(173), 126(173), 127 (173), 134, 396(540), 397(540), 453 Huang, W. Y . , 121(167), 126(167), 134 Hub, L., 274(141), 328 Huber, C. P., 492(154), 511 Huber, R., 567(376), 568(376), 569(376), 589 Hubley, E., 556(357), 588 Huebner, C. F., 89(134), 107(153), 133, 143(20), 174(62), 176(62), 202, 203 Huffman, W. T., 531 (210), 584 Hug, M. H., 468(56), 508
Hughes, C. A,, 316, 318(208), 330 Hughes, D. W., 340(226), 341(226), 400 (226), 401(225, 226), 412(226), 414 (226), 415(225, 226), 444 Hui, W. H., 435(7), 438 Humber, L. G., 137(8), 142(8), 176(67), 202, 204 Hung, S. H., 122(171), 126(171), 134 Huq, M. E., 463(32), 507 Hurst, E., 524(95), 581 Hiirzeler, H., 213(29), 214(29), 215(29), 217(29), 221(29), 244 Husbands, G. E. M., 351(203, 520c), 353 (203), 363(204), 364(204), 366(204, 443, 444, 452, 469 (63), 508 Hutchings, R. J., 527 (120), 582 Huxley, A., 540(287), 572(287), 586 Hwaqg, B., 492(152), 511
I Ibuka, T., 348 (529), 350 (530), 352 (530), 353(530), 358(530,531), 362(530), 453 Ichikawa, N., 295(176), 329 Ihare, M., 384(235, 237b), 385(236), 389 (237b, 237c), 390(235, 236), 445, 464 (40), 507 Iida, H., 384(234a), 444, 464(39), 507 Iitake, Y., 142(15, 16), 202 Ikan, R., 471 (67), 508 Ikeda, N., 335(228a), 336(251a), 444, 445 Ikram, M., 463(32), 454, 468(56), 507, 508 Iliescu, C., 35, 131 Imaseki, H., 308(191), 317(205), 329, 330 Imaseki, I., 384(227), 385(521), 388(227, 521), 422(521), 444, 452 Imato, S . , 15(158), 59(99), 132, 133, 182(83), 204 Immer, H., 195(106), 201(106), 205 Inone, S., 26(56), 131 Inoue, S., 185(92), 204, 486(129), 510 Inubushi, Y., 475(80), 508 Ionescu-Matin, E., 336(177), 337(177), 443 Ireland, R. E., 163(46), 199(46), 203 h i e , H., 429(227a), 444, 502(186, 187), 512
603
AUTHOR INDEX
Irikawa, H., 472(69, 70, 71), 473(72), 474(74), 508 Isbell, H., 536(263, 265), 538(277), 572 (265, 277), 586 Ishii, H., 506(206), 512 Iskandarov, S., 486(127, 128), 510 Ismalov, Z. F., 460(21), 507 Israilov, I. A., 337(227b), 444 Ito, S., 137(8, l l ) , 138(11), 142(8), 202 Ivanov, L., 337(226), 444 Ivanova, L. B., 337(228), 444 Iverach, G. G., 162(43), 203, 345(49), 350 (1, 49), 356(49), 358(49), 362(49), 345 Iwai, I., 202(113, 114, 115, 116, 117, 118, 119), 205 Iwasa, J., SO(l08,) 123(108), 127(108), 132, 335(228a, 228b), 444
J Jackson, A. H., 350(231), 356(229), 358 (231), 359(229, 231), 362(229, 230, 231), 441 Jackson, J. Y., 552(329), 666(370), 567 (370), 568(370), 569(370), 570(370), 587,588 Jacobs, W.A.,41,42(81),46(77,78,89),52 (94),64(94, 114), 66(80,94), 68(94), 89 (133,134),94(139), 107(145,146,153), 108(145,146), 118(145, 146), 132,133, 143(18, 20, 21), 144(24), 166(48), 167 (51), 171(48),174(61,62), 176(62),190 (18), 202, 203 Jacobsen, E., 540(293), 572(293), 586 Jain, T. C., 195(107), 205 James, L. F., 531 (210, 213), 584 James,R., 363(29, 33), 364(29, 33), 366 (29), 438 Jaminet, F., 566(367), 567(367), 588 Janda, M., 270(124), 327 Jarreau, F. X., 482(107, log), 509 Jeffs, P. W., 351(133, 145), 353(133, 145), 363(133a, 144), 364(133a, 144), 384 (232), 385(232), 442,444,459(18), 469 (62), 507, 508 Jeger, O., 531(180, 181), 532(180, 181), 584 Jennings, J. P., 347(41), 439 Jepsen, E., 528(146), 583
Jepsen, J. B., 567(375), 589 Jeschke, J. P., 42(81a), 57(81a), 132 Jeio, I., 270(128), 327 Jirkovskf, I., 270, 328 John, F. H., 522(67), 581 Johne, S., 486(130), 510 Johns, S. R., 254(71), 275(71), 300(71), 301(71), 326, 455(2), 458(14, 17), 463 (34), 465(45), 466(46), 476(85, 86,88), 480(99, loo), 483(113), 485(123, 126), 488(136), 492(155), 494(160a), 497 (170), 499(177), 505(203, 204), 506, 507, 509,510,511,512 Johnson, E. I., 531 (183), 584 Johnson, L. F., 440 Johnston, V. S., 543(305), 587 Joneja, M. P., 489(138), 510 Jones, R . A. Y., 212(23), 244 Jones, T. H., 522 (67), 581 Jones, T. J., 528(148), 583 Jordan, A., 458(16), 507 Joshi, B. S., 213(29, 30), 214(29, 30), 215(29, 30), 217(29), 221(29, 30), 244, 467 (54), 508 Judah, J. P., 320(225), 330 Julian, P. L., 385(501), 452 Jusiak, L., 335(233), 338(187), 339(187, 233a), 344 (233), 347 (233), 443, 444
K Kaempe, B., 528(142), 583 Kajima, K., 86(132), 89(132), 90(132), 92(132), 133 Kakimoto, S., 182(85), 204 Kakizawa, M., 202(124), 205 Kal&E,V., 270(128), 327 Kalayci, S., 551 (324), 587 Kallos, G., 370(515), 452 Kallos, J., 2(64c), 35(64c), 97(64c), 98(64c), 99(64c), 131 Kamalitdinov, D., 486(128), 510 Kamat, V. N., 467(54), 508 Kamata, S., 182(88),184(88), 187(93), 204 Kametani,T., 335(241,242,244),336(245), 345(241a), 346(241), 347 (241), 358 (250), 362(240, 250), 363(234b), 369 (234, 239a, 245, 246, 247, 248, 249), 270 (239), 384 (234a, 237b, 238, 242,
604
AUTHOR INDEX
243, 244), 385(236), 389(237b, 237c, 238, 242, 243,244), 390(235, 236), 429 (249a), 444, 445, 464 (39), 484 (115), 507, 509 Kemiya, K., 456(6, 7), 506 Kaneko, H., 336(251a), 417(356a), 418 (356a), 419(356a), 420(356a), 448,468 (58), 508 Kaneko, M., 2(54), 26(52, 54), 27(54), 60(104), 132, 185(70), 204 Kan-Fan, C., 478(92), 509 Kao, K., 60(110), 123(110), 127(110), 128(110), 132 Kapedia, G. J., 488(135), 510 Kapil, R. S., 456(9), 506 Kapur, K . K., 247(6), 253(6, 59), 255(6), 274, 309(6), 324, 325, 328 Karplus, M., 11(10), 132 Katarao, E., 475(80), 508 Kataoka, H., 485(125), 510 Kato, A., 348(529), 350(530), 352(530), 353(530),358(530, 531), 362(530), 453 Katritzky, A. R., 212(23), 244 Katsui, N., 15(158), 121(168, 169), 122(170), 126(168, 169, 170), 134 Kaul, P. N., 361(252), 400(430), 402(430), 406(430), 407(430), 409(430), 412 (430), 414(430), 445 Kawakami, E., 202(124), 205 Kawatani, T., 340(8), 435(8), 438 Kawazu, K., 171(57), 172(57),173(59,60), 174(60), 194(59, 60), 195(59, 60), 301 (59), 203 Keast, J. C., 519(25), 580 Keeler, R. F., 531 (213), 532(214), 584 Keely, S. L. Jr., 490(143), 510 Keith, L. H., 35(64e), 59(102a), 60(102a), 85(64e, 102, 131a), 99(64e, 102, 102a), 100(64e, 131a), 101(64e, 131a), l02(64e, 131a), 103(64e, 131a), 104 (64e, 131a), 106(64e, 131a), 131, 132, 133, 175(66a), 204 Kelly, R. B., 429(61a), 439 Khaimova,M. A., 117(162),120(165a),123 (165a), 128(165a),134 Khan, Z. M., 236(10a), 238(10a), 243 Khmel, M. P., 256 (92), 326 Kidd, A. A., 528(132), 582 Kier, L. B., 370(253, 330, 494), 371(253, 330, 495), 376(253, 330, 331, 495), 445, 447, 452
Kikuchi,T.,348(529),369(239a),370(239), 384(234a, 238), 389(238), 444, 445, 453, 456(6, 7), 464(39), 506, 507 Kim, J. H., 496(165), 511 Kim, K. L., 490(144), 510 Kimura, Y., 495(161), 511 King, J. F., 137(8), 142(8), 202 King, M. L., 345 (278), 446, 504 (196), 512 Kingsbury, J. M., 528(128), 530(128), 532 (128), 582 Kinstle, T. H., 364(542), 366(542), 453 Kirby, A. J., 363(34), 364(34), 438 Kirby, G. W., 26(43), 131, 340(36), 348(32), 349(31, 35), 350(206, 207, 208, 209), 351(207, 208, 209), 353 (203), 356(27, 28), 359(27), 360(27), 362 (27, 28, 36, 208), 363 (29, 33, 34, 36), 364(29, 33, 34), 366(29, 36, 255), 376(32),3 9 2 ( 3 2 ) , 4 3 2 ( 3 1 , 3 2 ) , 4 3 8 , 4 3 9 , 444, 445, 494(160), 511 Kirk, H., 522 (64), 581 Kiryakov, N. G., 463(33), 507 Kisaki, T., 491 (147), 510 Kiselev, V. V., 342(256), 350(256), 445 Kishi, T., 208(9, lo), 223(9), 224(9), 225(9), 228(9, lo), 230(16), 231(10), 232(10), 233(10), 235(10), 243 Kishi, Y., 486(129), 510 Kishimoto, T., 429(227a), 444 Kitzsato, Z., 359(259), 385(189), 388(257, 258), 443, 445 Kitova, M. S., 463(33), 507 Kiyamitdinova, F., 248(21), 249(24), 250 (21), 255(24), 257(24), 258(21, 24), 324, 481 (104), 509 Klasek, A., 247(10), 251(38), 256(38), 274 (141), 311,324, 325,328,383(222),403 (259a), 444, 445 Klee, W., 359(260), 361 (260), 445 Klein, F. K., 466(48, 49), 508 Kleinschmidt, G., 340 (261, 262), 343 (264), 366(263, 265), 445 Klementschitz, W., 566(373), 567 (373), 568(373), 569(373), 572(373), 588 Klendshoj, N. C . , 549, 571 (322), 587 Klyne, W., 212(24), 244, 347(41), 396(78), 397(78), 439, 440 Knabe, J., 345(267), 445 Koch, J. H., 527(118, 119), 582
605
AUTHOR INDEX
Kochetkov, N. K., 260(106), 266(111), 270,276(144, 145), 286,287,302(144), 327,328 Kodaira, S., 385(367), 395(366, 367), 396(367, 368), 397(367, 368), 448 Kohli, J. D., 16(16), 130 Koizumi, S., 495(161), 511 Kollmar, H., 392(167), 443 Kolonitz, P., 497 (167), 511 Komaki, T., 506(206), 512 KompiE;, I., 253(65), 255(65, S O ) , 256(65), 326 Kondo, H., 345(268), 445 Kondo, T., 345(268), 445 Konig, K., 567 (374), 568(374), 588 Konovalova, R. A., 26(53), 73(125), 99 (142), 100(143), 120(143), 131, 133, 254(69), 257(96), 262(96), 281(150), 286(160a), 288(160a), 305(187), 315, 326, 327, 328, 329,340(269), 341 (269), 342(256),345(551), 350(231,256), 364 (269), 4%7(269),445, 454 Koretskaya, N. I., 253(63), 254(70), 256(63), 273(63, 70), 274(70, 288, 293, 309, 311, 313, 314), 326, 328, 329 Korth, T., 211 ( s l a ) , 244 Kosak, A. I., 466(50), 490(50), 508 KovBf, J., 396(79), 397(79), 440 Kowala, C., 499(177), 511 Kowalewski, Z., 337(176), 426(176), 443, 481 (103), 509 Kozuka, M., 350(530), 352(530), 353(530), 358(530, 531), 362(530), 453, 489 (139), 510 Kozyreva, 0.V., 253(61), 256(611), 311 (611), 326 Koyama, T., 182(89), 204 Kray, L. R., 270(121), 327 Krishnaswamy, P. R., 460(23), 507 Kritikos, P. G . , 342(270), 446 Kristsyn, A. M., 266(111), 327 Kropman, M., 294(174), 298, 329 Krueger, H., 525(104), 536(266), 582, 586 KubliEek, R., 255(82), 326 Kubo, A., 479 (95), 509 Kubota, S., 341(271), 348(271), 446 Kuchkora, K . I., 504(197), 512 Kuck, A. M., 347(2), 362(2), 435(2), 438 Kuffner, F., 418(502, 503), 419(503), 452 Kugo, T., 345(272), 446
Kuhn, L., 340(88a, 226, 273, 277, 391a), 341(226, 273, 274, 276, 277, 390, 391a), 344(273), 349(275), 350(391), 359(390, 391), 362(275), 366(275), 398(397a), 400(88a, 226), 400(226), 412(889, 226), 414(88a, 226), 415 (226), 440, 444, 446, 449 Kulakov, V. N., 260(106), 276(145), 302, 327, 328 Kumar, B., 202(130), 205 Kumari, S., 253(59), 325 Kumra, S. K., 213(31), 223(31), 244 Kunimatsu, Y., 182(89), 204 Kunitomn, J., 345(532), 346(277a), 446, 453 Kuntze, F., 359 (168), 443 Kupchan, S. M., 256(85), 320(85), 326, 345(278), 348(271), 446, 501(183), 504(195, 196), 512 Kuriyama, K., 396(368), 397(368), 448 Kuzovkov, A. D., 2(19), 18(19, 24), 20(19, 35), 21(19, 37), 22(38), 24(38), 25(19,37,38), 27(58), 36(58),60(105), 100(144), 101(144), 102(144), 103 (144), 104(144), 106(144), 110(441), 111(144), 117(160, 161), 120(165), 121(24, lei), 123(117), 125(161, 165), 126(24), 130. 131, 133, 134, 137(9, lo), 187(94), 202, 204, 314, 321, 330, 331, 335(402), 337 (402), 339(402), 422(402), 425(402), 449
L Labenskii, A. S., 259(50), 260, 262(50), 325, 327 Labriola, R. A., 335(279), 446 Lahey, F. N., 456(3a), 506 Lalich, J. J., 320(219, 229, 230), 330 Lamberton, J. A., 252(49), 253(49), 254 (71), 275(49,71), 300(49,71),301,325, 326, 455(2), 458(14, 17), 463(34), 465 (45), 466(46), 476(85, 86, 88), 480(99, loo), 483(113), 485(123, 126), 488 (136), 492(155), 494(106a), 497(170), 499(177),505(203,204), 5 0 6 , 5 0 7 , 5 0 9 , 510, 5 1 1 , 5 1 2 Lan, P. K., 371(284), 389(284), 446 Landesman, H., 655(346), 567(346), 568(346), 569(346), 572(346), 588
606
AUTHOR INDEX
Last, H., 497(171, 172), 511 Lavenir, R., 454 Lavie, D., 480(102), 509 Lazur'evskii, G. V., 463(35), 504(197), 507, 512 Leander, K., 471 (66), 475(79), 489(140), 508, 510 Le Count, D. J., 366(46), 439 Ledingham, A. E., 426(324), 447 Lee, Kuo-Hsiung, 376(272a), 446 Leete, E., 366(280), 420(281), 446 Legler, G., 362(537), 453, 467(51), 508 Leisegang, E. C., 307(189), 329 Le Men, J., 502(188), 512 Lenz, G. R., 361(546), 390(282), 446, 453 Leonard, J., 391 (283), 392(283),'446 Leonard, N. J., 169(54), 170(54), 203, 246 (1, 4), 247(1, 4), 248(1, 4), 249(1, 4), 250(1, 4), 251(1), 252(1, 4), 253(1, 4), 254(1, 4), 255(1, 4), 256(1, 4), 257(1, 4), 258 (1, 4), 259 (1, 4), 307 (308), 324, 329, 518(14, 15), 520(15), 529(172, 173), 579, 583 Le Page, R . N., 520(46), 580 Lerner, M., 540 (297), 569 (297), 586 Leschke, E., 531 (206), 584 Letcher, R., 316(202), 330 Leung, A. Y., 468(59), 508 Levchenko, S. N., 286 (156), 287 (158), 328 Levi, A. J., 532(217), 584 Levi, L., 356(351, 357), 588 Levinson, H. S., 202(121, 122), 205 Levy, N., 366(416), 449 Lewandowska-Rogalla, K., 337(176), 426 (176), 443 Lewandowski, L., 531 (188), 584 Li, S. T., 371 (284), 389(284), 446 Light, K. K., 270(120), 327 Likhosherstox, A. M., 260, 266(111), 270(131, 132), ,276(144, 145), 302 (144), 327, 328 Likhosherstov, L. M., 270(131, 132), 328 Lin, K.-S., 396(540), 453 Lin, M.-S., 397(540), 420(342, 344), 421 (342, 343, 344), 429(343, 344a), 447, 491 (150), 511 Linde, H. H. A., 209(18), 243, 446 Linden, E., 124(178), 128(178), 134 Lindert, A., 361 (99), 441
Lindfors, R. 0,, 549, 587 Lindwall, O., 476(87), 509 Lippman, A. E., 166(50), 167(50), 203 Lisbourne, T., 527 (124), 582 Lister, R. E., 537(273, 274), 572(273, 274), 586 Lloyd, J. T. A., 524(101), 581 Lo,S.I., 122(172), 126(172),134,363(114), 364(114), 441 Lo, S. Y., 363(224), 364(224), 444 Lobato, J. B., 542(301), 572(301), 587 Lacke, D. M., 155(36), 165(36), 203 Locket, S., 524(97), 526(97), 529(97), 581 Loder, J. W., 463(36), 507 Loewenstein, A., 529(155), 583 Long, H. C., 526(109), 582 Loo, S. N., 497 (170), 511 Los, M., 12(13), 14(13), 15(13), 16(13), 130 Loudon, A. G., 358(22), 436(22), 438 Loudon, J. D., 526(106, 114), 582 Lovell, C. H., 537(268), 586 Lovenberg, W., 532(221), 585 Lu, C. C., 253(60), 325 Lu, S.-T.,471(65), 491(148), 453, 508, 510 Lubs, H. J., 349(149), 363(149), 364(149), 442 Luckner, M., 476(84), 508 Luff, A. P., 72(119, 120), 133 LukBs, R., 270(124), 327 Lumb, J. W., 528(131), 582 Luning, B., 471(66), 475(79), 489(140), 508,510 Lutomski, J., 481 (103), 509 Lvava, J. L., 336(418a), 450 Lwo, S. Y., 370(515), 452 Lyman, C. M., 532(223), 585 Lynn, E. V., 524(198), 581 Lythgoe, B., 534(246), 585
M McArdle, C., 546(308), 587 Macarie, I., 522(59), 580 McCaldin, D. J., 45(85), 132, 366(45), 439 McCalvin, D. J., 397(57a), 439 McCamish, M., 456(3a), 506
AUTHOR INDEX
Maccio, Z., 463(31), 507 Maccoll, A., 358(22), 436(22), 438 McCoubrey, A., 537 (273), 572 (273), 586 Macdonald, A. C., 421(343), 429(343), 447 McDonald, C. E., 162(43), 203 MacDonald, D. M., 495(162), 511 McDonald, E., 484(116, 117, 120), 510 MachovicovA, F., 361 (371), 448 MacGrath, R. E., 522(68), 581 McGregor, I. S., 529(155), 583 Machata, G., 555(343), 571 (343), 588 Macheboeuf, M., 555(339), 566(339), 567 (339), 568(339), 569(339), 570(339), 588 MacKay, A., 517 (12), 579 MacKay, M. F., 481(106), 484(122), 509, 510 McKenzie, J. S., 319(214), 320(235), 330, 331 McLaughlin, J. L., 468(59), 508 MacLean, D. B., 335(107), 383(107), 384 (107), 421(436a), 429(436a), 441, 450, 468(53), 508 McLean, E., 518(20), 580 McLean, S., 420(342, 344), 421(342, 343, 344), 429(343, 344a), 447, 491(150), 511 McLennan, G. C., 533(231), 585 Mc. L. Mathieson, A., 260(104), 309(104), 327 McMillian, A., 397(415), 449 MacMillan, J., 136(7a), 202 McMillan, J. A., 322, 331 McNally, W. D., 529(158), 583 McPhail, A. T., 464(38), 507 Magat, P. L., 19(31), 20(31), 22(31), 24(31), 25(31), 121 (31), 125(31), 130 Magaztari, A., 522(65), 581 Magee,P. N.,320,330,331,519(26,27), 580 Mahan, J. E., 266(110), 327 Mair, G. A., 32, 131 Majima, R., 2(100), 41(79), 59(100), 60 (lll),132 Majumdar, P. M., 362(106), 441 Majumder, P. L., 208(14), 209(14, 15, 16, 17), 211(14), 243 Makoshi, K., 58(98), 132 Malik, M. S., 153(32), 203 Malik, M. Y., 388(133b), 390(133b), 442, 503(19), 512
607
Malukha, N. N., 316(200), 330 Mamedov, G. M., 18(25), 123(175, 176), 128(175, 176), 130, 134 Manalo, G. D., 208(11), 243 Mandelbaum, A., 366(9, 285), 435(9), 438, 446 Mender, L. N., 481 (105), 509 ManiB, V., 251 (44), 254(44), 255(44), 256(44), 257(44), 325 Manitto, P., 477(90), 509 Manjunath, B. L., 460(23), 507 Man’ko, I. V., 248(20), 320(232), 324, 330 Manley, C. H., 524(88), 581 Mann, I., 340(88a, 393), 341(393, 395), 342(287, 288, 392, 394, 395, 395a, 397), 352(288), 353(288, 395a), 385 (397), 386(397), 398(397a), 400(88a, 118, 286, 383, 392, 396, 397), 401(286, 287), 409(118), 412(88a, 118, 287, 396), 414(88a, l18,286,393,395a), 415 (286), 440,441,446, 449 Mann, J. D., 515(5), 579 Manohar, H., 213(26), 244 Manske, R. H. F., 335(107, 242, 244, 297, 316), 336(297, 318,319, 326,327), 345 (316), 346(242, 244), 347(73), 358 (209), 361 (307), 368(73, 318), 369(73, 305, 313, 318, 319), 370(73), 371(105, 327, 328), 376(105, 311, 328), 379 (328), 383( 107), 384(107,242,244,299, 306,312,315,323,325), 385(300,304a, 310,317), 388(310), 389(242,244,297, 316,321), 391(290,292,307,321), 396 (290, 294, 297, 314), 420(344), 421 (299, 344, 436a), 422(297, 311), 423 (301, 302,304, 305, 307, 308,309,314, 325), 424(289,295,297,310), 425(291, 293,296,297,299,322), 426(303,324), 429(436a), 441,445,446,447,450,494 (194), 511, 532(225), 582(137), 582, 585 Mantle, P. G., 561(184), 512, 528(134), 582 Manzur-i-Khuda, M., 208(5), 243 Marchand, J., 482(169), 509 Margraf, F., 344, 444 Marini-Bettolo, G. B., 503(192, 193), 512 Marion, L., 2(4, 5, 6, 46, 55, 60, 64, 75, 76, 112, 113, 123, 127, 129, 131, 135, 137), 8(3), 10(3, 4), 11(5, 6, 8, 9), 12(5, 13),
608
AUTHOR INDEX
14(13), 15(13, 63), 16(5, 13, 15), 19 (30), 26(46, 55), 27(55,60, 61), 28(46), 29(62), 30(63), 31(63), 32(63, 64), 34 (46, 55, 63), 35(67, 68), 36(68, 80), 39 (135),41(75,76),45(85,86),46(90),54
(76,) 57(90, 112, 113), 60(112), 63 (113), 72(75, 76), 73(123, 127), 74(86, 95, 122), 76(85, 127), 77(86, 129), 78 (95,129), 79(129), SO(127, 129), 81(90, 123), 82(90, 129), 83(131), 84(127, 131), 85(131), 86(132), 89(3, 132), 90 (132), 91(90, 135), 92(132, 135), 93 (135, 137), 94(137), 107(149), 124 (178), 128(178), 130, 131, 132, 133, 134, 390(5, 352), 426(324), 438, 447, 448, 521(56), 527(121), 528(137, 143), 529 (150), 580, 582, 583 Markson, L. M., 320(231), 330, 518(23), 580 Markwood, L. N., 35, 131 Marquis, E., 559, 571 (363), 588 Marsh, C. D., 529(160), 534(240), 583, 585 Marsh, H., 534(240), 585 Marsh, R. E., 213(27), 244 Marshall, M. A., 396(329), 447 Martell, M. J. Jr., 370(330), 371(330), 376(330, 331), 447 Martin, E. W., 19(31), 20(31), 22(31), 24(31), 25(31), 121 (31), 125(31), 130 Martin, H. M., 518(22), 580 Martin, J. A., 350(231), 356(229),358(231), 359(229,231), 362(229,230,231), 439, 444 Martin, R. O., 340(50), 346(50), 366(58, 332), 439, 447 Martin-Smith, M., 345(120), 347(120), 368(120), 441 Marumo, S., 468(55), 508 Masaki, N., 502(187), 512 Masamune, S., 194(102, 103, 104), 195, 201(103, 104), 205, 288, 289(169), 290(169), 291, 309, 329 Mashkovskit, M. D., 321 (244), 331 Maden, E. N., 492(155), 511 Mason, S. F., 371 (333, 334), 376(333, 334), 447, 494(158), 511 Maasagetov, P. S., 117(160,161), 120(165), 121(161), 124(180), 125(161, 165, 180, 182), 128(180), 129(180), 134, 300(183), 305(187), 314, 329, 330, 335
(402), 337(402), 339(402), 422(402), 425(402), 449, 461(26), 464(37), 507 Massingill, J. L., 464(41), 505(41, 198). 507, 512 Masui, T., 348(271), 446 MCttB, C., 251 (43), 325 Mateesku, G . H., 208(1), 243 Mathes, P., 568(373), 569(373), 588 Mathieson, A. McL., 345(153a), 442, 484 (122), 510 Matoba, K., 456(5, 6, 7), 506 Matsumoto, T., 202(123, 124), 205, 275 (142), 283, 286(159, 160), 287(169, 160), 328 Matsunaga, M., 202(124), 205 Matthews, F. B., 526(112), 582 Mattocks, A.R., 247(7), 250(36, 37), 257(95), 274, 276, 286(161), 288, 301,302, 303, 309, 31 1, 319, 320 (216), 321, 324, 325, 327, 328, 329, 330, 331, 520(43), 521(48), 580 MaturovB, M., 338(433), 339(339, 433), 340(433), 341 (339,433, 442), 342(336, 337, 339, 431), 343(336, 337), 348 (341), 352(431), 353(431), 358(335, 431), 363(335), 364(335), 376(429), 377(429), 380(429), 383(429), 390 (117, 336), 391(117, 336, 339), 392 (117, 337, 339), 399(432), 400(337, 338), 403(338, 432), 412(338, 414 (328), 412(427), 418(427), 419(427), 426(336, 433), 427(336, 337, 340), 428 (336), 441,447, 450 Maudgal, R. K., 137(8), 142(8.), 202 May, H. L., 541 (298), 586 Mayo, D. W., 2(36), 19(31), 20(31),21(36), 22(31, 36), 24(31, 36), 25(31, 36), 121 (31), 125(31), 130, 496(164), 511 Mazenko, V. V., 316(200), 330 Meadow, M., 396(541), 453 Meinwald, J., 262(108), 327 Meinwald, Y. C., 262(108), 327 Melchior, H., 333(345), 334(345), 447 Melendez, N., 488(134), 510 Melkumyan, I. S., 127(181), 129(181), 134 Mel-Mathieson, A., 481 (106), 509 Melrose, T. A., 270(114), 311(114), 327 Mendez, A. M., 251(42), 254(72), 325 Men’shikov, G . P., 260 (105), 280 (147), 321 (243, 244), 327, 328, 331
AUTHOR INDEX
Merchant, J. R., 456(9),506 Merck, E.,398, 447 Meyer, C., 494(157),511 Meyer, W.L., 202(121, 122),205 Miana, L.A., 454 Michael, S. J., 535(256),585 Micheel, F.,270(129), 327 Michel, K . H., 480(101),509 Miet, C., 491 (149),510 Miedzobrodzki, K., 524(89), 531 (188), 581, 584 Mijovic, V., 335(195), 337(195),338(195), 339(195), 340(195), 341(195), 342 (195), 343(195), 417(195), 432(195), 443, 533(227, 230), 585 Mikai, M. D., 522 (59),580 Miles, D.H.,202(130), 205 Miller, M. R., 384(325), 423(325),447 Miller, R.A., 208(4),243, 523(82),581 Milligan, J. B.,531 (185),584 Milne, M. D.,532(217), 584 Minatsakanyan, V. A., 338(348), 341 (552, 553), 350(552), 356(349), 362(349), 447, 448, 454 Minker, E., 498(173, 174),511 Minko, A. F., 316(200), 330 Minors, E.H., 523(80), 581 Mirza, R.,396(347), 447 Mislow, K., 441 Mitchell, M. J., 492(152), 503(189), 511, 512 Miyamura, M., 251 (48), 315(48), 325, 487(131),510 Miyano, S., 270(115), 272(135), 311(115), 327,328 Mizusaki, S., 491 (147), 510 Modi, N. J., 521(57), 522(57), 525(57), 529(57),533(57),580 Moffat, A. C., 556(350), 588 Mohelskh, 0..361(371), 448 Moir, R.Y . , 396(419),397(419),450 Mollov, M. M., 479(94), 509 Mollov, N. M., 117(162), 120(165a), 123 (165a),128(165a), 134, 338(350),425 (350),448 Molodozhnikov, M. M., 187, 204 Monache, F.D., 503(192, 193), 512 Monakhova, T. E., 60(105), 123(177) 128(177),132, 134 Monroy, A. C . , 335(132),442 Monseur, X.,482 (log),509
609
Montidome, M., 251(39), 254(39, 72), 255(39, 72), 325, 326 Moon, B. J., 420(134a), 442, 462(28), 499(176),507, 511 Moore, R. M., 527(118,120),582 Moran, E.A., 528(139), 583 Morimoto, Ki, 539(293),571 (283),586 Morin, R. D.,543 (305),587 Morio, S. I., 2(100), 41(80), 59(100), 60 (103),132 Morozumi, S., 385(366, 367), 395(366, 367),396(365,366,367,368),397(365, 366, 367, 368), 448 Morrison. J. D., 253(51),269(51),325 Mortimer, P.H., 247(15), 257 (15).324 Mosbauer, S.,282(162), 329 Moser, C., 479(96),482(110),509 Mosettig, E., 160(41, 42), 203, 384(504, 506), 385 (169, 505, 507), 386 (leg), 443,452 Moss, M. S., 552(329),556(370), 558(361), 568(370), 569(370), 570(370), 572 (370),587, 588 Mothes, K., 343 (193, 362), 366 (265,351). 400(193), 412(193), 414(193), 443, 445,448 Mottus, E. H.,390(352),448 Moynehan, T.M., 212(23),244 Moyse, H.,539(286), 586 Moza, B. K . , 208(3), 243, 343(336), 390(336), 391 (336), 426(336), 427 (336),428(336),447 Moze, P. N., 495(163), 511 Mukhamedova, K. S., 459 (19), 497 (166), 51 1 Mukhamedzhanov, S. Z., 459(19), 507 Mukherjee, B.,208(8), 243 Mukherjee, R., 362(106), 441 Muller, D.,391(196), 392(196),443 Mumford, J., 129(156),583 Munakata, K.,468(55),508 Munier, R.,555(339), 566(339), 567(339), 568(339),569(339), 570(339), 588 Munro,M. H.G . , 483(114),484(117,121), 509,510 Murase, N., 389(445a, 445b), 390(445a, 445b),450 Murav’era, D. A., 253(67), 255(67), 256(67),326 Murphy, J. W., 342(405),385(405), 44.9 Murrill, S. J. B., 420(281), 446
610
AUTHOR INDEX
Musso, H., 347(353), 349(363), 358(353), 432 (363), 448
N Nabors, J., 202(130), 205 Nadeau, G., 566(369), 567(369), 568(369), 569(369), 588 Nagai, U., 26(52), 60(104), 131, 132, 177 (70), 185(70), 204 Nagai, Y., 346(277a), 446 Nagarajan, K., 210(20), 243 Nagarajan, S., 248(18), 249(27), 324, 325 Nagata, W., 190(98), 191, 205 Nair, M. D., 271, 272(135), 328 Nakamura, S., 489(137), 510 N a h u m , T., 366(525), 453 Nakano, T., 360(354), 448, 474(75), 500 (18), 508, 511 Nakasato, T., 352 (355,356), 448,488 (133). 510 Nankivell, J. H., 528(147), 583 Namba, K., 448 Naoi, F., 335 (363a), 448 Narato, S., 60(108), 123(108), 127(108), 132 Narisuda, M., lQO(97, 98), 191(99, loo), 205 Naruto, S., 335(228a, 228b), 336(251a), 417(356a), 418(356a), 419(356a), 420 (356a), 444, 445, 448, 468(58), 508 Natsume, M., 86(132), 89(132), 90(132), 92(132), 133, 142(15), 177(74), 179 (74), lSZ(86, 88, 90, 91), 183(90), 184 (88,91), 187(93), 202,204,476(81,82), 508 Nelson, D. A., 531 (207), 584 NBmeEkovB, A., 338 (359), 361, 433), 339(357, 359, 361, 433, 434, 436), 340(433), 341 (433), 385(358), 386 (358), 399(359, 432, 435), 401 (367, 434), 403(360, 432), 412(367, 434), 414(357,360,434), 426 (433), 427 (359, 361), 448, 450 Neubauer, D., 343(362), 448 Neuss, N., 208(214), 243 Newberne, P. M., 320(262), 331 Newman, L. F., 522(60), 580 Ng, Y. L., 436(7), 438 Nicholson, A. J. C., 253(51), 269(51), 325
Nicholson, J. A., 536(247), 585 Nickolls,L.C.,649(314), 572(312,313),587 Nielsen, B., 340(88a, 89, go), 366(91), 400(88a), 412(88a), 414(88a), 440 Niggli, A., 238(34), 244 Nijland, M. M., 340(363), 448 Nikishchenko, T. K., 129(183), 134 Nishikawa, K., 251 (48), 253(62), 315, 325, 326 Nishikawa, M., 456(6, 7), 487(131, 132), 506,510 Niuwland, I. C. H., 526(116), 582 Noble, A. C., 345(180), 443 Noguchi, I., 335(244), 346(244), 362(240), 384(243, 244), 389(243, 24l), 445 Nomura, K., 349(100), 350(100), 356(100), 362(100), 441, 503(189), 512 Nordman, C. E., 213(31), 223(31), 244 Nordskog, A. W., 528(136), 582 Norin, T., 476(87), 480(101), 508, 509 Novak, I., 498(173, 174), 511 Novhk, V., 376(103), 441, 494(157a), 511 Novelli, A., 256(84), 326 Nowacki, E., 316(201), 330 Nuriddinov, R. N., 486 (127), 510 Nusshag, W., 631 (189), 584 Nye, E. R., 532(220), 585
0 Occlowitz, J. L., 458(17), 480(99), 507, 509 Ochiai, E., 2(54), 26(52, 54, 56), 27(54), 69(101), 60(101, 104, 107), 131, 132, 133, 138(12), 177(68, 69, 70, 71, 72, 73, 74), 178(72, 76), 179(74, 77). 185(70), 185(92), 202, 204 O’Donovan, G. M., 253(53), 264(68, 76), 257(68), 308(76), 314(68), 325, 326 Oestreicher, P. B., 666(351), 588 Ogilvie, D. D., 523(84), 531(187), 581, 584 Ogiso, A., 202(113, 114, 116, 116, 117, 118, 119), 205 Ohashi, M., 348 (364), 362 (364), 397(364), 448 Ohkubo, K., 335(241,242,244), 346(241a), 346(241,242,244), 347(241), 384(242, 243, 244), 389(242, 243, 244), 445
AUTHOR INDEX Ohta, M., 385(366, 367), 295(366,367), 396 (365,366,367,368), 397(365,366,367, 368), 448 Oka, K., 499(175), 511 Okamoto, T., 2(54), 26(52, 54,56), 27(54), 59(101), 60(101,104,107), 86(132), 89 (132), 90(132), 92(132), 131, 132, 133, 138(12),142(15), 177(68,69,70,71,72, 73, 74), 178(72, 76), 179(74, 77), 182 (87, 88), 184(88), 185(70,92), 187(93), 202, 204, 475(81, 82), 508 Okamoto, Y., 456(6, 7), 506 Oki, M., 308(192, 193), 329 Okuda, S., 485(125), 510 Okuno, T., 202(124), 205 Oleksandruk, A. M., 316(200), 330 Omi, J., 202(124), 205 Onaka, T., 475(81, 82), 508 Onda, M., 335(336a), 392(363, 363c), 448 Ono, M., 340(8), 435(8), 438 Onouchi, T., 138(12), 202 Oppenheim, P., 397(152), 442 Orazi, 0. O . , 463(30), 507 Orekhov, A. P., 120(143), 133, 281(150), 328,340(269), 341 (269), 345(551), 364 (269), 427(269), 445, 454 Oregcanin-Majhofer,B., 270(122,123), 327 Orgell, W. H., 531 (182), 584 Orr, A. B., 516(7), 579 Orr, D. E., 495(162), 511 Ortiz, V. Z., 538(279), 572(279), 586 Osaki, K., 456(6, 7), 502(187), 506, 512 Ose, S., 448 Othman, A. A., 202(120, 136), 205 Otto, J., 549(311), 587 Ownbey, G. B., 448
P Pachler, K., 435(17), 436(17, 18), 438, 448 Pachler, K. G . R., 360(370), 362(17, 18, 370), 448 Page, J. E., 18(20), 130 Pai, B. R., 208(12), 209(12, 15), 210(15), 211(12, 15), 243, 479(98), 509 Pais, M., 482 (107, log), 509 Pakrashi, S. C., 456(11), 506 Pak-tsun Ho, 58(97a), 132 Pal, J. G., 537(270), 586
61 1
Palamareve, M. D., 120(165a), 123(165a), 128(165a), 134 Palmer, K. H., 19(30), 130, 464(38), 507 Panov, P. P., 120(165a), 123(165a), 128(165a), 134, 338(350), 425(360), 448 Papadaki, S. P., 342 (270), 446 Paris, R., 454, 539(286), 586 Parker, H. I., 366(80), 440 Pan-, W. H., 530(169), 583 Parrak, V., 361 (371), 448 Parry, G. V., 364(52), 366(52), 368(52), 439 Paraearathy, P. C., 35(64e), 85(64e, 131a), 98(64e), 100(64e, 131a), 101(64e, 131a), 102(64e, 131a), 103(64e, 131a), 104(64e, 131a), 106(64e, 13Ia), 110 (64e, 131a), 111(64e, 131a), 131, 133, 144(23), 145(23), 146(23), 147 (23), 148(23), 175(66a), 188(96), 190(96), 191(96), 195, 200, 201(96), 203, 204 Paslarascu, N., 208(1), 243 Patel, M. B., 208(6), 243 Paver, H., 516(8), 579 Pavesi, V., 339 (372), 448 Paul, A. G., 468(59), 508 PavlBskoyB, D., 342(337), 343(337), 392(337), 400(337), 427(337), 447 Pearson, J., 535(254), 585 Pedley, E., 524(101), 581 Pegel, K. H., 504(194), 512 Pelhgri, G., 361, 448 Pelletier, S. W., 35(64e), 42(81), 46(78), 52(94), 69(102a), 60(102a), 64(94, 114), 66(80, 94), 68(94), 85(64e, 102, 131a). 98(64e, 102, 102a), 100(64e, 131a), 101 (64e, 131a), 102(64e, 131a), 103(64e, 131a), 104(64e, 131a), 106 (64e, 131a), 107(147, 148, 161, 152), 108(151, 155), 109(151), 110(64e, 131a), 111(64e, 131a). 114(152), 115 (152, 157), 116(152, 157), 118(151), 119(147, 151, 152), 131, 132, 133, 136 (1, 2, 3), 143(18), 144(22, 23), 146(23, 25), 147(22, 23), 148(3, 23, 25), 149 (27, 28), 151(27, 28), 153(34), 155(3, 35, 36), 159(28), 160(28), 163(35), 165 (35,36), 167(2,3,51), 170(55), 171(66, 57). 172(57), 173(59, 60), 174(60, 63, 64), 175(3,63,66a),176(66b), 177(63), lSS(22, 96), 190(18, 22, 96), 191(96),
612
AUTHOR INDEX
194(59, 60), 195(59, 60), 200,201(59), 202,203,204
Pelter, A., 495(163), 511 Pelz, K., 270, 328, 390(374), 448 Perkin, W. H., 391 (201), 392, 396(377), 448
Perkin, W. H. Jr., 359(200), 385(197), 388(375), 391(198, 376), 443, 448 Peterson, P. C., 523(83), 581 Petrova, M. F., 280, 320(232), 328, 330 Pfeifer, S., 338(386), 339(889, 226, 273, 277, 379, 380, 381, 384, 393, 398), 341(226, 273, 274, 276, 277, 386, 390, 391, 391a, 395, 399), 342(218, 219, 220, 287, 288, 386, 388a, 392, 394, 295, 395a, 397, 400), 343(386, 401), 344(382, 385), 349(275), 350 (219, 391), 352(288), 353(288, 395a), 359(220, 390, 391), 362(275), -366 (275), 377(401), 383(526b), 385(218, 397), 386(218, 397), 388(400), 389 (400), 398, 399(378, 382, 386), 400 (88~3,118,226,286,380,383,392, 393, 396, 397, 453), 401 (226, 286, 287, 387, 388, 388a, 398), 403(388), 409(118, 453), 412 (88a, 226,287,387,388,396), 414(88a, 118, 226, 286, 383, 385, 393, 395a, 453), 415(226, 286, 453), 426 (401), 440,441,444,446,448,449,451, 453
Phang, S. E., 551 (325), 587 Philipott, E., 566(367), 567(367), 588 Philipp, A., 58(97a), 132, 195(108) 198 (108), 201(112), 202(137), 205, 206 Phillips, G. F., 542(302), 543(302), 571 (302), 587 Pijewske, L., 396(79), 397(79), 440 Pillai, P. M., 210(20), 243 Pinder, A. R., 136(5), 202, 396(202), 443
Plat, M., 502(188), 512 Platonova, T. F., 2(19), 18(19, 24), 20(19), 21(19, 37), 22(38), 24(38), 25(19, 37, 38), 21(58), 36(58), 60 (105), 100(144), 101(144), 102(144), 103(144), 104(144), 106(144), 110 (144), 111 (144), 117(161), 120(165), 121(24, 161), 123(177), 125(161, 166), 126(24), 128(177) 130,131,132, 133, 134, 335(402), 337(402), 339 (402), 422(402), 425(402), 449
Plattner, P. A., 456(8), 506 Plekhanova, N. V., 250(34, 35), 258(34), 284(34, 35, 153, 154), 307(34, 153, 190), 325, 328, 329 Pohl, L., 348(403), 449 Pohlondek-Fabini, R., 567 (374), 568 (374). 569 (374), 588 Poindexter, E. H., 528(140), 583 Poisson, J., 208(6, 7), 243, 491(149), 510 Poll, E., 522(69), 580 Polonovsky, M., 321, 331, 478(92), 509 Polson, C. J., 522(63), 529(63), 581 Popelak, A., 456(10), 506 Popli, S. P., 456(9), 506 Popp, F. D., 345(180), 443 Porter, L. A., 247(12, 13). 255(13), 309, 324
Posega, R., 385(508), 452 Potemkin, G. F., 120(163, 164), 134 PotBHilovB, H., 253(65), 255(65, 82). 256(65), 326, 338(433), 339(433), 340(433), 341 (433), 399(435), 400 (338), 403(338), 412(338), 414(338), 426(433), 427(433), 447, 450, 484 (119), 510 Potier, P., 478(92), 509 Potter, L. M., 523(76), 581 Pourguier, H., 527 (124), 582 Pousset, J. L., 208(6, 7), 243 Powell, D. E. B., 532(218), 585 Powell, H., 555(341), 588 Prager, R. H., 481 (105), 509 Preininger, V., 338(410, 433), 339(339, 410,433), 340 (410,411,433), 341 (339, 404,409a,410,433), 342(339,405,409, 410, 411, 433), 343(409a), 345(406), 348(406), 360(404), 361 (407,454), 363 (409), 385(358, 405, 408a), 386(358, 454), 388(408), 389(408a, 454), 390 (408a, 485). 391(339, 410), 392(339, 410), 426(410,433), 427 (404,410,433). 447,448,449,450,451,452
Prelog, V., 24,130,270(125),327,531 (180, 181). 532(180, 181), 584 Price, J. A., 488(136), 510 Priestap, H. A., 460(22), 507 Prigozhina, S. M., 320(221), 330 Proskurnina, N. F., 257(96), 262(96), 315, 327
Przyborowske, M., 2(4, 6), 16(18), 27(18), 36(18), 130
AUTHOR INDEX
Przybylska, M., 2(76, 76). 10(4), 11(6), 32, 41(76, 76). 64(76), 72(76. 76). 107(160), 119(160), 130, 131, 133, 176(66, 66). 204 Pua, R., 348(616), 452 Pugh, J. C., 623(86). 581 Pukhalskaya, E. Ch., 320(232), 330 Pybus, J., 622(66), 581 Pyman, F. L., 346(412. 414), 386(413), 396(329), 447, 449
Q Qaaseem, M. A., 202 (136), 206 Quevedo, J., 336(132), 442 Quinlan, J., 628(133), 582 Quitt, P., 160(41, 42). 203
R Rabe, P., 397(416), 449 Rabinovich, M. S., 20(33), 26(63), 99(142), 130, 131, 133 Rac, R., 619(29), 580 Radeleff, R. D., 630(179), 584 Rader, C. P . , 261(107), 327 Radunz, H., 211 ( 2 1 4 , 244 Raffauf, R. F., 249(23), 263(23), 313(23), 324, 349(100), 360(100), 366(100), 362(100), 441, 603(189), 512 Regab, M. S., 446 Rajagopalan, T. R., 263(58), 269(100), 325, 327, 469(60), 508 Rall, G. J. H., 462(29), 507 Ramaohandran, C., 637(270), 586 Ramage, G. R., 270(113), 327, 483(114), 484(116, 117), 120, 509, 510 Ramanathan, V. S., 637(270), 586 Ramaseshan, S., 213(26), 244 Ramuz, H., 340(36), 362(36), 363(36), 366(36, 46), 439 Randall, L. O., 636(264), 670(264), 671 (264), 672(264), 586 Rankin, J. E . F., 628(136), 582 Rao, K. V . , 249(23), 263(23), 313(23), 324 Rao, S. V., 460(23), 507 Rapoport, E., 471(67), 508
613
Rapoport, H., 340(60), 346(60), 360(181), 362(181), 368(181), 362(181), 366(80, 416, 417, 617, 332), 439, 440, 443, 447, 449, 452, 466(48, 49). 508, 637(268), 586 Raamussen, M., 481 (106), 509 Rattle, G., 482(107), 509 Rawlings, A., 624(86), 581 Ray, A. B . , 208(8, 13, 14), 209(14, 16, 17, 17a, 19). 210(19), 211(14), 243, 468(16), 507 Ray, B. J., 320(228), 330 Rebuffo, S., 463 (31), 507 Reddy, J., 320(224), 330, 620(47), 580 Red’ko, A. L., 270(126), 327 Reed, T. A., 390(101, 102). 441 Reeks, H. C . , 632(224), 585 Reeves, W. P., 497(169), 511 Rehse, K., 450 Reichelt, J., 666(366), 667(366), 668(366), 669(366), 670(366), 671 (366), 588 Reichstein, T., 261 (38), 325 Reinecke, M. G., 270(121), 327 Reisch, J., 498(173, 174), 511 Reti, L., 632(216), 639(216), 584 Retief, G. P., 621 (61), 580 Reutel, I., 490(142), 510 Revazova, L. V . , 124(181), 129(181), 134 Reynolds, A. K . , 636(264), 670(264), 671 (264), 672(264), 586 Rheingans, J., 467(61), 508 Rhodes, H. L. J., 340(8), 442 Ribeiro, O., 360(181), 362(181), 368(181), 362(181), 443 Richardson, M. E., 260(32), 312, 325 Richey, J. M . , 211(22), 212(22), 244 Ricroch, M. N . , 478(92), 509 Rinehart, K, L. Jr., 364(642), 366(642), 453, 601 (182), 512 Rising, L. W . , 624(98), 581 Ritohie, E., 478(91), 481(106), 509 Robertson, J., 627(126), 582 Rodger, M. N . , 16(17), 130 Rodriguez, F. Diaz., 261 (42), 264(42), 325 Robinson, C. N., 280(146), 328 Robinson, Sir, R., 316, 330 Robinson, R., 390(3), 391 (3), 396(192, 329, 347, 377). 418(19, 418), 436(3), 436(19), 438, 443, 447, 448, 450
614
AUTHOR INDEX
Rogers, E. F., 95(141), 133, 266(109), 267(109), 268, 327 Rogers, N. A. J., 202(120, 136), 205, 206 Rogers, S. E., 519(25), 580 Rojas, P . , 335(132), 442 Rondest, J., 478(92), 509 Ronsch, H., 342(193), 400(193), 403(80c), 412(193), 440, 443 Rosca, I., 522(59), 580 Rose, A. L., 520(37), 580 Rosendahl, H. V., 124(179), 134 Rostotskii, B. K., 336(418a), 424(21), 436(21), 438, 450, 468(57), 508 Rothlin, E., 540(291), 272(291), 586 Rothschild, M., 500(179), 511 Rovelli, B., 455(3), 506 Rowson, J. M., 208(6), 243 Roy, S. K., 345(120), 347(73,120,122), 362 (121), 368 (73, 120), 369 (73), ‘370 (73),
441 Royce, R., 520(38), 580 Rozwadowska, M. D., 403(520a)’, 452 Rull, T . , 366(9), 435(9), 438 Russell, C. B., 463(35), 507 Russell, R. H., 254(68), 257(68), 374(68), 326 Russo, G., 477 (go), 509 Rutledge, P. S., 160(42), 203 Ruveda, E. A., 417(55), 418(55), 420(55), 439, 460(22), 507 Ruzicka, L., 24(39), 130
S Sabirov, K. A., 505(199), 512 Sadritdinov, F., 320(227), 330 Sadykov, A. S., 459(19), 507 Saki, S., 270(116), 300(116), 311(116), 32 7 Saeki, Y., 474(75), 508 Safe, S., 396(419), 397(419), 450 Saha, S. K., 362(77), 441 Sainsbury, M., 420(134a), 442, 462(28), 499(176), 507, 511 Saito, A., 60(107), Sakabe, N., 187(95), 204, 472(69, 70, 71), 473(73), 502(185), 506(205), 508, 512 Sakai, S., 26(52, 56). 59(101), 60(101, 104, 107), 131, 132, 133, 138(12), 177(70,
71, 73, 74), 179(74, 77, 78, 79, 80, 81). 181(81), 185(70, 92), 202, 204, 479(95), 509 Saksena, A. K., 467(54), 508 Saksi, S., 179(77), 204 Sakurai, H., 472(71), 473(73), 474(74), 506(205), 512 Sallay, I., 386(420), 450 Saleb, M., 484(118), 510 Salgar, S. S., 456(9), 506 Sam, J., 348(420a), 450 Samek, J., 361(407), 449 Samuelsson, G., 532(216), 584 Sanchez, E., 347(2), 348(421), 362(2), 435(2), 438, 450 Sandburg, F., 124(178), 128(178), 134, 476(87), 480(101), 509 Sanders, D. A., 519(32, 33, 34), 580 Sandstede, G., 388(141), 442 Sangster, A. W., 362(422), 450 Rantavf, F., 247(10), 251(38, 44), 253(44, 66), 255(44, 65, 80, 81, 82), 256(44, 65), 257(44), 274(141), 311(10), 319, 325, 326, 328, 330, 338(359, 361, 410, 433), 339(339, 357, 359, 361, 410,433, 435), 340(410, 433), 341 (339, 409a, 410, 433, 442), 342(336, 337, 339, 405, 409, 409a, 410), 343(336, 337), 344(425), 345(406), 348(223, 341, 406), 352(431), 353(431), 358(335, 431), 361 (407), 362(223), 363(335, 409), 364(335), 366 (423), 376(429), 377(429), 380(223, 429), 383(222, 429), 385(358, 405, 408a, 454), 386 (358, 454), 388(408), 389(408a, 454), 390(117,223,336,408a, 423,485), 391 (117,336,339), 392(117,223,337,339, +410), 396(78,79), 397 (78,79,423), 399 (359,432,435), 400(337,338,428,430), 401 (357), 402(430), 403(259a, 338, 360, 426, 432), 406(430), 407(430), 409(430), 412(338,357,430,434), 413, 414(338, 357,360,426,430,434, 539), 415(426), 417 (427), 418 (427), 419 (427), 420(25, 423), 426(336, 410, 433), 427 (336,337,340,359,361,410,433), 428 (336), 429,437(25), 438, 440,441,445, 447, 448, 449, 450, 451, 452, 453, 484 (118, 119, 121), 497(167), 510 Santroch, J., 54(97), 132 Sarfati, R., 482(107), 509
AUTHOR INDEX
Sargent, T., 543(304), 587 Sarkar, S. N., 335(436), 418(436), 450 Sasada, Y., 464(40), 507 Sasaki, K., 187(95), 204, 456(4), 502(185), 512 Sasaki, S., 369(247), 445 Sasaki, Y., 456(6, 7), 506 Sato, F., 484(115), 509 Sato, Y., 89(133), 133 Sauers, R. R., 169(54), 170(54), 203, 391 (283), 392(283), 446 Saunders, J. K., 421 (436a), 429(436a), 450, 485(123), 510 Savchenko, Ya, S., 129 (184), 134 Savitri, T. S . , 208(12), 209(12, 15), 210 (12, 15), 211(12, 15), 243 Sawhney, R. S., 247(8), 248(17), 251(45), 253(8), 258(8), 307(17), 324 Saxton, J. E., 527(117, 122), 528(144, 145), 529(151), 582, 583 Scales, B., 534(246), 585 Schenck, G., 418(509), 452 Schermerhorn, J. W., 370(437), 376(437), 450 Schlemmer, F., 418(509), 452 Schlessinger, R. H., 349(100), 350(100), 356(100), 362(100), 441,503(189), 512 Schlingloff, G., 347(148), 349(148), 356 (148), 362 (148), 442 Schlosser, F. D., 250(33), 312, 318(208), 330 Schmid, H., 208(9, 10, 10e), 213(29, 30), 214(29, 30), 215(29, 30), 217(29), 221 (29, 30), 223(9), 224(9), 226(9), 228(9, lo), 230(10), 231(10), 232(10), 233 (lo), 235(10), 236(10a), 238(10a, 35), 240(35), 243(35), 243, 244, 342(193), 400(193), 412(193), 414(193), 443 Schmid, L., 399(610), 452 Schmidt, E., 389(438), 438 Schmittle, S. C . , 320(230), 330 Schmitz, M. B., 520(36), 580 Schneidewind, U., 335(636), 423(536), 453 Schnoes, H. K., 501 (183). 512 Schoegel, E. L., 556(348), 588 Schoental, R., 249(26), 250(36), 254(74), 302(36), 306, 319(210, 211, 212, 213), 320(215,216,217,218,234,236), 324, 325,326,330,331,519(26,27), 520(42, 43), 521 (52, 64), 580
615
Schofield, K., 212(23), 244, 371 (333), 376(333), 447, 498(158), 511 Schopf, C., 345(441), 370(439), 380, 414(440), 450 Schroder, P., 476(84), 508 Schroter, H. B., 253(65), 255(65), 256(65), 326, 338(433), 339(433), 340(433), 341 (433,442), 426(433), 427(433), 450 Schubert, B., 517(13), 579 Schulze, H., 2(140), 94(138), 95(140), 117(159), 133, 134 Schumacher, H., 566(371, 372), 667(371, 372, 376), 568(371, 372, 376), 569 (371), 588, 589 Schiitte, H. R., 335(443), 344(443), 366(351), 434, 448, 450 Schwarz, H., 390(352), 448 Schweickert, M., 414(440), 450 Schweizer, E. W., 270(120), 327 Sclare, A. B., 523(74), 581 Scopes, P. M., 347(2, 4 l ) , 362(2), 435(2), 438 Scott, A. I., 349(445), 362(445), 450 Sebe, E., 389(445a, 445b), 390(445a, 445b), 450 Seelye, R. N . , 254(68), 257(68), 314(68), 326 Seiber, J. N., 335(518), 371(518, 519), 376(518, 519), 452 Seino, S., 369(248, 249), 445 Seiwerth, R., 270(117, 122, 123, 127), 327 Seka, R., 345(511), 452 Seo, M., 212(25), 244 Seoane, E., 335(446), 417(447), 418(447), 420 (447), 450 Serfontein, W. J., 296(179), 329 Serova, N. A., 260(105), 327 Servis, R. E., 466(50), 490(50), 508 Seshadri, T. R., 253(58), 259(100), 325, 327, 469(60), 508 Shabel’nyuk. V. S., 316(200), 330 Shakirov, T. T., 260(30), 325, 505(199), 512 Shamma, M., 211(22), 212(22), 244, 347(73), 348(364), 352(349), 358(461), 359(451,452), 361 (450), 362(364,448, 449, 450, 451,452), 368(73), 369(73), 370(73, 449), 376(449), 389(449a), 397(364), 400(453), 409(453), 414 (453), 416(453), 441, 448, 451
616
AUTHOR INDEX
Shamsutdinov, R. I., 505(199), 512 Shani, A., 361(546), 453 Shanks, P. L., 520(41), 580 Sharma, B. D., 213(27), 244 Sharma, M. L., 320(228), 330 Sharma, R. K., 251(47), 258(47), 312, 320(228), 325, 331 Sharp, T. M., 73(126), 74(126), 133, 228, 238, 244 Shaver, T., 526(113), 582 Shaw, D. F., 371(328), 379(328), 447 Shealy, A. L., 519(33), 580 Shepherd, D. R. C., 525(102), 581 Sheppard, N., 348(77), 362(77), 440 Shibata, Y., 389 (445b), 390(445b), 450 Shibuya, M., 201(110), 205 Shibuya, S., 336(245), 369(245, 246, 247, 248, 249), 445 Shima, K., 389(237c), 445 Shima, T., 26(51), 32, 34(64b), 131 Shimanouchi, F., 182(82), 204 Shimanouchi, H., 464(40), 507 Shimizu, B., 202(113, 115, 116, 117, 118), 205 Shimizu, M., 475(81, 82), 508 Shin, K. H., 336(326, 327), 371(327, 328), 376(328), 379(328), 447 Shingu, T., 348(534, 535), 453 Shishido, H., 359(259), 445 Shone, D. K., 524(96), 581 Shoolery, J. N., 440 Shreter, A. I., 60(105), 123(177), 128(177), 132,134 J., 543(304), 587 Shulgin, 9. Shun, T., 335(491), 422(491), 452 Shupe, J. L., 531(212, 213), 584 Sichkova, E. V., 120(163, 164), 134 Siddiqui,S.,208(5), 243,456(12),489(141), 506,510 Sim, G. A., 464(38), 507 SimBnek, V., 385(408a, 454), 386(454), 389(408a, 454), 390 (408a), 403(259a), 445, 449, 451 Simic, W. J., 531(205), 584 Simmons, D. L., 2(64c, l l 6 ) , 24(41), 35 (64c), 41 (74),43 (74,82),46(82),47(74, 82), 48(82), 50(74), 51(74), 54(82), 57 (74, 82), 68(74, 116, 117), 71(82, 117), 72( 116), 97(64c), 98(64c), 99(64c), 130,131,132,133 Simpson, C. F., 519(35), 580
Sims, S. R., 523(77), 581 Singh, A., 153(32), 203 Singh, G. B., 320(228), 330 Singh, M. G., 123(174), 127(174), 134 Singh, N., 123(174), 127(174), 134, 153(31, 32, 33), 203 Singh, T., 167(52), 173(58), 203 Sioumis, A. A., 455(2), 458(14), 465(45), 466(46), 476(85, 86), 480(100), 492 (155), 499(177), 505(203, 204), 506, 507, 509, 511, 512 Sitar, J., 343(336), 390(336), 391 (336), 426(336), 427(336), 428(336), 447 Sjoerdsms, A., 532(221), 585 Sjolander, J. R., 276(143), 328 Skaric, V., 2(55, 60), 15(63), 26(55), 27(55, 60), 30(63), 31(63), 32(63), 34(55, 633), 36(60), 131 Skew, E. A., 546(308), 587 Skoldinov, A. P., 257(97, 98), 315, 327 Slater, B. L., 529(153), 583 Slavik, J., 335(455, 456, 473, 480, 482, 491), 336(457, 474, 479, 484, 488, 490), 337(456,458, 461 465, 466, 475, 477, 478, 481, 489), 338(459, 460, 465, 469, 483), 339(457, 462, 468), 340 (277, 457, 468), 341(277, 404, 468), 347, 348(490), 349, 350(460, 463, 464), 351 (483), 359 (460, 463), 360 (404, 483), 371(480, 484), 376(484), 377(129), 383(127, 129), 384(485, 489), 391(128), 392(128), 396(465), 399 (119),400(471), 403(472), 412(119, 471, 472), 414(119, 457), 418(470, 476, 482, 484), 419(458, 477, 482), 422(491), 425(479), 427(404), 441, 442, 446, 449, 451, 452, 477(89), 509 SlavikovB, L., 335(473, 480, 482, 491), 336 (474, 479, 484, 488, 490), 337 (475, 477, 478,481,486,487,489), 338(469, 483), 341(404), 347(479, 480), 348 (490), 351(483), 360(404, 483), 371 (480, 484), 376(484), 383(483), 384 (489), 390(485), 418(476, 482, 484), 419(477, 482), 422(491), 425(479), 427(404), 449, 451, 452, 477(89), 509 Slusarchyk, W. A., 347(73), 348(364), 358(451), 359(451, 452), 361(450), 362(364, 450, 451, 452), 368(73), 369(73), 370(73), 397(364), 440, 448, 451
AUTHOR INDEX
Small, L. F., 340(392), 452 Smit, J. D., 320(40), 580 Smith, C. R., 166(50), 167(50), 203 Smith, H. C . , 523(83), 581 Smith, I., 566(368), 567(368), 588 Smith, J. P. C., 533(229), 585 Smith, L. W., 247(5, 6, 8), 248(5, 16, 17), 249(16, 22), 250(31), 251(8, 22, 46, 47), 252(22), 253(6, 51, 52, 53, 54, 55), 254(46, 76, 77), 255(6, 46), 257(22, 94), 258(8, 46, 47), 266(31, 54, 55), 267(31), 268(52), 269(31, 51, 52), 272(77), 283, 302, 306, 307(17), 308(76), 309(6), 311(46), 324, 325, 326, 327, 329, 471(68), 508 Smith, S., 549(319), 587 Smythe, R. H., 531 (96), 584 Smythies, J. R., 543(305), 587 Snatzke, G., 350(493), 351(493), 356, 358, 363(493), 364(493), 396(78), 397(78), 440, 452, 469(61), 508 Snehalata, S., 248(18), 324 Snyder, J. J., 501(182), 512 Sobolewski, G., 566(369), 567(369), 568(369), 569(369), 588 Soczewinski, E., 27(57), 36(57), 131, 338(187), 339(187, 233a), 443, 444 Soifer, H., 535(255), 585 Soine, T. O . , 370(253, 330, 437, 494), 371(105, 253, 330, 495), 376(1, 105, 253, 272a, 330, 331, 437, 495), 435(1), 438, 441, 445, 446, 447, 450, 452, 494(158), 511 Sojo, M., 506(208), 522 Solo, A. J., 146(25), 148(25), 170(56), 171(56), 174(63, 64), 175(63), 176(66b), 177(63), 203 Sonoda, J., 182(85), 204 Sorm, F., 534(243), 585 Sotclo, A., 371 (183), 443 Southgate, R., 384(59), 385(59), 390(59), 397(53, 57a), 398(53), 417(53), 420 (53), 439, 497(168), 511 Sowter, S., 558(359), 588 Spangler, R. J., 360(99), 442 Sparatore, F., 35(68), 36(68), 131 Spiith, E., 345(496, 499, 511), 359(497), 384(398,504, 506), 385(169, 501, 505, 507, 508), 386(169), 399(510), 418 (500, 502, 503, 509), 419(503), 443, 452
617
Spencer, H., 396(60), 397(60), 439, 483(112), 509 Spenser,I.D.,362(512), 366(512),397(174, 194), 422(512), 432(512), 443, 452 Spingler, H., 456(10), 506 Staples, E. L. J., 516(9), 579 Stas, J. S., 522(62), 549(62), 581 Siastnf, V., 340(411), 449 Stauton, J., 364(52), 366(52), 368(52), 385(59), 390(59), 397(53, 57a), 398 (53), 417(53, 55), 418(55), 420(53, 55), 432(54), 439, 497(168), 511 Stauton, R. S., 418(418), 450 Steel, J. D., 527(118), 582 Steglich, W., 340(36), 349(35), 362(36), 363(36), 366(36), 439 Steinegger, E., 479(96, 97), 482(110), 509 Stenlake, J. B., 345(120), 347(120), 368 (120), 441 Stephenson, C. F., 518(21), 580 Stermitz, F. R., 335(518), 338(513, 514), 346(513,514), 348(514,516), 366(416, 417, 517), 370(515), 371(518, 519), 376(518, 519), 390(514a), 391(514), 449,452 Stern, E. S . , 2(1), 6(1, 2), 11(2), 18(1), 19, 27(2), 40(1), 52(2), 89(1), 129, 136(6), 143(6), 202, 533(235, 236), 534(235, 236), 585 Sternberg, H., 399(510), 452 Stevens, H. M., 549, 571(320), 587 Stevens, R. V., 490(145), 510 Stevens, T. S., 391(201), 443 Stewart, C. P., 549, 587 Stewart, D. K. R., 2(5), 11(5), 12(5), 16(5), 230 Steyn,D. G., 518(17,18), 520(18), 526(18), 579 St. George-Grambauer, K. J., 519(29), 580 Stickel, A., 418(170), 443 Stingl, H. A., 280(146), 328 Stojanac, Z., 16(15), 130 Stoll, A., 527 (123), 582 Stoll, W. A., 540(292), 572(292), 586 Stolman, A., 555(344), 588 Strouf, O., 389(221), 390(221), 392(221), 397(221), 420(221), 444 Strunz, G. M.,505(201, 202), 512 Stuart, K. L., 340(520, 520b), 349(519a), 350(205, 206,207, 208,209), 351(203, 207, 208, 209, 520c), 353(203, 209),
61 8
AUTHOR INDEX
356(28), 358(22), 365(27, 205, 208, 422), 363(104, 104a, 204, 205, 520), 364(204, 520), 366(204), 436(22), 438, 441, 443, 444, 450, 452, 469(63), 470(64), 508, 518(19), 579 Subramanian, P. S., 479(98), 509 Subramanian, S. S . , 248(18), 249(27), 324, 325 Sudzuki, H., 506(5), 506 Suffness, M. I., 256(85), 320(85), 326 Suquhara, T., 363 (234b), 444 Suqasawa,T., 138(12,13,14),139(14),142, 177(68, 69, 71, 73), 179(77), 190(97, 98), 191 (99, loo), 202, 204, 205 Sugaya, H., 389(445a), 390(445a), 450 Suginoine, H., 2(100), 11(7), 15(158), 41(79), 59(99, loo), 93(48), 121(168), 126(168), 130, 131, 132, 134, 182(82, 83, 84, 85, 89), 204 Sugiura, S., 486(129), 510 Sula, B., 251(44), 254(44), 255(44), 256 (44), 257(44), 325,338(410), 339(410), 340(410), 341(410), 342(410), 392 (410), 426(410), 427(410), 449 Sullivan, P. J., 531(211), 584 Sumi, A., 489(137), 492(153), 510, 511 Sunshine, I., 549, 555(345, 346), 556(354), 558, 567(346), 556(354), 567(346), 568(346), 569(346),571(345), 572(345 346), 587, 588 Suszko, J., 403(520a), 452 Sutor, J. D., 260(104), 327 Suzuki, A., 26(50), 131, 202(123), 205 Svoboda, D., 320(224), 330, 520(47), 580 Svoboda, G. H., 208(2), 243 Swan, R. J., 212(24), 244, 347(2), 362(2), 396(78), 397(78), 435(2), 438, 440 Sykulsta, Z., 250(29), 325 Syrneva, Yu. I., 253(61), 256(61), 311(61), 326 Szab6, S., 340(80a), 440 SzBntay, C., 497(167), 511 Szendrei, K., 340(520d), 452, 498(173, 174), 511
T Taber, W. A., 540(290), 570(290), 586 Tagahara, K., 385(523,524),423(523), 453 Taguohi, H., 384(227), 385(521), 388(227, 521), 422(521), 444, 453
Tahara, A., 201(111), 202(133, 134, 135), 205 Tahk, F. C., 490(143), 510 Takano, S., 385(523, 524), 429(249a), 445" Takao, N., 335(523a, 523b), 336(522, 524), 385(523, 524), 420, 423(523), 453 Takao, S., 336(524), 419(522), 423(523), 453 Takido, M., 495(161), 511 Takiguchi, K., 335(363a), 448 Talapatra, S., 16(16a), 130 Talapatra, S. K., 213(32), 244, 362(106), 441, 503(189), 512 Taldykin, 0. E., 256(87), 316(200), 326, 330 Tamaki, E., 491 (147), 510 Tamminen, V., 556(356), 588 Tamura, K., 60(111), 132 Tani, H., 26(52), 60(104), 131, 132, 177(68, 69, 70, 71), 179(77), 185(70), 204, 335(523a, 523b), 336(524), 385 (366, 367, 523, 524), 395(366, 367), 396(365, 366, 367, 368), 397(365, 366, 367, 368), 422(523), 448, 453 Tarpo, E., 208(1), 243 Tatematsu, A., 366(525), 453 Tattersall, R. N., 522(63), 581 Tatum, E. L., 276(143), 328 Taussig, R. A., 523(83), 581 Taylor, H., 340(8), 442, 534(238), 572 (238), 585 Taylor, W. C., 478(91), 481(105), 509 Taylor, W. I., 2(46), 26(46), 28(46), 34(46), 131, 194(101), 195(101), 205, 208(9, lo), 212(24), 213(29, 30), 214(29, 30), 215(29, 30), 217(29), 221(29, 30), 223(9), 224(9), 226(9), 228(9, lo), 230(10), 231(10), 233(10), 235(10), 238(35), 240(35), 243(35), 243, 244, 362(526), 453 Teige, J., 340(398), 401 (398), 449 Teitel, S., 345(92), 440 Telang, S. A., 176(66b), 204 Temperton, H., 53(192), 584 Terblanohe, M., 533 (232), 585 Terent'eva, I. V . , 463(35), 507 Tertzakian, G., 462(27), 507 T6tBnyi, P., 340(526a), 453 Tewari, S. N., 516(6), 579
619
AUTHOR INDEX
Thacker, E. J., 531 (210), 584 Thienes, C. H., 554(334), 587 Theissen, M., 419(171), 443 Thierfelder, K., 345(441), 450 Thomas, D., 341 (399, 400), 343(401), 377 (401), 383(526b), 388(400), 389(400), 426(401), 449, 453 Thomas, G. M., 340(36), 349(35), 362(36), 363(36), 366(36), 439 Thompson, E., 549(315), 587 Thorsen, R., 124(178), 128(178), 134, 476(87), 509 Thum, J., 384(12), 435(12), 438 Timoshenko, A. G . , 316(200), 330 Tistze, L. F., 349(150), 362(150), 442 Toke, L., 497(167), 511 Tokoushige, Y., 177(75), 204 Tolbert, B. M., 537(268), 586 Tomita, M., 345(528, 532), 348(529, 534, 535), 350(530), 352(530), 353(530), 358 (530, 531), 359 (527), 362 (530), 453, 456(4, 6, 7), 489(139), 492(151), 506, 510, 511 Tomko, J., 506(209), 512 Tompsett, S. L., 549, 587 Tookey, H. L., 322, 331 Toube, T., 343(405), 385(405), 449 Trabert, H., 335(536), 422(536), 453 Trevett, H. F., 11(10), 18(20), 19, 130 Trevett, M. E., 11(10), 18(20), 19, 26(29), 130 Trippett, S., 534(246), 585 Trojanek, J., 208(3), 243 Trothandl, O., 385(507), 452 Trotter, J., 421(343), 429(343), 447 Troxler, F., 540(288), 570(288), 571 (288), 586 Trueb, W., 494(157), 511 Tschesche, R., 362(537), 453, 467(51, 52), 490(142),497(171,172),500(178),508, 510, 511 Tschu-Shun, 348 (341), 447 Tsuda, K., 270(116), 300(116), 311(116), 327 Tsuda,Y., 2(113, 123, 129), 8(3), 10(3),45 (86), 46(90), 54, 57(90, 113), 73(123), 74(86, 95), 77(86, 129), 78(95, 129), 79(129), 80(129), 81(90, 123), 82(90, 129), 83,86(132),89(3,132), 90(90,91, 132), 92(132), 130, 132, 133, 475(80), 485(125), 508, 510
Tsyrul’nikova, L. G., 259(50), 262(50), 325 Tucker, G. T., 556(350), 588 Turner, J. C . , 483(112), 509 Turner, R. B., 42(81a), 57(81a), 132
U Uchimaru, F., 475(81, 82), 508 Ulfert, F., 117(159), 134 Umelaws, S., 11(7), 130 Umezawa, S., 182(84), 204 UskokoviO, M., 210(21), 244, 443 Utkin, L., 300(183), 329 Utkin, L. M., 253(61, 63), 254(70), 256(61, 63), 273(63, 70), 274(70), 288(171), 293, 300(182), 309(173), 311(61), 313, 314, 326, 328, 329, 335(402), 337(402), 339(402), 422(402), 425 (402), 449, 461 (26), 507 Utkina, L. M., 259(50), 262(50), 325 Utsui, Y., 335(228b), 444 Uyeo, S., 429(227a), 444, 502(186, 187), 512
V VBcha, P., 338(410), 339(410), 340(410), 341(410), 392(410), 426(410), 427 (410), 449 Vhguifalvi, D., 340(526a), 453 Vaidya, K. A., 531 (182), 584 Valenta, Z., 12, 13(12), 15(12), 43(83), 64(83, 115),130,133, 136(7), 137(7, 8, Il), 138(7, ll), 142(8), 167(7), 175, 176(67), 195(107, 108), 198(108, log), 199(108, log), 201(106), 202, 204,205 Valov, P., 549, 552(318), 553(318), 587 van de Vooren, L. J., 534(245), 585 van Duuren, B. L., 286 (16Ob), 288 (160b), 296(180), 327, 329 Vane, G . W., 371 (333, 334), 376(333, 334), 447, 494(158), 511 Vansoest, H., 534(245), 585 Vartan, C. K., 129(157), 583 Vasil’ev, A. E., 286(156), 287, 328 Vaughan, G. N., 455(3), 506 Vember, P. A., 463(35), 507 Vernengo, M. J., 347(2, 4l), 348(77), 362(2, 77), 435(2), 438, 440
620
AUTHOR INDEX
Vetter, W., 228(10), 230(10), 231(10), 232 (lo), 233 (lo), 235 (lo), 243 Villandy, J., 549(315), 587 Vining, L. C., 540(290), 570(290), 586 Viscontini, M., 270(119), 327 Viswanathan, N., 208(12), 209(12, 15), 210(12, 15, 20), 211(12, 15), 243, 460 (24), 505(200), 507, 512 Vitali, D., 559, 588 Vogel, V. H., 536(263), 570(263), 571(263), 572(263), 586 Vogt, H., 524(93), 581 Vokac, K., 400(471), 403(472), 412(471, 472), 451 Volker, R., 526(108), 582 von Bruchhausen, F., 384(166),. 388(166), 418(94, 95), 419(94), 441, 443 Von Klemperer, M. E., 246(101), 327 von Planta, C., 210(21), 244 Vorbrueggen, H., 160(40, 41), 163(40), 195,203 Voss, A., 384(538), 385(538), 453 Vrublovskf, P., 340(411), 449 Vrublovsky, P., 247(10), 311(10), 324 Vyas, H., 348(516), 452
w Wa, M. T., 503(190), 512 Wachtmeister, C. A., 346(137), 347(137), 349,442 Wada, K., 468(55), 508 Waight, E. S., 501 (184), 512 Wagner, G., 569(378), 589 Waiss, A. C., Jr., 272(137), 328 Wakabayashi, T., 190(97, 98), 191(99, loo), 205 Waksmundzki, A., 338(187), 339(187, 233a), 443, 444 Waldner, E. E., 238(35), 240(35), 243(35), 244 Wali, B. K., 256(88), 326 Waldroup, P. W., 519(35), 580 Walker, J., 335(195), 336(195), 337(195), 339(195), 340(195), 341(195), 342 (195), 343(195), 417(195), 432(195), 443, 533(227, 230), 585 Wall, M. E., 464(38), 507 Walles, W. E., 2(46), 26(46), 28(46), 34(46), 131
WatteravA, D., 413, 414(539), 453 Wani, M. C., 464(38), 507 Warren, F. L., 246(3, 101), 250(32, 33), 255(78), 286(161), 288, 294, 296, 298, 307(189), 312(33, 177), 316(202), 318 (208),319(323), 324,325,326,327,329, 330,331,464(42,43). 465(44), 507 Warren, M. E. Jr., 340(50), 346(50), 366 (332), 439, 447 Warsi, S. A., 454, 463(32), 468(56), 507, 508 Watanabe, Y., 492(152), 511 Waters, J. A., 160(41), 203 Watt, J. M., 523(81), 526(8l), 527(81), 581 Way, E. L., 544(307), 587 Weber, K., 390(173), 443 Weber, P., 479(97), 482(110), 509 Weisbach, J. A., 249(23), 253(23), 313, 324, 349(100), 350(100), 356(100), 362(100), 457(17), 436(17), 438, 441, 492(152), 503(189), 511, 512 Weiss, J. A., 400(453), 409(453), 414(453), 415(453), 451 Weiss, U., 366(37), 439 Weitman, R., 480(102), 509 Weitnauer, G., 358(23), 360(23), 436(23), 438 Wellbourne, R. B., 523(73, 75), 529(73), 581 Wells, R. J., 371(333), 376(333), 447, 494(158), 511 Welters, R., 500(178), 511 Welzel, P., 362(537), 453 Wenkert, E., 350 (181), 352 (181), 358 ( l a ) , 362(181), 443 Wentland, M. P., 490(145), 510 Whaley, W. M., 396(541), 453 Wheeler, D. M. S., 364(542), 366(542), 453 Whelm, J., 429(344a), 447, 491(150), 511 White, E. P., 247(15), 257(15), 304, 324, 329 White, J. I., 338(514), 346(514), 348(514), 390(514), 391(514), 452 Whitehurst, J. S., 371 (333, 334), 376(333, 334), 447, 494(158), 511 Whittem, J. H., 520(50), 580 Wichmann, H., 384(12), 435(12), 438 Wickberg, B., 350(181), 352(181), 358(181). 362(181), 443 Wicks, Jr. G. E., 261 (187), 327
621
AUTHOR INDEX
Wiechens, E., 341 (543), 342 (543), 453 Wiechers, A., 296, 312(177), 329 Wiegrebe, W., 348(403), 358(335), 363(335), 364(335), 447, 449 Wiesner, K., 2(64c, 116), 24(40, 41), 35 (64c), 41(74), 43(74, 82, 83, 84), 45 (87), 46(82), 47(74,82), 45(82), 50(74), 51(74), 52(84, 93), 54(82. 97), 57(74, 82), 58(97a), 64(83, 115), 65(84, 87, 93), 66(84, 87, 93), 68(74, 117), 71(82, 84, 87, 93, 117), 72(116), 97(64c, 93), 98(64c),99(64c),131,132,133,136(7), 137(7, 8, ll), 138(7, ll), 142(8), 166 (49), 167(7, 49, 53), 169(53), 175, 176, 194(101),195(101,107, lOS), 198(108, log), 199(108, log), 201(106,112), 202 (137),202,203,205,206,499(162), 511 Wigderson, F. J., 535(257), 585 Wiggins, A. M., 520(36), 580 Wightman, R. H., 24(41), 68(117), 71(117), 130, 133 Wilcox, E. V., 530(170), 534(241), 583, 585 Wildman, W. C., 526(107, 115), 582 Wilkins, C. K. Jr., 124(178), 128(178), 134 Will, W., 396(153), 442 Williams, D. H., 323, 331, 356 (96), 358(96), 362(96), 370(96), 441, 464 (44), 507 Williams, M., 559(365), 588 Williams, R. T., 544(306), 571(306), 587 Williams, T., 210(21), 244 Willimott, S. G., 531(193), 584 Willis, J. B., 309, 329 Wilkinson, G. R., 556(349), 588 Wilson, B. J., 524(91), 581 Wilson, G. S., 531(184), 584 Wilson, J., 494(157), 511 Wilson, J. M., 348(364), 362(364), 397 (364), 448 Winder, N. T.,524(88), 581 Winkler, W., 339(13, 544), 399(13, 14, 15, 16, 544), 403(16), 435(13, 14, 15), 436(15), 438, 453 Winterfeld, K., 419(172), 443 Winterfeldt, E., 211, 244 Winternitz, F., 478(93), 509 Witthaus, R. A., 515(4), 579 Wolf, M. J., 474(77), 508 Wolff, P. O., 538(280), 571(280), 586
Wollenberg, G., 360(493), 351 (493), 356, 358, 363(493), 464(493), 396(78), 397(78), 440, 452, 469(61), 508 Womack, A. M., 532(219), 585 Wong, C. M., 195(107), 201(106), 205 Wood, P. J., 538(282), 571(282), 586 Worthing, C. R., 418(20), 436(20), 438 Wrede, F., 396(545), 453 Wright, C. R. A., 72(119, 120), 133 Wright, H., 176(66b), 204 Wright, H. N., 549, 587 Wright, I. G., 12(12), 13(12), 15(12), 130 Wright, L., 153(34), 203 Wright, W. G., 323, 331, 464(42, 43), 504(194), 507, 512 Wulf, H., 238(34), 244 Wunderlich, J. A., 253(64), 260(64), 273, 285, 308, 326, 499(177), 509, 511
Y Yagi, H., 358(250), 362(250), 384(234a, 237b), 389(237b), 444, 445, 464(39, 40), 484(115), 507, 509 Yakimov, G. I., 338(350), 425(350), 448, 479(94), 509 Yamada, S., 15(14, 158), 16, 130, 134 Yamaguchi, S., 366(525), 453 Yamamura, S., 472(69, 70), 473(72), 474(74), 508 Yanagiya, M.,202(124), 205 Yang, N. C., 361(282, 546), 446, 453 Yang, P. C., 121(167), 126(167), 134 Yrtng, T. Y., 504(196), 512 Yasuda, S., 202(124), 205 Yates, G., 531 (195), 584 Yates, S. G., 322, 331 Yeowell, D. A., 376(61), 377(61), 380(61), 439 Yo, F., 60(110), 123(110), 127(110), 128 (110), 132 Yokoyama, N., 504(195), 512 Yonezawa, K., 392(363b, 363c), 448 Yoshino, A., 142(15, 16), 182(88), 202, 204 Yuge, E., 346(277a), 446 Yunosov, M. S., 120(165b), 134 Yunusov, M. S., 444, 453, 454 Yunusov, S., 18(21,22, 23), 130, 345(551), 364(269), 454
622
AUTHOR INDEX
Yunusov, S. M., 336(554), 337(227b, 547), 338(549, 550), 377 (550), 383(550), 384(548), 396(554), 424(548, 554), 454 Yunusov, 8. Y., 72(118), 120(163, 164), 133, 134, 460(21), 481 (104), 486(127, 128), 497(166), 507, 509, 510, 511 Yunusov, 8 . Yu., 120(165b), 134, 248(21), 249(24), 250(21, 30, 34, 35), 255(24), 257(24), 258(21, 24, 34), 284(34, 35, 153, 154), 307 (153, 190), 322, 324, 325, 328,329,336(554), 337 (227b, 547), 338 (348,549,550), 340 (269),341(269,552,
553), 350(552),356(349),362(349), 377 (550), 383(550), 384(548), 396(554), 424(548, 554), 427(269), 444,445, 447, 448, 453, 454
Z Zalkow, L. H., 163(44, 45), 202(125, 126, 127, 128, 129, 130), 203, 205 Zalkow, V. B., 202(129), 205 Zenda, H., 182(88), 184(88), 204 Zolotnikskayrt, S. Ya., 124(181), 129(181), 134 Zoutendy, K. J. Y., 255(78), 326
SUBJECT INDEX Botanical names are printed in italics. Prefixes such as aci-, apo-, iso-, nor-, proto-, pseudo-, are printed in italics and disregarded for indexing purposes.
A Acacia berlandieri, 455, 532 Acacia complanuta, 455 Acacia longifolia, 455 Acacia phlebophylla, 455 Acetorphine, 538, 576 0-Acetyldiaboline, 503 Acetylindicine, 301 0-Acetylmonocrotalic acid, 279 0-Acetylsenecic acid, 279 Acronychia haplophylla, 456 Acronychia tetrandra, 456 Acrophyllidine, 456 Acrophylline, 456 Aconitine, 1, 40, 68, 561 dconitum altaicum, 60 Aconitum anthora, 123 Aconitum bullatifolium, 40, 60, 122 Aconitum carmichaelz, 40, 60, 123 Aconitum chasmanthum, 73, 83, 86,93, 533 Aconitum excelsum, 119, 121 Aconitumfalconeri, 123 Aconitum fauriei, 40 Aconitum ferox, 72 Aconitum fLscheri, 40 Aconitum grossidentatum, 40 Aconitum hakusanense, 40 Aconitum heterophyllum, 109, 149, 174 Aconitumjaponicum, 26, 60, 177. 185 Aconitum kamtschuticum, 181 Aconitum koreanum, 60, 123 Aconitum lucidusculum, 26, 181 Aconitum majimai, 185 Aconitum mitakense, 59, 60 Aconitum miyahei, 121 Aconitum mokchangense, 40 Aconitum napellus, 40, 95 Aconitum nemorosum, 123 Aconitum nemorum, 120 Aconitum orientale, 119 Aconitum rotundifolium, 121 Aconitum sachalinense, 59, 181 623
Aconitum sayonense, 60, 177 Aconitum septentrionale, 177 Aconitum spicatum, 73, 78 Aconitum subcuneatum, 59 Aconitum talassicum, 99 Aconitum tasiromontanum, 177 Aconitum variegatum, 123 Aconitum yesoensis, 182 Aconitum zuccarini, 40 9-Acridanone, 478 Acsinatine, 121, 125 Acsine, 121, 125 Acsinidine, 125 Actinodaphnine, 465 Aculeatine, 343, 427 Acutumidine, 456 Acutumine, 456 Adlumidine, 396, 435 Adlumine, 337, 396, 435 Adouetine, 466, 489 Aethwa cynapeum, 522 Agave lecheguilla, 526 Agroclavine, 471 Agrostis alba, 528 Ajacine, 1 , 16, 18 Ajaconine, 135, 150 Alangicine, 456 Alangimarckine, 456 Alangium lamarckii, 456, 457 Alangium s a l v ~ o l i u m ,457 Albertine, 486 Alborine, 342 Aldotripiperideine, 480 Alkaloids color tests, 573 F, 422-427 R, values, 561 UV spectra, 570 Allocryptopine, 335, 340, 343, 391, 463, 497, 504 Alpinigenine, 342, 400 Alpinone, 342, 391
624
SUBJECT INDEX
Alseodrrplme nrcheboldhna, 458 Alstonin mncrophylln, 208, 213, 228, 236, . . 238 ALvtonin muellerinnn, 213 A Intonin scholnris, 208 Alstonatr venenntra, 208, 458 Alstoniline, 207, 211 Alstophylline, 207, 223, 231 Ambaline, 247, 263, 278, 302 Americine, 466 Anikorine, 456 Ammodendrine, 479 Amphetamine, 517, 539, 547, 577 ilmsinckin hispidn, 249, 251, 252 Amsinckin intermedin, 249, 251, 252, 257 Am.sinckia lycopsioides, 249, 251, 252 Amurensine, 342, 343, 377 Amurensinine, 342, 343, 377, 381 Amurine, 341, 342, 363, 458 Amurinol, 363 Amuroline, 343, 351 Amuronine, 343, 351 Anabasamine, 459 .4nnbasis nphylln, 459 Anacrotine, 247, 263, 274, 279, 309 Anagarine, 466 Anatalline, 491 Androcephalum quercqolium, 488 Angelic acid, 277 7-Angelylheliotridane, 247 7-Angelylretronecine, 247 Angularine, 247, 264, 278, 309 Anhnlonium Zewinii, 540 Anhydroignavinol, 135, 177 Anhydromacralstonine, 230 Aniflorine, 458 Anisessine, 458 Anisotes sessiliflorus, 458 Anisotine, 458 Anolobine, 489 Anonaine, 338, 359, 489 Anthotroche pnnnoscl, 460 Anthranoyllycoctonine, 1, 16, 125 Antirhine, 458 Antirrhoerr putaminosa, 458 Apomorphine, 360 Aporheidine, 338 Aporheine, 338, 359 Aquaticine, 247 Aquilegia k w e l i n i , 460 Ayuilegia vulgrwia, 460
Areca catechou, 521 Arecoline, 521 Argemone nenen, 355 Argemone alba, 335, 422 Argemone hispida, 335, 392 Argemone mexicana, 335, 392,533 Argemone munita, 335 A rgemone platycerus, 335 Argemonine, 335, 371,494 Aristolochia orgentinn, 460 Aristolochia indictc, 460 Aristolochine, 460 Armepavine, 341,345 Arundo donux, 460 Astragnlus tibetunus, 461 Atrtluntiu buxifoliu, 500 Atidine, 135, 149 Atisine, 135, 143, 146, 155, 161, 163, 172, 188 Atropu belladonnn, 523 Atropine, 517, 523 Aurotensine, 337, 384, 435 Avadharidine, 1, 16 Avena pubescens, 528 Avicine, 419, 461 Axillarine, 247 Azcarpine, 462 Azimu tetracantha, 462 Azimine, 462
B &lfourodendrom riedellianum, 462 Baptifoline, 466 Benzoic,acid, 277 $'-Benzoyltyramine, 500 Berberastine, 464 Berbenine, 463 Berbericidine, 463 Berbericine, 463 Berberine, 335,336, 338-340, 388, 463 Berberis laurinrc, 463 Rerberis lycium, 463 Bicuculine, 336, 337, 396, 435 HikhacQnitine, 1, 78 Bishaconitine, 123 Risnorargemonine, 335, 371 Bocconio arboreu, 422 Bocconia cordatn, 335, 463 pocconia frutescens, 335 Bocconia latisepuln, 335
SUBJECT INDEX
Bocconia perarcei, 335 13occonine, 335 Uoehmeria pltrtyphyllra, 463 Holdine, 485 Brachyglottine, 247, 264, 277, 304 Brtrchyglottis repnndtr, 247, 257 Bractaminc, 342 Bractavine, 342, 385 Bracteine, 342, 350 Bracteoline, 342, 359 Brasilinecine, 247 Brevicoline, 463 Brevicolline, 463 Bromus inermis, 528 Browniine, 1, 36 Brucine, 525, 561 Brugine, 463 Bruguiera sexangula, 463 Bufotenine, 460, 540 Rulbocapnine, 360 Rullatine, 122, 129 Buphoiae distichre, 526 Buphanine, 527 Buphthulmum speciosum, 464 Buxus sempervireris, 534
C Crccrclicijoridtcnci, 249, 253 Ctccalirc hastcitre, 249 Cacnlirr robusta, 249 Caffeine, 517, 535 Culderonia klugei, 500 Californidine, 336, 371 Callimorpha jacobuerr , 500 Calycanthus occidentcdis, 48 1 Cammoconinc, 123, 128 Campestrine, 247 C(rmptotheccc ciocurninakc, 464 Camptothecine, 464 Canadine, 384, 385 Candicine, 506 6-Canthinone, 506 Capauridine, 384, 435 Capaurimine, 384,436,464 Capaurine, 335,384,435 Capnoidine, 396, 435 Curnegio gigrmtten, 464 Carnegine, 464 Carpaine, 462 Carthamoidine, 247
625
Caryachine, 371 Cascadine, 335, 384, 436 Caseanline, 335, 384, 436 Cascanine, 385 Cnssipouren gcrrardii, 464 Chssipourerc gurnmiJun, 323, 464 Cassipourine, 245, 323, 464 Cmsythn glabellrr., 465 Crcssytha melanthn, 465 Crcssythn racemom, 466 C!ussythicine, 465 Crithta edulis, 539 Ctrthriranthus roseus, 208 Caulophyllum thtrlictroides, 466 Ceanothamine, 466 Ceanothine, 490 Ceroi othus nmericrrnus, 466 Cctr,iiothusinteclerrimus, 4G6, 497 Cephacline, 458 Chesmaconitine, I , 83 Chasmmine, 1, 86 Chasmanthinine, 1, 83 Cheilanthifoline, 384, 435 Chelamidine, 335 Chelamine, 335, 419 Chelerythrine, 335-338, 418, 505, 506, 532 Chelidamine, 335, 419, 422 Chelidonine, 335, 336, 338, 418, 468, 532 Chelidonium rnctjus, 335, 422, 434, 532 Cholilutinc, 335, 336, 338, 418 Chelirubine, 335-338, 418 Chlordiazepoxide, 547 1-Chloro - 2,5 -dihydroxy - 3 -methylhoptan 2,5-dicarboxylic acid dilactono, 278 Chlorpromazine, 547 Cinchoninc, 561 C l f f u s e l l r eheptrrphylltc, 467 Olrtviceps purpureri,, 527 Clivonecic acid, 296 Clovorine, 247, 265, 278, 296, 311 Cocaine, 517, 524, 538, 561 Cocculidine, 468 C'0cculu.u trilobus, 468 Coclaurinc, 345, 458, 466, 505 Codamine, 340,348 Codaphniphylline, 471 Codeine, 340, 365, 517, 525, 544, 547, 561 Codeinone, 340, 365 Colchicine, 484, 526 Colchicum autumnale, 526 Colchicum cwnigerwn, 484
626 Columbamine, 335, 503 Condclphine. 1, 99 Coniine, 522 Cotiium maculatum, 522 Consolida regnlis, 27 Coptisine, 335-343, 388 Coraminc, 384, 424 Cordrastine, 396, 435 Coreximine, 384, 436 Corlumidine, 396, 435 Corlumine, 396,435 Corpaverine, 335, 345, 435 Corybulbine, 384 Corycavamine, 391 Corycavidine, 391 Corycavine, 391 Corycidine, 468 Corydaline, 335, 384 Corydalis ambigua, 422 C'orydulis aurea, 335, 422, 435 Corydalis bulbosa, 335 Corydalis caseam, 335, 423, 436 Corydulis cava, 335, 423 Corydalis claviculata, 336, 423, 436 Corydalis incisa, 336, 423, 437, 468 Corydalis rnicrantha, 423, 436 Corydalis montuna, 423, 436 Corydtdis nakaii, 336 Corydalis nobilis, 436 Corydalis ochotensis, 423, 436 Corydtrlis ochroleuca, 423, 436 Corydalis platycarpa, 423 Corydrrlis pseudoadunca, 424 Corydal is sempervirens, 424, 435 Corydalis sewertzowii, 336, 424 Corydalis sibirica, 424, 435 Corydalis stewartii, 468 Corydalis stricta, 424, 468 Corydalis thalictrifolia, 424, 437 Corydalis tuberosn, 335 Corydalmine, 384, 502 Corydicine, 468 Corydine, 336, 337, 359, 502 Corydinine, 468 Corynoline, 336, 419, 468 Corypalline, 435 Corypalmine, 336, 384 Coryphanthn mncromeris, 468, 505 Coryphrcntha runyonii, 468 Corysamine, 335-388 Corytuberine, 336, 340, 359
SUBJECT INDEX
Coulteropine, 338, 391 Crispatic acid, 278, 282 Crispatine, 248, 263, 278, 306 Crosemperine, 248, 265, 279, 307 Crotalaburnine, 248 Crotalaria agatifolia, 253, 320 Crotalaria anagyroides, 247, 253, 255, 266 Crotalaria aridicola, 253, 268 Crotalaria axillaris, 247 Crotalaria brevifolm, 251, 258 Crotalaria crassipes, 254 Crotalaria crispata, 248, 249, 520 Crotalarin danznrensis, 253, 266 Crotnlaria dura, 520 Crotolaria fulva, 249, 418 Crotalaria giantstricta, 520 Crotalaria globifera, 520 Crotalario goreensis, 253, 267 Crotularia grahumiana, 253 Crotalaria incana, 247 Crotalaria laburniifolia, 247, 248, 259 Crotalaria madurensis, 253 Crotalaria naitchellii, 254 Crotalaria mucronata, 253, 258 Gratcclnria novae-hollandiae, 254 Crotularzu paniculata, 249 Crotularia retusa, 253, 254, 262, 518, 520 Crotalaria rubiginosa, 251, 258 Crotalaria sagittarius, 520 Crotalaria semperjlorens, 248 Crotalaria spartioides, 254 Crotalaria spectabilis, 257, 519 Crotalaria trifoliolinstrum, 253, 268 Crotalaria usaramoensis, 251, 254, 255, 258 Crotanecine, 245, 262,263, 274 Croton, 349 Croton balsamifera, 469 Croton Javescens, 469 Crotalaria labumifolia, 469 Croton linearis, 469 Croton wilsonii, 470 Crotonosine, 350 Crotsparine, 350 Cruentine, 148 Crychine, 371 Crykonosine, 471 Cryptocaria konishii, 471 Cryptocavine, 391, 435 Cryptopine, 335-343, 391, 497 C>yptostylisfulva, 471 Cuauchichicine, 135, 136, 166
SUBJECT INDEX
Cularicine, 336,367 Cularidine, 336,369,435 Cularimine, 369 Curine, 460 Cuseuta mongynu, 471 Cynaustine, 248,263,278,302,471 Cynaustraline, 248,264,278,302,471 Cynoglossophidine, 264 Cynoglossophine, 248,264,277,303 Cynoglossum amabile, 247,248,471 Cynoglossum uustrule, 248,471 Cynoglossum goreensis, 250 Cynoglossum lutifolium, 247,252 Cynoglossum oflccinule, 248,250,317,520 Cynosurus cristutus, 528 Cyprenorphine, 538,577 Cytisine, 485,505,530 Cytisus laburnum, 530
D Ductylis glomerata, 528 Daphmacrine, 474 Daphmacropodine, 474 Daphnimacropine, 474 Daphniphyllamine, 474 Daphniphylline, 471 Daphniphyllum mucropodium, 472 Datura stramonium, 523 Decaline, 474 Decodon verticillatus, 474 Dehydrobrowniine, 1, 36 Dehydrocorybulbine, 388 Dehydrocorydaline,335,388 Dehydrocorydalmine, 388,503 14-Dehydrodelcosine,1, 26 Dehydrodicentrine,492 Dehydrothalicarpine,504 Dehydroorientalinone,342 Dehydrothalictricavine, 388 Dehydrothalictrifoline, 388 Delatine, 135,174 Delavaconitine, 121,126 Delcosine, 1, 26 Delflexine, 124,128 Delfrenine, 124,128 Delorine, 121,126 Delphamine, 1,26 Delphelatine, 1, 19 Delpheline, 1, 19 Delphinine, 1, 64
627
Delphinium aerophilum, 121 Delphinium ajacis, 26, 150 Delphinium ururaticum, 18,123 Delphinium burbeyi, 19,534 Delphinium brownii, 36 Delphinium curdinale, 40,174 Delphinium confusum, 99,125 Delphinium consol&, 26,35,150,534 Delphinium cyphoplectmm, 125 Delphinium da*ycarpum, 129 Delphinium denudatum, 100,153,175 Delphinium elutum, 20 Delphinium jlemosum, 124,129 Delphinium foetidum, 125 Delphinium freynii, 124 Delphinium ilienae, 124 Delphinium lineurilobum, 125 Delphinium nelsonii, 534 Delphinium occidentale, 19,121 Delphinium orientale, 18,27 Delphinium oreophylum, 125 Delphinium poltoratzkii, 125 Delphinium pyrumidutum, 124 Delphinium rugulosum, 123 Delphinium schmulhausenii, 129 Delphinium semibarbatum, 124 Delphinium stuphisagria, 64 Delphinium tricorne, 534 Delphoccine, 121,125 Delpyrine, 124,128 Delsemine, 1, 16,18 Delsoline, 1, 35 Deltaline, 1, 19 Deltamine, 1, 19 7-Demethyl-O-rnethylarmepavine, 345 0-Demethylnuciferine,341,360 Dendramine, 475 Dendrobium a,nosmum, 474 Dendrobium nobile, 475 Dendrobium parishii, 474 Dendroxine, 475 Denudatine, 135,153 Deoxo-N-methyllitsericinone,352 Deoxotetrahydrostepharine, 353 Deoxyaconitine, 1, 60 Deoxyaniflorine, 458 Des-N-methylacronycine,479 Desmethyldecaline, 474 Des-N-methylnoracronycine, 479 Desmethylpsychotrine, 456 Desmethylvertaline, 474
628
SUBJECT INDEX
Desoxyretronecine, 262 N,O-DimethyldeoxohexahydrocrotonoDiaboline, 503 sine, 353 Dicentra canadensis, 424, 435 N,O,o-Dimethylhernovine,470 Dicentra chrysantha, 425, 435 Dimethylmalic acid, 289 Dicentra cucullaria, 336 N,O-Dimethyloridine, 353 Dicentra eximia, 425, 435, 436 N,N-Dimethyltryptamine, 455, 460, 527, Dicentra oregana, 425 540 Dicentra spectabilis, 336, 392 Diphenoxylate, 538, 577 Dicentrine, 359, 492 Diphylline, 337, 338, 418 Dicranostigma .franchetianurn, 336 1,2 - Dithiolane - 3 - carboxylic acid, 463 Domesticine, 337, 359 Dicranostigma lactucoides, 336, 425 Domestine, 359 Dicrotalic acid, 276 Douglasiine, 248 Dicrotaline, 248 Duboisia leichhardtii, 475 Dictamnine, 478, 506 Dihydroamuroline, 353 Dihydroamuronine, 353 E Dihydroanhydromonocrotalic acid, 277 Echimidine, 248, 304, 519 Dihydroergosine, 501 Echimidinic acid, 281 Dihydrogirinimbine, 491 Echinatine, 248,481 Dihydrolinearisine, 353 Echinopsine, 475 Dihydro-N-methylcrotonosinol, 351 Echinops ritro, 475 Dihydronorsalutaridine, 363, 469 Echinops sphaerocephalus, 475 Dihydroorientalinone, 351 Echinorin, 475 Dihydrosalutaridine, 363, 469 Echitamidine, 207 Dihydrosalutaridinol, 363 Echitamine, 207, 211 Dihydrosanguinarine, 335,418 Echitovenidine, 208 Dihydrosenecic acid, 287 Echitovenine, 208 Dihydroxydimethoxyaporphine, 460 2,ll-Dihydroxy- 1,lO-dimethoxyaporEchiumidine, 519 Echiumine, 249, 278, 304 phine, 494 5,6 Dihydroxy - 2,4 -dimethylhexan- 3,5 -di. Echium plantagineum, 519 carboxylic acid, 279 Elaeagnus angustifolia, 481 Elaeocarpine, 476 Dihydroxyheliotridane, 261 2,4-Dihydroxy-3-methylhept-S-ene-2,5-di. Elaecarpinine, 476 Elaeocprpus archboldianus, 476 carboxylic acid, 278 3,4-Dihydroxy-2-methyl-3-pentanecar- Elaeocarpus polydactylus, 476 Elatidine, 18 boxylic acid, 277 2,3-Dihydroxy-3-methylvaleric acid, 277 Elatine, 1, 16 3,4-Dihydroxypentan-2,3-dicarboxylic Eldeledine, 1, 19 Eldeline, 1, 19 acid, 277 Ephedrine, 517, 532, 534 2,4-Di-p-hydroxyphenylcyclobutan1,3dicarboxylic acid, 279 Epiamuroline, 351 4,5-Dimethoxycanthin-6-one, 495 Epiglaudine, 400 Epiguaipyridine, 496 1,5-Dimethoxygramine, 480 7,s - Dimethoxy - 2,3 - methylenedioxyEpiisorhoeadine, 401 benzo[c]phenanthridine, 505 Epiroemeramine, 351 3,4 - Dimethoxy- w - ( 2-piperidy1)acetophe- 3’-Epitubulosine, 456 none, 463 Eremophiline, 249 2,3- Dimethylacrylic acid, 2 77 Ergot, 527 3 Dimethylallyl - 4 - dimethylallyloxy - 2 - Erythrophleguine, 476 Erythroph.leum chlorostachys, 533 quinolone, 480 ~
~
629
SUBJECT INDEX
Erythrophleum guineense, 476 Erythroxylum australe, 476 Erythroxylum coca, 538 Escholamine, 336, 348, 477 Escholine, 336, 425 Eschscholtzin californica, 336, 425 Eschscholtzia douglasii, 336 Eschscholtzia glauca, 336, 477 Eschscholtzia lobbii, 336, 477 Eschscholtzia oregana, 336,477 Eschscholtzidine, 336, 371 Eschscholtzine, 336, 371 Etorphine, 537, 577 Europine, 249 Euxylophora paraensis, 477 Euxylophoricine, 477 Euxylophorine, 477 Evodia alata, 478 Evodia belahe, 478 Evolitrine, 478 Evoprenine, 478 Evoxanthine, 478
I? Fagara leprieurii, 478 Fagara martinicense, 506 Festuca arundinaceae, 322 Festucine, 245 Flavinantine, 363 Flavinine, 363, 469 Flindersine, 480 Floribundine, 341 Floricaline, 249, 265, 313 Floridanine, 249, 265, 313 Floripavidine, 341 Floripavine, 341, 363 Florosenine, 249, 265, 313 Franchetine, 249 Franginine, 489, 497 Frangufoline, 489, 497 Frangulanine, 466 Fuchsisenecionine, 249, 263 Fugapavine, 350 Fulvine, 249, 263, 278, 282, 305 Fulvinic acid, 278, 282 Fumaramine, 337 Fumaria densifiora, 425 Fumaria micrantha, 337, 425, 436 Fumaria o$cinalis, 338, 425, 436, 479 Fumaria parviJora, 337
Fumaria schleicheri, 425 Fumaria vaillantii, 337 Fumaridine, 337, 425 Fumariline, 421 Fumarimine, 425 Fumaritine, 425 Fumarophycine, 338, 479 Fumvalline, 425
G Gardneramine, 479 Gardneria angustQ'olia, 479 Gardneria nutans, 479 Gardnerine, 479 Gardnutine, 479 Garryfoline, 135, 136, 169, 163 Garryine, 166, 191 Gelseniine, 529 Gelsemium elegans, 529 Gelsemium sempervirens, 528 Genista hystrix, 479 Gerrardamine, 464 Gerrardine, 464 Gerrardoline, 464 Gigantine, 464, 505 Glaucamine, 339, 340, 343, 400 Glaucentrine, 435 Glaucidine, 342 Glaucine, 336, 337, 341, 342, 359 Glaucium corniculatum, 337 Glaucium elegans, 337 Glauciumjavum, 337,426,436 Glaucium leiocarpum, 337 Glaucium oxylobum, 337 Glaucium squamigerum, 337 Glaudine, 339, 340, 400 Glauflavine, 337, 426 Glaupavine, 340 Glaziovine, 341, 350 Gloriosa superba, 526 Glycosmis pentaphylla, 479 Gnoscopine, 340, 396 Gramine, 460 Graminifoline, 249 Grantianic acid, 285 Grantianine, 249 Grewia salvifolia, 457 Gymnacranthera paniculatn, 480 Gynotroches axillaris, 480
630
SUBJECT INDEX
H Halosaline, 480 Haloxine, 480 Haloxylon salicornicum, 480 Haplophyllum tuberculatum, 480 Harman, 463,481,492,500 Harmine, 481, 528 Hastacine, 249 Hastanecine, 261, 264 Heleritrine, 463 Heleurine, 249 Heliosupine, 250 Heliotridane, 246, 261 Heliotridine, 250, 262, 264, 301 Heliotrine, 250, 302, 320, 481 Heliotropium dasycarpum, 250 Heliotropium europeum, 519 Heliotropium indicum, 250 Heliotropium olgae, 250, 481 Heliotropium strigosum, 257 Heliotropium supinum, 247 Heptaphylline, 467 Hernovine, 470 Heroin, 517, 536, 561 Heteratisine, 1, 107 Heterophyllidine, 1, 115 Heterophylline, 1, 115 Heterophyllisine, 1, 115 Hetisine, 135, 174 Hexahydrofugapavine, 352 Hexahydropronuoiferine, 353 Hieracifoline, 250 Himgaline, 481 Hodgkinsine, 481 Holcus lanatus, 528 Homaline, 481 Homalium ajricana, 481 Homoamericine, 466 Homochasmanine, 1,93 Homochelidonine, 419, 532 Homolinearisine, 350 Hordenine, 455, 532 Hunnemannia fumariaejolia, 337, 426, 437 Hunnemannine, 337,391,437,482 Hydrastine, 338, 561 a-Hydrastine, 337, 396 p-Hydrastine, 396 Hydrocotarnine, 340 2 - Hydroxy - 3 - acetoxy - 3 - methylpentan. 2,4-dicarboxylic acid, 279 p-Hydroxycinnamic acid, 277
10-Hydroxycodeine, 340, 365 Hydroxygardnutine, 479 Hydroxylycoctonine, 11 10 - Hydroxy - 1,2 - (methy1enedioxy)aporphine, 494 2 - Hydroxy - 3 - methylhept - 5 - ene - 2,6 dicarboxylic acid, 278, 279 2 - Hydroxy - 3 - methyl - 3,5 - hexadiene 2,S-dicarboxylic acid, 278 2 - Hydroxy - 3 - methylhexan - 2,4 - dicarboxylic acid, 278 1 - Hydroxymethyl - 2 - hydroxypyrrolizi dine, 272 1-Hydroxymethylpyrrolizidine,270 Hygroline, 480 Hygrophylline, 250, 264, 278, 293, 311 Hygrophyllinecic acid, 278, 293 Hylomecon vernalis, 337 Hymenocardia acida, 482 Hymonocardine, 481 Hyoscine, 523 Hyoscyamine, 460, 523 Hyoscyamus niger, 524 Hypaconitine, 1, 60 Hypecoum leptocarpum, 337 Hypecoum procumbens, 337 Hypecoum trilobum, 337 Hypognavine, 135, 178 Hypognavinol, 135, 178 Hystrine, 479, 482
I Ignavine, 135, 177 Imiprine, 547 Incanic acid, 279, 284 Incanine, 250, 263, 279, 307 Indaconitine, 1, 72 Indicine, 250, 263, 278, 301 Indicinine, 250, 301 Integerrimine, 251, 255, 257 Integerrine, 467 Integerrinecic acid, 279, 285 Integerrinine, 467 Integerrisine, 466 Intermedine, 251 Inuline, 1, 16 Ipecoside, 482 Isatidine, 251, 254 Isoaconitine, 122, 126
63 1
SUBJECT INDEX
Isoatisine, 135, 143 Isoboldine, 337, 340, 359, 466 Isocorybulbine, 384 Isocorydine, 336, 337, 342, 359, 492, 494, 502 Isocorypalmine, 340, 384,436 Isodelphinine, 121, 126 Isoelaeocarpine, 476 Isofugapavine, 359 Isohypognavine, 135, 185 Isonorargemonine, 371 Isopavine, 377 Isoretronecanol, 261, 264, 271, 301, 471, 487 Isorhoeadine, 338, 339, 342, 401 Isorhoeagenine, 338-400 Isoroemerine, 341 Isosalutaridine, 363 Isoseneciphyllic acid, 295 Isotalatizidine, 1, 99 Isothebaine, 342, 359 Isovenenatine, 207, 209
J Jacobine, 251, 260, 288, 309 Jacodine, 251 Jacoline, 251, 288, 309 Jaconecic acid, 288 Jaconine, 251, 288, 309 Jacozine, 251, 309 Jacularine, 351 Jasminine, 483 Jasminum species, 483 Jatrorrhizine, 503 Jesaconitine, 1, 40 Jobertine, 503 Junceine, 251
K Kaurene, 135, 160 Kobusine, 135,181, 184 IZopsinine, 208 Kreysigine, 483 Kreysiginine, 484 Kukusaginine, 478 Kumokorine, 251, 265,315,487 Kuramerine, 251, 315, 486
1 Laburnine, 252,264, 271, 315,489 Laburnum anagyroides, 530 Lamprolobine, 485 Lamprolobiumfruticomm, 485 Lanigerosine, 252 Lanthopine, 340 Lappeconitine, 1, 118 Lasiocarpic acid, 280 Lasiocarpine, 252, 519 Latericine, 338, 341, 342, 345 Latifolic acid, 277, 282 Latifoline, 252, 263, 277, 304 Lauberine, 463 Laudanidine, 340, 345, 491 Laudanine, 330, 345 Laudanosine, 340, 345 Laudanosoline, 345 Laurelia novae-zelandiae, 485 Laurofolino, 506 Laurolitsine, 485, 494 Laurotetanine, 466, 492 Lauroscholtzine, 336 Leontalbine, 486 Leontice alberti, 486 Leonurine, 486 Lignocaine, 524 Ligularia clivorum, 247 L.zgustrum novoguineense, 483 Linaria species, 486 Lindelofia macrostyla, 252, 259, 262 Lindeloja stylosa, 248, 258, 481 Lindelofidine, 252, 264, 301, 487 Lindelofine, 252 Linearishe, 361 L i p a r k kumokiri, 251, 487 L i p a r k kurameri, 250,486 Liparis nervosa, 253, 487 Liriodenine, 338 Litsericine, 352, 487 Lobelia infata, 521 Lobelia portoricensis, 488 Lobeline, 521 Lolium cuneatum, 322 Lolium perenne, 528 Loline, 245, 322 Lolinine, 245, 322 Longilobine, 252 Lophophora williamsii, 488 LSD, 547 Lucaconine, 1, 26
632
SUBJECT INDEX
Luciculine, 135, 137 Lunasia quercifolia, 488 Lupanine, 530 Lupinus argenteus, 530 Lupinus caudatus, 530 Lupinus leucophyllus, 530 Lupinus perennis, 530 Lupinus sericeus, 530 Lycaconitine, 1, 16, 18 Lycoctonal, 19 Lycoctonine, 1, 10, 125 Lycopsamine, 252 Lycorine, 526 Lysergic acid, 540 Lysergic acid diethylamide, 547 Lythramine, 489 Lythranidine, 489 Lythranine, 488 Lythridine, 474 Lythrum anceps, 488
M Macarpine, 336,338, 418 Machilus acuminatissima, 471 Machilus konishii, 491 Machilus macrantha, 489 Macralstonidine, 207, 238 Macralstonine, 207, 228 Macranthine, 489 Macrodaphnidine, 474 Macrodaphnine, 474 Macrodaphniphyllamine, 474 Macrodaphniphyllidine, 474 Macroline, 215, 231 Macromerine, 464, 468, 505 Macronecine, 261, 264 Macrophylline, 252, 300 Macrosalhine, 207, 235 Macrotomic acid, 281 Macrotonine, 253 Madurensine, 253, 274, 279, 309 Mrtgnoflorine, 337, 340, 360,466, 503 Magnolia grandifiora, 489 Malaxine, 489 Malaxis congesta, 489 Mandragora o f f ~ i n a l i s523 , Marcine, 457 Marckidine, 457 Marckine, 489 Mecambridine, 342, 343, 385
Mecambrine, 338, 341, 350 Mecambroline, 338, 341, 359, 485 Meconopsis heterophylla, 338 Melochia corchorifolia, 489 Melodinus australis, 209 Mesaconitine, 1, 60 Mescaline, 540 Mesembrine, 490 Mesperidine, 538 Meteloidine, 476 Methadone, 578 Methoxyamphetamine, 578 5-Methoxy-6-canthinone,506 Methoxychelidonine, 419 9-Methoxyellipticine, 491 5-Methoxy-N-methyltryptamine, 460 1-Methoxy-13-oxoallocryptopine, 342, 391 0-Methylandrocymbine, 484 0-Methylarmepavine, 345 N-Methylcoclaurine, 345 N-Methylcrotonosine, 341, 350 N-Methylcrotsparine, 350 N-Methylcytisine, 466, 486 4 -Methyl - 2,5-dimethoxyamphetamine,543 N-Methylhernovine, 470 10-0-Methylhernovine, 470 1- (3,4 - Methylenedioxyphenyl) - 2 -methyl 6,7 - dimethoxy - 1,2,3,4- tetrahydroisoquinoline, 471 0-Methylisoboldine, 470 0-Methylisothalicberine, 463 0-Methyllatericine, 345 N-Methyllaurotetanine, 336, 360, 466 8-Methyllevulinic acid, 289 N-Methyllitsericine, 352 N-Methyllitsericinol, 352 N-Methyllitsericinone, 352 Methyllycoctonine, 1, 16, 18, 125 N-Methyloridine, 352 0-Methyloridine, 353 3-Methylpentan-2,4-dicarboxylic acid, 278 N-Methyl-,3-phenethylamine, 532 0 -Methylplatycerine, 37 1 0-Methylpukateine, 485 N-Methyltetrahydro-8-carboline, 480 N-Methyltetrahydrocrotonosine, 353 N-Methyltetrahydroharman, 455 3-Methylthiopropenic acid, 275 N-Methyltrachelanthamidine,487 N-Methyltyramine, 455, 532 Mikanecic acid, 276
633
SUBJECT INDEX
Mikanecine, 261 Mikanoidine, 253, 255 Miltanthine, 341, 350 Mimusops elengi, 644 Minovincinine, 208 Monoacetyldelcosine, 1, 26 Monocrataline, 253, 518, 519 Morphine, 340, 365, 517, 525, 536, 561 Mucronatine, 253, 313 Munitagine, 335, 371 Muramine, 335, 341-343,391 Murraya koenigii, 491 Murrayacine, 491
N Nalorphine, 538, 578 Nantenine, 359, 466 Napelline, 135, 137 Napellonine, 135, 137 Narceine, 340, 396 Narcotine, 340, 396, 561 Narcotoline, 340, 396 h'elumbo, 349 Neoline, 1, 95 Neolitsea, 349 Neolitsea sericea, 488 Neopelline, 1, 95 Neopine, 340,365 Neoplatyphylline, 253, 264, 279, 311 Neoyuzurimine, 472 Nervosine, 253, 264, 315, 487 Nicotiana tabacum, 491, 522 Nigakinone, 495 Nitidine, 419, 461, 506 Noracronycine, 479 Norargemonine, 335, 371 Norarmepavine, 345,458, 491 Norchelidonine, 337, 419 Norisocorydine, 336 Norlaudanosoline, 345 Norloline, 245, 322 Nornantenine, 466 Nornarceine, 340, 397 Nornuciferine, 489 Norpseudoephedrine, 539 Norsinoacutine, 363 Nothaphoebe konishii, 491 Nuciferine, 341, 342, 359, 502 Nuciferoline, 341, 359 Nudaurine, 343, 363,459 Nudicaulinole, 343
0 Obaberine, 463 Ochotensimine, 421,436, 491 Ochotensine, 336,421 Ochrobirine, 391 Ochrosia borbonica, 491 Ocokryptine, 492 Oconovine, 492 Ocopodine, 492 Ocotea, 349 Ocotea macropoda, 492 Onetine, 253,265, 313 Ophiocarpine, 385 Ophiorrhiza japonica, 492 Oreodine, 342, 400 Oreogenine, 342, 400 Oreoline, 121, 125, 342, 352 Oreophiline, 343, 385 Oreophylline, 342 Oridine, 342, 352 Orientalidine, 342, 385 Orientaline, 342, 345 Orientalinol, 350 Orientalinone, 342, 350 Oripavine, 342, 365, 537 Otonecine, 245,265, 273 Otosenine, 253, 257, 313 13-Oxoallocryptopine, 391 13-0xocryptopine, 39 1 13-Oxomuramine, 342, 343, 391 Oxonine, 44 Oxonitine, 41 13-Oxoprotopine, 339, 341, 391 Oxotuberostemonine, 492 Oxyavicine, 419 Oxychelidonine, 419 Oxyheliotridane, 261 Oxynitidine, 419 Oxysanguinarine, 335, 336, 338-343, 418
P Pachycarpine, 505 Pahybrine, 339 Palaudine, 492 Palmatine, 341, 388, 503 Palmeria fengeriana, 492 Palustrine, 494 Papaveraldine, 340, 348 Papaveramine, 340 Papaverine, 338,340,348
634 Papaverubine, 338-343,401,412 Papaver aculeatum, 343, 427 Papaver alboroseum, 342 Papaver alpinum, 342, 426 Papaver anomalum, 343,426 Papaver apulum, 339 Papaver arenarium, 338 Papaver argemone, 339, 426 Papaver armeniacum, 340 Papaver atlanticum, 341, 426 Papaver bracteatum, 342 Papaver californicum, 338, 426 Papaver caucasicum, 341, 427 Papaver commLtatum, 338, 427 Papaver dubium, 338, 427 Papaver feddei, 341 Papaver Joribundum, 341, 427 Papaver fugnx, 341 Papaver glaucum, 340,427 Papaver gracile, 340 Pa.paver heldreichii, 341 Papaver hispidum, 339 Papaver hybridum, 339 Papaver intermedium, 339 Papaver latericium, 341, 427 Papaver litwinovi, 339, 427 Papaver macrostmum, 340, 427 Papaver monanthum, 341,427 Papaver nudicaub, 343, 427, 533 Papaver oreophilum, 342 Papaver orientale, 342 Papaver paeoniflorum, 340 Papaver pannosum, 342 Papaver pavoninum, 339 Papaver persicum, 341 Papaver pilosum, 342 Papaver polychaetum, 341 Papaver pyrenaicum, 343 Papaver rhoeas, 339 Papaver rupifpngum, 342 Papaver setigerum, 340 Papaver somniJerum, 340 Papaver strigosum, 339 Papaver suaveolens, 343 Papaver triniaefolium, 341 Patchoulipyridine, 496 Pavanoline, 343, 426 Peepuloidin, 495 Peganine, 486 Peganum harmala, 528 Pentazocine, 538, 578
SUBJECT INDEX
Persea macropoda, 492 Pethidine, 538, 578 Peyonine, 488 Phalaris arundinacea, 528 Phalaris tuberosa, 527 p-Phenethylamine, 532 Phenothiazine, 547 Phleum pratense, 528 Phoebe clemensii, 494 Physostigma venenosum, 529 Physostigmine, 529 Picrasma ailanthoides, 495 Picrinine, 207 Piper peepuloides, 495 Piperidine, 480 Pithecolobine, 495 Planchonella antheridifera, 252, 253 Planchonella thyrsoidea, 252, 253 Planchonelline, 253, 264, 277 Platycerine, 335, 371 Platynecine, 261, 264 Platyphylline, 253 Platystswbon calqornicum, 337 Pleiocarpamine, 213 Pleiocarpa mutica, 213 Pleurospermine, 463 Pogostemon heyneanus, 496 Pogostemon patchouli, 496 Polygala tenuifolia, 496 Porphyroxine, 340 Prangosine, 496 Procaine, 524 Pronuciferine, 341, 350 Pronuciferinol, 350 Promazine, 547 Protoemetine, 497 Protopine, 335-343, 391, 463, 497 Pseudaconine, 72 Pseudaconitine, 1, 72 Pseudocodamine, 346 Pseudoheliotridane, 261, 270 Pseudokobusine, 135, 181, 184 Pseudolaudanidine, 346 Pseudomorphine, 340, 365 Psilocin, 540 Psilocybe mexicana, 540 Psilocybin, 540 Psychotria ipecacuanha, 482 Pterophine, 253 Pyrrolizidine, 465 Pyrrolizidine alkaloids, 517
SUBJECT INDEX
Q Quinidine, 529, 561 Quinine, 517, 529, 547, 561
R Rauwolja werticillata, 497 Rauwolja womitoria, 208 Reframidine, 338, 377 Reframine, 338, 377 Reframoline, 338,377 Remrefine, 338, 377 Renardine, 254, 257, 279 Reserpine, 208 Reticuline, 335, 338, 340, 345, 458 Retronecanol, 261, 271 Retronecanone, 246,260 Retronecine, 260, 262, 264, 272, 301 Retrorsine, 252-264, 258, 520 Retusamine, 254, 260,265, 278, 308 Retusaminecic acid, 278 Retusine, 254,264, 277, 283, 307 Rhamnus frangula, 497 Rhoeadine, 338-343, 401 Rhoeagenine, 338,341-343, 400 Ribalinidine, 462 Ricinus communis, 5 17 Riddellic acid, 295 Riddelliine, 254 Rivularine, 254 Roemeramine, 338, 351 Roemeria refracta, 338 Roemeridine, 339 Roemerine, 338,341,342,359,360,485,502 Roemeroline, 338, 360 Roemeronine, 338, 351 Rogersine, 360 Romneya coulteri, 338 Romueyine, 338, 346 Rosmarinecine, 261, 264 Rosmarinine, 255 Rotundine, 371 Royline, 1, 10 Ruacridone, 498 Ruta graveolens, 498 Ruta tuberculata, 480 Ruwenine, 255 Ruzorine, 255
S Sachaconitine, 121 Salutaridine, 340, 341, 342, 363
635
Salutaridinol, 340, 363 Samandarone, 498 Samanea saman, 495 Sanguilutine, 338,418 Sanguinaria canadensis, 338 Sanguinarine, 335-343, 418, 463, 499, 532 Sanguirubine, 338, 418 Sarracine, 253, 255 Sarracinic acid, 275 Sceleranecic acid, 278, 296 Sceleratine, 255, 278, 312 Sceleratinic dilactone, 278 Schelhammera pedunculata, 499 Schelhammericine, 499 Schelhammeridine, 499 Schelhammerine, 499 Scoulerine, 336, 340, 385 Scutia buxifolia, 499 Scutianine, 499 Sendaverine, 335, 346 Senecic acid, 279, 285 Senecifolidine, 255 Senecifoline, 255 Senecine, 255 Senecio alpinus, 251, 256 Senecio angulatus, 247, 255 Senecio borysthenicus, 256 Senecio brasdiensis, 251, 254, 255 Senecio burchelli, 518 Senecio cineraria, 256 Senecio cruenlus, 248 Senecio crysanlhemoides, 256 Senecio discolor, 254, 255 Senecio douglasii, 316 Senecio erraticus, 253, 255, 256 Senecio erucqoolius, 255 Senecio francheti, 249, 255 Senecio fuchsii, 249 Senecio grandifolia, 253, 256 Senecio griesbachii, 254 Senecio h a l i m ~ o l i u s255 , Senecio hygrophyllus, 250 Senecio ilicifolius, 518 Senecio incanus, 251, 256 Senecio jacobaea, 500 S e m i 0 kirkii, 254, 257 Senecio kleinia, 251, 254, 255 Senecio wwgniJcus, 251, 256 Senecio mikanioides, 255 Senecio othonnae, 253, 256 Senecio palmatus, 256
636
SUBJECT INDEX
Senecio paludosus, 256 Senecio pampeanus, 256 Senecio platyphylloides, 253, 256 Senecio platyphyllus, 253, 255, 256, 316 Senecio racemosus, 256 Senecio renardi, 254 Senecio rhombifolius, 255, 256 Senecio rivularis, 247, 254 Senecio subalpinus, 251, 256 Senecio triangularis, 256 Senecio viscosus, 251, 256, 257 Senecio vulgaris, 500 Senecionine, 255, 309 Seneciphyllic acid, 278, 295 Seneciphylline, 251, 252, 256, 311 Senkirkine, 254, 257 Sessiflorine, 458 Severinia buxifolia, 500 Sickingia klugei, 500 Silvasenecine, 257 Sinactine, 338, 385 Sinoamidine, 257 Sinine, 474 Sinoacutine, 363 Skimmianine, 479,506 Slaframine, 501 Smirnovine, 461 Solamine, 501 Solanine, 531 Solanum carolinense, 501 Solanum dulcarnara, 531 Solanum elaeagnifolium, 531 Solanum nigrum, 531: Solanum rostzatum, 531 Solanum tripartitum, 501 Solapalmine, 501 Solapalniitine, 501 Solapartine, 501 Solenanthus coronatus, 481 Songorine, 135, 137 Sophora secundifiora, 530 Sophoridine, 486 Sorghum vulgare, 501 Sparteine, 335 Spartioidine, 257 Spectabiline, 257, 263, 279 Sphacelia sorghi, 501 Spiradines, 187 Spiraeajaponica, 135, 187, 501 Spirodane, 501 Squalidine, 251, 257
Stemona tuberosa, 502 Stenine, 502 Stephania, 349 Stephania dinklagei, 502 Stephania glabra, 502 Stephania rotunda, 503, 506 Stepharanine, 503 Stepharine, 350, 485, 502, 503 Stepholidine, 502 Stevane, 135, 160 STP, 543,579 Strigosine, 257, 264, 277, 303 Strychnine, 517, 524, 56L Strychnos gardneri, 503 Strychnos jobertiana, 503 Strychnos mittscherlichii, 503 Strychnos rondeletioides, 503 Strychnos smilacina, 503 Stylomecon heterophylh, 338 Stylophomm diphyllum, 337 Stylophylline, 338, 396 Stylopine, 335, 337-339, 385 Supinidine, 262, 264, 301, 471 Supinine, 257,302
T TalatisEmine, 1, 118, 123 Talatisine, 1, 118 Talatizidine, 1, 99 Tambetarine, 506 Taxine, 534 Teclea natalensis, 503 Tecleanine, 503 Telekia speciosa, 464 Telekine, 464 Tenuidine, 496 Tetrahydroalstonine, 207, 21 1 Tetrahydroberberine, 337, 338, 385 Tetrahydrocolumbamine, 335 Tetrahydrocorysamine, 385 Tetrahydrofugapavine, 352 Tetrahydroglaziovine, 352 Tetrahydroharman, 481 Tetrahydromecambrinole, 352 Tetrahydropalmatine, 385, 436, 463, 502 Tetrahydropronuciferine,353 Tetrahydrosalutaridinol, 363 Tetrahydrostepharine, 353 Tetramethylputrescine, 475 Thalictricavine, 385
637
SUBJECT INDEX
Thalictrifoline, 385, 437 Thalictrirnine, 504 Thalictum dasycarpum, 504 Thalictrum minus, 504 Thaspine, 486 Thebaine, 339, 340, 342, 365 Thelocactus macromeris, 505 Theobromine, 535 Theophylline, 535 Thermopsis dolichocarpa, 505 Thesine, 257, 262, 264, 279, 315 Thesinecine, 257 Thesinic acid, 279 Thesinine, 262, 264, 277, 315 Thesium minkwitzianum, 257, 262 3-Thiomethoxyacrylic acid, 277 Tiglic acid, 277 TMA, 543, 579 Toddalia aculeata, 505 Tomentosine, 253, 257, 313 Trachelanthamidine, 261, 264, 270, 301 Trachelanthamine, 257, 302 Trachelanthic acid, 276, 277 Trachelanthidine, 264 Trachelanthine, 258 Trachelanthus hissaricus, 257, 258 Trachelanthus korolkovii, 257, 258 Trichodesm incanum, 520 Trichodesmic acid, 283 Trichodesmine, 258, 307 1,2,5-Trihydroxy- 3 -methylheptan-2,5 -dicarboxylic acid, 278 Trimethoxyamphetamine, 543 Tritopine, 345 Tropine, 463 Tryptamine, 527 Tuberostemonine, 502, 505 Tubulosine, 456, 489 Turneforcidine, 261 Turneforcine, 258 Tyramine, 455, 532
U Usaramine, 258 Usaramoensine, 258
V Vasicine, 488 Veatchine, 135, 155, 166, 191
Venalstonidine, 209 Venalstonine, 208 Venenatine, 207, 209 Venoterpine, 208, 458 Venoxidine, 207, 209 Veratramine, 532 Veratrum californicum, 531 Vertaline, 474 Villalstonine, 207, 213 Villalstoninol, 213 Villamine, 215 Villoine, 215 Vinca rosea., 208 Viridifloric acid, 276, 278 Viridiflorine, 258, 302, 481 Viscum album, 532
W Waltheria indica, 489 Wilsonirine, 470 Worenine, 388
X Xanthaline, 348 Xylopia papuana, 505
Y Yohimbine, 517 Yuzuramine, 506 Yueurimine, 473
Z Zanthoxylum ailanthoides, 506 Zanthoxylum caribaeum, 506 Zanthoxylum clavaherculis, 506 Zanthoxylum elephantiasis, 606 Zanthoxylum follis oblongo-ovatis,506 Zanthoxylum leprieurii, 478 Xanthoxylum martinicense, 506 Zygacine, 532 Zygadenine, 532 Zygadenus gramineus, 532 Zygadenus nuttalli, 532
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