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The Alkaloids Chemistry and Physiology v18 Volume
The Alkaloids Chemistry and Physiology v18 Volume
The Alkaloids Chemistry and Physiology v18 Volume
Volume XVIII
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THE ALKALOIDS
Chemistry and Physiology
Foutzding Editor
R. H. F. MANSKE
Edited by
R. G. A . RODRIGO
Wilfrid Laurier University
Wrrrerloo, Ontario, Canudu
VOLUME XVIII
1981
ACADEMiC PRESS
NEW YORK 0 LONDON 0 TORONTO 0 SYDNEY 0 SAN FRANCISCO
81 82 83 84 9 8 7 6 5 4 3 2 1
CONTENTS
LISTOF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . vii
PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
CONTENTS OF PREVIOUS VOLUMES. . . . . . . . . . . . . . . . . . . . . xi
V
vi CONTENTS
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
I1. Lactonic Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . 266
I l l . Lactonic Biphenyl Ether Alkaloids . . . . . . . . . . . . . . . . . 281
IV. Simple Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . 284
V. Ester Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . 286
VI . Piperidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . . 288
VII . Quinolizidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . 294
VIII . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
IX . Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
X . Physiological Activity . . . . . . . . . . . . . . . . . . . . . . . 319
References . 3 20
INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
LIST OF CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' contributions begin.
vii
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PREFACE
R. G. A. RODRICO
ix
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CONTENTS OF PREVIOUS VOLUMES
Contents of Volume I
CHAPTER
1 . Sources of Alkaloids and Their Isolation B Y R . H . F. MANSKE . . . . . 1
2 . Alkaloids in the Plant B Y W . 0. JAMES . . . . . . . . . . . . . . . . 15
3 . The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . . . . . . 91
4 . Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . . . . . . 107
5 . The Pyridine Alkaloids B Y LEOM A R I O N . . . . . . . . . . . . . . . 165
6 . The Chemistry of the Tropane Alkaloids B Y H . L . HOLMES. . . . . . . 271
7 . The Strychnos Alkaloids B Y H . L . HOLMES. . . . . . . . . . . . . . 375
Contents of Volume II
8.1. The Morphine Alkaloids I B Y H . L . HOLMES . . . . . . . . . . . . . 1
8.11. The Morphine Alkaloids B Y H . L . HOLMESA N D ( I N PART) GILBERTSTORK 161
9. Sinomenhe B Y H . L . HOLMES. . . . . . . . . . . . . . . . . . . . 219
10. Colchicine BY J . W . COOKA N D J . D . LOUDON. . . . . . . . . . . . 261
1 1. Alkaloids of the Amaryllidaceae B Y J . W. COOKA N D J . D . LOUDON. . . 33 1
12. Acridine Alkaloids B Y J . R . PRICE . . . . . . . . . . . . . . . . . . 353
13. The Indole Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . . 369
14. The Erythrina Alkaloids BY LEOMARION. . . . . . . . . . . . . . . 499
I5. The Strychnos Alkaloids . Part I1 B Y H . L . HOLMES . . . . . . . . . . 513
Contents of Volume IV
25 . The Biosynthesis of Isoquinolines B Y R . H . F. M.4NSKE . . . . . . 1
26. Simple Isoquinoline Alkaloids B Y L . RETI . . . . . . . . . . . . 7
xi
xii C O N T E N T S OF P R E V I O U S V O L U M E S
CHAPTER
27 . Cactus Alkaloids B Y L . RETI . . . . . . . . . . . . . . . . . . . . 23
28 . The Benzylisoquinoline Alkaloids B Y ALFREDBURGER. . . . . . . . . 29
29. The Protoberberine Alkaloids B Y R . H . F . MANSKE A N D WAL.TER R .
ASHFORD. . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
30. The Aporphine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . 119
31 . The Protopine Alkaloids BY R . H . F. MANSKE . . . . . . . . . . . . 147
32. Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€KA N D R . H . F.
MANSKE . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
33 . Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . . . 199
34. The Cularine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . . 249
35 . a-Naphthaphenanthridine Alkaloids B Y R . H . F. MANSKE . . . . . . . 253
36. The Erythrophletcrn Alkaloids BY G . DALMA . . . . . . . . . . . . . 265
37 . The Aconitum and Delphinium Alkaloids B Y E . S. STERN . . . . . . . 275
Contents of Volume V
38 . Narcotics and Analgesics B Y HUGOKRUEGER. . . . . . . . . . . . . 1
39 . Cardioactive Alkaloids BY E . L . MCCAWLEY. . . . . . . . . . . . . 79
40. Respiratory Stimulants B Y MICHAEL J . DALLEMACNE. . . . . . . . . 109
41 . Antimalarials BY L . H . SCHMIDT . . . . . . . . . . . . . . . . . . 141
42. Uterine Stimulants B Y A . K . REYNOLDS . . . . . . . . . . . . . . . 163
43. Alkaloids as Local Anesthetics B Y THOMAS P. CARNEY . . . . . . . . 211
44. Pressor Alkaloids BY K . K . CHEN . . . . . . . . . . . . . . . . . . 229
45 . Mydriatic Alkaloids BY H . R . ING . . . . . . . . . . . . . . . . . . 243
46. Curare-like Effects B Y L . E . CRAIG . . . . . . . . . . . . . . . . . 259
47 . The Lycopodium Alkaloids B Y R . H . F . MANSKE . . . . . . . . . . . 265
48 . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE. . . . . . 301
Contents of Volume VI
1. Alkaloids in the Plant B Y K . MOTHES . . . . . . . . . . . . . . . . 1
2. The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . . . . . . 31
3. Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . . . . . . 35
4. The Pyridine Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . 123
5. The Tropane Alkaloids BY G . FODOR . . . . . . . . . . . . . . . . . 145
6. The Strychnos Alkaloids BY J . B . HENDRICKSON. . . . . . . . . . . 179
7. The Morphine Alkaloids B Y GILBERTSTORK . . . . . . . . . . . . . 219
8. Colchicine and Related Compounds BY W. C . WILDMAN. . . . . . . . 247
9. Alkaloids of the Amaryllidaceae B Y W. C . WILDMAN . . . . . . . . . 289
CHAP^-ER
15. Steroid Alkaloids: The Holarrhena Group B Y 0 . JECERA N D V. PRELOG. 319
16. Steroid Alkaloids: The Solanum Group B Y V. PRELOGA N D 0. JEGER . . 343
17. Steroid Alkaloids: Verarrum Group B Y 0. JECERA N D V. PRELOC. . . . 363
18. The Ipecac Alkaloids B Y R . H . F. MANSKE. . . . . . . . . . . . . . 419
19. Isoquinoline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . . 423
20. Phthalideisoquinoline Alkaloids B Y JAROSLAV STANEK . . . . . . . . . 433
21. Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . . . 439
22. The Diterpenoid Alkaloids from Aconirum. Delphinium. and Garrya Species
B Y E . S. STERN . . . . . . . . . . . . . . . . . . . . . . . . . 473
23 . The Lycopodium Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . 505
24 . Minor Alkaloids of Unknown Structure B Y R . H . F. MANSKE. . . . . . 509
Contents of Volume IX
1 . The Aporphine Alkaloids B Y MAURICE SHAMMA. . . . . . . . . . . 1
2 . The Proroberberine Alkaloids R Y P. W . JEFFS . . . . . . . . . . . . . 41
3 . Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€K. . . . . . . . . 117
xiv CONTENTS OF PREVIOUS V O L U M E S
CHAP TER
4 . Bisbenzylisoquinoline and Related Alkaloids by M. CURCUMELLI-
RODOSTAMO A N D MARSHALL KULKA . . . . . . . . . . . . . . . 133
5 . Lupine Alkaloids BY FERDINAND BOHLMANN A N D DIETER SCHUMANN 175
6 . Quinoline Alkaloids Other than Those of Cinchona B Y H . T. OPENSH.AW 223
7 . The Tropane Alkaloids B Y G . FODOR. . . . . . . . . . . . . . . . . 269
8 . Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae B Y V.
C E R NA ~N D F. SORM. . . . . . . . . . . . . . . . . . . . . . . 305
9 . The Steroid Alkaloids: The Salamandra Group B Y GERHARD HABERMEHL 427
10. Nuphur Alkaloids B Y J . T. WROBEL . . . . . . . . . . . . . . . . . 441
11. The Mesembrine Alkaloids B Y A . POPELAK A N D G . LETTENBAUER . . . 467
12. The Erythrina Alkaloids B Y RICHARD K . HILL . . . . . . . . . . . . 483
13 . Tylophora Alkaloids B Y T. R . GOVINDACHARI . . . . . . . . . . . . . 517
14. The Galbulimima Alkaloids B Y RITCHIEA N D W. C. TAYLOR. . . . . . 529
IS. The Stemona Alkaloids B Y 0 . E . EDWARDS . . . . . . . . . . . . . 545
Contents of Volume X
1. Steroid Alkaloids: The Solanun Group BY KLAUSSCHRIEBER . . . . . . 1
2 . The Steroid Alkaloids: The Veratrum Group B Y S . MORRIS KUPCHAN
A N D A R N O L D W . B.Y. . . . . . . . . . . . . . . . . . . . . . 193
3 . Erythrophleum Alkaloids BY ROBERT B. MORIN. . . . . . . . . . . . 287
4 . The Lycopodium Alkaloids BY D . B . MACLEAN. . . . . . . . . . . . 306
5 . Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . . . . . . 383
6. The Benzylisoquinoline Alkaloids B Y VENANCIO DEULOFEU, JORGE
COMIN,A N D MARCELO J . VERNENGO. . . . . . . . . . . . . . . 402
7 . The Cularine Alkaloids B Y R . H . F . MANSKE. . . . . . . . . . . . . 463
8. Papaveraceae Alkaloids B Y R. H . F. MANSKE. . . . . . . . . . . . . 467
9 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . . . . 485
10. The Simple Indole Bases B Y J . E . SAXTON. . . . . . . . . . . . . . 491
11. Alkaloids of Picralima nitida B Y J . E . SAXTON . . . . . . . . . . . . 501
12. Alkaloids of Mitragyna and Ourouparia Species B Y J . E . SAXTON . . . . 521
13. Alkaloids Unclassified and of Unknown Structure B Y R . H . F . MANSKE . 545
14. The Tuxus Alkaloids B Y B. LYTHGOE . . . . . . . . . . . . . . . . 597
Contents of Volume XI
1. The Distribution of Indole Alkaloids in Plants B Y V. SNIECKUS . . . . . 1
2. The Ajmaline-Sarpagine Alkaloids BY W. I. TAYLOR. . . . . . . . . . 41
3. The 2.2‘-Indolylquinuclidine Alkaloids B Y W . I . TAYLOR. . . . . . . . 73
4. The Zboga and Voacanga Alkaloids B Y W. I . TAYLOR. . . . . . . . . 79
5. The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . 99
6. The Eburnamine-Vincamine Alkaloids BY W. I . TAYLOR. . . . . . . . 125
7. Yohimbine and Related Alkaloids B Y H . J . MONTEIRO. . . . . . . . . 145
8. Alkaloids of Calabash Curare and Srrychnos Species B Y A . R . BATTERSBY
A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . 189
9. The Alkaloids of Aspidosperma. Ochrosia. Pleiocarpa. Melodinus. and
Related Genera B Y B . GILBERT . . . . . . . . . . . . . . . . . . 205
10. The Amaryllidaceae Alkaloids B Y W. C . WILDMAN. . . . . . . . . . 307
C O N T E N T S O F PREVIOUS VOLUMES xv
CHAPTER
1 1 . Colchicine and Related Compounds B Y W. C . WILDMAN A N D B. A.
RJRSEY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
12. The F'yridine Alkaloids B Y W. A . AVERA N D T. E . HABCOOD. . . . . . 459
Contents of Volume XV
CHAPTER
1. The Ergot Alkaloids B Y P. A. STADLER A N D P. STUTZ . . . . . , . . . 1
2. The Daphniphyllum Alkaloids B Y SHOSUKE YAMAMURA A N D YOSHI-
MASA HIRATA . . . . . . . . . . . . . . . . . . . . . . . . , . 41
3. The Amaryllidaceae Alkaloids B Y CLAUDIO FUCANTI . . , . . , . . . 83
4. The Cyclopeptide Alkaloids B Y R. TSCHESCHE A N D E. U. K A U B M A N. N. 165
5 . The Pharmacology and Toxicology of the Papaveraceae Alkaloids B Y V.
FREININGER . . . . . . . . . . . . . . . . . . . . . . . , . . , 207
6. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE . 263
I. Introduction . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . , , , . . . . . , 1
11. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
A. Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
B. Isolation and Detection . . . . . . . . . . . . . . . . ......................... 6
C. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
111. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
B. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
C. Structure Determination . . . . . . . . . . . . . , . . . . . . . . . . , . . . . . . . . 31
IV. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
B. Structure Determination . . . . . . ...... . .. ... . .. 45
V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
A. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
B. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
C. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . , , . . . . . . . . , . 59
VI. ..... ...... ..... .. ..... . ..... 61
.............................................. 61
B. Homoerythrina Alkaloids . . . . _ . _ . . _ . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
C. Cephalotasus Alkaloids . . . . . . . . .............. ............. 16
V11. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
1. Introduction
The last review in this series (1)covered the literature to the end of October,
1966. At that time 10 Erythrina alkaloids were known, and the structures
and stereochemistries of most of them had been established. The total syn-
thesis of erysotrine had been described by Mondon’s group in a preliminary
communication (2),but nothing was known about the biosynthesis of these
alkaloids, although some speculations had been reported.
* Present address: Department of Chemistry. Queensland Institute of Technology, Brisbane.
Queensland, Australia.
’ CSIRO postdoctoral fellow, 1979. Present addrcss: Research and Dcvclopment Depart-
ment. Riker Laboratories, Thornleigh, New South Wales, Australia.
THE ALKALOIDS. VOL. X V l l l
Copyright @ I Y 8 1 by Academic Press. Inc.
All rights of reproduction an any rorin reserved.
ISBN 0-12-469SlR-3
2 S . F. DYKE AND S. N. QUESSY
Frc;. 1. The structures and accepted numbering system for A : 1,6-diene skeleton and B :
A1(6)-alkene skeleton.
A. OCCURRENCE
There are now over 60 Erythrina alkaloids of known structure 1-61 (see
Figs. 2-4) and several more, the structures of which are yet to bz assigned
(12). The alkaloids occur in species of Erythrina (Leguminosae), a genus of
wide distribution in tropical parts of the world, and in species of Cocculus
R' R2 R3 X R' R2 R3
-
1 Erysotrine CH30 2H 18 Erythrartine CH, CH3 OH
2 Erysotramidine CH,O 0 19 Erythristemine CH, CH 3 OCH ,
3 Erythravine CH30 2H 20 Erythrascine CH 3 CH, OAc
4 Erythraline -OCH2- 2H 21 Erythrinine -CH,-~- OH
5 Erysovine CH30 2H 22 1 I -Methoxyerythraline -CH, OCH
6 Erysoline CH,O 2H 23 1 I-Oxoerythraline CH, ~~ -0
7 Erysodine HO 2H 24 I I-Hydroxyerysovine CH, H OH
8 Erysonine HO 2H 25 I I-Methoxyerysovine CH, H OCH,
9 Erysopine HO 2H 26 1 I-Oxoerysovine CH, H -0
10 Erysothiovine CH30 2H 27 1 I-Hydroxyerysodine H CH.3 OH
11 Glucoerysodine h 2H 28 1 I-Methoxyerysodine H CH 3 OCH,
12 Eryso thiopine U 2H 29 1 I-Oxoerysodine H CH, -0
13 Erysophorine CH30 2H 30 I I-Methuxyerysopine H H 0ch3
14 Coccuvinine H 2H 31 1 1-0xoerysopine H H -0
1s* Coccolinine H 0
16 Coccuvine H 0
17* Coccoline H 0
FIG.2. Erj,llrrina alkaloids: 1,6-diene series. a : H0,CCH2S0,-, b : I-/~-glucosyl,c: hypaphorine ester, d : alkaloid is possible artifact.
R1orJp
4 S. F. DYKE AND S. N. QUESSY
CH,O" CH,O'
R' R2 X 36 Isococculidine R = CH,
X
R' R2 R3 X
CH,O
CH 3 0
0 0
57 3-Demethoxyerythratidinone 58 Erysodienone
they do not occur in all parts of each plant (12, 15-17); the sections Breviflora
and Edules are low in alkaloid but high in amino acid content (13,42);
the major alkaloids of E. folkersii are of the 1,6-diene type whereas those
of E. salvizjlora are of the l(6)-alkene type ( 1 5 ) ; the American species do
not contain 1 1-oxygenated alkaloids and presumably lack the capacity to
hydroxylate ring C (12, 21). However, Ito has reported the isolation of
erythrinine (21) from E. crysta galli L., an American species (30).
The hybrid species E. x bidwillii elaborated two new alkaloids, erythrinine
(21) (24, 25) and the dibenzo[e,f]azonine base erybidine (62), (23, 26) which
had not been found in the parent species E. crysta galli and E. herbacea
(13). Erythrinine has since been isolated from E. crysta galli (30) and ery-
bidine has been isolated from several other Erythrina species (12, 27, 30,31).
Although the alkaloidal profile of Erythrina species is often character-
istic, there is considerable quantitative variation in different samples (17).
Differences have been noted in the content of the bark, seed, and leaves
of the plant (33, 35, 43, 4 4 , and some striking variations have been re-
ported. In their GC-MS examination of E. folkersii, Rinehart’s group (15)
failed to detect erythraline (4),which had been reported in an earlier study
of this plant (45),although 4 could be detected in other species (16).Ghosal
et al. reported erysotrine (1) to be the major component by far in the bark
of E. variegata var. orientalis, with only minor amounts of 5 present (33),
whereas Singh et al. (41) in a more recent investigation reported only 5
from the bark of the same species.
Whereas some of the variation may result from the location of the plant
or its age at harvest, there is some evidence for chemical variants within
species. Barton et al. (21)reported a thorned variety of E. lithosperma Blume
(E. variegata L.) that contained only erysotrine and a smooth variety that
contained 1 along with erythratidinone (40), 3-demethoxyerythratidinone
(57), and traces of erythraline (4).Letcher referred to two varieties of E.
lysistemon harvested in Southern Rhodesia which contained either 1 or
1 1-methoxyerythraline (22) but not both. Although erythristemine (19) had
been isolated from E. lystistemon from South Africa none was found in
the varieties from Southern Rhodesia, and no change in the nonpolar al-
kaloids present in the leaves could be detected over a period of four months.
It was therefore suggested that there are at least three chemical variants
of E. lysistemon (46).
B. ISOLATION
AND DETECTION
DETERMINATION
C. STRUCTURE
I . X-Ray Crystal Structures and Absolute Stereochemistry
The absolute stereochemistry of the aromatic Erythrina alkaloids has
been determined. An X-ray analysis of the 2-bromo-4,6-dinitrophenolate
8 S. F. DYKE AND S. N. QUESSY
CH,O'-
19 Erythristemine 56 R = H Cocculine
52 R = CH,O Coccutrine
2. Spectral Characteristics
a. Infrared and UV Spectra. The 1,6-diene alkaloids show IR absor-
bances a t 1610 cm-' and UV absorbances around 285 (dioxygenated
aromatic ring) and 230-235 nm (diene). The 8-0~0-1,6-dienegroup exhibits
a lactam absorbance at 1665 cm-' and an additional UV absorbance at
256 nm arising from the dienone chromophore (21).
The Al(6)-alkene group absorb in the UV around 225 nm, whereas the
enone group usually shows UV absorbance around 230 nm and IR absor-
bance in the region of 1675-1698 cm-'. Erysodienone (58) exhibits UV
1. E R Y ? . H R / N A AND RELATED ALKALOIDS 9
IcJn71+.
RO
+ m ~
2m~
.c trj CY RO
l+.
SCHEME
I . Mujor u t i o r i fhr
M S ~ f r a g i ~ ~ c ~ t ~ tpatterii 1.h-drene srries (R = H,CH, or TMS)
/ -C,I!,O
\b
-C,H ,OR\
q7’+ HC
//
C * , O V
C
0 I1
0
CHO
SCHEME 3. Frugmenmthn puirern .for enone f?‘pes
1. ER YTHRIiVA A N D RELATED ALKALOIDS 11
parent ion (12, 20, 22, 46). The 1 1-oxoalkaloids show a characteristic frag-
mentation ion resulting from cleavage at ring C. For example, the TMS
derivative of 11-oxoerysodine (29) exhibits a characteristic ion with m/e 222
(12)(see Scheme 4).
SCHEME 4
HO
OH
A B
FIG.5 . Stereochemistries in ring A
1. ER YTH-HRINA A N D RELATED ALKALOIDS 13
3. 1,6-Diene Series
a. Simple Types. Resolution of the final ambiguities in the structures of
erysodine (7), erysovine (5), and erysonine (8) was discussed in the previous
review (1)of this treatise on the basis of a preliminary communication (18).
The complete details of this work have now been published (19). Erysotrine
(l),long known only as a synthetic product, was isolated from E. suberosa
Roxb. in 1969 (38,39) and has since been identified in a large number of
Erythrina species (12, 16, 17, 31, 33, 44).
An investigation of E. folkersii by Krukoff and Moldenke by GC-MS
(15) revealed the existence of two new 1,6-diene alkaloids erythravine
(C,,H,,NO,) and erysoline (C,,H,,NO,). Erythravine was identified as
3-desmethylerysotrine (3) from its MS fragmentation pattern. Erysoline
appeared to bear a similar relationship to either 5 or 7. Demethylation of
samples of both 5 and 7 resulted in the identification of erysoline with
3-desmethylerysovine (6) (see Scheme 5), from GC retention time and
spectroscopic comparisons.
R'O
R20
-
CH,O" HO'
5 R' = CH,, R2 = H Erysovine 6 R' = CH,, R2 = H Erysoline
7 R' = H, R Z = CH, Erysodine 8 R' = H, R 2 = CH, Erysonine
SCHEME
5
13 R = Hypaphorine 64 Hypaphorine
33 Crqstdmidinr 65 4 Erjthralme
SCHEME
6
1. E R Y T H R I N A A N D RELATED ALKALOIDS 15
19 Erythristemine
they gave the name erythrinine. The IR spectrum showed a hydroxyl func-
tion, which was further demonstrated by the preparation of an 0-acetate,
and the UV and MS data suggested a 1,6-diene structure. Catalytic reduction
of erythrinine followed by hydrogenolysis over Palladium black in aqueous
hydrobromic acid gave tetrahydroerythraline (66) (see Scheme 7). This
established the basic structure and the stereochemistry at C-5 and C-3. The
hydroxyl group was placed at C-1 1 because of the ease of hydrogenolysis,
and since oxidation gave a ketone in conjugation with the aromatic ring
(vmaX1680 cm- I ) . Therefore, structure 21 was established for erythrinine
although the configuration at C-1 1 was not determined. Erythrinine has since
been isolated from E. x bidwillii (24, 25), E. crysta galli (30, 32), Eryrhrina
species from Singapore (31),and old world species (12).
OH
(iJPtO,-H,
,
(ii) P d ~H , HBr
21 Erythrinine 66 Tetrahydroerythraline
I
SCHEME
CH,O’
20 R = CH,CO Erythrascine
18 R = H ll-Hyroxyerysotrine (erythrartine)
4. A1(6)-Alkene Series
a. Without C-2 Oxygenation. Dihydroerysovine (44) and dihydroeryso-
dine (47) have been isolated from Cocculus species (see Section II,C,5),
although dihydroerysotrine (38) is still known only as a reduction product of
erysotrine (1).
Erythramine (47), previously known as a reduction product of erythraline
(4) (62).was detected in E. crysta galli and in E. glauca Willd. (now classified
as E. fusca Loureiro) (19). Since there was insufficient sample isolated,
erythramine was prepared from erythraline and its structure established by
NMR. In addition, erythramine was prepared by an alternative route from
erythratine (42) (see Scheme 8) by chlorination and reduction. Since 42 could
also be converted to erythraline (19),an alkaloid of known stereochemistry
(631, the position of the double bond as well as the configurations a t C-3 and
C-5 in erythramine were firmly established.
18 S. F. DYKE AND S. N. QUESSY
42 Erythratine 41 Erythramine
8
SCHEME
0 OH
SCHEME
9
1. ERYTHRINA AND RELATED ALKALOIDS 19
for the configuration at C-2 in 39 came through the analysis of its NMR
spectrum (see Section II,C,2d). The absolute configuration at C-5 in both
39 and 40 was established by dehydration of 39 to give erysotrine (1) (see
Scheme 9) along with 2-chlorodihydroerysotrine. A second enone alkaloid
(CI8H,,NO,) was isolated from E. lithospernza Blume in the same study and
identified as 3-desmethoxyerythratidinone (57) by the similarity of its
spectroscopic properties to those of erythratidinone (40).
In the first GC-MS examination of Erythrina species, several new A1 (6)-
alkene-type alkaloids were discovered in E. salvi$ora Krukoff and Barneby
(15). Erysotinone (49), previously known only as a synthetic racemate (66),
was identified from its MS fragmentation pattern. The substitution pattern
in ring D was established by conversion of the isolated alkaloid to dihydro-
erysodine (47)which was prepared from a sample of erysodine (7)(see Scheme
10). Another G C fraction which gave an identical MS to that of 49 was
assigned the isomeric structure 46 and given the name erysosalvinone. A
further fraction exhibiting a n enone fragmentation pattern similar to both
46 and 49 but with a molecular ion at 58 amu higher, due to an extra TMS
(67) and one fewer CH, (15) group, was assigned structure 51 and named
erysoflorinone.
Fractions with MS fragmentation patterns similar to that of erythratidine
were isolated and one identified with the reduction product of erysotinone
(49). This product 48 was previously prepared from 49 by Barton et al. (68)
and given the name erysotine, but neither erysotine (48) nor erysotinone (49)
had been previously obtained from natural sources. Erysotine was found to
have an N M R spectrum similar to that of erythratidine (39),and methylation
of 48 using diazomethane gave a product that had identical melting point
and G C retention time to that of 39 (see Scheme 11). In view of the fact that
the structure given by Millington et al. (15) was that of 2-epierythratidine
rather than 39, their stereochemistry for erysotine was also incorrect. This
would seem to suggest that erysotine, like erythratidine, has the 2 s configu-
ration; however the structures given by Millington et al. for both erysotine
and erythratidine (Fig. 6 in ref. 1 5 ) were of the 2R configuration [as in
erythratine (42)]. The alternative positional isomer [related to erysosalvinone
(46)] was also identified in this study and named erysosalvine (45).
Erysopitine (C,,H,,NO,) was isolated from E. uariegata L. and its
structure (50) assigned from spectroscopic evidence (35).Conversion of 50
to erysotrine (1) (see Scheme 12) established the stereochemistry at C-3 and
C-5, but the configuration at C-2 has not yet been defined.
Of biogenetic interest (see Section V,A) was the isolation of erysodienone
(58) along with N-norprotosinomenine (67) and protosinomenine (68) from
E. lithosperma Blume (now E. variegata L.) (34,35).Erysodienone had been
previously synthesised (54, 66, 6H), but this was the first report of its isolation
0
49 R’ = H, RZ = CH, Erysotinone 47 Dihydroerysodine 7 Erysodinc
46 R’ = CH,, R Z = H Erysosalvinone
51 R’ = R 2 = H Erysoflorinone
10
SCHEME
HO CH,O
OH
50 Erysopitine 1 Erysottine
SCHEME
12
HO
0 CH30
cH30?R
OH
58 Erysodienone 67 R = H
68 R = C H 3
TABLE I
ERYTHRIXA ALKALOIDS
FROM COCCLLUS SPECIES
A 70
Cocculidine 86-87 (93-95) + 260 A 51, 55, 58
Isococculidine 95-96 + 124 A 55
Coccutrine 263 -265 + 232 B 60
Coccoline 245-246 + 233 A 55
Coccolinine 174- 175 A 71
Coccuvine 137-1 38 A 72
Coccuvinine 103- 104 ~
A 56
Erythroculine 193-196b.C + 194 A 73
Cocculitine 142-1 43 + 93 A 74
Dihydroerysovine h + 233 B 57
Dihydroerysodine 208-209 + 224 A 75
Cocculolidine 144- 146 + 273 B 76
C 69
CH,O’
56 R = H Cocculine 69 R = H
54 R = CH, Cocculidine 70 R = C H ,
1. E R ) TliRI,\ A A N D RELATED ALKALOIDS 23
AcO
56 Cocculine 71
SCHEME13
52 Coccutrine 53 Erythroculine
I BC'I, CH,CI,
! (I) AC,O
( i t ) yon Braun
(iii) L A H
(iv) CH,O,'NaBH,
&
NCH3
75
73
SCHEME
14
1. E R Y T H R l N A A N D RELATED ALKALOIDS 25
53
i
performic
acid
76 Tetrahydroerysotrine
SCHEME 15
Scheme 16) gave coccuvinine (141, which was reduced catalytically to give
cocculidine, the structure and absolute stereochemistry of which was already
established. The 8-0x0 counterparts of both coccuvine and coccuvinine were
also isolated and given the names coccoline and coccolinine. Structures 17
and 15 (see Fig. 2) were assigned on the basis of spectroscopic studies in-
cluding detailed examination of NMR spectra (55, 71). In addition methyl-
ation of 17 gave 15. The stereochemistry at C-3 was determined from
coupling-constant data (see Section II,C,2d)and the configuration at C-5 was
HO 9% -
&izHH1,
-
CH,O -;I
assumed. It was suggested, however, that 17 and 15 were artifacts produced
during the drying process.
CH,O p
SCHEME16
37 R = H Isococculine 55 Cocculitine
36 R = CH, Isococculidine
47 Dihydroerysodine 44 Dihydroerysovine
A. OCCURRENCE
AND ISOLATION
TABLE I1
PROPERTIES
PHYSICAL OF HOMOERYTHRINA
ALKALOIDS
Plant sourceh
Alkaloid Formula m P ( C) [.I; (Ref.)
88 186-1 88 f 143 E
89 133 + 140 E
8-Oxoschelhammeridine 170-171 + 35 A
1 la-Oxoschelhammeridine 151 -173 - 41 A
Schelhammeridine 118 - 108 A
3-Epischelhammeridine 131-133 f24 A
86 (Alkaloid 6) 126 f63 D
Schelhammericine 76-77 +I22 A
3-Epischelhammericine 169-172' f 123 A, B, C
170- 17I' +98 D
~
+ I23 F, G
Ma (Alkaloid A) 188-1 89c - 100 A
84b (Alkaloid 1) 260d + 15 D
Schelhammerine 173- 174 + 186 A
3-Epischelhammerine 182-185 + I67 A
184-185 + 172 D
96 e f76r F
83 (Alkaloid B) 152-153 +I11 A, C
150-152 +115 F
Wilsonine 150-151 -51 G
3-Epiwilsonine 244 decd +
58 D
82a e +I18 F
82b e + 122 F, G
85 (Alkaloid 2) I43 -145' +
72 D
97 (Alkaloid 5) 100-1 01 +91 D
Solvent: chloroform.
A, S . peduncula/a F. Muell: B, S. niul/iflora R. Br.; C , S. Uiidulatu R. Br.. D. P.
coniosa Labill: E. P. billardieri; F. C. harringroiria K. Koch var. hurr.iiiy/oiiiu: G, C.
wilsoniuna Hay.
Picrate.
Hydrochloride.
Noncrystalline.
Doubtful value due to impure sample.
1. ERYTHRINA AND RELATED ALKALOIDS 29
ture are shown in Figs. 6 and 7. Within the three genera, the alkaloid profile
is fairly distinctive, with only 3-epischelhammericine (81b) occurring in all
three.
The alkaloids have been isolated either by alcohol extraction of the dried
plant material (82,90) or by ether extraction of the basified plant material
(87). The crude mixture is then fractionated by countercurrent distribution,
followed by chromatographic purification and recrystallization.
The Homoerythrina alkaloids have not been reviewed before, except
briefly in conjunction with Cephalotaxus alkaloids, with which they occur
in Cephalotaxus species (9).
Y
R' R2 R3 R4 X Y
R2 R2 R3 R4 X
-
80a Schelhammerine ~~CH2 CH,O H OH
80b 3-Epischelhammerine -CH,- H CH,O OH
81a Schelhammericine -CH2- CH,O H H
81b 3-Epischelhammericine -CH,- H CH,O H
82a 3-Epi-2,7-dihydrohomoerysotrine CH, CH, CH3O H H
82b 2,7-Dihydrohomoerysotrine CH, CH, H CH,O H
83 2.7-Dihydrohomoerysovine CH, H H CH,O H
RZO
k4
R1 R2 R3 R4
R4
R' R2 R3 R4
88 R = H 90 Phellibiline'
89 R = CH,
B. NOMENCLATURE
Nomenclature for the Homoerythrina group is a problem because only
a few of the alkaloids have been given trivial names. Since the structures of
the Homoerythrina group parallel those of the Erytlzrina group we have
1. EK > 7 H R I . V A A N D RELATED ALKALOIDS 31
11
6
%:s 14 7
3
2 2
91 92
DETERMINATION
C. STRUCTURE
1. Spectroscopic Characteristics
In many ways the spectroscopic properties of the Homoerythrina group
parallel those of the Erythrina series (cf. Section II,C,2). The UV and NMR
characteristics are similar, particularly in rings A and B. The mass spectra of
the 1,6-diene series show a simple fragmentation pattern, similar to that in
the Erythrina 1,6-diene series, with the major fragmentation pathway
involving loss of the allylic substituent (see Scheme 17). The A1(6)-alkene
series shows a more complex fragmentation pattern, as do their A1(6)-alkene
Erythrina counterparts. The same retro-Diels-Alder fragmentation occurs,
but other important modes of fragmentation are initiated in ring C (see
Scheme 18).
As in the Erythrina group, the stereochemistry at C-3 may be assigned
from coupling constant data; however, chemical shift data can also be used
as an indicator of stereochemistry. For example, in the schelhammericine
(81a) series (3S-methoxyl), the methoxyl resonance occurs at 6 2.74 ppm
32 S. F. DYKE AND S . N. QUESSY
Ic I -CH,OH
with a quartet for the axial C-4 proton near 6 1.78 ppm. In the 3-epischel-
hammeridine (81b) series (3R-methoxyl), the methoxyl resonance occurs
at 6 3.17 ppm, with an apparent triplet for the axial C-4 proton around
6 1.52 ppm.
19
SCHEME
of the signals for the C-7 and C-8 protons in the NMR spectrum of schelham-
meridine, which clearly indicated a five-membered ring.
The complete structure of schelhammerine (except for stereochemistry at
C-2 and C-5) was deduced as 80a from a careful analysis of its 100-MHz
NMR spectrum, with the aid of decoupling experiments. Values of 5.0 Hz
for J3,4eq and 3.2 Hz for J3,4ax suggested that the proton at C-3 was equa-
torial; but a value of 3.0 Hz for J 2 , 3did not allow definitive assignment of
the stereochemistry at C-2, although it suggested that the proton at C-2,
was also equatorial. The absolute stereochemistry (as shown in 80a) was
established by X-ray analysis of schelhammerine hydrobromide (92).
The stereochemical assignments made from the NM R spectrum were
further supported by the isolation of an alkaloid (alkaloid H) isomeric with
schelhammerine, with similar UV and identical MS spectra. A value of 12 Hz
for J3,4ah indicated that the proton at C-3 was axial, but lack of large trans-
diaxial couplings for J 2 , 3 suggested that the hydroxyl group at C-2 was
axial, as in 80a. The alkaloid therefore had the structure 80b and is
3-epischelhammerine.
The assignment of structure 77a for schelhammeridine followed from the
NMR analysis and from the interconversion reaction (Scheme 19), which
also established the absolute configuration at C-3 and C-5. In addition, a
minor constituent (alkaloid G) was isolated, isomeric with 77a, having iden-
tical UV and MS spectra but with a value of 11 Hz for J3,4ax. The alkaloid
therefore appeared to be 3-epischelhammeridine (77b), demonstrated by a
series of interconversions summarized in Scheme 20.
Vigorous hydrolysis of 77a in acid gave a complex mixture of products,
the major one being the alcohol 93, That epimerization at C-3 had occurred
was evident from the values of 3.5 and 12 Hz for J3,4in the N M R spectrum.
A minor product with values of 2.0 and 4.8 Hz for J3,4was found to be the
alcohol, with retention of configuration at C-3. Methylation of 93 gave 77b,
and conversely acid hydrolysis of 77b gave 93 thus establishing the con-
figurations at C-3 and C-5 in 77b (83).
34 S. F. D Y K E AND S. N. QUESSY
SCHEME
20
The two isomeric alcohols 94a and 94b were isolated and identified among
the minor products of the hydrolysis reaction. This finding revealed that
94a R’ = OH, R 2 = R 3 = H
94b R’ = R’ = H, R 2 = OH
94c R’ = OAc, R 2 = H, R3 = AC
3. Oxoschelhammeridines
Two alkaloids (C,,H,,NO,) were isolated from S. pedunculata, of which
one was a base and the other was nonbasic (84). The base (alkaloid J) ex-
hibited an IR absorbance at 1665 c m p l and UV absorbances at 232 (3,100),
277 (4,600) and 313 nm (5,000), suggesting an aryl ketone. Comparison of
its NMR spectrum with that of schelhammeridine revealed a lack of C-1 1
methylene protons and a downfield shift of the C-17 proton. The ketone
function was therefore located at C-lla. The stereochemistry at C-3 was
assigned from the value of 4.0 Hz for J3,4ax
and the configuration at C-5 was
assumed. Structure 79 was proposed for the basic alkaloid, which is therefore
1 1a-oxoschelhammeridine.
The NMR spectrum of the nonbasic alkaloid (alkaloid K) showed the C-7
olefinic signal as a singlet, in contrast to the usual multiplet, and there were
no signals attributable to the protons at C-8. A downfield shift observed for
the protons at C-10 was consistent with the expected deshielding effect of a
carbonyl group at C-8, which also accounted for the nonbasic nature of the
alkaloid. An intense IR band at 1685 c m p l also supported the lactam struc-
ture 78. The value of 5.0 Hz for J3,4ax supported the stereochemical assign-
ment at C-3, but rigorous proof of the structure 78 was obtained by oxidation
of schelhammeridine using mangenese dioxide to give 8-oxoschelham-
meridine (78) (see Scheme 22). This established the configuration at C-5
and proved the stereochemistry at C-3.
36 S. F. D Y K E A N D S. N. QUESSY
CH,O CH,O
77a Schelhammeridine 78
SCHEME
22
(9
-.::-
0 -::Cy+
reduction, as shown in Scheme 23 (87). Cephalotaxus harringtonia var.
harring ton ia has also yielded 3-epischelhammericine ( 9I ) .
CH,O,- ’
-
CH,O,’ CH,O,’ ,
OH
77b 3-Epischelhammeridine Slb 3-Epischelhammericine 80b 3-Epischelhammerine
SCHEME
23
Other alkaloids in the Al(6)-alkene series have been reported. Two isomeric
alkaloids (C,,H,,NO,) were obtained from Cephalotaxus harringtonia
K. Koch var. harringtonia. Their spectroscopic properties closely resembled
those of schelhammericine except that their NMR spectra revealed the
presence of two aromatic methoxyl groups in place of the methylenedioxy
group of schelhammericine. The alkaloids were therefore 3-epihomo-2,7-
1. E R YTHR/.\ 1 A N D RELATED ALKALOIDS 37
R4
82a R ' = R 2 = CH,, R3 = CH,O, R 4 = H
82b R' = R Z = CH,, R 3 = H, R4 = CH,O
83 R ' = CH,, R2 = R' = H, R4 = CH,O
CH,O'
96 97
38 S . F. D Y K E A N D S . N. QUESSY
5. A2(1)-Alkene Series
The first alkaloid of the A2(1)-alkenetype was obtained from S.peduncufata
(84). An alkaloid (CI9H,,NO3, alkaloid A) was isolated that was isomeric
with both schelhammericine (81a) and 3-epischelhammericine (Sib), but
which clearly contained an allylic methoxyl group, as indicated by the NMR
spectrum and the ease of hydrolysis of the methoxyl group. Hydrolysis
proceeded with inversion of configuration at C-3 to give alcohol 98 (see
Scheme 24), the structure of which was supported by its NMR spectrum.
Structure 84a was proposed for the alkaloid, and this was further supported
by its reduction to a product identical with tetrahydroschelhammeridine
95 (see Scheme 25), which fixed the configurations a t C-3 and C-5, but the
6ci-configuration was assumed. The alkaloid 84a is therefore 3-epi-6~,7-
dihydrohomoerythraline.
The C-3 epimer 84b ( 6 4 7-dihydrohomoerythraline) was not reported in
S. pedunculata but was later isolated from P. C O ~ O S U(87). From its NMR
'H 'H
84a 98 84b
24. Relationship bertveen 84a and 84b.
SCHEME
84a 95 77a
SCHEME 25
1. ER YTHRI.VA A N D RELATED ALKALOIDS 39
81b 84b
SCHEME
26
CH,O. R'
85 86 87a R' = CH,O. R Z = H
87b R' = H , R 2 = CH,O
40 S. F. DYKE A N D S. N. QUESSY
to the two alkaloids from the spectroscopic evidence and on the basis of the
transformations summarized in Schemes 27 and 28.
Reduction of 87b using LAH gave the tertiary alcohol 99 with preserva-
tion of the double bond (Scheme 27). The position of both the double bond
and the hydroxyl group was clear from the NMR and MS data of 99. The
downfield shift experienced by the proton at C-14 (A6 1.36 ppm) could be
accounted for if the hydroxyl group had the 68-configuration as this would
place it spatially near the aromatic proton at C-14. Similar reduction of
86 gave the corresponding tertiary alcohol 100. Catalytic reduction of 87b
gave rise to a secondary alcohol 101 as the major product. The MS and
NMR data clearly revealed that isomerization of the double bond to the
A1(6)-position had occurred. The signal for the methine to which the hy-
droxyl group was attached (i.e., C-7 proton) was located at 6 4.53 ppm by
the use of N M R experiments involving deuterium exchange and acetylation.
Irradiation of this signal produced a small (< 1 Hz) decoupling effect on
the olefinic signal and a significant decoupling effect at the methylene pro-
tons attached to C-8. The data were consistent only with the hydroxyl group
being attached at C-7, but the coupling values of 5.0 and 6.7 Hz for J7,* did
not permit assignment of configuration. A similar reduction of 86 gave the
secondary alcohol 102 which exhibited spectroscopic properties similar to
those of 101. Further support for the structure of 102 was obtained from its
86 R + R = C H z
87b R = CH,
RO
OH OH
/
CH,O”
99 R = C H , 101 R = CH,
100 R + R = C H , 102 R + R = CH2
1. E R Y T H R l N A A N D RELATED ALKALOIDS 41
I,) SOCI,
(9
111) LAH
A
CH,O"
28
SCHEME
transformation to 3-epischelhammericine (Slb), as outlined in Scheme 28,
which established the configurations at C-3 and C-5. That the original al-
kaloids 86 and 87b contained a 6,7-epoxy group was an inescapable con-
clusion of the reduction experiments; and the presence of such a group
poses an interesting biogenetic problem. The stereochemistry of the epoxide
remains uncertain. The alkaloid 87b was later isolated from C. wilsoniunu
along with its C-3 epimer 87a (90). The name wilsonine has been given to
87a and 3-epiwilsonine to 87b. Since the alkaloid 86 has no trivial name
and is not related to any members of the Erythrinu group, it is referred to
here as 6,7-epoxy-3a-methoxy-15,16-methylenedioxy-C-homoerythrinan-
2(1)-ene.The structure of wilsonine was established in the way just described.
6. Homoerythroidines
The two major alkaloids from P . billurdieri were found to have the chem-
ical compositions C,,H2,N03 and C1,H2,N03. Their NMR spectra were
similar, both contained a trisubstituted double bond but no aromatic pro-
tons. The former alkaloid exhibited one exchangeable hydroxyl proton,
whereas the latter contained an aliphatic methoxyl group. The relationship
between the two alkaloids was established when demethylation of the C,,
alkaloid gave the C,, alkaloid. An absorbance at 1745 cm-' in the IR
spectra suggested a 6- or elactone, an observation which was supported by
LAH reduction to a diol (v,,,3450 cm-') in quantitative yield. The MS data
suggested a A1(6)-alkene structure, and from the combined spectroscopic
and degradative data the partial structures 103a and 103b were proposed
RO
103a R
103b R
- =H
= CH,
90 104
42 S. F. DYKE AND S. N . QUESSY
for the alkaloids. It was found that 103a isomerized on column chroma-
tography to a product for which either the partial structure 90 (without
the stereochemistry) or 104 was deduced. Structure 90 was favored on bio-
genetic grounds and on consideration of the N M R spectrum (88). The
complete structure of this base, named phellibiline, was established by X-ray
analysis, which revealed the absolute configurations at C-3, C-5, and C-12
as shown in stereostructure 90 (93).Since 90 was derived from the naturally
occurring hydroxylic alkaloid and since this alkaloid has been related to
its 0-methyl analog, structures 88 and 89 could be assigned to them. Al-
kaloid 89 is therefore 2,7-dihydrohomo-P-erythroidine, and the two major
88 R = H
89 R = CH,
A. OCCURRENCE
AND ISOLATION
OR3
R’ R2 R3
co-o- OH CO-O-
“ t
a = CH,-C-(CH,),
CH,
OH
CH,CO,CH,
b = CH,-C-(CH,),+OH
CH,
I
CH,COzCH,
U b
H CO-O- H CO-O-
= CH,-~--(CH,),&OH d = CH,-C-(CH,),-OH
I
CH, H 9 OH CH, CH,COzCH3
CO,CH,
1 d
F I ~8.. Ceptiaiofa.xus alkaloids.
during the isolation and purification procedures. It has been noted that
cephalotaxine obtained by transesterification of deoxyharringtonine (110)
has the same optical rotation as natural cephalotaxine, and yet the harring-
tonines do not occur as diastereomers. If cephalotaxine does occur as a
partial racemate, then the acyl portion of the harringtonines should also
be partly racemic, and this would have some significance in structure-activity
studies (9, 100).
B. STRUCTURE
DETERMINATION
1. Cephalotaxine and Epicephalotaxine
Pure cephalotaxine was first isolated from C. fortunei Hook. and C.
harringtoniu var. drupacea [formerly referred to as C. drupacea ( I O l ) ] (102).
The pioneering work on the structure of cephalotaxine (C,,H,,NO,) was
reported in 1963 by Paudler et ul. (102, 103), and on the basis of chemical
and spectroscopic evidence structure 116 was tentatively proposed. The
fact that the olefinic proton appeared as a singlet in the NMR spectrum was
rationalized by proposing a dihedral angle with the adjacent proton of 90"
and hence zero coupling. Powell et al. (104) reexamined the structure of
cephalotaxine and suggested two structures, 105 and 117, which accommo-
dated all the data, although the former structure was favored on biogenetic
grounds.
116
OCH,
105 117
46 S . F. DYKE AND S . N. QUESSY
OCH,
105a Cephalotaxine
2. Esters of Cephalotaxine
During the structure elucidation work, cephalotaxine was shown to form
a mono-0-acetate (106) (102), and this compound was later found as a
minor alkaloid in C.fortunei (98).An impure sample of acetylcephalotaxine
was also obtained from C. wilsoniana Hay. (90).
When the alkaloidal extracts of C. harringtonia var. harringtonia were
found to possess antileukemia properties, a search for the responsible al-
kaloids was initiated, since the major component, cephalotaxine, was inac-
tive. Four alkaloids (the harringtonines) that exhibited anticancer properties
were isolated. The structures of harringtonine, isoharringtonine, and homo-
harringtonine were reported in 1970 (107),and that of deoxyharringtonine
was reported in 1972 (108).
1. E R Y T H R I N A A N D RELATED ALKALOIDS 47
OH CH 3 OH CHS
118 119
H C02CH3 H C0,CH3 H
CO,CH, H CO,H H
HO,C-CH,--C (CH,), C - CH3 CH30,C-CHZ C-(CH2), C -CH,
OH CH3 OH CH,
122 123
CO - H
CH,02C-CH, C (CH,),-C-CH,
,
OH CH3
124
triplet in the NMR spectrum shifted to 6 6.09 ppm. The AB part at b 3.26
ppm was assigned to the protons at C-10, hence the hydroxyl group was
located at C-1 1. It did not prove possible to prepare 1 l-hydroxycephalo-
taxine from cephalotaxine because of the sensitivity of the C-3 hydroxyl
group to oxidation, and therefore the configurations at C-4 and C-5 were
assumed.
Drupacine also exhibited an ABX pattern in its NMR spectrum, with a
triplet centered at 6 4.87ppm. The position of this signal remained un-
changed upon acetylation, which gave a mono-0-acetate. There was no
olefinic signal in the NMR spectrum but geminal coupling in the methylene
signals attributable to C-1 was observed. That drupacine is the 2,ll-bridged
structure 115 was demonstrated by its preparation under mild acid condi-
tions from 1 1-hydroxycephalotaxine (see Scheme 29). Furthermore, treat-
ment of 114 with tosyl chloride in pyridine gave the 3,ll-bridged ether 125.
These reactions require a cis relationship between the 1 1-hydroxyl group
and the cyclopentene ring, so that the stereochemistry of the hydroxyl
group in 11-hydroxycephalotaxine must be as shown in 114, where the
hydroxyl groups are in close proximity. Further support for this assignment
came from the finding that the diacetate of 114 could be readily epimerized
at C-1 1, a reaction which obviously relieves the steric congestion.
OCH, OCH,
114 11s
I
OCH,
12s
SCHEME
29
50 S. F. DYKE AND S. N. QUESSY
OCH, OCH,
105a Cephalotaxine 112 Cephalotaxinone
30
SCHEME
vigorous H *
>
'CH ,CH,CHIOCH,), , H +
OCH, 0
112 Cephalotaxinone 113 R = H Desmethoxycephalotaxinone
126 R = CH,
31
SCHEME
V. Biosynthesis
A. E R Y T H R ~ N AALKALOIDS
At the time of the last review in this treatise ( I ) very little was known
about the biosynthesis of the Erythrina alkaloids. The essential postulate was
that the aromatic bases are derived from tyrosine, with a phenolic coupling
as a key step (Scheme 32) involving the symmetrical intermediate (127a)
derived from 3,4-dihydroxyphenylalanine (DOPA). In one suggestion.
oxidation of 127a to 128 (route 1, Scheme 32) and ring closure to 129,
followed by cyclization to 132a was envisaged, whereas in the alternative
proposal (route 2, Scheme 32) 127a undergoes phenolic coupling to 130a,
followed by oxidation to the diphenoquinone (131a) and cyclization to 132a.
The overall scheme was supported by the observation (66,112) that when
127a was oxidized with alkaline potassium ferricyanide ( )-erysodienone +
(58) was isolated in 35% yield. Mondon and Ehrhardt (66) also described
the further in aitro conversion of (58)to ( f)-erysodine (7) via 133.
Tyrosine L DOPA
I OH
R20
OH OH
130
128
RZO
I steps 0
131
HO
0
129
0
132
a : R, = R, = H Me0 H
b : R, = R, = Me
R'O
7
OH
133
SCHEME
32. A postulated biosynrhetic whet?ir.forErythrinu alkaloids
Hoq-$H
1. E R YTHRf.VA A N D RELATED ALKALOIDS 53
58 - -
Me0 %: :M
< H
/
Me0 Me0
QH
133 7
Since that time dramatic advances have been made in our understanding
of the biosynthetic pathways to these alkaloids, almost entirely as a result
of I4C-labeled feeding experiments. In an early study (113) [2-14C]tyrosine
(34)was found to be incorporated equally at C-8 and C-10 of /l-erythroidine
(60),a type of Erythrina alkaloid always believed (114)to arise from aromatic-
type compounds. This observation was regarded as a strong piece of evidence
in favor of Scheme 32.
Barton et al. (115) found acceptable levels of incorporation of 134 into
mH;zH
erythraline (4), but when 127b, tritiated in the otherwise unsubstituted
HO ---+ o%* -
MeO,'
134 60
positions ortho and para to the phenolic hydroxyl groups, was fed to E.
crista galli very low levels of incorporation were found. It was concluded
that a secondary amine such as 127 is not a precursor of the aromatic Ery-
thrina alkaloids and an alternative biosynthetic route (Scheme 33) was
proposed (115). In a key experiment (115) it was shown that (+)-(S)-nor-
protosinomenine (135) was incorporated into 4 100 times more efficiently
than its enantiomer, strong evidence that 135 is a specific precursor of 4
(19,61,116).The intermediacy of 130b was also established (68).Interestingly,
dibenzazonine alkaloids have been isolated from various erythrina species
(21, 23). Furthermore, erysodienone (58) has been isolated (22, 23,34),
Tyrosine
DOPA
OMe
OH
135 136
OH OH
I
M e/ o g H Meox& /
\ \
Me0 Me0
OH OH
130b 137
Me0
Me0
138 58 Erysodienone
Me0
OH
Me0
MeO" Me0
0
Me0
0
48 Erysotrine
Me0
MeO'
MeO'
OH
140 42 Erythratine
I
i J
I
Erysovine (5) Erythraline (4)
+
Erysopine (9)
+
etc.
33 (continued)
SCHEME
139
54 R = M e
56 R = H
Me0
Me0
0
144
OH
141
I
/
\
Meo%H
M e0
OH
142
J.
M eO MeO,'
0
36
143
58 S . F. DYKE AND S. N. QUESSY
ALKALOIDS
B. HOMOERYTHRINA
The first two homoerythrina alkaloids to be isolated (82)were schelham-
merine (80a) and schelhammeridine (77a), and since various species of
OH
80a 17a
OH
I
OH
1. E R Y T H R I N A AND RELATED ALKALOIDS 59
C. C E P H A L O T AALKALOIDS
XCS
Arguing from structural similarities, it was originally suggested (10)that
the Cephalotaxus alkaloids could be derived in viuo from the same precursor
as the aromatic erythrina bases, but since Cephalotaxus and homoerythrina
alkaloids have been isolated (90)from E. wilsoniana, it has been postulated
(lob, 89) that both groups have a 1-phenethyltetrahydroisoquinoline as a
common precursor (Scheme 36). Tyrosine is incorporated (122)into cepha-
lotaxine, but the labeling pattern did not seem to be consistent with a
benzilic
rearrangement
RO
HO CO,H 0
.L
etc
SCHEME
36. Possible biosynrhetic route to the Ci~phulotaxusalkaloids.
60 S. F. D Y K E A N D S. N. QUESSY
OMe
105a
CO,H
OH 0
*C02H
CO,H
-
acetyl-Co A
&COZH
0
cephalotaxine
1
\COZH
110
S C H ~37.
M ~Bios.vnthrsi3 uf dro.iy/turrittylottirtr
1. E R YTHRl’VA AND RELATED ALKALOIDS 61
VI. Synthesis
A. ERYTHRINA
ALKALOIDS
A synthesis of erysotrine (1) was achieved by Mondon and his associates
and reported in preliminary form in the previous review in this treatise (1).
This work, which has now been published in full (125-129), is summarized
in Scheme 38. Condensation of homoveratrylamine with the glyoxalate
derivative of 4-methoxycyclohexanone gave the enamide (147) which, with
phosphoric acid, was cyclized to the tetracyclic material (148). Reduction
with Raney nickel followed by treatment with sulfuric acid gave the oxide
(149) in which the rings A/B must be cis-fused. When 149 was subjected,
after O-acetylation, to acid treatment, a mixture of two alkenes (150) was
formed. These were separated and the correct one epoxidized to 151. Ring
opening of 151 with dimethylamine yielded 152 which, on Cope elimination
from the derived N-oxide, gave the alkene (153). Allylic rearrangement
occurred when 153 was treated with acidified methanol to yield 154 as a
mixture of epimers. These were separated by chromatography and each was
carried through the remainder of the synthesis. Reduction of the amide
carbonyl group of 154 gave 155, and this was followed by dehydration to 1.
Finally, resolution of 1 was effected with dibenzoyltartaric acid to provide
the (+)-isomer, identical with erysotrine obtained from natural sources.
Mondon (125) was also able to convert the isomers (150), where the
cis-A/B ring junction is established, to the dihydro derivative (156). This
was then reduced to 157, where the A/B ring junction must be cis. Later,
Kametani et al. (130, 131) reported that the tetracyclic compound (160)
could be obtained as a mixture of cis-trans isomers merely by heating
together the amine (158) and the ketoester (159). However, Mondon (132,
133) has cast doubt on this work and concludes that Karnetani’s product is
62 S. F. D Y K E A N D S. N. QUESSY
147
\
149 148
150 151
Me0
, 'OH
NMe,
153 152
SCHEME38. The ,first sythesis of erysotrine
1. ER Y T H R I X A A N D RELATED ALKALOIDS 63
HC I !&OH
1.53 A
Me0
M e O ‘ U
154
I
(111
( 1 1 separation 01
cpimeis
LAH
Me0
“OH
1 155
SCHEME
38 (continued)
150 % Meo%
Me0
‘OH Meo%
Me0
156 157
a mixture of the cis isomer (157) and the uncyclized material (161). Kametani
et al. (131) also described the condensation of 158 with 162 and with 163
to form 164 and 165, respectively, but Mondon (132) concludes that these
structures too are incorrectly assigned.
HO
Me0
159 160
64 S. F. DYKE AND S. N. QUESSY
Me0
U
161
158
164 165
BzO HO
T N H 0
Me0 Me0 Y
Me0 M eO d M e
166 167
98" HCO H
I H,SO, DMF
&
Me0
169 168
1. ER Y T H R I X A A N D RELATED ALKALOIDS 65
acid. When the isomeric amide (170)was subjected (135)to a similar sequence,
the overall yield of 172 reached 90%. Ketalization of 172 with ethylene
Me0
170 171
I H,SO,. DM F
0 0
L/
173 172
/
3'"' ' (il Li+NR,
lii) 0,
THF
H OH H "OAc
0
LJ
174 175
i 35""
'OAc
/ /
MeO"
1 Erysotrine 176
ill
(I,) HC'I
MeSO,CI m+ Meo%
dcelone
Me0 Me0
OH OS0,Me
O w 0 O w 0
174 177
85",,
!
NdOH MeOH
180 178
PhSeCl
\ Zn HOAc
";"-::6,.
Me0
Me0
SePh Y
0
CI w I
C I
I
W
SCH,Ph
179
SCH,Ph
181 182
*
15"" H,Oi ps
loo",
i
Me0 Me0
4gYO. MrOH RdNl
182
MeO" MeO"
1. ER YTHRINA A N D RELATED ALKALOIDS 67
glycol followed by 0-methylation gave 173, the lithium enolate of which was
hydroxylated with oxygen to yield 174, which has the wrong stereochemistry
at C-7. Epimerization was achieved by oxidation followed by reduction.
Acetylation of the hydroxyl group and deketalization then yielded the keto-
amide (175), which was reduced and dehydrated to 176. The conversion of
176 to erysotrine had been reported previously by Mondon and Nestler (136).
The total synthesis of (+)-Erysotramidine (2) has been described by Ito
et al. (137) starting from the amide (174) (Scheme 39). After 0-mesylation
to 177, base-catalyzed reaction gave the cyclopropane derivative (178) which
with zinc in acetic acid was reduced to 179, which was identical to the product
(135) of 0-methylation of 172. Conversion of 178 to the thioketal(l80) was
followed by reaction with phenylselenyl chloride. A mixture of two com-
pounds, 181 and 182, was produced; the former could be transformed
quantitatively to the latter. Finally, treatment of 182 with silver nitrate in
methanol gave 183, which was then desulfurized to yield erysotramidine (2).
An interesting short synthesis of the erythrane skeleton has been achieved
by Wilkens and Troxler (138). Ethyl cyclohexanone-2-carboxylate was
MeO. L
M e o w ,
Et
184 185
alkylated with ethyl bromoacetate, followed by condensation with homo-
veratrylamine to yield 184. Cyclization of 184 with phosphoric acid yielded
185. Stevens and Wentland (139) have prepared the erythrane derivative
MeorMe
(187) by reacting the endocyclic enamine (186) with methyl vinyl ketone.
+M e 0
rn i
Me0
O f l
Meo”i-.
POCI,
Me0-Meo Me0
H
0
187 186
68 S. F. D Y K E AND S. N. QUESSY
Me0 rn188
189
191
HO
Me0 R
OH OH
192 193
I NaOH
130b -
NaBH,
194
SCHEME
40. Kupchan's sjnthesis of bcvrxcenes
HO
Ms
Me0 Me0
OH OH
195 196
OH
I
63",, BF,IEt,O
Meek
?H
Me0 M e o w \ Ms
OH
w OH
198 197
I99
SCHEME
41. Preparation of 14-metho~q.erq.sodienone.
K,FelCNI,
Me0
Me0 OMe
Hoq
OH
200 201
Me0 \
0
202
OH
I
Me0
\
Me0 Me0
SCHEME
42. S~ttrltesisof Er.rhidiltc. by pliorolFsis.
72 S. F. DYKE AND S. N. QUESSY
C:r C0,Et
IPhCHO
(iiJ HCILMeOH
v
SCHEME
43. Preparation oj rlir e r j tliroidiiie skelerori.
ALKALOIDS
B. HOMOERYTHRINA
The ring system of the homoerythrina alkaloids has been prepared (149)by
oxidative coupling of the 1-phenethyltetrahydroisoquinoline (206, R =
COCF,) (Scheme 44). The diphenol (208) was obtained in 76% yield from
207, but all attempts to oxidize the N-trifluoroacetate of 208 to a dipheno-
quinone failed-probably because the two aromatic rings are orthogonal to
each other. However, oxidation of the secondary arnine (208) itself with
potassium ferricyanide gave a mixture of 209 (45”/d yield) and 210 (15%);
1. ER YTHRINA AND RELATED ALKALOIDS 73
5?M:e ‘OCF3
\
Me0 ‘
Me0 OH
OH
206 201
OH
I (I) NaOH
(11)
(111)
HCI
NdBH,
208
0
HO
209
M e 00 9
210
The dienone (210) has also been prepared (152, 153) by oxidation of the
amide (211) with potassium ferricyanide, when 212 was obtained in 67%
yield. After protection of the phenolic hydroxyl group, reduction with LAH
211 212
removed the amide carbonyl and reduced the dienone to the dienol. Re-
oxidation and removal of the 0-benzyl group then yielded 210. An alter-
native preparation of 209 was described (152) in which 210 was converted
(I) BrCl
(11) LAH
(111) CrO,
Me0
210
eH
89"o
?H
I
chromous
chloride
209
45. A n alternative preparation of 209
SCHEME
1. E R Y T H R I N A A N D RELATED ALKALOIDS 75
to the amide (213)in 89% yield by reaction with chromous chloride; the amide
(213), after 0-benzylation, reduction with LAH, and de-0-benzylation,
gave the amine (208) in 53% yield. Finally, a 60% yield of 209 was realized
when the diphenol 208 was oxidized with alkaline potassium ferricyanide
(Scheme 45).
Interestingly, when the dienone (207) is treated with BF,/etherate (154),
rearrangement occurs to give the homoaporphine (214). Oxidation of the
M::ycoc
tetramethoxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (215) with VOF,
gave (142) a little of the dienone (210, together with a 64% yield of 217.
However, when each was treated with acid, rearrangement occurred to give
218 and 219, respectively.
Me0Y
Me0
Me0 \
OH Me0 .6'
OMe
214 215
OMe
0
M e 0P \C O C F 3
OMe OMe
M:Ip 216
COCF,
M e
217
o w
Me0
OMr OMe
218 219
76 S. F. DYKE AND S. N. QUESSY
c. CEPH.4LOTAXL.S ALKALOIDS
1. Cephalotaxine
The total synthesis of alkaloids of the cephalotaxine type has attracted
considerable attention (75) because of the anticancer activity reported for
certain derivatives (100) (see Section IV,A). The first synthesis of cepha-
lotaxine (105a) was reported by Auerbach and Weinreb (155,156),closely
OMe
105a
220
224
\
225
46. The prc'paration of the tricyclic enamine (225).
SCHEME
1. ER Y T H R I N A A N D RELATED ALKALOIDS 77
(9
(90
I 228
0A C H ,
227
(yq-&-<W
0 0
AcO
P- 0
&Me
229 230
52“,
I Mg(OMe),
232 233
235 234
236 231
lLAH
238
SCHEME
48. Dolbj's preparation o/ enaminc2 225.
240
239 241
I
0 0
239
R = C0,Et
242 243
(I) TFAA
(iil SnCI,
238 244
1Hg(OAc1,
225
SCHEME
50. A n alternatice preparation of enaminr 225
Yet another method has been described (162)(Scheme 50) for the prepara-
tion of the tricyclic enamine (225). N-Alkylation of ethyl pyrrole-2-carbox-
ylate with 242 in the presence of sodium hydride gave, after hydrolysis, the
amino acid (243). This was cyclized to 244, reduced to 238, then oxidized
to 225. Alkylation of 225 with propargyl bromide, followed by hydration
with a mercuric salt gave the ketone (227), but this could not be cyclized,
thus confirming the observation made by Weinreb and Auerbach (156)but
contrasting with the report of Dolby et al. (160).
A photochemical route to the key amine (238) has been described by Tse
and Snieckus (163) (Scheme 51). The maleimide (245) was iodinated in the
245 246
241
5 1. A photochemical prc,parution of tricyclic amine 238
SCHEME
82 S . F. DYKE AND S . N. QUESSY
248 249a X = C1
249b X = I
250 251
n i
254 253
L
Me,SiO
Me,SiCI
255
OSiMe,
1
J
+H Z 0 -
256
3 248
257a X = C1 112
257b X =I 7
258
53. The cyc1i;atiorr rcvictions t o cephalotasinone
SCHEME
NCOCF, * "OF, '$ NCOCF,
/ BzO \
\ OMe
BzO
OMe
260 26 1
INaOH
OMe GMe
OMe OMe
263 262
M e O I ( I ) TFA
In) CH,N,
g /
(1) Pd C H,
1111 K K O ,
Meo$~
OMe
NCOCF,
HO \
/
OMe
BzO \ 265
OMe
264 .i
266
SCHEME
54. A hii~genriicull.vputteriicd approach to cc~phali~rurinr.
1. E R Y T H R I X A AND RELATED ALKALOIDS 85
from the complex mixture. The reaction was presumed to involve the benzyne
anion (258) as an intermediate. No improvement in yields could be gained
by using the iodo compound (257b) or by variation of the conditions. The
yield of 112 was raised to 35% when the anion (259) derived from 257b was
treated with a Ni(0) complex to induce nucleophilic displacement of iodine.
In an alternative procedure, the anion (259) was treated with a sodium-
potassium alloy to form cephalotaxinone (112) in 45% yield. However
cephalotaxinone was obtained in 94% yield when 25713 was treated with
potassium tert-butoxide in refluxing ammonia with simultaneous irradiation
with a Hanovia 450-W medium pressure lamp. These conditions caused
radical cleavage of the aromatic ring-iodine bond in the anion (259),followed
by coupling of the aromatic radical with the nucleophilic center. Finally,
reduction of 112 with diisobutyl aluminium hydride gave ( -t)-cephalotaxine
(105a)
An approach to the cephalotaxine skeleton, based upon the presumed
biogenetic route, has been reported (164) and involves the oxidation of the
I-phenethylisoquinoline derivative (260) with VOF, (Scheme 54). Alkaline
cleavage of the dienone (261)gave 262 which, as the hydrochloride salt, was
reduced 263. N-trifluoroacetylation followed by 0-methylation yielded 264
which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide
to give the dienone (266).
2. Esters of Cephalotaxine
Although cephalotaxine itself exhibits no significant antileukemic activity,
a number of naturally occurring esters of the alkaloid, the harringtonines
(107-110), are active against L1210 and P388 leukemias in mice (89, 100,
108), and so some attention has been devoted to the synthesis of the dicar-
boxylic acid side chains (see also Section IV,A).
The hydroxydicarboxylic acid (270), derived by hydrolysis of deoxyhar-
ringtonine, was synthesized by the method shown in Scheme 55 to confirm
the structure deduced by spectral methods (see Section IV,A). Convention-
al chemistry was employed; methyl isopentyl ketone (267)was reacted with
diethylcarbonate in the presence of sodium hydride to yield the ketoester
(268).Addition of HCN gave 269, hydrolysis of which provided the hydroxy-
dicarboxylic acid (270). The overall yield was 48%. Esterification with
diazomethane gave the diester, which was partially hydrolyzed to the half-
ester (122), the most hindered ester function remaining intact. This, after
conversion to the half-ester acid chloride, was used to acylate cephalotaxine.
A pair of diastereomorphs was produced, neither of which proved to be
identical to deoxyharringtonine. It was concluded that the latter must have
structure 110 in which the ester linkage to cephalotaxine involves the tertiary,
86 S. F . DYKE AND S. N. QUESSY
0
261 268
OMe
0
%OH
0
122 123
rather than the primary carboxyl group. However, when the isomeric half-
ester (123) was prepared, acylation of cephalotaxine could not be achieved,
presumably because of steric hindrance at the carboxyl group. An alternative
synthesis of 123 (165) (Scheme 56) started from the commercially available
dimethyl itaconate (271, R = Me). Epoxidation to 272 (R = Me) was
achieved with trifluorperacetic acid, and this, with isobutyllithium and
cuprous iodide, gave the diester (273, R = Me). The benzyl ester (273, R =
CH,Ph) was prepared in a similar way from 271 (R = CH,Ph) and 272 (R =
CH,Ph). Catalytic hydrogenolysis of 273 (R = CH,Ph) gave the required
half-ester (123). Finally 123 was resolved with ephedrine. Auerbach et d.
(165)also failed in their attempts to acylate cephalotaxine to deoxyharring-
tonine.
However, deoxyharringtonine (110)has been synthesized (166-168) by the
method summarized in Scheme 57. The lithium salt (274) of 3-methyl-l-
butyne was condensed with ethyl tert-butyloxalate to give 275 which, after
1. E R Y T H R I X A AND RELATED ALKALOIDS 87
CF,CO,H
'C0,Me
271 272
C0,Me
273 ( R = Me = 121)
273 (R = H = 123)
SCHEME
56. A n alternatioe synthesis of the acid 123.
0
Ll+-C-c
i i
EtO CC0,t-Bu
P o=c-c-c=
1
0-t-Bu
274 275
1(i) HJPdiC
+
(ii) TFA
(i) SOCI,
(ii) cephalotaxine HO,C
276
"
I /I
-c' OMe
0
277
\ MeC0,Me;LDA
110
57. Synthesis of deoxyharringtonine
SCHEME
88 S. F. DYKE AND S. N. QUESSY
with the lithium salt of methyl acetate. The mixture of diastereomorphs was
separated by thin layer chromatography.
The hydroxyacid (118) obtained by the hydrolysis of harringtonine was
synthesized (169) by the route shown in Scheme 58. Condensation of the
lithium salt (278) with ethyl tert-butyloxalate gave 279, which with the
lithium salt of methyl acetate was converted to 280. Hydrolysis with tri-
fluoracetic acid yielded 281 (R = H) which with diazomethane gave the
dimethyl ester (281, R = Me). Catalytic hydrogenation and hydrogenolysis
with 10% palladium on carbon yielded 118 which, apart from optical
rotation, was found to be identical to material obtained from harringtonine,
thus confirming the structure of harringtonine deduced by spectral methods
(see Section IV,A). When the half-ester (281, R = H) was treated with
hydrogen over palladium on charcoal, the lactone (282)was produced.
Harringtonine (107) has been synthesizcd (170) by the method shown in
Scheme 59. Claisen condensation between 283 and ethyl oxalate in the
presence of NaH gave 284 which, when heated under reflux with aqueous
HCl, was converted to a mixture from which the oxide (285) was isolated.
Without purification, 285 was treated with HCl/MeOH to yield 286, sapon-
ification of which yielded the unsaturated acid as its sodium salt 287. After
conversion to the acid chloride, reaction with cephalotaxine yielded 288.
Li+-Cec 4- Me,COCOCO,Et
t-Bu0,C
"--J? C=C
218
1
219
MeCO:g,LDA
OBz OBz
OH
+ t-BuOZC
\CO,Me
281 280
H, Pd C
EtOAc
w 0 2 M e &H
C0,Me
C0,Me
118 282
SCHEME58. Synthetic proof o j structure of harrinytonine
1. E R YTHRINA A N D RELATED ALKALOIDS 89
286 285
LCO*Me
107
SCHEME
59. S?;nthesis of harringronine
90 S. F. DYKE A N D S. N. QUESSY
base to 291 and then by esterifying to 283. A very similar route to harring-
tonine has been described by Chinese workers (171).
: i-x
CHO CH=CHCO,H
290
283 - 1
BF, EtOH >,:HCH2COzH
KOH H,O
29 1
_j____l_ C0,Et
COMe -!(LL!?KOH
%, WCozH CO,H
292 293
/ *o H
C0,Me C0,Me
0
d%C02Me
=5 . 8 5 3 294
H?
6 = 6.8
295 297
I
OSO, H,O,
I
.."..x
0 5 0 , H,O,
0,Me
, C0,Me
OH MeO,C&H
OH
296
298
60. Relatiue configuration of side chain of i.so/zarringtorzine.
SCHEME
1. ERYTHRI,VA AND RELATED ALKALOIDS 91
CO,H COzH
299 300
VII. Pharmacology
OCH,
301 R = COC(=CH,)CH,CO,Me
302 R = COCH=CHCO,Me(trans)
H ,,,, ,OCO,CH2CC1,
303 R = CO-C,
Ph
304 R = CO2CH2CCI3
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C. Young, and K. L. Rinehart, Jr., Llojdia 37, 569 (1974).
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94 S. F. DYKE AND S. N. QUESSY
131. T, Kametani, H. Agui, K. Saito, and K. Fukumoto, J . Heteroc.)d. Chem. 6, 453 (1969).
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135. M. Haruna and K. Ito, Chem. Commun. 345 (1976).
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137. K. Ito, F. Suzuki, and M. Haruna, Chem. Commun. 733 (1978).
138. H. J. Wilkens and F. Troxler, Helc. Chim. Aeta 58, 1512 (1975).
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Chem. Res. 10, 193 (1977).
140. H. Iida, S. Aoyagi, K. Kohno, N. Sasaki, and C. Kibayashi, Heterocycles 4, 1771 (1976).
141. S. M. Kupchan, Chang-Kyn Kim, and J. T. Lynn, Chem. Cornmun. 86 (1976).
142. S. M. Kupchan, A. J. Liepa, V. Kameswaran, and R. F. Bryan, J . Am. Chem. Soc. 95,
6861 (1973).
143. S. M. Kupchan, V. Kameswaran, J. T. Lynn, D. K. Williams, and A. J. Liepa, J . Am.
Chem. SOC.97, 5622 (1975).
144. T. Kametani, R. Charubala, M. Ihara, M. Koizumi, and K. Fukumoto, Chem. Commun.
289 (1971).
145. B. Franck and V. Teetz, Angew. Chem., In/. Ed. Engl. 10,411 (1971).
146. T. Kametani and T. Kohno, Chem. Pharm. Bull. 19,2102 (1971).
147. K. Ito and H. Tanaka, Chem. Pharm. Bull. 22,2108 (1974).
148. T. Kitahara and M. Matsui, Agric. Biol. Chem. 38, 171 (1974); CA 80, 96193R (1974).
149. J. P. Marino and J. M. Samanen, J . Org. Chem. 41, 179 (1976).
150. T. Kametani and K. Fukumoto, Chem. Commun. 26 (1968).
151. T. Kametani and K. Fukumoto, J . Chem. Soc. C 2156 (1968).
152. E. McDonald and A. Suksamrarn, Tet. Lett. 4425 (1975).
153. E. McDonald and A. Suksamrarn, Tet. Lett. 4421 (1975).
154. J. P. Marino and J. M. Samanen, Tet. Lett. 4553 (1973).
155. J. Auerbach and S. M. Weinreb, J. Am. Chem. Soc. 94, 7172 (1972).
156. J. Auerbach and S. M. Weinreb, J . Am. Chem. Soc. 97,2503 (1975).
157. M. F. Semmelhack, B. P. Chong, and L. D. Jones, J . Am. Chem. Soc. 94, 8629 (1972).
158. M. F. Semmelhack, B. P. Chong, R. D. Stauffer, T. D. Rogerson, A. Chong, and
L. D. Jones, J . Am. Chem. Soc. 97,2507 (1975).
159. M. F. Semmelhack, R. D. Stauffer, and T. D. Rogerson, Tet. Lett. 4519 (1973).
160. L. J. Dolby, S. J. Nelson, and D. Senkovich, J. Org. Chem. 37, 3691 (1972).
161. W. I. Taylor and M. M. Robison, U.S. Patent 3,210,357 (1966): CA 65, 2235 (1966).
162. B. Weinstein and A. R. Craig, J . Org. Chem. 41, 875 (1976).
163. I. Tse and V. Snieckus, Chem. Commun. 505 (1976).
164. S. M. Kupchan, 0. P. Dhingra and C-K. Kim, Chem. Commun. 847 (1977); J . Org. Chem.
43, 4464 (1978).
165. J. Auerbach, I. Joseph, W. Touran, and M. Steven, Tet. Lett. 4561 (1973).
166. K. L. Mikolajczak, C. R. Smith, D. Weisleder, R. T. Kelly, J. C. McKenna, and P. A.
Christenson, Tet. Lett. 283 (1974).
167. K. L. Mikolajczak and C. R. Smith, U.S. Patent 3,959,312 (1976); CA 85,108881G (1976).
168. S.-W. Li and J.-Y. Dai, Hua Hsueh Hsueh Pa0 33, 75 (1975); CA 84, 150812q (1976).
169. T. R. Kelly, J. C . McKenna, and P. A. Christenson, Tet. Lett. 3501 (1973); T. R. Kelly,
R. W. McNutt, M. Montury, and N. P. Tosches, J . Org. Chem. 44,63 (1979).
170. K. L. Mikolajczak and C. R. Smith, J . Org. Chem. 43. 4762 (1978).
171. Anonymous, K’o Hsueh T’ung Pao 21. 509. 512 (1976): CA 86, 171690e (1977).
172. T. Ipaktchi and S. M. Weihreb, Tct. Lert. 3895 (1973).
98 S. F. D Y K E A N D S. N. QUESSY
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
I1. Vedtchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............ 102
A . Veatchine and Garryine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
B. Garryfoline, Ovatine, and Lindheimerine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
C . Cuauchichicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
D . Garryfoline-Cuauchichicine Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
E . Napelline (Luciculine), Isopapelline, Lucidusculine, and 12-Acetylnapelline 112
F. Songorine (Napellonine or Shimoburo Base I), Norsongorine, Songorine
N-Oxide, and Songoramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
G. Anopterine, Anopterimine, Anopterimine N-Oxide, Hydroxyanopterine,
and Dihydroxydnopterine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
I11. Atisine-Type Alkaloids . . . . . . . . . ..... ....... 122
A . Atisine and Isoatisine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
B . Dihydroatisine and Atidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
C . Ajaconine and Dihydroajaconine . . . . . . . . . . . . . . . . . . . ........... 124
D . Kobusine and Pseudokobusine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
E . Ignavine and Anhydroignavinol ............................. 128
F . Hypognavine and Hypognavin ...................... 129
G . Isohypognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
H . Denudatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... 131
I . Vakognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-32
J . Hetisine (Delatine) and Hetisinone . . . . . . 133
K . Hetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
L . Miyaconitine and Miyaconitinone ............................. 136
M . Delnudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
N . Spiradine A, Spiradine B, and Spiradine C . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
0. Spiradine D and Spiredine . . . . . . . . . . . . ........ ......... 140
P . Spiradine F and Spiradine G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Q . Spireine . . . . . . . . . .......................................... 143
IV . Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . 144
A . Staphisine and Staphidine . . . . . . . . . . . . . . . . 144
B . Staphinine and Staphimine . . . . . . . . . . . . . . . . ................... 146
C . Staphigine and Staphirine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
D . Staphisagnine and Staphisagrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
V . Behavior and Formation of the Carbinolamine Ether Linkage in Diterpenoid
Alkaloids: The Baldwin Cyclization Rules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
lr1. "C-NMR Spzctroszopy of C,,- Diterpenoid Alkaloida. . . . . . . . . . . . . . 160
VII . Mass Spectral Analysis of C,,- Diterpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . 163
I. Introduction
(iii) Delnudine
19./N\,20.
H3FyJ2'
6' \ 10'
H,C--
(iv) Stdphisine
The numbering system for the alkaloids with the basic atisine (i), veatchine
(ii), and delnudine (iii) skeletons used in this chapter is in accord with pro-
posals initiated by Dr. J. w. Rowe and cosponsored by the author (3).
The earlier work on the chemistry of C20-diterpenoid alkaloids has been
reviewed in Volumes IV(4), VII(5), and XIl(6) of this treatise, in books on
102 S. WILLIAM PELLETIER AND NARESH V. MODY
alkaloids by Boit (7) and Pelletier (8),in The Alkaloids, Specialist Periodical
Reports (9-11) and in other reviews (12-18). This chapter deals with the
chemistry of C,,-diterpenoid alkaloids reported in the literature available
to us since the last review in Volume XI1 of this treatise, as well as certain
unpublished works from our institute.
Included in this chapter is a catalog of ali known C,,-diterpenoid alkaloids
showing the correct structures, physical properties, plant sources, and key
references. Previously published books (19-21) and recent reviews (15-16)
have reported incorrect structures for several well-known C,,-diterpenoid
alkaloids. This catalog should be very useful for it presents in a single place
important structural information on the C,,-diterpenoid alkaloids that has
been scattered through hundreds of papers and dozens of review articles.
A. VEATCHINE
AND GARRYINE
for example, the P-configuration was assigned to the C-20 proton in veatchine
(lb) and related alkaloids without any evidence (26). Recently, Pelletier and
Mody reported (27,28) unusual findings about the conformation of the
oxazolidine ring of veatchine and related alkaloids by 13C-NMR spectro-
scopy. The I3C-NMR spectrum of veatchine shows two sets of signals for
the oxazolidine ring and the piperidine ring carbons in CDCl, solution at
room temperature. On the basis of this unusual observation they concluded
that veatchine exists as a mixture of C-20 epimers ( l a major and l b minor)
in solution. When veatchine is regenerated from veatchinium chloride (3), in
which C-20 is trigonal, by treatment with base, formation of the oxazolidine
ring takes place from both sides of the trigonal C-20 carbon to give epimers
l a and lb.
lb 2 Garryine
la
B. GARRYFOLINE,
OVATINE,
AND LINDHEIMERINE
Ovatine (6) and lindheimerine (7) have been isolated (33)for the first time
from the bark and leaves of G. ocata var. lindheimeri Torr., a plant that has
shown confirmed antitumor activity in vivo. These two new alkaloids are
accompanied by the known alkaloid, garryfoline (S), which also occurs in the
Mexican tree, G. laurifolia Hartw (34).
The structure of the major alkaloid, ovatine (6),was assigned on the basis
of ‘H- and 13C-NMR data of ovatine and garryfoline and was confirmed by
conversion of ovatine to garryfoline and vice versa. The ‘H-NMR data of
ovatine revealed the presence of two different sets of signals for the C-4
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 105
methyl group and the C-20 proton in a 1 :3 ratio and one set of signals for
an aceloxy group, the N-CH,-C group, and the exocyclic double bond.
The 13C-NMR spectrum of ovatine in CDCl, at room temperature also
exhibited the presence of two different sets of signals for the oxazolidine
ring F, the piperidine ring E, the C-4 methyl group, and certain other carbon
atoms. Comparison of the 'H- and 13C-NMR spectra of ovatine with those
of garryfoline revealed that the only difference between these alkaloids was
the presence of an acetoxyl group at C-15. Each of these alkaloids exists as
a mixture of C-20 epimers in solution. It is worth noting that in the structure
assigned to garryfoline (6B) (25,26),a P-configuration was assumed without
evidence for the C-20 hydrogen.
6 R = Ac Ovatine 7 Lindheimerine
8 R = H Garryfoline
6a R = Ac 6b R = AC
8a R = H 8b R = H
9 10
C. CUAUCHICHICINE
During investigation of the constituents of G . ouatu var. lindheimeri, two
well-known alkaloids, garryfoline (8) and cauchichicine, as well as ovatine
and lindheimerine, were isolated (33); Djerassi and co-workers (25, 34) had
previously isolated the former alkaloids from the Mexican tree, G. luurifoliu,
and established their gross structures.
Treatment of garryfoline with dilute hydrochloric acid at room tempera-
ture results in rapid isomerization to cuauchichicine. The latter was assigned
structure 11 by Vorbrueggen and Djerassi in 1962 (25,35).They assigned the
a-configuration for the C-16 methyl group in cuauchichicine on the basis of
chemical correlation of cuauchichicine azomethine (12) with ( - )-“a”-
dihydrokaurene (13). The structure of the latter, a minor hydrogenation
product of ent-kaurene (14),was based on the behavior of ent-kaurene during
catalytic hydrogenation. A a-configuration was assigned for the C-20
hydrogen in cuauchichicine without any evidence.
Recently, Pelletier and co-workers (36) revised the structure of cuauchi-
chicine to 15 on the basis of I3C-NMR spectral analysis and X-ray crys-
tallography. A 3C-NMR study of cuauchichicine indicated that it exists
as a single C-20 epimer unlike other normal-type oxazolidine ring-containing
diterpenoid alkaloids such as veatchine, ovatine, garryfoline, and atisine. An
a-configuration was assigned to the C-20 hydrogen on the basis of compar-
ison of the I3C-NMR spectrum of cuauchichicine with those of veatchine and
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 107
11 12
I
c c
13 “p”-Dihydrokaurene
4%
I
H,. NI
14 ent-Kaurene 18 “r”-Dihydrokaurene
15 Cuauchichicine 19
13a R = CH,OH
13b R = CHO
13c R = CH, “8”-Dihydrokaurene
2. THE CHEMISTRY OF C ~ O- DI T E R P EN O I DALKALOIDS 109
to the sc-methyl group in 17. These results afforded evidence for the presence
of the 8-methyl group at C-16 in cuauchichicine (10.1 ppm) and therefore
structure 15 was assigned to cuauchichicine. Subsequently, this structure was
confirmed by a single-crystal X-ray analysis of cuauchichicine (36).
The incorrect structure 11 originally assigned to cuauchichicine requires
that either the structure of the final degradation product, ( - )-“P”-dihydro-
kaurene (13), is incorrect or that the C-16 methyl group must have epimerized
somewhere in the six-step correlation sequence. Because the structural
assignments of more than 100 natural products depend on ( -)-“P”-dihydro-
kaurene, the structure of this important diterpene was reinvestigated. Cata-
lytic hydrogenation of ent-kaurene (14) afforded a mixture of ent-kauranes
consisting mainly of ( - )-“a”-dihydrokaurene. The ‘‘P’-epimer was pro-
duced in too small a yield to permit its isolation in a pure state. X-ray
crystallography of ( -)-“a”-dihydrokaurene demonstrated the structure to be
18. Therefore, the structure previously assigned for ( - )-“P”-dihydrokaurene
(13) is correct. These results indicate that epimerization of the C-16 methyl
group must have taken place during degradation of cuauchichicine to (-)-
“P”-dihydrokaurene. This unanticipated epimerization most likely occurred
during Wolff-Kishner reduction of the intermediate ketone 19 and accounts
for the error in the assignment of configuration of the C-16 methyl group
in cuauchichicine. The absolute configuration of cuauchichicine was deter-
mined as 4.9, 5S, 8R,10R, 16R, and 20s. It is worth noting that cuauchichi-
cine is the first normal-type oxazolidine ring-containing alkaloid that does
not exist as a pair of epimers at C-20, either in solution or in the solid state.
D. GARRYFOLINE-CUAUCHICHICINE
REARRANGEMENT
20 R = H 21 R = H 22
23 R = D 24 R = D
25
31 30 33
SCHEME
1
112 S . WILLIAM PELLETIER AND NARESH V. MODY
E. NAPELLINE
(LUCICULINE),
ISONAPELLINE, LUCIDUSCULINE,
AND
12-ACETYLNAPELLINE
Napelline (34) was isolated by Freudenberg and Roger (40) in 1937 from
the poisonous roots of Aconitum napellus L. Recently, napelline has been
isolated (41) from the tubers and roots of A . karakolicum, which were
collected in the Terskei Ala-Tau ranges of the Kirghiz S.S.R.
Early work on the chemistry of napelline has been reviewed by Wiesner
and Valenta (12)and later by Pelletier and Keith (6).On the basis of extensive
chemical work (42-47) and X-ray analysis (48, 49) of lucidusculine (35),
structure 34 was assigned to napelline. Recently, Wiesner and co-workers
OH OH
34 Napelline 35 Lucidusculine
2. THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS 113
36 37 Isonapelline
0Ac OR
38 12-Acetylnapelline 39 R = AC
40 R = H
OAc 0Ac
41 42
F. SONGORINE OR SHIMOBURO
(NAPELLONINE BASEI), NORSONGORINE,
SONGORINE
N-OXIDE,AND SONGORAMINE
CH,
OH
43 44 Songorine
&CH2 - -H \ ;‘ ,^. ~ . \ \
C H -..-.-N
oY&CH2 - -H
,, ..
H... -.N
2 5 ,
OH OH
‘ CH, ’ CH,
45 Norsongorine 46 Songorine N-oxide
2
,,
,&CH2 , .T..
I
C H .+---.N
5 ,
,
4..:.:
,
,
CH3
47 Songoramine
.
,
- -H
OH
&
C2 H 5 ... ..N
”
*, .
,,~ .
CH,
48
,’
--H
OH
‘H
H3
116 S. WILLIAM PELLETIER AND NARESH V. MODY
49 R = AC
50 R = H
Tau range). Occurrence of the same alkaloid was also reported earlier in the
roots of A . soongoricum Stapf (66,67).
The structure of songoramine was established on the basis of mass spec-
tral analyses and conversion to songorint: (44).The spectral and chemical
properties of songoramine are very similar to those of songorine. Hydrogena-
tion of songoramine over platinum yielded a tetrahydro derivative (48), which
proved to be identical to dihydrosongorine. Acetylation of 47 with acetic
anhydride and pyridine gave an unusual immonium salt (49). Treatment of
songoramine with hydrochloric acid also gave a quaternary immonium salt
(SO). Thus, the presence of a carbinolamine ether in 47 was demonstrated
by reductive opening and immonium salt formation. Finally, oxidation of
songorine with silver oxide afforded songoramine, which confirmed its
structure. The mass spectral data of songoramine, songorine, dihydro-
songorine, and their acetate derivatives were analyzed. These results are
discussed in Section VII.
G. ANOPTERINE,
ANOPTERIMINE,
ANOPTERIMINE
N-OXIDE,
A N D DIHYDROXYANOPTERINE
HYDROXYANOPTERINE,
Anopterine (Sl),the major alkaloid of the leaf and bark of Anopterus
macleayanus F. Meull and bark of A . glandulosus Labill., has been isolated
(68,69) by Lamberton and co-workers. Crude extracts of both Anopterus
species have shown some preliminary antitumor activity in a number of test
systems. The structures of anopterine and its hydrolysis product, anopteryl
alcohol (S2), were assigned on the basis of a single-crystal X-ray analysis
(68) of the azomethine iodide (53). The latter was formed on treatment of
tetraacetylanopteryl alcohol (54) with methyl iodide in acetone after several
weeks. Anopterine fails to form salts with mineral acids and simple organic
acids because one of the C-2 and C-5 hydroxyl groups is strongly hydrogen
bonded to the nitrogen.
In order to confirm that no other change apart from the formation of the
C-19 imine bond had occurred during the transformation of the tetraacetate
2. THE CHEMISTRY OF C ~ ~ - D I T E R P E N O IALKALOIDS
D 117
H3 7
H A , p 3
,CH3
,c=c 0-CO-c=c, OR
H 2H. ?HO..
;:- ' co-0.. 'H
H,C------N OH
' CH,OH
51 Anopterine 52 R = H
54 R = AC
OAc
53
55 56
118 S. WILLIAM PELLETIER AND NARESH V. MODY
(52) confirmed that no skeletal rearrangement had occurred other than the
formation of an imine bond during the transformation of 54 to 53. These
results also confirmed the structure of anopteryl alcohol and its tetraacetate.
::;,5:--CH2
H,C------N
HO.. OH
OH
'~ CH,;
\-- .....0
57
H O . @CH2
~ ,. ......
-. -, AcO.. @CH2
, , --- --
9- ,
... .......
OAc &CHz OR
CH, 0
54 R' = R 2 = AC 63 R = H
60 R' = Ac, R 2 = H 64 R = A c
61 R' = H, RZ = AC
62 R' = R 2 = H
OH
65
67 68
120 S. WILLIAM PELLETIER AND NARESH V. MODY
CH, OAc
69
Formation of the diacetyl compound (69) from the triketone (66) indicated
that all of the ketones which underwent this anomalous acetylation reaction
must have a C-2 0x0 group. Evidently a C-6 hydroxyl group is not necessary
for this unusual acetylation reaction to form compounds such as 69. This
idea was supported by the formation of only a monoacetyl derivative from
the tetraketone (68). The conformational argument was that if ring A
assumed a boat form, formation of an acetal at C-2 with an oxygen bridge
between C-2 and C-5 could occur by reaction of the C-5 hydroxyl group
with the C-2 0x0 group. Then ring B could assume a boat conformation
with the piperidine ring changing from boat to chair form to minimize ring
strain. On the basis of the arguments presented above, the tertiary acetoxyl
group was assigned to C-2 in 69. Mild hydrolysis of 69 in dilute methanolic
potassium hydroxide regenerated the original ketone 66, a result that indi-
cated that no skeletal rearrangement was involved during this anomalous
acetylation reaction. All the reaction products reported here were supported
by detailed 'H-, 13C-NMR,and mass spectral data.
In 1976, Lamberton and his colleagues reported (70)the isolation of two
minor alkaloids, anopterimine and anopterimine N-oxide, from the leaves
of A . macleuyanus F. Muell. These alkaloids were not encountered in the
related species, A . glandulosus Labill. On the basis of extensive 'H- and
13
C-NMR analyses, structures 70 and 71 were assigned to anopterimine and
anopterimine N-oxide, respectively.
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 121
CH, OH
72 Hydroxyanopterine 73 Dihydroxyanopterine
122 S . WILLIAM PELLETIER AND NARESH V. MODY
A. ATISINE
AND ISOATISINE
the basis of a 'H-NMR study that atisine exists as two different conformers
of the piperidine ring (chair 77a and boat 77b) in 1 : 2 ratio, respectively, in
CDC1, solution at room temperature. Subsequently, on the basis of a deu-
terium study, Pradhan and Girijavallabhan (79) suggested that atisine in
solution is a mixture of isomers which differ in configuration at C-20 and
which are interconvertible via a zwitterion. On the basis of a 13C-NMR
study of atisine and related alkaloids, Pelletier and Mody (27, 28) demon-
strated that atisine exists as a mixture of C-20 epimers 4a and 4b in nonionic
solvents (e.g., chloroform, benzene etc.). The presence of two different sets
of signals for the oxazolidine and piperidine rings in the I3C-NMRspectrum
of atisine in CDCI, solution at room temperature suggested the existence of
a pair of epimers. The fact that the oxazolidine ring of atisine is regenerated
from atisinium chloride (5), in which (2-20 is trigonal, by treatment with base
suggested that formation of the oxazolidine ring takes place from both sides
of the trigonal C-20 carbon to give epimers 4a and 4b. Thus, atisine can be
represented by structure 4, indicating the presence of both C-20 epimers in
the same formula.
y
' CH, ' CH, CH,
4a 4b
has been described in detail in several reviews (6, 8, 13) published between
1960 and 1970.
B. DIHYDROATISINE
AND ATIDINE
78 Dihydroatisine 79 Atidine
AND DIHYDROAJACONINE
C. AJACONINE
Ajaconine, the major alkaloid of the seeds of Delphinium ajacis syn.
Consolida ambigua (garden larkspur) and D. consolida, has been known
since 1913 (83).Recently, ajaconine has been isolated from the whole plants
of D . virescens Nutt (84)and D. carolinianum (85),two relatively rare plants
native to the southeastern United States. In 1961, Dvornik and Edwards
(86) reported a full account of the structure elucidation of ajaconine as 80.
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 125
The chemical work on ajaconine has been reviewed ( 6 )in Volume XI1 of this
treatise. Recently, Pelletier and Mody reported (87) an unusual rearrange-
ment of ajaconine to 7%-hydroxyisoatisine(82) via a disfavored 5-endo-
trigonal ring closure, which is discussed in Section V.
81 Dihydroajaconine 80 Ajaconine
D. KOBUSINE
AND PSEUDOKOBUSINE
R2
?.
.,
~..-
"' '' OH
N--- ..
CH 3 CH 3
83 R' = OH, R2 = H 85
84 R' = H. R2 = OH
2 : $ N - - - .~ OH
CH, R
86 R = H Kohusine
87 R = OH Pseudokobusine
86 88
90 89
91 R’ = Ac, R 2 = C6H5 94 R = H
92 R’ = H, RZ = C,H5 95 R = CI
93 R’ = H, RZ = CHzC6H5
96 91
,.CH,
99 R' = C1, R2 = H 98
100 R' = C1, R2 = AC
101 R' = H, R 2 = AC
E. IGNAVINE
AND ANHYDROIGNAVINOL
Ignavine was isolated by Okamoto and co-workers (97) in 1952 from the
roots of A . sayoense Nakai. Subsequently, this alkaloid was also isolated
from the roots of A . tasiromontanum Nakai (97, 98) and A . japonicum (99).
Alkaline hydrolysis of ignavine gave an amino alcohol, anhydroignavinol,
and benzoic acid.
On the basis of spectral and chemical studies (loo),the tentative structures
102 and 103 were assigned to ignavine and anhydroignavinol, respectively.
Anhydroignavinol was reported to have a molecular formula of C20H25N04
(MW 343) and was assumed to arise from hydrolysis of the benzoate ester
102 103
2. THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS 129
104 Anhydroignavinol
F. HYPOCNAVINE
AND HYPOGNAVINOL
105a R = Bz 105b R = Bz
106a R = H 106b R = H
OH
1
CH,
107 Hypognavinol
G. ISOHYPOGNAVINE
Isohypognavine has been isolated (99, 106) from the roots of A . majijai
Nakai and A . juponicurn Thumb. Its name is unfortunate since it is not an
isomer of hypognavine. This alkaloid has not been isolated from any other
Aconitum species. On alkaline hydrolysis, isohypognavine gave an alkamine
known as isohypognavinol. On the basis of chemical correlation (107) of
isohypognavine with kobusine, the partial structures 108 and 109 were
HO. ,CH,
108 109
110 R = Bz Isohypognavine
111 R = H Isohypognavinol
2. THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS 131
H. DENUDATINE
In 1961, Singh (108) isolated denudatine (C,,H,,NO,, MW 331) as a
minor alkaloid of the roots provisionally identified as D.denudutum Wall.
On the basis of chemical and spectral evidence, Indian chemists (109, 110)
tentatively assigned structure 112 to denudatine. Later work indicated that
the 'H NMR and mass spectra of denudatine did not agree with the assigned
structure. Canadian (111) and American (112) chemists independently
showed that the correct molecular formula for denudatine is CZ2H3,NO2as
evidenced by the mass spectrum (mle 343). The 'H-NMR spectrum of
denudatine revealed the absence of an N-methyl group. On the basis of
spectral and degradation studies, Wiesner and Gotz (111) indicated that
denudatine can be assigned any one of four possible structures 113,114,115,
or 116, in which C-20 could be connected to C-7 or C-14 and the secondary
hydroxyl group can be at C-1 1 or C-13. Subsequently, Brisse (113) and the
American investigators (112) reported independently a single-crystal X-ray
diffraction analysis of denudatine and its methiodide and established the
structure and stereochemistry of denudatine as 117.
It is noteworthy that denudatine is the first C,,-diterpenoid alkaloid with
an atisine skeleton possessing both an N-ethyl and a C-7-C-20 bridge. The
biosynthetic implications of this alkaloid were mentioned by the Canadian
chemists (212).
RZ
OH
I. VAKOGNAVINE
Vakognavine has been isolated by Singh and Singh (114)from the indige-
nous crude drug known as “uakhma”, which was identified as the roots of
A . palmatum Don. On the basis of the isolation of 1,9-dimethyl-7-ethyl-
phenanthrene from the selenium dehydrogenation products, Singh and
Jaswal (115) postulated a songorine-type skeleton (118) for vakognavine.
Spectral data revealed the presence of a tertiary methyl, an N-methyl, a
benzoate, and three acetate groups in vakognavine. They also mentioned
(115)that vakognavine is an highly oxygenated alkaloid of the atisine group.
In 1971, Pelletier and co-workers (116) reported a single-crystal X-ray
analysis of vakognavine hydriodide (119) and established the structure of
vakognavine to be 120. The presence of the C-19 aldehyde in vakognavine
was indicated by a singlet at 6 9.43 in the ‘H-NMR spectrum in chloroform
solution. The aldehyde singlet disappeared on the addition of trifluoroacetic
acid and the unchanged free base was recovered on basification.
Later Singh and co-workers (117) published additional chemical and
spectral data supporting structure 120 for vakognavine. On hydrogenation
with Adams catalyst, vakognavine gave the hexahydro compound 121 in
which the exocyclic double bond and both the carbonyl groups were reduced.
Vakognavine formed a bishydrazone, which was characterized as the
118 119
2. THE CHEMISTRY OF Cz,-DITERPENOID ALKALOIDS 133
BzO..
120 Vakognavine
OH 0
'5. \\
J. HETISINE
(DELATINE)
AND HETISINONE
RO
om N---
:,
RO\
R 0 . . H H 2
CH3
__
HO
H O . . e Z
RO
130 R = H 133
131 R = MS
134 135
K. HETIDINE
Hetidine has been isolated (80) in very small quantity from the strongly
basic fraction of the extracts of the roots of A . heterophyllwn Wall. The
presence of an N-methyl group, a tertiary methyl group, two acetylable
hydroxyl functions, two ketones, and an exocyclic double bond in hetidine
136 S . WILLIAM PELLETIER AND NARESH V. MODY
was revealed by chemical and spectral data. Because hetidine was not avail-
able in sufficient quantity, the structure of this alkaloid was established by
a single-crystal X-ray analysis of hetidine hydriodide (128). The latter was
prepared by prolonged treatment of hetidine with methyl iodide in dimethyl-
formamide. The structure of hetidine hydriodide was established as 138;
thus hetidine was assigned structure 139. The masked aminoketone group
of hetidine hydroiodide is analogous to that existing in pseudokobusine and
miyaconitine.
HO..
L. MIYACONITINE
AND MIYACONITINONE
144
0
&H2
HRO..@
C . . ...N
5
'OR
:, H
CH, 0
145 R = H Miyaconine 147 R = H Apomiyaconine
146 R = Ac 148 R = Ac
M. DELNUDINE
During the isolation of denudatine, Gotz and Wiesner (135)also isolated a
new alkaloid, designated as delnudine (149),from the seeds of D.denudutum.
Preliminary spectral data revealed the presence of two hydroxyls, a cyclo-
hexanone, and an exocyclic double bond in proximity with the ketone. The
presence of the tertiary carbinolamine moiety was demonstrated by the
formation of a basic diacetate (150) and a neutral 0,N-diacetate (151) on
acetylation with acetic anhydride in pyridine. They demonstrated that one
of the ketones in compound 151 was derived from the carbinolamine moiety.
Finally, the structure of delnudine was established as 149 by a single-crystal
HO..
N. SPIRADINE
A, SPIRADINE
B, AND SPIRADINE
C
In 1964 Molodozhnikov and co-workers (137) reported the isolation of
several diterpenoid alkaloids from the shrub Spiraea japonica L. fil. of the
Roseaceae family. Later Goto and co-workers (138) examined alkaloids
of the same plant (Japanese name “Shimotsuke”) and isolated 10 new al-
kaloids. The structures of 3 of these, spiradine A (152), spiradine B (153),
and spiradine C (154) have been determined by chemical correlations cou-
pled with a single-crystal X-ray analysis (139) of spiradine A methiodide
(155).
Reduction of spiradine A with sodium borohydride in methanol at room
temperature afforded spiradine B. Oxidation of the latter with CrO, in
pyridine regenerated spiradine A. Hydrolysis of spiradine C with potassium
hydroxide in ethanol yielded spiradine B. Treatment of spiradine A with
acetic anhydride in pyridine gave an 0-acetate (156) and an N-acetate (157).
The structures of these acetylation products were based on IR and ‘H-NMR
data. When treated with methyl iodide in methanol, spiradine A gave a
CH, 0
155 157
140 S. WILLIAM PELLETIER AND NARESH V. MODY
methiodide (155), which was treated with silver oxide in 50% aqueous meth-
anol to yield an N-methyl diketone (158). The latter was heated with
methyl iodide at 100" in a sealed tube followed by treatment with silver
oxide to afford 159. These transformations provided evidence for the
I
-N-C-CH,-& functionality in spiradine A. Finally, the structure
OH
of spiradine A was determined by an X-ray analysis (138, 139). With the
structure of spiradine A elucidated as 152, the structures of spiradine B
(153), and spiradine C (154) were assigned accordingly.
0. SPIRADINE
D AND SPIREDINE
Spiradine D was also isolated from S. japonica by Goto and Hirata (140)
in 1968. The structure of spiradine D (160) was elucidated by chemical
correlation between spiradines A and D.
164 165
166 167
P. SPIRADINE
F AND SPIRADINE
G
In 1968, Toda and Hirata (142) reported the isolation and structure de-
termination of two major alkaloids of S. juponicu, spiradine F and spiradine
G. Spiradine F is an acetate of spiradine G. On the basis of extensive chemi-
cal and spectral studies, the Japanese chemists (142) assigned structures
171 and 172 to spiradine F and spiradine G, respectively.
176 177
178
Q. SPIREINE
In 1964, Soviet chemists (137)reported the isolation of a new alkaloid,
spireine, from S. japonica and later they proposed (143) alternative struc-
tures 180 or 181 for this new alkaloid. Chemical and spectral studies
144 S. WILLIAM PELLETIER AND NARESH V. MODY
revealed the presence of two keto groups, a tertiary hydroxyl group, two
tertiary methyl groups, and an exocyclic double bond in spireine.
180 181
CHO
184
A. STAPHISINE
AND STAPHIDINE
H,C-- H,C--
In 1976, the same group (148) found that Jacobs' "staphisine" is a mixture
of alkaloid 185 and a companion nonmethoxyl-bearing alkaloid designated
as staphidine, C4,H,,NZ0. The structure of staphidine (187) was elucidated
by a comparison of its 'H- and I3C-NMR, IR, UV, and mass spectra with
those of staphisine (185). The presence of a conjugated diene system was
confirmed by observing UV absorption at i,,, 268 nm ( E 17,300). The IR
spectrum exhibited no N H or OH absorption. The mass spectrum showed
an intense molecular ion peak at mje 606 corresponding to the molecular
formula, C4,H5,N,0. The 'H-NMR spectrum of staphidine revealed the
presence of two tertiary methyl groups at 6 2.13 and 6 2.21 and a vinyl
proton at 6 5.85. Comparison of its 'H-NMR spectrum with staphisine
showed the absence of a methoxyl singlet at 6 3.30 and an upfield shift of
one N-methyl group from 6 2.27 to 6 2.21 in staphidine. The observed
change (A6 = 0.06) in the chemical shift of the N-methyl was explained
by the steric interaction between the NCH, and OCH, group in the A unit
of staphisine. On the basis of this observation, the chemical shift at 6 2.13
was assigned to the N-methyl group in unit B of staphisine and staphidine
and that at 3 2.27 and 2.21 to the N-methyl group in unit A in staphisine
(185) and staphidine (187), respectively. Further correlation of staphidine
with staphisine was made through their respective I3C-NMR spectra. This
comparison afforded evidence for the absence of a methoxyl group at 57.8
ppm and a C-13 methine carbon at 89.4 ppm in staphidine. Based on these
data, structure 187 was assigned to staphidine.
B. STAPHININE
AND STAPHIMINE
Besides the two bisditerpenoid alkaloids discussed earlier, two new imine-
containing alkaloids designated as staphinine and staphimine have been
isolated (148)from the seeds of D.stuphisagria. The structures of staphinine
(188) and staphimine (189) were also assigned on the basis of I3C- and
'H-NMR spectral analysis.
The 'H-NMR spectrum of staphinine revealed the presence of two an-
gular methyl groups at 6 0.94 and 6 1.00, one N-methyl group at 6 2.13,
a methoxyl group at 6 3.30, a vinyl proton at 6 5.85, and an imine proton
at 6 7.30. The 'H-NMR spectrum of staphimine was similar except for
the absence of a methoxyl singlet at 6 3.30. The 'H-NMR data indicated
that these two alkaloids are very similar to each other and are related to
the earlier reported alkaloids staphisine and staphidine. The presence of
an imine (-N=CH-) group in staphinine and staphimine was established
'
by comparison with 3C-NMR shifts of known atisine derivatives contain-
ing an imine group, e.g., atisine azomethine. The presence of an imine group
in the A unit of these alkaloids was consistent with the observed downfield
2. THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS 147
shift of the C-4 carbon and the upfield shift of the C-20 carbon in staphinine
(188) and staphimine (189) relative to the known alkaloids staphisine and
staphidine, respectively. This was also confirmed on the basis of an N-methyl
singlet at 6 2.13 in the 'H-NMR spectrum of both alkaloids. On the basis
of these spectral data, structures 188 and 189 were assigned to staphinine
and staphimine, respectively.
The authors were unable to carry out any transformation of staphinine
and staphimine to staphisine and staphidine, respectively, because of the
instability of these alkaloids toward various mild reducing agents (e.g.,
sodium borohydride, sodium cyanoborohydride). Staphimine and staph-
inine occur in extremely small amounts in the seeds of D . stuphisagria. It
has been suggested that the imine-containing alkaloids may be biogenetic
precursors of staphisine and staphidine.
C. STAPHIGINE
AND STAPHIRINE
Y
H,C--
methyl groups at 6 0.94 and 1.12, two N-methyl groups at 6 2.13 and 2.98,
a methoxy singlet at 6 3.30, and a vinyl proton at 6 5.85. The 'H-NMR
spectrum of staphirine was identical to that of staphigine except for the
absence of a methyl singlet at 6 3.30. The downfield tertiary methyl singlet
at 6 1.12 in these alkaloids confirmed the presence of the lactam and this
value was in perfect agreement with the value observed for the methyl
singlet (6 1.12) of the atisine lactam derivative (192). The presence of the
lactam in the A unit of these alkaloids was established by the appearance
of an N-methyl singlet at 6 2.13 in the 'H-NMR spectra and the constant
13Cchemical shifts shown by the C-19, C-20, and NCH, carbons of staphi-
gine and staphirine by comparison with the known alkaloids staphisine (185),
staphinine (188), and staphimine (189). The authors indicated that these
lactam alkaloids did not arise as artifacts by oxidation of staphisine and
staphidine during isolation.
D. STAPHISAGNINE
AND STAPHISAGRINE
H,C--
The IR and 'H- and I3C-NMR spectra of these alkaloids showed some
similarity to the known alkaloids staphisine (185) and staphidine (187).
The 'H-NMR spectrum of staphisagnine revealed the presence of two ter-
tiary methyl groups at 6 0.82 and 0.93, one N-methyl group at 6 2.27, a
methoxyl group at 6 3.30, an N-CH-0 proton as part of an oxazolidine
ring at 6 4.06, and a vinyl proton at 6 5.93. The 'H-NMR spectrum of
staphisagrine was identical to that of staphisagnine except for the absence
of a methoxyl singlet at 6 3.30. The presence of the oxazolidine ring in the
B unit of these alkaloids was established by 'H-NMR analysis. The latter
was confirmed through a comparison of their 13C chemical shifts with
those of the known oxazolidine ring-containing alkaloids, veatchine,
garryine, atisine, and isoatisine.
It is interesting to note that these two bisditerpenoid alkaloids did not
contain the conjugated diene system, which is present in the other six bis-
diterpenoid alkaloids. Biogenetically, it is worth noting that all these bis-
diterpenoid alkaloids occur as methoxyl and desmethoxyl pairs in the seeds
of D.staphisagria.
MeOH
OH
80 82
OCH, OCH,
195 196
OCH, OCH,
197 198
204 205
205
80 Ajaconine
209 82
210 1 Veatchine
2. THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS 155
78 R = H 10 R = AC
211 R = Ac 212 R = H
80 214
I
A CHCI,
213 215
156 S. WILLIAM PELLETIER AND NARESH V. MODY
“OH
80 R = H Ajaconine 82 R = H
216 R = AC 217 R = AC
7 Lindheimerine 6 Ovatine
4 Atisine 75 Isoatisine
Unlike ethylene oxide, oxetane reacted very slowly with the alkaloid
imine derivatives to afford low yields of tetrahydro-l,3-oxazine derivatives.
Treatment of veatchine azomethine acetate (10) with oxetane in acetic acid
at 50" afforded the six-membered carbinolamine ether, homoveatchine
acetate (220), in 25% yield. The latter was isolated as a mixture of C-20
epimers.
158 S. WILLIAM PELLETIER AND NARESH V. MODY
10 220
221 222
On the basis of these results, the authors designed (152) a reaction with
imines in which either a five- or six-membered carbinolamine ether might
be formed. Treatment of veatchine azomethine acetate with glycidol af-
forded compound 221 as the major product. The structure of 221 was es-
tablished by 3C-NMR spectroscopy and confirmed by a single-crystal
X-ray analysis. The presence of a five-membered ring containing compound
222 was not detected in the reaction mixture. In a similar reaction, atisine
azomethine acetate (218) reacted with glycidol to yield a mixture of the
C-20 epimers of compound 223. Surprisingly, treatment of ajaconine azo-
methine acetate (215) with glycidol gave the single C-20 epimer (224). This
218 223
“OAc
CH 3
215 224
2. THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS 159
4a 4b
227 228
162 S. WiLLIAM PELLETIER A N D NARESH V. MODY
229 R = H 231 R = H
230 R = CH3 232 R = Ac
233 R =H
234 R = CH,
A). Loss of rings C and D to form an ion with m/e 246 was considered to be
the one-state transition. The latter was supported by a metastable peak. All
the fragments containing ring C eliminate a formyl group or carbon mon-
oxide. Formation of an ion with m/e 180 occurs directly from the molecular
ion (Pathway B) by the expulsion of ring A, C, and D atoms. The metastable
peak for rnje 180 ion was also observed. On the basis of the given pathway
for the formation of rnje 180 ion, we have reassigned the structure of this ion.
The fragmentation pattern of the mass spectrum of songorine diacetate
(Pathway C) was not particularly revealing compared with that of songorine.
The splitting off of the C- 15 acetyl group is manifested by the M - 43 peak
+
(m/e 398). The strongest peak in the mass spectrum of songorine diacetate
is the M f -59 peak (mje 382). This ion is further fragmented to a small
extent with the expulsion of ketene or carbon monoxide as observed in the
case of songorine. There are no major peaks in the lower mass region.
For dihydrosongorine and its diacetate. major fragmentations were
postulated to involve loss of ring D (Pathway D and E). In the case of di-
hydrosongorine, the ion-radical with rnje 301, in which loss of ring D has
occurred, is the base peak, whereas in the diacetate mje 384 (loss of the C-1
acetoxyl group) is the strongest peak. Comparison of the mass spectrum of
dihydrosongorine with that of its diacetate reveals that the presence of two
acetate groups has some influence on the fragmentation patterns. Metastable
peaks are observed for both transitions.
44 Songorine M + 357 (100)
/ m / e 328 (16)
0 0
II
-
II
N’
OH ;! H,C’ OH
CH 3 CH3
Pathway B
\ 0
/I
m ’ e 398 ( 5 7 )
Pathway C
166 S. WILLIAM PELLETIER AND NARESH V. MODY
I 0
J I
C,H 5- Lq$
N/
C,H,--
I
CH 3
M e 242 m P 284
Pathway E
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 167
The molecular ion peak is the strongest peak in the mass spectrum of
songoramine (Pathway F). The fragmentation of songoramine begins with
the cleavage of the carbinolamine ether linkage and ring A. The ion-radical
with m/e 299, which arises from the explusion of acrolein, fragments further
into an ion with mje 122. Both transitions are confirmed by metastable
peaks. The ion with mje 299 also originates from the radical-ion with mle
327 by the loss of carbon monoxide, which was confirmed by the metastable
peak. Some assignments for songorine and dihydrosongorine were confirmed
by deuterium labeling of the hydroxyl groups and exocyclic methylene group.
0 0
CH 3
m/e 299 (46)
C2H5
In 1978 Yunusov and colleagues (59) reported the mass spectral data of
napelline and several of its derivatives. The fragmentation data for napelline.
1-acetylnapelline, 12-acetylnapelline, triacetylnapelline, anhydrohydroxy-
acetylnapelline, isoacetynapelline, dihydronapelline, and isonapelline were
tabulated showing the intensities of various ion peaks.
Sastry and Waller (89, 160) analyzed a deuterated trimethylsilyl derivative
of ajaconine on a gas chromatograph-mass spectrometer (GC-MS) system.
They found that the crystalline sample earlier identified as pure ajaconine
was a mixture of five compounds. Peak 1 with retention time (R,) of 12.7 min
had a molecular ion of 477. Peaks 2 ( R , = 17.3 min), 3 (R, = 21.0 rnin),
and 4 (R,= 25.5 min), all with a molecular ion of 521 (503 for the non-
deuterated TMS derivatives), accounted for the di-TMS derivatives of
168 S . WILLIAM PELLETIER AND NARESH V. MODY
ajaconine. Peak 5 ( R , = 27.8 min) had a molecular ion of 604 which indi-
cated the presence of three deuterated TMS groups. Structural assignments
for the five compounds were made on the basis of their fragmentation
patterns.
A. TOTALSYNTHESIS
OF OPTICALLY
ACTIVE
VEATCHINE
In 1970, Professor Wiesner and co-workers (161)reported the first total
synthesis of optically active veatchine (l),the major alkaloid of G. veatchii.
An improved synthesis (162) of ketones 244 and 245 from compound 235
has been reported. These ketones had been synthesized (163) previously
and transformed to veatchine.
Lithium aluminium hydride reduction of 235 followed by mesylation
afforded 236. The latter was oxidized with osmium tetroxide and sodium
metaperiodate to yield the cyclobutanone 237. Treatment of 237 with acid
afforded in 48% yield the ketoacid (238), which was esterified with diazo-
methane to 239. The latter was converted to the ketal240 by treatment with
ethylene glycol and p-toluenesulfonic acid. Compound 240 was reduced
with lithium aluminium hydride to the alcohol 241. This alcohol had been
synthesized previously by Nagata and co-workers (164) by an entirely dif-
ferent route. The azide 242 was prepared in 80% yield by mesylation of
241 and treatment of the product with sodium azide. Lithium aluminium
hydride reduction of 242 gave the primary amine, which was converted to
the urethane 243 by treatment with ethyl chloroformate. The ketal group
of 243 was removed by acidic hydrolysis and the resulting ketone was nitro-
sated with N,O, and sodium acetate. Decomposition of the nitrosourethane
with sodium ethoxide in refluxing ethanol afforded the ketone 244 in 65%
yield. The latter had been also synthesized previously by Japanese chemists
(165). The ketone 244 was converted to the ketal 246 and the latter to 247
R--
244 R = Ms 246 R = MS
245 R = COCH, 247 R = COCH,
248 R = H 1 Veatchine
0
'I
249 R = C(CH,),CO,H
170 S. WILLIAM PELLETIER A N D NARESH V . MODY
and the half-esters were hydrolyzed. The resulting alcohols were oxidized to
the respective ketones. The identity of the synthetic enantiomer with the
same absolute configuration as the natural ketone 244 was established by
mixture melting points and their ORD curves. The naturally derived ketone
244 was prepared for comparison purpose from 245 in the same manner,
substituting acetylation for mesylation as mentioned earlier. The naturally
derived ketone 245 had previously been prepared from veatchine by Vor-
bruggen and Djerassi (25).
Since Canadian chemists had earlier published (163) work on the con-
version of the degradation product 245 ofveatchine to garryine and veatchine,
the total synthesis of the natural optically active form of these alkaloids is
thus completed.
B. TOTALSYNTHESIS
OF NAPELLINE
250 34 Napelline
2. THE CHEMISTRY OF C2,-DITERPENOID ALKALOIDS 171
OCH, OCH,
;-"
0
251
COZCH, %COzCH3
HO
252
QCOzCH3
253
@. oc3H 0
0
254 255 R = CO,CH, 258
256 R = CHzOH
257 R = CHO
C,H,CH,O
CH, ORZ
HO
CH, 0
263 264
OCH ,
CH, 0
OAc
265 266
R
I
I
Ac-1--r*
CH, CH,
267 R' = H, RZ = CH,CHO 271 R = O
268
269
R'
R'
= Ac, R 2 = CH=CHOAc
= Ac, R 2 = CHO
272 R = <"I
0
270 R' = H, RZ = C02CH,
2. THE CHEMISTRY OF C2 0-DITERPENOID ALKALOIDS 173
yield. The latter was heated under reflux with methanolic sodium methoxide
to yield the lactam 273 in a yield of 80%. During this reaction, the C-5 center
was epimerized to form the A,B-trans-isomer as expected. Compound 273
was converted to 274 by Wolff-Kishner reduction. The desired intermediate
250 was obtained (169, 171, 172) by deketalization of 274 with a mixture of
hydrobromic and acetic acids.
213 R =0 250 R = H
274 R = H, 275 R = CH,CH=CHCH3
The phenol 250 was converted to the crotyl derivative 275 by treatment
with crotylchloride and potassium carbonate in DMF. Compound 275 was
rearranged by heating at 180-185" for 2 hr to afford a mixture of methyl
epimers 276 in 8 1.5"/0yield. This mixture was methylated with methyl iodide
and potassium carbonate to yield the methyl ether 277. Oxidation of 277
with osmium tetroxide and sodium periodate afforded the aldehyde 278
in 80% yield. Conversion to the diketal279 and reduction of 279 with lithium
in liquid ammonia followed by work-up yielded a dehydro compound, which
was treated with p-toluenesulfonic acid in a mixture of benzene and acetone
to give the diastereoisomeric mixture 280 in 50% yield. This mixture under-
went a vinylogous aldol condensatation on treatment with methanolic po-
tassium hydroxide. The products were isolated by preparative TLC and
oxidized with chromium trioxide and pyridine in CH,C12 to yield the di-
ketones 281, 282, 283, and 284. The diketone 281 was identical by TLC,
and mass and infrared spectra with the optically active compound prepared
216 R = H 278
211 R = CH,
174 S. WILLIAM PELLETIER A N D NARESH V. MODY
R FH3
219 280
281
0
II
289
OAc
295
C. CONSTRUCTION
OF THE DENUDATINE
SKELETON
The New Brunswick group's synthetic studies have led to the elaboration
of the carbon skeleton of denudatine (117). The synthesis (173) of inter-
mediate 296 from 258 should eventually lead to the total synthesis of denu-
datine.
Compound 258 was prepared according to the procedure described during
the synthesis of napelline in Section VII1,B. The hydroxyl group of 258
was removed by mesylation and subsequent lithium aluminium hydride
reduction to give 297. The latter was converted to the pentacyclic aromatic
intermediate 298 using a reaction sequence employed for the synthesis (169)
258 R = OH 298
291 R =H
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 177
299 300
301 R = H 303
302 R = SO,CH,
C2H5-SvH C2H5-S
quantitative yield. Treatment of 312 with 70% perchloric acid in THF gave
the a$-unsaturated ketone 313. Compound 313 was treated with an excess
of methanethiol to furnish the addition product 314. Hydroboration followed
by oxidation with hydrogen peroxide afforded an epimeric mixture 315 in a
total yield of 85%. Acetylation of 315 with acetic anhydride and pyridine
gave 316. Partial hydrolysis of 316 furnished the monoacetate 317 which
was oxidized with N,N-dicyclohexylcarbodiimideand DMSO to give the
ketoacetate 318. Hydrolysis of 318 to 319 and subsequent treatment with
methyl iodide gave the ternary sulfonium iodide which by refluxing with
aqueous potassium carbonate afforded the hydroxyketone 304. The struc-
ture of 304 was determined by a single-crystal X-ray analysis of its p-
bromobenzoyl derivative 320.
D. A SYNTHETIC TO AJACONINE
APPROACH AND ATIDINE
CH 3
323
CH3
80 Ajaconine
180 S. WILLIAM PELLETIER AND NARESH V. MODY
d3d3
of 329 with maleic anhydride in refluxing toluene followed by esterification
@
H H OH
'~~ 'I \ ~ \ H
CH,O,C CH3 CH30,C CH3 CH30,C CH3
324 325 326
OAc OAc
afforded a mixture of the triesters 330 and 331. Compound 330 was selec-
tively hydrolyzed with potassium hydroxide to give the monoester 332, which
was hydrogenated using platinum on carbon in acetic acid to afford 333.
Oxidative bisdecarboxylation of 333 with lead tetraacetate afforded the olefin
334, which was hydrolyzed to the acid 335. Treatment of 335 with thionyl
chloride followed by sodium azide in aqueous dioxane furnished the azide
336. Photolysis of the azide afforded the lactam 323. This lactam is a key
intermediate for the synthesis of ajaconine and atidine.
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 181
..... CO,H
I\\ H
CH,O,C
CH,O, CH, R02C CH3
333 334 R = C H ,
335 R = H
CH ,
0
336 323
yield. The aldehyde was treated with the Grignard reagent prepared from
5-bromopent-1-ene in THF to give the epimers 342 and 343. These alcohols
were converted to the methoxyl derivatives 344 and 345 by methylation
with methyl iodine and sodium hydride in dioxane.
The aldehydes 346 and 347 were prepared from the methoxyl derivatives
by osmic acid-sodium chlorate oxidation and deketalization followed by
base-catalyzed condensation in an overall yield of 50%. Acetalization of 346
withp-toluenesulfonic acid and ethylene glycol in refluxing benzene afforded
the acetal 348. The latter has an active site at C-6 suitable for the intro-
duction of oxygen substituents at this position.
OCH, OCH
I I
CHO
The acid 350 was demethylated with pyridine hydrochloride, then realkyl-
ated with benzyl bromide in aqueous potassium hydroxide to give 351. The
latter was converted to the diazoketone 352 by the sequential treatment
of 351 with oxalyl chloride and etheral diazomethane. Reaction of 352 with
concentrated hydrobromic acid gave the bromoketone 353. The latter was
reduced with sodium borohydride at pH 8 -9 to yield a mixture of diastere-
omeric bromohydrins 354. Protection of the free hydroxyl as a tetrahydro-
pyranyl ether and hydrogenolysis of the benzyl residue afforded 355. The
phenol 355 was heated under reflux with potassium tert-butoxide in tert-
butyl alcohol for 5 hr to give a 3 : 1 epimeric mixture of dienone ethers 356
and 357 in about 507; yield. Treatment of this mixture with dilute acid gave
/ / /
/ \ \
0 RO C6H,CHz0
349 350 R = CH3 352 R = C H N ,
351 R = CHzC6H, 353 R= CH , B r
CH(0R' )CH,Br
360 361
184 S. WILLIAM PELLETIER AND NARESH V. MODY
CH,O cH3QLj
0
CH,O CH,O
371 372 R = OH 374
373 R = C H N ,
&A
CO,H CO,H CO,H
CH,O AcO
375
376
In 1974 Johnson and Mander (180) reported the synthesis of the tricyclic
ketones 378 and 380 containing the 3.2.1 and 2.2.2-bicyclooctane ring sys-
tems incorporating a cyclohexa-2,4-dienone moiety. The Australian chemists
prepared the diazoketones 377 and 379 by the earlier standardized method.
377 378
186 S. WILLIAM PELLETIER A N D NARESH V. MODY
The acid-catalyzed rearrangement of 377 and 379 afforded 378 and 380,
respectively, in good yields. The tricyclic ketone 380 contains all appro-
priate functionality for the synthesis of the atisine-type alkaloids, ajaconine
and atidine.
COCHN,
319 380
38 1 382 R = CH,OH
383 R = C H O
384 385
2. THE CHEMISTRY OF C,,-DITERPENOID ALKALOIDS 187
386 387
388 389
0
CN CN CH,-CH=CH,
390 39 1 392
0
Br
0
393 R = H
394 R = C,H, 395
0 0
396 397
CN CN CN
@o+(yJoJ3@
C,H,O,C CH, CH, 'C0,C,C2H5 CH, COzC,H5
0 +
45% 55%
0
398
SCHEME
3
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 189
@CH3
,' H
R--6 CH,
11
0
400
399 R = OH
401 R = C1
402 R = NHNH,
403 R = N 3
@cH3
NH
CH3
0
404 1 Veatchine
The racemic acid 399 was treated with oxalyl chloride to afford an acyl
chloride 401, which on reaction with anhydrous hydrazine yielded the hydra-
zide 402. The latter was converted to the azide 403 by treatment with nitrous
acid. Photolysis of 403 which a high-pressure mercury lamp afforded the
lactam 404. This lactam was synthesized earlier by Japanese chemists by an
entirely different method (187).
In 1972, Indian chemists developed (188, 189) a method of introducing
the C-20 functionality utilizing a regioselective intramolecular carbenoid
190 S. WILLIAM PELLETIER AND NARESH V. MODY
( $ 7 0 C H 3 c= 0
&OCH3
RC CH, CH,
I/
405 R = O H 407
406 R = C H N ,
408 409
410 411 R = O
412 R = H,
Kametani and co-workers (193, 194) have synthesized the key arnine 412
by a thermolytic intramolecular cycloaddition reaction. Methyl methylaceto-
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 191
c1
A
CH302C CH3
CH,O,C CH3 CH,O,C CH3
413 414 R = COCH, 416 X = C1
415 R = CHOHCH, 417 X = I
CN
q \C H 3 8 0 C H 3
BrV O C H 3
CH,
CH,O,C CH3
R+ CN
CH30,C
p (p H
CH3
\
-
CH30,C CH3
422 423
In order to obtain the trans-fused octalin, the cis-fused octaline 423 was
oxidized with chromium trioxide in acetic acid to yield the ketone 424. The
latter was treated with bromine in acetic acid to produce the a-bromoketone
425 in a yield of 98",. Dehydrobromination of 425 with N-phenylbenz-
amidine afforded the ap-unsaturated ketone 426 in 90-95% yield. The
192 S. WILLIAM PELLETIER AND NARESH V. MODY
ketone 426 was hydrogenated on 10% PdjC in ethanol to give the trans-
fused compound 427. Reduction of 427 under high pressure gave the lactam
428 in 80% yield. Lithium aluminium hydride reduction of 428 furnished
the key amine 412 that has been used in the total synthesis of veatchine,
atisine, and gibberellin A, 5 . Earlier the same investigators (195) reported
the synthesis of the related secondary amine 429.
426
424 R =H
425 R = Br
NH
0
421 428
@OCH3
NH
CH3
412 429
The synthesis of the tetracyclic amide 437 has been reported by Meyer and
co-workers (196) in work directed toward a general diterpenoid synthesis.
The enantiomer of this amide has been prepared earlier by Tahara and
colleagues (197)and converted to atisine, veatchine, and garryine.
The synthesis (184) of the starting compound 430 is discussed in Section
VIII,E,4. The ketone 430 was condensed with ethyl formate in the presence
of NaH to give the hydroxymethylene ketone 431. Treatment of 431 with
DDQ and acidic dioxane for 5 min at room temperature furnished the
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 193
A c - D 0 Ac-@ 0HoH
‘CH, ‘CH,
430 431
A c - D o H ’ H
‘CH,
432 433
Ac--N &gg
/
‘CH
0
Ac- -N
‘CH,
0
434 435
0
AC-
.@ -N
’CH,
436 437
194 S. WILLIAM PELLETIER AND NARESH V. MODY
6 R=Ac 9
;_I$--..
8 R=H
OAc OAc
CH, CH,
7 438
and Bhattacharyya (200). For example, isoatisine (75) was prepared from
dihydroatisine (78) by treatment with active MnO, in chloroform in 55-61%
yields. Similarly dihydroveatchine (231), dihydrogarryfoline (439) and
dihydrocuauchichicine (440)were converted to garryine (2), isogarryfoline
(29)and isocuauchichicine (16), respectively, in 45 -65% yields. Interestingly,
oxidative cyclization occurs in preference to oxidation of the allylic
hydroxy group in compounds 78, 231, and 439. The advantages of this
method over earlier reported methods using mercuric acetate and osmium
tetroxide are discussed.
231 R’ = OH, R2 = H 2 R’ = O H , R2 = H
439 R’ = H. R2 = OH 29 R’ = H ; R2 = OH
440 16
225 441
12-Acetylnapelline
C,4H35N0,; MW 401
mp 205-206”; [a]D--
Aconitum karakolicum
Chemically correlated with napelline;
’H-NMR and mass spectral data
Refs. 58, 59
Ajaconine
CZ2H3,NO3;MW 359
mp 167”; [.ID - 122” (EtOH)
HO-. .._1
Delphinium ajacis; D. consolida;
Consolida ambigua; D. oirescens; D.
,\. .r;r
.. . o... carolinianum
Chemically correlated with atidine;
13C-NMRand other spectral data
CH,
Refs. 83-87
Anhydroignavinol
C,,H,,NO,; MW 345
rnp 302-304”; [a]D-
Hydrolysis product of ignavine
Chemical and X-ray analysis
Refs. 97-101
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 197
Anopterimine
0 C,,H,,NO,; MW 395
H mp 235-238"; [.ID + 106' (Chf)
I1
0-c-c=c, /
Anopterus mncleuyanus
'H- and "C-NMR spectral analysis
Ref. 70
Anopterimine N-oxide
Cz5H3,N0,; MW 411
mp 233-235"; [ o L+95'
] ~ (Chf)
Anopterus mucleuyunus
'H- and I3C-NMR spectral analysis
Ref. 70
Anopterine
C3,H,,N0,; MW 541
mp 222-223"; [.ID - 12" (Chf)
Anopterus macleuyunus; and A .
glundulosus
Chemical studies; 'H- and I3C-NMR
data, and X-ray analysis
Refs. 68, 69
OH
Atidine
C,,H,,NO,; MW 359
mp 182.5-183.5'; [.ID -47.0 (Chf)
Aconitum heterophyllum
Chemically correlated with ajaconine;
'H-, I3C-NMR, and X-ray analysis
Refs. 28, 78, 80, 81, 82
198 S. WILLIAM PELLETIER AND NARESH V. MODY
Atisine
C,,H33N0,; MW 343
mp 329-331' (HCIj; [.ID + 26.6'
(EtOHj HC1 salt
Aconitum heterophyllum; A .
heterophylloides; A . anthara
Correlated with veatchine; Chemical,
'H- and I3C-NMR analysis; X-ray
analysis of HCl salt
Refs. 27,28,30, 71 -80
Cuauchichicine
C,,H,,NO,; MW 343
mp 152-154"; [a],, -69" (Chf)
Garrya laurifolia; G. ovata var.
lindheirneri
Chemically correlated with garryfoline;
"C-NMR and X-ray analysis
Refs. 25, 26, 34-36
Delnudine
C,,H,,NO,; MW 327
mp 235-237"; [@ID-
Delphinium denuda turn
Chemical, spectral, and X-ray analysis
Refs. 135, 136
Denudatine
C,,H,,NO,; MW 343
mp 248-249" C ; [.ID f0.15' (EtOHj
Delphinium denudntum
Chemical and X-ray analysis
Refs. 109-113
Dihydroajaconine
C,,H,,NO,; MW 361
mp 99-100°C; [aID -35' (EtOH)
Consolida ambigua
Chemically correlated with ajaconine;
13C-NMR and other spectral data
Ref. 88
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 199
Dihydroatisine
C,,H35N0,; MW 345
mp 159-161 ; [zID -44.5' (EtOH)
Aconitum heterophyllum
HO----\ OH Correlated with atisine and isoatisine;
'H-, I3C-NMR, and X-ray analysis
Refs. 28,30, 71, 78, 80
Dihydroxyanopterine
0 C,,H,,NO,; MW 573
and 11 /H mp 242-244; [zID -9; (MeOH)
Anopterus macleayanus
'CHzoH Chemically correlated with anopterine
"C-NMR and other spectral data
Refs. 69, 70
C-3
Garryfoline
C,,H,,NO,; MW 343
mp 130-133.'; [.ID -60:- (Chf)
Garrya laurifvlia; G. ocata var.
lindhrimeri
Chemically correlated with veatchine;
Chemical and ',C-NMR analysis
Refs. 18, 25, 26, 33-36, 39
Garryine
C,,H,,NO,; MW 343
mp 74-82- (hydrate); [XI - 84- (Chf)
Garrva ueatchii
Chemically related to veatchine;
Chemical and %-NMR analysis
Refs. 22-31
Heterophylloidine
0 C,,H,,NO,; MW 383
resin, [.ID - 8 2 (Chf)
Aconitum heterophylloides
AcO,. d ,----
C -< H 2 ' H and 13C NMR analysis; X-ray
analysis of HBr salt.
CH ......N Ref. 76
CH, 0
200 S. WILLIAM PELLETIER AND NARESH V. MODY
Hetidine
CZ1HZ7NO4; MW 357
mp 218-221'; [rID-
Aconitum heterophyllum
Spectral and X-ray analysis
Refs. 80, 128
Hetisine (Delatine)
CZoH,,N03 ; MW 329
+
mp 256.5-259"; [aID 109' (Chf)
Aconitum heterophyllum; Delphinium
cardinale
Chemical and X-ray analysis
Refs. 80, 118-124
Hetisinone
HO C,,H,,NO,; MW 327
+
mp 268-270"; [&ID 18"
Delphinium cardinale; D. denudatum ;
Aconitum heterophyllum
0 Chemically correlated with hetisine
Refs. 80, 120, 126, I27
Hydroxyanopterine
OTig C3,H4,NOs; MW 557
mp 247-249; [.ID - 1 4 (MeOH)
Anopterus macleayanus; A . glandulosus
at Chemically correlated with anopterine,
c-1 I3C-NMR, and other spectral data
Refs. 69, 70
c-3
Tig = C-C=C
TH3 ,CH3
\
H
0
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 20 1
Hypognavine
C,,H,,NO,; M W 449
mp239-241'; [.ID +127.1' (MeOH)
Aconitum sanyoense
Correlated with hypognavinol
Refs. 102-105
Hypognavinol
C,,H,,NO,; MW 345
mp 307-308 : [.ID +67.7 (MeOH)
Hydrolysis product of hypognavine :
Chemical and X-ray analysis
Refs. 102-105
Ignavine
C,,H,,NO,; MW 449
mp 172-174"; [%ID f85.3" (EtOH)
Aconitum sayoense: A. juponicum; A .
tusiromontunum
Chemically correlated with
anhydroignavinol
Refs. 97-101
Isoatisine
C,,H,,NO,; MW 343
mp 149.5-152;; [ K ] ~-22.4 (EtOH)
A conif um he terophyllum
Correlated with atisine; Chemical,
I3C-NMR, and X-ray analysis
Refs. 27, 28,30, 71, 78, 80
Isocuauchichicine
C,,H,,NO,; MW 343
mp 134-136; [.ID -84' (Chf)
G a r r w luurifolia.
Chemically correlated with
cuauchichicine; Chemical and spectral
(>
data
CH, Refs. 18, 25,26,34-36
202 S. WILLIAM PELLETIER AND NARESH V. MODY
Isogarryfoline
C,,H,,NO,; MW 343
mp 140-144.; {%ID-57 (Chf)
Garrya laurifolia
Chemically correlated with garryfoline;
< Chemical and spectral data
Refs. 18, 2 5 , 2 6 , 3 3 - 3 6 , 3 9
Isohypognavine
C,,H,,NO,; MW 433
mp 135"; [zID--
Aconitum majimai; A . japonicum etc.
Chemically correlated with kobusine
Refs. 99, 106, 107
Kobusine
C,,H,,NO,; MW 313
mp 267-267.5"; [a],, + 104.4" (MeOH)
Aconitum sachlinense: A . yesoense, A .
lucidusculum, etc.
Chemical and X-ray analysis
Refs. 93-95
Lindheimerine
C,,H,,NO,; MW 341
resin; [a]* - 113.8" (Chf)
Garrya ovata var. lindheimerz
Chemically correlated with ovatine
I3C-NMR and other spectral data
Ref. 33
Lucidusculine
C,,H,5N0,: MW 401
mp 170-171"; [@ID-
Aconitum lucidusculum
Chemical and X-ray analysis
Refs. 48-57
0Ac
2. THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS 203
Miyaconitine
0 C,,H,,NO,; MW 415
\ mp 218' (decomp.); [%ID -87.8' (Chf)
Aconitum miyabei
Chemical, spectral, and X-ray analysis
Refs. 54. 129-133
Miyaconitinone
CZ,Hz7NO6;MW 413
mp 285" (decomp.); [ a ] - 2 7 . 6 (AcOH)
Aconitum miyabei
Chemically correlated with miyaconitine
Refs. 54, 129-133
Napelline (Luciculine)
OH C,,H,,NO,; MW 359
mp 116-117" (hydrate); [.ID -13"
(MeOH)
Aconitum napellus; A . karakolicum
Chemically correlated with songorine
and lucidusculine
Refs. 40 -49
Norsongorine
C20H,,N0,; MW 329
8 I/ mp 284-286.; [a]D-
A . monticola
Correlated with songorine
Ref. 62.153
204 S. WILLIAM PELLETIER AND NARESH V . MODY
Ovatine
C,,H,,NO,; MW 385
mp 113-114"; [dID -79.4'(Chf)
Gnrrya ouata var. lindheimeri
Chemically correlated with garryfoline;
',C-NMR and other chemical data
Ref. 33
Pseudokobusine
C,,H,,NO,; MW 329
mp 271"; [.ID-
Aconitum yesoense ; A . lucidusculum
Correlated with kobusine
Refs. 93-95
Songoramine
9 C,,H,,NO,; MW 355
mp 211-212"; [.ID---
A . karakolicum ; A . soongoricum
Chemically correlated with songorine;
Chemical and spectral analysis
Refs. 62, 66, 67
Songorine
0 C,,H,,NO,; MW 357
mp 212"; [EJ-
A . soongoricum ; A . karakolicum;
A . monticola
Correlated with napelline; Chemical and
spectral data
Refs. 41 -48,60-64
Songorine N-Oxide
C,,H,,NO,; M W 373
mp 253-255"; [.ID-----
Aconitum moticola
Chemically correlated with songorine;
'H-NMR and mass spectral data
Ref. 65
2. THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS 205
Spiradine A
C,,H,,NO,; MW 311
mp 281-282'; [aID----
Spiracea japonica
Chemical, spectral, and X-ray analysis
Refs. 137-139
Spiradine B
C,,H,,NO,; MW 313
mp 259-260'; [%ID---
Spiraea japonica
Chemically correlated with spiradine A
Refs. 137-139
Spiradine C
C,,H,,NO,; MW 355
mp 248-249': [oL]~----
Spiraea japonica
Chemically correlated with spiradine B
Refs. 137, 138
Spiradine D
C2,H,,N0,; MW 339
mp 134-135-; [.ID-
Spiraea japonica
Chemically correlated with spiradine A
Ref. 140
206 S. WILLIAM PELLETIER AND NARESH V. MODY
Spiradine F
C,,H,,NO,; MW 399
mp 114-1 17‘ (hydrochloride); [%ID--
Spiraea juponica
Chemical and spectral analysis
Ref. 142
---
‘0
Spiradine G
C,,H3,N0,; MW 357
mp 168-17OC; [%ID-
Spiraea japonicu
Chemical and spectral analysis
Ref. I42
Spiredine
C Z 2 H 2 , N 0 3MW
; 353
mp 163’;
Spiraea japonica.
Chemically correlated with spiradine A
Ref. 141
Spireine (Structure 1)
C22H,,N0,; MW 369
mp 230’ ; [a]D-
Spiraea juponica
Chemical and spectral analysis
Refs. 137, 143
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 207
Spireine (Structure 2)
C,,H,,NO,. MW 369
mp 230 , [xlD-
Spiraea iaponica
Chemical and spectral analysis
Refs 137, 143
0 0
Staphidine
C,,H,,N,O, MW 606
mp213-216 . [%ID-160 (C,H,)
Delphinium stuphisagria
'H- and I3C-NMR analysis
Ref 148
Staphigine
C,3H,,N,0,; MW 650
mp 225-227 , [.ID - 116 (C,H,)
Delphinium stuphisugr iu
'H- and I3C-NMR spectral analysis
Ref. 149
208 S. WILLIAM PELLETIER AND NARESH V. MODY
Staphimine
C,,H5,N,O; MW 590
Amorphous; [xID -58.5 (C6H6)
Delphinium stuphisagria
‘H- and I3C-NMR spectral analysis
Ref. 148
Staphinine
C,,HS6N,0,; MW 620
Amorphous; [uID -57.5‘ (C6H6)
Delphinium stuphisagria
‘H- and ‘-’C-NMR spectral analysis
Ref. 148
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 209
Staphirine
C,,H,,N,O,: MW 620
mp 222-225 : [.Il, - 126 (C,H,)
Delphinium staph isagriu
'H- and I3C-NMR spectral analysis
Ref. 149
Staphisagnine
C H 3 0 - 0
h
210 S. WILLIAM PELLETIER AND NARESH V. MODY
Staphisagrine
.’ . C 4 3 H 6 0 N 2 0 2MW
: 636
mp 229-231 , [.ID - 105.6 (C,H,)
Delphinium stuphisagria
‘H- and 13C-NMR spectral analysis
.: ,’ Ref. I50
Staphisine
CH, C,,H,,,N,O,: MW 636
mp 211-213’; [%ID -148.4’(C6H,)
Delph iniuni s tuph isagr iu
Chemical, spectral, and X-ray analysis
i;..
Refs. 144-148
H C... ..N
CH3
Vakognavine
0 C3,H3,XO,,; MW 619
\ mp 298.’: [%ID---
Aconiturn pulnuirurn
Chemical, spectral, and X-ray analysis
Refs. 1I4 1 17
-
2. THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS 21 1
Veatchine
C,,H,,NO,; MW 343
mp 122-126 C ; [rID -69 (Chf)
Garrya ceatchii
Chemically correlated with atisine
3C-NMR and X-ray analysis
Refs. 22-31
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CHAPTER
3-
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
11. 1,2,3,4-Tetrahydro- and 3-4-Dihydroisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . 219
111. Benzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
IV. Bisbenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
V. Cularine . . . . . . . . . . . . . . . . . .... .... ..... 221
VI. The Morphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
VII. Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
VIII. Pavine Alkaloids . . . . . . . . . . . . . . . . . . . .... ....... 234
IX. Aporphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
X. Reduced and Nonreduced Proaporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
XI. Tetrahydroprotoberberine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
XII. Protopine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
XIII. Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . ................... 245
XIV. Modified Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
XV. Benzo [clphenanthridine Alkalo ........................... 250
XVI. Spirobenzylisoquinoline Alkaloi ...................... 252
XVII. Rhoeadine . . . . . . . . . . . . . . . . . . . . . . . . ....... .............. 251
XVIII. Secoberbine Alkaloids . . . . . . . . . . . . . . ....... .............. 257
XIX. Emetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
XX. Miscellaneous Alkaloids . . . . . . ................................. 260
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 1
1. Introduction
C HO
,
1 R
1
= R
2
=R3=H
2 R, = R = OCH3; Rg = H 4
2
3 R, = R
2 = OCH3; R3 = CH 3
5 6 7
23.9
8
FIG.1. 1,2,3,4-Tetrahydroisoquinolines
and model compounds.
3. THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 219
TABLE I
SHIFTS
l 3 C CHEMICAL OF
1.2,3,4-TETRAHYDROlSOQ~lNOLlNES“
Carbon 1 2 3 4
2, deshielded these carbons and at the same time shielded C-5, C-8, C-4a,
and C-8a. The chemical shifts of the aromatic carbon atoms agreed with
those expected from application of empirically determined substituent
parameters derived from veratrole (7) for o-dimethoxyl groups (C-1, + 20.8 ;
C-2, -16.9; C-3, -7.6 ppm, relative to benzene, 128.6 ppm) (14). The
specific assignment of C-5 and C-8 in 2 was achieved by selective 'H de-
coupling. The chemical shifts of the aliphatic carbon atoms are not signifi-
cantly different from those of 1.
In O-methylcorypalline (3) C-1 and C-3 are deshielded by +9.8 and
+9.1 ppm, respectively, because of the N-methyl group fi to them (18).
Similar results have been observed for the pair, piperidine (5) and N-
methylpiperidine (8) (8).
Another common structural component of the isoquinoline alkaloids,
particularly in the protoberberines, is the 7,s-disubstituted 1,2,3,4-tetrahy-
droisoquinoline unit. The spectrum of 7,8-dimethoxy- 1,2,3,4-tetrahydroiso-
quinoline (4) showed two interesting chemical shift changes other than the
expected shifts in the aromatic carbon atoms (14). First, it was found that
C-1 was shielded relative to the corresponding carbon atom of 2 by -4.6
ppm. This was attributed to the y steric effect of the C-8 methoxyl group on
9 Rl = OCH3, R2 = H 12 R1 = R2 = OCH3, R3 = CN
10 R1 = R = OCH3 13 R1 = R2 = OCH3, R3 = CONH2
2
11 R1 = H , R 2 = OCH3 14 R1 = R 2 = OCH3, R3 = CH2N02
15 R1 + R 2 = CH2, R3 = OH
16 17 R, + R 2 = CH2, R 3 = H
18 R1 = R2 = CH3, R3 = H
19 R, = R2 = R3 = CH 3
FIG.2. C-1 substituted 1,2,3,4-tetrahydroisoquinolines
and model compounds
3. THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 221
TABLE I1
3cCHEMICAL SHIFTS OF 1,2,3,4-TETRAHYDROISOQUINOLINESSUBSTITUTED AT c-1
AND OF SOME ISOQUINOLONES
Carbon 9" 10" 11" 12' 13' 14' 15'.d 17' 18' 19'
1 51.2 51.3 51.8 56.5 70.2 61.3 85.7 166.6 167.0 164.8
3 41.9 41.9 42.0 48.4 50.9 45.4 45.5 40.2 40.3 48.3
4 30.5 29.6 29.2 28.1 29.0 23.0 29.6 28.4 27.9 27.5
4a 136.1 127.1 126.9 121.5 124.2 123.8 132.4 134.6 132.9 131.8
5 113.8 112.3 129.9 111.7 111.7 111.9 109.1 107.9 110.2 110.6
6 157.8 147.5 111.2 149.4 148.3 148.6 147.5 150.9 152.2 151.9
7 112.2 147.6 157.8 148.0 147.0 148.0 146.4 146.9 148.1 148.1
8 126.9 109.6 111.8 109.7 109.4 110.2 108.8 107.3 109.8 109.5
8a 133.1 132.8 141.7 126.3 125.9 127.2 129.1 118.2 121.7 122.1
6-OCH3 55.1 55.9 56.1 56.0 56.0 56.1 56.0
7-OCH3 56.1 55.0 55.8 55.9 55.9 56.1 56.0
6,7-OCH,O 101.8 101.5
NCH, 43.5 44.8 42.0 43.1 35.0
1-CH , 22.8 22.8 22.6
1-CN 116.8
1-CON H 176.4
1-CH zNO, 79.3
atoms of the isoquinoline system. With the exception of CN, these substi-
tuents deshielded C-1. In general the c( effect of nitriles on aliphatic systems
is small (8, ZZ), and in 12 the magnitude of the substituent effect may be
further reduced by gauche interactions with the N-methyl group. The
aromatic carbon atoms of 12, 13, and 14, relative to those of 3, were not
appreciably affected by the substituent at C- 1.
In hydrastinine (15) the aromatic chemical shifts were assigned by com-
parison with the spectrum of the model compound, methylenedioxybenzene
(16), from which the following substituent parameters were derived : C-1,
+ 19.2; C-2, - 19.8; C-3, -6.8 ppm, relative to benzene (14, 21).
Several isoquinolones have also been examined (17).The carbonyl group
at C-1 in the isoquinolones, noroxohydrastinine (17) (7), corydaldine (18)
(17), and N-methylcorydaldine (19) (17),not only affected the chemical shifts
of the aliphatic carbon atoms but also influenced the chemical shifts (Table
IT) of the aromatic carbon atoms through a resonance effect. The upfield
shift of C-1 in 19 relative to 18 (-2.2 ppm) and of the N-methyl of 19 relative
to 3 (- 1I .O ppm) indicated the presence of a steric interaction between the
carbonyl and the N-methyl groups. This result is typical of an amide carbonyl
existing in a cis geometry with the nitrogen substituent (8, 9).
The 3,4-dihydroisoquinoline system is also encountered in this family of
alkaloids. The assignment of chemical shifts to the aromatic carbon atoms
of the substituted 3,4-dihydroisoquinolines(21-25 in Fig. 3 and Table 111)
followed directly from the application of the appropriate substituent param-
eters to the shifts reported for 20 (22) and from a consideration of the
resonance effect of the carbon-nitrogen double bond. This latter point is
especially evident in the methiodide salts, 24 and 25, where charge delocaliza-
tion causes C-4a, C-6, and C-8 to appear at lower field than their counter-
parts C-8a, C-7, and C-5, respectively. Carbon- 1 was readily recognized as
the lowest field resonance because of its imine character.
20 R = R = R 3 = H 24 R, = R2 = CH
1 2 3
21 R1 = R2 = OCH3, R3 = H 25 R, + R2 = CH2
22 R, = R 2 = OCH3, R3 = CH 3
23 R1 = OCH3, R2 = H, R3 = CH3
FIG.3. 3,4-Dihydroisoquinolines.
3. THE 13C-NMR SPECTRA OF ISoOUINOLINE ALKALOIDS 223
TABLE 111
I3cCHEMICAL
SHIFTS OF THE 3,4-DIHYDROISoQuINOLINES
Christ1 (22).
Hughes et al. (14).
Verchire et al. (20).
Hughes and Maclean. (17).
TABLE IV
"C CHEMICALSHIFTSOF
LALDANWNE (28) AND
ITS QUATERNARY
SALT(32)
1 65.5 71.3
3 46.8 54.7
4 25.3 23.1
4a 125.8 120.6
5 112.8 111.0
6 146.9 148.9
7 146.9 146.6
8 110.7 110.5
8a 132.2 119.1
9 40.4 37.4
1' 129.0 126.3
2' 110.7 113.1
3' 148.3 148.9
4' 146.0 147.9
5' 110.7 110.1
6 121.5 122.3
6-OCH3 55.5' 56.4'
7-OCH, 55.5' 55.4e
3'-OCH, 55.3' 54.9'
4'-OCH, 55.3' 54.7'
NCH, 42.4
NCH,), 52.3, 50.3
Wenkert et al. ( 6 ) .
a
* Marsaioli et
al. (23); Solvent: CDC1, +
CH,OH.
Assignments may be interchanged.
parallel those between 2 and 3. Except for the absence of two 0-methyl
resonances, there are minimal differences between the spectra of 26 and 28.
The presence of an N-oxide function in alkaloids 29 and 30 has a large
deshielding effect on each of C-1, C-3, and the N-methyl group relative to
28. The results, which are of similar magnitude to those observed in other
N-oxides (8. 24. 25). may be attributed to the combined inductive effect of
the positively charged nitrogen atom and to the p effect of the oxygen. The
important feature of these N-oxide shifts is their dependence on the stereo-
chemistry of the nitrogen substituents. In the cis configuration 29, gauche
interactions may occur between the N-methyl group and C-9, causing the
signals of these carbons to appear at higher field than they appear in the trans
isomer 30. The largest chemical shift difference between the two isomers is
at C-3 which is shielded by 3.5 ppm in 30. This result may possibly be
3. THE I3C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS 225
26 R
1
= R
4
= R5 = CH3, R2 = R
3
= H
27 R = R2 = R3 = R = Chi3, R5 = H
1 4
28 R
1
= R
2
= R
3
= R
4
= R
5
= C H3
ee. 2
cH30TN
a::
C HO
, 'CH,
OCH, 32
31
FIG.4. Benzylisoquinoline alkaloids.
Marsaioli et al. (23) have reported the 13C chemical shifts of several
benzylisoquinoline alkaloids and their N-methyl salts. When 28 is N-
methylated to the corresponding quaternary salt 32 there was a deshielding
of C-1 and C-3 whereas C-4, C-4a, and C-8a, and C-1' were shielded. The
shielding of C-9 is caused by the 7 effect of the additional N-methyl group.
From the similarity in chemical shifts for the carbon atoms of ring B and
the corresponding carbon atoms in N-methyltetrahydroprotoberberines(27,
28), it was proposed that the B ring had a half-chair conformation in which
the benzyl carbon was pseudoaxial. Additional evidence for this proposal
came from the observation of a 5.0 Hz vicinal coupling between C-8 and
H-1 which indicated a 45" dihedral angle between these atoms. The spectrum
of 32 is recorded in Table IV.
IV. BisbenzylisoquinolineAlkaloids
33
3. THE 13C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 227
TABLE V
I3cCHEMICAL SHIFTS OF
(33)
ISOCHONDODENDRINE
1 58.0 9 129.0
3 44.0 10 127.2
4 25.8 11 114.3
4a 122.9 12 153.3
5 107.3 13 117.4
6 149.9 14 128.6
7 135.7 15 33.8
8 139.4 6-OCH3 55.2
8a 124.8 NCH.3 40.5
and C-8a. Carbon-5 was assigned to the highest field aromatic signal, 107.3
ppm, whereas the protonated carbon atoms of the benzyl units were as-
signed by taking into account the substituent effect of the oxygen group
at C-12.
V. Cularine
The I3C spectrum of cularine (34) (Fig. 6, Table VI), has been reported
by Wenkert et al. (6). The chemical shifts of the aliphatic carbon atoms
were assigned by comparison with those of laudanosine (28) and follow
also from those of the simple isoquinolines (Section 11). In the aromatic
region the resonances of the pair of protonated carbon atoms at C-5 and C-6
were differentiated from those at C-2' and C-5' by the observation of
4
.CH,
CH,O OCH,
34
228 D. W. HUGHES A N D D. B. MACLEAN
TABLE VI
’ 3C CHEMICALSHIFTSOF C U L A R ~ N E ~
Carbon Carbon
~
1 56.7 1’ 118.3
3 47.5 2‘ 113.6
4 26.0 3’ 144.8
4a 126.3 4 147.3
5 124.3 5’ 105.1
6 110.4 6 148.4
7 148.9 7-OCH3 55.8
8 144.8 3’-OCH, 56.0
8a 132.5 4’-OCH, 56.0
9 35.3 NCH, 42.4
NR
6CH,
35 R = H 37
38
36 R = CH3
39 R1 = CH3. RE = H 40
41 R, = RE = H
42 R1 = R2 = COCH3
TABLE VII
I3C CHEMICAL
SHIFTSOF MORPHINE A K D MODELCOMPOVNDS
ALKALO~DS
reported on the spectrum of morphine (41), its monoacetyl and its diacetyl
derivative (42) (Table VII), as well as on several analogs of codeine and
morphine modified in ring C. In addition several 6,14-endo-etheno- and
6,14-endo-ethanotetrahydrothebaineswere examined. In their work they
examined dihydromorphine, dihydrocodeine, and dihydrocodeinone in
order to aid the interpretation of the signals of ring C. 14-Hydroxyl deriva-
tives of the alkaloids and their derivatives were also used for the same
purpose.
43 R,=R = H
2
44 R , + R 2 = 0
45 4, = R2 = H
46 R, + R 2 = 0
TABLE VIII
13C CHEMICAL SHIFTSOF CANCENTRINE
(43),
10-OXOCANCENTRINE(44),CODEINONE
(45),
AND 10-OXOCODEINONE(46)
position of C-10 in both the morphine and cancentrine alkaloids was atrib-
uted to the y steric effect of the NCH, group (32, 33). C-8, C-13, and C-14
were assigned from the off-resonance spectrum. Although the residual
coupling patterns of C-9 and C-32 were partially obscured by the methoxyl
signals in the off-resonance spectrum, C-9 was assigned to 58.8 ppm and
C-32 to 57.8 ppm. The lowest field signals in the aliphatic region at 97.5 and
79.1 ppm were assigned to C-5 and C-6, respectively.
The assignment of the aromatic resonances was difficult in this complex
system because of the large number of signals. For purposes of study they
were conveniently divided into two main spectral regions, 100-130 ppm for
those aromatic carbon atoms bonded to hydrogen or another carbon, and
135-150 ppm for those aromatic carbon atoms bonded to oxygen substi-
tuents. Off-resonance decoupling differentiated the protonated carbon atoms
from those bonded to another carbon atom, but there were cases where the
residual coupling overlapped quaternary carbon signals and made the assign-
ment of the latter quite difficult. This problem was solved by the technique
of selective enhancement of quaternary carbon signals (37). A low power and
modulated decoupling field was applied to the sample, producing a spectrum
composed of only quaternary carbons. As a result of this procedure it was
found that the peak at 119.7 ppm was a composite of signals arising from
C-1 and C-29.
The aromatic carbon atoms of the morphine moiety of cancentrine were
assigned by comparison to codeine (32,33).For example, C-4 was assigned
to 145.1 ppm because of its low intensity. Since this carbon atom does not
have any neighboring protons to provide dipolar relaxation, it therefore
should have a longer T I and a lower intensity because of partial saturation
owing to the short delay between the rf pulses. The similar chemical shifts
of C-11, C-12, and C-30 did not allow unambiguous assignments to be made.
A similar analysis of the cularine portion of cancentrine resulted in the
tentative assignment of the remaining aromatic carbon atoms (36). The
signals at 194.0, 160.1, and 104.3 pprn were assigned to C-7, C-25, and C-24,
respectively. The assignment of the oxygenated carbon atoms can at best be
considered tentative.
These data were used to good advantage in the structural elucidation of
10-oxocancentrine (44). Other physical data had suggested that the new
alkaloid differed from cancentrine only at C-10. To provide additional sup-
'
port for these observations the 3C spectrum of 10-oxocancentrine and the
model compounds, codeinone (45) and 10-oxocodeinone (46),were recorded.
In the latter the carbonyl group at C-10 appears at 190.4 ppm. This change
in functionality caused a deshielding of carbons C-9, C-14, C-3, and C-12
relative to codeinone.
234 D. W. HUGHES AND D. B. MACLEAN
p "/ OR,
' m
Rp 2\ 12.
'CH,
o
l\, 9 OR, FIG.9. Argemonine (47) and eschscholtzine (48).
II 10
47 R = R =R3=R4=CH
1 2 3
48 R, + R2 = R2 + R3 = CH2
TABLE IX
I3C CHEMICAL
SHIFTS
OF THE
PAVINE
ALKALOIDS
49 R = H 51 R1 = CH3, R p = H
50 R = CH3 52 R, = H, R2 = CH
3
CHO
,
R,
53 R1 = R2 = H 55 R, = R2 = OCH3 57 R1 = R2 = CH
3
54 R1 = Od, R2 = H 56 R, + R2 = OCHEO 58 R1 + R2 = CH2
(FCH
CHO
, \
bCH,
59
FIG.10. Aporphine alkaloids
Carbon 49a 50" 51b 52h 53' 54" 55' 56' 57' 5Sb 59" 60d
I 141.6 141.6 140.7 142.3 144.6 144.3 143.9 144.0 141.7 140.4 141.2 143.1
2 146.5 146.5 145.8 148.2 151.4 151.3 151.5 151.4 150.8 145.9 147.2 148.5
3 110.9 110.3 108.7 113.5 110.9 111.6 110.1 110.3 110.8 107.7 106.4 106.4
3a 127.3 127.4 123.9 129.6 127.5 127.7 127.0 127.0 128.8 127.4 126.2 121.8
4 28.4 28.4 29.0 28.7 28.9 28.7 29.1 29.0 29.1 29.3 28.7 24.0
5 42.1 52.9 53.5 53.3 52.8 52.5 53.1 52.9 52.4 53.0 52.9 61.8
6a 53.2 62.1 62.7 62.5 61.9 62.3 62.3 62.1 62.6 62.8 61.9 69.8
7 36.8 34.4 34.5 34.2 34.8 33.5 34.4 34.9 35.6 35.4 33.4 28.7
7a 135.7 135.7 128.9 129.2 135.9 126.6 129.1 130.4 129.6 129.7 128.3 123.3
8 128.1 128.1 110.9 110.7 127.1 128.4 110.6 107.8 118.6 119.2 110.7 111.6
9 128.1 127.5 147.6 148.1 126.7 114.5 147.7 146.0 110.7 110.8 148.2 148.8
10 126.2 126.2 147.1 147.6 126.4 155.7 147.1 145.9 149.0 148.3 146.0 148.2
11 125.9 126.0 112.0 110.0 127.3 114.0 111.4 108.4 143.6 142.9 111.9 110.2
lla 132.4 132.4 124.8 124.1 131.6 132.1 124.2 125.1 119.8 118.5 122.6 122.0
Ilh 119.7 119.2 119.5 126.3 126.3 125.9 126.5 126.4 125.4 125.8 115.8 116.7
1 Ic 123.5 123.5 127.2 125.8 128.1 128.6 128.6 128.2 129.8 128.9 126.5 117.9
10-CH3 60.3 59.7 59.6 59.8 59.8 61.7
2-OCH3 55.8 55.8 56.0 55.3 55.5 55.5 55.4 55.5
1,2-OCH,O 100.2 100.4 101.3
9-OCH3 56.0 56.0 55.5 55.4 55.9
10-OCH3 55.9 55.8 55.7 55.8 56.2 55.6 55.9
9,lO-OCH ,O 100.4
NCH, 43.6 44.0 43.8 43.5 43.5 43.4 43.6 43.6 44.0 43.5
N(CH312 43.6.54.3
61 62
63 R1 = OH, R2 = H 65 R = H
64 R1 = H, R2 = OH 66 R = CH3
TABLE XI
,C CHEMICAL
SHIFTS
OF THE REDUCEDAND
NONREDUCED
PROAPORPHINES'
Carbon 61 62 63 64 65 66
CH,O
OCH,
OCH, 73
72 R, = CH3, R p = H
74 R = H , R2 = CH3
1
75 R, = CH3, R2 = H
77 Ho”o: OCH,
CH3
TABLE XI1
13
C CHEMICAL
SHIFT^ TETRAHYDROPROTOBERBERINES
OF THE
Carbon 61" 68" 69" 70b 71" 72" 13' 74' 75' 76' 11'
a Hughes e t a / . (14).
Moulis rt a/. (49).
Kametani e t a / . (44).
' Takao et a/. (28).
Manske et a/. (21).
by +4.3 ppm. This change is caused by the removal of the steric effect of
the C-9 substituent. It should also be noted that the C-9 hydroxyl group in
nandinine is just as effective as a methoxyl group in shielding C-8.
The conformation of the tetrahydroprotoberberine alkaloids is such that
the B and C rings exist as half-chairs and the entire quinolizidine system
may equilibrate between one trans and two cis forms (Fig. 13) (28, 43, 44,
47, 48). Corydaline (71) and mesocorydaline (72) are 13-methyltetrahydro-
protoberberines in which the conformational equilibrium lies towards pure
trans and pure cis, respectively, as shown by IR (51) and PMR spectroscopy
(52). In CMR spectroscopy (14, 28) the change from a trans (in 71) to a cis
(in 72) conformation is evident from the upfield shift of C-5, C-6, C-8, and
C-13. This change has been attributed to the increased number of y inter-
actions which occur in cis-quinolizidines (47, 48). Carbon- 14, however, is
slightly deshielded, perhaps caused by changes in the P-substituent effect
of both the C-methyl and C-6 (48). As the C-13 methyl changes from axial
in corydaline to an equatorial position in mesocorydaline it is also deshielded.
This is a reflection of a change in its steric environment. These chemical shift
differences allow one to distinguish readily between the cis and trans con-
formations of the 13-methyltetrahydroprotoberberines.
78 R, + R2 = R3 t R4 = C H 2
79 R, = R2 = CH3. R3 t R4 = CH2
80 R, + R2 = CH2, R3 = H, R 4 = CH3
TABLE XI11
I3C CHEMICAL
SHIFTSOF THE PROTOPINE
ALKALOIDS’.~
Carbon 78 19 80
that in the case of 80 the equilibrium between the tricyclic and tetracyclic
forms shown in Fig. 14 was shifted toward the latter because of the acidic
phenolic function. It was shown that the spectrum of protopine (78) was
altered by the addition of an equimolar amount of phenol and that the
carbonyl resonance now resembled that of 80. It is apparent therefore that
CMR spectroscopy is an effective tool to study transannular reactions in
these systems.
/ 0
OCH,
' OCH,
OCH,
81 R = H 82
90 R = OCH3
83 R1 = R2 = CH 84 R, = R2 = CH 3
3
85 R, + R2 = CH 86 R1 + R 2 = C H 2
2
FIG.15. Phthalideisoquinoline alkaloids.
have been reported on naturally occurring a-hydrastine (81) and its di-
astereomer, a-hydrastine (82), and the natural diastereomers, corlumine (83)
and adlumine (84)(14), and bicuculline (85) and capnoidine (86) (17)(Fig. 15
and Table XIV).
The carbon resonances of rings A and B of these alkaloids were assigned
by comparison to the spectra of the isoquinolines substituted at C-1 (Table
11). Phthalide (87), meconin (88), and 6,7-methylenedioxyphthalide(89)
served as models in the assignment of the signals of rings C and D (Fig. 16
and Table XV). The signals of the phthalide spectrum were assigned through
a study of the spectrum of 6-deuterophthalide and by selective proton
decoupling experiments. The aromatic carbon atoms of 88 and 89 were
3. THE 3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 247
TABLE XIV
"C CHEMICAL
SHIFTSOF PHTHALIDEISOQUIKOLIXE
THE ALKALOIDS
87 88 89
FIG.16. Phthalide and substituted phthalides.
248 D . W. HUGHES AND D. B. MACLEAN
TABLE XV
I3C CHEMICAL SHIFTS
OF PHTHALIDE
AKD ITS DERIVATIVES~
Carbon 87 88 89
TABLE XVI
l 3 C CHEMICAL
SHIFTSOF THE MODIFIED
PHTHALIDEISCQUINOLINE
ALKALOIDS
91 92
93
FIG. 17. Modified phthalide isoquinoline alkaloids.
94 R 1 = R = R = R = H
2 3 4
95 R1 = COCH3, R2 = R3 = R 99
= H
4
96 R1 = R3 = R4 = H, R2 = CH
3
97 R = R =H,R =R3=CH
1 4 2 3
98 R, = R = H, R2 = R4 = CH
3 3
fl
36.1
"91. 1w.g
100.2
/N
0L O 100
C-14 experienced the deshielding p effect of this methyl group. Since C-12
is y to the angular methyl group this would account for its higher field
position in 96.
The equatorial and axial 6-methylcorynolines, 97 and 98, respectively,
were differentiated by observing the chemical shifts of C-6, C-14, and the
methyl group at C-6. In 98 these carbon atoms underwent a strong shielding
as a result of the 7 steric effect of the axial methyl group.
An indication of the NCH, conformation was provided by the chemical
shift of C-4. In compounds where the NCH, is axial such as 14epicorynoline
(99), which has a trans BjC junction, this carbon was shielded relative to
those alkaloids with an equatorial NCH,.
The structural elucidation of a new benzophenanthridine alkaloid,
luguine (100) was reported (61) in which the 13C spectrum confirmed both
the aromatic nature of ring B and the presence of a hydroxyl group at C- 11.
The spectrum showed four aliphatic carbon resonances and these were
assigned by off-resonance decoupling.
252 D. W. HUGHES AND D. B. MACLEAN
TABLE XVII
l3cCHEMICAL SHIFTS OF THE HYDROBENZO[C]PHENANTHRIDINE ALKALOIDS’
Carbon 94 95 96 97 98 99
These alkaloids are a relatively small group within the isoquinoline family.
Ochotensimine (101) was the first to be studied and it and ochotensine are
the only compounds of the group that have an exocyclic methylene on the
five-membered ring (2, 3. 62). The most common functional groups are
carbonyl, hydroxyl, or acetoxy at one or both of C-8 and C-13. The spectra
of a series of these alkaloids were reported in 1977 (63)and these data were
used recently in the structural elucidation of a new alkaloid (64). The
structures and spectral data on the alkaloids discussed in this section may be
found in Fig. 19 and Table XVIII, respectively. They are ochotensimine
(101), sibiricine (102), corydaine (103), ochrobirine (104), fumaritine (105),
and fumaritine N-oxide (106).
3. THE 13C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 253
c H30
c H,O
101 102 R, = H, R2 = OH
103 R, = OH, R2 = H
104
106
FIG.19. Spirobenzylisoquinoline alkaloids.
1-Methyleneindane (107) was used as a model in the assignment of the
resonances of the carbon atoms of rings C and D of 101 (Fig. 20 and
Table XIX). A recent examination (65) of the spectrum of deuterated 107
has shown that the original assignments (63) of aromatic carbon atoms 3a
and 7a should be reversed. In the case of the alkaloids with a carbonyl group,
indanone (108), 6-deuteroindanone7 and 4,5-dimethoxy-l-indanone(109)
254 D. W. HUGHES AND D. B. MACLEAN
TABLE XVIII
' 3C CHEMICAL SHIFTS OF THE SPIROBENZYLlSoQulNOLINE ALKALOIDSn
Carbon 101" 102" 103" 104" 105b lMb.'
CH 3 0
107 108 109
FIG.20. Model indanes and indanones.
3. THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 255
TABLE XIX
SHIFTSFOR MODEL
I3C CHEMICAL
COMPOUSDS
107-109
C-8 and C-13 were verified by selective 'H decoupling (63).It would be ex-
pected that the chemical shifts at C-8 and C-I3 would be diagnostic of the
stereochemistry at these centers but this could not be verified because other
isomers were not available for study.
The elucidation of the structure of fumaritine N-oxide (106) was aided by
the use of CMR spectroscopy (64).When the spectrum of fumaritine (105)
TABLE XX
l3C CHEMICAL
SHIFTSOF
RHOEADINE
(110)"
Carbon 110
1 77.6
2 55.5
4 55.1
5 33.2
5a 136.5
6 110.5
7 147.5
8 147.3
9 108.3
9a 130.9
1Oa 130.9
10 123.0
11 112.2
12 145.8
13 145.5
13a 117.2
14 96.2
7,S-OCHZO 101.8
12,13-OCH20 101.1
14-OCH3 60.6
NCH, 41.5
was compared with that of 106 it was apparent that the N-oxide function
strongly deshielded the adjacent carbon centers, C-6,C- 14,and N-methyl.
The differences in the resonances of the aromatic carbon atoms of ring A
between 105 and 106 reflect the change from phenol to phenoxide at C-2.
(The spectrum of 106 was recorded in alkaline D,O.)
XVII. Rhoeadine
111
258 D. W. HUGHES AND D. B. MACLEAN
TABLE XXI
3C CHEMICAL
SHIFTSOF
HYPECORININE
(111)"
Carbon 111
1 108.2
2 146.0
3 147.8
4 108.2
4a 125.5
5 24.9
6 45.8
8 57.6
8a 123.2
9 142.1
10 152.2
11 108.8
12 124.3
12a 125.9
13 192.4
14 91.8
14a 129.8
2,3-OCH,O 101.1
9,lO-OCHZO 102.7
NCH, 37.7
OCH,
112
3. THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 259
XIX. Emetine
The I3C spectrum of emetine (112)(Fig. 23 and Table XXII) was examined
by Wenkert and co-workers (69).The chemical shift assignments were made
by comparison with the shifts recorded for the simple isoquinolines and pro-
toberberine alkaloids such as tetrahydropalmatine (69) (6, 14), and with
indolic analogues of emetine (69). The shifts of C-4 and C-6 are charac-
teristic of a trans-quinolizidine conformation for this ring system by analogy
TABLE XXII
l3C CHEMICAL
SHIFTSOF EMETINE
A N D EMETINE
DIHYDROCHLORIDE
1 36.7 34.8
2 36.7 35.8
3 41.6 39.2
4 61.2 58.7
6 51.7 50.7
7 29.1 26.4
7a 126.7 124.8
8 111.5 111.6
9 147.1 149.2
10 147.1 149.2
11 108.6 110.6
lla 130.1 125.7
llb 62.2 62.6
12 40.0 40.0
1' 52.1 53.6
3' 40.6 37.1
4 29.1 25.2
4'a 126.7 124.8
5' 111.5 113.5
6' 147.1 148.4
7' 147.1 148.4
8' 109.1 113.7
8'a 132.0 125.2
9-OCH3 55.7 56.8
10-OCH, 55.7 56.8
6-OCH3 55.7 57.0
7'-OCH3 55.7 57.0
CH3CH2-~
23.3 23.1
CHSCHI-
__ 10.9 10.7
Acknowledgments
Much of the spectral data cited in this chapter has been published elsewhere and is reproduced
here by permission of the respective publishers and authors. To the publishers listed below and
to the authors whose names appear in the cited references we express our sincere gratitude. The
National Research Council of Canada for 13Cdata taken from Can. J . Chem. on the following
compounds: 1-4, 21, 24, 67-69, 71, 72, 81-84, 87-89 (14);15, 76, 77 (21);43, 44, 46 (36):91
(57); 101-104,107-109 (63);105,106 (64).Heyden and Sons, Inc. for 13Cdata taken from Org.
Magn. Reson. on the following compounds: 9-11, 22, 23 (20);20 (22);61-66 (41);70 (49);
78-80 (54). Plenum Publishing Corp. for 13Cdata taken from “Carbon-13 N M R Shift Assign-
ments of Amines and Alkaloids” by M. Shamma and D.M. Hindenlang on the following
compounds: 17, 51, 52, 58 (7). John Wiley and Sons, Inc. for 13C data taken from “Topics in
Carbon-13 NMR Spectroscopy, Vol. 2,” edited by G. C. Levy on the following compounds:
28, 34, 47, 53, 55-57 (6). Pergamon Press, Inc. for 13C data taken from Ter. Lett. and Phyro-
chemistry on the following compounds: 32,33(2.3);35-40,45(32);60(39); lOO(61).The American
Chemical Society for 13C data taken from 1. Org. Chem. on the following compounds: 41,42
(33);73(44); 112 (69).Societa Chimicd Italiana for I3Cdata taken from Gazz. Chim. Ira/. on the
following compounds: 49, SO, 54,59 (40). Pharmaceutical Society of Japan for I3C data taken
from Chem. Pharm. Bull. and Yakugaku Zasshi on the following compounds: 74, 75 (28);
94-99 (60); 110 (67).
3. THE 3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 26 1
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-CHAPTER 4-
THELYTHRACEAEALKALOIDS
W . MAREKGOLFBIEWSKI
AND JERZY
T . WROBEL
Depar-tmmr of Chemistry.
Unifiersit) of Warsaw. Warsaw. Poland
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
I1. Lactonic Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
A . Lactonic Trans-Fused Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
B . Lactonic Cis-Fused Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
C . General Features of the Stereochemistry of Lactonic Biphenyl Alkaloids . . . 273
D . Chemistry of Lactonic Biphenyl Alkaloids Trans- and Cis-Fused . . . . . . . . . . 275
111. Lactonic Biphenyl Ether Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
IV . Simple Phenylquinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . ..... 284
V . Ester Alkaloids . . . . . . . . . . . . . . . . . . . . . . ............................. 286
VI . Piperidine Metacyciophane Alkaloids . . . ............................. 288
A . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
B. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
C. Stereochemistry . . . . . . . . . . . . . . . . . . . . . . ..... ... 292
VII . Quinolizidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
A . Structure and Chemistry 294
B. Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
C . Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
D . Oxoquinolizidine Metacyclophane Lythraceae Alkaloids . . . . . . . . . . . . . . . . . 302
VIII . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
A . Early Synthetic Approaches 303
B . Pelletierine-Benzaldehyde Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
C . Lactonic Biphenyl Ether Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
D . Lactonic Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
E . Piperidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
IX . Biosynthesis . . . . . . . . . . . . ......................................... 313
X . Physiological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
I . Introduction
13
HN Y * OR 2 1 N 9 8
24 l1 12 24 12
23 / 25
19
l9 13
120 / 14
22 \
21 21
A B C
isolated by Fujita et al. from Lythrum anceps in 1971 (7, 8) and by Ferris
et al. from Lythrum Ianceolatum in 1973 (9).* Forty-three alkaloids have
been identified in these plants. Alkaloids were detected only in the aerial parts
of the plants. The structures of almost all the bases have been established by
chemical and spectroscopic data and/or X-ray analysis.
Brief references to the Lythraceae alkaloids have been made in Volumes
X, XII, and XIV of this treatise. A short review on the alkaloids from
Lythrum anceps was published in Japanese (14). A review on the Lythraceae
alkaloids has appeared recently, covering mainly structure elucidation (15).
* The numbering system used for lactonic Lythraceae alkaloids is that introduced by Spenser
(10) and originally employed by Schopf et al. (11).The system closely corresponds to the that
introduced by Fujita et nl. (Z2,13) for metacyclophane alkaloids (B and C). The new system
is attractive since the carbon atoms that correspond in biogenetic origin to the three types (A,
B, C) maintain corresponding numbers.
TABLE I
LACTONIC
TRANS-FUSED ALKALOIDS
BIPHENYL
Compound Formula M P ( C) M P of derivatives ('C) [.I, (CHC1,) I,,,nm (log E ) Plant" Source Ref.
A. LACTONIC
TRANS-FUSED
BIPHENYLALKALOIDS
Nine alkaloids belong to the trans-fused group: lythrine (l),decinine (2),
lyfoline (3),sinine (4), nesodine (5),decodine (6),dehydrodecodine (7),ALC-1,
and ALC-2. All of them have a trans-fused quinolizidine ring, a 12-membered
lactone ring, and the biphenyl group. The p-hydroxycinnamoyl moiety is
12,13-dihydro in decinine (2)and decodine (6),and 13-hydroxy-12,13-dihydro
in sinine (4). The other aromatic ring is oxygenated at C-22 and C-23 in
compounds 1-4 or at C-22 and C-21 in compounds 5-7. Alkaloids of this
group are listed in Table I (1-4, 16-21).
The structure and relative configuration of lythrine (1) was established by
chemical and X-ray crystallographic studies of 0-methyllythrine (8) hydro-
bromide (22). The structure of other alkaloids in the group was assigned
from a combination of chemical and spectral studies as well as by correlation
with the structure of lythrine.
Lythrine (1) was isolated from Heimia salicifolia Link and Otto by Blomster
et al. (I), from Heimia myrtifolia Cham and Schl. by Douglas et al. ( 4 ) ,
and from Lagerstroemia fauriei by Fuji et al. (16).The absolute configuration
of the biphenyl system was established by comparison of CD curves of
0-methyldihydrolythrine (9) (0-methyldecinine), a-methyldihydrothebaine
(lo), and neodihydrothebaine (11) which agreed in sign and wavelength
between 200 and 250 nm. These studies have determined that the chirality
of the biphenyl chromophore of all biphenyl alkaloids is the same (23).The
relative configurations of all the chiral carbons in lythrine were already
known. Establishing the absolute configuration at any one chiral center
13 @
/ H R
R3" 4 H N
H T
9
/ /
l6 \
llS20, 24
\ /
Me
OCH,
10 R = M e
11 R = H
Me
OMe
12
L-alaninol (24). Decinine (2) was isolated by Ferris from Decodon uerti-
cillutus (2, 171, from Lugerstroemiu indicu L. (25), and from Lythrum lun-
ceolutum (9).This alkaloid was shown to be identical to the dihydro derivative
of lythrine (22).
Lyfoline (3) was isolated from H . salicifolia by Appel et ul. (3) who estab-
lished the identity of 0,O-dimethyllyfoline and 0-methyllythrine. On the
basis of this fact and biogenetic considerations(oppheno1 coupling), struc-
ture 3 was assigned to lyfoline (26). Shine (4) was isolated from H . sulicifolia
by Blomster et al. (I). Later, this alkaloid was shown to be identical to
lythridine isolated by Douglas et ul. ( 4 )from H . myrtifoliu and by Fuji et ul.
(16)from Lagerstroemiu fuuriei. Structure 13 was proposed for this alkaloid
on the basis of its mass spectrum and its dehydration to lythrine (18). How-
ever, X-ray analysis of sinine (lythridine) methiodide has verified its structure
as 4 (19).
268 w. MAREK GOLEBIEWSKI AND JERZY T. WROBEL
OMe
13
Two new alkaloids, ALC-1 and ALC-2, were isolated from H . salicifolia
by Dominquez et al. (20). Mass spectral fragmentation and properties of
methyl ethers suggested that they were stereomers of lythrine.
Nesodine (5) and dehydrodecodine (7) were isolated from H . salicifolia by
Schwarting et al. (3, 21). Decodine (6)was isolated from D. uerticillatus by
Ferris (2, 17). These three alkaloids differ from the lythrine-type alkaloids
(1-4) in the oxidation pattern of the aromatic nuclei This was established
by comparison of UV and NMR spectra and from oxidation studies. Methyl
decinine has i,,,293 ( E 7180) and methyldecodine has i,,,285 ( E 4980). The
permanganate oxidation of 0-methyldecinine (9)and 0,O-dimethyldecodine
(14; structure 2 with R2 = OMe and R' = R2 = R3 = H) yielded 4 3 -
dimethoxyphthalic acid and 3,4-dimethoxyphthalic acid, respectively, along
with 4-methoxyisophthalic and succinic acid (see Scheme 3).
Structure 15 was proposed for nesodine by Schwarting et al. (3) on the
basis of a broad phenolic hydroxyl absorption at 2700-2500 cm-I and a
15
1-
OMe
OMe
B. LACTONIC
BIPHENYL BIPHENYLALKALOIDS
CIS-FUSED
Seven alkaloids belong to this group : vertine (cryogenine) (17), decamine
(18), heimidine (19), verticillatine (20), dihydroverticillatine (21), sinicuichine
(22), and lagerstroemine (indicamine) (23). All have a cis-fused quinolizidine
system, a 12-membered lactone ring, and a biphenyl group oxygenated at
C-17, C-22, and C-23 in 17-19 and at C-17, C-21, and C-22 in 20-23. These
alkaloids are listed in Table 11. ( I , 2, 16, 17, 25, 27-29). Vertine (17) differs
from lythrine (1) only in the configuration at C-5. The same close relationship
exists between decamine (18) and decinine (2), heimidine (19) and sinine (4),
TABLE I1
LACTONIC
CIS-FUSED
BIPHENYL
ALKALOIDS
Compound Formula MP ("C) MP of derivatives ('C) [.ID (CHCI,) i,,,nm (log c) Plant' source Ref.
Q OH
L A \
OMe
OMe
-U
OMe
17 R = H, A" 20 R ' = R 2 = H, A12
18 R = H 21 R' = R2 = H
19 R = O H 22 R' = Me, R 2 = H, A12
23 R' = Me, R2 = H
24 R' = R 2 = Me, A''
epimer at C-5, respectively. ORD and CD effects of the biphenyl system and
the N-nitroso group can be observedindependently as the absorption maxima
of both chromophores are sufficiently removed from one another [290 mm
( E 7000) and 350 nm ( E 200), respectively].
The Cotton effect at 350 nm reflects the configuration at C-5. The ORD
and CD curves are opposite in sign in this region, thus confirming that the
two types of alkaloids differ in configuration at C-5 (24).
Decamine (18) was isolated by Ferris from D. verticiffatus (2) and from
Lagerstroemia indica by Ferris et a f . (25). Ferris established the identity of
decamine with dihydrovertine.
Heimidine (19), a minor alkaloid isolated from Heimia saficifofia by
El-Olemy et al. (28),is hydroxydihydrovertine. Dehydration of heimidine on
alumina gives vertine (17). Structure 19 was assigned on the basis of similar
mass, NMR (aromatic region), and Ik spectra (apart from the lack of
Bohlmann bands) to those of sinine (4). The absolute configuration of the
C-13 OH group was not established.
Verticillatine (20) was isolated by Ferris from Decodon verticiflatus (2).
Dihydroverticillatine (21) and lagerstroemine (23) were isolated by Ferris
et a f . from Lagerstroemia indica (25)and sinicuichine (22) by Blomster et al.
from H . saficifolia (1).Lagerstroemine was also detected in Plantago psylium
(30, 31).
These four alkaloids have the same aromatic oxygenation pattern as
decodine (6)and nesodine (5). The methoxylation pattern of verticillatine was
established in the same way as described for decodine. Enantiomerism of
the dimethyl ethers of dihydroverticillatine (25) and decodine at C-5 was
demonstrated by a parallel series of degradations to N-nitroso derivatives
OMe OMe
25 26a R = Me
26b R = CN
26c R =H
26d R=NO
4. THE LYTHRACEAE ALKALOIDS 273
shown for 25 (cf Scheme 1). The ORD curves of 26d and the corresponding
product from decodine show extrema opposite in sign at 350 nm (24). 0-
methylsinicuichine proved to be identical to 0,O-dimethylverticillatine (24).
(29).
Lagerstroemine (23), on methylation with diazomethane, afforded 0,O-
dimethyldihydroverticillatine (25). Lagerstroemine has two methoxyl and
one phenolic hydroxyl group. The methoxylation pattern was established by
conversion of the alkaloid to the benzopyran (27) via the methiodide of the
diol (28).
Me
I
OMe OMe
21 28
C. GENERAL
FEATURES
OF THE STEREOCHEMISTRY
OF LACTONIC
BIPHENYL ALKALOIDS
The Lythraceae alkaloids have four centers of chirality-three chiral
carbon atoms at the quinolizidine ring C-1, C-3, and C-5, and the dissy-
metric biphenyl or biphenyl ether link. The chirality of the biphenyl system
in all alkaloids of the group is the same. The chirality of the biphenyl ether
link is also the same for all alkaloids in this class (22,23, 32).
All lactonic alkaloids have the same absolute configuration at C-1 and
at C-3. The C-1 phenyl substituent is always equatorial. The C-1 hydrogen
appears in the N M R spectra as a doublet of doublets with large (10-12 Hz)
and small (1-2 Hz) coupling constants. The coupling requires that this
hydrogen be axially oriented. The lactonic oxygen at C-3 is always axial.
The C-3 hydrogen absorbs at 6 5.0-5.4 ppm with the half-height width of
7.5-9 Hz. This result indicates that H-3 is equatorial in all alkaloids (24).
The axial nature of the C-2 oxygen substituent was confirmed by its
epimerization to the equatorial configuration. Treatment of methyldecinine
274 w. MAREK G ~ E F B I E W S K IAND JERZY T. W R ~ B E L
1
OMe
29
D. THECHEMISTRY TRANS-
BIPHENYLALKALOIDS
OF LACTONIC AND
CIS-FUSED
1. Cleavage of the Lactone Ring
Hydrolysis of the lactone ring in dimethyldecodine (14) was carried out by
prolonged refluxing of the alkaloid in aqueous methanolic sodium hydroxide
(17). Ferris reported that the starting material could be recovered in 18%
yield using thionyl chloride in chloroform. However, in the total synthesis
of the biphenyl ether alkaloid decaline, the yield of lactonization of the
corresponding hydroxyacid did not exceed 5% (39,40). This reaction was
usually carried out in much better yield in benzene with p-toluenesulfonic
acid (39).
The lactone ring of dimethylodecodine (14) was cleaved by lithium
aluminium hydride reduction to the corresponding diol. The same diol was
formed from the lithium aluminium hydride reduction of the hydroxyester
prepared from the product of alkaline hydrolysis (I7).
Reductive cleavage of the lactone in methyldecinine (9)followed by formic
acid dehydration afforded the olefin (29).
(i)PhMgBr
(ii) HCO,H+
I
OMe OMe
9 29
Me,SO,
1- MeOSO;
I I
OMe OMe
30 31
Methylation of the phenolic OH in the product of Emde degradation of
decinine (32) with trimethylanilinium hydroxide (24) resulted in cleavage of
the lactone ring to yield derivative 33.
Me Me
OMe OMe
32 33
H ye
I I
OMe OMe
34 35a R = H
35b R = Me
OMMe
36 R = C N
37 R = H
38 R = N O
SCHEME
1
OMc OMc
39 40
41
Me Me
(i) Na-EtOHiNH,
(1;) H, Pt
[iii) PhNMe,OH-
0Me
42 43 R = H
44 R = M e
SCHEME
2
3. Oxidation
N-oxides of alkaloids could be easily prepared using m-chloroperbenzoic
or peracetic acids (17, 24). On pyrolysis of the N-oxide of dimethylodecodine
a mixture of products was obtained, and only dimethyldecodine (14) could
be characterized.
4. THE LYTHRACEAE ALKALOIDS 279
OMe OMe
OMe
14 45 46
-
CO,H
I
KMnO,
OMe OMe
OMe
9 45 47
KMnO,
___f
/
CO,H 'OMe
1
OMe
1 48
3
SCHEME
TABLE 111
LACTONIC
BIPHENYL
ETHERALKALOIDS
a 36
Vertaline (51) C,6H,,NO, 194-196 - 170 293 (3.81) a 2, 36, 41
264 (3.29)
Demethylvertaline (52) C2,HZ9NO, 120-160 - ~
a 36
Lagerine (53) C2SH29N0S 210 - 184 275 (3.49) C 25
232.5 (4.31)
Methyllagerine (54) C26H31N05
~
- ~
C 25, 42
Heimine C,6H,,N05 247.5-249 +43 ~
b 1
a a, Decodon uerticillatus (L) Ell; b, Heimia salicifolia Link and Otto; c, Lagerstroeniia indica L.
4. THE LYTHRACEAE ALKALOIDS 281
Y O M e Y O M e
OMe OMe
49
Me
I! Me
- 2e
3H
4r
7z
OMe OMe
Me
I!
L O H RoA
I
OMe
57 R = H
58 R = Me
55 R = H
l+
Rob
\
OMe
59
Me0
60 R = H
56 R = Me 61 R = M e
(the reaction must proceed with methyl transfer from C-21 to C-17 oxygens
to yield 59 and 62):
Me
OMe OMe
HO Q OMe
54 59 62
Extracts from young seedlings of Heirnia salicifolia plants were the source
of three minor alkaloids. Rother and Schwarting have isolated two isomeric
1-(12-hydroxy-l3-methoxy)phenylquinolizid-3-ols (63a) and (@a) and de-
tected 1-(12-hydroxy- 13-methoxy)phenylquinolizid-3-one(65a or 65b or
both) (47, 48).* These alkaloids were absent in extracts of plants obtained
at later stages of growth (49). These three compounds are intermediates in
the current biogenetic hypothesis.
* The absolute stereochemistry of nonlactonic alkaloids (63-70) has not been established
TABLE IV
SIMPLE
QUINOLIZIDINE
A N D ESTERALKALOIDS
Compound Formula MP ("C) [.ID (MeOH) I.,,, nm (log E) Planth source Ref.
We use the name demethyllasubine-I and -11 for quinolizidols 64a and 65b.
a, Heirnia salicifolia Link and Otto; b, Lagerstroemia subcosiaia Koehne.
286 w. MAREK ~ ~ E F B I E W S KAND
I JERZY T. WROBEL
The structures of both quinolizidols (63a and 64a) have been established
by analysis of NMR, IR, and MS data and by comparison with synthetic
compounds.
The hydroxyl group is axial in the trans-fused quinolizidol (63a) and the
phenyl group is equatorial. The NMR signal of H-3 in 63a appears as multi-
plet at 6 4.1 ppm with a 1/4-height (W1,,) band-width of about 11 Hz. In the
synthetic equatorial epimer this proton absorbs at 6 3.6 ppm with W, ,
32 Hz.
The NMR spectrum of the cis-fused quinolizidol(64a) and its derivatives
showed the presence of an equilibrium mixture of conformers where the
form with an axial OH and equatorial phenyl group was only a minor
component. The signal of H-1 in 64b-d appears at 6 4.0-4.1 ppm as a triplet
with a coupling constant of 4-5 Hz and W1,, of 13-14 Hz. H-3 was in part
unresolved from H-1 in 64a,e and in 64c,d was a broad multiplet (a triplet
of triplets with J 8-9 and 4.5 Hz) with W,,, equal to 25-28 Hz. These
couplings of H-1 and H-3 favor that conformation with an axial phenyl
and an equatorial hydroxyl. Compound 64a was synthesized by reduction
of cis-fused quinolizidone (65b) with NaBH, to yield mixture of 64a and its
epimer in 1.3: 1 ratio or with lithium tri-sec-butylborohydride, where 65%
conversion to axial alcohol was observed.
The identity of natural and synthetic quinolizidols (63a and 64a) was
conclussively established by radioactive dilution analysis. This technique
made it possible to detect 1-( 12-hydroxy-13-methoxy)phenylquinolizid-3-
one (65a or 65b or both) in the seedlings of Heimiu sulicifoliu.
Fuji et al. (16) have recently isolated lasubine-I (64b) and lasubine-I1
(63b) from Lugerstroemiu subcostutu Koehne. The structures of these
alkaloids have been established by correlation with synthetic compounds
(63a and 64a) as well as by analysis of IR, PMR, I3C-NMR, and mass spectra.
These alkaloids are listed in Table IV (16,47,48,50,51).
V. Ester Alkaloids
0;: Rlo
R 1l 6 \
66 R'
17Q
ORZ
= OMe,
zQ::
OMe
RZ = R3 = H
OR^
69 R'
\
ORZ
'
= OMe, R Z = R3 =
OMe
H
OR^
fragment ions m/e 276 and 177, corresponding to 63a and ferulic acid. The
quinolizidine ring of abresoline is trans-fused as indicated by Bohlmann
bands and NMR absorption of benzylic proton H-1 at 6 3.22 ppm as double
doublet ( J = 10, 1 Hz). The equatorial orientation of H-3 was deduced from
NMR absorption at 6 5.18 ppm with a half-height width of 8 Hz. The
proposed structure was confirmed by synthesis of its dihydroderivative from
isovanillin, pelletierine, and methyl benzyloxyferulate (50).
Demethoxyabresoline (67) was obtained as a noncrystalline solid. Spec-
troscopic investigation revealed the presence of a phenolic OH, a l-phenyl-
quinolizidine system, and a trans-cinnamyl group. The stereochemistry at
C-1, C-3, and C-5 was the same as in abresoline. The molecular formula
C,,H,,NO, was established by mass spectrometry. The presence of frag-
ment ions at mje 259 (M - 164) and 258 was characteristic of p-hydroxy-
cinnamyl esters of the phenylquinolizidol (63a). The assigned structure 68
was confirmed by basic hydrolysis to 63a and p-hydroxycinnamic acid as
well as by catalytic hydrogenation to a known dihydro derivative (52).
5-Epidemethoxyabresoline (70) shows a mass spectrum similar to that of
its stereoisomer 68. The absence of Bohlmann bands and the NMR chemical
shift of H-1 at 6 4.0 ppm demonstrate the presence of cis-quinolizidine
system.
Trans-cis isomerization of the olefinic bond of 70 has been observed on
silica gel, and the conversion was accelerated by UV light, The structure of
70 was established by synthesis. Cis-fused quinolizidol 64a in which the
phenolic OH was protected with a p-bromophenacyl group was esterified
with trans-4-bromophenacylcinnamic acid in the presence of p-toluenesul-
fonic acid to yield a mixture of two major esters (70a and 70b). Removal of
the protective group from both esters gave 5-epidemethoxyabresoline.
Two minor ester alkaloids, subcosine-I (69) and subcodine-I1 (67), have
been isolated recently by Fuji et al. (16) from Lagerstruemia subcostata.
288 w. MAREK ~ ~ E E B I E W S KAND
I JERZY T. WROBEL
A. INTRODUCTION
Three piperidine alkaloids; lythranine (72), lythranidine (73), and ly-
thramine (74) belong to this group. All have a piperidine ring disubstituted
at two c( positions by two aralkyl C,-C, groups joined by a biphenyl bond.
Lythramine contains an extra 0,N-methylene bridge. The alkaloids
were isolated from Lythrwn anceps Makino by extraction with buffers (72
pH 4.8, 73 pH 6.0, 74 1N HC1) (5,6). These alkaloids are listed in Table V.
TABLE V
PIPERIDINE
METACYCLOPHANE
ALKALOIDS
B. CHEMISTRY
Methylation of lythranidine (73) with diazomethane in methanol afforded
0-methyllythranidine (76). 0,N-Dimethyllythranidine (77) was formed on
prolonged standing. Lythramine (74), on methylation with the same reagent,
gave 0-methyllythramine and 0-methyldeacetyllythramine (75) (12).
Acetylation of lythramine at room temperature gave O,O-diacetyllythranine,
whereas the same reaction at 45" gave an amorphous O,O,N-triacetate.
Acetylation of Iythranidine at room temperature afforded an O,O,O-triacetyl
derivative, identical to 0,O-diacetyllythranine (7).
Mild oxidation of 0-methyllythranidine (76) with permanganate under
alkaline conditions afforded the symmetrically substituted biphenyl di-
carboxylate characterized as its dimethyl ester 78. This reaction established
the presence of a 2,2',5,5'-tetrasubstituted biphenyl system in the alkaloids.
Oxidation of 0-methyldeacetyllythramine (75) with chromic anhydride-
pyridine complex yielded the ketone (79) which exchanged four hydrogens
on treatment with sodium deuteroxide in deuterium oxide and deutero-
methanol (12).
Dehydrogenation of lythranine at 260" on palladium black followed by
oxidation with permanganate gave a mixture of carboxylic acids. The
78 79
290 w. MAREK GOLEBIEWSKI AND JERZY T. WROBEL
methyl esters were separated into neutral and basic fractions. From the
basic fraction a dimethyl dipicolinate was isolated. Thus, the presence of a
piperidine ring in these alkaloids was demonstrated (12).
Hofmann degradation of 0,N-dimethyllythranidine (77) methiodide
followed by catalytic hydrogenation gave a product whose methiodide
underwent the same sequence of reactions yielding de-N-product 80 (mp
133.5-1 35'). Oxidation with chromic anhydride in pyridine afforded a
diketone 81 (mp 116-1 18').
J "
n
81
In the NMR spectrum of 81 the (2-12 and C-13 (C-1 and C-2) methylene
protons showed an A,B,-type signal at 6 2.83 ppm. Another active methylene
at C-10 (C-4) absorbed as a triplet at 6 2.32 ppm. The remaining protons
resonated at 6 1.O-1.8 ppm. Compound 81 was oxidized with permangamate
under the alkaline conditions to yield a mixture of C6 to C9 dicarboxylic
acids. These were analyzed as methyl esters by gas chromatography. Thus,
the presence in the molecule of seven methylene groups between the carbonyl
groups was established.
Refluxing 0-methyllythranidine (or lythranidine acetate) with ethyl
orthoformate yielded an amidoacetal(82). The new singlet signal of the one
central proton appeared at 6 5.26 ppm in the NMR spectrum of the product.
4. THE LYTHRACEAE ALKALOIDS 29 1
82
HO
17 83 R' = C1, R2 = H 85
84 R' = R2 = C1
+ h C H 0
OMe OMe
86 R = H 88
87 R = I
I
bI
CO,R CO,R
OMe
89 R = H 91 R = H
90 R = M e 92 R = M e
85 96 93 R = C0,Me
94 R = C H , O H
95 R = CH,C1
C. STEREOCHEMISTRY
Piperidine-type metacyclophane alkaloids have four chiral carbon atoms :
C-3, C-5, C-9, and C-11. With 96 in hand, Fujita et nf. hydrogenated its
pyridine ring over Adams catalyst and Raney nickel in order to define the
relative stereochemistry of C-5 and C-9. They obtained a single crystalline
hexahydro derivative in quantitative yield. Catalytic hydrogenation of
substituted pyridines generally results in cis products. Therefore, one can
assume the cis relationship of C-5 and C-9 hydrogens in the foregoing
4. THE LYTHRACEAE ALKALOIDS 293
98a 85a
91 R = H
98 R = M e
The chemical shift of the piperidine protons CI to the nitrogen in the
synthetic cis compound 98 was lower (6 2.30 ppm) than in the trans product
of degradation of lythranidine (6 2.68 ppm) (54). In the dominant con-
formation of N-methylpiperidine the methyl group is equatorial and the
lone pair is axial. Therefore, the conformation of the piperidine ring in the
cis form (98) is presumably 98a, and 85a reflects the dominant conformation
in the trans isomer. In the cis stereomer 98a there are two hydrogen atoms in
a trans-diaxial relationship to the free electron pair on nitrogen, and in the
trans form 85a there is only one such hydrogen. Piperidine is conforma-
tionally a labile system, and the chemical shift of the protons a to nitrogen
takes an average value. The greater the number of trans-diaxial protons, the
lower the chemical shift of the cx hydrogens atoms. In the quinolizidines the
signal of the a axial proton appears at 0.5-1 ppm higher field than the signal
of equatorial r protons (55, 56). The observed chemical shifts of r protons
in 85 and 98 were consistent with the assigned structures. The optical activity
of 85 further demonstrated the trans relationship of H-5 to H-9.
The same criterion was used to assign the relative stereochemistry of C-3
and C-11. The de-N-base (80) was optically active in contrast to the cor-
responding diketone (81). This means that C-3 and C-11 have the same
configuration and that H-3 and H-11 are trans to one another.
Finally, the relative and absolute stereochemistry of bromolythranine
(99) hydrobromide was established by X-ray studies (57).The cis relationship
of H-3 to H-5 and H-9 to H-11 was confirmed.
The absolute configuration of piperidine Lythrum alkaloids was es-
tablished by analysis of ORD and CD spectra of biphenyl compounds.
The absolute structures 72, 73, and 74 were assigned to lythranine,
lythranidine, and lythramine, respectively, on the basis of the positive sign
294 w. MAREK WLFBEWSKI AND JERZY T. WROBEL
99
13
Compound Formula MI' ("C) [.ID (MeOH)" i.,,,nm (log E ) Planth source Ref.
Lythrancine-I (100) +
65 8 , 5 8 -60
Lythrancine-I1 (101) 274-275 +125 289 (3.90) 8,X-60
Lythrancine-III(lO2) 134-1 35 +
38 290 (3.79) 8.58-60
Lythrancine-IV (103) 237-238 +
27 290 (3.76) 8,58-60
Lythrancine-V (104) 133-134 +91 290 (3.91) 8, 61
Lythrancine-V1 (105) +
25.5 8, 61
Lythrancine-VII (106) f101.5 _- 8, 61
Lythrancepine-1 (107) 149 15 1
- +
59 290 (3.80) a 8,58-60
Lythrancepine-II(1OS) 187-189 +
44 290 (3.78) 8,58-60
Lythrancepine-I11 (109) 175-177 +7 290 (3.83) 8,58-60
Lythramine (123) 214-216 - 8" 294 (3.83) 9
Acetyllythramine (1 24) 184-185 - 34" 292.5 (3.90) 9
Me0,C 0
H CH,CO,Me
equatorial C-4 OH. The structure of the product 114 was established on the
basis of NMR and mass spectra. Oxidation of 114 with the Jones reagent in
acetone gave diacetoxyquinolizid-3-one, which was reduced selectively
with sodium borohydride in methanol to the axial quinolizid-3-01 (115)
epimeric at C-3 with 114 and lythrancine-111.
Acetylation of 115 afforded lythrancine 104. This conversion was crucial
in establishing the structure and absolute stereochemistry of lythrancines
104, 105, and 106 (58).
114 115
B. STEREOCHEMISTRY
Lythrancepine 108 was oxidized with Jones reagent to the quinolizidone
(116) which underwent a retro-Michael-type reaction to a mixture of a,P-
unsaturated aminoketones 117 and 118. The more polar ketone 117 readily
isomerized to the less polar compound 118 either on a chromatographic
column or on standing in a chloroform solution. The original mixture was
then catalytically hydrogenated and the saturated ketones 119 and 120
separated by chromatography on silica gel. The quinolizidone 119 was
selectively reduced and acetoxy alcohol hydrolyzed and formylated with
formic acid and acetic anhydride. The crystalline N,O,O-triformate 121
+
(mp 211-212", [a],, 70") proved to be an enantiomer of the product of
methylation and formylation of lythranidine (73). Thus, the absolute con-
figuration of lythrancines-I and -IV, and lythrancepines-I to -111at C-5, C-9,
and C-l 1 was established as S , S , and R,respectively (59).
The IR spectra of quinolizidine metacyclophane alkaloids do not show
the presence of Bohlmann bands (33, 34). This suggests a cis-quinolizidine
ring fusion. Analysis of the NMR spectrum of lythrancine 103 led to the
same conclusion. The diagnostic proton H-l absorbed at 6 4.17 ppm as a
double doublet. It corresponded well to the absorption of the benzylic
-
proton tl to the nitrogen in the cis-4-phenylquinolizidines (35) and cis-
-
lactonic Lythraceae alkaloids (24) at 8 4 ppm. In the corresponding
trans-fused quinolizidines this proton absorbs at 6 3 ppm. The coupling
H’
OAc
,
108 116
OAc
, ,OAc
117 118
I H2
I 1
OAc
I
119 120
121 122
4. THE LYTHRACEAE ALKALOIDS 299
Me0
A B
of H-1 in lythrancine-IV (J 11 and 4 Hz) indicates the axial configuration
given the chair-chair conformation of quinolizidine.
The resonance of H-3 at 6 5.15 ppm as an octet ( J 11.5, 6 , and 3 Hz)
suggested an axial configuration and a triplet at 6 4.91 ppm (J 3 Hz) due to
H-4 implied an equatorial position. Thus, H-1 and H-3 are cis to one another
and H-3 and H-4 have the same cis relationship. The cis relationship of
acetoxyl substituents at C-3 and C-4 of lythrancine 103 was confirmed by
the ease of formation of a five-membered ring carbonate in reaction of
lythrancine 101 with phosgene.
The trans relationship of H-5 and H-9 was established as a result of
oxidation of lythrancine 101 with Jones reagent to a trans-piperidine
derivative (110).
Analysis of all the above results led to only two possible structures, A
and B, for lythrancines I-IV and lythrancepines 1-111. Structure A is pre-
ferred because the molecular models show large interactions between the
10-methylene group and the aromatic hydrogen atoms in B and the 13-
membered ring is highly strained. X-ray crystallographic studies of ly-
thrancine 101 0-brosylate confirmed stereochemistry A. Thus, the absolute
stereochemistry of seven quinolizidine alkaloids was established as 100-103
and 107-109 (104).
Chromatography of the mother liquors of lythrancepine 102 afforded three
minor alkaloids: lythrancines 104, 105, and 106. The structure and stereo-
chemistry of these bases was elucidated by analysis of NMR and mass
spectra and by comparison with those of lythrancine 103. The assigned
structure 104 for lythrancine-V was unequivocally confirmed by the pre-
viously described conversion of lythrancine 102 to this alkaloid via isomer
114 (61).
C. MASSSPECTROMETRY
The mass spectra of 10 quinolizidine Lythrum alkaloids including 4-
epilythrancine-IV, 3-epilythrancepine-111, 4-deuterolythrancine-IV, and 3-
deutero-3-epilythrancepine-I11were investigated by Fujita and Saeki (60).
N . N
z T
0
-8
d
a!
d
0
n ZY
O O T
II II I/
222
2522222
II II II /I II I1 I1
2222222
300
R2
! C'II,C'H,
I
/ J 2
H
il
c d g
111 1' n?:e 1ll:IC
R2 =OH 390 R ' = H, R 2 = OH 408 R ~ = O H 295
R2=OAc 432 R 1 = Ac, R 2 = OH 450 R 2 = O A c 337
R2 = H 314 R ' = Ac, R2 = OAC 492 R2= H 219
R' = R 2 = H 392
R ' = Ac, R 2 = H 434
310
302 w. MAREK GOEFBIEWSKI AND JERZY T. WROBEL
D. OXOQUINOLIZIDINE
METACYCLOPHANE
LYTHRACEAE
ALKALOIDS
Five new alkaloids have been isolated from the Lythraceae plant Lythrum
Lanceolatum by Wright et al. (9). The structure and absolute configuration
of two of these bases, lythrumine (123) and monoacetyllythrumine (124),
were established on the basis of the X-ray analysis on lythrumine hydro-
bromide. On acetylation both the alkaloids yielded the same diacetate
(125).
123 R' = R Z = H
124 R' = Ac, RZ = H
125 R' = R 2 = AC
The lactonic alkaloid decinine (2) was also isolated from L. lanceolatum
(9). This alkaloid was found previously in the Decodon uerticillatus, Heimia
salicifolia and H. myrtifolia (as the 12,13-dehydro derivative, lythrine),
and Lagerstroemia iizdica. This fact supports the taxonomical grouping of
Lythrum with the Decodon, Heimia, and Lagerstroemia genera in the
4. THE LYTHRACEAE ALKALOIDS 303
Lythraceae plant family and suggests that the metacyclophane and lactonic
alkaloids have a common biosynthesis.
VIII. Synthesis
A. EARLYSYNTHETIC
APPROACHES
The common intermediate in two published biomimetic routes to Lythra-
ceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach
based on a biogenetic hypothesis of Ferris et al. (62),Wrobel and Golebiewski
condensed pelletierine (126)* with isovanillin (128) and obtained a trans-
fused quinolizidine derivative (130, P H-5) (64) in 75% yield. A model con-
densation of pelletierine (126)with benzaldehyde which resulted in a mixture
of quinolizidones was reported earlier by Matsunaga et al. (65). In another
approach Rosazza et al. (52)condensed A'-piperideine (132)with P-ketoester
133 to get 134. The next stage in both approaches was reduction of the ketone
and esterification or transesterification with derivatives of p-hydroxycinna-
mic acid (135 or 136). Investigations into the oxidative coupling of 137 were
unsuccessful.
B. PELLETIERINE-BENZALDEHYDE
CONDENSATION
This is a key stage in the synthesis of lactonic Lythraceae alkaloids
published by Hanaoka et al., Loev et al., and Wrobel and Golebiewski. This
reaction was studied by several groups of chemists (64, 66-69). It proceeds
in good yield for a variety of aromatic aldehydes usually in dilute aqueous or
alcoholic solutions of sodium hydroxide to yield 2-quinolizidones. Two
diastereomers, 138 and 139, defined by the relative stereochemistry at C-4
and C-10 are formed in the condensation." In the trans-quinolizidone (139)
the C-4 and C-10 hydrogens are trans to one another. In the cis-quinolizidone
(138) they are cis.
Compound 140 is presumably the most stable conformation for dia-
stereomers 138 and 141, or its flexible form represents the conformation of
lowest energy for configuration 139 (66, 67).
R'
127 R' = R 2 = H 129 R' = R2 = H 134 133
128 R' = OMe, R 2 = OH 130 R' = OMe, RZ = OH
131 R' = OMe, R2 = OCH2Ph
1
K . O q C O z R '
135 R ' = R 2 = R 3 = H. A'
136 R' = H, R 2 = CH2Ph, R' = Me
0Me
137
4. THE LYTHRACEAE ALKALOIDS 305
Ar Ar
126 138 139
Ar
140 141
The trans- and cis-fused forms are clearly identifiable by Bohlmann bands
in the IR spectra (33,34)and by the NMR chemical shifts and coupling of
the benzylic proton at C-1. In the spectra of trans-fused quinolizidones the
diagnostic proton absorbs in the region 6 2.70-3.30 ppm where, as in the
cis-fused forms, the absorption is shifted to lower field by 0.5-2 ppm.
Condensation under thermodynamic control yields mainly the trans-fused
quinolizidine system whereas in a kinetically controled reaction predom-
inantly cis products are obtained (66, 67). The latter isomerize to the cor-
responding trans forms in an alkaline medium. An isomerization in dilute
hydrochloric acid was also reported (68).The stereoselectivity of the reaction
was influenced by the solubilities of the starting aldehydes and products,
since the first-formed cis-quinolizidones isomerize easier in a soluble state.
Several mechanism have been suggested for this reaction. Hanaoka et al.
(66) have described it as a Mannich reaction.
Condensation of pelletierine and arylaldehyde affords the imminium salt
(143) which is transformed to the cis-quinolizidone (141) via the unstable
trans-fused quinolizidone (144).The cis form (141)comes to equilibrium with
the trans isomer (140) via the unsaturated aminoketone (145) by the action
of hydroxide anion.
Lantos et a1. (68)suggested a modification of Hanaoka’s mechanism where
an imminium intermediate (143) would undergo a retrograde conjugate
addition to a Schiff base (146). Its cycloaddition reaction via the enolate
would produce the cis compound selectively.
Wrobel and Golqbiewski (67)interpreted the condensation in terms of a
two stage reaction : a Claisen-Schmidt condensation resulting in an amino
alcohol (147) followed by nucleophilic intramolecular substitution of the
OH group. Quick and Oterson (69) suggested a modification of the latter
'= -
306 w. K I JERZY T. W R ~ B E L
MAREK C O ~ . ~ B I E W ~ AND
+ArCHO O m
1 -
126 HC-OH
qo-dp Ar
AI
146 141
I
140 Ar
145
HO"
Ar
/
126
ArdHO -
Ar
kr
145
C. LACTONIC
BIPHENYL
ETHERALKALOIDS
1. Introduction
In the lactonic alkaloid molecule one can find three synthons: pelle-
tierine, a 4-methoxybenzaldehyde derivative, and p-hydroxycinnamic acid.
In all published syntheses of lactonic Lythraceae alkaloids they are the
building blocks.
'CHO
R'
2. Trans-Fused alkaloids
Decaline (43)was the first synthesized Lythraceae alkaloid. The synthesis
was achieved independently and concurrently by a Japanese and a Polish
group. Three approaches were used in these syntheses. In the first method,
308
or
Br /
'
w. MAREK GOLEBIEWSKI AND JERZY T. WROBEL
OR
d
R
Br
/
'
' H
OM2
r
152 +
d:ZMe
/
'
+
OM2 OM2 OH
149 R = H 151 R' = OH, R2 = H 155
150 R = M e 152 R' = OAc, R2 = H
153 R' = H, RZ = OH
154 R' = H, R Z = OAc
OM2 OMe
156 R' = OAc, R 2 = Me 49 R = Me
157 R' = R' =H 50 R = H
OMe V O M e V O M e
OM2 OM2 OMe
cinnamate (155) gave the biphenyl ether derivative (156) in 34% yield.
Alkaline hydrolysis of 156 and lactonization of the resulting hydroxyacid
(157) in benzene in the presence of toluene-p-sulfonic acid yielded (?)-
decaline (49) in 55% yield.
In another similar approach (40, 72) Wrobel and Golcbiewski obtained
the methyl ether (150) in the same way. The Ullmann condensation with
methyl 4-hydroxycinnamate afforded a mixture of stereoisomers 160 and
161. Catalytic reduction of the trans-fused quinolizidone (160) gave a
mixture of axial and equatorial epimers (162 and 163) in 4: 1 ratio. Hydrolysis
of the axial hydroxyester (162) followed by lactonization with thionyl
chloride in chloroform yielded racemic decaline.
In the third approach (39,40, 72)the quinolizidone ester was alternatively
prepared. The Ullmann reaction of 6-bromoveratraldehyde with methyl
4-hydroxycinnamate afforded biphenyl ether aldehyde (164)in 55% yield. The
alkaline condensation of 164 with pelletierine gave a mixture of stereo-
isomeric quinolizidone acids (158 and 159). Esterification with dimethyl
sulfate yielded a mixture of trans- and cis-fused quinolizidine esters (160
and 161) in a 13 : 1 ratio after separation on silica gel.
Demethyldecaline (50) was synthesized by the first method from the 0-
benzyl derivative of 6-bromoisovanillin by Hanaoka et al. (44).
CHO
OCH,
OMe
55 R = H 53 R = H 166 R = M e
56 R = M e 54 R = Me 167 R = C H , P h
OMe
167a
+
O m
126
-
165
Hoa
Me0
164
and equatorial alcohols in the ratio of 19:l. The synthetic product 55 was
proven not to be identical with the natural lagerine. On the basis of the
NMR data and biogenetic considerations structure 54 was proposed for
methyllagerine.
The synthesis of 54 was similarly performed from 2-bromoveratraldehyde
(166), methyl 4-hydroxycinnamate, and pelletierine. The product was
shown to be identical to the natural alkaloid and the structural assignment
was confirmed (42).
Finally, lagerine (53) was synthesized in the same way starting from the
benzyl ether of 2-bromoisovanillin (167). The synthesis has demonstrated
that the phenolic hydroxyl group is at C-21 (46).
D. SYNTHESIS
OF LACTONIC ALKALOIDS
BIPHENYL
1. Trans-Fused Alkaloids
Methyldecinine (14) was synthesized independently by Loev et al. (77)
and Hanaoka et al. (78, 79). The crucial unsymmetrical biphenyl aldehyde
(168) was obtained by the Ullmann reaction of 6-bromoveratraldehyde
with 3-iodo- or 3-bromo-4-methoxy hydrocinnamate. Condensation with
pelletierine afforded the biphenyl quinolizidone (171) which was reduced
with Henbest catalyst followed by hydrolysis and lactonization.
4. THE LYTHRACEAE ALKALOIDS 31 1
Decinine (2) was prepared similarly by Lantos and Loev (80), from the
biphenyl aldehyde (169). Calcium hydroxide-catalyzed condensation with
pelletierine afforded biphenyl quinolizidone (172) in 20% yield. This com-
pound was obtained in better yield from the acid-catalyzed epimerization of
the cis-fused diastereomer (173) of the decamine synthesis (68).
* *
OMe 0Me
168 R' = Me, R 2 = OMe or OEt 171 R' = Me, R 2 = H, R3 = BH
169 R' = SO,Me, R 2 = OMe or OEt 172 R' = SO,Me, R Z = H, R3 = PH
170 R' = Me, R2 = N(Me), 173 R' = SO,Me, R Z = H, R 3 = aH
I
OMe
14 R' Me, R2 = BH
=
2 R' H, RZ = PH
=
18 R' H, RZ = IH
=
174 R' = Me. R2 = aH
312 w. MAREK GOLFBIEWSKI AND JERZY T. WROBEL
METACYCLOPHANE
E. PIPERIDINE ALKALOIDS
The first total synthesis of the metacyclophane alkaloid ( f)-lythranidine
(73) was achieved by Fuji et al. (82).
94 R = C H , O H 176 I77
175 R = CHO
178 R = H 180 73
179 R = NO
IX. Biosynthesis
Several biogenetic schemes have been suggested to account for the origin
of biphenyl and biphenyl ether lactonic alkaloids (52, 62, 83, 84). The pro-
posals differ in the mode of biogenesis of the phenylquinolizidine moiety.
Steps common to all the proposals are the reduction of 0x0 group in the
phenylquinolizidone (130)followed by esterification with ofp-coumaric acid
(C,-C,) unit derived from phenylalanine via cinnamic acid.
Most of the work on the biosynthesis of Lythraceae alkaloids has been
done by Spenser et al. (10, 84-87). First, the validity of the pelletierine
hypothesis (c) of Ferris et al. (62) has been tested. The pelletierine (126)
nucleus is generated from L-lysine (181)via cadaverine (182),and presumably
A'-piperideine (132) and its side chain originate from the acetate. Incor-
poration of radioactivity from 4C-labeled samples of these precursors to
decodine (6) and decinine (2) in Decodon oerticilutus has been investigated
(85,87).
The active alkaloids isolated from the plants to which [2-14C]lysine or
[6-'4C]lysine had been separately administered were partially degraded to
establish a distribution of activity.
Chromic acid oxidation yielded 2-piperidylacetic acid (183) containing
C-5 and C-9, y-aminobutyric acid (lM),and 8-alanine (185)containing C-9.
Since the entire activity of decodine and decinine was recovered in 2-piper-
ydylacetic acid it was likely that an intact C, unit composed of C-2 to C-6
of lysine was incorporated into ring A. y-Aminobutyric acid and b-alanine
contained one-half of the activity of the intact alkaloids, regardless of
whether [2-14C]- or [6-14C]lysine had been the precursor. Thus, the C,
fragment of the alkaloids must originate from lysine by way of a symmetrical
intermediate. The carboxyl carbon of lysine does not enter the alkaloids.
When [ l-'4C]lysine was administered to D. uerticillatus the alkaloid fraction
was totally inactive.
The chirality of a precursor-product relationship was determined by the
use of doubly labeled lysine, in which one enantiomer was labeled only with
tritium and the other with tritium and 14C (88).Comparison of the 3H/14C
ratios of substrate and products demonstrated that decodine and decinine
were derived from L-lysine, whereas pipecolic acid (186) was derived from
D-lysine. Thus, pipecolic acid does not serve as a precursor of Lythraceae
alkaloids (87).
314 w. MAREK GOLFBIEWSKI AND JERZY T. WROBEL
8q;
HO \
OMe
HO
OMe
186
132
OMe
I
OMe
I
ALKALOIDS
SCHEME4
4. THE LYTHRACEAE ALKALOIDS 315
n C o 2 H
NH, N H ,
n NH,
C 0 NH,
2 H TiNH, NH,
OMe
2 R' = H, R 2 = OMe
6 R' = O H , R 2 = H
Y O M e
OMe CO,H OMe
47 (31"") 48 (920,)
*
C0,II
I 1
OMe OMe
45 (467;) 47 (33",)
@
,
OMe OM>
OMe OMe OMe
zm-
15 188 189 R = OTs
190 R = H
+
Jones
KMnO, *
PhC0,H
191 192
H
H H
t 2
/
187
+
g*: 7: q
\
H
/
2
/
d
\
HO
\ \ \ \
HO HO
OH OMe OH OMe
2 45.4 19 2s
- = 0.83 -= 0.83 - = 0.83
55.6 23 30
SCHEME5
This body of evidence led to the conclusion that two intact C,-C, units
derived from phenylalanine are incorporated into lactonic Lythraceae al-
kaloids. One unit is the precursor of the phenylpropanoid part of the alka-
loids (C-11 to C-19) and the other gives rise to the C-3 to C-1, C-20 to C-25
segment of the phenylquinolizidine part."
Thus, hypotheses a and c, which demanded participation of a C,-C, unit
in the biosynthesis of the phenylquinolizidine moiety, have been disproved.
The mode of incorporation of lysine and its metabolites has eliminated
routes b and d. The accumulative evidence demonstrates that only path e
is consistent with all experimental results. This route predicts an extension
of the side chain of the phenylpropanoid precursor by a two-carbon unit
supplied by a donor such as acetyl- or malonyl-Coenzyme A. The results
of the final experiment with [2-'4C]malonate were consistent with hy-
pothesis e but inconclusive.
OH OH
193 194
X. Physiological Activity
REFERENCES
1. R. N. Blomster, A. E. Schwarting, and J. M. Bobbit, Lloydia 27, 15 (1964).
2. J. P. Ferris, J . Org. Chenz. 27. 2985 (1962).
3. H. Appel, A. Rother, and A. E. Schwarting, Lloydia 28, 84 (1965).
4. B. Douglas, J. L. Kirkpatrick, R. F. Raffaut, 0. Ribeiro, and J. A. Weisbach, Lloydiu
27, 25 (1964).
5. E. Fujita, K. Fuji, K. Bessho, A. Surni, and S. Nakamura, Tet. Lett. 4595 (1967).
6. E. Fujita, K. Fuji, and K. Tanaka, Tet. Lett. 5905 (1968).
7. E. Fujita, K. Bessho, K. Fuji, and A. Sumi, Chem. Pharm. Bull. 18, 2216 (1970).
8. E. Fujita, K. Bessho, Y. Saeki, M. Ochiai, and K. Fuji, Lloydia 34, 306 (1971).
9. H. Wright, J. Clardy, and J. P. Ferris, J . Am. Chem. Soc. 95, 6467 (1973).
10. P. Horsewood, W. M. Golqbiewski, J. T. Wrobel, I. D. Spenser, J. F. Cohen, and F.
Comer, Can. J . Chem. 57, 1615 (1979).
11. C. Schopf, E. Schmidt, and W. Brau, Ber. B 64, 684 (1931).
12. E. Fujita, K. Fuji, K. Bessho, and S. Nakamura, Chem. Pharm. Bull. 18, 2393 (1970).
13. E. Fujita and Y. Saeki, Chem. Commun. 368 (1971).
14. E. Fujita, Farumashia 9. 599 (1973).
15. E. Fujita and K. Fuji. Int. Rec. Sci.: Org. Chem., Ser. Two 9, I19 (1976).
16. K. Fuji, T. Yamada, E. Fujita, and H. Murata, Chem. Pharm. Bulf. 26, 2515 (1878).
17. J. P. Ferris, J . Org. Chem. 28. 817 (1963).
18. M. Appel and H. Aschenbach, Tet. Lett. 5789 (1966).
19. S. C. Chu, G. A. Jeffrey, B. Douglas, J. L. Kirkpatrick, and J. A. Weisbach, Chem. Ind.
(London) 1795 (1966).
20. X. A. Dominquez, J. Marroquin, S. Quintero, and B. Vargas, Phytochemistrj 14, 1883
(1975).
21. R. B. Horhammer, A. E. Schwarting, and J. M. Edwards, Z . Naturforsch., Teil B 26,
970 (1971).
22. D. E. Zacharias, G. B. Jeffrey, B. Douglas, J. A. Weisbach, J. L. Kirkpatrick, J. P. Ferris,
C. B. Boyce, and R. C. Briner. Experientia 21, 247 (1965).
23. J. P. Ferris, C. B. Boyce, R. C. Briner, U. Weiss, I. H. Qureshi, and N. E. Sharpless,
J . Am. Chem. Soc. 93, 2963 (1971).
24. J. P. Ferris, C. B. Boyce, and R. C. Briner, J . Am. Chem. Soc. 93, 2942 (1971).
25. J. P. Ferris, C. B. Boyce, and R. C. Briner, J . A m . Chem. Soc. 93, 2958 (1971).
26. J. P. Ferris, C. B. Boyce, R. C. Briner, B. Douglas, J. L. Kirkpatrick, and J. A. Weisbach,
Tet. Lett. 3641 (1966).
4. THE LYTHRACEAE ALKALOIDS 321
H. L. HOLLAND
Department of Chemistry, Brock University,
St. Catharines, Ontario, Canada
I. Introduction
A. GENERAL
CONSIDERATIONS
With the exception of ester, amide, and glycoside hydrolysis, the trans-
formation of alkaloids by biological systems is invariably an oxidative or
(less commonly) a reductive process. The enzymes involved therefore fall into
only two of the six main groups of enzyme types (18), namely hydrolases
and oxidoreductases. The former includes enzymes that catalyze the hydroly-
sis of esters, amides, glycosides, and other functional groups. The latter
includes enzymes such as the dehydrogenases responsible for the reversible
alcohol oxidation-carbonyl reduction reaction and CH-CH dehydrogena-
tion, the oxygenases that perform C-hydroxylation (and hence indirectly
0-and, N-dealklyation), N-oxidation, and S-oxidation, and the peroxidases
capable of performing oxidative coupling of phenols.
Whether used in a purified state or in the form of the intact organism,
many of the enzymes involved in the transformation of alkaloids are working
on unnatural substrates. It has been assumed (17)that these biotransforma-
tions are performed largely by the detoxification systems of the organism
involved, which possess oxidative, reductive, and hydrolytic capability (17).
For this reason, purified enzyme systems capable of transforming alkaloids
are frequently derived from mammalian livers, the major site of removal of
foreign chemicals from the organism. Many microorganisms also possess
enzyme systems capable of performing analogous transformations. A sub-
sequent or parallel step in the normal detoxification process is “conjugation,”
or the linking by ester, acetal, or other bond of the foreign chemical or its
metabolite to a normal constituent of the organism. Such conjugative
reactions involving N-acetylation by acetyl coenzyme A and an N-acetyl-
transferase, and N- and 0-methylation by S-adenosylmethionine and a
methyltransferase are encountered in alkaloid biotransformations.
B. HYDROLASES
The substrate specificity of many esterases is not high (19) and the same
is true of some proteases (amide-hydrolyzing enzymes), such as a-chymo-
trypsin (12, 20). Amides may also serve as substrates for some esterases (21).
Since esterases and proteases are widespread, hydrolysis of ester or amide
linkages often accompanies other transformations by intact organisms.
Soluble hydrolases are often present in supernatant fractions of mammalian
microsomal preparations, and hydrolytic reactions may also occur when
extracts of this type are used. Glycosidases, which catalyze the hydrolysis of
326 H. L. HOLLAND
C. OXIDOREDUCTASES
1. Monooxygenases
Oxidative biotransformations account for the majority of detoxification
processes and of these, reactions involving monooxygenases are the most
important. Monooxygenases are responsible for hydroxylation at saturated
and aromatic carbon and for N- and S-oxidation (22, 23). A characteristic
feature of these enzymes is the direct introduction of one atom of molecular
oxygen into the substrate, the other being incorporated into a molecule of
water. Saturated carbon hydroxylation is thought to involve direct insertion
of an enzymically produced electrophilic oxygen species (an enzymic equiva-
lent of oxene) into an unactivated C-H bond of the substrate (24): activation
of the substrate by enolization can also result in hydroxylation at a position
CI or vinylogous to carbonyl functionality (25).The low substrate specificity
normally associated with this reaction means that oxidative transformations
of this type are common, and the fact that oxidation frequently occurs at a
position remote from any other functionality results in products that are
valuable because of their relative inaccesibility by other means. Similar
hydroxylation CI to nitrogen results in the formation of a hemi-aminal and
hence to N-dealkylations (26),and hydroxylation at the CL carbon of an ether
leads in an analogous fashion to 0-dealkylation (27). Monooxygenase en-
zymes are also responsible for hydroxylation of aromatic systems to produce
phenolic metabolites. The mechanism of this reaction, which involves
formation of an arene oxide intermediate, has been extensively investigated
(28).Less well-characterized from the mechanistic standpoint are the enzyme
systems that convert sulfides to sulfoxides and sulfones and amines to N-
hydroxylated metabolites (10, 17).
2. Peroxidases
Enzymes of the peroxidase-type which use hydrogen peroxide as the
oxidizing species, are capable of performing oxidative coupling of phenolic
alkaloids (16).The commercially available horseradish peroxidase as well as
peroxidase preparations from potatoes and other sources have been used in
conjunction with hydrogen peroxide to perform these transformations. The
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 327
3. Dehydrogenases
Dehydrogenases capable of the introduction of an olefinic bond into a
saturated substrate are present in several microorganisms. In many cases,
the double bond is introduced into conjugation with a carbonyl group of
the substrate, but the presence of an activating carbonyl is not a rigid require-
ment for dehydrogenase activity. The mechanism and stereochemistry of
action of the steroid dehydrogenases has been reviewed recently (2, 12).
4. Alcohol Dehydrogenases
This large and diverse group of enzymes catalyzes the reversible alcohol
dehydrogenation<arbonyl reduction reaction. A detailed discussion of the
utility of this enzyme-catalyzed process in organic synthesis, together with
details of the mechanism and stereochemistry of the reaction, has appeared
recently (12). The enzymology of alcohol dehydrogenases has also been
recently discussed (31). The key role played by these enzymes in normal
metabolism is reflected by their widespread occurrence (31).This, together
with the low substrate specificity of several common enzymes of this type,
such as the liver alcohol dehydrogenases, has ensured that alcohol-carbonyl
interconversion is a frequently observed biotransformation.
D. CONJUGATION
Reaction of a substrate with a common constituent chemical of an orga-
nism (“conjugation”) may occur in several ways. Generally, these reactions
represent a method of detoxification by conversion of a foregin chemical to
a less toxic and more polar (and therefore more water-soluble and more
easily excretable) derivative. Alcohol or phenol substrates may be converted
to acetals of glucuronic acid (“glucuronidation”), sulfate derivatives, or to
methyl ethers. Amines may be converted to acetamide derivatives or sul-
famate esters, whereas carboxylic acids can be conjugated with the amino
group of glycine to give glycine conjugates (9). These reactions, which are
common in intact mammals, occur much less commonly with enzyme
preparations and are not observed with microorganisms.
328 H. L. HOLLAND
E. PRACTICAL
CONSIDERATIONS
The methodology of preparing and working with purified enzyme prepara-
tions is often limited by the difficulty of access of the source material (espe-
cially for enzymes of mammalian origin) and by the limited stability of the
enzymes themselves (32).The scale of such preparations, the low aqueous
solubility of most substrates, and the inability of many of the enzymes
involved to retain their activity in the presence of even moderate concentra-
tions of organic solvents, severely limit the quantities of substrate that can
be transformed. In the majority of cases, only micro- or millimole amounts
can be conveniently handled, although in favorable cases gram quantities
can be transformed (33, 34).For preparative-scale reactions, transformations
with intact microorganisms such as fungi and bacteria are more conveniently
carried out. With a growing or resting culture of a microorganism, the
quantity of substrate is usually limited only by the volume of the microbial
medium present: quantities of 1 mg of substrate per ml of medium are com-
mon (24, 25, 35), and higher concentrations can be used (36, 37). With little
specialized equipment, transformations of up to 10 g of substrate can there-
fore be readily carried out in the average chemical laboratory. The techniques
of enzymic (12) and microbial (17 ) transformation have been recently
discussed and compared.
A. BRUCINE
Following their earlier observation that the urine collected from rabbits
that had been administered brucine (1) contained the phenolic metabolites
2-methoxy-3-hydroxystrychnine(2) and 2-hydroxy-3-methoxystrychnine
(3), Watabe et al. (38)obtained a rabbit liver homogenate preparation that
would effect the same transformations. Incubation of 1 with the 90009
supernatant fraction of rabbit liver homogenate for 1 hr at 37" resulted in
0-demethylation to produce 2 and 3, albeit in low estimated yield. An uniden-
tified nonphenolic metabolite was also formed in low yield. The same
preparation was also capable of performing specific 0-demethylations of 4-
nitroveratrole and 4-acetamidoveratrole. Microbiological systems capable
of 0-demethylation of brucine or strychnine have not been identified. The
major route of metabolism of these alkaloids by the bacteria and fungi so
far investigates is N-oxidation, which in the case of brucine can proceed in
yields of up to 50% (55, 56).
TABLE I
TRANSFORMATIONS
OF INDOLE ALKALOIDS
A. Brucine
Brucine (1) Rabbit liver microsomes (2-Hydroxy-3-rnethoxystrychnine)(3) 38
(2-Methoxy-3-hydroxystrychnine) (2) 38
(Unidentified nonphenolic base) 38
B. Corynantheidine and related alkaloids
Corynantheidine (4) Rabbit liver microsomes LO-(17)-Demethylcorynantheidine] (8) 39,40
Dihydrocorynantheine (5) LO-(17)-Demethyldihydroco rynan theine ?] 39,40
lsocorynantheidine (6) [0-(17)-Demethylisocorynantheidine?] 3Y, 40
Hirsutine (7) (Unidentified) 39.40
Speciogynine (9) [0-(17)-Demethylspeciogynine?] 40
Mitraciliatine (10) (Unidentified) 40
Mitrdgynine (11) [0-(17)-Demethylmitragynine?] 40
Speciociliatine (12) LO-(17)-Demethylspeciociliatine?] 40
Paynantheine (13) [0-(17)-Demethylpaynantheine ?] 40
Mitrajavine (javacillin) (14) (Unidentified) 40
Tetraphylline (15) (Unidentified) 40
Aricine (16) (Unidentified) 40
Reserpinine (17) (Unidentified) 40
Ajmalicine (18) (Unidentified) 40
Gonyronella urceolifera 10-Hydroxyajmalicine (20) 41
Polystictus versicoior (Unidentified) 42
Piricularia oryzae (Unidentified) 42
Tetrahydroalstonine (19) Rabbit liver microsomes (Unidentified) 40
Reserpine (21) Mouse liver homogenate (3,4,5-Trimethoxybenzoicacid) 43
(Methyl reserpate) (22) 43
(3,4,5-Trimethoxybenzoicacid) 44
(continued)
TABLE I (continued)
CH,O H
H configuration
4 Corynantheidine x x
5 Dihydrocorynantheine 2 B
6 lsocorynantheidine B x
7 Hirsutine B B
B. CORYNANTHEIDINE ALKALOIDS
AND RELATED
CH,O
I
CH,O H
I I
8 0-(17)-Demethylcorynantheidine CH,O H
H configuration
9 Speciogynine a B
LO Mitraciliatine B B
I1 Mitragynine z 2
12 Speciociliatine /I z
The same phenomenon was observed for mitraciliatine (10) and the
closed ring E alkaloids 14-19, where the percentage metabolism by 0-
-
demethylation estimated by formaldehyde production ( 1%) was much less
than the degree of total metabolism (25-69%). Nevertheless, both hirsutine
and mitraciliatine gave detectable amounts of a compound assumed by TLC
analysis to be an 0-(17)-demethyl metabolite, whereas such was not the case
with 14-19. Hirsutine and mitraciliatine were also metabolized (to unidenti-
fied products) by both rat and guinea pig liver microsomes, which did not
metabolize alkaloids 4-6, 9, and 11-13.
Beckett and Morton did not comment on the inability of their rabbit liver
microsomal preparation to metabolize the closed ring E alkaloids 14-19.
They found no correlation of partition coefficients or pK, values with the
degree or type of metabolism of the corynantheidine-type alkaloids 4-7 and
9-13, but explained the observed differences on the basis of the preferred
conformations of the members of this series, noting that significant metabo-
lism by a route other than 0-demethylation occurred only with the pseudo
334 H. L. HOLLAND
normal pseudo
R
R
epiallo
is R
CH,O H
13 Paynantheine
R'
I
H configuration
CH ,O,C+OR -
OCH,
22 R
23 R
=
=
H
0
--C-CH=CH
a
OCH,
Methyl reserpate
C
:H
OCH,
Rescinnamine
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 337
24 R = H Corynanthine
25 R = OH 10-Hydroxycorynanthine
27 R : H Harman
28 R = OCH, Harmine
26 Rauwolscine (r-Yohimbine) 29 R = OH Harmol
338 H. L. HOLLAND
although in ciuo studies on harmine metabolism have found that the initially
formed harmol is subsequently conjugated to form the sulfate ester or
gluconuride (62, 63).
ACIDAND
C. LYSERGIC RELATED ALKALOIDS
Alkaloids of this group are susceptible to oxidative biotransformations by
many microorganisms resulting in N-demethylation, C-hydroxylation, or
ring-closure reactions (11). Many of the observed biotransformations
parallel or are closely related to processes thought to occur in the normal
biosynthesis of the ergot alkaloids and may indeed involve the same or
similar enzyme systems to those responsible for the normal production of
the alkaloids themselves (11, 64, 65).
Several key reactions of this type are also performed by mammalian liver
preparations. Thus, lysergic acid derivatives of type 30 are susceptible to
N-(6)-demethylation and to side-chain hydroxylation by isolated rat liver
preparations (46);and in a direct parallel to its normal biogenesis (66,67),
elyrnoclavine (32) is produced, although in low yield, from chanoclavine (31)
in the presence of a commercial preparation from pigeon liver (77, 68).
3 T ; J &;;F3 K J ;
HOH,C
&
I 1 I / \. 1 1
R' H H
30 3 I Cha noclavine 32 Elymoclablne
Hllll
I 1
H
33 R = CH, Agroclavine
34 R = H Noragroclavine
H
35 R' = OH, R 2 = CH, Setoclavine
36 R ' = CH,, RZ = OH Isosetoclavine 38 R = COCH, Vindoline
37 R' = OH, R 2 = CH,OH Penniclavine 39 R =H Deacetylvindoline
D. VINDOLINE
AND RELATED
ALKALOIDS
The pharmacological significance of the antineoplastic agents vinblastine
(46) and vincristine has promoted considerable interest in biological trans-
formations of alkaloids of this type in the search for new and more effective
antitumor agents. Following an initial report of the screening of over 400
microorganisms for their capacity to transform vindoline (38) (72),the Eli
Lilly group has published details of the transformations of vindoline (38)
deacetylvindoline (39), and vinblastine (46) by Streptomyces species (49-51,
53). In a parallel study, Rosazza and co-workers (52) have also investigated
the transformations of vindoline by Streptonzyces grisrus.
The Eli Lilly workers found that incubation of vindoline with Strepproniyces
sp. A1 7000 gave a complex mixture of products, from which they were able
to isolate dihydrovindoline ether (40) and 16-dehydroxy-14,15-dihydro-
15,16-epoxy-l4-0~0-3-norvindoline (43) in low yield (49). The structure of
40 was determined by comparison of its PMR and mass spectral data with
those of the previously described dcacctyldihydrovindoline ether (41) and
the alkaloid cathanneine (cathoclavine) (53) (73-75). Confirmation of the
340 H. L. HOLLAND
ether linkage to C-15 was obtained by spin decoupling of the C-14 and C-15
hydrogens. Irradiation at 6 2.02 ppm (C-14 hydrogens) caused the doublet
of doublets at 6 4.05 ppm assigned to the C-15 hydrogen to collapse to a
singlet. The same phenomenon was observed for 41 (vide il2fua) (49). The
structure of the other product isolated from this incubation 43 was assigned
by a combination of spectral data. The absence of a strongly basic nitrogen
atom, the presence of an additional band at 1750 cm-' in the infrared spec-
trum assigned to a lactam carbonyl, and the appearance in the PMR spectrum
of the C-15 hydrogen as a sharp singlet all indicated the presence in 43 of
the five-membered lactam ring E. This structure was also in agreement with
220-MHz PMR data, which indicated the presence of only two methylene
groups (apart from that of the C-20 ethyl unit), namely those at C-5 and C-6.
The mass spectrum of 43 contained several ions absent from the spectra of
related compounds such as vindoline, those at mle 124 and 297 being assigned
the structures shown in Fig. 2 by high-resolution analysis, and again indi-
cating the presence in 43 of the five-membered lactam moiety (49).
43 16-Dehydroxy-14,15-dihydro-l5,16-epoxy-14-oxo-3-norvindoline
and these, together with the appearance of N-H stretching in the IR spec-
'
trum at 3420 cm- and the lack of the N-CH, signal in the PMR spectrum,
suggested that this metabolite was the N-demethyl compound 44. Final
confirmation of this structure was obtained by conversion of 44 to vindoline
by reaction with formaldehyde in the presence of hydrogen and palladium
(50).
The transformation of vindoline by a related microorganism, Srreptomyces
yriseus, has also been reported (52). The major product was once again
dihydrovindoline ether (40), isolated in 28% yield. A second metabolite,
isolated in 10% yield, was formulated as the dihydrovindoline ether dimer
45. High-resolution MS analysis showed a molecular ion at m/e 908 of
composition C,,H,,N,O,,. The mass spectral fragments of 45 which reveal
the dimeric nature of this metabolite are shown in Fig. 5. The other fragment
ions observed in the mass spectrum of this compound are formed by processes
characteristic of related alkaloids such as vindoline and dihydrovindoline
ether (49, 76). The structure of 45 was eventually determined by a combina-
tion of CMR and PMR spectral analysis (52)of the compound itself and of
the sodium borohydride or hydrogen-palladium reduction product. The
latter showed a molecular ion at mje 910, suggesting the presence in 45 of
M-C,H,
m/e 879 (1 7)
M-CH,CO,
m/e 849 ( 3 3 )
a+b
-CH,CO,
OCH,
mle 661 (12)
45
m / e 908 (42)
m/e 454 (52) mle 395 (31)
one double bond relative to starting material, and its availability by sodium
borohydride reduction indicated the existence of this additional unsaturation
as an enamine. The CMR spectra of dihydrovindoline ether and of the dimer
45 were tentatively assigned by Rosazza and co-workers, and their assign-
ments are listed in Table 11. The resonances were assigned by comparison
with published spectra of similar alkaloids (77, 78) and by the analysis of
broad band and off-resonance data (52). The CMR data, together with a
TABLE I1
I3CMR ASSIGNMENTS OF
DIHYDROVINDOLINE ETHER(40)
A N D THE DIMER45
Carbon 40 45
OCH,
44 N-Demethylvindoline 45 Dihydrovindohne ether dimer
detailed analysis of the PMR spectrum of 45, allowed the site of linkage of
the monomer units to be identified as C-3’-C-14. The location of one site of
attachment as C-14 of a vindoline ether unit was confirmed by the observa-
tion of a singlet olefinic hydrogen (that at C-3) in the PMR spectrum at 6
6.1 1 ppm and a singlet at 6 4.26 ppm, assignable to the C-15 hydrogen of
the same moiety. A band at 1653 cm-’ in the infrared spectrum of 45 was
attributed to the presence of an enamine unit, as was the reactivity with
sodium borohydride. The conclusion that the site of attachment to the other
monomer unit was C-3’ was made by analysis of the PMR signal at 6 4.1 pprn,
assigned to the C-15’ hydrogen. This appeared as a broad signal whose
multiplicity and breadth was attributed to the presence of two nonequivalent
hydrogens at C-14’. Nevertheless, as the authors point out (52), their data
does not absolutely preclude the site of attachment to this unit from being
C-5’ or C-6’.
Rosazza et al. (52)have proposed the mechanism shown in Fig. 6 for the
formation of both dihydrovindoline ether and its dimer from vindoline. This
mechanism, which proposes an intermediate enamine-immonium ion species
54-55 produced by N-oxidation, followed by intramolecular attack of the
C-I6 hydroxyl oxygen, also accounts for the formation of 3-acetonyldihydro-
vindoline ether 42 from vindoline by Streptomyces albogriseolus (49). Re-
duction of the immonium ion 55 thus leads directly to dihydrovindoline
ether, whereas its capture by acetoacetate or the enamine 54 (79) leads to
42 and 45, respectively.
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 345
\-oxidation
A
OAc
R R
38
i
R
$
(
R
OAc
54
acetodcetate
OAc 40
R
55
cH3u
C H&,02
: RC
7 -
with other unidentified metabolites (53). The structure of the ether 50 was
determined by IR, PMR, and MS analysis. The I R spectrum of 50 revealed
the absence of the N-H band characteristic of the spectrum of the starting
material; this was also apparent from PMR data. Bands attributable to a
strongly hydrogen bonded OH were present in both the I R (2700-2800 cm- ')
and P M R (6 9-10 ppm) spectra of 50. The structure of 50 was confirmed by
high-resolution MS data, which is summarized in Fig. 7. The fragmentation
pattern was deduced by analogy with that established for vinblastine (46) (80).
Vinblastine is also transformed by Streptomyces punipalus A361 20 to give
10'-hydroxyvinblastine (48) in 9% yield (53). Hydroxylation of indole
alkaloids at C-10 had been observed previously with yohimbine and related
compounds (81, 82). The structure of 48 was deduced from spectral analysis
of the phenol and of the methoxyl derivative 49 produced by treatment of
48 with diazomethane (53). The appearance of signals at 6 6.91 (singlet,
C-9' hydrogen) and 6.71/6.95 ppm (AB quartet, C-11' and C-12' hydrogens)
in the PMR spectrum of 48 were particularly characteristic of the presence
of the C-10' hydroxyl function.
In a study using a commercially available horseradish peroxidase prep-
aration, Stuart and co-workers accomplished the conversion of 3',4'-
anhydrovinblastine (51) to leurosine (52) in a maximum yield of 65'1, (54).
This conversion can be carried out by a variety of oxidizing agents including
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 347
-CH,CO,
m e 749 4 50 m e 808 (C,,H,,N,O,)
540 (C,,H,,N,O,)
FIG.7. Mass spectral fragmentation of vinblastine ether (50)
CH,O
51 3’,4’-Anhydrovinblastine
A. APORPHINES
The pharmacological properties of the natural and synthetic aporphines
such as apomorphine (119, 120) have ensured the thorough investigation
of the ir? vivo mammalian metabolism of this class of compounds. Reported
reactions include glucuronidation (124, 0-methylation (91, 122) O-demeth-
ylation ( 1 2 4 , and N-demethylation (123). Studies in vitro with enzyme
preparations and in uivo with microorganisms reveal a similar pattern of
metabolism.
Smith and Sood (87) examined the transformations of nuciferine (57) and
its IV-alkyl analogs 58-63 by liver microsomes from the rat, rabbit, and
guinea pig. With the enzyme preparation from the latter source they observed
TABLE 111
TRANSFORMATIONS
OF ISJQUINOLINE
ALKALOIDS
-
Substrate Reagents ProductQ Yield’ Ref.
-
A. Aporphines
Nornuciferine (56) Rat liver microsomes (Lysicamine) (64) x7
Rabbit liver microsomes (Lysicamine) (64) x7
Nuciferine (57) Rat liver microsomes (Nornuciferine) (56) 87
(Lysicamine) (64) 87
Rabbit liver microsomes (Nornuciferine) (56) N7
(Lysicamine) (64) 87
Guinea pig liver microsomes (Nornuciferine) (56) 87
58 Rat liver microsomes (Nornuciferine) (56) x7
Rabbit liver microsomes (Nornuciferine) (56) 87
Guinea pig liver microsomes (Nornuciferine) (56) x7
59 Rat liver microsomes (Nornuciferine) (56) x7
Rabbit liver microsomes (Nornuciferine) (56) x7
Guinea pig liver microsomes (Nornuciferine) (56) 87
60 Guinea pig liver microsomes (Nornuciferine) (56) 87
61 (Nornuciferine) (56) 87
62 (Nornuciferine) (56) 87
63 (Nornuciferine) (56) 87
(S)-Boldine (65) Horseradish peroxidase Bisboldine (68) 88
Bisboldine ether 70 NU
Piricularia oryzar (Unidentified) 42
10,l I-Dimethoxyaporphine (72) Cunninghamella bainieri (Isoapocodeine) (75) X9
ATCC 3065 (Unidentified) 89
Cunninghamella hlukeslreana (Isoapocodeine) (75) 89
ATCC 9245 (Unidentified) 89
Cunninghamella echinulata (Apocodeine) (74) x9
NRRL 3655 (Isoapocodeine) (75) 89
(Unidentified) XY
W
VI
TABLE 111 (continued)
0
(continued)
W TABLE 111 (conlinued)
z
Substrate Reagents Product‘ % Yieldb Ref.
Gliocladium deliquescens +
[N-(2’)-Nor-( )-tentrandrine] (112) 104
UI 1086
Streptomyces spectabilicus [N-(2’)-Nor-(+)-tetrandrine] (112) 104
C632
Mucor microsporus UI-1700 (Unidentified) 104
Rhizopus arrhizus QM 1032 (Unidentified) 104
Stremphlium solani UI 1805 (Unidentified) 104
Streptomyces platensis (Unidentified) 104
ATCC 13865
Cunninghamella bainieri [N-(2’)-Nor-(+)-tetrandrine] (112) 104
UI 3065
Helicostylum piriforme [N-(2’)-Nor-(+)-tetrandrine] (112) 104
QM6945
Mucor paraciticus M 2652 [N-(2’)-Nor-(+)-tetrandrine] (112) 104
Thalicarpine (114) Fusarium solani ATCC 12823 (Unidentified) 105
Streptomyces punipalus (+)-Hernandalinol(116) 105
NRRL 3529 (Unidentified) 105
Strpptomyces griseus UI-1158 (Unidentified) 105
Cpninghamella blakesleeana (Unidentified) 105
ATCC 8688a
Mucor mucedo UI 4605 (Unidentified) 105
Hernandaline (115) Streptomyces punipalus (Hernandalinol) (116) 105
NRRL 3529
D. Morphine and related alkaloids
Morphine (117) Horseradish peroxidase (Unidentified) 106
Rat liver homogenate (Normorphine) (119) 107
(Morphine N-oxide) (121 and/or 123) 107
(Morphine-3-gluconuride) (126) 107
(Morphine-3-gluconuride) (126) 108
2-Hydroxymorphine(?) (128) (6-7) 107
Rat brain homogenate 2-Hydroxymorphine(?) (128) (9-10) 107
Guinea pig liver homogenate Normorphine (119) 9 109,110
Morphine N-oxide 123 0.9 109,110
Codeine (118) 5.3 109,110
Codeine (118) Guinea pig liver microsomes Norcodeine (120) 9.1 109, 110
Codeine N-oxide 124 19.5 109,110
Codeine N-oxide 122 0.1 109, 110
Morphine (117) 7.9 109,110
Normorphine (119) 2.4 109, 110
E. Phenethylisoquinolines
N-Methylhomococlaurine (130) Potato peel homogenate Promelanthiodine (132) 2 111
Wasabia japon ica Dimer 134 3 112
Matsumura homogenate Dimer 136 0.3 112
Unidentified 4 112
Homoorientaline (138) Potato peel homogenate 1-Hydroxyhomoorientaline (139) 0.5 100
F. Miscellaneous
Colchicine (142) Hamster liver microsomes [O-(2)-Demethylcolchicine] (144) (1.3) 113
[0-(3)-Demethylcolchicine] (143) (15) 113
[0-(10)-Demethylcolchicine] (145) (Trace) 113
[O-(3)-Demethylcolchicine gluconuride] (-1 113
(Unidentified) (-1 113
Rat liver microsomes [0-(2)-Demethylcolchicine] (144) (Minor) 133
[0-(3)-Demethylcolchicine] (143) (Major) 113
[0-(10)-Demethylcolchicine] (145) (Minor) 113
[0-(2)-Demethylcolchicine gluconuride] (-1 113
Mouse liver microsomes [0-(2)-Demethylcolchicine] (144) (Minor) 113
[0-(3)-Demethylcolchicine] (143) (Major) 113
[0-(10)-Demethylcolchicine] (145) (Minor) 113
Mescaline (146) Mouse brain homogenate (3,4,5-Trimethoxyphenylaceticacid) (2-8) 114
(3,4,5-Trimethoxyphenylacetic acid) (Major) 115
W (3,4,5-Trimethoxybenzoicacid) (Minor) 115
tn
-
(continued)
TABLE 111 (continued)
R'O
56 R = H Nornuciferine
57 R = CH, Nuciferine
58 R = CH,CH,
59 R = CHlCH2CH3
60 R =C H , 4 65 R' = R2 = H (S)-Boldine
61 R = CH,CH=CH, 66 R' = R2 = CH, (S)-Glaucine
62 R = CH2C-CH 67 R' = H, R2 = CH,
63 R = CH,C,H, 64 Lysicamine (S)-O-(9)-Methylboldine
6
CH30
OR OR
68 R =H Bisboldine
69 R = AC
358 H. L. HOLLAND
OR
70 R = H Bisboldine ether
71 R = AC
C H , O V
OCH, OCH,
78 Norglaucine 79 6a,7-Dehydroglaucine
shift of the resonance assigned (127) to the C-3 hydrogen of 67. Further
evidence for the structure of 67 was obtained by comparison with a sample
produced by monomethylation of boldine (65) with diazomethane.
The dehydrogenation of 66 to 6a,7-dehydroglaucine (79) proceeded in a
yield of 60% with Fusarium solani ATCC 12823. This microorganism also
produced a 21% yield of the oxoaporphine 80, but control experiments
indicated that the latter was an artifact produced by air oxidation of 79
during the incubation.
CH,O
OCH, OH
80 81 N-Methylcoclaurine
B. BENZYLIS~QUINOLINES
As part of their program of study of neuroamine metabolism in mam-
mals, Davis and co-workers investigated the biotransformations of nor-
laudanosoline (87) by rat liver and by brain preparations. They were
successful in isolating a catechol 0-methyltransferase enzyme system from
rat liver which performed methylations of 87 to give two upidentified pro-
ducts (94); and later they obtained soluble enzyme preparations from rat
brain and liver which, in the presence of [14C]methyl-S~denosylmethio-
nine, gave three radioactive metabolites identified by mass spectral analysis
as 90, 93, and a ring A monomethyl derivative of 93 (95, 96).
Other investigations of benzylisoquinoline biotransformations have been
made by the groups of Kametani and Rosazza. The Japanese workers
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 36 1
0 b\
' OR2
/
\ OR'
82 R1 = RZ = H
83 R' = R2 = Ac
84 R' = CH,, R2 = H Neferine
NCH,
85 R = H
86 R = A c
362 H. L. HOLLAND
R'oqNR
'
R20
OR2
87 R' = RZ = H Tetrahydropapaveroline 90 R ' = R 2 = H
(Norlaudanosoline) 91 R' = CH,, RZ = H Coreximine
88 R' = CH,, R2 = H Reticuline 92 R' = R 2 = CH, Xylopinine
89 R' = R2 = CH, Laudanosine
OH
93 R' = R2 = H 100 R =H Isoboldine
94 R' = CH,, R2 = H Scoulerine (Aurotensine) 101 R =D
95 R' = R2 = CH, Tetrahydropalmatine
,
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 363
N-oxidation C-hydroxylation
7=v
I CH,O
I
HO HO
y
7
J \ OCH,
OCH,
U O C H Zure
91 o r 9 4
FIG.8. Biotransformations of (+)-reticuline (88)by rat liver homogenate (97,98).
364 H. L. HOLLAND
CH30
RO
OR
CH,O
0
96 R = H Norreticuline 98 R = H Pallidine
97 R = CH, Norlaudanosine 99 R = D
CH30
CH,O
102 Corytuberine 103 Salutaridine
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 365
104 R = H Pseudocodamine
105 R = C,H,
blakesleeana, neither product 104 nor recovered substrate showed any op-
tical activity, indicating that this microbial 0-demethylation is not a stereo-
selective process (vide supra, 92).
The mammalian metabolism of the isoquinoline papaverine (106) has
been studied both in vivo and in vitro (102, 103), and its microbial degra-
dation has also been examined (103). The 0-demethylation and conjuga-
tion observed in vivo is paralleled by 0-demethylation with rat liver
homogenate, which gave the 0-(4)-, 0-(6)-, and 0-(7)-demethyl compounds
107-109 (102, 103). The 0-(4',6)-didemethyl compound 110, formed in
vivo (102), is not produced in vitro or in microbial degradations. Of over
60 microorganisms screened for their capacity to metabolize papaverine,
10 gave detectable 0-demethylation products (103). A good yield of 0-(6)-
demethylpapaverine (110) (40%) could be isolated after incubation of pa-
paverine with Aspergillus alliaceus 3 15, and Cunninghamella echinulafa
ATCC 9244 gave the 0-(4')-demethyl compound 107 in a yield of 27% (103).
The phenolic metabolites formed from papaverine were all identified by
comparison with authentic samples, the chemical shifts of the 0-methyl
hydrogens being particularly useful in diagnosis (see Table IV).
TABLE IV
CHEMICAL SHIFTSOF THE 0-METHYL HYDROGENS
OF PAPAVERINE AND ITSPHENOLIC METABOLITES'
6(PP4
R E
RZO '\ O W N
C. BISBENZYLISOQUINOLINES
AND RELATED
ALKALOIDS
Microbial transformations of bisbenzylisoquinoline alkaloids have been
reported which include N-demethylation and oxidative removal of a sub-
stituted benzyl group from C-1 of an isoquinoline ring (ZOZ, 104, 105). The
microbial N-demethylation of (+)-tetrandrine (lll),an antitumor (134)
and cytotoxic (135) agent, occurs specifically at either the N-(2) or N-(2')
position to give 112 or 113. The highest yield of the N-(2) nor metabolite
113 was obtained with Cunninghamella blakesleeana ATCC 8688a (104),
whereas Streptomyces yriseus gave a 50% yield the N-(2')-nortetrandrine
(112) (101). The structure of 112 was determined (101) by spectral com-
parisons with an authentic sample of synthetic origin (136), and that of
113 (104) by high-resolution MS and PMR spectral analysis. In the latter
case, the absence of the signal assigned to the N-(2)methyl (136) was charac-
teristic. The capacity of a microorganism to remove selectively one of the
N-methyl groups of ( +)-tetrandrine makes microbial demethylation of this
compound the method of choice for the production of either 112 or 113.
Chemical N-demethylation of 111 occurs nonselectively, giving mixtures
of 112, 113, and the bis-N-demethyl compound (104).
The antitumor agent thalicarpine (114), a benzylisoquinoline-aporphine
dimer, is metabolized by a series of microorganisms, but the only identified
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 367
OCH, CH,O
H
OCH,
114 Thalicarpine
OR
I
CH30
I
OCH,
115 R = CHO Hernandaline
116 R = CH,OH Hernandalinol
D. MORPHINE ALKALOIDS
AND RELATED
The metabolic fate of morphine and its derivatives in mammals has been
extensively investigated, and the formation of metabolites by glucuroni-
dation at C-3 and C-6 (to produce 125 and 126), sulfate formation at C-3 to
produce 127, N-dealkylation and oxidation, and 0-methylation and
368 H. L. HOLLAND
HO *
123 R = H Morphine N-oxide
R20
125 R' = gluconuride, R2 = H Morphine-6-gluconuride
124 R = CH, Codeine N-oxide 126 R' = H, R 2 = gluconuride Morphine-3-gluconuride
127 R' = H, R 2 = sulfate Morphine-3-ether sulfate
H0
HO
5.
/
gNCH, H;gN
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
HO
/
369
E. PHENETHYLIS~QUINOLINES
Kametani et al. have studied the biotransformations of N-methyl-
homococlaurine (130) and homoorientaline (138) by peroxidase enzyme
preparations (100, 111, 112). The peroxidase activity of a potato peel homo-
genate-hydrogen peroxide preparation resulted in dimer and trimer forma-
tion when benzylisoquinolines were used as substrate (Section IV,C), and
370 H. L. HOLLAND
I
OR
130 R = H N-Methylhomococlaurine
131 R = C H ,
OR OR
132 R = H Promelanthiodine
133 R = AC
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 371
CH,N H,
OR OR
134 R = H
135 R = Ac
OR OR
136 R = H
131 R = Ac
Rzoy
372 H. L. HOLLAND
CH,O
H3
OR2
138 R' = R2 = H Homoorientaline
139 R' = OH, R2 = H 1-Hydroxyhomoorientaline
140 R' = R2 = OAc
In the absence of hydrogen peroxide, the final oxidizing agent in the
peroxidase enzyme system, homoorientaline (138), is transformed to the
one-hydroxy derivative 139 by potato peel homogenate (ZOO). The related
benzylisoquinoline reticuline (88) is also hydroxylated at saturated carbon
HO
-oxidation
HO
ORZ
88 (n = 1, R' = H, R Z = CH,) 139 155
138 (n = 2, R' = CH,, RZ = H)
CH,O
OR'
I
reduction
156
141
141 /I-Hydroxyreticuline
ZOCH,
OR, OCH,
142 R' = R 2 = R 3 = CH, Colchicine 146 R = H Mescaline
143 R' = H, R2 = R3 = CH, 0-(3)-Demethylcolchicine 141 R = Ac
144 R' = R 3 = CH,, RZ = H 0-(2)-Demethylcolchicine
145 R' = R2 = CH,, R3 = H 0-(10)-Demethylcolchicine
F. MISCELLANEOUS
Colchicine (142), classified as an isoquinoline alkaloid because of its
biogenesis (147), undergoes oxidative demethylation at 0-(2), 0-(3), and/or
0-(10) by liver microsomes from the rat, hamster, and mouse (113). Only
monodemethylation was observed, 0-(3)-dernethyl colchicine (143) being
the predominantly formed isomer. In general, hamster liver microsomes
374 H. L. HOLLAND
were the most efficient of those tested for their capacity to metabolize
colchicine, converting about 40% of the total substrate to metabolites :
this may be related to the fact that the hamster is remarkably tolerant to
colchicine poisoning (148). Colchicine is also demethylated at the 0-(10)
position to give 145 by Streptomyces griseus (1491, and is susceptible to
microbial oxidative attack at the nitrogen atom and to hydrolysis of the
amide function (150). Although the 0-(10)demethyl compound 145 (col-
chiceine) may be produced from colchicine by a hydrolytic process that
does not depend on oxidative 0-dealkylation ( 1 5 4 , the production of
143, 144, and 145 (113) appeared to involve a monooxygenase enzyme.
The other anticipated product of enzymic demethylation, formaldehyde,
was obtained in stoichiometric amounts from incubations of 0-(3)- and
0-(10)-14CH,-labeled colchicines, and no significant transformation of
colchicine occurred in the absence of oxygen (113). The formation of both
143 and 144 and the variation in their relative amounts with the method of
preparation and nature of the enzyme extract prompted the suggestion of
the mechanisms for their formation shown in Fig. 10 (213),in which both are
produced competitively from a single intermediate (157). Although arene
oxides are well established as intermediates in the hydroxylation of arenes
(28) and although there appears to be some evidence for the existence of
an intermediate such as 157 in 0-dealkylation reactions (152),the observed
formation of 143 and 144 in the oxidative degradation of colchicine can
142 - CH,O
O q -
CH,O
OCH,
I
157
1
I 144 +CH,O
OCH,
I
143 +CH,O
FIG. 10. Proposed mechanism of the 0-(2)- and 0-(3)-demethylation of colchicine by liver
microsomes (113).
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 375
I
, ,Jl NHRZ
1
CH,
148 R' = OH, RZ= CH, Ephedrine 152 R = H Salsolinol
149 R' = OH, RZ= H Norephedrine 153 R = CH, Salsoline
150 R' = H, R Z = CH, N-Methylamphetamine
151 R' = RZ = H Amphetamine
The in uitro and in uiuo metabolism of the tobacco alkaloids has been
thoroughly reviewed in recent years (159), and their microbial transforma-
tions have also been discussed (11).A detailed discussion of the biosynthesis
and metabolism of tobacco alkaloids supplementary to reference 159 has
also been presented (160).
B. ARECOLINE
The ester function of arecoline (159) is quantitatively hydrolyzed by both
rat liver and brain homogenates to produce arecaidine (160) (determined by
TLC anaylsis) (161).
C. MISCELLANEOUS
In preliminary communication of their work, a Russian group identified
a number of Nocardia and Arthrobacter species that oxidized 3-meth-
ylpyridine to nicotinic acid (162) but did not report the use of any related
alkaloids as substrates.
A. Monoester alkaloids
Heliotrine (161) Small Gram-ve coccus 7a-Hydroxy-1-methylene-8cl-pyrrolizidine (173) 165
(Heliotric acid) 165
Peptococcus heliotrinreducans (7cr-Hydroxy-1-methylene-la-pyrrolizidine) (173) 166
Supinine (163) Small Gram-ve coccus (Unidentified) 165
Peptococcus heliotrinreducans (1-Methylene-8cr-pyrrolizidine)(174) 166
Heleurine (164) Peptococcus heliotrinreducans ( 1-Methylene-lcr-pyrrolizidine) (174) 166
Europine (165) Peptococcus heliotrinreducans (7~-Hydroxy-1-methylene-8cr-pyrrolizidine) (173) 166
B. Diester alkaloids
Lasiocarpine (162) Small Gram-ve coccus (Unidentified) 165
Peptococcus heliotrinreducans (175) 166
Retrorsine (166) Rat 16er microsomes (Retrorsine N-oxide) (167) 167,168
(Pyrrolic derivative) (168) 167-169
Mouse liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168) 168
Hamster liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168) 168
Guinea pig liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168)
Fowl liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168) 168
Quail liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168) 168
Sheep liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168) 168
(continued)
TABLE V (continued)
Retrorsine N-oxide (167) Rat liver microsomes (No metabolism to pyrrolic derivatives)
Monocrotaline (169) Guinea pig liver microsomes (Monocrotaline N-oxide) (170)
(Pyrrolic derivative) (172)
Rat liver microsomes (Monocrotaline N-oxide) (170)
(Pyrrolic derivative) (172)
Peptococcus heliotrinreducans (Unidentified)
Hamster liver microsomes (Pyrrolic derivative) (172)
Rabbit liver microsomes (Pyrrolic derivative) (172)
Mouse liver microsomes (Pyrrolic derivative) (172)
Cattle liver microsomes (Pyrrolic derivative) (172)
Lamb liver microsomes (Pyrrolic derivative) (172)
Chicken liver microsomes (Pyrrolic derivative) (172)
Crispatine (171) Peptococcus heliotrinreducans (Unidentified)
C. Miscellaneous
Crude alkaloid Rat liver microsomes (Pyrrolic derivatives)
preparation from Hamster liver microsomes (Pyrrolic derivatives)
Senecio jacobaea Rabbit liver microsomes (Pyrrolic derivatives)
Mouse liver microsomes (Pyrrolic derivatives)
Cattle liver microsomes (Pyrrolic derivatives)
Lamb liver microsomes (Pyrrolic derivatives)
Chicken liver microsomes (Pyrrolic derivatives)
A. M O N O E S ~ALKALOIDS
R
Workers in Australia, where chronic liver disease of sheep has been re-
lated to pyrrolizidine alkaloid intake (173, have isolated microorganisms
from sheep rumen capable of reductive cleavage of the side-chain ester
function of heliotrine (161), supinine (163), heleurine (la),and europine
(165) (165,166).In the earlier report (165),a small gram-negative coccus
& CH~O-C-C-CH-CH,
I I
I1 OHOR'
0
Clm2R1
CH,
162 R' = CH,, R2 = 0-C
R3 = H Lasiocarpint
CH3
CH,
II'c=c/
o/ H
'
CH 3
I
$H
CH, CH20H y 3
/I I / CH CH3 CHzOH
O=C-C-CHz-CH-C-OH
I I /I I /
O=C-C-CH,-CH-C-OH
I I
CH,-O-C=O
166 Retrorsine
167 Retrorsine N-oxide 168
B. DJESTER
ALKALOIDS
Both the microorganisms mentioned above metabolized lasiocarpine
(162), the gram-negative coccus leading to unidentified product@) (165),
and Peptococcus heliotrinreducans producing the 1-methylene derivative
175 (166).
Metabolism of the cyclic diesters retrorsine (166), monocrotaline (169),
and crispatine (171)by a variety of mammalian liver microsome preparations
and by Peptococcus heliotrinreducans has been reported. Mattocks and
co-workers have studied the metabolism of retrorsine by liver microsome
preparations from several sources (167-169) and have demonstrated the
conversion of this alkaloid to the corresponding N-oxide 167 and a pyrrolic
metabolite formulated as 168. The formation of 168 via 167 and dehydration
is mitigated against by the observation that retrorsine N-oxide (167) does
not give rise to a pyrrolic metabolite on incubation with rat liver microsomes
(167), even though the enzyme system responsible for the production of
168 from retrorsine has many of the properties of the mixed-function oxy-
genases capable of N-oxidation (167, 174). The metabolites of retrorsine
169 R = OH Monocrotaline
170 R = OH Monocrotaline N-oxide
171 R = H Crispatine
I
CH,-0-C=O
172 173 R = OH
174 R = H
175 R = 0-C ,CH3
Il\C=C,
o / H
H3C
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 38 1
C. MISCELLANEOUS
The crude alkaloid preparation from Senecio jacobaea (tangsy ragwort)
is converted to pyrrolic derivatives by mammalian liver microsomes.
Highest yields were obtained with microsomes from the hamster liver (171,
172).
The antitumor alkaloid acronycine (176) has been the subject of several
studies employing microorganisms : these studies are summarized in Table
VI (176-179). With one exception (178), all the microorganisms studied
that are capable of biotransformation of 176 gave 9-hydroxyacronycine
(177) as the major product, in one case (177) in an isolated yield of 30%.
The minor products reported include 11-hydroxyacronycine (178), 9,ll-
dihydroxyacronycine (179), and 3-hydroxymethyl-1l-hydroxyacronycine
(181) (176-179). The microbial metabolism of acronycine is therefore
closely related to its metabolism in mammals, where 177 is obtained as
the major metabolite along with smaller amounts of 178 and 179 (180).
The exception to this generalization is the microorganism Streptomyces
spectabilicus NRRL 2494, which is reported to convert acronycine to the
3-hydroxymethyl derivative 180 in 14% yield (178).
In a major study of the microbial metabolism of acronycine (177),Rosazza
and co-workers examined 47 cultures for their capacity to transform this
alkaloid, 10 of which were active in producing metabolites more polar
than the starting material. The major metabolite was identified as the
9-hydroxy derivative 177 following isolation from the incubation of 176
with Cunninghamella echinulata NRRL 3655. This product was charac-
terized as the acetate 182 by MS and PMR analysis, the latter technique
TABLE VI
TRANSFORMATIONS
OF QUINOLINE
ALKALOIDS
Acronycine (176) Aspergillus niger ATCC 9142 (9-Hydroxyacronycine) (177) (Major) 176,177
(11-Hydroxyacronycine) (178) (Minor) 176
(9,ll-Dihydroxyacronycine)(179) (Minor) 176
Cunninghamellablakesleeana ATCC 8688a (9-Hydroxyacronycine) (177) (Major) 176
(11-Hydroxyacronycine) (178) (Minor) 176
(9,ll-Dihydroxyacronycine)(179) (Minor) 176
(3-Hydroxymethyl- 11-hydroxyacronycine) (181) (-) 177
Cunninghamellablakesleeana ATCC 9245 (9-Hydroxyacronycine) (177) (-1 177
Cunninghamella blakesleeana NRRL 1369 (9-Hydroxyacronycine) (177) (-1 177
Streptomyces rimosus ATCC 23955 (9-Hydroxyacronycine) (177) (Major) 176,177
(11-Hydroxyacronycine) (178) (Minor) 176
(9,ll-Dihydroxyacronycine)(179) (Minor) 176
Cunninghamellabainieri ATCC 9244 (9-Hydroxyacronycine) (177) (Major) 176, 177
(11-Hydroxyacronycine) (178) (Minor) 176, I77
(9,ll-Dihydroxyacronycine)(179) (Minor) 176
(3-Hydroxymethyl- 1 1-hydroxyacronycine) (181) (-1 176
Cunninghamella echinulata NRRL 3655 9-Hydroxyacronycine (177) 30 176, I77
(11-Hydroxyacronycine) (178) (-1 177
(3-Hydroxymethyl-l l-hydroxyacronycine) (181) (-1 177
Cunninghamella echinulata SP-WISC 1386 (9-Hydroxyacronycine) (177) (-1 177
Cunninghamellaechinulata SP-WISC 1387 (9-Hydroxyacronycine) (177) (-) 177
Zygorhynchus japonicus UI-1234 (9-Hydroxyacronycine) (177) (-) 177
Aspergillus alleaceus QM 1915 (9-Hydroxyacronycine) (177) 80 178
(9-Hydroxyacronycine) (177) (-1 179
Streptomyces spectabilicus NRRL 2494 3-Hydroxymethylacronycine (180) 14 178
0 OCH,
CH,
176 R' = R2 = R3 = H Acronycine
177 R' = OH,R 2 = R3= H 9-Hydroxyacronycine
178 R' = R3 = H,R2 = OH 1 1-Hydroxyacronycine
179 R' = R 2 = OH, R3 = H 9,1 I-Dihydroxyacronycine
180 R' = R Z = H,R3 = OH 3-Hydroxymethylacronycine
181 R' = H, R2 = R3 = OH 3-Hydroxymethyl-ll-hydroxyacronycine
182 R ' = OAc. R2 = R 3 = H
W
VI
W ’Parentheses indicate not isolated.
Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting material.
386 H. L. HOLLAND
A. TOMATANINE-BASED
ALKALOIDS
Belic's group in Yugoslavia has examined the metabolism of several
alkaloids of this type with Nocurdia restrictus CBS 157.45, a microorganism
capable of oxidative transformations of steroids (1, 195). With 3-keto
steroidal substrates, introduction of A1 unsaturation constitutes a major
metabolic pathway for this organism ;and with tomatidine (183)as substrate,
this fungus gave rise to the formation of the corresponding 3-ketone,
tomatanin-3-one (189), and the unsaturated A', A4, and A1j4 compounds
190, 191, and 192, respectively (185, 186). The biotransformation products
were unambiguously identified by mass spectral, IR, and UV analysis of
isolated material. Mycobacterium phlei gave a similar series of products
with the same substrate, although in this case product identification was
by TLC analysis only (186). The efficient steroid dehydrogenator, Fusarium
soluni (194, failed to give biotransformation products with tomatidine
as substrate (186).
In a later study, the same group reported that during the early stages
of the incubations with N . restrictus a metabolite was formed that did not
correspond to any of the previously identified products on TLC, and that
was not present at the termination of the incubation (24 hr). By stopping
the incubation after only 4 hr they were able to isolate this intermediate
* For details of the structure of the glycoside portion of 188 see Volume VII (p. 344) and
X (p. 20) of this treatise.
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 387
-
R' H
196 R' = OH, R2 = H Soladulcidine (Solasodanol, [22R, 25R]-Sci-tomatanin-3~-01)
197 R' = H, R2 = OH 3-Episoladulcidine
O W
198 Solasoda-1,4-diene-3-one
compound with opened rings E and F (206) was simply converted to the
N-acetyl derivative 207 by N. restrictus. N. restrictus is capable of both
nuclear and side-chain degradation of steroids (194), and its capacity to
perform side-chain degradation of the alkaloid substrates employed in
this study has been attributed by Belic et al. to the presence of the heteroatom,
even though there is precedent for oxidative degradations by this organism
of some steroidal substrates that do not involve reaction at the C-17 side
chain (2, 194, 195). The capacity of another microorganism, Arthrobacter
simplex, to degrade oxidatively the side chain of tomatidine was demon-
strated by the isolation from the incubation of 183 with this microorganism
of androsta-l,4-dien-3-one (208) in a yield of 2.4-4.5% (188).
HO
H
199 Dihydrotomatidine-A ([22S, 25S]-22,26-Epimino-Sa-cholestan-3~,
16P-diol)
200 A'34-3-Ketone
204 [20S,22~,25~]-26-Acetylamino-Sa-furostan-3~-ol
205 ~I'-~-Diene-3-one
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 389
&y CH,
$
CH-CH2-CH,-CH-CH,-NHR
HO -
H
206 R = H [25<]-26-Amino-5~-cholestane-3/?,16/?,22<-triol
207 R = A c
RO
210 R = H Solasodine
211 R = glycoside* Solamargine
212 R = glycoside* Solasonine
ALKALOIDS
B. SOLANIDANINE-BASED
Demissidine (213)is converted to the A4-3-ketoand A',4-3-keto derivatives
214 and 215, respectively, by Nocardia restrictus (189). The corresponding
A5 compound, solanidine (216), is transformed to unidentified products by
both Trichotheciwn rosewn and Fusarium linii, the latter microorganism
producing three metabolites (42). Wolters also reports (42) the biotrans-
formation of a rubijervine/isorubijervine mixture (218/219), and that of
solanine (217) by a variety of microorganisms to unidentified products
(42). The microbiological conversion of solanine (217) to solanidine (216)
by hydrolysis of the glycoside substituent at C-3 has been reported (35).
Two strains of the potato blight fungus Phytophthora infestans perform this
reaction in low yield but are not capable of subsequent biotransformations
of 216. The endogenous conversion of 217 to 216 during infection of the
CH,
I
HO u
218 R' = OH, R2 = H Rubijervine
220 Scc-Conanin-3~-01
221 A's4-3-Ketone, cona-l,4-dienin-3-one
219 R' = H, R2 = OH Isorubijervine 222 A4-3-Ketone, con-4-enin-3-one
C. MISCELLANEOUS
Nocardia restrictus is capable of oxidizing the conessine derivative 5a-
conanin-3/3-01(220) to both the A4-3-ketone 222 and the A1,4-3-ketone221,
the latter being the major product of the incubation (289). Preliminary
screening experiments have demonstrated that Trichotheciwn rosewn trans-
forms conessine (223), solanocapsine (224),jervine (225), and pseudojervine
(226) (42). Transformation of the latter is claimed to produce 20-30%
jervine by glycoside hydrolysis, along with an unidentified product that
may be further biotransformation product of jervine. Jervine is also me-
tabolized by Polystictus versicolor and Piricularia oryzae, but no products
have been identified (42).
225 R =H Jervine
226 R = O-a-D-glUCOpyranOSylPseudojervine
The use of tropane alkaloids and their derivatives as medicinal agents has
ensured that the investigation of the metabolism of these compounds has
received considerable attention. The metabolism of tropane alkaloids in the
TABLE VIII
TRANSFORMATIONS
OF TROPANE
ALKALOIDS
Aspergillus niger
Atropine N-oxide (*)-235
Atropine N-oxide (+)-236
Unidentified
1 199
199
200
Cunninghamella echinulata (Tropine?) (232) 200
(Noratropine?) (229) 200
(-)-Hyoscamine (228) Aspergillus niger (Unidentified) 200
(-)-Hyoscine (237) Guinea pig liver microsomes Norhysocine (238) 199
Hyoscine N-oxide (240) 199
Noratropine (229) Guinea pig liver microsomes N-Hydroxynoratropine (231) 199
Norhyoscine (238) Guinea pig liver microsomes N- Hydroxynorhyoscine (239) 199
Cocaine (241) Rat liver microsomes (Norcocaine) (242) 201
(Benzoyl ecgonine) (243) 201
(Unidentified) 201
animal body has been discussed in an earlier volume of this treatise (196),
and the microbial transformations of tropanes has been reviewed by Kieslich
(11). The material present in Table VIII (197-201) supplements that of the
previous reviews.
The metabolism of atropine (227) by rat and guinea pig liver microsomes
has been studied (197-199). French workers noted the formation of nora-
tropine (229), apoatropine (233), and a phenolic metabolite formulated as
the ortho-phenol 230 (197, 198) by liver microsomes from the rat, and they
reported that hydrolysis of the ester function of 227 did not occur with
enzymes from this source (197, 198). The structure of 229 was determined
by TLC comparisons of the metabolite with an authentic sample and by
correlation of the formation of the metabolite with the release of formal-
dehyde in the incubation mixture. The structure of 233 was deduced by TLC
and UV spectral comparisons of isolated metabolite with authentic sample,
and the phenol 230 was identified by TLC color reactions and by com-
parison with a phenolic sample obtained by Udenfried oxidation of atropine.
In the absence of more definitive data on the phenolic products of this
reaction, the structure 230 proposed for the phenolic metabolite of atropine
R'
I
N
I\
0-C-CH
0
R2
227 (k),R' = CH,, R2 = H Atropine
228 (-), R' = CH,, R2 = H Hyoscamine
b OR
H
229 R' = R2 = H Noratropine
230 R' = CH,, R2 = OH 232 R = H Tropine
231 R' = OH, R2 = H N-Hydroxynoratropine 233 R = COC(=CH2)C6H, Apoatropine
R2
CH-CO,H bH 0-C-CH
II
0
235 R' = CH,, R2 = Oe
234 Tropic acid 236 R' = O e , R2 = CH,
394 H. L. HOLLAND
must be regarded as tentative. The same group also examined the metab-
olism of atropine by liver microsomes from the guinea pig and in addition
to the products discussed above obtained the hydrolysis products tropine
and tropic acid, 232 and 234, respectively (197, 198).In a more recent study
of the same system, Gorrod and co-workers reported the formation of
noratropine in an isolated yield of 4.3% and the formation of the isomeric
atropine N-oxides 235 and 236 in a combined yield of 4.6% (199). They did
not observe the formation of apotropine or the phenol 230. Similar products
were obtained with hyoscine (237) as substrate, where norhyoscine (238)
and the N-oxide 240 were formed (199).The capacity of the guinea pig liver
microsomes to perform N-oxidation of atropine and hyoscine was con-
firmed by the use of the corresponding noralkaloids 229 and 238 as substrates.
The products obtained were the N-hydroxy derivatives 231 and 239, re-
spectively (199). The structures of all the metabolites formed in this study
were confirmed as follows : the N-oxides 235,236, and 240 were reduced with
titanous chloride to yield the corresponding parent alkaloids, atropine and
hyoscine: similar reduction of the N-hydroxy derivatives 231 and 239 also
produced 227 and 237. All metabolites were correlated by TLC and mass
spectral comparisons with authentic samples.
R
I
N
R'
I
In contrast to the observation of the French group that rat liver micro-
somes did not possess an esterase capable of hydrolyzing tropane alkaloid
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 395
esters (197,198), more recent work established that cocaine (241) is hy-
drolyzed to benzoyl ecgonine (243) by a microsomal preparation from the
rat liver (201). Norcocaine (242) was also observed as a minor product. The
difference in the hydrolylic properties of liver microsomal preparations may
be due to the mode of preparation, which can result in the presence or absence
of the soluble esterases of the supernatant fraction of the initial centrifugate.
The microbial transformation of tropane alkaloids has not received much
attention in recent years. A single report (200) describes the incubation of
atropine with Aspergillus niger, which resulted in the formation of one un-
identified product, and with Cunninghamellaechinulata, which gave products
tentatively identified as tropine and noratropine. The (-)-isomer hyoscamine
(228) also gave a single product with A . niger, but this fungus was unable to
metabolize tropine or scopolamine.
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5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 397
Pharmacology Quinolizidine
Erythrinu alkaloid, 91-93 metacyclophane alkaloid,
Lythraeae alkaloid, 31S320 chemistry, 294-297
Phellibiline, 30, 42 mass spectra, 299-302
Phelline, -77 oxoquinolizidine, 302-303
Phelline billurdieri, 28, 41 stereochemistry, 297-299
Phelline comosu, 28, 36, 38, 39 ring degradation, 276-278
Phenethylisoquinoline, bio-transformation,
369-373
Phenylalanine, alkaloid precursor, 61, 315- R
3 18
I-Phenylisoquinoline, 58, 61 Rauwolscine, 330, 337
I-Phenyl-1,2-propanediol, 356, 375 Rescinnamine, 330, 336
Phenylquinolizidine alkaloid, simple, 284- Reserpine, 329, 336-337
286 Reserpinine, 329, 335
I-Phenyltetrahydroisoquinoline,59, 72 Reticuline, 223, 351, 362-363, 372
Phthalide, 246 Retrorsine, 377, 379, 380
Phthalideisoquinoline alkaloid, 245-249 N-oxide, 377, 378, 379
Phyrophthoru infestuns, 385, 390 Rheumatism, 100
Pipecolic acid, 313 Rhizopus arrhizus, 354
2-Piperdylpropanone, 303 Rhoeadine, 256, 257
Piperidine, 220, 3 19 Rubijervine, 385, 390
Piperidine nietacyclophane alkaloid, 288-
294
chemistry, 289-292 S
stereochemistry , 292-294
synthesis, 312-313 Salsolinol, 356, 375-376
2-Piperidylacetic acid, 313 Sarcoma 180, 92
Piriculuriu oryzue, 329, 330, 336337, 349, Schelhummeru mult(floru, 28, 36
358, 384, 385 Schelhummeru pedunculutu, 27, 28, 32, 35,
Podocarpic acid, 187 36, 37, 38
Polysticrus versicolor, 329-330, 336-337, Schelhummeru undulatu. 28, 37
384, 385 Schelhammericine, 28, 29, 36
Proaporphine, 13C spectra, 238-239 Schelhammeridine, 28, 32-34, 58
Promelanthiodine, 355, 370 Schelhammerine, 28, 29, 32-34, 58
Pronuciferine, 239 Scopolamine, 395
Protoberberine, 220, 363-364 Scoulerine, 35 I , 362
Protopine alkaloid, 13C spectra, 243-245 Secoberbine alkaloid, 257-258
Protosinomenine, 19 Senecio jucobueu, 378, 381
Pseudocodamine, 352, 364 Sepedonium chryospermum, 350, 353
Pseudojervine, 385, 391 Setoclavine, 331, 338, 339
Pseudokobusine, 126, 204 Shimoburo base I, 114
Pyridine alkaloid, biotransformation, 376 Shimotsuke, 139
Pyrrolizidine alkaloid, biotransformation, Sibiricine, 252
376-38 1 Sinicuichine, 269, 270, 272
Shine, 265, 266, 267
Q Sinomenine, 229
Soladulcidine, 384, 387
Quinoline alkaloid, biotransformation, Solamargine, 385, 389
38 1-383 Solanid-Cene-3-one, 385, 390
4 10 INDEX
Veatchinone, 110 X
Veatchinium chloride, 103
Veratrole, 220 Xylopinine, 241, 352, 362
Vertaline, 264, 280, 281-283
synthesis, 309-3 10
Verticillatine, 264, 269, 270, 272-273 Y
Vertine, 264, 269, 270-272, 279, 320
Vinblastine, 331, 339, 345-347 Yew,plum, 42
ether, 331, 345 a-Yohimbine, 330, 337
Vincdstine, 339
Vindoline, 331, 339
Vinoline, biotransformation, 339-348 2