The Alkaloids Chemistry and Physiology v18 Volume

THE ALKALOIDS
Chemistry and Physiology
Volume XVIII
This Page Intentionally Left Blank
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
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L i b r a r y o f Congress Cataloging i n P u b l i c a t i o n Data

Manske, Richard k l r m t h Fred, Date.
The a l k a l o i d s ; chemistry and physioloqy.
Vols. 8-16 e d i t e d by R. H. F. Manske. v o l s . 17-

e d i t e d by R . H. F. Manske, R . G . A. Rogrigo.
Includes bibliographical references.
1. Alkaloids. 2 . Alkaloids--Physiological e f f e c t .
I . tblmes, Henry Lavergne, j o i n t a u t h o r . 11. Title:
Thru physiology.
W421. M3 547.7'2 50-5522
ISBN 0-12-469518-3 ( v . 18) AACRl
PRINTED IN THE UNITED STATES OF AMERICA
81 82 83 84 9 8 7 6 5 4 3 2 1
CONTENTS
LISTOF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . vii
PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
CONTENTS OF PREVIOUS VOLUMES. . . . . . . . . . . . . . . . . . . . . xi
Chapter 1. Erythrina and Related Alkaloids

S. F . DYKEA N D S. N . QUESSY
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
I1 . Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . 2
111. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . 27
IV. Cephalotaxus Alkaloids . . . . . . . . . . . . . . . . . . . . . . 42
V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
VI . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
VII . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Chapter 2. The Chemistry of Cz,. Diterpenoid Alkaloids

S. WILLIAM PELLETIER A N D NARESH V. MODY
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
I1 . Veatchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . 102
111. Atisine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 122
IV. Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . 144
V. Behavior and Formation of the Carbinolamine Ether Linkage in
Diterpenoid Alkaloids: The Baldwin Cyclization Rules . . . . . . . . . 149
VI . W-NMR Spectroscopy of CZrDiterpenoid Alkaloids . . . . . . . . . 160
VII . Mass Spectral Analysis of Czo-Diterpenoid Alkaloids . . . . . . . . . 163
VIII . Synthetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . 168
IX . A Catalog of CZo-DiterpenoidAlkaloids . . . . . . . . . . . . . . . 1%
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Chapter 3 . The 'T-NMR Spectra of Isoquinoline Alkaloids

D . W. HUGHESA N D D . B . MACLEAN
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
I1. 1,2,3,4 Tetrahydro and 3-4-Dihydroisoquinolines . . . . . . . . . . . 219
111. Benzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . 223
IV. Bisbenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . 226
V. Cularine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
VI . The Morphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . 228
V
vi CONTENTS
VII . Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 230

VIII . Pavine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . 234
IX . Aporphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . 235
X . Reduced and Nonreduced Proaporphines . . . . . . . . . . . . . . . 238
XI . Tetrahydroprotoberberine Alkaloids . . . . . . . . . . . . . . . . . 239
XI1 . Protopine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . 243
XIII . Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . 245
XIV. Modified Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . 249
XV. Benzo[c]phenanthridie Alkaloids . . . . . . . . . . . . . . . . . . 250
XVI . Spirobenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . 252
XVII . Rhoeadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
XVIII . Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 257
XIX . Emetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
XX . Miscellaneous Alkaloids . . . . . . . . . . . . . . . . . . . . . . 260
References . . . . . . . . . . . . . . . . . . . . 261
Chapter 4 . The Lythraceae Alkaloids

W. MAREKGCKFBIEWSKI A N D JERZY T. WROBEL
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
Chapter 5 . Microbial and in Vitro Enzymic Transformations of Alkaloids

H . L . HOLLAND
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
I1 . Enzymes Involved in Alkaloid Transformations . . . . . . . . . . . . 325
111. Transformations of Indole Alkaloids . . . . . . . . . . . . . . . . . 328
IV. Transformations of Isoquinoline Alkaloids . . . . . . . . . . . . . . . 348
V. Transformations of Pyridine Alkaloids . . . . . . . . . . . . . . . . . 376
VI . Transformations of Pyrrolizidine Alkaloids . . . . . . . . . . . . . . 376
VII . Transformations of Quinoline Alkaloids . . . . . . . . . . . . . . . . 381
VIII . Transformations of Steroidal Alkaloids . . . . . . . . . . . . . . . . 383
IX . Transformations of Tropane Alkaloids . . . . . . . . . . . . . . . . . 391
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
LIST OF CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' contributions begin.
S. F. DYKE"( l ) , School of Chemistry, The University of Bath, Bath BA2

7AY, England
W. MAREKG O K ~ B I E W (263),
S K I Department of Chemistry, University of
Warsaw, Warsaw 02-093, Poland
H. L. HOLLAND (3231, Department of Chemistry, Brock University, St.
Catharines, Ontario L2S 3A 1, Canada
D. W. HUGHES(217), Department of Chemistry, McMaster University,
Hamilton, Ontario LSS 4M1, Canada
D. B. MACLEAN (217), Department of Chemistry, McMaster University,
Hamilton, Ontario L8S 4M1, Canada
NARESHV. MODY(99), Institute for Natural Products Research, Depart-
ment of Chemistry, University of Georgia, Athens, Georgia 30602
S. WILLIAMPELLETIER (99), Institute for Natural Products Research,
Department of Chemistry, University of Georgia, Athens, Georgia
30602
S. N. Q U E S S Y(l),
~ School of Chemistry, The University of Bath, Bath
BA2 7AY, England
JERZYT. WROBEL(263), Department of Chemistry, University of Warsaw,
Warsaw 02-093, Poland
* Present address: Department of Chemistry, Queensland Institute of Technology, Bris-

bane, Queensland, Australia.
f Present address: Research and Development Department, Riker Laboratories,
Thornleigh, New South Wales, Australia.
vii
PREFACE
This volume of “The Alkaloids” presents timely reviews of three

groups, the Erythrim, Lythraceae, and C,,-diterpenoid alkaloids. The
chapters are organized in the traditional manner and cover all aspects of
the recent chemistry of these groups. A useful catalogue of Czo-
diterpenoid alkaloids is also included. One chapter is devoted to a discus-
sion of the I3Carbon spectra of benzylisoquinolines and the fifth chapter
collects and reviews work on the microbial and it? cirro transformations of
the alkaloids. Both subjects have attracted increasing attention in recent
years.
The editor wishes to thank the authors for their cooperation in making
this volume possible. We hope that it will be as useful to researchers in
alkaloid chemistry as the previous seventeen have been and we welcome
advice or criticism from our readers.
R. G. A. RODRICO
ix
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 111

16. The Chemistry of the Cinchona Alkaloids B Y RICHARD B. T U R N E R
A N D R . B . WOODWARD . . . . . . . . . . . . . . . . . . . . . . 1
17 . Quinoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 65
18. The Quinazoline Alkaloids B Y H . T . OPENSHAW. . . . . . . . . . . . 101
19. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . . . 119
20 . The Imidazole Alkaloids B Y A . R . BATTERSBY A N D H . T. OPENSHAW. . 20 1
21 . The Chemistry of Solanum and Veratrum Alkaloids B Y V . FRELOG
A N D .OJEGER . . . . . . . . . . . . . . . . . . . . . . . . . . 247
22 . P-Phenethylamines BY L . RETI . . . . . . . . . . . . . . . . . . . 313
23 . Ephreda Bases B Y L . RETI . . . . . . . . . . . . . . . . . . . . . 339
24 . The Ipecac Alkaloids B Y MAURICE-M.~RIE JANOT . . . . . . . . . . . 363
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
Contents of Volume VII

10. The Indole Alkaloids BY J . E . SAXTON. . . . . . . . . . . . . . . . 1
11. The Eryrhrina Alkaloids BY V. BOEKELHEIDE . . . . . . . . . . . . . 201
12. winoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 229
13. The Quinazoline Alkaloids B Y H . T . OPENSHAW . . . . . . . . . . . . 247
14. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . . 253
...
C O N T E N T S OF P R E V I O U S V O L U M E S Xlll
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 VIII

1. The Simple Bases BY J . E . SAXTON. . . . . . . . . . . . . . . . . 1
2. Alkaloids of the Calabar Bean B Y E . COXWORTH . . . . . . . . . . . 27
3. The Carboline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . 47
4. The Quinazolinocarbolines B Y R . H . F. MANSKE . . . . . . . . . . . 55
5. Alkaloids of Mirragyna and Ourouparia Species B Y J . E . SAXTON. . . . 59
6. Alkaloids of Gelsemiurn Species B Y J . E . SAXTON. . . . . . . . . . . 93
7. Alkaloids of Picralirna nitida B Y J . E . SAXTON . . . . . . . . . . . . 119
8. Alkaloids of Alsronia Species B Y J . E . SAXTON . . . . . . . . . . . . 159
9. The Iboga and Voacanga Alkaloids B Y W . I. TAYLOR . . . . . . . . . 203
10. The Chemistry of the 2,2'-Indolylquinuclidine Alkaloids B Y W. I . TAYLOR 238
11. The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids BY
W . I . TAYLOR . . . . . . . . . . . . . . . . . . . . . . . . . . 250
12. The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . 272
13. Rauwolfia Alkaloids with Special Reference to the Chemistry of Reserpine
B Y E . SCHLITTLER . . . . . . . . . . . . . . . . . . . . . . . . 287
14. The Alkaloids of Aspidosperma. Diplorrhyncus. Kopsia. Ochrosia. Pleio-
carpa. and Related Genera BY B . GILBERT . . . . . . . . . . . . . 336
15. Alkaloids of Calabash Curare and Strychnos Species B Y A . R . BATTERSBY
A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . 515
16. The Alkaloids of Calycanthaceae BY R . H . F. MANSKE. . . . . . . . . 581
17. Srrychnos Alkaloids B Y G . F. SMITH . . . . . . . . . . . . . . . . . 592
18. Alkaloids of Haplophyton cimicidum B Y J . E . SAXTON. . . . . . . . . 673
19. The Alkaloids of Geissospermum Species B Y R . H . F. MANSKE AND
W . ASHLEYHARRISON. . . . . . . . . . . . . . . . . . . . . . 679
20 . Alkaloids ofPseudocinchona and Yohimbe B Y R . H . F. MANSKE . . . . 694
21 . The Ergot Alkaloids B Y S. STOLLA N D A . HOFMANN . . . . . . . . . 726
22 . The Ajmaline-Sarpagine Alkaloids B Y W . I . TAYLOR. . . . . . . . . . 789
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 XZZ

The Diterpene Alkaloids: General Introduction B Y S . W. PELLETIER AND
L . H . KEITH . . . . . . . . . . . . . . . . . . . . . . . . . . xv
1 . Diterpene Alkaloids from Aconiturn. Delphinium. and Garrya Species:
The CIgDiterpene Alkaloids B Y S . W. PELLETIER A N D L . H . KEITH . . 2
2. Diterpene Alkaloids from Aconitum. Delphinium. and Garrya Species:
The C2,,- Diterpene Alkaloids B Y S . W. PELLETIER A N D L . H . KEITH . . 136
3 . Alkaloids of Alstonia Species B Y J . E . SAXTON . . . . . . . . . . . . 207
4 . Senecio Alkaloids B Y F R A N K
L . WARREN. . . . . . . . . . . . . . . 246
5 . Papaveraceae Alkaloids B Y F . SANTAVY. . . . . . . . . . . . . . . 333
6 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE . 455
7 . The Forensic Chemistry of Alkaloids B Y E . G . C . CLARKE. . . . . . . 514
Contents of Volume XZI1

1 . The Morphine Alkaloids BY K . W. BENTLEY . . . . . . . . . . . . . 1
2 . The Spirobenzylisoquinoline Alkaloids B Y MAURICE SHAMMA . . . . . . 165
3 . The Ipecac Alkaloids B Y A . BROSSI.S . TEITEL.A N D G . V. PARRY . . . 189
4 . Alkaloids of the Calabar Bean B Y B . ROBINSON. . . . . . . . . . . . 213
5 . TheGalbulimima Alkaloids B Y E . RITCHIEA N D W. C . TAYLOR. . . . . 227
6. The Carbazole Alkaloids B Y R . S . KAPIL . . . . . . . . . . . . . . . 273
7 . Bisbenzylisoquinoline and Related Alkaloids B Y M . CURCUMELLI-
RODOSTAMO . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
8 . The Tropane Alkaloids B Y G . FODOR . . . . . . . . . . . . . . . . . 351
9 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE . 397
Contents of Volume XZV

1 . Steroid Alkaloids: The Veratrum and Buxus Groups B Y J . TOMKOA N D
. VOTlCKf' . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 . Oxindole Alkaloids BY JASJITS. BINDRA . . . . . . . . . . . . . . . 83
3 . Alkaloids of Mitragyna and Related Genera BY J . E . SAXTON. . . . . . 123
4 . Alkaloids of Picralima and Alstonia Species B Y J . E . SAXTON . . . . . 157
5 . The Cinchona Alkaloids BY M . R . USKOKOVIC A N D G . GRETHE. . . . . 181
6 . The Oxaporphine Alkaloids B Y MAURICE S H A M MA A N D R. L .
CASTENSON. . . . . . . . . . . . . . . . . . . . . . . . . . . 225
7 . Phenethylisoquinoline Alkaloids BY TETSUJIKAMETANI A N D MASUO
KOIZUMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
8 . Elaeocarpus Alkaloids B Y S . R . JOHNSA N D J . A . LAMBERTON. . . . . 325
9 . The Lycopodium Alkaloids B Y D . B . MACLEAN. . . . . . . . . . . . 347
10. The Cancentrine Alkaloids B Y RUSSELL RODRIGO . . . . . . . . . . . 407
1 1 . The Securinega Alkaloids B Y V. SNIECKUS. . . . . . . . . . . . . . 425
12. Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE . 507
xvi CONTENTS OF P R E V I O U S VOLUMES
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
Contents of Volume XVI

1. Plant Systematics and Alkaloids B Y DAVIDS. SIEGLER. . . . . . , . , 1
2. The Tropane Alkaloids B Y ROBERTL. CLARKE . . . . . . . . . . . . 83
3. Nuphar Alkaloids B Y JERZYT. WR6BEL . . . . . . . . . . . . . . . 181
4. The Celestraceae Alkaloids B Y ROGERM. SMITH . . . . . . . . . . . 215
5. The Bisbenzylisoquinoline Alkaloids-Occurrence, Structure, and Phar-
macology BY M. P. CAVA,K. T. BUCK,A N D K. L. STUART. . . . . 249
6. Synthesis of Bisbenzylisoquinoline Alkaloids B Y MAURICE SHAMMA
A N D VASSILST. GEORGIEV, , . . . . . . . . . . . . , , . , , . 319
7. The Hasubanan Alkaloids B Y YASUOINUBUSHI A N D TOSHIRO
I B U K A. , 393
8. The Monoterpene Alkaloids B Y GEOFFREY A. CORDELL . . . . . . . . 43 1
9. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE . 511
Contents of Volume XVZI

1. The Structure and Synthesis of C,,Diterpenoid Alkaloids
B Y S. WILLIAM PELLETIER A N D NARESH V. MODY . . . . . . . . , 1
2. Quinoline Alkaloids Related to Anthranilic Acid BY M. F. GRUNDON , . 105
3. The Aspidospmrna Alkaloids BY GEOFFREY A. CORDELL. . . . . . . , 199
4. Papaveraceae Alkaloids, I1 B Y F. S A N T ~ V. ) . . . . . . . . . . . . . 385
5. Monoterpene Alkaloid Glycosides B Y R. S. KAPILA N D R. T. BROWN . , 545
-CHAPTER 1-
ER YTHRINA AND RELATED ALKALOIDS

S. F. DYKE*AND S. N. QUESSY~
School o/Chei?iisfry.The Uniuersitj. of Bath. Bath, A t o i l , Encqland
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.
In the intervening 13 years the subject has expanded dramatically; over

60 compounds are now classified as Erythrina alkaloids, and the structures
of most of these have been deduced from a combination of mass spectral
fragmentation analysis, H-NMR spectral interpretations, and chemical
correlations with alkaloids of known structures. Some ‘‘unusual’’ alkaloids
have been obtained from certain Cocculus species and a new, as yet small,
subgroup, the Homoerythrina alkaloids, has been recognized. The bio-
synthetic pathway from tyrosine through the aromatic bases to the ery-
throidines has been elucidated, and some significant advances have been
made in methods of total synthesis. Reviews of the Erythrina alkaloids
since 1966 have appeared (3-6).
Because of the postulated biosynthetic derivation of the Cephalotaxus
alkaloids from the Homoerythrina bases, the former, relatively new group
is included in this chapter. Anticancer activity has been found in certain
members of the Cephalotaxus group, so the subject has already been re-
viewed several times (7-9). Annual coverage is given to the Erythrina, Homo-
erythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports
of the Chemical Society (20-ZZa).
The Erythrina alkaloids are conveniently divided into two main struc-
tural groups: the 1,6-diene group and the A1(6)-alkene group (see Fig. 1).
The biogenetically important alkaloid erysodienone cannot be classified
in this way.
The present chapter covers the literature from November 1966 to the
end of May 1979.
11. Evythvitza Alkaloids
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
RZO - " ' oR
CH,O" CH,O'
R' R2 X 36 Isococculidine R = CH,
32" Erythrabine CH, CH, 0 37 Isococculine R = H

33" Crystamidine -CH2- 0
34* 10,ll-Dehydroerysovine CH, H 2H
35* 10,ll-Dehydroerysodine H CH, 2H
* means an alkaloid is a possible artifact.
X
R' R2 R3 X
38 Dihydroerysotrine H CH,O CH,O H

39 Erythratidine H CH,O CH,O OH
40 Erythratidinone H CH,O CH,O =O
41 Erythramine H -OCH,O- H
42 Erythratine H -OCH20- OH
43 Erythratinone H -OCH,O- =O
44 Dihydroerysovine H CH,O HO H
45 Erysosalvine H CH,O HO OH
46 Erysosalvinone H CH,O HO =O
47 Dihydroerysodine H HO CH,O H
48 Erysotine H HO CH,O OH
49 Eryso tinone H HO CH,O =O
50 Erysopitine H HO HO OH
51 Erysoflorinone H HO HO =O
52 Coccutrine CH,O H OH H
53 Erythroculine H CH,O CH,O,C H
54 Cocculidine H H CH ,O H
FIG.3 . Erythrinu alkaloids: Al(6) alkene series.

1. E R Y T H R I N A AND RELATED ALKALOIDS 5
CH,O
CH 3 0
0 0
57 3-Demethoxyerythratidinone 58 Erysodienone
59 r-Erythroidine 60 [I-Erythroidine 61 Cocculolidine
FIG.4. Erythrina alkaloids: miscellaneous
(Menispermaceae), a genus of more limited distribution in tropical areas

(13). A conspectus of the genus Erythrina was published by Krukoff who
listed 108 species and 9 hybrids (14), and over half of these have been ex-
amined for their alkaloidal content. Attention must be drawn to the fact
that Krukoff has reclassified several species. Notably, E. lithosperma has been
subdivided such that E. lithosperma Blume is now a synonym for E. variegata
L., wherer.5 E. lithosperma Miguel is a synonym for E. subumbrans Merril.
In addition, E. orientalis, E. variegata uar. orientalis, and E. indica are
synonyms for E. variegata L. (14).This reclassification has resulted in some
misleading claims and doubtful identifications in the literature (15).
Most studies have concentrated on examination of the seeds, which typi-
cally contain 0.1% alkaloids, although alkaloids have been isolated from
the leaves, stalks, stems, bark, roots, pods, and flowers of Erythrina species.
An extensive survey of Erythrina species has been made by two groups
using combined GC-MS; Rinehart and co-workers at Illinois have ex-
amined American species (15, 16) and Jackson and co-workers at Cardiff
examined old world species (12, 17). Other major investigations have been
carried out by Barton and co-workers (18-21), by Ito and co-workers in
Japan (22-32), and by Ghosal and co-workers (33-37), and Singh and
Chawla in India (38-41). From the results of these studies it is apparent
that individual species are often distinctive in their alkaloid profile, although
the sections and subgenera are not clearly marked. Several patterns do
emerge, however. Erysovine (5)and erysodine (7) are ubiquitous, although
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
The procedure of Folkers, where the ground plant material is extracted

with hexane to remove fats, is widely used; but Rinehart and co-workers
(16) pointed out that a significant quantity of alkaloid could be detected
1. ERYTHRI.VA AND RELATED ALKALOIDS 7
by GC-MS analysis of the hexane fraction, so that earlier examinations

where this fraction was discarded must be regarded as incomplete. Alcoholic
extraction of the remaining marc gave the “free” alkaloids, whereas acid
hydrolysis gave rise to the liberated alkaloids (usually the largest fraction).
Ghosal(35) has described a detailed flow chart for the isolation of a variety
of alkaloids from E. variegata.
The greatest advance in the isolation and identification of Erythrina al-
kaloids has come from the powerful combination of GC-MS, which has
provided a methodology for comprehensive taxonomic investigation of the
whole genus. Its value derives from the facile identification of the alkaloids
from their fragmentation patterns, the speed and accuracy of the method,
the avoidance of large-scale extraction and chromatography, and the re-
quirement of only milligram quantities of crude alkaloid extract. The power
of the technique has been demonstrated by the number of new alkaloids
detected and the number of species investigated using it (12, 15, 16).
There are rarely more than eight alkaloids present in a species, and the
possibility of the same GC retention time is not normally a problem. In
cases where overlap has been observed it has proved possible to identify
both components from the mass spectrum of the mixture. The crude al-
kaloid extracts are treated with trimethylsilyldiethylamine to form vola-
tile TMS derivatives of the hydroxylated components. The presence of
a free phenolic or hydroxyl group is then detected by an ion with mje 73
[(CH,),Si+]. Positional isomers [e.g., erysovine (5) and erysodine (7)] are
resolved although u- and 8-erythroidine are not. The presence of p-
erythroidine (60) can be estimated since it shows some enol content under
the silylation conditions and gives rise to a monotrimisyl derivative with
m/e 345 (15).
As a supplement to electron impact MS, field ionization MS, which allows
identification of the alkaloids by their molecular formula, has been intro-
duced (47). The combination of HPLC-field desorption MS, which utilizes
the greater resolving power of HPLC over GC, has been applied; and the
presence of alkaloids not detected by GC-MS was revealed in one case (12).
Various other alkaloids have been found concurrently with the Erythrina
group. Hypaphorine is by far the most common, but choline, N-nororienta-
line, and erybidine (62) are not uncommon.
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
salt of erythristemine confirmed the assumption that the 3R,5S configura-

tion of the erythroidines exists in the aromatic group. This result also con-
firms the common biosynthetic origin of the two types. The configuration
of the methoxyl group at C-11 was found to be S. The use of 2-bromo-
4,6-dinitrophenol for the preparation of a heavy-atom derivative was novel
and may be applicable in other cases (20,48).
The absolute stereochemistry of the A1(6)-alkene alkaloids cocculine (56)
and coccutrine (52) has also been established by X-ray analysis. It was
found that the cyclohexene ring A exists preferentially in an approximate
half-chair conformation in the free base, but this was altered to an envelope
conformation on protonation of the nitrogen atom (49).
R
I
CH,O'-
19 Erythristemine 56 R = H Cocculine
52 R = CH,O Coccutrine
The crystal structures of the alkaloids containing a hydroxyl group at

C-2 have not been determined. The stereochemistry of erythratine (42) was
established as 2R,3R,5S by Barton et al. (19) and that of erythratidine (39)
as 2S,3R,5S by the same group (21)on the basis of optical rotation and N MR
data for both pairs of C-2 epimers (see Section II,C,4b). The configuration
at C-2 for erysosalvine (45), erysotine (48), and erysopitine (50) has not
been defined.
The absolute stereochemistry of other alkaloids rests on comparison
of their CD and NMR characteristics with those of alkaloids of known
stereochemistry as well as on chemical interconversions.
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
absorbances at 240-242 and 285nm and IR bands at 1672, 1655, and

1614 cm-' (34).
b. Circular Dichroism. The 1,6-diene alkaloids exhibit strong positive

Cotton effects and previous attempts to relate this to the absolute configu-
ration, using diene rules, have led to assignments of configuration opposite
to that found by X-ray analysis. An explanation for the failure of the diene
rules for Erythrina and other systems has been advanced. The allylic methoxyl
system (at C-3) has helical chirality opposite to that of the diene chromo-
phore, and it appears that the sign of the diene Cotton effect is determined
by the former group (50).
Members of the A1(6)-alkene group also show a positive Cotton effect,
and this was used to assign the absolute configuration of cocculine (56) and
cocculidine (54), later supported by X-ray analysis (51, 52).
c. Mass Spectrometric Characteristics. Because of the heavy reliance on

MS identification of Erythrina alkaloids, several studies of their fragmenta-
tion patterns have been made. A comprehensive analysis of the fragmenta-
tions of erythrinanes was described by Migron and Bergmann (53)but is not
discussed here. The MS of a variety of Erythrina alkaloids were studied by
Boar and Widdowson (54) who proposed fragmentation schemes based on
the usual techniques of accurate mass measurement of major ions and on
metastable analysis. Further elaboration was made through the use of
deuterium-labeled samples. Only the general MS features will be discussed
here, as several detailed schemes can be found in the literature (15, 21, 54).
All the 1,6-diene structures show a simple fragmentation pattern, summa-
rized in Scheme 1. The main pathway involves loss of the allylic substituent
at C-3 which allows distinction between the isomeric groups. For example,
erythravine (3) can be distinguished from erysovine (5) and erysodine (7) by
the nature of RO. However, distinction between pairs isomeric in ring D,
that is, between 5 and 7 or between 6 and 8, cannot be made by MS alone.
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)
The A1(6)-alkene alkaloids show a more complex fragmentation pattern

in which loss of the allylic substituent is of only minor importance. A major
fragmentation pathway involves a retro-Diels-Alder reaction (path a in

Scheme 2), and an alternative pathway involves loss of the C-2-C-3 unit
(path b in Scheme 2). Each ion subsequently loses a hydrogen atom. The
nature of the substituent at C-3 is readily established from path a and for all
known Al(6)-alkene types is methoxyl. The substituent at C-2 is then defined
by M + -C3H,0R, where R is usually H or OH (15, 16, 54). Distinction
between A1(6)-alkene types and the isomeric A2( I)-alkene types [e.g.,
isococculine (37)] can be made by MS. For example, 37 exhibits a fragmenta-
tion pattern similar to the l ,6-diene types.
/ -C,I!,O
\b
-C,H ,OR\
q7’+ HC
//
2. Mujor M S Jkugmentutionpatiern for A1(6)-aNceneseries (R = H or OH)

SCHEME
The enone alkaloids, such as erythratidinone (40), do not undergo frag-

mentation by path b in Scheme 2, but exhibit loss of CO as shown in Scheme
3 (21, 54). Alkaloids containing 1 I-hydroxyl or 11-methoxyl groups show
additional ions arising from loss of H,O or CH30H, respectively, from the
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
d. NMR Characteristics. Once the erythrinane skeleton is established,

it is possible to deduce the complete structure from detailed NMR data
with the aid of decoupling, NOE, and INDOR techniques. Assignments of
stereochemistry at C-2, C-3, and C-11 have been made from the values of
coupling constants by comparison with data from related alkaloids in the
group, for which crystal structures have been determined (19-21,43,55-58).
In a review of the NMR of the alkaloids (59) coverage is given to the
Erythrina group.
Protons attached to C-14 and C-17 in the aromatic ring can be readily
distinguished. Irradiation in the benzylic region causes a sharpening in the
signal due to H-17 (19),whereas irradiation of the axial C-3 proton produces
about 15% NOE for the signal due to H-14 (57). The NOE effect arises
because H-14 lies over ring A and spatially near the axial C-3 proton. The
INDOR technique can also be used to locate H-14 (58). Combinations of
these techniques have been used to determine the position of substituents in
the aromatic ring (43,56-58). For example, dihydroerysovine (44)was found
to contain methoxyl and hydroxyl groups at C-15 and C-16, and their relative
positions were determined by NMR. The resonance for the proton at C-14
(6 6.99) was located by INDOR and confirmed by NOE. When the other
aromatic proton (6 6.30) was monitored a NOE and decoupling effect was
observed at the aromatic methoxyl signal (6 3.27), but this effect was not
observed when the C-14 proton was monitored. This established that the
methoxyl group was near C-17, i.e., at C-16 (57).
The usefulness of the technique has also been demonstrated with
cocculidine (54), which is of firmly established structure (60).The position
of the aromatic methoxyl group could be established using INDOR by
monitoring each aromatic proton in turn. It was found that the aromatic
proton (6 6.93) with J value of 2.5 Hz was spatially near the C-3 axial proton,
hence the methoxyl group was at C- 15 (58).This was supported by synthesis

of the alternative C-16 methoxyl isomer (63) and comparison of its NMR
spectrum using INDOR and NOE techniques (58).
HO
44 Dihydroerysovine 54 R' = H , R Z = CH,O Cocculidine

63 R' = CH,O, RZ = H
The stereochemistry at C-3 in the 1,6-diene series can be determined from

the value of J 2 , 3 . In all cases this value is small, about 2 Hz, suggesting that
the proton at C-3 is quasi-axial and hence that the methoxyl group is equa-
torial. This assignment is supported by the observation of diaxial couplings
(J3ax,4axz 10 Hz) between protons at C-3 and C-4 (19-21,55, 56).
The stereochemistries at C-2 and C-3 in erythratine (42) and erythratidine
(39) were established partly by NMR (19, 21). With the aid of INDOR the
value of J3,4was found to be 5.5 and 12 Hz for both alkaloids, suggesting
that the C-3 proton was axial in both cases, This was supported by inter-
conversion studies (see Section II,C,4b). In erythratine (42) the value of
was found to be 7.5 Hz and in its C-2 epimer 3-4 Hz. This suggested stereo-
chemistries A and B, respectively (as shown in Fig. 5), for erythratine and
its C-2 epimer. The values off,,, (4.25 Hz) and 52,3(4.25 Hz) in erythratidine
(39) suggested that the proton at C-2 is equatorial and that the stereo-
chemistry is that of B in Fig. 5. Thus, 42 and 39 have opposite stereochemistry
at C-2.
The position of the extra methoxyl group in erythristemine (19) was
established at C-11 when it was found that irradiation of the proton at C-17
caused slight narrowing of the methine signal at 6 3.94. The shift of this
OH
A B
FIG.5 . Stereochemistries in ring A
1. ER YTH-HRINA A N D RELATED ALKALOIDS 13
methine suggested an attached methoxyl group, thus identifying the methoxyl

group at C-l 1. This was confirmed by X-ray analysis, which also gave the
,
absolute configuration. The value of J,,,, (4 Hz) was found with the aid of
INDOR since the methoxyl signals partly obscured the methine signal. The
stereochemistry at C-1 1 in the other 11-oxygenated alkaloids have been
related to erythristemine by comparison of the value J,,,,,, which all lie
around 4 Hz, suggesting the same configuration at C- 11 (43).
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
Erysophorine (13)was isolated from the water-soluble extract of the seeds

of E. arborescens Roxb. (37). The molecular formula C,,H,8N,0,C1 was
established by analysis. The mass spectrum of 13 gave no molecular ion but
exhibited fragments consistent with a 1,6-diene Erythrina alkaloid and a
carboxylated indole-3-alkylamine. Erysophorine appeared to be a combined
alkaloid, and its UV spectrum was similar to that of an equimolar mixture
13 R = Hypaphorine 64 Hypaphorine
of 5 and hypaphorine (64). The presence of three quaternary N-methyl groups

and two methoxyl groups was evident from the NMR spectrum. Hydrolysis
of 13 in dilute hydrochloric acid proceeded readily affording 5 and 64, and
erysophorine was deduced to be erysovine linked by esterification at C-15 to
hypaphorine. This was the first example of a phenolic Erytkrinu alkaloid
esterified to an acid other than sulfoacetic or hexuronic acids.
Recently, another combined alkaloid has been isolated, this time from the
seeds of E. oariegata L. (43).Hydrolysis of the alkaloid yielded 7 ; and since
64 was also positively identified in the extracts, it is possible that this alkaloid
could be the complementary positional isomer of erysophorine.
b. 8-0x0Types. Ito's group isolated two new alkaloids, erythrabine

(C,,H,,NO,) (32)and erysotramidine (C,,HzlNO4) (2), from E. arborescens
Roxb., which were both of higher oxidation level than the 1,6-diene types
(27,28).The structures were assigned on the basis of spectroscopic and chem-
ical investigations. Later, a similar alkaloid, crystamidine (C, *HI,NO,),
was isolated from E. crysta galli L.; and MS data indicated an alkaloid of
the 1,6-diene type. The NMR spectroscopic data established the presence
of a methylenedioxy group, a methoxyl group, and two para-oriented
aromatic protons. The UV and IR data suggested a heteroannular conjugated
system, and the carbonyl group ( v ,,,1695 cm-I) was placed at C-8 after
detailed examination of the NMR spectrum. The structure of crystamidine
(33)was proved by correlation with erythraline (4), (see Scheme 6). Catalytic
reduction of 33 gave a product (65) identical to that obtained by oxidation
33 Crqstdmidinr 65 4 Erjthralme
SCHEME
6
1. E R Y T H R I N A A N D RELATED ALKALOIDS 15
of 4 with potassium permanganate, followed by catalytic reduction (32).This

also established the stereochemistry at C-5 and C-3 in crystamidine.
Two other 8-0x0 derivatives [coccoline (17) and coccolinine (15)] have
been isolated from Cocculus species, and these are discussed separately later
(see Section 11,C,5). It has been recognized that, since oxidation at C-8 is
relatively facile, the 8-0x0 derivatives are probably artifacts produced in
the drying process (55). Both 10,ll-dehydroerysovine (34) and 10,ll-
dehydroerysodine (35), which have been detected in GC-MS studies, are
thought to be artifacts produced by an elimination reaction from 11-methoxy-
or 11-hydroxyalkaloids (12).
c. C-11 Oxygenated Types. The first Erythrina alkaloid with oxygen-

ation at C-11 was isolated from E. lysistemon Hutchinson and given the
name erythristemine (20). The molecular formula C,oH25N04was estab-
lished by analysis and confirmed by high resolution MS. The IR spectrum
showed no hydroxyl nor carbonyl absorbances and the UV spectrum was
almost identical to that of erythraline 4. The MS data were consistent with
a 1,6-diene structure containing an additional methoxyl group in ring C or
D. Careful examination of the NMR spectrum with the aid of INDOR (see
Section II,C,2d) suggested that the methoxyl group was at C-11. Structure
19 was proposed and confirmed by X-ray analysis of the 2-bromo-4,6-
dinitrophenolate salt (20,48),which also established the complete stereo-
chemistry shown in structure 19.
19 Erythristemine
A little later 11-methoxyerythraline (22), isolated as a pale yellow gum,

was obtained from the same species (46).The spectroscopic properties of 22
were similar to those of erythristemine except that a methylenedioxy group
was present instead of the two aromatic methoxyl groups in 19. The NMR
spectrum of 22 could be interpreted completely without the necessity of
INDOR, as the signals did not obscure one another. The coupling data
were consistent with H-3 being quasi-axial, as in 19.
At about the same time, Ito et al. (22) reported the isolation of an alkaloid
C,,HIgNO4 from E. indica Lam. (now classified as E. variegata L.) to which
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
The name erythrinine had been assigned to an alkaloid isolated in 1969

from E. lithosperma (61). The formula for this alkaloid was found to be
C30H,,N,0,, and little structural information was known except that it
contained four methoxyl groups and one amide function and that all four
nitrogen atoms were present in rings. No further elaboration of the structure
has been reported.
Erythrascine (C,,H,,NO,) was isolated from the seeds of E. arborescens
Roxb. collected in India (36).The MS fragmentation pattern was typical of
a 1,6-diene type, and the IR spectrum exhibited an absorbance at 1728 cm-
with no hydroxyl absorption. The MS and NMR spectroscopic data were
consistent with erythrascine being 11-acetoxyerysotrine (20). Soon after-
wards the Japanese group reported the isolation of 1 I-hydroxyerysotrine
(CI9Hz3NO,)from the seeds of the same species (27). Structure 18 was
established from spectroscopic and chemical correlation studies. It is not
clear whether both alkaloids 18 and 20 are natural products, since the
possibility that erythrascine was an artifact was not discussed and since no
other 11-acetoxyalkaloids have been reported. Further studies by Ito and
co-workers (31) have resulted in the isolation of erythrinine (21) and 11-
hydroxyerysotrine (18) from other Erythrina species. Recently, examination
1. E K Y T H R I . Y A A N D RELATED ALKALOIDS 17
CH,O’
20 R = CH,CO Erythrascine
18 R = H ll-Hyroxyerysotrine (erythrartine)
of the flowers of E. uariegata L. collected in Egypt resulted in the isolation

of an alkaloid (CI9H,,NO,) to which the name erythrartine was given.
Erythrartine was deduced to be 1l-hydroxyerysotrine (18) on spectroscopic
evidence (43).The authors were unable to compare their sample with that
reported by the Japanese group. The statement that 18 is the first example
of an ll-oxygenated Erythrina alkaloid from E. variegata (43) is incorrect
since erythrinine (21) was isolated by Ito et al. in 1970 from E. indica Lam
(22),a synonym for E. variegata L. (14).
It has been suggested (43) that the absolute configurations of the 11-
oxyerythrina alkaloids 18, 20, 21, and 22 are the same as that of ery-
thristemine (19), that is llj? (or 1lS), on the basis of correlation of optical
rotations and since the value of J,,,,, is the same.
Examination of old world Erytlzrina species by GC-MS has revealed the
existence of a larger variety of 1 1-oxygenated alkaloids 23-31 (see Fig. 2),
including examples with 1I-0x0 functions. The assignment of the structures
of these compounds rests entirely on MS evidence (12)(see Section II,C,2c).
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.
42 Erythratine 41 Erythramine
8
SCHEME
Several other alkaloids like 41 but with abnormal substitution pattern in

ring D, have been isolated from Cocculus species and are discussed in
Section II,C,5.
b. With C-2 Oxygenation. Erythratinone (43), which was synthesised

by oxidation of 42 (19), has been isolated by Barton et al. (19) as a major
alkaloid in E. crysta galli. Further work by the same group has resulted in
the isolation of a similar alkaloid erythratidinone (C, 9H23N04)from
E. lithosperma Blume (now classified as E. variegata L.) (21). This alkaloid
exhibited spectroscopic data similar to those,of 43 and erythratidinone was
established as a 1(6)-en-2-one structure. The NMR data established the
presence of three methoxyl groups and the dpbstitution pattern of ring D.
With the aid of INDOR it was concluded that the proton at C-3 was axial
from coupling values of 5.5 Hz with H-4e, and 12.0 Hz with H-4a. Structure
40 was proposed for erythratidinone since borohydride reduction (see
Scheme 9) gave the known erythratidine (39, [a],, +
273-) and its C-2
epimer ([.ID +
142"). Erythratidine had been isolated earlier from E.Jufcata
Bentham (64),but its stereochemistry was unknown. By application of Mills'
rule (65)39 was assigned the 2 s configuration (as 39), which was opposite to
that established for erythratine (42)by the same group (19). Further evidence
0 OH
40 Ervthratidinone 39 Erqthratidine 1 Erysotrine

( + C-2 epimer)
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
49 Erysotinone 48 Erysotine 39 Erythratidine

( + C-2 epimer)
11
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
from plant material. Identification of 58 was made by comparison of its

melting point and spectroscopic properties with the reported data and by
reduction to the known transformation product erysodienol(35).
5. Abnormal Alkaloids from Cocculus Species

Only 3 of the 12 species of Cocculus (Menispermaceae) have been examined
for alkaloids and most studies have concerned C. laurifolius, which has
yielded the greatest number of alkaloids (see Table I) (51, 55-58,60, 69-76).
The Erythrina-type alkaloids obtained from Cocculus are abnormal in the
sense that they contain no oxygen function at C-16, the only exceptions
being dihydroerysovine (44), dihydroerysodine (47), and erythroculine (53).
Erythroculine is, however, unusual in that it has a methoxycarbonyl group
at C-16. The two alkaloids isococculidine (36) and isococculine (37) are of
the A2( 1)-alkene type rather than the A1 (6)-alkene type.
The insecticidal alkaloid cocculolidine (61), a lower homolog of
B-erythroidine (60) (see Fig. 4), was mentioned in the previous review ( 1 )
where its isolation from C. trilobus DC was reported. It has now been
isolated from C. carolinus DC, a species native to the Southeastern United
States (69).
22 S. F. DYKE A N D S. N. QUESSY
TABLE I
ERYTHRIXA ALKALOIDS
FROM COCCLLUS SPECIES
Alkaloid mP( C ) [.ID Plant source‘ Ref.
Cocculine 217-218 +271 A 51,55

B 60
C h9
Isococculine ~
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
“A. C. luurfolius DC (leaves); B, C. trilobus DC (leaves); C, C. carolinus

DC (fruits).
Oil.
Styphnate.
Cocculine (C, , H 2 , N 0 2 ) and cocculidine (Cl8H2,NO,) were isolated

from C. laurijolius in 1950 (77) but escaped mention in previous reviews of
this treatise because only a partial structure, unrelated to the Erythrina
alkaloids, had been advanced (78). On the basis of the spectroscopic prop-
erties of the alkaloids and their Hofmann degradation products, structures
56 and 54 (without stereochemistry) were proposed for cocculine and
cocculidine, respectively (79); however, a different group (80) proposed
structures 69 and 70, respectively, on the basis of similar evidence. The
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
former group established the spiro structure of 56 by conversion to the 0 , N -

diacetate 71 (51) (see Scheme 13), and X-ray analysis of the hydrobromide
salts of 56 and 54 established the structures originally proposed (51, 52).
Although the absolute stereochemistry was stated to be 3 R 3 the structures
were ambiguously represented as the mirror image of this configuration. A
rigorous definition of the absolute configuration of cocculine was reported
by McPhail and Onan in 1977 (49) whereby stereostructure 56 (i,e., 3R,5S9
was established for cocculine. It follows that cocculidine has stereostructure
54 since it has been demonstrated that methylation of cocculine using
diazomethane gives cocculidine (77). Cocculine has also been isolated from
C. trilobus (60)and C. carolinus (69).
52 Coccutrine 53 Erythroculine
A related alkaloid coccutrine (CI8H,,NO,) was isolated from C. trilobus

(60)and structure 52 established spectroscopically, with the positions of the
aromatic hydroxyl and methoxyl groups being defined by X-ray analysis.
Coccutrine is the only example of an Erythrinu alkaloid containing an
oxygen function at C- 17.
An unusual alkaloid, erythroculine (C,,H,, NO,) was obtained from the
leaves of C. luurifolius (67)and its structure (53) deduced from spectroscopic
and degradative evidence (73). The MS data were consistent with a Al(6)-
alkene structure and the IR spectrum exhibited an absorbance at 1710 cm-'.
The N M R spectrum established the presence of three methoxyl groups and
two para-oriented aromatic protons. Reduction of 53 gave erythroculinol
72 Erythroculinol 74
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
(72) (see Scheme 14) which contained an IR absorption attributable to a

hydroxyl group, but no carbonyl band was observed. Since one of the
methoxyl groups in the NMR spectrum had disappeared, a methoxycarbonyl
group was established. Demethylation of 53 gave a phenolic base 73 (Scheme
14)which showed a large bathochromic shift in the UV spectrum. This led to
the assignment of the methoxyl function in 53 ortho to the methoxycarbonyl
group, and the position of these groups was made on the basis of detailed
NMR studies, including the observation of deuterium exchange ortho to the
methoxyl group in erythroculinol. The environment of the nitrogen atom
was established by Hofmann degradation of 72 (Scheme 14) and spectro-
scopic analysis of the degradation product 74. Erythroculinol was degraded
by a combination of von Braun and Hofmann methods (see Scheme 14) to
the biphenyl 75, whose structure was proved by an unambiguous synthesis.
Finally, the stereochemistry at C-3 and C-5 was established by transforma-
tion of erythroculine (53) to tetrahydroerysotrine (76) as shown in Scheme
15. The presence of the methoxycarbonyl group in 53 is interesting from a
biogenetic point of view.
53
i
performic
acid
76 Tetrahydroerysotrine
SCHEME 15
Continued examination of the pharmacologically interesting species

C. laurifolius, particularly by Singh et al. (55,56,70-72, 74) has led to the
isolation of more Erythrina alkaloids that have structures related to cocculine
(56) and cocculidine (54). Coccuvine (C, 7H19N02) and coccuvinine
(C,,H,,NO,) were found to be of the 1,6-diene type (56, 72) and the struc-
tures 16 and 14, respectively, were established on the basis of spectroscopic
evidence and chemical interconversions. Methylation of coccuvine (16) (see
26 S. F. D Y K E AND S. N. QUESSY
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
CH,O~’ ’ CH,O-’ ’ CH,O,’

16 Coccuvine 14 Coccuvinine 54 Cocculidine
SCHEME16
Two further alkaloids, isococculine (C, ,H2 NO2) and isococculidine

(C, sH2,N02),were isolated and found to be isomeric with cocculine 56 and
cocculidine (54), but were discovered to have novel structures with respect
to the position of the double bond (55, 70). Structures 37 and 36 for iso-
37 R = H Isococculine 55 Cocculitine
36 R = CH, Isococculidine
cocculine and isococculidine, respectively. followed from the analysis of the

physical data. For example, the UV spectrum of 36 showed an isolated
double bond, but the MS fragmentation pattern was similar to that of the
1,6-diene Erythrina structure rather than the A1(6)-alkene type. The A2(1)-
alkene structure was supported by the NMR spectrum which exhibited two
olefinic protons at 6 6.06 and 5.85 ppm ( J , , 2 = 10.5 Hz). The absolute
stereochemistry was not determined since a correlation between 36 and
cocculidine (54) through their dihydro derivatives was not possible because
1. t R > THRl.tA A N D RELATED ALKALOIDS 27
of the resistance of 54 to hydrogenation (55).However, the configurations at

C-3 and C-6 were supported by coupling-constant data obtained from the
NMR spectrum.
A new alkaloid cocculitine (C,,H,,NO,) was isolated recently from
C. laurijolius (74). The IR spectrum indicated the presence of a hydroxyl
group (3460 cm- ’) which was further established by the formation of a
mono-O-acetate (1715 cm-I). The NMR spectrum of cocculitine was very
similar to that of erythratine (42),except in the aromatic region. The aromatic
methoxyl group was located at C-15 on the basis of detailed decoupling
experiments, and the stereochemistry at C-3 was determined from the
coupling data, which suggested that the proton at C-3 was axial. A value of
8.5 Hz for J,,, suggested that the proton at C-2 was also axial and hence
structure 55 was proposed for cocculitine.
Only two “normal” Erythrina alkaloids have been isolated from Cocculus
species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter
recently from C. trilobus (57).Neither alkaloid has been found in Erythrina
species. The structure 44 for dihydroerysovine was deduced from the spectro-
scopic evidence and by methylation using diazomethane to give the known
dihydroerysotrine (38). The positions of the aromatic substituents were
determined by detailed N M R experiments using NOE and INDOR tech-
niques (see Section II,C,2d).
47 Dihydroerysodine 44 Dihydroerysovine
111. Homoerythrina Alkaloids
A. OCCURRENCE
AND ISOLATION
The C-Homoerythrina alkaloids are a relatively recently identified group,

the first examples being isolated and identified from Schelharnnzera
~ ~ ~ u F. ~MueI1. c uin /I968 ~ ~Homoerythrina alkaloids have been
~ (81).
isolated from all three species of Schelhanziwera (Liliaceae), in which they
constitute a further addition to the various biosynthetically related alkaloids
within the family Liliacea (82-85); from the leaves of species of Phelline
(Ilicacea), where their presence raises some doubts about the taxonomic
classification of the genus (86-88); and from the roots and stems of species
28 S . F. DYKE AND S . N. QUESSY
of Cephalotaxus (Cephalotaxaceae), particularly C. wilsoniana Hayata in

which they are the major alkaloids (89-91) (see Table 11).
Many members of the Homoerythrina group occur with their C-3 epimers,
in contrast to the Erythrina group, and despite the fact that they appear in
relatively few plant species, over 20 individual Homoerythrina alkaloids
have been isolated, although the structures of two of them remain incomplete
because of insufficient amounts of samples. Those alkaloids of known struc-
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
77a Schelhammeridine -CH2- CH,O H H, H2

77b 3-Epischelhammeridine -CH2- H CH,O H2 H,
78 8-Oxoschelhammeridine -CH2- CH,O H 0 H2
79 1 la-Oxoschelhammeridine -CH2- CH,O H H2 0
PIG. 6a. Homoerythrina alkaloids: 1,6 diene series
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
FIG.6b. Homoerythrina alkaloids: Al(6) alkene series.

RZO
k4
R1 R2 R3 R4
84a 3-Epi-6~,7-dihydrohomoerythraline -CH,- CH30 H

84b 6~,7-Dihydrohomoerythraline -CH - H CH,O
85 6a,7-Dihydrohomoerysotrine CH, CH, H CH,O
FIG.7a. Homoerythrina alkaloids: A2(1) alkene series
R4
R' R2 R3 R4
86 3~-Methoxy-l5,16-methylenedioxy-6,7-epoxy- -CH2- H CH,O

C-homoerythrinan-2(1)-em
87a Wilsonine CH, CH, CH,O H
87b 3-Epiwilsonine CH, CH, H CH,O
FIG.7b. Homoerythrina alkaloids: epoxy- A2( 1) series
88 R = H 90 Phellibiline'
89 R = CH,
FIG.7c. Homoerythrina alkaloids : the homoerythroidines.
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
decided to refer to the unnamed members as homo analogs of the corre-

sponding Erythrina alkaloid. This has the advantage of illustrating the
structural relationship between the two groups (as they are biogenetically
related) and keeps the names relatively simple. When this is not possible the
Chemical Abstracts system, which is based on the C-homoerythrinan ring
91, is used. We have used the Chemical Abstracts numbering system for the
sake of consistency, even though it differs from that used in the literature
(cf. 92).
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
SCHEME 18. Major fiagmentation pathway f o r A I ( 6 ) d k e n e - t y p eHomoerythrina alkaloids
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.
2. Schelhammerine, Schelhammeridine, and Their C-3 Epimers

The structural determination of the first Homoerythrina alkaloids,
obtained from Schelhammera, was the subject of an elegant series of papers
by the CSIRO group in Australia (81-85). Two major alkaloids from S.
peduncufata F. Muell. were named Schelhammerine (C, ,H,,NO,) and
~ c h e l ~ a ~ ~ (CI9H2,NO3)
e ~ ~ ~ i n e(82). The alkaloids had similar NMR
characteristics in that both exhibited resonances attributable to a methy-
lenedioxy group, a nonaromatic methoxyl group, and two para-aromatic
protons ; but schelhammeridine contained two olefinic protons in its N M R
spectrum and exhibited an isolated alkene absorption in the UV spectrum,
whereas schelhammerine showed absorption arising from only one olefinic
proton in the NMR spectrum, and the extra oxygen atom was found to be in a
hydroxyl group. Furthermore, treatment of schelhammerine in pyridine
with methanesulfonyl chloride gave schelhammeridine in 20% yield (see
Scheme 19), revealing that the two alkaloids were structurally related.
Since the nitrogen atom was tertiary, and evidence for N-methyl was not
observed, a tetracyclic system was considered. The possibility that the fused
heterocyclic rings were both six-membered was excluded through analysis
1. E R Y 7 H R / , C A A N D RELATED ALKALOIDS 33
80a Schelhammerine 77a Schelhammeridine

(20"f; yield based on recovered 80a)
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).
77a 93 (70“,) 77b

( + C-3 epirner lo“,)
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
the “apo rearrangement,” which occurs on acid hydrolysis of the Erythrina

alkaloids, does not occur with the Homoerythrina group, where a bridged
biphenyl system is formed. The ease of cleavage of the N-C-5 bond in
schelhammeridine is also unparalleled in the Erythrina series. When
schelhammeridine was heated at reflux in acetic anhydride a single stereo-
isomer 94c was obtained. It was then shown that the stereochemical outcome
of the acid-hydrolysis reaction was temperature-dependent, because of
limited rotational freedom of the biphenyl system.
Hydrogenation of schelhammeridine (77a) in acetic acid gave rise to five
products, and the structures of four of them were determined spectro-
scopically (83). The two major products were the 2,7-dihydro- and the
tetrahydro derivatives 81a and 95, respectively (see Scheme 21). Hydro-
genolysis and N-C-5 bond cleavage products were also observed. It was
found that the yield of the dihydro derivative 80a was increased when ethanol
was used as the solvent for the hydrogenation. The 6a-configuration in 95
was assigned on the assumption that hydrogenation would occur from the
less hindered a-side of the molecule. In the Erythrina group, this assumption
proved to be incorrect ( I ) , so the configuration at C-6 in 95 and in the A2( 1)-
dihydro series (Section 111,C,5) remains to be proved.
1. E R Y T H R I V A A N D RELATED ALKALOIDS 35
77a 81a (30',,)

(Schelhammencine)
SCHEME21
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
4. Schelhammericine and the A l(6)-Alkene Series

Schelhammericine ( C ,,H,,NO,) was recognized as a A1(6)-alkene struc-
ture from its MS fragmentation pattern (see Section III,C,l) and structure
81a was determined through analysis of its NM R spectrum. Values of 3.5
and 5.0 Hz for J3,4 suggested that the proton at C-3 was equatorial. Schel-
hammericine was identified as the dihydro product 81a obtained on catalytic
hydrogenation of schelhammeridine (refer to Scheme 2 1) (84).
An isomeric alkaloid (alkaloid E) was isolated from S. pedunculata and
found to be the major alkaloid in 5’. rnultzj2ora R.Br. (85). Values of 4.0
and 11 Hz for J3,4suggested that it was the C-3 epimer 81b of schelham-
mericine. Structure 81b was proved by identification of 3-epischelham-
mericine with 2,7-dihydro-3-epischelhammeridine(see Scheme 23) (84).
Later on, another group reported the isolation of 81b from P.comosa, and
was able to convert 3-epischelhammerine (80b) to 81b by chlorination and
(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
dihydroerysotrine and homo-2,7-dihydroerysotrine, with structures 82a

and 82b, respectively. Distinction between the two epimers was made on the
basis of the NMR data (see Section III,C,l). The configuration at C-5 was
considered the same as that in schelhammericine, since their optical rotations
were of the same sign and magnitude (89).
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
An alkaloid (C,,H,,NO,, alkaloid B) isolated from S. pedunculutu

exhibited UV characteristics similar to those of schelhammerine (80a) and
an IR absorbance at 3600 cm-' suggested a phenolic hydroxyl group. The
NMR spectrum was similar to that of 3-epischelhammericine and revealed
the presence of one aromatic methoxyl group, a phenolic proton, and para-
oriented aromatic protons. The position of the phenol group was located at
C-15 by an NMR experiment that involved deuterium exchange of the
aromatic proton ortho to the phenol group. The remaining aromatic proton
was broadened because of benzylic coupling and was therefore at C-17. The
stereochemistry at C-3 was deduced from the observation of a large value
for J3,4ax,and the configuration at C-5 was assigned by the sign and mag-
nitude of the optical rotation. The data were consistent with structure 83
for this alkaloid, which is therefore homo-2,7-dihydroerysovine (84). This
same alkaloid was found in S. undulutu (85)and has also been isolated from
C. harringtoniu var. hurringtoniu along with a similar base which, from its
NMR spectrum was epimeric at C-3. However, the positions of the aromatic
methoxyl and hydroxyl groups could not be defined because of a lack of
pure sample, and partial structure 96 was proposed (89).
H
CH,O'
96 97
38 S . F. D Y K E A N D S . N. QUESSY
An alkaloid (C2,H19N04, alkaloid 5 ) , isolated from Plicllinr c o m u a

Labill., has a MS fragmentation of the A1(6)-alkene type. The N M R spec-
trum revealed the presence of three aromatic methoxyl groups, and the
methoxyl group at C-3 was found to be equatorial from the large value of
J3,4ax(1 1.5 Hz). The configuration at C-5 was assumed to be 5s on the basis
of the sign and magnitude of the optical rotation. The partial structure 97
was proposed and it was suggested, on steric and biogenetic grounds, that
the aromatic substitution pattern was 15,16,17-trimethoxy.
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
10" HCI 10"" HCI

A
(35"")
0
'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
spectrum this alkaloid (alkaloid 1) was found to contain an allylic methoxyl

group, and the coupling data suggested that the C-3 proton was axial.
Hydrolysis of 84b gave the allylic alcohol 98 as the major product; this
product had properties identical to those reported for the demethylation
product of 84a (84)(see Scheme 24). The interconversion reactions outlined
in Schemes 24 and 25 allowed the complete stereochemistry of 84b to be
assigned. In addition, it was found that the von Braun degradation product
of 84b was identical to that of 3-epischelhammeridine 81b (87),as shown in
Scheme 26.
81b 84b
SCHEME
26
From the same plant a similar alkaloid (C,,H,,NO,, alkaloid 2) was

isolated and found to differ from 84b in that it contained two aromatic
methoxyl groups in place of the methylenedioxy group. The C-3 proton was,
from the N M R coupling constants, found to be axial, and structure 85 was
consistent with the data. The configuration at C-5 was assumed, although its
CD curve was the inverse of that of 84b in the region 235 nm. Structure 85
corresponds to 6~~,7-dihydrohomoerysotrine.
Two alkaloids, C,,H,,NO, and C,,H,,NO, (alkaloids 6 and 7), isolated
from P.comosa exhibited similar NMR characteristics (87).Both contained
an allylic methoxyl group, a disubstituted double bond, and para-oriented
aromatic protons ; however, the former contained a methylenedioxy group
and the latter two aromatic methoxyl groups. Their IR spectra showed the
absence of hydroxyl or carbonyl functions, which suggested that the fourth
oxygen atom was contained in a ring. The MS fragmentation patterns of
the two alkaloids were almost identical, showing that they differed only in
the aromatic substituents. Structures 86 and 87b, respectively, were assigned
CH,O. R'
85 86 87a R' = CH,O. R Z = H
87b R' = H , R 2 = CH,O
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"
102 81b 3-Epischelhammericine
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,
alkaloids from P. billardieri are the only examples of the homoerythroidine

series yet isolated.
IV. Cephalotaxus Alkaloids
A. OCCURRENCE
AND ISOLATION
Cephalotaxus is a genus of plum yew natural to Eastern Asia, although

it is now cultivated in many parts of the world (94). There are about seven
species and most have been examined for alkaloids, which have been ob-
tained from all parts of the plants. Since the alkaloidal extracts were re-
ported in 1969 to exhibit antitumor activity (95), an intense investigation
of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation
work, structural elucidation, and pharmacological assay has come from
the Northern Regional Research Laboratory in Illinois (8).
The alkaloids were best isolated from the ethanol extract of the plant mate-
rial, partially fractionated by counter-current distribution, and subsequently
purified by preparative chromatography. Of the 11 known Cephalotasus
alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a)is ubiquitous
and the most abundant (up to 64% of the total alkaloid extract) in all species
examined. C. wilsoniana Hay., which yields only minor quantities of ceph-
alotaxine, is the exception, however ; it is rich in Homoerythrina alkaloids,
1. E R Y T H R I Y A AND RELATED ALKALOIDS 43
OR3
R’ R2 R3
105a Cephalotaxine HO H CH,

105b Epicephalotaxine H HO CH,
106 Acetylcephalo taxine CH,CO H CH,
107 Harringtonine a H CH,
108 Homoharringtonine b H CH3
109 Isoharringtonine C H CH,
110 Deox yharringtonine d H CH,
111 Desme thylcephalotaxine HO H H
112 Cephalotaxinone 0 CH3
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.
OCH, OCH, OCH,

113 Desmethylcephalotaxinone 114 1I-Hydroxycephalotaxine 115 Drupacine
FIG.9. Ceplialotauus alkaloids.
companion alkaloids in Cephalotaxus species (90).Seven Homoerythrina al-

kaloids have been identified in Cephalotaxus, including 3-epischelhammeri-
cine (Sob), wilsonine (87a), 3-epiwilsonine (87b), and structures 82a, 82b,
83, and 96 (8).
The other Cephalotaxus alkaloids are structurally related to cephalotaxine
(105a)and the most important group are the harringtonines 107-1 10, which
are C-3 esters of cephalotaxine, since they have antitumor activity (see
Section VII). The harringtonines constitute less than 10% of the total alka-
loid extract and are in greatest abundance in C. harringtonia K. Koch var.
harringtonia (89). The demand for the harringtonines for use in clinical
trials has exceeded their supply from natural sources, resulting in many
attempts to synthesize them from the more abundant cephalotaxine (see
Section V1,C).
In a very recent examination of C. msnii Hook., a new antitumor alkaloid
was isolated but found to be structurally unrelated to the usual Cephalotaxus
alkaloids. In view of the chemical results the botanical classification of
the plant is being reexamined (96).
Recently, a GC-MS method for the separation and quantitative identi-
fication of extracts from Cephalotaxus species (97)has been described. Most
of the alkaloids were resolved, particularly the biologically active esters.
The seven Homoerythrina alkaloids were only resolved into two groups
of five and two components, respectively, under the conditions described.
Acetylcephalotaxine (106), 1 1-hydroxycephalotaxine (114), and desmethyl-
cephalotaxinone (113) were not resolved by retention time, but could be
identified within the mixture by their MS fragmentation patterns. Cepha-
lotaxinone (112) gave two GC peaks after silylation, presumably due to
a contribution from the enol component. The artifact peak overlaps partly
with the peak for drupacine (115) and hence introduces a slight error for
this component and makes it difficult to quantify cephalotaxinone.
It has been observed that the melting points and optical rotations of
several alkaloids differ by more than can be attributed to experimental
variation and must thus depend on the plant source (9,89,98).The most
striking example is cephalotaxinone which has [mID-57" (0.3 c/g cmP3,
CHCI,), from C. harringtonia var. drupacea and [.ID - 125' (0.6 c/g cm-,,
CHC1,) from C. harringronia var. harringtonia, but that obtained by oxida-
tion of cephalotaxine has [.I, -155" (0.63 c/g ern-,, CHCI, (89, 98). It
has been suggested that Cephalotaxus alkaloids may occur as partial race-
mates. Although cephalotaxine is optically active ([.], - 183"),its crystalline
methiodide is racemic. The amorphous residue was found to be optically

+
active ( [ a ] , 1127, and it was suggested that racemization occurred during
recrystallization from hot methanol (99).It is not clear whether Cephalotaxus
alkaloids do occur as partial racemates or whether some racemization occurs
1. ER YTHRINA AND RELATED ALKALOIDS 45
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
In an accompanying publication (105), the X-ray crysial structure of

cephalotaxine methiodide, which proved structure 105 for cephalotaxine,
was reported. Although the methiodide was prepared from optically active
([.ID - 183”) cephalotaxine, the crystalline product was racemic, so that
only the relative stereochemistry was obtained. It appears that all four
chiral sites in the methiodide undergo inversion, presumably by facile cleav-
age and re-formation of the N-C-5 bond. This could also explain the early
difficulties in the structural elucidation by chemical transformation. Re-
cently, the absolute configuration has been established by X-ray analysis
of cephalotaxine p-bromobenzoate (99, 106) as 3S,4S,5R (as shown in 105a).
The seven-membered heterocyclic ring exists in a boat conformation with
the nitrogen atom at the prow.
17 11
OCH,
105a Cephalotaxine
A minor alkaloid from C. fortunei (98) showed an IR spectrum identical

to that of cephalotaxine, but its melting point was depressed by it. The
physical properties of this alkaloid were found to be identical to the minor
product obtained by reduction of cephalotaxinone (112) using LAH (102).
The alkaloid was therefore 3-epicephalotaxine (105b). Although a small
amount of 105b was produced on reduction of cephalotaxinone with LAH,
the use of borohydride or DIBAL-H gave only cephalotaxine (98).
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).
Examination of the NMR spectra of the harringtonines revealed a spec-

trum nearly identical to that of cephalotaxine as well as the presence of
signals arising from a side chain. This observation led to the discovery that
alkaline hydrolysis of the harringtonines gave cephalotaxine in each case,
plus a complex dicarboxylic acid. This was further supported by the MS
data, since each alkaloid exhibited a prominent fragmentation ion with
nz/e 298, due to loss of the side chain (M' -OR). The same peak was ob-
served in the MS of cephalotaxine (M' -OH). It was therefore established
that the harringtonines were C-3 esters of cephalotaxine, differing only in
the nature of the ester side chain. The structures of these side chains were
deduced from a careful examination of the NMR spectra of their dimethyl
esters, obtained from the natural alkaloids by transesterification using
sodium methoxide in methanol (100, 107, 108). The number and nature of
free hydroxyl groups was determined by examination of the NMR spectra
in DMSO-d, before and after deuterium exchange.
The N M R spectra of the esters obtained from harringtonine and homo-
harringtonine exhibited two equivalent methyl groups and two different
carboxymethyl signals, two tertiary hydroxyl groups, and an isolated meth-
ylene group. The spectra were consistent with structures 118 and 119, re-
spectively, for these diesters. The spectrum of the diester obtained from
isoharringtonine differed in that it contained an isopropyl function, a singlet
due to an isolated methine bearing a hydroxyl group, and only one tertiary
hydroxyl group. Structure 120 was proposed for this diester. By a combina-
tion of IR and NMR evidence the diester obtained from deoxyharringtonine
was found to contain only one hydroxyl group, which was tertiary, and
structure 121 was consistent with the data. The structures of these diesters
were confirmed by synthesis (see Section V1,C).
C0,CH3 OH CO,CH, OH
CH,OZCpCH,-C~~(CH,),pCpCH, CHAOIC CH, 7 ICHZ),pCpCHA
OH CH 3 OH CHS
118 119
H C02CH3 H C0,CH3 H
CH,O,C-C-C-(CH,), -C-CH, CH,O,C-CH,~C~(CH~),~~~CH;

OH OH CH, OH CH,
120 121
The problem now remained as to which carboxyl group was attached

to the cephalotaxine skeleton. The two possible half-esters, 122 and 123,
were synthesized (see Section VI,C), and esterification of cephalotaxine
with 122 gave rise to a mixture of diastereomers, neither of which was
48 S. F. DYKE AND S . N. QUESSY
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
identical to deoxyharringtonine (108). This result suggested that the tertiary

carboxyl group was linked to cephalotaxine in deoxyharringtonine ; but
all attempts to esterify cephalotaxine with the half-ester 123 failed, and
it was concluded that both reactants were sterically hindered. It was found
that in the MS fragmentation patterns of the half-esters, cleavage at the
tertiary center was preferred. Thus, 122 and 123 exhibited M-CO,H
(m/e 173) and M-CO,CH, (m/e 159) fragmentation ions in the ratios
1 :8 and 3: 1, respectively. Deoxyharringtonine showed a ratio ofmle 1731159
of 3:1, suggesting linkage through the tertiary carboxyl group (108). The
structures of deoxyharringtonine and the other harringtonines have been
proved by partial syntheses from cephalotaxine and are discussed in Sec-
tion V1,C. The absolute configurations of the acyl side chains are also
discussed in that section as they depend, in part, on stereospecific synthesis.
Recently, tissue cultures of C. harringtonia var. harringtonia were found
to yield Cephalotaxus alkaloids in the same ratio as the parent plant, al-
though in lower total yield. It was hoped that this method would help to
offset the shortage of harringtonines, since the alkaloids could be obtained
after six months, whereas the Cephalotaxus tree was slow to mature. A
new harringtonine was discovered in the culture. The GC-MS evidence
suggested that it was a homolog of deoxyharringtonine, and structure 124
was proposed for the side chain from the MS data. The name homodeoxy-
harringtonine was suggested for the alkaloid (109).
3. 11-Hydroxycephalotaxine and Drupacine

Two minor alkaloids (C1,H,,NO,), obtained from C. harringtonia var.
drupacea (Sieb and Zucc) Koidz., were deduced to be 1 l-hydroxycephalo-
taxine (114) and its related ketal drupacine (115) (101, 104). The NMR
spectrum of the former exhibited features similar to that of cephalotaxine,
with the addition of a triplet at 6 4.78 ppm, which was part of an ABX
system. The alkaloid formed a diacetate wherein the position of the methine
1. ER YTHR1,VA A N D RELATED ALKALOIDS 49
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
The ready conversion of 114 to 115 suggested that drupacine might be

an artifact produced during the isolation procedure. However, it was dem-
onstrated that the isolation conditions could not account for all the ma-
terial, so that some drupacine must be present in the plant (101). Both
alkaloids are unique to C. harringtonia var. drupacea, and an alkaloid with
properties similar to those of drupacine was also reported by Asada in
the same species, although no structure was given (110).
4. Cephalotaxinone, Desmethylcephalotaxine, and

Desmeth ylcephalo taxinone
Cephalotaxinone (C, ,H ,NO,) was first isolated and characterized from
C. harringtonia var. harringtonia (89) and later from C. fortunei (98). In
the IR spectrum of this material, the hydroxyl group of cephalotaxine was
absent but a carbonyl absorbance at 1720 cm-' was present. A shift in the
olefinic absorbance from 1665 to 1625 cm-' suggested an enone structure.
Cephalotaxinone was found to be identical to the product 112 formed by
Oppenauer oxidation of cephalotaxine (105a) (see Scheme 30). This also
established the stereochemistry of 112 at C-4 and C-5.
OCH, OCH,
105a Cephalotaxine 112 Cephalotaxinone
30
SCHEME
Desmethylcephalotaxine (111) was first prepared by mild acid hydrolysis

of cephalotaxine, during the early structure elucidation work (102). The
same workers later identified this material as a minor constituent of C.
fortunei (98). Desmethylcephalotaxine is not an artifact, since pure cepha-
lotaxine can be subjected to the isolation procedure without loss.
It was noted that chromatography of Ceplra~otasus alkaloid fractions over
neutral alumina resulted in considerable losses (111). Further elution with
dilute aqueous acetic acid resulted in the isolation of a new alkaloid, des-
methylcephalotaxinone ([.ID + 2.3"). The IR spectrum of this alkaloid
was consistent with the presence of a vinylic hydroxyl group (3520 cm-l)
and a conjugated carbonyl group (1690 cm-I). The NMR spectrum ob-
tained in deuterochloroform contained features of the cephalotaxine struc-
ture, but included a singlet attributable to an isolated methylene (6 2.54
ppm). In DMSO-d, this resonance appeared as an AB quartet. Acetylation
1. ER Y 7 H R I N A A N D RELATED ALKALOIDS 51
produced an enol acetate, which exhibited a signal due to an isolated meth-

ylene at 6 2.59 ppm in the NMR spectrum.
Structure 113 was established by interconversion reactions. Cephalo-
taxine was oxidized to cephalotaxinone (112) (as in Scheme 30) which, on
vigorous hydrolysis in acid, gave desmethylcephalotaxinone ([.ID 40") +
in less than 30% yield after 3 hr at 80' (see Scheme 31). This material was
identical to the natural product except for its optical rotation. It appeared
that the natural product was nearly racemic since methylation gave optically
inactive cephalotaxinone (see Scheme 31) plus a small quantity of the iso-
meric ether 126. The spectroscopic evidence suggested that desmethylceph-
alotaxinone exists in the tautomeric structure 113. The possibility that 113
was an artifact was considered unlikely under the conditions of isolation.
The alkaloid has been found as a minor component in C. harringtonia var.
harringtonia and in C. harringtonia var. drupacea ( I l l ) .
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
3 3 . The biosynthetic route to the Erythrina alkaloids

SCHEME
1. E R YTHRlh'A A N D RELATED ALKALOIDS 55
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
together with (S)-norprotosinomenine, from E. lithosperma (but see Section

II,A about this species). When ['4C]4-methoxynorprotosinomenine was
fed to E. crista galli, the erythraline (4) that was isolated was found to be
equally labeled at the methoxyl and methylenedioxy group carbon atoms,
thus confirming the involvement of a symmetrical intermediate such as 130b.
The important point concerning stereochemistry was also considered by

Barton et al. (117, 118), who pointed out that the conversion of chiral 136
to 130b, thence into chiral erysodienone (as 139), must either involve an
139
inversion of configuration or a symmetrical intermediate. They showed (118)

that chiral 130b is very rapidly racemized at room temperature and that
only (-)-(55’)-erysodienone is the precursor of erythraline and of both a- and
P-erythroidine.
The biosynthesis of the “unusual” Erythrina alkaloids such as isococculi-
dine (36), cocculidine (54),and cocculine (56) proceeds (119, 120) from (+)-
54 R = M e
56 R = H
(S)-norprotosinomenine (135).This was established (120) in feeding experi-

ments with C. laurifolius DC. The proposed route is summarized in Scheme
34, where reduction of 136 to 141 was originally thought to occur, followed
by a dienol-benzene rearrangement to 142. However, cyclization of 142 to
isococculidine (36) is hard to visualize, although intermediate 143 was
postulated. An alternative route (11a) involves reduction of the diphe-
noquinone 144 to 145, followed by cyclization to 146 and further elaboration
to 36.
The biosynthesis of z-and p-erythroidines has been investigated (118)by
feeding 17-rnonotritioerysodine, 14,17-ditritioerysopine, and 1,17-ditritio-
erysodienone, when high levels of incorporation were observed, thus
confirming that these lactonic alkaloids are derived in vivo from the aromatic
compounds. The remaining point of ambiguity concerns the position of
cleavage of ring D; the feeding experiments are compatible with either
C-15-C-16 or C-16-C-17 cleavage, with the loss of C-16 and retention of
tritium at C-17.
135
I
4
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
Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested

(82) that the homoerythrina derivatives are biosynthesized along a pathway
analogous to that followed by the Erythrina alkaloids themselves (Scheme
35). Some preliminary results from feeding experiments (121) support this
view; ( +)-[2-14C]tyrosine causes specific labeling of C-8 in 77a.
?H
Me0
OH
I
OH
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.
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
l-phenethylisoquinoline intermediate. Thus, [3-14C]tyrosine gave cepha-

lotaxine (105a) with 68% of the activity at C-11 and 32% at C-4, but
[2-14C]tyrosine labeled C-10 (37% of the activity); no label was found at
C-7 or C-8. However, it was realized subsequently (123) that tyrosine was
being catabolized, and the aromatic ring was not being incorporated into
cephalotaxine. It was found (123)that phenylalanine is the precursor, in line
with the derivation of other l-phenethylisoquinolines,and that ring D is
derived from the aromatic ring of phenylalanine with the loss of one carbon
atom.
The biosynthesis of the acyl side chain of deoxyharringtonine (110) has
been found (124) to involve L-leucine (Scheme 37).
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
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
Me0
U
161
158
164 165
A new approach to the synthesis of the Erythrina alkaloids involves (134)

a Birch reduction of the amide (166) to 167, followed by cyclization, first
to 168 with sulfuric acid in DMF, then to the ketolactam (169) with formic
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
Me0e O y $ ( +K;z:xFJ MHe 0 O V
0 0
L/
173 172
/
3'"' ' (il Li+NR,
lii) 0,
THF
(I) Oxidation Me0

M e0 e 0 9 f;":', Me0
H OH H "OAc
0
LJ
174 175
i 35""
Me0 e 0 -9 +--- Me0

MeO%
'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
The enamine (186) was itself prepared from homoveratrylamine and y -

butyrolactone. Yet another approach to the erythrane skeleton (140)involved
Birch reduction of 6-methoxyindoline to 188, followed by N-acylation with
3,4-dimethoxyphenylacetyl chloride to yield 189. When this product was
reacted with POCl, the ketoamide (190) was obtained in poor yield; the
major product was 191.
Me0 rn188
189
191
Synthetic studies along the biosynthetic route have attracted considerable

attention. A very early success mentioned in the previous review ( I ) and in
the biosynthesis section of this chapter (Section V,A) involved the oxidation
of the diphenol(127a) with alkaline potassium ferricyanide to erysodienone
(132a) via the benzocene (13Oa) and the diphenoquinone (131a) (Scheme 32).
The mechanism of this reaction has been discussed by Barton et al. (68).The
dienone (132a) has been converted to erythratine and dihydroerysodine (see

Section V,A).
A particularly interesting and useful synthesis of 130b has been described
by Kupchan et al. (141-143), who oxidized the l-bemyltetrahydroisoquino-
line (192, R = COCF,) with vanadium oxyfluoride (Scheme 40). Earlier
Kametani et al. (144) had oxidized 192 (R = C0,Et) with potassium fer-
ricyanide and had obtained 193 (R = C0,Et) in 2% yield.
HO
Me0 R
OH OH
192 193
I NaOH
130b -
NaBH,
194
SCHEME
40. Kupchan's sjnthesis of bcvrxcenes
Oxidation of the 1-benzyltetrahydroisoquinoline(195) with VOCl, (145)

yielded the dienone (196) in 34% yield; reaction of this with boron trifluoride
etherate provided 197, and this was converted, as shown in Scheme 41, to
14-methoxyerysodienone (199). Oxidation of the secondary amine (200) gave
(146)the methoxyerysodienone (201) in only 6% yield. The alternative mode
of oxidation, leading to 202, was not observed.
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.
A photochemical method has been employed by Ito and Tanaka (147) to

synthesize erybidine (62) (Scheme 42). Irradiation of the bromoamide (203)
gave a mixture of lactams 204 and 205. After chromatographic separation,
the former was reduced and N-methylated to erybidine.
Alkaloids of the erythroidine type have not yet been synthesized, but the
parent ring system has been obtained (148) by the method summarized in
Scheme 43.
1. E R YTHRI.CA A N D RELATED ALKALOIDS 71
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.
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%);
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
SCHEME bF ozridarice coupling

44. Preparatiori of’ a honioer~.rl~ritia
these were separated by preparative thin layer chromatography. Sometime

previously, Kametani and Fukumoto (150) described the oxidation of 206
(R = H) with potassium ferricyanide and assigned structure 210 to the
product, but later they (151)altered this to 209.
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
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
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
followed by that of Semmelhack et al. (157-159) by a very different route.

The former method can be conveniently divided into two stages, with the
tricyclic enamine (225) as the first target; the route adopted is summarized
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
in Scheme 46. Acylation of 1-prolinol (221) with 3,4-methylenedioxyphen-

acetyl chloride (220) at - 20" in acetonitrile solution gave the N-acylated
compound (222), with only minor amounts of the 0-N-diacyl derivative.
Oxidation of 222 to 223 was effected with dimethyl sulfoxide, dicyclohexyl-
carbodiimide, and dichloracetic acid. Cyclization of 223 to the tricyclic amide
(224) was achieved using boron trifluoride etherate. The required enamine
(225) was obtained in quantitative yield by reducing 224 with lithium
aluminium hydride.
The second phaseof the synthesis by Auerbach and Weinreb wasconcerned
with the construction of ring D. This proved to be rather difficult and initial
attempts failed. Thus, alkylation of 225 with propargyl bromide gave 226,
which upon hydration with aqueous mercuric sulfate yielded the expected
ketone 227. However, all attempts to cyclize 227 failed. In a modified
225
(9
(90
226 Me0 C0,Et
I 228
0A C H ,
227
approach, 225 was alkylated with 4-bromo-3-methoxycrotonate, but again

the alkylated material (228) could not be cyclized. The a-dicarbonyl com-
pound (230)was prepared (Scheme 47) by acylating 225 with a 2-acetoxypro-
pionyl chloride in acetonitrile to give 229, which, after hydrolysis with
potassium carbonate, was oxidized to 230 with lead dioxide. In a better
procedure, wherein 230 was obtained directly in 73% yield, the tricyclic
enamine (225) was treated with the mixed anhydride obtained from the
interaction of pyruvic acid with ethyl chloroformate. An intramolecular
Michael addition was achieved by treating 230 with magnesium methoxide,
(yq-&-<W
0 0
AcO
P- 0
&Me
229 230
52“,
I Mg(OMe),
231 112 Cephalotaxinone

47. Auerharh and Weinreb‘s synthesis of rrp/ialora\-ine.
SCHEME
leading to demethylcephalotaxinone (113). A study of the N MR spectrum

revealed that none of the tautomer (231) was present. Demethylcephalotaxi-
none has been isolated from C. harringtonia ( I l l ) , and the synthetic product
was found to be identical to the natural product. However, when 113 was
heated under reflux with an excess of 2,2-dimethoxypropane in methanol/
dioxan, cephalotaxinone (112) was formed and isolated in 40% yield. Finally,
reduction of 112 with sodium borohydride proceeded in a stereospecific
fashion to give racemic cephalotaxine (105a).
An alternative route (Scheme 48) was used by Dolby et al. (160)to prepare
the tricyclic enamine (225).A Vilsmejer reaction between 3,4-methylenedioxy-
N,N-dimethylbenzamide (232),and pyrrole gave the amide (233)in 80% yield.
Reduction with sodium borohydride provided the benzyl pyrrole (234),which
232 233
235 234
236 231
lLAH
238
SCHEME
48. Dolbj's preparation o/ enaminc2 225.
was further reduced to 235 catalytically over a rhodium-alumina catalyst.

N-Acylation with chloroacetyl chloride gave 236 which on irradiation was
cyclized to the tricyclic amide (237). Reduction with 1ithiu.m aluminium
hydride yielded the saturated amine (238), and this was converted to the
required enamine (225)by treatment with mercuric acetate. A chelating ion-
exchange resin was used to remove excess of mercuric acetate-a procedure
superior to precipitation of the sulfide with hydrogen sulfide. Attempted
annulation of 225 with ethyl x-bromoacetoacetate led to the rearranged
tetracyclic compound 239 (R = C0,Et) and not to the expected product
(240). Hydrolysis and decarboxylation of 239 (R = C0,Et) gave the ketone
(239, R = H) which on further reduction yielded the amine (241). identical
to the material prepared some years ago (161) by an independent route.
240
239 241
Alkylation of 225 with bromoacetone (160)gave the expected product 227,

but attempts to cyclize this material gave the rearranged compound 239
(R = H) once more. It was postulated by Dolby et al. that the initially formed
product was the desired compound 240 which then rearranged to the
observed product 239 (R = C0,Et) by the mechanism summarized in Scheme
49.
0
I1
BrCH,~-C--CH,CO,El
225 f 240
I
0 0
239
R = C0,Et
49. Dolby's mec~huiiisnt.fbr reurraizgeimwt of' 240

SCHEME to 239.
1. ER )ITHRI.VA AND RELATED ALKALOIDS 81
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
presence of silver trifluoroacetate at the 6-position, then treatment with

methyl magnesium iodide, followed by dehydration gave 246. A 40% yield
of 247 was obtained on irradiation of the alkene 246, and reduction then
gave 238.
The second total synthesis of cephalotaxine (157-159) was very different
conceptually since it was a convergent synthesis involving the two interme-
diates 248 and 249. The azabicyclic intermediate (248) was prepared from
pyrrolidone (250) (Scheme 52), which with the Meerwein reagent gave 251.
The latter was treated with an excess of ally1 Grignard reagent to yield 252.
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
52 Seriimelhach's synthesis of cephalota.uine

SCHEME
1. ER Y T H R I N A AND RELATED ALKALOIDS 83
N-Acylation with tert-butoxycarbonyl azide to 253 was followed by oxidative

ozonolysis and esterification to 254. The yield of 254 from 252 was 61% in
a procedure whereby the intermediates were not isolated. The diester (254)
was subjected to the acyloin condensation with a potassium-sodium alloy
and the product was isolated as the O,O,N-trisilyl compound (255). This was
oxidized immediately with bromine to 256 and treatment with diazomethane
gave 248. The yield of 248 from 254 was 55%. Intermediates 249a and 249b
were obtained from piperonal by standard methods.
The essential intermediate 257 required for ring closure to the cephalotaxus
skeleton was obtained (about 60% yield) by combining 248 and 249 in
acetonitrile solution. A number of methods of cyclization of 257 was studied
(Scheme 53). In the first approach 257a was treated with sodium triphenyl-
methide, when a 13-16% yield of cephalotaxinone (112) could be isolated
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
55. S.vnthetic proof of structure of deoxyharringtonine.

SCHEME
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.
reduction and hydrolysis, yielded the cc-ketoacid (276). Conversion of 276

to the acid chloride followed by reaction with cephalotaxine provided the
ester (277). Deoxyharringtonine (110)was produced when 277 was condensed
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
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
Hydration of the double bond of 288 gave 289, on which a Reformatski

reaction was performed to yield harringtonine (107) together with epiharring-
tonine (because of the two modes of hydration of the double bond in 288)
(Scheme 59). The required ester (283) was prepared by first condensing iso-
butyraldehyde with malonic acid to form 290, followed by isomerizing with
0
I1
CHCH2C02Et
(CO,Et),
NaH ’ CHCHCC0,Et
) I
C02Et
283 284
286 285
LCO*Me
107
SCHEME
59. S?;nthesis of harringronine
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
In the structural analysis of isoharringtonine (109),the relative configura-

tion of the diacid side chain was solved (172) by a synthesis (Scheme 60).
_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
Trans-esterification of the alkaloid with sodium methoxide gave a single

dimethyl ester which possessed either the threo (298) or the erythro
configuration (296). Ethyl isoamylacetoacetate (292) was converted to 293
by a method developed by Vaughn and Anderson (173). Esterification of
293 gave the trans-dimethyl ester (297) which, with osmium tetroxide and
hydrogen peroxide, yielded the single diol (298). This was assigned the
threo configuration, in view of the known cis-hydroxylation achieved by
osmium tetroxide. In an alternative sequence, the diacid (293)was dehydrated
with P,O, to the anhydride (294), which in turn was esterified to the cis-
diester (295). The vinyl proton absorption at 6 5.85 for 295 compares with
the value of 6 6.8 for the trans structure (297). Cis-hydroxylation of the
cis-diester (295) yielded the erythro compound (296). The PMR spectrum
of 296 was found to be identical with that of the diol diester derived from
isoharringtonine.
The absolute configuration of the side chain of isoharringtonine has been
deduced (174)to be 2R,3S(299)by comparing the C D spectra of its molybdate
complexes with those of piscidic acid (300)of known absolute configuration.
CO,H COzH
299 300
An alternative synthesis of 295 involves (175)the addition of diisoamyl-

lithium cuprate to dimethylacetylene dicarboxylate. The major product (89%)
was the required 295 together with some 297. The mixture was separated by
chromatography.
VII. Pharmacology
Many Erythrina alkaloids possess curare-like action. Alkaloidal extracts

from different parts of Erythrina species have been used in indigenous
medicine, particularly in India ( 176).Many pharmacological effects, includ-
ing astringent, sedative, hypotensive, neuromuscular blocking, CNS depres-
sant, laxative, and diuretic properties, have been recorded for total alkaloid
extracts, although not all these properties can be associated with the ery-
thrinane structure alone (38, 177, I78).
A few purified Erythrina alkaloids have been shown to have useful pharma-
cological properties. Cocculine (56) and cocculidine (54) nitrates have been
reported to show hypotensive action in dogs, due mainly to ganglionic

blocking action. Neither alkaloid had a significant effect on the CNS (179).
Isococculidine (37)was shown to be a weak blocking agent at the cholinergic
receptor in frogs (180).The juice of the leaf and bark of E. suberosa Roxb.
was reported to have antitumor activity and the major alkaloid isolated was
erysotrine (1)(181).Erysotrine was found to exhibit properties consistent with
those of a competitive neuromuscular blocking agent in anaesthetized dogs
(182). Cocculolidine (61) was reported to be an insecticidal alkaloid (76).
Analogs of Erythrina alkaloids that lack the aromatic ring have been pre-
pared for structure-activity studies (183).
Antitumor activity in P388 and L1210 experimental leukemia systems was
detected in extracts from the seeds of C. harringtonia K. Koch var. harring-
tonia (8,95).It was soon discovered that the major component, cephalotaxine
(105a), was inactive and that the activity resided in the esters 107-110 (the
harringtonines) ( 184187).
Harringtonine (107) and homoharringtonine (108) had about the same
activity in the P388 system and both were more active than deoxyharring-
tonine (110) and isoharringtonine (109).The latter two were only marginally
active in the L1210 system (8).The optimum dose (for mice) was in the range
2-12 mg/kg by intraperitoneal injection over a period of 9 days (186, 187).
Harringtonine appears to be the most effective agent and recent studies in
the People’s Republic of China have shown that it is effective against L615
leukemia, L7212 leukemia, sarcoma 180, and Walker carcinosarcoma 256
(188).Harringtonine also appeared to be effective in the treatment of acute
and chronic myelocytic leukemia in humans (189).
The mode of action of the harringtonines has been investigated. All
inhibit protein synthesis in eukaryotic cells (190-192). The principal effect
of harringtonine was inhibition of protein biosynthesis in HeLa cells (193).
Homoharringtonine, a potential antineoplastic alkaloid ( 194, was cytotoxic
in HeLa, KB, and L cells growing in monolayer cell cultures (194).
In view of the difficulty in obtaining a sufficient supply of the active esters
for biological screening, considerable effort has been applied to the problem
of preparing the esters from the more readily available cephalotaxine (105a)
(see Section V1,C). This effort has also resulted in the preparation of many
analogs containing ester groups that do not occur in the natural alkaloids
and that have been used to obtain structure-activity relationships (168, 171,
195). Although some degree of structural variation must be tolerated, since
homo-, iso-, and deoxyharringtonine show activity, most of the synthetic
esters were found to be inactive (195).From a large number of cephalotaxine
esters, the only synthetic ones to show significant activity in the P388 systems
are those having the side-chain structures 301-304 (196).There appears to
be little rationality in the structure-activity relationship.
1. E R Y T H R l N A AND RELATED ALKALOIDS 93
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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CHAPTER2-
THE CHEMISTRY OF C... DITERPENOID ALKALOIDS

S . WILLIAM V . MODY
AND NARESH
PELLETIER
Institute f o r Naturul Products Research and Department of Chemistry.
University of Georgia. Athens. Georgia
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
THE ALKALOIDS. VOL. X V I l l

Copyright @ 1981 by Academic Press. Inc.
All rights of reproduction in any farm reserved.
ISBN 0 12 469518 3
100 S . WILLIAM PELLETIER AND NARESH V. MODY
VIII. Synthetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

A. Total Synthesis of Optically Active Veatchine. . . . . . . . . . . . . . . . . . . . . . . . . . I68
B. Total Synthesis of Napelline . . . . . . . . . . . . . . . . .
C. Construction of the Denudatine Skeleton. . . . . .
D. A Synthetic Approach to Ajaconine and Atidine.. . . . . . . . . . . . . . . . . . . . . . . 179
E. Intermediates for the Veatchine- and Atisine-Type Alkaloids. . . . . .
F. Construction, Degradation. and Selective Reduction of the Oxazolidine
Ring of C,,-Diterpenoid Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
IX. A Catalog of C,,-D kaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
References . . . . . . . . ........................................ 211
I. Introduction
The diterpenoid alkaloids, isolated mainly from Aconitum and Delphinium

species (Ranunculaceae), have been of great interest since the early 1800s
because of their pharmacological properties. Extracts of Aconitum species
were used in ancient times for treatment of gout, hypertension, neuralgia,
rheumatism, and even toothache. Extracts have also been used as arrow
poisons. Some Delphinium species are extremely toxic and constitute a serious
threat to livestock in the western United States and Canada. Delphinium
extractsalso manifest insecticidal properties. In the last 30 to 40 years, interest
in the diterpenoid alkaloids has increased because of the complex structures
and interesting chemistry involved.
The diterpenoid alkaloids may be divided into two broad categories : those
based on a hexacyclic C,,-skeleton and those based on a C,,-skeleton. The
highly toxic C, ,-diterpenoid alkaloids, commonly known as aconitines, have
been reviewed ( I ) in Volume XVII of this treatise. The C,,-diterpenoid
alkaloids contain three basic skeletons : Atisine-type (i), Veatchine-type (ii),
and Delnudine-type (iii). The atisine skeleton incorporates an ent-atisane
nucleus and does not obey the isoprene rule. The veatchine skeleton, which
occurs in the Garrya alkaloids, is modeled on an ent-kaurane nucleus and
obeys the isoprene rule. It differs from the atisine skeleton in that ring D is
five- rather than six-membered. Biogenetically, these alkaloids are probably
derived from tetracyclic or pentacyclic diterpenes in which the nitrogen atom
of methylamine, ethylamine, or P-aminoethanol is linked to C-19 and C-20
in the diterpenoid skeleton to form a substituted piperidine ring. There have
been no detailed biogenetic studies on these alkaloids. The delnudine skeleton
is an interesting curiosity in that it is difficult to explain how delnudine is
derived from an atisine skeleton or from a pimaric acid skeleton.
Recently, a new class of diterpenoid alkaloids, known as bisditerpenoid
alkaloids, has been isolated from the seeds of Delphinium staphisagria (2).
The bisditerpenoid alkaloids (e.g., staphisine, iv) may be formally derived by
2. THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS 101
( i ) Atisine skeleton (ii) Veatchine skeleton
(iii) Delnudine
attachment of two different molecules of C,,-diterpenoid alkaloids at the

C-16 position.
y 3
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.
11. Veatchine-Type Alkaloids
The veatchine-type alkaloids are also known as the Garrya alkaloids

because they were first isolated from Garrya species. In 1946, Oneto reported
(22)the isolation of two isomeric crystalline alkaloids, veatchine and garry-
ine, from the bark of Garrya veatchii Kellogg. Later, Karel Wiesner and
co-workers at New Brunswick initiated work on the structure elucidation of
veatchine and garryine and pointed out the striking similarity between the
chemistry of atisine and veatchine. They elucidated the structures of veat-
chine and garryine, and their results greatly assisted progress in the structure
elucidation of both veatchine- and atisine-type alkaloids. Since structures of
the veatchine-type alkaloids were first to be completed, their chemistry will
be reviewed first.
A. VEATCHINE
AND GARRYINE
Veatchine, the major alkaloid of G. veatcliii Kellogg, is a strong tertiary

base (pK, 11S)that undergoes a facile isomerization of the oxazolidine ring
to garryine (pK, 8.7) by treatment with base or even by simple refluxing in
methanol. Veatchine forms the ternary immonium salt known as veatchinium
chloride by treatment with hydrochloric acid and may be regenerated from
veatchinium chloride by treatment with cold base. On the basis of chemical
and degradation studies, Wiesner and co-workers elegantly established (23,
24) the structures of veatchine and garryine as l b and 2, respectively. Early
work on the chemistry of veatchine and garryine has been reviewed by
Wiesner and Valenta (12),and later by Pelletier and Keith (6,8).
The stereochemistry of the normal-type oxazolidine ring in veatchine,
atisine, and other related alkaloids was ill-defined in the literature (2j),
2. THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS 103
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
1 Veatchine 3 Vedtchinium chloride
These findings were confirmed (29,30)by demonstrating the coexistence

of C-20 epimers in the same crystal of veatchine by a single-crystal X-ray
analysis. Crystallization of two epimers in a disordered relationship is a
highly unusual observation. Even though veatchine exists as a mixture of
epimers, separation of these epimers would be extremely difficult because

veatchine is not particularly stable in hydroxylic solvents such as methanol
(see Section V). Because of the inconvenience of presenting two structures
each time veatchine is referred to, structure 1 will be used to represent both
epimers l a and l b .
4 Atisine 5 Atisinium chloride
Veatchine has been chemically related to atisine (4) by conversion to a

common intermediate (34,and the absolute configuration of atisine has been
established by a single-crystal X-ray analysis of atisinium chloride (30) (5).
Therefore, the absolute configuration of veatchine is assigned as 4S, 5S, 8R,
9S, 10R, 13R, 15R, and 20SR. The designation of the absolute configuration
of C-20 as “SR” was chosen to indicate that, in any given sample of
veatchine, both epimers exist and that the 20s (ex0 configuration of the
oxazolidine ring) epimer predominates.
The 3C-NMR spectrum of garryine (2)exhibits (28)only one set of signals
for the oxazolidine ring carbons, the piperidine ring carbons, and the C-4
methyl group, a fact which indicates that garryine does not exist as a pair
of C-19 epimers. During recent work on the isolation of veatchine from the
bark of G. veatchii (32), the presence of garryine was not detected. This
observation suggests that veatchine may have isomerized to garryine during
the earlier isolation work and that garryine may be an artifact.
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
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
Mild hydrolysis of ovatine at room temperature gave the known alkaloid

garryfoline, a fact which indicates that the acetoxyl group is present at C-15
in ovatine. Garryfoline afforded the unusual immonium salt (9) instead of
ovatine on treatment with acetic anhydride and pyridine at room tempera-
ture. Treatment of ovatine with acetic anhydride and pyridine also gave 9
106 S. WILLIAM PELLETIER AND NARESH V . MODY
in quantitative yield. Garryfoline was converted to ovatine via lindheimerine

(7) in two steps. Refluxing 9 in chloroform yielded lindheimerine (7) in 90%
yield. Treatment of 7 with ethylene oxide in acetic acid gave ovatine in almost
quantitative yield. Thus, the structures of ovatine and garryfoline can be
represented as an epimeric mixture at C-20 of 6a and 6b for ovatine and 8a
and 8b for garryfoline, with the a epimer predominating.
Structure 7 was assigned to the minor alkaloid, lindheimerine, from
spectral data. The ‘H- and I3C-NMR spectra revealed the presence of one
acetoxyl group, a C-4 methyl group, an exocyclic double bond, and a C-20
imine group on a veatchine-type skeleton. Comparison of the 13C-NMR
spectrum of lindheimerine with that of veatchine azomethine acetate (10) gave
evidence for the presence of the C-15 6-acetoxyl group in lindheimerine. The
structure of lindheimerine (7)was confirmed by comparison with the degrada-
tion product of compound 9, which was identical with lindheimerine.
Lindheimerine occurs in extremely small quantity by comparison with
ovatine. Since these two alkaloids are closely related chemically, we suggest
that lindheimerine may be a biogenetic precursor of ovatine. These alkaloids
did not exhibit any antitumor activity in uiuo or in uitro.
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
atisine. To establish the stereochemistry of the C-16 methyl group in cuau-

chichicine by I3C-NMR spectral analysis, a pair of stable C-16 epimers was
prepared. Cuauchichicine was heated at reflux in methanol to afford isocuau-
chichicine (16) in quantitative yield. During this rearrangement the C-16
methyl group did not epimerize. Heating of cuauchichicine o r isocuauchi-
chicine in a methanolic solution of 2% sodium hydroxide at reflux gave a
mixture of (2-16 methyl epimers of isocuauchichicine. These epimers were
separated by chromatography over alumina using hexane and benzene as
the eluting system to yield pure samples of isocuauchichicine (16) and epi-
isocuauchichicine (17).Comparison of molecular models of 16 and its epimer
17 revealed that the methyl group at C-16 is partially crowded in the p-
position in contrast to the @-position.Steric compression would be expected
to cause the p-methyl group to appear at higher field in the I3C-NMR
spectrum than the r-methyl group. Accordingly, the signal a t 10.1 ppm was
assigned to the p-methyl group in 16, and the signal at 15.9 ppm was assigned
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
In 1955, Djerassi and co-workers reported (34) that the treatment of

garryfoline (8) with dilute mineral acid at room temperature results in rapid
isomerization to cuauchichicine (15). A similar rearrangement has been also
observed in atisine, kobusine, napelline, and other terpenoids containing a
methylene group at C-16 and a C-15 P-hydroxyl group. In contrast to the
facile rearrangement of garryfoline, the C-15 epimer, veatchine (1), is stable
even when heated in dilute hydrochloric acid. To explain the striking dif-
ference in the behavior of these two epimers toward acid treatment, a non-
classical structure for the intermediate carbonium ion has been suggested
(12).
Barnes and MacMillan reported (37)an investigation of this rearrangement
using the epimeric (-)-kaur-16-en-l5-01~ as models. The 158-01 (20) rear-
ranged rapidly to 16-(-)-kaur-l5-one (21) in mineral acid at room tempera-
ture whereas the 15a-01(22)was stable under these conditions. The English
workers proposed a 15 + 16 hydride-shift mechanism on the basis of the
20 R = H 21 R = H 22
23 R = D 24 R = D
rearrangement of [15-~]-(-)-kaur-l6-en-15P-ol (23) to (16R)-[16-~]-(-)-

kaur-15-one (24) in hydrochloric acid. Later work by the same group, how-
ever, demonstrated (38)that compound 24 exchanges deuterium at C-16 with
hydrogen in dilute acid with complete retention of configuration to give 21.
Pelletier, Desai, and Mody prepared (39)several deuterated derivatives of
garryfoline and cuauchichicine and studied the mechanism by I3C-NMR
spectroscopy. Deuterated (C- 15) dihydrogarryfoline diacetate (26) was pre-
pared from veatchinone (25) in three steps. Compound 26 in 10% HCl at
25
28 26 R' = OAc; R 2 = D Major

27 R' = D; RL = OAc Minor
29 32 D'
31 30 33
SCHEME
1
room temperature rearranged to 28, a compound which showed no deuterium

incorporation at C-16 on the basis of 13C-NMR spectral analysis. These
results indicated that the C-15 deuterium did not shift to C-16 during the
rearrangement and therefore the garryfoline-cuauchichicine rearrangement
does not take place via a 15 -+ 16 hydride-shift mechanism.
Treatment of isogarryfoline (29) with 10% DCI in D,O at room tempera-
ture followed by treatment with base, afforded deuterated isocuauchichicine
(30) in quantitative yield. Analysis of the I3C-NMRspectrum of 30 revealed
the presence of deuterium at C-16 and C-17. In dilute hydrochloric acid no
exchange of deuterium by hydrogen in compound 30 was detected in 24 hr,
but after 96 hr, exchange was observed to give compound 31. On the basis
of these results, the mechanism outlined in Scheme 1 was suggested. The
mechanism involving the enol accounts for incorporation of deuterium at
C-16 and C-17 and also explains the C-16 a-D, /3-CH2D stereochemistry
observed. During ketonization of the enol 32, transfer of D + would be
expected to occur from the less-hindered exo side of the molecule to give
compound 33 containing the C-16 a-D and C-16 P-CH,D groups. These
results demonstrated (39) that a 15 + 16 hydride shift is not involved but
rather a mechanism involving formation of an enol followed by exo-
pro tonation.
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
reported an elegant total synthesis of napelline and thus confirmed its

structure. The synthesis of napelline is discussed in Section VII1,B.
Treatment of napelline with dilute mineral acid results in rapid isomeriza-
tion to isonapelline (42,43). The structure of isonapelline was represented
as 36 with undetermined stereochemistry at C- 16. Recently, we established
the stereochemistry of the C-16 methyl group in the related alkaloid, cuau-
chichicine, an acid-catalyzed rearrangement product of garryfoline. By
analogy, the acid-catalyzed rearrangement of napelline to isonapelline should
result in a C-16 P-methyl group in isonapelline. Thus structure 37 can be
assigned to isonapelline.
Lucidusculine was first isolated in 1931 by Japanese chemists (50, 51) from
the roots of A . lucidusculurn Nakai, which is also known as A . yesoense var.
Structural work on this alkaloid was carried out by Suginome and co-workers
(52-57) from 1950to 1961.The structure of lucidusculine (35)was established
in 1965 by a Japanese group by X-ray crystal analysis of its hydriodide
(48, 49). Basic hydrolysis of lucidusculine afforded the parent alkamine
known as luciculine. The latter was found to be the same as napelline. The
X-ray crystal structure of lucidusculine provided a basic foundation for
elucidating the structures of related alkaloids, e.g., napelline, songorine,
songoramine. The chemistry of lucidusculine has been reviewed in detail
earlier by Stern ( 4 , 5 ) and later in Volume XI1 of this treatise (6).
12-Acetylnapelline has been isolated by Soviet chemists (58, 59) from the
epigeal parts of A . karakolicum collected in the upper reaches of the R. Tyup
(Kirghiz S.S.R.) during the budding period. Chemical transformations and
mass spectral analyses of 12-acetylnapelline and its derivatives have led to
the assignment of structure 38.
Alkaline hydrolysis of 12-acetylnapelline (38) yielded an amino alcohol
identical to napelline (34). This result indicated that the new alkaloid was
napelline monoacetate. Treatment of 12-acetylnapelline with acetic anhy-
dride and pyridine gave the triacetate 39. The latter was selectively hydrolyzed
by alkali to afford l-acetylnapelline (40). Oxidation of 38 with silver oxide
yielded dehydro derivative 41, a result that revealed the presence of an a-
hydroxy group at C-1 in 38. Hydrogenation of 12-acetylnapelline over a
114 S. WILLIAM PELLETIER A N D NARESH V. MODY
0Ac OR
38 12-Acetylnapelline 39 R = AC
40 R = H
OAc 0Ac
41 42
platinum catalyst afforded dihydroacetylnapelline (42). Formation of iso-

acetylnapelline (43)from 38 indicated that the hydroxy group at C-15 is not
acetylated. On the basis of these chemical transformations, structure 38
was assigned to 12-acetylnapelline.
In the earlier papers (58, 59) on the structure of 12-acetylnapelline, the
choice between attachment of the acetyl group at position 12 or 15 was made
on the basis of the mass spectral data of 12-acetylnapelline, l-acetylnapelline,
and triacetylnapelline. The detailed mass spectral analysis of 12-acetylnapel-
line and its derivatives is discussed in Section VII.
F. SONGORINE OR SHIMOBURO
(NAPELLONINE BASEI), NORSONGORINE,
SONGORINE
N-OXIDE,AND SONGORAMINE
Songorine (44)was isolated as the major alkaloid of A . soongoricum Stapf

by Yunsov (60) in 1948. This alkaloid was also found (61) in a Japanese
Aconitum variety ( A . japonicum var.) and was provisionally named
“Shimoburo Base 1.” Recently, Soviet workers reported the occurrence of
songorine in the epigeal parts and tubers of A. karakolicurn (41,59, 58, 62)
and the roots of A . monticola (63).The structure of songorine was intensively
investigated by Canadian (42, 43), Japanese (46, 47), and Soviet (44, 45, 60,
64) groups between 1950 and 1960. Finally, in 1961, Sugasawa (47)proposed
the correct structure of songorine. Later, in 1965, the structure of songorine
(44) was confirmed (48)by direct comparison of its lithium aluminum hydride
reduction product with napelline (34).The chemical work on songorine has

been reviewed in detail by Pelletier and Keith (6) in Volume XI1 of this
treatise.
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
In 1974, Soviet researchers reported (63)the isolation of “norsongorine”

(45), a known derivative of songorine, from the roots of A . monticolu. No
physical properies or spectral data for norsongorine were reported by the
authors.
Recently, songorine N-oxide (46) has been isolated (65)for the first time
from A . monticola collected in the Dzhungarian Ala-Tau on the Kuyandysai
River. The structure of songorine N-oxide was elucidated from the ‘H-NMR
and mass spectral data and on the basis of reduction of 46 to songorine (44)
by zinc and 10% hydrochloric acid at room temperature.
In 1970, Yunusov and co-workers reported (62)the isolation and structure
elucidation of a new alkaloid, songoramine (47), from the tubers of A .
karakolicum, collected in the upper reaches of the Tyup River (Terskei Ala-
2
,,
,&CH2 , .T..
I
C H .+---.N
5 ,
,
4..:.:
,
,
CH3
47 Songoramine
.
,
- -H
OH
&
C2 H 5 ... ..N
”
*, .
,,~ .
CH,
48
,’
--H
OH
‘H
H3
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
54 to the azomethine iodide 53, the conversion of the azomethine iodide to

anopteryl alcohol was attempted. Reaction of the azomethine iodide with
aqueous ammonia or sodium bicarbonate yielded the C-19 epimers (5: 1) of
compound 55. Alkaline hydrolysis of 55 gave a major product containing the
carbinolamine ether linkage having either structure 56 or 57. Interestingly,
the hydrolysis product (56 or 57) of compound 55 can not be reduced to
anopteryl alcohol by treatment with sodium borohydride. On acetylation
with acetic anhydride and pyridine followed by the usual work-up, the
carbinolamine ether (56 or 57) gave back the epimeric alcohol 55. However,
reduction of the azomethine iodide (53) with cold sodium borohydride gave
tetraacetylanopteryl alcohol (54). The latter on alkaline hydrolysis afforded
anopteryl alcohol in good yield. Thus, conversion of 53 to anopteryl alcohol
55 56
(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- ,
... .......
H C... ..N H,C------N OH

2
CH, CH, O A c
58 59
Oxidation of anopteryl alcohol with alkaline potassium ferricyanide

yielded the carbinolamine ether (56 or 57) as a minor product (8%) and
compound 58 as the major product. The structure of 58 was elucidated by
an X-ray crystal analysis. Compound 58 was isolated from the oxidation
reaction mixture only after acetylating the mixture, from which the car-
binolamine ether was first removed, and then hydrolyzing the acetylated
product. Acetylation of compound 58 gave triacetyl derivative 59, in which
the epoxide ring was opened.
Treatment of anopteryl alcohol with acetic anhydride and pyridine at 100"
for 4 hr or longer gave tetraacetylanopteryl alcohol (54) in high yield. Less
drastic acetylation conditions gave a mixture of compound 54, triacetyl
derivatives 60 and 61, and diacetylanopteryl alcohol 62. The structures of
these acetylated derivatives were based on 'H-NMR data.
The presence of two tigloyl groups at C-1 1 and C-12 in anopterine was
established on the basis of oxidation products of anopterine and anopteryl
alcohol. Oxidation of anopterine with chromic acid in pyridine gave a
diketone ditiglate, which on alkaline hydrolysis afforded the diketone 63. On
the basis of the 'H-NMR spectra of the diketone 63 and its diacetate de-
rivative 64,the authors established that the carbonyl group was not present
at either C-1 1 or C-12 in 63. These results indicated that two tigloyl groups
were present at C-1 1 and C-12 in anopterine.
2. THE CHEMISTRY OF C,-,-DITERPENOID ALKALOIDS 119
OAc &CHz OR
" ... .......,

R'O.. 0
H,C------N OH
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
Oxidation of anopterine with Jones reagent followed by alkaline hydrolysis

afforded a monoketone, which was assigned probable structure 65. Reduc-
tion of the monoketone with sodium borohydride in methanol at room
temperature gave a 4:1 mixture of two products, with anopteryl alcohol as
the major product. Oxidation of anopteryl alcohol with Jones reagent yielded
a yellow triketone and a diketone. The latter was not identical with the
diketone 63. Structure 66 was assigned to the yellow triketone. Partial
structure 67 was assigned to the diketone that was obtained from Jones
oxidation of anopteryl alcohol. Further oxidation of 63 with chromic acid
by the Jones method gave the yellow tetraketone 68.
67 68
On treatment with acetic anhydride in pyridine, the yellow tetraketone

(68), the yellow triketone (66), and the diketone (67) afforded monoacetyl,
diacetyl, and triacetyl derivatives, respectively. All these derivatives con-
tained a tertiary acetoxyl group. However, comparisons of 'H-NMR spectra
of the parent ketones with those of the acetyl derivatives indicated that a
rearrangement of the molecule or a major conformational change must have
occurred. On the basis of extensive 'H-NMR spectral analysis, structure 69
was proposed for the diacetyl derivative which was derived from the triketone
66. Structure 69 was justified on the basis of conformational arguments.
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.
70 Anopterimine 71 Anopterimine N-oxide
During the isolation of anopterine, the Australian chemists isolated a new

alkaloid, hydroxyanopterine, from the bark and leaves of A . macleayanus
and A . glandulosus. A closely related new alkaloid, dihydroxyanopterine,
was also encountered as a minor component in the bark of A. macleayanus.
’
Comparison of the ‘H- and 3C-NMR spectral data of hydroxyanopterine
and dihydroxyanopterine with those of anopterine afforded evidence for
the partial structures 72 and 73 for hydroxyanopterine and dihydroxy-
anopterine, respectively. Each of these alkaloids has a hydroxyl group at
C-1 or C-3 on the A ring. On the basis of the 13C-NMR assignments. the
presence of the additional skeletal hydroxyl substituent was preferred at
the C- 1 position. The presence of another hydroxyl group in an acid moiety
of dihydroxyanopterine was confirmed by hydrolysis. Alkaline hydrolysis
of hydroxyanopterine and dihydroxyanopterine gave the identical amino
alcohol, a result which confirmed that the second hydroxyl group in dihy-
droxyanopterine was a part of a new hydroxytiglic acid moiety. A biosyn-
thetic pathway for the Anopterus alkaloids has been proposed involving a
hetisine-type precursor.
CH, OH
72 Hydroxyanopterine 73 Dihydroxyanopterine
111. Atishe-Type Alkaloids
A. ATISINE
AND ISOATISINE
Atisine, the principal alkaloid of the rhizomes of A . heterophyllum Wall,

has been the subject of extensive study since 1942 because of its interesting
chemical features and complex structure (72). In 1954, Wiesner and co-
workers (72)proposed a gross structure for atisine and subsequently Pelletier
and Jacobs (73) supported this structure independently. Later, the structure
of atisine as 74 was confirmed by two total syntheses (74, 75). Recently,
atisine has been isolated from A . heterophylloides (76),A . gigas Ler. et Van.
(77)and A . antharu (16).Atisine is an amorphous strong base (pK, 12.5) that
undergoes a facile isomerization of the oxazolidine ring to isoatisine (75)
(pK, 10.3) by treatment with alkali or even by simple refluxing in methanol.
Atisine and isoatisine form the corresponding quaternary immonium salts
5 and 76, respectively, by treatment with hydrochloric acid. Atisine and
isoatisine can be regenerated from the corresponding immonium salts by
treatment with base. Atisinium chloride (5) is more stable in refluxing polar
solvents than isoatisinium chloride (76). One can quantitatively isomerize
isoatisinium chloride to atisinium chloride by refluxing in DMSO, DMF,
or high-boiling alcohols. Thus, depending on reaction conditions, atisine,
and isoatisine can be interconverted easily.
The stereochemistry of the oxazolidine ring of atisine has been of great
interest for a long time. In 1968, Pelletier and Oeltmann (78) postulated on
5 Atisinium Chloride 76 Isoatisinium Chloride

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.
77a 77b 4 Atisine
y
' CH, ' CH, CH,
4a 4b
The structure of atisinium chloride as 5 was confirmed recently by a

single-crystal X-ray analysis (30). The absolute configuration of atisinium
chloride was determined as 4S, 5S, 8R, 10R, 12R, and 1 5 s by Hamilton's
method and confirmed by examination of sensitive Friedel pairs. A recent
X-ray crystallographic study of isoatisine confirmed the assigned structure
75. The absolute configuration was established as 4S, 5S, 8R,10R, 12R, 15S,
and 19s for isoatisine. It is worth noting that isoatisine does not exist as a
mixture of C - 19 epimers. Early work on the chemistry of atisine and isoatisine
has been described in detail in several reviews (6, 8, 13) published between
1960 and 1970.
B. DIHYDROATISINE
AND ATIDINE
Dihydroatisine, a minor alkaloid of the roots of A . heterophyllum Wall,

was isolated (80) from the strong base fraction and its structure (78) was
established by comparison with the sodium borohydride reduction product
of atisine or isoatisine. Recently, an X-ray analysis of dihydroatisine con-
firmed (30)its structure and determined the absolute configuration as 4S, 5S,
8R, 10R, 12R, and 15s. So far dihydroatisine has not been reported in any
other plant.
78 Dihydroatisine 79 Atidine
The isolation and structure elucidation of atidine (79), a minor alkaloid

of the roots of A . heterophyllum Wall, was reported in 1965 (81).Atidine was
chemically correlated with dihydroatisine (78) and dihydroajaconine, a
reduction product of ajaconine (80).Reduction of atidine with sodium boro-
hydride in 80% methanol afforded dihydroatidine, which was identical to
dihydroajaconine. Huang-Minlon reduction of atidine furnished dihydro-
atisine. A I3C-NMR analysis of various C,,-diterpenoid alkaloids estab-
lished (28) that the carbonyl group in atidine is present at C-7. Recentiy, the
structure of atidine as 79 was confirmed by a single-crystal X-ray analysis
(82). It is worth noting that there are intermolecular hydrogen bonds between
the hydrogen of the C-22 OH group and oxygen of the C-7 group and between
the hydrogen of C-15 OH and oxygen of C-22 in crystalline 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.
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
In 1978, dihydroajaconine was isolated (88) from the mother liquors

accumulated during the isolation of ajaconine from garden larkspur
(C. ambigua). On the basis of I3C- and 'H-NMR analysis, structure 81 was
assigned to dihydroajaconine. Reduction of ajaconine with sodium boro-
hydride in aqueous methanol gave a product that was identical with natural
dihydroajaconine. 3C-NMR spectra of ajaconine, dihydroajaconine, and
related alkaloids were also reported. It was suggested that dihydroajaconine
may be an intermediate between ajaconine and atidine in the plant.
In 1972, Sastry and Waller (89)reported the presence of dihydroajaconine
during GC-MS studies of ajaconine isolated from D. ajucis. A sample of
what had been earlier identified as pure ajaconine furnished a mixture of
five compounds when the deuterated trimethylsilyl derivative was analyzed
on the GC-MS. The temperature on the GC column (215") and the time
required for elution (12.7-27.8 min) may have given rise to rearrangement
products.
D. KOBUSINE
AND PSEUDOKOBUSINE
Kobusine has been isolated (52, 90-92) from A . sachalinense, A . yesoense

Nakai, A . lucidusculunq and A . kamtschaticum, Aconitum species native to
Japan. Okamoto and co-workers (93) initially assigned structure 83 or 84
to kobusine on the basis of extensive chemical and spectral studies. Later,

the same group revised (94)the structure of kobusine to 85 without presenta-
tion of evidence to eliminate structure 84. After unsuccessful attempts to
correlate hetisine with kobusine, in 1970 Pelletier and co-workers (95)
reported the structure of kobusine as 86 on the basis of a single-crystal
X-ray analysis of its methiodide.
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
By virtue of the previous correlation (93)of kobusine with pseudokobusine,

structure 87 was assigned to pseudokobusine. The latter was also isolated
along with kobusine from A . yesoense Nakai and A . lucidusculum Nakai (91).
The chemistry of kobusine and pseudokobusine has been discussed ( 6 )in a
previous chapter in this treatise.
Japanese chemists (96)have reported the chemical conversion of kobusine
into the chloramine (95). The latter was treated with sodium methoxide in
methanol to afford compound 96 in which the bridged C-14-C-20 bond
was cleaved. Reduction of kobusine with sodium in n-propanol, followed
by acetylation afforded compound 88. Treatment of 88 with excess phenyl
chloroformate in refluxing o-dichlorobenzene gave the carbamate 89. The
latter was hydrogenated over Pd-C in methanol to obtain compound 90 in
94% yield. Further hydrogenation of 90 in the presence of platinum in acidic
solution gave 91. Acidic hydrolysis of 91 afforded compound 92. The
carbamate 92 was converted to the benzyl derivative 93 by treating with
benzyl alcohol and sodium hydride in dimethoxyethane. Hydrogenation of

93 over Pd-C in acidic methanol yielded 94 in 95% yield. The latter was
chlorinated with N-chlorosuccinimide to afford the chloramine 95 in good
yield.
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
Treatment of the chloramine 95 with sodium methoxide in refluxing

methanol afforded a mixture of products 96,97, and 98 in 36%, 28%, and
13% yield, respectively. The structure and stereochemistry of 96 was estab-
lished by X-ray analysis. Reduction of 96 with sodium borohydride in
methanol afforded 99. The latter was acetylated with acetic anhydride in
pyridine and subsequently hydrolyzed with hydrochloric acid to give the
N-acetate 100. Dechlorination of 100 was effected by Raney nickel hydro-

genolysis to afford compound 101 in 50% yield. The cleavage of the C-14-
C-20 bond in the chloramine 95 is a novel fragmention for which no
satisfactory mechanism has been offered.
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
at C-3 and the formation of an ether group by dehydration of two hydroxyl

groups of ignavine. A high-resolution mass spectral study by Pelletier's
group (101) indicated that the molecular ion of anhydroignavinol was
m/e 345.1936 and therefore the molecular formula must be C,oH27N0,. In
1970, Pelletier, Page, and Newton (101) reported the correct structure 104
for anhydroignavinol from a single-crystal X-ray analysis of its methiodide.
104 Anhydroignavinol
Since previous work led to assignment of the benzoate group at C-3 in

ignavine, the position and functionality of the remaining oxygen required
by the ignavine formula, C2,H3,N06, requires explanation. Either the
molecular formula originally assigned to ignavine is incorrect and should be
C2,H3,N0, or an unusual rearrangement occurs during the hydrolysis of
ignavine to anhydroignavinol. Considering the correct structure for anhydro-
ignavinol, ignavine may be a hydrate of the benzoate ester of anhydro-
ignavinol. The position of the benzoate group in ignavine still needs to be
determined. Earlier work on ignavine and anhydroignavinol has been
reviewed in Volume XI1 of this treatise (6).
F. HYPOCNAVINE
AND HYPOGNAVINOL
Hypognavine was first isolated from certain varieties of A . sanyoense Nakai

in 1953 by Okamoto and co-workers (102). Alkaline hydrolysis of hypo-
gnavine afforded an alkamine, hypognavinol. On the basis of extensive
chemical studies and spectral data, the Japanese chemists (102-104) assigned
either structure 105a or 105b for hypognavine and structure 106a or 106b for
hypognavinol. Since PMR spectral examination of hypognavinol was
unsuccessful in differentiating structures 106a and 106b, the structure of
hypognavinol was established as 107 (105) from a single-crystal X-ray
analysis of its methiodide.
On the basis of steric effects, Sakai (104) proposed that the benzoate
group of hypognavine is in a /?-configuration. A careful examination of
models suggested that the steric difference between a C-1 P-benzoate group
and a C-2 a-benzoate group would be slight. Therefore, the location of the
benzoyl group in hypognavine remains uncertain.
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
assigned to isohypognavine and isohypognavinol, respectively. Although

isohypognavine has been known more than 30 years, the complete structure
has not been established. Early chemical work on these two compounds is
discussed in Volume XI1 of this treatise (6).
On the basis of the stereochemistry of the C-11 and C-15 hydroxyl groups
in related alkaloids (e.g., kobusine, pseudokobusine), the C-1 1 and C-15
hydroxyl groups are most likely in a p-configuration in isohypognavine and
isohypognavinol. We can therefore tentatively suggest structures 110 and
111 for isohypognavine and isohypognavinol, respectively.
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
112 113 R' = OH, RZ = H

114 R' = H. RZ = OH
115 R’ = OH, R2 = H 117 Denudatine

116 R’ = H . R 2 = 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. \\
OH 122 R' = Bz, R Z = Ac

123 R' = H, R 2 = Ac
121
124 R' = R 2 = H
reineckate salt. Selective hydrolysis of vakognavine with 50% sulfuric acid

yielded compound 122 after 4.5 min, the monoacetate 123 after 13.5 min
and the completely hydrolyzed product 124 after 2 hr. The structures of the
hydrolysis products were based on 'H-NMR data.
Vakognavine is the first example of an N, C- 19-seco-diterpenoid alkaloid
reported and an interesting alkaloid for biogenetic speculation. The authors
(116) suggested that the C-19 aldehyde may be a plausible alternate to the
pseudokobusine structure as an intermediate in the biosynthesis of the
modified atisine-type skeletons such as hetisine. The C-19 hydroxyl of
vakognavine hydriodide (119) is reminiscent of the oxazolidine oxygen
of isoatisine.
J. HETISINE
(DELATINE)
AND HETISINONE
Hetisine (125) was isolated as a minor alkaloid from the roots of A .

heterophyllurn Wall (80)in 1942 by Jacobs and Craig (118, 119). Later it was
also isolated from D.cardinale Hook (120).Several papers were published
(121, 122) regarding the chemistry and structure elucidation of hetisine, but
the structure of hetisine (125) was eventually established by an X-ray dif-
fraction study (123. 124). Earlier work on the chemistry of hetisine has been
reviewed in Volume XI1 of this treatise (6).
RO
om N---
:,
RO\
R 0 . . H H 2
CH3
__
HO
H O . . e Z
125 R = H Hetisine 127 R = AC

126 R = AC 128 R =H Hetisinone
RO
130 R = H 133
131 R = MS
During an attempted chemical correlation of hetisine and kobusine,

Wright, Newton, and Pelletier (125) observed an unusual rearrangement of
a hetisine derivative to a cyclopropane derivative by lithium aluminium
hydride reduction. The correlation route involved oxidation of hetisine
diacetate (126) to the ketodiacetate 127, and hydrolysis to hetisinone (128).
Wolff-Kishner reduction of hetisinone gave the diol 129. Selective Sarett
oxidation of 129 yielded compound 130, which was converted into the
mesylate 131. Theoretically, reduction of the latter and introduction of an
allylic hydroxy group should have produced kobusine (86).However, lithium
aluminium hydride reduction of 131 afforded the cyclopropane derivative
132. The 'H-NMR spectrum of 132 indicated the presence of an extra
tertiary methyl group at 6 1.18, which was considerably more deshielded
than any of the tertiary methyl groups previously encountered in this type of
alkaloid. The structure of 132 was established (125) by an X-ray analysis
of its methiodide. The authors suggested that coordination of the oxygen of
the mesylate group with some aluminium species provided at least partial
ionization, and then hydride attack on species 133 could have occurred at
C-17 to give the cyclopropyl compound 132. This reaction represented the
first reported example of this type of skeletal rearrangement among the
C,,-diterpenoid alkaloids.
Hetisinone (128) has been reported to occur in D . cardinale (120), D .

denudatum (126),and A . heterophyllum (80).Structure 128 originally assigned
for hetisinone was confirmed (127) by ‘H-NMR and mass spectral studies.
Two other possible structures for hetisinone (134 and 135) were discarded
on the basis of the following arguments.
134 135
Dehydration of hetisine diacetate (126) with phosphorus oxychloride and

pyridine followed by basic hydrolysis afforded a mixture of olefins 136 and
137, whose structures were analyzed by ‘H-NMR spectroscopy. These
olefins can only be derived from hetisine diacetate if its structure is 126, a
fact requiring the structure of hetisinone to be 128. Furthermore, hetisinone
is stable to bases, behavior that is consistent with the assigned structure but
less likely for either of the alternative B-ketoalcohols 134 and 135. When
hetisinone was heated in D,O-CH,OD containing sodium deuteroxide, a
mixture of deuterated hetisinones was obtained. Mass spectral analysis
revealed the presence of 14% d , , 53% d,, 24% d , , and 6% d4 species. These
data further confirmed that hetisinone is correctly represented as 128.
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
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..
138 139 Hetidine
L. MIYACONITINE
AND MIYACONITINONE
Miyaconitine and miyaconitinone, two highly oxygenated alkaloids, were

isolated from the Japanese species A . miyabei Nakai in 1946 (129).On the
basis of chemical and spectral data (54, 129-132) and biogenetic consider-
ations, structures 140 and 141 were assigned to miyaconitine and miyacon-
itinone, respectively.
High-resolution mass spectra confirmed the earlier established molecular
formula, C,,H,,NO, , for miyaconitine and C,,H,,NO, for miyacon-
itinone. Both alkaloids failed to form acetylation products with either acetyl
chloride or acetic anhydride in pyridine. These alkaloids have been correlated
by converting miyaconitine to miyaconitinone by oxidation with CrO, or
Bi,O, in acetic acid. Hydrogenation of miyaconitine over platinum in
ethanol gave its dihydro derivative. Acidic hydrolysis of miyaconitinone
afforded miyaconinone (143). The latter was reconverted to 141 by acetyl-
ation with acetyl chloride. Oxidation of 143 with CrO, in sulfuric acid or
MnO, in chloroform yields the dehydro derivative 144. On formation of the
perchlorates of miyaconitine and miyaconitinone, the remarkably low fre-
quency (1678and 1676 cm-') IR carbonyl maxima disappeared. In addition,
the absorption at 2 ,,,432 nm (log E l.6),which is characteristic of an
x-diketone moiety, also disappeared in the W spectrum of miyaconitinone
perchlorate. Miyaconitine has been shown to contain an a-ketol group,
whereas miyaconitinone contains an x-diketone moiety. On the basis of
spectral analysis of compound 144, the authors suggested that the new
carbonyl formed in compound 144 by oxidation of 143 has an adjacent active

methylene group and is near the nitrogen atom. On the basis of spectral
data and the color tests, the Japanese chemists (132)represented structures
140 and 141 for miyaconitine and miyaconitinone, respectively. Subse-
quently, the structure of miyaconitine was confirmed by a single-crystal
X-ray analysis of its hydrobromide (142) (133).
0
\\
140 Miydconitine 141 R = Ac Miyaconitinone

143 R = H
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
In 1974, the same workers (134)reported an unusual skeletal rearrange-

ment of miyaconitine. Treatment of miyaconitine (140)with 1 N methanolic
potassium hydroxide for 1 hr yielded miyaconine (145). The latter on acetyl-
ation with acetyl chloride afforded diacetylmiyaconine (146). Reaction of
miyaconine with 1 N methanolic potassium hydroxide under reflux for 2 hr
yielded apomiyaconine (147).Acetylation of the latter with acetic anhydride
in the presence of a catalytic amount of p-toluensulfonic acid on a steam
bath for 1 hr afforded diacetylapomiyaconine (148).Treatment of compound

143 with 5% hydrochloric acid under reflux for 2 hr also afforded miyaconine
(145). The latter was also obtained by mild oxidation of miyaconitine (140)
with an alkaline solution of triphenyltetrazolium chloride (TTC) at room
temperature. The structures of miyaconine (145) and apomiyaconine (147)
were assigned on the basis of 'H- and 13C-NMRdata. Complete assignments
'
of 3C chemical shifts of 145 and 147 are also presented by the authors. On
the basis of I3C-NMR data and Dreiding models, the Japanese workers
assigned a P-configuration to the hydrogen at C-5 in 145 and 147.
Miyaconitine and miyaconitinone were postulated as biogenetic inter-
mediates in the formation of the modified atisine-type compounds from the
normal atisine-type system.
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..
149 Delnudine 150
151 125 Hetisine

X-ray analysis (136) of delnudine hydrochloride. It is worth noting that

delnudine represents a novel type of skeleton.
The Canadian chemists (135) speculated that delnudine may be bio-
genetically derived from hetisine (125) by the concerted rearrangement
portrayed by the arrows in structure 125 and by introduction of the
carbinolamine moiety.
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
152 R = H Spiradine A 153 R = H Spiradine B

156 R = AC 154 R = Ac Spiradine C
CH, 0
155 157
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.
160 Spiradine D 161

Spiradine D formed a quaternary salt (161)on treatment with methanolic

hydrochloric acid at 0'. This salt was reconverted to spiradine D by shaking
with silver oxide in methanol. This experiment suggested that spiradine D
has a masked aminoketone group as exists in other diterpenoid alkaloids
(e.g., hetidine). The presence of a carbinolamine ether (N-C-0-C)
linkage in spiradine D was detected by the following chemical transforma-
tions. Reduction of spiradine D with sodium borohydride in methanol
afforded compound 162. The latter was hydrogenated in ethanol to give
the dihydro derivative 163. Spiradine D was correlated with spiradine A
through this dihydro derivative. Spiradine A was converted to the azine
164 by treatment with hydrazine in diethylene glycol at 180" and then with
164 165
166 167
acetone at 20'. Wolff-Kishner reduction of 164 gave a mixture of com-

pounds 165 and 166. When this mixture was heated at reflux with ethylene
chlorohydrin and methanol in the presence of potassium carbonate, the
N-P-hydroxyethyl derivative 167 was obtained. Catalytic hydrogenation
of 167 in ethanol gave the dihydro derivative 163. The latter was identical
to one prepared from spiradine D. On the basis of this chemical correlation,
structure 160 was assigned for spiradine D.
Spiredine has been isolated recently from S. juponicu by Gorbunov and
co-workers (141). On the basis of spectral data and chemical correlation
with spiradine A, structure 168 was assigned to this new alkaloid. Catalytic
hydrogenation of spiredine in a mixture of ethanol and acetic acid afforded
tetrahydrospiredine (169). The latter was identical with the compound ob-
tained by the addition of ethylene oxide to dihydrospiradine A (170).
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.
171 R = Ac Spiradine F 173

172 R = H Spiradine G
The presence of a tertiary methyl group and an exocyclic double bond

in spiradine G was demonstrated by 'H-NMR analysis. Mild reduction of
spiradine G with sodium borohydride afforded the trio1 173, which indi-
cated that the remaining two oxygen atoms exist as a part of two carbinol-
amine ether (N-C-0-C) linkages in spiradine G. The presence of an
exocyclic double bond in the six-membered ring was confirmed by catalytic
hydrogenation of spiradine G to compound 174 and oxidation of 172 with
potassium permanganate to compound 175.
176 177
178
Oxidation of 172 with chromium trioxide in pyridine gave the monoke-

tone 176, whereas oxidation of spiradine F under the same conditions af-
forded the hydroxylactam 177. Catalytic hydrogenation of compound 176
afforded the a-ketol 178. The latter was treated with sodium methoxide
in benzene to give an enolated a-diketone (179), which definitely fixed the
position of the hydroxyl group at C-6 in spiradine G. Comparison of an
ORD curve of compound 178 with that of 5a-cholestane-6-one established
the indicated absolute configuration for these alkaloids. It is worth noting
that these alkaloids bear many structural similarities to the earlier mentioned
alkaloid ajaconine.
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
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
On reduction, spireine afforded di- and tetrahydro derivatives. The

location of two keto groups in spireine was revealed by 'H-NMR and
mass spectral analysis of deuterated spireine and tetrahydrospireine. When
spireine was heated with selenium at 340", a compound with molecular
formula C20H2,N0, was obtained. Structure 182 was proposed for this
compound on the basis of spectral data. Since the C-19 imine bond is usu-
ally unstable and cannot be isolated in that form, we suggest that the imine
bond is present at C-20 rather than at C-19 in the selenium degradation
product (C,oH2,N0,). Thus, structure 183 should be considered for the
latter. Each of the structures considered for spireine has unusual features.
The exocyclic double bond in 181 bears some resemblance to lycoctamone
(184), a rearrangement product of lycoctonine.
1V. Bisditerpenoid Alkaloids
A. STAPHISINE
AND STAPHIDINE
In 1941, Jacobs and Craig (144) reported the isolation of a diterpenoid

alkaloid designated as staphisine from the seeds of D. straphisagria. On
the basis of chemical studies (144, 145), they indicated that staphisine is
a diterpenoid aIkaloid dimer with molecular formula C,,H,,N,O (Iater
revised to C4,H60N,0) (146), which contains two NCH, groups and no

methoxyl group (despite the presence of 1.36% OCH,). During the column
chromatographic separation of staphisine they found that the combustion
analysis of several samples of staphisine fluctuated between the limits of
82.13 and 82.85% for carbon and 9.47 and 9.77% for hydrogen. On the
basis of this observation, Jacobs and Craig cautioned that the so-called
staphisine could still be a persistent mixture of bases which are very difficult
to separate. Attempts to separate “staphisine” by crystallization of the
hydrobromide, hydrochloride, and nitrate salts met with failure.
H,C-- H,C--
185 R = OCH, Staphisine 186

187 R = H Staphidine
From the same mother liquors, in 1972 Pelletier and co-workers (247)
isolated a methoxyl group-containing bisditerpenoid alkaloid, which they
named staphisine, and elucidated its structure as 185 by X-ray analysis
of its monomethiodide (186). Chemical studies of staphisine were hindered
by its instability to light and heat and by the fact that attempted degrada-
tion led to complex changes involving numerous unstable products. High-
resolution mass spectral and elemental analysis of staphisine established
its molecular formula as C,,H,,N,O,. The presence of two tertiary methyl
groups, two N-methyl groups, a cyclopropyl ring, a methoxyl group, and
a conjugated double bond in staphisine was revealed by I3C-NMR, PMR,
IR, and UV spectal data. Jacobs’ selenium dehydration experiments had
afforded pimanthrene and 1,3-dirnethyl-7-isopropylphenanthreneas deg-
radation products, which are compatible with structure 185. Thus, the
structure of staphisine (185) elucidated by X-ray analysis is in agreement
with observed spectral and chemical data for Jacobs’ staphisine.
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
188 R = OCH, Staphinine

189 R = H Staphimine
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
Staphigine and staphirine have been isolated (149) in extremely small

amounts from the seeds of D. stuphisagria. Staphigine and staphirine are
the C- 19 lactam derivatives of staphisine and staphidine, respectively. The
structures of staphigine (190) and staphirine (191) were determined on the
basis of their I3C- and 'H-NMR spectra.
The IR spectra of these alkaloids revealed the presence of a lactam. The
'H-NMR spectrum of staphigine indicated the presence of two tertiary
148 S. WILLIAM PELLETIER AND NAFESH V. MODY
Y
H,C--
190 R = OCH, Staphigine

191 R =H Staphirine
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
Staphisagnine (193) and staphisagrine (194) were also isolated (1.50)

in extremely small amounts from the mother liquors accumulated during
the isolation of delphinine from the seeds of D. stuphisagria. These alka-
loids are unusual in containing an oxazolidine ring of the atisine and veat-
chine type in addition to many of the uncommon features of the staphisine
skeleton.
H,C--
193 R = OCH, Staphisagnine

194 R = H Staphisagrine
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.
V. Behavior and Formation of the Carbinolamine Ether Linkage in

Diterpenoid Alkaloids: The Baldwin Cyclization Rules
Recently, Pelletier and Mody (87) reported an unusual rearrangement of

ajaconine (80), via a disfavored 5-endo-trig ring closure, to the more stable
oxazolidine ring-containing compound, 7cc-hydroxyisoatisine (82). They
called attention to apparent violations of Baldwin's cyclization rules (151)
MeOH
OH
80 82
in certain of the carbinolamine ether (N-C- 0-C) linkage-containing

diterpenoid alkaloids and their derivatives (152). Results on 5- and 6-endo-
trig cyclizations involving nucleophilic attack of oxygen on immonium salts
derived from C,,-diterpenoid alkaloids will be discussed in this section.
Atisine, an amorphous alkaloid (pK, 12.5), is usually isolated in the form
of its hydrochloride salt, a compound that is really a tertiary immonium
salt (5). Atisine (4) can be regenerated from atisinium chloride by treat-
ment with base. The fact that the oxazolidine ring closes in two different
directions to give a pair of epimers suggested the operation of unusual
constraints on the mechanism of ring closure. Examination of a Drieding
model of atisinium chloride revealed that closure of the oxazolidine ring
on the pro-20R side of the plane is sterically hindered, especially by H-14,
which is situated almost directly over C-20. Across to the pro-20s side of
the bond is almost equally restricted by H-2. The authors indicated that
cyclization of the ternary immonium salt to form the five-membered ox-
azolidine ring is an example of a “disfavored” 5-endo-trig ring closure. Yet
this ring closure is a very facile one. The same phenomenon was also ob-
served during the conversion of isoatisinium chloride (76)to isoatisine (75),
of veatchinium chloride (3) to veatchine (l),and of garryfoline hydrochlo-
ride to garryfoline.
The formation and behavior of five- and six-membered carbinolamine
ethers in various diterpenoid alkaloids were examined to determine whether
any further violation of Baldwin cyclization rules occurs in these alkaloids.
In 1957, Marion and co-workers (153) reported the preparation of several
six-membered ring-containing carbinolamine ethers from C, ,-diterpenoid
4 Atisine 5 Atisinium chloride

75 Isoatisine 76 Isoatisinium chloride
alkaloid derivatives. Subsequently, dehydrocondelphine (196) was pre-

pared (152) from condelphine (195) by treatment with aqueous potassium
permanganate. Dehydrocondelphine is a weak base that forms a ‘NH-type
salt (197) with hydrochloric acid rather than the Schiff salt (198). This be-
havior is not because of a special stability of six-membered carbinolamine
ethers, but due to the prohibitively high energy of the transition state for
the opening of the ether (196) to the quaternary Schiff salt (198). Examina-
tion of the Drieding model for 198 indicated that this Schiff salt cannot
close easily to the ether for steric and vectorial reasons. Consequently, the
transition state for 0-protonation and opening of the ether linkage of de-
hydrocondelphine to the Schiff salt would be expected to be unfavorable.
OCH, OCH,
195 196
OCH, OCH,
197 198
The oxazolidine rings (199) of C,,-diterpenoid alkaloids in hydroxylic

solvents such as methanol are in equilibrium with the corresponding Schiff
salts (200) and consequently are strong bases. Examination of a Drieding
model of such a Schiff salt indicated that it is vectorially poorly arranged
for ring closure. Although such a cyclization is “disfavored” according to
Baldwin’s rules, experimental evidence demonstrated (154) that an equilib-

rium does exist between the oxazolidine ring (199) and the Schiff salt (200).
This observation suggests that the Baldwin rules are less prohibitive for
quaternary immonium salts bearing a full charge on the nitrogen. These
salts resemble carbocations to a greater extent than uncharged groups. The
authors indicated that an attack on a carbocation (201) exhibits less vecto-
rial specificity than an attack on a carbonyl group (202). Because the im-
monium salts (200) are intermediate between an uncharged group and a
carbocation, the equilibrium between oxazolidine (199) and Schiff salt is
probably slower than a ring closure which is not disfavored.
Ajaconine (80) was the first example of a C,,-diterpenoid alkaloid con-

taining an internal carbinolamine ether linkage between C-7 and C-20. An
attempt by Dvornik and Edwards (86)to rearrange ajaconine in methanolic
base resulted in a mixture that was not studied further. On the basis of
chemical reactions and hydrogen-interaction theory, they concluded that
a driving force for rearrangement of the internal carbinolamine ether is
absent. The Canadian chemists (86) also mentioned that an entropy factor
must favor the internal ether over the oxazolidine ring, and thus the C-7-
C-20 ethers should be more stable than the oxazolidine ring derivatives.
Treatment of ajaconine with hydrochloric acid afforded a ternary im-
+
monium salt (203) instead of a protonated (-NH-) type salt. Treatment
of the immonium salt (203) with base regenerated ajaconine (80) instead
of 7a-hydroxyatisine (205), which would parallel the formation of atisine
(4) from atisinium chloride (5). Transformation of ajaconium chloride to
ajaconine is an example of a 6-exo-trig ring closure, which is a “favored”
process according to Baldwin’s rules.
The I3C-NMR spectral analysis of ajaconine in nonionic and ionic sol-
vents indicated that in hydroxylic solvents the ether linkage of ajaconine
ionizes and covalent solvation takes place (87). This observation accounted
for the formation of the Schiff salt, with the resultant high pKa value (1 1.8)
of ajaconine in aqueous solution-behavior which parallels that of atisine
(pK, 12.5) and veatchine (pKa 11.5). These results suggested that ajaconine
may be rearranged by refluxing in an ionic solvent to a compound in which
the C-7-C-20 ether linkage is absent.
204 205
Refluxing ajaconine in methanol afforded a mixture from which a new

compound identified (87) as 7a-hydroxyisoatisine (82) was isolated. The
structure of the latter was established by ‘H- and I3C-NMR spectroscopy.
When ajaconine was refluxed in CH,OD under nitrogen, a mixture of C-19,
C-20-deuterated ajaconine (206) and C- 19,C-2O-deuterated 7a-hydroxy-
isoatisine (207) was formed. Incorporation of deuterium in 206 and 297
indicated that ajaconine ionized and rearranged to 207 and that these species
are in equilibrium in refluxing methanol.
The authors also suggested (87) a mechanism for this rearrangement in

refluxing methanol. In alkaline solution the normal-type immonium species
208 closes to ajaconine (80) and not to 7%-hydroxyatisine(205) because the
latter closure, being a “disfavored” 5-endo-trig process, is much slower
154 S . WILLIAM PELLETIER A N D NARESH V. MODY
than the “favored” 6-endo-trig closure of the normal-type immonium

species to ajaconine. However, species 208 undergoes an isomerization to
the isoimmonium salt 209 which is known in the case of the isomerization
of atisine to isoatisine and of veatchine to garryine. The intermediate 209
closes to 7%-hydroxyisoatisine(82) in spite of the closure being partially
disfavored because there is no faster process in competition with this ring
closure.
205
80 Ajaconine
209 82
Veatchine acetate (210) was hydrolyzed to veatchine (1) in methanol a t

room temperature without using any external base (152). This unusual hy-
drolysis was explained by participation of methoxide ion which was formed
by opening of the oxazolidine ring by methanol. Diterpenoid alkaloid
derivatives lacking the oxazolidine ring, such as dihydroatisine diacetate
(211) and veatchine azomethine acetate (lo), failed to give compounds 212
and 78, respectively, in methanol under these conditions.
210 1 Veatchine
78 R = H 10 R = AC
211 R = Ac 212 R = H
The hydrolysis of veatchine acetate to veatchine suggested an examina-

tion of the behavior of 7a-acetoxyatisine acetate (213) which was prepared
from ajaconine (SO) via the corresponding imine. Acetylation of ajaconine
with acetic anhydride and pyridine at room temperature afforded the tri-
acetate salt 214 in quantitative yield. A Hofmann-type degradation of the
triacetate salt was achieved by heating at reflux in chloroform to give the
imine 215 in 95% yield. The latter reacted with ethylene oxide in acetic acid
to afford 7a-acetoxyatisine acetate (213) in quantitative yield (152). When
213 was stirred in methanol at 25", a mixture of 7a-hydroxyisoatisine (82),
ajaconine (SO), and their C-15 acetates (216 and 217) was formed. No start-
ing material was detected after 36 hr. The formation of these products was
explained on the basis of opening of the oxazolidine ring by methanol and
formation of methoxide ion. The latter hydrolyzes the C-7 acetate group
of 7-acetoxyatisine acetate. The resulting anion can close on the immonium
80 214
I
A CHCI,
213 215
“OH
80 R = H Ajaconine 82 R = H
216 R = AC 217 R = AC
species at C-20 to form ajaconine. And as mentioned earlier, the normal-

type oxazolidine ring derivatives isomerize readily in methanol to the iso-
type oxazolidines.
Recently, Pelletier, Nowacki, and Mody (155) reported that treatment of
alkaloid imine derivatives with ethylene oxide in acetic acid or methanol
afforded the oxazolidine ring-containing alkaloids in excellent yield. Treat-
ment of lindheimerine (7) with ethylene oxide in acetic acid afforded ovatine
(6) in 98% yield. Similarly, veatchine azomethine acetate (10) afforded veat-
chine acetate (210) in 97% yield. Formation of the oxazolidine ring in these
7 Lindheimerine 6 Ovatine
10 210 Veatchine acetate
compounds occurs via a “disfavored” 5-endo-trig ring closure. When meth-

anol was used instead of acetic acid, 7 gave 6 in 90% yield within 3 hr. Under
longer reaction times, 7 afforded only garryfoline (8) in a yield of 96%.
Comparable results were also obtained with veatchine azomethine acetate
(10). Under short reaction times, veatchine acetate (210) was produced
and under longer reaction times, veatchine (1) was formed.
Depending on the reaction time, treatment of atisine azomethine acetate
(218) with ethylene oxide afforded either atisine acetate (219), atisine (4), or
I R' = H, R 2 = OAc 6 R' = H, R 2 = OAc Ovatine

10 R' = OAc, Rz = H 210 R' = OAc, R 2 = H
1 R' = OH, R 2 = H Veatchine

8 R' = H, R2 = OH Garryfoline
isoatkine (75). Thus, in 3 hr atisine acetate was isolated, in 12 hr a mixture

of atisine and isoatisine was formed, and in 24 hr only isoatisine was obtained.
218 219 Atisine acetate
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.
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
behavior suggested that the 7%-acetoxylgroup in 224 exerts a profound

influence on the direction of closure of the carbinolamine ether linkage.
In summary, certain reactions with diterpenoid alkaloid imines proceeded
by a “disfavored” 5-endo-trigonal process, whereas in other cases, such
as the reactions with glycidol, a “favored” 6-endo-trigonal process was
followed. The Baldwin rules should be modified to accomodate the ex-
ceptional behavior of the tertiary immonium salts. Recently, examples of
similar reactions demonstrating the violation of the Baldwin cyclization
rules have been reported (156-158).
4a 4b
In 1970, Pradhan and Girijavallabhan (79)concluded that atisine in so-

lution contains an equilibrium mixture of the C-20 epimers (4d and 4b),
which are interconvertiable via a zwitterion. This conclusion was based
on a ‘H-NMR study of atisine in different polar solvents. Later, Pelletier
and Mody (154) reported that atisine in nonionic solvents exists as a mixture
of C-20 epimers which do not interconvert via a zwitterion and that in
ionic solvents atisine slowly isomerizes to isoatisine. This idea was supported
by a I3C-NMR study of atisine in deuterated solvents. The results reported
by Pelletier and Mody (154) were questioned by Pradhan (159)in 1978. The
rebuttal paper was submitted prior to the publication of the X-ray crystal-
lographic studies in which Pelletier and co-workers (30)reported additional
evidence supporting their earlier conclusion. Recent work (36)on the struc-
ture of cuauchichicine further confirmed this conclusion. The normal-type
oxazolidine ring of cuauchichicine does not exist as a mixture of C-20 epi-
mers in solution. This unusual finding was confirmed (36)by a single-crystal
X-ray analysis of cuauchichicine.
VI. ' 3C-NMR Spectroscopy of C,,-Diterpenoid Alkaloids
Recent developments in instrumentation and techniques have made

possible the application of 13C-NMR spectroscopy to the study of many
'
natural products. 3C-NMR spectroscopy has become exceedingly im-
portant in the area of structure elucidation and synthesis of naturally oc-
curring organic substances since its availability to organic chemists just
over 10 years ago. Recently, 13C-NMR data have become important for
the comparison of natural and synthetic compounds or degradation pro-
ducts. I3C-NMR spectral data have proved critically important in estab-
lishing the stereochemistry of compounds that are not available in crystalline
form for X-ray analysis, such as atisine (4). The I3C-NMR spectra of di-
terpenoid alkaloids not only indicate the number and type of carbon atoms
in the system but also reveal close structural and family resemblances and
give detailed information about the sites of various functional groups. The
usefulness of the I3C-NMR technique in solving difficult structural problems
of complex diterpenoid alkaloids is reviewed here.
In 1974, Japanese chemists (134) demonstrated the utility of 13C-NMR
spectroscopy in the field of C,,-diterpenoid alkaloids. They determined
the structures of miyaconine (145) and apomiyaconine (147), two rearrange-
ment products of miyaconitine, by the aid of I3C-NMR spectroscopy.
In 1976, Lamberton and co-workers (69, 70) demonstrated the use of
3C-NMR studies in elucidating the structures of several new C,,-diter-
'
penoid alkaloids and their derivatives. The 3C-NMR spectra of several
veatchine-type alkaloids and their derivatives [e.g., anopterine (51), anop-
teryl alcohol (52), tetraacetylanopteryl alcohol (54), triacetylanopteryl
alcohol (61), compound 58, compound 59, anopterimine (70), anopterimine
N-oxide (71), hydroxyanopterine (72), and dihydroanopterine (73)] were
examined. The noise-decoupled and off-resonance proton-decoupled 3C-
NMR spectra of anopterine provided evidence for many unusual structural
features and confirmed the structure of anopterine, which was established
by a single-crystal X-ray analysis of tetraacetylanopteryl alcohol azomethine
'
iodide (53). These 3C-NMR data were utilized in the structure determina-
tion of four new alkaloids (anopterimine, anopterimine N-oxide, hydroxy-
anopterine, and dihydroxyanopterine) isolated in small amounts from A .
macleayanus and A , glandulosus.
The power of the 3C-NMR spectroscopic technique was demonstrated
(148-150) in the elucidation of the structures of some very complex natural
products, the bisditerpenoid alkaloids, isolated from D. staphisagria. On
the basis of 13C-NMR data of the known alkaloid, staphisine (185), the
structures of seven new related alkaloids, staphidine (187), staphinine (1881,
staphimine (189), staphigine (190), staphirine (191), staphisagnine (193),
and staphisagrine (194),were determined. Partial chemical shift assignments

for these alkaloids were presented in tabular form. A complete correlation
of 3C- chemical shifts of staphisagnine and staphisagrine with those of
staphisine and staphidine was also presented.
In 1977, Pelletier and Mody (27) determined that atisine (4), veatchine (l),
and related normal oxazolidine ring-containing derivatives exist as a mix-
ture C-20 epimers in nonionic solvents with the help of 13C-NMR spectral
data. Later, this claim was confirmed by a single-crystal X-ray analysis of
veatchine. The same authors have also examined (154)the unusual behavior
of the oxazolidine ring of atisine in ionic and nonionic solvents by 13C-NMR
analysis and shown that the C-20 epimers of atisine are neither intercon-
vertible via a zwitterion, as reported by Indian chemists (79), nor in equi-
librium with each other. A comprehensive 13C-NMR study of the atisine and
veatchine-type alkaloids as well as certain of their derivatives has been
reported (28).The 3C-NMR spectra of atisine (4), atisinone (225),isoatisine
(75), isoatisinone (226), dihydroatisine (78), dihydroatisine diacetate (211),
atidine (79), atidine diacetate (227), atisine azomethine (228), atisine azo-
methine acetate (218), dihydroatisine azomethine (229), N-methyldihydro-
atisine azomethine (230), veatchine (l),garryine (2), dihydroveatchine (231),
dihydroveatchine diacetate (232), veatchine azomethine (212), veatchine
azomethine acetate (lo),dihydroveatchine azomethine (233); and N-methyl-
dihydroveatchine azomethine (234) have been analyzed. Self-consistent
assignments of nearly all the resonances were made in these compounds with
the aid of single-frequency off-resonance proton decoupling techniques,
additivity relationships, and the effectsinduced by certain structural changes.
225 Atisinone 226 Isoatisinone
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,
The I3C-NMR spectra of these compounds were analyzed to identify and

distinguish skeletal features of the atisine and veatchine-type alkaloids for
use in the structure elucidation of new C,,-diterpenoid alkaloids.
The structures of two new C,,-diterpenoid alkaloids designated as
ovatine (6) and lindheimerine (7), isolated from G . ovata var. Iindheimeri,
have been elucidated (33)with the help of 13C-NMRspectroscopy. Similarly,
the structure of dihydroajaconine (81) was also established (88) with this
technique.
Pelletier and Mody (87) have studied the behavior of ajaconine (88) in
ionic and nonionic solvents with the aid of I3C-NMR spectroscopy. They
established the structure of 7a-hydroxyisoatisine (82) and reported the 3C-
NMR spectra of 80,82, atisinium chloride (5), and ajaconium chloride (203).
The stereochemistry of the C-16 methyl group and the oxazolidine ring
in cuauchichicine was recently reassigned as a result of examining the I3C-
NMR spectra of isocuauchichicine (16) and its C-16 epimer (17). The oxa-
zolidine ring of cuauchichicine was shown to exist as a single C-20 epimer
in solution. Subsequently, the revised structure for cuauchichicine (15) was
confirmed by X-ray analysis.
1 3C-NMR spectroscopy has proved to be a powerful technique for solving
complex structural and conformational problems among the diterpenoid
alkaloids. In the future we may expect an increasing use of this technique
over traditional techniques such as IR, 'H-NMR, and MS for solving
difficult structural problems in natural products chemistry. Unambiguous
assignments of chemical shifts in these alkaloids will be useful in future
biogenetic studies of C,,-diterpenoid alkaloids.
VII. Mass Spectral Analysis of C,,-Diterpenoid Alkaloids
The mass spectra of C,,-diterpenoid alkaloids are complex, and there is

a paucity of information concerning their fragmentation patterns. The first
systematic mass spectral analysis of these alkaloids was reported by Soviet
chemists in 1970. Yunusov and colleagues (62) analyzed the mass spectra
of songorine (44),songoramine (47), napelline (M), and their derivatives.
Songorine and many related compounds give the parent ion as the base
peak. In the case of some acetylated derivatives, M - 59 is the base peak.
+
The fragmentation of these alkaloids occurs in several directions in contrast

to the regular splitting pattern of the lycoctonine-type alkaloids. N-Methyl
group-containing compounds exhibit a M + - 15 peak, which arises through
the splitting of a methyl radical from the N-ethyl group. The cleavage of
ring A is an important process in the mass spectra of songorine and related
derivatives. The initial cleavage of the C-7-C-20 bond is common. The ions
resulting from the cleavage of the C-7-C-20 bond of songorine are presented
in pathways A and B. One of the strongest ions is m/e 298 (M' - 59), which
is postulated to arise from the cleavage of the C-1-C-10 bond via the inter-
mediate ion-radical with rnje 299. On the basis of the structure of the ion-
radical of mje 299, we have revised the structure of the M - 59 ion (Pathway
+
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)
m / e 246 ( I 3) m/e 270 (7)

:Pathway A
0 0
II
-
II
‘ZH5 &CH, - -H ‘ZH5 &CH,N‘ - -H
N’
OH ;! H,C’ OH
CH 3 CH3
Pathway B
m/e 441 (60) m/e 382 (100)
\ 0
/I
m ’ e 398 ( 5 7 )
Pathway C
m/e 443 (13) m/e 400 (8)
I 0
R =H nde 354 (26) R = H mje 301 (100)

R = Ac m,’e 443 ( I 3) R = Ac mle 343 (28)
J I
C,H 5- Lq$
N/
C,H,--
I
CH 3
M e 242 m P 284
Pathway E
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
m,'e 327 (10) m r 122 (29)

Pathway F
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
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.
VIII. Synthetic Studies
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
235 236 R = CHI

231 R = 0
238 R = H 240 R=CO,CH,

239 R = CH, 241 R=CH,OH
242 R = CH,N,
243 R = CH,NHCO,C,H,
by reduction with lithium in ammonia followed by acetylation. Deketa-

lization of 247 afforded the desired ketone 245. The latter was identical with
the optically active ketone prepared from veatchine.
To complete the total synthesis of the optically active form of veatchine,
the successful resolution of the synthetic racemic ketone 244 was accom-
plished. Compound 244 was reduced stereoselectively with sodium boro-
hydride to give the alcohol 248. The latter was heated with succinic anhydride
and pyridine in xylene to yield the racemic half-ester 249. Treatment of
249 with brucine afforded the diastereoisomeric brucine salts, which were
separated by fractional crystallization. The separated salts were decomposed
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
In 1974, Wiesner and colleagues completed an elegant total synthesis of

racemic napelline (34) (166). A series of model studies on this type of system
was reported (167, 168). They developed (169)an efficient route to the inter-
mediate ketolactam (250)and have used this compound to complete a formal
synthesis of napelline (166, 170).
The starting compound 251 was reduced to 252 with sodium borohydride.
The latter was heated under reflux in 6% sulfuric acid in methanol to afford
compound 253. Treatment of the latter with maleic anhydride at 170" for
3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl
bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux
temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter
was reduced with lithium aluminium hydride to the primary alcohol 256,
which was oxidized to the aldehyde 257 with N,N-dicyclohexylcarbodiimide,
dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde
257 with an excess of the Grignard reagent prepared from l-bromo-3-
benzyloxybutane afforded a mixture of diastereoisomers represented by the
structure 258.
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
The mixture 258 was converted to the unstable benzenesulfonyl aziridine

259 by treatment with an excess of benzenesulfonyl azide in benzene. Ace-
tolysis of 259 with acetic acid and sodium acetate at room temperature for
several days afforded the crystalline mixture of diastereoisomers represented
by the formula 260. The aziridine rearrangement was regiospecific and 260
was the only product detected during this rearrangement. Lithium alu-
minium hydride reduction of 260 followed by acetylation yielded the mixture
261 in 85% yield. Selective hydrolysis of 261 afforded 262 in quantitative
yield. The diastereoisomeric mixture 262 was converted into the diols 263
by hydrogenolysis. The diol mixture was oxidized with chromium trioxide
OCH,
I
C,H,CH,O
CH, ORZ
260 R' = H, R2 = Ac, R 3 = SO,C,H,.

261 R' = R z = R3 = AC
262 R' = R 2 = Ac. R3 = H
in pyridine to afford the epimeric diketones 264. An aldol condensation of the

mixture of the two diketones 264 in refluxing methanolic potassium car-
bonate gave the crystalline mixture of two epimers 265 in 88% yield. Photo-
addition of vinyl acetate to 265 yielded the two epimers of compound 266.
0% OCH,
HO
CH, 0
263 264
OCH ,
CH, 0
OAc
265 266
This mixture was saponified with methanolic potassium hydroxide to give

the two epimers of 267 in quantitative yield. By enol acetylation, 267 was
converted to 268 which in turn was oxidized by osmium tetroxide and
periodate to the noraldehydes 269. The mixture 269 was converted to 270
via oxidation, esterification, and mild alkaline hydrolysis. The hydroxyesters
270 were oxidized by the Jones' method to afford the single crystalline
diketoester 271. Ketalization of 271 yielded the ketal 272 in quantitative
?CH3 ?CH,
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,
R FH3
219 280
from napelline (34) or lucidusculine (35). Hydrogenation of 282 over 10%

palladium on charcoal afforded 285 in quantitative yield. The latter was
identical with the corresponding optically active compound of the same
structure prepared from napelline or lucidusculine.
281 R' = H, R2 = CH, 283 R' = H, R 2 = CH3

282 R' = CH,, RZ = H 284 R' = CH3, R2 = H
285 R' = CH,, RZ = H 35 R = Ac Lucidusculine

288 R' = H, R 2 = CH, 34 R = H Napelline
Lithium aluminium hydride reduction of lucidusculine (35) afforded

napelline (34) in quantitative yield. Napelline was hydrogenated with plati-
num oxide in acetic acid to afford dihydronapelline (286). Treatment of
286 with mercuric acetate in aqueous acetic acid followed by oxidation
with chromium trioxide in pyridine afforded 287 in 16.5%yield. Ketalization
of 287 yielded 285 in a yield of 71%. On refluxing 285 with methanolic base,
a 4 :6 equilibrium mixture of 285 and 288 was obtained. These compounds
were separated by preparative TLC. Bromination of 288 with bromine in the

presence of HCl at 0'' afforded 289 in 92% yield. Dehydrobromination of
289 with lithium bromide and lithium carbonate yielded the ketone 281.
0
II
281
0
II
289
The synthesis of napelline was completed from compound 285. Hydrolysis

of the ketal 285 by treatment with aqueous acetic acid yielded compound
287. The latter was reduced with lithium aluminium hydride to afford a
trihydroxyamine, which was acetylated to give compound 290 in 20% yield.
The dihydroxyacetate 291 was prepared in 45% yield by hydrolysis of 290
with potassium carbonate in aqueous methanol. Acetylation of 291 afforded
292, which on oxidation with chromium trioxide in methylene chloride
gave 293. Bromination of 293 with bromine in a mixture of ether and
chloroform containing HCl yielded the bromoketone 294. The latter was
OR' OAc
290 R ' = R2 = AC 293 R = H

291 R' = R 2 = H 294 R = Br
292 R ' = Ac. R 2 = H
OAc
295
dehydrobrominated with lithium bromide and lithium carbonate in DMF to

give 295. Reduction of 295 with lithium aluminium hydride afforded
napelline (34).
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)
117 Denudatine 296
258 R = OH 298
291 R =H
of an intermediate for napelline (see Section VIII,Ei). Birch reduction of

298 followed by reacetylation afforded the enol ether 299. Hydrolysis of 299
with dilute oxalic acid gave the p, punsaturated ketone 300 in 95% yield.
Compound 300 was relatively unstable and therefore was immediately
reduced to the alcohol 301 with sodium borohydride. Mesylation of 301 gave
compound 302, which on treatment with potassium tert-butoxide in
DMSO afforded the unstable diene 296. The Diels-Alder addition of 296 to
maleic anhydride afforded the desired adduct 303 in a yield of 60%. In order
to use this reaction sequence for the synthesis of denudatine, the cyclic diene
system must contain appropriate functional groups.
299 300
301 R = H 303
302 R = SO,CH,
In 1976 Wiesner’s group reported (174) the synthesis, from compound

305, of the model compound 304, which contains the C-D ring system of
denudatine. Alkylation of 305 with bromomethyl acetate and potassium
carbonate in acetone gave compound 306 in a yield of 95:;. This compound
was hydrolyzed to the acid 307, which on treatment with a solution of
aqueous sodium acetate and N-bromosuccinimide in methylene chloride
yielded the masked quinone 308. The latter was treated with an excess of
ethyl vinyl sulfide in ether to give 309. Hydrolysis of 309 in aqueous meth-
anolic potassium carbonate afforded the diketone 310 in 92% yield. Reaction
of 310 with an excess of trimethylsilylmethyl magnesium chloride in THF
gave 311. The latter was desulfurized with Raney nickel to yield 312 in
304 305 306 R' = Ms, R2 = CH3

307 R' = R 2 = H
C2H5-SvH C2H5-S
308 309 310
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.
311 R = S C 2 H , 313 314

312 R = H
Application of this synthetic sequence to the earlier reported intermediate

321 should lead to the total synthesis of denudatine.
315 R' = R2 = H 318 R = AC 304 R =H

316 R' = R 2 = AC 319 R = H 320 R = COC,H,-p-Br
317 R' = Ac, R 2 = H
D. A SYNTHETIC TO AJACONINE
APPROACH AND ATIDINE
In 1971, Zalkow and co-workers reported (175) the conversion of

podocarpic acid (322) to a key intermediate 323 for the synthesis of the
enatiomers of ajaconine (80) and atidine (79). Compound 323 contains the
CH 3
323
CH3
80 Ajaconine
functionalities necessary for conversion into the enatiomers of these alka-

loids. The ORD curves of a number of optically active tetracyclic inter-
mediates (obtained during this synthesis) containing a carbonyl group at
C-7 and a bicyclo[2.2.2]octane C-D ring system have been compared.
Methyl 0-methyl-7-ketopodocarpate (324)was reduced with sodium boro-
hydride to the hydroxyester 325. Birch reduction of 325 followed by acidic
hydrolysis and esterification with diazomethane afforded the dienone 326.
Reduction of 326 with sodium borohydride followed by acetylation and
treatment of the epimeric mixture with m-chloroperbenzoic acid afforded
327. The latter was rearranged with BF, in ether to yield the ketone 328
which on chromatography over alumina gave the dienone 329. Reaction
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
327 328 329
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.
330 R = CH, 331

332 R = H
..... CO,H
I\\ H
CH,O,C
CH,O, CH, R02C CH3
333 334 R = C H ,
335 R = H
CH ,
0
336 323
FOR THE VEATCHINEAND ATISINE-TYPE

E. INTERMEDIATES ALKALOIDS
1. A New Method for Construction of Ring A
In 1973, Wiesner, Vlahov, and Muzika reported (176)a relatively simple
annelation procedure for the construction of ring A as an alternative to the
Robinson annelation method.
7-Methoxy-2-tetralone was methylated by the Stork method to yield 337.
The latter was treated with sodium hydride and benzyl chloromethyl ether
to furnish compound 338 in 60% yield. Ketalization of 338 afforded the
ketal339 which was hydrogenated with palladium on calcium carbonate to
give the alcohol 340 in a yield of 92%. The alcohol 340 was oxidized with
chromium trioxide in pyridine to afford the aldehyde 341 in quantitative
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.
337 R = H 339 R = CHzOCHzC6H, 342 R' = H, RZ= OH

338 R = CHZOCHzC6Hs 340 R = CHZOH 343 R' = OH, R' = H
341 R = C H O 344 R' = H, RZ= OCH,
345 R' = OCH,, R' = H
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
346 R' = H, RZ = OCH, 348

347 R! = OCH,, RZ = H
2. Synthesis of the BCD Ring System

Beams and Manders reported (177) the synthesis of the tricyclic dione
349 via two different synthetic routes. The Australian chemists utilized an
approach analogous to one developed earlier by Masamune ( I 78) during
the synthesis of atisine and kaurene. They prepared tetrahydro-7-methoxy-
2-naphthoic acid (350) from 7-methoxytetral- 1-one by published procedures.
2. THE CHEMISTRY OF '220-DITERPENOIDALKALOIDS 183
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
& & &

the epimeric alcohols 358 and 359, This mixture was oxidized with Jones
reagent to afford the diketone 349.
/ / /
/ \ \
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
354 R' = H, R Z= CH,C,H, 356 R = THP 357 R = T H P

355 R' = THP, RZ = H 358 R = H 359 R = H
The second approach to the tricyclic dione 349 was simple and direct.
Acetylation of 360 was followed by sequential treatment with oxalyl chloride
and diazomethane to give, after hydrolysis, the diazoketone 361. The latter
COCHN,
YOOH I
360 361
was treated with boron trifluoride in nitromethane to afford 349 in 30%

yield. Boron trifluoride etherate in nitromethane proved to be the best system
for this cyclization. This method seems useful for providing intermediates
for the synthesis of the atisine-type alkaloids.
Beams, Halleday, and Mander (279)reported the preparation of the BCD
ring system intermediates of the atisine- and veatchine-type alkaloids by
intramolecular carbenoid addition reactions.
Birch reduction of 6-methoxynaphth-2-oic acid (362) with an excess of
lithium and tert-butyl alcohol afforded the hexahydro derivative 363, which
was hydrolyzed to the ketoacid 364. The latter was reduced with lithium
tri-tert-butoxyaluminium hydride to furnish the hydroxyacid 365 in a yield
of 90%. Acetylation of 365 yielded 366. Treatment of 366 with oxalyl chloride
in pyridine yielded the acid chloride, which was converted to the diazoketone
367 by reaction with diazomethane. The decomposition of 367 over copper
powder afforded 368 in yields of 70-80%. Hydrolysis of 368 gave 369,
which was oxidized with Jones reagent to afford the cyclopropyldiketone
370. Treatment of 370 with dilute acidic acetone gave the enedione 371, via
a retrograde Michael reaction, in quantitative yield. This method was sim-
plified by using compound 363. The latter was treated with methanol in
p-toluenesulfonic acid to afford the acetal carboxylic acid 372, which was
converted to the acid chloride with oxalyl chloride in pyridine. Conversion to
the diazoketone 373 was affected in yields of 55-65%. Decomposition of 373
over copper powder in cyclohexane gave 374 and subsequent acidic hydroly-
sis afforded the enedione 371. This compound possesses the BCD ring sys-
tem of the veatchine-type alkaloids.
362 363 364
365 R' = H, R Z = OH 368 R = A c 370

366 R' = Ac, R 2 = OH 369 R = H
367 R' = Ac, RZ = CHN,
CH,O cH3QLj
0
CH,O CH,O
371 372 R = OH 374
373 R = C H N ,
To establish the generality of this procedure, the Australian chemists

synthesized (179) the enedione 376 from 375 as shown in Scheme 2. Com-
pound 376 contains the BCD ring system of the atisine-type alkaloids.
&A
CO,H CO,H CO,H
CH,O AcO
375
376
SCHEME 2. (a)Li, NH,, (CH,),COH; (b)CH,OH-H20-(COOH),; (c) Li, tri-t-butoxyalu-

minium hydride; ( d ) Ac,O, C,H,N; (e) (COCI),C,H,N, CH,N,; ( f ) Cu-C6H,,; ( g ) K,CO,-
H,O-CH,OH; ( h ) Cr0,-H,S04-H,0-CH,COCH,; ( i ) HCI-H,O-CH,COCH,.
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
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
3 . Formation of a C-N-C-6 Bridge

During the chemical interconversion of gibberelin-A, and enmein, Somei
and Okamoto (281)investigated a nitrone photolysis reaction which gave the
veatchine-type compound 381.
Enmein was converted to 20-hydroxykaur-6-en-15a-pyranylether(382),
which was oxidized with chromium trioxide in pyridine to afford the aldehyde
383. The latter was converted with hydroxylamine to the oxime 384. The
nitrone 385 was prepared by treatment of 384 with bromine azide. Photolysis
of 385 gave the desired compound 381 in 46% yield. This intermediate
possesses several useful functionalities (e.g., carbinolamine ether linkage),
which may be of interest for synthesis of C,,-diterpenoid alkaloids after
minor changes in this scheme.
38 1 382 R = CH,OH
383 R = C H O
384 385
2. THE CHEMISTRY OF C,,-DITERPENOID ALKALOIDS 187
In 1974, Mander and colleagues (182) synthesized the antipodal lactam

386 from podocarpic acid. This lactam contains the nitrogen bridge system
of C,,-diterpenoid alkaloids. One of the routes explored was via the nitrile
387 obtained by the ethyl chloroformate dehydration of O-methylpodo-
carpamide followed by oxidation. Oxygenation of 387 with potassium tert-
butoxide and oxygen afforded a mixture of the diosphenol 388 and the
ketolactam 389 in yields of 9 and 62%, respectively. The ketolactam 389 was
hydrogenated for a prolonged period to give the desired lactam 386.
386 387
388 389
4. Synthesis of the ABE Ring System

In 1975, van der Baan and Bickelhaupt (183) reported a new approach
to the ABE ring system of C,,-diterpenoid alkaloids. Reaction of 390 with
cyanoacetamide afforded compound 391. The latter was alkylated with ally1
bromide to give 392. A Cope-type rearrangement of 392 at 100-1 10" gave
393, which was treated with ethyl iodide in DMF to afford 394. Treatment
of 394 with N-bromosuccinimide in H,O and DMSO yielded 395. Protection
of the secondary hydroxyl group in 395 as the tetrahydropyranyl ether fol-
lowed by treatment with NaOH in DMF gave the tricyclic product 396.
Compound 397 was obtained from 396 by removal of the THF group
followed by Jones oxidation. This model study suggests that synthesis of
some of the complicated alkaloids can be achieved by choosing the proper
starting materials.
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
Meyer and co-workers reported (184) a simple synthesis of a tricyclic

intermediate containing the ABE ring system. The sequence for the synthesis
of 398 is outlined in Scheme 3. Compound 398 is of interest as an inter-
mediate for synthesis of C,,-diterpenoid alkaloids containing a substituent
at the C-7 position, e.g., ajaconine, atidine, and spiradine.
5. Synthesis of Tetracyclic Intermediates Containing Ring E

In 1971, Mori, Saeki, and Matsui converted (185) the tricyclic acid 399,
during their synthesis of kaur-16-en-19-oic acid (400), into the tetracyclic
lactam 404 by the well-established photolytic method (186). The lactam
404 has previously been converted to veatchine and garryine by Wiesner's
group.
@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
insertion reaction. The starting compound 405 was prepared earlier by

Ghatak and Chatterjee (190) in work directed toward a general synthesis
of diterpenoids. Compound 405 was converted to the diazoketone 406. The
latter was treated with anhydrous copper sulfate in boiling cyclohexane-
tetrahydrofuran to give the tetracyclic ketone 407 in 20-25% yield. Con-
densation of 407 with ethyl formate in the presence of NaOH gave the
hydroxymethylene derivative 408, which was oxidized with alkaline H,02
to afford the dicarboxylic acid 409. The latter was converted to the imide
411, via the anhydride 410, by treatment with urea. Lithium aluminium
hydride reduction of 411 furnished 412, which has been used as the key
intermediate in the total synthesis of racemic atisine (191) and veatchine
(192) by Nagata’s group.
( $ 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-
acetate (413) was alkylated with 1-bromo-3-chloropropane in the presence

of NaH-DMF to give 414. Sodium borohydride reduction of 414 afforded
the alcohol 415, which was dehydrated with celite and phosphorus pentoxide
to afford the olefin 416. Treatment of 416 with sodium iodide in boiling
methyl ethyl ketone furnished the iodide 417. Compound 418 was heated
under reflux in N,N-dimethylacetamide to furnish 419. The latter was stirred
with sodium amide in liquid ammonia to afford 1-cyano-4-methoxybenz-
ocyclobutane (420).The iodide 417 was condensed with 420 to give 421 in
76% yield. Thermolysis of 421 in toluene at 230" afforded the cycloaddition
product 423 in 52% yield via the intermediate 422.
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
418 R = COOH 420 421

419 R = H
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
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
aldehyde 432. Addition of the sodium enolate of tert-butyl acetoacetate to

432 yielded compound 433, which was treated with p-toluenesulfonic acid
in acetic acid to give the tetracyclic product 434. Reaction of 434 with
pyridine hydrobromide perbromide afforded the ketophenol 435 in good
yield. Compound 435 was converted to 436 by treatment with 2-chloro-
benzoxazole and potassium carbonate in acetone at reflux temperature.
Hydrogenation of 436 over 30% PdjC gave the desired amide 437.
A c - D 0 Ac-@ 0HoH
‘CH, ‘CH,
430 431
Ac- -Npro ‘CH,

t-BuO,CJ(H
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
F. CONSTRUCTION, DEGRADATION, AND SELECTIVE REDUCTION

OF THE
OXAZOLIDINE RINGOF C,,-DITERPENOID ALKALOIDS
Recently, Mody and Pelletier reported (198)a simple and efficient method
for the degradation of the oxazolidine ring system of C,,-diterpenoid alka-
loids. This method involved a one-pot reaction and proceeds with almost
quantitative yield. An earlier reported (199) method for this degradation
involves four steps and proceeds with erratic yields. Treatment of ovatine
(6)or garryfoline (8) with acetic anydride and pyridine, followed by complete
removal of the excess pyridine and acetic anhydride, afforded the chloro-
form-soluble diacetate salt 9. Without purification, this salt was heated
under reflux in chloroform to yield lindheimerine (7) in 90% yield. In similar
manner, atisine (4) and veatchine (1) were degraded to their corresponding
imines 218 and 10 in yields of 90%. The analogous imines from the iso-
oxazolidine ring containing alkaloids, isoatisine (75) and garryine (2), were
formed in about 50% yields.
A convenient method for constructing oxazolidine and thiazolidine rings
from the imine-containing C,,-diterpenoid alkaloid derivatives has been
reported by Pelletier, Nowacki, and Mody (155).Treatment of lindheimerine
(7) with ethylene oxide in glacial acetic acid or with excess neat ethylene
sulfide afforded the corresponding oxazolidine (6) and thiazolidine (438),
respectively, in almost quantitative yields. Details of this method are dis-
cussed in Section V.
6 R=Ac 9
;_I$--..
8 R=H
--H :....* --H
OAc OAc
CH, CH,
7 438
A new method for converting the N-CH,-CH,OH group in

diterpenoid alkaloid derivatives into the isooxazolidine derivatives
using active manganese dioxide has been reported by Pelletier, Mody,
2. THE CHEMISTRY OF CzO-DITERPENOID ALKALOIDS 195
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
Recently, a method for formation of the “iso-type” oxazolidine ring from

-NCH,CH,OH group-containing alkaloids by oxidative cyclization with
silver oxide was reported (201). This method afforded higher yields of the
“iso-type” oxazolidine ring-containing compounds than any previously
reported method, e.g., treatment of dihydroatisine (78) with silver oxide at
96°C for 2.5 hr gave isoatisine (75) in a yield of 90%.
In 1980, the first one-step oxidation method for converting
-NCH,CH,OH group-containing alkaloid derivatives simultaneously into
196 S. WILLIAM PELLETER AND NARESH V. MODY
both the “normal” and “iso-type” oxazolidine ring-containing alkaloids

was reported (202). Thus, dihydroveatchine (231) was converted into
veatchine (1) and garryine (2) in a total yield of 95% using alkaline
ferricyanide. Compared to other methods, this high-yield procedure is sim-
ple, reliable, and uses an inexpensive oxidizing reagent.
In 1979, Pelletier and co-workers reported (203) a method for selective
reduction of the oxazolidine ring of C,,-diterpenoid alkaloids in the presence
of a ketone or an a$-unsaturated carbonyl group. Reduction of atisinone
(225) with sodium cyanoborohydride at pH 6-7 at room temperature fur-
nished dihydroatisinone (441) in almost quantitative yield. They generalized
this reduction method by using various alkaloid derivatives containing
either an &unsaturated ketone or a simple ketone moiety.
IX. A Catalog of C,,-Diterpenoid Alkaloids
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
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
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
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
Dihydroatisine
C,,H35N0,; MW 345
mp 159-161 ; [zID -44.5' (EtOH)
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
Hetidine
CZ1HZ7NO4; MW 357
mp 218-221'; [rID-
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
Refs. 80, 118-124
Hetisinone
HO C,,H,,NO,; MW 327
+
mp 268-270"; [&ID 18"
Delphinium cardinale; D. denudatum ;
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 :
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
Isogarryfoline
C,,H,,NO,; MW 343
mp 140-144.; {%ID-57 (Chf)
Garrya laurifolia
< 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.
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
Refs. 48-57
0Ac
Miyaconitine
0 C,,H,,NO,; MW 415
\ mp 218' (decomp.); [%ID -87.8' (Chf)
Aconitum miyabei
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
',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
Spiradine A
C,,H,,NO,; MW 311
mp 281-282'; [aID----
Spiracea japonica
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
Ref. 140
Spiradine F
C,,H,,NO,; MW 399
mp 114-1 17‘ (hydrochloride); [%ID--
Spiraea juponica
Ref. 142
---
‘0
Spiradine G
C,,H3,N0,; MW 357
mp 168-17OC; [%ID-
Spiraea japonicu
Ref. I42
Spiredine
C Z 2 H 2 , N 0 3MW
; 353
mp 163’;
Spiraea japonica.
Ref. 141
Spireine (Structure 1)
C22H,,N0,; MW 369
mp 230’ ; [a]D-
Spiraea juponica
Refs. 137, 143
Spireine (Structure 2)
C,,H,,NO,. MW 369
mp 230 , [xlD-
Spiraea iaponica
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
Ref. 149
Staphimine
C,,H5,N,O; MW 590
Amorphous; [xID -58.5 (C6H6)
‘H- and I3C-NMR spectral analysis
Ref. 148
Staphinine
C,,HS6N,0,; MW 620
Amorphous; [uID -57.5‘ (C6H6)
‘H- and ‘-’C-NMR spectral analysis
Ref. 148
Staphirine
C,,H,,N,O,: MW 620
mp 222-225 : [.Il, - 126 (C,H,)
Delphinium staph isagriu
Ref. 149
Staphisagnine
,-., C,,H,,N,O,; MW 666

Resin; [?I1, - 104.5' (C,H,)
H3C$.-. ''i 'H- and I3C-NMR
spectral analysis
.,~.
_ , -0
Ref. I50
. \
H %-.
C H 3 0 - 0
h
Staphisagrine
.’ . C 4 3 H 6 0 N 2 0 2MW
: 636
mp 229-231 , [.ID - 105.6 (C,H,)
‘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
i;..
Refs. 144-148
H C... ..N
CH3
Vakognavine
0 C3,H3,XO,,; MW 619
\ mp 298.’: [%ID---
Aconiturn pulnuirurn
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-
THE 13C-NMR SPECTRA OF

ISOQUINOLINE ALKALOIDS
D. W. HUGHESAND D. B. MACLEAN
Department of Chemistry, McMaster University, Hamilton, Ontario, Canada
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
Since the late 1950s PMR spectroscopy has contributed immensely to

many areas of the chemistry of alkaloids ( I ) . With the advent of Fourier
transform spectrometers CMR has rapidly approached the level of PMR in
its application to problems of structural elucidation and stereochemistry.
In the case of the alkaloids many classes of the isoquinoline family have been
studied. These alkaloids are of particular interest not only because of their
widespread occurrence in nature but also because of their pharmacological
activity (2-5). Wenkert et nl. (6)were the first to review progress in this area.
More recently, Shamma and Hindenlang (7) have made an extensive compi-
lation of chemical shift data on amines and alkaloids that includes many
T H E ALKALOIDS, VOL X V l l l
Copyright @ 1981 by Academic Press. Inc
All rights of reproduction m any form reserved
ISBN 0-1 2-4695 18-3
218 D. W. HUGHES A N D D. B. MACLEAN
examples from the isoquinoline group. In this chapter we have extended

these reviews to cover the literature to mid-1979. We have not attempted to
provide a comprehensive listing of all the data that are available. Instead,
we have selected examples that are characteristic of a particular structural
feature within a given class. We have attempted to show where novel experi-
mental techniques have been used to advantage in the assignment of chemical
shifts, and we have tried to show how the chemical shift of a particular
carbon atom may be influenced by change in functionality, substitution, or
stereochemistry at neighboring centers. We have also emphasized the value
of this technique in differentiating among diastereomers and conformational
isomers and its utility in structural elucidation.
The chemical shifts reported here were obtained from spectra recorded
using CDCl, as the solvent unless otherwise stated and are in ppm downfield
from TMS. For those not familiar with CMR and the associated experi-
mental procedures references (8-13) should be consulted.
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
11. 1,2,3,4-Tetrahydro- and 3,4-Dihydroisoquinolines
In a systematic examination of the CMR spectra of the isoquinoline

alkaloids it is appropriate to begin with a discussion of the spectra of several
simple isoquinolines (Fig. 1 and Table I) since this structural unit is common
to the alkaloids. The 3C spectrum of 1,2,3,4-tetrahydroisoquinoline (1)
has been reported by two groups (14,15).The chemical shift assignments of
the aliphatic carbon atoms followed from comparison to piperidine (5) and
tetralin (6) (8, 9, 16). In the case of the two carbon atoms adjacent to the
nitrogen atom in 1, that at C-1 is at lower field because of the larger a-
substituent effect of the phenyl group (8, 12). These assignments have been
verified by selective ’H decoupling (17) (the chemical shifts given in refer-
ence 15 for C-1 and C-3 should therefore be reversed). Comparison of the
chemical shifts of the aromatic carbon atoms of 1 with those of tetralin (6)
permitted the tentative assignments given in Table I.
The introduction of rnethoxyl groups at C-6 and C-7 into the tetrahydro-
isoquinoline system, a common substitution pattern in the alkaloids, as in
TABLE I
SHIFTS
l 3 C CHEMICAL OF
1.2,3,4-TETRAHYDROlSOQ~lNOLlNES“
Carbon 1 2 3 4
1 48.2 47.8 57.6 43.6

3 43.8 43.9 53.0 43.6
4 29.1 28.6 28.8 28.5
4a 136.1’ 127.9’ 126.7’ 129.9‘
5 129.2’ 112.2 111.6 124.4
6 125.6’ 147.5’ 147.7’ 110.8
7 125.9’ 147.3’ 147.3’ 145.5
8 126.1’ 109.3 109.5 150.3
8a 134.8’ 126.6’ 125.8’ 128.0’
6-OCH3 55.9 55.9
7-OCH3 55.9 55.9 55.9
8-OCH3 60.0
NCH, 46.0
Hughes et a/. (14).

The chemical shifts within a vertical column are
not unambiguously assigned and may be inter-
changed. However, some carbon atoms which have
nearly identical chemical shifts such as those of
o-dimethoxyl groups have not been indicated by
footnotes. The original papers should he consulted
in these cases.
220 D. W. HUGHES AND D. B. MACLEAN
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
C-1. Second, although the two methoxyl groups would be expected to be

nonequivalent, the most sterically crowded methoxyl group at C-8 appeared
at lower field (60.0 ppm). Similar observations were made by Dhami and
Stothers in the case of o-disubstituted anisoles (19). Experimental verification
of this assignment is provided in the discussion of canadine in Section XI.
The 3C spectra of three 1-methyl-1,2,3,4-tetrahydroisoquinolines(9-11)
(Fig. 2 and Table 11) were recently reported by Verchere et al. (20). The
methyl substituent of 10 caused chemical shift changes relative to 2 in the
aliphatic carbon atoms (C-1, f3 .5 ; C-3, -2.0; C-4, 1.0 ppm) that were +
similar to those observed at C-2 for the pair, piperidine, and 2-methyl-
piperidine (9). The deshielding of C-8a in 10 relative to 2 may be attributed
to the fl effect of the C-1 substituent (8).
Several N-methyl- 1,2,3,4-tetrahydroisoquinolines(12-15) substituted at
C-1 (Fig. 2) have been prepared in this laboratory as synthetic intermediates
and their I3C spectra recorded (Table 11). Compound 3 served as a model
for evaluating the effect that these substituents had on the aliphatic carbon
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
a Verchere et ul. (20).

Hughes and MacLean. (17).
Manske c.t a/. (21).
Solvent. DMSO-d6
' Shamma and Hindenlang. (7)
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
Carbon 20" 21h 22' 23' Uh 25d
1 159.8 159.5 163.5 163.4 164.6 164.8

3 47.3 47.4 47.1 46.9 50.5 49.8
4 25.0 24.7 25.8 26.7 25.5 25.5
4a 136.2 129.8 131.3 139.5 132.3 136.4
5 126.9 110.5 110.6 111.8 111.3 109.6
6 130.8 151.3 151.1 161.2 157.6 155.6
7 127.3 147.9 147.7 112.9 148.8 147.7
8 126.9 110.5 109.5 127.0 115.7 112.0
8a 128.4 121.6 122.7 123.2 117.2 119.0
6-OCH3 56.0 56.0 55.1 57.0
7-OCH3 56.1 56.4 57.2
6,7-OCH,O 103.9
1-CH, 23.4 23.1
NCH, 48.1 47.7
Christ1 (22).
Hughes et al. (14).
Verchire et al. (20).
Hughes and Maclean. (17).
111. Benzylisoquinoline Alkaloids
The benzylisoquinoline alkaloids are widely distributed in nature and are

intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not
surprising therefore that several groups (6, 7, 15, 23) have examined their
spectra. Among the alkaloids that have been studied are reticuline (26) (7),
norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-N-
oxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of
laudanosine are recorded in Table IV and the structures of the alkaloids may
be found in Fig. 4.
The assignments of the 13Cchemical shifts of laudanosine were first made
by Wenkert et al. (6) and confirmed later (15). It is now apparent that com-
pounds 2 and 3 (14) and 3,4-dimethoxyphenethylamine(6, 15) serve as sat-
isfactory models of the isoquinoline and benzyl moieties, respectively. The
substitution of a 3,4-dimethoxybenzyl group at C-1 of 3, as in laudanosine
(28), caused changes to occur in the chemical shifts of the aliphatic carbon
atoms of the tetrahydroisoquinoline moiety analogous to those of the
+
compounds with substituents at C-1 listed in Table I1 (C-1, 7.9; C-3, - 6.2;
C-4, -3.5; NCH,, -3.6). The chemical shift changes between 27 and 28
TABLE IV
"C CHEMICALSHIFTSOF
LALDANWNE (28) AND
ITS QUATERNARY
SALT(32)
Carbon 28" 32b
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.
accounted for by a conformational change of ring B in order to minimize

steric interactions at the pseudoaxial N-methyl group.
Castedo et al. (26) have used I3C NMR to resolve the structure of an
0-denethylation product of papaverinol(31) obtained by treatment of the
compound with sulfuric acid. It is known that when a phenol is transformed
to its phenoxide the para carbon is shielded (8).When the spectra of the
demethylation product and its anion were examined it was observed that
C-1' was shielded by - 8.3 ppm in the anionic compound. It was apparent
therefore that demethylation had occurred at C - 4 and not at C-3' as orig-
inally suggested.
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
The bisbenzylisoquinoline alkaloid, isochondodendrine (33), (Fig. 5 and

Table V) and its O-methyl and O-acetyl derivatives have been studied by
13C NMR (23). The aliphatic carbon atoms of this symmetrical molecule
were assigned by comparison to the benzylisoquinoline alkaloids and by
the off-resonance spectrum. The oxygen substituent at C-8 caused a shielding
of C-1. In the aromatic region of the spectrum C-9 and C-12 had chemical
shifts which remained essentially constant in all derivatives examined.
Methylation and acetylation of the phenolic group produced charac-
teristic shift changes which allowed the assignment of C-4a, C-6, C-7, C-8,
33
3. THE 13C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 227
TABLE V
I3cCHEMICAL SHIFTS OF
(33)
ISOCHONDODENDRINE
Carbon 33".h Carbon 334.h
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
a Solvent CDCI, + CH,OH

Marsaioli et al. (23).
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,
FIG.6 . Cularine (34).
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
” Wenkert et ill. (6)
second-order coupling effects that the authors attributed to virtual coupling

(12, 29,30). Carbon-6 was assigned to higher field than C-5 since it is ortho
to the methoxyl group at C-7, and C-5’ to higher field than C-2’ since it is
ortho to both methoxyl and aryloxy substituents. It is of interest that the
study of the 13C spectrum clarified the ‘H spectrum. Thus, in correlating
the I3C and ‘H chemical shifts in a series of off-resonance spectra (11, 12)
the authors found that the original proton assignments at H-5’ and H-2’
(31) were in error and should be reversed.
Selective irradiation of the aromatic protons allowed the assignment of the
resonances to C-l’, C-4a, and C-8a by the observation of coupling to benzylic
and homobenzylic protons. Carbon- 1’ appeared as a triplet being coupled
to the protons at C-9 whereas C-4a and C-8a were broad multiplets. Under
the same conditions the chemical shifts of the oxygenated aromatic carbons
were determined from three bond coupling to methoxyl protons as well
as by comparison to the laudanosine data.
VI. The Morphine Alkaloids
Thc alkaloids of this group are renowned for their pharmacological

activity and it is not surprising therefore that several groups have examined
their spectra or those of derivatives (32-34). The first complete assignment
of spectra to these alkaloids was made by Terui et a/. (32), and shortly
thereafter a more comprehensive report by Carroll et a/. (33) appeared.
The alkaloids and model compounds that are discussed are shown in Fig. 7
and 3C data are recorded in Table VII.
3. THE 13C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS 229
NR
6CH,
35 R = H 37
38
36 R = CH3
39 R1 = CH3. RE = H 40
41 R, = RE = H
42 R1 = R2 = COCH3
FIG.7. Morphine alkaloids and model compounds
Terui et al. used 3-methoxymorphinan (35)and several derivatives of it

as models in assigning the chemical shifts of the alkaloids. The data that
they obtained for 35 and its N-methyl derivative (36)are listed in Table VII.
The assignments were made using conventional techniques and by noting
the shifts resulting from introducing various substituents at C-6 (carbonyl
and a-hydroxyl), and at C-14 (hydroxyl). Compound 37 was also used as a
model.
The information obtained from the model studies was then applied to the
spectra of sinomenine (38), codeine (39), and thebaine (40), the spectra of
which are also recorded in Table VII. Except for the assignment of the
quaternary carbon atoms in 39 and 40 the other assignments followed readily
from model studies and from application of shift parameters. The quater-
nary carbon atoms of codeine had already been examined by Wehrli (35)
using spin lattice relaxation time ( T I )measurements. In this way an unambig-
uous assignment of the signals at C-3, C-4, C-11, and C-12 was achieved.
Carroll ef a/. confirmed the assignments made by Terui et a/. for codeine
and thebaine and investigated a large number of related compounds. They
230 D . W . HUGHES AND D. B. MACLEAN
TABLE VII
I3C CHEMICAL
SHIFTSOF MORPHINE A K D MODELCOMPOVNDS
ALKALO~DS
Carbon 35" 36" 31" 38" 39" 40" 41' 42'
1 128.3 128.2 128.3 117.9 119.3 119.1 118.6 119.1

2 11 1.O' 110.9' 110.9' 109.1 112.8 112.9 116.4 121.6
3 158.0 158.0 158.0 145.2' 142.0 142.7 138.5 132.0
4 110.6' 110.6' 112.0' 144.8' 146.2 144.6 146.3 149.1
5 37.1 36.6 49.5 49.1 91.3 89.0 91.5 88.5
6 22.2 22.3 197.2 193.4 66.4 152.3 66.4 67.9
7 26.Sd 26.8* 130.9 152.3 133.2 95.8 133.4 129.2
8 26.7d 26.6d 149.4 115.3 128.1 111.3 128.5 128.2
9 51.3 57.9 56.1 56.6 58.7 60.7 58.1 58.7
10 33.8 23.4 23.8 24.4 20.4 29.5 20.2 20.4
11 130.1 129.7 128.2 130.3 127.0 127.6 125.5 131.5
12 141.7 141.5 138.8 122.1 130.9 133.1 131.0 131.2
13 38.4 37.2 39.9 40.5 43.0 46.0 43.0 42.6
14 46.2 45.4 45.6 45.7 40.7 132.3 40.6 40.4
15 42.9 42.1 39.9 35.8 35.8 37.0 35.6 34.9
16 39.2 47.2 46.4 47.1 46.4 46.0 46.1 46.3
NMe ~
42.7 42.7 42.5 43.0 42.3 42.8 42.8

3-OMe 55.2 54.9 55.0 55.8 56.2 56.2
OMe ~ - ~~
54.6 ~
54.7
3-m,CO 20.4
3-CH,C_O 168.2
6-=,CO 20.4
6- CH 3C_0 170.2
" Terui ti a/. (32).

Carroll ei a!. (33)
"
c.d Assignments may be interchanged
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.
VII. Cancentrine Alkaloids
Cancentrine (43) is a complex alkaloid that embodies within its structure

a modified codeine skeleton and a cularine skeleton. Its I3C spectrum along
with that of some derivatives was studied (36)in order to obtain chemical
3. THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 231
shift data useful in structural elucidation of other alkaloids of this group.

Structures and 13C data are found in Fig. 8 and Table VIII, respectively.
The spectrum of cancentrine was interpreted primarily by comparison with
the previously discussed spectra of cularine and the morphine alkaloids,
particularly codeine. The assignments of C-10, C-15, C-16, and the NCH,
of cancentrine followed by analogy from the corresponding carbon atoms
of codeine and were confirmed by the off-resonance spectrum. The high-field
43 R,=R = H
2
44 R , + R 2 = 0
45 4, = R2 = H
46 R, + R 2 = 0
FIG.8. Cancentrine (43)and related compounds.

TABLE VIII
13C CHEMICAL SHIFTSOF CANCENTRINE
(43),
10-OXOCANCENTRINE(44),CODEINONE
(45),
AND 10-OXOCODEINONE(46)
Carbon 43" 44" 4Sb 46"
1 119.7 120.2 119.7 120.0

2 115.3 115.3 114.7 115.0
3 142.7 146.6 142.3 149.6
4 145.1 143.3 144.6 144.9
5 97.5 96.7 88.0 87.7
6 79.1 78.3 194.1 193.2
7 194.0 193.2 132.2 132.7
8 40.2 40.0 149.1 148.3
9 58.8 68.0 58.9 68.5
10 20.4 196.3 20.4 190.4
11 127.4 124.4 126.1 125.1
12 127.7 135.6 129.0 137.1
13 51.4 52.5 43.1 44.6
14 46.2 48.9 41.4 44.4
15 33.2 32.1 33.9 33.9
16 46.6 47.3 46.7 47.2
17 124.3 124.2
18 116.3 115.9
19 149.8 149.5
20 138.0 137.8
21 146.8 146.6
22 109.2 108.9
23 116.6 115.9
24 104.3 104.3
25 160.1 160.4
26 121.4 121.0
27 147.7 146.8
28 140.7 140.5
29 119.7 119.2
30 127.8 127.5
31 29.0 28.8
32 57.8 57.3
3-OCHx 56.5 56.3 56.7 56.3
19-OCH3 56.5 56.3
21-0CH3 56.5 56.3
NCH, 43.2 43.3 42.9 43.4
Holland ef al. (36)

Terui et al. (32).
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.
In the aliphatic region of the 10-oxocancentrine spectrum the signal at

20.4 ppm corresponding to C-10 in cancentrine was absent. Both C-9 and
C-14 were deshielded as in the model discussed above. These results con-
firmed the location of the carbonyl at C-10 in oxocancentrine. The assign-
ments made to the quaternary aromaticand carbonyl carbons were considered
to be tentative by the authors.
VIII. Pavine Alkaloids
The I3C chemical shifts of the symmetrical pavine alkaloids argemonine

(47) (6) and eschscholtzine (48) (17) (Fig. 9) are presented in Table IX. The
difference in chemical shifts between the two alkaloids in large measure
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
Carbon 47" 4Sb
1,7 109.9 107.1

23 147.3 146.1
3,9 147.7 146.5
4,lO 111.4 108.7
4a,10a 123.7 125.6
5,ll 33.3 34.1
6,12 66.2 56.8
6a,12a 129.7 131.1
2,8-OCH, 55.4
3,9-OCH3 55.8
2,3-OCH,O 100.6
8,9-OCH,O 100.6
NCH, 40.6 40.8
" Wenkert et al. (6).

Hughes and MacLean (17).
reflect the difference in substituents on the aromatic rings. A discrepancy is

present between the two alkaloids in the chemical shift of C-6 but the reason
for this is not apparent.
IX. Aporphine Alkaloids

'
Several groups have examined the 3C spectra of the aporphine alkaloids
(6, 7,38-40); examples are found in Fig. 10. The chemical shift assignments
(Table X) for the aliphatic carbon atoms of rings B and C were made by
comparison to laudanosine (28) (6) and to the reduced proaporphines (41).
In the case of caaverine (49) a comparison with ( f)-lirinidine (50) revealed
the p deshielding effect of the N-methyl group on C-5 and C-6a and the
shielding of C-7 by a y effect.
The analysis of the aromatic carbon atoms was aided by the use of selective
'H decoupling and long-range I3C-lH coupling (6, 40). For example, in
thaliporphine (51) C-1 is bonded to a hydroxyl group and is split into a
doublet ( 3 J z 7.0 Hz) by coupling to H-3. Carbon-2, which carries the
methoxyl substituent, appeared as a broad multiplet owing to coupling to
the methoxyl protons. Irradiation of H-3 caused C-1 to collapse to a singlet.
When the positions of the hydroxyl and methoxyl groups are reversed as in
predicentrine (52), C-1 was now broad with unresolved coupling to the
methoxyl protons whereas C-2 was a singlet owing to the small ortho coupl-
ing to H-3 ( 2 J e 1.0 Hz). C-1 and C-2 in compounds such as nuciferine (53),
which have ortho dimethoxyl groups at these positions, can be differentiated
by measuring the changes in the width at half-peak height of the unresolved
multiplets in the coupled spectra. If H-3 was irradiated the width at half
height for C-1 was reduced from 16 Hz to 9 Hz whereas that for C-2 was
virtually unaffected (40). Similar experiments were performed to assign the
oxygenated carbon atoms of ring D.
The chemical shifts of the nonoxygenated quaternary aromatic carbon
atoms were more difficult to assign because of the additional coupling to
benzylic protons. Only C-1l b was determined by selective proton irradiation
since it was coupled through the biphenyl linkage to H-1 1. The assignment
of the other carbon-substituted carbon atoms relied on comparing the effects
of different substituents on these atoms. This is illustrated for C-7a and
C- 1l a if one examines the series nuciferine (53), nuciferoline (54), glaucine
(559, and nantenine (56).
In alkaloids such as isocorydine (57) and bulbocapnine (58),which contain
substituents on C- 10 and C-11, the chemical shifts of the ring D carbon atoms
were determined not only by the methods discussed above but also by the
observation of second-order effects in the off-resonance spectra of C-8 and
C-9 (6).
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
The effect of nitrogen quaternization on the chemical shifts of several

OCH,
60
aporphine alkaloids was studied by Marsaioli et al. (39). The conversion of

dicentrine (59) to its methiodide salt (60)caused deshielding of C-5 and C-6a
whereas C-3a, C-4, C-7, C-7a, and C-1Ic were all shielded. The shielding of
the aromatic carbon atoms may be caused by the electric field effect similar
to that observed in nitrogen protonation (8, 12). C-4 and C-7 were most
likely experiencing the y steric effect of the new methyl group.
TABLE X
-'C CHEMICAL
SHIFTS
OF THE 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
' Ricca and Casagrdnde (40); Solvent: DMSO-d,.

Shamma and Hindenkdng (7).
' Wenkert et al. ( 6 ) .
Marsdioh et d.( 3 9 ) ;Solvent: CDCI, + C H 3 0 H .
238 D. W . HUGHES AND D. B. MACLEAN
X. Reduced and Nonreduced Proaporphines
The 3C chemical shifts of several reduced (61-64) and nonreduced (65,

66) proaporphine alkaloids (Fig. 11 and Table XI) have been reported by
Ricca and Casagrande (41). The authors studied several pairs of diastereo-
mers and found the I3C chemical shifts to be sensitive to the relative stereo-
chemistry in these compounds.
A comparison of the data for compounds 61 and 62 showed that the
double bond could be located by examining the chemical shift of C-7. From
molecular models it was found that when the double bond was between C-8
and C-9 a y gauche interaction existed between the axial proton on C-1 1 and
the a proton on C-7. This interaction was used to explain the higher field
shift of C-7 in compounds with the 8,9-double bond such as 61. When the
double bond was between C-1 1 and C-12 these interactions were no longer
present and C-7 appeared at lower field in 62. The chemical shift at C-7 was
61 62
63 R1 = OH, R2 = H 65 R = H
64 R1 = H, R2 = OH 66 R = CH3
FIG.11. Reduced and nonreduced proaporphines.

3. THE 13C-NhXRSPECTRA OF ISOQUINOLINE ALKALOIDS 239
TABLE XI
,C CHEMICAL
SHIFTS
OF THE REDUCEDAND
NONREDUCED
PROAPORPHINES'
Carbon 61 62 63 64 65 66
1 140.9 140.8 141.5 140.9 141.5 143.7

2 148.0 147.9 148.5 147.6 147.6 152.7
3 110.0 110.2 111.2 109.4 110.7 111.9
3a 130.3 129.2 129.3 129.7 124.7 132.9
4 26.9 26.8 26.7 26.8 26.8 27.0
5 54.6 54.6 54.7 55.0 54.6 54.3
6a 65.3 64.6 64.4 65.1 65.2 65.0
7 43.0 48.8 40.4 37.9 46.7 46.9
7a 47.0 47.8 51.4 52.7 50.5 50.7
7b 134.0 134.5 134.1 134.5 134.8 134.8
7c 121.5 121.5 121.0 120.9 122.0 127.5
8 157.5 33.1 75.5 69.0 154.7 154.3
9 126.8 35.2 46.0 48.5 127.7 127.7
10 198.9 198.5 209.2 209.6 185.5 185.3
11 35.2 126.8 38.4 32.0 126.7 126.6
12 30.7 155.1 26.1 28.7 150.8 150.9
1-OCH, 60.2
2-OCH, 56.3 56.4 56.2 56.3 56.4 56.1
NCH 43.4 43.4 43.5 43.5 43.3 43.2
Ricca and Casagrdnde (41).
also shown to be diagnostic of the stereochemistry of the alcohol function

at C-8 in compounds 63 and 64. In 64 the hydroxyl group is in a configuration
which results in a steric shielding effect at C-7.
In the nonreduced proaporphines, ( -)-glaziovine (65) and ( -)-pronu&
ferine (66), the additional double bond in ring D results in a shielding of the
carbonyl carbon. Similar observations have been made in other cross-
conjugated system (8, 42).
XI. Tetrahydroprotoberberine Alkaloids
The tetrahydroprotoberberine alkaloids have a tetracyclic ring structure

which is based on the dibenzo [a,g]quinolizidine system (Fig. 12). Carbon- 13
NMR has been used extensively to study the quinolizidine conformation
(14, 27, 28, 43-50).
The chemical shift assignments (Table XII) for the majority of the carbon
atoms were made by comparison with the appropriately substituted simple
isoquinolines such as 2 and 4. Since the chemical shifts of the aliphatic
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
FIG.12. Tetrahydroprotoberberine alkaloids.
carbon atoms, in particular that at C-6, reflect changes in the quinolizidine

conformation, definitive assignment of these carbon atoms was requisite.
Reduction of berberine chloride with NaBD, yielded ( +)-canadhe (67)
labeled with deuterium at C-8 and C-14 (14). In the spectrum of the labelled
compound the signals at 59.6 and 53.4 ppm were virtually absent and these
were assigned to C-14 and C-8, respectively. C-6 and C-8 were also dif-
ferentiated by the observation of virtual coupling effects at C-6 (6). The
3. THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 24 1
TABLE XI1
13
C CHEMICAL
SHIFT^ TETRAHYDROPROTOBERBERINES
OF THE
Carbon 61" 68" 69" 70b 71" 72" 13' 74' 75' 76' 11'
1 105.5 105.7 108.9 108.7 109.0 112.1 151.9 113.0 105.6

L 146.0 146.1 147.6 147.5 147.3 146.7 140.2 146.1 146.1
3 146.2 146.2 147.6 147.5 147.8 148.0 150.1 147.9 146.5
4 108.4 108.5 111.5 111.6 111.3 111.1 107.4 110.9 108.4
4a 127.8 128.0 127.8 126.8 128.5 127.7 130.6 130.0 128.5
5 29.5 29.7 29.1 29.1 29.4 28.1 30.0 24.9 23.9 30.7 29.3
6 51.4 51.4 51.5 51.4 51.5 47.0 48.3 63.8 52.1 46.3 50.8
8 53.4 53.5 54.0 58.3 54.5 51.1 53.3 64.0 61.6 60.9 53.8
8a 127.8 121.4 126.9 126.5 128.6 126.5 128.3 126.9 127.2
9 150.3 141.7 150.3 109.1 150.2 150.2 150.9 150.7 151.6
10 145.2 144.2 145.2 147.7 145.1 145.4 145.3 149.6 144.5
11 111.1 109.1 111.1 147.7 111.7 111.1 110.9 111.7 111.1
12 123.8 119.4 123.7 111.5 124.1 123.2 124.0 123.6 123.4
12a 128.7 128.1 128.7 126.5 135.1 133.0 128.6 134.2 129.4
13 36.4 36.5 36.4 36.5 38.4 34.6 33.0 32.9 38.7 69.0 69.8
14 59.6 59.7 59.3 59.7 63.1 64.2 55.5 70.8 72.9 78.3 64.6
14a 130.9 131.1 129.9 129.9 128.6 130.7 124.2 130.0 130.9
15 68.7
1-OCH, 60.6
2-OCH3 55.8 55.8 55.9 55.9 60.1 55.9
3-OCH3 55.8 56.0 55.8 55.9 55.8 56.0
9-OCH3 60.1 60.1 60.1 60.4 60.6 60.9 60.0
10-OCH, 55.8 56.2 56.1 55.8 56.2 56.4 55.8 55.9 55.7
11-OCH, 56.0
1,2-OCH,O 100.7 100.8 100.7
13-CH3 18.4 22.4 22.0
NCH, 44.2 52.0
a Hughes e t a / . (14).
Moulis rt a/. (49).
Kametani e t a / . (44).
' Takao et a/. (28).
Manske et a/. (21).
methoxyl group at C-9 of canadine was labeled with deuterium by treating

nandinine (68) with diazomethane in D,O (14). The resonance at 60.1 ppm
was absent in the spectrum of the labeled compound, thereby confirming the
lower field position of the sterically crowded methoxyl group. Because of the
similarity in chemical shift for C-2 and C-3, for C-42 and C-l4a, and for
C-8a and C-12a these signals could not be unambiguously assigned.
The chemical shift of C-8 may be used to determine the position of the
oxygenated substituents in ring D. A comparison of the spectra of tetrahydro-
palmatine (69) and xylopinine (70) (49) showed that C-8 in (70) is deshielded
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.
FIG.13. Conformations of the BIC rings in the tetrahydroprotoberberines.

3. THE I3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS 243
Kametani and co-workers ( 4 3 , 4 4 )have used 13CNMR to study the effect

of C-1 substituents on the stereochemistry of the quinolizidine system in this
group of alkaloids. In 0-methylcapaurine (73), which has a methoxy group
at C-1, the quinolizidine system was considered to be in the cis form. This
conclusion was based on the upfield shift of C-6. Comparison of 73 with 71
and 72 revealed some interesting differences. C-5, C-6, C-8, and C-13 were
all shielded in the cis form of the 13-methyltetrahydroprotoberberines
relative to the trans form but only C-6 and C-13 were affected in 73. Carbon-
14 in 73 was shifted upfield relative to 72 in a manner analogous to that
found for C-1 in compound 72, and this steric shielding is probably greater
than any chemical shift change associated with cis-trans interconversion.
C-5 and C-8 of 73 did not show any upfield shift as they did in the 13-methyl
compounds. These results indicated a difference in the cis conformation of
the two types of compounds and it has been proposed that this was caused
by different cis-trans equilibrium .constants (28, 48).
Other cis-trans isomers have been examined by 13C NMR; these include
the 8-methyltetrahydroprotoberberines (46,47)which have also been studied
by PMR spectroscopy (53),the N-oxides of tetrahydropalmatine (45),and
several N-methyl salts such as the methochlorides of thalictricavine (trans)
(74) and mesothalictricavine (cis) (75) (28, 45).
The structure of a new tetrahydroprotoberberine alkaloid solidaline (76)
was established in part by 3C NMR (21).The chemical shifts were assigned
primarily by comparison with the data for ophiocarpine (77), mesocorydaline
(72), and hydrastinine (15). By this procedure C-5, C-6, and C-15 were
readily identified. The presence of the structural unit CH2-CH was indi-
cated by an ABX pattern in the PMR spectrum. These carbon atoms were
assigned to 68.7 ppm (CH,) and 60.9 ppm (CH) in the 13C spectrum. The
quaternary carbon atom resonances at 69.0 and 78.3 ppm were assigned to
C-13 and C- 14, respectively. A cis-quinolizidine conformation was evident
based on the chemical shifts of C-5 (30.7 ppm) and C-6 (46.3 ppm) which
are similar to those of the corresponding carbon atoms in mesocorydaline.
This conformation was further supported by the methyl signal of C-13 at
22.2 ppm which was nearly identical with that in 72. It appears that any
deshielding of the C-methyl group by the p-hydroxyl group at C-13 is
countered by the 7 shielding effect of the C-14 oxygen substituent.
XII. Protopine Alkaloids
The protopine alkaloids have a 10-membered ring containing a carbonyl

group and a tertiary nitrogen atom. Even though they do not have an
isoquinoline ring they are properly classified in the isoquinoline family
because of their biosynthetic derivation from the protoberberines. An

interesting feature of these alkaloids is the conformational flexibility of the
central ring that allows a transannular interaction between the carbonyl
group and the nitrogen atom. This interaction, which is promoted by acids,
has been studied by numerous physical methods (2). In a study by CMR
spectroscopy (54) a number of representative alkaloids were examined,
among which were protopine (78), cryptopine (79), and hunnemanine (80)
(Fig. 14 and Table XIII).
In addition to using standard methods of assigning chemical shifts, such
as additivity relationships, selective H decoupling, and deuterium labeling,
the authors used gated decoupling (55,56) to differentiate among the
protonated aromatic carbon atoms. C-1 and C-1 1 appeared as doublets with
lJCH= 160 Hz, whereas C-4 and C-12 showed additional coupling to the
methylene protons at C-5 and C-13, respectively.
In hunnemanine (80), which differs from the other alkaloids in having a
phenolic hydroxyl group, the carbonyl resonance was shielded by 15-20 ppm
relative to the other alkaloids and was also broadened. It was considered
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
FIG.14. Protopine alkaloids.

TABLE XI11
I3C CHEMICAL
SHIFTSOF THE PROTOPINE
ALKALOIDS’.~
Carbon 78 19 80
1 107.5 111.8 108.1

2 145.9 146.7 145.5
3 147.5 149.0 147.5
4 109.9 112.2 109.7
4a 135.8 134.3 135.0
5 31.2 31.8 31.0
6 57.4 57.2 56.7
8 50.4 49.9 49.8
8a 117.5 117.1 120.7
9 145.5 145.9 145.0
10 145.4 145.6 143.5
11 106.1 106.2 108.5
12 124.6 124.5 122.3
12a 128.5 128.9 128.0
13 46.0 45.7 45.4
14 194.1 194.7 173.8
14a 132.2 130.8 131.8
2,3-OCH,O 100.6 100.6
9,lO-OCH20 100.3 100.3
2-OCH 55.4
3-OCH3 55.4
10-OCH, 55.4
NCH, 40.9 40.8 40.5
Nakashima and Maciel(54)

Shamma and Hindenlang (7).
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.
XIII. Phthalideisoquinoline Alkaloids
Among the phthalideisoquinoline group of alkaloids there are several

pairs of diastereoniers. It is shown below that CMR spectroscopy is an
effective means of differentiating between such a pair of isomers. Spectra
/ 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
TABLE XIV
"C CHEMICAL
SHIFTSOF PHTHALIDEISOQUIKOLIXE
THE ALKALOIDS
Carbon 81" 82" 83" 84" 85ib.' Wb 90b
1 66.0 66.2 65.7 65.7 66.0 66.2 60.9

3 49.0 51.3 49.5 51.7 49.5 51.4 50.1
4 26.7 29.2 26.5 29.1 27.0 29.1 28.1
4a 124.5 125.3 123.4 123.9 124.8 125.2 132.2
5 108.1 108.2 111.3 111.0 108.5 108.2 102.4
6 146.3 146.3 148.2 147.4 146.8 146.4 148.5
7 145.4 145.8 147.2 146.9 146.0 146.0 134.1
8 107.3 107.4 110.7 110.0 107.8 107.5 141.3
8a 130.0 130.0 129.5 128.4 130.7 130.1 117.2
1' 82.7 81.8 84.9 82.1 85.0 82.9 81.9
3' 167.0 168.0 167.2 167.7 167.2 167.5 168.2
3'a 119.4 119.3 110.3 109.7 110.3 110.0 120.3
4 147.5 147.6 144.5 144.1 144.5 144.2 147.8
5' 152.6 152.3 149.1 148.8 149.1 148.9 152.3
6' 118.5 118.4 113.1 112.8 113.1 112.9 118.4
7' 117.3 118.1 115.5 116.1 115.6 116.0 117.8
7'a 140.4 141.1 140.8 140.9 140.5 140.9 140.6
NCH, 44.7 44.9 45.1 44.9 45.3 45.0 46.3
6,7-OCH,O 100.5 100.7 101.0 100.8 100.8
4'-OCH, 62.0 62.2 62.2
5'-OCH, 56.7 56.7 55.9
6-OCH, 55.9 55.6
7-OCH3 55.9 55.9
4',5'-OCH,O 103.3 103.1 103.3 103.1
8-OCH3 59.4
Hughes et al. (14).

In Sharma and Hindenlang (7) a similar set of data is ascribed to capnoidine.
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
1 170.4 168.7 171.7

3 69.5 68.5 71.8
3a 146.3 139.6 139.4
4 122.0 116.7 115.1
5 133.6 119.9 114.7
6 128.5 152.6 149.5
7 124.9 148.6 145.6
7a 125.2 118.1 108.0
6-OCH3 57.0
7-OCH3 62.3
6,7-OCH20 103.8
a Hughes et al. (14).
assigned by applying to phthalide the additivity parameters for o-dimethoxyl

groups and methylenedioxy groups, respectively. It was noted that C-7a in
meconin (88) appeared at lower field by 10 ppm than its calculated value and
the corresponding carbon atom of 89. This shift was attributed to steric
inhibition of resonance of the C-7 methoxyl group (14, 19). A steric inter-
action with C-1 was invoked to explain the lower field resonance of the
methoxyl group at C-7. In compounds 88 and 89 C-4 and C-5 were differ-
’
entiated by selective H decoupling.
When the partial structures corresponding to the substituted phthalides,
88 and 89, are incorporated into the alkaloids, 81-86 there was relatively
little change in chemical shifts from those of the models except for the
expected changes at the benzylic carbon atoms (C-1’).
A close examination of the chemical shifts of the aliphatic carbon atoms
of the diastereomeric pairs, 81 and 82,83 and 84, and 85 and 86, has shown
that the diastereomers may be differentiated by CMR spectroscopy. The
change in stereochemistry at C- 1’ between erythro-p-hydrastine (81) and
threo-a-hydrastine (82)caused deshielding in 82 at C-3, C-4, and the N-methyl
group by +2.3, +2.5 and +0.2ppm, respectively, whereas C-1’ was
shielded by - 0.9 ppm. Chemical shift differences of similar magnitude were
observed for the pairs, 83 and 84, and 85 and 86 except that in these systems
C- 1’ underwent a slightly larger shielding.
The chemical shift at C-1 was influenced by the presence of a substituent
at C-8. In narcotine (90)(17) C-1 was shielded by -5.1 pprn relative to 81.
This shielding was similar to that observed in 4 (Table I).
XIV. Modified PhthalideisoquinolineAlkaloids
A number of compounds that appear to be biogenetically derived from

phthalideisoquinolines have recently been examined by CMR spectroscopy.
They are bicucullinine (91) (57),fumaramine (92) (17), and the hydrated
fumaramine (93) (17), an alkaloid recently isolated from F. schleicherii (58)
(Table XVI, Fig. 17). In the case of 91 the carbonyl groups and the car-
boxylate group were easily identified by their chemical shifts. The aromatic
carbon atoms of all three were tentatively assigned by comparison to
aromatic systems carrying methylenedioxy groups and the aliphatic carbon
atoms of the side chain by comparison to I3C data on phenethylamines (59)
and by the intensity of the resonances attributed to the N-methyl groups.
The 13C spectrum of 93 was particularly valuable in elucidating its structure.
TABLE XVI
l 3 C CHEMICAL
SHIFTSOF THE MODIFIED
PHTHALIDEISCQUINOLINE
ALKALOIDS
Carbon 91" 92b 93*.'
1 104.9 108.6 109.2

2 142.5 146.8 144.7
3 148.9 147.5 145.7
4 108.8 110.3 110.8
4a 137.8 132.6' 126.9
5 28.0 31.5 30.3
6 56.2 60.3 60.6
8 168.0 166.0 164.9
8a 121.4 111.4 113.8
9 142.0 143.6 142.6
10 149.8 149.5 148.7
11 109.4 112.1 111.0
12 118.9 113.3 115.8
12a 122.4 133.7' 142.2
13 190.4 131.9' 87.6
14 190.0 102.6 37.0
14a 125.1 126.9' 133.1
3-OCHZO 99.3 101.4 100.5
10-OCHzO 99.7 103.1 102.4
N(CH 3 12 40.5 45.2 45.0
a Solvent: alkaline D,O; aromatic car-
bon assignments are tentative, Ref. (57).

Solvent : DMSO-d,.
' Assignment may be interchanged.
91 92
93
FIG. 17. Modified phthalide isoquinoline alkaloids.
XV. Benzo[c]phenanthridine Alkaloids
Takao and co-workers (60) have examined a number of hydro-

benzo[c]phenanthridine alkaloids and their derivatives by a variety of
physical methods in order to determine the conformation of the BjC rings
(Fig. 18). The I3C chemical shifts (Table XVII) were particularly sensitive
to the influence of substituents on the conformation of the B and C rings.
Chelidonine (94) for example, with a cis ring junction, has both the B and C
rings as half-chairs [see Fig. 1 in (60)l. Acetylation of the hydroxyl group to
form 95 shielded C-6, C-12, and C-13 relative to 94. The interpretation of
these observations was that ring C in 94 adopted a twist half-chair con-
formation which increased the number of gauche interactions for these
carbons.
The chemical shift changes caused by the methyl group at C-13 in coryno-
line (96) were characteristic of the substituent effects for an angular methyl
group at a ring junction (8, 12). The C-13 was shielded whereas C-11 and
3. THE ,C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS 25 1
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
FIG.18. Benzo[c]phenanthridine alkaloids.
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.
TABLE XVII
l3cCHEMICAL SHIFTS OF THE HYDROBENZO[C]PHENANTHRIDINE ALKALOIDS’
Carbon 94 95 96 97 98 99
1 107.4 108.2 107.7 107.7 107.8 107.3

2 145.3’ 145.3‘ 145.2’ 145.4‘ 145.3’ 145.3’
3 145.6‘ 146.6‘ 145.4’ 145.7’ 145.5’ 146.2’
4 111.9 106.4 112.8 112.9 112.5 106.8
4a 128.9 127.6 128.0 128.2 127.9 129.5
6 53.9 45.4 54.4 58.5 54.8 52.1
6a 117.1 117.3 116.9 122.7 123.3 117.6
7 143.1 144.1 142.9 143.1 142.9 145.3
8 148.2 147.0 148.2 148.1 148.0 146.5
9 109.2 108.2 109.4 109.4 109.4 108.8
10 120.4 121.5 118.7 119.1 118.9 117.6
10a 131.4 129.5 136.2 136.0 135.8 135.5
11 72.4 12.7 76.1 75.4 75.7 74.1
12 39.7 31.3 36.8 37.4 36.6 33.7
12a 125.8 126.6 125.3 126.9 125.5 126.9
13 42.1 33.1 40.8 41.2 40.3 39.4
14 62.9 62.0 69.8 68.8 60.5 58.3
6-CH3 19.6 10.6
13-CH3 23.5 24.1 23.3 23.9
N-CH3 42.4 41.6 43.2 39.7 39.2 38.1
2,3-OCH,O 101.1’ 100.9 101.0* 100.8’ 101.0’ 100.7’
7,8-OCH,O 101.4’ 100.9 101.4’’ 101.0’ 101.2b 101.3*
CH3CO- 21.4
CH3CO- 175.4
Takao et al. (60).

’ Assignments may be reversed
XVI. Spirobenzylisoquinoline Alkaloids
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)
TABLE XVIII
' 3C CHEMICAL SHIFTS OF THE SPIROBENZYLlSoQulNOLINE ALKALOIDSn
Carbon 101" 102" 103" 104" 105b lMb.'
1 110.5 106.9 105.8 109.7 111.2 117.4

2 147.5 147.4 146.9 146.2 144.2 156.8
3 147.7 147.4 146.9 146.8 146.4 153.0
4 110.5 109.6 108.2 110.0 112.9 112.9
4a 126.1 125.0 129.3 126.0 127.4 118.2
5 29.1 29.2 29.5 22.8 23.3 27.6
6 48.1 48.9 50.2 47.6 47.6 64.8
8 37.0 70.3 75.0 73.4 82.3 77.2
8a 123.8 132.7 134.3 121.5 125.5 124.2
9 143.0 146.1 144.4 144.7 144.2 145.4
10 148.2 154.8 154.5 148.6 147.5 148.6
11 108.0 1 10.9 110.6 107.1 108.9 110.9
12 113.6 119.9 119.6 116.1 113.3 117.9
12a 136.1 132.5 131.2 140.0 135.0 135.3
13 155.5 201.5 202.2 79.5 44.0 38.8
14 71.9 77.2 72.0 75.2 74.5 90.6
14a 137.2 130.6 129.8 129.5 127.9 127.2
NCH, 39.0 39.7 41.7 37.7 38.1 53.7
2,3-OCH20 101.3 101.1 101.0
9,lO-OCH20 101.3 103.2 103.1 101.9 101.6 103.1
2-OCH3 56.1
3-OCH3 55.8 56.0 57.4
13-CH2 106.7

Kiryakov et al. (64).
Solvent: D,O + 2 drops 40% NaOD.
were examined as models (Fig. 20 and Table XIX). By comparison of the

spectra of 108 and its deuterated analog it was possible to assign all the
resonances of the aromatic carbon atoms. The signals of 109 were then
assigned by application of the substituent parameters for o-dimethoxy groups
to 108. There was good agreement between observed and calculated values.
Accordingly the spectra of 4,5-methylenedioxy-l-methyleneindaneand
CH 3 0
107 108 109
FIG.20. Model indanes and indanones.
TABLE XIX
SHIFTSFOR MODEL
I3C CHEMICAL
COMPOUSDS
107-109
Carbon 107",* 108" 109"
1 150.5 206.5 205.2

2 31.1 36.0 36.4
3 30.0 25.5 22.5
3a 146.6 155.0 145.6
4 125.3 126.6 147.9
5 128.3 134.4 157.6
6 126.4 127.1 112.5
I 120.6 123.4 120.0
7a 141.1 137.0 131.2
1-CH, 102.3
4-OCH3 60.3
S-OCH3 56.3

Buchanan et al. (65)
4,5-methylenedioxy-I-indanonewere calculated by applying substituent

parameters for the methylenedioxy group to 107 and- 108, respectively.
These values were then used to aid the assignment of the signals of the
aromatic carbon atoms of rings C and D in the alkaloids with similar
functionalities.
In the assignment of the resonances of the carbon atoms of rings A and
B compound 3 served as a convenient model. However, the spiro carbon
atom present in the alkaloids caused significant changes in the resonances of
the carbon atoms of ring B. Thus for example in 101, C-6 and the N-methyl
group were shielded by -4.9 and -7.0 ppm, respectively, as a result of y
steric interactions with C-8 and C-13, and C-14 was deshielded by +14.3
ppm. Other spiro compounds are known to exhibit similar behavior (66)
and qualitatively similar effects were found in other alkaloids of this series
(63).
Pairs of diastereomers such as 102 and 103 may be differentiated by CMR
spectroscopy. In the case of the compounds in question there is hydrogen
bonding between the amino group and the hydroxyl group in 103 but not in
102. This may account, through conformational changes, for the observed
differences in their spectra. Thus C-6, C-8, and NMe are shielded while C-14
is deshielded in 102 relative to 103. Other pairs of diastereomers showed
similar changes at these centers (63).
In the dihydroxy compound 104 the chemical shifts of the two carbon
atoms bearing hydroxyl groups are distinctly different. The assignments at
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)
FIG. 21. Rhoeadine (110)
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
' Tan1 and Tagahara (67).

3. THE 3C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS 257
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
The structural features that characterize the rhoeadine alkaloids are a

seven-membered ring B and the presence of a cyclic acetal or hemiacetal
function (2,3)(Fig. 21). In the 13Cspectrum of rhoeadine (110) (67)(Table XX)
both C-4and C-5appear at lower field than the corresponding carbon atoms
in most of those alkaloids that have a six-membered ring B. The acetal
carbon C-14is readily differentiated by its low field position relative to other
resonances in the aliphatic region of the spectrum. The chemical shifts of the
aromatic carbon atoms are similar to those of other classes of alkaloids that
carry methylenedioxy substituents on rings A and D.
XVIII. Secoberbine Alkaloids
Hypecorinine (111) (3,68) is the only example of this class of alkaloids on

which 13Cdata have been reported (Fig. 22 and Table XXI) (17). Like the
spirobenzylisoquinolines these alkaloids have a spiro carbon atom in the iso-
quinoline unit. In this system C-14is strongly deshielded because of the
presence of oxygen at the spiro junction, but C-5, C-6,and N-methyl are
shielded relative to the corresponding carbon atoms of the spirobenzyl-
isoquinoline alkaloids. The shielding of C-6 and the N-methyl group may
be attributed to the 7’ effect of the oxygen atom, and the upfield shift of C-5
may reflect a conformational change in ring B.
FIG.22. Hypecorinine (111)
111
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
" Hughes and MacLean (17).
FIG.23. Emetine (112)
OCH,
112
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
Carbon Emetine" Emetine dihydrochlorideb
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
Solvent : CHCl,--Koch ct a/. (69)

Solvent: D,O-Buzas er al. (70).
260 D. W . HUGHES AND D. B. MACLEAN
with the corresponding carbon resonances in the protoberberine series

(14, 44,48).
Buzas et al. (70) recorded the spectrum of emetine dihydrochloride as well
as several emetine analogs and synthetic intermediates. Most of the assign-
ments correlated with Wenkert’s data; however, C-1 to C-7 and C-3’ and
C - 4 were shielded upon nitrogen protonation (8, 12). It was observed that
protonation of the nitrogen had an additional effect on the quinolizidine
portion of emetine since C-1 lb, C-3, and C-6 were not observed at ambient
temperatures; C-4 was also quite broad. These signals became visible and
sharpened at higher temperatures.
XX. Miscellaneous Alkaloids
The I3C spectra of several l-phenyl-3,4-dihydro-, l-phenyl-l,2,3,4-tetra-

hydro-, and 1-naphthyl-3,4-dihydroisoquinolines have been reported in the
compilation of Shamma and Hindenlang (7). The chemical shifts that have
been assigned to the isoquinoline moieties in these molecules agree with
those of similar systems discussed in previous sections of this article. The
chemical shifts of the carbon atoms in the 3,4-dimethoxyphenyl groups are
remarkably similar to those of the same unit in laudanosine (28). In the 1-
naphthyl series the spectra of three compounds differently substituted in
the naphthalene unit were recorded and assignments made to all carbon
atoms.
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
The plants of Lythraceae family are moderately well distributed in different

regions of the world. from the tropics to the temperate zones. and are
especially abundant in Latin America . The family consists of 22 genera
composed of about 500 species. including several economically important
THE ALKALOIDS. VOL. XVlIl
Copyright 0 1981 by Academic Press Inc . .
All rights of reproduction in any farm reserved.
ISBN 0-12-46951X-3
264 w. MAREK GOEFBIEWSKI AND JERZY T. WROBEL
species of the genera Woodfordia, Lafoensia, Lythrum, Cuphea, Ammannia,

Lagerstroemia, and Lawsonia (1). One reason for the early investigation of
the Lythraceae plants has been the pronounced physiological activity dis-
played by the Heimia species.
The first isolation of the Lythraceae alkaloids from Decodon fierticillatus
(L) Ell was reported by Ferris in 1962 (2). Those were lactonic biphenyl
alkaloids (type A) decinine, decodine, verticillatine, decamine, vertine,
lactonic ether alcaloids, decaline, and vertaline.
This report was followed by isolation of other lactonic alkaloids from
Heimia salicifolia Link and Otto by Schwarting et al. ( I , 3) and from Heimia
myrtifolia Cham and Schl. and H . salicifolia by Douglas et al. ( 4 ) .
In 1967, Fujita et al. (5,6)isolated three piperidine metacyclophane alka-
loids (type B) from Lythrum anceps Makino. The third structural variant of
the Lythraceae alkaloids, quinolizidine metacyclophane (type C), was
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.
Lythrine (1) 241 -243" HCl, 325-331 +32.5 285 (4.14) b, c, f I . 4 , 16

241 -242 OAc, 172-173 + 40.6 260 (4.04)
Decinine (2) 222-224 OAC, 197-198 -142 294 (3.86) a, d, e 2, 17
269 (3.46)
Lyfoline (3) 2' 5 2 7 No 5 223 -224 0,6-diMe,231-233 282 (4.15) b 3
246 (4.04)
Sinine (4) C26H31N06 217.5-219" HC1, 330 - 174.2 292.5 (3.85) b, c, f 16, IN, 19
ALC-1 C26H29N05 335-345 OAc, 126-128 +115.6 b 20
ALC-2 C26H29N05 309-310 + 72.3 b 20
Nesodine ( 5 ) C26H29N05 190 OMe, 95-1 10 281 (4.10) b 3
258 (3.92)
Decodine (6) C25H29N05 193- I97 0 . 0 - d i Ac, 202-203 - 97 287 (381) a
261 (3.29) 2, 17
Dehydrodecodine (7) C25H27N05 181-183 2'77 (4.06) b 21
262.5
Corrected melting point.

a, Decodon uerticillatus (L) Ell.; b, Heirnia salicifolia Link and Otto; c, H . rnyrtifolia Cham and Schl.; d, Layrrstroemia iedica L.; e. Lythrurn
lanceolatum; f, Layerstrocvnia fauriei.
11. Lactonic Biphenyl Alkaloids
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
\ /
RZ ' R' R2 \ R'

OR^ OMe OH OMe
1 R' = OMe, R 2 = R3 = H 2 R' = OMe, R 2 = R3 = R4 = H
3 R' = OH, R Z = R3 = H 4 R' = OMe, R 2 = R3 = H, R4 = OH
5 R ' = R3 = H, R 2 = OMe 6 R' = R 3 = R4 = H, R Z = OH
7 R' = H, R 2 = O H , R 3 = H 9 R' = OMe, RZ = R3 = R4 = H, 17-OMe
8 R' = OMe, R Z = H, R 3 = Me
4. THE LYTHRACEAE ALKALOIDS 267
Me
OCH,
10 R = M e
11 R = H
should solve the problem of absolute configuration of the quinolizidine part.

The absolute configuration at C-5 was assigned by comparison of the sign
of the end absorption in the 200-250-nm region of the O R D spectrum of a
degradation product (12) of lythrine with L-( -)-2-methylpiperidine and
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
lack of hydroxyl reactivity. This was attributed to hydrogen bonding to the

nitrogen atom. However, an alternative structure 5 was assigned to nesodine
by Ferris et al. ( 2 4 ) in agreement with the above data. A phenolic hydroxyl
would be unreactive because of steric effects, and its IR absorption represents
partial proton transfer from oxygen to nitrogen in the solid state to give an
ionic species.
The methoxylation pattern of lactonic alkaloids was established by a

combination of spectral and chemical studies. Methoxyl groups at positions
ortho to the biphenyl link (at C-17 or C-21) resonate at relatively high field
(6 3.8 - 3.7 ppm) because of shielding by the adjacent aromatic ring.
Methoxyl groups at the other positions absorb at 6 3.95 - 3.85 ppm. For-
mation of an internal ether demonstrates the presence of 17-OH (24).
1-
OMe
OMe
The methoxyl groups of nesodine absorb in the NMR at 6 3.98 and

3.69 ppm. The former signal may be assigned to 22-OMe and the latter to
21-OMe. The data do not eliminate an alternative structure (16) (structure
1 with R' = H, R Z= OH, R3 = Me) for nesodine. Ferris et al. preferred 5
to 16 on the basis of the fact that no naturally occurring Lythraceae alkaloid
has a 21-OMe. It would, however, be necessary to confirm this structure by
internal ether formation.
Decodine (6) exhibits a methoxyl resonance at 6 3.87 ppm in the NMR
spectrum which was assigned to a 22-OMe since dimethyl decodine has
methoxyl peaks at 3.87, 3.69, and 3.69 ppm. The presence of a 17-OH group
was established by formation of an internal ether. In view of the above data
structure (6)was assigned to decodine.
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.
Vertine (17) C,,HZ9NOs 245-247 HCI, 322-323 + 39 285 (4.13) a, b, c, e I , 2, 16, 27

253-255" OAC, 183-185 +61 260 (4.09)
Decamine (18) CZ6H3,NOS 223-224 OAC, 197-198 - 145 294 (3.87) a,d 2, 17
268 (3.51)
Heimidine (19) CZ6H,,NO, 221-223" HCI, 316-318" - 292 (3.8) b 28
Verticillatine (20) C,,H,,NO, 312 HC1.240 + 1 19b 292 (4.07) a 2, 17
260 (3.91)
Dihydroverticillatine (21) C,,H,,NO, 263 288 (3.83) d 25
266 (3.57)
Sinicuichine (22) C,,H,9NO, 187-188" HCI, 265-266" +77.8 285 (4.01) b 29
Lagerstroemine (23) CZ6H3,NOs 240" CH,I, 266 - 137 294(3.68) d 25
'Corrected melting point.

DI.[of verticillatine hydrochloride measured in methanol.
a, Decodon verticillatus (L) Ell. ;b, Heimia salicifolia Link and Otto; c, H . myrtifoliu Cham and Schl. I. d, Lagerstroemiu indicu: e, L.,/uuriei.
4. THE LYTHRACEAE ALKALOIDS 27 1
U
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''
verticillatine (20) and dehydrodecodine (7), dehydroverticillatine (21) and

decodine (6), as well as sinicuichine (22) and nesodine (5).
These pairs of trans- and cis-fused alkaloids have the same UV spectra
and O RD curves and very similar IR (apart from the Bohlmann bands
region) and mass spectra. These data demonstrate that both groups have the
same skeleton and the same aromatic substitution pattern, as well as identical
configuration at the biphenyl linkage. Vertine (17) was first isolated by Ferris
from Decodon verticillutus (2) and then by Douglas et al. from Heimia
myrtijolia and H. salicifoliu (4). Independently, Blomster et al. isolated
cryogenine from H . salicifolia (1);its identity with vertine was shown later
(22). This alkaloid was extracted recently by Fuji et al. (16) from Lager-
stroemiu fauriei.
Enantiomerism of lythrine (1) and vertine (17) at C-5 was established as
discussed in Section II,C by spectroscopic and chemical criteria and con-
clusively confirmed by two series of degradations carried out on both
alkaloids.
In the first series (see Scheme 2) lythrine (1) was transformed to N-methyl-
piperidine (44). The optical rotation was -31' in 43 and +31' in the cor-
responding derivative of vertine. The plain positive OR D curve of the
0-methyl derivative of the latter compound corresponded to those of D-
+
(+ )-coniine and D-( )-2-methylpiperidine.
Comparison of physical properties of compound 41 (in Scheme 2 ) with the
corresponding product from vertine showed that both compounds were
diastereomers as predicted (24). There were significant differences in the
NMR and IR spectra, and the melting point of 41 (84-85') was depressed
(77-92") on admixture with the corresponding derivative from vertine.
In the second degradation shown for dihydrolythrine (see Scheme 1 ) both
lythrine and vertine were converted to N-nitrosamine derivatives (38) and an
272 w. MAREK WFBIEWSKI AND JERZY T. WROBEL
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
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
and methyldecamine with phenylmagnesium bromide followed by dehydra-

tion with formic acid yielded 29. The acetate of 29 showed an H-2 signal
with a half-height width of 13-14 Hz for trans- as well as cis-fused alkaloids.
This result indicates the axial configuration of this proton.
The quinolizidine ring of Lythraceae alkaloids can exist in both trans and
cis configurations. Both forms are clearly identifiable by combination of
spectral and chemical criteria. First, Bohlmann bands are present in the IR
spectra of trans-fused alkaloids and absent in the spectra of cis forms (33,
34). When the lactone ring of the trans alkaloids is cleaved by lithium
aluminium hydride the Bohlmann bands are still present, but they do not
appear on cleavage of the lactone ring in the cis alkaloids. Hence, the
conformation of the quinolizidine ring remains unchanged in the products
of lactone opening in both trans and cis bases, confirming the equatorial
configuration of phenyl group. Second, the diagnostic benzylic proton at C-1
absorbs in lower field in the NMR spectra of cis-fused alkaloids (6 3.32-
4.60 ppm) than in the corresponding trans isomers (6 2.95-3.75 ppm). This
difference for the natural alkaloids (or their derivatives) is equal to 0.37-
1.O ppm (24).These results correspond well with the data of Bohlmann et al.
(35) for simple 4-phenylquinolizidines where resonance of H-4 is at lower
field in the cis-fused isomer.
The NMR spectra of the methiodides showed a similar relationship. N-
Methyl resonances of cis-fused alkaloids are about 0.4 ppm at lower field
than in the corresponding trans forms.
The NMR spectra of N-oxides of biphenyl lactonic alkaloids (0-methyl
and 0-acetyl derivatives) show the signal of low-field aromatic proton H-24
at 6 8.1-8.7 ppm. The Dreiding models indicate that this proton is deshielded
by the N-0 group. H-24 resonates in the cis-fused derivatives at 0.13-0.28
pprn lower field than in the corresponding trans forms (24).The same relation
is observed in the NMR spectra of biphenyl ether alkaloids where H-24
absorbs at 6 7.6-8.2 ppm (25, 36).
The stereochemistry at C-5 is also reflected by relative rates of quarterniza-

tion. The cis-fused bases react much faster than the trans stereomers.
Inspection of models shows that the trans-quinolizidine has four axial
hydrogens blocking axial attack of the alkylating agent whereas the cis-
quinolizidine shows only two 1,3-diaxial interactions (24, 37, 38).
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
Cleavage of the lactone was observed in methylation of phenolic hydroxyl

group. In the alkylation of lythrine with dimethyl sulfate the major product
was the betaine (30).
In the case of dihydrolythrine (decinine) the lactone ring was not opened
and the product was isolated as the 0, N-dimethylmethyl sulfate salt (31)(27).
276 W . MAREK W E B I E W S K I A N D JERZY T. WROBEL
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
2. Degradation of the Quinolizidine Ring

The quinolizidine system of Lythrdceae alkaloids does not lend itself very
readily to the reactions commonly employed to degrade the carbon skeleton
of a molecule. Hofmann degradation of several decodine derivatives was
unsuccessful ( 2 4 ) , and the attempted Hofmann degradation of lythrine
yielded a complex mixture of products that failed to yield a definable com-
pound. It was possible to cleave the quinolizidine ring in decinine methiodide
via an Emde degradation where, as expected, the bond between nitrogen and
benzylic carbon was ruptured to yield 29. This reaction proceeds most
efficiently when a free phenolic hydroxyl group is present. Presumably, the
negative charge on the phenoxide anion protects the biphenyl system from
reduction (24).
The lactone ring in decinine (2) was reduced to the cyclic ether (34)with
diborane generated from sodium borohydride and boron trifluoride.
The Emde degradation of (34) afforded a piperidine derivative (3%). The
Cyanogen bromide N-demethylation of the methyl ether (3Sb)followed by
H ye
NaBH, (I) BrCN

BF, (1) Me0 (ii) LAH
2 - (1111 HNO,
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
lithium aluminium reduction resulted in the secondary amine (37).Treatment

with nitrous acid yielded crystalline N-nitrosamine derivatives in both trans
and cis series (Scheme 1) (24).
A further interesting cleavage of the quinolizidine ring in a degradation
product of lythrine (1) proceeded with an internal SN2 displacement of the
quarternary nitrogen by the C-17 phenoxide anion to chroman (41). The
N-propyl derivative (40) was prepared by catalytic hydrogenolysis of the
cinnamyl alcohol (39) resulting from the LAH reduction of lythrine (1).
Higher yields were obtained by using lithium aluminium hydride-aluminium
trichloride directly on lythrine or by hydrogenolysis of 39 with sodium-
ammonia-ethanol followed by catalytic hydrogenation. The latter procedure
was more efficient as it did not involve separation of the reaction products
from aluminium salts. The hydroxyl group of the chroman (41) was elimi-
nated via the mesyl derivative to yield a trans olefin (42). Hydrogenolysis of
the allylic benzylic ether of 42 followed by hydrogenation of the olefin
afforded 43 (Scheme 2) (24).
278 w. MAREK GQLFBIEWSKI AND JERZY T. WROBEL
LAH ($1 Na-EtOH NH,

1 - (iij HI,'Pt
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.
Attempts at mild oxidation of dimethyldecodine (14) to the lactam with

neutral potassium permanganate in acetone or chromic anhydride in
pyridine were unsuccessful and only the starting material was recovered.
Vigorous permanganate oxidation of dimethyldecodine gave 4-meth-
oxyisophthalic acid (45) and 3,4-dimethoxyphthalic acid (a), isolated as
the anhydride, along with succinic acid. The same reaction with decinine
afforded 45 and 4,5-dimethoxyphthalic acid (47) (17). Oxidation of lythrine
(1) and vertine (17) afforded lactone (48) along with (47) (Scheme 3) (27).
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
Compound Formula MP ("C) [c(ID(CHCI,) i.,,,nm (log E ) Plant" source Ref.
Decaline (49) CZ6H31N0, 102-118 ~ 136 293 (3.79) a 2, 17, 36, 41

264 (3.28)
Demethyldecaline (50) ,
C, H, NO, - - ~
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. Etherification of Phenolic Hydroxyl Group

Phenolic methyl ethers were usually prepared by treatment of the alkaloid
with dimethyl sulfate and sodium hydroxide or with diazomethane (17).
In the first case a side reaction was N-methylation or even cleavage of the
lactone (3). In decodine (6) the C-17 OH group was methylated on treat-
ment with ethereal diazomethane. The hindered C-21 OH group was al-
kylated with methanolic CH,N, (17).
111. Lactonic Biphenyl Ether Alkaloids
Six alkaloids belong to this group : decaline (49), demethyldecaline (50),

vertaline (51), demethylvertaline (52), lagerine (53),and methyllagerine (54).
In the first two alkaloids the quinolizidine ring is trans-fused and in the
latter four it is cis-fused. These compounds are listed in Table I11 (1, 2,
17, 25, 36, 41, 4 2 ) . Decaline and vertaline were isolated by Ferris from
Decodon verticillatus (2).
An X-ray study of vertaline hydrobromide established the structure and
absolute stereochemistry of vertaline as shown in 51 (32, 43). The relative
stereochemistry at C-1 and C-3 in all alkaloids in the group is the same as
in the biphenyl alkaloids; for example, the biphenyl ether and lactone group
are linked to the quinolizidine ring in axial and equatorial configurations,
respectively.
On the basis of the previously described spectroscopic and chemical cri-
teria (Section I1,C) Ferris et al. (36) showed that decaline had the same
structure as vertaline with the exception of opposite configuration at C-5.
This assignment was verified by degradation studies. Sodium-ammonia
OR2 yooq TOT RO

OMe OMe
49 R' = BH, R2 = Me 53 R = H 55 R = H
50 R' = BH, RZ = H 54 R = M e 56 R = M e
51 R' = rH, R 2 = Me
52 R' = aH, R 2 = H
282 w. MAREK GOLEBIEWSKI AND JERZY T. W R ~ B E L
reduction of the methiodides of decaline and vertaline yielded 3-phenyl-

propanol and N-methylpiperidine derivatives (57 for decaline) resulting
from cleavage of three bonds.
Decaline and vertaline were not degraded under the conditions wherein
methiodides were cleaved. Consequently,, the cleavage of the C,-N bond
must trigger the scission of the biphenyl ether and ester bonds. A mechanism
proposed by Ferris et al. (36) is shown for the case of decaline methiodide.
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
The optical rotation of 58 was -36' and the corresponding product

from vertaline showed [.ID +59". This result demonstrated that the pro-
ducts were diastereomers. Consequently, these data confirmed the assign-

ment of absolute structure 49 for decaline.
The de-0-methyl derivatives of decaline and vertaline were isolated by
Ferris et ul. from D. uerticillatus (36,41)and assigned structures 50 and 52,
respectively, on biogenetic grounds. The proposed structure for demethyl-
decaline was confirmed by total synthesis (44).
Lagerine was isolated by Ferris et al. from Lagerstroemiu indicu (17),
and methyllagerine was isolated by Hanaoka et al. (42) from L. indica
grown in Japan. The structure of lagerine is unique since it was not possible
to convert this base to any known Lythraceae alkaloid. The basic skeletons
of 0-methyllagerine and vertaline are the same since the mass spectra of
the two alkaloids are almost identical. The alkaloids differ in the substi-
tution pattern on the biphenyl ether chromophore, a fact which is reflected
in the UV spectra.
Structure 55 was proposed for lagerine by Ferris et al. (25) mainly on
the basis of sodium-ammonia cleavage of 0-methyllagerine methiodide.
This reaction afforded p-methoxyhydrocinnamyl alcohol (59) and the N-
methylpiperidine, for which structure 60 was proposed by a combination
of chemical and spectral methods.
55 R = H
l+
Rob
\
OMe
59
Me0
60 R = H
56 R = Me 61 R = M e
The same N-methylpiperidine derivative was obtained by sodium-

ammonia degradation of 0-acetyllagerine methiodide. It was difficult,
however, to distinguish the NMR spectra of 61 from an isomer with 4-
alkylpyrocatechol structure. This possibility could not be excluded by
analysis of UV spectrum of the N-oxide of 61.
The relative stereochemistry of lagerine is the same as that of vertaline.
Compound 55, proposed as the structure of lagerine, was synthesized by
Hanaoka et al. (45)and shown not to be identical to the natural alkaloid.
On the basis of the NMR spectrum and biogenetic considerations, structure
53 are assigned to lagerine and confirmed by total synthesis (42, 46). There-
fore, the Emde degradation of 0-methyllagerine can be depicted as follows
284 w. MAREK GOLFBIEWSKI AND JERZY T. W R ~ B E L
(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
Heimine was isolated by Schwarting et al. (1) from Heinzia saliciJblia,

but its structure has not been established.
1V. Simple Phenylquinolizidine Alkaloids
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.
OMe OMe OMe
63a R = H 64a R' = R' = H H

63b R = Me 64b R1 = H. R' = Me 6Sa { = BH
64c R ' = .4c. R' = Me H
64d R' = R' = AC 65b { = XH
64e R ' = Ac, R' = H
* 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.
Demethyllasubine-I (64a)" - ~ -_ 47.48

C16H23N03
Demethyllasubine-II(63a) 16 2 3
- - - 48
Lasubine-I (64b) C,,HZ3N03 120.5-122 - 8.8 279.5 (3.5) 16
Lasubine-II(63b) - - 34.7 279.5 (3.6) 16
C17H23N03
Abresoline (66) - - 284 (3.73) SO
C26H31N06
323 (3.76)
Demethoxyabresoline (68) - - 51
c 2 5H29N05
10-Epidemethoxyabresoline(70) C25HZ9N05
~ - 51
Subcosine-I (69) C28H35N06 f68.0 232.5 (4.7) 16
287.5 (4.1)
323.5 (4.2)
Subcosine-I1 (67) c2 8 35N06 +85.3 232.5 (4.3) 16
287.0 (4.1)
323.0 (4.2)
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
Three minor ester alkaloids, abresoline (66),demethoxyabresoline (68),

and 5-epidemethoxyabresoline (70), have been isolated from Heimiu sulici-
foliu by Schwarting et ul. (51).
Abresoline" on basic hydrolysis gave trans-4-hydroxy-3-methoxycinnamic
acid (ferulic acid) and the quinolizidol(63a). The presence of these units was
also apparent in the mass spectrum of the alkaloid which showed strong
* Abresoline (66) was prepared recently by Quick and Ramachandra by transesterification
of MB-methoxyethoxymethyl (MEM) ether of methyl ferulate with M E M derivative of quino-
lizidol (63a)and cleavage of protective groups with trifluoroacetic acid (10.3).
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^
67 R' = OMe, RZ = R3 = Me 70 R' = R2 = R3 = H

68 R' = RZ = R 3 = H 70a R' = H, R Z = R 3 = CH,COC,H,Br(p)
70b R' = R 3 = H, R2 = CH,COC,H,Br(p)
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
The structure of these bases has been elucidated by spectroscopic and

chemical methods. A basic hydrolysis of both subcosine-I and subcosine-I1
resulted in 3,4-dimethoxycinnamic acid as well as lasubine-I for 69 and
lasubine-I1 for alkaloid 67.
Occurrence of simple quinolizidone alkaloids, ester alkaloids, and lactonic
alkaloids in the same Heimia salicifolia plant species provides further
evidence in support of current biogenetic hypothesis.
VI. Piperidine Metacyclophane Alkaloids
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
MP [aID I,,,nm Plant

Compound Formula Ref.
MP ("') of derivatives (MeOH) (log E) source'
Lythranine C,,H,,NO, - HCI, 189-191 - 278 (3.62) a 5-7, 12

(72)
AcOH, 154-156
Lythranidine C,,H,,NO, ~ AcOH, 136-139 - 289(3.83) a 5-7, 12
(73)
Lythramine C,,H,,NO, 150-152 OMe, 169-171 -85 287(3.80) a 5-7, 12
(74)
a a, Lythrum anceps Makino.
The functional groups of these alkaloids were identified by analysis of

spectral and chemical data. The major alkaloid of the group, lythranine
(72), was shown to contain a secondary amine group, a secondary acetoxyl
group, a phenolic hydroxyl, an aromatic methoxyl group, and six aromatic
hydrogens. Lythranine was found to be an 0-acetyl derivative of lythranidine
(73) by a sequence of hydrolysis and acetylation reactions.
Lythramine (74) was obtained on treatment of lythranine with formalin.
The presence of a methylene bridge between a hydroxyl and an amine group
of lythramine was confirmed by lithium aluminium hydride reduction of
U-methyldeacetyllythramine (75) to N,O-dimethyllythranidine(77) (7).
72 R' = R 3 = H, R Z = AC 74 R' = Ac, RZ = H

73 R' = R Z = R3 = H 75 R1 = H, R2 = Me
76 R1 = R Z = H, R 3 = Me
77 R' = R3 = Me, R Z = H
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.
82
The reaction of O,N,-dimethyllythranidine (77) with phosphoryl chloride

in pyridine followed by catalytic hydrogenation gave a crystalline chloro
compound (83) as a major product and an amorphous dichloroderivative
(84). Both products underwent hydrogenolysis of the chlorine atom with
sodium in iso- and n-propyl alcohol, respectively, to yield bisdeoxy-0,N-
dimethyllythranidine (85).
HO
17 83 R' = C1, R2 = H 85
84 R' = R2 = C1
Compound 85 was dehydrogenated at 300" over palladium black under

reduced pressure to a pyridine derivative 96 which was independently
synthesized by the following route. Anisaldehyde (86)was treated with iodine
monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann
reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde
(88). The Knoevenagel condensation with malonic acid yielded the un-
saturated diacid 91. The methyl ester (92)was also prepared alternatively by
a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-
cinnamic acid (89), followed by the Ullmann reaction of its methyl ester
(90). The cinnamic diester was catalytically hydrogenated and reduced with
lithium aluminium hydride to the diol94. Reaction with phosphoryl chloride
afforded an amorphous dichloro derivative (95) which was condensed with
2,6-lutidine in liquid ammonia in the presence of potassium amide to yield
pyridine the derivative 96 in 27% yield (53).
292 w. MAREK GOL~BIEWSKIAND JERZY T. WROBEL
+ 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
piperidine derivative (97). Compound 97 was converted to its N-methyl

derivative 98 which turned out to be different from the bisdeoxy-N,O-
dimethyllythranidine (85). This suggested a trans relationship for the
analyzed protons in 85 and in the three piperidine alkaloids. The NMR data
supported this conclusion.
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
of the Cotton effect of lythranine hydrochloride at 232 nm due to a nwc*

transition (54).
VII. Quinolizidine Metacyclophane Alkaloids
AND CHEMISTRY
A. STRUCTURE
Ten alkaloids, lythrancine-I (loo), -11 (101), -111 (102), -1V (103),-V (104),
-VI (105), -VII (106), lythrancepine-I (107), -11 (log), and -111 (109), belong
to this group. All have a cis-fused quinolizidine ring and a biphenyl group.
These compounds are listed in Table VI (8, 9, 58-61).
Lythrancine-type alkaloids have a hydroxyl or an acetoxyl group at
carbons 3, 4, and 11. Lythrancines 100-103 and lythrancines 104, 105, and
106 are epimeric at C-3. Lythrancepines 107, 108, and 109 are C-4 deoxy
derivatives of lythrancines I-IV. This was demonstrated by lithium alu-
minium hydride reduction of the 0-tosylate of lythrancine 102 and acetyl-
ation of the product to lythrancepine 109 and its C-3 epimer.
All alkaloids of the group have methoxyl groups at C-17 and C-21 and
the same skeleton. The structure of these alkaloids was established by a
combination of chemical and spectral methods.
13
100 R' = R' = R3 = H 104 R' = RZ = AC 107 R1 R2= H

:
101 R' = RZ = H, R3 = AC 105 R' = Ac, R' = H 108 R' = H, R 2 = AC

102 R' = R3 = Ac. R' = H 106 R 1 = H, R Z = AC 109 R1 = R Z = AC
103 R' = R 2 = R 3 = AC
TABLE VI
QUINOLIZIDINE METACYCLOPHANE
ALKALOIDS
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
[.ID measured in methanol.

a, Lythrum anceps Makino : b, Lythrum lanceolatum.
296 w. MAREK ~ ~ B I E W S K I JERZY T. W R ~ B E L
AND
Lythrancine 100 has no acetoxyl group as shown by IR and NMR spectra.

Lythrancine 101 is the monoacetate of lythrancine 100, and lythrancines 102
and 103 are, respectively, the diacetate and triacetate of lythrancine 100.
Lythrancine 101, on treatment with acetic anhydride in piperidine at room
temperature, furnished the C-3 0-acetate (102). In the reaction at 110- for
3 hr the two hydroxyl groups at C-3 and C-4 were acetylated to yield ly-
thrancine 103.
Lythrancine 104 has three acetoxyl groups. The C-1 1 OH in lythrancine
(105) and the C-4 OH in lythrancine 106 are unsubstituted. It was possible
to establish the position of the acetoxyl group on the basis of the NMR
spectrum. The H-3 signal in the 3-acetates was observed at 6 4.99-5.15 ppm.
In the 11-acetates H-11 resonated at 6 5.34 i 0.01 ppm.
Oxidation of lythrancine 101 with Jones reagent in acetic acid at room
temperature yielded a mixture of acids which were esterified and separated
into a basic and a neutral fraction. From the basic fraction methyl trans-6-
carbonylmethoxy-2-piperydylacetate(110) was isolated. Thus, the trans
relationship of H-5 and H-9 was established ;chromatography of the neutral
fraction afforded symmetrical 6,6’-dimethoxybiphenyl-3,3’-dicarboxylate
(78). Mild oxidation of lythrancine 101 with chromic anhydride in acetic
acid gave a dihydroxyketone (111).
The Jones oxidation of lythrancine 102 yielded a monoketone (112) and
a diketone (113). The UV and IR spectra of the diketone suggested the
presence of a benzoyl group. The structure of 113 was established by detailed
analysis of the N M R spectrum.
Periodate oxidation of the cis-diol in lythrancine 101 and Hofmann
degradation of lythrancine 101,102, and 103 were tried but all attempts were
unsuccessful (58).
Treatment of lythrancine 102 with activated neutral alumina in benzene
resulted in a shift of the acetyl group from the axial C-3 acetate to the
Me0,C 0
H CH,CO,Me
110 111 112 R = H ,

113 R = O
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
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
All alkaloids of the group showed a similar fragmentation pattern. All

fragmentations described were supported by the observation of the meta-
stable ions. The constitution of the ions was determined by high-resolution
mass spectra. The three observed fragmentation routes were triggered by
elimination of an acetoxyl radical (hydroxyl for lythrancine-I). Elimination
of acetic acid from C-2 and C-3 of the common intermediate ion a yields ion
b which undergoes the retro-Diels-Alder reaction to give ion c.
An alternative decomposition path consists in loss of ethylene from a by
the retro-Diels-Alder cleavage to yield ion d which can further eliminate
acetic acid. The third route involves cleavage of the benzylic position. The
loss of acetic acid from e affords ion f. The further retro-Diels-Alder
reaction off gives rise to the strong peak at m / e 82 and the remaining fragment
ion g. As a result of this analysis it was possible to assign the locations of the
hydroxyl and acetoxyl groups in all alkaloids of the group.
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
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).
* 2-Piperydylpropanone (126). known for many years as isopelletierine, is now referred to

as pelletierine, following the suggestion of Gilman and Marion (63).The pelletierine originally
described by Tanret was never later isolated o r synthesized.
+ A condensation of pelletierine with aliphatic aldehydes to 2-quinolizidones has been also
reported (70).
126 132
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
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
hypothesis which involved a dehydration of the amino alcohol 147 followed

by intramolecular Michael addition in 145. Some positive information on
the mode of condensation was provided by these authors who prepared the
aminoketone 145 (Ar = Ph) by an independent route. Treatment of 145 with
excess aqueous sodium hydroxide afforded a mixture of quinolizidones of a
similar composition, as in the condensation of pelletierine with benzaldehyde.
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
Hanaoka et al. (39, 71) condensed pelletierine (126) with 6-bromoisovanillin

and obtained in quantitative yield the trans-quinolizidone (149). The methyl
ether (150) was selectively reduced with Henbest catalyst, and the axial (151)
and equatorial (153) alcohols were separated in 9 : 1 ratio. The Ullmann
condensation of the acetyl derivative (152) with methyl 4-hydroxyhydro-
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
164 158 R' = BH, R2 = H 162 R' = OH. RZ = H, R3 = Me

159 R' = rH, R2 = H 163 R' = H, R 2 = OH, R3 = Me
160 R' = BH. R2 = Me 157 R ' = OH, R 2 = H, R3 = H
161 R' = rH, R 2 = Me
4. THE LYTHFUCEAE ALKALOIDS 309
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).
3. Cis-Fused Biphenyl Ether Alkaloids

Vertaline (51), a cis counterpart of decaline (49),was prepared by Hanaoka
et al. (73, 74). The crucial cis-fused analog of 149 was obtained in 25%
yield by condensation of pelletierine with 6-bromoveratraldehyde in tetra-
hydrofuran. The carbonyl group was reduced with sodium borohydride
in methanol to mixture of axial and equatorial alcohols in a 3: 1 ratio in
96% yield.
An effective new method for the synthesis of macrocyclic lactones has
been developed by Corey and Nicolau (75).In this method both the hydroxyl
and the carboxyl groups have been activated by formation of a 2-pyridin-
ethiol ester. Vertaline was obtained in 67% yield when this procedure was
applied to the corresponding hydroxyacid (76).
The compound proposed as having the structure of lagerine (55) was
synthesized by Hanaoka et al. ( 4 5 ) in a similar way from o-vanillin (167a),
pelletierine, and methyl 4-benzyloxy-3-bromohydrocinnamate. In the con-
densation of pelletierine with 167a in aqueous sodium hydroxide two com-
pounds were formed, a trans-fused quinolizidone (164) and a cis-hemiacetal
(165) in the ratio of 1 :3.
The products were interconverted on treatment with aqueous sodium
hydroxide. Reduction of 165 with sodium borohydride produced the axial
310 w . MAREK GCEFBIEWSKI AND JERZY T. WROBEL
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.
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).
2. Cis-Fused Biphenyl Alkaloids

Methyldecamine (174) was synthesized from pelletierine and the alkali-
insoluble amide 170 by Hanaoka et al. (81). Decamine (18) was synthesized
by Lantos et al. by the kinetically controlled condensation of pelletierine
with biphenyl aldehyde (169) which afforded the cis-quinolizidone (173) in
50% yield. Reduction of the carbonyl group with Henbest catalyst followed
by alkaline hydrolysis produced the undesirable trans-fused quinolizidols
as a major product. However, hydrogenation with platinium catalyst in an
alkaline solution afforded the less stable cis-fused axial carbinol, which
on cyclization followed by a mild basic hydrolysis yielded decamine (18).
RZOC R20,C R3
* *
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
A generalized scheme has been presented wherein the cis-fused quino-

lizidone (173) is epimerized to the trans form (172) (68).
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
The Wittig reaction of dialdehyde 175, prepared by chromic anhydride-

pyridine oxidation of diol 94 (54, with 176 in dilute methylene chloride
solution produced cyclophane 177 in 86% yield. Epoxidation of 177 with
m-chloroperbemoic acid followed by hydrogenolysis over Pd/C, acetylation,
and Pt0,-Raney Ni-catalyzed hydrogenation afforded the cis-substituted
piperidine derivative (178).
The N-nitroso compound (179) was equilibriated with tert-butoxide-
dimethyl sulfoxide to the trans-cis mixture which was denitrosated over
Raney nickel and hydrolyzed to yield a mixture of diols (180). Refluxing
180 in ethyl orthoformate resulted in isolation of the crystalline amidoacetal
which exhibited IR and NMR spectra identical to those of the amidoacetal
(82)derived from the natural lythranidine. Monodemethylation of synthetic

82 with aluminium chloride in EtSH-CH,Cl, followed by acidic hydrolysis
afforded ( +)-lythranidine.
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).
8q;
HO \
OMe
HO
OMe
186
132
OMe
I
OMe
I
ALKALOIDS
SCHEME4
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
183 184 185
Decodine derived from [ l-14C]cadaverine showed a distribution of label

identical to that of the lysine-derived samples. Activity was equally divided
between C-9 (p-alanine) and C-5 (Zpiperydylacetate minus 8-alanine). In
decodine, into which A'-[6-'4C]piperideine was incorporated, the label was
confined to C-9. This was consistent with the established evidence that the
double bond in A'-piperideine does not migrate from one side of the nitrogen
to the other (89,90).
In the ultimate test of hypothesis c, Decodon plants were treated with
(RS)-[6,2-'4C,]- and (RS)-[6-3H,2'-'4C]pelletierine to yield inactive alka-
loids, whereas in concurrent experiments labeled decodine and decinine
were obtained from other substrates. The accumulated evidence favored
hypothesis e (see Scheme 4).
The next experiments concerned biosynthesis of the phenylalanine-derived
fragments. First, Rother and Schwarting reported the specific incorporation
of [3-'4C]phenylalanine (187) into cryogenine (vertine; 17) in Heimiu
sulicifoliu. The lactone (48), a product of partial degradation, contained
92% of the molar activity of cryogenine. This fragment constitutes two
C,-C, units: C-13 to C-19 and C-I,C-20 to C-25. 4,5-Dimethoxyphthalic
anhydride (47), comprising C-1. contained 31% of the activity of the
alkaloid (84). In the other experiment with [3-14C]phenylalanine, 33% of
Y O M e
OMe CO,H OMe
47 (31"") 48 (920,)
*
C0,II
I 1
OMe OMe
45 (467;) 47 (33",)
the activity of cryogenine was located in 47 and 46% in 4-methoxyisophthalic

acid (45). p-Hydroxy- and p-methoxybenzoic acids obtained by decarboxyl-
ation of 45 showed essentially the same specific activity as 45 (91).
These results indicated that the label was localized at C-13 (46 and 61%)
and very probably at C-1 (33 and 31%). Thus, in conclusion, phenylalanine
is the donor for both the aromatic rings and the adjacent carbon atoms C-1
and C-13. This result was consistent with any one of the five biogenetic
hypotheses shown in Scheme 4. To distinguish among the hypotheses, it
was essential to examine the incorporation of such other radiomers of
phenylalanine as [ 1-I4C]- and [1,3-'4C,]phenylalanine.
Degradation of decodine derived from [3-l4C]pheny1alanine showed that
58% of the label was located at C-13 and 33% at C-1. Thus, there is a close
correspondence of the origins of the two lactonic biphenyl alkaloids of dif-
ferent stereochemistry at C-5 and with different oxygenation patterns.
The results of experiments with radioisomers of phenylalanine are shown
in Scheme 5 for decodine. For the case of decinine a very similar distri-
bution of activity was obtained.
When [l-'4C]phenylalanine was tested as a precursor, the entire activity
of decinine and decodine was unequally divided between C-1 1 and C-3.
The carbonyl carbon at C-11 [isolated as benzophenone oxime as a result
of phenylation with the Grignard reagent, dehydration, and chromic acid
oxidation ( 1 0 , 2 4 ) ] contained 71% of the activity of decodine and 76% of

the activity of decinine. The remaining activity (28 and 20%, respectively)
was present at C-3, i.e., at the carbinol carbon. This carbon was extruded
as benzoic acid in the following degradation, shown for decodine. Lithium
aluminium hydride (LAH) reduction of dimethyldecodine (15) resulted in
a diol (188) that was selectively tosylated at the primary hydroxyl group.
Reduction of the tosylate (189) with LAH afforded the desoxy derivative
(190). Mild oxidation of 190 with Jones reagent to 191 followed by reaction
with phenyl lithium yielded a mixture of epimeric phenylcarbinols (192)
which on oxidation with permanganate gave benzoic acid.
@
,
OMe OM>
OMe OMe OMe
zm-
15 188 189 R = OTs
190 R = H
+
Jones
KMnO, *
PhC0,H
191 192
When [2-'4C]phenylalanine was administered to Decodon plants about

two-thirds of the activity of decodine and decinine was located at C-2.
This carbon was isolated as the m-naphthylamide of acetic acid by the Kuhn-
Roth oxidation of the n-propyl derivative.
In the fourth experiment incorporation of intermolecularly doubly la-
beled phenylalanine (at carboxyl carbon and at the p carbon of the side
chain) was investigated. The labeled decodine and decinine contained ra-
dioactivity only at the expected four carbon atoms C-1, C-3, C-1 1, and C-13
which were isolated and assayed for radioactivity. The ratios of relative
specific activities calculated from these data (C-3/C-1, C- 11/C-13) were in
good agreement with the activity ratio of the precursor (CO,H/B-CH,).
318 w. MAREK WFBIEWSKI AND JERZY T. W R ~ B E L
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.
* In a preliminary communication (86)46% of the activity of intact decodine was found at

C-1 in harmony with the pelletierine hypothesis. A complete reinvestigation of the degradation
on the sample of original decodine derived from [1,3-14C2]phenylalanine has shown that the
earlier result was in error (10).
Although 2-piperydylacetic acid contained the entire activity of decodine,

the label was not confined to C-4 and two other degradation products,
a-alanine and a-aminobutyric acid, contained -40% of the activity of
the alkaloid.
OH OH
193 194
In light of the present evidence the biogenesis of metacyclophane Ly-

thraceae alkaloids required revision, since the only published proposal (9)
was based on pelletierine. A new biogenetic scheme was proposed which
invoked intermediacy of A'-piperideine and two C,-C, units [derived from
P-ketoester (193)]. An intermediate disubstituted piperidine (194) would
give rise to two types of metacyclophane alkaloids as a result of reduction
and phenol coupling as well as Michael addition in the case of the quinoli-
zidine bases (10).
X. Physiological Activity
For centuries, the American Indians used plants of Heimiu species to

prepare intoxicating and stimulating beverages. The beverage prepared from
H . sulicifoliu is reported to produce a mild psychosomimetic effect. This
plant was used as a panaceum for a wide spectrum of diseases ranging from
common indigestion to syphilis. Heimia sulicfoliu was used as an appetite
stimulant, a remedy for bronchitis, dysentery, inflammation of the womb,
and slow healing ulcers. The aerial parts of the plants are diaphoretic,
diuretic, purgative, and show emetic, hemostatic, and astringent action ( I ) .
Early work was not, however, directed toward isolation of physiologically
active compounds.
The preliminary biological studies on isolated Heimiu alkaloids did not
confirm any central nervous system activity in rats ( 4 ) . Later biological
studies have demonstrated the pronounced activity of several Lythraceae

alkaloids. Vertine (cryogenine) (92-96) and decinine [as a free base (97)
or an alkanesulfonic acid salt (98)] are antiinflammatory agents in rats
and guinea pigs (95).Decinine shows a diuretic activity in rats (97, 99)
and dogs (99) and may be used as a diuretic hormone.
Vertine increases blood glucose level (94)and lowers mean blood pressure
(100).Vertine and nesodine show sedative activity in dogs and guinea pigs.
Decamine is a fungicide (101). Decamine-modified polyethylene prepara-
tions show antithrombotic properties in rabbits (102). The capacity of the
polymer to inhibit blood coagulation and clot formation was impaired by
incorporation of decamine.
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5-
CHAPTER
MICROBIAL AND IN VITRO ENZYMIC

TRANSFORMATION OF ALKALOIDS
H. L. HOLLAND
Department of Chemistry, Brock University,
St. Catharines, Ontario, Canada
1. Introduction ............ ... ................ 324

........................... 325
A. General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
B. Hydrolases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
C. Oxidoreductases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
D. Conjugation . . . . . . . . . . . . . . . ...._ 327
E. Practical Considerations . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
111. Transformations of Indole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
A. Brucine ................................ .. 328
B. Corynant Ikaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
C. Lysergic Acid and Related Alkaloids ........... 338
D. Vindoline and Related Alkaloids . , . , , . . . , , . , . . . . . . . . . . . . . . . . . . . . . . . . . 339
IV. Transformations of Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
A. Aporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
B. Benzylisoquinolines . . . . . . . . . , , . . . . , , , . , . , , . . . . . . . . . . . . . . . . . . . . . . . . . 360
C. Bisbenzylisoquinolines and Related Alkaloids . . . 366
D. Morphine and Related Alkaloids . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . 367
E. Phenethylisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
F. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
V. Transformations of Pyridine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
A. Nicotine and Related Alkaloids , , , , . , . . . . . . . . . . . . . . . . .. 316
B. Arecoline . . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
............... 376
Vl. Transformations of Pyrrolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
A. Monoester Alkaloids . . . . . . . . . .... .. .. . . . . ... .. . .. ... . .. . ... .. .. 319
B. Diester Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
C. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
VII. Transformations of Quinoline Alkaloids . . . .............. 381
VIII. Transformations of Steroidal Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
A. Tomatanine-Based Alkaloids . . , , . , . . . , . , . , . . . . . . . . . . . . . . . . . . . . . . . . . . 386
B. Solanidanine-Based Alkaloids . , . ............................ 390
C. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 391
IX. Transformations of Tropane Alkaloids . . . . . . . . . . , , , 39 1
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
THE ALKALOIDS, VOL. XVlll

Copyright @ 1981 by Academic Press, Inc.
All nghts of reproduction in any form reserved.
ISBN a i z - 4 6 9 ~ 1 8 - 3
324 H. L. HOLLAND
I. Introduction
Chemical transformations carried out by biological reagents such as

purified enzyme preparations and by intact organisms such as fungi and
bacteria have done much to ease the lot of the synthetic chemist in recent
years. Regio- and stereoselective reactions such as C-hydroxylation (1, 2),
S-oxidation (3, 4 ) , carbonyl reduction (5, 6 ) and oxidation (7, 8), N- and 0-
dealkylation (9), N-oxidation (lo),and hydrolytic reactions carried out by
biological systems have been widely used in many areas of organic chemistry
(11, 12).
Although biological reagents have found increasing use in alkaloid chem-
istry, this aspect of the subject has not been recently reviewed. However, a
number of reviews of the use of biological systems relevant to the chemistry
of alkaloids have appeared. These include the microbial transformation of
alkaloids (13-15), the use of purified enzymes in heterocyclic chemistry (16),
a compendium of microbial transformations of nonsteroid cyclic compounds
(11),a review of the metabolic N-oxidation of medicinal amines (lo),and
articles on the use of microbial systems as models for the mammalian me-
tabolism of drugs and other chemicals (9,17).The present chapter will discuss
the use of purified enzyme preparations and of intact microorganisms in
effecting transformation of alkaloid substrates. In vivo animal studies have
not been included since these are of limited applicability to the alkaloid
chemist. Similarly, those studies which are principally enzymic in direction
and those which are concerned only with the structure or properties of
enzymes that effect transformations of alkaloids will not be discussed, nor
will aspects of normal biosynthesis be included. It is rather the intention of
this chapter to draw attention to the possible synthetic uses of biological
reagents in alkaloid chemistry, and perhaps to stimulate further research in
this underdeveloped field. To this end, the literature up to and including
references appearing in Volume 88 (1978) of Chemical Abstracts (with the
exception of the material reviewed in references 11 and 13-16) has been
surveyed.
The tables in Sections III-IX summarize the transformations discussed
below. Yields given are the percentage recovery of product based on total
substrate used. In many cases, products were not isolated (indicated in
parentheses) ; and published yields have been based on spectrophotometric
analysis, on the measured release of other metabolites (e.g., formaldehyde
in the case of O-demethylation), or on consumption of starting material. In
these cases, yields are also given in parentheses.
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 325
11. Enzymes Involved in Alkaloid Transformations
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
specific glycosidic bonds, are also widespread ; and alkaloids containing

these linkages are therefore susceptible to glycosidase action during bio-
transformation. The mechanism of action of hydrolases and their applica-
tions in organic chemistry have been reviewed recently (12).
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
substrate specificity and regiospecificity of product formation of these

systems is usually low, the enzymes apparently serving merely to catalyze
the oxidation of the substrate to a phenoxyl radical, which then couples
nonenzymically and therefore usually nonspecifically (29, 30).
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.
111. Transformation of Indole Alkaloids
A summary of the transformations of indole alkaloids is presented in

Table I(38-54).
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
Substrate Reagent Products" li;, Yieldb Ref.
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)
Substrate Reagent Products" <: Yieldb Ref.
Rat liver homogenate (3,4,5-Trimethoxybenzoicacid) 44

Guinea pig liver (3,4,5-Trimethoxybenzoicacid) 44
homogenate
Dog liver homogenate (3,4,5-Trimethoxybenzoicacid) 44
Cat liver homogenate (3,4,5-Trimethoxybenzoicacid) 44
Polystictus versicolor (Two products) 42
Rescinnamine (23) Polystictus versicolor (Unidentified) 42
Rauwolscine (a-yohimbine) (26) Polystictus versicolor (Unidentified) 42
Corynanthine (24) Gongronella urceolifera 10-Hydroxycorynanthine (25) 41
Polystictus versicolor (Unidentified) 42
Harman (27) Polystictus versicolor (Unidentified) 42
Harmine (28) Cow liver homogenate (Harmol) (29) 45
Mouse liver homogenate (Harmol) (29) 45
Rabbit liver homogenate (Harmol) (29) 45
Guinea pig liver (Harmol) (29) 45
homogenate
Rat liver homogenate (Harmol) (29) 45
Cat liver homogenate (Harmol) (29) 45
Polystictits versicolor (Unidentified) 42
C. Lysergic acid and related alkaloids
LysLrgic acid derivatives (30) Isolated rat liver (N-Demethylation) 46
Chanoclavine (31) Pigeon liver preparation (Elymoclavine) (32) 47
Agroclavine (33) Rat liver microsomes (Noragroclavine) (34) 48
(Elymoclavine) (32) 48
(Setoclavine) (35) 48
(isosetoclavine) (36) 48
(Penniclavine) (37) 48
Guinea pig liver (Noragroclavine) (34) 48
micromes (Elymoclavine) (32) 48
(Setoclavine) (35) 48
(Isosetoclavine) (36) 48
(Penniclavine) (37) 48
D. Vindoline and related alkaloids
Vindoline (38) Streptomyces sp. A17000 Dihydrovindoline ether (40) 49
16-Dehydroxy-14,15-dihydro-15, 49
16-epoxy-14-0x0-3-norvindoline (43)
Streptomyces albogriseolus 3-Acetonyldihydrovindoline ether (42) 49
A17178
N-Demethylvindoline (44) 50,51
Streptomyces griseus Dihydrovindoline ether (40) 52
UI 1158
Dihydrovindoline ether dimer (45) 52
Deacetylvindoline (39) Streptomyces cinnamonensis Deacetyldihydrovindoline ether (41) 49
A15167
Vinblastine (46) Streptomyces albogriseolus N-Demethylvinblastine (47) 51
A1 71 78
Vinbkdstine ether (50) 53
Streptomyces punipalus 10-Hydroxyvinblastine (48) 53
A36120
3',4'-Dehydrovinblastine(51) Horseradish peroxidase Leurosine (52) 54
Parentheses indicate products not isolated.

Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
332 H. L. HOLLAND
1 R' = R 2 = CH, Brucine

2 R' = CH,, R Z = H 2-Methoxy-3-hydroxystrychnine
3 R' = H, R Z = CH, 2-Hydroxy-3-methoxystrychnine
CH,O H
H configuration
Alkaloid C-3 C-20
4 Corynantheidine x x
5 Dihydrocorynantheine 2 B
6 lsocorynantheidine B x
7 Hirsutine B B
B. CORYNANTHEIDINE ALKALOIDS
AND RELATED
In an attempt to correlate pharmacological activity with the rate of bio-

transformation, Beckett and Morton have studied the metabolism of a series
of indole alkaloids and related model systems by a variety of enzyme prepara-
tions of mammalian origin (39, 40, 57-59). Of the systems studied, rabbit
liver microsomes were effective in performing O-demethylation ; liver
microsome preparations from rat and guinea pig were not very effective in
transforming alkaloids 4-7 and 9-19 (but vide infra) (40). In the case of
corynantheidine (4), the product of metabolism was identified as the 0-(17)-
demethyl compound 8 by TLC comparison with authentic material.
In all cases, the degree of metabolism was estimated by monitoring both
formaldehyde production and the concentration of unmetabolized alkaloid
(39, 40). The related alkaloids 5 , 6 , and 7, which differ from corynantheidine
only in configuration at C-3 and/or C-20, and the 9-methoxyl analogs 9-13,
also produced formaldehyde on incubation with rabbit liver microsomes,

together with a single Dragendorff-positive nonphenolic metabolite on TLC,
which was assumed by analogy with the corynantheidine metabolite to be
an 0-(17)-demethyl compound. In the case of hirsutine (7) however, the total
metabolism (21%) estimated by determination of remaining substrate was
considerably greater than the degree of 0-demethylation indicated by
formaldehyde production (lx),indicating appreciable metabolism of this
alkaloid by another (unidentified) route.
CH,O
I
CH,O H
I I
8 0-(17)-Demethylcorynantheidine CH,O H
H configuration
Alkaloid c-3 c-20
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
isomers 7 and 10 (42).The preferred conformations of the normal (as in 5, 9,

and 13),pseudo (as in 7 and lo), allo (as in 4 and ll),and epiallo (as in 6 and
12) configurations of these alkaloids have been investigated (60)and discussed
earlier in this treatise (61): they are presented in Fig. 1. The normal and all0
members of this series show the greatest degree of metabolism, virtually all
of which is by 0-demethylation. The alkaloids of epiallo configuration are
metabolized to a lesser extent, but still by 0-demethylation, whereas the
normal pseudo
R
R
epiallo
is R
FIG. 1. Preferred conformations of corynantheidine-type alkaloids

pseudo alkaloids show negligible 0-demethylation, being metabolized by a

different route. Beckett and Morton (40) speculate that this is due to the non-
planar nature of the latter, and postulate the existence of an active site on the
0-demethylating enzyme which prefers a more nearly planar substrate such
as the normal or allo configuration provides. The epiallo configuration can
approach planarity in a conformation (Fig. 1, lower) that is present to the
extent of 25% or more under the conditions of the incubation (40), whereas
the pseudo configuration is inevitably nonplanar. The same authors also
speculate that the increased degree of metabolism observed with the 9-
methoxyl series 9-13 compared with the unsubstituted analogues 4-7 may
be caused by a higher electron density in the indole ring of the former com-
pounds resulting in better binding to the enzyme surface (40), but there is no
direct evidence of this.
CH,O
I
CH,O H
13 Paynantheine
R'
I
H configuration
Alkaloid C-3 C-20 R' R2 R3
14 Mitrajavine (Javacillin) B B OCH, H H

15 Tetraphylline 1 B H OCH, H
16 Aricine z 1 H OCH, H
17 Reserpinine 2 z H H OCH,
18 Ajmalicine 1 B H H H
19 Tetrahydroalstonine 5( z H H H
20 10-Hydroxyajmalicine 2 B H OH H
336 H. L. HOLLAND
Although the closed ring E alkaloids 14-20 were metabolized by the

rabbit liver preparation of Beckett and Morton (40), the structures of the
metabolites were not discussed beyond the observation that their metabolism
was not linked to formaldehyde production. Alkaloids of this type are, how-
ever, hydroxylated by several microorganisms in the 10 or 1 l positions (11).
A recent report on the incubation of ajmalicine (18) and corynanthine (24)
with Gongronellu urceoliferu states that the organism introduces a 10-
hydroxyl group, giving 20 and 25, respectively, 10-hydroxycorynanthine (25)
being produced in a yield of 68% (41). Ajmalicine is also transformed by
Polystictus uersicolor to give 75% of an unidentified metabolite more polar
than the starting material and by Piriculuriu oryzue to give unstated products
(42).
In contrast to the oxidative reactions discussed above, the only reported
biotransformations of reserpine (21) and rescinnamine (23) (42-44) appear
to involve hydrolytic processes. Reserpine is readily metabolized by liver
homogenates from the mouse (43),rat, guinea pig, dog, and cat ( 4 4 )to yield
methyl reserpate (22) and 3,4,5-trimethoxybenzoic acid in yields of up to
70% (43).The use of reserpine labeled with tritium in the 2 and 6 positions
of the trimethoxybenzoate residue indicated that no significant metabolism
of reserpine by another route occurred before hydrolysis, reserpine and
3,4,5-trimethoxybenzoic acid being the only detectable radioactive com-
ponents of the incubation mixture at the conclusion of the reaction (44). An
CH ,O,C+OR -
OCH,
22 R
23 R
=
=
H
0
--C-CH=CH
a
OCH,
Methyl reserpate
C
:H
OCH,
Rescinnamine
apparent requirement of reserpine metabolism for molecular oxygen and

NADPH, the normal cofactors of monooxygenase enzyme systems, is
unexplained, although the formation of a short-lived intermediate by an
oxidative step, which precedes the hydrolytic reaction, has been postulated
(43). Resperine is also transformed by Polystictus versicolor and by
Piriculariu oryzue (42), the former microorganism giving two products. In
neither case were the products identified beyond the statement that
Dragendorff-negative blue or green fluorescent spots were detected on TLC.
The same microorganisms are capable of biotransformation of rescinnamine
(23), Polystictus versicolor producing 90% of an unidentified Dragendorff-
positive metabolite. This organism also transforms rauwolscine (26), giving
50% of a substance analyzed only by TLC (42).
The simple indole alkaloids harman (27) and harmine (28) are also SUS-
ceptible to biotransformation. Polystictus versicolor metabolizes both 27
and 28 to unidentified products, formed in a yield of 50% in the case of 28
(42). Mammalian liver preparations perform an oxidative 0-demethylation
of harmine (28) to produce harmol(29) (45).The supernatant fraction from
the 10,OOOg centrifugation of liver homogenates of cow, mouse, rabbit,
guinea pig, rat, and cat were all effective in 0-demethylation, the highest
yields (90%)being obtained after incubation for 30 min with the preparations
from cow and mouse liver (45). No other products were detected from the
biotransformation of harmine by the liver preparations mentioned above,
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
The key position of agroclavine (33) in the production of clavine-type

alkaloids (69)prompted Ramstad and co-workers to investigate the metabo-
lism of this alkaloid by preparations of rat liver and guinea pig adrenal micro-
somes (48). Previous work with isolated horseradish peroxidase (70) had
shown that agroclavine was converted to setoclavine (35) and isosetoclavine
(36) by this enzyme, and indeed these were among the products formed by
the mammalian microsomal systems. The enzyme preparations from both
rat and guinea pig converted agroclavine to noragroclavine (34), elymo-
clavine (32), setoclavine (35), isosetoclavine (36), and penniclavine (37) (48).
The N-demethylation carried out by these systems was monitored by release
of formaldehyde and by the conversion of [ 4C]agroclavine (produced bio-
synthetically from ['4C]tryptophan) to [14C]noragroclavine. The other
oxidative reactions carried out by the microsomal preparations are stated
to be comparable to normal biosynthetic processes involving agroclavine

(71).
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).
niie 124 (C,HIoNO) iw:e 297 (C,,H,,N,O,)
FIG.2. Characteristic fragment ions of 43 (49).
The same group also studied the transformation of vindoline by Strep-

tomyces albogriseolus A1 7178 and again were able to isolate two metabolites,
3-acetonyldihydrovindoline ether (42)and N-demethylvindoline (44) (49-51).
The major product of metabolism 42 contained 56 mass units more than
40 R L= H, R' = COCH, Dihydrovindoline ether

41 R ' = R 2 = H Deacetyldihydrovindoline ether
42 R' = CH,COCH,, R 2 = COCH, 3-Acetonyldihydrovindolineether
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS 34 I
43 16-Dehydroxy-14,15-dihydro-l5,16-epoxy-14-oxo-3-norvindoline
dihydrovindoline ether and, like the latter, exhibited a one-proton multiplet

in the PMR spectrum at 6 4.06 ppm which collapsed to a singlet on irradition
at 6 2.0 ppm. The signal at 4.06 ppm was thus assigned to the C-15 hydrogen
in a dihydrovindoline ether-type linkage and that at 6 2.0 ppm to the C-14
methylene hydrogens. The PMR spectrum of 42 also contained a three-
proton singlet at 6 2.17 ppm not present in starting material or 40 and an
additional carbonyl absorption in the IR spectrum at 1710 cm- The struc-
ture was thus formulated as 42, the extra 56 mass units being contributed by
an acetonyl side chain. The site of attachment of the latter was determined
to be C-3 by a combination of PMR and mass spectral analysis. The char-
acteristic fragment ions of the spectrum of 42 which led to this conclusion
are in Fig. 3 (49). The other product of this incubation, the N-demethyl
compound 44, was again identified by spectral analysis (50).High-resolution
mass spectral data led to the identification of the fragments shown in Fig. 4,
m:’e 338 (C,,H,,NO,) m,e 353 (C2,H2,NZ02)

FIG 3. Characteristic fragment ions of 42 (49).
m e 174(CllH12NO) w e 283 (C,,H,3N,0)

FIG.4. Characteristic fragment ions of 44 (50).
342 H. L. HOLLAND
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
A mie 749 (100)

a
-CH,CO,
OCH,
mle 661 (12)
45
m / e 908 (42)
m/e 454 (52) mle 395 (31)
FIG5. Mass spectral fragmentation of dihydrovindoline ether dimer (45) (52).

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
2 84.9 84.8, 83.7

3 46.6* 46.0*
3-olefin 136.2
5 50.9 52.0, 5 1. I
6 46.3* 49.1*, 46.0"
7 52.3* 53.3*, 51.5*
8 130.3 130.5, 130.3
9 120.8 121.7, 121.0
10 103.2 103.7, 103.2
11 160.9 161.0, 160.9
12 94.6 95.0, 94.7
13 150.5 151.7, 150.5
14 22.2 22.3
14-olefin 111.9
15 77.6 79.3, 76.8
16 88.1 88.3, 85.8
17 74.8 74.8, 74.1
18 9.0 9.1, 8.5
19 24.8 32.5, 29.7
20 41.Q 48.5*, 46.6*
21 67.1 67.6, 66.2
Acetyl carbonyl 169.8 170.2, 169.9
Ester carbonyl 168.9 169.3, 168.9
Aryl OCH, 55.2 55.3, 55.2
Ester OCH, 54.4 52.4, 53.0
N-CH, 36.0 36.9, 36.0
Acetyl-CH, 20.8 20.9, 20.9
Chemcial shifts marked with asterisks

may be interchanged.
344 H . L. HOLLAND
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.
\-oxidation
A
OAc
R R
38
i
R
$
(
R
OAc
54
acetodcetate
OAc 40
R
55
FLG.6. Mechanism of the metabolism of vindoline (38)by Streptornyces griseus
Deacetylvindoline (39) is transformed by Streptomyces cinnamonensis

A151 67 in a manner analogous to the major transformation route of vindo-
line by similar organisms, giving deacetyldihydrovindoline ether (41) in low
yield (49).The structure of 41 followed from analysis of the PMR spectrum
in which decoupling of the C-14 and C-15 hydrogens at 6 1.93 and 4.22 ppm
once again confirmed the presence of the C-15-C-16 ether bridge (49).
Transformations of the dimeric alkaloid vinblastine (46) by Streptoniyces
species have been reported which involve N-demethylation (54,aromatic
hydroxylation (531,and intramolecular ether formation (53).With Strep-
tomyces albogriseolus, N-demethylation occurs in an undisclosed yield to
produce 47 (51).The same organism in the hands of the same workers is also
reported to lead to the formation of vinblastine ether (50) in low yield, along
346 H. L. HOLLAND
cH3u
C H&,02
: RC
7 -
46 R ' = H. R 2 = CH, Vinblastine 50 Vinblastine ether

47 R 1 = R 2 = H N-Demethylvinblastine
48 R ' = OH, R Z = CH, 10'-Hydroxyvinblastine
49 R 1 = OCH,. R 2 = CH,
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
-CH,CO,
m e 749 4 50 m e 808 (C,,H,,N,O,)
m)’e 352 (100) (C,,H,,N,O,)
540 (C,,H,,N,O,)
FIG.7. Mass spectral fragmentation of vinblastine ether (50)
atmospheric oxygen (83-86), an observation which led to the proposal that

leurosine may be an oxidative artifact of isolation (86). However, Stuart
et al. (54) were able to demonstrate that the conversion of 51 to 52 was
performed efficiently by horseradish peroxidase in the presence of hydrogen
peroxide and, less efficiently, by a cell-free extract of Catharanthus roseus
leaves under the same conditions. Hydrogen peroxide alone did not lead to
the formation of significant amounts of leurosine under the conditions of
incubation. They therefore suggested that leurosine is in fact a “natural”
product, and that it may be formed by the action of a peroxidase-type enzyme
on 3’,4‘-anhydrovinblastine.
34 8 H. L. HOLLAND
CH,O
51 3’,4’-Anhydrovinblastine
52 Leurosine 53 Cathanneine (Cathoclavine)
IV. Transformations of Isoquinoline Alkaloids
The transformations discussed below are summarized in Table I11 (42,

8 7- 118).
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
(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
Cunninghamella echinulata (Apocodeine) (74) x9
NRRL 3655 (Isoapocodeine) (75) 89
(Unidentified) XY
W
VI
TABLE 111 (continued)
0
Substrate Reagents Product" 7" Yield' Ref.
Helicostylum piriforme (Apocodeine) (74) HY

QM 6945 (Isoapocodeine) (75) HY
Microsporum gypseum (Isoapocodeine) (75) 89
Mucor mucedo SP-WlSC 4605 (Isoapocodeine)(75) 89
(Unidentified) 89
Penicillium ducluuxi (Isoapocodeine) (75) 89
NRRL 2020 (Unidentified) 89
Sepedonium ch ryospermum (Unidentified) 8')
ATCC 13378
Streptomyces .species Apocodeine (74) 89
SP-WISC 1158 Isoapocodeine (75) 89
(Unidentified) HY
Streptomyces rimosus (Apocodeine) (74) HY
ATCC 23955 (Isoapocodeine) (75) 89
Apocodeine (74) Rat liver microsomes (Apomorphine) (73) Y0
(Unidentified) Yf)
lsoapocodeine (75) Rat liver microsomes (Apomorphine) (73) 90
(Unidentified) 90
10-Hydroxyaporphine (77) Rat liver microsomes (Unidentified) YO
10-Methoxyaporphine (76) Rat liver microsomes (10-Hydroxyaporphine) (77) 90
Apomorphine (73) Rat liver homogenate (Apocodeine) (74) 91
(Isoapocodeine) (75) 91
(S)-Glaucine (66) St,vsunus stemonites SC 2831 (6a,7-Dehydroglaucine) (79) 92
(Unidentified) 92
Penicillium cluviforme (6a,7-Dehydroglaucine) (79) 92
MR376 (Unidentified) 92
Cunninghumella echinulutu [0-(9)-Methylboldine] (67) 92
Cunninghamella bainieri [0-(9)-Methylboldine] (67) 92
ATCC 3065
Streptomyces punipalus [0-(9)-Methylboldine] (67) 92
Streptomyces griseus UI 1 158 0-(9)-Methylboldine (67) 92
Norglaucine (78) 92
Penicillium brevicompactum (Norglaucine) (78) 92
ATCC 10418
Fusariwn solani ATCC 12823 6a,7-Dehydroglaucine (79) 92
Oxoaporphine 80 92
(RS)-Glaucine (RS)-66 Fusarium solani ATCC 12823 (6a,7-Dehydroglaucine) (79) 92
(R)-Glaucine [(R)-661 Y2
B. Benzylisoquinolines
N-Methylcoclaurine (81) Potato peel homogenate Dimer 82 93
Trimer 85 93
Nelumbo nucifera Gartner p - Hydroxybenzaldehyde 93
homogenate
Norlaudanosoline (87) Rat liver homogenate (Two unidentified methylated products) Y4
Rat liver homogenate (90) 95. 96
(93) 95, 96
(Ring A monomethyl 93) 95, 96
Rat brain homogenate (90) 95, 96
(93) 95, 96
(Ring A monomethyl 93) 95. 96
(R,S)-Reticuline (88) Rat liver homogenate (R,S)-Coreximine (91) 97.98
99
(R,S)-Scoulerine (94) 98
99
(R,S )- N orreticuline (96) 98
Pallidine (98) 99
Isoboldine (100) 99
W Papaver rhoeas homogenate p-Hydroxyreticuline (141) 100
-
(continued)
W
ul
h, TABLE 111 (continued)
Substrate Reagents Product" % Yieldb Ref.
(R,S)-Laudanosine (89) Rat liver homogenate (R,S)-Xylopinine (92) 0.02 98

(-)-Tetrahydropalmatine (95) 0.007 98
(R,S)-Norlaudanosine (87) 14.1 98
Cunninghamella blakesleeana (R,S)-Pseudocodamine (104) 44.4 101
ATCC 8688a
Stysanus microsporus UI 2833 (Unidentified) (-1 101
Aspergillus niger ATCC 10581 (Unidentified) (-1 101
Cunninghamella echinulata (Unidentified) (-1 101
ATCC 9244 (Unidentified) (-1 101
Microsporum gypsewn (Unidentified) (-1 101
ATCC 11395
Papaverine (106) Rat liver homogenate [O-(4')-Demethylpapaverine] (107) (-1 102, 103
[O-(7)-Demethylpapaverine] (108) (-1 102, 103
[6-(6)-Demethylpapaverine] (109) (-1 102,103
Aspergillusjlavus X- 158 [O-(6)-Demethylpapaverine] (109) (Good) 103
Aspergillus alliaceus 3 15 0-(6)-Demethylpapaverine (109) 40 103
Cunninghamella bainieri 3065 [0-(3')- or -(4)-Demethylpapaverine] (-) 103
[O-(7)-Demethylpapaverine] (108) (Trace) 103
[0-(6)-Demethylpapaverine] (109) (Trace) 103
Cunninghamella blakesleeana [0-(3')- or -(4)-Demethylpapaverine] (-1 103
ATCC 8688a [O-(7)-Demethylpapaverine] (108) (Trace) 103
Cunnin$hamella echinulata [ 0 - ( 3 ' ) - or -(4)-Demethylpapaverine] (-1 103
NRRL 3655 ,, [O-(7)-Demethylpapaverine] (108) (Trace) 103
~
Cunninghamella echinulata 0-(4)-Demethylpapaverine (107) 21 103

ATCC 9244 [0-(7)-Demethylpapaverine] (108) (Trace) 103
[O-(6)-Demethylpapaverine] (109) (Trace) 103
Cunninghamella elegans [0-(3’)-or -(4)-Demethylpapaverine] 103
ATCC 9245 [0-(7)-Demethylpapaverine] (108) 103
[0-(6)-Demethylpapaverine] (109) 103
Sepedonium chryospermum [043’)-or -(4)-Demethylpapaverine] 103
Streptomyces griseus UI 1158 [043’)- or -(4)-Demethylpapaverine] 103
Streptomyces platensis [0-(3‘)- or -(4)-Demethylpapaverine] 103
C. Bisbenzylisoquinolines and related alkaloids
(+)-tetrandrine (111) Cunninghamella blakesleeana (Unidentified) 101
ATCC 8688a N-(2)-Nor-(+)-tetrandrine (113) 104
Cunninghamella blakesleeana (Unidentified) 104
ATCC 9245
Cunninghamella echinulata “+‘)-Nor-( +)-tetrandrine] (112) 101
NRRL 3655 [N-(Z)-Nor-( +)-tetrandrine] (113) 104
Cunninghamella echinulata [N-(T)-Nor-( +)-tetrandrine] (112) 104
ATCC 9244
Mucor mucedo U1-4605 [N-(2’)-Nor-(+)-tetrandrine] (112) 101,104
Penicillium brevi-compactum [N-(2‘)-Nor-(+)-tetrandrine] (112) 101,104
ATCC 10418
Streptomyces griseus UI-1 I58 [N-(T)-Nor-( +)-tetrandrine] (112) 101, 104
Streptomyces griseus UI-L103 (Unidentified) 104
Streptomyces punipalus “-@‘)-Nor-( +)-tetrandrine] (112) 101,104
NRRL 3529
Streptomyces lincolnensis [N-(T)-Nor-( +)-tetrandrine] (112) 101, 104
ATCC 25466
Microsporum gypseum “+‘)-Nor-( +)-tetrandrine] (112) 104
W ATCC 11395 (Unidentified) 104
w
v1
Aspergillus ochraceus UI 398 [N-(Z‘)-Nor-( -t)-tetrandrine] (112) 104
(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
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)
Substrate Reagents Product" % Yieldb Ref.
Mouse liver homogenate (3,4,5-Trimethoxybenoic acid) 115

(3,4,5-Trimethoxyphenylaceticacid) 115
Mouse kidney homogenate (3,4,5-Trimethoxybenzoicacid) 115
(3,4,5-Trimethoxyphenylaceticacid) 11.5
Mouse heart homogenate (3,4,5-Trimethoxybenzoicacid) 115
(3,4,5-Trimethoxyphenylaceticacid) 115
D-( -)-Ephedrine (148) Rabbit liver microsomes (Norephedrine) (149) 116
(Benzoic acid) 116
(1 -Phenyl- 1,2-propanediol) 116
Rabbit liver homogenate (Norephedrine) (149) 116
supernatant (Benzoic acid) 116
(I-Phenyl- 1,2-propanediol) 116
L-( +)-Ephedrine (148) Rabbit liver microsomes (Norephedrine) (149) 116
(Benzoic acid) 116
(1 -Phenyl- 1,2-propanediol) 116
Rabbit liver homogenate (Norephedrine) (149) 116
supernatant (Benzoic acid) 116
(l-Phenyl-l,2-propanediol) 116
Salsolinol(l52) Rat liver homogenate (Mono-0-methylsalsolinol) 94
(+)-Tubocurarine' (154) Isolated rat liver (No biotransformation) 117
(+)-2,3-Dehydroenhetine (158) Rat liver microsomes (No biotransformation) 118
a Parentheses indicate not isolated.

* Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
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
N-dealkylation in all cases, leading to the formation of nornuciferine (56)

in low yield. The rates of N-dealkylation of 57-63 were inversely pro-
portional to the size and complexity of the N-alkyl group. In addition to
nornuciferine, both rat and rabbit liver microsomes coverted nuciferine to
the oxoaporphine (64) in a yield of less than 1%. Lysicamine was identified
by TLC and spectral comparisons with a sample produced by the photo-
chemical air oxidation of nornuciferine in chloroform solution (87, 124).
Although lysicamine may therefore be formed by autoxidation of nornuci-
ferine, the use of the appropriate blanks in the enzymic studies indicated
that the transformation was indeed an enzymic one under the incubation
conditions used (87). No 0-demethylation was observed in the above study,
but Smith and co-workers later reported (90) a preparation of rat liver
microsomes which performed the 0-demethylation of apocodeine (74) to
apomorphine (73),of isoapocodeine (75)to 73, and of 10-methoxyaporphine
(76) to 10-hydroxyaporphine (77). The same group has also isolated a
catechol 0-methyltransferase from rat liver, which was used to carry out
the methylation of apomorphine to yield both apocodeine and isoapocodeine
in a ratio of 81 : 1 (91).
6
CH30
OR OR
68 R =H Bisboldine
69 R = AC
358 H. L. HOLLAND
OR
70 R = H Bisboldine ether
71 R = AC
The only other reported transformation of an aporphine alkaloid by a

purified enzyme preparation involves the dimerization of (S)-boldine (65)
by horseradish peroxidase in the presence of hydrogen peroxide (88). Two
products were isolated, both in moderate yield, and were formulated as 68
(12%) and 70 (8%). In spite of the description of the major product as an
(S,S)-dimer, the configurations at C-6a and C-6a’ were given as shown in
structure 68 [C-6a(S), C-6a’(R)]. The (S,S)-dimer has the opposite config-
uration at C-6a‘ to that shown. Similar comments apply to dimer 70 which,
as formulated by Stuart and Callendar (88), is an (R,R)-isomer. Irrespec-
tive of the configurations at C-6a and C-6a’, the gross structures of 68 and
70 were determined as follows. The PMR spectrum of 68 showed signals
in the aromatic region at 6 6.05 (2H, C-3 and C-3’ hydrogens) and 7.56
ppm (2H, C-11 and C-11’ hydrogens), assigned by comparison with the
spectrum of starting material, and indicative of a C-8-8’ linkage. The mass
spectrum of 68 did not show a molecular ion, but that of a tetraacetate
derivative 69 was interpreted on the basis of the mass spectral behavior
of the aporphines (125, 126) as diagnostic of the carbon-carbon dimeric
structure proposed. Stuart and Callendar point out that although restricted
rotation about the C-8-8’ bond of 68 leads to the possibility of the existence
of 68 as a pair of diastereomers, only one isomer was formed in the enzymic
dimerization. The structure of dimer 70 was determined by PMR spectro-
scopy of 70 and the triacetate derivative 71, the appearance in the aromatic
region of the spectrum of 70 of signals at 6 6.03 (2H, C-3 and C-3’ hydrogens),
7.20 (1H and C-8 hydrogen), and 7.57 ppm (2H, C-11, and C-11’ hydrogens)
indicating the formation of an 0-(9)-C-8’ dimer (87).
Transformations of aporphines by microorganisms involving 0- and
N-demethylation (89,92) and CH-CH dehydrogenation (92) have been
reported. In a preliminary screening study, Wolters reported the metabolism
of boldine and a related alkaloid of undisclosed structure to unidentified
products by Piricularia oryzae (42). More detailed studies with a series of
microorganisms have been carried out by Rosazza and co-workers (89,92).
In a study aimed at identifing microbial systems that would mimic the

mammalian metabolism of 10,ll-dimethoxyaporphine(72), they screened
65 microorganisms for their capacity to transform 72 (89). Of these, 10
produced identifiable metabolites in reasonable yield (see Table 111). These
transformations involved 0-demethylation to produce apocodeine (74)
and/or isoapocodeine (75), maximum isolated yields being given by
Streptomyces species sp-Wisc. 1158(74,24%and 75,19.5%).Cunninghamella
blakesleeana ATCC 9245 converted 72 quantitatively to isoapocodeine,
assayed by spectral analysis but not isolated. Highly polar, unidentified
metabolites were formed along with 74 and/or 75 by most of the micro-
organisms investigated.
72 R' = R2 = OCH, 10,ll-Dimethoxyaporphine

73 R' = R 2 = OH Apomorphine
74 R' = OCH,, R2 = OH Apocodeine
75 R' = OH, R2 = OCH, Isoapocodeine
76 R' = OCH,, R2 = H 10-Methoxyaporphine
77 R' = OH, R2 = H 10-hydroxyaporphine
C H , O V
OCH, OCH,
78 Norglaucine 79 6a,7-Dehydroglaucine
In a later investigation of the microbial transformation of (S)-glaucine

(66), Rosazza's group identified microorganisms that performed 0- and
N-demethylation as well as stereospecific CH-CH dehydrogenation (92).
Maximum isolated yields of norglaucine (78) (1 1%) were produced by
Streptomyces griseus UI 1158, which also produced the 0-(2)-demethyl
metabolite, 0-(9)-methylboldine (67), in a yield of 14%. The site of 0-
demethylation in 67 could not be determined by PMR analysis of the sig-
nals for the remaining methyl hydrogens, but was confirmed by titration
of a solution of 67 in DMSO-d,/D,O with NaOD. Demethylation at 0 4 2 )
relative to glaucine was indicated by the observation of a large upfield
360 H. L. HOLLAND
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
In an attempt to determine whether the metabolism of glaucine was a

stereospecific process, (R,S)-glaucine was incubated with both Streptomyces
griseus (giving 67 and 78) and Fusarium solani (giving 79 and 80). In the
former case, recovered starting material was not optically active, indicating
no preference for either enantiomer of the substrate in either 0-or N-demeth-
ylation. However, glaucine recovered after six days incubation with F. solani,
when approximately one-half of the substrate remained, was determined to
be 75.4% enantiomerically pure (R). Monitoring of the incubation indicated
that after seven days, the residual glaucine was essentially the pure (R)
enantiomer, although at this time little substrate remained unmetabolized.
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
began their investigations of the biotransformations of this group of alka-

loids with a study of the metabolism of N-methylcoclaurine (81) by potato
peel homogenate and by homogenized rhizome of Nelumbo nucifera Gartner
(93). The latter preparation gave p-hydroxybenzaldehyde as the only isol-
able product, a result in line with the earlier work of Baxter et al. (128)on
the oxidation of related synthetic benzylisoquinolines by horseradish per-
oxidase-hydrogen peroxide. Incubation of 81 with potato peel homoge-
nate-hydrogen peroxide, however, led to the formation of the head-to-tail
dimer 82 and trimer 85, isolated as the corresponding acetates 83 and 86,
respectively, in low yield (93). The determination of the structures of 83
and 86, obtained in only milligram quantities, relied heavily on the inter-
pretation of mass spectral data. Major fragment ions in the spectrum of
83 were interpreted as arising from the cleavage of bonds a-d, and subse-
quent breakdown of fragments so produced. Cleavage of the analogous
bonds a-c of 86 resulted in a fragmentation pattern which accounted for
the major ions of its spectrum. Other spectral data obtained for 83 and 86
did not permit unequivocal structure determination to be made, but the
structure proposed for 83 was strengthened by a detailed comparison of
its mass spectrum with that of the known alkaloid neferine (a), a consti-
tuent of Nelumbo nucifera Gartner (129).
CH,O
R'O%
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
The tetrahydroisoquinoline alkaloids reticuline (88), a common precursor

in the biogenesis of many isoquinoline and related alkaloids (130, 131), and
laudanosine (89) are susceptible to biotransformation by both mammalian
and microbial systems. In the case of the former it is interesting to note
that many of the reported biotransformations appear to parallel reactions
thought to be involved in the biosynthetic processes that involve reticuline
as substrate (97-99). Following their observation that ( +)-reticuline was
converted to coreximine (91) by female rats (132),Kametani and co-workers
extended their investigation of reticuline biotransformation to include rat
liver homogenate and were able to demonstrate the conversion of (R,S)-
reticuline to (R,S)-coreximine (91) (97-99), (R,S)-scoulerine (94) (98,99),
(R,S)-norreticuline (96) (98), pallidine (98), and isoboldine (100) (99). No
detectable amounts of the 0-0 coupled corytuberine (102) or p-o coupled
salutaridine (103) were present in any of the incubations with reticuline
as substrate (99).They also demonstrated the analogous conversion of (R,S)-
laudanosine (89) to (R,S)-xylopinine (92) (98), ( -)-tetrahydropalmatine
(95) (98),and (R,S)-norlaudanosine (97) (98).
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
,
The biotransformations of reticuline involve N-demethylation (to 96),

phenolic oxidative coupling in a manner analogous to that observed in
alkaloid biosynthesis (to 98 and loo), and ring closure similar to that ob-
served in protoberberine biosynthesis (to 91, 92, 94, and 95). Kametani
et al. (97,98) have suggested that N-demethylation and protoberberine
formation may occur through the intermediacy of an immonium cation
derived from the N-methyl group of reticuline either by N-oxidation fol-
lowed by rearrangement or by C-hydroxylation and loss of OH-, as shown
in Fig. 8. However, in a later paper (99)they reported the biotransformation
of reticuline-d, labeled with deuterium at the N-methyl group, C-1, and
the attached benzylic methylene position. Mass spectral analysis of the
isoboldine (101)and pallidine (99)so derived indicated that all the deuterium
was retained intact during their formation. However, some of the scoulerine
and coreximine produced from the same incubation contained two deu-
terium atoms fewer than anticipated. The characteristic mass spectral frag-
mentation pattern of the protoberberine alkaloids (133) indicated that the
deuterium label at C-1 and the benzylic u positions had remained intact,
and that loss of label had occurred from the N-methyl (now C-8) position.
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
This observation was explained by the assumption that a portion of the

protoberberine was formed via norreticuline (96) present in the same in-
cubation mixture and derived from enzymic demethylation of reticuline.
Reaction of 96 with an unlabeled one-carbon fragment and subsequent
ring closure would then lead to C-8 unlabeled protoberberines. The authors
suggest that this one-carbon fragment may be derived from S-adenosyl-
methionine, and that the product of its combination with 96 may be con-
verted directly to 91 or 94 without the intermediacy of free reticuline (99).
If their assumption is correct, the conversion of norreticuline to the pro-
toberberine alkaloids may not involve the formation of reticuline itself, a
suggestion that is at variance with the known intermediacy of reticuline
in the biosynthesis of alkaloids of this group.
In addition to the transformations by rat liver enzymes discussed above,
(R,S)-laudanosineis metabolized by a variety of microorganisms to produce
products that include the 0-demethyl compound pseudocodamine (104)
(101). Of over 60 microorganisms screened, Cunninghamella blakesleeana
ATCC 8688a gave the highest isolable yield of 104 (44%). The structure of
104 was confirmed by a classical oxidative degradation of the 0-ethyl ether
105 to 4-ethoxy-3-methoxybenzoicacid (101). In incubations of 89 with C .
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
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
Compound 6-OCH3 7-OCH3 4'-OCH, 3'-OCH,
106 3.99 3.89 3.81 3.76

107 4.00 3.89 - 3.17
10s 4.02 - 3.77 3.12
109 ~
3.92 3.82 3.77
a From Rosazza et al. (103).

366 H. L. HOLLAND
R E
RZO '\ O W N
106 R' = R2 = R3 = CH, Papaverine

107 R' = R2 = CH,, R3 = H 0-(4)-Demethylpapaverine
108 R' = R3 = CH,, R2 = H 0-(7)-Demethylpapaverine
109 R' = H, R2 = R3 = CH, 0-(6)-Demethylpapaverine
110 R1 = R3 = H, RZ= CH, 0-(4', 6)-Didemethylpapaverine
111 R' = R Z = CH, (+)-Tetrandrine

112 R' = CH,, RZ= H N-(2)-Nor-(+)-tetrandrine
113 R' = H, RZ = CH, N-(2)-Nor-(+)-tetrandrine
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
product is (+)-hernandalinol (116),produced in 12% yield by Streptomyces

punipalus NRRL 3529 (205).The structure of this metabolite was confirmed
by comparison with an authentic sample produced by reduction of the
known alkaloid hernandaline (115) (205). The observation that hernandaline
is quantitatively reduced to 116 by S. punipalus under conditions identical
to those used for the conversion of thalicarpine to 116 suggests that the initial
product of the metabolism of thalicarpine may be the aldehyde hernandaline,
which is subsequently enzymically reduced to the final product 116. Thali-
carpine is therefore presumably attacked oxidatively at the benzylic position
adjacent to C-l’, a reaction paralleled by its chemical oxidation which results
in cleavage of the same bond (237).
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
demethylation has been reported (107,110,138).In addition, the transforma-

tion of morphine and related compounds by microorganisms has received
considerable attention, and the results have been surveyed (11). Recent
work in the area of morphine biotransformation has centered on the use of
isolated enzyme systems and on the investigation of the properties of the
enzymes themselves. In the former area, enzyme preparations from the rat
liver and brain (107) and the guinea pig liver (109, 110) have been most
effective in producing morphine metabolites in reasonable yield. Incubation
of morphine (117) with rat liver homogenate resulted in the formation of
normorphine (119) (107),morphine N-oxide of undetermined stereochem-
istry (121 and/or 123) (107),morphine-3-gluconuride (126) (107, 108), and a
metabolite not fully characterized but thought to be 2-hydroxymorphine
(128) on the basis of TLC color reactions, and the supposed formation of a
similar compound on incubation of morphine with horseradish peroxidase-
hydrogen peroxide (106).The isolation of a morphine metabolite described
as the 2,3-dihydrodiol 129 from in uiuo studies, the established enzymic
oxidation of morphine at C-2 (139),and the chemical oxidation of morphine
at C-2 by ferricyanide have been proposed by Misra et al. (107) as addi-
tional evidence for the structure of 128. The oxidized metabolite 128 was the
only product obtained from incubation of morphine with an enzyme prep-
aration from rat brain (107).
117 R' = H, R2 = CH, Morphine 121 R = H Morphine N-oxide

118 R' = R2 = CH, Codeine 122 R = CH, Codeine N-oxide
119 R' = R2 = H Normorphine
120 R' = CH,, R 2 = H Norcodeine
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
128 2-hydroxymorphine 129 Morphine 2,3-dihydrodiol
Phillipson and co-workers have recently investigated the metabolism of

morphine and codeine (118) by a microsomal preparation from guinea pig
liver (109, 110). Whereas previous in uitro studies with rat liver enzymes had
revealed only traces of N-oxide formation (107), the preparation from
guinea pigs carried out this conversion relatively efficiently, especially with
codeine as substrate. The in uitvo N-oxidation of normorphine and nor-
codeine had been reported earlier (140). With morphine as substrate, the
guinea pig liver microsomes produced normorphine as the major metabolite
(973, in addition to codeine (5.3%) and the morphine N-oxide 123 (109,110).
The N-oxides 121-124, all of which (except 122) are natural products (141),
were used as reference standards for the identification of the metabolites of
morphine and codeine in this study. The same enzyme preparation with
codeine as substrate gave norcodeine (120), morphine, normorphine, and
the isomeric codeine N-oxides 122 and 124 as products (109, 110). When
compared with the yield of isomer 122 (0.1%),the formation of the N-oxide
124 in a yield of 19.5%suggests that with morphine as substrate the N-oxide
(121) isomeric with that isolated (123,0.9%)may well have been present but
undetected in the incubation mixture. The relatively efficient conversion of
morphine to codeine by the guinea pig liver microsomes in the absence of
any added methyl donor such as S-adenosylmethionine has tempted
Phillipson et al. (110) to speculate that the N-methyl group of morphine
N-oxide may be the source of the methyl required to methylate the C-3
phenolic function of morphine with simultaneous production of normor-
phine, but there is no direct evidence in support of this suggestion.
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
an analogous head-to-tail dimer 132 was formed from N-methylhomo-

coclaurine in low yield (111).The dimer 132, isolated as the triacetate 133,
was characterized by a combination of PMR and mass spectral data. The
molecular ion of 133 (m/e 750), underwent characteristic fragmentation at
“a” to give a peak of mje 587. Additional evidence for a head-to-tail coupled
structure for 133 (and hence 132) was provided by comparison of its PMR
spectrum with that of related bisbenzylisoquinoline dimers. The absence
of dienones as products of the enzymic coupling of 130 is noteworthy for
two reasons: first, inorganic coupling reagents such as ferric chloride and
ferricyanide generally lead to significant dienone formation (142); second,
the enzyme preparation used in the coupling of 130 carries out the classic
conversion ofp-cresol to Pummerer’s ketone in a yield comparable with that
of 132 from 130 (111).
In a further study involving the same substrate, but with an enzyme
preparation from Wusubiu juponicu Matsumura, Kametani et ul. (112)
demonstrated the formation of the head-to-head coupled dimers 134 and
136, together with an unidentified product. The 0-methyl substrate 131 was
not metabolized by the enzyme preparation used in this study. The major
I
OR
130 R = H N-Methylhomococlaurine
131 R = C H ,
OR OR
132 R = H Promelanthiodine
133 R = AC
CH,N H,
OR OR
134 R = H
135 R = Ac
product 134, isolated as the triacetate 135, was characterized as a head-to-

head C-0-C dimer by high-resolution mass spectral data: cleavage of
bond a or b leads to the observed base peak at m/e 587, and subsequent
cleavage of the unbroken homobenzylic bond produces a substituted bisiso-
quinoline ion of m/e 212 (21%). Loss of the acetyl function from m/e 212 then
produces the ion at m/e 191 (51%), characteristic of bisbenzylisoquinolines
with head-to-head coupling (143, 144). The minor product 136, again
isolated as the acetate derivative 137, was also characterized by high-
resolution mass spectral data, the molecular ion (m/e 792) undergoing
fragmentation at bonds a and/or b to produce fragment ions at m/e 629 and
233. As in the previous study with 130 as substrate ( I l l ) , no dienone forma-
tion was observed. The formation of head-to-tail dimers of 130 with potato
peel homogenate and of head-to-head dimers with homogenate of Wasabia
juponica has prompted Kametani et al. (112) to comment on the nature of
the enzymes involved. However, in the absence of any definitive data on
the nature of these enzymes and their mode of action, such commentary is
at best speculative.
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
FIG.9. Enzymic oxidation c( and to nitrogen of benzyl- and phenethylisoquinolines 88 and

138.
to give B-hydroxyretixuline (141) on treatment with homogenized Papaver

rhoeas and hydrogen peroxide. The latter reaction probably proceeds
through an enamine intermediate 156, which would render the position
B to nitrogen susceptible to attack by an electrophilic oxidizing species
(25),whereas in the absence of such an oxidizing agent nucleophilic attack
at the C-1 position of an immonium ion species 155 to produce 139 may
occur. These proposals are summarized in Fig. 9. The initial oxidation to
155 may well involve N-oxidation followed by loss of OH- (see Fig. 8):
N-oxidation by Papaver somniferum latex has been reported (145). In
any event, the facile reversible oxidation-reduction of reticuline to the
corresponding 1,2-dehydroisoquinolinium salt has been shown to occur in
P . sonniferwn (146).The synthesis of the acetate derivative 140 by the addi-
tion of acetate to a 1,2-dehydroisoquinoliniumsalt confirmed the structure
of enzymically produced 139 (ZOO) and lends credibility to the mechanistic
proposals shown in Fig. 9.
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).
be readily rationalized without invoking an epoxide intermediate, for

which there is little direct evidence at the present time.
The enzymic oxidative deamination of simple phenethylamines is ex-
emplified by the reported biotransformations of mescaline (146) (114, 115)
and ephedrine (148) (116). Mescaline is metabolized to 3,4,5-trimethoxy-
phenylacetic acid by tissue homogenates of mouse brain, liver, kidney,
and heart (114, 115). 3,4,5-Trimethoxybenzoic acid is also formed as a
minor metabolite. The formation of N-acetylmescaline (147, a significant
metabolite in uiuo, was not observed in the in uitro studies. Both D-(-)-
and L-( + )-ephedrine have been incubated with enzyme preparations from
rabbit liver ; norephedrine (149), benzoic acid, and 1-phenyl-1,Zpropanediol
were characterized as metabolites (116). The D-( -)-isomer was the better
substrate, being more rapidly converted. Similar results were previously
reported with rabbit liver slices as the source of enzyme (153, 154). The
enzymic degradation of the side chain of 8-phenethylamines has been
extensively investigated with nonalkaloid substrates such as amphetamine
(151) and N-methylamphetamine (150) (10, 155-157), and the reader is
referred to these studies for a more comprehensive coverage of this aspect
of the subject.
Thd simple isoquinoline salsolinol(152), a relative of the alkaloid salsoline
(153), k msno-0-methylated by an enzyme preparation from rat liver,
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
154 (+)-Tubocurarine 158 2,3-Dehydroemetine

376 H. L. HOLLAND
giving either 153 or its 0-(6)-methylated isomer (94). Salsolinol is of interest

in that it represents one of the products of ethanol metabolism, the result
of the reaction of ethanol-derived acetaldehyde with dopamine (158).
A study of the uptake and excretion of (+)-tubocurarine (154) and its
trimethyl derivative in the rat reported no evidence for biotransformation of
either substrate in uiuo or in uitro with isolated perfused livers (117). A
similar study with ( ? )-2,3-dehydroemetine (158) showed that although
metabolism occurred in uiuo to give unidentified product(s) no in uitro bio-
transformation was carried out by rat liver microsomes (118).
V. Transformations of Pyridine Alkaloids

A. NICOTINE
AND RELATEDALKALOIDS
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.
VI. Transformations of Pyrrolizidine Alkaloids

The toxicity of plants that contain pyrrolizidine alkaloids has been
discussed in an earlier volume of this series (163), and the relationship
between the toxic nature of the plants and the metabolism of their alkaloids
by the victim has been reviewed (164). Since the toxicity of the pyrrolizidine
alkaloids in mammals seems to be due to their metabolites rather than to the
alkaloids themselves (164), considerable effort has been expended in the
identification of the metabolites produced both in uiuo and in uitro by
mammalian systems. The material summarized in Table V (165-172) is
supplementary to that discussed in reference 164.
TABLE V.
TRANSFORMATIONS
OF PYRROLIZIDINE
ALKALOIDS
Substrate Reagent Product' % Yieldb Ref.
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
Guinea pig liver microsomes (Retrorsine N-oxide) (167) 168
(Pyrrolic derivative) (168)
Fowl liver microsomes (Retrorsine N-oxide) (167) 168
Quail liver microsomes (Retrorsine N-oxide) (167) 168
Sheep liver microsomes (Retrorsine N-oxide) (167) 168
(continued)
TABLE V (continued)
Substrate Reagent Product" 7; Yieldb Ref.
Retrorsine N-oxide (167) Rat liver microsomes (No metabolism to pyrrolic derivatives)
Monocrotaline (169) Guinea pig liver microsomes (Monocrotaline N-oxide) (170)
Rat liver microsomes (Monocrotaline N-oxide) (170)
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)

Parentheses indicate yield based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
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
161 R' = CH,, R2 = OH, R3 = H Heliotrine
Clm2R1
CH,
162 R' = CH,, R2 = 0-C
R3 = H Lasiocarpint
CH3
CH,
II'c=c/
o/ H
'
163 R' = RZ= R3 = H Supinine

159 R = CH, Arecoline 164 R' = CH,, R2 = R3 = H Heleurine
160 R = H Arecaidine 165 R' = CH,, R2 = R3= OH Europine
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
was isolated which converted heliotrine to heliotric acid and 7a-hydroxy-

1-methylene-8a-pyrrolizidine (173), both identified by comparison with
authentic samples. The same microorganisms also metabolized supinine,
but the product was not identified. In a later study, an anaerobic micro-
organism, Peptococcus heliotrinreducans, was obtained from sheep rumen
contents. This organism also produced 173 from heliotrine (166).In addition,
it produced the 1-methylenederivativesfrom supinine (163 4 174),heleurine
(164 4 174), and europine (165 + 173).
380 H. L. HOLLAND
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
were identified only by specific reaction with a modified Ehrlich reagent

(175).
Similar products were obtained on incubation of monocrotaline (169)
with a variety of liver microsomes of mammalian origin (170, 171). The
N-oxide 170 was produced by liver microsomes from the rat and guinea
pig, along with a pyrrolic derivative presumed to be 172 (170, 174, whereas
microsome preparations from other sources led to the production of only
the pyrrolic derivative (171). Both monocrotaline and crispatine (171)
were transformed to unidentified products by Peptococcus heliotrinreducans
(166).
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).
Vn. Transformations of Quinoline Alkaloids
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
Substrate Reagent Product" % Yieldb Ref.
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
(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
Cunninghamellabainieri ATCC 9244 (9-Hydroxyacronycine) (177) (Major) 176, 177
(11-Hydroxyacronycine) (178) (Minor) 176, I77
(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

Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
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
being used to confirm the position of oxygenation in ring A. The hydrogen

at C-8 of both acronycine and 182 resonates at lower field than the remaining
aromatic hydrogens due to the presence of the ortho carbonyl substituent,
and in 182 it appears as a doublet (J = 2 Hz) at 6 7.93 ppm with meta coupling
to the C-10 hydrogen. The latter hydrogen interacts with both the C-8 and
C-11 hydrogens and appears as part of a well-resolved ABC spin system.
The microbial hydroxylation of aromatic substrates with activating
substituents appears to follow the normal rules of electrophilic substitution
in that ortho and para products predominate (176, 181), and the formation
of 177 (major) and 178 (minor) in both the microbial and mammalian
metabolism of acronycine has been attributed (177) to the directing in-
fluence of the nitrogen atom in a process involving a monooxygenase
enzyme.
In spite of the investigation of the in uiuo mammalian metabolism of
other alkaloids of the quinoline type, such as the biotransformations of
quinidine in man (182), and the characterization of the metabolites (183,
184), there have been no other reports of microbial or in v i m enzymic
transformations of other alkaloids of this group.
VIII. Transformations of Steroidal Alkaloids
Although the microbial transformation of steroids is a well-developed

aspect of steroid chemistry (1, 2), the corresponding branch of steroidal
alkaloid chemistry has remained largely undeveloped and was last reviewed
in 1968 (13). The material summarized in Table VII (35, 42, 185-189) is
supplementary to that of the previous review.
TABLE VII
TRANSFORMATIONS
OF STEROIDAL ALKALOIDS
W Substrate Reagent Product" % Yieldb Ref.

E
A. Tomatanine-based alkaloids
Tomatidine (183) Nocardia restrictus CBS 151.45 Tomata-l,4-dienin-3-one (192) 185
186
Tomatanin-3-one (189) 186
Tomat-I-enin-3-one (190) 186
Tomat-4-enin-3-one (191) 186
3-Epitomatidine (184) 187
Mycobacterium phlei (Tomata-1,4-dienin-3-one) (192) 186
(Tomatanin-3-one) (189) 186
(Tomat-1-enin-3-one) (190) 186
(Tomat-4-enin-3-one) (191) 186
Piricularia oryzae (Unindentified) 42
Trichothecium roseum (Unidentified) 42
Helicostylum pirijorme (Unidentified) 42
Arthrobacter simplex (208)
Androsta-l,4-diene-3,17-dione 188
Soladulcidine (solasodanol) (196) Nocardia restrictus Solasoda- 1,4-diene-3-one (198) 188
3-Episoladulcidine (197) 187
Dihydrotomatidine A (199) Nocardia restrictus 200 188
Dihydrotomatidine B (201) Nocardia restrictus 202 188
3-Epidihydrotomatidine B (203) ' 187
(20S,22(,25()-26-Acetylamino-Scc- Nocardia restrictus (20S,22(,25()-26-Acetylaminofurosta- 188
furostan-3P-01 (204) 1,4-diene-3-0ne (205)
(25()-26-Amino-Sa-cholestane- Nocardia restrictus 201 188
3P,168,22{-triol (206)
N-Acetyltomatidine (185) Nocardia restrictus CBS 151.45 3-Epi-N-acetyltomatidine (186) 187
N-Acetyltomatanin-3-one (193) 189
N-Acetyltomata-l.4-dienin-3-one(194) 189
N-Methyltomatidine (187) Nocardia restrictus CBS 151.45 N-Methyltomata-l,4-dienin-3-one (195) 189
(Unidentified) 189
Tomatidenol(209) Polystictus versicolor (Unidentified) 42
Solasodine (210) Piricularia oryzae (Unidentified) 42
Heliostylum piriforme (Unidentified) 42
Tomatine (188) Trichothecium roseum (Unidentified) 42
Solamargine (211) Trichotheciwn roseum (Unidentified) 42
Solasonine (212) Trichothecium roseum (Unidentified) 42
B. Solanidanine-based alkaloids
Demissidine (213) Nocardia restrictus CBS 157.45 Solani-l,4-diene-3-one (215) 189
Solanid-Cene-3-one (214) 189
Solanidine (216) Trichothecium roseum (Unidentified) 42
Fusarium lini (Unidentified) 42
Rubijervine/isorubijervine Trichothecium roseum (Unidentified) 42
(218/219) Polystictus versicolor (Unidentified) 42
Solanine (217) Trichotheciwn roseum (Unidentified) 42
Phytophthora infestans Solanidine (216) 35
ATCC 16981
Phytophthora infestans N B Solanidine (216) 35
C. Miscellaneous (Unidentified)
5a-Conanin-3p-o 1 (220) Nocardia restrictus CBS 157.45 Cona- 1,4-dienin-3-one (221) 189
Con-Cenin-3-one (222) 189
Conessine (223) Trichothecium roseum (Unidentified) 42
Solanocapsine (224) Trichothecium roseum (Unidentified) 42
Jervine (225) Trichothecium roseum (Unidentified) 42
Pseudojervine (226) Trichothecium roseum (Jervine) (225) 42
(Unidentified) 42
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).
183 R' = OH, R z = R 3 = H Tomatidine ([22S,25S]-Sa-tornatanin-3~-01)

184 R' = R 3 = H, R 2 = OH 3-Epitomatidine
185 R' = OH, R2 = H, R3 = Ac N-Acetyltomatidine
186 R' = H, R2 = OH, R 3 = Ac 3-Epi-N-acetyltomatidine
187 R' = OH, R2 = H, R 3 = CH, N-Methyltomatidine
1W R' = U-glycoside, R2 = R3= H Tomatine
189 R 1+ R 2 = 0, R 3 = H Tomatanin-3-one
190 R' + R2 = 0, R3 = H ; A' Tomat-1-enin-3-one
191 R' + RZ = 0 , R 3 = H; A4 Tomat-4-enin-3-one
192 R' + R2 = 0, R3 = H ; A'x4 Tomata-l,4-dienin-3-one
193 R' + R 2 = 0, R3 = Ac N-Acetyltomatanin-3-one
194 R' + R2 = 0, R 3 = Ac; A's4 N-Acetyltomata-l,4-dienin-3-one
195 R' + R 2 = 0, R3 = CH,; A',4 N-Methyltomata-l,4-dienin-3-one
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.
in high yield (70%) and to identify it as the C-3a alcohol, 3-epitomatidine

(184) (187). The mass spectrum of 184 was identical to that of tomatidine,
and the structure of this metabolite was confirmed by the chemical shift
of the proton attached to C-3, which now appeared at 6 4.04 ppm, downfield
from its position (6 3.58 ppm) in tomatidine. This shift, along with the
multiplicity observed for the new signal, was reported to be consistent with
data for other Solanum alkaloids and related compounds (192, 193). Belic
and co-workers (187) stated that 3-keto intermediates were observed in this
and the other epimerizations described below and suggested that oxidation
at C-3 may be an intermediate step in the epimerization.
In addition to tomatidine (183),the N-acetyl derivate (185) was epimerized
at C-3 to give 186, and both soladulcidine (solasodanol, 196) and dihydro-
tomatidine B (201) were transformed in a similar manner, giving 197 and
203, respectively. The Solanum alkaloid demissidine(213)was not epimerized
at C-3 by N . restrictus (187).
H
-
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
In an extension of their earlier work with tomatidine itself, the same

group has also examined the transformations of a series of related com-
pounds with the same microorganism (188). Soladulcidine (solasodanol,
196) is converted to the corresponding A1."-3-keto derivative 198 in un-
specified yield, and both ring E-opened tomatidine derivatives 199 and
201 are similarly transformed. The ring F-opened derivative 204 underwent
analogous transformation to give 205 in low yield, but the corresponding
388 H. L. HOLLAND
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
201 R' = OH, RZ= H Dihydrotomatidine-B

16p-diol)
([22R,25~-22,26-Epimino-5a-cholestan-3~,
202 R' + RZ = 0; A'.4-3-Ketone
203 R' = H, RZ = OH 3-Epidihydrotomatidine-B
204 [20S,22~,25~]-26-Acetylamino-Sa-furostan-3~-ol
205 ~I'-~-Diene-3-one
&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
In addition to the epimerization at C-3 discussed above (187), N-acetyl-

tomatidine (185) is converted to the corresponding 3-ketone 193 and the
A'.4-dien-3-one 194 by N. restrictus when the incubation times are prolonged
(189). N-Methyltomatidine 187 is similarly transformed to 195 together
with other unidentified metabolites (189). The structures of 193-195 were
again confirmed by MS, IR, and UV analysis.
The biotransformation of alkaloids of the tomatanine type has also
been examined by Wolters (42).In a study with a variety of microorganisms
he observed the formation of metabolites of tomatidine (183), tomatidenol
(209), soladulcidine (196), solasodine (210), tomatine (188>, solamargine
(211), and solasonine (212). The products were not isolated and thus no
208 Androsta-l,4-diene-3,17-dione 209 Tomatidenol

H
RO
210 R = H Solasodine
211 R = glycoside* Solamargine
212 R = glycoside* Solasonine
*See footnote. structure 188.

390 H. L. HOLLAND
structural information is available except the unsubstantiated observation

that there was no liberation of aglycones during the transformations of
188, 211, and 212.
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
213 Demissidine (Solanidan-3/l-ol)

214 A4-3-Ketone, solanid-4-ene-3-one 216 R = H Solanidine
215 A'14-3-Ketone, solani-1,4-diene-3-one 217 R = Glycoside* Solanine
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
*See footnote, structure 188

potato with P. infestans remains to be demonstrated, but the above study

performed with isolated solanine and P. infestans has demonstrated that
significant alteration in the solanine/solandine levels of the potato may occur
on its infection with the blight fungus.
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).
223 Conessine 224 Solanocapsine
225 R =H Jervine
226 R = O-a-D-glUCOpyranOSylPseudojervine
IX. Transformations of Tropane Alkaloids
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
Substrate Reagent Product" % Yieldb Ref.
Atropine (227) Rat liver microsomes Noratropine (229) 197, 198

Apoatropine (233) 197, 198
230 197, 198
Guinea pig liver microsomes Tropine (232) 197, 198
Tropic acid (234) 197, 198
Noratropine (229) 197, 198
199
Apoatropine (233) 197, I98
230 197,198
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
Parentheses indicate not isolated.

* Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting
material.
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
237 R = CH, Hyoscine

238 R = H Norhyoscine
239 R = OH N-Hydroxynorhyoscine
R'
I
I1 241 R' = RZ = CH, Cocaine

0
242 R' = H, R Z = CH, Norcocaine
240 Hyoscine N-oxide 243 R' = CH,, RZ = H Benzoyl ecgonine
In contrast to the observation of the French group that rat liver micro-
somes did not possess an esterase capable of hydrolyzing tropane alkaloid
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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INDEX
A Ajmalicine, 329, 335, 336

Alkaloid
ALC-I, 265, 266, 268 A , 28
ALC-2, 265, 266, 268 B, 28
Abresoline, 285-287 1, 28
3-Acetonyldihydrovindolineether, 33 1, 340 2, 28
26-Acetylaminofurosta- 1,4-diene-3-one, 384 5, 28
Acetylaminofurostanol, 384, 388 6, 28, 39
Acetylcephalotaxine, 43, 44, 46 I , 39
Acetyll ythramine , 295 Aminocholestanetriol, 384, 389
N-Acetylmescaline, 375 Ammannia, 264
12-Acetylnapelline, 112-1 14, 196 Amphetamine, 375
N-Acetyltomata-1,4-dienin-3-one, 384, 386 Androsta-1,4-diene-3, 17-dione, 384, 388,
N-Acetyltomalidine, 384 389
N-Acetyltomatidine, 386, 387 Anhydroignavinol, 128-129, 1%
Aconitum, 100 Anopterimine, 120-121, 197
Acontium antharu, 122, 198 N-oxide, 197
Aconitum gigas, 122 Anopterine, 116-121, 166, 197
Aconitum glandulosus, 116, 120, 121 N-oxide, 120-121
Aconitum heterophylloides, 122, 198, 200 Anopterus glandulosus, 116, 120, 121, 160,
Aconitum heterophyllum, 122, 124, 133, 135, 197, 200
197, 198, 199, 200, 201 Anopterus macleayanus, 116, 120, 121, 160,
Aconitum japonicum, 114, 201 197, 199, 200
Aconitum kamtschaticum, 125 Anopteryl alcohol, 116- 1 19
Aconitum karakolicum, 112, 113, 114, 115, Antiinflammatory agent, 320
I%, 203, 204 Antileukemia property, 46
Aconitum lucidusculum, 113, 125, 202, 204 Antithrombotic activity, 320
Aconitum majimai, 202, 203 Antitumor activity, 44, 104, 366, 381
Aconitum miyabei, 136 Aphorine, biotransformation, 348-360
Aconitum monticola, 114, 115, 128, 203,204 Apoatropine, 392, 393-394
Aconitum napellus, 112, 203 Apocodeine, 349, 350, 357, 359
Aconitum palmatum, 132, 210 Apomiyaconine, 137, 138, 160
Aconitum sachalinense, 125, 202 Apomorphine, 350, 357, 359
Aconitum sayoense, 128, 129, 201 Aporphine alkaloid, 13C spectra, 235-237
Aconitum soongoricum, 114, 116, 204 Arecaidine, 376, 379
Aconitum tasiromontanum, 128, 201 Arecoline, 376, 376
Aconitum jesoense, 113, 125, 202, 204 Argemonine, 234
Acronycine, 38 1-383 Aricine, 329, 335
Adumine, 246 Arrow poison, 100
Agroclavine, 330, 338, 339 Arthrobacter, 376
Ajaconine, 124-125, 152-154, 167, 196 Arthrobacter simplex, 384, 385
synthesis, 179-181, 186, 189 Aspergillus alliaceus, 352, 382
402 INDEX
Aspergillus jlavus X - 158,352 Carckosarcoma, Walker 256,92

Aspergillus niger, 352,392,395 Cathanneine, 339,348
Aspergillus ochraceus, 353 Catharanthus roseus, 347
Atidine, 124,161,197 Cathoclavine, 339,348
diacetate, 161 Cephalotaxine, 42-48,59,60,92
synthesis, 179-181,186,189 synthesis, 76-85
Atisine, 100,101,104,122-124,150,156, Cephalotaxinone, 43,44,50-51
159,161,198 Cephalotaxus, 2
acetate, 156-157 Cephalotaxus alkaloid,
azomethine, 161 biosynthesis, 59-61
intermediate synthesis, 181-193 occurrence and isolation, 42-45
Atisinium chloride, 104,122-124,150 structure determination, 45-51
Atisinone, 161 synthesis, 76-91
Atropine, 392-395 Cephalotaxus fortunei, 46,50
N-oxide, 392 Cephalotaxus harringtonia var. drupacea,
Aurotensine, 362 44,48,51
Cephalotaxus harringtonia var. har-
ringtonia, 28,36,37,44,46,48,50, 92
B Cephalotaxus manii, 44
Cephalotaxus wilsoniana, 28, 41,42,46
Baldwin cyclization rule, 149 Chanoclavine, 330,338
Benzoic acid, 356,375 Chiral, 56
Benzo[c]phenanthridine alkaloid, 250-252 erysodienone, 56
Benzoyl ecgonine, 392,394,395 Chloramine, 126,127
Benzylisoquinoline alkaloid, 223-226 Choline, 7
biotransformation, 360-366 Cocaine, 392,394,395
Berberine chloride, 240 Coccoline, 3, 8,15,22,26
Betaine, 275 Coccolinine, 3, 15, 22,26
Bicuculline, 246,249 Cocculidine, 4,9,11, 12,21,22,23,26,56,
Biotransformation, 325-328 91
see also individual alkaloids Cocculine, 9,22,23,56,91
Bisbenzylisoquinoline alkaloid, 226-227 Cocculitine, 22,26,27
biotransformation, 366-367 Cocculolidine, 5 , 22
Bisboldine, 349 Cocculus, 2, 15, 17. 18
ether, 349,358 erythrina alkaloid, 21-27
Bisditerpenoid alkaloid, 144-149 Cocculus carolinus, 21,22,23
Bohlmann band, 274 Cocculus laurifolius, 21-27,56
Boldine, 349,357,358 Cocculus tritobus, 21,22,23,27
Brain, alkaloid transformation, 355,366,375 Coccutrine, 4,8,22,23
Brucine, transformation, 328,332 Coccuvine, 3,22,25
Bulbmapnine, 235 Coccuvinine, 3, 22,25-26
Codeine, 229,231,233,355,368
N-oxide, 355,368
C Codeinone, 232,233
Colchicine, biotransformation, 355,373-375
Caaverine, 235 Cona-I,4-dieNn-3-one, 385,390
Cadaverine, 313 5a-Conanin-3P-01, 385,390
Canadine, 240 Condelphine, 151
Cancentrine, 13C-NMR spectra, 230-234 Con-Cenin-3-one, 385,390
Capnoidine, 246,247 Conessine, 385,391
INDEX 403
Conicine, 27 I Delnudine, 100-101, 138-139, 198

Conjugation reaction, 327-328 Delphinium, 100
Consolida ambigua, 124, 196, 198 Delphinium ojacis, 124, 1%
Coreximine, 351, 362 Delphinium cardinale, 133, 135, 200
Corlumine, 246 Delphinium carolinianum, 124, 196
Corydaine, 252 Delphinium consolida, 124, 1%
Corydaline, 242 Delphinium denudatum, 131, 135, 138, 198,
Corynantheidine, 329, 332 200
Corynanthine, 330, 336, 337 Delphinium staphisagria, 100, 144- 149,
Crispatine, 378, 380, 381 160, 207-210
Cryogenine, 269, 27 1, 3 15 Delphinium virescens, 124, 1%
Cryptopine, 244 Demethoxyabresoline, 285-287
Crystamidine, 4, 14 3-Demethoxyerythratidinone,5 , 6, 19
Cuauchichicine, 106-112, 159, 198 Demethylcolchicine, 355, 373
garryfoline rearrangement, 109-1 12 0-17-Demethylcorgnantheidine,329, 333
Cularine, 227-228 Demethyldecaline, 280, 28 1
Cunninghamella bainieri, 349,35 1,352,354, 0-17-Demethyldihydrocorynantheine,329
382 0-17-Demethglisocorynantheidine, 329
Cunningha mella bla kesleea nu, 349, 352, Demethyllasubine-I, 285
353, 354, 359, 364, 366, 382 Demethyllasubine-11, 285
Cunninghamella echinulata, 349, 350, 352, 0-17-Demethylmitragynine, 329
353, 381, 392, 395 Demethylpaperine, 352-353, 365, 366
Cunninghamella elegans, 353 0-17-Demethylpagnantheine,329
Cuphea, 264 Demethylvertaline, 280, 281
N-Demethylvindoline, 33 1, 340
0-17-Demethylspeciociliatine,329
D 0-17-Demethylspeciogynine,329
N-Demethylvinblastine, 33 1
Deacetyldihydrovindoline ether, 33 1, 339, Demissidine, 385, 390
340 . Denudatine, 131, 198
Deacetylvindoline, 33 1, 339, 345 synthesis, 176-179
Decaline, 264, 280, 281-283 Detoxification reactions, 326-327
synthesis, 307-309 Deoxyharringtonine, 43, 45, 46-48,60, 92
Decamine, 264, 269, 270, 272, 311, 320 synthesis, 86-88
Decinine, 264-267, 275-276, 302, 311, 320 Desmethyoxycephalotaxinone , 5 1
biosynthesis, 3 13-3 19 Desmethylcephalotaxine, 43, 44, 50
Decodine, 264, 265, 266, 269, 272 Desmethylcephalotaxinone, 50-5 1
biosynthesis, 3 13-3 19 3-Desmethylerysovine, 13
Decodon verticillatus, 264, 265, 267, 268, Dicentrine, 236
270, 280, 313 Dihydroacetylnapelline, 114
Dehydrocondelphine , 151 Uihydroajaconine, 124-125, 198
Dehydrodecodine, 265, 266, 268 Dihydroatisine, 124, 161, 195, 199
Dehydroemetine, 356, 375, 376 azomethine, 161
l0,ll-Dehydroerysodine, 4, I5 diacetate, 161
10,ll-Dehydroerysovine, 4, 15 Dihydroatisinone, 196
6a,7-Dehydroglaucine, 350, 35 1, 359, 360 Dihydrocorynantheine, 329, 332
3,4Dehydrovinblastine, 33 1, 346 Dihydroerysodine, 4, 17, 19, 20, 21, 22, 27,
16-Dehydroxy-14,U-dihydro- 15,16-epoxy- 69
14-0xo-3-norindoline, 33 I , 339, 341 Dihydroerysotrine, 4, 17
Delatine, 133, 200 Dihydroerysovine, 4, 12, 17, 21, 22, 27
404 INDEX
Dihydrogarryfoline diacetate, 110-1 12 Ephedrine, 356, 375

2,7-Dihydrohomoerysotrine,29 3-Epi-N-acetyltomatidine,386
6a,7-Dihydrohomoerysotrine, 30, 39 Epicephalotaxine, 43, 45
2,7-Dihydrohomoerysovine,29 14-Epicorynoline, 251
6a,7-Dihydrohomoerythraline, 30 5-Epidemethoxyabresoline, 286, 287
2,7-Dihydrohorno-P-erythroidine, 42 10-Epidemethoxyabresoline,285
Dihydroisoquinoline, 222 3-Epi-2,7dihydrohomoerysotrine, 29, 36-37
Dihydrokaurene, 107- 109 3-Epi-6a ,7-dihydrohomoerythraline,30, 38
Dihydrolythrine, 271, 275 3-Epidihydrotomatidine P , 384, 388
Dihydrosongorine, 163, 166 3-Epischelhammericinene, 28, 29, 36, 41
Dihydrotomatidine 3-Epischelhammeridine, 28, 29
A, 384, 388 3-Epischelhammerine, 28, 29, 36
B, 384, 387, 388 3-Episoladulcidine, 384
Dihydroveachine, 161, 1% 3-Epitomatidine, 384, 386, 387
azomethine, 161 3-Epiwilsonine, 28, 36
diacetate, 161 6,7-Epoxy-k-methoxy-15,lGmethyl-
Dihydroverticillatine, 269, 270, 272 enedioxy-C-homoerythrinan-2-ene1 41
Dihydrovindoline ether, 331, 339, 340, 342- Erybidine, 6,7, 70,71
344 Erysodienone, 5 , 8, 19, 21, 53-55, 56
9,11-Dihydroxyacrongcine,38 1-383 Erysodine, 3, 5 , 7, 9, 13, 19, 20, 51
Dihydroxyanopterine, 121, 199 Erysoflorinone, 4, 20
10,11-Dimethyoxyaporphine, 349, 359 Erysoline, 3, 13
3,4Dihydroxyphenylalanine, 5 1 Erysonine, 3, 13
Dhnethyldecodine, 275, 278-280 Erysophorine, 3, 13
Dirnethyldihydroverticillatine,273 Erysopine, 3, 55
0.N-Dimethyllythranidine, 291 Erysopitine, 4, 8, 19, 20
C2,-Diterpenoid alkaloid, 99-215 Erysosalvine, 4, 8
atistine-type, 122- 144 Erysosalvinone, 4, 19, 20
Baldwin cyclization rule, 149-159 Erysothiopine, 3
bisditerpenoid group, 144- 149 Erysothiovine, 3
catalog of, 196-211 Erysotine, 4, 8, 19, 20
mass spectral analysis, 163-168 Erysotinone, 4, 19, 20
nuclear magnetic resonance, 160-163 Erysotramidine, 3, 14
synthesis, 168-1% synthesis, 6 6 6 7
veatchine-type, 102- 122 Erysotrine, 1, 3, 6, 13, 19, 21, 55, 92
1,17-Ditritioerysodienone,56 synthesis, 61-67
14,17-Ditritioerysopine,56 Erysovine, 3, 5 , 7, 9, 13, 55
Diuretic, 320 Erythrabine, 4, 14
Drupacine, 43, 48-50 Erythraline, 3, 6, 14, 15, 17, 53, 55, 56
Erythramine, 4, 17, 18
Erythrartine, 3
E Erythrascine, 3, 16
Erythratidine, 4, 8, 12, 18, 19, 20
Elymoclavine, 330, 331, 338 Erythratidinone, 4, 6, 10, 18, 19
Emde degradation, 276 Erythratine, 4, 8, 12, 16, 69
Emetine, 259-260 Erythratinone, 4, 18
Enamine, 76 Erythravine, 3, 9, 13
D preparation, 76-77, 7%81 Erythrina alkaloid,
Enedione, 185 biosynthesis, 51-57
Enmein, 186 isolation, 6-7
INDEX 405
occurrence, 2-6 Garryfoline, 104-106, 199

structure, 7-27 cuauchichicine rearrangement, 109- 112
synthesis, 61-72 Garryine, 102-104,189,194,1%, 199
Erythrina arborescens, 13, 16 Gibberdin-A,,, 186,192
Erythrina crysta galli, 6,14,16,17,18,55 Glaucine, 350-351,357,359-360
Erythrina falcara, 18 Glaziovine, 239
Erythrina folkersii, 6,13 Gliocladium deliquescens, 354
Erythrina fusca, 17 Glucoerysodine, 3
Erythrina glauca, 17 Glucuronidation, 327
Erythrina herbacea, 6 Gongronella urceolifera, 329,330,336
Erythrina indica, 5 , 15, 17 Gout, 100
Erythrina lithosperma, 5 , 6,16,18,19,55
Erythrina orientalis, 5
Erythrina salviijlora, 6,19 H
Erythrina lysistemon, 6 , 15
Erythrina suberosa, 13, 92 Harman, 330,337
Erythrina subumbrans, 5 Harmine, 330,337
Erythrina variegata, 5 , 14, 17,18, 19 Harmol, 330,337
Erythrina varigata var. orientalis, 5 , 6 Harringtonine, 43,44,46-48,92
Erythrina x bidwillii, 6 , 16 action, 92
Erythrinine, 3, 6, 16 synthesis, 88-90
Erythristemine, 3, 8,12,15, 17 HeLa cell, 92
Erythroculine, 4,21,22,23 Heimia, 264
Erythroculinol, 23-25 Heimia myrtifolia, 264,265,266,270
a-Erythroidine, 5 Heimia salicifolia, 266268,270,280, 284,
P-Erythroidine, 5, 7,21,53, 56,72 285,315,319
Eschscholtzine, 234 physiological activity, 319-320
Ester alkaloid, 286-288 Heimidine, 269,270,272
Europine, 379 Heimine, 280,281,284
Heleurine, 377,379
Helicostylum piriforme, 350,354,385
F Heliotrine, 377,379
Hermandaline, 354,367
Ferulic acid, 286 Hermandalinol, 354,367
Fumaramine, 249 Heterophylloidine, 200
Fumaras schleicherii, 249 Hetidine, 135-136,199
Fumaritine, 252 Hetisine, 133-135, 138,200
N-oxide, 252,256 Hetisinone, 134-135, 200
Fungicide, 320 Hirsutine, 329,332,333
Fusarium h i , 385,390 Homo-2,7-dihydroerysotrine, 37
Fusarium solani, 351,354,360,386 Homoerythrina alkaloid, 2
biosynthesis, 58
isolation, 29
G nomenclature, 30-3 1
occurrence, 27-29
Garrya laurifolia, 104,106, 198,199,201, structure determination, 3 1-42
202 synthesis, 72-75
Garrya ovata var. Lindeheimeri, 104,106, Homoharringtonine, 43,85,92
198,199,202,204 Homoorientaline, 355,369-373
Garrya veatchii, 102,104,199,211 Homoveatchine, 157
406 IN DEX
Hunnemanine, 244-245 Insecticide, 92, 100

Hydrastine, 246, 248 Isoapocodeine, 349, 350, 357, 359
Hydrastinine, 222 Isoatisine, 122-124, 151, 157, 195, 201
H ydrobenzo[c]phenanthridine alkaloid, Isoatisinone, 161
250-252 Isoboldine, 35 1, 362
1 I-Hydrocephalotaxine, 43, 44, 48-50 Isochondodendrine, 226-227
9-Hydroxyacronycine, 382, 383 Isocorydine, 235
9-Hydroxyacronycine, 38 1-383 Isocorynantheidine, 329, 332
I I-Hydroxyacronycine, 381, 382 Isocuauchichicine, 107-108, 112, 201
10-Hydroxyajmalicine, 329, 335, 336 Isocucculidine, 4, 21, 22, 26
Hydroxyanopterine , I2 1, 200 lsocucculine, 4, 10, 21, 22, 26, 56, 57
10-Hydroxyaporphine, 350, 359 Isogarryfoline, 112, 202
p-Hydroxybenzaldehyde, 351 Isoharringtonine, 43, 46-48, 90-91
10-Hydroxycorynanthine, 330, 337 Isohypognavine, 130-131, 202
Hydroxydihydrovertine, 272 Isohypognavinol, 130- 131
1 I-Hydroxyerysodine, 3 Isonapelline, 112-1 14
1 1-Hydroxyerysotrine, 16 Isopelletierine, 303
11-Hydroxyerysovine, 11 Isoquinoline alkaloid, Y - N M R spectra,
1-Hydroxyhomoorientaline, 355, 372 217-262
4-Hydroxy-3-methoxycinnamicacid, 286 Isorubiiervine.. 385,. 390
1-(12-H ydroxy- 13-methoxy)phenyl- Isosetoclavine. 33 1. 338, 339
quinolizid-3-01, 284
1-(12-Hydroxy- 13-methoxy)phenyl-
quinolizid-3-one, 284, 286 J
2-Hydroxy-3-methoxystrychnine,328, 332
Javacillin, 329, 335
7a-Hydroxy- I-methylene-801-pyrro1izidine1
Jervine, 385, 391
377, 379
3-Hydroxymethyl-1 I-hydroxy-acronycine,
38 1 K
2-Hydroxymorphine, 355, 368, 369
N-Hydroxynoratropine, 392, 393 ent- Kaurene, 106, 107
N-Hydroxynorhyoscine, 392, 394 Kidney, alkaloid transformation, 356, 375
P-Hydroxyreticuline, 35 1 Kobusine, 125-128, 134, 202
10-Hydroxyvinblastine, 33 1
Hyoscamine, 392, 393, 395
Hyoscine, 392, 394 L
N-oxide, 392, 394
Hypaphorine, 7, 14 Lactone ring cleavage, 275-276
Hypecorinine, 257-258 Lactonic biphenyl alkaloid, 266-28 1
Hypertension, 100 chemistry of trans- and cis-fused, 275-281
Hypognavine, 129, 201 ether alkaloid, 281-284
Hypognavinol, 129, 201 synthesis, 307-310
stereochemistry, 273-275
synthesis, 310-312
I Lufoensiu, 264
Lagerine, 280, 281, 283, 310
Ignavine, 128-129, 201 Lugerstroemiu. 264
Indanone, 253 Logerstroemio fuuriei, 265, 266,267, 270
Indicamine, 269 Lugerstroemiu indicu, 265, 267, 270, 280
Indole alkaloid, biotransformation, 328-348 Lugerstroemiu subcostutu, 285, 286, 287
INDEX 407
Lagerstroemine, 269, 270, 273 M

Larkspur, garden, 124-125
Lasiowpine, 377, 379, 380 Mass spectra,
Lasubine-I, 285, 286, 288 quinolizidine Lythrum alkaloid, 299-302
Lasubine-11, 285, 286, 288 songorine, 163- 165
Laudanosine, 223-225, 352, 362, 364 vindoline products, 339-344
oxide, 223-225 Meconin, 246, 248
Luwsoniu, 264 Mescaline, 355, 373, 375
Leucine, 61 Mesocorydaline, 242
Leukemia, Mesothalictricavine, 243
chronic nigelocytic, 92 10-Methoxyaporphine, 350, 357, 359
L 615, 92 Methoxycocculidine, I2
L 1210, 85, 92 Methoxyerysodienone, 69-70
L 7212, 92 1 I-Methoxyerysodine, 3
P 388, 85 1 I-Methoxyerysopine, 3
Leurosine, 331, 346-347 1 I-Methoxyerysovine, 3
Lindheimerine, 104-106, 156, 194, 202 1 I-Methoxyerythraline, 3, 6, 15
Lirinidine, 235 p-Methoxyhydrocinnamyl alcohol, 283
Liver, alkaloid transformation, 330, 332, 2-Methoxy-3-hydroxystrychnine, 328, 332
351, 354-356, 360, 363, 365, 368, 375, 3a-Methoxy- 15,16-methylenedioxy,6,7-
377-380, 392-395 epoxy-C-homoerythrinan-2-ene, 30
Luciculine, 112, 203 3-Methoxymorphinan, 229
Lucidusculine, 112-1 14, 174, 202 Methoxynorprotosinomenine, 55
Luguine, 251 0-Methylacetyllythramine, 289
Lyfoline, 265, 266, 267 N-Methylamphetamine, 375
Lysergic acid, 330, 338 0-9-Methylboldine, 350-35 I
Lysicamine, 349 0-Methylcapaurine, 243
Lysine, alkaloid precursor, 3 13 N-Methylcoclaurine, 351, 360, 361
Lythraceae alkaloid, 263-322 N-Methylcorydaline, 222
biosynthesis, 3 13-3 19 &Methylcorynoline, 251
ester, 286-288 0-Methylcorpyalline, 220
lactonic biphenyl, 266-284 Methyldecamine, 3 1 I
synthesis, 307-312 Methyldecinine, 275, 3 10
physiological activity, 3 19-320 N-Methyldihydroatisine azomethine, 161
piperidine metacyclophane, 288-294 N-Methyldihydroveatchine azomethine, 161
synthesis, 312-313 4,5-Methylenedioxy- I-methyleneindane, 254
quinolizidine metacyclophane, 294-303 6,7-Methylenedioxyphthalide,246
simple quinolizidine, 284-286 I-Methyleneindane, 253
Lythramine, 288, 293, 295, 312-313 I-Methylene-&-pyrlizidine, 377
Lythrancepine, 294, 295, 297-299 N-Methylhomococlaurine, 355, 36%37 I
Lythrancine, 294-297, 299 Methyllagerine, 280, 281, 283-284
Lythranidine, 288, 289, 293, 297 0-Methyllythranidine, 289, 290
Lythranine, 288, 289-291, 293 2-Methylpiperidine, 27 1
Lythridine, 267 N-Methylpiperidine, 220, 283
Lythrine, 265, 266267, 271, 275, 277, 279 3-Methylpyridine, 376
Lythrum, 264 Methyl reserpate, 329, 336
Lythrum unceps, 264, 288, 295 N-Methyltomatidine, 384, 386, 389
Lythrum lunceolutum, 264, 265, 267, 295, Microsome, alkaloid transformation, 329-
302 330, 332, 349-350, 355, 357, 373, 377-
Lythrumine, 302 378, 392-395
408 INDEX
Microsporum gypseum, 350, 352, 353 Norlaudanosine, 223, 352

Mitraciliatine, 329, 333 Norlaudanosoline, 35 I , 360, 362
Mitragynine, 329, 333 Normorphine, 354, 355, 368
Mitrajavine, 329, 335 Nomuciferine, 349, 357
Miyaconine, 160 N-Nororientaline, 7
Miyaconite, 136-138, 203 Noroxohydrastine, 222
Miyaconitinone, 136-138, 203 N-Norprotosinomenine, 19, 53, 56
Monoacetyllythmmine,302 Norrecticuline, 351, 362
Monocrotaline, 378, 380, 381 Norsongorine, I IS, 203
N-oxide, 378, 380 N-2’-Nortetrandrine, 353-354, 366
Mono-0-methylsalsolinol,356, 375 Nuciferine, 348, 349, 357
17-Monotritioerysodine,56
Morphine, 228-230
biotransformation, 354, 367-369
N-oxide, 354, 355, 368 0
Morphine-3-gluconuride, 354, 368
Mucor microsporus, 354 Ochotensimine, 252
Mucor mucedo, 350, 353, 354 Ochrobirine, 252
Mucor puruciticus, 354 Ophiocarpine, 243
Mycobucterium phlei, 384, 386 Ovatine, 104-106, 156, 194, 204
Oxazolidine ring, reactions of, 194-1%
Oxidoreductase reaction, 326-327
N Oxoaporphine, 351, 360
Oxocancentrine, 232-234
W-NMR spectroscopy, 160-162, 219-222 Oxocodeinone, 232, 233
isoquinoline alkaloid, 217-262 I I-Oxoerysodine, 3, 1 1
pavine, 234-235 1 I-Oxoerysopine, 3
proaporphine, 238-239 1 I-Oxoerysovine, 3
protopine, 243-245 I I-Oxoerythraline, 3
tetrahydroi soquinoline, 2 19-222 8-Oxoschelhammeridine, 28, 29, 35
Nandinine, 241 1la-Oxoschelhammeridine, 28, 29, 35
Nappelline, 112-114, 203
synthesis, 170-176
Napellonine, 114 P
Narcotine, 248
Neferine, 361 Pallidine, 351, 362
Nelumbo nuciferu gurtner, 351, 361 Papuver rhoeus, 351, 373
Nesodine, 265, 266, 268-269, 272, 320 Papuver somniferum, 373
Neuralgia, 100 Papaverine, 352, 365, 366
Neuromuscular blocking, 92 Papaverinol, 225
Nicotine, 376 Pavine alkaloid, I3C-NMR spectra, 234-235
Nocurdiu, 376 Paynantheine, 329, 335
Nocurdiu restrictus, 384, 385,386,388, 389, Pelletierine, biosynthesis, 3 13
390, 391 Pelletierine-benzaldehydecondensation,
Noragroclavine, 330, 331, 338, 339 303-307
Noratropine , 392, 393 Penicillium brevicompucturn, 351, 353
Norcocaine, 392, 394, 395 Penicillium cluviforme. 350
Norephedrine, 356, 375 Penicillium ducluuxi, 350
Norglaucine, 351, 359 Penniclavine, 33 1, 339
Norhyoscine, 392, 394 Peptococcus heliotrinreducans. 377-380
INDEX 409
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
Solani- 1,4-diene-3-one,385, 390 Streptomyces spectabilicus, 354, 381, 382

Solanine, 385, 390 Stysanus rnicrosporus, 352
Solanidanine-based alkaloid, 390-391 Stysanus stemonites, 350
Solanidine, 385, 390 Subcosine-I, 285, 287
Solanocapsine, 385, 391 Subcosine-11, 285, 287
Solasodanol, 384, 387 Supinine, 377, 379
Solasoda- 1,4-diene-3-one, 384, 387
Solasodine, 385, 389 T
Solasonine, 385, 389
Solidaline, 243 Tetrahydroalstonine, 329, 335
Songoramhe, 115-116, 167, 204 Tetrahydroerysotrine, 25
Songorine, 114-116, 204 Tetrahydroerythraline, 16
mass spectra analysis, 163-165 Tetrahydroisoquinoline, T - N M R spectra,
N-oxide, 204 219-222
Speciocdiatine, 329, 333 Tetrahydropalmatine, 241, 352, 362
Speciogynine, 329, 333 Tetrahydropapaveroline, 362
Spkdine, 189 Tetrahydroprotoberberine alkaloid, 239-243
A, 139-141, 205 Tetrandrine, 353, 366
B, 139-140, 205 Tetraphylline, 329, 335
C, 139-140, 205 Thalicarpine, 354, 366367
D, 140-141, 205 Thalictricavine, 243
F, 142-143, 206 Thaliporphine, 235
G , 142-143, 206 Thebaine, 229
Spiraeajaponica, 139, 140, 142, 143, 205- Tomata- 1,4-dienin-3-one, 384, 386
207 Tomat-l-enin-3-one, 384, 386
Spiredine, 141-142, 206 Tomat-Cenin-3-one, 384, 386
Spireine, 143-144, 206-207 Tomatidenol, 385, 389
Spirobenzylisoquinoline alkaloid, 252-257 Tomatidine, 384, 386-389
Staphidine, 144-146, 207 Tomatine, 385, 389
Staphigine, 147-148, 207 Tomatanin-3-one, 384, 386
Staphimine, 146-147, 208 Transformation, enzymatic, 325-328
Staphinine, 146-147, 210 Trichothecium roseurn, 384, 385, 390
Staphirine, 147-148, 211 3,4,5-Trimethoxybenzoic acid, 329-330,
Staphisagnine, 148-149, 209 336, 356, 375
Staphiswine, 148-149, 210 3,4,5-TrimethoxyphenyIaceticacid, 356, 375
Staphisine, 144-146, 210 Tropane alkaloid, biotransformation, 391-
Steroidal alkaloid, biotransformation, 383- 395
39 1 Tropic acid, 393
Stremphlium solani, 354 Tropine, 392, 393, 395
Streptomyces, 331, 350, 359 Tubocurarine, 356, 375, 376
Streptomyces albogriseolus, 33 1, 340, 344, Tyrosine, alkaloid precursor, 51, 58, 59
345
Streptomyces cinnamonensir, 33 1, 345 V
Streptomyces griseus, 331, 339, 342, 351,
353, 354, 359, 366 Vakognavine, 132-133, 210
Streptornyces lincolnensis, 353 Veatchine, 100, 101, 102-104, 109, 154-156,
Streptomyces platensis, 353, 354 21 1
Streptomyces punipalus, 331, 351, 353,354, acetate, 154-156, 157
367 azomethine, 161
Streutornvces
.~ rimosus.,~350 synthesis, 168-170, 181-193, 1%
INDEX 41 1
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
Zygorhynchus japonicus, 382

W
Wasabia japonica, 370

Wilsonine, 28, 30, 41
Woodfordia, 264

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THE ALKALOIDS

Chemistry and Physiology

A Subsidiary of Harcourt Brace Jovanovich, Publishers

ACADEMIC PRESS, INC.

United Kingdom Edition published by

L i b r a r y o f Congress Cataloging i n P u b l i c a t i o n Data

Vols. 8-16 e d i t e d by R. H. F. Manske. v o l s . 17-

PRINTED IN THE UNITED STATES OF AMERICA

Chapter 1. Erythrina and Related Alkaloids

Chapter 2. The Chemistry of Cz,. Diterpenoid Alkaloids

Chapter 3 . The 'T-NMR Spectra of Isoquinoline Alkaloids

VII . Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 230

Chapter 4 . The Lythraceae Alkaloids

Chapter 5 . Microbial and in Vitro Enzymic Transformations of Alkaloids

S. F. DYKE"( l ) , School of Chemistry, The University of Bath, Bath BA2

* Present address: Department of Chemistry, Queensland Institute of Technology, Bris-

This volume of “The Alkaloids” presents timely reviews of three

Contents of Volume 111

Contents of Volume VII

Contents of Volume VIII

Contents of Volume XZZ

Contents of Volume XZI1

Contents of Volume XZV

Contents of Volume XVI

Contents of Volume XVZI

ER YTHRINA AND RELATED ALKALOIDS

In the intervening 13 years the subject has expanded dramatically; over

11. Evythvitza Alkaloids

RZO - " ' oR

32" Erythrabine CH, CH, 0 37 Isococculine R = H

* means an alkaloid is a possible artifact.

38 Dihydroerysotrine H CH,O CH,O H

FIG.3 . Erythrinu alkaloids: Al(6) alkene series.

59 r-Erythroidine 60 [I-Erythroidine 61 Cocculolidine

FIG.4. Erythrina alkaloids: miscellaneous

(Menispermaceae), a genus of more limited distribution in tropical areas

The procedure of Folkers, where the ground plant material is extracted

by GC-MS analysis of the hexane fraction, so that earlier examinations

salt of erythristemine confirmed the assumption that the 3R,5S configura-

The crystal structures of the alkaloids containing a hydroxyl group at

absorbances at 240-242 and 285nm and IR bands at 1672, 1655, and

b. Circular Dichroism. The 1,6-diene alkaloids exhibit strong positive

c. Mass Spectrometric Characteristics. Because of the heavy reliance on

The A1(6)-alkene alkaloids show a more complex fragmentation pattern

fragmentation pathway involves a retro-Diels-Alder reaction (path a in

2. Mujor M S Jkugmentutionpatiern for A1(6)-aNceneseries (R = H or OH)

The enone alkaloids, such as erythratidinone (40), do not undergo frag-

d. NMR Characteristics. Once the erythrinane skeleton is established,

hence the methoxyl group was at C- 15 (58).This was supported by synthesis

44 Dihydroerysovine 54 R' = H , R Z = CH,O Cocculidine

The stereochemistry at C-3 in the 1,6-diene series can be determined from

methine suggested an attached methoxyl group, thus identifying the methoxyl

Erysophorine (13)was isolated from the water-soluble extract of the seeds

of 5 and hypaphorine (64). The presence of three quaternary N-methyl groups

b. 8-0x0Types. Ito's group isolated two new alkaloids, erythrabine

of 4 with potassium permanganate, followed by catalytic reduction (32).This

c. C-11 Oxygenated Types. The first Erythrina alkaloid with oxygen-

A little later 11-methoxyerythraline (22), isolated as a pale yellow gum,

The name erythrinine had been assigned to an alkaloid isolated in 1969

of the flowers of E. uariegata L. collected in Egypt resulted in the isolation

Several other alkaloids like 41 but with abnormal substitution pattern in

b. With C-2 Oxygenation. Erythratinone (43), which was synthesised

40 Ervthratidinone 39 Erqthratidine 1 Erysotrine

49 Erysotinone 48 Erysotine 39 Erythratidine