THE ALKALOIDS Chemistry and Pharmacology VOLUME 34
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THE ALKALOIDS Chemistry and Pharmacology VOLUME 34
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THE ALKAL Chemistry and Pharmacology Edited by Arnold Brossi National Institutes of Health Bethesda, Maryland
VOLUME 34
Academic Press, Inc. Harcourt Brace Jovanovich, Publishers
San Diego New York Berkeley Boston London Sydney Tokyo Toronto
COPYRIGHT
0 1988 BY ACADEMICPRESS, TNC.
ALL RIGHTS RESERVED NO PART OF THIS PUBLICATION MAY B E REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC . San Diego, California 92101
United Kingdom Edition published by ACADEMIC PRESS LIMITED 24-28 Oval Road. London NW1 7DX
LIBRARYOF CONGRESS
CATALOG CARD
ISBN 0-12-469534-5
(alk. paper)
PRINTED IN THE UNITED STATES OF AMERICA
88 89 YO 91
9 8 7 6 5 4 3 2
I
NUMBER: 50-5522
CONTENTS
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vii ix
Chapter 1. Chemistry and Reactions of Cyclic Tautomers of Tryptamines and Tryptophans NAKACAWA TOHRU HINOAND MASAKO I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
...................... III. Cyclic Tautomers of Tryptophan-Containing Dipeptides . . ... IV. 3a-Hydroxypyrrolo[2,3-b]indoleDerivatives. ............................
1 4 17 18
V. 3a-Bispyrrolo[2,3-b]indole Alkaloids: Dimeric, Trimeric, Tetrameric, and Pentameric Tryptamines ............................... VI. 3a-Prenylpyrrolo[2,3-b]indolesand Related Alkaloids .................... VII. Other Pyrrolo[2,3-b]indoles .... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41 49 65 69
11. Cyclic Tautomers of Tryptamines and Tryptophans
Chapter 2. Alkaloids in Cannabis saliva L. RAPHAEL MECHOULAM
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Quaternary Bases, Amides, and Arnines . .
III. Spermidine Alkaloids ............................ . . . . . . . . . . . . . . . . . . . IV. Synthesis of Cannabinoid Spermidine Alkaloids ........................ V. Pharmacology ......................................................
...........................
77 79 80 83 91 92
Chapter 3. Aconitum Alkaloids AND HIDEO BANDO TAKASHI AMIYA
....... .... ...... .................................... 111. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Analytical Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Tabulation of New Diterpenoid Alkaloids. ............................. References . . s
V
95 96 126 132
133 174
vi
CONTENTS
Chapter 4. Protopine Alkaloids TAKAHASHI MASAYUKI ONDAAND HIROSHI I. 11. 111. IV. V. VI. VII. VIII. IX.
Introduction ....................................................... Occurrence ........................................................ Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conformation and Spectroscopy. . . Synthesis .......................................................... Transformation of Protopines to Related Alkaloids ..................... Biosynthesis ....................................................... Callus Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addendum .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
181 182 182 190 194 198 201 202 203 203 204
Chapter 5. African Sfrychnos Alkaloids AND CL~MENT DELAUDE GEORCES MASSIOT
Introduction ....................................................... Ethnobotany ....................................................... ... Chemical Scree ’ ......................... Alkaloid Conte ... Biosynthesis an ion. ............................. VII. Synthesis and Chemistry. ............................................ ........................................... VIII. Pharmacology. . . . . IX. Conclusion ........................................................ References ......................................................... I. 11. 111. IV. V.
21 1 215 217 218 288 301 305 319 321 322
Chapter 6 . Cinchona Alkaloids AND THEOVAN DER LEER ROBERT VERPOORTE, JANSCHRIPSEMA,
Introduction ....................................................... Isolation ............ ........................................... Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spectroscopy ....................................................... ............ Chromatography . . Biological Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism Biosynthesis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biotechnology ........................... References .........................................................
332 333 344 358 37 1 376 378 382 389 391
Cumulative Index of Titles.. .............................................. Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
399 405
I. 11. 111. IV. V. VI. VII. VIII. IX.
CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
TAKASHI AMIYA(99, Hokkaido Institute of Pharmaceutical Sciences, 7-1 Katsuraoka-cho, Otaru, 047-02, Hokkaido, Japan HIDEOBANDO(99, Hokkaido Institute of Pharmaceutical Sciences, 7-1 Katsuraoka-cho, Otaru, 047-02, Hokkaido, Japan (21 l), Faculte de Pharmacie, Universite de Reims, Reims, CLAMENT DELAUDE France TOHRUHINO(l), Faculty of Pharmaceutical Sciences, Chiba University Yayoi-cho, Chiba-shi 260, Japan GEORGES MASSIOT (21 I), Faculte de Pharmacie, Universite de Reims, Reims, France RAPHAELMECHOULAM (77), Department of Natural Products, Faculty of Medicine, Hebrew University, Jerusalem 91 120, Israel MASAKONAKAGAWA (l), Faculty of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Chiba-shi 260, Japan MASAYUKIONDA(1 81), School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan JAN SCHRIPSEMA (33 l), Department of Pharmacology, Center for BioPharmaceutical Sciences, Gorlaeus Laboratories, University of Leiden, 2300RA Leiden, The Netherlands HIROSHITAKAHASHI (18 1), School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan THEOVAN DER LEER(331), Department of Pharmacology, Center for BioPharmaceutical Sciences, Gorlaeus Laboratories, University of Leiden, 2300RA Leiden, The Netherlands ROBERTVERPOORTE(33l), Department of Pharmacology, Center for BioPharmaceutical Sciences, Gorlaeus Laboratories, University of Leiden, 2300RA Leiden, The Netherlands
vii
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PREFACE
Indole alkaloids represent a major class and were reviewed in a general fashion in Vols. 2 (1952) and 7 (1960) of this treatise, before they were broken up into subgroups. The chapter on “Chemistry and Reactions of Cyclic Tautomers of Tryptamines and Tryptophans” (not including physostigmines) discusses in detail the chemistry of the tricyclic alkaloids derived from biologically important indole precursors, which occur in plants, fungi, and mammals. “Alkaloids from Cannabis sutivu L.,” the source of the cannabinoids present in hashish, are minor constituents of little-known pharmacological actions and are presented here for the first time. The chapter on ‘2conitumAlkaloids” updates information already collected in Vols. 4 (1954), 7 (1960), 17 (1979), and 18 (1981) of this work and summarizes pharmacological and toxicological data on these alkaloids used in herbal compositions in Japan and in China. “Protopine Alkaloids” were first presented in Vol. 4 (1954) and later repeatedly referred to under the title “Papaveraceae Alkaloids” in Vols. 10 (1967), 12 (1970), 15 (1975), and 18 (1981). The information collected here updates the material presented in earlier reviews. More than 240 alkaloids isolated by the end of 1987 from African Strychnos are listed in the chapter on “African Strychnos Alkaloids,” which reviews the biochemistry, chemistry, and pharmacology of these interesting indole alkaloids. This chapter updates material discussed in Vols. 5 (1955), 8 (1965), and 11 (1968) of this treatise. The medically important group of “CinchonaAlkaloids” presented in Vols. 3 (1953) and 14 (1973) is again reviewed here. In addition to chemistry, the chapter discusses important analytical details and brings the pharmacology of these alkaloids up to par. It is pleasing to note that this volume continues to benefit from material collected and presented by an international group of collaborators. Such collaboration is vital in keeping this treatise moving. Arnold Brossi
ix
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-CHAPTER1CHEMISTRY AND REACTIONS OF CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
TOHRU HINOAND MASAKONAKAGAWA Faculty of Pharmaceutical Sciences Chiba University Yayoi-cho, Chiba-shi 260, Japan
I. Introduction 11. Cyclic Tautomers of Tryptamines and Tryptophans
111.
IV.
V.
VI.
VII.
A. Formation and Stereochemistry B. Reactions C. Biological Implications and Applications D. Dehydro Derivatives Cyclic Tautomers of Tryptophan-Containing Dipeptides 3a-Hydroxypyrrolo[2,3-b]indoleDerivatives A. Naturally Occurring 3a-Hydroxypyrroloindoles B. Dye-Sensitized Photooxygenation of Tryptophans C. Other Oxidations of Tryptophans D. Reactions of 3a-Hydroxypyrroloindoles 3a-Bispyrrolo[2,3-b]indole Alkaloids: Dimeric, Trirneric, Tetrarneric. and Pentameric Tryptamines A. Chimonanthine, Folicanthine, and Calycanthidine B. Hodgkinsine, Quadrigernines, and Psychotridine C. 3a-Bispyrrolo[2,3-b]indole Alkaloids Derived from Diketopiperazines D. Tryptophan Dimer Having C-3-N" Linkage 3a-Prenylpyrrolo[2,3-b]indolesand Related Alkaloids A. Flustramines B. LL S490p and Azonalenine C. Roquefortine D. Amauromine E. Synthetic Approaches to Prenylated Indoles Other Pyrrolo[2,3-b]indoles References
1. Introduction
In general, indoles are known to exist in two tautomeric forms: indole (1) (1H-indole) and indolenine (2) (3H-indole). Most indoles exist overwhelmingly in the indole form. The indolenine 3 was first isolated in 1 THE ALKALOIDS, VOL. 34 Copyright 01988 by Academic Press. Inc. All rights of reproduction in any form rescrved
2
TOHRU HINO AND MASAKO NAKAGAWA
2 -
1 -
3 -
crystalline form as 2-ethoxyindole by Harley-Mason. Some other indolenines are observed in an equilibrium mixture with the indolic form ( I ) . O n the other hand, three tautomeric forms are possible in tryptamines: the indole (4), the indolenine (5), and the cyclic tautomer (6). The cyclic H
H
6 -
5 -
4 -
tautomer was not recognized for a long time. The cyclic tautomeric structure 7 was first suggested to represent folicanthine, a calycanthaceaeous
m M e H Me
7 -
alkaloid, by Hodson and Smith in 1956 (2); however, the structure was later revised to the dimeric form (see Section V). Immediately after the proposal of the structure, Sugasawa and Murayama (3) attempted to prepare 7 by Ladenburg reduction of N",Nb-dimethyloxytryptaminebut instead obtained N",Nb-dimethyltryptamine. In 1960 Witkop and coworkers ( 4 ) investigated the presence of cyclic tautomers of tryptamines in neutral solution by NMR spectroscopy in the first application of NMR to indole chemistry. They found the indolic form to be the sole tautomer.
AC
H
COCH 3
OpMe
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
3
SCHEME1
The first example of a cyclic tautomer of tryptamines appeared in 1968 when Witkop’s group (5) prepared 10 from the tryptophan (8) with chlorination followed by catalytic hydrogenation. As the cyclic tautomer of tryptamines is of the indoline type, whose chemical reactivity is different from that of the indole, Baldwin and Tzodikov (6) proposed the cyclic tautomer as a hypothetical intermediate for the enzymatic prenylation of tryptophan at the 4 position (Scheme 1). In 1978, we developed a simple procedure for preparing cyclic tautomers of type 10 directly from Nb-acyl tryptophan esters, enabling cyclic tautomers of tryptamines to be used as versatile intermediates for the preparation of tryptophan derivatives (see Section 11). The concept of the cyclic tautomer of tryptamines may also be applied to the equilibrium between 3-substituted 3-aminoethylindolenines (11) and 3a-substituted pyrroloindoles (12). The cyclic tautomer 12 is the predominant form in this equilibrium, and the indolenine form is characterized in special cases. Many indole alkaloids having a pyrrolo(2,3-bJindole ring system (12) have been isolated and characterized from plants, fungi, and animals. Y
11 -
Y
12 -
In this chapter we discuss the chemistry and reactions of cyclic tautomers (13) derived from tryptamines in the broad sense. When E is a hydrogen, 13 is a true cyclic tautomer of tryptamines. Among indole alkaloids having the ring system 13 where E is other than hydrogen, physostigmine and related
4
TOHRU HINO AND MASAKO NAKAGAWA
alkaloids have long been known, and their chemistry and physiology are discussed in previous volumes of this treatise (7). Therefore, we have excluded physostigmines from this chapter.
11. Cyclic Tautomers of Tryptamines and Tryptophans
A. FORMATION AND STEREOCHEMISTRY Tryptamines exist exclusively in the indolic form as described above. However, the addition of a proton to the indole ring (14) might form the indolenium (15), which may easily cyclize to 16. Protonation of the indole
15 -
14 -
16 -
ring at the 3 position is well known (8,9). Tryptamines in acid media, however, are first protonated at Nb when R in 14 is hydrogen or alkyl. In more acidic media (6-1 1 M H2SO4)the diprotonated form (17) is obtained instead of the cyclic tautomer (16).
A &
H
17
‘NH2
RyJ-----LR*r2 Me
18
R
Me
19 -
Physostigmine analogs (18) undergo opening of the pyrrole ring to form 19 in strong acid (6 M HCl in EtOH) (10). The basicities (pK, values) of indole rings are reported by Hinman (11)as follows: indole, -3.5; skatole, -4.55; l,2-dimethylindole7+0.30; tryptamine, -6.31. 2-Phenylindole derivatives are known to be protonated at the 3 position of the indole ring
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
5
p'
I
DL-2 1
DL-20
DL-22
+
O2Me
2Me L2Me
DL-23
DL-24
in 85% phosphoric acid (12). In order to obtain cyclic tautomers of tryptamines it is necessary to reduce the basicity of Nbbelow that of the indole ring and to retain the nucleophilicity to attack at the 2 position of the indolenine (15). The methoxycarbonyl group was found to be the desired substituent for R in 14. When Nb-methoxycarbonyl-DL-tryptophan methyl ester (DL-20) was dissolved in 85% phosphoric acid at room temperature for 3 hr, after which the mixture was added to an excess of sodium carbonate solution with cooling, the cyclic tautomer (DL-21) was obtained as stable crystals in 85% yield (13). Acids other than phosphoric such as trifluoroacetic acid are also be effective, as shown in Table I. As the cyclic tautomer has new two chiral centers, two diastereomers are possible. The other isomer (DL-22)was observed in the reaction mixture along with 21 but could not be isolated. However, two diastereomers TABLE I FORMATION OF CYCLIC TAUTOMER DL-21in Various Acid Media
Acid
85% H,P04 70% H3P0, Conc H2S04 85% H,SO4 70% H2S04 50% H2S04 85% H,SO,-MeOH 50% H,SO,-MeOH 30% H,SO,-MeOH CF3COOH HCOOH AcOH
Reaction time 3 hr 4 hr 4 hr 30 min 2 hr 3 days 1.5 hr 4 hr 10 hr 2 hr
Yield of ~ ~ - (%) 2 1 85 0 0 61 57 0 60 38 0 75 0 0
6
TOHRU HINO AND MASAKO NAKAGAWA
TABLE I1 YIELDSOF N a - A c ~ 7 CYCLIC y~ TAUTOMERS
Yield (%) Cyclization conditions
DL-23
DL-24
85% H3P04,RT, 3 hr CF,COOH, RT, 2 hr CF,COOH, RT, 60min CF,COOH, RT, 30min CF,COOH, RT, 2-3 min CF,COOH, -1o"C, 30 min
82 79 56 32 2 5
6 8 13 35 38 38
(DL-23 and DL-24) were isolated after acetylation ( 1 4 ) . The yield of N"-acetyl cyclic tautomers DL-23and DL-24varies depending on the cyclization conditions as shown in Table 11. Formation of DL-24increases under mild cyclization conditions, indicating that DL-22,its precursor, is the kinetically controlled product and, therefore, that DL-21is the thermodynamically stable one. The stereochemistry of these cyclic tautomers was determined by comparing their NMR spectra with that of the 3a-hydroxypyrrolo[2,3-b]indole, whose stereochemistry had been established by X-ray analysis (see Section IV,B) (13,14).The characteristic features of the NMR spectra of the pyrrolo[2,3-b]indole-2-carboxylicacid methyl esters are as follows: (1) the methyl signal of the 2-carboxylic acid ester in the trans isomer, with relative stereochemistry of 2-carboxylic acid and 3a substituents (OH, OAc, or H), appears at higher field than that of the cis isomer irrespective of the 3a substituents and (2) two signals are observed for the methyl group owing to hindered rotation of the amide group at the 1 position. DL-21,DL-23,and DL-24are stable as crystals and can be kept at room temperature. DL-21can be reverted to 20 on dissolving in acetic acid, but it is stable in pyridine. On the other hand, Na-acetylatedcompounds DL-23and DL-24)are stable in acetic acid but can be reverted to 20 in 10% sulfuric acid in methanol at room temperature. The pattern of ring opening of the two isomers differs: DL-23gave 20, probably via 21, while DL-24gave 20 via the N"-acetyl derivative (25), which was detected on TLC. These results - ~more ~ susceptible to ring opening than ~ Y U ~ Z S - D L - ~ ~ , indicate that c ~ s - D L is probably owing to greater steric strain in 24. However, DL-23gave 25 in less nucleophilic media (10% H2S04in AcOH). Thus, cyclic tautomers (21,23, and 24) are easily formed and can also be reverted to the indolic tautomers under mild conditions. During these ring
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
(DL-23)
7
C02Me
1O%H 2 SO4 MeOH
closure and openings the chirality of tryptophan is retained. This has been proved by the isolation of optically active L-20 from L-23, obtained from L-20 in 85% phosphoric acid. Similar acid treatment of Nb-acetyl-Ltryptophan ethyl ester (26) gave the cyclic tautomer (27), though in low yield (29%). The difference in yield may be attributed to the lower nucleophilicity of the Nh-acetyl group compared to that of Nhmethoxycarbonyl group.
A similar situation was found in the tryptamine series. NbMethoxycarbonyltryptamine (28a) in 85% phosphoric acid cyclized to 29a, which was detected by NMR but could not be isolated because of its instability. After acetylation, 30 was isolated in 70% yield. 28b, however,
a :R-OCH 3
29 -
30 -
gave mostly dimeric products with a small amount of 29b under similar conditions. Acid-catalyzed dimerization to form 31 is a well-known reaction for indole derivatives (15). Not only simple indole derivatives but also the tryptophan derivative (26) have been known to give dimeric products
8
TOHRU HINO AND MASAKO NAKAGAWA
H
R
H
H
(31), although forcing conditions were necessary for dimerization of tryptophan derivatives (16). Therefore, cyclization to the cyclic tautomer in acidic media competes with the acid-catalyzed dimerization. The likely mechanism of formation of cyclic tautomers of tryptophans is shown in Scheme 2. Protonation of the indole ring may occur from both sides to form A and B at nearly the same rate. The subsequent cyclization of B to D proceeds more rapidly than that of A to C. However, the kinetically controlled product D gradually transforms to thermodynamically stable C through equilibrium between D and C via 32 under the reaction
dimeric p r o d u c t s
t
H
i-
H LOR
H
H
A
a*&, H
COR
33 -
SCHEME2
LOR
B -
-
32 -
H
H 34 L
COR
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
9
conditions. This mechanism is supported by two facts. First, under milder conditions 34, which was isolated as the N"-acetyl derivative, was obtained as the major product. Second, the equilibrium between D and C via 32 was proved by deuterium exchange C-3a and C-8a of 33 in 85% deuterated phosphoric acid. To obtain the cyclic tautomer of 32 efficiently the nucleophilicity of Nb is important. The methoxycarbonyl group is superior to the acetyl group in imparting nucleophilicity to N b . Another factor to be considered is the competition between cyclization and dimerization. Tryptamines are more readily dimerized in acid media than tryptophans, for steric reasons. Therefore, acid-catalyzed dimerization becomes a more important side reaction in the cyclization of tryptamines. 5-Methoxy- and 5chlorotryptophans (35, X = MeO, Cl) cyclized smoothly in trifluoroacetic acid, while the 5-nitro derivative did not (17).These results suggest that a sufficient amount of the protonated form, such as A and B, is necessary to form the cyclic tautomer.
Characteristic features of cyclic tautomers of tryptamines and tryptophans are as follows: (1) protection of the reactive enamine system, which has reactivity typical of the open chain tautomer, the indolic form; (2) activation of the benzene moiety of the indole ring to the aniline derivative; and ( 3 ) facile reversion to the open chain tautomer. Application of cyclic tautomers to the synthesis of 5- or 6-substituted tryptophans is described in the next section. Protection of the reactive enamine of the indole ring is usually carried out by conversion to the indoline (18) by reduction or by N-acylation. However, more severe conditions are required to reproduce the indole form than the cyclic tautomer. For the protection of simple indoles, the sodium bisulfite adduct of indoles reported by Thesing et al. (19) is an attractive device, but few applications have been reported, probably owing to instability of the adduct. B. REACTIONS There are many naturally occurring indole alkaloids that have substituents at the benzene moiety of the indole ring. For the synthesis of these
10
TOHRU HINO AND MASAKO NAKAGAWA
natural products, substituted tryptophans or tryptamines have been prepared from substituted benzene derivatives through indole ring closure. This situation arises from the fact that electrophilic substitution of tryptamines usually occurs at the 3 position of the indole to give 2-substituted derivatives, and a practical method of introducing a substituent at a specific position of the indole ring is not known. The nitration of tryptophan at the 6 position has been reported as an exception (20-22). Cyclic tautomers are suitable intermediates for introducing a substituent at the N " , 5 , and 6 positions of tryptophans, as the benzene moiety has aniline reactivity in the cyclic tautomer and facile reversion to tryptophans.
21 -
Alkylation of cyclic tautomer DL-21 with alkyl halides in acetonepotassium carbonate at room temperature gave N"-alkyl derivatives (36) which can be converted to the tryptophan derivatives (37) in good yields (23). This N"-alkylation may serve as a general method and employs milder conditions than the known method using sodium amide in liquid ammonia (24). Chlorination of DL-23 with N-chlorosuccinimide in acetic acid at room temperature gave the 5-chloro derivative (38, X = Cl) in excellent yield accompanied by a trace amount of the 7-chloro isomer. Acid treatment of 38 (X = C1) smoothly furnished the 5-chlorotryptophan derivative (39, X = Cl). Bromination of DL-23 with N-bromosuccinimide in acetic acid and nitration with fuming nitric acid at -5°C likewise gave the 5-bromoand 5-nitrotryptophans (39, X = Br, NO,) after acid treatment of 38. The preparative value of these reactions is exemplified by the 66% yield of the 5-nitro-DL-tryptophan derivative (39, X = NO2) from Nbmethoxycarbonyl-DL-tryptophan methyl ester (DL-20) (23).
23 -
38 -
X=CI. Br. NO?
39 -
Bromination and nitration of the cyclic tautomer of tryptamine (30) also afforded 5-substituted tryptamines in excellent yields. A different feature
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
30 -
40 -
11
41 -
was observed, however, in the chlorination reaction. In contrast to the chlorination of 23 that gave 38 (X = Cl), the reaction of 30 with N chlorosuccinimide in acetic acid gave a mixture of products such as 40 (X = CI), N"-acetyl-41 (X = Cl), and 42 (23). This result is interpreted as partial ring opening of 30 under the reaction conditions caused by the chlorination reaction being slower than bromination. Structure 42 was once proposed as an intermediate in the biosynthesis of pyrrolnitrin from tryptophan (25).
Oxidation of the indoline derivative (43) with Fremy's salt, ON(SO3K),, was reported to give the indole (44) and the 5-hydroxyindole (45) (26),
43 -
44 -
45 -
12
TOHRU HiNO AND MASAKO NAKAGAWA
and 5-hydroxytryptophan (47) was obtained by the oxidation of 2,3dihydrotryptophan (46) in low yield (27). On the other hand, the pyrroloindole derivative (48) which could not be oxidized to the indole, gave the quinoneimine (49) with Fremy’s salt in good yield (28).From these results and an observation that the cyclic tautomer (23) could not be oxidized to 50
50
with palladium-carbon or DDQ (17),it was thought that oxidation of the cyclic tautomer (23) with Fremy’s salt may give the quinoneimine. The unstable quinoneimine (51) was obtained in 50% yield by Fremy’s salt oxidation of 23. The quinoneimine gave the 5-hydroxytryptophan derivative (53) by sodium borohydride reduction and acid treatment (29,30).
CO 2 Me OzMe
A more practical method, using lead tetraacetate in trifluoroacetic acid as the oxidizing agent, has been reported for the hydroxylation of various methyl benzene derivatives (31-33). Nb-Methoxycarbonyl-DL-tryptophan ester (DL-20)was dissolved in trifluoroacetic acid at room temperature to form the protonated cyclic tautomer (DL-21). This solution was added to lead tetraacetate in methylene chloride at 10°C to form the quinoneimine (51). Zinc powder was added to the solution to give the 5hydroxytryptophan (53) in 60% yield from DL-20 (29,30). This procedure was also applied to the tryptamine derivatives (54) to give the 5-hydroxy derivatives (55) in good yield. Debenzylation of 55b gave serotonin (29,30). These methods allow the first practical and selective synthesis of 5-substituted tryptophan derivatives. Since not only DL-tryptophan but also
13
1. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
55 -
54 -
a :u-cn3
b :R-CH2 P h
L- and D-tryptophan have become commercially available at reasonable prices, these methods may increase their preparative value. The above examples involve the reaction of DL-tryptophans, but the method is also applicable to the optical isomers. Trimethylsilyl iodide was found to be a particularly good deprotecting reagent for the Nb-methoxycarbonyl group, and several optically active 5-substituted D- and L-tryptophans have been prepared (34). On the other hand, compared to the abundance of methods for preparing 5-hydroxytryptophan derivatives, only a few are known for 6-hydroxytryptophan derivatives. Cyclic tautomers of tryptophans provide a new approach to hydroxylation at the 6 position, although the selectivity of the reaction is not so high as that of the 5-hydroxylation. For example, oxidation of DL-23with lead tetraacetate (1 equiv) in trifluoroacetic acid at 1-2°C gave a mixture of hydroxylated products. After methylation the 6-methoxy derivative (DL-56, 42%) and the 5-methoxy derivative (DL-57, 17%) were obtained, accompanied by a trace amount of the 7-hydroxy and 7-methoxy derivatives. O n acid treatment DL-56and DL-57underwent
miA
+ M ~ o = ~ &H
AcH C 0 2 M e 23
OpMe
0p M e
Me0
AcH C02Me
AcH COpMe
I "
m
Me0
C
O
2
n
M
e M
e
O
m
C
O
H
k0,Me
OOpMe
24 -
-
Me0
T H
M
e
kOOpMe
59 -
58 -
H
p
OpMe
t Ye0
H
+ OpMe
14
TOHRU HINO AND MASAKO NAKAGAWA
ring opening to provide smoothly the 6-methoxy- and 5-methoxytryptophans (DL-58and DL-59)(30,35). Similarly oxidation of DL-24, the less stable cis isomer, gave the Smethoxy derivative (DL-61,30%), the 6-methoxy derivative (DL-60,2S%), and a trace amount of the 7-hydroxy derivative (30,35). Oxidation of the optically active isomer L-23 likewise gave the 6-methoxy-~-tryptophan (L-58) as well as the 5-methoxy derivative (L-59) (36). As the 58, especially the optically active isomer, has not been readily obtainable by other methods, this oxidation may serve as a preparative method for these compounds. 6-Methoxy-~-tryptophanmethyl ester prepared by this method has been utilized as the starting material for the total synthesis of fumitremorgin B (see Section V1,D) (37,38). C. BIOLOGICAL IMPLICATIONS AND APPLICATIONS As described above, the reactivity of cyclic tautomers differs from that of the open chain isomers, the indolic forms, and the S and 6 positions of cyclic tautomers are reactive sites for electrophilic substitution and oxidation. Biological oxidation of tryptophan to 5-hydroxytryptophan by a monooxygenase is well known, and the above finding suggests that cyclic tautomers play an important role in the enzymatic reaction, although the detailed mechanism is not established. Reaction of the cyclic tautomer of tryptophan gave the S-chloro, S-bromo, 5-nitr0, and 5-hydroxy derivatives selectively, but not 6substituted tryptophans except the 6-hydroxy derivatives. For preparation of 6-bromotryptamine derivatives, which are found in many marine natural products, the S-nitro derivative (62) was used as an intermediate. Catalytic hydrogenation of 62 followed by bromination with N-bromosuccinimide in dimethylformamide gave the 5-amino-6-bromo derivative (63) as the major product. Deamination of 63 smoothly gave the 6-bromo derivative (64),
H
Br
Br
H
1. CYCLIC TAUTOMERS OF TRYETAMINES
AND TRYPTOPHANS
15
which afforded the 6-bromotryptamine (65) on acid treatment. Overall yield of 65 was 25% from the tryptarnine (54a) (39). Synthesis of flustramine B from 65 will be discussed in Section VI,A.
D. DEHYDRO DERIVATIVES The dehydro derivative (9) of the cyclic tautomer of tryptophan has been prepared from tryptophan as described in Section I. A similar dehydro derivative was prepared from melatonin by the reaction with terf-butyl hypochlorite (40). Chlorination of 9 with fert-butyl hypochlorite resulted in the unstable chloroindolenine (66), which gave the aromatic pyrrolo[2,3-b]indole (67) on treatment with sodium acetate. The delocalization energy of 67 was calculated to be 6.18 /3 units by the HMO method (5). The fully aromatized pyrrolo[2,3-b]indole is 68, and thus 67 is a 1,8dihydropyrrolo[2,3-b]indole.Ring system 67 was found in an anhydrodethiosporidesmine (see Section IV,A,l).
9 -
66 -
67 4
3
5
6
2 1
8
1
68 -
Sodium borohydride reduction of 3-hydroxyiminoethyldioxindole(69) at 10°C provided the 1&dihydropyrroloindole (70). 70 was also obtained by acid treatment of 71, which was prepared by sodium borohydride reduction of 69 at room temperature (41). Recently the 1,8-dihydropyrroloindole derivative (73) has been prepared from the 3-indolecarboxyaldehyde by reaction with methyl azidoacetate via 72 (42). -
16
TOHRU HINO AND MASAKO NAKAGAWA
N3
I
Compound 9 has been found to be resistant to hydrolysis by achymotrypsin, in contrast to other simple tryptophan derivatives (43). Catalytic oxygenation of 9 followed by reduction gave the 3a-hydroxypyrroloindole derivative (75) (5) via the hydroperoxyindolenine (74). On the other hand, dye-sensitized photooxygenation of 9 in methanol gave the benzoazocine derivative (76) (44).
. & A
-
OfMe
O2Me
H 75 -
Ac
74 -
Ac
CO 2Me UB/hv/O~
-
MeOH
Compound 73 was readily allylated to give 77, which can be rearranged to 78 by irradiation (42). In another reaction, the dehydro cyclic tautomer (9) gave the oxindole derivative (79) on heating with hydrochloric acid (45). Reaction of 9 with mercaptans, including cysteine derivatives, however, furnished 2-alkylthiotryptophan derivatives (80) (46).
17
1 . CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
111. Cyclic Tautomers of Tryptophan-Containing Dipeptides
Formation and reactions of cyclic tautomers of tryptophan can be extended to dipeptides containing tryptophan. Cyclo-L-prolyl-L-tryptophan (81) gave the cyclic tautomer (82a) in excellent yield on dissolving in 85% phosphoric acid or trifluoroacetic acid at room temperature. At lower temperatures the less stable and kinetically controlled compound (83a) became the major product. In contrast to the tryptophan series, the less stable isomer (83a) can be isolated and characterized, and, furthermore, it was found that 83a can be converted to the stable isomer (82a) in phosphoric acid at room temperature. 7
H
H
/h
6 /H
+
L/ H 85 -
& p e
H
84
H
a :5 - M e 0 b :6 - M e 0
The stereochemistry of the stable isomer (82a) differed from that of the tryptophan series (DL-21)and was confirmed by X-ray analysis of the acetyl derivative (82b) (13,47,48). Sammes and Weedon ( 4 9 ) reported the formation of one isomer of the cyclic tautomer (82, 83) when 81 was dissolved in trifluoroacetic acid. Its physical data were not consistent with either 82 or 83, but the isomer may be 82. The stereochemistry of 82a and 83a reflects the reactivity of these compounds. Acetylation of 82a in acetic anhydride in pyridine smoothly gave 82b, but that of 83a gave 83b in poor yield under the same conditions. On the other hand, 82a can be reverted to the diketopiperazine (81) in 0.1 N HCl in EtOH gradually, while the
18
TOHRU HINO AND MASAKO NAKAGAWA
conversion 83a to 81 under the same conditions was rapid. These results indicate that the less stable isomer 83a is more crowded around the N-C-N group than 82a, although Dreiding models did not show the difference clearly. Oxidation of cyclic tautomers 82b and 83b with lead tetraacetate in trifluoroacetic acid gave results similar to those of tryptophan series. The 8-methoxy derivative was obtained as the major product from 82b, while the 9-methoxy derivative was the major product from 83b. These methoxylated compounds can be readily converted to the 5-methoxy- and 6methoxy diketopiperazines (84a and 84b) on acid treatment. Furthermore, hydroxylation at the 5 position of 81 is also possible under conditions similar to those used for the tryptophan series (47,48). Facile N"prenylation of the cyclic tautomer was also reported (49). Further examination of the formation of cyclic tautomers of other diketopiperazines discloses that the stereochemistry of diketopiperazines is reflected in the formation of cyclic tautomers. trans-Diketopiperazine 86 did not form the corresponding cyclic tautomer in trifluoroacetic acid, whereas both the cis and trans isomers of cycloalanyltryptophan (87 and 88) gave the corresponding cyclic tautomers in trifluoroacetic acid (48). Under the same conditions, however, the trans isomer of cyc1o-Nmethylphenylalanyltryptophan (90) gave the cyclic tautomer but not the cis isomer (89).
86 -
87 -
88
-
0
e
IV. 3a-Hydroxypyrrolo[2,3-b]indoleDerivatives A. NATURALLY OCCURRING 3a-HYDROXYPYRROLOINDOLES The 3a-hydroxypyrrolo[2,3-b]indolering system (91) has been found in some natural products such as sporidesmines, brevianamide E, and rhazidine. This ring system may form from tryptamine by oxidation in the
19
I. CYCLIC TAUTOMERS OF TRYPTAMINES AND TRYPTOPHANS
biological system via the hydroxyindolenine or 2,3-epoxyindole intermediates (Scheme 3). 1. Sporidesmins
Sporidesmin was first isolated from Pithomyces chartarum in 1959. This toxic metabolite is known to be the cause of the animal disease called facial eczema in New Zealand (50-52). Taylor's group has conducted extensive studies on the structure of sporidesmin and many other analogs isolated from the same fungus (53-66) (Table 111). Sporidesmins possess not only the 3a-hydroxypyrrolo[2,3-b]indole ring system but also an epidithiadiketopiperazine ring system. The latter ring system had been known only in gliotoxin at the time, but other examples have been recognized since (67). Another characteristic feature of sporidesmins is the presence of a chlorine atom as well as a methoxy group on the benzene ring. Chemical
-~ -
Sporidesmin d iacetate
'H3
anhydrodethiosporldesmin
OHMe
Hoot
,
........
!
HO..,
N
.......
..
82 R = a-OH
8 3 R = B-OH
H3
3. A C O N l T U M ALKALOIDS
109
6. Transformation of Pseudokobusine to Kobusine Pseudokobusine (84) was converted to kobusine (91) (28). Pseudokobusine (84) was first treated with trichloroethyl chloroformate to give ketocarbamate 85. Compound 85 was acetylated with acetic anhydride and pyridine to the diacetyl derivative 86. Sodium borohydride reduction of 86 yielded alcohol 87, which was converted to diacetylsecodihydropseudokobusine (88) by treatment with zinc in acetic acid at room temperature. Dehydration of 88 with thionyl chloride gave cyclic sulfinyl derivative 89 and diacetylkobusine (90), this reaction proceeding through 89 to give diacetylkobusine (90), which was hydrolyzed to kobusine (91).
OR2
1
2
= H R2 = Ac 1 2 91R = R = H
84 R 90 R
1
=OH; R = H;
85R=H 86 R = A c
87 R = C02CH2CC13 88R=H
D . SYNTHETIC INVESTIGATIONS
1. Total Synthesis of Chasmanine Starting from intermediate 92 the total synthesis of chasmanine (93) was achieved by Wiesner and co-workers (29). This synthesis was preliminarily studied by using model compounds (30). Photoaddition of vinyl acetate to 94 yielded a mixture of 95 and 96 in 96% yield. Compound 95, purified by
110
TAKASHI AMIYA AND HIDE0 BAND0
93
92
94
95
96
Br
98
97
crystallization, was brominated to 97 quantitatively. Dehydrobromination of 97 gave 98 in 82% yield. Treatment of 98 with dilute methanolic potassium hydroxide gave a mixture of epimeric alcohols 99 and 100 by retro-aldol cleavage of the hydrolysis product followed by aldol condensation of the resulting unsaturated keto aldehyde. Benzoylation of 99 and 100 gave a mixture of 101 and 102. Hydrogenation of the epimeric mixture (101 and 102) gave hexahydrobenzoates 103 and 104. The keto ester (103) was
99 R
100 R 101 R 102 R
1 1 1
1
=
OH; R 2
=
H; R 2 = OH
+
= H
= OCOC H5; R = H;R
2 = H
= OCOC6H5
111
3. ACONlTUM ALKALOIDS
103
104
105 R = COC6H11 106
R
107
= H
converted to 105, which was saponified to 106. Compound 106 was oxidized to 107. The overall yield of 107 from 94 was 13.7%. Reduction of 107 with sodium borohydride proceeded stereospecifically and yielded 108 quantitatively. Methylation of 108 gave the previously obtained methoxyl ketal(lO9). This compound was used as an intermediate in the synthesis of the aconitine model (110) (31). Compound 107 was also obtained by an alterate route from 94. The vinyl acetate adduct mixture of 95 and 96 was brominated to give a mixture of 97 and 111, which were converted to 98 and 112 by dehydrobromination. Base treatment of 98 and 112 followed by benzoylation gave the benzoates 101, 102, and 113, which were purified by chromatography. The conversion of both 101 and 102 to 107 was carried out as described above.
OR 108 R = H 109 R = CH3
OA c
110
112 R = Ac
111
113 R = COC6H5
A stereospecific synthesis of racemic chasmanine was also studied (29). The racemic intermediate (92) was reduced with lithium in a mixture of tetrahydrofuran and liquid ammonia. The dihydro compound was acetylated, and then the product was treated with 0.6 N methanolic hydrochloric acid. A series of these reactions gave compound 114 exclusively in 72% yield. Photoaddition of allene to compound 114 gave the stereospecific adduct (115) (86%), which was converted quantitatively to ketal 116 with ethylene glycol and p-toluenesulfonic acid. Compound 116 was ozonized, and the resulting product was reduced with sodium borohydride to alcohol 117. This alcohol (117) was acetylated to 118, which was treated with 0.1 N methanolic hydrochloric acid to yield ketone 119 in an overall yield of 72% from 116.
112
TAKASHI AMIYA AND HIDE0 BAND0
115 R 116 R
114
=
=
0
]:I
117 R1
=
118 R 1 119 R 1
=
]:I ]:I
=
; R2 = H ;
R
0; R 2
=
2
= Ac
Ac
Br
120
Compound 119 was brominated to yield 120 in 80% yield. Compound 120 was then heated with LiBr and Li,CO, to give the a,P-unsaturated ketone (121) in 87% yield. When 121 was treated with 0.3 N aqueous methanolic sodium hydroxide, a mixture of epimeric aldols (122) was obtained in 90% yield. Acetylation of 122 gave the acetate (123) quantitatively. Stereospecific hydrogenation of the acetate (123) was carried out
121
122 R = H 123 R
=
OAc
113
3 . ACONITUM ALKALOIDS
with rhodium on alumina at room temperature &d 95 psi. The hydrogenated products were oxidized with chromium trioxide in pyridine to give the epimeric acetates (124) in an overall yield of 86%. The epimeric acetates (124) were transformed to 125 in 80% yield by (1) formation of the acetals, (2) saponification with dilute potassium hydroxide solution, and ( 3 ) oxidation with chromium trioxide in pyridine. OA c
CH3C0
OCH3 OCH3
124
125
Stereospecific reduction of 125 was accomplished with sodium borohydride to yield 126 quantitatively. Compound 126 was methylated with sodium hydride and methyl iodide to give the methoxyacetal (127) in 82% yield, and then 127 was converted to the ketone (129) by heating in 80% acetic acid. Bromination of 129 gave the bromoketone (130) in 82% yield. The latter was converted to the acetal (128) quantitatively with diethylene orthocarbonate and p-toluenesulfonic acid in chloroform. Rearrangement of the bromoketal (128) yielded the 0x0-pyrochasmanine derivative (131) in 85% yield. H
//
OR1 H
OCH3
V
CH3CO-
dCH3
126 R 1 = H ; R 2 = H 127 R 1 = CH3; R 2 = H
128 R 1 = CH3; R 2
= Br
129 R
= H
130 R = Br
114
TAKASHI AMIYA AND HIDE0 B A N D 0
The transformation of 128 to 131 was accomplished by refluxing in a mixture of xylene and dimethyl sulfoxide (1: 1) in the presence of large excess of 1.5-diazabicyclo[3.4.0]non-4-ene. Oxymercuration of 131 gave 132 (65% yield), which was identical by IR, NMR, mass spectrometry, and TLC to the corresponding optically active derivative prepared from natural
CH3CO--
CH3CO-.
131
132
chasmanine. Compound 132 was heated in 80% acetic acid to give racemic 14-dehydro-a-oxochasmanine (133). Reduction of optically active 14dehydro-a-oxochasmanine (133) with lithium aluminum hydride gave chasmanine (93), which was found to be identical to the natural alkaloid by comparison of IR, TLC, mass, and NMR characteristics and by mixed melting point determinations.
6CH3 133
By 1978 Wiesner and co-workers (13,32,33) had developed a fundamentally different synthesis of chasmanine (93). In this approach they studied a model system starting with compound 134. Treatment of 134 with
134
135
136 R = CH3 137 R = H
115
3. A C O N Z T U M ALKALOIDS
triethyl phosphite followed by reduction with sodium in liquid ammonia gave 135. Hydrogenation of 135 in the presence of palladium yielded 136. Boron tribromide cleaved the methoxyl group in 136 to yield the phenol (137) in 89% yield. Compound 137 was converted to the dithian derivative (138) in 89% yield by treating with N-chlorosuccinimide and 1,3-dithian. Compound 138 was alkylated to 139 on treatment with methyl bromoacetate. When treated with mercuric oxide, 139 gave 140 in high yield.
142 R1 = OH; R 2 = C H 2 C 0 2 H
RO
3.
@$ 144 R
0 = CH2-C6H5
Oxidation of 140 with rn-chloroperbenzoic acid provided 141 in 86% yield. The latter was saponified to 142. Oxidation of 142 by N-bromosuccinimide gave spirolactone 143, which was treated with benzyl vinyl ether to give the epimeric adducts (144) in an overall yield (from 142) of more than 80%. Adducts 144 were hydrolyzed by potassium carbonate to yield epimers 145, which were converted to 146. Epimers 146 were reduced by lithium borohydride to a mixture of the epimeric alcohols (147), which were
145 R = CH2-C6H5
146 R = C H -C H
2 6 5
147 R = CF2-C6H5
treated with acetylacetone. The products obtained (148) were transformed to the corresponding mesylates (149), which were then reduced to the aldols (99 and 100) mentioned above. Compounds 99 and 100 were subjected to a sequence of reactions analogous to the one described above.
116
TAKASHI AMIYA AND HIDE0 B A N D 0
148 R1 = CH2-C6H5; 1 149 R = CH2-C6H5;
R2 = OH R
2
= OMS
In 1978 Wiesner and co-workers reported the direct synthesis of 13-desoxydelphonine (150) and a formal synthesis of chasmanine (93) by the new method related to the above-mentioned model system (13). The starting material was aromatic intermediate 151, which was prepared from vanillin by the aziridine rearrangement method (see Ref. 3 4 ) . Compound 151 was treated with sodium thioethoxide in dimethylformamide to give the phenol (152) in 95% yield. Phenol 152 was reacted with methyl
150
151 R = CH3
152 R = H 153 R = CH2-COOCH3
bromoacetate to provide ester 153 in 90% yield. Hydrolysis of 153 with hydrochloric acid followed by oxidation with N-bromosuccinimide gave the corresponding masked o-quinones, which were converted to adducts 154a and 154b on treatment with an excess of benzyl vinyl ester, in an overall yield of 70%. The adducts were separated by preparative TLC. The mixture of 154a and 154b was reduced with zinc in glacial acetic acid to 155 in 85% yield. Hydrogenolysis removed the benzyl group in 155 to give a mixture of epimeric alcohols (156) in 96% yield. On treatment with acetic anhydride in pyridine the alcohols (156) were acetylated to the acetates (157) in 80% yield after crystallization. Compounds 157 were transformed to 158 by stereospecific hydrogenation with rhodium on alumina at 85 psi, followed by oxidation with chromium trioxide in pyridine (88% yield).
117
3. ACONITUM ALKALOIDS
154a R = H 154b R
=
155
Br AcO
RO
t.
i.
H
156 R
=
157 R
= Ac
I58
Following reflux with p-toluenesulfonic acid and ethylene glycol in benzene, hydrolysis with methanolic sodium hydroxide, and oxidation with chromium trioxide in pyridine, compounds 158 gave the keto acetal (159) in over 88% yield. Reduction of 159 with sodium borohydride quantitatively yielded the alcohol (160), which was converted to 161 with sodium
OCH3 159
160 R 1 = H ; R 2
=
H
161 R1 = CH ; R 2 = H 3 2 162 R 1 = CH3; R = Br
118
TAKASHI AMIYA AND H I D E 0 B A N D 0
hydride and methyl iodide. On heating in 80% acetic acid 161 gave the corresponding ketone (162) (94% yield), which was brominated to 163 in 90% yield. The bromoketone (163) was converted to 164 (80%) by reflux with ethylene glycol and p-toluenesulfonic acid. Compound 164 was heated with DBN in mixture of dimethyl sulfoxide and xylene./The rearranged compound (165), obtained in 89% yield, was subjected to oxymercuration followed by sodium borohydride reduction. The alcohol (166), obtained in 65% yield, was heated in 80% acetic acid to give 167 quantitatively. The keto lactam (167) was reduced with lithium aluminum hydride to 150 in 64% yield after recrystallization from hexane. The racemic synthetic 13-desoxydelphonine (150) was identical with a compound of the same structure derived from the natural product (35). In 1979 the aromatic intermediate (151) was prepared from o-cresol (168) by the preferred route as follows (36). Compound 168 was converted
dCH,
J
OCH3 162 R
=
163 R
=
165
166 R , R = Ethyleneacetal 167 R , R = Carbonyl
H H 3 q OC 168
Fi2
CH2-CO-0 P c H 3 169
@CH3 O R
170 R = H 171 R = CH3
119
3 . ACONITUM ALKALOIDS
to the 3-chloropropionyl ester (169) on treatment with 3-chloropropionyl chloride. The latter was treated with aluminum chloride to give the indane (170). Methylation of 170 with dimethyl sulfate yielded 171. On treatment with trimethyl orthoformate, 171 was converted to the dimethyl acetal, which was transformed to the enol ester (172) by pyrolytic elimination of methanol. By carboxylation with n-butyl lithium and carbon dioxide and subsequent hydrolysis of the enol ester group, 172 provided the keto acid (173). Compound 173 was reduced with sodium borohydride to which was heated with phosphoric acid followed by esterification with methanolic hydrogen bromide to give the ester (175a), which exists in an equilibrium mixture with 175b. This mixture was added to maleic anhydride to give 176 quantitatively. Decarboxylation of 176 with bis(tripheny1phosphine)nickel carbonyl gave 177 in 85% yield.
d4,
HOOC,
/c\
" I72
OCH3
173
175a
I
I
OH
OCH3
174
176
CH300C
Q
C OCH3 H
3
175b
On treatment with trimethylsilyl azide followed by acetic acid and acetic anhydride, 177 gave the acetylaziridine (178). Compound 178 was rearranged by heating to give 179 in 70% yield. Compound 179 was oxidized with ceric ammonium nitrate in aqueous acetic acid to give the aldehyde
120
TAKASHI AMIYA AND HIDE0 B A N D 0
117
178
179
(180) in 75% yield. On treatment with methanol in the presence of potassium carbonate, 180 gave the alcohol (181), which was benzylated to 182. Oxidation of 182 with rn-chloroperbenzoic acid produced the formate ester (183), which was hydrolyzed in the presence of potassium carbonate to yield 184; the two steps were carried out in 96% yield. Alkylation of 184 with chloromethyl methyl ether yielded 185 in 93% yield.
OCH3
CH300C#cHo CH,$HN'
0 O - C H z O
bR 180 R = Ac
183 R = CHO
181 R = H
184 R = H
182 R = CHz-C6H5
185 R
=
CH2-O-CH3
By reduction with lithium borohydride, followed by reoxidation with dimethyl sulfoxide and dicyclohexylcarbodiimide, compound 185 was converted to 186. The overall yield of these reaction products was 86%. Compound 186 was reacted with 3-benzoyloxy-4-methoxy-n-butylmagnesium bromide to give the epimeric alcohols (187) in 87% yield. Alcohols 187 were then acetylated to the acetates (188), which were hydrogenolyzed over palladium to the diols (189). Oxidation of 189 with the pyridinechromium trioxide complex in dichloromethane gave the epimeric ketones (190) in 85% yield. On treatment of 190 with boiling methanol containing potassium carbonate, the a,P-unsaturated ketones (191) were obtained in 90% yield. Photoaddition of vinyl acetate to 191 gave the adducts (192) in 95% yield. Hydrolysis of 192 with base was followed by retro-aldol cleavage. The products (193) were obtained in 97% yield. Compounds 193 were converted to 194 and then acetylated to 195, which were heated to eliminate methanol. The yield of the products obtained (196) was 92%.
121
3. ACONITUM ALKALOIDS
0-CH2-C6H5
0-CH2-C6H5 186
187
R
=
H
188 R = Ac
CH30
190 -CH2-O-CH3
@
CH3
CH3C@--. "NH CH30
'OAc 192
1
0
C HO
193
Oxidation of 196 with permanganate-periodide followed by esterification with diazomethane gave the esters (197) in 81% yield. Epimers 197 were heated with dilute methanolic sodium methoxide under reflux to give 198 in 85% yield. Oxidation of the epimeric hydroxylactams (198) with the
122
TAKASHI AMIYA AND H I D E 0 B A N D 0
OCH3
'OCH,
196
194 R = H 195 R -
=
OAc
CH3d
19 7
198
pyridine-chromium trioxide complex yielded 199. Reduction of 199 with tri-tert-butoxyaluminum hydride gave 200, which was methylated with sodium hydride and methyl iodide to provide the aromatic intermediate (151).
199
200
2. Stereospecific Synthesis of Napelline Wiesner and co-workers (32) carried out a study aimed at the total synthesis of napelline (201). On treatment of 145 with trimethylsilylmethylmagnesium chloride, the epimeric alcohols (202) were obtained. Epimers 202 gave 203 on warming with methanolic perchloric acid. Reduction of 203 with sodium borohydride in methanol yielded 204 in 74% yield. On acetylation of 204 with acetic anhydride in pyridine, the acetates (205) were obtained. Hydrogenolysis of 205 over palladium on charcoal gave the
123
3. A C O N I T U M ALKALOIDS
OH
C6H5-CH -0
\,~
202
CH3
20I
alcohols (206), which were transformed to the mesylates (207). Epimers 207 were heated with glacial acetic acid, and a mixture of the rearranged epimers (208) was obtained in 90% yield. Saponification of 208 gave 209, which were oxidized with the chromium trioxide-pyridine complex to the diketone (210). Compound 210 was identical to the same compound previously synthesized by the other method (37).
203
204 R = H 205 R = Ac
RO
&CH3
“OAc
206 R = H 207 R = Ms
b.,,... & ‘
.
.
*:
-
.,CH3
“OR
208 R = Ac 209 R = H
0 2 10
Alternatively, the aromatic intermediate (211) (38) was reduced with lithium borohydride to the alcohol (212), which was heated with 6 N HC1 to give 213. These reactions proceeded quantitatively. Treatment of 213 with CaC03 and T1(N03)3 in tetrahydrofuran gave the quinone acetal (214) in 95% yield. Compound 214 was heated with benzyl vinyl ether to yield adducts 215. Epimers 215 were converted to the tetrahydropyranyl derivatives (216) by treatment with dihydropyran and pyridinium p toluenesulfonate quantitatively. On treatment of 216 with trimethylsilylmethylmagnesium chloride, the two epimeric alcohols (217) were
124
TAKASHI AMIYA AND H I D E 0 B A N D 0
211 R 1 OR1
R3
OR^
= CH20CH3
R~ = C H ~ C O ~ C H ~ = THP
212 R1 = CH20CH3
2
R = CH2CH20H R 3 = THP 1 3 213R = R = H
CH, J
CH3
R L = CH2CH20H
2 14 c6H5-cH2-0\.
215 R 216 R
= H
OH
217
= THP
obtained in 84% yield. These compounds were heated with 70% HC104 to give the a$-unsaturated ketones (218) in 85% yield. Compounds 218 were reduced with lithium borohydride and then acetylated with acetic anhydride and pyridine to give the diacetates (219). C6H5-CH -0
2
1
219 R 1 2 R 1 220 R
= CH2-C6H5 = COCH3 = H
R L = COCH3
221 R1 R2
=
Ms
= COCH3
218
Hydrogenolysis of 219 with palladium on charcoal in methanol gave the alcohols (220), which were mesylated with mesyl chloride and triethylamine to 221. By refluxing 221 in glacial acetic acid, the rearranged products (222) were obtained in 95% yield. Epimers 222 were saponified with 5% methanolic potassium hydroxide to 223, which were oxidized with the chronium trioxide-pyridine complex to 224. These two reactions
125
3. ACONITUM ALKALOIDS
222 R = COCH3 223 R = H
224
0
225
226
were carried out in an overall yield of 90%. Hydrogenation of 224 with palladium on calcium carbonate in ethanol gave 225 quantitatively. Compound 225 was reduced with lithium aluminum hydride to dihydronapelline (226) as shown previously (39). Dihydronapelline (226) has been transformed to napelline (201) (40). 3. Synthetic Approach to Kobusine
Synthesis of racemic 6,15,16-iminoprocarpane-8,11,13-triene (227), which constitutes a partial structure of kobusine (228), was reported (41). Kobusine is a C20 diterpenoid alkaloid and has been obtained from Aconitum species. On catalytic hydrogenation of 229 with palladium on 12
227
228
126
TAKASHI AMIYA A N D H I D E 0 B A N D 0
230 R = 0
229
231 R
=
232
OH,H
carbon, 230 was obtained in 73% yield. Reduction of 230 with sodium borohydride gave the epimeric alcohols (231). On treatment of 231 with Raney nickel in ethanol, epimers 232 were obtained in 63% yield.
233
234
235 R = C02CH2-C6H5
Dehydration of 232 with hydrochloric acid in ethanol gave 233. Treatment of 233 with lead tetraacetate gave the aziridine (234), which was treated with benzyl chloroformate to provide the chlorocarbamates (235) in 45% yield. These compounds were reduced with Raney nickel in ethanol to afford the amine (236) in 56% yield. Compound 236 was reacted with N-chlorosuccinimide to give the N-chloramine (237) in 85% yield. Photolysis of 237 in trifluoroacetic acid gave 227 in 38.7% yield.
236
237
111. Pharmacology
The roots of some Aconitum species are one of important herbal drugs that have long been in China and Japan. The roots, however, must be carefully applied in clinical settings because of the high toxicity. There are many kinds of treatments for reducing the toxicity, such as soaking in
127
3. ACONITUM ALKALOIDS
saline solution, heating, and covering with lime ( 4 2 ) . In Japan the drug is generally prepared by autoclaving at 120°C for 30 min. (43).In an Oriental medicinal remedy, herbal drugs are used necessarily in combination with other drugs. In particular, it has been stated empirically that Aconiturn roots improve hypometabolism and have cardiotonic, anodyne, febrifuge, and sedative effects. Recently, study of those pharmacological effects has been accelerated, and pharmacological activities have been reviewed with respect to diterpenoid alkaloids including aconitine (44-46). Bisset has also reported on the botany of Aconitum species, components of their alkaloids, and pharmacology (47). Toxicity and Oriental medicinal purposes are reviewed in this chapter.
A. TOXICITY Aconitine is a well-known toxic compound (see Table 11) responsible for the characteristic intoxication called aconitine syndrome. In mice, aconitine intoxication causes at first promotion of respiration followed by increased salivations, emesis, urination, paralysis of hindlegs, convulsion, paralysis of forelegs, and death. Table I shows the acute toxicity of raw and processed Aconiturn roots (48).The toxicity of processed samples, with the exception of Shirakawa-bushi, was obviously reduced, and Hikino et al. reported that the content of the major alkaloids, hypaconitine, aconitine, and mesaconitine, decreased but the content of benzoylaconines increased, based on quantitative determinations (48). TABLE I ACUTETOXICITY OF Aconiturn ROOTSI N MICE(48)
LD5" (g crude drug/kg)
Material Original Plant
Location
Preparation
PO
sc
iP
A . japonicum A . japonicum A . japonicum Aconitum sp. A . carmichaeli A . carmichaeli A . carmichaeli A . carmichaeli A . curmichaeli
Niigata Niigata Niigata
Raw Processed" Processed' Processed" Raw Processed" Raw Processed" Processed'
0.54 195 1.8 13 1.61 116 5.49 161 290
0.12 23.1 0.20 10.9 0.57 11.9 146
0.11 13.9 1.1 2.2 0.19 9.17 0.71 11.5 61.3
a
-
Hokkaido Hokkaido China China China
KukZ-bushi (Japan).
" Shirakawa-bushi (Japan). ' Ha-bushi (Hong Kong).
iv 0.06 4.9
0.14 1.3 0.49 2.8 16
-
128
TAKASHI AMIYA AND HIDE0 B A N D 0
TABLE I1 ACUTETOXICITY O F ACONlTlNE AND RELATED COMPOUNDS IN M I C E ~ Alkaloid
c-3
C-8
C-14
LDSo (mg/kg)
Ref.
iv 0.12, ip 0.380, sc 0.270, PO 1.8 iv 0.10, ip 0.213, sc 0.204, po 1.9 ip 0.35 iv 0.470 iv 0.47, ip 1.10, sc 1.19, PO 5.8 sc 5.2, PO 56.5 sc 100-200 iv 23, ip 70 iv 1160
49
Aconitine
OH
OAc
OBz
Mesaconi tine
OH
OAc
OBz
Jesaconi tine 3-Acetylaconitine Hypaconitine
OH OAc H
OAc OAc OAc
OAs OBz OBz
Aljesaconitine A
OH
OMe
OAs
Lipoaconitine Benzoylaconine
OH
OH
OOCR OH
OBz OBz
Aconine
OH
OH
OH
49
44 50 49
51 52 49
50
a OAc, OOCH,; OBz, OOC-C6Hs; OAs, OOC-C6H4-OCH3 (para); OCR, mixture of lineoyl, palmitoyl, oleoyl, stearoyl, and linoleoyl in the ratio 64 : 20 : 16 : trace : trace.
Table I1 shows toxicities of aconitine and related compounds. Two ester groups, an acetyloxy at C-8 and a benzoyloxy at C-14, seem to be responsible for toxicity, which decreases by a factor of 200 and 1000 in the cases of a partial hydrolysate at C-8 and a hydrolysate at both of C-8 and C-14, respectively. It is recognized that the toxicity of C-8 methoxy and lip0 compounds decreases to some extent. Judging from the tendency for such a decrease in toxicity, traditional processing methods of the herbal drug are considered to be performed mainly for the purpose of hydrolysis. The toxicity of 3-acetylaconitine does not decrease much but the analgesic activity of the compound has been reported to better by a factor of around 100 that of cocaine (53);qualitative differences in pharmacological action were recognized for even slightly changed substitution (50). As for neurotoxicity, some investigators have reported that the distance between nitrogen and oxygen atoms in substituents at C-8, C-14, and C-16 is important for the drug association with the same sodium channel
129
3. ACONITUM ALKALOIDS
receptors that also bind other popular toxins, such as batrachotoxin, veratridine, and grayanotoxin (54,55). In a neurophysiological study, Schmidt and Schmitt showed that aconitine altered sodium channel kinetics, eliminating inactivation, and lowering the threshold for activation by approximately 50 mV (56).The depolarizing effect on sodium channels of aconitine as well as as batrachotoxin and veratridine was found to be inhibited by tetrodotoxin (57,58). Aconitine is a popular reagent in the study of sodium channel kinetics, and a binding site on the channel receptor has been investigated (59-62). Interestingly, lappaconitine, which was about 40 times less toxic than aconitine on intravenous administration to mice, reportedly, blocked the calcium channels in Helix pomatia neurons without activating sodium currents (63,64).
B . ARRHYTHMIC ACTIVITY The arrhythmia induced by aconitine has been ascribed mainly to an effect of acetylcholine (65), and the mechanism of inhibition by atropine has been fully investigated (66). It has been also shown that antihistamine in isolated frog heart (67) and propranolol and lidocaine in cat (68) were effective inhibitors of the arrhythmia. OH
Denudatine
Lucicul ine
A matter of interest is that denutadine, Czo atisine-type alkaloid, showed prophylactic inhibition of arrhythmia (69). Luciculine at smaller doses (5-20 mg/kg, iv) also showed an antiarrhythmic effect on CaC1,- and aconitine-induced arrhythmia (70). In mice, intraperitoneal administration of 25-200 mg/kg luciculine before administration of a lethal dose of
130
TAKASHI AMIYA AND H I D E 0 B A N D 0
aconitine prevented death of the animals (70). Lappaconitine showed arrhythmic activity and caused a marked decrease in heart rate. The results of testing several diterpenoid alkaloids related to lappaconitine led to the proposal that substitution at C-4 must be important for arrhythmic activity (64). Aconitine-induced arrhythmia has been widely used in the development of antiarrhythmic agents ( 7 I ) , including prostaglandins (PGF2 and PGIJ (72,73), disopyramide (74), androstane derivatives ( 7 9 , ethylenediamine derivatives (76),quinidine derivatives (77), ethmosine derivatives (78), alpherol (79), 1,3-benzodioxazole (80), trimecaine (81), procaine amide derivatives (82), and verapamil (83).
C. CARDIOACTIVITY During recent years improved techniques in researching biologically active principles in combination with pharmacological screening have also been applied to Aconitum roots as well as other herbal drugs. Kosuge and Yokota isolated higenamine [ (*)-demethylcoclauline] from the aqueous portion of a crude extract of Aconitum japonicum, on the basis of its cardiac activity as tested by the Yagi-Hartung method (84). Higenamine has been also been also isolated from embryos of Netumbo nucifera (85), leaves and stems of Annona squamosa (86), and radices of Asiasarum heteropoides (87). It was reported that optically active (S)- (-)-higenamine has potent p-adrenergic activity and that the ( R ) - (+) compound has an antitussive effect (87,88).
Higenamine
Corynein c h l o r i d e
S a l s o l inol
Konno et al. isolated corynein chloride, a compound with hypertensive activity, from Aconitum carmichaeli (89). An interesting study on blood pressure and neuromuscular junctions has been reported for catecholamines including corynein bromide by Cuthbert (90). Salsolinol, possessing hypertensive activity (91-93), has been isolated from the same species ( A .carmichaeli)by a Chinese group (94).In connection with catecholamine activity, the following aminophenols were reported: N-methyladrenaline
131
3. A C O N I T U M ALKALOIDS
from tubers of Aconitum nusutum (95), noradrenaline, dopamine, and tyramine from tubers of A. nupellus ( 9 6 ) , and hordenine from whole plants of A . tanguticum (97).
D. ANALGESIC ACTIVITY In studies of the analgesic activity, of Aconitum alkaloids, mesaconitine was isolated from the active fraction of a crude extract (98). Its activity was related to responses involving the central catecholaminergic system (99) and was promoted through activation of the p-adrenergic system followed by an increase in cyclic AMP levels (100). Mesaconitine is more effective than aconitine and benzoylaconine (100). Kitagawa et al. also reported on the analgesic activity of aconitine, mesaconitine, and lipomesaconitine (52).Saito et ul. reported that ignavine, a C2" diterpenoid alkaloid, showed analgesic activity without inhibition of the mortality induced by mesaconitine (101). Finally, there was a interesting report that intraperitoneal administration of aconitine induced a painful writhing syndrome and was useful in evaluating analgesic activity (102). Such a syndrome may be affected by local responses according to the manner of administration.
E. OTHERBIOLOGICAL ACTIVITIES Regarding antiinflammatory activity, aconitine alkaloids at low doses showed inhibition of the increased vascular permeability induced by acetic acid in mouse peritoneal cavity or by histamine in rat skin as well as inhibition of edema induced by carrageenan, but these alkaloids showed no inhibition of adjuvant arthritis (103). Lipomesaconitine (0.5-2 mg/kg) (52) and ignavine (100 mg/kg) (101) also showed inhibition of carrageenan-induced edema. Mesaconitine was deduced to be effective in improving hypometabolism in feeble patients, as judged from activation of protein synthesis (104) and increase in incorporation of [5-3H]-orotic acid into polysomal RNA in mouse liver (105). Glaucine
: R
1
I
= R
3 3
= OCH ;
3 2
R
2
R
= H;
4
4
= CH3
Isoboldine : R = R = OH; R = H; R = CH3 3 4 + Magnoflorine: R1 = R2 = OH; R = H; NR = N ( C H 3 ) 2
R
132
TAKASHI AMIYA AND H I D E 0 B A N D 0
Glaucine, an aporphine alkaloid isolated from Aconitum yesoense (106), is known to have antitussive activity (107). Isoboldine, obtained from aerial parts of A . karakolicum (108), has been reported to possess antifeeding activity in Trimerisia miranda and Prodenia litura (109). Nijland reported the detection of magnoflorine ( I I O ) , which is known to show hypotensive activity through blocking ganglias, in tubers of A. carmichaeli, A . nappelus, and A . vulparia. A number of biologically active compounds will be available from Aconitum species in the future according to development of the means to bioassay them. It is important, however, for medicinal purposes to require constant quality and quantity of active components in herbal drugs when using traditional crude preparations.
IV. Analytical Methodology
Adequate analytical methods are required to study components of traditional herbal drugs, both processed and raw materials. In particular, for quantitative determination of the toxic alkaloid aconitine, UV spectroscopy (111), paper electrophoresis (112),thin-layer chromatography (113), and multibuffered paper partition chromatography (114) have been developed. Kurosaki et al. (115) determined the content of several aconitine, lycoctonine, atisine, and veatchine type alkaloids in tubers of Aconitum mitakense with dual wavelength TLC scan and gas chromatography. It was found, however, that some of aconitine-type alkaloids were decomposed by gas chromatography. Kurosaki et al. examined seasonal variation in alkaloid content of some Japanese Aconitum species in connection with the appropriate harvest period for the herbal drug. Hikino et al. (48) reported an improved gas chromatographic procedure to determine the content of trimethylsilylated aconitine-type alkaloids in processed and raw materials of A . japonicum and A. carmichaeli. Kosuge and Yokota (116) applied gas chromatography to determine the content of higenamine, a cardioactive isoquinoline alkaloid, in tubers of Aconitum species and commercial preparations. Since the first report on the application of high-performance liquid chromatography for quantitative determination of aconitine in tubers of some Aconitum species and commercial preparations was made by S.-J. Sheu et al. (117), many reports dealing with analysis by HPLC have been published (51,118-121). Commercially available preparations of aconitine have been evaluated with HPLC on CIS reversed-phase columns with a
3. ACONITUM ALKALOIDS
133
mixture of phosphate buffer (pH 2.7) and tetrahydrofuran (89 : ll), using the ion pair reagent, sodium hexanesulfonate, as the mobile phase (118). Recently, vacuum liquid chromatography (122,123) and a centrifugally accelerated radial thin-layer chromatographic instrument (Chromatotron) have been efficiently applied for preparative-scale isolation of diterpenoid alkaloids (123-125). The rotors of the Chromatotron were coated with a mixture of aluminum oxide gel and calcium sulfate hemihydrate, and the layer thickness was 1 mm. Commercial “Aconitine Potent Merck” (250 mg) gave deoxyaconitine (9 mg), aconitine (190 mg), and mesaconitine (4 mg) with the Chromatotron, using gradient elution with hexane, hexaneether, ether, and ether-methanol. This method demonstrates a significant advantage over classic time-consuming preparative-scale separation of diterpenoid alkaloids.
V. Tabulation of New Diterpenoid Alkaloids The configuration of C-1 group of base I (septentriodine), base V (puberaconitine), gigactonine, puberaconidine, and septentriodine has been revised on the basis of correlation with lycoctonine and derivatives. New Aconitum alkaloids discovered since 1978 are presented in Tables 111 and IV. Pelletier et al. have recently reported C19 diterpenoid alkaloids and derivatives obtained from Aconitum and Delphinum species together with ‘H- and 13C-NMR spectral data (126).
TABLE I11 CATALOG OF CI9 DITERPENOID ALKALOIDS FROM Aconitum SPECIES
Compound
3-Acetylaconitine
OH
14-Acetyltalatiramine
Physical characteristics; source; means of identification
Ref.
C36H49N012; 196-197"C, [&ID +18.6" (CHC13);A . Feavum;A. flavum; A . pendulum; spectral and chemical data
127-129
CZhH4,N06; amorphous, [.ID i-19.7' (CHCI,); A . japonicum; A . carmichaeli; A . colurnbianum; spectral data and correlation with talatizamine
130-134
14-Acetylneol i n e ( B u l l a t i n e C )
C26H41N07, amorphous, [a],+18.6“ (MeOH); A . yesoense; A . nagarum;
69,106,128,
135
A . jinyangense; spectral and chemical data
Aconif ine
C34HqNO12; 195-197”C, A . karakolicum
Aljesaconitine A
C34H4YNOl, ; amorphous, [.ID +7.5” (EtOH); A . juponicum; spectral and chemical data
[a]D-;
128,136, 137
51
(continues)
TABLE 111 (Continued)
Compound
Physical characteristics; source; means of identification
Ref.
~
Aljesaconitine B
Anisezochasmaconi t i n e
C35H5,NOll;amorphous, [.ID +5.8" (EtOH); A . japonicum; spectral and chemical data
51
C,,H,,NO,; 136-138.5"C, [.ID-; A . yesoense; spectral and chemical data
106,138
C,,H,2N2011;amorphous, [a],, f45"
13Y--141
(MeOH); A . gigus; A . seprenirionale; A . barbaturn; spectral and chemical data
139,141
C ~ - $ I ~ ~ N196-198"C, O~Z; [.ID-; A . kusnezofii; A . carmichaeli; spectral data
128,142
137
C36H5H50Nz0,,; amorphous, [.ID +34.0" (CHCI,); A . gigus; A.barbatum; spectral and chemical data
TABLE 111 (Conrinued)
Compound Benzoylheteratisine
Physical characteristics; source; means of identification
Ref.
C,gH,,NO,; 214-216°C. [.ID -; A . fanguticum; spectral and chemical data
97
C ~ ~ H ~ ~ 206-208"C, N O S ; [a] -; A . karakolicum; spectral and chemical data
143
C3,Hd3N07;amorphous, [.ID f9.1" (MeOH); A . subcuneatum; spectral data and correlation with neoline
1s
CH3 OBz 1-Ben z o y 1 k a r a s a ni in e
C2H5
14-Benzoyl neol i n e
OCH3
Colurnbianine
C,,H,,NO,;
202-205"C,
[ N ]-6" ~
I34
(EtOH); A. colurnbianurn; spectral and chemical data
6H Col umbi d ine
C26H43N05;amorphous, [.ID -6.4" (CHCI,); A . calurnbianurn; spectral and chemical data
144
Crassicaul ine A
C3,H,9NO,o ; 162.5-164.5"C, [.ID +31.5"(CHCI,); A. crassicaule; A . forrestii; A. pseudogeniculaturn; spectral and chemical data
145-147
(continues)
TABLE 111 (Continued)
Compound Crassicaulidine
OCH3
Physical characteristics; source; means of identification
Ref.
C24H39N08; 206-209"C, [.ID -; A . cvassicauk; spectral and chemical data
148,149
C30H42N209; 121-123"C, [.ID +34.9" (CHCI,); A . finetianurn; spectral data
150
'
N-Deacetylfinaconitine
N-Deacetyllappaconitine (Puberanidine)
C-,oH4~NZ07; 120-121"C, [ a ]+42" ~
(MeOH); A . ranuncalaefolium; A . finetianurn; A . barbatum;
64,141,150,
IS1
Delphinium cashmiranurn; spectral data and correlation with lappaconine
0 -c=o
N-Deacetylranaconitine
C ~ O H ~ ~ ;N125-127"C, ZO~ [.ID +43.7" (CHCl,); A. finetianurn; spectral and chemical data
150
N-Deacetylscaconitine
C3,HUNZO6; amorphous, [.ID -; A. scaposurn; spectral and chemical data
152
(continues)
TABLE 111(Continued) Compound
Physical characteristics; source; means of identification
Ref. ~
8-Deacetylyunaconitine
C33H47NOli; 101-105"C, [(~]j3-; A . forrestiz, spectral and chemical data
153
C,,H,,NO,, 128-I30"C, [o]D-, A suposhnikovzz, spectral data
154
C29H39N06;[oID-: A . deluvyi; spectral and chemical data
155,156
OCH3
14-Dehydrotalatisamine L
N e
OCH3 Delavaconitine ----_.___
___---
H
Delphinifol ine
CZ3H37N07; 218-220°C, [aID-;
157
A . delphinifoliurn; spectral and X-ray data
OCH3 Deoxydel sol ine
CZ5H41NO6; 134-135"C, [(YID-; A monticolu; spectral data
158
C35H49NOll;174-176"C, [a],, +52' (MeOH); A . subcuneatum; spectral and chemical data
159,I60
OCH, J
Deoxyjesaconitine
C2H5
(continues)
TABLE 111 (Continued)
Compound
Dihydromonticarnine
Physical characteristics; source; means of identification
Ref.
C ~ ~ H ~ S N 156-157"C, OS; [.ID -; A . monficola;spectral data
158
C34HJ7N010; 168-169"C, [.ID +23.8" (CHCI,); A . duclouxii; spectral data
161
CZ9H39N06; amorphous, [a],,-11.7" (EtOH); A . epkcopale; spectral data
162
OH
CL
P
dCH3 OCH3
Episcopal isine
E p i s c o p a l isinine
C,2H3sNOs, 152-154"C, [a]D-3.8"
I62
(EtOH); A . episcopale; spectral and
chemical data
Episcopal i t i n e
CZ4H37N05; amorphous, [.ID -0.9" (EtOH); A. episcopale; spectral and chemical data
I62
8-0-Ethylbenzoylmesaconine
C33H47NOIO; amorphous, [.ID +5.8" (MeOH); A. ibukiense; spectral and chemical data
163
"0B z __--OH
HO" OCH3
(conrinues)
TABLE 111 (Continued)
Compound
Ezochasmaconitine
Physical characteristics; source; means of identification
Ref.
C34H47N08; 163-165"C, [(YID-; A yesoense: spectral and chemical data
106,139
Ezochasmani ne
C25H41N07; 115-118"C, [.ID +40.3" (CHCl3); A. yesoense; spectral and chemical data
106,139
Finaconi tine
C3zH44N2010,220-22 I T , [ (Y]D-; A . finetianurn; correlation with rannaconitine
128
OCH3
C 2 H 5 - - -&- r ; N1 @ c H 3
I.
0-c=o
___----
OH
Flavaconitine
C 3 , H 4 , N 0 , , ; 165-166"C, [a],+36" (CHCI,); A . flavum; spectral data
I64
C35H49N09; 153-154"C, [.ID +30.5" (CHCI,); A . forrestii, A . vilmorianum; A . pseudogeniculatum; spectral and chemical data
146,147, 165-167
C Z ~ H ~ ~79-80"C, N O ~ ; [.ID -1.9" (CHCI,); A . forresfii; spectral data and correlation with chasmanine
168
O'CH3 Foresaconitine (Vilrnorrianine C)
OCH3
0 As = - ! D 0 C H 3
Foresticine QCH3
(continues)
TABLE 111 (Continued) Compound
Forestine
OCH3
Physical characteristics; source; means of identification &Hd7N09; amorphous, [ ( Y ] ~ - ; A. forrestii; spectral data
Ref. 168
0 As = -@)-OCH,
Franchetine
IOCH3
C3,H41N06;amorphous, [a],,-106.4” (CHCQ; A. franchetii; spectral and chemical data
169
Geniconitine
C32H*5NOR ;235--237.5-C (hydrochloride),
170
[a],-; A . geniculutum; spectral and
"OA s
chemical data
___----
')
OH
OCH3
Gigactonine
Guayewuanine B
nu
CZdH39N07; 168-169"C, [.ID +49" (EtOH); A . gigas; spectral and chemical data
139
C31H43N09; 120"C, [.ID +31,8"(CHCI-,); A . hemsleyanum; spectral and chemical data
171
0
OCH3 AS =
-!-@OCH3
(continues)
TABLE III(Continued)
Compound
Physical characteristics; source; means of identification
Ref
Gymnaconi t i ne
C34H47N04; llO-lll°C,[(Y]D + 18.2”, A . gymundrum; spectral data
172
Hokbusine A
C3ZH45N0,1; amorphous, [.ID +11.4” (MeOH); A . curmichaeli, A . juponicum; spectral and chemical data
51,173
“OBz
OH
OCH3
Hokbusine B
C ~ Z H I ~ N O183-l85"C, ,; [a],--; A . curmichueli; spectral and chemical
I 73
data
15n-Hydroxyneol ine (Fuzil i n e , Senbusine C )
c-
C24H39N07;206.5-207"C, [.ID +19.3" (CHC13),A. japonicum; A . ibukiense; A . carmichaeli; spectral and chemical data
132,163, 174-1 78
C23H3sN07;243-246°C (dec), [.ID +71.7" (MeOH); A . ibukiense; spectral and X-ray data
163,179
OH
E OCH3 I bukinami ne
OCH3
(continues)
TABLE 111 (Continued)
Compound
lsoaconitine
C2SH49NO,,; 144-146"C, [a]o-; A. deluvyi; spectral and chemical data
OH
6CH3
Ref. 128.155, 156
0
As
Karasamine
Physical characteristics; source; means of identification
=
-!@OCH,
112"C, [(Y]D-; A . karukolicum; spectral data
C23H37N04; 110-
143
Lipoaconitine
Oil, [aID+6.0” (CHC1,); A . carmichaeli;
‘‘3
131,133
spectral and chemical data
OH
i= a mixture
o f linoleoyl, palmitoyl, oleoyl, stearoyl, and linolenoyl (64:20:16:trace:trace)
Lipodeoxyaconitine
OCH3 R =
Oil, [aID+12.4“ (CHC1,);A. carmichaeli; spectral and chemical data
131,133
a mixture o f linoleoyl, palmitoyl, oleoyl, stearoyl, and 1 inolenoyl (61:19.5:19.5:trace:trace) (continues)
TABLE 111 (Continued)
Compound
Physical characteristics; source; means of identification
Ref.
~~~~~
Lipohypaconitine
Oil, [a],,+13.5" (CHC1,); A . carmichaeli; spectral and chemical data
131,133
Oil, [a],, +13.8" (CHCI,); A. carmichaeli; spectral and chemical data
131,133
OH
+ VI P
OCH3
R = a m i x t u r e o f 1 inoieoyi I palmitoy1 , oleoyl , stearoyl , and 1 inol enoyl (58:19: 23: trace: trace)
Lipomesaconitine
OCH3
R
=
a m i x t u r e o f linoleoyl, palmitoyl, oleoyl, s t e a r o y l , and linolenoyl (57:32:ll:trace:trace)
Liwaconitine
C4,HS3NO,,;201--202.5"C,1 ~ 1 .t133.3" 1~
146
(CHC1,); A . forresrii; spectral data and
correlation with bikhaconine
Methyl oyrnnaconi t i ne
C35H49N09; amorphous, [a]D-; A. gymundrum; spectral data
I72
8-0-Methyl t a l a t i z a m i n e
CZ5H4,N0,;amorphous, [ a ] D -4" (CHC13);A . columbianum; spectral data
134,144
and correlation with talatizamine
OCH3
(continues)
TABLE I11 (Continued)
Compound Monticamine
Physical characteristics; source; means of identification
Ref.
C ~ ~ H ~ T N163-164"C, OS; [a]D-; A . monticola; spectral and chemical data
180
CzZHi3N06; 166-167"C, [.ID-; A . monticola; spectral and chemical data
I80
1
Monticol ine
Nagarine
(Crassicaulisine)
CZ4H39N07;
1YO-19l0C,[ a ] D +20.3"
(CHCI,); A . nagarum; A. crassicaule; spectral data and correlation with delphisine and 15P-hydroxyneoline
128,148,174, 181,182
Nevadenine
C,,H3,N05 ;resin, [aID-; A . nevadense;
183
spectral data and correlation with isotalatizidine
Nevadensine
C23H3sN06;resin, [aID-; A . nevadense; spectral data and correlation with virescenine
183
OCH3 Pendul i n e
166-167"C, [a]D-; A . pendulum; A . japonicum; spectral data and correlation with jesaconitine and chasmanine
C34H47N09;
15,128,I29
(continues)
TABLE 111 (Conrinued)
Compound
Polyschistine A
Physical characteristics; source; means of identification C3hH51NOll;265-266“C, [a]D-;
Ref. 184
A . polyschistum; spectral data
OCH3
Polyschistine B
OCH3
C ~ ~ H ~ 1;~ 182-185”C, NOI [a]D-; A . polyschistum; spectral data
184
Polyschistine C
C31H41NOI~; amorphous, [elD-; A . polyschistum; spectral data
284
C32H52N2011 ; amorphous, [.ID +22.4” (CHCI,); A . barbarum; spectral data and correlation with septentrionine
141
OCH3
Puberaconidine
O-c=o
-
0
aNH-c (continues)
TABLE III(Conrinued)
Cornpou nd Puberani ne
Physical characteristics; source; means of identification
[.ID
Ref.
+16.6"
141
CZ5H3,NOS ; 124.5-127"C, [ L Y ] D+251" (MeOH); A . yesoense; spectral and chemicai data
106
C32H44NZ09; amorphous,
I
c=o
@- N H C O C H ~ Pyrochasman ine
Ranaconi t i n e
G ~ H ~ ~ ;N132-134"C, z O ~ [a]D+33.2" (CHCI,); A . ranunculaefolium;
128,141,
18.5
A . finetianurn; A . barbatum; spectral and chemical data
Scaconi ne
C2,H,,NOS; amorphous, [aID-; A . scaposum; spectral and chemical data
I52
OH
(continues)
TABLE I11 (Conlinued) Compound Scaconi t i ne
Physical characteristics; source; means of identification
Ref.
C33H46N20,;amorphous, [a]D-; A . scuposum; spectral data
152
C,,H,,NO,; amorphous, [@ID-; A . carmichueli; A . ibukiense; spectral data
132,163
0-c=o
NHCOCH3
Senbusine A
OCH3
Senbusine B
C23H37N06;amorphous, [a],--; A . carmichaeli; spectral data
I32
C38Hs4NZ0,1 ; 123-125"C, [a],,+21.2" (CHC13);A . septentrionale; A . barbaturn; spectral and chemical data
140,141
OCH3
Septentrionine
c W m
0-c-0
(continues)
TABLE 111 (Continued)
Compound Takaonine
Physical characteristics; source; means of identification
Ref.
C ~ ~ H ~ ~ N 0 ~ , 1 8 6 - 1 8 7 . 5 " C+52" , (CHCI,); A . japonicum; A . ihukiense; spectral and chemical data
130,163
CZ3H37N07; 174-175"C, [.ID +61.2" (CHCI,); A . japonicum; spectral and chemical data
130
Y
P ch
OCH3 Takaosamine
,
OCH3
'ZH5
a
i
m
u I
m I u 0
n t W .? t
m
m
I
u
m I
V
: i n :
; !
B
N 0
;r
L
=.
P-
.,.-
L
0
165
m I
0
o=v
m
TABLE IV CATALOG OF CzoDITERPENOID ALKALOIDS FROM Aconitum SPECIES
Compound
Physical characteristics; source; means of identification
Ref ~
1 -Acetyll uci cul ine
OH
12-Acetylnapelline N-oxide OAc
C24H35N04;amorphous, [.ID -; A . yesoense; spectral data and
106
C&,sNOs ; 235°C [.ID -; A . karakolicurn; spectral data
154
W
E
.r C
01 0 C
0 VI
W
+J
h
F
5
0
Y-
o\
Y-
x 1
167
TABLE IV (Continued) Physical characteristics; source; means of identification
Compound
Dehydrolucidusculine
Ref.
C24H33N04; 186-189"C, [(Y]D +2.6" (EtOH); A. yesoense; spectral data and correlation with lucidusculine
I90
C22H,,N0,; amorphous, [.ID -; A . finetianurn; spectral and chemical data
I91
C21H29NOZ; 236-238"C, [.ID -143.7" (EtOH); A . finetianurn; spectral data
191
OAc
1-Dehydrosongorine
n
Fineti anine n
Episcopalidine
0
I62
X-ray data
Guan-fu base A :OH
AcO
C30H3,N06;21O-22O0C, [ a ]-80.0" ~ (CHCI,); A . episcopale; spectral and
+49" (CHCI,); C24H3jN06; 199"C, A . bullatijolium; A . koreanum; spectral and chemical data and correlation with guan-fu base G
,.
Guan-fu base G ,OAc
C26H33N07; 178"C, [.ID +97.3" (CHC1,); A. bullatifolium; A . koreanum: spectral and chemical data; X-ray analysis
128,I92
(confinues)
TABLE IV (Continued) Physical characteristics; source; means of identification
Compound Hanamisine
9-Hydroxynominine
Ignavine
BzO..
OH
Ref.
C,,H,,NOs; 124-127"C, [.ID +122.6" (MeOH); A . sanyoense; spectral data
193
C2,HuNO,; 287-291°C (dec), [.ID +68.5" (MeOH); A . ibukiense; spectral data
163
C,7H31N05; A . japonicum; A . carmrchaeli; A . ibukiense; structure revised on the basis of X-ray analysis
163,173, 194,195
Jynosi ne
C24H3sN03; 254-256°C (dec, perchlorate), [a],,-37.4" (CHCI,);
69
A . jinyangense; spectral data and correlation with denudatine
HO
Nomi ni ne
Ryosenamine e
C20H27NO;251-254"C, [@]a +53.4"; A . sanyoense; spectral data and correlation with kobusine
I 96
CZ7H31N04; 213-215"C, [.ID +96.8" (MeOH); A . ibukiense; spectral data and correlation with ryosenaminol
163,179
(continues)
TABLE IV (Continued) Compound
Ryosenaminol
Sadosine
Physical characteristics; source; means of identification
Ref
C20HZ7NO3;287-290"C, [(Y]D +66.8" (MeOH); A . ibukiense; spectral and X-ray analysis
163,179
CZ7H31NO6; 222-224"C, [cY]D+53.1" (MeOH); A . japonicum; spectral and X-ray analysis
195,I97
Sanyonamine
C20H27N02;276-278"C, [aID+ 62.9";
I98
A . sanyoense; spectral and X-ray analysis
Talatisine
C,,H,7N0, ; [a],,-; A . talussicum;
199
X-ray data
Tanwusine
CzoH27N03, 144-15OoC, [.ID A . tanguticum
-;
97
174
TAKASHI AMIYA AND HIDE0 BANDO
Acknowledgments We wish to express our thanks to Mr. Koji Wada, who collected many references.
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178
TAKASHI AMIYA AND H I D E 0 B A N D 0
and Biological Perspectives,” (S. W. Pelletier, ed.), Vol. 2, Chap. 5. Wiley, New York, 1984. 127. X. Chang, H. Wang, L. Lu, Y. Zhou, and R. Zhu, Acta Pharm. Sinica 16,474 (1981). 128. Y. Zhu and R. Zhu, Heterocycles 17, 607 (1982). 129. L. Liu, H . Wang, and Y. Zhu, Acta Pharm. Sinica 18, 39 (1983). 130. S . Sakai, H. Takayama, and T. Okamoto, Yakugaku Zasshi 99, 647 (1979). 131. I. Kitagawa, M. Yoshikawa, 2 . L. Chen, and K. Kobayashi, Chem. Pharm. Bull. 30, 758 (1982). 132. C. Konno, M. Shirasaki, and H. Hikino, J . Nat. Prod. 45, 128 (1982). 133. I. Kitagawa, Z. L. Chen, and M. Yoshikawa, Yakugaku Znsshi 104, 848 (1984). 134. V. Boido, 0. E. Edwards, R. J. Kolt, and K. K. Purushorthaman, Can. 1. Chem. 62, 778 (1984). 135. H.-C. Wang, D.-2. Zhu, Z.-Y. Zhao, and R.-H. Zhu, Acra Chim. Sinica 38,475 (1980). 136. L. V. Beshitashvill, M. S. Yunusov, M. R. Yagudov, and S. Y. Yunusov, Khim. Prir. Soedin., 665 (1980). 137. S. W. Pelletier, N. V. Mody, C. S. Ying, Heterocycles 19, 1523 (1982). 138. H. Takayama, M. Ito, K. Koga, S. Sakai, and T. Okarnoto, Heterocycles 15,403 (1981). 139. S . Sakai, N. Shinma, S. Hasegawa, and T. Okamoto, Yakugaku Zasshi 98, 1376 (1978). 140. S. W. Pelletier, R. S. Sawhney, and A. J. Aasen, Heterocycles 12, 377 (1979). 141. Y. De-quan and B. C. Das, Planta Med. 49, 85 (1983). 142. J. Wang and G. Han, Acta Pharm. Sinica 20, 71 (1985). 143. M. N. Sultankhodzhaev, M. S. Yunusov, and S. Y. Yunusov, Khim. Prir. Soedin., 660 (1982). 144. S. W. Pelletier, S. K. Srivastava, B. S. Joshi, and J. D . Olsen, Heterocycles 23, 331 (1985). 145. F.-P. Wang and Q.-C. Fang, Planta Med. 42, 375 (1981). 146. C.-H. Wang, D. Chen, and W.-I. Sung, Planta Med. 48, 55 (1983). 147. D. Chen and W. Song, Acta Bot. Yunnunica 26, 82 (1984). 148. F.-P. Wang and Q.-C. Fang, Planta Med. 47, 39 (1983). 149. F.-P. Wang and X. Liang, Planta Med. 51, 443 (1985). 150. S. Jiang, Y. Zhu, Z. Zhao, and R. Zhu, Acta Pharm. Sinica 18, 440 (1983). 151. N. Mollov, M. Haimova, P. Tscherneva, N. Pecigargova, I. Ognjanova, and P. Panov, C. R. Acad. Bulgare Sci. 17, 251 (1964); Chem. Abstr. 61, 1234g (1965). 152. X. Hao, S. Chen, and J . Zhou, Acta Bot. Yunnanica 7, 217 (1985). 153. S. Chen and Y. Liu, Acta Bot. Yunnanica 6, 338 (1984). 154. M. N. Sultankhodzaev, L. V. Beshitaishvili, N. S. Yunusov, and S. Y. Yunusov, Khim. Prir. Soedin. 479 (1978). 155. C. J . Hung, Acta Chim. Sinica 21, 332 (1975). 156. C. J. Hung, H . S . Ha, and C. Y. Lee, Acta Chim. Sinica 23, 131 (1977). 157. V. N. Aiyar, P. W. Codding, K. A . Kerr, M. H. Benn, and A . J . Jones, Tetrahedron Lett., 483 (1981). 158. E. F. Ametova, M. S. Yunusov, and V. A. Telnov, Khim. Prir. Soedin., 504 (1982). 159. H. Bando, Y. Kanaiwa, K. Wada, T. Mori, and T. Amiya, Heterocycles 16, 1723 (1981). 160. T. Mori, H . Bando, Y. Kanaiwa, K. Wada, and T. Amiya, Chem. Pharrn. Bull. 31,2884 (1983). 161. C. Wang, J. Chen, Y. Zhu, and R. Zhu, Acta Pharm. Sinica 19, 445 (1984). 162. F.-P. Wang and 0 . - C . Fang, Acta Pharm. Sinica 18, 514 (1983). 163. S. Sakai, I. Yamamoto, K. Hotoda, K. Yamaguchi, N . Aimi, E. Yamanaka, J . Haginiwa, and T. Okamoto, Yakugaku Zasshi 104, 222 (1984). 164. Y.-Q. Lin and Q.-T. Chang. Pharm. Bulf. (China) 17, 243 (1982).
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C. Wei-shin and E. Breitmaier, Chem. Ber. 114, 394 (1981). C.-R. Yang, X.-J. Hao, D.-Z. Wang, and J . Zhou, A c f a Chim. Sinica 39, 147 (1981). C. Wang, D. Chen, and W. Song, Chinese Traditional Herbal Drugs 14, 5 (1983). S. W. Pelletier, C. S. Ying, B. S. Joshi, and H . K. Desai, J . Nut. Prod. 47, 474 (1984). D. Chen and W . Song, Acta Chim. Sinica 41, 843 (1983). X.-J. Hao, S.-Y. Chen, and J . Zhou, Acta Bot. Sinica 27, 504 (1985). H . Zhang, Y . Zhu, and R . Zhu, Acta Bot. Sinica 24, 259 (1982). S.-H. Jiang, S.-H. Gus, B.-N. Zhou, S.-X. Wang, Y.-P. Sheng, and L.-J. Ji, Chinese Traditional Herbal Drugs 16, 11 (1985).. 173. H. Hikino, Y. Kuroiwa, and C. Konno, J . Nut. Prod. 46, 178 (1983). 174. H. Takayama, S. Hasegawa, S. Sakai, J. Haginiwa, and T. Okamoto, Yukugaku Zasshi 102, 525 (1982). 175. H . Takayama, S. Hasegawa, S. Sakai, J. Haginiwa, and T. Okamoto, Chem. Pharm. Bull. 29, 3078 (1981). 176. D. Chen, H . Li, and W . Song, Chinese Traditionat Herbal Drugs 13, 481 (1982). 177. S. W . Pelletier, N. V. Mody, K. I. Varughese, and C. S. Ying, Heterocycles 18, 47 (1982). 178. J. Wang and G. H a n , Actu Pharm. Siniza 20, 71 (1985). 179. S. Sakai, K. Yamaguchi, I. Yamamoto, K. Hotoda, T. Okazaki, N. Aimi, J. Haginiwa, and T. Okamoto, Chem. Pharm. Bull. 31, 3338 (1983). 180. E. F. Ametova, M. S. Yunusov, V. E. Bannikova, N . D. Abdullaev, and V. A . Telnov, Khim. Prir. Soedin., 466 (1981). 181. N. V. Mody, S. W . Pelletier, and C. S. Ying. Heterocycles 17, 91 (1982). 182. S. W. Pelletier, N. V. Mody, and C . S. Ying, Heterocycles 19, 1523 (1982). 183. A . G . Gonzhlez, G. de la Fuente, T. Orribo, and R . D . Acosta, Heterocycles 23, 2979 (1985). 184. H. Wang, A . Lao, Y . Fujimoto, T. Tatsuno, Heterocycles 23, 803 (1985). 185. S. W. Pelletier. N. V. Mody, A . P. Venkov, and N. M. Mollov, Tetrahedron Lett., 5045 (1978). 186. C.-R. Yang, X.-J. Hao, and J . Zhou, Acta Bog. Yunnanicu 1, 41 (1979). 187. S.-Y. Chen, Acta Chim. Sinicu 37, 15 (1979). 188. C. Wang, D. Chen, and W . Song, Chinese Traditional Herbal Drugs 14, 5 (1983). 189. Zhamierashvili, R . A . Telnov, M. S. Yunusov, and S. Y. Yunusov, Khim. Prir. Soedin., 733 (1980). 190. K. Wada, H . Bando, and T. Amiya, Heterocycles 23, 2473 (1985). 191. L.-M. Tian, Y.-M. Cheng, B.-Y. Chen, a n d P . Liu, and B.-N Zhou, Chinese Tradirionai Herbal Drugs 16, 79 (1985). 192. J . Liu, H. Wang, Y. Gao, and R . Zhu, Chinese Traditional Herbal Drugs 12, 97 (1981). 193. T. Okamoto, H . Sanjoh, K. Yamaguchi, Y. Iitaka, and S. Sakai, Chem. Pharm. Bull. 31, 1431 (1983). 194. T. Okamoto, H . Sanjoh, K. Yamaguchi, A. Yoshino, T. Kaneko, Y. Iitaka, and S. Sakai, Chem. Pharm. Buit. 30, 4600 (1982). 195. H. Sanjoh, T. Okamoto, and S sakai, Yakugaku Zasshi 103, 738 (1983). 196. S. Sakai, I. Yamamoto, K. Yamaguchi. H. Takayama, M. Ito, and T. Okamoto, Chem. Pharm. Bull. 30, 4579 (1982). 197. T. Okamoto, M. Sanjoh, K. Yamaguchi. Y litaka, and S. Sakai, Chem. Pharm. Bull. 31, 360 (1983). 198. S . Sakai, K. Yamaguchi, H. Takayama, I . Yamamoto, and T. Okamoto, Chem. Phurm. Bull. 30, 4576 (1982). 199. Z . Karimov and M. G . Zhamierashvili, Khim. Prir. Soedin., 335 (1981).
165. 166. 167. 168. 169. 170. 171. 172.
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-CHAPTER 4-
PROTOPINE ALKALOIDS MASAYUKI ONDAAND HIROSHI TAKAHASHI School of Pharmaceutical Sciences Kitasato University Tokyo, Japan
I. Introduction 11. Occurrence 111. Structure A . Izmirine B. Protothalipine C. Thalictricine D. (-)-Oreophiline E. Protopine Methohydroxide F. . Protopine N-Oxide IV. Conformation and Spectroscopy A. Conformation in the Solid State B. Conformation in Solution V. Synthesis A. Synthesis from Tetrahydroprotoberberines B. Synthesis from Phthalideisoquinolines C. Total Synthesis via Benz[d]indeno[l,2-b]azepines VI. Transformation of Protopines to Related Alkaloids VII. Biosynthesis VIII. Callus Culture IX. Pharmacology Addendum References
I. Introduction
The protopines were first covered in Vol. 4 (p. 147) of this treatise in 1954 as a separate chapter. Since then, complementary information on protopines has been reviewed as a group of Papaveraceae alkaloids (Vol. 10, p. 467; Vol. 12, p. 333; Vol. 15, p. 207; Vol. 17, p. 385). The latest supplementary review appeared in 1981 in Volume 18 (p. 217) as a section of a review covering isoquinoline alkaloids. In addition, three reviews (1) on protopines were published in the 1970s. This chapter supplements the previous reviews in this treatise by incorporating recent 181
THE ALKALOIDS, VOL 34 Copyrlght 0 1988 by Academic Press, Inc All rights of reproduction in any form reserved
182
MASAYUKI ONDA AND HIROSHI TAKAHASHI
advances in this field and updating literature citations through mid 1987 as well as by covering valuable earlier data that have not yet been mentioned.
11. Occurrence
The protopines are widely distributed in the families Berberidaceae, Fumariaceae, Papaveraceae, Ranunculaceae, and Rutaceae. Table I covers the period from 1977 to mid 1987 and supplements previous data that appeared in this treatise (Vol. 4, p. 77; Vol. 9, p. 41; Vol. 10, p. 467; Vol. 12, p. 333; Vol. 17, p. 385).
111. Structure
The structures of protopines are characterized by the 7-methyl5,6,7,8,13,14-hexahydrodibenz[c,g]azecinering system containing a 140x0 group, except for one which has a 14-hydroxyl group. (The trivial numbering system is used throughout this chapter.) The benzene rings contain four or five oxygen functions, two or three in ring A and two in ring
1
312 \ y j
10 V
11
C. The variety and the number of substituents in each ring can be confirmed by ions in the mass spectrum arising from retro-Diels-Alder fragmentation (124). The substituted positions can be assigned from the absorption pattern of aromatic protons in the 'H-NMR spectrum. Protopines with a methyl group or oxygen functions at the 13 position are also known. The protopines that have been reported so far in the literature are shown in formulas 1-26. Among them, protopines 6, 7, 8, 18, 24, and 25 have not yet been mentioned in this treatise series. A. IZMIRINE
Izmirine (6), C20H21N05,amorphous, was isolated as a phenolic base [IR (CHC13) : 3540 cm-I (OH)] along with cryptopine (2) and hunnema-
183
4. P R O T O P I N E ALKALOIDS
TABLE I PLANTS AND THEIRPROTOPINE ALKALOIDS Plant Berberiaceae Berberis darwinii stems B. cordaia Wild.
B. frustescens L. B. gracilis Hartw. Nandia dorneslica Fumariaceae Fumaria bella P. D. Sell F. bracteosa Pomel F. capreolata L. F. densiflora DC.
F. gaillardoiii Boiss F. indica (Haussk.) Pugsley F. judaica Boiss
F. macrocarpa Parlatore F. oficinalis F. parvipora Lam. F. rostellata
F. schleicheri Soy-Will F. schrammii F. vaillanfii Papaveraceae Argemone mexicana L. A . orchroleuca Chelidonium japanium Thumb. C. majus Corydalis bulbosa C. cava (L.) Schw. et Koerte C. cheilantifolia Hemsl.
Alkaloid Protopine Allocryptopine, protopine Allocryptopine, protopine Cryptopine, pro topine Protopine Protopine Protopine Protopine Cryptopine, protopine Protopine Protopine Allocryptopine, protopine Protopine Cryptopine, protopine Cryptopine, hunnemanine, izmirine, protopine Cryptopine, protopine Cryptopine, protopine Protopine Cryptopine, protopine Allocryptopine, protopine Allocryptopine, protopine Protopine Protopine Protopine Allocryptopine, protopine Allocryptopine, protopine
Ref.
2 3 4 5 6
7 8 /
9.10 11 12,13 14,15
16,17 18,19
20-23
24 25 26 24,27, 28 29,30 31
32 33,34 35,36 37 38
(conrinues)
184
MASAYUKI ONDA AND IlIROSHI TAKAHASHI
TABLE I (Continued) ~
Plant ~
C. cornuta Royle C. decumbens C. delarayi Franch C. giganta C. gortschakovii Schrenk. C. hendersonii C. ledebouriana Kar et Kir.
C. lineariodes C. lutea (L.) DC. C. maius L. C. marshalliana C. rneifolia Wall. C. ochotensis var. raddeana C. ophiocarpa Hook et Thorn. C. palfida var. speaose Kom. C. paniculigera C. rasea C. remota C. repens C. rutifolia C. saxicola C. sheareri C. slivenesis C. solida (L.) Swarz.
C. stricta Steph C. suavelens C. taliensis Fr. C. tashiroi Makino C. turtschaninovii Yanhusuo
C. vaginanus C. yanhuso Dicentra macrocapnos Prain D. spectabilis L. D . leptopodium (Maxim.) Fedde Eschscholtzia californica
~~~
Alkaloid
Ref
~~~
Protopine Protopine Protopine Protopine Protopine Protopine Allocryptopine, cryptopine, protopine Protopine Protopine Allocr yptopine Pro topine Protopine Protopine Allocryptopine, protopine Protopine Protopine Protopine Protopine Protopine Allocryptopine, protopine Protopine Protopine Allocryptopine, protopine Allocryptopine, protopine Protopine Allocryptopine, protopine Protopine Protopine Allocryptopine, protopine Protopine Protopine Protopine Protopine Protopine Allocryptopine, protopine
39 40 41 42 43,44 45 46,47
48,49 50 51 42 52 53 54,5 56 57 42 42 58 59 60 61 62
63.64 49,65,66 67 68 69 70,71 42 72 39 73 74,75 76
185
4. P R O T O P I N E ALKALOIDS
TABLE I (Continued) Plant
E. californica Cham. E. douglusii (Hook et Am.) Walp. E. glauca Greene Glaucium corniculatum
G. corniculatum (L.) Rudolph. subsp. refractum (NAB) Cullen G. jimbrilligerum
G. flavum Grantz G. grandiflorum var. torguatum
C. oxylobum Boiss er Buhse C. pulchrum Staf. G. vitellium Boiss et Buhse
G. vitfinum Boiss et Buhse Hunnemania fumariaefolia Sweet Hypecoum erectum
H . lactiflorum H . leptocarpum H . ponticum Mowt.
H . procumbens Macleaya cordata (Wild.) R . Br. Meconopris rudis Prain Pupaver albiflorum
P. armeniacum P. atlaniicum Ball
Alkaloid Protopine Allocryptopine, protopine Allocryptopine, protopine Allocryptopine, protopine Allocryptopine Allocryptopine, protopine Allocryptopine, protopine Allocryptopine, cryptopine, protopine Allocryptopine, protopine Protopine Allocryptopine, protopine Protopine Allocryptopine, hunnemanine, protopine Allocryptopine, protopine Allocryptopine, protopine Protopine Allocryptopine, cryptopine, protopine Hunnemanine, 13-oxoprotopine Allocryptopine, protopine Allocryptopine, protopine Allocryptopine, protopine Cryptopine Cryptopine, muramine, pro topine
Ref 76,77 77 77 78,79
80 81 82-84 85,86
87,88 89 9# 91
90 92, 93
94 94 95 96
97
98 99 100 101
102
(continues)
186
MASAYUKI ONDA AND HIROSHI TAKAHASHI
TABLE I (Continued) Plant
P. hracteatum P. curviscapum Nabk P. decaisnei Hochst P. glaucum Boiss et Hauskn. P. kernevi Hayek
P. lateritium P. lecoguii Lamotte protopine P. lisae P. litwinowii Fedde ex Bornm.
P. macrostomum Boiss et Huet P. oreophilum P. pavonium Schrenk P. pseudo-orientale (Fedde) Medw. P. rohoeas L.
P. tatricsim (Nyar.) Ehrend P. tauricola Stylophorum diphyllum (Michx.) Nutt. Ranunculaceae Thalictrum revolutum T. revolutum DC. T. rugosum Ait. Rutaceae Xanthoxylum integrifoliolum (Merr.) Merr. (Fagara integrifoliolum Merr.) X . nitidum (Roxb.) DC.
Alkaloid
Ref.
Muramine, protopine Allocryptopine, protopine Protopine Allocryptopine, protopine Allocryptopine, cryptopine, protopine Protopine Allocryptopine, cryptopine, protopine Protopine Allocryptopine, cryptopine Protopine Allocryptopine, protopine Allocryptopine, protopine Allocryptopine, protopine Alocryptopine, protopine Allocryptopine, pro topine Cryptopine, protopine Allocryptopine, cryptopine, protopine
103-105 106
Allocryptopine Allocryptopine Protopine
119 120 121
Allocryptopine
122
Allocryptopine
123
107 102
I 0s
109 100
110 Ill
106 112,113 114 115 116 93,106, 117 108 101 118
187
4. PROTOPINE ALKALOIDS
1
R ' + R'= CH,
, R2=Me
allocryptopine
hunnemanine
u-fagarine
izrnirine protothalipine
p-, v-homochelidonine
thalictricine vaillantine
cryptopine cryptocavine thalisopyrine muramine cryptopalmatine protopine I
RO
corydinine
10 R r M e 1 1 R + R = CH,
fumarine
fagarine II pseudoprotopine
rnacleyine
12
R ' + R ' = R'+ R*=CH,
13
R'. R ' = C H ,
14
R'= Me
15
R ' + R'=R'. R >= C H ,
,
,
R'=Me
R'+ R'= CH,
coulteropine
17
1-methoxycryptopine
R ' * R ' = C H , , R'=Me
18
(+)-corycavamine
(+)-
,
R2:H
(+)-ochrobirine (+)-13-hydroxyprotopine
(?)-form = corycavine 16
R ' + R ' =CH,
1-rnethoxyallocryptopine
and ( i ) - c o r y c a v i d i n e
R'=R'.M~
(-)-areaphiline
188
MASAYUKI ONDA AND HIROSHI TAKAHASHI
OR' OR'
19
R'= H , R'= R'= Me
20
R' = O M e , R'
alipinone
24
protopine methohydroxide
25
protopine N - o x i d e
13-oxornuramine +
R'=cH,, oreonone
R'=M~ 21
R'=H , R ' + R ~ . c H , , 13-oxoa11ocryptopine R' = M~
22
R'=H
,R'=M~,
13-oxocryptopine
R3 * R'=CH,
23
R'=H
,
R ' * R'=
13-oxoprotopine
a:>
R 3 + R' =CH,
26
dihydroprotopine
nine (5) from Fumaria parviJEora by Shamma et al. (23). The 'H-NMR spectrum (CDCl,) of 6 revealed the presence of a methoxyl (6 3.90), an N-methyl (6 1.87), and a methylenedioxy group (6 5.94) in addition to four aromatic protons [6 7.01 (s), 6.75 (s), 6.71 (d, J = 7.9 Hz), and 6.67 (d, J = 7.9 Hz)]. Treatment of 6 with diazomethane gave 2, suggesting the presence of a hydroxyl group at either the 2 or 3 position. The 3-hydroxyl group was assigned by comparison of the IH-NMR chemical shifts due to the C-4 protons in 2 and 6 (A- = 0.08 ppm).
B. PROTOTHALIPINE Protothalipine (7), C21H25N05,mp 195-196°C (dec) (MeOH), was isolated as a phenolic base [IR (CHC13) : 3540 cm-' (OH)] from Thalictrum rugosum by Wu et al. (125). Treatment of 7 with diazomethane afforded muramine (3). The 'H-NMR spectrum (CDC1,) showed the presence of a hydroxyl (6 4.07, exchangeable with D20), three methoxyl (8 3.90), and an N-methyl group (6 1.87) in addition to four aromatic protons (6 7.05-6.68). Mass fragment ions ( m / z 222 and 150) arising from retro-Diels-Alder fragmentation (124) indicated a possible location of the hydroxyl group at either the 9 or 10 position. The hydroxyl group at C-9 was confirmed by aromatic solvent-induced shifts (ASIS) experiments in the 'H-NMR spectrum. The ASIS using pyridine indicated
4. P R O T O P l N E ALKALOIDS
189
M' , m / z 371 (5.6%)
that the C-8 protons (A = +0.25 ppm) and the 10-methoxyl protons (A = -0.25 ppm) in 7 are considerably shifted in comparison with those in 3. C. THALICTRICINE Thalictricine (8), C20H21N05, mp 261-263°C '(dec) (MeOH), was isolated as a phenolic base [IR (CHC13) : 3640 cm-' (OH)] along with allocryptopine (1) from Thalictrum simplex and T. amurense by Yunusov et al. (126). Treatment of 8 with diazomethane provided 1. The pattern of mass fragmentation ( m / z 206 and 150) demonstrated that a methylenedioxy group is located on ring A and that a hydroxyl and a methoxyl group occur on ring C (124). Since it was confirmed that 8 is different from hunnemanine (5) by comparison of the physiocochemical properties, it was concluded that 8 is an isomer of 5 containing the 9-methoxyl and 10-hydroxyl groups on ring C. D. ( -)-OREOPHILINE
(-)-Oreophiline (IS), CzzHzsN06, mp 177-178°C (MeOH), [a]'," -254 ? 5" (1, CHC13), was isolated along with protopine (4) from Papaver oreophilum and P. feddei by Pfeifer and Mann (127). The presence of three methoxyl, a methylenedioxy, and an N-methyl group was confirmed by means of chemical analysis and mass spectroscopy. The structure 13-methoxyallocryptopine was tentatively assigned to 18 by comparison of spectral properties with those of protopines.
E. PROTOPINE METHOHYDROXIDE Protopine methohydroxide (24), C21H23N06,mp 231-233"C, was isolated as a quaternary base [IR (KBr) : 3360 cm-' (OH)] along with protopine (4) from Fumaria indica by Satish and Bhakuni (128). The
190
MASAYUKI ONDA AND HIROSHI TAKAHASHI
‘H-NMR spectrum (CF,COOH) of 24 revealed the presence of two methylenedioxy (6 5.84 and 5.60) and two N-methyl groups (8 2.73 and 2.68) in addition to four aromatic protons [S 7.08 (d, J = 9 Hz), 6.79 (d, J = 9 Hz), 6.47 (s), and 6.32 (s)]. The structure of 24 was confirmed to be protopine methohydroxide by comparison of the ‘H-NMR data with those for 4. F. PROTOPINE N-Oxide Protopine N-oxide (25), CzoH19N06,mp 144-145°C (dec) (Me,COMeOH), was isolated along with 1 and 4 from Bocconia cordatu by Takao et al. (3).The ‘H-NMR spectrum (CDCl,) of 25 suggested the presence of two methylenedioxy (6 6.07 and 6.02) and an N-methyl group (6 3.16) in addition to four aromatic protons [6 7.23 (d, J = 7.9 Hz), 7.13 (s), 6.99 (d, J = 7.9 Hz), and 6.77 (s)] which are similar to those of allocryptopine N-oxide. Conclusive structure proof was obtained by direct comparison with an authentic sample prepared by oxidation of 4 with m-chloroperbenzoic acid.
IV. Conformation and Spectroscopy A. CONFORMATION I N THE SOLIDSTATE
Hall and Ahmed (129) reported an X-ray analysis of cryptopine (2) and protopine (4). It was shown that their crystal structures adopt the most stable conformations with following geometrical features. (1)The carbonyl group is at an angle of 39 t 2” out of the plane of ring A . This is responsible for a high-frequency shift of the carbonyl group in the IR spectrum owing to reduced conjugation. (2) The internuclear distance between the nitrogen atom and the carbonyl carbon is 2.57 I+_ 0.01 A, and the nitrogen lone pair is directed toward the carbonyl carbon. It is anticipated that the transannular (“amide-type”) interaction exists between these atoms and causes a low-frequency shift of the carbonyl group (130). The conformation of 4 in the solid state can be shown as the Dreiding model drawing 4a on the basis of the X-ray data (129) (see below). Onda et al. (131) investigated the conformations of allocryptopine (1) and 4 by means of spectroscopic studies. The difference = -6 cm-’) in carbonyl frequency between 4 (1654 cm-’, KBr) and acetopiperone (27) (1660 cm-l, KBr) suggested that the transannular inter-
191
4. PROTOPZNE ALKALOIDS
oO-comc
'0-