THE ALKALOIDS Chemistry and Pharmacology VOLUME 38
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THE ALKALOIDS Chemistry and Pharmacology VOLUME 38
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THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi National Institutes of Health Bethesda, Maryland
VOLUME 38
Academic Press, Inc. Harcourt Brace Jovanovich, Publishers San Diego New York Boston
London
Sydney
Tokyo
Toronto
@
This book is printed on acid-free paper.
COPYRIGHT 0 1990 BY ACADEMIC PRESS, INC. All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.
ACADEMIC PRESS, INC. San Diego, California 92101
United Kingdom Edition published by ACADEMlC PRESS LIMITED 24-28 Oval Road. London NW 1 7DX
LIBRARY OF CONGRESS CATALOG CARD NUMBER:
ISBN 0-12-469538-8
(alk. paper)
PRINTED IN THE UNITED STATES OF AMERICA 90 91
92 93
9 8 7
6
5
4
3 2
I
50-5522
CONTENTS
CONTRIBUTORS ....................................................................................... PREFACE................................................................................................
vii ix
Chapter 1 . Ergot Alkaloids AND TOSHIKOKlGUCHl ICHlYA NINOMIYA
I . Introduction ..................................................................... I1 . New Alkaloids ............................................................................... 111. Synthesis ...................................................................................... IV . Conformational Studies ............................................... V . Biosynthesis .................................................................................. VI . Pharmacological Properties of Related Compounds ............................... References ................................................................ ....
1
2 20 124 130
142 148
Chapter 2 . Spirobenzylisoquinoline and Related Alkaloids GABORB L A S K 6 I . Introduction .................................................................................. I1 . Occurrence and Structure Elucidation of Spirobenzylisoquinoline Alkaloids I11 . Synthesis of Spirobenzylisoquinoline Alkaloids .................................... IV . Synthesis of Indenobenzazepine Alkaloids .......................................... V . Miscellaneous Transformation Reactions ............................... V1. Enzymatic Transformations .............................................................. VII . Biosynthesis of Spirobenzylisoquinoline Alkaloids ................................ References ....................................................................................
157 I59 184 203 206 215 218 219
Chapter 3. Purine Alkaloids ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARV
I . Introduction ........ ................................................. I1 . Occurrence............................................................... 111. Isolation and Detection .................................................................... IV . Purine Alkaloids from Plants ......................... V . Purine Bases from Transfer RNAs of Plants and Animals ...................... VI . Purine Alkaloids from Animals ... ............................................... V
226 227 228 229 249 254
vi
CONTENTS
V11. Nucleoside Antibiotics and Related Compounds from Microorganisms. VIII. Synthesis of Purine Bases ................................................................ IX. Spectral Properties of Purine Alkaloids ...................... ............... X. Biological Activity of Purine Bases .......................................... References ....................................................................................
267 280 304 311 313
CUMULATIVE INDEX OF TITLES................................................................ INDEX ...................................................................................................
325 33 I
CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors’ contributions begin.
ICHIYANINOMXYA ( I ) , Kobe Women’s College of Pharmacy, Kobe, Japan TOSHIKOKIGUCHI( I ) , Kobe Women’s College of Pharmacy, Kobe, Japan GABOR BLASKO (157), EGIS Pharmaceuticals, Budapest H-1106, Hungary ATTA-UR-RAHMAN (225), H. E. J . Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan MUHAMMAD IQBALCHOUDHARY (225), H. E. J . Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan
vii
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PREFACE
Ergot alkaloids, because of their biological activities, represent an important group of the indole alkaloids, and useful medical applications have been found for several of them. At the same time, LSD, also a member of this group of indole alkaloids, is one of the most potent hallucinogens known. The first review on ergot alkaloids appeared in 1965 in Volume 8 of this series; it was followed by a second review in 1975 in Volume 15. Both reviews focused on isolation and structure determination and included a discussion of pharmacological properties. The third review in this volume focuses heavily on synthesis, which has been mostly accomplished since 1974. Included is a discussion of some novel drugs of this alkaloidal series. Spirobenzylisoquinoline alkaloids, when first discussed in 197 1 in Volume 13 of this series, comprised seven alkaloids. In the meanwhile, this group of alkaloids has grown in number to 38, and these are presented here with structures and details of their synthesis. Purine alkaloids are not derived from amino acids and are for this reason often not included among the alkaloids. The most important representatives are coffein, theophylline, and theobromine from coffee, thea, and cacao, respectively, and are consumed in huge quantities. The chemistry of purine alkaloids, their spectral properties, and their pharmacological effects are discussed in this series for the first time. Once again, without the help of serious and devoted collaborators, this volume could not have been published. Arnold Brossi National Institutes of Health
ix
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-CHAPTER -1
ERGOT ALKALOIDS ICHIYANINOMIYA A N D TOSHIKO KIGUCHI Kobe Women's College of Phurmucy Kobe. Jupim
I. Introduction
............................
11. New Alkaloids ...................................................................................
A. Background ................................... B. New Alkaloids ............................................................................. C. Classification of Ergot Alkaloids ..................................................... s ..................................................
Total Synthesis of Lysergic Acid .................................................... Total Synthesis of Other Ergoline Alkaloid Total Synthesis of 6.7-Secoergolene Alkaloids ................................... Total Synthesis of Clavicipitic Acid and Aurantioclavine ... Synthesis of Modified Ergot Alkaloids ..... ........................... .......... ... Synthetic Methodology I : Synthesis According to Synthetic Reaction Employed H. Synthetic I . Synthetic Methodology 3: Synthesis of Skeletons of Ergot Alkaloids ..... J. Useful New Synthetic Methods ... IV. Conformational Studies ....................................................................... A. Conformation of 9-Ergolen 9 . Conformation of Ergolines V. Biosynthesis ................................................. ..................................... A. Biosynthesis of Ergolenes €3. Biosynthesis of Peplide Alkaloids ..... ............................................... C. Biosynthesis of Clavicipitic Acid ..................................................... VI. Pharmacological Properties of Related Compounds .................. A. New Semisynthetic Compounds for Therapeutic Uses ........................ B. Central Serotonin Receptors .... ................................. ...................... C. Antitumor and Antimicrobial Activity References .................................................................................. B. C. D. E. F. G.
i
2 2 2 12 20 21 28 38 51 67 75 x5 100
103 I I3 124 124 127 130 131
139 141 142
142 145 147 148
I. Introduction The chemistry of ergot alkaloids was previously reviewed in this treatise by two noted specialists. The first review was written in 1965 ( I ) by one of the pioneers, Professor Stoll, who played an important role in 1
rnE ALKALOIDS. VOL. 38 Copyright CC 1990 hy Academic Pres. Inc. All rights of reproduction in any form reberved.
2
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
drawing the attention of chemists to this new group of alkaloids, thus firmly rooting ergot alkaloids in the well-cultivated soil of alkaloid research. The second review was written by his successor, Dr. Stadler, who covered the progress of the ergot alkaloids achieved in the period 19641973 (2). In the history and development of research on ergot alkaloids, this decade was particularly important because, as clearly seen from Stadler’s review written in 1975, much of the isolation and structure proposals of new components had been achieved during this period, thus making the section on “New Alkaloids” rich and extensive (2). However, the bulk of synthetic work remained to be done, and only a limited number of papers, including a pioneering work by Woodward and co-workers ( 3 ) , were included in the last review (2), thus leaving major synthetic achievements for the contents of this review. By the end of the 1980s, most ergot alkaloids had been successfully synthesized. Therefore, this third review should play an important role in covering most of the major synthetic works along with isolation of new alkaloids. 11. New Alkaloids
A. BACKGROUND By the time of publication of the second review on ergot alkaloids in 1975 by Stadler, the majority of known alkaloids from ergot fungi had been isolated, mostly in the last decade, and their structures were established and well documented. Relatively few newcomers were introduced thereafter. The main features of the isolation work during this decade may be characterized as follows: establishment of the structures of new types of alkaloids isolated from natural sources different from previously known sources, isolation of new alkaloids as minor components from already known sources, as well as unambiguous determination of the proposed structures of the alkaloids by revision o r confirmation. Thus, it is becoming possible to summarize and classify the ergot alkaloids by their structural features. Therefore, in order to have a better understanding of the research on ergot alkaloids and for the convenience of chemists, the structures of ergot alkaloids so far known are summarized in this section. B. NEW ALKALOIDS New alkaloids which have been isolated and for which structures were proposed in the period 1974-1988 are summarized below.
1.
3
ERGOT ALKALOIDS
I . Epicostaclavine Epicostaclavine (l),an epimer of costaclavine (2) with respect to the configuration of the methyl group at the 8 position, was first synthesized in 1976 by Ninomiya's group (Section III,C,l) as an unnatural isomer of 6,8-dimethylergoline alkaloids, and in 1981 it was isolated from a culture broth of Penicillium gorlenkoanum (4). Further, Sakharovsky and Kozlovsky suggested, based on 'H-NMR study of their conformations, that costaclavine exists in conformation 2 while epicostaclavine has conformation 1 (5).
1 Epicostaclavine
Me
2 costaclavine
The terms fumigaclavine and isofumigaclavine are used for alkaloids having a C/D-trans 6,s-dimethyl ergoline structure with an additional hydroxyl group at the 9 position, therefore consisting of a pair of diastereomers with respect to the configuration of the methyl and hydroxyl groups at the 8 and 9 positions. This group of alkaloids is often found in nature as the acetyl derivatives; they are thus designated as B isomers for 9-hydroxy alkaloids and A isomers for 9-acetoxy derivatives. Since the last review in this treatise ( 2 ) ,the following alkaloids were isolated to fill blank spaces in the list. The first group of alkaloids were designated as fumigaclavines while the alkaloids of the second group were inevitably called isofumigaclavines despite the fact that the former have the 801methyl configuration while the latter have the 8p configuration, thus producing a rather unusual situation concerning the nomenclature of isomers. a. Fumigaclavines A and B. The two blank-filling alkaloids fumigaclavines A (5) and B (4) were newly isolated from Aspergillusfumigatus, of which fumigaclavine B (4) had already been converted to lysergine (3) by Spilsbury and Wilkinson by treatment with soda lime (6). Thus, their structures were proposed as having a &methyl group in the p configuration. This proposed structure was later revised to one having both the 9-
4
dY
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
e
$
-
HN
3 Lysergine
$
(@
HN
HN
4 (R=H) Fumigaclavine B 5 (R=Ac) Fumigaclavine A
6 Fumigaclavine C
hydroxyl and 8-methyl groups in an axial orientation by Bach et al. (7), who reinvestigated the 'H-NMR spectrum. Therefore, the revised structure (4) has 8a-methyl and 9P-hydroxyl groups, thus suggesting that epimerization of 8a-methyl group in fumigaclavine B to the 8P-methyl in lysergine (3) would occur during the process of soda lime treatment. Further, the validity of the revised structure was proven by total synthesis (74), which also established the complete assignment of 'H-NMR peaks of fumigaclavine B (4), thus confirming the structure of the alkaloid by Bach et al. (7). b. Fumigaclavine C. In 1977, a new alkaloid was isolated from the same Aspergillus Jurnigatus strain by Cole et al. (8). From its structural resemblance, this new alkaloid was designated as fumigaclavine C (6). The structure was determined by NMR spectroscopy and X-ray analysis, though full details have not been reported. The structure of fumigaclavine C (6) reflects a biogenetic step of incorporation of an unsaturated fivecarbon side chain, which is commonly seen in some of the indole alkaloids at a relatively later stage of biosynthesis. c. Isofumigaclavines A and B. A pair of alkaloids isomeric to fumigaclavines having a 9-hydroxy-6, 8-dimethylergoline structure with 8P and 9a stereochemistry were also isolated in 1975 from Penicifliurnroquefortii, but their structures were erroneously proposed (9). In 1976, Scott Mc
&$e
HN 7 Isofurnigaclavinc B
8 Isofurnigaclavinc A
1.
ERGOT ALKALOIDS
dCC $le a,b
HN
+
$-yC
HN 9
5
HN 7
4
SCHEME I . Reagents: a, BZHh;b, H,O,, NaOH.
et al. isolated the same alkaloids (10) and determined their structures 7 and 8 by X-ray analysis (I / , 12). Further, their absolute configurations as ( R ) at the 5 position were concluded from the fact that hydroboration of agroclavine (9) afforded an epimeric mixture of fumigaclavine B (4) and isofumigaclavine B (7) as shown in Scheme 1.
3. Agroclavine I and Epoxyagroclavine I In 1982, Kozlovsky et al. (13) isolated two new ergolene-type alkaloids from Penicilfiiirn kapuscinskii, and structures 10 and 11 were proposed from spectral evidence as having a C/D-cis ergolene skeleton with an envelope-type form different from agroclavine (9), which is known to have a C/D-trans ring juncture. The alkaloids were designated as agroclavine 1 and epoxyagroclavine I, respectively. The absolute configuration, how-
10 Agroclavinc I
1 1 Epoxyagroclavinc I
I Mc
6
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
ever, remained to be clarified. The structures have recently been determined by total synthesis of (+)-agroclavine I (10) by three groups (Section III,C,5). The occurrence of these C/D-cis ergolene-type alkaloids suggested the possibility of an alternative biogenetic pathway because all of the previously isolated alkaloids have a C/D-trans ring stereochemistry. 4. 6,7-Secoergolines
Seeds of plants of the family Convolvulaceae have been known as an abundant source of ergot alkaloids as mentioned in the previous review (2). Further, chanoclavine I acid (12) was isolated from Ipomea violacea by Choong and Shough ( 1 4 , whereas Horwell and Verge (15) obtained 6,7-secoagroclavine (13) as a minor component from Claviceps purpurea along with agroclavine (9) and elymoclavine (48). Chanoclavine I aldehyde (14) was isolated from the alkaloid-blocked mutant of ergotoxineproducing Claviceps purpurea ( I6).
12 Chanoclavine I acid
13 6J-Sccoagroclavinc
14 Chanoclavine I aldcliyde
The structure of chanoclavine I acid (12) was unambiguously established by conversion of chanoclavine 1 (15) to this alkaloid (Scheme 2) (14). The structure of 6,7-secoagroclavine (13) was also established by interconversion from agroclavine (9) through intermediate 16 along with N M R evidence (15). Biogenetically, it is more plausible to suggest a pathway in which agroclavine (9) would undergo reductive cleavage to form the seco derivative 13, instead of a presumed route involving oxidation of the gem-dimethyl group to chanoclavine I (15) followed by formation of D ring and then agroclavine (9). The occurrence of chanoclavine I aldehyde (14) suggests a biogenetic pathway of oxidation of chanoclavine I (15) to form 14, which would then undergo cyclization to give agroclavine (9).
5. Rugulovasines In 1969, Abe ef al. ( I 7) isolated two new epimeric alkaloids from Penicillium concuvo-rugulosum,designated as rugulovasines A (17) and B (18).
1.
9
7
ERGOT ALKALOIDS
16
13
SCHEME 2. Reagents: a, Mn02; b, MnO,, NaCN, MeOH; c , I N NaOH; d, Mel; e , Na, Liq NH,; f, EtOCON=NCO,Et.
and proposed the in plane structure. In 1976, Cole e f al. (18) isolated two new components from Penicillium islandicum and called them 8-chlororugulovasines A (19) and B (20). Further, Cole e f al. (19) investigated the four rugulovasines by X-ray analysis of rugulovasine A (17) and thus established their structures. Rugulovasines, which feature a benz[c,dindole skeleton with a spirobutenolide side chain at the 5 position along with a methylamino group at the 4 position, undergo smooth interconversion in polar solvents according t o a mode of reverse Mannich reaction through intermediate 21; they therefore exist in nature only as racemates.
17 ( R = H ) Rugulovasine A 19 (R=CI) 8-Chlororugulovasine A
18 ( R = H ) Rugulovasinc B
21
20 ( R = C I ) 8-Clilororugulovasinc B
Rebek et al. (20) synthesized optically pure rugulovasine A (17) ([a],, L-tryptophan. They employed synthetic 17 for isomerization and racemization experiments and established that racemization of
+ 43") from
8
ICHIYA NlNOMlYA AND TOSHIKO KIGUCHI
' INI
Me
17
SCHEME 3
rugulovasine A (17) was much faster than isomerization to rugulovasine B (18) (Scheme 3). Further, the fact that optically active rugulovasine A (17) was resistant to racemization in nonpolar solvents suggested that the alkaloid exists in vivo as an active form but is vulnerable to racemization during the course of isolation procedures. The occurrence of 8-chlororugulovasines (19 and 20) is the first example of ergot alkaloids containing a chlorine in the molecule. The position of the chlorine was suggested from NMR data, but unambiguous proof has not been obtained. 6. Clavicipitic Acid and Aurantioclavine a. Clavicipitic Acid. Clavicipitic acid was first isolated in 1969 by Robbers and Floss (21), and a structure with an azecino[4,5,6-c,dlindoleskeleton was proposed. In 1977, King er al. (22) revised the proposed structure to one having an azepino[5,4,3-~,dlindoleskeleton, based on inspection of the NMR and mass spectra, and discovered the existence of two stereoisomers. Further, Floss er al. (23) carried out extensive isolation and separation studies on clavicipitic acid and established structure 22a for the major isomer by X-ray analysis, thereby proposing 22b as the structure of the minor isomer. Later, Natsume ef af. succeeded in the synthesis of these two isomeric alkaloids in pure form and proposed
I.
ERGOT ALKALOIDS
9
the designation clavicipitic acid I (22a) for the trans isomer and clavicipitic acid I1 (22b) for the cis isomer (Section IIl,E,2). b. Aurantioclavine. In 1981, Russian chemists (24) isolated an another new alkaloid from Penicillium aurantio-virens and designated as aurantioclavine (23). In 1983, they determined its structure as having an azepino[5,4,3-c,dlindole skeleton (25).
23 A u r ant ioc I av i n c
7. N-Methyl-4-dimethylallyltryptophan
N-Methyl-4-dimethylall yltryptophan (24), which was first isolated from the culture broth of Cfavicepsfusiformis under aerobic conditions (26), occupies an important position in the biosynthesis of ergot alkaloids. The isolation of this alkaloid provided an important clue to the biogenetic pathway of chanoclavine I (15) from 4-dimethylallyltryptophan as follows: 4-dimethylallyltryptophan would first be methylated on nitrogen followed by oxidation of the Z-methyl of the 4-dimethylallyl group. Subsequent decarboxylation and cyclization would yield chanoclavine I (15).
24 N-Mcthyl-4-dimcthylallyltryptophan
10
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
8. Peptide Ergot Alkaloids As well documented in the previous reviews in this treatise (1.21, there are a number of peptide ergot alkaloids consisting of lysergic acid and a peptide moiety. Structurally they are divided into two major groups, cyclol type alkaloids and noncyclol types, which are tentatively proposed to be called ergopeptines and ergopeptams, respectively (27). These alkaloids are classified as shown in Tables I and 11. a. Ergopeptine Alkaloids. Ergopeptines so far known are classified as in Table I, where new alkaloids isolated after 1974 are noted. Based on not only their systematic structural arrangement but also their biological activity, some of the newly isolated alkaloids had been already known from synthesis while some were expected to be isolated from natural sources. Ergoptine (25),ergonine (27), and ergovaline (26) were isolated in 1979 from Claviceps purpurea and synthesized (28). Ergobutine (28) and ergobutyrine (29), which were isolated in 1982 from Clavicepps purpurea (29), belong to an another new group carrying an a-aminobutyric acid at the 5' position. In addition, 5'-epi-P-ergocryptine (30), which is isomeric at the TABLE I ERGOPEPTINE ALKALOIDSO (CYCLOL TYPE)
R'
Ergotamines (R = Me)
Ergoxines (R = Et)
[R = CH(Me),]
Ergotoxines
CHLPh CH,CH( Me): CH(Me)Et CH(Me), Et
Ergotamine a-Ergosine P-Ergosine' Ergovaline (26)b Ergobine'
Ergostine a-Ergoptine (25)b P-Ergoptine' Ergonine (27)b Ergobutine (28)'
Ergocristine a-Ergocryptine P-Ergocryptine Ergopcornine Ergobutyrine (29)b
a The names of isomers derived from isolysergic acid characterized by the ending -inine are omitted here for simplicity. Isolated after 1974. ' Not yet found in nature.
TABLE I1 ERGOPEPTAM ALKALOIDS’ (NoN-CYCLOL TYPE)
Ergotamam (R = Me)
Ergoxams (R = Et)
Ergotoxams
Ergoannams
R‘
[R = CH(Me)J
[R = CH(Me)Et]
CHzPh CH2CH(Me)-, CH(Me)Et CH(Me), Et
Ergotamam” a-Ergosam” P-Ergosamb Ergovalamb Ergobamb
Ergostam” a-Ergoptamb P-Ergoptam” Ergonam” Ergobutam”
Ergocristam (32) a-Ergocryptam (33)‘ P-Ergocryptam (34)‘ Ergocornam (36)’ Ergobut yram”
a$-Ergoannam” P,P-Ergoannam (35)‘
The names of isomers derived from isolysergic acid characterized by the ending -inam are omitted here for simplicity. Not yet found in nature. ‘ Isolated after 1974. a
12
ICHIYA NlNOMlYA A N D TOSHIKO KlGUCHl
30 S'-Epi-B-ergocryptinc
3 1 X - H yd rox y ergot il m i ne
5' position to P-ergocryptine (30),and 8-hydroxyergotamine (31), an 8hydroxylated analog of ergotamine (31), were isolated. However, the stereochemistry of 31 at the 5 ' , I 1', and 8 positions remains unclear. b. Ergopeptam Alkaloids. Stadler et ul. (32) and then Cerny et ul. (33) isolated the noncyclol-type alkaloid ergocristam (32).Four additional ergopeptam alkaloids were also newly isolated (Table 11). These alkaloids, which differ from the cyclol-type alkaloids in the stereochemistry at the 11' position, are particularly interesting in view of biogenetic research. Ergocornam (36) and wergocryptam (33) were isolated in 1981 (34) from Cluviceps purprrreu, and P,P-ergoannam (35) and P-ergocryptam (34) were isolated in 1984 from field ergot (30). Of these, P,P-ergoannam (35) is the first alkaloid containing isoleucine in the peptide moiety. However, the corresponding cyclol-type alkaloid having isoleucine is not known, presumably because cyclol synthetase is ineffective owing to steric hindrance of a bulky substituent at the 2' position. Therefore, the fact that ergotoxine-type alkaloids [R = CH(Me)J exist with both noncyclol and cyclol types of structures, while ergotamines (R = Me) and ergoxines (R = Et) exist only as cyclol types, with noncyclol types found, can be reasonably explained.
9. Physical Properties Table 111 summarizes the physical properties of the new ergot alkaloids discussed above. C. CLASSIFICATION OF ERGOT ALKALOIDS Judging from structural features and consideration of biosynthetic pathways and based on the sufficient number of compounds so far isolated, ergot alkaloids can be classified into the following major groups based on the type of ergoline skeleton: (1) ergolines (Table IV), (2) 8-ergolenes (8,9Dehydroergolines, Table V), (3) 9-ergolenes (9,10-Dehydroergolines, Ta-
1.
PHYSICAL PROPERTIES
OF
13
ERGOT ALKALOIDS
T A B L E 111 NEW ERGOTALKALOIDS ISOLATED AFTER 1974
Alkaloid
Formula
Epicostaclavine (1) Fumigaclavine C (6) lsofumigaclavine B (7) lsofumigaclavine A (8) Agroclavine I (10) Epoxyagroclavine I (11) Chanoclavine I acid (12) 6.7-Secoagroclavine (13) Chanoclavine I aldehyde (14) 8-Chlororugulovasine A (19) 8-Chlororugulovasine B (20) Aurantioclavine (23) N-Methyl-4-dimethylallyltryptophan (24) a-Ergoptine (25) Ergovaline (26) Ergonine (27) Ergobutine (28) Ergobutyrine (29) 5'-Epi-P-ergocryptine (30) 8-Hydroxyergotamine (31) a-Ergocryptam (33) P-Ergocryptam (34) P.P-Ergoannam (35) Ergocornam (36)
C,,H2oN2 C,;H;oNKh CidJ'J20 Cl,H22N,02 CidmNz CidinN:O C,,Hi"N2OZ C itM:oN 2 CIdl"N20 C,,H,,N,O,CI Cw,Hi,N20XI CiYHinNz C,,Hi,N$A C,iHd@, C,YHd@, C,oHvN,O, C2YH&@5 CwH,,N@, C,JLiNQ? CuH,sN@, C,,H,lN,O, C,zH,i N@, C,,HaN@, C,,H,YN@,
mp ("C)
[a],, (solvent)
-
-
190
222-225 182 (dec.) 187-1 89 203-206 245-247 (dec.) 126-129
147" (pyridine)"
-
- 130" (pyridine) 155" (pyridine) -90" (pyridine)
-
-
-
-
-
232
I 98- 199 207-208 206207
-
188" (CHCI,) 172" (CHCI,) -
-
-
197
+ 14" (pyridine) + 31. I" (pyridine)
108-1 10
196198
-
-
+ 57.8" (pyridine)
" As the hydrochloride.
ble VI), (4)secoergolenes (Table VII), and ( 5 ) deformed ergot alkaloids (Fig. I). This classification is useful in understanding the ergot alkaloids as a whole. Further, these classes are subdivided according to substituents, particularly at the 8 position, for example, methyl, hydroxymethyl, formyl, or carboxyl. The most popular derivatives are the 9-ergolenes with an 8-carboxyl group, which are derived from lysergic acid. And the name "clavines" has often been used for the alkaloids having the (6aR)trans-4,6,6a,7,8,9,10,I0a-octahydroindolo[4,3-f,glquinolineskeleton of ergolines with 8 substituents other than carboxyl. In this chapter, we have attempted to summarize and classify ergot alkaloids based on structural features of the skeleton and substituents, thus intentionally avoiding the use of this trivial nomenclature.
14
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
1. Ergolines Alkaloids having the basic structure (6aR)-tvuns-4,6,6a,7,8,9,10, I0a-octahydroindolo[4,3-f,g]quinoline are included in the ergoline group, and they can be divided into two subgroups according to the presence or absence of substituents at the 9 position (Table IV). Further, the ergolines have a common feature in their substituents at the 8-position, namely, a methyl or hydroxymethyl group. 2. 8-Ergolenes (8,9-Dehydroergolines) Though the biosynthetic pathway has not been well clarified, grouping of the 8-ergolene-type alkaloids (Table V) seems worthwhile not only for synthetic study but also for future biogenetic study. The natural abunTABLE 1V NATURALLY OCCURRING ERGOLINES
Compound 8-Substituted ergolines Festuclavine (54) Pyroclavine (114) Costaclavine (2) Epicostaclavine (1) Dihydrolysergol I (560) Dihydrosetoclavine (145) 8,PDisubstituted ergolines Fumigaclavine B (4) Fumigaclavine A (5) Fumigaclavine C ( 6) Isofumigaclavine B (7) lsofurnigaclavine A (8) Epoxyagroclavine I (11)
Structure
1.
ERGOT ALKALOIDS
15
TABLE V NATURALLY OCCURRING 8-ERGOLENES
R
Compound
Structure
Paspalic acid (556) Elymoclavine (48) Elymoclavine-0B-D-fructoside
R = COZH, R' = H, R' = a-H R = CH'OH, R' = H , R' = a-H R = C H 2 0 , R' = H, R' = a-H
Moliclavine Agroclavine (9) Agroclavine I(10)
R = CH'OH, R' = OH, R' = MH R = Me, R' = H , R2 = a-H R = Me, R' = H, R' = P-H
dance of ergolines with a hydroxyl group at either the 8 or 9 position suggests a plausible relationship between these two groups of alkaloids. 8-Ergolenes vary structurally with respect to the substituent at the 8 position, either methyl, hydroxymethyl, or carboxyl.
3. 9-Ergolenes (9,IO-Dehydroergolines) For the same reasons 8-ergolenes are important and because of the presence of the most popular alkaloid, lysergic acid (38), the 9-ergolene group of ergot alkaloids (Table VI) have occupied the center of interest not only from a synthetic point of view but also pharmacologically. These alkaloids also vary in the structure and stereochemistry of substituents at the 8 position either as methyl, hydroxymethyl, or carboxyl, of which derivatives with lysergic acid, the 8-carboxy-substituted 9-ergoienes, exist in nature mainly as the amide form coupled with an amino acid or peptide. The use of ergot alkaloids in medicine is centered on this amide type of structure of lysergic acid (38a) with a peptide.
16
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
TABLE VI NATURALLY OCCURRING 9-ERGOLENES
B
A
C
Compound
Structure
Simple 9-ergolenes (general structure A) Lysergic acid (38a) R = Me, R' = CO'H. R' = H R = Me, R' = H. R' = CO'H lsolysergic acid (38b) Lysergol (49) R = Me, R 1 = CHZOH, R' = H lsolysergol (173) R = Me, R' = H, R' = CH'OH Lysergine (3) R = R' = Me, R' = H Penniclavine (43) R = Me, R' = CH'OH, R' = OH lsopenniclavine R = Me. R' = OH, R' = CH'OH R = R' = Me, R' = OH Setoclavine (165) lsosetoclavine (46) R = R' = Me, R' = OH Norsetoclavine R = H, R' = Me, R' = OH Lysergene ( 5 5 ) R = Me, R' =CH, R'
}
9-Ergolenes with an amino acid (structure A) Lysergic acid amide R = Me, R' = CONHI, R' = H (ergine) R = Me, R' = CONHCH(Me)OH, R' = H Lysergic acid a-h ydrox yethylamide R = Me, R' = CONHCH (Me) CH'OH, R' Ergonovine (357) Ergosecaline
-CONH,Jl,0
=
H
R'
=
Me
R
=
Me, R'
=
/Me
0
C?
H
Me
H
17
1. ERGOT ALKALOIDS
Compound
Structure
9-Ergolenes with a cyclol-type peptide (structure B)
Ergotamine (529) Ergostine Ergocristine a-Ergosine a-Ergoptine (25) a-Ergocryptine P-ergocry pine Ergovaline (26) Ergonine (27) Ergocornine Ergobutine (28) Ergobutyrine (29) 5'-Epi-P-ergocryptine (30) 8-Hydroxyergotamine (31)
R R R R R R R R R R R R R R
Me, R ' = CH,PH Et, R ' = CHIPh = CHIPh, R' = CH (Me), = Me, R ' = CH,CH (Me), = Et, R' = CH,CH (Me), = CH (Me),. R' = CH,CH (Me), = CH (Me),, R' = CH (Me) Et = Me, R' = CH (Me)2 = Et, R' = CH (Me), = R' = CH (Me), =
=
=
R 1 = Et
R' = Et CH (Me)?, R 1 = P-CH (Me) Et Me, R' = CH,Ph (8a-OH)
= CH (Me),, = =
9-Ergolenes with a noncyclol-type peptide (structure C)
Ergocristam (32) a-Ergocryptam (33) P-Ergocryptam (34) @$-Ergoamam (35) Ergocornam (36)
R = CH (Me),, R' = CH,Ph R = CH (Me):, R' = CH,CH (Me), R = CH (Me)?, R' = CH (Me) Et R = R' = CH (Me) Et R = R' = C H (Me),
18
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
4. Secoergolines
Although the position of the D ring-opened secoergolines (Table V11) has not been precisely established, their structural resemblance to ergoline-type alkaloids draws the interest of chemists in both synthetic and biogenetic studies. Floss et al. have postulated the intermediacy of secoergolines. particularly chanoclavine I (15), in the potential pathway to ergolines (Section V,A). TABLE VII NATURALLY OCCURRING SECOERCOLINES Compound
Chanoclavine I(15) Chanoclavine I1 (254) lsochanoclavine 1 (59) Norchanoclavine I Norchanoclavine I1 6.7-Secoagroclavine (13) Chanoclavine I acid (12) Chanoclavine 1 aldehyde (14)
Dihydrochanoclavine I lsodihydrochanoclavine I
Structure
R
R' = Me, R' = CH'OH, R' = a-H R' = Me, R' = CH'OH, R' = P-H = R' = Me, R' = CH'OH, R' = a-H = H, R' = CH'OH. R ' = Me, R' = a-H = H, R' = CH,OH. Rz = Me, R' = P-H R = R' = R' = Me, R3 = a-H R = R' = Me, R' = CO'H, R' = a-H R = R' = Me, R' = CHO, R' = a-H
R R R R
= =
R'
=
CHIOH, R' = Me = CH'OH
R' = Me, R'
1.
19
ERGOT ALKALOIDS
Structure
Compound Paspaclavine (226)
Paliclavine (61)
&
Me
HN
NHMc
R'
Rugulovasine A (17) Rugulovasine B (18) 8-Chlororugulovasine A (19) 8-Chlororugulovasine B (20)
R
R = P-H, R' = H R = a - H , R' = H R = P-H, R' = CI R = a-H,R' = CI
5. Deformed Ergot Alkaloids Dimethylallyltryptophan (546) (Fig. I ) occupies an important position as a precursor in the biosynthesis of many classes of ergot alkaloids. Clavicipitic acid (22) also is assumed to be formed in vivo from dimethylallyltryptophan (546); however, this biogenetic pathway seems to be different from the main route to lysergic acid (38) (Section V,A). In 1969. Stauffacher er al. (35)isolated cycloclavine (37)from the seeds of lpomeu hildebranrii Vatke. In 1982, Furuta er cil. isolated the identical alkaloid from Aspergillus japonicus Saito (36).
20
ICHlYA NINOMIYA A N D TOSHIKO KIGUCHI
22a ( R = a - H ) Clavicipitic acid 1 22b (R=P-H) Clavicipitic acid I I
23 Aurantioclavine
&
Me
NHR CO,H
HN
546 ( R = H ) Dimcthylallylr y plop h a n ( DMAT )
37 Cycloclavinc
24 (R=M e) N -M c t hy l-4-d i methylallyltryptophan FIG. I . Deformed ergot alkaloids.
111. Synthesis
The main feature of this chapter is certainly this section which deals with the synthetic work on ergot alkaloids mostly achieved in the period 1974-1988. As mentioned briefly in the introductory section, two previous reviews in this treatise (1,2) were written in the early period of research on ergot alkaloids and therefore lack fruitful syntheses, which mushroomed in the decade after 1974. For example, total synthesis of (+-)-lysergicacid (38) has been achieved by six groups within these 15 years. Therefore, the authors of this review emphasize the progress in synthetic studies and have devoted most of their effort to this section. In order to encourage a better understanding of the situation, this section is organized by starting with interconversions among natural alkaloids, which have often benefitted purely synthetic works. Then, total syntheses are presented according to the type of alkaloids. Of course,
I. ERGOT ALKALOIDS
21
lysergic acid (38) is placed as the first target and is followed by syntheses of the skeletal structural features as classified in the previous section. Another feature of this section is the organization of the synthetic methodology according to the reactions that were employed and specifically developed for synthetic work on ergot alkaloids, with the hope of imparting a better grasp of these strategies and how chemists have tackled synthesis. A. INTERCONVERSION OF ERGOT ALKALOIDS Prior to 1974, conversions of natural ergot alkaloids had been extensively carried out in order to establish the structures of then newly isolated alkaloids by intercorrelation. In later years, particularly after 1974, interconversions have been used to exploit an abundant supply of natural alkaloids produced either by isolation or by fermentation. Therefore, interest has been directed toward supplying less abundant components from the more abundant alkaloids, thus aiding what we call relay synthesis in addition to total synthetic works. The ergoline skeleton is the most common structure of many ergot alkaloids. Therefore, from the beginning of synthetic work on these alkaloids, through studies on mutual conversions of ergot alkaloids had been regarded as a very important and key step not only for facilitating total synthesis of many alkaloids but also for utilizing natural sources as supply reserves. Thus, consistently from the beginning of research on ergot alkaloids, as seen from the previous reviews (1,2), additional useful results have been reported in the 1980s, thus making the following total syntheses very efficient. In addition to the previous results (I ,2), a couple of new useful interconversions have accumulated. Owing to the development of an efficient procedure for producing lysergic acid (38) by fermentation, most interconversions have centered on the use of lysergic acid (38) as the starting material. Thus, lysergic acid (38) has been successfully converted to relatively rare and naturally nonabundant alkaloids, such as penniclavine (43), elymoclavine (48), lysergol (49), lysergene ( 5 9 , as summarized in Scheme 4. In addition, to establish the absolute configuration of less abundant alkaloids, further interconversions between major and already established alkaloids (Section 11) were studied, and agroclavine (9) and paliclavine (61) were obtained from chanoclavine I (15) and isochanoclavine 1 (59). Utilization of natural alkaloids for the synthesis of unnatural but structurally important compounds is summarized in Section II1,F.
il m
-0 .u
P
.-u
s
m
OD
5
J
"\ I
u C
ln l-
I.
23
ERGOT ALKALOIDS
I . Interconversions Starting from Lysergic Acid a. Conversion of Methyl Lysergate to Penniclavine, Isosetoclavine, and Elymoclavine. A group of Italian chemists took advantage of the ample supply of lysergic acid (38), which had been provided through the development in Milan of its production by fermentation, and studied conversion of lysergic acid (38) to other ergot alkaloids (37). Methyl lysergate (39), when treated with mercuric acetate in methanol solution followed by alkaline sodium borohydride, was converted to the didehydro derivative 40 instead of the expected 41 (Scheme 5). Product 40 was reduced with lithium aluminum hydride to afford 42, which has a methoxy group incorporated at the ring junction. Hydration of 42 in the presence of sulfuric acid
$Ye
MeO.,,
40
42
l e
44
45
46
SCHEME5. Reagents: a, Hg(OAc)?, MeOH; b, NaBH,, NaOH; c, LiAIH,; d, H2S0,, H1O; e, NH,NH2, MeOH; f, NaNO?, HCI; g. benzene, A; h, HCI; i, MeMgBr, anisole; j , vitride; k, tartaric acid; I, NaIO,; rn, MnOz or DCC, DMSO, A; n, Zn, AcOH; 0,LiAIH,-AICI,.
24
ICHIYA NINOMIYA A N D T O S H I K O KIGUCHI
proceeded smoothly with elimination of methanol to furnish penniclavine (43), thus completing the interconversion from lysergic acid (38). Conversion of the methoxycarbonyl group in methyl lysergate (39) t o a methyl group, and therefore conversion to isosetoclavine, was achieved via a route involving the 8-keto compound 45, which was obtained from the methanol adduct (40) of methyl lysergate (39) by hydrazinolysis, followed by treatment with nitrous acid and finally heating the corresponding isocyanate in benzene. The unsaturated ketone thus obtained (45) was treated with methyl magnesium bromide in anisole t o form isosetoclavine (46). In the above-mentioned conversion, the methanol adduct (40) played an important role for further conversions (Scheme 5). Bach and Kornfeld (38) applied 40 in different reactions for the conversion t o penniclavine (43) and elymoclavine (48). Hydride reduction of 40 with vitride afforded the 10-methoxy-substituted elymoclavine (42), which was then treated with 2% tartaric acid to give penniclavine (43) in good yield. Penniclavine (43) was further converted to the unsaturated ketone 45 by periodate oxidation. On the other hand, oxidation of 42 with manganese dioxide o r via Pfitzner-Moffatt conditions 1 I ,3-dicyclohexylcarbodiimide (DCC)-dimethyl sulfoxide (DMS0)-trifluoroacetic acid (TFA)], gave the unsaturated methoxy aldehyde 47, which was then subjected to hydrogenolysis with zinc and acetic acid to give elymoclavine (48) a s the sole product in good yield, though direct reduction of 42 with lithium aluminum hydride and aluminum chloride afforded a mixture of elymoclavine (48) and lysergo1 (49).
b. Conversion of Methyl Lysergate to Festuclavine, Lysergine, and Agroclavine. In 1986, the synthesis of lysergene (55) and agroclavine (9) via a route involving ketone 45 was reported by Wheeler, who performed the conversion because of the necessity of obtaining [ 1 7-14C]agroclavine (9) for biogenetic study (39). First, compound 45 was subjected t o the Wittig reaction t o prepare lysergene (55), but only a poor yield of 55 was obtained. Then, the indole nitrogen in 45 was protected by reaction with p-toluenesulfonyl chloride and cesium carbonate to afford 50, which was reacted with rnethylene triphenylphosphorane t o afford 51 as its hydrochloride in 47% yield. Compound 51 was then reduced under Birch conditions, lithium in liquid ammonia, to give agroclavine (9) in 52% yield along with a trace amount of agroclavine I (10) (Scheme 6). Partial synthesis of festuclavine (54), the principal 6,8-dimethylergoline alkaloid, was achieved starting from lysergic acid (38). Since reduction of agroclavine (9) did not give satisfactory results with respect t o stereochemistry, a much improved conversion was desired. Lysergic acid (38)
I.
45 50 R=Ts R=H
3
25
ERGOT ALKALOIDS
51
I
9
a
10 SCHEME 6. Reagents: a, p-TsCI, CsCO,; b. Ph,P=CH?. THF; c, Li. liq. N H ,
is known to be smoothly converted to the methylcyanides 52 and 53, both of which were found to undergo smooth reductive decyanation by means of potassium in hexamethylphosphoramide (HMPA) to yield festuclavine (54) in almost quantitative yield (Scheme 7) (40). For conformational studies, Nakahara et al. employed the readily available compound lysergic acid (38) for the synthesis of various clavines (41). At the start of their research, they investigated the esterification of lysergic acid (38) without any epimerization at the 8 position. Under traditional conditions, epimerization at the 8 position occurs to afford always an epimeric mixture of methyl lysergate (39a) and isolysergate (39b). However, treatment of lysergic acid (38a) with diazomethane using HMPA as the solvent gave methyl lysergate (39a) as the sole product in 86% yield (Scheme 7). Reduction of this homogeneous ester (39a) with lithium aluminum hydride afforded lysergol (49) in 78% yield. Further, Nakahara ef al. reinvestigated the reduction of some clavines. Dehydration of lysergol (49) was achieved by treatment with sodium butoxide to give lysergene (55) in 51% yield. Catalytic hydrogenation of the double bond formed by dehydration of lysergol (49) over palladium on barium carbonate gave a mixture of two saturated clavines, lysergine (3) and isolysergine (56), in 57 and 30% yield, respectively. Similarly, treatment of agroclavine (9) with sodium butoxide gave lysergine (3) in 67% yield along with isomeric 6,8-dimethylergolines as a result of migration of the double bond at the 8,9 position.
26
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
38
54
53
c
____, 39a
&Me
d L
HN
t1N 9
3
56
SCHEME 7. Reagents: a. K. HMPA: b. CH,N,. HMPA: c. LiAIH,: d. BuONa: e. H,/Pd-BaCO,; f. p-TsCI. py.
2. Conversion of Various Clavines to Lysergic Acid
There were several attempts at synthesis of lysergic acid (38) starting from other clavine alkaloids. This kind of conversion could provide an easy approach to lysergic acid (38) in a relatively few number of steps, thereby completing the total synthesis of optically active lysergic acid (38). Mayer and Eich first reported such conversions of elyrnoclavine (48) and lysergol (49) to lysergic acid (38) by Oppenauer oxidation in cyclohexanone, though the yield was only 1% (42). This strategy of intercon-
1.
27
ERGOT ALKALOIDS
version was soon taken up by Choong and Shough, who succeeded in smooth conversion of elymoclavine (48) to methyl lysergate (39) in comparable yield (Scheme 8) (43). Elymoclavine (48) was converted t o the methoxy-substituted aldehyde 57 in 55% yield by treatment with manganese dioxide in methanol. Compound 57 was further oxidized with cyanide-catalyzed manganese dioxide in methanol to the methoxylated ester 58 in 65% yield. Reduction of ester 58 with zinc and acetic acid afforded methyl lysergate (39) in 80% yield. Migration of the double bond in elymoclavine (48) was studied in order to complete a conversion to lysergol(49) (44). This migration has not been observed for treatment with catalysts, such as ruthenium on carbon, rhodium on carbon, o r platinum on carbon, but it did proceed in the presence of palladium-aluminum oxide or rhodium-aluminum oxide, thus yielding lysergol (49) in about 80% yield.
3. Conversion Starting from Secoergolines Some secoergoline-type alkaloids were effectively used for conversion to ergoline-type alkaloids by ring closure (45). Reaction of either chanoclavine I (15) or isochanoclavine I (59) with thionyl chloride in dioxane completed the conversion to agroclavine (9) in about 50-60% yield (Scheme 9). The fact that both clavines gave identical products may be explained by assuming a process involving a common intermediate (60).
49
39
SCHEME 8. Reagents: a. MnO,. MeOH: b. MnO,. KCN. MeOH: c. Zn, AcOH; d. Pd-AI,OI or Rh-AI,O,.
28
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
61
62 60 SCHEME 9. Reagents: a. SOCI,, dioxane; b. h v , H,SO,, dioxane. H,O.
Allylic rearrangement in the side chain of secoergolines would also provide a promising route for interconversion to other alkaloids (46). First, allylic rearrangement of chanoclavine I (15) to paliclavine (61) was attempted unsuccessfully under various acidic conditions. Success came when an acidic solution of chanoclavine I (15) was irradiated with ultraviolet light: an approximately 25% yield of paliclavine (61) was isolated along with unchanged starting clavine 15. Similarly, isochanoclavine I (59) was photochemically converted to paliclavine (61). These photochemical conversions proceed stereospecifically. On the other hand, when a neutral solution of chanoclavine I (15) was irradiated, isochanoclavine 1 (59) was obtained as a result of isomerization of the double bond in the side chain. Although the mechanism of this allylic rearrangement has not been clearly established, the involvement of the basic nitrogen in a cyclic transition state such as 62 was strongly suggested.
B. TOTAL SYNTHESIS OF LYSERGIC ACID Lysergic acid (38) was first isolated from hydrolytic solutions of ergot peptide alkaloids. From the fact that its derivatives, particularly amides, occur in nature as peptide alkaloids (and may also be synthetically prepared) and show remarkable pharmacological activities (thereby having
I.
29
ERGOT ALKALOIDS
been highly evaluated and used as clinically useful medicines) lysergic acid (38) itself has been regarded as the center of interest of not only medicinal chemistry but also synthetic chemistry. Thus, lysergic acid (38 is one of the major targets of synthetic organic chemists. So far total syntheses of this particular acid have been achieved by eight groups, clearly showing its everlasting popularity. The first total synthesis was achieved by the late Professor R. B. Woodward with the collaboration of a group of chemists led by E. C. Kornfeld in 1954 ( 3 ) ,which was followed by that of M. Julia et al. in 1969 (47), but the remaining six achievements have accumulated since 1974, particularly in the 1980s. The two early total syntheses were on the racemate of lysergic acid (38), and none achieved synthesis of the active form. Further, the ease of epimerization of the carboxylate at the 8 position of the ergoline skeleton in various solvents leads to formation of an equilibrium mixture of 8a and Sp isomers during synthesis. The conformational analysis of these isomers, which becomes a very interesting topic, is discussed later. In this section, all but the first and second total syntheses are described.
I . Total Synthesis by Ramage’s Group The third synthesis of lysergic acid by Ramage and co-workers (48) was apparently inspired by Woodward’s suggestion that epimerization or racemization of lysergic acid (38a) or isolysergic acid (38b) proceeds via the achiral intermediate 63 (Scheme 10). The synthetic strategy, as shown in Scheme 1 I , therefore involved construction of the related amine 68, which, as in Woodward’s original synthesis of (*)-lysergic acid (381, was destined to lead to 2,3-dihydrolysergic acid derivative 72, avoiding the possibility of undesired aromatization to a naphthalene derivative during the intermediate stages. The tricyclic aldehyde 64 was picked as the starting compound in this lengthy synthesis and was reacted with the Wittig reagent 65 prepared from the malonic ester to give the diester 66, which
CO,H I
.
P
63
3821
SCHEME 10
30
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
c0,nnc 1
BU'
($ COJl
BzN 66
64
67
68
71
SCHEME 1 1 . Reagents: a. benzene, r-BuOH; b. 90% CF,CO,H; c , Ph,POCI. N-methylmorpholine. CH,CI,; d, tetramethylguanidiniurn azide. MeCN; e . benzene, A; f. p-TsOH; g. HCHO, H C 0 , H ; h, conc HCI. MeOH: i. HCI. MeOH.
was then converted by treatment with 90% TFA to 67 in 70% yield. This carboxylic acid (67) was converted by treatment with tetramethylguanidinium azide in acetonitrile to the azide, which was then subjected to Curtius degradation to give the amine 68 in 80% yield. Although 68 did not undergo cyclization spontaneously, N-alkylation of 68 by formalinformic acid gave a mixture of the cyclized products 69, 70, and 71 as expected. Methanolysis of 69 or 70 gave an equivalent mixture of 72 and 73, which were identical to the compounds synthesized in the first synthesis of (+)-lysergic acid (38) by Woodward, Kornfeld, and co-workers (3). Synthesis of (+)-lysergic acid (38) by using an intermediate similar to 68 has recently been reported by two other groups (see Schemes 15 and 16).
31
ERGOT ALKALOIDS
1.
2. Total Synthesis by Oppolzer's Group Though seven other total syntheses of (*)-lysergic acid (38) used indoline derivatives as the starting compounds, Oppolzer et al. reported the first and only total synthesis beginning from an indole derivative (49). This strategy certainly has an advantage over the others because the strenuous step of oxidative conversion of an indoline to an indole ring could be avoided, and in addition no stereochemical problem at the carbon was involved. The Oppolzer synthesis relies on an intramolecular imino-Diels-Alder cycloaddition on the diene derived by thermolysis of the oxime ether 79 for the formation of rings C and D of the ergoline skeleton (Scheme 12). First they succeeded in the synthesis of (+)-chanoclavine I(15) (81) according to their unique strategy and proved the usefulness of the route
75
74
76
-
c, d
c,
___*
I'
77
78
80
38
79
SCHEME 12. Reagents: a, LiN(i-Pr),. THF; b. HC0,Me; c, NaH. DMSO: d. NaOH, MeOH: e . HCHO. H1O. Me,NH; f. MeNO,. MeOCOC=CCO,Me; g, NaOMe, MeOH: h. TiCI,, AcONH,. NH,OMe, MeOH, H,O; i. I ,2,5-trichlorobenzene, A; j, MeOSO?F, CH,CI,; k. AI-Hg, THF, H,O; 1, 0.5 M KOH. EtOH.
32
ICHlYA NINOMIYA AND TOSHIKO KIGUCHI
before achieving the total synthesis of 38. They picked methyl bicyclo[2.2. I]hept-5-enyl-2-carboxylate (74) as the starting compound in order to control the Diels-Alder reaction in the course of synthesis. Wittig reaction of the bicycloj2.2. Ilheptenealdehyde 75 with indolylmethylphosphonium bromide (76) afforded in 95% yield the vinylindole 77, which carries one component of the following Diels-Alder addition. Mannich reaction of indole 77 followed by treatment with nitromethane and dimethyl acetylenedicarboxylate yielded (48%) the 3-nitroethylindole 78, which is the desired compound for intramolecular Diels-Alder reaction on reduction of the nitro group to an oxime. Reduction of 78 as the nitronate anion was performed by treatment with titanium trichloride and ammonium acetate in the presence of O-methylhydroxylamine to give the corresponding oxime ether 79 in 64% yield. The desired intramolecular retro-Diels-Alder reaction and cycloaddition of oxime ether 79 proceeded smoothly by thermolysis at high temperature in refluxing 1,2,4-trichlorobenzene to give a 2 : 3 mixture of diastereorneric ergoline-type products (80) in 67% yield. Conversion of the substituent on nitrogen to methyl group was achieved by treatment with methyl fluorosulfonate followed by hydrogenolysis of the resulting salt with amalgamated aluminum foil. Finally, the resulting mixture was hydrolyzed and isomerized under basic conditions to give (?)-lysergic acid (38). 3. Total Synthesis by Ninomiya’s Group Ninomiya and co-workers developed a unique photochemical reaction called enamide photocyclization that has useful applications in the synthesis of nitrogen-containing heterocycles, including isoquinoline and indole alkaloids (50). In particular, photocyclization of enamides in the presence of sodium borohydride, what they called reductive photocyclization. is a useful synthetic method (50). Ninomiya and co-workers successfully applied reductive photocyclization to the enamide (82) prepared from the imine of tricyclic ketone 81 by acylation with 3-furoyl chloride (51,52).The tricyclic compound 81 used as their starting material was first synthesized by Woodward and co-workers ( 3 ) in their synthesis of (*)lysergic acid (38), and its preparation was later much improved by the studies of Nichols’s (53)and Ninomiya’s groups. Enamide 82 was irradiated in the presence of a large excess of sodium borohydride in benzene-methanol (Scheme 13). Photocyclization proceeded smoothly and reductively to afford a mixture of three lactams (83, 84, and 85) in 81% combined yield with the ratio 10 : 4 : I , of which the desired truns-lactam (83) was obtained as the major product. These photocyclized lactams have an ergoline skeleton with a cis-fused dihydro-
I.
il,
33
ERGOT ALKALOIDS
cp -
I,
c
BzN
82
81
&iC
83
g. 11, i d
II
BzN 86
87
-
___, J.
k,I,m
CF $ J (
BIN
88
I'
69 R=/I-CO>Mc
7 0 R=tr-C'OzMc
I iN 39a R=/I-<'O,Mc 3 9b It =(Y - C( 1 2 M c
SctirME 13. Reagents: a. MeNH,: b, 3-furoyl chloride. Et,N: c. h u , NaBH,. MeOH. benzene; d. LiAIH,: e . PhCOCI. Et,N: f, OsO,. Me,N+O; g. NalO,. MeOH. H,O: h. Na,CO,; i. CrO,. H,SO,, MeOH. acetone; j. POCI,. H,PO,. py: k. E l , O ' B F , ; I , S% HCI; m. (PhSeO),O. indole. THF.
furan ring. Therefore, the remaining steps for total synthesis are merely ring opening of the dihydrofuran and tailoring of the functional groups. Thus, photocyclized lactam 83 was reduced with lithium aluminum hydride followed by rebenzoylation to the corresponding amine 86, which was treated with osmium tetroxide in the presence of trimethylamine N oxide to introduce a glycol group into the dihydrofuran moiety. A mixture of a-and p-cis-glycols (87) was obtained in 83% yield. Oxidative cleavage of 87 with sodium metaperiodate followed by base treatment afforded the
34
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
9-hydroxy-S-aldehyde, which was further oxidized with chromium trioxide and sulfuric acid in methanol-acetone to give the corresponding hydroxyester 88 in 38% yield. Dehydration of 88 was performed according to the established procedure, that is, by heating with phosphoryl trichloride and 85% phosphoric acid in pyridine to afford a mixture of known unsaturated esters (69 and 70). Removal of the N-benzoyl group from 69 and 70 was readily achieved by alkylation with triethyloxonium tetrafluoroborate followed by hydrolysis to afford a mixture of two indolines in 55% yield. The final step in this synthesis, as others, was dehydrogenation of the indoline ring to an indole, which was performed by treatment with phenylseleninic anhydride in the presence of indole (88% yield of 39a and 39b). This procedure was developed as a general method for the conversion of indolines to indoles with collaboration of Barton’s group in Gif (54). This total synthesis involving enamide photocyclization features construction of the carbon skeleton of the alkaloids at the beginning followed by modification and introduction of functional groups, and the method clearly has wide applicability for the synthesis of not only one particular compound but also all members of a class of alkaloids. Indeed, Ninomiya’s group have succeeded in the total synthesis of many ergot alkaloids, mostly for the first time. 4. Total Synthesis by Rebek’s Group
Rebek’s synthesis of (+)-lysergic acid (38) started with racemic tryptophan and established a general synthetic route to not only lysergic acid (38) but also a wide range of other ergot alkaloids including lysergine (3), setoclavine (169, and rugulovasine A (17) (55,56). His synthetic methodology also proved to be enantioselective. Therefore, because of its usefulness and applicability, enantioselective synthesis is possible if commercially available optically active tryptophan is used. Racemic tryptophan was hydrogenated by 10% palladium on carbon in 1 N hydrochloric acid and then benzoylated to give a mixture of two diastereomers (89) in 70% combined yield, which then underwent acetylation with acetic anhydride followed by Friedel-Crafts reaction in the presence of aluminum chloride for cyclization to form the tricyclic ketone (90) as a single isomer in 60% yield upon equilibration of the intermediate stage (Scheme 14). Reformatsky reaction of 90 with a-(bromomethy1)acrylate gave the a-methylene-y-lactone (91) in 83% yield. Methylation with methyl iodide in the presence of sodium hydride in dimethylformamide (DMF) afforded the N-methylated product in 80% yield, which on treatment with hydrobromic acid in dichloromethane afforded 92. Without further purification, 92 was subjected to selective debenzoylation to
1.
35
ERGOT ALKALOIDS
89
90
92
91
Qp q.@yC C‘0:MC
v k
93
c;c
12
I
” 94
111
___)
HN
Mc
39a
+ 39b
1-1
I IN 95
SCHEME 14. Reagents: a. H,/Pd-C. I N HCI; b. PhCOCI; c. Ac,O; d. AICI,; e, H,C= C(CO,Et) CH,Br. Zn, I,, THF: f. NaH. Mel. DMF: g. HBr. CH,C12; h , Et,O + BF,-. CH,CI,; i. HCI. H,O: j. NaHCO,. H,O; k. SOCI,. MeOH; I. P,O,. MeSO,H: rn. MnO,.
give lactone 93, with an ergoline skeleton, in 55% yield. The lactone ring in 93 was cleaved by thionyl chloride in methanol to give the 10-hydroxyergoline (941, which was then dehydrated with phosphorus pentoxide in the presence of methanesulfonic acid to give unsaturated ester (95) in 95% yield. Ester 95 was partly converted to the Sp isomer by warming in methanol. Oxidative dehydrogenation of 95 furnished a mixture of methyl (?)lysergate (39a) and methyl (+)-isolysergate (39b). Thus, the Rebek’s synthesis paved the way for the first enantioselective synthesis of lysergic acid (38).
5. Total Synthesis by Kurihara’s Group Based on compound 63 suggested by Ramage, Kurihara’s group developed a modified synthetic route to aldehyde 64 (577, the compound Ramage’s group used as the key intermediate in their synthesis. Cyanophosphorylation of tricyclic ketone 96 with diethyl phosphorocyanidate and
36
ICHIYA NINOMIYA A N D T O S H I K O KIGUCHI
lithium cyanide gave the cyanophosphate 97, which was then treated with boron trifluoride etherate to afford unsaturated nitrile 98 in 90% yield (Scheme 15). Treatment of nitrile 98 with diisobutyl aluminum hydride (DIBAL) followed by rebenzoylation gave the key aldehyde 64 in 47% yield. Reaction of 64 with 99 in the presence of lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at - 78°C gave a diastereomeric mixture of alcohols 100 in a quantitative yield. Mesylation of 100 gave a mixture of 101 and 106. After removal of the tert-butoxycarbonyl group on nitrogen in the main product 101, the resulting hydrochloride (102) was treated with I ,8-diazabicyclo[5.4.O]undec-7-ene(DBU) in DMSO to give a mixture of 103 and 104 in 54% yield along with isomer 105 in 8% yield. Hydrolysis of 103, obtained as the major product in the above reaction, with concentrated hydrochloric acid and then esterification using dry hydro-
0
96
98
97
I
64
+
___t
Qt
uzN 100
101
106
102
SCHEME 15. Reagents: a. LiCN. (EtO)J'(O)CN; b. BF,-E1?0; c. DIBAL: d, PhCOCI; e. LDA: f, MsCI. Et,N. CH,CI?; g. 2.3 N HCI, AcOEt: h , DBU. DMSO; i. conc HCI. MeOH: j. HCI. MeOH: K. BzCI. MeOH.
1.
37
ERGOT ALKALOIDS
gen chloride gas and methanol followed by rebenzoylation afforded the known compound 69. Further, treatment of by-product 106 produced by mesylation of 100 with DBU in DMSO afforded the same mixture of 103, 104, and 105 in 86% combined yield (58). 6. Total Synthesis by Cacchi's Group A new synthesis of (+)-lysergic acid (38) was achieved via the key intermediates 69 and 70, which were previously prepared by Ramage, according to the newly developed reaction of oxidative addition of vinyl triflates to palladium(0) and the ability of the resulting vinylpalladium(11) species to undergo a Heck-type reaction (59). Tricyclic ketone 96 was converted to vinyl triflate 107 with triflic anhydride and 2,6-di-tcw-butyl4-methylpyridine in 91% yield (Scheme 16). Meanwhile, olefin 109 for the following coupling reaction was prepared from 3-(N-tert-butoxycarbonylN-methy1)aminopropionate(108) in three steps. Palladium-catalyzed reaction of 107 and 109 in the presence of palladium diacetate and triphenylphosphine afforded the coupled amine 110 in 26% yield. Cleavage of the tert-butoxycarbonyl group with 2.5 N hydrochloric acid followed by treatment with sodium bicarbonate gave a mixture of methyl dihydrolysergates (69 and 70) in 60% yield.
69 II=/I-C02Mc 7 0 R=m-COzMc SCHEME 16. Reagents: a, (F,CSOJ20. 2.6-di-rer-r-butyl-4-rnethylpyridine;b, Pd(OAc),, PPh,, Et,N. DMF; c , 2.5 N HCI. AcOEt; d, NaHCO,; e , LiN(i-Pr),, HCHO; f, MsCI. Et,N, CH2CIZ;g, DBU, benzene.
38
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
C. TOTALSYNTHESIS OF OTHERERGOLINE ALKALOIDS As mentioned previously (Section II), there exist a number of ergot alkaloids having an ergoline skeleton, and the ergolines are further subdivided according to their structural features (in particular the position of the double bond) into three groups, namely, saturated ergolines and two types of unsaturated ergolines (8- and 9-ergolenes). This classification fits with the synthetic strategy toward these alkaloids. 1. Total Synthesis of 6,s-Dimethylergolines
Four alkaloids having the simplest ergoline structure, 6, 8-dimethylergoline, are known. They are the C/D-trans-fused pair festuclavine (54) and pyroclavine (114) and the C/D-cis-fused costaclavine (2) and epicostaclavine (I). In 1976, Ninomiya’s group investigated the application of enamide photocyclization under nonoxidative conditions to the synthesis of these clavines (60). They attempted to prepare enamide 111 from tricyclic ketone 81 via its imine by acylation with methacryloyl chloride. However, probably owing to high reactivity, what they obtained was tetracyclic compound 112 in good yield, which had already cyclized to produce the ergoline skeleton (Scheme 17). Therefore, the remaining obstacles to synthesis of dimethylergolines were stereocontrolled reduction of the double bond at the ring junction, simple reduction of the lactam to an amine, and oxidative conversion of the indoline to an indole. First, C/D-trans alkaloids were synthesized by lithium aluminum hydride reduction of starting lactam 112 to give the amine with an enamine structure, which was susceptible to Birch reduction with sodium in liquid ammonia to afford the C/D-trans derivatives. Then, oxidative dehydrogenation of the indoline was performed with manganese dioxide to give saturated ergoline alkaloids, (+)-festuclavine (541, though yields were poor. Alternatively, the C/D-cis-fused alkaloids were synthesized by catalytic hydrogenation of the double bond at the ring junction as follows. Starting lactam 112 was first catalytically hydrogenated in the presence of platinum oxide, then hydrolyzed to give the saturated lactams (113) as a mixture of stereoisomers, which were separated by chromatography upon subsequent lithium aluminum hydride reduction and dehydrogenation with manganese dioxide. Thus, synthesis of a pair of C/D-cis alkaloids, (-+)-costaclavine (2) and its epimer (+)-epicostaclavine (l),was achieved. At the time of synthesis, however, only costaclavine (2) was known, and epimer 1 was viewed as unnatural; therefore, the stereochemistry was left to be established later. More recent isolation and structure elucidation studies of a “new” alkaloid, epicostaclavine (1) ( 4 3 , which
1.
ERGOT ALKALOIDS
f
J
111
39
/
HN
1-1
t1N
114 54 2 1 SCHEME 17. Reagents: a. MeNH?: b. H,C=C(Me)COCI: c . H,IPtO2:d. AcOH. conc. HCI: e. LIAIH,: f. MnO,; g. Na, liq. NH,.
was found to be identical to the already synthesized specimen, have unambiguously established the stereochemistry of this class of alkaloids. However, the presence of (k)-pyroclavine (114) posed a serious problem of identification because of difficulty in its separation from isomers owing to almost identical R , values on TLC, particularly when 114 was obtained as a mixture together with other alkaloids of this class. In 1983, in the course of synthesis aiming at lysergic acid (38), Oppolzer's group reported the synthesis of (*)-costaclavine (2) by application of intramolecular nitrone-olefin cycloaddition (imino-Diels-Alder reaction) (61). Starting from 4-formylindole (119, Horner-Emmons reaction with the anion prepared from methyl dimethylphosphonoacetate gave unsaturated E-ester 116, which on treatment with dimethylamine and formalin followed by methyl iodide and potassium cyanide gave the key synthetic precursor 117 in 86% yield (Scheme 18). Treatment of nitrile 117 with Raney nickel and sodium hypophosphite in pyridine and dilute acetic acid yielded the corresponding aldehyde (118), which was then subjected in situ to a sequence of reactions including condensation and cycloaddition as follows. Treatment of 118 with N-methylhydroxylamine hydrochloride and sodium methoxide and subsequent heating of the reaction mixture afforded a mixture of regioisomeric isoxazolidines 119 and 120 in the ratio
40
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
115
117
116
d
'
118
I1
r
120
I10
k
SCHEME 18. Reagents: a, (MeO),P(0)CHZC02Me.NaH; b, Me,NH, HCHO: c . KCN, Mel. i-PrOH; d , Raney Ni. NaH,PO,. py, AcOH, H?O; e , MeNHOH-HCI. NaOMe; f. CH,CI,, A; g. LiAIH,; h, H,/Raney Ni: i. ( I - B U O C O ) ~j.~ NalO,: ; k . EtN(i-Pr),; 1. Li'Me,SiC-(Me)CO,Me: m, H,/Pd-AI,O,; n, TFA: 0,Me,AI.
1.
ERGOT ALKALOIDS
41
4 : 1, which were chromatographically separated. Reduction of the major product 119 with lithium aluminum hydride followed by hydrogenolysis of the N - 0 bond with Raney nickel gave diol 121. which upon protection with terl-butoxycarbonyl was oxidatively cleaved to afford cis-aldehyde 122. Equilibration of 122 upon standing yielded the stable trans isomer 123 (For complete epimerization, treatment with ethyldiisopropylamine in chloroform was found most effective.) Both aldehydes 122 and 123 later served as important intermediates in the synthesis of ergot alkaloids. Using the cis-aldehyde (122), (+)-costaclavine (2) and (5)-epicostaclavine (1) were synthesized. Peterson’s olefination of 122 with lithiated methyl 2-trirhethylsilylpropionate afforded Z-ester 124, which was then hydrogenated by palladium on alumina t o give an unseparable mixture of two isomers (125). Without further treatment, deprotection of 125 with T F A followed by cyclization using trimethylaluminum afforded two lactams (126 and 127), which were readily separated. Reduction of 126 and 127 with lithium aluminum hydride furnished (+)-costaclavine (2) and (+)-epicostaclavine ( l ) ,respectively. 2. Synthesis of Dihydrosetoclavine Natsume and co-workers developed photooxygenation of pyrroles to prepare pyrrolylcrotonaldehyde 128, from which a new indole synthesis, namely, indolylethyl methyl ketone 129, was established (Scheme 19) (62.63).They successfully employed 129 for the synthesis of (I+_)-dihydrosetoclavine (145) via a route involving intramolecular aldol condensation (64,65).The key indole derivative 129 was brominated with N-bromosuccinimide (NBS) followed by treatment with alumina to give unsaturated ketone 130 in 91% yield. Conjugated addition of nitromethane to 130 yielded 131 in 93% yield, which, after protection of the carbonyl group as an ethylene ketal, was hydrolyzed with mild alkali to yield 132 in 93% yield. Vilsmeier-Haack reaction of 132 followed by treatment with alkali afforded 133 in 75% yield. Reduction of the unsaturated nitro group in 133 with lithium aluminum hydride gave a mixture of cis- and trunsamines which were separated as their carbamates 134 and 135 o r 136 and 137, respectively. Ketones 138-141 were obtained by deketalization in 50-95% yield (66). Carbamates 140 and 134 were used for further conversion t o (+)-dihydrosetoclavine (145) in two routes (Scheme 20). First, condensation of ketone 140 with tosylmethyl isocyanide in the presence of thallium ethoxide as base gave oxazolines 142 which then underwent ring opening in ptoluenesulfonic acid t o afford a diastereomeric mixture of formamides 143
42
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
128
129
6-71
X
130
131
132
NI iR1 I
I IN-
1
Y
HN
133
SCHEME 19. Reagents: a. 0,. methylene blue, hv: b. SnCI,, I-trimethylsilyloxy-I ,3-butadiene: c. MeCOCH,CH:MgBr; d. PCC: e. SnCI,. CICH,CH,CI: f. NBS, (PhCO,),. CCI,; g, AI,O,: h. MeNO,, KF, 18-crown-6, MeCN: i, 2-ethyl-2-methyl-I ,3-dioxolane. p-TsOH. benzene: j. 596 KOH. MeOH, H,O: k, Et,N. DMF. POCI,: I. KOH. MeOH. H,O: m. LiAIH,, THF: n. CIC0,Et or CICO,CH,Ph. Et,N. CH,CI,; o. p-TsOH. acetone.
and 144 in 33 and 20% yield, respectively. Compound 143 was then converted to (+)-dihydrosetoclavine (145) in three steps: catalytic hydrogenation for deprotection to convert the carbamate to an amine, treatment with alkali, and reductive methylation in the presence of formalin to furnish the N-methyl derivative 145. (+)-Dihydrosetoclavine (145) was thus synthesized in 12% overall yield (64). In the second route, reduction of intermediate 134 with lithium aluminum hydride followed by treatment with benzyl chloroformate afforded benzyl carbamate 146, which underwent treatment with methyl chloroformate to protect the indole nitrogen and finally removal of the ketal
1.
43
ERGOT ALKALOIDS
0
1 @ $ic
140
142
144
l('lIO
t c,tl, c-
I IN
I IN 145
143
I
I
148
149
II
150
SCHEME20. Reagents: a, p-TsCHINC. TIOEt: b, p-TsOH. DME, HIO; c, HI/lO% Pd-C; d, 5% KOH; e . 10% Pd-C, HCHO. HC0,H; f, LiAIH,; g. CICOZCHZPh; h , NaH. CIC0,Me: i. CuBrZ.CH(OEt),; j. Et,N: k, HCI. DMF. H,O; I . MeLi; m, 3% KOH, MeOH. HZO;n. p TsOH. acetone.
group. Bromination of 147 with cupric bromide in the presence of orthoethyl formate gave diethylketal 148 in 91% yield. Finally, the N-protective group in 148 was removed by catalytic hydrogenation, and the resulting amine was heated in triethylamine for cyclization to give ergoline 149. After hydrolysis of the acetal group in 149, reaction with methyllithium
44
ICHlYA NINOMIYA A N D TOSHIKO KIGUCHI
128
0
j, k, I
153
154
155
SCHEME 21. Reagents: a. (2.2-dimethyl-l.3-dioxolan-4-yl)ethylmagnesium bromide. THF: b. pyridinium chlorochromate (PCC). NaOMe, CH,CI,: c. SnCI,. CICH,CH,CI: d. Ag,CO,Celite or (Bu,Sn),O. Br,: e. Ac,O. py: f. NBS. (PhCO,),: g. A1,03: h. MeNO,. 18-crown-6. KF: i. p-TsOH. HOCH,CH,OH: j, KOH. MeOH. H,O: k, POCI,. DMF; I. KOH. H,O.
followed by treatment with 3% potassium hydroxide in aqueous methanol gave (?)-dihydrosetoclavine (145) and its isomer (150) in 28 and 57% yield, respectively, from 149 (65). Natsume et al. also described an alternative synthesis of key intermediate 155 starting from 128 via a route involving compound 151 (Scheme 21) (67).Brief mention of the synthesis of (*)-festuclavine (54), (+)-pyreclavine (114), and (*)-costaciavine (2) was also made (63).
3. Synthesis of Setoclavine and Lysergine The first total syntheses of (%)-lysergine (3) and (2)-setoclavine (165) were achieved (68,69) by employing spirolactone 91, which had played an important role in the synthesis of (+)-lysergic acid (38) (55.56).Reduction of the lactone and the conjugated double bond of 91 with sodium borohydride followed by rebenzoylation gave diol 156, with high stereoselectivity with respect to the 8 position, in 30% yield (Scheme 22). Diol 156 was then converted to the primary mesylate 157 with simultaneous elimination of the tertiary hydroxyl group. Base-catalyzed cyclization of 157 with sodium hydride in DMF produced 158, which was then subjected to debenzoylation with potassium tert-butoxide with concomitant dehydrogenation of the indole to an indole to give 159. Cleavage of Nh-benzoyl
1.
45
ERGOT ALKALOIDS
h.1 c
c
91
157
156
Ik 158
3 SCHEME 22. Reagents: a, NaBH,; b. PhCOCI; c , MsCI, Et,N; d , NaH, DMF: e. r-BuOK, HZO, THF; f, DIBAL; g. HCHO. NaBH3CN. 159
group in 159 with DIBAL and methylation by sodium borocyanohydride and formalin gave (*)-lysergine (3). For the synthesis of (+I-setoclavine (1651, the double bond in butenolide 91 was isomerized by rhodium chloride in quantitative yield, and alkylation with methyl iodide gave 160 (Scheme 23). Debenzoylation at ML:
91
160
161
162
163 164 165 SCHEME 23. Reagents: a, RhCI,; b. MeI, NaH; c, Et,O'BF,-; d. I N HCI; e, NaOMe. MeOH; f, LiAIH,, THF; g, MnO,.
46
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
both nitrogens on alkylation with Meerwein reagent (Et,O+BF,-) followed by mild hydrolysis gave 161 in 85% yield. Treatment of 161 with base (NaOMe-MeOH) led to lactam 162 in 75% yield, which was then reduced with lithium aluminum hydride to amine 163 in 80% yield. Oxidation of indoline 163 with manganese dioxide gave indole 164 in 75% yield. Finally, acid treatment of 164 resulted in stereoselective isomerization of the double bond coupled with migration of the hydroxyl to give (?)setoclavine 165 in 80% yield. 4. Synthesis of Lysergol, Isolysergol, and Elymoclavine
Ninomiya’s group also reported the first total syntheses of (-c-)-lysergol (49) (70),(2)-isolysergol (173),and (&)-elymoclavine(48) ( 7 / ) .They used photocyclized lactam 83 as the starting compound, which had been successfully employed in the total synthesis of (-+)-lysergic acid (38) (521, in the development of a synthetic route to the depyrrole derivatives of these alkaloids (72). The starting 8P-aldehyde (166), which was prepared by oxidative ring opening of the dihydrofuran of the photocyclized product, was converted to the corresponding 8P-acetate (167) on reduction with sodium borohydride and acetylation (Scheme 24). On the other hand, the 8a-alcohol (168) was prepared by oxidative cleavage (ozone) of the dihydrofuran ring
CHO
166
83
\ 169
SCHEME 24. Reagents: a, LiAIH,; b, PhCOCI, Et,N; c , OsO,, Me,N+O; d, NaIO,, MeOH, HzO; e, Na2C0,; f, NaBH,; g, Ac,O, py; h, 0,; i, H2/Pd-C, HCIO,, 10% HCI.
1.
47
ERGOT ALKALOIDS
of 83 followed by lithium aluminum hydride reduction. Debenzylation and acetylation of 168 gave acetate 169. Compounds 167 and 169 were found to be useful for the synthesis of various types of ergot alkaloids because of the presence of a hydroxyl group at the 9 position. When compounds 167 and 169 were treated with thionyl chloride, 167 produced the 9-chloro derivative 170 while 169 gave a mixture of the dehydrogenated product 171 and the 9-chloro derivative 172 (Scheme 25). Compounds 170 and 172 were dehydrochlorinated by treatment with DBU in benzene to give the unsaturated products. These products and 171 were deprotected, and subsequent dehydrogenolysis with phenylseleninic anhydride furnished the corresponding ergot alkaloids, (+-)-lysergol (49), (+)-isolysergol (173), and (*)-elymoclavine (48), respectively. The usefulness of phenylseleninic anhydride as the reagent of choice for conversion of indolines to indoles was clearly shown in these reaction
CI I,OAc
il
___, 170
49 CH.0Ac
yt1201-i &!4c
AcN 169
1
IiN 48
171
+
(1.1-1 2OAc
c :$(
I IN 172
173
SCHEME 25. Reagents: a, SOCIz; b, DBU; c , conc. HCI, MeOH; d, (PhSeO)zO, indole, THF.
48
ICHIYA NlNOMlYA A N D TOSHIKO KIGUCHI
schemes (54). Formation of by-products, even in the presence of ally1 alcohol, has not been observed.
5. Synthesis of Agroclavines, Lysergene, and Fumigaclavines Ninomiya’s group further applied photocyclized lactams to the synthesis of other ergot alkaloids, such as (+)-lysergene (551, (+)-agroclavine (9) ( 7 3 , and (+)-fumigaclavines (4) ( 7 4 , for the first total syntheses of these compounds. The common starting material (175) was modified by changing the protective group on the indoline nitrogen to a p-methoxybenzenesulfonyl group and then subjected to photocyclization. Irradiation of 175 in the presence of sodium borohydride afforded the photocyclized products as a mixture of rrum- and cis-lactams (176) with 80% combined yield in the approximate ratio 2 : I (Scheme 26). Without further sep-
180 R = t ~ - f l
179
55
181 R=/l-I-I
SCHEME 26. Reagents: a. MeNH?: b, 3-furoyl chloride. Et,N; c . h v , NaBH,. MeOH, benzene: d, 0,:e . LiAIH,: f. MsCI. py: g, r-BuOK. DMSO: h, (PhSeO)?O,indole, THF: i, Na, liq. NH,.
I.
49
ERGOT ALKALOIDS
aration, lactams 176 underwent subsequent oxidative cleavage of the dihydrofuran ring with ozone and reduction with lithium aluminum hydride. The 1.3-diols (177 and 178) thus obtained were separated and mesylated with mesyl chloride to give the corresponding dimesylates. Treatment of the dimesylates with strong base, potassium rerr-butoxide in DMSO, yielded the unsaturated amine (179) by double elimination. Lithium aluminum hydride reduction of 179 brought about deprotection of the nitrogen ofthe indoline skeleton. Finally, oxidative dehydrogenation of the indoline with phenylseleninic anhydride completed the first total synthesis of (+)-lysergene (55). On the other hand, when indoline 179 was subjected to Birch reduction, a 2 : 1 mixture of C/D-trans- and C/D-cis I ,4-adducts (180 and 181) was obtained. Trans adduct 180 was then converted to (+)-agroclavine (9) by treatment with phenylseleninic anhydride. Furthermore. on conversion of the methylol group at the 8 position in 177 to a methyl group, inversion of the 8P-hydroxyl via mesylate 183 furnished another total synthesis of (+)-fumigaclavine B (4) (Scheme 27). The 'H-NMR spectrum of (+)-fumigaclavine B (4) firmly established the assignment of all hydrogens (74). Additionally, compound 183 was used for the synthesis of unnatural (L)-isolysergine 56. Ninomiya and Naito also reported the first total synthesis of (2)-isofumigaclavine B (7) via a route involving Wolff-Kishner reduction of intermediate 166 (52). Recently, Kozikowski and Stein achieved the first total synthesis of (?)-agroclavine I(10) as shown in Scheme 28 (75). The synthetic strategy
177 I<=C'132011 182 R = M e
Ja ,
I,
183
MC
CI-K) I IO,,,
\ f, b, e
Mc
56
7 166 SCHEME 27. Reagents: a, MsCI. py; b, LiAIH,: c, K,O,, DMSO. 18-crown-6; d. Na. liq. NH,; e. (PhSeO),O. indole, T H F ; f. I-BuOK, DMSO; g, NH,NH,. KOH. HOCH,CH,OH.
50
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
10
SCHEME28. Reagents: a. Ph,P=CHOMe; b, Hg(OAc),. MeOH, benzene: c. Me,NH, HCHO. H,O. AcOH; d. Mel. KCN, i-PrOH; e. Ni. NaH,PO,. py. AcOH. H,O; f. CICO,Et, base: g. MeNHOH: h. MeHC=C(OMe)OSiMe,, Zn(OT0,. MeCN; i. HJRaney Ni; J. DMAP. toluene; k , MsCI. Et,N. py. CH,CI,; I, LiN(i-Pr),, THF; m. LiAIH,: n. MeHC= C(OMe)OSiMe,. TiCI,.
was based on the application of intramolecular cycloaddition of nitroneolefins. They developed a new route to 6-aminoesters via Lewis acidaided condensation of 5-methoxyisoxazoline derivative 187 with a ketene silyl acetal. The expected problem was whether the Lewis acid would coordinate with either one of the two oxygens in the nitrone-olefin cycloaddition product 187. Actually, the products were 188 when zinc triflate was used as the Lewis acid and 192 when titanium chloride was used. Treatment of 115 with methoxymethylenetriphenylphosphoranegave 184, which was readily isomerized to the E isomer (185) by treatment with
1.
51
ERGOT ALKALOIDS
Mc
Mc
178 R=CH2OI-l 193 R = M c
194
10
SCHEME 29. Reagents: a. MsCI, py; b, LiAIH,; c , SOCI,, benzene; d, (PhSeO)zO, indole, THF.
mercuric acetate in met hanol-benzene. Product 185 was then converted to 186 according to the procedure developed by Oppolzer et al. ( 6 / ) .Condensation of 186 with N-methylhydroxylamine afforded the nitrone intermediate, which was heated to effect cyclization to give the cis-fused isoxazolidine (187). Treatment of 187 with the ketene silyl acetal of methyl propionate in the presence of zinc triflate gave a stereoisomeric mixture of 188. Cleavage of the N-0 bond of 188 by catalytic hydrogenation using Raney nickel in a hydrogen atmosphere followed by treatment of the resulting mixture with dimethylaminopyridine (DMAP) afforded a diastereomeric mixture of lactarns 189 and 190. Deprotection of the N-ethoxycarbonyl group of lactam 190 was carried out by treatment with potassium hydroxide-methanol. The product was mesylated and then subjected to base treatment (LDA) to give the eliminated enamide 191, which was tinally reduced with lithium aluminum hydride to complete the total synthesis of (+)-agroclavine 1 (10). Ninomiya's group further extended the methodology to the synthesis of (+)-agroclavine I (10) (Scheme 29) (76). The synthetic intermediate 178 was used for the synthesis of 10. The methylol group at the 8 position in 178 was reduced t o a methyl group to produce 193. Treatment of 193 with thionyl chloride yielded dehydrated product 194, which was then subjected to deprotection with lithium aluminum hydride and dehydrogenation with phenylseleninic anhydride to complete the synthesis of (?)agroclavine I (10). D. TOTAL SYNTHESIS
OF
6,7-SECOERGOLENE ALKALOIDS
Since Plieninger achieved the first total synthesis of (+)-chanoclavine I (15) in 1976, eight groups have reported syntheses of 6,7-secoergolinetype alkaloids, including an asymmetric synthesis of ( - )-chanoclavine 1 (15).
52
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
1 . First Total Synthesis of Chanoclavine I
Synthesis of benz[c,dl indoles via a route including Diels-Alder reaction coupled with ozonolysis was extensively investigated by Plieninger’s group (77). They established a useful preparation of tricyclic 195 via Diels-Alder reaction of 5-nitro-2-naphthol and maleic anhydride (78). Compound 195 was then converted to its phenylhydrazone (196), which was reduced with activated aluminum to the diamine (197) (Scheme 30). Diamine 197 was then treated with ethyl chloroformate in pyridine to give a I : 3 mixture of the dicarbamates (198 and 199), from which the major isomer 199 was separated and ozonized to give the unstable aldehyde (200). On treatment with ethyl 2-(triphenylphosphoranylidene)propionate, aldehyde 200 was converted to the corresponding ester (201) as a mixture of stereoisomers at the 2 position. Dehydration of the hydroxyl group in 201 was smoothly carried out in the presence of oxalic acid. Reduction of the ester group to a carbinol with concomitant deprotection of the indole nitrogen and reduction of the carbamate to an N-methyl derivative completed the first total synthesis of (*)-chanoclavine 1 (15).
& \
)
NO:
___) ii
&NNl \ NO2
195
199
11%
1)
_____)
196
&NI4? \ NHZ
197
d
200
198 R = P - N I I ( : 0 2 E L 199 R = a - N H C O , E t
t---
15
20 1
SCHEME 30. Reagents: a, PhNHNH?: b. Al. EtOH. H 2 0 : c. CICO,Et. py: d . 0,:e , P h , e C(Me)CO,Et; f. (CO,H),, AcOH; g. LiAIH,.
I,
146
53
ERGOT ALKALOIDS
202
204
203
13
SCHEME 31. Reagents: a, p-TsOH, acetone; b, MeMgl: c , p-TsOH. benzene: d. Na. liq. NH,. THF.
2. Natsume's Synthesis of 6,7-Secoagroclavine and Chanoclavine I Natsume and Muratake applied their synthetic intermediate 146, which was used in the synthesis of (+)-dihydrosetoclavine (145) (see Scheme 20), to the first synthesis of (+)-6,7-secoagroclavine (13) (Scheme 3 I ) (79) via a route including the ketonic compound 202, which was also used for the synthesis of (?)-chanoclavine I(15) (see Scheme 32) (64).Compound
202
205
d
206
HO,
15 208 207 SCHEME 32. Reagents: a. P h , M H 2 , THF: b. OsO,, py, Et,O: c, AclO, py; d, p-TsOH, benzene: e , 2% KOH, /-BuOH, H1O: f, Na. liq. NH,. THF.
54
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
202 was treated with methyl magnesium iodide to give alcohol 203, which was then dehydrated to olefin 204 by treatment with p-toluenesulfonic acid. Deprotection of the 4-amino group of 204 was carried out under
Birch conditions (sodium in liquid ammonia) to afford (+)-6,7-secoagroclavine (13). Wittig reaction of 202 gave compound 205 with a methylene group, which underwent oxidation by osmium tetroxide followed by acetylation to give monoacetate 206 (Scheme 32). Dehydration of 206 in the presence of p-toluenesulfonic acid gave a mixture of isomers 207 and 208 with respect to the double bond. Deprotection of 208 with potassium hydroxide in aqueous tert-butanol followed by Birch reaction afforded (+)-chanoclavine I (15). 3. Kozikowski’s Synthesis of Chanoclavine I Kozikowski’s synthesis of (&)-chanoclavineI (15) (80)was published at the almost same time as the work by Oppolzer and Grayson (81). Though Kozikowski’s and Oppolzer’s works were quite similar as far as applying intramolecular [3 + 2]cycloaddition, they differed in the substrate, that is, nitrile oxide-olefin 209 (Kozikowski’s) versus nitrone-olefin 210 (Oppolzer’s). Nonetheless, the routes for conversion of the key intermediate to (&)-chanoclavine I (15) were quite similar.
209
210
Kozikowski’s group developed a preparative route to 4-formylindole (115) from dinitrotoluene involving the Leimgruber-Batcho reaction (82),
and they further discovered the usefulness of N,N-dimethyliminium chloride for the Mannich reaction (83). Based on the results, they not only applied the reaction to the synthesis of (&)-chanoclavine I(15) (80),but also further developed a novel intramolecular [3 21 cycloaddition of nitrile oxide-olefins and demonstrated its usefulness for the synthesis of a wide range of ergot alkaloids (172). 4-Formylindole (115) was treated with the anion form of ethyl diethylphosphonoacetate and then subjected to reduction with aluminum hydride followed by acetylation to afford 211, which was reacted with the newly developed Mannich reagent, N,N-dimethyliminium chloride, followed by nitromethane in the presence of dimethyl acetylenedicarboxy-
+
1.
55
ERGOT ALKALOIDS
late to afford 212 (Scheme 33). When the nitro group of 212 was converted to a nitrile oxide by treatment with phenyl isocyanate, [3 + 21 cycloaddition occurred smoothly to form isoxazoline 213. The protective group on the alcohol was changed from an acetyl to a revt-butyldiphenylsilyl group, and then the indole nitrogen was reprotected with acyl group. The imine moiety was converted to an N-methyl group to obtain a 1 : 1 mixture of trans- and cis-silylated products 214, which underwent deprotection, cleavage of the N-0 bond in the isoxazolidine ring, and finally reprotection of the amino group at the 4 position, thus forming 215. Periodate cleavage of glycol 215 afforded aldehyde 216, which was subjected to Wittig reaction with ethyl 2-(triphenylphosphoranylidene)propionate to give a homogeneous E-olefin (217). Compound 217 was then deacylated with triethyloxonium fluoroborate, followed by treatment with aqueous acetic
( )H
AcOl I,C ,,, NMcAc
g, h, i , .j, k
H
____*
213
214
215
216
217
15
d
SCHEME 3 3 . Reagents: a, (EtO),P(O)CH,CO,Et: b, AIH,; c , acetylation; d, Me,N CH,CI-. CHKI,; e. MeNO?, THF. MeOCOC=CCO,Me; f. PhNCO, NEt,; g. 0.5 M K,CO,, EtOH, H,O; h, r-BuPhzSiCI; i. N-acetylimidazole; j, Me,O'BF,-, MeNO,; k, NaBH,. EtOH; 1. B b N ' F - ; m. H,/Pd-C; n. Ac,O. py; 0, HIO,; p. Ph,P=C(Me)CO,Et; q, Et,O+BF,-. Na,CO,, CH,CI,; r, 3% AcOH. +=
56
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
acid to give the unsaturated ester, which was converted to the allylic alcohol by reduction with aluminum hydride to complete the total synthesis of (?)-chanoclavine 1 (15). The versatility of Kozikowski's route was proved by its smooth application to the first asymmetric total synthesis of (+)-paliclavine (61) and therefore ( + )-paspaclavine (226) (Scheme 34) (84). The asymmetry was introduced at the first stage by reaction of 4-formyl-N-tosylindole (218) with the optically active Wittig reagent 219. The intramolecular nitrile oxide cycloaddition of 220 was not stereospecific and gave a mixture of isoxazoline 221 and its diastereomeric isomer 222, epimeric at both the 9 and 10 positions. The mixture was separable, however, treatment with mesyl chloride, for mesylation of the primary hydroxyl group, and elimi-
, T . . P P , , 219
+
CHO
THI'O,
a, I), c , d
220 218
& L ti,
i, f, j
AcN 223
224
/
I IN 225
-
222
-
NHMc /
I IN 61
226
sCHEME 34. Reagents: a, A; b , dihydropyran, py, p-TsOH, CH2C12:C, KOH, MeOH; d , H,C=CHNO,: e , PhNCO, Et,N: f, Ac,O, DMAP; g, Dowex 50W-X8; h. MsCI. Et,N: i. PhSeNa; j , NalO,; k , Me,O'BF,-; I , LiAIH,: m, AI-Hg; n, MeCHO.
1.
ERGOT ALKALOIDS
57
nation of a selenoxide from 222 to give the homogeneous isoxazoline 223. Introduction of the final asymmetric center was achieved by methylation followed by reduction with sodium borohydride to give a homogeneous but undesired product 224 almost exclusively. When 223 was reduced with lithium aluminum hydride, however, a mixture of 224 and its C-5 epimer 225 was obtained, presumably owing to complex formation of the heterocycle with lithium aluminum hydride followed by delivery of hydride to the face of the molecule remote from the substituent at the 9 position. Although epimer 224 was still the major product, sufficient 225 was obtained to allow the total synthesis of (+)-paliclavine (61). This was the first total synthesis of an ergot alkaloid in optically active form. 4. Oppolzer’s Synthesis of Chanoclavine I
Starting from the key intermediate 119, which was prepared by nitroneolefin cycloaddition and used for the synthesis of 6,8-dimethylergolines (see Scheme 18), Oppolzer’s group succeeded in the total synthesis of four alkaloids, (?)-chanoclavine 1 (151, (*)-isochanoclavine 1 (59), (?)6.7-secoagroclavine (13),and (?)-paliclavine (61) (Scheme 35) ( 6 / , 8 / )As . mentioned in Section III,D,3, the key intermediate 123 employed by Oppolzer’s group was principally the same as Kozikowski’s, differing only in the protective group. Oppolzer’s group prepared the E-olefin 227 stereoselectively by Wittig reaction with ethyl 2-(triphenylphosphoranylidene)propionate, whereas the Z-olefin 228 was produced by HornerEmmons reaction with methyl (diethyl-2-phospho)propionate(anion form), which led to the total synthesis of (?)-chanoclavine 1 (15) and (k)-isochanoclavine I (59), respectively. Furthermore, they prepared 229 by Wittig reaction of 123 with isopropylene triphenylphosphorane and an isomeric mixture of 230 and 231 by Grignard reaction with isopropenylmagnesium bromide, which were then used to complete the total synthesis of (?)6,7-secoagroclavine (13) and (?I-paliclavine (61), respectively.
5 . Somei’s Synthesis of Secoergolines Somei’s group investigated the synthetic route to 4-substituted indoles and applied the methodology to the synthesis of several 6,7-secoergoline alkaloids. In 1980, they described a convenient two-step preparation of indolylvinyl methyl ketone 233, from 2-methyl-5-nitroisoquinoliniumiodide (232) (85), as a useful precursor for the synthesis of secoergoline alkaloids (86). Compound 233 was used as the starting material for the development of three approaches to (~)-6,7-secoagroclavine (13) (Scheme 36). The first route featured construction of ring C by Lewis
58
ICHIYA NlNOMlYA AND TOSHIKO KIGUCHI
SCHEME 35. Reagents: a, LIAIH,. THF; b. HJRaney Ni, MeOH; c. (t-BuOCO),O. NaOH, H,O. THF: d. NaIO,, MeOH. H,O; e. Ph,P=C(Me)CO,Et, CH,CI,; f, CF,CO,H. CH,CI,; g. DIBAL, THF; h. (EtO),P(O)CHMeCO,Me, NaH; i , LiAIH,, Et,O; j. HIC=C(Me)MgBr; k , Ph,P=CMe,.
acid-catalyzed intramolecular y-alkylation of 235, which was prepared from ketone 233 via a route involving Grignard reaction, Mannich reaction, and aldol condensation with nitromethane. The remaining two routes employed compound 237 as the key intermediate, which was readily prepared from ketone 233 via a route including Mannich reaction and condensation with nitromethane. These synthetic routes have problems concerning the yields of respective steps and the formation of isomeric products. a. Synthesis of 6,7-Secoagroclavine. A new and convenient synthesis of (~)-6,7-secoagroclavine(13) was reported by Somei and Yamada, who claimed a seven-step synthesis of (+)-6,7-secoagroclavine (13) from 3formylindole (241) with an overall yield of 36% (Scheme 37) (87). Thallation-iodination of 3-formylindole (241) afforded 4-iOdO derivative 242, which was treated with 2-methylbut-3-en-2-01 to afford the prenylated for-
1.
59
ERGOT ALKALOIDS
0
0
-
&
A
I-, 6
/ N M+c
232 233
I IN
234
235
236
!
21,
c
NIIMc 1-1
237
240
SCHEME36. Reagents: a. MeMgl: b, Me,N'=CH2CI-: c . MeNO,. Bu,P; d , ZnCI,. Et,N: e , TiCI,. AcONH,, H,O: f, Me2NH. HCHO, AcOH; g. MeNO,. Bu,P, MeCN: h. Ac,O. py: i, p-TsOH. benzene; j. HOCHICH,OH, p-TsOH, benzene; k. H,/Pd-C; I. CIC0,Et. Et,N CH,CI,; m. LiAIH,; n, MsCI. Et,N. py: 0 , I N HCI. acetone: p. CIC0,Me. NaH. DMF: q, Li, liq. NH,.
mylindole 243 in a temperature-dependent reaction. Aldol condensation of 243 with nitromethane followed by reduction afforded the nitrovinylindole derivative 244, which was subsequently subjected to acid-catalyzed and stereoselective cyclization to give the tricyclic nitro compound 245, which was converted to (+)-6,7-secoagroclavine (13) by conventional procedures. This revised synthetic route includes the following improvements. ( I )
60
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
24 1
242
244
243
245
j, k , j v 1 , ni C0:MC
C'f ): Mc a, I , c
&No! /
d
___t
S C ' H O HN 24 1
tlN 246
HN 247
SCHEME 37. Reagents: a. TI(OCOCF,),. CF,CO,H. then I,. Cul. DMF: b. H,C=CHC(OH)Me,. Pd(OAc),. DMF. NEt,: c. MeNO,: d. NaBH,. MeOH; e. 2 M HCI: f. Zn-Hg, 2 M HCI. MeOH: g. CIC0,Me: h. LiAIH,, THF; i. Pd(OAc),. methyl acrylate. DMF: j. MeMgl: k. Ac,O. py: I , p-TsOH. benzene: rn, TiCI,. AcONH,.
The conversion of 3-formylindole (241) to 3-formyl-4-iodoindole (242) was smoothly achieved by thallation-iodination in high yield. (2) Introduction of a substituent at the 4 position of 242 was achieved by applying the newly developed modified Heck reaction using palladium acetate as catalyst. (3) Acid treatment of the nitronate anion of 244 yielded the cyclized product 245 in good yield, also in a highly stereoselective manner. (4) Reduction of the nitro group in 245 to an amino group was carried out with zinc amalgam without any detectable isomerization. In further reactions, thallation-palladation of 241 followed by aldol condensation afforded compound 246. Michael addition of nitronateanion yielded 247, which was then converted to (-+)-6,7-secoagroclavine (13) (88,209).
b. Synthesis of Chanoclavine I. Somei's group in 1986 reported that 3formyl-4-iodoindole (242) was also applied in the modified Heck reaction
1.
61
ERGOT ALKALOIDS
using 2-methoxy-2-methyl-3-buten-l-ol, thus completing the total synthesis of (t)-chanoclavine I (15)and (+)-isochanoclavine l ( 5 9 ) (89).Alkenylation of 3-formyl-4-iodoindole (242) by the modified Heck reaction followed by condensation with nitromethane gave the 3-nitrovinylindole derivative 248, which on reduction with sodium borohydride in methanol followed by treatment with aqueous acid afforded a mixture of epimeric tricyclic compounds 249,250, and 251 (Scheme 38). Reduction of 249 and 250 followed by N-methylation gave (5)-chanoclavine I (15) and (+)-isochanoclavine I (59). the latter of which was converted t o (2)-agroclavine (9) by reaction with thionyl chloride. c. Synthesis of Chanoclavine I1 and Agroclavine I. Somei c’t al. found that the compound 245, used as a key intermediate in the synthesis of (+)-6,7-secoagroclavine (13), underwent smooth isomerization on base treatment to the cis isomer 252, (Scheme 39) (90).cis Isomer 252 was then oxidized with selenium dioxide to give the homogeneous compound 253 a s a result of stereoselective oxidation of a methyl group at the E position. The nitro group in 253 was converted to a methylamino group according
242
249 250
e,
r, g
. 15 R ’ = O l l , ‘ R ’ = H 5 9 R ’ ~ l 4 ,R2:01j
9
SCHEME 38. Reagents: a, H,C=CHCMe(OMe)CH,OH, Bu,N’ B r - , Pd(OAc),, DMF: b. MeN0:. AcONH,: c , NaBH,, MeOH; d. 2 M HC1; e , Zn-Hg, 2 M HCI, MeOH: f. ClCO,Me: g, LIAIH,, THF; h. SOCI,.
62
ICHIYA NINOMIYA AND TOSHIKO KlGUCHl
245
255
252
(& 256
253
254
0
I iN 10
SCHEME39. Reagents: a, NaOMe, MeOH: b, SeO?, dioxane, H,0; c, Zn-Hg, HCI, H,O; d, CIC0,Me. Et,N. CH,CI,; e, LiAIH,, THF; f , POCI,, K2C0,.
to the previously developed procedure to furnish the total synthesis of (2)-chanoclavine I1 (254). When cis isomer 252 was first converted to the methylamino derivative 255 (Scheme 39), subsequent selenium dioxide oxidation afforded 256 as a result of stereoselective oxidation of a methyl group at the Z position. A newly developed procedure for cyclization (phosphorus oxychloride and potassium carbonate) converted 256 to a cyclized ergolene, which was identical with (+)-agroclavine I (10). 6. Matsumoto’s Synthesis of 6,7-Secoagroclavine A route to the tricyclic intermediate 245 provided yet another synthesis of (~)-6,7-secoagroclavine(13), developed in 1986 by Matsumoto’s group. Previously, Matsumoto and co-workers had developed a preparative method for 4-substituted indoles via a route involving 4-0x0-N-tosyl-
I.
63
ERGOT ALKALOIDS
4,5,6,7-tetrahydroindole(257) (91), and they employed the 4-alkenylindole 260 in the synthesis of (+)-6,7-secoagroclavine (13) (92). Starting 4oxotetrahydroindole 257 was treated with the anion of methyl phenyl sulfone to give adduct 258, which was treated with cupric chloride to give the 4-phenylsulfonylmethylindole derivative (259) (Scheme 40). Sulfone 259 was then alkylated with methallyl tosylate followed by detosylation, formylation by Vilsmeier reagent, and then retosylation to give the compound 261. Isomerization of the double bond in 261 was effected by palladium catalyst, and the nitroethyl group was introduced into the 3 position to give 263. 1,3-Type migration of the phenylsulfonyl group in 263 proceeded smoothly to afford 264 in good yield, which was then treated with potassium hydroxide in methanol to bring about elimination of the tosyl group with concomitant cyclization. The products were a mixture of trans and cis isomers 245 and 252 that had already been synthesized by Somei’s group.
257
258
259
260
26 1
262
263
264
245 R=a-H 252 R=P-H
SCHEME40. Reagents: a. MeS0,Ph. BuLi, THF; b. CuCI,. AcOH, H,O: c. p-TsOCH, (Me)C=CH,. BuLi, THF: d. NaOMe MeOH. THF; e. POCI,. DMF, THF then NaH, THF; f. p-TsCI: g. PdCI,(PhCN),. CICH,CH,CI; h. MeNO:, AcONH,; i , NabH,, CH,CI,. MeOH; j. ZnCI,, CH,CI,; k. KOH, MeOH.
64
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
7. Genet's Synthesis of (-)-Chanoclavine I
In 1987, Genet and Grisoni investigated the Pd(0)-catalyzed coupling reaction and applied it to the synthesis of key intermediate 269 for 6,7secoergoline synthesis (93). The reaction was extended by applying a chiral ligand in the asymmetric synthesis of optically active 269, thus furnishing the first asymmetric synthesis of (-)-chanoclavine I (15) (Scheme 41) (94). The 4-(3-hydroxyalkenyl)indole 265 was prepared by a procedure similar to Kozikowski's route (80). After introduction of a nitroethyl group at the 3 position, the 3,4-disubstituted compounds 266 and 267 underwent Pd(0)-catalyzed cyclization in the presence of bis[l,2,-bis(diphenylphosphino)ethane]palladium [Pd(dppe)?] to yield the tricyclic compound 269. Encouraged by this success, Genet and co-workers investigated palladium-catalyzed cyclization in the presence of chiral catalyst and found that (-)-chiraphos (268) was the most effective in achieving the synthesis of chiral building block 269 (68% yield), which was converted to the key intermediate 123 by modifying the nitro group to a Boc-protected methyl-
'A
HN 115
266 R=OEI
265
267 R=Mc
268
269
270
1-10
123
,
27 1
15
SCHEMF 41. Reagents: a. (EtO),P(0)CH2C0,Et. K,CO,, THF: b, LiAIH,. Et,O; c, CIC02Et. Et,N or Ac,O, Et,N; d , HCHO. MeNH,, AcOH; e. O,NCH,CO,Et, toluene; f, Pd(dppe),. KF-alumina: g, Zn-Hg, MeOH. HCI: h. CIC0,Et. py, CH,CI,; i , LiAIH,. THF, ~, MeCN: k. 0,. CH,CI?; I. Me$. Et,O; j . U - B U O C O ) ~DMAP.
1.
65
ERGOT ALKALOIDS
amine (271), which was then subjected to ozonolysis followed by reduction with dimethyl sulfide. The conversion of 123 to the desired alkaloid (15) was carried out according to the route developed by Oppolzer's group (81). furnishing (-)-chanoclavine I (15) in 60% enantiomeric excess (ee), which showed an [a],value of - 143".
8. Ninomiya's Synthesis of Isochanoclavine I In 1989 as an extension of their synthetic strategy featuring enamide cyclization, which had shown its usefulness in the synthesis of a wide variety of ergoline alkaloids, Ninomiya and co-workers applied the synthetic intermediate 83 prepared by enamide photocyclization to the synthesis of ring-opened secoergoline alkaloids via a route involving a fragmentation reaction (Scheme 42) (95-97). The photocyclized lactam 83 was methylated at the position next to the lactam carbonyl in the presence of LDA to give 272. The dihydrofuran ring of 272 was oxidatively opened by ozone, and subsequent lithium aluminum hydride reduction and selective acetylation afforded 273, the key intermediate for the fragmentation reaction. The fragmentation developed by Grob was applied to the mesylate of 273 (96). Treatment of the mesylate with diethyl amine in ethanol at 50°C brought about fragmentation of the piperidine ring to give ringopened 274, which was subjected to hydrolysis with hydrochloric acid in methanol followed by dehydrogenation with phenylseleninic anhydride to furnish (+)-isochanoclavine I (59) (95).
I), c , tl
I
+
-& M~
272
83
c,
___)
r
___)
I;(;&
273
&I1
AcN
274
I-IN 59
SCHEME 42. Reagents: a , LiN(i-Pr)?,Mel; b. 0,:c. LiAIH,; d. Ac,O. py; e. MsCI. py: f, Et,NH, EtOH: g, conc. HCI. MeOH: h. (PhSeO)?O,indole. THF.
66
ICHIYA NlNOMlYA A N D TOSHIKO KICUCHI 110,
a, I,, c , rl
84
c , I, g, I1 ____)
275
15
SCHEME 43. Reagents: a. LiN(i-Pr),. Mel; b. 0,: c , LiAIH,; d. Ac,O. py; e . MsCI, py; f. HOCH,CH,OH. A; g, cone. HCI. MeOH; h. (PhSeO),O. indole, THF.
Starting from the photocyclized lactam 84 with a C/D-cis ring junction, which was obtained as a minor component of the photocyclization of enamide 82 (see Scheme 13), a similar conversion accomplished a total synthesis of (2)-chanoclavine 1 (15) through intermediate 275 (Scheme 43). Though the route was quite similar to the above (2)-isochanoclavine I synthesis, special attention had to be paid to the possibility of inversion of the stereochemistry of the ring junction from cis to trans (97). 9. Rebek's Synthesis of Rugulovasine
In 1980, Rebek's group succeeded in the synthesis of ( - )-rugulovasine A (17) starting from L-tryptophan via a route involving spiro y-lactones 160 and 276 (Scheme 44) (20, 98). As mentioned previously (Section
._
i l , I, ___c
\\
91 C02H
@ i .
160
276
\
I-IN 38b 277 17 SCHEME 44. Reagents: a, RhCI,: b. Mel, NaOH: c , NaOH, H,O, MeOH; d, MnO,, CH,CI,; e , Et,O'BF,L, CH,CI,, Na,CO,; f, 3% AcOH.
1.
ERGOT ALKALOIDS
67
III,C,3), the spirolactone 160 was prepared and subjected to hydrolysis under carefully adjusted and mild conditions followed by dehydrogenation with manganese dioxide to give 276, which was debenzoylated with Meerwein reagent (Et,O-BF,+) to furnish the first total synthesis of ( - ) rugulovasine A (17). Although rugulovasines (17 and 18) had been isolated in racemic form, Rebek's synthesis provided an optically active alkaloid of [a],+43" because they started their synthesis with L-tryptophan and the synthetic route preserved the chirality. The absolute configuration of rugulovasine was determined by the comparison of synthetic 277 derived from 91 with authentic 277 derived from isolysergic acid (38b), both of which showed the same optical activity (Scheme 44). From study of the isomerization and epimerization of the chiral product 17, it was observed that epimerization proceeds much faster than isomerization (Section II,B,5).
E. TOTAL SYNTHESIS OF CLAVICIPITIC ACIDA N D AURANTIOCLAVINE Clavicipitic acid (22) and aurantioclavine (23), alkaloids having a fused seven-membered azepinoindole skeleton, occupy important positions in the biosynthesis of a large group of ergoline alkaloids. By 1988, (?)-clavicipitic acid (22) had been synthesized by five groups and (+)-aurantioclavine (23) by two groups. From the biosynthetic relationship of these alkaloids with other major ergoline alkaloids, the syntheses of these alkaloids could clearly have been achieved through extension of the strategies applied to the synthesis of ergoline-type alkaloids.
1. Kozikowski's First Synthesis of Clavicipitic Acid
In 1982, Kozikowski and Greco achieved the first total synthesis of (2)-clavicipitic acid (22) by a route including intramolecular azide cycloaddition (Scheme 45) (99-101). Wittig reaction of 4-formylindole (115) afforded a mixture of (Z)- and (ad-alkenylindoles (278) in the ratio 3 : 1, which was converted to the 3,4-disubstituted indoles (279). Reaction of tosyl azide with the anion of 279 afforded the key intermediate 280, which was then heated in o-dichlorobenzene at 190-195°C to promote intramolecular [3 + 21 cycloaddition with concomitant evolution of nitrogen, thus affording azepinoindole 281. Tricyclic intermediate 281 was then brominated at the position allylic to the imine double bond, and the product was dehydrobrominated. Reduction of the imine double bond in the azepine ring of 282 followed by hydrolysis and decarboxylation gave (+)-clavicipitic acid (22) as a mixture of diastereoisomers, which were found t o be identical with the natural products.
68
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
Y
Y
278
115
-
279
2, h
L____,
282
22
SCHEME 45. Reagents: a. P h , b C H C H M e 2 ; b, HCHO, AcOH, Me2NH;c , H2C(COZMe)?, Bu,P; d. CICO,Et, E1,N; e, NaH then p-TsN,; f, o-dichlorobenzene. A; g, CuBr,, CHCI,, EtOAc; h. DBU, toluene; i , catechol-borane, CHCI,; j, 2 M KOH, MeOH then HCI. H,O.
In 1985, Kozikowski’s latest synthesis of (&)-clavicipiticacid (22) (102) arose out of an investigation in which labeled materials related to diol 283 were prepared for assay as a possible biosynthetic intermediate. 4Formylindole (115) was converted in two steps to the 4-ethinylindole (284), which was subjected to hydrostannylation to give 285 (Scheme 46). Metal-metal exchange promoted by butyl lithium afforded the anion of 285 which was then condensed with the tert-butyldimethylsilyl ether of acetol to form 286. Intermediate 286 was converted to gramine 287 and then condensed with dimethyl aminomalonate in the presence of tributylphosphine to yield the 3,Cdisubstituted indole 288, which on desilylation gave diol289. Diol289 was cyclized under Mitsunobu reaction conditions to give the E isomer 291 predominantly (85%). Removal of the primary hydroxyl group, hydrolysis, and decarboxylation gave (+)-clavicipitic acid (22).
1.
69
ERGOT ALKALOIDS
115
283
284
III
I IN 285
287
286
288
289
290
SCHEME 46. Reagents: a. CBr,. PPh,; b, BuLi; c. Bu,SnH: d. TBDMSO-CHICOMe: e. CHZCI,: f. H,NCH(CO,Me),. Bu,P, MeCN: g. Bu,N ' F THF: h. EtOMe,N '=CH,CI CON=NCOZEt. Ph,P. THF: i, N-phenylthiosuccinirnide.Bu,P, THF: j. Raney Ni. DMSO: k. 2 M KOH. MeOH.
.
.
During the course of investigation, the nearly exclusive formation of E isomer 291 with respect to the double bond was observed. This stereoselectivity was explained as follows: cyclization of 289 occurs via S,2' attack by the primary amino group on the vinyl cyclic 0.0-phosphorane (290), in the direction forming the less congested of the possible transition states, thus leading to E isomer 291.
70
ICHIYA NINOMIYA AND TOSHIKO KlGUCHl
2. Natsume's Synthesis of Clavicipitic Acid Natsume's synthesis of clavicipitic acid achieved in 1983 is the first example of separation of the two acids, clavicipitic acids I (22a) and 11 (22b) (Scheme 47) (103). The 4-alkenylindole 129, which was prepared from the pyrrole derivative, had been employed in the synthesis of (&)chanoclavines (66). N-Tosylated indole 292 was treated with methyl magnesium bromide followed by oxidation with rn-perchlorobenzoic acid to give epoxide 293. Ring opening of 293 with sodium azide afforded a-glycol derivative 294, in which the glycol moiety was protected via an acetonide exchange reaction, and the azide was then converted to the N-tosylglycine ester, thus providing 295 on removal of the N-protecting group
129 R=CX),Me 292 K=lk
295
22a R = n - H 22b R=/I-H
\
293
294
296
297
298 I < = t r - l I 299 R=/f-11
301 R=/I-H
300 R=tY-tI
r
?
SCHEME 47. Reagents: a, MeMgl; b. MCPBA, CH,CI,; c. NaN,, dioxane. H,O; d. Me,C(OMe),, p-TsOH; e. H,/Pt; f. p-TsCI. Et,N. CICH,CH,CI; g, BrCH,CO,Me. K,CO,. DMF; h, KOH, MeOH, H,O. DME; i , CH,N,, MeOH, Et,O; J. POCI,. DMF, Et,O; k. DBU. benzene; I. 1% HCI. MeOH. THF, H,O; m, S=CCI,, DMAP. CH,CI,; n. (MeO),P; 0. NaBH,, hv. Na,CO,, MeOH. DME. H,O; p, KOH, MeOH, H,O; q , Ac,O. py; r. Ac,O, MeOH.
1.
ERGOT ALKALPIDS
71
on the indole nitrogen. Introduction of a formyl group was carried out in the presence of the Vilsmeier-Haack reagent, and subsequent cyclization was achieved by refluxing in benzene with DBU to give azepinoindole 296. The acetonide group in 296 was removed by acid treatment, and reaction with thiophosgene followed by refluxing in neat trimethylphosphite gave 297. Photochemical reaction of 297 in the presence of sodium borohydride and sodium carbonate removed the tosyl group and reduced the olefin, thus giving rise to diastereoisomeric esters 298 and 299, which were separated. The cx isomer 298 was determined to make up 46% of the products, which were converted to (k)-clavicipitic acids I (22a) and I1 (22b) on alkaline hydrolysis.
Furthermore, treatment of 298 and 299 with acetic anhydride in pyridine afforded the corresponding N-acetyl derivatives 300 and 301, respectively, without causing any isomerization under these conditions. It was observed, however, that (2)-clavicipitic acid I (22a) was converted to the thermally stable (+)-N-acetylclavicipitic acid I1 (301) in 62% yield when treated with acetic anhydride in methanol. The isomerization of 22a to 301 was explained in terms of N,O-acyl migration including five-membered intermediate. 3. Somei's Synthesis of Aurantioclavine The first total synthesis of (+)-aurantioclavine (23) was achieved in 1985 by a direct, five-step process from 3-formylindole (241) via a route involving the 4-iOdO derivative, previously mentioned, and the nitromethane condensation product 302 (Scheme 48) (104). This total synthesis includes two crucial steps: the modified Heck reaction and a new reductive cyclization method. 3-Formylindole (241) was first iodinated at the 4 position and then condensed with nitromethane to give the styrene-type com-
72
ICHIYA NINOMIYA AND TOSHlKO KIGUCHI
- %.?--. ;I,
ptIN y
H
O
I,,
(I
c
I IN
24 1
HN
302
303
1
c ____)
/
N( )>
____)
I IN
/
I IN
304 23 SCHEME 48. Reagents: a, TI(OCOCF,),, CF,COZH; b, Cul, DMF; c, MeNO,. AcONH,; d, NaBH,. i-PrOH. CHCI,; e. HZC=CHC(OH)Mel, Bu,N Br , Pd(OAc),, DMF; f, Zn-Hg. MeOH. 2 N HCI. +
pound 302 which was hydrogenated to 3-nitroethylindole 303 by reduction with sodium borohydride. Clever application of the modified Heck reaction to 303 introduced a hydroxyisoprenyl group, giving 304 (80% yield), which was then reduced with amalgamated zinc in refluxing methanolic hydrochloric acid t o bring about cyclization t o a seven-membered ring, thus completing the total synthesis of (?)-aurantioclavine (23) in 31% overall yield over five steps from the starting compound 3-formylindole (241). 4. Harrington’s Synthesis of Clavicipitic Acid and Aurantioclavine (306) as the Harrington’s group picked N-tosyl-3-iodo-4-bromoindole starting material for the synthesis of both (2)-clavicipitic acid (22) and (*)-aurantioclavine (23), thus showing the close relationship of these two alkaloids. a. Synthesis of Clavicipitic Acid. In 1987, Harrington’s group synthesized the N-acetyl methyl ester of (*I-clavicipitic acid (22) in 18% overall yield from 2-bromo-6-nitrotoluene (305) (Scheme 49). Starting indole 306 was prepared in eight steps from 2-bromo-6-nitrotoluene (305) with 62% overall yield (Section I K J , I ) (185). N-Tosyl-3-iodo-4-bromoindole (306) was subjected t o the Heck reaction [Pd(O)-catalyzed oxidative olefin insertion] to give the Z-olefin 307 stereoselectively (105). Another Heck reaction to the 4-bromoindole (307)was also carried out to give the 3,4-alkenyl-substituted indole 308, which was then subjected
I.
308
73
ERGOT ALKALOIDS
309
300 I<-IY-II 301 11-/1-11
SCHEME 49. Reagents: a. H,C=C(NHAc)CO,Me. 5%, Pd(OAc),. E1,N. MeCN: b. H,C= CHC(OH)Me,. 8% Pd(OAc),. Et,N. (o-Tol),P. MeCN; c , 15% PdCI,(MeCN),. MeCN. or p TsOH. A; d. NaBH,. Na,CO,. hv. MeOH. DME. H,O.
to aminopalladation in the presence of bis(acetonitrile)palladium dichloride in acetonitrile under reflux to give the seven-membered ring system 309. Photochemical reduction of the double bond in the azepine ring of 309 with sodium borohydride also removed the tosyl group, thus providing 300 and 301 as a mixture of diastereoisomers. Shorter reaction times (10 hr) gave the cis derivative 301 almost exclusively in 61% yield, while longer reactions (20 hr) yielded approximately a 1 : I mixture of trans(300) and cis derivatives (301) in 74% combined yield. b. Synthesis of Aurantioclavine. By applying an analogous reaction sequence and using the same starting compound, N-tosyl-3-iodo-4-bromoindole (306), Harrington's group also succeeded in the synthesis of ( 2 ) aurantioclavine (23) in 13% overall yield from 2-bromo-6-nitrotoluene (305) (Scheme 50) (106). The 3-alkenylindole 310 was obtained from 306 by a nickel (0)-catalyzed oxidative addition-transmetallation reaction from zirconium. Enol ether 310 was hydrolyzed with tribromoboranemethyl sulfide and subjected to acetalization to give acetal 311. Analogously to the procedure for (2)-clavicipitic acid (22) synthesis ( / 0 5 ) ,acetal 311 was converted using palladium(0) catalyst to 312, which was then intramolecularly condensed with p-toluenesulfonamide in the presence of p-toluenesulfonic acid to give azepine 313. Reductive detosylation of 313 by sodium borohydride under photolytic conditions removed both tosyl-
74
ICHIYA NINOMIYA A N D TOSHIKO KlGUCHl
312 313 23 SCHEME50. Reagents: a. dicyclopentadienylzirconium chloride, EtOC=CH, Ni(PPh,),: b. BBr,SMe,; c. EtOH. NaHCO,; d. HIC=CHC(OH)Me,, Pd(OAc),. (o-Tol),P; e.p-TsNH,. p-TsOH. MeCN; f. NaBH,. h v , MeOH, DME, H,O.
ates on the nitrogens and saturated the ring double bond to afford (?)aurantioclavine (23).
5. Matsumoto’s Synthesis of Clavicipitic Acid In 1987, Matsumoto’s group succeeded in synthesizing (+)-clavicipitic acid (22) by incorporating the newly developed synthesis of 4-substituted indoles (107). As in their synthesis of 6,7-secoagroclavines, N-tosyl-4-cyanomethylindole (314) was treated with methallyl tosylate to introduce a methallyl group in the side chain, giving compound 315 (Scheme 51). The anion of 315 was then subjected to aerobic oxidation to remove the cyano group, giving 4-isobutenoylindole (316), which was converted to the 3,4disubstituted indole (317) by introducing a group equivalent to alanine at the 3 position of the gramine. The indolylmalonate (317) was then heated with hydrochloric acid in aqueous dimethoxyethane (DME) for elimination of the N-formyl group accompanied by condensation of primary amino group with the ketonic carbonyl to form azepinoindole 318. Production of (?)-clavicipitic acid (22) from 318 was carried out according to Kozikowski’s procedure (101) to complete the total synthesis. 6. Goto’s Synthesis of Clavicipitic Acid
Goto’s group had described the synthesis of azepinoindole 320 by intermolecular condensation of dehydrotryptophan methyl ester (319) with saturated aldehydes (108). They reported the application of this one-step
I.
314
315 I
317
75
ERGOT ALKALOIDS
316 \
318
22
SCHEME51. Reagents: a. BuLi, p-TsOCH2MeC=CH2; b, r-BuOK then 0,; c, NaOH, MeOH; d, MeZN'=CHZCI-; e, OHCNHCH(C02Et)2,MeOCOC=CC02Me; f. 1.2 N HCI, DME; g, catechol-borane; h, KOH, MeOH.
synthesis of azepinoindoles to the synthesis of (+)-clavicipitic acid (22) (Scheme 52) (109). However, no further details were reported.
F. SYNTHESIS OF MODIFIED ERGOTALKALOIDS 1. Modifications of Ergot Alkaloids by Partial Synthesis
Extensive efforts to develop novel classes of physiologically active derivatives of ergot alkaloids have focused on structural modification of natural ergot alkaloids (Fig. 2). Previously in this treatise, Stoll and Hofmann summarized the results of conversion of substituents at the 8 position ( I ) , and thenafter a number of conversions of naturally abundant alkaloids, such as dihydrolysergic acid I (110-114, dihydroisolysergic acid I ( 1 1 3 , elymoclavine (48) ( 4 3 , and lysergol(49) (116), to a wide variety of derivatives were reported. Here we summarize investigations of structural modifications of natural ergot alkaloids, particularly epimerization at the 8 position, substitution on nitrogen at the 6 position, carbon at the 2 position, and the indole nitrogen at the I position, as well as modification of the alkaloid skeleton. a. Epimerization of Carboxyl Group at the 8 Position. The synthesis of dihydrolysergic acid by catalytic hydrogenation of the double bond at the 9,lO position of lysergic acid (38) was summarized by Stoll and Hofmann ( I ) . Nakahara's group investigated the catalytic hydrogenation of lysergic
76
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
tiN
-
K=Mc, CII(MC)~, C'I IzC't I ( Mc),
319
320
\
32 1 SCHEME 52
acid diethylamide (LSD) (322) and observed results similar to those for lysergic acid (38) (41). Catalytic hydrogenation of LSD (322) gave dihydrolysergic acid diethylamide I(323) as expected by addition of hydrogen to the unhindered face of the double bond (Scheme 53). Equivalent hydrogenation of isolysergic acid diethylamide (324), however, proceeded much more slowly to give a mixture of two dihydro derivatives, dihydroisolysergic acid diethylamide I (325), as a minor product resulting from hydrogen attack from the relatively hindered a face, together with the major product dihydroisolysergic acid diethylamide 11 (326). The fourth stereoisomer, dihydrolysergic acid diethylamide I1 (3271, was not obtained by hydrogenation; however, 327 was formed by base-catalyzed equilibration of dihydroisolysergic acid diethylamide I1 (326), though only in small amounts. Convcrsion I
Substitution
,
I Substitution ' Fic. 2. Approaches to structural modification of natural ergot alkaloids.
I,
77
ERGOT ALKALOlDS
322
323
327
326 SCHEME 53
Mayer and Eich noticed that 8- or 9-ergolenes (328 or 329) could be reduced stereoselectively to give the 8p derivatives (330). The reduction was achieved by means of catalytic transfer hydrogenation using Raney nickel as the catalyst in solvents containing hydroxyl groups, especially methanol, as the hydrogen donor (Scheme 54) (117). As shown form the above results, 8a-UD-trans derivatives could not be obtained in good yield by catalytic hydrogenation of lysergic acid derivatives. Therefore, attention was focused on exploitation of the selec-
-
R
Rancy Nicy$$ ( 0
I IN 328
-
I<
Rancy N i
Rot1
ROI I
I IN
I IN
330 54 SCHEME
329
78
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
tive synthesis of the 8a-C/D-trans derivatives in view of finding novel pharmacologically active derivatives. Stadler's group succeeded in the selective preparation of 8a derivative 332 by catalytic hydrogenation of enamine 331, which was formed from methyl dihydrolysergate (330) (Scheme 55) (128). BeneS et al. also developed a procedure for obtaining 332 selectively via kinetically controlled proton attack on the enolate anion formed from 330 by LDA treatment (119). Sauer et al. found that reduction of isolysergic acid derivative 333 by lithium in liquid ammonia in the presence of a primary or secondary aromatic amine as the proton source proceeded stereoselectively to form 8a derivative 334 (120). b. Demethylation and Substitution at the 6 Position. Demethylation at the 6 position via the von Braun reaction had been partly discussed by Stadler and Stutz (2), and Nakarara et al. thoroughly investigated the stereochemistry of this reaction (Scheme 56) and observed that compounds 3, 54, 322, 323, and 326 underwent smooth demethylation whereas cornpounds 2, 114, 183, 324, 325, and 327 resisted demethylation (121). They explained the difference in reactivity by ascribing the resistance against demethylation to the stereochemistry of the compounds having a substituent in a 1,3-diaxial configuration with a lone pair on the nitrogen at the 6 position. On the other hand, Cernq et al. reported successful demethylation of compound 332 (122). Decyanation at the 6 position was extensively studied particularly with regard to reaction conditions. Reagents such as Raney nickel, sodium borohydride, and zinc-acetic acid were known to be effective for this
33 1
330
@y
;I.
332 I).10% AcOlI
l,iN(i-I'r):
-
@;C
Li
Iiq Nll,
I IN 333
l<'RLNIl
SCHEME55
II 334
n
I.
79
ERGOT ALKALOIDS
I<
li
1 IN
3 R=Me 322 R=CONEI:
No R eaclion
5
183 R=Mc 324 R=CONEf,
54
I<=Mc
326
323 Ii=CONEt,
r?
114 R=Mc 325 R=CONEi, 332 II==COzMc SCHEME56
2 R=Me 327 R=CIONEtz
reaction. Nakahara et al. discovered that 1.4% hydrochloric acid-dioxane yielded good results (123). A novel and versatile procedure for demethylation at the 6 position was reported by Crider et al. (124). The method was an application of dealkylation for the tertiary amines. Ergoline 330 was treated with trichloroethyl chloroformate to yield carbamate 335,which was then reductively cleaved by zinc and acetic acid to give 6-nor derivative 336 (Scheme 57). So far, the best alkylation of N-6-norergolines has been carried out by treating with the alkyl halide in the presence of potassium carbonate in DMF solution (125). c. Substitution at the 2 Position. In the preceding review (2), FriedelCrafts-type reactions of ergolines using 2-methoxy- 1,3-dithiolane were
80
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
330 335 336 SCHEME 57. Reagents: a. CI,CCH,OCOCI, KHCO,. CH,CIZ: b. Zn, AcOH.
thoroughly discussed. Product 337 was hydrolyzed to give 2-formylergoline 338 (Scheme 58). Further, conversion of 338, via Horner-Wittig reaction to the corresponding acrylate (339) (126), and the reaction of vinyltriphenylphosphonium bromide with 338 (/26), leading to the pyrrolo[ 1,2-a]ergolines (340) as the result of the Michael addition to the indolyl anion and intramolecular Wittig reaction, have been described (127). It was also reported that reaction of 2-formylergoline 338 with methyl isonitrilacetate in the presence of DBU gave 341, while the same reaction in the presence of sodium hydride afforded 342 (128). Condensation of ergolines with ketone in the presence of acid catalysts such as sulfuric acid or p-toluenesulfonic acid yielded the condensation R
@;
R
R
I I*..
337
340
338
339
34 1
342
SCHEME 58. Reagents: a. (EtO),P(O)CH,CO,Me, NaH: b. Ph,P'CH=CH,. CHICOZMe. DBU: d. CNCH,CO,Me. NaH.
NaH: c. CN-
I.
81
ERGOT ALKALOIDS
product 343 (129). Ergolines were reacted with acetic anhydride in the presence of boron trifluoride etherate to afford compounds of type 344 (130). I-Methylergolines afforded 2-cyanides (345)on anodic cyanation (131). Reaction of ergolines with methylsulfenyl chloride afforded 2-methylt hioergolines (346)(132).
R
$J
MeH...
R
343
344 R 1 = H , R 2 = C O M c
H
345 R ' = M c , R 2 = C N 346 R ' = H , R Z = S M c 347 R ' = H , Me, R 2 = C I , Br, I
R 348
Halogenation of ergolines at the 2 position was investigated with various halogenating reagents. Stanovnik et al. introduced a new brominating agent, namely, a 3-bromo-6-chloro-2-methylimidazo[ 1.2-hlpyridazine bromide complex, in the bromination of ergot alkaloids (133). Recently, electrochemical halogenation was also applied to the chemistry of ergot alkaloids for the synthses of 2-halogenated compounds 347 (134). Bach and Kornfeld obtained the dimeric product 348 from the reaction of ergolines with phosphorus oxychloride (135). Very recently, two papers appeared on the syntheses of 2-methylthioergolines and 2-substituted ergolines via 2-bromoergoline (300).
d. Substitution at the 1 Positiin. Previously, it was known that alkylation at the I position proceeds by reaction of ergolines with alkyl halides, and the reaction was carried out with sodium in liquid ammonia, thereby forming an indolyl anion as the actual species. Some new and convenient procedures using potassium hydroxide, sodium hydroxide, or sodium hydride for the formation of indolyl anions to react with alkyl halides have been introduced (136,137). However, the inevitable formation of olefins as a result of dehydrogenation of the alkyl halides was observed, thus spoiling the usefulness of the above procedure. Marzoni and Garbrecht established an effective method for alkylation at the I position, even in cases of bulky alkyl groups (138). First, the indolyl anion was formed by treatment with potassium hydroxide in
82
ICHIYA NINOMIYA AND TOSHIKO KlGUCHl
DMSO, and then reaction with alkyl tosylates instead of alkyl halides was carried out to yield products of type 349. Danieli et al. also succeeded in introducing a hydroxy-methyl group at the 1 position (350)in %-SO% yield by applying electrochemical methoxylation (139). R
R
349 R'=Mc, n-Pr, i - P r
350
Introduction of a nitroso group at the 1 position was achieved by treatment of ergoline derivatives or elymoclavine with sodium nitrite, yielding the N-nitroso derivatives 351 and 352 (140). Nitrosation of 6-norergoline derivatives was known to occur preferentially at the 6 position, giving a mixture of two nitroso derivatives 353 and 354 (141).
&
& ct-im
ONN
ON"
35 1
ONN
352
HN
353
354
e. Other Reactions Applied to Ergolines. Hydroboration of lysergic acid (38),followed by treatment with hydrogen peroxide afforded glycol 355, which was then treated with phosphorus oxychloride-hydrochloric acid in pyridine to form the seven-membered ring system 356 (Scheme 59) (142). This transformation could be explained in terms of WagnerMeerwein rearrangement involving C-9-OH and C-5-C- 10 bonds in an antiperiplanar configuration followed by loss of a proton, thus forming 356.
38
355
356
SCHEME59. Reagents: a, B2HB;b, KOH, MeOH, HzOz;c, POCI,, HCI,
py.
I.
83
ERGOT ALKALOIDS
For the synthesis of optically active benzov]quinolines, ergot alkaloids are employed as shown in Scheme 60 (143). Ergonovine (357) was oxidized with periodate to yield the formamidoketone 358, which on hydrolysis afforded the aminoketone that was then deaminated via diazotization and hypophosphorous acid reduction to give ketone 359. Reductive removal of the ketone function in 359 was effected by treatment with triethylsilane and boron trifluoride etherate in trifluoroacetic acid to yield 360. Similarly, agroclavine (9) was converted to depyrroloagroclavine 361. To summarize this section, by applying the reaction most suited for the target, lysergic acid (38) (144,143, dihydrolysergic acid 1 (146-1561, dihydroisolysergic acid 1 (157,158),elymoclavine (48) (159), lysergol (49) (160), agroclavine (9), and festuclavine (54) (161, f 6 2 ) ,which are abundant in natural sources, have been used for conversion to various types of ergoline derivatives. 2. Synthesis of Dihydrolysergic Acid and Other Ergoline Derivatives From a pharmacological point of view, dihydrolysergic acid has been the center of interest for synthesis. Two groups have achieved its synthesis. In addition, Kornfeld’s group prepared decarboxylysergic acid 374 and 8-arylergoline derivatives 377 from the synthetic intermediate prepared in the total synthesis of (+)-lysergic acid (38) by Woodward and co-workers. R
359
R
9
361
360
SCHEME60. Reagents: a. NalO,, H,O: b, NaOH, MeOH; c. NaNO,. H,O. H,PO,: d. CF,CO,H, Et,Si. BF,-Et,O.
84
ICHIYA NlNOMlYA A N D TOSHIKO KIGUCHI
a. Synthesis of Dihydrolysergic Acid. Tricyclic ketone 96 was converted to the tetracyclic enarnine 362 by reaction of the p-tetralone 81 with bromomethylacrylic ester and methylamine (Scheme 61). Catalytic hydrogenation of 362 afforded 363, whereas reduction with sodium cyanoborohydride afforded 364 (163). The respective dihydro derivatives were converted to (&)-methyldihydroisolysergate I1 (365) and (+)-methyl dihydrolysergate I (326) ( 1 64). Haefliger and Knecht established two methods for construction of the indole nucleus using nitrotetralin (165,166). By applying one of these methods, they successfully synthesized dihydrolysergic acid (167). This new synthesis of (+)-methyl dihydrolysergates 330 and 332 (Scheme 62) was started by building ring D onto 5-nitro-2-tetralone 366 by the GrobRenk procedure. After appropriate manipulation of product 367 at the final stage of synthesis, construction of the indole five-membered ring was effected by closure of a benzylic anion onto an isocyanate function
@
c,
d,
c‘
___)
l3/ N
326
96
81
362
363
365
SCHEME 61. Reagents: a, H,C=C(COZEt)CH,Br, MeNH,; b, H,/PtOZ; c, KOH, MeOH; d, MeOH, HCI: e, MnO,; f, NaBH,CN.
1.
C0,MC
N( l2 367
NO* 366 R = t l
d, c
&k
' N=C 369
C02Me
$HMc/ N o 2
368
C02Me
C0,MC
370 R = O M e c,
1,
&Mc
R
85
ERGOT ALKALOIDS
___c I
&Me R
' HN 330 R = H 332 R = H 371 R = O M c
SCHEME 62. Reagents: a, HLC=C(COZMe)CHLBr, MeNH?: b. NaCNBH,; c. HJPd-C: d , N-formylimidazole; e. POCI,, EtN(i-Pr),; f, LIN(i-Pr)?*diglyme.
generated from the nitro group. Although intermediates 368 and 369 contained the desired stereochemistry of dihydrolysergic acid I, strongly basic conditions were required for conversion of 369 to 330 and resulted in removal of a proton at the 8 position and formation of the two epimeric esters 330 and 332 in 25 and 28% yields. Further, 6-methoxy-5-tetralone 370 was used for the synthesis of 371.
b. Other Ergoline Derivatives. Kornfeld and co-workers picked compound 372, the key intermediate in the first total synthesis of (*)-lysergic acid (38), for the preparation of decarboxylysergic acid (374) and 8-arylergolines (377) (Scheme 63). They carried out the synthesis as follows: compound 372 was acetylated to give acetate 373, which was then subjected to electrolytic reduction to give 374, which was also obtained from 372 by direct oxidation with manganese dioxide to 45 followed by protection as the dithioethylene ketal 375 and desulfurization (168). On the other hand, compound 376 was also obtained from 372 as a mixture of isomers by treatment with trifluoroacetic acid and boron trifluoride etherate in the presence of an aromatic compound (169).
G . SYNTHETIC METHODOLOGY 1: SYNTHESIS ACCORDING TO REACTION EMPLOYED
SYNTHETIC
In this section, the major and potent synthetic reactions invented and applied for the total synthesis of ergot alkaloids are summarized. They are classified as follows: ( 1) intramolecular 1,3-dipolar addition, (2) enamide
86
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI OAC
I,, c , d H
/ ;.&
374
373
t
- J$
d
H
372
c
HN
\
375
-& 1‘
/
HN
H
376
/
HN 377
SCHEME 63. Reagents: a , Ac,O: b, electrolytic reduction: c , KOH; d , MnO,: e . HSCH,CH,SH. BF,-Et,O; f, Raney Ni. acetone, DMF: g, BF,-Et,O, CF,CO,H, ArH.
photocyclization, (3) Heck reaction, and (4)intramolecular cyclization by nitronate anions. 1. Intramolecular 1,3-Dipolar Addition 1,3-Dipolar additions have been one of the major reactions studied in the synthesis of various types of both carbocyclic and heterocyclic ring systems ( I 70). As a consequence, 1,3-dipolar reactions, both intermolecular and intramolecular, have been investigated with the aiming of synthesizing natural products, including terpenes and alkaloids. For the synthesis of ergot alkaloids, two types of 1,3-dipolar reactions, namely, additions of nitrone-olefins and nitrile oxide-olefins, have been extensively investigated and successfully applied. Oppolzer’s and Kozikowski’s groups independently picked the same isoxazoline-type com-
1.
87
ERGOT ALKALOIDS
pounds (378) as potential synthetic precursors for the synthesis of 6,7secoergoline alkaloids (Scheme 64). Oppolzer successfully synthesized isoxazoline 378 by the newly developed intramolecular nitrone-olefin addition of 379 (171), while Kozikowski independently made 378 by intramolecular nitrile oxide-olefin cycloaddition (INOC) of 380 (172). a. Intramolecular Nitrone-Olefin Addition. Preparation of isoxazoline ring systems by intramolecular nitrone-olefin addition had been reported in the literature ( 1 73) even before Oppolzer’s successful application to ergot alkaloids. Generally, the nitrone-olefin 382 was known to be prepared by condensation of an unsaturated aldehyde (381) with N-alkylhydroxylamine, and 382 was usually used without further purification for the thermal reaction leading to the addition product (Scheme 65). Nitrones 382 are isomerized to Z form 383 on heating, and subsequent cycloaddition would follow readily. It was observed, however, that cycloaddition of the nitrone-olefin always gave a mixture of annelated products 384 and bridged products 385, the ratios depending on the length of alkyl chain and the type of substituent. Further, annelated products 384 consisted of predominantly the cis isomer of the two possible isomers with respect to the ring junction. The predominant formation of the cis isomer would be explained in terms of the less strained transition state shown in 386. Oppolzer et al. also investigated nitrone-olefin addition to compounds 387-389 (61). They observed that reaction of 387, which is unsubstituted at the end of olefinic double bond, afforded only the bridged product 390,
NHMc I
HA 2 378
6.7-Secocrgolines
379 SCHEME 64
380
88
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
384
385
SCHEME65
whereas 388 and 389, which are substituted with either a methoxyl or a carboxyl group, yielded the annelated product predominantly (Scheme 66). Isolated products 119 and 120 underwent isomerization on heating to give an identical 1 : 4 mixture of 119 and 120, the former being the major product in dichloromethane and thus the kinetically controlled product and 120 being the thermodynamically controlled product. Oppolzer et al. succeeded in the total synthesis of (+)-chanoclavines by using 119 as the starting compound (61). Kozikowski and Stein also applied nitrone-olefin cycloaddition to the synthesis of (2)-agroclavine 1 (9) (Scheme 67) (75). b. Intramolecular Nitrile Oxideolefin Cycloaddition (INOC). Kozikowski investigated the reaction of nitroalkene 393 with phenyl isocyanate in the presence of a catalytic amount of triethylamine in benzene at
387 R 1 = R 2 = H 388 R'=OMe,R'=H 389 R'=H, RZ=C02MC
390 (56%) 391 (16%) 119 (40%) SCHEME66
392 (30%) 120 (20%)
I.
89
ERGOT ALKALOIDS MC
187
9
SCHEME 67
room temperature and obtained the isoxazoline 396 via an INOC reaction (Scheme 68) (172). Unlike nitrone-olefin cycloaddition, the INOC reaction does not afford the bridged product 397, owing to the presence of geometric constraints, and it has the advantage of avoiding the formation of stereoisomers with respect to the ring junction. Aiming at the synthesis
393
394
395
396
397
401 402 213
398 R'=R*=H 3 9 9 R1=OMc,R2=t4 400 R'=H,R'=CH20Ac
SCHEME 68
90
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
406
410
408
412
SCHEME69
lcss favorablc
m orc fuvo r a Id c FIG.3. Direction of approach of a nitrile oxide to an olefin containing an allylic asymmetric center.
1.
91
ERGOT ALKALOIDS
of (?)-chanoclavine 1 (15), Kozikowski and co-workers investigated the INOC reaction of three compounds (398400) and obtained the cyclized products 401,402 and 213 having tetracyclic ring systems in 70-90% yield (Scheme 68). Further, diastereoface selection of the INOC reaction was examined using the nitroalkenes 403 and 404 with substituents (Scheme 69) (174). The ratio of the two types of products obtained could be explained in terms of A'.' strain existing in the proposed transition state. In the case of Z-nitroalkene 403, the transition state 405 is assumed, but methyl-methyl interaction would lead to product 410 only. In case of E-nitroalkene 404, on other hand, the very similar transition states 407 and 408 would be suggested, thereby forming a mixture of the two products 411 and 412 in the ratio 3 : 1. Further, INOC of chiral nitroalkenes has also been applied to the synthesis of (+)-paliclavine (61). As shown in Fig. 3, it was thought that cycloaddition would occur from the opposite side of the large and bulky substituent present at the allylic asymmetric center. However, the products obtained from 413 were a mixture of 221 and 222 in the ratio 1.1 : 1 (Scheme 70). Kozikowski and co-workers successfully applied the INOC reaction to the synthesis of sarkomycin and key intermediates of prostaglandins (172) and further extended intramolecular azide cycloaddition (IAC) to the synthesis of (+-)-clavicipitic acid (22) (Scheme 71) (99,100). The 3,Cdisubstituted indole 279 was deprotonated with sodium hydride and subsequent reaction with tosyl azide afforded azide 280 in 62% yield. Compound 280 underwent smooth cyclization by heating in o-dichlorobenzene at 190195°C to yield azepine 281 in 62% yield. The reason for direct formation of the seven-membered ring system in 281 was ascribed to the extreme instability of the presumed fused aziridine 415, thus causing hydrogen migration via benzylic stabilization.
THPO
&P
+
/
XN 413
22 1
SCHEME 70
222
92
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
415
28 1 SCHEME
71
2. Enamide Photocyclization Ninomiya and co-workers extensively investigated enamide photocyclization as one of the most powerful potential synthetic methods for the synthesis of six-membered nitrogen-containing heterocyclic ring systems, including various types of isoquinoline and indole alkaloids (50,175). Enamide photocydization is briefly summarized in Scheme 72. On irradia-
421 rcductivc SCHEME
72
1.
93
ERGOT ALKALOIDS
tion of an enamide, the photocyclized product is always formed as a sixmembered lactam with different oxidation levels depending on the reaction conditions. The didehydrolactam 420 is obtained by irradiation in the presence of an oxidizing agent (oxidative conditions), whereas the monodehydrolactam 419, whose structure is isomeric to the starting enamide (416), is obtained under nonoxidative conditions. Finally, saturated lactam 421 is obtained by irradiation in the presence of a hydride agent, that is, under reductive conditions. Furthermore, chiral metal hydride complexes, readily prepared from metal hydrides and chiral amines or amino alcohols, were successfully applied in reductive photocyclizations, thus enabling asymmetric photocyclization. All these photocyclizations are well explained in terms of an electrocyclic mechanism in a nitrogen-containing, six-n electron conjugated system, according to the Woodward-Hoffmann rule, by postulating the intermediacy of a common trans cyclic structure from which the respective types of products are formed depending on the reaction conditions, nonoxidative, oxidative, or reductive. In order to see the applicability of enamide photocyclization to the synthesis of ergot alkaloids, construction of benzov]quinolines, the basic skeletal components of ergot alkaloids, was investigated. N-Methylacrylnaphthalide 422 was irradiated using a low-pressure mercury lamp to see if the skeleton of ergot alkaloids could be constructed in one step under nonoxidative conditions ( I 76). Photocyclization proceeded smoothly to yield (40-60%) the benzov]quinolone 423, which has skeletal structure similar to 6,8-dimethylergolines, lacking only a pyrrole ring (Scheme 73).
424
425 SCHEME 73
426
94
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
Similarly, irradiation of the tricyclic enamide 424 for well over 96 hr afforded lactam 425 in 42% yield, which was reduced with lithium aluminum hydride and then acetylated to give 426, which has an ergoline-type skeleton (I77). This method provided a simple route to construction of the clavine skeleton; however, its application to the total synthesis of actual alkaloids seemed unsuitable because of the presence in the system of an aromatic ring, which is resistant to reduction. The most useful application of enamide photocyclization to the synthesis of target ergot alkaloids has been achieved by reductive photocyclization, that is, irradiation of enamides in the presence of sodium borohydride. In order to test the fitness of the reaction in the synthesis of ergot alkaloids, depyrrole analogs of clavines were picked as the model targets. In fact, these analogs were readily synthesized by applying reductive photocyclization to the acryloyl and furoylenamine-type enamides 427 and 432. Irradiation of enamide 427, prepared from 2-tetralone and methacryloyl chloride in the presence of triethylamine, under nonoxidative conditions, afforded lactams 428 and 429 in yields of 45 and 10% (Scheme 74). Irradiation of 427 in the presence of sodium borohydride at low temperature (4-5"C), however, led to facile formation of hydrogenated lactam 430 as a mixture of isomers that were reduced with lithium aluminum hydride to afford the corresponding amines (431) (I78). These amines have structures corresponding t o the depyrrole analogs of three clavines, pyroclavine (1141, festuclavine (541, and epicostaclavine ( l ) , with respect to skeletal structure and stereochemistry. Similarly, photocyclization of the P-methoxy-substituted enamide 427 followed by two-step hydride reduction with lithium aluminum hydride and sodium borohydride furnished depyrrole analog 361 of agroclavine (9). MC
MC
428
429
430
36 1 SCHEME 74
43 1
I.
432
81
95
ERGOT ALKALOIDS
433 R=/l-tt 434 I<=n-H
435
83+84
The synthetic utility of reductive photocyclization has been markedly enhanced by the introduction of a furan ring in the acyl portion of the enamide. The enamide of N-(3-furoyl)enamine type 432 was irradiated in the presence of sodium borohydride at 4-5°C to give a mixture of two hydrogenated lactams 433 and 434,stereoisomeric with respect to the B/ C ring junction (cis and trans), which were separated (Scheme 75) (179). Product ratios depended on the solvent used. The B/C-trans lactam 433, which was the major product when irradiation was carried out in acetonitrile, was employed for the establishment of a synthetic route to ergot alkaloids (72,180), and the results obtained on the synthesis of depyrrole analogs of the alkaloids (435)were successfully applied to the (3-tetralone 81, thus furnishing the total synthesis of a number of ergot alkaloids, mostly for the first time (50).
3. Heck Reaction The Heck reaction has been designated as a carbon-carbon bond forming reaction of an alkenyl halide (436)with a vinylic compound (437) in the presence of palladium(0) catalyst and triphenylphosphine as the ligand (Scheme 76). It has been extensively investigated and established as a useful synthetic reaction (181). Somei et al. have applied the Heck reaction to the synthesis of 4-alkenyl substituted indoles (243)from 4-iodoindoles (242)(Scheme 77) and
96
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
436
437
430
SCHEME16
established the reaction conditions. Treatment of the reactants in the absence of ligands such as triphenylphosphine and in the presence of palladium acetate as the catalyst in triethylamine and DMF led to 243 in 83% yield (87,f82). However, subtle control of the reaction temperature is an essential factor, which makes application of the method difficult, and thus the development of a more useful procedure for this reaction was awaited. In 1984, Jeffery invented the modified Heck reaction procedure involving phase-transfer catalysis, that is, a procedure using tetrabutylammonium chloride as a phase-transfer catalyst in the presence of palla-
--b
243 X = Y = Z = t l , L=OH 439 X = Y = I l , Z=OlH, L=OMc 441 X=OMc, Y=Z=lH, L=OH
242 X=H 440 X=OMc
dX
q
1SN
fiN
'
442
qG1
443
T
1SN
6&y ISN
306 SCHEME
307 X = C 0 2 M c , Y = N H A c 310 X=OEI, Y = H 77
1.
97
ERGOT ALKALOIDS
0
96
107
110
SCHEME78
dium acetate in DMF solution. They have achieved good results with high reproducibility (183). Somei et al. applied Jeffery’s procedure to the synthesis of compounds 439 and 441 (Scheme 77), which are potential intermediates for alkaloid synthesis (89,182,184).Harrington and Hegedus investigated the Heck reaction of 4-bromoindole 442 (185) and applied it to the synthesis of the ergot alkaloids (+I-aurantioclavine (23) and ( 2)-clavicipitic acid (22) (105,106). Since it is known that an electron-deficient substrate is required for good results in the Heck reaction, Harrington and Hegedus succeeded in using N-tosyl-4-bromindole (442) as the substrate for the Heck reaction leading to the insertion of various olefinic groups at the indolic 4 position (Scheme 77). Also, by using N-tosyl-3-iodo-4-bromoindole (306). introduction of a double bond at the 3 position of the indole nucleus was carried out. The reaction proceeds smoothly and does not require the addition of phosphine, thus enabling regioselective and stereoselective introduction of a double bond at the 3 position. Cacchi et al. applied enol triflates in the Heck reaction and successfully introduced an olefinic group (186). Ketone 96 was first reacted with triflic anhydride to afford enol triflate 107, which was then subjected to the Heck reaction to introduce various types of olefinic groups at the 5 position (e.g., 110) (Scheme 78). Thus, enol triflates as well as alkenyl halides could be used for the Heck reaction (59). 4. Intramolecular Cyclization by Nitronate Anions
It has been known that palladium catalyst is effective in the intermolecular carbon-carbon bond forming reaction between the ally1 alcohol 444 and nitronate anion 445 (Scheme 79). Genet and co-workers also investigated the palladium-catalyzed intermolecular coupling reaction of the primary ally1 alcohol 447 with nucleophile 448 and found that potassium fluoride was the most effective base for formation of the anion and Pd(dppe)2 the most suited palladium(0) catalyst (187). They successfully showed the
98
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
446
OAc 447
+
@
?NO2
448
C02Et 449
269
266 SCHEME
79
usefulness of this reaction in the synthesis of (-)-chanoclavine 1 (15) (93,94). Somei and co-workers applied the palladium-catalyzed intermolecular reaction to the cyclization of 4-alkenylindole 450 to the tricyclic compound 245 (Scheme 80) but failed to obtain any cyclized product. Somei also investigated the reaction catalyzed by a combination of base and acid and succeeded in the synthesis of tricyclic 245 in 41% yield using zinc chloride and triethylamine in 1,2-dichloroethane. Further, Somei improved the yield of the trans-tricyclic compound 245 to 73% by using sodium borohydride and 2 N hydrochloric acid in aqueous solution, thus establishing a new cyclization reaction of ally1 alcohols and nitroalkanes (Scheme 80) (182). Intramolecular cyclization can be applied t o 244, the synthetic precursor to 450. Compound 244 was reduced with sodium borohydride in methanol to form the nitronate anion 451, which without isolation was subjected to the above-mentioned cyclization procedure to give 245 in 71% yield. The indole derivative 248 having a different substituent at the 4 position also underwent smooth stereoselective cyclization to 249-251. This suggested that transition state 452, having a nitro group in an equatorial orientation, would be the most stable structure, from which the reaction proceeded stereoselectively to afford 249 as a result of steric repulsion between the nitro group and a substituent (R3) in the allylic alcohol moiety.
1.
99
ERGOT ALKALOIDS
dl::2
+
0
H .
-
X
450
245
NO:
45 1
SCHEME80
Intramolecular cyclization was further applied to chiral derivative 453 (Scheme 8 I ) . 3-Formyl-4-iodoindole (242) underwent the Heck reaction with ( + )-(R)-p-tolylvinyl sulfoxide and subsequent reaction introducing a nitroalkane afforded optically active 453. Compound 453 was then subjected to cyclization in the presence of sodium borohydride to yield a mixture of four optically active isomers (454) (88).
242
453
SCHEME81
454
100
ICHIYA NINOMIYA AND TOSHIKO KlGUCHl
H. SYNTHETIC METHODOLOGY 2: SYNTHESIS ACCORDING TO STARTING COMFQUNDS Syntheses of ergot alkaloids may also be classified according to the type of starting compound. A survey of previous achievements is classified as follows: (1) use of indoline derivatives as the starting material, (2) use of indole derivatives, and (3) use of derivatives without indole skeletons, thus building up the indole ring at a later stage of synthesis. Approach (3) is discussed in Section 111, I in the context of 1,2 and 2,3 bond formation.
I . Synthesis of Ergot Alkaloids Starting from Indoline Derivatives The first synthesis of ergot alkaloids starting from indoline derivatives appeared in the first total synthesis of (?)-lysergic acid (38) by Woodward and co-workers (3). It is meaningful to see that this great and pioneering achievement had started from indoline derivatives. In order to promote cyclization of the substituent at the 3 position to the 4 position, the indole ring must be converted to the corresponding indoline derivative (455) (Scheme 82). This cyclization for the construction of a tricyclic ring system (benz[c,djindole) has been the most crucial step for the supply of a large quantity of starting material that is indispensable for the subsequent lengthy synthesis. Cyclization was achieved by Friedel-Crafts reaction of the N-benzoylindolinyl-3-propionyl chloride to yield the corresponding a-tetralone 96 in good yield. When indoles were used in this reaction, various restrictions and limitations arose owing to instability of the skeleton. The indolines are the most stable toward various reactions and thus furnished the first total synthesis of (+-)-lysergicacid (38). A couple of tricyclic derivatives were prepared for further syntheses, including the p-tetralone 81, the unsaturated aldehyde 64, and the unsaturated cyanide 98, The preparative methods have also been thoroughly investigated and established by later researchers, thus making these compounds available in large quantities. Kurihara’s method of the preparation of 64 can be regarded as widely applicable to other compounds (188). The a-tetralone 96 was treated with diethylphosphorocyanide and lithium cyanide to give the cyanophosphate 97, which was then treated with boron trifluoride etherate to give the a,p-unsaturated nitrile 98 in an overall yield of 90% (Scheme 82). Nitrile 98 was then reduced with DlBAL to afford the corresponding aldehyde (64). On the other hand, Rebek ef al. prepared aminoketone 90 from tryptophan via the dihydrotryptophan 89 and successfully applied it to total synthetic works (56). Julia et al. started their synthesis of (?)-lysergic acid (38) with the oxindole 456, which was reduced to indoline 457 followed by cyclization to construct the skeleton of the alkaloid (Scheme 83) (47).
I.
101
ERGOT ALKALOIDS
38
(‘I I 0
64
CN
90 X = N H B z 96 X=tI
97
98
SCHEME 82
As shown above, three indoline derivatives (90,96, and 456) have been prepared and used as key starting compounds, thus bringing about the success of the respective total synthesis. The crucial synthetic steps consist of the formation of the ring C by cyclization of a substituent at the 3 position to the 4 position of indoline, and the target alkaloids are mainly the ergot alkaloids having ergoline-type skeletons, such as lysergic acid (38).
102
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
458
459
460
SCHEME84
2. Synthesis Starting from Indole Derivatives Uhle et al. reported the intramolecular condensation of the diacid 459 obtained from 4-cyanoindole 458 to give ketone 460 (Scheme 84). The first synthesis beginning with an indole derivative was carried out with Uhle’s ketone (460) but failed to achieve the goal (189). However, prompted by the study of this approach, investigations on not only exploitation of the synthesis of indole derivatives having a substituent at the 4 position but also total synthetic work along these lines have drawn attention from many researchers (189,190). As the result, synthesis of ergot alkaloids via a route involving intramolecular cyclization to construct ring D has been fruitful. The first successful applications of this approach were obtained by both Kozikowski’s and Oppolzer’s groups. Both groups started their respective synthesis from 4-formylindole (115) and achieved total synthesis according to a plan in which the formyl group was converted to an ally1 group followed by formation of ring C by cyclization ( 1 72,f 73). Later, R’
115 X = H
46 1
SCHEME85
1.
103
ERGOT ALKALOIDS
newer synthetic routes were introduced by the synthesis of allylindole 461 not from 4-formylindole but directly from other common compounds
(Scheme 85) (63,91,f82,Z85). Target alkaloids of approaches starting with indole derivatives have been mostly the 6,7-secoergolines and azepinoindoles. Exceptions are the synthesis by Oppolzer’s group of (+)-lysergic acid (38)via a route involving the Diels-Alder reaction (49) and the Lewis acid-catalyzed synthesis of (+)-agroclavine I (10) by Kozikowski’s group (75). As summarized, all the syntheses of alkaloids beginning with indole derivatives have followed a route involving the intramolecular cyclization of two substituents at the 3 and 4 positions. Goto et al. developed a method for cyclization of 3-substituted indoles to the 4 position, thus constructing ring C (108), as discussed in Section III,I,5. I. SYNTHETIC METHODOLOGY 3: SYNTHESIS OF SKELETONS OF ERGOT ALKALOIDS
Ergot alkaloids are classified according to their skeletal structures into three groups: alkaloids having an ergoline skeleton, alkaloids having a 6,7-secoergoline skeleton, and alkaloids having an azepinoindole skeleton. Numbering of these skeletons has been developed from biogenetical considerations as shown.
8)-7
8 14 13
@ , I
15 HN 1
9 f
4
3 2
ergolinc
1
2
(,,i’-sccocrgoIin e
1
2
azepinoindole
In this section, syntheses of the skeletal structures of ergot alkaloids are further divided according to the final bond formation reaction. In fact, no synthetic approach involving formation of the 3,4 bond as the last step has been reported for any of the three skeletal types. And there have been no reports of synthesis of ergoline-type skeletons with 7,8 or 8,9 bond formation as the last step. 1. Synthesis with 1,2 Bond Formation as the Last Step Prior to 1970, nitration of benzo[flquinoline-6-carboxylates(462) had been extensively studied with the aim of forming the 1,2 bond as the last step in synthesis (189). This approach was seriously hampered by diffi-
104
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
462
463
464
465
198
200
SCHEME 86
culty in hydrogenating rings C and D. however, until 1976, when Plieninger et (11. succeeded in the synthesis of (?)-chanoclavine I (15) (78). They began the synthesis with nitration of P-naphthol 465 t o give 198 which carries all the required substituents (Scheme 86). Ozonolysis of 198 provided 1,2 bond formation (200).
2. Synthesis with 2,3 Bond Formation as the Last Step Haefliger and Knecht synthesized some benz[c,c/lindole derivatives by applying the Leimgruber-Batcho indole synthesis (165) and also via a route involving the isonitriles (166), and the synthesis of (2)-dihydrolysergic acid according to the latter route was successful (169). NitrobenzoLflquinoline 368 was converted t o the corresponding isonitrile (3691,
368
369
SCHEME 87
330
+ 332
I.
105
ERGOT ALKALOIDS
which was then cyclized t o form the indole ring and thus the alkaloid skeleton (330 and 332) (Scheme 87). 3. Synthesis with 4 3 Bond Formation as the Last Step A synthetic approach to the skeleton of ergot alkaloids has been extensively investigated by Natsume and co-workers ( 6 2 6 7 ) . They developed the useful and general synthetic route involving modification of the substituent at the 4 position of the indole ring, introduction of a formyl group at the 3 position of 132 and 295 by the Vilsmeier reaction, and then cyclization between the two groups at the 3 and 4 positions. In this way, they succeeded in the synthesis of (~)-6,7-secoagroclavine(13) and (+)-clavicipitic acid (22) (Scheme 88). More recently, Somei et al. developed a new and useful method of introducing various substituents at the 4 position by using (3-formylindol4-yl)thallium bis(trifluorob0rate) (466), thus providing the possibility of formation of the alkaloid skeleton by cyclization of two substituents at the 3 and 4 positions (Scheme 89). Although they did not apply the method t o total synthetic work, they discovered new applications of organotin compounds for the introduction of substituents at the 4 position (tin-thall reaction) (191) and another application of organoborane compounds for the boronation-thallation reaction (192). These interesting reactions may be useful in synthetic organic chemistry.
n
0
0
132
133
13
295
296
22
SCHEME 88
I06
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
467
(IiO)zB
0
CtlO
468
SCHEME 89
4. Synthesis with 5 , l O Bond Formation as the Last Step A synthetic strategy including 5 , l O bond formation as the last step has been investigated by five groups. Oppolzer’s and Kozikowski’ groups independently by I ,3-dipolar addition (172,173), Somei’s group by Michael addition and S,2’ reaction to allylic alcohols (182), and Matsumoto’s group (92) and Genet and Grisoni (93) also independently by S,2’ reaction have developed synthetic methodologies for construction of the skeleton of 6.7-secoergoline alkaloids and then achieved their total synthesis (Scheme 90). Further, Oppolzer et a l . succeeded in constructing ergoline skeleton 471 (Scheme 91) by applying the Diels-Alder reaction for formation of the 5,lO bond concomitantly with formation of the 6,7 bond. The reaction sequence was extended to the total synthesis of (-+)-lysergic acid (38) (49).On the other hand, Hegedus et al. investigated the Diels-Alder reaction of the 3,4-disubstituted indole derivative 472 but did not achieve fruitful results (106). Anderson and Lawton synthesized compound 474, which carries all the substituents required for the synthesis of ergot alkaloids via a route including 10,l I bond formation by intramolecular photochemical cyclization of compound 473, obtained readily from tryptophan (Scheme 92). However, they did not extend their research to 5,lO bond formation (193).
1.
379
107
ERGOT ALKALOIDS
378
380
- &:;)> R'
Michacl addition R=COY, R'=R'=H
:ON$$
SN2' R = Crcaction R1R20Y
XN
I IN
469
470
SCHEME 90
79
47 1
472
SCHEME 91
473
474
SCHEME 92
475
10s
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
476
477
319
478
320
SCHEME 93
5. Synthesis with 10,l I Bond Formation as the Last Step Before 1970, several investigations had been carried out on application of the Pschorr reaction (476 + 477) (Scheme 93) to 10,I I bond formation but without any promising results. Julia ef al. applied the benzyne reaction (457 + 72) to 10,l I bond formation and further extended the methodology to total synthesis of (&)-lysergic acid (38) (47). Goto ef al. succeeded in 10, I I bond formation of the azepinoindole ring system 320 via reaction between dehydrotryptophan methyl ester 319 with an aldehyde in the presence of camphorsulfonic acid o r boron trifluoride etherate (194).
6. Synthesis with 5,6 Bond Formation as the Last Step In 1976, Ramage and co-workers succeeded in the total synthesis of (+)-lysergic acid (38) via a route involving 5,6 bond formation as the last step (48). The methodology consists of intramolecular Michael addition
I.
C( )? M c
COzR
x$ /
109
ERGOT ALKALOIDS
&Y-
II
A
38
B/.N
BLN
479
69
+ 70
SCHEME 94
of an amino group to the unsaturated ester in 479 (Scheme 94). A reaction analogous to the above Michael reaction was applied to 479 by Kurihara et al. (57) and by Cacchi et al. (591, who independently succeeded in the total synthesis of (+)-lysergic acid (38). Furthermore, Kurihara and coworkers successfully applied intramolecular Michael addition of the model compound 481 to synthesize 482, but attempts at the synthesis of starting material 484 for the total synthesis failed (Scheme 95) (195). 7. Synthesis with 6,7 Bond Formation as the Last Step Rebek et al. developed a new method of 6,7 bond formation by a route involving Reformatsky reaction of compound 90, obtained from tryptophan, to the y-lactone ring compound 91, which was then cyclized to the ergoline skeleton (162) (Scheme 96). Thus, they succeeded in the synthesis of (5)-lysergine (3)and (*)-isosetoclavine (46) in addition to the ergoline skeleton (56). Rebek et al. also synthesized the ergoline skeleton 93
Mc ' ' NI
480
48 1
482
COJ3
483
.
484
SCHEME 95
110
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
MC
90
91
162
0
92
93
SCHEME96
and (+)-lysergic acid (38) by a route involving 6,7 bond formation via an exo double bond of y-lactone 91. Further, all syntheses of ergoline skeletons by conversion of the ring system from 6,7-secoergoline skeletons involved 6,7 bond formation in the last step (Scheme 97). Such an approach is exemplified by the synthesis of (*)-costaclavine (2) and others by Oppolzer et a / . (61), (*)-agroclavine I (10) by both Somei’s group (90) and Kozikowski’s group ( 7 3 , and (2)-dihydrosetoclavine (145) by Natsume ef a / . (64-66). 8. Synthesis with 9 , l O Bond Formation as the Last Step
The first skeleton synthesis involving 9 , l O bond formation as the crucial step was the first total synthesis of (-+)-lysergic acid (38) by Woodward and co-workers (485 3 486) (Scheme 98) (3). Ninomiya et al. investigated photocyclization of enamides involving 9,lO bond formation as the crucial step (82 += 83). Thermal reactions involving 9 , l O and 6,7 bond formation (81 += 112) are also included. Cassady and co-workers exploited the high reactivity of p-tetralone 81 in the synthesis of ergoline skeleton 362 by forming both the 9,lO and 5,6 bonds in one pot, as exemplified by the synthesis of (2)-dihydrolysergic acids (163,164). In addition, synthetic study of ergot alkaloid skeletons using Uhle’s ketone included 9,lO bond formation at the final step. However, all attempts to synthesize ergot alkaloids using derivatives of Uhle’s ketone
1.
111
ERGOT ALKALOIDS
Somci
10
256
Mc
-
Koyikowski
189
190
148
149
Scmm 97
were unsuccessful. Bowman also investigated the use of compounds prepared from Uhle's ketone in a synthetic study of ergot alkaloids but failed to reach the goal (196).
I12
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
,cg
qNM‘ NiiOMc
BzN
485
486
vNMc I
I13
1-1
-
b
-
BzN
82
83
SCHEME 98
9. Synthesis with 6,lO Bond Formation as the Last Step
All four synthetic approaches to azepinoindole skeletons were carried out according to the strategy of forming the 6,lO bond in ring C of the skeleton by condensation of the substituents at the 3 and 4 positions. Accordingly, Kozikowski and Greco succeeded in the total synthesis of (*)clavicipitic acid (22) via a route involving initially the construction of the azepinoindole ring by intramolecular azide cyclization (280 + 281) (Scheme 99) (101). Further, Kozikowski’s (102), Somei’s (104), and Harrington’s groups (105,106) applied the S,2’ reaction using ally1 alcohols 289, 304, and 308 and Matsumoto’s group applied condensation of the amino and carbonyl groups in 317 to form the 6,lO bond of the azepinoindole ring, thus completing the total synthesis of (+)-clavicipitic acid (22) and (+)-aurantioclavine (23) (107). Finally, Somei’s group reported a sim-
I.
113
ERGOT ALKALOIDS
-
Koz ik ow s k i Somci I i ;ir r i ngton 289, 304, 3 0 8
317
318
Somci
NI 1.
- ?2' I IN
487
488
SCHEME99
ple synthesis of the azepinoindole skeleton (487 + 488) using N-benzyltrimethylammonium hydroxide (triton B) (197). J . USEFULNEWSYNTHETIC METHODS As described in Section llI,H, syntheses of ergot alkaloids can be strategically divided into two groups (Scheme loo), namely, syntheses starting from indole (Route A) or indoline derivatives (Route B). In syntheses beginning with indole derivatives, the crucial obstacle has been prepara-
114
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
GX
Routc A
RN
\ Routc B
/
&. l iN crgoli n c
SCHEME 100
tion of the desired indole derivative in sufficient quantity. Of course, commercially available compounds are desirable starting materials, but most of the indole derivatives have to be prepared by methods exploited specifically for the purpose. On the other hand, in cases using indoline derivatives as the starting compounds, another problem has arisen concerning the dehydrogenolytic conversion of indolines to indoles, which was a serious hurdle to overcome because of the instability of indoles thus formed under conditions of dehydrogenolysis. To solve these two major problems in the synthesis of ergot alkaloids, there have been a number of devoted efforts that have not only effectively overcome these problems but also provided some practical procedures, thus benefitting progress in the chemistry of natural alkaloids. Here we summarize the major contributions that were applied to the total synthesis of ergot alkaloids. 1. Synthesis of 4-Substituted Indoles A number of general synthetic methods for the synthesis of indole derivatives, including those in the field of ergot alkaloids, have been developed and also reviewed by many chemists. For the synthesis of ergot alkaloids, practical preparations of 4-substituted indole derivatives have been the center of interests, as reviewed by Kozikowski in 1981 (198). However, a couple of novel preparative methods have been developed since Kozikowski’s review.
a. Leimgruber-Batcho Indole Synthesis. In 1970, a new reaction of onitrotoluene (489) with N,N-dimethylformamide dimethylacetal (DMFDMA) was reported to give (E)-dimethylamino-2-nitrostyrene(490), which was then reduced to form an indole derivative (Scheme 101). This
I.
I15
ERGOT ALKALOIDS
sequence of reactions, called the Leimgruber-Batcho indole synthesis has been highly evaluated and employed as a useful synthetic methodology, particularly for the synthesis of 4-substituted indoles (199). Kozikowski ef ul. applied the Leimgruber-Batcho reaction to the synthesis of 4-formylindole (115) from 3-nitro-2-methylbenzoic acid (491) in five steps with an overall yield of 55% (Scheme 102) (82). The preparation of 4-formylindole (115) was later improved by applying the LeimgruberBatcho reaction using 3-nitro-o-xylene (492) (200). Kozikowski et uf. also applied this reaction to the synthesis of the 4-substituted indole ester 493, which was then successfully converted to (+)-chuangxinmycin, an antibiotic alkaloid, as its first total synthesis (Scheme 103) (201,202). Somei et af. extensively investigated preparative methods for 4-substituted indoles (233) starting from 5-nitroisoquinolinium salts (232) (Scheme 104), but the yields were unsatisfactory (203-205). Further, Somei and co-workers developed another new procedure for the synthesis of 4-substituted indoles (494) via the Leimgruber-Batcho reaction with titanium trichloride as the reducing agent (206-208).
Mc
CHO
C IH(0M c): h, i NO2
H 492
115
SCHEME 102. Reagents: a. Mel. NaHCO,; b. Me,NCH(OMe),. DMF; c, H,/Pd-C; d. DIBAL; e. MnO,; f. CrO,, HZSO,, AcOH. Ac,O; g. MeOH. HCI; h, Me,NCH(OMe),. DMF. pyrrolidine; i. Raney Ni, NH,NH,.
I I6
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
d
4
-
)CozMc &
-)----*
H 493
H
<:
h ua ng x i n myc i n
SCHEME 103. Reagents: a. KOH. MeOH: b, Me,NCH(OMe),. DMF; c, 2 N HCI: d. FeSO,. NH,OH; e. conc HCI; f. CHzNZ.
b. Thallation Method. It had been known that when 3-formylindole (241) was treated with thallium trifluoroacetate, the 4-thallated indole
(466) was formed. However, its synthetic application to the introduction of substituents at the 4 position of the indole nucleus was unknown until Somei et al. discovered the useful thallation-palladation reaction.
0
232
233
1.
241
117
ERGOT ALKALOIDS
466
495
242
X
X
1 .
I{
II
H
496 X - I , Br, CI, C‘N 497 SCHEME 105. Reagents: a. TI(OCOCF,),. CF,C02H: b, Pd(OAc),. H?C=CHCOR. DMF; c. CuSO,.SH,O. dipyridine. DMF, H,O: d . I,. Cul. DMF. NaOR: e . I?. Cul, DMF; f. CuCN. DMF: g. CO. Pd(OAc),. MeOH; h. py. A.
Thallated indole 466 was reacted with methyl acrylate or methyl vinyl ketone in the presence of a catalytic amount of palladium acetate in DMF to give the 4-substituted indoles (495) (Scheme 105). Good yields of the indoles variously substituted at the 4 position were obtained (209). Yields of the 4-substituted 3-formylindoles were then improved by a procedure without isolation of the intermediary thallated compound 466. 3-Formyl4-iodoindole (242), prepared according to the thallation-palladation procedure ( 2 1 0 , 2 / / ) ,was successfully used in the total synthesis of some ergot alkaloids. 3-Methoxycarbonylindole (496) also underwent smooth reaction under these conditions to afford 4-halogenoindole 497, a useful key intermediate of this class, upon substitution by halogen followed by decarboxylation (2/2). c. Other Methods. Natsume developed a completely different type of synthesis of 4-substituted indoles starting from pyrrole derivatives (498), and the 4-substituted indoles thus prepared were applied to the synthesis
118
ICHIYA NlNOMlYA AND TOSHIKO KIGUCHI
of a wide variety of alkaloids, including (5)-a-cyclopiazoic acid and (?)teleocidin A in addition to ergot alkaloids (63). Pyrrole derivative 498 was irradiated in the presence of a photosensitizer such as methylene blue to form the unstable oxygen adduct 499, which was then reacted with various types of nucleophiles in the presence of stannous chloride at low temperature to afford the 2-substituted pyrrole 501 (Scheme 106). This result was explained in terms of the formation of stannous complex 500, which would then react with the nucleophile to form the stabilized aromatic pyrrole (501). To apply this reaction to the synthesis of indoles, N-methoxycarbonylpyrrole (498) was oxidized and then reacted with l-trimethylsilyloxy-1.3-butadiene as the nucleophile to give adduct 128. Cyclization of 128 was studied, and it was found that in the presence of stannic chloride indole 502 was obtained in 69% yield. Further investigation aimed at establishing a general preparation of 4-substituted indoles led to the development of a practical procedure in which adduct 128 was treated with Grignard reagent followed by oxidation with pyridinium chlorochromate (PCC) to give the a,P-unsaturated ketone (503), which was cyclized in the presence of stannic chloride to furnish 4 4 5 8 % yields of the 4-substituted indoles (504).
CO,MC 128
C0,Me
(‘0,Mc 502
Y R b (‘0,Mc 503
50 1
___, d
& N
COZMC 504
SCHEME 106. Reagents: a, O,, methylene blue, hu; b, SnCI,, nucleophile; c, I-trimethylsilyloxy-1,3-butadiene, SnCL; d, SnCI,; e, RMgl; f, PCC.
119
ERGOT ALKALOIDS
1.
Matsumoto and Watanabe synthesized 4-0~0-4,5,6,7-tetrahydroindole (257) from 1,3-cyclohexadione in three steps (Scheme 107) (213) and further applied compound 257 t o the synthesis of 4-substituted indoles and then to ergot alkaloids. Matsumoto and co-workers also investigated the reaction of 257 with umpolung anion and established a useful procedure (257) was refor the synthesis of indoles. 4-0~0-4,5,6,7-tetrahydroindole acted with methyl methylthiomethyl sulfoxide to give adduct 505, which was then subjected to dehydration, dehydrogenation, and hydrolysis to afford 4-formylindole 506 (Scheme 107) (214). Also, from the reaction of 257 with methyl phenyl sulfone, 4-substituted indole 259 was obtained and used for the total synthesis of (+)-6,7-secoagroclavine (13) (92). Matsumoto et al. extended the application of oxotetrahydroindoles 257 to 5hal0-4-0~0-4,5,6,7-tetrahydroindoles (507), which reacted with triethyl phosphonoacetate or diethyl cyanomethylphosphonate under HornerWittig reaction conditions to afford a mixture of E-and Z-olefins (508) (91,215). The mixture was subjected to dehydrohalogenation to give the 4-ethoxycarbonylmethylindoleor 4-cyanomethylindole (314). They succeeded in the total synthesis of (+)-clavicipitic acid (22) by using the 4cyanomethylindole (314) thus prepared ( 107).
1
a, I>, c
0
Y
505
r X
X
258
257
0
lh X
x 259
I< CH3R
___,&Jy 507
506
&J X
X 508
3 1 4 R = C N , X=Ts
It=<‘O>Mc,C‘N
SCHEME107. Reagents: a. CICH,CHO, NaHCO,, H,O; b. NH,OH, EtOH; c. XCI: d. MeSCH2SOMe, BuLi; e. CuCI,, MeOH. H,O: f, MeS0,Ph. BuLi, THF: g. CuCI2. AcOH, H,O; h, CuCI, or CuBr,; i, (EtO),P(O)CH,R; j, LICI, Li,CO,, DMF.
120
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
NO:
509
305
c,
510
Br
r
511
512
Ti
306 T i
SCHEME 108. Reagents: a, NaNO,. HBr; b, CuBr; c, Br,, (PhCO),O,; d, PPh,. HCHO: e , Fe. AcOH; f. p-TsCI. pv; g. p-benzoquinone, LiCI, PdCIJMeCN),, THF; h, Hg(OAc),. AcOH; i . I,.
Harrington and Hegedus prepared 4-bromoindole 512 by palladium(l1)catalyzed closure of N-tosyl-3-bromo-2-vinylanilide (511) (185). Sandmeyer reaction of 2-amino-6-nitrotoluene (509) afforded bromide 305, which was subjected to free-radical monobromination followed by the Wittig reaction with formaldehyde to give the 3-bromo-2-vinyl- l-nitrobenzene (510) (Scheme 108). Reduction of a nitro group in 510 afforded the N-tosylanilide 511 on tosylation. In the presence of bis(acetonitri1e)palladium dichloride as catalyst, 511 was subjected to cyclization to give the 4-bromoindole 512, which was then converted to 4-bromo-3-iodoindole 306 via a route including mercuration with mercuric acetate followed by iodination. 3-lodo-4-bromoindole 306 was then converted to 3,4-disubstituted indoles by the Heck reaction, thus completing the total synthesis of (*)-clavicipitic acid (22) and (+)-aurantioclavine (23) (105,106). 2. Dehydrogenation of Indolines into Indoles
Conversion of indolines to indoles by dehydrogenation has been regarded as one of the most important reactions in the synthesis of ergot alkaloids. The most frequently used reagents for this dehydrogenation step are chloranil, palladium on carbon, Raney nickel, manganese dioxide, and cupric chloride-pyridine (216). In the first total synthesis of (+)-lysergic acid (38), Woodward and coworkers devoted considerable effort to finding the most suitable reagent to complete the synthesis (3). The reagent they invented was hydrated sodium arsenate and Raney nickel, previously deactivated by boiling in xylene suspension. After this first synthesis, however, almost all the others employed manganese dioxide as the reagent of choice for the conversion of indolines to indoles. Since this reagent is one of the representative
I.
121
ERGOT ALKALOIDS
@ ---@ MnO,
HN
IiN 513
514 SCHEME109
oxidizing agents, there always exists a risk of undergoing further oxidation, particularly in cases where an allylic alcohol moiety is present in the molecule, forming the corresponding ketone (513 + 514, Scheme 109), and there is also a disadvantage in the amount of reagent used. Therefore, there have been many efforts to find o r invent a new reagent or new method for this dehydrogenation step. Most of the studies have been done on relatively simple compounds. In this section, we summarize the new inventions and findings that have been developed for this dehydrogenation route. Kikugawa et al. investigated dehydrogenation of indolines into indoles by two methods (Scheme 110) ( 2 / 7 , 2 / 8 ) .The first method consisted of treatment with dirnethyl sulfate and tert-butyl hypochlorite, forming the azasulfonium salts (515) as intermediates ( 2 / 7 ) . Thus, by treating with base, azasulfonium salts 515 would be formed via the intermediary carbanion, which would then trigger an intramolecular attack to form the indolenines, which spontaneously isomerize to indoles. lndoles were obtained in yields ranging from 61 t o 82%. The second method consisted of treatment with tert-butyl hypochlorite in the presence of DBU in ether (218).
/
'"'I
m:] CI
516
SCHEME 110. Reagents: a. Me$, r-BuOCI. CHICl2;b. Et,N: c, t-BuOCI, D B U . Et,O: d , DMF.
122
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
The N-chloro derivatives (516) first formed would be susceptible to dehydrohalogenation to afford the indole derivatives in yields of 4 0 4 4 % . Inada et al. employed salcomine (517) as the dehydrogenating agent (219). Indolines in methanolic solution in the presence of salcomine (517) under a stream of oxygen were converted to the corresponding indoles in yields of 5543%.
Barton et al. reported dehydrogenation using phenylseleninic anhydride (220). Indolines were treated with this relatively new reagent in T H F to form the N-selenoxides (518), accompanied by the liberation of phenylselenic acid (519), thus forming indoles (Scheme 1 1 I). When there is a substituent at the 3 position in indolines, dehydrogenation proceeded smoothly and homogeneously to give 3-substituted indoles, whereas in the cases of indolines having no substituent at the 3 position, the liberated phenylselenic acid reacted with the indoles, forming the 3-phenylselenylindoles (520) in quantitative yield, thus lowering the yield of the desired indoles considerably. Novel procedures for dehydrogenation under conditions of Swern oxidation (221) and dehydrogenation of N-protected indolines by manganese(ll1) acetate (222) have been reported (Scheme 112). Ninomiya et al. picked Barton’s phenylseleninic anhydride as the reagent of choice and regarded it as particularly suited for the total synthesis of a number of ergot alkaloids. In collaboration with Barton’s group, they developed a highly efficient and practical procedure for the conversion of indolines to indoles (223). When a-tetralone 521 was treated with phenylseleninic anhydride in T H F (Scheme 113), indole 514 was obtained in 42% yield along with a 20% yield of the 2-phenylselenide (522), which is considered to be formed by the coupling of indoles with phenylselenic acid (519) in the reaction mixture. To suppress the formation of this undesirable by-product (522), a couple of scavengers for phenylselenic acid (519) were investigated. As a result, indole itself was found to be the best scavenger to remove phenylselenic acid (519) as it forms in the reaction solution. The recommended procedure for this dehydrogenation was as follows. In the presence of indole (3 equivalents), indolines 521 and 513 were treated with phenylseleninic anhydride to form indoles 514 and 523 quantitatively without any detectable by-product. On the other hand, manganese-promoted oxidation of indoline 513 produced no indole (523); instead, oxidized ketone 514 was obtained in 33% yield.
1.
123
ERGOT ALKALOIDS
WR1 a ql;: ---j-*a:: R'
H
H
pi, /%()
PhSc( )H
518 519
"i
WR2 ScPh
H
520
SCHEME I 1 1 . Reagents: a. (PhSeO),O or PhSeO,H, THF.
m-m-m I,
a
H
X
X
X=CONI12, S 0 2 P h , COMc SCHEME 112. Reagents: a. DMSO. (COCI),, Et,N. CH,CI,: b, Mn(OAc1,. AcOH.
@
-@+* a
HN
HN
52 1
@ HN 513
HN
514
a
@ HN
523 SCHEME 113. Reagents: a, (PhSeO),O, indole, THF.
522
ScPh
124
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
TABLE V l l l DEHYDROGENATION WITH PHENYISELENINIC ANHYDRIDE IN THE PRESENCE OF INDOLE Substrate
Product
Methyl 2.3-dihydrolysergate 2.3-Dihydroelymoclavine 2.3-Dihydrolysergol 2.3-Dihydroisolysergol 2.3-Dihydroagroclavine 2.3-Dihydroagroclavine I 2.3-Dihydrofumigaclavine B 2.3-DihydroisofumigaclavineB 2.3-Dihydrolysergene 2.3-Dihydroisolysergine 2.3-Dihydrochanoclavine 1 2.3-Dihydroisochanoclavine 1
Methyl lysergate (39) Elymoclavine (48) Lysergol (49) lsolysergol (173) Agroclavine (9) Agroclavine I ( 1 0 ) Fumigaclavine B (4) lsofumigaclavine B (7) Lysergene ( 5 5 ) lsolysergine (56) Chanoclavine I (15) Isochanoclavine I (59)
Yield (76) 88 94 97 95 84
90 89 84 81
84 67
83
Dehydrogenation with phenylseleninic anhydride was successfully applied to all synthetic precursors of ergot alkaloids in the final steps of their total syntheses with yields of 6747%. Even in the cases of dihydroelymoclavine, which contains an ally1 alcohol moiety, and dihydrochanoclavine I, which contains a secondary amine moiety, the conversions proceeded highly chemoselectively to give the corresponding indoles, that is, the ergot alkaloids, in excellent yield as summarized in Table V111 (54). IV. Conformational Studies
Although lysergic acid derivatives are known to exist as an epimeric mixture with respect to the carboxyl at the 8 position, analysis of their stereochemistry and conformations has been one of the central problems and has provoked many interesting discussions, particularly on the relationship between conformation and pharmacological activity. In this section, recent progress in the stereochemistry and conformational analysis obtained from NMR spectroscopy and X-ray crystallography is summarized. A.
CONFORMATION OF 9-ERGOLENES
The suggested conformations of lysergiy acid (38a) and its C-8 epimer, isolysergic acid (38b), in solution are shodn in Fig. 4. In solution, lysergic acid (38a) exists in the conformation with the C-8 carboxyl group in a pseudoequatorial orientation (524, X = OH) whereas isolysergic acid
1.
I25
ERGOT ALKALOIDS
524
525
526
527
Fic. 4. Conformations of ring D in lysergic acid derivatives.
(38b) has the carboxyl in a pseudoaxial orientation in which the carboxyl group is hydrogen bonded with the nitrogen at the 6 position, thus stabilizing the molecule (525, X = OH) ( 1 ) . The stable conformations of 9-ergolenes vary depending on the substituent at the 8 position, particularly whether hydrogen bonding of the substituent with the nitrogen lbne pair at the 6 position takes place. Therefore, the conformations of 9-ergolenes with various substituents at the 8 position have been extensively investigated by using 'H-NMR spectra and results from the von Braun reaction. In 1972, Bailey and Grey (224) undertook an 'H-NMR analysis of 9ergolenes with an N,N-dimethylaminocarbonylgroup at the 8 position and suggested that, although it was established that lysergic acid dimethylamide has the same conformation (524, X = NMe2)as lysergic acid (38a), isolysergic acid dimethylamide has a conformation different from that of isolysergic acid (38b), with the dimethylamido group in a pseudoequatorial orientation (527, X = NMe2). Further, Kidric et al. investigated the 'H-NMR spectra of lysergamide and ergopeptines and suggested that lysergamide has one conformation (524, X = NHJ as the 8p isomer and another conformation (527, X = NH,) as the 8ci isomer (225). Nakahara e l al. (41) investigated the N-demethylation von Braun reaction of a series of ergolines and reached the conclusion that no demethylation would occur when the substituent at the 8 position is in a I ,3-diaxial relationship with the lone pair of electrons on the nitrogen at the 6 position. This explained the fact that isolysergic acid diethylamide did not undergo the von Braun reaction, and it was thus deduced that the substituent at the 8 position would be in an axial orientation (525, X = NEtJ under these reaction conditions. Later, Ninomiya et al. (226) examined the 'H-NMR spectra of methyl lysergate (39a), methyl isolysergate (39b), lysergol (49), and isolysergol (173) and found that all these derivatives
126
ICHIYA NlNOMlYA AND TOSHIKO KlGUCHl
have an identical conformation with respect to ring D and that all the substituents in the p orientation at the 8 position exist in an equatorial orientation (conformation (524) whereas the substituents in the cx orientation exist in a pseudoaxial orientation (conformation 525). Weber and co-workers at Sandoz examined the X-ray crystallography of ergopeptine analogs including bromocriptine (528) and discussed the relationship between structure and pharmacological activity (227). The ergoline moiety of ergotamine (529) has conformation (524), and bromocriptine (528) takes conformation (526) in which hydrogen bonding occurs between the amide NH group and the lone-pair electrons at the 6 position. On the other hand, in the case of ergotaminine (530), in which the substituent at the 8 position is in an cx orientation, conformation (525) is suggested. From these conformational analysis, Weber concluded that the conformations of these derivatives are as follows: ergotaminine (530) is stabilized by hydrogen bonding in conformation (525), which would not be changed by the conditions, whereas ergotamine (529) and bromocriptine (528), both having 8p substituents, have the flexible conformation depending on the conditions, with conformation (524) being the most important factor for the manifestation of pharmacological activity. Me Me
528
Bromocr i p t i n c
529 ( R = a - H ) E r g o t a m i n c 530 ( R = ~ - H )E r g o l a m i n i n e
Pierri ef a / . (228) also examined the conformations of neutral and protonated forms of ergotamine (529) and ergotaminine (530), as deduced from the 'H-NMR spectra, and suggested that, under neutral conditions, ergotamine (529), unlike lysergic acid (38a), has the 8 substituent in an axial orientation and hydrogen bonded with the lone-pair electrons on the nitrogen at the 6 position (conformation 526), whereas ergotaminine (530), like isolysergic acid (38b), has its 8 substituent in an axial orientation and also hydrogen bonded with the lone-pair electrons (conformation 525). On the other hand, under acidic conditions, ergotaminine (530) takes conformation (525) as under neutral conditions, whereas ergotamine (529), as in lysergic acid (38a), takes conformation (524). Kidric ef al. reached the same conclusion (225).
1.
ERGOT ALKALOIDS
127
FIG.5. Conformation of the central amide linked to the peptide backbone by an intramolecular hydrogen bond.
These results, discussed by many researchers, can be summarized as follows. The conformation of 9-ergolenes is changeable depending on the occurrence of hydrogen bonding of the C-8 substituent with the lone-pair electrons at N-6. In the cases of compounds with the C-8 substituent in a p orientation and not involved hydrogen bonding, the preferential conformation is (524), whereas in cases of hydrogen bonding, conformation (526) is favored though readily changeable to (524) depending on conditions, which is incidentally the biologically required conformation. On the other hand, in cases of compounds with the C-8 substituent in an a orientation, conformation (525) becomes predominant, irrespective of hydrogen bonding. However, in some cases, depending on the type of substituent, another conformation (527) must be taken into consideration. The results obtained from X-ray crystallography of ergopeptine analogs clearly show that all the cyclolamide moieties at the 8 position, irrespective of their orientation a or p, exist in a fixed conformation owing to hydrogen bonding between the hydroxyl and amide carbonyl groups as shown in Fig. 5 (227). B. CONFORMATION OF ERGOLINES
The assumed conformations of four stereoisomers of dihydrolysergic acid in solution can be depicted as in Fig. 6 (I). Zetta and Gatti (229,230) investigated the conformations of all four possible isomers of 10-methoxydihydrolysergic acid methyl ester (531), 10-methoxydihydrolysergamide (532), and dihydrolysergamide (533) as deduced from the 'H-NMR and I3C-NMR spectra in deuteriochloroform and suggested the conformations of these stereoisomers shown in Fig. 7. From the conformations shown, it is clear that all the C/D-trans derivatives have the same conformations (534 and 535) with respect to ring D while the conformations of the CIDcis isomers vary depending on the structure. In the case of C/D-cis 10methoxyergolines, the conformation having the 8-substituent in an equatorial orientation (536 and 537) is considered the favored one. Sa-C/D-cis Dihydrolysergamide is exceptional and is assumed to have conformation
C0:H
Dihydrolysergic acid I
CO,H Di hydroisolysergic acid 1
Dihydrolysergic acid I1
Diliydroisolysergic acid I 1
FIG.6. Conformations of ring D in dihydrolysergic acid derivatives.
534 C/D-trans R'=C(),Me o r C()Nt{, R 2 = H or O M e
535 C/D-trans R ' = C O ~ M Co r CONH2 RZ=H o r OMc
ll&R1MC
~2&
lNMe
H 536 C / D - c i s R 1 = C O Z M eo r CONH: R2=OMe
537 C / D - c i s R 1 = C 0 2 M eo r CONHZ R'=H o r O M e
NMe
a,,. o+ \ H
NH
538
FIG.7. Conformations of ring D in 10-methoxydihydrolysergicacid derivatives.
I.
129
ERGOT ALKALOIDS
I
H 2
1
FIG.8. Conformations of costaclavine (2) and epicostaclavine ( 1 ) .
(538) with the 8-substituent in an axial orientation and also hydrogen bonded with the lone-pair electrons on nitrogen, which in methyl-d, sulfoxide solution changes to the non-hydrogen-bonded conformation having the substituent in an equatorial orientation (537). Ninomiya’s (60) and Kozlovsky’s groups ( 5 ) have shown that the C/Dcis 6,8-dimethylergolines costaclavine (2) and epicostaclavine (1) (Fig. 8) have the same conformation with the 8-methyl group in an equatorial orientation but different conformations with respect to the ring D, judging from the ‘H-NMR spectra. Discussion of the conformations of compounds having a C/D-trans ergoline structure has been centered on their pharmacological activity with expectation of developing new aspects of drug design in ergot alkaloids and related compounds. Weber et a/.(231) examined the X-ray crystallography and ‘H-NMR spectra of dihydroergotamine (539), 5’-epidihydroergotamine (540), and 8-isodihydroergotamine (541) (Fig. 9) and discussed their conformations to draw the following conclusion. The cyclol moiety of these peptide alkaloids is strongly hydrogen bonded as shown in Fig. 5, and 8P-substituted ergolines have conformation 542 while the 8a isomers exist in conformation 543.
539 R ’ z a - H , R’=Mc, R’=n-CH,Ph 540 R1=tu-l-i, R Z = M c , R3=P-CI-IZPh 5 4 1 R ’ = P - H , R’=Mc, R ’ = n - C H Z P h
cox 543
FIG.9. Conformations of dihydroergotamine derivatives.
I30
ICHIYA NlNOMlYA A N D TOSHIKO KIGUCHI
a
CHZSMC
CH~SMC
CI
&zH2)2Mc
NK
HN 544
FIG.10. Conformation of pergolide.
Camerman and co-workers (232) performed an X-ray crystallographic analysis of the free base and mesylate of the dopaminergic ergoline derivative pergolide (544)and suggested that perigolide in either form takes the conformation shown in Fig. 10. Nordmann and Loosli (Sandoz) (233) have also examined the 'H-NMR spectra of compound 545, which has a carboxamidine group at the 6 position, and suggested its favored conformation (Fig. I I ) , particularly the boat form of ring D. This is the first example of a C/D-trans ergoline having this type of conformation, and it is explained in terms of steric interference of a planar guanidinium group with the equatorial proton (P-H) at the 4 position. V. Biosynthesis Among many papers and reviews on the biosynthesis of ergot alkaloids (234), those of Floss written in 1976 and 1980 (235) contain not only his own results but also superb coverage of all aspects of biosynthesis and are regarded as the most well documented. In this review, the focus is on the biosynthetic route from tryptophan to peptide alkaloids suggested on the basis of accumulated information obtained by the use of tracer techniques. At the moment, this route is considered as the most plausible major route for the biosynthesis of these alkaloids.
CHzSMe
545
FIG.1 I . Conformation of the compound having a carboxamidine group at the 6 position.
I.
ERGOT ALKALOIDS
131
OF ERGOLENES A N D LYSERGIC ACID A. BIOSYNTHESIS
It has been well documented and established that the skeleton of ergolene-type alkaloids is biosynthesized from dimethylallyltryptophan (DMAT) (546) whose precursors are thought to be L-tryptophan and mevalonic acid (Scheme 114, first step). Further, from many experimental results, the following route was suggested. The first step of the main route would be succeeded by a route forming chanoclavine I (15) (second step), followed by construction of ring D of ergolenes, thus giving rise to agroclavine (9) (third step), then to elymoclavine (48) (fourth step), and finally to lysergic acid derivatives (fifth step). In this proposed biosynthetic pathway (Scheme 114), feeding experiments using [2-'4C]mevalonic acid and (E)-[4'-'3C]dimethylallyltryptophan (546) have shown that the 4'-E-methyl group would be readily incorporated into the 3'-Z-methyl group of chanoclavine I(15) and further into the 17-methyl group in agroclavine (9). This corresponds to a double isomerization of the double bond in the alkaloid molecule. It is also known that the (4R)-hydrogen of mevalonic acid would be incorporated into the 9 position of agroclavine (9) and remain without further liberation. Further research has been detailed by many workers (235,236).
132
ICHIYA NINOMIYA A N D TOSHIKO KlGUCHl
I . First Step in the Biosynthesis of Ergot Alkaloids
Floss and coworkers (237) succeeded in the isolation and purification of the enzyme, DMAT synthetase, from mycelia of Cfuviceps sp. strain SD 58, that specifically catalyzes the first step in the formation of DMAT (546) from mevalonic acid and tryptophan. The enzyme is a single subunit protein, having a molecular weight of 70,000-73,000 and an isoelectric point of 5.8. Synthesis of DMAT (546) by this enzyme was shown to occur in the culture broth of intact cells and in protoplast suspensions of Cfuviceps sp. S D 58, and it was susceptible to feedback inhibition by elymoclavine (48) (238). The isolation of an enzyme that specifically catalyzes the first step of ergot alkaloid synthesis has confirmed that DMAT (546) is actually formed in vivo from mevalonic acid and tryptophan. The effect of tryptophan derivatives on this enzyme has also been investigated (239). Floss and co-workers showed that tryptophan not only serves as a biosynthetic precursor to the ergoline ring system but also can induce alkaloid synthesis. It was also found that naphthylalanines 547 and 548 are able to induce alkaloid production, presumably by mimicking tryptophan (240). R’
Palla and co-workers (24f)carried out feeding experiments on Cfuviceps p a s p a f i using doubly labeled tryptophans ([5,7-3H,: 3’-I4C]-and [4,6‘H?; 3’-14C]tryptophan) and measuring the retention of tritium in lysergic acid (38). They found that only the tritium at the 4 position of tryptophan disappears: therefore the isoprenylation to tryptophan occurs directly at the 4 position.
*
4, 6-’H,; .3‘-I4C
5, 7-’H,; 3’-I4C
2. Second Step in the Biosynthesis of Ergot Alkaloids The second step in the biosynthesis of ergot alkaloids has not been well studied, leaving a number of problems unclear, for example, whether Nmethylation of DMAT (546) o r decarboxylation occurs first. However,
1.
549
I33
ERGOT ALKALOIDS
48
550
SCHEME 115
feeding experiments with two tryptophan derivatives (549 and 550) synthesized in cell-free extracts of Clnviceps species showed that 549 was incorporated into the elymoclavine (48) subsequently formed whereas 550 was not incorporated (Scheme 115) (242,243).This shows that N-methylation of DMAT (546) precedes decarboxylation and that 550 is not used in building ring C of the ergolene skeleton. As for oxidation of the allylmethyl group in DMAT (546) in the second step of biosynthesis, there are several possible stages at which this oxidation may occur, though it seems certain that oxidation should occur prior to the formation of ring C of the ergolene skeleton. Anderson and Saini isolated 4-[(E)-4'-hydroxy-3'-methylbut-2'-enylj-~tryptophan (E-HODMAT) (551) from the culture broth of Claviceps purpurea PRL 1980 and found that 551 was formed from DMAT (546) in the ammonium sulfate fraction of the culture broth of the same strain in the presence of a n NADPH-generating system (244,245). Further, Petroski and Kelleher also obtained both DMAT (546) and E-HODMAT (551) from cell-free extracts of Claviceps paspali following treatment with L-tryptophan and isopentenyl pyrophosphate (246). However, from the fact that 551 was incorporated into elymoclavine (48) but not into agroclavine (9) o r chanoclavine 1 (15) (Scheme I16), it was suggested that a biosynthetic route from E-HODMAT (551) t o elymoclavine (48) could not be the main
15
55 1
SCHEME 116
40
134
ICHIYA NlNOMIYA AND TOSHIKO KIGUCHI
546
15
SCHEME 117
route in the biosynthesis of ergot alkaloids. Taking these results into consideration, Pachlatko er al. proposed the biosynthetic pathway shown in Scheme 117 for the formation of ring C (247). In 1988, Floss and co-workers (248,249) synthesized N-deuteriomethylglycol 552 and tertiary alcohol 553 and carried out feeding experiments with Claviceps sp. SD 58. They showed that 552 was not incorporated into elymoclavine (48) and, with a mass technique, observed that 33% of 553 was incorporated into elymoclavine (48). From these results, they proposed a route involving the formation of an epoxide (554) from 553 as the second step in the biosynthesis of ergot alkaloids (Scheme 118). 3. Third Step in the Biosynthesis of Ergot Alkaloids
The biosynthetic step from chanoclavine I (15) to agroclavine (9) also presents various problems. The Z-methyl group was known to be isomerCH:OH
552
553
1 15 Chanoclavine-I <&NHMc t
HN/
COZH
, $HM: HN
554
SCHEME 118
C02H
HO,
1
0.yI is I
C'I i:Ol I
I
R
NHMc
15
135
ERGOT ALKALOIDS
I.
I
-
NHMc
14
48
SCHEME 119
ized to an E-methyl group during this third step, and chanoclavine I aldehyde (14) was isolated from the culture broth of blocked mutant of Claviceps purpurea (16), thus suggesting that construction of ring D would occur via 14 (Scheme 119). Hassam and Floss prepared labeled chanoclavine I(15) with p r o 4 and pro-R tritiums at the 17 position, applied the radiolabeled compound to feeding experiments with cultures of Claviceps purpurea SD 58, and observed that only the p r o 4 hydrogen is incorporated into the 7 position of elymoclavine (48), thus supporting the biosynthetic route via 14 (250). Stadler and co-workers proposed the biosynthetic pathway of paliclavine (61) shown in Scheme 120 (251) and carried out feeding experiments with [N-'4CH,]paliclavine (61) in cultures of Claviceps paspali. They found that no incorporation of tritium into agroclavine (9) occurs, thus eliminating the possibility of a route from chanoclavine I (15) to agroclavine (9) via paliclavine (61).
546
136
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
4. Fourth Step in the Biosynthesis of Ergot Alkaloids It is well known that the hydroxylation step from agroclavine (9) to elymoclavine (48) is promoted not by a hydroxyl oxygen but by molecular oxygen. An extensive search for the enzyme responsible for this hydroxylation has been carried out. Anderson and co-workers demonstrated the conversion of agroclavine (9) to elymoclavine (48) using a microsomal fraction from Cluviceps sp. PRL 1980 and SD 58 in the presence of NADPH. The fact that addition of carbon monoxide blocks the activity suggests that this agroclavine hydroxylase would be cytochrome P-450 monooxygenase (252).Eich and co-workers carried out hydroxylation experiments using modified agroclavine derivatives as shown in Scheme 121 in a sucrose-asparagine culture of Cluviceps fusiformis SD 58 and found that an 8,9 double bond and a tertiary amine are required for the 17-hydroxylation step (253,254).
5. Fifth Step in the Biosynthesis of Ergot Alkaloids Concerning the biosynthetic route for the conversion of elymoclavine (48) to peptide ergot alkaloids, Quigley and Floss suggested direct conversion from aldehyde 555 rather than circuitous routes via lysergic acid (38) or paspalic acid (556) (255). Feeding experiments with "0-enriched oxygen in ergotamine-producing Cluviceps purpureu strain PCCE 1 were carried out, and the isotopic composition on the ergotamine (529) thus formed was measured. As a result, it was observed that the "O-enrichment was 46.7% in cyclooxygen and 41.2% in the amide carbonyl, thus MC I
R ' = A l k y l , R'=Br o r I , R'=Et N o t i yd r o x y I ;i I ion MC
HN
H A -! SCHEME 121
I.
ERGOT ALKALOIDS
I37
suggesting that ergotamine (529) is biosynthesized not by route a but by route b involving the aldehyde (555) (Scheme 122). Anderson and co-workers showed that in cell-free systems of C . puvpurea PCCE I , elymoclavine (48) was biotransformed to paspalic acid (556) in the presence of NADPH (Scheme 123), and this conversion was inhibited by the addition of carbon monoxide, suggesting the involvement of cytochrome P-450in an oxidation step (256). Conversion of elymoclavine (48) to paspalic acid (556) occurs only in this particular system, thus suggesting that paspalic acid (556) is not a biosynthetic intermediate in the biosynthesis of peptide alkaloids. Further, Philippi and Eich investigated the fermentation of elymoclavine derivatives of type 557 in Clavicrps puspali Stamm SO 70/5/2 and obtained not the peptide alkaloid (558) but the lysergic acid derivative (559) (Scheme 123) (257). The biosynthetic pathway of dihydroergosine (562), which belongs to the dihydroergotamine class of alkaloids and was isolated from the culture broth of the fungus Sphacrliu sorghi, has been discussed by Barrow's and Floss's groups (258,259). Barrow rt d. investigated the biosynthetic conversion of dihydroelymoclavine (560) and dihydrolysergic acid (561) to dihydroergosine (562) and found that not agroclavine (9) but festuclavine (54), dihydroelymoclavine (560), and dihydrolysergic acid (561) are possible precursors to dihydroergosine (562) (Scheme 124). Further, Floss and co-workers incubated dihydrolysergic acid (561) in cultures of
555
529 Ergotaminc SCHEME 122
138
ICHIYA NlNOMlYA A N D TOSHIKO KIGUCHI
. 48
556 CONHR
CH2OH
557
----.\"
R'=Pr o r C H 2 P h o r Cl~1201i R 2 = B r , R'=Et 559
SCHEME 123
54
560
56 1
9
562
SCHEME 124
1.
I39
ERGOT ALKALOIDS
an ergotamine-producing strain of Claviceps purpurea and found the formation of dihydroergosine (562).
B. BIOSYNTHESIS OF PEPTIDE ALKALOIDS As for the biosynthesis of the peptide portion of cyclol-type peptide alkaloids, there remains a number of unsolved problems. However, the information obtained from various fragmentary research may be patched together and summarized in the following biosynthetic pathway (Scheme 125) (260). Biosynthesis starts from the L-proline end to form the tripeptide which is then coupled with the activated form of the ergolene moiety and finally cyclized to form the lactam ring. The isolation of noncycloltype peptide alkaloids from the same culture broth suggests that hydroxylation at the 2' position occurs at the final stage of biosynthesis, that is, after intermediate 563 is biosynthesized. Intermediate 563 then undergoes a partially reversible epimerization to the noncyclol-type alkaloid 564, which cannot be further transformed to cyclol-type alkaloids. Various feeding experiments were also carried out with variously labeled dipeptides, diketopiperazines, and tripeptides (261-266). However,
564
SCHEME 125
I40
ICHIYA NINOMIYA A N D TOSHIKO KlGUCHl
the results were clear that none of these labeled precursors were incorporated but first hydrolyzed and then incorporated, therefore suggesting that biosynthesis of peptide moieties and coupling with the activated lysergic acid part proceed in a concerted fashion in the presence of a multienzyme complex without forming any free and isolable intermediates. The enzyme involved in this peptide biosynthesis would have a broad specificity that enables it to combine amino acids irrespective of origin natural or unnatural to form the peptide alkaloids. As shown in Scheme 126, Floss and co-workers presented three plausible routes (a, b, and c) for modification of the amino acid adjacent to the lysergyl moiety to an a-hydroxy-a-amino acid. First, they carried out feeding experiments with doubly labeled 2-[3-'-'C,3-D,]aminobutyric acid in the culture broth of C.purpurra PCCEl, and the ergosine isolated was then measured by mass spectroscopy, which showed that a methylene group in 2-aminobutyric acid stays without losing any radioactivity (267). Results indicated that this step does not proceed via a 2,3-dehydroamino acid intermediate as in the route a. Further, Quigley and Floss carried out fermentation with the ergotamine-producing C. purpurra PCCEl in an atmosphere of 91.7% "0-enriched oxygen (Scheme 127) (255). The enrichment of ''0 in ergotamine (529) was 46.7% in the cyclol oxygen. Thus, the results were compatible with mechanism c, direct oxygenation for the conversion of the a-amino to an a-hydroxy-a-amino acid moiety.
SCHEME126
I.
141
ERGOT ALKALOIDS
Ph
529
Ph
SCHEME127
C. BIOSYNTHESIS OF CLAVICIPITIC ACID Anderson and co-workers investigated the biosynthesis of clavicipitic acid (22). [3-I4C]DMAT(546) was bioconverted to clavicipitic acid (22) in cell-free extracts of Claviceps sp. SD 58 and Claviceps purpuren PRL 1980 (268). Oxygen was required, but there was no cofactor requirement for this bioconservation. The fact that carbon monoxide does not inhibit the bioconversion to clavicipitic acid (22) suggested that cytochrome P450 is not involved, but p-(hydroxymercuri)benzoic acid strongly inhibited conversion, thus suggesting the involvement of sulfhydryl groups in the enzyme catalyzing the reaction. Further, it was found that in the presence of a thioglycolate-iron(1I) system, [3-I4C]DMAT (546) was converted to clavicipitic acid (22) (269). Floss et al. carried out feeding experiments with ''C,3H-labeled tryptophan and mevalonic acid in cultures of Claviceps sp. SD 58. From results
546
22b
SCHEME128
142
ICHIYA NINOMIYA AND TOSHIKO KIGUCHI
showing that the side chain of tryptophan was retained and that two hydrogens at the 5 position of mevalonic acid, either pro-R and pro-S, disappeared during the course of biosynthesis, they proposed the biosynthetic pathway shown in Scheme 128 for the formation of clavicipitic acid (22) (23). However, whether clavicipitic acid (22) is formed by only one pathway, for example, route a, or by mixed pathways is not clear. Further, when labeled clavicipitic acid (22) was administered to normal cultures of Claviceps sp. SD 58, no incorporation into elymoclavine (48) was observed (270).
VI. Pharmacological Properties of Related Compounds
Many ergot alkaloids and derivatives have been reported to produce the following principal effects, among others: uterotonic action, increase or decrease in blood pressure, induction of hypothermia and emesis, control of the secretion of pituitary hormones. The effects are mainly responses mediated by noradrenaline, serotonin, or dopamine receptors. No other group of natural products exhibits such a wide spectrum of biological action. Naturally, there have been many reviews on the pharmacological activities of ergot alkaloids. General aspects were reviewed by Stadler and Giger (271), and Cassady and Floss (272) reviewed prolactin and mammary tumor inhibition. Cannon (273) reviewed dopamine antagonism. A. NEWSEMISYNTHETIC COMPOUNDS FOR THERAPEUTIC USES Many compounds having an ergoline skeleton have been synthesized in the hope of developing pharmacologically, active agents. However, attention has recently centered on the development of compounds with more selective activity rather than compounds with higher activity, as mentioned in detail by Stadler and Giger (271). In this section, we summarize briefly the therapeutic use of newly developed semisynthetic compounds related to ergoline derivatives. Nicergoline (565)was chosen from many derivatives synthesized in the I0a-methoxydihydrolysergolseries of compounds. It is a potent blocking agent for a,-adrenoreceptors and has thus found effective clinical use in neurology (274). It shows remarkable effects in lowering systemic blood pressure and dilating blood vessels, thereby increasing peripheral blood flow. Very recently, because of the need for medicinals for improving metabolism in the brain, nicergoline (565) has been clinically used for this purpose, particularly for the aged both in Europe and Japan (275).
1.
ERGOT ALKALOIDS
565
143
528
A great number of new ergopeptide alkaloids were prepared and tested with the aim of retaining the specific prolactin-inhibiting activity and eliminating the oxytocic and vasoconstrictor side effects of a-ergocryptine. This objective was finally fulfilled by the discovery of bromocriptine (528) (132), which became the first clinicaly useful prolactin inhibitor developed from ergoline-related compounds (276). Soon after, evidence for stimulation of central dopamine neurons by bromocriptine (528) was observed. Bromocriptine (528) is a direct postsynaptic dopamine receptor agonist, and it is also effective in the treatment of Parkinsonism. The efficacy of 528 may be limited, however, owing to both short-term and longterm adverse effects. Lergotrile (566) was chosen from a group of compounds related to homolysergic acid nitrile (271) because of its central dopaminergic activity. Hopes of developing 566 as another prolactin inhibitor, however, were spoiled by the finding of strong hepatotoxicity.
567
569
568
544
144
ICHIYA NlNOMlYA A N D TOSHIKO KlGUCHl
Among a series of derivatives prepared in the ergoline group, compounds with an amino group at the 801 position showed considerable activity, from which lisuride (567) (277) and terguride (568) (278) were further evaluated as promising. Lisuride (567) showed remarkable serotonin antagonist properties, and was therefore clinically used for the treatment of migraines; it also possesses potent prolactin inhibitory activity (279,280).Terguride (568) was prepared as the reduced form of lisuride (dihydrolisuride) and introduced as an agent binding with D2 striated dopamine receptors. Terguride (568) has both agonistic and antagonistic actions at striated dopamine receptors, but chronic administration did not produce any behavioral supersensitivit y . These pharmacological properties differ from those of other anti-Parkinson's agents. Terguride (568) may be effective for the chronic treatment of Parkinson's disease. From study of 8a-sulfonamide derivatives, mesulergine (569) was introduced as an anti-Parkinson's agent (281). Its considerable toxicity, however, soon put this agent off the list of agents for clinical use. Nonetheless, mesulergine (569) will remain an interesting compound for laboratory study because of its biphasic effects on dopamine receptors and the role that this property may have in reducing serious clinical adverse effects. As a simple derivative of thiolysergol, pergolide (544) was selected for the development of a new anti-Parkinson's agent (282). Pergolide (544) is currently being evaluated clinically for the treatment of Parkinson's disease, as well as for a number of hyperprolactinemia-characterized diseases (280). Its anti-Parkinsonism efficacy, like that of the other ergolines, can be attributed to the postsynaptic stimulation of central dopaminergic receptors. Studies on the structure-activity relationships between dopamine agonists and ergoline derivatives have been extensively carried out. A number of derivatives having partial and fragmentary ergoline structures as the dopamine agonist have been prepared, as reviewed in detail by Cannon (273). Further, structure-activity studies applying molecular electrostatic potentials (283) and using optically active derivatives (284) have also been reported.
570
57 1
I.
145
ERGOT ALKALOIDS
Recently it was reported that KSU-1415 (570), a 6.7-secoergoline-type compound, showed potent dopaminergic stimulating activity, comparable to bromocriptine (528) (285).compound CY 208-243 (571) was also shown to be a selective dopamine D, agonist (286).
B. CENTRAL SEROTONIN RECEPTORS Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter. Although the role of serotonin, namely, whether it plays a primary role or a modulatory role, has not yet been determined, extensive and active investigations on the central binding site of serotonin have been carried out (287). Central serotonin binding sites were initially labeled in 1974 with [3H]lysergicacid diethylamide (LSD). However, it was soon shown that the binding characteristics of ['HI serotonin and 13H]LSD were not identical. Thus, the high-affinity serotonin binding site was called the 5-HT, site, as it was suggested that LSD would bind not only to the 5-HT, site but also to another site, called the 5-HT2site. These days, the active sites are further divided into several subunits (288). Therefore, finding a compound that binds specifically to a single class of active site would be greatly instrumental in the elucidation of the in vi\v role of serotonin. that is, the role and mode of action of serotonin at the active sites. Many groups have researched along this line to uncover the relationship between serotonin active sites and ergot alkaloid derivatives. Generally, it is known that many ergoline derivatives show strong affinity toward serotonin binding sites but lack selectivity. The affinity of( + )-LSD for5-HTIand 5-HT, sites is reported as nearly identical. Methergoline (572) has been used for the treatment of migraine and vascular headaches, while methysergide (573) is regarded as the most effective substance for the prevention of migraine attacks. These two remarkable medicinals bind 50 to 100 times more strongly to 5-HT2sites than 5-HT, sites. Further, mesulergine (569), which was regarded as a potential agent for the treatment of Parkinson's disease, is known to have strong affinity for 5-HT2sites.
572
573
146
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
In connection with the study of structure-activity relationships, the binding sites on many compounds were searched, and LY-53857 (574) showed the most promising results (289). LY-53857 (574), which carries an ester group at C-8 of the ergoline skeleton, was found to be a highly potent and selective antagonist at 5-HT2receptors that possesses minimal affinity for adrenergic receptors. Thus, LY-53857 (574) caused sympathoexcitation without any change in blood pressure or heart rate, and it also increased femoral arterial conductance (290).
(p
.. i-PrN
i-PrN
57 5
574
Further structure-activity investigations on LY-53857 (574) and related compounds showed that changing the substituent at the 8 position from an ester to a carboxyl group diminished the affinity toward 5-HT2receptors (291-293). Affinity strengthened when greater branching was introduced into the ester side chain. The cyclohexyl ester derivative 575 possessed the strongest affinity among those tested. Further, an isopropyl substituent on the indole nitrogen also enhances affinity. Recently, a group at Eli Lily investigated serotonin-binding sites with simple ergoline derivatives and found that 2,3-dihydro-9,IO-didehydroergoline (576) possesses high selectivity in binding to 5-HT, receptors while exhibiting only diminished activity toward dopaminergic receptors and affinity to 5-HT2receptors (294). R
R=Mc, CH2011,ClI2SMc, C'tI,C"
576
1.
ERGOT ALKALOIDS
I47
C. ANTITUMOR A N D ANTIMICROBIAL ACTIVITY As reviewed by Cassady and Floss (272),it has long been known that ergot alkaloids in general possess activity inhibiting the growth of certain mammary tumors in animals and also in humans by blocking the release of prolactin from the anterior pituitary gland. Recently, Eich et al.also reported the marked antitumor activity of clavine-type alkaloids (295,296).Festuclavine (54) and agroclavine (9) exhibited some inhibitory activity against cell proliferation in the L5178y mouse lymphoma system, whereas lysergol (49), elymoclavine (48), and lysergic acid derivatives had no activity, thus suggesting a structural requirement for a C-8 methyl group for activity. Furthermore, changes in the substituents on N-1 and N-6 in festuclavine (54) resulted in the strongly active compounds 577579 having a propyl or allyl group on either of the two nitrogens. Derivatives 577-579 show stronger activity than camptothecin in the L5178y mouse lymphoma system (297,298).Similarly, in agroclavine analogs, the 1-propylagroclavine (580) was found to exhibit stronger activity than agroclavine (91, and the introduction of a propyl or allyl group at the 1 position in inactive elymoclavines brought about marked cytostatic effects, presumably owing to an inhibitory action on DNA synthesis.
580
Eich et al. investigated the antimicrobial activity of agroclavine (9), festuclavine (54), and derivatives and showed that agroclavine ( 9 ) and festuclavine (54) have weak antimicrobial activity against Staphylococcus aureus and Escherichia coli, with 6-allylfestuclavine (578) showing the strongest activity among the compounds tested (299).
ICHIYA NINOMIYA A N D TOSHIKO KlGUCHl
Acknowledgments The authors take advantage of this opportunity to express their gratitude to Professors M. Somei and M. Natsume, who provided valuable information and suggestions. The authors thank their colleagues a s well.
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202. A. P. Kozikowski and M. N. Greco, 1. Am. C h e m . Soc. 102, 1165 (1982). 203. M. Somei. Yrrki Gosei Kugrrku Kvokrrislii 40, 387 ( 1982). 204. M. Somei. Y. Karasawa, T. Shoda, and C. Kaneko. Cliem. Plictrm. Bull. 29, 249 ( I98 I ). 205. M. Somei. S. Inoue, S. Tokutake. F. Yamada. and C. Kaneko, Clieni. Plitrrni. Bull. 29, 726 (1981). 206. M. Somei and M. Tsuchiya. Chem. Pliccrin. Brill. 29, 3145 (1981). 207. M. Somei and T . Shoda, Hererocvcles 17, 417 (1982). 208. M. Somei, K. K i m , M. Kunimoto. and F. Yamada. Chem. PIicrrw~.Bull. 33, 3696 (1985). 209. M. Somei. T. Hasegawa. and C. Kaneko. He/i,rocycle.s 20, 1983 (1983). 210. M. Somei. F. Yamada. M. Kunimoto, and C. Kaneko, Hetcvvc.yi.les 22, 797 (1984). 211. M. Somei. E. Iwasa, and F. Yamada. Heterocycles 24, 3065 (1986). 212. F. Yamada and M. Somei, Heteroc~vclcs26, I173 (1987). 213. M. Matsumoto and N. Watanabe. Heterocycles 22, 2313 (1984). 214. N. Hatanaka, N. Watanabe, and M. Matsumoto, Heterocycles 24, 1987 (1986). 215. M. Matsumoto and N. Watanabe, Heterocycles 24, 2611 (1986). 216. R. J. Sundberg, "The Chemistry of Indoles," p. 132. Academic Press, New York. 1970. 217. Y. Kikugawa and M. Kawase, Cheni. L e t f . . 445 (1981). 218. M. Kawase, Y. Miyake, and Y. Kikugawa, J. Ckcwz. Soc., Perkin Trtrns. 1 . 1401 (1984). 219. A. Inada. Y . Nakamura, and Y . Morita. C h e m . Lrtt.. 1287 (1980). ~ 4727 (1985). 220. D. H . R. Barton, X. Lusinchi. and P. Milliet, T e r r t r h c d ~ w41, 221. D. Keirs and K. Overton, J . C/iem. Soc,.. Chem. Co/n/nrrn.. 1660 (1987). 222. D. M. Ketcha. Terrcrhedron Lett. 29, 2151 (1988). 223. 1. Ninomiya. T. Kiguchi, C. Hashimoto. D. H. R. Barton, X. Lusinchi, and P. Millet, Tetrdiedron Lett. 26, 4183 (1985). 224. K. Bailey and A. A. Grey, C o n . J. Clieni. 50, 3876 (1972). 225. J . KidriC. D. Kocjan. and D. Hadii. Pharrntrcocharn. Libr. 10, 214 (1987). 226. T. Kiguchi, C. Hashimoto. T. Naito. and I . Ninomiya, Heterocycles 22, 1719 (1984). 23, 25 (1980). 227. H. P. Weber. Adv. Biochem. Psve~iophcrrmrie~~l. 228. L. Pierri, 1. H. Pitman, I. D. Rae, D. A. Winkler. and P. R. Andrews, J . Med. Chem. 25, 937 (1982). 229. L. Zetta and G. Gatti, Tetrrrhedron 31, 1403 (1975). . 9, 218 (1977). 230. L. Zetta and G. Gatti. Org. M ~ g n Reson. 231. H. P. Weber, H. R. Loosli. and T. J . Petcher. Strtd. Phvs. Tlieor. Chem., 18,39 (1982). 232. L. Y. Y. Ma, N. Camerman. J . K. Swartzendruber. N. D. Jones, and A. Camerman. C m . J . C h m . 65, 256 (1986). 233. R. Nordmann and H. Loosli. Helv. Chim. Actrr 68, 1025 (1985). 234. H. Kobe1 and J . J . Sanglier, in "Biotechnology" ( H . Pape and H.-J. Rehm, eds.), Vol. 4, p. 569. Verlag Chemie, Weinheim. 1986. 235. H. G. Floss. Tetrciliedron 32, 873 (1976): H. G. Floss and J . A. Anderson, in "The Biosynthesis of Mycotoxins" (P. S. Steyn. ed.). p. 17. Academic Press, New York, 1980. 236. H. Plieninger. E. Meyer, W. Maier. and D. Groger, Liehigs Ann. Chenz., 813 (1978). 237. S.-L. Lee, H. G. Floss, and P. Heinstein. Arch. Bioc,liem. Bioplivs. 177, 84 (1976). 238. L.4. Cheng. J. E. Robbers, and H. G . Floss, J. Nut. Prod. 43, 329 (1980). 239. V. M. Krupinski. J. E. Robbers, and H. G. Floss. J. Btrcteriol. 125, 158 (1976).
1.
ERGOT ALKALOIDS
155
240. J. E. Robbers, S. Srikrai, H . G. Floss, and H. G. Schlossberger, J. Not. Prod. 45, 178 (1982). 241. M. Bellatti. G. Casnati, G. Palla, and A. Minghetti. Tetrulwdron 33, 1821 (1977). 242. H. Otsuka. J . A. Anderson, and H. G. Floss, J. C/iem. Soc.. Chem. Commctn.. 660 (1979). 243. H. Otsuka. F. R. Quigley, D. Groger, J. A. Anderson, and H. G. Floss, Plunfu Mad. 40, 109 (1980). 244. J. A. Anderson and M. S. Saini, Tefruhedron Left.. 2107 (1974). 245. M. S. Saini and J. A. Anderson. Phyfocliernisrry 17, 799 (1978). 246. R. J. Petroski and W. J. Kelleher, Lloydiu 41, 332 (1978). 247. P. Pachlatko, C. Tabacik, W. Acklin, and D. Arigoni, Chimia 29, 526 (1975). 248. A. P. Kozikowski, M. Okita, M. Kobayashi, and H. G. Floss, J. Org. Chem. 53, 863 (1988). 249. A. P. Kozikowski, J.-P. Wu, M. Shibuya, and H. G. Floss, J. A m . Chem. Soc. 110, 1970 (1988). 250. S. B. Hassam and H. G. Floss, J . Nut. Prod. 44,756 (1981). 251. W. Acklin. T. Fehr, and P. A. Stadler, Helv. Chim. Acta 58, 2492 (1975). 252. I.-S. Kim, S.-U. Kim, and J. A. Anderson, Phyfochemisrry 20, 2311 (1981). 253. R. Sieben, U. Philippi, and E. Eich, J. Nut. Prod. 47, 433 (1984). 254. E. Eich and R. Sieben, Planfa Med., 282 (1985). 255. F. R. Quigley and H. G. Floss, J. Org. Chem. 46,464 (1981). 256. S.-U. Kim, Y.-J. Cho, H. G. Floss. and J. A. Anderson, Planfa Mad. 48, 145 (1983). 257. U. Philippi and E. Eich, Planfa Med. 50, 456 (1984). 258. K. D. Barrow, P. G. Mantle, and F. R. Quigley, Tetrahedron L e f f . ,1557 (1974). 259. J. A. Anderson, I.-% Kim. P. Lehtonen, and H. G. Floss, J . N a f .Prod. 42,271 (1979). 260. H. G. Floss, M. Tcheng-Lin, H . Kobel, and P. Stadler, Experientia 30, 1369 (1974). 261. A. Baumert, D. Groger, and W. Maier, Experienfia 33, 881 (1977). 262. E. Beacco, M. L. Bianchi, A. Minghetti, and C. Spalla, Experientia 34, 1291 (1978). 263. N . Crespi-Perellino, A. Guicciardi, A. Minghetti, and C. Spalla, Experientia 37, 217 (1981). 264. W. Maier, D. Erge, B. Schumann, and D. Groger, Biochem. Biophys. Res. Commun. 99, 155 (1981). 265. S. M. Atwell and P. G. Mantle, Experienria 37, 1257 (1981). 266. A. Baumert, D. Erge, and D. Groger, Planra Med. 44, 122 (1982). 267. C. M. Belzecki, F. R. Quigley, H. G. Floss. N. Crespi-Perellino, and A. Guicciardi, J . Org. Chem. 45, 2215 (1980). 268. R. S. Bajwa, R.-D. Kohler, M. S. Saini, M. Cheng, and J. A. Anderson, Phytochemisf r y 14, 735 (1975). 269. M. S. Saini. M. Cheng, and J. A. Anderson, Phyfochemisfry 15, 1497 (1976). 270. R. S. Bajwa and J . A. Anderson, J. Phurrn. Sci. 64,343 (1975). 271. P. A. Stadler and K. A. Giger, in "Natural Products and Drug Development" (P. Krogsgaard-Larsen, S. B. Christensen. and H. Kofod, eds.), p. 463. Munksgaard, Copenhagen, 1984. 272. J . M. Cassady and H. G. Floss, Llo-vdio 40, 90 (1977). 273. J. P. Cannon, Prog. Drug Res. 29, 303 (1985). 274. M. Lievre, M. Ollagnier, and G. Faucon. Arzneim.-Forsch. 29, 1227 (1979). 275. T. Komatsu, Farumashia 25, 146 (1989). 276. C. Theohar, K. Fischer-Cornelseen. H. 0. Akesson, J. Ansari, J. Gerlach, P. Harper, R. Ohman, E. Ose, and A. J. Stegink, Curr. Ther. Res. 30, 830 (1981).
156
ICHIYA NINOMIYA A N D TOSHIKO KIGUCHI
277. H. Wachtel and R. Dorow, Life Sci. 32, 421 (1983). 278. W. C. Koller and G. Herbster, Neurology 37, 723 (1987). 279. M. Schachter, J. Blackstock, J. P. R. Dick, R. J. D. George, C. D. Marsden, and J. D. Parkes, Lancet, 1129 (1979). 280. A. N. Lieberman, M. Leibowitz, A. Neophytides, M. Kupersmith, S. Mehl, D. Kleinberg, M. Serby, and M. Goldstein, Lancet, I129 (1979). 281. R. F. Pfeiffer, Clin. Neuropharmacol. 8, 64 (1985). 282. W. Fuller, J. A. Clemens, E. C. Kornfeld, H. D. Snoddy, E. B. Smalstig, and N. J . Bach, Life Sci. 24, 375 (1979). 283. D. Kocjan. M. HodSEek, and D. HadZi, J. Med. Chem. 29, 1418 (1986). 284. H. Wikstrom, B. Anderson, D. Sanchez, P. Lindberg, L.Arvidsson, A. M. Johansson, J. G. Nilsson, K. Svensson, S. Hjorth, and A. Carlsson, J . Med. Chem. 28, 215 (1985). 285. H. Watanabe, M. Somei, S. Sekihara, K. Nakagawa, and F. Yamada, J p n . J. Phurmacol. 45, 501 (1987). 286. R. W. Foote. H . H. Biischer, D. Romer, R. Maurer, A. Enz, B. H. Gahwiler, G. T. Shearman, M. P. Seiler, and H. Wiithrich, Life Sci. 42, 137 (1988); R. A. Siege1 and M. Marko, Experientiu 44, 764 (1988). 287. D. G. Grahame-Smith, D. P. Jeaney, M. Schacher, and J. M. Elliot, Experientia 44, 142 (1988). 288. R. A. Glennon, J . Med. Chem. 30, 1 (1987). 289. M. L. Cohen, R. W. Fuller, and K. D. Kurz, J. Pharmacol. Exp. Ther. 227,327 (1983). 290. A. G. Ramage, Eur. J . Pharmcol. 113, 295 (1985). 291. M. L. Cohen, K. D. Kurz, N. R. Norman, R. W. Fuller, G. P. Marzoni, and W. L. Garbrecht, J . Pharmacol. Exp. Ther. 235, 319 (1985). 292. G. Marzoni. W. L. Garbrecht, P. Fludzinski, and M. L. Cohen, J. Med. Chem. 30, 1823 (1987). 293. W. L . Garbrecht, G. Marzoni, K. R. Whitten, and M. L . Cohen, J. Med. Chem. 31, 444 (1988). 294. J. S. Ward, R. W. Fuller, L. Merritt, H. D. Snoddy, J. W. Paschal, N. R. Mason. and J. S. Horng, J. Med. Chem. 31, 1512 (1988). 295. E. Eich, D. Eichberg, and W. G. Miiller, Biochem. Pharmacol. 33, 523 (1984). 296. E. Eich, C. Becker. D. Eichberg, A. Maidhof, and W. E. G. Miiller, Pharmazie 41, 156 (1986). 297. E. Eich, C. Becker, R. Sieben, B. KureleC, A. Maidhof, and W. E. G. Miiller, J. Anriohiot. 39, 804 (1986). 298. E. Eich, C. Becker. K. Mayer, A. Maidhof, and W. G. Miiller, Planta Med.. 290 (1986). 299. E. Eich, D. Eichberg, G. Schwarz, F. Clas, and M. Loos, Arzneim.-Forsch. 35, 1760 (1985). 300. G. Sauer, J. Heindl, and H. Wachtel, Tetrahedron Lett. 29, 6425 (1988); G. Sauer, B. Schroter, and H . Kiinzer, Tetrahedron Lett. 29, 6429 (1988).
-CHAPTER
2-
SPIROBENZYLISOQUINOLINE AND RELATED ALKALOIDS GABORB L A S K ~ EGIS Pharmaceuticals Budapest H-1106. Hungary
I. Introduction ........................................... 11. Occurrence and Structure Elucidation of Spi
111.
IV.
V.
Vl. V11.
A. Reisolation of Previously Known Spirobenzylisoquinolines .................. B. Structure Revisions ........................................... C. New Spirobenzylisoquinolines ........................................................ D. New lndenobenzazepines ............................ Synthesis of Spirobenzylisoquinoline Alkaloids ........................................ A. 1,2.-Indandione and 1,2,3-ln B. Thermolysis of Benzocyclobutanes . C. Transformation of Protoberberines .................................................. D. Transformation of lndenobe E. Transformation of Phthalide Synthesis of lndenobenzazepine Alkaloids .............................................. A. Transformation of Spirobenzylisoquinolines B. Transformation of Protoberberines .................................................. C. Transformation of D. Transformation of Protopine Miscellaneous Transformation ........................ A. Ring D Inversion of Proto ..................................... B. Synthesis of Rhoeadines ..................................... C. Synthesis of Phthalideisoquinolines ................................................. Enzymatic Transformations Biosynthesis of Spirob References .......................................................................,................
i57 i59 159 I60 163 182 184 184 I86 I 89 199 199 203
203 203 204 206 206 206 212 215 215 218 219
I. Introduction
The spirobenzylisoquinoline alkaloids represent a rapidly growing group of isoquinoline alkaloids. In 1971, at the time of the last review in this treatise (Z), only 7 alkaloids were known which possessed the common spirobenzylisoquinoline nucleus presented in formula 1. In 1980, a compendium of spirobenzylisoquinoline alkaloids appeared (2) covering the physical and spectral data of 29 alkaloids. Since that time it has been demonstrated that 3 alkaloids, namely fumarofine, fumaritrine, and fu157
THE ALKALOIDS. VOL. 38 Copyright 8 19yo by Academic Presr. Inc. All rights o f reproduction in any form reaerved.
158
GABORBLASKO
maritridine, are indenobenzazepine alkaloids rather than spirobenzylisoquinolines. Additionally, 12 new spirobenzylisoquinoline alkaloids have been isolated from different plant sources including two N-norspirobenzylisoquinolines, a type of alkaloid which was previously unknown, one glycosidic alkaloid, parviflorine, and the first secospirobenzylisoquinoline alkaloid.
11 10
3
2
1
Spirobenzylisoquinolinealkaloids have thus far been found only within the plant family Fumariaceae, and, more specifically, with few exceptions they occur within the genera Fumaria and Corydalis. A direct relationship is observed between the plant source and the oxygenation pattern of ring C of the spirobenzylisoquinolines. The genus Fumaria yields spirobenzylisoquinolines bearing only one oxygenated function in ring C in the form of a hydroxyl or a ketone group located at C-8. On the other hand, spirobenzylisoquinolinesisolated from Corydalis species possess two oxygenated substituents in ring C, usually in the form of two hydroxyl groups or one hydroxyl and a ketone. In the latter case the hydroxyl group is usually located at C-8 and the ketone at C-13. There is a small subgroup of spirobenzylisoquinoline alkaloids consisting so far of ochotensine, ochotensimine, raddeamine, ochotensidine, and corystewartine, found mostly in Corydalis species, which possess an exocyclic methylene or a geminal methyl and hydroxyl at C-13. The absolute configuration of spirobenzylisoquinoline alkaloids is determined by CD spectroscopy applying the aromatic chirality rule. Dextrorotatory spirobenzylisoquinolines,for example, ( + )-ochotensine, ( +)-ochotensimine, ( + bochrobirine, and ( +)-fumariline, possess the absolute configuration depicted in formula 1. Throughout this chapter the structures are drawn according to this antipode; however, it must be realized that the corresponding absolute configuration could eventually prove not to be the case. The numbering system used in this chapter is in accordance with that generally accepted for spirobenzylisoquinolines.
2.
159
SPIROBENZYLISOQUINOLINE ALKALOIDS
In the period since the last review in this treatise by Shamma (I), many significant advances have been made in the isolation, structure elucidation, and chemistry of spirobenzylisoquinoline alkaloids. Chapters were devoted to this group of alkaloids in Isoquinoline Alkaloids (3),Isoquinoline Alkaloids Research 1972-1977 ( 4 ) , and MTP International Review of Science, Organic Chemistry, Volume 9 (5). The spirobenzylisoquinoline alkaloids have also been reviewed regularly in the Specialist Periodical Reports of the Chemical Society (6) and later in Natural Products Reports (7). Phytochemical studies with regard to the spirobenzylisoquinoline alkaloids were summarized in the chapters covering alkaloids of the Papaveraceae in this treatise (8,9). This chapter is a sequel to the previous review published in 1971 in this treatise (1)and covers the literature on the occurrence, isolation, structure elucidation, spectroscopy, synthesis, and transformations of spirobenzylisoquinoline alkaloids to the end of 1988. 11. Occurrence and Structure Elucidation of
Spirobenzylisoquinoline Alkaloids
A. REISOLATION OF PREVIOUSLY KNOWN SPIROBENZYLISOQUINOLINES Previously known spirobenzylisoquinoline alkaloids (1) of established structure, namely, fumaritine (2), fumaricine (3), fumariline (4), ochrobisibiricine (6), ochotensine (7), and ochotensimine (S), have been rine (9, isolated from a number of new plant sources. The additional occurrences of these alkaloids are listed in Table I.
0
CH,O
CH,O
OH
OCH, 3
2
4
5
160
GABORBLASKO
0
-
6
7 R=H 8 R=CH,
B. STRUCTURE REVISIONS I. Fumarofine and 0-Methylfumarofine The structure of the alkaloid fumarofine, C,,H,90,N, mp 255"C, [a],, 0" (MeOH), isolated initially from Fumaria officinalis L. (33), was established as the spirobenzylisoquinoline 9 on the basis of 'H-NMR studies TABLE I REISOLATION OF KNOWN SPIROBENZYLlSOQUlNOLlNE ALKALOIDS A N D THEIR SOURCES ~~
Alkaloid Furmaritine (2)
Fumaricine (3) Fumariline (4)
Ochrobirine ( 5 ) Sibiricine ( 6 ) Ochotensine (7)
Ochotensimine (8)
Plant
Ref.
Fiinzuriu purvifloru Lam. F . /nirrulis ssp. boruei (Jord.) Pugsley
11
F. guillurdortii Boiss. F. juduicu Boiss. F. cupreolutu L. F. densifliiru DC. F. offic,inulis L. F . ,quillurdottii Boiss. F . officinulis L. F. pnrviflora Lam. F . ~niirulisssp. boruri (Jord.) Pugsley F . densifloru DC. F. ofJicinulis L. F . cupreoluru L. F . willuntii Loisel. F . indicu (Haussk.) Pugsley" F . rosfelluru Knaf. Coryduli.~vuginuns Royle C. pcinicrrligeru Regel C. Iedrbouritinu K. et K. C. ochotensis Turcz. var. ruddeunu (Regel) Nakai C . solidu (L.) Swartz C. stenwrii Fedde C. ocliotensis Turcz. var. ruddeunu (Regel) Nakai C. s t e n w t i i Fedde
13
'' Fiimuruiu purvifliwu Lam. is identical with F. indicu (Haussk.) Pugsley (2).
12 14 15.16 17 18 13 18.19
/I 12 17 18.19 20
21 22-24 25 26
27 28 29 30 32 31 32
161
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
including NOE measurements. The alkaloid was reisolated from Furnuria microcarpa Boiss. (34),and its identity was verified by melting point, 'HNMR and mass spectra, and by comparison of the physical and spectral data of the 0-methylated product, obtained by diazomethane treatment, with corresponding data of the previously described 0-methylfumarofine (10) (33).The latter compound was also isolated as a natural product from Furnuria kralikii Jord. ( 3 9 , together with fumarofine. It has been shown (34) by reinterpretation of the data available for fumarofine and O-methylfumarofine and particularly by 'H- and I3C-NMR analysis that fumarofine is not a spirobenzylisoquinoline,but that it possesses the cis-B/C-fused indenobenzazepine structure 11. Consequently, 0-methylfumarofine can be described by structure 12 (34).
9 R=H 10 R = C H , R' 11 H
R2 H
12 CH3 H 13 CH, COCH,
It was noted that the two methoxyl signals in the 'H-NMR spectrum of 0-methylfumarofine are relatively close together at 6 3.87 and 3.94. This is never the case in 2,3-dimethoxyspirobenzylisoquinolinederivatives, where the C-2 methoxyl usually appears between 6 3.50 and 3.65 and the C-3 methoxyl is found in the 6 3.70-3.94 range (2). The N-methyl signal in the 'H-NMR spectrum of 12 is at 6 2.55 while in spirobenzylisoquinolines the corresponding signal is located between 6 2.25 and 2.40. The 1H absorption of spirobenzylisoquinolines is normally found near 6 6.25, so that the downfield singlet in fumarofine (11) and 0-methylfumarofine (12) found at 6 7.15 and 7.28, respectively, cannot be associated with the 1-H on a spirobenzylisoquinoline structure. These chemical shift values are characteristic for the 1-H absorption of the indenobenzazepine moiety. The singlet at 6 4.43 in 0-methylfumarofine (12) had been originally assigned as 13-H, which is geminal to a hydroxyl in the old structure of fumarofine. Among true spirobenzylisoquinolines,however, such protons uniformly appear downfield from 6 4.90. 0-Acetylation of O-methyl-
162
GABOR B L A S K ~
fumarofine (12) yielded 0-methylfumarofine acetate (13). The singlet proton absorption at 6 4.43 in 12, which is now assigned to 8-H of the indenobenzazepine structure, is found at 6 4.95 in 13, resulting in a downfield shift of 0.51 ppm on acetylation. If this absorption were due to a hydrogen geminal to a hydroxyl, as required in the old assignment, the downfield shift on acetylation should have been of the order of 1.1 ppm. Conclusive evidence concerning the nature of the ring fusion was obtained by 'H- and I3C-NMR spectroscopy. The acetoxy methyl singlet in 0-methylfumarofine acetate (13) is at 6 2.22. This value is in accord with a cis-B/C fusion, since in the alternate trans arrangement the corresponding resonance is at 6 2.00 (36).The chemical shifts for C-5 and C-6 at 6 33.05 and 50.12, respectively, also support a B/C-cis-fused indenobenzazepine structure. Final proof for the new structural assignments was furnished by the total synthesis of 0-methylfumarofine (12) (34) (see Section IV), which evidently confirmed the structural revision of fumarofine (11) and 0-methylfumarofine (12) 2. Fumaritridine and Fumaritrine Following the finding that fumarofine is an indenobenzazepine alkaloid rather than a spirobenzylisoquinoline,a search was undertaken for other indenobenzazepines that may have been erroneously assigned (37). Two more alkaloids proved to be misassigned: fumaritridine, C,,H,,O,N, mp 198-2OO0C, [a],+ 18" (MeOH), isolated from Fumaria rostellata Knaf. (38,39)and originally established as spirobenzylisoquinoline 14, and fumaritrine, C,,H,,O,N, mp 153-155°C ([a],not available), found both in F. rostellata Knaf. (39) and F. officinalis L. (40,41),which was stated to be represented by structure 15. Reinvestigation of available spectral data in the view of the characteristic data obtained for indenobenzazepines 16 and 17, which were synthesized by a series of stereocontrolled reactions (see Section IV), led to the confirmation that fumaritridine and fumaritrine are not spirobenzylisoquinolines, but rather indenobenzazepines represented by structures 16 and 17, respectively (37).
14 R = H 15 R = C H 3
16 R = H 17 R = CH,
2.
SPlROBENZYLlSOQUlNOLI"
163
ALKALOIDS
C. NEW SPIROBENZYLISOQUINOLINES 1. Norfumaritine
Recently, the first two N-norspirobenzylisoquinolinealkaloids were [a], - 16" (CHCl,), was isolated found. Norfumaritine (18), C&&N, from Fumuriu krulikii Jord. (42) as an amorphous material, and its structure was established by 'H-NMR Table 11) and mass spectroscopy. Eschweiler-Clarke N-methylation of 18 provided the known fumaritine (2), confirming unambiguously the structure of norfumaritine (18) (42).
2. Lederine Lederine (19), C2,H,907Nrmp 208-209"C, [a],+ 13 (CHCI,), has been isolated from Corydulis ledebouriunu K. et K. and Dicentru peregrinu (Rud.) Fedde (42,43).The 'H-NMR spectrum of 19 contains one acetyl
TABLE I1 'H-NMR SPECTRAL ASSIGNMENT OF NORFUMARlTlNE (18). LEDERINE (19). (20). A N D 0-METHYLFUMAROPHYCINE (21)" FUMAROPHYCINE ~
Proton
I-H 4-H 8-H 1 I-H 12-H 13-H 2-OCH, 3-OCH3 2.3-OCHz0 9.10-OCH,O N-CH, 8-OCOCHx
18
6.60 (s) 6.68 (s) 5.32 (s) 6.76 (d. 7.8) 6.68 (d. 7.8) 3.08 (d. 16.0) 3.46 (d. 16.0)
-
3.86 (s) 5.96 (d, 1.3) 6.01 (d. 1.3) -
(' Spectra were recorded in CHCI,.
~
19
6.51 (s) 6.66 (s) 6.18 (s) 6.78 (s) 6.78 (s) 5.23 (s)
5.86 (d, 2.0) 5.89 (d. 2.0) 6.00 (d. 2.0) 6.03 (d, 2.0) 1.90 (s)
~~
~
20
21
6.50 (s) 6.67 (s) 6.48 (s) 6.79 (d, 8.0) 6.66 (d, 8.0) 3.32 (d. 16.0) 3.55 (d, 16.0) 3.94 (s) -
6.54 (s) 6.62 (s) 6.50 (s) 6.83 (d, 8.0) 6.74 (d, 8.0) 3.39 (d. 17.0) 3.57 (d, 17.0) 3.73 (s) 3.85 (s) -
5.94 ( s )
5.96 (d. 1.5) 5.98 (d. 1.5) 2.33 (s) 1.73 (s)
2.32 (s) I .74 (s)
164
GABOR BLASKO
singlet at 6 1.90 and two pairs of doublets at 6 5.86, 5.89 and 6.00, 6.03 representing the resonances of the two methylenedioxy groups at C2,C-3 and C-9,C-10, respectively (Table 11). Two one-proton singlets at 6 5.23 and 6.18 could be assigned as protons geminal to hydroxyl and acetoxyl groups, respectively. The position of the acetyl group was determined by chemical means as follows. 0-Acetylsibiricine was prepared by acetyletion of sibiricine (6) with acetic anhydride in pyridine. Reduction of 0-acetylsibiricine with sodium borohydride led to O-acetyldihydrosibiricine, which was identical to N-methyllederine obtained by Craig's methylation of lederine (19). The identity of the two semisynthetic products established the location of the acetoxyl in lederine (19) at C-8.
19
3. Fumarophycine Fumarophycine (20), C,,H,,O,N, mp 107-109"C, [a],- 67.5" (CHCI,), was originally isolated from Fumaria officinalis L. (44,45) and subsequently from F. muralis ssp. boraei (Jord.) Pugsl. (12) and F. kralikii Jord. (46),and its structure was established by 'H-NMR spectroscopy (45)(Table 11). The two ring A aromatic singlets were found at 6 6.50 and 6.67, while the ring D protons appeared at 6 6.66 and 6.79 as a doublet of doublets. The methylene protons at C-13 exerted a large geminal coupling (J = 16 Hz) at 6 3.32 and 3.55. The downfield chemical shift of 8-H at 6 6.48 indicated that this hydrogen is syn to the nitrogen atom, thereby establishing the relative stereochemistry at stereo center C-8.
0
CH,O
OH 20
2.
SPIROBENZYLISOQUINOLINE ALKALOIDS
165
4. 0-Methylfumarophycine The alkaloid 0-methylfumarophycine (21), C,,H,,O,N,
mp 124-1 26"C,
[a],-51" (CHCI,), isolated from Fumaria officinalis L . (40,44,47)and F.
kralikii Jord. (46), has been described in the literature only briefly. Its structure was assumed by comparison of the isolate with the diazomethane 0-methylation product of fumaricine (20) obtained from the same sources. Subsequently, 0-methylfumarophycine (21) was reisolated from F. officinalis L. (49,and a careful 'H-NMR study was performed (Table 11) in order to establish its structure and relative stereochemistry. The absolute configuration of 0-methylfumarophycine (21) at stereo centers C-1 and C-8 was ascertinated by comparative C D measurements. The C D curve of both 21 and fumaricine (3), of established absolute configuration (49),displayed a minimum in the range of 261-262 nm followed by a maximum between 290 and 292 nm, suggesting that the two alkaloids possess identical absolute configurations at C-1 and C-8.
0
21
5. Parfumine Parfumine (22), C,,,H,,O,N, mp 11 1-1 12"C, [a]+ 18" (CHCI,), has been isolated from the following Fumaria species: F. parviflora Lam. ( I1,5052), F . muralis ssp. boraei (Jord.) Pugsl. (12), F . densiflora DC. (17), F. capreolata L. (20),F. bella P. D. Sell (20),F. vaillantii Loisel. (21,53,54), F. kralikii Jord. (34,55), F . rostellata Knaf. (39,F . judaica Boiss. (56), F. schleicheri Soyer-Willem ( 5 3 , and F. schrammii (Acherson) Velen (58). The structure of parfumine (22) was determined originally by lowresolution 'H-NMR and mass spectroscopy (50). High-resolution 'HNMR data of 22 were obtained at 200 MHz and are summarized in Table 111 (2). The complete X-ray structure determination of parfumine (22) has been published (51).
22
166
GABORBLASKO
TABLE I11 'H-NMR SPECTRAL ASSIGNMENT OF FUMARILINE (4). PARFUMINE (22), ISOPARFUMINE (23). A N D PARFUMIDINE (24)" 4
22
23
24
6. I8 (s) 6.54 (s) 7.07 (d, 8.0) 6.86 (d, 8.0) 3.32 (d, 18.0) 3.50 (d, 18.0) 5.80 (s) 6.12 (s) 2.36 (s)
6.30 (s) 6.58 (s) 7.10 (d. 8.0) 6.89 (d, 8.0)
6.26 (s) 6.59 (s) 7.20 (d, 7.9) 6.93 (d, 7.9)
6. I7 (s) 6.60 (s) 7.12 (d, 8.0) 6.92 (d, 8.0)
3.85 (s) 6. I6 (s) 2.37 (s)
3.52 (s)
3.59 (s) 6. I8 (s) 2.35 (s)
Proton I-H 4-H 1 I-H 12-H 13-H 2-OCH3 3-OCHJ 2.3-OCHz0 9.10-OCH20 N-HCH,
-
6.15 (s) 2.28 (s)
" Spectra were, recorded in CDCI,.
6. Isoparfumine
Isoparfumine (23), CzoHI9O5N, mp 206-208"C, [a],+ 54" (CHCI,), has been isolated from Rupicapnos africana (Lam.) Pomel. (Fumariaceae) (59). In the mass spectrum of isoparfumine (23) the molecular peak appeared at mlz 353 (52%), and an M' - 29 fragment characteristic for 8ketospirobenzylisoquinolines was observed at mlz 324 ( 100%) as the base peak. The 'H-NMR data of isoparfumine (Table 111) confirmed structure 23, with singlets at 6 2.28 (N-CH,), 3.52 (0-CH,), 6.15 (O-CH,-O), 6.26 (4-H), 6.59 (1-H), and an AB system centered at 6 6.93 and 7.20 (12-H and 11-H, respectively). The methoxyl group of isoparfumine (23) was placed at C-2 on the basis of its appearance at 6 3.52. It is known that in 8-ketospirobenzylisoquinolinesa methoxyl group at C-2 should appear at 6 3.50-3.65, whereas the corresponding group at C-3 resonates at 6 3.703.94. 0-Methylation of isoparfumine (23) with diazomethane afforded thereby further supporting the structural assignment of parfumidine (U), isoparfumidine (23).
23
167
2. SPlROBENZYLISOQUlNOLINE ALKALOIDS
7. Parfumidine mp 170-171°C, [aID+33.3" (CHCI,), has Parfumidine (24), C2,HZ1O5N, been isolated from the following Furnuria species: F. parvifloru Lam. (11,60,61),F . officinalis L. (47),F . densifloru DC. (13,F. bellu P.D. Sell (20), and F. vuillantii Loisel. (53).The structure of parfumidine (24) was originally assigned on the basis of its low-resolution 'H-NMR spectrum (60). Later, the high-resolution 'H-NMR spectral data of 24 were published as a result of a careful review of the physical and spectral data of spirobenzylisoquinolinealkaloids (2) (Table 111).
24
8. Fumaritine N-Oxide mp 204"C, has been isolated from Fumaritine N-oxide (25), C20Hz106N, Furnuria kralikii Jord. (34,35)and F . officinalis L. (19). The structure of this highly polar alkaloid was established by 'H-, I3C-NMR (Table IV), and mass spectroscopy and was confirmed by reduction of 25 to fumaritine (2) with sulfur dioxide (34).
CHSO
OH 25
TABLE IV 'H- A N D "C-NMR SPECTRAL ASSIGNMENTS OF FUMARITINE (2) A N D FUMARITINE N-OXIDE (25) (3.5)
Proton 1-H 4-H 8-H
2
6.47 (s) 6.59 (s) 5.42 (s)
25" 6. I5 (s) 6.65 (s) 6.23 (s)
Carbon I 2 3
25"
2 111.2 144.2 146.4
117.4 156.8 153.0
(continued)
168
GABOR BLASKO
TABLE IV (Conrinrred) 2
25”
Carbon
I I-H 12-H 13-H
6.74 (d, 7.9) 6.58 (d. 7.8) 3.29 (s)
3-OCH3 9.10-OCH20 N-CH,
3.85 (s) 5.95 (s) 2.41 (s)
6.89 (d, 7.9) 6.89 (d, 7.9) 3.34 (d, 16.7) 3.90 (d, 16.7) 3.73 (s) 5.92 (s) 3.11 (s)
4 4a 5 6 8 8a 9 10 I1 12 12a 13 14 14a 3-OCH3 9, 10-OCH20 N-CH,
Proton
I’
2 112.9 127.4 23.3 47.6 82.3 125.5 144.2 147.5 108.9 113.3 135.0 44.0 74.5 127.9 56.0 101.6 38. I
25”
112.9 118.2 27.6 64.8 77.2 124.2 145.4 148.5 110.9 117.9 135.3 38.8 90.6 127.2 57.4 103.1 53.7
Spectra were recorded in CDCI,. Spectra were recorded in D,O + 2 drops of 40% NaOD.
9. Dihydrofumariline Dihydrofumariline (26), C2,,H,,0,N, mp 191-193”C, has been isolated from Fumaria ojficinalis L. (19,62),and its structure was established by ‘H-NMR spectroscopy (Table V) and by comparison with the reduction products of fumariline (4). Reduction of 4 with sodium borohydride yielded two products, dihydrofumariline I (26), identical with the alkaloid isolated from F. officinalis L., and dihydrofumariline I1 (27), obtained previously as the sole product of the LiAIH, reduction of fumariline (4) (18). The ‘H-NMR spectrum of dihydrofumariline I1 (27) displayed a signal at 6 5.52 assigned to the proton at C-8 geminal t o the hydroxyl group (Table V). The chemical shift of this signal is close t o that of the corresponding signal in fumaritine (2) and fumaricine (3), in which the C-8 hydrogen is syn to the nitrogen atom (18). Dihydrofumariline (26) displays the corresponding 8-H signal at 6 4.82; consequently, it must be the C-8 epimer of 27. It should be noted that the isolation of a “dihydrofumariline” has also been reported from Fumciriu schrammii (Acherson) Velen (581, in which the chemical shift of the hydrogen at C-8 is similar to that of dihydrofumariline I1 (27). The reported melting point of this natural product, however, was found to be much higher than that of the corresponding semisynthetic sample obtained by the reduction of fumariline (4). It is possible
169
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
TABLE V 'H-NMR SPECTRAL ASSIGNMENTS OF F U M A R ~ C (3). ~ NDIHYDROFUMARILINE E 1
(26), AND DlHYDROFUMARlLlNE 11 (27)"
Proton
3
26
27
1-H 4- H 8-H 1 I-H 12-H 13-H 2-OCHX 3-OCH3 2.3-OCH,O 9,IO-OCHZO N-CH,
6.39 ( s ) 6.57 (s) 5.44 ( s ) 6.73 (d, 8.0) 6.58 (d, 8.0) 3.29 (s) 3.49 (s) 3.81 ( s )
6.26 (s) 6.51 (s) 4.82 ( s ) 6.70 (s) 6.70 (s) 3.29 ( s )
6.35 ( s ) 6.55 (s) 5.55 (s) 6.68 (s) 6.68 (s) 3.24 (d. 14.0) 5.78 (s) 5.94 ( s ) 2.37 (s)
"
-
5.78 (s) 5.94 ( s ) 2.41 (s)
5.91 (s) 2.40 (s)
Spectra were recorded in CDCI,.
that both dihydrofumariline (26) and its C-8 epimer (27) are true natural products; however, more evidence is required to clarify this point.
R' R 2 26 OH H 27
H
OH
10. Ledebouridine
Ledebouridine (ledeboridine) (281, C,OH,lO,N, mp 140-14 "C, [a],
+ 114" (MeOH), has been isolated from Corydulis ledebouriuna K. et K.
(63). Its structure was determined by means of 'H-NMR (Table VI) and mass spectrometry (63). H OH
28
170
GABOR BLASKO
TABLE VI 'H-NMR SPECTRAL ASSIGNMENTS OF LEDEBOURIDINE (28). RADDEANINE (29). YENHUSOMINE (30). A N D SEVERZININE (31)" Proton
28
29
30
31
I-H 4-H 8-H 1 I-H 12-H 13-H 2-OCH3 3-OCH3 2.3-OCH2O 9. IO-OCH,O
6.19 (s) 6.59 (s) 5.33 (s) 6.77 (s) 6.77 (s) 5.1 I (s) 3.75 (s) 5.91 (s)
6.16 (s) 6.65 (s) 5.42 (bs) 6.80b (d. 8.0) 6.76h (d, 8.0) 5.21 (bs) 3.40 (s) 3.81 (s) 5.97 (s)
6.14 (s) 6.56 (s) 5.33 (s) 6.76 (s) 6.76 (s) 5.10 (s) 5.76 (s) 5.92 (q)
N-CHI
2.50 (s)
2.60 (s)
6.10 (s) 6.70 (s) 4.91 (s) 6.94 (s) 6.94 (s) 5.52 (bs) 3.39 (s) 3.83 (s) 5.99 (d, 1.3) 6.02 (d, 1.3) 2.71 (s)
"
"
-
2.47 (s)
Spectra were recorded in CDCI,. Interchangeable.
1 1. Raddeanine
Raddeanine ( 1 3-epiyenhusomine) (29), C2,H,,0,N, mp 200-202"C, [a],,
+ 79.4 (MeOH), has been isolated from Corydalis ochotensis Turcz. var.
raddeana (Regel) Nakai (29,64,65).There is also another alkaloid known by this name obtained earlier from Fritillaria raddeana (66), and, therefore, 13-epiyenhusomine would be a better common name for this spirobenzylisoquinoline alkaloid. Structure 29 was established by IR, 'HNMR, and mass spectroscopy. In the 'H-NMR spectrum of 29 (Table VI) two methine protons appear at 6 5.21 and 5.42, suggesting the location of the two hydroxyl groups anti to the nitrogen atom. Unambiguous assignment of the 13C-NMRspectrum of 13-epiyenhusomine (29), isolated from Corydalis govaniana Wall., was achieved by the judicious use of selective INEPT spectroscopy (67) (Table VII).
CH 29
2. SPlROBENZYLlSOQUlNOLI"
171
ALKALOIDS
TABLE VII ''C-NMR SPECTRAL ASSIGNMENTS OF S l B l R l C l N E (6).RADDEANINE (29). RADDEANONE (36). YENHUSOMIDINE 37). A N D CORYDAINE 38)"(70)
6
29
36
37
38
106.9 147.4 147.4 147.4 109.6 125.0 29.2 48.9 70.3 132.7 146. I 154.8 110.9 119.9 132.5 201.5 77.2 130.6 -
109.8 146.3 147.7 147.7 112. I 130.6 23.6 48.0 76.8 122.6 147.9 142.5 108.5 115.6 137.6 78.3 80.6 120.2 55. I 55.4 101.3 38.7
110.7 147.2 148.9 148.9 112.5 124.0 28.5 48.9 70. I 132.9 145.0 154.5 110.4 119.5 132.5 201.7 76.9 129.7 56. I '' 56.0 103. I 39.7
110.7 148.5 148.6 148.6 111.4 128.7 29.3 50.3 75. I 134.6 144.4 154.6 109.5 119.6 131.3 202.7 72.0 128.7 56.5' 56.1"
105.8 146.9 146.9 146.9 108.2 129.3 29.5 50.2 75.0 134.3 144.4 154.5 110.6
Carbon 1
2 3 3 4 4a 5 6 8 8a 9 10 11
12 12a 13 14 14a 2-OCH3 3-OCH7 2.3-OCHzO 9. 10-OCH20 N-CH, "
-
101.3 103.2 39.7
-
103.2 41.9
119.6
131.2 202.2 72.0 129.8
-
101.1 103.1 41.7
Spectra were recorded in CDCI,. Interchangeable.
The racemic form of raddeanine (13-epiyenhusomine) (29), mp 219220"C, has also been obtained from Corydalis ledebouriana K. et K. (63) as a natural product. It is likely that its precursor, the corresponding 13ketospirobenzylisoquinoline, undergoes racemization by a retro-aldol cleavage followed by recyclization, and reduction of this racemate yields (?)+addeanhe (29). 12. Yenhusomine Yenhusomine (301, C2,H2306N,mp 127-128"C, [aID+48" (MeOH), has been found in Corydalis ochotensis Turcz. (31,68) and in C . meifolia Wall. (69). In the 'H-NMR spectrum of yenhusomine (30) (Table VI), the C-8 and C-13 protons appear at 6 4.91 and 5.52, respectively. These chem-
172
GABOR BLASKO
ical shifts are similar to those of ochrobirine (5); therefore, the relative stereochemistry of the C-8 and C-13 hydroxyls are determined to be syn and anti to the nitrogen atom, respectively. The 13C-NMRassignments of yenhusomine (30) appeared as a part of the I3C-NMR investigation of a number of spirobenzylisoquinoline alkaloids (70).
30
13. Severzinine Severzinine (sewerzinine) (31), C,,H,,O,N, mp 90-91"C, [a]D + 109" (CHCI,), has been isolated from Corydafissewerzowi Regel. Structure 31 was established on the basis of 'H-NMR evidence (Table VI) as an 8,13dihydroxyspirobenzylisoquinoline possessing both hydroxyl groups in anti positions relative to the nitrogen (71). H OH
31
14. Raddeanidine
+
Raddeanidine (32), C,,H,,O,N, [a], 82.7" (MeOH), was isolated from Corydalis ochotensis Turcz. var. raddeana (Regel) Nakai as an amorphous material (29,64,65). Hydrolysis of 32 furnished raddeanine (29), supporting the fact that 32 is an acetyl derivative of 29. A single hydroxyl absorption at 3580 cm-' in the IR spectrum and only one acetyl methyl signal at 6 1.93 in the 'H-NMR spectrum established that raddeanidine (32) is a monoacetyl derivative of raddeanine (29). The chemical shift values of the two methine protons at 6 5.15 and 6.57 (both syn to the nitrogen atom) suggested that the acetoxyl group is located at C-8.
2.
173
SPIROBENZYLISOQUINOLINE ALKALOIDS
32
15. Corpaine The isolation of corpaine (33), CzoH,90,N, mp 204"C, was initially reported from Corydulis puczoskii N . Busch (72,73). Subsequently, corpaine (33) was reisolated from C. solidu (L.) Swartz, mp 190-192"C, [a], - 105" (MeOH), and its unambiguous structure elucidation was completed by high-resolution 'H-NMR measurements (74) (Table VIII).
33 TABLE V l l l 'H-NMR SPECTRAL ASSIGNMENTS OF SlBlRICINE (6). CORPAlNE (33). CORYSOLlDlNE (34). A N D LEDEBOURINE (35)" 6
33
34
35
12-H 2-OCH3 3-OCH3 2.3-OCHZO 9,10-OCHZ0
6.04 (s) 6.54 (s) 5.57 ( s ) 7.01 (d, 8.0) 7.51 (d. 8.0) 5.84 (s) 6.18 (s)
6.19 (s) 6.58 (s) 5.04 (s) 6.98 (d, 8.0) 7.40 (d. 8.0) 3.87 (s) 6.18 (s)
5.70 (s) 6.31 (s) 5.62 (bs) 6.70 (d. 8.0) 7.25 (d. 8.0)
N-CH,
2.43 (s)
2.28 ( s )
6.1 I ( s ) 6.67 ( s ) 5.64 (s) 7.02 (d, 8.0) 7.53 (d, 8.0) 3.86 (s) 6.21 (d, 1.2) 6.22 (d, 1.2) 2.47 (s)
Proton I-H 4- H
8-H 1 I-H
I'
Spectra were recorded in CDCI,
3.40 ( s ) 5.70 (s) 2.67 (s)
174
GABOR B L A S K ~
16. Corysolidine Corysolidine (M), C,,H,,O,N, was obtained from Covydalis solida (L.) Swartz as an amorphous racemic spriobenzylisoquinoline alkaloid (74). The 'H-NMR spectrum of 34 exhibits an aromatic methoxyl signal at 6 3.86, indicating that this group is at C-3 rather than at C-2. A significant feature of the 'H-NMR spectrum of corysolidine (34) is that 8-H appears relatively downfield at 6 5.64, in contrast to the corresponding signal in corpaine 33), which appears at 6 5.04. The chemical shifts observed are consonant with an anti relationship between 8-H and the nitrogen atom in 33, and with the alternate syn relationship in 34 (74) (Table VIII). 0
34
17. Ledebourine Ledebourine (ledeborine) ( 3 9 , C,,H,,O,N, mp 184-185"C, was isolated from Corydalis ledebouriana K. et K. (75). Originally, structure 34 was proposed for ledeborine but was later modified when the positions of the phenolic hydroxyl and methoxyl groups in the molecule were reversed in accordance with the 'H-NMR data (Table VIII). These data included a relatively upfield three-proton singlet at 6 3.40 typical of a C-2 methoxyl signal in a spirobenzylisoquinoline system.
35
18. Raddeanone Raddeanone (36), CZ,HZ,OhN, mp 168-170°C, [a],0" (MeOH), has been isolated from Corydalis ochotensis Turcz. var. raddeuna (Regel) Nakai (29,64,65). The UV, IR, and mass spectra of raddeanone (36) suggested
2.
175
SPIROBENZYLISOQUINOLINE ALKALOIDS
TABLE IX 'H-NMR SPECTRAL ASSIGNMENTS OF RADDEANONE (36),YENHUSOMIDNE (37), A N D CORYDAINE (38)" Proton
36
37
38
1-H 4-H 8-H 1 I-H 12-H 2-OCH3 3-OCH3 2,3-OCH20 9,IO-CHzO
6.05 (s) 6.66 (s) 5.58 (bs) 7.01 (d, 8.0) 7.51 (d, 8.0) 3.53 (s) 3.84 (s)
6. I I ( s ) 6.64 (s) 5.14 (s) 7.02 (d, 8.0) 7.51 (d. 8.0) 3.66 (s) 3.88 (s)
6.06 (s) 6.55 (s) 5.02 (s) 6.99 (d, 8.0) 7.45 (d, 8.0)
N-CH3 "
6.24 ( s )
6.15 (d. 1.0) 6.20 (d, 1.0) 2.37 ( s )
2.33 (s)
5.82 (m) 6.16 (d, 1.2) 6.19 (d, 1.2) 2.28 (s)
Spectra were recorded in CDCI,.
a 13-ketospirobenzylisoquinolinestructure, which was further confirmed by 'H-NMR measurements (Table IX). The 'H-NMR spectrum of 36 resembled that of sibiricine (6),whose structure was confirmed by X-ray analysis (28). The presence of an N-methyl signal at 6 2.37 and a methine proton at 6 5.58 in the 'H-NMR spectrum of raddeanone (36)established the stereoorientation of the C-8 hydroxyl to be anti to the nitrogen atom. Raddeanone (36)occurs in nature as a racemic alkaloid, probably owing to its easy epimerization by a retro-aldol cleavage followed by an aldoltype recyclization, both of which are reactions that take place in nature. Consequently, racemic raddeanone (36) is considered a true natural product.
36
19. Yenhusomidine Racemic yenhusomidine (37),C,,H,IO,N, mp 240-241°C, has been isolated from Corydulis ochotensis Turcz. (31,68).The 'H-NMR spectrum of yenhusomidine (37) established the 13-ketospirobenzylisoquinoline
176
CABOR BLASKO
skeleton, and from the chemical shift of the C-8 methine proton at 6 5.14, a syn relationship of the C-8 hydroxyl and the nitrogen atom was anticipated (Table IX). The ',C-NMR data (70) of yenhusomidine (37)were in agreement with the proposed structure. In contrast to the 13-ketospirobenzylisoquinoline raddeanone (36),which was found in nature only in racemic form, there are reports of the isolation of optically active yenhusomidine. For example, ( - )-yenhusomidine (0-methylcorpaine), mp 220221"C, [a],+36.7" (CHCI,) was found in Corydalis vuginans Royle (76), and (+)-yenhusomidine, mp 175"C, [a], +98.3 (CHCI,) was obtained from Corydalis rneijolia Wall. (69). The disparate [a],values suggest that reevaluation of optical purity of the isolates is warranted. 0
31
20. Corydaine The isolation of corydaine (38), CzoH1906N,mp 184°C [a], + 145" (CHCI,), was initially reported from Corydalis paczoskii N . Busch; however, no final decision was made between two structural possibilities (one of which was 38) (77). The unambiguous structure elucidation of corydaine (38) was completed on the basis of available 'H-NMR data (2) (Table IX) and I3C-NMR measurements (70). 0
38
21. Densiflorine A new type of spirobenzylisoquinoline alkaloid, densiflorine (39), CzoHIS06N,mp 249-25 I"C, possessing a unique oxygen bridge between C-6 and C-13, has been isolated from Fumaria densiflora DC. (78). The
2. SPlROBENZYLlSOQUlNOLI"
ALKALOIDS
177
TABLE X 'H-NMR SPECTRAL ASSIGNMENTS O F D E N S l F L O R l N E (39) A N D AFRICANINE (40) Proton
I -H 4-H I I-H 12-H 13-H 3-OCHJ 2,3-OCH,O 9,10-OCH2O N-CH,
39"
40'
6.37 (s) 6.75 (s) 7.19' (d. 7.8) 7.15' (d, 7.8) 5.34 (s) 5.93 (s) 6.21 (d. 1.0) 6.23 (d, 1.0) 2.75 (s)
6.46 (s) 6.78 (s) 7.25' (d, 7.8) 7.23' (d. 7.8) 6.05 (s) 3.88 ( s ) 6.28 (d, 1.0) 6.28 (d, 1.0) 3.32 (s)
Spectrum was recorded in CDCI,. Spectrum was recorded in CDCI, plus TFA-d, ' Interchangeable.
"
"
molecular composition of densiflorine (39) was determined by high-resolution mass spectrometry, and its structure was established by U V and 'H-NMR spectroscopy (Table X). No [ a ] D value has been published for densiflorine (39); however, the absolute configuration of the stereo centers was determined by CD spectroscopy. The CD curve of 39 in methanol showed four Cotton effects, three negative, at 296, 227, and 210 nm, and one positive, at 259 nm, suggesting, in accordance with the aromatic chirality rule, the stereostructure denoted in formula 39.
39
22. Africanine
Africanine (40), C,,H,,O,N, mp 237"C, [a],+ 22"(CHCI,), was isolated from Rupicapnos africana (Lam.) Pomel. (Fumariaceae) (59). Its U V spectrum, with absorption maxima at, ,X, (EtOH) (log E) 206 (4.29), 233 (4.42), 259 (sh, 4.00), 290 (3.62), and 346 (3.261, reveals the presence of
178
GABORBLASKO
an 8-ketospirobenzylisoquinolineskeleton. The 'H-NMR spectrum of africanine (40) (Table X) is very similar to that of densiflorine (39), the only significant difference being the presence in africanine (40) of a methoxyl singlet at 6 3.88, instead of a methylenedioxy signal at 6 5.93 as in densiflorine (39). The chemical shift value of the methoxyl singlet places this group at C-3, which was further confirmed by 'H-NMR for of africanine acetate (41) obtained by acetic anhydride-pyridine treatment of 40.
40 R = H
41 R = A c
23. Parviflorine Parviflorine (42), C,,H,,O,,N, mp 320-232"C, [a],+ 1" (MeOH), isolated from Fumaria parvij7ora Lam. (79), is the first known glycosidic spirobenzylisoquinoline alkaloid. Acid hydrolysis of parviflorine (42) yielded D-glucose and the known spirobenzylisoquinoline ( + )-parfurnine (22). The stereochemistry of the anomeric center in parviflorine (42) was assigned on the basis of Klyne's rule, indicating that 42 is a parfumine-(3D-glucoside.
CI
I
OH 42
OH
2.
SPIROBENZYLISOQUINOLINE ALKALOIDS
I79
24. Hyperectine A unique spirobenzylisoquinoline alkaloid, hyperectine (43), C,,H,,O,N,, mp 237-238"C, was isolated from Hypecoum erectum L. (go), and its structure was established by IR and 'H-NMR spectral methods. The IR spectrum of hyperectine (43) displays two bands at 1730 and 1775 cm- ' that are characteristic for substituted maleinimides. The 'HNMR spectrum of 43 in pyridine-d, showed the signals of two pairs of aromatic protons located in para and ortho positions, respectively, at 6 6.41 (s), 6.87 (s) and 6 6.63 (d, J = 7 Hz), 6.68 (d, J = 7 Hz), two aromatic methylenedioxy groups centered at 6 5.60 and 5.74, an N-methyl group at 6 2.18, a methine proton at 6 5.03 (s), and three exchangeable hydrogens at 6 4.86 (bs). Final confirmation of the structure of hyperectine (43) was achieved by X-ray analysis of its methiodide. The X-ray investigation also established that the isolate consists a mixture of enantiomers having the 8(R),14(S) and 8(S), 14(R) absolute configurations.
43
25. Raddeanamine Raddeanamine (44),C,,H,,O,N, [aID + 166" (MeOH), was isolated from Corydalis ochotensis Turcz. var. ruddeana (Regel) Nakai as an amorphous material (29,64,65).The mass spectrum of raddeanamine (44) was similar to that of ochotensimine (8), except for peaks at mlz 383 (M') and 368 (M' - 15). The hydroxyl absorption at 3240 cm-' in the 1R spectrum and a quaternary methyl signal in the 'H-NMR spectrum at 6 1.23 indicated that instead of an exocyclic methylene group at C- I3 as in ochotensimine (8), raddeanamine (44)possesses a hydroxyl group at C-13 oriented syn to the nitrogen atom and a methyl group at C-13 in the anti position to the nitrogen atom. Dehydration of raddeanamine (44) by heating with potassium hydrogen sulfate afforded ochotensimine (8), thereby providing chemical proof of proposed structure 44.
180
GABORBLASKO
44
26. Ochotensidine
Recent reinvestigation of Corydulis stewurtii Fedde resulted in the isolation of four spirobenzylisoquinolines, namely, ochotensine (7), ochotensimine (8), ochotensidine (45), and corystewartine (46) (32). The availability of ochotensine (7) and ochotensimine (8) allowed detailed analysis of their high-resolution 'H-NMR spectra (Table XI). The 'H-NMR spectrum of the new, amorphous alkaloid ochotensidine, C,,H,,O,N, [a], +44" (MeOH), showed a close resemblance to that of ochotensimine (8). The main difference was the methylenedioxy substituent on ring A of ochotensidine (45) instead of the two methoxyl groups of ochotensimine (8).The mass spectrum of 45 exhibited a molecular ion at mlz 349, which
TABLE X I 'H-NMK SPECTRAL ASSIGNMENT OF OCHOTENSINE (7), OCHOTENSIMINE (8). OCHOTENSlDlNE (45). A N D CORYSTEWARTINE (46)" Proton
I
8
4s
46
I-H 4- H 8-H
6.26 (s) 6.61 (s) 2.93 (d. 17.8) 3.45 (d. 17.8) 6.81 (d. 8.1) 7.12 (d, 8.1) 4.91 (s) 5.64 ( s ) 3.66 (s) -
6.29 (s) 6.53 (s) 2.96 (d. 18.0) 3.45 (d. 18.0) 6.80 (d, 8.1) 7.1 I (d. 8. I) 4.90 (s) 5.64 (s) 3.64 (s) 3.85 (s)
6.26 (s) 6.50 (s) 2.90 (d, 17.8) 3.49 (d. 17.8) 6.79 (d, 8. I ) 7.08 (d, 8.1) 4.94 (s) 5.64 ( s ) 5.84 (s)
6.21 ( s ) 6.58 (s) 3.12 (d. 15.8) 3.48 (d. 15.8) 6.75 (d, 8.0) 6.84 (d. 8.0) 1.26 (s)
9.10-OC H 2 0
6.05 ( s )
6.00 (s)
5.99 (s)
N-CH,
2.14 (s)
2.15 (s)
2.16 (s)
11-H 12-H 15-H 2-OCH3 3-OCHt 2.3-OCH20
"
Spectra were recorded in CDCI,.
5.83 (d. 1.4) 5.86 (d. 1.4) 5.98 (d, 1.4) 6.04 (d, 1.4) 2.56 ( s )
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
181
was also the base peak. Loss of a methyl group also resulted in a significant ion at mlz 334. In the CD spectrum of ochotensidine ( 4 3 , a positive Cotton effect was centered at 279 nm, suggesting the same absolute configuration at the spiro center of ochotensidine (45) as previously determined for ochotensine (7).
45
27. Corystewartine
+
Corystewartine (46), C,,H,,05N, [a], 82" (CHCI,), was isolated from Corydalis stewartii Fedde as an amorphous material (32). From the 'HNMR spectrum (Table XI) the lack of vinylic proton absorption was apparent, replaced by a quaternary methyl singlet at 6 1.26. Complete analysis of the 'H-NMR spectrum of 46 suggested that corystewartine (46) is a 2,3-methylenedioxy analog of raddeanamine (44)with a 2,3-dimethoxy substitution pattern on ring A. The absolute configuration at the spiro center of corystewartine (46) was determined by chemical transformation to ochotensidine (49, whose absolute configuration at C-14 had been previously established.
46
28. Secodensiflorine The first secospirobenzylisoquinoline alkaloid 47, C,,H,,O,N, mp 142"C, was isolated from Fumaria densiflora DC. (81). Unfortunately, it was called densiflorine, a name given earlier to the first spirobenzyliso-
182
GABOR BLASKO
quinoline alkaloid possessing an oxygen bridge between C-6 and C-13 isolated from the same plant source. Therefore, it is suggested that the name secodensiflorine be used for the first secospirobenzylisoquinolinealkaloid. The mass spectrum of secodensiflorine (47) exhibits a molecular ion at mlz 397 (13.6%) and a base peak at m/z 58, the latter being characteristic for secoisoquinoline alkaloids possessing a dimethylaminoethyl side chain. The 'H-NMR data for 47, 6 2.82 (s, 6H, N(CH,),), 2.87 (s, lH), 2.91-3.12 (m, 4H, CH,-CH,-N), 3.91 (s, 3H, OCH,), 3.98 (s, 3H, OCH,), 5.95 ( s , 2H, O - C H , - O ) , 6.61 ( s , lH, 1-H), 6.68 (s, IH, 4-H), 6.84 (d, J = 8.5 Hz), and 7.24 (d, IH, J = 8.5 Hz), are in agreement with the proposed secospirobenzylisoquinoline structure.
47
D. NEWINDENOBENZAZEPINES
Following the discovery that fumarofine, fumaritridine, and fumaritrine are indenobenzazepine alkaloids rather than spirobenzylisoquinoline alkaloids (34,37),the indenobenzazepine alkaloids emerged as a new group of isoquinoline alkaloids. Because of the close biogenetic between the indenobenzazepine and spirobenzylisoquinoline alkaloids, recently discovered new indenobenzazepine alkaloids are briefly discussed here. 1. Lahorine
The quaternary indenobenzazepine alkaloid lahorine 48, C,,JI,,O,N T I - , rnp 253-255"C, was isolated from Fumaria parviflora Lam. as the chloride salt (82). The mass spectrum of 48 showed a molecular cation peak mlz 332, which was also the base peak. The UV spectrum of freshly purified lahorine (48) suggested a highly conjugated system different from that of any other known isoquinoline alkaloid. The 'H-NMR spectrum of 48
2.
183
SPIROBENZYLISOQUINOLINE ALKALOIDS
showed no aliphatic protons, with the exception of those associated with the N-methyl and the two methylenedioxy substituents. The fully aromatic ring system of lahorine (48) displayed two downfield singlets at 6 7.89 and 9.66 representing 1-H and 13-H, respectively, and two pairs of aromatic doublets of doublets at 6 7.86, 8.43 and 6 8.14, 8.3 1 assigned as 5-H, 6-H and 1 1-H, 12-H, respectively (Table XII). Final confirmation of the structure of lahorine (48) was established by synthesis (see Section IV).
48
2. Lahoramine Lahoramine (49), C2,H,,04N+C1-, was isolated from Furnuria parvifloru Lam. as an amorphous material (82). The mass, UV, and 'H-NMR spectra of lahoramine (49) (Table XII) indicated that this alkaloid is the ring A dirnethoxy analog of lahorine (a),isolated from the same plant source, and this structure was subsequently verified by synthesis (see Section IV). TABLE XI1 'H-NMR SPECTRAL ASSIGNMENTS OF LAHORINE (48).LAHORAMINE (49). A N D BULGARAMINE (50)" Proton
48
49
50
I-H 4-H 5-H 6-H
7.89 ( s ) 7.45 (s) 7.86 (d, 9.1) 8.43 (d, 9. I ) 8.14 (d, 8.8) 8.31 (d, 8.8) 9.66 (s) -
7.90 (s) 7.44 ( s ) 7.84 (d, 9.0) 8.42 (d, 9.0) 8.13 (d, 8.8) 8.30 (d, 8.8) 9.70 ( s ) 3.87 (s) 3.99 ( s ) 6.46 (s) 4.95 (s)
7.02 (s) 6.71 ( s ) 2.99 (dd, 8.5, 4.2) 3.24 (dd) 6.72 (d, 7.7) 6.90 (d, 7.7) 3,83 (bs) 3.94 (s) 3.90 ( s )
I I-H 12-H 13-H 2-OCH3 3-OCH, 2,3-OCH20 9.IO-OCH20 N-CH,
6.27 ( s ) 6.47 (s) 4.95 ( s )
" Spectra were recorded in CDCI,.
-
6.02 ( s ) 2.93 (s)
184
GABORBLASKO
49
3. Bulgaramine Bulgaramine (50, C21H2104N, mp 209"C, [a],0" (MeOH), was obtained from the herb Fumaria officinalis, of Bulgarian origin (83).The U V spectrum of bulgaramine (50) showed a complex absorption pattern, with a strong maximum at 341 nm, suggestive of a stilbenoid system. The mass spectrum of 50 exhibited a molecular ion peak at mlz 35 1, which is also the basic peak. Final confirmation of the structure of bulgaramine (50) was obtained from its high-resolution 'H-NMR spectrum (Table XII).
111. Synthesis of Spirobenzylisoquinoline Alkaloids
A. 1,2-INDANDIONE A N D 1,2,3-INDANTRIONE APPROACHES The first total synthesis of (?)-ochotensimine (8) was completed in 1968 by Canadian researchers via Pictet-Spengler condensation of 4,5-methylenedioxyindan-1,2-dione (51) with 3-hydroxy-4-methoxyphenylethylamine (52) followed by subsequent O-methylation with diazomethane and N-methylation by the Eschweiler-Clarke method to produce the 13-ketospirobenzylisoquinoline54 (Scheme 1). Wittig reaction of 54 with methylenetriphenylphosphorane yielded (*)-ochotensimine (8) (84,85). (*)-Ochotensine (7)and (+)-fumaricine (3) have been prepared by the same sequence (86-89). Kametani and co-workers introduced the use of 1,2,3-indantrione (55) which on Pictet-Spengler condensation with homopiperonylamine (56)
2.
SPIROBENZYLISOQUINOLI"
0
185
ALKALOIDS
0
+
2, HCHO HCOOH
0
J$$O
52
51
53
8
54 SCHEME I
gave the 8,13-diketospirobenzylisoquinoline(58) (Scheme 2). N-Methylation of 58 followed by borohydride reduction gave (-+)-ochrobirine(5) as the sole product (90). (+)-Yenhusomine (30) and (2)-yenhusomidine (37) were prepared by similar route from indantrione 55 and homoveratrylamine (57) (91). Mild reduction of 8,13-diketospirobenzylisoquinoline59 with sodium borohydride in tetrahydrofuran (THF) resulted in (+)-yenhusomidine (37) in 45% yield. The original method for the synthesis of spirobenzylisoquinolinesutilizing indandiones has been developed into a more general approach by the introduction of a bromine substituent into the 1,2-indandione, thus providing, in principle, routes to any known spirobenzylisoquinoline alkaloid (92-94). Displacement of the halogen substituent of the 13-keto-8-bromospirobenzylisoquinoline62, obtained by Pictet-Spengler condensation of indandione 60 with 3,4-dihydroxyphenylethylamine(61), by means of silver acetate, followed by hydrolysis and O-methylation with diazomethane o r 2,3-methylenedioxy formation with diiodomethane, resulted in either 2,3-dimethoxy- or 2,3-methylenedioxyspirobenzylisoquinoline64 o r 65, respectively (Scheme 3 ) . Acid-catalyzed deformylation of 64 or 65 followed by an attempted Eschweiler-Clarke N-methylation did not led to the expected N-methylspirobenzylisoquinolineproducts owing to the formation of oxazolidines 66 and 67. The latter compounds, however, could be reduced selectively to (+)-corydaine (38) and (2)-yenhusomidine (37), respectively, by means of sodium cyanoborohydride. Epimer-
-
q;
186
GABOR BLASKO
-
+
0
56 R ' + R ~ = C H ,
55
5 1 R'= R2=CH,
FH,
MeOH
*
a R'0 5
d
58 R ' + R ~ = C H ~ 59 R'= R 2 =CH,
@ , H
H
o-/"
ORZ R'+ R2=CH,
30 R'= R 2 = C H ,
SCHEME2
ization of intermediates 64 and 65 with lithium diisopropylamide and hexamethylphosphoramide in THF gave in equilibrium 68 and 69, respectively. Hydrolysis of the diastereomeric mixtures of 63/68 and 65/ 69, followed by N-methylation, and separation from the corresponding C8 epimers 38 and 37, respectively, afforded (*)-raddeanone (36) and (*)sibiricine (6), respectively (92-94). The synthesis of (+)-ochrobirine (5) was also achieved by construction of 2-phenyl- 1,3-indandione 70 followed by a modified Pomeranz-Fritsch sequence via intermediate 71 leading to the 8,13-diketospirobenzylisoquinoline 72 (Scheme 4). Replacement of the N-acetyl group with an Nmethyl group followed by sodium borohydride reduction yielded (k)-ochrobirine (5) with a high degree of stereoselectivity (95). Manske and co-workers also showed that 2-phenyl-l-indanone 73 can be cyclized to 13-ketospirobenzylisoquinoline 74 in a three-step reaction sequence (Scheme 5) (96). B. THERMOLYSIS OF BENZOCYCLOBUTANES It was demonstrated previously that o-quinomethides, derived from protoberberines, are the biogenetic precursors of spirobenzylisoquinoline alkaloids (97-101). For this reason, attempts were made to utilize substituted benzocyclobutanes (e.g., 75) as precursors for these types of oquinomethides (102-104). Accordingly, amide 76 was methylated with
'8; 0
H
+
0
HO
O
\
P N H2
61
-@ \
HO
63 R' = R 2 COCH, 64 R ' * R 2 = CH, 65 R'= R 2 = CH,
68 R ' + R 2 = CH, 69 R ' = R * = c H ,
B,.
oJo
OH
11 ClCO2 CH 3
)
2,AgOAc AcOH
62
60
1,
/
66 R ' + R 2 = C H , 67 R ' = R 2 = C H ,
\
NaCNBH,
36 R ' + R ~ = C H ,
38 R ' + R ~ = C H ,
6 R'=R2=CH,
37 R ' = R 2 = C H ,
SCHEME3
188
GABORBLASKO
EtO OEt
71
70
methyl iodide in the presence of sodium amide to furnish 77 which on treatment under Bischler-Napieralski conditions resulted in spirobenzylisoquinoline 80 (Scheme 6). The reaction probably proceeded via o-quinodimethide 79 (102,103). On the other hand, air oxidation of imine 81, obtained via Bischler-Napieralski cyclization of amide 76, gave the unstable hydroxyimine 82, which produced 13-ketospirobenzylisoquinoline83 spontaneously (104).
- &Q HO/H,O
Br,
/ HOAc
-
Et,N
CH,O
,
OC H,OCH,
OCH,
74
OCH,
73 SCHEME 5
189
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
-
CN
$-
CH,O
cHB
Me I
NaNH,
OCH,
CH,O
CH,O
OCH,
OCH,
77
75
J
cH30qN $4 CH,O
76
Ra
CH,O
OCH,
7
cH3Q
CH,O
OCH,
-
7a
81 R = H 82 R = O H
79
/
83
80
SCHEME6
C. TRANSFORMATION OF PROTOBERBERINES The recent comprehensive review by Hanaoka (105) in this treatise affords a discusses transformation reactions of protoberberine alkaloids in detail. Therefore, only a brief summary is presented here regarding the synthesis of spirobenzylisoquinoline alkaloids via protoberberines.
190
GABORBLASKO
1. Base-Induced Rearrangement via Quinomethides
Biomimetic synthesis of ochotensine-type spirobenzylisoquinolineshas been achieved from phenolic dihydroprotoberberine metho salts via quinomethides. Base-induced rearrangement of protoberberine derivatives 84 and 85 yielded quinomethides 88 and 89, respectively, which were transformed to the corresponding ochotensimine analogs 90 and 91 through enolization (Scheme 7) (97-101). 2. Photoinduced Rearrangement via Quinodimethides Photolysis of the 13-ketotetrahydroprotoberberinesalt 92 in basic medium afforded spirobenzylisoquinoline 95 in 45% yield (Scheme 8) (106). 13-Methyl- or 13-methoxydihydroprotoberberine metho salts similarly gave the corresponding spirobenzylisoquinolines in 23-54% yield. The
OH
H
a4 R = H
86 R =
a5 R = CH,
a7 R = CH,
aa
90 R = H
R=H
89 R = C H ,
91 R = CH,
SCHEME7
191
2. SPIROBENZY LISOQUINOLINE ALKALOIDS
93
92
OCH,
OCH,
95
94
SCHEME 8
key reaction step is the formation of a quinodimethide intermediate, which spontaneously rearranges to the corresponding spirobenzylisoquinoline system (107). 3. Stevens Rearrangement
Three Japanese research groups independently investigated the basecatalyzed rearrangement of tetrahydroprotoberberine metho salts (108114). In the presence of a strong base such as butyllithium, phenyllithium, dimsylsodium, or sodium bis(2-methoxyethoxy)aluminumhydride, tetrahydroprotoberberine metho salts rearrange to the corresponding spirobenzylisoquinolines in 2 5 4 2 % yield. The rearrangement is stereospecitk, for example, ( - )-canadine methochloride (96) was converted to dextrorotatory spirobenzylisoquinoline 97 with retention of the absolute configuration of the stereo center (Scheme 9). Although the Stevens rearrangement is a suitable method for the construction of the spirobenzylisoquinoline ring system, there are no reports of synthesis of spirobenzylisoquinoline alkaloids with proper substitution patterns by this approach.
I92
GABOR BLASKO
OCHl
96
SCHEME 9
4. Cleavage of 8,14-Cycloberbines Nearly all types of spirobenzylisoquinoline alkaloids have been synthesized by Hanaoka and co-workers from 8, 14-cycloberbines, obtained by photocyclization of appropriately substituted protoberberinephenolbetaines, via regioselective cleavage of the C-8-N-7 bond. Irradiation of phenolbetaine 98 gave 8,14-cycloberbine 99 in good yield (Scheme 10).
-
C ICO I E t
THF
99
CI
0
3
100
SCHEME 10
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
193
Reaction of 99 with ethyl chloroformate resulted in selective fission of the C-8-N-7 bond to furnish spirobenzylisoquinoline 100. Catalytic hydrogenation of 100 followed by LiAIH, reduction gave (*)-fumaricine (3) ( 1 f 5 , 16) f with high stereoselectivity. The orientation of the hydroxyl group at C-8 could also be controlled. syn-8-Hydroxyspirobenzylisoquinolines, such as (+)-fumaricine (3), could be obtained selectively by hydride reduction of the 8-keto group after the fission of the C-8-N-7 bond. anti-8-Hydroxyspirobenzylisoquinolines, on the other hand, could be prepared by reduction of the 13-keto group on a properly substituted 8,14cycloberbine prior to fission of the C-8-N-7 bond. Using this route, a highly stereoselective synthesis of (?)-dihydrofumariline I (26) was achieved (Scheme 11). Reduction of 8,14-cycloberbine 101 with sodium borohydride selectively afforded alcohol 103, and regioselective fission of the C-8-N-7 bond was performed with sodium cyanoborohydride treatment in T H F in the presence of p-toluenesulfonic acid. The secondary amino group of 104 was N-methylated via an oxazolidine intermediate,
101
102
104 103
26
SCHEME II
R= H
R = CH,
\ /
O v O
E?
0-0
In
L
I
t s
0 I
t
2.
SPlROBENZYLISOQUINOLlNE ALKALOIDS
195
obtained by formaldehyde treatment and followed by sodium cyanoborohydride reduction, to yield (2)-dihydrofumariline I (26) (117). The spontaneous formation of oxazolidines from spirobenzylisoquinoline secondary amino alcohols by formaldehyde treatment yielded the opportunity to synthesize 13-keto-8-hydroxyspirobenzylisoquinoline-type alkaloids utilizing the oxazolidine moiety as a protecting group during functional group manipulations (Scheme 12). Photolysis of 105 led to 8,14cycloberbine 106, which was reduced with lithium aluminum tri-tcrt-butoxyhydride to afford alcohol 107 with high stereoselectivity. Cleavage of the C-8-N-7 bond with ethyl chloroformate followed by potassium hydroxide treatment resulted in 8-syn-13-anti-dihydroxyspirobenzylisoquinoline 108. Reaction of 108 with formaldehyde gave oxazolidine 109, oxidation of which with silver carbonate on Celite (Fetison reagent) yielded the corresponding 13-ketospirobenzylisoquinoline110. Sodium cyanoborohydride reduction of 110 resulted in (+)-corydaine (38), which could be further reduced with sodium borohydride to (?)-ochrobirine (5)with high stereoselectivity (118). N-Methylation of norspirobenzylisoquinoline 108, on the other hand, gave (2)-ochrobirine (5) directly (219). It has been established that oxidative photolysis of 8-methoxyberberinephenolbetaines in methanol yields 8,13-dieketospirobenzylisoquinolines in monoketal form (120). (&)-Sibiricine(6) and (2)-raddeanone (36) were synthesized by this route from 8-methoxyberberinephenolbetaines 111 and 112, respectively, via oxidative photolysis, reduction, N-methylation, and deketalization (Scheme 13) (121). Reduction of (+)-6 and ( 2 ) 36 with sodium borohydride yielded (k)-severzinine (31) and (+)-raddeamine (29), respectively. (2)-Yenhusomidine (37) was also obtained from spirobenzylisoquinoline ketal 116 through inversion of the C-8 hydroxyl group followed by deketalization and N-methylation. (+)-Yenhusomidine (37) was later reduced by sodium borohydride to afford (2)-yenhusomine (30) (122). (&)-Raddeamine (44) and (+)-ochotensimine (8) were similarly synthesized starting from 8-methyl-8,14-cycloberbine119, obtained from 8-methylprotoberberinephenolbetaine 118 by photolytic cyclization (Scheme 14). Compound 119 was transformed to a mixture of diastereomeric syn and anti 13-hydroxyspirobenzylisoquinolinederivatives (120 and 121) by subsequent sodium borohydride reduction, C-8-N-7 bond fission, and formaldehyde treatment. Removal of the hydroxyl group from 120 and 121 was accomplished by chlorination with SOClz followed by reduction with tributyltin hydride. Finally, sodium cyanoborohydride reduction of the oxazolidine moiety of 122 yielded (2)-raddeanamine (44), which could be converted to (+)-ochotensimine (8) by thermolysis (123).
115 R'+ R Z = CH, 116 R': R 2 = CH,
117 R ' = R'=CH,
113
R'+ R 2 = CH,
114
R' = R 2 = CH,
6 R1+ R 2 = CH, 36 R ' = R 2 = CH,
30
SCHEME13
31 29
R ' + R ' = CH, R ' = R 2 = CH,
31
/-\
m c
m c r
197
t
N c N
2.
SPIROBENZYLISOQUINOLINE ALKALOIDS
199
D. TRANSFORMATION OF INDENOBENZAZEPINES Blasko et al. developed a one-step stereoselective rearrangement of indenobenzazepines via an aziridinium intermediate to spirobenzylisoquinolines (Scheme 15) (124). Treatment of (+)-O-methylfumarofine (12), synthesized earlier (33), with trifluoroacetic anhydride in pyridine at room temperature, followed by work-up with ammonium hydroxide, afforded spirobenzylisoquinoline 124 in 86% yield. The stereochemistry of the product was established by 'H-NMR spectroscopy. The relative downfield chemical shift of 13-H at 6 5.41 suggested the anti orientation of the C-13 hydroxyl to the nitrogen atom. Consonant with this steric assignment, sodium borohydride reduction of 124 yielded uniformly (+)-raddeanine (29). Similar rearrangement of dihydro-O-methylfumarofine (125) afforded (+)-raddeanine (29) in one step. Regardless of the stereochemistry at C- 14, subsequent treatment of diastereomeric indenobenzazepines 126 and 127 with trifluoroacetic anhydride in pyridine and with ammonium hydroxide resulted in (+)-yenhusomine (30) as the sole product (Scheme 16). The mechanism of the rearrangement explains the stereochemical consequences of the transformation. First, an aziridinium intermediate (128) is formed as a result of intramolecular nucleophilic attack of the nitrogen at C-14. In the second step of the reaction, hydroxide anion attacks the aziridinium intermediate at C-13, resulting in regioselective cleavage of the C-13-N-7 bond. Walden inversion takes place at C-13 during the second nucleophilic substitution reaction, and consequently the rearrangement leads without exception to spirobenzylisoquinolinespossessing the C- 13 hydroxyl group anti to the nitrogen atom.
E. TRANSFORMATION OF PHTHALIDEISOQUINOLINES I ,9-Dehydrophthalideisoquinolines,obtained either from protoberberines or by Bischler-Napieralski cyclization of the corresponding phthalide-a-carboxamides, proved to be suitable intermediates in the synthesis of spirobenzylisoquinoline alkaloids (Scheme 17) (125,226). Diisobutylaluminum hydride reduction of dehydrophthalideisoquinoline 131 leads to equimolar amounts of the diastereomeric spirobenzylisoquinolines (2)corydaine (38) and (+)-sibiricine (6). The reaction proceeds by reductive opening of the lactone ring followed by cyclization of the resulting enolate (133). (+)-Yenhusomidine (37) and (2)-raddeanone (36) were similarly obtained from dehydrophthalideisoquinoline 132 via enol aldehyde 134 (126).
c N
I-
200
N
c
0)
I 0
0
0
c)
38 R ' + R 2 = CH2
6
37 R'= R2= CH,
36
SCHEME17
R'+ R 2 = C H ,
R'= R ~ = C H ,
133
R' + R 2 = C H
134
R'
= R 2 =CI
26
135
R~+R,=cH,
136
R' + R * = CH,
= R2 = CH,
137
R1=R2=CH3
R'
140 R' + R 2 = CH, 141 R1 = R2 = C H I
SCHEME 18
138 R'+ R 2 = CH, 139 R'
48
R 1 + R 2 = CH,
49
R ' = R 2 = CH,
R 2 =CH,
J
2.
SPlROBENZYLlSOQUINOLINE ALKALOIDS
203
IV. Synthesis of Indenobenzazepine Alkaloids
A. TRANSFORMATION OF SPIROBENZYLISOQUINOLINES It has been shown by Irie el ul. that treatment of spirobenzylisoquinolines having a hydroxyl group on ring C anti to the nitrogen with methanesulfonyl chloride in the presence of triethylamine results in indenobenzazepines with a carbon-carbon double bond at C-13,C-14 (127,128).This rearrangement was utilized for the synthesis of the aromatic indenobenzazepines lahorine (48) and lahoramine (49) (Scheme 18). Dihydroparfumidine (135) was reacted with methanesulfonyl chloride and triethylamine in T H F to yield the indenobenzazepine derivative 139, which was oxidized with iodine in ethanol to provide lahoramine (49) (82). Dihydrofumariline I1 (26) was similarly converted to lahoramine (48) (82). Treatment of synthetic 13-hydroxyspirobenzylisoquinoline 142 with methanesulfonyl chloride in the presence of triethylamine furnished indenobenzazepine 143 (Scheme 19). Reaction of the latter compound with osmium tetroxide resulted in approach of the reagent from the less hindered side of the molecule with concomitant formation of the cis-dihydroxyindenobenzazepine 144 in 71% yield. Oxidation of 144 with pyridinium chlorochromate in methylene chloride gave (2)-O-methylfumarofine (12), which was spectrally and chromatographically identical with material obtained by diazomethane O-methylation of natural fumarofine (11) (34). Fumaritridine (16) and fumaritrine (17) were synthesized similarly starting from dihydroparfumine (145) and dihydroparfumidine (135), respectively (Scheme 20). 8-Hydroxyspirobenzylisoquinolines145 and 135 were treated separately with trifluoroacetic acid in methylene chloride, and the reaction mixtures were quenched with methanol to afford (+)-fumaritridine (16) and fumaritrine (17), respectively (37). Bulgaramine (50) was obtained from indenobenzazepine 141, prepared from 135 by methanesulfonyl chloride treatment in the presence of triethylamine, via potassium [err-butoxide-induced C=C double bond migration (Scheme 2 1) (127). OF PROTOBERBERINES B. TRANSFORMATION
Hanaoka and co-workers synthesized fumarofine (11) and O-methylfumarofine (12) utilizing 8,14-cycloberbine 147 as a key precursor (Scheme 22) (128). After photocyclization of the protoberberinephenolbetaine derivative 146 to give 8,14-cycloberbine 147, compound 147 was refluxed with methanesulfonic acid in aqueous T H F to afford a 2 : I mixture of cis- and rruns-indenobenzazepines 148 and 149, respectively, in 92%
204
&q
GABOR BLASKO
H OH OH
MsCl
CH,O
0
Et,N
-
OCH, 142
-
CH,O
PCC
b0 12
144
SCHEME 19
yield overall. The mixture was methylated with methyl iodide to give B/C-cis-fused indenobenzazepine 150 in addition to the unchanged B/C-trans-fused N-norindenobenzazepine 149,which is more resistant to N-methylation than the corresponding cis isomer 148.Debenzylation of 150 by catalytic hydrogenation yielded (*)-fumarofine (ll),which was later converted to (*)-0-methylfumarofine (12)by treatment with diazomethane. Berberinephenolbetaine 151 was cyclized to 8, ICcycloberbine 152 in the established way, and the latter was reduced with sodium borohydride to yield 13-hydroxy-8, ICcycloberbine 153 (Scheme 23). Treatment of 153 with p-toluenesulfonic acid in methanol and subsequently with methyl iodide resulted in B/C-cis-fused indenobenzazepine 154 in almost quantitative yield. Removal of the C-13 hydroxyl was accomplished by treatment of 154 with methanesulfonyl chloride followed by sodium borohydride reduction, resulting in (&)-fumaritrine(17)(129). C. TRANSFORMATION OF PHTHALIDEISOQUINOLINES p-Hydrastine (155)was converted to ene lactone 156 via C-1-N bond cleavage with p-nitrophenyl chloroformate in 88% yield. Base treatment
I
I
2
E
-
$' -
0-2
I
0
t
P
O
CI
I I 0
206
GABOR BLASKO
+CH,O KOBu
CH,O
HOBu,
50
141
SCHEME 21
of 156 resulted in indandione 157, which was hydrolyzed to 158 with sodium hydroxide in methyl sulfoxide (DMSO). Recyclization of 158 with p-toluenesulfonic acid gave the two regioisomeric indenobenzazepines 159 and 160 in 32 and 14% yield, respectively (Scheme 24) (130).
D. TRANSFORMATION OF PROTOPINES Von Braun reaction of protopines 161 and 162 led to 163 and 164, respectively, which were cyclized with base to the corresponding indenobenzazepines 165 and 166, respectively (Scheme 25) (131). 13-Oxoallocryptopine (167) was converted directly to indeobenzazepine 168 by exposure to sunlight in tert-butyl alcohol in the presence of potassium tert-butoxide (Scheme 25) (132). V. Miscellaneous Transformation Reactions OF PROTOBERBERINES A. RINGD INVERSION
Ring D inversion of protoberberines can be achieved via 8,14-cycloberbine and spirobenzylisoquinoline intermediates (Scheme 26). For example, berberine (169) was converted to 13-hydroxy-8, 14-cycloberbine 171 by phenolbetaine formation, photolytic cyclization, and sodium borohydride reduction. Subsequent treatment of 171 with ethyl chloroformate, silver nitrate, and pyridinium dichromate in dimethylformamide (DMF) afforded 8-ketospirobenzylisoquinolineoxazolidinone 172, which, after hydrolysis in wet ethanolic sodium hydroxide, underwent retro-aldol cleavage to give intermediate 174, cyclization and dehydration of which provided epiberberinephenolbetaine (175) (133,134). 8-Methoxyberberinephenolbetaine (176) was converted to 175 via 8-keto- 13-hydroxyspirobenzylisoquinoline 177 by similar reaction steps (133,134).
CH,O BzO%
146
L O 148 @ - O H 149 a - O H
147
N-CH,
N-CH, Bz 0
cH30%
\ /
-
RO
b0 \ /
cH30%
\
150
0b0 \ /
11 R = H 12 R = CH, SCHEME
22
X 0
I
0
t
.-
In
01
208
X
0
I
0
I.-
d In
.-
N m
0
I 2
\ /
-
\ /
+
0
I
o
n
0
F
!P O V 0
209
I
0 U=O
210
00
L
I-
I
vi N
t
F
c r-
L
0)
OW0
21 I
r-
c
(u
0-0
O"0
In
Ic
212
GABORBLASKO
CIC0,Et
OCH,
178
179
cnp-
OCH,
0-U
y
CH,O 180
181 SCHEME
21
Similar ring D inversion of berberine (169) was achieved through 8,14cycloberbine 178, obtained by photolytic cyclization of the corresponding berberinephenolbetaine (170). Selective fission of the C-8-N-7 bond with ethyl chloroformate gave spirobenzylisoquinoline 179 (Scheme 27). Hydrogenolysis of the urethane moiety followed by hydrolysis afforded 13ketospirobenzylisoquinoline 180, irradiation of which resulted in protoberberine derivative 181 with the 1 I , 12-oxygenated substitution pattern ( 133,1341.
B. SYNTHESIS OF RHOEADINES The skeletal transformation of indenobenzazepines to rhoeadine-type alkaloids was first achieved by Irie et al. (135,136) and was reviewed in this treatise by Rijnsch (137). Sequential osmium tetroxide and sodium periodate oxidation of indenobenzazepine 182 followed by sodium borohydride reduction gave (*)-rhoeageninediol (186) (Scheme 28). On the other hand, a similar reaction sequence starting from indenobenzazepine 183 resulted in (*)-alpigenine diol 189 and its diastereomer 187. Manganese dioxide oxidation of 189 yielded (+)-alpigenine (191) in moderate yield (135,136).
I1
%%
II
I"<
0 0
8" Na
0
\ / 0
-a
0
-a
0
2
0
I
0,
:" 0
2. SPlROBENZYLlSOQUlNOLI"
ALKALOIDS
215
Photosensitized oxidation of the enaminoketone-type indenobenzazepine 192 afforded ketonic y-lactone 194 through rearrangement via a dioxetane (Scheme 29) (138). Sodium borohydride reduction of 194 followed by acidification led to the 8-lactone 195, whose B/C ring connection was established to be cis. Reduction of the b-lactone moiety of 195 with diisobutylaluminum hydride yielded (2)-cis-alpigenine (196), and further methylation provided (+)-cis-alpinine (197) (138). Similar interconversion of an indenobenzazepine model compound (198) to the corresponding rhoeadine skeleton was performed by sodium periodate oxidation of 198 to the keto lactone 199, which was transformed to the rhoeadine analogs 200 and 201 using the previously described method (Scheme 30) (139).
C. SYNTHESIS OF PHTHALIDEISOQUINOLINES Recently, Hanaoka and co-workers demonstrated that spirobenzylisoquinoline N-oxides could be transformed to phthalideisoquinolines via sequential Polonovski reaction and reduction (Scheme 31) (140). Separate oxidation of the spirobenzylisoquinolines 202, 203, and 204 with rn-chloroperbenzoic acid yielded the corresponding unstable N-oxides, which were immediately treated with trifluoroacetic anhydride. Polonovski reaction of intermediates 205, 206, and 207 afforded dehydrobicuculline (208), dehydrohydrastine (209), and dehydrocordrastine (210), respectively, in about 40% overall yield. Hydrogenation of the products in acetic acid over platinum oxide yielded the corresponding threo- and erythrophthalideisoquinolines (+)-adlumidine (211) and (+)-bicuculline (212), (+)-P-hydrastine (213) and (+)-a-hydrastine (214), and (+)-cordrastine I (215) and (+)-cordrastine I1 (216), respectively (140). VI. Enzymatic Transformations
Iwasa and co-workers have extensively studied the biotransformation of 13-hydroxytetrahydroprotoberberineN-metho salts by callus cultures derived from the stems of Corydalis ophiocarpa, C. ochotensis var. raddeana, C. pallida var. tenuis, and C. platycarpa (141-143). It was demonstrated that ( - )-epiophiocarpine N-metho salt (217), with a cis-quinolizidine structure, can be biotransformed to spirobenzylisoquinoline 219 and indenobenzazepine 168 via 13-hydroxyallocryptopine (218) and 13-oxoallocryptopine (167) (Scheme 32), using cell cultures of C. ophiocarpa and C. pallida var. tenuis. It is important to note that the ( + ) isomer of 217 was found to be an inactive substrate in the cell culture systems studied.
II
I1
r
~a N
0
O
0
N
00
3
m 0
2. SPIROBENZYLlSOQUINOLI"
202 R'
+ R 2 = R 3 t R4 = CH,
217
ALKALOIDS
205 R'+ R 2 = R 3 + R4=CH,
203 R'+ R2=CH,, R 3 = R4=CH,
206 R'+ R2=CHz,R3=R4=CH,
204 R'= R Z = R3= R 4 =CH,
207 R'
R2= R3 = R4=CH,
211 R'
+ RZ= R3+ R4= CH,
213 R' + R2=CH,, R3= R'= CH, 215 R'= R z = R3= R 4 =CH,
R'O R20
O
' OR^
OR,
Rzo
R' 0
+ R 2 = R3+ R 4 = C H 2 R' + R 2 =CH2,R3= R 4 =CH,
208 R' 209
210 R1= R Z =R3= R4=CH,
\ / OR,
212 R'+ R2= R3+ R4=CH, 214
R'+ R2=CH,, R3= R4 CH,
216
R1= R2- R3= R'zCH,
SCHEME 31
218
GABORBLASKO
0
219
168
SCHEME32
VII. Biosynthesis of Spirobenzylisoquinoline Alkaloids
It was Shamma who originally proposed that phenolic protoberberine N-metho salts are the possible biogenetic progenitors for spirobenzylisoquinoline alkaloids (97-fOf).These salts can undergo cleavage to quinoid intermediates that could form the spiro system by an electrocyclic Michael condensation process; a tautomeric shift would yield phenolic spirobenzylisoquinolines, which could lead to the corresponding alkaloids via modification of the oxygenated substituents. The hypothesis has been supported by chemical transformation of phenolic protoberberine Nmetho salts to spirobenzylisoquinolines (97-101) and established by in vivo feeding experiments (144). The biogenesis of ochotensimine (8) was examined by feeding of [methyl-'4C]methionineand [3-'4C]tyrosineto Corydulis ochotensis. Radioactivity from labeled methionine was found at C-9 and the exocyclic methylene group of ochotensimine (81, whereas label originating from tyrosine was located at C-14. The results are com-
2. SPIROBENZYLISOQUINOLINE ALKALOIDS
219
pletely in accord with a biogenesis of ochotensimine (8)from a corydainetype protoberberine (144). Further evidence for the biogenesis of ochotensimine (8) was obtained by feeding of [3-’4C]dihydroxyphenylalanine to C. ochotensis, which led to the same conclusion regarding the biosynthetic pathway (145). The most salient feature of known spirobenzylisoquinoline alkaloids is that they all possess a methylenedioxy substituent in ring D. It has been suggested that the formation of this group from its biogenetic o-methoxyphenol precursor is encouraged by steric compression around the C-9 methoxyl substituent, which is relieved substantially on formation of the methylenedioxy group in vivo (146). Biogenetic possibilities for the indenobenzazepine alkaloids have been described; however, no in vivo studies are available. It has been suggested that lahoramine-type alkaloids with a 9,lO-methylenedioxy group could form in nature from 8-hydroxyspirobenzylisoquinolinesby way of the spirobenzylisoquinoline-indenobenzazepine rearrangement through an aziridinium intermediate (82). Fumarofine-type alkaloids with a 1 I , 12methylenedioxy group, however, could be formed in nature from 8-ketospirobenzylisoquinolines by p-elimination followed by subsequent intramolecular Michael addition and benzylic oxidation at C- 14 (34). Acknowledgments The author is grateful to Prof. G. A. Cordell for suggestions during preparation of this chapter. The work was supported, in part, by a grant from the Hungarian National Research Council (OTKA). REFERENCES I . M. Shamma, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.), Vol. 13, p. 165. Academic Press, New York, 1971. 2. R. M. Preisner and M. Shamma, J . Naf. Prod. 43, 305 (1980). 3. M. Shamma, “lsoquinoline Alkaloids: Chemistry and Pharmacology,” p. 381. Academic Press, New York, 1972. 4. M. Shamma and J. L. Moniot, “lsoquinoline Alkaloids Research 1972-1977,” p. 325. Plenum, New York, 1978. 5 . D. B. MacLean and J. Whelan, in “MTP International Review of Science, Organic Chemistry, Series One, Vol. 9” (K. Wiesner, ed.), p. 161. Butterworth, London, 1973. 6. V. A. Snieckus, Alkaloids (London)1, 113 (1971); H. 0. Bernhard and V. A. Snieckus, Alkaloids (London) 2 , 166 (1972); M. Shamma, Alkaloids (London) 3, 152 (1973); V. A. Snieckus, Alkaloids (London) 4, 183 (1974); H. 0. Bernhard and V. A. Snieckus, Alkaloids (London) 5 , 163 (1975); N . J . McCorkindale, Alkaloids (London) 6 , 160 (1976); N . J. McCorkindale, Alkaloids (London) 7 , 145 (1977); K. W. Bentley, Alkaloids (London)8, 109 (1978); K. W. Bentley, Alkaloids (London)9, 112 (1979); K. W. Bentley, Alkaloids (London) 10, 106 (1980); K. W. Bentley, Alkaloids (London) 11,96 (1981); K. W. Bentley, Alkuloids (London) 12, 116 (1982); K. W. Bentley, Alkaloids (London) 13, 138 (1983).
220
GABOR BLASKO
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22 1
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222
GABOR BLASK6
66. K. A. Aslanov and A. S. Sadykov, Zh. Obshch. Khim. 26, 579 (1956); Chem. Abstr. 50, 13971d (1976). 67. S. Mukhopadhyay, S. K. Banerjee, C. K. Atal, L.-J. Lin, and G. A. Cordell, J. Nut. Prod. 50, 270 (1987). 68. S.-T. Lu. T.-L. Su, T. Kametani, A. Ujiie, M. Ihara, and K. Fukumoto, J . Chem. SOC.,Perkin Trans. I , 63 (1976). 69. D. S. Bhakuni and R. Chaturvedi, J. Natl. Prod. 46, 320 (1983). 70. D. W. Hughes, B. C. Nalliah. H. L . Holland, and D. B. MacLean, Can. J. Chem. 55, 3304 (1977). 71. T. Irgashev, 1. A. Israilov, M. S. Yunosov, and S. Y. Yunusov, Khim. Prir. Soedin., 536 (1978); Chem. Nut. Compd. (Engl. Transl.), 464 (1978). 72. K. S. Baisheva, D. A. Fesenko, M. E. Perel’son, and B. K. Rostotoskii, Khim. Prir. Soedin.. 574 (1970); Chem. Nut. Compd. (Engl. Transl.), 590 (1970). 73. D. A. Fesenko and M. E. Perel’son, Khim. Prir. Soedin., 166 (1971); Chem. Nut. Compd. (Engl. Transl.), 157 (1971). 74. M. Rahimizadeh, R. R. Miller, M. A. Oniir, T. Gozler, and M. Shamma, Phytochemistry 25, 2245 (1986). 75. I. A. Israilov, M. S. Yunusov, and S. Y . Yunusov, Khim. Prir. Soedin., 268 (1975); Chem. Nut. Compd. (Engl. Transl.), 284 (1975). 76. N. N. Margvelashvili, 0. E. Lasskaya, A. T. Kir’yanova, and 0. N. Tolkachev, Khim. Prir. Soedin., 123 (1976); Chem. Nut. Compd. (Engl. Transl.), 118 (1976). 77. K. S. Baisheva, D. A. Fesenko, B. K. Rostotskii, and M. E. Perel’son, Khim. Prir. Soedin., 456 (1970); Chem. Nut. Compd. (Engl. Transl.), 465 (1970). 78. M. E. Popova, V. Simanek, J. Novak, L. Dolejs, P. Sedmera, and V. Preininger, Planta Med. 48, 272 (1983). 79. S. F. Hussain and M. Shamma, Tetrahedron Lett. 21, 1909 (1980). 80. M. E. Perel’son, G. G. Aleksandrov, L. D. Yakhontova, 0. N. Tolkachev, D. A. Fesenko, M. N. Komarova, and S. E. Esipov, Khim. Prir. Soedin., 628 (1984); Chem. Nut. Compd. (Engl. Transl.), 592 (1984). 81. B. Sener, I n t . J. Crude Drug Res. 22, 79 (1984). 82. G. Blasko, S. F. Hussain, A. J. Freyer, and M. Shamma, Tetrahedron Lett. 22, 3127 (1981). 83. G. I. Yakimov, N . M. Mollov, J. E. Leet, H. Guinaudeau, A. J. Freyer, and M. Shamma, J . Nut. Prod. 47, 1048 (1984). 84. S. McLean, M.-S. Lin, and J. Whelan, Tetrahedron Lett., 2425 (1968). 85. S. McLean, M.-S. Lin, and J. Whelan, Can. J. Chem. 48, 948 (1970). 86. H. hie, T. Kishimoto, and S . Uyeo, J . Chem. SOC.C , 3051 (1968). 87. H. hie, T. Kishimoto, and S. Uyeo, J. Chem. SOC.C , 1645 (1969). 88. T. Kishimoto and S. Uyeo, J . Chem. SOC.C , 2600 (1969). 89. T. Kishimoto and S. Uyeo, J . Chem. SOC.C , 1644 (1971). 90. T. Kametani, S. Hikino, and S. Takano, J. Chem. SOC.,Chem. Commun., 925 (1971). 91. H. hie, A. Kitagawa, A. Kuno, J. Tanaka, and N. Yokotani, Heterocycles 4, 1083 (1976). 92. S. McLean and J. Whelan, Can. J. Chem. 51, 2457 (1973). 93. S. McLean and D. Dime, Can. J . Chem. 55, 924 (1977). 94. D. Dime and S. McLean, Can. J. Chem. 57, 1569 (1979). 95. N. E. Cundasawmy and D. B. MacLean, Can. J. Chem. 50, 3028 (1972). 96. S. 0. d e Silva, K. Orito, R. H. F. Manske, and R. Rodrigo, Tetrahedron Lett., 3243 ( 1974). 97. M. Shamma and J. F. Nugent, J. Chem. SOC.,Chem. Commun., 1642 (1971). 98. M. Shamma and J. F. Nugent, Tetrahedron Lett., 2625 (1970).
2.
SPIROBENZYLISOQUINOLINE ALKALOIDS
223
M. Shamma and J. F. Nugent, Tetrahedron 29, 1265 (1973). M. Shamma and C. D. Jones, J . A m . Chem. Soc. 91,4009 (1969). M. Shamma and C. D. Jones, J. Am. Chem. Soc. 92,4943 (1970). T. Kametani, T. Takahashi, and K. Ogasawara, J. Chem. Soc., Perkin Trans. 1. 1644 (1973). 103. T. Kametani, Y. Hirai, H. Nemoto, and K. Fukumoto, J. Heterocycl. Chem. 12, 185 ( 1975). 104. T. Kametani, H . Takeda, Y. Hirai, F. Satoh, and K. Fukumoto, J . Chem. Soc.. Perkin Trans. 1 , 2141 (1974). 105. M. Hanaoka, in “The Alkaloids” (A. Brossi, ed.), Vol. 33, p. 141. Academic Press, New York, 1988. 106. B. Nalliah, R. H. F. Manske, R. Rodrigo, and D. B. MacLean, Tetahedron Lett., 2795 ( 1973). 107. T.-T. Wu, J. L. Moniot, and M. Shamma, Tetrahedron Lett., 3419 (1978). 108. Y. Kondo, T. Takemoto, and K. Kondo, Heterocycles 2, 659 (1974). 109. J. Imai, Y. Kondo, and T. Takemoto, Tetrahedron 32, 1973 (1976). 110. J. Imai, Y. Kondo, and T. Takemoto, Heterocycles 3, 467 (1975). 111. S. Kano, T. Yokomatsu, E. Komiyama, S. Tokita, Y. Takahagi, and S. Shibuya, Chem. Pharm. Bull. 23, 1171 (1975). 112. S. Kano, T. Yokomatsu, T. Ono, Y. Takahagi, and S. Shibuya, Chem. Pharm. Bull. 25, 2510 (1977). 113. T. Kametani, S.-P. Huang, A. Ujiie, M. Ihara, and K. Fukumoto, Heterocycles 4, 1223 ( 1976). 114. T. Kametani, A. Ujiie, S.-P. Huang, M. Ihara, and K . Fukumoto, J. Chem. Soc., Perkin Trans. I , 394 (1977). 115. M. Hanaoka, K. Nagami, Y. Hirai, S. Sakurai, and S. Yasuda, Chem. Pharm. Bull. 33, 2273 (1985). 116. M. Hanaoka, S. Yasuda, Y. Hirai, K. Nagami, and T. Imanishi, Heterocycles 14, 1455 ( 1980). 117. M. Hanaoka, M. Iwasaki, and C. Mukai, Tetrahedron Lett. 26, 917 (1985). 118. M. Hanaoka, A. Ashimori, and S. Yasuda, Heterocycles 22, 2263 (1984). 119. M. Hanaoka, S. Sakurai, T. Oshima, S. Yasuda, and C. Mukai, Chem. Pharm. Bull, 30, 3446 (1982). 120. M. Hanaoka and C. Mukai, Heterocycles 6 , 1981 (1977). 121. M. Hanaoka, M. Kohzu, and S. Yasuda, Chem. Pharm. Bull. 33, 2621 (1985). 122. M. Hanaoka, M. Kohzu, and S. Yasuda, Chem. Pharm. Bull. 36,4248 (1988). 123. M. Hanaoka, M. Kohzu, and S. Yasuda, Chem. Pharm. Bull. 33, 41 13 (1985). 124. G. Blasko, N. Murugesan, A. J. Freyer, D. J. Gula, B. Sener, and M. Shamma, Tetrahedron Lett. 22, 3139 (1981). 125. H. L. Holland, D. B. MacLean, R. Rodrigo, and R. H. F. Manske, Tetrahedron Lett., 4323 (1975). 126. B. C . Nalliah, D. B. MacLean, H. L. Holland, and R. Rodrigo, Can. J . Chem. 57, 1545 (1979). 127. G . Blask6, unpublished results. 128. M. Hanaoka, A. Ashimori. H. Yamagishi, and S. Yasuda. Chem. Pharm. Bull. 31, 2172 (1983). 129. M. Hanaoka. M. Iwasaki, S. Sakurai. and C. Mukai, Tetrahedron Lett. 24, 3845 (1983). 130. H. L . Holland, M. Curcumelli-Rodostamo, and D. B. MacLean. Crrn. J. Chein. 54, 1472 (1976). 131. B. Nalliah, R. H. Manske. and R. Rodrigo. Tetrrihedron Lett.. 2853 (1974).
99. 100. 101. 102.
224
GABOR BLASKO
132. G. Blasko, V. Elango. N. Murugesan, and M. Shamma, J. Chem SOC.,Chem. Commun., 1246 (1981). 133. M. Hanaoka, M. Inoue, M. Takahashi. and S. Yasuda, Heterocycles 19, 31 (1982). 134. M. Hanaoka, M. Inoue, M. Takahashi, and S. Yasuda, Chem. Pharm. Bull. 32,4431 ( 1984). 135. H. Ine, S. Tani, and H. Yamane, J. Chem. SOC., Chem. Commun., 1713 (1970). 136. H. hie, S. Tani, and H. Yamane, J. Chem. SOC.,Perkin Trans. I , 2986 (1972). 137. H. Ronsch, in “The Alkaloids” (A. Brossi, ed.), Vol. 28, p. I . Academic Press, New York, 1986. 138. K. Orito, R. H. F. Manske, and R. Rodrigo, J . A m . Chem. SOC.96, 1944 (1974). 139. N . Murugesan, G. Blasko, R. D. Minard, and M. Shamma, Tetrahedron Lett. 22,3131 (1981). 140. M. Hanaoka. T . Mitsuoka, S. Yasuda, and S. K. Kim, Chem. Pharm. Bull. 36, 3739 (1988). 141. K. Iwasa, A. Tomii, and N. Takao, Heterocycles 22, 33 (1984). 142. K. Iwasa, A. Tomii, N. Takao, T. Ishida, and M. Inoue, J. Chem. Soc., 16 (1985); K. Iwasa, A. Tomii, N. Takao, T. Ishida, and M. Inoue, J. Chem. SOC.,303 (1985). 143. K. Iwasa, M. Kamigauchi, and N. Takao, J. Nar. Prod. 51, 1232 (1988). 144. H. L. Holland. M. Castillo, D. B. MacLean, and 1. D. Spencer, Can. J. Chem. 52, 2818 (1974). 145. H. L. Holland, P. W. Jeffs. T. M. Capps, and D. B. MacLean, Can. J. Chem. 57, 1588 (1979). 146. G. Blasko, S. F. Hussain, and M. Shamma, J. A m . Chem. Soc. 104, 1599 (1982).
-CHAPTER
3-
PURINE ALKALOIDS ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY H . E. J . Ruscwrcli
Insiiirric, of C1it~tni.sir.v Utiiiwxiiy of Kortrclii Ktrrtrclii-75270. Ptrkistrrtl
I . Introduction IV. Purine Alkaloids from Plants .............. ........................ A. Caffeine .............................................................. B. Theobromine ...............................................................................
E. F. G. H.
Deoxyeritadenine 3-(6-Amino-YH-pu Triacanthine ............ ..... .................................................. ............. trtrns-Zeatin ..................................................
L. M. N. 0. P. Q.
Lupinic Acid ....................................................... 64y.y-Dimeth Discadenine.. ...................................... 640-Hydroxyb 6-(o-Hydroxyb ........................... Saxitoxin ......
.........................
A. Y (Wye) Base .............................................................................. B. Yt (Wybutine) C. Peroxy-Y Base (Wybutoxine) ................................. A. €3. C. D. E. F. G. H.
Doridosine .... .................................................. lsoguanosine ............................. Hypoxanthine .............................................................................. Paraxanthine . ........................... Phidolopin ........................................................... Agelasine Series ........................................................................... 9-P-D-Arabinofuranosyladenine(AraA) ........................
9-P-o-Ribofuranosyl-2-methoxyadenine ...........................
1. 9-[S'-Deoxy-5'-(methylthio)-~-~-xylofu~anosyl]adenine ......
........................
225
226 227 228 229 229 230 232 233 234 235 236 237 239 240 24 I 242 243 244 245 246 247 249 249 25 I 252 254 254 255 256 257 257 258 26 I 262 263 263 265
THE ALKALOIDS, VOL. 3X Copyright 0 IYW by Academic Preis. lnc. All rights of reproduclion in any form reserved.
226
VII.
V111. IX.
X.
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
L. Nh-Acetyl-6-imino-l.Y-dimethyl-8-oxopurine ...................................... M. Spongopurine ............... N . Herbipoline ................................................................................. Nucleoside Antibiotics and Related C Synthesis of Purine Bases ............... A . Synthetic Approaches to the Puri ..................................... B . Synthesis of Some Individual Purine Bases ....................................... Spectral Properties of Purine Alkaloids ....... A. Ultraviolet Spectroscopy ............................................................... B. Infrared Spectroscopy ............................................................... C. Nuclear Magnetic Resonance Spectroscopy ..... D. Mass Spectroscopy ....................................................................... Biological Activity of Purine Bases References ........................................................................................
265 266 267 267 280 280 292 304 304 306 307 310 31 I 313
I. Introduction
Alkaloids bearing a purine nucleus form a small but important group of natural products. They are often not classified as alkaloids because of their almost universal distribution in living matter and their mode of biosynthesis which shows no relationship to amino acids from which most alkaloids arise (1,2). Some purine alkaloids are major constituents of plants such as tea and coffee which are used throughout the world as stimulating beverages. Many of the physiologically important purine alkaloids possess a xanthine (1)nucleus. Xanthine itself has not been found naturally, but several simple N-alkyl derivatives of xanthine are of considerable significance. Prime among these are 1,3,7-trimethyIxanthine (caffeine), I ,3-dimethylxanthine (theophylline), and 3,7-dimethylxanthine (theobromine). Other purine alkaloids are derivatives of adenine (2) and guanine (3), with some of the N6-alkylated adenines possessing considerable cytokinin-like activity. The cytokinins are plant growth substances which promote cell divi-
H 1
2
3
3.
PURINE ALKALOIDS
227
sion. Several reviews on the chemistry and physical properties of purine alkaloids have been published (3-27).
11. Occurrence
The purine ring system is undoubtedly one of the most commonly encountered structural classes found in nature. Two purines, adenine (2) and guanine (3), are essential constituents of nucleic acids, and a large number of biochemical reactions involve purine derivatives such as adenosine or guanosine mono-, di-, and triphosphates, associated cyclic phosphates, and nucleotide coenzymes. The coffee plant Coffea arabica (Rubiaceae) is indigenous to Abyssinia and parts of East Africa, but it is also widely cultivated in Indonesia, Sri Lanka, and parts of South America, particularly Brazil. The seeds of various species of coffee plants contain 1-2% caffeine. Cola nitida (Vent.) Schott and Endl. is the principal source of kola nuts, which are important because of their caffeine (3-5%) and theobromine contents. Cola (kola) is the dried cotyledons of various species of cola trees (Sterculiaceae), which are native to the West Indies, Brazil, Java, and West Africa. Besides cola, many other plants also contain caffeine in relatively low quantities. The leaves and buds of Camellia sinensis (L.) 0. Kuntze (Theaceae) constitute the common tea. This plant is indigenous to East Asia and is now widely cultivated in China, Sri Lanka, Japan, India, Bangladesh, and Indonesia. The caffeine content of tea is in the range of 1 4 % , together with small quantities of theobromine and theophylline. The seed kernels of Theobroma cacao (Sterculiaceae)contain 0.9-3 .O% theobromine. The plant occurs widely in Columbia, Brazil, Venezuela, West Indies, Nigeria, Ghana, Sri Lanka, and Java. Some purine alkaloids have also been obtained from Holarrhena mitis (Apocynaceae), Leontinus edodes (Tricholomataceae), Lupinus angustifolius (Leguminosae), Paullinia cupana, Banisteriopsis inebrians, and Dictyostelium discoideus. A number of purine bases have been isolated from transfer or soluble RNAs of different animal organs and biosecretions as well as from plants. These are discussed in Section V. Several glycosyl purines have been isolated from certain microorganisms, and some proved to have substantial antibiotic activity. These purine nucleosides are described collectively in Section VII. In addition to the naturally occurring purine bases such as caffeine, purines with modified structures of both natural and
228
AlTA-UR-RAHMAN A N D M U H A M M A D IQBAL C H O U D H A R Y
synthetic origin have proved to be a rich source of a wide variety of biologically active materials.
111. Isolation and Detection
The common chromatographic techniques used for the isolation of purine bases from mixtures include paper chromatography, reversed-phase ion-pair chromatography, thin-layer chromatography (TLC), and highperformance liquid chromatography (HPLC). Similarly, a number of physical methods and chemical reagents are available for their detection. Several reports have been published on the TLC analysis of purines under neutral, basic, and acidic conditions on silica gel plates (28), with the substances being detected with UV light on fluorescent plates. Dragendorff's reagent with 10% H,S04-20% HNO, and iodine may also be used for detecting the bases on TLC plates. Caffeine has been analyzed by high-pressure TLC with an operating pressure of 1 million Pa (pascals) (29).Paper chromatography may be used for fast and accurate determination of caffeine and theobromine in cocoa powders. The paper chromatograms are developed with n-BuOH saturated with NH, for 1.5-2 hr (30). Reversed-phase ion-pair chromatography using an alkyl-S0,Na ionpair reagent has been employed to study the relationship between the R , values of the alkaloids and the chain length of the alkyl groups (31).Gas chromatography has also been used for the isolation and detection of purine alkaloids. The stationary phases used for isolation include SE-30, SE-52, QF-1, OV-I, OV-17, XE-60, neopentylglycol sebacate, and polyvinylpyrrolidone. Flame-ionization detection (FID), nitrogen-sensitive FID, and alkaline flame detectors have been used for detection (32). HPLC techniques are now also widely employed for separation of purine derivatives. Separations have been achieved employing normal phase columns (silica gel) in combination with mixtures of CH,CI,, iPrOH, MeOH, AcOH, and HCOOH as the mobile phase, ion-exchange columns (cation-exchange resins, chemically bonded strong cation exchangers on pellicular beads, or cross-linked cation-exchange resins) in combination with acidic aqueous solutions and buffers for the mobile phase, and reversed-phase C,, columns in combination with mixtures of MeCN-MeOH and acidic aqueous buffers with tetrahydroammonium hydrogen sulfate ion-pair reagent added to the solvent systems (33). The caffeine content of soft drinks was determined by HPLC using the strong cation exchanger Partisil-lOSCX, which was eluted with 0.1 M NH4H,P0, and detected at 214 nm (34).Three methylxanthine derivatives from food products (cocoa, cola, coffee, chocolate, green tea, and black tea) were
3. PURINE ALKALOIDS
229
analyzed by HPLC with a U V photometer at 275 nm on LiChrosorb C-8, eluted with MeOH-H,O-0.2 M phosphate buffer (pH 5.0) after pretreatment (35). Several reviews and reports have been published on the isolation, detection, and quantitative analysis of purine derivatives (35-37). IV. Purine Alkaloids from Plants
Plant-derived purine alkaloids may be structurally divided into two major types: (a) compounds in which a xanthine moiety (1) is present and (b) compounds in which the purine nucleus is not xanthine or a derivative thereof. A. CAFFEINE Caffeine (4) (theine, guaranine, coffeine), the first purine base to be isolated from any plant source, was reported by Runge in 1820 (38).It is the major alkaloid in the seeds of Coffeaarabica L., occurring in amounts up to 1-2%. It is also found in Coffea excelsa, C . canephora, C . liberica, C . salvatrix (39),Theobroma cacao, Cola nitida, C . acuminata, Camellia sinesis, C . thea, Paullinia cupana (40),Banisteriopsis inebrians (41),Ilex paraguairensis (42),etc. Methods for the isolation and quantitative analysis of caffeine are summarized in several articles and books (39,4345). 35.8 30.4
I m3
32.3
4
Caffeine (4), C,H,,N,O,, mp 235"C, showed UV absorptions at 272 nm 10,500) (pH 6.0) characteristic of an N-methyl-substituted xanthine nucleus (46). The IR spectrum of the compound showed bands at 1700 and 1600 cm-', indicating the presence of C-2 and C-9 imidic carbonyls. Detailed IR studies on several N-methylated purines have been carried out (E
230
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
(47). The 'H-NMR spectrum of caffeine (4) in trifluoroacetic acid (TFA) showed three three-proton singlets at 6 3.59, 3.80, and 4.33, representing
the N-1, N-3, and N-7 methyl groups, respectively. The 'H-NMR spectrum of 4 recorded in D20 showed only one signal at 6 7.88 arising from the C-8 aromatic proton (48,49). The I3C-NMR chemical shifts (in D20) for various carbons of caffeine (4) are shown around structure 4. The spectrum showed three low-field signals at 6 30.4, 32.3, and 35.8 corresponding to the three N-CH, carbons in the molecule. Signals at 6 158.5 and 155.0 were due to C-2 and C-6 carbonyls of ring A (50). The mass spectrum of compound 4 showed the molecular ion at mlz 194, in agreement with the formula C,H,,N,O,. The peak at mlz 165 was due to loss of an N-methyl group, whereas the peak at mlz 137 arose from a further loss of carbon monoxide. A peak at mlz 109 was due to the tropylium ion analog 5. The main fragmentation path is outlined in Scheme 1 (51). Syntheses of caffeine as well as its formation from theobromine (3,7-dimethylxanthine) and theophylline (1 ,Zdimethylxanthine) (52-54) and X-ray data (55)provided confirmatory evidence for structure 4. B. THEOBROMINE The physiologically important purine base theobromine (6) was first isolated from the beans of Theobroma cacao L. (56) and later from Camellia thea, Cola acuminata, Paullinia cupana, among others, Ilex caroliniana, and from some other Ilex and Cascarilla species (40,57-59). Theobromine (6), C7H8N4O2,mp 351"C, exhibited a UV absorption maximum at 274 nm (E 10,100) and a minimum at 251 nm (E 3980) (pH 10.6), indicating the presence of a substituted imidazole ring in its structure (60,61). The IR spectrum displayed strong absorptions at 1680 and 1703 cm-',
32.8
F 3
0
138 *9
I cH3
37.4
6
23 1
3. PURINE ALKALOIDS
I
\
m
k3
- co
m / z 137
cH3
m / z 165
SCHEME 1
corresponding to the presence of an enolic 1,3-dicarbonylgroup (47). The 'H-NMR spectrum [lo0 MHz, dimethylsulfoxide-d, (DMSO-d,)] showed two three-proton singlets at 6 3.33 and 3.84 for the N-3 and N-7 methyl groups, respectively. The C-8 aromatic proton appeared as a singlet at 6 7.94, and another singlet at 6 11.05 was assigned to an N-H proton, indi-
232
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
cating that theobromine was an N,N-dimethylxanthine derivative (48). The I3C-NMR spectrum of theobromine (in D,O) is summarized around structure 6 (50). The mass spectrum of theobromine (6) showed the molecular ion at mlz 180, in agreement with the molecular formula C,H,N402, indicating the presence of six double bond equivalents in the molecule. The mass spectrum showed a close resemblance to that of caffeine (4). The peak at mlz 123 was due to the loss of a H,C-N'+=C=O group from the molecular ion, while the peak at mlz 109 was due to the tropylium ion analog (51). The X-ray crystal structure of (theobromine),H,I, showed it to be a polyiodide salt with alternating cationic (hydrogen-bonded protonated theobromines) and anionic (Ijm ions) layers (62). Theobromine is a weak base, and its salts are decomposed by H,O. The imine nitrogen is readily alkylated to afford, for instance, caffeine (by N-methylation) or the corresponding N-ethyl and N-propyl derivatives (63). C. THEOPHYLLINE Theophylline (7)(theocin), the major purine constituent of Camellia thea (64), was first reported by Kossel(65). It had also been isolated from Theobroma cacao (66), Ilex paraguairensis, and Paullinia cupana (27,40). Theophylline (7),C,H,N,O,, mp 268°C showed a UV absorption at 235 nm (pH I1 .O), indicating the presence of an N-methyl-substituted xanthine nucleus (46). The IR spectrum exhibited bands at 1690 and 1720 cm-' for the nonenolic 1,3-dicarbonyl grouping in the structure (47).The 'H-NMR spectrum (100 MHz, DMSO-d,) showed two three-proton singlets at 6 3.24 and 3.44, representing two N-methyl groups. A singlet at 6 13.50 was due to the N-H proton, whereas the aromatic C-8 proton appeared as another singlet at 6 7.98 (48). The "C-NMR spectrum (in D,O) of 7 summarized around the structure showed two signals at 6 30.8 and 32.8 for the two N-methyl groups. A peak at 6 158.7 was assigned to the C-2 carbonyl carbon flanked between the two nitrogens (50). H
0
30.8
7
3.
PURINE ALKALOIDS
233
The mass spectrum of theophylline (7) showed the molecular ion at mlz 180 (100%) in agreement with the formula C,H,N,O,, indicating the presence of six double bond equivalents in the molecule. The large peak at mlz 95 was assigned to the N-demethyltropylium ion analog (51). These studies led to structure 7 for theophylline (1,3-dimethylxanthine), which was further confirmed by X-ray diffraction studies (67). Theophylline (7) is commercially converted to caffeine (4) by N-methylation. Theophylline itself has great clinical importance, and a large number of theophylline derivatives and analogs that exhibit a variety of pharmacological activities have been prepared (68).
D. ERITADENINE Rokujo et af. reported the isolation of an active component from Leontinus edodes (Berk.) Sing., named lentysine (69). The same substance was independently isolated by Chibata et al. from the same mushroom and named lentinacin (70).Later, both groups agreed to use the name eritadenine for this compound. Eritadenine (8), C,H,,N,05, [a],,+50° (0.1 N NaOH) was obtained as colorless needles, mp 279°C (dec.). The compound showed a UV absorption maximum at 261 nm (E 14,3000), suggest-
50-C
-H
I
2
R20--- C -H 1
I
OOR3
8
R =R. = R =H 1 2 3
9
R =R = H , 1 2
R =CH 3 3
10
R =R =COCH3, 1 2
11
R1,
R3=CH3
R2=C(CH3)2,
R3=m3
234
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
ing the presence of a substituted adenine nucleus. The IR spectrum revealed the presence of hydroxyl groups (3500 and 2200 cm-') and a carboxylic acid group (1689 cm-'). The 'H-NMR spectrum of compound 8 showed two one-proton singlets at 6 8.01 and 8.15 arising from the two aromatic protons. Treatment of eritadenine (8) with diazomethane gave the corresponding methyl ester 9, acetylation of which afforded the diacetate 10, thereby confirming the presence of one carboxyl and two hydroxyl groups in the side chain. The vicinal glycol was assumed to bear an erythro configuration by analogy with the nucleoside. This assumption was supported by the 'HNMR spectrum of the acetonide 11, CI3H1,N5O4,which was obtained by treatment of 9 with acetone-phosphorus oxychloride. The C-4 methylene signal in 11 (which appeared at 6 3.90-4.40 in 9) was shifted downfield to 6 4.92. This deshielding suggested that the C-4 methylene group was oriented cis with respect to the carboxyl group (erythro configuration) (71). The absolute configuration of eritadenine (8), was determined to be D-erythro [2(R),3(R)] by related experiments (72). The structure 8 for eritadenine has been confirmed by synthesis. The compound has marked hypocholesterolemic activity, and several synthetic analogs have been prepared (73,74).
E. DEOXYERITADENINE
A minor purine base, deoxyeritadenine (12), was isolated from the mushroom Leontinus edodes (75). The overall spectral data of 12 were closely related to those of the previously reported compound eritadenine (8). Deoxyeritadenine, C,H,,N,03,[a], + 18.4" (0.1 N NaOH), mp 270°C (dec.), showed a UV absorption of 262 nm (E 139,00), indicating the presence of a 9-substituted adenine nucleus. The IR spectrum showed bands at 3280, 3120, and 1700 cm-', which indicated the presence of amino, hydroxyl, and carboxyl groups in the molecule. The 'H-NMR spectrum of 12 was particularly informative, especially with regard to the position of the hydroxyl group on the side chain moiety. Two protons appeared at 6 2.71 as a broad quartet while another two protons resonated as a triplet at 6 4.28, indicating the presence of an N - C H , - C H , group. The C-1 proton resonated as a broad triplet at 6 3.97. On the basis of these data, deoxyeritadenine was recognized to be 6-amino-a-hydroxy-9H-p~rine-Pbutanoic acid (12). The carbon atom carrying the hydroxyl group was shown to have the (R) configuration by transformation of the resolved amino acid (13) to the corresponding lactone, which exhibited a negative Cotton effect. The structure and stereochemistry of 12 have been confirmed synthetically (75). Deoxyeritadenine (12), like other Leontinus alkaloids, showed
235
3. PURINE ALKALOIDS
'I"2
'i"2
r2
(32
T2
I*
H O WC W H
H O I c C -H
1
I
COOH
12
13
COOH
marked hypocholesterolemic activity. Two structural features necessary for this activity in such systems appear to be the presence of a purine ring and an NH, or a similar basic substituent at the 6 position (76).
F.
3-(6-AMlNO-9H-pUrin-9-YL)PROPIONICACID
The new purine base 3-(6-amino-9H-purin-9-y1)propionic acid (14) was isolated in minute quantities from the mushroom Leontinus edodes along with eritadenine (8) and deoxyeritadenine (12). Compound 14, C,H,N,O,,
'COOH 14
236
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
mp 277°C (dec.), showed a UV spectrum closely resembling those of 8 and 12, with an absorption maximum at 259 nm (E 13,800), indicating the presence of a 9-substituted adenine nucleus. The 'H-NMR spectrum showed two two-proton triplets at 6 2.90 and 4.39, corresponding to the presence of a CH,--CH,-N grouping. The data led to structure 14 for the compound, which was verified by comparison with an authentic specimen synthesized from adenine and ethylacrylate according to Lira's procedure (75).
G. Triacanthine The purine base triacanthine (15) (chidlovine, togholamine) was first isolated from the basic fraction of the leaves of Gleditsiu triucanthos (77). The compound was later also isolated from Holarrhenu Jloribundu, H . mitis, and Chidlowiu sunguinea (78-80). Triacanthine ( 1 9 , C,,H,,N,, mp 227-229°C showed a UV absorption maximum at 273 nm (E 12,500) indicative of a substituted adenine derivative. The IR spectrum displayed bands at 3400,3240 (N-H), 1682, 1630, and 1557 cm-' (aromatic skeletal vibrations). The 'H-NMR spectrum of triacanthine (15) showed a six-proton singlet at 6 1.87 for the methyl protons of the allylic dimethyl group. A doublet at 6 4.99 (J = 7.6 Hz) was assigned to the methylene protons of CH-CH,-N group. A triplet centered at 6 5.51 (J = 7.6 Hz) was due to a vinylic proton and showed coupling with the neighboring methylene protons. Two downfield singlets at 6 8.05 and 8.19 corresponded to the two protons on the purine nucleus. These observations suggested the presence of a CH,--CH=C(CH,), group substituted on the adenine nucleus.
3
15
3.
PURINE ALKALOIDS
237
The mass spectrum of the compound showed the molecular ion at mlz 203 in agreement with the molecular formula C,,H,,N,. The peak at mlz 188 (C,H,,N,) arose from loss of a methyl group from M’. Another peak at mlz 135 (C,H,N,) represented the ion resulting from loss of the side chain. The lack of any detectable optical activity suggested the absence of an asymmetric center in triacanthine (15). Evidence for the presence of a double bond in the side chain attached to the adenine nucleus was provided by the catalytic hydrogenation of triacanthine to dihydrotriacanthine, C,,H,,N,. In order to establish the nature and position of the side chain, triacanthine (15) was subjected to “exchange amination.” Reaction of triacanthine with benzylamine and benzylamine hydrochloride in a sealed tube yielded N-benzyltriacanthine, Cl7Hl9N5,leading to the conclusion that the adenine nucleus in triacanthine was unsubstituted on the exocyclic nitrogen atom. Further studies established the substitution site as N-3 of the adenine nucleus (81).In a later publication, Leonard and Fuji reported the synthesis of triacanthine (15) (82).An alternative structure having the y-dimethylallyl group at N-7 instead of N-3 was proposed by Belikov based on a series of chemical degradations of triacanthine (83),but Goutare1 and co-workers, who isolated triacanthine from H. miris, have confirmed structure 15 (79). H. trUns-ZEATIN Zeatin (16), a highly active cytokinin (plant hormone), was isolated from Zea mays (sweet corn) and later from many other plants (84-88). Kefford questioned its existence in the kernel of the plant (89),but Miller showed that zeatin does occur naturally in its unsubstituted form as well as in the form of a nucleotide and nucleoside (90). rrans-Zeatin [(E)-zeatin], C,,H,,N,O, mp 207”C, showed U V absorptions at 207 (E 14,500) and 275 nm (E 14,650), indicating the presence of a substituted adenine nucleus. The IR spectrum showed C-H, C=C, C=N, and C-0 stretching vibrations (91). The ‘H-NMR spectrum (60 MHz, D,O, pyridine-d,) of (E-)zeatin picrate showed a three-proton singlet at 6 1.53, assigned to the allylic methyl group. An asymmetric doublet resonated at 6 3.83, owing to the oxomethylenic protons. The olefinic proton appeared as a multiplet at 6 5.42, while two singlets at 6 7.88 and 7.96 were due to the C-8 and C-2 protons, respectively, of the purine nucleus (92). The I3C-NMR spectrum (CD,OD-D,O) of the compound is summarized around structure 16 (93). The mass spectrum of (E)-zeatin (16) showed the molecular ion at mlz 219. The base peak appeared at mlz 202 owing to loss of the OH group.
238
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY 13.0
b7.3
39.0
N' I
140.5
16
The peaks at mlz 135 and mlz 108 were attributed to the adenine ion. The mass spectrum recorded after deuterium exchange indicated that zeatin must contain at least three exchangeable hydrogens, two of which were present in the aminopurinyl moiety and the third in the substituent. An M' - 31 peak indicated the presence of a CH,OH group, which was
(a-
17 R=OH 18 R=H
3. PURINE ALKALOIDS
239
confirmed by acetylation, thereby accounting for the third exchangeable hydrogen atom in the substituent (92). These studies established trans1-01. Structure 16 zeatin to be 2-methyl-4-( lH-purin-6-ylamino)-2-butenwas later confirmed by synthesis (91,94) When zeatin was supplied to Raphanus sativus (radish) seedlings with excised roots (sweet corn), a number of metabolites were formed. These included adenine, adenosine 5'-phosphate, zeatin riboside, and zeatin 5'phosphate. However, the major metabolite was a glucoside of zeatin which differed from 9p-~-glucopyranosylzeatin.This metabolite, termed raphanatin (17), was active as a cytokinin and occured mainly in the cotyledons of the seedlings (95). In addition to the unsubstituted trans-zeatin (16), a ribosylzeatin, identified as 6-(3-methylbut-2-enylamino)-9-p-~-ribofuranosylpurine (18) was isolated from immature sweet corn kernels (96). 0-Glucosylzeatin has also been found in some Populus species (96a).
I. 1'-METHYLZEATIN 1'-Methylzeatin (19) was isolated from Pseudomonas syringae (97). The compound (19), C,,HI5N,O, [a],- 52.6" (0.13, EtOH) afforded U V absorption at 269 nm (E 11, 842) (pH 7.0), characteristic for an N6-substituted adenine derivative. The 'H-NMR spectrum (270 MHz, CD,OD) revealed the presence of two singlets at 6 8.22 and 8.05, assigned to H-2 and H-8, respectively, typical for a 6-substituted purine system. A complex doublet at 6 5.53 and two broad singlets at 6 3.95 and 1.78 were assigned
14. I
CH
-'21.8
I
LJ/ 138.3
153.
R
19 R=H 20 R = r i b o s y l
240
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
to H-2’, CH,-4’, and CH,-5’, respectively. The C-I’ methyl group resonated at 6 1.36. The I3C-NMR spectrum of 19 indicated the presence of I 1 carbons. The chemical shifts were in agreement with the proposed structure and are summarized around structure 19 (97). Its mass spectrum exhibited the molecular ion at mlz 233. The base peak mlz 216 corresponded to loss of the OH group. Other major peaks were at mlz 202, 174, 162, and 136. The occurrence of ions at mlz 216, 174, and 162 was consistent with a fragmentation pathway for a ]’-methyl derivative of trans-zeatin (16) (98). The N9-ribosyl derivative (20) of 1’-methylzeatin (19) was also isolated from Pseudomonas syringae (99). The absolute configuration at C-I’ was established as (R). Both structures were confirmed by synthesis (100). J. cis-ZEATIN The cis (Z) form of zeatin was isolated from Covynebacteriumfascians (101), and it also occurs as a 9-(3-ribonucleoside in Nicotinia tabacum (102). Ribosyl-cis-zeatin (9-ribosyl-2) was also isolated from the tRNA of tissues of certain plants such as pea, spinach, and corn (103,104). cisZeatin (21), C,oH,3N,0, mp 206-208”C, was found to be 50 times less active than the trans isomer with respect to cytokinin activity (105). The
UV spectrum showed absorption at 274 nm (E 17,850). The U V and mass spectra of 16 and 21 are practically indistinguishable.
NH
21
The ‘H-NMR spectrum (DMSO-d,) of cis-zeatin was similar to that of trans-zeatin (16). The allylic methyl group appeared at 6 1.80, while the hydroxymethylene protons resonated as a singlet at 6 4.20. A multiplet centered at 6 4.30 was assigned to the methylene protons (Y to the nitro-
3.
24 1
PURINE ALKALOIDS
gen. The vinylic protons appeared as a singlet at 6 5.50, and two singlets at 6 8.20 and 8.30 could be assigned to the C-8 and C-2 protons of the purine nucleus (106). The structure of cis-zeatin (21) was confirmed through synthesis, and several zeatin analogs have been prepared (105107).
K. (S)-DIHYDROZEATIN (S)-Dihydrozeatin (22), a unique saturated isoprenylated adenine, was isolated from immature seeds of Lupinus futeus (108). The substance (22), C,oH,sNsO,[(~],-15.4" (aq. EtOH), mp 167"C, showed U V absorptions at 275 (E 17,300) and 282 (E 13,600) nm, characteristic of a substituted adenine nucleus. The 'H-NMR spectrum (60 MHz, pyridine-d,) displayed a three-proton doublet at 6 1.13 ( J = 6.0 Hz) for the secondary methyl protons. A doublet centered at 6 3.78 (J = 6.0 Hz) was assigned to the C-4' methylene protons (Y to the hydroxyl group. A two-proton sextet at 6 4.12 was due to the C-1' methylene protons (Y to N-6. Downfield singlets at 6 8.35 and 8.82 were due to the C-8 and C-2 aromatic protons, respectively (109). The spectrum, in contrast to those of 16 and 21, showed a lack of any vinylic proton. The I3C-NMR spectrum (CD,OD) of 22 was almost identical to that of 16 except for the carbons of the N-6 side chain. The assignments for the various carbons are summarized around structure 22. Structure 22 was confirmed by formation from 16 through catalytic hydrogenation. The (S) absolute configuration of ( - )-dihydrozeatin (22) was established by ORD studies on a synthetic compound prepared from 6-chloropurine and (S)2-methyl-4-aminobutan-1-01 oxalate (110). Structure 22 for (S)-dihydrozeatin was also confirmed by synthesis of its ( R ) - + isomer ( 1 1 1 ) . Synthetic (+)-(R)-dihyrozeatin (23) was found to be 10 times more active as a cytokinin than the naturally occurring (S)-dihydrozeatin (22) ( 1 12,113). 68.2
CH20H 34-71
H-C
-
34.2
CH 2-
I
39.9
CH2\
NH
17.1
H3C 140.4
22
242
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
2'
13'
1'
NH
I
H
23
L. LUPINIC ACID Lupinic acid (24), C,3H,8N603r mp 216°C is a metabolite of trans-zeatin (16) and occurs in seedlings of Lupinus angustifolius. It represents the first example of a naturally occurring purine derivative that bears an amino acid residue on a ring nitrogen (114). Its UV spectrum exhibited a maximum at 270 nm, characteristic of N6,9-disubstituted adenines. The mass spectrum below mlz 220 was typical of an intact zeatin nucleus
cH2 ,COOH
24
I d C L NH2
243
3. PURINE ALKALOIDS
(1151, except for a large mlz 44 (CO,) peak, while significant higher mass
ions were present at mlz 288 (M' - H,O), 271 (M' - H 2 0 - O H ) , 262 (M' - CO,), 257 (M' - H,O-CH,OH), 245 (M' - OH), and 231 (M' - CO,-CH,OH). The physical data were rationalized in terms of structure 24, which was later confirmed by synthesis (114-116).
M.
6-(y,y-DIMETHYLALLYL)PURINE
Skoog and co-workers reported a new purine base, 6-(y,y-dimethylal1yl)purine (25), from tobacco tissue culture (Corynebucteriurn fusciuns) (117). The compound (25), C,,H,,N,, mp 216"C, is a bright yellow solid showing a UV absorption maximum in the region 260-280 nm, typical of N6-alkyladenines (117). The mass spectrum of 25 was particularly informative. It showed the molecular ion at mlz 203, consistent with the formula C,,H,,N,. Other major peaks were at mlz 188, 160 148, 135, 119, and 108. The fragmentation pattern observed in the mass spectrum was consistent with the suggestion that 25 was an adenine derivative, since a similar fragmentation pattern was observed in triacanthine (15) and trunszeatin (16). The strong peak at mlz 135 arising from the adenine ion, C,H,N,+, was particularly diagnostic. The difference of 68 amu between the molecular ion C,,H,,N,' (mlz 203) and the adenine ion C,H,N,+ was accounted for by the loss of the C,H, side chain. The mass spectral fragmentation of zeatin (16) (after loss of CH,OH) corresponded closely to that of 25 (after loss of CH,) (118).
H
25
The soluble RNA of yeast contains the nucleoside of base 25 (119). This nucleoside also occurs in soluble RNAs of several mammalian tissues (120), spinach, and garden peas (121). It is N6-(A2-isopenteny1)adenosine (IRA) (26) and possesses exceptionally high cytokinin activity (122).
244
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
3c
gC
HO
-CH1 2
P
H
26
N. DISCADENINE
Discadenine (27) is a unique purine alkaloid that was isolated from spores of the slime mold Dicfyosfeliumdiscoideum (123).The substance, C,,H,,N,O,, [a],, +27.3" (0.7, 0.1 N HCI), mp 205-207"C, showed a U V absorption maximum at 289 nm, indicating the presence of a substituted adenine nucleus (124). The 'H-NMR spectrum (DMSO-d,) showed a sixproton singlet at 6 1.77 that was attributed to the vinylic methyl groups. A doublet at 6 4.25 (J = 7.0 Hz) was assigned to the CH, group attached to N-6, whereas a triplet at 6 4.73 ( J = 10.0 Hz) was due to the N-3 CH, group. The vinylic proton appeared as a triplet at 6 5.37 ( J = 7.0 Hz). Two downfield singlets at 6 8.66 and 9.05 were due to H-8 and H-2, respectively (125). The '-'C-NMR spectrum (15 MHz) of 27 showed a signal at 6 170.0 for the carbonyl carbon, whereas peaks at 6 152.0, 147.0, 140.0, and 112.0 were assigned to the four quaternary carbons. The chemical shifts for the various carbons are presented around expression 27. The structure of discadenine (27) was supported by high-resolution mass measurements. The molecular ion at mlz 304.1657 (C,,H,,N,OJ indicated the presence of eight double bond equivalents in the molecule. and The major peaks at mlz 260.1761 (C13H,oN6),230.1429 (C12H16Ns), 217.1348 (C,,H,,N,) arose by degradative loss of the carbon chain at N-3.
3.
245
PURINE ALKALOIDS
31.0
cH2
H
27
** 47.0 I
170.0
C 4 COOH
I NH2
The fragmentation pattern below mlz 203 was similar to that of 6-(3-methyl-2-butenylamino)purine (126). Discadenine (27) is the first natural purine derivative possessing an a-amino acid residue at the 3 position of the purine ring. The compound exhibits significant cytokinin activity. Structure 27 for discadenine has been confirmed by synthetic studies (125,127).
0. 6-(O-HYDROXYBENZYLAMINO)-~-meth~~thiO-9-~-DGLUCOFURANOSY LPURINE
6- (0-H ydrox ybenzylamino) - 2- methylthio -9- p - ~-glucofuranos ylpurine (28) was isolated from fruits of Zantedeschia aethiopicu (cuckoopint fruits) and showed endogenous hormonal (cytokinin) activity. The substance (28), C,,H2,NSO6S,showed a UV absorption at 286 nm, indicative of substitution at N-6 and at the 9 position of an aminopurine. The mass spectrum of 28 suggested that it was a hexose derivative of 432 (M' adenine. Prominent peaks were at mlz 449 (M+, C,,&N,SO,), - OH), 357 (M' - C,H,O), 343 (M' - C,H60), and 328 (M' C,H,NO), indicating the presence of a hydroxybenzylamino group at the 6 position of the purine nucleus. This was confirmed by the presence of fragment ions at mlz 122 (C,H,NO), 107 (C,H,O), and 93 (C,H,O). Other
246
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
I
OH
I
H
OH
28
significant ions appeared at mlz 326, 313, 299, 295, 279, 254, 239, 224, 210, 195, 192, 181, 151, 92,91, 71, and 58. It is interesting to note that many of these fragments corresponded to the ones shown by the hexose derivative of adenine but shifted 46 amu higher, suggesting the presence of a methylthio group, which was confirmed by the signal at 6 2.51 in the 'H-NMR spectrum (60MHz, DMSO-d,) of the compound. This substituent is probably at C-2of the purine nucleus, which is in agreement with the one-proton singlet at 6 8.27 assigned to the adenine C-8 proton. The above studies led to structure 28 for this new cytokinin purine base (128).
P.
6-(~-HYDROXYBENZYLAMINO)-9-~-D-RIBOFURANOSYLPURINE
A new cytokinin purine base, 6-(o-hydroxybenzylamino)-9-~-~-ribofuranosylpurine (29), was isolated from leaves of Populus robusta as the first naturally occurring cytokinin having an aromatic side chain. Compound 29, C,,HI9N5O5,showed a UV absorption at 266 nm, characteristic of an N6-substituted adenosine. The mass spectrum of 29 showed the molecular ion at mlz 373.1413, in agreement with the formula C,,H,,N,O,. Other peaks were at mlz 284, 270, 241, 224, 178, 164, 148, 135 (loo%),
3.
PURINE ALKALOIDS
247
OH OH 29
121, 120, 119, 108, 106,78, and 66, suggesting that the compound was an N6-(hydroxybenzy1)adenosine. Compound 29 was prepared by reaction of 6-chloropurine-9-p-~-ribosidewith ortho-hydroxybenzylamine (129).
Q. SAXITOXIN Saxitoxin (30), an unusual purine base, was isolated from marine dinoflagellates such as Saxidomus giganteus, Mytilus californianus, Gonyau[a],, lax catanelfa, and G . tamarensis (130). Saxitoxin (30), CIOH1,N7O4, + 130°, is considered to be the most toxic nonprotein compound known. Its structure was established on the basis of extensive spectral and X-ray studies (131). The 'H-NMR spectrum showed two quartets at 6 4.27 ( J , = J2 = 9.0 Hz) and 4.05 (J, = 11.0 Hz, J , = 5.0 Hz), which were assigned to the two protons on C-16. A multiplet at S 3.87 was due to the H-6 methine, whereas the C-5 methine proton appeared as a doublet at F 4.77 (J = 1.0 Hz). The C-11 methylenic protons resonated as multiplets at 6 3.85 and 3.50, and the multiplet at 6 2.37 was attributed to the C12 protons (131). Saxitoxin (30) contains three rings and is conveniently described as a 3,4,6-trialkyl tetrahydropurine.
248
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
NH HN
OH OH
30 R=H
31 R=OH
A stereospecific total synthesis of saxitoxin (30) was also achieved (132). The related N-hydroxysaxitoxin, neosaxitoxin (31), and the sulfo derivatives gonyautoxin I (32),gonyautoxin I1 (33), gonyautoxin 111 (34), gonyautoxin IV ( 3 3 , gonyautoxin V (36), gonyautoxin VI (371,gonyautoxin VII (38), toxin C , (39), toxin C , (40), and protogonyautoxin I (41)
I
OH
R1
32 R 1=-OSO 33 R 1=-OSO
H , R =OH, R3=H 3 2
3H , R2'H,
R =H 3
34 R 1=-OSO 3H ( e p i r n e r i c ) , R2=H, R 3=H 35 R 1=-OS03H ( e p i m e r i c ) , R2 =OH, R3=H 36 R1=H, R2=H, R 3=SO 3H 37 R l = H , R2=OH, R3=S03H 14 38 R =-oSo H ( e p i m e r i c ) , R = H , R = N - s u l f o n i c a c i d 1 3 142 3 39 R =-()SO H , R =OH, R = N - s u l f o n i c a c i d 1 3 2 3 14 40 R =-oSo H ( e p i m e r i c ) , R =OH, R = N - s u l f o n i c a c i d
1 3 41 R 1=-OS03H,
R =H, 2
,9
14 3 =N-sulfonic a c i d 3 -
3.
PURINE ALKALOIDS
249
were also isolated from Gonyaulax and Protogonyaulax species (133136). V. Purine Bases from Transfer RNAs of Plants and Animals
A number of purine bases have been isolated from the RNAs of different plants and animals. Nucleosides of several purine bases of plant origin, such as M-ribosyl-cis-zeatin, were isolated from tRNA of certain plants, for example Nicotinicr t&~cum, pea, spinach, and corn (102-104). Similarly, the nucleoside of (y,y-dimethylallyl)purine (26) was isolated from RNAs of yeast, spinach, garden peas, and several mammalian tissues (121). Methylated adenines including 6-methylaminopurine and 6dimethylaminopurine commonly occur as constituents of yeast and other RNAs. The nucleoside 2-methylthio-N-carbonyl(N-threonyl)adenosine was isolated from tRNA of mammalian tissues (137). Some of the purine bases derived from RNAs are described below. A. Y (WYE)BASE A hydrophobic fluorescent purine base was isolated from the phenylalanine tRNA of bakers' yeast (138), and it was later also isolated from the tRNA of Torulopsis utilis (139), wheat germ (140), rat liver (141), and Saccharomyces cerevisiae (242). The base (Y, wye, 42), C,,H,,N,O,, showed U V absorption maxima at 235 (E 23,500), 263 (E 4500), and 313 nm (E 3500), indicating a highly conjugated system. The IR spectrum displayed absorptions at 1725 (ester carbonyl), 1715 (ester and amidic carbonyl), and 1600 cm'- ( C S ) . The 'H-NMR spectrum (100 MHz) of 42 showed four singlets at 6 2.26, 3.68, 3.71, and 3.96, representing a vinylic methyl, two carbomethoxyl methyls, and the N-methyl protons, respectively. One deuterium-exchangeable singlet at 6 5.60 was assigned to the N-H proton, whereas three multiplets resonating at 6 2.15, 3.20, and 4.40 were due to the unit CHCH,CH, attached to an aromatic nucleus. The mass spectrum of base 42 showed the molecular ion at mlz 376.1495. The occurrence of the base peak at mlz 216 in the mass spectrum and the possible presence of a CHCH,CH,Ar grouping suggested that the side chain and the nucleus consisted of C,H,,NO, and C,H,N,O moieties, respectively. The presence of two weak C D Cotton effects at wavelengths corresponding to the nuclear UV absorptions further suggested that the side chain methine carbon was the chiral center. Moreover, the CD curves remained unchanged when the solutions were maintained at pH 3 and 9 for 24 hr, which excluded any possibility of a readily enolizable group
250
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY n
2 16
I CH 3
3 .96
42
being attached to the chiral methine. The attachment of the side chain and vinylic methyl to C-10 and C-11, respectively, was established by comparing the 'H-NMR chemical shifts with those of compound 43 (143). The configuration of the side chain has been determined as (S). A synthesis of Y base was reported by Nakanishi and co-workers (144). The same research group later reported that guanine (3) can be a biogenetic precursor of Y base. The p - g l y c o Y base (wybutosine) (44)was also isolated from tRNAs in bakers' yeast (138) and rat liver (141). The lability of the sugar made assignment of its position difficult; however, structure 44 was subsequently confirmed by synthesis (142,144,145).
43
3.
PURINE ALKALOIDS
25 I
44
B. Yt (WYBUTINE) The highly fluorescent Y-like base Yt (wybutine) (45) was isolated from the tRNA of Torulopsis utilis (146). Compound 45, C,H,N,O, showed UV absorption maxima at 230, 265, and 305 nm, indicating the similarity of the chromophoric system to that of Y base (42). The 'H-NMR spectrum of 45 (100 MNz, D,O) showed a three-proton doublet at 6 2.24 (J = 1.O Hz), which was assigned to the C-1 1 methyl protons. Another three-proton singlet at 6 3.82 was due to the N-methyl protons. The aromatic C-6 proton appeared as a singlet at 6 8.07, whereas a close quartet at 6 7.32 (J = 1.O Hz) was assigned to the C-10 aromatic proton. A small coupling of about 1.O H z between the methyl protons at 6 2.24 and the proton at 6 7.32 is attributable to a long-range spin-spin coupling between the methyl and olefinic protons in a CH,C = CH grouping. Thus, Yt base has two methyl groups, one on C-10 or C-11 and the other on N-3, N-7, or N-9. A comparison of the 'H-NMR spectra of compound 45 and Y base (42) established their positions at C-11 and N-3.
252
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
45
0
-OH
Hb
H 2
46
The high-resolution mass spectrum of Yt base (45) showed the molecular ion at mlz 203.0802, in agreement with the molecular formula C,H,N,O. A peak at mlz 188.0590 (C,H,N,O) resulted from loss of the '. A peak at mlz 174.0767 (C,H,N,) was due to loss methyl group from M of HCO from M'. These observations suggested that the molecule has a very stable nucleus with C = 0 and CH, substituents (146). Structure 45 for Yt base was further confirmed by synthesis (147). A naturally occurring Yt base nucleoside named wyosine (46) was isolated from the anticodon of yeast tRNA, and it is very readily (and characteristically) hydrolyzed to the aglycone (146). C. PEROXY-Y BASE(WYBUTOXINE) The fluorescent purine base peroxy-Y base (wybutoxine) (47) was isolated from tRNA of bovine liver (148) and later from the livers of beef, calf, rat, and chicken (149). Interestingly, it was also found in tRNA of
3.
PURINE ALKALOIDS
253
the plant Lupinus luteus (150) and in wheat germ (151). It represents the first peroxy-Y base to be isolated from a higher plant source. Compound 47, Cl,H,,N6O,, showed a UV spectrum identical with that of wye base (42). The structure of the calf liver peroxy base was determined as 47 by comparing its 'H-NMR and high-resolution mass spectra with those of 42. The 'H-NMR experiment (100 MHz) on a 30-pg sample allowed the detection of four methyl peaks at 6 2.20, 3.71, 3.76, and 3.94. These compare favorably with the values obtained for 42, namely, 6 2.26,3.68, 3.71, and 3.96.
47
The mass spectral pattern of 47 also closely resembles that of wye base established by accurate mass measurement, indicated the presence of two additional oxygen atoms in comparison to 42. An intense peak at mlz 216 indicated that an aromatic nucleus and an a-methylene group were present. The ions at mlz 262 and 246 indicated that both tidditional oxygen atoms were located on the (3 carbon, either as a hydroperoxide or as a gem-diol grouping. The latter possibility is unlikely because a loss of 17 or 18 amu would be expected, which was not observed. On the other hand, hydroperoxides are known to lose oxygen in the mass spectrometer. The mass spectral behavior of 47, namely, formation of peaks differing by 16 amu by loss of oxygen atoms (mlz 376 and 360; mlz 262 and 246), further indicated that the compound contains a hydroperoxide group (149,150). The presence of the rare hydroperoxide group in the naturally occurring compounds was supported
(42). The formula C,,H,,N,O,
254
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
i -
7
H3C-C r-CH
by a specific color test employing ferrous thiocyanate solution (150). A number of experiments were also carried out to exclude the chances of compound 47 being an artifact of the yeast base (149). Along with the peroxy-Y base, its N2-gluco derivative, wybutoxosine (48), was also isolated from Lupinus luteus (150), bakers' yeast, and rat liver (149). VI. Purine Alkaloids from Animals
A. DORIMSINE A new N-methylpurine riboside, doridosine (49), was isolated from the digestive glands of the nudibranch Anisodoris nobilis (152,153)and from the marine sponges Tedania digitata (154) and Madaracis mirabilis (155). Doridosine (49), C,,H,,N,O,, mp 250-255"C, [aID +66.2", showed UV absorptions at 292 (E 8500) and 248 nm (E 6500). The 'H-NMR spectrum (100 MHz) showed a three-proton singlet at 6 3.50, which was assigned to the N-methyl group, whereas a doublet at 6 3.88 was due to the C-1 proton. One-proton multiplets at 6 4.29, 4.35, and 4.51 were assigned to
3.
30.
PURINE ALKALOIDS
255
NH
gC 137.9
I
61.9
49
the C-2', C-3', and C-4' protons, respectively, of the sugar moiety. Other peaks were at 6 5.87 (d, 1H) and 8.00 (s, IH), the latter being due to the C-8 aromatic proton (252). Direct comparison of the 'H-NMR spectrum of doridosine (49) with those of isoguanosine (SO) and N6-methylisoguanosine revealed remarkable similarity except for the signal for the methyl protons. The I3C-NMR spectrum of 49 (25 MHz, DMSO-d,) showed a peak at 6 137.9 corresponding to the C-8 methine of the purine ring. The signal at 6 30.17 was assigned to the methyl carbon. A downfield signal at 6 153.67 was due to the C-2 carbonyl carbon of the main purine skeleton. The I3CNMR assignments for the various carbons are presented around structure 49. High-resolution mass spectroscopy established the exact mass of 49 to be 297.1075, in agreement with the molecular formula C,,H,,N,O,. The base peak at mlz 165.0651 (C,H,N,O) correspond to a methylguanine ( - H) fragment or its isomer (153). The above studies led to structure 49 for doridosine, which was later confirmed through synthesis (256). The compound showed potent muscle-relaxant activity, as well as blood pressure lowering and anti-inflammatory activities (154). B. ISOGUANOSINE Isoguanosine (SO), CloH13Ns05,[a], - 60°, mp 237-241°C, was first isolated from Croton tigfium (157)and then from the wings of the butterfly Prioneris thestyfis (158). The 'H-NMR spectrum (100 MHz, D,OCD,OD) showed signals at 6 3.90, 4.32, 4.36, 4.49, and 5.90, which were
256
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
assigned to the C-5', C-4', C-3', C-2', and C-1' protons of the sugar moiety, respectively. A downfield singlet at 6 8.05 was due to the C-8 methine proton of the purine skeleton. The I3C-NMR assignments are presented around structure 50 ( 1 5 3 , which has been confirmed by synthesis (159).
I
61.8
86.6
H
71.5
74.5
50
51
A closely related compound, 1-methylisoguanosine (51), C, ,H,,N,O,, was isolated from the marine sponge Tedania digitata (160,161). Its UV spectrum showed maxima at 250 (E 8600) and 294 nm (E 11,400). The I3CNMR spectrum (33 MHz, DMSO-d,) is summarized around structure 51, which was also confirmed by synthesis (161).
C. HYPOXANTHINE Hypoxanthine (sarcine, sarkin) (52) is a xanthine derivative which was first isolated from cattle spleen (162). It occurs widely in plant and animal tissues. Compound 52, C,H,N,O, mp 360°C, showed UV absorptions in the range of 250-260 nm (Z63,164). The 'H-NMR spectrum (60 MHz, DMSO-d,) showed only two singlets, at 6 8.12 and 7.97, which were assigned to the C-2 and C-8 protons. The N-1 and N-8 protons were not observed in the spectrum (265,266). The "C-NMR spectrum (25 MHz DMSO-d,) showed signals at 6 144.6, 153.1, 119.2, 155.3, and 140.2, which were assigned to C-2, C-4, C-5, C-6, and C-8, respectively (167).
3. PURINE ALKALOIDS
257
On the basis of spectroscopic and X-ray crystallographic studies (168), structure 52 was established for hypoxanthine, which was later synthesized by several groups.
52
Hypoxanthine (52) exhibits protropic (imidazole moiety) and lactamlactim (pyrimidine portion) tautomerism. A number of alternative tautomeric forms are therefore possible, and different techniques have been employed to ascertain the relative populations of the various contributing structures. It was concluded 52 occurs in the 1,7-dihydro-, 1,Pdihydro-, 3,7-dihydro- (minor), 3,9-dihydro- (minor), and 7,9-dihydroimidazolium betain forms (167).
D. PARAXANTHINE Paraxanthine (53), C,H,N,O,, was isolated from whale liver and human urine and showed marked antithyroid activity. Compound 53 showed a U V maximum at 268 nm. N'-Demethylation of caffeine yielded paraxanthine, thereby establishing its structure (169).
H
53
E. PHIDOLOPIN An interesting purine derivative, phidolopin (54), was isolated from Phidolopora pacz~7ca.Phidolopin (54), C,,H,3N,0,, mp 226°C. showed U V absorptions at 353 (E 3300) and 275 nm (E 16,800). The IR spectrum
258
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
includes absorptions at 3300 (O-H), 1697 (arnide carbonyl), 1627 (imidic carbonyl), and 1532 crn-' (C=C). The 'H-NMR spectrum (270 MHz, CDCI,) showed two three-proton singlets at 6 3.39 and 3 3 9 , indicating two N-methyl groups. A two-proton singlet at 6 5.46 was due to the benzylic methylene protons. The downfield singlet at 6 7.63 was assigned to the C-8 proton of the purine nucleus, whereas the phenylic aromatic protons resonated in the range 6 7.16-8.08. A one-proton singlet at 6 10.56 exchanged with D,O and was assigned to the hydroxyl proton.
N 0,
7u
m / z 152
.o* 140.6
N
149.3
I
CH 3
23.7*
54
The mass spectrum of 54 included the molecular ion at mlz 331.0917. The peak at mlz 180 was due to the loss of the benzylic group from the molecular ion. The base peak at mlz 152 (C,H,NO,) was due to the 4hydroxy-3-nitrobenzyl residue resulting from the benzylic cleavage. The ',C-NMR spectrum of 54 (100 MHz, CDCI,) showed two N-CH, peaks at 6 28.0 and 29.7. The chemical shifts are given around structure 54. The structure of phidolopin (54) was solved by X-ray diffraction analysis. The compound contains a nitro functionality, which is relatively rare in natural products (170,171). Phidolopin has been synthesized by Hirota et al. (171).
F. AGELASINE SERIES A series of compounds including agelasidine A (56), agelasidine B (57), and agelasidine C (58) as well as agelasines A (59), B (60), C (61), D (62),
3.
PURINE ALKALOIDS
259
CII
55
E (63), and F(64) and ageline B (65) that have a cationic moiety (55) attached to diterpenoid units were isolated from marine sponges of the genus Agelus. These compounds exhibit interesting bioactivities such as inhibitory effects on the growth of microorganisms, the contractive response of smooth muscles, and enzymatic reactions of Na,K-ATPase (172).
56
57
58
260
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
.c& &y
15
'
3
Y
7
I
4
1
59
60
Y
61
1
Y
2
3
63
3.
26 1
PURINE ALKALOIDS
Y
64
65
G.
9-P-D-ARABINOFURANOSYLADENINE (AraA)
9-P-~-Arabinofuranosyladenine (AraA) (spongoadenosine) (66) along with its 3-acetate 67 was isolated from the marine organism Eunicella cavolini and from Streptomyces antibioticus. AraA (66) is clinically used as a powerful antiviral and antitumor agent. The compound (67), C,,H,,N,O,, showed a UV absorption at 258 nm (E 14,000). The IR spectrum showed a strong absorption at 1710 cm-', indicating the presence of an ester carbonyl group. The 'H-NMR spectrum (CD,OD-CDCI,) displayed two singlets at 6 8.45 and 8.30, owing to the C-2 and C-8 aromatic protons. A three-proton singlet at 6 2.20 was assigned to the acetyl methyl protons, while a oneproton multiplet at 6 5.30 was due to the C-3' proton a to the acetyl group. The mass spectrum showed the molecular ion at mlz 309. The base peak at mlz 135 resulted from loss of the sugar unit from the molecular ion. Other major peaks were at mlz 279, 266, 178, 164, 136, 135 (loo%), and 108 (173).
262
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
y2
66 R=H 67 R=-COCH3
H.
9-P-D-RIBOFURANOSYL-2-METHOXYADENINE
9-p-~-Ribofuranosyl-2-methoxyadenine (spongosine) (68) was isolated from Cryptotethia crypta. The compound, C,,H,,N,O,, [aID- 42.5", mp 192"C, showed a UV absorption at 267 (E 12,500) nm. Other spectroscopic properties were not reported in the literature (1 74).
Ho-H2G H OH OH
68
3. PURINE ALKALOIDS
I.
263
9-[~'-DEOXY-~'-(METHYLTHlO)-~-D-XYLOFURANOSYL]ADENINE
9-[5'Deoxy-5'-(methylthio)-~-~-xylofuranosyl]adenine (69), was isolated from the marine nudibranch Doris verrucosa. Compound 69, C,,H,,N,SO,, [aID-270°, showed a UV absorption at 260 nm, indicating the presence of a 9-substituted adenine nucleus. The 'H-NMR spectrum (250 MHz, DMSO-d& of 69 showed a three-proton singlet at 6 2.10 arising from the S-methyl protons. The C-2 and C-8 aromatic protons appeared at 6 8.14 and 8.24, resectively. The C-5' methylenic protons appeared as double doublets at 6 2.86 and 2.74 (J = 13.5 Hz, J = 6.8 Hz). The exact mass measurement of the molecular ion (mlz 297) indicated the formula C,,H,,N,SO,. A peak at mlz 250 arose from the loss of SCH, from M'. Compound 69 was the first naturally occurring analog of methylthioadenosine (MTA), which is attracting increased attention owing to its highly diverse regulatory function (175).
69
J. AGELASIMINES Two novel bicyclic diterpenoidal purines, agelasimine A (70) and agelasimine B (71) were isolated from the orange sponge Agelas mauritiana. The UV spectrum of agelasimine A (70), C,7H,,N,0, [a], +2.3" (CH,OH), showed maxima at 209 (E 7911), 227 (E lO,OOO), and 285 nm (E 10,277), characteristic of an adenine-type molecule. The IR spectrum of the compound showed a strong absorption at 1642 cm-' characteristic of a C=N group. The 'H-NMR spectrum (400 MHz, CDCl,) of 70 exhibited two N-methyl singlets at 6 3.22 and 3.66 and two singlets for the aromatic
264
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
protons at 6 7.50 and 7.65. These signals account for the eight protons present in the heterocyclic nucleus, a dimethyladenine derivative. The mass fragmentation pattern revealed that 70 fragments into two different portions, a nitrogen-containing heterocyclic nucleus (C,H,N,) and an oxygen-containing hydrocarbon portion (C,,H,,O). The major fragmentation is presented around structure 70. The partial I3C-NMR assignments (100 MHz, CDCI,) are also summarized around structure 70. 17.4 20
118.1
.2
..
', OH
m / z 162
I 3 4 . iEH3
70
+
Agelasimine B (71), C2,H,5N,0, [a],, 2.46"(CH,OH), showed distinct spectral similarities with agelasimine A. Analysis of the mass fragmentation patterns showed that 71 also consists of two portions, a heterocyclic nucleus (C,H,,N,) and a hydrocarbon portion (C,,H,,O). Inspection of the mass spectrum as well as the 'H- and ',C-NMR spectra indicated that the C,,H,,O portion of 71 was similar to the diterpene portion of agelasimine A (70). The IR spectrum of 71 displayed absorptions at 3400-3300 cm-' 17. I
71
3.
PURINE ALKALOIDS
265
(OH and/or NH) and also exhibited a C=N absorption at 1619 cm-'. Two exchangeable protons (OH at 6 1.20 and N H at 6 5.30) were detected in the 'H-NMR spectrum. Two methyl singlets were present at 6 2.90 and 3.02. The presence of only one aromatic proton at 6 7.26 as well as a singlet at 6 4.17 for two hydrogens indicated the difference in the heterocyclic portion of 70 and 71, leading to structure 71 for agelasimine B (176).
K. CAISSARONE Caissarone (72), a novel purine derivative, was isolated from the sea anemone Bunodosoma caissarum. The substance, C,H, 'N,O, mp 285290°C, showed absorptions in the UV spectrum at 228 (E 21,600) and 302 nm (E 17,710). Caissarone hydrochloride possessed IR absorption bands at 3450 (N-H), 3200 (O-H), 1680 (imidic carbonyl and C=N), and 1610 cm-' ( C S ) . The 'H-NMR spectrum (360 MHz, D,O) showed a methine singlet at 6 8.20, characteristic for the proton at C-2 or C-6 of the pyrimidine ring or at C-8 of the imidazole ring. The 3H singlets at 6 3.17, 3.74, and 4.20 corresponded to the the presence of three N-methyl groups. The "C-NMR spectrum recorded in D,O (60 MHz) revealed the presence of two N - C H , groups along with an N+--CH, group; the assignments to various carbons are presented around structure 72. The mass spectrum showed the molecular ion at mlz 193. Structure 72 was established by single-crystal X-ray diffraction analysis (177).
CH I
28.e3
b 3
30.6*
72
L. N6-ACETYL-6-IMINO-1,9-DIMETHYL-8-OXOPURINE N6-Acetyl-6-imino- I ,9-dimethyl-8-oxopurine (73) was isolated from the sponge Hymeniacidon sanguinea after acetylation of the crude mixture.
266
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
The compound, C,H,,N,O,, mp 245"C, showed UV absorptions at 237 (E 16,500) and 326 nm (E I5,OOO). The IR spectrum included bands at 1730 cm-', attributable to a carbonyl group in the purine skeleton, and at 1645 cm-', arising from the carbonyl group of the acetyl substituent. The 'HNMR spectrum (100 MHz, CDCl,) is in accordance with the depicted structure (73),showing singlets at 6 8.10 (H-2), 3.75 (N-CH,), 3.35 ( N CH,), and 2.22 (CH,CO). X-Ray analysis of 73 established that the compound has a purine skeleton with an unusual 0x0 function at position 8 (278). Compound 73 and its deacetyl parent base 74 were synthesized by Fuji et ul. The UV spectrum of the free base showed maxima at 220 (E 24,500) and 285 nm (E 12,000) (179).
73
R=COCH3
74
R=H
M. SPONGOPURINE I-Methyladenine (spongopurine) (79, C,H,N,, was isolated from the English channel sponge Hymeniucidon sunguinea Grant and from Geodiu gigas along with its N6-acetyl derivative (76).The 'H-NMR spectrum (100 RNH
75
R=H
76
R=COCH3
3. PURINE ALKALOIDS
267
MHz, DMSO-d,) of the Nb-acetyl derivative showed two three-proton singlets at 6 2.1 and 3.0, which were assigned to the Nb-acetyl methyl and N-1 methyl groups. Two downfield singlets at 6 8.45 and 8.60 were due to C-2 and C-8 aromatic protons. The mass spectrum showed the molecular ion at mlz 191, whereas the base peak at mlz 176 was due to loss of the methyl group from M'. Another peak at mlz 149 represented loss of the acetyl group from M' (178,180). N. HERBIPOLINE Herbipoline (77), C,H,N,O, mp 315"C, was extracted from the giant sponge Geodia gigas. Structure 77 was established by chemical degradation (181).
77
VII. Nucleoside Antibiotics and Related Compounds from Microorganisms
A number of glycosylpurines have been isolated from microorganisms, many of which proved to have substantial biological activity (182). Synthesis of these C-nucleosides has also attracted much attention because of the unique structures of the C-glycosylated heterocycles and the interesting antibiotic, antiviral, and antitumor activities which have led to their being candidates for clinical studies. Puromycin (stylomycin or achromycin) (78), C,,N,,N,05, isolated from Streptomyces alboniger, has been extensively studied as an inhibitor of protein biosynthesis in both bacterial and mammalian cells (183,184). Nucleocidin (79), C,,H,,FN,O,S, which contains the first fluorosugar to be obtained from a natural source (S.clavus), is a more potent inhibitor of protein synthesis in vivo than puromycin (78) (185,186). Nebularine
268 H3C\
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
N
y C H 3
$p)
HoH2d N
H
r H2N
C"
OH
4H
H2NS020H2C
G
F
HO
78
1
I
OH
79
(nebuline) (80,) C,,H,2N,0,, was isolated from the mushroom Agaricus (Clitocybe) nebularis and from S . yokosukanensis (187,188). It has some activity against tumor cells as well as some antibacterial action, and it has been synthesized (189,190). The carbocyclic nucleoside analog aristeromycin (81), C,,H15N50,, was isolated from Streptomyces citricolor and Actinoplanes sp. (191-196) and has antimicrobial activity. Several syntheses of aristeromycin have been reported (192-296). A closely related compound, aristeromycin M (82), C,,H,,N,O,, was also isolated from the same source (197). The 4',5'-dehydro derivative of 81, namely, neplanocin A (83) (NPC-A), was isolated from Actinoplanacea ampullariella (198) and Ampullariella regularis (199-201). It exhibited antitumor as well as antiviral activity and has been
3.
PURINE ALKALOIDS
269
4T) HoH2JH
OH OH
81
80
H3cdH ""'ld H
HO
82
OH
83
synthesized (200-204). There is great interest in neoplanocin A (83) as a clinical candidate. A series of structurally related nucleoside antibiotics, neplanocin B (& CllH13NS04r I), neplanocin C (85), ClIH,,N,04,neplanocin D (86), C,,H,,N,O,, and neplanocin F (87),C,,H,,N,O,, were also isolated from Ampullariella regularis (205).A nucleoside purine, cordy-
270
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
H6 84
cepin (88), C,,H,,N,O,, was isolated from Cordyceps rnilitaris and Aspergillus nidulans and later synthesized (206-208); it is a strong inhibitor of RNA synthesis and shows cytostatic activity.
86
87
88
The antibiotic amipurimycin (89), C,,H,,N,O,, was isolated from Streptornyces novoguineensis (209), whereas the purine nucleoside antibiotic AT-265 (90), C,,H,,N,O,SCI, was isolated from S. rishiriensis (210). A number of terpenoidal purine antibiotics have been isolated from Strepto-
27 1
3. PURINE ALKALOIDS
P2
QJ
H2N A" ?)
c1
-N
H
H
NH2
HO
k20H
OH
90
89
myces saganonensis (211). These are herbicidin A (91), C,,H,,N,O, ,, herbicidin B (92), C,,H,,N,O, (212), herbicidin C (93), C,,H,,N,O,, herbicidin E (94), C,,H,,N,O,,, (213, herbicidin F ( 9 3 , C2,H2,N5010,and herbicidin G (96), C,,H,,N,O,, (214). These compounds showed pro-
272
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
nounced herbicidal activity. Ascamycin (97), C,,H,,N,O,SCI, isolated from some Streptomyces species (215), showed considerable antibiotic activity. It is an alanyl derivative of AT-265 and has been synthesized (216). The antifungal nucleoside purine chryscandin (98), C,,H,,N,O,, was obtained from Chrysosporium pannorum and later synthesized (217,218).
c1
I
co I I
OH
OH
97
98
Guanine 7-oxide (99), C,H,N,O,, an antibiotic isolated from some Streptomyces species, exhibits antitumor activity (219-222). The closely related 7-hydroxyguanine (100) was obtained from S . purpurascens (222).
99
100
3.
PURINE ALKALOIDS
273
The antibiotic A-201A (IOI), C,,H,,N,O,,, ( 2 2 3 , antibiotic A-201C (102), C,,H,,N,015, antibiotic A-210D (103), C2sH3,N,0,0, and antibiotic A-210E (104), C,,H,,N,O,,, were obtained from Streptomyces capreolus (224). Griseolic acid (IOS), C,,H,,N,O,, was isolated from Streptomyces griseoaurantiucus (225). Oxetanocin (106), C,,H,,O,N,, isolated from Bacillus megaterium (226), has an interesting sugar ring attached to the purine nucleus. The structure was determined by X-ray crystallography, and the compound was later synthesized (227,228). Exotoxin (107), isolated from Bacillus thuringiensis (229), has been synthesized by the same group (230). Sinefungin (108), C,,H,,N,O,, isolated from S. griseolus and S . incarnatus, showed activity against plant fungal diseases. It also has antiviral properties (231). Adenomycin (109), C,,H,,N,O,,S, was reported from Streptomyces hygroscopicus and S . griseofluvus. Adenomycin (109) is active against gram-positive and gram-negative bacteria and tumors (232). Septacidin (110), C,oH,,N,O,, was isolated from Streptomycesfimbriatus and shows activity against fungi and tumors (233).
101
102
0
103 214
W20H OCH
0
I
H3c0@cH2 H
104
H
H3C0
OH
I
105
275
106
CHz OH
HO-C 0-C-H
COOH
H
108
H
*HOH2 9H H03S0
109
I
I
107
H2*
I -H
6H
OH
3.
277
PURINE ALKALOIDS
Psicofuranine (or angustmycine) (lll),CIIH,,N,O,,was isolated from Streptomyces hygroscopicus (234) and Micrornonospora echinospora (235). Another ketohexose nucleoside, decoyinine or angustmycin A (112), C,,HI3N,O,, was also isolated from S. hygroscopicus (236). Compound 112 shows antibacterial and antitumor activity, and its synthesis has been reported (237).
N
N
HOH2 C
I
H2c-iY CH2 OH
H G OH ! ! H 2 0 H
111
bH
OH
112
3'-Amino-3'-deoxyadenosine(113), C,,HI,N,03, was found in culture filtrates of Helminthosporium sp., Cordyceps rnilitaris, and Aspergillus nidulans; it has antitumor and antimitotic activity (238). 3'-Acetamido-3'-
278
A’ITA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
deoxyadenosine (114), C,,H,,N,O,, was also found in culture filtrates of Helminthosporium sp. along with 3’-amino-3’-deoxyadenosine(113) (239). Actinomadura sp. produced a nucleoside antibiotic that inhibits several strains of Mycoplasma and shows antitumor properties. Its structure was established as 2’-amino-2’-deoxyadenosine (115), C,,,H,,N,O, (240).
113
114
115
Homocitrullylaminoadenosine (116), CI7H2,N9O5,was isolated from culture filtrates of mycelia of Cordyceps militaris. It exhibits inhibition of poly (U)-directed polyphenylalanine synthesis. Lysylaminoadenosine (117), C,,N,,N,O,, a nucleoside antibiotic, was also obtained from mycelia of Cordyceps militaris (241).Another nucleoside antibiotic, 9-(p-~-ribopyranosy1)hypoxanthine (118), C,,H,,N,O,, was isolated from Streptomyces antibioticus (242) along with 9-p-~-arabinofuranosyladenine (vidarabine). 2-Chloroadenosine (119), C,,H,2N50,Cl, was isolated from Streptomyces rishiriensis. 2-Chloroadenosine (119) is weakly active against gram-positive and gram-negative bacteria, and it is also a blood platelet aggregation inhibitor (243,244). The nucleoside antibiotic adenylosuccinic acid (120), C,,H,,N,OI,P, was isolated from mycelia of Penicillium chrysogenum and Fusarium nivale (245).Miharamycins A (121) and B (122) are antibiotics produced by Streptomyces miharaensis SF-489 and are active against rice blast disease. They have been shown to be novel l-substituted 2-aminopurine nucleoside antibiotics (246,247). Several other compounds such as kinetin
279
3. PURINE ALKALOIDS
COOH I
I I
H
0
3,
bC~ C H ~ C O O H I
g t J ANO N)
N
Hq I
c1
I
HO
118
119
120
280
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
COOH
NH2
121
R=OH
122
R=H
HO'
(6-furfurylaminopurine) and 6-succinoaminopurine have also been isolated from natural sources. VIII. Synthesis of Purine Bases
Efforts to synthesize the purine alkaloids began just after the characterization of the pharmacologically important caffeine and derivatives. A considerable amount of work was subsequently done on interconversions of different purine derivatives. The leading references for the earlier synthetic work may be obtained from reviews published in 1960 and 1971 (248-250). The major contributions, which have been made since 1960, relate to new and improved routes to the synthesis of naturally occurring purine bases. The first part of this section briefly reviews some important purine syntheses. The next part presents some of the synthetic efforts aimed at naturally occurring purines. A comprehensive account of the enormous amount of work that has been done in the synthesis of various purine derivatives is beyond the scope of this chapter. Experimental details and additional references concerning the synthesis of other purine derivatives can be obtained from reviews published in this area (24,22-26,248-251). Methods for the synthesis of purine bases may be conveniently separated into two steps: (A) synthesis of the purine nucleus and (B) condensation of the purine nucleus with a suitable unit to afford the actual purine base.
A. SYNTHETIC APPROACHES TO THE PURINE NUCLEUS Two commonly used strategies for the synthesis of purines are ( I ) synthesis from pyrimidines by completion of the imidazole ring and (2) synthesis from imidazoles by completion of the pyrimidine ring. Salient features of these methods aiming at the synthesis of some common purine
28 1
3. PURINE ALKALOIDS 6
7
6
N
N
9
123 SCHEME 2
bases such as xanthines, guanines, and adenines are briefly presented below. 1. Synthesis from Pyrimidines
The most widely used general synthetic route to purines involves the addition of an imidazole ring to an appropriate pyrimidine. This procedure dominated the early literature because of the relative ease of synthesis of the requisite pyrimidines compared with the lack, until recently, of useful routes to imidazole precursors. The pyrimidine moiety (123) in such an approach includes substituents at the eventual, 1, 2 , 3, and 6 positions in the resulting purine, whereas the added imidazole ring incorporates the C-8 substituents. Substituents at N-7 o r N-9 could come from either moiety, but they are usually incorporated in the pyrimidine, according to the precise intermediates used (Scheme 2 ) . The Traube method is considered to be the first and most important route for the synthesis of the purine ring. It involves the condensation of a 4,5-diaminopyrimidine with any suitable cyclization reagent such as formic acid, the purpose of which is to supply a one-carbon fragment to bridge the two pyrimidine amino nitrogen atoms. Guanine (3) can be (124) synthesized by heating 6-0~0-2,4,5-triamino-l,6-dihydropyrimidine with formic acid via the N-formyl intermediate (125) (Scheme 3) (252).
124
125
SCHEME 3
3
282
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
126
1
127
CH2 R 128
SCHEME 4
Reduction of 126 with LiAlH, affords the alkylaminopyrimidine (127), cyclization of which with formic acid then produces a 7-alkylpurine (or N’alkyladenine) (128) (Scheme 4) (253). The ease of cyclization of the 4-amino-5-formamidopyrimidines has been associated with their acidity. Thus, the weakly acidic methylated pyrimidine derivative 129 cyclized to caffeine (4) (Scheme 5) (253,
4
129
SCHEME 5
3.
283
PURINE ALKALOIDS
f5
H
H
130
1 SCHEME 6
whereas the much more strongly acidic 4-amino-5-formamido-2,6-dioxy1,6-dihydropyrimidine (130) was converted to xanthine only by heating its sodium salt to 220°C (Scheme 6) ( 2 5 3 ~ ) . Later it was shown that formamide alone is superior to formic acid as a formylating agent, and its effectiveness is improved by the presence of an acid catalyst. It tends to give better yields than formic acid, as in the synthesis of adenine (2) (92 versus 62% yield using formic acid) (254). However, the high temperatures normally associated with reactions in boiling formamide (160-180°C) may displace any acyl groups attached to the aminopyrimidines. Thus, reaction of the acetyl derivative 131 with formamide gave xanthine (1) (Scheme 7) and not 8-methylxanthine as might have been expected (255,256). Both formic acid and formamide were found to be unsatisfactory as cyclizing agents when the pyrimidine contained labile, easily hydrolyzed, or acid-sensitive groups such as halogens or sugars. For example, reaction of 4,5-diamino-6-chloropyrimidinewith formic acid furnished hypoxanthine (52) (257). In such cases, one-carbon transfer agents have been developed that react with diaminopyrimidines under milder conditions
H
1
131 SCHEME 7
284
ATTA-UR-RAHMAN A N D MUHAMMAD lQBAL CHOUDHARY
132 SCHEME 8
than formic acid or formamide. These include dithioformic acid, which was introduced during earlier investigations into the synthesis of purine nucleosides. Thioformarnidopyrimidines, produced in aqueous solution with this reagent, may be cyclized by heating in solvents such as pyridine, as in the formation of 2-methyladenine (132)(Scheme 8) (258). Another cyclizing agent is the Vilsmeier-Haack reagent prepared from dimethyl-
H
S
N
A IN '
NH2
H
133
52 SCHEME
9
y -C-H O
3. PURINE ALKALOIDS
285
formamide (DMF) and phosphoryl chloride; this reagent permits the formylation and cyclization at very low temperatures (259). Extensive experimentation led to the development of improved conditions for imidazole ring closure. Pyrimidine derivative 133 with a desulfurizing agent (Raney alloy containing a catalytic amount of nickel) in formic acid afforded hypoxanthine (52) in high yield (Scheme 9) (260). A minor extension of the Traube synthesis involves reduction of a 4 3 diaminopyrimidine precursor in the presence of an acylating agent such as formic acid. For example 4-amino-5-nitrosopyrimidine in 90% HCOOH/Zn gave the purine (261). Similarly, 5-amino-6-nitrosouracil yielded xanthine (1) under conditions involving the use of Ni-H,-NaOAc, H,S-HCONH,, or HCONH,-Na,S,O, (262,263).Another purine synthesis involves the treatment of 6-nitrouracil derivatives (134) with arylhydrazone to give theophylline and xanthine derivatives in good yield (Scheme 10) (264). A new unambiguous route to 9-ethylxanthine (135) has been developed which involves a mixture of formic acid and formamide as the cyclizing reagent (Scheme 1 1) (265).Treatment of 5-benzylamino- 1,3-dimethyIuracil (136) with 4-amino-6-chloro-2-methylpyridine (137) in the presence of excess N-nitrosodimethylamine gives a mixture of the dimethylaminopyrimidine (138) and 8-phenyltheophylline (139) in 16 and 84% yield, respectively (Scheme 12) (266). An alternative approach to 9-substituted 8-phenyltheophylline (140) involves the reaction of oxazolopyrimidines (141) with primary arnines (Scheme 13) (267). The facile substitution of the halogen atom in 6-amino- 1-benzyl-5-bromouracil (142) by treatment with methylamine opens a new route to 7-methylxanthine (143) (Scheme 14) (268).
134
R,
SCHEME 10. Theophylline derivative, R , = CH,.
=
CH,, Rz = H. Xanthine derivative. R ,
=
H,
z
c
z-E
m xm
9 7
0X
@a
X
8 u 7 xm
8
X
z-
X
3.
CI
0
136
m3
0
287
PURINE ALKALOIDS
137
H
+ a3
138
139
SCHEME12
Direct cyclization of 4-alkylamino-5-nitrosopyrimidines to purines has been used in recent years. For instance, benzylaminonitrosopyrimidine (144) cyclizes in hot xylene or n-butanol to afford 8-phenyltheophylline (145) (Scheme 15) (269). The vigorous conditions normally required for cyclization may be avoided by employing 0-acyl derivatives such as 146, which cyclizes in hot ethanol to give theophylline (7) (270). Similarly, Nmethylation and cyclization of the nitrosopyrimidine proceeded smoothly via the intermediate N-oxide (147) to afford caffeine (4) (Scheme 16) (272). Phenylazopyrimidines behave like the nitroso analogs; thus, heating derivative 148 produced theophylline (7) (Scheme 17).
2. Synthesis from Imidazoles The synthesis of purines from imidazoles involves the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives such as carboxamides, carboxamidines, carboxamidoximes, nitriles, and esters. The intermediates are generally the formic and carbonic acid derivatives. The conditions required are much milder than those for pyrimidine cycliza-
0
m X N d
u
0
rn
I
cr:
a" 2 - x \"'
II
c
A.
m
z
X
-8
m
i3
m
289
3. PURINE ALKALOIDS
n
I
CH3
I
I
CHZ-Ph
CH3
144
145 SCHEME 15
tions. The resultant purines may have various substituents at C-2 and C-6. Formic-acetic anhydride reacts with aminoimidazoles to give N-formyl derivatives (149), which cyclize on prolonged heating or treatment with weak base to the corresponding hypoxanthines (52) (Scheme 18) (272). Aminoimidazolenitrile (150) reacts with formamide to give adenine (2) (Scheme 19) (273). An excellent yield of adenine (2) was also obtained on heating 150 with formamidine acetate (274,275). Adenine (2) was also obtained by formylation of the aminoimidazole carboxamide 151 and cyclization of the intermediate N6-formyladenine (152) (Scheme 20) (276). Oxopurines such as xanthine (1) can be prepared by reacting diethyl carbonate with 5-aminoimidazole-4-carboxamidein refluxing ethanolic sodium ethoxide (277). amino ester 153, on reaction in hot pyridine with urea, also gave xanthine (1) (Scheme 21) (278). I-Methyl-4-methylaminoimidazole-N5-methylcarboxamide(154) reacts with urea at 140°C in the presence of HCI to give ureidoimidazole 155, which can be cyclized to
146
?
4
R = H , R =H 1 2 R1=H, R2=m 3
SCHEME 16
147
1y2* CI
H3C
c1
0
N -CH
I I
I H
0
H
heat
L
I
3
7
cH3
m3
c1
148
SCHEME 17
I
H
OHC
52
149
SCHEME 18
N S C
HCONH2
H2N
150
2
H
SCHEME 19 NHCHO
IN) i HCO Ac
H2N-
H2N
Hc%) I
I
H
151
H
152 SCHEME 20
29 1
3. PURINE ALKALOIDS
153
1 SCHEME 21
theobromine (6) with hot acid (Scheme 21) (279). Potassium cyanate can sometimes replace urea, and with this reagent 154 was readily converted to caffeine (4) (Scheme 22) (279). The more reactive alkyl or aryl chloroformates can be used to produce 2-oxopurines under milder conditions than those obtained in urea fusions.
-H3C-HN
H 3 c \ N k : A
N
0
-
-C
H3C-
urea
HN
-
I 0
cH3 4
cH3
155
154
1
-CH3NH2
HC1
1 k3
6
SCHEME 22
292
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
n
1 5 i-'i
H2N H5C 20-
-c
heat
N H
-
0
HN
A 5 N
I
H
H
156
1
SCHEME 23
For instance, xanthine (1) was prepared by reaction of aminoimidazolecarboxamide (156) and ethyl chloroformate at 0°C followed by cyclization of the intermediate urethane, either by fusion or by heating with aqueous ammonia (Scheme 23) (280). An alternative route to xanthine (1)involves prior reaction with phenylthiochloroformate (281). In some cases, cyclization to the 2-oxopurine may occur very readily as with the trimethylimidazole 154, which on treatment with ethyl chloroformate in aqueous sodium hydrogen carbonate readily furnished caffeine (4) (Scheme 24) (281). B. SYNTHESIS OF SOME INDIVIDUALPURINE BASES 1 . Eritadenine Early syntheses of eritadenine (8) were carried out by imidazole ring closure. The overall yields were low, primarily owing to epimerization at the N-9 side chain (70,282). A typical synthesis (Scheme 25) involves the (157) with potassium reaction of 2,3-O-isopropylidene-~-erythronolactone phthalide to give the acid (I%), which is condensed with 4-amino-6-chlo-
CH 3
154
4
SCHEME24
293
3. PURINE ALKALOIDS
.+-@0
Hydrazine hydrate
157 N
F
8,
0
2 CH2-NH
I
C1
I 0-
CH
LOOH
I
158 0
II
HCOOH
I
I AOOH
160 0-
CH
I
f
COOH
aq. NaOH
HO-
CH
HO-
CX
I
LOOH
SCHEME25
294
AlTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
ro-5-nitropyridine to give the nitro acid (159). Catalytic hydrogenation and treatment with formic acid afforded the formyl amino acid (160), which cyclized to eritadenine (8) under basic conditions (71). The same group later described the synthesis of L-threo-entadenine (283). Further attempts to synthesize eritadenine involved the condensation of purines with 2,3-O-protected D-erythronolactone (284).The reaction of adenine (2) with methyl-2,3-0-isopropylidene-5-O-tosyl-f3-~ribofuranoside (161) afforded eritadenine (8) in 90% yield through the intermediate
Tsv3W' adenine
x
N a , DMF
H
161
O K
&> I
N
HHO-
% I CH I CH
I
COOH 162
8
SCHEME26
3. PURINE ALKALOIDS
295
“reversed” nucleoside (162) (Scheme 26) (72,285,286). Successful synthetic approaches to eritadenine (8) were also reported that involve the condensation of 2(R),3(R) 0-protected dihydroxybutyrolactone (163) with sodium salts of various purines (Scheme 27) (287). Seki and co-workers reported a novel synthesis of eritadenine (8) by direct condensation of (164) under baadenine (2) and 2,3-O-isopropylidene-~-erythronolactone sic conditions (Scheme 28) (288). 2. Deoxyeritadenine Deoxyeritadenine (12) has been obtained from the condensation of 4chloro-5-nitropyrimidine with four-carbon amino acid 166. The synthesis
X
+ N+JNw h I H 2 X=NH2
a
H O C 6 d
H
I H O C C 4
H
X = N H ~ , Z=H
SCHEME27
296
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
i ) N a Z -C03-DMF
c reflux i i ) 10% AcOH
+
m2
x0-r I
2
164
0-
CH
I
COOH
N
+
I
I
CHZ
I I
HO-
H
F"2
CH HO-CH HO-
I
CH
I
COOH
COOH
8
( m i n o r product)
SCHEME28
involves formation of the imidazole ring with the four-carbon substituent at the right place. Treatment of 2-hydroxybutyrolactone (165) with potassium phthalimide in DMF gave the acid, C,,H,,NO,. Resolution of the acid was accomplished by conversion to its f-amphetamine salt. Hydrolysis of the optically pure salt yielded the amino acid, C,H,O,N (166), which was condensed with 4-chloro-5-nitropyrimidine to yield deoxyeritadenine (12) after cyclization (Scheme 29) (75). Similarly, 3-(6-amino-9H-purine9-y1)propionic acid (14) was synthesized by reacting adenine (2) with ethyl acrylate (167) (Scheme 30) (75).
297
3. PURINE ALKALOIDS
165 &(OH)
I
HC1
I 1-Amphetamine
i""
NH
CH"
i"
HO-CH
a 2
HO -CH
I
I
HOOC
a 2
I
$z
,,P HOOC
12
SCHEME29
3. Zeatins
The synthesis of trans-zeatin (16) is of continuing interest to organic and agricultural chemists not only because of the challenge of constructing the small but highly functionalized key intermediate 168 (Scheme 3 I ) , but also because of the potential importance of the plant hormones in
Nky
-k H2C=HC
h
-C-
0C2H5
N H
167
2
c"'
COOH 14
SCHEME30
16 and 21
171
168
SCHEME31
3.
299
PURINE ALKALOIDS
agricultural and biological research. The overall synthesis comprises two steps. The first step involves the synthesis of the highly functionalized intermediate 168 (Camino-2-methylbut-trans-Zen- 1-01), which is condensed with 6-chloropurine in the second step (91,289-291). Another approach involves oxidation of isopentenyl phthalimide (169) with selenium dioxide to produce acetoxybutenylphthalimide (170), which on hydrolysis gives aminobutenol (171). Condensation of 171 with 6-chloropurine afforded cis- (21) and trans-zeatin (16) (Scheme 31) (292). In another synthesis, the allylic oxidized species 172 was used for the synthesis of aminobutenol(168), which on reaction with 6-chloropurine yielded a mixture of cis and trans isomers of zeatin, from which the latter could be separated in 51% yield (Scheme 32). Most of the above-mentioned syntheses involve many steps, provide low yields, and require difficult separations of the geometric isomers (293,294). Leonard’s approach involves the synthesis of 174 through Diels-Alder reaction of 1-chloro-I-nitrosocyclohexane (173) with isoprene followed by
i) AcOH/Ac,O
H*C
/
“HZ
HOW. C
6‘
---2
-
168
172
H
16 and 21
SCHEME32
300
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
EtOH
‘gH6
-h O
- NHB c1-
O
=
6
KOH
173
Zn AcOH
h 0-N
H
H2
1
174
6-Ch l o r o p u r i n e
21 SCHEME 33
30 I
3. PURINE ALKALOIDS
reduction and condensation with 6-chloropurine to give predominantly cis-zeatin (21) (Scheme 33) (105). An efficient synthesis of trans-zeatin (16) proceeds with the Gabriel synthesis to give a mixture of cis and trans isomers of 175. Separation at this stage ensures the formation of pure cisor trans-zeatin after condensation (Scheme 34) (295). Another approach to trans-zeatin (16) involves a Mannich reaction to convert propargylic alcohol (176) to the corresponding dialkylamino-4-butyne-2-ol (177). which after anti addition and acetylation gives the tetrasubstituted alkene (178). trans-Zeatin (16) is produced in high yield after condensation with 6-chloropurine (Scheme 35) (296).
H3C'
175
i )Separa1ii)g;t ion
1)
NaOCH3-CH30H
-
CH NH i i ) N2H4-EtOH " OH 3 H C Z C H H 2
168
2
SCHEME 34
302
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
20
HO-
cH2-C
E C H
176
H -O HNBu 2
-CH2-
i )CH3MgC1
C
C-
CH2-NBu
177
NBu2
I
x
HOH2C
H3C
H2C
16
SCHEME35
An efficient synthesis involves the condensation of pyruvaldehyde dimethylacetal (179) with excess acetonitrile in the presence of a strong base to give an isomeric mixture of the corresponding acetal of 3-formylbut-2-enenitrile (180) ( E : Z = 88 : 12). Hydrolysis and reduction of the E isomer gave an intermediate (181). 181, after further reduction, forms 168, which can be condensed with 6-chloropurine to give trans-zeatin (16) and (+)-dihydrozeatin (22) in good yield (Scheme 36) (111). 4. Discadenine
The N3-(~-amino acid) substituent of ( +)-discadenine (27) was synthesized through bromine-induced ring opening of L-a-phthalimido-6-butyro-
3.
303
PURINE ALKALOIDS (CH30)2HZC
(CH30)2CHCOCH3
+
NaOCH3 CH3CN
1
\ /c=M--CN
H3C
179
180
181
1
LiA1H4
SCHEME36
lactone (182) to give L-4-bromo-2-phthalimidobutanoicacid ethylester (183). Compound 183 was then reacted with iV-(3,3-dimethylallylamino)purine to yield L-discadenine (27) in high yield (Scheme 37) (225). 5. 6-(o-Hydroxybenzylamino)-9-~-~-ribofuranosylpurine
6-(o-Hydroxybenzylamino)-9-~-~-ribofuranosylpurine (29) was prepared by reaction of 6-chloropurine-9-P-~-ribosidewith ortho-hydroxybenzylamine (Scheme 38) (129).
304
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
182
183
( i i ) NH2-NH2/CH30H ( i ii
E tOH-NaOH
NH-CH2CH=C( C H 3 ) 2
I
27
SCHEME 37
IX. Spectral Properties of Purine Alkaloids
A. ULTRAVIOLET SPECTROSCOPY
UV absorption spectroscopy has been used in structural and tautomeric studies of different purine bases. A considerable amount of work has been reported, and many reviews have been published on the UV absorption properties of purine derivatives (297-300). The UV spectra of purines are broadly categorized as having three groups of bands, each resulting from a specific type of transition. (1) At
305
3. PURINE ALKALOIDS
c1
+
HO--
CH2
Ft
H OH OH 29
SCHEME 38
longer wavelengths (300 nm and above), a weak band (E 1000) arises from an n + T* forbidden transition, which shows a bathochromic shift in passing from polar to nonpolar solvents. These transitions are probably localized at N-3 (301,302).(2) The second group of transitions, which absorb in the range of 230-300 nm, are T + r * transitions of lower energy. The transition produces a strong band with a relatively high extinction coefficient (E 20,000), and hypsochromic shifts are observed in passing to less polar solvents. This transition may be localized toward C-6. (3) The third group of transitions are 7~ + r * transitions of higher energy, which occur below 230 nm. The extinction coefficient is high (E 20,000). The positions and intensities of the absorption peaks in the U V spectra of purines are greatly dependent on pH and polarity of the solvents. This results from lactam and lactim tautomerism in the purine nucleus. The positions and nature of the substituents also cause significant effects. The positions of substituents affect the spectra by increasing the intensity and causing bathochromic shifts, usually in the order 6 < 8 < 2, and also by increasing hypsochromic effects, in the order 2 > 6 > 8, for the longer wavelength band. Polar substituents cause marked effects when at the 2 position, while C-8 and C-6 substituents have progressively less effect. The effects of substituents in polysubstituted derivatives are, however,
306
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
TABLE I UV ABSORPTION MAXIMA OF PURINES
,A
Purine Purine Guanine Adenine Xanthine H ypoxanthine Uric acid Kinetin Xanthosine Caffeine Theophylline Theobromine Paraxanthine Isocaffeine Tricanthine Guanosine Isoguanosine Crotonoside Herbipoline trans-Zeatin
nm
(E x
w3)
260 (6.2) 263 (7.9) 249, 276 (11.4, 7.4) 246, 276 (10.7, 8.2) 263 (13.2) 261 (13.4) 231, 260 (6.4, 9.2) 246 (10.3) 248 (10.5) 249 (5.2) 231, 283 (8.5, 11.5) 274 (16.9) 273 (17.4) 235, 263 (8.4, 9.0) 249, 278 (10.2, 8.9) 272 (10.5) 271 (10.2) 271 (12.0) 271 (10.5) 234, 273 (7.1, 10.2) 268 (10.2) 233, 288 (5.0, 8.7) 237, 268 (9.8, 10.0) 274 (17.5) 273 (13.8) 257 (12.2) 253 (13.7) 240, 286 (7.8, 7.9) 235, 284 (5.3, 12.3) 235, 283 (6.1, 12.7) 247, 293 (8.9, 11. I ) 253, 279 (11.8, 7.6) 252, 282 (5.9, 8.3) 207, 275 (14.5, 14.6)
PH 0.3 5.7 1
7 2 7 0.8 7 0.7 5.2 2.3 1
13 2 8 6 7 11
7 13 6 11
6 1
7 1
6 7 11.1
1.3 6 4 9.5 6
not additive. UV absorption maxima of some important naturally occurring purines are summarized in Table I.
B. INFRAREDSPECTROSCOPY IR spectroscopy provides valuable information about the structures of purines (303-305). The fundamental stretching vibrations of the OH, NH,
3. PURINE ALKALOIDS
307
CH, and SH groups occur in the region 3600-2000 cm-'. The solid-state spectra for oxohydropurines do not show strong absorptions in the OH (3600-3590 cm- ') or hydrogen-bonded OH (3600-3200 cm- ') regions, implying that they exist in the 0x0 not in the hydroxy forms. The aminopurines show bands in the region 3400-3100 cm-' with a strong characteristic band at 3300 cm-'. The band position for stretching modes of amino groups and their variation with the point of attachment to the purine nucleus have been tabulated by Katritzky and Ambler (306). The N H stretching vibration of purines is broad (3000-2500 cm-'), and similar broad bands occur in the oxopurines centered at 3100 cm-'. C-2-H, C-CH, and C-8-N stretching frequencies for several purines including purine, adenine, hypoxanthine, and guanine occur at 3023, 3060, and 3098 cm-', respectively, and weak bands may be revealed in aminopurines by conversion of NH to ND. Absorptions in the region 2000-1500 cm-' would be expected to arise from skeletal vibrations of the purine nucleus together with, for example, deformation modes of exocyclic amino groups and stretching modes of carbonyl groups. The carbonyl stretching absorption bands in oxohydropurines are found in the region 1700-1620 cm-', whereas the C=N and C=C bands occur at about 1600 cm-'. Addition of a primary amino group to the purine nucleus gives rise to a band at 1670 cm-' mainly owing to the inplane deformation mode of this group. Thus, the solid-state IR spectrum of guanine shows bands at 1701,1681, and 1618 cm-'; the first band represents the carbonyl group stretching vibrations, and the last two are due to the NH, deformations. Purines show three sharp bands at 1100, 804, and 790 cm-' that after deuteration at C-6 are replaced by two bands at 770 and 760 cm-'. The first three bands are therefore assigned to C-6-H deformation motions while the latter pair are due to C-6-D deformations. Absorption bands in the ranges 980-900 and 890-860 cm-' have been attributed to the purine ring system. The purine nucleosides show absorptions with slightly different intensities as compared to those in the spectra of the corresponding aglycones. The carbohydrate portions of the molecules give strong, broad OH stretching bands at 3400 cm-', as expected, which are normally distinguishable from the NH, stretching bands. C. NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY Initially, molecular spectroscopy was used for correlating the theoretical calculation of charge densities and related physical properties of purine ring atoms with the order and position of the resonance peaks. Subse-
308
ATTA-UR-RAHMAN AND MUHAMMAD IQBAL CHOUDHARY
quently, it has been employed more toward resolution of structures and for studying tautomerism in different purines. Recent developments in I3C- and "N-NMR spectral techniques have resulted in a greater understanding of the molecules. Many reviews and papers have been published dealing with experimental and interpretational aspects of purine N M R spectroscopy (307-3f3). 1. 'H-NMR Spectroscopy
'H-NMR spectra of purines in neutral aqueous solutions show three sharp signals for the C-2, C-6, and C-8 protons. Assignment of these protons may be made by studying the 'H-NMR spectra of various specific deuterated purine derivatives. The singlet for H-8 appears at the highest field, followed by H-2 and H-6. This order is maintained in nonaqueous solvents although all three singlets are shifted downfield. An alternative to deuterium exchange involves measurements on purines in which each CH is systematically replaced by a methyl group, with the Cmethyl groups having little effect on the chemical shifts of the remaining protons. In both 2- and 6-substituted purines, the chemical shift of the H-8 singlet depends on the nature of the substituents. In the case of nucleosides, the ribofuranosyl group exerts a deshielding effect on the adjacent C-8 proton. As in adenine, singlets for H-2 and H-8 appear at 6 8. I I and 8.14, while these protons resonate at 6 8.27 and 8.45, respectively, in case of adenosine. the effect on H-8 being more pronounced. The 'H-NMR spectra of purines and purine nucleosides are dependent on pH, solvent, temperature, and added chemicals. As in the spectra of neutral molecules, the spectra of anionic purines show higher field shifts of C-2, C-6, and C-8 protons. In the spectra of cationic materials, the resonance peaks appear in the same order as in the neutral molecule but are moved downfield. The 'H-NMR spectra of purine solutions at low pH show considerable downfield shifts of the H-6 and H-8 protons. The spectra of purines in TFA solution show broadening of the three resonance peaks as the pH decreases. The addition of aniline to the aqueous solution causes the proton signals to be shifted upfield, presumably owing to weak complex formation. The chemical shift of H-8 is also affected by the choice of solvent, owing to hydrogen bonding between t h e H-8 proton and the solvent molecule, the degree of which varies according to the strength of the proton acceptor groups present in the solvent. 'H-NMR spectral data of some simple purines are presented in Table 11
(3f4).
3.
309
PURINE ALKALOIDS
TABLE 11 'H-NMR SPECTROSCOPY OF PURINES Chemical shift ( 8 ) Compound
Solvent
I-CH,
H-2
3-CH3
H-6
7-CH3
H-8
Purine 6-Dimethylpurine Xanthine H ypoxanthine Caffeine
DMSOd, DMSOd6 DMSOd, DMSOd, DzO TFAd, PhNOZd,
-
8.99 8.20 8.12 -
-
9.19 -
-
8.68 8.17 7.85 7.95
Theobromine
DZO
Theophylline
TFAd, PhNO,d, D,O TFAd, PhNO,d,
U
3.59 3.23 U
-
3.65 3.27
-
-
U
3.80 3.28
-
-
-
-
3.75 3.35
-
U
-
3.86 3.45
-
-
-
7.97 a
4.33 3.82
-
4.28 3.81
-
U
U
7.88
-
7.95 a U
"Signals not observed.
2. I3C-NMR Spectroscopy 13
C-NMR spectroscopy is particularly important in the structure elucidation of purines and purine nucleosides. The chemical shifts are generally reported relative to CS,, benzene, or DMSO. The 13C-NMRspectrum of purine shows the relative positions of the carbons in the sequence C4 > C-2 > C-8 > C-6 > C-5. The assignment of the higher field chemical shift to C-5 is based on the assumption that it would have the highest Telectron density. It is interesting to compare these shifts with those in the 'H-NMR spectra in which the order is C-6 > C-2 > C-8. The I3C-NMR assignments for adenine were found to have the order of C-6 > C-2 > C4 > C-8 > C-5. The concentration dependence of the chemical shifts in aqueous solution as well as solvent effects of all eight 'H and I3C resonances of several purines have been studied (309). 3. "N-NMR Spectroscopy
Four of the nine atoms in the purine nucleus are nitrogens, which are often substituted in the various purine derivatives. I5N-NMR spectroscopy therefore plays an important role in revealing the structural properties as well as biosynthetic routes to purines. The study of 13C-''N and
310
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
TABLE 111 ''N NMR SPECTROSCOPY OF PURINES Chemical shifts (6) Compound
Solvent
N-1
N-3
N-4
N-5
Purine Adenosine Inosine Guanosine
DMSO DMSO DMSO DMSO
94.5 139.6 200.7 228.0
113.6 152.7 161.2 209.5
187.0 134.7 126.7 128.5
187.0 205.6 200.7 205.3
NH*
293.8
-
302.0
'H-"N coupling constants in "N-NMR spectra can provide valuable information about the nature and site of substitutions. It is also useful in predicting the presence of absence of complexation between the nucleoside bases and metal atoms (315).Table 111 summarizes the I5N chemical shifts of some purines and purine derivatives (313).
D. MASSSPECTROSCOPY Mass spectral studies on purine bases have provided extensive information about structures despite the low volatility of many purines. The major advantage of this technique is the small amount of sample required. The molecular ions in the mass spectra of many purines are also the ions of the highest intensity, reflecting the inherent stability of the purine ring system. The initial fragmentation takes place in the pyrimidine part of the purine system, but the fragmentation pathway depends on the nature of substituents and site of substitution. The mass spectrum of purine shows the loss of two HCN molecules derived by cleavage of the C-2-N3 and C-6-N-1 bonds. Similarly, 2-, 6-, and 8-methylpurines also produce HCN and methylcyanide, whereas adenine liberates three molecules of HCN (316,317). The most intense peak in the mass spectrum of guanine is M', which and an ion at mlz fragments to cyanamide (derived from N-l-C-2-NHJ 109 which loses CO and HCN (317). The fragmentation of oxohydropurines such as xanthine, hypoxanthine, and uric acid is very similar to that of guanine, the key route involving the elimination of HCN from N-l-C2 followed by the loss of CO and another molecule of HCN. In xanthine and uric acid, the loss of HCNO and CO is observed (317). The mass spectra of alkylxanthines, e.g., caffeine (4), theobromine (6), and theophylline (7), show intense molecular ion peaks characteristic of the highly stable purine derivatives. Initial fragmentation occurs at N-1 in
3. PURINE ALKALOIDS
31 I
all cases with the liberation of the imidazole fragment. The considerably intense peaks arise by formation of the seven-membered heteroaromatic ion, namely, the tropylium ion analog (S), which arises from the molecular ion by rearrangement of the initial degradation product [e.g., in the mass fragmentation pattern of caffeine (4)] (51). X. Biological Activity of Purine Bases
Both naturally occurring and synthetic purine bases exhibit a broad spectrum of biological activity. Xanthine derivatives show several common pharmacological properties, namely, (1) central nervous system and respiratory stimulation, (2) skeletal muscle stimulation, (3) diuresis, (4) cardiac stimulation, and ( 5 ) smooth muscle relaxation. Caffeine (4) is the major purine constituent of coffee and tea. Investigations of the biological effects of caffeine began well before isolation of the pure substance, and caffeine remains a subject of active biological research. The compound increases CNS activity, mainly affecting the cerebral cortex. It is also a respiratory stimulant and is frequently used in headache powders. Chemosterilant activity against stored-grain pests has also been reported. Theobromine (6), another xanthine derivative, is strongly diuretic and forms soluble complexes with salts of various organic acids, which aids its oral use. It is also an effective cardiac stimulant and arterial dilator. Theophylline (7), a I ,3-dimethylxanthine, is a powerful diuretic and has been used clinically for this purpose (generally as an adduct with salts of organic acids) as well as in the treatment of bronchial conditions (318,319).A large number of 7-substituted theophylline derivatives have been synthesized as a result of the observed pharmacological activity of theophylline. For example, various 7-aminoethyltheophyllinederivatives have been shown to possess spasmolytic activity similar to that of papaverine (320). Some other theophylline derivatives have been tested as potential new antiatherosclerosis agents (321). l ,7-Dimethylxanthine (paraxanthine) (53), a constituent of various animal and plant tissues, is also an efficient diuretic and, in addition, possesses antithyroid properties (322). Caffeine and related alkaloids exhibit antimitotic or cytostatic effects on human blood lymphocytes in culture. An interesting proposal has been advanced that the lack of mutagenic activity of these compounds in humans may be due to the fact that the antimitotic threshold is the same as the mutagenic threshold, thus not allowing the reproduction of the mutant cells which are produced (323). Eritadenine (S), an adenine derivative, shows significant hypocholest-
3 12
ATTA-UR-RAHMAN A N D MUHAMMAD IQBAL CHOUDHARY
erolemic activity. Several analogs of eritadenine have been synthesized and tested (37). Deoxyeritadenine (12), a naturally occurring analog of eritadenine (8), exhibits weak hypocholesterolemic activity, whereas 6amino-9H-purine-9-propionic acid (14), another constituent of Leontinus edodes, also exhibits anticholesterolemic activity (67). The cytokinins are plant growth substances that promote cell division. They are adenine derivatives, with trans-zeatin (16) being the first isolated from a natural source (Zea mays). trans-Zeatin (16) is the most effective naturally occurring plant hormone. The cis isomer of zeatin also occurs naturally but was found to be 50 times less active than the trans isomer in the standard tobacco callus bioassay (105). (S)-Dihydrozeatin (22), isolated from immature seeds of Lupinus luteus, also shows cytokinin activity (123).A synthetic adenine derivative, N6-benzyladenine, exhibits strong cytokinin activity; it has been used commercially (verdan) in minute amounts to keep vegetables green for extended periods (324). Discadenine (27) was the first recorded naturally occurring purine to contain an amino acid residue in the 3 position. The compound has pronounced activity against spore germination, and, in addition, it has cytokinin activity, showing two-thirds of the activity of kinetin at lO-’M in the standard tobacco pith test (126). 6-(0-Hydroxybenzylamino)-9-P-~ribofuranosylpurine (29) is the first naturally occurring cytokinin having an aromatic side chain (129). Saxitoxin (30), an unusual tetrahydrodiaminopurine derivative isolated from various marine dinoflagellates, is one of the most toxic, nonprotein compounds known, and its presence in shellfish has created serious health and economic problems along the North Atlantic coast (130,232). The related sulfo derivatives of hydroxysaxitoxin are relatively nontoxic but are readily hydrolyzed to toxic materials (233-236). Doridosine (49), a purine base of animal origin, shows potent muscle-relaxant activity, as well as blood pressure lowering and anti-inflamatory activities (254). Several glycosylpurines have been isolated from microorganisms and proved to have substantial biological activity (182,324).The most important is 9-(P-~-arabinofuranosyl)adenine(AraA) (66), which is a powerful antiviral and antitumor agent that is used clinically for these purposes (173). Puromycin (78) has been extensively studied as an inhibitor of protein biosynthesis in both bacterial and mammalian cells; it blocks peptide chain extension by reacting with the growing polypeptide at the peptidyltRNA site on the ribosome to produce a peptidylpuromycin derivative. Puromycin (78) is highly toxic to mammals, which restricts its clinical use (184). Homocitrullylaminoadenosine (116) and nucleocidin (79), structurally related compounds, also inhibit protein synthesis. The ketosylpurines psicofuranine (111) and decoyinine (112) both show antimicrobial activity
3.
PURINE ALKALOIDS
313
as well as activity against adenocarcinoma in rats (237). Neplanocin A (83), septacidin (110), and nebularine (80) also exhibit antitumor activity, whereas the carbocyclic nucleoside aristeromycin (81) possesses antimicrobial activity (195).
184
The role of purine alkaloids in trace-metal metabolism, disease resistance, mutagenesis, and chemotaxonomic considerations in plants has been reviewed (326). Recently, the U.S. government was reported to be assessing applications from pharmaceutical companies to make 2,3-dideoxyadenosine (DDA) (184) which is believed to be effective against the AIDS-producing virus (HIV) (327). REFERENCES I . S. W. Pelletier, in “Chemistry of the Alkaloids” (S. W. Pelletier, ed.), p. 2. Van Nostrand-Reinhold, New York, 1970. 2. S. W. Pelletier, in “Alkaloids: Chemical and Biological Perspectives” (S. W. Pelletier, ed.), p. 6. Wiley (Interscience), New York, 1984. 3. G. E. W. Wolstenholme and C. M. 0. Conner (eds.), “Ciba Foundation Symposium on the Chemistry and Biology of Purines.” Churchill, London, 1957. 4. J. H. Lister, Adv. Heterocycl. Chem. 6 , I (1966). 5 . R. K. Robins, Heterocycl. Compd. (1967). 6. W. W. Zorbach and R. P. Tipson (eds.), Synth. Proced. Nucleic Acid Chem. 1 (1968). 7. M. Luckner, “Biosyntheses der Alkaloide” (K. Mothes and H. R. Schutte, eds.), p. 568. Deutscher Verlag der Wissenschaften, Berlin, 1%9. 8 . B. Pullman and A. Pullman, Adv. Heterocycl. Chem. 13, 77 (1971).
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PURINE ALKALOIDS
323
320. A. Lespagnol, M. Debaert, A. Blears, M. Devergnies, J. C. Cazin, and M. Cazin, Ann. Pharm. Fr. 31, 751 (1973). 321. K. Harsanyi, R. Szebeni, and D. Korbonits, Acta Pharm. Hung. 43, 235 (1973). 322. F. G . Mann and F. W. G . Porter, J . Chem. SOC.,751 (1945). 323. J. Timson, Mutat. Res. 15, 197 (1972); Chem. Abstr. 77, 84051 (1972). 324. G. Shaw, in “Comprehensive Heterocyclic Chemistry” (A. R. Katritzky and R. W. Rees, eds.), Vol. 5, p. 602. Pergamon, Oxford, 1984. 325. J . A. Williams, W . Afr. J . B i d . Appl. Chem. 14, 10 (1971). 326. G . B. Elion, Angew Chem. Znt. Ed. Eng., 28, 870 (1989). 327. Chem. B r . , 931 (1987).
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CUMULATIVE INDEX OF TITLES Aconirum alkaloids. 4, 275 (1954). 34, 95 (1988) diterpenoid, 7, 473 (1960) C,, diterpenes, 12, 2 (1970) C,, diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1, ( 1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8, 789 (1965), 11, 41 (1968) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure minor alkaloids, 5, 301 (1955). 7, 509 (1960) unclassified alkaloids, 10, 545 (1967). 12, 455 (1970). 13, 397 (1971), 14, 507 (19731, 15, 263 (1973, 16, 51 I (1977) Alkaloids in Cannabis sativa L., 34, 77 (1988) the plant, 1, I5 (1950) 6, I (1960) Alkaloids from Ants and insects, 31, 193 (1987) Aspergillus, 29, 185 (1986) Pauridianrha species, 30, 223 (1987) Tubernuemontuna. 27, I (1986) Alsronia alkaloids, 8, 159 (1965). 12, 207 (1970). 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1968), 15, 83 (1975). 30, 251 (1987) Amphibian alkaloids, 21, 139 (1983) Analgesics, 5, I (1955) Anesthetics, local, 5, 21 I (1955) Anthranilic acid, related to quinoline alkaloids, 17, 105 (1979), 32, 341 (1988) Antimalarials, 5, 141 (1955) Antitumor alkaloids, 25, I (1989, 37, I , 205 (1990) Taxus alkaloids, 25, 6 (1985) Sesbania alkaloids, 25, 18 (1985) Pyrrolizidine alkaloids, 25, 21 (1985) Acronycine, 25, 38 (1985) Emetine, 25, 48 (1985) Cephalotaxus alkaloids, 25, 57 (1985) Colchicine, 25, 69 (1985) Camptothecine, 25, 73 (1985) Ellipticine, 25, 89 (1985) Maytansinoids, 25, 142 (1985)
325
326
CUMULATIVE INDEX OF TITLES
Phenanthroindolizidines.25, 156 (1985) Bisisoquinolines. 25, 163 (1985) Benzophenanthridines, 25, 178 (1985) Protoberberines, 25, 188 (1985) Amaryllidacea alkaloids, 25, 198 (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids. 4, 119 (1954). 9, I (1967). 24, 153 (1985) Arisfolochiu alkaloids. 31, 29 (1987) Arisfoteliu alkaloids, 24, I13 (1985) Aspidospermu alkaloids. 8, 336 (1965). 11, 205 (1968), 17, 199 (1979) Azafluoranthene alkaloids. 23, 301 (1984) Bases simple, 8, I (1965) simple indole. 10, 491 (1967) Benzophenanthridine alkaloids, 26, 185 ( 1985) Benzylisoquinoline alkaloids, 4, 29 (1954). 10, 402 (1967) Bisbenzylisoquinoline alkaloids, 4, 199 (1954). 7, 439 (1960). 9, 133 (1967). 13, 303 (1971). 30, I (1987) occurrence, 16, 249 (1977) structure, 16, 249 (1977) pharmacology, 16, 249 (1977) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, l(1981). 37, I (1990) isolation, structure elucidation, and biosynthesis of, 37, I (1990) medicinal chemistry of, 37, 145 (1990) Pharmacology of, 37, 205 (1990) Theraputic Use of, 37, 229 (1990) Buxus alkaloids, steroids, 9, 305 (1967). 14, I (1973) Cactus alkaloids, 4, 23 ( 1954) Calabar bean alkaloids, 2, 438 (1952). 8, 27 (1965). 10, 383 (1967). 13, 213 (1971). 36, 225 (1989) Calabash curare alkaloids, 8, 515 (1965). 11, 189 (1968) Calycanthaceae alkaloids. 8, 581 (1965) Camptothecin, 21, 101 (1983) Cancentrine alkaloids, 14, 407 (1973) Canthin-6-one alkaloids, 36, 135 (1989) Cupsicurn species, pungent principle of, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971). 26, I (1985) Carholine alkaloids, 8, 47 (196.5). 26, I (1985) P-Carboline congeners and ipecac alkaloids. 22, I (1983) Cardioactive alkaloids, 5 , 79 (1955) Celestraceae alkaloids, 16, 215 (1977) Cephulotuxrrs alkaloids, 23, 157 (1984) Chemotaxonomy of papaveraceae and fumariaceae, 29, I (1986) Chinese medicinal plants, alkaloids, 32, 241 (1988) Chromone alkaloids, 31, 67 (1987) Cinchona alkaloids. 14, 181 (1973). 34, 331 (1988) chemistry, 3, I (1953) Colchicine, 2, 261 (1952). 6, 247 (1960). 11, 407 (1968). 23, I (1984)
CUMULATIVE INDEX OF TITLES
327
Configuration and conformation. elucidation by X-ray diffraction. 22, 5 I ( 1983) Corynantheine. yohimbine. and related alkaloids, 27, 131 ( 1986) Cularine alkaloids, 4, 249 (1954). 10, 463 (1967). 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclic tautomers of tryptamines and tryptophans, chemistry and reactions. 34, I ( 1988) Cyclopeptide alkaloids, 15, 165 (1975) Daphniphyllum alkaloids, 15, 41 (1975). 29, 265 (1986) Delphinium alkaloids, 4, 275 (1954) diterpenoid. 7, 473 (1960) C,,-diterpenes. 12, 2 (1970) C,-diterpenes, 12, 136 (1970) Dibenzopyrrocoline alkaloids. 31, 101 (1987) Diplorrhyncits alkaloids, 8, 336 (1965) C,,-Diterpene alkaloids Aconitwn. 12, 2 (1970) Delphinium. 12, 2 (1970) Gurryu, 12, 2 (1970) structure, 17, I (1970) synthesis, 17, I (1979) C,-Diterpene alkaloids Aconiturn. 12, 136 (1970) chemistry, 18, 99 (1981) Delphinium. 12, 136 (1970) Gurrycc. 12, 136 (1970) Distribution of alkaloids in traditional Chinese medicinal plants. 32, 241 (1988) Diterpenoid alkaloids Aconitum. 7, 473 (1960). 12, 2 (1970) Delphinium. 7, 473 (1960). 12, 2 (1970) Gurryu. 7, 473 (1960). 12, 2 (1960) general introduction, 12, xv (1970) C,,-diterpenes, 12, 2 (1970) C2,-diterpenes. 12, 136 (1970) Eburnamine-Vincamine alkaloids, 8, 250 (1965). 11, 125 (1968). 20, 297 (1981) Elaeocarpus alkaloids, 6, 325 (1960) Elucidation, by X-ray diffraction structural formula, 22, 51 (1983) configuration, 22, 51 (1983) conformation, 22, 51 (1983) Enamide cyclizations. application in alkaloid synthesis, 22, 189 ( 1983) Enzymatic transformation of alkaloids, microbial and in vitro, 1.8, 323 ( 198 I ) Ephedra bases, 3, 339 (1953). 35, 77 (1989) Ergot alkaloids, 8, 726 (1965). 15, I (1975). 38, I (1990) Erythrina alkaloids, 2, 499 (1952). 7, 201 (1960). 9, 483 (1967). 18, I (1981) Eiythropl~leiimalkaloids. 4, 265 (1954). 10, 287 (1967) Eupomutiu ulkuloids. 24, I (1985) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32, I (1988)
328
CUMULATIVE INDEX OF TITLES
Galbulimima alkaloids, 9, 529 (1967),13, 227 (1971) Cardneria alkaloids, 36, 1 (1989) Garrya alkaloids diterpenoid, 7,473 (1960) C,, V-diterpenes, 12, 2 (1970) C,-diterpenes, 12, 136 (1970) Geissospermum alkaloids, 8,679(1969,33, 84 (1988) Gelsemiurn alkaloids, 8, 93 (1965). 33,83 (1988) Glycosides, monoterpene alkaloids, 17, 545 (1979) Guarreria alkaloids, 35, 1 (1989) Haplophyron cimicidum alkaloids, 8,673 (1965) Hasubanan alkaloids, 16, 393 (1977),33, 307 (1988) Holarrhena group, steroid alkaloids, 7, 319 (1960) Hunreria alkaloids, 8, 250 (1965)
8,203 (1965).11, 79 (1968) Imidazole alkaloids, 3, 201 (1953),22, 281 (1983) Indole alkaloids, 2, 369 (1952).7, 1 (1960).26, I (1985) distribution in plants, 11, 1 (1968) simple. including P-carbolines and P-carbazoles, 26, I (1985) Indole bases, simple, 10, 491 (1967) Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2,2'-lndolylquinuclidinealkaloids, chemistry, 8,238 (1965).11, 73 (1968) I n virro and microbial enzymatic transformation of alkaloids, 18, 323 (1981) Ipecac alkaloids, 3, 363 (1953),7, 419 (1960),13, 189 (1971),22, I (1983) P-Carboline alkaloids, 22, 1 (1983) Isolation of alkaloids, 1, I (1950) Isoquinoline alkaloids, 7,423 (1960) biosynthesis, 4, 1 (1954) "C-NMR spectra, 18,217 (1981) simple isoquinoline alkaloids, 4, 7 (1954).21, 255 (1983) lsoquinolinequinones, from actinomycetes and sponges, 21, 55 ( 1983) Zbogu alkaloids,
Kopsiu alkaloids, 8, 336 (1965)
Lead tetraacetate oxidation, 36,69 (1989) Local anesthetics, alkaloids, 5 , 21 1 (1955) Localization of alkaloids in the plant, 1, 15 (1950),6, I (1960) Lupine alkaloids, 3, 119 (1953),7, 253 (1960).9, 175 (1967).31, 116 (1987) Lycopodium alkaloids, 5, 265 (1955),7, 505 (1960),10, 306 (1967).14, 347 (1973).26, 241 (1985) Lythracae alkaloids, 18,263 (1981).35, 155 (1989) Mammalian alkaloids, 21, 329 (1983) Marine alkaloids, 24, 25 (1985) Maytansinoids, 23, 71 (1984) Melanins, chemistry of, 36,253 (1989) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986)
CUMULATIVE INDEX OF TITLES
329
Microbial and in vifro enzymatic transformation of alkaloids. 18, 323 (1981) Mitrugvna alkaloids, 8, 59 (1965), 10, 521 (1967). 14, 123 (1973) Monoterpene alkaloids, 16, 431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part I . 1952). 2, 161 (part 2. 1952). 6, 219 (1960). 13, 1 (1971) Muscarine alkaloids, 23, 327 (1984) Mydriatic alkaloids, 5 , 243 (1955) a-Naphthaphenanthridine alkaloids, 4, 253 (1954). 10, 485 (1967) Naphthyl isoquinoline alkaloids, 29, 141 (1986) Narcotics, 5 , 1 (1955) "C-NMR spectra of isoquinoline alkaloids. 18, 217 (1981) Nuphur alkaloids, 9, 441 (1967). 16, 181 (1977). 35, 215 (1989) Ochrosiu alkaloids, 8, 336 (1965). 11, 205 (1968)
Ourorcpuriri alkaloids, 8, 59 (1965). 10, 521 (1967) Oxaporphine alkaloids, 14, 225 (1973) Oxazole alkaloids. 35, 259 (1989) Oxindole alkaloids, 14, 83 (1973)
Papaveraceae alkaloids, 10, 467 (1967). 12, 333 (1970), 17, 385 (1979) pharmacology, 15, 207 (1975) toxicology, 15, 207 (1975) Pavine and isopavine alkaloids, 31, 317 (1987) Pentuceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids, 19, 193 (1981) P-Phenethylamines, 3, 313 (1953), 35, 77 (1989) Phenethylisoquinoline alkaloids, 14, 265 (1973). 36, 171 (1989) Phthalideisoquinoline alkaloids, 4, 167 (1954). 7, 433 (1960). 9, I17 (1967). 24, 253 (1985) Picrulimu alkaloids, 14, 157 (1973) Picralimu ni/idri alkaloids, 8, 119 (1965). 10, 501 (1967) Piperidine alkaloids, 26, 89 (1985) Plant systematics, 16, 1 (1977) Pleiocurpu alkaloids, 8, 336 (1965), 11, 205 (1968) Polyamine alkaloids, putrescine, spermidine, spermine, 22, 85 (1983) Pressor alkaloids, 5, 229 (1955) Protoberberinr alkaloids, 4, 77 (1954). 9, 41 (1967). 28, 95 (19861, 33, 141 (1988) Protopine alkaloids, 4, 147 (19541, 34, 181 (1988) Pseudocinchonu alkaloids, 8, 694 (1965) Purine Alkaloids, 38, 225 (1990) Putrescine and related polyamine alkaloids, 22, 85 (1983) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960). 11, 459 (1968). 26, 89 (1985) Pyrrolidine alkaloids, 1, 91 (1950). 6, 31 (19601, 27, 270 (1986) Pyrrolizidine alkaloids, 1, 107 (1950). 6, 35 (1960), 12, 246 (1970). 26, 327 (1985) Quinazolidine alkaloids, see ldolizidine Alkaloids Quinazoline alkaloids, 3, 101 (1953). 7, 247 (1960). 29, 99 (1986) Quinazolinocarbolines, 8, 55 (196% 21, 29 (1983)
330
CUMULATIVE INDEX OF TITLES
Quinoline alkaloids other than Cinchoncr. 3, 65 (1953). 7, 229 (1960) related to anthranilic acid, 17, 105 (1979). 32, 341 (1988) R u t r ~ ~ ~ l ctliicrloids. fitr 8, 287 ( 1965)
Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine. chemistry, 8, 287 (1965) Respiratory stimulants, 5, 109 (1955) Rhoeadine alkaloids, 28, I (1986) Sciluinrrndrtr group, steroids, 9, 427 (1967) Scelefirrirn alkaloids, 19, 1 (1981) Seneeio alkaloids. see Pyrrolizidine alkaloids Secoisoquinoline alkaloids, 33, 23 I (1988) Secrrrinegcr alkaloids. 14, 425 (1973) Sinomenine, 2, 219 (1952) Solrrnrrm u1ii~loid.s c h o n i s l r ~3, , 247 (1953) steroids. 7, 343. (1960). 10, l(1967). 19, 81 (1981) Sources of alkaloids. 1, I (1950) Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983) Spermine and related polyamine alkaloids, 22, 85 (1983) Spirobenzylisoquinoline alkaloids, 13, 165 (1971). 38, 157 (1990) Sponges. isoquinolinequinones. 21, 55 (1983) Sfefnonualkaloids, 9, 545 (1967) Steroid alkaloids Apocynaceae. 9, 305 (1967). 32, 79 (1988) Brixrrs group. 9, 305 (1967). 14, I (1973). 32, 79 (1988) Holrrrrliencr group. 7, 319 (1960) Sirlrrin~rndrmgroup, 9, 427 (1967) Solonrnn group. 7, 343 (1960). 10, I (1967). 19, 81 (1981) V e r m r r m group. 7, 363 (1960), 10, 193 (1967). 14, I (1973) Stimulants respiratory, 5, 109 (1955) uterine. 5, 163 (1955) Structural formula. elucidation by X-ray diffraction, 22, 51 (1983) SfryVinos alkaloids, 1, 375 (part 1-1950). 2, 513 (part 2-1952). 6, 179 (1960). 8, 515, 592 (1965). 11, 189 (1968). 34, 211 (19881, 36, I (1989) Sulfur-containing alkaloids. 26, 53 (1985) Tcrxrrs alkaloids, 10, 597 (1967) Toxicology, Papaveraceae alkaloids, 15, 207 (1975) Transformation of alkaloids, enzymatic, microbial and in v i m , 18, 323 (1981) Tropane alkaloids, 1, 271 (1950). 6, 145 (1960). 9, 269 (1967), 13, 351 (1971), 16, 83 (1977). 33, (1988) Tropoloisoquinoline alkaloids, 23, 301 ( 1984) Tropolonic Colcliicirm alkaloids, 23, 1 ( 1984) Tvlophorcr alkaloids, 9, 517 (1967)
CUMULATIVE INDEX OF TITLES
33 I
Uterine stimulants, 5, 163 (1955) Verutritm alkaloids
chemistry, 3, 247 (1952) steroids. 7, 363 (1960). 10, 193 (1967). 14, 1 (1973) Vinblastine. 37, 133 (1990) Vinblastine-Type Alkaloids, 37, 77 (1990) “Vinca” alkaloids, 8, 272. (1965). 11, 99 (1968). 37, 1 (1990) Voacungu alkaloids, 8, 203 (1965), 11, 79 (1968) X-Ray diffraction, elucidation of structural formula, configuration, and conformation, 22, 51 (1983) Yohimbe alkaloids, 8, 694 (1965) Yohimbine alkaloids, 11, 145 (1968). 27, 131 (1986). see u h Coryantheine
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INDEX A
C
A-201 A-E, 273 Acetylimino- I ,9-dimethyloxopurine, 265 Achromycin. 267 Adenine, 226 Adenomycin, 278 Adenylosuccinic acid, 278 Africanine, 177 Agelasidines A-C. 258 Agelasimines A, B, 263 Agelasines A-F, 258, 259 Ageline B. 259 Agroclavine, 15, 24 synthesis of, 48 Agroclavine I, 5 , 13, 15 synthesis of, 49 6-Allylfestuclavine, 147 Aminodeoxyadenosine, 277 Aminopurinylpropionic acid, 235 Amipurimycin, 270 Antibiotic A-201 A-E, 275 Antibiotics nucleoside antibiotics, 267 Antimicrobial activity of ergot alkaloids, I42 Antitumor activity of ergot alkaloids, I42 AraA. 262 Arabinofuranosyladenine,262 Aristeromycin, 268 Asamycin, 272 AT-265. 270 Augustomycin, 277 Aurantioclavine, 8. 13, 20 synthesis of, 67
Caffeine, 227. 229 biological activity of, 31 I Caissarone, 265 Chanoclavine 1. 6, 13 Chanoclavine I acid, 6, 13 Chanoclavine 11. synthesis of, 61 Chidlovine. 236 2-Chloroadenosine. 278 8-Chlororugulovasines A. B. 7. 13. 19 Chryscandine. 272 cis-Zeatin, 240 Clarines conversions of. 26 Clavicipitic acid, biosynthesis of, 141 Clavicipitic acids, 8, 18, 20 synthesis of, 67, 71 Cordycepin. 270 Corpaine. 173 Corydaine, 176 synthesis of, 185 Corysolidine, 174 Corystewartine, 181 Costaclavine, 3, 14, 41 CY-208-243. 145 Cycloclavine, 20
D Decoyinine. 277 Densiflorine. 176 Deoxyeritadenine. 234 synthesis of, 295 Deoxymethylthioxylofuranosyladenine, 263 Dideoxyadenosine. 3 I3 Dihydrochanoclavine. 18 Dihydrofumariline. 168 Dihydrolysergol, 14 Dihydrosetoclavine. 14
B Bromocriptine, 143 Bulgararnine, 184 333
334
INDEX
Dihydrosetoclavines, synthesis of, 41 Dihydrozeatin. 241 Dimethylallylpurine, 243 6,8-Dimethylergolines, synthesis of. 38 Discadenine. 244 synthesis of, 302 Doridosine. 254
E
Eloymockdvine. 6, 15 synthesis of, 46 Elymoclavine, correlation with, 22 synthesis of, 23. 46 Epicostaclavine, 3, 13. 14, 41 5’-Epi-P-ergocryptine. 10, 13, 17 13-Epiyenhusomine, 170 Epoxyagroclavine I, 5, 13, 14 Ergoannam, 11, 13, 17 Ergobam. I I Ergobine, 10 Ergobutam, I I Ergobutine, 10. 13, 17 Ergobutyram, I I Ergobutyrine, 10, 13, 17 Ergocornine, 10. 17 Ergocristam, I I , 17 Ergocristine, 10, 17 Ergocryptam. I I , 13 Ergocryptine. 10. 17 8-Ergolenes. 14 9-Ergolenes, 16 Ergolines. 14 conformation of, 127 9-Ergolines, conformation of. 124 Ergonam. 11. 17 Ergonine. 10. 13, 17 Ergonovine, 16 Ergopeptam alkaloids, 12 Ergopeptine alkaloids, 10 Ergoptam, I I Ergoptine, 10, 13 Ergosam, I I Ergosecaline, 16 Ergosine, 10. 17 Ergostam. I I Ergostine. 10 Ergot alkaloids, biosynthesis of, 130 chemical modification of, enamide photocyclization of, 92
cyclization of nitronate anions of, 97 demethylatin at N(6). 78 epimerization at C(8). 75 Heck reaction of, 95 hydroboration of, 82 substitution at C(2). 79 substitution at N(I), 81 deformed alkaloids, 20 interconversion, 21 new alkaloids, 13 peptide alkaloids of, 10, 139 synthesis of, 20 from indoles, 102 from indolines, 100 Ergotamam, 1 I Ergotamine, 10, 17 Ergovalam, I I Ergovaline, LO, 13, 17 Eritadenine, 233 synthesis of, 292 Ethylxanthine, 285 Exotoxin, 273
F Festuclavine. 14, 24 Fumaitine N-oxide, 167 Fumaricine, 160 Fumariline, 159 Fumaritine, 159 Fumaritridine, 162 Fumaritrine, 157, 162 Fumarofine, 157, 160 Fumarophycine, 164 Fumigaclavines A-C, 3. 13. 14 synthesis of, 48
G
Gonyautoxin I-VII, 248 Guanine, 226 Guanine-7-oxide, 274
H Herbicidin A-G, 271 Herbipoline. 267
335
INDEX
Homocitrullylaminoadenosine, 278 Hydroxybenzylaminomethylthioglucofuranosylpurine. 245 H ydroxybenzylaminoribofuranos ylpurine, 246 synthesis of, 303 8-Hydroxyergotamine, 12, 13, 17 Hydroxyguanine. 274 Hyperectine. 179 Hypoxanthine, 256
LY-53857, 146 Lysergene, 16 Lysergic acid, from clavines, 16, 26 synthesis of, 28 Lysergic acid amide, 16 Lysergic acid hydroxyethylamide. 16 Lysergine, 3, 24, 45 synthesis of, 44 Lysergol, 16 synthesis of, 46 Lysylaminoadenosine, 278
I lndenobenzazepine alkaloids, 182 synthesis of, 202 Indoles, synthesis of, dehydrogenation of indolines, 120 Leimgruber-Batcho synthesis of, I14 thallation of, 116 Isochanoclavine. 18 synthesis of, 65 lsodihydrochanoclavine. 18 Isofumigaclavines. 4, 13, 14 Isoguanosine. 255 Isolysergic acid, 16 Isolysergol. synthesis of, 44 Isoparfumine, 166 Isopenniclavine, 16 Isosetoclavine. 16 synthesis of, 23
M Mesulergine, 144 Methergoline, 145 I-Methyladenine. 266 0-Meth ylcorpaine, I76 N-Methyl-4-dimethylaIlyltryptophan. 9. 13 0-Methylfumarofine, 160 0-Methylfumarophycine. 165 N-Methyllederine, 164 Methylzeatin, 239 Methysergide, 141, 145 Miharamycins A, B. 278 Moliclavine, 15
N K KSH-1415, 145
l.
Lahoramine, 183 Lahorine, 182 Ledebouridine, 169 Ledebourine, 174 Lederine. 163 Lentinactin. 233 Lentysine, 233 Lergotrile, 143 Lisuride. 144 Lupinic acid. 242
Nebularine, 268 Nebuline. 268 Neosaxitoxin, 247 Neplanocin A, B. 269 Nicergoline. 142 Norchanoclavine 1. 18 Norfumaritine, 163 Norsetoclavine. 16 Nucleocidin, 267
0 Ochotensidine, 180 Ochotensine, 159 Ochotensinine, 160 synthesis of, 184
336
INDEX
Ribufuranosylmethoxyadenine, 262
Ochrobirine. 159 synthesis of, 186 Oxetanocin. 273
Rugulovasines A. B, 6, 19 synthesis of, 66
P Paliclavine. 19, 28 synthesis of, 56 Paraxanthine. 257 Parfumidine, 167 Parfumine. 165 Parviflorine. 178 Paspaclavine, 19 Paspalic acid. 15 Penniclavine. 16. 23 Pergolide , 144 Peroxy-Y-base. 252 Phenyltheophylline. 285 Phildolopin. 257 I-Propylagroclavine. I47 Protogonyautoxin I. 248 Psicofuranin. 277 Purine alkaloids. biological activities of. 31 I from animals, 154 from plants. 229 isolation of, 228 occurence of, 227 spectral data of. 304 MS data of, 310 NMR data of. 307 UV-spectral data of, 304 synthesis of, 280 from inmidazoles. 287 from pyrimidines, 281 Puromycin. 267 Pyroclavine. 14
R Raddeanidine, 172 Raddeanine. 170 Raddeanone. 174 synthesis of. 186 Raddeanamine. 179 Raphanatin. 239 Rhoeadine. synthesis of, 212 Ribosylzeatin. 239
5
Saxitoxin, 247 6.7-Secoagroclavine, 6, 13, 18 6.7-Secoagroclavine, synthesis of, 53, 58 Secoergolenes. 18 Secoergoline alkaloids, conversion into ergolines. 27 synthesis of, 57 6,7-Secoergolines, 6 synthesis of. 51 Secondensiflorine, 181 Septacidin, 273 Setoclavine, 16 Setoclavine, synthesis of, 44 Severzinine, 172 Sibiricine, 159 synthesis of. 186 Sinefugin, 273 Spirobenzylisoquinolines. 157 absolute configuration of, 158 biosynthesis of, 217 by enzymatic transformation, 214 by photolysis, 190 by Stevens rearrangement, 191 from benzocyclobutanes, 186 from cycloberbines, 192 from indan-l.2-diones, 184 from indenobenzazepines. 198 from phthalidoisoquinolines, 198. 204 from protoberberines, 189. 203 occurrence of, 159 Spongoadenosine, 261 Spongopurine, 266 Spongosine, 262 Stylomycin. 267
T Terguride. 144 Theobromine. 227, 230 Theophylline. 232, 31 I Togholamine. 236 Toxin C,, 248
337
INDEX
Toxin C,. 248 frans-Zeatin. 237 synthesis of, 297 Triacanthine, 236
Wye-Base, 249 Wyosine. 252
X Xanthine, 226
W Wybutine, 251 Wybutosine. 250 Wybutoxine. 252 Wybutoxosine. 254
Y Y-Base. 249 Yenhusomidine, 175 synthesis of. 185 Yenhusomine. 171
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