摘要:

Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor M. I. Page The Polytechnic Huddersfield Professor T. J. Simpson University of Leicester ~~~~~~ Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1989 Annual Subscription Price U.K. f169.00 Rest of World f194.00 U.S.A. $388.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Second-Class postage paid at Jamaica NY 11431 -9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1989 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1989 U.K. f169.00 Overseas f194.00 U.S.A. US $388.00 Subscription rates for back issues are U.K. (I 984) f120.00 (1985) f125.00 (1986) f130.00 (1987) f142.00 (1988) f159.00 Overseas f126.00 f131.OO- f143.00 f159.00 f183.00 U.S.A. US $240.00 US $242.00 US $252.00 US $280.00 US $342.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP98906FX017

出版商:RSC    

年代:1989

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP98906BX019

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Recent Progress in the Chemistry of lndole Alkaloids and Mould Metabolites J. E. Saxton School of Chemistry The University of Leeds Leeds LS2 9JT Reviewing the literature published between July 1987 and June 1988 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 1). 1 General 2 Simple Alkaloids 2.1 Non-tryptamines 2.2 Non-isoprenoid Tryptamines 3 Isoprenoid Tryptamine and Tryptophan Derivatives 3.1 Ergot Alkaloids 4 Monoterpenoid Alkaloids 4.1 Alkaloids containing an Unrearranged Monoterpenoid Unit 4.2 Corynantheine-Heteroyohimbine-Yohimbine Group and Related Oxindoles 4.3 Sarpagine-Ajmaline-Picraline Group 4.4 Strychnine Group 4.5 Ellipticine-Uleine-Apparicine Group 4.6 Aspidospermine-Vincamine Group 4.7 Catharanthine-Ibogamine Group 5 Bisindole Alkaloids 6 Biogenetically Related Quinoline Alkaloids 6.1 Cinchona Group 6.2 Camptothecin 7 References 1 General A recent volume in the Manske-Brossi series includes a review of alkaloids of Pauridiantha species.' A compilation of I3C n.m.r.data of 298 naturally-occurring and synthetic indole derivatives includes a wide range of indole alkaloids ;however only the data for the indole nucleus is included.2 The synthesis of alkaloids via the addition of stabilized carbon nucleophiles to N-alkylpyridinium salts has been reviewed ;this naturally includes reference to several syntheses of indole alkaloid^.^ For the Japanese reader Natsume has reviewed his own contributions to the synthesis of indole alkaloids e.g.cyclopiazonic acid substituted ergolines and the teleocidins A- 1 and A-2 from pyrrole derivatives4 The occurrence and chemical and biological properties of indole glucosinolates (glucobrassicins) have also been reviewed. 2 Simple Alkaloids 2.1 Non-tryptamines Several invertebrate marine organisms have recently been shown to contain simple alkylated or halogenated indole derivatives. The acorn worm of Glossobalanus species contains 4,6-dibromoindole and 2,4,6-trimethylind0le,~"and Ptychodera flava contains 3,5,7-tribromo-6-methoxyindoleand 3,5,7-tribromoindole. 6b In addition 6-bromo-3-chloroindole 3,6- dibromoindole 3- bromoindole and 3-chloroindole were de- tected ;these last two indole derivatives appear to be responsible for the odour of this organism.3,4,6-Tribromoindole has been shown to be present in Balanoglossus carnosus,6b and among other constituents in a new acorn worm of the genus Ptychodera found in deep underwater caves of the Hawaian island of MauLGC Syntheses of 4,6-dibromo- 4,6-dibromo-2- methyl- and 3,4,6-tribromo-indole have been reported.6d 1-Methoxyindole-3-carboxaldehydehas been isolated from cauliflowers (Brassica oleracea),6a while indole-3-acetonitrile and indole-3-carboxaldehyde have been found in various edible Cruciferae.6b Indole 3-carboxylic acid and indole 3-carbinol were detected only in trace amounts and it is concluded that hitherto the occurrence of this latter indole derivative in plants has been grossly overestimated.Neobetanin has been reported to be a major constituent of the fruits of Opuntia ficus-indica; the relatively high con-centration found substantiates the claim that neobetanin is a natural constituent of this species.' It has also been found in fresh juice from red beet root tissue but not in the aerial parts of Beta vulgaris and it was not detected in betanin samples stored for months in the dark at -20 "C. This evidence would appear to discredit the claim8 that neobetanin is an artefact. The structure deduced for uvarindole D9has been confirmed by X-ray crystal structure analysis.'* Indobine (1)lla and indobinine (2)llb are two simple esters of indole propionic acid which have been isolated from the roots of Thai specimens of RauwoIfia serpentina; indobine is the benzyl ester and indobinine is the cyclohexyl ester.3-Farnesylindole (3) is a new indole derivative which has been found in the leaves of West African Uvaria pandensis Verdcourt .l2 lndobine (1) R = CH2Ph lndobinine (2) R = CsHll H 3-FarnesyI indole (3) 433 434 NATURAL PRODUCT REPORTS 1989 SIt SCOEt A new ~ynthesis'~ of the antibiotic chuangxinmycin (4) from Actinoplanes tsinanensis relies for its critical stage on the insertion into a C-H bond of a carbene generated by a C Bamford-Stevens reaction ; apparently none of the normal &"HTS 'Me product (the alkene) is obtained (Scheme 1). This route to chuangxinmycin is superior to previous syntheses via 3,4-dehydrochuangxinmycin for which a new synthesis has been Ts H reported,14 because the hydrogenation of the 3,4-double bond is inevitably accompanied by some desulphurization.. The synthesis of some chuangxinmycin analogues containing lv substituents (CN NO, C0,Et) on the methyl group has also been reported ; these show some antitumour activity against P388 leukaemia cells in vitro.15 vi vii The culture broth of Streptoverticillium ehimense has yielded Ae-Ae two new carbazomycins G and H which contain an unusual quinol part-structure.16 The structures (5) and (6) were deduced H \ I\ from their mass and n.m.r. spectra and that of carbazomycin G which exists as the racemate was confirmed by the X-ray H method.Carbazomycin G is stated to exhibit moderate Chuangx inm yci n ( 4) inhibitory antifungal activity e.g. against Trichophyton species. The structure of carbazomycin C (7) has also been confirmed Reagents i ClCH,CN H,NCH,CH,NH,; ii C,HllONa; iii by X-ray crystal structure analysis ;16 this necessarily confirms MeCOCl SnCl,; iv TsNH.NH, AcOH EtOH; v NaH diglyme; also the structure of carbazomycin D (8). vi NaOH EtOH heat; vii separation of epimers New synthetic work reported recently includes a synthesis of Scbeme 1 girinimbine from 2-hydroxycarbazole-3-carboxylicacid," and syntheses of murrayaquinone A and pyrayaquinones A and B.18 0 These three quinonoid compounds [e.g.murrayaquinone-A (9) Scheme 21 were very simply prepared by DDQ oxidation of the related 1-oxotetrahydrocarbazole derivative synthesized by well-known methods.Full details of Moody's syntheses of murrayafoline-A HO Me murrayaquinone- A lga and murrayaquinone- BlSb have been published. Carbazomycin G (5) R = H Carbazomycin C (7)R = H In the first synthesis20 of (+)-cis-trikentrin A (lo) one of a Carbazomycin H (6) R = OMe Carbazomycin D (8) R = OMe group of biologically active indoles isolated from the sponge TrikentrionJZhbellijiorme,21the cyclopentane ring is formed by a radical cyclization on the bromoalcohol (1 l) prepared by a 0 II Grignard reaction on o-bromoacetophenone. Subsequent stages to the azidoester (12) are conventional and the indole ring is then formed by Moody's method (Scheme 3). Three new indoloditerpenes related to the tremorgenic mycotoxin paxilline have been isolated from mycelial extracts of Emericella desertorum Samson and Mouchacca strain CBS Murrayaquinone A (9) 653.73 and E.striutu (Rai Tewari and Mukerji) Malloch and Reagents i DDQ dioxan heat 24 h Cain strain 80-NE-22. The structure and relative configuration of emindole DA (13) were ~ieterrnined~~.~~ by X-ray crystal Scheme 2 ii iii I BrQ HO +--OH iv v iii vi 1 Et c--.@-A ~ E -ecHo C02H viii ix q Y C O Z t vii cis-TrikentrinA ( 10) (12) Reagents i Bu,SnH AIBN; ii H+,CHCl,; iii H, Pd/C; iv MeCOCl AlCl,; v NaBH,; vi Cl,CHOMe TiCl,; vii EtO,CCH,N NaOEt EtOH; viii PhMe heat; ix KOH H,O dioxan; x F.V.P. (600 "C 0.003 mm) Scheme 3 NATURAL PRODUCT REPORTS 1989-5.E. SAXTON 435 Ernindole DA (13) R = H (14) R =Ac Ernindole DB (15) Reagents i BF;Et,O; ii KOH EtOH; iii NaBH,CN TFA Scheme 4 Me lviii Me I EtOC H02C ix-xi -9&ol HO 0 v xiv-xviii I (19) (-)-Paspaline (18) Reagents i PhCH,NH, PhMe TsOH heat; ii MeCOCH=CH, EtOH; iii NaH C6H6 heat; iv ZnMe, Ni(acac),; v TMSCl NEt,; vi O, DMS; vii EtOCH=CH, TsOH; viii LiN(SiMe,), THF -78 "C; ix TFAA DMSO NEt,; x 0.2 M-HCl; xi 70% HClO, CH,Cl, 0 "C; xii PhSH NEt, CH,O EtOH 60 "C; xiii Li NH, H,O THF CH,=CHCH,Br; xiv NaBH,; xv separation of epimers; xvi ButMe,SiOTf py CH,Cl,; xvii citric acid MeOH; xviii PCC CH,Cl Scheme 5 structure analysis of its acetate (14). Emindole SA isolated like These metabolites contain a regular diterpenoid framework emindole DA from both Emericella species is the 9-epimer of and may be precursors of the paxilline group which are formed emindole DA.22 The absolute configuration of emindole DA by further cyclization and rearrangement.Alternatively paxil- was deduced by application of Horeau's method.23 The third line may arise via an alternative cyclization pathway of a indoloditerpene derivative emindole DB isolated only from E. tryptophan-geranylgeraniol precursor. desertorurn contains one oxygen atom more than emindole A stereoisomer (1 7) of polyveoline has been synthesized by DA and is a tertiary alcohol. Since it can be prepared by cyclization of the 2-(E,E)-farnesylindole derivative (16) fol- oxidation of emindole DA by means of m-chloroperbenzoic lowed by appropriate transformations (Scheme 4).24It seems at acid it must have the structure and absolute configuration least possible that polyveoline or its 3-epimer may be capable expressed in (15); only the configuration at C-21 is of being synthesized by an analogous route from the 2-(Z,E)-However a nuclear Overhauser effect between the protons at isomer of (16); whether this is so remains to be seen.C- 17 and C-2 I in emindole DB (1 5) reveals that these protons A second synthesis of (-)-paspaline (18),25 by Smith and are in a 1,3-diaxial relationship and hence C-21 has the (3-Leenay consists essentially of a new route to the advanced configuration as shown. intermediate (19) via the tricyclic diketone (20) which is NATURAL PRODUCT REPORTS 1989 I ?42 H H (22) (23) Br (26) X = H R = Me (27) X = Br R =Me (23) X = Br R = H (29) X= R= H 0 Hinckdentine A (32) intended as a common intermediate for the construction of several members of this class of indole-diterpene tremorgenic mould metabolites.In the first synthesis considerable difficulty was experienced in setting up stereoselectively the vicinal quaternary centres C-12b and C-12c. The new approach to (20) involves Robinson annulation of the ketone-acetal (21) itself prepared readily from the Wieland-Miescher ketone followed by stereospecific 1,4-addition of zinc dimethyl by Luche’s method and silyl enol ether formation. Ring con- traction by a modern variant of a long-established method then gave the cyclopentanone derivative (20).25a Further elaboration of (20) as outlined in Scheme 5 then gave the tricyclic ketone (19) in seven steps in overall yield of 21.9 %.256 This ketone has previously been converted into (-)-paspaline (18)? 2.2 Non-isoprenoid Tryptamines N-( -)-Jasmonoyl-($)-tryptophan (22) has been found in the flowers of Vicia faba;26 a second tryptophan conjugate from the same source is probably N-( +)-cucurbinoyl-(9-tryptophan (23) but definitive proof of this structure is at present lacking.Following an unequivocal synthesis of (R)-and (9-4-chlorotryptophan Thiruvikraman et al. have confirmed the presence of the (9-enantiomer in the crude seed protein of the pea Pisum sativ~m.~~~. The amide of N-methylanthranilic acid with tryptamine has been shown to occur in the fruits of Evodia rutae~arpa;~~’ it seems probable that this compound could be an important biogenetic precursor of evodiamine.Two cyclopeptide alkaloids that contain an N,N-dimethyl- H Frangufoline(24) R = CH2CHMe2 Nummularine R (25) R = CH(MeICH2Me Barettin (?) (31) tryptophancomponent have been isolated from Zizyphusspecies. Frangufoline (24) was found in the bark of 2.jujuba and 2. nummularia and nummularine R (25) a new alkaloid in 2. nummularia.28 Psilocybin and baeocystin (but not psilocin) have been shown to be present in the dried fruit bodies of Pluteus salicinus (Pers. ex Fr.) K~mm.,~~ and in an examination of ten Finnish fungi both psilocybin and psilocin have been found in dried specimens of P.salicinus and in Panaeolus subbalteatus (Berk. et Br.) Sacc. Psathyrella candolleana (Fr.) R. Maire Conocybe cyanopus (Atk.) Kuhn and Psilocybe semilanceata (Fr.) Kumm. Psilocybin was also detected in Pluteus atricapillus Sing. Panaeolus olivaceus Moller and P. foenisecii (Pers. ex Fr.) R. Maire and in an unidentified Agrocybe species while in Conocybe kuehneriana psilocin but not psilocybin was detected.30 3’-Deimino-3’-oxoaplysinopsin(26) and its 6-bromo de- rivative (27) have been isolated as (E/Z)-mixtures from a coral of the Tubastraea genus found at Palawan in the phi lip pine^.^^ The related bis-demethyl compounds (28) and (29) have been extracted also as (E/2)-mixtures from Leptopsammia pruvoti collected near Marseilles. The structures of these aplysinopsin derivatives were established by condensation of indole-3-carboxaldehyde or its 6-bromo derivative with the appropriate hydantoin which gave the (@-isomers of (26) and (28) and the (2)-isomers of (27) and (29).The geometrical isomers which represent the minor components of the naturally-occurring mixtures were then obtained by photoisomerization. Since this photoisomerization occurs under ordinary daylight conditions in the laboratory the proportions of (E:2)-isomers isolated from the natural material gives no clue to the isomeric composition in the original corals.31 The structure (30) originally for barettin a constituent of the cold-water sponge Geodia baretti has been di~credited~~ following the synthesis of both geometrical isomers of structure (30) and it is suggested but without supporting evidence that barettin may well be the cyclic tetra-peptide (3 1).Hinckdentine A yet another bromine-containing indole derivative from a marine organism has been isolated from the bryozoan Hincksinojustra den ticulata collected from the eastern coast of Tasmania.34 Its unusual structure (32) and NATURAL PRODUCT REPORTS 1989-5. E. SAXTON Me Me Me -... Ill-lv I II * ".OQ-) Me Me H Meh I I Me l!l Me CON HCHPh S (+) -Physostigmine (33) t 34) (35) Reagents i (-)-(3-PhCHMeNCO; ii chromatographic separation; iii Me(CH,),OH Me(CH,),ONa heat; iv CH,O NaBH,; v BBr,; vi MeNCO Scheme 6 MeOfi-'w Geneserine (36a) (36b) Me0qqJ9 \ / Harrnalanine (39) Nitramarine (40) Reagents i NH,OH PhMe heat Scheme 7 absolute configuration were established by the X-ray method which show hinckdentine A to possess the previously un- described pyrimidino[3',4 :1,2]pyrrol0[2,3,d]azepine ring sys- tem.An improved synthesis of (+)-physostigmine (33) the unnatural enantiomer which has useful pharmacological properties has been reported.35 This simply involves resolution of the racemic synthetic base (34) by reaction with (-)-S-a-0w (38a) R'=Et R2=H (38b) R' =Me R2 = H (37) (384 R' = Et R2 = Br methylbenzylisocyanate and chromatographic separation of the diastereoisomeric urea derivatives (35) thus obtained. The urea group was then removed by an improved method and the synthesis completed by well-known methods (Scheme 6).Details of the first total synthesis32 of geneserine (36a) have and been p~blished,~~" an independent short and efficient route to the important oxindole intermediate (36b) in this synthesis has been developed.366 The Tasmanian marine bryozoan Costaticeffa hastata collected from Eaglehawk Neck has been shown to contain harman 1-ethyl-8-carboline and (9-1-(1-hydroxyethyl)-P-carboline; this last alkaloid is new.37 A second sample of C. hastata collected at the River Derwent estuary contained these three alkaloids together with 1-vinyl-P-carboline (pavettine). It is believed that this is the first report of these simple P-carboline derivatives in marine organisms. Harman has also been isolated together with norharman from the root bark and stem bark of Strychnosjohnsonii3*and together with harmine harmol harmalol and harmaline from the roots of Grewia viffosa Willd.a Sudanese tree extracts of which are reputedly used locally in admixture with other Grewia species in the treatment of tuber~~lo~i~.~~ Other simple P-carboline derivatives recently encountered include 1-meth-oxy-8-carboline in the stem bark of Alstonia constrict^,^^" 1-vinyl-4,8-dimethoxy-~-carboline, l-methoxycarbonyl-p-carbo- line and 3-methylcanthin-2,6-dione(37) in the wood of Quassia amara L.,406 and the three brominated B-carbolines (38a-38c) which have been obtained from the lipophylic extract of the marine hydroid Agfaophenia pluma L. collected from the Bay of Salerno.41 The bark of Picrasma javanica a tree long used as a medicinal plant in Western Sumatra contains two new alkaloids l-vinyl-5-hydroxy-4-methoxy-~-carboline (5-hydro-xydehydrocrenatine) and 1-ethyl-5-hydroxy-4-methoxy-P-car-boline (5-hydroxycrenatine) together with dehydrocrenatine (previously isolated) and crenatine., Two new P-carboline lactams have been isolated from the seeds of Peganum h~rmafa;,~ harmalacidine is simply 1-0xo-7-methoxy-1,2,3,4-tetrahydr0-/3-carbolineand harmalanine has the tetracyclic structure (39). Two syntheses of nitramarine (40) have been reported by .~~ Hibino et ~ 1The first of these simply involved condensation of tryptophan ethyl ester with quinoline 2-aldehyde followed by hydrolysis decarboxylation and dehydrogenation ; the second more interesting route involved cyclization and dehydration of the oxime (not isolated) of the unsaturated ketone (41) (Scheme 7).NATURAL PRODUCT REPORTS 1989 (42) R' = OH R2 = H (43) R'=H R2=OH MeO2C (45) OMe OMe v-vii -f CO2Me 1-Methoxycanthin-6-one (44) (47) Reagents i Me02CCOCH,CH2C02Me MeOH heat; ii DDQ THF H20; iii HCl AcOH heat ; iv HC(OMe), TsOH MeOH ;v NH,OH MeOH heat; vi TsOH DMF PhH heat; vii DDQ dioxan heat Scheme 8 Eudistomin K sulphoxide (48) The stem bark of Quassia kerstingii Little originating in Ghana contains 2-hydroxycanthin-6-one (42) and 1 l-hydroxy- canthin-6-one (43);45 of these the latter is reported to exhibit activity against the P388 lymphocytic leukaemia cell line.The first synthesis4s of another antileukaemic alkaloid of this group 1-methoxycanthin-6-one (44),involves the introduction of oxygen into the future position-1 of the canthinone ring system by DDQ oxidation of the tetrahydro-p-carboline lactam (45) (Scheme 8). The most notable stage in the synthesis is that in which the tetracyclic lactam (46) is converted in a one-pot process into the 4-methoxy-P-carboline derivative (47) by reaction with toluene p-sulphonic acid in methanol in the presence of trimethyl orthoformate ;methanolysis of the lactam function formation of the enol ether and dehydrogenation to the fully aromatic P-carboline occur and no oxidizing or dehydrogenating reagent appears to be required.The remaining stages of the synthesis are unexceptional. Eudistomin K sulphoxide (48)is an antiviral agent active Manzamine 8 (49) against Herpes simplex Type 1 and Polio vaccine Type 1 viruses which accompanies the parent sulphide eudistomin K in the ascidian Ritterella sigillinoides (Brewin 1958).,' Although it is present in only 0.0003 % in the organism it is not regarded as an artefact. The oncolytic alkaloid manzamine A was earlier isolated from a marine sponge of the Haliclona genus.21 Further extractions of the same sponge have recently resulted in the isolation of two more oncolytic alkaloids manzamines B and C.48The structure and relative stereochemistry of manzamine B (49) determined by the X-ray method reveal that it is very closely related to manzamine A and differs only in the presence of an epoxide function instead of the allylic alcohol grouping present in manzamine A and the lack of an N-27 to C-34 bond.The absolute configuration implied in (49) is assumed by analogy with that of manzamine A. Manzamine C (50) whose structure was obtained by X-ray crystal structure determination of its monohydrate is con- NATURAL PRODUCT REPORTS 1989-J. E. SAXTON Manzamine C (50) Manzamine E (51) R = H Manzamine F(52) R = OH H (53) Prosurugatoxin (54) R = 6-myo-inositol li, ii * (57) Surugatoxin (55) R = 6-myo-inositol Reagents i *O, 1 YOAcOH/H,O r.t. 2 days; ii h.p.1.c. separation Scheme 9 siderably simpler and consists of the (so far) unique 1 I-membered nitrogen-containing ring attached via a two-carbon unit to a P-carboline ring Yet more cytotoxic alkaloids have been isolated from a sponge of the Xestospongia genus found near Miyako Island Okina~a.~" Manzamine E (51) and manzamine F (52) also have structures closely related to those of manzamines A and B.Surprisingly manzamine F was shown to be identical with keramamine B from a third sponge which belongs to the Pellina genus for which a different incorrect structure had earlier2I been proposed. By use of methods analogous to those adopted in the synthesis21 of neosurugatoxin the pentacyclic oxindole acid (53)21 has recently been converted into prosurugatoxin (54).50 Since the autoxidation of prosurugatoxin in the presence of 1802 results in the formation of surugatoxin (55) enriched with l80 at positions 4 and 6 it is proposed that the conversion proceeds by formation of an intermediate oxetan (56) derived from the enamine tautomer of prosurugatoxin which then collapses to form a 10-membered dilactam intermediate (57) (Scheme 9).50 NATURAL PRODUCT REPORTS 1989 0 0 Br R' R2 R3 ChartellineA (58)CI Br Br Chartellamide A (62) R = H Chartelline B (59) CI Br H Chartellarnide B (63) R = 6r Chartelline C (60) CI H H Dechloro-methoxy-Chartelline A (61) OMe Br Br HR Pseudophrynamine A (64) Pseudophrynaminol (65) R = CH20H (66) R = C02Me 0 substituted pyrrolidine ring are fused in trans fashion to a tetracyclic indoline-azepine-imidazole-piperazinone Three new alkaloids which possess an isoprenoid unit attached to a physostigmine-type ring system have been isolated from the skin of the Australian burrowing frog Pseudophryne ~oriacea.~~ Pseudophrynamine A has the ester structure (a), and pseudophrynaminol the major alkaloid is the constituent alcohol (65).The third alkaloid obtained in varying amounts is the methyl ester (66); it is not presently regarded as an artefact . A synthesis of N-allylneoechinulin B (67) from the N-Verrucofortine (69) hydroxytryptophan amide (68) has been described ;54 however it has not proved possible so far to develop a method for the removal of the N-ally1 group. Verrucofortine (69) a major metabolite of Penicillium verrucosum var. cyclopium is a dioxopiperazine composed of 3 lsoprenoid Tryptamine and Tryptophan prenyltryptophan and leucine units.Neither verrucofortine nor Derivatives the non-nitrogenous metabolite verrucosidin isolated earlier The marine bryozoan Chartella papyracea (Ellis and Solander) appears to be responsible for the reported tremorgenic from which chartelline A (58) was recently isolated,32 has properties of the parent microorganism although verrucosidin Chartellines B (59) and C is a potent paralytic toxin.55 yielded five further metab~lites.~l*~~ (60) simply differ from chartelline A in the pattern of Details of the synthesis2' of (+)-fumitremorgin B by halogenation in the ring system while a third metabolite Nakagawa and Hino and their co-workers have been pub- dechloromethoxychartelline (61) is strictly an artefact which lished.56 can be prepared by methanolysis of chartelline A.51 The two The route reported earlierz1 for the synthesis of 14a-epi-remaining metabolites chartellamides A (62) and B (63) have desmethoxyfumitremorgin C has been modified and developed an unusual structure in which a fl-lactam ring and a bromo- and has resulted in the first total synthesis of (-)-fumitremorgin NATURAL PRODUCT REPORTS 1989-5.E. SAXTON H i ii Me0 \ Me0 H HI' OH OH (71) H Ho vi = OCI pc CI Me0 OH OH (74) (77) vii lv I 0 Fumitremorgin C (70) (76) viii ix I H OH Verruculogen TR-2 (78) Reagents i see above NEt, CH,Cl,; ii separation by column chromatography; iii DBU CHCl, 45 "C; iv Zn,MeOH heat 3 days; v SOCl, py -40 "C; vi see above CH,CI, MeOH; vii TFA CH,Cl,; vii OsO, py; ix NaHSO Scheme 10 C (70)57(Scheme 10).The racemic tetrahydrocarboline ester (71) prepared by the method described earlier for its unmethoxylated analogue was acylated by means of N-(2,2,2-trichloroethoxycarbony1)-L-proline acid chloride to give a separable mixture of the ester-amide (72) and its diastereo- isomer epimeric at both positions 1 and 3. Equilibration of (72) by means of DBU gave a mixture also separable of the desired cis-ester-amide (73) and (72) from which the latter could be recovered and subjected to re-equilibratioh. In this way virtually all the material could be converted into the cis-ester-amide (73). Deprotection of the proline nitrogen and slow cyclization completed the formation of the pentacyclic framework to give NATURAL PRODUCT REPORTS 1989 Okaramine A (79) R = H 0-Acetylokaramine A (80) R = Ac CH2 BlastmycetinB (82) R =a-OH BlastmycetinC (83) R = P-OH BlastmycetinA (81) (100) R = H (both epimers) MeNf? '\OMe xoH Olivoretin A (85) Blastmycetin D (84) Reagents i Phosphoric acid 0 "C,2 h Scheme 11 the penultimate product (74) from which (-hfumitremorgin C (70) was obtained by dehydration (Scheme 10).Un-fortunately the yield in this last stage was only 4% the predominant product being the result of Hofmann elim-ination.57 By an entirely analogous process the ester amide (72) was converted into the pentacyclic dioxopiperazine derivative (79 which was then dehydrogenated to (76) via the 13b-methoxy- indolenine derivative (77) by reaction with 2,3,4,5,6,6-hexa- chlorocyclohexa-2,4-dien- 1-one in methanol followed by elim- ination of methanol.Oxidation with osmium tetroxide finally resulted in the first total synthesis of (-)-verruculogen TR-2 (78) (Scheme Okaramine A is a metabolite having the unusual heptacyclic structure (79) which has been isolated from Penicillium simplicissimum AK-40 grown on okara the insoluble residue of whole soybean.5e The structure of okaramine A was determined from n.m.r. data and an X-ray crystal structure analysis of 0-acetylokaramine A (80) which reveals that it contains a dioxopiperazine structure in which one component is derived from prenyltryptophan; the origin of the other component is not at present evident.Okaramine A is stated to exhibit insecticidal properties and to show marked activity against the larvae of the silkworm Bombyx muri. Four new metabolites of the lyngbyatoxin-indolactam series have been found in the mycelia of Streptuverticillium blast- NATURAL PRODUCT REPORTS 1989-5. E. SAXTON COCCIZPr' 1 ... Ill H (87) (88) 1v.v (89) (-) -Indolactam V (86) (90) Reagents i Pr'CCl,COCl NaHCO, CH,Cl, H,O; ii NaBH, EtOH r.t.; iii hv MeCN H,O; iv NaN, CHCl, TFA; v hv MeCN; vi NaBH,CN MeOH; vii MeI NaHCO, MeOH Scheme 12 myceticurn NA34-17. Blastmycetin A (81) is in a formal sense simply composed of two indolactam V units joined via a single carbon atom at position 7 of both indole units and blastmycetin B (82) and C (83) are simple oxidation products of indolactam V.sOIn consonance with these formulations both blastmycetins B and C were converted into the related indole (-)-indolactam V by appropriate reduction methods.Blastmycetin D exhibits an n.m.r. spectrum similar to that of olivoretin A except for the monoterpenoid unit attached to C-7 of the indole ring which has a structure more akin to lyngbyatoxin. The structure (84) deduced for blastmycetin D receives support from its conversion (Scheme ll) by means of phosphoric acid into olivoretin A (85) and probably its C-19 epimer olivoretin B but this latter product was not unequivocally identified.61 An elegant stereoselective synthesis of (-)-indolactam V (86) in seven stages from tryptophan methyl ester uses photochemical reactions in its two critical stages (Scheme 12).62 The first of these involves the photocyclization of a,a-dichloroisovaleroyl tryptophan01 (87) to the pyrrolobenz-azocine derivative (88) and the second involves the rearrange- ment of the nitrene produced by loss of nitrogen from the azide derived from (88).Inevitably in this latter stage some isomeric imine (89) was obtained by alternative migration of the isopropyl group in the nitrene rather than ring expansion. The product (90) of the ring expansion was then converted into (-)-indolactam V (86) by conventional methods; a point of interest however is that reduction of (90) by means of sodium cyanoborohydride proved to be highly stereoselective and less than 5% of the epimer was produced.62 The first total synthesiss3 of teleocidins B-3 (91) and B-4 (92) consists of a lengthy 34-stage sequence in which the tetracyclic ester (93) was first prepared from indole 3-carboxylic ester (Scheme 13).64 A geranyl group was first attached to the indole nitrogen but unfortunately the product (94) did not respond to attempts at a double cyclization at positions 6 and 7; hence the cyclizations were carried out in two separate stages.The first of these was on the benzoate ester (99,obtained after removal of the terminal isopropylidene group and the second on the tertiary alcohol (96) produced after reconstruction of the side chain and introduction of the required additional methyl Oxidation adjacent to the indole nitrogen atom provided a function that could eventually be transformed into the terminal vinyl group and a nitro group was introduced at position-4 of the indole nucleus.Obvious transformations then gave a tetracyclic lactam from which the desired trans-isomer (97) (with respect to the methyl groups) was isolated by fractional crystallization. The stabilizing ester group in (97) having served its purpose was removed and a series of conventional stages then led to the polyfunctional tricyclic compounds (98) which were obtained as a mixture of four stereoisomeric racemates. Chromatographic separation gave two products (98a) and (98b) each of which presumably consisted of two racemates.Elaboration of (98a) initially gave the tetracyclic lactam (99); its epimer was not isolated. The synthesis of teleocidin B-3 (91) was then completed from (99) by a series of conventional steps. In an exactly analogous fashion teleocidin B-4 (92) was obtained from the tricyclic intermediate (98b) (Scheme 13).63 The tumour-promoting activity of indolactam and the teleocidins has excited considerable interest and they have in consequence been the subject of a number of different investigations. These include studies on the preferred conform- ations of these and several related corn pound^,^^^^^ and extensive structure-activity relationship ~tudies.~~"~~ The metabolism of (-)-indolactam V by rat liver microsomes has also been examined;s7c apparently it is converted into the much less toxic oxindole analogue (loo) but N-demethylation also occurs.NATURAL PRODUCT REPORTS 1989 vii-x I (93) xiii-xviiI (96) 02NYc02Me C02Me xviii xix H (97) Y H02CANH I xxii-xxiv / I / Y ANH I C02Me02NyH02C x xi i-xx ivI ""YC02Me xxv xxvi H (99) I xxvii-xxixI (98a) (98b) I xxv-I xxxii Teleocidin 8-3 (91) Teleocidin B-4 (92) Reagents i NaH; ii geranyl bromide; iii rn-CPBA; iv HIO,; v NaBH,; vi PhCOCl py; vii BF;Et,O; viii CH,N,; ix NaOMe; x PCC; xi Me,CHMgBr; xii MeLi; xiii (PhCO,), AIBN; xiv AcONO, Ac,O; xv NaOH (1M); xvi MnO,; xvii fractional crystallization; xviii 6M- NaOH 60 "C; xix BH;THF; xx CH,=hMe OAc 60 "C; xxi O,NCH,CO,Me NEt, PhCl 100 "C; xxii Na,S,O, Net, MeOH H,O; xxiii Pr'COCO,H NaBH,CN; xxiv chromatographic separation; xxv SuOH DCC; xxvi H, Pt ; xxvii MsCl py ; xxviii NaSePh ; xxix NaBH, LiCl; xxx KIO,; xxxi 60 "C; xxxii MeI NaHCO, Na,S,O, 70 "C Scheme 13 NATURAL PRODUCT REPORTS 1989-5.E. SAXTON R3 &H2sMe NCH2CH2Me dMe \ R'N HN HN-J R' R2 R3 Pergolide (106) O-l2'-MethyIergocornine (101) R = CHMe2 0 0-12'-Methyl-a-ergokryptine(102) R = CH2CHMe2 K cH2Nqo (104) Me OMe CH2CH20CO Me Nicergoline (105) Me OMe CHzOCO ,OEt II EtoY OE Br ii iii &)-I -Ts TS Ts vi -4" Ts Ts Aurantioclavine (107) (108) Reagents i Cp,ClZrCH=CHOEt Ni(PPh,), THF ;ii BBr * SMe,; iii NaHCO, EtOH H,O; iv CH,=CHCMe,OH Pd(OAc), P(o-MeC,H,), argon NEt, MeCN 100 "C; v TsNH, MeCN TsOH 90 "C; vi NaBH, DME MeOH H,O hv Scheme 14 in the United States and it seems more than likely that fescue 3.1 Ergot Alkaloids toxicity (' summer slump ' or 'summer syndrome ') suffered by Because wild Ipomoea (morning glory) species often infest soya livestock grazing on these pastures is entirely due to the bean plantations a survey of the ergot alkaloid content of four ergopeptide alkaloids known to be present in the fungus.Ipomoea species was undertaken in order to assess the possible Two new ergopeptide alkaloids isolated from saprophytic psychotomimetic hazard resulting from the ingestion of cultures of Claviceps purpurea strain 23 1FI have been shown to contaminated soya bean products.g8 Chanoclavine and elymo- be (101) and (102) i.e.the 0-methyl ethers of ergocornine and clavine were found in the seeds of all four species examined i.e. a-ergokryptine. 'O Ipomoea heterifolia L. I. quamoclit L. I. coccinea L. and I. The X-ray crystal structure determination of the ergolines wrightii Gray; other alkaloids identified in one or more of these (103) and (104) together with a molecular orbital study and species included penniclavine ergonovinine agroclavine ergo- comparison with nicergoline (103 have been rep~rted.~' The sine and ergosinine. However the total alkaloid content in all structures and conformations of pergolide (106) and its mesylate four species was much less than that reported for the cultivated salt have also been determined by the X-ray method.' variety I. tricolor Cav. cv.Heavenly Blue and was not regarded The approach to clavicipitic acid developed by Hegedus and as presenting a psychotomimetic hazard. his collaborators,21 which placed heavy emphasis on An analytical method involving h.p.1.c. and fluorescence palladium-catalysed reactions has been modified and has detection has been developed for the separation and quan- resulted in a new synthesis of (&)-auradoclavine (107) titative estimation of ergot alkaloids in tall fescue (Festuca (Scheme 14).73Notable stages in this synthesis include the arundinacea) contaminated with Acremonium coenophialum ;'j9 cyclization of (108) to (109) which presumably involves acid- this endophytic fungus infects most of the tall fescue pastures catalysed S,2' displacement of the allylic hydroxy-group by the NATURAL PRODUCT REPORTS 1989 0 dNHMe HN (1 10) @ @ ~ \ @;oEt'2\ ii~\ PhCON PhCON PhCON (1 13) Ii' C02Et @2cF3 &MeBoc \ \ \ -iv 0 PhCON PhCON PhCON (1 18) (112) $ 4ie "-.....\\.$* Ixiv OyC NMeBoc COzEt \ \ PhCON PhCON H PhCON '"''''\. Iiii-xi \(j: YO LII .c---PhCON PhCON Lysergic acid (115) (114) Reagents i (EtO),P(O)CN LiCN THF; ii BF;Et,O; iii DIBAL; iv BocNMe(CH,),CO,Et LDA -78 "C; v MsCl NEt,; vi 2.3 M-HCl EtOAc; vii DBU DMSO; viii fractional crystallization; ix conc. HC1 MeOH; x HC1 (dry) MeOH; xi benzoylation; xii DBU DMSO 120 "C ;xiii (CF; SO,)>O,2,6-di-t-butyl-4-methylpyridine;xiv BocNMeCH,C(CO,Me)=CH (1 19) Pd(OAc), PPh, NEt, DMF 60 "C; xv 2.5 M-HCl EtOAc; xvi NaHCO Scheme 15 NATURAL PRODUCT REPORTS,1989-5.E. SAXTON tosylenamide nitrogen atom and the reduction of (109) under photochemical conditions which selectively reduces the double bond conjugated with the indole ring and removes both tosyl groups. A new synthesis of the intermediate (110) constitutes an alternative route to (+)-6,7-secoagroclavine (1 1 l).74 The known tricyclic aldehyde (1 12) for which an improved preparation from Uhle's ketone (1 13) has been developed has been by a new route into the 2,3-dihydrolysergic acid derivative (1 14) (Scheme 15) a late intermediate in an earlier synthesis of lysergic acid (1 15). One of the stages in the sequence involves the mesylation of the hydroxy-ester (1 16). This reaction gives a by-product the oxazinone ester (1 17) 8;\ \ $9 NHCHO H Anhydrohapaloxindole A ( 121) Fontonarnide (122) which it was later discovered,75b could equally well be transformed into the desired ester (1 14).The conversion of Uhle's ketone (1 13) into the dihydro- lysergic acid ester derivative (1 14) by an independent method constitutes yet another formal total synthesis of lysergic In this approach the enol triflate (118) is coupled with the acrylic ester derivative (1 19) in a palladium-catalysed reaction to give the unsaturated ester (120) (cf. 116). Deprotection of the amino group followed by cyclization and fractional crystalliz- ation then gave the ester (114) (Scheme 15).76 4 Monoterpenoid Alkaloids 4.1 Alkaloids Containing an Unrearranged Monoterpenoid Unit Anhydrohapaloxindole A (121) and fontonamide (122) are two of the minor constituents of the blue-green alga Hapalosiphon fontinali~.~~ Both metabolites appear to be oxidation products of hapalindole A (123) the major alkaloid of this alga.In fact hapalonamide A (124) the putative precursor of fontonamide is formed together with anhydro- hapaloxindoIe A (121) and fontonamide (122) when hapalindole A is photochemically oxidized (Scheme 16) ; however hapalon- amide A (124) has not so far been detected in H. f0ntina1i.s.'~ Recent extractions of Aristotelia species have resulted in the isolation of eleven monomeric alkaloids of which eight are new and two bisindole alkaloids (q.v.)Aristofruticosine a new alkaloid from A.fructicosa Hook. f. has the novel structure (125) in which the hydroaromatic portion consists of fused pairs of five- and six-membered rings a ring system that has not previously been encountered in natural or synthetic compounds.7d Aristotelia australasica (mountain wineberry) the last of the $c N /\ NHCHO five species of the Aristotelia genus to be examined has yielded ' / -8: H aristoteline (1 26) aristotelinone (1 27) and aristoserratenine Hapalindole A ( 123) Hapalonarnide A (124) together with seven new alkaloids all of which are closely related biogenetically to aristoteline. 79 The first of these 3-epi-Reagents i 0, H,O MeOH pH8 Rose Bengal hv r.t. aristoserratenine (128) presumably arises as does aristo- Scheme 16 serratenine by cyclization of makomakine (129) (Scheme 17).R' QT@ OT@H Aristofruticosine (125) R2 R' I Aristoteline (126) H2 Aristotelinone (127) 0 Aristolasicone (132) H2 (133) H2 Aristolasicol (134) H2 \ N+ he Aristocarbinol (135) H2 3epi-Aristoserratenine ( 128) Aristolasicolone (136) 0 ii ... OH Makomakine ( 129) Aristocarbinol (135) Reagents 5% H,SO, heat 8 h; ii H'; iii enzymic oxidation Scheme 17 17 R2 R3 H2 H H2 H 0 H H,P-OH H H,a-OH H H2 OH H,a-OH H NPR 6 NATURAL PRODUCT REPORTS 1989 YH H-"-% 1 lepi-Aristoteline (130) OHC 9,1 O-Dehydroaristoteline ( 131) In accordance with this structure 3-epi-aristoserratenine gives (+)-arktoteline (126) on acid-catalysed rearrangement.The second alkaloid exhibits very similar spectra to those of aristoteline and is presently regarded as 11-epi-aristoteline (1 30). However further evidence relating to the constitution of this alkaloid would be highly desirable since the structure (1 30) is very highly strained and impossibly crowded. A third alkaloid which contains an imine function and can be reduced to aristoteline (126) must be 9,lO-dehydroaristoteline (131). Aristolasicone contains a carbonyl group which from an examination of its spectra is placed at C-15 as in (132). Unfortunately attempts to reduce aristolasicone to aristoteline were unsuccessful ;the major product of reduction by means of lithium aluminium hydride was the 8-alcohol (133) and the minor product the a-alcohol was identified with the fifth new alkaloid aristolasicol (1 34).Aristocarbinol (135) contains a primary alcohol group and only two methyl groups and presumably arises biogenetically from makomakine by an oxidative cyclization (Scheme 17). The seventh new alkaloid aristolasicolone contains both carbonyl and secondary alcohol functions and since the carbonyl oxygen can be removed completely by reduction with LiAlH the carbonyl group must be conjugated with the indole nucleus; aristolasicolone therefore has the structure (1 36).79 4.2. Corynantheine-HeteroyohimbineYohimbine Group and Related Oxindoles The alkaloid content of the previously unexamined Strychnos johnsonii Hutch. et M. B. Bass a Central and West African liane appears to be different from that of typical Strychnos species.Extractions of the root bark and stem bark have resulted in the isolation of 23 alkaloids of which 18 belong to this group.38 These include O-ethylakagerine (1 37) dihydro- cycloakagerine (1 38) O-ethylakagerine lactone (1 39) tetra- hydroakagerine (140) isoantirhine (141) antirhine lactone (142) a Al9-yohimbene (143) normalindine (144) and nor- epimalindine (145) all of which are new together with antirhine demethoxycarbonyl- 3,14-di hydrogam birtannine di hydro- corynantheol angustine akagerine (146) akagerine lactone U-Ethylakagerine (137) R = Et (138) Akagerine (146) R = H O-Ethylakagerine lactone (139) R = Et (147) R = H lsoantirhine (141) Antirhine lactone (142) Normalindine (144) @-Me at C-19 Norepimalindine (145) a-Me at C-19 OH (148) (147) dihydrodecussine tetrahydroalstonial and ajmali~inial.~~ (-)-Antirhine has also been obtained from the aerial parts of Melodinus celastroides H.and 1O-hydroxy-N,-methyl-corynantheol (148) as its chloride from the stem bark of Strychnos usam barensis Gilg .81 Rescinnaminol C,,H,,N,O, m.p. 241-243 "C,a new constituent of the roots of Thai specimens of RauwoBa serpentina is reported to have the structure (149).82 Although no evidence that is obviously contradictory to the constitution (149) is presented such a hemiacetal structure would not be expected to be stable or isolable and it is clear that this alkaloid merits further investigation. Strictine a new alkaloid from the leaves of Rhazya stricta is formulated83 as (150) mainly on the basis of its n.m.r.spectra. 14-Ketoalstonidine (151) also a new alkaloid has been found in the stem bark of Alstonia constricta together with alstonilidine and alstonidine which have previously been isolated from the root bark of this species;4oo and ajmalicine has been isolated from the leaves and twigs of Petchia ceylanica (Wight) Livera NATURAL PRODUCT REPORTS 1989-J. E. SAXTON CH2 Rescinnaminol (?) (149) H/ Vinoxine (1 52) Reagents i NaBH, MeOH WLi+ \ N Li I TMS Et F lavopereirine (1 58) COMe Me02C A il A -0Me Strictine (1 50) 14- Ketoalstonidine ( 151) C02Et ( 153) 0-H at C-3 ( 154) a-H at C-3 (157) Deplancheine (1 56) Scheme 18 Eto2ca 'Et ( 159) vii SOzPh 'Et (160) Reagents i THF -78 OC+r.t.; ii NaH THF 0 "C;iii PhS0,Cl; iv BuLi THF -78 "C;v BrCH,CHO; vi AcOH; vii NaOH H,O MeOH Scheme 19 The revised stereochemistry proposed for vinoxine (1 52)85a has been confirmed by a detailed proton and n.m.r.examination.85b The acid-induced equilibration at C-3 in some indoloquino- lizidines containing a vinylogous urethane function has been re-investigated.86 Apparently those containing the simple vinylogous system such as (153) give equilibrium mixtures in which the predominant isomer (154) is the one in which the C-3 and C-15 hydrogen atoms are cis. In contrast the doubly vinylogous urethanes containing a trans disposition of hydrogen at positions 3 and 15 [e.g.(155)] are almost completely unaffected by trifluoroacetic acid.s6 An improved version of Gribble's synthesise7" of (+)-elaeocarpidine has been A new synthesise8 of (i-)-deplancheine (156) involves as critical stage the reduction of the dihydropyridinium salt (1 57) obtained via a Polonovski reaction (Scheme 18); the synthesis is brief and direct but unfortunately this last stage produces three by-products in addition to deplancheine. Another significant contribution to synthesis in this sub- group of alkaloids by Gribble and his collaborators is illustrated by a new synthesis of flavopereirine (158) (Scheme 19).89Here a pyridylindole (159) is constructed from the dianion of N-trimethylsilyl-o-toluidine by application of Smith's synthesis NATURAL PRODUCT REPORTS 1989 \ Et co; Flavocarpine (161) Sernpervirine (162) Q-Q+ / NSiMe3 + SiMe3 R’ R2 (166a) H H (166b) CH=CH;! H (166c) H Me R’bN R2 R’ R2 13b,l4-Dihydroangustine (164) Nauclefine (163a) H H R’ = CH=CH2 R2 = H Angustine (163b) CH=CH2 H Angustidine (163c) H Me Reagents i THF -65 “C; ii 20% KOH H,O dioxan; iii I, MeOH heat 15 h Scheme 20 - Br HO - - xv-xvii xii-xiv vii-xi Et H‘ OH OCH2Ph Dihydrocorynantheol (167) +-Reagents i ButMe,SiC1 Et,N DMAP; ii DMSO (COCl), NEt,; iii Ph,P=CHCO,Et; iv BuiNF; v CH,=CHOEt NBS; vi Bu!$nH AIBN C,H, heat; vii LiAlH,; viii PhCH,Br KH 18-crown-6; ix HCl THF; x CrO,; xi separation by h.p.1.c.;xii tryptamine heat; xiii MeSO,Cl NEt,; xiv KH 18-crown-6; xv POCl, MeCN; xvi NaBH,; xvii H, PdCl, CHCl, MeOH Scheme 21 45 1 NATURAL PRODUCT REPORTS 1989-5.E. SAXTON -I iii vi vii - iv v H' c-- H' COZBU~ viii ixI ( 173) H CHO OMe Hirsuteine (171) Reagents i 3-furoyl chloride NEt,; ii NaBH, Et,O MeOH hv; iii PtO, H,; iv LiCH2C02But (5 equiv.) -78 'C+ 10 "C; v separation of epimers; vi o-O,NC,H,SeCN PBu,; vii H,O,; viii AIH,; ix HCO,Me LDA; -40 "C; x dry HCI MeOH; xi CH,Nz Scheme 22 and following protection of the indole nitrogen atom the remaining two carbon atoms required for completion of the carbon skeleton and addition of ring c were attached by reaction of the 3-lithio species derived from (160) with bromoacetaldehyde as 1,2-bis-e1ectrophile.Deprotection and dehydration then gave flavopereirine (1 58). Flavocarpine (16 1) was synthesizeda9 by essentially the same route and with appropriate modifications so were 5,6-dihydroflav~pereirine~' and sempervirine (162).'* Details of the synthesisz1 of N-benzyl-l3b 14-dihydro- nauclefine and N-benzyl- 13b 14-dihydroangustine by MacLean and his collaborators have been p~blished,~' and an extension of the same approach has led to synthesis of nauclefine (163a) angustine (163b) angustidine (163c) and (+)-13b,l4-dihydro- angustine (164) (Scheme 20).92 Since the N-benzyl group could not satisfactorily be removed from the synthetic" N-benzyl- 13b lCdihydroangustine a modified approach was needed and this was found in the condensation of the bis-trimethylsilyl derivative (1 65) prepared from 3,4-dihydro-P-carboline,with the appropriate lithium derivative (1 66).The product from (1 65) and (166b) following work-up and alkaline hydrolysis was 13b 14-dihydroangustine (164) which after dehydrogenation gave angustine (163b). Similar syntheses starting from (165) and (166a) or (166c) gave nauclefine (1 63a) or angustidine (1 63c) (Scheme 20).92 Other synthetic work in this area reported recently includes new approaches to intermediates for the synthesis of ajmali-cine93a and yohimbine alkal~ids,~~*.~ and full details of the earlier syntheses'~ 32 of vallesiachotamine 94 reserpine and a-yo him bine 95 and 9- 0-deme thy1 tu bulosine .'$ In a new approach to the synthesis of (+)-dihydro-corynantheol (167)97a tetrahydropyran ring destined to become ring D was formed by a stereoselective cyclization of the radical derived from the bromoacetal (168).Four stereoisomers of the structure (169) were obtained but those containing a trans disposition of hydrogen at the future 15 and 20 positions predominated. After reduction protection of the primary alcohol group and conversion to the corresponding blactone separation of the 4 1 mixture by h.p.1.c. gave the trans-isomer (1 70) which was converted into dihydrocorynantheol (167) by conventional methods (Scheme 2 l).07 The first total synthesisg8 of (+)-hirsuteine (171) involves an application of Ninomiya's reductive photocyclization route for the synthesis of the tetracyclic intermediate (172).In a one-pot process the oxygen attached to C-15 was then eliminated by means of an excess of the lithium derivative of t-butyl acetate; Michael addition of this anion (CH,CO,Bu') then gave an equimolecular mixture of cis-and trans-epimers at positions 15 and 20 from which the pure trans-isomer (173) was obtained. Elimination of the hydroxy-group from C-18 was achieved via the o-nitrophenylselenoxide,and the synthesis was completed by standard methods (Scheme 22).98 452 NATURAL PRODUCT REPORTS 1989 FH20CH2Ph qHZOCH2Ph 7HzOCHZPh C02Et I I II COzEt i-iii ~ Hcd-0 H-- iv C-OH HDC-0 AH0 'i \OH ]vi ... Vlll - oxo (1 76) ix x OW0\ H' '%=Me xi xii oHcO#% #Me xiii xiv ~ P hCH20- &o \o H' Me02C Me02C lxv -%//Me xvi \o Me02C (177a) 0-CHO xxc ( 177b) a-CHO xvii (-1 -Ajmalicine (1 74b) P-H at C-20 3,CsHs Reagent xv = Me2AIN (-) -Tetrahydroalstonine (174a) a-H at C-20 i-Reagents :i (a-MeCH=CH .CH(OEt), C,H,NHOTs C,H, heat; ii NaBH, MeOH ;iii PhCH,Br NaH ;iv DIBAL; v NaIO ;vi Meldrum's acid (CH,~H,),(OAC)~ MeOH ;vii heat ;viii MeOH heat; ix LiEt,BH ;X TsOH ;xi debenzylation ;xii Swern oxidation ;xiii Zn THF HCl(cat.); xiv Ag,CO, celite; xv see above; xvi tryptamine HCIO, NaBH,CN; xvii PriNH py; xviii Lawesson's reagent; xix O,NC,H,CH,Br MeCN 60 "C; xx silica gel CH,CI, r.t.Scheme 23 A new stereocontrolled synthesisg9 of (-))-tetrahydro-ring junction; similarly the isomer of (175) derived from the alstonine (174a) and (-)-ajmalicine (174b) takes advantage in (2)-alkene gives the isomer of (176) with a trans ring junction.its crucial stage of the specificity of the internal Diels-Alder Elaboration of (176) by unexceptional methods with pres- cyclization on the complex chiral unsaturated enone (175) in ervation of the stereochemistry at the future positions 15 19 which the isolated double bond has the (a-configuration. The and 20 eventually gave rise to (-)-tetrahydroalstonine (174a) product is the tricyclic compound (1 76) which contains a cis (Scheme 23). Alternatively isomerization of the intermediate 453 NATURAL PRODUCT REPORTS 1989-5. E. SAXTON HO 0 ... ~ H"'Bi:OH i,ii %:.OM; -* Ill \o Me02C Me02C Loganin aglucone ( 179) Me02C FHO H 0 2 C s e)2 Me02Cp vi vii H /' Me ~ IV v H/' Me02C Me02C0' H 6-Epielenolic acid methyl ester (182) 6-Epielenolic acid dimethyl acetal " OMe (181b) viii-x l xi xii Me 19-Epiajmalicine (178) Reagents i PCC CH,Cl,; ii rn-CPBA NaHCO, CH,Cl,; iii HCl MeOH; iv KOBu' PhMe; v 1 M-HCl;vi TFA H,O THF; vii CH,N,; viii tryptamine PhH; ix NaBH,; x heat at 50 "C; xi POCI, PhH; xii NaBH Scheme 24 Me02C H Rhazine [ (€1-Akuammidine] Vellosimine (183) Reagents i PCC; ii 2 M-KOH MeOH; iii 2 M-HCI heat Scheme 25 aldehyde (177a) gave the epimer (177b) from which by an HO entirely analogous series of reactions ( -)-ajmalicine (1 74b) was ~btained.~~ Finally 19-epiajmalicine (178) has been prepared by a synthesis from loganin aglucone (1 79) obtained by hydrolysis OCO QOMe of loganin isolated from Strychnos nux vomica (Scheme 24).loo OMe Oxidation stages gave a S-lactone (1 80) which was converted H by anhydrous hydrogen chloride in methanol into a mixture of acetals (I 8I) which without separation were converted into 6-Ajmalimine (184) epielenolic acid methyl ester (182).The synthesis was then completed by the standard route. 25).lo1 Vincorine has been shown to occur in Petchiu ceyl~nica,~~ and ajmalimine a new alkaloid from the roots of Thai 4.3 Sarpagine-Ajmaline-Picraline Group specimens of RauwolJia serpentina is the 2 1-0-trimethoxy-Vincamedine and quebrachidine have been isolated from the benzoyl ester (184) of ajmaline.lo2 stem bark of Alstonia constricta ; 3,4,5-trimethoxybenzoyl-Extractions of the leaves of Sri Lankan Alstoniu macrophylla quebrachidine previously isolated from the root bark was also Wall.have yielded N,-methyl- 1,2-dihydrostrictarnine,lo3 vinca-found.40o Vellosimine (183) has been obtained from RauwolJia majine,lo4 and two new alkaloids. The first of these on the reflexu and has been partially synthesized from rhazine (Scheme basis of its spectra is formulated as 16-hydroxy-N,-demethyl- NATURAL PRODUCT REPORTS 1989 Me0 16-Hydroxy-Nb-demethy I alstophy IIine Alstopicralamine (186) oxindole (185) 0-q a;--\ N. \ H2°H Q.-COzMe 21 I H0. H H" \ 20 Hd OMe 19 I4 HO Koumidine (187) (Z)-Akuammidine (188) 16-Epivoacarpine (189) 19(R) -19-Hydroxydihydrogelsevirine (190) /C02Me 18 N,-Demethylquaternine ( 191) Me0 \ Me0 &?Me/ M e o m '02Me Me0 Me0 \ Corialstonine (192) (194) (193) Scheme 26 alstophylline oxindole ( 185).'03 The second ( + )-alsto-picralamine is a picraline relative of structure (186).lo4 An investigationlo5into the constituents of the roots of Thai specimens of Gelsemiurn ereguns Benth.has resulted in the isolation of several known alkaloids and two new ones. The known alkaloids are koumidine gelsemine gelsevirine koumine gelsenicine 14-hydroxygelsenicine and humante-nine ; I 4-hydroxygelsedine was also isolated from the seeds. In the course of this study it was shown that koumidine (187) has the (a-configuration a conclusion that was also reached independently by Schun and Cordell;lo6both groups of workers based their conclusion on n.m.r.spectral studies. Similarly the akuammidine isolated from G. eIegans differed from authentic akuammidine from Picralima nitida Stapf which is known to have the (&)-configuration. N.m.r. spectral studies and X-ray crystal structure analysis revealed that the akuammidine from G. eIegans has the (2)-configuration and therefore has the structure (188).'05 Two new bases isolated from this same material were identified as 16-epivoacarpine (189) and ( 19R)-19-hydroxydihydrogelsevirine(190).lo5 Na-Demethylquaternine (191) is the major alkaloid of the stem bark of AIstonia coriucea a species endemic in New Caledonia. lo7A second alkaloidal constituent is the quinoline base corialstonine (192) which is included in this group because a biogenetic relationship with Na-dimethylquaternine can be postulated.Self-evident stages lead from (191) to the dihydroquinoline derivative (193) in which aromatization of the pyridine ring is accompanied by migration of C-I6 to C-2 (+194). Attachment of the final carbon atom to give corialstonine (192) poses no problems (Scheme 26)lo7 Rhazicine and rhazimine have recently been iso1ated1O8from the leaves of Australian Mefodinus acutijlorus S. V. Mull. and have been identified with the alkaloids obtained earlier from Rhazya sttictag The improbable structures initially proposed for these two alkaloids have now been shown108to be incorrect on the basis of an X-ray crystal structure determination of NATURAL PRODUCT REPORTS 1989-5.E. SAXTON 16-Epirhazinaline (197) Rhazimine (196) Rhazicine (195) R = H Reagents i CH,O NaBH,CN AcOH Lanceomigine (198) R = Me Scheme 27 Bharhingine (203) R' R2 12-Hydroxy-1 l-methoxyhenningsamine (199) OH Ac 1 l-Methoxyhenningsamine (200) H Ac 12-Hydroxy-l l-methoxydiaboline (201) OH H 11 -Methoxydiaboline (202) H H rhazicine (1 93 which is a tetrahydroquinoline derivative containing carbinolamine ether and hemiacetal functions in addition to the ester group. Rhazimine must then be the dihydroquinoline derivative (196) and if the biogenetic relationship with 16-epirhazinaline (197) outlined in Scheme 27 is correct (195) and (196) must represent the absolute configuration of rhazicine and rhazimine.A further point of interest is that this structure shows that rhazicine is nor-lanceomigine ;accordingly methylation of rhazicine (195) gave a product which was almost certainly identical with lanceo- migine (198).'08 No new completed syntheses of alkaloids in this group have been reported during the past year but the preparation of intermediates potentially capable of being transformed into strictaminelOg and ge1semine"O has been described. 4.4 Strychnine Group A new alkaloid 12-hydroxy- 11-methoxyhenningsamine (199) has been obtained together with 1 1 -methoxyhenningsamine (200) 12-hydroxy- 1 1-methoxydiaboline (201) and 1l-methoxy-diaboline (202) from the leaves root bark and stem bark of Strictici ne (204) Strychnos staudtii an erect tree from the rain forests of Cameroun ;lll although the presence of alkaloids has previously been noted this is the first systematic investigation of this particular species.Stemmadenine and vincanicine have been found in the leaves of Rhazya stricta;112*113 this is the first report of the occurrence of these alkaloids in this genus. Bharhingine (2O3)ll3 and stricticine (2O4)ll4are two new alkaloids from the same source. Bharhingine exhibits a mass spectrum similar to that of nofluorocurarine and its 'Hn.m.r. spectrum is consistent with structure (203). The (3-configuration of the double bond is postulated on the basis of nuclear Overhauser effects on the C- 18 protons when either of the two protons at C-21 is irradiated.lI3 Stricticine exhibits an n.m.r.spectrum consistent with that of epoxyakuammicine and since it is strongly dextrorotatory ([a],+5 15") it is presumed to be derived from (+)-akuammicine. Appropriate nuclear Overhauser effects are interpreted in terms of an (9-configuration at positions 19 and 20 as shown in (204). The only other new alkaloid of this group reported recently is strychnochromine a constituent of the root bark of Strychnos gossweileri Exell. from Zaire for which the unusual structure NATURAL PRODUCT REPORTS 1989 OH Strychnochromine(205) a-Colubr ine (206) I C02Me CO2Me C02Me C02Me (209) (210) I l c-- 'N \ H \ N' 0 0 H H C02Me C02Me C02Me (213) (212) (211) [a]~ -187" v,vi I C02Me Reagents i MeCH,CH,CHO AcOH PhMe heat; ii H, Pd/C; iii NaOMe; iv MeLi; v SeO,; vi NaBH Scheme 28 (205) has been on the basis of its proton and 13C for carbon atoms 6 14 15 16 and 22 and it is suggested116 n.m.r.spectra. Tentatively it is suggested that all the rings in that the earlier assignments"' for all the alkaloids in this series (205) are cis-fused; the absolute configuration is unknown. The may have to be revised. biogenesis of a molecule such as (205) is at present obscure; Recent synthetic work in this area includes an enantioselective again confirmation of the proposed structure would be route to the tubotaiwine skeleton,l18 a generalized approach to welcome. the strychnine ring and a synthesis of (&)-a-Colubrine (206) was isolated by Warnat in 1931 and tu bi folidine.2o shown by chemical means to be almost certainly 11-The construction of the tubotaiwine skeleton as in (207) methoxystrychnine a conclusion that was subsequently sup- involves initially the reaction of the tetrahydro-P-carboline ported if not unequivocally proved by its n.m.r. spectrum. derivative (208) with butyraldehyde in the presence of acid. The However it now appears"' that a-colubrine was originally product which is presumably formed via the intermediates isolated from (probably) Strychnos nux vomica as early as (209) and (210) is a single stereoisomer (21 I) the chiral 1854 in the laboratories of Mcfarlan Smith as an examination auxiliary (the a-phenylethyl group) obviously being responsible of the original specimen has established.The position of the for the very high asymmetric induction observed. Hydro- methoxy-group at C-11 has been confirmed by the existence of genolysis followed by base treatment then gave the pentacyclic nuclear Overhauser effects between the protons of this methoxy- lactam (21 2) which afforded the aminoketone (213) on reaction group and the protons at C-10 and C-12 but not the one at C-with methyl-lithium and the synthesis of (207) was completed 9. This study also resulted in a reassignment of the 13C signals by familiar methods (Scheme 28).l18 NATURAL PRODUCT REPORTS 1989-5. E. SAXTON vi vii ___) (216) viii I Me \ ix --H HH Et Tubif oIidi ne (2 14) Reagents i 4% Ba(OH), H,O dioxan 80 "C; ii PPA 85 "C; iii LiAIH, dioxan heat; iv H, Pd(OH), MeOH; v separation of epimers; vi BrCH,CH(OEt), Na,CO, dioxan heat; vii MeSH BF * Et,O CH,CI,; viii Me,kMe BF, CH,CI, 0 "C; ix Raney Ni EtOH heat Scheme 29 Angustilobine A (217) R = H Angustilobine B (218) 15-Hydroxyangustilobine A (219) R = OH 4,6-Secoangustilobinal A (220) R = CHO nor-6,7-SecoangustilobineA (224) R = H The latest synthesis120 of (& )-tubifolidine (214) differs from its predecessors in which rings c and E have been formed in one simultaneous transannular cyclization ;here the critical stage is the closure of ring E by formation of the 6,7-bond.The diastereoisomeric mixture of indolopiperidine esters (219 prepared earlier,121 was converted by standard methods into the tetracyclic thioacetal (216) (Scheme 29).Closure of ring E was then achieved by generation of the electrophilic thionium ion under very mild conditions by means of dimethyl-(methy1thio)sulphonium tetrafluoroborate and the synthesis was completed by hydrogenation and desulphurization in the presence of Raney nickel.120 4.5 Ellipticine-Uleine-Apparicine Group A total of 32 alkaloids has been isolated from the leaves stem bark and root bark of Indonesian AZstonia angustiloba Miq. and A. pneumatophora Backer ex. L. G. Den Berger.12 Of these ten are closely related to vallesamine and details of the elucidation of their structures have been published.lZ2 The two known alkaloids isolated are vallesamine and O-acetyl-vallesamine. Two new alkaloids contained two fewer hydrogen atoms than vallesamine ;neither contained a hydroxy-group or additional unsaturation and hence are formulated as allylic ethers.Angustilobine A possesses a vinyl group and hence is formulatedas(217). Angustilobine B hasonlyoneolefinicproton and hence is the alternative ally1 ether (21 8). If it is assumed that C- 15 has the same configuration as in almost all indole alkaloids then (217) and ((218) represent the complete absolute con- figuration of angustilobine A and B. A third alkaloid contains an additional oxygen atom but has the same skeleton as angusti- lobine A. Since according to the n.m.r. spectral data C-15 does not carry a proton and its 13C signal is shifted downfield by 41.5 p.p.m. the additional oxygen atom must be at C-15 and the alkaloid is 15-hydroxyangustilobine A (219); again this almost certainly gives the correct absolute configuration.The sixth alkaloid resembles angustilobine A in its hydroaromatic portion but is a secondary amine and contains an aldehyde group attached to the indole ring; both functions presumably result from fission of the 4,6-bond. This alkaloid is thus 4,6-seco- angustilobinal A (220). A seventh alkaloid has a free indole position and an N-methyl group; it has no olefinic protons but has an isolated three- proton system at C-18 and C-19. Hence C-20 must be fully substituted and in view of the chemical shifts observed a 19,20- NATURAL PRODUCT REPORTS 1989 CN R loQ=-m Me Me (225) R = H 6,7-Seco-19,20-epoxyangustilobine B 6,7-Seco-6-cyanostemmadenine(222) (226) R =CH20H (22 1 ) ; 19,2O-epoxide 6,7-Secoangustilobine B (223) n it l5 Et A'4-Vincanol (227) R = a-OH O-Methyl-1 6-epi-A'4-vincanol (229) R = P-OMe Aspidosperm idose (23 1) Vincanol (230) R = a-OH; 14,15-dihydro with greater solubility in water several glycosides of 18-hydroxyellipticine (226) 12' and several quaternary N,-glyco- sides of 1O-hydroxyellipticine,128 have been prepared.Finally a comprehensive on cytotoxic ellipti- \ 'Et \ I 1 cines is mainly focused on biochemical oxidation and the pyg QNpoH '\Et ability of the oxidized forms to form adducts with nucleophiles 'N as a key to structure-activity relationships but also includes H H C02Me (232) R'=O R2=H2 4P-Hydroxyquebrachamine (234) (233) R'= H2 R2 =O epoxide function seems the most likely.Hence this alkaloid is formulated as 6,7-seco- 19,20-epoxyangustilobineB (22 l).* The eighth alkaloid is unusual in possessing a nitrile function and on the basis of its mass and n.m.r. spectra is regarded as 6,7-seco-6-cyanostemmadenine(222). The remaining two alka- loids exhibit n.m.r. spectra similar to those of angustilobine B and A but the signals owing to H-6 are absent. These two bases are formulated as 6,7-secoangustilobine B (223) and nor-6,7- secoangustilobine A (224) respectively.122 It seems more than likely that the absolute configuration at C-15 in alkaloids (220)-(224) is the same as in vallesamine and angustilobine A (217) but the stereochemistry at the other centres is at present unknown.A further examination of the n.m.r. spectra of 10-methoxy- ellipticine has been reported with the aim of resolving the discrepancies between earlier sets of data. By means of 2D lH-13C chemical shift correlations assignments that are now claimed to be unambiguous and definitive have been made.123 Full details of the synthesisg of ellipticine by May and Moody have been p~blished.'~" The most recent synthesis of ellipticine is reported to give a 12% yield of the alkaloid in five stages from ind01e.l~~ In conception it involves a combination of the approaches of Woodward and Sainsbury. A synthesis of N,-methyl- 18-demethylellipticine (225) needed for pharmacological evaluation has also been de- scribed,126 and in attempts to prepare ellipticine derivatives It should be noted that in ref.122 the structures for (220) and (221) have been transposed. many useful data including electrochemical oxidation para- meters biological activities electronic properties of oxidized forms (e.g. CND0/2 calculations on the derived quinone- imine) molecular electrostatic isopotential maps and n-electron densities in the ellipticine ring system. 4.6 Aspidospermine-Vincamine Group Lochnericine has been obtained from the stem leaves of Petchia ceyl~nica,~~ and (-)-tabersonine venalstonidine and 16-epi- A14-vincanol from the aerial parts of Melodinus celastroides.80 Four new alkaloids were also isolated from this plant ;these are A14-vincanol (227) A14-vincamenine (228) O-methyl- 16-epi- Al4-vincano1 (229) and vincanol (230).A related species M. henryi has been reported to contain scandine and A'"-vincine in its fruits and Strictanol occurs in the leaves of Rhazya ~tricta,~l~ from which yet another new alkaloid has been is01ated.I~~ This is aspidospermidose (23 I) a glycosidic alkaloid which contains a sugar unit unusually in an oxidized form attached to the dihydroindole nitrogen atom. Hydrolysis of aspidospermidose gave aspidospermidine and a glycone containing a carbonyl group which on reduction gave a product inseparable from glucose on co-chromatography. The structure (231) was deduced from this evidence together with extensive n.m.r. studies. Other extractions have resulted in the isolation of 5-oxovincadifformine (ervinidine ?) (232) from the leaves of Pterotaberna incon~picua,~~~ which is suspected to be a parent together with Daturicarpa elliptica of the spontaneous Kisantu hybrid; and 16 alkaloids from the leaves and seeds of Stemmadenia grandzjiora (Jacq.) Miers a latex-producing shrub from Central and South America which does not appear to have been thoroughly investigated bef0~e.l~~ These alkaloids include 3-oxovincadifformine (233) and 14P-hydroxy-quebrachamine (234) previously unknown as natural products together with quebrachamine conoflorine tabersonine vinca- NATURAL PRODUCT REPORTS 1989-J.E. SAXTON Me0& '' Kopsijasminilam (235) R = OH 20-Deoxykopsijasminilam (236) R = H A'4-Kopsijasminilam(237) R = OH; A14 OH Jasminiflorine (240) R = OMe 160-OH Fruticosine (241) R = H 160-OH Fruticosamine (242) R = H 16a-OH difformine pachysiphine 3-oxotabersonine and 3-oxopachy- siphine from this group.Another species that has not been previously studied is Kopsia jasminzjlora endemic in Thailand whose leaves have now been shown to contain eight alkaloid^.'^^,^^^ Three of these belong to a new structural group which contains the 20,21- secokopsinine ring system. The structure of kopsijasminilam (235) was determined134 by the X-ray method from which it was deduced by comparison of spectroscopic data that the two related alkaloids are 20-deoxykopsijasminilam (236) and A14-kopsiJasminilam (237). Of the three other new alkaloids isolated the n.m.r.spectroscopic data for the non-aromatic moiety of one of them kopsijasmine strongly resembled those exhibited by deoxy- kopsidasine (238) and on this basis is formulated as 10-demethoxy-21 -deoxykopsidasine (239). Another new alkaloid jasminiflorine contains the fruticosine ring system and is formulated as 12-methoxyfruticosine (240) ; it was isolated d02Me Deoxykopsidasine (238) R = OMe Kopsijasmine (239) R = H CO2Me Kopsidasinine (243) R = OMe 0-Demethoxykopsidasinine (244) R = H together with the two known relatives fruticosine (241) and fruticosamine (242).134 The remaining alkaloid is also new and is only the second member of the rare kopsidasinine (243) series to be encountered. On the basis of a detailed examination of its proton and 13C n.m.r.spectra the structure (244) i.e. 10-demethoxykopsidasinine has been proposed for this alkaloid. In the course of this study detailed proton n.m.r. data were reported and revised 13C n.m.r. assignments were made.135 X-Ray crystal structure data for kopsamine and N-methoxy- carbonyl-11 -methoxy- 12-hydroxykopsinaline have been re-and the structure of the monoclinic form of the vincadifformine derivative (245) has been determined also by the X-ray method.13' In both the monoclinic and orthorhombic form (previously studiedz1) of this compound (245) rings A and B are planar ring D adopts a chair and ring E a boat conformation; however in the orthorhombic form ring c is a half-chair and in the monoclinic form it is described as having a sofa c~nformation.'~' NATURAL PRODUCT REPORTS 1989 Me0 C02Me 17-0x0-17-desacetoxyvindoline (246) " OC02Me 0 I (2471 C02Me Reagents i NaH THF Scheme 30 I) % Ho ]I6 ,I' Me02C Et C02Me I Vincadifformine (248a) Tabersonine (248b); A14 (251a) (250a) A"-Vincamine (253) 16P-OH (251b); A14 (250b); A14 A1*-16-Epivincamine(254) 16a-OH Reagents i Fremy's salt; ii 0.1 M-TFA H,O r.t.90 h; iii 1 M-HCI,70 "C 90 min; iv 0.1 M-TFA H,O 70 "C 2 h; v Zn,AcOH; vi Bu'ONO THF 0 "C Scheme 31 When treated with sodium hydride 17-0x0- 17-desacetoxy- vindoline (246) undergoes rearrangement and the product whose structure was also studied138 by the X-ray method is the carbonate ester (247); this may well be formed via an intermediate epoxide as outlined in Scheme 30.In a fascinating investigation Palmisano and his collaborators have examined the reaction of vincadiffarmine (248a) and tabersonine (248b) with Fremy's salt in an attempt to gain insight into the rearrangement of Aspidosperma to Hunteriu alka10ids.l~~ Oxidation of vincadifformine by Fremy's salt gave an 0-hydroxylamine sulphonate derivative (249a) (Scheme 31) whose structure was deduced from its spectroscopic properties and confirmed together with complete stereochemistry by X- ray crystal structure analysis. This is believed to constitute the first authenticated example of such an intermediate although analogous intermediates have been widely held to participate in oxidations with Fremy's salt.Reaction of (249a) with hy- drochloric acid at 70°C gave a mixture of the isoxazolidine derivative (250a) and the azepino[2,3-b]indole derivative (25 la). Gentler treatment of (249a) with dilute trifluoroacetic acid at room temperature gave (250a) which could be further converted into (251a) by hot dilute trifluoroacetic acid. The compounds (249b)-(25 1b) derived from tabersonine (248b) were obtained in exactly analogous fashion and the structures of the derivatives (250b) and (25 la) were confirmed in all respects by X-ray crystal structure analysis. Reductive fission of the nitrogen-oxygen bond in (250b) gave a hydroxyaminoester (252) which on diazotization NATURAL PRODUCT REPORTS 1989-J. E. SAXTON 46 I vi xv (258) lvi OMe ii iii I 0 OH + vii viii o+oH\ ix-xi I OMe 0s-C0.H ‘ N’ (260) kiii r OH iiv v -5 HO it xii / (+)-Cluebracharnine(255) lxiv 5-55 0 Et xiii xiv I Et (-)-Aspidospermidine (256) (-)-Eburnamon ine (257) Reagents i TiCl, MeOH pH 5; ii tryptamine AcOH heat; iii LiAlH, THF; iv MeSO,Cl NEt, CHCl,; v Na NH,(liq) EtOH; vi TiCl, DME; vii NaBH,; viii 5% HC1 H,O heat; ix CrO, H,SO, MeCOMe; x DIBAL Et,O; xi TsOH MeOH heat; xii CF;SO,H 110 “C; xiii LiAlH, Et,O; xiv CrO, py;XV TSOH C6H6 Scheme 32 provided an appropriate leaving group.Loss of nitrogen from the diazonium ion thus produced with concomitant fission of the 2,16-bond followed by cyclization then gave an equi- molecular mixture of A14-vincamine (253) and 16-epi-A14-vincamine (254) (Scheme 31).ls9 The most recent of (+)-quebrachamine (255) (-)-aspidospermidine (256) and (-)-eburnamonine (257) is convenient and enantioselective and starts with the chiral lactone (258) which is readily available from 2-ethyl-6-valerolactone.141The syntheses (Scheme 32) consist essentially of refined approaches to the chiral intermediates (259) (260) and (261) the racemic forms of which have already been converted into (&)-quebrachamine (&)-aspidospermidine and (&)-eburnamonine respectively. The chiral lactone (258) was also efficiently converted into the bicyclic lactone (262) which has already been used in independent syntheses of (-)-eburnamonine (257) (+)-eburnamine and (-)-eburna-menine.lQ2 In a formal sense the synthesis of (259) also constitutes the synthesis in optically active form of a number of other alkaloids e.g.vincadine vincaminorine vinca-difformine and minovine which in racemic form have already been prepared from the racemate of (259). NATURAL PRODUCT REPORTS 1989 I I C02Me C02Me (263a) R = H a-PhS at C-6 (263b) R = Et IX !(on263b) S xi,xli ____) \ Me0&-gEt -Me0o-gEtMe0oTgEt \ \ x \ 1 I I Me02C Me02C Me02C (266) (267) xiii-xvi i .xvii-xix \ Me0ayvEtMe0OTvEt \ \ C02Me Me026 CHO (-)-1 1-Methoxytabersonine (264) Reagents i EtAlCl,; ii resolution; iii BuMe,SiCl imidazole DMF; iv Zn CH,Br, TiCI, THF; v KF H,O THF; vi (COCI), PhMe 10 OC then DBMP PhMe heat; vii m-CPBA NaHCO, CH,CI, H,O; viii TFAA DBMP; ix 210OC; x Raney Ni (W-2) EtOAc; xi (p-PhOC,H,PS,), THF 0 "C; xii p-MeC,H,SOCl PriNEt, PhMe 110 OC; xiii MeI; xiv NaBH, MeOH; xv POCl, DMF; xvi 2 M-NaOH; xvii NaClO, H,O H,NSO,H MeCOMe CH,=CMeOAc; xviii CH,N,; xix 1 M-NaOMe MeOH r.t.Scheme 33 The synthesis21 of the important intermediate (263a) es- the latter was deliberately removed during the desulphurization tablished the compatibility of the indole-2,3-quinodimethane procedure. The double bond was reintroduced into the product strategy for the synthesis of Aspidosperma alkaloids carrying a (267) and the synthesis of (-)-I I-methoxytabersonine (264) methoxy-group at position 11. Details of the preparation of was completed again by use of methods previously devised.143 (263a) have now been published and the synthesis has been An exactly analogous synthesis of (+)-1I-methoxytabersonine modified to give a new synthesis of 1I-methoxytabersonine from the enantiomer of (265) was also carried out.(264) (Scheme 33).14 For this purpose the chiral unsaturated A new of the pentacyclic dienes (268a) and acid obtained as its more stable potassium salt (265) was (268b) from the previously prepared intermediate (269) prepared as illustrated and converted into the pentacyclic (Scheme 34) constitutes a formal synthesis of kopsinine intermediate (266) by the previously developed route via the aspidofractine pleiocarpine and pleiocarpinine which have intermediate (263b). Since the phenylsulphide group in (266) already been prepared from these dienes by Kuehne and his could not be removed without affecting the 14,15 double bond collaborators via the adducts (270a) and (270b).32 NATURAL PRODUCT REPORTS 1989-J.E. SAXTON I I___) (269) iii = CHp\,CHp 0 Iii iii IV v C02Me COzMe vi-viii iX ___I) OCH20Me C02Me kO2Me II (268a) kiii x-xii ... Xlll CO2Me (270a) R = H (270b) R =Me Reagents i (TMS),NLi HMPA THF -70 "C then NC.CO,Me; ii H, Pd/C; iii ethylene oxide iv MeSO,CI K,CO, CH,Cl,; v ButOK HMPA THF -75 "C ->20"C; vi NaBH,; vii MeOCH,CI Pr'NEt, 40 "C; viii AcOH MeOH r.t.; ix phenyl seleninic anhydride NEt, 65 "C; x (TMS),NK THF -70 "C; xi Me,SO,; xii 2% TsOH MeOH; xiii PhSO,CH=CH, 120 "C 3 days Scheme 34 0 II Levy's synthesis2I of tuboxenine (271) has been much improved by carrying out the 2,19 bond formation on the 0-v-a-g, \ N' \ N' lactam (272a) instead of the corresponding N,-tertiary base ;in this way fission of the tryptamine bridge (ring E) was avoided H and 3-oxotuboxenine (272b) was obtained in 55 YOyield (Scheme C02Me (272a) 35).Ig5 Reduction by means of lithium aluminium hydride then (273) gave ( +)-tuboxenine (271).The intermediate A'8-3-oxovinca- difformine (273) was prepared by a very similar route to that iii described earlier by other workers,21 and differed only in the very early stages and in the order of intermediate steps. Other synthetic work reported recently includes some preliminary experiments that preceded the synthesis of obscuri- 0-v-0-g -4 iii 44 nervidine,Ig6 a full account of a relatively old synthesis of eburnamonine and dehydroaspidospermidine,lg7a promising \ \ N H Me \ N H 'Me new approach to the aspidospermine syntheses of desethylvin~adifformine,~~~ desethyleburnamonine 150 9- lo-, Tuboxenine (271) (272b) and 11-bromovincamines and 9- lo- and 1l-bromoapovinc-Reagents i HCI H,O heat; ii Na THF heat; iii LiAlH arnines.l5I Several nor derivatives of eburnamenine have also Scheme 35 been prepared in which ring D~~~ or ring E~~~ is five-membered.18 NPR 6 NATURAL PRODUCT REPORTS,1989 R' R2 (19SI-Heyneanine hydroxyindolenine (274) H OH Coronaridine hydroxyindolenine (275) H H Voacangine hydroxyindolenine (276) OMe H Voacristine hydroxyindolenine (277) OMe OH (278) \ 3 "/ N H Monodoroindole (279) Isomonodoro i ndo le (280) OH (282) + (285) J 4.7 Catharanthine-Ibogamine Group The sixteen alkaloids isolated recently133 from the seeds and leaves of Stemmadeniu grundzjlora include coronaridine 1 1 -hydroxycoronaridine voacangine and isovoacangine from this group.Extraction of whole plants of Ervatamia coronaria var. plena from Thailand has yielded a new alkaloid (19s)- heyneanine hydroxyindolenine (274) together with coron-aridine coronaridine hydroxyindolenine (275) voacangine voacangine hydroxyindolenine (276) (-)-(19S)-heyneanine voacristine voacristine hydroxyindolenine (277) 3-oxocoron- aridine and 3-0xovoacangine.'~~ This plant is used for the treatment of cancer in Taiwan although its activity is in doubt; the principal cytotoxic alkaloid would appear to be coron- aridine.X-Ray crystal structure data for ib~gamine'~~ and 19-e~iheyneanine'~~ have been reported; this latter study has confirmed the configuration at C-19 originally deduced by Wenkert et al. Very little synthetic work has been reported during the last year. The preparation of the quinuclidine derivative (278) constitutes a new formal synthesis of ibogamine,15' the C-16 epimeric carbomethoxydesethyldihydrocleavamines have been prepared,149 and progress towards the synthesis of desethyl- coronaridine has been reported. 158 5 Bisindole Alkaloids The seeds of Monodora myristica contain two non-basic indole derivatives each of which is composed of two indole units attached to a regular monoterpenoid component.Mono-doroindole is formulated as (279) and isomonodoroindole as (280).'59 A (283) iiiA Annonidine A (284) Annonidine C (286) Reagents i 2M-HCl THF; ii 0,,salcomine; iii TFA light petroleum Scheme 36 NATURAL PRODUCT REPORTS 1989-5. E. SAXTON QJ-f cH 2 -+ y I -N H 2 Me Br-H Dragmicidin (287) (291a) i (+288) I 0 -I R' R2 (291 b) Topsentin A (288) H H Topsentin B (289) OH H Topsentin C (290) OH Br Reagents i MeCH,CH,OH N, heat 34 h Scheme 37 Me Q7 Me &X \ + Oe0 Br Br MgBr H ii,iii I 0:fi;n Q-KkD II II /R iv,v 'OThp H H Boc H Arcyriarubin A (292) R = H Arcyriarubin B (294) R = OH Reagents i THF; ii (Boc),O DMAP THF 0 "C; iii see above; iv KOH H,O; v NH,OAc Scheme 38 Annonidines A-D have been synthesized by appropriate condensations between isopentenylindole units.lG0 As example acid-catalysed condensation between 7-isopentenylindole (28 1) and the indoline derivative (282) gave a dihydroannonidine A (283) which could be dehydrogenated to annonidine A (284).160a Alternatively direct acid-catalysed condensation of (281) with 7-isopentadienylindole (285) gave a mixture of annonidine A (284) and annonidine C (286) (Scheme 36).lGob Dragmicidin (287) is a cytotoxic metabolite isolated from a deep-water marine sponge Dragmidon sp.Hallman 1917 which inhibited the in vitro growth of P388 murine leukaemia cells.1s1 This metabolite is clearly derived from two tryptophan units which are combined in the form of an unoxidized piperazine ring; this particular structural feature is so far unique.Topsentins A-C are constituents of another marine sponge Topsentia genitrix which are formulated as the imidazole derivatives (288)-(290). 162a The structure of topsentin A (288) has been confirmed by synthesis. Thus thermolysis of the quaternary hydrazine derivative (291 a) prepared by reaction of 3-bromoacetylindole with 1,l -dimethylhydrazine gave top- sentin A (288) presumably by the Koga reaction which involves self-condensation of two molecules of the intermediate (291b) obtained by rearrangement of (291a) followed by elimination (Scheme 37).lG2* The reaction of indolyl magnesium bromide with dibromo- N-methylmaleimide has been used earlier for the synthesis of the slime mould pigment arcyriarubin A (292) since in toluene solution the N-methyl derivative of arcyriarubin A is produced.In tetrahydrofuran solution however the 1 1 adduct (293) can be obtained and this has given the opportunity for the synthesis of unsymmetrically substituted maleimides. For example protection of the indole nitrogen in (293) followed by reaction with 6-(tetrahydropyrany1oxy)indolyl magnesium bromide and removal of protecting groups gives rise to arcyriarubin B (294) (Scheme 38).lG3 NATURAL PRODUCT REPORTS 1989 & H H (298) H ... -QQ-J- Vlll (297) \Q-M -vi,vii OH 0 (300) (299) Yuehchukene (296) Reagents i Bu"Li; ii CO,; iii Bu'Li; iv (297) -78 "C; v MnO, CH,Cl, r.t.; vi TFA CH,Cl, heat; vii LiBEt,H THF; viii indole HCI MeOH CH,C1 Scheme 39 CI-R' R2 Picrasidine G chloride (301) H H Picrasidine S chloride (302) OMe OMe Picrasidine T chloride (303) OH OH A new biomimetic synthesis of the ring system present in rebeccamycin aglycone [as in (295)Jhas been reported.164 A new five-stage synthesis of the anti-implantation factor yuehchukene (296) has the advantage of both regio- and stereo- chemical control and in principle is capable of modification for the preparation of close structural Reaction of indole with the aldehyde (297) by Katritzky's method gave the secondary alcohol (298).Subsequent stages included a Nazarov cyclization on the ketone (299) and attachment of indole to the tetracyclic benzylic alcohol (300) both of which were stereo- specific (Scheme 39).165 Three more new bis-8-carboline alkaloids have been isolated from the root bark of Picrasma quassioides,166 which have been shown to be very closely related quaternary alkaloids.Picra- sidine G chloride has the structure (301) picrasidine S is the dimethoxy derivative (302),166a and picrasidine T chloride is the corresponding dihydric phenol (303).lSsb Five oligomers of N,-methyltryptamine have been found in the leaves of Psychotriu oleoides Schlechter from New Caledonia and two have been found in the trunk bark of Culycodendron milnei (A. Gray) A. C. Smith from the New Hebrides.ls7 The structures of the new alkaloids were de-termined mainly from their mass spectra and no stereochemical detail is available.Three new alkaloids were isolated from P. oleoides together with psychotridine and hodgkinsine ; these are quadrigemine C (304) isopsychotridine A (305a) and isopsychotridine B (305b). The alkaloids obtained from C. milnei are hodgkinsine and a new base calycosidine whose structure has not yet been divulged except to note that it is an isomer of hodgkinsine. 16' Two new bases from the leaves and branchlets of Aristotelia australasica F.V.M. are the first bisindole alkaloids to be found in this genus.16* The 13C n.m.r. spectra of both bisaristone A (306) and bisaristone B (307) show a marked resemblance in the NATURAL PRODUCT REPORTS 1989-5.E. SAXTON Me H H Me lsopsychotridineA (305a) Quadrigemine C (304) lsopsychotridine B (305b) wM6' 0 i or ii ____t (+307) OH Aristone (308) 5 1309)I Q q q i;$F w OH / \ "'H Bisaristone A (306) MG' 0 Bisaristone B (307) Reagents i K,Fe(CN), CH,Cl, H,O. NaHCO, Bu,NHSO,; ii hu CH,Cl Scheme 40 non-aromatic region to that of aristone (308); in fact both (308) gives a possible clue; in (308) H-3 is sufficiently close to alkaloids are formed by oxidative union of two aristone the carbonyl oxygen to participate in a Norrish type I1 reaction molecules the attachment being between the indolic nitrogen giving the biradical (309). Transfer of hydrogen from nitrogen of one component and aromatic position 5' or 7' of the other.to position 3 of the indole ring generates a more stable biradical In accordance with this conclusion bisaristone B (but not (3lo) in which delocalization gives radical character to bisaristone A) was formed by chemical or photochemical positions 5 and 7 thus providing a mechanism for the coupling oxidation of aristone (Scheme 40). reaction with formation of bisaristone A (306) and B (307). The formation of bisaristone B (307) in the photochemical Details of the isolation and structure elucidationB of reaction is of some interest because this type of reaction has oxojanussine and janussines A and B from Strychnos johnsonii not previously been reported. The stereochemistry of aristone have been p~blished.~* NATURAL PRODUCT REPORTS,1989 Peceyline (311) R = Me Demethylpeceyline (313)R = H ,CH20H C02Me Kisantine (318) Also available is a description of the isolation and structure determination of peceyline (31 l) peceylanine (312)* and pelankine from Petchia ceyf~nica.~~ A fourth alkaloid isolated very recently from this plant is regarded as demethylpeceyline (3 13).170 The structure was deduced mainly from its n.m.r. and mass spectra and the position of the N-methyl group in the isovincorine unit rather than the oxidized vincorine unit from its mass spectral fragmentation pattern. The alternative structure in which both N-methyl and ethylidene groups are contained in the vincorine unit and the amino group and oxidized ethylidene group in the isovincorine unit appears not to have been convincingly * The structure illustrated for peceylanine in ref.84 differs from that proposed in the preliminary communication1s8 in that the substituents at positions 10 and I1 in the (left-hand) isovincorine unit have been transposed thus depicting peceylanine*' as the symmetrical dimer that might be expected if it were formed by oxidative dimerization of two isovincorine units. However it is clearly stated in the earlier communicati~n~~~ that 'the 'H n.m.r. spectra of peceylanine had exhibited an aromatic hydrogen singlet pattern indicative of a lack of symmetry of substitution between the two benzene rings' and hence structure (312) must be preferred. No comment is made in ref. 84 concerning this (inadvertent?) discrepancy or a possible revision of structure that might be implied.Peceylanine (312) (315) (163 (316)(16R) excluded. Certainly a relationship with peceyline is assumed but there is no record of an attempt to interrelate the two bases by a simple methylation. On the basis of nuclear Overhauser studies demethylpeceyline (3 13) has the (2)-configuration at the ethylidene group [rather than the (a-configuration depicted earliera4-169] and the oxirane function is the result of epoxidation of an (a-ethylidene group at positions 19' and 20'. If the assumed relationship between peceyline and demethylpeceyline is cor- rect peceyline obviously has the same stereochemistry at positions 19/20 and 19'/20' but additional unequivocal evidence concerning the structures of these alkaloids would be welcome.Macrospegatrine a new quaternary bisindole alkaloid isolated from Rauwo@a verticilfata as the has the structure (314) in which an N,-methylsarpaginium unit is attached via two bonds to a previously unknown macroline- derived unit according to X-ray crystal structure analysis.171b This alkaloid would appear to contain a 5,20 bond in the secondary basic unit which is a new variant of macroline; the alternative biosynthesis which would result in this bond being a 5,16 bond would require the unknown configuration at C-15 opposite to that observed in all the other alkaloids of this series. Bisnordihydrotoxiferine is stated to be the major alkaloid of Strychnos triner vis. 72 Two new bisindole alkaloids isolated from the roots of Rhazya stricta have been shown to be (16S),16'-decarbo- methoxytetrahydrosecamine (3 15) and its (1 6R)-epimer (316),173 and voacinol a new base from the leaves of Voacanga grandifolia (Miq.) Rolfe is 14,14'-methylene-bis- 18-hydroxy- tabersonine (3 17).174 Kisantine is another bis-aspidosperma alkaloid which has been found in the leaves of Pterotaberna inc~nspicua.'~~ Its structure (318) reveals that it is composed of two highly NATURAL PRODUCT REPORTS 1989-5.E. SAXTON Me02C *cOzEtEt 14,15-Dehydrotetrastachynine(320) I _I___) I C02Me COzMe Et I Et bOzMe Et 15,20-Anhydrovinblastine (321 Reagents i FeCl, vindoline pH2-3 ;ii NaBH, NH,OH H,O Scheme 41 oxidized tabersonine units attached via an oxygen atom at C-10 in one component to C-3 in the other.No fewer than seven additional oxygen atoms have been introduced the oxidation pattern in the aromatic rings being reminiscent of that in pandicine. Details of the preparation and structure elucidation of the dimeric products prepared3 by Polonovski reaction of mono- meric N-oxides of eburnane derivatives with acetic anhydride have been published;175 the structure of one of these products i.e. the ester (319) prepared from ethyl apovincaminate was confirmed by X-ray crystal structure analysis. Two bisindole alkaloids are among the 16 alkaloids encountered in the seeds and leaves of Stemmadenia grandi- flora.193One of these is 12,12’-bis(Il-hydroxycoronaridinyl) which is already known but the other 14,15-dehydro-tetrastachynine is new and was shown to have the structure (320) a phenol oxidative coupling product of 1 l-hydroxy- coronaridine and 12-hydroxytabersonine.Apparently this alkaloid has also been found in Tabernaemontana citrifolia.176 Its 14,15-dihydro derivative tetrastachynine was isolated earlier from the leaves of Bonafousia tetrastachya. 177 New methods for the synthesis of vinblastine and its derivatives continue to be explored. Recent contributions in this area include a direct new synthesis of 15,2O-anhydrovinblastine (321) via the oxidative coupling of catharanthine and vindoline by ferric ion; a yield of 77% has been reported. A possible mechanism is outlined in Scheme 41 .178 15,2O-Anhydro-vinblastine can also be obtained by an enzymic synthesis from catharanthine and vindoline through the agency of horseradish peroxidase-hydrogen peroxide followed by sodium boro-hydride;179a this synthesis is presumed to proceed via the same iminium ion intermediate (322) as is implicated in the coupling reaction initiated by ferric ions.The coupling reaction is also promoted by crude enzyme preparations obtained from suspension cultures of Catharanthus roseus.lf9** A number of coupling reactions between vindoline and various model indole derivatives have also been studied with a view to developing improved chemical routes to vin-blastine.180v181 These experiments have .culminated in the synthesis of 20’-desethyl-20’-deoxyvinblastineand 20-desethyl- 20’-deoxyvincovaline.l8OC 181 In vivo vinblastine and vincristine bind to the protein tubulin NATURAL PRODUCT REPORTS.1989 \ Vindoline + Me026 kCH2Ph C02Me (324) (325) + Reagents i HBF, PhCH,SH THF 20 "C Scheme 42 ';1 Me02Cm NCOPhle MeadN @)N H (327) (328)R'= H R2 = OH (10R) (329)R' = Oh R2 = H (10s) (330)R =OH (331)R = H and thus affect the accessibility of cysteine-SH groups. It is also noteworthy that a number of antitumour agents act by S-alkylation of -SH groups in target enzymes or coenzymes. The behaviour of vinblastine towards thiols is thus of considerable interest. This problem has been approachedls2 via a study of vinblastine models e.g. the vindoline-derived bisindole species (323) which on reaction with benzyl mercaptan in acid solution gave vindoline and the thioether (324).This presumably arises via acid fission of (323) followed by nucleophilic attack by the thiol on the intermediate iminium ion (325). Some ester (326) generated by reduction of (324) by means of benzyl mercaptan was obtained together with dibenzyl disulphide (Scheme 42). If an analogous fission of vinblastine can be achieved enzymically under physiological conditions it may well be able to act as a scavenger for thiol groups. It is of significance that vincristine which differs from vinblastine in having a formyl group instead of a methyl group on the vindoline nitrogen is not readily cleaved and cannot therefore function as an alkylating agent. In consequence the pharmacological activity (and toxicity) of vincristine is markedly different from that of vinblastine.6 Biogenetically Related Quinoline Alkaloids 6.1 Cinchona Group Relatively little new work in this area has been reported during the period under review. Details of the total of hydrocinchonidine and hydrocinchonine by Kametani and his collaborators have been published,ls3 and a new synthesis of the quinine intermediate (327) has been described.e3a Applications of the Cinchona alkaloids as chiral auxiliaries e.g. in the preparati~n~~ of stationary phases for the chromato- graphic resolution of race mate^,'^* in the asymmetric mono- esterification of malonic acids,lS5 in the stereoselective addition of diethylzinc to benzaldehyde,lS6 and as phosphinate deriva- tives in the rhodium-catalysed enantioselective hydrosilylation of aryl and alkyl ketones,lS7 have also been reported.The mass spectra of quinine quinidine and their N-oxides have been fully discussed,1s8 mainly with the object of developing a facile differentiation between the mono N-oxides which have been stated to be the initial metabolic products of the alkaloids. NATURAL PRODUCT REPORTS 1989-J. E. SAXTON 47 1 Et i ii ____) 0 (+) -(333) (334a) 0-OH a-Et 20(R) (334b) ~Y-OH, 0-Et 20(S) (332a) (20R) (335a) (20R) Camptothecin(332b) (20s) (335b) (20s) Reagents i (+)-(R)-a-methylbenzylamine N, 70 “C 20 h; ii trituration with PhMe; iii AcOH 70 “C 2 h; iv H,SO, H,O DME 50 OC N, 8 h; v o-H,NC,H,CHO TsOH(cat) PhMe heat 1 h Scheme 43 The 10,ll -dihydroxy- 10,ll-dihydroquinidines (328) and (329) which have been shown to be metabolites of quinidine in the rat,lsg have now been prepared pure for the first time by osmylation of acetylquinidine followed by separation of the diols via their isopropylidene derivatives and regeneration of the diols by acid hydrolysis.The major isomer whose structure and stereochemistry were established by the X-ray method was the (10R)-isomer (328).lgo The reduction of dihydrocinchonine by means of sodium and alcohol gives a product of m.p. 122-123 “C which has been shown by X-ray crystal structure determination to be a 1:l complex of b-lr,2‘,3’,4,1O,1 1-hexahydrocinchonine (330) and its 9-deoxy derivative (33 l).lgl 6.2 Camptothecin The synthetic approach to camptothecin derivatives by Wall and his c~llaborator~~~~ has been refined and has culminated in a synthesis of both camptothecin enantiomers (332a) and (332b).lg3 The important racemic tricyclic keto-pyridone- lactone protected as its ethylene acetal (333) was converted into the corresponding amides by reaction with (+)-(R)-a-methylbenzylamine.Trituration of the product with toluene followed by recrystallization of the less soluble diastereoisomer gave the (R,R)-amide (334a) which gave the (R)-lactone (335a) on removal of the amide group by mild acid hydrolysis. Completion of the synthesis by regeneration of the ketone from the acetal(335a) followed by Freidlander condensation with 0-aminobenzaldehyde then gave (20R)-camptothecin (332a) (Scheme 43).Mild acid hydrolysis of the less polar more soluble fraction obtained from the trituration with toluene of the mixture of (334a) and (334b) gave a sample of the pyridone- lactone enriched with the (20S)-enantiomer (335b). Repetition of the sequence of reactions outlined in Scheme 43 with use of (-)-(9-a-methylbenzylamine in the amide-forming stage finally yielded natural (209-camptothecin (332b).lg3 The racemic intermediate (333) has also been used by the same group of workers to prepare a series of 19 racemic camptothecin derivatives with substituents in the aromatic ring with the purpose of studying cytotoxic structure-activity relationships in vitr~.”~ With the notable exception of the 11-cyano and 11-hydroxy derivatives which exhibited marked activity the 11-substituted camptothecins showed only modest activity and there appeared to be a remarkable insensitivity to the nature of the substituent.In contrast the 9- and 10-substituted derivatives exhibited a higher level of dose potency and activity both in vitro and in vivo. 7 References 1 R. A. Jacquesy and J. Levesque Alkaloids of Pauridiantha Species in ‘The Alkaloids’ Vol. 30 ed. A. Brossi Academic Press New York 1987 Chapter 2. 2 M. S. 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Waterman and I.Moham-mad Acta Crystallogr. Sect. C 1987 40,326. 11 (a) S. Siddiqui S. I. Haider and S. S. Ahmad Z. Naturforsch. 1987 42B 783; (b) S. Siddiqui S. S. Ahmad and S. I. Haider Indian J. Chem. 1987 26B 279. 12 M. H. H. Nkunya H. Weenen and N. J. Koyi Phytochemistry 1987 26 2402. 13 M. Matsumoto and N. Watanabe Heterocycles 1987 26 1775. 14 M. Murase T. Koike Y. Moriya and S. Tobinaga Chem. Phatm. Bull. 1987 35 2656. I5 M. Matsumoto and N. Watanabe Heterocycles 1987 26 1743. 16 M. Kaneda T. Naid T. Kitahara S. Nakamura T. Hirata and T. Suga J. Antibiotics 1988 41 602. 17 D. P. Chakraborty S. Roy and A. K. Dutta J. Indian Chem. SOC.,1987 64 215. 18 K. Ramesh and R. S. Kapil J. Nut. Prod. 1987 50 932. 19 (a) T. Martin and C.J. Moody J. Chem. Soc. Perkin Trans. 1 1988 235; (b) T. Martin and C. J. Moody ibid. 1988 241. 20 J. K. Macleod and L. C. Monahan Tetrahedron Lett. 1988 29 391. 21 See J. E. Saxton Nut. Prod. Rep. 1989 6 2. 22 K. Nozawa S. Udagawa S. Nakajima and K. Kawai J. 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Griesser Tetrahedron Lett. 1987 28 4275. 34 A. J. Blackman T. W. Hambley K. Picker W. C. Taylor and N. Thirasasana Tetrahedron Lett. 1987 28 5561. 35 Q.-S. Yu and A. Brossi Heterocycles 1988 27 745. 36 (a) K. Shishido K. Hiroya H. Komatsu H.Fukumoto and T. Kametani J..Chem. Soc. Perkin Trans. I 1987 2491; (b) C. Wright M. Shulkind K. Jones and M. Thompson Tetrahedron Lett. 1987 28 6389. 37 A. J. Blackman D. J. Matthews and C. K. Narkowicz J. Nut. Prod. 1987 50 494. 38 G. Massiot P. Thepenier M.-J. Jacquier L. Le Men-Olivier R. Verpoorte; and C. Delaude Phytochemistry 1987 26 2839. 39 A. K. Bashir M. F. Ross and T. D. Turner Fitoterapia 1987,58 141. 40 (a) K. Allam J. A. Beutler and P. W. Le Quesne J. Nut. Prod. 1987 50 623; (b) P. Barbetti G. Grandolini G. Fardella and I. Chiappini Planta Med. 1987 289. 41 A. Aiello E. Fattorusso S. Magno and L. Mayol Tetrahedron 1987 43 5929. 42 D. Arbain and M. V. Sargent Aust. J. Chem. 1987 40 1527. 43 S. Siddiqui 0.Y. Khan S. Faizi and B.S. 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Shudo Tetrahedron 1987 43 3695. 66 K. Irie N. Hagiwara and K. Koshimizu Tetrahedron 1987 43 525 1. 67 (a) M. J. Mass J. A. Lasley C. M. Marr J. T. Arnold and V. E. Steele Carcinogenesis 1987 8 179; (b) K. Irie N. Hagiwara H. Tokuda and K. Koshimizu ibid.p. 547; (c) N. Hagiwara K Irie H. Tokuda and K. Koshimizu ibid. p. 963. 68 R. E. Wilkinson W. S. Hardcastle and C. S. McCormick J. Sci. Food Agric. 1987 39 335. 69 S. G. Yatesand R. G. Powell J.Agric. FoodChem. 1988,36,337. 70 N. Crespi-Perellino M. Ballabio B. Gioa and A. Minghetti J. Nut. Prod. 1987,50 1065. 71 E. Foresti P. Sabatino L. R. Di Sanseverino R. Fusco C. Tosi and R. Tonani Acta Crystallogr. Sect. B. 1988 44,307. 72 L. Y. Y. Ma N. Camerman J. K. Swartzendruber N. D. Jones and A. Camerman Can. J. Chem. 1987,65 256. 73 L. S. Hegedus L. J. Toro W. H. Miles and P. J. Harrington J. Org. Chem. 1987 52 3319. 74 M. Somei F. Yamada H. Ohnishi Y. Makita and M. Kuriki Heterocycles 1987 26 2823. 75 (a) T. Kurihara T. Terada S. 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Wenkert P. D. R. Moeller and Y.-J. Shi J. Org. Chem. 1988 53 2383. 87 (a) G. W. Gribble J. Org. Chem. 1970 35 1944; (6) G. W. Gribble and F. L. Switzer Synth. Commun. 1987 17 377. 88 R. Jokela A. Juntunen and M. Lounasmaa PIanta Med. 1987 386. 89 G. W. Gribble and D. A. Johnson Tetrahedron Lett. 1987 28 5259. 90 G. W. Gribble T. C. Barden and D. A. Johnson Tetrahedron 1988 44 3195. 91 Jahangir M. A. Brook D. B. MacLean and H. L. Holland Tetrahedron 1987 43 5761. 92 D. B. Repke Jahangir R. D. Clark and D.B. MacLean J. Chem. Soc. Chem. Commun. 1988 439. 93 (a)T. Naito 0.Miyata and I. Ninomiya Heterocycles 1988,27 1321; (b) A. Brandi S. Garro A. Guarna A. Goti F. Cordero and F. De Sarlo J. Org. Chem. 1988 53 2430; (c) U. K. Pandit B. Das and A. Chatterjee Tetrahedron 1987 43 4235. 94 D. Spitzner T. Zaubitzer Y.-H. Shi and E. Wenkert J. Org. Chem. 1988 53 2274. 95 S.F. Martin H. Rueger S. A. Williamson and S. Grzejszczak J. Am. Chem. SOC.,1987 109 6124. 96 T. Fujii M. Ohba and H. Hatakeyama Chem. Pharm. Bull. 1987 35 2355. NATURAL PRODUCT REPORTS 1989-J. E. SAXTON 97 M. Ihara N. Taniguchi E. Fukumoto and T. Kametani J. Chem. SOC. Chem. Commun. 1987 1438. 98 T. Naito 0.Miyata and I. Ninomiya Heterocycles 1987 26 1739. 99 S.Takano S. Satoh and K. Ogasawara J. Chem. Soc. Chem. Commun. 1988 59. 100 E. G. Baggiolini G. Pizzolato and M. R. Uskokovid Tetra-hedron 1988 44 3203. 101 J. Banerji B. Das R. Chakrabarti and J. N. Shoolery Indian J. Chem. 1987 26B 709. 102 S. Siddiqui S. S. Ahmad and S. I. Haider Planta Med. 1987 288. 103 Atta-ur-Rahman M. M. Qureshi A. Muzaffar and K. T. D. De Silva Heterocycles 1988 27 725. 104 Atta-ur-Rahman R. Nighat M. I. Choudhary and K. T. D. De Silva Heterocycles 1988 27 961. 105 S. Sakai S. Wongseripipatana D. Ponglux M. Yokota K. Ogata H. Takayama and N. Aimi Chem. Pharm. Bull. 1987,35 4668. 106 Y. Schun and G. A. Cordell Phytochemistry 1987 26 2875. 107 A. Cherif G. Massiot and L. Le Men-Olivier Heterocycles 1987 26 3055.108 W.-L. Hu J.-P. Zhu U. Piantini R. Prewo and M. Hesse Phyto-chemistry 1987 26 2625. 109 M.-L. Bennasar E. Zulaica M. Lopez and J. Bosch Tetrahedron Lett. 1988 29 2361. 110 C. Clarke I. Fleming J. M. D. Fortunak P. T. Gallagher M. C. Honan A. Mann C. 0.Nubling P. R. Raithby and J. J. Wolff Tetrahedron 1988 44 3931. 11 1 P. Thepenier M.-J. Jacquier G. Massiot L. Le Men-Olivier and C. Delaude Phytochemistry 1988 27 657. 112 N. K. Mariee A. A. Khalil A. A. Nasser M. M. Al-Hiti and M. M. Ali J. Nut. Prod. 1988 51 186. 113 Atta-ur-Rahman Habib-ur-Rehman Y. Ahmad K. Fatima and Y. Badar Planta Med. 1987 256. 114 Atta-ur-Rahman S. Khanum and T. Fatima Tetrahedron Lett. 1987 28 3609. I 15 L. Angenot C. Coune J. Quetin-Leclercq and D.Tavernier Phytochemistry 1988 27 595. 116 J. M. Culver and M. Sainsbury J. Chem. Res. 1987 304. 117 S. P. Singh V. I. Stenberg S. S.Parma and S. A. Farnum J. Pharm. Sci. 1979 68 89. 118 B. Legseir J. Henin G. Massiot and J. Vercauteren Tetrahedron Lett. 1987 28 3573. 119 (a) M. Alvarez R. Lavilla and J. Bosch Tetrahedron Lett. 1987 28,4457 ;(b)J. Bonjoch J. Quirante M. Rodriguez and J. Bosch Tetrahedron 1988 44 2087. 120 M. Amat A. Linares M.-L. Salas M. Alvarez and J. Bosch J. Chem. Soc. Chem. Commun. 1988 420. 121 J. Bosch M. Rubiralta A. Domingo J. Bolos A. Linares C. Minguillon M. Amat and J. Bonjoch J. Org. Chem. 1985 50 1516. 122 M. Zeches T. Ravao B. Richard G. Massiot and L. Le Men- Olivier J. Nut. Prod. 1987 50 714. 123 G.Commenges and R. C. Rao Heterocycles 1988 27 1395. 124 C. May and C. J. Moody J. Chem. Soc. Perkin Trans. I 1988 247. 125 S.-H. Zee and H.-P. Su J. Chinese Chem. Soc. 1987 34 135. 126 N. S. Narasimhan and D. D. Dhavale Indian J. Chem. 1986 25B 12. 127 A. Langendoen G. J. Koomen and V. K. Pandit Tetrahedron 1988 44 3627. 128 T. Honda M. Inoue M. Kato K. Shima and T. Shimamoto Chem. Pharm. Bull. 1987 35 3975. 129 G. Meunier D. De Montauzon J. Bernadou G. Grassy M. Bonnafous S. Cros and B. Meunier Mol. Pharmacol. 1988 33 93. 130 C. Li S. Wu G. Tao J. Zhang C. You Y. Zhou and L. Huang Zhongcaoyao 1987 18 52 (Chem. Abstr. 1987 107 93546). 131 Atta-ur-Rahman Habib-ur-Rehman I. Ali M. Alam and S. Perveen J. Chem. SOC. Perkin Trans. 1 1987 1701.132 G. Massiot B. Richard L. Le Men-Olivier J. De Graeve and C. Delaude Phytochemistry 1988 27 1085. 133 R. Torrenegra J. A. Pedrozo P. H. Achenbach and P. Bauereiss Phytochemistry 1988 27 1843. 134 N. Ruangrungsi K. Likhitwitayawuid V. Jongbenprasert D. Ponglux N. Aimi K. Ogata M. Yasuoka J. Haginiwa and S. Sakai Tetrahedron Lett. 1987 28 3679. 135 M. 0.Hamburger G. A. Cordell K. Likhitwitayawuid and N. Ruangrungsi Phytochemistry 1988 27 2719. 136 J. Wu P. Zheng J. Zheng and Y. Zhou Jiegou Huaxue 1987,6 47 (Chem. Abstr. 1988 108 204851). 137 P. Toffoli N. Rodier G. Lewin and J. Poisson Acta Crystallogr. 1987 43C 1231. 138 R. Z. Andriamialisoa A. Chiaroni N. Langlois Y.Langlois and C. Riche C.R. Sbances Acad. Sci. 1986 Ser. 2 303 677.139 G. Palmisano B. Danieli G. Lesma and F. Trupiano J. Org. Chem. 1988 53 1056. 140 M. Node H. Nagasawa and K. Fuji J. Am. Chem. SOC.,1987 109 7901. 141 K. Fuji M. Node H. Nagasawa Y. Naniwa and S. Terada J. Am. Chem. Soc. 1986 108 3855. 142 S. Takano M. Yonaga and K. Ogasawara Heterocycles 1982 19 1391. 143 K. Cardwell B. Hewitt M. Ladlow and P. Magnus J. Am. Chem. Soc. 1988 110 2242. 144 M. Ogawa Y. Kitagawa and M. Natsume Tetrahedron Lett. 1987 28 3985. 145 D. Cartier M. Ouahrani G. Hugel and J. Levy Heterocycles 1988 27 657. 146 J. W. Blowers J. P. Brennan and J. E. Saxton J. Chem. Soc. Perkin Trans. 1 1987 2079. 147 E. Wenkert and T. Hudlickf J. Org. Chem. 1988 53 1953. 148 A. H. Jackson P. V. R. Shannon and D. J. Wilkins Tetrahedron Lett.1987 28 4901. 149 M. E. Kuehne and T. C. Zebovitz J. Org. Chem. 1987,52,4331. 150 R. Jokela E. Karvinen A. Tolvanen and M. Lounasmaa Tetra-hedron 1988 44 2367. 151 L. Szabo L. Dobay G. Kalaus E. Gaes-Baitz J. TamaS and Cs. Sdntay Arch. Pharm. 1987 320 781. 152 G. Kalaus J. Galambos M. Kajtar-Peredy J. TamaS L. Szabo J. Sapi and Cs. Szantay Leibigs Ann. Chem. 1987 745. 153 R. Z. Andriamialisoa N. Langlois Y. Langlois B. Gillet and J.-C. Beloeil Tetrahedron 1988 44 1953. 154 P. Sharma and G. A. Cordell J. Nut. Prod. 1988 51 528. 155 M. Soriano-Garcia F. Walls A. Rodriguez and I. Lopez Celis J. Crystallogr. Spectrosc. Res. 1988 18 197. 156 I. Vencato Y. P. Mascarenhas and R. Braz F. Acta Crysrallogr. Sect. C 1987 43 762. 157 G.R. Krow D. A. Shaw B. Lynch W. Lester S. W. Szczepanski R. Raghavachari and A. E. Derome J. Org. Chem. 1988 53 2258. 158 R. J. Sundberg M. Amat and A. M. Fernando J. Org. Chem. 1987 52 3151. 159 I. Muhammad and C. M. Hasan J. Bangladesh Acad. Sci. 1987 11 1 (Chem. Abstr. 1987 107 172452). 160 (a)M. Somei T. Funamoto and T. Ohta Heterocycles 1987,26 1783; (b) H. Achenbach and D. Franke Arch. Pharm. 1987,320 91 and 574. 161 S. Kohmoto Y. Kashman 0.J. McConnell K. L. 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Yu X. Lin and Y. Zhang Yaoxue Xuebao 1987 22 833 (Chem.Abstr. 1988 108 164701); (b) X. Lin Q. Zheng Y. Zhang M. Lin D. Yu and X. Liu Jiegou Huaxue 1987 6 89 (Chem. Abstr. 1988 108 167761). 172 M. de F. F. Melo C. A. de M. Santos A. de A. Chiappeta J. F. De Mello and R. Mukherjee J. Ethnopharmacol. 1987 19 319 (Chem. Abstr. 1988 108 272). 173 Atta-ur-Rahman and K. Zaman Phytochemistry 1988 27 1926. 174 T. R. Govindachari G. Sandhya S. Chandrasekharan and K. Rajagopalan J. Chem. SOC. Chem. Commun. 1987 1137. 175 I. Moldvai Cs. Szantay Jr. G. Toth A. Vedres A. Kalman and Cs. SGntay Rec. Trav. Chim. 1988 107 335. 176 P. Potier personal communication cited in ref. 133. 177 M. Damak A. Ahond and P. Potier Bull. SOC. Chim. Fr. Part 2 1981 213. 178 J. Vukovic A.E. Goodbody J. P. Kutney and M. Misawa Tetrahedron 1988 44 325. 179 (a) A. E. Goodbody T. Endo J. Vukovic J. P. Kutney L. S. L. Choi and M. Misawa PIanta Med. 1988 136; (b)M. Misawa T. Endo A. Goodbody T. Vukovic C. Chapple L. 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ISSN:0265-0568    

DOI:10.1039/NP9890600433

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Triterpenoids J. D. Connolly and R. A. Hill Department of Chemistry Glasgo w University Glasgo w G 12 8QQ Reviewing the literature published between July 1985 and December 1987 (Continuing the coverage of literature in Natural Product Reports 1986 Vol. 3 p. 421 ) 1 Introduction 2 The Squalene Group 3 The Fusidane-Lanostane Group 4 The Dammarane-Euphane Group 4.1 Tetranortriterpenoids 4.2 Quassinoids 5 The Lupane Group 6 The Oleanane Group 7 The Ursane Group 8 The Hopane Group 9 Miscellaneous Compounds 10 References 1 Introduction This article follows the pattern of the previous report. Reviews have appeared on the constituents of Azadirachta indica' and cycloartanes.2 2 The Squalene Group The absolute configuration of the botryococcene (1) has been determined.Studies on the biosynthesis of the botryococcenes in Botryococcus braunii reveal that acetate is incorporated into the C, botryococcenes and additional carbons are derived from methi~nine.~ (4) Calculations on model systems support the following pathway for the biosynthesis of ~qualene.~Initial enzymatic allylic attack on farnesyl pyrophosphate is followed by an S,2' reaction with a second molecule of farnesyl pyrophosphate to form a n-complex which loses a proton to give presqualene pyrophosphate (2). Ionization of (2) followed by a cyclo- ..-OH H I..-/ CO;?H7 propylcarbinyl rearrangement and hydride reduction yields squalene without the involvement of a cyclobutane inter- mediate. The diol (3) another postulated intermediate in the biosynthesis of squalene is favoured neither by calculation5 nor by studies using the homogenate of Rhizopus arrhizus.6 Terbinafin (4) is a potent inhibitor of fungal squalene epoxidase.' Labelling studies suggest that 5a-stigmast-9( 1l)-en-3@-01 is biosynthesized in Costus speciosus via As(ll)-lan~~ter~lrather than AS-lanostero1.* --OH H 7C02 H 3 The Fusidane-Lanostane Group Several interesting rearranged lanostanes have been reported from Abies species.Mariesiic acids A (3,B (6) and C (7) and isomariesiic acid C (8) occur in the seeds of A. matiesii.Q*lo -COPH f71 I-, (8) ~14(15) 475 NATURAL PRODUCT REPORTS 1989 H as (11) I (13) R =O (11) R =O (12) R =O (14) R =O;23-epi as (15) [so n (17) R = H,O-OH (20)R = H,P-OH (18) R =H,wOH (19) R =O Abiesonic acid (9) the ring A seco-derivative of mariesiic acid C (7) has been obtained from oleoresin of A.sibirica." The structures of (5),9 (7),9 and (9)l' were established by X-ray analysis. The corresponding 23-0x0 derivatives of mariesiic acids A (5) and B (6) have been found in several species including A. mariesii,'. lo A. Jirma,' and A. sibirica.12 A. sibirica is the source of several other lanostanes including the seco-derivative abiesolidoic acid (1 0) whose structure was established by X-ray analysis,I3 and the 24E- and 242-isomers of 3,23-dioxoIanosta-7,24-dien-26-oic acid.14 The 242-isomer has been isolated as firmanoic acid (1 1) from A. jirma where it occurs with isofirmanoic acid (12)and the ketals firmanolide (1 3) and isofirmanolide (14).15 Javeroic acid (1 5) and phellinic acid (16) are degraded lanostanes from the fungus Phellinus pamaceus which is found on laurisilva trees.I6 The structure of javeroic acid (15) was confirmed by X-ray analysis." Several lactones astrahygrol (I 7) its 3-epimer (18) and astrahygrone (19) from the fruiting bodies of Astraeus hygrometricus," and onekotanogenin (20) from Psolus fabricii,18 have been reported.The structure of squarrofuric acid (21) from Thalictrum squarro~urn'~has been confirmed by X-ray analysis. 2o Coccinic acid from Kadsura coccinea is 3-oxolanosta-9( 1I) 24Z-dien-26-oic acid.ll Other new lanostanes are 3p,2 1 -dihydroxylanosta-8,24-diene (22) from Inonotus obliquus22 and Uvariastrum ~enkeri,~~ 3P,22,25-trihydroxylanosta-8,23-diene (23) from I.obliquus,22 24-methylenelanosta-7,9( 1 I)-dien-3P-ol from Artabotrys odoro- ti~simus.~* The sarasinosides are glycosides of the norlanostane (24) from the marine sponge Asteropus sarasino~um.~~ Other lanostane saponins include picfeltarraenin 11 from Picria fel- tarrae26 and the muscarisides D E and F from Muscari cornosum.27 The rate of isolation of compounds from the mushroom Ganoderma lucidum continues unabated and is exceeded only NATURAL PRODUCT REPORTS 1989-5. D. CONNOLLY AND R. A. HILL as (22) [OH as (22) cd" R' (51) R' (52) R' (53) R' (54) R' (55) R' (22) R5 (40) R' = H,a-OAc; R2 = OAc; R3 = H (41) R' H,a-OAc; R2 = OH; R3 = H (42) R' = H,a-OH; R2 = R3 = OAc (43) R' = H,a-OAc; R2 = OH; R3 = OAC (44) R' = H,a-OAc; R2 = H; R3 = OAc (45) R' = H,a-OH; R2 = H; R3 = OAc (46) R' = H,a-OAc; R2 = R3 = OAc (47) R' = H,P-OAc; R2 = OAC; R3 = H (48)R' =O;R2 = R3 = H (49) R' = H,a-OAc; R2 = R3 = H I = 0; R2 = H; R3 = H,a-OH = H,P-OH; R2 = H; R3 = 0 = H,P-OH; R2 = H; R3 = H,a-OH = R3 = 0; R2 = H = R3 = 0;R2 =OH I H (23) (24) {co2H ! OF OH by the proliferation of trivial names and the resultant confusion (see Nat.Prod. Rep. 1986,3,421). The compound (25) already described as ganoderic acid C and D has now appeared as ganoderic acid E while ganoderic acid E (26) has reappeared as F.28The new ganoderic acids fall into three broad groups.Ganoderic acids K (27),29 L (28),30M (29),31 N (30),31 and 0 (31)31 are based on an 11-oxolanost-8-ene system with an oxygen function at C-7. Ganoderic acids Ma (32),32M (33)32 (also 033) and its 7-methyl ether,33 M (34),32M (35),32M (36),34M (37),34Mi (38),34and M (39)34 are also lanost-8-enes but lack the 1 1-0x0 group. The third group based on a lanosta- 7,9(1l)-diene includes ganoderic acids Me (40),32M (41),32P (42),33Q (43),33 R (44),33735 S (45),33-35and T (46)33,35 (also M,34). The structure of ganoderic acid T (46) has been confirmed by X-ray analysi~.~~.~~ Ganoderic acid Me has also been described as ganoderic acid R.3s In the same paper 3p,l Sa-diacetoxylanosta-7,9( 1 1),24-trien-26-oic acid (47) is de- scribed as ganoderic acid S,36a name also given to 3-oxolanosta- 7,9( 1 1),24-trien-26-oic acid29 [the corresponding 3a-acetate (49) has also been and 3a,22S-diacetoxylanosta-7,9( 11),24-trien-26-oic acid (45).33* 35 Ganolucidic acid D which lacks C-7 oxygenation has structure (50).30Ganoderenic acids A (51),38B (52),38C (53),38D (54),38 and E (55)31 have a side- NATURAL PRODUCT REPORTS 1989 R' (64) R' (65) R' (66) R' C02H R2 as (64) = 0;R2 = CHO = 0; R2 = CH20H = H,P-OH; R2 = CH20H HO4v (74) (76) CH2 OH R2 as (64) {g-f:::H I k3 HOw (75) (77) (78) cucumarioside G from Cucumaria fr~udatrix,~~ and neothyo- nidioside from Neothyonidium magnum.46 The full details of echinosides A and B antifungal glycosides of 38,12a 17a,20S- tetrahydroxylanost-9( 11)-en- 18,2O-olide from Actinopyga echinites have appea~ed.~' Acidic hydrolysis of synaptosides S-2 and S-3 from Synapta macuZata and the crude saponins of Holothuria atra and H. scabra has yielded respectively synaptogenin (74)48 and the 1 1-oxoholothurinogenin (75).49 The roots of kidney beans contain interesting rearranged and degraded cycloartane derivatives [cf. mariesiic acid A (S)]. Glycinoeclepin A (76) (1.25 mg isolated from ca. 1 ton of powdered roots) is a natural hatching stimulus for the soybean cyst nematode; its structure was determined by X-ray analysis.50 chain enone system which undoubtedly arises by p-elimination of a 20-hydroxyl group.Several additions to the series of trisnor-derivatives the lucidenic acids G (56),30 H (57),31 I (58),31 J (59),31 K (60),31 L (61),31 and M (62),31 have been reported. A further hexanor-derivative lucidone C (63) has been isolated.30 Other neutral compounds include ganoderal A (64),29 ganoderol A (65),29 ganoderol B (66),29 ganoderiol A (67),39 ganoderiol B (68),39 ganodernenonol (69),40 gano- dermadiol (70),40 ganodermanondiol (71),41 ganodermatriol (72),40 and ganodermanontriol (73).39. 41 Different strains of G. Zucidum produce different lucidenic and ganoderic New holostane saponins include psolusoside A from Psolus fabri~ii,~~ caudinoside A from Paracaudina ran~onetii,~~The related compounds glycinoeclepins B (77) and C (78) have NATURAL PRODUCT REPORTS 198!2-J.D. CONNOLLY AND R. A. HILL OH @oAc OH HOWO p-xyl0 (79) (82) I OMe also been i~olated.~' The structure of beesioside (79) a cycloartane xyloside from the rhizomes of Beesia calthaefolia has been established by X-ray analysis.52 Cyclo-orbigenin (80) is a new genin from Astragalus orbiculat~s.~~ It occurs as the 3- 0-fl-xylopyranoside cyclo-orbicoside A.54 A vast amount of n.m.r. time was expended on the identification of triterpenoids from the guayule bush (Partheniurn argentaturn) as the cycloartane (8 1) and the corresponding lanost-8-ene in addition to known No stereochemistry was deduced. The cycloartane (8 1) has also been isolated as desoxyisofruticin B from P.lozanianum together with its epoxide precursor desoxyprefruticin B (82).56 It seems probable that the trisnor- lactone (83) arises from the hemiketal(84) with which it occurs in Viguiera ~ienfafa.~~ Methyl jessate la,l la-epoxide (85) has been isolated from Combreturn eleaegnoide~.~~ Other new cycloartanes include the 24,24-dimethyl derivative H (80) (83) (84) mixture of 23-epimers (86) as (87) cyclopholidonol(86) from Pholidota ~hinensis,~~ cycloart-25-en-3p-01 from Euphorbia nivuliu,60 the 22-methylene derivative cyclopterospermol (87) and the related 30-norcyclo-pterospermol (88) and 30-norcyclopterospermone (89) from Pterospermum heyneanum,61 the dimethyl acetal (90) from the latex of Euphorbia broteri,62 the seco-acid (91) from Abies sibiricas3 and ganwuweizic acid (92) from Schisandra sphen- ai~thera.~~ Quadranguloside a glycoside from Pass@ora quadrangularis is the 3,26-di-O-gentiobioside of 242-cycloartane-3#3,2 1,26-tri01.~~ The crystal structure of 24-methyl- enecycloartanyl acetate has been reported.66 The results of a detailed study of the biosynthesis of cycloartenol using [1,2-13C]acetate support the expected mech- anism of f~rmation.~' Several of the 13Cn.m.r.assignments of cycloartenol have been revised. The c.d. spectra of several cycloartane ketones have been published.68 NPR 6 NATURAL PRODUCT REPORTS I989 .. (93)R =Me f (100) R’ = OH; R2 = H,H; R3 = R4 = Me (101) R’ = OMe; R2 = H,H; R3 = R4 = Me (102) R’ = H; R2 =O; R3 =Me; R4 =CH20H (103) R’ = H; R2 = 0; R3 = CH20H; R4 =Me (104) R’ = H; R2 = H,a-OH; R3 = Me; R4 = CH20H There is still considerable interest in cycloartane saponins.New genins reported include quisvagenin (93) from Astragalus quisquali~,~~ cyclofoetigenins A (94)’O and B (95)” from Thalictrum foetidum and 3-dehydrocycloasgenin C (96) from Astragalus taschkendi~us.’~ The following saponins have been investigated astrambrannins I and I1 from Astragalus mem- brana~eus,~~ the astrasieversianins from A. sie~ersianus,~~-~~ cyclo-orbicioside G from A. orbi~ulatus,~~ the glycosides of PassiJlora quadrangulari~,’~ mollic acid 3-cc-~-arabinoside from Combretum m~lle,’~cyclofoetosides A80 and B81 from Thalictrum foetidum and the saponins of A.pamirensis.82 The full details of the structure of the Nervilia purpurea sterols cyclonervilasterol dehydrocyclonervilasterol and their C-24 epimersS3 and the C-24 configuration of cyclo- homonervilols4 have appeared. Cyclohomonervilasterol (95) and neocyclonervilasterol (96) are two further compounds from N. p~rpurea.’~ The C-24 configuration remains uncertain. Studies of the 13C n.m.r. assignments of cycloeucalenol and related sterols from N. purpurea have been published.83* 86 The ABC ring system of pollinastanol has been synthesized by a benzocyclobutane route.87 Fevicordin A (99) and its 2-glycoside from Fevillea cordo- foliaS8 are the first examples of norcucurbitacins with an aromatized ring A.The poisonous mushroom Hebeloma vinosophyllum contains a series of cucurbitacin glycosides the hebevinosides I-XI.89* The aglycones are hydroxyhebevino- genin (100) and methoxyhebevinogenin (101). The carniflosides are cucurbitacin glycosides from Hemsleya carn~sflora.~~ They are based on the aglycones (102) (103) and (104). The taste of these glycosides ranges from bitter to tasteless to sweet depending on the functionality. Structure (105) has been proposed for the aglycone of 22-deoxocucurbitosides A and B from Bryonia ~llba.’~ Other new cucurbitacins include 23,24- dihydro-epi-iso-cucurbitacin D (I 06) from Acanthosicyos horrid~s,~~ cucurbitacin F 25-acetate (107) from Hemsleya gracil~jlora,~~ and amarinin (log) a plant growth inhibitor from Lufla amara.S5 Transformation of 3,7,9,11-tetraoxygenatedlanostane de- rivatives into 3,7,11-trioxygenated cucurbit- 1(10)-enes and cucurbit-5( 10)-enes has been a~hieved.’~ Several papers have appeared dealing with the problems of conversion of bile acids into antibiotic triterpenoid~.~~-~~ 3/3-Acetoxylanostan-7a-o1 has been converted into 32-oxygenated derivatives for use in biosynthetic studies.loo NATURAL PRODUCT REPORTS 1989-5.D. CONNOLLY AND R. A. HILL 48 1 H (109) R =O (112) R = OAc (1 10) R = H,P-OH (113) R = H as (114) R' (115) R' = 0; R2 =OH I (117) R' =H,a-OH; R2=OH (114) R = H,@-OH (120) R' = H,@-OH; R2 = H ( 1 16) R = H,P-OAc as (118) {p (118) R' = 0; R2 = OH as (118) HOzC as (118) {fY {pH I (122) R' as (118) {P (124) R' = H,P-OH R2 = H 4 The Dammarane-Euphane Group = H,P-OH; R2 = H (1 13) from Cleome brachy~arpa,'~~ and the hexanor-derivative (114) from Euphorbia sup in^.'^^ Isofouquierone (1 15) occurs in Commiphora dalzielii with the 3-acetate (1 16) of cabraleadiol.lo6 Dammar-23E-ene-3a,20S,25-triol (1 17) the 3-epimer of iso- fouquierol has been isolated from the leaves of Betula nana and B. exilis.loS The leaves of B. pendula contain 12@,20S,25-trihydroxydammar-23-en-3-one(1 18) and the pentol (1 19).lo7 Other dammarane derivatives include damrnar-23-ene-3&25- diol (1 20) 3@-acetoxydammara-20,25-dien-17a-01 (1 2 1) and dammara-20,23-diene-3&25-diol(1 22) from Santolina oblongi- folia,'08 12-deoxyalnustic acid (123) from the female flowers of Alnus penduZa,'OQ /3-alnicanol (124) from A.maximowiezii,l10 and 3-0-malonylbetulafolientrioloxide I from B. nana subsp. exiles."' Actinostemmosides A B C D G and H are dammarane- 20-0-glycosides from Actinostemma lobaturn.'l2+'13 The aglycones involved are dammar-24-ene-3@,6a,20S,27-tetrol Three octanordammaranes mansumbinone (1 09) mansum-binol (1 lo) and 3,4-seco-mansumbinoic acid (1 1 1) have been reported from the resin of Commiphora incisa.'l' These unusual triterpenoids may be formed from 16/3,20R-dihydroxydarnmar-24-en-3-one which also occurs in the resin.lol Other degraded dammaranes include brachycarpone (1 12) whose structure was confirmed by X-ray analysisY1O2 and deacetoxybrachycarpone NATURAL PRODUCT REPORTS 1989 (125) R' = H,P-OH; R2 = OH; R3 = R4 = H (126) R' = H,P-OH; R3 = OH; R2 = R4 = H (127) R' = H,P-OH; R2 = H; R3 = R4 = OH (128) R' = H,P-OH; R2 = R3 = OH; R4 = H OH {as ( 132) (132) R=O (133) R = H,P-OH (134) R = HJOH as(132) { as ( 132) { (135) R = 0 (136) R = H,o-OAc (137) R = 0 (138) R=O (1 25) and its 20R-epimer dammar-24-ene-3/?,7P,20S,27-tetrol (1 26) dammar-24-ene-3P,7/? 18,20S,27-pentol (1 27) and dammar-24-ene-3#?,6cc,7P,20S,27-pentol(l28). Kizuta saponins K7* KIB,K, and K, from Hedera rhombe~"~ have similar aglycones namely 6aY20S,2 1,26-tetrahydroxydammar-24-en-3-one (l29) dammar-24-ene-3P,6a,205',21,26-pentol(130) and dammar-24-ene-3&6a,20,26-tetrol(1 3 1).Publications have appeared on the saponins of Nepalese Fanax species including two new compounds 24s-pseudoginsenoside F, and mono- acetylginsenoside Rd,lI5 the saponins of Chinese Bupleurum species,116 a Japanese Panax j~ponicus,~~~ ginsenoside RA from Punax quinquefolius,118 and sapanins GF-VI and GF-VII from P.gin~eng."~ Alkaline cleavage of 20s-ginsenoside Rg2peracetate afforded pure 20s-protopanaxatriol. 120 Similar alkaline treatment of saponin D from Hovenia dulcis gave jujubogenin and 20-0-a-~- rhamnopyranosyljujubogenin a new prosapogenin.121 Ziziphin the sweetness-inhibiting substance from the leaves of Zizziphusjujoba is 3-044- 0-a-L-rhamnopyranosyl-a-L-arabino-pyranosyl)-20-0-(2,3-di-O-acetyl)-cr-~-rhamnopyranosyl deri-vative of jujubogenin.122 Papers have appeared on the glycosyl- ation of dammarane~~~~-l~~ and the reaction of dammaranes with m-chloroperbenzoic acid.lZ6 The structure of wallenone (132) an interesting C, tiru-callane derivative from the leaves of Gyrinops wullu has been confirmed by X-ray analysis. 12' 3~,23S,25-Trihydroxytirucall-7-en-24-one (133) occurs in Simaba multlJIora with the known hispidol B (1 34) whose side-chain stereochemistry has now been confirmed by X-ray analysis.lZ8 The C-23 configurations of these compounds were wrongly assigned in the publication. Other tirucallanes include 21,23-epoxytirucalla-7,24-dien-3-0ne (135) and the related acetate (136) from Cornus ~apitata,~~~ nimbocinone (1 37)130 and nimbolinone (1 38)131 from Azadi- ruchta indicu and lipomelianol a crystalline mixture of the 3-0-stearate myristate palmitate and laurate of melianol from the fruits of MeIia too~endan.~~~ Details of the crystal structure analysis of methyl masticadienonate (methyl 3-oxotirucalla- 7,24-dien-26-oate) have been published.The 5-epi-euphane system has been ~ynthesi2ed.l~~ The uncertainties concerning the side-chain stereochemistry of some tirucallane and apotirucallane derivatives have been resolved by the X-ray analysis of 2 1-0-acetyltoosendontriol NATURAL PRODUCT REPORTS 1989-5. D. CONNOLLY AND R. A. HILL AcO (139) 0 (142) R =H (143) R =H; 8a,9aepoxide (144) R =OAc (145) R= BroCOO-p @OH -R3 as (149) {Xr (149) R' =H; R2=0; R3 =OAc (151) R=Ac (153) R' =H (150) R' =OMe; R2 =H,H; R3 =H (152) R =HO-)-CO (139) from M.to~sendon.~~~ Azadirachtol (14O)ls6 and its 20,22-dihydro-derivative azadirachno1,l have been isolated from Azadirach ta indica. 4.1 Tetranortriterpenoids Interesting new skeletal types continue to appear. The structure of guyanin (141) from Hortia regia was assigned on the basis of spectroscopic analysis and has since been confirmed by X-ray ana1y~is.l~~ Full details of the structure of dukunolide A (142) have been published. ls8 Two related compounds dukunolide B (143) and C (144) have also been isolated from Lansium d~mesticum.'~~ The absolute stereochemistry of dukunolide C (144) was confirmed by an X-ray analysis of thep-bromobenzoyl derivative (145).Trijugins A (146) and B (147) from Heynea trijuga are unusual ring c-contracted derivatives of methyl ang01ensate.l~' A further ring A spiro-lactone pedonin (148) from Harrisonia abyssinica has been reported. 140 Pedonin whose structure was established by X-ray analysis shows insect antifeedant activity.140 Azadirachta indica is apparently an endless source of tetranortriterpenoids. Recent additions include the modified furan derivatives isonimolicinolide (149),141 isonimolide (150),142isolimbolide (1 51),142 and isonimbocinolide (1 52),143 the degraded derivative nimolicinoic acid (I 53),14' and deacetyl- NATURAL PRODUCT REPORTS 1989 p 0JPR2 (154) R' = H,a-OH; R2 = 0 (155) R' = 0; R2 = H,H OAc co AcO" (157) R' =H; R2=Ac; R3 =H (158) R' = Ac; R2 = H; R3 = >CO (159) R' = H; R2 = Ac; R3 = >CO azadiradione (nimbocinol) (1 54).144 The above group of compounds illustrates the problems created by the use of so many similar trivial names.7-Deacetoxy-7-oxoazadirone(155) occurs in Teclea ouabanguiensis together with the ring D ketone ouabanginone (1 56).145 The bark of Turreafloribunda contains OAc 0 (163) R' = H,H; R2 = 0; R3 = H; 5a-H (164) R' = 0; R2 = H,P-OH; R3 = H; 501-H (165) R' = 0;R2 = H,P-OH; R3 = OH; 5P-H the highly oxygenated compounds A (157) B (158) and C (159).146Trichilinin (160) is a further constituent of Trichilia roka.14' Glycosides of reduced forms of anthothec01'~~ and ged~nin'~~ have been reported from Melia azedarach.A versatile synthetic route to the limonoid system (161) has been described. 150 The modified furan derivatives (1 62) and (1 63) of obacunone and limonin respectively have been isolated from Phello-dendron amurense.15' Rutaevinexic acid (164) is a modified furan derivative from Tetradium glabrifolium. 15* Graucine A (165) from Evodia grau~a'~~ has the unusual feature of a cis-fusion of rings A and B. Two further limonoids cleaved at ring A are dysoxylin (1 66) from Dysoxylurn ri~hii'~~ and the nomilin derivative (1 67) from ca1am0ndin.I~~Several papers have appeared on the biosynthesis of citrus limonoids.156-158 NATURAL PRODUCT REPORTS 1989-5. D. CONNOLLY AND R. A. HILL (173) R' (174) R' (176) R' (177) R' = tig; R2 = Ac; R3 = OH = tig; R2 = cinn; R3 = OH = R3 = H; R2 = tig = tig; R2 = R3 = H C02Me R4 RZ R 0" (180) R' = tig; (181) R' = tig; R2 = Ac; R3 = 0; R4 = H,H R2 = Ac; R3 = H,H; R4 = 0 (182) 4°C02Me (183) R' =O; R2 = H,OH (184) R' =H,OH; R2 = 0 Me02C.(185) R' = 0; R2 = H,OH (186) R' = H,OH; R2 = 0 Obacunone is the precursor Tracer work demonstrates that in the young seedlings of calamondin the open ring A lactone form of nomilin is converted into (1 67) and subsequently into isocalamin (168) which also has a cis-fusion of rings A and Treatment of atalantin (169) with boron trifluoride etherate affords the spiro- product ( 170).161 The assumed stereochemistry of merolimonol a base-induced degradation product of limonin has been confirmed spectroscopically.'62 An interesting reaction leading to the ring A system of limonin has been described.163 Photolysis of the hemiketal (171) in the presence of iodosobenzene diacetate and iodine in an oxygen atmosphere leads directly to the lactone (1 72).163 The details of the X-ray analyses of methyl angolen~ate'~~ and mexi~anolide'~~ have appeared.Amoorinin from Amoora rohituka is andirobin with the 3-carbonyl group reduced to a P-hydroxyl group.166 of limonin in Citrus fim~n.'~~ hydroxyl group. It seems probable168 that Kubo's deacetyl-azadirachtinol (see Nut. Prod. Rep. 1986 3 421) is the 1- tigloyl isomer (1 77) of (1 76). 3-Acetoxy-7-tigloylvilasinin lactone (178) was also isolated from A. indica and its structure established by X-ray analysis.168 The structure (1 79) ascribed173 to 1-cinnamoylmelianolone from Mefia azedarach seems un- likely.The reported methyl chemical shifts [a 1.78 and Sc21 .42] are more consistent with a shielded acetate methyl than a methyl ketone. A simplified procedure for the isolation of azadirachtin has been described.174 Several ring c-cleaved tetranortriterpenoids usually with modified furans related to nimbin and salannin have been reported from A. indica. The most unusual are the lactones (180) and (181).175 The others include 4-epinimbin (182),'76 desacetylnimbinolide (1 83),177 desacetylisonimbinolide (1 84),17' margosinolide (1 85),17* isomargosinolide (1 86),178 and isoaza- dirolide (1 87).179 n Detailed accounts of the work of the groups who contributed to the structural elucidation of the insect antifeedant aza-dirachtin (173) from Azadiracta indica have been pub-li~hed.'~~-'~~ These accounts are prefaced by an overview of the azadirachtin saga by Taylor.170 Several compounds related to azadirachtin have been reported. Kra~s'~~~ l'l isolated 3-deacetyl-3-cinnamoylazadirachtin(1 74) l-tigloyl-3-acetyl- 11-R2=H methoxyazadirachtinin (1 79 which arises by the opening of (187) R' =pCothe epoxide ring by the 7a-hydroxyl group and 3-tigloyl- azadirachtol (azadirachtin B172)(176) which lacks an 11- NATURAL PRODUCT REPORTS 1989 H H so & & OH (188) (190) (191) R=H (192) R =Ac I ocoY (196) R' = H,a-Me; R2 = 0 (198) R = H,P-OH (197) R' = CH2; R2 = H,a-OH (199) R = H,a-OH OMe (2021 The acetal (1 88) has been synthesized and shows antifeedant activity almost as great as that of azadirachtin.lsO The dihydrofuran derivatives (189) and (190) have also been prepared but are inactive.lsl 4.2 Quasinoids Klaineanolide A (191) whose structure was confirmed by X-ray analysis and klaineanolide B (192) from the root bark of Hannoa kfaineana182provide further examples of C, quas-sinoids.Bruceanol A (193) and B (194) are antileukaemic compounds from Brucea antidysenterica.la3The related species B.javanica is the source of bruceine H (195).ls4Two additional chaparrin derivatives (196) and (197) have been obtained from the fruits of Simaba m~ftijlora.'~~ The structure of 7-epicedronin (198) which occurs with cedronin (199) in S.cedron has been established by X-ray analysis.186 The neoquassin derivative (193) R =PhCO (195) (194) R = Me(CH2)aCO Me0 .*-O OH I I ( 2001 (2011 (203) R' = H,a-OH; R2 = H,(Y-OH (204) R' = 0; R2 = H,P-OH (200) has been isolated from Quassia amara.18' Quassin and several of its congeners in the root bark of Picrasma quassioides show acute insecticidal activity against the American cock-roach.la8 During this study a new compound 14P-hydroxy-picrasin (20l) was isolated.188Attempts to oxidize quassin with Jones' or Collins' reagents afforded the unexpected product (202) whose structure was established by X-ray analysis.1aaThe details of the crystal structure analysis of bruceine B have appeared.lgo The antimalarial activity of some quassinoids is dependent on the nature of the ester group attached to C-15.1g1 Methods for converting inactive quassinoids into cytotoxic compounds by introduction of acyl or alkyl substituents at C-15 have been described.lg2 The quassinoid glycosides reported include shinjuglycosides E (203) and F (204) from Ailanthusaltis~ima,'~~ bruceantinoside C (205) from Brucea antidysenterica,la* and yadanziosides K (206) M (207) N (208) and 0 (209) from B.javani~a.~~~~'~~ NATURAL PRODUCT REPORTS 1989-5.D. CONNOLLY AND R. A. HILL (207) R = OCPh (205) R = OAc (209) R = (208) R =H (206) R = OMOM (210) (214) I I (216) (219) R' = 0; R2 =CH2; R3 = Me (220) R' = 0; R2 = Me,OH; R3 = Me (221) R' = H,P-OH; R2 = 0; R3 = Me (222) R' = H,P-OH; R2 = CH2; R3 = CH20I-l Progress towards the total synthesis of quassimarin con- tinues.The pentacyclic intermediate (2 10) represents the furthest advance towards this g0a1.l~' The tricyclic synthon (21 1) has been prepared in optically active form.198 The full (212) (213) ao OHMe Me0 -0 I A CH20Me (217) (2'181 details of two other approaches have appeared.199.200 The hydroxy-enone system (2 12) essential for the biological activity of many quassinoids has been prepared on a steroidal model by tautomerism of the precursor (213).210 The bruceantin intermediates (214),202 (215),203 and (216)204 have been syn- thesized. Other synthetic reports concern the tricyclic analogue (2 17) of quassin205 and tricyclic quassinoid precursor (2 18).206 Reaction of quassin with sodium borohydride in the presence of alkali results in reduction of only the C-1 carbonyl with formation of a la-hydroxy deri~ative.~~' Efforts to modify ring A of ailanthone have been described.208 5 The Lupane Group lp,l la-Dihydroxylation is a common feature of (219) and (220) from Salvia deserta2Og and of nepetidone (221) and nepedinol (222) from Nepeta hindostuna.210 Six new lupanes NATURAL PRODUCT REPORTS 1989 GCH20H (223) R’ = H; R2 = CHO (224) R’ =Ac; RZ =CHO (225) R’ = H; R2 =C02H (226) R’ =Ac (227) R = H (228) R = H H0‘-O W C 0 Z H HOzC as (229)I as (223) { -i-R.,..CH200CPh (230) (231) R’ =Ac as (223) {fY(232) R’ =H ic as (223) {TY(233) R’ =H H’ H {as (234) (235) (236) R = H,F-OH (238)R = H,p-OH (237) R = H,a-OH (223)-(228) have been isolated from the lichen Pseudo-cyphellaria rubella.211 Divaroside a 3,4-secolupane glycosyl ester from the leaves of Acanthopanax divaricatus has the same aglycone (229) as chusanoside (see Nat.Prod. Rep. 1986 3 421) and differs from it only in the lack of a rhamnose unit.212 Isochusanoside has also been isolated together with its methyl ester ;213 its aglycone has the structure (230). Methyl helicterate (23 1) from Helicteres angustifolia has a 27-0-benzoyl Other lupane derivatives include :opigenin (232) a rearranged lupane from Opilia ~eltidifolia;~~~ nepehinol (233) a dia-stereoisomer of lupeol from Nepeta hindostana ;216 3,4-secolup-20(29)-en-3-oic acid from Hoya parasitica ;217 the 3-0-palmitate and 3-0-myristate of 16fl-hydroxylupeoi from Inula britan- nica;218the 3-0-caffeate of lupane-3P,20,28-triol from Betula maximowicziana ;219 betulinic acid 3-O-fl-~-maltoside from Acacia leucophloea ;220 and 20-hydroxylupan-3-one from Afnus maximawiezii.‘lo Studies on the conformation of ring A in I-0x0-and 3-0xo-triterpenoids,~~~-the preparation223 and X-ray con- 222 formations of 2/?-meth~l-~~~ and 2a-methyl-3-oxolupane-28-nit rile^,^^^ the oximes of 30-norlupan-20-one and its deriv- atives,226 and the preparation and spectroscopic properties of the C- 18 epimers of 20,29,30- trisnorlupane derivative^^^' have appeared.Peracetic acid reacts with lupane derivatives largely at C-19 albeit in low yield.228 Detailed ‘H and I3C spectroscopic analyses of lupe01~~~ and 3a-hydroxylup-20(29)-ene-23,28-dioic acid and have been published.6 The Oleanane Group Crystal structure analysis of radermasinin a cytotoxic com- pound from Radermachia sinica revealed the unusual ring E-cleaved structure (234).231 The authors suggest it is derived from an oleanane precursor. Retro-Prins cleavage of a 21-hydroxylup-20(29)-ene (235) represents a more attractive mode of formation. The tissue cultures of Akebia quinata produce the 30-nor-oleanadienoic acids (236) and (237) together with the aldehyde (238).232 Several glycosides of (236) the guianins have NATURAL PRODUCT REPORTS 1989-5. D. CONNOLLY AND R.A. HILL HO& OzH K ,CH20Hx HO HO R2 R' (239) R' = C02H; R2 = CH2OH (240) R' = R2 = CHzOH (242) R' = CH20H; R2 = Me; R3 = OH (243) R' = Me; R2 = CH20H; R3 = H (241) R' = CH20H; RZ = Me 04@(242) (247) (248) R =Me (249) R = CO2H (252) R' = H; R2 = OH; R3 = Ac (253) R' = OH; R2 = OH; R3 = Ac (255) R' = OH; R2 = H; R3 = H (2571 been reported from Guiacum Crystal struc- ture analysis of the and 18p-e~imers~~' of methyl 3p- acetoxy-1 1 -oxo-olean- 12-en-28-oate and of P-amyrin acetate238 have been published. The genins of the trachelosperosides from Trachelospermum asiaticum include trachelosperogenin D (239) E (240) and F (24 Butyacic acid (242)240 and arboreic acid (243)241 have (246) 'H as (250) (251 (254) (256) been isolated from Madhuca butyacea and Myrianthus arboreus respectively.2a,3a,24-Tri hydroxyolean- 12-en-28-oic acid (244)242 and the corresponding 1 1,13( 18)-diene (245)243 have been foupd in Prunella vulgaris. The 28-a-~-arabinopyranosyl ester and the 29-P-~-glucopyranoside of 38,23,27,29- tetra- hydroxyolean- 12-en-28-oic acid (246) are saponins from Poly-The gala ~harnaebuxus.~~~ remaining acid derivatives are rubonic acid (247) from Rubus rn01uccanus,~~~ 3a,24-di-hydroxyolean- 12-en-28-oic acid (248) and the corresponding 28,30-dioic acid (249) from Salvia ni~olsoniana,~~~ the 29- carboxylic acid as its methyl ester (250) from Trypterygium ~ilJbrdii,~~' 3-acetylmaslinic acid from Terminalia alata,24a and helicterilic acid (25 1) and its methyl ester from Helicteres angustifolia.214 Other new oleananes include 3P-acetoxyolean- 12-ene-2a 1la-diol(252) and the corresponding 18,201 1la-trio1 (253) from Salvia argentea,249 3p,22#?,24-trihydroxy-olean-12-en- 19-one (254) (sapogenin 11) from Astragalus g1ycophyll0s,~~~ olean-12-ene-l/3,3P,1la-trio1 from Maytenus h~rrida,~~~ 28,29-dihydroxyolean- 12-en-3-one (256) from Orthosphenia mexi~ana,~~~ olean- 13( 18)-ene-2a,3a-diol (hirsudiol) (257) from NATURAL PRODUCT REPORTS.1989 (258) (259) R' = Me; R2 = CH20H 0 as (260) R' = 0;R2 = OH (264) R' =H; R2=Me (262) R' = H,P-OH; R2 = H (265) R' = OH; R2 = H (263) R' = H,P-OH; 1 la,l2a-epoxide (266) R =Me (267) R = Me (269) R=CO;,H (270) R = C02H Coccufushirs~tus,~~~ lp 1 1 a-dihydroxyolean- 18-en-3-one (258) from Safvia de~erta,~~~ and the 21-angelate 22-acetate (pitto- bre~igenin),~~~ and 2 1(or 22)-tiglate 22(or 2 1)-angelate (hippo- caesc~lin)~~~ of R,-barrigenol from Pittosporum brevicalyx and Aescufis hippocastanum respectively.Olean- 12-ene- 3P,16P,23,28-tetrol (259) is the genin of corchorusin C from Corchorus acutang~fus.~~~ The structure of 12a-hydroxy-3-0~0- oleanan-28,13/3-olide (260) a constituent of dammar resin,257 has been confirmed by X-ray analysis.258 Uralenolide from Gfycyrrh'hizia urafensis is 2P,24-dihydroxyoleana- 11,13( 18)-dien- 30,228-olide (26 l).259 Two other lactones 3/3-hydroxyoleanan- 28,13P-olide (262) from Safvia fanigeraZBo and 1la 12a-epoxy- 3~-hydroxyoleanan-28,13~-olide(263) from Lepechinia glornerata,261have been reported.Full papers on bartogenic acid and congeners from Barringtonia speciosa262 and lantanilic acid from Lantana ~arnara~~~ have appeared. Treatment of methyl 12P 13/3-epoxyoleanolate with mild acid affords the 13aH- 12-0x0-derivative (264) which is readily epimerized to the more stable 13PH-e~imer.~~~ The crystal structure analysis of the 13~H-12-oxo-derivative (265) of echinocystic acid has been Reaction of 3-0x0-olean- 12-en-29-oic acid (266) with acetic anhydride and perchloric acid gave either the enol acetate (267) or the pyrone derivative (268) whose structure was established by X-ray analysis.266 It is clear from this work that the unknown product obtained by Turch and his colleagues in 1965 on treatment of the keto-acid (269) with acetic anhydride and perchloric acid is the enol acetate (270).Oxidation of methyl 3-0-acetyl-glycyrretate under electrolytic conditions resulted in a skeletal rearrangement with the formation of (271).267A similar rearrangement occurred with the corresponding glycoside glycyrrhizin trimethyl ester.267 Homoannular 9( 1l) 12-dienes are among the many products obtained by partial hydrolysis of saikosaponins a b and c under acidic or enzymatic con- ditions.268 Hydrogen peroxide-selenium dioxide in t-butyl- alcohol converts olean- 12-enes and urs-12-enes into the corresponding 1 la 12ol-epo~ides.~~~ Doubt has been cast on the validity of the structures of the supposed C-27 carboxylic acid derivatives azizic acid and manevalic acid following a 13Cn.m.r.study of quinovic acid an 491 NATURAL PRODUCT REPORTS 1989-J. D. CONNOLLY AND R. A. HILL (273) (275)R' = 0;R2 = H (272) (274) 21,22dihydro (276)R' = H,H; R2 =OH X R (280)R = H (277) (279) (281)R=Me ursane C-27 carboxylic acid.270 It is possible to distinguish between 1801- and 18P-isomers in a series of 11-0x0-olean-12- en-28-oic acid derivatives on the basis of their 13C n.m.r. shifts.271 The 13C n.m.r. spectra of a series of 18a-and 18p- glycyrrhetic acid derivative^,^'^ of glabrolide and glycyrrhetic and of acutangulic acid and tangulic have been analysed. The following investigations in the oleanane series have been published the oxidation of 1-ketones and 3-ketones with peracid;275 the study of the ring A conformation of 2- methyl-l-ketone~~~' and A-nor-derivatives ;277 the mass spectral fragmentation of ring A thioketals;278 and the modification of glycyrrhetic A novel method for cleavage of glycosidic bonds of saponins by an alcoholic alkali metal solution containing a trace of water has been reported.28L Studies on the alfalfa saponins have demonstrated the value of COSY and delayed COSY techniques for the determination of the sequence and points of attachment of residues in a sugar chain.282 It has been demonstrated that heating certain saponins above their melting points affords simple cleavage of sugar-sugar and sugar-aglycone bonds.283 Saponins D, E F, F, and G from Gymnocladus chinensis are of interest since they contain glycosyl monoterpene carboxylic acid 285 Publications have appeared on the fol- lowing oleanane saponins camellidins I and I1 from Camellia 287 japonica,286* silphiosides A288 and C28s from Silphium perfoliatum ;aridanin from Tetrapleura teraptera ;2g0 saponins of Ilex corn~ta;~~~ saponin S 1 from Bupleurum chinense ;292 thalicoside B from Thalictrum minus ;293 molluscicidal saponins Entada phaseoloides ;319 aesculusides A320 and B321 from Aesculus indica; anagallosides A B and C from Anagallis ar~enis;~~~ ruddeanins saponins from Calendula arven~is;~~~ B324and D325from Anemome raddeana ;huzhangosides A B C and D from Anemone riv~laris;~~' anchusosides qs2' and 5328 from Anchusa oficinalis ;saponins of Polygala jap~nica~~~ and Fagus sylvatica;330 uralsaponins A and B from Glycyrrhiza uralensis;331 saponins from Caltha p01ypetala~~~ and Gardenia latifolia;333tauroside E from Hedera taurica ;334 kizuta saponins K and K, from Hedera rh~mbea;~~~ saponins of Hedera nepalen~is~~' and Galega oficinalis ;337 sophoraflavoside I from Sophoraflavescens ;338 liangwanosides I and I1 from Nothopanax dela~ayi;~~' ilexosides A and B from Ilex chinensis ;340 saponin D from Gymnocladus chinen~is;~~' and zanhin and medicagenin new prosaponins from Zanha golingensi~.~~~ Studies on the solubilizing properties of saponins have been Borate ion-exchange HPLC has been used effectively for the analysis and separation of ~aponins.~~~ Glycyrrhizin P-D-glucuronidase has been isolated from a Eubacterium species.345 The structure of 5P,24-cyclofriedelan-3-one(272) a novel cyclopropane triterpenoid from Euphorbia neriifolia has been established by X-ray analysis.34s Two further members of the pachysanane group pachysana- 16,21 -diene-3P,28-diol (273) and pachysan- 16-ene-3P,28-diol(274) have been isolated from Pachysandra terminali~.~~~ The evidence for two triterpenoids supposedly glut-5( lO)-en-3-one (275)348 and glut-5( 10)-en- 1P-01 (276)349 from Adrachne cordfolia is highly suspect.The structure of the 'glut-5( 10)-en- 1-one ' used as a reference has Aesculus indi~a,~~~ and Xeromphis spinosa ;2g7 arvenosides A and B from Calendula arvensis ;298 3-@P-~-xylopyranoside of oleanolic acid from Xeromphis spinosa ;299 saponins of Tetra-panax papyriferum;300 rotundiosides A B C D and G from Bupleurum rotundifolium ;301 saponins of Sapindus delavayi;302 hemsloside 'H from Hemsleya chinensis ;303 medicosides C,304 I,305 and J306 from Medicago sativa ;saponins from Bupleurum kunmingense ;307 saxifragifolins A B C and D from Anrosace saxifragifolia ;308 saponins of Quillaja saponaria309 and Phyto-lacca dodecandra ;310 glochidioside from Glochidion heyneanum ;311 saponins of Cyamopsis tetragonoloba312 and Glycine antiviral saponins of Anagallis arvensis;314 saponins of Phytolacca americana ;315 ardisiacrispins A and B from Ardisia crispa ;316 saponins of Spilanthes a~mella~,~ and Maesa chisia var.ang~stifolia;~~~ entada saponin I11 from from Cussonia ~picata,~'~ been shown to be incorrect.350 The full details of zeylasteral and Swartzia madagascarien~is,~~~ its congeners from Kokoona ~eylanica~~' and the antileukaemic maytenfoliol and its congeners from Maytenus diver~ifolia~~' have appeared.Maytensifolin B (277) is a further compound from M. di~ersifolia.~~~ Treatment of friedelin with oxygen and potassium t-butoxide affords inter alia the ring A-cleaved products (278) and (279).353 A detailed lH and 13C n.m.r. of bryonolic acid (280) and some derivatives leads to the conclusion that the con- formation in solution of rings D and E in the D:C-friedo- oleanane series is dependent on the nature of C-29. If it is tetrahedral rings D and E adopt a mixture of chair-chair and boat-boat conformations.In contrast a trigonal C-29 results in a chair-chair conformation. It is unfortunate that the summary of this reference states the opposite conclusion. The crystal structure of methyl bryonolate (28 1)355 reveals a chair-chair NATURAL PRODUCT REPORTS 1989 I, (282) R' =O; R2 =Me; R3 =OH (283) R' = H,P-OH; R2 = CH20H; R3 = H (284) R3=H (286) R' = Me; R2 = CH20H; R3 = H (287) R' = CH2OH; R2 = Me; R3 = OH (288) R' = R2 = Me; R3 = OH (289) R' = Me; R2 = C02H; R3 = H (290) R' = R2 = CH20H; R3 = H (291) R' = C02H; R2 = CH20H; R3 = H 130 HO.. (293) R =OAc (304) R = H; Am'30) conformation for rings D and E albeit distorted to relieve the spinosa in which it occurs interaction between C-27 and C-29.In 1985 Gottlieb and his glycoside desfontainoside. colleagues arrived at the conclusion that the conformation of friedelanes depended on the nature of (2-29 on the basis of 13C n.m.r. Subsequent n.m.r. studies on friedelin357 and glycosides have also been 7-0xofriedelin~~~ support the boat-boat conformation for rings D and E. Later papers358 on the assignment of the 13Cresonances glycosides in of friedelin derivatives have ignored Gottlieb's paper and his suggested reassignments. What are the correct 13C chemical Rosa ro~burghii.~~~ Erantic shifts of C-26 and C-27? hydroxyurs- 12-en-28-oic acid The taraxerane derivatives reported include the hydroxy- ketone (282) from Myrica r~bra,~~~ taraxer- 14-ene-3P,24-diol (283) from Parsonia lae~igata,~~~ and the 3,4-seco-acid (284) and (297) from Stizophyllum ripari~m,~'~ from Euphorbia broteri6* 7 The Ursane Group Desfontainic acid (285) the first example of a triterpenoid linked to an iridoid has been isolated from Desfontainia (285) I (295) R1 = E-feruloyl; R2 = H (296) R' =Z-feruloyl; R2 = H with the corresponding 28-0- Three related compounds 24- hydroxytormentic acid (286) 7a,23-dihydroxytormentic acid (287) and 7a-hydroxytormentic acid (288) and their 28-0- obtained from D.spino~a.~~* Trachelosperogenins A (289) B (290) and C (291) are found as Trachelospermum a~iaticum.~~~ Another 19a-hydroxy derivative roxburic acid (292) has been isolated from acid (293)365 and 2P,3a,23-tri-(294)366 are constituents of Actinidia eriantha and Nepeta hindostana respectively.Ursanes with cytotoxic activity include the ferulate esters (295) (296) regelin (298) whose structure was confirmed by X-ray analysis and regelinol (299) from Tripterygium regelii.368 A third compound from T. regelii regelide was shown by X-ray analysis to be identicaI with the oleanane lactone abruslactone A (wilforlide B) (see Nat. Prod. Rep. 1985 2 l).368 3P-Acetoxy-2a,l la-dihydroxyurs- 12-ene (300) and the acetoxy-trio1 (301) occur in Salvia argentea with NATURAL PRODUCT REPORTS 1989-5. D. CONNOLLY AND R. A. HILL $02Me *R2 \i\ (300) R' = R2 = H (298) R =Me (301) R' = OH; R2= H (302) R' = H; R2 =OH (306) R (307) R (299) R = CH20H (303) R' = R2 = OH (308) R I as (306) as (306) = C02H; 180-H; 20a-Me = Me; 180-H; 20P-Me = C02H; 18a-H; 200-Me (309) R = Me (310) R =Me (311) 180-H; 20a-Me R (313) R' =H; R2 =gly (315) R' = H,P-OH; R2 = H (314) R' = gly; R2 = H (316) R' =O; R2=Me (317) R' = 0; R2 = OH; R3 = H (318) R' = H,a-OH; R2 = H; R3 = OH (319) R' = H,a-OH; R2 = R3 = OH the corresponding 20P-hydroxy-derivatives (302) and (303).249 Two ursa- 12,20(30)-dienes (304) and (305) have been obtained from Prunella ~ulgaris.~~~ Several saponins have been isolated from Ilex pubescens.Japanese workers have published the structures (306) and (307) for ilexgenins A369and B,370respectively. The latter is unusual in having the configuration at C-20 reversed i.e. 20s (not 30s as published).Chinese workers have proposed the 18a-H structure (308) for the sapogenin of their ilexsaponin A.371 Carissol from Carissa corandas is claimed to be the 19R,20S- diastereoisomer (309) of ~z-amyrin.~~~ Other ursanes include The 13C n.m.r. resonances of quinovic acid (3P-hydroxyurs- 12-ene-27,28-dioic acid) have been assigned. 270 Two glycosides of quinovic acid have been reported from Guettarda A 2D n.m.r. study of the ring A of 3-ketotriterpenoids supports the chair c~nformation.~~~ A crystal structure analysis of methyl 3-oxours- 12-en-28-oate has been X-Ray analysis has revealed the taraxastane structure (3 12) for a compound from OpiIia celtidif~Iia~~O (published as 3p- acetoxyursan-28,20-olide).Two taraxastane saponins (3 13) and (3 14) have been reported from Fagonia indi~a.~~~ Detailed analyses of the lH and I3C n.m.r.spectra of taraxasterol and @-taraxasterol have appeared.230 3P-Hydroxybaur-7-en-28-oic acid (3 15) and the methyl ester (316) of terebenthifolic acid have been isolated from the stem bark of Davidsonia pr~riens.~~~ Reduction of terebenthifolic acid with sodium borohydride afforded the corresponding 3a- and 3p-alcohols. The 3a-alcohol is different from myrtifolic acid which had previously been assigned this structure. The authors suggest that myrtifolic acid may be the C-27 carboxylic acid. 8 The Hopane Group 21a-hydroxyursolic acid (3 10) from Amaracus dictamnu~,~~~ The structures of 22,25-dihydroxyhopan- 1-one (3 17) and and cecropiacic acid (311) from Musanga ce~ropioides,~~~ la 11a922-trihydroxyhopane (3 18) from the fern CheiropIeuria kaneric acid (lP93P-dihydroxyurs- 12-en-28-oic and the bicuspis were established by X-ray analysis.383 A third con-Z-and E-2-O-coumaroyl esters of 2a-hydroxyursolic stituent of this extract is la 1 1 a,22,25-tetrahydroxyhopane from leaves of Nerium oleander.(3 19). Two further ring A-secohopanes swertialactones D (320) NATURAL PRODUCT REPORTS 1989 . n o...'o&-f as (320) {W (320) (3211 (322) R = 0 (323) R = H,P-OH (324) &x6H OH R (325) R' = R3 = OH; R2 = H (327) R' = Me; R2 = C02Me; R3 = H (326) R' = OAc; R2 = OH; R3 = H (328) R' = C02H; R2 = Me; R3 = OAc (332) (333) )as (335) lip'as (335) AcO (334) (335) (336) and C (321)' have been reported from Swertiu pei~lata.~~~ The 13C n.m.r.assignments of eight hopane The relative stereochemistry of boehmerone (322) and boehmerol and several other hopane derivative^^'^ have been published. (323) from the bark of Boehmeriu excelsu is uncommon.385 Some corrections have been made to the previous set of These compounds are clearly related to arborinol. The structure literature values for hopane and 17a-hopane. A detailed 'H and of (323) was established by X-ray analysis. Other hopanes in- 13C spectroscopic examination of moretenone and 3-acetyl- clude missouriensin (324) from Iris mis~ouriensis,~~~ 3p 15a,22- aleuritolic acid has been carried trihydroxyhopane (325) from the entomogenous fungus The Chinese drug 'Qian Cao Gen' (Rubia cordifoliu) contains Aschersoniu alcyrodes 387 3P-ace tox y-12P,22-di hydrox yhopane rubiatriol (33 1).39s During a detailed investigation of the acid- (326) from Parmelia tinctor~m,~~~ methyl 168'22-catalysed rearrangement of mono-enes of the hopane and dihydroxyhopan-23-oate (327) from Supium eugnifoli~m,~~~ migrated hopane series three new compounds 9PH-fern-7-ene 6a-acetoxy-16&22-dihydroxyhopan-24-oic acid (328) from the (332) 8/3H-fern-B(ll)-ene (333) and adian-5(10)-ene (334) frond exudate of Notholaena candidu var.~opelandii,~'~ and p-were prepared.3g7 Acid-catalysed backbone rearrangement of coumaroyldryocrassol (329) from Lygodium Jlexuosum.391 901'1 la-epoxyisoarborinyl acetate (335) affords inter uliu the Bacterihopanetetrol (330) has been isolated from an ethanol- ketone (336).398 Spergulacin3" and spergulacin A4Oo are producing Gram-negative bacterium Zymomonus mobili.~.~~~ saponins from MolZugo spergula.NATURAL PRODUCT REPORTS 1989-J. D. CONNOLLY AND R. A. HILL OH H (3371 (339) 16/ as (340)<*R HO# + BrM I (342) R = P-Me,cr-OH (340) R' =P-Me,cr-OH; R2 = H as (340) (343) R=CH; (345) R' = CH2; R2 = Ac (3411 (344) R = Me; (346) R' =Me; A15; R' = Ac +op::z HH OH Br(\I (3471 Arigoni that dimerization via a Diels-Alder reaction of a sesquiterpenoid precursor (339) was involved has now been tested e~perimentally.~~~ Racemic (339) was synthesized and undergoes dimerization to officinalic acid (338) in 42% yield.The dimerization of the intermediate (339) was first observed in R#-> 1960 during work on the sesquiterpenoid lactone d~irnenin.~~~ Venustatriol (340) an antiviral tetracyclic ether from Laurencia venu~fa,~~~ is a diastereoisomer of thyrsiferol (341). The structure of (340) was established by X-ray analysis which also permitted the absolute configuration of thyrsiferol to be deduced. Misdrawing of the relative configurations at C-14 C-(350)R = 0 15 C-19 and C-22 in the original X-ray paper on thyrsiferol (351) R = H,P-OAc has resulted in some unnecessary confusion in this series. Five new squalene ethers have been reported from Laurencia obt~sa.~O, These include magireols A (342) B (343) and C (344) and the and A'5-anhydrothyrsiferol diacetates (345) and 9 Miscellaneous Compounds (346).The tricyclic compound (347) containing three rings of The most fascinating 'triterpenoid 'in this report is undoubtedly thyrsiferol has been synthesized in optically active form.4o6 sapanaceolide A (337) a cytotoxic C, compound from Neviotine A (348) from the Red Sea sponge Siphonochalina Tricholoma saponaceum the structure of which has been siphonella has a novel pentacyclic carbon It is established by X-ray analysis.4o1 Its biogenesis is a matter of related to the sipholanes and siphonellanes previously found in speculation but presumably involves union of two C, units in this sponge. Detailed 'H and 13C spectroscopic analyses of a rather unusual fashion. The mystery surrounding the origin sipholenol A and sipholenone A have appeared.408 Tricyclo- of officinalic acid (338) (see 'Terpenoids and Steroids' A hexaprenol (349) postulated as an early evolutionary tri- Specialist Periodical Report The Royal Society of Chemistry terpenoid but never isolated has been Two new 1981 Vol.10 p. 137) has been solved. The suggestion of malabaricane derivatives (350) and (35l) have been isolated 20 NPR 6 496 NATURAL PRODUCT REPORTS 1989 (352) from Pyrethrum santolinoides.410 14/3,26-Epoxyserratane-3/3,2la-diol(352) is a further example of this type of compound in Primula ro~ea.~ll The triterpene alkaloid methyl homo- daphniphyllate (353) has been Retro-Michael reactions of triterpenoid 1,5-diketones using superheated steam over a basic catalyst provide a convenient route to tri- and tetra-cyclic intermediates of defined stereochemistry.413 The route e.g. (354) -+ (355) +(356) is useful for the preparation of biological markers from sediments and petroleums. Aply- kurodins A (357) and B (358) are undoubtedly degraded triterpenoids (steroids). They were isolated from the mollusc Aplysia kurodai and the structure of A (357) was established by X-ray analysis. 414 10 References 1 S. Siddiqui B. S. Siddiqui S. Faizi and T. Mahmood J. Nut. Prod. 1988 51 30. 2 M. I. Isaev M. B. Gorovits and N. K. 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Paternostro S.Passannanti and E. Gaco-Baitz Phytochemistry 1986 25 539. 374 D. Lontsi B. L. Sondengam J. F. Ayafor and J. D. Connolly Tetrahedron Lett. 1987 28 6683. 375 S. Siddiqui F. Hafeez S. Begum and B. S. Siddiqui J. Nat. Prod. 1986 49 1086. 376 S. Siddiqui B. S. Siddiqui F. Hafeez and S. Begum Planta Med. 1987 53 424. 377 M. E. 0.Matos M. P. Sousa M. I. L. Machado and R. Braz Filho Phytochemistry 1986 25 1419. 378 D. Loganathan G. K. Trivedi and K. V. Chari J. Org. Chem. 1986 51 3366. 379 A. Romo de Vivar J. M. Gonzalez and A. L. Perez C. Rev. Latinoam. Quim. 1985 16 51. 380 D. Druet L. C. Comeau R. Viani A. Baldy J. Estienne and M. Pierrot Can. J. Chem. 1987 65 851. 381 A. A. Ansari L. Kenne and Atta-ur-Rahman Phytochemistry 1987 26 1487.382 D. Meksuriyen N. P. D. Nanayakkara C. H. Phoebe Jr. and G. A. Cordell Phytochemistry 1986 25 1685. 383 N. Tanaka H. Wada M. Kojina T. Murakami Y. Saiki C.-M. Chen and Y. Iitaka Chem. Pharm. Bull. 1987 35 4016. 384 S. Bhan R. Khumar A. K. Kalla and K. L. Dhar Phyto-chemistry 1987 26 3363. 385 M. L. Oyarzun J. A. Garbarino V. Garbarino J. Guilhem and C. Pascard Phytochemistry 1987 26 22 1. 386 S.-M. Wong J. M. Pezzuto,H. H. S. Fang,andN. R. Farnsworth J. Nat. Prod. 1986 49 330. 387 G. W. van Eijk H. J. Roeijmans and D. Seykens Tetrahedron Lett. 1986 27 2533. 388 Y. Goto T. Takada and A. Sakurai Rep. Fac. Sci. Shizuoka Univ. 1987 21 59 (Chem. Abstr. 1987 107 194875). 389 M. Saxena and S. K. Srivastava Curr. Sci. 1987 56 147. 390 F.J. Arriaga-Giner and E. Wollenweber Phytochemistry 1986 25 735. 391 B. Achari K. Basu C. R. Saha and S. C. Pakrashi Planta Med. 1986 329. 392 Y. Tahara H. Yuhara Y. Ogawa and Y. Yamada Agric. Biol. Chem. 1986 50 1345. 393 A. L. Wilkins P. W. Bird and P. M. Jager Magn. Reson. Chem. 1987 25 503. 394 A. L. Wilkins K. J. Ronaldson P. M. Jager and P. W. Bird Aust. J. Chem. 1987 40,1713. 395 S. McLean M. Perpick-Dumont W. F. Reynolds H. Jacobs and S. S. Lachmansing Can. J. Chem. 1987 65 2519. 396 M. Arisawa H. Ueno M. Nimura T. Hayashi and N. Morita J. Nat. Prod. 1986 49 1114. 397 H. Ageta K. Shiojima and Y. Arai Chem. Pharm. Bull. 1987,35 2705. 398 P. L. Majumder and A. Pal Indian J. Chem. Sect. B 1985 24 614. 399 A. K. Barua S.Ray P. K. Dutta and R. V. Venkateswaran Phytochemistry 1986 25 1762. 400 A. K. Barua P. K. Dutta S. Ray and R. V. Venkateswaran Phytochemistry 1986 25 2557. 401 M. A. Bernardi L. Garlaschelli G. Galti G. Vidari and P. Vita Finzi Tetrahedron 1988 44,235. 402 B. Erb H. J. Borschberg and D. Arigoni Croat. Chem. Acta 1985 58 653. 403 H. H. Appel J. D. Connolly K. H. Overton and R. P. M. Bond J. Chem. Soc. 1960 4845. 404 S. Sakami T. Higa C. W. Jefford and G. Bernardinelli Tetra-hedron Lett. 1986 27 4287. 405 T. Suzuki S.Takeda M. Suzuki E. Kurosawa A. Kato and Y. Imanaka Chem. Lett. 1987 361. 406 M. Hasimoto T. Kan M. Yanaiya H. Shirahama and T. Matsu- moto Tetrahedron Lett. 1987 28 5665. 407 S. Carmely and Y. Kashman J. Org. Chem. 1986 51 784.408 S. Carmely and Y. Kashman Magn. Reson. Chem. 1986,24,332. 409 E. J. Corey and R. M. Burk Tetrahedron Lett. 1987 28 6413. 410 J. Jakupovic F. Eid F. Bohlmann and S. El-Dahmy Phyto-chemistry 1987 26 1536. 411 R. Kapoor A. K. Rishi K. K. Bhutani and C. K. Atal Planta Med. 1985 334. 412 C. H. Heathcock S. K. Davidsen S. Mills and M. A. Sanner J. Am. Chem. Soc. 1986 108 5650. 413 F. R. Aquino Neto J. M. Trendel and P. Albrecht Tetrahedron 1986 42 5621. 414 T. Miyamoto R. Higuchi and T. Komori Tetrahedron Lett. 1986 27 1153.

ISSN:0265-0568    

DOI:10.1039/NP9890600475

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Muscarine Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J. R. Lewis Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen AB9 2UE Reviewing the literature published between July 1986 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1988 Vol. 5 p. 351) 1 Muscarine Oxazole Isoxazole and Thiazole Alkaloids 2 Peptide Alkaloids 3 Miscellaneous Alkaloids 4 References (3) (4; 2S,4R,5S) (DCB = 2,6-dichlorobenzyl) 1 Muscarine Oxazole Isoxazole and Thiazole Alkaloids A new total synthesis of L( +)-muscarine (1) and its enantiomer has been achieved in eight steps from D-and L-threonine (2) respectively. A highly stereoselective iodocyclization of the y,bunsaturated benzyl ether (3) obtained from the D-amino- acid gave the iodofuran (4) which upon trimethylamination generated the natural product (1).An interesting and expeditious total synthesis of acivicin (5) has been reported2 using a procedure based on the dipolar cycloaddition of a nitrile oxide to vinylglycine derivatives. When the nitrone (6) and a suitable sterically protected L-vinylglycine (7) were reacted a high stereoselectivity based on a double asymmetric induction was obtained. The resulting isoxazolidine (8) could be converted into the isoxazoline through acid (perchloric) hydrolysis and NCS oxidation ; C-3 chlorination and 0-deprotection then gave acivicin (5). The isoxazolidone y-lactone lactivicin (9) obtained from bacterial strains of the gliding bacteria Empedobacter lactamgenus and Hysobacter QZ~US,~showed both high Gram positive and Gram negative activity.It also possessed a high affinity for proteins known to bind to penicillin (PBPs). On this basis it was suggested that the p-lactam ring is not essential for PBP interaction a speculation which could lead to the discovery of (9) new types of antibiotics. The structures of the oxazolines boxazomycin A B and C three novel antibiotics4 isolated from a Pseudonocardia sp. were CONH2 determined by n.m.r. spectroscopy to be (10; R1 = R2 = OH) (10; R’ = OH R2 = H) and (10; R’ = H R2 =OH) res-pec tively. The polyether5 Ac7230 is 3-hydroxycezomycin (1 1) and has been obtained from the culture broth of Dactylosporangium sp. I Ac7230. This antibiotic possessed potent Gram positive activity Me but was only weakly active against Gram-negative bacteria.Its stereochemistry has yet to be determined. An intuitively designed synthesis of the polyether oxazole 503 504 NATURAL PRODUCT REPORTS 1989 Me Me Me Me Me N-C02 C H 2 CCI3 CO2Me 0 CO R (12) (13) HN/ C\HMe2 BocH N -3 dNHBoc HN H Me C02Me HOzC S-S’ C02H \/ (14) 7’’ HNBoc (17) (211 antibiotic calcimycin (13) has been obtained by a kinetically controlled acid-catalysed intramolecular cyclizations of the unsaturated alcohol (12). In multistep procedures ascidiacyclamide (1 5) and ulithia- cyclamide (19) have been synthesized in two ways,’ each starting from the thiazole amino-acid derivative (14).Ulithiacyclamide (19) has also been synthesized using a twofold ring closures involving thiazole (16) and the cystein derivative (17) via (18). A facile synthesis of cytotoxic ulicyclamide (20) has been efficiently accomplished by the solid phase method using diethylphosphorocyanidate for the coupling and trimethylsilyl triflate for the final depr~tection.~ To Boc-4-Pro-polystyrene resin were added sequentially Boc-L-Phe-OH Boc-D(a1a)- (22) TL2-OH Boc-~-(ihe)THZoH and (2)-L-athr(But)-OH through the use of DEPC-triethylamine in DMF. Introduction of the thiazole amino-acids and removal of the peptide from the resin preceded Boc deprotection and high dilution cyclization. Oxazoline formation was accomplished as a final step in all four cases by treatment of the threonine components in the macrolide with SOCl,.The structures of all the patellamides have now been revised. Patellamides B and C were described in the previous report’l (cJref. 10a) and A has now been assigned structure (21) which is based on an unambiguous synthesis.12 The oxazole ring of virginiamycin MI (22) is derived from (9-serine by loss of the 3-(pr0-S)-hydrogen’~ (see Scheme I). NATURAL PRODUCT REPORTS 198-J. R. LEWIS Scbeme 1 0 OMe (23) 0 (25) OH ?J H2 (27) Egg-masses of certain nudibranches protect themselves from predation by the presence of toxic substances. Hexabranchus sanguineus and a Halichondria species contain trioxazole macrolides which have been shown to possess antifungal and toxic properties (cf.ref. 10 b). In another unidentified species of a Halichondria sponge a similar physiologically active metab- olite called halichondramide has been isolated. It bears a close structural resemblance to kabiramide C' and by n.m.r. measurements structure (23) has been proposed.'* 2 Peptide Alkaloids Two reviews on cyclopeptide alkaloids have appeared. One describes those alkaloids which contain a styrylamine unit.15 The other is more specific;16 it covers basic cyclic peptides which embody an ansa structure in which the ten- or twelve- membered peptide-type bridge spans the 1,3-or 1,4-positions of a benzene ring and it also reviews linear peptide alkaloids. The latter are defined as those compounds that can be derived formally from cyclic peptide alkaloids by scission of the bridge in an elimination reaction.The reviewer finds that classification of these alkaloids must still remain much a matter for personal choice however. The /?-lactone abafluorin (24) produced by Pseudomonas 0 (24) OH H (26) Me (28) LCO I jluorescens fermentation and found to be active against selected Staphyloccus Penicillin Sarcina Escherichia Enterobacter and Proteus organisms (cf. ref. 1Oc) is now under patent protection. l7 Piperlongumine is an effective drug for the treatment of asthma and chronic bronchitis. Its structure long thought to be the A5-isomer has now been revised,'* X-ray diffraction establishing it as the A3-isomer (25). A group of novel antibiotic peptides [26; R = Me(CH,),-1 126; R = Me(CH,),CH=CH(CH,),-] and [26; R = Me(CH,),-] are produced by fermentation using the soil myxobacterium Polyangium bran~hysporum.'~These com-pounds are active against Staphyloccus aureus and Aspergillus fumigatus.On proteolytic hydrolysis cleavage occurred at the exo-amide linkage releasing the ansa-amine. Cultivation of a Streptomyces species identified only as G0069A has yielded the antibiotic and antitumour agent G0069A (27).,O Two novel seven-membered ring heterocyclic compounds bengamide A (28; R = H) and bengamide B (28; R = Me)21 have been found in a Fijian sponge belonging to the Jaspidae family. Both are biotoxic to eucaryotic cells nematodes and bacteria. Two metabolites obtained from a sponge tentatively NATURAL PRODUCT REPORTS 1989 0 (29) (30) HNCHO HOm0 \ HO \ Phd/NH (37) MeHN Ph identified as Thorectopsamma xana appear to be derived from bromotyrosine and cysteine (or cystine).Psammaplin A (29) and bisaprasin (30) both contain disulphide linkages22 and are somewhat related to the bastadins (cJ ref 104. A new derivative of 3,5-dibromotyrosine has been obtained from the sponge Ianthella ~rdis.~~ Ianthelline (3 1) contains the interesting terminal iminoimidazoline group. of erbstatin (33) in six steps (38 YOoverall yield) from the commercially available lactone (32) makes this epidermal growth factor inhibitor now available for studying the mechanism of tyrosine kinase inhibitors and their potential as antitumour agents.A NATURAL PRODUCT REPORTS 1989-5. R. LEWIS OH Me Me RHNCHCOO (411 Antibiotic U-56,407 (34) which has only Gram positive activity is the metabolite produced by fermentation of Streptomyces hagronensin. 25 Dehydropipernonaline an amide (35) isolated from the fruit of Piper longum is a coronary vasorelaxant.26 A number of new spermidine alkaloids have been character- ized after extraction from the bark or root bark of various species. Capparisine (36; R = OMe),' and capparisine (36; R = H)28were obtained from Capparis dicidua nummularine 0 (37) from Zizyphus n~mmufaria,~~ sativanine H (38) from and Zizyphus ~ativa~~ N-desmethyljubanine A (39) from Zizyphus n~mmularia.~' Mauritine D and nummularine B have been isolated for the first time from Zizyphus ~ylopyra~~ and jubanine A jubanine B with mauritine C were also found to be present in Zizyphus nummul~ria.~~*~~ By mutant selection of Penicilfium rugufosum the biogenesis of OF4949- 1 (40; R =H) and OF4941 (40; R = Me) has been shown to involve L-tyrosine and L-asparaginine the former being concentrated in the isodityrosine or 4-methylisodityrosine moieties respect- ively.33 The absolute configuration of the spermine alkaloid aphel- andrine (41) was determined by X-ray analysis.34 Reversal of the H atom configuration at C- 17 gives orantin which can also be obtained by treatment of (41) with base.Related alkaloids such as ephedradin B C and D now have established configurations. Three trienomycin antitumour antibiotics have been pro- CNH 0 y NHCOYHNHMe CHMe2 CHMeEt (43) Me HO-CO2H CH tI ,CONHCCONHCCO~H II c /\ Me Et (45) H duced in a Streptomyces 83-16 FERM P-7981 fermentation.Following h.p.1.c. the three compounds trienomycin A (42; R = hexahydrobenzoyl) trienomycin B (42 ; R = isovaleryl) and trienomycin C (42; R = 2-methylbutyryl) were separated and characterized.35 A new fourteen-membered ring peptide alkaloid discarine- 1 (43) and its known relative discarine B have been isolated from Discaria febrif~ga.~~ Jaspamide which has insectidal and antifungal activity has been isolated from a Jaspis sponge. From its n.m.r. and m.s. data a modified peptide structure (44)has been assigned to this metabolite which classifies it as one of the new types of cyclic dep~ipeptides.~' The nineteen-membered ring contains a num- ber of structural features which are also common to other cyclic peptides found in sponges (cf.ref. 10e). The structure of the mycotoxin isolated from Phomopsis Ieptostromiformis has been determined by X-ray analysis. This hexapeptide with a thirteen-membered ansa-ring is formulated as (45). The thirteen-membered spermidine alkaloids (+)-cela-benzine (46; R = PhCO=CHCO) and (-)-dihydrocelacinnine (46; R = PhCH,CH,CO) have been synthesized using an intramolecular cyclization of amino-aldehydes (47) to give cyclic imines ; borohydride then generated the natural products.3g The unsymmetrical spermine alkaloids of the Homafium group have been synthesized using phenylazetidinones and NATURAL PRODUCT REPORTS 1989 %Me 0 HO Me OMe RCOHN (Me) HCOIC~ their conversion into diazacyclooctan-2-ones.40Typically hop- romine (48) was obtained when azetidinone (49) was trans- amidated with liquid NH in a sealed tube to form the azalactam (50; R' = R2 = H) which upon reductive N-methyl- ation and coupling with (a-lY4-dibromobut-2-ene gave (50 ; R1= Me R2 = CH,CH=CHCH,Br).Further coupling of (50; R' = Me R2 = CH,CH=CHCH,Br) with the appropriate azalactam (51) followed by hydrogenation gave (48). Using this procedure4' thirteen-membered azalactam (52) was converted into the azalactam (53; R = H) which upon acylation with trans-cinammoyl chloride gave (_+ )-dihydroperiphylline (53 ; R = COCH=CHPh).Streptomyces species continue to yield interesting pharmaco- Ph (55) OH logically active peptides with a variety of structural conno- tations. Azinomycin A (54; X = CH,) and Azinomycin B (54; X = C=CHOH) are Gram-positive and Gram-negative anti- bacterial agents42 produced by Streptomyces griseofuscus S 42227. They have also been shown to possess antitumour activity.43 Also active against Gram-positive and Gram-negative bacteria is L 681217 (55) a new member of the efrotomycin family of antibiotics produced by Streptomyces ~uttZeyu.~~ The isolation of macrocylic lactams containing quinone and naphthoquinone units continue unabated. These compounds possess antibacterial and often antitumour activity and patent protection on them indicates their potential for pharmaceutical NATURAL PRODUCT REPORTS 1989-J.R. LEWIS 0 Me OMe c=o (63) H Me OH Me OH HO OH Me Me Me COzMe (64) he Me (62) a; R = CI b; R=OH c; R=H ,C02Me d; R=CH,F NHCOMe A e; R = CH(MeIC02H development. Herbimycin C (56) has been obtained from the culture fluid of Streptomyces hygroscopi~us~~ and together with trienomycin A (57; R = cyclohexyl) trienomycin B (57; R = CH,CHMe,) trienomycin C (57; R = CHMeEt) and awa-mycin (58) has ken found in an unidentified Streptomyces species.48 The mycotrienes (ansatriene A and B) T23-VIII and T23-IX produced by Streptomyces strain T23 which is thought to be Streptomyces ri~hiensis,~' are closely related in that T23- IX is the hydroquinone of T23-VIII (59).The biosynthesis of the ansamycin (60) obtained from Streptomyces collinus has been investigated and the aromatic unit and one of the ansa- ring carbons is produced from 3-amino-5-hydroxybenzoicacid and the other ansa-ring carbons from acetate and propionate. The cyclohexylcarboxylic acid comes from shikimic acid and the side-chain from ~-alanine.~* Naphthomycins are the yellow pigments associated with 1 :4-ansa-substituted naphthoquinones produced by Streptomyces. Naphthomycin H (61) is obtained from the culture fluid of species Y-836403-694B naphthomycin A (62a) naphthomycin D (62b) naphthomycin E (62c) naphthomycin F (62d) and naphthomycin G (62e) from strain Tu 2357.50 Two sulphur-containing analogues metabolites of Strepto-myces aZbolongus5' C46366 have been designated awamycin (63)and its cyclized relative ansathiazin (64).Kibdelin AAD-609 is a glycopeptide antibiotic complex isolated from Kidbelosporangium aridium largum. Through reversed phase h.p.1.c. the complex was separated into five components which by carbohydrate and fatty acid analysis OH man nose-060H Met H HO Y NHCORW (65) Me Me HO NH H C 0 OH (69) coupled with FAB mass spectrometry were identified52 as [65; R = (CH,),Me] [65; R = (CH2),CHMe2] [65; R = (CH,),CHMeJ [65; R = (CH,),,Me] and [65; R = CH,CH=CH(CH,),Me]. The first second and third of these compounds are known as aridicin A B and C respectively; A incidentally shows improved biological activity if the mannose is replaced.53 Biosynthetic studies on aridicins A B and C using Kibdelosporangium aridium have established that the aglycone portion comes from tyrosine acetate and L-meth- ionine.The preformed aglycone is first mannosylated the glycolipid is then attached and the terminal step is oxidation to the glycuronic Cultivation of Micropolyspora SANK 60983 on a soya bean-glucose medium gave two antibiotics chloropolysporin B (66; R1= ristomine R2 = mannose R3 = glucose R4 = rham-nose) and chloropolysporin C (66; R' = ristosamine R2 = mannose R3 = glucose R4 = H).55 NATURAL PRODUCT REPORTS 1989 HMe (66) (70) Interesting observations have been made on the structures of halomycin B a member of the ansamycin group of antibiotics in the solid state and in solution.X-Ray analysis showed that only one conformer (67) exists in the crystal but that in chloroform solution two conformers (67) and (68) exist with 80% in the form of (67).56 A new lipopeptide antibiotic mul~ndocandin~~ has been isolated from strain Y-30462 of Aspergillus syduwi. This antifungal compound (69) was obtained as an amorphous powder. In two communication^^^^ 59 the total synthesis of echino-candin D (70) a twenty-one-membered cyclic lipopeptide has been accomplished. Using vinylglycine and allylglycine as starting materials a cyclic hexa-peptide was synthesized by the novel use of the thiopyridyl ester as a protecting group.The last step formation of a hemi-aminal bond was achieved by treatment with diphenylphosphoxylazide. NATURAL PRODUCT REPORTS 1989-5. R. LEWIS 511 0 CH2CONH2 I NH NH I CH2CON H2 o=c c=o H ,c=o N2 SC N rn(CH2),/3\ NCS SC N m( Meso CH2)7Ho (73) (74) (76) H2 MeNKNH 0 (78) (79) CH20H H2 O2 {gN Me OH NH I CO I /NH2 CH2CH By natural selection and mutagenesis Streptomyces ZasaZiensis now produces more quinomycin A (71) at the expense of the ionophenic ether lasalocid A.so Cultivation of the bacterium (Bacillus subtilis) that inhibits cell division of the embryos of the starfish Asterina pectinifera has enabled the active principle iturin A-2 (72) to be characterized.61 3 Miscellaneous Alkaloids In an article entitled 'Further Explorations of Unnatural Alkaloids ' the importance of enantiospecificity in naturally occurring alkaloids used in medicine was examined by making comparisons with their unnatural optical isomers.In some cases optical purity was not a requirement for maximizing pharmacological activity.62 A new antibiotic SQ 30,957 namely 4-diazo-3-methoxy- cyclohexa-2,5-dien-1-one (73) has been produced by Penicillium '( CH2)3NH2 funiculosum. This diazo-compound has excellent activity against anaerobic bacteria.s3 From a species of Fijian sponge of the genus Pseudaxinyssa twenty-one aliphatic a,o-bisisothiocyanates have been ob-tained. As these isocyanates (74; n = 8,. ..14) (75;n = 9,.. . 18) and (76; n = 9 15 16) are unaccompanied by isocyano- or formamido-analogues their biogenesis was suggested via chain elongation of methi~nine.~~ The origin of the isocyanide functionality in xanthocillin monomethylether (77) is however the cyanide Two bioactive metabolites have been generated in rabbit skin tissue through viral infection. The hydantoins (78 ;R = H) and (78; R = OH) so-produced have germination promotion activity in flowers and microorganisms.66 The structure has been proposeds7 of a novel bromine- containing metabolite found in the Madagascar marine sponge AcantheZIa carteri. Dibromoisophakellin (as its hydrochloride) upon X-ray analysis was shown to be (79). An antibacterial streptothricin derivative albothricin (80) has been isolated NPR 6 NATURAL PRODUCT REPORTS 1989 (811 (82) (85) (86) from the fermentation broth of the Streptomyces species SIPI-2985.ss Dithiosecoemestrin (81) a new metabolite related to emestrin is to be found in the culture fluid of EmericelIu striutu strain 80NE-22.69 When rice is artificially inoculated with Pseudullescheria boydii the mould produces two hyrazine metabolite^.^^ One is reported70 to be pseurotin A (82).The root nodules generated on Lotus tenius when it is inoculated with Rhizobium loti NZP2307 contain an opine-like metabolite rhizolotine (83).7* Auranthine (84) is produced by the sporing cultures of Penicillium aurantiogriseum its benzodiazepinone ring system is made from glutamine and anthranilic The molecular structure of phlegmariurine A a constituent of Phfegmariurus fordii together with its absolute configuration (85) has been determined by X-ray diffraction.73 Two cyclic carbamates possessing plant growth regulator properties have been isolated from an unknown Streptoverticillium species;74 X-ray analysis coupled with spectrometric methods gave structure (86; R = CH,CHMe) for cyclocarbamide A and [86; R = (CH,),Me] for cyclocarbamide B. 4 References 1 R. Amouroux B. Gerin and M. Chastrette Tetrahedron 1985 41 5321. 2 S.Mzengeza C. M. Yang and R. A. Whitney J. Am. Chem. SOC.,1987 109 276. 3 Y. Nozaki N. Katayama H. Ono S.Tsubotani S.Harada H. Okazaki and Y. Nakao Nature 1987 325 179. 4 T. Kusumi T. Ooi and H. Kakisawa Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 28th 1986 49 (Chem.Abstr. 1987 106 119520). 5 S.Yaginuma M. Awata N. Muto K. Kinoshita and K. Mizuno J. Antibiot. 1987 40,239 (Chem. Abstr. 1987 106 210633). 6 D. P. Negri and Y. Kishi Tetrahedron Lett. 1987 28 1063. 7 S.Kato Y. Kondo T. Sugiura Y. Hamada and T. Shioiri Pept. Chem. 23rd 1985 67 (Chem. Abstr. 1987 106 214342). 8 U. Schmidt and D. Weller Tetrahedron Lett. 1986 27 3495. I 9 T. Sugiura Y. Hamada and T. Shioiri Tetrahedron Lett. 1987 28 2251. 10 J. R. Lewis Nat. Prod. Rep. (a) 1986,3 588; (b) 1988,5 352; (c) 1986 3 587; (d)1984 1 388; (e) 1988 5 351. I1 M. Shibata Y.Hamada and T. Shioiri Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 27th 1985,267 (Chem. Abstr. 1987,106 156 837).12 Y. Hamada M. Shibata and T. Shioiri Tetrahedron Lett. 1985 26 6501. OH (83) 13 B. Purvis D. G. I. Kingston N. Fujii and H. G. Floss J. Chem. SOC.,Chem. Commun. 1987 302. 14 M. R. Kernan and D. J. Faulkner Tetrahedron Lett. 1987 28 2809. 15 A. H. Shah and V. B. Panday J. Chem. SOC.Pak. 1985 7 363 (Chem. Abstr. 1986 105 60784). 16 U. Schmidt A. Lieberknecht and E. Haslinger Alkaloids 1985 26 299. 17 R. B. Sykes and A. Tymiak U.S.US 4600786 (Chem. Abstr. 1986 105 170627). 18 T. Banerjee and S. Chaudhuri Can. J. Chem. 1986 64 876. 19 M. Konishi K. Tomita M. Oka and K. Numata Ger. Offen. DE 3,629,465 (Chem. Abstr. 1987 106 212569). 20 N. Seki K. Den T. Marunaka Y. Miyake Y. Minami A. Kajitani and N. Ishida Jpn.Kokai Tokkyo Koho JP61212587 (Chem. Abstr. 1987 106 100846). 21 E. Quinoa M. Adamczeski P. Crews and G. J. Bakus J. Org. Chem. 1986 51 4494. 22 A. D. Rodriguez R. K. Akee and P. J. Scheuer Tetrahedron Lett. 1987 28 4989. 23 M. Litaudon and M. Guyot Tetrahedron Lett. 1986 27 4455. 24 D. G. Hangauer Tetrahedron Lett. 1986 27 5799. 25 T. F. Brodasky and D. W. Stroman U.S. US 4595770 (Chem. Abstr. 1986 105 77584). 26 N. Shoji A. Umeyama N. Saito T. Takemoto A. Kayiwara and Y. Ohizumi J. Pharm. Sci. 1986 75 1188 (Chem. Abstr. 1987 106 149 163). 27 V. U. Ahamad S.Arif A-ur-Rahman Amber and K. Fizza Liebigs Ann. Chem. 1987 161. 28 V. U. Ahmad S.Arif A-ur-Rahman Amber and M. A. Nasir 2. Naturforsch. Teil B 1986 41 1033. 29 V.B. Pandey S.P. D. Dwivedi A. H. Shah and G. Eckhardt Phytochemistry 1986 25 2690. 30 A. H. Shah G. A. Miana S.Devi and V. B. Pandey Planta Medica 1986 500. 31 G. A. Miana and A. H. Shah Fitoterapia 1985 56 363 (Chem. Abstr. 1986 105 75886). 32 V. B. Pandey S.Devi J. P. Shah and A. H. Shah J Nat. Prod. 1986 49 939. 33 S. Sano M. Ueno K.Katayama T. Nakamura and A. Obay- ashi J. Antibiot. 1986 39 1697. 34 A. Guggisberg R. Prewo and M. Hesse Helv. Chim. Acta 1986 69 1012. 35 K. Komiyama and S.Funayama Eur. Pat. Appl. EP189330 (Chem Abstr. 1986 105 224589). 36 P. Hennig A. Morel and W. Voelter Z. Naturforsch. Teil B 1986 41 1180. 37 T. M. Zabriskie J. A. Klocke C. M. Ireland A. H. Marcus T. F. Molinski D. J. Faulkner C.Xu and J. C. Clardy J. Am. Chem. SOC.,1986 108 3123. 38 M. F. Mackay A. Van Donkelaar and C. C. J. Culvenor J. Chem. SOC.,Chem. Commun. 1986 1219. 39 H. Iida K. Fukuhara M. Machiba and T. Kikuchi Tetrahedron Lett. 1986 27 207. 40 L. Crombie R. C. F. Jones and D. Haigh Tetrahedron Lett. 1986 27 5147. 41 L. Crombie R. C. F. Jones and D. Haigh Tetrahedron Lett. 1986 27 5151. 42 K. Nagaoka M. Matsumoto J. Ono K. Yokoi S.Ishizeki and T. Nakashima J. Antibiot. 1986 39 1527 (Chem. Abstr. 1987 106 81 277). NATURAL PRODUCT REPORTS 1989-J. R. LEWIS 43 S. Ishizeki M. Ohtsuka K. Irinoda K. Kukita K. Nagaoka and T. Nakashima J. Antibiot. 1987,40 60 (Chem. Abstr. 1987 106 13 1 353). 44 A. J. Kempf K. E. Wilson 0.D. Hensens R.L. Monaghan S. B. Zimmerman and E. L. Dulaney J. Antibiot. 1986 39 1361 (Chem. Abstr. 1987 106 29748). 45 K. Shibata S. Satsumabayashi A. Nakagawa and S. Omura J. Antibiot. 1986 39 1630 (Chem. Abstr. 1987 106 81 278). 46 S. Funayama A. Nakagawa and S. Omura Tennen Yuki Kago- butsu Toronkai Koen Yoshishu 28th 1986,73 (Chem. Abstr. 1987 106 119521). 47 N. Otake H. Seto T. Sasaki M. Sugita and S. Hiramoto Jpn. Kokai Tokkyo Koho JP 61 22070 and U.S. US 4587237 (Chem. Abstr. 1986 105 77566 77574). 48 T. S. Wu J. Duncan S. W. Tsao C. J. Chang P. J. Keller and H. G. Floss J. Nat. Prod. 1987 50 108. 49 H. W. Fehlhaber C. M. M. Franco G. C. S. Reddy T. Murkho- padhyey and B. N. Ganguli Ger. Offen. DE 3512 194 (Chem. Abstr. 1987 106 100843).50 M. Meyer W. Keller-Schierlein S. Megahed H. Zachner and A. Segre Helv. Chim. Acta 1986 69 1356. 51 S. Tanida S. Shinagwa M. Takizawa T. Takahashi S. Harada and T. Hasegawa Experientia 1986 42 1167. 52 G. Folena-Wasserman B. L. Poehland E. W. K. Yeung D. Staiger L. B. Killmer K. Snader J. J. Dingerdissen and P. W. Jeffs J. Antibiot. 1986 39 1395 (Chem. Abstr. 106 29749). 53 R. D. Sitrin G. W. Chan F. Chapin A. J. Giovenella S. F. Grappel P. W. Jeffs L. Phillips K. M. Snader and L. J. Nisbet J. 4ntibiotics. 1986 39 68 (Chem. Abstr. 1986 105 3357). 54 S. K. Chung P. Taylor Y. K. Oh C. DeBrosse and P. W. Jeffs J. Antibiot. 1986 39 642 (Chem. Abstr. 1986 105 75568). 55 T. Haneishi A. Torikata T. Okazaki M. Nakajima R. Enokita T. Katayama and S.Iwado Eur. Pat. Appl. EP 187722. (Chem. Abstr. 1987 106 17026). 56 S. K. Arora and A. M. Kook J. Org. Chem. 1987 52 1530. 57 K. Roy T. Mukhopadhyay G. C. S. Reddy K. R. Desikan and B. N. Ganguli J.Antibiot. 1987,40,275 (Chem. Abstr. 1987 106 210646). 58 N. Kurokawa and Y. Ohfune J.Am. Chem. SOC.,1986,108,6041. 59 N. Kurokawa and Y. Ohfune J.Am. Chem. SOC.,1986,108,6043. 60 N. Steinerova H. Lipavska K. Stajner J. Caslavaska M. Blum- auerova J. Cudlin and Z. Vanek Folia Microbiol. (Prague) 1987 32 1 (Chem. Abstr. 1987 106 210672). 61 N. Tsuchimori S. Ikegami S. Miyashiro T. Tsuji T. Kida and H. Shibai Comp. Biochem. Physiol. C.,Comp. Pharmacol. Toxicol 1986 84 381 (Chem. Abstr. 1986 105 149409). 62 A. Brossi J. Nut. Prod. 1985 48 878.63 P. D. Singh J. H. Johnson C. A. Aklonis and J. OSullivan J. Antibiot. 1986 39 1054 (Chem. Abstr. 1986 105 187429). 64 P. Karuso and P. J. Scheuer Tetrahedron Lett. 1987 28 4633. 65 K. M. Cable R. B. Herbert and J. Mann Tetrahedron Lett. 1987 28 3159. 66 K. Ienaga K. Nakamura T. Goto and J. Konishi Tetrahedron LRtt. 1987 28 4587. 67 S. A. Fedoreyev N. K. Utkina S. G. Illyin M. V. Reshetnyak and 0.B. Maximov Tetrahedron Lett. 1986 27 3177. 68 K. Ohba H. Nakayama K. Furihata A. Shimazu H. Seto N. Otake Z. Yang L. Xu and W. Xu J. Antibiot. 1986 39 872 (Chem. Abstr. 1986 105 94 198). 69 H. Seya K. Nozawa S. Udagawa S. Nakajima and K. Kawai Chem. Pharm. Bull. 1986 34 2411. 70 Y.Maebayashi Y. Horie Y. Satoh and M. Yamazaki Maikoto-kishin (Tokyo) 1985 22 33 (Chem.Abstr. 1986 105 3147). 71 G. J. Shaw R. D. Wilson G. A. Lane L. D. Kennedy D. B. Scott and G. J. Gainsford J. Chem. SOC.,Chem. Commun. 1986 180. 72 S. E. Yeulet P. G. Mantle J. N. Bilton H. S. Rzepa and R. N. Sheppard J. Chem. SOC. Perkin Trans. I 1986 1891. 73 Z. Wan J. Zhang J. Dai and D. Liang Kexue Tongbao 1986,31 489 (Chem. Abstr. 1987 106 5290). 74 A. Isogai S. Sakuda K. Shindo S. Watanabe A. Suzuki S. Fujita and T. Furuya Tetrahedron Lett. 1986 27 1 161.

ISSN:0265-0568    

DOI:10.1039/NP9890600503

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Pyrrolidine Piperidine and Pyridine Alkaloids A. R. Pinder Department of Chemistry University of Central Florida Orlando Florida 328 16 U.S.A. Reviewing the literature published between July 1987 and June 1988 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 67). 1 Pyrrolidine Alkaloids An efficient syethesis of racemic truns-2,5-dialkylpyrrolidines 2 Piperidine Alkaloids from the Lukes-Sorm dilactam (3) has been described (Scheme 3 Pyridine Alkaloids 2);it has been used to prepare truns-2-butyl-5-heptylpyrrolidine 3.1 Azafluorene and Aza-anthracene Alkaloids (4) and analogues occurring in venoms of varieties of ants3 3.2 Bispyridine Alkaloids Further studies on the bryozoa Amuthiu wilsoni Kirkpatrick 4 References have resulted in the isolation of four new amidic bases 1 Pyrrolidine Alkaloids A new alkaloid piriferine has been isolated from the leaves of Agfuiu piriferu a plant native to Thailand.Spectral study has revealed that it is N-cinnamoyl-2-(2-methylpropanoylamino)-NHCOC H Me2 pyrrolidine (l).I A new stereoselective synthesis of trichonine (2) an alkaloid of Piper trichostuchyon has been reported Piriferine (11 (Scheme 1);2 it involves two consecutive reactions of arsonium salts. 8 Trichonine (2) Reagents i Ph,As+CH,CHO Br- THF Et,O K,CO, trace H,O at 25 OC; ii (A) MeCN K,CO, trace H,O at 25 "C Scheme 1 n (3) vi vii n -n cis + trans (separated1 (4) Reagents i BuMgC1 CH2Cl, at 0 "C then NH,CI H,O; ii HS(CH,),SH BF,.Et,O at r.t.; iii H, Raney Ni; iv P,S in benzene reflux; v MeI CH,CI, r.t.;vi NaBH, MeOH 30 min. at r.t.; vii HCHO Pd-C AcOH H, 6 h at r.t. Scheme 2 515 516 OMe Amathamide C (5) R = Br R'= Me Br Amathamide E (7) R = Br R' = H Br H Amathamide D (6) Amathamide F (8) NATURAL PRODUCT REPORTS 1989 amathamides C D E and F. Their structures (5) (6) (7),and (8) have been deduced from n.m.r. spectral observations.* The main component of the leaves of the Chinese plant Clausena lansium is clausenamide a hepatoprotective agent against chemical toxins. Its structure (9) has been settled by X-ray diffraction analysis its relative configuration being 3S,4R,5R,7S. Surprisingly it is a racemate. The structure has been confirmed by a diastereoselective total synthesis of the racemate (Scheme 3) and a concurrent enantioselective synthesis of the (+)-enanti~mer.~ 2 Piperidine Alkaloids Piperine has been isolated from the mycelium of the fungus of Ulocludium ~pp.~ Details of an earlier briefly reported synthesis of ( +)-sedamine have been published ; (+)-norallosedamine occurring in Lobelia infata has also been synthesized.' Phyllanthimide is a new alkaloid isolated from the leaves and stem of Phyllanthus sellowianus Muell.Arg. Its structure (10) has been established by mass and n.m.r. spectroscopy. The compound is optically inactive possibly owing to the lack of stability of the asymmetric centre which is adjacent to a carbonyl group.* A new enantioselective synthesis of solen- opsin B (1 l) the major saturated component of the group of % Et02C +Ph OYMe "Yco2Et COzEt .I. I II Me Ph iii - Me Me - Me Me O q H 1vii 0 vi CH2OHoqv86% cis + trans 2:l (separated) - U vi o qPh * O-Ph viii 45-50%I Clausenamide (9) Reagents i NaOEt EtOH reflux for 24 h; ii NaH DMF then MeI 1 h at r.t.; iii Ba(OH) (0.5 equiv.) at 70 "C 30 min then dil. HCl; iv 140 "Cfor 10 min; v LiBEt,H at -20 "C on cis isomer; vi DMSO (CF,CO),O then Et,N at -60 "Cto r.t. ;vii PhMgBr THF at 0 "C;viii LDA at -70 "C (EtO),P then 0 at -70 "C Scheme 3 NATURAL PRODUCT REPORTS 1989-A. R. PINDER Phyllanthimide (10) (Ar = 1-naphthyl) 87% iii iv 1 ~ viii ix vii v vi HO-(CH2 h2Me .' a(CHzh2Me * 71% 1 1 83% 85% OH H (-)-(R,R)-Solenopsin B (1 1) ye3 % BuiAlO++ taphthyl / CMe3 (12) Reagents i LDA MeCO,Me THF at -78 "C to r.t.30 min.; ii alcohol (12) (0.33 equiv.) 4-DMAP toluene reflux for 40 h; iii DIBAL/BHT (13) toluene at -65 to -60 "C for 1.5 h; iv LiAlH, THF at 0 "C; v TsCl (1.1 equiv.) 4-DMAP CH,Cl, at -30 "C to r.t.; vi CH = CHCH,MgCl THF at 0 "C for 30 min. then at reflux for 3 h; vii Ph,P DEAD (PhO),(PO)N, THF at r.t. for 24 h; viii heat at 165 "C for 2.5 h; ix LiAIH, Me,Al THF at -78 to 0 "C. Scheme 4 R 7 K + RCX -R $2 0 A L i (15) 0 (14) alkaloids isolated from the venom of the fire ant Solenopsis invicta has been reported (Scheme 4).9 Synthetic studies on cis-2-alkyl-6-methylpiperidines have been described. They involve reaction of 5-lithio-2-pentanone 2,2-dimethylpropylene ketal (or the corresponding dialkyl- cuprate) (14) with various carboxylic acid derivatives (15) leading to selectively protected I ,5-dicarbonyl compounds (16).Reductive amination of the last followed by acid-catalysed deprotection afforded 3,4,5,6-tetrahydropyridines (piperi-deines) (1 7) stereoselectively reducible to cis-2,6-disubstituted piperidines (I 8). The sequence has been applied successfully to syntheses of dihydropinidine (19) and the fire ant venoms cis-2- methyl-6-undecylpiperidine (20) and 2-methyl-6-undecyl-3,4,5,6-tetrahydropyridine (2 1). lo NATURAL PRODUCT REPORTS 1989 major product (separated) Ar = 2,4,6-trimethoxyphenyl v vi R Me0goH ~ VII N Me Me (23)R = H Tubastraine (24) R = BrUC(0)-Reagents i HOAc HCl A; ii B,H, then H,O, -OH; iii DMSO,(COCI), Et,N; iv NaBH,; v resolution of cis isomer; vi BF, Ac,O Et,O on (+)-,(-)- and (*)-forms separately then -OH; vii EtOAc then H+ pyridine hydrochloride Scheme 5 (p OH N 7 Ac (+) -Ammodendrine (25) Isoursuline (26) ( -)-6-N-Normethylskytanthineis the major alkaloidal com- ponent of the bark of Tecoma arequipensis.Its structure and stereochemistry (22) have been revealed by X-ray diffraction analysis of its N-thiourea derivative. The stereochemistry is enantiomeric with that of natural (+)-skytanthine at all four asymmetric centres.l' An anti-inflammatory and immunomodulatory alkaloid has been isolated from the stem bark of Dysoxylum binectariferum.It is a piperidinylchromone (23) the structure of which has been established by spectroscopy and X-ray diffraction analy- sis.12 This structure is that of rohitukine the principal alkaloid of the leaves of Amoora rohituka isolated in 1979,13 but the two may be enantiomeric. The total synthesis of (23) and resolution to afford the natural (+)-base have been reported (Scheme 5).12 A new alkaloid tubastraine has been found in the marine coral Tubastraea micrantha. Its structure arrived at by spectroscopic methods is (24). It is apparently a bis p- bromobenzoate of the unnamed (23) although its stereo-chemistry has not been established. It has been synthesized by regioselective bis-p-bromobenzoylation of r0hit~kine.l~ Full details of earlier outlines of syntheses of the spiro- piperidine alkaloids nitramine and isonitramine (both as racemates) have been p~b1ished.l~ A further synthesis of (+)-perhydrohistrionicotoxin has been described ; it utilizes a regiospecific N-acyliminium ion-initiated furan-terminated cyclization to assemble the desired azaspiro[5,5]bicyclo-undecane skeleton.lG *q o$j \ OH \ OMe OH (27) (28) (+)-Ammodendine occurring in the plant Spartidium sahare has been found by spectroscopic study to be the bispiperidine (25)" 3 Pyridine Alkaloids In the nicotine group new syntheses of myosmine (-t)-nornicotine and (& )-nicotine have been reported.Details of a previously outlined total synthesis of natural (+)-sesbanimide A and (-)-sesbanimide B starting with (+)-xylose have been re1ea~ed.l~ The same authors have reviewed the total synthesis of sesbanimides.20 3.1 Azafluorene and Aza-anthracene Alkaloids Isoursuline (26) is a new alkaloid of the trunk bark of Unonopsis spectabilis ;its structure has been settled by analysis of physical and spectral data.21 Isoursuline (26) and two new azafluorene bases have been isolated from Oxandra xyfo-pioides; they are 6-hydroxyonychine (27) and 2,6-dimethoxy-7- hydroxyonychine (28).Their structures have been advanced on the basis of spectral measurements and through various comparisons with synthetic products of unequivocal structure.22 The structures of three alkaloids isolated recently from Gutteria diefsiana viz. 6-methoxyonychine dielsine and dielsin01,~~ formulated as I -azafluoren-9-ones must now be regarded as 4-azafluoren-9-ones as a consequence of synthetic work and the NATURAL PRODUCT REPORTS 1989-A.R. PINDER EtO2C qN + A X = B(OH)2 or SnMe3 R = H or OMe Reagents i Pd(PPh,), THF at reflux for 24 h [plus Na,CO when X = B(OH),]; ii PPA Scheme 6 (30)R'= H R2 =OMe (31) R'=OMe R2= H (32) 0 OMe Q I I 0 0 0 Orellanine (33) -0 0 I Me0 0 iv Br 42% 27% I I 0 viiI11% OMe vi OH2 Br * 80% QNH2 Reagents i conc. H,SO, fuming H,SO, 100% HNO, at 100 "C for 1 h; ii NaOMe MeOH at r.t. for 24 h; iii (Ph,P),Ni at 50 "C for 12 h; iv H,O, Ac,O then at 100 "Cfor 12 h (53%); v HBr HOAc reflux I h (77%); vi Br, conc. HC1 warm for 1 h; vii Schiemann reaction Scheme 7 general structure pattern now well established for Annonaceae formulated as either (30) or (3 I) as yet indistinguishable from alkaloids.24 Onychine alkaloids occurring in the root bark of the spectral data presented.2' the tropical tree Cfeistophofis patens have significant anti- candidal activity as does the bispyrldine base eupolauridine 3.2 Bispyridine Alkaloids which is also An efficient synthetic route to 3,4'-Di hydroxy-2,3'- bipyridine (32) has been synthesized azafluorenone alkaloids by way of transition metal-catalysed by coupling of 2-iodo-3-methoxypyridine and 3-bromo-4-cross-coupling tactics has been outlined (Scheme 6); 6-methoxypyridine catalysed by nickel followed by ether methoxyonychine (29; R = OMe) for example was obtained cleavage.28 It appears not to be identical with an alkaloid in 80YOyield.26 isolated recently from the wood of Broussonetiu zeyfandicu,and Geovanine is a new ma-anthracene alkaloid found in the formulated as (32).29 trunk-wood of Annonu umbotuy.On spectral evidence it is to be Two new syntheses of orellanine (33) the main poisonous NATURAL PRODUCT REPORTS 1989 (34) iii J Orelline (36) (35) Reagents i NaH ClCH,OCH,CH,SiMe, at 25 "C for 1.5 h; ii NiCl, Ph,P DMF 50-60 "C for 25 min.; .iii BuLi 3-phenyl-2- phenylsulphonyloxaziridine,THF 75 min. at -20 "C (22 % yield) or bistrimethylsilyl peroxide Et,O at -5" to 20 "C (10 % yield);iv MeOH HCl reflux 1 h Scheme 8 "'%Br Br (39) CO2Et N\9CN I 53% * L27% iii 76% * CO2Et iv 67% * (37) 0 (+)-Sesbanine (38) Reagents i Et,CO, NaH toluene at reflux; ii K,CO, EtOH (39); iii Mitsunobu reaction [inversion of CH(0H) group]; iv H,O, -OH EtOH H,O Scheme 9 principle of the toadstool Cortinarius orellanus have been 4 References reported (Scheme 7).,O A new synthesis of orelline (36) an 1 E.Saifah V. Jongbunprasert and C. J. Kelley J. Nat. Prod. accompanying alkaloid has also been described (Scheme 8). A 1988 51 80. point of interest here is intermediate (34),in which the chelating 2 L. Shi J. Yang M.Li and Y.4. Huang Liebigs Ann. Chern. effect of the two di-ether groups allows selective formation of 1988 377. a 4,4'-dilithio-compound which is oxidizable to (35). Attempts 3 W. Gessner K. Takahashi A. Brossi M.Kowalski and M.A.to oxidize orelline (36) to its bis-N-oxide (33) (orellanine) Kaliner Helv. Chim. Acra 1987 70 2003. failed.31 4 A. J. Blackman and R. D. Green Aust. J. Chem. 1987,40 1655; cf. A. R. Pinder Nat. Prod. Rep. 1987 4 527. A review of the addition of stabilized carbon nucleophiles to 5 W. Hartwig and L. Born J. Org. Chem. 1987 52 4352. N-alkylpyridinium salts contains a section on sesbanine 6 J. S. Dahiya D. L. Woods and J. P. Tewari Phytochemistry, synthesis.32A total synthesis of natural (+)-sesbanine (38) has 1988 27 2366. been described via a steroselective cycloannelation reaction 7 K. T. Wanner and A. Kartner Arch. Pharm. 1987,320 1253. (Scheme 9). The optically active dibromide (39) was synthesized 8 M.S.Tempesta D. G. Corley J. A. Beutler C. J. Metral R.A.from (-)-malic acid by an established procedure. The success Yunes C. A. Giacomozzi and J. B. Calixto J. Nat. Prod. 1988 of the synthesis proves that (38) represents the absolute 51 617. configuration of (+)-sesbanine. Applications of steps iii and iv 9 D. F. Taber P.B. Deker H. M. Fales T. H. Jones and H. A. Lloyd J. Org. Chem. 1988 53 2968. to intermediate (37) led to episesbanine synthesized earlier. 10 D. M.Ryckman and R. V. Stevens J. Org.Chem. 1987,52,4274. Both sesbanine and episesbanine whether optically active or 11 G. H.Harris E. C. Fixman F. R. Stermitz and L. Castedo J. racemic show only marginal cytotoxic Nat. Prod. 1988 51 543. NATURAL PRODUCT REPORTS 1989-A. R. PINDER 12 R. G. Naik S. L. Kattige S.V. Bhat B.Alreja N. J. de Souza and R.H. Rupp Tetrahedron 1988 44 2081. 13 A. D. Harmon U. Weiss and J. V. Silverton Tetrahedron Lett. 1979 721; cf. A. R. Pinder in ‘The Alkaloids’ (A Specialist Periodical Report) ed. M. F. Grundon The Royal Society of Chemistry London 1981 vol. 10 p. 33. 14 M. Alam R. Sanduja and G. M. Wellington Heterocycles 1988 27 719. 15 W. Carruthers and R. C. Moses J. Chem. SOC.,Perkin Trans. I. 1988 1625; cf. A. R. Pinder Nut. Prod. Rep. 1989 6 67. 16 S. P. Tanis and L. A. Dixon Tetrahedron Lett. 1987 28 2495. 17 D. Bourquin R. Brenneisen and K. Wicky Pharm. Acta Helv. 1987 62 297. 18 S. Mahboobi and W. Wiegrebe Arch. Pharm. 1988 321 175. 19 F. Matsuda and S. Terashima Tetrahedron 1988 44 4721. 20 F. Matsuda and S. Terashima J. Synth.Org. Chem. (Japan) 1987 45 983 (in Japanese). 21 0.Laprkvote F. Roblot R. Hocquemiller and A. Cavt J. Nut. Prod. 1988 51 555. 521 22 J. Zhang A.-R. 0. el-Shabrawy M. A. el-Shanawany P. L. Schiff jr. and D. J. Slatkin J. Nat. Prod. 1987 50 800. 23 cf. A. R. Pinder Nat. Prod. Rep. 1989 6 67. 24 D. Tadic B. K. Cassels A. Cad M. 0.F. Goulart and A. B. de Oliveira Phytochemistry 1987 26 155 1. 25 C. D. Hufford S.Liu A. M. Clark and B. 0.Oguntimein J. Nut. Prod. 1987 50 961. 26 T. Alves A. B. de Oliveira and V. Snieckus Tetrahedron Lett. 1988 29 2135. 27 A. B. de Oliveira G. G. de Oliveira F. Carazza and J. G. S. Maia Phytochemistry 1987 26 2650. 28 E. V. Dehmlow and H.-J. Schulz Liebigs Ann. Chem. 1987 1123. 29 cf. A. R. Pinder Nat.Prod. Rep. 1985 2 187. 30 E. V. Dehmlow and H.-J Schulz Liebigs Ann. Chem. 1987 857. 31 H. A. Hasseberg and H. Gerlach Helv. Chim. Ada 1988 71 957. 32 M.-L. Bennasar R. Lavilla M. Alvarez and J. Bosch Hetero-cycles 1988 27 789 (pp. 806-808). 33 K. Tomioka and K. Koga Tetrahedron 1988 44 4351.

ISSN:0265-0568    

DOI:10.1039/NP9890600515

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

lndolizidine and Quinolizidine Alkaloids (The late) M. F. Grundon Department of Applied Physical Sciences The University of Ulster at Coleraine Co. Londonderry Northern Ireland B T52 7SA ~~~~~~ ~ ~ ~ Reviewing the literature published between July 1985 and June 1987 (Continuing the coverage of literature in Natural Product Reports 7987 Vol. 4 p. 41 5) 1 Swainsonine alkaloids monomerine I ipalbidine tylophorine and the 2 Castanospermine metacyclophane lythrancepine 11. 3 Dentrobatid Alkaloids 3.1 Occurrence and Structural Studies 3.2 Synthesis 1 Swainsonine 4 Monomerine I 5 Tpalbidine The synthesis of swainsonine (5) by Fleet and co-workers 6 Prosopis Alkaloids which was described briefly in a previous report (cf. ref 1) has 7 Phenanthroindolizidine Alkaloids now been published in full2 and a synthesis of an epimer (6) of 7.1 Occurrence and Structural Studies swainsonine has been reported by the same group3 (Scheme 1).7.2 Synthesis By procedures similar to those used in the swainsonine synthesis 8 The Lupinine-Cytisine-Sparteine-Matrine Group the aide (1) was prepared in three steps from diacetone 8.1 Occurrence glucose; selective removal of an isopropylidene protecting 8.2 Structural Studies group followed by tosylation and ring closure gave the key 8.3 Synthesis intermediate (2) (53 YOyield from diacetone glucose). Treatment 9 Furylquinolizidine Alkaloids of intermediate (3) with base resulted in an intramolecular 10 Lythraceae Alkaloids Wadsworth Emmons reaction to give an a,/l-unsaturated 6-11 References lactam which after reduction to compound (4) was converted into 8-epi-swainsonine (6) in 26% overall yield from intermediate (2).The complex and biologically-active indolizidine and quinolizi- Suami and co-workers4 have described syntheses of 8-epi-dine alkaloids continue to provide synthetic challenges and the swainsonine (6) and 1,8-di-epi-swainsonine (7) from carbo- research published during the period under review is dominated hydrate derivatives by methods analogous to those employed in by syntheses of swainsonine castanospermine Dendrobates their recent synthesis of swainsonine (cf. ref 1). COCHZPO(OM~)~ (2) (3) vi iii I HO YYH (7) Swainsonine (5) R' = H R2 = OH (4) (6) R' =OH R2 = H Reagents i AcOH MeOH H,O at 50 "C; ii TsCI pyridine; iii H, Pd EtOH; iv HO,CCH,PO(OMe), DCC DMF; v.aq. F,CCO,H; vi K,CO, 18-crown-6 DMF; vii Ac20 pyridine; viii BH,-Me$ THF; ix MeOH trace NaOMe then F,CCO,H scheme 1 523 NATURAL PRODUCT REPORTS 1989 0% -,,OMS (8) (9) (10) i-iv v-x ____) ____) TBDMSO CHO OH (12) (13) (14) /i xii xiii bI Cbz \NHCbz (17) ii xiv xv Ip-H at C-1) H O B H N3 H0'. (18) (1 1) [Cbz = -COOCH2Ph TBDMSO = Bu'MezSi-1 Reagents i PhCOCI pyridine; ii ButMe,SiC1 imidazole DMF at 80 "C;iii NaOH MeOH; iv DMSO DCC THF pyridine PhH; v K,CO, MeOH; vi H,NOH EtOH at 60 "C; vii LiAIH, THF; viii PhCH,OCOCI aq. THF; ix TsOH aq. MeOH; x MsCI pyridine; xi MeONa MeOH ;xii CrO * 2pyridine CH,Cl ;xiii LiCH,CO,But; xiv H, Pd-C EtOH ;xv MeOCH,CH,OH reflux ;xvi BH,-THF THF reflux then 6N-HC1 THF reflux Scheme 2 Nucleophilic displacement reactions of mesylate (8) derived J,, compared to castanospermine indicate that the angle from swainsonine (5) resulted in partial rearrangement to between the H-6 bond and H-7 H-5u and H-58 is near 90 O and compounds (10; X = N,,OCOPh or C1) apparently via the that the OH group at C-6 is consequentially 8 and axial.aziridinium derivative (9). Hashimoto's synthesis of castanospermine' (Scheme 2) begins with the diol (12) which is readily prepared from D-mannose. Protection of one hydroxyl group and oxidation of the other 2 Castanospermine gave aldehyde (13) which was converted into the protected As well as castanospermine (1 l) seeds of the Australian tree amine (14).Treatment with base furnished epoxide (15) and Castanospermum australe were shown to contain the minor then its isomer (16). The key epoxide intermediate (17) as a alkaloid 6-epicastanospermine cf. (1 l).' In contrast to castano- mixture of epimers suffered double cyclization first to give a spermine 6-epicastanospermine is a potent inhibitor of amylo- piperidine ring (process a) and then a pyrrolidine ring (process glucosidase but a poor inhibitor of /I-glycosidase. The structure b). The resultant mixture of stereoisomers (18) was separated; of the new constituent was determined by spectroscopy. In the the isomer with 8-H at C-1 was converted into castanospermine 'H n.m.r. spectrum the lower coupling constants J6,, Jsa.6and (1 1) and the a-isomer gave 1-epicastanospermine.525 NATURAL PRODUCT REPORTS 1989-M. F. GRUNDON i-v vi ___) 9- (+ C -2-a- isom er 1 Cl (33) (34) vii lndolizidine 223 AB (19) R' = R2 = H lndolizidine 239 AB (20) R' = OH R2 = H lndolizidine 239 CN (21) R' = H R2 = OH Reagents i NH,OH*HCL NaOAc MeOH; ii MsCl NEt, CH,Cl,; iii Al(Pr"), CH,Cl, PhMe; iv DIBAL CH,CI,; v NCS Et,O; vi CuCl-CuCl, THF AcOH H,O;vii Bu,SnH AIBN PhH scheme HQ &&-0R' RV' Me Me Me I R2 92 ACH/ lndolizidine 205A (26) Pumiliotoxin 307A' (22) R = Me y R = CHS-Amidine 222 (28) R' = R2 = H OH lndolizidine 2358 (27) Amidine 236 (29) R' = Me R2 = H Me R = MeCH2-CHfCH-Amidine 252 (30) R' = Me R2 = OH $ 2 ,c, Pumiliotoxin 307F (23) R= Me9 $ H CH2' 0 Me CH2 6 Pumiliotoxin 321 (24) R = Me' 'CHO *CHO OMe HQH \ Me Azatricyclododecene 205B (31 ) (32) Homopumiliotoxin2236 (25) on the basis of the mass spectrum and the 'H n.m.r.spectrum. Two indolizidines (26) and (27) and three amidines (28)-(30) were also isolated. Trace quantities of the azatricyclododecene 3 Dendrobatid Alkaloids derivative (31) were also obtained; this ring system has not 3.1 Occurrence and Structural Studies been found in nature before but is reminiscent of the 9b- More than 200 alkaloids have been obtained from poison azaphenalene alkaloids of ladybird beetles particularly hip- frogs and a study of the skin extracts of Dendrobates histrionicus pocasine (32).from northwestern Columbia by Daly et aZ.* using g.1.c.-m.s. The 'H and 13C n.m.r. spectra of gephyrotoxin have been techniques has resulted in the detection of forty alkaloids. Two assigned completely." new indolizidine alkaloids of this group were given the names indolizidine 239 AB (20) and indolizidine 239 CD (21) (Scheme 3) and were shown by lH and 13Cn.m.r. spectroscopy to be w-3.2 Synthesis )-indolizidine 223 AB (gephyrotoxin 223 hydroxy derivatives of the parent alkaloid gephyrotoxin 223 Two syntheses of (-t AB (19); the authors now propose the name indolizidine 223 AB) have been described. Broka and Eng' prepared the AB for the latter compound the structure of which has been alkaloid in nine steps from 2-carbomethoxycyclopntanone confirmed by X-ray analyskB A similar investigation of the (Scheme 3).Alkylation of the latter compound with (a-1- skin constituents of the Panamanian poison frog Dendrobates mesyloxyhept-3-ene followed by removal of the ester group pumilio yielded the nine new alkaloids (23)--(31).1° This group gave the ketone (33) the anti-oxime of which was converted includes pumiliotoxin alkaloids (23) and (24) of which the into the N-chloropiperidine derivative (34). Homolytic cycliz- methoxy derivative (24) may be an artefact formed by reaction ation then furnished a mixture of stereoisomeric indolizidines of alkaloid (22) with methanol. The unusual quinolizidine (35) which was separated and each reduced to indolizidine 223 structure (25) was assigned tentatively to one of the alkaloids AB (19) and its isomer.NATURAL PRODUCT REPORTS 1989 i-v -CO2Et -(36) (37) vii viii (40) (39) (38) x xi I vii -(19) i Reagents i AIH, Et,O; ii PBr, light petroleum; iii PPh,; iv Bu"Li THF then Me(CH,),CO,Me then hu I, hexane; v NH,OH KOH MeOH; vi Pr",N(IO,) CHCI,; vii H, Pd-C MeOH; viii Pr"MgBr Et,O; ix NaCNBH, MeOH at pH 3.8-5.4; x Zn AcOH H,O then PhCH,OCOCI aq. Na,CO, CHCI,; xi MsCI NEt Scheme 4 - OAc +OBn NC i-iv Me3Si-CGCLoBn v vi (42) CH20Bn ___)xiii Ph3P &Me vii-ixII M,e H + dCHo 0siP hz But Me 0siP h2 But (45) Me "OH xiv xv (44) I (A) Pumiliotoxin B (41) Reagents :i Bu',AIH then LiCECH ;ii resolution via carbamates from (R)(+)-a-methylbenzylamine;iii MeLi then Me,SiC1 ;iv Ac,O pyridine; v Me,CuMgBr THF; vi Bu',AIH then MeLi then (A); vii KOH EtOH at 90"C then paraformaldehyde then camphor sulphonic acid MeCN reflux; viii Li NH, THF; ix (COCI), Me,SO; x Ph,P THF diethyl azodicarboxylate then p-nitrobenzoic acid; xi K,CO, &OH then Ph,Bu'SiCI DMF imidazole; xii KOH MeOH then EtOAc 2-pyridinethiol DCC; xiii Bu'Li EtPh,PBr THF; xiv CH,CI, reflux; xv LiAIH, THF Scheme 5 NATURAL PRODUCT REPORTS 1989-M.F. GRUNDON Pumiliotoxin 2510 (47) R = Bun Pumiliotoxin A (48) R = 4 Me R' I i-iii iv ____) Me ____) PH q' Me oH CO2Me (511 (50)R' = H R2 = Bu" (52) R' = Bun R2 = H Reagents; i K,CO, DMF; ii LiOH THF H,O; iii MeLi Et,O at 24-40 "C; iv AlCl, CH,CI Scheme 6 H H i-v ii \ (54) (53) Reagents i MeMgBr Et,O; ii H, Pd-C MeOH; iii Zn,AcOH H,O at 60 "C; iv PhCH,OCOCl aq.Na,CO, CH,C1,; v CrO .2 pyridine CH,Cl Scheme 7 Me i-iii + -BrMgCsC-C,(CH2)3Me 0' 0 Reagents i THF; ii H, Pt-C MeOH then (CH,OH), TsOH PhH; iii KOH H,NNH, (CH,OH), H,O; iv; H, Pd-C aq.HC1 MeOH Scheme 8 In the synthesis of indolizidine 223 AB (19) carried out by (46)]led to elaboration of the side-chain to give pumiliotoxin B. complete stereochemical control A similar method also employing epoxide (A) was used to Kibayashi and co-worker~,'~ was achieved using an intramolecular Diels-Alder reaction of prepare (+)-pumiliotoxin A (48) in thirteen steps from alcohol an acyl nitroso intermediate that was obtained by oxidation of (49)(5% yield).ls the hydroxylamine derivative (36) (Scheme 4).The cyclo- Overman and Lesuissel' studied the synthesis of (a-addition product (37) was converted into enamine (38) which alkylidene analogues of pumiliotoxin A illustrated in Scheme on hydride reduction gave compound (40); stereoelectronic 6 for the butyl derivative (50). The ketone (51) was prepared control apparently occurred through reaction of a transient from methyl prolinate and when submitted to a Lewis acid- immonium salt via the most stable transition state (39). The catalysed intramolecular ene reaction gave compound (50) and synthesis was completed by reduction and then ring closure of its stereoisomer (52) in a ratio of 3 1. the five-membered ring. Overman's successful synthesis of pumiliotoxin 251 D (47) by an iminium-vinylsilane cyclization was reported earlier (cf.4 Monomerine I The Interest in the synthesis of monomerine I (53) a trail pheromone ref. 14a) and a full account has since been p~b1ished.l~ same approach has been applied to a convergent synthesis of of the Pharaoh ant continues (cf. ref. 18). Using similar pumiliotoxin B (41) (Scheme 5).ls Substitution of the acetate methods to those employed in their synthesis of gephyrotoxin prepared group of compound (42) by a methyl group with inversion 223 AB (Scheme 4) Kibayashi and co-worker~'~ followed by partial reduction of the triple bond and reaction monomerine I (53) from the 2-piperidone (54) in six steps with epoxide (A) (prepared previously) gave intermediate (43) (Scheme 7). Another synthesis of monomerine I reported by which was converted into aldehyde (44).A Wittig reaction with Yamaguchi et al.,O (Scheme 8) involves regioselective a-compound (45) [obtained in four steps from the hydroxy ester alkynylation of a 1-arylpyridinium salt.22 NPR 6 NATURAL PRODUCT REPORTS 1989 RO lpalbine (55) R = P-D-glycosyl lpalbidine (56) R = H I ii iii -(Fo2Me qoEt Ar 0 Reagents i p-MeOC,H,CH,COCl K,CO, MeCN; ii NaH THF; iii (EtO),CH HCl EtOH; iv AIH, THF; v HCI; vi MeLi Et,O; vii aq. H,SO,; viii AIBr, CS Scheme 9 ~ CO2Et ii iii iv .(561 \ OTBS + N dMe 9 -MeG Mep Me0 \ Ar Ar OEt 0 (581 (571 (591 [Ar = p-OMeCeH5-l Reagents i LDA THF HMPA then ButMe,SiC1 ;ii BF,etherate CH,Cl at -78 "C ;iii LiAlH,-AlCl ;iv BBr, CH,CI Scheme 10 COzMe 'OCH2Ph (611 i-iii + ___) ___) Ar (60) (62) (56) vii-ix c;Gxo" Ar [Ar = p-acetoxyphenyl] Reagents i KOBu' aq.DMSO; ii H, Pd-C EtOH; iii N-methylmorpholine CH,Cl, MeCOCl at 0 "C; iv ClCO,Bu' N-methylmorpholine Et,O then CH,N, Et,O; v Rh,(OAc), CH,CI,; vi H, PtO, EtOH AcOH; vii CrO, H,SO, Me,CO; viii MeLi THF Ac,O; ix 48 YOHBr at 80 "C Scheme 11 NATURAL PRODUCT REPORTS 1989-M. F. GRUNDON R' H Juliprosopine (63) R' = R2 = Julifloricine (64) R' = :"Q( CH2 )' 0-14-Hydroxyisotylocrebine (65) R' = OMe R2 = H or substituents reversed 5-Hydroxy-0-methyltylophorinidine (66) R' = H R2 = OH M:(& (+) -1sotylocrebine (67) R' = H R2 = OMe (-) -Tylophorine (68) R' = OMe R2 = H / 4-Desmethylisotylocrebine (69) R' = H R2 = OH Me0 \ OMe OMe 14-Desoxy-13a-methyl ty loh irsutin id ine (70) 5 lpalbidine (+)-Ipalbidine (56) the agylcone of natural (+)-ipalbine (55) has been shown to have the (S) configuration by c.d.analysis,21 by correlation with (S)-proline,21 and by X-ray analysis22 of its hydrobromide monohydrate. Liu et al.23synthesized (9-( +)-ipalbidine from (%-proline in twelve steps (overall yield approximately 6%) (cf. Scheme 9 for last eight steps). Two additional syntheses have been reported. Danishefsky and V0ge1~~ showed that the silyl ketene acetal (57) which was prepared from the known olefin (58) undergoes acid-catalysed cyclocondensation with an imine to give the indolizidone (59); reduction and cleavage of the methoxy group yields ipalbidine (Scheme 10).Jefford et aZ.25carried out a synthesis of (+)-ipalbidine by an intramolecular carbene cyclization of diazo ketone (60) (Scheme 11). The latter intermediate was prepared by Michael addition of a methyl arylpropenoate (61) to pyrrole followed by reaction of a carbonic anhydride with diazomethane. The cyclization (60) + (62) was catalysed by rhodium(I1) acetate and the product was converted in four steps into ipalbidine (56). OMe Tylohirsuticine (71) 6 Prosopis Alkaloids The structure of julifloricine which is a non-crystalline constituent of Prosopis julijlora has been studied by Ahmad and Qazi.26 The mass spectrum of julifloricine is almost identical to that of juliprosopine (juliflorine) (63) (cf.ref 14b) and on the basis of lH and 13Cn.m.r. data for the two alkaloids alternative structures (64)are proposed for julifloricine. 7 Phenant hroi ndol izidi ne Alkaloids 7.1 Occurrence and Structural Studies The phenanthroindolizidine alkaloids found in cultivated Tylophora hirsuta plants (cf. ref. 27) are not present in wild plants which have been shown to contain the known alkaloids 14-hydroxyisotylocrebine (65) (+)-isotylocrebine (67) (-)-tylophorine (68) and 4-desmethylisotylocrebine (69),28and the new alkaloids 13a-hydroxytylophorine (72),29 14-desoxy- 1301- meth yltylo hirsutinidine (70),28 5-hydroxy- 0-meth yltylop hor- inidine (66),28 and tylohirsuticine (71).28 Structures were determined as indicated earlier for related alkaloids (ref.27) NATURAL PRODUCT REPORTS 1989 I II OH (75) OMe 13a-Hydroxyty lop hor ine (72) 0 Reagents i CrO, Me,CO; ii LiAlH, Et,O; iii conc. HCl heat; iv NaBH, MeOH Scheme 12 OMe ii iii + c’ocb COCF3 -/ OMe (77) OMe (78) liv OMe OMe Reagents i CH,Cl, reflux; ii Et,SiH BF,-Et,O; iii NH,; iv HCHO HCl EtOH reflux (76) Scheme 13 OMe Me0 / Me03 C\ O 2H i ii Ar OEt ArIyiLI iii iv Ar::LY0 H 0 OMe (79) OMe vii-ix c-- Me0 ’ OMe [Ar = 3,4-dimethoxyphenyll (811 Reagents:i (COCI),; ii H,N(CH,),CH(OEt), NaHCO,; iii AcOH H,O; iv Ph,P=CHCO,Et; v ButMe,SiOSO,CF, Et,N CH,CI,; vi TTFA BF;Et,O CH,Cl,-CF,CO,H; v11 KOH MeOH; viii HMPA at 230 “C; ix NaAl (OCH,CH,OMe),H, dioxane reflux Scheme 14 NATURAL PRODUCT REPORTS 1989-M.F. GRUNDON by i.r. 'H n.m.r. and mass spectroscopy and in the case of the phenolic phenanthroindolizidines (66) (70) and the seco-compound (71) by the observation of positive Gibbs tests. 1301- Hydroxytylophorine (72) which is the principal alkaloid of the wild plant was oxidized to the optically inactive ketone (73) and reduced to the amine (74) (Scheme 12).2s Reaction of alkaloid (72) with acid was thought to give the chloride salt (75) but since this product was reported to give a molecular ion containing chlorine on electron impact and to be reduced to optically active tylophorine (68) with sodium borohydride further investigation of these reactions is required. Tylophorine and tylophorinine were isolated from Tylophora molli~sima.~~ 7.2 Synthesis Nordlander and Njoroge3' reported a four-step enantiospecific synthesis of (S)-tylophorine (76) that occurred in approximately 12% overall yield (Scheme 13).The critical stage was Friedel-Crafts reaction of a tetramethoxyphenanthrene with the protected proline derivative (77) to give intermediate (78). Kametani's intramolecular Diels-Alder reactions previously carried out at elevated temperatures (cf. ref. 32) can now occur at room temperature by employing silyl trifluoro-methanesulphonates. Application to the synthesis of tylo- phorine (Scheme 14) involved cyclization of intermediate (79) to the diarylindolizidinone (80) followed by coupling with a thallium reagent to give the phenanthroindolizidinone (8 l).33 8 The Lupinine-Cytisine-Sparteine-Matrine Group Wink has reviewed the biological function34 and chemical ecology35 of quinolizidine alkaloids.8.1 Occurrence New alkaloids and known alkaloids obtained from new sources are listed in Table 1.36-47. Methyl and ethyl esters of (-)-12- cytisineacetic acid isolated from flowers of Echinosophora koreensis are believed to be artefacts derived from the parent acid.48 Seeds from American Sophora secundijlora contain alkaloids of cytisine sparteine and lupanine types but only quinolizidines of the cytisine group were found in leaves of plants growing in Pakistan.46 8.2 Structural Studies The new alkaloid (-)-lusitanine (82) has been obtained from fresh stems of Maackia amurensis var.buergeri and of M. ta~hiroi,~~ although the enantiomer has been isolated from a Genista species (cf. ref. 49). The absolute stereochemistry of the alkaloid was shown to be (1 R,6S) by catalytic reduction of ( -)- lusitanine to a stereoisomeric mixture one constituent of which was identical with a synthetic compound derived from (+)-epilupinine (91). The epimerization of (-)-lupinine into (+)-epilupinine can be carried out in 85% yield with sodium in xylene at 100 "C in the presence of oxygen.50 The structure of (+)-9#?-hydroxylamprolobine(83) isolated from Sophora velutina var. zimbabweensis was determined by i.r. 'H,and I3Cn.m.r. spectroscopy compared with the data for lamprolobine which is a constituent of the same plant.47 53I Table 1Isolation of alkaloids of the lupinine-cytisine-sparteine-matrine group Species Alkaloid Ref.Calpurnia aurea subsp. * Digittine (87) 1 aurea 4/3,13a-Dihydroxylupanine(88) 36 Chamaecy tisus Anagyrine eriocarpus Cytisine I Lupanine 37 Cytisus scoparius (-)-3P 13a-Dihydroxylupanine (90) ( +)-13-Hydroxylupanine Gen ista acant hoclada Anagyrine Cytisine Lupanine N-Methylcytisine Retamine Sparteine Genista anatolica Anagyrine (+)-Calycotamine Cytisine 13-H ydroxysparteine N-Methylcytisine Lupanine Lupinus graecus 13-Hydroxylupanine 13-Hydroxymultiflorine (+)-Lupanine Multiflorine Sparteine Maackia amurenses (-)-Anagyrine var. buergeri (-)-Baptifoline Camoensidine (-)-Cytisine N-Formylcytisine (-)-13P-Hydroxymamanine (85) (-)-Lupanine (-)-Lusitanine (82) (-)-N-Methylcytisine Maackia tashiroi (-)-Lusitanine Petteria ramentacea 5,6-Didehydrolupanine Rhombifoline Sophora alopecuroides Matrine Sophocarpine Sophora Jlavescens Matrine Oxymatrine Sophocarpine Sophoridine Sophora secundijlora N-Acetylcytisine (-)-Baptifoline N-Form ylcytisine (+)-11-Oxocytisine (84) Sophora veiutina var Cytisine zimbab weensis (/)-9/3-Hydroxylamprolobine (83) (+)-Lamprolobine Sophora subprostrata Matrine Oxymatrine * New Alkaloids H NHCOMe \/ Lusitanine(82) (+)-90-Hydroxylamprolobine (83 NATURAL PRODUCT REPORTS 1989 R’*..R3 o%oH R2 0 (po H Lupanine (86) R’ = R2 = R3 = H 0 HOCH2 Digittine (87) R’ = OH R2 = H R3 = O-2‘-pyrrolylcarbonyI (+)-1 1-Oxocytisine (84) (+)-13/3-Hydroxymamanine(85) 4P,13a-Dihydroxylupanine (88) R’ = R3 = OH R2 = H (89) R’ = R2 = H R3 = O-2’-pyrrolylcarbonyI 3/3,130c-Dihydroxylupanine (90) R’ = H R2 = R3 = OH ... ... iv % Ill CO2Et 6e3 ‘‘‘I Et Et H + Et02C(CH2)4CI C02Me COzMe (92) CI CI lv (94) (95) (96) (93) + CH20H Hi (97) Reagents i LDA ZnC1 then ClCO,Me THF; ii (CO,H), THF H,O; iii H, PtO, HOAc; iv HBr HOAc; v NaOEt EtOH; vi LiAlH, Et,O; vii HgCl, MeOH; viii DIBAL-H NEt, THF; ix (HSCH,), CF,CO,H BF;OEt,; x Raney Ni EtOH reflux; xi 5% KOH then 20% HC1 Scheme 15 Other new alkaloids include (+)-1 1-oxocytisine (84) from Sophora ~ecundiflora~~ and (+)-13P-hydroxymamanine (85) from Maackia amurensis var.b~ergeri;~~ the structures of both alkaloids were apparent from their m.s. and ‘H and 13Cn.m.r. spectra. Two novel derivatives of lupanine (86) have been isolated lupanine group was isolated from Cytisus scoparius and shown to be (-)-3/3,13a-dihydroxylupanine (90) by spectroscopic studies and by correlation with (+)-13-hydro~ylupanine.~~. The latter alkaloid which is also a constituent of C. scoparius reacted with oxygen in the presence of LDA to give an inseparable mixture of steroisomers of 3,13-dihydroxylupanine ; from the leaves of Ethiopian CaZpurnia aurea ssp. c~urea.~~acetylation gave (-)-3,!3,13a-diacetoxylupanine which was Digittine (87) gave an i.r. spectrum showing the presence of a hydroxyl group and lactam and ester carbonyl groups; hydrolysis furnished pyrrole-2-carboxylic acid and the second new alkaloid 4p 13a-dihydroxylupanine (88).The position of the ester linkage at C-13 was indicated by dehydration of digittine with phosphorus pentoxide followed by hydrogen- ation to give calpurnine (89); by similar dehydration-hydrogenation alkaloid (88) was converted into lupanine (86). The position of hydroxy groups in the two alkaloids was established by spectroscopy. Another new alkaloid of the identical with the diacetate of alkaloid (90). The ‘H n.m.r. spectra of sparteine and its 0x0 derivatives have been studied further. ’ 8.3 Synthesis Following the recent synthesis of epilupinine (91) by intra- molecular Diels-Alder reaction (cf.ref. 32) several other routes to the alkaloid have been described. Comins and Brown5 used 4-(trimethy1tin)pyridine to introduce an appro- NATURAL PRODUCT REPORTS 1989-M. F. GRUNDON Reagents i Bu"Li then Me,SiCH,I; ii Ni(OAc), NaBH, EtOH; iii MeSO,Cl Et,N CH,Cl,; iv DMF; v NaBH, EtOH; v; F,CCO,H CH,Cl,; vii 0,,MeOH-CH,Cl, then Me,S; viii LiAlH, THF Scheme 16 V (101) (102) I N vi iv vii viii gH-& H N 0 (99) ( 100) Reagents i LiAlH, Et,O; ii glutaric anhydride CHCl,; iii Ac,O CHCl, reflux; iv L-Selectride CH,Cl,; v MeSO,H CHCI,; vi 33% H,SO,; vii 1,1 '-thiocarbonyldi-imidazole,(CICH,), reflux ; viii Bu",SnH xylene reflux Scheme 17 priate side-chain at C-2 (Scheme 15). A mixture of dia-Cyclization of an N-acyliminium ion is also a key feature of stereoisomers (92) was converted by base into the more stable the stereoselective synthesis of the antiulcerogenically active isomer (93).In the five-step synthesis of epilupinine carried out alkaloid matrine (99) by Chen et aZ.5s (Scheme 17). Formation by Yamazaki and co-w~rkers~~ (Scheme 15) addition of thio of intermediate (100) by treatment of the glutarimide derivative derivative (94; n = 2) to an @-unsaturated ketone gave the (101) with acid appears to occur via the ion (102). quinolizidine derivative (99 which was reduced stereo-selectively to compound (96). The corresponding five-mem- bered ring compound (94; n = 1) gave the indolizidinone derivative (97) which is a key intermediate in the synthesis of 9 FuryIqui no1izidine AlkaI oids the elaeokanine alkaloids (cf.ref. 54). In a study of the Intramolecular Diels-Alder reaction of an N-acylazadiene is a synthetic value of intramolecular reactions of N-acyliminium key step in a new synthesis of (-)-desoxynupharidine (103) ions with alkyl- and propargyl-silanes Speckamp and co-carried out by Hwang and Fowler5' (Scheme 18). Two worker~~~ prepared epilupinine by cyclization of intermediate approaches were explored. In one case cyclization of diene (98) (Scheme 16). (104) gave a 1 1 mixture of quinolizidinones (105) epimeric at C- 534 NATURAL PRODUCT REPORTS 1989 MeI + MeCHCO; t *Me 0 ( 105) tp0 iv ___) 0 Me vi - Reagents i HMPA THF; ii SOCl, reflux; iii CH,=CHCH,NHOAc NEt, CCI,; iv heat; v CH,=C(Me)CH,NHOAc NEt, CCl,; vi H, Pd-C; vii 3-lithiofuran then BH,-Me$ Scheme 18 0 i-iii ~ flOH sxsAr H (109) (110) vi-ixI ~ x xi [Ar = 3,4-dimethoxyphenyl] OMe ( 108) Lasubine I1 (111) Reagents :i BrCH,CH(OMe), Bu"Li; ii H,O+; iii CH,=C(OLi)CH,CH,CH=CH,; iv PhCH,ONH * HC1 pyridine; v LiAlH, KOMe; vi Boc-S; vii NCS AgNO, H,O; viii CF,CO,H; ix LiAlH, NaOMe; x [Me,CCH(Me)],BH then H,O, NaOH; xi TsCI pyridine Scheme 19 NATURAL PRODUCT REPORTS 1989-M.F. GRUNDON OH C02Me ... 53 . .. III iv Ar-CH=NOH -OyJ/('1 I I1 ____) Ar + ____) v vi ArL 0 4-8:o) (112) Arq COzMe Ivii (1 13) Lasubine I1 [Ar = 3,4-dimethoxyphenyl1 Reagents i CCl, reflux; ii MeO,C(CH,),CHO CH,Cl,; iii xylene reflux; iv Zn AcOH; v Me$ imidazole then 2-pyridinol at 160 "C; vi EtO,CN=NCO,Et Ph,P PhC0,H ;vii LiAlH, THF Scheme 20 H i ii Oq Ar 0 Ar 0 vi vii I H Ar PAr HO H (1 15) xi xii xiii \ [Ar = 3-iodo-4-methoxyphenyl1 Reagents i HC0,H; ii NaOH MeOH then Swern oxidation; iii LiBHEt,; iv NaH PhCH,Br DMF; v Lawesson's reagent; vi ICH,CO,Et CHCl, then DABCO Ph,P reflux; vii NaBH,CN MeOH ;viii (MeO),P(O)CH,Li ; ix NaH DME 3-iodo-4-methoxybenzaldehyde; x TsNHNH, NaOAc DME-H,O; xi acetylation ;xii tetrakis(triphenylphosphine)nickel(O) DMF at 55 "C; xiii BBr, CH2C12 Scheme 21 9a whereas heating diene (1 06) resulted mainly in formation of stereoisomeric oximes the syn-isomer of which was reduced to compound (107) which was converted into (-)-desoxy-intermediate (110).Protection of the amino group and nupharidine in two steps. hydrolysis of the thioacetal function resulted in generation of a The structures and stereochemistry of methiodides of piperidine derivative which was reduced to compound (1 11); thiobinupharidine alkaloids were studied previously by n.m.r. hydration and further cyclization gave lasubine 11. Lasubine I1 spectroscopy (cf. ref. 32) and now an X-ray analysis of was previously obtained by intermolecular nitrone cyclo-N'-monomethylthiobinupharidine iodide dihydrate has been addition (cf. ref. 60) and now an intramolecular route has been carried described by Hoffmann and EndesfeldeP (Scheme 20). Cycliz- ation of the requisite nitrone (1 12) followed by reduction gave the piperidine derivative (1 13) which was converted into 10 Lythraceae Alkaloids lasubine I1 by successive cyclization to a quinazolidinone A stereoselective synthesis of (+)-lasubine I1 (108) from an Mitsunobo inversion and hydride reduction.acylic syn-1,3-amino alcohol has been reported (Scheme 19).59 Hart and Hongs2 have reported a synthesis of the macrocyclic The /3-hydroxyketone (109) which was prepared from 3,4- alkaloid (+)-lythrancepine I1 (1 14) (Scheme 21) involving dimethoxybenzaldehyde was converted into a 1 :1 mixture of some of the methods used in the earlier synthesis of vertaline 536 NATURAL PRODUCT REPORTS 1989 (cf. ref. 63). The stereochemistry of the alcohol (115) was 30 N. Viswanathan and B. R. Pai J. Nut. Prod. 1985 48 997. confirmed by X-ray analysis.Acetylation was followed by the 31 J. E. Nordlander and F. G. Njoroge J. Org. Chem. 1987 52 critical Ullman reaction to give a metacyclophane which on 1627. cleavage of the protecting benzyl group gave the target alkaloid. 32 M. F. Grundon Nut. Prod. Rep. 1987 4 421. The seventeen-step route from rn-iodoanisaldehyde occurred in 33 M. Ihara M. Tsurata K. Fukumoto and T. Kametani J. Chem. SOC. Chem. Commun. 1985 1159. an overall yield of approximately 1 % and is the first total 34 M. Wink Plant Syst. Evol. 1985 150 65. synthesis of this type of alkaloid. 35 M. Wink ACS Symp. Ser. 1987 330. 36 K. Asres J. D. Phillipson and P. Mascagni Planta Med. 1986 302. 11 References 37 B. Damadyan N. Gamer A. H. Mericli and B. Cubakcu Planta 1 M. F. Grundon Nut.Prod. Rep. 1985 2 236. Med. 1986 504. 2 B. P. Bashyal G. W. J. Fleet M. J. Gough and P. W. Smith 38 I. Murakoshi Y. Yakashita S. Ohmiya and H. Otomasu Phyto-Tetrahedron 1987 43 3083. chemistry 1986 25 521. 3 G. N. Austin P. D. Baird G. W. J. Fleet J. M. Peach P. W. 39 F. Tosun M. Tanker T. Ozden and A. Tosun Akara Univ. 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ISSN:0265-0568    

DOI:10.1039/NP9890600523

出版商:RSC    

年代:1989

数据来源: RSC