摘要:

Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr C. Abell University of Cambridge 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 Bristol 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. 1991 Annual Subscription Price E.C. f 198.00 Overseas f228.00 U.S.A. $467.00. 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 11 003. Second-Class postage paid at Jamaica NY 11 431 -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 1991 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 1991 E.C. f198.00 Overseas f228.00 U.S.A. US$467.00 Subscription rates for back issues are U.K. (1986)f 130.00 (1 987) f 142.00 (1 988) f 159.00 (1 989) f 169.00 (1990)f 177.00 Overseas f 143.00 f 159.00 f 183.00 f 194.00 f 204.00 U.S.A. US $252.00 US $280.00 US $342.00 US $388.00 US $398.00 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/NP99108FX001

出版商:RSC    

年代:1991

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99108BX003

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

N 0265-0568 NPRRDF 8 1-1-1-60 (1991) Natural Product Reports A journal of current developments in bio-organic chemistry Volume 8 Indexes CONTENTS ... 111 Preliminary pages for Volume 8 1-1 Index of Authors Cited 1-33 Subject Index ISSN 0265-0568 Coden NPRRDF Natural Product Reports A journal of current developments in bio -organic chemistry Volume 8 1991 The Royal Society of Chemistry Cambridge Natural Product Reports (ISSN 0265-0568) 0The Royal Society of Chemistry 1992 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 ISSN 0265-0568 NPRRDF 81-612 1-1-1-60 (1991) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 8 CONTENTS 1 Diterpenoids J. R. Hanson Reviewing the literature published during 1989 17 Steroids Reactions and Partial Synthesis A. B. Turner Reviewing the literature published during the period November 1987 to October 1988 53 Quinoline Quinazoline and Acridone Alkaloids J. P. Michael Reviewing the literature published mainly between July 1988 and June 1989 69 Terpenoid Glycosides H. Pfander and H. Stoll Reviewing the literature published during 1987 and 1988 97 Marine Natural Products D. J. Faulkner Reviewing the literature published during 1989 149 The Biosynthesis of Shikimate Metabolites P.M. Dewick Reviewing the literature published during 1989 171 Mwscarine Oxazole Thiazole Imidazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J. R. Lewis Reviewing the literature published between August 1988 and July 1989 185 The Biosynthesis of Plant Alkaloids and Nitrogeneous Microbial Metabolites R. B. Herbert Reviewing the literature published between August 1988 and July 1989 21 1 Corrigenda 213 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1989 and June 1990 223 Carotenoids and Polyterpenoids G. Britton Reviewing the literature published in 1988 25 1 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites J.E. Saxton Reviewing the literature published between July 1989 and June 1990 309 The Occurrence and Biological Activity of Drimane Sesquiterpenoids B. J. M. Jansen and A. de Groot Reviewing the literature to January 1990 319 The Synthesis of Drimane Sesquiterpenoids B. J. M. Jansen and A .de Groot Reviewing the literature to January 1990 I 339 /3-Phenylethylamines and the Isoquinoline Alkaloids K. W. Bentlej Reviewing the literature published between July 1989 and June 1990 NATURAL PRODUCT REPORTS 1990 CONTENTS 367 391 415 441 455 465 499 527 553 573 603 Terpenoid Phytoalexins C. J. W. Brooks and D. G. Watson Reviewing the literature published between August 1984 and December 1989 Modern Separation Methods A.Marston and K. Hostettmann Withanolides and Related Ergostane-type Steroids E. Glotter Biosynthesis of C,-C, Terpenoid Compounds M. H. Beale Reviewing the literature published during I989 The Lycopodium Alkaloids W. A. Ayer Reviewing the literature published between January 1986 and October 1990 Marine Sterols R. G. Kerr and B. J. Baker Reviewing the literature published to July 1990 Diterpenoid Alkaloids M. S. Yunusov Reviewing the literature published between the middle of 1985 and the end of 1989 A Unified Mechanistic View of Oxidative Reactions Catalysed by P-450 and Related Fe-Containing Enzymes M. Akhtar and J. N. Wright Indolizidine and Quinolizidine Alkaloids J. P. Michael Reviewing the literature published between July 1989 and June 1990 The Biosynthesis of Polyketides T.J. Simpson Reviewing the literature published between January I986 and December 1988 Tropane Alkaloids G. Foder and R. Dharanipragada Reviewing the literature published between January I990 and December 1990 Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. 6.Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Nottingham 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. This journal includes reviews of books relating to natural products. Volumes for review should be sent to the editorial office for which the address is The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF and marked for the attention of the Senior Editor Reviews.Contributors to Volume 8 Akhtar M. 527 Faulkner D. J. 97 Marston A. 391 Ayer W. A. 455 Baker B. J. 465 Fodor G. 603 Glotter E. 415 Pfander H. 69 Robins D. J. 213 Beale M. H. 441 Hanson J. R. I Saxton J. E. 251 Bentley K. W. 339 Britton G. 223 Herbert R. B. 185 Hostettmann K. 391 Simpson T. J. 573 Stoll H. 69 Brooks G. J. W. 367 Jansen B. J. M. 309 319 Turner A. B. 17 de Groot A. 309 319 Kerr R. G. 465 Watson D. G. 367 Dewick P. M. 149 Dharanipragada R. 603 Lewis J. R. 171 Michael J. P. 53 553 Wright J. N. 527 Yunusov M. S. 499 Nomenclature It is the policy of The Royal Society of Chemistry to en-courage the use of IUPAC and IUB Recommendations on nomenclature.Although many of the appropriate nomen-clature documents are included in the new edition of the IUB publication ‘ Biochemical Nomenclature and Related Documents’ (published by The Biochemical Society London 1989) a selection of recent Recommendations that will be of particular interest to those who investigate the chemistry occurrence or biosynthesis of natural products includes Nomenclature of tetrapyrroles (Recommendations 1986) Pure Appl. Chem. 1987 59 779-832. Nomenclature and symbols for folic acid and related compounds (Recommendations 1986) Pure Appl. Chem. 1987 59 833-836; Eur. J. Biochem. 1987 168 251-253. Nomenclature of prenols (Recommendations 1986) Pure Appl.Chem. 1987 59 683-689; Eur. J. Biochem. 1987 167 181-184. Extension of Rules A- 1.1 and A-2.5 concerning numerical terms used in organic nomenclature (Recommendations 1986) Pure Appl. Chem. 1986 58 1693-1696. [The original versions of these Rules are in ‘Nomenclature of Organic Chemistry Sections A B C D E F and H’ 1979 Edition] Nomenclature of glycoproteins glycopeptides and peptidoglycans (Recommendations 1985) Eur. J. Biochem. 1986 159 1-6. ‘ Enzyme Nomenclature (Recommendations 1984) ’ Supplement 1 Corrections and additions Eur. J. Biochem. 1986 157 1-26. Recommendations for the presentation of thermodynamic and related data in biology (1985) Eur. J. Biochem. 1985 153 429434. Nomenclature for incompletely specified bases in nucleic acid sequences (Recommendations 1984) Eur.J. Biochem. 1985 150 1-5 (see also Eur. J. Biochem. 1986 157 1). ‘ Enzyme Nomenclature 1984 ’ (Recommendations of the Nomenclature Committee of the International Union of Biochemistry on the nomenclature and classification of enzyme-catalysed reactions) Academic Press Orlando Florida 1984. Nomenclature and symbolism for amino acids and peptides (Recommendations 1983) Pure Appl. Chem. 1984 56 595-624; Eur. J. Biochem. 1984 138 9-37 (see also Eur. J. Biochem. 1985 152 1 and the Newsletter 1985 of NC-IUB and JCBN ibid. 1985 146 pp. 238 and 239 and the Newsletter 1986 ibid. 1986 154 pp. 485 and 486). Abbreviations and symbols for the description of conformations of polynucleotide chains (Recommendations 1982) Pure Appl.Chem. 1983 55 1273-1280; Eur. J. Biochem. 1983 131 9-15 (see also the Newsletter 1984 of NC-IUB and JCBN Eur. J. Biochem. 1984 138 p. 7). Symbols for specifying the conformation of polysaccharide chains (Recommendations 1981) Pure Appl. Chem. 1983 55 1269-1272; Eur. J. Biochem. 1983 131 S7. Nomenclature of retinoids (Recommendations 198 l) Pure Appl. Chem. 1983 55 721-726; Eur. J. Biochem. 1982 129 1-5. Symbolism and terminology in enzyme kinetics (Recommendations 1981) Eur. J. Biochem. 1982 128 281-291. Polysaccharide nomenclature (Recommendations 1980) Pure Appl. Chem. 1982 54 1523-1526; Eur. J. Biochem. 1982 126 439441. Abbreviated terminology of oligosaccharide chains (Recommendations 1980) Pure Appl. Chem.1982 54 1517-1522; Eur. J. Biochem. 1982 126 433437. Nomenclature of vitamin D (Recommendations 198 l) Pure Appl. Chem. 1982 54 1511-1516; Eur. J. Biochem. 1982 124 223-227. Nomenclature of tocopherols and related compounds (Recommendations 1981) Pure Appl. Chem. 1982 54 1507-1510; Eur. J. Biochem. 1982 123 473475. The most recent of the lists of restriction endonucleases and their isoschizomers (compiled by R. J. Roberts) was in Nucleic Acids Res. 1988 16 R271-R313 its predecessors being ibid. 1987 15 R189-R217 ibid. 1985 13 r165-r200 and ibid. 1983 11 r135-r167. Recent codes of nomenclature for organisms include ‘International Code of Nomenclature of Bacteria and Statutes of the International Committee on Systematic Bacteriology (1976 Revision)’ ed.S. P. Lapage P. H. A. Sneath E. F. Lessel V. B. D. Skerman H. P. R. Seeliger and W. A. Clark American Society for Microbiology Washington D.C. U.S.A. 1976. [Appendix 2 of this publication (Approved Lists of Bacterial Names) appeared in Znt. J. Syst. Bacteriol. 1980 30,22-20.] ‘International Code of Botanical Nomenclature (1987)’ ed. W. Greuter H. M. Burdett W. G.Chaloner V. Demoulin R. Grolle D. L. Hawksworth D. H. Nicholson P. C. Silva F. A. Stafleu E. G. Voss and J. McNeill Koeltz Scientific Books Konigstein Federal Republic of Germany 1988. ‘International Code of Zoological Nomenclature ’ 3rd edn. ed. W. D. L. Ride C. W. Sabrosky G. Bernardi R. V. Melville J. 0. Corks J. Forest K. H. L. Key and C. W. Wright International Trust for Zoological Nomenclature in association with the British Museum (Natural History) London U.K. and the California Press Berkeley and Los Angeles U.S.A. 1985.

ISSN:0265-0568    

DOI:10.1039/NP99108FP015

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Steroids Reactions and Partial Synthesis A. B. Turner Chemistry Department University of Aberdeen Aberdeen AB9 2UE Scotland Reviewing the literature published during the period November 1987 to October 1988 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 539) 1 Reactions acetoxymethyl- 17p-tosylate (5) in acetic acid or dimethyl-1.1 Alcohols and Carboxylic Acids and their Derivatives sulphoxide gives the 17a-acetoxy-derivative (6) via participation Halides and Epoxides of the neighbouring acetoxymethyl group as demonstrated by 1.1.1 Oxidation Substitution and Reduction studies of the solvolysis of the tosylate (7).8 1.1.2 Ethers and Esters 1.1.3 Opening of Epoxide Rings 1.2 Unsaturated Compounds 1.2.1 Electrophilic Addition 1.2.2 Other Reactions of Olefinic and Aromatic Steroids 1.3 Carbonyl Compounds 1.3.1 Reduction and Dehydrogenation 1.3.2 Other Reactions 1.3.3 Reactions of a$-Unsaturated Carbonyl Compounds and Enols or Enolic Derivatives 1.4 Compounds of Nitrogen Phosphorus Sulphur and other Hetero-elements 1.5 Molecular Rearrangements 1.6 Remote Functionalization Reactions 1.7 Photochemical Reactions 2 Partial Synthesis 2.1 Derivatives and Analogues of Cholestane 2.2 Vitamins D their Derivatives and their Metabolites 2.3 Cholanes Norcholanes and Dinorcholanes 2.4 Pregnanes 2.5 Androstanes and Oestranes 2.6 Cardenolides and Bufadienolides 2.7 Heterocyclic Compoounds 2.8 Cyclopropano-steroids 2.9 Microbiological Transformations 3 References During the year the following topics have been reviewed backbone rearrangements,l aromatase inhibitors,2 synthesis of naturally occurring polyhydroxy~teroids,~ synthesis of vitamin D metabolite^,^ and stereo-controlled side-chain con~truction.~ Other reviews are mentioned in the relevant sections.Me 1 Reactions 1.1 Alcohols and Carboxylic Acids and their Derivatives Halides and Epoxides 1.1.1 Oxidation Substitution and Reduction The iodoxybenzene method for the direct oxidation of 5p-cholan-3a-01s to 1,4-dien-3-ones has been applied to a wider (5) R = CH20COMe range of cholanoic esters.6 The oxidation involves the use of benzene seleninic anhydride as catalyst in refluxing toluene (7) R = H and good yields are obtained when hydroxyl groups in rings B and c are protected.Both 6- and 7-hydroxy esters give complex mixtures of products whereas methyl deoxycholate (1) gives the OCOMe 1,4-diene-3,12-dione (2) cleanly. N,N'-Sulphinyldiimidazole prepared from imidazole and thionyl chloride can be used to dehydrate steroidal alcohol^.^ Thus the 1lp-alcohol(3) is converted into the dienedione (4) in 45% yield by brief reaction in tetrahydrofuran at room temperature. Tertiary alcohols are also dehydrated without rearrangement or ester formation. Solvolysis of the 16a-17 2-2 NATURAL PRODUCT REPORTS 1991 I CF3 R’O (8) R’ = COMe R2 = F 19) R’ = H R2 = OMe R’ & k2 (10) R’ =BOH R2= H (11) R’=aCI R2= H (12) R’ =PCl R2= H (14) R’ = POH R2 = BOCOMe (75) R’ = aCI R2 = BOCOMe (16) R’ = POCOMe R2 = aCI (17) R’ = BOCOMe R2 = POH (13) 0 (18) (20) (22) Aerial oxidative defluorination of 6-fluoroandrost-5-en-3-one occurs with phenylhydrazine to give the 3-phenylhydrazone of the 4-ene-3,6-dione in 70 YOyield.gA related oxidation to the 4-ene-3,6-dione itself occurs in toluene containing sodium methoxide and also in chloroform.One fluorine atom of the hexafluoride (8) is mysteriously replaced by a methoxyl group during hydrolysis of the ester groups with methanolic potassium hydroxide.lo The methoxy- pentafluoride (9) can be isolated in 20 % overall yield from the original cholesterol derivative via bromination dehydro-bromination and saponification. Reactions of steroidal alcohols with triphenylphosphine- carbon tetrachloride can involve neighbouring group par- ticipation of acetoxyl groups and allylic and homoallylic double bonds. Thus 3P-hydroxy-androst-Sen- 17-one (10) gives both 301- and 3~-chloro-derivatives (1 1) and (12) and 3cc,5-cycloandrost-6-en-17-one (1 3) a product mixture similar to that originally obtained from cholesterol. Only minor amounts of 17-dichloromethylene derivatives are formed. l14p-Acetoxydehydroepiandrosterone (14) by contrast gives the (19) R = H,OH,CI,OCOMe C8H17 MeOCH20& H (21) gH20CHzR Bu‘Me2SiO (23)R = H,Ph 3a- and 4a-chloro-derivatives (1 5)and (1 6) and its isomer (1 7) gives the 4,6-diene (18) as the major product probably via a 6P-chloro intermediate.Cholestene epoxides (19) are readily reconverted to 5-enes in ethereal solution by treatment with alumina impregnated with silver nitrate. l2 I .I.2Ethers and Esters Treatment of the stannylmethyl ether (20) with an excess of n- butyllithium in tetrahydrofuran causes [2,3] sigmatropic re-arrangement to the 14a-hydroxymethyl compound (21) in 79 % yield.13 1,2-Glycol monoethers of type (23) are readily obtained from the 17-ketone (22) and a-alkoxyacid chlorides by samarium diiodide mediated decarbonylation. l4 Reaction occurs within a few minutes at room temperature and isolated yields are 52% for the 17a-methoxymethyl-l7~-ol and 60% for the 17a-benzyloxymethyl- 17p-01.Reaction of unsaturated esters of type (24) with lithium NATURAL PRODUCT REPORTS 1991-A. B. TURNER (24) (25) Reagents i PriNLi THF; ii MeI THF HMPA Scheme 1 (26) R = H (27) R = CI Reagents i CH,=CHCH,NCS AlCl, DMF R R + + 4? 0 -37% R=OCOMe 50% -38% R =CI 46% -36% R=H 47% 51% R=OH 36% Scheme 2 for alkylation of the enolate anions. The absolute configuration of the C(20)methyl groups in these A16-steroids can be determined by 'H NMR analysis. In the 20-Ha-isomers the C(20)methyl groups consistently resonate at higher field (0.05-0.1 ppm) than those in the 20-H~-compounds.Fur- thermore the C(20) stereochemistry of ethyl 20-alkylpregn- 16- en-21-oates can be assigned from CD data. 1.1.3 Opening of Epoxide Rings The 5P,6P-epoxide (26) is oxidized to the ketol(28) by chromium trioxide whereas the 3a-chloroepoxide (27) is unreactive. l7 The latter epoxide is obtained by peracid oxidation of 3a-chloroandrost-5-en- 17-one and the chlorine atom can be removed by reduction with tributyltin hydride. Trans-diaxial opening of 7a 8a-epoxy- 5a-choles tan- 3/3-01 acetate with lithium in ethylamine gives the 7a-alcohol whereas the 8P-01 is formed from the epimeric 7P,8P-epoxide with lithium aluminium hydride. No trans-diaxial products were isolated on treatment of the 7a,8a-epoxide with mineral acids or Lewis acids.Instead the C-8 carbocation gives rise to a mixture of the 7-ketone allylic 7a-o1s and dienes. Cleavage reactions of 5a,6a-epoxycholestanes with lead tetraacetate,l9 and ally1 isothiocyanate in the presence of aluminium chloride,20 lead to products such as isothiocyanates (29) and oxazolidine thiones (30) (Scheme 2). Copper catalysed 1,4-addition of methyl magnesium iodide to the unsaturated epoxide (31) gives the 3/3,15a-diol (32).,l Similar stereospecific addition occurs with benzyl alcohol and benzyl chloride to give related 15-oxygenated sterols. diisopropylamide followed by treatment with alkyl halides gives predominantly the A16-(20S)alkylation products (25) which can be isolated in 82-92 % ~ie1d.l~. l6 This means that this type of alkylation can now be used to construct both 20s and 20R side chains since the analogous alkylation of the saturated esters is well known to give the opposite configuration at C-20 (Scheme 1).The remarkable selectivity difference between the saturated and unsaturated esters is explained by the differing degrees of steric congestion in the transition states NATURAL PRODUCT REPORTS 1991 (33) f N\ OR (40) R = Me,Et 1.2 Unsaturated Compounds I .2.1 Electrophilic Addition Epoxidation of the allylic alcohol (33) with 3-chloroperbenzoic acid or with (+)-or (-)-diethy1 tartrate-t-butyl peroxide-titanium isopropoxide leads stereospecifically to the spiro- epoxide (34).22 Thus the usual directive effect of the hydroxyl group in this type of oxidation is absent the oxygen being delivered to the methylene group exclusively from the a-face.This is probably due to steric hindrance to formation of a p-face peracid complex by the angular methyl group and the axial 2p-and 6p-hydrogens. Unlike normal steroids the A-norandrost-5-enes (35) and (36) react with 3-chloroperbenzoic acid to give the 5p,6P-epoxide~.~~ A further difference is that in the normal steroid series the directive effect of a neighbouring hydroxyl group is lost upon acetylation and epoxidation then occurs from the a-face whereas in the A-nor series epoxidation still occurs from the p-face. Reaction of cholesteryl acetate with the pyridine-trifluoro- acetic anhydride-molecular oxygen system gives a mixture of the a-and p-epoxides and the 5-en-7-one together with various trifluor~acetates.~~ The mechanism involves a hydroperoxide intermediate.A ruthenium porphyrin is an efficient catalyst for the stereospecific epoxidation of cholest-5-enes by oxygen. 25 Cholesteryl acetate gives nearly pure (> 99 YO)5P,6P-epoxide although cholesterol itself does not react. Photo-oxygenation of cholesterol in the presence of titanium tetraisopropoxide provides a convenient route to the epoxyalcohols (37) and (38).26Oxygen transfer in the intermediate cholesterol hydro- peroxide takes place much faster than radical promoted ( M eCOO12 HC (35) (36) *\ OR isomerization. In dichloromethane the product ratio is approx. 1 :1 whereas the alcohol (37) predominates after oxidation in chloroform or pyridine.Neighbouring group participation of allylic and homoallylic ester groups occurs in the addition of hypobromous acid to the A5-bond of chole~tenes.~’ All the stereoisomers of the 3,7- diacetates as well as some 3,7,19-triacetates have been used in studies of the relative importance of steric electronic and stereoelectronic effects in controlling the product distribution. The results have predictive value and establish that in-troduction of a neighbouring group is a useful method for directing the course of the electrophilic addition. The stereochemistry of cis-dihydroxylation of 3a,5-cyclo- androst-6-en- 17-one (13) via permanganate or osmate cyclic ester intermediates is controlled by the cyclopropane ring leading to predominant p-face attack upon the double bond.28 The conformation (39) of the cyclo-steroid allows much greater access to the p-face of the A6-bond than is possible in the corresponding 5a-cholest-6-enes (which undergo a-face attack).The presence of the cyclopropane ring forces the angular methyl group away from the p-face of the double bond and at the same time increases steric hindrance on the a-face of the molecule. Hydroboration/oxidation gives the 6a,7a- and 7p- alcohols in yields of 7 and 55 % (1 1 mixture) respectively. This also indicates some degree of control by the three- membered ring. Hydroxylation of stigmastadienone oximes (40) by silver acetate and iodine in aqueous acetic acid followed by acetylation with acetic anhydride in pyridine gives 4548 % of the cis-diacetates (41) and l&l 1 YOof the trans-iodoacetates (42).29 NATURAL PRODUCT REPORTS 1991-A.B. TURNER HO (48) (52) (54) X = H2 (55) x = 0 Cycloaddition of dichloroketene (generated from trichloro- acetyl chloride and zinc) to 3- 7- 17- and 20-methylene steroids affords the corresponding cyclobutanones.30 Yields reflect the steric crowding around the double bond. Thus 3-methylene-5a-cholestane (43) gives the epimeric cyclo-butanones (44)and (49 in yields of 17 YOand 64 YOrespectively. 1.2.2 Other Reactions of OleJinic and Aromatic Steroids The suprafacial rearrangements of the allylic peroxide (46) to its isomer (47) does not involve exchange of oxygen with the atmosphere suggesting a concerted mechanism whereas the subsequent rearrangement of the 7a-hydroperoxide (47) to the 7P-hydroperoxide is susceptible to exchange indicating a dissociative me~hanism.~~ Regioselective hydroboration of the sterol 8,14-diene system followed by deoxygenation via thiocarbonate formation and subsequent treatment with tributyltin hydride in the presence of a radical initiator is a key sequence in the introduction of the A8-bond in the synthesis of zymosterol (48).32 Reproducible conditions for the isomerization of ergosterol or its benzoate to (49) R = No2 0 NO2 (56) (57) the 8,14-dienes (49) with hydrogen chloride in chloroform have been e~tablished.~~ In the case of the benzoate the SP-isomer is formed.7-Dehydrocholesterol likewise gives the 8,14-diene (50) in 65 YOyield on a lOOg scale. A revised mechanism is proposed for the low temperature isomerization of 7-dehydrocholesteryl- benzoate to the 5a-7,14-diene (51).34 Two by-products the 5P-isomer and the 5,8-8,14-diene were isolated from the reaction together with a new intermediate the 3~-benzoyloxy-6a-chloro-5a-cholest-7-ene. An improved procedure for the synthesis of the diene (51) minimizes the levels of these and other contaminants. Under the optimum conditions this sterol can be obtained with only minor amounts of the 5a-8,14-diene and 5-15% of the SP-8,14-diene which can be removed by recrystallization. Activated tritium generated by microwave discharge in tritium gas has been used to label the steroid nucleus.35 Addition to isolated double bonds occurs in the order A' > A4 > A5.The oestrapentaene (52) has been converted into the ring D-tritiated norgestrel (53) in four The action of chromic acid upon 6-nitrocholesta-3,5-diene (54) gives the oxidation products (55)-(57).37 NATURAL PRODUCT REPORTS 1991 OAc 0 Ac OAc (58) (59) OAc Reagents i HBr AcOH (1 :10) (60) Scheme 3 OSiMe2Bu' Me0@ (c0)3& Me0 (62) (63) C8H17 \(\/C02Me HO& 0& @FCozMe 0 0 0 (65) (66) 7p 17~-Diacetoxy-4-methyleneandrost-5-ene (58) reacts with hydrogen bromide in acetic acid to give the 174-dimethyl-oestratriene (59) in 95% yield in spite of the presence of an apparent blocking methylene group at C-4.38 Incorporation of deuterium from deuterium bromide/deuterioacetic acid at the C-4 methyl group is consistent with methyl migration from C- 10 to C-1 (Scheme 3).The 3,4-dimethyl isomer (60) is also isolated in 3% yield but no anthrasteroids are obtained. The reaction between the lithium anion of 173-dithione and a mixture of a and p complexes (61) leads to insertion of the heterocycle predominantly at the C-1 .39 The resulting dithiane (62) can be converted into several 1-substituted derivatives. The isoindole (63) has been developed as a precolumn derivatization reagent for oestr~gens.~~ It reacts with the phenolic hydroxyl group under alkaline conditions to give fluorescent products which are readily separated by HPLC on a reversed-phase column using aqueous methanol as eluent.1.3 Carbonyl Compounds 1.3.1 Reduction and Dehydrogenation The proportion of the 6a-alcohol in the product mixture from aqueous potassium borohydride reduction of the ketone (64) absorbed into polymer supports (e.g.polystyrene and Amberlite XAD2) varies from zero to 90% according to the type of polymer Phase transfer agents also affect the product ratio and the greatest variations arise when substrates are adsorbed onto the inner surfaces of the polymers. Similar selectivities are found in the reduction of other ketones using this system. The 3,6-diketocholanate (65) gives the A2-6-ketone (66) in 67 '/O yield with trimethylsilyl chloride and zinc amalgam.42 Reduction of unconjugated carbonyl groups occurs selectively in alkoxide reductions catalysed by zirconocene and hafnocene complexes.43 Thus 4-androstene-3,17-dione and progesterone give 17-hydroxyandrost-4-en-3-oneand 20-hydroxypregn-4- en-3-one7 respectively in 80 YOand 67 YOyields.1.3.2 Other Reactions Ketones having an adjacent tertiary carbon are oxidized by superoxide anion radicals in an enol dependent process to give tertiary a-hydroperoxide which are readily reduced to a-ketokg4 Thus pregnan-20-ones gives 17a-hydroperoxy-20- ones with potassium superoxide and 18-crown-6 in benzene at 67 "C. Reaction is faster in the presence of oxygen under NATURAL PRODUCT REPORTS 1991-A. B. TURNER OR @+ 0' (80) R =COMe (67) R = COCH20H (81) R = SiMe3 (82) (68) R=C02H (69) R = H iio N iii I # bMe iv [aOMe pressure and the yields of hydroperoxide are somewhat enhanced.The hydroperoxides can be efficiently reduced by triphenylphosphine to the tertiary a-ketols (64-72 YOoverall yield). 3P-Hydroxy-5a-cholestan-6-oneis similarly converted into 3P,5a-dihydroxycholestan-6-onein an overall yield of 66 YO.The isolation of the hydroperoxides supports mechanisms previously proposed for the reaction of steroidal 3-lactones with superoxide ion. Oxidative degradation of (67) gives the acid (68) in 88% yield together with the androstane (69) in 7.5 YOyield.45 Baeyer-Villiger oxidation of the ketone (70) with perbenzoic acid in chloroform in the presence of toluene-p-sulphonic acid gives the lactones (71) and (72).46 The 4-en-3-one (73) behaves in a similar way.Oxidation of the ketones (74) and (75) with perbenzoic acid gives a range of lactone-derived products including the acid chloride (76).47 Details of the rearrangement of 16P-hydroxy- 17-ketones to 17P-hydroxy- 16-ketones have appeared.48 Rate studies on the acid- and base-catalysed rearrangement of the ketols (77) and (78) to the isomer (79) reveal a marked kinetic isotope effect (K,/K = 4.5or 3.0). The ketol (79) derived from the labelled precursor (78) retains deuterium to the extent of 16-65 YO.The stereospecific intramolecular 1,2-hydride shift is the principal (73) R' = H R2 = CI (74) R' = CI R2 = H (75) R' = Br R2 = H (76) mechanism involved in the rearrangement and the 16-0x0 group enolizes preferentially towards the 17-position under these conditions.The enol acetate (80) and enol silyl ether (81) of oestrone have been fluorinated with fluorine gas xenon difluoride fluoroxytrifluoromethane and caesium fluoroxysulphate. 49 The reaction between the silyl ether (81) and xenon difluoride exhibits high selectivity for the a-isomer (82). Bromination of 5a-cholestan-6-one oxime with N-bromosuccinimide in carbon tetrachloride in the presence of dibenzoyl peroxide gives 6P- nitro-7a-bromocholest-4-ene 7-bromocholesta-4,6-dien-6-one 5a-cholestan-6-one and 6-nitro~holest-5-ene.~~ Similar product mixtures are formed from 3P-acetoxy-and 3P-chloro-5a-cholestan-6-one oximes. Bromination of 5a-cyanocholestan-6- one (83) and treatment of the resulting 7a-bromo de'rivative H (77) R = H H (79) (84) with potassium cyanide gives the Sa,7P-dicyano-6-one (85).51 An alternative route to this product involves the epoxide (85) (Scheme 4).Similar reactions can be carried out with the (78) R = D corresponding 3P-chloro- and -hydroxy compounds.NATURAL PRODUCT REPORTS 1991 CH2 I SH (88) (89) (91) x=s (92) X = 0 OR’ 0 R’ (94) R’ = R2 = H (95)R’ = R2 = H (93) (96)R’ = Ac R2 = Tos (97)R’ = Ac R2 = Tos OAC (98) 0 R’ (100) R’ = H R2=Ph R’ = R2 = Me R’ = Me R2 = Et (991 Reaction of the cyclocholestenone (87) with 1,2-ethanethiol in acetic acid containing boron trifluoride etherate gives the dithiolanes (88) and (89) together with the thi~ether.~~ The 12,12-ethane-dithioacetal(91) can be selectively formed from the triketone (90).The 12-monoacetal(92) can also be prepared by exchange dioxolanation. 53 1.3.3 Reactions of a#-Unsaturated Carbonyl Compounds and EnoIs or EnoIic Derivatives Borohydride reduction of the acetoxymethylene ketone (93) gives epimeric diols (94) and (99 which can be converted to the tosylates (96) and (97).54 Solvolysis of (96) in dry acetic acid gives diacetate (98) by inversion at C-17 via a cyclic cation which can be trapped as the orthoester (99). This neighbouring group participation is absent in the solvolysis of the tosylate (97). Peracid oxidation of 16-alkylidene- and arylidene- 17-ones (100) leads to products of direct oxidation of the olefinic double No bond mainly epoxide~.~~ unsaturated &lactones are obtained.NATURAL PRODUCT REPORTS 1991-A. B. TURNER Yo AcO& (101) (107) R' = R2 = H 0& (108) R' =OMe R2 = H (109) R' = H R2 = OMe (110) Reaction of the enone (101) with iodosobenzene diacetate in methanolic potassium hydroxide gives the epoxides (102) and (103) together with the ether (104).56 The 16-methyl derivative (105) under similar conditions undergoes Favorskii rearrange- ment to the carboxylic acid (106) and its methyl ester.57 The reaction of the enedione (107) with o-iodosylbenzoic acid in methanolic potassium hydroxide gives methoxy products (1 08) and (109) together with the dienone (110).5s The 17P-alcohol (1 1 1) gives similar products. Oxidation of enones by tetrazolium {fi=OMe (103) (104) vo OH 0dP 0d?' (1 12) OH salts and related oxidants leads to y-oxygenated Thus enone (1 11) gives enedione (1 12) in 8 1 YOyield with Blue Tetrazolium.Kinetic studies lead to a postulated mechanism involving addition of the 3,5-dienolate anion to the tetrazolium salt to give the adduct (1 13) which is cleaved by an ionic process allowing attack of hydroxide ion at C-6. Oxidation of S-cis and S-trans a$-unsaturated ketones with 3-chloroperbenzoic acid show the former to be more reactive producing the corresponding a,P-epoxy ketones in higher NATURAL PRODUCT REPORTS 1991 (1 16) Me0@C8H17 (120) R’ =OH R2 = H (121) R’ = H R2 =OH OAc MeO*’ @ 0& (125) ( 126) OR ‘I 0 OR (131) yield.60 Baeyer-Villiger products are formed only in low yield.The dienone (1 14) gives predominantly the epoxyketone (1 15) in violation of the rule that linear conjugated dienones are oxidized at the double bond more distant from the carbonyl group. This is in accord with the behaviour of S-cis a,P-unsaturated ketones. vie-Diols of P-seco-cholestanes arise from Baeyer-Villiger oxidation of the 7-ketone (1 16) to the lactone (1 17) followed by lithium aluminium hydride reduction to the diol (1 1Q61 Dehydration of the derived monoacetate (1 19) with phosphoryl chloride and osmium tetroxide oxidation of the resulting mixture of olefins gives the vic-diols (1 20)-( 122). The rearranged cholestane (123) has been degraded to the (117) (118) R= H (119) R=Ac C8H17 Me0&N\ OAc CH2 (1 23) (1 24) OAc OH (127) R’ 7 H R2 = CH2CH=CH2 (129) (128) R1 = CH2CH=CH2 R2 = H (130) I I\ OmC H 2C H =C H bicyclic ketone (124) by an improved route involving acid catalysed fragmentation of the 9,lO-seco derivative (125).62 7a-Allyloestradiol(l29) and its 7p-epimer (1 30) are obtained from oestra-4,6-dien-3-one (1 26) by allylation with allyl-trimethylsilane in the presence of tetra-n-butylammonium fluoride the intermediates (127) and (128) being aromatized with cupric bromide-lithium Attempted allylation of dienones (126) using titanium tetrachloride as catalyst leads to 6P,6P’-dimers (1 3 1).63+64 The related dienone (1 32) affords the 7a-ally1 derivative (133) in 73 YO yield under similar condition^.^' The angular methyl group at C-10 inhibits dimerization on the p-face at C-6.Allylation at C-7 of 19-nor- dienone (126) is also possible using allyltributyltin in the NATURAL PRODUCT REPORTS 1991-A. B. TURNER COCH20Ac X N-N 0 Ph/ (136) X=H2 (138) X=H2 (137) X=O (139) X=O GPN-N Ph' (142) 0& (144) (146) R' =OH R2 = H (147) R' = H R2 = OH (149) presence of aluminium chloride as catalyst with the 7a-ally1 derivative (127) being isolated in 35% yield.64 Addition of 3- mercaptopropanoic acid to the dienone (134) gives the 7a- adduct (135) which is suitable for conjugation with bovine serum albumin.65 Addition of phenylhydrazine to stigmast-4-en-6-ones (1 36) and (137) gives the pyrazoles (138) and (139).66 Cyclization of the dienone (140) with phenylhydrazine gives the pyrazole (141).Reduction of testosterone with potassium tri-(R,S)-sec-butylborohydride gives mainly the allylic 3/3-alcoho17 whereas 2a-fluoro-testosterone and -androstenedione give only the allylic 3a-al~ohols.~~ Tritium-labelled canrenone (142) is ob- tained by catalytic reduction of a 1,4-dien-3-0ne precursor followed by exchange of the enolizable label at C-2.6s Canrenone labelled with 14C at the lactone carbonyl group is formed by reaction of a 17-ethynyl precursor with 14C0,. The stable trienol (143) ketonizes in aqueous solution to give the 4,7- and 5,7-dien-3-ones (144) and (145).69 At pH 2-8 the unconjugated ketone (145) is the major product while at pH -1 the conjugated ketone (144) predominates.1.4 Compounds of Nitrogen Phosphorus Sulphur and Other Hetero-elements 17a-Amino-5a-androstan-3a-01 (147) has been prepared from the 3/3-01 (146) by a sequence involving N,O-diformylation selective 0-deformylation Mitsunobu reaction and 0-de-f~rmylation.~~ The -corresponding 17P-amine (148) has been prepared from 5a-androstan-3/3-01- I7-one by tosylation epi- merization formamidation and hydr~lysis.~' Further bis-quaternary androstanes (149) active as neuromuscular blockers have been prepared by standard method^.'^ Some new amino- and nitro-cholestanes have been evaluated as inhibitors of 4-methylsterol ~xidase.~~ These are obtained from NATURAL PRODUCT REPORTS 1991 CSH17 R R (150) R = H (152) R=N02 (151) ( 153) (154) R = NO;! (157) R = NO2 (155) R=NH2 (158) R=NH2 (156) R = CH2NH2 R Br G Rd? N @;HO R’ J$ R2 I No2 NO2 ‘0 H No2 (159) R = OAc ( 160) (161) R=OAc (162) R = H (164) R’ =OH R2=N02 (166) R = CI (167) R =CI (163) R = Br (165) R’ =OH RZ= NH2 (168) R’ =CI R2 = NO2 0 02N 0Ac No2 NO2 (1 69) (171) (1 72) \/ NHCONHPh Ph R&N’ 5a-cholest- 1-en-3-one (150) by interaction of the derived dienol acetate (1 51) with ammonium nitrate-trifluoroacetic anhydride.The resulting 4-nitro compound (1 52) gives the nitroketone (1 53) upon hydrogenation over palladium and this is reduced to the nitro-alcohol (1 54) with borohydride. Reduction of the nitro group itself to give the amino-alcohol (1 55) requires protection of the 3-hydroxyl group in the form of its tetrahydropyranyl ether.The amine (1 56) has also been prepared. Catalytic transfer hydrogenation of the axial nitro group of the cholestane (157) using ammonium formate and palladium-charcoal gives the 6P-amine (1 58) in 82 YOyield.74 This and other examples show this method of reduction to be stereospecific and there is no inversion at C-6 via an oximino intermediate leading to the more stable 6a-amine. Lithium aluminium hydride reduction of the nitrocholestene (1 59) in ether gives the products (160)-(165).75 The stability of the enamine (165) which is the major product (37% yield) is surprizing. The other products are formed in 8-20% yield.The corresponding 3P-chloro compound (1 66) is similarly reduced to the oxime (167) and the debrominated product (168) in yields of 41 YOand 29 YO,respectively. Oxidation of the dinitrocholestadiene (1 69) with lead tetraacetate gives the lactones (170) and (171) together with the triene (172).76 Reaction of cholestenes with N-amino-phthalimide in dichloromethane in the presence of lead tetraacetate leads to phthalimidoaziridines of type (1 73). 77 Cyclization of the phenylsemicarbazones (1 74) with chloro- acetic acid in the presence of anhydrous sodium acetate gives the N-phenyloxazolidones (1 75). 78 The related thiazolidones (1 76) and (177) are obtained by cyclizing thiosemicarbazones NATURAL PRODUCT REPORTS 1991-A. B. TURNER N& (177) (178) (179) &c8H17 (jp H H ( 180) (181) H13 with chloroacetic acid.7s Isomeric structures are excluded by the spectral data.Rearrangement of the dithioacetals (178) with phenylselenenyl chloride in dichloromethane gives the dihydrodithiin (1 79) in 95 YOyield.*O In the androstan- 17-one series the yield is reduced to 80 %. 1.5 Molecular Rearrangements Acid-catalysed rearrangement of 5a-cholest-7-ene leads initially to 5a-cholest-8(14)- and -14-ene~.~' In the presence of boron trifluoride etherate or anhydrous toluene-p-sulphonic acid further transformation to the ring c/D-rearranged cholestene (180) and its 20-isomer occurs. The (20S)-isomers (181) and (182) are also formed as well as the 14p-methyl-18-nor-cholestenes (1 83).Minor products in the backbone rearrange- ment of cholest-Sene with boron trifluoride etherate include H (182) 78H17 (187) R = H (189) R =Me Additional products formed with anhydrous toluene-p-sul- phonic acid include some which are isomeric at C-20 as well as C-10 and have a spiro C/D ring junction e.g. (184) and (185). Backbone rearrangement of des-A-cholestene (1 86) and con- geners yields products (187) isomeric at C-20 with the methyl group at C-10 in the more stable equatorial The 5-methylene compound (1 88) yields similar isomeric products (189) with both C-5 and C-10 methyl groups equatorial. Allylic bromination of the alkene (186) with three equivalents of N-bromosuccinimide followed by dehydrobromination with collidine in boiling p-xylene gives a mixture of products containing the des-~-cholesta-5,7,9-triene (190).Treatment of this mixture with lithium aluminium hydride gives a product containing 90 YOof the aromatic hydrocarbon (1 90). These compounds have been used as standards to confirm their widespread occurrence in a variety of marine shales having a the lop-isomers of the well known diacholest-13( 17)-ene~.~~ mild thermal history and with ages ranging up to the Jurassic NATURAL PRODUCT REPORTS 1991 Me P a' HO OCHMe2 COMe OCHMe2 (191) R = H (192) ( 194) (193)R = COMe Me COMe (195) OCOCMe3 0 CI 0& I COMe (200) R = Et (201) R=COMe period (1-2 x lo6 years). Their origin may lie in micro- biological degradation of the sterols of organisms present at the time of sediment deposition.Solvolysis of the tosylate (191) in isopropanol gives the B-homocholestenol (192) as the sole product but a complex mixture is formed from the corresponding 3P-acetate (193).s4 If pyridine is present the alcohol (191) gives the mixture of products but in the case of the acetate (193) only the cyclosteroid (194) is Acetolysis of the cyclo-OH propane tosylate (195) gives the rearranged products (196)-( 198).86 (207) Oxidation of the 19-iodoandrostane (199) with 3-chloro- perbenzoic acid in ether gives the rearranged acetates (200)-(202) via a transient hypervalent iodine i~~termediate.~~ The thermal rearrangement of 4-chlor0-4~5-epoxides (203) and (204) leads to diosphenols (205) and (206),88 after removal of chlorine with zincsopper couple.Treatment of the cyclosteroid (207) with hydrogen bromide in acetic acid gives the anthrasteroid (208) as a minor product whereas the l3a-methyl epimer of (207) gives the enantiomeric 13a 14a-anthrasteroid without isomerization at C-14?' The stereochemistry of the anthrasteroids is established by NOE measurements. Use of deuterium bromide leads to extensive deuteriation. The major aromatic steroid formed in each case is (2091 the oestratriene (209). Heating a solution of the pregnadienone NATURAL PRODUCT REPORTS 1991-A. B. TURNER vo (210) HO** (2lo) and 2-acetylcyclopent-4-ene-I73-dione in benzene in a sealed tube yields c-nor-D-homosteroid (21 I).’’ Carbanion formation at C-12 could lead to bond formation between C-12 and C-14 but the precise mechanism is not clear.Dienone- phenol rearrangement of androsta- I ,4-diene-3,12,17-trione (90) with toluene-p-sulphonic acid in boiling benzene gives the phenol (212) in 13 YOyield.53 The kinetics of dehydrogenation of both rearranged (21 3) and unrearranged (214) C-aromatic hydrocarbons to the phenanthrenes (215) have been studied in connection with maturity and thermal history assessment of sedimentary organic material.’l In sealed tubes in the presence of sulphur-treated cretaceous carbonate sediment at moderate temperatures the aromatization rate for the non-rearranged isomers is greater than that for the rearranged series. 1.6 Remote Functionalization Reactions The (3-benzoylphenyl)acetoxy group at the 6P-position is an excellent template for selective functionalization at C- 15.92 It allows ready conversion of the cyclocholestane (216) into 15-HO&Po OH A A (222) 0J3Pe & H (221) oxocholesterol (2 17).The androstenolone (2 19) prepared in 95% yield from the relay chlorinated ester (218) has been converted into the fluorohydrin (220) in four Oxidation of the non-activated 5a714a-androstane (221) and its 3p-acetoxy derivative with chromium trioxide in a mixture of dichloromethane acetic acid and acetic anhydride gives the androstenones (222) and the corresponding acetate in yields of 47 YOand 68 YO,re~pectively.’~ The initial site of oxidation presumably is the tertiary 14a-CH bond.1.7 Photochemical Reactions Transformations leading to the four-membered carbocyclic ring have been reviewed.’j Details of the extensive work formation of an additional fused to the steroid nucleus on the photolysis of steroid ketols have ap~eared.’~-’~ 5-Hydroxy-Scr-and -i&cholestan-6- ones rearrange stereospecifically with retention of configuration at C-5 to give the corresponding lactones 6-oxa-~-homo- cholestan-7-0nes.~~ The corresponding 7a-deutero compounds NPR X NATURAL PRODUCT REPORTS 1991 H (223) (224) H also undergo stereospecific rearrangement to the 5-deuterio- lactones and irradiation of the 5-deuterioxy-6-ketones give 1 :3 and 7 1 mixtures respectively of the 7aa- and 7aP-deuterio- lactones.Photolysis of the 5a-methoxy-6-ketone in ethanol leads to stereoselective formation of ethyl 5-methoxy-5,6-seco- 5a-cholestan-6-oate while that of 3P-acetoxy-5a-cholestan-6-one gives mainly products of photoreduction. Irradiation of acetone or dioxan solutions of 3P-acetoxy-(E)- and (2)-19-nor-5,1 O-seco-cholest- 1 (1 O)-en-5-ones prepared from 19-norcholesterol gives 9-29 % E/Z isomerization product and 1 1-28 YOla-hydroxy- 19-norcholesteryl acetate." Irradiation through pyrex of 2P-nitro-5a-cholestan-3-one in ethanol gives 5a-cholestane-2,3-dione and its 3-oxime. loo A nitro-nitrite pathway is proposed for the formation of the oxime. The 4,4-dimethyl derivative of the 2P-nitro-3-one similarly gives the a-hydroxyimino ketone and 3-nitro-501- cholestan-2-one gives the a-diketone.The 4P-nitro-SP-3-0ne and the 6a-nitro-5a-7-one give only the a-hydroxy-iminoketones. These arise through hydrogen abstraction by the n,n* excited nitro group followed by elimination of water. The a-diketones are formed by nitro-nitrite rearrangement of the excitged nitro group of the enol forms. Photolysis of nitroamines in the presence of iodine and various oxidants affords neutral nitroaminyl radicals which undergo intramolecular hydrogen abstraction to give N-nitroimines.lO1 Thus the 6P-nitroamine (223) gives the bridged N-nitro compound (224). The most efficient combination is that of iodine with iodosobenzene diace ta te. Photodeconjugation of the oxime (225) involves an in-tramolecular stereospecific transfer of the hydroxyimino hy- drogen atom.lo2 The product (226) is formed in 69-75 yield O/O in aprotic as well as protic solvents.Thus the presence of the methyl group at C-1 prevents the ring opening to the nitrile oxide and the subsequent isoxazole formation observed earlier A (229) (230) with the C-1 unsubstituted analogue. The mechanism is again based upon deuterium labelling studies. Photolysis of three isomeric cholestenone oximes (E)-and (Z)-cholest-4-en-3-one oximes (E)-2,2-dimethylcholest-4-en-3-oneoxime and (E)-cholest-5-en-7-one oxime in protic solvents takes place regio- selectively to give in each case < 33% enamino-lactam e.g. (227) from the first oxime pair as the sole product.The alternative enone-lactams are not formed from the photo- excited a$-unsaturated ketone oximes although they are the sole products from Beckmann rearrangement of these oximes. lo3 The photochemical behaviour of various conjugated ketones in concentrated sulphuric acid has been examined.lo4 Some (e.g. 4-en-3-ones and 5-en-7-ones) are recovered unchanged but the 1-en-3-one (228) gives the rearranged products (229) rather than the [2 +2lphotodimer usually formed in neutral solution. Organoselenium reagents are useful for the generation of alkoxyl radicals from alcohols prior to intramolecular hydrogen abstraction reactions.105 Thus photolysis of 2P-hydroxy-cholestane in the presence of diphenylselenium hydroxyacetate and iodine gives the cyclic ether (230) in 89% yield.Similar functionalization of the C-10 angular methyl group occurs with the 4P-alcohol (74%) and the 6P-alcohol (97%). In the case of 20-hydroxypregnanes functionalization of the C-13 angular methyl group gives the cyclic ethers in yields of 54% and 68 Oh for the 20R and 20s epimers respectively. The p-scission of alkoxyl radicals has been used as a method for the aromatization of ring A of cholesterol and androst-5-en- 3P-01-17-one (Scheme 5). lo6 The cholesterol-derived cyclic hemiacetal (23 1) undergoes regioselective p-scission through photolysis of the corresponding hypoiodite to give a 5 1 mixture of the formates (232) and (233) in good yield. Reductive elimination with zinc in acetic acid affords the dienol acetate (234) which after hydrolysis and Swern oxidation gives the 33 NATURAL PRODUCT REPORTS 1991-A.B. TURNER 5steps + 2\ HO AcO Br AcO Br AcO Br OCHO OCHO ,CSH17 R = H or =O (2311 (232) (233) 'H Reagents i HgO I, PhH; ii hv;iii Zn AcOH 115 "C; iv KOH MeOH EtOH; v TFAA DMSO Et,N CH,Cl, -78 "C Scheme 5 {:'I {so '0. yp OH OH OH h'l 0tJ (240) 26% OH - 7 huorheat' (239) f0L0 CP-OOH & OH Scheme 6 (241) 20% phenol (235) in an overall yield of 16%. In the 17-0x0-slowly converted into its 6a-epimer with hydrochloric acid in androstane series the overall yield of oestrone is 27%. The acetic acid.lo7 trifluoroacetate is a by-product in the final step of this Irradiation of the cardenolide epoxide (238) prepared from sequence.gitoxigenin gives 16-ketone (239) as the primary photo-Photolysis of the triflate (236) in pyridine in the presence or product.lo8 This undergoes oxa-di-m-methane rearrangement absence of trifluoroiodomethane gives the enone (237) which is (Scheme 6) to give the bicycloheptanes (240) and (241). 3-2 NATURAL PRODUCT REPORTS 1991 0& 0GP (242) X=OH (243) (244) (245) X = H OAc OAc OAc 0Ac (249) OCOCMe3 I (2511 On treatment with titanium(1v)tetraisopropoxide the oes-trone-derived hydroperoxide (242) gives the epoxyquinols (243) and (244) together with the quinol (245).lo9 The epoxides (243) and (244) are readily obtained by Sharpless oxidation of the quinol (245) with t-butylhydroperoxide in the presence of titanium(1v) or vanadium(v) catalysts.Use of 3-chloro-perbenzoic acid leads mainly to Baeyer-Villiger oxidation in ring D. The 5a-alcohol (246) is confirmed as the major photo- oxidation product of norethindrone (247) following its synthesis from the ketone.ll" Lead tetraacetate oxidation of the 9a-alcohol (248) in benzene solution by irradiation in the presence of calcium carbonate gives the secosteroid (249) as the major product (-61 9'" yield) whereas photochemically in-duced oxidation with mercuric oxide and iodine involves mainly a-epoxidation of the double bond to give the epoxide (250) in 58 % yield."l The hydroxyl group at the 9a-position appears to control the course of this oxidation perhaps by (252) coordination with the reagent prior to attack upon the olefinic bond.Only one of five different crystalline forms of the prednisolone ester (251) suffers aerial oxidation catalysed by ultraviolet light.'12 The reactive one is a solvated and loosely packed crystal form (space group P6,) in which the molecules are arranged in a helix along the six-fold axis. The reactivity towards oxygen may be due to the presence of a large tunnel parallel to the hexagonal axis which allows air to penetrate the crystal. In studies on the origin of the wavelength dependent photochemical behaviour of the homoannular diene (252) the fluorescence spectrum and quantum yield of the ring-opened triene have been determined at 302 and 307 nm and both the intensity distribution and fluorescence quantum yields are found to be independent of excitation energy.'13 The large Stokes shift which is observed is consistent with an excited state torsional relaxation about the central double bond of the NATURAL PRODUCT REPORTS 1991-A.B. TURNER OH @'0 (255) (256) 0 (258) (259) H Me I CHCH20Si-CH 2Br I Me @ -I OMe HvH X e VlI --X=OH -01 HOS' 0 @ AcO AcO VIII IX X=H \ H Reagents i Bu,SnH AIBN PhH 80 "C; ii KOBuL DMSO 20 "C; iii Ac,O pyridine; iv H,O, KF DMF; v BuLi THF toluene-p-sulphonyl chloride; vi BuLi THF ;vii LiC-CCMe,OTHP BF .Et,O; viii toluene-p-sulphonyl chloride pyridine; ix LiAIH, THF; x H, Pd-CaCO, EtOH ;xi toluene-p-sulphonic acid aqueous dioxane Scheme 7 product triene.Photolysis of the oestradiene (253) gives an equilibrium mixture of 5,7-dienes and 9 IO-seco-5( 10),6,8- trienes together with the thermally unstable bicyclohexene (254).l14 Divergence from the photochemistry of the 10-methyl series can be ascribed to conformational differences. The epoxyketones (255) photolyse in the same manner as the ketone (256) in methan01.l'~ The major products are the methyl 5- isopropyl-4-nor-3,5-secoesters. In ether the 5P76P-epoxyketone (255) photodecarbonylates via a souble hydrogen shift (C- 2 -,C-4 and C-1 -,C-2) suggesting that the epoxide cleavage takes place under stereoelectronic control. Similar photo- reactions occur in the cholestane series. 2 Partial Synthesis 2.1 Derivatives and Analogues of Cholestane The deuteriated cholesterol (257) has been prepared for use as an internal monitor of cholesterol oxidation products in biological fluids and tissues.116 Palladium-catalysed reaction of alkanes with the acid chloride (258) in the presence of N-ethylmorpholine gives 3-alkenylcholest-2-enes (259) in yields of 15-20 Reductive radical cyclization of bromomethyl silyl ethers involves the 5-ex0 mode allowing the stereoselective synthesis of 20(S),25-hydroxycholesterol (Scheme 7).11* NATURAL PRODUCT REPORTS 1991 OH YCHO I OMe (261) (263) I ii liii n iv -v,vi {P BrMkId a= 00 U (265) Reagents i NaOCl; ii; ButMe,SiC1 4-dimethylaminopyridine Et,N CH,Cl,; 111 LDA (Ph,P+Et)Br- THF; iv CuCN reagent a THF; v H,.pt-c EtOAc ;vi toluene-p-sulphonic acid aq. acetone; vii ;Ac,O pyridine ;viii NaH (EtO),P(O)CH,CN THF ;ix (Me,CHCH,),AlH hexam PhMe; x Ac,O pyridine; xi MeCOOCHO pyridine; xii CrO, CH,Cl, 3,5-dimethylpyrazole; xiii aq. K,CO Scheme 8 can be prepared from the 14a-The four epimers of 7,22-dihydroxycholesterol (260) have 14P-Cholesta-5,7-dien-3P-ol been prepared from the aldehyde (261).11' A high degree of epimer in six stages.'" Inversion at C-14 is best achieved by asymmetric induction is observed in its condensation with an selective hydration of the A5-bond prior to selenium dioxide arsenic ylide to give the 22(S)-alcohol. Deprotection of the iso- oxidation and reduction of the resulting 8( 14)-en-7a-o1 with ether acetylation of the 22-hydroxyl group and allylic oxidation zinc and sulphuric acid.A four-step synthesis of 3P-hydroxy- are achieved in one pot. The allylic oxidation at C-7 is best 5a-cholest-8( 14)-en- 15-one (262) from 7-dehydrocholesterol achieved with sodium chromate or dichromate in acetic acid giving an overall yield of 39% can be carried out on the with final hydride reduction in the presence of cerium trichloride kilogram scale.lZ1 A major by-product of the final stage in methanol for the 7P-alcohol or L-selectride for the 7a- hydrolysis of the epoxide (31) to the enone (262) is the C-alcohol. aromatic sterol (263). NATURAL PRODUCT REPORTS 1991-A. B. TURNER (270) X = N,S (271) (273) 3P-Acetoxyandrost-5-en- 17-one has been converted via 15p-hydroxy-24-oxocholesterol(264)into 1SP,29-dihydroxy-7-0~0-fucosterol (265) (Scheme 8).lZ2Dehydromarthasterone (266) is prepared from asterone diacetate (267) in eight steps via coupling of the ally1 chloride (268) with the anion of the dithiane (269).lZ3 The configuration of the A17(20)-bond in the starfish sterol (266) was established by NOE studies.The 24- heteroatom-substituted cholestanols (270) have been prepared from 501-pregan-20-one (27 1) via treatment of the tosylate (272) with the sodium salt of 2-propane-thiol or with 2-(methyl- amino)propane. 12* (274) (275) 22R,23R Key intermediates (e.g. 273) for brassinosteroid synthesis have been prepared stereoselectively and in high yield by reaction of arsonium salts Ph,AsCH,COR Br-with C-22 aldehydes (274) under solid-liquid phase transfer conditions.125 The effect of temperature variation upon the sterochemistry of the products of the aldol reaction of this aldehyde (274) with 3- methylbut-2-enolide anion have been studied. 126 The optimum temperature for production of the brassinolide intermediate (275) is -78 "C. A number of new brassinolides bearing hydroxyl groups at C-20 and C-28 have been prepared from pregnen01one.l~' A new route for the synthesis of the 2a,3a- 38 NATURAL PRODUCT REPORTS 1991 OH I OSiMe3 (276) (277) HO& (279) (280) R = H,Me,Et,Pr,CH2CHMe2,CH2CMe20H C8H17 AcOl$P0 OH (281) (282) (283) R' = R2 = H (284) R' =OH R2 = OCO(CH2),Me HO&A HO R A R (285) t I 0 0 Reagents i (CF,CO),O 2,6-di-t-butyl-4-methylpyridine CH,Cl ; ii Bu,N HCOOH Pd(OAc),(Ph,P), DMF ;iii NaOMe MeOH PhMe Scheme 9 NATURAL PRODUCT REPORTS 1991-A.B. TURNER OH \ CHO ‘4 dihydroxy-7-oxa-6-oxo-~-homo structural unit of brassinolide involves ozonolysis of enol silyl ethers e.g. (276).12* The naturally occurring 25-methyl dolichosterone (277) and the tetrol-lactone (278) a more potent plant growth regulator than brassinolide itself have been synthesized from stigmasterol. lZ9 Acetylenic cholesterol derivatives (279) and (280) have been prepared from pregnenolone and stigmasterol. 130 These C-22 alkynes were devised as suicide inhibitors of the cytochrome P- 450 dependent monooxygenase responsible for the C-22 hydroxyfation involved in ecdysone biosynthesis.The trio1 (279) inhibits ecdysone synthesis in follicular cells under in vitro conditions the inhibition being selective for the C-22 hydroxyl- ase system. Two routes have been developed for the conversion of 5a-cholest-7-en-3p-01 into the ecdysteroid precursor (28 l).I3l By one of these 5,6-dihydroergosterol can be converted into the AZ2-24-methyl analogue (282) which has the complete range of functionalities required for the synthesis of naturally occurring ecdysteroids. 2,22-Dideoxyecdysone (283) another putative precursor in the biosynthesis of ecdysone has been prepared from ergoster01.l~~ Several fatty acid esters of type (284) are available from ecdysone via acylation of its 2,3- acetonide at C-22 with the appropriate anhydride.133 The protecting acetonide group can be removed using O.1M hydrogen chloride in dioxan with overall yields up to 70%.The long-standing problem of the regio-controlled synthesis of the ergosterol B-isomers (285)-(287) has been solved in the regiospecific genera tion of trienol triflate intermediates (Scheme 9).13“Previously mixtures of these isomers have always been obtained under acidic conditions and the realization that the relative order of stability of these isomeric trienes is (285) > (286) > (287) suggested their possible synthesis from suitable enones via enol triflate formation. Reaction of the appropriate enones under thermodynamic control gives the corresponding trienol triflates in excellent yield and these intermediates are readily reduced to the pure trienes in 75-80 YO overall yield.Routes from the cholenediol derivative (288) to zymosterol and related compounds have been developed. 135 Oxidation with pyridinium chlorochromate gives the 24-aldehyde which is protected as its acetal during modifications in ring B prior to the final Wittig reaction with isopropylidenetriphenyl phos- phorane. 2.2 Vitamins D their Derivatives and their Metabolites The C-22 aldehyde (289) and its la-hydroxy derivatives have been prepared from bisnorcholenic They are useful for the synthesis of side-chain modified analogues. The dienyne (290) which is readily labelled in the side-chain is prepared via enol-triflate coupling catalysed by bis(tripheny1phosphine)-palladium (11) ~hloride.’~’ An efficient synthesis of 10,19-dihydroercalciol and analogues (291) and (292) involves regioselective hydrometalation with titanocene dichloride in combination with lithium aluminium hydride or Red-Al.138 Under optimal conditions for the hydrotitanation-protonation process the former system affords good stereoselectivity and allows efficient labelling at the C-19 position.la-Hydroxy- ercalciol(293) is prepared from the diacetate (294) by irradiation with a high-pressure mercury lamp followed by thermal AcO isomerization and saponification. 13’ The diacetate (294) is prepared from ergosta-4,6,22-trien-3-one (295) in eleven steps. iii I Bu ‘Me$30°0~OSiMe2Bu (290) H (291) R’ = Me R2 = H (292) R‘=H R2=Me H0’.AH (293) (294) 40 A multistep conversion of ergosterol into a 24-hydroxycalcidiol precursor makes use of 1,4-dihydrophthalazine- 1,4-dione as the diene protecting agent.lgO It is compared with an established route which uses 4-phenyl- 1,2,4-triazoline-3,5-dionefor pro- tection of the Giene system in ring B. The new sequence allows the overall yield to be doubled. The 1,4-dioxo- 1,2,3,4-tetra- hydrophthalazin-2,3-ylenegroup proved to be the better diene protecting group in the ozonolytic degradation of the ergosterol side-chain and maintaining the protecting group in the next steps in the sequence is advantageous in diminishing the sensitivity of the intermediates towards air and light. Among the intermediates prepared this year are 3-deoxy- A9(11)-calcitriol,141 radiolabelled photoaffinity analogue of a side-chain modified calciol~,~~~~ calcitri01,~~~ lg4 di ethyl ana-logues,lg5 2-0xa-analogues,~~~ side-chain fluorinated ercal-cidio1,1g7 and 24(R)-fluorocalcitriol.lg8 The vitamin precursors 1a,3P-diacetoxy- lp-methylcholesta- 5,7-diene,lg9 and la 1~,25-triacetoxy-21-norcholesta-5,7-diene,150 have been prepared from cholesterol and 3P-hydroxy- androst-5-en-1T-one respectively. Conversion of (62)-tacalciol into calciol at 20 "C is acceler- ated at high pressure (15 K bar) in various s01vents.l~~ Rate constants are 3-5 times larger than the corresponding rate constants at 1 bar. A concerted [1,7] sigmatropic hydrogen shift mechanism is indicated by AVt of -5.14 cm3 mol-' or lower by analogy with the values obtained for concerted [1,5] sigmatropic shifts.The significant rate increase together with the quantitative recovery is of potential use in the production of calciol analogues when the [1,7] hydrogen shift is slow or when the compounds are thermally labile. Kinetic studies of this type of shift in the transformation of 3-deoxy- 1 -hydroxy- (6Z)-tacalciol epimers to 3-deoxy- 1 -hydroxycalciol show a primary deuterium kinetic isotope effect of approximately 6.152 This is very much lower than that (-45) reported previously for the isomerization of the naturally occurring (62)-tacalciol to calciol. Complete assignment of the 'H and 13C NMR chemical shifts of (6Z)-tacalciol are reported. 153 Two-dimen-sional NOE experiments provide the first direct experimental evidence for the existence of two types of conformation in solution.2.3 Cholanes Norcholanes and Dinorcholanes The four C-24,25-diastereomers of varanic acid (296) have been separated by a combination of flash chromatography and preparative HPLC on a reversed phase column.154 These diastereomers were all converted into cholic acid by incubation with rat liver micro some^,'^^ showing that the configuration at the 24- and 25-positions has no effect upon the efficiency of the side-chain degradation. New routes to the three stereoisomers of 3a,6a-dihydroxy-5P-cholanic acid (297) involve inversion at C-3 of 3a-hydroxy-6-ones with diethylazodicarboxylate-triphenylphosphine-formic acid and with dimethylformamide without epimerization at C-5.156 Samples of the acid (297) and its methyl ester previously isolated are shown to be mixtures epimeric at C-3.Among conjugates prepared by standard methods are disulphates of unconjugated and glycine- and taurine-con- jugated cholic and glycine conjugates of the 3-0x0- derivatives of bile The condensation is effected by the peptide coupling reagent N-ethoxycarbonyl-2-ethoxy-1,2-di hydroquinoline. An efficient one-carbon degradation of the bile acid side- chain which involves treatment of formylated bile acids with sodium nitrite in a mixture of trifluoro-acetic acid and its anhydride gives 24-nor-23-nitriles via a second order Beckmann rearrangement. 159 Hydrolysis with alkali gives the nor-bile acids in high yield.The nor- and bisnor-lactones (298) have been prepared from the acid (297) and its homologue for evaluation of their growth-promoting activity.160 Treatment of the chiral acetal (299) (S-R,R-isomer) with allyltrimethylsilane 9-allyl-9-borabicyclononane,or allyltributylstannane in the NATURAL PRODUCT REPORTS 1991 HO (296) (2971 (3 (298) R = C02H,CH2C02H OH I SiMe2Bu' (299) presence of titanium (IV) chloride gives the (S,S)-isomer of the alcohol (3O0).l6l The corresponding reaction of the acetal (301) (S-S,Sisomer) leads to the same homoallylalcohol with the first two reagents but the isomeric alcohol (302) [(S,R)isomer] is obtained preferentially with allyltributylstannane. Similar results are obtained with a stannylacetylene.Thus the extent of NATURAL PRODUCT REPORTS 1991-A. B. TURNER 41 OH I OMe (304) (303) AcO.ci.’i (306) (307)R = CI (308) R = H II 1:-1-1 C02Me (309) vii viii @ C02Me (310)1 :1 mixture of ! 17aand 170 epimers Ratio 1-7:1 Reagents:i dichlorodicyanobenzoquinone,PhH ;ii MeOH thallium (111) nitrate trihydrate ;iii KH THF BEt, BrCH,CO,Me; iv (CH,SH),, BF;Et,O CH,Cl,; v NaOH EtOH; vi H,PO, P,O,; vii thallium (111) nitrate trihydrate MeOH THF; viii H, Pd-C AcOH Scheme 10 asymmetric induction depends upon the nucleophilicity of the organometallic reagents and the results show that bond formation and cleavage must be concerted in the reactions in which a high degree of asymmetric induction is achieved.The ene reaction of (Z)-A17(20)-01efin (303) with acetylenic aldehydes in the presence of dimethylaluminium chloride gives (22R)-22-hydroxy-23-ynes (304) thereby allowing control over both chiral centres (C-20 and C-22).162 The ability of the a-face ene reaction to control the stereochemistry at C-20 is known and similar diastereofacial selectivity has been reported in 1986 for titanium (IV) mediated alkynylation with stannylacetylenes. Glyoxylate ene reactions promoted by certain Lewis acids also proceed with high erythro or threo diastereoselection.163 The utility of this ene reaction is demonstrated by the stereo-controlled synthesis of the 22R-hydroxy-23-carboxylate side-chain e.g. in the conversion of alkene (303) into the ester (305) which was isolated as a single stereoisomer in 67 YOyield using dimethylaluminium chloride as catalyst.Reaction of dichloroketene with the 20-methylene derivative of 164 17a-epoxy-3P-acetoxy- 5-pregnene (306) gives the lactone (307) in 85 YOyield.164 Zinc dust dechlorinates the lactone (307) completely but tributyltin hydride gives the monochloro derivative (308) in 80% yield. The structure and C-20 configuration of the lactone (308) was established by X-ray analysis. 2.4 Pregnanes 2,2,3,4,4-Pentadeuteriopregnanediol 3-gl~curonide’~~ and 1,1,19,19,19-pentadeuteriocortisol 166 have been synthesized from progesterone and prednisone respectively. Phospholipid- linked cortisol and dexamethasone with widely varying length and degree of unsaturation of the lipid side-chains have been prepared.16’ In the synthesis of the aldosterone biosynthesis inhibitors 18- vinyl- and 18-ethynyl-progesterone the protective group at C- 3 influences the efficiency of diisobutylaluminium hydride reduction of the 18-cyanomethyl group.16s The 18-carbox-aldehyde intermediates are formed in good yield in the presence of the 3P-t-butyldimethylsilyl ether and 3,3-ethylenedithio groups but not with the 3P-acetoxy or 3,3-ethylenedioxo groups.These appear to be the first examples of conformational transmission outside the steroid nucleus at an angular methyl group. Methyldehydroabietate (309) has been converted into the epimeric C-aromatic- 18-norpregnanes (3 10) via initial func- NATURAL PRODUCT REPORTS 1991 (311) OH OH (31 3) A (316) (317) R = H (319) (318) R = Br tionalization of the isopropyl group by oxidation with dichlorodicyanobenzoquinone (Scheme lo).169 This oxidation is selective enough to be used as a preparative method although unreacted starting material has to be separated by chromatography. Oxidation of 3a75a-cyc10cho1estanes using the Gif system gives the corresponding pregnan-20-ones as the major products in -7% yield.170 2.5 Androstanes and Oestranes SP-Andro~t-6-ene-3~17-dione (3 1 1) is obtained in 84 YOyield by cyclization of the all-trans cyclotetradecatriene (3 12) in xylene at 180 "C,using a catalytic amount of methylene blue.171 Sa-Androst-2-ene-5a 17P-diol (3 13) is the common inter-mediate in the synthesis of the 2-deuteriated androstenes (314) and (3 1 5).172The diol(3 13) prepared by an improved route is converted via epoxidation reductive epoxide ring-opening HO& HO oxidation and dehydration to the 2P-labelled-4-en-3-ones.Use of hexadeuteriodiborane in a similar sequence of reactions leads to both 2a- and 2P-labelled 4-en-3-ones. 174-Additionof methyl magnesium iodide to the D-homo- androstenone (3 16) gives the C/D-C~S 13a-androstane (3 17). 173 Favorskii rearrangement of the bromo derivative (3 18) gives 13a-androstane- 16a-carboxylic acid (3 19) and its 16P-epimer. The ketone (317) is oxidized to the acid (319) by thallium (III) salts. These acids can be converted into methyl ketones alcohols and 13a-androstan- 16-one.The sandaracopimaric acid derivative (320) can be converted into the 1 Sketoandrostadiene (321) by acid-catalysed cycliza- ti~n.'~~ 2,3,17- and 19-Oxygenated androstanes e.g. the tetrol (322) and deuterium or deuterium-tritium labelled analogues have been prepared from 19-hydroxyandrostenedione. Jones oxidation of androsta-5,16-dien-3/3-01(323) gives androsta-4,16-diene-3,6-dione (324) which has a penetrating urinous odour similar to that of andr0~tenone.l~~ The 1 la- NATURAL PRODUCT REPORTS 1991-A. B. TURNER OA & 0& (325) (326) OH (327) (328) OH MeOcs;”’ OH OH HO HO k2 (331) (332) (3331 OH Reagents i MeMgI Et,O; ii Br, H,O; iii LiAlH Scheme 11 hydroxyandrostenone (325) and its 11 a-ylhemisuccinate have been prepared from adrenosterone (326).177 New spirolactones (327) and (328) have been synthe-179 An efficient ring D expansion of 17-0x0-androstanes and -0estranes involves condensation of ketones with ethyl- diazo(1ithio)-acetate to give a-diazo-P-hydroxy esters which are smoothly converted into p-oxoesters by reaction with dirhodium (11) tetra-acetate.lsO This sequence allows the preparation of D-homo- 17a-ketones. The 16,8-alcohols (329) and (330) have been prepared from the respective 15-hydroxymethylene- 16-ketones. 181 Nucleophilic attack by the cyanomethylene carbanion on the diastereomeric chromium tricarbonyl complexes of 3-methoxy- oestra- 1,3,5-trienes gives 3-cyanomethyl complexes which are readily converted into 3-alkylated oestratrienes.182 Birch re- duction (lithium-liquid ammonia-ethanol) of the ether (33 l) followed by hydrolysis with acetic acid bromination-dehydro- bromination with pyridinium perbromide in pyridine and dehydration catalysed by hydrochloric acid in chloroform gives trenbolone (332).183 2-Isopropyloestradiol (333) is ob- tained from 2-acetyloestradiol by standard reactions. la42- and 4-Methoxyequilin (334) and (335) respectively have been prepared from 2-iodo- and 4- bromoequilin derivatives by nucleophilic displacement of the halide ion by methoxide ion in the presence of copper(r1) chloride and 15-cr0wn-5.’~~ 2- and 4- Methoxyequilenin have been obtained in similar fashion from 2- and 4-iodo-7,8-epoxyoestrone.Selenium dioxide oxidation of the equilins can also be employed. Chlorination of oestradiol with N-chloro imides such as N-chlorosuccinimide and trichloroisocyanuric acid in acetonitrile gives 1 OP-chloro- 17P-hydroxyoestra- 1,4-dien-3-0ne which is readily reduced to the starting phenol. lE6 Also produced are the 2 lop- and 4,l OP-dichloro- and 2,4,1 OF-trichloro-oestra- 1,4- dien-3-ones. Thus only substitution of the aromatic ring occurs in contrast to the results of bromination with N-bromoimide reagents. Preferential removal of the 1OP-chlorine atom of the di-and tri-chloro-compounds using sodium borohydride allows efficient syntheses of 2-or 4-chloro-and 2,4-dichloro-oestradiol. 18’ 16,16-Dimethyl- 17P-hydroxy- androstanes and -0estranes have been prepared by treatment of 16-methylene- 17-ketones with methylmagnesium iodide.la8 In-itial 1,2-addition of the Grignard reagent gives the 17a-methyl derivatives which add hypobromous acid and rearrange (Scheme 11). Ring B functionalized oestrane and oestradiol NATURAL PRODUCT REPORTS 1991 0 OH (336) (337) OAc OAc AcO (339) (340) MeO (345) R’= H R2=OAc (347) (346) R’R2 = 0 analogues (336) and (337) suitable for coupling to proteins have been prepared from adrenosterone by introduction of the carboxymethyl side-chain at C-7 followed by aromatization of ring In further studies on placental aromatase support for the proposed a-hydroxy-iron (1x1) peroxide mechanism is provided by model studies of the action of hydrogen peroxide on the intermediate (338).lgo Aromatization of this compound is accompanied by formation of one equivalent of formic acid per mole of oestrogen obtained.In the absence of peroxide little conversion occurs. The (2)-and (E)-l9-nor-seco ketones (339) and (340) both undergo acid catalysed transannular cyclization with con-comitant aromatization of ring A to give the oestratriene (341) in yields of 76 % and 83 YO,respectively. In the 19-methyl series the (2)-form is rather inert towards acid whereas the (E)-isomer gives the A-nor-B-homo derivative (342) in 68 YOyield.lgl Transannular cyclization of the (E)-seco ketone having the 19- methyl group also occurs thermally in the absence of protonation.0&0/ca I SiMe2But (338) AcO’ (3411 (342) OH Me0 (349) (+)-Dehydroabietic acid can be converted into the hexa- hydrophenanthrene (343) by introduction of oxygen functions at C-5 and C-l7a and migration of the methyl group to C-13.Ig2 Ring contraction gives the des-A steroid (344). 2.6 Cardenolides and Bufadienolides Substituted 14,2 1-epoxy-SP,14P-card-20(22)-enolides(345) and (346) are formed from furylandrostanediols by chromic acid 0xidati0n.l~~ The former is dehydrogenated to the 9(11)-en- 12- one by selenium dioxide. Elimination of methane sulphonic acid from 12a-or 12/3-methanesulphonyloxy-14P-hydroxy steroids proceeds with rearrangement of the steroid nucleus. lg4 Thus the 12P-mesylate of (347) gives the bridged abeo-cardadienolide (348) whereas its 12a-epimer gives the abeo derivative (349).Elimination of the 12~-methylsulphonyloxy group to give the All-alkene only occurs when there is steric fixation of the migrating carbon atoms at positions 14 and 17 as in the case of the 20,14P-lactone. Reaction of gomphoside (350) and its 3’-epimer with NATURAL PRODUCT REPORTS 1991-A B. TURNER Q HO HO HO & )nyjkd40H Ac AcO HO H H (353) (354) I Reagents i. HCl gas CHCl,; ii 0, CH,Cl, then Zn/AcOH; iii BuiN-BH, CH,C1 then aq. HCl followed by Ac,O 4-N,N-dimethylaminopyridine; iv 0, CH,Cl, then Me$; v Pr'COMe LDA THF; vi H, Pd-CaCO,/Pb; vii KzCO3 MeOH; viii (PhO),P(O)N3 EtO,CN=NCO,Et Ph,P THF ; ix Ph,P; x Ph,P+MeBr- KOCMe,Et PhMe Scheme 12 diazomethane gives two products in each case.lS5 These are 2'-epimeric spiro-oxiranes formed by reaction of diazomethane with the ring-opened 2'-keto forms.Digitoxigenin (351)can be efficiently converted into synthetically useful derivatives of 2,6- dideoxy-D-ri bohexose (the terminal sugar residue) by a sequence involving exhaustive benzoylation. lS6 The synthesis of y-isobufalin from testosterone involves the oxidation of the furan ring of the intermediate (352) to a carboxyl group.lS7 Synthesis of the unnatural 1401-and 16a- epimers of bufotalin acetate (353) and 16-deacetylcinobufagin (354) involves reduction of the corresponding 16-ketones. lS8 2.7 Heterocyclic Compounds The preparation of steroidal tetrazoles by the Schmidt reaction of ketones has been reviewed,lS9 and reports have appeared on related syntheses of tetrazoles and Beckmann rearrangements leading to lactams have been reviewed205 and further ,07 The antifungal antibiotic (355) has been NATURAL PRODUCT REPORTS 1991 CO R (356) (357) R = OH,NEt*,OMe,NHBu' CH(Me) Et,0SiMe3 HO M eO HA (358) (359) SO2QMe-0' (362) R =CHO v vi \ OSOzCF3 x xi vii-ix 0RP c-- I IA I Me Me Me (360) Reagents i NaBH, EtOH ;ii toluene-p-sulphonyl chloride pyridine ;iii toluene-p-sulphonic acid Me,CO; iv LDA THF hexane ;v KMnO, NaIO, aq.ButOH; vi MeNH, (CH,OH),; vii H, Pt AcOH; viii CrO, H,SO ;ix (CF,SOJ,O 2,6-di-t-butyl-4-methylpyridine CH,Cl ; x Pd(PPh,),(OAc), CO PriNH CH,Cl,; xi H, Pt EtOAc Scheme 13 prepared from ergosterol acetate using an intramolecular aza- Wittig reaction in the penultimate cyclization step (Scheme 12)? 4-Aza-3-oxosteroids (356) give the corresponding Al-lactams (357) with dichlorodicyano benzoquinone and N,N-bis(tri-methylsily1)trifluoroacetamide in 85-90 % yields.209 These silylation-mediated oxidations are shown to involve quinone- substrate adducts (358) which have been isolated as two diastereomers one of which undergoes thermolysis to the A1-lactam at four times the rate of the other.Under similar conditions the methyl ether (359) is unreactive showing that formation of the 0-trimethylsilyl imidate is a prerequisite for C-C bond formation. This could involve either a single electron transfer mechanism between the quinone and the 0-silylated imidate or nucleophilic attack by its enamine tautomer upon the quinone ring.Collapse of the adducts (358) is likely to be an ionic process involving loss of a proton from C-1 rather than the long-accepted hydride ion transfer mechanism. The bridged lactam (360) has been prepared for evaluation as a 5a-reductase inhibitor by a route (Scheme 13) starting from 19-hydroxyandrostenedione, 210 via intermediates (36 1)-(365). The structure of the bridged enone (361) was confirmed by X-ray analysis. It differs little from androstenedione as far as the conformations of rings B c,and D are concerned but there are significant differences between the A-rings particularly with regard to the position of C-1.NATURAL PRODUCT REPORTS 1991-A. B. TURNER (366)R' = R2 = H R3 = bond (367)R' =OH R2 = H R3 = bond (368)R' = OH R2 = Me R3 = bond (369)R' = OH R2= H R3 = 0 R AcO I Me AcO 0 (373) (374) (375) Cephalostatin (366) a powerful cell growth inhibitor isolated from a marine worm apparently results from condensation of two 2-amin0-3-ketocholestanes.~~~~ Three related dimers (367)-(369) have been isolated from the same source.212 The bis-quaternary salts (370) and (371) exhibit much less neuromuscular blocking activity than chandonium iodide.213 The structures of isoxazolidines (372) produced from the secosteroid (373) by reaction with N-methyl hydroxylamine (376) (377) have been established by X-ray analysis.214Thallium (111) nitrate reacts with y,b-unsaturated alcohols to give tetrahydrofuran derivatives and y-hydroxyketones.Oxidation of the latter leads via 1,4-dicarbonyl compounds to pyrrole or furan deriv-ative~.'~~ Thus the alcohol (374) gives the pyrrole (375). Reaction of 3,6-dioxocholest-4-ene and 6-oxocholest-4-ene with ethyl acetoacetate in the presence of fused zinc chloride gives pyrans (376) and (377).?-16 Many other compounds having a NPR 8 NATURAL PRODUCT REPORTS 1991 (378)X = O (379)x = s 00 (379) // Reagents i NaH THF DMSO; ii Me,SOI THF DMSO; iii Al(OPr'), PhMe cyclohexanone; iv Ph,PS PhH picric acid; v CF,CO,H Scheme 14 (380) variety of nitrogen oxygen and sulphur-containing hetero- ~~ ~ cyclic systems attached to rings A,~ A/B,~" -B ~ ~ ~ ~ and~ ~224-229 ha ve been prepared.1OP-Oxiranyl steroids (378) are prepared from 19-0x0-androstanes by ylide reactions (Scheme 14).230 The oxiranes are converted into thiiranes (379) with inversion at C-19 using triphenylphosphine and picric acid. The R isomers have aromatase inhibiting activity. 2.8 Cyclopropano-steroids Four stereoisomers of the cholanoic acid (380) a side-chain cyclopropyl analogue of ursodeoxycholic acid prepared by rhodium-catalysed decomposition of ethyl diazoacetate in the presence of a A22-24-norcholene have been separated by medium-pressure chromatography. Their configurations have been determined by 13C NMR spectroscopy and each was The synthesized independentl~.~~~ four isomers differ sig-nificantly in physical properties and in their interaction with intestinal bacterial enzymes.Only one is conjugated with glycine or taurine in the liver and secreted into bile in the form of these conjugates. ~~ -~The 1,24-dihydroxycalciol analogue (38 1) is prepared from ercalciol in twelve steps. 232 The side-chain is constructed by addition of cyclopropylcarbonylmethylenetriphenyl-phosphorane to a 22-aldehyde intermediate. The compound shows comparable activity to calcitriol with regard to inhibition of proliferation and induction of differentiation of cells but is at least two orders of magnitude less potent in its effects on NATURAL PRODUCT REPORTS 1991-A. B. TURNER OH OAc OH I H0" & (382) calcium metabolism.Hence it is a promising drug for the treatment of psoriasis. A stereoselective synthesis of glaucasterol (382) involves complete chirality transfer from C-22 of the benzoate (383) to C-24 of the cyclopropane (382) by means of a zerovalent palladium 2.9 Microbiological Transformations Two hydrolytic enzymes Chromobacterium viscosum lipase and Bacillus subtilis protease can be used to esterify 5a-androstane- 3p 17P-diol in acetone.234 Whereas the lipase exclusively acylates the 3P-hydroxyl group the protease acts principally upon the 17P-hydroxyl group Gram quantities of 3P- and 17P- monobutyryl derivatives can be obtained. In the case of the 3p- ester of 5a-pregnane-3/3,20P-diol, the remaining free hydroxyl group was oxidized with pyridinium chlorochromate in dichloromethane prior to alkaline hydrolysis to give 3P- hydroxy-5a-pregnan-2O-onein 63 YOisolated yield.This com- bined microbiological and chemical route provides a useful alternative to enzymic oxidation catalysed by hydroxysteroid dehydrogenases. Incubation of ring A-aza-androstanes with Cunninghamella elegans leads to hydroxylation at positions la lp 6/3 7P 9a and lSP in transformed yields ranging from 615Y0.~~~ The 6P-hydroxylation of the 4-aza-androstane (384) resembles that previously observed with ring-D-aza analogues but lp-hy-droxylation was not noted with the latter compound. 9a-(385)R = H (386)R =OH OAc Hydroxylation occurs both with 3-aza- and 4-aza-~-homo- steroids this being the major site of hydroxylation of 17a-aza- D-homoandrostanes.In the case of the 5a-hydroxy compound (385) hydroxylation is directed to ring D and the 15P-alcohol (386) is obtained in 15% yield whereas with the 5P-acetoxy compound (387) the unusual 7P-hydroxylation is observed. In both cases the more usual 7a-hydroxylation is subject to steric hindrance. Inversion of the C-3 hydroxyl group of a range of bile acids can be achieved in two steps through sequential use of 301- and 3P-hydroxy steroid dehydrogenases in free or immobilized forms. Transformations are almost quantitative and products > 98 YOpure. Low concentrations of organic solvents such as ethanol and ethyl acetate produce favourable effects on reaction rates.236 The preparative use of cholesterol oxidase has been extended to polyphoric The enzyme is active in micro- emulsions with an organic phase consisting of mixtures of cyclohexane and chloroform.Kinetic data for the oxidation of 7a- and 7P-hydroxycholestero1 in microemulsions with the enzymes from Streptomyces are similar to those obtained for cholesterol itself. The oxidase is active in the two-phase system of butyl acetate and aqueous buffer and preparative enzymic conversion of 7P-hydroxycholestero1 to 7P-hydroxycholest-4- en-3-one can be carried out in this medium. Conversion of cholesterol to cholestenone can also be performed in liquid/ solid systems in buffer with cholesterol adsorbed on silica gel in an organic medium using cholesterol oxidase and catalase entrapped in silica.3 References 1 A. V. 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Mukawa T. Suzuki. M. Ishibashi and F. Yamada J. Steroid Biochem. 1988 31 867. 188 G. Schneider J. Wolfling E. Mesko and G. Dombi Steroids 1988 51 317. 189 B. Charpentier A. Dingas J. Cassan R. Emiliozzi and D. Duval Steroids 1988 52 609. 190 P. A. Cole and C. H. Robinson J. Am. Chem. SOC. 1988 110 1284. 191 L. Lorenc M. Rajkovic A. Milovanovic and M. L. Mihailovic J. Chem. SOC. Perkin Trans. I 1988 1495. 192 T. Matsumoto S. Imai Y. Sunaoka and T. Yoshinari Bull. Chem. SOC. Jpn 1988 61 723. 193 K. Courault and C. Lindig J. Prakt. Chem. 1988 330 445. 194 P. E. Hammann and G. G. Habermehl Liebigs Ann. Chem. 1988 149. 195 H. T. A. Cheung A. E. Mutlib and T.R. Watson J. Chem. Res. (S) 1988 360. 196 R. W. Binkley and J. S. Schneider J. Carbohydr. Chem. 1988 7 157. 197 S. Lociuro T. Y. R. Tsai and K. Wiesner Tetrahedron 1988,44 35. 198 Y. Kamano G. R. Pettit M. Inoue M. Tozawa C. R. Smith and D. Weisleder J. Chem. SOC.,Perkin Trans. I 1988 2037. 199 R. P. Reddy A. Ravindranath T. S. Ramaiah and M. V. Rao Indian J. Chem. Sci. 1987 1 45. 200 M. S. Ahmad and Z. Alam Indian J. Chem. Sect. B 1988 27 1001. 201 Shafiullah S. Ahmad and I. H. Siddiqui Indian J. Chem. Sect. B 1988 27 1136. 202 Shafiullah and I. H. Siddiqui J. Indian Chem. SOC. 1988 65 293. 203 M. Husain R. Habib Shahabuddin A. Fazal and M. Husain Indian J. Chem. Sect. B 1988 27 435. 204 M. S. Ahmad and Z. Alam Indian J. Chem.Sect. B 1988 27 336. 205 P. Catsoulacos Epitheor. Klin. Farmakol. Farmakokinet. Znt. Ed. 1988 2 91. 206 C. Camoutsis and P. Catsoulacos J. Heterocycl. Chem. 1988,25 1617. 207 A. H. U. Siddiqui D. Ramesh N. S. Rao and T. S. Ramaiah Indian J. Chem. Sect. B 1988 27 61. 208 R. E. Dolle and L. I. Kruse J. Chem. SOC. Chem. Commun. 1988 133. 209 A. Bhattacharya L. M. DeMichele U. H. Dolling A. W. Douglas and E. J. J. Grabowski J. Am. Chem. Soc. 1988 110 33 18. 210 H. Y. Lan-Hargest J. D. Elliott D. S. Eggleston D. A. Holt M. A. Levy and B. W. Metcalf Tetrahedron Lett. 1987 28 61 17. 211 G. R. Pettit M. Inoue Y. Kamano D. L. Herald C. Arm C. Dufresne N. Christie J. M. Schmidt D. L. Doubek and T. S. Krupa J. Am. Chem. SOC. 1988 110 2006.NATURAL PRODUCT REPORTS. 1991 212 G. R. Pettit M. Inoue Y. Kamano C. Dufresne N. Christie M. L. Niven and D. L. Herald J. Chem. SOC.,Chem. Commun. 1988 865 (Corrigendum p. 1440). 213 T. R. Bhardwaj S. Kapoor C. C. Shekhar D. P. Jindal and H. Singh Indian J. Chem. Sect. B 1988 27 209. 214 B. Tinant J. P. Declercq M. Van Meerssche M. L. Mihailovic L. Lorenc M. Rajkovic and A. Milovanovic Bull. SOC. Chim. Belg. 1988 97 485. 215 M. L. Forcellese L. Cardillo and E. Mincione Gazz. Chim. Ital. 1988 118,465. 216 M. S. Ahmad and S. M. Ali Indian J. Chem. Sect. B 1988 27 177. 217 M. Mushfiq and N. Iqbal Indian J. Chem. Sect. B 1988,27 173. 218 A. L. Feliu J. Labelled Compd. Radiopharm. Sect. B 1988 25 1245. 219 M. S. Ahmad and Z. Alam Indian J.Chem. Sect. B 1988 27 486. 220 Shafiullah Shamsuzzaman and R. K. Pdthak J. Chem. Res. (S) 1988 376. 221 B. Osipowicz Pol. J. Chem. 1988 62 269. 222 Shafiullah and I. H. Siddiqui Chem. Ind. 1988 727. 223 Shafiullah I. H. Siddiqui and S. Ahmad Indian J. Chem. Sect. B 1988 27 279. 224 Y. A. Sharanin and G. V. Klokol Khim.. Geterotsikl. Soedin. 1988 943. 225 A. P. Krymov A. V. Kamernitskii A. I. Terekhina B. I. Demchenko I. V. Vesela A. V. Skorova G. I. Gritsina L. I. Ioanis’yan V. I. Tropina and N. I. Kislenko Khim.-Farm. Zh. 1988 22 822. 226 A. V. Kamernitskii A. M. Turuta T. M. Fadeeva and A. A. Korobov Izv. Akad. Nauk SSSR Ser. Khim. 1988 1150. 227 A. V. Kamernitskii A. M. Turuta and T. M. Fadeeva Izv. Akad. Nauk SSSR Ser. Khim.1988 1146. 228 A. M. Turuta A. V. Kamernitskii T. M. Fadeeva A. Nabinger V. S. Bogdanov S. V. Lindeman and Y. T. Struchkov Zzv. Akad. Nauk SSSR Ser. Khim. 1988 2392. 229 S. Nikolaropoulos and P. Catsoulacos J. Heterocycl. Chem. 1988 25 1607. 230 W. E. Childers P. S. Furth M. J. Shih and C. H. Robinson J. Org. Chem. 1988 53 5947. 231 R. Pellicciari B. Natalini S. Cecchetti B. Porter A. Roda B. Grigolo and R. Balducci J. Med. Chem. 1988 31 730. 232 M. J. Calverley Tetrahedron 1987 43 4609. 233 J. P. Genet and J. M. Gaudin Tetrahedron 1987 43 5315. 234 S. Riva and A. M. Klibanov J. Am. Chem. SOC. 1988 110,3291. 235 T. A. Crabb and N. M. Ratcliffe J. Chem. Res. (S) 1988 207. 236 S. Riva R. Bovara L. Zetta P. Pasta G. Ottolina and G. Carrea J.Org. Chem. 1988 53 88. 237 K. M. Lee and J. F. Biellmann Tetrahedron 1988 44 1135.

ISSN:0265-0568    

DOI:10.1039/NP9910800017

出版商:RSC    

年代:1991

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99108BP023

出版商:RSC    

年代:1991

数据来源: RSC

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Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting U n iversity of Notti ng ham 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. 1992 Annual Subscription Price E.C. f222.00 Overseas f250.00 U.S.A. $474.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. SG6 1HN 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 11 003. 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 1992 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 1992 E.C. €222.oo Overseas €250.00 U.S.A. US $474.00 Subscription rates for back issues are U.K. (1 987) f142.00 (1 988) f159.00 (1989) f169.00 (1990) f177.00 (1991) f198.00 Overseas f159.00 f183.00 f194.00 f204.OO f228.00 U.S.A. US $280.00 US $342.00 US $388.00 US $398.00 US $467.00 Members of the Royal Society of Chemist@ 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/NP99108FX025

出版商:RSC    

年代:1991

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99108BX027

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Quinoline Quinazoline and Acridone Alkaloids J. P. Michael Department of Chemistry University of the Witwatersrand Wits 2050 South Africa ~~~ ~ Reviewing the literature published mainly between July 1988 and June 1989 (Continuing the coverage of literature in Natural Product Reports 1990 Vol. 7 p. 131) 1 Quinoline Alkaloids 1.1 Occurrence and Detection 1.2 Non- terpenoid Quinolines and Quinolinones 1.3 Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids 1.4 Sesquiterpenoid Quinoline Alkaloids 1.5 Furoquinoline Alkaloids 1.6 Dimeric Quinolinone Alkaloids 2 Quinazoline Alkaloids 3 Acridone Alkaloids 3.1 General 3.2 Occurrence and Structural Studies 3.3 Synthesis 4 References A proposal for radical revision of the taxonomy of the Rutaceae is based on careful appraisal of the wealth of published phytochemical data for numerous genera belonging to this family as well as on morphological characters.' The proponents of this revision recognize an evolutionary trend in which species containing alkaloids derived from anthranilic acid occupy an intermediate stage between those containing benzylisoquinoline alkaloids and those containing coumarins or limonoids.A significant recommendation is that the subfamily Toddalioideae be entirely dispensed with and its members relocated to the Rutoideae. A separate study of the chemical systematics of the African Toddalioideae has revealed a striking uniformity in alkaloid profiles which may in consequence offer less useful insights into phylogenetic relation- ships than limonoids do.2 1 Quinoline Alkaloids A recent supplement to Rodd's 'Chemistry of Carbon Compounds ' contains a short review of developments per- taining to the quinoline alkaloid^.^ 1.1 Occurrence and Detection Table 1 includes new quinoline and quinolinone alkaloids that have been reported during the period of coverage of this review together with known alkaloids isolated from new sources.2 4-30 Quinoline alkaloids have been reported for the first time from the genus Dictyoloma,* a discovery of taxonomic significance since there has been some doubt of the location of this genus in the Rutaceae. The most noteworthy new compound is OMe A3 haplodimerine (95),13 a dimeric quinoline alkaloid with a unique skeleton incorporating a cyclobutane ring.Synchronous fluorescence spectrometry has been used for the first time in identifying the components of a mixture of dihydrofuro- and pyrano-quinolinium alkaloids from in vitro cultures of Ruta gra~eolens.~' A further report on the variability of production of dihydrofuroquinolinium alkaloids (mainly platydesminium and balfourodinium) from tissue cultures of Choisya ternuta has been published.32 1.2 Non-terpenoid Quinolines and Quinolinones Although the widely-distributed hydroxyquinolinecarboxylic acids of the animal kingdom (kynurenic and xanthurenic acids) have generally not been included in past reports in this series a recent systematic investigation of 29 species of the fly Drosophila is worthy of mention here.All but two species contained xanthurenic acid (2a) in the head parts ;additionally ten species all of them eye-colour mutants accumulated xanthurenic acid 8-O-P-~-glucoside (2b) a side metabolite of the tryptophan-xanthommatin pathway in the eyes.33 Several simple quinolines are among the alkaloids reported in the review period from organisms other than higher plants. The presence of the zoochrome uranidine (3) was confirmed in the sponge Aplysina ~erophoba.~ The first natural source of 2- aminoquinoline (4) at impressive concentrations of about 2g per kg of fresh weight is a North American woodland mushroom Leucopaxillus albissimus var. paradoxus form a1biformis.l8 The compound has a wide spectrum of biological activity and may be responsible for the resistance of the fungus to bacterial decay.Another fungus Penicillium verrucosum var. cyclopium contains a tryptophan-derived diketopiperazine two benzodiazepinediones and the known fungal metabolite 3- O-methylviridicatin (5).'l The culture filtrate of Streptomyces OR H OH H (2a) R = H Uranidine (3) (2b) R = P-D-gtu Ph H O-Methylviridicatin (5) 53 NATURAL PRODUCT REPORTS 1991 Table 1 Isolation and detection of quinoline alkaloids Species Alkaloid (Structure) Ref. Acronychia pedunculata Dictamnine (1 R' = R2 = R3 = H) 4 Skimmianine (1 R' = H R2 = R3 = OMe) Aplysia aerophoba Araliopsis tabouensis (A. soyauxii) Uranidine (3) N-Methylpreskimmianine (13 R' = Me R2 = CH,CH=CMe, R3= OMe) Vepridimerine A (91) 5 6 Vepridimerine B (92) Vepridimerine C (93) Vepridimerine D (94) Veprisine (29) Clausena anisata *N-Methylswietinidine-B (12 R' = Me R2 = OMe) 7 Dictyoloma vandellianum Casimiroine (1 4) 4,7,8-Trimethoxy-l-methylquinolin-2-one(13 R' = R2 = H R3 = OMe) 8 Evodia gracilis (-)-Edulinine (12 R' = Me R2 = CH,CH(OH)C(OH)Me,) 9 (+)-Isoplatydesmine (36) Evodia lepta (-)-Ribahnine (37) Kokusaginine (1 R' = R2 = OMe R3 = H) 9 Skimmianine Evodia rutaecarpa *1-Methyl-2-[(Z)-6-pentadecenyl]quinolin-4-one(7)*1-Methyl-2-[(Z)-IO-pentadecenyl]quinolin-4-one(8)*1-Methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]quinolin-4-one(9)*1-Methyl-2-[(4Z77Z)-4,7-tridecadienyl]quinolin-4-one (10)* l-Methyl-2-[(Z)-6-undecenyl]quinolin-4-one(1 1) 10 Glycosma pentaphylla Haplophyllum bungei *Alkaloid (30) (glycolone) Folimine (13 R' = Me.R2 = R3 = H) *Haplobunghe (13 R' = R2 = H. R3 = OMe) 11 12 4-Methoxy-2-quinolinone (12 R' = R2 = H) Haplophyllum foliosum Haplophyllum perforatum Haplophyllum ramosissimum *Haplodimerine (95) *Haplosidine (69) *Haploshine (70) Evodine (I R' = H R2 = OCH,CH(OH)C(Me)=CH, R3= OMe) Haplopine (67) Methylevoxine (1 R1= H. R2 = OCH,CH(OH)C(OMe)Me, R3 = OMe) 13 14 15 16 Robustine (1 R' = R2 = H R3 = OH) Haplophyllum tuberculatum Leucopaxillus albissimus var. Dihydroperfamine (73) *2-Aminoquinoline (4) 17 18 paradoxus form alblformus Melicope t riphy lla Kokusaginine Skimmianine 19 Murraya paniculata Penicillium verrucosum Ptelea trifoliata Edulitine (13 R' = R2= R3= H) 3-Methoxyviridicatine (5) *Ptelefolidonium (35) 20 21 22 Ruta chalepensis var.latlfolia Dictamnine Graveoline (I 5) 23 Graveolinine (1 6) Kokusaginine Sarcomelicope pembaiensis Stigmatella aurantiaca *5-Methoxydictamnine (7 1) Acronydine (74) *Aurachin E (59) 24 25 *Aurachin F (60) *Aurachin G (61) *Aurachin H (62) Streptomyces griseofulvus Teclea grandifo lia *Aurachin I(63) *3-Hydroxyquinoline-2-carboxylic acid (4) calcium salt Flindersiamine (75 R1 = H R2 = OMe) Kokusaginine Maculosidine (1 R' = R3= OMe R2 = H) 26 27 Montrifoline (1 R' = OCH,CH(OH)C(OH)Me, R2 = OMe R3 = H) Tecleamine (75 R' = H. R2 = OCH,CH=CMe,) Tecleaverdoornine (75 R' = CH2CH=CMe2 R2 = OH) Vepris dainelli Tecleine (75 R' = H R2 = OH) Kokusaginine Skimmianine 2 Vepris glomerata Ko kusaginine Skimmianine 2 Zanthoxylum austrosinense Zanthoxylum coreanum Zan t hoxy lum sarasin ii Dictamnine Skimmianine Skimmianine 28 29 30 * New alkaloids NATURAL PRODUCT REPORTS 1991-5.P. MICHAEL Me OMe OMe (13) OMe I (14) OMe griseofavus subsp. (GO 3592) was found to contain a new natural product the calcium salt of 3-hydroxyquinoline-2- carboxylic acid (6) the structure of which was deduced from its spectra and confirmed by synthesis from 3-hydroxy-2-methyl- quinoline-4-carboxylic acid.26 A reinvestigation of Evodia rutaecarpa long known as a source of 2-alkyl-4-quinolinones cf. ref. 34(a) has confirmed the presence of four known alkaloids of this type (evocarpine dihydroevocarpine 1-methyl-2-undecyl-4-quinolinoneand 1 -methyl-2-pentadecyl-4-quinolinone), and led to the isolation of five new alkaloids (7)+11) bearing unsaturated side chains.'O The structures were supported by both spectroscopic techniques and chemical degradation.The degree of unsaturation in the side chains was substantiated by catalytic hydrogenation to known compounds; while the positions of the double bonds were determined by Lemieux-Johnson oxidation with osmium tetroxide-sodium periodate and detection of the resulting aldehydes as the 2,4-dinitrophenylhydrazonederivatives. The Z geometry was deduced from the 13C NMR shifts of the allylic carbon atoms (8 25.5-27.4). Compounds (7) and (8) were inseparable and the assumed ratio of 2 3 is based on the ratio of pentanal and nonanal produced in the Lemieux-Johnson oxidation.Only carbazole alkaloids have previously been isolated from the genus Clausena but C. anisata has now been shown to produce a new quinolinone alkaloid N-methylswietinidine-B (12 R1 = Me R2 = OMe).' The UV spectrum in neutral and acidic solution a carbonyl stretch at 1630 cm-l in the infrared spectrum and a resonance at 161.2 ppm in the 13C NMR spectrum indicated the quinolin-2-one structure. The lH and 13C NMR spectra could be fully assigned. The similarity of the former to that of swietinidine-B which lacks the methyl resonance at 6 3.70 clinched the structural assignment. 4-Methoxyquinolin-2-one (12 R1 = R2 = H) has been detected for the first time in the genus Hapfophyllum.12The new alkaloid haplobungine (13 R' = R2 = H R3 = OMe) isolated from Haplophyllum bungei was shown to have the spectroscopic characteristics of other alkaloids of the 4-methoxyquinolin-2- one series.12 The substitution pattern was confirmed by comparing spectroscopic and physical properties of its N-methyl derivative with those reported in the literature.12 The isolation of the structurally similar alkaloid edulitine (robust- inine 13 R' = R2 = R3 = H) along with methyl N-methyl- anthranilate from Indonesian samples of Murraya panicufata is of chemotaxonomic interest since these and other con-stituents are absent in prenylindole-containing samples of the plant collected in Taiwan.20 The finding is perhaps indicative of two distinct chemotypes of the species.NATURAL PRODUCT REPORTS 1991 (17) VI vii b; R = CSHll 32% 1a 70% Q y H2 aR ~ bii% R a VIII 70-80% I H (20) (19) (18) Reagents i NCS cat. pyridine CHCl,,.reflux; ii phenylacetylene or 1-heptyne NEt, CHCl, reflux; iii H, Raney Ni AcOH 20 h; iv NaNO, H,SO, 0 "C to 5 "C; v H, Raney NI 45 min; vi AcC1 NEt, CHCI,; vii cat. boric acid Raney Ni MeOH-H,O; viii cat. conc. HC1 EtOH reflux; ix NaOMe MeOH reflux Scheme 1 C02Et C02Et I II Ill IV NHCOCH3 NCOCH3 I OH OR Me OR Me (23) Daurine (21) R = CH2CH=CMe2 Folidine (22) R = CHzCOCHMe2 Reagents Daurine series i prenyl bromide K,CO, acetone reflux; ii 18-crown-6 t-BuOK Mel Et,O reflux; iii t-BuOK Et,O reflux; iv CH,N, Et,&MeOH r.t.Folidine series i l-bromo-3-methylbutan-2-one, K,CO, acetone reflux then (CH,OH), Me,SiCl r.t. ;ii iii as for daurine; iv CH,N, Et,O-MeOH r.t. then conc. H,SO, acetone reflux Scheme 2 /t\ OH Fabianine (25) Reagents i pyrrolidine p-TsOH C,H, reflux; ii methyl vinyl ketone C,H, reflux; iii NH,OH-HCl EtOH 150 "C (autoclave); iv 80% H,SO, 75 "C Scheme 3 NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL Kametani’s synthesis of quinolines by [4 +21 cycloaddition and the application of this approach to the synthesis of some simple 2-substituted quinoline alkaloids has been reviewed.35 A synthetic approach to 2-substituted 4-quinolinones exploits the dipolar cycloaddition of o-nitrobenzonitrile oxide to appropriately substituted terminal alkynes (Scheme l).36 Cata- lytic reduction of the adducts (17) was initially at the nitro group after which the isoxazole ring was cleaved by hydro- genolysis.The intermediate vinylogous amides (18 X = H) isolable as the acetanilides (18 X = COCH,) underwent cyclization to 4-aminoquinolines (19) faster than they under- went hydrolysis necessitating the completion of the syntheses of the alkaloids (20 R = Ph and pentyl) by diazotization of (19). The acetanilides (18 X = COCH,) were also fortuitously found to undergo acid-or base-induced cyclization and deacylation to give 2,4-dimethylquinazoline an alkaloid of Pseudomonas species. The structures of the alkaloids daurine (21) and folidine (22) previously inferred from spectroscopic data cf.refs. 37(a) (b) have now been confirmed by synthesis from ethyl 3-hydroxy- anthranilate (23) (Scheme 2).38 The 8-alkoxy groups that distinguish the two alkaloids were introduced comparatively early in the synthesis. In the case of daurine base-promoted N-methylation of the prenyl ether of (23) followed by base- induced cyclization and O-methylation with diazomethane gave the alkaloid (21) in 18% overall yield from 3-hydroxy- anthranilic acid. For folidine additional protection and deprotection steps were necessary for the ketonic group in the side chain and an overall yield of 10% was obtained. (+)-Pulegone (24) was the starting material for a short synthesis of fabianine (25) the principal alkaloid of Fabiana imbricata (Scheme 3).39 The pyrrolidine-derived enamine of pulegone underwent conjugate addition with methyl vinyl ketone after which the crude adduct (26) was heated in an autoclave at 150 “C with ethanol and hydroxylamine hydro- chloride to form the pyridine ring of (27).Hydration with sulphuric acid afforded an inseparable mixture (1 :1) of the cis and trans compounds (25) in modest yield. The alkaloid itself is apparently an isomeric mixture in which the cis isomer is dominant. 1.3 Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids Debate on the presence or absence of monomeric and dimeric quinolin-2-ones in Araliopsis tabouensis6 appears to have stemmed from confusion in the use of the species names Araliopsis soyauxii and A. tabouensis and the conspecificity or otherwise of these species.4o If as seems likely the species are conspecific then A.soyauxii is the correct name to use. Differences in alkaloidal composition probably arise as a result of local adaptations since Ghanaian populations of the plant were studied in the earlier work cf. ref. 34(b),(c) and Cameroonian populations in the later cJ ref. 37(c). Further information on the new alkaloid (+)-araliopsinine (28) from the Cameroonian population discussed in last year’s review in this serie~,~’‘~) has now become available and its spectra have been reported.6 The structure was confirmed by synthesis from veprisine (29) in two ways by treatment with m-chloro-peroxybenzoic acid followed by hydrolysis of the resulting epoxide and by oxidation with chromic oxide in acetic acid followed by basic hydrolysis.It is unfortunate that the new alkaloid (30) isolated from Glycosmis pentaphyllall has been given the name glycolone since this name has previously been assigned to 4,8-dimethoxy- 3-prenyl-2-quinolinone isolated from the same species cf. ref. 37(d). The new alkaloid has unusual features it is one of a mere handful of naturally occurring 4-ethoxyquinolinones cf. ref. 37(e) and the but-2-en- 1-yl substituent is unprecedented among the anthranilate-derived quinoline alkaloids. The compound is in fact the butenyl analogue of the 3-prenylquinolinone alkaloid homoglycosolone (3 1) cf. ref. 370 also from Glycosmis pentaphylla. The presence of the 2- OMe he OMe Me Araliopsinine (28) Veprisine (29) OEt F! I OH Me OH he (30)R = H (32) (31) R = Me I1 OMe OMe Me Ptelefolidonium (33) Ptelefolid ine (34) R1-R2 = OCH20 Ptel ecu Itiniu m ( 35) R’ = H; R2= OMe 0 II 8 I Me Me lsoplatydesmine (36) Ribalinine (37) quinolinone unit in (30) was supported by UV data and by an infrared carbonyl absorption at 1640 cm-l but the location of the phenolic OH group was tentatively assigned from biogenetic considerations only.Heating with 6N hydrochloric acid converted the alkaloid to the furo[3,2-~]quinolinone (32) in 47 YOyield a somewhat unusual result in view of the tendency of 3-allylquinolin-2-ones to cyclize to pyranoquinolines under similar conditions. That lavish source of natural products Ptelea trifoliata has been shown to produce yet another hitherto unknown dihydrofuroquinolinium alkaloid ptelefolidonium (33).28 It had previously been surmized that (33) might be a natural product cf.ref. 34(d) since base-promoted cleavage of a mixed fraction of quaternary alkaloids from Ptelea trifoliata had produced amongst others the alkaloid ptelefolidine (34). The alkaloid ptelecultinium (35),41 introduced in last year’s review as a metabolite from cell cultures of the same plant was suspected to be an intermediate for more complex alkaloids possessing a higher degree of oxygenation and perhaps therefore unlikely to be present in sufficiently large amounts for detection in intact plants. However it has now been isolated from the roots of P.trifoliata.22 58 NATURAL PRODUCT REPORTS 1991 I Me Almeine (38) \ NI R ___) O \ NI R O R I R I R (39) Scheme 4 (41) R = Me (43) (44) R' = R3 = R4 = H; R2 = OMe (42) R = H (45) R' = Me; R2 = R3 = R4 = H (46) R' = Me; R2 = OMe; R3 = R4 = H (47) R' = Me; R2 = R4 = H; R3 = OMe (48) R' = Me; R2 = H; R3 = R4 = OMe Reagents i HCO,H CHCl, reflux; ii Hg(OAc), THF r.t.then NaC1 H,O; iii NaBH, 3M aq. NaOH CH,Cl, 0 "C; iv DDQ C,H, reflux Scheme 5 II II R' H R' H (56) R' = R2= R3 = H (52) R' = R2 = R3 = H (57) R' = OMe; R2 = R3 = H (53) R' = OMe; R2 = R3 = H (58) R' = R2 = H; R3 = OMe (54) R' = R3 = H; R2 = OMe (55) R' = R2 = H; R3 = OMe Reagents i prenyl bromide NaOH H,O 50 "C; ii Te NaBH, AcOH pH 7.5 -20 "C to reflux; iii CH,N, Et,O-EtOH 0 "C; iv DDQ C,H, reflux Scheme 6 59 NATURAL PRODUCT REPORTS 1991-5.P. MICHAEL Reisch and Iding have synthesized almeine (38) very simply in 28 Yo yield merely by heating 4- hydroxy-N-methylquinolin-2-one with dibromoisoprene (1,4-dibrom0-2-methyl-2-butene) sodium iodide and sodium hydrogen carbonate in acetone." The previously discussed approach of Reisch cf. ref. 37(g) to the synthesis of pyrano[3,2-~]quinolinonealkaloids based on the reaction of 4-hydroxyquinolin-2-ones with 3-chloro-3-H/'Ao methyl- I-propyne has now been extended.43 Model studies with a variety of substrates support the hypothesis that a 4- Aurachin E (59) propargyl ether (39) is formed initially and that this undergoes Claisen rearrangement prior to a series of prototropic shifts and eventual cyclization (Scheme 4).A versatile new synthesis of pyranoquinolinones permits the formation of either angular or fused tricyclic products regioselectively from the same substrates the isopentenyl- quinolinones (40) simply by changing reaction conditions (Scheme 5).44 Heating (40) with formic acid in chloroform brought about cyclization to dihydropyrano[2,3-b]quin-olinones and in this way the alkaloids N-methylkhaplofoline (41) and khaplofoline (42) were obtained in 88% and 59% 0-yields respectively together with 612 YOof the angular isomers. Aurachin F (60) Alternatively treatment of (40) with mercuric acetate followed by reductive demercuration afforded dihydropyrano[3,2-c]-quinolinones (43) as the only detectable products.These could be dehydrogenated with 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) in boiling benzene to produce the angularly fused alkaloids N-desmethylzanthobungeanine(44) N-methylflindersine (49 zanthobungeanine (46) 8-methoxy- xkyY N-methylflindersine (47) and oricine (48). The overall yields (y$ for the three-step process were in the range 32-39 YO. R In view of the manifold difficulties that normally accompany the direct 3-prenylation of quinoline-2,4-diones and related methyl ethers a new procedure devised by Shanmugam and co- I workers is of considerable interest (Scheme 6).45 The strategy 0-involved bisprenylating the 4-hydroxyquinolin-2-ones(49) after which the products (50) were partially deprenylated to Aurachin G (61) R = H; XY = HC=CH (51) with sodium hydrogen telluride in 5&92% yields arguably by an electron-transfer pathway.Treatment of the Aurachin H (62) R = H; XY = CH2CH2 products (51) with diazomethane gave the alkaloids atanine Aurachin I (63)R = OMe; XY = CHzCH2 (52) and glycolone (53) and the alkaloid analogues (54) and (55) in 8(1-90% yields. Alternatively heating (51) with DDQ in boiling benzene produced the pyrano[3,2-~]quinolinone alkaloids flindersine (56) 8-methoxyflindersine (sic; more correctly 7-methoxyflindersine 57) and haplamine (58) in yields of 68-80 YO. OMe OMe 1.4 Sesquiterpenoid Quinoline Alkaloids Aurachins A-D unique sesquiterpenoid quinoline alkaloids from the myxobacterium Stigmatella aurantiaca were described in last year's review cf.ref. 37(h). Structural work on these compounds has still to be published but in the meanwhile another five aurachins (59)-(63) have been described in the R patent literat~re.~~ These compounds were produced when the Anhydroperfori ne (66) organism was cultured in the presence of added anthranilic Haplophyllidine (64) acid. Full reports on these fascinating metabolites are awaited R = CH=CMe2 with interest. Perforine (65) R = CH2C(OH)Me2 1.5 Furoquinoline Alkaloids The 13CNMR spectra of the rare 5,6,7,8-tetrahydrofur0[2,3-6]-quinoline alkaloids haplophyllidine (64) perforine (65) and OMe anhydroperforine (66) have been assigned c~mpletely.~~ When one considers the large number of quinoline alkaloids bearing free phenolic groups it is surprising how few glycosides of these compounds have been isolated.In fact the only confirmed aglycone alkaloid to date has been haplopine (67) whose a-L-rhamnoside and P-D-glucoside (glycoperine (68) and glycohaplopine) occur naturally. The recent literature has OH OH revealed that the aerial parts of HaplophyIIurn perforaturn OMe contain two more glycosides of haplopine which are in fact the first known biosides of the quinoline alkaloids. These com- Haplopine (67) Glycoperine (68) NATURAL PRODUCT REPORTS 1991 HOCH2 I 0 OR How OH Haplosidine (69) R = COCH3 5-Methoxydictamnine (71) R' = OMe; R2 = H Haplosinine (70) R = H y-Fagarine (72) R' = H; R2 = OMe OMe Dihydroperfarnine (73) Acronydine (74) (75) lsomaculosidine (76) Dictarnnine (81) R = H H Evolitrine (82) R = OMe (80) (79) (83) R = Me Reagents i SOCl, C6H6 reflux; ii NH, CHCl, 0 "C; iii POCI, reflux; iv NaOH 30% H,O, MeOH 40 "C to 60 "C; v NaOBr H,O 0 "C to 70 "C; vi conc.HCl NaNO, H20 10 "C then CuCl conc. HCl 5 "C to r.t.; vii 5% HCl-EtOH reflux; viii PPA 120 "C; ix NaOMe MeOH reflux; x DDQ dioxan reflux Scheme 7 pounds are haplosidine (69),14 which is haplopine 7-0-[p- Few recent syntheses of furoquinoline alkaloids have been ; D-glucopyranosyl( 1 +3)]-a-~-(2'-O-acetyI)-rhamnopyranoside published. Haplopine (67) and skimmianine (1 R' = H and haplosinine (70),15 the corresponding 7-0-[p-~-R2= R3= OMe) have been converted to kokusagine (1 glucopyranosyl(I -,3)]-a-~-rhamnopyranoside.Acid hydro-lysis of both gave haplopine and the constituent sugars. Both compounds yielded the same hexaacetate on peracetylation and haplosidine could be saponified under alkaline conditions to give haplosinine. The terminal sugar in the bioside unit was established after enzymatic hydrolysis of haplosinine to D-glucose and glycoperine (68). The sites of linkage and the position of the acetate in (69) were deduced from the 'H and 13C NMR spectra. A new alkaloid with the rather rare 5-methoxyfuroquinoline structure has been isolated from Ruta chalepensis var. latifolia along with several more common alkaloid^.,^ The alkaloid 5- methoxydictamnine (71) was characterized spectroscopically the substitution pattern being inferred from the presence of three adjacent aromatic proton signals and mass spectrometric and TLC comparisons with the 8-methoxy isomer y-fagarine (72).R' = H R2R3 = OCH,O) in about 30% yield by demethyl- ation with boron tribromide followed by methylenation with bromochloromethane and anhydrous potassium carbonate in dry a~etone.~' Kokusaginine (1 R1 = R2= OMe R3 = H) was converted to maculine (1 R' R2 = OCH,O R3 = H) in 23 YO yield by a similar procedure. A preparation of isomaculosidine (76) in 25% yield by a fairly standard approach the modified Tuppy-Bohm method beginning with the condensation of 2,4-dimethoxyaniline chloroacetyl chloride and diethyl sodio-malonate is virtually identical to previously published syntheses in which anilines with other substitution patterns have been used as substrates cf.ref. (37i).48 A novel approach to the synthesis of furoquinoline~~~ is based on transformations of 3-vinyl-2-quinolinones (77) themselves available from N-(but-3-enoyl)isatins (78) (Scheme 7). A sequence of functional group interconversions was used to prepare the key intermediates (79) which cyclized to NATURAL PRODUCT REPORTS 1991-J. P. MICHAEL r 1 IR2 I Me (84a) R' = R2 = OMe (85) (86) (84b) R' = OMe; R2 = H (84c) R' = R2 = H OMe OMe OMe Me Skimm iani ne lsoskimmianine (87) Reagents i conc. H2S0,; ii MeI reflux 24 h; iii 2M NaOH-MeOH r.t.; iv MeI reflux 6 h; v MeI sealed tube 80 "C,5 h Scheme 8 dihydrofuro[2,3-b]quinolines (80) on heating with poly-phosphoric acid.The required oxidation level was introduced by DDQ dehydrogenation and in this way syntheses of dictamnine (81) and evolitrine (82) as well as the unnatural derivative 6-methyldictamnine (83) were completed in approxi- mately 28% overall yield based on (77). In a model study aimed at the synthesis of 3-(3-methyl-2- oxobutyl)quinoline-2-one alkaloids Gaston and Grundon showed that the furo[2,3-b]quinolin-4-ones (84a4) formed pseudobase hydroiodide salts (85) on prolonged refluxing with methyl iodide (Scheme 8).50 The bridgehead methoxy group probably arises from gradual hydrolysis of methyl iodide by adventitious moisture. The salts were cleaved on treatment with sodium hydroxide to give the desired ketones (86) in 60-81 % yields.Under similar conditions skimmianine could be converted by way of the corresponding pseudobase salt to isoskimmianine (87) in 62% yield a conversion that has mechanistic implications for the well-studied 'is0 rearrange- ment ' of 4-methoxyfuro[2,3-b]quinoline alkaloids. The hydroxylated linear dihydrofuro[2,3-b]quinolin-4-ones (88a-c) were shown to undergo acid-catalysed conversion to a mixture of (84) and the angularly fused furo[3,2-~]quinolinones (89) the proportion of the latter increasing with time. The suggested pathway involves dehydration of (88) to (84) protonation of the enol ether moiety followed by cleavage to ketones (90) and recyclization to the observed products. In support of this proposal (84a) was found to convert partially into a 2 1 mixture of (84a) and (89 R1= R2 = OMe) on treatment with concentrated sulphuric acid for two hours.The mutagenicity of furoquinoline alkaloids continues to be of interest. Structure-mutagenicity relationships of the alkaloids anhydroevoxine evolitrine flindersine maculine maculo-sidine and tecleaverdoornine have been st~died,~' as has the modification of the mutagenicity of dictamnine y-fagarine and skimmianine by enzyme inducers and inhibitor^.^^ 1.6 Dimeric Quinolinone Alkaloids The occurrence structures characterization synthesis and reactions of these alkaloids have recently been Haplodimerine (99 isolated from the fruits of Hapfophyflum fofios~m,~~ possesses a new and most unusual skeleton. Its structure has been established by spectroscopic methods and more securely X-ray crystallographic analysis.This alkaloid is effectively derived from an angular pyranoquinolinone (flindersine 56) and a furo[2,3-b]quinoline (skimmianine 1, R'= H R2= R3 = OMe) the latter of which (but not apparently the former) has previously been isolated from this species. The involvement of a furo[2,3-b]quinoline in dimer formation is novel all known dimeric quinolinone alkaloids hitherto isolated have been derived from hemiterpenoid quinolinones or their tricyclic derivatives. The most striking structural feature is of course the all-cis-substituted cyclo- butane ring formally derived from [2 +21 cycloaddition of the constituent halves. Could this imply a photochemical origin for the dimer ? There are intriguing synthetic possibilities implicit in such a suggestion.Investigations of the dimerization of N-methylflindersine (45) under thermal conditions have resulted in the synthesis of known and novel paraen~idimerines.~~ There is a striking NATURAL PRODUCT REPORTS 1991 Me R Vepridimerine A (91) (Y-Hd.a-He;R = OMe Vepridimerine B (92)a-Hd,fl-H,; R = OMe ParaensidimerineA (96) (Y-Hd,(Y-t-i,; R = H ParaensidimerineC (97) a-Hd,fl-He; R = H Vepridimerine C (93)a-H,,a-H,; R = OMe Vepridimerine D (94) a-Hd,O-He; R = OMe ParaensidimerineA' (100) &Hd,(Y-H& R = H ParaensidimerineC' (101) a-Hd,p-He; R = H ParaensidimerineF (99) O-Hd,a-tie; R = H Paraensidirnerine F' (102) P-Hd,a-H,; R = H H Me I H I OMe Me0 MeO OMe I H Haplodimerine (95) ParaensidimerineD (98) (703) OH OH II OH ( 104) (105) Vasicinone ( 106) X = 0 temperature dependence on the outcome of the reaction.At 105"C low yields of paraensidimerines A (96,6%),C (97,3%) and D (98,3%) were isolated together with unconverted N-methylflindersine (88YO).At 150 "C the hetero Diels-Alder adduct paraensidimerine D was not formed. Starting material was recovered (16YO),together with paraensidimerines A (1 5 YO),C (6YO),and F (99,5 YO).In addition three new mixed quinolin-2-one/quinolin-4-one dimers were formed. These were named paraensidimerines A' (100 3 %) C' (101,7 %) and F' (102 6%) and their structures were elucidated on the basis of spectroscopic data. Paraensidimerine F' is the bis(N-methyl) derivative of the alkaloid geijedimerine cf.ref. 37(g) from which it had previously been prepared. Thermal dimerization of N-methylflindersine at 210 "C yielded only paraensidimerines A (18%) C (18 YO),and F (44%). In a separate study dimerization of haplamine (58) at 220-230 "C was shown to give in 42% yield a product (103)of the same skeletal type and stereochemical series as paraensidimerine F.55 2 Quinazoline Alkaloids Alkaloids have been isolated for the first time from Galium aparine (Rubiaceae) aerial parts of which apparently contain the quinazoline alkaloids (-)-8-hydroxy-2,3-dehydrodeoxy-Vasicine (107) X = 2H peganine (1 04) (-)-1-hydroxydeoxypeganine (105) and ( )-vasicinone (106)as minor constituent~.~~ All three were claimed as new alkaloids the last-named on the grounds that it has never before been obtained from natural sources in racemic form.The unusual geminal amino-alcohol structures for (104) and (105)were deduced from UV IR 'H NMR and high resolution mass spectral data. In particular detailed spin decoupling studies were used to establish the bonding sequences in the non-aromatic parts of both alkaloids. ( +)-Vasicinone has been isolated from Adhatoda vasica well known as a prolific producer of quinazoline a1kaloids.j' This appears to be the first reported isolation of the (+)-enantiomer of the alkaloid though the (-)-and (+)-forms are both known as natural products. The plant displays a marked seasonal variation in the production of its major alkaloid vasicine (107),which occurs in highest concentrations in the inflorescence^.^^ Two distinct morphological types of the plant showed quite different seasonal fluctuations of alkaloids though alkaloidal composition was qualitatively the same in both.59 In view of the suspected occurrence of glucosides of vasicine and vasicinone in Adhatoda vasica materials for comparison have been prepared by converting both alkaloids to their P-D-glucopyranosides.'' The bridgehead-hydroxy structure (108) formerly assigned NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL (108) Vasicol (109a) X = H (110) (109b) X= Br 0 'N 7% LOAc LO" Reagents i HOCH,CH,NH, K,CO, Cu NaI DMF 70 "C; ii Ac,O pyridine r.t.; iii CH(OEt), Ac,O reflux; iv NaOMe MeOH r.t.Scheme 9 r 1 (1 13) Deoxyvasicinone (1 12) Reagents i triphenylphosphine xylene 140 "C 5 h; or tributylphosphine r.t. 2 h Scheme 10 Glycosminine (114) to the alkaloid vasicol cf-ref. 34(e) is wrong.61 The lactam structure (109a) has been proposed instead on the basis of spectroscopic evidence an X-ray crystallographic study of the p-bromo derivative (109b) and a variety of chemical trans- formations. The structure (1 10) for echinozolinone an alkaloid isolated from Echinops echinatus cf. ref. 37(j) has been called into question.62 An unambiguous synthesis of compound (1 10) from 4(3H)-quinazolinone and 2-chloroethanol gave a product whose spectroscopic characteristics were quite different from those reported for the alkaloid.A possible alternative structure (1 1 l) was dismissed after spectra of synthetic material prepared as shown in Scheme 9 also failed to correspond with those of the alkaloid. The authors doubt that the reported NMR spectra indicate either a quinazoline structure or the presence of a hydroxymethyl terminus. For the moment the problem remains unresolved. A quantitative HPLC procedure has been devised to cast light on the course of an old synthesis of deoxyvasicinone (I 12) from anthranilic acid and pyrrolidin-2-one cf. ref. 34(fJfi3 A short new synthesis of deoxyvasicinone makes interesting use of an intramolecular aza-Wittig reaction (Scheme The key step in the synthesis involved Staudinger reaction of the azide (1 13) with a phosphine the resulting iminophosphorane condensing with the lactam carbonyl group to form the alkaloid.With triphenylphosphine the reaction required heating in xylene under reflux to produce the desired alkaloid in 99.5 % yield whereas the reaction with tributylphosphine proceeded at room temperature in 99 O/O yield. The method has also been applied to the cyclization of succinimide-and glutarimide-based a~ides.~~ A one-pot preparation of glycos- minine (1 14) in 40 % yield from N-(o-bromopheny1)-phenylacetamide carbon monoxide the titanium isocyanate reagent [3THF * Mg,CI,O. TiNCO] and tetrakis(tripheny1-phosphine)palladium(O) as catalystfi6 is the only other note- worthy synthesis of a quinazoline alkaloid in the period under review. 3 Acridone Alkaloids 3.1 General An important new review deals with the isolation of new acridone alkaloids since 1970 and with their 13C NMR spectra biosynthesis and biological activity.67 Advances in the field have also been summarized in Rodd's Chemistry of Carbon Compounds.68 The elegant work of Funayama and Cordell on the synthesis and structure of polymers of acronycine and related compounds presented in several past reports in this journal has now been consolidated in the form of a review.69 Recent biological studies on acridone alkaloids include the testing of rutacridone and rutacridone epoxide for muta-genicity ;70 investigations of the anti-herpes virus activity of citrusinine I ;71 the antitumour activity of acronycine in mice;72 and the testing of thirty acridone alkaloids both in vitro and in vivo against rodent mala~ia.'~ In the latter study atalaphyllinine completely suppressed the formation of malaria parasites without obvious acute toxic effects when injected intra-peritoneally into mice infected with Plasmodium berghei or P.vinckei. NPR 8 64 NATURAL PRODUCT REPORTS 1991 Table 2 Isolation and detection of acridone alkaloids Species Alkaloid (Structure) Ref. Araliopsis tabouensis Arborinine (1 15 R = Me) 6 (A. soyauxii) A talan t ia buxifolia *Atalafoline-B (1 17) 74 Citrus funadoka *( -)-Acrimarine-A (1 2 I) 75 *(-)-Acrimarine-B (122) *(-)-Acrimarine-C (123) Grandisine-I1 (125) Natsucitrine-I1 (126) Citrus grandis *Buntanhe (1 18) 76 Citrus nobilis Citracridone-I (128 R1 = OMe R2 = OH) 77 Citropone-A (1 29) Citrusinine-I (1 30 R' = R3 = OH R2 = H) 11-Hydroxynoracronycine (128 R1 = OH R2 = H) Ruta chalepensis var.latifolia 1-Hydroxy-N-methylacridone(13 1) 23 1-Hydroxy-N-methylfuracridone (1 32) 78 Surcomelicope argyrophylla *( +)-Acronycine epoxide (1 20) 79 Sarcomelicope pembaiensis Acronycine (1 19) 24 Melicopicine (130 R1 = R2 = OMe R3= H) Sarcomelicope simplicifolia *( +)-Acronycine epoxide 79 subsp. neo-scotica Saussureu nepalensis Arborinine 80 Teclea borenensis Arborinine 2 Vepris duinelli Xanthoxoline (1 15 R = H) 2 * New alkaloids &OMe O.+LO I OMe 1340 OR2 R (1 15) (116) R' = OMe; R2 = H; R3 = R4 = Me Atalafoline B (1 17) (118) R' = CH2CH=CMe2; R2 = R4 = H; R3 = Me (125) R' = R2 = H; R3 = R4 = Me (126) R' = R3 = H; R2 = R4 = Me (127) R' = R3 = R4 = H; R2 = Me o.'-H\ HO OMe O M e r n o Me I OMe t R' Me0 Acronycine epoxide (120) Acrimarine A (1211 R' = Me; R2 = OH Acrimarine C (123) Acrimarine B (122) R' = H; R2 = OMe 3.2 Occurrence and Structural Studies Six new acridone alkaloids have been reported during the period covered by this report.These compounds together with known alkaloids isolated from new sources are listed in Table 2.2.6,23.24.74-80 At alantia buxifolia shown previously to contain the alkaloid atalafoline (1 16) cf. ref. 37(k) has now yielded atalafoline-B (1 17) which was characterized by standard Me0mo spectroscopic method^.'^ This is the first 1,3,4,5,6-penta-oxygenated acridone to be isolated from a natural source and Suberosin ( 124) it brings to six the number of simple pentaoxygenated acridone alkaloids.Buntanine (1 1S) a new prenylacridone from the root NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL Citropone A (129) ( 133) bark of Citrus grandis was also characterized spectro-s~opically.~~ In this case AB signals in the 'H NMR spectrum at S 6.92 and 8.05 served to identify the ortho-coupled H-7 and H-8 respectively while NOE experiments on the 3,6-bis-(methoxymethyl) ether of (1 18) were performed to establish the relative positions of methoxy and hydroxy groups. Reinvestigation of the bark of Sarcomelicope (= Bauerella) simplicifolia subsp. neoscotica led to the isolation of an optically active minor alkaloid whose spectroscopic properties were in the main similar to those of acronycine (119) though its molecular ion was 16 mass units higher.79 Signals in the 'H NMR spectrum typical of a 3,4-epoxydimethylchroman system supported the proposal that the compound was acronycine epoxide (120).The compound proved to be identical to an unstable minor metabolite previously isolated from S. argyro-phylla. The compound is biogenetically interesting as the probable intermediate between acronycine and the acronycine diols described in an earlier report cf. ref. 37(k). In view of the biological activity of certain epoxides it is also possible that (120) may be the active form of acronycine in vivo. The most notable new acridone alkaloids are the three optically active compounds (12 1)-(123) isolated from the roots of Citrus funadoka seedlings.75 The acrimarines as they have been called are novel dimeric compounds in which an acridone unit has been coupled to a coumarin.The monomeric precursors are well known as constituents of Citrus species but their union as dimers is unprecedented. In all cases the mass spectra showed molecular ions for the dimers as well as prominent ions for the acridone and coumarin fragments. The latter was the same in all three cases (m/z 242; C,,H,,O,). NMR characteristics typical of 1-hydroxy-9-acridones and a (130) (132) (134) common coumarin nucleus were also apparent. For the latter the diagnostic signals were an AB double doublet (6 ca.6.2 7.6) for the vinylic protons of the pyrone ring; the lactonic carbonyl signal (8 ca. 161.5); and two allylic methyl groups a vinylic proton signal (aI4ca. 5.9) and a vicinal methine proton (6 ca. 5.6) characteristic of a prenyl group linking two aromatic moieties. Nuclear Overhauser effects served to locate the prenyl unit on C-6 of the coumarin and further NOE experiments as well as IH-l3C long-range COSY experiments established not only the remaining connectivities within the coumarin but also the position of linkage of the prenyl side chain to the acridone nucleus. The coumarin turned out to be suberosin (124) which was also isolated from the plants ;and the acridone partners of acrimarines A B and C respectively were grandisine 11 (125) linked at its 2-position natsucitrine I1 (126) linked at its 2-position and natsucitrine I (127) linked at its 4-position.The first two of these were found in the plant alongside the dimers. The absolute configurations of the dimers were not determined but the measured [a] values for acrimarines A B and C were -9.76' (c 0.082 CHCl,) -7.14" (c 0.056 CHCl,) and -6.17" (c 0.081 CHC1,) respectively. The mass spectra of a variety of simple acridones prenyl- acridones linear and angular pyranoacridones and furo-acridones have been examined with a view to elucidating characteristic fragmentation patterns.H' Amongst the most significant fragments are the intense [M-11' peaks from N-methylacridones due to the comparatively stable iminium ions (133); and the [M-151' fragments from pyrano[2,3-c] acridones which are favoured because of the formation of pyrylium ions (134).The fragmentation pathways of 2- and 4- prenylacridones were also elucidated. NATURAL PRODUCT REPORTS 1991 o...H\ o..+ko 0 = iii OH R i OMe I OMe HO,& OMe H Me k (135) (138) R = H (139) R = CHZCH=CMez Reagents i ZnCl, n-BuOH reflux; ii MeI K,CO, acetone reflux; iii CH,N, Et,O-MeOH r.t.; iv Me,C(OH)CH = CH, BF;Et,O dioxan r.t. or reflux Scheme 11 Atalaphylline (137) Reagents i N-methylaniline NEt, 90 "C,then 240 "C; ii PPA heat Scheme 12 3.3 Synthesis A short but conventional synthesis of l-hydroxy-3-methoxy-N- methylacridone (1 35) involves the zinc chloride-induced con- densation of anthranilic acid with phloroglucinol followed by selective methylation of the 3-hydroxy and N-H groups (Scheme 1l).82 1-Hydroxy-3,5-dimethoxy-N-methylacridone (1 36) was prepared similarly during a projected synthesis of the prenylated acridone alkaloid atalaphylline (1 37).83In attempts to prenylate (136) at room temperature with 2-methyl-3-buten- 2-01 and boron trifluoride etherate only the borondifluoro chelate (138) was isolated.At reflux in dioxan prenylation occurred at the 2-position7 but again a boron chelate of the desired product (139) was formed. A new acridone synthesiss4 makes use of chloroalkyl-idenemalonates like (140) readily accessible from acyl-malonates. Reaction of (140) itself with N-methylaniline (Scheme 12) gave the substituted malonate (141) thermolysis of which led to formation of the anthranilate (142) in 56% yield.Cyclization to the alkaloid I -hydroxy-N-methylacridone (131) was effected in 70% yield by heating (142) in poly- phosphoric acid. This method would seem to have potential for the synthesis of other 1-hydroxy-9-acridones. NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL 0 OMe 0 OMe CI H2N / OMe OMe OMe OMe I H H CHO Me CHO 64% iiv COCH3 Hallacridone (143) ( 144) Reagents i Cu K,CO, DMF 80 "C; ii POCl, DMF r.t.; iii MeI Ag,O r.t.; iv BCl, CH,Cl, r.t. 72 h; v ClCH,COCH, K,CO, acetone reflux Scheme 13 0 OMe qMe \ Acronycine (1 19) /70% \ qL&MeH0'. Br Me II ____)35% iv ii 14% (7y$&Me HO ( 145) oy&Me HO" I OH OH (146) Reagents i NBS THF-H,O 1 1,0 "C to 20 "C; ii Bu,SnH AIBN toluene reflux; iii OsO,; iv N,N'-thiocarbonyldiimidazole,2-butanone reflux Scheme 14 Last year's report cf.ref. 37(1) made passing mention of a acronycine (1 19) with N-bromosuccinimide in aqueous medium synthesis carried out to distinguish between possible alternative followed by debromination with tributyltin hydride. The 2-structures for hallacridone (143).s5 The synthesis (Scheme 13) hydroxy isomer (146) was prepared by benzylic reduction of the began with an Ullman coupling of o-chlorobenzoic acid and 1,2-diol formed by reaction of acronycine with osmium 3,5-dimethoxyaniline and exploited a Darzens condensation tetroxide (Scheme 14). on intermediate (144) for the construction of the fused furan ring of the alkaloid.The overall yield was 1.5%. Plausible biosynthetic relationships between hallacridone and other References furoacridones isolated from Ruta gravedens were also presented in this publication. 1 M. F. das G. F. da Silva 0.R. Gottlieb and F. Ehrendorfer Plant Syst. Evol. 1988 161 97. Efforts to Prepare water-so1ub1eacronYcine derivatives that 2 E. Dagne A. Yenesew p. G. Waterman and A. 1. Gray Biochpm. may act as acronycine prodrugs have resulted in the synthesis Syst. Ecol. 1988 16 179. of both hydroxydihydroacronycine regioisomers (1 45) and 3 M. Sainsbury in 'Rodd's Chemistry of Carbon Compounds' ed. (146) from the parent alkaloid.86 The 1-hydroxy compound M. F. Ansell Elsevier Amsterdam 1987 Supplement to the (145) was made in a two-step procedure by treatment of second edition Vol.IV Part G pp. 209-244. 4 V. Kumar V. Karunaratne M. R. Meegalle and K. Sanath Phytochemistry 1989 28 1278. M. Norte M. L. Rodriguez J. J. Fernandez L. Eguren andD. M. Estrada Tetrahedron 1988 44 4973. 6 B. T. Ngadjui J. F. Ayafor and B. L. Sondengam Bull. Chem. SOC. Ethiop. 1988 2 21 (Chem. Abstr. 1989 110 209293). 7 B. T. Ngadjui J. F. Ayafor B. L. Sondengam and J. D. Connolly Phytochemistry 1989 28 1517. 8 P. C. Vieira A. R. Lazaro J. B. Fernandes and M. F. dasG. F. da Silva Biochem. Syst. Ecol. 1988 16 541. 9 Y. Gunawardana G. A. Cordell N. Ruagrungsi S. Chomya and P. Tantivatana J. Sci. Soc. Thailand 1987 13 107 (Chem. Abstr. 1988 109 190621). T.Sugimoto T. Miyase M. Kuroyanagi and A. Ueno Chem. Pharm. Bull. 1988 36 4453. 11 S. K. P. Sinha and P. Kumar Indian J. Chem. Sect. B 1988 27 460. 12 I. A. Bessonova and S. Y. Yunusov Khim. Prir. Soedin. 1989 23 (Chem. Abstr. 1989 111,74797). 13 B. Tashkhodzhaev S. V. Lindeman I. A. Bessonova D. M. Razakova E. N. Tsapkina and Y. T. Struchkov Khim. Prir. Soedin. 1988 838 (Chem. Abstr. 1989 111 4246). 14 K. A. Rasulova I. A. Bessonova M. R. Yagudaev and S. Y. Yunusov Khim. Prir. Soedin. 1988 94 (Chem. Abstr. 1988 109 5 1 698). K. A. Rasulova I. A. Bessonova M. R. Yagudaev and S. Y. Yunusov Khim. Prir. Soedin. 1987 876 (Chem. Abstr. 1988 109 70 326). 16 I. A. Bessonova D. Kurbanov and S. Y. Yunusov Khim. Prir. Soedin. 1989 46 (Chem.Abstr. 1989 111 54177). 17 M. A. Abd-El-Kawy E. A. El-Kashoury A. M. El-Fishawy A H. Atta and F. M. Soliman Egypt. J. Pharm. Sci. 1989 30 299 (Chem. Abstr. 1990 112 95524). 18 J. R. Pfister J. Nut. Prod. 1988 51 969. 19 T.-T. Jong and T.-S. Wu Phytochemistry 1989 28 245. F. Imai K. Itoh N. Kishibuchi T. Kinoshita and U. Sankawa Chem. Pharm. Bull. 1989 37 119. 21 R. P. Hodge C. M. Harris andT. M. Harris J. Nut. Prod. 1988 51 66. 22 G. Petit-Paly M. Montagu C. Merienne J. D. Ambrose M. Rideau C. Viel and J.-C. Chenieux Planta Med. 1989 55 209. 23 A. Ulubelen H. Guner and M. Cetindag Planta Med. 1988 54 551. 24 S. Mitaku and J. Pusset Plant. Med. Phytother. 1988 22 83. H. Augustiniak K. Gerth G. Hoefle H. Irschik R. Jansen B.Kunze H. Reichenbach H. Steinmetz and W. Trowitzch- Kienast Ger. OfSen. DE 3520229 11 Dec 1986 (Chem. Abstr. 1989 110 73858). 26 S. Breiding-Mack and A. Zeeck J. Antibiot. 1987 40,953. 27 B. T. Ngadjui J. F. Ayafor and L. B. Sondengam Ann. Fac. Sc. Chim. 1988 2 71. 28 Y. Lu S. Jin and Q. Xing Beijing Daxue Xuebao Ziran Kexueban 1988 24 245 (Chem. Abstr. 1988 109 70400). 29 C.S. Yook C. M. Kim and E. T. Shin Saengyak Hakhoechi 1987 18 180 (Chem. Abstr. 1988 108 81927). J. Simeray J. P. Chaumont J. Pusset F. Bevalot and J. Vaquette Planta Med. 1988 54 189. 31 M. Montagu G. Petit-Paly P. Levillain A. Baumert D. Groger J.-C. Chenieux and M. Rideau Pharmazie 1989 44,342. 32 J. Tremouillaux-Guiller H. Kojda F. Andreu J. Creche J.-C.Chenieux and M. Rideau Plant Cell Rep. 1988 7 456. 33 M. D. Real and J. Ferre Insect Biochem. 1989 19 111. 34 M. F. Grundon in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1977 7 81 ; (b) 1976 6 104; (c) 1978 8 79; (d) 1977 7 88; (e) 1982 12 90; (f)1976 6 108. T. Kametani and H. Kasai in ‘Studies in Natural Products Chemistry’ ed. Atta-ur-Rahman Elsevier Amsterdam 1989 3 pp. 385-398. 36 I. Thomsen and K. B. G. Torssell Actu Chem. Scand. Sect. B 1988 42 309. 37 M. F. Grundon Nut. Prod. Rep. (a) 1984,1 195; (6) 1988,5,295; (c) 1990,7 133; (d) 1987,4,227; (e) 1988,5293;(f)1988,5296; (g) 1988,5,298; (h) 1990,7 134; (i) 1985,2 198; (j)1988,5 300; (k) 1988 5 302; (I) 1990 7 137.38 J. Reisch and G. M. K. B. Gunaherath Monatsh. 1988 119 1169. 39 J. Elguero and B. Shimizu An. Quim. Ser. C 1988 84 198. P. G. Waterman Bull. Chem. Soc. Ethiop. 1988 2 87 (Chem. Abstr. 1989 111 20852). NATURAL PRODUCT REPORTS 1991 41 G. Petit-Paly M. Montagu C. Viel M. Rideau and J.-C. Chhieux Plant Cell Rep. 1987 6 309. 42 J. Reisch and M. Iding Monatsh. 1989 120 363. 43 J. Reisch R. A. Salehi-Artimani A. Bathe and M. Miiller Monatsh. 1988 119 781. 44 P. Bravo G. Resnati F. Viani and G. Cavicchio Gazz. Chim. Ital. 1988 118 507. 45 N. Shobana P. Yeshoda and P. Shanmugam Tetrahedron 1989 45 757. 46 M. P. Yagudaev and I. A. Bessonova Khim. Prir. Soedin. 1989 25 (Chem. Abstr. 1989 111 233302). 47 J. Banerji A. K. Das N.Ghoshal and B. Das Indian J. Chem. Sect. B 1988 27 594. 48 T.-P. Lin B. Shieh and S.-C. Kuo J. Nut. Prod. 1987 50 631. 49 P. Rajamanickam and P. Shanmugam Indian J. Chem. Sect. B 1987 26 910. 50 J. L. Gaston and M. F. Grundon J. Chem. Soc. Perkin Trans. 1 1989 905. 51 H. Paulini R. Waibel and 0.Schimmer Mutat. Res. 1989 227 179. 52 F. Haefele and 0.Schimmer Mutugenesis 1988 3 349. 53 I. A. Bessonova and S. Y. Yunusov Khim. Prir. Soedin. 1989 4 (Chem. Abstr. 1989 110 189344). 54 B. T. Ngadjui J. F. Ayafor S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch J. Nut. Prod. 1989 52 300. 55 D. M. Razakova 1. A. Bessonova and S.Y. Yunusov Khim. Prir. Soedin. 1989 51 (Chem. Abstr. 1989 111,233303). 56 B. Sener and F. Ergun Gazi Univ.Eczacilik Fak. Derg. 1988 5 33 (Chem. Abstr. 1989 110 111673). 57 R. Poi and N. Adityachaudhury J. Indian Chem. Soc. 1988 65 814. 58 L. S. R. Arambewela C. K. Ratnayake J. S. Jayasekera and K. T. D. de Silva Fitoterapia 1988 59 151. 59 K. Pundarikakshudu and G. C. Bhavsar Int. J. Crude Drug Res. 1988 26 88. 60 S. M. Jain and C. K. Atal Indian J. Chem. Sect. B 1987,26 585. 61 M. V. Telezhenetskaya B. Tashkhodzhaev M. R. Yagudaev B. T. Ibragimov and S. Y. Yunusov Khim. Prir. Soedin. 1989,18 (Chem. Abstr. 1989 111,233 319). 62 J. Reisch and G. M. K. B. Gunaherath J. Nut. Prod. 1989,52,404. 63 K. R. Nuriddinov K. Sargazakov and S. Abdullaev Khim. Prir. Soedin. 1989 293 (Chem. Abstr. 1990 112 77672). 64 H. Takeuchi and S. Eguchi Tetrahedron Lett.1989 30 3313. 65 S. Eguchi and H. Takeuchi J. Chem. Soc. Chem. Commun. 1989 602. 66 Y. Uozumi N. Kawasaki E. Mori M. Mori and M. Shibasaki J. Am. Chem. Soc. 1989 111 3725. 67 D. Groger Pharmazie 1988 43 815. 68 M. Sainsbury in ‘Rodd’s Chemistry of Carbon Compounds’ ed. M. F. Ansell Elsevier Amsterdam 1987 Supplement to the second edition Vol. TV Part G pp. 245-258. 69 S. Funayama and G. A. Cordell Heterocycles 1989 29 815. 70 H. Paulini and 0.Schimmer Mutagenesis 1989 4 45. 71 N. Yamamoto H. Furukawa Y. Ito S. Yoshida K. Maeno and Y. Nishiyama Antiviral Res. 1989 12 21. 72 R. T. Dorr J. D. Liddil D. D. von Hoff M. Soble and C. K. Osborne Cancer Res. 1989 49 340. 73 H. Fujioka Y. Nishiyama H. Furukawa and N. Kumada Antimicrob.Agents Chemother. 1989 33 6. 74 G. Gu Yaoxue Xuebao 1987 22 886 (Chem. Abstr. 1988 108 183 612). 75 M. Ju-ichi M. Inoue I. Kajiura M. Omura C. Ito and H. Furukawa Chem. Pharm. Bull. 1988 36 3202. 76 T.-S. Wu Phytochemistry 1988 27 3717. 77 T.-S. Wu Phytochemistry 1987 26 3094. 78 A. Ulubelen and H. Guner J. Nut. Prod. 1988 51 1012. 79 M. Brum-Bousquet S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch Planta Med. 1988 54 470. 80 S. K. Talapatra B. Karmacharya S. C.De and B. Talapatra Indian J. Chem. Sect. B 1989 28 356. 81 S.-T. Lin and T.-S. Wu J. Chinese Chem. Soc. 1989 36 335. 82 M. H. Bahar and B. K. Sabata Indian J. Chem. Sect. B 1987,26 782. 83 M. H. Bahar and B. K. Sabata Indian J. Chem. Sect. B 1987,26 863.84 0.E. H. Hormi J. Org. Chem. 1988 53 880. 85 J. Reisch and G. M. K. B. Gunaherath J. Chem. Soc. Perkin Trans. 2 1989 1047. 86 S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch Planta Med. 1988 54 24.

ISSN:0265-0568    

DOI:10.1039/NP9910800053

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Terpenoid Glycosides H. Pfander and H. Stoll Institute of Organic Chemistry University of Berne Berne Switzerland 1 Introduction 2 Mono terpenes 2.1 Acyclic Monoterpenes 2.2 Cyclic Monoterpenes 2.3 Iridoides 3 Sesquiterpenes 3.1 Acyclic Sesquiterpenes 3.2 Bisabolanes 3.3 Germacranes 3.4 Elemanes 3.5 Eudesmanes 3.6 Guaianes 3.7 Caryophyllenes 3.8 Iphionanes 3.9 Alloaromadendranes 3.10 Cubebanes 3.1 1 Miscellaneous 4 Diterpenes 4.1 Acyclic Diterpenes 4.2 Ladbane Diterpenes 4.3 Clerodane Diterpenes 4.4Serrulatane Diterpenes 4.5 Kaurane Diterpenes 4.6 Nordi terpenes 5 Triterpenes 5.1 Dammaranes 5.2 Baccharanes 5.3 Lanostanes 5.4 Cucur bi tanes 5.5 Cycloartanes 5.6 Lupanes 5.7 Oleananes 5.8 Ursanes 5.9 Biological Activity 5.10 Chemical Reactions 6 Glycosidation 7 Conclusions 8 References 1 Introduction Terpene glycosides are widely distributed in nature and comprise a great variety of different structures due to the individual aglycones or carbohydrates.An immense number of papers have been published in the last few years describing the isolation and characterization of terpene glycosides. This review covers the chemistry published during the period 1987-1988 and is based on a computer search of Chemical Abstracts Service (CAS). It is not comprehensive since limitations of space have meant for example that part of the patent literature has not been included.The approach that we have adopted is based on the chemistry of the individual compounds and not on the biological activity. Therefore the review is divided according to the structure of the aglycone. Publications in which the isolation of a known compound from a new organism is described and tentative structure assign- ments were not included. On the other hand glycosylesters i.e. compounds in which the carbohydrate is bound through an ester to the aglycone and which in a strict sense are not glycosides have been included. 69 2 Monoterpenes In 1987 two reviews on monoterpene glycosides appeared. In both articles the literature is covered until 1986 and the iridoid and secoiridoid glycosides were not included.In the article of Stahl-Biskupl (36 refs.) 22 monoterpene glycosides mainly glucosides from 25 different plants are described. It is noted that geraniol nerol linalol and a-terpineol are the mono- terpenoids most often detected. Glycosides with uncommon terpene structures as aglycones are also described. The analysis of monoterpene glycosides and especially their functions in the plants (biosynthesis of terpenes as reactants or in essential oil accumulation as transport derivatives of free monoterpenes) are discussed. In the review of Mulkens' (57 refs.) the glycosylesters of monoterpenoid aglycones were also included. From 28 plants 25 different aglycones are listed. In this article particular attention is paid to isolation methods and the r6le of the monoterpene glycosides.It is pointed out that in spite of the widespread occurrence and great variety in the structure of the aglycones the monoterpene glycosides are not of great interest for the taxonomy of the plants. Special mention is made of the importance of these compounds in oenology. 2.1 Acyclic Monoterpenes From the roots of Sambucus ebulus L. which are used in traditional medicine and contain a variety of iridoid glycosides a novel open-chain rnonoterpene glycoside was isolated. The compound was identified as the P-D-glucopyranoside of 8-hydroxy-2,6-dimethyl-oct-2-enoic acid (1). From the whole plants of Polemoniurn viscosum which exudes a very pungent skunk-like scent two new monoterpene glycosides were isolated which contain characteristically diacyl derivatives of p-D-xylopyranose as carbohydrate residue and geraniol(2) and 2,3- dihydrogeraniol (3) as agly~ones.~ AOR (2) R = 2-0-ac-3-0-(2'-methyIbutyl)-~-D-xylp AnArOR (3) R = 2-0-ac-3-0-(2-methylbutyI)-0-D-xylp R (4) R = CH2-0-13-D-glcp(6~1)P-D-apif (5) R = CH2-O-P-D-glcp(6-l)cr-L-rhaf HO (9) (10) 0’ Q 4) 2.2 Cyclic Monoterpenes From the roots of Aster tataricus L.f.(Compositae) two glycosides which contain L-endo-camphanol as aglycone were i~olated.~ Both compounds contain a disaccharide with D-glucose. Shionoside A (4) is the P-D-apiofuranosyl-( 1 +~)-P-D-glucopyranoside and shionoside B (5) the a-L-rhamno-pyranosyl-( 1 -+ 6)-P-~-glucopyranoside.Two glucosides with enantiomeric aglycones have been isolated6 from Berchemia racemosa Sieb. et Zucc. and characterized as (+)-(6) and (-)-angelicoidenol-2-0-~-~-glucopyranoside A preliminary (7). biological screening of root extracts of Coleus forskohlii Briq. (syn. C. barbatus) indicated hypotensive and spasmolytic activities.’ From this extract a new monoterpene glycoside was isolated and identified as cuminyl-0-P-glucopyranosyl-( 1 +2)-P-D-galactopyranoside (8). 2.3 Iridoides From the twigs of Eranthemum pulchellum Andrews (Acan- thaceae) a new iridoid glucoside eranthemoside (9) was isolated and its structure established by spectroscopic means.* The compound appeared to be rather unstable.A novel 3-0-P-~-glucopyranosyl-3,4-dihydroiridoid, verbraside (lo) which is a y-lactone was isolated from a complex iridoid-containing NATURAL PRODUCT REPORTS 1991 (‘‘R (1 1) R = /3-D-ribohexos-3-ulose (13) (12) R = p-D-gIcp( 1-4)P-D-allop 16) fractiong of Verbena brasiliensis Vell. Noteworthy is the unusually facile cleavage of the glycosidic bond during hydrolysis and methanolysis under basic conditions. Numerous iridoid glycosides have been isolated from several species within the genus Penstemon. Besides a known iridoid glycoside two new ester iridoids of the valeriana type have been isolated from dried leaves of P. confertus.1° These two compounds dihydroserruloside (1 1) and confertoside (12) contain the same aglycone and the very rare carbohydrate moieties ~-~-~bohexos-3-ulose (1 1) and P-D-allopyranosyl- (1 -+ 4)-P-~-glucopyranose(1 2).A new compound of the same type penstebioside (1 3) has also been isolated from dried leaves of P. richardsonii and was identified as penstemide-aglucone- 11-0-P-cellobioside.l1 From P. hirsutus patrinalloside (patrino- side-aglucone- 1 1-0-P-D-allopyranoside) (14) along with its aglycone were isolated.12 Also from Sambucus ebulus L. novel valeriana type ester iridoid glycosides have been i~olated.~ 6’-0-apiosylebuloside (15) is the first glycoside containing apiose and 7,7-0-dihydroebuloside (16) represents a possible bio- genetic equivalent of loganine in the series of iridoids of the Valerianaceae.Ajuga decumbens is widely distributed in East Asia and has been used as a folk remedy for sore throats and alleviating fever. From an extract of the whole dried plant four new iridoid glucoside p-coumaroyl esters decumbesides A-D NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL OH OH OH OR (17) R = 2’-O-trans-p-coumaroyl-~-D-g~cp (19) R = ~‘-~-trans-p-coumaroy~-~-D-g~cp (211 (18) R = 2’-O-cis-p-coumaroyl-~-D-glcp (20) R = 3’-O-cis-p-coumaroy~-~-D-g~cp RO-6OH (23) R’ = P-D-glcp R2 = H (25) R = OH (24) R’ = H R2 = P-D-glcp (26) R = H OH (27) (1 7-20) have been isolated. l3 Decumbeside A (1 7) was identified as galiridoside 2’-trans-p-coumaroyl ester decum- beside B (18) as the cis-isomer decumbeside C (19) as the 3’-trans-p-coumaroyl ester of ELacetylharpagide and decumbeside D (20) as the cis-isomer.Kickxia spuria (L.) Durmort. (Scrophulariaceae) is a small herbal species that contains a complicated mixture of iridoid glucosides. The major com- ponent kickxioside (2 l) was isolated and identified as the (-)-2,6-dimethyl-6(R)-hydroxyl-2-trans-2,7-octadienoic acid (menthiafolic acid) ester of antirrhinoside. l4 In the course of a comparative study of two chemotypes of Gelsemium sempervirens (L.) J. St. Hil. five new iridoid glucosides have been is01ated.l~ Their structures were de-termined as gelsemide 7-O-P-~-glucopyranoside (22) gelsemiol 1-glucoside (23) and gelsemiol 3-glucoside (24) ((23) and (24) were inseparable even as acetates and occur in a ratio of ca.2 :l) 9-hydroxysemperoside (25) and semperoside (26). The iridoids (22) and (25) both carry a hydroxyl group at C-9 and the compounds (25) and (26) a glucopyranosyloxy moiety at the 3-position. Neither of these features have previously been encountered among the approximately 300 iridoids reported so far. (29) (30)R’ =CH3 R2= H (31) R’ = H R2 = CH3 C hec kerspo t butterflies (Euphy dry as anicia) utilize two species of Scrophulariaceae as host plants Castilleja integra Gray and Besseya plantaginea (James) Rydb.. From C. integra eight iridoid glucosides were isolated including the novel compound 6-P-hydroxy-adoxoside (27). The new 6-isovanill- ylcatalpol (28) was found in B. plantaginea and B. a1pina.l6 From Barleria lupulina Lindl. (Acanthaceae) 6-O-acetyl-shanzhiside methyl ester (29) was isolated and its structure confirmed by a single-crystal X-ray determination.l7 It was found that this compound along with shanzhiside methyl ester and its 8-O-acetyl- and 6,8-O-diacetyl derivatives which have been isolated previously from the same plant inhibit the growth of wheat embryos. Relatively few iridoid diglucosides have been reported in the literature. Two new diglucosides have been isolated from the aerial parts of Campsidium valdivianum (Phil.) Skottsb. during the systematic investigation of iridoid components in Chilean flora.18 They were identified as stansiosigenin 1 -0-P-gentiobioside (30) and plantarenalosigenin 1 -0-P-gentiobioside (31). During the investigation of plants of the genus Verbascum of the Armenian flora different new iridoid glycosides have been NATURAL PRODUCT REPORTS 1991 2‘ HoH 0-0-0-glcp (32) R = 3”-O-p-coumaroyl-a-L-rhap (34) R = 3”-O-p-coumaroyl-a-~-rhap (33) R = 2”,3“-di-O-acyl (ac,p-methox y-trans-cinnamoyl) -a-L-rhap HO* 0-4’-p-cou maroy I-0-D-gkp (36) R = H (37) R=CHB (35) CH -0-2’-O-ac-P-0-glcp HI R &+ ..HYo HoH 2c OCOCH 2CH (CH3) 2 (44) R = H (45) R =OH isolated. In the epigeal part of V.laxum Filar. et Jav. 6-0-(3”- 0-p-coumaroyl-a-L-rhamnopyranosy1)aucubin (32) was identi- I -CH ,OH (41) R’=H R2=OH (42) R’ =OH R2 = H acid.22 This is the first report of iridoid glucosides with the 4’- oxygen of the glucose moiety esterified.Besides three known glucosides a new compound gibboside (38) was isolated23 from the roots of Patrinia gibbosa Maxim. X-Ray crystallographic studies confirmed the structure of this compound which is the first example of an iridoid glucoside to have a D-gluco-pyranosyloxy group at the C-7 position of the iridoid. Avicennioside (39) a C,-iridoid glucoside and 7-cinnamoyl-8- epiloganic acid (40) which is in the plant accumulated as salt were isolated from the leaves of Avicennia oficinalis L..24 From the leaves of Syringa reticulata (Blume) Hara two new iridoid glucosides syringopicroside B (41) and syringopicroside C (42) have been isolated along with their agly~ones.~~ A minor iridoidal component 5-deoxypulchelloside I (43) was isolated besides known iridoid glucosides from the leaves of Citha- rexylum fructicosum L.f.subserratum (Sw.) Mold. (Verbenaceae).26 Viburnum species are a rich source of iridoid compounds and are used in folk and official medicine as uterotonic chemostatic sedative and diuretic drugs. From the dried bark of V.Lantana two new iridoids with an isovaleroyl group at C-1 and a carbohydrate at C-1 1 were isolated and their structures characterized as 2’-O-acetyl-dihydropenstemide (44) and 2’-O-acetylpatrinoside (45).2i fied and from the roots 6-0-(2”,3”-di-0-acyl[acetyl,p-methoxy-trans-cinnamoyll-rhamnopyranosy1)aucubin (33) was iso-lated.’ A positional isomer of saccatoside with the structure 6- 0-(3”-O-p-coumaroyl-a-~-rhamnopyranosyl)catalpol (34) was identified in an extract of the epigeal parts of V.sinutavum L.20 From Swertia japonica Makino (Gentianaceae) a new com- pound senburiside 11 was isolated and identified as 7-epi- loganic acid (35) esterified with two m-hydroxy-benzoyl residues.21 From flowers and leaves of Gentiana pedicellata (Gentianaceae) 4’-p-coumaroyl loganic acid (36) and 4’-p- coumaroyl loganin (37) have been isolated along with loganic NATURAL PRODUCT REPORTS 1991-H.PFANDER AND H. STOLL (46) (47) R = 2”,4”-di-0-ac-3”-0-p-methoxy-trans-cinnamoyI-a-L-rhap (491 (48) R = 2r’-0-ac-3’’,4r’-di-0-trans-cinnamoy I-a-L-rhap \ I (50) CH300C oAo*oH Sesamum angolense Welw. (Pedaliaceae) is a plant which grows in tropical Africa and which is of interest due to its hemostatic properties.A new iridoid glucoside sesamoside (46) was isolated from the root bark of this plant and was identified as methyl antirrhinoside-4-carbo~ylate.~~ It is the first example of an iridoid glucoside containing an epoxide function at C-7 and C-8 together with a carbomethoxy group at C-4. Various derivatives of rhamnopyranosylcatalpol have been reported earlier. From Scrophularia scopolii (Hoppe ex) Pers. var. scopolii (Scrophulariaceae) two highly acylated com-pounds scropolioside A (47) and B (48) have been isolated and R’ (51) R’ = H R2=CH3 OH (52)R’=OH R2=OH (53) R’ = OH R2 = CH2-CHzGOH stereochemistry deduced as 4R 5S 7R 8R and 9S based on NMR spectroscopy and chemical conversion^.^^ Besides the iridoid glycosides mentioned above a series of new secoiridoides have been isolated from various sources.From Nepeta cataria nepetariaside (50) was isolated and its structure elucidated by chemical spectral and X-ray crystallo- graphic analysis. 31 The aglycone possesses an opened di hydro- pyrone ring and it is noteworthy that the configurations at C-5 and C-9 of (50) are different from those of other iridoids from the same plant. Three new secoiridoid glycosides isoligustroside (5l) isooleuropein (52) and neooleuropein (53) were isolated from the leaves of Syringa vulgaris Lir~n..~~ Their structures were elucidated mainly on the basis of 13C NMR spectra. Compound (5 1) consists of two identical oleoside aglycones three glucose units and a p-hydroxyphenethyl residue whereas (52) has one oleoside and two glucose units with a p-hydroxyphenethyl residue.The crude drug ligustri fructus is the fruit of Ligustrum japonicum Thunb. (Oleaceae) and has been used as a stamina1 tonic in Oriental medicine. Along with already known compounds two new secoiridoid glucosides with complex structures oleonuezhenide (54) and iso-nuezhenide (59 have been isolated from the fruits of this plant .33 were characterized as 6-0-(2”,4”-di-0-acetyl-3”-0-p-methoxy-Along with various well known secoiridoid glucosides which trans-cinnamoy1)-a-L-rhamnopyranosylcatalpol(47) and 6-0-(2’I-0-acet y 1-3/’ ,4’I -di-0-trans-cin n a m oy 1)-01-L-rhamno-pyranosyl-catalpol (48).29 These are the first examples of iridoid diglycosides having triacyl residues.From the aerial part of Nepeta cataria L. (Lamiaceae) a plant indigenous to Europe a new compound nepetaside (49) was isolated and the have recently been isolated from olive (Olea europaea) the new compound oleuroside (56) was isolated and its structure elucidated as secoxyloganin 3,4-dihydroxyphenethyl ester.34 The occurrence of this compound provides supporting evidence for the intermediacy of secologanin in the biosynthetic pathways of oleoside type secoiridoids. NATURAL PRODUCT REPORTS 1991 (57) R = H (59) (60) (58) R =OH o-0 (62) COOCH3 $o O-p-D (64) Two new secoiridoid glucosides syringalactone A (57)and B (58) were isolated from the leaves of Syringa vulgaris Linn.35 From the hot water extract of aerial parts of Lonicera japonica Thunb.(Caprifoliaceae) epi-vogeloside (59) was isolated along with the known secologanin dimethylacetal (60) -the first time it has been isolated from a natural (63) From Jasminum sambac (L.) Ait. sambacolignoside (6 l) a new lignan-secoiridoid glucoside has been isolated and elucidated as 7-0-[( +)-1-hydroxypinoresinol-~-~-glucoside-(7-6”)]-oleoside 1 l-methyl ester. This is the first example of a lignan linked secoiridoid glu~oside.~’ Jasminum sambac is an oleaceous shrub indigenous to Southeastern Asia India and Arabia and its flower is used to add fragrance to Jasmine tea. The isolation of bisiridoids tri-and tetrameric iridoid glucosides has also been reported. From Argylia radiata several iridoid glucosides have been isolated including two bisiridoids radiatoside B (62) and radiatoside C (63).38Their structures are based on the junction of a catalpol unit esterified at the 6 position and of a carboxyl iridoid glucoside.A new bitter trimeric-iridoid diglucoside named pulosarioside (64) was isolated from an Indonesian folk-medicine the air- dried bark of Alyxia reinwardtii BL. (Apocyanaceae). It has been used for various intestinal diseases and diarrhea.39 The structural elucidation was based mainly on extensive NMR studies. From the fresh leaves of Jasminum sambac (L.) Ait. seven new oligomeric iridoid glucosides sambacosides A-G have been isolated. The structural elucidation of three of these 75 NATURAL PRODUCT REPORTS 1991-H.PFANDER AND H. STOLL P 0'I I o=c KCH3 II 0 0 ' C=O COOCH3 I CH3%0 /o 0-0-D-gICP A O-0-D -9 I Cp CH20R (68) R = fl-D-glcp(2-+1 )a-L-rhap f3m7j0-D-xylp compounds sambacosides A (65) E (66) and F (67) has been reported.40 This represents the first isolation of tetrameric iridoid glycosides. It is well known that iridoid and secoiridoid glucosides show a great variety of biological activities such as hypotensive sedative antipyretia antitussive and tonic activities. Different biological studies have been published with insect~~l-~~ and with mice where the antitumor activity of iridoid derivative^,^^ the chloretic activitie~,~' and the effects on sex- and learning behaviour in chronic stressed mice were studied.48 A HPLC method for the separation and quantitative determination of secoiridoid glucosides in fruits extracts from Ligustrum vu/gare has been describedg9 and a comparison of circular and linear over-pressure layer chromatography (QPLC) for iridoid glycosides reported.50 In various other publications HPLC methods for the separation isolation and quantitative determination of iridoid and secoiridoid glycosides has been described.51-54 * 0-0-D-glcp(6-+ 1)a-L-rhap (69) f237) a-l-rhap(4-l)a-L-rhap 3 Sesquiterpenes 3.1 Acyclic Sesquiterpenes During studies on surface active oiigosaccharides from Supindus species a new sesquiterpene oligosaccharide trifolioside TI (68) was isolated from the pericarps of S.trifoliutus L. (Sapindaceae).55 The aglycone was identified as 15-hydroxy- farnesol- its hydroxyl groups glycosylated with a trisaccharide containing D-glucose L-rhamnose and D-xylose. The leaves of Eriobotryu japonica (Thunb.) Lindle (Rosaceae) are well known as components in Chinese and Japanese folk medicine (antitussive and anti-inflammatory agent for chronic bronchitis diuretic digestive and antipyretic agent). It is known that nerolidol accounts for up to 74% of the essential oil of the leaves. A glycoside of nerolidol loquatifolin A was isolated from the same source56 and the structure was established as a-L-rhamnopyranosyl-( 1 +4)-a-rhamno-pyranosyl( 1 -+2)-[a-~-rhamnopyranosyl(1 -+6)]-p-~-gluco-pyranosyl- nerolidol (69). NATURAL PRODUCT REPORTS 1991 0-6 ’-0-ac-fl-D-gIcp (70) (74) R’ = H R2 = glcp R3 = H (75) R = P-D-fUCp (76) R = 2’-O-ang-3’-O-ac-P-D-fucp (77) R = 2’-U-ac-3’-0-[2-rnethylbutyryl]-0-D-fucp (78) R = 2’,3’-di-U-ang-fl-D-fucp (79) R = Z’-O-ang-P-D-fucp ‘0 (80) I (83) (84) R = 0-D-arap (85)R = 3’,4’-di-O-ac-O-D-arap From the aerial parts of Gailfardia coahuifensis an acetylated glucoside of 9-hydroxy-nerolidol gaillardoside (70) was i~olated.~’ The stereochemistry at C-3 and C-9 were not assigned.Certain species of the genus Gailfardia show inhibitory activity against certain human carcinoma as described earlier. A series of new acyclic sesquiterpene glucosides were isolated from the aerial parts of Epimedium grandzjlorum Morr.var. thunbergianum (Miq.) Nakai which has been used since ancient times as a tonic in China and Japan.5s These compounds icariside C (71) C (72) C (73) and C (74) all possess the carbon skeleton of 10,ll-dihydroxy-nerolidol. Compounds (71) (72) and (73) differ in the site of glucosidation having the (S)-configuration at C-10 whereas (74) is the epimer of (71) at C-10. The stereochemistry at C-3 was not established. b-(Z’-O-ang) -0-D-fucp 3.2 Bisabolanes In a reinvestigation of different species of Osteospermurn a-bisabolol-P-D-fucopyranoside (79 and the esters thereof (76) (77) and (78) were isolated from the aerial parts of 0. microcarpum subsp. septentrionafe T. N~rl.~’ A similar com- pound (79) was also identified in Gibbaria ilicifofia L.3.3 Germacranes A variety of new sesquiterpene glycosides have been isolated from Sonchus oferaceus L.60(see also 3.5). Two new glucosides sonchuside A (80) and B (8 l) were identified as germacranolide- type compounds. Compound (81) possesses compared to (80) an additional p-methoxyphenylacetic acid residue at C-9 with P-stereochemistry. Besides other sesquiterpene glycosides (see 3.5 and 3.9) a germacrane-type fucopyranoside (82) was isolated from extracts of Calendula persica C. Mey.‘l The carbohydrate moiety is esterified at C-2’ position with angelic acid. An interesting new germacrane-type glycoside pittosporato-biraside (83) was isolated from the fresh flowers of Pittosporum tobira Ait.62 The carbohydrate residue was identified through extensive lH and 13CNMR experiments as 3-angeloyloxy-2,6- dideoxy-xylo-4-hexosulopyranose which is additionally bound from C-2 of the carbohydrate through a C-C-bound to the agl ycone.3.4 Elemanes An extract from the aerial parts of Lessingia glanduffera (Asteraceae) yielded nine new sesquiterpene glyco~ides,~~ (see 3.5 and 3.6) two of them with an elemane skeleton and b-D-arabino-pyranose (84) and its 3’,4’-0-diacetyl derivate (85) respectively as the carbohydrate residue. NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL (86) R = H (88) (89) R = H (87) R =OH (90) A5 (91) R =OH (6‘-0-ac-0- D-g lcp) -0 (102) R’ (103) R’ = OH R2 = a-D-arap (104) R’ = H R2 = a-D-arap (105) I?’ = H R2 = 3’,4’-di-U-ac-a-D-arap 3.5 Eudesmanes In various reports a variety of glycosides of a- p-and y-eudesmol and their derivatives with xylose fucose chinovose and arabinose have been described.An extract from the aerial parts of Iphonia scabra (Compositae) gave a complex mixture of sesquiterpene xylopyranosides which could not be separ- ated.64 The ‘H NMR data suggested this was a mixture of 2-0- acetates of xylopyranosides. After peracetylation the mixture (94) R = -2’-O-ang-P-D-fucp (95) R = -2‘-O-ang-P-D-chinop was separated into seven eudesmol a-xylopyranosides with p- eudesmol (86) 3a-hydroxy-p-eudesmol (87) a-(88) and y-eudesmol (89) (inseparable mixture) ;5,6-dehydro-a-eudesmol (90) ;15-hydroxy-y-eudesmo1(91)and carisson (92) as aglycone.Furthermore a secoeudesmane derivative 4,5-dioxo-seco-y- eudesmol-a-xylopyranoside (93) and two compounds with a new skeleton (see 3.8) were identified. Further glycosides of /3-eudesmol have been described in Calendula persica (see 3.3),61 namely the p-~-fucopyranoside-2’-O-angelate (94) and the p-D-chinovopyranoside-2’-O-angelate (95).The latter was character- ized as the diacetate. Lessingia glandulifera is a rich source for sesquiterpene glyc~sides~~ (see 3.4). Besides the two elemanes (84) and (85) 4 eudesmane derivatives a-D-arabinopyranosides of a-eudesmol (96) and p-eudesmol (97) and their 3’,4’-di-O-acetyl derivatives (98) and (99) have been characterized. Also new eudesmanolide- type glucosides have been found in Sonchus oleraceus (see 3.3) such as sonchuside C (100) and D (101).60 From the aerial parts of Bahia absinthifolia var.absinthifolia (Compositae) a new glucoside absinthifolide (1 02) was isolated and its structure determined as 15-0-(6’-acetyl-/3-~-gluco-pyranosyl)-eudesman-4,11(13)-dien-8~, 12-0lide.~~ 3.6 Guaianes From Lessingia gland~lifera~~ (see 3.4 and 3.5) were identified three guaiane-type glycosides 1 1 -O-a-~-arabinopyranosyl-4-hydroxyisobulnesol (lessingioside) (103) 11-0-a-D-arabino-pyranosyl-isobulnesol (104) and 1I -0-a-~-(3’,4’-0-di-acetyl-arabinopyranosy1)-isobulnesol (1 05) ; (104) and (1 05) were identified as an inseparable mixture. A number of guaiane-type lactone glucosides have been isolated from different sources.In various glucosides the carbohydrate residue is esterified with a carboxylic acid as in NATURAL PRODUCT REPORTS 1991 RO 0 (106) R = 3‘-O-(p-hydroxy-phenyl-acetyl)-P-D-glcp RO %-OH -0 (108)R = Z’-O-caffeoyI-P-D-glcp R’q R*HO” 0 0 (110)R’ = 0-p-glcp,R2 = OH (1 11) R’ = H R2 = 0-0-glcp QI I 0-Z‘-O-ang-P-D-glcp (1 15) (106) which is the 3’-0-[p-hydroxyphenyl acetate] of crepi- diaside A and has been isolated from Picris cyanocarpa Boiss. (Compositae).66 The same acid occurs in prenantheside B (107) which was isolated from Prenanthes acerfolia Benth. (Com- p~sitae)~’ together with prenantheside C (108) which contains caffeic acid and prenantheside A (109).During the search for sesquiterpene glycosides with anti- tumour activity in Compositae plants three closely related compounds diaspanoside A (1 lo) B (1 1 l) and C (1 12) have been identified in Diaspananthus unflorus (Sch. Bip.) Kitam..68 From the roots of Lactuca sativa L. (Compositae) lactuside C (113) was isolated along with already known terpene glycosides.69 Besides various triterpene glycosides a new guaiane-type sesquiterpene glucoside cynaroside A (1 14) was isolated from Cynara cardunculus L.’O Roy 0 (107)R = 6’-O-(p-hydroxy-phenyl-acetyl)-P-D-glcp (0-D-glcp-)O 0 -OH (1 17) 3.7 Caryophyllenes A glucoside from an epoxycaryophyllene derivative has been described which is esterified with angelic acid (115) (13- hydroxy-4a 5~-epoxy-caryophyllen-[2’-angeloyl-/?-~-gluco-pyran~side]).~~ 3.8 Iphionanes A new type of carbon skeleton for sesquiterpene glycosides was detected in compounds originating from Iphiona scabrd4 and were named iphionane and isoiphionane.The compounds isolated as peracetates were assigned the structure of the 2‘-0-acetates of 5P,1 1 -dihydroxy-iphionane-4-one-1 1 -0-[a-xylo-pyranoside] (1 16) and 3a 11-dihydroxy-isoiphionane-4-one-11-0-[a-xylopyranoside] (1 17). NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL (1 18) R = 0-D-fUCp (1 19) R = 2‘-O-ac-P-D-fucp (120) R = 2’-O-(2’~me-butanoyl)-@-D-fucp (121) R = 2’-0-(3‘~rne-pent-2’’-enoyI)-P-D-fucp \ \ (1 27) O-P-D-gIC 0-13-D-glcp (130) 3.9 Alloaromadendranes Independently two groups reported the isolation of sesqui-terpene glycosides with the alloaromadendrane skeleton from Calendula arvensis L.(C~mpositae),~~ which in Italian folk medicine is used as an anti-inflammatory and antipyretic remedy and C. persica.61 Arvoside B (118) is 4-0-(p-D-fucopyranosyl)-4-alloaromade~drole,71 and the three other compounds (1 19) (120) (12 1) were bound to be acyl derivatives at the 2’-position of the fucopyranosyl residue. The extracts of C. persicdl afforded 5 glycosides of viridiflorol(l22-126) with either P-D-chinovopyranose or Pa-fucopyranose which are partially esterified with senecio- or 4-methyl-senecio acid. (1 22) R = P-D-fUCp (123) R = 0-D-chinp ( 124) R = 2’-O-mesen-O-D-fucp (125) R = 2’-O-sen-p-D-fucp (126) R = 2’-O-sen-P-D-chinp OH (1 29) 3.10 Cubebanes Again from Calendula arvensis L.a glycoside arvoside A with the very rare 4-epi-cubebol as aglycone and P-D-fucopyranose (127) was identified.72 3.11 Miscellaneous From the aerial parts of Osteospermum rigidum var. elegans (Bol.) Norl. an acetylated derivative of silphiperol-5-ene (I 28) was isolated.5g 4 Diterpenes 4.1 Acyclic Diterpenes A novel acyclic diterpene glycoside capsianside A (1 29) was isolated from the fruits of Capsicum annuum L. var.fasciculatum 1ri~h.l~ Its structural elucidation was based on extensive ‘H and 13C NMR experiments (especially NOE) negative FAB-MS and the identification of the carbohydrates after acid hydrolysis. Furthermore (129) was hydrolyzed with alkali to (129A) and (1 29B) which were identified as 3-O-/3-~-glucopyranosyl-13-hydroxygeranyl-linalol l6-oic acid and 16-hydroxygeranyl-linalol 16-0-ol-~-rhamno-pyranosyl-( 1 +6)-P-~-gluco-pyranosyl-( 1 -+3)-a-~-rhamnopyranoside.4.2 Labdane Diterpenes A new diterpene lactone glucoside phloganthoside was isolated from the leaves of Phlogacanthus thyrsijlorus Nees and its structure established as phlogantho1ide-A- 19-0-,!I- glucopyranoside (1 30).74The aglycone was isolated earlier from NPR 8 NATURAL PRODUCT REPORTS 1991 OH p Cti20-P-cellobiose (131) (132) (133) il i)R OR (134) R = P-D-glCP (137) R = P-D-gICp (139) (135) R = p-D-glcp; C-12 epirner of (134) (138) R = 0-D-gkp; C-8epirner of (137) (136) R = 0-D-glcp; C-8epirner of (135) this plant and identified as 2p 15,19-trihydroxy-ent-labd-8( 17) 13-dien- 16-oic acid lactone.From the dried root bark of Melodinus monogynus a diterpene glycoside medinin (1 3 l) and its aglycone medigenin have been i~olated.'~ The structure of the glycoside was established as the 19-O-P-cellobioside of 16,19-dihydroxy-ent-labd-8( 17) 13-dien- 15-oic lactone. In the course of a chemotaxonomic study of the genus Gutierrezia (Compositae) a diterpene xyloside was isolated from the aerial parts of G. ~phaerocephala.~~ Based on a X-ray investigation the structure of methyl (4R,5R,6S 9R IOR 13S)-6,13-dihydroxy-labd-7,14-dien- 18-oate 6-O-p-~-xyloside (132) was attributed to this compound.The 13C NMR spectra of six recently isolated diterpene glycosides with a labdane skeleton and an aldehydic group at C-4 [e.g. (133)] were analy~ed.'~In contrast to the usual observations the C-4 13CNMR signals appeared as doublets in their Single Frequency Off-resonance Decoupled spectra whereby the magnitude of their separation was 8-10 Hz. The aldehyde group can be in an equatorial or axial position. An explanation of this phenomenon cannot be given but this observation may be useful in the structure elucidation of other compounds of this type. 4.3 Clerodane Diterpenes A series of new furanoid diterpene glycosides isolated from the dried roots of Jateorhizapalmata Miers (= J. columbo Miers; Colombo root; Radix columba used as a tonic and dysentery remedy) were reported independently and almost simul-taneously by two Japanese groups.Yonemitsu et ~1.~' named these compounds palmatoside B-G. Palmatoside B was identified as 4-O-(p-~-glucopyranosyl)chasmanthin(I 34). Compound (1 35) (palmatoside F = 4-O-(p-~-glucopyranosyl) jateorin) and (I 36) (palmatoside E = 4-O-(p-D-glUCO-pyranosy1)isojateorin) differ in their stereochemistry from (1 34) at C-8 and C-12. Palmatoside C (137) (4-O-(p-gluco-pyranosy1)columbin) and palmatoside D (138) (4-0-(p-D- glucopyranosy1)isocolumbin) are epimers at C-8. The aglycone of palmatoside G (139) is a C,,-compound lacking the C-1 to C-4 lactone bridge and is glucosylated at C-19. Compounds (135) (136) and (137) were also reported by the group of It~kawa.~~ However the physical data for these compounds are not identical in the two publications (e.g.melting point).Also compound (138) has been isolated by another group from the extract of the rhizomes of Tinospora capillipes and was named tinoside.'O From the plant Rhynchospermum verticillatum (Compositae) two new diterpene glucosides rhynchospermoside A (140) and B (141) were isolated.'l Based on I3C NMR experiments it was suggested that the two compounds are epimers at C-12. NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL (1 42) R = a-arap (143) R = 2'-0-ac-arap (1 44) R = 3'-O-ac-arap (1 45) R = 4I-O-ac-arap 4.4 Serrulatane Diterpenes A new class of diterpene pentosides the seco-pseudopterosins A-D (142-145) has been isolated from a Caribbean sea whip of the genus Pseudopterogorgia.s2These new compounds are a-arabinosides (D or L not determined) and mono-acetate positional isomers.They are related to the recently described pseudopterosins. It is noted that the seco-pseudopterosins possess potent anti-inflammatory and analgesic activities equivalent to commercial anti-inflammatory drugs. 4.5 Kaurane Diterpenes Different aspects (isolation taste characteristics toxicity synthetic analogues properties as plant growth regulators) of the rebaudosides A-E were covered in a review (64 refs.).83 Pronounced CNS activity has been attributed to an unidentified glycoside in Turbina corymbosa (L.) Raf. (Convolvulaceae). Investigation of the seeds of the Jamaican variety of the plant revealed a new diterpene diglucoside (146).s4 For the structure elucidation of this compound with a kaurane backbone extensive 2D NMR spectroscopy was used.4.6 Norditerpenes From the aerial parts of Drymaria arenarioides Willd. (Caryo- phyllaceae) a new norditerpene glucoside atractyligenin 2-0-p- D-glucopyranosyl-( 1 -.) 2)-P-~-glucopyranoside (1 47) has been isolated.85 It is likely that this compound is in part responsible for the plants toxicity to sheep and chicks previously reported. 'H dOOH (154) R = p-D-glcp(2-+1 )a-L-arap 5 Triterpenes In 1988 a review on triterpenoid saponins covering the literature during the period 1979-1986 (333 refs!) appeared.s6 Isolation structure elucidation reports of new triterpenoid saponins and their biological activity were covered.The following is in part a continuation of this review. 5.1 Dammaranes Six triterpene glycosides of the dammarane-type actino-stemmosides A-D G and H [( 148)-(153)] have been isolated from the dried herb of Actinostemma lobatum Maxim. (Cucurbita~eae).~'-This herb has been traditionally used in China as a diuretic for the treatment of nephrotic edema and as an antidote for poisonous snake bite. Actinostemmosides A (148) B (149) C (150) and G (152) were identified as the 20-0-/3-glucopyranosides of 3P,6a,20,27-tetrahydroxy-(20S)-dammar-24-ene (1 48) 3P,7/3,20,27-tetrahydroxy-(2OS)-dammar-24-ene (149) 3p,7/3,18,20,27-pentahydroxy-(20S)-dammar-24-ene (150) and 3/3,6~~,7/3,20,27-pentahydroxy-(20S)-dammar-24-ene (1 52) respectively ; and actinostemmo- side H (153) as the 20,27-bis-O-/3-~-glucopyranoside of 3p,7/3,18,20,27-pentahydroxy-(2OS)-dammar-24-ene.Remark-able is the structure of actinostemmoside D (151) the a-~-rhamnopyranosyl-( 1 -+ 2)-p-~-glucopyranoside of 3P,6a,20,27- tetrahydroxy-(20R)-dammar-24-ene,which is the first naturally occurring (20R)-dammarane glycoside. Three new glucosides tubeimoside I1 (256) 111 (257) (see 5.7) and IV (154) were isolated from the bulbs of Bolbostemma paniculatum (Maxim) NATURAL PRODUCT REPORTS 1991 OH H I Franquet (Cucurbita~eae).~~ Tubeimoside IV (1 54) was identi- fied as 3-0-[a-~-arabinopyranosyl-( 1 -,2)-,8-~-glucopyrano-syl]-3p,7p,18,20,26-pentahydroxy-(20S)-dammar-24-ene.5.2 Baccharanes In continuation of the investigations of Actinostemma Iobatum mentioned above the structure of two further compounds actinostemmosides E (155)and F (1 56) have been determined.g0 They possess the very rare baccharane-skeleton and were identified as the 3-O-P-~-galactopyranosyl-(1 -,2)-p-~-gluco-pyranoside of 3p,17/3,21,26-tetrahydroxybacchar-24-ene (1 55) and 3-0-P-~-galactopyranosyl-( 1 -+ 2)-a-~-arabinopyranoside of 3p 17&2 1,26,3O-pentahydroxybacchar-24-ene(1 56) respect- ively. 5.3 Lanostanes In search of biologically active marine natural products nine new ichthyotoxic norlanostane-triterpenoid oligoglycosides sarasinosides A1-A3 Bl-B3 and Cl-C3 have been isolated from the Palauan marine sponge Asteropus sarasinosum .91 The structures of sarasinoside A (1 57) B (1 58) and C (1 59) have been elucidated which are specified as having one molecule of N-acetylglucosamine and N-acetylgalactosamine.This is the first report of triterpene oligoglycosides from marine organisms other than the sea cucumber. The ichthyotoxicity against killifish Poecilia reticulata and the inhibition against cell-division of fertilized eggs of the starfish Asterina pectinifera was investigated for (157) and (158). New glycosides cucumaroside C (160) C (161) and H (162) have been isolated from the Far Eastern holothurian Eupentacta fraudatrix Djakonov et Baran~va.~~. 93 Cucumaro-side C (160) was identified as 16P-acetoxy-3-{[3-0-methyl-P-~-xylopyranosyl-( 1 -+ 3)-/3-~-glucopyranosyl-( 1 -+ 4)][P-~-xylo-pyranosyl-( 1 -+ 2)]-P-~-quinovopyranosyl-(1 -+2)-p-D-XylO-pyranosyloxy}holosta-7,22,24(2)-trieneand cucumaroside C (1 6 1) as the (22E)-isomer.Cucumaroside H (1 62) contains a sulphate group at position 4 of the xylose moiety bound to the aglycone. As well as a number of known compounds a new triterpene glycoside was identified in the acid hydrolysates of the methanol extracts of the sea cucumbers Holothuria atra and H. scabra (Holothurideae). Its structure was established as 3-0-(p-D-xylopyranosyl)-22,25-oxidoholothurinogenin(163).94 Two new glycosides cladoloside A (164) and B (1 65) have been isolated from the holothurian Cladolabes sp.95 It was shown that these substances were completely identical with previously described progenins obtained on the enzymatic cleavage by cellulase of holotoxin A from the holothurian Stichopus japonicus.As natural products (164) and (165) were previously unknown. The bulbs of Muscari comosum Miller (Liliaceae) contain six oligoglycosides muscarosides A-F with spirocyclic nor-triterpenoid aglycones. During the investigation of the bulbs of M. armeniacum Leicht and M. botryoides Miller eight novel glycosides muscarosides G-N (1 66-1 73) have been isolated all of them structurally related to the muscarosides A-F.96 (1 57) R = fl-D-Xylp(4-+1 )fl-D-N-ac-galarninep 1 ~-D-N-ac-gluarninep(6+1 )p-D-gIcp(2-+1 )p-D-gtcp (158) R = fl-D-xylp(4-.l)fl-D-N-ac-gatarninep .I If fl-D-N-ac-gluarn inep( 6-+l)fl-D-xyIp(2 -+ 1 )@-D-glcp (159) R = p-D-xylp(4-+1 )P-D-N-ac-galarninep 1 p-D -N-ac-g Iu a rn inep( 6-+ 1) fl-D-xy I p (162) 4-O-sutfato-D-xylp(2-tl )@-D-quinp(2-+1 )p-~-xylp 1 p-D-glcp(3+1)3-O-rne-fl-D-xytp R2 (160) (161),(162) (163) R = p-D-xylp NATURAL PRODUCT REPORTS 1991-H.PFANDER AND H. STOLL 0 II HOHzC . (166) R = 0-D-glcp(6-1 )cu-L-arap(2+1 )P-D-glcp(3-1 )P-L-arap(2-1 )P-D-glcp 1 a-L-rhap (167) R = fl-D-gIcp(G-l)a-L-arap(2+1 )P-D-glcp(3-1 )P-L-arap 1 a-L-rhap (169) R = 0-D-glcp(6-1 )a-~-arap(2-+1 )P-D-glcp (171) R = P-O-glcp(6+1 )a-L-arap(2-+l)~-D-glcp (172) R = P-O-gICp (173) R = P-D-gIcp(G~l)a-L-arap(21 )fl-D-glcp(2+1 )a-L-rhap The monose units of their di- tri-; tetra- or hexasaccharide one for muscaroside I (1 68) K (1 70) M (1 72) and N (I 73) were chain are P-D-glucopyranose a-L-arabinopyranose a-~-identified.rhamnopyranose Pa-galactopyranose a-L-arabinofuranose and P-D-apiofuranose. The aglycones (23s)- 17,23-epoxy-3P,3 1 -dihyroxy-27-nor-5a-lanost-8-ene- 15,24-dione (eucosterol) for 5.4 Cucurbitanes muscaroside G (1 66) H (167) J (169) and L (1 71) and (23s)- The structure of five new glycosidic metabolites hebevinosides 17,23-epoxy-3P,30,31-trihydroxy-27-nor-5a-lanost-S-ene-24-I-V from a poisonous mushroom Hebeloma vinosophyllum NPR 8 NATURAL PRODUCT REPORTS 1991 (174) R' = 0-D-xylp R2 = 0-D-gICp (175) R1 = 0-D-xylp R2 = (4,6-di-O-ac)-P-D-glcp (1 76) R' = (4-O-ac)-P-D-xylp R2 = (4,6-di-O-ac)-P-D-glcp (177) R' = 0-D-xylp R2 = H (178) R1,R2 = 0 R3 = H R4 = CH20-gentio R5 = CH3 (184) p-D-glcp(2-1 )a-L-rhap (1 79) R',R2 = 0 R3 = P-D-gkp R4 = CH20-~ph R5 = CH3 (180) R1,R2 = 0 R3 = 0-D-glcp R4 = CH20-gentio R5 = CH3 (181) R' R2 = 0 R3 = p-D-glcp R4 = CH3 R5 = CH20-gentio (182) R1,R2 = H,aOH R3 = P-D-gkp R4 = CH20-soph R5 = CH3 (183) R',R2 = H,aOH R3 = p-0-glcp R4 = CH20-gentio R5 = CH3 Hongo was reported and it was demonstrated that part of these compounds were the toxic principles of this mushr~om.~' From the same source four new triterpene glycosides hebe- vinosides VI-IX (174-177) whose common aglycone is 3p,7p 1 6p- tri hydroxycucurbi ta- 5,24-diene (hydroxy-hebevinogenin) have been isolated and identified as 3-0-p-D- xylopyranoside-16-O-/3-~-glucopyranoside (1 74),3-O-p-D-XJdO- pyranoside-16-0-(4,6-di-O-acetyl)-/?-~-glucopyranoside (1 75) 3-0-(4-O-acetyl)-P-~-xylopyranoside-16- O-(4,6-di -O-acetyl)-/3-D-glucopyranoside (1 76) and 3-O-P-~-xylopyranoside (1 77).The relationship between the structure and toxicity of heb- evinosides was also investigated. The plants of the genus Hemsleya are abundant in Yunnan and Sichuan China and have been used as herbal medicines by minor nationalities in these provinces. During the investigation of sweet and bitter principles of rhizomes of H. carnoszjlora C. Y. Wu et Z. L. Chen sp. nov. six cucurbitane glycosides carnosifloside I-VI (178-1 83) have been identified.98 Carno- sifloside I-IV (1 78-1 81) have the same aglycone (cucurbita- 5,24-diene-3/3,26-dihydroxy-11-one) with D-glucose gentio- biose or sophorose as carbohydrate residues.The two other OH (186) R' = 0-D-xylp; R2 = fl-D-glcp compounds (1 82) (1 83) possess cucurbita-5,24-diene-3p,l la,26-triol as aglycone and gentiobiose or sophorose as carbohydrate. Some observations on the structure-taste re-lationship of cucurbitane glycosides are also reported. From Picria fel-turrae Lour. the structure of picfeltarraenin (184) was assigned as 3-O-[a-~-rhamnopyranosyl-(1 -+ 2)]-p-~-gluco-pyranoside of picfeltarraegenin II.99 5.5 Cycloartanes As previously reported the main glycoside of Astragalus orbiculatus Ledeb. (Leguminosae) is cycloorbicoside A. A further glycoside cycloorbicoside G was isolated from the epigeal part of this plant and identified as (23R,24S)-16~,23,16a,24-diepoxycycloartane-3~,7~,25-triol 25-0-/3-~-glucopyranoside 3-O-P-~-xylopyranoside (1 85).loo Another new glycoside of the cycloartane series cyclocanthoside D was isolated from A.tragacantha Habl. and identified as (24s)- cycloartane-3@,6a,16/3,24,25-pental 16-O-P-~-glucopyranoside 3-O-/3-~-xylopyranoside(186).lo' From the leaves of PassiJlora quadranguluris L. two new NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL -0-gentio @gentio-0 (187) K (190) R' = a-arap(2-+l)a-rhap R2 = P-glcp(6-tl)P-glcp(4-+l)a-rhap (191) R' = a-arap R2 = P-glcp(G+l)~-gIcp(4+l)a-rhap (192) R' = a-arap(2+1 )a-rhap R2 = P-glcp(6+1)6-O-ac-~-glcp(4+1)a-rhap (196) R' = a-arap R2 = P-glcp(6+1)6-O-ac-P-glcp(4+l)a-rhap (197) R' = a-arap(2+1)a-rhap R2 = H R2 (193) R' = a-arap R2 = P-glcp(6-+1)8-glcp(4~l)a-rhap (194) R' = a-arap(2-1 )a-rhap R2 = ~-glcp(6-+1)6-0-ac-~-glcp(4+1 )a-rhap (195) R' = a-arap R2 = ~-glcp(6+1)6-O-ac-P-glcp(4+1)a-rhap triterpenes have been isolated and the structures determined 5.7 Oleananes as the 3P-O-gentiobiosides of 22,25-epoxycycloartane- From the leaves of A.senticosus (Rupr. et Maxim) Harms 3p,2 1,22(R)-triol (1 87) and 21,24-epoxycycloartane-3P,25,26-eleven triterpenoid glycosides were isolated ;three were identi- trio1 (188).102 fied as known compounds. Oleanolic acid and 30-norolean- 12,20(29)-dien-28-oic acid were identified as aglycones of eight new compounds named ciwujianosides B (190) C (191) C 5.6 Lupanes (192) C (193) C (194) D (195) D (196) and E (197).Acanthopanax species (Araliaceae) are used in Korean and Arabinose rhamnose and glucose were identified as carbo- Chinese folk medicine as a tonic an antirheumatic an anti- hydrates. lo4 inflammatory and prophylactic for chronic bronchitis hy- Roots of Ardisia crispa (Thunb.) A.DC. are in combination pertension and ischaemic heat disease. A new 3,4-secolupane with other plants used in Thai traditional medicine by women type triterpene divaroside has been isolated from the leaves of who suffer from menstrual pains. It was shown that the main A. divaricatus Seem. The structure of the new compound was utero-contracting activity is due to two new triterpenic established as the P-gentiobiosyl ester of chiisanogenin (1 89)."' glycosides.lo5 The structure of these two compounds ardisia- NATURAL PRODUCT REPORTS 1991 XCH0 \ (198) R’ = a-L-arap(4-1 )fl-D-glcp(2-+1 )p-D-xylp R2=H 1 p-D-gICp (199) R’ = a-~-arap(4+1 )p-D-glcp(2-+1 )cu-L-rhap R2= H 1 0-D-g ICP /-SOOH (209) R’ = a-L-arap R2 = P-D-glcp (210) R’ = a-L-arap R2 = (3-D-glcp(6+1)p-D-glcp(4-+1)a-L-rhap crispin A (198) and B (199) were determined as ~P-O-{P-D-xylopyranosyl-(1 -+ 2)-O-P-~-glucopyranosyl-( 1 +4)-[0-P-~-glucopyranosyl-(1 -+ 2)]-a-~-arabinopyranosyl)-16a-hyroxy-13~,28-epoxy-olean-30-a1(198) and 3P-O-(a-~-rhamno-pyranosyl-( 1 -+ 2)-O-P-~-glucopyranosyl-( 1 t4)-[0-,8-~-glucopyranosyl-( 1 -+ 2)]-a-~-arabinopyranosyl}-16a-hydroxy-13/3,28-epoxy-olean-30-a1 (1 99) respectively.Two new triterpenoid pentasaccharides saxifragifolins C (200) and D (201) isolated from the aerial part of Androsace suxifrugifolia were identified as the 3-O-{/3-~-xylopyranosyl-(200) R2 = Uac (201) R2 = H (I -+2)-P-~-glucopyranosyl-( 1 +4)-[P-~-glucopyranosyl-(1 -+ 4)-,8-~-glucopyranosyl-( 1 -+ 2)]-a-~-arabinopyranoside) of androsacenol (200) and cyclamiretin A (2O1).lo6 A new triterpene glycoside was isolated from Aesculus indica L. (Hippocastanaceae) and was named aesculuside-B.lo’ The structure was determined as 3~-O-[{~-~-glucopyranosyl-(1 +2)-/3-~-glucopyranosy1-( 1 -+ 4))-~-~-glucuronopyranosyl]-16a,21P722a,24,28-pentahydroxy-olean-12-ene (202). Previously the isolation of glycosides of 2a 19a-dihydroxy- ursuloic acid derivatives which have an additional oxygen function from Trachelospermuln asiaticum have been described.The corresponding oleanane- type glycosides have now been isolated.lo* Six new glycosides of 2a 19a-dihydroxyoleanolic acid derivatives trachelosperoside D-1 (203) D-2 (204) E-1 (205) F-2 (206) arjungenin-23,28-bis-O-glucopyranoside (207) and arjungenin-28-O-xylopyranosyl-(1 -+ 2)-glucopyranoside (208) along with two known glycosides were characterized. The aglycones of the compounds (203-206) trachelo-sperogenins D E and F were described for the first time. From the leaves and leafstalks of Nothopanax delavuyi (Fr.) Harms (Araliaceae) a plant that is used in folk medicine in China as an anti-pyretic and anti-inflammatory two new triterpene glycosides liangwanosides I (209) and TI (210) have been isolated.1os The structures were determined as the 28-P-~- NATURAL PRODUCT REPORTS 1991-H.PFANDER AND H. STOLL (21 1) R1 = 2-O-ac-a-L-arap R2 = OH R3 = P-D-glcp(6-rl)p-D-glcp (212) R' = a-L-arap(2-rl)a-L-rhap(3~l)P-D-glcp, R2 = R3 = H (213)R1 = a-L-arap(2+1)a-~-rhap(3-tl)P-D-glcp R2 = H R3 = fl-D-glcp(6+1 )fl-D-glcp (214) R = P-D-glcp (215) R = P-soph 'AcooR' SOOH (216) R' = P-D-glucuronp R2 = H R3 = fl-D-glucuronp(2-+1)fl-D-g~ucuronp,R4 = =O (218) P-D-glucuronp(2+1 )P-D-glucuronp (217) R' = R2 = H R3 = ~-D-g~ucuronp(2-+1)~-D-g~ucuronp, R4 = H,H (219) R1 = H R2 = OAc R3 = ~-D-glucuronp(~~~)~-D-glucuronp(~~1)a-L-rhap, R4 = H,H (220) R = ~-D-g~ucuronp(2-+1)~-D-g~ucuronp glucopyranosyl (209) and 28-or-~-rhamnopyranosyl-( 1 +4)-P-D-glucopyranosyl-( 1 -+ 6)-/3-~-glucopyranosylesters (2 10) of 3-O-~-L-12- ene -28,29-dioic arabinopyranosyl-3P-hydroxyolean- acid respectively.In the course of biological screehing of Chinese drugs it was found that the butanol-soluble fraction of an alcohol extract from the roots of Patrinia scabiosaefolia (Valerianaceae) exhibited hepatotoxic activities. 110 Three new glycosides have been isolated from the roots and they were identified as the 2'- acetate of 3-O-a-~-arabinopyranosylhederagenin ~S-P-D-~IUCO-pyranosyl-( 1 -+ 6)-P-~-glucopyranoside (2 1 I) 3-O-p-D-gluco- pyranosyl-( 1 +3)-or-~-rhamnopyranosyl-( -,2)-a-~-arabino-I pyranosyloleanolic acid (2 12) and its 28-O-P-~-gluco-pyranosyl-( 1 -+ 6)-/3-~-glucopyranoside (2 13).As well as other compounds two new triterpene glycosides glochidioside N (214) and Q (215) were isolated from Glochidion heyneanum."' Compound (214) was identified as ~-O-P-D-glucopyranosyl- 16/3-benzoyloxy-olean- 12-ene-21/3,23,28-trioI whereas (21 5) contains sophorose as the carbohydrate moiety. Glycyrrhizae Radix (licorice root the root of Glycyrrhiza sp.) is a Chinese drug used in Japan for many purposes and it was shown that glycyrrhizin is one of its most important principle and used clinically to treat gastric ulcer allergic symptoms and liver disease. From Chinese Glycyrrhizae Radix the dried root of G. uralensis Fischer (Leguminosae) ten new oleanane-type triterpene oligoglycosides were isolated and the structures of five compounds named licorice-saponins A3 (216) B2 (217) C2 (218) D3 (219) and E2 (220) were determined.l12 These compounds differ in their aglycone as well as the carbohydrate residue.NATURAL PRODUCT REPORTS 1991 (222) R = H (224) R = ar-~-arap(2+1 Ia-L-rhap (223) R = Ac It is known that seeds of Phaseolus vulgaris Linn. (French bean; Leguminosae) are rich in glycosides and it was shown that crude extracts show antifertility activity. A new triterpenoid glycoside was isolated from these seeds and characterized as 3P,22P-di hydroxy-olean- 1 2-ene-24-0-p-~-glucopyranoside (221).113 Two new acidic triterpenoid rhamnopyranosides were iso- lated from the leaves of Combreturn imberbe (leadwood tree) and identified as 23-0-a-~-rharnnopyranoside (222) of 23- hydroxy-imberbic acid and its 1-acetate (223) respectively.'14 The high physiological activity of triterpene glycosides from plants of the family Araliaceae is generally known.The structure of tauroside E the predominating triterpene glycoside from the leaves of Crimean ivy Hedera taurica Carr. was established as 3-0-(a-~-rhamnopyranosyl-( -+ 2)-a-~-arabino-1 pyranosy1)hederagenin (224);'15 and from the berries a new glycoside of oleanolic acid the 3-0-(,8-glucopyranosyl-( 1 -+ 2)-P-D-glucopyranosyl) derivative (hederoside E,) (225) was isolated.116 Another glycoside of oleanolic acid the 3-0-,3-~- xylopyranoside (songoroside A) (226) was isolated from Scabiosa soongorica Schrenk.11' This compound has been mentioned previously in the literature as a product of the acid R'OW \\ (229) R' = O-D-glucuronp(2-+1 )cr-L-arap R2 = P-D-glCp R3 = H (230) R' = O-D-glucuronp(2-+1)a-~-arap,R2 = H R3 = OH (2311 R' = P-D-glucuronp(2-+1 )a-L-arap R2 = O-D-glCp R3 = OH hydrolysis of other glycosides and was also obtained by partial synthesis.Xeromphis spinosa (Thunb.) Keay (Rubiaceae) is well known in the Indian system of medicines and in a reinvestigation of the fruits of this plant two new molluscicidal triterpenoid glycosides have been isolated.lls They were identified as 3-0-/3-~-glucopyranosyl-( 1 -+3)-P-~-galactopyranoside (227) and 3-0-p- D-glucopyranosyl-( 1 +2)-P-~-glucopyranosyl-( 1 +3)-p-~-galactopyranoside (228) of olean- 12-ene-3/3-01-28-oic acid.Besides a new guaiane-type sesquiterpene glycoside (1 14) (see 3.6) and seven ursane-type glycosides [(259)-(265)] (see 5.8) three new oleanane-type glycosides cynarasaponins H-J (229)-(23 1) have been isolated from Cynara cardunculus L.'O They were identified as 3-O-a-~-arabinopyranosyl-(1 -+ ~)-P-D-glucuronopyranosido-28-0-~-~-glucopyranos~de oleanic of acid (229) 3-0-ol-~-arabinopyranosyl-( 1 -+ 2)-P-~-glucurono-pyranoside of machaerinic acid (230) and 3-0-a-~-arabino- p y ra n o sy 1-( 1 -+ 2)-P-D -g 1u c u r o no p y r a n o si do-2 8-0-/3-D-ghcopyranoside of machaerinic acid (231). During chemical studies on tannin and related compounds the isolation and characterization of ellagitannins has been reported. In continuation of these studies a series of novel ellagitannins NATURAL PRODUCT REPORTS 1991-H.PFANDER AND H. STOLL 'X ?H / HO OH (232) R = H (233) R = galloyl i'i OH HO Ho* 0 / HO -0' HO Hof$ OH OH (235) (236) HO 0Ho~oo-o-D-glcp II H2HO HO c-0 /c-0 II 0 6H2 /CH2o \ 0I 0I OH c=o c=o HO OH OH H O W O H (237) OH OH OH OH -p-D-glcp HO named castanopsinins A-H [(232)-(239)] which contain a triterpenoid glucoside core have been isolated from Castanopsis cuspidata var. sieboldii Nakai (Fagaceae).lI9 It was shown that HO these compounds consist of a mixture of two structural isomers I (oleanane- and ursane-type triterpenoids) which were separated HO except for (239) by preparative HPLC.Physical and spectro- scopic data were obtained for these samples whereas the OH chemical conversions were carried out with the mixtures containing the oleanane and ursane isomers. Based on these H O V O i data it was shown that the oleanane-type compounds were OH derivatives of 201,3p,23,24- tetrahydroxyolean- 12-ene-28-oic 239) acid 28-O-P-~-glucopyranoside.Furthermore all these com- (242) R' (243) R' (244) R' pounds contain a hexahydroxydiphenyl moiety and some of them are esterified with gallic acid. The whole plants of Patrinia scabiosaefofia Fischer (Valer- ianaceae) have been used in China as a drug for various purposes. Two new sulphated glycosides were isolated as major constituents of the seeds of this plant.120 These two compounds sulfapatrinoside I and I1 (240) were structural isomers (ursane- and oleanane-type).For (240) the structure was determined as the 23-sulphate of 3P-hydroxyolean- 12-ene-28-oic acid 28-0- [P-D-glucopyranosyl-( 1 +6)-/?-~-glucopyranosy~]ester. Aescufus indica L. (Hippocastanaceae) is reputed to cure various ailments and has been shown to be active against P-388 lymphocytic leukemia and human epidermoid carcinoma of the nasopharynx. From the seed-coats of this plant a new compound was isolated and identified as 3-0-[{/3-~-glucopyranosyl-(1 +2)}-{,8-~-glucopyranosyl(1 +4)}-P-~-glucuronopyrano-sy1121,22-diangeloyl-barringtogenolC (241).121 It was found to be lethal against Biomphafaria gfabrata the vector of the tropical disease schistosomiasis at a conc.of 10 ppm. Nine triterpene glycosides derived from hederagenin and named polypetalosides A-I where found in the aerial and underground parts of Caltha pofypetala Hochst. (great marsh marigold Ranunculaceae). 122 123 Polypeteloside A (242) was identified as the 3-O-a-~-rhamnopyranoside,the glycoside G NATURAL PRODUCT REPORTS 1991 OW R' XH20H = a-L-rhap R2 = H = a-L-arap R2 = ~-D-gIc(6~1)~-D-g1~(4~~ )a-L-rhap = a-L-arap(2~1)p-D-gtcp,R2 = P-D-glc(G+l )p-D-glc(4->1 )a-~-rhap (246) R' = P-D-glcp(3-tl )P-D-gaIap(2-+1 )P-D-galap R2 = H (247) R' = P-D-glCp R2 = P-D-glcp (248) R1 = P-D-glcp(2-1 )P-D-glcp R2 = P-D-glcp (249) R' = P-D-glcp(4-+1 )P-D-gtcp(4-+1 )P-D-atlop R2 = P-D-gtcp (243) is the 3-0-a-~-arabinoside 28-0-[0-a-~-rhamno- pyranosyl-( 1 +4)-0-,8-~-glucopyranosyl-(1 -+6)-/3-~-gluco-pyranoside] and the glucoside I (244) is 3-O-[p-~-gluco-pyranosyl-(1 -+ 2)-a-~-arabinopyranoside]28-O-[ O-a-~-rham- nopyranosyl-(1 44)-0-,8-~-glucopyranosyl-( 1 -+ 6)-P-~-gluco-pyranoside].A Chinese crude drug leaves of Ifex chinensis Sims (Aqui- foliaceae) has been used as a remedy for bronchitis pneumonia and ulceration and as an external treatment for scald chilblain etc. Two major glycosides have now been isolated and one ilexoside A (245) was identified as 3/3-0-(P-~-xylopyrano-sy1)siaresinolic Species of the genus Phytofacca (Phytolaccaceae) are noted for their use in popular medicine against ailments of the joints edema rheumatism and dermatitis. Phytofacca thyrszflora Fenzl ex Schmidt is used in Brazil for a series of alleged therapeutic properties.It may also contain potential molus- cicides and is known to intoxicate and sometimes to kill cattle. In an investigation of the different parts of P. thjwzflora it was shown that the roots contain a series of known glycosides whereas new compounds have been isolated from the berries and leaves. lZ5These glycosides [(246)-(249)] are all based on the well known serjanic acid and were identified as its 3-0-(p-~- galactopyranosyl-( 1 -+ 2)-P-~-galactopyranosyl-(1 +3)-p-D- NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL #O CH20H H R ’ OCH2RW (250) R’ = p-D-galap R2 = H (252) R’ = 0-D-galap R2 = OH (251) R’ = 0-D-galap R2 = OH (253) R’ = fl-D-galap(2-tl )p-D-glcp R2 = H (254) R’ = 0-D-gIC.p (255) R’ = p-D-glcp(3-tl)p-O-glcp (2541 (255) R2= @-D-fuCOp(2+1 )a-~-rhap(4+1 )P-D-xylp(3+1 Ia-L-rhap glucopyranoside) (246) 3-O-(P-~-glucopyranoside)28-0-P-~- glucopyranoside (247) 3-0-(P-~-glucopyranosyl-(1 +~)-P-D- glucopyranoside) 28-0-/3-~-glucopyranoside(248) and 3-0-[p- D-allopyranosyl-( 1 -+ 4)-P-~-glucopyranosyl-(1 -+ ~)-P-D- glucopyranoside] 28-0-P-~-glucopyranoside (249) respec- H tively.Corchorus acutangulus Lam. (Tiliaceae) is a medicinal plant occurring throughout the hotter parts of India. From the aerial part of this plant four new triterpenoid glycosides corchorusins A-D [(250)-(253)] have been isolated and identified as L---R---J longispinogenin 3-O-P-~-galactopyranoside(250) saikogenin F 3-O-P-~-galactopyranoside (251) 23-hydroxylongi-spinogenin 3-O-P-~-galactopyranoside(252) and saikogenin E 3-0-~-~-glucopyranosyl-(1+2)-P-~-galactopyranoside(253) respectively.lZ6 From Solidago virgaurea L.two oleanane- type glycosides virgaureasaponins 1 (254) and 2 (255) have been isolated.127. 128 Their structures were determined as 28-O-a-~-rhamno-pyranosyl-(1 -+ 3) -P-D-xylopyranosyl- (1 -+ 4) -a -L -rhamno- -01- P2-0 L-arap (2 -1 )a-L-rhap(4-410 1 pyranosyl-( 1 -+2)-P-~-fucopyranosid of 3-O-P-~-glucopyrano- syl polygalacic acid (254) and of 3-0-P-~-glucopyrano-syl-(1 -+3)-~-~-glucopyranosy1polygalacic acid (255) respec- tively. In tubeimoside I1 (256) and 111 (257) two novel macrocyclic triterpene glycosides of the oleanane-type from Bolbostemmapaniculatum (Maxim) Franquent (Cucurbitaceae) a dicrotalic acid moiety bridges across the two carbohydrate chainssg (see 5.1).Through the concerted application of 2D-homonuclear and heteronudear chemical shift correlations total assignments of (257) R = I3C and lH NMR spectra of the previously reported hedera- saponin C was achieved. 13C NMR data for hederasaponin B and saponin K10 were also reported.12g (28)-C<> -a-L-arap( 2’1 )a-L-rhap(4+ 1) 0 5.8 Ursanes 13 As mentioned in 5.7 the ursane-type isomers of [(232)-(239)]11’ and sulfapatrinoside I (240),120 have been isolated. Besides NATURAL PRODUCT REPORTS 1991 R’O (259) R’ = fl-D-glucuronp(2-+1)a-L-arap R2 = P-0-glcp R3 = R4 = H (260) R’ = P-D-glucuronp(2~1)a-L-arap,R2 = R3 = R4 = H (261) R’ = 0-0-glucuronp; R2 = P-D-glcp R3 = R4 = H (262) R’ = P-D-glucuronp(2-tl)cx-L-arap R2 = p-o-glcp R3 = H R~ = OH (263) R’ = P-D-glucuronp R2 = 0-D-gkp R3 = H R4 = OH (264) R’ = P-D-giucuronp(2’1)a-L-arap R2 = R4 = H R3 = OH (265) R’ = P-D-glucuronp(2~l)cx-L-arap,R2 = 0-0-glcp R3 = OH ~4 = H I OH (266) (267) COOH (270) acid 3-0-/3-~-g~ucuronopyranos~do-~8-0-/3-~-g~ucopyranos~de (26 1 C) ; 23-hydroxyursolic acid 3-O-a-~-arabinopyranosyl-(1 +2)-~-~-g~ucuronopyranos~do-~8-~-~-~-g~ucopyranos~de (262 D) ; 23-hydroxyursolic acid 3-0-/3-~-glucuronopyrano-sido-28-0-/3-~-glucopyranoside (263 E) ; 2 1/3-hydroxyursolic acid 3-O-a-~-arabinopyranosyl-( 1 -+2)-~-~-glucuronopyrano-side (264 F) ; and 2 lp-hydroxyursolic acid 3-O-a-~-arabino- pyranosyl-( 1 -+ 2)-/3-~-g~ucuronopyranosido-28-/3-~-gluco-pyranoside (265 G) respectively.From the berries of Rubus coreanus the triterpene glycoside 28-O-/3-~-glucopyranosyl 2a,3/3,19a,23-tetrahydroxyurs-12-ene-28-oate (266) was isolated.130 The leaves of Aphloia theiformis (Vahl.) Benn. (Flacourtiaceae) are used in Mauritius against rheumatism jaundice diabetes and bladder disorders. ilexoside A (245) (see 5.7) the methyl ester of ilexoside B 3/3-0-It was also shown that extracts of the leaves were active against (P-D-xylopyranosy1)pomolic acid methyl ester (258) with an Biomphalaria gIabrata snails the intermediate host of Schisto-ursane-type aglycone was isolated from IIex chinensis Sims.124 soma mansoni. It was subsequently shown that the methanol Seven new ursane-type glycosides cynarasaponins A-G extract of the leaves also contains besides known glycosides [(259)+265)] have been isolated from Cynara cardunculus L.6/3-hydroxytormentic acid ester glucoside (267) -a new nat- (see also 5.7).” They were identified as ursolic acid 3-0-a-~- urally occurring glycoside. 131 arabinopyranosyl-( 1 -+ 2)-/3-~-glucuronopyranosido-28-O-/3-During the re-examination of the methanolic extract of the D-glucopyranoside (259 A) ; ursolic acid 3-U-a-~-arabino-roots of Guettarda platypoda DC. a plant used in folk-medicine pyranosyl-( 1 -+ 2)-/3-~-ghcuronopyranoside (260 B) ; ursolic as a febrifuge the new glycoside quinovic acid-3P-O-P-~- NATURAL PRODUCT REPORTS 1991-H. PFANDER AND H. STOLL g~ucopyranosyl-28-~-~-D-glucopyranosyl ester (268) was found.132 From the whole plant of Trachelospermum asiaticum Naka (Apocynaceae) sixteen triterpenoid glycosides were isolated whereby six new compounds were determined to be 28-0-or 3,28-bis-O-glucosides of 19a-hydroxyursolic acid derivatives except for one 28-O-xylosyl-glu~oside.~~~ These new glycosides were identified as 3-0-glucopyranoside of suavissimoside R 1 (269) the 28-0-P-glucopyranoside of 2a,3,8,19a-trihydroxyurs- 12-ene-24,28 dioic acid [(270) trachelosperoside A- I] the 28-0-glucopyranoside [(27 l) trach-elosperoside B-1 major glycoside]; and 28-0-P-~-xylo-pyranosyl-( 1 2)-P-~-glucopyranoside [(272) trachelo-speroside B-21 of 2a,3P 19a,23,24-pentahydroxyurs-12-ene-28-oic-acid the 28-0-glucoside of 2a,3P 19,24-tetrahydroxyurs- 12-ene-23,28-dioic acid [(273) trachelosperoside C- 11 and the 3-0-glucoside of (273) [(274) trachelosperoside C-21.For asiaticoside an ursane-type glycoside which is known for its antileprotic activity the single-crystal X-ray determination of the complete structure was re~0rted.l~~ 5.9 Biological Activity In a series of reports a great variety of investigations on the biological activity of triterpene glycosides are described. The inhibitory effect of triterpene glycosides on 12-0-tetra-decanoylphorbol- 13-acetate (TPA) and teleocindin B in the Epstein-Barr virus activation in Raji cells are known. In vitro structure-activity studies using a biological test system on a variety of triterpene glycosides having one or two carbohydrate chains and an acyl side-chain were re~0rted.l~~ It was shown that triterpene 3-0-glycosides and acylated compounds exhib- ited an effective inhibition of Epstein-Barr virus activation ; therefore the carbohydrate at C(3) is essential to the inhibitory activities.The antitumour activity of the triterpene glycosides foetoside C and cyclofoetoside B from Thalictrum foetidum and thalicoside A from T. minus was studied in rats with implanted tumour~.~~~ It was shown that these compounds are promising agents for the development of new neoplasm inhibitors. Triterpenoic glycosides have been reported to have spermi- cidal potential. It was shown that with an ethanolic extract of Pentapanax leschenaultii (DC) a 100YO immobilization of human spermatozoa was achieved.137 Similar observations were made with tri terpene glycosides from Hedera nepalensis K.Koch whereby an increased activity was observed with increased hydrophilicity of the individual glycosides.13*9 139 Contraceptive activity in rats was also observed for glycosides from Thalictrum minus L. and T.foetidum L.140 Antimycetic activity was reported for glycosides of Solidago virgaurea L.lgl In a patentlg2 the anti-inflammatory mucolytic and antiedemic activities of oleanane-type glycosides con- taining a tetra- or pentasaccharide residue at C(28) which were isolated from Crossopteryx febrifuga were reported. Triterpene glycosides isolated from AIfaIfa roots showed growth-regulating activity for cotton.lg3 5.10 Chemical Reactions The electrochemical oxidation of triterpenes has been ex-tensively studied and some of the results It was shown by anodic allylic oxidation that various olean- 1Zene glycosides were readily converted into 1 1 a,12a-epoxy-oleanan-28,13P-olide olean- 1 1 -ene- 13P,28-oxide and olean- 12-ene- 11-one derivatives.By use of an indirect electro-oxidation reaction mediated with an intramolecular carbonyl residue a novel triterpenoid which possesses a modified A-B-ring system has been synthesized from an olean- 12-ene- 11 -one derivative.145 For these reactions protection of hydroxyl groups is not required and the electrochemical conversions can be applied directly to the oligosaccharides. The thermal effect of acetates of triterpenoid glycosides was examined.lg6 Contrary to the case of free glycosides on heating the acetates in a melting point apparatus the cleavage reactions of carbohydrate-aglycone and carbohydrate-carbohydrate linkage did not take place and no aglycones were obtained. The relationship between the thermal effects of the acetates and their FD mass spectra revealed an interesting suggestion in the study of the mechanism of FD mass fragmentation of glycosides. 6 Glycosidation Glycosidation of an aglycone is a reaction which in many cases still causes problems especially on preparative scale. In a series of papers different experimental procedures for the glyco- sylation of terpenes have been described. The glucosidation of different dammarane hydroxyketones with a-acetobromo-glucose in the presence of silver oxide with different molar ratios where described lg7 whereby the desired peracetylated compounds were isolated in yields of 13.9-59.9%.In the lupane series a series of compounds were investigated with a-acetobromoglucose in acetonitrile in the presence of mercury cyanide and in toluene in the presence of cadmium car-bonate. lg8The yields varied between 30 and 88 %. Glycyrrhetic acid and ursolic acid 3-acetate were glycosylated with a-acetobromorhamnose. lg9After saponification of the peracetates the rhamnosides were obtained in yields of 40 and 77.6% respectively. Silver trifluoroacetate as a soluble catalyst in the Koenigs-Knorr reaction was used for P-D-glucosylation of 20 different monoterpene alcohols (some bicyclic).150 The overall yields vary between 5 and 60%. Farnesyl P-D-galactoside and a-and P-D-mannosides were prepared by glycosidation of farnesol with the tetra-0-acetyl-a- glycosyl The reaction of different iridoid aglucone acetates with trimethylsilyl P-glucopyranoside in the presence of catalytic amounts of trimethylsilyl trifluoro-methane-sulfonate in acetonitrile or liquid sulfur dioxide at -30 "C and -50 "C respectively followed by solvolysis gave in excellent yields nearly exclusively the P-glucosides. 15' It is known that cell cultures may effectively convert terpenoid alcohols into glycosides. In a systematic investigation it was shown that a culture of peppermint (Mentha piperita) was the most active among the species examined.153 The synthesis of the glycosides was effected by the concentration of substrate incubation period cell age and aggregation and by light.Conversion rates of the alcohols (linalol menthol geraniol and farnesol) varied between 14-58 YO. 7 Conclusions Our literature search has shown that interest in terpene glycosides (chemistry biological activity etc.) is still increasing. In the period covered ca. 250 new compounds have been isolated and characterized. Most of the new compounds belong to the iridoids and triterpenes and in this field both Japanese and Russian researchers were very active. Due to the fact that terpene glycosides consist of two different parts of natural products (carbohydrate and aglycone) the isolation and structure elucidation is very interesting but also demanding.Regarding isolation techniques it is noteworthy that HPLC has not yet been routinely used. The use of this modern technique in future may perhaps help to overcome unsolved analytical problems. For structural elucidation extensive use of 13C and 2D NMR spectroscopy was made. However it has to be pointed out that the term 'structure' also includes the absolute configuration and in many investigations conclusive evidence is lacking. The broad and often very promising biological properties of terpene glycosides are very well known. Therefore the starting point for many investigations is the use of plants in traditional medicine followed by the search of their active principles.In several cases the isolated compounds were tested for their biological activities and interesting properties have been detected. Lacking -or perhaps not published -are in our opinion systematic structure-activity studies with cell cultures or other biological models which might give insight into the 94 NATURAL PRODUCT REPORTS 1991 mechanism of their activity on the molecular level. This might 38 A. Bianco P. Passacantilli G. Righi M. Nicoletti M. Serafini be a promising direction in which work in the field of terpene J. A. Garbarino V. Gambaro and M. C. Chamy Planta Med. glycosides may proceed as interdisciplinary research and a 1987 53 385. 39 I. Kitdgawa H. Shibuya N. I. Baek Y. Yokokawa A. Nitta H. further example of modern natural product chemistry.Wiriadinata and M. Yoshikawa Chem. Pharm. Bull. 1988 36 4232. Acknowledgements. 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ISSN:0265-0568    

DOI:10.1039/NP9910800069

出版商:RSC    

年代:1991

数据来源: RSC