摘要:

Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor M. I. Page The Polytechnic Huddersfield Professor T. J. Simpson University of Leicester Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1989 Annual Subscription Price U.K. f169.00 Rest of World f194.00 U.S.A. $388.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. SG6 1 HN England.Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 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 1989 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1989 U.K. f169.00 Overseas f194.00 U.S.A. US$388.00 Subscription rates for back issues are (1984) (1985) (1986) (1987) (1988) U.K. €1 20.00 f125.00 f130.00 f142.00 f1 59.00 Overseas f126.00 f131.OO f143.00 f159.00 f183.00 U.S.A. US $240.00 US $242.00 US $252.00 US $280.00 US $342.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP98906FX021

出版商:RSC    

年代:1989

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP98906BX023

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

ISSN 0265 NPRRDR 6(6)537-645 (1989) Natural Product Reports A journal of current developments in bio-organic chemistry Volume 6 Number 6 CONTENTS 537 Obituary Michael F. Grundon 1926-89 539 Steroids Reactions and Partial Syntheses A. B. Turner Reviewing the literature published between November 1986 and October I987 577 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1987 and June 1988 591 Coumarins R. D. H. Murray Reviewing the literature published between mid- I980 and mid- I988 625 Recent Advances in the Use of Enzyme-catalysed Reactions in Organic Synthesis N. J. Turner Reviewing the literature published between January 1986 and June I988 645 Book Review The Dictionary of the Alkaloids ed. I. Southon and J.Buckingham Reviewed by R. B. Herbert NPR 6 Cumulative Contents of Volume 6 Number 1 I Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July 1986 to June 1987) J. E. Saxton 55 Erythrina and Related Alkaloids (July 1985 to June 1987) A. S. Chawla and A. H. Jackson 67 Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids (July 1986 ro June 1987) A. R. Pinder 79 Amaryllidaceae Alkaloids (July 1985 to June 1987) M. F. Grundon 85 Recent Advances in Chemical Ecology (July 1985 to December 1987) J. B. Harborne Number 2 1 I1 The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products Two-Dimensional Methods A. E. Derome 143 Biosynthetic Studies on Marine Natural Products (to April 1988) M.J. Garson 171 The Biosynthesis of Porphyrins Chlorophylls and Vitamin B, (1986 and 1987) F. J. Leeper 205 The Polyether and Macrolide Antibiotics Biogenetic Analysis and Structural Correlations D. O’Hagan Number 3 221 Pyrrolizidine Alkaloids (July 1986 to June 1987) D. J. Robins 231 Fatty Acids and Glycerides (1986 to 1987) M. S. F. Lie Ken Jie 263 The Biosynthesis of Shikimate Metabolites (1987) P. M. Dewick 291 Limonene A. F. Thomas and Y. Bessiere Number 4 311 Enzyme Inhibitors in Medicine (to December 1987) C. S. J. Walple and R. Wrigglesworth 347 Diterpenoids (January to December 1987) J. R. Hahson 359 Carotenoids and Polyterpenoids (January 1986 to December 1987) G. Britton 393 Steroids Physical Methods (mid 1985 to December 2987) D.N. Kirk 405 /3-Phenylethylamines and the Isoquinoline Alkaloids (July I987 to June 1988) K. W. Bentley Number 5 433 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July 1987 to June 1988) J. E. Saxton 475 Triterpenoids (July 1985 to December 1987) J. D. Connolly and R. A. Hill 503 Muscarine Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1986 to June 1987) J. R. Lewis 515 Pyrrolidine Piperidine and Pyridine Alkaloids (July 1987 ro June 1988) A. R. Pinder 516 Indolizidine and Quinolizidine Alkaloids (July 1985 to June 1987) M. F. Grundon Articles that will appear in forthcoming issues include Natural Sesquiterpenoids (1987) B. M. Fraga Studies in Plant Cell Culture Biosynthesis and Synthesis of Indole and Bisindole Alkaloids J.P. Kutney The Biosynthesis of C,-C, Terpenoid Compounds (1987) M. H. Beale The Biosynthesis of Plant Alkaloids and Microbial Metabolites (July 1987 to July 1988) R. B. Herbert Quinoline Quinazoline and Acridone Alkaloids (July 1987 to June 1988) M. F. Grundon The Chemistry of the Gibberellins (to April 1989) J. R. Hanson Diterpenoids (2988) J. R. Hanson The Biosynthesis of Shikimate Metabolites (1988) P. M. Dewick Steroidal Alkaloids (July 1985 to December 1987) D. M. Harrison Indole Alkaloids and Mould Metabolites (July 1988 to June 1989) J. E. Saxton Applications of Interactive Computer Graphics in Analyses of Biornolecular Structures D. J. Barlow and T. D. J. Perkins /3-Phenylethylamines and the Isoquinoline Alkaloids (July 1988 to June 1989) K. W. Bentley Lignans Neolignans and Related Compounds (January 1986 to December 1988) D. A. Whiting Marine Natural Products (December 1987 to December 1988) D. J. Faulkner

ISSN:0265-0568    

DOI:10.1039/NP98906FP025

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

It was with great sadness that we learnt of the death in March this year of Professor Michael Grundon. Michael had a long and distinguished association with The Royal Society of Chemistry publications first as Senior Reporter for the Specialist Periodical Reports series ‘The Alkaloids ’ and later as a founder member of the Editorial Board of Natural Product Reports. His long-standing interests in natural products began during studies for his doctorate under the supervision of F. E. King first in Oxford and later in Nottingham. Following post- doctoral work in America and at the University of Glasgow Michael was then appointed to a lectureship at Queen’s University Belfast and in 1968 was made the first Professor of Chemistry at the New University of Ulster. Michael Grundon’s interests in the chemistry of natural products ranged from the structural determination of flavanoids to the design of chiral reducing agents. He will be best remembered however for his contributions to the chemistry of alkaloids and particularly for his elegant studies on the structure synthesis and biosynthesis of the furoquinolines produced by higher plants. 537

ISSN:0265-0568    

DOI:10.1039/NP9890600537

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Steroids Reactions and Partial Syntheses A. 6. Turner Chemistry Department University of Aberdeen Aberdeen A69 2UE Scotland Reviewing the literature published during the period November 1986 to October 1987 (Continuing the coverage of literature in Natural Product Reports 1988 Vol. 5 p. 31 1) 1 Reactions 1.1 Alcohols and Carboxylic Acids and their Derivatives Halides and Epoxides 1.1.1 Oxidation Substitution and Reduction 1.1.2 Esters and Ethers do-a} 1.1.3 Opening of Epoxide Rings 1.2 Unsaturated Compounds HO" H F3 H A. 1.2.1 Electrophilic Addition 1.2.2 Other Reactions of Olefinic and Aromatic Steroids 1.3 Carbonyl Compounds Reagents i EtO,CN=NCO,Et PPh, CF,CO,H PhCO,Na THF 1.3.1 Reduction and Dehydrogenation Scheme 1 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 and Sulphur 1.5 Molecular Rearrangements 1.6 Remote Functionalization Reactions 1.7 Photochemical Reactions Qp 2 Partial Synthesis 2.1 Derivatives and Analogues of Cholestane CI 2.2 Vitamins D their Derivatives and their Metabolites 2.3 Cholanes Norcholanes and Dinorcholanes Br 0 2.4 Pregnanes (1) (2) 2.5 Androstanes and Oestranes 2.6 Cardenolides and Bufadienolides 2.7 Heterocyclic Compounds 2.8 Cyclopropano-steroids 2.9 Microbiological Transformations p Lp 3 References 0 0 (3) (4) During the year the following topics have been reviewed the detection and control of the abuse of anabolic steroids in horse racing,' cytochromes P-450 and the regulation of steroid synthesis,2 radical reactions, brassino-~teroids,~.~ sapogenins,6 CI JftOMe and biologically active fluoro-steroids;'+* other reviews are mentioned in the relevant sections.A monograph in the Cambridge series on cancer research is devoted to cyclo- pen ta[ alphen an threnes. following mechanistic studies of the Mitsunobu reaction using 1 Reactions trifluoroacetic acid.12 The reaction proceeds either by slow conversion of a protonated betaine into an alkoxyphosphonium 1.1 Alcohols and Carboxylic Acids and their Derivatives salt or by rapid conversion of a dialkoxyphosphorane into the Halides and Epoxides same phosphonium salt with recycling of the liberated alcohol I .I .I Oxidation Substitution and Reduction by the betaine pathway.Sodium benzoate markedly accelerates Oxidation of 5a-cholestan-3/?-01 in dimethylformamide con- the reaction leading to trifluoroacetates in high yield (Scheme taining bromobenzene and potassium carbonate in the presence l).l2 Epimerization of 5-hydroxy-6-oxysteroids occurs with of the homogeneous catalyst (PPh,),Pd gives 5a-cholestan-3- trifluoroacetic acid containing potassium hydrogen sulphate one in 95 % yield but polymer-supported palladium (11) chloride toluene-p-sulphonic acid or Lewis acids.13 These combinations or (Ph,P),PdCl are less effective catalysts giving the ketone in are superior to basic reagents as they can be used with yields of 85 Oh and 45 YO,respectively.10 Dehydrogenation of halogenated and C-7 substituted steroids.Epimerization of 6-cholesterol proceeds further under these conditions to give bromoprogesterone in deuteriochloroform has also been cholesta-4,6-diene-3-one, presumably because of the ease of studied.l4 formation and oxidation of the intermediate 3,5-dien-3-01. Dehydrohalogenation of the dihalogenocholestane (1) with Epimerization of secondary alcohols occurs readily in the lithium chloride in demethylformamide gives the cholestenones presence of the Pd(PPh,),/p-benzoquinone redox system (2) (31 and (4V5 providing a convenient synthesis of epicholesterol from The epimers of the cholestene (5) undergo stereoselective cholesterol.l1 Even milder conditions have been developed transformation to the cyclosteroid (6),isolated in 80% yield 539 540 NATURAL PRODUCT REPORTS 1989 following the formation of organo-magnesium or -lithium The 2-hydroxymethylandrostenes (8)-( 10) and the 2-salts.16 The cyclizations occur in spite of the unfavourable methylene-4-en-3-one (I 1) have been obtained by borohydride equilibrium between the ring-opened and ring-closed Grignard reduction of 2-hydroxymethylene-4-en-3-ones(7) followed by intermediates owing to transformation of the alkylmagnesium oxidation or elimination processes (Scheme 2).l7 Selective halide into the thermodvnamicallv favoured alkoxymagnesium reduction of the carboxyl group in the formylated bile acids halide derived from the- ring-closkd Grignard intermediates.(12) and (13) occurs with diborane-THF to give the bile alcohols (14) and (15) in yields of 81-82%.18 I. I .2 Esters and Ethers Gelation properties of the cholesteryl anthryloxybutyrate (1 6) towards a range of organic solvents are reported.19 The ester molecules appear to stack helically with the anthracene residues AR -HOlic'al overlapping one another. HoHcm 0 Several esters of testosterone containing either an alkoxy (7)R = H Me or C-H group or a halogen atom in the acid chain have been prepared for testing as long-acting injectable contraceptives. 2o HO (li:i Cholestanyl 2H-perfluorobutanoate (17) reacts with sec-ondary amines to give the p-enamino-ester (18) which is hydrolysed to the P-keto-ester (19) by acid (Scheme 3).21Mono-, > HoH2c'x3} 0 bis- and tris-(perfluoro-octanoy1)oxy derivatives of sterols and bile acids have been prepared in connection with synthetic blood formulations.22 In the bile acid reactions 4-(dimethyl- HoH2c=a (10) R =Me (9) amino)pyridine was required to catalyse the esterification of the /-hydroxyl group at C-12. Steroids containing perfluoroalkyl groups at C-3 C-7 and C-20 have been prepared for testing as co-emulsifying agents for aqueous perfluoro-octyl bromide blood substitutes by coupling of perfluoroalkyl copper reagents with allylic bromides and by Grignard reactions.23 The perfluoroalkyl Grignard reagents did not react with 6-ketosteroids and radical additions of perfluoroalkyl iodides to Hzcal double bonds were also unsuccessful.0 Perfluoroalkenyl ethers of sterols are obtained by base- (11) R=Me catalysed addition of the alcohols to perfluoroalkenes.24 Use of butyllithium gives 1-perfluoroalkenyl ethers in high yields Reagents i NaBH, MeOH; ii TsOH CHCl,; iii MnO, CHCl,; iv whereas potassium hydride is less effective for deprotonation of K,CO, MeOH the sterol and affords mixtures of 1-and 2-peduoroalkenyl ethers in low yields. Scheme 2 OHC? 0 I OHCO' tl (12) R' = OCHO; R2 = C02H \ (13) R' = H; R2 =C02H (16) (14) R' = OCHO; R2 = CH20H (15) R' = H; R2 = CH20H R2 = Et ,-(CH2I4-(CH 1 2 5-CF3CF2CHFC02R' -[CF,CF=CCFCO,R'] -CF,C=CFCO,R' -CF,CCHFCO,R' I.II (17) Reagents i R,NH CH,Cl,; ii aq. HCl Scheme 3 NATURAL PRODUCT REPORTS 1989-A. B. TURNER 1.1.3 Opening of Epoxide Rings The terminal epoxide (20) reacts with sulphuryl choloride in dry dichloromethane to give a mixture of the allylic aldehydes (21) and (22) in 35% yield.25 Several unidentified chlorinated by-products are also formed. Sharpless epoxidation of the norcholest-24-ene (23) followed by organocuprate cleavage of the resulting epoxide (24) and removal of the protecting groups with acid gives the cholestanetriol (25).26 This sequence provides a diastereo-selective route (Scheme 4) to the (24R,25S)-triol (25). Epoxidation of the 8(14)-double bond of the cholenoates 541 (26) with m-chloroperbenzoic acid gives mixtures of a-and p-epoxides which yield the 8,14-dienes (27) upon treatment with boron trifluoride etherate in dichloromethane.27 Acid-catalysed ring-opening also proceeds without skeletal rearrangement for acylhydrazone derivatives of the analogous 12-0x0-cholanes leading to the corresponding 7,14-dienes. 16a,1701-Epoxypregn-5-en-3,8-01-2O-one(28) undergoes 21-hydroxyl-ation upon treatment with iodosobenzene diacetate and methanolic potassium hydroxide followed by water.28 The product (29) affords a mixture of the hydrazone (30) and the adduct (3 1) after reaction with ethoxycarbonylhydrazine in OHCDl OHC GI H H (20) (21) (22) (24) 111 IV OH Reagents i Ti(OPr'), (-)-diethy1 D-tartarate BdOOH CH,Cl,; ii aq. NaOH; iii Me,CuLi, THF; iv TsOH MeOH Scheme 4 MeO C02Me C02Me&jy HOJ3P H (26) R = H C02Me (27) R = H,C02Me (28) OMe HOH&,,// 0Me NNHC0,Et NNHC0,Et (29) (30) (311 NATURAL PRODUCT REPORTS 1989 (32) (34) 08, HO3C NNHC0,Et H {5 (35) (36) (37) (38) AcO /&y I H (39) (40) (411 @ -+ CI Q X O*N 0 ON02 CIQ + + CI m 0 CI Scheme 5 acetic acid.The epoxypregnenolone derivative (32) reacts with chloroperbenzoic acid followed by cleavage with lithium hydrogen thiocyanate to give the iminooxathiolane (33) which aluminium hydride gives the side-chain epoxide. In mechanistic cyclizes to the oxadiazine (34) with ethanolic ammonium studies of the oxygenation of cholesteryl acetate by tetra-hydroxide.29-31 The carbethoxyhydrazone (35) likewise under- phenylporphinato iron(I11) peroxide systems both allylic goes cyclization to the derivative (26).oxidation and p-selective epoxidation are Epoxi-5a-Androstane-3P,14P 17P-trio1 (37) is formed from 501-dation of cholest-5-ene by sodium hypochlorite in the presence androst- 14-ene-3P 17p-diol (38) by epoxidation of its di-of manganese (porphyrin) acetate or halide as catalyst gives a urethane derivative followed by hydride reduction of the mixture of a-and P-epoxides with the latter slightly pre- epoxide mixture.32 dominating. 35 Addition of pyridine leads to predominance of the a-epoxide (ratio 3:2). Reaction of nitroxyl chloride gas with cholesta-3,5-diene at 1.2 Unsaturated Compounds 0 "C gives 5-chloro-3,6~-dinitro-5a-cholest-3-ene (39).Similar I .2.1 Electrophilic Addition reaction with 3a,5-cyclocholestanes gives a variety of ring-Selective epoxidation of the A22-bond of ergosterol can be opened products (Scheme 5).36 Neighbouring group partici- carried out by protection of the A5.'-diene system with N-pation is most significant in the case of the 19-carbamoyloxy Reaction of the cycloadduct with m-group in the cholestenes (40)-(42) for the addition of ~henylmaleimide.~~ NATURAL PRODUCT REPORTS 1989-A. B. TURNER 543 0@OCOEt 0a' 1 dAc I H F R (42) (43) R = H (45) R = F HOa0 I' HO ; OH Ht) OH (46) (47) {j-$JR2R2 Me0flR H (50)R = CN COMe (51 1 R' = CN COMe R2 = H Me { H . AcO jo (49) (52) (53) hypobromous acid. 37 trans-Iodoacetates are readily formed gives epoxydiols (47) and (48) but cleavage of double bonds from nng A-unsaturated cholestenes 5a-and SP-cholest-1- -2- also occurs in this less hindered diene.and -3-ene in 76-85 YOyield by the action of iodine-copper(i1) Diels-Alder reaction of ergosteryl benzoate and 1,2,3,4-acetate in acetic The fluoroacetate (44),formed in 89 % tetrahydrophthalazine- 1,4-dione in dichloromethane in the yield by addition of acetyl hypofluorite to testosterone presence of lead tetra-acetate gives the adduct (49) in 87% propanoate (43) eliminates acetic acid quantitatively in the yield.43 Diels-Alder reactions of 17-substituted- 16-enes (50) presence of ethyl acetate to give the monofluoro-derivative with 1,3-dienes in dichloromethane at 80 "C and 14 kbar gives (45).39 The reagent AcOF is prepared directly from elemental adducts of type (51).44 The dehydropregnenolone (52) reacts fluorine and the reaction can be used for incorporating the 18F similarly with trans-penta-l,3-diene in the presence of tetra-isotope into molecules required for positron emitting tomo- methylpiperidine N-oxide to afford the endo adduct (53) in graphy.5-Enes react with iodosobenzene and sodium azide in 90 YOyield.45 acetic acid to give 7-azido Thus cholesteryl acetate Thirty 5a-cholestan-6-ones with various substituents at gives 7a-azidocholest-5-en-3P-ylacetate in 95 YOyield. positions 1 2 and 3 have been prepared from cholesterol as substrates for investigation of the regioselectivity of the Baeyer-Villiger oxidation.46 Hydro boration/ oxida tion was 1.2.2 Other Reactions of Olefnic and Aromatic Steroids used to introduce the 6-0x0 group and the 3a-isomers were Deuterium labelling studies indicate that the allylic re-formed by inversion of the configuration of the 3P-tosylate with arrangement which accompanies the oxidation of 5-enes by tetra-n-butylammonium acetate in boiling butan-2-one.The mercury(r1) trifluoroacetate involves loss of the 4P-h~drogen.~~ 2P-isomers were derived from the 2-ene via lithium aluminium Oxidation of 3/3-acetoxycholesta-5,7-diene with per-hydride reduction of the bromohydrin and the inversion of the manganate/periodate gives the epoxytriol (46) in almost 2P-hydroxyl group involved Jones oxidation followed by Birch quantitative yield.42 Similar oxidation of cholesta-2,4-diene reduction of the intermediate 2-oxocholestane.NATURAL PRODUCT REPORTS 1989 Me0 (54) Reagents i BuLi THF TMEDA; ii MOO, pyridine HMPA; iii hv Scheme 6 OR (55) R = H CH20Me (56) (57) Reagents i Bu"Li THF; ii Me,SiCl; iii NBS CHCl,; iv NCS NaI AcOH Scheme 7 Deprotonation of chromium carbonyl complexes of 3-methoxyoestra- 1,3,5( 10)-trienes (54) by butyllithium followed by reaction with molybdenum pentoxide allows efficient regioselective 2-hydroxylation (Scheme 6).47 o-Lithiation of the methoxymethyl ethers (55) of oestradiol using s-butyl-lithium followed by treatment with trimethylsilyl chloride gives the 2- trimethylsilyl derivatives (56),which are readily converted into 2-bromo- and 2-iodo-oestradiol(57) and (58) (Scheme 7)." The cobalt complex (59) catalyses the oxygenation of oestrone and oestradiol at C-10.49Solvent participation is evident as in methanol the p-quinol (60) and the enedione (61) are obtained from oestrone whereas in dichloromethane the p-quinol (60) is accompanied by the epimeric chloromethyl derivatives (62).1.3 Carbonyl Compounds I .3.1 Reduction and Dehydrogenation 5a-Cholestan-2-one is reduced sterospecifically by chloroiridic acid and trimethyl phosphite to the axial 2P-hydroxy-chole~tane.~~ 0x0 groups at other positions were unreactive. Studies on the stereoselectivity of the reduction of 7-ketones by complex metal hydrides hydrogenation over platinum catalysts and sodium in t-butyl alcohol are reported."' The 7p- equatorial alcohols were the major products with 4,4-dimethyl- 3-hydroxy-7-ketones upon catalytic hydrogenation whereas their 3-acetates gave mainly the 7P-alcohols.The dissolving metal system gave mainly the 7P-alcohols but the epimeric 7cr- NATURAL PRODUCT REPORTS 1989-A. B. TURNER (63) R = H CHzCN CH2N3 X HO H (65) X = 0 (66) X = 0 (67) X = 0 (68) X = 0-OH a-Me HO H (70) X = 0-OH CX-CH~CH=CH~ (71) X=H2 01s were the major products with lithium tri-s-butylboro- hydride. The stereoselectivity of reduction with sodium boro- hydride and lithium aluminium hydride was markedly de- pendent upon neighbouring double bonds and the gem-dimethyl groups at C-4. In the reduction of 12-0x0-groups of bile acids with calcium in liquid ammonia great stereoselectivity for 12p- alcohols (78-98 YO)is observed if methanol is present whereas reduction in the presence of a less acidic proton donor (t-butyl alcohol) or in the absence of a proton donor the 12P-alcohols are the main products (63-79 The bromination/dehydrobromination sequence for the dehydrogenation of oestr-5(1O)-3-ones (63) to oestra-4,9-dienones (64) can be carried out with polymeric Yields of 83-86 YOare obtained using polyvinylpyridinium bromide perbromide and polyvinylpyridine in either chloroform or dichloromethane.1.3.2 Other Reactions The reactivity of A1-4-,A4- and unsaturated 3,17-diketones towards Grignard reagents has been studied Methyl (72) X = 0 I IH OCH2Ph magnesium bromide adds to 5a-androstane-3,17-dione to give the 3a-methyl-3P-alcohol (65) in 65 YOyield.Androst-4-ene- 3,17-dione gives the analogous alcohol (66) in 73% yield and androsta- 1,4-diene-3,17-dione gives the methylene derivative (67) in 84% yield together with the alcohol (68). Barbier- Grignard reactions of 3- and 17-ketones with ally1 magnesium bromide yield the cholestanols (69) and the androstanol (70) which give 1,3- and 1,4-diols by hydroboration/~xidation.~~ The diols can be further quantitatively transformed into spiro- ethers (71) by intramolecular etherification with toluene-p- sulphonyl chloride in pyridine or into spiro-lactones (72) by oxidation with Jones reagent thereby providing an effective sequence of reactions for the spiroannelation of these ketones.The spiro-lactones have previously been obtained by Baeyer- Villiger oxidation of spirocyclobutanone cholestanes. Epimeric alcohols (74) are formed in the addition of aryl Grignard reagents to 6-0x0-oestradiol 3-methylether (73).56 Various transformation products of the alcohols (74) including the styrene (75)exhibit only weak oestrogenic activity. Tautomerization of the ketol (76) to the conjugated ketol NATURAL PRODUCT REPORTS. 1989 II AcOa. 0m Ho 6H 0 (77) (79) (80) Ac 0JXx" HO AcOr n 0 H HO (82) (83) (84) (85) Reagents i Me,C(OH)CN NaCN H,O Scheme 8 F (77) is a key step in a method for the construction of the sensitive ring A hydroxyenone system of the q~assinoids.~~ Diketoaldehydes (80)and (81) formed by oxidative cleavage of rings A and B of cis-cholestanediols (78) and (79) cyclize to the acetals (82) and (83).58 The cyanohydrin formed from 18-hydroxyandrostenedione (84) and acetone cyanohydrin under neutral conditions is hydrolysed in situ to the lactone (85) by attack of the neighbouring 18-hydroxyl group (Scheme 8).59 1.3.3 Reactions of a#-Unsaturated Carbonyl Compounds and Enols or Enolic Derivatives A dienolate intermediate has been observed in the base- catalysed isomerization of androst-5-ene-3,17-dione to androst- 4-ene-3,17-di0ne.~OThe kinetics of the isomerization in aqueous sodium hydroxide and in particular the variation of the rate constants with hydroxide ion concentration can be attributed to formation of significant amounts of dienolate ion.A spectral scan of the reaction mixture in 1M sodium hydroxide reveals the presence of the intermediate (A,, 256 nm) and stopped flow measurements allow determination of the rates of formation and reprotonation of the dienolate anion to regenerate the starting androst-Sene-3,17-dione. Conjugated and unconjugated 3-ketones can be selectively protected as their heptafluoro-p-tolyl enol ethers.61 Reaction with perfluorotoluene occurs at below 100 "C in the presence of caesium fluoride. Enones are normally regenerated from their enol ethers by acid hydrolysis. In the case of the dihydro- testosterone derivative (86) hydrolysis is sluggish but the parent compound can be regenerated with sodium methoxide.An application of the use of this protecting group outlined in Scheme 9 is in the synthesis of the deuterium-labelled testosterone (87). (86) . ... I -111 &-F F F CF3 a!P 0 (87) +-Reagents i D,O (C,H,,),NCl NaOD PhMe; ii NaBD, EtOD iii H,O; iv aq. H,SO, THF Scheme 9 NATURAL PRODUCT REPORTS 1989-A. B. TURNER EsH17 (88) R = H (90) R =OCOEt (91) R=OCOMe NOZ (96) R = H CI AcO \-iv (99) \ MeO" / v,vic /vii,viii (102) (92) (94) (95) RQ NHAC H (97) (98) n = 1,2,or 4 H (100) R=CHO (101) R =S02Me Oxidation of the 5-en-7-one (88) by manganese(n1) acetate in a boiling mixture of propanoic acid and propanoic anhydride gives the lactone (89) together with the 4P-acyloxy derivatives (90) and (91) and cholesta-3,5-dien-7-one (92).62 3a-Acetoxy- and 3/?-chlorocholest-5-ene-7-onesgive the same products whereas the 3,5-dien-7-one (92) gives the lactone (89).Reduction of 4-en-3-ones 5-en-3-ones and 3,5-dien-7-ones with lithium in boiling ethylenediamine gives saturated equa- torial alcohols.s3 Similar reduction of the 16-en-20-one (93) gives the (20R)-alcohol(94) in 95 % yield whereas with sodium borohydride the alcohol (94) is accompanied by an equal amount of the allylic alcohol (95).64 The four possible allylic alcohols derivable from progesterone have been prepared in 13-38 % yield using aluminium isopropoxide in isopropyl alcohol as reducing agent in order to confirm the structure of allylic pregnenediols isolated from gonad and breast tissues.65 1.4 Compounds of Nitrogen Phosphorus and Sulphur Reduction of nitro-olefins (96) with zinc/acetic acid without added water gives the N-acetylated enamines (97) together with the corresponding 6-oximes and 6-ket0nes.~~ 1,3- 1,4- and 1,6-Diphosphines (98) have been prepared for evaluation as ligands in metal-catalysed chiral ~ynthesis.~' The 1,4-diphosphines were useful ligands in asymmetric hydrogen- ations the 301- and 3P-derivatives producing opposing enantio- selection preferences when used in these reactions.The 3a- 1,3- diphosphine caused similar enantioselection as the 3a- 1,4- diphosphine in the hydrogenations but use of the 1,6-diphosphine led to lower optical yields.These ligands were less effective in asymmetric C-C bond-forming reactions. The 1 1-thiapregnane (102) is prepared by replacing the I I -0x0-group of the pregnane (99) via the ring c seco-steroids (100) and (101) as shown in Scheme Reaction of triphenylphosphine sulphide and picric acid with the epoxide Reagents i AcOH conc. H,SO, K,S,O,; ii DIBAL PhMe; iii HgO I, PhH; iv hv PhH; v DIBAL PhMe; vi MeSO,Cl pyridine; vii Na,S .9H,O MeCN; viii Me,SiI CHC1 Scheme 10 NATURAL PRODUCT REPORTS 1989 0 Ac 0J37 II HO 11 0 0 (103) X=O (104) X=S 0 Ph R (106) R= H (107) C(108) R = OH Scheme 11 (yytjR -Cg. I L\ H A (109) R = 0-COCl (1 10) (111) R=a-COCI (112) R = CY-OCOC~H~-CI(~) (113) R =cY-OH (114) R = a-COMe (1 15) R P-OAC + (1 16) R = CY-OAC + AcOMO@ 6Ac Scheme 12 (1 19) R = CI OS02Me (120) R’ = Bz R2 = OH or R’ = R2 = H (103) gives the 19-thiiranyloestr-4-ene-3,17-dione (104) the (19R)-enantiomer of which is 75 times more effective as an inhibitor of placental aromatase than the (19S)-enanti0mer.~~ 1.5 Molecular Rearrangements Reaction of (diethy1amino)sulphur trifluoride with the aldehyde (105) is the key step in a new synthesis (Scheme 11) of 19,19-difluoroandrost-4-ene-3,17-dione (106).’O The rearranged linear steroid (107) is also formed.The gem-difluoro compounds (106) and (108) inhibit human placental aromatase in vitro but are not as potent as 4-hydroxyandrost-4-ene-3,17-dione. The influence of the geometry of the cyclobutane ring and the relative configurations of its substituents in the skeletal rearrangement of D-norsteroids to abeohomodinorsteroids has been Treatment of the l3a-compound (109) with rn-chloroperbenzoic acid in the presence of pyridine gives the abeohomodinorsteroid (1 lo) previously obtained from the 13P-epimer as the virtually exclusive product.However the isomeric 16a-carbonyl chloride (1 11) reacts with the peracid to give the rn-chlorobenzoate (1 12) via a carboxy inversion of the initially formed acyl aroyl peroxide followed by decarboxyl- ation. The ester (112) is hydrolysed by base to 17-nor-5a,13a- androsten- 16a-01 (1 13) the product of Baeyer-Villiger oxi-dation of the 16a-acetyl compound (I 14). Solvolysis of the tosylates (1 15) and (1 16) leads to products with rearranged bi- and tri-cyclic AB rings (Scheme 12).72 Westphalen rearrangement of 501-hydroxy-6-0x0-steroidscan be carried out at room temperature in tetrahydrofuran or trifluoroacetic acid in the presence of potassium hydrogen sulphate and trifluoroacetic anhydride.73.74 The SP-hydroxy-6- oxocholestane (1 17) also rearranged to the cholestan- 1,3,5- trienone (1 18) with potassium hydrogen sulphate and acetic anhydride in dimethylacetamide. 74 The action of nucleophilic reagents such as potassium and silver acetate and lithium aluminium hydride on 6j3-substituted 5/3-methylcholest-9-enes (1 19) gives mainly products of type (120),75 and the complete metal hydride also gives the cyclo-steroid (121) and the seco- steroid (1 22).A spiran has been isolated from the acid-catalysed re-arrangement of a p-quinol thereby providing direct evidence 549 NATURAL PRODUCT REPORTS 1989-A. B. TURNER pJs 0 0 0& (123) ( 124) (125) 0 (126) H OR (128) R = H (130) X2=0 X'=s (129) R=COMe orx' =x2=S I ____) ?CON Reagents i Cl,CHCHCI, 140 "C; ii KOH triethyleneglycol (127) H (131) ( 132) a / L-cd + (31%) (43%) (31%) \ ?H (43%) {DI NH2 Scheme 13 for the long-accepted mechanism for the dienone-phenol rearrangement. '15 Depending upon the acidic conditions the p-quinol (123) yields the spiran (124) or the usual phenolic products of the dienone-phenol rearrangement. The spiran is the neutral form of the spirocation intermediate in the dienone-phenol rearrangement of the p-quinol.Treatment of the p-quinol (123) with toluene-p-sulphonic acid in boiling water followed by neutralization with bicarbonate and column chromatography gives the spiran (124) and the acetone adduct (125) in a ratio of 3 :1. This follows the isolation of the related spiran (127) from the acid-catalysed rearrangement of 3-boromocholest-2-en-4-one (1 26) which is thought to aromatize by a dienone-phenol type pathway." Boiling a solution of the bromo-enone (126) in acetic acid containing an excess of potassium acetate produces a mixture of the spiran (1 27 ;22 YO) and the aromatic steroids (128 ;32 YO)and (129; 6 YO). Dienone-phenol type rearrangement occurs in the reaction of oxathiolane and dithiolane derivatives of 501-and 5p-3- ketones (130) with copper(I1) bromide to give the cholesta- 1,3,5(10)-trienes (131).78 Oxidative rearrangement of 5a-cholestan-3-one with thallium (111) nitrate in acetic acid at room temperature gives a mixture of 2a-carboxy-~-nor-5a-cholestane (1 32) and its 2p-epimer the former pred~minating.'~ The pure 2a-acid is obtained by resolution with dehydroabietylamine.1.6 Remote Functionalization Reactions The applications of azidoformates in steroid functionalization via oxycarbonylnitrene intermediates have been reviewed.8u 1 7-Substituted oestrone-derived nitrenoformates insert into either the 12p (from 17p) or 14a (from 17a) carbon-hydrogen bonds (Scheme 13) whereas 17-derivatives having the nitrene on the end of a long inert chain abstract hydrogen from the steroid B-ring.*l NATURAL PRODUCT REPORTS.1989 H =-;q 0 0 (133) (136) The 3a-ester (133) prepared by Mitsunobu reaction of thioxanthone- 3-carboxylic acid with 5a-cholestan-3/3-01 under- goes selective photochemical chlorination at the 9a-position with iodobenzenedichloride thereby providing an authentic example of a free radical relay reaction directed by the thioxanthone template.62 Hydrolysis of the product esters with methanolic potassium hydroxide and acetylation of the neutral fraction gives the olefin (134) in 62-71 YOyield together with recovered thioxanthone-3-carboxylic acid (97 YO).The nicotin- ate ester (135) similarly reacts with C-9 whereas the iso- nicotinate ester (136) chlorinates both at C-6 and C-14.83 The 17-nicotinate esters of cortexolone acetate and its 16a-methyl derivative both chlorinate at C-9 as expected for a chain reaction involving transfer of a chlorine atom from PhICl’ to the pyridine ring nitrogen followed by delivery of the chlorine atom to a geometrically accessible hydrogen.Such pyridine complexes are reasonably stable as well as selective. 1.7 Photochemical Reactions The photochemistry of steroidal ketones has been reviewed.84 Irradiation of the 12-oxocholane (137) obtained from deoxycholic acid gives the cholenol (138) in 75% yield.85 Deoxycholic acid forms complexes with a variety of aceto-phenones and propiophenones. These undergo photoaddition to give a single diastereomer in the case of 4-fluoroacetophenone and diastereomeric mixtures in other cases.86 The product configurations are rationalized in terms of the crystal packing of the initial host-guest complexes.Irradiation of the cyclopropane (139) in benzene gives the ring-D expanded enone (140) in 50% yield providing a convenient route to ~-homosteroids.~’ 5,6-Epoxy-4,4-dimethyl-3-ones photolyse in the same way as the corresponding 4,4- dimethyl-3-ones in methanol in that little epoxide cleavage occurs and the products formed are the methyl 5-isopropyl-4- nor-3,5-seco esters.86 In ether the 3-oxo-SP,6/3-epoxide photo- decarbonylates by a stereoelectronically controlled process. Irradiation of (E)-Sa-cholest- 1-en-3-one oxime (141) in protic or aprotic solvents with a low pressure mercury arc gives the isoxazole (142) by a stereospecific ~earrangement.~’ A proposed mechanism involving ring-opening to a nitrile oxide followed by intramolecular stereospecific 1,3-dipolar addition is supported by deuterium labelling work.The solid state reactivity of the crystal modifications of hydrocortisone esters has been studied.g0 The hexagonal crystal 0 tie Me OMe (145) (1 44) Scheme 14 forms react with oxygen in the presence of ultraviolet light to give the corresponding 11-ketones but the orthorhombic forms are not photo-oxidized. The antioxidant butylated hydroxy- toluene inhibits the oxidation of the hexagonal forms. The sensitized photo-oxidations of the N-methylated lactams (143) and (144) affords the fragmentation products (145) and (146) via the corresponding dioxetanes (Scheme 14).91 However the enamine (147) gives the ketol (148) paralleling the previously reported behaviour of the unmethylated lactam (149) which gives the ketol (150).Lone pair availability at the nitrogen atom is a possible factor underlying these differences although the possible influence of the remote substituents at C-17 has not been investigated. Intramolecular functionalization of amides occurs upon photolysis in the presence of iodosobenzene diacetate/iodine leading to lactams as with the amide (151) which gives a mixture of the spirostane lactams (152) via a 1,6-hydrogen shift.g2 NATURAL PRODUCT REPORTS 198GA.B. TURNER 55 1 0 xqh 0-H Me (147) X= Hz; R = H (148) X=Hz; R=H (151) (149) X=O; R=Ac (150) X=O R-Ac 17 H OMe (152) R=H,I (153) ( 155) R ~ HO/’ I 0 I RO43 ti H (156) (157) R = H Ac (158) R = SPh Sneus ( 159) Photolysis of the cyanamides (153) and (155) in the presence of iodine and lead tetraacetate gives N-cyanoepimino com- pounds (1 54) and (1 56) via intramolecular hydrogen abstraction iV ____) in the intermediate cyanimyl radicals.93 Better yields are HO obtained with iodine and iodosobenzene diacetate e.g. the tormatidine analogue (154) can be isolated in 85 YOyield. The H-t-j starting cyanamides are prepared by hydride reduction of Me + oximes or amides followed by cyanation with cyanogen bromide i-iii-(160) R = H or with sodium cyanate and subsequent dehydration of the b(161) R=OH HO urea derivatives with methane sulphonyl chloride.Photolysis of hypoiodites of alcohols generated in situ in benzene with three molar equivalents each of lead tetraacetate 0 and iodine gives the corresponding lactol acetates in yields of up to 66 Yo.94 Thus cholesterol gives 4-oxa-~-homocholest-5- Reagents i Et,N DMF Me,SiCI ; ii m-ClC,H,CO,H C,H1 ; iii en-3-01 (157) and its acetate in 53 ‘YOyield. A dimeric acetal is +-Bu,NF SO,; iv PhMe 1 10°C argon also isolated in 8 % yield. Photolysis of the 8-lactols (1 58) in the presence of iodosobenzene diacetate/iodine gives the lactone Scheme 15 (159) by 1,4-fragmentation of the intermediate y-thiyl and y- stannyl alkoxy radicakS5 In this way two features of ring A of vernolepin (the &-lactone ring and the angular vinyl group) are introduced in the model compound in a single step.The allylcholestanone (160) formed from cholestenone by photoaddition of allene followed by photobromination and cleavage with lithium-ammonia in tetrahydrofuran has been converted into the ketol (161)? Further transformations lead to ethano-bridged steroids (Scheme 15). The iodoester (162) derived from methyl pimarate undergoes radical cyclization upon irradiation in the presence of tributyltin hydride to give the ester (163) in 67% yield.g’ This type of C0,Me cyclization increasingly used for the construction of cyclo- pentane rings provides an efficient approach to the steroid (162) ( 163) skeleton from a diterpene.NPR 6 NATURAL PRODUCT REPORTS 1989 (166) rn = 0,l; n = 1,2 5,6-dihydro; rn = 0 n = 1,2 @0 NO* (167) (168) (169) 2 Partial Syntheses 2.1 Derivatives and Analogues of Cholestane (25R)-26-Deuteriocholesterol (164;X = D) has been prepared from yamogenin via the (25S)-26-alcohol(164; X = OH) which was reduced with lithium aluminium de~teride.~~ Conditions were developed for the resolution of (25R)-and (259-26- hydroxycholesterol by reversed-phase HPLC. Several examples of a new class of lariat ethers having cholestane (165) and cholestene (1 66) side-arms and including both carbon and nitrogen pivot systems exhibit only weak binding to alkali metal cationsOg9 Surprisingly the high lipophilicity of the side-arms fails to enhance the cation binding powers of the molecules.The X-ray crystal structure of hi-(cholestery1oxycarbonyl)aza-15-crown-5 (1 66; m = 0 n = 1) shows the inwardly- turned ring methylene characteristic of uncomplexed 18-membered ring crown ethers. Details have appeared of the synthesis from pregnenolone of fluorescent cholesterol analogue probes containing three conju- gated double bonds in the side-chain.loo The preparation and properties of analogues containing two double bonds linked to aromatic systems are also described. A new paramagnetic analogue of cholesterol 27-nor-25-doxylcholest-5-en-3~-ol contains the nitroxide group in the side-chain,lol but retains three vital molecular interactions of cholesterol itself.These are the abilities to interact with polyene antibiotics to widen the transition temperature of dimyristoylphosphatidylcholine to the same extent as cholesterol and to assume an orientation perpendicular to the phospholipid bilayer with the nitroxide group buried in the membrane core. Thus despite having a side-chain different from cholesterol it promises to help to answer many questions relating to the distribution and mobilization of cholesterol in biological systems. The overall orientation of these spin-labelled analogues of cholesterol and also of androstanol in egg phosphatidylcholine bilayers have been determined by spectroscopic studies. lo2 The cholestanes show a single orientation in each monolayer with the acyl chain pointing towards the centre of the phospholipid bilayer whereas the androstane appears to experience two opposite orientations in the same monolayer although rapid reorientation may occur.Several liquid-crystalline quaternary ammonium deriva- tives of cholesterol some of which are polymerizable meth- acrylates are found to have vesicle-forming properties as shown by (14C)-sucrose entrappment experiments. lo3 Details of the syntheses of 5-hydroxy-6-oxocholestanesand their 7a-deuterio derivatives used in recent photochemical studies have appeared.lo4 Reaction of the Sa-ketol (167) with potassium t-butoxide gives the 5P-ketol (168) in 58% yield together with the isomeric 2-ene (3%). The isomers were separated by flash chromatography on silica gel impregnated with silver nitrate.Reaction of 6-nitrocholesteryl acetate (1 69) with lithium dimethylcuprate in ether gives the cyclosteroid oxime (1 70) in 65 YOyield. Thermolysis of the 5a-cholestane-6- NATURAL PRODUCT REPORTS 1989-A. B. TURNER R N\ (171) R = H,OAc R * Rrn /N\ iN\ H NO 0 OAc L (174) R = H,CI,OH (175) (176) X=H2 (177) X=O HOmOH R = Ph Me I. ... lI,III HOJZt0" Reagents i Cr(CO), ButOOH MeCN; ii NaBH, CeCl, MeOH THF; iii Na,CO,; iv LiB(CHMeEt),H THF Scheme 16 H*l storage.lo6 6-Nitrocholest-5-enes can be reduced to oximes in 78-85 Oh yield with zinc and methylamine.lo7 Hydroboration of 5a-cholest-8-ene and 5a,14P-cholest-7-and -8-enes provides a convenient route to ring D-oxygenated + CH,SO,P h derivatives of the 14P- and 8414P-~eries.'~* The oxidation of cholesterol to cholestanone by potassium dichromate deposited OCH,OEt upon various inert solids has been studied.lO@ L Solids with small surface areas and large pore diameters give more active i-iv reagents than solids with high surface areas and large pores.Allylic oxidation of cholesterol derivatives with chromium- based reagents has been further investigated.'1°-l12 Th us reaction of cholesteryl esters with pyridine dichromate in pyridine or pyridinium chlorochromate in benzene or dimethyl sulphoxide gives yields of 7-ketones in the range 63-89 %.llo The cholestenone (176) gives the enedione (177) in 61 YOyield upon treatment with excess of t-butyl hydroperoxide in the presence of catalytic amounts of chromium trioxide at room temperature.'l' Epoxidation of the double bond is minimal.(178) Use of chromium hexacarbonyl as catalyst is also effective in the allylic oxidation of cholesteryl esters.l12 Reduction of the 7- Reagents i LDA HMPA THF; ii Na-Hg EtOH; iii 3M-H,S04 oxocholesteryl acetate so produced with the sodium boro- THF; iv conc. HCl THF hydride-cerium(II1) reagent gives exclusively the 7a-alcohol Scheme 17 whereas use of L-selectride gives mainly the 7P-isomer (Scheme 16).11' During work on pentacyclic steroids attempts to achieve led only to nitroimines (171) in boiling xylene gives complex mixtures of conjugate alkylation of 3-alkoxycholest-4-en-3-ones products following homolytic cleavage of the N-nitro bond.'05 attack at the carbonyl group.113 Cholest-4-ene-3,6-dione is (1 72) similarly attacked at C-3 but 4a-alkylation is favoured during Similar treatment of 3~-chloro-7-nitroiminocholest-5-ene gives only cholestadiene (1 73).The mi-nitroamines (174) react reductive methylation. (25S)-26-Hydroxycholesterol (1 78) has with acetic anhydride in pyridine at ro6m temperature to form been prepared from stigmasterol and (S)-( -)-ethyl 4-hydroxy- the acetate (1 79 which gives alkenes upon prolonged 3-methylbutanoate (Scheme 17).l14 22R-Hydroxy-desmosterol NATURAL PRODUCT REPORTS 1989 OH HO (179) R' = H; R2=OH (180) R = OH ( 182) (183) (181) R' =Ac; RZ = H (184) R = H Me (186) Scheme 18 HO I I (188) (179) and -1anosterol (180) have been prepared via coupling reactions with arsenic ylides.'15 Desmosterol acetate (18 1) is obtained in 83% yield by isomerization of 25-dehydro-cholesteryl acetate (182) with iodine in benzene.l16 The diene (182) is isolated in 69% yield after condensation of the 22- (189) hydroxycholadiene (1 83) with 1 -(dimethylamino)- 1-methoxy-prop- 1 -ene using a simplified procedure.1401-Methylcholestero1 has been prepared in nineteen stages from lanosterol (184) in I 1-2 YOoverall yield.'l' The synthesis of trimethylcholestenone (185) from lanosterol (184) involves the 7,ll-dione (186) as a key intermediate (Scheme 18).l18 Separation of the epimers of OH 24-isopropenylcholesterol (187) by reversed-phase HPLC allows determination of the side-chain configuration of the unusual orchid sterol (188) as 24S.l19 The stereochemistry at C-24 of each epimer was established by chemical correlation with sitosterol or clionasterol.Many fatty acid esters of 3p-hydroxy-5a-cholest-8( 14)-en- 15-one have been synthesized for testing as inhibitors of sterol biosynthesis.120 Highly tritiated antheridiol (1 91) and its deoxy-derivative (190) are prepared by aldol condensation of the aldehyde (1 89) with the carbanion derived from 3-isopropyl-2-butenolide i-iiic(190) X = H2 (Scheme 19).121 The product with the desired 22S,23R stereo- (191) x = 0 chemistry was separated and reduced with tritium using homogeneous catalysis. The tritiated male-activating steroids Reagents i Me,SiCl pyridine; ii CrO, dimethylpyrazole ; iii H,Oi have been used to detect a protein receptor in the cytosol of the Scheme 19 aquatic fungus Achyla.NATURAL PRODUCT REPORTS 1989-A. B. TURNER 555 OH 0H HO 0 (192) (195) R HO ?H 0 Ac 0 R= .-A? -OAc A 0 OMe (194) R = OOH (199) (196) R = OH (198) C D-(201) R’ =OH; R2 = H (203) (202) R’=H; R2=OH Homodolichosterone (1 92) and related 2-deoxy derivatives are prepared by a sequence involving initial reaction of the epoxide (193) with phenylselenyl anion followed by heating {&+ with hydrogen peroxide to effect syn-elimination.122 The dCHO ;* epoxides of the resulting ally1 alcohols are readily separated by column chromatography and the desired epimer is ring-opened AcO” with aluminium isopropoxide in refluxing toluene.Ferrous bo-I sulphate causes rearrangement of the 14a-hydroperoxy-7-en-6- Hf OAc one (194) to the 13(14+8)-abeo compound (195) which was .. ... previously obtained by irradiation of 20-hydroxyecdysone 11,lII (*04) A = (196).123 The hydroperoxide is efficiently prepared by exposure of the diacetonide of the ecdysone (196) to lithium in liquid ammonia-tetrahydrofuran without exclusion of oxygen fol- lowed by deprotection with acid. Cyclosteroids (197) and (198) from stigmasterol and (199) from pregnenolone are key intermediates in the synthesis of (202) -naturally occurring brassinosteroids including brassinolide (200) teasterone (20 l) and typhasterol (202).124-127 Side-chain deuteriated derivatives of these compounds have been Reagents i A THF; ii H Pt AcOH; iii LDA MeI THF prepared from the crinosterol (203).128 Typhasterol (202) has also been synthesized stereoselectively from the aldehyde acid Scheme 20 (204) via a side-chain butenolide intermediate (Scheme 20).NATURAL PRODUCT REPORTS 1989 OH I (205) AcO AcO (208) (209) as (207) (215) (216) €andZ (219) (220) 22S,23S-Homobrassinosteroids based on stigmasterol have been prepared,130 the 22S,23S-diol system being introduced by hydroxylation with osmium tetroxide or via epoxidation. Cholesta-5,22E-dien-3P-o1 has been converted into 28-norbras- sinolides and the related cholestanes (2O5).l3l The pregnan- 21-oic acid (206) prepared from the androstane carboxylic acid (207) by a sequence starting with an Arndt-Eistert reaction showed poor plant growth promoting 19-Hydroxycholesteryl acetate (208) reacts with lead tetra- acetate and copper(I1) acetate in boiling toluene to give the diene (209) and the diacetate (210).133 These were converted into the phenol (21 1) by hydrolysis with methanolic potassium hydroxide followed by oxidation with Jones’ reagent.The corresponding series of 19-nor-spirostanes can be similarly prepared from 19-hydroxydiosgenin. Prolonged reaction of pennogenin 3,17-diacetate (212) with boron trifluoride etherate is now found to give the diene (214) as well as the spiroketal- orthoester (21 3).134 Both of these products are probably formed via the common intermediate (215) which arises by neigh- (207) AcO A HO /xxl OAc (210) (213) OAc (222) bouring group participation of the 17a-acetoxyl group.The structures (213) and (214) are supported by detailed spec- troscopic studies. Oxidation of diosgenin and its acyl derivatives with hydrogen peroxide in glacial acetic acid gives a series of polyols oxygenated at carbons 3,4,5 and 6.135 The structures of the internal acetals (217) and (218) have been determined by X-ray ana1~sis.l~~ The alcohol (217; R = H) is prepared from (Z)-3/?-acetoxy-5,10-secocholest-1(1 O)-en-5-one (2 16) by epoxidation acid-catalysed cyclization and deacetylation. Osmylation of the (@-isomer of (216) gives the acetals (217; R = Ac) and (218).Thermolysis of 5,801-epidioxy-5a-cholestan-3/?-ylacetate (2 19) under acidic con-ditions gives the rearranged 5a,8a-epoxide (220) in addition to the 5,lO 8,9-diseco derivatives No products of the competing reductive 8,14-m0nofragmentation process previ- ously observed in the androstane series were found. The Diels-Alder reaction of ergosteryl acetate with propynal gives the adduct (222) which undergoes a retro reaction driven by aromatization of the cyclohexadiene ring to form the ansa- NATURAL PRODUCT REPORTS 198P-A. B. TURNER But Me$ i0 L (230) R = CH(SeMe)z (243) R = CH=CHCHMeCHMe CHO C (224) 0 AcO Ph (228) (229) R' OH MeOC H2? MeOCH20 (231) X = OH R2 = H (233) R' = (CH2)2C(OH)Mez (232) X = OH RZ = H R' = CHzC(0H)MeEt (234) R' = X = H R2 = CHMe2 or R2 = X = H R' = CHMez secosteroid (223).13' The regioselectivity of the cycloaddition is confirmed by an X-ray crystal structure determination on the dimethyl acetal of the aldehyde (223).2.2 Vitamins D their Derivatives and their Metabolites Recent developments in methods for the synthesis of calciol and related compounds have been reviewed,139 and the first part of Vol. 49 of the journal 'Steroids' is a special issue devoted entirely to this An improved route to the ring A precursors (224) and (225) of calcitriol is now available from (9-( +)-carvone.141 The chiral synthon (226) prepared from (R)-(+)-malic acid and acetone dimethyl acetal is readily converted into 24(R)-hydroxy~alcidiol.~~~ Elaboration of the side-chain diol system is achieved by base-catalysed condensation of the derived iodide (227) with the ester (228) followed by reduction of the ester group to methyl and deprotection by standard methods.24- Hydroxyercalcidiol and 22,24-dihydroxyercalcidiolhave been prepared together with several related metabolites from ergosterol via the ketol (229).143 Reductive alkylation with isoamyl bromide of a selenoacetal intermediate (230) available by functional group modification of la-hydroxyercalciol derivatives gives two diastereoisomers the configurations of which are determined by spectroscopic methods.144 Photo-induced deselenation generates the calciol side-chain en route to la-hydroxycalciol.Two side-chain homologues (23 1) and (232) of calcitriol have been prepared in order to identify a new metabolite of 24-epi-ercal~idiol.'~*~ The 26-homo compound (232) proved to be identical to the metabolite. Orthester Claisen rearrangement of the allylic alcohol (233) was used for construction of the side-chains and the 22,23-dihydro analogues were also prepared. These homo- logues are as active as calcitriol in their bone-calcium mobilizing activities. (229- and (22Z)-Calciols (234) synthesized stereo- specifically from C-22 aldehyde precursors differ in their ability to mobilize bone calcium and to cure rickets in rats.lA6 The E-isomer is as effective as calciol or ercalciol but the Z-isomer is less effective. NATURAL PRODUCT REPORTS 1989 ’ OH OCH20Me Br HO‘ (235) (236) (238) R = H (239) R=OH F‘x31 Ac 0 0 0Ac (240) (2411 (242) Scheme 21 ‘gH17 65.t iMe2Buf CH A stereoselective synthesis of la-hydroxycalciol involves solvolysis of the bicyclohexane (235) prepared by condensation ‘BH17 of the aldehyde (236) with the vinyl bromide (237).14’ The synthesis of la-hydroxy-22-oxacalciol(238)and its 25-hydroxy derivative (239) has been carried out starting from dehydro- epiandrosterone.14* Reaction of 3,6P-diacetoxycholest-2-ene (240) with caesium fluoroxysulphate gives 6P-acetoxy-231- c;d OMe fluorocholestan-3-one (241) which can be converted into 231- fluorocalciol (242) as outlined in Scheme 21.’49 Reaction of the p bis-silylether (243) with butyllithium gives the n-pentyl derivative (2M).150 R Two routes to the labelled intermediate (245) have been developed in the synthesis of epimer cis-isotacalciol analogues R’ = H HO/’ (246).151 This has been used to confirm the antarafacial stereochemistry of the thermal [ 1,7]sigmatropic hydrogen shifts (248) (250) which the alcohols (246; R’ = OH R2 = H) and (247) undergo at 67-98 “C.Chiral cyclohexanones derived from ( + )-and (-)-carvone have been condensed with the ethyne (248) to give adducts of type (249) from which dihydrocalciol (250) and related compounds are formed by reductive eliminations induced by low-valent titanium complexes. 152 (249) Cholesta-4,6-dien-3/3-01(251) is formed by dehydrobromin- ation of 7-bromocholesterol with base in the presence of a NATURAL PRODUCT REPORTS 1989-A.B. TURNER ii.iii (2511 (2521 (253) Reagents i DDQ dioxane;ii TsOH butyl acetate isopropenyl acetate ;iii Ca(BH,), EtOH MeOH Scheme 22 I 1 I catalytic amount of tetrabutylammonium bromide.lS3 Oxi-dation of the di-allylic alcohol (251) with dichloro-dicyanobenzoquinone then gives the trienone (252) which is converted into the 1,5,7-trien-3,8-01 (253) by enol acetylation followed by hydride reduction (Scheme 22). HO 2.3 Cholanes Norcholanes and Dinorcholanes HO Various aspects of inclusion phenomena continue to excite interest and among those related to chemical reactivity there is the possible use of inclusion compounds in solar energy storage. The isomerization yield of norbornadiene to quadri- cyclane under solar irradiation in the presence of pinacolone is found to be highest in the channels of deoxycholic acid as compared to the isomerization in hexane solution or in deoxycholic acid on a quartz ~1ate.l~~ The formation of by- R = H,Me products is also markedly reduced when the bile acid is present.The mechanism of the photoaddition of guest acetophenone (254) and p-fluoroacetophenone molecules to host deoxycholic acid has been studied by X-ray diffra~ti0n.l~~ The analysis revealed that there is minimal motion of the phenyl ring during the course of the photoconversion although considerable rotation Rq of the acetyl group is evident together with displacement of unreacted and reacted molecules.The crystal structure of a 1 :1 complex between cholic acid and methanol shows that the alcohol molecules are trapped within the host molecules by hydrogen Inclusion compounds of cholic acid with a wide variety of organic compounds have been further studied.lS7 In almost every instance the molar ratio of host to guest components is 1 :1. However a 2 :1 complex is formed between R deoxycholic acid and ferrocene. Its structure has been de- termined by X-ray crystallography. 158 This is the first example of an organometallic compound to be found tightly bound in the lattice channel of deoxycholic acid. New synthetic hosts (254) incorporating two molecules of cholic acid linked by a rigid diamine have been designed.lS9 Spectral studies indicate that the compounds have a rigid conformation with the steroid hydroxyl groups intramolecularly hydrogen bonded.Addition of methanol leads to conformational isomerization owing to the introduction of methanol into the cavity and similar (255) changes are caused by heating. Membrane-spanning steroidal metalloporphyrins have been prepared for use as site-specific catalysts in synthetic vesicles. 160 The iron porphyrin (255) is prepared by condensation of the aminophenylporphyrin with 3P-hydroxychol-5-enic acid using the mixed anhydride method to form the amide linkages. Intercalation of this complex into a phospholipid bilayer produces an assembly which functions as a regioselective catalytic oxidation system. Epoxidation of polyunsaturated sterols and fatty acids takes place at the double bond closest to the hydrophobic terminus of the molecule.Thus for example epoxidation of desmosterol or fucosterol leads exclusively to side-chain epoxidation (ca. 30% yield in each case). Regio- selectivity is controlled by membrane rigidity as addition of cholesterol alters the selectivity of the system for epoxidation of polyunsaturated fatty acids towards increased selectivity for oxidation at the hydrophobic terminus. The action of dichloro- ethyl phosphate upon 3a-acetoxy- 12a-hydroxy-5~-cholanic / RO ’ acid in dichloromethane in the presence of triethylamine gives H the bislactone (256) containing a sixteen-membered ring. 161 (256) R=Ac Hydrolysis of this diacetate with base gives the diol (257) the (257) R = H structure of which has been determined by X-ray analysis.NATURAL PRODUCT REPORTS 1989 (260) X = Br (258) (259) (261) X= H (R3M)2 H DCA (262) R = Me or Ph M = Si Sn,Pb H3DCA= 3a,l2a-dihydroxy-5P-cholan-24-oicacid k' H (263) R' = R2 = H; R3 = OH (266) R = CH20H; X = P-H a-OH (264) R' = OH; R2 = R3 = H (269) R = W2Me; 'X-= 0 (265) R' = R3 = H; R2 = OH (270) R = C02Me; X = P-H a-OH (268) Catalytic hydrogenation of the ester (258) prepared from lithocholic acid has been studied under a wide variety of conditions.162 Hydrogenation in acetic acid over platinum leads to the Sa-dihydro derivative without affecting the A8 bond of Ianosterol thereby overcoming a major obstacle to the conversion of bile acids into tetracyclic triterpene antibiotics.Sulphation of 3a,7P-dihydroxycholanic acid with chloro- sulphonic acid in pyridine gives readily separable mixtures of the two monosulphates and the disulphate. 163 7-Acyl-cheno-and -urso-deoxycholic acids are obtained in good yields from the corresponding acids by diacylation followed by selective hydrolysis with potassium hydroxide in aqueous methanol. 164 In the case of 7-oleyl derivatives an efficient method involves selective protection of the 3u-hydroxyl group with methyl chloroformate prior to acylation with oleyl chloride and selective removal of the protecting group with base. Bromo- fluorination of the 11-ene (259) with N-bromosuccinimide and tetra-n-butylammonium fluoride followed by treatment of the resulting 1 Ip-fluoro- 12a-bromoester (260) with tributyltin hydride in situ provides an efficient route to the lib-fluorocholanoate (261).165 Tributyltin taurocholate taurodeoxycholate and glyco-cholate prepared by reaction of the bile acids with di(tributy1- tin) ether show some promise as antitumour agents.166 Organo- silicon -tin and -lead derivatives of deoxycholic acid of type (262) have tetrahedral geometries around the central metal atoms in solution although for the tin compound a polymeric structure with both tin atoms pentacoordinated in the solid state is proposed.lG7 The unusual bile acids (263)-(265) have been prepared from the 3-0XO derivatives of deoxycholic and lithocholic acids respectively to provide samples for the assay of these compounds by GC-MS in cases of abnormal metabolism of bile acids.lG8 Petromyzonal(266) a rare bile substance produced by the lamprey in its larval form before it becomes parasitic has been prepared from cholic acid.169 The inversion of configuration at C-5 is accomplished by oxidizing the 7,12- diformyl ester (267) with m-iodoxybenzoic acid in the presence of a catalytic amount of benzeneseleninic anhydride to the 1,4- dien-3-one (268) followed by deformylation with methanolic sodium carbonate at room temperature and hydrogenation over chlorotFis(tripheny1phosphine)rhodium to give the 5u-3-ketone (269).Reduction of the 3-0x0 group with potassium tri- s-butylborohydride at -78 "C gives the methyl allocholate (270) in 95 YOyield and final reduction of the ester group gives the bile alcohol (266).The chemical degradation of the plant aglycone sarverogenin to several known bile acid derivatives establishes that it contains the steroid skeleton and confirms the structure (271) proposed in 1969 on the basis of spectroscopic data.170 Further applications of the [2,3]Wittig and [3,3]Claisen rearrangements in side-chain synthesis allow stereocontrolled NATURAL PRODUCT REPORTS 1989-A. B. TURNER p“ 12.31 Wittig OMe (272) (274) R =H (274) R=Me OCH2Ph I [3,3] Claisen (273) (275) R =H CH2N*L (275) R=Me Scheme 23 HO H (276) (277) H (280) X =S=O (282) (279) f281) X=O formation of the (225)- and (22R)-hydroxy-23-carboxylicacids (274) and (275) respe~tive1y.l~~ These are isolated as their methyl esters in 82-88 YOyield as single stereoisomers (Scheme 23) following rearrangement of the 17(20)-pregnenes (272) and (273).3P-Hydro~y[21-~~C]-5P-pregn-8( 14)-en-20-one (278) has been prepared by degradation of the side-chain of 3a,7a- dihydroxy-5P-cholanoic acid (276).172 The intermediate etianoate (277) undergoes dehydration in ring B with con-comitant migration of the double bond to the 8(14)-position. Conversion of the cholanic acid (279) into the pregnanedione (282) via the sulphine (280) and the keto-ester (281) provides another efficient degradation of the bile acid ~ide-chain.”~ The a-sulphine ester (280) is obtained by reaction of the acid (279) with thionyl chloride in the presence of an excess of pyridine followed by quenching with methanol.Cleavage of the sulphine group is readily achieved with a variety of oxidants but for large-scale work the best method is non-oxidative and involves treatment of the sulphine (280) with acetic anhydride in the presence of catalytic amounts of sulphuric acid. The keto-ester (281) which is obtained in >79% yield is then exposed to air in the presence of copper(r1) ions and base to give the 20- ketopregnane (282) in 59 YOoverall yield. Use of copper(1) ions allows isolation of the intermediate 22-aldehyde in high yield. 2.4 Pregnanes Sulphation of aldosterone using the triethylamine-sulphur trioxide complex in pyridine coupled with a purification procedure involving adsorption on a reversed-phase C,,‘Sep-pak ’cartridge provides a convenient synthesis of aldosterone 21 -sulphate.17* This improved general procedure can be extended to the preparation of other steroid sulphates.For larger scale syntheses where a single ‘Sep-pak ’cartridge is unsuitable owing to its limited loading capacity (ca. 10 mg) the same effect can be achieved (after extraction of any unchanged starting material) by pumping the aqueous steroid sulphate solution through a conventional HPLC system equipped with a C,,-reverse phase bonded packing washing the system free of inorganic salts and finally pumping methanol through the column to elute the conjugate. It is also possible to carry out ion exchange on the reversed phase column after retention of the conjugate by washing with an aqueous solution of the NATURAL PRODUCT REPORTS 1989 ,cH20Si M~~EI~' OH H 0JdFj 041 (283) (284) CH-OH &cH20H OH 0#H2R3 0 (287) R' = OH; R2 = R3 = OAc (286) (288) R' = R2 = R3 = OH (289) R'R2 = -0-;R3 = OH C H-OH I L c=o CHO I 0DY- (290) R=OH (292) (293) (291) R = H -.I ..II {b\\ H CH,SnBu ...Ill ~ &OH 7 iv - OMe (295) (294) Reagents i KH THF; ii ICH,SnBu,; iii ButLi THF; iv H, Pd-C Scheme 24 appropriate cationic acetate prior to elution with methanol.Protection of the side-chain of aldosterone as the 21-t-butyldimethylsilyl ether masks the 21-0x0 group by locking the molecule into its 11,18 18,2O-diepoxy tautomeric form.175 Catalytic hydrogenation of this ether (283) can then proceed to give the 5a-or SP-dihydro derivative (284) depending upon the solvent used.Subsequent reduction of the 3-0x0 group using potassium tri-s-butylborohydride to form the 3P-axial alcohol or lithium tri-t-butoxyaluminium hydride to form the 301- equatorial alcohol leaves the side-chain unscathed and provides convenient routes to the four isomeric tetrahydroaldosterones. 18,19-Dihydroxycorticosterone(286) is prepared from the lactone (285) by reduction with sodium aluminium bis(methoxy- ethoxy)hydride acetylation treatment with perchloric acid in acetic acid and saponification under mild condition^."^ 18-Hydroxy- 19-norcorticosterone (288) is prepared from the bis(ethy1ene ketal) of 21-hydroxy-3,20-dioxo-19-norpregn-15-ene- 18 1 lp-lactone and its A5(10)-isomer.177 Hydride reduction of this mixture yields the 11/3,18,21,-triol convertible by acetylation and deketalization to the dione (287) which is hydrolysed to the trio1 (288).In the solid state and probably also in neutral solution this has the 18,2O-hemiacetal structure. When treated with acid it yields 18-deoxy- 19-noraldosterone (289) for which the P(axia1) configuration of the C-10 hydrogen is established by 2D n.m.r. COSY measurements. In further studies on the mechanism of colour reactions used for the determination of corticosteroids the structures of the condensation products of pyrrole with cortisone (290) and In deoxycorticosterone (291) have been ~0nfirmed.l~~ the presence of copper (11) acetate the oxidation products (292) are formed and these react with pyrrole in hydrochloric acid to give the coloured adducts (293).These show absorption maxima between 480 nm and 510 nm in dichloromethane and (293; R = OH) shows fluorescence at 562 nm with excitation at 516 nm by virtue of the hydrogen bond between the chromo- phore and the hydroxyl group at C-17. A variety of new routes to pregnanes have appeared. Routes from 17-oxoandrostanes include azlactone synthesis for con- struction of the corticosterone ~ide-chain,~~~ conversion of 17a-halogenoethynyl- 17P-nitrooxy derivatives into corticoids by NATURAL PRODUCT REPORTS 1989-A. B. TURNER Reagents i 2-Ethyl-2-methyl- 1,3-dioxolan TsOH ; ii MeLi TMEDA; iii Ac,O AcOH CH,Cl, TsOH ; iv KOH EtOH ; v pyridinium chlorochromate; vi H,O, NaOH; vii LiAIH, THF; viii DMSO (COCI),; ix Me,CO TsOH; x pyrrolidine Pr'OH; xi HCI EtOH Br,; xii KOAc Me,CO Scheme 25 (298) (299) R = H (3011 (300)R=S02Me "0- \ (304) R = H,Me acid-catalysed rearrangement in the presence of silver (I) ions,18" palladium (0)-mediated coupling of Reformatskii reagents with vinyl triflates to prepare pregn- 16-en-21-0ates,'~l and reaction of methyllithium with cyanohydrins to give 17-hydroxy-20-ketones.182 The ethylidenepregnane (294) gives the (20R)-pregnane (295) via etherification with iodomethyltri- butyltin followed by /?-face 2,3-sigmatropic rearrangement with t-butyl-lithium (Scheme 24).183 The unusual chirality at C-20 is found in some steroids of marine origin.Guggulsterones (E-and Z-pregna-4 17(2O)-diene-3,16-dione (296)] which constitute 2% of the gum resin from Commiphora mukul can be converted into the 3,20-dione (297) a known dexamethasone intermediate in a twelve-stage sequence (Scheme 25) in an overall yield of 15Yo.184 Muricin aglycone (298) has been prepared by an improved route. 185 This involves borohydride reduction of pregnenolone acetate to the 20R-alcohol (299) which after conversion into the mesylate (300) gives the dienol (298) with potassium t-butoxide in boiling toluene. The overall yield is 83 YO.14P-Hydroxyprogesterone (301) prepared from 14a-hydroxyprogesterone in five steps with an overall yield of 35% is the first in a series of progesterone derivatives which bind to the digitalis receptor both to possess the C/D-cis ring junction and to enhance the contractile properties of isolated cardiac tissues.Base-catalysed methylation of the 15-one (302) yields a 5 :1 mixture of the 1401- and 14P-methyl derivatives whereas similar treatment of the related ketone (303) gives only the 14a-methyl product which can be converted into 1461- methyl- 19-norprogesterone. 18' The stereoselectivity of methyl- ation at C-14 depends upon the preferred conformation of ring D in the derived enolate. The spirooxetanones (304) are obtained by reaction of 1701- hydroxypregnanolone and its 16a-methyl derivative with iodosobenzene diacetate in methanolic potassium hydroxide. 188 NATURAL PRODUCT REPORTS 1989 0 cop 0& 0& Ho+ (305) R1R2 = 0 R3 = H (306) (307) R' = OCHO R2 = H R3 = CI L (309) OH 0&? X (313) X = 2H or 3H (3 14) The spirolactone (305) a metabolite of canrenone (306) in rats is readily prepared from the dienone (306) via the chloroformyloxy derivative (307).189 A synthesis of the hemisuccinate (308) involves a protected hemisuccinate inter- mediate into which the unsaturated ester grouping is introduced only in the final stage.lgo The succinate was blocked with 2-(trimethylsily1)ether or 2,2,2-trichloroethyl groups.A similar strategy has been used to prepare the corresponding p-D-glucopyranoside which was protected in the form of its tetra-acetate. The pregnenoate (309) has been converted into the furan (3 10) by two pathways previously used for compounds with an unfunctionalized steroid nucleus.1g1 Funtumine (31 1) has been prepared from pregnenolone by reduction to 5a-pregnanolone protection of the 20-0x0 group Mitsunobu reaction with azide reduction to the amine and deprotection.lg2A Gabriel synthesis can also be employed.The latter route has also been used to prepare 2 1-aminopregnanes. lg3 Thus treatment of 21 -mesylates with potassium phthalimide followed by hydrazinolysis gives the aminohydroxylacetone 0 (3081 (310) R = glucosyl CONHR I 0& (315) side-chain. Various 20-carboxamides of type (3 12) have been prepared as anti-inflammatory agents.lg4 The (20R)-isomers were more potent than the (20S)-isomers.The ring B-labelled norpregnenediones (3 13) have been prepared by selective catalytic reduction of the A6-derivative which is obtained from the 19-hydroxy compound (314).lg5 17- Hydroxylation of pregnan-20-ones using oxygen sodium t-butoxide and triethylphosphate has been extended to C-aromatic pregnanes of type (31 5).lg6 At temperatures above -50 "Cand in the absence of triethyl phosphite side-chain cleavage leads to 17-ketones. 2.5 Androstanes and Oestranes Details have appeared of two routes for the synthesis of dehydroepiandrosterones which are chiral at C-19 by virtue of isotopic substitution. lg7These are based on the stereoselective reduction of 17,17-ethylenedioxy-3~-methoxy[ 19-3H]androst-Sen- 19-a1 to (19R)-and (19S)-alcohols of high diastereo- NATURAL PRODUCT REPORTS 1989-A.B. TURNER R1O (317) (320)R',R2 =CH20 or OCH2 \SC02Et (324) (325) (328) isomeric purity. The alcohols are converted with retention of configuration into 19-iodo derivatives without loss of diastereoisomeric purity and then hydrogenolysed with inversion to the chiral An improved procedure for preparing androst- 15-en- 17-ones (3 16) involves sulphinylation of androsterones with methyl benzenesulphinate and pyrolysis of the resulting 16-phenyl-sulphinyl derivatives.lg8 Selenium dioxide oxidation of the 15-en- 17-ones then gives the corresponding 14P-hydroxy deriva- tive~.~~~ Oxidation of the picolyl derivative (317) of de-hydroepiandrosterone acetate with chromium trioxide-pyridine complex at room temperature gives the epoxides (318) and (319) in low yield.200 The configurations of the epoxides were established by crystal structure analysis.Synthesis of [5a76a-3H]androst- 16-en-3-one by the vinyl iodide route gives material of >99 YO radiochemical purity.*O1 Starting from epi-androsterone the four stereoisomeric 3P7l7-dihydroxy- 16- (319) OMe (323) + ,C0; NHEt (326) amino-5a-androstanes have been prepared.202 The 16a- and 16P-amino- 17a-01s are obtained via 3P-hydroxy-5a-androst-16-ene and the 1601- and 16P-amino-17/3-ols are prepared via 3P-hydroxy- 16a-bromo-5a-androstan- 17-ones. 1701- and 17P- Amino derivatives of 5a-androstan-38-01 are formed by Leukart-Wallach reaction of 3P-acetoxy-5a-androstan-17-one (53 YOoverall yield) or indirectly via the 17~-alcohol its tosylate and azide (30 YOoverall yield).2o3 In further work on aromatase inhibitors the diastereomeric 10-(epoxyethyl)estr-4-ene-3,17-diones (320) are found to be powerful inhibitors of human placental aromatase.204 They are obtained by reaction of a 19-0x0-androstene with either dimethylsulphonium methylide or dimethyloxysulphonium methylide and their conformations and configurations have been established by X-ray crystallographic analysis. The hydroperoxide (321) an analogue of a proposed aromatase intermediate is prepared by ozonolysis of the enol ether (322) in the presence of Although it does not produce oestrone directly it does give the aldehyde (323) apparently by a stereospecific intramolecular epoxidation.Bridged-ring androstanes having a bicylo[3.3. llnonane ring A system have been prepared by Michael addition of ethyl acetoacetate to 1,4,6-trien-3-0nes.~~~ Aldol condensation then gives the bicyclic derivative (324) which has been converted into the oxa-adamantane analogue (325). Several spirolactones derived from androsta-4,ll -diene-3,17-dione have been pre- pared for testing as aldosterone antagonists but only the tetraenone (326) was effective.207 Similar spirolactones (328) are obtained by hydrogenation of androstene and nor-androstene propiolic acid salts (327) over palladium.208 Further brassinolide analogues having the androstane skeleton have been p~epared,~~~.~~~ but all were less active than epibrassinolide.566 NATURAL PRODUCT REPORTS 1989 3~-Rhamnosyloxy-5,8,14~-androstan-14/3-01 (329) and its 17- hydroxy and 17-acetoxy derivatives have been prepared by three different methods from the 14a-15-en-17-one (316; R1 = H R2 = P-H)"l The glycosidation involves a modified Koenigs- Knorr procedure using 2,3,4-tri-O-benzoyl-a-~-rhamno- pyranosyl bromide silver(x) carbonate on Celite and benzene. Glucuronidation of the two monoacetates of 5a-androstane- 3a 17P-diol by the Koenigs-Knorr procedure gives the p-anomers of both the 3- and 17-gl~curonides.~~~ A procedure utilizing imidates also gives the P-anomers but in lower yield whereas reactions catalysed by trimethylsilyl trifluoro-methanesulphonates give only the a-anomers. HO OH (329) The synthesis of gestodene (332) from 18-methyl-4-estran- 3 17-dione (330) has been accomplished by several The double bond in ring D is introduced via microbiological hydroxylation to the 15a-alcoho1(33 I) followed by elimination as the acetate or mesylate either before or after ethnylation at C- 17.The oral progestational activity of gestodene is greater than that of levonorgestrel and it is used in combination with ethinyloestradiol in a recently developed oral contraceptive. 3-Substituted 5b-oestr-8( 14)-enes are obtained in good yield by selective hydrogenation of 5,8( 14)-oestradienes over pal- ladium in the presence of a trace of hydrogen bromide.214 Epoxidation of 8( 14)-enes with rn-chloroperbenzoic acid gives the a-oxides whereas bromination with N-bromocuccinimide followed by treatment with base gives the 17-Substituted 5a-oestr-8( 14)-en-3-ones (333) are prepared from (330)R = H (331)R=OH the oestrenedione by selective ketalization at C-3 methylen- ation of the 17-0x0 group and cleavage of the oxirane with sodium cyanide sodium azide or hydrogen chloride.216 4-Oestren-3-ones are prepared by oxidation of 2,4-dibromo- oestrone or -0estradiol with nitric acid in acetic acid at room temperature followed by hydrogenation over palladium and treatment with the superacid resin Nafion-H.217 The 19-nor steroids can be obtained in overall yield of ca. 50% from oestrone and oestradiol without isolation of the inter- mediates. Iodination of oestradiol 17-monoacetate using iodinesopper (11) acetate in acetic acid gives the 2-iodo derivative regioselectively in 88 YO yield.218 Apparently the copper is coordinated to the oxygen of the phenolic hydroxyl group and attack occurs at the less hindered C-2 position.There is no reaction with the corresponding 3-methoxy compound unless the more powerful Lewis acid iron(rI1) chloride is used and in this case a mixture of 2- and 4-iodo derivatives result. Use of iodine-copper(r1) bromide gives the 4- bromo derivative. Copper(I1) salts also catalyse the acetylation of the 17P-hydroxyl group in acetic acid. 2-Formylben-zenesulphonyl chloride is a useful reagent for the protection of phenols since the resulting 2-formlybenzenesulphonate esters are rapidly cleaved by alkali leaving carboxylate esters H (333)R = CN NJ CI untouched.219 Oestradiol 17-monoacetate can be obtained from the oestradiol using this protecting group but only in 70% overall yield.This compares with an 87 O/O yield by the copper(I1) salt method above.218 Treatment of the ether (334) with sodium bromide and N-chlorosuccinimide in methanol followed by hydrolysis with dilute hydrochloric acid gives the 6P-methoxy- 7a-bromo-oestradiol (335) in good yield.220 This base-sensitive compound does not deteriorate significantly during storage. The cyclopentadiene(336) has been used as a chiral template for the conversion of butynone to the optically pure (a-alkene (337).221 Cycloaddition of butynone to the diene (336) gives the (334) pentacycle (338) which undergoes conjugate trans-addition of lithium dimethylcuprate (Scheme 26). The final retro- Diels-Alder reaction of the bicycloheptene (339) gives the alkene (337) in > 98% optical purity as shown by the use of a chiral europium shift reagent.Further 16methyloestra-1,3,5(10)-trienes have been pre- pared.222r223Hydroboration of A9(l1)-bonds in the 14a-series proceeds almost exclusively on the a-face leading to 1la- alcohols.222 Routes to a number of new oestratrienes containing unsaturated side-chains have also been developed. 224-228 These include the 17a-vinylstannane (340)224 and the derived OMe (335) NATURAL PRODUCT REPORTS 1989-A. B. TURNER Ph (336) H (338) I -(336) + CHOAc Me Me (337) (339) Scheme 26 OSiMe3 I BF + -CH2-C-CHPCOi6 (340)R = SnBu3 (342)R = SiMe3 SiEt3 SiPr3 (344) (341)R = "'At SiMe2P r SiEt2(CMe3) (345)R =Me (343)R = CH2NH2 1346) R = CH20Me 0 0 'Cq'"co,(co)6 "2 c~~4-c~ T \ Me001 CO,(CO) (349)R = Me (347) (348) (352)R = CHzOMe astatinated steroid (34 1),225 the ethynylsiianes (342),226 and the propynylamine (343).,,' In studies on the selective introduction of transition metal carbonyls into oestrogens as markers for steroid hormone receptor assays specific alkylation at an enolic site in ring D occurs in spite of the presence of the activated ~~~ aromatic ring A.This is possible because the reactivity of the (351)R' = H; R2 = CH2C-CH (prop-2-yny1)hexacarbonyldicobal t cation (344) is dramatically c02(co16 modified by hexamethyldisilazane. Reaction of the cation (344) with enol ether (345) gives a mixture consisting of three monoalkylated products (347)-(349) and two dialkylated 0 products (350) and (351).The two nucleophilic sites in the methyl ether (345) show similar reactivity but the methoxy- methyl ether (346) is alkylated only in ring A probably owing to preferential complexation of the cation (344) to the -OCH,O-moiety. However this reactivity is reversed in the presence of two equivalents of hexamethyldisilazane with alkylation occurring only at C-16 to give complex (352) in 80% OMe yield. Decomplexation with iron(II1) nitrate in ethanol gives (353) the 16a-prop-2-ynyloestrone (353). Labelled chromium tri-3 NPR 6 NATURAL PRODUCT REPORTS 1989 Cr(CO1 (354) R = H,2H 3H (355) R = H HCS; n = -66 -133 R H OH (356) R = H (359) (360) (357) R=CHO (358) R = Me 0 OH H (361) (362) (363) 0 AcO OH H (364) (365) R’ = H a-Me 0-Me; R2 = H (369) R = OAc SAC OMe (366) R’ = H; R2 = OAc (367) R’ = P-Cl; R2 = OAC (368) R’ = a-F 0-F,a-CN 0-CN a-N3 P-N3; R2 = OAC carbonyls (354) are prepared by reduction of the oestrone permanganate can be dehydrated to the 22-acyloxy-complex with sodium borohydride borodeuteride or boro- cardenolides (361) after selective acylation of the 22-hydroxyl tritiide.229 The radioactive hormone transition metal complex group.232 Wittig reaction of the carboxaldehyde (362) with is obtained as a solid with a specific activity of 4.1 Ci/mmole (2-carboxy- 1 -ethoxycarbonylethyl- triphenylphosphorane fol-which is high enough for hormone receptor binding studies.lowed by reduction of the half ester and cyclization of the y-Polymer-linked oestrogens of type (355) have been shown to hydroxy acid gives the 3-alkylidene-butan-4-olide (363).233 retain oestrogenic D-Homo ketones (358) are Isomerization on basic alumina gives the cardenolide homo- obtained by formylation of the ether (356) with methyl logue (364) which shows markedly reduced biological activity. dichloromethyl ether in nitrobenzene in the presence of The formation of Meisenheimer complexes between cardeno- aluminium chloride followed by hydrogenation of the resulting lides [(365)-(369)] and rn-dinitrobenzene depends upon the aldehyde (357) over palladium.231 nature of the substituent at C-21 .234 The synthesis of cardenolides and bufadienolides from deoxycholic acid has been reviewed,235 and the model bufa- 2.6 Cardenolides and Bufadienolides dienolide (371) has been prepared in four steps from the Cardenolides (359) and (360) which are intermediates in the deoxycholic acid-derived methylene-pregnenal (370).236 Initial oxidative degradation of digitoxigenin 3-acetate by potassium oxidation of the 12a-hydroxyl group was essential in order to NATURAL PRODUCT REPORTS 1989-A.B. TURNER 569 0 0 *OAc OAc HOH O W AcO” H IH (370) (372) 0 (373) (374) 0 I Me (376) 0ii OAc (377) (378)X=NH (380)R = H (379)x = 0 (381)R = CrCH avoid dimer formation. Details of the formal synthesis of the toad venom constituent bufotoxin have appeared.237 Bufalin is used as a relay and converted into 14-dehydrobufalin 3-acetate which is selectively oxidized to the 16-ketone with a chromium trioxide-pyridine reagent thereby also completing formal total syntheses of bufotalin and cinobufagin. Con-densation of bufalin with suberic anhydride followed by a mixed anhydride sequence using arginine gives bufalitoxin and the analogous route from bufotalin yields bufotoxin. 5a-Cinobufagin (372) has been prepared in three steps from cinob~fagin.~~~ Oxidation of the derived 3-ketone with dichlorodicyanobenzoquinonegives a mixture from which the 4-en-3-one can be separated by chromatography and re-duction with lithium borohydride in pyridine completes the sequence. 2.7 Heterocyclic Compounds Details of the synthesis of tetrahydrooxazine-2-ones (374) from 16a-aminomethyl- 17-tosylates (373) in dimethyl sulphoxide containing sodium hydrogen carbonate have appeared.239 Under similar conditions the corresponding 16P-aminomethyl compounds give 16-methylene- 17-ones.Various steroids have been attached to opiates via azine linkages.240 The hybridazine (375) is formed by condensation of pregnenolone hydrazone with naltrexone. Spectroscopic measurements show that it is a mixture of two geometrical isomers and X-ray analysis of the major isomer reveals a C=N-N=C torsion angle of 123O indicating gauche geometry for the azine bond. An analogous conjugate can be prepared from oestrone and androst-4-ene- 3,17-dione gives a bis-opiate derivative. Dihydronicotinic esters (376) and (377) of oestrone and oestradiol have been prepared for improved delivery of oestrogens through biological mem- branes particularly in the brain.241 This chemical method of delivery is based on a redox xystem analogous to the NADeNADH coenzyme system.The phenol (377) is more effective for sustained brain-directed delivery of oestrogen in the rat. Treatment of 17/?-acetoxy-3-methoxyoestra-1,3,5(lo),14-tetraene with chlorosulphonyl isocyanate followed by reductive hydrolysis gives the azetidinone (378).242 Ring cleavage of the p-lactam gives the amino acid which can be converted into the /?-lactone (379) by deamination. 11-Oxatestosterone (380)243 and its 17a-ethynyl derivative (38 1)244 have been synthesized from the hecogenin-derived starting materials 1 I-oxa-5a-androstane-3,17-dione and 1 I -3-2 NATURAL PRODUCT REPORTS 1989 X &3FCOCH*N% -R 0 0 (382) X = a-H P-OH (383) X = 0 OAc H (386) (387) R = H (390) (388) R =CI (389) R =SPh as(390) 1 RmNOH (391) R = CI OAc (392) R (395) (396) (399) oxa-5a-pregnone-3,2O-dione,respectively.In comparison with testosterone the 1 1 -oxa analogue (380) shows diminished androgenic and anabolic activity while (38 1) shows significant progestational activity. The oxadiazoles (382) are obtained from 4-hydroxytestosterone by heating its 3,4-bis-oxime with potassium hydroxide in ethylene Jones’ oxidation gives the 17-ketones (383) which have also been prepared from diosgenin.Analogous oxadiazoles of the pregnane series have been prepared.246 R@ 0 (393) (394) R = H OAc OCOEt (397) (398) 21-Imidazol- 1-ylpregnenes (384) and (385) are readily ob- tained by reaction of 1-(trimethylsi1yl)imidazole or 1-(t-butyldimethylsily1)imidazolewith the respective 2 1-iodo deriva- tive~.~~’ 21-Aminopregnenediones prepared from cortisone and deoxycorticosterone have been converted into 2-0x0-imidazolines e.g. (386) by cyclization of their carbamoyl derivatives.248 Other corticosteroid derivatives prepared include 17-furoyl and -thenoyl e~ter~,~~~.~~~ and an oxazolidinethione. 251 Chlorination of azasteroid lactams (387) with N-chloro- succinimide gives N-chloro derivatives (388) which form sulphides (389) with benzenethi01.~~~ 38-Hydroxy-6-azacholest-4-en-7-one (390) is prepared from 3P-acetoxycholest-5-en-7-one via ozonolysis followed by ammon~lysis.~~~ Boron trifluoride-catalysed Beckmann rearrangement of the oximes (391) gives the unsaturated lactams (392) and (393) in roughly equal Condensation of cholestenones (394) with 2-aminothiophenol gives the 1 ,5-benzothiazepines (395) in 6& 71 % yield.255 In the case of cholesta-2,4-dien-6-one double conjugate addition produces the cyclo adduct (396) in 70% yield.Initial attack is by sulphur in all instances. Reaction of the NATURAL PRODUCT REPORTS 1989-A. B. TURNER 57 1 0 0 0 'SAC OH (400) (4011 L (403) 0 (408) 25% 75% HO 75% f (407) (409) 82% Reagents i 2M-H2S0, Me,CO; ii CF,CO,H (trace) CH,Cl Scheme 27 acetylene (397) with isopropionitrile oxide gives the isoxazole The acetal dimer (405) is formed in low yield by Simmons- (398) which yields the dihydrofuranone (399) by hydrogenation Smith methylenation of 3-methoxyloestra- 1,3,5( lo) 14-tetraen-over Raney nickel.256 17p-01.~~~ Similar stereospecific methylenation of 501-and 5p-hydroxy-oestr-9-enes gives the cyclopropanes (406) and (407).260Acid treatment of these compounds gives the expected 2.8 Cyclopropano-steroids rearrangement products (408) and (409) of the intermediate Various cholesterol derivatives have been prepared for use as cyclopropyl carbenium ion (Scheme 27). probes for mechanisms of cholesterol rnetaboli~m."~ These include cyclopropa[5,6]cholestane-3,7-diols and their oxidized forms ring B gem-difluorocholestanols and the 6-azachole- 2.9 Microbiological Transformations stenone (390).The androstenone (400) has been converted into This topic has been reviewed.261 A batch reactor converts the aldosterone antagonist (402) via the dienone (401).257 testosterone to androstenedione by an enzyme-catalysed pro- Treatment of the spirolactone (401) with a 1:1 mixture of acetic cess in the presence of excess cofactor.2s2 High concentrations acid and conc. hydrochloric acid gives the cleavage products of testosterone are maintained within poly(dimethylsi1oxane) (403) and (404).258 beads suspended in the aqueous enzyme solution. Mass transfer NATURAL PRODUCT REPORTS. 1989 0 0 0 (410) (411) HOA24 (414) R = C=CCO2Me (415) R = CH2C=CC02Me (416) R = CH2CHBrC02Me (417) R = CH2CF2C02Me (418) R = CH2CH2CF2C02Me is used to control the degree and rate of conversion.The androstenedione is recovered in the polymeric beads from the enzyme solution. Parallels between electrochemical and mi- crobial transformations are noted in the anodic oxidation of 3,9-dimethoxyoestra- 1,3,5( lO)-trien-17-one (410) in methanolic sodium cyanide which leads to the secosteroid (411) as the major The styrenes (412) and (413) are also formed although the intended product the 1OP-cyano- 1,4-dien-3-one is not obtained. The conversion of various 19-hydroxy-cholesterol derivatives into oestrone by Mycobacterium phlei has been An optimum yield of 8.6% is obtained with the 3P 19-diacetate.The methyl esters (414)-(418) have been prepared as analogues of the C-24 carboxylic acid involved as an intermediate in the degradation of sterol side-chains by Myobacterium spp.265 All of the esters inhibited the degradation. Selection of mutants of Rhodococcus spp. which preferentially attack the side-chain of sterols allows the efficient production of 20-carboxypregna- 1,4-dien-3-0ne from cholesterol or p-sitosterol.266 During the transformation of cholesterol by one mutant from a wild-type strain the temporary accumulation of the keto-acid (419) is observed. The nature of an unidentified acid m.p. > 330 “C first reported in 1957 from the incubation of dehydrocholic acid with Streptomyces gelaticus has become clearer.267 It is a mixture of dimers (4,4’ 6,6’- or 4,6‘ 4’,6-bisteroids) derived from cholanic acid 23,24-dinorcholanic acids in which carbons 4,4’ 5,5’ 6 and 6’ comprise a benzene nucleus (420)-(422).Both cis- and trans-forms are possible and similar dimers (423) are formed by oxidative coupling of cholest-5-ene-3,7-dione both chemically and microbiologically. Use of alkaline pot- assium ferricyanide gives two dimerization products m.p. 249-250 “C and 283-284.5 OC whereas incubation with S. Relaticus gives only the lower-melting compound. Thus it is likely that the immediate precursors of dimers (420) and (422) in the microbiological process are 3,7,12-trioxochol-4-en-24-oic acid and its 23,24-dinor analogue respectively and that cross- coupling of these acids yields the dimer (421).3 References 1 M. S. Moss and E. Houghton Chem. 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ISSN:0265-0568    

DOI:10.1039/NP9890600539

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Pyrrolizidine Alkaloids D. J. Robins Department of Chemistry University of Glasgow Giasgow G 12 8QQ Reviewing the literature published between July 1987 and June 1988 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 221) 1 The Synthesis of Necines double bond debenzylation and formation of a lactam. 2 The Synthesis of Necic Acids Reduction of the ester and lactam functions in the 3 The Synthesis of Pyrrolizidine Alkaloids and pyrrolizidinone (3) afforded (+_ )-isoretronecanol (4) in an Analogues overall yield of 21 YO. 4 Alkaloids of the Apocynaceae Moriwake et al.3 have described a synthesis of (-)-5 Alkaloids of the Boraginaceae jsoretronecanol (4) and (-)-trachelanthamidine (12) from (3-6 Alkaloids of the Compositae proline (Scheme 2).The protected (3-proline (5) when 7 Alkaloids of the Ehretiaceae 8 Alkaloids of the Graminae C02Me 9 Alkaloids of the Leguminosae 10 Alkaloids of the Linaceae COCH2 C H2C02 Me -Yco2,. 11 Alkaloids of Orchidaceae 12 Alkaloids of the Scrophulariaceae COCH2CH2C02Me 13 Alkaloids in Lepidoptera (1) 14 General Studies I ii 15 X-Ray Studies 16 Pharmacological and Biological Studies MeOCO ... 17 References Ill -PhCH2N Progress on the synthesis of pyrrolizidines including natural d bases has been reviewed. The pyrrolizidine bases (necines) (3) remain attractive targets for a variety of synthetic efforts. Only I a few new pyrrolizidine alkaloids have been identified although iv these alkaloids have been isolated from two plant families -Ehretiaceae and Linaceae -for the first time.H CH20H 1 The Synthesis of Necines d A route to (+)-isoretronecanol (4) has been reported by (4) Celerier et aL2This involves a nucleophilic homoallylic addition to the activated cyclopropane (1) by a primary amine to form Reagents i BrCH,CH,Br K,CO, DMF; ii PhCH,NH, MeOH the dihydropyrrole (2) (Scheme 1). Catalytic hydrogenation 140 "C; iii H, Pd/C; iv LiAlH produced the pyrrolizidinone ester (3) by reduction of the cis Scheme 1 i ii iii i ~ cj" NCO~BU' (5) (6) (71 viii (12) (11) (9) (8) lviii (4) Reagents i DIBAL; ii (Pr'O),POCH,CO,Et NaH; iii BF,.OEt, CH,Cl, -78 "C; iv MeC(OEt), EtCO,H 140 "C; v RuCl, NaIO, CC1,-MeCN-H,O; vi CH,N,; vi AlMe,; viii LiAlH Scheme 2 577 NATURAL PRODUCT REPORTS 1989 Reagents i Sn(OSO,CF,), N-ethylpiperidine THF; ii 5-acetoxy-Zpyrrolidinone THF; iii LiAlH, 0 "C then heat at reflux in THF Scheme 3 Reagents i 95 "C/O.OI mmHg; ii Me,SiI CH,Cl, -50 "C; iii H, PtO, AcOH; iv A1,0, CH,Cl,; v LiAIH Scheme 4 vii viii Bu'Me;!S&y I ~ i? ROh X ix c- C02Me (26) (24) R = H (25)R = Bu'Me2Si (28) (29) R=C02Me (30) R=CHZOH (311 (32) Reagents i O, CH,Cl, Me$; ii Ph,PCHCHO CH,CI, heat; iii CH,=CHMgBr THF 45 "C; iv MnO, hexane-CH,Cl, I I ; v NaN, AcOH-H,O I 1;vi NaBH, CeCI, MeOH 0 "C; vii Bu'Me,SiCl imidazole DMF; viii PhMe heat; ix flash vacuum pyrolysis 480 "C; x H, 5% Pd/C MeOH; xi LiAlH,; xii MnO, CeCl Scheme 5 NATURAL PRODUCT REPORTS 1989-D.J. ROBINS subjected to a Wittig reaction gave mainly the (.!?)-ester (6) which was reduced to the alcohol (7) by using boron trifluoride etherate before the addition of the reducing agent to reduce the amount of 1,4-reduction. Claisen rearrangement via the orthoester derived from alcohol (7) afforded a mixture (8) of diastereoisomers in a ratio of 2.6 :1. This mixture was oxidized and the acidic products were esterified to yield the diesters (9). Removal of the N-protecting group followed by lactam formation gave the pyrrolizidinone esters (10) and (1 1) which were separated. The major product was the endo-ester (10). Reduction of the ester and lactam function in compounds (10) and (1 1) afforded (-)-isoretronecanol (4) and (-)-trachelanthamidine (1 2) respectively.Another route to (-)-trachelanthamidine (12) due to Nagao and co-workers is shown in Scheme 3.4 Alkylation to the optically active enamine (13) occurred in a highly diastereo- selective fashion to give the pyrrolidinone (14) in 64% yield with a 97 YO diastereoisomeric excess. The absolute configuration of the pyrrolidinone component of compound (14) was established by conversion into (-)-trachelanthamidine (12) by treatment with lithium aluminium hydride under carefully controlled conditions. This caused reduction of the amide followed by reductive annulation to give the necine (12) in 44YOyield. The hydrogenolysis product (1 5) was also formed in 10% yield. Hudlicky and co-workers previously used the intramolecular [4+ I] annulation of the azidodiene (16) to produce the 1,2- didehydropyrrolizidine ester (1 9) using flash vacuum pyrolysis via the vinylaziridine (1 7) (Scheme 4) although yields were very low (10 A quantitative yield of the ester (19) was obtained by the same workers on nucleophilic cleavage of the vinylaziridine (1 7) with trimethylsilyl iodide presumably via the intermediate iodide (18).6 Conversion of the unsaturated pyrrolizidine ester (19) into (+)-trachelanthamidine (12) (+)-isoretronecanol (4) and (_+)-supinidine (20) was carried out by known procedures (Scheme 4).1 0 (34) SPh MeOC H 20 I xiii-xvi (40) (411 This work has been extended to the preparation of necines with 7-hydroxyl groups by introduction of oxygen at an early stage in the synthetic route (Scheme 9.’The triene ester (22) was prepared from methyl hexadienoate (21) in 16% yield.Addition of azide and reduction of the ketone gave the azide (23). This azide could be transformed into the vinylaziridine (24) in 50% yield. Better yields (70%) with improved diastereo- selectivity were obtained with silyl ethers derived from alcohol (23). However it was found that when a mixture (25) of isomers was subjected to flash vacuum pyrolysis a single product (26) was formed. Catalytic hydrogenation of the unsaturated pyrrolizidine (26) was accompanied by deprotection to afford the ester (27) from which dihydroxyheliotridane (28) can be prepared. Isomerization of the ester (27) at C- 1 produced the la-ester (29) which can be converted into hastanecine (30).Known reactions could also be used to obtain turneforcidine (31) from the la-ester (29) and platynecine (32) from the IF-ester (27). Unfortunately the py-unsaturated ester (26) could not be isomerized to the ap-unsaturated ester using a variety of bases thus precluding the synthesis of heliotridine and re tronecine. (& )-Trachelanthamidine (12) (-t)-isoretronecanol (4) and (f)-supinidine (20) were previously prepared following an intramolecular carbenoid displacement reaction on the diazosulphide (33).5b A full account of this work is now available ;this includes the use of selenium in place of sulphur although the cyclization then proceeded in lower yield.s This line of research has been extended by Kametani and co-workers to the synthesis of (+)-heliotridine (42) and (+)-retronecine (47).9 The optically active imide (34) prepared from (9-malic (33) (42) Reagents i HOCH,CH,OCOPh Ph,P EtO,CN=NCO,Et ;ii NaBH,; iii EtOH HCl ; iv PhSH p-MeC,H,SO,H ; v Na,CO, MeOH ; vi MeOCH,Cl; vii A benzene Rh(OAc), viii H, Pd/C MeOH; ix K2C03 MeOH; x MsCl base; xi I-; xii LiN(SiMe,), THF; xiii LiAlH,; xiv rn-ClC,H,COH, heat; xv HCI MeOH; xvi Ac,O Et3N Scheme 6 NATURAL PRODUCT REPORTS 1989 SPh (43) 0 viii ix (47) (46) (45) Reagents i ButMe,SiC1; ii K2C0, MeOH; iii ButCOC1 pyridine ether; iv N,=C(CO,CH,Ph), Rh(OAc), benzene; v Raney Ni EtOH; vi H, Pd/C MeOH; vii heat in toluene; viii Bu,N+F- THF; ix EtO,CN=NCO,Et Ph,P Scheme 7 OCOCF3 H@20H ACO\qu4 ' SPh /SiMe3 CH2 i-ii iii-iv V ~ ____) N 0 0 Reagents :i K,CO, MeOH-H,O; ii CF,CO,-Ag+ PhSeC1 THF; iii NaHCO, MeOH-H,O; iv H,O ;v Ac,O Et,N 4-dimethylaminopyridine Scheme 8 I.I NCO~BU' -(52) (53) A /i viii 91 (3.. CI-(54) Reagents i Bakers' yeast 24 h; ii KOH MeOH-H,O; iii Ac,O pyridine; iv (COCI), cat. DMF pyridine; v CH,N,; vi cat. PhCOiAg' Et,N MeOH; vii K,CO, MeOH-H,O; viii 3M-HCI in EtOAc Scheme 9 acid was N-alkylated selectively reduced and the hydroxyl group was displaced by ethoxyl to give compound (35) (Scheme 6). Introduction of sulphur led to a mixture (36) of diastereoisomers in a ratio of 1.87:1. Deprotection and reprotection of the hydroxyl group in the mixture (36) was carried out and the major isomer (37) was subjected to an intramolecular carbenoid displacement reaction with a-diazomalonate to yield sulphide (38).Catalytic hydrogenation followed by decarboxylation and hydrolysis of the benzoate ester furnished alcohol (39) which was converted into the corresponding iodide. This underwent intramolecular alky-lation to afford the pyrrolizidinone (40). Selective reduction of the ester group and thermal elimination of the sulphoxide derived from sulphide (40)served to introduce the desired 1,2- unsaturation. The diacetate (41) was isolated after cleavage of the methoxymethyl protecting group. Conversion of the diacetate (41) into ( +)-heliotridine (42) was previously achieved using lithium aluminium hydride.0 4GNR (55) R = COMe (56) R = H-HCI (+)-Retronecine (47) was prepared from the sulphide (36) as shown in Scheme 7.9 The acetate was cleaved as before (Scheme 6) and the free hydroxyl was silylated. The benzoate ester was removed and replaced as the pivaloyl ester (43). The in- tramolecular carbenoid displacement reaction was then carried out to give the sulphide (44).Removal of the sulphur followed by hydrogenation and decarboxylation yielded the acid (45). The inversion of stereochemistry required was achieved by NATURAL PRODUCT REPORTS 1989-D. J. ROBINS 58 1 ; 2CO2Me (57) (58) (59) v vi I Hm20H Reagents i BrCH,CO,Et Et,N THF; ii CF,CO,H; iii ButMe,SiC1 imidazole DMF; iv KOEt PhMe then AcOH; v NaBH, EtOH; vi Ac,O pyridine; vii DBU CH,Cl,; viii DIBAL; ix F-Scheme 10 iii I (68) Reagents i base l-bromo-3,3-(ethylenedioxy)butane;ii Li NH ;iii C,H,,MgBr ; iv H, Pd/C MeOH-HCI Scheme 11 means of a Mitsunobu reaction after removal of the silyl protecting group.The lactone (46) formed had previously been converted into (+)-retronecine (47). Another route to (+)-heliotridine (42) (Scheme 8) via the diacetate (41) has been reported by Kano et aLIO This is similar to the route shown in Scheme 6 in starting from (9-malic acid and using a sulphide (48). Radical cyclization of the acetylene (48) to the pyrrolizidinone (49) had been carried out pre- vio~sly.~~ The alcohol formed by hydrolysis of the acetate (49) was subjected to trifluoroacetoxyphenylselenenylation to give the compound (50).Hydrolysis of the ester followed by thermal elimination of the selenoxide yielded the unsaturated diol (51). Acetylation of this diol afforded the known diacetate (41). An improved synthesis of the Geissman-Waiss lactone (54) in optically active form [cf the N-alkylated version (46) in Scheme 71 has been devised by Knight and co-workers.'l Bakers' yeast reduction of the protected ketoproline (52) gave (+)-cis-3-hydroxyproline derivative (53) with 99 YOcis-form and 93 YOenantiomeric excess. Hydrolysis of compound (53) gave (2R,3S)-3-hydroxyproline and served to establish the stereo- chemical course of the reduction. The ester (53) was homo- logated to the Geissman-Waiss lactone (54) by a straight-forward sequence of reactions as shown in Scheme 9.This procedure constitutes a formal synthesis of the non-natural enantiomers of retronecine (47) platynecine (32) and croal- bine~ine.~" A synthesis of an N-acetyl form (55) of the Geissman-Waiss lactone and the corresponding 4-benzyloxy derivative from D-glucose has been published.12 Buchanan and co-workers had previously reported a route to optically active compound (56).sd A full account of this work is now available13 with an extension for the preparation of (+)-crotanecine from the intermediate (57) made previously. The secondary amine (57) was alkylated and the isopropylidene protecting group was removed from the product which enabled the lactone (58) to be formed (Scheme 10).The free hydroxyl group in compound (58) was protected and the product was subjected to Dieckmann cyclization. The resulting pyrrolizidinone (59) was immediately reduced and the acetylated product (60) was obtained as a mixture of diastereoisomers. Base elimination of acetic acid gave the unsaturated ester (61) and crotanecine (62) was formed by reduction and deprotection steps albeit in low yield. A better route from lactone (58) is available from previous Enantioselecti~e~~~'~ and stereoselectivesf syntheses of the ant venom alkaloid (68) have been reported before. Husson and co- workers have devised another route to optically active (68) shown in Scheme 11.15 The nitrile (64) was prepared from (R)-(-)-phenylglycidol (63) and has been used in the construction of a number of heterocyclic systems.For this route the nitrile (64) was alkylated to yield a mixture (65) of diastereoisomers then the nitrile group was removed stereospecifically to give compound (66). The stereochemistry of this product was NATURAL PRODUCT REPORTS 1989 T O H iii-vi vii ____) (70) (71) (72) I 0 xi-xvi Yy oa I C02 H CH20H (76) (75) Reagents i HC1 -5 "C then NaOH; ii LiAlH,; iii pyridinium chlorochromate CH,Cl,; iv CH,=N+Me,I- LDA THF; v MeI MeOH; vi Na,CO, CH,CI, NaBH, CeCl, MeOH ; vii cumene hydroperoxide cat. diisopropyl (-)-tartrate cat. Ti(OPr) ; viii 3 5-dinitrobenzoyl chloride pyridine DMAP; ix cat. RuCl, NaIO, K,CO, MeOH; x HCl CHC1,; xi cat. RuCl, HJO,; xii CH,N,; xiii MeCHO LDA HMPA; xiv Ac,O Et,N; xv DBU; xvi LiOH THF H,O 0 "C Scheme 12 0-confirmed by X-ray analysis and n.m.r.spectroscopy. The required heptyl chain was then introduced by Grignard reaction to afford the trans-isomer (67) together with the cis-form in a ratio of 77 :23. Separation of these diastereoisomers was achieved by column chromatography and the trans-isomer (67) was hydrogenated in acid to yield the target alkaloid (68) by removal of the chiral auxiliary and protecting group formation of an imine and reduction of the imine. The product (68) had the opposite rotation to the supposedly same enantiomer prepared earlier by Takano et all4 suggesting that the absolute configuration of the product from the previous work should be reversed.2 The Synthesis of Necic Acids White and co-workers previously synthesized (+)-integerrinecic acid as part of their route to the macrocyclic alkaloid integerrimine.5g The same group has now developed a different route to the &lactone (76) of (+)-integerrinecic acid from monoterpene precursors shown in Scheme 12.16 Optically pure (R)-( +)-/I-citronellol (70) was best prepared from (R)-(+)-pulegone (69). The alcohol (70) was oxidized to the aldehyde and the enolate was alkylated with Eschenmoser's salt. The amine formed was quaternized and subjected to Hofmann elimination followed by reduction of the aldehyde to give the dienol (71). Asymmetric epoxidation of the allylic alcohol catalysed by diisopropyl (-)-tartrate gave a 3:1 mixture of the epoxides (72) and (73) respectively.The epoxides were separated as their 3,Sdinitrobenzoates and the major isomer (72) was reduced to the diol(74). A series of steps led to the lactone (75) whose structure was confirmed by X-ray crystallography. The alcohol (75) was oxidized to the acid and esterified. Introduction of the ethylidene substituent was carried out by a known procedure leading to the lactone (76). Improved stereoselectivity in the Sharpless oxidation was achieved using (+)-tartrate which resulted in a mixture of epoxides (72) and (73) in a 4:96 ratio. The latter epoxide was converted into the target lactone (76) in eight steps of which the key one was the acid-catalysed opening of the epoxide with inversion of configuration at the quaternary centre.A full account of the first enantioselective synthesis of (+)-and (-)-trachelanthic acids has been reported by Nishimura et 3 The Synthesis of Pyrrolizidine Alkaloids and Analogues The enantiomeric trachelanthic acids mentioned in the previous section were converted into their acetonides and coupled in separate experiments with (-)-and (+)-retronecine (47) using dicyclohexylcarbodi-imide to produce all four possible diastereoisomers after removal of the protecting group.l7 Indicine N-oxide (77) formed from (+)-retronecine (47) and (-)-trachelanthic acid is known to show anti-tumour activity whereas the three diastereoisomeric N-oxides had no anti-tumour activity. The semi-synthetic analogue (78) displayed better anti-tumour activity than indicine N-oxide.Zalkow et af. have prepared monoesters and diesters of heliotridine (42) and retronecine (47) with optically active forms of 2-hydroxy-2-phenylbutyric acid using N,N-carbonyldi-imidazole.'* The N-oxides of the heliotridine esters showed less anti-tumour activity than the corresponding retronecine ester N-oxides. Several 1 1-membered pyrrolizidine alkaloids have previously been made by Vedejs and co-w~rkers.~~ Now they have degraded and reconstructed monocrotaline (79) as shown in Scheme 13.19 Monocrotaline was converted into the acetal(80) which was saponified and the anhydride (81) was formed from the diacid. Opening of the anhydride (81) with 2-(trimethylsily1)ethanol gave a 6 :1 mixture of the esters (82) and NATURAL PRODUCT REPORTS 1989-D.J. ROBINS fi I * ix .. ... II Ill ____) O t N d (81) (79) (80) vii viii / Iiv C02(CH&SiMe3 0;;;" ~ v vi (83) Reagents i methylal P,O, CHCl,; ii LiOH 35 "C; iii DCC THF; iv Me,Si(CH,),OH pyridine THF; v Bu"Li THF -78 "C;(EtO),POCI; vi HF THF; vii MsCl Et,N CH,Cl,; viii Bu,N+F- MeCN; ix HCl HO(CH,),OH Scheme 13 R' R2 "%OH MeN (90) (91) (85)R'= R2 = H (89) R' =Me R2 = H (86) R' = R2 = Me and R' = H R2 = Me (87) R',R2 = (CH2)4 (88) R' ,R2 = (CH2)5 H CI-(92) the isomeric monoester. The selective attack at the more highly substituted carbonyl group is usually attributed to the approach trajectory of the nucleophile but may also be due to the electronic effect of the a-alkoxy group.The major isomer (82) was coupled with the protected derivative (83) of (+)-retronecine (47) to yield alcohol (84) after selective removal of one of the silyl protecting groups. Lactonization was achieved by displacement of the mesylate after removal of the second silyl protecting group. Finally careful hydrolysis of the acetal afforded monocrotaline (79). No macrocyclic diesters containing heliotridine (42) have been isolated. Hagan and Robins have prepared a series of 11-membered dilactones containing ( +)-heliotridine.,' Esterification of ( +)-heliotridine with various glutaric an-hydride derivatives produced chiefly the corresponding 9-monoesters of ( +)-heliotridine. Lactonization was carried out via the pyridine-2-thiolesters to yield the 11-membered dilactones (85)-(89).Attempts to make 10-membered macro-cyclic diesters of heliotridine were unsuccessful. Synthanecine A (90) is a monocyclic analogue of retronecine (47). Robins and co-workers previously prepared a range of 1 1-membered dilactones of synthanecine A.,' Now the same group has extended the range of these analogues available by making a series of 10-membered macrocyclic diesters of synthanecine A.21Synthanecine A (90) was monoesterified with succinic anhydride and the monoester mixture was lactonized using the pyridine-2-thiolesters. The formation of the 10-membered ring (91) was confirmed by X-ray crystallography. The ester carbonyl groups are antiparallel. Other 10-membered dilactones were prepared from trans-2,3-dimethylsuccinic anhydride cyclohexane trans-1,2-dicarboxylic anhydride and pthalic anhydride.Substitution at the a-positions of the diacid portions was shown to increase the hepatotoxicity of these pyrrolizidine alkaloid analogues.22Barbour and Robins have also reported a different procedure for making 11-membered dilactones of synthanecine A.23Treatment of synthanecine A (90) with thionyl chloride produced the allylic chloride (92) whose structure was confirmed by X-ray crystall~graphy.~~ Treatment of the allylic chloride (92) with various anhydrides in the presence of base (DBU) gave the corresponding macrocyclic NPR 6 NATURAL PRODUCT REPORTS. 1989 R' R2 (93) R = H (94) R = Me (95) R,R = (CHd4 (96) R' = R2 = H (100) R = H (103) R' = R2 = H (97) R' = CI R2 = H (101) R=Me (104) R' = R2 = Me (98) R' = R2 = CI (102) R,R = (CH2)4 (105) R',R2 = (CH2I5 (99) R' = R2 = Br (106) R' =OH R2= Me I (107) a; R' = Me R2 = H and (109) n = 1 (112) n=4 b; R' = H R2 = Me (110) n=2 (113) n=5 (108) R' = R2 = Me (111) n=3 G20Et 11 14) (1 15) (1 16) HO CH20COC(OH)CHMe2CH(OR)Me (1 17) R = COCH2CHMe2 (118) R = COMe diesters (93)-(108) directly.A further extension of the analogues available was made by Barbour and Robins by a combination of the two lactonization methods described above to produce analogues containing synthanecine A with ring sizes of 12-1 6.25Nucleophilic displacement of the allylic chloride (92) with adipic acid in the presence of DBU gave the monoester of synthanecine A.Lactonization of this monoester was achieved via the pyridine-2-thiolester to give adipoy- lsynthanecine A (109). Dilactones (1 10)-(113) with 13- to 16-membered rings were made from pimelic suberic azelaic and sebacic acids respectively. 4 Alkaloids of the Apocynaceae Pyrrolizidine alkaloids have been isolated previously from only a few Parsonsia species.26A new alkaloid has been isolated cp 6-(1 19) from stems of P. laevigata Alston.27 Parsonine (1 14) was identified by spectroscopic studies including 'H n.m.r. n.0.e. difference spectroscopy and 13C-lH 2D n.m.r. correlation spectroscopy (COSY). The structure (1 14) was confirmed by hydrolysis with 1 % potassium hydroxide in ethanol to give (-)-viridifloric acid and the ethyl ether (1 15).This alkaloid (114) is the first example of a dihydropyrrolizinone to have been isolated. Larvae of Idea Ieuconoe Erichson were observed to feed on this plant. It is of interest to note that other butterflies from the same family manufacture danaidone (1 16) for use as a pheromone from pyrrolizidine alkaloids in their diet. 5 Alkaloids of the Boraginaceae Previous investigations of Heliotropium curtlssavicum L. from various parts of the world have revealed different pyrrolizidine alkaloid contents.5i A new alkaloid namely 9-(3'-isovaiery1)viridiflorylretronecine (1 17) has been isolated from Argentinian varieties argentinum and curassavicum.28 The former variety also contained the acetate (1 18).The absence of acylation at C-7 in alkaloid (117) was demonstrated by a downfield shift of the C-7 proton in the 'H n.m.r. spectrum upon acetylation. The acidic moieties of the esters (1 17) and NATURAL PRODUCT REPORTS 1989-D. J. ROBINS Table 1 Pyrrolizidine alkaloids in Boraginaceae Species Pyrrolizidine alkaloids Ref. Arnebia hispidissima (Lehm.)DC echimidine monocrotaline 32 Caccina crassifolia supinine trachelanthate ester 33 of heliotridine or retronecine Cynoglossum viridijlorum viridiflorine N-oxide 33 Echium sericeum Vahl echimidine symiandine 32 or symphytine Heliotropium bacciferum Forssk. heliotrine europine 34 H. bursferum 9-angelylretronecine N-oxide 35 H.circinatum curassavine echinatine europine 36 heliotrine lasiocarpine H. dasycarpum heliotrine 37 H. ellipticum Ledeb. heliotridine lasiocarpine 38 europine lasiocarpine N-oxide Moltikiopsis ciliata (Forssk.) heliotrine echinatine 39 Rindera austroechinata 7-angelylheliotridine 33 rinderine echinatine Symphytum sp. lasiocarpine 40 Tournefortia sogdiana echinatine 33 Trachelanthus koralkovi trachelanthamidine 33 trachelanthamine +N-oxide 33 Trichodesma ehrenbergii Schweinf. senkirkine supinine 32 (1 18) could not be obtained by hydrolysis to confirm their identities. H. curassavicum is widely used as a herbal medicine. The alkaloids (1 17) and (1 18) contain the structural features believed necessary for hepatotoxicity (i.e. 1,2-unsaturation in the necine and acylation at C-9).A most unusual structure (1 19) was proposed by Malik and Rahman for what they believed to be a new alkaloid from H. ~ubulaturn.~~Extensive n.m.r. spectroscopic studies were employed to assign this structure including homonuclear and heteronuclear correlation spectroscopy. Two group^^^.^^ have been quick to point out that the chemical shifts given for the oxetane protons at 6 3.55 and 3.77 and the geminal coupling constant of 12.7Hz for the OCH group cannot be correct. Most of the reported spectral data are similar to those of a known epoxide (120). The two groups30*31 advise that care should be exercised in making structural assignments even when sophisticated modern spectral techniques are employed. The constituents of a number of species from the Boraginaceae are listed in Table 1.32-40 Arnebia hispidissima is the first member of this genus to be Senkirkine is the first alkaloid containing otonecine to be isolated from the Boraginaceae.32 Comfrey (Symphyturn oficinale) is widely used to aid healing of broken bones and for the treatment of ulcers.Methods for the analysis of the toxic pyrrolizidine alkaloids present in Me capsules and tea bags of comfrey have been It is concluded that use of comfrey carries a risk of contracting cancer. (122) 6 Alkaloids of the Compositae Emiline is a dilactone containing otonecine which was previously isolated from Emilia Jammea Cass.42 The structure has been revised by Barbour and Robins from the 1 1-membered compound (121) on the basis of detailed spectroscopic e~amination.~~This revision (1 22) resolves a chemotaxonomic anomaly; all otonecine diesters isolated so far from the Compositae contain 12-membered rings.A new alkaloid was isolated from Senecio adonidifolius and structure (123) was assigned on the basis of 2D n.m.r. COSY data.44 The occurrence of known alkaloids from the Compositae Table 2 Pyrrolizidine alkaloids in Compositae Species Senecio adonidifolius S. brasiliensis (Spreng.)Less. S. cilicius S. cisplatinus Cabrera S. gallicus S. glabellus S. grisebachii Baker S. heterotrichus DC S. leptolobus De Candolle S. longilobus S. murorum S. selloi S. vulgaris is shown in Table 2.44-51 Damage to plant leaves of S.jacobaen did not affect the concentration of pyrrolizidine alkaloids in the plants.52 Root cultures of Senecio vulgaris S.vernalis S. erucqolius and S. squalidus all produce similar patterns and quantities of alkaloids as in the ~1ants.j~ Alkaloids are accumulated as the N-oxides in the vacuoles54 apart from senkirkine which contains otonecine as the base portion. 7 Alkaloids of the Ehretiaceae Floridanine has been isolated from the leaves of the tree Cordia sinensis and macrophylline is present in C. mj~xa.~~ This represents the first isolation of pyrrolizidine alkaloids from the Ehretiaceae although this was formerly part of the Boraginaceae. 8 Alkaloids of the Graminae Senecionine is present in aerial parts of Schismus barbatus.j” This is the first report of pyrrolizidine alkaloids from Schismus.N-Formyl- and N-acetyl-loline present in fescue seed (Festuca arundinacea Schreb.) may play in important role in fescue toxicity; the reproductive potential of male rats was lowered after feeding on these seeds.56 The occurrence of an endophytic fungus Acremonium spp. in seeds of various Czechoslovakian varieties of F. arundinacea which may be responsible for production of these alkaloids has been studied.j’ 9 Alkaloids of the Leguminosae A new alkaloid alexine has been isolated from dried pods of the tree Alexa leiopetala (tribe Sophoreae) and its structure (124) was established by n.m.r. spectroscopy and confirmed by X-ray cry~tallography.~~ This is the first alkaloid to be identified from this genus and the first example of a pyrrolizidine alkaloid with a carbon substituent at C-3.Alexine shows some structural resemblance to the pyrrolidine tetraol(l25) which is found in other species of the Leguminosae and is a glucosidase inhibitor. Alexine (124) was shown to be a poor inhibitor of several glucosidases. 58 A pyrrolizidine alkaloid isolated from Crotalaria leschenaulti was previously reported to be cri.spatine.jy Reinvestigation of this species has shown that this alkaloid is an isomer of crispatine.sO The structure (126) of this new alkaloid crotaleschenine has been established by X-ray crystallography. The ester carbonyl groups are syn-parallel. Basic hydrolysis of NATURAL PRODUCT REPORTS 1989 Pyrrolizidine alkaloids Ref.florosenine 44 Integerrimine retrorsine 45 +N-oxides integerrimine senecionine 46 plat yphylline retrorsine senecionine 47 ligularizine senkirkine 44 senecionine +N-oxide senecionine integerrimine 48 +N-oxides retrorsine senecionine 49 integerrimine retrorsine 47 neosenkirkine integerrimine 47 florosenine senecionine integerrimine 48 seneciphylline retrorsine +N-oxides Integerrimine usaramine 50 retrorsine senecionine 47 spartioidine usaramine 51 A CH20H HO ,CH20H w crotaleschenine (126) gave an acid identical to that previously obtained by hydrolysis of retusine.61 Thus the stereochemistry of the acid portion of retusine (127) is also established. Three macrocyclic alkaloids containing crotanecine as the base portion have been isolated from Crotalaria rosenii.“ Two of these were identified as known compounds viz.madurensine and acetylmadurensine. The third alkaloid crotaflorine was isolated previously from C. agatiJEoraand assigned the probable structure (128).63 This structure has now been confirmed by detailed n .m. r. spectroscopic techniques including correlation spectroscopy by long range couplings which established the mode of attachment of the diacid to crotanecine in madurensine.‘j2 Integerrimine is the major alkaloid in several species of Buchenrocdera and Lotonis section Krebsia.64These genera are therefore believed to be more closely related to Crotalaria than to Lebeckia as previously thought.NATURAL PRODUCT REPORTS. 1989-D. J. ROBINS 21 HO C02Me (131) R = H (133) (132) R = OH 10 Alkaloids of the Linaceae Pyrrolizidine alkaloids have been shown to be present in the Linaceae for the first time. Absouline (129) and its N-oxide with the unusual I -aminopyrrolizidine structure are the major alkaloids in Hugonia oreogena and H. penicillanthemum.65 The corresponding cis-p-methoxycinnamoyl ester and N-oxide were also present in smaller amounts. 11 Alkaloids of the Orchidaceae Phalaenopsine T (130) is a known constituent of Phalaenopsis spp:'j6 It has been shown to have growth inhibitory activity against lettuce seedlings and against Colanthe biscolor (Orchidaceae).'j7 12 Alkaloids of the Scrophulariaceae Pyrrolizidine alkaloids have been isolated previously from Castilleja ~pp.~~ These alkaloids can be obtained by root parasitism on host plants of Senecio atratus and S.triangularis.'j* 13 Alkaloids in Lepidoptera Butterflies from the Danainae and Arctiidae are known to feed on plants that produce pyrrolizidine alkaloids and store them possibly for defence against predators.Monarch butterflies (Danaus plexippus) in North America were found to store both macrocyclic diesters and m~noesters.~~ Some butterflies convert the pyrrolizidine alkaloids into volatile compounds for use as pheromones. Hydroxydanaidal (1 32) and danaidal (1 3 1) were identified from scent organs of male Arctiid butterflies Phragmatobia fuliginosa L. and Pyrrharctia isabella J.E. Smith.70 Male scent organs of a number of Ithomiine butterflies were found to contain the methyl ester (133).71 14 General Studies The solubility of monocrotaline increases in supercritical carbon dioxide with the addition of This finding may be useful for the extraction of alkaloids from seeds. Capillary supercritical fluid chromatography has been used for the first time as an efficient method for separating the alkaloids from Senecio anonym~s.~~ Extracts of pyrrolizidine alkaloids from Senecio spp. have been separated by fused silica capillary gas chromatography (GC) and identified by mass spectrometry (MS).'14 GC-MS was also used to study the constituents of a number of species from (135) the C~mpositae.~~ Positive and negative ion chemical ionization was also employed in this and in others on the constituents of Eupatorium ~annabinum'~ and E.rotundifolium L. var. ov~tum.~~ Metabolites of pyrrolizidine alkaloids from extracts of mouse hepatic microsomal incubations have been identified using tandem MS and GC-MS.78 MS has often been used for determining the mode of attachment of the diacid to the necine diol in macrocyclic pyrrolizidine alkaloids. The unreliability of this method has been discussed by Bredenkamp and Wiecher~.~~better A method is the n.m.r. spectroscopic selective population in-version technique which depends upon long range couplings to establish bond connectivities.80 In merenskine N-oxide (1 34) irradiation of H-9 pro-S affected the 13C carbonyl signal at 8 178.17 whereas irradiation of H-21 affected the other carbonyl signal which establishes the mode of attachment shown (1 34).15 X-Ray Studies (-)-Platynecine (32) obtained by hydrogenation of (+)-retronecine (47) was shown to have an exo-endo conformation with ring A exo-buckled.81 Echinatine (1 35) is a monoester of heliotridine with (-)-viridifloric acid. The pyrrolizidine nucleus in echinatine is em-puckered (endo-puckering is present in heliotrine and lasiocarpine -two other alkaloids containing heliotridine).82 In the I I-membered macrocyclic diester (86) of heliotridine the ester carbonyl groups are antiparallel with the allylic ester carbonyl orientated in the same direction as H-8.83 The alternative antiparallel conformation of the macrocycle has been observed for trichodesmine (an 11-membered alkaloid containing retronecine) whereas other 1 I -membered macro- cyclic diesters of retronecine have ester carbonyl groups that are synparallel and pointing in the same direction as H-8.In the 1 1-membered analogue (1 36) which contains retronecine the ester carbonyl groups are antiparallel as for trichodesmine. 84 The conformations of three macrocyclic diesters of synthanecine A have been established by Robins and Sim.H5 The alkaloid analogue (107a) has an unsymmetrical con-formation with both ester carbonyl groups directed away from the 2-H. The dilactones (104) and (105) have conformations that approximate closely to C symmetry with ester carbonyl groups that are antiparallel.16 Pharmacological and Biological Studies Pyrrolizidine alkaloids are included in a book on naturally occurring plant carcinogens.86 Some of the alkaloid N-oxides do possess anti-tumour activity. Extracts from more plants were screened for anti-tumour activity. Arnebia hispidissima showed the strongest effect.87 588 Poisoning of sheep in New South Wales Australia which is due mainly to Echium pfantagineum and Heliotropium europaeum has been reviewed.** Horses suffered liver disease after ingesting alfalfa hay containing 10YOSenecio vufgari~.~~ Extracts of S. othonnae produced little toxicity in mice and cats.’O Monocrotaline caused lesions to the lungs liver kidneys and hearts of rats.g1 The pulmonary vascular responses to monocrotaline in rats have been Administration of extracts of Senecio vufgaris to rats increased the number of abnormal foetuse~.’~ The effects of senecionine and its metabolites on rat hepatocytes have been ~tudied.‘~ 1,2-Unsaturated bases [as in (136)] are converted by liver oxidase enzymes into the corresponding pyrrole derivatives which are alkylating agents.The rates of reaction of these pyrroles with 4-@-nitrobenzyl)pyridine have been st~died.’~ Hepatic microsomes from guinea-pigs produced higher levels of pyrroles from senecionine than those from rats pigs cows and High concentrations of pyrrole metabolites were observed after administration of decoctions of Crotafaria assarnica to mice.” The mechanisms by which monocrotaline pyrrole causes pulmonary injuries have been investigated.Elevated serum copper concentrations were observed in rats with pulmonary hypertension caused by monocrotaline pyrrole.loo The release of thromboxane and prostaglandin metabolites from rats treated with monocrotaline pyrrole has been studied. lol 17 References 1 M. Ikeda T. Sato and H. Ishibashi Heterocycles, 1988 27 1465. 2 J. P. Celerier M. Haddad D. Jacoby and G. Llommet Tetra-hedron Lett. 1987 28 6597. 3 T. Moriwake S. Hamano and S. Saito Heterocycles 1988 27 1135. 4 Y. Nagao W.-M. Dai M. Ochiai S. Tsukagoshi and E. Fujita J. Am. Chem. SOC. 1988 10 289. 5 D. J. Robins Nat. Prod. Rep. (a) 1987 4 581; (b) 1987 4 579; (c) l985,2,214;(d) 1986,3,298; (e) 1985,2,215;(f)1989,5,6,222; (g) 1989,5,6,226; (h) 1985,2,216; (i) 1987,4,586; (I] 1985,2,217; (k) 1989 5 6 227.6 T. Hudlicky G. S.-Zingde and G. Seoane Synth. Commun. 1987 17 1155. 7 T. Hudlicky G. Seoane and T. C. Lovelace J. Org. Chem. 1988 53 2094. 8 T. Kametani H. Yukawa and T. Honda J. Chem. Soc. Perkin Trans. I 1988 833. 9 T. Kametani H. Yukawa and T. Honda J. Chem. SOC. Chem. Commun. 1988 685. 10 S. Kano Y. Yuasa and S. Shibuya Heterocycles 1988 27 253. 11 J. Cooper P. T. Gallagher and D. W. Knight J. Chem. Soc. Chem. Commun. 1988 509. 12 M. K. Gurjar V. J. Patil and S. M. Pawar Indian J. Chem. Sect. B 1987 26 1115. 13 J. G. Buchanan V. B. Jigajinni G. Singh and R. H. Wightman J. Chem. Soc. Perkin Trans. 1 1987 2377. 14 S. Takano S.Otaki and K. Ogasawara J. Chem. SOC. Chem. Commun. 1983 1172. 15 S. Arseniyadis P. Q. Huang and H.-P. Husson Tetrahedron Lett. 1988 29 1391. 16 J. D. White and L. R. Jayasinghe Tetrahedron Lett. 1988 29 2139. 17 Y. Nishimura S. Kondo T. Takeuchi and H. Umezawa Bull. Chem. Soc. Jpn. 1987 60,4107. 18 L. H. Zalkow J. A. Glinski L. T. Gelbaum D. Moore D. Mel-der and G. Powis J. Med. Chem. 1988 31 1520. 19 E. Vedejs S. Ahmad S. D. Larsen and S. Westwood J. Org. Chem. 1987 52 3937. 20 D. B. Hagan and D. J. Robins J. Chem. SOC. Perkin Trans. I 1988 1165. 21 R. H. Barbour A. A. Freer and D. J. Robins J. Chem. Sue. Perkin Trans. 1 1987 2069. 22 A. R. Mattocks H. E. Driver R. H. Barbour and D. J. Robins Chem.-Biol. Interact 1986 58 95.23 R. H. Barbour and D. R. Robins J. Chem. Soc. Perkin Trans. I 1988 1169. NATURAL PRODUCT REPORTS 1989 24 A. A. Freer and D. J. Robins Acta Crystallogr. Sect. C 1987.43 2240. 25 R. H. Barbour and D. J. Robins J. Chem. Soc. Perkin Trans. I 1988 1923. 26 D. J. Robins in ‘The Alkaloids,’ A Specialist Periodical Report. ed. M. F. Grundon The Royal Society of Chemistry London 1981 Vol. 11 p. 50. 27 F. Abe and T. Yamauchi Chem. Pharm. Bull. 1987 35 4661. 28 J. G. Davicinio M. J. Pestchanker and 0.S. Giordano PhJ.to-chemistry 1988 27 960. 29 A. Malik and K. Rahman Heterocycles 1988 27 707. 30 F. R. Stermitz and K. M. L’Empereur Tetrahedron Lett. 1988 29 4943. 31 T. Winkler and R. Heckendorn Heterocycles 1988 27 2331. 32 G.Wassel B. El Menshawi A. Saeed and G. Mahran Actu Pharm. Suec. 1987 24 199. 33 M. V. Telezhenetskaya A. D. Matkarimov S. N. Khadzhibekov and S. Yu. Yunusov Khim. Prir. Soedin. 1987,463(Chem. Abstr. 1987 107 151 274). 34 A. M. Rizk F. M. Hammouda E. Roeder H. Wiedenfeld S. I. Ismail N. M. Hassan and H. A. Hosseiny Sci. Pharm. 1988,56 105. 35 G. Marquina A. Laguna H. Velez and H. Ripperberger Phar-mazie 1988 43 55. 36 N. Guner Acta Pharm. Turc. 1988 30 53. 37 D. A. Rakhimova and T. T. Shakirov Khim. Prir. Soedin. 1987 384. (Chem. Abstr. 1987 107 141 188). 38 S. C. Jain and R. Sharma Chem. Pharm. Bull. 1987 35 3487. 39 A. M. Rizk F. M. Hammouda S. I. Ismail N. M. Hassan H. A. Hosseiny E. Roeder H. Wiedenfeld H. A. Ghaleb and M. K. Madkour Int.J. Crude Drug Res. 1988 26 112. 40 J. Sendra I. Przenioslo and M. Szpakowska Herba Pol. 1987 33 185. 41 J. J. Vollmer N. C. Steiner G. Y. Larsen K. M. Muirhead and R. J. Molyneux J. Chem. Educ. 1987 64 1027. 42 S. Kohlmuenzer H. Tomczyk and A. Saint-Firmin Diss. Pharm. Pharmacol. 1971 23 419. 43 R. H. Barbour and D. J. Robins Phytochemistry 1987,26 2430. 44 J. G. Urones P. B. Barcala I. S. Marcos R. R. Moro M. L. Esteban and A. F. Rodriguez Phytochemistry 1988 27 1507. 45 G. S. Hirshmann E. A. Ferro L. Franco L. Recalde and C. Theoduloz J. Nat. Prod. 1987 50 770. 46 N. Guner Acta Pharm. Turc. 1988 30 79. 47 G. G. Habermehl W. Martz C. H. Tokarnia J. Dobereiner and M. C. Mendez Toxicon 1988 26 275. 48 A. C. Ray H. J. Williams and J.C. Reagor Phytochemistry 1987 26 2431. 49 G. S. Hirschmann E. A. Ferro B. C. Cespedes L. Recalde and C. Theoduloz Fitoterapia 1987 58 263. 50 L. H. Villarroel P. Varea and R. Caceres Bol. SOC. Chil. Quim. 1988 33 107. 51 L. A. Pieters and A. J. Vlietinck Planta Med. 1988 54 178. 52 K. Vrieling and J. Bruin Meded. Fac. Landbouwwret. Rijksuniv. Gent 1987 52 132. 53 G. Toppel L. Witte B. Riebesehl K. V. Borstel and T. Hart- mann Plant Cell Rep. 1987 6 466. 54 A. Ehmke K. V. Borstel and T. Hartmann NATO AS1 Ser. Ser. A. Plant Vacuoles 1987 134 301. 55 G. Wassel B. El-Menshawi A. Saeed G. Mahran and J. Reisch Sci. Pharm. 1987 55 163. 56 P. M. Zavos D. R. Varney L. P. Bush R. W. Hemken J. A. Jackson and M. R. Siegel Drug Chem.Toxicol. 1988 11 113. 57 J. Bumerl J. Hofbauer and V. Mika Sb. Ved. Pr. Vyzk Sle- chtitelskeho Vstavu Picninarskeho Troubsku Brna 1987 10 177 (Biol. Abstr. 1988 85 72 404). 58 R. J. Nash L. E. Fellows J. V. Dring G. W. J. Fleet A. E. Derome T. A. Hamor A. M. Scofield and D. J. Watkin Tetra-hedron Lett. 1988 29 2487. 59 0.P. Suri and C. K. Atal Curr. Sci. 1967 36 614. 60 L. W. Smith J. A. Edgar R. I. Willing R. W. Gable M. F. Mackay 0.P. Suri C. K. Atal and C. C. J. Culvenor Aust. J. Chem. 1988 41 429. 61 C. C. J. Culvenor and L. W. Smith Aust. J. Chem. 1957 10 464. 62 B. Abegaz G. Atnafu H. Duddeck and G. Snatzke Tetrahedron 1987 43 3263. 63 C. C. J. Culvenor and L. W. Smith Anal. Quim. 1972 68,883. 64 B.-E. Van Wyk and G.H. Verdoorn Biochem. Syst. Ecol. 1988 16 287. 65 K. Ikhiri A. Ahmond C. Poupat P. Potier J. Pusset and T. Sevenet J. Nat. Prod. 1987 50 626. NATURAL PRODUCT REPORTS 1989-D. J. ROBINS 66 S. Brandange and B. Luning Acta Chem. Scand. 1969,23 1151. 67 K. Fujieda Y. Shoyama H. Matsunaka and I. Nishioka Phyto-chemistry 1988 27 1564. 68 F. R. Stermitz and G. H. Harris J. Chem. Ecol. 1987 13 1917. 69 R. B. Kelley J. N. Seiber A. D. Jones H. J. Segall and L. P. Brower Experientia 1987 43 943. 70 S. B. Krassnoff L. B. Bjostad and W. L. Roelofs J. Chem. Ecol. 1987 13 807. 71 S. Schultz W. Francke J. Edgar and D. Schneider 2. Natur-.forsch. Teil C. Biosci. 1988 43 99. 72 S. T. Schaeffer,L. H. Zalkow and A. S. Teja Fluid Phase Equilib.1988 43 45. 73 G. Holzer L. H. Zalkow and C. F. Asibal J. Chromatogr. 1987 400 317. 74 R. B. Jeppsen D. J. Weber and S. L. Welsh Phyton 1987 47 121. 75 P. Schmid J. Luthy U. Zweifel A. Bettschart and C. Schlatter Mitt. Geb. Lebensm. Hyg. 1987 78 208. 76 H. Hendriks W. Balraadjsing H. J. Huizing and A. P. Bruins Planta Med. 1987 456. 77 H. Hendriks H. J. Huizing and A. P. Bruins J. Chromatogr. 1988 428 352. 78 C. K. Winter H. J. Segall and A. D. Jones Biomed. Environ. Mass Spectrom. 1988 15 265. 79 M. W. Bredenkamp and A. Wiechers Tetrahedron Lett. 1987,28 3725. 80 M. W. Bredenkamp and A. Wiechers Tetrahedron Lett. 1987,28 3729. 81 A. A. Freer H. A. Kelly and D. J. Robins Acta Crystallop-. Sect. C. 1987 43 2020. 82 R.W. Gable M. F. Mackay and C. C. J. Culvenor Acta Crystallogr. Sect. C. 1988 44 1478. 83 A. A. Freer D. B. Hagan and D. J. Robins Acta Crystallogr. Sect. C. 1988 44 666. 84 H. Stoeckli-Evans and D. J. Robins Acta Crystallogr. Sect. C. 1987 43 1638. 85 D. J. Robins and G. A. Sim J. Chem. SOC. Perkin Trans. 2 1987 1379. 86 ‘Naturally Occurring Carcinogens of Plant Origin -Toxicology Pathology and Biochemistry,’ ed. I. Hirono Elsevier Amsterdam and New York 1987. 87 G. Wassel B. El-Menshawi A. Saeed G. Mahran and M. El-Merzabani Pharmazie 1987 42 709. 88 J. T. Seaman Aust. Vet. J. 1987 64 164. 89 V. E. Mendel M. R. Witt B. S. Gitchell D. N. Gribble Q. R. Rogers H. J. Segall and H. D. Knight Am. J. Vet. Res. 1988,49 572. 90 D.A. Gasanova D. S. Khalikov K. T. Mamedova and K. M. Mirzoev Azerb. Med. Zh. 1988 65 54 (Chem. Abstr. 1988 109 162 942). 91 P. K. Sriraman N. R. Naidu and P. R. Rao Indian J. Anim. Sci. 1987 57 1060. 92 P. J. Schubat W. J. Banner and R. J. Huxtable Toxicon 1987 25 995. 93 Z. Tu C. Konno D. D. Soejarto D. P. Waller A. J. Bingel R. J. Molyneux J. A. Edgar G. A. Cordell and H. H. S. Fong J. Pharm. Sci. 1988 77 461. 94 D. S. Griffin and H. J. Segall J. Biochem. Toxicol. 1987 155; Cell. Biol. Toxicol. 1987 3 379. 95 J. J. Karchesy B. Arbogast and M. L. Deinzer J. Org. Chem. 1987 52 3867. 96 C. K. Winter H. J. Segall and A. D. Jones Comp. Biochem. Physiol. C Comp. Pharmacol. Toxicol. 1988 90,429. 97 X.-L. Zhao M.-Y. Chan C. R. Kumana and C.W. Ogle Am. J. Clin. Med. 1987 15 59. 98 L. H. Bruner K. J. Johnston G. 0.Till and R. A. Roth Am. J. Physiol. 1988 254 H 258. 99 R. A. Roth and P. E. Ganey Toxicol. Appl. Pharmacol. 1988,93 463. 100 P. E. Ganey and R. A. Roth Biochem. Pharmacol. 1987 36 3535. 101 P. E. Ganey and R. A. Roth J. Toxicol. Environ. Health 1988 23 127.

ISSN:0265-0568    

DOI:10.1039/NP9890600577

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Coumarins R. D. H. Murray Department of Chemistry University of Glasgow Glasgow G 72 800 Reviewing the literature published between mid-1 980 and mid-1 988 1 Introduction 2 Separation and Identification 3 Coumarin 4 7-Hydroxycoumarin and its Derivatives 5 C-Substituted 7-Oxygenated Coumarins 6 Disubstituted 7-Oxygenated Coumarins 7 5,7-Dioxygenated Coumarins 8 6,7-Dioxygenated Coumarins 9 7,8-Dioxygenated Coumarins 10 5,6,7-Trioxygenated Coumarins 11 5,7,8-Trioxygenated Coumarins 12 6,7,8-Trioxygenated Coumarins 13 5,6,7,8-Tetraoxygenated Coumarins 14 4-Oxygenated Coumarins 15 4-Hydroxy-3-phenylcoumarins and Coumestans 16 Miscellaneous Coumarins 17 Biscoumarins 18 References 1 Introduction This review covers the literature on natural coumarins reported between mid-19801 and mid- 1988 (Chemical Abstracts 108)but excludes ellagic acid derivatives ellagotannins and benzo- naphthopyranones.The 3,4-benzocoumarins which can also be classified as isocoumarins have been omitted since the natural isocoumarins have recently been reviewed. In the last major review of coumarins,' details were included pertaining to their structural elucidation and synthesis from their discovery in 1812 to mid-1980. In an endeavour to enable others to ascertain whether or not a newly isolated coumarin was a new or a known compound the 786 coumarins known at that time were listed in Appendix 1 principally according to the number and orientation of oxygen atoms on the benzenoid ring. Thus 7-oxygenated coumarins were considered before 5,7- dioxygenated coumarins and 6,7- and 7,8-dioxygenated cou- marins before those trioxygenated on the benzenoid ring.A similar approach has been adopted here these types being considered before coumarins having oxygen atoms on the pyrone ring and before biscoumarins. Within each section coumarins are presented by and large in the following order (i) phenols (ii) phenol ethers which are considered in order of increasing numbers of carbon atom in the alkyl substituent and in increasing oxidation level within each of these groups (iii) phenol glycosides and (iv) phenol esters. Thereafter within each section an attempt has been made to consider coumarins carrying one or more alkyl or aryl substituent in a similar way according to the increasing number of carbon atoms in the substituent its oxidation level and its position on the nucleus.Dihydrofuranocoumarins are con- sidered before furanocoumarins and dihydropyranocoumarins before pyranocoumarins. The growth in the discovery of new natural coumarins witnessed during the past three decades has shown no signs of abating; in the past eight years around another 500 have been identified. The structures of some of these were not unexpected for example esters and/or glycosides of previously known phenols and/or alcohols. On the other hand a number of coumarins have been discovered possessing unexpected struc- tural features such as the coumarinolignoids in which a vicinally oxygenated coumarin nucleus is linked with a phenylpropanoid unit through a dioxane bridge or compounds in which a coumarin nucleus is bonded directly to a naphthoquinone.Particular mention should be made of the isolation from the Compositae of a remarkable array of 3- substituted-4-oxygenated-5-methylcoumarins and of terpenoid ethers derived from 6,8-dimethoxy-7-hydroxycoumarin.The absolute configurations of the latter and those of similar derivatives of 7-hydroxycoumarin have been established. Unusual structural features include the discovery of coumarin sulphates of coumarins possessing a C-isopropyl group and the identification of 3,4,7-trimethylcoumarin and of 5,6,7,8- te trame t hox ycoumarin. 2 Separation and Identification Scopoletin (7-hydroxy-6-methoxycoumarin) and other known mono-phenolic coumarins have been efficiently extracted from Fraxinus species with supercritical carbon dioxide using ethanol as entrainer ;3 however neither esculetin (6,7-dihydroxy-coumarin) nor fraxetin (7,8-dihydroxy-6-methoxycoumarin) could be extracted although present.Sequential centrifugal-layer chromatography a new powerful preparative technique which combines the advantages of preparative centrifugal-layer chromatography and thin-layer chromatography has been utilized for the efficient separation of furanocoumarin isomers.' Preparative on-line overpressure- layer chromatography is another potentially extremely useful technique which has also been used to separate a complex furanocoumarin mi~ture.~ Gradient thin-layer chromatogra- phic separations have also been The usefulness of high-performance liquid-chromatographic separation methods has been reported by a number of research The combination of ultrasensitive bioassay which detects photo-sensitizing furanocoumarins with sensitivities as high as 1 x g and high-performance liquid chromato- graphy has been employed to reveal furanocoumarins not previously detected in a number of umbelliferous plants.19-*1 A complete assignment has been made of the proton chemical shifts of coumarin all monomethoxycoumarins and the six dimethoxybenzenoid-substituted coumarins utilizing Pr(fod) as the shift reagent.22 The natural abundance 170 n.m.r. spectra of a series of coumarins have been described,23 and the "0 chemical shifts of furanocoumarins can be predicted.3 Coumarin Reaction of coumarin with superoxide anion radical followed by trapping with excess methyl iodide gave methyl o-methoxy- cis-cinnamate in 80 YOyield indicating that the primary process is attack by superoxide anion radical at the lactone-carbonyl carbon." Coumarin has been obtained in 75% yield from o-hydroxybenzaldehyde by condensation with carbomethoxy- methylenetriphenylarsorane followed by heating at 150 0C.2*5 59 1 NATURAL PRODUCT REPORTS 1989 (1) R=H (2) R = H2C+ (18) R = """P (4) R= H2Cq (19) R= (5) R = H2C/\yC02Me (6) R= H 2 C m (7) R= H2C (21) R = H0.. (22) R = (9) R = H z C W HO 0 OH (23) R = HO'. (11) R=H2C OH (24) R = HO ?Ac (25) R = (13) R = H 2 C W HO (14) R= HO qy (26) R = (15) R = 5PH0,.(27) R = HO (16) R = H0'. (28) R = Ac (29) R = fjm0 NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 4 7-Hydroxycoumarin and its Derivatives X-Ray crystallographic analysis of umbelliferone [7-hydroxy- coumarin (1)] has provided further evidence that hydroxylation at C-7 changes the resonance system of the coumarin moiety.26 7-Methoxycoumarin has been prepared in good yield by photocyclization of p-methoxycinnamic acid in the presence of 1,4-dicyanonaphthalene as electron acceptor.27 In polyphos- phoric acid and in the presence of resorcinol monomethyl ether p-methoxycinnamic acid undergoes a biogenetic- type oxidative self-cyclization to give 7-methoxycoumarin in 80 O/O yield.28 Since no reaction occurs in the absence of resorcinol monomethyl ether it is believed the reaction proceeds through addition of this compound across the cinnamic acid double bond.The epoxide (2) and the corresponding diol (3) have been isolated from Coleonema album2’ and the allylic alcohol (4) and the ester (5) from C. ~alycinum.~~ Large amounts of auraptene the geranyl ether of umbelliferone have been isolated from aerial parts of Baccharis darwinii together with two new derivatives 5’-hydroxyauraptene (6) and the ketone (7).31 ( +)-Epoxyaurapten and its acid-hydrolysis product ( +)-marmin the prenylogues of (2) and (3) respectively have been synthesized optical activity being introduced by a Sharpless epoxidati~n.~~ A new geometric isomer of diversin has been isolated from the roots of Ferula litwinowiana and the E-stereochemistry (8) The configuration of diversin which was originally assigned this structure is now shown to be Z.33The epoxy ketone (9) and the related diol (lo) both of unknown stereochemistry have been isolated from Phebalium squameum leaves.34 The antitumour activity of geiparvarin (1 1) has stimulated the development of a wide variety of interesting and practical syntheses.35-45 Karatavicin the monoacetate (12) of karatavicinol has been isolated from a Ferula species,46 as has deacetyltadzhikorin which was identical with the hydrolysis product of tadzhikorin (13).47 Reoselin has been shown to be the P-sophoroside of karatavicinol at the tertiary hydroxyl group.48 ( +)-Farnesiferol C the antipode of the natural farnesyl- derived coumarin has been ~ynthesized.~’ The absolute configuration of latilobinol (14) has been e~tablished.~~ Lehm-ferin (1 5) is the double-bond isomer of k~petdaghin.~~ Absolute configurations have also been assigned to kopeolin (16)52and the new coumarins fekrol the stereoisomer of kopeolin having the axial orientation of the secondary hydroxyl group,53 and kopeolone the corresponding ketone.52 Analysis of its 300 MHz ‘H n.m.r.spectrum has resulted in a structural revision for galbanic acid (17).54 Fekrynol has been shown to be the corresponding primary A total synthesis of (-t )-karatavic acid (18) has been effected by a route involving mercury(I1) triflate/N,N-dimethylaniline-inducedbicyclization of umbelliprenin the E,E-farnesyl ether of umbelliferone followed by a ring cleavage.56 Lehmferidin (19) from Ferula lehmanni is a new isomer of cauferidin differing only in the orientation of the hydroxyl The same compound was later isolated from F.iliensis and named ferilir~,~~ yet another example of a natural coumarin isolated from different sources being given two or more trivial names. A possible structure for a diene from F. sinaica is (20).58 Cauloside (21) has been shown to be the cellobiosyl derivative of cauferin. 59 The hydroxyenone (22) and three structurally related coumarins have been isolated from F. galbanz$ua it would seem much more likely that these compounds possess the opposite absolute stereochemistry to those given in the publication.The isobutyrate of ferucrin (23) and the cor-responding ketone ferucrinone have been isolated from F. foetidissima. Fepaldin (24) from F. pallida is the eighth samarcandin isomer to be described all of which differ only in configuration at C-3’ C-8’ and C-9’.62 A controversy of many years concerning the stereochemistry of samarcandin (25) has finally 593 been resolved by X-ray crystallographic analysis,63 which disclosed a configuration at C-8’ opposite to that which had been previously preferred.64 Isosamarcandin is the stereoisomer of samarcandin having the opposite configuration at C-3’ while feshurin differs from samarcandin only at C-8’ with nevskin being its C-3’ e~imer.~~ Feshurin acetate has been isolated from F.kokanica and given the trivial name koka- nidin.65 Microlobin (26) is the hydroxy derivative of the known coumarin kamolone to which it is chemically related.66 However microlobiden (27) which occurs with microlobin in F. microloba possesses a new type of terpenoid ~keleton.~’ The ketone from chromium trioxide oxidation of microlobiden was found to be identical with that from dehydration of galbanic acid (1 7) with phosphorus pentoxide. The circular dichroism spectra of 16 natural sesquiterpene umbelliferone ethers have been recorded and a new compound kamolonol the C-9’ epimer of microlobin has been isolated from the gum resin from F. assa-foetidea.68 As often seems to happen during structural elucidation of new coumarins three different groups independently reported the isolation of umbelliferone P-D-apiosyl-( 1 +6)-P-~-gluco-pyranoside from Gmelina arb ore^,^^ Phlojodicarpus sibiri-CUS,~O.and Adina ~ordifolia.~~ 71 Fortunately only one group assigned a trivial name adi~ardin.~~ Daurosides A and B from Haplophyllum dauricum are the first acylated disaccharides of umbelliferone to be found ;the former is 7-[6’-(4-0-acetyl-o-~- rhamnopyranosyl)-/3-~-glucopyranosyloxy]cournar~n, the latter 7-[6’-~-(~-~-rhamnopyranosyl)-2’-O-(p-coumaroyl)-/3-~-gluco-pyranosyloxy]coumarin.73 Two natural esters of umbelliferone have been reported the acetate (28) from Daphne gnidi~des,~~ and the phenylacetate (29) from Limonia ~renulata.~~ Oxidative cleavage of the pyrone ring of 7-acetoxycoumarin with ruthenium tetroxide gave 4- acetylsalicylic acid in good yield.76 5 C-Substituted 7-Oxygenated Coumarins The structure of angustifolin (30) from Ruta angustifolia was confirmed by preparation of its methyl ether,’17 a known natural product which has been synthesized from 4-prenyloxy-7-methoxycoumarin by ortho-Claisen rearrangement followed by removal of the C-4 hydroxyl group by reduction of the corresponding tosylate using zinc and hydrochloric The occurrence of 6-methylcoumarins in nature has been reported for the first time with the isolation of 7-hydroxy-6- methylcoumarin (31) and its methyl ether from Trachyspermum roxburghianum The latter has been synthesized by the Vilsmeier-Haack reaction on 2,4-dimethoxytoluene demethyl- ation of the product (32) with aluminium chloride followed by pyrone-ring formation using carbethoxymethylenetriphenyl-phosphorane.80 6-Acetyl-7-hydroxycoumarin is a constituent of parsley seeds.’l Structure (33) has been proposed from spectroscopic evidence for tenuidin from Haplophyllum tenue.82 HO Memo (31) 0 Me0 OMe MencHo (32) (33) NATURAL PRODUCT REPORTS 1989 I .H R%o Ho%o Me0 Me0 (34) R = H (35) R=H&T (36) (53) Eto+o Me0 Me0 Me0 Rmo (54) (37) (38) R = fiy Although 6-prenyl-7-hydroxycoumarin [demethylsuberosin 0 (34)] can be looked on as the precursor of a considerable number of natural coumarins introduction of the prenyl unit by a Claisen rearrangement is not straightforward 7-allyloxy- (39) = 0fi-f coumarins being known to undergo highly regioselective rearrangement to C-8.However three new routes to demethyl- suberosin have been devised to circumvent this problem. The first utilizes the known blocking effect of an 8-iodo substituent directing the ortho-rearrangement of 7-( 1,l -dimethylallyloxy)-8-iodocoumarin in N,N-dimethylaniline to C-6.s3 The second Me0 synthesis also involved an ortho-Claisen rearrangement in this (40) case via a 4'-( I I-dimethylally1oxy)coumaric acid derivative and boron tri~hloride.~~ The same Oxford group later greatly extended the synthetic possibilities in this area. Conversion of 7-benzyloxycoumarin into the corresponding methyl couma- rate then heating the derived 2-0-prenyl ether furnished the "OLOH corresponding C-6 prenylated-7-benzyloxycoumarin by sequen- tial thermal para-Claisen rearrangement and relactonization.Not only did debenzylation afford demethylsuberosin in good overall yielda5 but the higher prenylogue ostruthin (35) was also Me0 readily obtained.86 Homo Me0 Dihydrosuberenol(36) has been obtained from defatted root bark of Limonia acidissimas7 while ethylsuberenol(37) has been found in Citrus sinensis root bark." The first total synthesis of geijerin (38) has been achieved from 7-methoxycoumarin by a I1 highly regioselective Fries rearrangement of the derived ester CA/ 0 (40) followed by dehydrogenative ring closure.89 Dehydro- geijerin (39) was also prepared though in much lower yield.(42) R = \ The roots of Angelica pubescens have afforded seven closely II related coumarins 91 angelol B (42) angelol C (43), 0 0 angelol D (45) angelol E (48) angelol F (49) angelol G (51) and angelol H (52) together with angelol A formerly known as L (47) R = fi"f angelol. The structures and absolute configurations of these (43) = fi 0 compounds have been assigned while that of angelol has been 0 revised from (46) to (41).90 Angelols (C) and (F) are mixtures (44) R = of diastereoisomeric esters of ( & )-2-methylbutanoic acid.91 A fiy further investigation provided the trio1 (50).92 Later roots of 0 Coelopleurum gmelinii provided angelol I (44)and angeloside A the P-D-glucoside of angelol A (41) at the tertiary hydroxyl group.93A separate study of A.pubescens has reported the isolation of isoangelol a geometric isomer of angelol being the Ho&.oR tiglate (45) rather than the angelate.94 However this assignment is based on the original structure (46) for angelol rather than the revised structure (41). It would seem more likely that isoangelol is angelol B (42) rather than (45) and that the co- Ho-o Me0 Me0 occurring isovalerate anpubesolS4 is angelol I (44) rather than that proposed (47). The epoxylactone ring of micromelin (53) opens very I (48) R = fiy easil~.~~*~~ Under strongly basic conditions the main product is the methoxy acid (54) while under very mild conditions the five- 0 (51) R =C II membered ring may be opened and closed to give either 0 micromelin or its C-4' epimer isomicromelin.Three dihydro- micromelin derivatives have been extracted from Micromelum (52)R = E"( minutum dihydromelin A (55) and dihydromelin B (56) 0 isolated as a mixture of hemiacetals and acetyldihydromelin A (50)R = H (57) hydrolysis of which gives the hemiacetal rnixt~re.~' Four NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY (55) R' = H R2 = OH (56) R' = OH R2 = H (57) R' = H R2 = OAc (58) R = 0-gentiobiosyl (59) R = 0-isomaltosyt (60) R = 0-maltosyl (61) R = 6"-apiosyI-~-D-glucosyI glucosya. 1-0 (62) OH 2-m0 (63) R =Ac 0 (74) R = H (75) R=O Ph 1 (80) R' = Ac R2 = (81) R' =Ac R2=C (82) R' =Ac R2 = C 0 0 II 0 nodakenetin disaccharides have been isolated from Peucedanum decursivum roots decuroside I (58),98 decuroside I1 (59),98 decuroside I11 (60),98 and decuroside IV (61).99 In tests for inhibition of ADP-induced aggregation of human platelets in vitro decurosides III and IV had the strongest activity whereas the co-occurring decuroside V (62)99enhanced ADP-induced ?R aggregation.98 Marmesin acetate (63) has been discovered in Amyris OAc 0 elemifera.lOOThe corresponding tiglate ( -)-sprengelianin (64), +-ao previously known only as the racemate has been reported as a 0-glucosyl (67) R = Ac (66) 0 (69) (70) (72) R = H (71) (73) R = H2C- constituent of Cachrys sicula'O' and Eryngiurn ilicijolium.102 On the other hand tortuosinin the angelate of racemic marmesin has been found in Seseli tortuosum where it occurs with tortuosinol (65) the senecioate of prandi01.'~~ Two dihydro- furanocoumarin P-D-glucosides (66) and the C-2' epimer of (62) have been isolated from a water-soluble root extract of Angelica archangelica subsp.litorali~.'~~ By correlation with the aglycone obtained in this work the absolute configurations were established for smirniorin (67) and smirnioridin (68).lo3 A novel synthesis of psoralen (69) is based on the neopentyl acetal (70) derived from ethyl acetoacetate. Heating to 200 "C in the presence of palladium-charcoal induced an intramol- ecular Diels-Alder cycloaddition with concomitant aromatiza- tion.Deprotection of (7 1) followed by Baeyer-Villiger oxi-dation and dehydrogenation afforded p~oralen.~~~ A synthesis of prangosine (72) has confirmed the structure.loG Condensation of 6-bromo-7-hydroxycoumarin with the copper(i) salt of N,N-diallyl-1 I -dimethylpropargylamine gave N,N-diallylprango-sine (73) which was de-allylated with tris-(tripheny1phosphine)-chlororhodium. The simple coumarin dihydroxanthyletin (74) has been isolated for the first time from aerial parts of Seseli tortuo~um,~~~aegelinol benzoate (75) from Eryngium and campestre roots.10s Although ( + )-decursidinol (76) is still unknown as a natural product six new esters have been obtained from Peucedanum decursivum roots Pd-C-I (77) Pd-C-I1 (78) Pd-C-I11 (79),Io9 and Pd-C-IV (80).'1u Pd-C-V is a 50:50 mixture of the isovalerate (81) and the angelate (82).l1° Mass spectrometry was used to determine the locations of the ester moieties thereby avoiding alkaline hydrolysis.11° In 3',4'-diacyloxydihydropyranocoumarins the 3'-acyloxy group is split out preferentially as the carboxylic acid and can be distinguished from the 4'-acyloxy group which is eliminated mainly as the carboxyl radical and much less as the carboxylic acid.l A number of syntheses of xanthyletin (83) have been reported. l-ll3 The leaves of Murraya exotica and M. paniculuta have provided a rich array of new 8-substituted-7-methoxycoumarins (83) A (84) R=CHO (85) R=Y'lf Ho H NATURAL PRODUCT REPORTS 1989 in addition to a number already known.Paniculal (84) from the latter source is purportedly a new natural product114 but was first isolated in 1977 from Peucedanurn hispani~um."~ Osthenon (85) has been isolated from M. exotica116 and its geometric isomer cis-osthenon (86) from M.paniculata.118 The stereochemistry of ci+dehydroosthol(87) the geometric isomer of which is already known follows from the coupling constant of 12 Hz for the vicinal olefinic The absolute configuration of auraptenol (88) has been firmly established as S by the Horeau method.'lg Previously auraptenol was thought to be an artefact derived from the corresponding epoxide meranzin (89) also known as auraptene with which it normally co-occurs but now it is believed to be a genuine constituent of M.ex~tica."~ Peroxyauraptenol (90) from the same source116p117and only the second example of a hydroperoxy- generated coumarin has the same chirality since auraptenol (88) was obtained after treatment with triphenylphosphine. The 0 (107) R=HbV QAc (108) R =4C,y H OH I H (99) R = H2CToH OH (88) R=H2CT 0u (89) R=H2CT (100) R = ~ 2 ~ y ~ ~ OOH (90) R= H2Cy (101) R=H*C %I OMe (102) R = HzC%oH OAc ' OH (103) R = H2CYOMe (113) R =CII 0 (94) R = C/A I (1 14) R = HCTCHoI OH CHO QH (115) R = HCTI OH OH (116) R = HCVoH9 (96) R= HC (106) R=HCY I (0Ac OEt NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY coumarin CM-c, m.p. 138-141 "C of unassigned stereo-chemistry from Cnidium monnieri120 has been synthesized by the palladium acetate-catalysed condensation of 7-methoxy-8- iodocoumarin with 2-methylbut-3-en-2-01 and shown to be the (E)-isomer (91).12' In its 'H n.m.r.spectrum at low field the olefinic protons resonate as a two-proton singlet. Murraol from M. exotica,'16,117 was deduced to have the same structure but had a much lower melting point 105-107 "C.The dilemma remained until the higher-melting form was isolated from M. paniculata ;bimorphism was then confirmed.122 The structure of murralongin the sole product of re-arrangement of phebalosin (92) with boron trifluoride-etherate has been revised from (93) to (94) and confirmed by a single crystal X-ray ana1y~is.I~~ Three other members of this new series of prenylated coumarins in which neither the head nor the tail of an isoprene unit is attached to the nucleus have been discovered.Microminutin (95) is a cytotoxic constituent of Micromelum min~tum.'~~ The optically active isomurralonginol acetate (96) has been isolated from Murraya exotica,'16 and the corresponding nicotinate (97) the first such coumarin ester from M. paniculata.l'* Paniculin (98) from the same plant,'14 was identical with the potassium permanganate oxidation product of the corresponding aldehyde citrusal. The latter is a minor product of rearrangement of auraptene (89) with trifluoroacetic acid. 125 Hydrolysis of the monoformate coumurrin (99) from M. panicul~ta~'~ gave meranzin hydrate of known absolute configuration.The stereochemistry of the related isovalerate murrayatin (100) from M. exotica126 was similarly assigned. Chloticol (101) is possibly an artefact.'16 The diol monomethyl ether (102) from the same plant not only may be an artefact since methanol was used for its isolation but its structure may have to be reassigned as (103) since it gave a monoacetate with acetic anhydride in the ~0ld.l~~ In 1984 minumicrolin m.p. 132-135 "C was isolated from Micromelum minutum and shown to be a diastereoisomer of murrangatin.97 Since an erthyro-configuration (1 04) had earlier been deduced for murrangatin it followed that minumicrolin was the threo-isomer. Some three years later however two Japanese groups isolated these two coumarins from Murraya paniculata116 and proposed that the relative stereochemistry of the glycol moieties were such that murrangatin was the threo- isomer and minumicrolin the erythro.These reassignments were based on differential nuclear Overhauser experiments on the derived acetonides. Furthermore the absolute stereochemistry of murrangatin was proposed as R,R (105) based on the exciton chirality method applied to tetrahydromurrangatin dibenzoate and that of minumicrolin as (104). Earlier murpanidin m.p. 163-164 "C was isolated from the same source M.paniculata along with murrangatin and deduced to be the diastereoisomer of the latter.128 Thus murpanidin and minumicrolin should be identical and it is difficult to account for the significant difference in the reported melting points.Two ethyl ethers murpanicin'28 and murrax~cin'~~ have been isolated from M.paniculata and M. exotica respectively and have been assigned the same structure (106) but no stereochemistry. Not only are these two species believed to be identical but in each case ethanol was used as the extraction solvent and the epoxide phebalosin (107) is a known con-stituent.' Consequently it is probable that murpanicin and murraxocin are artefacts. (-)-Phebalosin has been isolated from M. gleinei leaves;130 previously only the racemate was known.' Murrangatin acetate (108) has been isolated from M. exotica116 and the interesting ether derivative (109) of murran- gatin and 5,7-dihydroxy-3,6,8,4'-tetramethoxyflavone ob-tained from Micromelum min~tum.'~ The hygroscopic diol (1 10) was separated from aurapten phebalosin (1 07) and murrangatin (109 from an extract of Polygala paniculata possessing molluscidal and antifungal properties by flash chromatography and centrifugal thin-layer chromatography.13' The benzylic alcohol (1 11) has been isolated from M. exotica as a dextrorotatory oil named murranganon,I16 and from M. 597 paniculata as an optically inactive solid named murpanicol. 'l4 Independently the optically active acetate hainanmurpanin (1 12) has been isolated from the latter source and stated to give murpanicol on alkaline hydrolysis. 13 Isomurrangonon sene- cioate (1 13) is yet another new coumarin from M. exotica leaves.I16 The double bond stereochemistry of panial (1 14) from M.paniculata derives from the nuclear Overhauser enhancement of the signal for the vinyl proton on irradiation of the aldehyde proton.'18 The 'H n.m.r. spectrum of phlojodicarpin (1 15) from the epigeal parts of Phlojodicarpus sibiricus is complex since the compound can exist as various conformers stabilized by intramolecular hydrogen bonds of the hydroxyl group with the other oxygen atoms. 133 The 2-configuration has been assigned to the substituents on the oxirane ring of the co-occurring isophlojodicarpin (1 16) from the coupling constant of 5 Hz for the epoxide In this respect it differs from its analogue phebalosin (107) for which an E-relationship has been established. The structure (1 17) of a supposed coumarin from Erythrina stricta bark is suspect since a coupling constant of 15 Hz between H-3 and H-4 is reported instead of the expected 9.5 Hz.134 Interestingly no other coumarin has yet been reported from the genus Erythrina and its spectral data are very similar to these of the cinnamate erythrinasinate (1 18) which has been isolated from three other Erythrina species.135 Galipein (1 19) the prenyl analogue of phebalosin (107) with which it occurs in Galipea trifoliata has the same stereo-chemistry.136 Triphasiol (1 20) from Triphasia trifoliata leaves has been shown not to be an Another Rutaceous plant Sargentia greggii contains 0-geranylosthenol(l2 1) in its OH (1 18) (1 19) Ho&oq30 k (120) NATURAL PRODUCT REPORTS 1989 Ro&OH HO HO (123) R = H (124) R = P-D-gIUCOSyI (125) R = P-D-apiosyi \ (1 27) (128) R' = fiy, R2 =Ac 0 (129) R' = P-D-glucosyl R2 = H 0 0 0 (134) R' = Ac R2 = C 0 (137) R = H (138) R=S03K roots.13' The corresponding diepoxide tortuosidin (122) has been found in Seseli tortuo~um'~~ and osthenol-7-0-P-gentio- bioside in Glehnia littor~1is.~~~ Columbianetin 0-P-D-glucoside (123) is a constituent of bitter orange flavedo.140 Columbianin was originally believed to have this structure but later work showed it to be the gentiobioside ( 124).14'These two glycosides together with the 6'-P-~-apiosyl derivative (125) have also been isolated from a water-soluble extract of Lomatium dissectum ; centrifugal countercurrent chromatography afforded excellent resolution of these three g1y~osides.l~~ The ether (126) isolated from Ammi majus fruits is in all probability an artefact.143 On the other hand the enone saxicolon (127) from the roots of Seseli saxicolum has been shown not to be an artefact.144 It has been prepared from peucenidin (128) with which it co-occurs.The absolute configuration of apterin (1 29) has been confirmed by enzymatic hydrolysis to vaginidi01.l~~ Its true optical rotation is + 229" and not the opposite which was a misprint in the original literature. The related diester cniforin B (130) has been isolated from Cnidium monnieri fruit.146 The co-occurring known' diester (13 1) has been named cniforin A. Two additional diesters from Angelica edulis roots edulisin I (132) and edulisin I1 (133) inhibit platelet aggregati~n.'~' From chemical studies and X-ray crystallographic analysis the absolute configuration of the co-occurring isopeucenidin (1 34) has been The sign of the optical rotation in chloroform given originally for isopeucenidin is incorrect and the rotation should be +94.9".The glycol (135) has been found in Apium graveolens This compound cannot as claimed be an optical isomer of prandiol since the latter is the corresponding linear dihydrofuranocoumarin.149 It would seem to this reviewer that the structure (136) of libanotin A from Libanotis buchtormensis roots is incorrect. It seems more probable that this is the known alcohol lomatin (137) the isovalerate and senecioate of which have previously been isolated from the same source.Coumarin sulphates crystallized as potassium salts have been reported in plants for the first time with the isolation of lomatin sulphate (1 38) and NATURAL PRODUCT REPORTS 198!9-R.D. H. MURRAY OR2 0R’ (139) R’ = S03K R2= H (141) R’ =$m R2=H 0 (143) R’ = fiy R2 = H 0 II 0 (145) R1 = H R2 = Me (146) R’ = H R2 = C I1 0 (147) R’ = H R2=C 0 (148) R’=CA R2=H II 0 (149) R’ =CL,R2= H I1 0 0 (152) R’=Ac R2=C I1 0 II 0 0 the 3’-sulphate (139) of ( + )-cis-khellactone from Seseli libanotis roots.151 Seseli campestre roots have afforded three new (+)-cis-khellactone derivatives campestrol (140) campestrinol (14 I) and campestrinoside (1 42).152Campeselol previously isolated from the same source,’ was shown to be a mixture of (143) and (144) while the methyl ether (161) of (-)-trans-khellactone was shown to be an artefact.*52 Later however the 4’-O-methyl ethers (145) and (161) of (+)-cis- and (-)-trans-khellactone were considered to be genuine natural products when isolated from an ethanolic extract of Phlojodicarpus sibiricus aerial parts.153 0 I Wo YOR’ i,R’ A (154) R’ =Ac R2=C II 0 (155) R’ =fi \ R2 = fiy 0$ 0 (156) R’=fiT R2=Ac 0 (157) R’ = R2= II 0 -(158) R’ =Ac R2 = C II 0 0 0 0 I po OR2 OR’ (161) R’= H R2= Me (162) R’ R2= H = fiy 0 Eighteen khellactone derivatives of which five are novel (1 46>-( 150) have been isolated from Musineon divaricatum.15? The successful high-performance liquid-chromatographic sepa- rations utilized a nitrile bonded-phase column with hexane- isopropanol solvent combinations. Identification of the mixed esters was accomplished by reliance on the mass spectral fragmentation patterns and the absolute configurations based on that of anomalin (151) the most abundant of the series. Among the known khellactones were seravschanin (I 52) isolated earlier from Seseli seravschanicum roots,’-j5 and praeruptorin E (1 53) from Peucedanum praeruptorum roots. 156 However it is possible that seravschanin and praeruptorin E from their original sources are the enantiomers (1 54) and (1 55) respectively.(+)-Samidin (156) from the roots of P. japoni-cum157 has been shown to be the antipode of samidin from Ammi visnaga.l P.austriaca contains the diepoxide (1 57).lS8 The first khellactone diester (1 58) with an aromatic acid moiety has been isolated from Polygala paniculata. 159 Two further khellactone derivatives have been found in Peucedanum praeruptorum roots the diester Pd-I11 (159) and the keto ester Pd-Ib (163).160 The first synthesis of (+)-praeruptorin A also known as Pd-Ia (160) has been described.161 cis-Hydroxylation NPR 6 of seselin (168) was achieved by the catalytic osmium tetroxide hydroxylation procedure using a stoicheiometric amount of N-methylmorpholine N-oxide. Partial acetylation at C-4' was achieved regiospecifically using acetic anhydride in the presence of boron trifluoride-etherate.Treatment of the monoacetate with angelic acid dicyclohexylcarbodiimide and 4-pyrrolidino- pyridine gave ( -t)-praeruptorin A in 6 % yield and 80 YOof the corresponding tiglate. The synthesis of the corresponding isovalerate ( & )-dihydrosamidin was achieved in high yield. 161 The ( -)-trans-khellactone ester junosmarin (1 62) has been isolated from Citrus junos rootbark.162 While isolation of (-)-trans-khellactones is usually considered to be the result of epimerization at C-4' during the isolation process no cis-khellactone derivatives could be detected in this case. The enantiomer of (163) has been obtained from the aerial parts of Arracacia ne1~onii.l~~ Turgeniifolin A from Peucedanum tur-geniifolium is either (163) or its anti~0de.l~~ The stereo-chemistry of turgeniifolin B (164) and C (165) is as yet undefined.le4 This reviewer agrees with the referee who suggested from mass spectroscopic evidence that bocconin (166) from Seseli bocconi should have the alternative structure (167).165 In the mass spectra of such compounds the 3'-acyloxy group is split out preferentially as the carboxylic acid the 4'- acyloxy group being eliminated mainly as the carboxyl radical and much less as the acid.' Osthenol (7-hydroxy-8-prenylcoumarin) readily undergoes cyclodehydrogenation to seselin (1 68) with trityl tetrafluoro- borate.166 0 I Po WOR2 0R' = fiy (164) R' R2 = H 0 = fiy (165) R' R2= H 0 (166) R'=f R2=AC /I 0 (167) R' =Ac R2 =C A II 0 ?mo NATURAL PRODUCT REPORTS 1989 6 Disubstituted 7-Oxygenated Coumarins 7-Ethoxy-3,4-dimethylcoumarin(1 69) from Edgeworthia gard- neri is the first 7-ethoxycoumarin from a natural source.167 Syntheses of gravelliferone (1 70),168.170-172 balsamiferone (171),168*'69 (f)-chalepin (172)170,172and its acetate (f)-rutamarin,170 have been effected from 7-hydroxycoumarin utilizing repeated sequences of [3,3]sigmatropic rearrangements. Swietenocoumarin I (173) is another constituent of Chloro- xylon swieteniu bark.173 The absolute configuration of (1 74) from Amyris elemifera has been shown to be the same as that of the co-occurring marmesin acetate (63).loo The stereo-chemistries of elemiferone (175) its monoacetate (I 76) and diacetate (177) are as yet ~nassigned,'~~ but that of swieteno- coumarin H (1 78) is The stereochemistry of ulismoncadin * HO (170) R=C% EtO /\ (169) (171) R=H2C HO (172) VR2 (175) R' = R2 = H (176) R' = Ac R2 = H (177) R' = R2 = Ac x OH (168) (178) NATURAL PRODUCT REPORTS 1989-R.D. H. MURRAY A (1 79) from Helietta parvifolia is ~nkn0wn.l~~ Its racemate and the corresponding chromene have been ~ynthesized.'~~. 176 The fronds of Macrothelypteris torresiana contain 7-hydroxy-4- isopropyl-6-methylcoumarin.177 Ulismoncadin (1 80) from Thamnosma texana interestingly contains two adjacent prenyl The trivial name ulismoncadin A was assigned prior to its structure being deduced when it was believed there might be a close relationship with ulism~ncadin.~~~ Again the name pablohopin was coined before it was realised that the compound from T.texana was dehydr~geijerin.'~~ 179 7 5,7-Dioxygenated Coumarins 5,7-Dihydroxycoumarin has been found for the first time as a natural product in the roots of Haplophyllum dauricum.lEO The 4-phenyl analogue serratin and its 7-P-~-glucoside have been isolated from Passij?ora serratodigitata.lal Nivegin (18 l) from Echinops niveus is the first 4-arylcoumarin reported in the Compositae.lE2 The structures of five 4-arylcoumarins (182)-(1 86) isolatedla3* la4 from Coutarea hexandra have been con- la5 firmed by ~ynthesis.'~~.Seshadrin (1 87) from Dalbergia volubilis is so-named as a tribute to the late Professor T. R. Seshadri who studied the first naturally occurring 4-phenyl- coumarin dalbergin in detail.ls6 C. hexandra has also provided the 4-arylcoumarin glycosides (1 88)-( 191).la7 The P-D-galacto- side corresponding to (189) was found in Exostema caribaeum stem bark where it occurs with (192) and (193).la8 The corresponding monomethyl ether (194) which exhibits a striking violet fluorescence is a constituent of Coutarea lat~j?ora.~~~ C. hexandra has also been found to contain (195).lg0 Neutral potassium permanganate oxidation of voludal (196) from Dalbergia volubilis gave oxalic acid and 3-hydroxy-4- methoxybenzoic acid. lgl Mulberroside B from the cultivated mulberry tree Morus lhou has been shown to be the C-P-D-glucoside (197) hydrolysis with iron(m) chloride giving 5,7-dihydroxycoumarin and arabinose.lg2 Dauroside D from Haplophyllum dauricum probably has the same structure despite the melting point and optical rotation differences.la0,lg3 (1 79) (180) OR^ R' 0A0 0R2 R' 0 ' 0 (184) R' =Me R2 = R3 = H (185) R' = R2 = Me R3 = H (186) R' = Me R2R3 = CH2 (187) R' = R3 = H R2 = Me ,OR2 HO R' 0 (188) R' = R2 = H (189) R' = Me R2 = H (190) R' = Me R2 = p-D-apiosyl (191) R' = Me R2 = P-~-xylosyl OR2 R' 0gH (192) R' = R2 = H (193) R' = R2 = Me (194) R' =Me R2 = H Me0 (195) (181) R' = R2 = R3 = H (182) R' = R2 = Me R3 = H (183) R' = R2 = R3 = Me (197) 5-2 NATURAL PRODUCT REPORTS 1989 OMe (202) R = H (203) R = H2CW OR I (206) R = H 2 C T H2CmoH (207) (208) R = H 2 C m (210) R = HzCT 5-Methoxysuberenone (198) has been found in Toddalia aculeata where it occurs with (199) and (200).lg4It should be noted however that there are some discrepancies between the data for natural and synthetic (198) prepared from 6-formyl- 5,7-dimethoxycoumarin which had been isolated from T.a~iatica.'~~ Toddanone (1 99) and toddanol (201) were earlier isolated from T. asiaticalg6and their structures later confirmed by synthesis.lg7 Celereoin (202) is a new constituent of Apiurn graveolens seeds.lg8 The related ether jumutinol (203) also of unassigned stereochemistry is present in Seseli jornuticum.lg9 Racemic 5-hydroxymarmesin (202) has been synthesized.200 The ethyl ether (204) of oxypeucedanin hydrate previously known as an oil from Ruta oreojasme and R. pinnata has been isolated in crystalline form from Angelica orfticinalis var. himaliaca.201The stereochemistry of oxypeucedanin hydrate acetonide (205) from Peucedanurn tuvcomanicurn is also unassigned.202 Anhydronotoptol (206) notoptol (207) and the optically inactive notopterol (208) have been isolated from three Notopterygium species.2o3 Tortuosin (209) is a further component of Seseli tortuo~um.'~~ Anisolactone (210) and the corresponding epoxide (21 1) are constituents of Clausena ani~ata.~~~ Linear and angular 5-methoxyfuranocoumarins can readily be differentiated from the 'H chemical shift of the methoxyl resonance.2o5 Diseased celery infected with the fungus Sclerotinia sclero-tiorum had greatly increased levels of psoralen (69) 5-methoxypsoralen and 8-methoxypsoralen which are causative agents for skin photosensitivity.206 In spoiled or diseased parsnips freely available to the public total furanocoumarin levels increased by 2500 % over normal levels in fresh parsnips and in some instances mixed crystals of furanocoumarins could even be detected on the surfaces of parsnip roots by conventional low-powered microscopy.207 Reviews have ap- peared on furanocoumarin phytoalexin formation in fungus- infected plants and elicitor-treated cell cultures of parsley,208 on furanocoumarin photochemistry and its main biological impli- cations,209the biological actions and metabolic transformations of furanocoumarins,210 and on the photogeneration of singlet oxygen by furanocoumarins.211 Berenbaum has extended her studies on the role of furanocoumarins in the protection of plants against phytophagous insects211 to studies on the level of furanocoumarin production in parsnips possibly resulting from selection imposed by herbivores and pathogens in natural populations.212.213 An unambiguous synthesis of (& )-eriobrucinol (2 12) using intramolecular cycloadditions has been The prob- able absolute configuration of (-)-bruceol (2 13) has been assigned from X-ray crystallographic evidence.215 The crystal structures of hydroxyeriobrucino1216 and deoxybruce01~~~ have also been determined.NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 603 OMe I 0 I / Me0J$Oo 0pokp0 A -(214) R=C/T k o (228) (229) OH I A (230) R=HzC (231) R = H (218) R=H2C ? (232) R=,C,-OH (219) R = H2CyoH Toddalenone (214) the C-8 isomer of (198) has been (220) R=!YoH isolated from Toddalia asiatica and synthesized by Vilsmeier- Haack formylation of 5,7-dimethoxycoumarin followed by 0 aldol condensation with acetone.lg5 Murraya gleinei root has afforded gleinene (215) which contains a five-carbon side chain novel to natural coumarins and gleinadiene (21 6).217 The structure of the latter was confirmed by its preparation2I7 by phosphoryl chloride dehydration of omphamurin (21 7).218This optically active alcohol from M.omphalocarpa leaves has been 04 assigned2I8 the same structure as sibirinol of unspecified optical activity.l The spectroscopic data for these two coumarins are similar but they differ in melting point by 10°C.Earlier M. gleinei leaves had been found to contain (-)-sibiricin (218) and (-)-mexoticin (219) both of which were known naturally only as the dextrorotatory (-)-Mexoticin has also been isolated from M.paniculata leaves but unfortunately given the Me0+lo trivial name isomexoticin.128 A reinvestigation of Angelica pubescens roots has revealed nine more coumarins including the P-hydroxyketone (220) and angelin (222) the structures of which were both confirmed by conversion into glabralactone (223) R=Me (LL1).The structure of 5-methoxyseselin (223) from Citrus grandis (222) (224) R = H rootbark221 has been confirmed by synthesis.222 5-Prenyloxy-7- acetoxycoumarin in refluxing acetic anhydride underwent a para-Claisen rearrangement virtually quantitatively to 8-prenyl- 5,7-diacetoxycoumarin providing a convenient alternative to the previously established seven-step sequence for this trans- formation.223 Hydrolysis and oxidative cyclization with DDQ afforded the angular pyranocoumarin (224) methylation of which gave 5-methoxyseselin. 222 A fourth coumarin glycycoumarin (225) has been isolated from licorice roots Glycyrrhiza uralensi~.~~~ The structure of (226) has been revised to (227) and the true compound (225) possessing structure (226) isolated from Heracfeum thomsoni Heating lanatin (228) in acetic anhydride and N,N-dimethylaniline at reflux gave the acetate of (227) which on prolonged heating with potassium carbonate in aqueous OH methanol rearranged to (226).225 Honyudisin (229) yet another constituent of Citrus grandis rootbark was shown to be isomeric with trachyphyllin (230).226 Treatment of 5-hydroxyseselin (224) with methanolic alkali gave an equimolar equilibrium mixture of (224) and the linear isomer (231) which were readily separated.The prenyl ether of Wo (231) was converted into trachyphyllin in quantitative yield by -para-Claisen rearrangement in refluxing acetic anhydride followed by hydrolysis.222 Nordentatin (232) has also been (226) (227) synthesized in excellent overall yield from the ortho-Claisen NATURAL PRODUCT REPORTS 1989 OHI OMe I (233) (234) (235) H (236) R=OH (237) R = H O (238) Y (239) R = CII 0 (240) R =$”( 0 Me0bo (241) R = Ac (243) R’ =OH R2 = H (242) R = H (244) R’= H R2=OH A rearrangement of the prenyl ether of (224) followed by lactone- ring is~merization.~~~ Ponfolin the 1,l -dimethylally1 ether of nordentatin has been isolated from Poncirus trifoliutu roots228 and has been ~ynthesized.~~’ On refluxing in acetic anhydride it underwent an out-of-ring Claisen rearrangement providing an alternative more efficient synthetic to clausarin (233) than that reported earlier.229 Significantly nordentatin and clausarin exhibit pronounced cytotoxic activities.23n Hortiolone (234) has been synthesized in five steps from 7-hydroxy-5- prenyloxycoumarin in 76 % overall yield.231 Spectroscopic evidence for the co-occurring hortinone has been reassessed and the proposed revised structure (235) confirmed by synthesis.231 Aflatoxin M (236) has been synthesized in thirteen steps with an overall yield of 5 Yn from phloroglucinol monobenzene- sulphonate and 1,4-anhydroerythritol.232 Aflatoxin B (237) has been converted chemically into aflatoxin MI but in very poor overall yield.233 In a series of excellent papers total syntheses of most of the Mummeu coumarins have ben rep~rted.~~~-~~’ Pechmann condensation of an acylphloroglucinol with an appropriate /I-keto ester was followed by C-alkylation with prenyl bromide or geranyl chloride in aqueous potassium hydroxide.Oxidative modification of the prenyl group led to the mammea cyclo E and cyclo F coumarin~.~~~ Mammea B/BB has been shown by synthesis to be the S-( -)-compound (238).237 Mammea E/BB (239) E/BA (240) and surangin B (241) which have topical insecticidal properties have also been prepared despite the additional synthetic constraints imposed by the 1’-acetoxy s~bstituent.~~~ Surangin C (242) has been isolated from the bark of M. 10ngifolia.~~~ The first report of two 4-methylcoumarins cordatolide A (243) and B (244) co-occurring in leaf extracts of Culophyllum corduto-oblongurn with oblongulide (245) the O-methyl de- rivative of their probable biogenetic precursor is of biogenetic ~ignificance.~~~ The structures of two 4-phenylcoumarins (246) and the corresponding angular pyranocoumarin from Ochro-carpus siumensis flowers have been confirmed synthetically.24n NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 8 6,7-Dioxygenated Coumarins Convenient syntheses of aesculetin (247) and related 6,7-dioxygenated coumarins have been reported. Condensation of a 2-nitrobenzaldehyde with malonic acid is followed by denitrocyclization and decarboxylation of the resultant o-nitrobenzylidenemalonic acid using copper in quinoline.241 Aesculetin was isolated from a reaction mixture containing phenolase and cis-caffeic acid. Since the oxygen atom in the lactone ring of aesculetin was not derived from molecular oxygen or water it is suggested that the carboxyl group of caffeic acid may be Aesculetin its 7-prenyl ether prenyletin and haplopinol (248) are responsible for the antimicrobial activity of Haplopappus multifoli~s.~~~ Floribin present in trace amounts in the bark of Fraxinus JEoribunda has been assigned the structure 5-hydroxy-6-methoxyc~umarin,~~~ the first report of a 5,6-dioxygenated coumarin from a natural source.However 6,7-dioxygenated coumarins are commonly found in Fraxinus species and from the data presented for floribin the reviewer is of the opinion that it is impure scopoletin (249). The structures of obtusinol (250)245and obtusinin (25 1)246 from Haplophyllum obtusifolium have been confirmed by Obtusoside (252) is obtusinin /3-~-glucoside.~~* Bungeidiol (253) is a constituent of H.bungei aerial 250 The known scopoletin farnesyl ether (254) has been isolated from Artemisia persica and given the trivial name scopofarnol. 251 The absolute configuration of the co-occurring scopodrimol A (255) has been e~tablished.~~’ A number of glycosylated and/or acylated derivatives of scopolin scopoletin P-D-ghcopyranoside (256) have been reported. Lariside from Salsola laricifolia is 2’-P-~-apiosyl- scopolin (257). 252 Haploperoside A from Haplophyllum per- foratum aerial parts was originally believed to be 2’-a-~- rhamnosylscopolin (258)253 and haploperoside B its 4”-acetyl derivative.254-255 However when haploperoside D was isolated it was deduced to have structure (258) which necessitated structural revision of A and B.256Haploperoside A is now believed to be 6’-a-~-rhamnosylscopolin(259) B its 4”-acetate and C the 2’-a~etate.~~~ Haploperoside E is 2’,6’-di(a-~-rhamnosylscopolin) (260)256 and dauroside C from H.dauricum a monoacetyl derivative of (259).257 2’,6’-Diacetylscopolin (26 1) has been isolated from Viburnum suspensum leaves258 and also from V. awabuki leaves where it occurs with 2’-acetyl-(262) 6’-acetyl-(263) and 3’,6’-diacetyl- scopolin (264).259 6’-Feruloylscopolin (265) is another con-sti tuent of Haplophylum obtusijiolium. 260 6-Geranyloxy-7-methoxycoumarinhas been isolated from H. pedicellatum.261Two new syntheses of ayapin (266) have been recorded. 262 263 Piperonal with nitroethane gave the /3-methyl-P-nitrostyrene which on treatment with acetyl chloride and aluminium chloride gave 2-hydroxy-4,5-methylenedioxy-benzaldehyde.Condensation with carbethoxymethylenetri-phenylphosphorane gave ayapin.262 In boiling 1,2-dichIoro- ethane 3-ethoxyacryloyl chloride reacts with phenols to give 3- ethoxyacrylates which on treatment with fuming sulphuric acid cyclize to give coumarins in good yield.263 Two compounds which may be the (+)-and (-)-enantiomers of obliquin hydrate (267) have been isolated from Cononcliniopsis pra~iijiolia~~~ respectively. 13- and Eupatorium lan~ifolium,~~~ Hydroxyobliquin (268) has been obtained from the roots of ti Helich rysum st irling ii . Mo1ucc ani n (2 69) from A leu r it es moluccana is the first coumarinolignoid in which the mode of “RO O m o (247) R = H 605 Meorno RO (249) R (250) R (251) R (252) R (253) R (255) R = (256) R’ = R2 = R3 = H (257) R’ = P-D-apiosyl R2 = R3 = H (258) R’ = a-L-rhamnosyl R2 = R3 = H (259) R’ = R2 = H R3 = a-L-rhamnosyl (260) R’ = R3 = a-L-rhamnosyl R2 = H (261) R’ = R3 = Ac R2 = H (262) R’ = Ac R2 = R3 = H (263) R’ = R2 = H R3 = Ac (264) R’ = H R2 = R3 = Ac (265) R’ = R2 = H R3 = C 1 (268) Me0 HO$:m0 OMe (269) NATURAL PRODUCT REPORTS 1989 R' R' 0QOo 0R2 (279) R' = R2 = H (280) R' = H R2 = H2C Me0 (271) R' = OH R2 = H (281) R' = HzCY R2 = H (270) (272) R' = H R2 =OH (282) R'=H R2=H2Cv (283) R' =Me R2 = H2C HO MeoP 0 (284) R' = Me R2 = H2CT OH (273) R = H (275) (274) R =Me (285) R' = Me R2 = H2CVoH (286) R' = Me R2 = H2CTH MeoFo HO (287) R' = Me R2 = H 2 C e OH (288) R' =Me R2= H2C *OH (289) R' = H2CT R2 = Me Meopo HO (290) R' R2=Me = H2CT OH (291) R' = H2CYoH R2 = Me Meopo Me0 reported.275 The results of labelling experiments on the biosynthesis of daphnetin in Daphne mezereum are consistent (278) fusion of the nine-carbon unit to the coumarin is linear.267 3- Carboxyaesculetin (270) has been isolated from fronds of the fern Microsorium fortunei268 and 4-methylayapin from Achillea ~chishkinii.~~' Melanettin (27 1) and stevenin (272) have been Obliquetol (273) has been synthesized in high yield by ortho-Claisen rearrangement of 7-prenyloxy-6-hydroxy-coumarin in refluxing acetic anhydride containing sodium acetate followed by hydrolysis.271 Obliquetin (274) was obtained on similar treatment of 7-prenyloxy-6-methoxycoumarin, but simply heating a mixture of the latter ether and sodium acetate to 190 "C gave nieshoutin (275) as the sole product."l 8-Acetyl-7-hydroxy-6-methoxycoumarin (276) has been obtained from FraxinusJl~ribunda,~~~ 8-farnesylscopoletin (277) from Brocchia cine re^,^^^ and O-methylcedrelopsin (278) from Zantho-uylum usambarense .274 9 7,8-Dioxygenated Coumarins Conditions for the preparation of daphnetin (279) by the Pechmann reaction of pyrogallol and malic acid have been with the concept of daphnetin formation by additional hydroxylation of umbelliferone (1) at C-8.276 The tracer experiments also support the theory that unbelliferone is the general precursor of coumarins bearing two or more hydroxyl functions in the aromatic ring.The biochemistry of plant coumarins has been reviewed.277 The two monoprenyl ethers (280) and (281) of daphnetin have been isolated from Melampodium divaricatum and their structures confirmed by Prenylation of daphnetin in the presence of sodium hydrogencarbonate and acetone gave a 67% yield of the 7- prenyl ether (28 1) whereas with sodium hydride in hexamethyl- phosphoric triamide a 79% yield of (280) was obtained.27i" Ferujol (282) which has contraceptive activity has been obtained from Ferula j~eschkeana.~~~ Daphnetin 7-methyl-8- prenyl ether (283) has been isolated from Artemisia caruifolia.280 Later it and the corresponding epoxide (284)29 and diol (285)30 were found in Coleonema species.Desoxylacarol (286) is present in a number of Artemisia species.2s1 The optically inactive epoxide villosin (287) has been isolated from Haplo-phyllum villosum282 and the corresponding diol tenudiol (288) from H. villosum and H. tenue.2s2The known 7-prenyloxy-8- methoxycoumarin (289) has been given the trivial name lacinartin and the optically active epoxide lactinartinepoxide (290) and diol lacinartindiol (291) both of unknown absolute configuration have also been isolated from Artemisia laciniata leaves.283 NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 0mo HO OH bMk? (292) (293) Me0 "Ope Me0&Lo OH OMe (295) (296) (297) OH I h-0 90 OR OR (299) R =H (301) R=H (298) (300) R =P-D-gIUCOSyI (302) R =Me (303)R =P-D-gIUCOSyI Ko3so'-~o (304) R =H JpH OH (305) R=C OMe (306) II 0 The structure of the optically inactive coumarinolignoid Apigravin (297) has been synthesized from daphnetin (279) daphneticin from Daphne tangutica roots has been elucidated the last step C-prenylation of 7-hydroxy-8-methoxycoumarin as (292) on the basis of chemical and particularly n.m.r.proceeding in poor yield however.2g2 The structure (298) of 285 and apparently confirmed by synthesis. 286 Al-leptophyllidin has been revised the phenolic hydroxyl group evidence284* though it is clear that the two hydrogens of the 1,4-dioxane now being placed at C-8.From the published data it would should have not only the moiety are trans related controversy has remained on the seem probable that lept~phyllidin~~~ orientation of the substituent groups. The SINEPT pulse same structure but also the same stereochemistry as apiumetin programme is claimed to provide an unambiguous method for (299) the P-D-glucoside (300) of which has been isolated from determining the orientation in such ring systems and from this Apium graveolens Racem01,~~~ from A talantia race- evidence a revision of structure to (293) is required.287 mosa is not a new compound being known previously as Ruta chalepensis roots in addition to containing the known rutaretin (301).' The absolute configuration of rutaretin methyl 3-( 1,1 -dimethylallyl)coumarins chalepin and chalepensin have ether (302) has been determined by chemical interrelation with provided rutalpinin for which structure (294) has been (S)-(+)-marme~in.~~~ suggested288 from mass spectral and IH n.m.r.evidence. The antibiotic activity of rutarin (303) against fungi is ten- Since the U.V. maxima of rutalpinin at 293 and fold greater than its aglycone r~taretin.~~' Like leptophyllidin 235 nm differ significantly from those of 7,8-methylenedioxy- the structures of leptophyllin and leptophylloside have been coumarin at 318 262 and 254 nm the structural assignment revised to those of rutaretin and its P-D-glucoside isorutarin must be suspect. It has been shown by that the (304).293The 6"-sinapinoyl ester (305) of the latter is yet another structure (295) assigned291 to celerin from celery seeds is constituent of Apium graveolens It should be noted incorrect.Following the syntheses of four alternative structures that enantiomeric absolute configurations have been drawn for for celerin in which efficient routes to sibiricol coumurrayin (300) and (305) in the publication. Rutaretin sulphate (306) has and pinnarin were established its structure has been revised to been isolated from Seseli libanotis roots along with (138) and (296) only the second example of a coumarin with a 1,l-(1 39).151 dimethylallyl group at C-5.2g0 A seven-step 20 O/O overall yield synthesis of methoxsalen (xanthotoxin) (307) used in the treatment of vitiligo and other dermal diseases has been effected from commercially available 1,2,3-trimetho~ybenzene.~~* The key intermediate is 2-chloro- 2'-hydroxy-3',4'-dimethoxyacetophenone.Methoxsalen IT-labelled at C-5 has also been prepared.299 The structure (308) assigned to marmelide has been ~ynthesized.~" The non-identity of synthetic and natural material has led to the structural revision of marmelide as (309).300 Two further OR (307) R = Me (308) R =C% /\ (309) R=H2C ?ill (310) R = H2CToH ?u (311) R = H2CToH (312) R = H2Cm0 R' i,R2 (313) R' = R2 = H (314) R' = OMe R2 = H NATURAL PRODUCT REPORTS 1989 heraclenol derivatives the isovalerate (3 10) and the senecioate (311) of unassigned stereochemistry have been obtained from Angelica ar~hangelica.~'~ The alkene (3 12) of unassigned configuration from which indicolactonediol obtains its name has been isolated independently from three Clausena species C.lan~ium,~"~ am pi,^'^ and C. ~nisata,~'" C. and given three trivial names dehydroindicolactone wampetin and indico- lactone respectively. Anhydrorutaretin (3 13) is a minor constituent of Apium leptophyllum 8-Methoxypeuce-danin (3 14) co-occurs with peucedanin in Peucedanum rutheni- cum Seseloside (315) the P-D-glucoside of a laevo- rotatory hydroxydihydropyranocoumarin of unknown con-figuration has been isolated from Seseli peucedanoides root^.^'' Benahorin (316) the first of only two coumarins with a C-5 1,1 -dimethylally1 substituent has been 10 5,6,7-Trioxygenated Coumarins The aldehyde (3 17) and the corresponding primary alcohol the 5-methoxy analogue of (268) have been isolated from Australian Helichrysum species.266 The prenyl ether (3 1 8) the epoxide (319) and the corresponding vicinal diol have been reported as constituents of Pterocaulon balansae and P.l~nutum,~~* the epoxide having previously been isolated from Pteronia g1abrata.l The same group later synthesized these three structures from aesculetin (247) by 7-O-benzylation and successive hydroxylation methylenation prenylation epoxi- dation and hydrolysis.309 However to their surprise none of the synthetic products possessed physical constants in agree- ment with those of the natural products which consequently require revision. Murragleinin (320) has been isolated from Murraya gleinei leaves.130 m0 RO Orbo p-D-gI UCOSYI-O (318) R=H2C +f OH (319) R= H2Cq (315) M'"-" Me0 &00 OMe OH (3 16) (320) 0' NATURAL PRODUCT REPORTS 1989-R.D. H. MURRAY 11 5,7,8-Trioxygenated Coumarins D-glucosides (328; 2'-R) and (329; 2'-R) of (+)-byakangelicin The prenyl ether neoartanin (321) and the optically active but and of (334).310 s-U-Acetylbyakangelicin (330) has been of unknown absolute configuration neoartaninepoxide (322) obtained in dextrorotatory form from Angelica pubescens and neoartanindiol (323) have been obtained from Artemisia roots311 and in laevorotatory form from A. dahurica in laciniata leaves of Chinese origin the lacinartins (290) and both cases (+)-byakangelicin was also isolated.Similarly t-U- (29 1) being obtained from the Japanese Earlier methylbyakangelicin has been found in laevorotatory form desoxylacarol (286) lacarol (324) methyllacarol (325) prenyl- from the latter source312 and its enantiomer from unripe fruits lacarol (326) and artanin (327) had been isolated in a study of of A. pa~hycarpa.~'~ Byakangelicin 2'-U-isovalerate (332) is a A. laciniata and other Artemisia species.281 Although the first further constituent of A. ar~hangelica.~~~ four possess a chiral centre no optical activity could be The P-D-glucoside (333) is yet another constituent of Apium detected. The assignment of the different ether groups to their grave~lens.~'~ Apaensin (335) has been obtained in optically position on the ring was made with the assistance of aromatic active form from AngeZica apaensis314 and the diepoxide sen- solvent-induced shifts to higher fields of methoxy or methylene- byakangelicol (336) from A.dahuri~a.~~~ oxy resonances depending or the availability of an ortho Ceylantin from Atalantia ~eylanica,~~~ incorrectly was proton.281 formulated as (337). Nuclear Overhauser experiments have Reverse-phase high-performance liquid chromatography has confirmed the identity of ceylantin with racemosin (338),317 a led to the isolation from Angelica archangelica roots of both p-synthesis of which has been OR I OR I Me0QCX0 OMe OMe Me0wo o T 0 H (322) R= H2CT (324) R = H ?H (325) R =Me (323) R = H2CToH (326) R=H2C (327) ?Me R' = H R2 = fi-D-glucosyl R' = P-D-glucosyl R2 = H R' = Ac R2 = H R' = H R2 = Me (;Me ~'=fi"( R~=H (333) (334) 0 OR' I OMe (335) R' = H2C R2=Me OMe OMe (336) R' = R2 = H2C (337) (338) NATURAL PRODUCT REPORTS.1989 RO OH I OH (340) R = H OHI (341) R= H2C (339) (342) R = H2CyOH “ RO O w o OMe (343) R = H (344) R=H2C ? OH (354) R = AcO (364) R 0 (345) R = H2CVoH (355) R = HO@ (365) R = 0 (356) R =AcO@ (366) R = I (357) R = HO@ (367) R = HO (358) R =AcO@ (368) R = AcO (359) R = (360) R = (370) R = HO& (353) R= HO@ (361) R = (362) R = 0@ 0@ (371) R = (372) R = 0@ 0@ $H2 (363) R = NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 12 6,7,8-Trioxygenated Coumarins The structure (339) of erioside from Lasiosiphon eriocephalus has been deduced from nuclear Overhauser experiments on its dimethyl ether hydrolysis of which gave isofraxidin (343).319 The aglycone named eriosnin could not be isolated on hydrolysis turning brown on exposure to air.Stylosin from Fraxinus stylosa bark is the 8-0-rhamnosyl-rhamnosyl-glu-coside of fraxetin (340).320Haplophyllum obtusifolium has afforded two fraxetin derivatives the optically inactive haptu- sinol (341),321 and obtusitsin (342).322 The optically active epoxide (344) and diol (345) of the prenyl ether puberulin are present with the latter in Pterocaulon Ian~tum.~~~ Labelling experiments have indicated that a feasible biosynthetic route for the formation of puberulin by Agathosma puberula is p-coumaric acid -+ umbelliferone -,aesculetin -+ scopoletin -+ fraxetin -+ isofraxidin +p~berulin.~~~* 324 In a series of excellent papers recently reviewed,325 an impressive array of sesquiterpene ethers mainly of isofraxidin have been isolated from Achillea and Artemisia species and their structures and absolute configurations determined.Farno- chrol (346),326 epoxyfarnochrol (347) and oxofarnochrol (348)327 represent the acyclic series with deparnol (349) acetyldeparnol (350)328 and more recently secodriol (35 1) and secodrial (352) the monocyclic farnesyl derivatives.329 The last two compounds have the same absolute configuration as galbanic acid (1 7). The absolute configuration330 of the trans-decalin skeleton in twelve of the drimenyl-derived sesquiterpene moieties (353)-(364) is 4a-S,8a-R; only pectachol B (365)273 and drimartol B (367)326 and their respective acetyl derivatives (366)273 and (368)326 have the opposite absolute configuration with 4a-R,8a-S.The absolute configurations were determined by the Horeau method only 1.5 mg of natural product being required. 330 The twelve compounds have been trivially named as follows pectachol (353),326 acetylpectachol (354),326 albartol (355),328 albartin (356),331 drimartol A (357),326 acetyldrimartol A (358),331 isodrimartol A (359),327 acetylisodrimartol A (360),327 pectanone (36 1),332 dehydropectanone (362),332 dri- manthone (363),332 and 7-acetoxypectanone (364).332 Recently drimartol A (357) or its antipode has been isolated from Tanacetum heterotumum together with (369) of undefined absolute configuration.333 The skeletally rearranged derivatives tripartol (370),329 drimachone (371),329 and isodrimachone (372)332 have also been characterized. Fraxetin 7-O-/3-~-glucopyranoside (373) is purportedly a new glycoside of Haplophyllum obtusifolium .260 However isofraxoside which melts more than 50 "C higher has already been deduced to have this structure. (-)-8-Methoxyobliquin (374) of unassigned absolute stereochemistry has been obtained from Helianthus heterophyllu~.~~~ The supposed 6,7-methylene- dioxy-8-methoxycoumarin from Artemisia v~lgaris~~~ has been shown to be identical with dracunculin (375) and this structure Synthetically dracunculin has been obtained in high yield by reaction of the diphenoxide ion from fraxetin (340) generated with sodium hydride in hexamethylphosphoric triamide with diiodomethane.337 Coumarinolignans are a new class of natural product in which a coumarin moiety is linked with a phenylpropanoid unit through a dioxane bridge. The occurrence of fraxetin and two regioisomeric pairs of coumarinolignans cleomiscosin A (376),338-340B (379),339.340c (377),339 and D (380),341 is strong circumstantial evidence to infer that in their biosynthesis the linking of the two C6-C3 units follows the same mechanism as in their synthesis the coupling of fraxetin with a para-hydroxycinnamyl alcohol which could be effected by chemical or enzymic Thus it was found that treatment of fraxetin and coniferyl alcohol (382) with silver(1) 343 or with horseradish peroxidase in buffered aqueous gave a mixture of cleomiscosin A and B in moderate yield.When sinapyl alcohol (383) was employed cleomiscosin C and D were the latter before it had been recognized as a natural product and the former before it was shown to be identical with aquillochin isolated earlier from Aquilaria 611 OH (373) bMe (374) Meo-OMe (376) R' = H R2 =OH (377) R' = OMe R2 = OH (378) R' = R2 = H Meorno 0 R' OMe OH OH (379) R' = H R2 =OH (382) R' = H R2 =OH (380) R' = OMe R2 = OH (383) R' = OMe R2 =OH (381) R' = R2 = H (384) R' = R2 = H Replacement by isoeugenol (384)3423 ~gallocha.~~~ 343 gave propacin (378) from Protium op~cum,~~~ the regioisomer (381) of which has been obtained in optically active form from Jatropha gl~ndulifera.~~~ Cleomiscosin A which has cytotoxic properties has now been isolated from a number of species by bioactivity-directed fractionation347.348 and like the other three cleomiscosins is optically inactive. After structure (376) was established for cleomiscosin A cleosandrin which had been isolated from seeds of Cleome ico~andra,~~~ a synonym for C. viscosa was shown to have the same Structural assignments of coumarinolignans have proved very difficult despite the eventual isolation of regioisomeric pairs of compounds and structural revisions have taken place. Apart from ~ynthesis,~~~-~~~ extensive use has been made of lH and 13C n.m.r.in these studies the SINEPT pulse programme reputedly providing an unambiguous method for determining the orientation of the trans-related substituent groups on the 1,4-dioxane It has been predicted that more coumarinolignans will be found formed from other ortho-dihydroxycoumarins such as aesculetin (247) and daphnetin (279) and examples of each have been found in moluccanin (269)267 and daphneticin (293).284. 287 2853 NATURAL PRODUCT REPORTS 1989 HO bH (385) TR Meowo HO OH (386)R = H (387)R =OH Me0 Hoqko OMe ?Me LO (389) Haplophyllum obtusifolium has provided three other com- pounds related to obtusitsin (342) namely obtusidin (385),353 obtusiprenin (386),353and obtusiprenol (387).354 Obtusidin has been obtained by an out-of-ring Claisen rearrangement from capensin 6-methoxy-7-prenyloxy-8-hydroxycoumarin.353 Ben-zene-induced solvent shifts of the C-4 methyl group have been used to show that troupin (388) from Tamarix troupii leaves has no methoxy group at C-5.355 13 5,6,7,8-Tetraoxygenated Coumarins The 'H n.m.r. characteristics of 5,6,7,8-tetramethoxycoumarin isolated from the Chinese tallow tree Sapium sebiferum are closely comparable to those published for a synthetic sample.356 It has been concluded from the reported spectral data that the only previous identification of this compound trivially named artelin from Artemisia tridentata is erroneous. A study has been made of lanthanide-induced shifts of sterically hindered aromatic ortho-dimethoxy as a consequence of the isolation of isosabandin (389) from A.la~iniata.~~~ 14 4-Oxygenated Coumarins Foetidin (390) from Ferula assa-foetida roots has the same relative configuration and probably the same absolute stereo- R2 (391)R' = R~ = H (392)R' = H R2 =OH (393)R' =OH R2 = H (394) chemistry as colladonin its 7-hydroxycoumarin analogue.358 Factors involved in alkylation of 4- hydroxycoumarin have been investigated.359 3-Methyl-4-hydroxycoumarin from F. communis is probably an artefact formed from ferulenol (391) during dry distillation of a plant extract.36o The 2'E,6'E- stereochemistry of ferulenol has been established from its 13C n.m.r. 12'-Hydroxyferulenol (392) has also been isolated.360 However w-hydroxyferulenol from the same source has been assigned the isomeric structure (393) from nuclear Overhauser experiment^.^^' The structure (394) of ferprenin also from F.communis has been established from spectral data its synthesis from E,E-farnesal and 4-hydroxycoumarin and by a chromium(vr)-mediated oxidative cyclization of ferulen01.~~* A remarkable array of 5-methylcoumarins has been reported by Bohlmann and his co-workers mainly from South American Compositae. 4-Geranyloxy-5-methylcoumarin(399 twenty- two of its derivatives (396)-(416) (421) and mutisifuro- coumarin (422) have been obtained from Mutisia orbignyana aerial The parent 4-hydroxy-5-methylcoumarinhas been isolated from Gerbera anandria where it occurs with the corresponding P-D-glucoside (41 7),364 which was initially reported as a constituent of Ethulia conyzoide~~~~ and later of Leibnitzia anandria,366 Onoseris gnaph~lioides~~~ and Gerbera jame~onii,~~~cellobioside (4 18) and the gentiobioside the (419).364 The rutinoside (420) has also been Nine closely related derivatives of longipesin (423) which itself is as yet unknown as a natural product have been isolated from Bothriocline longipes and from B.eupatoriode~.~~~ The five phenols (424)+428) could only be separated after preparation of their 0-methyl ethers mixtures of isomeric 4-methoxy- coumarins and 2-methoxychromones being obtained. The nine compounds have been trivially named longipesin 9-0-acetate NATURAL PRODUCT REPORTS 1989-R.D. H. MURRAY (396) R = H 2 C v (404) R = H2CyCH0 (397) R = H 2 C v (405) R= H2C* (398) R= H 2 C 7 (406) R = H 2 C m OH (399) R = H 2 C q (407) R=H2C (408)R=H2C* (401) R=H2C +Zy OH (409) R=H2C-00. OH (402) R=H2C m OH OOH (410) R=H2C (423) R = CH20H (424) R = CH20Ac (425) R=CH2O L (426) R = CHMeOH (427) R = CHMeOAc (428) R = CHMeO (411) R=H2C * \ OH (412) R = H2CwOoH (413) R=H2C* (414) R = H 2 C d (415) R = H 2 C m (416) R=H2C 4 -0 H (417) R = p-D-gIUCOSyI (418) R = cellobiosyl (419) R = gentiobiosyl (420) R = rutinosyl OH NATURAL PRODUCT REPORTS 1989 (429) R = H (431) R=Ac (430) R=Me (432) R=fi" (433) 0 (434) (437) p /\ *. ' 0 0 (444) (445) (446) (435) R' =Me R2 = H (436) R' = H R2 = Me (438) (439) R = 0-H (440) R = a-H (424) longipesin 9-0-propionate (425) 9-methyllongipesin (426) 9-methyllongipesin 9-0-acetate (427) 9-methyllongipesin 9-0-propionate (428) cyclolongipesin (429) 9-methylcyclo- longipesin (430) homocyclolongipesin 9-0-acetate (43 1) and homocyclolongipesin 9-0-propionate (432).369 Brachycou- marin (433) has been isolated from Brachyclades rnegalanth~s~~~ and its structure has been confirmed by It occurs with the optically active cyclobrachycoumarin (434) cycloiso- brachycoumarin (439 and 2'-epicycloisobrachycoumarin (436).370 Cyclobrachycoumarin has been prepared in good yield by heating 4-geranyloxy-5-methylcoumarin (395) in N,N-dimethylaniline at 180 0C.371 The first-formed rearrangement product undergoes a rapid abnormal Claisen rearrangement prior to cyclization.Alkylation of 4-hydroxy-5-methylcoumarin with geranyl bromide gave (395) and piloselloidan the C-geranyl derivative.372 Roots of Mutisia spinosa contain piloselloidan and the farnesyl derivative (437); the aerial parts contain mutisi- coumarin (438).370 Lycoserone (439) 1'-epilycoserone (440) cyclolycoserone (441) and three related compounds (444)- (446) have been obtained from Lycoseris latif~lia.~~~ Six further lycoserone derivatives (442) (443) (447)-(450) and aphyllo- denticulide (45 1) have been isolated from Aphyllocladus denticulat~s,~~~ these structures also being elucidated by high field n.m.r. techniques with extensive nuclear Overhauser enhancement measurements.Isogerberacoumarin (452) has been prepared in 15 YOyield by condensation of 4-hydroxy-5-methylcoumarin with 3-chloro-3- methylbutyne followed by catalytic hydrogenation. 375Erlangea- fusciol (453) and isoerlangeafusciol (454) of unassigned configuration are constituents of Erlangea f~sca.~'~ It is believed that onognaphalin (459 from the roots of Unoseris gnapha-lioides is most likely formed by degradation of a 5-methyl- NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY *% \ (448) R=H (447) (449) R=OH & &H \ 0 '00 (452) (453) (456) R = H (467) R =Me (458) &!+ \ (462) Me OMe Me OMe Me0@&. A2 A (466) I?' =OH RZ = H (468) R = H (467) R' = H R2 =OH (469) R =OMe coumarin which was linked with a geranyl moiety.367 Roots of Vernonia cinarescens contain the known ethuliacoumarin (456) and its precursor preethuliacoumarin (458).377 Ethulia- coumarin and 5-methylethuliacoumarin (457) co-occur in Bothriocline ripen~is.~~' Two groups have reinvestigated Ethulia conyzoides aerial parts.One group has reported the isolation of (450) (451) dH ,r_y \o '0 (454) (455) (459) (460) (464) R'=COzH R2=Me (465) R' = Me R2 = COZH isoethuliacoumarin A (459) B (460) and C (461),378 and later (462),379 all of undefined stereochemistry at the secondary carbinol. The other group has reported two fractions seemingly homogeneous on thin-layer chr~matography.~~~ The less polar fraction however was a mixture of the four diastereoisomers of (463); the more polar a mixture of four acids the two diastereoisomers of (464) and the two of (465).A number of mono- and di-oxygenated derivatives of 4- methoxy-5-methylcoumarin,pereflorin have been discovered. The 6-hydroxy derivative (466) has been isolated from Gerbera jarne~onii~~' and 8-hydroxypereflorin (467) from Perezia ala- n~ani.~~~ The synthesis of 3-methoxypereflorin has been ef- fe~ted.~~~ The previously undescribed 3,5-dimethyl substitution pattern is present in coumarsabin (468) and 8-methoxy-coumarsabin (469) from Juniperus sabina leaves.384 Both structures have been confirmed by ~ynthesis."~. 386 NPR 6 616 NATURAL PRODUCT REPORTS 1989 Me ?Me R2“WoMeR3 CHO OMe (470) R’ =OH R2 = R3 = H (-?& Me (471) R’ = OMe R2 = R3 = H (472) R’ = R3 = H R2 = OH OMe (473) R’ = R2 = H R3 = OH (474) R’ R2 ’0 0‘ 00 OMe (475) R = H (477) R’ R2 = OCH2O (476) R= Me (478) R’ = OMe R2 = H e’ &OH \ (482) R’ =OH R2 = H ‘-glucosyl-o \ o o (480)R’ = H2Cy R2 = H (483) R’ = H R2 = OMe (479) (481) R’ = H R2 = H2CT (484) R’ = H R2 = H2C HO OMe (485) R=H (487) R’ = OMe R2 = H (486) R=Me (488) R’ = H R2 =OMe (489) Four oxygenated 3,4-dimethoxy-5-methylcoumarins(470)-(473)have been isolated from Dolichlasium lagascae leaves387 and the 5-formylcoumarin (474) from Perezia coerulescens 15 4-Hydroxy-3-phenylcoumarins and Coumestans The angular pyranocoumarins (475)and (476)corresponding to the linear robustin and robustin methyl ether respectively have been isolated from Derris spruceana and thonningine A (477) and B (478)from Millettia thonningii Coumestrin (479),a P-D-glucoside of coumestrol has been isolated from soybean roots Glycine max,391 and isosojagol (480)from Phaseolus coccineus seedlings treated with aqueous copper(1r) An isomeric prenylated coumestan phaseol (481) has been obtained with aureol (482)from the mung bean Phaseolus a~reus.~’~ The roots of Sophora fran-chetiana have provided sophoracoumestan A (485)394 and B (488).395 Tuberostan (486)from Pueraria tuberosa has been formulated as the methyl ether of the former but direct comparison has not yet been made.396 The structure (484)of psoralidin oxide from Psorafea corylifolia has been confirmed by the synthesis of its diacetate from p~oralidin.~~’ The structure of wairol (489),present in extracts of Medicago sativa infected with Stemphylium botryosum but not in fresh healthy foliage,398 has also been confirmed by Tephrosia harniltonii roots contain (483)400and T.villosa roots contain tephrosol (487),the methyl ether of which has been synthesized via the dehydrogenative coupling of 4-hydroxy-6,7-dimethoxycouma-rin with catech01.~~~ NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY OH MeGo& Meme (490) (492) OMe Me HO &k0 (495) (496) OMe (493) R = H (494) R =OH OR (498) R =OH (500) R' = OMe R2 = Me (502) R = H (499) R = H (501) R' = R~ = H (503) R=Me q& 0*Et Me0 OMe HO (504) (505) 16 Miscellaneous Coumarins The coumarins in this section have been arranged as before according to the number of oxygen substituents attached to the nucleus and to their positions thereon.Coumarins lacking oxygen substituents are of very rare natural occurrence. However trigoforin 3,4,7-trimethyl-coumarin (490) has been isolated from Trigonella foenurn- graecum stems402 and its structure confirmed by two syntheses one from the acid-catalysed condensation of rn-cresol with ethyl 2-methylacetoacetate,40zthe other from a Wittig reaction on 2- hydroxy-4-me thy lace tophenone. 403 Naphtho herniarin (491) an orange pigment from the roots of Ruta graveolens represents an unusual link between coumarins and naphtho- quinones.404 Canaliculatin (492) from Diospyros canaliculata also represents a new class of natural product consisting of a combination of juglone and 4-hydroxy-5-methylcoumarin.405 Ventilatone A (493) and B (494) are yellow and orange-red pigments respectively of Ventilago calyculata root bark.406 Necatorin (495) is a highly mutagenic compound from the wild edible mushroom Lactarius necator 408 5-Methoxy-4-met hyl- .4079 coumarin (496) occurs with (I 69) in Edgeworthia gardr~eri.'~~ 8-Methoxycoumarin from Fraxinus floribunda leaves,272 has been synthesized by a novel high-yield process for the synthesis of coumarins based on Claisen rearrangement of aryl ally1 ethers in which the allylic a-carbon is further A second 4-isopropylcoumarin (497) has been isolated from Macrothelypteris torresiana The marine prosobranch mollusc Lamellaria sp.contains the four aromatic metabolites lamillarin A (498) B (500),C (499) and D (501).410The structure of lamillarin A was determined by single-crystal X-ray diffraction analysis. In solution lamillarin A exists as a 1 :1 mixture of geometric isomers due to restricted rotation about the bond to the 4- hydroxy-3-methoxyphenyl ring. Gomortega keule bark has afforded the two 6,8-dioxygenated coumarins (502) and (503).411 The original structure assigned to trigocoumarin from Trigon-ellafoenurn-grae~um,~~~ has been revised to (504) on the basis of benzene-induced shifts in its 'H n.m.r. spectrum and by comparison with a synthetic sample.413 3,6,7-Trihydroxy- coumarin (505) has been identified in Dasycladus vermicularis and other members of the siphonalean green algal family Da~ycladaceae.~'~ NATURAL PRODUCT REPORTS 1989 Me OMe R’Omo MeOF R2 00 Me0 0 (506) R’ =R2=H 0 (511) R’ = R2 = H (507) R’ =Me R2 = Ac (509) R = H (512) R’ = H R2 =Me (508) R’ = R2 = Me (510) R=Me (513) R’ = R2 = Me OMe Me0 HO rhamnosyl-0& OMe I OH Me Me O W Me OMe (516) (517) (518) 17 Biscoumarins is linked through both oxygen and carbon to the lactone ring of A review has recently been compiled of all the natural the second biscoumarins isolated from plant sources and micro-organisms Gerberinol (516) 5,5’-dimethyldicoumarol from Gerbera has and includes their spectral proper tie^.^'^ Demethyldaphnoretin lan~nginosa,~~~been synthesized from m-cresol via 4-(506) and 7-0-acetyldaphnoretin (507) are constituents of hydroxy-5-methylcoumarin.423 It would seem likely despite the Daphne gnidi~des’~ respectively.23 “C difference in reported melting points that toddasin from and Edgeworthia g~rdneri,~~~ and mexolide from Murraya are Daphnoretin methyl ether (508) has been synthesized the key Toddalia a~iatica,~~~ step being reaction of a preformed complex of N,N-diethyl the same compound. Both are optically inactive and have been coumarin-7-oxyacetamide and phosphoryl chloride with 43- assigned the same structure (517). A review of formal Bhubaneswin (509) the mono- Diels-Alder dimeric coumarins has appeared.426 The structure dimeth~xysalicylaldehyde.~~~ methyl ether of bicoumol has been isolated from Boenning-of ismailin (518) from the stem bark of Diospyros ismaifii the hausenia albgora along with matsukaze-lactone (5 The second homologue of juglone bearing two 4-hydroxy-5-mould Emericella desertorum has afforded desertorin A (5 1 l) methylcoumarin-3-yl units has been confirmed by B (512) and C (513) the last being optically active because of restricted rotation about the carbon-carbon single bond joining the two monomer Ipomopsin (514) from Ipomopsis 18 References aggregata is the first member of a new series of biscoumarins in 1 R.D. H. Murray J. MCndez and S. A. Brown ‘The Natural which the aryl unit of one ring is linked to a lactone-ring carbon Coumarins Occurrence Chemistry and Biochemistry’ Wiley of the Eriocephaloside (515) also represents a new Chichester 1982.group of furanobiscoumarins in which the aryl ring of one unit 2 R. A. Hill Fortschr. Chem. Org. Naturst. 1986 49 I. NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 3 H. Miyachi A. Manabe T. Tokumori Y. Sumida T. Yoshida S. Nishibe J. Agata T. Nomura and T. Okuda Yakugaku Zasshi 1987 107,435 (Chem. Abstr. 1987 107 102510). 4 C. A. J. Erdelmeier Sz. Nyiredy and 0.Sticher J. High Resolut. Chromatogr. Chromatogr. Commun. 1985 8 132. Sz. Nyiredy C. A. J. Erdelmeier K. Dallenbach-Toelke K. Ny- iredy-Mikita and 0.Sticher J. Nut. Prod. 1986 49 885. 6 K. Glowniak G. Matysik M. Bieganowska and E. Soczewinski Chromatographia 1986 22 307 (Chem.Abstr. 1987 106 98 754). 7 K. Glowniak and M. L. Bieganowska J. Liq. Chromatogr. 1985 8 2927. 8 P. Pietta E. Manera and P. Ceva J. 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Soedin. 1981 718 (Chem. Abstr. 1982 96 181 532). 256 M. P. Yuldashev E. Kh. Batirov A. D. Vdovin V. M. Malikov and M. R. Yagudaev Khim. Prir. Soedin. 1985 27 (Chem. Abstr. 1985 103 101990). 257 E. Kh. Batirov. D. Batsuren and V. M. Malikov Khim. Prir. Soedin. 1984 244 (Chem. Abstr. 1984 101 87464). 258 T. Iwagawa and T. Hase Phytochemistry 1984 23 467. 259 M. Kuroyanangi M. Shiotsu T.Ebihara H. Kawai A. Veno and S. Fukushima Chem. Pharm. Bull. 1986 34 4012. 260 E. Kh. Batirov A. D. Matkarimov V. M. Malikov and E. Seit- muratov Khim. Prir. Soedin. 1982 691 (Chem. Abstr. 1983 98 122 8 17). 261 A. Z. Abyshev and N. F. Gashimov Khim. Prir. Soedin. 1979 846 (Chem. Abstr. 1980 93 41498). 262 S. L. Kelkar C. P. Phadke and Sister Marina Indian J. Chem. Sect. B 1984 23 458. 263 T. Ziegler H. Mohler and F. Effenberger Chem. Rev. 1987 120 373. 264 F. Bohlmann C. Zdero F. M. King and H. Robinson Phyto-chemistry 1980 19 1547. 265 W. Herz S. V. Govindan and N. Kumar Phytochemistry 1981 20 1343. 266 J. Jakupovic V. P. Pathak F. Bohlmann R. M. King and R. Robinson Phytochemistry 1987 26 803. 267 T. Shamsuddin W. Rahmann S. A.Khan K. M. Shamsuddin and J. P. Kintzinger Phytochemistry 1988 27 1908. 268 T. Murakami N. Tanaka T. Satake Y. Saiki and C. M. Chen Yakugaku Zasshi 1985 105 655 (Chem. Abstr. 1985 103 157319). 269 A. Ulubelen S. Oksuz and E. Tuzlaci Planta Med. 1987,53,507. 270 V. K. Ahluwalia and Sunita Dhingra Heterocycles 1980 14 1329. 271 R. D. H. Murray and Z. D. Jorge Tetrahedron 1983 39 3163. 272 G. R. Nagarajan U. Rani and V. S. Parmar Phytochemistry 1980 19 2494. 273 H. Greger and 0.Hofer Phytochemistry 1985 24 85. 274 J. 0.Kokwaro I. Messana C. Galeffi M. Patamia and G. B. Marini Bettolo Planta Med. 1983 47 251. 275 H. Shimomura Y. Sashida and Y. Ohshima Chem. Pharm. Bull. 1980 28 347. 276 S. A. Brown Z. Naturforsch. Teil C 1986 41 247. 277 S.A. Brown Recent Adv. Phytochem. 1986 20 (Shikimic Acid Pathway) 287. 278 J. Borges-del-Castillo A. I. Martinez-Martir F. Rodriguez-Luis J. C. Rodriguez-Ubis and P. Vazquez-Bueno Phytochemistry 1984 23 859. 279 M. M. Singh D. N. Gupta V. Wadhwa G. K. Jain N. M. Khanna and V. P. Kamboj Planta Med. 1985 268. 280 N. C. Barua R. P. Sharma K. P. Madhusudanan G. Thyagara- jan and W. Herz Ph-vtochemistry 1980 19 2217. 281 G. Szabo H. Greger and 0.Hofer Phytochemistry 1985 24 537. 282 A. Z. Abyshev N. Ya. Isaev and Yu. B. Kerimov Khim. Prir. Soedin. 1980 800 (Chem. Abstr. 1981 94 171 045). 283 0.Hofer G. Szabo H. Greger and A. Nikiforov Liebigs Ann. Chem. 1986 2142. 284 L.-G. Zhuang 0.Seligmann K. Jurcic and H. Wagner Planta Med. 1982 45 172.285 L.-G. Zhuang 0.Seligmann and H. Wagner Phytochemistry 1983 22 617. 286 H. Tanaka I. Kato and K. Ito. Chem. Pharm. Bull. 1986 34 628. 287 L.-J. Lin and G. A. Cordell J. Chem. Soc. Chem. Commun. 1986 377. 288 A. Ulubelen and B. Terem Phytochemistry 1988 27 650. 289 W. Herz S. V. Bhat and P. S. Santhanam Phytochemistry 1970 9 891. NATURAL PRODUCT REPORTS 1989 290 R. D. H. Murray and Z. D. Jorge Tetrahedron 1984 40,5229. 291 S. K. Garg S. R. Gupta and N. D. Sharma Planta Med. 1980 38,186. 292 M. B. Raizada S. K. Garg and S. R. Gupta Indian J. Chem. Sect. B 1981 20 918. 293 B. R. Sharma and P. Sharma Indian J. Chem. Sect. B 1979 17 647. 294 V. K. Ahluwalia D. R. Boyd A. K. Jain C. H. Khanduri and N. D. Sharma Phytochemistry 1988 27 118 1.295 K. K. Purushothaman A. Sarada A. Saraswarthy K. Vanaja and A. Rajendran Indian Drugs 1986 23 487 (Chem. Abstr. 1986 105 168851). 296 H. Ishii F. Sekiguchi and T. Ishikawa Tetrahedron 1981 37 285. 297 B. Wolters and U. Eilert Planta Med. 1981 43 166. 298 P. Nore and E. Honkanen J. Heterocycl. Chem. 1980 17 985. 299 Y.-Y. Liu E. Thom and A. A. Liebman J. Heterocycl. Chem. 1979 16 799. 300 R. D. H. Murray Z. D. Jorge and D. M. Boag Tetrahedron 1984 40 5225. 301 H. Sun and J. Jakupovic Pharmazie 1986 41 888. 302 Y. C. Kong K. H. Lau Y. Y. Tam K. F. Cheng P. G. Water- man and R. C. Cambie Fitoterapia 1983 54 47. 303 N. U. Khan S. W. I. Nagri and K. Ishratullah Phytochemistry 1983 22 2624. 304 V. Lakshmi D. Prakash K.Raj R. S. Kapil and S. P. Popli Phytochemistry 1984 23 2629. 305 B. R. Sharma R. K. Rattan and P. Sharma Phytochemistry 1980 19 1556. 306 V. Kozovska and A. Zheleva Planta Med. 1980 (Suppl.) 60. 307 V. Yu. Bagirov and M. B. Belyi Khim. Prir. Soedin. 1981 796 (Chem. Abstr. 1982 96 177940). 308 A. F. Magalhdes E. G. Magalhdes H. F. Leitho Filho R. T. S. Frighetto and S. M. G. Barros Phytochemistry 1981 20 1369. 309 A. F. Magalhdes and R. T. S. Frighetto Quim. Nova 1983 6 165. 310 0.Thastrup and J. Lemmich Phytochemistry 1983 22 2035. 31 1 K. Hata T. Nishino Y. Hirai Y. Wada and M. Kozawa Yuku-gaku Zasshi 1981 101 67 (Chem. Abstr. 1981 94 153448). 312 M. Kozawa K. Baba K. Okuda T. Fukumoto and K. Hata Shoyakugaku Zasshi 1981 35 90 (Chem. Abstr.1981 95 209 449). 3 13 J. Mindez and J. Castro-Poceiro Phytochemistry 1983 22 2599. 314 H. Sun Z. Lin F. Niu and J. Ding Acta Bot. Yunnanica 1981,3 279 (Chem. Abstr. 1982 96 48961). 315 H. Fujiwara T. Yokoi S. Tani Y. Saiki and A. Kato Yukugaku Zasshi 1980 100 1258 (Chem. Abstr. 1981 94 136088). 316 J. Ahmad K. M. Shamsuddin and A. Zaman Phytochemistry 1984 23 2098. 317 R. D. H. Murray and D. A. Hall Phytochemistry 1985 24,2465. 318 V. K. Ahluwalia I. Mukherjee and K. Mukherjee Indian J. Chem. Sect. B 1984 23 270. 319 P. Bhandari S. Tandon and R. P. Rastogi PhJtochemistry 1980 19 1554. 320 X. Guo and Y. Zhang Acta Pharm. Sinica 1983 18,434 (Chem. Abstr. 1984 100 56723). 321 A. Z. Abyshev and N. F. Gashimov Khim. Prir. Soedin. 1979,845 (Chem.Abstr. 1980 93 66024). 322 E. Kh. Batirov A. D. Matkarimov V. M. Malikov M. R. Yagu- daev and E. Seitmuratov Khim. Prir. Soedin. 1980 785 (Chem. Abstr. 1981 94 171043). 323 S. A. Brown D. E. A. Rivett and H. J. Thompson Z. Natur-forsch. C 1984 39 3 1. 324 S. A. Brown R. E. March D. E. A. Rivett and H. J. Thompson Phytochemistry 1988 27 391. 325 0.Hofer Oesterr. Chem.-Ztg. 1987 88 96 (Chem. Abstr. 1988 108 72007). 326 H. Greger 0.Hofer and A. Nikiforov J. Nat. Prod. 1982 45 455. 327 H. Greger 0.Hofer and W. Robien J. Nat. Prod. 1983,46 5 10. 328 0.Hofer and H. Greger Monatsh. Chem. 1984 115 477. 329 H. Greger 0.Hofer and W. Robien Phytochemistry 1983 22 1997. 330 0.Hofer W. Weissensteiner and M. Widhalm Monatsh. Chem.. 1983 114 1399.331 H. Greger E. Haslinger and 0.Hofer Monatsh. Chem.. 1982 113 375. 332 0.Hofer and H. Greger Liebig!. Ann. Chem. 1985 1136. 333 N. Goren A. Ulubelen and S. Oksiiz Phytochemistrj. 1988 27 1527. NATURAL PRODUCT REPORTS 1989-R. D. H. MURRAY 334 W. Herz and M. Bruno Phytochemistry 1986 25 1913. 335 M. Stefanovid M. Dermanovid and M. VerenEevid Glas. Hem. Drus. Beograd 1982 47 7 (Chem. Abstr. 1982 96 177968). 336 R. D. H. Murray and M. Stefanovid J. Nut. Prod. 1986 49 550. 337 P. Castillo J. C. Rodriguez-Ubis and F. Rodriguez Synthesis 1986 839. 338 A. B. Ray S. K. Chattopadhyay C. Konno and H. Hikino Tetrahedron Lett. 1980 21 4477. 339 A. B. Ray S.K. Chattopadhyay S. Kumar C. Konno Y. Kiso and H. Hikino Tetrahedron 1985 41 209.340 A. B. Ray S. K. Chattopadhyay C. Konno and H. Hikino Heterocycles 1982 19 19. 341 S. Kumar A. B. Ray C. Konno Y. Oshima and H. Hikino Phytochemistry 1988 27 636. 342 L. J. Lin and G. A. Cordell J. Chem. SOC. Chem. Commun. 1984 160. 343 A. Arnoldi A. Arnone and L. Merlini Heterocycles 1984 22 1537. 344 P. Bhandari P. Pant and R. P. Rastogi Phytochemistry 1982 21 2147. 345 M. Das Graqas B. Zoghbi N. F. Roque and 0.R. Gottlieb Phytochemistry 1981 20 180. 346 M. R. Pathasarathy and K. Pardha Saradhi Phytochemistry 1984 23 867. 347 M. Arisawa S. S. Handa D. D. McPherson D. C. Lankin G. A. Cordell H. H. S. Fong and N. R. Farnsworth J. Nut. Prod. 1984 47 300. 348 S. S. Handa A. D. Kinghorn G. A. Cordell and N. R. Farns- worth J.Nut. Prod. 1983 46 359. 349 A. G. R. Nair Indian J. Chem. Sect. B 1979 17 438. 350 H. Tanaka I. Kato and Kazuo Ito Chem. Pharm. Bull. 1985,33 3218. 351 H. Tanaka I. Kato and Kazuo Ito Heterocycles 1985,23 1991. 352 M. R. Parthasarathy and K. P. Saradhi Indian J. Chem. Sect. B 1984 23 1105. 353 A. D. Matkarimov E. Kh. Batirov V. M. Malikov and E. Seit-muratov Khim. Prir. Soedin. 1982 173 (Chem. Abstr. 1982 97 123 923). 354 A. D. Matkarimov E. Kh. Batirov V. M. Malikov and E. Seit-muratov Khim. Prir. Soedin. 1981 795 (Chem. Abstr. 1982 96 214258). 355 V. S. Parmar J. S. Rathore S. Singh A. K. Jain and S. R. Gupta Phytochemistry 1985 24 871. 356 P. Yang and A. D. Kinghorn J. Nut. Prod. 1985 48 486. 357 0.Hofer J. Chem. Soc. Perkin Trans.2 1986 715. 358 J. Buddrus H. Bauer E. Abu-Mustafa A. Khattab S. Mishaal E. A. M. El-Khrisy and M. Linscheid Phytochemistry 1985 24 869. 359 A. G. Gonzalez Z. D. Jorge and F. Rodriguez Luis An. Quim. Sect. C 1983 79 265. 360 M. G. Valle G. Appendino G. M. Nano and V. Picci Phyto-chemistry 1987 26 253. 361 D. Lamnaouer B. Bodo M.-T. Martin and D. Molho Phyto-chemistry 1987 26 16 13. 362 G. Appendino S. Tagliapietra G. M. Nano and V. Picci Phyto-chemistry 1988 27 944. 363 C. Zdero F. Bohlmann and J. Solomon Phyochemistry 1988 27 891. 364 L.-H. Gu. S.-X. Wang X. Li and T.-R. Zhu Acta Pharm Sinica 1987 22 272 (Chem. Abstr. 1987 107 93500). 365 Z. F. Mahmoud T. M. Sarg M. E. Amer S. M. Khafagy and F. Bohlmann Phytochemistry 1980 19 2029.366 K. Imamura S. Nagumo T. Inoue and M. Nagai Shoyakugaku Zasshi 1985 39 173 (Chem. Ahstr. 1986 104 56274). 367 F. Bohlmann M. Grenz C. Zdero J. Jakupovic R. M. King and H. Robinson Phytochemistry 1985 24 1392. 368 S. Nagumo K. Imamura T. Inoue and M. Nagai Chem. Pharni. Bull. 1985 33 4803. 369 J. Jakupovic R. Boeker A. Schuster F. Bohlmann and S. B. Jones Phytochemistry 1987 26. 1069. 370 C. Zdero F. Bohlmann R. M. King and H. Robinson Phyfo-chemistry 1986 25 509. 371 F. Bohlmann and A. Steinmeyer Tetrahedron Lett. 1986 27 5359. 372 P. Venturella A. Bellino and M. L. Marino Gax. Chim. Ital. 1982 112,433. 373 F. Bohlmann J. Jakupovic L. N. Misra and V. Castro Liebigs Ann. Chem. 1985 1367. 374 C. Zdero F. Bohlmann and H. M.Niemeyer Phytochemistry 1988 27 1821. 375 R. Chikevert J. Pagk and N. Voyer Synth. Commun. 1984 14 737. 376 A. Rustaiyan L. Nazarians and F. Bohlmann Phytochemistry 1980 19 1254. 377 F. Bohlmann and C. Zdero Phytochemisrry 1982 21 2263. 378 S. I. Balbaa A. F. Halim F. T. Halaweish and F. Bohlmann Phytochemistry 1980 19 1519. 379 F. Bohlmann S. Balbaa A. Halim and F. Halaweish Phyto-chemistry 1981 20 177. 380 V. S. Shukla S. C. Dutta R. N. Baruah R. P. Sharma G. Thya- garajan W. Herz N. Kumar K. Watanabe and J. F. Blount Phytochemistry 1982 21 1725. 381 A. F. Halim El-Sayad M. Marman and F. Bohlmann Phyto-chemistry 1980 19 2496. 382 P. Joseph-Nathan J. D. Hernandez. L. U. Roman E. Garcia G. V. Mendoza and S. Mendoza Phytochemistry 1982 21 1129.383 V. K. Ahluwalia Chandra Prakash and R. P. Singh Chem. Ind. (London) 1980 464. 384 J. de Pascual A. San Feliciano J. M. Miguel del Corral A. F. Barrero M. Rubio and L. Muriel Phytochemistry 1981 20 2778. 385 V. K. Ahluwalia and I. Mukherjee Indian J. Chem. Sect. B 1984 23 272. 386 P. Venturella A. Bellino and M. L. Marino Gazz. Chim. Ital. 1983 113 819. 387 C. Zdero F. Bohlmann R. M. King and H. Robinson Phyto-chemistry 1986 25 2873. 388 L. R. Angeles 0.Lock de U. I. C. Salkeld and P. Joseph- Nathan Phytochemistry 1984 23 2094. 389 M. Garcia M. H. C. Kano D. M. Vieira M. C. do Nascimento and W. B. Mors Phytochemistry 1986 25 2425. 390 S. A. Khalid and P. G. Waterman Phytochemistry 1983 22 1001. 391 N. Le-Van Phytochemistry 1984 23 1204.392 M. J. O’Neill S. A. Adesanya and M. F. Roberts Phytochemistry 1984 23 2704. 393 M. J. O’Neill Z. Naturforsch. C 1983 38 698. 394 M. Komatsu I. Yokoe and Y. Shirataki Chem. Pharm. Bull. 1981 29 532. 395 M. Komatsu 1. Yokoe and Y. Shirataki Chem. Pharm. Bull. 198I 29 2069. 396 A. V. K. Prasad R. S. Kapil and S. P. Popli Indian J. Chem. Sect. B 1985 24 236. 397 B. K. Gupta G. K. Gupta K. L. Dhar and C. K. Atal Phyto-chemistry 1980 19 2232. 398 D. R. Biggs and G. J. Shaw Phytochemistry 1980 19 2801. 399 G. J. Shaw M. K. Yates and D. R. Biggs Phytochemistry 1982 21 249. 400 P. Rajani and P. N. Sarma Phytochemistry 1988 27 648. 401 P. Pulla Rao and G. Srimannarayana Phytochemistry 1980 19 1272. 402 S. K. Khurana V.Krishnamoorthy V. S. Parma R. Sanduja and H. L. Chawla Phytochemistry 1982 21 2145. 403 R. S. Mali S. G. Tilve K. S. Patil and G. Nagarajam Indian J. Chem. Sect. B 1985 24 1271. 404 Zs. Rozsa I. Mester J. Reisch and K. Szendrei Planta Med. 1980 39 219. 405 J. A. D. Jeffreys M. Bin Zakaria P. G. Waterman and S. Zhong Tetrahedron Lett. 1983 24 1085. 406 T. Hanumaiah D. S. Marshall B. K. Rao J. U. M. Rao K. V. J. Rao and R. H. Thomson Phytochemistry 1985 24 2669. 407 T. Suortti and A. von Wright J. Chromatogr. 1983 255 529. 408 T. Suortti A. von Wright and A. Koskinen Phytochemistry 1983 22 2873. 409 J. A. Panetta and H. Rapoport J. Org. Chem. 1982 47 946. 410 R. J. Andersen D. J. Faulkner H. Cun-heng G. D. Van Duyne and J. Clardy J.Am. Chem. Soc. 1985 107 5492. 41 1 S. Espinoza R. Gaona A. Urzua and B. K. Cassels Bol. SOC. Chil. Quim. 1982 27 283 (Chem. Abstr. 1982 96,214310). 412 V. S. Parmar H. N. Jha S. K. Sanduja and R. Sanduja Z. Naturforsch. B 1982 37 521. 413 V. S. Parmar S. Singh and J. S. Rathore J. Chem. Res. (S), 1984 378. 414 D. Menzel R. Kazlauskas and J. Reichelt Bot. Mar. 1983 26 23 (Chem. Abstr. 1983 98 140544). 415 S. C. Basa Phytochemistry 1988 27 1933. 416 R. Chakrabarti B. Das and J. Banerji Plzytochemistry 1986 25 557. 417 C. P. Phadke S. L. Kelkar and M. S. Wadia Synthesis 1986 413. 418 S. C. Basa D. P. Das R. N. Tripathy V. Elango and M. Shamma Heterocycles 1984 22 333. 419 K. Nazawa H. Seyea S. Nakajima S. Udagama and K. Kawai J.Chem. SOC. Perkin Trans. 1 1987 1735. 420 M. Arisawa A. D. Kinghorn G. A. Cordell and N. R. Farns- worth J. Nat. Prod. 1984 47 106. 421 P. Bhandari and R. P. Rastogi Phytochemistry 1981 20 2044. NATURAL PRODUCT REPORTS 1989 422 P. Sengupta M. Sen P. Karuri E. Wenkert and T. D. J. Halls J. Indian Chem. SOC. 1985 62 916. 423 J. N. Chatterjea K. R. R. P. Singh I. S. Jha Y. Prasad and S. C. Shaw Indian J. Chem. Sect. B 1986 25 796. 424 P. N. Sharma A. Shoeb R. S. Kapil and S. P. Popli Pliyto-chemistry 1980 19 1258. 425 D. P. Chakraborty S. Roy A. Chakraborty A. K. Mandal and B. K. Chowdhury Tetrahedron 1980 36 3563. 426 D. L. Dreyer Recent Adv. Phytochem. 1986 20 317.

ISSN:0265-0568    

DOI:10.1039/NP9890600591

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Recent Advances in the Use of Enzyme-catalysed Reactions in Organic Synthesis N. J. Turner Department of Chemistry University of Exeter Exeter EX4 400 Reviewing the literature published between January 1986 and June 1988 (Continuing the coverage of literature in Natural Products Reports 1986 Vol. 3 p. 489) I Introduction 2 Immobilization of Enzymes 3 Hydrolytic Enzymes 3.1 Lipases and Esterases 3.2 Pro teases 3.3 Lipases and Esterases in Organic Solvents 3.4 Lipase- and Protease-catalysed Peptide Synthesis 4 Reduction 4.1 Reduction of Ketones and Aldehydes 4.2 Reduction of 1,2-and 1,3-Dicarbonyl Compounds 4.3 Miscellaneous Reductions 5 Oxidation 5.1 Hydroxylation of Aromatic Rings 5.2 Hydroxylation at Non-aromatic Positions 5.3 Miscellaneous Oxidations 6 Other Biotransformations 6.1 Aldolases for Carbon-Carbon Bond Formation 6.2 Lyases and Enzymes other than Aldolases Catalysing Bond Formation 6.3 Halogenoperoxidases 6.4 Penicillin and Cephalosporin Formation 6.5 Transaminases 6.6 Glycosyl Transferases and Glycosidases 6.7 Kinase/Phosphorylase 7 Multi-enzyme Reactions 7.1 Preparation of Monosaccharides and Nucleosides 7.2 Preparation of Oligosaccharides 7.3 Others 8 Novel Approaches to the Preparation of Biocatalysts 8.1 Catalytic Antibodies 8.2 Modification of Existing Enzymes 9 Conclusions 10 References 1 Introduction Synthetic organic chemistry currently requires a wide range of reactions that proceed with high stereoselectivity and in high yield.This requirement arises from the need to prepare pharmaceuticals and agrochemicals in homochiral form and from the complexity of the targets being synthesized. Interest continues to grow in the application of enzymes to meet some of these demands with emphasis on providing practical procedures that complement the traditional chemical method- ologies available. lP5 Four characteristics of enzymes can be identified that make them attractive for use in organic synthesis :(i) they are catalytic and enhance the rate of reactions often by several orders of magnitude ; (ii) they operate under mild conditions (ambient temperature pH 6-8) and are therefore compatible with substrates bearing sensitive functionality ; (iii) they exhibit stereoselectivity especially in their discrimination between enantiomeric molecules and enantiotopic groups; (iv) they are able to functionalize non-activated positions with considerable regioselectivity.In common with the previous review in this series this Report emphasizes the importance of hydrolytic enzymes and oxidoreductases since these two groups of enzymes account for approximately 90 YOof literature reports on biotransformations. Their main application is in providing mmol-mol quantities of optically active intermediates for further chemical synthesis. Sufficient work has been carried out on certain enzyme systems (e.g.bakers 'yeast pig-liver esterase) such that they can now be used to provide products with predictable absolute stereochemistry. Most other enzymes are generally being applied to carry out pmol-mmol scale reactions on often quite complex structures to provide if not the target molecule itself then a fairly late stage intermediate. 2 Immobilization of Enzymes For most enzyme preparations immobilization onto a solid support offers considerable practical advantages e.g. (i) an increase in the stability and lifetime of the protein and (ii) easier recovery of the catalyst from the reaction medium. Lactobacillus bulgaricus has been immobilized in the shell side of an industrial hollow-fibre ultrafiltration module. The enzyme system was then used to produce lactic acid from acid whey permeate.6 A novel immobilized enzyme system was developed that has glycoamylase on the surface of and glucose oxidase within polyurea microcapsules.The system was found to carry out its sequential enzymatic reaction effectively. A polyethyl-eneglycol-modified lipase from Pseudornonas JEuorescens has been used to prepare retinyl palmitate and retinyl oleate by transesterification using palmitic acid or oleic acid in benzene. The properties of a PEG-modified lipase from Candida rugosa have also been studied.8 A useful technique for the efficient manipulation of enzymes has been described in which the enzyme in soluble form is enclosed in commercially available dialysis membranes. The technique (mem brane-enclosed enzymatic catalysis M EEC) which has been tested on a representative number of enzymes has the advantage over immobilization on solid supports of being operationally simpler and of eliminating the loss in enzyme activity encountered with immobili~ation.~ In order to find optimal conditions for the immobilization of enzymes it is necessary to determine both the enzyme content and activity and thereby derive the specific activity.An infra- red based method for determining the enzyme content has been developed and applied to a-chymotrypsin immobilized on ~ilica.~ The amide-I and amide-I1 bands of the enzyme at 1650 and 1540 cm-' respectively are integrated to provide quanti- tative data for the enzyme content.l0 3 Hydrolytic Enzymes 3.1 Lipases and Esterases The use of rneso-compounds as substrates for lipases and esterases continues to be a well exploited strategy for the preparation of optically active intermediates for synthesis.625 NATURAL PRODUCT REPORTS 1989 -ace,, -A \-4OH (8) OAc HOA-H (10) YHX R Me A Me02CXC02Me MeO2C C02Me Thus the meso-diester (1) was subjected to porcine pancreatic lipase (PPL)-catalysed hydrolysis yielding the half ester (2) in 77 % isolated yield and 55 % enantiomeric excess (e.e.). Further chemical synthesis converted (2) into (3) a constituent of a glandular secretion of the civet cat (overall yield 18%)." Analogous work has been reported by another group." Gais has published the details of a large scale (90 g) pig liver esterase (PLE) catalysed hydrolysis of meso-dimethyl 4-cyclohexene dicarboxylate to give the mono-ester (4) in 99% yield and with > 98% e.e.The ester (4)was used for an enantiodivergent synthesis of lactones (5)and (6).13Further use of the chiron (4) has been made by Ohno who converted it to the aminocyclitol (-)-fortamhe (7).14A further illustration of H (4) (5) H2NQNIMeH0' HO OH loAc u- V-C02Me OH n -p&Q-) 0 I I H-(12) meso-selectivity is given by the lipase (Rhizopus delemar) mediated preparation of the optically active half-ester (8) [69 YO yield 99 YO e.e.1 from the corresponding meso-substrate. Compound (8) was subjected to a further eight chemical steps to provide (9) a key intermediate for the synthesis of 11-deoxyprostaglandins.l5 Finally the pro-(R)enantiotopic speci- ficity of PLE-catalysed hydrolysis of the meso-diacetate to give (10) (78 YOyield and 96 % e.e.) enabled this chiron to be used via the lactone (1 l) in an efficient enantioselective synthesis of (-)-alloyohimbane (12).16 A number of studies have been carried out aimed at changing the stereoselectivities of hydrolytic enzymes particularly in connection with the hydrolysis of prochiral substrates. Jones et al. have studied the effect of co-solvents temperature and pH on the enantioselectivity of hydrolysis of 3-substituted dimethyl glutarates (13) catalysed by pig-liver esterase. Thus under optimum conditions (10-29 % aqueous methanol and -10 "C) the enantiomeric excesses obtained with the 3-methyl diester [(13) R' = Me R2 = H)] increased from 79 % to 97 %.Further the hydrolysis is pro-S selective for diesters with small C-3 substituents but reverses to pro-R preference when C-3 substituents are large. Lowering the pH from 7 to 6 caused a decrease in the e.e. of the product." Bjorkling carried out a similar study on dialkylated malonate diesters (14) in DMSO-H,O mixtures. Marked increases in stereoselectivity were observed (up to 50% DMSO) accompanied by a marked lowering (-10 fold) of enzyme activity.l8 Ohno has studied the hydrolysis of derivatives of dimethyl-3-aminoglutarates (15)19 NATURAL PRODUCT REPORTS 1989-N. J. TURNER H OCH2Ph HO OAc n (16) I OAc A 8 rac-(27) OAc e.e.).The results were again interpreted in terms of the binding site geometry. Two groups have developed methods for the preparation of chiral glycerol derivatives. Schneider et al. diacetylated 2-0- benzyl-glycerol and hydrolysed the diester with a number of enzymes. Best results were obtained with porcine pancreatic lipase (PPL) and a lipoprotein lipase which gave the (R)-monoester (16) with 80% and 91 % e.e. respectively.20 Similar results were reported by Suemune et a1.21 Two fundamental studies on pig-liver esterase (PLE) have OAc been conducted. First the stereospecificities of the isozyme components of commercially available pig-liver esterase have been shown to be essentially the same towards representative (19) monocyclic and acyclic diester substrates.This removes previous concerns that the isozymal composition of PLE a widely used catalyst for chiral synthon production might result in its not behaving consistently when applied as a catalyst for R2 R3 Me asymmetric synthetic purposes.22 Secondly a study has been R'Hco2 made of the preferred orientations of the ester groups in PLE-(20) catalysed hydrolyses using conformationally rigid substrates e.g. 4-t-butyl-cyclohexanecarboxylic acid These studies confirm the previous work by Tamm24 showing that equatorial ester groups are preferentially cleaved. Racemic (1 7) has been subjected to kinetic resolution with porcine pancreatic lipase to provide (18) [95 YOe.e.1 which is to be used as a bicyclic intermediate for the synthesis of forskolin (19).25 Pig-liver esterase hydrolysis of variously substituted racemic allenic esters (20) proceeded with predictable enantio- meric selectivity [i.e.(3-ester selectivity when the C-4 substit- uents are small or acyclic and (R)-ester selectivity when they are large or cyclic].The highest enantiomeric excesses (93 YO)were observed with the most highly substituted substrates.26 The racemic alkynyl ester (21) has been resolved enzy- matically by two groups. Thus treatment of (21) with lyophilized yeast gave the desired (3-alcohol (22) with > 97% e.e.27 Roberts has carried out an alternative resolution using Mucor miehei lipase to provide (22) with an e.e. of 80%. He also described the use of racemic (21) for a convergent synthesis of *OAc racemic 13-hydroxy-92,ll E-octadecadienoic acid (23).Interest lies in the 13s isomer of (23) (coriolic acid) which is reported to (24) act as a chemorepellent that influences platelet/endothelial cell interactions and may have a role in controlling thrombosis.2X The diacetates of trans-1,2-~yclobutanediol cyclopentane- diol and cyclohexanediol were hydrolysed selectively with pig-liver esterase. Best results were obtained with the cyclo- butane derivative (24). With the cyclohexane derivative recovered diacetate and diol were of high optical purity but the monoacetate had an e.e. of 58%.29 An interesting dem- onstration of the versatility of esterases is provided by the resolution of the racemic organometallic ester (25) by pig-liver (25) esterase.Both products (26) and recovered substrate (25) were obtained in 85% e.e.30 and the same trend in relation to the steric bulk of the C-3 Candida cylandricea lipase is another broad spectrum lipase. substituent (NHX) was observed as by Jones.17 The half-ester It has been used to hydrolyse the racemic acetate of endo-formed had the (R)-configuration with smaller substituents norbornenol (27). After 40 YO conversion the ( +) -alcohol (e.g.X = MeCO- 100 '30e.e.) changing to the (S-configuration (28) was obtained with 90% e.e. on a 10 g scale. Compound with increasing steric bulk (e.g. X = MeCH=CHCO- 100YO (28) is a useful intermediate for the synthesis of nucleoside NATURAL PRODUCT REPORTS 1989 AcOA (29) R = C0"Bu OAc OAc (40) Site of hydrolysis Fig.1. analogues. The exo-acetate (29) was hydrolysed very slowly and non-enantio~electively.~~ The esterase of Corynebacterium equi shows high enantioselectivity in the hydrolysis of racemic sulphoxides (30). The best results were achieved when n = 1 2 and R = Me.32 A commercially available lipase from a Pseudomonas species has emerged as a highly selective catalyst. Thus a series of optically active secondary alcohols (31) were prepared via enzymatic hydrolysis of the corresponding racemic acetates or chloroacetates. The use of chloroacetates accelerated the hydrolysis by a factor of 30-40 fold without significantly affecting the optical purity of the products. The (R)-ester is selectively hydrolysed with e.e.s of 72-99 A three-site model for PseudomonasJEuorescenslipase has been proposed by studying the enantioselective hydrolysis of various cyclic acetates all of which gave optically active alcohols with the (R)-configuration (Figure 1).34 Racemic y 6 and elactones have been ring opened with concurrent resolution using as catalyst either PPL PLE or horse-liver esterase to give optically active lactones [e.g.conversion of (32) into (33)].35 By conducting an enzymatic resolution under conditions in which the substrate is able to racemize in situ yields of > 50 YO can be achieved. This approach not only obviates the need to recycle unreacted starting material as for a standard kinetic nproco% -Ho$o .p QIC R0 OR2 OAc (41) R' =Ac R2 = H (42) R' = H R2 =Ac resolution but the e.e.of the product is now independent of conversion and the process becomes apparently more enantio- specific. An elegant example of this is provided by Sih's work on the asymmetric hydrolysis of ketorolac esters (34). Ketor- olac 5-benzoyl- 1,2-dihydr0-3H-pyrrolo[ 1,2-u]pyrrole- 1-car-boxylic acid (39 is a compound of considerable therapeutic interest because of its potent anti-inflammatory and analgesic activities. Furthermore the (-)-(8-isomer of (35) is con-siderably more potent than the (+)-(@-isomer in animal studies. After testing a number of possible lipases and proteases under various conditions it was found that the protease from Streptomyces griseus gave the desired (S)-enantiomer (35) in 92% chemical yield and with an e.e.of 87Y0.~~ Several recent studies have begun to examine the application of hydrolytic enzymes to carbohydrate synthesis. For example selective deprotection of the primary (6-0)ester group from the fully protected glucose derivative methyl 2,3,4,6-tetra-O-pentanoyl-D-glucopyranoside (36) was carried out using Can-dida cylandricea lipase (CCL) in acetone :water (1 10) to afford (37) in 90 YOyield on a 50 mmol scale.37 Kloosterman et ul.have also examined the potential for using hydrolases to selectively deprotect various glycerides and glycosides in the presence of acid- and base-sensitive groups. For example the protected sugar (38) could be selectively deprotected to give (39) in 90% yield using CCL.It was found that many factors influenced the regioselectivity of hydrolysis including (i) chain length and bulkiness of the acyl protecting group (ii) origin of lipase selected (iii) the amount and polarity of the co-solvent used and (iv) the physical properties of the emulsion or Enzyme-catalysed deacetylation of 1,6-anhydro-2,3,4-tri-O-acetyl-D-glucopyranose (40) led to the preferential hydrolysis of either the C-3 or C-4 acyl group depending on the enzyme used. Thus porcine pancreatic lipase gave (41) in 42 YOyield whereas Wheatgerm lipase gave (42) in 51 YOyield.39 NATURAL PRODUCT REPORTS 1989-N. J. TURNER (43) (44) C O 2 " WOHA C02R rac-(45) 3.2 Proteases Further examples of kinetic resolution with in situ racemization are provided in the amino acid field.Thus the racemic hydantoin (43) was transformed to D-p-hydroxyphenylglycine using intact cells from a species of Pseud~rnonas.~~ In a related reaction the racemic oxazolidinone (44)was hydrolysed enantioselectively to L-serine using Pseudornonas testeroni with concomitant racemization of the unreacted substrate effected by a second organism Bacillus subtifi~.~' The erythro (SS;RR) phenyl serinates (45) were hydrolysed with a-chymotrypsin. The recovered ester after 49 YOhydrolysis had an e.e. of 92 YO.The threo isomer was not hydroly~ed.~~ 3.3 Lipases and Esterases in Organic Solvents The opportunities for using hydrolytic enzymes in organic solvents have become much more widely appre~iated.~~ By replacing water with a biphasic aqueous/organic solvent reaction medium the water activity is lowered and the thermodynamic equilibrium of the reaction is shifted towards the synthetic direction.The equilibrium may also be further displaced towards synthesis if the product(s) shows greater solubility in the organic phase than the reactant(s). Among the classes of hydrolytic enzymes that have been shown to operate effectively in organic solvents (e.g. proteases amidase lipases etc.) the microbial lipases (E.C. 3.1.1.3) are well suited since they are relatively stable to non-polar organic media and can catalyse reactions efficiently at the lipid-water interface. To provide a quantitative basis for these types of reactions Sih has developed new expressions that relate the kinetic and thermodynamic parameters that govern the stereospecificity of enzyme-catalysed resolution of enantiomers in biphasic aqueous/organic media.These results complement those he reported for the use of these enzymes under the more conventional hydrolytic condition^.^^ In addition to the lipase-catalysed hydrolysis of esters of carbohydrates (vide supra)Klibanov has examined the acylation of a range of sugars catalysed by porcine pancreatic lipase (PPL) in pyridine. As a representative example galactose was acylated with 95 % regiospecificity to give 6-0-acetyl galactose (46) in 60 YOisolated yield. Other acyl donors investigated were the 2,2,2-trichloroethyl esters of butyric caprylic and lauric Partially purified PPL can be used to prepare the (R)-monoacetate of propane- 1,3-diol derivatives by enantio-selective transesterification of the diols with methyl acetate as donor.The highest e.e.s were obtained with (47). The corresponding (3-enantiomer was prepared by PPL hydrolysis of the diacetate (> 90% e.e. for both enantiomer~).~~ The enzyme was absorbed on Hyflo SuperCel. The chemical synthesis of macrocyclic lactones often results in low yields the undesired dimer being formed in equal or greater amounts than the lactone. A number of groups have looked at the ability of hydrolases in organic solvents to ""& HO OH OH Hb 6Ac 0 (48) (49) (50) Me-0 (511 Me (52) (53) (54) synthesize macrocyclic lactones.The hydroxyester methyl 16- hydroxyhexadecanoate (48 ; n = 15) underwent cyclization in benzene in the presence of lipase P from a species of Pseudowonas to give a mixture of the desired lactone (49 ; n = 15) in -80 YOyield and the diolide (50 ; n = 15) in -3 '340 yield. When n = 12 the yield of corresponding lactone (49; n = 12 was 38 YOand the diolide (50; n = 12) was 25 YOi.e. the relative amount of diolide formation increased with decreasing chain length. The stereospecificity of the reaction was shown by the conversion of racemic methyl 10-hydroxyundecanoate into the (R)-isomer only of the corresponding la~tone.~' The optically active [ > 94 % e.e.1 y-methyl butyrolactone (5 1) was obtained by lactonization of racemic MeCH(OH)(CH,),CO,Me in dry ether catalysed by porcine pancreatic lipase in 36% yield.48 Under similar conditions p y and s-hydroxyacid methyl esters generally undergo oligomerization rather than lact~nization.~~ In a related series of reactions Amano-P lipase can catalyse the asymmetric ring opening of 3-substituted glutaric anhydrides (52) with t-butyl alcohol to afford the (R)-half esters (53) [60-90 YOe.e.].50 Candida cyfandricea lipase and porcine pancreatic lipase catalyse the enantioselective esterification of racemic allene alcohols with lauric acid in hexane to give (54) [35% yield; 72% e.e.].51 'Lipozyme' is a preparation of fungal Mucor miehei lipase on an ion-exchange resin and is commercially available from NOVO Industri.The immobilized form is a very effective catalyst for the esterification of racemic alcohols with octanoic acid in hexane the (R)-enantiomer generally being preferentially esterified.Thus (R3-hexan-2-01 underwent esteri- fication to give (3-hexan-2-01 [87% e.e.1 and the octanoate ester of (R)-hexan-2-01 [83 YOe.e.].52 630 3.4 Lipase- and Protease-catalysed Peptide Synthesis The applications of enzymes in peptide synthesis have been reviewed.53 Wong has developed procedures for using non- proteases (e.g. PPL PLE and CCL) to catalyse peptide synthesis. These reactions are carried out in ether or ethyl acetate containing 5-10 Yo aqueous buffer or pyridine using N-acyl amino acid esters as substrates. The advantages offered by lipases over proteases for this reaction are twofold (i) competing hydrolysis of the newly formed peptide bond is reduced and (ii) lipases are more efficient than amidases or proteases at operating in anhydrous environment^.^^ Anal-ogously PPL in either toluene or THF catalyses the synthesis of peptides in yields of 48-86 More conventionally the protease papain has been used in 49% methanol and high pH (pH = 9) to synthesize peptides containing unusual amino acids.Under these conditions papain acts as an esterase with an activity 103 times that of an amidase such that the coupling of a benzyloxycarbonyl-amino acid ester and an amine should be faster than enzyme-catalysed hydrolysis of the amide bonds. Using this kinetic approach a number of dipeptides containing D-amino acids have been prepared [yields 55-92 The C-terminal tetrapeptide fragment of cholecy- stokinin has been synthesized by sequential protease-catalysed reactions in organic-buffer systems.57 Polyethylene glycol- modified thermolysin was found to catalyse peptide synthesis in organic solvents with altered substrate specificity. Thus in benzene-2 YO diisopropylethylamine-methanol both hydro-philic and acidic amino acids were better acyl group donors than hydrophobic residues contrary to the situation for thermolysin-catalysed synthesis and hydrolysis of peptide bonds in water.58 To improve the stability of a-chymotrypsin under the required operating conditions the methionine residue at 192 was selectively modified to methionine sulpho~ide.~~ The modified enzyme [Met(O) 192-chymotrypsin] was then used to prepare N-benzyloxycarbonyl-L-Tyr-D-Met-OMe from Z-Tyr- OMe and D-Met-OMe with 92% of the enzyme activity being recovered compared with only 20 YOif the wild type enzyme was used.6o The substrate specificity of a-chymotrypsin can be reversed by carrying out transesterifications in octane rather than hydrolysis in water.Upon transition from hydrophobic phenylalanine to hydrophilic serine in the series of esters of N-acetyl-L-amino acids the K,,,/K for enzymatic hydrolysis drops nearly 50000 fold. However in the transesterification reaction in octane the ester of N-acetyl-L-serine is three times more reactive than that of N-acetyl-L-phenylalanine.61 4 Reduction 4.1 Reduction of Ketones and Aldehydes Reduction of the prochiral ketone 6-methylhept-5-en-2-one with Thermoanaerobium brockii gives ( +)-(3-sulcatol (55) [quantitative yield; 99 % e.e.1 an aggregation pheromone produced by males of Gnathotrichus sulcatus.Reduction of the same ketone with Aspergillus niger gave (-)-(R)-(55) [80YO yield; 96 YOe.e.].62 Asymmetric reduction of ketones by the enzyme alcohol dehydrogenase from Thermanoaerobium brockii has been extensively investigated by another group.63 Bakers ’ yeast has been used to prepare a range of optically pure amino alcohols from the corresponding keto amide~.~ Mevalonolactones stereospecifically deuterated at C-5 are required to study the biosynthesis of oxygenated trichothecenes. Their synthesis has been achieved from the alcohol (56)’ in turn prepared by stereospecific reduction of the corresponding deuterated aldehyde with horse liver alcohol dehydrogenase (HLADH) in the presence of ethanol.Compound (56) was subsequently converted in four steps to (3RS)(5S)(5-2H)-mevalonolactone (57) in 35 YOoverall yield. The isotopomer (3RS)(5R)(5-2H)-mevalonolactone was similarly prepared by starting with the protio aldehyde and carrying out the reduction with HLADH in [2H,] NATURAL PRODUCT REPORTS 1989 (56) (57) ?Ac (59) ’\ HO OH (58) A combined chemical-enzymatic synthesis of 4-deoxy-~- lyxo-hexapyranose (4-deoxy-~-mannose) (58) has been carried out by using bakers’ yeast reduction of (59) as the key step. The major product alcohol (60) formed in 20 YOyield was separated and taken through to the product (58).66 Glycerol dehydrogenase from Enterobacter aeroges or a Cellulomonas species has been used to prepare a range of optically active 1,2-diols and a-hydroxy ketones.Its substrate specificity was shown to be quite different to that of horse-liver alcohol dehydrogenase yeast alcohol dehydrogenase and lactate dehydrogenase. As representative transformations I -hydroxy-2-propanone and 1-hydroxy-2-butanone were reduced to the corresponding (R)-1,2-diols [95-98 YOe.e.].,’ A convergent chemo-enzymatic synthesis of leukotriene B has been accomplished using both bakers’ yeast and an esterase to provide the key chiral precursors. The dithiane (61) was prepared by bakers’ yeast reduction of the corresponding ketone [65 YOyield; 97 YOe.e.1 and converted in three steps to the aldehyde (62).The alcohol (63) was prepared by hydrolysis of the racemic acetate with Klebsiella pneumoniae [ > 98 % e.e.1 and converted in three steps into the aldehyde (64). Subsequent chemical synthesis coupled (62) and (64) in seven steps to give leukotriene B (65).6s Differentially protected optically pure L-glyceraldehydes are difficult to obtain by standard chemical methods. They have been obtained by bakers’ yeast reduction of the ketones (66) and (67) both types of products possessing the (9-stereo- chemistry at the site of reducti~n.~~ The prochiral diketone (68) was reduced with Curvularia lunata in the presence of glucose to provide the optically pure NATURAL PRODUCT REPORTS 1989-N.J. TURNER 631 Eto (63) (64) 166) (67) R’ R2 0 (9-ketol (69). Subsequent oxidation with m-chloroperoxy- H3CuOEt benzoic acid and spontaneous lactone rearrangement gave the chiral lactone (70). If the glucose is omitted from the initial fungal reduction then the (q-ketol(69) is slowly converted into (71) R’ =OH R2 = H the lactone (70) indicating the presence of a Baeyer-Villiger (72) R’ = H R2=OH type ~xygenase.~~ The ketol (69) has previously been used as a synthon in the synthesis of optically active cis-chrysanthemic acid.71 4.2 Reduction of 1,2- and 1,3-Dicarbonyl Compounds Much work continues to be carried out on the reduction of both acyclic and cyclic P-keto esters largely due to the usefulness of the available models for predicting the absolute (73) stereochemistry of the products.72 Ethyl acetoacetate (ethyl 3- oxobutanoate) can be reduced on a 40 g scale with bakers’ yeast to give the (9-alcohol (71) with high selectivity [85-95 YO H OH 0 e.e.1 and in good yield [59-76%0].’~ The enantiomeric (3R)- hydroxybutanoate (72) can be produced by microbial P-H3C~0c8H17 -qo hydroxylation of n-butyric acid using cells of Zoogloea rumigera (from Kanegafuchi Chemical Ind. Co. Ltd. in Japan). (75) Both (71) and (72) are useful starting materials for the synthesis of certain insect pheromones. Thus (72) has been (74) converted into (R)-(73) whereas (3S)-(71) prepared from Succharomyces bailii reduction of the ketone 196 O/O e.e.1 was converted into (9-(73).Both enantiomers of (74) were prepared i via reduction of octyl-3-oxopentanoate to give (75) [96 YOe.e.1. Each enantiomer of (74) was then converted into the cor- responding enantiomer of (76). Compounds (73) (74) and (76) are the three main components of the pheromone blend of the male swift moth Hepiulus hect~.~~ Deshong also used the (3s)- q alcohol (75) in a synthesis of (+)-(74) in six steps and overall yield of 16 %. He also transformed (+)-(74) to (+ )-(76) albeit in low yield.75 (76) NPR 6 NATURAL PRODUCT REPORTS 1989 (80) H OH 0 H ,OH 0 EtOzC% ___) Et02Cv EtO2Cw ~ HO4 (87) QoEt -Et02CQoEt EtO2C OH 0 (85) (86) Substituents can be tolerated at the 2- and 4-positions of the oxobutanoate system.Reduction of octyl-2-methyl-3-oxo-butanoate (77) with bakers ’ yeast gave octyl-(3S)-hydroxy- (2R)-methylbutanoate (78) [82 YOyield ; 99 % e.e.],76 whereas ethyI-4-t-butoxy-3-oxobutanoategave the hydroxyester ethyl (R)-4-t-butoxy-3-hydroxybutanoate(79) [72% yield ; 97 YO e.e .I. 77 When 8-keto-esters are reduced by the yeasts from the species Kroekera and Hansenula polymorpha which have been grown on methanol rather than glucose or sucrose the products generally are enriched more in the D (R)-is~mer.’~ Asymmetric reduction of 3-0x0-octadecanoic acid with fermenting bakers’ yeast gave (80) in 40% yield and with an e.e. > 98 YO.Further chemical synthesis converted (80) into optically pure (+)-(2R,3R)-corynomycolic acid (8 1) an acid constituent of trehalose diesters isolated from the cell wall of Corynebacteria.79 HO OH Cyclic P-keto esters are reduced with equally high stereo- control as their acyclic counterparts. The ketone (82) gave the optically pure alcohols (83) and (84)in 57% yield [ratio of erythro threo = 1 :9.5).80Reduction of the substrate (85) gave (86) as a diastereomeric mixture. The mixture was subsequently converted into the fungal toxins talaromycin A (87) and B (8 8). 81 Bakers’ yeast reduction of the keto-proline (89) yielded the alcohol (99 YOdiastereomeric excess-cis; 80 YOe.e.) which after subsequent hydrolysis and crystallization gave (+)-cis-(2R 3S)-3-hydroxyproline (90). This was converted chemically into the (1 S SS)-Geissman-Waiss lactone (91) and provided also for a formal total synthesis of (-)-retronecine and related pyrrolizidine alkaloids.82 The cyclic P-keto-ester (92; n = 1)’ is reduced to the corresponding cis-hydroxyester in excellent chemical and optical yields [~OOYO yield; > 99% e.e.1 using Mucor racemosus or M.circinelloides while the corresponding NATURAL PRODUCT REPORTS 1989-N. J. TURNER (92) (94) (93) HO $ph H + phH$HPh Phhph ____) Ph 0 \ OH H (951 (96) (97) F‘ 4 0 CI 2 EI t ACHO OH (100) (98) (99) trans-hydroxyesters are obtained from Rhizopus arrhizus [87 YO PI 1. Bakers’ Yeast ri u yield; > 99 YO e.e.1 and Absidia gluaca [80 YO yield; > 99 YO e.e.].83 The natural insect pheromone sitophilure (4R,5S)-( -)-/=(-4-methyl-5-hydroxyheptan-3-one (93) has been prepared via a CI2HC C02Me two-step chemoenzymatic synthesis.Under anaerobic condi- tions resting cells of Geotrichum candidurn were employed as the catalyst for reduction of the prochiral 4-methylheptan-3,5- dione (94) to give (93) [~OOYO e.e.1. Under aerobic conditions the (4S,5S)-( +)-diastereomer of (93) is obtained [70 YOe.e.].84 Finally a-dicarbonyl compounds (e.g. a-diketones a-keto esters) have proved to be successful substrates for oxido- reductases. Thus benzil (95) gave the (S,S)-diol (96) [40% yield; 94 YOe.e.1 with the yeast Saccharomyces uvarum whereas the (R,R)-isomer (97) was obtained [55% yield; 96% e.e.1 using the micro-organism Rhodotorula mucilagin~sa.~~ Bakers ’ yeast reduction of the racemic a-keto-ester (98) gave (99) as a diastereomeric mixture [threo :erythro = 4 11 in 90 YOyield (102) each diastereomer with > 99 % e.e.The erythro-(2S,3R)-isomer was separated and converted to the epoxy aldehyde (2R,3S)-2 3-epoxyoctanal (100) [e.e. SOYO],a key intermediate for the synthesis of 14,l 5-leukotriene A (101).86 Klibanov has extended the concept of using enzymes in organic solvents by carrying out alcohol dehydrogenase-catalysed reductions in water-immiscible organic solvents. One possible benefit of this approach is to improve the stability of substrates and products that are particularly unstable in water. (105) (106) The biocatalyst was prepared by immobilization of horse-liver alcohol dehydrogenase and NADH together on glass beads.Both NADH and NAD’ are effectively regenerated in such a system with alcohol dehydrogenase-catalysed oxidation of The naturally occurring L-amino acid armentomycin (102) has ethanol and reduction of isobutyraldehyde respectively.*’ been prepared using bakers’ yeast reduction of an ap-unsaturated ester as the key step. Thus the E-substrate (103) was reduced and re-esterified with diazomethane to give (104) 4.3 Miscellaneous Reductions [65% yield; 92% e.e.1 which was converted into (102). Several examples have been published of the chemo-selective Analogous reduction of the 2-isomer (105) gave the cor-reduction of double bonds in the presence of carbonyl groups. responding enantiomer (1 0QSs2-Enoates and alkanoates (107) NATURAL PRODUCT REPORTS 1989 CO or H2 or HC02H r pH 7.5 CO or HCOzH pH 5.5 I I R 7-4=Ci (107) R',R2 = aryl,alkyl i I COorHC02H I * pH 5.5 OH (114) (1 17) can be reduced with resting cells of Clostridium thermoaceticum in the presence of CO and 1 mM methyl viologen to give different products depending on the conditions used.Thus with CO HCOOH or H at pH 7.5-8 (108) is formed whereas with (118) Methyl-substituted pentadien- 1-01s (1 15) have been both regio and stereo-selectively reduced by bakers' yeast to give (116). The product (116) was converted into (s)-(-)-2-methylsuccinic acid dimethyl ester and found to be optically pure [~OOYO e.e.1 by n.m.r. studies with chiral shift reagents.g1 Geraniol was reduced to (R)-( +)-citronello1 (1 17) [98 YOe.e.1 using bakers' yeast and (1 17) was then converted into (1 18) the C, side-chain of vitamin E.92 The N-0 bond of dihydrooxazines [e.g.(1 19)] can be cleaved enzymatically to give (1 20).For instance Methanobacterium thermoautotrophicum in the presence of methyl viologen and hydrogen chemoselectively cleaves the N-0 bond of (1 19) in 73 YO yield thereby providing an alternative to chemical cleavage.g3 CO or HCOOH at pH 5.5 (109) or (110) pred~minate.~~ 5 Oxidation Reduction of the chloroketones (1 11) with bakers' yeast gave the (5')-chloroketones (1 12) selectively [44-84 % e.e.1. Further reduction gave the diastereomers of (3s)-and (3R)-chloroalkan- 2(S)-ols (1 13 and 114) with very high selectivity [ca.98 % e.e.1.N.B. (i) reduction of the double bond precedes reduction of the carbonyl function and (ii) reduction of the carbonyl group was stereospecific regardless of the configuration of the neigh- bouring asymmetric centre.'O 5.1 Hydroxylation of Aromatic Rings The conversion of benzene (and substituted analogues) into the corresponding cis-cyclohexa-3,5-diene-1,2-diols[e.g. (121) and (12211 by species of Pseudomonas is a striking example of a biotransfonnation that has no chemical equivalent. The current importance of this reaction is reflected in the number of papers using the diols in natural product synthesis. (i-)-Pinitol (123) NATURAL PRODUCT REPORTS 1989-N. J. TURNER OH HO“ ! OH (121) R= H (122) R=Me ( 123) J PCHO Mle (125) F F (126) (127) 6”Br @OHBr OH (128) (129) Q Q b”” OH &OH OH ( 130) (131) has been prepared from benzene in six steps and overall yield 35 YO,using the conversion of benzene into (121) by Pseudo-monas putida as the key step.94 The chiral methyl analogue (122) prepared from toluene using the same organism has been converted into a prostaglandin intermediate (124) and the synthon (125).95 Fluorinated aromatic compounds (126) can similarly be converted into optically active cis-diols (127) by Pseudomonas putida with the advantage that the bioconversion can be monitored by 19F n.m.r.96 Analogously 4-bromobenzoic acid (128) is converted into a single enantiomer of 4-bromo-cis-2 3- dihydroxycyclohexa-4,6-diene- 1-carboxylic acid (129) by Pseudomonas p~tida.~’ Biphenyl has been converted into (130) and subsequently biphenyl-2,3-diol (13 1) by Pseudomonas cru~iviae.’~ 5.2 Hydroxylation at Non-aromatic Positions The toluene dioxygenase of Pseudomonas putida has been shown to effect benzylic monooxygenation.Thus indene (1 32) was converted into ( +)-(1 S)-indenol (1 33) [26 YOe.e.1 whereas s’ R (136) (137) (138) OH / OR (139) (19) indan (134) gave (-)-(1R)-indanol (135) [84% e.e.1. The latter reaction could also be carried out by a naphthalene dioxygenase giving (+)-(1 S)-indanol (1 35) [92 % e.e.).g9 A range of ethyl-substituted aromatic compounds were found to be hydroxylated by Mortierella isabellina to give predominantly 1 -phenyl ethanols (1 36) mostly with the (R)-configuration.Yields were up to 45% and e.e.s varied from 540 YO. The enantioselectivity was not due to the hydroxylase but to a subsequent dehydrogenase which preferentially oxidized the (S)-isomer.loo Bornylamide derivatives [e.g.(1 37)] can be regioselectively hydroxylated by Beauveria sulfurescens to give the em-products (1 38) in approximately 35 YOyield. However the products derived from racemic starting materials showed no optical activity.lol The terpenoid forskolin (19; R = Ac) is important in cyclic-AMP-mediated physiological processes and promises to be a useful drug for the treatment of glaucoma congestive cardiomyopathy and asthma.The 7- deacetylated compound (19; R = H) has been prepared via dihydroxylation of 7-deacetyl- 1,9-dideoxyforskolin (139) although in very low yield (0.78%). As (139) occurs in approximately equal amounts to forskolin in the indian herb Coleus forskohlii this represents a way of obtaining larger amounts of forskolin.lu2 ( 140) Me (144) Treatment of the arachidonic acid analogue 16,17(E)-de-hydroarachidonic acid (140) with soybean lipoxygenase at 23 "C in air gave the conjugated alcohol (141) as the major product [88% yield]. Under the same conditions the analogue 16,17(E)-18,19(E)-bisdehydroarachidonic acid (142) was not a substrate but at 50 atmospheres of 0 and 23 OC it became one and gave the allylic hydroperoxide (143) as the major product.lo3 5.3 Miscellaneous Oxidations Aldehyde oxidase converted the iminium ion (144) into the lactam (145) with concomitant kinetic resolution [70 YOyield; ratio R:S = 5.5 :l].lo4 An activity from Saccharomyces cer-evisiae capable of introducing double bonds into long-chain fatty acids is also able to process the sulphur analogue 6,13-dithiastearic acid (146) to (147) as major product.lo5 Oxidation of a number of dithioacetals with cells of Corynebacterium equi has been investigated.Two chiral sulphoxides (148) and (149) of high optical purity were obtained. lo6 The w-hydroxylase from Pseudomonas okovorans is a hy-drocarbon mono-oxygenase capable of carrying out hydrox-ylation at the terminal methyl of alkanes as well as epoxidation of terminal olefins.It has been shown to hydroxylate methyl thioethers (150) stereoselectively. The absolute configuration of the product (151) was (R) in all cases and the highest enantiomeric excesses were obtained when R = n-propyl. The enzyme is also capable of catalysing oxidative 0-demethylation of branched alkyl and branched vinyl methyl ethers to 2" alcohols and ketones respectively.lo' NATURAL PRODUCT REPORTS 1989 I OH (141) I OOH (143) IS\ 2, -Me 8 Me R R 6 Other Biotransformations 6.1 Aldolases for Carbon-Carbon Bond Formation Rabbit muscle aldolase (RAMA) has continued to find use as a versatile synthetic catalyst particularly in the preparation of carbohydrate analogues. Wong has used a multienzyme approach to couple various aldehyde substrates (152) with dihydroxyacetone phosphate (DHAP) (153) in the presence of RAMA followed by dephosphorylation with acid phosphatase to give (154).In some cases the aldol product is also a substrate for glucose isomerase thereby generating various sugar analogues (155). By this method he was able to prepare 5-deoxy-D-fructose 6-deoxy-~-glucose 6-0-methyl-~-glucose and 6-deoxy-6-fluoro-~-glucose.lo8Five analogues of natural substrate DHAP (153) and 13 of glyceraldehyde-3-phosphate (152; R1 = OH R2 = CH,OPO,H,) have been synthesized as potential substrates for RAMA,lo9and a large scale practical synthesis of DHAP (153) has been reported.l10 RAMA has been used to catalyse the stereospecific aldol condensation of DHAP (153) with a variety of pentose-5-phosphates and hexose-6-phosphates.The products were dephosphorylated with acid phosphatase to yield C and C sugars.ll' Finally the glycosidase inhibitors 1-deoxymannojirimycin (156) and 1-deoxynojirimycin (157) have been prepared using RAMA for the key carbon-carbon bond forming step.'l2 N-Acetyl-neuraminate aldolase responsible for the synthesis of the biologically important sialic acid has been found to accept mannose rather than N-acetylmannosamine as the electrophilic component of the reaction.In this way the natural deaminated neuraminic acid analogue (158) has been prepared in 84% isolated yield.l13 NATURAL PRODUCT REPORTS 1989-N. J. TURNER 637 .R2 - 7 HO&HO OH OH 0 HOAOPOJH~ (154) (155) (153) “ a C COH HO I 2 H (159) (160) OH 1 OH H0213CD113c02HD - C02H Although not strictly an aldolase transketolase from either Succharomyces cerevisiue or spinach has been shown to have a fairly wide substrate specificity.By using hydroxypyruvic acid (159) as the ketol donor a wide range of aldehydes (phosporyl- ated and non-phosporylated) (160) can act as acceptors to give (161). For instance when glycolaldehyde (160; R = CH,OH) is used the product is L-erythrulose (161 ; R = CH,OH).Il4 6.2 Lyases and Enzymes other than Aldolases Catalysing Carbon-Carbon Bond Formation Extensive investigation of the substrate specificity of com-mercially available pig-heart fumarase (E.C. 4.2.1 .12) con- cludes that the enzyme is not broadly useful as a catalyst.However it was used effectively to convert chlorofumaric acid (I 62) into L-threo-chloromalic acid (1 63) a useful chiral precursor for the preparation of 2-deoxy-~-ribose and D-H H2N Br H-)-+M~ HO2C H (171) erythro-sphingosine (164).l15 The two enantiomers of chiral malonate (R)-[l-13C,2-2H]malonate 1-13C,2-2H]-(165) and (9-[ malonate (166) have been prepared by using fumarase-catalysed addition of either H,O and D,O to the precursors (167) and (168) respectively followed by oxidative cleavage to (1 69) and (170)? 8-Methyl aspartase has been used to prepare the isosteric L-valine analogue (2R,3R)-3-bromobutyrine (1 7 l) the key step being conversion of mesaconic acid to (2S,3S)-3-methylaspartic acid with 8-methyl aspartase followed by chemical conversion into (171).11’ The substrate specificity of P-methyl aspartase NATURAL PRODUCT REPORTS 1989 MexMe H HgCl H -H (172) (173) + *Et H ,OH E t F HO Et 0 0 0 k" (182) R = Me (184) R = COzMe from Clostridium tetanomorphum has been investigated re-vealing that certain structural changes can be tolerated by the enzyme i.e.it can accept certain 3-halogeno- or 3-alkylfumaric acids.l18 Bacterial organomercury lyase has been used to protonolyse organomercury substrates [e.g.conversion of (172) into (173)and(174)into (175)] with retention ofc~nfiguration.'~~ The enzyme mandelonitrile lyase [E.C. 4.1 .2.10 (R)-oxynitrilase] from bitter almonds (Prunus amygdalus) has been used to catalyse cyanohydrin formation in organic solvents (ethyl acetate).The use of organic solvents is necessary since the non-catalysed addition of cyanide ion to the aldehyde was found to compete in aqueous systems thereby lowering the optical purity of the products. The use of an immobilized form of the enzyme (on cellulose) in an organic solvent suppressed the chemical reaction but had little effect on the enzymatic reaction. For example 3-phenoxy-benzaldehyde was converted into (1 76) in 99% yield and with an e.e. of 98Y0.l~~ A new lyase activity of hydrolytic enzymes has been discovered. For example Candida cylandricea lipase catalyses the Michael addition reaction of nucleophiles to 2-(trifluoromethy1)propenoic acid (1 77) generating optically active trifluoromethyl compounds (178).The yields varied from 39-77% and the e.e.s from 39-70 YO.lZ1 Acetolactate decarboxylase catalyses the stereospecific de- carboxylation of both enantiomers of 2-ethyl-2-hydroxy-3-0~0-butanoate (179) to give the isomeric ketol products (180) and (1 8I) both with high enantiomeric excesses (93 % and 95 YO respectively). It was suggested that (1 8 1) arises from enzymic rearrangement of the initially produced (R)-( 180) followed by stereospecific decarboxylation.lZ2 Ultrasonically stimulated (183) R=Me (185) R=COiH bakers ' yeast converts the racemic squalene epoxide (1 82) on a gram scale into the steroid lanosterol (183) [42 YOyield; 95 O/O e.e.1. Similarly cyclization of (184) followed by alkaline hydrolysis gave the cytotoxic agent ganoderic Z (185) [31 YO yield; > 95% e.e.].lZ3 6.3 Halogenoperoxidases The chloroperoxidase from Caldariomyces fumago and the bromoperoxidase from Corallina pilulifera have been used to prepare various halogenated nucleic acid bases.Thus uracil can be converted into 5-chloro- bromo- or iodo-uracil by varying the halogen donor i.e. HCl HBr HI respecti~ely.'~~ Another group has used the same halogenoperoxidase from Caldario-myces fumugo to prepare some halogenated heterocycles e.g. the conversion of 2-aminopyridine into 2-amino-3-chloro-pyridine albeit in low yield (9-1 8 %).Iz5 6.4 Penicillin and Cephalosporin Formation Demain and co-workers have isolated and examined the substrate specificity of &(L-a-aminoadipyl)-L-cysteinyl-D-vahe (186) synthetase (ACV synthetase) the first enzyme in the pathway leading to the production of penicillins and cephalo- sporins.Thus a cell-free extract from Cephalosporium acre- monium containing ACV synthetase activity was shown to have a broad substrate specificity. L-a-Aminoadipic acid could be replaced by L-carboxymethylcysteine to give (1 87) whereas L-valine could be substituted by L-allo-isoleucine and L-a-aminobutyric acid.126 639 NATURAL PRODUCT REPORTS 1989-N. J. TURNER (186) R’ =A R2 = Me (189) R1=C R2=Me (192) R’ =C (187) R’ = B R2=Me (190) R’ = A R2 = OMe (188) R’ = C R2 = Me (191) R’ = A R2 = OMe A= Ho2cm C= ““‘“v H NH2 B= H NH2 As part of their studies on the biosynthesis of penicillins and cephalosporins Baldwin and colleagues have found that the rR OH tripeptide (1 88) in which the L-a-aminoadipic acid side-chain of (186) is replaced by an aromatic group having an equivalent spatial requirement proved to be an efficient substrate for highly purified isopenicillin N synthetase from Cephalosporium OH HoqJ+ acremonium CO 728 yielding the isopenicillin N analogue (189).12’ A new antibacterial penicillin containing a 2-a-methoxy group (190) has been prepared by enzymatic synthesis from the corresponding tripeptide (191).12* Further on in the sequence the ring expansion of penicillins to cephalosporins has been studied with respect to the side-chain specificity.Again the meta-carboxy analogue (189) was found to be an roH effective replacement for the natural D-a-aminoadipic acid side- chain to give (192).129 6.5 Transaminases A large-scale enzymatic synthesis of diastereomeric y-hydroxy- OH I L-glutamic acids has been carried out by transamination of cysteine sulphinic acid and DL-y-hydroxy-a-ketoglutaric acid using glutamic-oxaloacetic aminotransferase immobilized on activated polyacrylamide gel in 86 YOyield.Cysteine sulphinic HOe&04° ‘OH acid is used since the corresponding transamination product is 6H easily decomposed to pyruvic acid and sulphur dioxide thereby shifting the equilibrium.130 Isotopically labelled L-tyrosine (195) (labelled with either 13C or 15N or both) has been prepared in 80% yield and 95% e.e.using Escherichia coli aspartate transaminase. 131 A further investigation of the substrate A number of papers have appeared describing the use of specificity of the enzyme demonstrated that a number of a-keto glycosidases for the preparation of glycosides by reversing the acids could substitute for p-hydroxyphenylpyruvate to give the glycosidase activity. A problem with this approach is that the corresponding amino acids all with > 90 YOe.e. Since the E. coli equilibrium for the reaction lies towards the monosaccharide. enzyme has been cloned this provides a ready way of producing However it is easy to separate the product disaccharides from L-amino acids in high optical yield. Either aspartate or the monosaccharides by circulating a mixture of the reactants glutamate can act as amino donor.132 Phenylpyruvic acid can through an immobilized glycosidase column and an activated be converted into L-phenylalanine using a strain of Pseudornonas carbon column in series the latter to remove the synthesized fluorescens with high transaminase activity.The optimum disaccharides from the reaction medium. In this way the catalyst concentration was 1 YO(w/v) dry cells giving a 97% equilibrium can be displaced towards synthesis. Thus a solution conversion.133 of glucose (90% w/v) at 27 “Cfor 24 h in the presence of p-glucosidase from almond could be condensed to give a mixture of four glucose disaccharides the major component 6.6 Glycosyl Transferases and Glycosidases being gentiobiose. 135 Similarly lactulose and allolactulose Oligosaccharides are becoming increasingly recognized as were produced from the condensation of galactose and fructose a-D-Glucosyl-D-fructoseswere synthesized by having an important role in biological recognition processes.[l 1.3 YO~ield1.l~~ Their ability to carry biological information is due partly to the use of a reversed hydrolysis activity of a-glucosidase from a large number of different oligomers that can be formed from a species of Saccharomyces in a solution containing 10YOw/v of small number of monomers (e.g. three different hexoses can D-glucose and 100% w/v of D-fructose. With a simple batch combine to form 1056 different trisaccharides). From the method the major product was a-D-glucosyl-( 1 -+ 1)-D-fructose synthetic point of view the selective reaction of one hydroxyl (194) with smaller amounts of cc-(1-+4) (1-+5) and (146) group in the presence of many similarly reactive others presents linked Rather than simply reverse the glycosidase considerable problems.The ability of enzymes to carry out reaction in some cases it has been found to be effective to highly regioselective reactions suggests they will have a major transglycosylate using activated sugars as substrates for the impact in this field. glycosidases. Thus o-nitrophenylgalactose or lactose in the A method of preparing fructosyl disaccharides [e.g. (1 93) R presence of P-galactosidase and racemic 2,3-epoxypropanol = H or CH,X where X = 0-alkyl] has been described that gave 1 -0-P-D-galactopyranosyl 2,3-epoxypropanol (1 95) [28 Yo utilizes a fructosyltransferase isolated from Bacillus ~ubti1is.l~~ yield].13* NATURAL PRODUCT REPORTS 1989 0 0 II Kinase S’Nucleotidase OH OH (196) (197) 0-Fructose ,-* A N (200) (2011 6.7 Kinase/Phosphorylase Cytidine 5’-monophosphate-N-acetylneuraminicacid (CMP- The carbocyclic nucleoside 9-(2’-deoxy-2’-~-fluoro-~rubino-NANA) (201) has been enzymatically prepared from N-furanosyl) guanine (196) a potent new anti-herpetic agent has been enzymatically phosporylated using herpes simplex virus type 1 thymidine kinase to give the phosphorylated product (197) but with no enantioselectivity.However when racemic (197) was treated with 5’-nucleotidase from Crotalus atrox venom the product nucleoside (196) was found to be optically active although the enantioselectivity was not determined.139 7 Multi-enzyme Reactions 7.1 Preparation of Monosaccharides and Nucleosides 3-Deoxy-~-arabino-heptulosonic acid 7-phosphate (DAHP) (198) an intermediate on the shikimic acid pathway has been prepared from D-fructose using a multi-enzyme system [85Yo yield].DAHP (198) was then dephosphorylated with alkaline phosphatase and chemically converted in six steps into 3-deoxy-D-arabino-heptulosonicacid 7-phosphonate (1 99) a potential inhibitor of plant aromatic amino acid biosynthesis. 140 3-Deoxy-~-manno-2-octulsonate-8-phosphate (KDO-8-P) (200) an intermediate in the biosynthesis of the lipopoly- saccharide wall of Gram negative bacteria has been prepared from D-arabinose.Thus three enzymes (used in soluble form enclosed in a dialysis membrane) efficiently produced KDO-8-P (200) from D-arabinose and phosphoenol pyruvate. 141 acetylneuraminic acid (NANA) and cytidine 5’-triphosphate (CTP) using four immobilized enzymes on agarose. The conversions were achieved on 0.5 mmol scale with average 50-60%0 yield. The key step is the reaction of cytidine monophosphate (CMP) with two molecules of phospho- enolpyruvate to give CTP using pyruvate kinase and nucleoside monophosphokinase. 142 An alternative approach uses adenyl- ate kinase (E.C. 2.7.4.3) together with pyruvate kinase to convert a mixture of CMP and phosphoenolpyruvate into CTP in a yield of 74% (on a scale up to 5 g) after four days reaction at pH 8.CTP which is expensive relative to CMP is important in the biosynthesis of several nucleotide sugars e.g. CMP-NANA and CMP-KD0.143 7.2 Preparation of Oligosaccharides The trisaccharide Neu-5-Ac-a(2+6)Gal-P-( 1+4)GlcNAc (202) the terminal constituent of many N-linked glycoproteins (e.g. glycophorin a surface glycoprotein of erythrocytes) has been prepared from N-acetyl lactosamine and cytidine-5’-mono- phosphate-N-acetylneuraminicacid (CMP-NANA) (201) (in turn prepared from NANA and CTP) using a sialyl trans- fera~e.~~~ a-D-Glucose- 1-phosphate has been used as the starting point for the enzymatic preparation of branched penta- and hexa-saccharides associated with blood group 1 epitopes.145 NATURAL PRODUCT REPORTS 1989-N. J.TURNER A?0-P-0-P-OH ? I I OH OH (204) I (203) D-Glucose - HO ,-\OH - HA Me (205) (206) 7.3 Others The absolute configuration of 4-methyl juvenile hormone I (203) has been determined by enzymatic synthesis from dihomogeranyl diphosphate (204) using the sequence farnesyl diphosphate synthase alkaline phosphatase and Corpora allata organ culture (the insect organ responsible for juvenile organ production). 14' NADPH regeneration induced by visible light effects the production of glutamic acid which mediates transamination and formation of aspartic acid and alanine in the presence of enzymes. The method uses photogenerated N,N'-dimethyl4,4'-bipyridinium radical (methyl viologen MV") to mediate the formation of NADPH in the presence of the enzyme ferredoxin-NADP' reductase (E.C.1 .18.1.2).14' Treatment of D-glucose with Clostridium thermosaccharo-Iyticum resulted in formation of (28-hydroxypropanol (205) [82 % yield; > 99 YOe.e.1. Subsequent chemical steps converted (205) into (+)-(R)-methyloxirane (206) [88 YO yield > 99 YO e.e.1 on a multi-gram s~a1e.l~~ (+)-2-Aminobutyrate can be prepared from racemic threonine by treatment with threonine deaminase to give 2-ketobutyrate followed by treatment with transaminase C.14' 8 Novel Approaches to the Preparation of BiocataIysts 8.1 Catalytic Antibodies Several papers have appeared describing the use of antibodies to catalyse specific reactions. 150-153 The principle of this method is to generate an 'enzyme-like' active site that will bind tightly the transition state for the reaction and thereby catalyse the process.Several antibodies are raised to a stable mimic of the transition state and then screened to find the one with the best characteristics. Since antibodies can be produced against virtually any antigen with precise structural specificity this methodology may provide a general way for producing novel biological catalysts. Initial studies concentrated on catalysing hydrolytic reactions (e.g. hydrolysis of carbonates and esters). Recently Schultz has generated an antibody capable of catalysing the Claisen rearrangement of chorismic acid (207) to prephenic acid (208) a reaction carried out in nature by chorismate mutase. The thermal 3,3-sigmatropic rearrangement of chorismate to prephenate was postulated to proceed through an asymmetric chair transition state and thus the transition state analogue (209) had been synthesized and shown to be the most potent inhibitor of chorismate mutase with a K of 0.15 pM.One of co; co; I OH OH (207) (208) 0 co OR the antibodies raised against (209) was found to catalyse effectively the conversion of (207) to (208) with impressive kinetic parameters [kCat/ku,,,,= 1 x lo4 compared with 3 x 10' by chorismate mutase from Escherichia ~0li.l~~ 8.2 Modified Enzymes The ability to alter enzymes by site-directed mutagenesis to produce mutants with improved catalytic properties offers a powerful way of designing new catalysts for synthetic chemistry.An example of this is provided by the studies on the protease subtilisin where changes at position 166 in the substrate binding pocket have produced a number of enzymes with increased catalytic efficiencies towards substrates that are less reactive with the wild-type enzyme. 155 In another example aspartate aminotransferase from Escherichiu coli has been engineered such that cationic amino acids (e.g. L-lysine and L-arginine) are better substrates for the mutant enzyme than are the natural substrates L-aspartate and L-glutamate. 15' By replacement of asparagine residues at the subunit interfaces of the dimeric enzyme yeast triosephosphate isomerase with other amino acids more resistant to heat-induced deterioration the thermal stability of the protein has been increased.Thus the replacement of Asn-14 by Thr-14 and Asn-78 by Ile-78 nearly doubled the half-life of the enzyme at 100 "C and pH 6.15' An alternative approach to producing novel catalysts makes use of existing enzymes which are then covalently modified to produce the desirable characteristics. For example the relatively non-specific single-stranded deoxyribonuclease staphylococcal nuclease (DNase) has been selectively fused to an oligo-nucleotide binding site of defined sequence to generate a hybrid enzyme. The resulting hybrid enzyme cleaved single-stranded DNA at sites adjacent to the oligonucleotide binding site with greater selectivity of hydrolysis. 15* 9 Conclusions The aim of this review has been twofold (a) primarily to provide a state-of-the-art report on those biotransformations currently finding use in academic and industrial laboratories and (b) to identify those areas in which enzymes are beginning to have a positive impact and will continue to do so in the future.In category (a) the hydrolases and oxidoreductases continue to dominate their range of reactions now being extended by the use of organic solvents as the reaction medium. Within category (b) certain groups of enzymes are emerging especially lyases (e.g. aldolases for carbon-carbon bond formation) hydroxylases capable of effecting remote functional- ization kinases for the preparation of biologically important phosphates and glycosyl transferases/glycosidases to overcome the inherent difficulties of selective chemical glycosidation methods.10 References I J. B. Jones Tetrahedron 1986,42 3351. 2 S. Butt and S. M. Roberts Nut. Prod. Rep. 1986 3 489. 3 A. Akiyama M. D. Bednarski M.-J. Kim E. S. Simon H. Wald- mann and G. M. Whitesides Chem. Br. 1987 23 645 4 ‘Enzymes as Catalysts in Organic Synthesis,’ ed. M. P. Schneider Reidel Publishing Co. Dordrecht Holland 1986. 5 S. Butt and S. M. Roberts Chem. Br. 1987 23 127. 6 M. A. Mehaia and M. Cheryan Appl. Biochem. Biotechnol. 1987 14 21. 7 T. Komori N. Muramatsu and T. Kondo Appl. Biochem. Bio- technol. 1987 14 29. 8 A. Ajima K. Takahashi A. Matsushima Y. Saito and Y. Inada Biotechnol. Lett. 1986 8 547; Y. 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Chem. 1986 14 176. 19 K. Adachi S. Kobayashi and M. Ohno Chimia 1986 40,31 1. 20 D. Breitgoff K. Laumen and M. P. Schneider J. Chem. SOC. Chem. Commun. 1986 1523. 21 H. Suemune Y. Mizuhara H. Akita and K. Sakai Chem. Pharm. Bull. 1986 34 3440. 22 L. K. P. Lam C. M. Brown B. De Jeso L. Lym E. J. Toone and J. B. Jones J. Am. Chem. SOC. 1988 110,4409. 23 L. K. P. Lam and J. B,Jones J. Org. Chem. 1988 53 2637. 24 P. Mohr N. Waespe-SarEevib C. Tamm K. Gawronska and J. G. Gawronski Helv. Chim. Acta 1983 66 2501.25 G. Bold S. Chao R. Bhide S.-H. Wu D. V. Patel and C. J. Sih Tetrahedron Lett. 1987 28 1973. 26 S. Ramaswamy R. A. H. F. Hui and J. B. Jones J. Chem. SOC. Chem. Commun. 1986 1545. 27 B. I. Glanzer K. Faber and H. Griengl Tetrahedron 1987 43 5791. 28 C. Chan P. B. Cox,and S. M. Roberts J. Chem. SOC. Chem. Commun. 1988,971 ;note that the compound 13(S)-hydroxy-92 11E-octadecadienoic acid has previously been prepared by reduction of the corresponding ketone with yeast; H. Suemune N. Hayashi K. Funakoshi H. Akita T. Oishi and K. Sakai Chem. Pharm. Bull. 1985 33 2168. 29 D. H. G. Crout V. S. B. Gandet K. Laumen and M. P. Sch- neider J. Chem. SOC. Chem. Commun. 1986 808. 30 N. W. Alcock D. H. G. Crout C. M. Henderson and S. E. Thomas J.Chem. SOC.,Chem. Commun. 1988 746. 31 G. Eichberger G. Penn G. Faber and H. Griengl Tetrahedron Lett. 1986 27 2843. 32 H. Ohta Y. Kato and G.-I. Tsuchihashi Chem. Lett. 1986 217. 33 K. Laumen and M. P. Schneider J. Chem. Soc. Chem. Commun. 1988 598. 34 Z.-F. Xie I. Nakamura H. Suemune and K. Sakai J. Chem. SOC. Chem. Commun. 1988 966. 35 L. Blanco E. Guibe-Jampel and G. Rousseau Tetrahedron Lett. 1988 29 1915. 36 G. Fulling and C. J. Sih J. Am. Chem. SOC. 1987 109 2845. 37 H. M. Sweers and C.-H. Wong J. Am. Chem. SOC.,1986 108 642I. 38 M. Kloosterman E. W. J. Mosmuller H. E. Schoemaker and E. M. Meijer Tetrahedron Lett. 1987 28 2989. 39 J. Zemek S. Kucar and D. Anderle Collect. Czech. Chem. Commun. 1987 52 2347. 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Boltansky and T. Bravdo Tetra-hedron Lett. 1987 28 5367. 50 K. Yamamoto T. Nishioka J. Oda and Y. Yamamoto Tetra-hedron Lett. 1988 29 1717. 51 G. Gil E. Ferre A. Meou J. Le Petit and C. Triantaphylides Tetrahedron Lett. 1987 28 1647. 52 P. E. Sonnet J. Org. Chem. 1987 52 3477. 53 W. Kullman ‘Enzymatic Peptide Synthesis,’ CRC Press Boca Raton 1987. 54 J. B. West and C.-H. Wong Tetrahedron Lett. 1987 28 1629; J. R. Matos J. B. West and C.-H. Wong Biotechnol. Lett. 1987 9 233.55 A. L. Margolin and A. M. Klibanov J. Am. Chem. SOC. 1987 109 3802; A. M. Klibanov Chem. Technol. 1986 6 354. 56 C. F. Barbas and C.-H. Wong J. Chem. SOC. Chem. Commun. 1987 533. 57 K. Sakina K. Kawazura and K. Morihara Agric. Biol. Chem. 1987 51 1717. 58 A. Ferjancic A. Puigserver and H. Gaertner Biotechnol. Lett. 1988 10 101. 59 R. P. Taylor J. B. Vatz and R. Lumry Biochemistry 1973 12 2933. 60 J. B. West and C.-H. Wong J. Chem. SOC. Chem. Commun. 1986 417. 61 A. Zaks and A. M. Klibanov J. Am. Chem. SOC. 1986,108,2767. 62 A. Belan J. Bolte A. Fauve J. G. Gourcy and H. Veschambre J. Org. Chem. 1987 52 256. 63 E. Keinan E. K. Hafeli K. K. Seth and R. Lamed J. Am. Chem. SOC.,1986 108 162. 64 T. Fujisawa H. Hayashi and Y.Kishioka Chem. Lett. 1987 129. 65 L. 0.Zamir F. Sauriol and C.-D. Nguyen Tetrahedron Lett. 1987 28 3059. 66 G. Fronza C. Fuganti P. Grasselli and S. Servi J. Org. Chem. 1987 52 2086. 67 L. G. Lee and G. M. Whitesides J. Org. Chem. 1986 51 25; cofactor regeneration was achieved with formate dehydrogenase using formate as the ultimate hydride donor Z. Shaked and G. M. Whitesides J. Am. Chem. SOC., 1980 102 7104. 68 C.-Q. Han D. DiTullio Y.-F. Wang and C. J. Sih J. Org. Chem. 1986 51 1253. 69 G. Guanti L. Banfi and E. Narisano Tetrahedron Lett. 1986.27 3547. 70 J. Ouazzani-Chahdi D. Buisson and R. Azerad Tetrahedron Lett. 1987 28 1109. 71 J. d’Angelo G. Revial R. Azerad and D. Buisson J. Org. Chem. 1986 51 40. 72 C. J.Sih and C.-S. Chen Angew. Chem. Int. Ed. Engl. 1984 23 570; see also D. Seebach P. Renaud W. B. Schweizer and M. F. Ziiger and M.-J. Brienne Helv. Chim. Acta 1984 67 1843 73 J. Ehrler F. Giovannini B. Lamatsch and D. Seebach Chimia 1986 40,172. 74 K. Mori and H. Kisida Tetrahedron 1986,42,5281; for the use of 3(R)-hydroxybutyric acid in the synthesis of I,&methylcarbapenem antibiotics see T. Iimori and M. Shibasaki Tetrahedron Lett. 1986 27 2149. 75 P. Deshong M.-T. Lin and J. J. Perez Tetrahedron Lett. 1986 27 2091. 76 K. Nakamura T. Miyai K. Nozaki K. Ushio S. Oka and A. Ohno Tetrahedron Lett. 1986 27 3155. NATURAL PRODUCT REPORTS 1989-N. J. TURNER 77 D. Seebach and M. Eberle Synthesis 1986 37. 78 K. Ushio K. Inouye K.Nakamura S. Oka and A. Ohno Tetra-hedron Lett. 1986 27 2657. 79 M. Utaka H. Higashi and A. Takeda J. Chem. SOC. Chem. Commun. 1987 1368. 80 S. Tsuboi E. Nishiyama M. Utaka and A. Takeda Tetrahedron Lett. 1986 27 1915. 81 K. Mori and M. Ikunaka Tetrahedron 1987 43 45. 82 J. Cooper P. T. Gallagher and D. W. Knight J. Chem. Soc. Chem. Commun. 1988 509. 83 D. Buisson and R. Azerad Tetrahedron Lett. 1986 27,2631 ; for a synthetic use of a cyclohexane-cis-hydroxyester towards a partial synthesis of Avermectin A2 see A. G. M. Barrett and N. K. Capps Tetrahedron Lert. 1986 27 5571. 84 A. Fauve and H. Veschambre Tetrahedron Lett. 1987 28 5037. 85 D. Buisson S. El Baba and R. Azerad Tetrahedron Lett. 1986 27 4453. 86 S. Tsuboi H. Furutani and A.Takeda Bull. Chem. SOC. Jpn. 1987,60,833;R. Zamboni S. Milette and J. Rokach Tetrahedron Lett. 1983 24 4899. 87 J. Grunwald B. Wirz M. P. Scollar and A. M. Klibanov J. Am. Chem. SOC. 1986 108 6732. 88 M. Utaka S. Konishi T. Ukubo S. Tsuboi and A. Takeda Tetrahedron Lett. 1987 28 1447. 89 H. Simon H. White H. Lebertz and I. Thanos Angew. Chem. Int. Ed. Engl. 1987 26 785. 90 M. Utaka S. Konishi and A. Takeda Tetrahedron Lett. 1986 27 4737. 91 P. Gramatica P. Manitto D. Monti and G. Speranza Tetra-hedron 1988 44 1299. 92 P. Gramatica P. Manitto D. 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ISSN:0265-0568    

DOI:10.1039/NP9890600625

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Book Review The Dictionary of Alkaloids ed. I. Southon and J. Buckingham; 1989; Chapman & Hall London; 1834 pp. in 2 volumes; f675 (US $1 295 in North America) ; ISBN 0-41 2-2491 0-3 There are those who hold the view that the presence of nitrogen within an organic molecule introduces necessary spice and more challenging chemistry. Compounds containing nitrogen which are naturally occurring constitute the alkaloids which have diverse structure chemistry and biological activity. Until recently if one wanted to find information on alkaloids quickly one would refer to the Manske or the Pelletier series of reviews; for a dictionary one used R. A. Raffauf ‘A Handbook of Alkaloids and Alkaloid-containing Plants ’ which since it was published in 1970 is now seriously out of date.Following the introduction of the invaluable ‘Dictionary of Antibiotics’ Chapman and Hall have published a two volume ‘Dictionary of Alkaloids ’. This dictionary has the same format as ‘Dictionary of Antibiotics ’ and ‘Dictionary of Organic Compounds ’; both of the more specialist dictionaries are ultimately based on the last-named dictionary. ‘Dictionary of Alkaloids ’ documents the whole multitude of alkaloids of known structure to the end of 1987. In compiling the listing the editors have sensibly used the widest of definition for an ‘alkaloid ’ and nitrogenous compounds of animal and mi- crobial origin as well as of the more orthodox plant origin are included to make this a most informative and impressively comprehensive dictionary.Inevitably some compounds appear in both this dictionary and the one on antibiotics (‘tuberin’ in one is incidentally quite a different compound to ‘tuberine ’ in the other). The listing of alkaloids is alphabetical from ‘aaptamine’ on page 1 to ‘zygosporin G’ on page 1161. The entries under a particular name include alternative trivial names CAS names and archaic names which as the editors say means that you must use the name index $a particular name for an alkaloid does not appear in the alphabetical listing. (I have found this to be true for e.g. harman and eleagnine.) Physical data biological activity structure with stereochemical detail (absolute stereochemistry where known is listed) and a very useful and careful selection of references (which includes publications on biosynthesis) constitutes each entry in a clear and detailed way.I noted the absence in a few cases of up-to-date references to biosynthesis so one should look elsewhere also (there is a much smaller book which is on biosynthesis and is also published by Chapman and Hall now in second edition -the author’s name escapes me). The listing in the main body of the work which constitutes most of the first volume is supported by a second volume which contains five different indexes for name molecular formula CAS registry number species (invaluable) and type of compound. This last index is not alphabetical and needs to be used in conjunction with a ‘Description of Main Alkaloid Types’ which is done in a masterly way and which includes extra references to reviews and books.This assignment of alkaloids to groups though heavily underpinned by biosynthetic knowledge is because of lack of such knowledge in many cases very properly based more on structural relationships than biosynthesis. I noted three small errors (on pp. xx and xxi) the benzylisoquinoline precursor from which Erythrina alkaloids are derived is not formed from an N,N-bis(2-arylethy1)amine; similarly cryptostyline-I ; cephalotaxine alkaloids are phenethylisoquinolines rather than benzylisoquinolines. If one may ask for more than five indexes I would like to be able to do a sub-structure search on a computer data base. In the mean time I will continue to browse through the many pages of this dictionary turning up new and interesting structures. In truth there is much more variety in the ‘Dictionary of Antibiotics’ but this is chiefly due to the profligacy of Streptomyces species. The editors say in their preface ‘In setting out to compile this Dictionary we have had the simple aim of including accurate and critical data on every known alkaloid...the number of alkaloids contained in this Dictionary (9900_+ 100) considerably exceeds any previous informal estimate of the number of known alkaloids’. I think the editors and their advisers have succeeded very handsomely in their aim. This is a very valuable work. It is (of course) very expensive but the cost per alkaloid is a mere 6.82 f0.07 p. R. B. Herbert 645

ISSN:0265-0568    

DOI:10.1039/NP9890600645

出版商:RSC    

年代:1989

数据来源: RSC