摘要:

ISSN 0265-0568 NPRRDF 6 (3) 221-309 (1989) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 6 Number 3 CONTENTS 221 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1986 and June 1987 231 Fatty Acids and Glycerides M. S. F. Lie Ken Jie Reviewing the literature published during 1986 and 1987 263 The Biosynthesis of Shikimate Metabolites P. M. Dewick Reviewing the literature published during I987 291 Limonene A. F. Thomas and Y. Bessiere Cumulative Contents of Volume 6 Number 1 1 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 to 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 11 1 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 Articles that will appear in forthcoming issues include Enzyme Inhibitors in Medicine (to December 1987) C.S. J. Walpole and R. Wrigglesworth Diterpenoids (1987) J. R. Hanson Carotenoids and Polyterpenoids (1986 and 1987) G. Britton Triterpenoids (July 1985 to December 1987) J. D. Connolly and R. A. Hill Muscarine Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1986 to June 1987) J. R.Lewis Steroids Physical Methods (mid 1985 to December 1987) D. N. Kirk 8-Phenylethylamines and the Isoquinoline Alkaloids (July 1987 to June 1988) K. W. Bentley Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July 1987 to June 1988) J. E. Saxton Indolizidine and Quinolizidine Alkaloids (July 1985 to June 1987) M. F. Grundon Steroids Reactions and Partial Syntheses (November 1986 to October 1987) A. B. Turner Pyrrolidine Piperidine and Pyridine Alkaloids (July 1987 to June 1988) A. R. Pinder Recent Advances in the Use of Enzyme-catalysed Reactions in Organic Synthesis (January 1986 to June 1988) N. J. Turner Professor M. F. Grundon We are sad to announce that Professor M. F. Grundon of the University of Ulster at Coleraine a member of the Editorial Board of this journal died suddenly on March 20th this year.

ISSN:0265-0568    

DOI:10.1039/NP98906FP005

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine 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 Burlington House London W1 V OBN 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 lHN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. Second-Class postage paid at Jamaica NY 11431 -9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 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 f 1 94.00 U.S.A. US $388.00 Subscription rates for back issues are U.K. (1984) f1 20.00 (1985) f125.00 (1986) f130.00 (1987) f142.00 (1988) f1 59.00 Overseas f1 26.00 f131.OO f143.00 f1 59.00 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/NP98906FX009

出版商:RSC    

年代:1989

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP98906BX011

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 Glasgow G 12 800 ~~ Reviewing the literature published between July 1986 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 577) 1 The Synthesis of Necines Intramolecular alkylation of the chloro-ester (3) afforded the 2 The Synthesis of Necic Acids thermodynamically more stable pyrrolizidine ester (4) in 86 YO 3 The Synthesis of Macrocyclic Pyrrolizidine Alkaloids yield. The conversion of this ester into (f)-trachelanthamidine and Analogues (5) has been reported.2 When the ester (3) was treated with 4 Alkaloids of the Boraginaceae excess base the enolate (6) could be trapped with phenyl- 5 Alkaloids of the Compositae selenenyl chloride to give approximately equal amounts of the 6 Alkaloids of the Gramineae two diastereoisomeric selenides (7) in 36% yield.After the 7 Alkaloids of the Leguminosae isomers had been separated they were each converted (by syn-8 Alkaloids of the Scrophulariaceae elimination of the corresponding selenoxides) into (f)-9 Alkaloids in Streptomyces supinidine (9) and (+)-isoretronecanol 10 Alkaloids in Animals The key intermediate in the first synthesis4 of the most 11 General Studies common pyrrolizidine base retronecine (12) is now known as 12 Pharmacological and Biological Studies the Geissman-Waiss lactone (1 1). Enantioselective routes to 13 References this lactone have recently been reported from 4-hydroxy-~- pr~line,~.~~ from diethyl from carbohydrate prec~r~~r~,~~~~~~*-~ (+)-tartrate,8b~10 and from (S)-malic A very different route to an N-protected form (15) of the Geissman-Waiss 1 The Synthesis of Necines lactone from (+)-(R)-malic acid (13) has been developed by Kametani and co-workers have used aziridine in their synthesis Niwa Yamada and co-workers (Scheme 2).12 ( +)-(R)-Malic of the known pyrrolizidine esters (4) and (€9,which can be acid (13) was converted in one pot into the imide (14) in 99 YO converted into (& )-trachelanthamidine (9,(& )-suphidine (9) yield.Hydrolysis of the acetate (14) and re-esterification and (+)-isoretronecanol (lO).l Michael addition of aziridine to produced the bromoacetoxy-imide (1 5). Intramolecular Wittig the @-unsaturated ester (1) led to the pyrrolidine ester (3) in reaction on this imide afforded the conjugated lactone (16).The 72% yield probably via the aziridinium salt (2) (Scheme 1). double-bond in the lactone (16) was hydrogenated and selective CI-CHO COzEt i ii ~ CI-CH2OH C02 Et (5) (4) lii v' + 4 4" Reagents i (EtO),POCH,CO,Et NaH ;ii aziridine heat; iii Pr',NH Bu"Li ;iv LiAlH ;v PhSeCl ; vi m-ClC,H,CO,H Scheme 1 221 222 0 11 reduction of the lactam carbonyl group was achieved via the thiolactam to yield the desired lactone (17). The overall yield of the lactone (1 7) from (+)-(R)-malic acid was 62 YO, and this lactone can be converted into (+)-retronecine (12) in ca. 50% yield.I3 A very similar but lower-yielding route was used by the same workers to prepare the protected lactone (18) (Scheme 3).14 This lactone was converted into the phenylselenide (19) which was cyclized under carefully controlled conditions to the phenylselenopyrrolizidine (20).Reduction of the lactone fol- lowed by oxidation and thermal elimination of the selenoxide gave (+)-retronecine (12). The overall yield of retronecine was 5.5% from (+)-(R)-malic acid (13) and it was required for a synthesis of the macrocyclic pyrrolizidine alkaloid ( -)-integerrimine (see Section 3). Loline (30) is a representative of a small class of seven related alkaloids that have been be isolated from Lolium cuneatum and Festuca ar~ndinacea.'~ The formation of the unusual ring system in loline was reported previously.66*'6 In earlier work Tufariello and co-workers made use of nitrone intermediates such as the compound (21) to prepare supinidine (9)l' and retronecine ( 12).6C,1a They have now developed this strategy into a long-awaited first synthesis of loline (30) and norloline (31).19 The pyrrolizidine ester (23) which was used in the synthesis of retronecine was prepared from the nitrone (21) and methyl 4-hydroxycrotonate (22) (Scheme 4).It was necessary first to invert the configuration at C-1 of the ester (23). This was achieved with a base to give the thermo- dynamically more stable a-ester and .the free hydroxyl group .. NATURAL PRODUCT REPORTS 1989 was protected as the acetate (24). (This was carried out to avoid intramolecular transketalization when a ketone group was generated in a later step.) The methyl ester (24) was reduced and the diacetate (25) was formed.The ketone was then released and selectively reduced from the less hindered convex face of the pyrrolizidine to afford the alcohol (26). Replacement of the 7P-hydroxyl group in compound (26) by chlorine proceeded with inversion of configuration. Treatment of the resulting chloro-compound (27) with an alkoxide cleaved the acetates and promoted ring-closure to the desired loline ring system (28). The exocyclic carbon in the tricyclic compound (28) was then removed by a Curtius-type rearrangement to yield the carbamate (29). A final reduction step with lithium aluminium hydride gave ( & )-loline (30). Alternatively basic hydrolysis of the carbamate (29) afforded norloline (31).Nitrones have also been utilized by Lathbury and GallaghePo in a synthesis of the pyrrolizidine alkaloid that has been obtained from the thief ant Solenopsis xenoveneum. The key step in the synthesis of this alkaloid (36) shown in Scheme 5 was the cyclization of the (9-allenic oxime (32) to produce a 5-substituted nitrone (33) which was trapped with methyl vinyl ketone to give a mixture (34) of diastereoisomers. Hydro- genation of this mixture afforded the hydroxypyrrolizidine (35) by hydrogenation of the double-bond cleavage of the N-0 bond and intramolecular reductive amination. Removal of the hydroxyl group in compound (35) was achieved by Jones oxidation to a single ketonic product formation of the 1,3- dithiolane and desulphurization to yield the ant alkaloid (36).The sex pheromone danaidal (40) is produced by Danaid butterflies by degradation of the pyrrolizidine alkaloids they have obtained in their diet. A synthesis of danaidal has been reported by Roder et a1.21and is shown in Scheme 6. The unsaturated pyrrolizidine ester (37) was previously prepared by Leonard and Sato.22 The corresponding pyrrole ester (38) was formed by oxidation. (This ester can also be formed in one step by 1,3-dipolar cycloaddition of N-formylproline with ethyl pr~piolate.~~) Reduction of the ester (38) gave the hydroxy- methyl-pyrrole (39) and oxidation of the alcohol (39) produced danaidal (40). Reagents i AcCI; ii H,NCH,CO,Et; iii AcCl EtOH; iv BrCH,COBr pyridine; v Ph,P in MeCN then Et,N; vi H, 5% Rh/AI,O,; vii Lawesson's reagent at 105 "C; viii Et,O' BF then Na(CN)BH Scheme 2 0 iii-v _,-SePh vi vii -(13) -Go (20) Reagents i Pri,NH Bu"Li at -78 OC then PhSeC1; ii HCI; iii Bu"Li THF at -78 "C; iv TsCI; v Pri,NH Bu'ILi HMPA; vi LiAIH, THF at -10 "C; vii 30% H,O, AcOH Scheme 3 NATURAL PRODUCT REPORTS 1989-D.J. ROBINS Me0 OMe HOCH2 H '0-(211 (22) Me0 Me0 Me0 CH~OAC --OAc 1v.v --0Ac -H& (30) R = Me (31)R = H Reagents i NaOMe MeOH; ii acetylation; iii LiAlH,; iv CF,CO,H then Na,CO,; v H, PtO, AcOH; vi SOCI, DMF; vii Jones oxidation; viii EtOH. benzene H,SO,; ix N,H;H,O; x isoamyl nitrite HCl EtOH Scheme 4 OH 0-(32) 133) Reagents i. AgBF,; ii MeC(O)CH=CH,; iii H, PdCI, EtOH; iv Jones oxidation; v HSCH,CH,SH BF,.Et,O; vi Raney nickel Scheme 5 (37) (38) (39) Reagents i.S or MnO,; ii LiAIH,; iii MnO Scheme 6 NATURAL PRODUCT REPORTS 1989 ' "0'r;r-O COMe II 111 N-0 .. ... * Me3sio*oH Me,SiO &OSiMe3 + ~ Me (43) (44) iv-viii I H02C&C02 H H02C&C02H c--HO&C02Me Ix v (47) (46) (451 Reagents i heat at 150-165 "C; ii Ph,P=CH,; iii BH;Me,S; iv RuO,; v CH,N,; vi HF; vii H, Raney nickel boric acid; viii. aq. MeOH. boric acid; ix HIO,; x Ba(OH) Scheme 7 ii -iv -*OH OH OH -c5?-oAc (50) (48) (49) (511 vi vii HO& CH2-O-CO HO &;&i" H,fCHMe2 OH CHMe OH N' N' I Me I Me OH 0-0-(54) (53) (52) Reagents i Me,CHMgBr; ii PhCH,CI NaH DMF; iii AcOH-HCI; iv Ac,O pyridine; v NaBH, EtOH; vi NaIO, KMnO, Na,CO, in Bu'OH-H,O; vii H, 10% Pd/C MeOH ; viii 2,2-dimethoxypropane HCI ; ix (-)-retronecine ; x N,N'-dicyclohexylcarbodi-imide,4-(dimethy1amino)pyridine; xi HCI ; xii m-CIC,H,CO,H acetone Scheme 8 The diastereoisomeric acid (47) was formed in analogous 2 The Synthesis of Necic Acids fashion from the diastereoisomer of (45).Curran and Fenk24 have prepared crispatic acid (46) and a The first enantioselective synthesis of ( + )-trachelanthic acid A Grignard diastereoisomer (47).The route utilizes a cycloaddition reaction (52) has been reported by Nishimura et dZ5 as a means to generate a highly substituted P-hydroxy-ester (45) reaction on the ketofuranose (48)occurred stereospecifically to via the isoxazolines (43)and (44) (Scheme 7).The geometry of give the isopropyl derivative (49) (Scheme 8). The tertiary the alkene starting material (42) that is used in the cycloaddition hydroxyl group in (49) was protected and the product was process with the diene component (41) controls the relative hydrolysed and then acetylated to afford the protected stereochemistry at the two new chiral centres that form in the compound (50) as a mixture of anomers. Reduction of this isoxazoline (43). The additional carbon atom that was required mixture gave the selectively protected tetraol(51). The primary was introduced by a Wittig reaction and hydroboration of the hydroxyl group was oxidized to the corresponding acid and product produced the third chiral centre in the isoxazoline (44) removal of the protecting group yielded (+)-trachelanthic acid with no diastereoselectivity.(Subsequent use of 9-bora-(52). bicyclo[3.3. llnonane in the hydroboration step gave only one This acid was used in a synthesis of the enantiomer (53) of ( -)-Retronecine (synthesized previously by diastereoisomer albeit in low yield. This isomer could be indicine N-o~ide.~~ converted into the diastereoisomer (47) of crispatic acid.) The these workers9) was coupled with the acetonide of (+)-alcohol (44) was oxidized to the corresponding acid and trachelanthic acid (52). The product was treated with acid to methylated. Desilylation and hydrogenolysis of the N-0 bond afford (-)-indicine and this was converted into the N-oxide led to the keto-ester (45) and a diastereoisomer via an (53).(+)-Indicine N-oxide is the first pyrrolizidine alkaloid to intermediate /3-hydroxy-imine (from n.m.r. evidence). The be selected for clinical trials as an anti-cancer agent. Intermedine diastereoisomers were separated chromatographically and one N-oxide (54)was made in a similar fashion from (+)-retro- isomer (45) was converted into crispatic acid (46)by oxidative necine (12).25 cleavage methylation of the product and alkaline hydrolysis. In an extension of previous work,8d Drewes and co-workers NATURAL PRODUCT REPORTS 1989-D. J. ROBINS 225 (55) (56) -OH COZH C02 H (61) wOCHzSMe \ COzH COzH . (62) Reagents i. Bu'OOH diethyl (+)-tartrate. (Pr'O),Ti; ii Me,AI; iii 3.5-dinitrobenzoyl chloride.pyridine; iv RuO,; v p-MeC,H,SO,,H (catalytic); vi NaOMe. MeOH ;vii. CH,N,; viii Pr',NH Bu"Li CH,,CHO; ix. MeSO,CI pyridine; x I .8-diazabicyclo[5.4.O]undec-7-ene; xi MeSCH,CI xii KOH MeOH Scheme 9 0 HO SEMO SEMO 0 vi. vii viii-xi I-IV iii LCOCH3 (& k+OzMe I I I I I 1 (63) (66) AcO wOSiButMe2 c-xv. xvi xiii. xiv \ Y-Lf--LiOiyfi COz [CH212SiMe3 XVIl -xx 0hC02H COZH (70) (69 (68) (71 (SEM = CHzOCH2CH2SiMe3) Reagents i Me,,SiCH,CH,OCH,CI Pr',NEt; ii. LiAIH,; iii ClC(OJC(O)Cl Me,SO at -78 "C then Et,,N; iv. MeMgBr; v. H,C=CHMgBr at -78 "C; vi Bu,NF HMPA at 100 OC; vii N.N'-carbonyldi-imidazole,at 90 "C; viii MeONa MeOH; ix. p-MeC,H,SO:,H pyridine; x. NaI. butan-2-one; xi Ac,O 4-(dimethy1amino)pyridine; xii Pr',NH Bu"Li at -78 "C; xiii CH,,CHO; xiv Ac,O.Et,,N catalytic 4-(dimethy1amino)pyridine; xv. catalytic RuCl:, NaIO ; xvi 1.8-diazabicyclo[5.4.O]undec-7-ene;xvii Me,SiCH,CH,OH. 2-chloro-I -methyl-pyridinium iodide Et:,N; xviii LiOH H,O, aq. THF; xix Bu'Me,SiOSO,CF,, 2,6-lutidine; xx AcOH-THF-H,O (3 3 1) Scheme 10 have prepared several allylic functionalized acrylate derivatives series of transformations was used to convert the lactone ester which could be useful for the formation of necic acids.26 (60) into the protected form (62) that was required for the Yamada and co-workers2' have synthesized a protected form synthesis of (-)-integerrimhe (75). of (+)-integerrinecic acid (61) for use in their preparation of The lactone (70) of integerrinecic acid was also prepared in (-)-integerrimine (75) [discussed in Section 31.The allylic optically active form by White and Ohira by a lengthy route alcohol (55)was subjected to Sharpless asymmetric epoxidation from methyl (-)-(R)-3-hydroxy-2-methylpropionate(63) as to give the (-)-epoxy-alcohol (56) with 96 % enantiomeric outlined in Scheme 10.29Chelation-controlled Grignard re-excess (Scheme 9). Regioselective ring-opening of the epoxide action of the ketone (64) with vinylmagnesium bromide took gave a 1,2-diol which was selectively protected. Oxidative place to give a 4 I mixture of the desired alcohol (65) and a cleavage of the double-bond in (57) led to the lactone (58) diastereoisomer. These isomers were separated by h.p.1.c. as which was converted into the methyl ester (59).(+)-Integer-their cyclic carbonates which were formed after the protecting rinecic acid lactone methyl ester (60) was formed by a group had been removed. The major isomer (66) was converted modification of a route reported for the racemic material.'" 2H into the iodoacetate (67) via the tosylate. Condensation of the Since the conversion of this ester (60) into integerrinecic acid enolate (68) with acetaldehyde yielded a hydroxy-acid which is also a known procedure,6d.2a this constitutes the first was protected as the acetate (69). Oxidative cleavage of the enantioselective route to (+)-integerrinecic acid (61). A further vinyl group followed by base-catalysed elimination gave only HO COzH ' (62) iii (74) (75) Reagents i Bu,SnO ii dicyclohexylcarbodi-imide; iii benzene at 0 "C to room temperature 3 hours; iv 2,4,6-trichlorobenzoyl chloride Et,N.then slow addition to toluene containing 4-(dimethylamino)pyridine heat at reflux for 2 hours; v triphenylcarbenium tetrafluoroborate Scheme 11 the (0-isomer (integerrinecic acid lactone) (70). For the synthesis of integerrimine (75) that is described in Section 3 the lactone acid was selectively protected as (71). 3 The Synthesis of Macrocyclic Pyrrolizidine Alkaloids and Analogues (_+ )-Integerrimhe (75) was first synthesized by Narasaka el 30 Two syntheses of this twelve-membered macrocyclic ~1.~~4 dilactone in optically active form have now appeared ;the two esterification reactions were carried out in different orders. For the route of Niwa Yamada and co-workers,Y1 shown in Scheme 11 the syntheses of (+)-retronecine (12) and (+)-wOSiButMe2 \ COzCHzCH Si Me HO CHzOSiBu'Mez \HI (76) NATURAL PRODUCT REPORTS 1989 intcgerrinecic acid in a protected form (62) were described in previous Sections.(+)-Retronecine was converted into the cyclic stannoxane (72). and this underwent regioselective monoesterification with the cyclic anhydride (73) in almost quantitative yield when the two compounds were mixed. Lactonization of the monoester (74) was carried out in 75% yield vicr the mixed anhydride with 2,4,6-trichlorobenzoyl chloride followed by heating at reflux at high dilution in toluene. A deprotection step afforded ( -)-integerrimine (75)in 81 YOyield. The second synthesis of ( -)-integerrimhe (79 due to White and Ohira is outlined in Scheme 12.29 (+)-Retronecine (12) which was obtained by hydrolysis of monocrotaline was selectively protected to give the silyl ether (76).Esterification of the sterically hindered secondary alcohol (76) with the acid (71) (see Section 2) required vigorous conditions to produce the ester (77) in 51 YOyield. The silyl ether protecting group was removed and replaced by a mesylate. Cleavage of the silyl ester resulted in a spontaneous intramolecular displacement to give a dilactone which yielded (-)-integerrimhe (75) on de-protection. . It is somewhat surprising that all syntheses of twelve-membered pyrrolizidine alkaloids have been confined to integerrimine (75).Attention should now be directed towards the many other known twelve-membered pyrrolizidine alka- loids. In a continuation of their work on the preparation of analogues of macrocyclic pyrrolizidine alkaloids Robins and co-workers have made the dimethyl- 1,2-didehydrocrotalanines (78) and (79) (Scheme 13).32 Treatment of (+)-retronecine (12) with meso-2,4-dimethylglutaric anhydride followed by lacton- ization via the pyridine-2-thiolesters gave the two macrocyclic products (78) and (79) which were separated by column chromatography. The absolute configuration of the acid portion in each analogue was established by a sequence of two selective reactions. Hydrogenolysis of the allylic ester followed by reduction of the remaining ester in the presence of the carboxylic acid gave the optically active pyran-2-ones (80) and (81).An X-ray crystal structure analysis of the (12S I4R)-isomer (78) showed that the ester carbonyl groups are syn-parallel and directed in the same direction (a) as 8-H. This is the usual arrangement of the ester groups in eleven-membered macro- cyclic diesters of (+)-retronecine. 4 Alkaloids of the Boraginaceae Flowers of borage (Borago oficinalis L.) are used medicinally and in salads and beverages. The only alkaloid found in the flowers was thesinine (82) which is the trans-p-hydroxy-cinnamate ester of (+)-isoretronecanol This has been found only once previously in Thesiumminkwitzianum. 34 Seeds of B. oficinalis also contained thesinine (82) and a small amount of amabiline (84).Leaves of borage were previously shown to contain lycopsamine (85).35 Pyrrolizidine alkaloids C02CH CH SiMe3 -(75) H CHzOSiButMez iv-vii I l a N Reagents i (EtO),P(O)Cl Et,N; ii Bu"Li; iii catalytic 4-(dimethylamino)pyridine; iv NH,F MeOH at 60 "C;v MeSO,Cl Et,N at 0 "C; vi Bu,NF MeCN; vii aq. HF MeCN Scheme 12 NATURAL PRODUCT REPORTS 19%)-D. J. ROBINS ii + (78) (79) li li Iii /ii (80) (811 Reagents i 2,2'-dithiodipyridine Ph,P; ii H, PtO, AcOH ; iii LiBH Scheme 13 0 ct 2-o-c& HO H HO-tCHMe2 N -Me (84) R = H 0 (82) R = -CCH&CH G O H (85) R =OH " (83)R = kC=O :z*EHMez Me with 1,2-unsaturation [as in (84) and (85)] are generally hepa to toxic. Cynaus t rali ne (83) is present in Cynoglossum zeylunicum.'sf' Heliotrine lasiocarpine and europine were isolated from Heliotropium merjfblium Retz. together with small amounts of the N-oxides of lasiocarpine and indi~ine.~' Heliotrine lasio- carpine europine and supinine were present in H.hirsutissimum Grar~er.~~ The major alkaloid of H. rumosissimum is probably heliotrine as previously Alkaloids were detected in tissue cultures of H. merfi~lium.~" (86) (87) 11 +.NH (881 5 Alkaloids of the Compositae The occurrence of pyrrolizidine alkaloids in Japanese members of the Compositae and their biological activities have been reviewed.41 Senkirkine has been isolated from aerial parts of Chersodoma jodopappa (Sch. Bip.) Cabr.42 This is the first report of alkaloids from this genus of the Tribe Senecioneae.Senkirkine and doronine were present in aerial parts of Emilia sonchifolia (L.) DC.43 The constituents of a number of species of Senecio are shown in Table 1 with major components listed fir~t.~~-~~ It should be noted that flowers of S. grisebachii are commonly used to make herbal teas although retrorsine is known to be hepatotoxic. Root cultures of S. vulgaris accumulated pyrrolizidine alkaloids almost entirely as their N-0~ides.j~ These compounds did not appear to undergo significant turnover. This illustrates the importance of allowing for the presence of N-oxides when extracting pyrrolizidine alkaloids from plants. Cell suspension cultures of plants which produce pyrrolizidine alkaloids are able to take up the N-oxides whereas plants that do not produce these alkaloids are not able to take up these N-It has been suggested that the N-oxides of pyrrolizidine alkaloids may be formed for ease of translocation and storage in the plant (perhaps for defensive purposes).6 Alkaloids of the Gramineae Impaired performance by animals feeding on pastures of tall fescue (Festuca arundinacea) is associated with a fungal endophyte Acremonium coenophiulum. N-Formyl-loline (30; R = CHO) and N-acetyl-loline (30; R = Ac) occur in tall fescue which is infected with this endophyte.j5 7 Alkaloids of the Leguminosae Concentrations of pyrrolizidine alkaloids were measured in seeds of 35 species of Crotularia. The highest concentration was found in C.spectubifis.56Monocrotaline was present in seeds of C. ussumicu Benth. (2.9%) and C. calycina Schrank (0.9%).j7 8 Alkaloids of the Scrophulariaceae Pyrrolizidine alkaloids were found in CustilltJjurhe.uijbliu and some populations of C. sulphureu (others contained quinoliz- idine alkaloids or no alkaloids).5" 9 Alkaloids in Streptomyces Clazamycins were first isolated from Streptomyces puniceus in 1977. They possess anti-tumour activity. In aqueous solution clazamycin exists as a mixture of two diastereoisomers (86) and (88) with the former predominating at neutral pH. Studies NATURAL PRODUCT REPORTS 1989 Table 1 Pyrrolizidine alkaloids in Senecio species Species Pyrrolizidine alkaloids Ref. S. argentinus Baker uspallatine senecionine 44 S.fdaginoides (H. et A.) DC. retrorsine senecionine 44 S. seratophiloides Griseb. retrorsine senecionine uspallatine senecivernine usaramine 44 S. leucostachys Baker uspallatine senecionine integerrimine 44 S. ragonesei Cabr. senecionine retrorsine integerrimine 44 S. gilliesianus senecionine retrorsine 44,45 S. vira-vira Hieron uspallatine anacrotine neoplatyphylline 46 S. phillipicus Rogel et Koern retrorsine seneciphylline 47 S. illinitus Phil. senkirkine acetylsenkirkine senecionine 47 S.sjdvaticus L. triangularine sarracine 7-O-angelylretronecine 48 S. Ieptolobus neosenkirkine 49 S. pseudo-orien t alis Schi schk in retronecine platyphylline retrorsine riddelline jacoline 50 S..fuberi 'squalidine' (=integerrimine) platyphylline 51 S.grisebachii retrorsine 52 I I1 Me0 Me0 OMe OAc OMe OAc (94) JL(.iii fi p-0 ix-I \ (95) (96) Reagents i. propylene oxide; ii Ac,O; iii Br, MeOH K,CO,,; iv H, Rh/AI,O,; v 50% AcOH ; 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride. Et,,N ; vii H,O,; viii NH,OAc Na(CN)BH,, MeOH; ix KSeCN Scheme 14 using 'H n.m.r. spectroscopy have indicated that inter-The major alkaloidal component extracted from the ant conversion of the diastereoisomers occurs viu the azacyclo- Cheluner unturcticus White was identified as the pyrrolizidine octenone species (87) rather than an iminium ion.59 (96) by spectroscopic analysis ('H n.m.r. and mass spectro-metry) of the 1 mg that was obtained.61 The structure was confirmed by the synthesis outlined in Scheme 14.61Oxidative 10 Alkaloids in Animals methoxylation of the furan (89) gave a mixture (90) of isomers.Pyrrolizidine alkaloids are ingested by a number of species of Selective hydrogenation of the double-bond in (90) (avoiding Lepidoptera. The alkaloids may then be used for defensive hydrogenolysis of the methoxy-groups) was achieved with purposes or metabolized to form pheromones. This absorbing rhodium on alumina. Hydrolysis of the product (91) yielded an area has been reviewed by Schneider.60 unstable mixture of (%a) and (92 b) which was condensed with NATURAL PRODUCT REPORTS 1989-D. J. ROBINS 229 contamination of cereal grains; deliberate use of plants that contain pyrrolizidine alkaloids as herbal preparations (e.g.comfrey6’); and through normal food chains (e.g. milk from animals that have grazed on plants which contain these alkaloids). Some animals are particularly susceptible to poisoning by --OH pyrrolizidine alkaloids. Four horses died after 20 had inadver- tently ingested alfalfa that was contaminated with Senecio vulgarzs.68 Out of 77 Holstein calves that were poisoned by (97) (98) Echium plantagineum 28 died.69 The rumen plays a protec- tive role in the natural resistance of sheep to pyrrolizidine alkaloids.70 Microsomal oxidation of pyrrolizidine alkaloids in which there is 1,2-unsaturation in the necine component produces pyrroles which are the toxic rnetabolite~.~~~’~ The dihydro- pyrrolizine (98) was the main metabolite when alkaloids from Senecio jacobaea were incubated with rat liver micro some^.^^ Lasiocarpine showed the highest rate of formation of pyrroles whereas monocrotaline displayed the lowest with rat micro- some~.~~ The effects of phenobarbital’j and of 2-t-butyl-4- yCHO hydro~yanisole~~ the production of pyrrolic metabolites on OH S ii RO CH2OCH2CH2CNH2 \HI N (101) R = H S II (102) R = CH2CHZCNHZ the enone (93) to afford the trione (94).After selective epoxidation of the diene (94) reductive amination yielded the pyrrolizidine (95). Deoxygenation of this epoxide (95) gave a mixture of four diastereoisomers which were separated by preparative gas-liquid chromatography. The relative stereo- chemistry shown for the natural product (96) was deduced from ‘H n.m.r.spectroscopic data. 11 General Studies Improved field tests for detection of toxic pyrrolizidine alkaloids have been described by Mattocks and Jukes6 Alkaloids (or N-oxides) with 1,2-unsaturated base components (except oto- necine) are converted into the corresponding pyrrole deriva- tives which then give a magenta derivative with Ehrlich’s reagent. The use of ‘“Cn.m.r. spectroscopy to identify the proportion of each alkaloidal constituent in Senecio vulgaris has been described.63 Signals for carbon atoms which displayed a short were preferred for this study. Fast-atom-bombardment and tandem mass spectrometry have been used to investigate the fragmentation patterns of a number of different nucleoside and nucleotide adducts bonded to various pyrrolic metabolites of pyrrolizidine alkaloids.64 An X-ray crystal structure analysis of rosmarinine (97) has shown that the carbonyl groups are antiparallel.65 This is the first rosmarinecine-containing alkaloid to be studied by X-ray crystallography.The conformation is similar to those of all other twelve-membered pyrrolizidine alkaloids whose X-ray structures have been established. 12 Pharmacological and Biological Studies Poisoning of humans is a problem of public health in many areas of the world.66 There are three main causes accidental have been studied. Monocrotaline pyrrole causes pulmonary damage77 which was not alleviated by defer~xamine.~~ Immune mechanisms are probably not involved in this damage,79 and the production of neither platelet 5-hydroxytryptamine nor thromboxane B is affected.80 Lung damage can be recognized by a decrease in endothelial transport of serotonin,s’ and may be ameliorated by ACE inhibitor^.^'.^^ Senaetnine (99) represents an unusual type of pyrrolizidine alkaloid.It did not appear to be hepatotoxic to rats but did cause damage to pulmonary vascular tissue when given intraven~usly.~~ Anacrotine is hepatotoxic to rats.85 Sene- cionine was isolated from Senecio jistulosus Poepp. ex Less. and its effects on contraction of isolated guinea-pig atria were recorded.@ Phosphatidylcholine showed a beneficial effect on injury to hepatocyte membranes caused by heli~trine.~‘ Some pyrrolizidine alkaloids are carcinogenic. Studies have been reported on jacobine in ratsB8 and on integerrimine in mice.89-91 The genotoxicity of monocrotaline in rats is modu- lated by pretreatment with phenobarbital and a dietary anti- oxidant.92 Hepatic microsomal oxidation of senecionine produces trans-4-hydroxyhex-2-enal(100).This metabolite produces necrosis in ratsg3 as well as genoto~icity.~~ The thioamides (101) and (102) which were prepared from retronecine (1 2) showed appreciable hypotensive effects in animals.95 13 References 1 T. Kametani K. Higashiyama H. Otomasu and T. Honda Isr. J. Chem. 1986 27 57. 2 R. F. Borch and B. C. Ho J. Org. Chem. 1977 42 1225. 3 D. J. Robins and S. Sakdarat J. Chem. Soc. Perkin Trans. I 1979 1734. 4 T. A. Geissman and A. C. Waiss J. Org. Chem.1962 27 139. 5 H. Rueger and M. H. Benn Heterocycles 1982 19 23. 6 D. J. Robins in ‘The Alkaloids,’ ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1983 Vol. 13 p. 70; (b) 1980 Vol. 10 p. 50; (c) 1981 Vol. 11 p. 45; (6)1983 Vol. 13 p. 66. 7 J. G. Buchanan G. Singh and R. H. Wightman J. Chem. Suc. Chem. Commun. 1984 1299. 8 D. J. Robins Nut. Prod. Rep. (a) 1986 3 298; (b) 1987 4 583; (c) 1987 4 579; (d) 1987 4 584. 9 Y. Nishimura S. Kondo and H. Umezawa J. Org. Chem. 1985 50 5210. 10 K. Shishido Y. Sukegawa K. Fukumoto and T. Kametani Heterocycles 1985 23 1629. 11 A. R. Chamberlin and J. Y. L. Chung J. Org. Chem. 1985 50 4425. 12 H. Niwa 0.Okamoto Y. Miyachi Y. Uosaki and K. Yamada J. Org.Chem. 1987 52 2941. 13 H. Rueger and M. H. Benn Heterocycles 1983 20 1331. 14 H. Niwa Y. Miyachi 0.Okamoto Y. Uosaki and K. Yamada Tetrahedron Lett.. 1986 27 4605. 15 K. Kh. Batirov S. A. Khamidkhodzhaev V.M. Malikov and S. Yu. Yunusov Khim. Prir. Soedin. 1976 60 [Chem. Nut. Compd..,(Engl. Trans/.). 1976. 12 501. 16 S. R. Wilson. R. A. Sawicki and J. C. Huffman J. Org. Chem. 1981 46 3887; R. S. Glass D. R. Deardorff and L. H. Gains Tetrahedron Lett. 1978 2965. 17 J. J. Tufariello and J. P. Tette J. Chem. Soc. Chem. Commun. 1971 469. 18 J. J. Tufariello and G. E. Lee J. Am. Chem. Soc. 1980 102 373. 19 J. J. Tufariello. H. Meckler. and K. Winzenberg J. Org. Chem.. 1986 51 3556. 20 D. Lathbury and T. Gallagher J. Chem.Soc. Chem. Commun. 1986 1017. 21 E. Roder H. Wiedenfeld and T. Bourauel Liebigs Ann. Chem. 1986 1645. 22 N. J. Leonard and T. Sato J. Org. Chem. 1969 34 1066. 23 M. T. Pizzorno and S. M. Albonico J. Org. Chem. 1974 39 731. 24 D. P. Curran and C. J. Fenk Tetrahedron Lett. 1986 27 4865. 25 Y. Nishimura S. Kondo and H. Umezawa Tetrahedron Lett.. 1986 27 4323. 26 F. Ameer S. E. Drewes P. T. Kaye G. Loizou D. G. Malissar and G. H. P. Roos S. dfi. J. Chem. 1987.40 35. 27 H. Niwa Y. Miyachi Y. Uosaki. and K. Yamada Terrahedron Lett. 1986 27 4601. 28 K. Narasaka and T. Uchimaru Chem. Lett. 1982 57. 29 J. D. White and S. Ohira J. Org. Chem. 1986 51 5492. 30 K. Narasaka T. Sakakura T. Uchimaru and D. Guedin-Vuong J. Am. Chem. Soc.1984 106 2954. 31 H. Niwa Y. Miyachi Y. Uosaki A. Kuroda H. Ishiwata and K. Yamada Tetrahedron Lett. 1986 27 4609. 32 K. Brown M. Burton D. J. Robins and G. A. Sim J. Chem. Soc. Perkin Trans. I 1986 1261. 33 C. D. Dodson and F. R. Stermitz J. Nut. Prod. 1986. 49 727. 34 A. P. Arendaruk and A. P. Skoldinov Zh. Ohsch. Khim. 1960 30,489. 35 K. M. Larson M. R. Roby. and F. R. Stermitz J. Nat. Prod.. 1984 47 747. 36 Z.-W. Chen J. Tang J.-S. Li Q. Zhang X.-F. Zhao and J.-H. Hu Zhongguo Yaoke Daxue Xuehao 1987 18 51 (Chem. Ahstr. 1987 107 46 142). 37 S. C. Jain and M. Purohit Chem. Pharm. Bull. 1986 34 5154. 38 N. Guner Plant. Med. Phytother. 1986 20 287. 39 M. J. Mahmoud F. M. J. M. Redha M. J. Al-Azawi W. A. Hussein and Y. T. Behnam J.Bid. Sci. Res. 1987 18 127. 40 S. C. Jain and M. Purohit Herba Pol. 1985 31 35. 41 S. Natori and I. Ueno Bioact. Mol. 1987 2 25. 42 G. Morales J. Borquez A. Mancilla S. Pedreros and L. A. Loyola J. Nut. Prod. 1987 49 1140. 43 D. Cheng and E. Roder PIanta Med. 1986 484. 44 M. J. Pestchanker and 0.S. Giordano J. Nut. Prod. 1986 49 722. 45 F. H. Guidugli M. J. Pestchanker M. S. De Salmeron and 0.S. Giordano Phytochemistry 1986 25 1923. 46 E. Jares and A. B. Pomilio J. Nut. Prod. 1987 50 514. 47 A. G. Gonzalez G. de la Fuente M. Reina and L. A. Loyola Planta Med. 1986 160. 48 E. Roder T. Hille and H. Wiedenfeld Sci. Pharm. 1986 54 347. 49 W. Martz and G. G. Habermehl Planta Med. 1986 503. 50 B. Sener S. Kusmenoglu F. Ergun and A.E. Karayaka Gazi Univ. Eczacilik Fak. Derg. 1986 3 105 (Chem. Ahstr. 1987 107 53 864). 51 D.-Q. Cai Y.-Q. Lu F.-R. Gao Y.-Z. Wang and Q.-F. He Zhongyao Tongbuo 1987 12 168 (Chem. Ahstr. 1987 107 28 259). 52 G. S. Hirschmann and C. Cespedes J. Ethnopharmacol. 1986,17 195. 53 T. Hartmann and G. Toppel Phytochemistry 1987 26 1639. 54 K. V. Borstel and T. Hartmann Plant Cell Rep. 1986 5 39. 55 D. P. Belesky J. D. Robbins J. A. Stuedemann S. R. Wilkinson and 0.J. Devine Agron. J. 1987 79 217. NATURAL PRODUCT REPORTS. 1989 56 M. C.Williams and R. J. Molyneux Weed Sci.,1987 35 476. 57 D. L. Cheng S. B. Tu A. A. Enti and E. Roder Sci. Pharm.. 1986 54 351. 58 F. R. Stermitz G. H. Harris and J. Wang Biochem. Syst. Ecol. 1986 14 499.59 D. D. Buechter and D. E. Thurston J. Nut. Prod. 1987 50 360. 60 D. Schneider Perspect. Chemorecept. Behav. (Symp.) 1985 (publ. 1987) p. 132 Springer New York. 61 T. H. Jones R.H. Highet A. W. Don and M. S. Blum J. Org. Chem. 1986 51 2712. 62 A. R. Mattocks and R. Jukes J. Nut. Prod. 1987 50 161. 63 L. A. C. Pieters and A. J. Vlietinck Magn. Reson. Chem. 1987 25 8. 64 K. B. Tomer M. L. Gross and M. L. Deinzer Anal. Chem. 1986 58 2527. 65 A. A. Freer H. A. Kelly and D. J. Robins Acta Crystallogr. Sect. C. 1986 42 1348. 66 K. K. Anand and C. K. Atal Indian Drugs 1986 23 658. 67 M. L. Saito and F. de Oliveira Rev. Bras. Farmacogn. 1986 1 74. 68 P. Lessard D. Wilson H. J. Olander Q. R. Rogers and V. E. Mendel Am. J.Vet. Res. 1986 47 1776. 69 M. D. C. Mendez F. Riet-Correa A. L. Schild and J. T. C. Garcia Pesyui Vet. Brus. 1985 5 57. 70 A. M. Craig L. L. Blythe E. D. Lassen and M. L. Slizeski Isr. J. Vet. Med. 1986. 42 376. 71 L. H. Bruner L. J. Carpenter P. Hamlow and R. A. Roth Tosi-col. Appl. Pharmacol. 1986 85 416. 72 R. R. Dalvi J. Pharm. Pharmacol. 1987 39 386. 73 H. S. Ramsdell B. Kedzierski and D. R. Buhler Drug Metah. Dispos. 1987 15 32. 74 D. R. Buhler and B. Kedzierski Adv. €.up. Med. Biol. 1986 197 61 I. 75 H. S. Ramsdell and D. R. Buhler Tosicol. Lett. 1987 37 241. 76 J. 0.Dickinson and R. C. Braun Vet. Hum. Tosicol. 1987 29 11. 77 M. N. Gillespie J. W. Olson C. N. Reinsel W. N. O'Connor and R. J. Altiere Am. J. Phssiol. 1986 251 H109.78 L. H. Bruner K. Johnson L. J. Carpenter and R. A. Roth J. Tosicol. Environ. Health 1987 21 205. 79 L. H. Bruner R. W. Bull and R. A. Roth Tosicol. Appl. Pliarmcicd.. 1987 91 I . 80 P. E. Ganey and R. A. Roth Tosicol. Appl. Pharmacol. 1987,88 157. 81 P. D. Crowe W. M. Lafranconi S. Croswell and R. J. Huxtable Proc. West. Pharmacol. Soc. 1987 30 89. 82 D. J. Shade M. S. Wiseman and W. 0.L. M. Cookson Thoras 1986 41 914. 83 A. Molteni. W. Ward C. Ts'ao and N. Solliday Clin. ESP. Hypertens. Part A 1987 9 381. 84 A. R. Mattocks and H. E. Driver To.uicol. Lett. 1987 38 315. 85 A. R. Mattocks and H. E. Driver Chem.-Biol. Interact. 1987,63 91. 86 E. Gonzalez R. Garcia I. Lemusa and S. Erazo An. R. Acad. Farm. 1986 52 123.87 0.V. Dobrynina S. Z. Skatinina and A. I. Archakov Byull. Eksp. Biol. Med. 1987 103 413. 88 T. W. Petry G. T. Bowden D. R. Buhler and K. G. Sipes Tosi-col. Lett. 1986 32 275. 89 K. Kuitko and M. C. Gimmler Rev. Bras. Genet. 1986 9 439. 90 M. C. Gimmler E. K. Marques and R. C. Johnston Rev. Bras. Genet. 1987 10 31. 91 C. L. S. Cardosa da Rocha and J. Lucio de Azevedo Rev. Bras. Genet. 1986 9 393. 92 T. W. Petry and 1. G. Sipes Carcinogenesis (London) 1987 8. 415. 93 D. W. Wilson H. J. Segall and M. W. Lame Adv. ESP. Med. Bid. 1986 197 853. 94 D. S. Griffin and H. J. Segall Toxicol. Appl. Pharmacol.. 1986,86. 227. 95 K. A. Suri 0.P. Suri N. Singh and C. K. Atal Indian Drugs 1986. 23 209.

ISSN:0265-0568    

DOI:10.1039/NP9890600221

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Fatty Acids and Glycerides M. S. F. Lie Ken Jie Department of Chemistry The University of Hong Kong Pokfufam Road Hong Kong Reviewing the literature published during 1986 and 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 95) 1 Books and Reviews 2 Natural Compounds Occurrence and Structure 2.1 Unbranched Acids 2.2 Cyclic and Branched-chain Acids 2.3 Oxygenated Acids 2.4 Icosanoids and Related Compounds 2.5 Other Long-chain Compounds 3 Synthetic Procedures and Compounds 3.1 Synthetic Procedures for Long-chain Compounds 3.2 Compounds with Less than Eighteen Carbon Atoms 3.3 C, Compounds 3.4 C, Compounds 3.5 Compounds with More than Twenty Carbon Atoms 3.6 Lactones 3.7 Glycerol Derivatives 4 Physical Properties 4.1 Gas Chromatography 4.2 Liquid Chromatography 4.3 N.M.R.Spectroscopy 4.4 Mass Spectrometry 4.5 Other Spectroscopic Properties 4.6 Polymorphism and Crystal Structure 5 Chemical Reactions 5.1 Oxidation 5.1.1 Autoxidation 5.1.2 Oxidation by Singlet Oxygen 5.1.3 Enzymic Oxidation and Secondary Products of Lipid Oxidation 5.1.4 Antioxidants 5.1.5 Detection of Oxidation 5.2 Epoxides Formation and Reactions 5.3 Hydrogenation 5.4 Other Reactions of Acetylenic and Olefinic Systems 5.5 Reactions of Oxygenated Acids 5.6 Reactions of the Carboxyl Group 6 Metabolism of Fatty Acids 6.1 C, Acids 6.2 C, Acids 7 Biotechnology 8 References 1 Books and Reviews Books published include five handbooks on lipids in general (with a very useful dictionary section),' the physical states of lipids,2 icosanoids and prostaglandin^,^ fat ab~orption,~ and phosph~lipases.~ Several books have appeared on the bio- chemistry of lipids6- and methods for the isolation analysis and identification of oils fats and their derivatives,s-ll and on chromatographic techniques.12-15 More specialized texts include a report on palm oil16 and summaries of recent advances in the chemistry and technology of fats and oils,l7 non-traditional seed oils,1s oxidation of lipids,Ig autoxidation of lipids,20 metabolism of lipids,2126 le~kotriene,~' lipid mediators,2s lipid mernbrane~,~~ nutrition flavour and health aspects of lipid~,~O-~, and protein-lipid interaction^.^^ Reviews have appeared that deal with the following topics 23 1 furanoid fatty insect lipids,35* 36 Paramecium lipids,37 very-long-chain fatty acids from lower organisrn~,~~ the use of bacterial lipids for taxonomic identifi~ation,~~-*~ metathesis of fatty acid ester^,"^ mechanism of peroxidation of lipids,4** l5 oilseeds as sources of essential fatty the characterization of lipids by chromatographic method^,^^-^^ the characterization of unsaturated aliphatic compounds by gas chromatography- 56 mass spectrometry (g.~.-m.s.),~~ the synthesis of sterol esters by lipase,.j7 stearyl alcohol and its derivatives;j8 the manufacture of lipids by biotechn~logy,~~ dietary trans-isomers of fatty acids,60.61 the determination of cis- and trans-isomers of fatty acids,62 polymorphism of lipids,63 the biosynthesis of fatty acids and the role of pyridine nu~leotides,~~ the metabolism of polyunsaturated fatty acids in fish,65* 66 composition and biochemistry of the lipids of freshwater fish,67 metabolism of fatty acids in mammalian cells,68 biosynthesis of polyunsat- urated fatty acids and of prostaglandin^,^^ 71 the role of essential fatty acids and icosanoids in cellular function^,^ 74 the arachidonic acid cascade in the brain,75 the effects and metabolism of polyunsaturated acids in 78 extraction and purification of arachidonic acid metabolites from cell prostaglandins and nutrition,80*81 and the role of leukotrienes,82v83 the synthesis of prostaglandin^,^^^ 85 thrombox-anes,86* leukotrienes,88 and prostacy~lins,~~~ 87 the search for prostaglandins in plant^,^' platelet activating g3 the regulation and pharmacological modulation of biosynthesis of leukotriene~,~~, 95 the formation of epicuticular wax in maize,96 waxes and their role in plant-microbe interaction^,^^ lipids in radioiodinated fatty acids for cardiological diagnosis,99 the structure and chemical synthesis of Lipid A,lo0 fatty amine chemistry and bio~urfactants,~~~-'~~ the history of the royal substance (9-oxodec-2-enoic acid) of the honey bee,'04 and the synthesis of deuteriated ic~sanoids.'~~ 2 Natural Compounds Occurrence and Structure 2.1 Unbranched Acids Species of the genera Calendula and Coriandrum are being cultivated as potential oil crops for industrial uses as the seed oil of Calendula species is rich in calendic acid [18:3(82,102 12E)I (up to 63 YO)while Coriandrum seed oil contains high levels of oleic acid and petroselinic acid [18 1(62)] (up to 82Y0).'06 The seed oils of Aucuba japonica and Griselinia littoralis also contain large amounts of petroselinic acid (33 YO and 28 YO,respectively).lo7Several species of Amaranthus for which the composition of the seed oil is similar to that of corn or cottonseed oil are being farm-tested as potential oil crops in arid and infertile regions in sub-tropical countries and methods of extraction and the nutritional value of their oils are being examined.'08.109 A high-altitude (over 1500 m) species of the genus Valenzuela appears to be another potential crop; its main fatty acids are palmitic (9.6 %) oleic (62.3 YO),linoleic (10.1 %) and gadoleic acid [20 :1(92)] (12.9 YO).^^^ Centrifugal separation is a new method that has been recommended for the extraction of avocado oiI,'l1 and intensive studies have been conducted on its oxidative stability112 and on the effectiveness of antioxidants in refined avocado oiP3 For the hydrogenation of Canola 0iP4 (a rape oil that is produced in Canada and which contains less than 2 YOof erucic acid) several catalysts (including palladi~m,"~ nickel and a methyl benzoate-chromium tricarbonyl complex116) have been tried and the effects of isothiocyanate"' and chlorophyll"* on hydrogenation have been studied.The total sulphur content (residue from catalysts) of hydrogenated Canola oil has been asses~ed"~ and the reactivities of the fatty acids in the different positions of the triglycerides during the hydrogenation of Canola oil have been examined.120 The use of ultrasound in the hydrogenation of soybean oil has been investigated and appears to result in an oil of good quality at lower cost than is achievable with present methods.121 A comparative analysis of fatty acids in the pollen and seed of rape (Brassica napus) has shown that the fatty acids lO:O 12:0 and 16:3 are present in the pollen but do not occur in the seeds.122 Germinating seeds of Cuphea species which are valued as rich sources of medium-chain fatty acids have been subjected to labelling studies with acetate and with mevalonate; the incorporation of label into triacylglycerols and into medium- chain fatty acids occurs during the period of deposition of endogenous 1i~ids.I~~ Intensive feeding experiments have been carried out with medium-chain trigly~erides'~~ to investigate their effects on the growth of adipose on the metabolism of human adipose tissue,'26 and on the role of brown adipose tissue in the mechanism of medium-chain- triglyceride-induced thermogenesis 12' their influence on the development of mammary tumours,'2* and their use as a non- glucose energy source in hyperalimentation.129 cis-Vaccenic acid [18 1(1 lZ)] is present in pulp lipid (20%) of mango (Mangifera indica) but only in trace amount in the seed (0.5YO) where 18:0 and 18 :I(9z) are the major fatty acids.130. 131 High levels of 18:1 (1 1 Z) are also found in the lipid extracts of some other fruit pulps [Japanese persimmon (Diospyros kaki) 29 YO; grapefruit (Citrus paradisi) 19.4Yo; sweet orange (Citrus sinensis) 16.9YO;Japanese mandarin (Citrus unshiu) 22.3 The distribution of fatty acids in nineteen strains of Spirulina has been studied; all but one were found to contain y-linolenic acid [18 :3(6Z,9Z 12231 with the highest level of y-linolenic acid being produced when the organisms are cultured at a temperature of between 30 and 35 0C.133 Seed oils of borage evening primrose and blackcurrant have again been reported to contain high levels of y-linolenic acid (21.1 8.1 and 14.8YO respectively).'34*135 The beneficial effects of dietary oil of evening primrose (Oenothera biennis) on mammary tumori- genesis'36 and a process for preparing zinc y-linolenate for treatment of gastric disorders13' have been reported.It has been suggested that a relative deficiency in dietary y-linolenic acid may contribute to the development of acquired immuno-deficiency syndrome (AIDS).138 Large amounts of arachidonic acid have been isolated (68.5-78.8 YOof the total lipids; 25 YOof the dry weight of cells) from the filamentous fungus Mortiereffu ulpina.la' An effective process for the isolation of 22 6 from cod liver oil via a selective iodolactonization procedure has been described by Corey and co-~orkers.'~~ Intensive studies on the use of supercritical carbon dioxide for the extraction of components (including 20:5 and 22:6 acids) of fish and Canola 148 ha ve been reported.The analysis of the fatty acid composition of triglycerides and 2-monoglycerides in butterfat that has been adulterated with beef tallow and with cottonseed oil allows the degree of adulteration to be assessed.lQ4 The major components of the lipids from seeds of Pinus koraiensis are oleic acid (25-28 YO),linoleic acid (42-48 YO) and 18 :3(52,92,122) (1 1-1 7 YO),with small amounts of 19 :0 20:2(52,1lz) and 20:3(5Z,1 iZ,14Z).14s~146 The lipid fraction of the aquatic fern Azoflu curoliniana contains 16 0 (5 1.6YO) during the summer but the level decreases to 38.8% in the autumn.This seasonal change also causes the amount of linolenic acid to increase from 12.7in summer to 21 .O % during the autumn.lJ7 Punicic acid [18:3(9Z,I 1 E 13Z)] and a-eleo- NATURAL PRODUCT REPORTS 1989 stearic acid [18 :3(9Z,I 1 E I3Q] are major components of the seed oil of Momordica bal~amina.'~* A study of the lipid extract of eighteen species of seaweeds (red algae) from the coast of Karachi has shown that they contain large amounts of 16:O (up to 91.38Y0),'~'while a brown alga (lyengaria stellata) from the same area contains odd- and even-carbon-chain fatty acids (15:0 16:0 I7 :0 and 18:O) together with palmitoleic acid and oleic acid.150 The Japanese red alga Gracilaria verrucosa and two macroscopic red algae (Chondrus crisps and Polysiphonia lanosa) of British waters contain the unsaturated fatty acids 20 :4 and 20 :5.l5l,152 Two new fatty acids [20 5(52,7E,9E,142,172) and 20 5(5E 7E,9E,142,172)] have been isolated from a temperate marine red alga Ptilota ~5filicina.l~~ Investigation of the fatty acid composition of the red-tide flagellates Heterosigma akashiwo and Chattonella antiqua has revealed the presence of 14:0 16:0 16 1 18 :4 and 20:5 which provide a unique signature profile for taxonomic purposes.154 The lipid extracts of two strains of the hot-spring alga Cyanidium caldarium contain odd- and even-carbon-chain fatty acids.These are 15:0 (8.6 Yo) 16:O (12.7%) 17:O (10.5%) 18:0 (9.8%) and 18:2 (53.1 %) in the extract of Cyanidium RK-1 while Cyanidium M-8 contains mainly 16:O (33.5%) 18 1 (33.3%) 18:2 (23.7%) and 18 :3 (7.3 A novel acetylenic acid 18 :2(6A,9Z) has been identified in the lipid extract of the thalli of the liverwort RicciaJuitans.'j6 The distributions and the chemotaxonomic significance of acetylenic fatty acids in mosses of four Families of the Order Dicranales have been rep~rted.'~' The green part of the turf- forming moss Dicranum efongatum contains long-chain hy- droxy-acids (44.9%) fatty acids (39.7%) a range of a,w-dicarboxylic acids (C16-C24) and fatty alcohols (C1,-C,6).158 The phosphatidylethanolamine fraction of the lipid extract of another moss has been shown to be rich in arachidonic acid.'j' A large amount of 20 l(1l.Z) (25 YO)has been isolated from the seed oil of Consolida regafis,16' while lower levels (1-5 YO)of 23 l(142) have been obtained from three marine species of echinoderm of the Class Holothuroidea.lG1 An unusual acid 16:2(5Z,92) is present in the marine sponge Chondrilla nucufa.'62Several long-chain monounsaturated fatty acids have been detected in the lipids of the antarctic sea-ice diatom Nitzschia cyfindrus by g.c.-m.s.analysis of the dimethyl disulphide adducts ; 24 1 (13Z) 24 1 (1 5Z) 26 1(15Z) and 26 l(172) are the major component^.'^^ In another marine diatom Phaeodactylum tricornutum the major fatty acid components of the total lipid are 14:O (5.8%) 16:O (26.7%) 16:1(3E) and 16:1(92) (34.2%) 18.1 (~OYO) and 20:5 (6.4 The fatty acid composition of lacustrine phyto- plankton depends on the types of algae present.When species of the Divisions Cyanophyta and Chlorophyta are dominant linolenic acid is present; where species of the Divisions Bacillariophyta and Dinoflagellida predominate 20 :5 is the principal polyunsaturated fatty The unusual fatty acid 24 :6(6Z,92,122,15Z 18Z,2 1 Z) has been identified together with several more common As-unsaturated fatty acids [18:1(5Z) 20 1(5Z) 20:2(5Z,IlZ) and 20:2(52,13Z)]in two species each of marine invertebrates of the Classes Crinoidea and Ophiuroidea.166 The fatty acid composition of a large number of species of sea urchins (Strongylocentrotus species) have been examined and all contain high levels of 5-olefinic 16' mono-and poly-unsaturated C, and C, fatty Several polyunsaturated C, acids have been identified in the marine mollusc Cerethidea cingufata (20:5)17"and in the soft coral Lobophytum carnatum (18 :3 20:3 and 20 :4).I7l A comparative study of the fatty acids of hatchery-fed smolting and wild specimens of Atlantic salmon (Safmo safar) has shown that there is a higher proportion of arachidonic acid (8.0 YO)in the lipid of wild fish than in that of hatchery fish (0.5?40).'~' Large amounts of the fatty acids 18:2 18:3 20:2 20:3 20:4 and 20:5 have been identified in eight species of insects and the functional role of these polyunsaturated fatty acids has been discussed.'':'~ Th e pheromone gland of females of NATURAL PRODUCT REPORTS 1989-M.S. F. LIE KEN JIE Spodoptera littoralis contains methyl esters of 14 1(9Z) 14:l(llE and llz) 14:2(92,12E) 14:2(92,11E) and 16:1 (1 1 and the triglyceride fraction of the exoskeleton of the Colorado beetle (Leptinotarsa decemlineata) consists of trioleylglycerol and 1,2-dioleyl-3-palmitoylglycerol(total 91 Oh).,'' 2.2 Cyclic and Branched-chain Acids When the bacterium Methylococcus capsulatus is cultured in low-oxygen- tension biomass medium large amounts (up to 25 % of the total lipid) of C, cyclopropane fatty acids (with the cyclopropane ring at Ag AIO and All) are detected.177 Cyclopropene acids (malvalic and sterculic) are found in the seed oils of Bombax mung~ba,'~~ Gnetum scandens and Sterculia pall en^,'^^ Abutilon ramosum,laO Cassia grandis and Delonix elata Gamble (syn.Poinciana elata L.),lal Argyreia cuneata,la2 and Plumbago zej~lanica.'~~ 11-Cyclohexylundecanoic acid (47%) has been identified in the lipid extract of a species of Curtobacterium along with 12-methyltetradecanoic acid (23 YO) and 12-methylhexadecanoic acid (22 %0).la4 A study of the cyclic fatty acid monomers that are formed in frying fats (soybean sunflower and linseed oils ) has revealed the presence of several C, z-disubstituted cyclohexane and cyclopentane isomers.1a5. Two 4-methyl branched acids 14 l(9) and 14:2(9,12) have been identified in the lipid extract of the roots of Onosma Ireter.~p/iylla.'~~ The seed oil of the pomegranate (Punica granatum) contains punicic acid [18:3(92,11E,13a] (33 YO) with traces of 4-methyl- 12 :0 and 13-methyl- 18 :0 but it is void of oleic acid and linoleic acid.la8 Several novel isoprenoid fatty acids have been isolated from marine sponges Anthosigmella varians and Spheciospongia vesparium contain 4,8,12-trimethyl- I3 :0 (5.2 YOand 23 YO, respectively) while Chondrilla nucula and Agelas dispar contain 3,7,11,15-tetramethyl-16:0(13.8 % and 8.6 YO,respecti~ely).'~~ A study involving l4C-label1ed 10-methyl- 16 0 of the biosynthesis of lipids in the marine sponge Aplysina jistularis has demonstrated that the substrate is converted into the acid 22-methyl-28 :2(5,9).lgo Analysis of fifteen species of basidiomycete fungi has shown that there is an array of methyl-branched saturated and unsaturated fatty acids including very long (C20-C30) homologues.Ig1 A short-chain dimethylated branched fatty acid 4,5-di- methyl-8 :0 has been identified in the submerged mycelium of the fungus Claviceps purp~rea.'~~ (2E,4E)-2,7-Dimethylocta-2,4-dienedioic acid is derived from abscisic acid (1) in the tomato plant.lg3 A trimethylated dihydroxy- 12 2 acid (2) has been isolated from the root of Hortia regia which bears close resemblance to the insect juvenile hormone methyl farnesate (3).194 2.3 Oxygenated Acids High levels of isoricinoleic acid [9-hydroxy- 18:1(1 22)] have been found in the seed oils of Wrightia tinctoria (70%) and W. coccinea (76 Y0).lg5 The separation and identification of 9,lO- dihydroxy-18:0 (30.5 YO)in the seed fat of sal (Shorea robusta) has been rep~rted.'~,Two novel hydroxy-fatty acids (12- hydroxy- 17 :0 and -20 :0) have been identified in the seed oil of Securinega suflr~ticosa.'~~ The lipid extract of the stromata of Epichloe typhina contains four fungitoxic hydroxy-fatty acids (4)-(7)."' The seed oil of Plantago ovata contains besides isoricinoleic acid the corresponding keto-acid 9-0x0- 18:I (1 22) (7.4 Y0).lg9A novel dioxo-acid 7,12-dioxo- 18 :2(8E,IOE) has been isolated from the stem and fruit of Ostodes paniculata,200 while the rhizome of Costus speciosus contains three new long- chain 0x0-acids and two esters.These are 14-0x0-23 :0 14-0x0-27 :0 15-0x0-28:0 tetradecyl 13-rnethylpentadecanoate,and tetradecyl 1 1 -methyltridecanoate.201 12,13-Epoxy- 1 1-hydroxy-18:2(92,152) has been isolated from rice plants that were suffering from rice blast disease (Pyricularia oryzae).""2 An unusual prostaglandin-like hydroxy-oxocyclopentenyl C, acid (3) OH (4) CO,H OH (5) OH C OtH C 02H OH (71 NATURAL PRODUCT REPORTS 1989 I I HO OH 0 HO 6H (10) E Me[CH 1 CHICH I CCH=CH[CH216Me 7 “If CO,H 0 (11) n = 7 (12) n = 9 HH 32 Z MeC-C [C=CI2CH=CHC0,Me \*I u (8) has been isolated from the aquatic plant Lemna trisulca which also contains (12S)-12-hydroxy-16 3(82,1OE,142) 16:1(112) 16:2(82,1lZ) and 16:3(82,11Z,14Z).203Lemna minor has two other cyclopentanoid C, fatty acids [(9) and (lo)] in addition to (lOR)-lO-hydroxy-16:3(72,1IE,13Z) and 16:3(72,10Z,132).204 A C,,and a C, fatty acid [(1 1) and (1 2)] have been isolated from the marine sponge Ficulina ficus in which the carboxyl group is attached to C-8 of the alkyl chain.205 The lipid extract of the aerial parts of Erigeron philadelphicus affords two novel short-chain C, epoxy-fatty acid esters (13) and (14).206 The presence of 8,9- and 14,15-epoxy-20 3 in the lipid extract of female rabbit kidney suggests the role of arachidonate epoxygenase in the metabolism of arachidonic The seed oils of Acacia mollissima A.torta A. lenticularis and A. nilotica contain 3-6 % of coronaric acid [9,1 O-epoxy- 18 1(122)].208 The seed oil of Cupania anacardioides is a rich source of the cyanolipids (15) and (16).209 Several furanoid fatty acids (1 7)-(20) have been identified in the liver of cattle where they are found in the cholesteride and glyceride fractions.Enzymatic degradation of these furanoid Me Me (17)rn=4,n=6 (18) rn = 4 ,n = 8 (19)m = 4 ,n = 10 (20)rn = 3 ,n = 8 acids results in the production of the hydroxy-oxocyclopentenyl acid derivatives (21) and (22) by way of the unsaturated dioxo- intermediates (23).210 The furanoid acid (18) has been shown to be metabolized to pentylurofuranic acid (24) and a furanoid dioic acid (25) by humans while rats are only able to convert (18) into (25).,11 Chondrillin (26) and four other related cyclic peroxides (27F(30) of long-chain fatty acids have been isolated from a marine sponge Plakortis lita which exhibit anti-tumour activities against P388 cells.212 An antifungal agent triyne- carbonate L-660 631 (31) has been isolated from the fermenta- tion broth of actinomycetes.213 Ether lipids in oncology have been the subject of a symposium held in Gottingen and the results of the discussion (37 papers) have appeared in a collective issue.214 Marine sponges have been shown to be sources of ether lipids. Tethya aurantia contains three alkyl glycerol monoethers (32)-(34)215 and Raspailia pumila and R. ramosa have furnished several novel long-chain acetylenic enol ethers of glycerol; the oxidation of these labile enol ethers has been studied.216.217 2.4 Icosanoids and Related Compounds In an effort to standardize the naming of related compounds derived from arachidonic and icosapentaenoic acid via the lipoxygenase pathway Serhan Wong and Samuelsson have recommended that the general term ‘lipoxin (LX)’ be ex-clusively used to describe such metabolites; where metabolites are derived from 20:4 and 20:5 a subscript 4 or 5 should be used respectively.Positional and geometric isomers and stereoisomers are indicated as illustrated by the examples LXA (39 6(S)-LXA (36) LXB (37) 8-trans-LXB4 (38) and 14(S)-8-trans-LXB (39). 218 The presence of leukotriene B (40-50 ng per 5 cm3) in lung lavage has been determined by g.c.-m.s. in the negative-ion chemical-ionization mode. 219 Arachidonic acid has been con- verted into the three 0x0-derivatives 12-oxoicosa-5,8,10,14-tetraenoic acid and two geometric isomers of 12-oxododeca- 5,8,10-trienoic acid in human platelets involving a possible NATURAL PRODUCT REPORTS 1989-M.S.F. LIE KEN JIE [ C Hzl 4M e Me4$ [ C HZl,,,C 0 Me 0 0 (21) m = 5,7 or 9 (22) n = 6,8 or 10 (23) n= 6,8 or 10 Me[C H l4 [ CH2I ,CO ,H MeO”Rn>COZMeo-o (26) (27) R = [CH2],1Me (28) R = [CH219WMe Me (29) R = [CH,],M (30) R = [CH,],MMe 0 OH HO-0-[ CHz114 C H R ’C H R R3 OH (32) R’ = R2= R3= H (311 (33) R1 = H ,R2= R3= Me (34) R’ = RZ = Me R3 = H OH OH I OH I OH (35) (361 (37) OH C02H OH (38) OH CO,H I OH (39) NATURAL PRODUCT REPORTS 1989 j2"d2, (40 )2H (411 (42) OH (43) haem-catalysed transformation of 12-hydroperoxyicosatetra-enoic acid."'" Human platelets have also been shown to convert 20:4(8,11,14,17) into 12-hydroxy-20:4(8,10,14,17) which is further metabolized to 12-hydroxy-17 3(8,10,14).221 Hamberg and co-workers have investigated the interaction of homogenates of the fungus Saprolegnia parasiticu with arachi- donic acid which results in a number of stereoisomers of 1 1 12-epoxy- 15-hydroxy-20 3(5,8 I3) 13,14-epoxy- 15-hydroxy- 20 3(5,8,1I) and several trihydroxy-20 3 acids.222 Trout gill tissue contains 12-lipoxygenase activity which allows 20 4 and 20 5 to be metabolized to I2-hydroxy-20:4 and 12-hydroxy- 20 5 respectively while 22 6 gives 14-hydroxy-22 further metabolism of these monohydroxy-derivatives results in the production of trihydroxylated unsaturated fatty acid deriva- tives.226 A (n -9)-and (n-6)-specific lipoxygenase activity in the human and rat epidermis converts 20:4 into 12-hydroxy- 20 4 and 15-hydroxy-20 4 respectively and linoleic acid into 13-hydroxy- 18 2.227 Several metabolic pathways have been investigated and have been found to lead to the formation of leukotriene B from human leukocytes with a primary reduction of a double-bond;"* of leukotriene C from leukotriene A by human platelets ;229 of leukotriene A from human leukocytes stimu- lated by ionophore A23187 or the chemotactic peptide met- Leu-Phe;230 of leukotrienes B, C, D, and E and several monohydroxy-20 4 acids from rat brain tissue with ionophore A23 187 ;231 20-hydroxy- and 20-carboxy-leukotriene B from leukotriene B by rat heptocytes;232 and of leukotrienes A and B from 15-hydroperxy-20 5 in a suspension of porcine leuko- cytes.'".234 Three dehydroarachidonic acid derivatives (40)-(42) have been subjected to oxidation with soybean lipoxygenase and the results suggest that organo-iron intermediates occur in the lipoxygenation The enzymic conversion of I0,lO-difluoroarachidonic acid into various hydroxylated products with prostaglandin-H synthase and with soybean lipoxygenase has been A range of prostaglandins (PGA, PGB, PGE, and PGF,) have been isolated from leaves of onion (Allium ~epa),~, while PGE and PGF isomers are found in the extracts of the housefly (Musca domestic^).^^^^ 239 A n ew prostaglandin 5,6-dihydro- prostaglandin E, has been detected in an extract of ram seminal vesicle,24o while 20-hydroxyprostaglandins El and E are found in ram seminal The two novel prostaglandins 18,19-didehydroprostaglandins El and E have been isolated from human seminal The absolute configuration of chlorovulone (43) has been determined by measuring its circular dichroism.243 The con- version of 20:4 into preclavulone A (44) by Clavularia viridis appears to involve (8R)-8-hydroperoxy-20 3 as an inter-mediate,244 and the structure of (-)-preclavulone A has been confirmed by total 0 (44) .2.5 Other Long-chain Compounds Many long-chain hydrocarbons (C,,-C,,) wax esters (C2,- C5J aldehydes (C,,-C,,) fatty acids (C12-C3J and alcohols (C2,-C28) have been identified in the leaf wax of Euphorbia species246 and in Cistus ~lbanicus.~~~ Wax esters composed of alcohols (Cl,-C3,) and fatty acids (16:0 18:0 18 1 18 2 and 18 3) have been isolated from mangrove leaves together with saturated normal and branched-chain hydro- carbons (Cl6-CI6).24* Nine unusual 2,3,4- tri- 0-acylglucose esters have been characterized from the polar fraction of the leaf wax of Lycopersicon pennellii which contains methyl- branched short- and medium-chain (C3-Cl,,) fatty acids.24Y Several esters of benzoic acid and long-chain fatty acids occur in Euphorbia dendroide~.~~' Esters of benzyl alcohol and 2- phenylethanol are present in the epicuticular wax of jojoba (Simmondsia ~hinensis).~~~ The leaf waxes of Isocoma drumondii and I.coronopifolia contain low concentrations (less than 5o/o) of alkanes esters and ketones with C, fatty acids and alcohols as the predominant components.252 This is why the waxes are so hydrophobic and hence why spraying the leaves of these species with herbicides causes widely varying effects. The lipid extracts of four species of freshwater dinoflagellates show that methyl and ethyl esters of fatty acids (C12-C18)are present in Woloszynskiu coronatu Ceratium furcoides and Peridinium fomnickii while phytyl esters are also present in Peridinium cincturn.'.j3 Sterol fatty acid esters have been found in liverworts2j" and disteryl ethers have been isolated and identified from vegetable oil and from margarine.255 The extracts of the bark of three species of Virofu contain an unusual series of esters derived from C,,-C, o-hydroxy-fatty acids and ferulic acid.25fi The novel triterpene fatty acid esters 3P I6P-dihydroxylupeol 3-palmitate and 3P 16P-dihydroxylupeol 3-myristate have been identified in the extract of the aerial parts of the plant Inula britanni~a.~~~ Several diesters of 3-hydroxy-fatty acids are produced by the uropygial glands of female mallards during the mating season.25s The reaction of jojoba wax with ozone leads to diozonides which are useful intermediates for the production of dialdehydes and dicarboxylic acids.,,' A novel C,chlorodiacetylenic trio1 (45) has been identified as a metabolite of the fungus Pneumutospora obcoronata.260 Two unusual C, acetylenic ketones (46) and (47) have been isolated from the roots of Echinacea pullidu261 and three C, acetylenic diols (48)-(50) from the roots and callus of Punax gin-seng.262-2s3 Four new C, acetylenic polyenes [(51)-(54)] of biogenetic significance have been identified in the extract of the red alga Laurenciu okamurui and their structures confirmed by ~ynthesis."~ The enantiomeric epoxy-iso-C, hydrocarbons (55) and (56) have been identified as a sex pheromone of the gypsy The (all-Z)-icosa-3,6,9-trieneand henicosa- NATURAL PRODUCT REPORTS 1989-M.S. F. LIE KEN JIE E CICH-CHCGCCZCC H(OH)CH(OH)CH,OH (451 0 II E Z Me C [CH,l,C H (OH)C H=CHC=CC H=C H Me (47) 0 HO ?H II Me C H,C C=CC=C CH,-HH (49) z Me CH CH=C HI C ZEC H (511 Z E Me [C H,C H==C H1,C H2C H=CHCeC H (53) z Me C H,15C H-I H C H I C H0 (57) 3,6,9-triene (female sex pheromone of the grass looper moth Mocis di,ssc.vc.runs) have been prepared and tested in field Lipids of the green alga Botryococcus bruunii contain (2,Z)-and (E,E)-unsaturated odd-chain (C2:s-C:il) alkadienes in which the double-bonds are located at the a-and the w-position of the hydrocarbon chain."" A C, Unsaturated aldehyde (57) has been isolated from the marine sponge Hulkhondriu puniceu.""' Very-long-chain polyenoic Fdity acids (C2?<:$ have been identified in mammalian and evidence exists for specific elongation enzymes for the synthesis of very-long-chain fatty acids (C2,,-C,4) in tubers of the potato (Solununi tuherosum)."" Such compounds (C,,;-C:J 0 II E MeC [CH,l,CH(OH)CH=CHC~CC~ C Me (461 HO OH ii Z Me [ C H21J CH,CH=C H1,CEC H (52) Z E Me[ C ti2],[ C H,C H=CH 12C H2C H=C HCEC H (54) have also been detected in abnormal amounts in the brain ex- tract of peroxisome-deficient patients (Zellweger syndrome)."l 3 Synthetic Procedures and Compounds 3.1 Synthetic Procedures for Long-chain Compounds Some general procedures are described which are useful for the synthesis of long-chain compounds.Aldehydes are very much needed for the Wittig reaction for the purposes of chain extension and creation of an ethylenic system. A facile procedure for the reduction of saturated and unsaturated carboxylic acids and their salts to aldehydes by thexylbromoborane and dimethyl sulphide has been de- scribed.272 An improved procedure for the conversion of alkynes into 1,2-diketones involves indirect electro-oxidation with ruthenium tetr~xide.~?~ A novel route to ap-unsaturated esters via a Reformatskii- type reaction using sodium telluride has been reported.274 A general method for the synthesis of conjugated diacetylenic acids by treating wbromo-acids with lithium acetylide deriv- ative followed by the Cadiot-Chodkiewics coupling reaction with 1-iodo-acetylenes2'" has been described.Several new routes to 1,3-dienes have been developed. These are hydro- cupration of alkyne~,*~~ a hydroboration-bromoboration se-quence of two alkyne~,~'~ and viu palladium-catalysed cross- coupling between alk- I -enylboronates and I -bromoalkenes.A new route to optically pure propargylic alcohols has been achieved by reductive cleavage of a/?-alkynyl acetal~.'~~ Halogeno-acids or -esters are of great value for chain-extension purposes. The syntheses of 7-chloroheptanoic acid,"" 5-bromopen tanoic ethyl 5-bromopen tanoa te 'Lx2 methyl 7-i0doheptanoate,"'~ and m-iodo-alkan- 1 -OIS'~~ have been de- scribed. An improved method for the preparation of I-iodo- alkynes involves sodium and bis(pyridine)iodine( I) tetrafluoro-borate in methanol.2H5 A convenient synthesis of 1 -chloro- NATURAL PRODUCT REPORTS 1989 Me I C0,Et R2' (58) R' = Ph,Et or Hi R2 = Et or H (59) R' = Ph,Et or H; R2 = Et or H TOH (62) WCOzMe (64) R = CH, C,H, or C5H1 (65) OH CO,H (66) R L C02Me (67) R = CH, C2H5 C3H7 C,H, C5H11 C,H,, or H,C=CHCH,CH HC~C[CH,I,CO,H (68) n = 3-10 alkan-2-ones from 3-0x0-alkanoates has been reported.286 5-Aminolaevulinic acid [H,NCH,C(O)CH,CH,CO,H] has been prepared by the Gabriel 3.2 Compounds with Less than Eighteen Carbon Atoms Many long-chain aliphatic compounds with chain length below C, have been synthesized.These include the ethyl (2E)-5- hydroxy-4-methyl-alk-2-enoates (58) from the epoxy inter- mediates (59),,** methyl 7-iodohept-5-yn0ate,~~~ substituted C and C trienes and the tetraenes (60) and (61),,,O (E)-and (2)-isomers of 5-methylocta-3,7-dienoic acid via umpolung and Cope ~earrangement,~" ethyl oct-4-enoate from BrZnCH,- C0,Et,292 3-methyloct-6-yn- 1-01 from the isopropylidene olefin (62),293 (4E)-non-4-en-2-ynoic (3E)-2-methyl-6-methyl-eneocta-I ,3,7-t~iene,,,~ (2E,4E)- and (22,4E)-isomers of the alka-2,4-dienoates (63) and (64),296 ethyl (2E,4Z)-deca-2,4- dien~ate,,,~ (2E)-9-oxodec-2-enoic acid (honeybee phero-m~ne),~~, (5Z)-dec-5-en-1-yl acetate,,, (E)-and (2)-isomers of undeca- 1,3,5-t~iene,~OO (59-3-(5Z)-undec-5-en-2-0ne,~O~ acetoxyundeca- 1,5-diene and (5Z,82)-3-acetoxyundeca-1,5,8-t~iene,~', dodeca-9,ll -dien- 1-01 and its acetate,303 (7E)-dodeca- 1,7-diene,3n42-(6-methoxycarbonylhexyl)cyclopent-2-en-1-one (65),305(8S,9S)-8,9-epoxy-5-hydroxydodec-6-enoic acid (66),3n6 analogues of methyl (2E)-4-oxo-alk-2-enoates (67),307 (all-R)- 2,4,6,8-tetramethylundecanoicacid (the preen-gland wax of the Graylag goose),3o8 (6E)-7-methyltridec-6-en-1-01,~~~ 13-hydr-oxytridecanoic acid,310 alk-o-ynoic acids (68) from a,o-diols via the 2-nitrophenyl selenides,"l (32,52)- and (3E,SZ)-tetradeca- 3,Sdienoic acids (constituents of pheromones of the beetles Attagenus elongatulus and A.rnegat~rna),~~~ I I -and 12-hydroxy- (3Z)-dodec-3-enoic acid I 1-and 12- hydroxy-(32,62)-dodeca- 3,6-dienoic acid and (52,82)-13-hydroxytetradeca-5,8-dienoic acid (pheromones of grain beetles of the genera Cryptolestes and Ory~aephilus),"~ethyl ( -)-(2E,6S,82)-6-hydroxytetradeca-2,8-dienoate from ( +)-(3-glutamic (3E,SZ)-tetradeca-3,Sdienoic acid (pheromone of the black carpet beetle),315 pentadec- 14-enoic acid by electrolytic condensation,316 two deuterium-labelled aldehydic esters (69) and (70),317 isomers of tetradeca-5,8 I 1-trien-2-0ne,~l~ (4E 102)-tetradeca-4,1O-dienyl and (1 02)-tetradec- 10-enyl acetate,319 several disubstituted C,-C, alkenes that contain an acetate a hydroxy or an aldehyde group via organ~boranes,~~~ 1-14C-labelled 12- methyltridecanoic and 12-methyltetradecanoic w-trideuteriated hexadec- 1-ene and hexadecanoic 16-(4-iodopheny1)hexadecanoic acid (for use as a myocardial imaging agent),"23 several a,or,o,o-tetrahalogeno-a,f~~-C,, dicarboxylic (1 3E)- 13-fluorohexadec- 13-en- I 1-ynyl acetate,325 some monofluorocarboxylic ( +)-(R)-a-lipoic acid (7 1),327 methyl ( +)-nonactate (72),32s homologues of (3a-alk-3-enoic acids by modified Knoevenagel condensation of aldehydes,329 diethyl 3-methyl-4-oxohex-2-ene-1,6-dioate and ethyl 4-met h yI-3-oxohex-4-ene- 1,6-dioa te 330 and 3,7-dimethyloct-2- NATURAL PRODUCT REPORTS 1989-M.S. F. LIE KEN JIE D D C02Me C02Me OHC OHC D D D (69) (70) J+y C0,Me s-s +co2H \ -0Me Me02C \ (73) ... [C H2 laO H A 1 0 lC217c O2H OH t lie;; m C c H O dH2 7C02H OH (75) V vi iiI - [C H2I7CO2H vii 1 OH OH Reagents; i BrMg[CH,],OMgBr THF; ii NH,CI (aq.); iii oxidation DMF; iv NaBH, CeCl,,; v BrMg[CH,I7MgBr THF HMPA; vi CO,; vii CH,N, Et,O Scheme 1 ene-1,8-dioic acid (the pheromone of a seed beetle) from 2- 18:2(9E,122) have been carried out by chain extension of methyl-6-oxoheptanoic The synthesis of strobilurin A Br[CH,],CO,H using acetylenic intermediates and with re-(73) and its (9E)-isomer (74) has been duction or partial hydrogenation of the acetylenic bonds at appropriate stages of the synthetic sequence.334 The syntheses of several hydroxylated unsaturated C, fatty acids that 3.3 C,,Compounds are associated with rice blast disease have been reported.The acid 18:1 (1 32) has been prepared by chain extension (f)-Dimorphecolic acid (75) has been prepared by the reaction of myristoleic acid [14 1(92)] which was obtained from of (2E,4Z)-deca-2,4-dienal with Grignard reagents (Scheme 1)335 beef The total syntheses of 18:2(9Z,12E) and or by chain extension involving HCGCCH=CHCH,OH NATURAL PRODUCT REPORTS.1989 ... 1.11 ... OH + --OH Ph OC(0)Ph 0C(0) viii I OH (75) Reagents LiNH,. NH:,; ii C,H,,Br; iii MnO, CHCl,,; iv BrMg[CH,],OThp (Thp = tetrahydropyran-2-y1) THF; v PhCOCl pyridine; vi pyridinium toluene-p-sulphonate EtOH; vii oxidation. CH,CI,; viii Ag,O KOH; ix. CH,N, Et,O; x H, Lindlar catalyst; xi K,CO, MeOH H,O Scheme 2 -/--OThp HO-OC(0)Ph I --/-OThp --OThp OHC-VIII IX x xi 1 Ph 0C (0) 0C(0) Ph I I ---'-CHO XI1 .XI1 I OC(0)Ph OH c0,Me xv C02H (76) Reagents i LiNH, NH:,; ii C,H,,Br THF; iii NaNH, H,NCH,CH,NH,; iv DHP toluene-p-sulphonic acid CH,Cl,; v. BrC-CCH,OH. CuCl NH,OH .HCI Pr'NH,; vi LiAIH, Et,O; vii MnO,. CHCI,; viii BrMgC,H,, Et,O; ix PhCOCI.pyridine; x pyridinium toluene-p- sulphonate EtOH; xi oxidation CH,Cl,; xii Ag,O KOH; xiii CH,N,. Et,O; xiv H,. Lindlar catalyst; xv K,CO:, MeOH H,O Scheme 3 24I NATURAL PRODUCT REPORTS. 1989-M. S. F. LIE KEN JIE I I OH OH 0C(0) Ph Reagents i. (A). PdCI,(PPh:,),. Cul. Pr"NH,. benzene [If (B) is used instead of (A) (R)-(76)is obtained]; ii LiAIH, THF; iii. PhCOCI pyridine; iv. TsOH. pyridinr EtOH v. pyridiniurii chlorochroniate. CH,CI,; vi. Jones oxidation vii KOH MeOH H,O Scheme 4 ?H ?H C0,H (77) OHC (Scheme 2).336 (+)-Coriolic acid (76) another fatty acid that is related to rice blast disease has been synthesized by similar chain-extension procedures involving acetylenic intermediates (Scheme 3)338 or in its pure enantiomeric forms by coupling of vinyl bromide with an optically pure propargyl alcohol intermediate (Scheme 4).337 Two other geometric isomers (77) and (78) of coriolic acid have also been synthesized by the latter approach.337 (-)-Vernolic acid and (+)-coriolic acid have been prepared from a carbohydrate (79).338 The stereoselective syntheses of 16-hydroxy- 18 :3(92,122,14E) 9-hydroxy-CO,H (78) 18 :3( I OE,122,1523 9-hydroxy- 18 :1(1OE) and 1O-hydroxy-18:1(8E) have been achieved by using 1,4-dichlorobut-2-yne and propargyl alcohol as Methyl 13-hydroxy- octadec-11 -en-9-ynoate has been prepared by the reaction of propargyl alcohol with 8-bromo-octanol followed by a chain extension that involved the Wittig The synthesis of vinylically deuteriated trans-parinaric acid [18:4(92,11 E 13E 1 SZ)] has been A biomimetic approach to the synthesis of colneleic acid (80) from (9s)-9- hydroperoxy- 18 :2( 1 OE,122) has been designed by Corey and co-workers.342 Rakoff has prepared the deuterium-labelled compounds methyl (9E 152)- and (92,l 52)-[6,7-2H2]octadeca-9,15-dieno-ate and some of the geometric isomers of [6,7-2H2]- 18 :3(9,12,15) by coupling methyl 12-0~0-[6,7-~H~]dodec-9-enoate with 1-bromohex-3-ene via the Wittig Methyl esters of [17,17,18,1 tb2H,]-1 8 :2(82,11Z) and [17,17,18 18-2H,]- 18 :3(82,11 2,142) have been synthesized by deuteriation of HC=C[CH,],OThp (n = 1 or 4; Thp = tetrahydropyran-2-yl) followed by chain extensions involving acetylenic intermediates or olefination by Wittig reaction.344 2-Fluorostearic acid has been derived by displacement of bromide from 2-bromostearate with moist silver(1) Methyl 7-and 12-fluoro-oleates have been prepared and biomethylation of the unsaturated centre to the cyclopropane derivative has been achieved by the micro-organism Lacto-bacillus plantar~m.~~~ A series of heteroatom-substituted ana- logues of stearic acid in which a methylene group in the alkyl chain has been replaced by an oxygen or a sulphur atom or by a sulphinyl group have been produced to study their spectroscopic Buist and co-workers have further synthesized 6-thiaoleic acid (8 l) which is converted into 9,lO- methylene-6-thiastearic acid by Lactobacillus plantarum while 5-thiastearic acid is desaturated by the micro-organism Sac-charomyces cerevisiae to 5-thiaoleic 1 0-Thiastearic acid has been shown to inhibit both the biosynthesis of dihydro- sterculic acid and the growth of the protozoan Crithidia fascic~lata.~~~ A number of thiophene fatty acids (82) have been prepared by acylation of alkyl-thi~phenes.~~~ Methyl 12-0x0- 18 l(9Z) gives methyl 9,12-epoxyoctadeca- NATURAL PRODUCT REPORTS 1989 C,H,,C=CCH,C=CCH,I (83) Me [CH214C H=C OR HC H zC H CEC C H=C I HC H,OH (84) R = SiPh2Bu' C0,Me (85) COzMe H (87) ."2' " 1 OH (88) (89) OH u::o ;HO ',OH I I OH (90) CO,H (92) OH OH CO,H (93) C02Me OH Pt Ph,B r (96) 9,ll-dienoate when treated with zinc or cadmium in the presence of di-iodomethane and 1,2-dimethoxyethane under concomitant ultrasonic irradiation while under similar condi- tions copper causes cyclopropanation across the ethylenic bond in methyl oleate and methyl ficin01eate.~~~ 3.4 C,,Compounds The partial synthesis of 20 :3(82,11Z 142) has been achieved by chain extension of y-linolenic acid via the Arndt-Eistert or the malonate procedure.352 (82,llZ,142)-Icosa-8,11,14-trien-5-ynoic acid has been synthesized from (83) in four Icosa-5,8,11,14-tetraynoic acid has been synthesized from acetylenic intermediates via the Grignard reaction and its partial hydrogenation gives arachidonic A stereoselective synthesis of cis-disubstituted olefins via 2,3-sigmatropic rearrangements has been reported for leukotrienes (lipoxins) in which (84)plays a key role as an intermediate.355 Hydroxylated unsaturated C, acids which have been prepared include (5S)- (8S)- (9S)- (1 IS)-,(12S)- and (12R)-mono- hydroxy-20 4,336-359 5,15-dihydroxy-20 :3,360(5S)-5,20- (1 59-15,20-,361 (12S)-12,20- (125,19R)-12,19- and (12&19S)-12,19- dihydroxy-20 :4,362 and several trihydroxy-20 :4 from acetylenic intermediate^.^^^ The isomers of epoxy-20 3 that have been prepared include (14R 15S)- (14S 15S)- (14R 15R)- and (14S 15s)-14,15-epoxy-20:3,:j6 both enantiomers of 8,9- and I I 12-epoxy-20:3,365 and (5S,6 R)-5,6-epoxy-20-hydroxy-and (I 4R,15s)-14,15-epoxy-20-hydroxy-20: 3."' The syntheses of prostaglandins thromboxanes leukotrienes and prostacyclins have been reviewed.H4 The methyl ester of Leukotriene A (85) has been prepared from hept- I -yne and 2-(3-bromopropyl)- I ,3-dio~olane"~ or by a Wittig reaction involving the intermediates (86) and (87).36i Leukotriene A (88) has been synthesized from (R)-glycidol (89) and but- 1-yne and leukotriene B (90) from but- 1-yne and the epoxide (9 I ).:""Some acetylenic analogues of leukotrienes A and D have been prepared and shown to have lower bronchostrictive activity than leukotriene D,.3(i''An elegant synthesis of a cyclopropyl-containing analogue (92) of leuko- tricne A has been described by Mori et a/.who used homochirdl protecting groups.:'i0 Leukotriene B (93) has been prepared from ~-mannitol,~~' from D-xylose,:"' or by coupling of acetylenic intermedi-ates*:373* 874 Corey and co-workers have synthesized (94) viu the coupling of (95) with (96).37*i The total synthesis of 20-hydroxy- and 20-carboxy-leukotriene B has been reported by Nicolaou and co-w~rkers."~~ A practical method for the multi-gram-scale synthesis of leukotrienes A and B has been reported.377.37H Several leukotriene analogues that contain a substituted aromatic nucleus have been prepared.These are a trifluoro- )2” NATURAL PRODUCT REPORTS 1989-M. S. F. LIE KEN JIE 243 es-co2ue (103) H OH C02Me (104) S C H,CH C02Me I NH2 (98) I I OH (105) 1 S-PeP OHC C02H (99)S-pep = glutathion-S-yl (cysteinylg1ycin)-S-yl or cystein-S-yl 0 OH (106) \R (1001 R = H or C,H, I i I HO OH (107) C02Me ‘H (101) I HO/ I OH acetamido-substituted aryl analogue (97),37garyl analogues leading to thromboxane antagonists have been reviewed by (98) and (99) in which there is a cystein-5’-yl a (cysteinylg1ycin)- Lee.389 S-yl or a glutathion-S-yl group at C-6,380.381 the dihydroxy- The total synthesis of punaglandin 4 has been de~cribed.~~‘).~~~ aryl compounds (100) and a hydroxy-pyridinyl analogue Several new synthetic routes to prostaglandins have been (IOI),” and a diary1 derivative (I02).383The synthesis of the developed which include a one-flask operation involving 0-methyl ester of (+)-3-thialeukotriene A (103) has been methyl-oximes,” intramolecular cycloaddition of keteni-The syntheses repOrted38J.385 and those of the isomers 7,7- 10,lo- and 13,13-minium salts,g9g and the use of n~rbornadienes.~~~ difluoroarachidonic acid.:3n6 of fluorinated prostaglandins prostacyclins and thromboxanes The photochemical synthesis of an analogue (104) of have been reviewed.395 Analogues of prostaglandins that thromboxane A via intramolecular trapping of an oxacarbene contain a sulphur atom (thia-analogues) have been prepared396 by a hydroxyl group has been reported.387 The dithiathrom- and the total synthesis of levuglandin D (106) has been boxane A (105) has been synthesized based on conjugate reported.”’ The novel prostacyclin analogues (I 07) and (108) addition reactions of thiin-4-0nes.”~ Several synthetic routes have been prepared.3g8.3w H0[ C Hzl 6C H (0H CH ( OH ) IC H 1 7C 0 H (109) (111) R’ = H or CH ; R2= HI CH, or R; R3 = H or R = 0 C C H I,[ C H=C H C H I M e or CH,O,C [CHz17[ CHZCH C H2121 C Hzl 3Me 0 \\ 1 ‘1 8H3 7 R-C H (115) 0 R = Br @ #NHZ LnL 0 (117) I I 0 C H zC H=C Me2 (118) 0 CH,CH=CMe (119) NATURAL PRODUCT REPORTS 1989 H (110) R R-6 H \ //c-N,c’8H37 0 (116) 8,$ror qMe I I I AP-M 3.5 Compounds with More than Twenty Carbon Atoms The synthesis of hexadecyl hexadecanoate from the C, acyl bromide and alkanol has been described along with those of sterol esters wax esters and triacylglycerols.400 The total synthesis of (+)-disparlure (56) has been 402 The enantiomers of (32,62,9S 10R)-9,1 O-epoxyhenicosa-3,6-diene have been prepared by employing the Sharpless asymmetric epoxidation reaction.402 Pougny and Rollin have synthesized the pheromones (32,62)- and (32,6E)-cis-9,lO-epoxyhenicosa-3,6-diene and (6Z)-~is-9,10-epoxyhenicos-6-ene~~~~ 404 from D-xylose.A one-pot synthesis (involving cuprate-acetylene- vinyltriphenylphosphonium bromide-aldehyde) for (62,92)- henicosa-6,9-diene has been developed.405 A short convergent synthesis of (32,62,92)-1,3,6,9-tetraene hydrocarbons (C18 and C20) [pheromones of the winter moth (Operophtera brumata)] by alkylation of BrCH,C=CCH,-CH,Br has been (9Z)-Tricos-9-ene (muscalure ; housefly pheromone) and n-triacontanol (a plant growth regulator) have been synthesized from aleuritic acid (109).407,408 3,ll-Dimethyl-nonacosan-2-one and 29-hydroxy-3,ll -dimethylnonacosan-2- one (pheromones of the cockroach BfatelZa ger-manica) have been derived from undec- 10-enoic acid.409 The enantioselective synthesis of (+)-(lOR 1 la)-squalene 10,l I-epoxide (1 10) confirmed the structure of this compound which has been isolated from the red alga Laurencia ~karnurai.~~~ Several 1,lO-phenanthroline esters (1 1l) containing un- NATURAL PRODUCT REPORTS 1989-M.S. F. LIE KEN JIE 245 saturated C, side-chains have been prepared to study their antimicrobial proper tie^.^^' The synthesis of two anacardic acids (1 12) and (1 13) and of ginkgoic acid (1 14) which are inhibitors of prostaglandin synthase via a directive metallation reaction has been described.412 Some interesting amphiphiles 0 (1 20) (1 15) and (1 16) have been produced from malonic acid that contain pyridinium ylide head-groups and which will be useful for studies of vesicular surfaces.*13 Specifically labelled [18-1*C]octatriacontane has been syn- thesized from [1-l*C]stearic 3.6 Lactones Oehlschlager and co-workers have synthesized (32)- I I -and (33-1 2-hydroxydodec-3-enoic (32,62)-11- and (32,62)-12-hydroxydodeca-3,6-dienoic and (SZ,SZ)-13- hydroxytetra- deca-5,g-dienoic acids which are precursors of the macrolide aggregation pheromones that are produced by males of grain beetles of the genera Cryptofestes and Oryzaephifus."'" The synthesis of similar macrolides has been described by Sakai a1.316.417 A convenient synthetic route to the (4R)- and the (4s)-y- (122) lactone (I 17) [a sex pheromone of the Japanese beetle (Popilfia japonica)] from D-and from L-arabinose respectively has been reported.J18( f)-Eldanolide (1 18) has been prepared from 2- trimethylsilyloxyfuran and Me,C=CHCH,Br which react to give a butenolide (1 19); this on reaction with Me,CuLi furnishes eldanolide.JIY Optically active litsenolide C (120) has (123) been synthesized.J20 The preparation of the mosquito phero- mone 6-acetoxyhexadecan-5-olide has been described.321 Octadecan- 18-olide (which is a constituent of the secretion of the Dufour's gland of bees of the genus Cofletes) has been C02H synthesized from hydrogenated kamlolenic acid [18-hydroxy-18:3(92,1 I E I 3E)].325 Both enantiomers of invictolide (I 2 1) [the pheromone of the red fire ant (Solenopsis invicta)] have been synthesized by alkylation of propargyl alcohol partial (124 1 reduction and asymmetric epoxidation followed by cyclization of the ring-opened epoxy intermediate.426 ( +)-(4S,6Z)-Dodec- 6-en-4-olide (I 22)j2' and cerulenin (1 23)428have been synthe- sized via acetylenic intermediates.A general diastereoselective synthesis of 4-(I -hydroxyaikyl)butan-4-olides has been de-A new method for the preparation of acarenoic acid 4 0 (124) by the stereo- and regio-selective alkylation of alkylidene- malonates has been rep~rted."~ (125) Many macrolides have been isolated from insects and plants. Examples are y-decanolactone (125) (the pheromone of males of the butterfly Lethe nzarginalis),'"' the trisacetoxy-compound boronolide (1 26) from a leaf extract of Tetradenia barber~e,~~~ hyptolide (1 27) from a leaf extract of Hyptis pectin at^,'^^ oxacyclononadec- 10-en-2-one from the seed coat of Hibiscus abelrn~schus,~~~and a novel unstable acetylenic lactone (1 28) from the root extract of Peucedanum alsutic~m.~~~ 3.7 Glycerol Derivatives An improved method for the synthesis of optically active I-or 0 3-acyl-sn-glycerols has been developed in which 2,3- or 1,2-isopropylidene-sn-glycerols are condensed with appropriate long-chain saturated or unsaturated fatty acids.The iso- propylidene group is removed by treatment with Me2BBr at -50 0C.436A detailed strategy for the synthesis of enantio- OAc (127) merically pure glyceryl esters and ethers has been proposed by which enantiomerically pure 1,2-isopropylidene-sn-glycerolcan be protected by either a benzyl an allyl or a trityl group.Selective deprotection methods provide means for specific HO acylation of the various positions of the glycerol A facile preparation of 1,2-diacyl-glycerols has been achieved by using an 0-iodobenzoyl moiety to protect the 3-hydroxyl group; the protection can readily be removed by chlorination (128) followed by mild basic hydrolysis.438A new asymmetric synthesis involves titanium-assisted nucleophilic opening of (8-glycidol with stearic acid which gives ( +)-(S)-1-stearoyl- sn-glycerol. The 3-hydroxyl group can be protected with t-butyldimethylchlorosilane and the silyl group can be removed (by using N-bromosuccinimide DMSO THF and H,O) without migration of the acyl group.This synthetic route offers a new entry to the synthesis of optically active mono- di- and tri-acyl glycerides and phospholipids.439 A method for the large-scale production of highly Unsaturated fatty acid mono- glycerides that involves the transesterification of the ethyl ester of 20 5 or 22 6 with 2,z-dimethyl- 1,3-dioxolan-4-methanol in the presence of sodium methoxide followed by hydrolysis with aqueous acetic acid has been described.44o Cholesteryl ethers have been prepared from mesylates of fatty alcohols which on treatment with the sodium salt of cholesterol in toluene in the presence of anhydrous DMF give high yields of the desired pr~ducts.'~' Compounds resulting from side-reactions during the acylation reaction of primary amines with fatty acid chlorides have been investigated.The by-products include 4-alkylidene-3-alkyl-oxetanones that can be further acylated with amino-compounds to give a-alkyl-p-keto-amide 4 Physical Properties Reviews have appeared on the characterization of lipids by chromatographic methods" j3 and by gas chromatography- mass ~pectrometryj~ ''; and on the polymorphism of lipids.a" 4.1 Gas Chromatography Reviews have appeared on the gas-chromatographic analyses of free fatty acids,4g on the recent advances in capillary gas chromatography applied to analysis of lipids,50 and on fish 1ipids.j' The capillary-gas-chromatographic analysis of Iinear fatty alcohols and acids in the wax esters of jojoba and from some marine organisms has been investigated.443 447 Quantita-tion of the components of transesterified soybean oil and chocolate fats by gas chromatography has been 449 German standard methods for the investigation of fats and fatty products have been described in detail for the deter- mination of conjugated dienes in fats by spectrometry and for the methylation of fatty acids in a fat or an oil for subsequent analysis by gas chr~matography.~~~ The use of a robotic station for the preparation of fatty acid methyl esters allows the automatic preparation of esters for gas-chromatographic analysis.45' Special gas-chromatographic methods have been developed for the characterization of volatile fatty acids in biological specimens,452 of the fatty acid esters of chloropropanediol that have been isolated from goat milk,453 of medium- and long-chain fatty acids in human milk,454 and of fatty primary amide~,~~~ for the localization of double-bond positions in fatty and for hexafluoro- isopropyl esters.457 Effort has also been directed to examining the accuracy and reliability of quantitative gas-chromato- NATURAL PRODUCT REPORTS.1989 three to six double-bonds) by column chromatography using porous styrene-divinylbenzene copolymer as the column packing and solvents that contain 1-50% of water as the eluent has been des~ribed."~ High-performance liquid chromatography has been widely used in the separation of lipid molecules. It has been applied to thc scparation of anthrylmcthyl esters'"" and C,,-C, fatty acid phenacyl Stable silver-loaded columns have been used for the separation of polyunsaturated fatty esters468.469 and trigly~erides,~'~ and h.p.1.c. has been used to separate hydroxylated metabolites of Clo-C18 fatty fatty acids (saturated branched and un~aturated),~'~.~~~ in the assessment of the number of double-bonds in fatty acids from fats and oils (using pentafluorobenzyl in the determination of the position of the double-bond (via the 2,4-dinitrophenyl-hydrazones of reduced ozonides) of unsaturated fatty in the analysis of cyclopropene fatty and cholester- 01,"' in the separation of a,p-isomers of trigly~erides,~'~. 479 diglycerides,4ao-4E2 483-485 and rnon~glycerides,~~~. in the analysis of milk fat4a6.487 and peanut in the separation of sucrose esters of fatty in the quantification of sterols glycerides and phospholipid^,^^^ in the separation of unusual branched and unsaturated phospholipids followed by fast-atom-bombardment mass-spectrometric analysis,491 and in the separ- ation of picolinyl esters of fatty acids for identification by mass of 20:4 and 20:5 in fish of prostaglandins El and E as their panacyl [p-(9-anthroyloxy)- phenacyl] bromide derivative^,^^' and of le~kotrienes.~~".496 4.3 N.M.R. Spectroscopy Results from the non-destructive estimation of the oil content of seed oils by pulsed n.m.r. techniques have revealed that the effect of the hydrogen content (defined as the number of hydrogen atoms per unit mass of oil) can be different not only for different oils but also for the same oil if it has been extracted from different varieties of the seeds creating an error in the estimation of values of oil contents by this technique.497 A new proton n.m.r.pulse sequence has been designed to provide spectral editing and solvent suppression which permits the observation of the terminal methyl group in fatty acids of the 0-3 series as in linolenic acid. When this technique is applied to the analysis of the sartorius muscle of the frog the signals of the terminal methyl group of members of the tI]-3 series of fatty acids are distinctly exhibited while in the analysis of rat brain the results suggest that the w-3 fatty acids 18:3 and 22:6 have higher mobility than those of the saturated fatty acids.49s Low-resolution pulsed n.m.r.measurements of whip- pabIe emulsion (cream topping) permit the phenomenon of spontaneous crystallization of fats to be followed during the process of reconstitution which is important for the texture and for the foam stability of the whipped cream.499 By graphic analyses of studying the structure-retention relationship for positional isomers of unsaturated fatty acid methyl 4.2 Liquid Chromatography Several 8.I3-I5 on the chromatographic analysis of lipids including a book12 and two reviews on high-performance liquid chromatography (h.p.l.~.),~~ 53 have been published. A novel thin-layer-chromatographic procedure for the separation of fatty esters including positional and geometric isomers by alumina argentation has been de~cribed.~" The use of the fluorescent dye nile red (9-diethylamino-5H-benzo-[a]phenoxazin-5-one) permits various classes of lipids to be quantitated in situ on thin-layer chr~matograms.~~~ The qualitative and quantitative analyses of total cholesterol fatty acids plasmalogens and other neutral lipids on chromarods using a flame-ionization detection (Iatroscan) show the versatility of this techniq~e.~~~.~~~ A purification method for long-chain (C18 24) polyunsaturated fatty esters (containing and to measuring the intensity of the carboxyl proton in the n.m.r.unsaturated fatty e~ter~~~~*~~~ spectrum and comparing it to that of the signal from a-methylene protons the rate of conversion of palm stearin into mono- and di-carboxylic acid by oxidative cleavage has been Lie Ken Jie and Lao have recorded the proton n.m.r.spectra of a series of azido-fatty A general rule for the assignment of the I3C n.m.r. peaks in the hydrocarbon chains of fatty acids has been proposed; the chemical shifts of the methylene carbon nuclei of homologous compounds result in systematic ordering allowing the lines of methylene carbon nuclei to be completely assigned for the aliphatic chains of unknown fatty The 'H and 13C n.m.r. shifts of a complete series of C, furanoid fatty acid esters have been recorded and the analysis of the results indicates that it is possible to identify through a study of 13C n.m.r. peaks all positional isomers of C, furanoid Carbon-13 n.m.r. spectroscopy has been applied to the study of saturated fatty acids that are bound to bovine serum albumin with regard to their filling504 and to the electrostatic interactions that exist in individual fatty-acid-binding The inter- NATURAL PRODUCT REPORTS 1989-M.S. F. LIE KEN JIE pretation of the I3C n.m.r. spectra of 7-substituted 9,l I-dideoxy-PGF analogues506 and of 120 prostanoids in which there is oxygen at C-9 and their intermediates has been reported. 507 4.4 Mass Spectrometry Reviews on the mass-spectral analysis of aliphatic compounds and fatty acids have been pre~ented.~~-~~ In the continuing effort to determine the positions of double-bonds in long-chain fatty acids mass-spectrometric analyses have been conducted on disulphide adducts of the unsaturated fatty acids that have been isolated from microbial monocultures and complex positional isomers of methyl undecenoates (carpet beetle picolinyl esters of isomeric 18 :1 and 18:2,492.510-512 and picolinyldimethylsilyl esters of unsaturated fatty Fast-atom-bombardment and tandem mass spectrometry permits iso- and anteiso- (methyl-branched) fatty acids to be readily disting~ished,~'~ and allows the positions of the double-bonds of unsaturated fatty acids (by collisional act/- vation of the alkali-metal-cationized fatty acids) to be deter- mi ned.5 15 This technique has also been applied to the analysis of organic acids (as the calcium triethanolamine complex) in Freon extracts from oil-well production water516 and to methyl 9,lO-epoxy~tearate.~" The more conventional electron-impact mass-spectrometric technique has been applied to the analysis of benzyl esters of C2-€, fatty acids,51s of a mixture of 18:1(92) and 18:l-(1 1E),519 of dimethyl esters of a,w-dicarboxylic acids (C3- C24),520 of cyclic amides of long-chain fatty acids and alco- hol~,~~~ of t-butyldi- of positional isomers of tetradecenol~,~~~ methylsilyl esters of deuteriated 18 :0 18 1 and 18:2 in blood plasma,523 and of allyldimethylsilyl ethers of prostaglandins leukotrienes and Saturated and monounsaturated fatty esters have been found to give abundant carboxyl anions under negative-ion chemical ionization.525 The quantitative measurement of monohydroxy- 20:4 together with 12-hydroxy-17:3 has been achieved by stable-isotope-dilution gaschromatography-negative-ionchem-ical-ionization mass Frankel and co-workers have used the chemical-ionization mass-spectrometric tech- nique to study the secondary oxidation products derived from 18:2 and 18:3:j2' The application of the Finnigan MAT ion- trap-detector mass spectrometer for structural determination in some isopropylidene derivatives of glyceryl ethers (from cod flesh) and of phenolic acetates has been investigated where the protonated molecular ion (M+ 1) appears in high intensity.52s Dissociative electron-capture mass spectrometry of fatty acids and their pyrrolidides and methyl esters has been studied.sz2" Field-desorption mass spectrometry of lipids has been applied to the investigation of natural waxes (jojoba wax preen-gland wax of goose spruce wax epicuticular wax from coniferous needles and wool wax); intense molecular ions of the components allow their ready identification in complex mixtures of lipids without the need for deri~atization.~~" 532 The application of gas-chromatographic-mass-spectrometric techniques to the analysis of prostaglandins and related substances has been reviewed."j3 Thermospray high-perform- ance liquid chromatography-mass spectrometry is a very useful technique for the characterization of prostaglandin^,"^-^""^ thromboxanes HETE and other metabolites of arachidonic 4.5 Other Spectroscopic Properties Supercritical fluid chromatography of free fatty acids with on-line detection of the acids by Fourier-Transform infrared spectroscopy that can be extracted from butter soap soybean and coconut oil has provided information as to the extent of dimerization and the degree of unsaturation in the eluted components.The absorbances at 1700 3000 and 3500 cm-' in the infrared spectrum were examined.537 Analysis of the cyclic fatty acids from heated linseed oil by gas chromatography (using Fourier-Transform infrared spectroscopy to detect them) indicates the presence of (2,E)-and (2,-diene isomers of cyclic fatty acid monomers whereas heated sunflower oil furnishes mainly (2)-monoethylenic cyclic fatty acid monomers and some (@-isomers as observed by the absorption bands at about 712 cm-I for the (2)-isomers and 968 cm-I for the (E)-isomers.538 The pre-melting phenomena of fatty acids have been studied by infrared and Raman spectroscopy; there is a sudden onset of conformational disorder prior to melting.539 The Raman- spectroscopic behaviour of long-chain alkanes and fatty acid esters has been examined in detail for the region of 850-900 cm-l and has provided an insight into motion and conformation at the chain termini and the backbones of alkanes and lipid molecules.540 Zero-order and second-order ultraviolet analyses of mixtures of (E,E)-and (2,E)-isomers of conjugated diene fatty esters give different absorbance minima which permits the concen- trations of individual isomers in the mixture to be determined without any prior Electron spin resonance studies have been conducted into the motion of lipid peroxyl radicals and free radicals that are generated during the autoxidation of unsaturated lipid molecules at low temperatures.542. 543 4.6 Polymorphism and Crystal Structure A review of the polymorphic phase behaviour of several of the major classes of lipids that occur in biological membranes has been pre~ented.~~ A study on the polymorphism of hydro- genated Canola oil has been made;544 the polymorphic structures crystal growth and phase transitions of fatty acid triglycerides have also been reviewed.545 The structural aspects their biological implications,546 and the role of lipids in different polymorphic phases in membranes have been The rates of crystallization of the melt and of phase transformations of three polymorphs of tripalmitin have been examined by optical microscopy X-ray diffractometry and differential scanning calorimetry.548 The presence of one two or three a-alkyl groups in the fatty acid components of a triglyceride molecule has been shown to shift the liquid-to-solid transition to lower temperature^.^^^ The crystallization patterns of a- p- and y-polymorphs of ultra-pure oleic acid in acetonitrile and decane have been examined; the solubility of the p-form is lower than that of the a-or the y-form at any temperature.550 The transformation from the a-to the P-phase of tristearin has been studied as a function of the annealing temperat~re.~~' The effect of diglycerides on the phase transition of various polymorphic forms of the normal triglycerides of sal fat (from Shorea robusta) has been investigatedjS2 and a study of the crystallization kinetics of palm oil has shown that crystal size is influenced by crystallization conditions as the rate of growth of crystals is proportional to the degree of super- saturation.""" Crystallization of cottonseed and sunflower oils and their blends produces ,&-type The kinetics of the p' to /I transition of PPP and of PPP-PSP and PPP-POP mixtures have been studied by variable-temperature X-ray diffraction and n.m.r.spectroscopy.jj" The dissociation con- stants of stearic acid dimer have been determined in different solvents using a Fourier-transform infrared technique and the results have been found to be relevant to the process of crystallization of stearic acid leading to the different poly- morphic f0rms.j"" Polymorphism in even-numbered fatty acids (stearic acid) has been studied by infrared Raman and Brillouin spectroscopy giving an insight into the states of molccular asscmbly of long-chain fatty acids.""' A study of the effect of unsaturation and substitution in position 2 of the triglyceride molecules has revealed an interesting transform- ation of the F-to the P-phase that depends on the nature of the acyl moiety at position 2."jx The polymorphic behaviour of cocoa butter in the presence NATURAL PRODUCT REPORTS 1989 of food emulsifiers serving as modifiers of crystal structure has been investigated.The effect of emulsifiers has been found to be to increase the liquid fraction of the fat prior to its transition.559 Mechanistic considerations of polymorphic trans- formations of tristearin and stearic acid in the presence of 561 emulsifiers or surfactants have also been HO (129) 5 Chemical Reactions 5.1 Oxidation H There have been four reviews on oxidation of lipids19*20*44*45 and two special issues of Chemistry and Physics of Lipids are devoted to the peroxidation of lipids with an emphasis on the bi'ochemical and biophysical aspects and the pathological implications of such derivatives.562 Oxidation of saturated fatty acids (1 2 :0 14:0 I6 :0 and I8 :0) with ozone gives mixtures of mono-and di-carboxylic acids in which there are half the number of carbon atoms of the starting fatty acids and some oxocarboxylic The reaction of jojoba wax with ozone yields a diozonide which is useful as a starting material for the production of pelargonaldehyde and pelargonic 5.I .I Auto-uidation Diffusion studies have shown that benzophenone-photo-sensitized autoxidation of linoleate in solution and in micelles of sodium dodecyl sulphate exhibits characteristics of a free- radical chain reaction with the formation of conjugated hydropero~ides.~~~ The prostaglandin-like substances (129-1 32) that are formed during autoxidation of methyl linolenate have been identified after they had been allowed to react with amino The kinetics of the autoxidation of polyunsaturated fatty acids with increasing degrees of unsatura- tion and of the mono- di- and tri-glycerides of linoleic acid in homogeneous chlorobenzene solution at 37 "C and under 760Torr of oxygen have been The rates of autoxidation of non-methylene-interrupted polyenoic fatty acids 18:2(52,92) 18:3(52,92,122) and 18:3(5E,9Z,12Z) are much lower than those that have been measured for linoleic acid and for linolenic acid.-567 The extents of oxidation of 20 5 and 22 6 have been compared quantitatively with those of 18:2 and 18 :3 by monitoring the uptake of oxygen and the formation of conjuga ted dienes hydroperoxides and secondary oxidation products.js8.js9The study on the autoxidation of the cyclic fatty acid ester (1 33) revealed that several hydroperoxide isomers (1 34)-( 141) are formed. These results provide infor- mation on the chemistry the detection and the effect OR their quality of heat-abused polyunsaturated cooking The autoxidation of cholesterol has also been re~iewed."~ 5.1.2 Oxidation by Singlet Oxygen The photo-oxidation of unsaturated fatty acids in the presence of pigment sensitizers has been reviewed.572 Dye-sensitized (by methylene blue erythrosin haematoporphyrin and riboflavin) photo-oxidation of phenyl oleate and the methyl and phenyl esters of linoleic acid shows that there is a dual mechanism involving both singlet oxygen and a radical attack across the double-bonds of the The diunsaturated C, cyclic fatty acid ester (1 33) forms the hydroperoxy-derivatives (1 34) (1 36) and (I 38)-(141) when photo-oxidized in the presence of methylene blue.j7* Iron is required for the initiation of peroxidation of lipids and evidence has been presented to indicate that this per- oxidation requires both Fe"' and Fe" ions with oxygen to form a Fel"-dioxygen-Fel' complex.The mechanism of initiation involving iron-catalysed formation of hydroxyl radicals has been The study of the effects of iron and ascorbic acid on the oxidation of micelles of methyl linoleate has shown that ascorbic acid functions as a reducing agent for the Fellr ion to give the more reactive Fe" RL (130)a;R' = H OH; R2 = 0 b;R'= O;R2= H,OH (131) a;R' = H,OH; R2 = 0 b; R' = 0; R 2 = H,OH R' (132) a; R'= H,OH;R2= 0 b; R' = O;RZ= H,OH Oxidation of Fe" ions in the presence of unsaturated lipid molecules is accelerated when phosphate ion or EDTA is also present in the 5.1.3 Enzymic Oxidation and Secondary Products of Lipid Oxidation Incubation of all-cis-18 3(6,9,12) -20:4(5,8,11,14) -20 5-(5,8,11,14,17) and -22:6(4,7,10,13,16,19) with soybean lip- oxygenase-1 at pH 9.0 yields 84 86 60 and 40% of the conjugated 18 :2 acid respectively.The low extent of formation of the diene product in the case of 22:6 is due to its further oxidation into conjugated diene monohydroperoxides to give conjugated triene products. However the secondary oxidation of conjugated diene monohydroperoxides is completely in- hibited if the reactions are carried out at pH 11.0.578 Bovine polymorphonuclear leukocytes exhibit 12-lipoxygenase activi- ties and metabolize arachidonic acid to (I 29- 12-hydroxyicosa- tetraenoic acid.The system is independent of concentration of calcium ion as well as of ATP. Unlike platelet 12-lipoxygenase the polymorphonuclear leukocyte 12-lipoxy- genase is able to convert linoleic acid into 13-hydroxy-octadecadienoic Lipoxygenase isolated from the tomato plant (Lycopersicon esculenturn) produces 9-to 13-hydroperoxide isomers of linoleic acid with the (10E 123-9- hydroperoxyoctadeca- 10,12-dienoic acid as the major pro- NATURAL PRODUCT REPORTS 1989-M. S. F. LIE KEN JIE (133) OOH (1361 (139) OOH (140) Arachidonic acid is converted into (8R)-8-hydroperoxy- 20:4(5,9,11,14) by a C-8 lipoxygenase that has been isolated from the-gorgonian coral Pseudoplexaura poro~a.~*~ Eggs of the sea-urchin Strongylocentrotus purpuratus contain a (1 1 R)-and (1 2R)-lipoxygenase activity which metabolizes arachidonic acid to (1 1R)-1 1-and (12R)-12-hydroxy-20:4(5Z,8Z,1OE,14Z) and the corresponding (1 1 R)-1 1- and (14R)- 14-hydroxy-analogues of 20 5.582 (9Z)-I 3-Hydroxy- 12-0x0-octadec-9-enoic acid is formed from (92,ll E,13s)-13-hydroperoxyoctadeca-9,11 -dien-oic acid in the presence of corn hydroperoxide isomerase via a labile intermediate (92,139- 12,13-oxido-octadeca-9,1 l-dien-oic The effect of glutathione on lipoxygenase products generated from 20:4 and 22:6 by enzymes in trout gill tissue has been Enzymic oxidation of linolenic acid in the presence of a protein fraction from a mushroom (Psalliota bispora) gives an intermediate 10-hydroperoxy-18:3(8E,12Z 15Z) which is further metabolized to a mixture of (5Z)-octa- 1,5-dien-3-01 (2Z,5Z)-octa-2,5-dien- 1-01 and (80-10-oxodec-8-enoic Frankel has reviewed the chemistry of the secondary products of peroxidized lipid molecules which form a wide range of carbonyl compounds hydrocarbons and furan derivatives,586 and also the biological significance of their secondary oxidation Irradiation of a solution of methyl (1 3s)- 13- hydroperoxy- 18 :2(9Z 1 1 E) in methanol with ultraviolet light yields stereoisomers of methyl 9,13-dihydroxy- 1O-methoxy-18 I (1 1E) and methyl 9,13-dihydroxy- 12-methoxy- 18 :1-(~OE‘).~~* A study of the chemiluminescent decomposition of hydroperoxides of methyl linoleate on alumina and silica gel has been reported.589 Thermal decomposition of methyl linolenate hydroperoxides at 150 “C gives methyl octanoate (60.1 YO)and hepta-2,4-dienal (0.5 Oh) while metal-catalysed (ferric chloride and ascorbic acid) decomposition of the same hydroperoxide at room temperature gives methyl octanoate (13.2 %) and hepta-2,4-dienal (60.8 Treatment of methyl (1 351- 13-hydroperoxy- 18:2(9Z 11E) with vanadium oxyacetyl- acetonate forms two diastereomeric a$-epoxy-alcohols which are readily hydrolysed to the corresponding trihydroxy- 18 1 derivative^.^" 10 OOH (134) (135) 00H (141) 5.1.4 Antioxidants The role of antioxidants in relation to peroxidation of lipids has been reviewed592 and several short reviews covering some biological and nutritional aspects including the oxidation and metabolites of antioxidant^,^'^ their actions in biological 595 and nutritional aspects of vitamin E,596have been published.A monograph in which the chemistry of antioxidation flavour reversal in edible oil and natural and synthetic antioxidants are described has also been p~blished.~” Leaves of the oil palm contain high levels of a-tocopher~l,~’~ and the content of tocopherols and tocotrienols in Finnish foods has been A new class of natural antioxidants consisting of a polyhydroxynaphthoquinone system has been identified600 while an antioxidative metabolite that has a synergistic effect on the action of tocopherol has been isolated from Penicilliurn herquei.601 The effect of antioxidants and the oxidative stability of avocado oil have been studied.112*113 A lignan compound sesaminol appears to possess strong antioxidative activity and is found in unroasted sesame-seed The claim that tempeh oil contains a potent fat antioxidant has been ruled Nitrite-treated cooked and processed meats have greater (up to three-fold) antioxidant activity than that of untreated meats.604 a-Tocopherol at high concentration exhibits a pro-oxidant effect during the autoxidation of 18:2 18:3 and 20:4.605.606 This pro-oxidant activity can be inverted into antioxidant activity when a-tocopherol is associated.with various com- pounds including amino acids BHT hydroquinone and ascorbyl palmitate.607-609 Stearic acid has been found to act as a pro-oxidant as it accelerates the rate of autoxidation of methyl linoleate and the decomposition of methyl linoleate hydroperoxide.610 Ingold has studied the chiral discrimination in the exchange of isomers of a-tocopherol between plasma and red blood cells611 and the biokinetics of dietary (R,R,R)-and (S,R,R)-a-tocopherols in male rats.612 A study of the mechanism of stabilization of biomembranes by a-tocopherol indicates that the longer the isoprenoid chain in the antioxidant the easier it is to penetrate and diffuse in the membrane.613 The NPR 6 (142) reaction of ozone with a-tocopherol and with 18 1 and 18 2 in micellar solvents demonstrates the ready formation of a-tocopheroxyl radicals by the e.s.r.technique supporting the radical-scavenging ability of a-tocopherol in animal A method for the formation of radicals from antioxidant-type compounds by polyunsaturated lipid molecules has been described."'j No significant sign of deficiency of essential fatty acids has been observed in vitamin-E-deficient rats.616 The synthesis of the optically active side-chain of vitamin E by a chemico-enzymatic approach has been reported6I7 while the properties of seventeen synthetic analogues and derivatives of a-tocopherol have been evaluated for their antioxidant activity."* I -Thio-a-tocopherol (142) has been synthesized in ten steps in an overall yield of 2%.'19 Analytical methods for the identification of antioxidants in food have been reviewed.620 A sensitive test to evaluate antioxidants in oils and fatty esters by the sesamol dimer- haemoglobin method has been described."l Individual toco- pherols can be determined by ultraviolet spectral analysis622 or by chromatographic method^.^^^.^^^ Analysis of headspace volatiles of soybean oil has been applied to evaluating the oxidative and the thermal stability of the hydrogenated oil and the effect of additives.625 5.1.5 Detection of Oxidation A short review outlining the advantages of using a luminescence spectrometer based on photon-counting techniques for the detection of peroxidation of lipids has been published.626 A highly sensitive and simple chemiluminescent method for the quantitation of lipid hydroperoxides at the picomole level has been described.The method is based on detecting the chemiluminescence that is generated during the oxidation of luminol by its reaction with a hydroperoxide and cytochrome c under mild conditions and is found to be highly sensitive to methyl linoleate hydroperoxide arachidonic acid hydro-peroxide and cholesterol hydropero~ide.~~~ Parinaric acid [I8 :4(9Z I 1E,I3E 15Z)Ihas been used as a sensitive fluorescent probe for the determination of peroxidation of lipids in liposomal membranes by monitoring the decrease in fluores- cence intensity against other peroxidation assay systems.62* A new fluorometric determination of hydroperoxides of lipids has been proposed where non-fluorescent diphenyl-(pyren-1-yl)phosphine is oxidized quantitatively by hydro- peroxides to a strongly fluorescent diphenyl(pyren- 1-yl)phos-phine oxide that has 10000-times higher sensitivity than conventional iod~metry.~~~ The applications of electron spin resonance spectroscopy to the identification of the radicals that are produced during the peroxidation of lipids have been reviewed with emphasis being given to the metabolism of xenobiotic chemicals and the interaction of such species with lipid rn01ecules.~~~ Studies on the photolytic breakdown of hydroperoxides and peroxidized fatty acids by using electron spin resonance spectroscopy have been carried out.Spin trapping using 5,Sdimethyl- 1-pyrroline N-oxide has been used to detect and distinguish between the carbon-centred alkoxyl and peroxyl radicals that are produced during the photolytic decomposition of hydroperoxides of lipid mole- cules.63 An electroanalytical method has been developed for the determination of lipid peroxides in physiological fluids.The method is based on separation of the peroxides by h.p.1.c. and direct determination by using a modified polarographic detector NATURAL PRODUCT REPORTS 1989 system; the detection limit is 2x mole of fatty acid hydro peroxide^.^^^ High-performance liquid chromatography has been found to be an effective method for the determination of the absolute configuration in the products of the lipoxy- genase-catalysed oxygenation of polyunsaturated fatty acids. The fatty acid hydroperoxide is reduced to the corresponding alcohol and subsequently converted into the ( + )-a-methoxy-a-(trifluoromethy1)phenylacetic acid esters.Diastereoisomeric esters of enantiomeric alcohols are readily resolved by normal- phase h.p.l.~.~~~ A method for the detection and characterization of lipid hydroperoxides at picomole levels by h.p.1.c. of the lipid hydroperoxides and detection of the chemiluminescence that is emitted by isoluminol in the presence of a hydroperoxide and microperoxidase has been 5.2 Epoxides Formation and Reactions Emphasis has been directed to the preparation of epoxy fatty acid esters from unsaturated esters by their epoxidation with hydrogen peroxide in the presence of catalysts such as an alkali-metal tungstate or tungstic Amberlite IR-120,636 or molybdenum oxide-tributyltin chloride on char-Acetic acid has been used as an oxygen carrier between two phases for the epoxidation of oleic acid with hydrogen peroxide as the oxygen source.638.639 Linseed oil and castor oil have been successfully epoxidized by isopropylbenzene hydroperoxide in the presence of molybdenum or vanadium acetylacetonate;640.641 in the presence of cobalt(rrr) ions and benzaldehyde oleic acid is epoxidized with oxygen.642 Samarium(r1) iodide induces highly regioselective reduction of a,,$epoxy-esters and y,S-epoxy-up-unsaturated esters to give b-hydroxy-derivatives in > 98 % enantiomeric ex~ess.~*~ Epoxides furnish 2-oxalines when they react with PhCN in the presence of boron trifluoride etherate,644 and are converted into tetrahydrofuran derivatives by reaction with iodine a~ide.~~'j The reaction of methyl trans-2,3-epoxyoctadecanoate with phenyl isocyanate furnishes the corresponding 3-phenyl-oxazolidin-2-0nes.~~~ Treatment of 2,3-epithio-C, and -C18 fatty esters with NOCl gives thionitrite derivative^.^^' The position of the epoxide function in methyl 9,lO-epoxystearate can be located by application of a collision- activated mass-spectrometric technique.648 The total assign- ment of the 'H and I3C n.m.r.spectra of the methyl ester of (5R,6S)-5,6-epoxy-20 3(82,112,14Z) has been achieved by application of the selective inverse INEPT and 13C-f 'H -f 'H heteronuclear relayed-coherence-transfer pulse-sequence method.649 5.3 Hydrogenation A comprehensive review has been published on homogeneous heterogeneous and catalytic- transfer hydrogenation re-actions.6s0 Allen has provided an outline of his research on hydrogenation of fats,6s1 while several mini-reviews have been published on the manufacture and use of hydrogenated fats and oils.6552-657 Methods for partial hydrogenation to produce oils that contain low levels of trans-unsaturated components have been summarized with emphasis on the effect of process variables and the type of catalyst on hydrogenation."j" Studied on the mechanism of selective hydrogenation of vegetable oils have been conducted with the following results hydrogenation of rape oil in the presence of nickel produces a range of cis/trans positional isomers of 18 1 and 18:2;"j9 the use of a rotating packed-disc reactor of nickel/silica gives improved transfer of hydrogen during the hydrogenation of soybean oil ;660 nickel-copper fused catalysts have been pro- moted with Pd Rh Ge Re Sn or Ru and the Ge-promoted catalyst gives the highest catalytic activity but there is greatest selectivity if the Rh-promoted catalyst is used on cottonseed oil."' Aqueous solutions of inorganic salts of formic acid have been successfully used in the palladium-catalysed transfer hydrogenation of soybean NATURAL PRODUCT REPORTS.1989-M. S. F. LIE KEN JIE Me N H C [C H2I8C0,Me MeC N H [C H,I& 02Me It II 0 0 (143) (144) Intensive studies have been carried out on the hydrogenation of Canola oil variable temperature and pressure conditions with palladium black produce partially hydrogenated fats with a low content of rrms-isomers,115 formation of trans-acids is suppressed and removal of linolenate is improved when the hydrogenation is carried out at low temperatures (-100 "C)'"" with Pd-Ag and Pd-Ni on silica the catalytic activities and selectivities between a ruthenium catalyst and nickel have been compared,"4 hydrogenation in the presence of nickel and methyl benzoate-chromium tricarbonyl complex allows ad- vantages to be derived by combining homogeneous and heterogeneous catalysts,116.665 and the reaction rates in position 2 and in positions 1 and 3 of the glycerides have been investigated when Canola oil is hydrogenated under selective and non-selective conditions.120 Partially hydrogenated soybean oil contains 2.7 YOlinolenic acid and 1.2 YOof a mixture of geometric isomers of 18:3.666 Hydrogenated rice-bran oil can be used as a substitute for animal tallows.66i A naphthalene<hromium tricarbonyl com- plex has been developed for use as an effective hydrogenation catalyst for vegetable oils.66H The effect of solvents on the efficiency of hydrogenation of sunflower oil in the presence of Ni-Cu catalyst has been studied; ethanol and propanol are the best and benzene is the worst solvent with respect to the degree of hydr~genation.~~' The use of hydrazine in the presence of urea during hydro- genation of linoleic and linolenic acid prevents isomerization of the ethylenic The effect of some isothiocyanates on the hydrogenation of Canola oil is to increase the content of solid fat and the level of trans-isomers as the level of sulphur in the oil is increased,"' while the presence of chlorophyll reduces the formation of trans-isomers but reduces the rate of hydrogenation.118 The effects of operating conditions on the quality of soybean oil during continuous ultrasonic hydrogenation in the presence of a nickel catalyst have been examined.The results show that good quality products can be obtained at lower cost than by present methods. 121 A computer-assisted chromatographic method for controlling the hydrogenation of fats has been reported6" and a computer program for calculating the catalytic selectivity in hydrogenation of vegetable oils based on kinetic considerations has been published.67z 5.4 Other Reactions of Acetylenic and Oiefinic Systems Osman and co-workers have studied the allylic oxidation of 18 l(2E) methyl ester by chromium trioxide,"'" the addition of MeOBr to unsaturated fatty esters to give brorno-ester~,~~~ the transformation of 4-oxo- 18 :l(2E) methyl ester into 4-acetoxy- I8:2(2E,4Z) methyl ester with acetic anhydride and toluene-p- sulphonic and the reaction of iodine azide with oxygenated olefinic acids to form tetrahydrofuran deriva-tive~."~ Thioethers have been derived from methyl ricinoleate and methyl isoricinoleate with 3-mercaptopropane-I ,2-diol.677 Ahmad and co-workers have described the reaction of acetylenic esters with phthalimid~nitrene~~~ and the nitration reaction of /I-and y-acetoxy-olefinic fatty Soybean lipoxygenase has been used in the conversion of methylene-interrupted polyunsaturated CIS,C,,, and C, fatty acids into conjugated diene and triene isomers."(' Photo-isomerization of 18:2(9,12) gives a mixture of geometric isomers of I8:2(9,11) and 18 :2( 10,l 2),681 and the catalytic isomerization of safflower oil (containing 18 :2) with rhodium complexes has been studied.682 The cis-trans isomerization of oleic acid and of refined sunflower oil with a nickel catalyst has 25 1 Me [ CH,l,NHC[ CH,l,oC OzMe II 0 0 (145) (146) been investigated.683 Two improved methods for the isolation of the isomers of I8:3(9,12,15) from natural and from heated linseed oil have been described.684 5.5 Reactions of Oxygenated Acids Reactions of methyl 1O-oxoundecanoate and methyl 12-oxostearate with excess hydrazoic acid give mixtures of the amides (1 43)-( 146).685 Oxathiolanes,6R6 bis-~xathiolane,~~~ and thiazoneP8 have been prepared from similar keto-fatty acids.The transformation of epoxy-fatty esters into 2-oxazoline~~~"~ 690 has been and 3-phenyloxazolidin-2-0nes~~~~ reported. Several azide-containing fatty esters have been derived from methyl ricinoleate and methyl dihydroxystearate. jol 5.6 Reactions of the Carboxyl Group 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been used in the decarboxylation of long-chain fatty acids in the presence of Cu'Br under high temperatures (34&360 "C) to give the corresponding hydrocarbon^.^'^ Ferric stearate (a useful water repellent thickener and surfactant) has been prepared by allowing a solution of stearic acid in THF to react with Fe(OMe), under argon.692 The sodium salt of sunflower oil has been directly converted into the methyl esters when treated with 4-MeC6H4S0,Me or Me,SO in the presence of Bu,NCI.~''" An improved method for the catalytic preparation of t-butyl esters of fatty acids has been recommended and involves t-butyl alcohol in dicyclohexyl- carbodi-imide (DCC) catalysed by 4-(dimethy1amino)pyri- dine (DMAP).694 Unsaturated fatty acid piperazides have been prepared and found to be useful anticoagulant^.^^^ A facile synthesis of N-chlorinated fatty amides has been described in which long-chain amides were treated with chlorine in water at 100 0C.696The use of ultrasound (20-50 kHz) to achieve the hydrolysis of wool grease fats and oils at 60 "C in the presence of an alkali using tricapryl(methy1)ammonium chlor-ide as a phase-transfer catalyst has been de~cribed.~'~ The reaction of fatty acids with thiourea gives the irninothiazol- idinones (147) which on acid hydrolysis yield the thiazolid- inediones (148).@" 6 Metabolism of Fatty Acids 6.1 C,,Acids Mukherjee has studied the elongation of (n -9) and (n-7) cis-monounsaturated and saturated fatty acids that occurs in the seeds of Sinapis ah where there is preferential stepwise (147) n = 13'15,or 19 (148) n = 13'15 or 19 OH Me[C H21,4 ,!,,CO,H I (1491 addition of C units to pre-formed oleoyl-CoA over addition to vaccenoyl-CoA by acetyl-CoA or malonyl-CoA to yield (n-9) icosenoyl-CoA (n-9) docosenoyl-CoA and (n -9) tetracos-enoyl-C~A.~~~ An active A‘-desaturase is present in seeds of Borago oficinalis (common borage) that converts linoleate into y-linolenate and involves the desaturation of linoleoylglycero- phosphocholine to y-linolenoylglycerophosphocholinein the presence of NADH.’OO The synthesis of linoleic acid de novo has been demonstrated in eight species of insect.701 Oleic acid is oxidized 35-40 YOfaster than its trans-isomer (elaidic acid) by rat heart homogenate but the two compounds are oxidized at equal rates by human heart homogenate suggesting that the presence of the trans-double-bond in elaidic acid does not impair its utilization for energy by human heart muscle.7o2 Hepatic metabolism of oleic acid and elaidic acid has been compared and the results indicate that the rates of peroxisomal and mitochondria1 oxidation of fatty acids are different for the different geometric isomers of 18 1 and depend on the strains of rats (Wistar or Sprague-Dawley) that are used in the experiment^.'^^ The acids trans-16 1 and 18 1 are distributed from 0.3 YOin the brain to 4.0 YOin adipose tissue in humans whereas trans-18:2 has not been detected in the brain and only in small quantity (0.4 YO)in the adipose A study of the metabolism of I8 2( 122,152) in humans shows that it causes no adverse effects although it has been found that 18 2( 122,152) is metabolically more similar to 18 0 and 18 1 than to 18 :2(9Z 122).’O5 Incubation of oleoyl-CoA in soybean cell suspension cultures gives 3-hydroxyoleate 18 :2(2,9) and 18 :2(9,12); linoleoyl- CoA yields 3-hydroxylinoleate and 18 :3(2,9,12) but no 18:3(9,12,15) under the same conditions.706 Both 18 1(1 22) and 18:2(9E,12E) have been readily metabolized by lipogenic enzyme activities in mouse liver and are incorporated into hepatic lipids.707 ( 142)-14,15-Didehydrocrepenynic acid [I 8 3(92,12A 142)] is converted into NC[CrC],CH=CHCO,H by the fungus Lepistu diemii into HO,C[CrC],CH,CH,CO,H by Serpulu lucrymuns (Merulius lucrymuns) and into H[C-C],CH(OH)- CH(OH)CH,OH by Coprinus yuadriJidus.’08 Crepenynic acid [ I8 2(92,12A)] is a precursor of C,-C, polyacetylenes when incubated in fungal The ‘green odour’ of green leaves consists of six volatile compounds of C aldehydes and C alcohols which are metabolites derived from linoleic and linolenic acids.’l‘’ Aspergillus ruber and A.repens metabolize coconut oil to a mixture of C,-C, methyl ketones.’ll 343x0- octadecanoic acid has been enantioselectively reduced by fermenting bakcr’s yeast (Succharomyccls crrclvi.siuc) to (3R)-3- hydroxyoctadecanoic acid which forms a crucial intermediate for the synthesis of optically pure ( + )-(2R,3R)-corynomycolic acid (1 49).712 The lipolysis of synthetic (mixed) triglycerides that contain the cyclic fatty acid (133) has been studied and the results indicate that partial cyclic fatty acid triglycerides (often found in heat-abused fats) can undergo lipolysis and are likely to be absorbed like normal dietary fats.71:’ Several unsaturated fatty acids have been found to inhibit enzyme activities.Crepenynic acid [ 18 2(92,12A)] and ximenynic acid [I 8 :2(9A,11E)] inhibit the biosynthesis of thromboxanes B and B,.7’4 Aerobic incubation of soybean lipoxygenase with (I OZ,132)-12-methylidencnonadcca-IO,I3-dienoic acid results in irreversible deactivation of the en~yme.~’.’ Jacarandic acid [ I8:3(82,1OE 12231 which can be isolated from the seed oil of Jucurundu mimo.sifi,liu and the synthetic isomer 18:3(82,1OE,12E) are strong inhibitors of NATURAL PRODUCT REPORTS 1989 cyclo-oxygenase Colneleic acid (80) inhibits the activity of the lipoxygenase that has been isolated from potato (Solanum tuberos~m).~~~ The metabolism of several furanoid fatty acids (17)-(20)210.211 has been covered in Section 2.3.6.2 C, Acids The metabolism of some C, acids has already been described in Section 2.4. The elongation of C, polyunsaturated fatty acids by human skin fibroblasts to their respective C, derivatives has been studied.‘17 Poly-methylene-interrupted dienoic fatty acids 20:2(5,11) and 20:2(5,13) are similarly elongated to 22 :2(7,13) and 22 :2(7,15) respectively by the mollusc Scapharca bro~ghtoni.~’~ Rats that are deficient in essential fatty acids can retro-convert arachidonic acid into linoleic acid in viva."' The effect of icosatetraynoic acid which is the acetylenic analogue of arachidonic acid is to block the A6-desaturase activity of the membrane lipids in trout liver and intestine.720 Derivatives of 20 :4(6,8,11,14) that contain NH(0H) or CH,C(O)NH(OH) groups at C-5 show potent inhibitory activities towards lip~xygenase.~~’ 7 Biotechnology A review on production of lipids by biotechnology has been published.59 Some technical feature articles on this subject include those on plant lipid biotechnology,i22 the use of micro- organisms in the oils and fats enzyme technology for the lipid industry,724 and agricultural biotechnology in the development of oil crops.725 Lipases from germinating seeds of rape (Brussica napus) and mustard (Sinapis ah),and from the cotyledons of seedlings of lupin (Lupinus albus) have been isolated and exhibit highest lipolysis activities between pH 8 and 9 with specificity for positions sn-1 and sn-3 of triglycer- 01s.’~~ A study of the lipase-catalysed hydrolysis of palm oil with lipase from Candidu rugosa has shown that there is an op- timal activity at 37 “C and at pH 7.5.7” The continuous use of lipases in hydrolysis of and the hydrolysis and esterifica- tion of fats by the lipase from Hurnkolu lunuginosu have been inve~tigated.’~, A laboratory-scale and pilot-scale study on the enzymic interesterification of fats has been reported.‘“” 8 References I ‘The Lipid Handbook’.ed. F. D. Gunstone J. L. Harwood and F. B. Padley Chapman and Hall London 1986. 2 ‘Handbook of Lipid Research Volume 4.The Physical Chemistry of Lipids from Alkanes to Phospholipids’ ed. D. M.Small Plenum New York 1986. 3 ‘ Handbook of Eicosanoids Prostaglandins and related Lipids ’ ed. A. L. Willis CRC Press Boca Raton 1987. 4 ‘Fat Absorption’ ed. A. Kuksis CRC Press Boca Raton 1986. 5 ‘The Phospholipases’. ed. M. Waite Plenum New York 1987. 6 ‘The Biochemistry of Plants. A Comprehensive Treatise Lipids Structure and Function’ ed. P. K. Stumpf E. E. Conn and D. D. Davies Academic Press New York 1987. 7 J. F. Mead R. B. Alfin-Slater and D. R. Howton ‘Lipids Chem-istry. Biochemistry and Nutrition‘ Plenum New York 1986. 8 M. Kates ‘Techniques of Lipidology Isolation Analysis and Identification of Lipids’ (2nd rev. edn.) Elsevier Amsterdam 1986. 9 C. Paquot and A. Hautfenne ‘Standard Methods for the Analysis of Oils Fats and Derivatives’ Blackwell Oxford 1987.10 ‘Topics in Lipid Research from Structure Elucidation to Biological Function’ ed. R. Klein and B. Schmitz Royal Society of Chemistry London 1987. I1 ‘Methods for Nutritional Assessment of Fats’ ed. J. Beare-Rogers American Oil Chemists Society Champaign 1986. 12 W. W. Christie ‘High Performance Liquid Chromatography and Lipids A Practical Guide’ Pergamon New York 1987. 13 ‘Chromatography of Lipids in Biomedical Research and Clinical Diagnosis’ cd. A. Kuksis Elsevier Amsterdam 1987. NATURAL PRODUCT REPORTS 1989-M. S. F. LIE KEN JIE 14 R. J. Hamilton and S. Hamilton ‘Thin Layer Chromatography’ Wiley New York 1987. 15 D. Ranny ‘Thin-Layer Chromatography with Flame Ionization Detection’ Reidel Dordrecht 1986.16 ‘Palm Oil Critical Reports on Applied Chemistry Vol. 15’ ed. F. D. Gunstone Wiley New York 1987. 17 R. J. Hamilton and A. 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Abstr. 1987 107 21 1 897). 76 K. Wikmar and I. B. Gustafsson Naeringsforskning 1986 30,38 (Chem. Abstr. 1986 105,77 838). 77 K. Schroer Verh. Dtsch. Ges.Inn. Med. 1986 92,610 (Chem. Abstr. 1987 106,78 822). 78 W. S. Powell and C. D. Funk Prog. Lipid Res. 1987 26 183. 79 C. Bedetti and A. Cantafora Adv. Biochem. Eng./Biotechnol. 1987 35,47. 80 T. Suzuki Fukushima Igaku Zasshi 1986 36,205 (Chem. Ahstr. 1987 107 174831). 81 E. A. Higgs S. Moncada and J. R. Vane Prog. Lipid Res. 1986 25,5. 82 9. Samuelsson Prog. Lipid Res. 1986 25 13. 83 B. Samuelsson S. E. Dahlen J. A. Lindgren C. A. Rouzer and C. N. Serhan Science 1987 237,1171. 84 M. P. L. Caton and T. W. Hart Adv. Prostaglandin Throm-boxane Leukotriene Res. 1985 14,73. 85 R. L. Jones Top. Lipid Res. 1986 65. 86 R. A. Johnson Adv. Prostaglundin Thrombo.uune Leukotriene Res. 1985 14 131. 87 N. H. Wilson and R. L. Jones Adv. Prostaglandin Thromhoxane Leukotriene Res.1985 14,393. 88 A. Marfat and E. J. Corey Adv. 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Ahstr. 1987 106,67 574). 101 W. Jerzykiewicz and W. Misiurny Przem. Chem. 1987 66 67 (Chem. Abstr. 1987 107 236 001). 102 R. H. Kung Hwahak Kwa Kongop Ui Chinbo 1987 27 312 (Chem. Abstr. 1987 107 236 004). 103 Z.-Y. Li Youji Huaxue 1986 177 (Chem. Abstr. 1986 105 45 276). 104 M. Barbier Apidologie 1986 17 1 (Chem. Abstr. 1986 105 78 101). 105 C. 0.Meese J. Labelled Compd. Radiopharm. 1986 23 295.106 H. Meier zu Beerentrup and G. Roebbelen Fett Wiss. Technol. 1987 89 227 (Chem. Abstr. 1987 107 130 952). 107 B. Breuer T. Stuhlfauth H. Fock and H. Huber Phytochemistry 1987 26 1441. 108 L. A. Garcia M. A. Alfaro and R. Bressani J. Am. Oil Chem. Soc. 1987 64 371. 109 C. K. Lyon and R. Becker J. Am. Oil Chem. Soc. 1987 64 233. 110 J. M. Aguilera A. Fretes and R. San Martin J. Am. Oil Chem. Soc. 1986 63 1568. 1 I1 M. J. Werman and I. Neeman J. Am. Oil Chem. Soc. 1987 64 229. 112 M. J. Werman and I. Neeman J. Am. Oil Chem. Soc. 1986 63 355. 113 M. J. Werman and I. Neeman J. Am. Oil Chem. 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Abstr. 1986 105 41 712). 139 N. Totani and K. Oba Lipids 1987 22 1060. 140 S. W. Wright E. Y. Kuo and E. J. Corey J. Org. Chem. 1987 52 4399. 141 Y. Suzuki and K. Arai Kemikaru Enjiniyaringu 1986 31 364 (Chem. Abstr. 1986 105 99 463). 142 M. B. King T. R. Bott M. J. Barr R. S. Mahmud and N. Sanders Sep. Sci. Technol. 1987 22 1103. 143 A. K. K. Lee N. R. Bulley M. Fattori and A. Meisen J. Am. Oil Chem.Soc. 1986 63 921. 144 M. A Soliman and N. A. Younes J. Am. Oil Chem. Soc. 1986 63 248. NATURAL PRODUCT REPORTS 1989 145 T. H. Yoon Han'guk Yongyang Siklyong Hukhoechi 1987 16.93 (Chem. Absrr. 1987 107 174 660). 146 S.-J. Peng B.-Q. Tan D.-C. Zhang Y.-P. Guo and L.-Y. Yang Nanjing Linye Dame Xuebao 1986 No. 4 p. 24 (Chem. Abstr. 1987 107 55 762). 147 C. Paoletti F. Bocci G. Lercker P. Capella and R. Materassi Phytochemistry 1987 26 1045. 148 E. M. Gaydou J. Miralles and R. Rasoazanakolona J. Am. Oil Chem. Soc. 1987 64 997. 149 R. Qasim J. Chem. Soc. Pak. 1986 8 223. 150 K. Usmanghani M. 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ISSN:0265-0568    

DOI:10.1039/NP9890600231

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

The Biosynthesis of Shikimate Metabolites P. M. Dewick Department of Pharmaceutical Sciences University of Nottingharn Nottingham NG7 2RD Reviewing the literature published during 1987 (Continuing the coverage of literature in Natural Product Reports 1988 Vol. 5 p. 73) 1 The Shikimate Pathway 1.1 DAHP Synthase 1.2 3-Dehydroquinate Synthase 1.3 3-Dehydroquinase and Shikimate Dehydrogenase 1.4 Quinate Dehydrogenase 1.5 EPSP Synthase 1.6 Chorismate Mutase 1.7 Phenylalanine Tyrosine and Dopa 1.8 Anthranilic Acid p-Aminobenzoic Acid and Related Compounds 2 Tryptophan and Related Compounds 2.1 Tryptophan Synthase 2.2 Indole-3-acetic Acid and Related Metabolites of Tryptophan 3 Phenols and Phenolic Acids 4 Phenylpropanoids 4.1 Phenylalanine Ammonia-lyase 4.2 Hydroxycinnamic Acid Esters 4.3 Tropic Acid 4.4 Coumarins 4.5 Lignins 5 Flavonoids 1 The Shikimate Pathway 1.1 DAHP Synthase The first reaction of the shikimate pathway (Scheme I) is catalysed by the enzyme 3-deoxy-~-arabino-heptulosonate-7-phosphate synthase (DAHP synthase) [phospho-2-dehydro-3- deoxyheptonate aldolase; E.C.4.1 .2.15] and involves the formation of DAHP (3) by condensation of phosphoenol-pyruvate (PEP) (1) with erythrose 4-phosphate (2). In any particular organism one or more forms of this enzyme may exist these forms being characterized by different sensitivities towards feedback inhibition by the aromatic amino acids.The human pathogen Neisseria gonorrhoeae possesses a single form @o 2' co; PEP (1) + I NAD+ 5.1 Chalcone Synthase 5.2 Chalcone-Flavanone Isomerase O0''H@ aoH I 5.3 Flavanones and Flavones 5.4 Anthocyanidins 5.5 Methylation and Glycosylation of Flavonoids 5.6 Sulphation of Flavonoids 5.7 Quinol Ethers Chalaurenol 5.8 Retro-chalcone Echinatin 5.9 Isoflavonoids 6 Quinones and Quinols 7 Miscellaneous Shikimate Metabolites 7.1 Diarylheptanoids 7.2 Mycosporines 7.3 Ansatrienin 7.4 Isocyanide Derivatives 7.5 Flexirubin-type Pigments 7.6 Fungal Pigments 8 References This report reviews the literature that was published during 1987 on the biosynthesis of compounds mainly non-nitro- genous that are derived wholly or partly from shikimate and continues the coverage in Volumc 5 of Nuturd Product Reports.' A recent volume of Methods in Enzymology2 is devoted to the metabolism of aromatic amino acids and amines and gives procedures for the isolation and purification from microbial and plant sources of the majority of the enzymes that are known to function in the biosynthetic pathways to phenylalanine tyrosine and tryptophan.Enzymes- involved in the catabolism of the aromatic amino acids (mainly from animal sources) are also described. These articles are not referred to further in the subsequent sections. OH HO" +o DAHP (3) OH Erythrose 4-phosphate (2) co; I 0fiiH I OH OH 3 -Dehydros hi ki mate ( 5 1 3-Dehydroquinate (4) I I OH OH Shi kimate (6) Quinate (7) Enzymes i DAHP synthase; ii 3-dehydroquinate synthase iii 3-dchydroyuinase; iv shikimatc dehydrogenasc; V quinate &hydro- genase Scheme 1 263 NATURAL PRODUCT REPORTS 1989 OH ?* OH OH H DAHP (3) I L:B (hemiketal form) NAD+ ~H -0 ,c -0,c +q, -\ OH OJ H" B I OH 3-Dehydroquinate (4) Scheme 2 ?H -0,c JJ& o@ (8) (9) Enzyme i 3-dehydroquinate synthase Scheme 3 of DAHP synthase sensitive to feedback inhibition by L-phenylalanine (DAHP ~ynthase-phe),~ whereas the pseudo- monad Serpens Jexibifis has two isozymes DAHP synthase- Tyr and DAHP synthase-Trp which are sensitive to feedback inhibition by L-tyrosine and L-tryptophan respecti~ely.~ A single activity DAHP synthase-Tyr is encountered in Achofe-plnsnia luidht?ii this being a member of the class of cell- wall-less prokaryotes that are often termed mycopla~mas.~ In enteric bacteria DAHP synthase-Tyr and DAHP synthase-Trp are uniformly present in contrast to the phenylalanine-sensitive isozyme which is thus thought to be the last of these isozymes to evolve.6 Isozymes of DAHP synthase in plants are differentiated by their requirement for the divalent cations Mn2+ or Co2+.The manganese-dependent isozyme is plastid-related whereas the cobalt-dependent form is found in the cytosol.Studies of cultured cells of tobacco (Nicotiana silvestris) have indicated that the ratio of the two forms varies quite considerably during growth.' 1.2 3-Dehydroquinate Synthase The conversion of DAHP (3) into 3-dehydroquinate (4)involves a complex sequence of reactions catalysed by a single enzyme 3-dehydroquinate synthase [E.C.4.6.1.3]. This sequence requires oxidation at C-5 which facilitates a /+elimination of phosphate then reduction at C-5 followed by ring-opening and an internal aldol reaction (Scheme 2). None of the postulated intermediates has been isolated and more data are required before there can be a detailed understanding of the processes. The 2-deoxy-analogue (8) of DAHP has been synthesized and used as a substrate for 3-dehydroquinate synthase from an overproducing strain of Escherichia cofi.8.This analogue was slowly converted (at a rate about 2% of that observed with DAHP) into the enol ether (9) (Scheme 3) showing that the first three steps of the sequence had occurred and that ring- opening must therefore take place after the reduction step. To investigate the stereochemical course of the /3-elimination of phosphate isomers of (8) that were stereospecifically labelled with 2H at C-7 were incubated with the enzyme. Labelled enol ether (9) was converted into a bicyclic lactone to facilitate n.m.r. analysis of the labelling and this showed that a syn elimination of phosphate was operative. Since the overall conversion of DAHP into 3-dehydroquinate inverts the configuration at C-7 the aldol reaction may be accommodated by three transition states two that are boat-like and one that is chair-like.Consideration of steric effects and of minimal motion strongly favours the chair-like transition state (lo) in which rotation NATURAL PRODUCT REPORTS 1989-P. M. DEWICK J OH Ha -02c*; HO -[-02cq+RH] 3-Dehydroquinate (4) (10) Enzyme i 3-dehydroquinate synthase Scheme 4 co; I + HO'* 60 ATP ' @O= OOH 6H OH Shikimate (6) Shikimate 3-phosphate (11) co; I .. 42- c o*-6H bH Chorismate ( 3) EPSP (12) \ shikimate dehydrogenase shikimate kinase and EPSP synthase activities and thus catalyses the conversion of DAHP through to 5-enolpyruvylshikimate 3-phosphate (12). A nucleotide sequence for the gene that codes for the pentafunctional arom enzyme has been determined and this has allowed the complete amino-acid sequence to be deduced.lo Functional regions within the polypeptide have been identified by comparison with the five corresponding monofunctional enzymes from E.coli. Observed homologies demonstrate that the arum polypeptide is a mosaic of monofunctional domains and this is consistent with the theory that the S. cerevisiae gene probably evolved by linking of ancestral E. coli-like genes. 1.3 3-Dehydroquinase and Shikimate Dehydrogenase The dehydration of 3-dehydroquinate (4) to 3-dehydro-shikimate (5) is catalysed by 3-dehydroquinase [3-dehydro- quinate dehydratase; E.C. 4.2.1. lo] and the reversible reduc- tion of (5) to shikimate (6) is catalysed by the enzyme shikimate dehydrogenase [shikimate oxidoreductase; E.C.1 . 1 . 1 .25]. In plants these enzymes are generally associated as a bifunctional system. Seedlings of pea (Pisum sativum) contain the bifunc- tional enzyme separable into three isozymes," two of which were found in chloroplasts. I .4 Quinate Dehydrogenase Quinate (7) does not lie on the main shikimate pathway but is produced in a reversible reaction from 3-dehydroquinate by the action of quinate dehydrogenase [E.C. 1.1.1.241. Quinate is frequently encountered in plants usually in combination with -O2PCoF other materials (e.g. with caffeic acid in chlorogenic acid ; see Prephenate (14) Enzymes i shikimate kinase; ii EPSP synthase; iii chorismate syn- thase; iv chorismate mutase Scheme 5 about only one bond [C(5)-C(6)] is involved (Scheme 4).The results are thus in accord with enzymic precedent and chemical expectations. 3-Dehydroquinate synthase is the first of five enzyme activities catalysed by the arom enzyme complex in Saccharo-myces cerevisiae. The complex also includes 3-dehydroquinase Section 4.2). The enzyme quinate dehydrogenase from needles of pine (Pinus sylvestris) has been isolated and purified and shown to be highly labile.12 Degradation of the enzyme could be lessened by adding the cofactors NAD' or NADP' to the incubation medium. 1.5 EPSP Synthase The enzyme EPSP synthase [3-phosphoshikimate 1-carboxy-vinyltransferase ; E.C. 2.5.1 . 191 has attracted considerable attention in recent years since it represents the site of action for the successful herbicide glyphosate being inhibited strongly by this compound.The enzyme catalyses the condensation of shikimate 3-phosphate (1 1) with phosphoenolpyruvate to produce the enol ether 5-enolpyruvylshikimate 3-phosphate (EPSP) (12) (Scheme 5). Study of the plant-derived enzyme is frequently hampered by the non-availability of sufficient amounts. Larger quantities have now been made accessible through genetic engineering.13 DNA from Petunia hybrida encoding for EPSP synthase has been cloned into E. coli and this allowed large-scale production of homogeneous plant enzyme. The E. coli clone also complemented the EPSP synthase deficiency of an E.coli mutant and antibodies that had been raised to the plant enzyme reacted with EPSP synthase derived from cultures of normal E. coli. The adaptation of some plant species to glyphosate can be traced to their overproduction of EPSP synthase which enables the shikimate pathway to function normally. A review on this subject has been presented. Cells of Corydalis sempervirens that have adapted to growth in the presence of high levels of glyphosate display this overproduction of enzyme and the enzyme has been shown to be located exclusively in plastids.'" The new protein appears to have a higher molecular weight than the normal enzyme and it has been suggested that this may be a precursor of the normal enzyme probably combined to some transit peptide.16 The sensitivity of bacterial EPSP synthases to glyphosate depends on their state of activation this being induced by monovalent cations.li The enzyme from Bacillus subtilis has negligible catalytic activity in the absence of such cations with ammonium ion being by far the best activator. Failure to recognize this requirement has probably led to some erroneous results concerning the sensitivity of the bacterial enzymes to glyphosate. 1.6 Chorismate Mutase The Claisen-like rearrangement of chorismate (1 3) to pre-phenate (14) transfers the phosphoenolpyruvate-derived side-chain so that it becomes directly bonded to the carbocycle and generates the basic skeleton of the phenylpropanoids. This reaction may occur thermally but the rate increases some lo6-fold in the presence of the enzyme chorismate mutase [E.C.5.4.99.51. Both reactions are believed to proceed through a chair-like transition state in which the substituents are pseudo- axial. Proton n.m.r. studies have shown that in aqueous -0,c <' 0 / -0,c OH NATURAL PRODUCT REPORTS 1989 solution at 25 "C chorismic acid exists in an equilibrium mixture that contains 10-20 YOof the pseudo-diaxial conformer ( 16).18 In MeOH solution however chorismic acid exists entirely as the pseudo-diequatorial isomer (15) and the thermal Claisen rearrangement is considerably slower than in aqueous solution. The relatively small difference in free energy between the two conformers suggests that in the enzymic reaction chorismate mutase selectively binds the diaxial conformer and there is no need to postulate any enzyme-catalysed conformational change.To probe the enzymic mechanism secondary tritium isotope effects arising from labelling at C-4 of chorismate were determined using an E. coli-derived bifunctional chorismate mutase-prephenate dehydrogenase.lg An observed small inverse effect ruled out the possibility that there is general acid catalysis at the 4-hydroxyl group. Coupled with the other pieces of evidence (namely a solvent deuterium isotope effect and the absence of tritium isotope effects due to labelling at C-5 and C-9) certain mechanisms can now be excluded. These are pathways that involve a conformational isomerization of bound pseudo-diaxial substrate that exploit the 4-hydroxyl to yield a carbo-cation that proceed via an oxirinium ion intermediate and that involve anionic participa- tion of the oxygen at C-4.The results are best accommodated by the sequence shown in Scheme 6. The thermal Claisen rearrangement has also been studied by observing how the rate of reaction correlates with structure using synthetic analogues of chorismate and by determining solvent and isotope effects.*O The investigations were carried out concurrently by two groups of workers who presented their data jointly. Both groups agreed that the rearrangement proceeded via a transition-state structure in which there was substantial but not complete cleavage of the C-0 bond that links the side-chain to the ring but little formation of the bond at the terminus of the side-chain.The two groups however put differing emphasis on radical or zwitterionic structures con- tributing to the transition state and thus differing implications for the enzymic reaction. In the case of polar structures stabilization of the transition state may be by hydrogen- bonding or by electrostatic interaction with complementary centres in the active site of the enzyme. If radical stabilization (15) (16) -0,c A OH Prephenate (14) Enzyme chorismate mutase Scheme 6 NATURAL PRODUCT REPORTS. 198% -P.M. DEWICK 267 H several different routes (Scheme 7). The pathway that is employed is dependent on the organism and often more than one route may operate in a particular species as a result of the enzyme activities available.In the mycoplasma Acholeplasma /aidhc*ii,biosynthesis of phenylalanine proceeds solely through the phenylpyruvate (18) route via the enzyme prephenate dehydratase [E.C.4.2.1 .5 11 since no arogenate dehydratase OH was detectable.5 Although arogenate dehydrogenase was (17) detected the biosynthesis of L-tyrosine occurs mainly by the similar sequence through 4-hydroxyphenylpyruvate (21) with NAD+-linked prephenate dehydrogenase [E.C. 1 .3.1.12] is important. the role of the enzyme may be to exert rather than through arogenate (20). Similarly the pseudo-conformational control. The mode of action of chorismate monad Serpens j7exibilis contains the bifunctional P-protein mutase has also been outlined in a paper in which the synthesis (chorismate mutase-prephenate dehydratase) no arogenate of molecular systems that were designed to mimic the enzyme dehydratase and demonstrated both prephenate dehydro-is described.'I genase and arogenate dehydrogenase a~tivities.~ In this case The bicyclic diacid (17) which is a transition-state analogue the latter two enzyme activities co-elute and seem to originate for the chorismate mutase reaction has been shown to be a from the same enzyme.A single NAD+-linked activity of potent inhibitor of the bifunctional chorismate mutase-broad specificity termed cyclohexadienyl dehydrogenase is prephenate dehydrogenase from E. co/i.** also inferred in Neisseria gono~rhoeae,~ Klebsiella pne~moniae,~~ and E. ~o/i.'~ In the latter two organisms this activity appeared as part of the bifunctional T-protein (chorismate mutase-1.7 Phenylalanine Tyrosine and Dopa prephenate dehydrogenase).A phenylalanine-requiring mutant Biosynthesis of the aromatic amino acids L-phenylalanine (19) of Pseudomonas aeruginosa has been isolated and shown to lack and L-tyrosine (22) from chorismate (13) may proceed by the bifunctional P-protein though it retains monofunctional ti iii PL P -.$. -JNH2 -OH J Prephenate (14) Phenylpyruvate (18) L -Phenylalanine (19) (enzyme-bound) Tv co; I -O2 I -4$L PLP I I I OH OH OH Chorismate (13) Prephenate (14) L -Arogenate (20) jN*.+ vii TNH2 (PLP = pyridoxal 5'-phosphatel ... Vtll j;. c PLP OH OH 4 -Hydroxyphenylpyruvate (21) L -Tyrosine (22) Enzymes i chorismate mutase (monofunctional); ii chorismate mutase-prephenate dehydratase (bifunctional); iii phenylpyruvate amino-transferase;iv prephenate aminotransferase; v arogenate dehydratase;vi arogenate dehydrogenase;vii prephenate dehydrogenase;viii 4-hydroxyphenylpyruvateaminotransferase Scheme 7 NATURAL PRODUCT REPORTS.1989 (Tyr) ( Dopal Phe Tvr Enzymes i phenylalanine hydroxylase ; (ii tyrosine hydroxylase) Scheme 8 OH (251 Anthranilate (26) Chorismate (13) I I 6 NHZ H2 HZ p -Am inobentoate ( 27) Enzymes i anthranilate synthase; ii p-aminobenzoate synthase Scheme 9 chorismate mutase and a cyclohexadienyl dehydratase. 24 This observation indicates that although phenylalanine is capable of being produced in this organism by the arogenate pathway the phenylalanine-dependence of the mutant means the pathway is inadequate to supply the full metabolic demand for this amino acid.Members of the Order Actinomycetales similarly synthesize phenylalanine via phenylpyruvate whilst using exclusively arogenate for the biosynthesis of tyro~ine.~~ An aromatic-amino-acid aminotransferase [E.C. 2.6.1 -571 that was isolated from the thermophilic bacterium Bacillus caldolyticus was extremely thermostable retaining its activity at 60 "C for several hours and appears to function in the biosynthesis of phenylalanine and tyrosine rather than in the catabolism of amino acids.26 Enzymes involved in the biosynthesis of phenylalanine and tyrosine that have been demonstrated to be present in methylotrophic Pseudomonas species include prephenate de- hydratase and prephenate dehydrogenase but not arogenate dehydratase or arogenate dehydr~genase.~' In addition phenyl- alanine hydroxylase activity was observed.Phenylalanine hydroxylase [phenylalanine 4-mono-oxygenase ; E.C. 1 . 14.16.13 is more commonly encountered in mammalian systems and catalyses the direct hydroxylation of phenylalanine to tyrosine. Human liver phenylalanine hydroxylase has now been produced in E. coli via recombinant techniques.2H The related tyrosine hydroxylase [tyrosine 3-mono-oxygenase; E.C. 1 . 14.16.21 hydroxylates tyrosine to 3,4-dihydroxy-phenylalanine (dopa) and detailed studies show that this enzymic transformation is mechanistically similar to that of phenylalanine hydroxylase.29 Both enzymes require a tetra-hydropterin cofactor (23) and use molecular oxygen as the oxygen source converting the cofactor into a 4a-carbinol-amine (24) concomitant with hydroxylation of the substrate2" 'H' (Scheme 8).However tyrosine hydroxylase can also utilize H,O, a result not observed for phenylalanine hydroxylase suggesting that subtle differences may exist between the two systems. An extensive review on aromatic-amino-acid hydroxylase has been p~blished,~~ and the biosynthesis of the aromatic amino acids phenylalanine tryrosine and tryptophan in Escherichia coli and in Salmonella typhimurium has been An NAD+-dependent phenylalanine dehydrogenase activity that catalyses the reversible oxidative deamination of phenyl-alanine and the reductive amination of phenylpyruvate had previously been found in the bacterium Sporosarcina ureae (see ref.33) but its natural role was uncertain. A similar activity has been reported in Bacillus badius and the enzyme has been purified and gene-cloned into E. ~oli.~' This enzyme had high specificity for L-phenylalanine in the oxidative deamination but a lower specificity in the reductive amination accepting phenylpyruvate 4-hydroxyphenylpyruvate and 2-0x0-hexanoate and thus probably plays a role in the degradation of L-phenylalanine. Enzymes from both S. ureae and Bacillus sphaericus have now been crystallized and studied further.35 The enzyme from S.ureae had high specificity for L-phenylalanine although that from B. sphaericus would also act on L-tyrosine. Reductive amination was again less substrate- specific and this reaction has been exploited in the synthesis of amino acids giving high yields of both aromatic and aliphatic amino acid~.~~.~' An inducible phenylalanine dehydrogenase in cells of Corynebucterium eyui can also be used for the synthesis of phenylalanine,38 and a Rhodococcus species provides a further source of this 1.8 Anthranilic Acid p-Aminobenzoic Acid and Related Compounds Anthranilate (o-aminobenzoate) (26) is an intermediate in the biosynthetic pathway to L-tryptophan and is derived from chorismate in a reaction that is catalysed by anthranilate NATURAL PRODUCT REPORTS 1989-P.M. DEWICK co c0,-c 0,-I I' I OoL bx c0,-\ c 0,-I (28) OH 0 M H2 e o G C 0 2Me H HZN OMe Streptonigrin (31) 0 I OH (32) synthase (AS) [E.C. 4.1 .3.27] (Scheme 9). However it may also be produced by metabolism of L-tryptophan. Anthranilic acid and its derivatives may then function as precursors of a wide range of alkaloids and antibiotics. Thus the levels of acridone alkaloids and furoquinoline alkaloids in callus cultures of rue (Ruta graveolens) have been shown to correlate with and be dependent on the glutamine-dependent AS activities in the cells.41 The biosynthetic pathway to p-aminobenzoate (27) (Scheme 9) shares many features of the anthranilate synthase sequence and properties of the two enzymes AS and p-aminobenzoate synthase (PABS) are very similar.They are both two-subunit enzymes with the low-molecular-weight subunit possessing glutaminase activity. The larger subunit is involved with binding of chorismate and the sequence involving regiospecific amination and elimination of pyruvate. In a recent study on PABS these similarities were explored and the mechanisms of the two reactions were c~mpared.~' The enzyme was isolated from a clone of E. coli that had been genetically engineered to overproduce the larger subunit of the enzyme and partial purification was achieved despite earlier reports that PABS was inactivated during attempts at its purification. A variety of synthetic chorismate analogues were then tested in the PABS system of E.coli and in the AS enzyme system of Serratia marcescens. The initial amination step was investigated by identifying chorismate analogues that were potentially able to accept an active-site nucleophile at C-6 prior to the addition of ammonia. The cycloheptadienyl analogue (28) proved to be the most potent inhibitor of both enzymes. The aromatization step was examined by replacing the C pyruvyl side-chain with lactyl and glycolyl substituents. Results suggested that the elimination-aromatization step may be rate-limiting with AS but not with PABS. This observation prompted a search for accumulation of intermediates in the AS reaction and the (R)- lactyl analogue (29) was indeed transformed into the amino- (29) (30) HO..To m2 02 - H H (33 1 L -Tryptophan (34) QQH (OC and 0 refer to subunits of tryptophan synthase) Scheme 10 derivative (30).Based on previous work in which synthetic (25) was transformed by AS into anthranilic acid this is the predicted intermediate. Intermediate (30) on re-incubation with AS was slowly converted into anthranilic acid. Studies on the biosynthesis of the antibiotic streptonigrin (31) in Streptomyces Jlocculus have shown that the quinoline portion has its origins in 4-aminoanthranilic acid and D-erythrose 4-pho~phate.~~ This represents a new route to quinolines and the involvement of a previously unknown shikimate metabolite 4-aminoanthranilic acid. The remainder of the streptonigrin molecule is known to arise from B-methyltryptophan.3-Hydroxyanthranilic acid has been implicated as a precursor of antibiotic LL-C10037a (32) in a species of Streptomyces and this has been demonstrated by feeding experiment^.^^ This compound is also a precursor of actinomycins where its origin is from tryptophan via kynurenine and 3-hydroxy-kynurenine. The enzymic methylation of 3-hydroxyanthranilic acid to 3-hydroxy-4-methylanthranilic acid as an early step in the biosynthesis of actinomycins has been demonstrated in extracts of Streptomyces antibioti~us.~~ 2 Tryptophan and Related Compounds 2.1 Tryptophan Synthase The final reaction in the biosynthesis of tryptophan which is the synthesis of L-tryptophan (34) from L-serine and indole-3- glycerol phosphate (33) is catalysed by tryptophan synthase [E.C.4.2.1 .20]. This is a multi-enzyme complex (the a$ complex) comprising two a subunits and a p dimeric subunit. The enzyme also catalyses the aldolytic cleavage of indole-3-glycerol phosphate to indole (35) and the formation of tryptophan from L-serine and indole (Scheme lo). These reactions are also catalysed by the a and p subunits NATURAL PRODUCT REPORTS 1989 respectively of tryptophan synthase. The complex from Salmonella typhimurium has been obtained in microcrystalline form and the microcrystals themselves were shown to be catalytically active when suspended in a Comparison of the amino-acid sequences of the P-chain of tryptophan + Ho2cyl-YJ synthase and threonine synthase showed that there is a H significant extent of homology.47 Some of the catalytic properties of the two enzymes are similar and this suggests they may well (36) have evolved from a common ancestor that possessed broad substrate specificity and was active in several metabolic pathways.A review on tryptophan synthase has been published.48 Tryptophan synthase is able to catalyse a wide range of pyridoxal-5’-phosphate-dependentreactions including /3-re- placement p-elimination racemization and transamination. It has now been shown that the apo-a,P complex (formed by CHO removal of pyridoxal phosphate) will bind two unnatural substrates namely pyridoxamine phosphate (36) and indole-3- pyruvic acid (37) and convert them into pyridoxal phosphate (38) and L-tryptophan (34) these being the natural coenzyme and the natural product respectively.lg This single-turnover H half-transamination reaction has been shown to remove the Pyridoxal 5’-phosphate (38) L -Tryptophan (34) 4’@ro-4’S)-proton (Scheme 1 I ).However presumably the reaction is unlikely to have any significance in normal metabolic Enzyme i tryptophan synthase sequences. Scheme 11 2.2 Indole-3-acetic Acid and Related Metabolites of Tryptophan CHZCOzH Indole-3-acetic acid (IAA) (39) is an essential plant growth hormone (auxin) that is derived from tryptophan by oxidative metabolism. Several pathways may operate via the inter- mediates indole-3-pyruvic acid tryptamine indole-3-acet-H amide or indole-3-acetaldoxime (Scheme 12). Indole-3-acetic 1 IAA (39) acid may then be metabolized further yielding a variety of TryptophanI Indole-3- acetaldoxime / I ndole -3 -pyru v ic acid I- Try pt arni ne Indole-3- acet amide Indole-3- acetaldehyde f------) Indole -3 -e t ha n ol i (Tryptophol) Indole -3- acetic acid I ndole-3- methanol Indole -3 -car balde h yde Indole -3- car box y Iic acid Scheme 12 NATURAL PRODUCT REPORTS 1989-P.M. DEWICK 27 1 L -Tryptophan ___) D -Tryptophan c----) N-Malonyl-D-tryptophan J. Indole -3-pyruvic acid Indo Le -3-acet ic acid Scheme I3 CH,CO,H +moH H IAA (39) (40) Scheme 14 indole and oxindole derivatives depending on the species under investigation. In Chinese cabbage (Brassica campestris subsp. pekinensis) a sequence to IAA through indole-3-acetaldoxime and indole-3-acetaldehyde has been dem~nstrated,~~ an and enzyme preparation that can convert indole-3-acetaldoxime into IAA has been isolated.The co-substrates NAD+ NADP' and FAD were all accepted. During germination of the seeds of Pinus sylvestris bound forms of IAA and indole-3-ethanol are hydrolysed liberating active hormone for the development of the seedling.51 Cultured crown-gall cells of sunflower that have been induced by Agrobacterium tumefaciens probably possess two pathways for conversion of tryptophan into IAA.52 A pathway via indole-3-acetamide is operative as well as the more common pathway in plants through indole-3-pyruvic acid and indole-3-acetaldehyde. Micro-organisms such as Agrobacterium tumefaciens produce their characteristic effects on plants by supplementing or altering their host's capacity for the biosynthesis of IAA.Tryptophan aminotransferase and tryptophan dehydrogenase activities which are present in cultures of both normal and tumour tissue of tobacco (Nicotiana species) were modified in the crown gall tissues though not sufficiently to account for the observed increase in IAA content.53 Root-nodulation processes have also been suggested to involve increased production of IAA though this is still unproven. However cultures of Rhizobium phaseoli have been shown to produce IAA indole- 3-ethanol and indole-3-methanol and a sequence from tryptophan through these metabolites has been demonstrated by feeding experiment^.^^ Indole-3-acetamide was not detected and was not converted into IAA in this organism.Indole-3- ethanol is regarded as a storage product that is involved in the regulation of the biosynthesis of IAA via its reversible conversion into indole-3-acetaldehyde. An indole-3-ethanol oxidase enzyme that converts indole-3-ethanol into indole- 3-acetaldehyde has been isolated from Phycomjws b1ukeslec~- anus.ss.56 Study of two species of Streptomyces namely S. mutabifis and S. atroolivaceus has suggested that the synthesis of IAA follows different pathways in the two organisms. A route via indole-3-acetamide appears to operate in S. mutabifis but S. atroolivaceus utilizes the tryptamine pathway.j7 Both organisms also accumulated indole-3-lactic acid as a metabolite this being a compound that was also isolated along with IAA from cultures of Azotobacter vinelandii that had been supplemented with trypto~han.~~ A tryptophan aminotransferase activity was present in the cultures explaining the first step in the sequence to IAA but the presence of an indolelactate dehydrogenase activity has not been confirmed.A series of experiments with stem segments of pea plants (Pisum sativum) has suggested that D-tryptophan rather than L-tryptophan may be the more direct precursor of IAA."' Thus the addition of IAA or its precursors except for L-tryptophan induced stem growth whereas L-tryptophan required the addition of gibberellin A to stimulate growth. However D-tryptophan induced stem growth without GA,.Growth in the presence of both DL-tryptophan and GA was inhibited by the D-aminotransferase inhibitor cycloserine. Furthermore trypto- phan racemase activity which is enhanced by treatment with GA, was detected in the apices. In intact untreated plants labelled D-tryptophan was incorporated into IAA and indole- 3-acetylaspartic acid more readily than L-tryptophan though treatment with GA increased the conversion of L-tryptophan into IAA and the conjugate more than three-fold. A further conjugate N-malonyl-D-tryptophan also became labelled. It was proposed that treatment with the gibberellin increases the biosynthesis of IAA by regulating the conversion of L-tryptophan into D-tryptophan which is then transformed into IAA (Scheme 13).Oxindole-3-acetic acid (40) has been identified in germinating seeds of Scots pine (Pinus sylvestris) and shown by labelling studies to be derived from IAA (39).'" This conversion has now been observed in several different plants. In germinating kernels of maize (Zea mays) further metabolism of (40) to the 7-hydroxyoxindole (41) and its glucoside (42) has been demonstrated61.62 (Scheme 14). The glucoside (42) is meta- bolized further to as yet uncharacterized products. The biosynthesis and metabolism of IAA is reviewed in a recent book. 63 3 Phenols and Phenolic Acids Simple phenols and phenolic acids may be produced and modified by a wide variety of sequences according to the organism involved and the function that the metabolite fulfils.Many of the reactions will be catabolic and part of a degradative sequence that is employed by a particular organism and such NATURAL PRODUCT REPORTS 1989 HT H2N OH t -Ser DH CO,H .. ... T 'k A DH 0 T xo, L-Tyr Enzymes or reagents i tyrosine phenol-lyase ; ii lactate dehydrogenase NADH ;iii K,Cr,O, H,SO Scheme 15 ,0 c 0; ""4 H I B2 /O 0 c 0; 02-H* I Enzyme i tyrosine phenol-lyase Scheme 16 sequences can be induced because of the presence of the compound. Purely catabolic sequences are thus excluded from this section. Tyrosine phenol-lyase (TPL) [E.C. 4.1 .99.2]is a pyridoxal- 5'-phosphate-dependent enzyme that catalyses the reversible a$-elimination of phenol from tyrosine giving pyruvate and ammonia.The enzyme shows rather broad substrate specificity catalysing or$-elimination reactions with several amino acids and accepting both L-and D-forms. In addition P-replacement reactions of amino acids that contain suitable leaving groups on the p-carbon are observed. Stereochemical studies on TPL from Escherichia intermedia have shown that the a,p-elimina- tions on L-serine L-tyrosine and D-tyrosine that are catalysed by the enzyme proceed with retention of configuration at the p-carbon (Scheme 15).64 Serine is extensively racemized at C-3 during incubation with TPL. Deuterium from the or-position of L-tyrosine is partially transferred to C-4 of phenol when the reaction is carried out in H,O though no exchange of unlabelled tyrosine with solvent 'H,O was noted.This result implies that abstraction of the a-proton and protonation at C-4 of the phenyl ring is catalysed by the same base and favours tautomerism of the 4-hydroxyphenyl to a cyclohexadienonyl system prior to cleavage of the carbon-carbon bond (Scheme 16). Tyrosine phenol-lyase catalyses the racemization of D-and L-alanine at about 2.5% of the rate of degradation of L-tyrosine. In this reaction some recycling of or-hydrogen was observed and this points to a single-base racemization mechanism as opposed to a two-base mechanism (as is seen in NATURAL PRODUCT REPORTS 1989-P. M. DEWICK 2x + D-Glucose fl-Glucogallin (43) (44) Scheme 17 some other systems). A single-base mechanism for deprotona- tion/protonation on opposite faces of the coenzyme-substrate complex requires that there be relative movement of the base and the substrate during the reaction.Attempts to demonstrate that there is movement of the cofactor during racemization by the reduction (with NaBH,) of the complexes of pyridoxal phosphate-enzyme with D-and with L-alanine failed but showed that the holoenzyme is reduced preferentially from the re face with respect to C-4' of pyridoxal phosphate and that the enzyme-substrate complexes are reduced preferentially from the siface. These conform to observations with other pyridoxal- phosphate-containing enzymes. The effects of introducing substituents on to the aromatic ring for the TPL enzymic reaction have also been studied.65 A hydroxyl group in the para-position is necessary but steric parameters of other substituents on the ring also influence the reaction.The rate-limiting step has been shown to be abstraction of the a-proton and not elimination of the phenol moiety. The reverse reaction for TPL has been exploited by using cells of Citrobucter. intermedius to synthesize L-tyrosine from DL-serine and phenol.66 This sequence requires the initial decomposition of D-serine to pyruvate by the action of D-serine dehydratase. Residual unreacted serine was significantly en- riched in the L-isomer. The TPL from Citrobacter intermedius is a tetramer containing four identical sites responsible for binding of pyridoxal 5'-pho~phate.~~ The enzyme tryptophanase [E.C. 4.1 .99.1] catalyses a similar cleavage of indole from L-tryptophan and TPL and trptophanase seem to have many other features in common.Both enzymes will accept 0-benzoyl-L-serine as substrate eliminating benzoate in an apparently irreversible reaction.6H Detailed study of these reactions has led to the suggestion that binding energy from the aromatic ring of 0-benzoyl-L-serine is used to lower the transition-state barrier for the elimination reactions and that the enzymes undergo a conformational change during catalysis. The formation of simple benzoic acids by cleavage of the side-chain of cinnamic acids is well established particularly in plant systems and this route operates in the formation of benzoic acid itself in Penicillium hrevicompuctum.In this organism benzoic acid is found in the estcr form as the pebrolides (scsquitcrpcnc bcnzoatcs) and as thc N-bcnzoyl derivatives N-benzoyl-~-phenylalanine,N-bcnzoyl-L-phcnyl-alaninol and asperphcnamate."!' Feeding experiments in cul-tures showcd that thcrc is convcrsion of phcnylalaninc into cinnamate and bcnzoale and of cinnamate into benzoate and bcnzoyl derivatives. Phenylalaninc ammonia-lyasc was purified from the culturcs. Cell-free extracts from leaves of oak (Quercus robur) catalyse the transfer of the galloyl moiety of P-glucogallin (1 -0-galloyl-p-D-glucose) (43) to position 6 of the same compound yielding 1.6-di-O-galloyl-/~-~-glucose (44) which is an intermediate of thc biosynthcsis of gallotannins (schcmc I7)."' /l'-Glucogallin thus acts as both a donor and an acccptor molcculc.The enzyme has been partially purified and shown to be inactive with 6-O-galloyl-P-~-glucose.The affinity of the acyltransferase is not restricted to the galloyl ester since 1-0-benzoyl-P-D-glucose was also accepted as a substrate. Enzymes that are involved in the biosynthesis of gallotannins have also been isolated from callus cultures of Q. rob~r.~' A P-glucogallin- forming UDPglucose-dependent glucosyltransferase and an acyltransferase that catalyses rapid exchange between p-glucogallin and free glucose were identified. These activities had been demonstrated earlier in leaf extracts. 4 Phenylpropanoids 4.1 Phenylalanine Ammonia-lyase Phenylalanine ammonia-lyase (PAL) [E.C. 4.3.1 .5] catalyses the stereospecific elimination of ammonia from L-phenyl-alanine producing trans-cinnamic acid.This enzyme effectively controls the flow of material from the shikimate pathway into many of the important phenylpropanoid-based secondary metabolites e.g. lignins and flavonoids and the regulation of its activity has been ascribed to feedback inhibition by cinnamic acid. Recent evidence suggests that effects other than feedback inhibition may regulate the biosynthesis of phenylpropanoids. 72 Many standard methods for the determination of PAL activity have been found to give measurements for activities of both PAL and phenylalanine aminotransferase (PAT) [E.C. 2.6.1 .13 together. A more accurate estimation of PAL activity is obtained by specifically inhibiting PAT using L-aspartate.Phenylalanine aminotransferase is almost certainly responsible for some of the properties that have been ascribed to PAL and for some of the controversies regarding the control mechanisms which regulate PAL activity. Thus data have been presented from studies on the production of phaseollin in bean (Phaseolus vulgaris) to show that regulation of the biosynthesis of phenylpropanoids depends greatly on the supply and availability of substrates rather than on feedback inhibition of PAL. Phenylalanine ammonia-lyase has been the subject of a recent review,73 and an equilibrium study of the reaction that is catalysed by PAL has allowed its thermodynamic parameters to be ~alculated.~~ The biosynthesis of flavonoids from both L-and D-phenylalanines in cotyledons of buckwheat (Fagupyrum escu-lentum) has been studied.'" Although D-phenylalanine can give rise to flavonoids if large doses are provided (probably via a racemase enzyme) it was concluded that in feeding experiments involving racemic phenylalanines only incorporation of the L-isomer is of any significance and the appropriate corrections should be applied to any calculations of incorporation.Commercial demand for L-phenylalanine due to the success of the sweetening agent aspartame (methyl N-L-a-aspartyl-L- phenylalaninate) has generated considerable study of the reaction that is catalysed by PAL and of the prospects for synthesizing L-phenylalanine from cinnamic acid by exploiting the reverse reaction.76 "'I Feedback inhibition of PAL due to cinnamic acid provides problems of course and effort has been devoted to stabilizing the en~yme,?~ to finding cinnamate- resistant enzymes,'? and to using whole cell ~ystems.?~-~~ 4.2 Hydroxycinnamic Acid Esters The biosynthesis of derivatives of cinnamic acid often requires an activated form of the acid to be produced initially and both coenzyme A esters and glucose esters may function in this role.Protein preparations from primary leaves of rye (Secalecereale) contain acyltransferases which catalyse the formation of a range of hydroxycinnamic esters using the corresponding coenzyme A esters as substrates.*' Rye primary leaves contain a complex pattern of more than twenty different hydroxy- cinnamjc acid esters with sugar acids the major constituents being 4-coumaroylglucarate feruloylglucarate feruloylgalac- tarate feruloylglucarolactone and sinapoylglucarolactone.Enzymes were partially purified into distinct acceptor-specific activities each capable of using 4-coumaroyl-CoA caffeoyl- CoA feruloyl-CoA and sinapoyl-CoA as acyl donors though to differing extents. Activities for glucarate glucarolactone galactarate gluconate and the cyclohexane acids shikimate and quinate as acceptor molecules were identified and changes in enzyme activities during leaf growth correlated with accumulation patterns for the major rye esters. An acyl- transferase from cotyledons of Amaranthus cruentis utilizes caffeoyl-CoA and to a lesser extent 4-coumaroyl-CoA and feruloyl-CoA but not sinapoyl-CoA to accumulate esters of hydroxycinnamic acids with isocitric acid.82 The enzyme had strict specificity for isocitrate and related materials such as citrate malate tartrate and quinate were not accepted.The glucose ester of 4-coumaric acid is involved in the biosynthesis of 2-0-acetyl-3-0-(4-coumaroyl)-meso-tartaric acid (45) by enzymes in cotyledons of spinach (Spinacia olera~ea).~~ Two acylations are involved the first of these being transesterification of 1-0-(4-coumaroyl)-~-~-glucosewith nteso-tartaric acid giving (4-coumaroyl)-meso-tartaric acid and the second being acetylation of this product with acetyl-CoA as the acetyl donor. The first step occurs exclusively via the glucose derivative and CoA activation was not acceptable.The reaction was also highly specific in respect of the tartaric acid isomer ;although meso-tartaric acid was a substrate neither the D-nor the L-form was acylated. The second acyltransferase could utilize several other CoA esters (e.g.valeryl-CoA butyryl- CoA hexanoyl-CoA and propionyl-CoA) in addition to acetyl-CoA but would not acylate free tartaric acid. The formation of glucose esters of hydroxycinnamic acids in anthers of tulip (7'uIipa cv. Apeldoorn) is catalysed by a UDPglucose- dependent glucosyltransferase. 84 Ferulic acid and 4-coumaric caffeic and sinapic acids all acted as substrates and the feruloylglucose that is produced is believed to function as a starter molecule for the biosynthesis of di- and tri-feruloyl sugars in tulip antlers.A second different glucosyltransferase enzyme from this source catalysed the UDPglucose-dependent glucosylation of the same free hydroxycinnamic acids to give the corresponding 0-glucosides. 0-Glucosylferulic acid is also a constituent of tulip anthers in the early stages of their development. Chlorogenic acid (5-0-caffeoylquinic acid) (47) appears to be formed in plants by a number of routes. Transesterification of both glucose esters and coenzyme A esters of caffeic acid with quinic acid has been reported; alternatively in some species hydroxylation of 5-0-(4-coumaroyl)quinic acid (46) occurs. The latter sequence seems to operate in cell suspension cultures of carrot (Daucus carota).85 Thus (46) is hydroxylated to chlorogenic acid (47) by a light-induced microsomal prepara- tion from carrot the reaction being strictly dependent on the presence of 0 and NADPH as cofactors.The enzyme appears to be a cytochrome-P-450-dependent mixed-function mono-oxygenase and converts the shikimate analogue of (46) to about the same extent as the quinate derivative. A single enzyme is responsible for both of these reactions. However 3-NATURAL PRODUCT REPORTS 1989 OR OH (46) R = H Chlorogenic acid (47)R = OH OH 00. OH Isochlorogenic acid (48) 6OH OH Rosmarinic acid (49) and 4-0-(4-cournaroyl)quinate and the (2)-isomer of (46) were not substrates. Feeding experiments in leaves of coffee (Coflea excelsa) also suggest that chlorogenic acid is produced there by a sequence that does not involve caffeic acid.86 Thus radio- activity resulting in chlorogenic acid from feeding [14C]phenyl- alanine was suppressed most strongly in the presence of unlabelled cinnamic acid and 4-coumaric acid but much less NATURAL PRODUCT REPORTS.1989-P. M. DEWICK L -Phe (S)-Tropic acid (50) Scheme 18 intramol/Yo' intermol c 02~ Hb (52) Scheme 19 so when unlabelled caffeic acid was supplied. These results were interpreted to indicate that whilst both cinnamic acid and 4- coumaric acid were on the main pathway caffeic acid was not. In roots of sweet potato (Ipomoea batatas) the biosynthesis of chlorogenic acid proceeds by the route from caffeoylglucose and quinic acid.A further modification which can then occur is conversion into isochlorogenic acid (48). This reaction involves transfer of a caffeoyl group from one molecule of chlorogenic acid to a second molecule and quinic acid is released. The enzymic reaction in sweet potato does not require any cofactor and has strict substrate specificity for chlorogenic The corresponding 4-coumaroyl- and cinnamoyl-quinic acids were not accepted. The reaction bears similarity to those by which digalloylglucose (see Section 3) and disinapoylglucose are generated from two molecules of the appropriate glucose esters. Somewhat unexpectedly the biosynthetic pathway to caffeoylglucaric acid (2-0- or 5-0-caffeoylglucaric acid but the exact structure unconfirmed) also involves chlorogenic acid.88 A protein preparation from cotyledons of tomato (Lycopersicon esculentum) catalysed the formation of caffeoylglucaric acid from chlorogenic acid as the acyl donor and glucaric acid as the acceptor.Both caffeoylglucaric acid and chlorogenic acid are major components of tomato cotyledons. The monocarboxylic acid gluconic acid was not a substrate for the enzymic reaction but galactaric acid was also efficiently acylated. Chlorogenic acid itself is synthesized in tomato from caffeoyl-CoA rather than from glucose esters. Rosmarinic acid (49) is an ester composed of caffeic acid and 3,4-dihydroxyphenyl-lacticacid. Feeding experiments have demonstrated that the caffeic acid moiety is derived from phenylalanine via cinnamic acid and 4-coumaric acid but tyrosine supplies the remaining fragment probably via 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyl-lactic acid.Extracts of rosmarinic-acid-producing cell cultures of Anchusa oficinalis and Coleus blumei have been shown to contain high activities of tyrosine aminotransferase (TAT) [E.C.2.6.1 .5] though low tyrosine oxidase activity.89 During culturing activities for TAT and PAL and the rate of synthesis of rosmarinic acid changed in a co-ordinated manner. Tyrosine aminotransferase has been shown to be the entry-point enzyme for the tyrosine-derived pathway of rosmarinic acid bio-synthesis. It had high substrate specificity for tyrosine phenylalanine being much less effective and the enzyme activity was inhibited by L-2-amino-oxy-3-phenylpropionic acid.This inhibitor also blocked the entry of tyrosine into rosmarinic acid in vivo confirming the role of TAT as the entry-point enzyme. In further three different TAT activities were identified in cell suspension cultures of Anchusa oficinalis. All showed a pronounced preference for L-tyrosine over other aromatic amino acids though two could also utilize L-aspartate and L-glutamate as substrates. Oxaloacetate and 2-oxoglutarate served as amino-acceptors though efficiencies varied with each enzyme. All three enzyme activities were inhibited by 3,4- dihydroxyphenyl-lactate and two by rosmarinic acid. 4.3 Tropic Acid The biosynthetic origins of tropic acid (50) from phenylalanine by a rearrangement process which involves an intramolecular migration of the carboxyl group have been known for many years but the mechanism of the rearrangement still eludes investigators.The stereochemistry of the process was studied by two groups of workers in 1984 (see ref. 91) who unfortunately presented conflicting data. It has now been confirmed in further studies with Datura innoxia plants that migration of the carboxyl group occurs with retention of configuration at the benzylic centre of phenylalanineg2 and that there is also migration of one of these benzylic hydrogens to form the methylene of tropic acid (Scheme 18). In D. innoxia (8-tropic acid is found in the form of the tropane ester alkaloids hyoscyamine and scopolamine and interpretation of the results is complicated by the facile racemization of the tropic acid moiety in these alkaloids.This is held to be the reason why the earlier results appeared contradictory. Thus in a series of feeding experiments with stereospecifically 3-3H- labelled L-phenylalanines the 3(pro-3R)-hydrogen was found to be substantially retained and located at the chiral centre of the tropic acid fragment and able to be removed by base- catalysed racemization. Any retention of the 3bro-3S)-hydrogen was due to migration as demonstrated by degrada- tion and lack of exchange on racemization. A similar migration sequence is seen in the vitamin-B,,-dependent transformation of (2R)-methylmalonyl-CoA (5 I) into succinyl-CoA (52) (Scheme 19) where an intramolecular migration of the ester unit with retention of configuration is accompanied by an intermolecular migration of hydrogen.Whether an inter-molecular or an intramolecular migration occurs in the case of tropic acid is not known. NATURAL PRODUCT REPORTS. 1984 CH,OH R OH Xanthotoxol (53) R = OH Bergaptol (55) R = OH Xanthotoxin (54)R = OMe Bergapten (56) R = OMe R\0OMe OH 0 (60)R = H Isoliquiritigenin (62) R = H Liquiritigenin (64)R = H (61) R = OMe Naringenin-chalcone (63) R = OH Naringenin (65) R = OH 4.4 Coumarins Levels of the furanocoumarins xanthotoxin (54) and bergapten (56) increase significantly in plants and cell cultures of parsley (Petrosefinum crispum) when they are challenged with the fungus Phytophthora megasperma f.sp.glycinea or with elicitor preparations that have been derived from this fungus. In a review of this phytoalexin response,g3 changes in the levels of the key enzymes PAL 4-coumarate-CoA ligase and two 0-methyltransferases have been described. The O-methyl-transferases catalyse the last stages of the biosyntheses of xanthotoxin and bergapten i.e. the S-adenosylmethionine-dependent methylation of xanthotoxol (53) and bergaptol (59 respectively. Furanocoumarins including xanthotoxin and bergapten and the two 0-methyltransferases are also detectable in uninfected parsley plants highest levels for both furano- coumarin content and enzyme activity being recorded at the onset of senescence of cotyledons at which time hydrolytic enzymes also increased from low to high levels of activity."' In contrast PAL and 4-coumarate-CoA ligase activities decreased during the development of cotyledons.0-Methyltransferase activities were so high at this period that it was not possible to detect further changes in enzyme activity as a result of fungal infection. 4.5 Lignins Lignins are natural polymers believed to arise by phenolic oxidative coupling of monomer hydroxycinnamyl alcohol units. The most important of these are 4-hydroxycinnamyl alcohol (57) coniferyl alcohol (58) and sinapyl alcohol (59). These are derived from cinnamic acid precursors viu the corresponding coenzyme A esters and aldehydes. Three 0-methyltransferases that are involved in lignification in leaves of tobacco (Nicotiana tabacum) have been obtained in highly purified form and specific antibodies to the enzymes have been raised to allow their detection.95 The three enzymes were shown to be isozymes catalysing the methylation of caffeic acid and catechol.Lignification often increases dramatically when plant cells are challenged with fungi or bacteria as part of a defence mechanism. A 4-hydroxy-cinnamate :CoA ligase activity from mesocotyls of maize (Zea mays) showed multiple peaks of activity and significant changes in response when the plant was infected with Helminthosporium maydis indicating the existence of isozyrne~.~~ 4-Coumaric caffeic and ferulic acids were all substrates for the enzymes. Treatment of cell suspension cultures of bean (Phaseolus vulgaris) with an elicitor preparation from Cofletotrichum lindemuthianum gave a five-fold increase in extractable cinnamyl-alcohol dehydrogenase activity again reflecting in- creased lignification.'' Lignification had been assumed to occur exclusively by oxidative polymerization of the (0-cinnamyl alcohol mono- mers though the recent isolation of significant amounts of (2)-coniferyl alcohol (60) and (2)-sinapyl alcohol (6 I) but not the corresponding (8-isomers from bark of beech (Fagus grandifblia) had called this assumption into question (see ref. 1). Further studies with beech bark have been directed towards the E/Z isomerization step in the biosynthesis of these (Z)-cinnamyl alcohols.g8 Labelling experiments showed that when (a-ferulic acid was fed to the bark it gave both (Q-and (Z)-coniferyl alcohols and was a much better precursor than (Z)-ferulic acid.Also (a-coniferaldehyde was efficiently incor- porated into both (E)-and (Z)-coniferyl alcohols and (0-coniferyl alcohol was converted into (2)-coniferyl alcohol. A crude cinnamyl-alcohol dehydrogenase preparation had a strong substrate preference for (0-coniferyl alcohol over (Z)-coniferyl alcohol. These results indicate that the (E) to (Z) isomerization most probably occurs at the cinnamyl alcohol oxidation level. In the terpenoid field a similar E/Z isomerization is encountered in the conversion of geraniol into nerol but in marked contrast this is known to occur at the aldehyde oxidation level. Monitoring of the biosynthesis of lignins in situ has been carried out by solid-state l:{C n.m.r.using seedlings of Feland wheat (Triticum aestivum) that had been fed ferulic acid precursors that were specifically labelled with 13C in the side- chaingg Major resonances due to specific carbons in the propanoid side-chains of the resultant cell-wall polymers could be identified with a fair degree of confidence based on similar resonances in model compounds. Signals were found to differ significantly from those of synthetic lignins that had been derived by enzymic dehydrogenative polymerization of coni- feryl alcohols which had usually been considered to be a good approximation to the structure of natural lignans. The incorporation data thus do not support an identical bonding pattern in the intact plant though significant changes in 13C n.m.r.signals are likely to arise because of bonding of the NATURAL PRODUCT REPORTS. 1989-P. M. DEWICK 0 0 Naringenin (65) Eriodictyol (66) 0 0 Apigenin (67) Lut eo lin (681 Enzymes i flavonoid 3’-mono-oxygenase; ii flavone synthase I1 Scheme 20 lignins to carbohydrate phenolic or hydroxycinnamic acid moieties in the plant cell wall. The nature of this bonding has yet to be established. 5 Flavonoids 5.1 Chalcone Synthase Chalcone synthase [naringenin-chalcone synthase ; malonyl-CoA :4-coumaroyl-CoA malonyltransferase (cyclizing) ; E.C. 2.3.1 .74] is a crucial enzyme for flavonoid biosynthesis producing naringenin-chalcone (63) [usually isolated as narin- genin (65)] from 4-coumaroyl-CoA and malonyl-CoA.Whilst the enzyme is generally believed to be soluble recent studies on the enzyme from buckwheat (Fagopyrum esculentum) have demonstrated that in the epidermis of the hypocotyls of this plant it is associated with endoplasmic reticulum membranes. loo This finding supports the hypothesis that the biosynthesis of phenylpropanoids and flavonoids takes place partially or perhaps fully on membrane-bound enzyme complexes. Although there are many reported isolations of naringenin- chalcone synthase proof for the existence of a related enzyme catalysing the synthesis of the deoxychalcone isoliquiritigenin (62) remains elusive. All attempts to demonstrate the synthesis of (62) or of the flavanone liquiritigenin (64) in cell suspension cultures of soybean (Glycine max) failed.l0’ The naringenin- chalcone synthase that was obtained from this source was used to raise specific antibodies and these cross-reacted with chalcone synthase from parsley (Petroselinurn sp.).5.2 Chalcone-Flavanone Isomerase Cyclization of the chalcone naringenin-chalcone to the (2s)- flavanone naringenin (65) is catalysed by the enzyme chalcone- flavanone isomerase [chalcone isomerase; E.C. 5.5.1 .6]. A highly purified enzyme from flowerbuds of Petunia hybrida has been obtained and a highly specific antiserum raised against it.lo2 The absence of immunoreactive chalcone-flavanone isomerase in a mutant plant which accumulates naringenin- chalcone in its anthers demonstrated that this accumulation is a direct consequence of the lack of enzyme activity.A chalcone- flavanone isomerase preparation that was isolated from seedlings of Amorpha fruticosa transformed the deoxychalcone isoliquiritigenin (62) into liquiritigenin (64) and could be resolved into two iso~ymes.’~~ 5.3 Flavanones and Flavones Studies on the substrate specificity of chalcone synthase from flowers of Sinningia cardinalis (syn. Rechsteineria cardinalis) have shown that the 3’,4’-dihydroxylated flavonoids that are produced by this plant are formed by hydroxylation at the flavonoid stage rather than by incorporation of caffeoyl- CoA.lo4 A flavonoid 3’-hydroxylase activity that was demon- strated to be present in a microsomal fraction of flower extracts catalysed the hydroxylation of the flavanone naringenin (65) and the flavone apigenin (67) giving eriodictyol (66) and luteolin (68) respectively ;NADPH was an essential cofactor.A further NADPH-dependent enzyme activity catalysing the transformation of naringenin (65) and eriodictyol (66) into apigenin (67) and luteolin (68) respectively was also observed (Scheme 20). This flavone synthase activity was abolished completely by treatment with the cytochrome P-450 inhibitor ancymidol though flavonoid 3’-mono-oxygenase activity was not impaired. The same NADPH-dependent conversion of (2s)-naringenin into apigenin was observed in microsomal fractions from osmotically stressed cells of soybean (Glycine max).lo5 This type of flavone synthase activity (flavone synthase 11) is now known from several sources e.g.Antirrhinurn rnajus Verbena hybrida and Taraxacum oficinale; it differs from the flavone synthase I from cell cultures of parsley (Petroselinum crispurn) which is a soluble Fez+- and 2-oxoglutarate-dependent dioxygenase. Flavone synthase I1 from soybean has an absolute requirement for NADPH and 0 and is inhibited by CO cytochrome c and a number of inhibitors of cytochrome P-450. This suggests that flavone synthase I1 is a cytochrome-P-450- dependent mono-oxygenase. A hypothetical 2-hydroxy- NATURAL PRODUCT REPORTS 1989 HoqQ OH Genistein (69) Naringenin (65) 0 Apigenin (67) Enzymes i isoflavone synthase; ii flavone synthase I1 Scheme 21 RL RL 0 OH Dihydrokaempferol (71) R'= R2= H Leucopelargonidin (74) R'= R2 = H Dihydroquercetin (72) R'= OH RZ = H Leucocyanidin (75) R' = OH R2 = H Dihydromyricetin (73) R1= R2= OH Leucodelphinidin (76) R' = RZ = OH Pelargonidin (77) R'= Rz = H Cyanidin (78) R' = OH R2 = H Delphinidin (79) R'= R2 = OH Scheme 22 flavanone intermediate (70) has been proposed (Scheme 2 I).The flavone synthase I1 preparation from soybean also converted (2S)-eriodictyol(66) into luteolin (68) but would not accept (2R)-naringenin or (2R,3R)-dihydrokaempferol (71) as substrates. In marked contrast to the presence of flavone synthase 11 in osmotically stressed soybean cells normal cells catalyse the conversion of (2Qnaringenin into the isoflavone genistein (69) via the enzyme isoflavone synthase (Scheme 21).It can be concluded that osmotic stress causes a switch from the synthesis of isoflavones to flavones. This is almost certainly due to lack of induction of isoflavone synthase by the osmotic stress (in glucose solutions) since other enzymes of the glyceollin pathway (PAL trans-cinnamate 4-mono-oxygenase chalcone synthase and dihydroxypterocarpan 6a-hydroxylase) are all increased by both treatment with an elicitor and osmotic stress.'O' However enzymes for the later stages of glyceollin biosynthesis e.g.prenyltransferase were poorly induced by the latter treatment. 5.4 Anthocyanidins The pattern of anthocyanidin derivatives in the flowers of Petunia hybrida can be traced back to the substrate specificity of dihydroflavonol 4-reductases.lo' The enzyme preparation catalyses NADPH-dependent reduction of dihydroflavonols to 2,3-trans-3,4-cis-flavan-3,4-cis-diols (leucoanthocyanidins) (Scheme 22) converting dihydroquercetin (72) into leuco-cyanidin (75) and in particular dihydromyricetin (73) into leucodelphinidin (76). In contrast dihydrokaempferol (71) was not reduced to leucopelargonidin (74). Anthocyanins that are based on delphinidin (79) and to a lesser extent on cyanidin (78) are the main pigments in Petunia,but anthocyanins that are based on pelargonidin (77) are rarely found. The production of dihydromyricetin from dihydrokaempferol and dihydro- quercetin naturally depends on the presence of flavonoid 3'- mono-oxygenase and flavonoid 3',5'-hydroxylase activities but the dihydroflavonol reductase activity could also be demon- NATURAL PRODUCT REPORTS 1989-P.M. DEWICK Quercetin (80) Chrysoeriol (81) strated in flower extracts from lines that lack these enzymes. Substrate specificity based on the pattern of hydroxylation of ring B is however not encountered for dihydroflavonol reductase Erom species of Matthiola Callistephus Sinningia Dianthus and Dahlia. An NADPH-dependent dihydro-quercetin reductase activity has also been demonstrated in crude extracts from wild-type maize (Zea mays) and its expression in mutants is dependent on genotype. lo* 5.5 Methylation and Glycosylation of Flavonoids An 0-methyltransferase was isolated from cultured cells of Glycjwhiza echinata and found to methylate several flavones and flav~n~l~.'~~ Maximum activity was observed with quer- cetin (80) and luteolin (68) and in the case of the latter substrate the product was identified as the 3'-0-methyl ether chrysoeriol (81).r 0 (82) R = H L (83) R = OH Glc HO 0 0 (84)R HOeR(85) R / The range of 0-methyltransferases and 0-glucosyltrans-ferases that are involved in the biosynthesis of polymethoxylated flavonol glucosides in Chrysospienium americanum has been discussed in a recent review."O Separation of two 0-glucosyl- transferases derived from C. americanum that show substrate specificity for the 2'-or the 5'-position of partially methylated flavonols has been achieved via the use of affinity chromato- graphy. ll1 Earlier feeding experiments had indicated that although flavanones might act as precursors of flavone C-glucosides flavones themselves were not incorporated.From subsequent enzymic studies it was then suggested that oxidation of a flavanone perhaps to a 2-hydroxyflavanone might be involved though it proved impossible to isolate any such intermediates. By working with flavonoid derivatives that contained no (or minimal) hydroxylation in ring B evidence for the involvement of 2-hydroxyflavanones has now been presented.l12 Thus a C-glucosyltransferase preparation from seedlings of buckwheat (Fagopyrum escuientum) catalyses the transfer of glucose from UDPglucose or ADPglucose to 2-hydroxynaringenin (83) giving a mixture of vitexin (87) and isovitexin (89) and to 2,5,7- trihydroxyflavanone (82) giving 8-and/or 6-C-glucosyl-chrysin [(86) and (88)].Naringenin naringenin-chalcone and the flavones apigenin and chrysin were not C-glucosyl acceptors though some 0-glucosylation was detected in the case of naringenin and naringenin-chalcone. Therefore C-glucosyla- tion occurs after oxidation of flavanones and a scheme (Scheme 23) involving 2-hydroxyflavanones and/or their 0 0 = H = OH 0 0 (86) R = H (88) R = H Vitexin (87) R = OH Scheme 23 Isovitexin (89) R = OH NATURAL PRODUCT REPORTS 1989 OH m x n process e H I (6 radical P H+ HO Chalaurenol (92) Scheme 24 dibenzoylmethane isomers has been proposed. 112 The inter- mediate C-glucosyldibenzoylmethanes(84) and (85) may cyclize in two ways to yield eventually the flavone 6-and 8-C-glucosides.Flowers of aster (Callistephus chinensis) contain a malonylated pelargonidin 3-0-glucoside pigment. An enzyme preparation from the flowers catalyses malonylation of 3-0-glucosides of pelargonidin (77) cyanidin (78) and delphinidin (79) with malonyl-CoA as donor but without the need for any other c~factor."~ The 3,5-di-O-glucoside of cyanidin was a poor acceptor and other dicarboxylic acid esters e.g. glutaryl-CoA succinyl-CoA and methylmalonyl-CoA were utilized to a considerably lesser extent. Acylation of anthocyanidin 3-0- glycosides with 4-coumaric acid has been observed in petals of stock (Matthiola in~ana).''~ These flowers typically produce anthocyanidin 3-0-glucosides or 3-0-sambubiosides acylated with 4-coumarate or caffeate.An enzyme fraction demonstrated acylation of anthocyanidin 3-0-glycosides but not of 33-di-0- glycosides with 4-coumaroyl-CoA and caffeoyl-CoA as acyl donors. Feruloyl-CoA was a poorer substrate whilst cinnamoyl-CoA and sinapoyl-CoA were not. accepted. The extent of accumulation of acylated 3-0-glycosides during the development of buds correlated well with acyltransferase activity. A highly specific P-glucuronidase that was isolated from primary leaves of rye (Secale cereale) hydrolysed the 4'-glucuronic acid moiety from a luteolin triglucuronide (luteolin 7-0-diglucuronide LZ'-O-glucuronide) which is the major flavonoid of the leaf."j Whilst the enzyme had similar properties to most plant glycosidases it showed very high specificity hydrolysing the triglucuronide but not the product luteolin 7- 0-diglucuronide.In contrast luteolin 7-0-glucuronide was NATURAL PRODUCT REPORTS 1989-P. M. DEWICK (93) hydrolysed. Presumably this enzyme is involved in the turnover of luteolin triglucuronide in vivo. 5.6 Sulphation of Flavonoids The biosynthesis of a range of flavonol sulphate esters in Flaveria species appears to involve a number of distinct position-specific sulphotransferases. 116 Cell-free extracts from Flaveria bidentis and F. chioraefolia catalysed the transfer of sulphate groups from 3'-phosphoadenosine 5'-phospho-sulphate to a variety of hydroxylated and U-methylated flavonols but not to flavones or phenylpropanoids.Sulphation was predominantly but not exclusively at position 3. Quercetin (80) gave a mixture of mono- di- tri- and tetra-sulphate esters. Differences were noted between the two species. 5.7 Quinol Ethers :Chalaurenol A full report on the isolation and structure elucidation of chalaurenol (92) a novel quinol ether metabolite that is obtained from incubating 2',4,4'-trihydroxychalcone (iso-liquiritigenin) (62)with a peroxidase preparation from Amorpha fruticosa (see ref. 91) has been pub1i~hed.l~~ Whilst this compound is produced by the enzyme of A. fruticosa from a substrate that is normally present in the plant it has not yet been demonstrated as a natural product and its role is still unclear. A slightly modified hypothesis for its biochemical origin has been proposed (Scheme 24).A radical chain process yields the hydroperoxide (90) which may be converted into chalaurenol by a spiro-epoxide intermediate (9 1) (route A) or by an aryl migration (route B). The range of products that form in the peroxidase-catalysed reaction has been shown to be analogous to that formed in a photochemical reaction and the hydroperoxide (90) has similarly been proposed as an inter- 28 1 mediate in the formation of chalauren~l.''~ The proposed dioxetane precursor (93) of the hydroperoxide (90) in the photochemical reaction has been criticizedlo3 by the other workers however who suggest that the analytical data for (93) could well be accommodated by structure (90).5.8 Retro-chalcone :Echinatin The unusual retro-chalcone echinatin (94) is produced in Glycyrrhiza echinata from isoliquiritigenin (62) by a sequence in which the functionality of the C chain becomes reversed. The dibenzoylmethane licodione has been shown to be an intermediate in this pathway (Scheme 25) and the enzymic methylation of licodione has been demonstrated. In recent studies,log three 0-methyltransferase activities have been characterized in callus cultures of G. echinata. The S-adenosylmethionine-dependentO-methylations of licodione or flavone/flavonol or caffeic acid/5-hydroxyferulic acid were catalysed by the isolated enzymes. When cells of a suspension culture were stressed by the addition of yeast extract (a procedure which causes rapid production of echinatin in the cells) it was discovered that only the licodione U-methyl- transferase activity was stimulated and the other two activities were not affected.This results in selective induction of the retro-chalcone pathway in the cultured cells. 5.9 Isoflavonoids Isoflavonoids differ from flavonoids in having a rearranged C,C,C skeleton. During the biosynthesis of isoflavonoids from flavonoid precursors the shikimate-derived aromatic ring migrates to the adjacent carbon of the C unit in a rearrangement that is catalysed by the enzyme isoflavone synthase. Further substitution of the basic isoflavonoid skeleton and modification of the oxidation level in the heterocyclic ring are then responsible for the production of the wide variety of natural isoflavonoid structures.Many of these sequences have been deduced from precursor-incorporation studies using intact plants taking advantage of the phytoalexin role of many isoflavonoids. Treatment of plant tissue with various biotic or abiotic elicitors results in rapid synthesis of the phytoalexins. Recent work at the enzymic level supports these proposed pathways. The pterocarpans medicarpin (98) and maackiain (102) are synthesized by elicitor-challenged tissues of chickpea (Cicer arietinum) and their formation from the isoflavone formo- nonetin (95) has been deduced from feeding experiments to be HOWOH \ \ ~0-0~___) P HOWOH 0 0 0 0 0 (621 Licodione H O W O H u "WO" 0 OH 0 Echinatin (94) Scheme 25 I1 NPR 6 NATURAL PRODUCT REPORTS.1989 NADPH ____) 02 Formononetin (95) Calycosin (99) kDPH (96) NADPHI \y-Baptigenin (100) Vest itone ( 97) (1011 NADPH1 1 J (-)-Medicar p in (98) / (-1-Maackiain (102) Scheme 26 as shown in Scheme 26. Hydroxylase enzymes that catalyse 2‘-hydroxylation of (95) to (96) and 3’-hydroxylation of (95) to calycosin (99) have been demonstrated in microsomal fractions from chickpea cell suspension cultures that had been challenged with yeast-extract elicitor.”* The enzyme activity appeared concomitantly with the accumulation of pterocarpans required NADPH and 0 as cofactors and also hydroxylated biochanin A (103) to the corresponding 2’-and 3’-hydroxylated iso- flavones.Hydroxylation of biochanin A was in fact rather more efficient than hydroxylation of formononetin though no pterocarpans derived from biochanin A are synthesized in Cicer arietinum. Daidzein (104) and genistein (69) were poor substrates. In some experiments only 3’-hydroxylation was observed and this suggests that two distinct hydroxylases are involved. Occasionally the methylenedioxy-derivative$-bapti-genin (1 00) was isolated from incubations with formononetin demonstrating the next step of the sequence to maackiain. Non-induced microsomes were without any detectable iso-flavone hydroxylase activities. The biosynthesis of pterocarpans involves a sequence of reduction steps prior to cyclization and initially isoflavones are reduced to isoflavanones.Yeast-extract-challenged cell suspen- sion cultures of Cicer arietinum have yielded a soluble isoflavone oxidoreductase that catalyses the reduction of 2’-hydroxy- formononetin (96) to vestitone (9’7).ll9 The enzyme was unstable required NADPH as cofactor and was specific for isoflavones that contain a 2’-hydroxyl group. Thus whilst 2’-hydroxy-$-baptigenin (101) also served as a substrate daidzein (1 04),genistein (69) formononetin (99 biochanin A (103) and calycosin (99) were not converted. Again these results support the proposed sequence to medicarpin and maackiain (Scheme 26). Feeding experiments have also indicated that 6a-hydroxy- pterocarpans are derived by direct hydroxylation of the NATURAL PRODUCT REPORTS 1989-P. M.DEWICK Daidzein (104) R = H Biochanin A (103) Genistein (69) R = OH (105) R = H (106) R = OH (+)-P isatin (108) Phaseollin (110) pterocarpan skeleton. This has been demonstrated at the enzymic level for the conversion of (105) into (106) during the biosynthesis of the glyceollins in soybean where a cytochrome- P-450-dependent mono-oxygenase was implicated and the 6a- hydroxyl was derived from molecular oxygen (see ref. 91). Fungal 6a-hydroxylation of (-)-maackiain (102) by Ncvtriu haematococca similarly gives (-)-6a-hydroxymaackiain (107) into which label was incorporated in the presence of 1802 but no labelling occurred if H,'*O was supplied instead.',O This again implicates a mono-oxygenase but surprisingly a completely different pattern of labelling results when pisatin (108) is synthesized as a phytoalexin in pods of pea (Pisum sati~um).'~~ The pisatin that was isolated from incubations with 1802 or H,180 was a mixture of molecules containing up to three labelled oxygen atoms.Detailed analysis of the products using tandem mass spectrometry showed that the 6a-oxygen of pisatin was derived from water not from 0,. The remaining five oxygen atoms were labelled as expected i.e. oxygens 3 and 5 from H,O (via malonyl-CoA) and oxygens 8,9 and 11 from 0 (via hydroxylations). Although feeding experiments had indicated that the pathway to pisatin involves 6a-hydroxylation of (+)-maackiain followed by methylation the enzymic mechanism seems to vary markedly from those participating in the biosynthesis of glyceollin and fungal 6a-hydroxylation.Phaseoliidin (1 09) 0 II CH,OC C H ,C0,H "H+o HO (111) R = H (112) R = OH Prenylation of isoflavonoid molecules generally seems to occur late in the biosynthetic sequence after modified skeletons have been produced from the isoflavone precursors. Phaseol- lidin (109) has been shown in feeding experiments to be an intermediate between (105) and phaseollin (1 10) in stressed tissues of bean (Phaseolus vulgaris).A dimethylallyltransferase from a microsomal fraction of bean cell suspension cultures that had been treated with a yeast-extract elicitor has now been identified.'*' This enzyme catalysed the 10-prenylation of (+)-(105) to give phaseollidin using dimethylallyl diphosphate as the prenyl donor though it was not completely specific for the pterocarpan (105).Medicarpin and the coumestan coumestrol were also prenylated though the products have not been identified. This enzyme was strongly inhibited by both phaseollidin and phaseollin. Malonate hemiesters of isoflavone 7-0-glucosides accumu- late in chickpea (Cicer arietinum) and these appear to act as a store of isoflavone materials that are available after hydrolysis for the biosynthesis of pterocarpan phytoalexins. A malonyl-esterase activity that is involved in this sequence (see ref. I) has been further characterized and its substrate specificity investi- gated.'* Although biochanin A 7-0-glucoside 6"-O-malonate (1 12) and the corresponding formononetin derivative (1 I I) were efficiently hydrolysed to the isoflavone glucosides no 11-2 NATURAL PRODUCT REPORTS 1989 “ZH C02H 0;f Isochorismate (113) I 0 Chorismate (13) TPP 0-Succinylbenzoic acid (114) TPP 2 -0xoglu ta rate R = CHZCHZCOZH OH OH 0 TPP = thiamin diphosphate (117) (116) (115) Scheme 27 0 C(0) S -COA S- C OA C (0) QV 0 0 c05-OA Qvco2H (118) (119) Vitamin K (120) OH I 0 1 6\7@3 3 H 5 4 0 (121) (122) other substrates could be identified.This membrane-bound Nature via the intermediates o-succinylbenzoic acid (OSB) enzyme thus appears to be highly specific. (1 14) and 1,4-dihydroxynaphthoic acid (1 17). Details of the The biosynthesis of isoflavonoids that is induced by means of early parts of this pathway (Scheme 27) previously reported in biotic and abiotic stress in legumes of the tribe Trifolieae with preliminary form have now been published.124-127 Cell-free especial reference to coumestans has been briefly reviewed. 123 preparations from the vitamin-K-producing bacteria E. coli and Aerobacter aerogenes (Klebsiella pneurnoniae) contain an enzyme OSB synthase and produce OSB when incubated with 6 Quinones and Quinols isochorismate (1 13) and 2-oxoglutarate in the presence of A range of naphthoquinone and anthraquinone derivatives thiamin dipho~phate.~~~ Some mutants of E. coli apparently including the menaquinones (vitamin K2),are produced in blocked between chorismate (1 3) and isochorismate (1 13) but NATURAL PRODUCT REPORTS 1989-P.M. DEWICK geranyl COzH OH OH I (123) (124) 0 Shikonin (126) Geranylquinol (125) (127) Scheme 28 still able to synthesize vitamin K have been shown to be ‘leaky ’rather than ‘blocked ’,and the role of isochorismate in this sequence has now been confirmed. Decarboxylation of 2- oxoglutarate by the enzyme OSB synthase has again been demonstrated to be independent of 2-oxoglutarate dehydro- genase (see ref. 1). An enzyme activity that has been separated from E. coli fractions that contain OSB synthase and which is capable of decarboxylating 2-oxoglutarate in the presence of thiamin diphospate has been referred to as the decarboxylating ‘subunit’ of OSB synthase and both the subunit and the holoenzyme have been characterized.125 Incubation of the decarboxylating fraction with these substrates gives succinic semialdehyde and treatment of the incubation mixture with phosphorylase gives a product that is believed to be the thiamin adduct of succinic semialdehyde. o-Succinylbenzoic acid is transformed into 1,4-dihydroxy- naphthoic acid (1 17) via a coenzyme A ester and enzyme preparations from Mycobacterium phlei Escherichia coli and the plant Galium mollugo are all capable of giving this intermediate when incubated in the presence of OSB ATP coenzyme A and Mg2+.126 Comparison with synthetically produced CoA has confirmed this intermediate to be the ‘aliphatic’ CoA ester (115). Minor amounts of the ‘aromatic’ ester (1 18) and the diester (1 19) were also produced in certain cultures but these were not enzymically convertible into 1,4-dihydroxynaphthoic acid whereas (1 15) was smoothly transformed.An activated naphthoic acid CoA ester (1 16) has been postulated as a further intermediate between (1 15) and (1 17). Alkylation of 1,4-dihydroxynaphthoic acid subsequently leads to the more complex naphthoquinones and anthra-quinones. Vitamin K (phylloquinone) (1 20) results from phytylation and methylation steps. A novel metabolite of vitamin K that is formed enzymically when the quinone is incubated with plasma or serum from the blood of a number of animal species including sheep pig calf and rabbit has been identified as the chromanol (1 21).12* OSB-derived anthra- quinones have acquired extra skeletal carbons by alkylation with a prenyl group followed by cyclization.Further 0-glucosylation of several such anthraquinones has been observed in cell suspension cultures of Cinchona s~ccirubra.’~~ Five distinct glucosylating activities were purified their preferred substrates being the di- and tri-hydroxylated anthraquinones 1,4-dihydroxy- 1,8-dihydroxy- 2,6-dihydroxy- and 1,2,7-trihydroxy-anthraquinone and 1,6,8-trihydroxy-3-methyI-anthraquinone [see (1 22)]. The enzymes had fairly broad substrate specificity and would also accept some flavonoids. The reaction products also formed in the cell cultures were not fully characterized. Shikonin (126) is an example of another group of naphtho- quinones which have their origins in 4-hydroxybenzoic acid rather than in OSB.The rest of the skeleton of shikonin is derived from geranyl diphosphate and an enzyme that catalyses the alkylation of (123) with geranyl diphosphate [giving 3-geranyl-4-hydroxybenzoic acid (1 24)] has been isolated from cell cultures of Lithospermum erythrorhizon. l3O9 131 The enzyme preparation was also able to synthesize (124) from dimethylallyl diphosphate and isopentenyl diphosphate demonstrating the presence of isopentenyl-diphosphate isomerase and prenyl- transferase enzymes in the preparation. Enzyme activity was considerably higher in shikonin-producing cultures than in non- shikonin-producing lines. Shikonin-free cultures were shown to accumulate dihydroshikonofuran (127).132 This is not con-sidered to be a precursor of shikonin but is probably related to some similar furan derivatives that had previously been isolated from Lithospermum erythrorhizon and probably arises from geranylquinol (1 25) (Scheme 28).The biosynthesis of the isoprenoid quinones ubiquinones (from 4-hydroxybenzoic acid) and menaquinones (from OSB) has been covered in a recent review.133 7 Miscellaneous Shikimate Metabolites 7.1 Diarylheptanoids Feeding experiments in young shoots of Acer nikoense have shown that phenylalanine and cinnamic acid are precursors of the diarylheptanoid acerogenin A (129).134 Carbon-2 of acetate and of malonate were also efficiently incorporated but neither C-1 of acetate nor the S-methyl of methionine was utilized. The labelling patterns were analysed by degradation and a sequence NATURAL PRODUCT REPORTS 1989 CO,H 0 I rC H~ HOo"K,-coA \ I C-0 I S-COA J OH (128) Acerogenin A (129) Scheme 29 &OMe G'u~min~ &OMe ,cHzoH Seri nel HO HO HO OH N-CH H02C HOCH2 HOCHZ H \ [CHzl ,C (0) NH 3-Dehydroqui nate (4) My c 0spor i ne g lut am i no1 (1301 Scheme 30 as shown in Scheme 29 has been proposed.Two phenylpropane glutaminol probably arises from serine and glutamine (Scheme units and the methylene carbon of malonate provide the carbon 30). Acetate and also 3-dehydroquinate labelled this portion skeleton and (-)-centrolobol(128) which has also been found presumably via the ketoadipate pathway. Thus 3-dehydro- in A.nikoense has been postulated as an intermediate. This quinate appears to be a key compound for both anabolic and sequence fits in with long-held speculations on the origins of catabolic pathways in this organism. diarylheptanoids but contrasts markedly with that proposed for curcumin in which four carbons of the C chain and possibly one aromatic ring were shown to be derived from 7.3 Ansatrienin acetate/ malona te. The ansamycin antibiotic ansatrienin (mycotrienin) (134) which is produced by cultures of Streptomyes coiiinus contains two carbocylic rings that are potentially derived from shikimate. 7.2 Mycosporines Preliminary feeding experiments showed that the quinonoid Fungal mycosporines originate from the shikimate pathway C,N unit which would be expected to be derived from 3-amino- and a series of precursor-incorporation experiments using 5-hydroxybenzoic acid was not labelled when shikimic acid Trichothecium roseum has confirmed this for mycosporine was supplied to the culture,136 though the seven-carbon glutaminol (130).135 The production of (130) is improved if cyclohexanecarboxylic acid moiety was.Benzoic acid was not a glucose in the culture medium is replaced with quinic acid and precursor of the cyclohexanecarboxylic acid fragment though labelled 3-dehydroquinic acid proved to be a precursor of the the partially reduced systems 2,Sdihydro- and 1,4-dihydro- cyclohexenone ring. The glutaminol portion of mycosporine benzoic acid and cyclohexanecarboxylic acid itself were NATURAL PRODUCT REPORTS 1989-P.M. DEWICK C0,HI HOO/aI OH ___I) 6OZH OH (132) (133) (1 311 J 0 'OCH3 (0 ='3C) A n sat r ien in (134) Scheme 31 NHCHO Tuberin (135) incorporated. 2,5-Dihydrophenylalaninewas not incorporated and neither the D-nor the L-form of cyclohexane-carbonylalanine was incorporated intact. The detection of a new ansatrienin derivative containing a cyclohex- 1 -ene ring instead of the cyclohexane of (1 34) suggested that sequential reduction of shikimic acid to (133) proceeded via 2,5-dihydrobenzoic acid (1 32) rather than via the 1,4-analogue (Scheme 3 1). Further studies with (-)-[2-13C]shikimic acid (1 3 1) confirmed the 14Cdata giving a single 13Cenhancement for (1 34). 13' Degradation of ansatrienin to cyclohexane-carboxylic acid and derivatization to the ( +)-(8-mandelic ester allowed the stereochemistry of labelling to be determined.Thus C-2 of shikimic acid was incorporated specifically into C-6 of cyclohexanecarboxylic acid and this showed that the reductive sequence had followed the same steric course as observed earlier in the biosynthesis of cyclohexyl fatty acids (see ref. 1). However (-)-[6-*H,]shikimic acid gave no detectable deuterium in the product indicating that there had been loss of both methylene hydrogens and this contrasts with the cyclohexyl fatty acids where hydrogen labels were retained. Thus the reductive sequence may be more complex. The non- incorporation of shikimic acid into the quinone C,N fragment is unexplained though the 4-amino-analogue of DAHP which may be formed via a variant of the DAHP synthase reaction has been proposed as a precursor.Ill C- Xanthocillin monomethyl ether (136) 7.4 Isocyanide Derivatives The mould metabolites tuberin (1 35) and xanthocillin mono- methyl ether (136) are derived from tyrosine with loss of the carboxyl carbon and attachment of an extra carbon to the nitrogen giving N-formyl or isocyanide derivatives respectively. The extra carbon in the case of tuberin is derived from glycine through C,-tetrahydrofolate derivatives though the origin of the isocyanide carbons in (136) is unknown. Details of earlier studies on the biosynthetic origins of tuberin (see ref. 91) have now been published.138 In addition C-3 of L-serine was shown to label the 0-methyl and N-formyl groups equally again via tetrahydrofolate-dependentmetabolism.In further studies on the origins of tuberin in Streptomyces amakusaensis the stereochemistry that is associated with the incorporation of C-3 of serine into the N-formyl group has been investigated. 139 It was shown from feeding experiments with specifically 2H-labelled L-serines that there was preferential retention of the 3(pro-3S)-proton in the N-formyl group of (133 though the retention was only partially stereospecific. These results suggest that if dehydrogenation of 5,lO-methylenetetrahydrofolate to 5,lO-methenyltetrahydrofolateis specific for removal of the I 1(pro-11 R)-hydrogen (as is known for the reaction in liver) then the 3(pro-3R)-hydrogen of serine must become the 11(pro-1 1 R)-hydrogen in 5,l O-methylene- NATURAL PRODUCT REPORTS 1989 HO H2N H L -Serine (137) R = CGH,-P-C(O)-G~U,-H Scheme 32 tetrahydrofolate (137) (Scheme 32).The results are analogous to those observed with liver enzymes where there is also incomplete stereochemical control in the process. The origin of the isocyanide functions in xanthocillin monomethyl ether (1 36) still poses some problems. Results from feeding experiments in Dichotornomyces cejpii suggest that the nitrogen atoms derive primarily from the amino-group of tyrosine. 140 [15N]Tyrosine was a significantly better precursor than [15N]ammonium ion or [arnido-15N]glutamine and although multiply labelled cyanide and the cyanohydrin 2-hydroxy-4-methylvaleronitrilewere incorporated label ap- peared only in the 0-methyl group.Cyanate carbamyl phos- phate and citrulline were not utilized. Other studies had suggested that the isocyanide groups of the hazimicins originated by sequential oxidation of N-methyl derivatives (see ref. 33) but these results suggest that the isocyanide carbons of (1 36) originally formed part of a unit that was larger than just a single carbon. 7.5 Flexirubin-type Pigments The biosynthesis of pigments that are related to flexirubin (1 38) which is known to briginate from a shikimate-derived phenylpropane unit and acetate/malonate is reviewed in an article devoted to these 7.6 Fungal Pigments An extensive review on pigments from fungi of the Macro- mycete~’~* covers a wide variety of different structural types and subdivides them according to biogenetic origins.Un- fortunately in many cases there is still no experimental support for the biosynthetic pathways proposed but several distinct groups of pigments are undoubtedly of shikimate origin and all available biosynthetic data are given. 8 References P. M. Dewick Nut. Prod. 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Chem. 1987 65 226. 93 D. Scheel K. D. Hauffe W. Jahnen and K. Hahlbrock in ‘Re- cognition of Microbe-Plant Symbiotic and Pathogenic Inter- actions’ (NATO Ass. Ser. Ser. H Vol. 4) 1986 p. 325. 94 W. Knogge E. Kombrink E. Schmelzer and K. Hahlbrock Planta 1987 171 279. 95 C. Hermann M. Legrand P. Geoffroy and B. Fritig Arch. Biochem. Biophys. 1987 253 367. 96 J. R. Vincent and R. L. Nicholson Physiol. Mol. Plant Pathol. 1987 30 121. 97 C. Grand F. Sarni and C. J. Lamb Eur. J. Biochem. 1987 169 73. 98 N. G. Lewis P. Dubelsten T. L. Eberhardt E.Yamamoto and G. H. N. Towers Phytochemistry 1987 26 2729. 99 N. G. Lewis E. Yamamoto J. B. Wooten G. Just H. Ohashi and G. H. N. Towers Science 1987 237 1344. 100 G. Hrazdina A. M. Zobel and H. C. Hoch Proc. Natl. Acad. Sci. USA 1987 84 8966. 101 R. Welle and H. Grisebach Z. Naturforsch. Sect. C 1987 42 1200. 102 A. J. van Tunen and J. N. M. Mol Arch. Biochem. Biophys. 1987 257 85. 103 M. J. Begley L. Crombie A. M. London J. Savin and D. A. Whiting J. Chem. Soc. Perkin Trans. I 1987 2775. 104 K. Stich and G. Forkmann 2. Naturforsch. Sect. C 1987 42 1193. 105 G. Kochs and H. Grisebach Z. Naturforsch. Sect. C 1987 42 343. 106 G. Kochs R. Welle and H. Grisebach Planta 1987 171 519. 107 G. Forkmann and B. Ruhnau 2.Naturforsch. Sect. C 1987,42 1146.108 A. R. Reddy L. Britsch F. Salamini H. Saedler and W. Rohde Plant Sci. 1987 52 7. 109 S. Ayabe A. Udagawa K. Iida T. Yoshikawa and T. Furuya Plant Cell Rep. 1987 6 16. 110 R. K. Ibrahim V. De Luca H. Khouri L. Latchinian L. Brisson and P. M. Charest Phytochemistry 1987 26 1237. 111 L. Latchinian H. E. Khouri and R. K. Ibrahim J. Chromatogr. 1987 388,235. 112 F. Kerscher and G. Franz. Z. Naturforsch. Sect. C 1987 42 519. 1 13 M. Teusch and G. Forkmann Phytochemistry 1987 26 2 18 I. 114 M. Teusch G. Forkmann and W. Seyffert Phytochemistry 1987 26 991. 115 M. Schultz and G. Weissenbock Phytochemistry 1987 26 933. 116 L. Varin D. Barron and R. K. 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ISSN:0265-0568    

DOI:10.1039/NP9890600263

出版商:RSC    

年代:1989

数据来源: RSC

摘要:

Limonene A. F. Thomas Firmenich SA Research Laboratories 12I I Geneva 8 Switzerland Y. Bessiere 126I Borex Switzerland 1 Introduction 2 Hydrogen Shifts and Disproportionation ; the Action of Acids and Bases 3 Addition of Water Alcohols and other HX-type Molecules 4 Addition of Halogens Sulphur etc. 5 Hydrogenation of Limonene 6 Hydroboration and Related Reactions 7 Oxidation (except Epoxide Formation) 8 The Limonene Epoxides 9 Addition of a C Unit to Limonene 10 Addition of C or More to Limonene 11 Pyrolysis and Miscellaneous Reactions 12 Biological Reactions of Limonene 13 References 1 Introduction The production of (+)-limonene (I) in Brazil is about 12500 tonnes per year from orange stripper oil 15 000 tonnes per year from cold-pressed orange oil [over 90% of which is (+)-limonene] and about 11000 tonnes per year from other sections of the citrus industry (orange-essence recovery water ete.),' making the annual world production of (+)-limonene about 50000 tonnes.Smaller amounts of more or less racemic limonene (dipentene) are produced as a by-product from the hydration of turpentine; distillation of turpentine is a source of (-)-limonene which can also be distilled from oil of Eucalyptus sfqyriana,although the purity is not as high as that of the (+)-enantiomer. (+)-Limonene is one of the cheapest chiral starting materials suitable for organic synthesis and this review is intended to survey its chemistry. Until 1877 when Tilden distinguished between terpenes of the 'turpentine group' and the 'orange group' by the characterization of crystalline nitroso-derivatives,' there was considerable confusion regarding the hydrocarbons obtained from essential oils.Wallach pointed out that hesperidene citrene carvene di-isoprene terpilene kautschine cynene cajeputene and isoterebentine were all identical to (+)-limonene.3 The discovery of (-)-limonene (from Pinus sil-vrstrisJ)came a little later making clear the constitution of the racemate dipentene which had been obtained from the distillation of rubber." The correct formula was given by Wagner in 1894,6 and the first rational synthesis was by Perkin in 1905.' Racemic limonene is one of the products of the pyrolysis of (-)-(S)-a-pinene (2),8 and the conversion of turpentine into limonene over catalysts such as sodium sulphide on alumina at 350 "C has been patented.' We shall use the name 'limonene' for both the racemate and optically active forms.The major uses for limonene are in the flavour and fragrance industries as a solvent and in the manufacture of polymers and adhesives. Its uses as a solvent will not be discussed further but there are patents and such use has been increasing on account of the low toxicity pleasant odour. and bio-degradability of (+)-limonene Because (+)-limonene that has been distilled from orange oil is over 95 % pure there is sometimes doubt in the literature as to whether the limonene that was used in any experiment was further purified or not. The major impurity in the material from orange oil is myrcene (3); this can be removed by clathration with tetrakis(4-methy1pyridine)di thiocyanatonickel.l1 About 1 YOof aldehydes (mainly octanal) is also present and there are traces of other monoterpenes. The aldehydes can be removed by distillation over 0.5 YOsodium hydroxide. The presence of these impurities has led to widely different values being determined for the flavour threshold concentration in water. This has been given as 0.21 p.p.m. and the effect of non-volatiles on this value has been measured,12 but the limonene was only 96.5 YOpure and was probably only distilled orange oil so the figures are meaningless. Values of 0.01 p.p.m.13 and 229 p.p.b. (also for 96% pure limonene)" have been published but in these papers we are not even informed which enantiomer was tested and it is known that the organoleptic properties of the (+)-and the (-)-isomer are different.I5 Again the promotion of mouse skin tumours by orange oil was long assumed to be caused by (+)-limonene but pure (+)-limonene does not exert this effect.16 The toxicology of limonene is well known;" its metabolism is mostly by allylic oxidation or formation of an epoxide.lx One of the major metabolites uroterpenol glycoside (4) was isolated from urine especially of subjects with adrenal hyperplasia or in pregnancy; this does not occur as an optically pure enantiomer presumably because of the variety of enantiomers in dietary limonene.19 (Uroterpenol will be discussed later.) Other metabolites are known,')" and the conversion of (+)-limonene (I) into (+)-perillic acid (5) by Pseudonioncrs incognita has been described .zl Limonene is reportedly insecticidal ;BB.')B it is toxic to cat fleas (Ctmocephalidesjeli~),~' for example and may play a part in conferring resistance to trees against attack by insects.'" There is a simple school experiment to demonstrate the insecticidal properties of ( +)-limonene."' (3) COOH (4) (5) 29 1 + (7) Q + Scheme 1 An interesting recent application of limonene is in the purification of cyclodextrins from gelatinized starch with some of which it forms filtrable solid^.^' The variation of optical activity of limonene with temperature is known.28 Nuclear magnetic resonance spectrometry in the presence of Ag' and an optically active lanthanide complex has been used to measure the chirality,29 and the n.m.r.spectrum of limonene based on 13C-'3Ccouplings has been reported three times"" with somewhat different figures. Natural- abundance deuterium n.m.r. spectroscopy provides a rapid means of locating the positions from which protons are lost during its biosynthesis; these positions will have excess deuterium on account of the isotope effect. By this means Epstein et al. have shown that C-9 and C-I0 are not equivalent during the bio~ynthesis.~' This result was suggested by feeding experiments but difficult to prove because of the low incorporation of precursors.32 The mass spectrum of limonene appears to consist of two fragments of isoprene one of which is charged (m/z 68),3'3 but NATURAL PRODUCT REPORTS.1989 the situation is complex this fragment does not arise in the field-free zone directly from the molecular ion that is formed by collision-induced fragmentation.:'' 2 Hydrogen Shifts and Disproportionation ; the Action of Acids and Bases The carbenium ion (a) that is derived from limonene by the action of acids rearranges as shown in Scheme 1 .33 Formation of the ion (a) is also the initiation step in the Friedel-Crafts- catalysed and acid-promoted polymerization of Iim~nene,:'~ the chemistry of this ion going back to 1789 when turpentine [i.cl. r-pinene (2)] was treated with sulphuric acid."' When (+)-limonene (I) is homopolymerized by Ziegler-Natta catalysts the resulting polymer is optically inactive and consists of both the monocyclic structure (6) and the bicyclic structure (7)."x The properties of such dipentene resins which are used as tackifiers mainly in hot-melt adhesives (packaging materials) have been summarized by Ruckel et Although in principle all of the hydrogen shifts of Scheme 1 are reversible in practice (a) >(I).does not occur much because the formation of terpinolene (8) is preferred followed by further shifts to CL-(9) and y-terpinene Other menthadienes are also formed [particularly isoterpinolene (1 1) which is better prepared from car-3-ene (12)"] but careful distillation of the products is necessary for preparative purposes. There is always some disproportionation (Scheme 1 ) leading to the menthenes and p-cymene (1 3) and ref.35 notes how to avoid this. Much work has been invested in studying the differences between various acids effecting hydrogen transfers and dis- prop~rtionation,~' and the kinetics have been studied using trifluoroacetic The results vary somewhat with the strength of the Acid forms of ion-exchange resins effect the same transformation^.“^ The chirality of limonene is lost in all of these products [ion (b) is already achiral] and the recovered limonene gradually loses optical activity because of the reaction (a) >(1). Heating limonene in dipolar aprotic solvents also causes slow rearrangement of double bonds and disprop~rtionation.~~ These hydrogen shifts are encountered in many other reactions of limonene and can significantly lower the yields of the desired products (e.g.in the hydration of limonene to a-terpineol or in catalytic hydrogenation). Three isomeric dimethylbicyclo[3 .2. Iloctenes (14) were mentioned after the action on limonene of phosphoric acid on a silica support had been investigated first in 1947 (with a different and then in 1974.47 The latter paper includes an identification of the n.m.r. spectrometer that was used but not a single n.m.r. spectrum; one of us (AFT) repeated this work but found only the usual hydrogen shifts and disproportionations. Many years earlier phosphoric acid had been reported to give an unidentified compounddx which was dehydrogenated over sulphur to 2,6,9-trimethylphen-anth~ene,"~ the structure of which was confirmed by an independent synthesis.jn The unlikely compound (I 5) is also reputed to be formed by the action of phosphoric acids5' Other reactions that have led to the isolation of dimers from limonene or its disproportionation products are treatment with chloranil for 2 hours at 130-170 "C [to form (16)l" and the reaction of limonene with p-cymene (13) which has been reported to give the tetracyclic compound (17) in 20-25 YO NATURAL PRODUCT REPORTS 1989-A.F. THOMAS AND Y. BESSIERE conversion of p-cymene and in over 40% selectivity.j3 The action of BF;OEt in CCI or toluene apparently also gives dimerS..54.j.5 The formula in ref. 54 would be the result of the cycloaddition of the two methylene groups to form a cyclobutane which seems unlikely.There are a vast number of patents and publications dealing with the copolymerization of limonene with ethylene and propyIene,jfi with norbornadiene,j7 and with other alkenes as well as on the influence of limonene as a chain-transfer agent in the styrenation of vinyl ether polymers.j8 and the polymerization of vinyl monomers (styrene vinyl acetate etc.)."' Double- bond rearrangement of limonene also occurs in the presence of bases3*5.fio such as potassium t-butoxide in dimethyl sulphoxide61 or calcium oxide at 290-380 oC.6' Dispropor-tionation to p-cymene (1 3) is readily carried out with potassium hydride in pyrrolidine or ethylenediamine,'? a reaction which led to the suggestion that limonene could be used to measure the proton-removing power of 'superbases '.The formation of the limonene anion (c) by metallation with butyl-lithium and N,N,N',N'-tetramethyle thylenediamine was described by .~~ Erman et ~1This anion can be transformed into mentha- 1,8( IO)-dien-9-01(18)6.5and was used in several syntheses which will be referred to in later sections. Katzenellenbogen and Crumrine also converted the anion (c) into the alcohol (I 8) and then into the corresponding bromide for further synthesis."" Other derivatives (including some sulphides) have been made by Suemune et UI.,~~ and tin and silicon derivatives have been prepared from the anion (c).~' In all of these reactions the chirality of limonene is retained.The dianion (d) of limonene can be formed by treatment with butyl-lithium and potassium t-butoxide (Lochmann's base) or potassium t-amyloxidc at reflux; quenching this dianion with deuterium oxide yielded 7,IO-dideuteriated limonene (1 9) and some dideuteriated dimethylstyrene (20).69 3 Addition of Water Alcohols and other HX-type Molecules The carbo-cations that are formed by the action of acids on limonene (see Scheme I) can lead to addition products. Thus a- terpineol (21 ; R = H) can be formed by the addition of watcr; this is generally accompanied by some /j-(22) and y-tcrpineol (23) from addition of water to the endocyclic double bond. The reaction was first described by Bouchardat and Lafont in 1886,"' and it is surprising that the addition of methanol was only described 50 years later,7' although the product a-terpinyl f D D !? X OR methyl ether (21 ; R = Me) had been made [by etherification of a-terpineol (21 ; R = H)j2] and its odour described:" in 1883.Actually a-terpineol was known before Bouchardat's experiment having been made by the hydration of turpentine with acid catalysts,j4 but the structure was only established in 1895.75a-Terpineol was also known from dehydration of 1,8-terpin (24; X = OH),7(ithis also being obtained from turpentine. The a-terpineol that is obtained from limonene is generally (though not invariably; see below) racemic because of the isomerizations in Scheme 1 and the racemate was one of the first substances to be purified (m.pt 35 "C) by low-temperature crystallization.ii Some of these early experiments were conducted in glacial acetic acid when the main product is terpenyl acetate (21 ;R = Ac) from which the alcohol was obtained by Sulphuric acid in acetic anhydride also yields a-and /j-terpenyl acetate^.^" The terpineols are themselves hydrated under acid conditions 5 O/O aqueous sulphuric acid hydrating z-terpineol with /)-and y-terpineols reacting more slowly while Iimonene is unchanged under these conditions.x0 This further hydration was well known to the early workers,70.i'~'' who believed that a-terpineol (21 ; R = H) gave only cis-terpin [cis-(24; X = H). 'cis' referring to the hydroxyl and the hydroxypropyl groups] while the y-isomer (23) gave both isomers of (24; R = H).'? More recently it was shown that cis-terpin is the major but not cxclusivc product of hydration of all of the terpineols.':' Consequently many hydration processes of limonene produce large amounts of the diols (24; R = H) besides the terpineols but these diols may be dehydrated to the terpineols.Sur- prisingly 1,4-cineole (25),but not 1,8-cineole (26) is said to be NATURAL PRODUCT REPORTS 1989 d c1 Br (31) (32) formed in additi~n,'~ although 1,8-cineole (26) is a major component of the products resulting from treatment of a-terpineol (21 ; R = H) with an acid.84 Surprises here are however common ; for example terpin of unspecified stereo- chemistry is dehydrated by aluminium phosphate and alu- minium oxide to give limonene (l) p-cymene (13) and unidentified pr~ducts.~~ The authors of this paper were surprised by the p-cymene but we are surprised by the limonene since we would have expected terpinolene (8) ! Innumerable different conditions have been described for the preparation of a-terpineol (21 ; R = H) from terpene hydro- carbons mostly from turpentine.The most efficient way from limonene seems to be by using chloroacetic acids and a cation- exchange resin ; this gives optically active a-terpineol in 85 O/O conversion and 99 O/O selectivity;*' alternatively formic acid in the presence of zeolites gives 87-100% conversion and high selectivity.8i From limonene and acetic acid with ferric sulphate as a catalyst a 6:4 mixture of a-and /3-terpinyl acetates is efficiently made.8H Oxymercuration of limonene followed by reduction with sodium borohydride gives a-terpineol (21 ; R = H) [70%] the rest being the diol (24; X = OH) and 1,8- cineole (26).89 In fact it has long been known that if this procedure is applied to a-terpineol it leads to 1,8-~ineole.~~) If the mercuration of limonene is carried out in the presence of sodium lauryl sulphate the formation of micelles causes the ionized part of the molecule to be exposed to attack by water on the periphery and monohydration raises the yield of terpineol to 97 The addition of methanol to limonene in the presence of an acid could not be repeated by Treibs,92 who reported that there was mainly dimerization with a small amount of double addition.The reaction was taken up again in 1949 when Royals showed the reaction to be reversible by the fall in the optical activity of the product (21 ; R = Me) with increasing reaction time. Royals prepared other terpenyl ethers.93 (See also refs. 54 and 71). By-products from this reaction would be expected; although they have not been described those from the very similar reaction of pinene and methanol have,94 notably the ethers (27) (28) and (29). Bicyclic systems arising from the reaction of pinene would of course be absent from the products from limonene. Diol monoethers are known being made for example from limonene and ethylene glycol in the presence of an ion-exchange resin.g" (See also ref. 96). The light-induced addition of methanol to limonene takes a different course from the acid-catalysed reaction yielding 52 '/o of the ethers (27) and (28) with about 13 YOof mentha-1(7),8-diene (30).9i The microbiological addition of water to limonene is mentioned later.The addition of hydrogen chloride to limonene to give its monohydrochloride (31)98 works well only in the absence of (35) R=Me R'=iPr (33) (34) (36) R=iPr R'=Me SR (37) (-)-(38) R=H (39) (40) R=Ph NCHO moisture and in a solvent e.g. carbon disulphide,99 petroleum ether,'OO or dichloromethane. lnl Hydrogen bromide reacts similarly and the halides are converted into a-terpineol by the action of magnesium and air,'"O or with 2% potassium hydroxide (a stronger base yields hydrocarbons mostly dipentene).lo2 Zinc oxide (in 80 YOacetone for a-terpineol or in acetic acid for the acetate) has also been recommended.103 Because the chloride that is made in this way is optically active so is the terpineo1.lo2 The di-addition products (24; X = C1) and (24; X = Br) have also been known for a long time;'"' they are best made by the action of concentrated halogen acids in methanol"" or acetic acid on limonene and can be converted into the terpineols by adding a base.ln5 The safest route from limonene to y-terpineol (23) is still the original one from Baeyer,lo6 consisting in brominating the dihydrobromide (24; X = Br) to obtain 1,4,8-tribromomenthane (32),loi and then reducing this with zinc in acetic acid to the acetate of (23) with overall yields of 50-60 YO.'''' A method that is said to produce 72% of y-terpineol (23) consists in dehydrating terpin (24; X = OH) in isopropyl alcohol and 95 Yo sulphuric acid at room temperature for 80 The reaction of limonene with phenols dates from 1922,"" and the products have been patented as resins and lacquers."' These products could arise either by aromatic substitution or by formation of a phenol ether,112 further reaction giving polymers.l13 The reactions are more complex than those of camphene or pinene (cf the vague description of the reaction of limonene with 2,4-dimethylphenol compared with the precision of the same reaction with camphene in 1960114) and while two products [(33) and (34)] have been described from the reaction of phenol and limonene in the presence of boron trifluoride,'l" this cannot be the whole story.In the presence of a cationic ion- exchange resin for instance limonene reacts with cresols o-cresol yielding the ethers (35) and (36)11' [another surprise since these products require a carbenium ion that is derived NATURAL PRODUCT REPORTS 1989-A. F. THOMAS AND Y. BESSIERE from a-terpinene (9)]. Dimethylphenols with one free ortho-position"' and sesamol (3,4-methylenedioxyphenol)'18 give similar compounds. The reaction of limonene with phenol has also been studied in the USSR,"' but the publication was not available to us. Addition of nitric acid to limonene has been The ester that was obtained was reduced (by zinc dust) to a-terpineol. 120 The racemization of ( +)-limonene in sulphur dioxide occurs via the addition complex (37).122 Menth- I-ene also racemizes in liquid The addition of hydrogen sulphide to limonene was shown to give menth-1-ene-8-thiol (38) in 1979,124 this compound also being obtainable by the EtAlCIBr- or AlBr,-catalysed addition of H,S to pinenes.12j This compound is characteristic of grapefruit flavour in which it occurs naturally and has the lowest recorded flavour threshold of any naturally occurring substance.126 It is converted into 2,8-epithio-cis-p-menthane (39) by radical cyclization.126 The acid-catalysed addition of thiophenol to limonene yields 40 YOof 8-phenylthiomenth- I -ene (40) but it is difficult to purify the latter above 82% and Fourneron et al.preferred to protect the double bond at C-1 of (+)-limonene by treating it with N-bromosuccinimide in methanol [which yielded (41)] before acid-catalysed addition of thiophenol and removal of the protecting groups (using zinc and acetic acid) to obtain (-)-(40),12' which they required for a synthesis of car-2-ene (42).Di(p-toly1)methyl chloride adds to one double bond of limonene in the presence of zinc chloride (to the double bonds at C-8 and C-1 in the ratio of 2.5 1).12R In three hours at 55 "C hydrogen cyanide in 55 YOsulphuric acid also adds to both double bonds of limonene. From the product (43) 1,8-di-isocyanomenthane was prepared by using phosgene rearrangement of the isocyano-compounds to 13-dicyanomenthane taking place with o-dichlorobenzene at 250 "C.The stereochemistry of the products was not dis-cussed.'29 The addition of isocyanic acid in the presence of BF * OEt gave only a-terpinyl isocyanate.130 4 Addition of Halogens Sulphur etc. The addition of halogens to limonene has been known since the time of Walla~h.'~' Addition of chlorine is not clean because of the intervention of free-radical substitution. The matter was re- investigated by Carman and Venzke who have given a method (using iodobenzene dichloride) to achieve clean formation of a tetrachloro-compound (44).They have also described the photochemical chlorination of limonene dihydrochloride (24 ; X = Cl) which leads to the 1,2,4,8-tetrachloride (45).'"2 Addition of bromine to limonene is a two-stage process,133 but the rate slows well before the first mole has been added and a mixture of the dibromide (46) two tetrabromides and some other compounds were identified but no dibromide arising from addition only to the C(7tC(8) double bond.',' 'Limonene tetrabromide' had long been used as a crystalline derivative of limonene (cf.Mosher13*) and Carman and Venzke showed that the crude bromination mixture consisted of 70 YOof a crystalline tetrabromide and 30 YOof another tetrabromide which was oily if (+)-limonene was used but crystalline if the racemate was used. At first they considered the crystalline tetrabromide from ( +)-limonene to have the (8S)-~onfiguration,'~~ but X-ray crystallography showed it to be the (8R)-isomer (47).136 A related dichlorodibromide (48) which was made135 by partial debromination of racemic limonene tetrabromide followed by chlorination of the double bond was shown similarly to have the same ~0nfiguration.l~~ Somewhat similar to halogenation is the addition of iodine azide to both double bonds of (+)-lim~nene.'~' Addition of benzenesulphenyl chloride to limonene also occurs across both double bonds ;138 one mole adds 70 YOto the C(8)-C(9) double bond and the main isomers of the double addition are (49) and (50).139 The formation of volatile sulphides from the reaction of &Cl &SPh c1 SPh (47)X=Br (48)x=€1 (54) sulphur with limonene was noted by Nakatsuchi in 1930,'J0 but it was only in 1959 that Weitkamp deduced the formulae (51)-(54) and discussed the possible mechanism of their f~rrnation.'~~ Weitkamp's major product (54) is isomeric with one of the compounds (39) that were described by Demole and Enggist (see above).126 Actually Weitkamp had also obtained this isomer (39) mixed with (54) by catalytic reduction of (53).14' These products must have been the main components of a mixture that had earlier been patented as a flotation agent.lJ2 More recently refluxing limonene with sulphur for two hours was shown to give a complex mixture consisting of ten hydrocarbons and 22 sulphur-containing aromatic and terpenyl compounds.The mass spectra of these substances were taken and proposals of several new structures were made including the trisulphide (55),ld3 but it would be desirable to have further proof.Sulphurized limonene has been patented by oil com- panies as an additive in lubricating and oxidation-resistant The reaction of diphenyl diselenide with hydrogen peroxide gives phenylseleninic acid 'PhSeOH ' which adds to limonene to yield oxabicyclic selenium compounds (56) reduction of which (by tributyltin hydride) leads to 1,8-cineole (26) in high yield.145 5 Hydrogenation of Limonene The first catalytic hydrogenations of limonene which were carried out by Sabatier and Senderens at the turn of the NATURAL PRODUCT REPORTS 1989 century yielded menth-l-ene (57) over copper"" and the menthanes (58) over nickel."' These results were rapidly followed by others e.g. the use of platinum black which caused addition of hydrogen in two stages,"$ and the use of pressure."" It was soon recognized that many catalysts effccted not only hydrogenation but disproportionation (c).g.copper'"'!' and platinum on charcoal'j'). Some catalytic supports favour hydrogenation more than dehydrogenation (ZrO and Tho,) while some favour dehydrogenation (MgO CaO and La20:3).'.i' The occurrence of undesired disproportionation reactions has led to the discovery of many methods that give high yields of menth-1-ene for example sodium borohydride and platinum salts (98 YOyield)'"" or nickel chloride and polyvinylpyrrolidone with hydrogen.'.j4 A catalyst that contained neodymium and a silane gave menthene after 1.5 hours'jj and a complex that contained rhodium trichloride and triphenylphosphine and which was used as a catalyst in water give menthene after 32 hours and menthane after 76 For preparative purposes Newhall has confirmed'"' the utility of Vavon's platinum catalystlA8 rather than palladium or copper for menth-l-ene and we have found that a small amount of Raney nickel is adequate to give over 90 YOof (57).ljX The configuration of the fully reduced menthanes (58) has been well established,'"!' and catalytic reduction generally gives preferentially the tram-isomer but catalytic amounts of cob(1)alamin in aqueous acetic acid give nearly 70% of the cis-isomer.'"' The readiness of double-bond rearrangement in limonene during reduction has been exploited by using hydrogenation over a deactivated palladium catalyst; this yielded a mixture from which menth-3- ene (59) could be isolated the unchanged limonene being recycled (racemization was not mentioned but we can suppose it to have occurred).161 The reason for this rearrange-ment-hydrogenation was to make menthone [( +)-(60)] from the epoxide of (59).162 Most of the catalytic reductions that have been mentioned yield optically active menthene but reducing conditions involving isomerization are known.Thus menth- 1-ene slowly racemizes when heated in toluene with sodium and o-chlorotoluene because of the reversible reaction that occurs between menth- 1-ene (57) and menth-3-ene (59) the equilibrium mixture containing 63% of the latter [together with 5% of menth-4(8)-ene (6 I )].lfi3 Dehydrogenation of limonene to p-cymene is reported to occur best over a catalyst of PdO and sulphur on active charcoal at 220-230 "C,giving 97 YOyield of p-cymene (1 3) in 96% purity.164 On a small scale iodine yields 65% of p-cymene.165 The disproportionation of limonene to p-cymene (I 3) and menthane (58) has been known since 1924 with palladium151 or platinum on charcoal166 as catalyst.The dehydrogenation occurs in two stages; initially 52-53 YOof p-cymene is formed together with 4-2 of menth-8-enes (62). Longer reaction O/O QOH H H p. OH OH H (67) Rae (68) R=CMe2CHMe2 (71) R=H "p (72) X=OH (74) (73) X=I times lead to the menthanes; with mesityl oxide as the hydrogen acceptor yields of up to 94% of p-cymene can be obtained.lfii The hydrogen that is available from limonene has also been used in the hydrogenation of double bondslfiH and of nitriles to methyl groups1"!' (both with palladium on charcoal as catalyst) and by adding ferric chloride to the same catalyst of carbonyl groups to hydrocarbons."" Reductions of limonene other than catalytic ones have not been used; Semmler showed in 1904 that sodium in alcohol was without action."' Reduction of limonene vici hydroboration is mentioned below.6 Hydroboration and Related Reactions The first attempted monoaddition of diborane to limonene resulted in a statistical mixture of the diols (63).li2 Using disiamylborane Brown showed how menth- 1-en-9-01 (64) was obtained in 79 % yield after oxidation,"" similar results having been obtained with aluminium alkyls."' Brown did not mention the stereoisomerism at C-8 of (64) which was pointed out by Albaiges et ci1.li5 Using the addition of di-isobutylaluminium hydride to (+)-limonene followed by aerial oxidation Ohloff et al.described the stereochemistry of the isomers of (64) and the corresponding aldehydes (65) a diastereoisomeric mixture of which occurs in Bulgarian rose oil."" X-Ray crystallography of the (lR,3R,4S,8R)-isomer of the diols (66)l" and of the (4R,8R)-isomer of menth- I-en-9-01 (64)liX established the stereochemistry of each of them. More recently it was reported"" that boron dihydrogen chloride gave 81 '/o of the alcohols although thexylboron hydrogen chloride seems to be more stereoselective and oxidation of the menth- 1-en-9-yl-borane that was obtained with the latter gave 68% of menth- 1 -en-9-als directly.1H" Direct reductive alumination of limonene with aluminium and hydrogen in hexane at 160 "C and then aerial oxidation leads to (64).I8l Some methods of reduction of limonene involving boron and cobalt compounds and then an acid have been described,"' but treatment of the adduct of NATURAL PRODUCT REPORTS.1989-A. F. THOMAS AND Y. BESSIERE Q QOl1OQ / or1 (79) (80) (811 HO #*a 2' 9' OOH HO+, OH \ RO.*,9 0 / (83) (84) (85) disiamylborane and limonene with acetic acid at 100 "C gives completely racemized menth- 1-ene.lH3 A preliminary note by Brown and Pfaffenberger in 1967IH4 was followed by a rather different full paper in 1975l"j in which the preparation of the cyclic boron compounds (67) and (68) is described.The diols (69) were obtained from (67) (the stereochemistry at C-8 again not being specified) while 83 YOof D-( -)-( 1R,2R,4R)-carvornenthol (70) was obtained from (68) this being the most efficient way of making a single carvo- menthol from limonene. Hydroboration of ( +)-limonene with BH,Cl .OEt and then reduction with lithium aluminium hydride gives a borane (71) that is said to be useful for asymmetric induction in the hydroboration of alkenes.1N6 Acetoxyborohydride is made from NaBH and Hg(OAc) in tetrahydrof~ran.'~'? This reagent hydroborates limonene on the double bond at C-1 then treatment with hydrogen peroxide yields dihydrocarveol (72) (stereochemistry unspecified) and iodine yields 2-iodomenth-8-ene (73).lHH Hydroboration can be used on functionalized limonenes such as the epoxides,lxg and the alcohol (64) can be converted into the corresponding chloride with CCI and Ph3P,190 leading to a wide variety of synthetic routes. (+)-Limonene has been silylated to (74) with triethoxysilane at 80 "C and a catalytic amount of platinum on charcoal. The product was patented as a waterproofing agent for concrete. lB1 7 Oxidation (except Epoxide Formation) Since 1914 it has been knownlg2 that limonene is very sensitive to air or oxygen rapidly acquiring a high peroxide number and it has been used as an anti0~idant.l~~ The peroxides are slowly converted into other substances under various conditions (this oxidation is partly responsible for the 'off-flavour' of aged citrus oils).A full explanation has been given by Schenck et ~1.'~'' The effect of an acid on the hydroperoxides was noticed by Bain,1g5.196 and we have noticed that the rise in temperature that often occurs when limonene is hydrated under mild conditions (weak aqueous acid in organic solvent) is due to the presence of hydroperoxides. Ig7 Autoxidation is not stereo-specific racemic alcohols being formed after reduction of the hydroperoxides (cis:trans = ca. 1 :1) and racemized through the intermediacy of the radical (e). Decomposition of the hydroperoxides with heavy-metal catalysts can alter the distribution of the products (after reduction) between carvone [(+)-(75)] and the menthadienol(76) which has predominantly cis hydroxyl and isopropenyl There are many patents and papers concerning such reactions (with Co Mn and Ni The products that were formed by leaving a drum of limonene open in Australian sunlight included a trace of perilla alcohol (77),lg9 and heating a solution of limonene in dimethyl sulphoxide at 100 "C in air for 48 hours is reported to give 95 O/O of 4-methylacetophenone via dimethylstyrene (78),'0° whereas in dimethylformamide or hexamethylphosphoric triamide as the solvent cymenol (79) is the main product.'" Autoxidation in the presence of ammonia (' ammonoxidation ') yields a complex mixture of terpene hydrocarbons pulegone (SO) and more interestingly some trimethylpyridines in-cluding the 2,3,6-i~omer.~~* Dye-sensitized photo-oxygenation (by '0,)of limonene leads to hydroperoxides the stereoisomers of which have been separated and chara~terized.'~~ The reduction products of the laiter are stereoisomers of the menthadienols -(76) (8 I) and (82) but in contrast to the autoxidation the alcohols with cis hydroxyl and isopropenyl groups are predominant particularly (76) and they are optically active.204 Improvements (of the lamp or by supporting the Rose Bengal catalyst on magnesium oxide) have been claimed.*05 Reaction rates have been determined.206Uranyl-acetate-catalysed photochemical oxida- tion of limonene leads to a hydroperoxide (83) hydrogenation of which (over Pd) gives the tvans-menthane-trans- 1,2-diol (84).'07 Catalysis of the photo-oxidation of menth- 1-ene with ferric chloride which has not been reported with limonene gives 38 YOof ring-opened products.'08 Oxidations that are supposed to permit greater selectivity especially for avoiding racemization via the radical (e) include the use of t-butyl peracetate or perbenzoate in the presence of cuprous bromide.The cis-carveol (82) and the trans-carveol (85; R = H) which are obtainable from (+)-limonene were then converted into (-)-carvone (75).'09 Wacker conditions of oxidation (air and copper chloride with a catalytic amount of palladium chloride in acetic acid) give a highly stereoselective oxidation to trans-carveyl acetate (85 ;R = Ac) in 63 YOyield,210 PdCl(NO,)(MeCN) being without catalytic action.'" The oldest method of converting limonene into carvone is through the nitroso-chlorides (86) which were first made by Tilden from gaseous nitrosyl chloride,212 this preparation being improved by Wallach by using an alkyl nitrite and HCl."'" The action of base then gave carvone oxime,214 from which carvone was obtained by the action of an acid.This route is both industrialz1" and academic there being an undergraduate experiment for making carvone from orange There are variants using nitrosylsulphuric acid,"'? dinitrogen tetroxide in formic acid,'18 and so forth. Direct allylic oxidation has been carried out with t-butyl chromate this giving 21 YO of carvone (75) and 13YO of isopiperitenone (87),'l9 with the Cr0,-pyridine complex to give 36 YOof (75) and 31 YOof (87),220 with t-butyl hydroperoxide and hexacarbonylchromium to give net yields of 39% of (75) and 28.5% of (87) (with 47.7% of the limonene being recovered),221 and with pyridinium chlorochromate to give (75) and (87) in the ratio of 2 1.222 Pyridinium dichromate and NATURAL PRODUCT REPORTS 1989 (92) (93) t-butyl hydroperoxide in the presence of Celite is reported to give a 48 YOconversion and 23 YOyield of piperitenone (88) but the 'H n.m.r.figures that are given223 correspond neither to piperitenone (88) nor to isopiperitenone (87). It should be noted that (88) is readily prepared by oxidation by dichromate ion of the major product (76) from the photo-oxidation of limonene.2n4 The first experiments on the electrochemical oxidation of limonene concerned the experimental technique but no products were isolated.224 Later it was suggested that in an aqueous medium hydration occurred before oxidation."5 In methanol a mixture was obtained mostly of ally1 methyl ethers;226 a-terpineol (21 ;R = H) and trans-carveol (85; R = H) have also been reported."' On a graphite electrode in NaCIO, the major products from (+)-limonene are (-)-dihydrocarvone (89) and the trans-diol (90); both antipodes of limonene were examined.22H The cis-hydroxylating oxidant potassium permanganate yields the tetraol 'limonite' (91) (m.pt 192 0C),"9 which was also obtained with hydrogen peroxide and catalytic amounts of osmium tetroxide.'"" The 1,2-diol that is obtained by the reaction of limonene in acetic acid2"' arises by a different mechanism from ring-opening of the epoxide (see below).The first work on the oxidation of limonene by selenium dioxide contained no spectral data,*"' and Sakuda'"" and one of showed that the main product from the reaction in ethanol is racemic mcntha- 1,8-dien-4-01 (92) together with a certain amount of mentha- 1,8( 1 O)-dien-9-01(1 8) and optically active truns-carveol (85; R = H). The isolation of supposedly optically active mentha- 1,8-dien-4-01 has been described in later papers one using the same method,':'" the other using H202 and catalytic SeO,,':'" this reaction also being described el~ewhcrc.~"' Sharpless confirmed our work and showed that the spurious optical activity was due to The reaction is indeed complex (Sharpless mentions 27 products and the carbonyl-containing products have been analysed'"!') but the main product is always (92).Oxidation by selenium dioxide in acetic acid takes a different course leading mainly to carveyl acetate [truns (85; R = Ac)/cis = 4 1 ; 40%] the acetate of (1 8) [30 %I and trans-mentha- 1(7),8-dien-2-yl acetate (93) [10Yo]. Oxidation of limonene by lead tetra-acetate is useful for making optically active derivatives of mentha- 1,8(1 O)-dien-9-01 (18) from the initial product (94) of the rea~tion'~' (cf the preparation of lanceo124') although it was first carried out on the ra~emate.'~" Although the limonene anion (c) makes this reaction apparently redundant it was still used to make the aldehydes (65) in 1979.244 Oxidation by manganese(rr1) acetate is discussed in Section 10.The oxidation of limonene by mercuric acetate in acetic acid OH OMe H-e R 0$CHO ODmEt fcHo (99)R=CHO (100) (1011 (102) (104)R=CH20H leads to a small amount of hydrocarbons (including mentha- 1,4,8-triene and p-cymene) and to mentha- 1,4(8)-dien-9-y1 acetate (95) and trans-carveyl acetate (85; R = Ac).'~ Under different conditions (and after reduction with NaBH,) z-terpineol (21 ;R = H) and P-terpineol (22) were obtained the terpins (24; X = H) also having been reported'lj (although the authors did not seem to appreciate the instability of these on gas chromatography). Oxidation of limonene by thallium(III) nitrate is one of the few routes from it to the bicyclo[3.2.Iloctane structure (another is mentioned in Section 8 under the 8,9-epoxide). In methanol 81 YO of the limonene was converted into a mixture of stereoisomers of (96) and (97) (1 :4) 19 YOof the products being unidentified.246 Early work on the oxidation of limonene by chromyl chloride mentioned a number of product~,'~' but later work led only to a small amount of dihydrocarvone (89).'48 When passed over vanadium pentoxide on pumice at 425 OC limonene yields maleic anhydride.249 The action of N-bromosuccinimide on limonene should lead to allylic bromination ; the first study reported unstable brominated products which were converted in 80 YOyield into p-cymene (13) by KOH in MeOH.'"" It is likely that the major brominated product is indeed the expected one (98; X = Br) Taher and Retamar having converted limonene into carvone by this route; they used aqueous KOH in dioxane for the hydrolysis.251 The action of t-butyl hypochlorite appears to be cleaner; the production of (-)-trans-carveyl chloride (98; X = C1) has been optimized'"' and the latter converted into carveyl esters with zinc carboxylates.23:j NATURAL PRODUCT REPORTS 1989-A. F. THOMAS AND Y. BESSIERE (107) (108) (109) X=Se(O)Ph Y=OH (110) X=OH Y=Se(O)Ph (111) X&1 Y=OH (112) X=OH Y=C1 (114) X=NMe2 Y=OH Br (115) X=OH Y=NMe2 Early work on the ozonolysis of limonene was restricted to the possible identification of some (methyloxocyclohexenyl) acetic acids;'j4 a diozonide was also reported.255 The reaction occurs very rapidly."j" The study of partial ozonolysis seems to date only from 1956 the aldehyde (99) and the corresponding acid being identified after oxidative decomposition (by CrO,) of the ozonide (with a small amount of 4-methylcyclohex-3- enyl methyl ketone from ozonolysis of the isopropenyl group)."j' The aldehyde (100) was mentioned (without its properties) but it was only compared with a degradation product from cembrene.'" The isolation of the C acid after reduction and then esterification to (IOI) rather than a C acid of the early work'j4 was also claimed.259 The cyclization of the aldehyde (99) to an aldehyde (102)260 or a ketone (103)''' was studied by Wolinsky [who made (99) from limonene epoxide]."' The optical activity of saturated (99) has been used in further syntheses."? Mono-ozonolysis has been exploited by a Polish group,?"3 who have also shown that electrochemical reduction of the ozonide of (+)-limonene leads to the optically active alcohol (104) the latter cyclizing to the tetrahydrofuran (105) in acid.?6J.?6.5 See also the description of the cyclization of (99) to a cyclopentanone (106) with a rhodium chloride catalyst."6 8 The Limonene Epoxides Direct oxidation of limonene with perbenzoic acid was first described by Prileshajew ;pfi7 peracetic acid was later used on (-)-limonene,'68 but only in 1957 on the ( +)-isomer.26g These and other oxidations with peracids lead to nearly 1 1 mixtures of the cis- and trans-I ,2-epoxides (I 07) and (I 08) or (in an early case when H,02 in acetic acid was used) to the menth-8-ene- 1,2-di0ls.'"~ The cis-oxide (1 07) was prepared stereospecifically by Polish workers who used the monotosylate of the 1,2-diol,"O and a full investigation of the two isomers was made by Newhall."' Oxidation by a peracid gives about 10 YOof the 8,9- epoxides (see be lo^),"^ and various other methods slightly alter this proportion.For example epoxidation of limonene with sodium hypochlorite in the presence of a manganese(1rr) porphyrin gives a ratio of 7 1 of l12-epoxides to 8,9-epo~ides,~'~ and iodosobenzene with an iron porphyrin (which is more electrophilic than manganese) gives a ratio of nearly 20 1 .278 Molybdenum-hexacarbonyl-catalysed t-amyl hydroperoxide yielded 70 YOof the cis-isomer ( 107),274 this work having been repeated in order to prepare the menthadienol (76) and the trans-isomer of (81) via the selenoxides (109) and (I (the latter had been briefly mentioned independently elsewhere2").A 1 1 mixture of (107) and (108) can be obtained from limonene in 60 Yo yield with pertungstate-catalysed hydrogen peroxide2" and in 87 % yield by the action of superoxide anion (potassium superoxide and 0-or p-nitrobenzenesulphonyl chloride) on limonene."' Although the isomers (107) and (108) can be separated by careful distillati~n,"~ details of several chemical methods have been published. One involved their conversion into the $0.-\OH OH chlorohydrins (1 11) and (1 12) with HCI in ether; only (1 12) [from the truns-epoxide (108)l gives a crystalline p-nitro- benzoate After separation KOH in MeOH enabled the pure epoxides to be recovered.280 The greater reactivity of the cis-epoxide towards acids means that this isomer will give trans- di hydrocarvone (89) before the trans-epoxide begins to react and the latter can then be isolated by fractional distillation.281 The cis-isomer (107) also reacts more rapidly with bromine; treatment of the bromides (1 13) that were obtained from the epoxide mixture by its reaction with tributyltin hydride gives 1,8-cineole (26) and the trans-epoxide ( 108).2H2 The products from treatment of the epoxide mixture with dimethylamine which were the amino-alcohols (1 14) and (1 15) can be readily separated and the methiodides then yield the pure epoxides with potassium hydroxide.283 The presence of the limonene 8,9-epoxides (I 16) and (1 17) among the epoxidation products was suspected as early as 1926,284 but they were in fact only described in 1961 as arising from the oxidation of limonene by air.lg6 They were later prepared285 by using the Payne epoxidation (H,02 and PhCN) 40-50 YOof the epoxidation then occurring in the isopropenyl group although the conversion is very low. An alternative synthesis from methyl 4-methylcyclohex-3-enyl ketone and dimethylsulphonium methylideZ8' has been preferred. 12j" Methyl 4-methylcyclohex-3-enyl ketone is usually made from isoprene and methyl vinyl ketone and is racemic but it can also be prepared from limonene in optically active form (by ozonolysis of limonene 1,2-epoxides and removal of the epoxides after separation of the isomers).288 The two 8,9-epoxides can be separated by careful distillation and they were assigned configuration by Horeau's method and correlated with the uroterpenols (limonene metabolites) (I 18) and (I 19) by Kergo- mard and Veschambre.289 Kergomard also converted the uroterpenols into the optically active a-bisabolols [u.g. (120) from (+ )-1im0nene],~~~ but there was a discrepancy between the stereochemistry of these and the stereochemistry of bisabolols that had been made in another way,290 and an X-ray study showed that the configuration of the bisabolol was not that attributed to it by Kerg~mard.~" A careful study by Carman has now shown that Kergomard's assignments of stereochemistries for the uroterpenols (1 18) and (1 19) are correct (as are therefore the stereochemistries of the epoxides).The mixture of uroterpenols is not separable and neither are the dibromides of the uroterpenols. Finally the p-nitro- benzoates of the uroterpenol dibromides were separable and X-ray crystallography of the recovered uroterpenols showed clearly that the lower-melting isomer has the stereochemistry (1 18).292Carman also showed that the higher-boiling (4R,8R)- isomer of the epoxide (1 16) was converted into (1 18) by tetramethylammonium hydroxide in dimethyl sulphoxide in 36 hours at 35-40 "C,the other epoxide (I 17) yielding (1 19) under p..kme the same conditions.293 The bisabolol discrepancy remains unexplained. The 8,9-epoxides have been used as intermediates in the conversion of limonene into the bicyclo[3.2. Iloctane system. Thermal rearrangement of the 8,9-epoxides to the menth- 1-en-9-als (65) was described in 1961,294 and this reaction also occurs with acid ion-exchange resins the reaction going further to yield optically active 2,6-exo-dimethylbicyclo[3 .2.l]oct-2-en-7-endo-01 (121) as the major product together with a little of the 6-endo-methyl isomer.295 The racemate of (1 21) had already been prepared from geranyl acetate.29' The mixture of the four possible diepoxides has been known as long as the 1,2-epo~ides.~~' Little work was carried out until 1955 when it was again described,297 and from 1956 onwards there are many patents describing the polymerization of 'limonene diepoxide 'with Friedel-Crafts catalysts298 or photo- sensitized cationic polymerization.299 Although this is a major use of limonene there exists no description of the individual isomers of the diepoxides (122) and they have only one Chemical Abstracts Service Registry Number. The 1,2-epoxide group is more reactive towards acid than the 8,9-epoxide group and the epoxides of (1 11) and (1 12) have been obtained by treating the mixture of the diepoxides (1 22) with hydrochloric acid under mild conditions.300 When the diepoxides are used in synthesis the mixture is employed without comment (e.g.the synthesis of hernandulcin by Mori and Kato301). The epoxides have been used to protect a double bond in limonene. Thus Ohloff et al. prepared optically active mentha- 1,8-dien-4-01 (92) by selenium-dioxide-catalysed oxidation of ( +)-limonene cis-1,2-epoxide (1 07) followed by removal of the epoxide group by treatment with zinc and acetic acid and sodium iodide,302 but the yield was not good. An alternative suggestion is to reflux the epoxide with lithium and 1 mol % of biphenyl in ethylene glycol dimethyl ether.303 Limonene diepoxide (122) has been examined for cytotoxic activity .,04 NATURAL PRODUCT REPORTS 1989 CIC1 The episulphides of limonene have been prepared indirectly from the epoxides by treating these with thiourea followed by a ba~e.~~~.~~~ 9 Addition of a C Unit to Limonene After an early study in which no compounds were identified,"06 Prins suggested structure (123) for a compound that was formed by the acid-catalysed reaction of formaldehyde and limonene.,07 In 1953 Lombard re-examined the reaction ; he used a zinc chloride catalyst and suggested that the main product was the homo-alcohol (124; R = H),8n8 this structure being well established by Ohloff (who used an uncatalysed reaction in acetic acid)309 and by Blomquist et al."" This work was soon followed by other~,~~.~~~."'" the dioxanes (125) and (126) also being identified from a perchloric-acid-catalysed reaction.313 The n.m.r.spectra of the products [including the a-terpenyl ether of (124; R = H)] were measured by Blomquist who obtained 80 Oh of the acetate (1 24; R = Ac) by using BF and acetic anhydride.,l4 The alcohol (124; R = H) was oxidized by Suga and Watanabe.315 The corresponding dihydrogenated aldehyde (127) is the main product from hydroformylation of limonene which was first carried out over Raney In methanol (using octacarbonylcobalt as catalyst) the main product is the saturated methyl ether (128) and the aldehydes (129) were reported from the reaction in acetone,317 although we question this structure.Later rhodium catalysts notably RhH(CO)(PPh,)3,31* were used and the rate of reaction of limonene was shown to be rather low compared to those of other alkene~,~~~ although the yields were After the initial patenting of (127)y other patents followed.321 Phosphite-modified rhodium catalysts increase the rate of Esters hydroformylation of lim~nene.~~~ of the acid cor-responding to (1 27)323 and a Mannich product (I 30)324have been made.NATURAL PRODUCT REPORTS 1989-A. F. THOMAS AND Y. BESSIERE 30 1 &. kOH Although the Vilsmeier reaction of [CICH=NMe,]+[CI,PO,]- with (+)-limonene gives a yield of only 40 % after 6 days it is very useful in that the (E)/(Z)ratio of the aldehydes (131 ; R = H) that are formed is 98 :2; this fact led Dauphin to a rapid synthesis of (E)-atlantone (1 32).325 An earlier synthesis of (1 31 ; R = H) was a multi-step one from methyl vinyl ketone.'s26 The isomers of (131 R = H) have been patented as flavour material^."^ Delay and Ohloff used the anion (c) for adding one carbon atom to (+)-or to (-)-limonene.Carbonation gives the /j'y unsaturated acid (1 33 ;R = OH).32H The corresponding ester is isomerized (by MeONa in MeOH) to the thermodynamic mixture of the conjugated esters (131 ; R = OMe) [(E)/(Z)= 82 181. After separation these were used in the synthesis of or-bisabolenes (1 34) of known stereochemistry.32'H Carbon tetrachloride reacts with limonene either in the presence of a or under the influence of ultraviolet light33n to yield an addition product (135) hydrolysis of which (by ethanolic KOH) leads to the optically active acid (131 ; R = OH),330.331 which was also used331 for synthesizing (R,E)-atlantone from (+)-limonene. Distillation of (1 35) in ethylene glycol (at 200-2 10 "C) gives methyl 4-methylcyclohex-3-enyl ketone.33 Carbon oxysulphide reacts with limonene in a dimethyl- or diethyl-aluminium-catalysed ene reaction to give (I 33; R = SH).332 The Simmons-Smith reaction of limonene was reported in 1958 to yield exclusively the product (136) of addition to the isopropenyl double bond the recovered limonene having undergone 'little or no racemization' despite a fall by 50% being recorded in the rotation.333 The structure was established by infrared spectrometry.""4 The same compound (1 36) was obtained by the palladium(n)-acetate-catalysed addition of diazomethane.335 Kropp et al.prepared all of the possible addition products by irradiation of methylene iodide and limonene in chloroethane; the yields were after three hours 7% of (136) 47% of (137) and 14% of (l38).""" The bicyclo[4.1.Olheptane (1 37) has also been prepared by the reaction of the readily accessible dichlorocarbene addition product (I 39) with naphthalenelithi~m,:~:~~ but in none of these papers were the spectral properties of (137) described; a paper in which the 13C n.m.r. spectra of the cyclopropanes (1 37) are given does not say how they were prepared and separated.:':'' One of us has confirmed that the major addition product from the Simmons-Smith reaction is indeed (136) but that the two isomers of (137) are also formed (the ratio is about 3 l) and the reason that the earlier papers missed this was probably that (145) (137) distilled with the limonene that was recovered thereby lowering the observed optical This preference for reaction on the exocyclic double bond is the contrary of that found in 4-vinylcyclohexene where 8 1 % of the monoaddition takes place on the endocyclic double bond.310 Addition of dihalocarbenes is difficult to stop at the stage of monoaddition3-'1 unless phase-transfer conditions are em-ployed."-' The products vary with the catalyst PhCH,NEt,+ C1- gives the diaddition products (l40) as does Me,,NC,,H,,+ Br-,"l" the more hydrophilic Me," CI- yielding specifically monoaddition products (1 39) being obtained in 68 YOyield."J-' 1,4-Diazabicyclo[2.2.2]octane leads to 100Oh of mono-addition .:IJ5 10 Addition of C or More to Limonene Acetylation of limonene with acetyl chloride in the presence of stannic chloride at -100 "C was examined by Cookson et ctl.in 1974. After dehydrochlorination of the product (using LiF and Li,CO:,) they obtained about 30% of the product (141) from reaction at the isopropenyl double bond with 22% of the unconjugated ketone (142) and 28'/O of the conjugated ketone (143) that had been formed by reaction with the trisubstituted double bond."-' With senecioyl chloride (3-methylbut-2-enoyl chloride) the same group synthesized a-atlantone (1 32) after dehydrochlorination about 60 YOof the reaction occurring in the isopropenyl group against 29% in the ring."li The acetylation was confirmed by Hoffmann who did not however mention Cookson.:34H Acetylation on C-I0 can be effected by trapping the limonene anion (c)~' with trimethyltin.The stannane (144) will then react with acetyl chloride to yield (133; R = Me) or with senecioyl chloride to give a ratio of 25 :75 of a-atlantone and the direct coupling product (/j-atlantone).:"!' Erman et al. converted the anion (c) into the alcohol (145) by allowing it to react with ethylene oxide and into a variety of sesquiterpenes (146) by its reaction with the appropriate alkyl halides RX."-' The anion (c) was again used for the synthesis of sesquiterpenes; its reaction with a functionalized isoprene (147) added a C unit giving (148) which is an intermediate in the synthesis of lanceol (146; R = CH,CH=CMeCH,OH).""" Oxidation of limonene by manganese(ri1) acetate in acetic acid results in radical addition giving the acid (149) in 38% yield,""' and the lactone (I 50).352Despite this relatively good yield the reported overall yield of the alcohol (145) was only 8 Gardrat converted (149) into (150) directly by the action of formic acid in 43% isolated yield from limonene.""" The isopropenyl group of limonene reacts in an ene reaction NATURAL PRODUCT REPORTS.1989 (154) 1,2,4-triazoline-3,5-dionewith limonene leads to a double adduct the structure of which was reported as (160); this supposedly arises in a type of ene reaction the initial attack on 4 &. ph9 COOEt the isopropenyl double bond and transfer of the proton at C-COOEt 4 being followed by a second addition on the C(4tC(8) double (159) bond.360 Unfortunately the published n.m.r.spectrum does not (157) QI. R". OH Ph I OYNYO R= yN"xH with methyl acrylate if aluminium chloride is present as a catalyst; the major product is the ester (151) with a small amount of double-bond-rearranged material (1 52). This work described the preparation of P-bisabolene (1 53) from (1 5 A similar reaction using methyl vinyl ketone yielded the ketone (1 54) which was also converted into P-bisabolene (1 53),355 but this reaction is difficult to reproduce and unsatisfactory in its application.356 The corresponding reaction with propargylates is more successful methyl propargylate in the presence of aluminium chloride giving 39% of the ester (155) with smaller amounts of the two esters (156).357 Snider has also described the Me,AICl-catalysed addition of alde- hyde~.~~* In place of a carbon-carbon double bond a carbon- oxygen double bond has been used; thus diethyl oxomalonate reacts with limonene in the presence of zinc chloride to give the diester (157) in one week.358 Benzyne reacts with limonene in an ene reaction to give the phenyl-substituted menthadienes (1 58) and (I 59) ;these might be optically active because the symmetrical radical is probably not involved but while a very small optical activity was determined in the corresponding reaction with menth- I-ene it was not measured in the case of lirn~nene.~~~ The reaction of include the signals for the vinyl protons and it is not clear why a mechanism like that proposed by Mehta and Singh for the benzyne reaction361 was not considered; this would lead to (161).This type of reaction is always complicated by the tendency of limonene to polymerize in the presence of Lewis acids or Ziegler catalysts (see above) which is the reason for using low temperatures in the reactions. The ene reaction between limonene and chloral (or bromal) nevertheless gives mostly unrearranged product (1 62) in the presence of aluminium chloride although the yield is rather In the presence of acids the tendency to rearrangement of the double bond has to be considered as well as the addition of water in aqueous milieu. Despite these problems Julia and co-workers realized the extremely simple addition of dimethylvinylcarbinol to limonene in formic acid and methylene chloride.They prepared the four isomers of a-bisabolol (I 20) [( +)-(4R,8R)-a-bisabolol from (+)-limonene] and isomers of the ring-substituted alcohol (163).363 The Ritter reaction of ( +)-limonene with acetonitrile and dilute perchloric acid gives the chiral iminium salt (164). The racemate of (164) is similarly obtained from terpinolene (8) while (-)-P-pinene (165) yields the enanti~mer.~'~ The same reaction if carried out on a-terpineol (21; R = H) with propionitrile is said to yield a product with the enantiomeric stereochemistry at what was C-1 of the menthene Cycloaddition of acetonitrile to limonene occurs exclusively on the isopropenyl double bond to give the isoxazoline (1 66).:"' An interesting photochemical addition of acetylacetone to (+)-limonene has been described by a Brazilian group.The major product (167) (for which full spectral data were given) was used to prepare octalones. [It would appear that they were hoping to prepare the eudesmane skeleton; although it was formed the major isomers that were produced were the cis-and the trans-isomer of (168).]367 A reaction that has given rise to some discussion is that between limonene and maleic anhydride. Hultzsch reported in 1939 that with maleic acid limonene underwent rearrangement to a-terpinene (9) which then gave a Diels-Alder product. He also reported a different reaction with maleic anhydride which NATURAL PRODUCT REPORTS 1989-A. F. THOMAS AND Y. BESSIERE Scheme 2 t Scheme 3 yielded an anhydride of uncertain structure.368 Alder and Schmitz re-investigated the reaction but apparently did not obtain the same anhydride.36Y Further re-investigation by Eschinazi and Pines led to the conclusion that limonene did not react with maleic anhydride under the conditions that were used by Hultzsch (i.e.simple heating)."7u Radical cyclo-copolymerization of limonene with maleic anhydride is well known and probable intermediates are shown in Scheme 2;3i1 conceivably the product that Hultzsch obtained was an anhydride derived from one of these. 11 Pyrolysis and Miscellaneous Reactions The pyrolysis of limonene (I) has been known since 1884 to yield primarily isoprene at 'just below red heat ';3i2 indeed this was the best way of preparing isoprene for many years."7" Pines and Ryer made the first serious mechanistic study and correctly deduced that the main reaction pathway was via allo-ocimene (1 69) which at somewhat lower temperatures than those that were required for a good yield of isoprene then yielded a mixture of products similar to those obtained after the pyrolysis of a-pinenc (2) (Scheme 3)."i'3 The whole problem was rc-investigated by Cocker et ul.who characterized a vast number of sub~tances"~" a mixture that was very similar to that in obtained from the pyrolysis of pin~ne.'~'" The pyronenes (1 70) and (1 71) are present and under the conditions that were used the Irish group found up to 25 YOof compound ( 172).:j7,j There are descriptions of a number of addition reactions with metals scattcrcd about thc oldcr litcraturc but mostly nothing definite was identified.We might however mention the reaction with antimony tri~hloride'~'~ and somc colour reactions with phosphomolybdic acid (pink or rcd-orange dcpcnding on the condi ti on s).'''' With pcntacarbonyliron limonene forms mixtures of diene-Fe(CO), compounds the dienes being isomers of the S02Me S0,Me SOZCHZAc starting material.3i9 The reaction of limonene(tricarbony1)iron with aryl-lithium derivatives has been described.'38o A new method for the addition of alkyl groups to the terminal isopropenyl group of limonene consists in the radical addition of methanesulphonyl iodide and elimination to form the methyl sulphone (173).Deprotonation (by butyl-lithium) and alkylation for example with prenyl bromide leads to the C-C-coupled product (I 74). The sulphonyl group is removed from (1 74) by acylating the anion to the /?-oxosulphone (1 73 which is reduced by aluminium amalgam to the allylic sulphinic acid. This loses SO in situ giving a regiospecifically defined alkene product. The (0-and (2)-a-bisabolenes (1 34) were made in this 12 Biological Reactions of Limonene It is not the intention of this article to discuss the biogenesis of limonene (leading references are given in a note about the use of natural-abundance deuterium n.m.r. spectrometry to es-tablish the difference between C-9 and C-10 during bio-genesis"82) nor do we deal in detail with its metabolic fate [although the uroterpenols (1 18) and (1 19) which are the products of its mammalian metabolism are mentioned above and are known to play a central role in the biogenesis of other monoterpenoids notably the 7-oxygenated menthanes of Perilla j,rut~scens"~].Nevertheless certain microbial reactions lead to possibly useful routes to optically active oxygenated menthanes. Pioneering work on the transformation of limonene by Aspergillus niger was made by Bhattacharyya et who obtained (+)-cis-carveol (82) carvone (75) a-terpineol (2 1 ; R = H) and p-mentha-2,s-dien-1-01 (76). Later Dhavalikar isolated a strain of a member of the Enterobacteriaceae which oxidized (+)-limonene to perillic acid (5) and a dihydro-acid.38.5 This led to the definition of three pathways for the metabolism of limonene these are ally1 oxidation leading to carveol or to the perilla series (the latter is the main pathway) epoxidation and rearrangement to dihydrocarvone.:IX6 Com- plete degradation by Pseudonionas PL-strain in the presence of arsenite gave a variety of ring-opened products and ultimately 2-methylpropionic acid for which a mechanism was pro-posed."8' A patent"" covers the efficient conversion of limonenc into carvone by Corynehac.tcv-iumh)~dr.occrrboc,lustus, which was isolated from soil.Limonene undergoes microbial hydroxylation with Corynespora cusiicolr giving 80 YOof the trans-1,2-diol from (+)-limonene and 76 YOof (90) from (-)-li~onene."~!' Other micro-organisms (members of the genera Fusarium Cihberella Aspergillus Streptomyw and others are mentioned) also work and the diols can be dehydrated to mentha-2,s-dien-1-01 (76).'3X9 The same workers have shown that (k)-limonene is converted into (+):a-terpineol (21 ; R = H) with Penicillium digitutum .'M 13 References I These figures have been made available from Brazilian sources by A.N. Henroz Firmenich Ltda. S. Paulo Brazil. 2 W. A. Tilden and W. A. Shenstone J. Chrm. Soc. 1877 31 554. 3 0.Wallach and W. Brass Lic4ig.v Ann. Ch~ni.,1884 225 291. 4 0.Wallach Lic+ig.v Ann. Chem. 1888 246 221. 5 C. J. Williams Proc. Roy. SOC. 1860 10 516; G. Bouchardat Bull. SOC. Chim. Paris 1875 24 108. 6 G. Wagner Ber. Dtsch. Chem. Ges. 1894 27 1636 2270. 7 W.H. Perkin jr. J. Chem. SOC. 1904 85 416; F. W. Kay and W. H. Perkin jr. ibid. 1906 89 1640. 8 J. J. Gajewski and C. M. Hawkins J. Am. Chem. Soc. 1986 108 838. 9 L. G. Wideman and L. A. Bente (Goodyear Tire & Rubber Co.) U.S. P. 4508930 April 2 1985 [Appl. 632746 July 20 19841 (Chem Abstr. 1985 103 123729). 10 For example in the manufacture of children’s balloons T. Ishihara (Polychem. Kogyo Co. Ltd) Jpn. P. 48-40894 Nov. 27 1973 [Appl. 45-68 144 Aug. 3 19701 (Chem. Abstr. 1975 83 60951); in household cleaning fluids Chem. Murk. Rep. 1987 231 No. 21 p. 30 although the low flash point has given rise to discussion about complete safety in such use (see ibid. April 11 1988 p. 38); as solvent for cleaning paint brushes H. Scheidel (Scheidel Georg Jr.GmbH) Ger. Offen. 2843764 April 10 1980 [Appl. Oct. 6 19781 (Chem. Abstr. 1980 92 217085); as solvent of varnishes for cleaning restoring art objects C. C. Goetz Br. P. 1176043 Jan. 1 1970 (Chem. Abstr. 1970 72 88296). See also Chem. Murk. Rep. Feb. 1 1988 p. 23. 11 F. P. McCandless Flavour Znd. 1971 2 No. 1 p. 33. 12 E. M. Ahmed R. A. Dennisom R. H. Dougherty and P. E. Shaw J. Agric. Food Chem. 1978 26 192. 13 R. G. Buttery R. M. Seifert D. G. Guadagni and L. C. Ling J. Agric. Food Chem. 1971 19 524; R. G. Buttery D. R. Black D. G. Guadagni L. C. Ling G. Connolly and R. Teranishi ihid. 1974 22 773. 14 J. Pino R. Torricella and F. Orsi Nuhrung 1986 30 783. 15 L. Friedman and J. G. Miller Science 1971 172 1044; J. Limacher Firmenich SA personal communication.16 J. A. Elegbede T. H. Maltzman A. K. Verma M. A. Tanner C. E. Elson and M. N. Gould Carcinogenesis (London) 1986 7 2047. 17 D. L. J. Opdyke Food Cosmet. Toxicol. 1978 16 809. 18 J. W. Regan and L. F. Bjeldanes J. Agric. Food Chem. 1976,24 377 and references cited therein. 19 A. P. Wade G. S. Wilkinson F. M. Dean and A. W. Price Biochem. J. 1960 101 727; F. M. Dean A. W. Price A. P. Wade and G. S. Wilkinson J. Chem. Soc.. C 1967 1893. 20 R. Kodama. T. Yano K. Furukawa K. Koda and H. Ide Xenohiotica 1976 6 377. 21 J. Rama Devi and P. K. Bhattacharyya /ndiun J. Biochem. Biophjvs. 1977 14 288 359. 22 C. Tsujigaito K. Nagata and K. Koyama (Shinto Paint Co. Ltd; Toyo Aerosol Industry Co. Ltd) Jpn.Kokai Tokkyo Koho 53- 93187 Aug. 15 1978 [Appl. 52-8031 Jan. 27 19771 (Chem. Ahsrr. 1979 90 17691). 23 V. Dotolo U.S. P. 4 379 168 April 5 1983 [Appl. 130 138 March 14 19801 (Chem. Ahsfr. 1983 99 1838). 24 W. F. Hink and B. J. Fee J. Med. Entomol. 1986 23 400 (Clicwt. Ahstr. 1986 105 129406). 25 M. A. Johnson and R. Croteau A.C.S. Meeting Miami Beach April 1986 Abstract 127. AGFC Division. 26 J. H. Beatty J. Chem. Educ. 1986 63. 768. 27 R. N. Ammeraal (American Maize Products Co.) Ger. Offen. 3716509 Nov. 26 1987 [U.S. Appl. 865059 May 20 19861 (Cliem. Ahstr. 1987 108 114587). 28 R. Lauricella. J. Kechayan and H. Bodot J. Phys. Chem. 1977 81 542. 29 W. Offermann and A. Mannschreck Org. Mugn. Reson. 1984,22 355. 30 G. Lukacs and A Neszmelyi.Tetrahedron Lett. 1981 22 5053; R. Richerz W. Amman and T. Wirthlin J. Mugn. Rcson. 1981 45 270; F. Bohlmann R. Zeisberg and E. Klein Org. Mugn. Reson. 1975 7 426. 31 M. F. Leopold W. W. Epstein and D. M. Grant J. Am. Clicm. Soc, 1988 110 616. 32 A. Akhila D. V. Banthorpe and M.G. Rowan Plij’roc.liemi.vtr~ 1980 19 1433. 33 R. Ryhage and E. von Sydow Actu Climi. Scund.. 1963 17 2025; A. F. Thomas and B. Willhalm Helv. Cliini. Actu 1964 47 475. 34 D. Harris S. McKinnon and R. K. Boyd Org. Muxv. Spi)c*trom. 1979 14. 265; see also F. Friedli ;bid. 1984 19 183. A very full discussion of the energetics of the retro-Diels-Alder fragmentation of limonene under various conditions in the mass spectrometer has been given by M.Vincenti S. R. Horning and R. G. Cooks Org. Muss Spectrom. 1988 23 585. NATURAL PRODUCT REPORTS. 1989 35 R. B. Bates E. S. Caldwell and H. P. Klein J. Urg. Chem. 1969 34,2615 give many earlier references. 36 W. J. Roberts and A. R. Day J. Am. Chem. Soc. 1950,72 1226. 37 E. H. Ruckel H. G. Arlt Jr. and R. T. Wojcik Polymer Sci. Technol. 1975 9A 395. 38 M. Modena R. B. Bates and C. S. Marvel J. Polymer Sci. Part A 1965 3 949. 39 J. P. McCormick and D. L. Barton Tetrahedron 1978 34 325. 40 A. N. Misra M. R. Sarma R. Soman and S. Dev (Camphor and Allied Products Ltd) Indian P. 147047 Feb. 10 1979 [Appl. 76 B0191 June 21 19761 (Chem. Absfr. 1980 93 8330); see A. F. Thomas and Y. Bessiere in ‘The Total Synthesis of Natural Products’ ed.J. W. ApSimon Wiley New York 1988 Vol. 7. 41 I. I. Bardyshev A. I. Sedel’nikov and T. S. Tikhonova V’estsi Akad. Navuk B. SSR Ser. Khim. Navuk 1974 No. 5 p. 61 (Chem. Ahstr. 1975 82 57954) list the action of sulphuric phosphoric perchloric nitric benzenesulphonic and toluene-p-sulphonic acids. I. I. Bardyshev L. A. Popova E. F. Bunova B. G. Udarov and Zh. F. Loiko ibid. 1975 No. 6 p. 85 (Chem. Abstr. 1976,84 I65 038) mention salicylic acid and the isoterpinolene rearrange- ment. See also I. I. Bardyshev V. A. Barkhash Zh. V. Dubo-venko and V. I. Lysenkov Zh. Org. Khim. 1978,14,1110 (Chem. Abstr. 1978 89 IIOOOO). This is only a minute amount of the work published by Bardyshev et al. but it is difficult to see any useful result from it all. 42 R.M. G. Roberts J Chem. Soc. Perkin Trans. 2 1976 1374. This did not include identification of the products and the rotation of the limonene remaining was not measured. 43 R. Ohnishi K. Tanabe S. Morikawa and T. Nishizaki Bull. Chem. Soc. Jpn. 1974 47 571. 44 E. Pottier and L. Savidan Bull. Soc. Chim. Fr. 1975 654. 45 A. Matawowski Pol. J. Chem. 1980 54 469. 46 V. N. Ipatieff H. Pines V. Dvorkovitz R. C. Olberg and M. Savoy J. Org. Chem. 1947 12 34; V. N. Ipatieff H. Pines J.-E. Germain and W. W. Thomson ibid. 1952 17 272. 47 G. Acrombessy M. Blanchard F. Petit and J.-E. Germain Bull. Soc. Chim. Fr. 1974 705. 48 P. G. Carter H. G. Smith and J. Read J. Soc. Chem. Ind. 1925 44,543T. 49 J. J. Ritter and J. G. Sharefkin J. Am. Chem.SOC.,1940,62 1508. 50 J. J. Ritter and V. Bogert J. Am. Chem. Soc. 1940 62 1509. 51 Yu. P. Klyuev and A. I. Lamotkin Izv. Vyssh. Uchebn. Zuved. Lesn. Zh. 1982 No. I p. 107 (Chem. Abstr. 1982 97 163268). 52 S. Fujita Y. Kimura R. Suemitsu and Y. Fujita Bull. Chem. Soc. Jpn. 1971 44 2841. 53 R.L. Cobb (Phillips Petroleum Co.) U.S. P. 4668835 May 26 1987 [Appl. 783999 Oct. 4 19851 (Chem. Abstr. 1987 107 77451). 54 K. Suga and S. Watanabe Nippon Kagaku Zasshi 1960,81 1139 (Chem. Abstr. 1962 56 5076). 55 A. C. Pinto M. A. Abla N. Ribeiro A. L. Pereira W. B. Kover and A. P. Aguiar 3. Chem. Res. (S) 1988 88; (M) 1988 1001. 56 R. W. Magin C. S. Marvel and E. F. Johnson J. Polynier Sci. Part A 1965 3 3815. 57 C. M. Samour (Kendall Co.) US.P. 3058930 Oct. 16 1962 [Appl. Sept. 8 19591 (Chem. Abstr. 1963 58 8108j). 58 L. E. Gast W. J. Schneider H. M. Teeter G. E. McManis and J. C. Cowan J. Am. Oil Chem. Soc. 1963 40,88. 59 K. Sugiyama K. Ohashi and T. Sengoku Kinki Duigaku Kogukubu Kenkyu Hokoku 1982 16 19 (Chem. Ahstr. 1983 99 122 658). 60 A. Ferro and Y.-R. Naves Helv. Chim. act^ 1974 57 I141. 61 E. F. Buinova T. R. Urbanovich B. G. Udarov and L. V. Izotova Khim. Prir. Soeciin. 1982 587 (Chem. Absrr. 1983 98 54 228). 62 M. Alberk Ch. Rav-Acha E. Gil-Av and 0.Schachter J. Cutul. 1971 22 219. 63 C. A. Brown J. Am. Chem. SOC.,1973 95 982. 64 R. J. Crawford W. F. Erman and C. D. Broaddus J. Am. Chem. Soc. 1972. 94 4298. 65 W. F. Erman and C. D. Broaddus (Proctor & Gamble Co.) U.S.P. 3658 925 April 25 I972 [Appl. 888 893 Dec. 29 19691 (Chem. Ahstr.. 1972 77 48668). 66 J. A. Katzenellenbogen and L. Crumrine J. Am. Cl7em. Soc. 1976 98 4925. 67 H. Suemune G. Iwasaka K. Ueno and K. Sakai Cheni. Phurm. Bull. 1984 32 4632. 68 M. Andrianome and B. Delmond. Tetrahedron Lett. 1985 26 6341. NATURAL PRODUCT REPORTS 1989-A. F. THOMAS AND Y. BESSIERE 69 D. Wilhelm T. Clark T. Friedl and P. von R. Schleyer Chem. Ber. 1983 116 751. 70 G. Bouchardat and J. Lafont C.R. Hebd. Seances Acad. Sci.. 1886 102 1555. 71 I. W. Humphrey (Hercules Powder Co.) U.S. P. 2 151769 March 3 1939 (Chem. Abstr. 1939 33 5007'); Hercules Powder Co. Br. P. 494504 and 494506 Oct. 10 1938 (Chem. Absrr. 1939 33 2535,) describe the acid-catalysed reaction of methanoi (and other alcohols) with dipentene protecting the product as a solvent and softener.72 A. Baeyer Ber. Dtsch. Chem. Ges. 1893 26 820. 73 A. Baeyer Ber. Dtsch. Chem. Ges. 1893 26 2558. 74 W. A. Tilden J. Chem. Soc. 1878 33 247. 75 0.Wallach Ber. Dtsch. Chem. Ges. 1895 28 1773. 76 0.Wallach Liebigs Ann. Chem. 1885 230 225. 77 G. Bouchardat and R. Voiry C.R. Hebd. Seances Acad. Sci. 1887 104 996 carried out the first crystallization. 0.Wallach Liebigs Ann. Chem. 1893 275 104 is credited with it in Beilsrein. but Wallach only raised the m.pt. The method has recently been patented by Z. P. Golovina A. I. Bibicheva and G. P. Kudryatseva (Kaluga Perfume) USSR P. 1066981 Dec. 30 1981 (Chenz.Abstr. 1984 100 192 113). 78 J. Bertram D. R. 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ISSN:0265-0568    

DOI:10.1039/NP9890600291

出版商:RSC    

年代:1989

数据来源: RSC