摘要:

Natural Product Reports A journal of current developments in bio-organic chemistry Volume 8 Number 3 CONTENTS 213 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1989 and June 1990 223 Carotenoids and Polyterpenoids G. Britton Reviewing the literature published in 1988 25 1 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites J. E. Saxton Reviewing the literature published between July 1989 and June 1990 309 The Occurrence and Biological Activity of Drimane Sesquiterpenoids B. J. M. Jansen and A. de Groot Reviewing the literature to January 1990 319 The Synthesis of Drimane Sesquiterpenoids B. J. M. Jansen and A. de Groot Reviewing the literature to January 1990 16 NPR 8 Cumulative Contents of Volume 8 Number 1 1 Diterpenoids (1989) J.R. Hanson 17 Steroids Reactions and Partial Synthesis (November 1987 to October 1988) A. B. Turner 53 Quinoline Quinazoline and Acridone Alkaloids (July 1988 and June 1989) J. P. Michael 69 Terpenoid Glycosides (1987 and 1988) H. Wander and H. Stoll Number 2 97 Marine Natural Products (1989) D. J. Faulkner 149 The Biosynthesis of Shikimate Metabolites P. M. Dewick 171 Muscarine Oxazole Thiazole Imidazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1988 to June 1989) J. R. Lewis 185 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (August 1988 to July 1989) R. B. Herbert Articles that will appear in forthcoming issues include Withanolides and Related Ergostane-type Steroids (to December 1989) E.Glotter Marine Sterols (to July 1990) R. G. Kerr and B. J. Baker /3-Phenylethylamines and the Isoquinoline Alkaloids (July 1989 to June 1990) K. W. Bentley Modern Separation Methods A. Marston and K. Hostettrnann Terpenoid Phytoalexins (August 1984 to December 1989) C. W. J. Brooks and D. G. Watson The Lycopodium Alkaloids (January 1986 to October 1990) W. A. Ayer A Unified Mechanistic View of Oxidative Reactions Catalysed by P-450 and Related Fe-Containing Enzymes M. Akhtar and J. N. Wright Biosynthesis of C,-C, Terpenoid Compounds (1989) M. H. Beale Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids (July 1989 to June 1990) A. R. Pinder Tropane Alkaloids (1990) G. Fodor and R. Dharanipragada

ISSN:0265-0568    

DOI:10.1039/NP99108FP007

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. 6. Herbert University of Leeds Professor J. Mann University of Reading Professor M. I. Page The Polytechnic Huddersfield Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1991 Annual Subscription Price E.C. f198.00 Overseas f228.00 U.S.A. $467.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. SG6 1 HN England. Air Freight and mailing in the U.S.by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. 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 1991 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1991 E.C. f198.00 Overseas f228.00 U.S.A. US$467.00 Subscription rates for back issues are U.K. (1 986) f130.00 (1 987) f142.00 (1988)f159.00 (1 989) f169.00 (1990)f177.00 Overseas f143.00 f159.00 f183.00 f194.00 f204.00 U.S.A. US $252.00 US $280.00 US $342.00 US $388.00 US $398.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99108FX009

出版商:RSC    

年代:1991

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99108BX011

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Pyrrolizidine Alkaloids D. J. Robins Department of Chemistry University of Glasgow Glasgow G 12 8QQ,UK Reviewing the literature published between July 1989 and June 1990 (Continuing the coverage of literature in Natural Product Reports 1990 Vol. 7 p. 377) 1 The Synthesis of Necines 1 The Synthesis of Necines 2 The Synthesis of Pyrrolizidine Alkaloids and Synthetic routes to optically active necines using L-proline Analogues derivatives the optically active malic acids carbohydrates and 3 Alkaloids of the Boraginaceae chiral auxiliaries have been reviewed by Dai et al.l 4 Alkaloids of the Asteraceae (Compositae) Another route to (+)-isoretronecanol (7) has been reported 5 Alkaloids of the Graminae by Celerier et Pyrrolidone was alkylated and converted into 6 Alkaloids of the Fabaceae (Leguminosae) the /3-enaminodiester (1) (Scheme 1).The unsaturated pyr- 7 Alkaloids in Insects rolizidine ester (4)was then formed by intramolecular alkylation 8 General Studies of the /3-enaminodiester (2) or following thermolysis of the 9 X-Ray Studies diester (1) in the gaseous phase (presumably via the intermediate 10 Pharmacological and Biological Studies aminomethylene ketene (3)). Stereospecific reduction of the 11 References unsaturated ester (4)afforded the saturated esters (5) or (6) depending on the conditions used. A final reduction step on the endo-ester (5) yielded ( & )-isoretronecanol (7). / J G02Et (6) R= Meor Et (4) R = Me or Et (5) R = Meor Et (7) Reagents i NaH toluene NBu,Br Br(CH,),Cl; ii COCl, toluene; iii CH,(CO,),CMe, Et,N; iv EtOH Et,O.BF,; v NaI CH,CN; vi heat; vii MeOH Et,N; viii H,-Raney Ni 100 "C; ix H,-Raney Ni 200 "C;x heat 200 "C;xi LiAlH Scheme 1 213 NATURAL PRODUCT REPORTS 1991 Et02C C02Et Et02C C02Et HN EtOzC(CH2)2N Y-Y (8) HO (12) Reagents i CH,=CHCO,Et; ii NaH xylene; iii AcOH heat; iv KBH, H,O; v LiAlH Scheme 2 MeOCH24 C02Me *‘O’qH 0 (13) J J (15) Scheme 3 S PhO S (+)-Platynecine (12) has been made by Roeder and co-workers (Scheme 2).3 The pyrrolidine cis-diester (8) was N-alkylated and the product (9) was subjected to Dieckmann cyclization to yield the pyrrolizidine diester (10).Saponification and decarboxylation of the P-ketoester (10) followed by reduction of the ketone afforded the lactone (1 1).Reduction of this lactone (1 1) gave (f)-platynecine (12). Full experimental details4 are now available for the prep- aration of (+)-heliotridine (15) from (5‘)-malic acid via the imide (1 3) using an intramolecular carbenoid displacement reaction to generate the pyrrolidone (14) (Scheme 3).5,6a (+)-Retronecine (16) was prepared in similar fashion from (R)-malic acid involving the lactone (1 1) at a late stage. Gruszecka-Kowalik and Zalkow have investigated the possibility of deoxygenating readily available (+)-retronecine (16) using free radical reactions to produce supinidine (1 9).’ (+)-Retronecine (16) was regioselectively silyated on the primary allylic hydroxyl group (Scheme 4).The phenylthiono- carbonate (17) was then prepared and treated with tri-n-butyltin hydride in the presence of a radical initiator. The structure (18) of the unexpected rearrangement product was established by X-ray crystallography. The observed radical cyclization was probably aided by the close proximity of the C-7 P-substituent to the 1,2-double bond. With the less readily available (+)-heliotridine (1 5) the desired product (-)-supinidine (19) was produced under the same conditions (Scheme 4). Keck and Enholm previously reported the use of allylstan- nanes as terminators for radical and cationic processes in their synthesis of (+)-isoretronecanol (7).6b*8 Full details of this work are now published with extensions for the synthesis of (f)-supinidine (19) (-)-dihydroxyheliotridane (12) and (+)-heliotridine (1 5).g The route to (+)-isoretronecanol started from succinimide and proceeded via the allylstannane (20) and the thermodynamically less stable vinylpyrrolizidine (21) formed by an acyliminium ion cyclization (Scheme 5).In order to make (+)-supinidine (19) the double bond of the vinyl- pyrrolizidine (21) was cleaved oxidatively to give an aldehyde. The unsaturation was introduced by thermal elimination of the phenylseleno group present in compound (22). Reduction of the aldehyde gave (+)-supinidine (19) in low yield. In order to extend the strategy to C-7 oxygenated necines it was necessary to start from (5‘)-malic acid and form the imide (13) (Scheme 6). Alkylation of the imide generated the allylstannane (23) which was subjected to acyliminium ion cyclization to form the vinylpyrrolizidine (24).Ozonolysis of the alkene (24) and treatment of the aldehyde with lithium aluminium hydride afforded (-)-dihydroxyheliotridane (25). Introduction of unsaturation as in the synthesis of (f)-supinidine yielded (+)-heliotridine ( C H 20siMe2‘B u I iii-Reagents i NaH ;ButMe,SiC1 THF ;ii PhOCSC1 4-DMAP MeCN ;iii BuiSnH AlBN toluene 75 “C 3 h; iv NH,F MeOH 60 “C 18 h Scheme 4 NATURAL PRODUCT REPORTS 1991-D. J. ROBINS (20) f iii iv (19) -4 (7) (22) Reagents i OsO, NaIO,; ii Et,NSePh; iii H,O,; iv AlH Scheme 5 Acq Po Acd HZ20" __t iv v ~ (13) I Aco-<NDnBu3 ii iii 0 0 (25) HOYnBu3 (23) (24) iv vi-viii I (15) Reagents i Ph,P DEAD THF; ii NaBH, MeOH -45 "C; iii Et,N MeSO,Cl CH,Cl,; iv 0, MeOH -78 "C; v LiAlH,; vi Et,NSePh; vii H,O,; viii allane Scheme 6 (26) (27) H-OHNCHZCOzEt v-vi 4 (28) ~NHCHZCOZEt1'.0 (29) (31) 0 (30) -+ -(16) (32) Reagents :i Sn(OSO,CF,), N-ethylpiperidine THF ;ii 5-hydroxy-2(5H)-furanone;iii 5 %HC1; iv H,NCH,CO,Et THF r.t. ;v NaH DMF 10 "C 5 h; vi AcOH -50 "C; vii Lawesson reagent 105 "C toluene; viii Et,OBF, CH,Cl,; ix NaBH,CN Scheme 7 The diasteroisomeric alkylation of tin (11) enolates onto cyclic in optically active form." This lactone has been a favourite acyl imines was previously used by Nagao and co-workers intermediate in the synthesis of retronecine (16) and other in their preparation of (-)-trachelanthamidine6u~10and necines.The optically active tin enolate (27) was prepared by (-)-supinidine (19).6c*11 This strategy has now been extended treatment of the thione (26) with tin (11) trifluoromethane-to make a derivative (31) of the Geissman-Waiss lactone (32) sulphonate and base (Scheme 7). The tin enolate (27) was NATURAL PRODUCT REPORTS 1991 -j;.a,, 0 137) CH20-CO But 0 OH H02C Hob I OH (35) (36) 3&OH Me I 0-(38) Reagents i LDA THF CH,CHO; ii IM HCI; iii camphorsulphonic acid benzene reflux 3 days; iv (+)-retronecine (16) DCC 4-DMAP; V m-CPBA Scheme 8 then reacted with y-hydroxybutenolide to form the optically active y-alkylated butenolide (28),whose absolute configuration was established by X-ray crystallography.Aminolysis of the butenolide (28) with ethyl glycinate yielded the amide (29). A stereocontrolled intramolecular Michael addition produced the bicyclic lactone (30) and deoxygenation of the amide led to the desired intermediate (3 l) which can be converted by established procedures into the optically active Geissman-Waiss lactone (32) and thence to (+)-retronecine (16).6d,13 2 The Synthesis of Pyrrolizidine Alkaloids and Analogues Indicine N-oxide (38) is the major alkaloid of Heliotropium indicum and has undergone clinical trials as an anti-cancer drug. Synthesis of optically active material has been reported by Niwa et aL1* in five steps with a 20% overall yield from the lactone (33) as shown in Scheme 8.Homochiral lactone (33) was alkylated with acetaldehyde to give two hydroxylactones which were separated by HPLC. The stereochemistry of the major product (34) was confirmed by its hydrolysis to (-)-trachelanthic acid (35). The minor product afforded (-)-viridifloric acid (36) on similar acid hydrolysis. Acid catalysed isomerization of the hydroxylactone (34) gave two diastereo- isomeric protected necic acids (37). These were separated and each was treated with (+)-retronecine (16) (previously synthesized by the same gro~p~',,'~) to yield the C-9 ester of (+)-retronecine. Subsequent removal of the diol protecting group and oxidation of the tertiary amine produced indicine N-oxide (38). White and co-workers previously developed a route to the S-lactone (41) of (+)-integerrinecic acid from the monoterpene (R)-pulegone (39) via the allylic alcohol (40) (Scheme 9).6e,16 This group has now extended this strategy to complete a lengthy synthesis of usaramine (52).l7 Sharpless oxidation of the allylic alcohol (40) in the catalytic version using (-)-di- isopropyl tartrate gave the epoxide (42) as the major product.The epoxide (42) was opened with pivalic acid assisted by intramolecular complexation with Ti'" to give a diol protected as its acetonide (43). The pivalate was transformed into the protected ester (44). Oxidative cleavage of the remaining double bond afforded the acid (49 which was converted into a 8-lactone and the free hydroxyl group was protected as the methoxymethyl ether (46).The lactone was condensed with acetaldehyde leading to the (@-olefin (47). The methoxymethyl ether was cleaved and the lactone hydrolysed to give a diol protected as the acetonide (48). For the basic component of the macrocyclic alkaloid (+)-retronecine (16) was obtained from natural sources. It was silylated regioselectively at the 9-position and converted into the pyrrolizidine borane (49) (in order to prevent pyrrole formation during the coupling step). The lithium salt of the alcohol (49) was treated with the acyl phosphate derived from the acid (48) to give the C-7 ester (50). The primary silyl ether was then removed and the free hydroxy group was mesylated. The remaining silyl protecting group was cleaved and lactonization took place to yield the borane (51).Ethanolysis removed the borane and acidic hydrolysis afforded usaramine (52). All naturally occurring macrocyclic diesters incorporating (-)-platynecine (12) so far isolated have 12-or 13-membered rings. Rodgers and Robins have shown that 10- and 11- NATURAL PRODUCT REPORTS 1991-D. J. ROBINS ko (39) (40) 40 (45) (44) xi-xiii 1 CH20CH20Me CH20CH20Me xiv-xvi+ 53 0J3 ..C 0 (CH2 12siM e3 0 *TO2(C H2) 2siM e3 (46) (47) -BH3 (49) C02(CH2)2SiMe3 xxiii-xxv xxvi xxvii ____) Reagents i PhCMe,OOH Ti(OPr'), (+)-di-isopropyl tartrate ;ii Me,CCO,H Ti(OPr'), toluene ; iii Me,C(OMe), camphorsulphonic acid ; iv LiAlH, ether; v PDC CH,Cl,; vi CH,N, H,O; vii Me,SiCH,CH,OH Ti(OEt), 100 "C; viii 0,,CH,Cl, -78 "C; ix Me$; x NaIO, RuCl,; xi AcOH 80 "C; xii 2-chloro-1-methylpyridiniumiodide 4-DMAP MeCN; xiii ClCH,OMe Pr'NEt, THF 40 "C; xiv MeCHO LDA THF -60 "C; xv Ac,O Et,N 4-DMAP CH,Cl,; xvi DBU CH,Cl,; xvii 3M HCl THF xviii LiOH H,O, THF-H,O; xix ButMe,SiC1 base; xx BH;THF; xxi (EtO),POCl Et,N THF; xxii Bu"Li 4-DMAP THF; xxiii NH,F MeOH-H,O 60-65 "C; xxiv MsC1 Et,N CH,Cl,; xxv BuiNF MeCN; xxvi EtOH 80 "C; xxvii 1M HC1-THF Scheme 9 NATURAL PRODUCT REPORTS 1991 (53) R1 = R2 = Me (54) R1 = R2 = H (55) R',R~= (CH2)4 (56) R',R~= (CH2)5 R'0 s:TCMe2 R2 co-0 Me2CH-$:L H OH N Me Me (60) R' = R2 = H (61) R' = tiglyl R2 = H (62) R' = tiglyl R2 = OH ho RO Me iI (66) R = Ac (67) R = H membered rings containing platynecine can exist by syn-thesizing the first examples.l* (-)-Platynecine (12) was pre- pared by catalytic hydrogenation of readily available (+)-retronecine (16).Esterificatiori of (-)-platynecine with a series of glutaric anhydride derivatives gave mainly the 9-monoesters of (-)-platynecine. Lactonization was achieved via the S-2-pyridylthioesters to yield the 11-membered macrocyclic diesters (53)-(56). Ten-membered pyrrolizidine alkaloid analogues (57H59) were also prepared in a similar way from (-)-platynecine and succinic anhydride derivatives. 3. Alkaloids of the Boraginaceae Roots of Lithospermum erythrorhizon Siebold et Zuccharini are used in oriental medicine.Three pyrrolizidine alkaloids were isolated from the roots of this plant by Roeder and Rengel.l9 The main constituent was intermedine (60). Present in much smaller amounts were myoscorpine (61)20u,21and a new alkaloid called hydroxymyoscorpine (62). The structure of hydroxymyoscorpine was established by detailed 2D-NMR spectroscopic experiments. Intermedine (60) has also been isolated from aerial parts of Cerinthe minor L.22 This is the first reported discovery of pyrrolizidine alkaloids from this genus. (57) R' = R2 = R3 = R4 = H (58) R',R3 = (CH2)4 R2 = R4 = H and R' = R3 = H R2,R4 = (cH~)~ (59) R',R4 = (CH2)4 R2 = R3 = H and R' = R4 = H R2,R3 = (cH~)~ Me270R CH20H N (63) (64) R = H (65) R = Ac Alkaloidal constituents of the medicinal herb Heliotropium keralense were shown by Herz and co-workers to be intermedine (60) (+)-retronecine (16) and a new alkaloid named iso- lycopsamine.23 Structure (63) was proposed for this new alkaloid with the unusual arrangement of a viridifloryl ester at C-7 on the basis of spectroscopic measurements.In particular the mass spectral fragmentation pattern was similar to that reported for 7-angelylretronecine. This assignment was sup- ported by hydrolysis of iso-lycopsamine (63) to (+)-retronecine (16) and (+)-viridifloric acid [enantiomer of (36)]. Europine (64) N-oxide was previously isolated from Heliotropium rotundifolium Sieber ex Lehm.20b*24 Heliotrine lasiocarpine and a new alkaloid have now been shown also to be The new alkaloid was formulated as 5'-acetyl- europine (65) by comparison of spectroscopic data with known alkaloids.In particular the possible presence of the acetyl group at the 7-position was ruled out by the observation of a multiplet at 6 4.13 for the 7-H which is typical for heliotridine derivatives with a free 7-hydroxyl group. The presence of the acetyl group at C-5' is inferred from Y-NMR spectroscopic data and by the downfield shift of the geminal dimethyl groups in 5'-acetyleuropine compared to europine. Lasiocarpine heliotrine supinine and 9-angelylretronecine N-oxide are present in Heliotropium bursiferum Wr. ex Groebach.26 Lasiocarpine was shown to have antimicrobial activity. Echinatine and its N-oxide were isolated from Lindelofia longflora (Bentham) Baill~n.~' The pyrrolizidine alkaloids of the genus Symphytum have been studied.28 4 Alkaloids of the Asteraceae (Compositae) In the only previous investigation of the alkaloids of the Cirsium genus (tribe Cynareae) heliotridane was reported from C.~teigerurn.~~ A new alkaloid has been isolated from roots of C. walZichii DC by Negi et al.30 The alkaloid was formulated as 0-acetyljacoline (66) because alkaline hydrolysis gave (+)-retronecine (16) and the lactone of jacolinecic acid. Fur- thermore partial hydrolysis yielded jacoline (67). The location of the acetyl group has not been rigorously established. NATURAL PRODUCT REPORTS 1991-D. J. ROBINS 219 (68) (69)R (70)R (73) Aerial parts of Senecio integrifolius (L.) Clairv.ssp. aucheri (DC.) Matthews were shown to contain senecionine sen- eciphylline integerrimine senkirkine retrorsine and retro-necine (16).31Structure (68) was proposed for a new alkaloid named aucherine. The contents of seven Australian Senecio species have been compared with those reported from South African species.32 A new acylpyrrole derivative was found in S. magnificus F. Muell. On the basis of its lH NMR spectrum this new alkaloid was shown to be desacetylsenaetnine (69). Senaetnine (70) was also present together with three other known acylpyrroles in very small quantity. A large amount of acetylsenecionine (71) was isolated providing the first example of the co-existence of a 'normal ' pyrrolizidine alkaloid (71) and the corresponding acylpyrrole (70) in S.magnzficus. Senaetnine (70) was also present in S. quadridentatus Labi11.32 Retrorsine and isatidine ( = retrorsine N-oxide) were isolated from aerial parts of S. othonnaeflorus DC.33 Otosenine senecionine and seneciphylline are present in aerial parts of S. aquaticus.34 GC-MS analysis of two S. nemorensis subspecies indicated that spp. fuschsii Celak contains platyphylline sarracine triangularine senecionine fuchsisenecionine and 1,2-dehydrofuchsisenecionine,whereas doronine retroisose-nine bulgarsenine and fuchsisenecionine are present in spp. nemorensis Celak.35 = H = Ac (74) 5 Alkaloids of the Graminae Loline (72) occurs in tall fescue (Festuca arundinacea) seed infected with the endophytic fungus Acremonium coenophialum.Loline has been isolated from tall fescue in quantity by Powell and co-workers and converted by standard methods into other naturally occurring loline alkaloids namely N-formylloline N-acetylloline N-methylloline norloline N-formylnorloline and N-a~etylnorloline.~~ 13C and 'H NMR spectroscopic data were presented for all seven loline alkaloids. The presence of these loline alkaloids confers resistance on tall fescue to insect pests but they are also responsible for several disease syndromes in cattle causing large financial losses. A routine method for the analysis of loline alkaloids in infected tall fescue has been developed using capillary GC.37 Water deficit was found to increase the concentration of loline alkaloids in infected tall fescue.38 Oral thiamine supplements may alleviate tall fescue toxicosis of beef cattle during warm dry weather when animals are particularly susceptible.39 6 Alkaloids of the Fabaceae (Leguminosae) Traces of a new alkaloid have been found in seeds of Crotalaria assarnica Benth. by Roeder and co-worker~.~~ Structure (73) was proposed for assamicadine mainly on the basis of 2D NMR spectroscopic methods. In particular 2D NOESY indicated the relative configuration of the lactone -the two hydrogens and the methyl group in between are on the same side of the lactone ring. The seeds of C. assimica also contain 3.5 % monocrotaline (74).40941 Alexine (75) isolated from Alexa leiopetala was the first example of a pyrrolizidine base with a carbon substituent at C-3.6g*42 Subsequently 3,7a-diepialexine (76)6h.43 and 7a-epi- NATURAL PRODUCT REPORTS 1991 (77) HO CHzOH (79) or enantiomer (80) 8 General Studies Monocrotaline (74) can be extracted from crushed seeds of Crotalaria spectabilis using supercritical carbon dioxide and carbon dioxide/ethanol mixtures.51 Ion pairs of some pyr- rolizidine alkaloids with BiI were formed and extracted.The metal content was then determined by flame atomic absorption (78) ~pectrometry.~~ Extracts of Senecio nemorensis fuchsii were shown by GC- MS to contain 14 alkaloid peaks.53 Some of the peaks were tentatively identified. The alkaloid contents of two Senecio species have been determined by positive and negative ion thermospray LC-MS.54 lH NMR spectrometry is recommended for the deter-mination of the total alkaloid levels in Senecio jacobaea whereas 13C NMR spectroscopy can be used to identify some individual alkaloids in extracts of S.ja~obaea.~~ Published 13C NMR spectroscopic chemical shifts of more than 130 pyr- rolizidine alkaloids have been listed.56 9 X-Ray Studies The X-ray crystal structure determination of otosenine (80) has been ~epeated.~~,~~ The ester carbonyl groups are antiparallel as in all other 12-membered pyrrolizidine alkaloids so far studied.Transannular distances between the nitrogen and carbonyl are compared with other otonecine macrocyclic diesters that have been studied by X-ray crystallography. 10 Pharmacological and Biological Studies Structure-activity relationships for pyrrolizidine alkaloids have been reviewed (in Chinese).59 A new method of shape alexine (australine) (77)6"944 were found in Castanospermum description has been used to correlate structures with acute australe A.Cunn. along with the indolizidine alkaloid lung and liver toxicities for a series of pyrrolizidine alkaloids. 6o castanospermine. Two more related bases have been isolated Unsaturated pyrolizidine alkaloids such as monocrotaline from C. australe. The structure of 1,7a-diepialexine (78) was (74) are converted by liver oxidase enzymes into the corre- established by X-ray crystallography on the hydr~chloride.~~ sponding pyrrole derivatives which are powerful alkylating agents responsible for the hepatotoxicity often observed after The structure (79) of the second new alkaloid 7,7a-diepialexine was assigned by mass spectrometry and NMR spectroscopy.The relative configuration of the substituents was established by NOE experiments. 7,7a-Diepialexine was also present in Alexa lei~petala.~~ 1,7a-Diepialexine (named epiaustraline) (78) was also isolated from C. australe by Harris and co-workers and identified by 2D NMR spectroscopy and NOE ex-periment~.~~ All alexine derivatives are weak inhibitors of mammalian digestive glycosidases when compared with cas- tanospermine but they are powerful inhibitors of fungal glycan An 1,4-a-glu~osidase.~~ analogue of the pyrrolizidine (78) without the 3-hydroxymethyl group has been synthesized by Carpenter et al.in optically active form from mann~se.~~ This analogue was a weak inhibitor of the broad specificity p-galactosidaselp-glucosidase. 7 Alkaloids in Insects Various insects belonging to different orders sequester pyr- rolizidine alkaloids from plants and use them for defensive purposes and in some cases as pheromone precursors. This fascinating area has been reviewed by B~pprC.~~ Larvae of danaid and ithomiine butterflies assimilated pyrrolizidine alkaloids when they were painted on leaves of the larval host plants.49 This finding supports the theory of the common ancestral use of these alkaloids by butterflies from these two families. Monarch butterflies (Danaus plexippus) contained pyr-rolizidine alkaloids and N-oxides when they arrived at their wintering site in California USA.5o After feeding on Senecio mikanoides which contains sarracine a platynecine (12) derivative there was surprisingly apparently an increase in the retronecine (1 6) content in the butterflies.Retronecine derivatives are more toxic than those of platynecine. ingestion of these alkaloids. Mattocks and co-workers have used o-bromanil to prepare some pyrrolic derivatives in good yields from unsaturated pyrrolizidine alkaloids.61 After carrying out tests on rats and mice it was concluded that no single animal model is suitable for predicting the hepatotoxicity of the type seen in humans after ingestion of pyrrolizidine alkaloids [including indicine N-oxide (38)].62 Alkaloid extracts of Symphytum oficinale (comfrey) damaged chromosomes in human lymphocyte Comfrey is a favourite herbal tea and remedy for various ailments.11 References 1 W.-M. Dai Y. Nagao and E. Fujita Heterocycles 1990 30 1231. 2 J. P. Celerier M. Haddad C. Saliou G. Lhommet H. Dhimane J. C. Pommelet and J. Chuche Tetrahedron 1989 45 6161. 3 E. Roeder T. Bourauel and H. Wiedenfeld Liebigs Ann. Chem. 1990 607. 4 T. Kametani H. Yukawa and T. Honda J. Chem. SOC. Perkin Trans. I 1990 571. 5 T. Kametami H. Yukawa and T. Honda J. Chem. SOC.,Chem. Commun. 1988 685. 6 D. J. Robins Nut. Prod. Rep. (a) 1989 6 579; (b) 1989 6 581; (c) 1990,7,379;(4 1985,2,214; (e) 1989,6,221; u> 1989,6 582; (g) 1989 6 586; (h) 1990 7,384. 7 E. Gruszecka-Kowalik and L.H. Zalkow J. Org. Chem. 1990 55 3398. 8 G. E. Keck and E. J. Enholm Tetrahedron Lett. 1985 26 331 1. 9 G. E. Keck E. N. K. Cressman and E. J. Enholm J. Org. Chem. 1989 54 4345. 10 Y. Nagao W.-M. Dai M. Ochiai S. Tsukagoshi and E. Fujita J. Am. Chem. SOC., 1988 10 289. 11 Y. Nagao W.-M. Dai and M. Ochiai Tetrahedron Lett. 1988 29 6133. NATURAL PRODUCT REPORTS 1991-D. J. ROBINS 12 Y. Nagao W.-M. Dai M. Ochiai and M. Shiro J. Org. Chem. 1989 54 521 1. 13 H. Rueger and M. Benn Heterocycles 1983 20 1331. 14 H. Niwa T. Ogawa and K. Yamada Tetrahedron Lett. 1989,30 4985. 15 H. Niwa 0.Okamoto Y. Miyachi U. Uosaki and K. Yamada J. Org. Chem. 1987 52 2941. 16 J. D. White and L. R. Jayasinghe Tetrahedron Lett.1988 29 2139. 17 J. D. White J. C. Amedio S. Gut and L. R. Jayasinghe J. Org. Chem. 1989 54,4268. 18 M. Rodgers and D. J. Robins J. Chem. SOC. Perkin Trans. 1 1989 2437. 19 E. Roeder and B. Rengel Phytochemistry 1990 29 690. 20 D. J. Robins in ‘The Alkaloids,’ ed. M. F. Grundon Specialist Periodical Reports The Royal Society of Chemistry London (a) 1983 Vol. 13 p. 73; (b) 1979 Vol. 9 p. 59. 21 J. F. Resch D. F. Rosberger and J. Meinwald J. Nut. Prod. 1982 45 360. 22 E. Roeder H. Wiedenfeld and K.-J. Kabus Sci. Pharm. 1990 58 9. 23 S. Ravi A. J. Lakshmanan and W. Herz Phytochemistry 1990 29 361. 24 L. H. Zalkow L. Gelbaum and E. Keinan Phytochemistry 1978 17 172. 25 C. F. Asibal L. T. Gelbaum and L. H. Zalkow J. Nut.Prod. 1989 52 726. 26 G. Marouina A. Laguna P. Franco L. Fernandez R. Perez and 0.Valiente Pharmazie 1989 44,870. 27 H. A. Kelly and D. J. Robins Fitoterapia 1990 61 89. 28 T. A. Jaarsma E. Lohmanns T. W. J. Gadella and T. M. Mal- ingre Plant Syst. Evol. 1989 167 113. 29 N. M. Ismailov Izvest. Akad. Nauk Azerb. SSR Ser. Biol. Iselsk. Nauk 1958 4 11 (Chem. Abstr. 1958 53 35776). 30 R. K. S. Negi T. M. Fakhir and T. R. Rajagopalan Indian J. Chem. Sect. B 1989 28 524. 31 B. Sener F. Ergun S. Kusmenoglu and A. E. Karakaya Gazi Univ. Eczacilik Fak. Derg. 1988 5 157 (Chem. Abstr. 1989 111 2 1I 907). 32 C. Zdero F. Bohlmann R. M. King and L. Haegi Phyto-chemistry 1990 29 509. 33 C. Zdero F. Bohlmann and J. R. Liddell Phytochemistry 1989 28 3532.34 E. Roeder H. Wiedenfeld and R. Kersten Sci. Pharm. 1990,58 1. 35 H. Wiedenfeld A. P. Bruins and E. Roeder Sci. Pharm. 1989 57 97. 36 R. J. Petroski S. G. Yates D. Weisleder and R. G. Powell J. Nut. Prod. 1989 52 810. 37 S. G. Yates R. J. Petroski and R. G. Powell J. Agric. Food Chem. 1990 38 182. 22 1 38 D. P. Belesky W. C. Stringer and R. D. Plattner Ann. Bot. (London) 1989 64 343. 39 L. M. Lauriault C. T. Dougherty N. W. Bradley and P. L. Cornelius J. Anim. Sci. 1990 68 1245. 40 D. Cheng Y. Liu T. T. Chu Y. Cui J. Cheng and E. Roeder J. Nut. Prod. 1989 52 1153. 41 D. L. Cheng S. B. Tu A. A. Enti and E. Roeder Sci. Pharm. 1986 54 351. 42 R. J. Nash L. E. Fellows J. V. Dring G. W. J. Fleet A. E. Derome T.A. Hamor A. M. Scofield and D. J. Watkin Tetra-hedron Lett. 1988 29 2487. 43 R. J. Nash L. E. Fellows J. V. Dring G. W. J. Fleet A. E. Derome M. P. Baird M. P. Hegarty and A. M. Scofield Tetra-hedron 1988 44,5959. 44 R. J. Molyneux M. Benson R. Wong J. E. Tropea and A. D. Elbein J. Nut. Prod. 1988 51 1198. 45 R. J. Nash L. E. Fellows J. V. Dring G. W. J. Fleet A. Girdhar N. G. Ramsden J. M. Peach M. P. Hegarty and A. M. Scofield Phytochemistry 1990 29 11 1. 46 C. M. Harris T. M. Harris R. J. Molyneux J. E. Tropea and A. D. Elbein Tetrahedron Lett. 1989 30 5685. 47 N. M. Carpenter G. W. J. Fleet I. C. di Bello B. Winchester L. E. Fellows and R. J. Nash Tetrahedron Lett. 1989 30 726 1. 48 M. Boppri J. Chem. Ecol. 1990 16 165.49 J. R. Trigo and P. C. Motta Experientia 1990 46 332. 50 M. E. Stelljes and J. N. Seiber J. Chem. Ecol. 1990 16 1459. 51 S. T. Schaeffer L. H. Zalkow and A. S. Teja Biotechnol. Bioeng. 1989 34 1357. 52 C. Nerin J. Cacho and A. Garnica Anal. Lett. 1989 22 3041. 53 R. Gottlieb Dtsch. Apoth. Ztg. 1990 130 285. 54 C. E. Parker S. Verma K. B. Tomer R. L. Reed and D. R. Buhler Biomed. Environ. Mass Spectrom. 1990 19 1. 55 L. A. C. Pieters A. M. van Zoelen K. Vrieling and A. J. Vlietinck Mag. Reson. Chem. 1989 27 754. 56 E. Roeder Phytochemistry 1990 29 1 1. 57 H. Wiedenfeld E. Roeder and F. Knoch Acta Crystallogr. Sect. C 1990 46 1345. 58 A. Perez-Salazar F. H. Cano G. Fayos S. Martinez-Carrera and S. Garcia-Blanco Acta Crystallogr.Sect. B 1977 33 3525. 59 C. Yu Zhongguo Yaoxue Zazhi 1989 24 585 (Chem. Abstr. 1990 112 171547). 60 D. R. Henry and A. M. Craig A.C.S. Symp. Ser. 1988 (Publ. 1990) 413 70. 61 A. R. Mattocks R. Jukes and J. Brown Toxicon 1989 27 561. 62 D. J. Moore K. P. Batts L. H. Zalkow G. T. Fortune and G. Powis Toxicol. Appl. Pharmacol. 1989 101 271. 63 G. Behninger G. Abel E. Roeder V. Neuberger and W. Goeggelmann Planta Med. 1989 55 518.

ISSN:0265-0568    

DOI:10.1039/NP9910800213

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Carotenoids and Polyterpenoids G. Britton Department of Biochemistry University of Liverpool P.O. Box 747 Liverpool L69 3BX Reviewing the literature published in 1988 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 359) 1 Introduction include retinoids and some carotenoid-like natural products 2 Carotenoids when this is considered to be relevant. 2.1 Introduction 2.2 New Structures and Stereochemistry 2.2.1 Carotenoids 2 Carotenoids 2.2.2 New Natural Products Related to Carotenoids 2.3 Carotenoid Interactions in Vivo 2.1 Introduction 2.3.1 Carotenoids in Photosynthetic Pigment-protein As usual there have been several reviews and chapters devoted Complexes to carotenoids. A book ‘Plant Pigments’ edited by Goodwin2 2.3.2 Carotenoids in Membranes and Films/Surfaces presents a review of progress since the earlier edition3 was 2.3.3 Carotenoproteins published in 1976.Almost half of this book deals with 2.3.4 Retinal-proteins carotenoids in chapters on distribution and analysis,2a bio- 2.3.4.1 Structures synthesis,2* function in chloroplasts and photosynthesis,2c and 2.3.4.2 Primary reactions and photocycles visual pigments functions other than in photosynthesis.2d A volume on the 2.3.4.3 Bacteriorhodopsin chemistry of pigments in fungi includes a section on car- 2.3.4.4 Other photoreceptors of halobacteria otenoids. A substantial review on the latest advances in 2.4 Biosynthesis and Metabolism carotenoid chemistry and biochemistry includes a section on 2.4.1 Biosynthesis carotenoprotein complexes.Two Japanese articles on p- 2.4.2 Metabolism carotene (1) as a food additive6 and the role of carotenoids in 2.5 Analytical Methods animals’ include information on the properties biosynthesis 2.5.1 Separation and Assay and metabolism of carotenoids. The regulation of carotenoid 2.5.2 Electronic Absorption Spectroscopy biosynthesis is discussed in an authoritative and comprehensive 2.5.3 Fluorescence Spectroscopy review.8 In areas related to carotenoids the proceedings of an 2.5.4 Raman and Infra-red Spectroscopy international conference on retinal-proteins have been pub- 2.5.5 NMR Spectroscopy lished in an extensive book.g A review on the bioorganic 2.5.6 Mass Spectrometry chemistry of irones and their precursors contains information 2.5.7 X-ray Methods on their isolation characterization and biosynthesis.lo 2.6 Synthesis and Chemistry 2.6.1 Carotenoids 2.6.2 Retinoids 2.2 New Structures and Stereochemistry 2.6.3 Car0 tenoid-li ke Compounds 3 Polyisoprenoids and Isoprenoid Quinones 2.2.1 Carotenoids 3.1 Polyisoprenoids The new structures that have been elucidated for naturally- 3.1.1 Occurrence and Properties occurring carotenoids are all variations on well-known struc- 3.1.2 Biosynthesis tural themes. The alga Euglena viridis has afforded two new 3. I .3 Analytical Methods bisacetylenic carotenoids which were identified as 3.1.4 Synthesis and Chemistry 3,4,7,8,3’,4’,7’,8’-octadehydro-P,P-carotene (2) and the related 3.1.5 Archaebacterial Ether Lipids 7,8,3’,4’ 7’,8’- hexadeh ydro-P,P-caro ten- 3-01 (3) by spectro- 3.2 Isoprenylated Quinones scopic methods especially NMR.l1 Two colourless com- 3.2.1 Natural Occurrence pounds isolated from leaves of the aquatic plant Myriophyllum 3.2.2 Analytical Methods verticillatum have been identified as hydroxy-derivatives of the 3.2.3 Biosynthesis and Metabolism C, hydrocarbon lycopersene (7,8,11,12,15,7’,8’ 1 1 ’,12’ 15’- 3.2.4 Synthesis and Chemistry decahydro-$,$-carotene) (16) a compound that was once 4 References considered to be a possible alternative to phytoene (7,8,11,12,7’,8’,11’,12’-octahydro-$,$-carotene),(17) as an intermediate in carotenoid biosynthesis.l2 Analysis by lH and 13C NMR allowed these compounds to be assigned 1 Introduction the structures 7,8,11,12,15,7’,8’,11’,12’,1 5’-decahydro-$,$-Although the general philosophy and format of this article caroten-15-01 (1 8) and 14,15-didehydro-remain similar to that used in previous ones,l they have been 7,8,11,12,13,14,15,7’,8’,11’,12’,15’-dodecahydro-$,$-caroten-modified somewhat.In particular the article does not seek to 13-01 (19). On neutral alumina compound (19) underwent provide an exhaustive survey of all published work on dehydration to give phytoene. Prephytoene alcohol (20) has carotenoids and polyterpenoids over the period covered but it been isolated from the same source.13 This is the first report of will be more selective and will concentrate on those aspects the natural occurrence of this compound in the free form that are of most interest from the viewpoint of bioorganic though its diphosphate is an intermediate in the biosynthesis of chemistry.As before the coverage of carotenoids will also p hy toene. 223 NATURAL PRODUCT REPORTS 1991 R2 a b C d e f h I i k I m n 0 P (1) R' = R2=a (6) R' = R2 =e (11) R'=c R2=m (2) R' = R2 = b (7) R' =g R2= f (12) R'=n R2=c (3) R' =c R2 =b (8)R' =h R2 = i (13) R' =m,R2 =i (4) R' = R2 =d (9)R' = j R2 =c (14) R' =c R2 =o (5) R' =e R2 = f (10) R' =k,or/ R2 =c (15) R' =p R2=g .*.+ ... % C d (16) X=a (19) X =d (17) X =b (20)X =e (18) X =c e NATURAL PRODUCT REPORTS 1991-G.BRITTON H a C (21) R’ =a (X = H) R2 = CH:CHCH20H (22) R2 =a (X = OH) R2 = CH:CHCH20H (23) R’ = 6 R2 = CH:CHCH20H (24) R’ = c R2 = CH:CHCH20H (25) R’ = d R2 = CH:CHCH2OH (311 The ,&ring in carotenoids readily undergoes epoxidation at C-5,6 especially in the presence of organic peroxides. p,P-Carotene epoxides that are found in natural extracts are usually artefacts. A sample of P,P-carotene diepoxide (5,6,5’,6’- diepoxy-5,6,5’,6’-tetrahydro-P,P-carotene) (4) isolated from the sweet potato Ipomoea batatas was however shown to be optically active with the (5R,6S,5’R,6’S) configuration and is therefore a true natural product produced by enzymic epoxidation of P,P-carotene.l4 Rose petals have afforded several new apocarotenoids.Thus 10’-apo-P-caroten- 10’-01 (2 1) and its (3R)-3-hydroxy-deriva- tive galloxanthin (22) were each present mainly in the (all-E) form but accompanied by a cis isomer tentatively identified as 9Z.15 The stereochemsitry of the epoxy derivatives of gal- loxanthin namely sinensiaxanthin [(3S,5R,6S)-5,6-epoxy-5,6-dihydro-1O’-apo-/3-carotene-3,10’-diol (23)] and its furanoid derivative sinensiachrome [(3S,5R,8RS)-5,8-epoxy-5,8-dihy-dro-1O’-apo-/3-carotene-3,lO’-diol, (24)] has been established. l6 The rose hybrid ‘Marechal Niel’ gave the related acyclic apo- carotenoid 10’-apolycopenol (1 0’-apo-+-caroten- 10’-ol) (25) and 10’-apolycopenoic acid (10’-apo-+-caroten- 10’-oic acid) (26).17 The strongly fluorescent and unstable 10,lO’-dia-pocarotene- 10,lO’-diol (27) rosafluene has also been isolated in small amounts from rose petals.18 Re-examination of persicaxanthin and persicachrome from cling peaches confirmed the structure of persicaxanthin as (3S,5R,6S,all-E)-5,6-epoxy-5,6-dihydro- 12’-apo-P-carotene-3,12’-diol (28) and that of persicachrome as the corresponding 5,8-epoxide (29) (8R and 8s epimers).Several Z-isomers were also present and the apozeaxanthinol (30) (3R)- 12’-apo-P- carotene-3,12’-diol was also identified.lg Two-dimensional ‘H NMR analysis has allowed four naturally occurring mono-cis isomers of lutein epoxide (5,6- b d (26) R’ = d R2 = CH:CHC02H (27) R’ = CH20H R2 = CH:CHCH20H (28) R’ =b R2 =CH20H (29) R’ =c R2=CH20H (30) R’ =a (X = OH) R2 = CH20H I b-i2~~~ (CH2)4~ H epoxy-5,6-dihydro-/3,s-carotene-3,3’-diol) (9, to be identified as (9Z) (9’Z) (132) and (13’Z) respectively.20 Similar work has led to the characterization of six mono-cis and di-cis isomers of violaxanthin (5,6,5,’ 6’-diepoxy-5,6,5’,6’-tetrahydro-P,P-carotene-3,3’-diol),(6) from petals of Viola tricolor.21 Several new structures have been reported for carotenoids that were isolated from animals.The yellow finlet of the big-eye tuna fish Thunnus obesus was found to contain a new stereoisomer (6R,3’R,6’S) of 3’-hydroxy-e,e-caroten-3-one (7). 22 Invertebrate animals continue to provide a variety of new carotenoid structures.The methoxy-compound 7,8-dide-hydroaaptopurpurin (3-rnethoxy-7,8-didehydro-P,X-carotene) (8) was obtained from the sea sponge Tedania digit at^.^^ Three new acetylenic carotenoids with 3,4-dihydroxy-P-end-groups namely pectenol B [(3S,4S,3’R)-7’,8’-didehydro-P,P-carotene-3,4,3’-triol (9)] and the (3S,4R,3’R) and (3S,4S,3’R) isomers of 4-hydroxyalloxanthin (7,8,7’,8’-tetradehydro-/I,P-~arotene-3,4,3’-triol) (lo) were obtained from the Japanese mussel Mytilus CO~USCUS.~~ Details of the structure elucidation of the mussel carotenoids mytiloxanthin [(3R,3’S,SfR)-3,3’,8’-trihy-droxy-7,8-didehydro-P,~-caroten-6’-one, (1 l)] and isomytilo- xanthin [(5R,6S,3’R)-6,3’-dihydroxy-7’,8’-didehydro-5,6,7,8-tetrahydro-P,P-carotene-3,8-dione, (1 2)] from Mytilus edulis These have been p~blished.~~.~~ structures and that of trikentriorhodin (3,8-dihydroxy-~,~-caroten-6-one), (1 3)27 were proved by synthesis.Among nineteen carotenoids isolated from several batches of Mytilus edulis28 were three minor components which were assigned the novel structures an-hydroamarouciaxanthin B (3-hydroxy-7,8,6’,7’-tetradehydro-7’,8’-dihydro-P,s-carotene-3’,8’-dione) (14) 19’-hexanoyloxy- isomytiloxanthin (6,3’,19’-trihydroxy-7’,8’-didehydro-5,6,7,8-tetrahydro-P,P-carotene-3,8-dione19’-hexanoate) (31) and hydratopyrrhoxanthinol (3,3’,5’,6’-tetrahydroxy-7,8-dide- 0&co2x (36) X = H Y = 0 Z = Me (41) X (37) X=H Y=O Z=CH;?OH (38) X = H Y = H,O-glucose Z = Me (39) X = glucosyl Y = H,OH 2 = Me (40) X = H Y = H,OH Z = Me hydro-5’,6’-dihydro-10,11,20-trinor-~,~-caroten-19’ 1 1’-olide) (32).The absolute configuration ofpapilioerythrone [(3S,6’R)-3- hydroxy-P,c-carotene-4,3’-dione,(15)] from the crab Para-lithodes brevipes has been determined.29 2.2.2 New Natural Products Related to Carotenoids Further natural products have been isolated that bear a structural resemblance to carotenoids and contain similar ring systems. Two cyclobotryococcenes from the green alga Botryococcus braunii have the methyl-y-ring and methyl-P-ring structures (33) and (34) respe~tively.~~.~~ The absolute stereo- chemistry of the former braunicene has been established as (2S,6R) by degradation CD and NMR.32These compounds are unlikely to be carotenoid metabolites.The C, compound xestodiol(35) which was isolated from the sponge Xestospongia vanilla is described as a new apocarotenoid and may be derived from a carotenoid Several compounds related to the plant growth regulator abscisic acid (36) have been identified. Nigellic acid (37) isolated from leaves (Vicia faba) for the first time,34 though previously found in cell suspension cultures and the /3-D-glucopyranosyl ester of phaseic acid (41) obtained from shoots of tomato (Lycopersicon esc~lentum),~~ are considered to be natural metabolites of abscisic acid. The 3-glucoside (38) and NATURAL PRODUCT REPORTS 1991 HO &CO*H = glucosyl the glucose ester (39) were isolated as metabolites of abscisic acid 3,6-diol (40) in avocado (+)-3-Hydroxy-y-ionylideneacetic acid (42) which was shown to have the (7E,9Z)-~onfiguration,~’is an intermediate in abscisic acid biosynthesis in fungi.2.3 Carotenoid Interactions in Vivo Most papers on the chemistry of carotenoids describe work on isolated molecules or on carotenoids in organic solutions. In living systems the carotenoids (and related retinoids) are present in an environment that is at least partly aqueous and their properties and functions usually depend critically on interactions with other molecules in the cell especially proteins and other lipids. Such interactions represent an essential aspect of the bioorganic chemistry of the carotenoids especially in relation to their functioning.Studies of the natural interactions and complexes and of related model systems are therefore extremely important. 2.3.1 Carotenoids in Photosynthetic Pigment-protein Complexes In photosynthetic plants and algae as well as in phototrophic bacteria the carotenoids that function as accessory light- NATURAL PRODUCT REPORTS 1991-G. BRITTON &*- a b C I \/ d e A OH f &*“0 - I k (43)R’ =a R2 = b (47)R’ = R2 =e (51)R’ = R2=i (44)R’ =c R2 =b (48)R’ = R2 =f (52)R’ =h R2 =C02Et (45)R’ = R2 =c (49)R’ =d R2 =g (53)R’ = R2 =j (46)R’ = R2 =d (50) R’ =d R2=h (54)R’ = R2 =k harvesting pigments and in photoprotection are localized within the cells in specific functional pigment-protein com-plexes in the photosynthetic membranes.2c Structural and functional aspects of carotenoids in photosynthesis have been reviewed.38 The geometrical configuration and conformation of the carotenoids and their orientation relative to other molecules especially chlorophyll is crucial to their functioning in both singlet state and triplet state energy transfer.The distribution of geometrical isomers of /3-carotene in the pigment-protein complexes of chloroplast photosystems I and I1 has been determined.39 In addition to the all-E isomer the 92 92,132 and 92,152 forms were present in greater amounts in the PSI1 complex CP47 than in PSI. The 92,9’2-isomer was present only in PSI. The GIC mutant of the phototrophic bacterium Rhodobacter sphaeroides contains neurosporene (7,8-dihydro- $,$-carotene) (43) as virtually its only carotenoid.Detailed analysis by HPLC electronic absorption resonance Raman and ‘H NMR spectroscopy has shown that the neurosporene in the photosynthetic reaction centre is the 152 isomer whereas that in the light-harvesting antennae is all-E.40 Similarly the spheroidene (1 -methoxy-3,4-didehydro- 1,2,7’,8’-tetrahydro- $,@-carotene) (44) isolated from the reaction centre of wild- type Rb. sphaeroides was also the 152 isomer.41 Surface- enhanced resonance Raman scattering spectroscopy was used to demonstrate that spirilloxanthin (1,l’-dimethoxy-3,4,3’,4’-tetradehydro-1,2,1’,2’-tetrahydro-$,$-carotene) (49 in the pigment-protein complexes of Rhodospirilfum rubrum is located asymmetrically on the cytoplasmic side of the photosynthetic membrane.42 Resonance Raman spectroscopy showed that the detergent lithium dodecyl sulphate induced isomerization of carotenoid to the 72 form in situ in the B800-850 light- harvesting complex of Rhodopseudomonas acidophila strain 7750.43 Energy transfer from carotenoid to bacteriochloro- phyll a in the B800-820 antenna complex of Rps.acidophifa strain 7050 has been shown to be highly efficient and to occur in approximately 3ps.,* Model synthetic triads consisting of porphyrin carotenoid and quinone components have been used as mimics of the photosynthetic reaction centre in studies of the relationship between pigment orientation and energy transfer.”-46 2.3.2 Carotenoids in Membranes and FilmslSurfaces A structural role for carotenoids as rigid molecules that can reinforce or strengthen bacterial membranes has been discussed.Thus in a study with the C, and C, carotenoids zeaxanthin (P,P-carotene-3,3’-diol) (46) and decaprenoxanthin [2,2’-bis(4- hydroxy-3-methylbut-2-enyl)-c,c-carotene, (47)] respectively in model phospholipid bilayer vesicles the incorporation and strengthening effects were greatest when the length of the carotenoid corresponded to the thickness of the bila~er.~’ Reconstituted lipid membranes from Halobacterium were reinforced by the inclusion of the main Halobacterium carotenoid bacterioruberin [2,2’-bis(3-hydroxy-3-methylbutyl)-3,4,3’,4’- tetradehydro- 1,2,1’,2’-tetrahydro-@,@-carotene-1,l ’-diol (48)].4s Lutein (P,e-carotene-3,3’-diol), (49) was shown to uncouple mitochondria1 oxidative phosphorylation because of its ability to integrate deep into the hydrophobic region of the bilayer and perturb the micr~environrnent.~~ Single monolayers of lutein or zeaxanthin or mixed bilayers NPR 8 R (55)R=CH20H (56) R =CHO (57)R=C02H of these carotenoids with synthetic phosphatidylcholine have been investigated by absorption and photoacoustic spectro- and by linear di~hroism.~’ sc~pies~~ The carotenoids were mainly in the monomeric state coexisting with crystals,50 and their angle of orientation relative to the plane of the solid support was determined.51 When p-carotene and chlorophyll a were incorporated into phospholipid vesicles their absorption spectra differed from those in organic solution and the presence of the pigments altered the ESR spectra of the vesicles.52 In an extensive series of papers Romanian workers report studies of the properties of carotenoids in monolayers at interface~.,~-~~ Much of the work involved the use of mixed monolayers of lipid (natural or synthetic lecithin or digalacto- syldiacylglycerols) with various carotenoids for studies at the air-water interface.The carotenoids that were incorporated included zeaxanthin P-cryptoxanthin (p,P-caroten-3-01) (50) lu tein and as taxanthin (3,3’-dihydroxy-P,P-caro tene-4,4’-dione) (51) in the free form or as acyl esters and 8’-apo-P- caroten-8’-oic acid ethyl ester (52). The molecular structures and properties of the monolayers were investigated and data such as compression isotherms collapse surface pressures and ejection curves were re~orded.~~-~~ Compression isotherms of monolayers of zeaxanthin or astaxanthin (X) at the air-water interface in the presence of metal ions M (Co2+ or Cr3+) gave results that were consistent with the formation of MX,-type surface complexes.6o The behaviour of astaxanthin at the benzene-water interface has also been studied and interfacial tension measurements have been performed.61 In the presence of Co2+ the formation of an MX,-type interfacial complex was again indicated.62 Investigations with similar lipid monolayers and bilayers containing retinoids have also been reported.Methods for the preparation of light-sensitive liposomes (‘photosomes ’) as carrier vehicles have been described the compounds prepared included mono-and bis-retinoyl esters of glycerophospho- choline.The membrane fluidity of phosphatidylcholine lip- osomes was increased by the incorporation of increasing amounts of retinol(55) or retinal (56).64 The state of protonation of lipid films was found not to modify the mixing pattern of phosphatidylserine with retinal in monolayer films.65 Details of retinoid-phospholipid interactions have been elucidated by NMR and ESR studie~.~~,~~ Retinol retinal and retinoic acid (57) restricted the motion of the acyl chains of the lipid to a similar extent but only retinoic acid reduced acyl chain ordering appreciably towards the membrane surface. Ab-sorption and surface-enhanced Raman spectra of monolayers of retinal and styrylpyridinium dyes gave information on the structures of the films.68 In another spectroscopic study the second harmonic signal from monolayers of retinal and retinal Schiff bases was rep~rted.~~ 2.3.3 Carotenoproteins Some of the most interesting examples of carotenoid-protein interactions are provided by the purple blue and green carotenoproteins that are obtained from invertebrate animals.A new example that has been reported is a purple caroteno- protein from the carapace of the squat lobster Galathea strigosa. This complex which has A,, at 597 nm contains approximately fifteen astaxanthin molecules in a 500 kDa aggregated Further information has been published NATURAL PRODUCT REPORTS 1991 about the crustacyanin-like blue carotenoprotein of the crayfish Astacus leptodactylus ; isoelectric points and amino acid compositions were reported for the carotenoprotein and its sub~nits.~’ Although most carotenoproteins have been obtained from marine animals one example containing canthaxanthin (P,P-carotene-4,4’-dione) (53) has been isolated from Helix pomatia as a representative land A carotenoid-protein complex from eggs of the salmon Salmo salar has A,, at 409,540,580 nm and is a 50 kDa protein consisting of four identical The carotenoid present is astaxanthin which is esterified mainly with palmitic and stearic acids.The existence of a carotenoid-binding protein in larval haemolymph of the yellow-blood strain of the silkworm Bombyx mori has been detected by polyacrylamide gel electroph~resis.~~ A water-soluble 44kDa carotenoprotein with A,, 460 nm has been isolated from the cyanobacterium Anacystis nid~lans.~~ The main carotenoid present was (3R,3’R)- zeaxanthin but the presence of 17 % of lutein (trans and cis) was also reported a result which is surprising since lutein has never been found in Anacystis nor in any other cyanobacterium.A protein-complexed form of the C, carotenoid ‘C.P. 450’ [2,2’-bis(4-hydroxy-3-methylbut-2-enyl)-~,~-carotene)], (54) has been isolated from Corynebacterium poin~ettiae.~~ The mechanisms of carotenoid-protein interactions esp-ecially those that are responsible for the large spectral shifts in the blue or purple complexes are of particular interest.Details of these interactions have not yet been elucidated but some spectroscopic studies have been reported. An analysis of the CD and absorption spectra of the lobster carotenoprotein a-crustacyanin in terms of a 3-state dimer approach showed that the forbidden ‘Ag+ state of the astaxanthin chromophore can be an important factor in determining the spectral properties. The transition dipole moments associated with ‘Ag+ 1 ‘Bu chromophore excitation cannot be coplanar in the astaxanthin dimer. This lack of coplanarity can explain the optical activity of the astaxanthin dimer when the chromophores interact weakly with tryptophan residues in the protein. A geometrical structure was proposed for the astaxanthin dimer.;17 Resonance Raman spectroscopy also provides valuable information about the complexes.Possible mechanisms for the spectral shifts have been discussed on the basis of the resonance Raman spectra of astaxanthin-protein complexes and of complexes prepared by reconstitution with astaxanthin and canthaxanthin analog- ue~.~~.~~ Interactions that cause greater delocalization of the n-electron system in the central rather than in the peripheral part of the chromophore and an important probably steric role for the C-13 and C-13’ methyl substituents are discussed. 2.3.4 Retinal-proteins Proteins containing retinal (56) linked as a Schiff base as chromophore are extremely important as photoreceptors in particular as visual pigments in the eye and as energy harvesting photoreceptors in Halobacterium species.The great interest in these pigments is reflected in the number of papers that have been published. In this section no attempt is made to provide an exhaustive coverage of the literature but the main features and advances will be discussed. The conference proceedings book previously mentionedg contains a wide variety of papers on all aspects of the subject. 2.3.4.1 Structures Although most published work deals with very specific details of the structures and functioning of the pigments often on a very short time-scale the gross structures of the photoreceptors and the membranes that contain them are considered in several articles. An extensive reviewao describes the primary structure chemistry and molecular modelling of the visual pigment rhodopsin.A more concise review of the structures and functions of rhodopsins8’ concentrates more on the chromo- phore than on the protein. The acidic amino acids that are NATURAL PRODUCT REPORTS 1991-G. BRITTON H*X Y H (58) X=OH Y=H (59) X = H Y = OH (60) X,Y = bond responsible for the negative point charge counter-ions in rhodopsin and the related red green and blue iodopsins have been identified.82 3-Hydroxyretinal (58) has been identified as the chromophore in the visual pigment in some insect eyes83*84 and also along with retinal in the silkworm brain in a photoreceptor that may be involved in photoperi~dism.~~ 4-Hydroxyretinal (59) was found to be the chromophore in a visual pigment in a bioluminescent squid Watasenia scintillans.86 The halobacteria use similar retinal-proteins for a number of purposes.The photocycle of the main one bacteriorhodopsin drives a proton-pumping mechanism that generates ATP. Halorhodopsin is involved in a chloride ion-pumping mech- anism whereas phoborhodopsin and sensory rhodopsin are involved in phototaxis and related phenomena. A review article describes knowledge of the structure functions etc. of the sensory rhodopsins of haloba~teria.~' The isolation of sensory rhodopsin as a 24 kDa monomer or 49 kDa dimer A,, 580 nm has been described.88 By means of fluorescence energy transfer on oriented membrane sheets the chromophore of bacteriorhodopsin has been shown to be closer to the cytoplasmic surface of the purple membrane.89 High- sensitivity neutron diffraction studies of bacteriorhodopsin have shown that the Schiff base end of the chromophore is located between helices 2 and 6 of the protein in the purple membrane.From an Australian Halobacterium species has been isolated a novel retinal-protein named archaerhodopsin that differs from bacteriorhodopsin but drives a similar proton- pump.g1 2.3.4.2 Primary reactions and photocycles :visual pigments The molecular mechanisms of the primary events photocycles and photo-bleaching of visual pigments in the visual process have been revie~ed~~~~~ and compared with those in bac- teriorhod~psin.~~ Raman microscopy Raman spectroscopy and quantum yield studies of the primary photochemical processes showed that the 9-cis isomeric form was photo-chemically more stable in goldfish rod visual pigments containing a 3,4-didehydroretinal (60) chrom~phore.~~ The primary processes in the photolysis of octopus rhodopsin have been investigated by low-temperature ps time-resolved spectroscopy and photoproducts identified.96,97 The excited state structure and isomerization dynamics of the retinal chromophore in rhodopsin have been deduced from resonance Raman excitation This allowed the detection of changes in geometry that occur on electronic excitation of the 11 -cis-retinal protonated Schiff base chromophore and hence gave information about the torsional deformations in the excited state that lead to isomerization.The primary photo- chemical events in rhodopsin and isorhodopsin (which has a 9-cis-retinal chromophore) have been compared by low-temperature spectroscopy and calculations.99 The apparent relationship between the quantum yields of rhodopsin and isorhodopsin is dependent on the photon density of the ps laser pulse used for excitation.loO Conformation changes in the chromophore and protein of rhodopsin and in associated lipids during photoexcitation of rhodopsin have been determined by FTIR difference spectroscopy. lol The photochemistry of rho- dopsin in which the lysine residues have been methylated has been studied.lo2 (61) X = Me,Et,F or CI Y = H (62) X = H Y = Me,Et,F or CI The incubation of bovine rhodopsin with 9,13-dicis-retinal gave not only a 9,13-dicis-rhodopsin but also a 9-cis-rhodopsin (isorhodopsin) by a one-photon-one-double- bond isomeriz-ation process.1o3 Attempts have been made to prepare rhodopsin analogues by regeneration of fish or gecko rhodopsin with 11-cis or 9-cis retinals containing methyl ethyl fluoro or chloro substitutents at C-10 or C-14 (61) and (62).lo4 Bulky groups at C- 14 prevented recombination ;substitution at C- 10 (except for fluorine) also prevented the formation of gecko pigments.A ns laser photolysis study showed that on this timescale spectro- scopically identical bathorhodopsin products were obtained from rhodopsin and isorhodopsin. lo5 The rhodopsin-lum-irhodopsin phototransformation has been investigated by a FTIR difference spectroscopic study of bovine rhodopsin that had been reconstituted with isotopically labelled retinals.lo6 A 10-s-cis conformation in lumirhodopsin can be excluded.The photochemistry of squid retinochrome at room temperature has been investigated by ns and ps time-resolved spectro- copy.'^' Fluorescence and spectroscopic studies on a wide variety of polyenes including retinal and other chain length homologues as models of the primary reactions of the visual pigments have been reviewed.108 Approximation formulae have been used to calculate the absorption spectra of visual pigments.log Resonance Raman spectroscopy showed great similarities between metarhodopsin I1 and a tetrahedral carbinolamine intermediate (63) in the hydrolysis of a model retinal Schiff base thus supporting the hypothesis that the metarhodopsin I-metarhodopsin I1 transition involves hydrolytic attack by water on the retinyl-lysine Schiff base 1inkage.l'O Factors that influence the C=N stretching frequencies of polyene Schiff bases have been analysed and the implications for rhodopsin and bacteriorhodopsin discussed.'11 The C=N and C=C frequencies are particularly sensitive to the mag- nitude of interactions between the protonated Schiff base and the counter-ions and to the hydrogen- bonding environment of the Schiff base nitrogen atom. The interactions between the protonated Schiff base nitrogen and carboxylate counter-ions have also been investigated by two-dimensional 'H NMR.'12 Ion-pair formation between the protonated Schiff base and various counter-ions in CDCl was indicated; the most likely location of the carboxylate group counter-ion is in the immediate vicinity of the charged nitrogen atom.2.3.4.3 Bacteriorhodopsin Several review articles have been published in which are described the structure photocycle intermediates and proton- pumping activity of bacteriorhodop~in'l~ and especially the use of NMR resonance Raman IR and electronic absorption spectroscopies to study the primary photochemical events and the structures of intermediates in the ~ycle.~'~-'~~ Calculations have shown that the spectra of retinal Schiff bases are much more sensitive to effects of protonation and charge environment than was previously assumed and thus show the importance of varying counter-ion distances in wavelength regulation in bacteriorhodopsin and intermed-iates.120 The first processes in the reaction of bacteriorhodopsin have been studied on the fs time~cale.~~~-'~~ The trans to 13-cis isomerization of the retinal chromophore occurs within 200 fs.123The photochemistry of bacteriorhodopsin in which one or all of the lysine residues have been methylated has been Kinetic resonance Raman spectroscopic studies have revealed different conformational states of bacterio- rh0dop~in.l~~ Other spectroscopic studies on the ps or ns timescale have provided information about the formation and structures of transient intermediates in the bacteriorhodopsin photocycle.The formation of an intermediate J within 500 fs has been confirmed. 12 A time-resolved (ns) spectroscopic study of the K and K intermediates has been rep~rted.'~' By FTIR and UV difference spectroscopy the intermediate K,, has been shown to have a 13-trans-154s chromophore.12s A ps and ns spectroscopic study has shown that at an acidic pH the formation of intermediate K is decreased and that of M b10cked.l~~ A new L intermediate has been identified by time- resolved resonance Raman spectroscopy. 130 Resonance Raman studies of bacteriorhodopsin that was prepared from [14,15-2H2]-retinal have shown that the L,, intermediate has a C( 14)-C( 15) S-trans chromophore. 131 By means of time-resolved flash-induced difference absorption spectroscopy it was shown that the fast-decaying and slow-decaying forms of the intermediate M are physically distinct and operate in different photocycles.132 A long-lived intermediate N(P,R,,,) and its M-like photoproducts have been identified at high pH.133 The concentration of intermediate N is enhanced at pH 9.5 in 3 molar KCl.134 Resonance Raman spectroscopy showed that N appears with a half-time of 4ms and its chromophore is a 13-cis 14-s-trans 15-anti(trans)-protonated Schiff base.The intermediate P is also a protonated Schiff base with the 134s configuration. It is suggested that the Schiff base nitrogen is protonated at the M to P tran~iti0n.l~~ Extensive use is still being made of bacteriorhodopsin models prepared by reconstitution with analogues of retinal.Analysis of NMR and absorption spectroscopic data for bacterio- rhodopsin reconstituted with dihydroretinal analogues re-vealed interactions between the chromophore and a negative charge near C-5 and a positive charge near C-7.13 The results also indicated that a C-6,7-s-cis conformation cannot be ruled out. A series of ring-demethyl retinals has been prepared (16- demethyl- 16,17-didemethyl- 16,l %didemethyl- and 16,17,18- tridemethyl retinals (64F(67) respectively and incorporated into bacteriorhodopsin. 13' These analogues gave opsin shifts lower than those with retinal itself a result that was ascribed to a difference in the conformation at C-6,7. The C-6,7 torsion angle in 5-methoxy-5-demethylretinal (68) and 5-ethyl-5-demethylretinal (69) was also different from that in retinal and affected the spectroscopic properties of bacteriorhodopsins that were prepared from these analogues.138 Bacteriorhodopsin analogues that were prepared with the resolved enantiomers of 5,6-epoxy-5,6-dihydroretinal (70) had different A,, 485 and 445 nm for the (+) and (-) isomers respectively.139 Recon- stitution with the racemic epoxide led to preferential binding of the (+)-isomer. Retinal analogues with H ethyl or propyl substituents in place of the methyl group at C-13 (74) all gave reconstituted bacteriorhodopsins which were able to participate in photo~ycling.'~~ Spectra have been obtained of ,us and ms intermediates in the photocycle of bacteriorhodopsin products containing ring phenyl (71) and fluorophenyl (72) analogues of retinal.141 The naphthylretinal (75) gave two distinct forms of bacteriorhodopsin analogue which had A,, at 503 and 442 nm re~pectively.'~~*~~~ Although the protein-chromophore inter-actions were different the binding sites were the same and the two forms could be interconverted by changes in pH or by NATURAL PRODUCT REPORTS 1991 (64) X= H Y =Z=Me (65) X = Y = H Z = Me (66) X = Z = H Y = Me (67) X=Y=Z=H (68) X = Y =Me 2 = OMe (69) X = Y = Me Z = Et a b C (70) R=a (71) R=b (72) R=c(X=f) (73) R=c(X=I) (74) R = H,Et or Pr (75) detergent solubilization.Analogues of retinal with an iodo- phenyl ring (73) or an anthryl group were synthesized and incorporated into bacteriorhodopsin to give products that exhibited opsin shifts again showing that the size and shape of the ring part of the molecule is not important for the primary interactions with the ~r0tein.l~~ 2.3.4.4 Other photoreceptors of halobacteria Three other retinal-protein photoreceptors have also been found in Halobacterium species namely halorhodopsin phoborhodopsin and sensory rhodopsin.Dark-adapted halorhodopsin is a mixture of 13-cis- and all-trans-retinal chromophore forms. Prolonged illumination with red light produces a third form isohalorhodopsin which has a 9-cis- chromophore. The absolute spectra of intermediates in the halorhodopsin photocycle have been obtained by flash photolysis and fast difference spectral measurements.146 The photocycle has also been studied by FTIR spectroscopy. 14' Halorhodopsin samples that were prepared by reconstitution with dihydroretinals gave absorption spectra very similar to those of the corresponding reconstituted products of bac- teriorhodopsin. 148 The chromophore-protein and chromophore- NATURAL PRODUCT REPORTS 1991-G. BRITTON counter-anion interactions in bacteriorhodopsin and halo-rhodopsin are therefore similar. The photochemical cycle of sensory rhodopsin has been studied by flash photolysi~~~~ and low-temperature spectro- phot~metry.’~~ Intermediates were detected and branching of the cycle has been identified by ns A CD study revealed a fundamental difference in sensory rhodopsin compared with bacteriorhodopsin and halorhodopsin.Whereas the CD spectra of bacteriorhodopsin and halorhodopsin showed exciton splitting that of sensory rhodopsin did not thus indicating differences in the positioning and orientation of the chr~mophores.~~~ Flash photolysis studies have been reported on the photo- cycles of sensory rhodopsin and of phoborhodopsin. 153 Phobo-rhodopsin has A,, 480 nm and a photocycle has been postulated on the basis of low-temperature spectrophoto-met ry .154 2.4 Biosynthesis and Metabolism 2.4.1 Biosynthesis General progress since 1976 on the biosynthesis of carotenoids is surveyed in a chapter of a book on plant pigments.26 Another extensive but more specialized review presents a detailed account of the regulation of carotenoid biosynthesis.The biosynthesis and functions of carotenoids in the context of nuclear-cytoplasmic interactions in higher plants are discussed in a shorter A review on isoprenoid biosynthesis in general contains much information that is relevant to the biosynthesis of carotenoids especially the early Little new information has been obtained about the pathways of carotenoid biosynthesis although the operation of alternative pathways from phytoene to /?-carotene involving the all-trans and 9-cis isomers respectively in the green alga Dunaliella bardawil has been ~uggested.’~~ A parallel pathway similar to that which operates in the tangerine tomato mutant has also been suggested for the biosynthesis of polycis-carotenes especially prolycopene (7Z,9Z,7’Z,9’Z)-lycopene (76) in the mutant C-6D of the green alga Scenedesmus ~bliquus.’~~ Steady progress is being made on the isolation and purification of the enzymes of carotenoid biosynthesis.Ger- anylgeranyl diphosphate synthase from Phycomyces blakes- leeanus has been purified. 159 Affinity chromatography pro- cedures have been used to purify to homogeneity phytoene synthase from chromoplasts of Capsicum annuurn.160 This single bifunctional monomeric protein (47.5 kDa) carried two enzyme activities and catalysed both the coupling of two molecules of geranylgeranyl diphosphate to yield prephytoene 23 1 diphosphate and also the conversion of the latter into phytoene. The enzyme was strictly dependent on Mn2+ ions and was inhibited by an arginine-specific reagent.In daffodil chromo- plasts isopentenyl diphosphate isomerase was found to work independently of the other enzymes of the phytoene synthase complex.161 Strains of Gibberella fujikuroi that were super-producers of phytoene or neurosporaxanthin [(4’-apo-P- caroten-4’-oic acid (77)] incorporated more of the isoprenoid precursor mevalonic acid into carotenoids than did the wild- type strain. 162 Isolated cytosolic fractions were capable of synthesizing phytoene but membrane fractions did not incorporate precursors into coloured carotenoids. The enzymic de-epoxidation of violaxanthin in etiolated leaves has been reported.163 Major advances in carotenoid biosynthesis are likely to result from detailed genetic studies.Such work with the phototrophic bacteria has now reached the stage at which a genetic-physical map has been obtained of the carotenoid biosynthesis gene cluster of Rhodobacter c~psulatus.~~~ Seven genes crtA-F and crt1 were identified and each was shown to be a single transciptional unit. The carotenoid gene cluster from Erwinia herbicola has been cloned in the non-carotenogenic Escherichia ~0li.l~~ The carotenoids that were synthesized afforded E. coli protection against damage by UV light and phototoxic molecules. In many organisms carotenogenesis is regulated by light. Studies with mutants of Neurospora crassa have shown a positive correlation between the photooxidation of NADH or NADPH and the rate of light-induced carotenogenesis.166 Three genes are involved in the photoregulation nada al-1 and al-2 which encode NADP glucohydrolase phytoene de-saturase and phytoene synthase respectively. In a strain of Aspergillus giganteus blue light but not red light induced carotenoid bio~ynthesis.’~~ By the use of inhibitors it was shown that photoregulation is induced at the transcriptional level and that the phytoene synthase desaturase and cyclase enzymes are totally photoinduced. End-product regulation of carotenogenesis in Phycomyces blakesleeanus is mediated by a complex of p-carotene and the protein products of two genes carA and cars. Substances such as retinol compete with /?-carotene and prevent the formation of this complex thus removing the end-product inhibition.168 Compounds that inhibit oxidative phosphorylation and gly- colysis stimulate carotenoid synthesis in Rhodotoruia glutinis.169 The metabolism and physiology of the plant growth regulator abscisic acid (36) have been reviewed.”O The controversy continues about whether this substance is formed via caro- tenoids or biosynthesized independently. Several studies in which labelling with l80has been used have given results that NATURAL PRODUCT REPORTS 1991 HOHzC &co2H/ HOW C H O HOe C O 2 H 0 (78) (79) (80) OH a b 0 OH e f HO&*** 0 i I (83)R' =a R2=b (87)R' (84)R' =b R2 =c (88)R' (85)R' =d R2=c (89)R' (86)R' =e R2=f (90)R' are consistent with the formation of abscisic acid and the related xanthoxin (78) from existing xanthophylls (e.g.vio-laxanthin) in leaves of Xanthium str~marium,~~~ 'wilty ' tomato and water-stressed bean 1ea~es.l~~ The conversion of xanthoxin into abscisic acid by cell-free preparations from bean leaves has been achieved174 and the biosynthesis of abscisic acid in a cell-free system from embryos of Hordeum vulgare has been dem0n~trated.l'~ The latter work provides the first demonstration of the biosynthesis of abscisic acid by a cell- free system derived from a non-vegetative higher plant tissue. The conversion of the hydroxymethyl abscisic acid derivative (79) into phaseic acid (41 X = H) in vivo has been achieved.176 In the fungus Cercospora abscisic acid is certainly formed directly as a sesquiterpene and not via carotenoids.The conformation of an intermediate (+)-(7E,9Z)-trans-3,6-di-hydroxy-y-ionylideneacetic acid (80) that was isolated from C. h k I = e R2 =g (91)R' = R2 =i = f R2 = 9 (92)R' =/ R2= C02H = R2 = f (93)R' =k R2=I = R2 =h cruenta has been determined and the incorporation of this compound into abscisic acid in tomato plants demonstrated. 177 The conversion of abscisic acid-3,6-diol (40) into abscisic acid has been shown to be a major biosynthetic route in C. pini-denszjlorae.17* Incorporation studies with labelled precursors have shown that the iridals and cycloiridals e.g. compound (8 l) which are biosynthetic precursors of the irones e.g. y-irone (82) in Iris pallida dalmatica are formed from squalene.The C-2 methyl substi tuent is derived from S-adenosylmethionine. 2.4.2 Metabolism Animals cannot biosynthesize carotenoids but are capable of many interesting structural modifications to carotenoids that are obtained from the diet. The atlantic salmon (Salmo salar) NATURAL PRODUCT REPORTS 1991-G. BRITTON COF CH~OAC XY & (98) X = Y = H (99) X,Y = 0 (100) X =OH Y = H can reduce dietary racemic astaxanthin to idoxanthin (3,3’,4’- trihydroxy-P,P-caroten-4-0ne) (83).180 The reduction of the 4’-0x0 group occurred stereospecifically to give the 4’R product irrespective of the absolute configuration at C-3’. Analysis of the carotenoids in the salmon skin suggested the operation of reductive metabolic pathways for astaxanthin via idoxanthin and adonixanthin (3,3’-dihydroxy-P,P-caroten-4-one), (84) to zeaxanthin (46) and thence to its 5,6-epoxide antheraxanthin (5,6-epoxy- 5,6-di hydro-P,P-caro tene- 3,3’-diol) (8 5); and for canthaxanthin to 4’-hydroxyechinenone (4’-hydroxy-&P-caroten-4-one) (86) echinenone (J,P-caroten-4-one) (87) isocryptoxanthin (J,p-caroten-4-01) (88) and P-carotene.181 In chickens also the reductive metabolism of canthaxanthin to 4’-hydroxyechinenone and isozeaxanthin (P,P-carotene-4,4’-diol) (89) has been reported.182 A different reductive pathway in which 0x0-groups at C-3 and C-3’ are reduced to give the e,e-carotene-3,3’-diol tunaxanthin (90) has been proposed to occur in the big-eye tuna fish Thunnus obesus.22 In another fish Tilapia nilotica metabolic processes for the inversion of chirality at C-3 or C-6 were recognized.lS3 In the liver of Tilapia p-carotene and canthaxanthin were shown to be precursors of vitamin A (retinol) whereas astaxanthin zeaxanthin lutein and tuna- xanthin gave vitamin A (3,4-didehydroretinol) (94).Views on the mechanism of the conversion of p-carotene into vitamin A have been and the accepted central cleavage of p-carotene to retinal in mammals has been questioned after an extensive series of experiments with rat intestinal mucosa failed to demonstrate any such enzyme a~tivity.’~~ The various apocarotenals that were detected are considered to be non-enzymic products. In contrast to this cytosol preparations from various rat tissues especially intestine testis lung and kidney converted p-carotene into retinoic acid in a process that appeared to be independent of the formation of retinal.186 The enzymic oxidation of retinal to retinoic acid by soluble fractions from rat tissues and in the livers of diseased rats has however been demonstrated.187,188 The synthesis and metabolism of vitamin A derivatives including retinoyl fluoride (95) and 4,4-difluororetinyl acetate (96) have been reviewed.lS9 The metabolism of [1l-3H,]-trans-retinyl-P-glucuronide into retinol and 5,6-epoxyretinol (97) has been demonstrated. lgo CH20H (101) X= H (102) X=OH The retinoid isomerase system of the eye has been charac- terized biochemically. Isomerization occurs at the retinol level.lgl The isomerization of all-trans to cis-retinoids is accompanied by stereochemical inversion at C- 15.lg2 The enzyme retinol isomerase will isomerize both retinol and 3,4-didehydroretinol but the conjugated polyene chain must be present; a series of dihydroretinols in which a chain double bond was saturated underwent no isomerization.lg3 The enzyme activity for the formation of 1 1-cis retinoids and retinyl esters is located exclusively in the pigment epithelium mem- branes. lg4 Pig liver homogenates showed different relative activities for hydrolysis of the all-trans 9-cis 13-cis and 9,13-dicis isomers of retinyl ~a1mitate.l~~ It was concluded from this that at least three distinct retinyl ester hydrolases were present. Factors that influence the level and interanimal variability of retinyl ester hydrolase activity in rat liver have been assessedlg6 and it has been shown that light and temperature can affect the activity.lg7 The microbial transformations of a-ionone (98) and p-ionone (101) have been studied as models for the metabolism of retinoids.lg8 Aspergillus niger produced oxidized metabolites whereas Cunninghamella blakesleeanus gave both oxidized and reduced products.The main products were ring-substituted compounds especially 4-hydroxy-P-ionone (102) and 3-0x0- and 3-hydroxy-a-ionone (99) and (100). 2.5 Analytical Methods 2.5.1 Separation and Assay Procedures that are suitable for the analysis of carotenoids in chloroplasts and their pigment-protein complexes have been given in detail.lg9 High-performance liquid chromatography (HPLC) is now the routine method of choice for both qualitative analysis of carotenoid compositions and for the quantitative determination of carotenoid contents.Few comprehensive systematic investigations and evaluations of HPLC methods have been undertaken however and there have also been few attempts to use a mechanistic approach to understanding and improving HPLC separations. Many papers are still being published which describe the application of favoured standard HPLC procedures both normal phase (adsorption) and reversed phase to the qualitative and quantitative analysis of carotenoids200-216 or retinoid~~l~-~~~ in particular tissues or extracts. Some papers are however of more general or fundamental interest.The powerful method for resolving geometrical isomers of p-carotene on specially prepared columns of calcium hydroxide has been re-evaluated and some peaks for dicis (7,9 9,9’ 9,13’ 13,13’) and tricis (9,13,9’) isomers have been reassigned.224The acidic diosphenol carotenoid astacene (3,3’- dihydroxy-2,3,2’,3’-tetradehydro-P,P-carotene-4,4’-dione) (91) and related compounds cause considerable difficulties in HPLC. A reversed-phase procedure has been developed which gave optimal resolution and good peak profiles for astaxanthin and astacene by use of acetonitrile-water containing the lipophilic acid bis-(2-ethylhexyl)-phosphate as the mobile phase.225 Interactions between the injection solvent and the mobile phase have been shown to cause multiple peaks for some carotenoids and this can give a false indication of the presence of cis- isomers.226 The increasing interest in the compositions of mixtures of carotenol esters that occur in many natural extracts is reflected in the publication of several papers that describe procedures for the separation of the ester mixtures on reversed- phase HPLC system~.~~’-~~l A review232 on the chromatography of fat-soluble vitamins in clinical chemistry includes much information on vitamin A and retinoids.Supercritical fluid chromatography (SFC) with cyano-propylpolysiloxanes and polyethylene glycols as stationary phases and mobile phases based on supercritical liquid CO has been applied to carotenoids and used for SFC-MS analysis.233 The extraction of carotene and lutein from leaf protein concentrates with supercritical CO has been shown to be efficient.234 The large-scale purification of the apocarotenoids NATURAL PRODUCT REPORTS 1991 (103) 2.5.4 Raman and Infra-red Spectroscopy Resonance Raman spectroscopy is extremely valuable for investigating the geometry and electronic configuration of the carotenoid and retinal chromophores in carotenoid-protein and retinal-protein complexes.The use of the technique in the carotenoprotein field has been reviewed7a and examples of its application to studies of carotenoproteins and retinal-proteins have been given earlier (sections 2.3.3 and 2.3.4). Raman and infrared spectra of the all-E 72 92 132 and 152 isomers of /?-carotene have been Key bands that allow linear stretched or peripherally-bent configurations to be distinguished from centrally-bent configurations have been identified.In particular bands at 1160 and 1140 cm-l (Raman) and at 827 and 775cm-’ (IR) can be used to distinguish linear or peripherally-bent forms from the centrally- bent 132 and 152 isomers. Bands at 1274 and 926 cm-’ (Raman) and 741 cm-’ (IR) are characteristic of the 72 isomer and bands at 1247 cm-’ (Raman) and 775 cm-‘ (IR) charac-teristic of the 152 form. Time-resolved resonance Raman spectroscopy of triplet states derived from the same series of /?-carotene isomers showed that the all-E and 152 isomers gave identical spectra and they and the 132 isomer all relaxed to the all-E form.The 72 and 92isomers gave different triplet e.g. cochloxanthin (6-hydroxy-3-oxo-8’-apo-e-caroten-8’-oicstate spectra and each relaxed without change in the con-acid (92) from Cochlospermum tinctorum by counter-current chromatography has been Solvents containing tertiary alcohols (especially t-butanol and t-pentanol) in mixtures with light petroleum were found to give better thin-layer chromatographic (TLC) resolution of xanthophylls than the more usual acetone-petroleum mix-tures.236 The mechanism of adsorption of some carotenoids namely p-carotene canthaxanthin and S’-apo-P-caroten-8’-0ic acid ethyl ester (52) at the silica-solvent interface during TLC on high-efficiency silica gel has been Free energies of adsorption were calculated and related to interactions between the adsorbed carotenoid film and the surface-reactive groups on the silica.An improved method has been described for the extraction of abscisic acid from plant A monoclonal antibody to (S)-abscisic acid has been characterized and used in a radio- immuno assay for abscisic acid in crude leaf 2.5.2 Electronic Absorption Spectroscopy Time-resolved absorption spectroscopy on a fs ps or ns time- scale was used in many of the studies of retinal-proteins and transient intermediates that are reported above (section 2.3.4). Picosecond absorption spectroscopy has been used to detect configuration changes in the triplet excited state of cis and trans isomers of p-carotene retinal and retinylideneacetaldehyde (103).2409241The rates of triplet state isomerization were dependent on the starting ground state configuration and were generally highest for ‘centrally-bent ’ isomers with an un-methylated cis-double bond and lowest for the all-trans isomer.The major product of photoisomerization of the cis isomers was the all-trans form. 2.5.3 Fluorescence Spectroscopy Fluorescence spectra of p-carotene in glassy pentane at 77 K and 4.2 K showed well-defined vibronic structure and were assigned to fluorescence from the I ‘Bu’ figuration.244 These studies are highly relevant to investigations of the isomeric forms in which carotenoids exist in functional photosynthetic pigment-protein complexes. Surface-enhanced resonance Raman scattering spectroscopy has been used to study the orientation of spirilloxanthin (45) in the membranes of Rhodospirillum r~brum.~ 2.5.5 NMR Spectroscopy Both ‘H and 13CNMR are now used routinely in the elucidation of carotenoid structures and in the characterization of synthetic intermediates and products.NMR data are given in most of the papers on structure elucidation and synthesis that are reported elsewhere in this article (sections 2.2 and 2.6). The use of NMR to establish the geometrical configuration of the carotenoids in the reaction centre of phototrophic bacteria as 1 5Z40s4’ has produced valuable information about the structure of this functional pigment-protein complex. Several of the papers discussed earlier (sections 2.3.4) describe the use of NMR to investigate details of the structures of the chromophores in the retinal-protein photoreceptors.A specialized NMR study has investigated 13C spin-lattice relaxation in (all-trans)-retinal and effects of the chemical shift anisotr~py.~~~ Relaxation time and nuclear Overhauser en-hancement factors were measured. 2.5.6 Mass Spectrometry Mass spectrometry is also used routinely as part of the elucidation of carotenoid structures. Some new or improved experimental procedures have been described however. An impoved monodisperse aerosol generation interface for HPLC- MS has been devised and its efficiency demonstrated by the analysis of cis-trans isomers of retin01.~~~ Full scan electron impact spectra were obtained after column injections of as little as 50 ng of sample.The potential of SFC-MS for carotenoids has also been explored.233 The extremely mild ionizing conditions that prevail NATURAL PRODUCT REPORTS 1991-G. BRITTON R2 a b a b C (105) R = CHO (108) R=CO (110) R’ = R2 = CHO (113) R’= R2=b (106) R = C:N(CH2)3CH3 (109) R =b (1 11) R’ = R2 = C:N(CH2)3CH3 (114) R’ = c R2 = C02Me (107) R =a (112) R’ = R2 =a \ I OHC%cHo (1 15) (1 16) (1 17) 3K -!$ 0 OH (1 18) (1 19) when supercritical CO is used as mobile phase give superior oxanthin (12) and of trikentriorhodin (13) and related P-quality mass spectra even for fragile and difficult carotenoids diketones. In this work three routes to polyene P-diketones like fucoxanthin (5,6-epoxy-3,3’,5’-trihydroxy-6’,7’-didehydro-have been des~ribed.~’ In the aldol condensation route the 5,6,7,8,5’,6’-hexahydro-P,P-caro ten- 8-one3’-ace ta te) (9 3) com- pared with conventional chemical ionization methods.The fragmentation patterns of the methyl ester of abscisic acid (36) and its E isomer in methane positive and negative chemical ionization MS have been elucidated by isotopic labelling.247 Differences were observed between the two isomers. The pentafluorobenzyl derivatives of abscisic acid and its metabolites gave simple chemical ionization mass spectra that could be used to assay abscisic acid in mixtures of plant growth regulators by selective ion 2.5.7 X-ray Methods X-Ray methods have never been widely used in the carotenoid and retinoid fields.The X-ray crystal structure of (all-trans)- 10- fluoro-a-retinal (1 04) has now been reported. 249 The cyclo- hexene ring is in the half-chair form and its unconjugated double bond in not planar with the polyene chain. 2.6 Synthesis and Chemistry 2.6.1 Carotenoids Full details have been given of the synthetic work that confirmed the structures of mytiloxanthin (1 1) and isomytil- reaction of 15,15’-didehydro-8’-apo-P-caroten-8’-al (105) or of 8,8’-diapocarotene-8,8’-dial(1 10) with butylamine in the presence of tri-isobutyl borate gave respectively the Schiff bases (106) and (1 1 l) from which the model P-diketones 6’-hydroxy-l5,15’-didehydro-l8’-n0r-3’-apo-~,$-caroten-4’-one (107) and 6,6‘-dihydroxy- 18,18’-dinor-3,3’-diapo-$,$-carotene-4,4’-dione (112) were obtained by reaction with the boric oxide complex of acetylacetone.A long series of reactions was used to prepare the Wittig salt (1 15) from pivalic anhydride. Wittig condensation of compound (1 15) with the C, dialdehyde (116) then gave the P-diketones (117) and (113). A Claisen condensation was achieved by the reaction of 15,15’-didehydro- 8’-apo-P-caroten-8’-oic acid methyl ester (108) with pinacolone (1 18) in the presence of lithamide as base to give the P-diketone (109) in almost quantitative yield. This route was used to prepare the natural product trikentriorhodin (13) via con-densation of methyl 8’-apo-~-caroten-8’-oate(1 14) with the trimethylsilyl derivative of the optically active hydroxy-ketone (119).The carotenoid P-diketones exist almost exclusively in the enolic form are pseudo-acidic and are tenaciously adsorbed on alumina but they are amenable to chromatography on silica. In basic solution the light absorption spectrum shows a shift of 14-18 nm (mono-enolate) or 20-30 nm (bis-enolate) to shorter wavelengths. Sodium borohydride reduces both keto-groups. NATURAL PRODUCT REPORTS. 1991 (1 20) (121) (124) a b c 0 -(129) R’ = R2=a (130) R’ = R2=b (131) R’ = R2=c (132) A similar Claisen condensation was also used to synthesize mytiloxanthin (1 1) as a cis isomer (presumably 9-ci.~).~~ The C, compound (120) was prepared by reaction of the ketone (121) with but-1-yne and was used as a model compound in NMR studies which proved the structure and relative configuration of isomytiloxanthin (1 2).26 The total synthesis of the poly-cis carotenoid prolycopene (72,92,7’Z,9’Z-+,+-carotene 76) has been reported.250 The procedure is based on elaboration of the 2Z,6E-carbinol (122) from a Pd-coupling reaction between the vinyl bromide (123) and the Zenynol(124) followed by a series of Wittig reactions and partial catalytic hydrogenation of the bis-acetylenic product (1 25). The epoxides (126) and (127) prepared by Sharpless-Katsuki oxidation of compound (128) in excellent yield and very high enantiomeric purity were used as synthons in the preparation251 of (3S,SR,SS,3’S,S’R,6’S) and (~R,~R,~S,~’R,~’R,~’S)-V~OI~-xanthins (6) and (129) as their all-E 9Z 132 and 152 isomers and also of the related apocarotenoids (+)-(8-didehydro-vomifoliol (1 32) the (+)-(6S,7E,9E) and (+)-(6S,7E,9Z)-isomers of abscisic acid ester (36) and the (-)-(3S,7E,9E) and (-)-(3R,7E,9E)-isomers of xanthoxin (78).The novel car- 237 NATURAL PRODUCT REPORTS 1991-G. BRITTON OH AcO6 AcO&” a b (134) R =a (135) R =b PPPh3 Ho R (136) R = H or OH (137) n=Oor 1 (139) otenoid violadione [(5R,6S,5’R,6’S)-5,6,5’,6’-diepoxy-5,6,5’,6’-tetrahydro-P,P-carotene-3,3’-dione] (1 30) was obtained from (all-E)-violaxanthin (6) by oxidation with DMSO/Ac,O and then converted by treatment with base into violadienedione [(6S,6’S)-6,6’-di hydroxy-e,s-car0 tene- 3,3’-dione] (1 3 1) which is a potential precursor of carotenoids with phenolic end-groups.The synthon (133) was also used to prepare a range of enantiomerically pure C20-,CZ5-,C27-,and Ca0-apoviola-xanthinoic acids apoviolaxanthinals and apoviolaxanthinols including persicaxanthin (28) and sinensiaxanthin (23).252 The ylidenebutenolide structure that is found in carotenoids such as peridinin (5’,6’-epoxy-3,5,3’-trihydroxy-6,7-didehydro-5,6,5’,6’-tetrahydro-lO,ll,20-trinor-~,~-caroten-l9’, 1 1’-olide 3-acetate) (134) presents a difficult challenge to the synthetic R (138) R = H or OH n = Oor 1 chemist. A method that involves a Wittig reaction between the appropriate conjugated phosphanylidenebutenolides (1 36) and the C, or C, aldehyde (1 37) provided an efficient route to the model compounds (138).253 Syntheses of the acetylenic and allenic C,,-apocarotenals (139) and (140) that are related to peridinin and pyrrhoxanthin (5’,6’-epoxy-3,3’-dihydroxy-7,8-didehydro-5’,6’-dihydro-1 1’- 10,11,20-trinor-~,~-caroten-19’ olide 3-acetate) (135) were achieved by a C15+C7 p-Hydroxysulphones can be prepared by the oxidative desulphonylation of primary sulphonyl anions with a molybdenum peroxide reagent.This route has been used to synthesize (1 5Z)-phyt0ene.~,~ In chlorinated solvents canthaxanthin and 8’-apo-P-caroten- 8’-a1 (141) underwent a one-electron electrochemical oxidation NATURAL PRODUCT REPORTS 1991 C02R (142) R = gentibiose (145) ( 148) (1 50) &y7-iCH0 )“0 (151) \\\\ to radical cations that were detected by EPR spectroscopy.p-Carotene formed a similar radical cation but apparently by a two-step process.25s Carotenoid radical cations were also produced by the interaction of these carotenoids with iodine.257 The quenching of singlet oxygen lo2 and other antioxidant mechanisms are important to the protective functioning of carotenoids in biological systems. In a chemical study it has been shown that both energy-transfer and electron-transfer mechanisms are involved in the quenching of lo by crocin (digentiobiosyl 8,8’-diapocarotene-8,8’-dioate)(142) and re-lated The efficiency of quenching of lo2by /?-carotene and canthaxanthin has been studied by means of steady-state luminescence experiments. The efficiency of quench- ing by /?-carotene was slightly lower than that by cantha- xanthin in non-polar solvents and was an order of magnitude lower in CD,OD due to the molecular aggregati~n.~~’ Variable wavelength time-resolved infrared luminescence methods have been used in the identification of both pre-equilibrium and diffusion limits for the reaction of lo with physical and chemical quenchers including /?-carotene.260 Polyphenyl-sulphides and aminophenol sulphides have been shown to be effective inhibitors of the oxidation of 2.6.2 Retinoids Many papers report methods for the synthesis of natural retinoids and analogues.A new prenylation reagent LiCH CMeCH :CHOSiMe, prepared by bromine-lithium exchange using ButLi in ether at -70 “C undergoes condensation with carbonyl compounds to give polyenals in good yields.This procedure was used to synthesize retinal from p-ionylidene- acetaldehyde (137 n = 1).262 Similar procedures with the reagent LiCH :CHCH :CMeCH :CHOSiMe were used to prepare retinal and +-retinal (143) from p-ionone (101) and +-ionone (144) respectively.263 The important intermediate (145) en route to retinyl acetate has been prepared by a direct route from the C, aldehyde (146) and the organolithium reagent (147).264 Condensation of the phosphonate (148) with the 7-cis,9-cis-C15 aldehyde (149) gave a mixture of geometical isomers of retinonitrile (150) from which the 7,9,1 l-tri-cis and 7,9,11,13-tetra-cis isomers were obtained by preparative HPLC and converted into the cor- responding tri-cis (72,92,112)- and all-cis (72,92,11Z 132)- retinols (151) and (152) by reaction with DiBAL.265These isomers were stable at room temperature.The 92 132 and all-E isomers of a-retinal (153) and 3,4- didehydroretinal (60) have been prepared by a route involving NATURAL PRODUCT REPORTS 1991-G. BRITTON (1 54) (155) X,Y =O (156) X =OH Y = H 7C02Et 02H (159) (161) X=Me Y = H Z = OMe (162) X = OMe Y = H Z = Me (163) X=Z=Me Y=OMe (164) X=CMe3 Y =H Z=Me (165) X=Me Y = H Z=CMe3 (166) CHO )CH20H ( 160) two Horner-Emmons condensations. 266 Geometrical isomers of (+)-2-hydroxyretinal (1 54) and (_+)-3-hydroxyretinal (58) have been synthesized to facilitate the identification of the chromophore of a visual pigment from a fly.s4 The all-E and 132 isomers of 4-oxoretinoic acid (1 55) and 4-hydroxyretinoic acid (156) which are major metabolites of retinoic acid have been synthesized by Wittig reaction with the C, Wittig salt (157).267 Methods for the preparation of tri tetra- and penta-deuterated forms of retinol have been described.26s An improved procedure has been reported for the synthesis of [11-3H,]- retinyl-P-glucuronide.190 The coenzyme A thioesters of (al1-E)-and (1 3Z)-retinoic acid have been prepared via activated succinimido esters or anhydrides.269 N-Acylation of esters of the aminoacids leucine phenylalanine alanine tyrosine and glutamic acid with retinoyl chloride (1 58) gave after alkaline hydrolysis the (all-a-or (13Z)-N-retinoylaminoacids.270 Retinonitrile (150) has been prepared in high yield by the reaction of retinal with ammonium hydroxide catalysed by ammonium molybdate in tetrahydrofuran containing pre-hydr01.~~~ Synthetic methods have been reported for many derivatives and analogues of retinol retinal and retinoic acid including 14-carboxyretinoic acid ethyl ester (1 59),272 16-demethyl- 16 17-didemethyl- 16,18-didemethyI- and 16,17,18-tridemethyl- retinals (64)-(67),67 the 10- or 14-methyl- -ethyl- -fluoro- ,or -chloro-retinds (61) and (62),'0° 5-ethyl-Sdemethylretinal (69),273 the silaretinol (160),2745-methoxy-5-demethylretinal (68),138 the 13-rnethoxy- 13-demethyl- 9-methoxy-9-demethyl- and 1 1-methoxyretinoids (161)-( 163),275 the aromatic ana-logues (71),276 (166),277 and (73);144 and the 19- and 20-t-butylretinols (1 64) and (1 65) and their 9,lO- and 11,12-allenic isomers (167) and (1 68).278 Oxidation of compounds (1 64) and (165) with the Dess-Martin reagent gave the corresponding retinal derivatives in good yield.279 The catalysed isomerization of p-allenic retinals has also been used to prepare 1 l-t- butylretinal (169).280 The aromatic retinoid (166) can exist in three crystalline modifications which give the different photocycloadducts NATURAL PRODUCT REPORTS 1991 (170) OMe (1 73) (170)-( 1 72).281 Related photosensitized [4 +21 cyclodimer- izations gave the cyclohexene products (1 73).282 Electrocyclic reactions of Schiff bases of a series of (13Z)-retinal analogues gave the dihydropyridine derivatives (174 R = Bu or But R1 = H R2 = Me or But; R = Bu or Me R1,R2= (CH2)5).283 Pulse radiolysis of (all-E)-retinol and its methyl ether in non- protic solvents produced transient species that were identified as radical anions.284 The photoisomerization of (all-&)-retinal in organic solvents and organized media e.g.lipid films has been studied and photostationary state isomeric compositions have been determined. 285 The photoisomerization of retinoic acid in approximately physiological aqueous solutions gave seven isomers that were identified by HPLC.286High-field 'H NMR was used to investigate the photoisomerization of retinal iminium salts (175 R = But or Bu R' = H; R' = R = Me).287 Several papers report theoretical calculations and analyses of the structures or geometrical isomerization of retinal retinol (175) and retinoic acid via anion radical intermediates and of retinal Schiff bases.288-293 2.6.3 Carotenoid- like Compounds Many new synthetic routes have been developed for ionones irones damascones and other compounds that are related structurally to the ring system of carotenoids. @-Ionone (101) has been prepared from the trimethylcyclohexenone (176) by way of enol sulphonation and the palladium-catalysed con- densation of the intermediate (177) with methylvinyl ketone.294 Conditions have been described for the formation of @-ionone (144) by the aldol condensation of citral (178) with acetone on basic alumina.295 Methyl y-dithiocyclogeranate (179) was obtained from the bromide (180) by a reaction that involved [2,3]-sigmatropic rearrangement.296 The key step in a stereo- selective synthesis of (+)-cis-y-irone (82) was the thermal NATURAL PRODUCT REPORTS 1991-G. BRITTON 24 1 K ErC02Me OzMe (181) (187) (189) (191) (192) ( 193) cyclization of the P-(alkeny1oxy)acrylate intermediate (1 81) to give the oxabicyclo-compound (1 82).297 The damascones which are isomeric with the ionones and the damascenones are important perfume constituents and many methods for their synthesis have been published ;a review of their synthesis has appeared.298 New methods for the preparation of racemic and optically active u-,y- and $-damascones (1 83)-( 185) have been described. 299-303 (f)-(7E,9Z)-trans-3,6-Dihydroxy-y-ionylideneacetic acid (180),304an intermediate in the biosynthesis of abscisic acid (36) in fungi and (f)-phaseic acid [as its methyl ester (41 X = Me)],305 a metabolite of abscisic acid in plants have been synthesized the latter from (-)-P-pinene.The stability of the cis-and trans-3,6-diols (40) of abscisic acid has been assessed. In acid conditions the diols were interconverted and oxidized to abscisic acid. The mechanism of the interconversion was The photochemical reactions of 4-hydroxy- 7,8-dihydro-P-ionone (186) have been studied. 307 Electrophilic cyclization induced by tin triflate has been used to synthesize (-t)-trans-tetrahydroactinidiolide(187).308Cyc-lization of the 2-substituted geranylacetic acid ester (1 88) gave the substituted spirolactones (189) and (190).309 The synthesis of the theaspirane analogues (191 192; R1,R2= combinations of H Me Et Pr Pr') has been described.310 Several other compounds that are structurally related to carotenoids but are unlikely to be derived from them biosynthetically have been synthesized including manoalide (193) and the related compounds secomanoalide (194) and neomanoalide (1 95),311-313 the y-hydroxybutenolide (1 96) from ambliol A (197),314and (&)-cavernosine (198).315 Two reviews have been published that deal mainly with the synthesis of strigol (199).3169317 3 Polyisoprenoids and lsoprenoid Quinones 3.1 Polyisoprenoids 3.I.I Occurrence and Properties Some relatively small (less than 100 kDa) and hitherto uncharacterized 1,4-polyisoprene latexes have been obtained from a variety of tropical trees and Recommendations for the nomenclature of prenols and related compounds are included in an IUB-IUPAC news-letter.319 The main biological interest of these substances is as membrane constituents and in the biosynthesis of complex sugar phosphate derivatives.The properties of model lecithin membranes into which were incorporated hexaprenol hepta- prenol or octaprenol (200 n = 6 7 or 8 respectively) have been The conductance and thickness of the membranes were modulated according to the prenol chain length whereas membrane elasticity depended on the con-centration of prenol present. 3.1.2 Biosynthesis Stereochemical aspects and stereospecifici ty of the biosynthetic prenyl chain elongation in vivo have been reviewed.321 Detailed studies on one example of prenyl chain formation have been reported.The stereochemistry of hydrogen elimination in the biosynthesis of polyprenyl diphosphates (C4,-C6,) by the prenyl transferase enzyme isolated from leaves of mulberry (Morus bombysis) was determined. The enzyme concerned catalyses the addition of Z isoprene units and the 2-pro-S-hydrogen atom of isopentenyl diphosphate (IDP) was lost in each case in contrast to the result obtained by feeding [4-3H]- labelled mevalonate to the leaves.322 NATURAL PRODUCT REPORTS 1991 Me L ‘ (0-a-8 (202) (E)-3-Methylpent-3-enyl diphosphate was used as an artificial substrate in the reaction with (E,E)-farnesyl diphosphate catalysed by undecaprenyl diphosphate synthase of Bacillus subtilis.The reaction proceeded with the same stereochemistry as that with the natural substrate isopentenyl diphosphate but stopped after one step yielding the chiral (Z,E,E)-(S)-4-methylgeranylgeranyl diphosphate (201) as The cis-prenyl transferase that is used in the biosynthesis of dolichyl phosphate in Saccharomyces cerevisiae has been character- i~ed.~,~ In rat liver synthesis of dolichol (202) de novo occurs via terminal condensation with IDP. This condensation and the saturation of the terminal isoprene residue are strictly con- ~erted.~~~ The a-saturase enzyme is very labile and appears to use as its substrate the free isoprenoid alcohols not their phosphates.The enzymic esterification of dolichol in rat liver has been 3.1.3 Analytical Methods An HPLC procedure for the isolation and quantitative determination of total and individual dolichyl esters has been rep~rted.~,’ Negative-ion fast atom bombardment MS has been used for the direct analysis of isoprenoid diphosphates and related analogues.32s 3.1.4 Syothesis and Chemistry Progress in the chemical synthesis of polyprenols has been reviewed.329 Several procedures have been reported for the synthesis of prenols and dolichols of various chain lengths (up to 20 isoprene residues) by stereoselective chain extensions mainly with the addition of Cl0 C15,or C, nit^.^^^-^^^ One method was based on the aldol condensation,330 but most procedures utilized condensations with halogenated derivatives and elimination of sulphone groups.A series of moraprenyl monophosphate sugars has been prepared in high yields by the phase-transfer-catalysed reaction NATURAL PRODUCT REPORTS 1991-G. BRITTON R (205) 8 (207) of moraprenol (203) with trichloroacetonitrile followed by acylation with the glycosyl phosphate and depr~tection.~~~ The sugars used were the a-and P-anomers of D-glucopyranose D-galactopyranose D-mannopyranose and 2-acetamido-2-deoxy- D-glucopyranose. N,W-Carboxy-bis-azoles have been shown to be effective activating agents for the synthesis of polyprenyl pyrophosphate sugars.337 Thus P1-moraprenyl-P2-a-D-gluco-pyranosyl pyrophosphate was prepared by phosphoryl-ation of moraprenyl phosphoazolidates with Ct-D-glUCO-pyranosyl phosphate.3.1.5 Archaebacterial Ether Lipids A growing interest in the ether lipids of Archaebacteria with their head-to-head C2,-C, isoprenoid components has been noted.338A review article proposes the classification of these lipids into seven groups on the basis of their major structural features.339 Another extensive review discusses details of their structures spectroscopic properties and distribution in the Ar~haebacteria.~,, The stereoselective synthesis of one example a bis-phytanyl tetraether glycerolipid (204) has been re-A method for the quantitative conversion of the diether and tetraether phospholipids into glycerophosphoesters by dealkylation with boron trichloride has been shown to be a useful tool in the structural analysis of the archaebacterial lipids.342 The lipids from a hydrothermal vent methanogen \(,-OH MeOAMe (206) 8 (208) including C,,-C3 isoprenoid hydrocarbons and diphytanyl ether lipids have been analysed by supercritical fluid chr~matography.~~~ Pathways for the biosynthesis of the ether lipids in Halobacterium cutirubrum have been proposed on the basis of pulse labelling experiments which suggested that the first intermediates produced contained ally1 ether-linked isoprenoid side-chains i.e.geranylgeraniol and phytol which were subsequently The biosynthesis of sn-2,3-0-di- phytanylglycerol in Archaebacteria has been shown to involve stereochemical inversion at C-2 of 3.2 Isoprenylated Quinones 3.2.1 Natural Occurrence Quinones bearing long isoprenoid sidechains occur universally in living organisms mainly as components of the electron- transport chains.The distribution and isolation of ubiquinone (205) and especially the regulation of its biosynthesis have been reviewed.346 A tetrahydroubiquinone- 10 isolated from a fungus Chaetomiumfuni~ola,~~~ had its two terminal isoprene residues saturated i.e. it had the structure ubiquinone- 10 [IX,X-H,] (206). Two dihydro-derivatives which are believed to be ubiquinone-10 [IX-H,] and ubiquinone- 10 [X-H,] (207) and (208) were also found. NPR 8 NATURAL PRODUCT REPORTS 1991 R (209) n = 1 M = 8 or 9 (210) n=2 m=7or8 OH (212) n = 7 (213)n = 8 (215) Menaquinones with partially saturated sidechains are now being found frequently.Some further examples that have been identified include the 11-H and 11,111-H derivatives (209) and (210) of menaquinones- 10 and -1 1 from Glycomyces rurgersensi~,~~~ rnenaquinone-9[III,VIII-H4](21 1) from and Actinomadura angiospo~a."~~ These derivatives are usually identified by MS and NMR but the use of MS-MS as a general method to locate the saturated isoprene units in menaquinones has been reported. 350 Heptaprenyl and octaprenylhydroquinones (21 2) and (21 3) have been isolated from the sponge Hippospongia communis. HPLC of these compounds on silica leads to the production of the corresponding quinones as artefacts.351 A hexaprenyl-hydroquinone sulphate (214) that was isolated from another sponge (Dysidea species) is an effective inhibitor of H,K- ATpa~e.~~~ OH (214) 3.2.2 Analytical Methods Many procedures have been reported for the HPLC separation and quantitative analysis of the isoprenylated quinones.Methods have been published for the general qualitative and quantitative analysis of ~biquinones~~~-~~~ and of the vitamins K [menaquinones (21 5) and phylloquinone (216)].356.357 A procedure for the simultaneous determination of phyllo-quinone menaquinone-4 and phylloquinone-2,3-epoxide(2 17) in plasma by HPLC used fluorometric detection.358 More complex separations have been reported notably the resolution of mixtures of menaquinones and demethylmenaquinones of various chain lengths from enterobacteria on a reversed-phase and the determination of phylloquinone and menaquinones-3 to -10 by HPLC with a mobile phase saturated with hydrogen gas and detection by reduction with a platinum oxide catalyst.360 NATURAL PRODUCT REPORTS 1991-G.BRITTON R (218) OH bH (219) 0 R*Me ..'d'r\UrH 2 or 8 (221) R1 = MeO R2 = MeNH (222) R1 = MeNH R2 = Me0 3.2.3 Biosynthesis and Metabolism Procedures that are used in the study of plastoquinone (218) biosynthesis in chloroplast and of ubiquinone biosynthesis in plant mitochondria362 have been described. Enzyme preparations from Mycobacterium phlei Escherichia coli and cell suspension cultures of Galium mollugo converted o-succinyl benzoate into its coenzyme A derivative (219) and thence into the naphthoquinol carboxylic acid (220) and menaquinone or phyll~quinone.~~~ The reduction potentials of ubiquinone-0 -7 -9 and -10 have been determined polarographically.The nature of the isoprenoid sidechain influenced both the half-wave potential and the diffusion current.370 A polarographic investigation of the two N-methylrhodoquinones (221) and (222) showed that the reversible reduction of the two isomers occurred at equal potentials which were 120mV more negative than those for ~biquinone.~?' The involvement of biological quinones in the formation of hydroxyl radicals via the Haber-Weiss reaction has been examined. 372 Vitamin K (phylloquinone) was among the lipid-soluble vitamins whose properties in egg albumin complexes have been investigated.373 4 References 1 G.Britton Nat. Prod. Rep. 1989 6 359. 2 Plant Pigments ed. T. W. Goodwin Academic Press London and New York 1988; (a)T. W. Goodwin and G. Britton p. 61 ;(b)G. Britton p. 133; (c) R. J. Cogdell p. 183; (d)W. Rau p. 231. 3 Chemistry and Biochemistry of Plant Pigments 2nd edition Vol. I and 2 ed. T. W. Goodwin Academic Press London and New York 1976. 4 M. Gill and W. Steglich Prog. Chem. Org. Nat. Prod. 1987,51 I. 5 J. Szabolcs Magy. Kem. Lapja 1987 42 52. 6 Y. Ito New Food Ind. 1987 29 22. 7 Y. Jto New Food Ind. 1988 30,30. 8 P. M. Bramley and A. Mackenzie Curr. Top. Cell. Regul. 1988 29 291. 9 Retinal Proteins Proc. Int. Conf. 1986 (publ. 1987) ed.Yu A. Ovchinnikov VNU Sci. Press Utrecht The Netherlands. 10 L. Jaenicke and F. J. Marner Prog. Chem. Org. Nat. Prod. 1986 50 1. 11 A. Fiksdahl and S. Liaaen-Jensen Phytochemistry 1988,27 1447. 12 R. Lanzetta P. Monaco L. Previtera and A. Simaldone Phyto-chemistry 1988 27 887. 13 P. Monaco M. Della Greca M. Onorato and L. Previtera Phytochemistry 1988 27 2355. 14 L. Bicudo de Almeida M. deV. C. Penteado G. Britton P. Uebelhart M. Acemoglu and C. H. Eugster Helv. Chim. Acta 1988 71 31. 15 E. Marki-Fischer and C. H. Eugster Helv. Chim. Acta 1987 70 1988. 16 E. Marki-Fischer and C. H. Eugster Helv. Chim. Acta 1988 71 24. 17 E. Marki-Fischer P. Uebelhart and C. H. Eugster Helv. Chim. Acta 1987 70 1994. The cluster of men genes that are responsible for the 18 E.Marki-Fischer and C. H. Eugster Helv. Chim. Acta 1988 71 biosynthesis of menaquinone in Bacillus subtilis has been 149 1. cloned and a preliminary genetic analysis has been under- I9 E. Marki-Fischer and C. H. Eugster Helv. Chim. Acta 1988 71 taken.364 The 2,3-epoxidation of phylloquinone occurs only 1689. 20 J. Deli P. Molnar G. Toth J. Szabolcs and L. Radics Phyto-half as efficiently in rat liver mitochondria as in rnicro~omes.~~~ chemistry 1988 27 547. 3.2.4 Synthesis and Chemistry A review on biomimetic syntheses that use reactions of allylic phosphates such as prenyl geranyl neryl and farnesyl diethylphosphates with organometallic compounds includes applications to the stereoselective synthesis of menaquinones and ubiquin~nes.~~~ A general method for the highly regio- and stereo-selective Pdo-catalysed stepwise allylic coupling of bifunctional monomers has been developed as a route to natural polyisoprenoids.367 As an example the total synthesis of ubiquinone-10 and ubiquinone-4 was achieved via the stereoselective coupling of C, monomers that are easily derived from geraniol and contain one or two reactive functional end- groups one of which is a latent allylic electrophile that is activated by the PdO catalyst the other a latent nucleophile that is activated by an appropriate base. Five-step and seven-step methods have been described for the chain elongation of ubiquinone-9 to ubiquinone-The key step was a Wittig reaction but the overall yield was only about 2 %.The same C homologation was achieved more efficiently by alkylation of the appropriate chloride with the C reagent RCH,CH :CMe (where R = PhS PhSO, or thiazo- linylthio) followed by an elimination reaction with NaOEt.369 21 P. Molnar J. Szabolcs and L. Radics Magy. Kem. Foly. 1987 93 122. 22 Y. Ikuno and T. Matsuno Bull. Jpn. SOC. Sci. Fish. 1987 53 1893. 23 Y. Tanaka and T. Inoue Bull. Jpn. Soc. Sci. Fish. 1988 54 155. 24 T. Maoka and T. Matsuno Bull. Jpn. Soc. Sci. Fish. 1988 54 1443. 25 A. K. Chopra A. Khare G. P. Moss and B. C. L. Weedon J. Chem. SOC. Perkin Trans. I 1988 1383. 26 A. Khare G. P. Moss and B. C. L. Weedon J. Chem. SOC. Perkin Trans. I 1988 1389. 27 A. K. Chopra G. P. Moss and B. C. L. Weedon J. Chem. Soc.Perkin Trans. I 1988 1371. 28 S. Hertzberg V. Partali and S. Liaaen-Jensen Acta Chem. Scand. Ser. B. 1988. 42. 495. 29 T. Matsuno 'and T. Maoka Bull. Jpn. Soc. Sci. Fish. 1988 54 1437. 30 M. David P. Metzger and E. Casadevall Phytochemistry 1988 27 2863. 31 Z. Huang C. D. Poulter F. R. Wolf T. C. Somers and J. D. White J. Am. Chem. Soc. 1988 110 3959. 32 Z. Huang and C. D. Poulter J. Org. Chem. 1988 53,4089. 33 P. T. Northcote and R. J. Andersen J. Nat. Prod. 1987,50 1174. 34 H. Lehmann and L. Schwenen Phytochemistry 1988 27 677. 35 N. J. Carrington G. Vaughan and B. V. Milborrow Phyto-chemistry 1988 27 673. 36 G. T. Vaughan and B. V. Milborrow Phytochemistry 1988 27 2441. 37 T. Sassa H. Mitobe and E. Haruki Agric. Biol. Chem.1988 52 1625. 38 R. J. Cogdell and H. A. Frank Biochim. Biophys. Acta 1987,895 63. 39 S. S. Brody D. Simpson and M. Rich 2. Naturforsch. Teil C 1988 43 577. 40 Y. Koyama M. Kanaji and T. Shimamura Photochem. Photo- biol. 1988 48 107. 41 M. Lutz W. Szponarski G. Berger B. Robert and J. M. Neumann Biochim. Biophys. Acta 1987 894 423. 42 R. Picorel R. E. Holt T. M. Cotton and M. Seibert J. Biol. Chem. 1988 263 4374. 43 B. Robert and H. A. Frank Biochim. Biophys. Acra 1988 934 401. 44 T. Gillbro R. J. Cogdell and V. Sundstrom FEBS Lett. 1988 235 169. 45 D. Gust T. A. Moore A. L. Moore D. Barrett L. 0.Harding L. R. Makings P. A. Liddell F. C. DeSchryver M. Van der Auweraer R. V. Bensasson and M. Rougee J. Am. Chem. SOC. 1988 110 321.46 D. Gust T. A. Moore A. L. Moore L. R. Makings G. R. Seely X. Ma T. T. Trier and F. Gao J. Am. Chem. SOC. 1988 110 7507. 47 T. Lazrak A. Milon G. Wolff A. M. Albrecht M. Miche G. Ourisson and Y. Nakatani Biochim. Biophys. Acta 1987 903 132. 48 T. Lazrak G. Wolff A. M. Albrecht Y. Nakatani G. Ourisson and M. Kates Biochim. Biophys. Acta 1988 939 160. 49 V. K. Chaturvedi and C. K. R. Kurup Curr. Trends Life Sci. 1987 13 145. 50 C. N. N’Soukpoe-Kossi and R. M. Leblanc Can. J. Chem. 1988 66 1459. 51 C. N. N’Soukpoe-Kossi J. Sielewiesiuk R. M. Leblanc R. A. Bone and J. T. Landrum Biochim. Biophys. Acta 1988 940 255. 52 S. Taneva Dokl. Bolg. Akad. Nauk 1988 41 93. 53 M. Tomoaia-Cotisel E. Chifu and J. Zsako Stud. Univ. Babes- Bolyai Chem.1986 31 80. 54 E. Chifu J. Zsako and M. Tomoaia-Cotisel Stud. Univ. Babes- Bolyai Chem. 1986 31 90. 55 M. Tomoaia-Cotisel J. Zsako E. Chifu and P. J. Quinn Stud. Univ. Babes-Bolyai Chem. 1987 32 35. 56 E. Chifu A. Chifu M. Tomoaia-Cotisel and J. Zsako Rev. Roum. Chim. 1987 32 627. 57 M. Tomoaia-Cotisel J. Zsako and E. Chifu Rev. Roum. Chim. 1987 32 663. 58 J. Zsako V. Neagu M. Tomoaia-Cotisel and E. Chifu Rev. Roum. Chim. 1987 32 739. 59 M. Tomoaia-Cotisel J. Zsako E. Chifu and P. J. Quinn Biochem. J. 1987 ,248 877. 60 E. Chifu M. Salajan M. Tomoaia-Cotisel J. Demeter-Vodnar and J. Zsako Stud. Univ. Babes-Bolyai Chem. 1987 32 50. 61 E. Chifu J. Zsako M. Tomoaia-Cotisel M. Salajan J. Demeter-Vodnar and C. Varhelyi Stud. Univ.Babes-Bolyai Chem. 1987 32 90. 62 J. Demeter-Vodnar M. Salajan M. Tomoaia-Cotisel J. Zsako and E. Chifu Stud. Univ. Babes-Bolyai Chem. 1987 32 92. 63 C. Pidgeon and C. A. Hunt Methods Enzymol. 1987 149 99. 64 S. Gurrieri and F. Castelli Thermochim. Acta 1987 122 117. 65 M. Auger C. Salesse and P. Tancrede J. Colloid Interface Sci. 1988 123 I. 66 S. R. Wassall and W. Stillwell Bull. Magn. Reson. 1987 9 85. 67 S. R. Wassall T. M. Phelps M. R. Albrecht C. A. Langsford and W. Stillwell Biochim. Biophys. Acta 1988 939 393. 68 J. Y. Huang A. Lewis and L. Loew Spectrochim. Acta Part A 1988 44,793. 69 J. Huang A. Lewis and T. Rasing J. Phys. Chem. 1988 92 1756. 70 R. Gomez I. Manzano A. M. Garate P. G. Barbon J. M. Macarulla and J. C. G. Milicua Comp.Biochem. Physiol. B 1988 90 53. 71 J. De las Rivas J. C. G. Milicua and R. Gomez Comp. Biochem. Physiol. B 1988 89 65. 72 B. Czeczuga Folia Biol. (Krakow) 1987 35 137. 73 J. W. Kim T. J. Min and T. Y. Lee Taehan Hwahakhoe Chi. 1988 32 377. 74 H. Fujii J. Morooka S. Tochihara Y. Kawaguchi and B. Sakaguchi Nippon Sanshigaku Zasshi 1988 57 94. NATURAL PRODUCT REPORTS 1991 75 M. Diverse-Pierluissi and D. W. Krogmann Biochim. Biophys. Acta 1988 933 372. 76 B. A. Wariso R. A. Meckel S. J. Robinett and A. S. Kester J. Gen. Microbiol. 1988 134 2577. 77 M. Pawlikowski Acta Phys. Pol. A 1988 74 145. 78 J. C. Merlin J. Raman Spectrosc. 1987 18 519. 79 J. C. Merlin J. D. Warburton and G. Britton ‘Proc. XZth Znt. Con$ Raman Spectroscopy’ ed.R. J. H. Clark and D. A. Long Wiley Chichester 1988 p. 647. 80 J. B. C. Findlay D. J. C. Pappin and E. E. Eliopoulos Prog. Retinal Res. 1988 7 63. 81 J. Lugtenburg R. A. Mathies R. G. Griffin and J. Herzfeld Trends Biochem. Sci. 1988 13 388. 82 E. M. Kosower Proc. Natl. Acad. Sci. USA 1988 85 1076. 83 W. Gartner and A. Plangger Z. Naturforsch. Teil C 1988 43 473. 84 M. Ito N. Matsuoka K. Tsukida and T. Seki Chem. Pharm. Bull. 1988 36,78. 85 K. Hasegawa and I. Shimizu Experientia 1988 44,74. 86 S. Matsui M. Seidou I. Uchiyama N. Sekiya K. Hiraki K. Yoshihara and Y. Kito Biochim. Biophys. Acta 1988 966 370. 87 J. L. Spudich and R. A. Bogomolni Ann. Rev. Biophys. Biophys. Chem. 1988 17 193 88 E. S. Schegk and D. Oesterhelt EMBO J.1988 7 2925. 89 J. Otomo A. Tomioka K. Kinosita H. Miyata Y. Takenaka and T. Kouyama Biophys. J. 1988 54 57. 90 M. P. Heyn J. Westerhausen 1. Wallat and F. Seiff Proc. Natl. Acad. Sci. USA 1988 85 2146. 91 Y. Mukohata Y. Sugiyama K. Ihara and M. Yoshida Biochem. Biophys. Res. Commun. 1988 151 1339. 92 H. Stieve Naturwissenschaften 1988 75 288. 93 T. Yoshizawa and S. Yoshida Seitai no Kagaku 1987 38 261. 94 M. Ottolenghi and M. Sheves Springer Proc. Phys. 1987,20 144. 95 B. Barry R. A. Mathies J. A. Pardoen and J. Lugtenburg Biophys. J. 1987 52 603. 96 H. Otani T. Kobayashi M. Tsuda and T. G. Ebrey Springer Proc. Phys. 1987 20 92. 97 H. Ohtani T. Kobayashi M. Tsuda and T. G. Ebrey Biophys. J. 1988 53 17. 98 G. R. Loppnow and R. A. Mathies Biophys.d. 1988 54 35. 99 R. R. Birge C. M. Einterz H. M. Knapp and L. P. Murray Biophys. J. 1988 53 367. 100 H. Kandori S. Matuoka H. Nagai Y. Shichida and T. Yoshizawa Photochem. Photobiol. 1988 48 93. 101 W. J. DeGrip D. Gray J. Gillespie P. H. M. Bovee E. H. M. Van den Berg J. Lugtenburg and K. J. Rothschild Photochem. Photobiol. 1988 48 497. 102 R. Govindjee Z. Dancshazy T. G. Ebrey C. Longstaff and R. R. Rando Photochem. Photobiol. 1988 48 493. 103 Y. Shichida K. Nakamura T. Yoshizawa A. Trehan M. Denny and R. S. H. Liu Biochemistry 1988 27 6495. 104 F. Crescitelli and R. S. H. Liu Proc. Roy. Soc. London 3 1988 233 55. 105 S. J. Hug J. W. Lewis and D. S. Kliger J. Am. Chem. Soc. 1988 110 1998. 106 U. M. Ganter W. Gartner and F.Siebert Biochemistry 1988 27 7480. 107 T. Kobayashi K. Ogasawara S. Koshihara K. Ichimura and R. Hara Springer Proc. Phys. 1987 20 125. 108 R. S. Becker Photochem. Photobiol. 1988 48 369. 109 V. V. Maksimov Sens. Sist. 1988 2 5. 110 A. Cooper S. F. Dixon M. A. Nutley and J. L. Robb J. Am. Chem. Soc. 1987 109 7254. 111 H. S. R. Gilson B. H. Honig A. Croteau G. Zarrilli and K. Nakanishi Biophys. J. 1988 53 261. 112 R. Ghirlando E. Berman T. Baasov and M. Sheves Magn. Reson. Chem. 1987 25 21. 113 H. G. Khorana J. Biol. Chem. 1988 263 7439. 114 M. Stockburger T. Alshuth D. Oesterhelt and W. Gaertner Adv. Spectrosc. 1986 13 483. 115 R. A. Mathies S. 0.Smith G. S. Harbison J. Herzfeld R. G. Griffin and J. Lugtenburg Springer Proc. Phys.1987 20 136. 116 K. J. Rothschild Photochem. Photobiol. 1988 47 883. 117 J. W. Petrich J. Breton and J. L. Martin Springer Proc. Phys. 1987 20 52. 118 T. Ogura A. Maeda M. Nakagawa and T. Kitagawa Springer Proc. Phys. 1987 20 233. 119 H. Otani and T. Kobayashi Reza Kenkyu 1987 15 586. 120 M. F. Grossjean and P. Tavan J. Chem. Phys. 1988 88 4084. 121 G. H. Atkinson Springer Proc. Phys. 1987 20 213. NATURAL PRODUCT REPORTS 1991-G. BRITTON 122 R. A. Mathies C. H. B. Cruz W. T. Pollard and C. V. Shank Science 1988 240 777. 123 W. Zinth Naturwissenschaften 1988 75 173. 124 R. Govindjee Z. Dancshazy T. G. Ebrey C. Longstaff and R. R. Rando Biophys. J. 1988 54 557. 125 R. Diller and M. Stockburger Biochemistry 1988 27 7641. 126 J.Dobler W. Zinth W. Kaiser and D. Oesterhelt Chem. Phys. Lett. 1988 144 215. 127 S. J. Milder and D. S. Kliger Biophys. J. 1988 53 465. 128 P. D. Roepe P. L. Ahl J. Herzfeld J. Lugtenburg and K. J. Rothschild J. Biol. Chem. 1988 263 5110. 129 H. Otani T. Kobayashi and A. Ikegami Springer Proc. Phys. 1987 20 193. 130 R. Diller and M. Stockburger Springer Proc. Phys. 1987,20 164. 131 S. P. A. Fodor W. T. Pollard R. Gebhard E. M. M. Van den Berg J. Lugtenburg and R. A. Mathies Proc. Natl. Acad. Sci. USA 1988 85 2156. 132 Z. Dancshazy R. Govindjee and T. G. Ebrey Proc. Natl. Acad. Sci USA 1988 85 6358. 133 T. Kouyama A. Nasuda-Kouyama A. Ikegami M. K. Mathew and W. Stoeckenius Biochemistry 1988 27 5855. 134 S. P. A. Fodor J. B. Ames R. Gebhard E.M. M. Van den Berg W. Stoeckenius J. Lugtenburg and R. A. Mathies Biochemistry 1988 27 7097. 135 L. A. Drachev A. D. Kaulen V. P. Skulachev and V. V. Zorina FEBS Lett. 1987 226 139. 136 H. S. R. Gilson and B. H. Honig J. Am. Chem. SOC. 1988 110 1943. 137 J. M. L. Courtin L. Verhagen P. L. Biesheuvel J. Lugtenburg R. L. Van der Bend and K. Van Dam Red. Trav. Chim. Pays- Bas; 1987 106 112. 138 E. Kolling D. Oesterhelt H. Hopf and N. Krause Angew. Chem. 1987 99,598. 139 K. Hiraki T. Hamanaka K. Yoshihara and Y. Kito Biochim. Biophys. Acta 1987 891 177. 140 W. Gaertner D. Oesterhelt J. Vogel R. Maurer and S. Schneider Biochemistry 1988 27 3497. 141 A. L. Drachev V. V. Zorina B. I. Mitsner L. V. Khitrina A. A. Khodonov and L. N. Chekulaeva Biokhimiya (Moscow) 1987 52 1559.142 F. Tokunaga M. Takao T. Iwasa and K. Tsujimoto Springer Proc. Phys. 1987 20 154. 143 T. Iwasa M. Takao K. Tsujimoto and F. Tokunaga Biochem-istry 1988 27 2416. 144 A. K. Singh M. Roy S. Sonar and M. Kapil J. Biosci. 1988 13 55. 145 L. Zimanyi and J. K. Lanyi Biophys. J. 1987 52 1007. 146 J. Tittor D. Oesterhelt R. Maurer H. Desel and R. Uhl Biophys. J. 1987 52 999. 147 K. J. Rothschild 0.Bousche M. S. Braiman C. A. Hasselbacher and J. L. Spudich Biochemistry 1988 27 2420. 148 J. K. Lanyi L. Zimanyi K. Nakanishi F. Derguini M. Okabe and B. Honig Biophys. J. 1988 53 185. 149 R. A. Bogomolni and J. L. Spudich Biophys. J. 1987 52 1071. 150 M. Ariki Y. Shichida and T. Yoshizawa FEBS Lett. 1987 225 255.151 H. Ohtani T. Kobayashi and M. Tsuda Biophys. J. 1988 53 493. 152 C. A. Hasselbacher J. L. Spudich and T. G. Dewey Biochem-istry 1988 27 2540. 153 N. Kamo H. Tomioka T. Takahashi and Y. Kobatake Springer Proc. Phys. 1987 20 117. 154 Y. Shichida Y. Imamoto T. Yoshizawa T. Takahashi H. Tomioka N. Kamo and Y. Kobatake FEBS Lett. 1988 236 333. 155 P. A. Scolnik UCLA Symp. Mol. Cell Biol. New Ser. 1987 62 383. 156 R. Lalitha and T. Ramasarma J. Sci. Ind. Res. 1987 46,386. 157 A. Ben-Amotz A. Lers and M. Avron Plant Physiol. 1988 86 1286. 158 S. Ernst and G. Sandmann Arch. Microbiol. 1988 150 590. 159 F. Lutke-Brinkhaus and H. C. Rilling Arch. Biochem. Biophys. 1988 266 607. 160 0.Dogbo A. Laferriere A. D’Harlingue and B. Camara Proc.Natl. Acad. Sci. USA 1988 85 7054. 161 M. Liitzow and P. Beyer Biochim. Biophys. Acta 1988 959 118. 162 J. Avalos A. Mackenzie D. S. Nelki and P. M. Bramley Biochim. Biophys. Acta 1988 966 257. 163 E. Pfundel and R. J. Strasser Photosynth. Res. 1988 15 67. 164 G. Giuliano D. Pollock H. Stapp and P. A. Scolnik Mol. Gen. Genet. 1988 213 78. 165 R. W. Tuveson R. A. Larson and J. Kagan J. Bacterial. 1988 170 4675. 166 E. K. Chernysheva and M. S. Kritskii Dokl. Akad. Nauk SSSR 1988 301 484. 167 M. El-Jack A. Mackenzie and P. M. Bramley Planta 1988,174 59. 168 E. R. Bejarano F. Parra F. J. Murillo and E. Cerda-Olmedo Arch. Microbiol. 1988 150 209. 169 M. V. Zalashko I. F. Koroleva and V. D. Andreevskaya Mikrobiologiya 1988 57 693.170 J. A. D. Zeevaart and R. A. Creelman Ann. Rev. Plant Physiol. Plant Mol. Biol. 1988 39 439. 171 R. A. Creelman D. A. Gage J. T. Stults and J. A. D. Zeevaart Plant Physiol. 1987 85 726. 172 A. D. Parry S. J. Neill and R. Horgan Planta 1988 173 397. 173 Y. Li and D. C. Walton Plant Physiol. 1987 85 910. 174 R. K. Sindhu and D. C. Walton Plant Physiol. 1987 85 916. 175 A. K. Cowan and I. D. Railton J. Plant Physiol. 1987 131 423. 176 B. V. Milborrow N. J. Carrington and G. T. Vaughan Phyto-chemistry 1988 27 757. 177 T. Oritani K. Sasaki and K. Yamashita Agric. Biol. Chem. 1988 52 21 19. 178 M. Okamoto N. Hirai and K. Koshimizu Phytochemistry 1988 27 2099. 179 F.-J. Marner D. Gladtke and L. Jaenicke Helv. Chim. Acta 1988 71 1331.180 K. Schiedt H. Mayer M. Vecchi E. Glinz and T. Storebakken Helv. Chim. Acta 1988 71 881. 181 K. Schiedt M. Vecchi E. Glinz and T. Storebakken Helv. Chim. Acta 1988 71 887. 182 J. K. Tyczkowski B. Yagen and P. B. Hamilton Poult. Sci. 1988 67 787. 183 M. Katsuyama and T. Matsuno Comp. Biochem. Physiol. B 1988 90 131. 184 Nutrition Rev. 1988 46 327. 185 S. Hansen and W. Maret Biochemistry 1988 27 200. 186 J. L. Napoli and K. R. Race J. Biol. Chem. 1988 263 17372. 187 P. V. Bhat L. Poissant P. Falardeau and A. Lacroix Biochem. Cell Biol. 1988 66 735. 188 S. K. Mandal and B. D. Chaudhuri Indian J. Exp. Biol. 1987,25 796. 189 A. B. Barua and J. A. Olson J. Sci. Znd. Res. 1987 46,345. 190 A. B. Barua R. 0. Batres and J. A. Olson Biochem.J. 1988 252 415. 191 P. S. Bernstein W. C. Law and R. R. Rando J. Biol. Chem. 1987 262 16848. 192 W. C. Law and R. R. Rando Biochemistry 1988 27 4147. 193 W. C. Law R. R. Rando. S. Canonica F. Derguini and K. Nakanishi J. Am. Chem. SOC. 1988 110 5915. 194 B. S. Fulton and R. R. Rando Biochemistry 1987 26 7938. 195 D. A. Cooper and J. A. Olson Arch. Biochem. Biophys. 1988 260 705. 196 D. A. Cooper H. C. Furr and J. A. Olson J. Nutr. 1987 117 2066. 197 A. T. C. Tsin and J. P. Chambers Experientia 1988 44,20. 198 D. A. Hartman M. E. Pontones V. F. Kloss R. W. Curley and L. W. Robertson J Nat. Prod. 1988 51 947. 199 H. K. Lichtenthaler Methods Enzymol. 1987 148 350. 200 S. H. Rhodes A. G. Netting and B. V. Milborrow J. Chromatogr.1988 442 412. 201 D. Siefermann-Harms J. Chromatogr. 1988 448,41 1. 202 Y. Kakutani and N. Kiku Kobe Joshi Daigaku Kiyo 1988 21 273. 203 J. Knoetzel T. Braumann and L. H. Grimme J. Photochem. Photobiol. B 1988 1 475. 204 E. Hoque J. Chromatogr. 1988 448,417. 205 R. B. H. Wills H. Nurdin and M. Wootton J. Micronutr. Anal. 1988 4 87. 206 B. Tan J. Food Sci. 1988 53 954. 207 A. C. Palmisano S. E. Cronin and D. J. Des Marais J. Microbiol. Methods 1988 8 209. 208 R. J. Carter D. J. Flett and C. F. Gibbs J. Chromatogr. Sci. 1988 26 121. 209 H. S. Nam S. Y. Cho and J. S. Rhee J. Chromatogr. 1988 448 445. 210 B. Stancher F. Zonta and L. G. Favretto J. Chromatogr. 1988 440 37. 211 W. Luf and E. Brandl Z. Lebensm.-Unters. Forsch.1988 186 327. 212 A. L. Sowell D. L. Huff E. W. Gunter and W. J. Driskell J. Chromatogr. 1988 431 424. 213 D. I. Thurnham E. Smith and P. S. Flora Clin. Chem. 1988,34 377. 214 L. A. Kaplan J. A. Miller and E. A. Stein J. Clin. Lab. Anal. 1987 1 147. 215 G. Cavina B. Gallinella R. Porra P. Pecora and C. Suraci J. Pharm. Biomed. Anal. 1988 6 259. 216 J. Kozub B. V. Milborrow and A. G. Netting Annals Clinic. Biochem. 1988 25 114. 217 G. M. Landers and J. A. Olson J. Chromatogr. 1988 438 383. 218 R. W. Curley D. L. Carson and C. N. Ryzewski Chromatogram 1987 8 7. 219 H. C. Furr and J. A. Olson Anal. Biochem. 1988 171 360. 220 J. C. Craft C. Echoff W. Kuhnz B. Loefberg and H. Nau J. Liq. Chromatogr. 1988 11 2051. 221 R. Wyss and F.Bucheli J. Chromatogr. 1988 424 303. 222 N. R. Al-Mallah H. Bun and A. Durand Anal. Lett. 1988 21 1603. 223 V. P. Chuev V. N. Lyagin and G. P. Chernysh Khim.-Farm. Zh. 1987 21 1512. 224 Y. Koyama M. Hosomi A. Miyata H. Hashimoto S. A. Reames K. Nagayama T. Kato-Jippo and T. Shimamura J. Chromatogr. 1988 439 417. 225 H. J. C. F. Nelis and A. P. De Leenheer J. Chromatogr. 1988 452 535. 226 F. Khachik G. R. Beecher J. T. Vanderslice and G. Furrow Anal. Chem. 1988 60,807. 227 F. Khachik G. R. Beecher and W. R. Lusby J. Agric. Food Chem. 1988 36 938. 228 F. Khachik and G. R. Beecher J. Agric. Food Chem. 1988 36 929. 229 T. Philip and T. S. Chen J. Chromatogr. 1988 435 113. 230 T. Philip T. S. Chen and D. B. Nelson J. Chromatogr. 1988 442 249.231 M. Knee Phytochemistry 1988 27 1005. 232 A. P. De Leenheer H. J. Nelis W. E. Lambert and R. M. Bauwens J. Chromatogr. 1988 429 3. 233 N. M. Frew C. G. Johnson and R. H. Bromond ACS Symp. Ser. 1987 (Pub. 1988) 336 208. 234 F. Favati J. W. King J. P. Friedrich and K. Eskins J. Food Sci. 1988 53 1532. 235 B. Diallo and M. Vanhaelen J. Liq. Chromatogr. 1988 11 227. 236 G. W. Francis and M. Isaksen J. Food Sci. 1988 53 979. 237 S. Gocan L. Olenic M. Tomoaia-Cotisel and E. Chifu Stud. Univ. Babes-Bolyai Chem. 1987 32 83. 238 B. R. Loveys and H. M. van Dijk Aust. J. Plant Physiol. 1988 15 421. 239 S. A. Quarrie P. N. Whitford N. E. J. Appleford T. L. Wang S. K. Cook I. E. Henson and B. R. Loveys Planta 1988 173 330. 240 Y. Koyama Reza Kenkyu 1987 15 983.241 Y. Koyama Y. Hirata and N. Mataga J. Phys. Chem. 1988 92 4649. 242 S. L. Bondarev S. S. Dvornikov and S. M. Bachilo Opt. Spektrosk. 1988 64 448. 243 Y. Koyama I. Takatsuka M. Nakata and M. Tasumi J. Raman Spectrosc. 1988 19 37. 244 H. Hashimoto and Y. Koyama J. Phys. Chem. 1988 92 2101. 245 C. Pattaroni and J. Lauterwein Magn. Reson. Chem. 1987 25 745. 246 P. C. Winkler D. D. Perkins W. K. Williams and R. F. Browner Anal. Chem. 1988 60,489. 247 A. G. Netting B. V. Milborrow G. T. Vaughan and R. 0. Lidgard Biomed. Environ. Mass Spectrom. 1988 15 37. 248 A. G. Netting and B. V. Milborrow Biomed. Environ. Mass Spectrom. 1988 17 281. 249 L. A. Ratnapala and K. Seff Acta Crystallogr. Sect. C 1988 44 1279.250 G. Pattenden and D. C. Robson Tetrahedron Lett. 1987 28 575 1. 251 M. Acemoglu P. Uebelhart M. Rey and C. H. Eugster Helv. Chim. Acta 1988 71 931. 252 P. Uebelhart and C.H. Eugster Helv. Chim. Acta 1988,71 1983. 253 M. Ito Y. Hirata Y. Shibata A. Sato and K. Tsukida J. Nutr. Sci. Vitaminol. 1987 33 313. 254 M. Ito Y. Hirata K. Tsukida N. Tanaka K. Hamada R. Hino and T. Fujiwara Chem. Pharm. Bull. 1988 36 3328. NATURAL PRODUCT REPORTS 1991 255 M. Capet T. Cuvigny C. H. Du Penhoat M. Julia and G. Loomis Tetrahedron Lett. 1987 28 6273. 256 J. L. Grant V. J. Kramer R. Ding and L. D. Kispert J. Am. Chem. SOC. 1988 110 2151. 257 R. Ding J. L. Grant R. M. Metzger and L. D. Kispert J. Phys. Chem. 1988 92 4600. 258 P. Manitto G. Speranza D.Monti and P. Gramatica Tetra-hedron Lett. 1987 28 4221. 259 P. Murasecco-Suardi E. Oliveros A. M. Braun and H.-J. Hansen Helv. Chim. Acta 1988 71 1005. 260 A. A. Gorman I. Hamblett C. Lambert B. Spencer and M. C. Standen J. Am. Chem. SOC. 1988 110 8053. 261 A. M. Kashkai and 0.T. Kasaikina Dokl. Akad. Nauk Az. SSR 1987 43 55. 262 L. Duhamel P. Duhamel and J. P. Lecouve Tetrahedron 1987 43 4339. 263 L. Duhamel P. Duhamel and J. P. Lecouve Tetrahedron 1987 43 4349. 264 T. Onishi M. Shiono S. Suzuki and Y. Fujita Synth. Commun. 1987 17 257. 265 A. Trehan and R. S. H. Liu Tetrahedron Lett. 1988 29 419. 266 M. F. Vaezi C. Y. Robinson K. D. Hope W. J. Brouillette and D. D. Muccio Org. Prep. Proced. Int. 1987 19 187. 267 E. Aig A. Focella D.R. Parrish M. Rosenberger J. W. Scott and G. B. Zenchoff Synth. Commun. 1987 17 419. 268 H. R. Bergen H. C. Furr and J. A. Olson J. Labelled Compd. Radiopharm. 1988 25 11. 269 A. Kutner B. Renstrom H. K. Schnoes and H. F. DeLuca Proc. Natl. Acad. Sci. USA 1986 83 6781. 270 Y. F. Shealy J. L. Frye and L. J. Schiff J. Med. Chem. 1988,31 190. 271 M. Varga A. A. Khodonov B. I. Mitsner and R. P. Evstigneeva Zh. Org. Khim. 1987 23 1123. 272 Y. F. Shealy C. A. Krauth J. M. Riordan and B. P. Sani J. Med. Chem. 1988 31 1124. 273 H. Hopf and N. Krause Liebigs Ann. Chem. 1987 943. 274 R. Munstedt and U. Wannagat J. Organornet. Chem. 1987 322 11. 275 H. Hopf and K. Natsias Liebigs Ann. Chem. 1988 705. 276 A. A. Khodonov B. I. Mitsner E. N.Zvonkova and R. P. Evstigneeva Bioorg. Khim. 1987 13 238. 277 S. M. Makin I. E. Mikerin 0.A. Shavrygina and T. I. Lanina Bioorg. Khim. 1988 14 541. 278 G. Y. Shen A. R. De Lera T. C. Norman A. Haces and W. H. Okamura Tetrahedron Lett. 1987 28 2917. 279 A. R. De Lera and W. H. Okamura Tetrahedron Lett. 1987 28 2921. 280 T. C. Norman A. R. De Lera and W. H. Okamura Tetrahedron Lett. 1988 29 1251. 28 1 K.-H. Pfoertner G. Englert and P. Schoenholzer Tetrahedron 1987 43 1321. 282 K.-H. Pfoertner G. Englert and P. Schoenholzer Tetrahedron 1988 44 1039. 283 W. H. Okamura A. R. De Lera and W. Reischl J. Am. Chem. SOC.,1988 110 4462. 284 K. Bhattacharyya K. Bobrowski S. Rajadurai and P. K. Das Photochem. Photobiol. 1988 47 73. 285 P. Deval and A.K. Singh J. Photochem. Photobiol. A. 1988 42 329. 286 R. W. Curley and J. W. Fowble Photochem. Photobiol. 1988,47 831. 287 R. F. Childs and G. S. Shaw J. Am. Chem. SOC. 1988 110,3013. 288 V. P. Chuev V. I. Zhuravlev V. M. Staroverov and Z. V. Polovinko Khim.-Farm. Zh. 1987 21 621. 289 G. J. M. Dormans G. C. Groenenboom W. C. A. Van Dorst and H. M. Buck J. Am. Chem. SOC. 1988 110 1406. 290 J. Koller M. Hodoscek and D. Hadzi Theochem 1988 45 287. 291 T. Sugimoto E. Ito and H. Suzuki J. Phys. SOC. Jpn. 1988 57 1497. 292 E. Ito H. Kikuchi and H. Suzuki J. Phys. SOC. Jpn. 1988 57 1842. 293 R. A. Poirier A. Yadav and P. R. Surjan THEOCHEM 1988 44 321. 294 T. Breining C. Schmidt and K. Polos Synth. Commun. 1987 17 85. 295 P.A. Vatakencherry and K. N. Pushpakumari Chem. Ind. (London) 1987 163. 296 P. Gosselin Synthesis 1987 267. 297 C. Nussbaumer and G. Frater Helv. Chim. Acta 1987 71 619. NATURAL PRODUCT REPORTS 1991-G. BRITTON 298 U. J. Park and J. H. Kim Hwahak Kwa Kongop Ui Chinbo 1988 28 246. 299 C. Fehr and J. Galindo J. Am. Chem. SOC. 1988 110 6909. 300 C. Fehr and J. Galindo J. Org. Chem. 1988 53 1828. 301 A. Amrollah-Madjdabadi and L. Stella Bull. SOC. Chim. Fr. 1987 350. 302 P. Gosselin Tetrahedron 1988 4 1979. 303 0.A. Gavrilyuk D. V. Korchagina I. Yu. Bagryanskaya Yu. V. Gatilov A. A. Kron and V. A. Barkhash Zh. Org. Khim. 1987 23 2124. 304 H. Yamamoto T. Oritani and K. Yamashita Agric. Biol. Chem. 1988 52 2683. 305 S. Takahashi T.Oritani and K. Yamashita Agric. Biol. Chem. 1988 52 1633. 306 G. T. Vaughan and B. V. Milborrow Phytochemistry 1988 27 339. 307 A. Pascual N. Bischofberger B. Frei and 0.Jeger Helv. Chim. Acta 1988 71 374. 308 N. Gnonlonfoun and H. Zamarlik Tetrahedron Lett. 1987 28 4053. 309 L. A. Yanovskaya R.Kh. Cherkasova V. S. Bogdanov and V. I. Kadentsev Izv. Akad. Nauk SSSR Ser. Khim. 1987 1068. 310 P. Weyerstahl B. Buchmann and H. Marschall-Weyerstahl Liebigs Ann. Chem. 1988 507. 31 1 S. Katsumura S. Fujiwara and S. Isoe Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1987 29 47. 312 L. J. Reynolds B. P. Morgan G. A. Hite E. D. Mihelich and E. A. Dennis J. Am. Chem. SOC. 1988 110 5172. 313 S. Katsumura S. Fujiwara and S. Isoe Tetrahedron Lett.1987 28 1191. 314 M. R. Kernan and D. J. Faulkner J. Org. Chem. 1988 53 2773. 315 C. W. Jefford D. Jaggi G. Bernardinelli and J. Boukouvalas Tetrahedron Lett. 1987 28 4041. 316 0.D. Dailey and A. B. Pepperman ACS Symp. Ser. 1987 355 355. 317 D. W. Brooks E. Kennedy H. S. Bevinakatti A. B. Pepperman and J. M. Bradow ACS Symp. Ser. 1987 355 433. 318 C. A. Nwadinigwe Phytochemistry 1988 27 2135. 3 19 IUB-IUPAC Joint Committee on Biochemical Nomenclature Arch. Biochem. Biophys. 1988 260 851. 320 T. Janas J. Kuczera and T. Chojnacki Stud. Biophys. 1987,121 45. 321 T. Suga T. Yoshioka and S. Ohta Yuki Gosei Kagaku Kyokaishi 1988 46 12. 322 T. Koyama Y. Kokubun and K. Ogura Phytochemistry 1988 27 2005. 323 T. Koyama M. Ito S. Ohnuma and K.Ogura Tetrahedron Lett. 1988 29 3807. 324 W. L. Adair and N. Cafmeyer Arch. Biochem. Biophys. 1987 259 589. 325 J. Ericsson T. Ekstrom T. Chojnacki and G. Dallner Acta Chem. Scand. Sect. B 1988 42 202. 326 0.Tollbom C. Valtersson T. Chojnacki and G. Dallner J. Biol. Chem. 1988 263 1347. 327 J. Ericsson T. Chojnacki and G. Dallner Anal. Biochem. 1987 167 222. 328 V. J. Davisson T. R. Sharp and C. D. Poulter Bioorg. Chem. 1988 16 11I. 329 N. Ya. Grigor’eva V. V. Veselovskii and A. M. Moiseenkov Khim.-Farm. Zh. 1987 21 845. 330 N. Ya. Grigor’eva 0.A. Pinsker V. N. Odinokov G. A. Tol- stikov and A. M. Moiseenkov Izv. Akad. Nauk SSSR Ser. Khim. 1987 1546. 331 S. Inoue 0.Miyamoto and K. Sato Kenkyu Hokoku-Asahi Garasu Kogyo Gijutsu Shoreikai 1986 49 161.332 S. Inoue T. Kaneko Y. Takahashi 0.Miyamoto and K. Sato J. Chem. SOC. Chem. Commun. 1987 1036. 333 L. Jaenicke and H. U. Siegmund Biol. Chem. Hoppe-Seyler 1986 367 787. 334 V. A. Koptenkova V. V. Veselovskii M. A. Novikova and A. M. Moiseenkov Zzv. Akad. Nauk SSSR Ser. Khim. 1987 817. 335 M. A. Novikova A. V. Lozanova V. V. Veselovskii V. A. Dragan and A. M. Moiseenkov Izv. Akad. Nauk SSSR Ser. Khim. 1987 356. 336 S. D. Mal’tsev L. I. Danilov and V. N. Shibaev Bioorg. Khim. 1988 14 69. 337 Z. P. Belousova P. P. Purygin L. L. Danilov and V. N. Shibaev Bioorg. Khim. 1988 14 379. 338 H. Goldfine and T. A. Langworthy Trends Biochem. Sci. 1988 13 217. 339 Y. Koga and M. Nishihara Seikagaku 1988 60 424. 340 M.De Rosa and A. Gambacorta Prog. Lipid Res. 1988,27 153. 341 C. H. Heathcock B. L. Finkelstein E. T. Jarvi P. A. Radel and C. R. Hadley J. Org. Chem. 1988 53 1922. 342 M. Nishihara and Y. Koga J. Lipid Res. 1988 29 384. 343 G. U. Holzer P. J. Kelly and W. J. Jones J. Microbiol. Methods 1988 8 161. 344 N. Moldoveanu and M. Kates Biochim. Biophys. Acta 1988,960 164. 345 K. Kakinuma M. Yamagishi Y. Fujimoto N. Ikekawa and T. Oshima J. Am. Chem. SOC. 1988 110 4861. 346 G. B. Donchenko I. V. Kuzmenko and E. P. Kozulina Wkr. Biokhim. Zh. 1988 60 104. 347 M. Ito Y. Katayama J. Sugiyama and H. Kuraishi Agric. Biol. Chem. 1988 52 1195. 348 M. D. Collins and R. M. Kroppenstedt FEMS Microbiol. Lett. 1987 44,215. 349 M. D. Collins R. M. Kroppenstedt J.Tamaoka K. Komagata and T. Kinoshita Curr. Microbiol. 1988 17 275. 350 J. Tamaoka K. Suzuki H. Nagaki T. Kinoshita and K. Komagata Iyo Masu Kenkyukai Koenshu 1987 12 229. 351 Y. F. Pouchus J. F. Verbist J. F. Biard and K. Boukef J. Nat. Prod. 1988 51 188. 352 N. Fusetani M. Sugano S. Matsunaga K. Hashinioto H. Shikama A. Ohta and H. Nagano Experientia 1987 43 1233. 353 S. Wu and Z. Lu Zhiwu Shenglixue Tongxun 1988 43. 354 T. Okamoto Y. Fukunaga Y. Ida and T. Kishi J. Chromatogr. 1988 430 11. 355 G. Billon-Grand J. Gen. Appl. Microbiol. 1987 33 38 I. 356 H. Hiraike M. Kimura and Y. Itokawa J. Chromatogr. 1988 430 143. 357 H. Isshiki Y. Suzuki A. Yonekubo H. Hasegawa and Y. Yamamoto J. Dairy Sci. 1988 71 627. 358 K. Hirauchi T.Sakano T. Nagaoka and A. Morimoto J. Chromatogr. 1988 430 21. 359 A. Hiraishi J. Appl. Bacteriol. 1988 64,103. 360 M. Shino Analyst 1988 113 393. 361 J. Soll Methods Enzymol. 1987 148 383. 362 F. Lutke-Brinkhaus and H. Kleinig Methods Enzymol. 1987 148,486. 363 R. Kolkmann and E. Leistner 2.Nuturforsch. Teil C 1987 42 1207. 364 P. Miller A. Rabinowitz and H. Taber J. Bacteriof. 1988 170 2735. 365 P. T. Inyangetor and M. Thierry-Palmer Arch. Biochem. Biophys. 1988 262 389. 366 Y. Butsugan M. Kawai and S. Araki Kenkyu Hokoku-Asahi Garasu Kogyo Gijutsu Shoreikai 1986 49 153. 367 D. Eren and E. Keinan J. Am. Chem. SOC. 1988 110 4356. 368 A. M. Moiseenkov A. B. Veselovskii T. M. Filippova E. A. Obolnikova V. M. Zhulin and G. 1. Samokhvalov Izv.Akad. Nauk SSSR Ser. Khim. 1987 2086. 369 A. B. Veselovskii A. M. Moiseenkov T. M. Filippova E. A. Obolnikova and G. I. Samokhvalov Zzv. Akad. Nauk SSSR Ser. Khim. 1988 695. 370 H. A. Wahab S. M. Khalil and M. Shanshal Stud. Biophys. 1987 118 75. 371 E. Yu. Katz A. N. Melkozernov 0.I. Vagabova 0.F. Korsunskii and V. A. Shuvalov Mol. Biol. (Moscow) 1987 21 1186. 372 H. Noh1 and W. Jordan Bioorg. Chem. 1987 15 374. 373 H. Shibata C. Kurosaki and H. Ochiai Agric. Biol. Chem. 1988 52. 605.

ISSN:0265-0568    

DOI:10.1039/NP9910800223

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Recent Progress in the Chemistry of lndole Alkaloids and Mould Metabolites J. E. Saxton School of Chemistry The University Leeds LS2 9JT Reviewing the literature published between July 1989 and June 1990 (Continuing the coverage of the literature in Natural Product Reports 1990 Vol. 7 p. 191) 1 2 2.1 2.2 3 3.1 4 4.1 4.2 4.3 4.4 4.5 4.6 4.7 5 6 6.1 6.2 7 General Simple Alkaloids Non-tryptamines Non-isoprenoid Tryptamines Isoprenoid Tryptamines Ergot Alkaloids Monoterpenoid Alkaloids Alkaloids Containing an Unrearranged Monoterpenoid Unit Cory nan theine-Hetero yo himbine-Y ohim bine Group and Related Oxindoles Sarpagine-Ajmaline-Picraline Group Strychnine Group Ellipticine-Uleine-Apparicine Group Aspidospermine-Vincamine Group Catharanthine-Ibogamine Group Bisindole Alkaloids Biogenetically Related Quinoline Alkaloids Cinchona Group Camptothecin References 1 General Volume 36 in the Manske-Brossi series of monograghs includes reviews of recent work on the alkaloids of Strychnos and Gardneria species,la the canthin-6-one alkaloids,lb and the alkaloids of the Calabar bean;l‘ while volume 37 is entirely devoted to the antitumour bisindole alkaloids from Catharanthus roseus.2 Three of the first four volumes in the series of monographs ‘Studies in Natural Product Chemistry’ are devoted to stereoselective synthesis and contain much material of interest to the indole alkaloids specialist including chapters on the indolocarbazole alkaloids the pentacyclic Strychnos indole alkaloids the zwitterionic indolo[2,3-a]quinolizine alkaloids and an account by Lounasmaa of the work of his own group (mainly the indoloquinolizidine alkaloids) in Volume 1.3a Volume 3 contains a review by Ninomiya and Miyata of the synthesis of yohimbine and related alkaloids by the enamide photocyclization route developed in their own laboratorie~.~~ A similar review but one which also includes their work on the synthesis of the ergoline alkaloids and lysergic acid is available in Japanesc4 Volume 4 includes a survey of recent developments in the synthesis of vindoline and related alkaloid^.^" Other surveys recently published include one on the alkaloids of Rhazya stricta and R.~rientalis,~ and one on the antimicrobial Tabernaemon tuna alkaloids.2 Simple Alkaloids 2.1 Non-tryptamines Continued attention is being devoted to the constituents of the Cruciferae both natural and those formed following in-oculation or infestation. The roots of Algerian Moricandia arvenis (L.) DC contain mainly I-methoxy-3-indolylmethyl ,N-OSO; (1) R =OMe (2) R = H Cyclobrassinin (7) R = SMe (11) R=SOMe Q-~cHo SMe H Brassicanal A (9) R2 (3) R’ = H R2 = OMe R3 = S (4) R’ = R2 = H R3 =S (5) R’ =OMe R2= H R3 =S (6) R’ = OMe R2 = H R3 = 0 H Spirobrassi nin (8) Me Brassicanal B (10) glucosinolate (1) together with its demethoxy analogue (2); the sole compound isolated from the extracts of the leaves appears to be 3-indolylethylene oxide.’ Inoculation of Brassica oleracea L.var. capitata (white cabbage) with Pseudomonas cichorii resulted in the elaboration of 4-methoxybrassinin (3) and the five known phytoalexins (4)--(8);8uthese compounds were not detected in uninoculated samples. Similarly inoculation of Brassica campestris L. ssp. pekinensis (Chinese cabbage) with the same micro-organism resulted in the formation of brassicanals A (9) and B (10) which were aIso synthesized spirobrassinin (8) and indole 3-carbaldehyde. 8b Compounds (3) (9) and (10) completely inhibit the conidial germination of Bipolaris leersiae. The infestation of Brassica napus L. (oilseed rape) by the cabbage stem flea beetle (Psyllodes chrysocephah L.) leads to a massive accumulation of the indoleglucosinolates (I) (2) and the 4-methoxy derivative of (2),9 but a simultaneous reduction in the aliphatic glucosinolate content.The leaves of Brassica juncea L. a species of mustard resistant to blackleg disease caused by the fungus Leptosphaeria maculans (Desm.) Ces. et de Not. have already yielded brassilexin,1° and have now been shown to contain cyclobrassinin (7) and cyclobrassinin sulphoxide (I I) which is 25 1 NATURAL PRODUCT REPORTS 1991 H H (12) R' = Br R2 = H (16) R' = R3 = H R2= Br (13) R' = R2 = Br (17) R' = R2=Br R3 = H Murrayacarine (1 9) (14) R' = SMe R2 = H (18) R' = R3 = H R2 = SMe (15) R' = SMe R2 = Br Q-fCHO Ts 0 li i Ill ...H Qj-+ H Murra pan i ne (20) Reagents i CH,=CMe.CH,Cl Mg THF 0 "C; ii 3 M NaOH H,O EtOH 50 "C; iii 2-methoxy-p-benzoquinone C,H, 125 "C Scheme 1 (22) iv-vii I H Ts S-Paniculidine A (21) Reagents i Pb(OAc), Cu(OAc), py C,H, 75 "C; ii KMnO, SO,; iii CH,N,; iv K,CO, MeOH; v CBr, Ph,P; vi Ph,P 80 "C; vii N-tosylindole 3-aldehyde; viii H,/Pd/C ;ix Na C,,,H Scheme 2 new;ll apparently this sulphoxide could not be prepared by direct oxidation of cyclobrassinin. Syntheses of the parent indole glucosinolate glucobrassicin (2),"" and brassilexin,12* from indole-3-aldehyde have been reported. Indole 3-carbaldehyde and its 6-bromo derivative have been isolated from a coral of the Dendrophyllia genus.l3 Several new bromoindole derivatives have been found in marine organisms.The demosponge Pleroma menouii collected at a depth of 500 m in the Coral Sea off New Caledonia contains ethyl 6-bromoindole 3-carboxylate and 3-hydroxyacetyl-6-bromoindole ;14 while the red alga Laurencia brongniartii of Okinawan origin has been shown to contain ten brornoind01es.l~ The isolation of two of these metabolites itomanindoles A and B was reported earlier in brief;1° the full paper15 records the extraction also of the seven polybrominated indoles (12)-( 18). The tenth constituent is a bisindole derivative. Four of these compounds have previously been isolated from L. brongniartii of Taiwanese origin,16 but the work has not been reported in detail ;the remaining six are new.The thallation-halogenation route has been applied1' to the synthesis of a series of mixed tetrahalogenoindoles e.g. 2,3,4,7-tetrabromoindole 2,3-dichloro-4,7-dibromoindole and 3-chloro-2,4,7-tribromoindole. These and other structures have been proposed,ls but not in all cases unequivocally proved for constituents of the marine alga Rhodophyllis mernbranacea Harvey. The most recent investigations into the constituents of the root bark of Murraya paniculata var. omphalocarpa Hayata have revealed the presence of two new alkaloids murrayacarine (19)19 and murrapanine (20);zO 3-formylindole and 12 known compounds mainly coumarin derivatives were also isolated. l9 The structure of the novel indole-naphthoquinone alkaloid murrapanine was established by X-ray crystal structure determination and confirmed by synthesis as outlined in Scheme 1.,O It was also reported that murrapanine exhibits significant cytotoxicity.The synthesis (Scheme 2) of the S-enantiomer (21) of paniculidine A has been reported in brief2la and in hence natural paniculidine A and paniculidine B the related NATURAL PRODUCT REPORTS 1991-5. E. SAXTON v OH Herbindole A (25) R = Me /t\ OH Herbindole B (26) R = Et Leiocarpol (23) Leioca rpad iol (24) Herbindole C (27) R = CH=CHEt TrO TrO i-iii L= -7 iv L=C"\ C02Et C02Et lv - viii-x vi vii K O T r \CHO C02Et lxi OTr OTr xii (29) (30) xiv vii xv xvi I Et I &4A -zp -@-M esO HO OMes OH cis-Trikentrin B (28) J Zcis-Trikentrin 6 (31) Reagents i Bu"Li THF -78 "C; ii BF,Et,O -78 "C to -20 "C; iii P,CH .CO,Et -20 "C; iv NEt, CHCl, r.t.; v cyclopentadiene 80 "C; vi LiAlH, THF 0 "C; vii PCC CH,Cl,; viii -CH,NH, Et,O 4A mol.sieves; ix NaH DME; x Me,C.COCl; xi CH,O PriNH CuBr dioxan 100 "C; xii PhMe 160 "C; xiii chloranil PhMe 110 "C; xiv CSA MeOH THF; xv OsO, NMO dioxan H,O; xvi NaOH H,O MeOH; xvii Ph,P=CHEt THF 0 "C; xviii NaIO, THF H,O; xix DIBAL PhMe -78 "C; xx MesC1 CH,Cl,; xxi Zn NaI DME 85 "C Scheme 3 NATURAL PRODUCT REPORTS 1991 (+)-cis-TrikentrinA (32a) (+)-trans-Tri kentrin A (33a) OSiMe3 OSiMeB lix R-(+)-Pulegone (36a) &-Me (36b) 0-Me NNM~~ N.NMe2 / Et XI Me SOzPh xii I (-)-cis-Trikentrin A (32b) (-)-trans-Trikentrin A (33b) Reagents i KMnO,; ii MeOH H+;iii NaNH,; iv NaOMe MeOH -18 "C; v MeI -18" to 20 "C; vi 47 % HBr/H,O 120 "C; vii LDA Me,SiCl THF -80 "C;viii hv O,,methylene blue CH,Cl, -63" to -40 "C; ix SnCl, EtOAc -4P,then 0 "C;x PhMe; Et,O -75 OC; xi H,SO, Me,CHOH heat; xii 20% KOH H,O MeOH DME 85 "C Scheme 4 primary alcohol carrying also an N-methoxy group have the be cytotoxic against KB cells and also exhibit fish antifeedant R-configuration.activity. The roots of Brazilian Esenbeckia leiocarpa Engl. (fam. The first synthesis of cis-trikentrin B (28) involves the Rutaceae) have yielded22 a variety of constituents including six application of a new route to polyalkyl indole derivatives which typical alkaloids of the quinoline and furoquinoline groups utilizes the intramolecular Diels-Alder cyclization of a 2,3-five compounds (three lignans one coumarin and one disubstituted allenic dienamide.As applied to the synthesis cinnamate) devoid of nitrogen and nine indole derivatives of (28) this required the preparation24b of the allenic dienamide viz. 5-isopentenylindole which is new and 6-and 7-(29) which afforded the tetracyclic intermediate (30) on isopentenylindoles two 7-isopentenylindole dimers cyclization. Elaboration of (30) by conventional methods then (annonidines A and C) 7-formylindole and 7-hydroxy-gave a mixture of (f)-cis-trikentrin B (28) and its 2-isomer methylindole neither of which has previously been found in (31) from which pure (28) was obtained by chromatography nature and two novel oxidized isopentenylindoles leiocarpol (Scheme 3).It should be noted that pure cis-trikentrin B (28) (23) and leiocarpadiol (24). has not yet been obtained from natural sources but has only Herbindoles A4 (25)-(27) are three close relatives of the been isolated in admixture with iso-trans-trikentrin B. trikentrins which have been found in a Western Australian The absolute configuration of natural (+)-cis-trikentrin A sponge of the Axinella genus.23 AH three herbindoles are said to (32a) and (+)-trans-trikentrin A (33a) has been established by NATURAL PRODUCT REPORTS 1991-5. E. SAXTON S02Ph Me n S02Ph -Me Ii jiii 2 (+)-cis-TrikentrinB (28) I Me S02Ph Me.. (38) (41) lii v vi Me (+)-trans-Trikentrin B (40) Et Me@y S02Ph Me Me- ( +) -37 Me I (~)-iso-trans-TrikentrinB (39) i (+)-cis-TrikentrinA (32a,b) and (+)-trans-TrikentrinA (33a,b) Reagents HOCH,CH,OH TsOH C,H,; ii Et .C(=CH,)OTMS TiCI, CH,CI,; iii 6 YOH,SO, MeCHOHMe heat; iv (42) PhMe Et,O; v RhCl, EtOH heat; vi 20% KOH H,O MeOH DME; vii (43) PhMe Et,O; viii (CO,H), DME H,O Scheme5 the total synthesis of their enantiomers (-)-cis-trikentrin A this route starting from 2,4-dimethylcyclopentanone.The (32b) and (-)-trans-trikentrin A (33b) from R-3-methyladipic conversion of the intermediates (36) into the indole derivatives acid (34) obtained by oxidation of R-(+)-pulegone (Scheme (37) could also be achieved but rather less efficiently via the 4).25a The synthesis proceeded without stereo- or regio-chemical ketones (38) (Scheme 5).256 control as far as the mixture of dimethyl-2-pyrrolyl-Appropriate modification of this synthesis also led to cyclopentanones when the unwanted regioisomers (35) were syntheses of (& )-iso-trans-trikentrin B (39) (f.)-cis-trikentrin separated.Further manipulation of the mixture of the desired B (28) and (+-)-trans-trikentrin B (40).256 Since derivatives of 3,5-dimethyl-2-pyrrolylcyclopentanones (36a) and (36b) finally conjugated carbonyl compounds could not be used directly in gave (-)-cis-trikentrin A (32b) and (-)-trans-trikentrin A this synthesis the unconjugated isomer (41) of iso-tvans-(33b) which were separated and identified as the enantiomers trikentrin B was prepared by condensation of the epimeric of the natural trikentrins A (32a) and (33a).Racemic cis-mixture (36a b) with the lithium derivative of hex-5-en-2-one trikentrin A and trans-trikentrin A were also synthesized by dimethylhydrazone (42) followed by cyclization/elimination NATURAL PRODUCT REPORTS 1991 H (45) R’ =OH R2 = H (46) R’ = R2= H (47) R’ = H R2,R2 = 0 29 281 25 25 A Tubingensin A (48) Nominine (49) Tubingensin B (50) Glycomaurin (51) Murrayazolinol (53) R = OH Murrayazoline (54) R = H with acid. (f)-iso-trans-Trikentrin B (39) was then obtained by isomerization of the double bond by means of rhodium trichloride followed by removal of the benzenesulphonyl protecting group. A very similar sequence of reactions using the lithium derivative of hex-5-enal N-cyclohexylimine (43) gave the epimers (44) which were converted into (+)-cis- trfkentrin B (28) and (+)-trans-trikentrin B (40) by isomerization of the double bond and deprotection of the indole nitrogen (Scheme 5).Three new aflavinines and two structurally-related carbazole derivatives have recently been isolated from sclerotia of the fungus Aspergillus tubingensis (Schober) Mosseray (NRRL 4700).26927 The first of these 14-epi- 14-hydroxy- 10,23-dihydro- 24,25-dehydroaflavinine (43 is the 14-epimer of a known aflavinine the second is the related 14-deoxy compound (46) and the third is the related ketone (47). Only the last of these the ketone (47) exhibited antifeeding activity against the crop pest Heliothis zea and the fungivorous beetle Carpophilus hemipterus L.26 The first of the two carbazole derivatives tubingensine A Glycomaurrol (52) (48) contains the 9H-octahydronaphtho[3,4-b]carbazole ring system which has not previously been found in a natural Its structure bears an obvious resemblance to that of nominine (49) recently isolated’O from Aspergillus nomius from which the structure of tubingensine A may be derived by attachment of C-27 to C-2.In fact nominine was detected as a component of A. tubingensis by HPLC Tubingensine A exhibits moderate activity against Heliothis zea and also against the Herpes simplex virus type 1 in an in vitro assay. Its isomer tubingensin B (50),27b also contains a ring system not previously encountered in a natural product.It is clearly derived from the same biosynthetic precursor as the aflavinines and nominine but by a much more complex process; presumably involving (e.g. from nominine) attachment of C-27 to C-2 and C-23 to C-12 with migration of C- 13 from C- 12 to C-23. Tubingensin B exhibits activity against Heliothis zea and the Herpes simplex virus but is much more cytotoxic than tubingensine A to HeLa cells.27b Among the simpler carbazole derivatives murrayanine (1-methoxycarbazole 3-carbaldehyde) has been isolated from the roots of Clausena indica Oliv.28 and two new alkaloids glycomaurin (51) and glycomaurrol(52) from the stem bark of Sri Lankan Glycosmis mauritiana (Lam.) Tanaka.29 In ac-cordance with these structures glycomaurin was synthesized from 3-hydroxy-6-methylcarbazole and 3-chloro-3-methylbutyne.Acid-catalysed cyclization of glycomaurrol afforded dihydroglycomaurin. Murrayazolinol (53) a new minor alkaloid from the root bark of Murray koenigii Spreng. has been shown to be a hydroxy derivative of murrayazoline (54).30 NATURAL PRODUCT REPORTS 1991-5. E. SAXTON Me Koenoline (56) Murrayanine (55) Reagents MeCN 25 "C; ii very active MnO, PhMe 25 "C; iii KBH, MeOH Scheme 6 OMe NH2 (60) R = H / (62)R=Me (59) R = H Reagents i MeCN r.t.; ii MnO, CH,Cl,; iii Me,NO MeCOMe; iv NaH Me,SO Et,O; v Ac,O py DMAP CH,Cl,; vi very active MnO, PhMe; vii 10% NaOH H,O heat Scheme 7 H (64) Paxilline R = H (65) 1'-0-Acetylpaxilline R = Ac Murrayanine (55)and koenoline (56) have been synthesized31 by an iron-mediated approach in which the first stage involves electrophilic substitution into 2-methoxy-p-anisidine by means of (~5-cyclohexadienyl)tricarbonyliron tetrafluoroborate.Cyclization of the product (57) by very active manganese dioxide was accompanied by oxidation of the aromatic methyl group to give murrayanine (55) directly; reduction then gave koenoline (56) (Scheme 6). Mukonine (3-methoxycarbonyl- 1-methoxycarbazole) was aIso synthesized by an analogous route from methyl 3-metho~y-4-aminobenzoate.~~ A similar route was used earlier'O in the first synthesis of carbazomycin A (58) and has been applied to a new synthesis of carbazomycin B [(59) +(60) +(61)] (Scheme 7). A simple modification of this synthesis has also led to an improved route to carbazomycin A (58).Here selective oxidation-cyclization of the iron tricarbonyl complex (62) by commercial manganese dioxide gave the iminoquinone de-rivative (63) which on demetallation by means of trimethylamine N-oxide followed by methylation gave carbazomycin (58) in 35 % overall yield from thecyclohexadienyl tricarbonyl iron cation.32 Details of Moody's synthesis of carbazomycins A and B and hyellazole have been published.33 The distribution of paxilline (64) in 19 Emericella species has been investigated but found to occur in only three viz. E. desertorurn E. foveolata and E. ~triata.~~ Emindole DA previously isolated from E. desertorurn 'has been found in E. quadrilineata (Thom et Raper) C.R. Benjamin strain IFM 42006 and 42021 and a new tremorgenic metabolite 1'4-acetylpaxilline (65) has been isolated from the mycelium of E. NATURAL PRODUCT REPORTS 1991 H Cyclopiamide (66) (67) (+I-lndolmycenic ester Metabolite F R 900452 (68) + 02Me Me (69) Reagents i BF; Et,O; ii NaOH Scheme 8 I (-+ 70,711 XQJ-JCHO H 2’-Demethylaplysinopsin (70) X = R = H (74) (71) X= Br R = H (72) X= H R =Me (73) X= Br R =Me Reagents i piperidine heat Scheme 9 striatu (Rai Tewari et Mukerji) Malloch et Cain strain 80-NE-Details of Smith’s first3ja and syntheses of paspaline have been published. Cyclopiamide a new metabolite of Penicillium cyclopium Westling has the structure (66) ac- cording to X-ray crystal structure analysis.36 Although it is not overtly tryptophan-derived it is suggested that cyclopiamide may arise from 4-dimethylallyltryptophan by decarboxylation N-methylation oxidative cyclization and aromatization.Finally a synthesis of ( +)-2S,3R-indolymycenic ester (67) constitutes a new formal total synthesis of ( -)-ind~lmycin.~’ 2.2 Non-isoprenoid Tryptamines Metabolite FR 900452 a potent PAF inhibitor isolated from Slreptomyces phaeofuciens No. 7739 has the structure (68) according to X-ray crystal structure analysis.38 In connection with the synthesis of structurally simple analogues of (68) the preparation of optically active p-methyltryptophan derivatives has been in~estigated.~~ An efficient method has been developed in which an N-substituted indole reacts with an aziridine 2-carboxylic ester (69) itself derived from D-threonine in the presence of a Lewis acid specifically boron trifluoride (Scheme 8).By this means the /3-methyltryptophans were obtained in very high optical purity. Simple tryptophans substituted only in the aromatic ring and not on the indole nitrogen or the side-chain can be prepared by an analogous method from N-benzyloxycarbonyl aziridine 2-carboxylic ester but here zinc triflate was found to be the only effective Lewis aid.40 Four compounds of the aplysinopsin group have been isolated from a coral belonging to the Dendrophyllia genus found in the Philippines.13 The Z-isomers (70)-(73) predominated over the E isomers found in the natural mixtures to the extent of more than 95%.Photoisomerization gives an equilibrium mixture richer in the E-isomers which then revert to the original mixture on thermal isomerization. Compounds (70) and (71) were very simply synthesized by base-catalysed condensation of the appropriate indole 3-aldehyde with 2- amino-3,5-dihydro-3-methyl-4H-imidazol-4-one (74) (Scheme 9) which gave Z/E mixtures identical with those occurring naturally. An ingenious new formal synthesis of ( f )-physovenine'l employs as critical stage the first example of an intramolecular [2+21 cycloaddition reaction of a carbamoylketene with an alkene (Scheme 10). The essential transient intermediate presumably (76) cyclized to give a cyclobutanone derivative (77) which on Baeyer-Villiger oxidation and conventional manipulation gave the known4 physovenine intermediate (78).Another new synthesis of (&)-physovenine (75) starts NATURAL PRODUCT REPORTS 1991-5. E. SAXTON Me C02Me 602Me (78) (77) (76) Me MeNHCOzO- xiv xv Me H Me H Physovenine(75) (79) Reagents i LiMe; ii 230 "C; iii NaH CIC0,Me; iv NaH BrCH,CO,Me; v LiOH; vi (COCI),; vii NEt, C,H, heat; viii rn-CPBA; ix DIBAL then Ac,O py; x Et,SiH BF, Et,O; xi ref. 42; xii BrCH,CO,Me NaOMe MeOH; xiii LiAlH, THF; xiv BBr, CH,Cl, N, r.t; xv Na MeNCO THF Scheme 10 4 Me I) OCH2Ph / 0 OCHZPh 'Hi-OC H2 Ph ii .) *o/ (82) Iiii iv .) Me vi vii OCH2Ph kOCH2Ph * "'F02Et Me x xi (81a) (81b) (+)-Eserrnethole (83b) Me O-yT ~ N"PN MeH Me MeH Me (-4 -Esermethole (83a) (-)-Physostigmine (80a) (-3-Norphysostigmi ne (84) Reagents i CH,CH=CHCH,MgCl THF ;ii phthalimide PPh, Pr'0,C * N=N * C0,Pr' ;iii NH .NH * H,O EtOH heat ;iv Cl .CO,Et NEt, CH,Cl,; v OsO, NaIO, THF H,O,then NaIO,; vi p-MeOC,H,NHNH;HCI py heat; vii CH,O NaBH,CN H,O MeOH; viii LiAlH, THF heat; ix separation ;x Na NH (liq.) ;xi (COCI), DMSO NEt, CH,Cl, then NH2S0,H then NaBH, EtOH heat; xii pyridinium dichromate CH,Cl,; xiii 10'YO HCI/H,O Scheme 11 19 NPR 8 NATURAL PRODUCT REPORTS 1991 0 lxi 0Y s-s+-o.(87) U J xvi xvii OH Me Me-f-7 I OH xxiii Me xxiv Me Me MeNHC02 a- NH Me Meh Me I C02Me (+1-Esermethole (83b) (+)-Physost igmine (80b) Reagents i SeO, dioxan H,O heat ;ii MeCOCl py C,H ;iii lipase phosphate buffer 5 days ;iv PCC CH,Cl ;v LiMe THF -70 "C;vi m-MeOC,H,MgBr CuBr.SMe, Me,SiCI HMPA -70 "C to r.t. ;vii o-C,H,Cl, heat; viii 30 YOH,O, NaOH MeOH; ix NH,NH .HCl NEt, MeCN; x H, Pd/C; xi TsS(CH,),STs Bu'OK THF Bu'OH; xii KOH BUtOH; xiii CH,N,; xiv m-CPBA NaHCO, -30 "C; xv TFAA PhMe 130 "C; xvi OsO, NMO H,O THF; xvii NaIO, H,O THF then NaBH,; xviii phthalimide PPh, THF Pr'O,C.N=NCO,Pr; xix NH,.NH;H,O EtOH; xx MnO, CH,Cl,; xxi NaH MeI DMF; xxii NaClO, NH,SO,H H,O Bu'OH; xxiii (PhO),PON, NEt, C,H, heat then MeOH heat; xxiv LiAlH, THF Scheme 12 essentially from Julian's physostigmine intermediate (79) and employs conventional reactions in a four-stage conversion (Scheme lo)., A new somewhat lengthier synthesis, of (-)-physostigmine (80a) and its unnatural enantiomer relies on the construction of two diastereoisomers (81a) and (81 b) from S-0-benzylglycidol (82).Separation of (81a) and (81b) followed by removal of the unwanted substituent at C-2 gave (-)-esermethole (83a) and its enantiomer (83b) which have already been converted into physostigmine (8Oa) and its enantiomer (80b) (Scheme 11). During the course of investigating the oxidation of the alcohol derived from the debenzylation of the ether (8 1b) by means of pyridinium dichromate it was observed that oxidation of the N,-methyl group to an N-formyl group occurred. When the same oxidation was applied to (-)-physostigmine (80) and the N-formyl derivative so obtained was hydrolysed the product was (-)-norphysostigmine (84).This constitutes the first synthesis of this alkaloid and completes the synthesis of all the alkaloids of the physostigmine group., A recent enantiospecific synthesis of unnatural (+)-physo-stigmine (80b) required for pharmacological evaluation particularly in connection with the treatment of Alzheimer's disease must qualify as the longest yet devised and executed in this group of alkaloid^.,^ Starting from the dimer of cyclopentadiene the key step in the initial stages was the lipase- catalysed hydrolysis of the racemic acetate (85) which gave the optically pure alcohol (86) together with unchanged acetate of the enantiomeric The alcohol (86) was then elaborated according to the sequence of reactions shown in Scheme 12 the purpose being the preparation of the strategic chiral dihydronaphthalene ester (87).45b Further manipulation of (87) ultimately gave (+)-esermethole (83b) which as noted above has already been converted into (+)-physostigmine (80b).45e A new alkaloid l-methoxycarbonyl-4,8-dimethoxy-~-carboline has been isolated together with the known 1-methoxycarbonyl-P-carboline from the leaves of Adanthus aZti~sima.~~ This latter alkaloid together with 1-acetyl-8- NATURAL PRODUCT REPORTS 1991-5.E. SAXTON 261 (88a) Arenarine A R' (88b) Arenarine B R' (89a) Arenarine C R' (89b) Arenarine D R' = COCH20Me R2 = H = CHOHCHzOMe R2 = H = COMe R2 = OMe = COMe R2 = OH &-fiN HR (90a) R = CH=CH2 (91a) Picrasmine I R = CH=CH2 (=8-H ydroxydehydrocrenatine) (90b) R = CH2Me (91b) Picrasmine J R = CH2Me (G8-Hydroxycrenatine) MeNHo (92) Goshuyuamide-I (93) Goshuyuamide-I1 (94) R(+)-Tetrahydroharmine carboline and four new alkaloids arenarines A-D (88a/b and 89a/b) have been found in Arenaria kansuensis Maxim a plant widely used in Chinese medicine for the treatment of influenza lung inflammation jaundice and rhe~matism.~' This appears to be the first report of the existence of alkaloids in the Arenaria genus (fam.Caryophyllaceae). Two alkaloids of Picrasma javanica Bl. which were earlierdsa formulated as the 5-substituted crenatine derivatives (90a) and (90b) have now been shown to be 8-hydroxydehydrocrenatine (91a) (= Picrasmine I) and 8-hydroxycrenatine (91 b) (= Picrasmine J) on the basis of an X-ray determination of the structure of (91a).48b Rutaecarpine has been shown to be present in the seeds and fruits of Zanthoxylum budrunga a plant that finds medicinal use in India.494 The most recent extraction of the fruits of Evodia rutaecarpa (Japanese name 'Goshuyu ') yet another plant that is widely used medicinally have resulted in the isolation of two new constituents goshuyuamide-I (92) and goshuyuamide-I1 (93).49b This latter compound has already been prepared in the laboratory but has not previously been found in nature.Because the reported values for the optical rotation of tetrahydroharmine [(94) and its enantiomer] differ widely the preparation of optically pure bases has been Resolution of (+)-tetrahydroharmhe by means of optically active 10-camphorsulphonic acid gave material which exhibited [&ID+ 70.9" and -69.6'; these values are considerably higher numerically than any previously recorded.It was estimated that the R( +)-tetrahydrohamnine (94) had an optical purity greater than 99 YO,and its S-enantiomer greater than 98 %. In acid solution the enantiomers slowly racemize. The synthesis of 1,3-disubstituted N-hydroxy- tetrahydro-p- carbolines required for the synthesis of a wide range of indole alkaloids particularly the eudistomins by the Pictet-Spengler reaction has been studied in detail.51 The preparation of a range of novel complexes of platinum or palladium with /3-carboline alkaloids (harmaline harmalol harmine and harman) has been described ;52 these generally have the empirical formula M (alkaloid)Cl, where M = Pd or Pt and are claimed to exhibit some antitumour activity.The pharmacology of these simple p-carboline alkaloids has also been investigated. 53 Harmine and harmaline hydrochlorides were found to exhibit antiviral activity against Herpes virus hominis type I but harmalol was inactive. All three alkaloids were inactive against influenza virus types A and B. There has been considerable activity recently in the eudistomin group of marine metabolites and particular attention has been paid to their synthesis. Eudistomidin A was isolated earlier from the Okinawan marine tunicate Eudistoma glaucus. The same organism has NATURAL PRODUCT REPORTS 1991 Ho&-QN 0 Me Me (95) Eudistomidin B (96)Eudistomidin C R = H (97) Eudistomidin D (99)S-10-0-Methyleudistomidin C R = Me KSMe i ii M~oOT~ MeoOTflNH + CbzH N " H SMe CbzH NO' J/ iii iv Br MeH N4' LSMe (98) R-10.0-M et h y Ieu d i sto midi n C Reagents i TFA -78 "C; ii DDQ C,H,; iii LiAlH, THF heat; iv Br2 AcOH Scheme 13 (102) R = C02Me (-+ 103) (103) R = H iii iv o\ I ' N flH2 + Bu'OCOCO-FO (104) /viii or ix Eudistomin I(100) py Boc (105) Reagents i 4-phthalimidobutanoyl chloride r.t.; ii AgBF, -20 "C; iii S, 200 "C; iv H,N*NH, MeOH; v TFA C,H, in air; vi ~-t- butoxycarbonyl L-proline DCC ;vii Polyphosphoric ester CH,Cl,; viii DDQ C,H ;ix NBS CH2Cl2 Scheme 14 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON 263 l’ll,l‘lh “-qN’” -Q)-% H COzMe 0 / (106) Eudistomin S R = Br (107) Eudistomin T R = H Reagents i OHC .CO,H; ii esterification; iii sulphur heat; iv PhCH,MgCl LEI Et,O Scheme 15 Me02CHNJLJ (109) R = H (1 111 (-)-Eudistomin F (110) R = OMe O YMe C02Me (112) now yielded three new metabolites eudistomidins B (95) C (96) and D (97);54 the known eudistomidins D E H and I previously obtained from Eudistorna olivaceurn were also isolated. The structure and absolute configuration of eudistomidin C were established by synthesis of R-10-0- methyleudistomidin C (98) which proved to be the enantiomer of the 0-methyl ether (99) of natural eudistomidin C (Scheme 13).All three eudistomidins B-D showed potent cytotoxicity against murine leukaemia L1210 and L5 178Y cells.54 Other synthetic work on the simple eudistomins has resulted in the synthesis of eudistomins I and T (three syntheses of each) H M P and S.55-57 One approach to eudistomin I (100) involved the acylation of the isonitrile (101) with 4-phthalimidobutanoyl chloride followed by cyclization with silver tetraflu~roborate.~~ The dihydro-P-carboline (1 02) was dehydrogenated by elementary sulphur ; removal of the methoxycarbonyl and phthalimido groups and cyclization then gave eudistomin I (100) (Scheme 14). Appropriate modification of this route afforded a synthesis of eudistomin T.55 Wasserman’s synthesis56 of eudistomin I consists essentially of an alternative route to the N,-unprotected dihydro-P-carboline (103) by means of condensation of tryptamine with the tricarbonyl compound (104).Subsequent stages were virtually identical with those already cited (Scheme 14). Again this synthesis could be modified for the preparation of other eudistomins e.g. eudistomins M and T.5s (113) The third of eudistomin I relies on a standard Bischler-Napieralski cyclization for the formation of the 3,4- dihydro-P-carboline derivative (105). In this reaction deprotection and oxidation to the pyrrolinyl stage of oxidation occurred fortuitously probably during work-up. The synthesis was then completed by dehydrogenation ; interestingly dehydrogenation to the fully aromatized pyrrole derivative was not observed (Scheme 14).This approach was also modified to afford syntheses of eudistomins H and P. Eudistomins S (106) and T (107) were very simply ~ynthesized~~ by formation of the P-carbolines (108) and (109) from the appropriate tryptamine and glyoxylic acid followed by esterification and dehydrogenation. A modified Grignard reaction then gave eudistomins S and T (Scheme 15). Some preliminary work aimed ultimately at the synthesis of eudistomins containing an oxathiazepine ring e.g. eudistomins C E and F has resulted in the synthesis of the parent ring system (108),59*60 (-)-debromoeudistomin L (109) (-)-0- methyldebromoeudistomin E (1 lo) and their stereoisomers.61 The synthesis of (-)-eudistomin F (1 11) by Hino Nakagawa and their co-workersB2 is essentially an adaptation of the route developed earlierlO for the synthesis of (-)-eudistomin L.Further exploratory work aimed at the synthesis of manzamine-A has been published. This includes the preparation of the tricyclic pyrroloisoquinoline derivatives (1 l 2y3 and (1 13)s4. The total synthesis of manzamine C (1 14)65 involves the preparation of 6-(2)-azacycloundecene (1 15) and the P- NATURAL PRODUCT REPORTS 1991 i; Manzamine C (1 14) (1 17) f-Reagents i Bu'Me,SiO(CH,),I base; ii H, Lindlar cat.; iii silylation; iv tosylation; v TsNH, NaOH Bu,NI C,H, heat; vi RedAl; vii ClCOCH,CO,Et; viii POC1,; ix Pd/C heat; x PhMe heat; xi LiAlH Scheme 16 OwOMe OWOMe VMe 0 t)H bH ( 1 18) 3-Methyl-4-methoxy-5-hydroxycanthin-( 1 19) 4-Methoxy-5-hydroxycanthin-(120) 3-Methylcanthin-5,6-dione 2,6-dione 6-one N3-oxide (Picrasidine L) carboline ester (1 16).Condensation of these two intermediates followed by reduction of the amide (117) so obtained afforded manzamine C (1 14) (Scheme 16). New canthin-6-one alkaloids isolated recently66a include 3- methyl-4-methoxy-5-hydroxycanthin-2,6-dione(1 18) and 4-methoxy-5-hydroxycanthin-6-oneN-oxide (1 19) which were extracted from the wood of Quassia amara L. together with the (121) R' = R2 = R3 = H known alkaloid 3-methylcanthin-5,6-dione (120) (= Picrasidine (122) R' = R3 = H R2 = OMe L66b). * The stem bark of Pierrodendron africanum (Hook. f.) Little (123) R' = R2 = H R3 = OH (fam. Simaroubaceae) from Zaire which has not previously (126) R'=OH R2=OMe R3=H been examined has yielded6' five alkaloids viz.canthin-6-one (127) R' = R2 = ti R3 = OMe (1 2 l) 5-methoxycanthin-6-one (1 22) 11 -hydroxycanthin-6-one (1 23) 3-methoxycanthin-2,6-dione(1 24) and canthin-2,6-dione (125). Six canthin-6-one derivatives have been isolated from cell suspension cultures of Brucea javanica (L.) Merr. the fruits of 0LJ which have a long history of use in Chinese medicine for the treatment of malaria and dysentery and also as an insecticide. * It should be noted that the molecular ion for alkaloid (1 18) is claimed to be observed at m/z 302; similarly (M' -Me) is observed at m/z287 and (M+ -H,O) (124) R=OMe at m/z 284. The authors do not explain how these data can be interpreted in terms (125)R = H of structure (I 18).265 NATURAL PRODUCT REPORTS 1991-5. E. SAXTON MeyR MeTco2Me MYco2Me R' R2 H Me (128) Pseudophrynarninol R = CH2OH (130) R' = H R2 = OH (134) R=OH (129) R = C02Me (131) R' =OH R2=OMe (135) R=OMe (139) R = CHO (132) R' = H R2 = OMe (138) R = H (133) R' = R2 = OMe MepH QRCoX ~ 'NN NN / HO6 H Me Me H Me (136) Pseudophrynarnine A R = OH ( 140) (137) R=OH suspension cultures of Ailanthus altissima grown in the presence of various microorganisms of the Phytophthora genus.6e For example the yields of canthin-6-one and 1-methoxycanthin-6-one were increased by factors of 125 and 2.5 within 96 hours in dark-grown cultures in the presence of Phytophthora megasperma.I 3 lsoprenoid Tryptamines In an extensive survey of the skin secretions of Australian ii iii amphibians it has been shown that alkaloids of the pseudophrynamine group are unique to frogs of the Pseudophryne genus. Ten alkaloids were isolated and identified these include pseudophrynaminol (128) and the related methyl ester (129) two phenolic derivatives (130) and (13 l) together MejrOH with their methyl ethers (132) and (133) the iminoquinone derivatives (1 34)* and (1 35) pseudophrynamine A (1 36) and a hydroxy-derivative tentatively formulated as (1 37) ; which & MeToH were found in some or all of the seven species investigated viz. P. australis Gray P. bibronii Gunther P. coriacea Keferstein H Me *;" P. corroboree Moore P. guentheri Boulenger P.occidentalis CF3CO C02Et Parker and P. semimarmorata Lucas. Nine further alkaloids of this group were detected in trace amounts in some populations Pseudophrynarninol (128) of one or more of these species. Five of these alkaloids are tentatively formulated as the aldehyde (1 39) the Na-methyl Reagents i Me,C=CH .CH,Br Mg(N0,),-6H20 pH 2.9 r.t, derivative of (1 28) the ar-hydroxyindolenine derivative (140), NaOAc AcOH H,O; ii TFAA NEt, CH,Cl,; iii SeO, ButOOH a double bond isomer of the ester (129) and an Na-methyl CH,Cl,; iv LiAlH, Et,O didehydro derivative of pseudophrynamine A (1 36) ; the Scheme 17 structures of the remaining four alkaloids are unknown. 'O The first total synthesis'l of (+)-pseudophrynaminol (128) employs as critical stages the Mg2+-mediated alkylation- A new alkaloid 4-hydroxy-5-methoxycanthin-6-one(126) cyclization of N,-ethoxycarbonyltryptamime by means of I -was identified from the cultures together with canthin-6-one bromo-3-methylbut-2-ene followed by N,-protection and (121) and its N-oxide 1-hydroxycanthin-6-one (1 23) 1 1 -regiospecific allylic oxidation of the intermediate by selenium methoxycanthin-6-one (1 27) and 5-methoxycanthin-6-one dioxide-t-butyl hydroperoxide.Reduction by lithium (122).68 The occurrence and abundance of alkaloids in intact aluminium hydride then completed the synthesis (Scheme 17). Brucea javanica plants appears not to have been reported but it is of interest that the yields of alkaloids obtained from their * This iminoquinone is described in ref 70 as having the molecular formula C,,H,,N,O and exhibiting m/z 300 neither of which is consistent with structure cell suspension cultures are vastly greater than those reported (1 34).If this alkaloid is indeed an iminoquinone derivative having a RMM of from intact Brucea antidysente ica root bark and stem wood. 300 it seems likely that it has the molecular formula C,,H,,N,O and structure Alkaloid formation is also reported to be stimulated in cell (1 38). NATURAL PRODUCT REPORTS 1991 (141) 12,13-Dihydroxyfumitremorgin C (142) Fructigenine A R = CH2Ph (143) Fructigenine 8 R = CH2CHMe2 I I1 C02MeQy,! iv-vi vii viii I + isomer ( 144) Demethoxyfumitremorgin C Reagents i HC=COMe CH,Cl,; ii TFA CH,CI, -35 "C; iii N-benzyloxycarbonyl-L-prolylchloride NEt,; iv NaBH,; v H, Pd/C; vi (COCl), DMSO NEt,; vii MeLi; viii SOCI, py Scheme 18 Four new metabolites have been isolated from the mycelium of Penicillium farino~um.~~ PF1 and PF3 are believed to be isomers of roquefortine and PF2 and PF4 isomers of 3,12- dih ydroroquefortine.12,13-Dihydroxyfumitremorgin C (141) has been isolated together with verruculogen (major alkaloid) and a minor metabolite suspected to be an analogue of (141) containing a cis-hexenyl substituent at C-3 from Aspergillus fumigatus Fres. DSM 790 when maintained under resting-cell conditions in Tris buffer.' Under fermentation conditions in a medium containing 1% glucose 1 ?4 universal peptone 2% malt extract and 0.3 YO yeast extract almost no indolic metabolites were produced.cis-12,13-DihydroxyfumitremorginC (141) has been prepared previo~sly,~~ together with two trans-dihydroxy isomers during experiments directed towards the synthesis of fumitremorgin B. Fructigenines A and B are two new metabolites of structure and absolute configuration (142) and (143) which have been isolated from Penicillum fructigenum Take~chi.'~ A new stereoselective approach to the fumitremorgins has so far resulted in the synthesis of demethoxyfumitremorgin C (144) (Scheme 18).76 Full details of the total synthesislo of (-)-brevianamide B have been published." NATURAL PRODUCT REPORTS 1991-5. E. SAXTON Lm + H F-Me Me% 0 Me 0 Me (145) Paraherquamide t (149) ( 148) R = a or OH a or PMe a or PEt a CH2Ph P CH=CHz ; X = H or Br Reagent i Et,N 9 SF Scheme 19 -OH -(153) 8-Hydroxyergine C-8 P-CONH; (155) R = H ( 154) 8-Hydroxyergi n i ne C-8 a-CO N H 2 (152) R = p:C H2 The discovery that paraherquamide (145) is a potent antiparasitic agent has stimulated investigations into structure-activity relationship^.^^ In an attempt to replace the hydroxy-group in (145) by fluorine by means of diethylamino- sulphur trifluoride the desired fluoride (146) proved to be one of two minor products the other being the endo-alkene (147).The major product was the exo-alkene (148) (Scheme 19) which is also reported to be a natural The endo- alkene (147) was the major product when (145) was reacted with carbonyldi-imidazole. Appropriate transformation of the exo-alkene (148) allowed a number of structurally modified paraherquamide derivatives (149) to be prepared several of which were tested for antiparasitic activity against Caenorhabditis elegans ; however most of these compounds were substantially less active than paraherquamide itself.78 Details of the isolation and structure elucidation of blastmycetins Deo and E,1° from Streptoverticillium blastmyceticum have been published.*' 7-t-Butylindolactam V (150) and 7-n-hexylindolactam V HOH2C (156) R = y0"V' H CHzOH OH H (15l) which are simplified analogues of the potent tumour promoter lyngbyatoxin A (152) have been synthesized in the search for protein kinase C activators.82 3.1 Ergot Alkaloids Two new epimeric alkaloids 8-hydroxyergine (1 53) and 8-hydroxyerginine (1 54) have been isolated from the culture broth following prolonged submerged fermentation of Claviceps paspali Stevens et Hall.83 The submerged culture of Claviceps fusiformis supplemented with chanoclavine-I leads to the formation of chanoclavine-I aldehyde agroclavine elymoclavine and two new glycosides which were identified as chanoclavine- I- O-P-D-fructofuranoside (155) and chanoclavine-I-U-P-D-fructofuranosyl (2 + l)-O-P-D-fructofuranoside (1 56).84 ',Carbon magnetic resonance data have been reported for methyl dihydrolysergate and several related esters with different N-6-substituents and their preferred conformations have been deduced.85 NATURAL PRODUCT REPORTS 1991 0 R 8-0x0-9-dehydrohobartine ( 157) 8-0x0-9-dehydromakomakine (158) A (on 162) (159) R=Me (162) R = Mes ( 163) / li H2N HNCHMe2 Aristomakinine (160) Aristomakine ( 161) Reagents i THF NEt, H,O 0 "C;ii NaBH,CN; iii H,O; iv MeCOMe NaBH,CN Scheme 20 A series of derivatives of 9,lO-dihydroergotamine and 9,lO- dihydroergocristine in which the N-6-methyl group has been replaced by a variety of substituents has been prepared for pharmacological evaluation.86 The benzeneseleninic anhydride method for the dehydrogenation of indolines which has been used with much success in the final stage of ergot alkaloid synthesis has been described in detail.87 Bromodimethylsulphonium bromide and bromodimethyl- sulphoxonium bromide are effective reagents for the intro- duction of bromine into position 2 of the indole ring in ergot alkaloids ;ss chlorodimethylsulphonium chloride similarly effects chlorination at position 2.For example a-ergocryptine and its 9,lO-dihydro derivative elymoclavine and lysergol and its 0-acetate give good yields of the corresponding 2-bromo derivative with either of the above brominating agents. 4 Monoterpenoid Alkaloids 4.1 Alkaloids Containing an Unrearranged Monoterpenoid Unit Two new alkaloids isolated from the aerial parts of Aristotelia chilensis have been shownsg to be 8-0x0-9-dehydrohobartine (1 57) and 8-0x0-9-dehydromakomakine (158). The structure of the latter was established by X-ray crystal structure and that of the former by comparison of the NMR spectra of (157) and (158).89b The recently-synthesizedlO anti-aristotelin- 15-01 (1 59) has been converted by a biomimetic route into (-t)-aristomakinine (160) and (f)-aristomakine (161).90 The mesylate (162) suffers a Grob-type fragmentation under extremely mild conditions to give an intermediate (163) which hydrolyses to aristomakinine or under appropriate conditions can be reduced to aristomakine (Scheme 20).The extremely mild conditions under which fragmentation of (162) occurs leaves little doubt concerning the stereochemistry of (160) and (161) which were originally formulated,91a as shown with a cis C/D ring junction; subsequently however it was suggestedg1' that these alkaloids possessed a trans C/D ring junction on the basis of comparison of the CD spectrum of (-)-aristomakine with those of various yohimbane derivatives.The validity of the cis C/D ring junction is further strengthened by the observation of significant nuclear Overhauser effects in aristomakine (161). Thus irradiation of the protons of the methyl group attached to C-17 results in enhancement of the signals owing to the protons attached to C-16 and C-1 1 while irradiation of the olefinic protons results in enhancement of the signal owing to H-10. Neither of these observations is consistent with a trans C/D ring junction in aristomakine (1 61). 4.2 Corynantheine-Heteroyohimbine-YohimbineGroup and Related Oxindoles Palicoside (164) is a new indole alkaloid glucoside which has been isolated from the leaves of a toxic Brazilian plant Palicourea marcgravii.g2a Palicoside is closely related to strictosamide into which it is said to be converted when heated at 120 "C in dimethyl sulphoxide.Vincoside lactam and two additional new glucosides NATURAL PRODUCT REPORTS 1991-5. E. SAXTON 269 @=<*H H H \p OGlc Palicoside (164) OH OGlc Naucleocosidine (166) Maxonine ( 167) (168) H H‘* MeoTH H“ -I OH mOH (+) -Nb-P-Methy la nt irh i n e ( 169) (170) 10-Methoxycorynantheol (171) 10-Methoxyantirhine R = Me naucleocoside (165) and naucleocosidine (1 66) have been found in the stems of Nuuclea oficinulis Pierre ex Pitard,g2b and angustoline has been reported to occur in Camptotheca acuminata.93 A new alkaloid maxonine (1 67) which has the same skeleton as normalindine has been isolated from the roots of a Costa Rican plant Simira maxonii (fam.Rubia~eae).~~ The structure of maxonine was elucidated mainly by 2D NMR spectroscopy. As an anhydronium base maxonine might be expected to yield an N,-alkyl-P-carbolinium ion on protonation. However in acid solution maxonine exhibits a bathochromic shift charac- teristic of additional conjugation and the protonated species is therefore regarded as (168) i.e. the product of protonation on oxygen. (+)-N,-P-Methylantirhine (isolated as its chloride) (169) is the only member of this group among the eleven alkaloids recently extracted from the stem bark of Alstonia angustifolia Miq.95 Ten alkaloids have been isolated from the leaves of New (172)10-Hydroxyantirhine R = H Caledonian Ochrosia alyxioides Guilla~min.~~ These include three new bases namely 10-methoxycorynantheol (1 70) 10-methoxyantirhine (1 7 l) and 10-hydroxyantirhine (1 72) together with tetrahydroalstonine reserpinine isoreserpiline isoreserpiline (or carapanaubine) oxindole B and 16s- 19,20E- 10-methoxyisositsirikine from this group.10-Methoxyantirhine (171) was also found in the stem bark together with nine other alkaloids including strictosidinic acid demethoxy-carbonyldihydrogambirtannine tetrahydroalstonine reser-piline isoreserpiline bleekerine and dihydrocorynantheol. The 28 indole alkaloids identifiedg7 among the constituents of the leaves of Tabernaemontana citrifolia L.from Guadeloupe consist of 25 known monomeric bases and three new bisindole alkaloids ; of the known monomers sitsirikine 16S-isositsirikine 16-epi-isositsirikine pleiocarpamine and fluorocarpamine belong to this group. Sitsirikine and 16Sisositsirikine have also been shown to occur together with 16R-isositsirikine and eight Strychnos alkaloids in the leaves stem bark and root bark of Strychnos NATURAL PRODUCT REPORTS 1991 Normavacurine (173) (175) Salacin (174) Reagents i Mg/THF ; ii EtCHO; iii benzylation; iv 2-hydroxytryptamine hydrochloride ; v H .CO,H Ac,O; vi debenzylation;vii (COCl), DMSO NEt Scheme 21 H#&Me Me02C ’ ‘&OMe Me02C (177) 7R (178) 7s (176) 3-0xo-7-hydroxy-3,7-seco-rhynchophylline Reagents i rn-CPBA CH,Cl,; ii TFAA TFA; iii NH,OH; iv 0,,CuC1 Scheme 22 pungens; a South African deciduous tree or shrub whose fruit is considered by some authors to be edible while others consider it responsible for stomach disorders headaches or diarrhoea if the fruits consumed are unripe or eaten in too large quantitie~.~~ The fruits have apparently not yet been investigated but the alkaloid content of the other organs of the plant does not inspire confidence in the edibility of the fruits.Ajmalicinine cabucine and fluorocarpamine have been isolated from the stem bark of Petchia ~eylanica.’~ Details of the production of indole alkaloids by in vitro hairy-root culture of Catharanthus trichophyllus infected by Agrobacterium rhizogenes have been published.looIn addition to the production of five new alkaloids (anthraserpine dimethoxyanthraserpine pseudoanthraserpine desanthra-serpidine and dimethoxydesanthraserpidine),whose structures were reported last year,l0 twelve alkaloids were identified including ajmalicine akuammigine and serpentine from this group. Tetrahydroalstonine and aricine are two of the six alkaloids recently found in the stem bark of RauwoIJia cubana A.DC.,lo1 and normelinonine-B is the one representative of this group so far found in the root and stem wood of Malaysian Strychnos ignatii P. Bergius.lo2 Normavacurine (173) is one of two novel alkaloids isolated from Strychnos minjiensis S. potatorum and S. longicaudata. lo3 This alkaloid was initially isolated from S.longicaudata in 1983 when it was mistakenly believed to be 1,2-didehydro- deacetylretuline.lo4 The leaves of Uncaria salaccensis (U. attenuata) having been studied previously the same group of workers have turned their attention to the stem bark and hooks of this plant from which five alkaloids were obtained.lo5 Rhynchophylline isorhynchophylline and corynoxine are well known but the two remaining alkaloids both oxindole derivatives are new. The relatively simple structure of salacin (1 74) was deduced from its spectroscopic properties and the relative stereochemistry by NOE spectroscopy. Confirmation of this structure was obtained by the synthesis of salacin (174) and its C-7 epimer (175) (both as racemates) by the route shown in Scheme 21.The second new oxindole proved to be 3-0x0-7-hydroxy-3,7-secorhynchophylline (1 76) ; again the structure was proved by synthesis from either rhynchophylline (177) or isorhynchophylline (1 78) as outlined in Scheme 22. Apparently both the natural alkaloid (176) and the synthetic material consist of mixtures of C-7 epimers.lo5 Further evidence has been obtained,loBa from 13C NMR NATURAL PRODUCT REPORTS 1991-5. E. SAXTON 27 1 OTMB I OMe Reserpine ( 179) TMB = trirnethoxybenzoyl OTMB I OMe (181) li 3,Nb-Dihydroreserpine (183) Reagents i MeOH HCl; ii Zn AcOH spectroscopy that the protonation of reserpine in concentrated (18 M) sulphuric acid occurs at position 7. The proton NMR spectra of isoreserpiline tetraphylline and reserpiline hydro- chloride and the I3C NMR spectrum of reserpiline hydrochloride have been re-examined;lo6' from which it has been shown that the configurations and conformations of these alkaloids can be assigned from the coupling constants of the protons at positions 3 14 15 19 and 20.Reserpiline base does not give a spectrum sufficiently clear for interpretation but it gives rise to two hydrochlorides whose conformations were deduced from their proton and 13C NMR spectra. The isomerization of reserpine (1 79) into 3-isoreserpine (1 80) has also been re-e~amined,'~' and it is now suggested that it (182) OMe (180) Isoreserpine Scheme 23 proceeds via the carbocation (181) (Scheme 23) formed by fission of the 3,N bond following protonation of reserpine; rather than via a retro Pictet-Spengler mechanism involving C-2 protonation and fission of the 2,3-bond as earlier postulated by Gaskell and Joule.lo8 This mechanism is consistent with all the available evidence including inter alia the preferential formation of the thermodynamically less stable isomer res- erpine on Pictet-Spengler cyclization of the immonium ion (1 82),Io9 and the formation of 3,Nb-dihydroreserpine (1 83) as the vastly predominant product rather than 2,3-dihydro-reserpine on reduction of reserpine with zinc and acetic acid.lo8 Oxidative rearrangement of tetrahydro-P-carboline alkaloids to the related indoxyl derivative followed by reduction and NATURAL PRODUCT REPORTS 1991 0Ac (184) Deformyl-3-isogeissoschizine I; ill IV (185) Reagents i Pb(OAc), CH,Cl,; ii NaOMe MeOH; iii NaBH,; iv MeOH 1M HCl heat Scheme 24 CH Me02C’ ‘C02Me 0 (1 86a) ( 186b) A mN S02Ar H ii i-vi i QQG lii ‘‘Et U I OUO 1 ( 188) viii ix x vii (187a) Guettardine C-15 a-H ( 187b) 15-Epiguettardine C-15 P-H Reagents i C,H, heat Dean-Stark; ii TsOH C,H,; iii MeI K,CO, MeCOMe; iv 10% NaOH H,O EtOH; v (COCI), CH,Cl,; vi MeOH; vii LiAlH, THF; viii 4MHC1 MeOH heat; ix (EtO),POCH,CO,Et NaH DME; x H, PtO, EtOH 200 psi Scheme 25 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON iii-vi H 15 HOA (189) 18,19-Dihydroantirhine iv vi I vii ( 193) (190) 3-€pi-18,19-dihydro-antirhine Reagents i NaBH, KCN; ii AcOH; iii (Bu'OCO),O NaOH H,O PhMe Bu,N.HSO, Ar; iv H, PtO,; v TFA; vi LiAIH,; vii 10%KOH H,O 60 "C Ar Scheme 26 I R' R' (195) 3P-H (194) (196) 3a-H Reagent i KOH H,O MeOH heat Ar Scheme 27 rearrangement affords a method of obtaining 'indole-inverted ' isomers.110 For example deformyl-3-isogeissoschizine(1 84) affords the tetrahydro-y-carboline isomer (1 85) (Scheme 24). New and improved routes for the synthesis of indolo- quinolizidine derivatives which may well find application in the synthesis of indole alkaloids have been These include the synthesis of both enantiomerically pure epimers of the tetracyclic keto-ester (1 86a) and the enantio- merically pure indoloquinolizidinone (1 86b). 113 A variant of the route developed by Rubiralta and his collaborators has resulted in a synthesis of guettardine (1 87a) and 1Sepiguettardine (187b)."ld The intermediate (188) used in the synthesis of indoloquinolizidinones was methylated and the P-hydroxyethyl group introduced into position 3 of the indole ring.Release of the ketone group and a Wadsworth- Emmons condensation followed by reduction stages then gave guettardine (1 87a) and 1Sepiguettardine (1 87b) (Scheme 25)."ld The most recent ~ynthesis''~ of 18,19-dihydroantirhine (1 89) and its 3-epimer (190) involves a simple and direct procedure from the known115 pyridinium salt (191) (Scheme 26). Re- duction trapping by cyanide ion and acid-catalysed cyclization gave an intermediate (192) which following N protection and reduction stages gave (& )-18,19-dihydroantirhine (1 89) which has a trans disposition of hydrogen atoms at positions 3 and 15.Alternatively reduction of the unprotected intermediate (192) by the same reagents gave (& )-3-epi- 18,19-dihydroantirhine (190) in which there is a cis relationship between the hydrogen atoms at positions 3 and 15. This work prompted the re-examination of an earlier report116 that alkaline hydrolysis and decarboxylative cyclization of the tetrahydropyridine derivative (193) gives (&)-18,19-dihydroantirhine (189). In the hands of Lounasmaa and Jokela,'14 however the only detectable product was (+)-3-epi-18,19,dihydroantirhine (190). In a more extended survey1126 it was concluded that the alkaline decarboxylative cyclization of 4-substituted tetrahydropyridine derivatives of type (194; R2= H) leads almost exclusively to products of type (195; R2 = H) in which the hydrogens at positions 3 and 15 (biogenetic numbering) have a cis relationship ; whereas cyclization of 5-substituted compounds of type (194 R' = H) leads predominantly to products of type (196 R' = H) in which the hydrogen atoms at positions 3 and 20 are trans (Scheme 27).With tetrahydropyridine derivatives of (194) that contain alkyl substituents at both positions 4 and 5 the result is heavily dependent on the stereochemical relationship (i.e. whether cis or trans) of the two alkyl substituents.'12b NATURAL PRODUCT REPORTS 1991 I !I iii iv I V -(201) Dehydronormalindine (200) jvi Normalindine (197) R' = Me R2 = H Norisomalindine (198) R' = H R2 = Me Reagents i NaBH,; ii Ac,O; iii POCI, 8@-90 "C; iv HClO,; v Me,C.COCI NEt, CH,Cl, 0-25 OC; vi NaBH,CN Scheme 28 OAc I r iv v (204a) R' = COzMe R2 = H (204b) R' = H R2 = COZMe (202a) Vinoxine R' = C02Me R2 = H (202b) 16-Epivinoxine R' = H R2 = COzMe Reagents i LDA THF -30 "C; ii HCI C,H,; iii Me,OBF, CH,Cl,; iv NaBH, MeOH; v 1.5 MHCI MeOH Scheme 29 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON I \ C02Me (208) (2071 MeNwo ML Ph Me0 AcO Me02C '-Et v. IV,VI Me02C Me02C' kC02Me C02Me Mk Ph (21 1) (210) Ill,VIII,IX I (213) (206) (212) Reagents i NEt, CH,Cl, heat; ii CH,N,; iii NaOMe; iv Ac,O PY;v LiAl(OBu),H; vi Me,SiCl NaI; vii NEt, CH,(CO,Me), CH,Cl, heat; viii NaBH,; ix HIO,; x PCC; xi AcOH heat Scheme 30 The first synthesis1" of (&)-normalindine (197) and (+)-norisomalindine (198) involves the reduction acetylation and cyclization of the readily available imine (199) to the dihydro- P-carbolinium salt (200) isolated as its bis-perchlorate (Scheme 28).Cyclization of (200) to dehydronormalindine (201) was effected by means of pivaloyl chloride and triethylamine; the initially formed pentacyclic dihydropyridine derivative undergoing spontaneous oxidation. Reduction then gave a separable mixture of (_+ )-normalindine (1 97) and (&)-norisomalindine (198). Details of Bosch's synthesis of vinoxine (202a) have been published,"* and an alternative synthesis based on the same synthetic strategy has been rep~rted."~ In this latest variant the precursor of the ethylidene group attached to C-20 is an acetyl group rather than an acrylic ester function placed at position 3 in the initial pyridinium salt (203).Condensation with indole N-acetic ester and elaboration more or less as before gave a tetracyclic intermediate (204) on which the remaining stages simply involved conversion of the vinylogous amide function into a 3E-ethylidenepiperidine unit and methanolysis of the acetate group. Separation of the intermediates (204a b) allowed the preparation of both vinoxine (202a) and its 16-epimer (202b) (Scheme 29)."' In this tetracyclic alkaloid series a synthesis of (&)-ochromianine and (-)-ochromianine has been reported,120 which employs the same lactim ether route used earlier in the synthesis of ochropposinine (ochromianine differs from ochropposinine only in the absence of a 10-methoxy group).The same group have also completed a new formal synthesis of (t-)-deplancheine.l2la This consists of a relatively unexceptional synthesis of the ketone (205) which has previously been converted into deplancheine by Pakrashi and his collaborator.121b Experimental details of an earlier synthesis of ( )-deplancheine have also been published.l2lC Brown's route to the synthesis of the Corynanthe alkaloids via the racemic lactol-ester [(&)-(206)] which constitutes a synthetic equivalent of secologanin has been refined and now affords an efficient asymmetric synthesis of these alkaloids.122 Thus replacement of malonic ester by the chiral oxazepine (207) prepared from (-)-ephedrine in the Michael addition to the cyclopentenolone ester (208) afforded after column chromatography the stereochemically pure trans adduct (209) NPR 8 NATURAL PRODUCT REPORTS.1991 H (-1-Methyl elenolate (214) 0 6' (221) (215) (+)-Elenolic acid v x-xii xi I (217) (+I-Ajmalicine vii vtii I (216) (+I-Epielenolic acid v x-xii xi I (218) (+I-Tetrahydroalstonine R' = H R2 = H (219) (+I-Aricine R' = OMe R2 = H (220) (+)-Reserpinine R' = H R2 = OMe Reagents i KOBut MeI DME; ii 6MHC1 heat; iii m-CPBA CH,CI, NaHCO,; iv NaH HCO,Me then HCl heat; v CH,N,; vi KOBut MeCOCl; vii OsO, NMO MeCOMe H,O; viii H,IO, Et,O; ix silica gel; x tryptamine C,H,; xi NaBH, MeOH; xii POCl, CH,Cl, heat Scheme 31 (Scheme 30).Manipulation of (209) as illustrated gave an intermediate (2 10 j in which the transformed Michael addend in the beta position with respect to the ketone group could be replaced by a malonic ester residue with complete preservation of the desired stereochemistry. The product conveniently isolated as the diacetate (211) was converted into the (-)-lactol ester (206) which was shown to have an enantiomeric excess > 96%. Condensation of (206) with tryptamine fol- lowed by Pictet-Spengler cyclization yielded the natural hirsutine precursor (21 2). An alternative sequence of reactions on the diacetate (21 1) gave the optically pure enol acetate (213) which in racemic form had earlier been a key intermediate in the preparation of dihydrosecologanin aglucone and E-secologanin aglucone.In a combined publi~ationl~~ Ninomiya and Winterfeldt have given details of the synthesislo of the eight isositsirikine isomers corynantheine and hirsuteine by the Kobe and Hannover research groups. New enantioselective syntheses of (-)-methyl elenolate (214),lZ4(+j-elenolic acid (215) and (+)-epielenolic acid (216) have been described.125 (-)-Methyl elenolate has previously been converted into (-)-ajmalicine. (+)-Elenoh acid was converted into (+)-ajmalicine (217) and (+)-epielenolic acid into (+)-tetrahydroalstonine (218) as shown in Scheme 31. Use of the appropriate methoxytryptamine also afforded ~yntheses'~~ of (+)-aricine (219) and (+)-reserpinine (220).Winterfeldt's synthesis of (+j-elenolic and (+j-epielenolic acids started from the chiral ketoester (22 l) obtained optically NATURAL PRODUCT REPORTS 1991-5. E. SAXTON n n i-iv H H-($H H- B -Me v'vi* 0 0 0 (223) vii viii ix tX -H" Me02C CHO (222) Methyl 20-epi-elenolate Reagents i LDA THF; ii MeI; iii rn-CPBA NaHCO, CH,Cl,; iv flash chromatography; v LDA THF HMPA; vi MeO,C.CN; vii DIBAL PhMe -78 "C; viii TsOH CH,Cl,; ix LDA THF Me,SiCl; x OsO, NMO MeCOMe H,O; xi Pb(OAc), MeOH Scheme 32 (224a) C-20 = P-H (225) (224b) (2-20 = CX-H pure by enzymic hydrolysis. In a closely similar approach to Other alkaloid intermediates which have recently been heteroyohimbine alkaloid synthesis Leonard and co-workers126 prepared by new routes include the optically active lactones have prepared (&)-methyl epielenolate (222) from monoketal (224)124and the tetracyclic enaminoketone (225).12' (223) as outlined in Scheme 32.This route also has potential A new procedure for the conversion of tetrahydro-P-for development into an enantioselective synthesis. carboline alkaloids into their oxindole analogues has provided NATURAL PRODUCT REPORTS 1991 . .. I II &O Me02C (226) (227) Pteropodine (229) lsopteropodine (228) Reagents i ButOC1 NEt,; ii AgClO, HClO, H,O MeOH; iii AIH, THF -50 "C; iv NaBH,CN MeOH AcOH; v AcOH heat Scheme 33 H (230) Nitraraine ? (231) Dihydronitraraine ? a new synthesis of pteropodine and isopteropodine.12* In compounds such as (226) which contain a lactam carbonyl group at C-2 1 the derived chloroindolenine obtained by reaction with t-butyl hypochlorite does not rearrange to an oxindole under conditions that achieve a satisfactory conversion with the corresponding tertiary bases. However rearrangement of the chloroindolenine from (226) by means of silver perchlorate in aqueous methanolic perchloric acid gave a high yield of the oxindole (227) in a highly stereoselective reaction. There was no evidence of epimerization at C-3 and very little isomerization at C-7; indeed the lactam (227) was not isomerized by acid under conditions that equilibrate the C-7 epimeric N tertiary bases.Selective removal of the (2-21 carbonyl group gave isopteropodine (228) from which pteropodine (229) could now be obtained by acid-catalysed equilibration (Scheme 33). The situation concerning the alkaloids nitraraine and dihydronitraraine constituents of Nitraria schoberi which have been assigned129 the structures (230) and (231) remains obscure. A lengthy chiral synthesis130 of the pentacyclic bases (230) and (23 1) afforded optically active material whose physical spectroscopic and optical properties did not accord with those reported for nitraraine and dihydronitraraine. In the yohimbine series a brief new synthesis of (+)-alloyohimbane and (+)-3-epialloyohimbane 131 and a synthesis of alloyohimb- 18-en- 1 have been reported.An in- genious asymmetric synthesis of (-)-alloyohimbane and (+)-3-epialloyohimbane has been described,132 and details of an earlier synthesis of (-)-alloyohimbane have been p~b1ished.l~~ Finally Stork's recent of reserpine (179) and 3-isoreserpine (180) constitutes the most notable contribution to indole alkaloid synthesis during the period under review. In a characteristically elegant conception chiral 4-benzyloxy-methylcyclohexenone (232) prepared from optically pure cyclohex-3-ene carboxylic acid was converted in only seven steps into the ring E precursor (233) in which all five asymmetric centres have the required stereochemistry and functionality for conversion into reserpine (Scheme 34). A Strecker reaction on (233) presumably using 6-methoxytryptamine in the presence of cyanide gave the aminonitrile (234) which could be cyclized at will to methyl reserpate or methyl isoreserpate ;esterification with 3,4,5-trimethoxybenzoyl chloride then gave reserpine (179) or 3-isoreserpine (180).The vitally important cyclization of the a-aminonitrile (234) was shown to give methyl 3-isoreserpate when heated in acetonitrile solution ; presumably (234) in which the nitrile group is axial is converted into a tight ion-pair (immonium ion/cyanide) in which axial approach to position 3 by the indole ring is blocked by the cyanide ion. NATURAL PRODUCT REPORTS 1991-5. E. SAXTON CH20CH2Ph i-iii 0 0 Me02C CH20Ts OH v vi i oHcMoTs vii ~ Me02C dMe (233) 6Me (234) viii ix x ix I MeO2CvOTMB 3-lsoreserpine (180) Reserpine (179) Reagents i Bu,NF THF; ii debenzylation; iii tosylation; iv m-CPBA KF DMF; v methylation; vi DIBAL; vii 6-methoxytryptamine KCN; viii MeCN heat; ix esterification; x AgBF or HCl THF H,O Scheme 34 The result is the formation of the 3-is0 series.On the other (methyl reserpate) corresponding to natural reserpine. So far hand if the ion pair is broken up either by the use of silver this brief and brilliant stereospecific synthesis has only been tetrafluoroborate or aqueous acid the liberated immonium ion reported in a very condensed form with even less detail than is allows unimpeded axial approach by the indole ring in the customary in a preliminary communication;134 it is to be hoped energetically preferred pathway with formation of the alcohol that full details will soon be forthcoming.NATURAL PRODUCT REPORTS 1991 H H (235) 16-Epiaffinine R = Me (236a) Amerovolfine R = H (236b) Amerovolfine R = H (237) Accedine R = Me H Amerovolficine (238) 10-Methoxy-N,-rnethylpericyclivine (239) R20H2C,,C02Me HYC02Me a;q R’O’ (240) Demethylechitamine R’= R2 = H Alstozine N-oxide (243) (241) Alkaloid W-10 R’ = H R2 = Ac (242) Alkaloid W-12 R’ = Me R2 = Ac 4.3 Sarpagine-Ajmaline-Picraline Group Ajmaline and 16-epiaffinine (235) have been found among the constituents of the stem bark of RauwolJia cubana together with two new alkaloids amerovolfine (236) which is the N,-demethyl derivative of accedine (237) and amerovolficine (238) which is 16-demethoxycarbonylpagicerine.lol Appar-ently amerovolfine is obtained as a mixture of the carbinolamine form (236a) and the acylindole form (236b) (minor constituent). Rhazinaline has been isolated from the leaves of Tabernaemontana citrifolia L.,97 and echitamine Nb-demethylechitamine pseudoakuammigine and Nb-methylakuammidine (as chloride) together with pseudo- NATURAL PRODUCT REPORTS 1991-5. E. SAXTON 28 1 OHC C02Me Me 3 (245) Vincamajine Iii (244)17-Hydroxy-6,17-O-dehydrovoachalotine Reagents i CrO, py; ii DDQ THF H,O Scheme 35 (246)19R-Kourninol (247)1 9s-Kourninol akuammigine N,-oxide (a new alkaloid) from the stem bark of Alstoniu ungustifoliu Miq.95 Alstonisine occurs in the leaves of Alstoniu mucrophyllu Wall,135 and 10-methoxy-N,-methylpericyclivine (239) in the leaves of Alstoniu undulutu.136 The presence of alschomine isoalschomine picrinine picralinal and nareline in the leaves of Taiwanese Alstoniu scholuris has been reported earlier.1° The leaves of Thai specimens of this plant contain the same alkaloids; however plants from the Philippines contain 6,7-secoalstonamine and N-demethyl-6,7-secoalstonamineas major alkaloids; while in Indonesian plants vallesamine and 6,7-secoalstonamine are the major constituents together with pseudoakuammigine picraline and N,-methylburnamine (N,-methyldeacetylpi-craline).137 The presence" of N,-methylraucubaine and N,-methylstrictamine both isolated as their chlorides in the leaves of Vincu minor has again been Macusine B and 0-methylmacusine B have been extracted from the root and stem wood of Strychnos ignutii.lo2 Echitamine and N,-demethylechitamine (240) have been obtained from Winchiu culophylh A.D.C. together with two new alkaloids which were identified as 22-0-acetyl-N,-demethylechitamine (241) (Alkaloid W-10) and 22-0-acetyl-3- 0-methyl-N,-demethylechitamine (242) (Alkaloid W-1 2).13' The 13C NMR spectral data for all four alkaloids were recorded and assigned. Alstozine-N-oxide a new alkaloid obtained from the leaves of Alstoniu macrophylla is formulated as (243) on the basis of its proton and 13C NMR spectra.lgO Two new epimeric alkaloids isolated from the leaves and roots of New Caledonian Alstoniu unduluta Guillaumin have been shown to be 17-hydroxydehydrovoachalotinesof structure (244); the 17 R epimer predominating in the natural product according to the interpretation of the NMR spectral data.141 A partial synthesis of 17-hydroxydehydrovoachalotine,one of the small group of alkaloids functionalized at C-6 was achieved from vincamajine (245) as summarized in Scheme 35.19R-Kouminol (1 9R-hydroxydihydrokoumine) (246) and 19s-kouminol (1 9S-hydroxydihydrokoumine) (247) are two new alkaloids which have been obtained from whole Gelsemium eleguns plants,142 together with koumine and ge1~emine.l~~~ The structures were deduced from their spectroscopic properties lg2 and confirmed by X-ray crystal structure ana1y~is.l~~~ The stereochemistry of (246) at C-19 was also confirmed by the application of Horeau's method.142a The reductive methylation of sandwicine by means of sodium borohydride in methanol in the presence of methyl iodide affords a convenient preparation of sandwicoline.lg3 Isosandwicine ajmaline and isoajmaline similarly give the corresponding Nb-methyl-4,2 1-seco products.The first total of ( +)-suaveoline (248) starts essentially from the tetracyclic ketone (249) obtained via a NATlJRAL PRODUCT REPORTS I991 xv ~ Me (254) (255) (249) I ii 1 COMe Me iii iv (257) (256) 1 1 xviii QQQq vi * (250) CHOH MeN COMe (-)-Alstonerine (253) I (258) Ivi Q-qH QJH Me / H (251a) R' = Et R2= H H COMe A COMe (251b) R' = H R2 = Et (259a) a-H XIX c Macroline (260) 1259b) 0-H IV VI vii VIII-x XI-XIII Me 'CHZPh Me (252) Suaveoline (248) Reagents i PhSOCH,Cl LDA THF -78 "C; ii 10M KOH THF; iii LiClO, BuiPO PhMe heat; iv LiAIH,; v (MeO),C.CH,CH,CH, Me,C,H,CO,H(cat.) 125 "C Ar; vi (COCI), DMSO NEt, CH,Cl, -78 "C; vii (CH,OH), TsOH PhH heat; viii 9BBN THF 50 "C; ix 3M NaOH H,O,; x (PhSeO),O PhCl 115 "C; xi 2M HCl THF; xii NH,OH.HCl EtOH heat; xiii H, Pd/C; xiv MeSO,CF, CH,Cl,; XV HCrC.COMe dioxan NEt,; xvi PhH 145 "C sealed tube; xvii NaBH, EtOH; xviii TsCl py then NEt,; xix NaOMe MeOH Scheme 36 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON OH OH ?SiMe2Bu' OH CH~OH CHO (264) Ajmaline (265) vii-ix I YSiMe3 OSiMezBu' x-xiii (268) OMes (266) XVII xi I HOT OMe (262) (263) Gelsedine (261) Reagents i H,N -NMe, H,SO (cat); 3A-mol.sieves EtOH; ii Cbz-Cl NaOH CH,Cl,; iii CuCl, H,O THF; iv ButMe2SiOS0,CF, NEt, CH,Cl,; v OsO, THF py H,O NaHSO,; vi NaBH, MeOH; vii NaIO, MeOH; viii Me,CHOH NaBH,; ix separation of epimers; x Ac20 py; xi BuYNF THF; xii Me,SiOSO,CF, CH,CI,; xiii Pb(OAc), CH,Cl, -70 "C; xiv AcOH THF. H,O; xv 5% KOH H,O MeOH; xvi MesC1 NEt, DMAP CH,Cl,; xvii H, Pd/C AcOH EtOH; xviii BrCN MgO PhH Scheme 37 seven-stage synthesis from (f)-tryptophan. Conversion of (249) into the homologous unsaturated aldehyde was achieved by condensation of the anion from (249) with chloromethyl phenyl sulphoxide followed by rearrangement ;reduction then gave the allylic alcohol (250) (Scheme 36).The carbon skeleton of suaveoline was then completed by a Claisen rearrangement of the keten acetal derived from reaction of (250) with trimethyl orthobutyrate. This rearrangement gave a 79% yield of a mixture of esters 93% of which were the epimeric products (251) formed via a boat-like transition state. Of these the structure of the major isomer (251a) was established by the X-ray method. The synthesis of suaveoline (248) was then completed by a sequence of unexceptional methods ; however difficulties were encountered in attempts to oxidize the anti- Markownikov hydration product of the alkene (252) by conventional methods. Oxidation was eventually achieved by intramolecular oxidation by means of phenylseleninic an-hydride but concomitant oxidation of the tertiary amino group also occurred.This ingenious route to suaveoline clearly has potential for modification to allow the synthesis of clther alkaloids of the macroline group and indeed has already enabled a synthesis of (-)-alstonerine (253) to be c0mp1eted.l~~ The optically pure laevorotatory tetracyclic ketone (249) prepared from D( +)-tryptophan was converted into its N,-methyl analogue which was then transformed into the allylic alcohol (254) by the route adopted for the racemic N-benzyl counterpart (249). Con- densation of (254) with butyn-3-one gave an enol ether (255) which when heated rearranged via a chair-like transition state to give the unsaturated aldehydoketone (256).Hydroboration- oxidation of the related diol then gave a triol (257) following preferential attack at the p-face of the double bond; presumably this approach avoids 1,3-diaxial repulsions between the axial N,-methyl group and reagent. This contrasts with the preferred mode of attack on the alkene (252) observed during the synthesis of suaveoline. The triol (257) was regioselectively cyclized to the tetrahydropyran derivative (258) and the synthesis completed by Swern oxidation to the related ketone which simultaneously introduced the desired 20,21 double bond with direct formation of (-)-alstonerine (253) (Scheme 36).lg5 The Swern oxidation of (258) also gave some dihydroalstonerine (259a) which could be epimerized by means of base to (259b).Since this has already been converted into macroline (26O),lg6 this also constitutes a formal total synthesis of macroline. The alkaloid gelsedine (261) may well be biosynthesized from a Corynanthe base via an intermediate containing the ring D norsarpagan skeleton in which C-21 has been lost. The preparati~n'~' of the D-norsarpagan derivative (262) and the 3,N,-seco compound (263) starting from ajmaline (264) is therefore particularly noteworthy. This sequence of reactions involved the removal of C-21 by periodate oxidation of the diol (265) prepared as outlined in Scheme 37. Reduction of the product gave a mixture of epimeric alcohols from which the desired S-alcohol (266) was separated. Further transformation of (266) proceeded via the indolenine (267) in which fission of the 7,17 bond occurred spontaneously following removal of the trimethylsilyl group.The five-membered ring D was eventually formed by displacement of a mesylate group at C-20 by N, liberated by hydrogenolysis of the benzyloxycarbonyl group in (268). Reaction of the D-norsarpagan derivative (262) thus obtained with cyanogen bromide then gave the ether (263) whose ring system is the indole counterpart of that contained in gelsedine (Scheme 37).I4 ' NATURAL PRODUCT REPORTS. 1991 n-+ OHC C02Me bMe (270) (2711 (272) iii IV I OMe 7-Epi-20-desethylgelsed ine (269) (273) Reagents i CH,Cl, -70 "C; ii SiO chromatography iii H, Pd/C EtOAc CH,Cl,; iv LiBuiBH CH,Cl,; v TFAA TFA CHCl,; vi Me,SiSiMe, I, PhMe heat Scheme 38 QqH "I *Ql$$H Gardnerine (274) Koumidine (275) Reagents i Ac,O py; ii TsCl Bu,N.HSO, 50% KOH C,H,; iii AlCl, EtSH CH,CI, -18 "C; iv (CF;SO,),O NEt;CH,CI, -20 "C; v l,l'bis(diphenylphosphino) ferrocene* Pd(OAc), NEt, H .CO,H DMF 60 "C; vi Mg PdCl, PPh, MeOH * DPPF Scheme 39 H OH 18-Hydroxygardnutine (276) 0 Koumine (277) 3 Reagents i LiAIH, THF; ii Ac,O py; iii TsCl Bu,N.HSO, 50% KOH PhH; iv AlCl, EtSH CH,Cl, -18 "C; v (CF,.S0,)20 NEt, CH,Cl, -18 "C; vi 5 70K,CO, H,O MeOH; vii Pd(OAc), DPPF NEt, HCO,H DMF 60 "C; viii ClCO,Me MgO THF H,O; ix NaH DMF; x Pd(OAc), PPh, 90 "C Scheme 40 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON The synthesis of 7-epi-20-desethylgelsedine(269) has also been re~0rted.l~~ This involved the condensation of the all-cis pyrrolidine lactone (270) with an appropriate N-methoxyindole derivative (271).Reduction stages on the product (272) gave a lactol (273) which could be cyclized by acid. Removal of the methoxycarbonyl group from Nb then gave 7-epi-20-desethylgelsedine (Scheme 38). Unfortunately none of the 7- epimer of (269) which contains the gelsedine stereochemistry was obtained. This may well be due to unfavourable interaction between the N,-methoxycarbonyl group and the oxindole carbonyl group in the conformation of the oxonium ion derived from the lactol (273) required for cyclization to the desired epimer. Partial synthetic work in this group includes the conversion of gardnerine (274) into koumidine (275),ld9 and the preparation of koumine (277) from 18-hydroxygardnutine (276).150 Both conversions (Schemes 39 and 40) involved the removal of a methoxy-group attached to an aromatic ring and in both cases this was achieved by dealkylation then removal of the derived O-triflate function by means of palladium acetate 1,l'-bis(diphenylphosphin0) ferrocene triethylamine and formic acid.The remaining stage in the preparation of koumidine (275) required the isomerization of the 19,20 double bond which was effected by means of magnesium in dry methanol in the presence of palladium acetate and triphenylphosphine ; removal of the toluene-p-sulphonyl and O-acetyl groups occurred concomitantly (Scheme 39).lg9 The final stages in the partial synthesis of koumine (277) were achieved by reaction of 18-hydroxy- 11 -demethoxygardnerine (278) with methyl chloroformate-magnesium oxide followed by reduction of the urethane-ether thus formed and acetylation of the 18-hydroxy group.Finally the 7,20 bond was formed by reaction of the anion derived from the intermediate (279) with palladium acetate and triphenylphosphine. Nucleophilic attack by C-7 at C-20 with S,2' displacement of the 18-acetoxy group gave koumine (277) this last stage proceeding in 80% yield (Scheme 4O).l5O Full details of the synthesislo of (+)-koumine (+)-taberpsychine and (+)-koumidine by Magnus et al. have been published . 4.4 Strychnine Group Recent extractions have revealed the presence of strychnine strychnine N-oxide pseudostrychnine isostrychnine protostrychnine and 10-hydroxystrychnine in the root and stem wood of Malaysian Strychnos ignatii P.Bergius;lo2 akuammicine and tubotaiwine in the leaves of Tabevnaemontana citrifolia ;97 and akuammicine among the 17 alkaloids produced by hairy root cultures of aseptic Catharanthus trichophyllus plants infected in vitro by Agrobacterium rhizogenes. loo 19-Hydroxytubotaiwine occurs in the leaves of specimens of Alstonia scholaris grown in the Philippines. 137 Tubotaiwine and akuammicine also occur in the stem bark of Alstonia angustifoliu together with akuammicine N,-oxide N,-demethylalstogustine (280) and its N,-oxide; these last three bases are new.95 Nb-Methylakuammicine isolated as its chloride is one of the quaternary alkaloids of the leaves of Vinca minor.13' Details of the isolation of norfluorocurarine and its N,-oxide from the bark of Leuconotis grzfithii have been published;152 the full paper also describes the isolation of a new alkaloid Alkaloid 376 from both L.grzfithii and L. eugenifolia which was assigned the structure (281) on the basis of its spectrographic properties. O-Acetylretuline diaboline 1 1 -methoxydiaboline 11-methoxy-neo-oxydiaboline 12-hydroxy-11 -methoxydiaboline henningsamine 11-methoxyhenningsamine and 12-hydroxy- 1 1-methoxyhenningsamine have been found in the leaves stem bark and root bark of S. African Strychnos pungen~.~~ Of these 11-methoxy-neo-oxydiaboline (282) obviously an oxidation product of 1 1-methoxydiaboline is new; its structure was ,,OH H C02Me Me (-)-Nb-Demethylalstogustine (280) C02Me (281 Alkaloid 376 1 1 -Methoxyneo-oxydiaboline(282) '0' \OAc 1 1-Methoxy-O-acetylisoretuline (283) l7LOH ,,/ Minf iensine (284) deduced from its mass and (mainly) its proton and 13C NMR spectra.The seeds of Strychnos variabilis which have not previously been examined contain O-acetylisoretuline and its 1 1-methoxy derivative (283) (this latter alkaloid is new) retuline isoretuline and 11-methoxyisoretuline.153 The alkaloid earlier form~lated'~~ 1,2-dehydrodeacetyl-as retuline has now been shown to be normavacurine (v. supra).lo3 Minfiensine an entirely new base from Strychnos minfiensis is an isomer of 2,16-didehydrodeacetylretuline and is formulatedlo3 as having the novel skeleton shown in (284); the NATURAL PRODUCT REPORTS 1991 0 0 (285) (286) Me I Me (288) Iii Ellipticine (287) Reagents i (289) Me,SiOSO,CF, CH,Cl,; ii NaHCO, H,O; iii LiAlH, THF; iv 10% Pd/C decalin heat Scheme 41 formation of which from a retuline-type precursor requires overall the migration of N-1 from C-2 to C-3.The nuclear magnetic relaxation times of the 13C nuclei in strychnine have been measured in deuteriochloroform solution and the data analysed in terms of several molecular dynamics m0de1s.l~~ The X-ray crystal structure determination of strychnine hydrochloride sesquihydrate has been reported. 155 A considerable amount of exploratory work directed ultimately at the synthesis of Strychnos alkaloids has been published.11s~156-159 This includes the first synthesis of N,-methyl-20-hydroxydasycarpidone (285)156b and the preparation of a model pentacyclic precursor (286) in six stages from 3-acetylindole.159 4.5 Ellipticine-Uleine-Apparicine Group Ellipticine and 10-methoxyellipticine have been isolated from the leaves of Ochrosia alyxioides Guillaumin 96 and apparicine and vallesamine from the leaves of Tabernaemontana citrifolia. loo Apparicine (pericalline) is one of 18 alkaloids produced by Cutharanthus trichophyllus following infection with Agrobacterium rhizogenes.lOO As noted above 6,7-secoalstonamine and N-demethyl-6,7-secoalstonamineare the major alkaloids of the leaves of Alstonia scholaris grown in the H Me (291a) R = a-L-arabinopyranosyl X = Br (291b) R = 0-D-Xylofuranosyl X = CI Philippines while vallesamine and 6,7-secoalstonamine are the major alkaloidal constituents of Indonesian plants.13’ An earlier synthesis of ellipticine (287) in which the pyridocarbazole framework was constructed by Diels-Alder addition of 3,4-pyridyne to the diene (288) suffered from an almost complete lack of regioselectivity. 160a It has now been shown that the use as dienophile of the dihydropyridone derivative (289) affords a markedly improved synthesis. 160b Although the yield in the Diels-Alder addition was modest (40 YO),the reaction was almost completely regiospecific and no isoellipticine could be detected in the ellipticine obtained following reduction then aromatization with concomitant debenzylation (Scheme 41).A Russian synthesis of ellipticine consists of a new preparation of 1,4-dimethylcarbazole which can be converted into ellipticine by the modified Cranwell-Saxton route. 161 Details of earlier syntheses of ellipticine162 and ~livacine~~~.~~~ by Yokohama et al. and by Sainsbury and his collaborators have been published. Yet more ellipticine derivatives have been synthesized for pharmacological evaluation. 2 1 -Amino- 1 0-methoxyellipticine (290) prepared along with several other 2 1 -alkylamino derivatives is stated to be as active against L1210 and P 388 tumours as any ellipticine derivative hitherto tested. 164a The two quaternary glycosides (291a b) are also the most active NATURAL PRODUCT REPORTS 1991-5.E. SAXTON CO2Me (292) Petchicine C02Me (296) R',R2 = -0-CH2-O-(297) R' = H R2 = OMe "0- Me02C L (298a) 16-Epicuanzine C-16 = &-OH (298b) Cuanzine (revised) C-16 = &OH against the L1210 leukaemia system of a group of synthetic glycosides and have been selected for further preclinical evaluation and possible clinical development. 164b 4.6 Aspidospermine-Vincamine Group Tabersonine and conoflorine are the two Aspidosperma alkaloids found among the 28 alkaloids of Tabernaemontana ~itrifolia.~~ Seven alkaloids of this group have been extracted from the hairy root cultures of Catharanthus trichophyllus following infection with Agrobacterium rhizogenes these are hoerhammericine vindolinine epivindolinine tabersonine lochnericine echi tovenine and minovincinine.loo (-)-Petchicine is a new monomeric indole alkaloid related to minovincinine which has been isolated from the stem bark of Petchia ceylani~a.~~ Its constitution (292) was deduced from its NMR spectra and the Rconfiguration at C-19 by the application of Horeau's procedure. Details of the isolation of leuconolam and its congeners from Leuconotis griJ6thii and L. eugenifolia and of the reaction of leuconolam with hydrochloric acid have been published. 152 An independent X-ray determination of the structure of leuconolam sesquihydrate has also been re~0rted.l~~ The Kopsia genus has been subject of two new investigations. The fruits of Kopsia oficinalis have not previously been examined but have now been shown to contain 16 alkaloids.166 Ten of these are already known namely (+)-vincadifformine eburnamenine kopsanone 5,18-dioxokopsan kopsinilam kopsinine pleiocarpine kopsamine Na-methoxycarbonyl- 12- methoxykopsinaline and N,-methoxycarbonyl- 1 1,12- dimethoxykopsinaline.Three new ones were identified as Na-methoxycarbonyl-11 -hydroxy- 12-methoxykopsinaline (293), Na-methoxycarbonyl- 1 1 -methoxy- 12-hydroxykopsinaline (294) and kopsamine N,-oxide (295). The remaining three were not obtained in sufficient quantity to permit structure elucidation. Na-Methoxycarbonyl- 1 1,l 2-methylenedioxy-A16- kopsinine (296) the dehydration product of kopsamine is one of two new alkaloids obtained from the stems of Malaysian Kopsia profunda Markgraf another species that has not previously been The second new alkaloid isolated N,-methoxycarbonyl- 1 2-methoxy-A16-kopsinine (297) is the dehydration product of Na-methoxycarbonyl- 12-methoxykop- sinaline.The failure of cuanzine hitherto formulated as (298a) to respond to base-catalysed epimerization at C-16 in contrast to 16-epivincamine which has the same configuration at C-16 prompted a re-examination of its stereochemistry. 16*The results of both molecular mechanics calculations and a reinterpretation of the 300 MHz proton NMR data for cuanzine resulted in revision of the stereochemistry to that shown in (298b) i.e. the same configuration at C-16 as that possessed by vincamine.This conclusion was then confirmed by the X-ray crystal structure determination of cuanzine hydrochloride.168 Two-dimensional COSY and HECTOR experiments have been performed on vindoline which have allowed complete proton and 13C assignments to be made. The proton-proton and protonxarbon coupling constants were also reported. 169 A procedure which involves a combination of moderate pressure chromatography on a C, adsorbent and preparative HPLC has been developed for the rapid separation of the alkaloids of Catharanthus rose~s."~ The procedure was optimized for vindoline and catharanthine. NATURAL PRODUCT REPORTS 1991 C02Me k02Me (299a) X = a-F Y = p-OH (300a) R1 =OH R2= H (299b) X = 0-F Y = a-OH (300b) R' =H R2=OH (299~)X = P-OH Y = a-F (299d) X = 0-Br Y = a-F (299e) X = p-F Y = a-Br n OH (302a) X= H2 Vindoline (301) (303) (302b) X=O (302~)X = H,OH / lii f C02Me (305) (304) OHC H ! MeOu,,, C02Me ME '.COzMe ( 3061 Reagents i Sarett's reagent; ii MnO, CH,CI, 40h Scheme 42 The reaction of tabersonine with hydrogen peroxide in HF- SbF yields a mixture of three fluorohydrins (299a)-(299c).17'" With bromine in a similar HF-SbF mixture the products obtained are the bromo-fluoro addition compounds (299d) and (299e) together with an aromatic (10- or 1 1-) bromo derivative of (299e). Vincadifformine however reacts with hydrogen peroxide in HF-SbF to give the 10-hydroxy and 11-hydroxy derivatives (300a) and (300b) but 2,16-dihydrovincadifformine gives mainly the 1 1 -hydroxy derivative.171b Oxidation of vindoline (301) by means of Sarett's reagent gives a mixture of lactams (302a)-(302c) together with a zwitterionic compound formulated as (303) (Scheme 42).''' The oxidation of vindoline by means of manganese oxide is more complex and gives a variety of With manganese dioxide prepared by Attenburrow's method and with much longer reaction time the major product (18%) is not the N-formyl analogue (304) obtained earlier,1i3b but the known ether-lactam (305). Also obtained was the unsaturated ether-lactam (306)(10 YO)and the dimer (307) (3 %) which has previously been isolated from the microbial oxidation of vindoline. However the most interesting product was the rearranged vincine derivative (308) (7 YO),which presumably arises by oxidative N-demethylation of vindoline followed by a rearrangement akin to the rearrangement of vincadifformine to vincamine (Scheme 42).Such a rearrangement has not previously been observed in this series. The structure of (308) is not in doubt since it was established by X-ray crystal structure analysis.173a The bromination of vincadifformine by bromodimethyl- sulphonium bromide or bromodimethylsulphoxonium bromide NATURAL PRODUCT REPORTS 1991-5. E. SAXTON NO2 or C02Me C02Me (31 3b) (31 3a) \ / Scheme 43 This view of the reaction is now untenable however since the phenazine (31 1) can be obtained by the oxidation of 11-OH aminovincamine with a variety of reagents e.g.potassium permanganate manganese dioxide silver nitrate or (most efficiently) Fetizon's reagent.175 The reaction is now believed to involve oxidation of 1 1-aminovincamine to a quinone-imine derivative (3 12) in which the positively-charged indole nitrogen PEt H/' ;@o 0 A (314) (315) (316) gives mainly the 10-bromo derivative. In contrast vincamine gives an unsatisfactory mixture of aromatic bromo derivatives.ss Nitration of ethyl apovincaminate results in nitration of the aromatic ring together with addition of the elements of nitric acid to the indole double bond; the product has the structure and stereochemistry expressed in (309).17* The reaction of 1 1-aminovincamine (3 10) with iodine was recently" shown to give a phenazine derivative (311); a reaction which was considered to proceed via elimination of hydrogen iodide from two molecules of the 12-iodo derivative.renders C-12 susceptible to nucleophilic attack by for example the imino nitrogen atom of a second molecule of (312). This presumes the intermediacy of a dihydrophenazine derivative (313a) or (3 13b) which then suffers oxidation to (3 1 1) (Scheme 43). There has again been no dearth of synthetic activity in this area during the period under review. Full details of the syntheses10-80of vallesamidine,176 quebrachamine aspidosper- mine eburnamonine and related alkaloids177 have been published. A new asymmetric synthesis of the tricyclic aminoketone (314) constitutes a formal total synthesis of unnatural ( +)-aspidospermine while asymmetric syntheses of the lactones (3 1 5)179a-I and (3 16)179a provide useful chiral intermediates for the synthesis of a range of Aspidosperma-Huntevia bases.New approaches to the synthesis of the aspido- NATURAL PRODUCT REPORTS 1991 0 OSiMe2But C02Me (317) (318) (319) C02Me \N 19 Me \N Me H Me HH HH C02Me (320) Vindol inine (321) 16-Epivindolinine (322) + I I II Reagents i ultrasound (500 w 20 KHz) THF Na Ar 0 "C; ii ultrasound (60 w 45 KHz) THF Na Ar 0 "C Scheme 44 . .. 1-111 IV v (324) Ar = 02SC6H40Me(p) (325) VI vii I ix VII Vlil Kopsine (323) Reagents i NaOH MeOH THF then HC1 H,O; ii Na C,,H, DME then ClCO,Me H,O K,CO, PhCH,NEt,Cl; iii Me,CHCH,O,C.Cl NEt, NaBH, THF; iv NCSeC,H,NO,(a) PBu, THF; v H,O,; vi OsO, NMO ButOH THF H,O; vii (COCl), DMSO NEt, CH,Cl,; viii LDA THF -78 "C; ix BH, THF then 5M HCl Scheme 45 spermine framework have so far resulted in the preparation of four 16,19 epimers were obtained.Under other conditions the pentacyclic aldehyde (3 17),180 ( -)- 19-noraspidospermidine (60 W 45 KHz) the reaction was cleaner and gave 34% (52% (3 18),181 and the 2 1-epi-aspidospermidine derivative (3 19).lS2 based on unrecovered starting material) of 16-epivindolinine. A synthesis of vindolinine (320) and 16-epivindolinine (32 1) The synthesislS4 of (+)-kopsine (323) by Magnus and his has been achieved by sonochemical cyclization of the radical collaborators makes use of the intermediate 5,22-dioxokopsane produced by treatment of 19-iodotabersonine (322) with sodium (324) prepared earlier18j during the synthesis of kopsinine.(Scheme 44).la3 The yields and proportions of the four possible Introduction of the hydroxy-group at C-16 into the skeleton of 16,19-epimers varied according to the conditions. At lower (324) was achieved by base-catalysed fission of the 6,22 bond ultrasonic intensities vindolinine (320) and 16-epivindolinine followed by a sequence of standard procedures as far as the (321) were formed in a 1 :2 ratio but at higher intensities all 16,22 methylene compound (325) which has hydroxylated by NATURAL PRODUCT REPORTS 1991-5. E. SAXTON 29 1 (co2Me A (COzMe Il-IV fCoZMe HzN+C02H H C02Me C02Me VIII IX Vll cf:::::t aco2Buf * CILXCOzBd H I I 9-PhF\ 9-PhFI (330b) lx Et (329) XVI v Vincamine (328) (330a) Reagents i CuCO,Cu(OH), EtOH H,O 70 "C; ii Me,SiCl CHCI,; iii 9-bromo-9-phenylfluorene Pb(NO,), NEt,; iv MeOH; v Pr'NH .C(OBu')=NPr' CH,CI,; vi KN(SiMe,), THF CI(CH,),OTf -78 "C; vii NaI MeCN NaHCO, heat; viii LDA -78 "C then EtI; ix 10% Pd/C H, AcOH; x tryptophyl bromide NaHCO, MeCN 70 "C; xi AcOH Pr'OH H,O; xii PhPOC1,; xiii TFA heat; xiv LiAlH, THF -70" -t r.t.; xv DMSO py 'SO, NEt,; xvi Me,NCH,CO,Me LDA THF DMSO; xvii Ac,O DMAP py then H,O; xviii Na,CO, MeOH ;xix CNCH,CO,Me THF BuOK -78" -+ -25 "C; xx HCl MeOH heat; xxi Na,CO (anhyd.) Scheme 46 osmium tetroxide then oxidized (Swern) to the a-a modified method of converting Oppolzer's aldehyde (329) hydroxyaldehyde (326).Base-catalysed reformation of the 6'22 into the a-ketolactam (330a) which gives vincamine (mainly) bond completed the formation of the kopsine skeleton and and 16-epivincamine when treated with methanolic base kopsine (323) itself was obtained by reductive removal of the C-(Scheme 46). Rapoport's improved synthesis of (+)-vincamine 5 lactam carbonyl group and a final Swern oxidation (Scheme (328) consists of a new enantioselective synthesis of Oppolzer's 45). This synthesis also constitutes a formal total synthesis of aldehyde (329) from L-aspartic acid via optically pure a-tert.- isokopsine fruticosine and fruticosamine. bu tyl-P-methyl(2S 3 R)-3-ethylhexahydroquinolinate (3 30b) A new synthesislg6 of vincamine (328) consists essentially of (Scheme 46).18' Four routes to this key compound were 21 NPR 8 NATURAL PRODUCT REPORTS 1991 (332a) 414 (332b) A15*20 H OHC AcO I (334) + (335) (331a) R' = C02Me R2 = OH (331b) R' = OH R2 = C02Me Reagents i LDA HMPA THF -70" -+ -40 "C; ii O(CH,),CHOCH,CH,I -40 "C; iii LiAlH, THF -70 "C; iv Ac,O py; v TsOH MeOH H,O heat; vi I, KIO, dioxan; vii H, PtO, MeOH; viii K,CO, MeOH; ix DMSO py.SO, NEt,; x LiN(SiMe,), CNCH,CO,Me THF -70" -+ -40 "C; xi MeOH HCl; xii Na,CO, MeOH Scheme 47 developed only one of which is illustrated.The synthesis was aldehyde (333) with methyl isocyanoacetate did not give the then completed by the route developed by Langlois and his expected product (334) when either potassium t-butoxide or collaborators.lS8 lithium di-isopropylamide was used as base.Eventually it was The synthesislsg of desmethoxycuanzine and its 16-epimer found that the reaction proceeded in the presence of the less paves the way for a synthesis of the alkaloid itself. The mixture basic lithium hexamethyldisilazide to give a mixture of (334) (332) of double bond isomers previously prepared,'" was and the ester (335) which could be converted without separation alkylated at the future C-20 by reaction of the derived anion in a two-stage one-pot process into desmethoxycuanzine with 2-(2'-iodoethoxy)-tetrahydropyran and the product (331a) and its 16-epimer (331b) (Scheme 47).lS9(Note that in elaborated as far as the aldehyde (333) as shown in Scheme 47. ref. 189 these compounds are named according to the older At this stage it was intended to complete the synthesis according view of the stereochemistry of cuanzine; in the light of the to the route developed for the conversion of Oppolzer's discussion above16' the names will presumably have to be aldehyde (329) into vincamine.However reaction of the reversed i.e. desmethoxycuanzine is (33 1b).) NATURAL PRODUCT REPORTS 1991-5. E. SAXTON CHzPh I iv 0 PhC H202C C02Me Et (337) viii 1 0 C02Me COZMe (+)-Catharanthine (338) Reagents i ClCO,CH,Ph; ii Br * iii 1,4-diazabicyclo-[2,2,2]-octane,MeCN; iv CH,=C C1 .COCl MeOH; v AcOH HBr; vi resolution with (+)-dibenzoyl-D-tartaric acid ;iii P-ind.CH,COOCOCMe, DMF NEt,; viii hv SnBu,Cl(cat.) NaBH, MeOH; ix BF;Et,O NaBH, THF Scheme 48 4.7 Catharanthine-Ibogamine Group Thirteen of the 28 alkaloids isolated from the leaves of Tabernaemontana citrifolia L.belong to this group. These are ibogamine ibogaine iboxygaine coronaridine 10-hydroxycoronaridine 1 1-hydroxycoronaridine voacangine voacangine 7-hydroxyindolenine voacangarine voacangarine 7-hydroxyindolenine pandoline 20-epipandoline and an dine.^' No other isolations have been reported during the past year. The X-ray crystal structure determination of voacangine has been reported.lgO The synthesis of (f)-desethylcatharanthine by Szantay et aZ.,lgl" has been published in detail.lglb A refinement of this synthesis which involves resolution at the quinuclidine stage affords syntheses of (+)-desethylcatharanthine and its enantiomer.An obvious modification of this synthesis in which 1-benzyl-3-ethyl-1,2,5,6,-tetrahydropyridine(336) was used as starting material afforded a synthesis of (*)-catharanthine.lg2 Again resolution at the quinuclidine stage (337) and completion of the synthesis as before resulted in the first total synthesis of (+)-catharanthine (338) (Scheme 48).lg2 Kuehne's second synthesis of pseudovincadifformine (339) is distinctly longer than the original one and employs the aldehydo-ester (340) instead of 5-brom0-4-ethylpentana1 in the initial condensation with the indolo-azepine ester (341) 294 NATURAL PRODUCT REPORTS 1991 f OHC -COzMe (340) 4- I____) H A C02Me rNCH2Ph N-Ph C02Me (344al C02Me (343a) 1 1 Et~~ C02Me IJ vi i1 Q)-$dHcNHOTs /NCH2Ph H C02Me 602Me C02Me (347a) (347b) (343b) viii1 viii1 iv-vi1 H I C02Me k02Me H I C02Me Pseudovincadifformine (339) DlE-trans-Pseudovincadifformine (348) (344b) viri1 /Ph b02Me C02Me 1 C02Me 20-€pi-pseudovincadifform ine (346) (345) Reagents i MeOH Ar; ii PhCH,Br Ar; iii MeOH NEt, Ar heat; iv LiAlH, THF; v TsCl py DMAP Ar; vi separation ofisomers; vii H, Pd/C AcOH; viii PhMe 110 "C Scheme 49 NATURAL PRODUCT REPORTS.1991-5. E. SAXTON e02Me (350) H C02Me C02Me C02Me (351a)+ 3,7-epimer (351b) (351c d) (351e) R’ = H R2 = Me (351f) R’ =Me R2= H C02Me lboxyphylline (349) Reagents i H, Pd(OH),/C MeOH; ii CH,O (gas) MeOH 0 “C; iii HCl Et,O heat; iv separation of isomers; v LiBu”,lH THF -78 “C Scheme 50 Candidine (GQingdainone) (352) (Scheme 49).lg3 Benzylation of the product (342) followed by treatment with base gave a fugitive secodine derivative which cyclized to a mixture of tetracyclic aminoesters (343a b); these were converted into the corresponding primary tosylates (344a b) and separated by chromatography.The epimer (344b) when heated at 1loo,epimerized and cyclized to an intermediate (345) which following debenzylation afforded 20-epipseudo-vincadifformine (346). For steric reasons the epimer (344a) did not cyclize as readily but did so after debenzylation (and partial epimerization) via (347a) and (347b). Chromatographic separation of the product then gave pseudovincadifformine (339) and D/E trans pseudovincadifformine (348) (Scheme 49).193 Yet another application of Kuehne’s biomimetic synthesis has resulted in a synthesis of iboxyphylline (349) (Scheme 5O).lg4 The tetracyclic base (350) prepared earlier,lg5 was debenzylated and the epimeric mixture obtained subjected to a Mannich reaction.Six ketonic products were obtained (351 ; a-f) which were separated by chromatography. One of these gave iboxyphylline (349) on reduction. Since the structure of iboxyphylline has been established by the X-ray method this ketone must have the stereochemistry shown in (351f). 5 Bisindole Alkaloids Annonidines A and C have been shown to occur in the roots of Esenbeckia leiocarpa Engl. grown in N.E. Brazil., Candidine a constituent of Candida lipolytica was as (352) by Bergman et al.in 1985. Subsequently the same structure was attributed to qingdainone isolatedlg6* from Baphicacanthus cusia. The identity of these alkaloids has now been formally established. 196c Topsentin B 2 (bromotopsentin)* is one of four brominated bisindole derivatives isolated from a deep water sponge of the Hexadella genus collected at a depth of 100-200 metres in Jervis Inlet British Columbia. 197a The other three which are * This compound was inadvertently named topsentin C in an earlier review80 and should not be confused with the new metabolite (353) of this name.’s7b NATURAL PRODUCT REPORTS 1991 (354) Dragmicidin A R = H (355) Dragmicidin B R = Me vii viii I FascapIysin (356) Reagents i (COCI), Et,O; ii indoline; iii AlH, THF; iv MnO, CHCl, heat; v TFA; vi Pd/C (EtOCH,CH,),O heat; vii MeCO,H THF; viii HCI EtOH.Scheme 51 (-1 -B ipolaramide (357) Reagents i DCC THF; ii Tl(OCOCF,), TFA; iii CuSO;SH,O DMF H,O 132 "C Scheme 52 new are topsentin C (353) dragmicidin A (354),* and and (-)-bipolaramide (357) (Scheme 52),lg9 a constituent of dragmicidin B (355).Ig7* Bipolaris sorokiniane have been reported. Syntheses of fascaplysin (356) the red pigment from the A recent synthesis200 of yuehchukene resembles an earlier Fijian sponge Fascaplysinopsis Bergquist sp. (Scheme 51)19* one in its critical stage which is the acid-catalysed dimerization of 3-isopentadienyl indole ;some trimer and tetramer were also * The authors of ref. 197b have elected to adopt the nomenclature and obtained.numbering systems proposed by Rinehart" for these metabolites. It would therefore seem logical to name compounds (354)and (355) as dragmicidins rather Two new indolocarbazole derivatives closely related to than dragmicidons as in ref. 197b. staurosporine have been isolated from culture broths of NATURAL PRODUCT REPORTS 1991-5. E. SAXTON TAN-999 (358) R' = H,NHMe R2 = OMe TAN-1030A (360) R' = NOH R2 O~E~DR~ = H staurosporine (359) R' = H,NHMe R2 = H R' &y+ Q)--7-co2H ' &&J Me Me Me N Me (361) Reagent i NEt Scheme 53 r 1 H Me (362) Alkaloid A8 (Vatine) n = 3 (363) Alkaloid A9 (Vatamine) n = 4 (364) Alkaloid A10 (Vatamidinel n = 5 C02Me H>) (365) Undulatine R = CH20H (366) Deformoundulatine R = H Nocardiopsis and Streptomyces species.2o1 TAN-999 obtained from Nocardiopsis dassonvillei C-7 1425 has the structure (358) it.10-methoxystaurosporine. TAN- 1030A produced by Streptomyces sp. C-71799 together with staurosporine (359) is the closely related oxime (360). These metabolites have macrophage-activating properties and therefore have potential for the treatment of microbial infection and cancer. Bisindolylmaleic anhydrides e.g. (361) are useful as possible intermediates in the synthesis of indolocarbazoles of the staurosporine and rebeccamycin groups and can readily be prepared by the reaction of indolyl-3-glyoxylyl chlorides with arylacetic acids in the presence of base;202 this procedure can obviously be adapted for the synthesis of unsymmetrically substituted diarymaleic anhydrides (Scheme 53).The reaction fails when the indole nitrogen is unsubstituted but succeeds with removable groups on the nitrogen e.g. benzyl or tosyl groups. In a continuation of the studyao of the alkaloids of Calycodendron milnei (A. Gray) A.C. Smith from Vat& (Efate) Island Vanuatu eight N,-methyltryptamine oligomers have been isolated from the aerial These are hodgkinsine quadrigemine G isopsychotridine D and psychotridine C these last two are pentamers; in addition four new bases of an entirely new type were isolated which are composed of six seven and eight N,-methyltryptamine units. Vatine (Alkaloid A 8) is formulated as (362) and vatine A is a stereoisomer; vatamine (A 9) is (363) and vatamidine (A 10) is (364).Undulatine and deformoundulatine are two new bases composed of cabucraline and N-methylpericyclivine units attached via C-10 of the former to C-6 of the latter. Undulatine (365) was found in the stem bark of Alstonia sphaerocapitata and the roots of A. ~ndu1ata.l~~ The recent demonstrationlgl of the vulnerability of sarpagine derivatives to oxidation at C-6 offers a possible route to the synthesis of alkaloids of the undulatine group. Indeed oxidation of N,-methyl- 16- NATURAL PRODUCT REPORTS 1991 (367) R = H (368) R =OH C02Me C02Me H’ Cabucraline (369) 16’-€pi-deformoundulatine(370) Reagents i DDQ THF; ii (369) 2MHC1 EtOH heat Scheme 54 Me02C C02Me TH HO 4 \ Vobasinol 1 e (+ 375,376) + aT&Et H (375) Ervahaimine A R’ R2 = =0 Connection 11‘ Me02C (376) E rvahaim ine B R’,R~= =o Connection 10’ 3-Oxocoronaridine (377) Ervahaimidine A R’ = H R2 = CHOHMe Connection 11’ (378) Ervahaimidine B R’ = H R2 = CHOHMe Connection 10’ Reagent i 2% HCl 75 “C 8 h Scheme 55 NATURAL PRODUCT REPORTS 1991-5.E. SAXTON HO C02Me 14,15-Didehydrotetrastachynine (379) I C02Me Taberso n ine C02Me iI (380) 3-Hydroxyvoafrine A R’ = OH R2 = aH c(3821 Voafrine A R’ = H R2 = OH (381) 3-Hydroxyvoafrine B R’ = OH R2 = OH iic (383) Voafrine B R’ = H R2 = OH Reagents i C. ruseus enzyme 0, MeOH r.t.; ii NaBH, MeOH Scheme 56 epipericyclivine (367) with DDQ gave the 6-hydroxy derivative (368) which in acid solution condensed with the nucleophilic cabucraline (369) to give 16’-epi-deformounduIatine (370) (Scheme 54).204 A series of four bisindoles (371)-(374) have been prepared205 by the acid-catalysed condensation of vobasinol with kopsinine venalstonine kopsinilam and kopsinyl alcohol.Three of these bases (371)-(373) showed marked activity against P-388 leukaemia cells in vitro. The roots of Ervatamia hainanensis Tsiang have yielded four new alkaloids (375)-(378) of the voacamine type in which a vobasine unit is attached to a coronaridine unit.206 Ervahaimine B (376) is 3’-oxoervahanine B and ervahaimine A is its isomer in which the 3-vobasinyl component is attached to C-1 1’ of the 3’-oxocoronaridine component.Both bases were obtained by the acid-catalysed condensation of vobasinol with 3-oxocoronaridine (Scheme 55). The other two bases are also isomers; ervahaimidine A (377) has a 3-vobasinyl unit attached to C-1 1’ of a 3-hydroxyethylcoronaridine unit whereas in ervahaimidine B (378) the attachment is to C- 10’. It is significant that both 3-hydroxyethylcoronaridine and vobasine occur in Ervatamia hainanensis however these bisindole alkaloids are not at present believed to be artifacts. The three bisindole alkaloids found together with 25 monomeric alkaloids in the leaves of Tabernaemontana citrifolia have been identified as 12,12’-bis-( 1 1-hydroxy-coronaridinyl) and 14,15-didehydrotetrastachyne,which are already known and 14,15-didehydrotetrastachynine (379) which is new; in accordance with this structure hydrogenation gives tetra~tachynine.~~ 3-Hydroxyvoafrines A (380) and B (381) have been prepared by the oxidative dimerizaton of tabersonine by means of oxygen in the presence of a crude enzyme obtained from Catharanthus roseus.Borohydride reduction of (380) and (38 1) then gave voafrine A (382) and voafrine B (383) (Scheme 56).207 The 13Cand proton NMR spectra of a number of vinblastine and vincristine derivatives have been recorded and with the assistance of heteronuclear shift correlation experiments com- plete assignments have been made. 208 Compounds examined included deacetylvincristine and its 0-(12-maleimido-dodecanoyl) derivative,208a the corresponding maleimido-dodecanoyl derivative of deacetylvinblastine and two amides containing isoleucine and tryptophan residues prepared from deacetylvinblastine.208b The mass spectra of eight semisynthetic vinblastine and vincristine relatives in which the velbanamine component has been replaced by a pseudoaspidosperma or pseudoeburnea unit have also been recorded and analysed.,09 In another substantial contribution to the biomimetic synthesis of indole alkaloids Kuehne and his collaborator have NATURAL PRODUCT REPORTS 1991 /-NCH,Ph rNCH2Ph HI C02Me Cl/ ‘C02Me (344b) (386) 1ii Ph I m’ rNCH2Ph OTs Ill IV OH *‘Et Me0 \ Me H I 602Me ( 388a) (387) (388b) v VI + ,vii 7 Me02C-20‘-Desoxyvinblastine (384a) R’ = H R2 = Et 20'-Desox yvinblastine (385) R1 = Et R2 = H (384b) R1 = Et R2 = H (392) R’ =OH R2 = Et (389) Me3CSiMe20CH 2yCHO Et H Reagents i ButOC1 NEt, CH,Cl, Ar; ii vindoline HCl AgBF, MeCOMe Ar; iii KBH, AcOH; iv separation of diastereoisomers; v PhMe heat 24 h; vi H, Pd/C MeOH -6 “C; vii PhMe heat Scheme 57 reported the synthesis of 20’-desoxyvinblastine (384) 20’-desoxyleurosidine (385) and their diastereoisomers 20’-desoxyvincovaline and 20’-epi-20’-desoxyvincovaline,which differ in the stereochemistry of the velbanamine component.lg3 As an example the synthesis of 20’-desoxyvinblastine (384) is illustrated in Scheme 57. The racemic tetracyclic anilinoacrylate ester tosylate (344b) an intermediate in the synthesis of 20-epi-pseudoaspidospermine (346) was converted into its 16-chloroindolenine derivative (386) which was condensed with vindoline.Reduction of the product [(387) and its 16’ 14’ 20’ diastereoisomer] with potassium borohydride gave a mixture of indole-indoline esters (388) from which the desired ester (388a) was separated by chromatography. Cyclization of (388a) followed by debenzylation then gave 20’-desoxyvinblastine (384). In like manner the intermediate (344a) was converted into 20’-desoxyleurosidine (385) and (388b) was converted into 20’-desoxyvincovaline. A subsequent stereospecific synthesis of the protected hydroxyaldehyde (389) and its enantiomer followed by condensation with the indoloazepine ester (341) elaboration of the product as shown in Scheme 49 and replacement of the silyl protecting group by a tosyl group afforded an enantioselective synthesis of the tetracyclic intermediates (344a b) ; which in turn offers a much more efficient synthesis of 20’-desoxyvinblastine (384) and 20’-desoxyleurosidine (385) since none of the vindoline used in the coupling reaction [e.g.(386) +(387)] is wasted in the formation of unwanted diastereo- isomers.lg3 NATURAL PRODUCT REPORTS 1991-5. E. SAXTON 30 1 V inblast ine or I ii (392) Reagents 1 The synthesis of napavin (390),a new photoreactive cytostatic derivative of vinblastine with potential for clinical application has been described.210 Reaction of deacetylvin blas tine with paraformalde hyde gives a spirocyclic lactone (391) which is said to show superior activity to vinblastine against P 388 leukaemia cells in ~ivo.~ll The oxidation of vinblastine (392) with hydrogen peroxide and horseradish peroxidase gives a single metabolite which was identified as catharinine (393).212a The reaction may well proceed via a 21’ N’,-iminium ion since in water enriched with l80the catharinine obtained contains l8O specifically on the formyl group.The oxidation of vinblastine by means of human serum ceruloplasmin in the presence of a shuttle oxidant (chlorpromazine) gives catharinine (393) an enamino ether (394) derived from oxidation of the vindoline component and a product (395) in which both components have been oxidized (Scheme 58). In the absence of the shuttle oxidant which presumably acts as a radical initiator no oxidation is observed.212* A radioimmunoassay has been developed2l3 for the quan- titative determination of vinblastine in tissue cultures of Catharan thus roseus.31 CHO 6 Biogenetically Related Quinoline Alkaloids 6.1 Cinchona Group Root cultures of Cinchona ledgeriana generated by infecting shoots cultured in vitro with Agrobacteriurn rhizogenes LBA 9402 have been shown to be capable of synthesizing alkaloids.214 Several alkaloids were identified among which the major ones were quinine quinidine and cinchonidine. Minor alkaloids included dihydroquinidine and dihydroquinine ;and traces of dihydrocinchonine dihydrocinchonidine cupreine (or cupreidine) and cinchonamine were also detected.The roots also contained quinamine and an unidentified indole alkaloid. The X-ray crystal structure determination of N-nitroso-1 ‘,2’,3’,4‘ 10,ll- hexahydrocinchonidine hydrochloride has been reported.215 The CD spectra of the Cinchona alkaloids and their salts with carboxylic acids have been recorded and interpreted;216 and an HPLC method for the separation of corynantheal (a key biosynthetic intermediate?) quinamine cinchonamine cinchonine cinchonidine quinidine and quinine has been developed. 217 An extensive study of the conformations of the principal Cinchona alkaloids and some of their derivatives by the application of molecular mechanics calculations and 2D NMR NATURAL PRODUCT REPORTS. 1991 (396) (398) ,C02Me VI-VIII U f--- OAc ix x H& C02Me "I XI XI1 XIII XIV b HO I H OH CH2Ph Meroquinene (397) Reagents i BF; Et,O Bu'OH; ii K,CO, MeOH; iii Ac,O py DMAP CH,CI,; iv (CH,=CH),CuCN(MgBr) THF then BrCH,CO,Me; v NEt, DMF; vi TsNHNH,; vii NaBH,CN; viii NaOAc.3HO; ix AcOH; x NaOMe; xi NaIO, H,O MeCOMe; xii PhCH,NH;HCI NaBH,CN pH 4.3 ; xiii C1.CO,Et PhH heat; xiv 10 % HCI heat Scheme 59 spectroscopic techniques has been reported.218a* A new model for the transition state for the alkaloid-catalysed addition of aromatic thiols to cyclohexenones has been proposed ;218a and the first X-ray structure of a Cinchona alkaloid with the 'closed' conformation i.e. p-chlorobenzoyldihydroquinidine(396) has been determined.218b The origin of enantioselectivity in the dihydroxylation of olefins by osmium tetroxide in the presence of Cinchona alkaloids has been and a new transition state model for the oxidation of stilbene in the presence of p-chlorobenzoyldihydroquinidine (396) which accounts satis-factorily for the experimental observations has been proposed.A new stereoselective synthesis220 of ( +)-meroquinene (397) starts essentially from the chiral precursor 2-acetoxy-~-glucal triacetate (398) derived from D-glucose. The two chiral centres in meroquinene were constructed by the addition of vinyl and acetic ester residues to the enone (399) by means of a mixed reagent prepared from vinyl magnesium bromide and cuprous cyanide followed by methyl bromoacetate. An almost exclusive trans addition gave the ester-acetal (400) which could be completely epimerized to the desired cis isomer (401) by base.Removal of the 3-0x0 group via the tosylhydrazone followed by a sequence of conventional steps then gave (+)-meroquinene (397) (Scheme 59).,,O Several relatives of quinine and quinidine including the metabolites 10,ll-dihydroxydihydroquinidine N-oxide 3-hydroxyquinine 2'-hydroxyquinine 10,ll-dihydroxydi-hydroquinine and the corresponding derivatives of quinidine NATURAL PRODUCT REPORTS 1991-5. E. SAXTON OH i ii H H 0-HH OMe OMe Qu inidine (402) iii-v I -vi vii HH OMe OMe (403) + C-3epimer Reagents i 5% H,O, MeCOMe; ii 1M KOH KMnO,; iii HBr 0 "C; iv DBU DMSO; v Ac,O py; vi OsO, AcOH Na,IO,; vii CH,=CH.MgBr THF Scheme 60 &0 OGIc 0 Deox ypum iloside (406) 0 1-111 ~ H H" (407) Pumiloside (405) Reagents i NaIO, MeOH; ii NEt,; iii NaOMe Scheme 61 have been prepared.221 As examples the routes to 10,ll-acuminata Decaisne.222This alkaloid is reported to show strong dihydroxydihydroquinidine N-oxide (402) and 3-hydroxy-cytotoxicity against P388 leukaemia cells. quinidine (403) are illustrated (Scheme 60). Proton NMR data In connection with the search for possible biosynthetic for all these derivatives were also presented. precursors of camptothecin the isolation of the 4-quinolone derivative pumiloside (405) and the related quinoline deoxypumiloside (406) from Uphiorrhiza pumila is of con-6.2 Camptothecin siderable interest.223 Pumiloside (405) has also been found very 20R-10-hydroxydeoxycamptothecin (404) is a new alkaloid recently in Camptotheca acuminata extracts.93 Its structure was which has been isolated from the seeds of Camptotheca established by synthesis from strictosamide tetra-acetate (407) i ii HO-&&Me Et 0 Ph (409) iv-vi f--(410) Reagents i KOH; ii HC1; iii MesC1 NEt, CH,Cl,; iv CsOAc DMF 18-crown-6; v K,CO ; vi 5 % HC1 Scheme 62 (412) R = OMe (413) R =OH (Scheme 61),223 by X-ray crystal structure analysis and by NMR spectros~opy.~~ The 13C NMR data for camptothecin and 10-hydroxy-camptothecin have been compiled and complete assignments made.224 The unwanted 20R-lactone (408) obtained by resolution of the racemic lactone via the amide (409) has been converted into its 20s-enantiomer (410) which is required for the synthesis of 20S-camptothecin by reaction of the mesylate (411) with caesium acetate followed by hydrolysis (Scheme 62).225 Details of the synthesislo of camptothecin by Ejima et al.have been published.226 A range of camptothecin derivatives in which ring E is modified have been prepared and evaluated for inhibition of DNA topoisomerase I and cytotoxicity to mammalian cells. 227 Compounds tested include those with the ring E lactone grouping replaced by lactam imide and thiolactone functions ; from which it was concluded that in camptothecin all the features of ring E including the hydroxy-group are critical for enzyme inhibition.In contrast the camptothecin analogues (412) and (413),prepared from the racemic lactone (408/410) were found to be more active against P388 leukaemia cells in mice and less toxic than camptothecin and hence have greater clinical NATURAL PRODUCT REPORTS 1991 7 References 1 (a) N. Aimi S. Sakai and Y. Ban in ‘The Alkaloids’ ed. A. Brossi Academic Press New York 1989 36 Chapter 1 ; (6) T. Ohmoto and K. Koike ibid. Chapter 3; (c) S. Takano and K. Ogasawara ibid. Chapter 5. 2 The Alkaloids ed. A. Brossi and M. Suffness Academic Press New York 1990 Volume 37. 3 Studies in Natural Product Chemistry ed. Atta-ur-Rahman Elsevier Amsterdam (a)Volume 1 1988; (b)Volume 3 1989; (c) Volume 4 1989. 4 I. Ninomiya T. Naito T. Kiguchi and 0.Miyata Yuki Gosei Kagaku Kyokaishi 1990 48 206.5 Atta-ur-Rahman M. M. Qureshi K. Zaman S. Malik and S. S. Ali Fitoterapia 1989 60 291. 6 T. A. Van Beek Rev. Latinoamer. Quim. 1990 270. 7 A. Belkhiri and G. B. Lockwood Pxytochemistry 1990,29 1315. 8 (a)K. Monde K. Sasaki and M. Takasugi Phytochemistry 1990 29 1499; (b)K. Monde N. Katsui A. Shirata and M. Takasugi Chem. Lett. 1990 209. 9 V. M. Koritsas J. A. Lewis and G. R. Fenwick Experientia 1989 45 493. 10 J. E. Saxton Nat. Prod. Rep. 1990 7 191. 11 M. Devys M. Barbier A. Kollmann T. Rouxel and J.-F. Bousquet Phytochemistry 1990 29 1087. 12 (a) M. C. Viaud and P. Rollin Tetrahedron Lett. 1990 31 1417; (b) M. Devys and M. Barbier Synthesis 1990 214. 13 G. Guella 1. Mancini H.Zibrowius and F. Pietra Helv. Chim. Acta 1989 72 1444. 14 G. Guella I. Mancini D. Duhet B. Richer de Forges and F. Pietra 2. Naturforsch. Teil C 1989 44,914. 15 J. Tanaka T. Higa G. Bernardinelli and C. W. Jefford Tetra-hedron 1989 45 7301. 16 H. H. Sun reported by K. L. Erickson in ‘Marine Natural Products :Chemical and Biological Perspectives’ ed. P. J. Scheuer Academic Press New York Vol. 5 1983. 17 T. Ohta and M. Somei Heterocycles 1989 29 1663. 18 M. R. Brennan and K. L. Erickson Tetrahedron Lett. 1978,1637. 19 T.-S. Wu M.-J. Liou T. T. Jong Y.-J. Chen and J.-S. Lai Phytochemistry 1989 28 2873. 20 T.-S. Wu M.-J. Liou C.-J. Lee T.-T. Jong A. T. McPhail D. R. McPhail and K.-H. Lee Tetrahedron Lett. 1989 30 6649. 21 (a) B.A. Czeskis and A. M. Moissenkov J. Chem. Soc. Perkin Trans. 1 1989 1353; (b) B. A. Czeskis I. G. Alekseev and A. M. Moiseenkov Zhur. Org. Khim 1990 26 425. See also A. M. Moiseenkov B. Czeskis Z. G. Makarova and V. M. Zhulin Izv. Akad. Nauk SSSR Ser. Khim. 1988 2647. 22 F. D. Monache G. D. Monache M. A. De Moraes e Souza M. Da Salete Cavalcanti and A. Chiappeta Gazz. Chim. Ital. 1989 119 435. 23 R. Herb A. R. Carroll W. Y. Yoshida P. J. Scheuer and V. J. Paul Tetrahedron 1990 46,3089. 24 (a) T. Yasukouchi and K. Kanematsu J. Chem. Soc. Chem. Commun. 1989 953; (b) T. Yasukouchi and K. Kanematsu Tetrahedron Lett. 1989 30 6559. 25 (a) H. Muratake and M. Natsume Tetrahedron Lett. 1989 30 5771 ;(b)H. Muratake M. Watanabe K. Goto and M.Natsume Tetrahedron 1990 46 4179. 26 M. R. TePaske J. B. Gloer D. T. Wicklow and P. F. Dowd Tetrahedron 1989 45 4961. 27 (a) M. R. TePaske J. B. Gloer D. T. Wicklow and P. F. Dowd J. Org. Chem. 1989 54 4743; (b) M. R. TePaske J. B. Gloer D. T. Wicklow and P. F. Dowd Tetrahedron Lett. 1989 30 5965. 28 D. Prakash V. Lakshmi K. Raj and R. S. Kapil Fitoterapia 1989 60,347. 29 V. Kumar J. Reisch and A. Wickramasinghe Aust. J. Chem. 1989 42 1375. 30 L. Bhattacharyya S. K. Chatterjee S. Roy and D. P. Chakraborty J. Indian Chem. Soc. 1989 66 140. 31 H.-J. Knolker and M. Bauermeister J. Chem. Soc. Chem. Commun. 1990 664. 32 H.-J. Knolker and M. Bauermeister J. Chem. Soc. Chem. Commun. 1989 1468. 33 C. J. Moody and P. Shah J. Chem.Soc. Perkin Trans. I 1989 2463. 34 K. Nozawa Y. Horie S. Udagawa K. Kawai and M. Yamazaki Chem. Pharm. Bull. 1989 37 1387. 35 (a) R. E. Mewshaw M. D. Taylor and A. B. Smith J. Org. Chem. 1989 54 3449; (b) A. B. Smith and T. L. Leenay J. Am. Chem. Soc. 1989 111 5761. NATURAL PRODUCT REPORTS 1991-J. E. SAXTON 36 C. W. Holzapfel M. W. Bredenkamp R. M. Snyman J. C. A. Boeyens and C. C. Allen Phytochemistry 1990 29 639. 37 H. Akita T. Kawaguchi Y. Enoki and T. Oishi Chem. Pharm. Bull. 1990 38 323. 38 S. Takase N. Shigematsu I. Shima I. Uchida and M. Hashimoto J. Org. Chem. 1987 52 3487. 39 I. Shima N. Shimazaki K. Imai K. Hemmi and M. Hashimoto Chem. Pharm. Bull. 1990 38 564. 40 K. Sat0 and A. P. Kozikowski Tetrahedron Lett.1989 30,4073. 41 K. Shishido T. Azuma and M. Shibuya Tetrahedron Lett. 1990 31 219. 42 J. E. Saxton Nar. Prod. Rep. 1989 6 1. 43 Y. Luo Q. Yu L. Chrisey and A. Brossi Heterocycles 1990 31 283. 44 S. Takano M. Moriya Y. Iwabuchi and K. Ogasawara Chem. Lett. 1990 109. 45 (a) S. Takano K. Inomata and K. Ogasawara J. Chem. Soc. Chem. Commun. 1989 271 ; (b) S. Takano K. Inomata T. Sato M. Takahashi and K. Ogasawara ibid. 1990,290; (c) S. Takano T. Sato K. Inomata and K. Ogasawara Heterocycles 1990 31 411. 46 C. Souleles and E. Kokkalou Planta Med. 1989 55 286. 47 F. E. Wu K. Koike T. Nikaido Y. Sakamoto T. Ohmoto and K. Ikeda Chem. Pharm. Bull. 1989 37 1808. 48 (a) D. Arbain and M. V. Sargent Aust. J. Chem. 1987 40 1527; (b) D. Arbain L.T. Byrne M. V. Sargent B. W. Skelton and A. H. White ibid. 1990 43 433. 49 (a) H. Banerjee S. Pal and N. Adityachaudhury Planta Med. 1989 55 403; (b) N. Shoji A. Umeyama A. Iuchi N. Saito S. Arihara K. Nomoto and Y. Ohizumi J. Nat. Prod. 1989 52 1160. 50 L. A. Chrisey and A. Brossi Heterocycles 1990 30 267. 51 (a) P. H. H. Hermkens J. H. van Maarseveen P. L. H. M. Cobben H. C. J. Ottenheijm C. G. Kruse and H. W. Scheeren Tetrahedron 1990 46 833; (b) P. H. H. Hermkens J. H. van Maarseveen H. W. Berens J. M. Smits C. G. Kruse and H. W. Scheeren J. Org. Chem. 1990,55,2200;(c)T. Hino A. Hasegawa J.-J. Liu and M. Nakagawa Chem. Pharm. Bull. 1990 38 59. 52 T. A. K. Al-Allaf M. T. Ayoub and L. J. Rashan J. Inorg. Biochem. 1990 38 47.53 L. J. Rashan Fitoterapiu 1990 56 153. 54 J. Kobayashi J. Cheng T. Ohta S. Nozoe Y. Ohizumi and T. Sasaki J. Org. Chem. 1990 55 3666. 55 B. C. Vanwagenen and J. H. Cardellina Tetrahedron Lett. 1989 30 3605. 56 H. H. Wasserman and T. A. Kelly Tetrahedron Lett. 1989 30 71 17. 57 T. Hino Z. Lai H. Seki R. Hara T. Kuramochi and M. Nakagawa Chem. Pharm. Bull. 1989 37 2596. 58 I. W. J. Still and J. McNulty Heterocycles 1989 29 2057. 59 P. H. H. Hermkens J. H. van Maarseveen C. G. Kruse and H. W. Scheeren Tetrahedron Lett. 1989 30 5009. 60 M. P. Kirkup B. B. Shankar S. McCombie A. K. Ganguly and A. T. McPhail Tetrahedron Lett. 1989 30 6809. 61 P. H. H. Hermkens J. H. van Maarseveen H. C. J. Ottenheijm C. G. Kruse and H. W. Scheeren J.Org. Chem. 1990 55 3998. 62 J.-J. Liu M. Nakagawa N. Harada A. Tsuruoka A. Hasegawa J. Ma and T. Hino Heterocycles 1990 31 229. 63 Y. Torisawa M. Nakagawa H. Arai Z. Lai T. Hino T. Nakata and T. Oishi Tetrahedron Lett. 1990 31 3195. 64 K. M. J. Brands and U. K. Pandit Heterocycles 1990 30 257. 65 Y. Torisawa A. Hashimoto M. Nakagawa and T. Hino Tetra-hedron Lett. 1990 30 6549. 66 (a) P. Barbetti G. Grandolini G. Fardella I. Chiappini and A. Mastalia Planta Med. 1990 56 216; (b) T. Ohmoto and K. Koike Chem. Pharm. Bull. 1985 33 3847. 67 R. Vanhaelen-Fastre M. Vanhaelen B. Diallo and H. Breyne Planru Med. 1990 56 241. 68 K. C.-S.Liu Y. Shi-Lin M. F. Roberts and J. D. Phillipson Phytochemisrrj 1990 29 141. 69 G. Krauss G.-J. Krauss R. Baumbach and D.Groger 2. Naturforsch. Teil C 1989 44,712. 70 J. W. Daly H. M. Garraffo L. K. Pannell T. F. Spande C. Severini and V. Erspamer J. Nut. Prod. 1990 53 407. 71 M. 0.Mitchell and P. W. LeQuesne Tetrahedron Lett. 1990 31 268 1. 72 A. G. Kozlovskii T. A. Reshetilova V. G. Sakharovskii V. M. Adanin and A. M. Zyakun Prikl. Biokhim. Mikrobiol. 1988 24 642 (Chem. Abstr. 1989 110 36554). 73 W. F. Abraham and H. A. Arfmann Phytochemistry 1990 29 1025. 74 S. Kodato M. Nakagawa M. Hongu T. Kawate and T. Hino Tetrahedron 1988 44 359. 75 K. Arai K. Kimura T. Mushiroda and Y. Yamamoto Chem. Pharm. Bull. 1989 37 2937. 76 P. D. Bailey S. P. Hollinshead and N. R. McLay Tetrahedron Lett. 1989 30 6421. 77 R. M. Williams T. Glinka E. Kwast H.Coffman and J. K. Stille J. Am. Chem. Soc. 1990 112 808. 78 T. A. Blizzard H. Mrozik M. H. Fisher and J. M. Schaeffer J. Org. Chem. 1990 55 2256. 79 (a)J. G. Ondeyka R. T. Goegelman J. M. Schaeffer L. Kelemen and L. Zitano unpublished work cited in ref. 78 ;(6)C. Wichmann and J. Liesch unpublished work cited in ref. 78. 80 J. E. Saxton Nat. Prod. Rep. 1989 6 433. 81 K. Irie S. Kajiyama A. Funaki K. Koshimizu H. Hayashi and M. Arai Tetrahedron 1990 46 2773. 82 A. P. Kozikowski K. Sato A. Basu and J. S. Lazo J.Am. Chem. Soc. 1989 111 6228. 83 M. Flieger R. Linhartova P. Sedmera J. Zima P. Sajdl J. Stuchlik and L. Cvak J. Nat. Prod. 1989 52 1003. 84 M. Flieger V. Kren N. F. Zelenkova P. Sedmera J. Novak and P. Sajdl J. Nat. Prod. 1990 53 171.85 K. Seifert H. Meyer S. Hartling and S. Johne Tetrahedron 1989 45 7291 86 M. Beran A. Cerny M. Kuchai H. A_damirova J. Holubek J. Tamir J. Vachek M. Friihaufova K. Reiabek M. Valchii and I. Krejzi Coll. Czech. Chem. Commun. 1990 55 819. 87 I. Ninomiya C. Hashimoto T. Kiguchi T. Naito D. H. R. Bar- ton X. Lusinchi and P. Milliet J. Chem. Soc. Perkin Trans. I 1990 707. 88 G. Megyeri and T. Keve Synth. Commun. 1989 19 3415. 89 (a) W. H. Watson A. Nagl M. Silva C. Cespedes and J. Jakupovic Acta Crystallogr. Sect. C 1989 45 1322; (b) C. Cespedes J. Jakupovic M. Silva and W. H. Watson Phytochemistry 1990 29 1354. 90 S. Burkard and H.-J. Borschberg Helv. Chim. Acta 1990,73,298. 91 (a) I. R. C. Bick and M. A. Hai Tetrahedron Lett. 1981 22 3275; (b) G.Snatzke I. R. C. Bick and M. A. Hai unpublished work reported by 1. R. C. Bick and M. A. Hai in ‘The Alkaloids’ ed. A. Brossi Academic Press New York 1985 Vol. 24 Chapter 3. 92 (a)H. Morita Y. Ichihara K. Takeya K. Watanabe H. Itokawa and M. Motidome Planta Med. 1989 55 288; (b) M. Lin S. Z. Li X. Liu and D. Q. Yu Yaoxue Xuebao 1989 24 32 (Chem. Abstr. 1989 111 74776). 93 B. K. Carte C. DeBrosse D. Eggleston M. Hemling M. Mentzer B. Poehland N. Troupe J. W. Westley and S. M. Hecht Tetrahedron 1990 46 2747. 94 C. P. Hasbun M. Calderon 0.Castro E. Gacs-Baitz G. D. Monache and F. D. Monache Tetrahedron Lett. 1989,30,6199. 95 W.-L. Hu J.-P. Zhu and M. Hesse Planta Med. 1989 55 463. 96 N. Boughandjioua L. Bengaouer F. Hotellier E. Seguin F.Tillequin and M. Koch J. Nat. Prod. 1989 52 1107. 97 J. Abaul E. Philogene P. Bourgeois A. Ahond C. Poupat and P. Potier J. Nat. Prod. 1989 52 1279. 98 P. Thepenier M.-J. Jacquier J. Henin G. Massiot L. Le Men- Olivier and C. Delaude Phytochemistry 1990 29 2384. 99 Atta-ur-Rahman A. Pervin A. Muzaffar K. T. D. De Silva and W. S. J. Silva Phytochemistry 1989 28 3221. 100 E. Davioud C. Kan J. Hamon J. Tempe and H.-P. Husson Phytochemistry 1989 28 2675. 101 J. A. Martinez C. Gomez T. Santana and H. Velez Planta Med. 1989 55 283. 102 B. Datta and N. G. Bisset Planta Med. 1990 56 133. 103 G. Massiot P. Thkpenier M.-J. Jacquier L. Le Men-Olivier and C. Delaude Heterocycles 1989 29 1435. 104 G. Massiot P. Thepenier M.-J. Jacquier J. Lounkokobi C.Mirand M. Zeches L. Le Men-Olivier and C. Delaude Tetra-hedron 1983 39 3645. 105 D. Ponglux S. Wongseripipatana N. Aimi M. Nishimura M. Ishikawa H. Sada J. Haginiwa and S. Sakai Chem. Pharm. Bull. 1990 38,573. 106 (a) M. A. Mufioz C. Carmona J. Hidalgo M. Balon and M. Lopez-Poveda Heterocycles 1989,29 1343 ; (b) A. De Bruyn W. Zhang and M. BudCSinsk9 Magn. Reson. Chem. 1989 27 935. 107 L.-H. Zhang A. K. Gupta and J. M. Cook J. Org. Chem. 1989 54 4708. 108 A. J. Gaskell and J. A. Joule Tetrahedron 1967 23 4053. 109 S. F. Martin H. Rueger S. A. Williamson and S. Grzejszczak J. Am. Chem. Soc. 1987 109 6124. 110 E. Wenkert and Y.-J. Shi Synth. Commun. 1989 19 1071. 11 1 (a)M. Rubiralta A. Diez J. Bosch and X. Solans J. Org.Chem. 1989 54 5591 ; (6) M. Rubiralta A. Diez and C. Vila Tetra-hedron Lett. 1990 31 3347 3779; (c) M. Rubiralta A. Diez and C. Vila Tetrahedron 1990 46 4443; (d) A. Diez M. Tona and M. Rubiralta Tetrahedron 1990 46 4393. 112 (a) D. Spitzner K. Arnold J. J. Stezowski T. Hildenbrand and S. Henkel Chem. Ber. 1989 122 2027; (b) M. Lounasmaa R. Jokela P. Makimattila and B. Tirkkonen Tetrahedron 1990 46 263 3. 113 S. Peng and E. Winterfeldt Liebigs Ann. Chem. 1990 313 319. 114 M. Lounasmaa and R. Jokela Tetrahedron 1989 45 7449. 115 L. Chevolot H.-P. Husson and P. Potier Tetrahedron 1975 31 249 I. 116 E. Wenkert P. W. Sprague and R. L. Webb J. Org. Chem. 1973 38,4305. 117 B. C. Maid V. S. Giri and S. C. Pakrashi Heterocycles 1990,31 847.118 M.-L. Bennasar M. Alvarez R. Lavilla E. Zulaica and J. Bosch J. Org. Chem. 1990 55 1156. I19 M.-L. Bennasar E. Zulaica J.-M. Jimenez and J. Bosch Tetra-hedron Lett. 1990 31 747. 120 T. Fujii M. Ohba T. Tachinami T. Ohashi M. Koch and E. Seguin Heterocycles 1989 29 1037. 121 (a)T. Fujii M. Ohba and N. Sasaki Chem. Pharm. Bull. 1989 37,2822; (b)S. B. Mandal and S. C. Pakrashi Heterocycles 1987 26 1557; (c) P. Rosenmund M. Casutt and M. Wittich Liebigs Ann. Chem. 1990 223. 122 R. T. Brown and M. J. Ford Tetrahedron Lett. 1990 31 2029 203 3. 123 I. Ninomiya T. Naito 0.Miyata T. Shinada E. Winterfeldt R. Freund and T. Ishida Heterocycles 1990 30 103 1. 124 S. Takano S. Satoh and K. Ogasawara Heterocycles 1990 30 583. 125 P. Holscher H.-J.Knolker and E. Winterfeldt Tetrahedron Lett. 1990 31 2705. 126 J. Leonard D. Ouali and S. K. Rahman Tetrahedron Lett. 1990 31 739. 127 P. Rosenmund and M. Hosseini-Merescht Tetrahedron Lett. 1990 31 647. 128 S. F. Martin and M. Mortimore Tetrahedron Lett. 1990 31 4557. 129 A. A. Ibragimov and S. Yu. Yunusov Khim. Prirod. Soedin. 1985 536 544. 130 S. Takano K. Samizu T. Sugihara S. Satoh and K. Ogasawara Chem. Lett. 1989 1777. 131 M. Lounasmaa and R. Jokela Tetrahedron 1990 46,615. 132 D. H. Hua S. N. Bharathi F. Takusagawa A. Tsujimoto J. A. K. Panangadan M.-H. Hung A. A. Bravo and A. M. Erpelding J. Org. Chem. 1989 54 5659. 133 J. Aubi Y. Wang M. Hammond M. Tanol F. Takusagawa and D. V. Velde J. Am. Chem. Soc. 1990 112 4879. 134 G.Stork Pure Appl. Chem. 1989 61 439. 135 Atta-ur-Rahman M. M. Qureshi S. S. Ali K. T. D. De Silva and W. S. J. Silva Fitoterapia 1990 61 91. 136 J.-M. Nuzillard T. M. Pinchon C. Caron G. Massiot and L. Le Men-Olivier Compt. Rend. Ser. II 1989 309 195. 137 F. Abe R. F. Chen T. Yamauchi N. Marubayashi I. Ueda G. A. Padolina,andF. M. Dayrit Tennen YukiKagobutsu Toronkai Koen Yoshishu 1989 31 570 (Chem. Abstr. 1990 112 195 196). 138 B. Proksa D. Uhrin E. Grossmann and Z. Voticky Planta Med. 1989 55 188. 139 X. He C. Li and Y. Zhou Huaxue Xuebao 1989 47 1076. 140 Atta-ur-Rahman F. Nighat G. Ahmed M. I. Choudhary Habib-ur-Rehman and K. T. D. De Silva Fitoterapia 1990 61 230. 141 A.-M. Morfaux D. Guillaume G. Massiot and L. Le Men-Olivier Compt.Rend. Ser. 11,1989 309 33. 142 (a) F. Sun Q. Y. Xing and X. T. Liang J. Nut. Prod. 1989 52 1180; (b) L.-Z. Lin G. A. Cordell C.-Z. Ni and J. Clardy. Phytochemistry 1990 29 965. 143 S. S. Ahmad S. I. Haider and S. Siddiqui Synthesis 1988 478. 144 M. L. Trudell and J. M. Cook J. Am. Chem. Soc. 1989 111 7504. 145 L. H. Zhang and J. M. Cook J. Am. Chem. Soc. 1990 112 4088. 146 R. L. Garnick and P. W. LeQuesne J. Am. Chem. Soc. 1978,100 42 13. NATURAL PRODUCT REPORTS 1991 147 H. Takayama M. Horigome N. Aimi and S. Sakai Tetrahedron Lett. 1990 31 1287. 148 A. S. Kende M. J. Luzzio and J. S. Mendoza J. Org. Chem. 1990 55 918. 149 H. Takayama and S. Sakai Chem. Pharm. Bull. 1989 37 2256. 150 H. Takayama M. Kitajima and S. Sakai Heterocycles 1990 30 325.151 P. Magnus B. Mugrage M. R. DeLuca and G. A. Cain J. Am. Chem. Sac. 1990 112 5220. 152 S. H. Goh A. R. M. Ali and W. H. Wong Tetrahedron 1989 45 7899. 153 P. Thipenier M.-J. Jacquier G. Massiot L. Le Men-Olivier and C. Delaude Phytochemistry 1990 29 686. 154 H. Fujiwara Y.-Z. Da T. Takagi and Y. Sasaki Chem. Pharm. Bull. 1989 37 2887. 155 R. Ghosh P. Roychowdhury D. Chattopadhyay and Y. Iitaka Acta Crystallogr. Sect. C 1989 45 1794. 156 (a) M. Rubiralta A. Torrens A. Palet D. S. Grierson and H.-P. Husson Tetrahedron Lett. 1989 30 6761 ; (6) M. Rubiralta A. Torrens I. Reig D. S. Grierson and H.-P. Husson Heterocycles 1989 29 2121. 157 (a) J. Bonjoch N. Casamitjana J. Gracia and J. Bosch Tetra-hedron Lett. 1989 30 5659; (b) J.Bonjoch N. Casamitjana J. Gracia M. C. Ubeda and J. Bosch ibid. 1990,31,2449; (c) M. Amat M. Alvarez J. Bonjoch N. Casamitjana J. Gracia R. Lavilla X. Gardias and J. Bosch ibid. 3453. 158 M. Rubiralta A. Diez and C. Vila Tetrahedron Lett. 1990 31 3347. 159 G. A. Kraus P. J. Thomas D. Bougie and L. Chen J. Org. Chem. 1990 55 1624. 160 (a) G. W. Gribble M. G. Saulnier M. P. Sibi and J. A. Obaza- Nutaitis J. Org. Chem. 1984 49 4518; (b) D. A. Davis and G. W. Gribble Tetrahedron Lett. 1990 31 1081. 161 A. G. Mustafin I. N. Khalilov 1. B. Abdrakhmanov and G. A. Tolstikov Khim. Prir. Soedin. 1989 816. 162 Y. Yokohama N. Okuyania S. Iwadate T. Momoi and Y. Muramaki J. Chem. Soc. Perkin Trans. I 1990 1319. 163 I. Hogan P. D. Jenkins and M.Sainsbury Tetrahedron 1990 46 2943. 164 (a) L. Larue C. Rivalle G. Muzard. C. Paoletti E. Bisagni and J. Paoletti J. Med. Chem. 1988,31,1951;(b)T. Honda M. Kato M. Inoue T. Shimamoto K. Shima T. Nakanishi T. Yoshida and T. Noguchi ibid. 1295. 165 W. Hiller K. Wurst Atta-ur-Rahman S. Khanum and P. Hutter Acta Crystallogr. Sect. C 1989 45 1258. 166 J. Zheng Y. Zhou and Z. Huang Acta Chim. Sinica (Engl. Ed.) 1989 168 (Chem. Abstr. 1990 112 95446). 167 T.-S. Kam and P.-S. Tan Phytochemistry 1990 29 2321. 168 G. Palmisano B. Gabetta G. Lesma T. Pilati and L. Toma J. Org. Chem. 1990 55 2182. 169 G. E. Jackson Spectrosc. Lett. 1989 22,31. 170 T. Naaranlahti M. Nordstrom S. P. Lapinjoki A. Huhtikangas and M. Lounasmaa J. Chromatogr.Sci. 1990 28 173. 171 (a) C. Berrier J. C. Jacquesy M. P. Jouannetaud and Y. Vidal Tetrahedron 1990 46 815; (6) 1990 46 827. 172 N. I. Zaletova G. G. Aleksandrov V. I. Yartseva N. A. Klyuev and 0.N. Tolkachev Khim. Prir. Soedin. 1988 551 (Chem. Abstr. 1989 111 174486). 173 (a) H. Bolcskei E. Gacs-Baitz and Cs. Szantay Tetrahedron Lett. 1989 30 7245; (b) Gedeon Richter Belg. Pat. 867 255 (Chem. Abstr. 1979 90 138081). 174 G. Toth Cs. Szantay Jr. I. Moldvai Cs. Szantay W. Dietrich, and A. Vedres J. Mol. Struct. 1989 212 271. 175 A. Kovacs G. Toth I. Moldvai and Cs. Szantay J. Chem. Res. (8,1990 124. 176 C. H. Heathcock M. H. Norman and D. A. Dickmann J. Org. Chem. 1990 55 798. 177 M. Node H. Nagasawa and K. Fuji J. Org. Chem. 1990 55 517.178 A. I. Meyers and D. Berney J. Org. Chem. 1989 54 4673. 179 (a) M. Ihara K. Yasui N. Taniguchi and K. Fukumoto Heterocycles 1990 31 1017; (6) A. I. Meyers J. Romine and A. J. Robichaud ibid. 339. 180 J. Mittendorf H. Hiemstra and W. N. Speckamp Tetrahedron 1990 46 4049. 181 J. d’Angelo and D. Desmaele Tetrahedron Lett. 1990,31 879; D. Desmaele and J. d’Angelo ibid. 883. 182 R. H. Huizenga J. van Wiltenburg and U. K. Pandit Tetrahedron Lett. 1989 30 7105. NATURAL PRODUCT REPORTS 1991-J. E. SAXTON 183 G. Hugel D. Cartier and J. Levy Tetrahedron Lett. 1989 30 4513. 184 P. Magnus T. Katoh I. R. Matthews and J. C. Huffman J. Am. Chern. Soc. 1989 111 6707. 185 P. Magnus and P. Brown J. Chem. SOC. Chem. Commun. 1985 184. 186 M.Lounasmaa and A. Tolvanen J. Org. Chem. 1990 55 4044. 187 P. Gmeiner P. L. Feldman M. Y.Chu-Moyer and H. Rapoport J. Org. Chem. 1990 55 3068. 188 D. Genin R. Z. Andriamialisoa N. Langlois and Y. Langlois J. Org. Chem. 1987 52 353. 189 J.-C. Ortuno N. Langlois and Y.Langlois Tetrahedron Lett. 1989. 30 4957. 190 M. Soriano-Garcia A. Rodriguez F. Walls and R. Toscano J. Crystallogr. Spectrosc. Res. 1989 19 725. 191 (a) Cs. Szantay T. Keve H. Bolcskei and T. Acs Tetrahedron Lett. 1983 24 5539; (b)Cs. Szantay H. Bolcskei E. Gacs-Baitz and T. Keve Tetrahedron 1990 46,1687. 192 Cs. Szdntay H. Bolcskei and E. Gacs-Baitz. Tetrahedron 1990 46 1711. 193 M. E. Kuehne and W. G. Bornmann J. Org. Chem. 1989 54 3407. 194 M. E. Kuehne and J. B.Pitner J. Org. Chem. 1989 54 4553. 195 M. E. Kuehne and J. C. Bohnert J. Org. Chem. 1981 46 3443. 196 (a) J. Bergman and U. Tilstam Tetrahedron 1985 41 2883; (b) J.-C. Zou and L. Huang Yaoxue Xuebao (Acta Pharm. Sinica) 1985 20 45; (c) J. Bergman Phytochemistry 1989 28 3547. 197 (a)S. A. Morris and R. J. Andersen Can. J. Chem. 1989,67,677; (b) S. A. Morris and R. J. Andersen Tetrahedron 1990 46 715. 198 B. Pelcman and G. W. Gribble Tetrahedron Lett. 1990 31 2381. 199 M. Somei and T. Kawasaki Chem. Pharm. Bull. 1989 37 3426. 200 J. X. Xie L. Xie Z. P. Gu Y. Z. Liu and Z. R. Wang Yuoxue Xuehuo 1988 23 732. 201 S. Tanida M. Takizawa T. Takahashi S. Tsubotani and S. Harada J. Antihiot. 1989 42 1619. 202 P. D. Davis R. A. Bit and S. A. Hurst Tetrahedron Lett.1990 31 2353. 203 Y. Adjibade H. Saad T. Sevenet B. Kuballa J. C. Quirion and R. Anton Plantu Med. 1990 56 212. 204 G. Massiot J. M. Nuzillard B. Richard and L. Le Men-Olivier Tetrahedron Lert. 1990 31 2883. 205 Z.-H. Huang J.-J. Zheng and Y.-L. Zhou Huaxue Xuebao 1989 47 884 (Chem. Abstr. 1990 112 158707). 206 X.-Z. Feng G. Liu C. Kan P. Potier and S.-K. Kan J. Nut. Prod.. 1989 52 928. 207 W. Fahn V. Kaiser H. Schiibel J. Stockigt and B. Danieli Phptochemutr~*, 1990 29 127. 208 (a) K. S. P. Bhushana Rao A. De Bruyn A. Trouet M. Verzele and J. Hannart Bull. SOC. Chim. Belg. 1989 98 125; (b) K. S. P. Bhushana Rao J. Cornet and A. De Bruyn ibid. 1990 99 187. 209 M. Mak J. Tamas K. Honty L. Szabo and Cs. Szantay Biomed. Environ.Mass Spec. 1989 18 576. 210 G. Nasioulas K. Grammbitter K. Gerzon and H. Ponstingl Tetrahedron Lett. 1989 30 588 1. 21 1 A. De Bruyn M. Verzele J.-P. Dejonghe K. S. P. Bhushana Rao M.-P. Collard A. Trouet and J. Hannart PIanta Med. 1989 55 364. 212 (a)S. A. Elmarakby M. W. Duffel A. Goswami F. S. Sariaslani and J. P. N. Rosazza J. Med. Chem. 1989 32 674; (b) S. A. Elmarakby M. W. Duffel and J. P. N. Rosazza ibid. 2158. 213 K. Hirata M. Kobayashi K. Miyamoto T. Hoshi M. Okazaki and Y. Miura Planta Med. 1989 55 262. 214 J. D. Hamill R. J. Robins and M. J. C. Rhodes Planta Med. 1989 55 354. 215 M. Gdaniec Z.Kosturkiewicz and B. Golankiewicz Actu Crystallogr. Sect. C 1989 45 1656. 216 J. Gawronski M. Brzostowska and J. Koput Croat. Chem.Actu 1989 62 97. 217 A. Hermans-Lokkerbol T. Van Der Leer and R. Verpoorte J. Chromatogr. 1989 479 39. 218 (a)G. D. H. Dijkstra R. M. Kellogg and H. Wynberg Rec. Trav. Chim. 1989 108 195; (b) G. D. H. Dijkstra R. M. Kellogg H. Wynberg J. S. Svendsen I. Marko and K. B. Sharpless J. Am. Chem. Soc. 1989 111 8069. 219 E. J. Corey and G. I. Lotto Tetrahedron Lett. 1990 31. 2665. 220 S. Hanessian A.-M. Faucher and S. Leger Tetrahedron 1990 46,231. 221 H. Diaz-Arauzo J. M. Cook and D. J. Christie J. Nut. Prod. 1990 53 112. 222 L.-Z. Lin J.-H. Shen T. Zhou C.-Y. Shen and M. M. Ke Huaxue Xuebao 1989 47 506. 223 N. Aimi M. Nishimura A. Miwa H. Hoshino S. Sakai and J. Haginiwa Tetrahedron Letr. 1989 30 4991. 224 L.-Z. Lin and G. A. Cordell J.Nut. Prod. 1990 53 186. 225 H. Terasawa M. Sugimori A. Ejima and H. Tagawa Chem. Pharm. Bull. 1989 37 3382. 226 A Ejima H. Terasawa M. Sugimori and H. Tagawa J. Chem. Soc. Perkin Trans. I 1990 27. 227 R. P. Hertzberg M. J. Caranfa K. G. Holden D. R. Jakas G. Gallagher M. R. Mattern C.-M. Mong J. O’L. Bartus R. K. Johnson and W. D. Kingsbury. J. Med. Chern. 1989 32 715. 228 A. Ejima H. Terasawa M. Sugimori S. Ohsuki K. Matsumoto Y. Kawato and H. Tagawa Chem. Pharm. Bull. 1989,37 2253. 22 NPR 8

ISSN:0265-0568    

DOI:10.1039/NP9910800251

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

22-2 NATURAL PRODUCT REPORTS 1991 Table 1 Isolated drimanes Compound R1 R2 Ref. Warburganal (5) PCHO OH H2 17 Polygodial (Tadeonal) (6) PCHO H H2 30 31 Isotadeonal (Isopolygodial) (7) aCHO H H 31 28 Polygonic acid (8) PCOOH H H 27 Cinnamodial (Ugandensidial) (9) PCHO OH POAc H 14 15 Mukaadial (10) PCHO OH aOH H 22a Pu'ulenal (1 1) (E)-CH(OAc) H2 57 p-Coumaroyloxypolygodial (1 2) PCHO H H2 20 Capsicodendrin (1 3)b PCHO OH POAc H 18 Cinnamolide (14) H2 H 14a Cinnamosmolide (15) POAc H OH 14a Bemarivolide (1 6) POAc H H 15 Pereniporin B (17) POH €3 OH 50 11-Ethoxycinnamolide (1 8) H2 H 27 9-Hydroxycinnamolide (19) H2 OH 22b 1I-Hydroxy- I-p-coumaroyloxy H2 H 20 cinnamolide' (20) Confertifolin (2 1) H2 H2 12 Valdiviolide (22) aOH H H2 13 Fuegin (23) aOH H aOH H 13 Fragrolide (24) H2 H2 15 Winterin (25) 0 H2 13 Purpuride (26) H H 41 Bemadienolide (27) H2 H A 15 Drimenin (28) H 0 12 3-Acetoxydrimenin (29) H 0 19 Isodrimeninol (30) H aOH H 29 Drimeninol (3 1) H POH €3 34 --e (32) H aOAc 54 Di(7-drimen-1l-oxy)-I 1,12-epoxy-7-H Cf 9c drimene (33) Olepupuane (34) aH aOAc 54 Acetoxyolepupuane (35) aH aOAc H 53 --(36) aH aORg 52a Euryfuran (37) A 55 Isodrimenin (38) H2 H2 12 Ugandensolide (39) aOH H POAc H 15 Acetoxyisodrimenin (40) H2 POAc H 18 Futronolideh (41) aOH H H2 18 Epoxyisodrimenin (42) H ,O ,H-32 Hydroxyisodrimenin (43) H2 POH H 26b Ketodihydrodrimenin (44) 0 H 43 Hydroxydihydrodrimenin (45) POH H H2 43 Dihydroxydihydrodrimenin (46) POH H aOH H 43 Drimanol (47) PCH, H PCH, OH 40 Drimanediol (48) PCH,OH H PCH, OH 40 Drimanetriol (49) PCH,OH H aCH, OH 48 Albicanol (50) PCH20H H CH 56b Albicanylacetate (5 1) PCH,OAc H CH 566 Cryptoporic acid A (52) PCH,OR Hi CH 45a Drim-9(1l)-en-8P-ol (53) CH aCH, OH 46 Drim-9( 1 l)-en-8a-o1 (54) CH PCH3 OH 46 Isoalbrassitriol (55) PCH,OH OH aCH, OH 49 Uvidin D (56) PCH,OH H PCH, H 44b Drimenon (57) CH3 As CH 39 Drimenol (58) PCH,OH H H 9a Albrassitriol (59) PCH,OH OH aOH H 49 Deoxy uvidin B (60) PCH,OH H 0 49 Drim-7-enyl-glyceride (6 1) PCOR Hj H2 56c Drim-7-enyl-glyceride acetate (62) PCOR Hk 56c t2 Uvidin E (63) PCH,OH H 44b Uvidin A (64) PCH,OH H 0 44a Uvidin B (65) PCH,OH H 0 44a Uvidin C (66) PCH20H,H POH 44b Dihydrocinnamolide (67) H H 34 Pebrolide (68) POBz H1 CH,OAc 42a Altiloxin A (69) H -51 Altiloxin B (70) c1 -51 Astellolide A (71) CH,OAc OBzl 47a Astellolide B (72) CH,OAc O-p-OH-Bzl 47a Parasiticolide A (73) CH,OAc OBz' 476 Periniporin A (74) 50 Cryptoporic acid B (75) 45a Cryptoporic acid C (76) 45b Cryptoporic acid D (77) 456 Cryptoporic acid E (78) 45b ent-Drimanes NATURAL PRODUCT REPORTS 1991-B.J. M. JANSEN AND A. DE GROOT 31 1 Table 1 (cont.) Compound R‘ R2 R3 Ref. Iresin (79) Isoiresin (80) Dihydroiresin (8 1) PH PH A PH A H H 6 7 7 8 nor-Drimanes Compound R1 Ref. Polygonone (82) Polygonal (83) Isopolygonal (84) 0 aOH H POH H 27 29 27 Rearranged drimanes Compound Ref. Muzigadial (85) 4,13-a-Epoxy muzigadial (86) Coloratadienolide (87) 21 24 21 10 -0,CCH = CH-C,H,OH.*Isolated as a tetramer. The authors named it (erroneous)-valdiviolide. N-acetyl-L-valinyl= O,CCH(i-C,H,) NHCOCH,. R acyl residues from several fatty acids of different unsaturated degree. The ‘Presumably obtained by allylic methanolysis of olepupuane (30). 7-drimene-11-oxy. = structure for this compound in ref. 13 is incorrect. * R = -CH(COOCH,)-CH(COOCH,)-CH,-COOH (ether of isocitric acid). OCH,-CH(0H)-CH,OH. *OCH,CH(OH)CH,OAc. Bz = benzoyl. PHO @O / / / R2 / R’ (5) -(13) (14) -(20) ($2Rl R2 (38) -(43) (44)-(46) R’ @OH t>.-(691 (70) (71) -(73) O-C-C-CH,-COOH COOCH3\COOCH3 / f OH HO’ (74) (75) NATURAL PRODUCT REPORTS 1991 0-\ C02R' c=o I I 0 I (76)R = R' = H (78)R =OH R' = H 2 Biosynthesis Most cyclizations of farnesyl pyrophosphate (FPP)58a are initiated by an enzyme-mediated solvolysis of the pyrophosphate group59 whereby an incipient or actual carbocation is formed at the tail position of the farnesyl chain.A small number of bicyclic sesquiterpenes including drimanes arise from a cyclization which is initiated by an electrophilic attack mostly by a proton on the double bond at the head position of FPP or onto the corresponding epoxide (see Scheme 1).60 The relative positions of the double bonds in the con-formation assumed by the FPP chain determines the structure and the stereochemistry of the final product. The trans ring junction is consistent with the stereoelectronic requirements of a concerted mechanism in which the sequential addition of the non-conjugated double bonds takes place.The chair-chair conformation of the polyenic chain during the cyclization can in principle exist in two enantiomeric forms from which the two enantiomeric drimane skeletons are derived. Examples of both are found in nature although not in the same plant. The hydroxyl group at C-3 probably originates from proton attack on an epoxide. It is reasonable to assume that protonation of this hydroxyl group followed by dehydration and rearrangement of the resulting carbocation accounts for the biogenesis of the rearranged drimanes (see Scheme 2). The co- occurrence of bicyclic nor-sesquiterpenes of the drimane class in some plants may arise through decarboxylation of drimanic carboxylic acids28 (see Scheme 3).3 Biological Activity of Drimanes Drimanes possess a wide variety of biological activity including antibacterial antifungal anticomplemental antifeedant plant- growth regulatory cytotoxic phytotoxic piscicidal and molluscicidal properties. Moreover the very hot taste of several biologically active drimanes to humans and their skin- irritant properties have attracted much attention. X = H Hal epoxide OPP x* PP H H ent-drimanes (iresi n) drirnanes (polygodial) Scheme 1 313 NATURAL PRODUCT REPORTS 1991-B. J. M. JANSEN AND A. DE GROOT JpR2-<+ Ho)'yH @& PR2-mR2 O) H' ' H+. Scheme 2 Scheme 3 Table 2 Antimicrobial activity of drimanic dialdehydes MIC Cug/ml) Microorganisms tested Polygodial (6) Warburganal (5) Muzigadial (85) Isotadeonal (7) Staphylococcus aureus > 100 > I00 > 100 > 100" Escherichia coli > 100" > 100 > 100 > 100" Pseudomonas aeruginosa Saccharomyces cerevisiae Hansenula anomala > 100 0.78 1.56 > 100 3.13 12.5 > 100 25 1.56 > 100" > 100 > 100 Candida utilis 1.56 3.13 3.13 > 100 Sclerotinia liber t iana 1.56 3.13 3.13 > 100 Mucor mucedo 6.25 25 25 > 100 Rhizopus chinensis Aspergillus niger 12.5 25 100 50 100 50 > 100 > 100 Penicillium crustosum 25 50 50 > 100 Trichophyton mentagrophytes 2 3 > 100 Bacillus subtilis > 100" > 100 > 100 > 100 An earlier research stated a somewhat lower value for the minimum inhibitory concentration.26 3.1 Antifungal and Antibacterial Activity In screening East African plants used in folk medicine Taniguchi et af.found several possessing antimicrobial activity.lb The plant materials were collected mainly on the basis of in-(85) (86) formation gathered from native people especially from the 'Bwana Mganga ' Swahili for 'medicine man '.61 In particular the species of the genus Warburgia (Canellaceae) showed broad activity. The extracts were fractionated and bioassayed62 leading to the isolation of the antimicrobial principles which were identified as the sesquiterpene dialdehydes polygodial (6) warburganal (5) muzigadial (85) and isotadeonal (7). The results of several bioassays are gathered in Table 2."-24 26 63-66 Polygodial (6) proved to be the most potent antifungal compound tested.It killed the cells of S. cerevisiae within ten (87) minutes when treated with a fungicidal concentration of 50,4m1.65 The related synthetic compounds (88) and (89) were also (OH tested but they were devoid of activity. Pereniporin A (74) a metabolite of Perenniporia meduffaepanis showed a remarkable effect on the growth of B. subtifis (MIC 6.25 ,ug/ml) but it was inactive against Gram-negative bacteria (MIC > 100 ,~g/ml).~O Cinnamolide (14) was active against T. rubrum (MIC > 20 ,ug/ml) T. menthagrophytes (MIC < 10pg/ml) and M. (88) (89) gypseum (MIC 20 ,~g/ml).~~~ 3.2 Plant-growth Regulatory Activity A few drimanes were examined for plant-growth regulatory properties.Polygodial (6) completely inhibited the germination of rice in husk at a concentration of ca. 100 ppm.2gj 33 .34 It also inhibited the root elongation of rice plants at a concentration of 100 ppm but at a concentration of less than 25 ppm a dramatic promotion of root elongation was observed.33' 34 Rice seed (Oryza sativa) germination was also inhibited by cryptoporic acid A (52) which produces the characteristic bitterness of the fungus Cryptoporous volvatus at 200 ppm con~entration.~~~ Polygonal (83) is also active but at a much higher concentration of 500 ~pm.~' The influence of drimenol (58) and confertifolin (21) was investigated on cuttings of Tradescantia virginiana L.f.albzjlora B. with regard to the elon- gation and increase in dry weight of adventitious roots.67. A lo-' molar solution of drimenol (58) proved as active as indole-3-acetic acid (auxin) or N-furfuryladenine (kinetin). Confertifolin (2 1) showed a somewhat higher production and elongation of the roots but it was not significant compared with exogenous auxin or kinetin. The root elongation of lettuce was completely inhibited by pereniporin A (74) at 100 ppm., Altiloxin A (69) and B (70) also had little effect on the root elongation of lettuce.51 The root production of asparagus on the other hand was diminished by 50 percent at a concentration of 10 ppm.jl The germination of wheat seed (Triticum aestivum var. Norman. Graminaceae) was only slightly reduced by polygodial (6) and warburganal (5) at a concentration of 0.1 %.A higher concentration improved the inhibition but the germinated seeds had twisted leaves instead of normal 3.3 Cytotoxic Activity Some drimane-type sesquiterpenes showed cytotoxicity in anti- cancer screens. Cinnamodial (9) and capsicodendrin (1 3) a tetrameric conjugate of cinnamodial had an ED, of 2.2 and 2.9 pg/ml respectively in the P-388 lymphocytic leukaemia test system in vitro. Cinnamosmolide (1 5) possessed an ED, of 1.2 pg/ml in the Eagle's 9KB carcinoma of the nasopharynx cell culture system. However these compounds were devoid of in vivo activity in the P-388 test system.l* The drimanic dialdehyde warburganal (5) was active at a concentration of 0.01 pg/ml against KB.28 The metabolites of Perenniporia medullaepanis pereniporin A (74) and B (17) were cytotoxic for Friend leukaemia cells (F5-5) at 130 and 3.91 pg/ml respectively in the bioassay reported by Morioka." As part of a general attempt to study structure-activity relationships for unsaturated dialdehydes from natural sources several compounds were investigated in the Salmonella-microsome assay (strains TA 98 TA 2637 and TA 100).Polygodial (6) and isotadeonal (7) showed no mutagenic activity at the highest non-toxic concentration. Unfortunately other drimanic compounds were not tested.?l 3.4 Taste Skin-irritant Properties and Anticomplemental Activity The leaves of Warburgia species are sometimes used locally as spices in food in East Africa.'" The fruit of Drimys lanceolata are said to have been used as a substitute for pepper in Tasmania.'2 In Japan the pungent hot tasting tade-jiru is made from squeezed Polygonum hydropiper L.leaves.66 Some liverworts are also known for this pungency.33' 36 It turned out that the drimanic aldehydes polygodial (6) warburganal (5) muzigadial (85) cinnamodial (9) and polygonal (83) a nor- drimane were responsible for this phenomenon. 28 73 The nor- drimane is fairly weak in comparison with the other compounds.2s The bitterness of the fungus Cryptoporous volvatus is caused by cryptoporic acid A (52) an albicanyl-ether of iso-citric acid.45Q Polygodial (6) has been reported on several occasions to display skin irritant properties.23% 30.36 NATURAL PRODUCT REPORTS. 1991 When guinea pigs were sensitized to polygodial (6) by using intradermal injections in Freund'si4 complete adjuvant they showed a high response when the skin was treated with polygodial (6) the primary sensitizer. Moreover related compounds e.g. warburganal (5) having the same configuration also showed an allergic contact dermatitis (ACD); and it was observed that the reaction was halved when a racemic mixture of warburganal was used so the allergenic response was stereospecific to enantiomers.' Several constituents of P.hydropiper L. leaves and seeds were tested for their anticomplemental properties. Polygodial (6) and polygonic acid (8) showed an IC, of 10pg/ml and 250 pg/ml respectively. It is surprising that the usually active drimanes like warburganal (5) and muzigadial(85) showed no activity.27 3.5 Piscicidal and Molluscicidal Activity Muzigadial (85) and warburganal (5) were tested as potential helicocides (snail-killers) because the extract of the bark of Warburgia ugandensis had been known for some time to have molluscicidal activity.A simple snail test was chosen because it could give a lead to agents useful for controlling the dangerous schistosomes and bilhar~ia.?~ Biomphalaria pfeifleri and B. glabratzis are killed within two hours by a 5 ppm solution and LjJmnaca natalensis is killed within two hours by a 10 ppm solution of these two cornp~unds.'~ Treatment of killie fish Oryzia latipes with polygodial (6) at 0.4 ppm killed them within 30 69 After an injection of 2 mg of polygodial (6) into the hepatopancreas of the nudibranch Dendrodoris limbata suffering of the animal was evident and death occurred between 3 and 16 hours.52c 3.6 Antifeedant Activity The insect antifeedant properties of the drimanes has been reviewed recently and will not be repeated here in detail.?* Seed treatment with appropriate chemicals to protect crops against pests is preferred to foliar or soil treatments as it is generally cheaper than soil application and since the pesticide is confined to the small area where it is needed it has less effect on other soil organisms.Polygodial (6) was used in laboratory and field tests to control slugs (Deroceras reticulatum) and wheat bulb flies (Delia coarctata) in winter 8o where its effect was marginal on clay loam soil but obvious on peaty loam soil though still inferior to commercial pesticides.It showed no toxicity towards slugs. Nudibranchs softbodied and apparently unprotected molluscs employ some drimanes as defensive chemicals to escape from predators. These drimanes are often derived from a dietary source predominantly if not exclusively of sponges. However the biosynthetic activity of a nudibranch to elaborate its own chemical defence has been shown by incorporation experiments with [2-14C]-mevalonic acid dibenzylethylene- diamine On injection into the hepatopancreas it gave rise to labelled polygodial (6) and labelled sesquiterpenoid esters (36).j2'-j3 The latter are products of further metabolism of polygodial (6) as a result of a detoxication process.j2' Polygodial (6) and olepupuane (34) inhibited feeding of the Pacific damsel fish (Dascyllus aruanus) with ED,,s of 15- 20 pg/mg of pellet.51 Polygodial(6) also inhibited feeding of the marine fish Chromis chromis and the fresh water fish Carassius carassius (ED,, 10 pg/mg of pellet)."2" The glyceride (61) found in some British Columbia nudibranchs was active against the tide pool sculpin Oligocottus rnaculosus at a level of 18 pg/mg of pellet.56L Albicanylacetate (51) and 6p-acetoxyolepupuane (35) showed antifeedant properties in a standard goldfish (Cnrassius auratus) bioassay with ED, of 5-10 ,ug/mg of pellet.52b On Chinese cabbage leaves treated with polygodial (6) or warburganal (9,at a concentration of 0.05 YO,ca.125 ppm compound/leaf few Myzus persicae settled and few nymphs NATURAL PRODUCT REPORTS 1991-B. J. M. JANSEN AND A. DE GROOT active inactive CHO warbu rganal //I CHO I I P\\ Ho+ I polygodI ial \ I ci nnarnod ial I I I I I I CHO 1 I I 4 I I I muzigad ia I I Scheme 4 were depo~ited.~~ 'I The transmission of potato virus Y,beet yellow virus and barley yellow dwarf virus was therefore three times with polygodial (6) at 50 g/ha in early autumn showed diminished damage caused by BYD virus and an improved yield of 136 YO. Warburganal (5) and muzigadial(85) inhibited the feeding of larvae of two species of African armyworm the monophagous Spodopteru exempta and the polyphagous S.littoralis at a concentration of 0.1 ppm in a regular leaf disk ~ethod.~' Polygodial (6) and ugandensidial (9) were also antifeedants for these insects but less active.1e* 17 84 The drimane dialdehydes turned out not to be uniformly active against all insects but showed some species specificity. Activity was also observed against S.Jrugiperda Heliothis armigera and H. virescens."* 85 brassicae at a concentration of 200 ppm.86 3.7 Phytotoxicity in the chemoreceptor membranes of insects thus an interference Some drimanes are potentially valuable crop protecting agents due to their aphid antifeedant activity. For that reason polygodial (6) warburganal (5) and cinnamolide (14) were further investigated because primary studies had suggested a possible phytotoxicity.82b When treated with a concentration of 0.1 O/O the leaves of Chinese cabbage (Brassica campestris var.scorched and yellowed but the leaves of sugar beet (Beta vulgaris) were ~nharmed.~~ The earlier claim of phytotoxicity for unnatural polygodial was not confirmed so the racemates reduced even by aphid variants highly resistant to insecticides.**. 83 Field trials with winter-sown barley treated which are more readily available by synthesis can be employed in the development of drimane-type antifeedants.82b Altiloxin A (69) and B (70) isolated from the culture filtrate of Phoma asparagi Sacc. are phytotoxic metabolites responsible for the stem blight disease on a~paragus.~~ 3.8 Mode of Action of Biologically-active Drimanes Since the drimanic dialdehydes are among the most active drimanes they are frequently used to investigate the mode of action at the molecular level Ma has studied the influence of warburganal (5) on the receptor response of Spodoptera exempta to the stimulant activity of sucrose or meso-inositol ~olutions.~~ Brief treatment with warburganal greatly reduced Polygodial(6) was active against diamond moth larvae down to 0.1 Yoand it inhibited food intake by fifth-instar larvae of Pieris the excitability of the receptors but when it was mixed with L-cysteine or dithiothreitol no decrease in excitability was 0bser~ed.l~M a suggested that the enal moiety of warburganal (5) may act as an -SH acceptor; thiol groups have been detected of warburganal with the stimulus transduction process in the chemoreceptor cell seemed likely.88 Additional evidence for this hypothesis was derived from the fact that the mercaptide forming organomercurial p-(chloromercuri)-benzoate gave a qualitatively similar reaction to ~arburganal.~~ Further investigations revealed that the active antifeedants all taste hot and spicy to the human tongue whereas all inactive derivatives Chinensis) showed slight pitting over the entire surface with some dry patches.Potato leaves (Solanum tuberosum) were are devoid of hot taste (see Scheme 4).le. 77739 NATURAL PRODUCT REPORTS 1991 CH,NH pH -9 Scheme 5 Scheme 6 From Scheme 4 it can be concluded that an enal and a 9P- aldehyde group are required for activity.Mild treatment with base inverted the 9P-aldehyde into a 9a-aldehyde group with concomitant loss of activity and hotness. The enhanced activity of the 9a-hydroxy compounds suggested an involvement of this functionality with the best fit of the molecule on the sensilla. Similar conditions were found by Sterner et al. in a structure-activity relationship study with regard to the mutagenicity of unsaturated dialdehydes. ’l The antifungal activity of polygodial (6) was studied by Taniguchi et al.63* 64 The yeast Saccharomyces cerevisiae was the most susceptible organism among those tested so the made of action on this yeast was carefully investigated. A variety of physiological effects due to polygodial (6) e.g.inhibition of growth alcohol fermentation and papain activity appeared to result from its irreversible reaction with sulfhydryl groups. However in a biomimetic reaction the inactive isopolygodial (7) also had a high reactivity with the sulfhydryl group of L-cysteine. Based on kinetic data Sodano et al. proposed that the biological activity of the enal-aldehydes is primarily related to their ability to form adducts with amino groups rather than sulfhydryl groups on the receptor^.^^ Similar reactivity was observed for both polygodial (6) and iso-polygodial (7) in a reaction with thiols while the reaction with substrates possessing both amino and sulfhydryl groups was dependent upon the stereochemistry of the 9-aldehyde group the 9P- isomer exhibiting the higher reactivity.With amines or amino acids a remarkable difference in reactivity was observed the 9a- isomer was practically unreactive. They were able under biomimetic conditions to obtain NMR evidence for their proposed mechanism (Scheme 5).’O After reaction with a model amine i.e. methylamine one single product the pyrrole (91) was observed which because of its instability was only examined by NMR spectroscopy. The inactive 9a-isomer cannot form intermediates of type (90) due to the greater distance between the C-9 axial aldehyde and the enal Several other suitable enal aldehydes were also investigated and gave rise to the same observation^.^^ The biological mechanism of hot tasting and antifeedant activity of 1,4-dialdehydes may also result from covalent binding to primary amino groups of the chemoreceptive sitesa4* rather than from Michael addition of membrane sulfhydryl groupsa7 even though both are available at the receptor site ;93 a model study of the reaction of muzigadial (85) with L-cystine methyl ester in vitro is in agreement with thisg2 (see Scheme 6).Cell permeability studies revealed that polygodial (6) preferentially damaged the cell membrane and caused an appreciable amount of leakage of cellular constituents e.g. proteins and saccharides. A decrease in cellular dry weight was also observed. The permeability changes were supported by microscopic evidence; the structural integrity of the cell membrane was markedly disrupted by p~lygodial.~~.However the polygodial binding site in the cell membrane is not yet established. 4 References 1 (a)I. Kubo and K. Nakanishi ‘ACS Symposium Series 62 Host Plant Resistance to Pests’ ed. P. A. Hedin American Chemical Society Washington DC. 1977 165; (b) M. Taniguchi A. Chapya I. Kubo and K. Nakanishi Chem. Pharm. Bull. 1978 26 2910; (c) J. 0.Kokwaro ‘Medicinal Plants of East Africa’ East African Literature Bureau Nairobi 1979 45; (6)J. M. Watt and M. G. Breyer-Brandwijk ‘ Medicinal and Poisonous Plants of Southern and Eastern Africa’ E. S. Livingstone Ltd. Edinburgh and London 1962 120; (e) K. Nakanishi ‘Insect Growth Regulators from Plants’ in ‘Natural Products and the Protection of Plants’ ed. G. B. Marini-Bettolo Pontificiae Academia Scientiarium Scripta Varia 1977 41 185.2 V. Zin ‘La salud por medio de las plantas medicinales’ 5th Ed. Ediciones Salesianas Santiago de Chile 1930. 3 H. H. Appel Scientia (Chile) 1948 15 31 (Chem. Abstr. 1948,42 9088d). 4 H. H. Appel B. Rotman and F. Thornton Scientia (Chile) 1956 23,19 (Chem. Abstr. 1957 51 57028). 5 (a) L. Ruzicka Experientia 1953 9 357; (b) A. Eschenmoser D. Felix M. Gut J. Meier and P. Stadler in ‘Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols’ ed. G. E. W. Wolstenholme and M. O’Connor Little Brown and Co. Boston Mass. 1959 217. 6 C. Djerassi P. Sengupta J. Herran and F. Walls J. Am. Chem. Soc. 1954 76 2966. 7 (a)C. Djerassi W. Rittel A. L. Nussbaum F. W. Donovan and J.Herran J. Am. Chem. SOC.,1954,76; 6410; (b)C. Djerassi and W. Rittel J. Am. Chem. Soc. 1957 79 3528; (c) C. Djerassi F. W. Donovan S. Burstein and R. Manli J. Am. Chem. SOC.,1958 80 1972; (d)C. Djerassi and S. Burstein Tetrahedron 1959 7,37. 8 (a)S. W. Pelletier and S. Prabhakar J. Am. Chem. Soc. 1968 90 5319; (b)S. W. Pelletier R. L. Chappel and S. Prabhakar J. Am. Chem. SOC.,1968 90,2889. 9 (a) H. H. Appel C. J. W. Brooks and K. H. Overton J. Chem. SOC.,1959 3322; (b) C. J. W. Brooks and K. H. Overton Proc. Chem. Soc. 1957 322; (c) A. J. Aasen T. Nishida C. R. Enzell and H. H. Appel Acta Chem. Scand. Ser. B 1977 31 51. 10 R. E. Corbett and T. L. Chee J. Chem. Soc. Perkin Trans. I 1976 850. 11 F. S. El-Feraly A. T. McPhail and K. D.Onan J. Chem. SOC. Chem. Commun. 1978 75. NATURAL PRODUCT REPORTS 1991-B. J. M. JANSEN AND A. DE GROOT 12 H. H. Appel J. D. Connolly K. H. Overton and R. P. M. Bond J. Chem. Soc. 1960 4685. 13 H. H. Appel R. P. M. Bond and K. H. Overton Tetrahedron 1963 19 635. 14 (a)L. Canonica A. Corbella G. Jommi and J. Krepinsky Tetra-hedron Lett. 1967 2137; (b) L. Canonica A. Corbella P. Gariboldi G. Jommi J. Krepinsky G. Ferrari and C. Casagrande Tetrahedron 1969 25 3895. 15 L. Canonica A. Corbella P. Gariboldi G. Jommi J. Krepinsky G. Ferrari and C. Casagrande Tetrahedron 1969 25 3903. 16 (a) C. J. W. Brooks and G. H. Draffan Tetrahedron 1969 25 2887; (b) C. J. W. Brooks and G. H. Draffan Tetrahedron 1969 25 2865. 17 I. Kubo Y.-W.Lee M. Pettei F. Pilkiewicz and K. Nakanishi J. Chem. Soc. Chem. Commun. 1976 1013. 18 I. I. Mahmoud A. D. Kinghorn G. A. Cordell and N. R. Farnsworth J. Nat. Prod. 1980 43 365. 19 J. R. Sierra J. T. Lopez and M. J. Cortes Phytochemistry 1986 25 253. 20 W. Vichnewsky P. Kulanthaivel and W. Herz Phytochemistry 1986 25 1476. 21 M. S. Al-Said S. I. Khalifa and F. S. El-Feraly Phytochemistry 1989 28 297. 22 (u) I. Kubo T. Matsumoto A. B. Kakooka and N. M. Mubiru Chem. Lett. 1983 979; (b) D. Kioy A. 1. Gray and P. G. Waterman J. Nat. Prod. 1989 52 174. 23 M. Cortes and M. L. Oyarzun Fitoterapia 1981 52 33. 24 1. Kubo I. Miura M. J. Pettei Y.-W. Lee F. Pilkiewicz and K. Nakanishi Tetrahedron Lett. 1977 4553. 25 (a)J. W. Loder Aust.J. Chem. 1962 15 389; (b)J. Calle M. T. Guerrero and A. Rivera Rev. Colomb. Quim. 1985 14 27; (c) J. F. Ciccio hg. Cienc. Quim. 1984 8 45. 26 (u) R. F. McCallion A. L. J. Cole J. R. L. Walker J. W. Blunt and M. H. G. Munro Planta Medica 1982 44 134; (6) N. Tanaka T. Kimura T. Murakami Y. Saiki and C.-M. Chen Chem. Phurm. Bull. 1980 28 2185. 27 Y. Fukuyama T. Sato I. Miura and Y. Asakawa Photochem-istry 1985 24 1521. 28 Y. Fukuyama T. Sato Y. Asakawa and T. Takemoto Phj-tochemistry 1982 21 2895. 29 Y. Asakawa and T. Takemoto Experientia 1979 35 1420. 30 C. S. Barnes and J. W. Loder Aust. J. Chem. 1962 15 322. 31 (u) A. Ohsuka Nippon Kagaku Zasshi 1962 83 757 (Chem. Abstr. 1963 59 6444e); (b) A. Ohsuka Nippon Kagaku Zasshi 1963 84 748 (Chem.Abstr. 1964 60,132770. 32 Y. Asakawa ‘Chemicalconstituents oftheHepaticae’in ‘Progress in the Chemistry of Organic Natural Products’ ed. W. Herz H. Grisebach and G. W. Kirby Springer Verlag Vienna and New York 1982 42 1-286. 33 Y. Asakawa Rev. Latinoamer. Quim. 1984 14 109. 34 Y. Asakawa S. Huneck M. Toyota T. Takemoto and C. Suire J. Huttori Bot. Lab. 1979 46 163 35 Y.Asakawa and T. Takemoto Bryophythorum Bibl. 13 (C.R. Congr. Int. Bryol. 1977) 1978 335. 36 Y. Asakawa and T. Aratani Bull. Soc. Chim. France 1976 1469. 37 Y. Ohta N. H. Andersen and C.-B. Liu Tetrahedron 1977 33 617. 38 C. R. Enzell I. Wahlberg and A. J. Aasen ‘Isoprenoids and alkaloids of tobacco’ in ‘Progress in the Chemistry of Organic Natural Products’ ed.W. Herz H. Grisebach and G. W. Kirby Springer Verlag Vienna and New York 1977 34 2-79. 39 (a) A. J. Aasen C. H. G. Vogt and C. R. Enzell Acta Chem. Scand. Ser. B 1975,29,51;(b)J. R. Hlubucek A. J. Aasen S.-0. Almquist and C. R. Enzell Acta Chem. Scand. Ser. B 1974 28 289. 40 (a) J. S. Roberts ‘Terpenes and Steroids’ Specialist Periodical Reports The Chemical Society London vol. 12 and preceding volumes; (b)J. S. Roberts and I. Bryson Nat. Prod. Rep. 1984 1 106; (c) B. M. Fraga ibid. 1985 2 147; (d)B. M. Fraga ibid. 1986 3 273; (e) B. M. Fraga ibid. 1987 4 474. 41 T. J. King J. C. Roberts and D. J. Thompson J. Chem. Soc. Perkin Trans. 1 1973 78. 42 (a)W. B. Turner ‘Fungal Metabolites’ Academic Press London 1971 230; (b) C. H.Calzadilla G. Ferguson S. A. Hutchinson and N. J. McCorkindale 5th Int. IUPAC Symp. Chem. Natural Products London Abstracts 287 1968. 43 W. A. Ayer and S. Fung Tetrahedron 1977 33 2771. 44 (a) M. De Bernardi G. Mellerio G. Vidari P. Vita-Finzi and G. Fronza J. Chem. SOC. Perkin Trans. 1 1980 221; (b) M. De Bernardi G. Mellerio G. Vidari P. Vita-Finzi and G. Fronza J. Chem. Soc. Perkin Trans 1 1983 2739. 45 (a) T. Hashimoto M. Tori Y. Mizuno and Y. Asakawa Tetra-hedron Lett. 1987 28 6303; (b) T. Hashimoto M. Tori Y. Mizuno Y. Asakawa and Y.Fukazawa J. Chem. Soc. Chem. Commun. 1989 258. 46 K. Wada S. Tanaka and S. Marumo Agric. Biol. Chem. 1983 47 1075. 47 (a) R. 0.Gould T. J. Simpson and M. D. Walkinshaw Tetra-hedron Lett. 1981 22 1047; (b) T.Hamasaki H. Kuwano K. Isono Y. Hatsuda K. Fukuyama T. Tsukihara and Y. Katsube Agric. Biol. Chem. 1975 39 749. 48 D. M. X. Donnelly J. O’Reilly A. Chiaroni and J. Polonsky J. Chem. Soc. Perkin Trans. 1 1980 2196. 49 W. A. Ayer and L. M. Pena-Rodriguez J. Nat Prod. 1987 50 408. 50 T. Kida H. Shibai and H. Seto J. Antibiot. 1986 39 613. 51 A. Ichihara S. Sawamura and S. Sakamura Tetrahedron Lett. 1984 25 3209. 52 (a) G. Cimino S. De Rosa S. De Stefano and G. Sodano Tetrahedron Lett. 1981 22 1271; (b) G. Cimino S. De Rosa S. De Stefano and G. Sodano Comp. Biochem. Physiol. 1982 73 471 ; (c) G. Cimino S. De Rosa S. De Stefano and G. Sodano Experientia 1985 41 1335; (6)G. Cimino S. De Rosa S. De Stefano G. Sodano and G.Villani Science 1983 219 1237. 53 G. Cimino S. De Rosa S. De Stefano R. Morrone and G. Sodano Tetrahedron 1985 41 1093. 54 R. K. Okuda P. J. Scheuer J. E. Hochlowski R. P. Walker and D. J. Faulkner J. Org. Chem. 1983 48 1866. 55 (a) J. E. Hochlowski R. P. Walker C. Ireland and D. J. Faulkner J. Org. Chem. 1982 47 88; (b) R. W. Dunlop R. Kazlauskas G. March P. T. Murphy and R. J. Wells Aust. J. Chem. 1982 35 95. 56 (a) J. E. Thompson R. P. Walker S. J. Wratten and D. J. Faulkner Tetrahedron 1982 38 1865; (b) J. Hellou R. J. Andersen and J. E. Thompson Tetrahedron 1982 38 1875; (c) K. Gustafson and R. J. Andersen Tetrahedron 1985 41 1101. 57 G. R. Schulte and P. J. Scheuer Tetrahedron 1982 38 1857. 58 (a) D. E. Cane in ‘Biosynthesis of Isoprenoid Compounds’ ed.J. W. Porter S. L. Spurgeon John Wiley New York 1981 Vol. I 283; (b) P. Manitto in ‘Biosynthesis of Natural Products’ Ellis Horwood Ltd. Chichester 1981 238; (c)W. Parker J. S. Roberts and R. Ramage Q. Rev. Chem. Soc. 1967 21 331; (d)D. E. Cane Ace. Chem. Res. 1985 18 220; (e) K. H. Overton and F. M. Roberts J. Chem. Sor. Chem. Commun. 1973 378; cr) Y. Suzuki and S. Marumo Tetrahedron Lett. 1972 1501; (g) B. Achilladelis P. M. Adams and J. R. Hanson J. Chem. Soc. Chem. Commun. 1970 51 I. 59 K. B. G. Torssell ‘Natural Product Chemistry’ John Wiley & Sons Chichester 1983 188. 60 J. S. Roberts ‘Chemistry of Terpenes and Terpenoids’ ed. A. A. Newman Academic Press London & New York 1972 92. 61 I. Kubo Farumashia 1977 13 646.62 M. Taniguchi and Y. Satomura Agric. Biol. Chem. 1972 36 2 169. 63 M. Taniguchi T. Adachi H. Haraguchi S. Oi and I. Kubo J. Biochem. 1983 94 149. 64 M. Taniguchi T. Adachi S. Oi A. Kimura S. Katsumara S. Isoe and I. Kubo Agric. Biol. Chem. 1984 48 73. 65 I. Kubo and M. Taniguchi J. Nat. Prod. 1988 51 22. 66 1. Kubo Drug News Persp. 1989 2 292. 67 H. H. Appel W. P. Quilhot S. B. Vidal M. L. Araneda and G. P. Campos Rev. Latinoam. Quim. 1980 11 140. 68 H. H. Appel W. P. Quilhot S. B. Vidal and M. L. Araneda Rev. Latinoam. Quim. 1980 11 54. 69 Y. Asakawa G. W. Dawson D. C. Griffiths J.-Y. Lallemand S. V. Ley K. Mori A. Mudd M. Pezechk-Leclaire J. A. Pickett H. Watanabe C. M. Woodcock and Z. Zhong-Ning J. Chem.Ecol. 1988 14 1845. 70 H. Morioka M. Ishihara M. Takezawa K. Hirayama E. Suzuki Y. Komoda and H. Shibai Agric. Biol. Chem. 1985 49 1365. 71 0.Sterner R. E. Carter and L. M. Nilsson Mutat. Res. 1987 188 169. 72 J. H. Maiden ‘Useful Native Plants of Australia’ Turner and Henderson Sydney 1889 23 168. 73 I. Kubo and I. Ganjian Experientiu 1981 37 1063. 74 G. Klecak H. Geleick and J. R. Frei J. SOC.Cosmet. Chem. 1977 28 53. 75 J.-L. Stampf C. Benezra and Y. Asakawa Arch. Dermatol. Res. 1982 274 277. 76 S. F. Dossaji M. K. Kairu A. T. Gondwe and J. H. Ouma Lloydia 1977 40,290. 77 K. Nakanishi and 1. Kubo Isr. J. Chem. 1977 16 28. 78 T. A. van Beek and Ae. de Groot Recl. Trav. Chim. Pays-Bas 1986 105 513. 79 G.C. Scott J. A. Pickett M. C. Smith C. M. Woodcock P. G. W. Harris R. P. Hammon and H. D. Koetecha ‘Pro-ceedings 1984 British Crop Protection Conference -Pests and Disease ’ 1984 133. 80 G. C. Scott ‘ Procer lings 198 1 British Crop Protection Conference -Pests and Disease’ 1981 441. 81 R. W. Gibson A. D. Rice J. A. Pickett M. C. Smith and R. M. Sawicki Ann. Appl. Biol. 1982 100 55. 82 (a) J. A. Pickett R. T. Plumb B. J. Pye L. E. Smart and C. M. Woodcock ‘Proceedings 1986 British Crop Protection Conference -Pests and Disease’ 1986 1001 ; (b) J. A. Pickett Phil. Trans. Royal SOC. London B 1985 310 235. 83 J. A. Pickett G. W. Dawson. D. C. Griffiths A. Hassanali L. A. Merritt A. Mudd M. C. Smith L. J. Wadhams C. M. Wood- cock and Zhang Zhong-Ning ‘Pesticide Science and Biotechnology ’ ed.R. Greenhalgh and T. R. Roberts Blackwell Scientific Oxford 1987 125. NATURAL PRODUCT REPORTS 1991 84 (a) J. Meinwald G. D. Prestwich K. Nakanishi and I. Kubo Science 1978 199 1167; (b)V. Caprioli G. Cimino R. Colle M. Gavagnin G. Sodano and A. Spinella J. Nat. Prod. 1987 50 146. 85 W. M. Blaney M. S. J. Simmonds S. V. Ley and R. B. Katz Physiol. Ent. 1987 12 281. 86 L. M. Schoonhoven and Yan Fu-Shun J. Insect. Physiol. 1989 35 725. 87 W.-C. Ma Physiol. Entomol. 1977 2 199. 88 D. M. Norris S. M. Ferkovich J. E. Rozental and T. K. Borg J. Insect. Physiol. 1971 17 85. 89 M. D’Ischia G. Prota and G. Sodano Tetrahedron Lett. 1982 23 3295. 90 G. Cimino A. Spinella and G. Sodano Tetrahedron Lett.1984 25 4151. 91 G. Cimino G. Sodano and A. Spinella Tetrahedron 1987 43 5401. 92 P. Y.-S. Lam and J. L. Frazier Tetrahedron Lett. 1987 28 5477. 93 J. L. Frazier and P. Y.-S. Lam Chem. Senses 1986 11 600. 94 M. Taniguchi Y. Yano E. Tada K. Ikenishi S. Oi H. Haraguchi K. Hashimoto and I. Kubo Agric. Biol. Chem. 1988 52 1409.

ISSN:0265-0568    

DOI:10.1039/NP9910800309

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

The Synthesis of Drimane Sesquiterpenoids B. J. M.Jansen and A. de Groot Laboratory of Organic Chemistry Wageningen Agricultural University Dre yenplein 8 6703 HB Wageningen The Netherlands Reviewing the literature to January 1990 1 Introduction H 2 Synthesis of Drimanes by Transformations of Natural Products 3 Synthesis of Drimanes by Biomimetic Polyolefin Cyclizations 4 Synthesis of Drirnanes from trans-decalones 5 Synthesis of Drimanes by a Diels-Alder Approach 6 Synthesis of Drimanes via a Metathesis Transannular Ene Sequence 7 References (2) royleanone 1 Introduction XO" The antifeedant activity of some drimane sesquiterpenes has greatly stimulated the development of general synthetic routes to this class of compounds. Total synthesis is a necessity since in most cases only minute amounts of material are available from natural sources.During these synthetic approaches towards drimanes many intermediates have been produced with a drimane-like structure. This has provided knowledge about the functional groups responsible for the activity at a molecular level and may well lead to the discovery of simple (3) glycyrrhetinic acid biologically active compounds with possibilities for commercial development. Numerous syntheses have appeared within the last twenty years and a rough division can be based on the starting materials and/or reaction types.' Synthesis has been accomplished by the transformation of other natural products or by total synthesis; whereby the decalin skeleton has been formed by biomimetic polyolefin cyclizations Robinson annellations Diels-Alder cycloadditions or a metathesis transannular ene sequence.(4) (5) levopimaric acid 2 Synthesis of Drimanes by Transformations of Natural Products Optically-active drimanes have been prepared from abietic acid (l) royleanone (2) glycyrrhetinic acid (3) methyl- 14,15-dinor- 7-labden- 13-oxo- 17-oate (4),levopimaric acid (9,manool (6) confertifolin (7) and drimenol (8). In most of these compounds superfluous carbon atoms are removed via ozonolysis at a suitable stage in the total synthesis. (6) manool (7)confertifolin (1 abietic acid (8) drimenol 319 NATURAL PRODUCT REPORTS 1991 (10) (11) (12) (7) (13) (14) Reagents i O, NaBH (1 1,12-dihydroxy compound) ;ii O, NaBH (13,14-dihydroxy compound) ;iii 0, Na,SO (Ibhydroxy compound) ;iv 0, NaBH (14-hydroxy compound); v CrO Scheme 1 ... I II (16) xi xii xi f--(20) (19) (18) Reagents i OsO, Me,NO; ii CH,N,; iii DHP H+; iv LiAlH,; v PCC; vi H,O,H+; vii H,NNH, KOH; viii Pb(OAc),; ix trimethylene glycol H+; x LDA HMPA TMSiCl; xi 0, Me,S; xii LDA TMSiCl; xiii LDA MoO;HMPA.pyr.; xiv H,O H+ Scheme 2 In the course of their studies on the chemical conversion of (-)-abietic acid to biologlcally active compounds Akita and Oishi achieved short but low yielding syntheses for several drimanic sesquiterpenes (see Scheme l).' (-)-Abietic acid (1) was converted into the phenolic dehydroabietane derivatives (10) and (12)3 which were cleaved by ozone.4 The mode of cleavage was determined by the substitution pattern of the hydroxyl group(s) on the aromatic ring.Subsequent reduction with the appropriate reagents afforded the drimanes (+)-isodrimenin (1 1) (+)-confertifolin (7) (+)-valdiviolide (I 3) and (+)-winterin (14). Ohno et al. reported the first synthesis of natural (-)-warburganal (2 I) also starting from (-)-abietic acid (1) by a 15 step sequence with an overall yield of 8 (see Scheme 2). The regioselective hydroxylation of the double bond of the c-ring was significantly improved to 86 % when a catalytic amount of osmium tetraoxide and trimethylamine-N-oxide as co-oxidant was used. The gern-dimethyl group was introduced in a straightforward manner in 50 % yield.Oxidative cleavage of the diol with lead tetraacetate afforded the ketoaldehyde (1 7). The aldehyde function was selectively protected as its acetal. The requisite C-9 aldehyde group was introduced by degra- dation of the C-9 substituent via the successive ozonolysis of two silyl enol ethers. The enolate of aldehyde (20) was then oxidized with the MOO,. HMPA .pyr . complex and deprotection afforded (-)-warburganal (2 1). NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT 32 1 ?H I 0 ii,iii iv 1I \\ " ($Y @ + c@ P" \\ II \\ \\ / \ o,CooMe vi vii pOMe Reagents i H,O, Na,CO, H,O then EtOH H,IO,; ii dimethylsulphate K,CO,; iii O, CH,Cl, then H,O, NaOH; iv Pb(OAc),; v CH,N,; vi LiAlH,; vii H,IO, EtOH; viii H20,Hf acetone Scheme 3 COOH (23) (27) (28) v.vi I Reagents i CH,N,; ii LiAlH,; iii Ac,O pyr.; iv hu 0, Bengal rose then Na,SO,; v p-TsOH silica gel; vi LiOH then H,O H+ Scheme 4 The abietane royleanone (2) readily isolated from the roots of several Salvia species was used as the starting material for the synthesis of (+)-winterin (14) (+)-isodrimenin (1 l) and (+)-confertifolin (7) (see Scheme 3). Several intermediates previously used in the synthesis of (+)-warburganal (21) and (+)-polygodial (91) were also produced. A total decomposition of royleanone (2) was observed with a variety of oxidation methods i.e. potassium permanganate ozonolysis Jones' reagent etc. but Hooker's oxidation' followed by treatment with periodic acid produced (+)-winterin (14) although in a poor yield of 10%.In contrast the ozonolysis2 of 12-0-methylroyleanone gave a clean reaction-product from which (22) was isolated in 80 YO yield together with a 10% yield of (+)-winterin (14). Treatment of (22) with lead tetraacetate in benzene led to the drimane derivative (23),used in the synthesis of other drimanes. Ketodiester (24) was reduced to a trio1 which was cleaved by periodic acid in ethanol to a mixture of diacetals (25). Hydrolysis of this mixture led to (+)-confertifohn (7) (67% yield) and (+)-isodrimenin (1 1) (3 YOyield). When (14) was reduced with lithium aluminium hydride a mixture of (7) and (1 1) was also obtained but with a reversed product ratio of 1 :9. The drimane ( +)-euryfuran (26) was synthesized in 40 Oh overall yield starting from the diacid (23) as described in Scheme 4.* Photo-oxidation of the diacetate (27) and subsequent reduction of the oxygenated intermediate led to the 901-hydroxydiacetate (28).Treatment with p-toluenesulfonic acid in the presence of silica gel followed by hydrolysis with lithium hydroxide and acidification gave (+)-euryfuran (26). Glycerrhetinic acid (3) is easily convertedg in good yield into the diene (29) which was used by Falck et al." for the synthesis 322 NATURAL PRODUCT REPORTS 1991 \ COOMe‘J ‘dC0OM X O H (30) ii-iv CHO Reagents i hv EtOH; ii m-CPBA; iii a,,Me,S; iv CH,N,; v HI EtOH; vi NaOMe MeOH; vii PhOC(S)Cl pyr.; viii Bu,SnH; ix SeO,; x LiAlH,; xi DMSO oxalyl chloride Et,N Scheme 5 (4) (34) (35) ($-I Ac ix ‘\ Reagents i m-CPBA; ii LiAlH,; iii DMP p-TsOH; iv CrO, pyr.; v Ac,O Et,N; DMAP; vi 0,,Me,S; vii MeOH p-TsOH; viii Ac,O pyr.; ix POCl, pyr Scheme 6 of (-)-warburganal (21) in an overall yield of 14% (see Scheme 5).Irradiation of (29) furnished the triene (30) after which epoxidation exhaustive ozonolysis and esterification gave the desired chiral building block (31). The epoxide (31) was readily isomerized with hydroiodic acid to the allylic alcohol (32). The acetoxy group was removed by methanolysis and Barton’s reduction procedure. Consecutive allylic oxidation ester reduction and Swern oxidation of the primary alcohols yielded (-)-warburganal (21). Methyl-l4,15-dinor-7-1abden- 13-0x0-17-oate (4) was ob-tained from the hexane extract of Halimium viscosum and transformed into the diacetoxy derivative (38) already shown to be a pivotal compound in the synthesis of (-)-polygodial (91) and (-)-warburganal (21)” (see Scheme 6).The dinor-labdenoate (4) was oxidized with m-CPBA over long periods (up to 15 days) to yield (34) as a mixture of epoxides. A trio1 was obtained after reduction of (34) and its 1,2-glycolprotected. The sidechain with the remaining hydroxy group was degraded via ozonolysis of the enol acetate (36). Finally dehydration of (37) with phosphorus oxychloride in pyridine led to (38) in an overall yield of 8 %.12 NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT i ii vii-ix I SPh (211 (44) (43) (42) Reagents i hv O, rose Bengal; ii 0, Me,S; iii ethylene glycol p-TsOH; iv NaBH,; v NaOMe MeOH; vi PhSH TFA; vii LiAlH,; viii i-PrS0,Cl; ix LiEt,BH; x m-CPBA; xi P(OMe), reflux xylene; xii 0, EtOAc then P(OMe),; xiii DBU; xiv KH THF then MOO,.HMPA .pyr. ; xv p-TsOH acetone Scheme 7 ref. 16 ___) _.... 11 Ill I Reagents i DDQ dioxane; ii 0, CH,Cl,; iii Red-Al; iv Ac,O pyr.; v POCl, pyr.; vi KOH MeOH Scheme 8 A major pine resin acid is levopimaric acid (5). Its isolation from the inexpensive oleorosin is ~traightforward'~ and thus it is an attractive chiral starting material. Ayer and Talamas used this acid for a synthesis of (-)-warburganal (21) in an overall yield of 2.7 YOin 15 steps14 (see Scheme 7).Photo-oxygenation followed by ozonolysis was used to oxidize the diene moiety in (5).An elegant base induced fragmentation of the alcohols (40) led to the removal of four of the unwanted carbon atoms. Reaction of the product with thiophenol gave a mixture of the hemithioacetals (41). The transformation of the C-4 carbomethoxyl group into ;Imethyl group was modified and performed in a modestly improved yield of 65 YO.Oxidation of the hemithioacetals and subsequent heating gave the enol ether (43) permitting degradation via ozonolysis. The enolate of (44) formed with potassium hydride in tetrahydrofuran was oxidized with the MOO,. HMPA * pyr *complex. Deprotection with acid in acetone gave (-)-warburganal (21). The degradation of the readily available (+)-man001 (6) provided an entry to drimanic sesquiterpenes as depicted in Schemes 8 and 9.Pelletier et a1.l5transformed (6) into (+)-ambreinolide (45)16 and dehydrogenation with DDQ in boiling dioxane afforded the double bond at C-11 in compound (48) which on ex-haustive ozonolysis and reduction with Red-A1 gave rise to (+)-drimane-8,1 I -diol (47) in 34 YOyield. Dehydration after protection of the primary alcohol function of (47) afforded a mixture of unsaturated acetates (48). Hydrolysis with base gave a mixture of alcohols from which (-)-drimenol (8) was isolated in 40% yield. The degradation of the sidechain of manool(6) via a Norrish NPR 8 NATURAL PRODUCT REPORTS 1991 ref. 17 ___) (26) (50) (51 (11) Reagents i hv 0, rose Bengal CH,Cl, MeOH; ii hv 0,,meso-TPP CCl,; iii FeSO,; iv m-CPBA; v CrO, pyr.; vi Fe(CO), DMF Scheme 9 iv v liii i (21 (54) (26) Reagents i Tl(OAc) ;ii K,CO, MeOH ;iii PCC ; iv PDC ; v trimethylene glycol p-TsOH benzene Scheme 10 type I1 cleavage to diene (49) was achieved by Nakano et a1.l' Oxidation of the diene (49) with thallium (IrI)-acetate in (see Scheme 9).acetic acid gave a mixture of acetates which yielded the Photooxygenation of (49) in dichloromethane containing corresponding alcohols (52) and (53) in 14% and 17% 5 YOmethanol furnished (+)-confertifolin (7) in 20 YOyield and respe~tively'~ (see Scheme lo). 36 O/O of the unreacted diene (49). When however the diene was Oxidation of (52) and protection of the aldehyde function irradiated in the presence of rneso-tetraphenylporphine in afforded (54).This had been synthesized previously as its carbon tetrachloride the endoperoxide (50) was isolated in racemate and converted into warburganal (21).20 (+)-65 YOyield. This endoperoxide proved not to be an intermediate Euryfuran (26) was obtained in 72% yield after oxidation of in the formation of (7) since it was unchanged under the above- the unsaturated diol (53) with pyridinium chlorochromate. mentioned irradiation conditions. The endoperoxide (50) was (+)-Confertifolin (7) and (-)-drimenol (8) both isolated in however rearranged in good yield to (+)-euryfuran (26) by large quantities from the bark of Drimys winteri Forst were various reagents. When it was oxidized with rn-CPBA the obvious starting materials for the synthesis of (-)-warburganal epoxide could be rearranged to the epoxylactol (51) which on (21)21.22 (see Scheme 11).oxidation followed by deoxygenation with pentacarbonyliron The diol (53) was epoxidized to a 7:3 mixture of a-and p-afforded (+)-isodrimenin (11) in 22% yield (based on epoxides from which the a-epoxide (55) could be separated in man001).~* 65 % yield. Treatment of (55) with lithium diethylamide led to NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT ... Ill -I gYH \\ ii* &H\\ (7) (53) (55) (56) vii iiv vi V 3" -/ \\ Reagents i LiAlH,; ii rn-CPBA; iii Et,NLi; iv DMSO TFAA; v Ac,O pyr.; vi SeO,; vii KOH MeOH Scheme 11 COOH COOH (OH -CYCIO-(62) farnesic acid (63) farnesol (59) linalool (60) P-ionone (6 1 ) MO~O farnesic acid (59) (65) Reagents i ethyl vinyl ether; ii malonic acid; iii MeOH H+; iv HCOOH H,SO,; v CrO,; vi Ph,PCH,Br NaNH, toluene; vii m-CPBA CH,Cl ;viii p-TsOH ;ix MeONa MeOH Scheme 12 the triol (56) which afforded (-)-warburganal (21) on higher efficiency the epoxide cyclization route may prove oxidation by the Swern procedure in 13 % overall yield.,l The advantageous even for the synthesis of deoxy same triol (56) was obtained starting from (-)-drimenol(8) as Starting materials for the biomimetic polyolefin cyclizations indicated in Scheme 11 in 28 % overall yield.The necessary were linalool (59) /?-ionone (60) mono-cyclofarnesic acid (61) allylic oxidation of (57) to (58) was improved by using a farnesic acid (62) and farnesol (63).catalytic amount of selenium dioxide and a suitable co-Linalool (59) was used as starting material for the synthesis 24 of keto-ester (66) which was transformed into (+)-drimenin (69) and (+)-isodrimenin (1 1) as indicated in Scheme 12.,& Eschenmoser established that the trans configuration of the 3 Synthesis of Drimanes by Biomimetic A2 double bond in (65) was the only requirement for the Polyolef in Cyclizations production of compound (66).29 The ester (67) was also The biogenetically patterned cyclization of acyclic polyenes or transformed into the (+)-acid which could be resolved to its polyene-epoxides has provided an elegant synthetic route to enantiomers via the diastereoisomeric salts with a-Because of its phenylethylamine in 31 sesquiterpenes of the bicyclofarnesol clas~.~~-~' NATURAL PRODUCT REPORTS.1991 MeoYoMe i ii iii iv v-vii I_) (70) liii Reagents i NaOCH, HCOOEt; ii MeOH pyr. HBr; iii ClCH,COOMe; iv p-TsOH; v SnCl, CH,CI,; vi KOH; vii Cu quinoline A; viii Pb(OAc),; ix A 170 "C; x KOH H,O; xi CrO,; xii NaBH Scheme 13 (OAC ~ i ii iii v vi @OH -\\ (74) (75) (76) -0H CHO xi xii viii-x '0H f-II (211 (78) (77) (56) Reagents i CrO, HOAc; ii ethylene glycol p-TsOH; iii LiAIH,; iv H,O H+; v Ac,O pyr. ;vi H,O, NaOH; vii N,H, HOAc; viii t-BDMSiCI DMF; ix N,W-carbonyldiimidazole; x MeOH H'; xi CrO,; xii NaOH xiii DMSO DCC Scheme 14 A large scale synthesis of (+)-confertifolin (7) and (+)-isodrimenin (I I) was achieved starting from dihydro-/3-ionone (70) which was obtained from /3-ionone (60) by partial reduction with Raney Ni see Scheme 13.32 The cyclization was performed with the furanic ester (72) and after saponification and decarboxylation (& )-euryfuran (26) was obtained.Further transformations of the furan ring afforded the drimanes (& )-confertifolin (7) ( +)-hodrimenin (1 I) and (+)-winterin (14). The total synthesis of (+)-warburganal (21) was accomplished using (4-)-isodrimenin (1 1) as is shown in Scheme 14.28bv 32. 33 Allylic oxidation of isodrimenin (1 1) and protection of the resulting keto function gave (74). The unsaturated diacetate (75) was obtained after reduction of the lactone moiety and acetylation of the diol.Epoxidation of (75) with hydrogen peroxide in sodium hydroxide solution gave ex- clusively the a-epoxide (76) thus securing the correct stereo- chemistry at C-9. A Wharton rearrangement followed by a series of protection deprotection and oxidation reactions as indicated in Scheme 14 finally gave (+)-warburganal (21) in an overall yield of 32 YOfrom (& )-isodrimenin and 9 YOfrom p-ionone. Later it was shown (see Scheme 30) that the direct oxidation of the trio1 (56) could also be achieved in moderate yield. 327 NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT COOH i ii iii-vi xi ~H \\ OAc (77) (79) (80) (84) liii vii /iii @HO viii ix X f-pyo \\ OAc '\ OAc \\ OAc Reagents i MeOH H+; ii trichloroethoxycarbonylchloride pyr.; iii CrO, HOAc; iv Zn(BH,),; v Ac,O pyr.DMAP; vi Zn HOAc; vii ethylene glycol p-TsOH; viii NaOH H,O; ix DMSO pyr. TFA; x p-TsOH acetone; xi CrO, large excess Scheme 15 (86) (87) (69) \v-vii ix ix v vi i vii viii -P \\ OOMe Reagents i SnC1,; ii CH,N,; iii hv 0,,rose Bengal; iv H,O H+; v LiAlH,; vi MnO,; vii CrO, pyr.; viii CH,OH NaOH; ix HC(OMe), p-TsOH ;x oxalic acid Scheme 16 COOMe COOMe COOMe \\ (86) (92) (93) (94) Reagents i KMnO, NaHCO,; ii PhSeC1 EtOAc H,O,; iii ethanedithiol BF,; iv n-Bu,SnH; v rn-CPBA; vi DBU 165 "C Scheme 17 The intermediate (77) was also used to synthesize (+)-moderate yield. This was cyclized with acid to (5)-drimenin cinnamodial (83) and ( +)-cinnamosmolide (85)34 (see Scheme (69).Reduction and subsequent oxidation yielded the lactone 15). The allylic alcohol in (77) was first protected as its (_+)-cinnamolide (88) which was converted into (f)-trichloroethoxycarbonate (79) which allowed selective depro- polygodial (91) as depicted in Scheme 16. tection. The required acetate group in (80) was introduced to Methyl bicyclofarnesoate (86) was also used as starting (58) via allylic oxidation followed by reduction and acetylation. material for the synthesis of the phytotoxic metabolite altiloxin (+)-Cinnamodial (83) was prepared from (80) as described for A (94) a drimane with an unusual substitution pattern.38 (+)-warburganal (21) in an overall yield of 14 % (see Scheme The ketol (92) was obtained from (86) by dihydroxylation 14).Oxidation of (80) with an excess of Jones reagent afforded and oxidation with potassium permanganate. Treatment of the acid (84) which after hydrolysis and reacetylation gave (92) with phenylselenylchloride followed by oxidation with (f)-cinnamosmolide (85) in an overall yield of 31 %. hydrogen peroxide converted the ketol into an a,P-unsaturated Kitahara et al. have synthesized several drimanes starting ketone from which the ketone function was removed via from mono-cyclofarnesic acid (6 1),35-37 derived from farnesic reduction of the thioacetal. Epoxidation of (93) proceeded acid (62) by acid-catalyzed cyclization.26 stereoselectively. Hydrolysis of the ester function by heating at Photooxidation of methyl drimenate (86) afforded (87) in 165 "C with DBU then gave (f)-altiloxin A (94).(Scheme 17). NATURAL PRODUCT REPORTS 1991 FOOMe COOMe CHO i,ii iii iv v. vi HO p ;J;.?":; I It \\ \\ \\ (95) (96) (97) (21) Reagents i SeO, ii ethylene glycol p-TsOH ;iii LiAlH ;iv CrO, pyr. ; v LiHMDS MOO,-pyr .HMPA ; vi H,O H+ Scheme 18 (98) Reagents i SnCl, -56 "C; ii LiAlH,; iii Ac,O pyr.; iv rn-CPBA; v LDA Scheme 19 ( 105) The first synthesis of ( +)-warburganal (21) which was reported by Ohsuka and Mats~kawa,~~ made use of methyl-9-epi-bicyclofarnesoate (95) obtained in low yield (5%) by an acid catalyzed cyclization of methyl farnesoate (see Scheme 18). The more abundant methyl bicyclofarnesoate (86) could not be used as starting material because complex mixtures were obtained in the allylic oxidation.The a configuration of the ester is also a problem in this approach. Elaboration of this ester function according to Scheme 18finally yielded compound (97) which also had the aldehyde function in the a position. The deprotonation of (97) necessary for the oxidative in-troduction of the 9a-hydroxyl group turned out to be difficult and proceeded in a rather low yield (25 %). Weiler et al. used the allylsilane (98) in an electrophilic cyclization to achieve a regioselective alkene formation in good yield (Scheme 19).,O The cyclization reaction was quite solvent and temperature dependent. A 95% yield of the la-and lp-isomers was obtained in a 1:4ratio with stannic chloride at -56 "C in dichloromethane. After reduction of (99) and acetylation (&)-albicanylacetate (100) was isolated in 75 YOoverall yield.The lactone (+)-isodrimenin (1 1) was also synthesized from (99) in 60% yield as shown in Scheme 19. 4 Synthesis of Drimanes from trans-decalones The appropriate trans-decalones for the syntheses of drimanes were obtained via Robinson annellations. The readily available trimethyldecalone (101) has been used as starting material for various drimanes like warburganal (21) isotadeonal (l05) confertifolin (7) valdiviolide (13) euryfuran (26) and isodrimenin (1 1). The synthetic strategies all employ a formylation reaction to introduce the required C-12 carbon atom and a nucleophilic addition of an appropriate reagent to the C-9 keto function to complete the drimane skeleton.Kende et aL41 and Goldsmith et aI.*O reported a total synthesis of warburganal (21) based on this approach (see Schemes 20 and 21 respectively). The addition of [methoxy (trimethylsilyl)methyl]lithium to the hindered carbonyl function of (106) gave a diastereoisomeric mixture of alcohols which underwent elimination of trimethylsilanol to afford a 1 :3 mixture of (a-and (2)-enol ethers (107). Upon epoxidation the (E)-isomer (107) gave exclusively the a-epoxide which could be hydrolyzed to (+)-warburganal (21) in 13% overall yield. Epoxidation of (2)-(107) gave a 4 1 mixture of the p-and a-epoxides (109) and (1 10) respectively which led after hydrolysis to a corresponding 4 1 mixture of (f)-epi-warburganal and (&)-warburganal (21).Moreover hydrolysis of (E)-(107) and (2)-(107) under more vigorous conditions afforded (&)-isotadeonal (105). Goldsmith et al. used a modified reaction sequence to obtain (111) in which the C-11 carbon atom was introduced via addition of methyllithium (see Scheme 21).20 NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT -i-iii + H OMe + ( 106)I____pI Vii - Z-(107) HO vii - E-(107) p I I \\ \\ '\ Reagents i NaH HCOOEt; ii DDQ; iii ethylene glycol p-TsOH; iv Me,Si(MeO)CHLi; v KH THF; vi m-CPBA; vii H,O H+ Scheme 20 vii viii ix* (21) -(101) (1 11) Reagents i HCOOEt NaH; ii PhSeC1 pyr.; iii H,O,; iv trimethylene glycol p-TsOH; v CH,Li; vi MeO,CNSO,NEt,; vii OsO, pyr.; viii DMSO pyr.TFA; ix p-TsOH acetone Scheme 21 vii + f-;.$, \\ (1 1) (7) (116) (13) Reagents i HCOOEt NaH; ii n-BuSH p-TsOH; iii (H,C),S=CH,; iv HgSO,; v 0, hv eosin; vi Br, MeOH; vii H,O HS Scheme 22 Dehydration employing the Burgess reagent42gave the diene Treatment of the n-butylthiomethylene derivative (114) with (1 12) which upon hydroxylation Swern oxidation and hy-trimethylsulphonium methylide gave via rearrangement of the drolysis yielded ( +)-warburganal (21) in an overall yield of intermediate epoxide the dihydrofuran (I 15) which on brief 15 Yo. treatment with mercury(1r)sulphate afforded a 70 % yield of The furan annellation method reported by Spencer4 et al. (+):euryfuran (26). Photooxygenation of (26) gave (+)-was used to synthesize (-t )-euryfuran (26) and some other valdiviolide (13) in 60 YOas well as the unnatural 1Ip-hydroxy drimanes as shown in Scheme 22.44 isomer.Oxidation of (26) with bromine in methanol followed 330 NATURAL PRODUCT REPORTS. 1991 SPh ... @Ph Ill ___) PSPheSph (1 17) (1 18) (1 19) (26) Reagents i PhS(Me0)CHLi ;ii SOCI, pyr. ; iii LiAlH Scheme 23 \ix iii lvi PhS v vi vii viii psau (114) ( 123) (122) Reagents i PhS(Me0)CHLi; ii HgCl, HgO H,O; iii H,O H+; iv,p-TsOH benzene A; v PhSCH,Li; vi H,O HgCI, H+;vii NaIO,; viii Ac,O 110 "C; ix SOCI, pyr Scheme 24 PhS fSPh i-iv v vi iv ___) Reagents i HCOOEt NaH; ii n-BUSH p-TsOH benzene; iii PhSCH,Li; iv H,O H+ HgCI,; v NaIO,; vi Ac,O 110 "C Scheme 25 by hydrolysis afforded (+)-confertifolin (7) in 75 YO yield cyclization gave a 1 :3 mixture of (+)-isodrimenin (1 1) and together with the regioisomer (+)-isodrimenin (1 1) in 10 YO (+)-confertifolin (7).47 Rearrangement of (121) followed by yield.mercury(I1)-assisted hydrolysis afforded the phenylthiofuran [Methoxy(phenylthio)methyl]lithium and [(phenylthio)-(122) which gave (+)-isodrimenin (1 1) after further hydrolysis methylllithium were used by de Groot et af. to introduce the in 45 YOoverall yield from (120). Drimanic lactones were also requisite functionality at C-9 as is shown in Schemes 23,24 and synthesized regioselectively via the addition of [(phenylthio)-25. methylllithium to the n-butylthiomethylene derivative (1 14). Addition of [methoxy(phenylthio)methyl]lithium to (1 17) The adducts were hydrolysed directly to the y-(pheny1thio)-a,@- gave a diastereoisomeric mixture of (1 18).These adducts could unsaturated aldehyde (123). Oxidation to the sulfoxide be rearranged to a-(pheny1thio)aldehydes (1 19).45 After re-followed by a Pummerer type reaction also led to the duction a spontaneous cyclization to (f )-euryfuran (26) was phenylthiofuran (122). After hydrolysis the lactone (+)-observed in an overall yield of 55 Oh based on (1 17).46 isodrimenin (1 1) was obtained in 30 YOoverall yield. Addition of [methoxy(phenylthio)methyl]lithium to the keto The ketone (102)48was used for the synthesisof the rearranged acetal (1 20) gave a mixture of stereoisomers (1 2 1). Hydrolysis drimane colorata-4( 13),8-dienolide (124) via the same to a mixture of hydroxy-dialdehydes followed by acid catalyzed regioselective lactone annellation as shown in Scheme 25.47" NATURAL PRODUCT REPORTS 1991-B.M. J. JANSEN AND A. DE GROOT 33 1 -@Me i-iv V vi vii ___) (102) (1 27) (128) ( 129) Reagents i HCOOEt NaH; ii PhSeC1 pyr. ;iii H,O,; iv HC(OMe),,p-TsOH; v LDA Ph,P(O)CH,OCH,; vi OsO, TBHP Et,NOH t-BuOH; vii H+ H,O acetone Scheme 26 CHO v vi CHO Reagents i NaH HCOOEt; ii PhSeC1 pyr. H,O,; iii KCN; iv n-BUSH p-TsOH; v NaBH, H,O H' HgC1,; vi ethylene glycol p-TsOH; vii DIBAH; viii KO-t-Bu HO-t-Bu; ix LDA MOO,-HMPA.pyr.; x H,O H+ Scheme 27 This same ketone (102) was used by Bosch and Meinwald et al. for a stereoselective total synthesis of (+)-muzigadial (129) (see Scheme 26).,' Ketone (102) was transformed into the protected dienol ether (128) as indicated and selective oxidation of the dienol ether was achieved in a subtle way using a catalytic amount of osmium tetraoxide with tert-butyl hydroperoxide as the oxidant.Hydrolysis of the resulting hydroxy aldehyde afforded (+)-muzigadial (129) in 11 Oh overall yield. The ketones (103) and (104) were used by de Groot et al. in a total synthesis of (&)-warburganal (21) (+)-polygodial (91) (f)-isotadeonal (l05) and (+)-muzigadial (129).50 Subsequently the chiral (103) and (104) decalones were to prepare an enolate which could be oxidized to introduce the 9a-hydroxyl group. It turned out that deprotonation of (97) was very difficult probably due to the steric crowding around the 9/3 proton.A nearly quantitative epimerization succeeded after a 10 minute treatment at reflux temperature with an excess of potassium tert-butoxide in tert-butyl alcohol. After this crucial epimerization the P-aldehyde (1 33) was easily deprotonated and subsequently oxidized as had been demonstrated in other ~yntheses.~ After hydrolysis (& )-warburganal (21) was obtained in 38% overall yield. (-I-)-Polygodial (91) was obtained from the intermediate (133) and (f)-isotadeonal(lO5) from (97) in 44 YOand 50 'YOoverall yield respectively. The same procedure was used to synthesize (f)-synthesized starting from (R)-and (3-carvone re~pectively.~~ muzigadial (129) from the ketone (104) in 24% overall yield.jO The carbonyl group at C-7 made it possible to introduce a Mori and coworkers have synthesized (-)-warburganal (21) formyl group at C-8 and via conjugate addition a cyano group starting from (S)-3-hydroxy-2,2-dimethylcyclohexanone(1 35) at C-9.Later this was used for the introduction of the A'** via ketone (103) according to the procedure depicted in Scheme double bond (see Scheme 27). 27.52 For the conversion of (97) into warburganal it was necessary The intermediate (134) was used to synthesize (-)- NATURAL PRODUCT REPORTS 1991 ( 103) ii-vi \ H4 ... Vlll f-vii -xii xiii i. \ I Me ix,xi w 1I ___) I OR fl fl & fi I 1 I ‘\H OH OR ‘\H OR ‘\H OR Reagents i H,O H+; ii NaBH,; iii 1,l’-carbonyldiimidazole;iv p-TsOH acetone; v NaClO, NaH,PO,; vi CH,N,; vii CrO, HOAc; viii NaBH, CeC1,; ix NaOH H,O; x t-BuMe,SiCl; xi LDA Red-Al; xii DMSO pyr.TFA DCC; xiii TBAF Scheme 28 (144) R = H (145) R = Nz (146) R = CH20H pereniporin A (143) and (-)-pereniporin B (139) as shown in 5 Synthesis of D imanes by a Diels-Alder Scheme 28.53 Conversion of (134) into the unsaturated ester (136) was Approach followed by allylic oxidation and reduction to the alcohol (138). The use of the Diels-Alder reaction to construct an ap-Alkaline hydrolysis followed by acidification gave (-)-propriately functionalized decalin in a concise manner is pereniporin B (139) in 1.8 % overall yield. In order to prepare especially attractive. In the Diels-Alder approach various 1-1-enes (144)-( 146) were used. pereniporin A (143) from (138) reversal of the oxidation state vinyl-2,6,6-trimethylcyclohex-of C-11 and C-12 was necessary.However all attempts under This concept was first used by Brieger54in his synthesis of (i-)-conventional conditions to reduce (140) to the triol (141) were winterin (14). Improvements of the initial process were in vain and resulted in the reductive removal of the tertiary introduced later and several drimanes have now been syn-hydroxy group. The reductive elimination could be avoided thesized following this approach.55.56 when the tertiary alcohol was protected as its lithium salt Nakanishi et al. used the Diels-Alder reaction in an efficient during the reduction procedure. The resultant triol (141) was total synthesis of (+)-warburganal (21) (+)-polygodial (91) transformed into (-)-pereniporin A (143) in a straightforward (5)-cinnamolide (88) and (+)-drimenin (69) as is shown in manner as depicted in Scheme 28.Scheme 29.28a NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT COOMe COOMe COOMe COOMe 111 i * POoMe ii ... po-pCoOOMe \\ Iiv-vii 0Ac xivTxvi II xii xiii ix -f.-( 150) x xi x Iiii xvii ,xviii \ I (69) (88) Reagents i dimethyl acetylenedicarboxylate 110 "C neat; ii CrO, pyr.; iii H, Pd on C; iv NaBH,; v MsC1 Et,N; vi DBU; vii LiAlH,; viii CrO,; ix t-Bu(Me),SiCl imidazole; x PCC; xi TBAF; xii Ac,O pyr.; xiii HOAc H,O; xiv MnO,; xv trimethylene glycol p-TsOH; xvi KOH MeOH ; xvii H,O H+ acetone ; xviii LDA MOO,. HMPA .pyr. Scheme 29 ~ @OMe @OMe ,fi ii OH iii or iv \ \ \\ \\ (147) (153) (88) HO ix vii viii f-P \\ " '\ "O (211 (38) Reagents i H,?.Pd on C trace of HCl; ii LiAlH,; iii BaMnO, 20 equivalents; iv Ag,CO on celite; v DMSO NEt, oxalyl chloride; vi Ac,O pyr.; vii SeO,; viii K,CO, MeOH; ix DMSO NEt, TFAA Scheme 30 The reaction of dimethyl acetylenedicarboxylate with the an overall yield of 18 YO.After selective protection of the allylic diene (144) provided the diester (147).The stereoselective hydroxy group the more hindered alcohol was oxidized and the catalytic trans reduction of the A5q6 olefinic bond in (147) was lactone ( +)-drimenin (69) was formed in 12 YOoverall yield. A achieved with difficulty since normally cis fused reduction sequence of protection deprotection and oxidation steps led to products are obtained.Several solutions for this problem are the monoprotected dialdehyde (1 33) which afforded (& )-currently available all based on the construction of a polygodial (91) in 21 YOoverall yield after hydrolysis. Com- conjugated system preceding the catalytic reduction. In this pound (133) was hydroxylated by the Vedejs procedure and case the problem was solved via allylic oxidation of (147) to the hydrolysis of the acetal gave (+)-warburganal (21) in 16% dienone (148) which gave the desired trans-fused ketone (149) overall yield. upon reduction. Ketone (141) was converted by standard The trans-fused decalin skeleton was obtained from (147) by reactions into the diol(l50). The exposed allylic alcohol reacted Ley et al.via hydrogenation under isomerizing conditions.l'v 57* 58 more readily than the hindered primary alcohol so a single The use of various protecting groups was avoided by a careful lactone ( f)-cinnamolide (88) was obtained upon oxidation in choice of oxidation reagents (see Scheme 30). 3 34 NATURAL PRODUCT REPORTS 1991 COOMe COOMe CHO COOMe COOMe -p ... A Ill-v i ii I Ho \\ (147) bi COOMe COOMe CHO CHO COOMe ... Ill -(155) Reagents i LDA -78 "C; ii H,SO, H,O -78 "C; iii H, Pd on C; iv LiAlH,; v DMSO NEt, oxalyl chloride; vi DBU toluene reflux; vii DMSO NEt, TFAA; viii DBN benzene reflux Scheme 31 Reagents i dimethyl fumarate xylene 140 "C; ii Ac,O reflux Scheme 32 COOMe P.~.J-. COOMe Reagents i Borane THF ;ii H,O, NaOH ;iii DIBAH ;iv PCC ;v Pb(OAc), benzene; vi DBU ;vii rn-CPBA ;viii MeOH HCl ;ix H,O HCl ; X Ac,O DMAP pyr.Scheme 33 Although direct introduction of the 9a-hydroxy group failed with the diol (150)' the corresponding diacetate (88) was easily oxidized by selenium dioxide. Deprotection led to the trio1 (56) which provided (*)-warburganal (21) on oxidation by Swern's protocol. An analogous approach was used by Lallemand et al.5gIn this case the isomerization of the diester (147) to the conjugated dienic diester (154) was effected by a separate treatment of (147) with lithium diisopropylamide followed by kinetic protonation. Under thermodynamic conditions the more stable 9a-isomer (155) was obtained which gave rise to the cis-fused diester (1 56) upon hydrogenation.Reduction followed by oxidation using the Swern procedure led to the cis-fused dialdehyde (157) (see Scheme 31). The diester (154) was also prepared via a Diels-Alder reaction of the dienamine (145) with dimethylfumarate. Elimination of pyrrolidine from (1 59) afforded (154) in a one- pot procedure in 81 YOyield60 as depicted in Scheme 32. The diester (147) was chosen by White et al. as the starting material to introduce an oxygen functionality at CP (see Scheme 33). The Diels-Alder adduct (147) was treated with diborane to NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT xii e- ( 170) (169) COOMe COOMe HO xii f- OH +ix xi OOMe viii x @\ OOMe \ \ \ Ho \ '\ \\ (+)-(91) (1 73) ( 172) (171) Reagents i Baker's yeast; ii t-BuMe,SiCl imidazole DMF; iii LDA MeI; iv sodium acetylide; v CuSO, xylene reflux; vi H, Pd on CaCO,; vii dimethyl acetylenedicarboxylate; viii DBU; ix H, Pd on C; x MsCl DMAP; xi LiAlH,; xii DMSO NEt, oxalyl chloride Scheme 34 0.Reagents i maleic anhydride; ii CH,N,; iii xylene reflux; iv LiAlH,; v p-TsOH benzene; vi CrO,; vii H, Pd on C; viii NaBH,; ix MsC1 pyr.; x DMSO 100 "C 2 h; xi DMSO NEt, oxalyl chloride Scheme 35 give a hydroxy-diester after alkaline oxidation. Contrary to an earlier assignment this product was shown to possess a trczns ring fusion.28a To firmly establish the configuration of this hydroxy diester it was correlated with a substance of known stereochemistry (+)-isodrimenin (1 1).Reduction of the diester with diisobutylaluminium hydride immediately followed by PCC oxidation afforded the keto-furan (160). The furan ring was oxidized and the intermediate diacetate was treated with base to provide the dienone (162) which led to (+)-fragrolide (163) upon hydrolysis in 33 % overall yield. Epoxidation of (162) yielded an a-epoxy compound (164) which was trans- formed into a suitably protected dialdehyde moiety upon treatment with acidified methanol. Reduction of the keto function to (165) followed by acetylation of the 6P-hydroxy group gave rise to (f)-cinnamodial (83) in 11 YOoverall yield. To prove the hypothesis that the phytotoxicity of the synthetic racemate (f)-polygodial (91) might be due to the unnatural enantiomer Mori et al.have developed a synthesis of both enantiomers,62 see Scheme 34. The dione (1 66) was chosen as the starting material for reduction using baker's yeast and (166) yielded the (5')-hydroxy compound (135) in good yield. The required diene (168) was obtained by a straightforward method in 50% yield. The Diels-Alder reaction was not diastereoselective but yielded a mixture of (169) and (171) in 33 YOand 35 YOrespectively. Reduction of diester (1 69) to the trans-fused compound (170) succeeded using an adaptation of the method of Lallemand.59 The natural (-)-polygodial (91) was finally obtained in an overall yield of 3.O YO.The unnatural ( +)-polygodial was synthesized via a slightly modified route in an overall yield of 2.9 Yo.An intra molecular Diels-Alder approach was studied by Wu et aL6 p-Ionone was treated with sodium hypobromite and then reduced to give the dienol (146) which was esterified with maleic anhydride to set the stage for the Diels-Alder reaction which finally proceeded in refluxing xylene (see Scheme 35). NATURAL PRODUCT REPORTS I991 v-vii i OMe PCHO xi xii \\ Reagents i hv; ii Ph,PCH,; iii CH,I, Zn Cu; iv 3,5-(NO,),C,H,CO,H; v H, PtO, HOAc; vi DIBAH; vii HC(OMe), H+; viii MICA; ix PDC; x Ph,PCHLiOMe; xi OsO,; xii H,O H’ acetone Scheme 36 The lactone ring of (175) had to be opened to enable the elimination of the extra carbon atom. Under vigorous conditions the lactone ring could be opened but it recyclized spontaneously on standing.This problem was solved by selec- tive reduction of the lactone functionality followed by an acid catalyzed cyclization to (1 76). This intermediate was transformed into (+)-drimenin (69) in a straightforward manner. Reduction of (-t )-drimenin (69) with lithium alu- minium hydride afforded the diol (150) which had been used frequently for the synthesis of drimanes.28a- 57 59*62 The substrate for the intramolecular Diels-Alder reaction (174) was also synthesized as its (-)-menthy1 ester to affect asymmetric induction. Cycloaddition yielded a mixture of the two possible diastereoisomers from which the desired product was easily isolated by recrystallization with an optical purity of 100% diastereoisomeric excess.6 Synthesis of Drimanes via a Metathesis Transannular Ene Sequence A transannular ene reaction was used by Wender et al. to construct a suitable trans-fused decalin system for drimane ~ynthesis.,~ With 2-substituted enones the [2 +21 photocyclo- addition gave no satisfactory results so the requisite substituent at C-9 had to be introduced afterwards (see Scheme 36). The [2 +21 photocycloadduct (180) was converted under special reaction conditions (sodium tert-amylate in toluene) into the unsaturated ester (181) via a Wittig reaction followed by the ene-reaction. The gem-dimethyl groups were introduced via a cyclopropanation-hydrogenolysissequence. Epoxidation of the double bond and conversion of the ester function into a protected aldehyde then provided (183).Eliminative ring opening of the epoxide introduced the A’ double bond. The keto acetal (184) was transformed into the enol ether (185) by reaction with an excess of [(diphenylphosphino)-methoxymethyl]lithium. Osmylation and hydrolysis gave ( -t )-warburganal (21) in 13% overall yield. 7 References 1 (a) J. Apsimon ‘The Total Synthesis of Natural Products’ J. Wiley and Sons 1973 Vol. 2 338 and 1983 Vol. 5 169; (b)S. V. Ley ‘Recent Advances in the Chemistry of Insect Control’ Royal Society of Chemistry Special Publication 53 1985 307; (c) S. V. Ley in ‘Synthesis of Insect Antifeedants ’ Pest. Sci. Biotechnol. Proc. Int. Congr. Pest. Chem. 6th 1986 ed. R. Greenhalgh and T. R. Roberts 25 Blackwell Oxford UK 1987; (d)Ae.de Groot and T. A. van Beek Red. Trav. Chim. Pays-Bas 1987,106 1 ;(e) T. Nakano in ‘Studies in Natural Products Chemistry’ Vol. 4 ‘Stereoselective Synthesis’ ed. Atta-ur-Rahman Elsevier Amsterdam 1989 403. 2 H. Akita and T. Oishi Chem. Pharm. Bull. 1981 29 1580. 3 H. Akita and T. Oishi Chem. Pharm. Bull. 1981 29 1567. 4 (a) S. W. Pelletier and Y. Ohtsuka Tetrahedron 1977 33 1021; (b) H. Akita and T. Oishi Tetrahedron Lett. 1978 3733. 5 H. Okawara H. Nakai and M. Ohno Tetrahedron Lett. 1982 23 1087. 6 J. A. Hueso-Rodriguez and B. Rodriguez Tetrahedron 1989 45 1567. 7 J. Hooker J. Am. Chem. Soc. 1936 58 1163 1174 and 1179. 8 J. A. Hueso-Rodriguez and B. Rodriguez Tetrahedron Lett. 1989 30 859. 9 S. Rozen I. Shahak and E. D. Bergmann Isr.J. Chem. 1975,13 234. I0 S. Manna P. Yadagiri and J. R. Falck J. Chem. SOC. Chem. Cornmun. 1987 1324. 11 D. M. Hollinshead S. C. Howell S. V. Ley M. Mahon N. M. Ratcliffe and P. A. Worthington J. Chem. SOC.,Perkin Trans. I 1983 1579. 12 J. G. Urones I. S. Marcos and D. Diez Martin Tetrahedron 1988 44 4547. 13 G. W. Hedrick and W. D. Lloyd Org. Synth. 1965 45 64. 14 W. A. Ayer and F. X. Talamas Can. J. Chem. 1988 66 1675. 15 S. W. Pelletier S. Laysic Y. Ohtsuka and Z. Djarmati J. Org. Chem. 1975 40 1607. 16 H. R. Schenk H. Gutman 0.Jeger and L. Ruzicka Helv. Chim. Acta 1952 35 817. 17 (a)T. Nakano and M. A. Maillo Synth. Commun. 1981 11,463; (b) M. A. F. Leite M. H. Sarragiotto P. M. Imamura and A. J. Marsaioli J. Org. Chem. 1986 51 5409.18 T. Nakano and M. E. Aguero J. Chem. SOC.,Perkin Trans. Z 1982 1163. 19 T. Nakano and M. A. Maillo J. Chem. SOC. Perkin Trans. I 1987 2137. 20 D. J. Goldsmith and H. S. Kezar 111 Tetrahedron Lett. 1980,21 3543. 21 1. Razmilic J. Sierra J. Lopez and M. Cortes Chem. Lett. 1985 1113. 22 M. L. Oyarzun M. Cortes and J. Sierra Synth. Commun. 1982 12 951. 23 I. Razmilic J. Lopez J. Sierra and M. Cortes Synth. Commun. 1987 17 95. 24 M. J. Cortes I. Razmilic J. R. Sierra and J. Lopez Chem. Ind. 1985 735. 25 (a)A. Caliezi and H. Schinz Helv. Chim.Acta 1949,32,2556; (b) ibid.,l950,33 1129; (c) ibid. 1952 35 1637; (d)P. A. Stadler A. Eschenmoser H. Schinz and G. Stork Helv. Chim. Acta 1957 40 2191. 26 G. Stork and A. W. Burgstahler J.Am. Chem. Soc. 1955 77 5068. NATURAL PRODUCT REPORTS 1991-B. M. J. JANSEN AND A. DE GROOT 27 (a)E. E. van Tamelen A. Storni E. J. Hassler and M. Schwartz J. Am. Chem. Soc. 1963 85 3295; (b) E. E. van Tamelen Ace. Chem. Res. 1968 1 168; (c) E. E. van Tamelen and K. B. Sharpless Tetrahedron Lett. 1967 2655. 28 (a) S. P. Tanis and K. Nakanishi J. Am. Chem. Soc. 1979 101 4398; (6) T. Nakata H. Akita T. Naito and T. Oishi J. Am. Chem. Soc. 1979 101 4400. 29 P. A. Stadler A. Nechvatal A. J. Frey and A. Eschenmoser Helv. Chim. Acta 1957 40 1373 2191. 30 M. Liapis V. Ragoussis and N. Ragoussis J. Chem. Soc. Perkin Trans. I 1985 815. 31 V. Ragoussis M. Liapis and N. Ragoussis J. Chem. Soc. Perkin Trans. I 1987 987. 32 (a)H.Akita T. Naito and T. Oishi Chem. Lett. 1979 1365. (b) H. Akita T. Naito and T. Oishi Chem. Pharm. Bull. 1980 28 2 166. 33 T. Nakata H. Akita T. Naito and T. Oishi Chem. Pharm. Bull. 1980 28 2172. 34 T. Naito T. Nakata H. Akita and T. Oishi Chem. Lett. 1980 445. 35 (a)Y. Kitahara T. Kato and S. Kanno J. Chem. Soc. (C) 1968 2397; (b) S. Kanno T. Kato and Y. Kitahara J. Chem. Soc. Chem. Commun. 1967 1257. 36 (a)Y. Kitahara T. Kato T. Suzuki S. Kanno and M. Tanemura J. Chem. Soc. Chem. Commun. 1969 342; (b) T. Suzuki M. Tanemura T. Kato and Y. Kitahara Bull. Soc. Chem. Japan 1970 43 1268; (c) H. Yanagawa T. Kato and Y. Kitahara Synthesis 1970 257. 37 (a) T. Kato T. Suzuki M. Tanemura A. S. Kumanireng N. Ototani and Y. Kitahara Tetrahedron Lett.1971 1961; (b) T. Kato T. Iida T. Suzuki Y. Kitahara and K. H. Overton Tetra-hedron Lett. 1972 4257. 38 A. Ichihara Y. Kawakami and S. Sakamura Tetrahedron Lett. 1986 27 61. 39 A. Ohsuka and A. Matsukawa Chem. Lett. 1979 635. 40 (a) R. J. Armstrong F. L. Harris and L. Weiler Can. J. Chem. 1982 60 673; (b) R. J. Armstrong F. L. Harris and L. Weiler Can. J. Chem. 1986 64 1002. 41 A. S. Kende and T. J. Blacklock Tetrahedron Lett. 1980 21 3113. 42 E. M. Burgess H. R. Penton Jr and E. A. Taylor J. Org. Chem. 1973 38 26. 43 M. E. Garst and T. A. Spencer J. Am. Chem. Soc. 1973 95 250. 44 (a)S. V. Ley and M. Mahon J. Chem. Soc. Perkin Trans. I 1983 1379; (b) S. V. Ley and M. Mahon Tetrahedron Lett. 1981 22 4747.45 B. J. M. Jansen R. M. Peperzak and Ae. de Groot Reel. Trav. Chim. Pays-Bas 1987 106 489. 46 B. J. M. Jansen R. M. Peperzak and Ae. de Groot Reel. Trav. Chim. Pays-Bas 1987 106 549. 47 (a) Ae. de Groot and B. J. M. Jansen J. Org. Chem. 1984 49 2034; (b) B. J. M. Jansen R. M. Peperzak and Ae. de Groot Reel. Trav. Chim. Pays-Bas 1987 106 505. 48 Ae. de Groot M. P. Broekhuysen L. L. Doddema M. C. Vollering and J. M. M. Westerbeek Tetrahedron Lett. 1982 23 4031. 49 M. P. Bosch F. Camps J. Coll A. Guerrero T. Tatsuoka and J. Meinwald J. Org. Chem. 1986 51 773. 50 B J. M. Jansen H. H. W. J. M. Sengers H. J. T. Bos and Ae. de Groot J. Org. Chem. 1988 53 855. 51 B. J. M. Jansen J. A. Kreuger and Ae. de Groot Tetrahedron 1989 45 1447.52 K. Mori and H. Takaishi Liebigs Ann. Chem. 1989 695. 53 K. Mori and H. Takaishi Liebigs Ann. Chem. 1989 939. 54 G. Brieger Tetrahedron Lett. 1965 4429. 55 J. A. Campos and F. G. Jimenez Rev. Soc. Quim. Mex. 1975,19 93. 56 J. C. Loperfido J. Org. Chem. 1973 38 399. 57 (a)S. C. Howell S. V. Ley and M. Mahon J. Chem. Soc. Chem. Commun. 1981 507; (b) S. V. Ley and M. Mahon Tetrahedron Lett. 1981 22 3909; (c) G. Green W. P. Griffith D. M. Hollinshead S. V. Ley and M. Schroder J. Chem. Sac. Perkin Trans. I 1984 681. 58 P. N. Rijlander Aldrichimica Acta 1979 12 53. 59 (a)M. Jalali-Naini G. Boussac P. Lemaitre M. Larcheveque D. Guillerm and J.-Y. Lallemand Tetrahedron Lett. 1981 22,2995; (6) M. Jalali-Naini D. Guillerm and J.-Y. Lallemand Tetra-hedron 1983 39 749; (c) D.Guillerm M. Delarue M. Jalali- Naini P. Lemaitre and J.-Y. Lallemand Tetrahedron Lett. 1984 25 1043. 60 R. L. Snowden Tetrahedron Lett. 1984 25 3835. 61 (a)L. P. J. Burton and J. D. White J. Am Chem. Soc. 1981 103 3226; (b) J. D. White ‘Chemistry of Natural Products’ Proc. Sino-Am. Symp. 1980 ed. Wang Yu Sci. Press Beijing Peop. Rep. China 1982 146; (c) J. D. White and L. P. J. Burton J. Org. Chem. 1985 50 357. 62 K. Mori and H. Watanabe Tetrahedron 1986 42 273. 63 J.-F. He and Y.-L. Wu Tetrahedron 1988 44 1933. 64 P. A. Wender and S. L. Eck Tetrahedron Lett. 1982 23 1871.

ISSN:0265-0568    

DOI:10.1039/NP9910800319

出版商:RSC    

年代:1991

数据来源: RSC