摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Professor D. J. Robins University of Glasgow Dr C. J. Schofield University of Oxford Dr D. A. Whiting University of Nottingham Editorial Staff Editorial Office Dr Sheila R. Buxton The Royal Society of Chemistry Managing Editor Thomas Graham House Dr Roxane M. Owen Science Park Deputy Editor Milton Road Miss Nicola P. Coward Cam bridge Production Editor UK CB4 4WF Dr Anthony P. Breen Mr Michael J. Francis Telephone +44 (0)1223 420066 Techn ica I Editors Facsimile +44 (0) 1223 420247 Miss Daphne E. Houston E-mail rsc1@rsc.org Miss Karen L.White RSC Sewer http://c hem istry. rsc.org/rsc/ Editoria I Secretaries ~ ~~ Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis biological activity and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. This is augmented by frequent reviews of the wider context of bioorganic chemistry including developments in enzymology nucleic acids genetics chemical ecology primary and secondary metabolism and isolation and analytical techniques which will be of general interest to all workers in the area.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 UK CB4 4WF. 1996 Annual Subscription Price EEA €325.00 USA $615.00 Rest of World €333.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. UK SG6 1HN. Air Freight and mailing in the USA 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 11003. Second-Class postage paid at Jamaica NY 11431-9998. All other despatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the UK. 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 UK CB4 4WF. ___~ 0 The Royal Society of Chemistry 1996 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 1996 EEA f325.00 USA $615.00 Rest of World f333.00

ISSN:0265-0568    

DOI:10.1039/NP99613FX009

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99613BX011

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Tadhg P. Begiey Department of Chemistry Cornell University lthaca New York 14853 USA Reviewing the literature published between January 1986 and January 1996 (Continuing the coverage of literature in Natural Product Reports 1986 Vol. 3 p. 395) 1 Introduction 2 Thiamin Biosynthesis in Escherichia coli and Salmonella typhimurium 2.1 Biosynthesis of Hydroxyethylthiazole Phosphate 2.2 Biosynthesis of Hydroxymethylpyrimidine Phosphate 2.3 Coupling of the Pyrimidine and the Thiazole Moieties 2.4 Kinases involved in Thiamin Biosynthesis 3 Cloned Genes Involved in Thiamin Biosynthesis in Escherichia coli 3.1 Function of ThiC 3.2 Function of ThiE 3.3 Function of ThiF 3.4 Function of ThiGH and ThiJ 3.5 Biosynthesis of 1-Deoxy-D-xylulose 3.6 Regulation of the Biosynthetic Pathway 4 Thiamin Biosynthesis in Bacillus subtilis 5 Thiamin Biosynthesis in Saccharomyces cerevisiue and Schizosaccharomyces pombe 5.1 Biosynthesis of Hydroxyethylthiazole Phosphate 5.2 Biosynthesis of Hydroxymethylpyrimidine 5.3 Coupling of the Pyrimidine and the Thiazole Moieties 5.4 Kinases Involved in Thiamin Biosynthesis 5.5 Cloned Genes Involved in Thiamin Biosynthesis in Yeast 6 Thiamin Degradation 7 Future Prospects 8 References and Notes 1 Introduction Thiamin pyrophosphate (1) was discovered as the anti-beriberi factor in the human diet.' Beriberi a neurological disease was particularly prevalent in Asia where the refining of rice resulted in the removal of the thiamin-containing husk.Thiamin was isolated from yeast in 1932 by Windaus and was the first vitamin discovered. Its structure was determined by Williams in 1936. The role of thiamin in the stabilization of the acyl carbanion was proposed by Breslow in 19582 and the mechanistic enzymology of thiamin dependent enzymes is now a well developed area.3 Thiamin pyrophosphate (1) plays a key role in carbohydrate metabolism and is the key cofactor in a-ketoacid decarboxylase a-ketoacid oxidase and transketolase. It is required for the conversion of pyruvate to acetyl-coenzyme A. In thamin deficient patients pyruvate and lactate accumulate and cause damage to the nervous and circulatory systems.Unlike microorganisms humans cannot synthesize thiamin. This vitamin is therefore an essential component of the diet (RDA = 1.4 mg). Annual production by chemical synthesis is in excess of 2000 tons.* After providing some general background material on thiamin biosynthesis this review will focus on the progress made on the biosynthesis and degradation of thiamin in Escherichia coli Bacillus subtilis and Sac~haromyces~ since the last Natural Product Reports article.6 2 Thiamin Biosynthesis in Escherichia coli and Salmonella typhimurium7 The biosynthesis of thiamin pyrophosphate in E. coli and in the closely related S. typhimurium involves the coupling of 4-methyl-5-(/3-hydroxyethyl)thiazolephosphate (5) (from here onwards referred to as hydroxyethylthiazole phosphate) and 2-methyl-4-amino-5-hydroxymethylpyrimidine pyrophosphate (30) (hydroxymethylpyrimidine pyrophosphate) as shown later in Scheme 5 followed by a final phosphorylation.The biosynthesis of the thiazole and the pyrimidine moieties will be discussed separately in the following sections. 2.1 Biosynthesis of Hydroxyethylthiazole Phosphate The precursors to hydroxyethylthiazole phosphate (5) are shown in Scheme 1. The sulfur is derived from cysteine (3),*the C2 and N3 of the thiazole are derived from the a-carbon and the amino group of tyrosine (4),'and the methyl group and the phosphoethyl groups are derived from C1 and C4/C5 of 1-deoxy-~-xylulose-5-phosphate (2) respectively.lo HopOPO~2-H OH + 7 COOH + pNH R COOH 0 SH HO 1 (5) The precursors to hydroxyethylthiazole phosphate (5) Scheme 1 The thiazole formation involves a complex oxidative con- densation.One possible mechanism is outlined in Scheme 2.11 Oxidation of 1-deoxy-~-xylulose-5-phosphate (2) to the dike- tone (6) followed by imine formation with the amino group of tyrosine would give (7). Addition of the thiol of cysteine possibly as the pyridoxal phosphate (PLP) adduct (8) would give (9). Loss of the p-hydroxybenzyl group as the quinone methde (1 1) followed by pyridoxal phosphate assisted cleavage of the cysteine carbon-sulfur bond in (10) would give (12). Cyclization followed by elimination of water and de-carboxylation would give the thiazole (5). 177 NATURAL PRODUCT REPORTS 1996 PLPa+ HCXX? Mechanistic proposal for the formation of hydroxyethylthiazole phosphate (5) Scheme 2 H PH ,*-H OH HO NA Ho+Opo3" (4) Enz-S-SH HOmm" sulfur transfer (15) HO I Alternative mechanism for the formation of hydroxyethylthiazole phosphate (5) Scheme 3 It has been demonstrated that p-hydroxybenzyl alcohol the recently discovered NifS system which is used in the presumably derived from the addition of water to (1 I) is a by- formation of an iron sulfur cluster involved in nitrogen product of thiamin biosynthesis12 and that loss of the quinone fixation.l7 methide occurs before thiazole f0rrnati0n.l~ Pyridoxal phos- The mechanism of the sulfur transfer is probably the most phate catalysed /3-elimination reactions of amino acids are well interesting aspect of the thiazole biosynthesis.The current level precedented.l* The testing of 2-carboxy-hydroxyethylthiazole of understanding of sulfur transfer in the biosynthesis of three as an intermediate is problematic as this compound undergoes other cofactors molybdopterin,l* biotinlg and lipoic acid,20 is decarboxylation under the conditions used to carry out the also poor. E. coli feeding experiments.15 An alternative pathway to the thiazole might involve sulfur transfer to the anion of (15) from an enzyme bound persulfide 2.2 Biosynthesis of Hydroxymethylpyrimidine Phosphate (Scheme 3). This chemistry is precedented in the rhodanese In contrast to the biosynthesis of the nucleic acid pyrimidines catalysed transfer of sulfur from thiosulfate to cyanide16 and in where the chemistry is relatively simple,21 the biosynthesis of NATURAL PRODUCT REPORTS 1996-T.P. BEGLEY HO OH N-glycosyl cleavage (19a) + NH2 H H H H (25) (26) (27) Mechanistic proposal for the formation of hydroxymethylpyrimidine phosphate (1 8) Scheme 4 the pyrimidine moiety of thiamin is complex and poorly understood. This pyrimidine (18) is derived from 5-aminoimidazole ribonucleotide (1 7a) an intermediate along the purine biosynthetic pathway [eqn. (l)]. C5 C7 and the C2 methyl group of the pyrimidine are derived from the C4' C5' and C2' of (17) respectively. The nitrogens N1 and N3 of the pyrimidine are derived from nitrogens N3 and N1 of the aminoimidazole respectively.22 HO OH (17a) R=H (17b) R = COOH Double label experiments suggest that this complex rear- rangement is an intramolecular reaction.23 A possible mech- anism is outlined in Scheme 4.Cleavage of the N-glycosyl bond of (1 7a) followed by tautomerization and retroaldol frag- mentation of the ribose would give (19b) (21a) and (21b). Alkylation of the aminoimidazole (19b) with (21a) followed by loss of two molecules of formaldehyde and reduction would give the methylated imidazole (25). Alkylation of (25) with glycolaldehyde phosphate (2 1 b) followed by fragmentation of the ring would give (27) which could tautomerize to (28). Electrocyclization of this hetero~umulene~~ followed by a final tautomerization would give the pyrimidine (1 8) with the observed distribution of label.An alternative pyrimidine biosynthetic pathway that is independent of the purine biosynthetic pathway has recently been discovered in S. typhimurium. This pathway involves the incorporation of pantothenate into the pyrimidine and is inhibited by oxygen.25 2.3 Coupling of the Pyrimidine and the Thiazole Moieties Coupling of hydroxymethylpyrimidine pyrophosphate (30) with hydroxyethylthiazole phosphate (5) gives thiamin phos- phate (31) as shown in Scheme 5. Low levels of this enzymatic activity have been detected in E. coli cell free extracts.26 Thiamin phosphate formation Scheme 5 2.4 Kinases Involved in Thiamin Biosynthesis The role of the five kinases involved in the biosynthesis of thiamin pyrophosphate in E.coli is complex and incompletely ~nderstood.~' and phos- Thiamin phosphate kinase (T~IL)~~ phomethylpyrimidine kinase (ThiD)29 are probably essential biosynthetic enzymes. Thiamin kinase (ThiK)30 and hydroxy- ethylthiazole kinase (ThiM) are probably salvage enzymes involved in the utilization of thiamin and thiazole from the growth medium because mutations in both of these genes lead to strains which do not require thiamin.31 It has not yet been determined whether hydroxymethylpyrimidine kinase (ThiN) is essential for thiamin biosynthesis. However it seems reasonable that phosphomethylpyrimidine is the product of the rear-rangement of (1 7) and therefore that hydroxymethylpyrimidine kinase is also a salvage enzyme.3 Cloned Genes Involved in Thiamin Biosynthesis in Escherichia coli The thiamin biosynthetic pathway was derived using iso- topically labelled precursors and either mass spectrometry or radiotracer experiments for analysis.32 Mechanistic studies have not been possible with wild type strains because of the very low levels of thiamin required for bacterial growth. Such studies require the overexpression of the thiamin biosynthetic genes. A 6.6 kb DNA fragment from the 90 minute region of the E. coli chromosome has been cloned sequenced and charac- teri~ed.~~ This fragment codes for five genes involved in the biosynthesis of thiamin (thiCEFGH).34Each of these genes has been overexpressed at a high level in E. coli. ThiC is required for the pyrimidine bio~ynthesis,~~ ThiFGH are required for the thiazole biosynthesis and ThiE catalyses the coupling of the pyrimidine and the thiazole moieties.36 A fourth thiazole biosynthetic gene3' thiJ mapping adjacent to nuvC in the 9.5 minute region of the chromosome has also been cloned and ~equenced.~~ The genes coding for thiamin kinase and thiamin phosphate kinase have been cloned but not yet sequenced or overexpressed.39 3.1 Function of ThiP The thiC gene complements all four characterized hydroxy- methylpyrimidine requiring mutants in E.cok4l The purified protein is a homodimer of 70.1 kDa subunits. Incubation with (17a) (17b) and dephosphorylated (17a) (see Equation I) in the presence of metal ions (Fe2+ Zn2+ Mg2+ Ca2+) nic- otinamide cofactors (NADH/NAD+ NADPH/NADP+) and (purE/P~rK~~ +ATP) did not result in the conversion of any of these putative pyrimidine precursors into a substance capable of sustaining the growth of an E.coli thiC mutant. Thus while ThiC is clearly involved in the biosynthesis of the pyrimidine moiety its exact function is currently unknown. 3.2 Function of ThiE ThiE catalyses the coupling of hydroxymethylpyrimidine pyrophosphate (30) and hydroxyethylthiazole phosphate (5) (Scheme 5). The purified protein is a monomer with molecular weight of 23 kDa and has a K for the pyrimidine (30) and the thiazole (5) of 1 and 2 pM respectively. The k,, for the coupling reaction is 14 min-1.43 3.3 Function of ThiF ThiF shows high sequence similarity to MoeB (46% identity over 216 amino MoeB is involved in the sulfur transfer during the biosynthesis of molybdopterin (34) (Scheme 6).45 The specific reaction catalysed is The similarity between the molybdopterin precursor (32) and the thiazole precursors (7) or (15) suggests that ThiF may play a role in the sulfur transfer.NATURAL PRODUCT REPORTS 1996 0 0 lNO N HO 0 H2N H (32) (33) 1 0 (34) The final steps in the biosynthesis of molybdopterin (34) Scheme 6 3.4 Function of ThiGH and ThiJ Mutants in thiG thiH and thiJ require thiazole. The specific reactions catalysed are currently unknown. Comparison with database sequences did not indicate significant similarity with other proteins of known function.3.5 Biosynthesis of 1-Deoxy-D-xylulose E. coli mutants in thiC thiE thiF thiG thiH and thiJ do not grow on 1 -deoxy-D-xylulose (37)47 demonstrating that none of these genes are involved in the biosynthesis of (37).48 Pyruvate dehydrogenase from B. subtilis will catalyse the formation of (37) from pyruvate (36) and D-glyceraldehyde (35) (Scheme 7).49 However as (37) is also a precursor to pyrid~xal~~ and pyruvate dehydrogenase mutants in E. coli do not require pyrid~xal,~' it is likely that 1-deoxy-D-xylulose is synthesized in E. coli by an alternative pathway or by more than one pathway. H OH (35) pyrwate dehydrogenase H$FOH + c COOH 0A / O* (37) (36) Proposed biosynthesis of 1 -deoxy-D-xylulose (37) in B. subtilis Scheme 7 3.6 Regulation of the Biosynthetic Pathway The thiamin biosynthetic pathway is tightly regulated.In S. typhimurium the expression of both the thiazole and the pyrimidine biosynthetic genes is repressed by intracellular thiamin pyrophosphate concentrations above approximately 30 pM.52 In addition the thiazole biosynthetic pathway is feedback inhibited by hydroxyethylthiazole at intracellular concentrations in excess of approximately 2 pM.53 The expression of the thiamin biosynthetic genes in E. coli is NATURAL PRODUCT REPORTS 1996-T. P. BEGLEY also repressed by intracellular thiamin pyrophosphate concen- trations in excess of 35 ,!AM.'* Reduced activities of hydroxy- methylpyrimidine kinase phosphomethylpyrimidine kinase hydroxyethylthiazole kinase thiamin phosphate synthase and thiamin phosphate kinase have been demonstrated in cell free extracts prepared from cells grown in the presence of thiamin.A regulatory mutant that maps close to the thiamin operon at 90 minutes has been identified. This mutant shows elevated levels of thiamin phosphate synthase and hydroxyethylthiazole kinase in thiamin repressed cells and has not yet been fully characterized.55 The thiamin pyrophosphate biosynthetic genes are scattered throughout the E. coli chromosome thiCEFGH map at 90 minutes,56thiJ maps adjacent to nuvC at 9.5 minute^,^' thiM and thiD map at 46 minutes," thiN maps in the 46-51 minute region,59 thiL maps at 10 minutes and thiK maps at 25 minutes.6o This delocalization of genetic information allows for complex regulation and greatly complicates in vitro recon-stitution of the biosynthetic pathway.4 Thiamin Biosynthesis in Baci//us subti/is Relatively little is known about the biosynthesis of thiamin in B. subtilis. N3 of the thiazole moiety is derived from glycine (39)'j' and C2 of the pyrimidine is derived from formate (38) (Scheme 8).62 The biosynthetic origin of the other atoms has not yet been determined. # HCOOH hOH (38) (39) 1 1 (5) Summary of the labeling studies on thiamin biosynthesis in B. subtilis Scheme 8 Hydroxyethylthiazole thiamin and hydroxymethylpyrimi- dine requiring mutants have been described.63 The thiamin phosphate synthase gene has been cloned and sequenced as part of the 8.subtilis sequencing project (ip~26d)'~ and shows significant sequence homology to thiE from E.coli (34% identity over 150 amino acids). Analysis of the ipa25d6' gene shows high similarity to the carboxy terminal region of the yeast thiamin phosphate synthase66 (36 % identity over 180 amino acids). As this region of the yeast enzyme is responsible for the hydroxyethylthiazole kinase activity it is likely that ipa25d codes for hydroxyethylthiazole kinase. A pyrimidine biosynthetic gene (thiA) has recently been cloned and sequenced and shows high sequence similarity to the E. coli thiC gene (79YOidentity over 406 amino acids). This gene complements all of the pyrimidine requiring mutants in B. subtilis6' and the thiC mutation in E. coli.6s Thiamin biosynthesis in Saccharomyces cerewisiae and ~chizosaccharom~ces pornbe The biosynthesis of thiamin pyrophosphate in Saccharomyces cerevisiae and in Schizosaccharomyces pombe also involves the coupling of hydroxyethylthiazole phosphate (5) and hydroxy- methylpyrimidine pyrophosphate (30).The pyrimidine and the thiazole biosynthetic pathways however are different from those used in-E. coli. 5.1 Biosynthesis of Hydroxyethylthiazole Phosphate The results of the labelling studies are summarized in Scheme 9. The sulfur is derived from cysteine (3).69In contrast to E. coli the C2 and the nitrogen of the thiazole are derived from the a-carbon and the amino group of glycine (39).50Carbons 4 and 5 of the thiazole as well as the methyl and the hydroxyethyl groups are proposed to originate from either the 5-phosphate or the 1,5bisphosphate of D-ribulose or ~-xylulose.~~ 9 nu NH2 H&-COOH + + 6 OH HO OP0a2-(39) (3) (40) I Proposed precursors to the hydroxyethylthiazole phosphate in S.cerevisiae Scheme 9 A mechanistic proposal for the formation of hydroxy-ethylthiazole phosphate (5) is outlined in Scheme Sulfur transfer via an enzyme bound persulfide as outlined in Scheme 3 is also a possibility. 5.2 Biosynthesis of Hydroxymethylpyrimidne Two pathways to the pyrimidine moiety (46) have been identified. In the major pathway (Scheme 1I) the C4 carbon of the pyrimidine is derived from formate the C2 and C8 carbons are derived from the C2 and C1 of pentulose (45) and the C5 C7 and C6 carbons are derived from C4 C5 and C3 of (45) respectively.In the minor pathway formate serves as the source of the C2 carbon and the C1 and C2 carbons of the pentulose serve as the source of the C5 and C4 carbons of the pyrimidine respectively. The origin of C8 C7 and C6 of the pyrimidine derived from the minor pathway is ~nknown.'~ More advanced precursors to the pyrimidine have been identified (Scheme 12). N1 and C2 of the pyrimidine are derived from N1 and C2 of pyridoxol (47)74and N3 C4 and the C4 amino group are derived from N1 C2 and N3 of histidine (48) re~pectively.~~ While none of the enzymatic activities involved have yet been identified it is clear that the formation of the pyrimidine moiety in yeast is significantly different from E.coli and equally intriguing. 5.3 Coupling of the Pyrimidine and the Thiazole Moieties The coupling of hydroxymethylpyrimidine pyrophosphate with hydroxyethylthiazole phosphate is catalysed by thiamin phos- NATURAL PRODUCT REPORTS 1996 OH (40) I PLP*hH I Mechanistic proposal for the formation of hydroxyethylthiazole phosphate in S. cerevisiae Scheme 10 0 NH2 HkH > majorpathay 8Aym OH OH OH (46) 06H (45) Proposed precursors to the hydroxymethylpyrimidine in S. cerevisiae Scheme 11 Advanced precursors to hydroxymethylpyrimidine phosphate in S. cerevisiae Scheme 12 phate synthase (Scheme 5). This enzyme has been purified.76 It is an octamer of 60 kD subunits and has an additional hydroxyethylthiazole kinase activity.77 5.4 Kinases Involved in Thiamin Biosynthesis Hydroxymethylpyrimidine kinase and phosphomethylpyrimi- dine kinase activities have been detected in cell free extract^.^' Hydroxyethyl thiazole kinase appears to be a salvage enzyme as mutations in this gene do not give rise to a thiamin requiring phenotype.79 A thiamin repressible acid phosphatase is also likely to be involved in thiamin salvage.s0 Surprisingly although thiamin phosphate is the product of thiamin phosphate synthase this is hydrolysed to thiamin and converted to thiamin pyrophosphate by thiamin pyrophosphokinase.81 5.5 Cloned Genes Involved in Thiamin Biosynthesis in Yeast In Saccharomyces cerevisiae the genes coding for thiamin pyrophosphokinase (tl~i80),~~ for thiamin phosphate synthase/ hydroxyethylthiazole kinase a gene involved in thiazole biosynthesis and a thiamin repressible acid phosphatase gene (ph03)~~ have been cloned and sequenced.Two regulatory genes thi2 and thi3 have also been cloned.86 Thi6 shows significant sequence similarity to ThiE from E. coli. There is no significant similarity between ThiFGH or ThiJ and Thi4. Several thiamin biosynthetic genes and two regulatory genes (thil and r~tfl+)~~ have been cloned and sequenced in Schizo-saccharomyces pombe. Thi2 is involved in the biosynthesis of the thiazole moiety,8s Thi3 is involved in the pyrimidine biosynthesissg and Thi4 is the thiamin phosphate synthase/ hydroxyethylthiazole kina~e.~O A thiamin repressible acid phos- phatase gene (phod) has been cloned and sequencedg* and two genes ptrl and ptr2 involved in the transport of thiamin into the cell have been identified.92 Thi4 shows significant sequence similarity to ThiE from E.coli. The reactions catalysed by Thi2 and Thi3 have not yet been identified and these proteins do not show significant sequence similarity to ThiCEFGH or ThiJ. 6 Thiamin Degradation During the course of studies to determine the thiamin content of various foods in Japan during World War 11 it was observed that some foods contained a thiamin degrading enzymatic activity. This thiaminase is fairly widespread and has been detected in several bacteria seafood and plant Animals and humans may develop symptoms of thiamin deficiency after ingesting thiaminase containing Two thiamin degrading enzymes have been isolated [eqn.(2)]. Thiaminase I catalyses the replacement of the thiazole moiety of thiamin by a wide range of nucleophiles (pyridine aniline quinolines cysteine) ;thiaminase I1 is specific for the NATURAL PRODUCT REPORTS 1996T. P. BEGLEY use of water as the nucleophile. The biological function of thiaminase is currently NLY y-42 )=k op0:-(5) Thiaminase I is the better characterized system. It is an extracellular enzyme and has been purified from Bacillus thiaminolyti~us.~~ Its gene has been sequenced and overexpressed in E. ~oli.~* Amino acid sequence analysis of thiaminase I shows that there is no appreciable sequence similarity between it and thiamin phosphate synthase from E.coli or other sequences in the protein databank. The recom- binant enzyme gives high quality crystals for X-ray diffraction studies and the crystal structure is close to completi~n.~~ The proposed mechanism for this substitution reaction is outlined in Scheme 13 Addition of an active site nucleophile to the C6 position of the pyrimidine gives (50). Loss of the thiazole followed by addition of the nucleophile (Y) gives (52). Departure of the active site nucleophile completes the reaction. This mechanistic proposal is supported by the observation of ping-pong lunetics for the reaction,loO by the mechanism based inactivation of the enzyme with 6-chloro-2-methyl-4-aminopyrimidine (53)lo1 and by the identification of the active site nucleophile as cysteine 1 13.1°2 Using chiral mono-deuteriothiamin (54) as substrate [eqn.(3)] it has been demonstrated that the substitution reaction proceeds with overall retention of configuration at the methylene position.lo3 HS-Enz I y2 ‘op0,2-(54) Me0mNH2] thiaminase (3) H2N H D +R Nm OMe op032-(55) (5) 7 Future Prospects The first Natural Product Reports article6 on thiamin bio- synthesis summarized information gained primarily using isotope-labelled precursors. Most of the progress over the past decade has resulted in the cloning isolation and charac- terization of several thiamin biosynthetic genes from E. coli S. cerevisiae S. pombe and B. subtilis. With the availability of many of the key biosynthetic enzymes in quantities suitable for mechanistic studies it is likely that much of the intriguing chemistry involved in the biosynthesis of this important cofactor will be elucidated over the next decade.Acknowledgements. I would like to thank my co-workers Allyson Backstrom Jessica Chiu Colleen Costello Neil Kelleher Cynthia Kinsland Austin McMordie Robb Nicewonger Anne Rammelsberg Sean Taylor Peter Vander Horn Long Vu and Yi Zhang for their excellent intellectual and experimental contributions. I would also like to thank my collaborators Nino Campobasso Steve Ealick Fred McLafferty Valley Stewart and Dolf Van Loon. Financial (49) 1 (5) -HS-Enz y2 (53)inhbitsenzyme Mechanistic proposal for thiaminase I Scheme 13 184 support from the National Institutes of Health (DK44083) and from Hoffmann-La Roche is gratefully acknowledged.8 References and Notes 1 For a review on the discovery of thiamin see R. Williams Vitamin B (thiamin) and its use in medicine The Macmillan Company New York 1938. 2 (a) R. Breslow J. Am. Chem. Sac. 1957,79 1762; (b) R. Breslow and E. McNelis J. Am. Chem. SOC. 1959 81 3080. 3 (a) Thiaminpyrophosphate biochemistry ed. A. Schellenberger and R.Schowen CRC Press Boca Raton Florida 1988; (b) P. Haake in Enzyme Mechanisms ed. M. I. Page and A. Williams. The Royal Society of Chemistry London and Cambridge 1987 ch. 19 p. 39W03; (c) R. Kluger Chem. Rev. 1987 863; (d) Y. Lindavist G. Schneider U.Ermler and M. Sundstrom EMBO J. 1992 11 2373; (e) Y.Muller and G. Schulz Science 1993 259 965; (f) F. Dyda W. Furey S. Swaminathan M. Sax B. Farrenkopf and F. Jordan Biochemistry 1993 32 6165. 4 W. Friedrich Vitamins Walter de Gruyter Berlin 1988 ch. 6. 5 Studies on thiamin biosynthesis in other systems are at an earlier stage. For key references see (a) J.-H. Julliard and R. Douce Proc. Natl. Acad. Sci. USA 1991,88,2042; (b) T. C. Charles and T. M. Finan Genetics 1991 127 5; (c) S. Kumar and S. B. Sharma Mol. Gen. Genet. 1986 204 473; (d) Y. Komeda M. Tanaka and T. Nishimune Plant Physiol. 1988 88 248. 6 D. W. Young Nut. Prod. Rep. 1986 3 395. 7 G. M. Brown and J. M. Williamson in Escherichia coli and Salmonella typhimurium ed. F. C.Neidhardt J. L. Ingraham K. B. Low B. Magasanik M. Schaechter and H. E. Umbarger American Society for Microbiology Washington DC 1987 ch. 34 p. 521. The thiamin biosynthetic pathway appears to be identical in both microorganisms. 8 (a) K. Tazuya K. Yamada K. Nakamura and H. Kumaoka Biochim. Biophys. Acta 1987 924 210; (b) E. DeMoll and W. Shive Biochem. Biophys. Res. Commun. 1985 132 217. 9 (a) B. Estramareix and M. Therisod Biochim. Biophys. Acta 1972 273 275; (b) E. Bellion D. Kirkley and J. Faust Biochim. Biophys. Acta 1976 437 229; (c) R. White and F. Rudolph Biochim. Biophys. Acta 1978 542 340. 10 S. David B. Estramareix J.-C. Fischer and M. Therisod J. Chem. Soc. Perkin Trans. 1 1982 213 1. The incorporation experiments were done with l-deoxy-D-xylulose (1 -deoxy-~-threo-2-pentulose).As hydroxyethylthiazole kinase mutants do not require thiamin the thiazole is biosynthesized as the phosphate. We therefore assume that the phosphorylation has occurred at the 1-deoxy-D- xylulose stage. 11 Several related schemes in which the order of the steps has been changed are equally plausible. 12 R. White Biochim. Biophys. Acta 1979 583 55. 13 A. Backstrom R. A. McMordie and T. P. Begley J. Am. Chem. SOC.,1995 117 2351. 14 P. Haake in Enzyme Mechanisms ed. M. I. Page and A. Williams The Royal Society of Chemistry London and Cambridge 1987 ch. 19 pp. 39W03. 15 (a) A. Backstrom R. A. McMordie and T. P. Begley unpublished results; (b) B. Estramareix and M. Therisod Biochem. Biophys.Res. Commun. 1980 95 1017. 16 N. Nagahara T. Okazaki and T. Nishino J. Biol. Chem. 1995 270 16230. 17 (a) L. Zheng R. White V. Cash and D. Dean Biochemistry 1994 33 4714; (b) L. Zheng and D. Dean J. Biol. Chem. 1994 269 18723. 18 D. M. Pitterle J. L. Johnson and K. V. Rajagopalan J. Biol. Chem. 1993 268 13506. 19 I. Sanyal G. Cohen and D. H. Flint Biochemistry 1994 33 3625. 20 (a) M. Eisenberg in Escherichia coli and Salmonella typhimurium ed. F. C. Neidhardt J. L. Ingraham K. B. Low B. Magasanik M. Schaechter and H. E. Umbarger American Society for Micro- biology Washington DC 1987 ch. 36 p. 544; (b) M. A. Hayden I. Huang D. E. Bussiere and G. W. Ashley J. Biol. Chem. 1992 267 9512; (c) M. A. Hayde I. Y. Huang G. Iliopoulos M.Orozco and G. W. Ashley Biochemistry 1993 32 3778. 21 J. Neuhard and P. Nygaard in Escherichia coli and Salmonella ryphimurium ed F. C. Neidhardt J. L. Ingraham K. B. Low B. Magasanik M. Schaechter and H. E. Umbarger American Society for Microbiology Washington DC 1987 ch. 29 p. 445. NATURAL PRODUCT REPORTS 1996 22 (a) B. Estrm~areix and M. Therisod J. Am. them. 1984 106 3857; (b) B. Estramareix and S. David Biochim. Biophys. Acta 1990 1035 154; (c) B. Estramareix and S. David Biochem. Biophys. Res. Commun. 1986 134 1136; (d) K. Tazuya M. Tanaka M. Morisaki K. Yamada and H. Kumaoka. Biochem. Int. 1987 14 769. 23 B. Estramareix and S. David Biochim. Biophys. Acta 1990 1035 154. 24 Analogous electrocyclization reactions of heterocumulenes have been reported A.Martinez A. Fernandez F. Jimenez A. Fraile L. Subramanian and M. Hanack J. Org. Chem. 1992 57 1627. 25 (a) D. Downs J. Bacteriol. 1992,174,1515;(b) D. M. Downs and L. Petersen J. Bacteriol. 1994 176 4858. 26 Y. Kayama and T. Kawasaki Arch. Biochem. Biophys. 1973,158 242. 27 H. Nakayama Bitamin 1990 64 619. 28 (a) N. Imamura and H. Nakayama J. Bacteriol. 1982 151 708; (b) T. Fujio M. Hayashi A. Iida T. Nishi and T. Hagihara Eur. Pat. Appl. 90-309617.0 1990; (c) H. Nakayama and R. Hayashi J. Bacteriol. 1972 109 936. 29 (a) T. Kawasaki A. Iwashima and Y. Nose J. Biochem. 1969,65 407; (b) T. Kawasaki and Y. Nose J. Biochem. 1969 65 417. 30 (a) N. Imamura and H. Nakayama J. Bacteriol. 1982 151 708; (b) T.Fujio M. Hayashi A. Iida T. Nishi and T. Hagihara Eur. Pat. Appl. 90-309617.0 1990; (c) H. Nakayama and R. Hayashi J. Bacteriol. 1972 109 936. 31 (a) H. Nakayama Bitamin 1990 64 619; (b) T. Mizote and H. Nakayama J. Bacteriol. 1989 171 3228. 32 (a) D. W. Young Nut. Prod. Rep. 1986,3 395; (b) G. M. Brown and J. M. Williamson in Escherichia coli and Salmonelfa typhimurium ed. F. C. Neidhardt J. L. Ingraham K. B. Low B. Magasanik M. Schaechter and H. E. Umbarger American Society for Microbiology Washington DC 1987 ch. 34 p. 521. 33 P. Vander Horn A. Backstrom V. Stewart and T. P. Begley J. Bacteriol. 1993 175 982. 34 Accession number M8870l. 35 We use the standard notation for designating genes and their corresponding gene products e.g.ThiC is the gene product of the thiC gene. 36 There are no additional thiamin biosynthetic genes immediately upstream or downstream of this cluster A. Backstrom V. Stewart and T. P. Begley unpublished data. 37 J. Ryals R.-Y. Hsu M. N. Lipsett and H. Bremer J. Bacteriol. 1982 151 899. 38 A. Backstrom V. Stewart and T. P. Begley unpublished results. GenBank accession number U34923. 39 T. Fujio M. Hayashi A. lida T. Nishi and T. Hagihara Eur. Pat. Appl. 90-309617.0 1990. 40 C. A. Costello and T. P. Begley unpublished results. 41 The mutants tested were thiC44 thiC39Tnl0 thiC34 and thiC43. 42 E. J. Mueller E. Meyer J. Rudolph V. J. Davisson and J. Stubbe Biochemistry 1994 33 2269. 43 A. Backstrom R. A. McMordie and T. P. Begley J. Am. Chem.SOC.,1995 117 2351. 44 Accession number M2 1151. 45 T. Nohno Y. Kasai and T. Saito J. Bacteriol. 1988 170 4097. 46 K. V. Rajago palan in Molybdenum Enzymes Cofactors and Model Systems ed. E. Stiefel D. Coucouvanis and W. Newton ACS Symposium Series no. 535 American Chemical Society Washington DC 1993 ch. 3 p38. 47 A. Backstrom R. A. McMordie and T. P. Begley J. Carbohydr. Chem. 1995 14 171. 48 A. Backstrom V. Stewart and T. P. Begley unpublished results. 49 A. Yakota and K. Sasajima Agric. Biol. Chem. 1986 50 2517. 50 I. A. Kennedy R. E. Hill R. M. Pauloski B. G. Sayer and I. D. Spenser J. Am. Chem. SOC.,1995 117 1661. 51 D. Langley and J. R. Guest J. Gen. Microbiol. 1977 99,263. As the strain used required thiamin it was not possible to determine if pyruvate dehydrogenase mutants do require thiamin.52 Calculated assuming that 1 g of dry cells is equivalent to 4ml of intracellular fluid T. Kawasaki A. Iwashima and Y. Nose J. Biochem. 1969 65 407. 53 P. C. Newel1 and R. G. Tucker Biochem. J. 1966 100 517. 54 T. Kawasaki A. Iwashima and Y. Nose J. Biochem. 1969 65 407. 55 T. Kawasaki and Y. Nose J. Biochem. 1969 65 417. 56 P. Vander Horn A. Backstrom V. Stewart and T. P. Begley J. Bacteriol. 1993 175 982. 57 J. Ryals R.-Y. Hsu M. N. Lipsett and H. Bremer J. Bacteriol. 1982 151 899. nuvC was originally mapped at 4246 minutes. NATURAL PRODUCT REPORTS 1996-T. P. BEGLEY 58 T. Mizote and H. Nakayama J. Bacteriol. 1989 171 3228. 59 H. Nakayama Bitamin 1990 64 619.60 N. Imamura and H. Nakayama J. Bacteriol. 1982 151 708. 61 K. Tazuya M. Morisaki K. Yamada H. Kumaoka and K. Saiki Biochem. Int. 1987 14 153. 62 K. Yamada M. Morisaki and H. Kumaoka Biochim. Biophys. Acta 1983 756 41. 63 (a) M. A. Vandeyar and S. T. Zahler J. Bacteriol. 1986,167,530; (b) M. S. Kelly Mol. Gen. Genet. 1967 99 333. 64 P. Glaser F. Kunst M. Arnaud M.-P. Coudart W. Gonzales M.-F. Hullo M. Ionescu B. Lubochinsky L. Marcelino I. Moszer E. Presecan M. Santana E. Schneider J. Schweizer A. Vertes G. Rapoport and A. Danchin Mol. Microbiol. 1993 10 371. The accession number for the ipa26d gene is X73124. 65 Accession number X73 124. 66 Accession number A55145. 67 The mutants tested were thiA78 :Tn917 thiA84:Tn917 and thiA75 and thiC34.68 Y. Zhang and T. P. Begley unpublished data. 69 K. Tazuya K. Yamada K. Nakamura and H. Kumaoka Biochim. Biophys. Acta 1987 924 210. 70 (a) R. L. White and I. D. Spenser Biochem. J. 1979,179,315; (b) P. E. Linnett and J. Walker Biochem. J. 1968 109 161. 71 R. L. White and I. D. Spenser J. Am. Chem. SOC. 1982 104 4934. 72 This proposal is a minor variant of that described in R. L. White and I. D. Spenser J. Am. Chem. SOC. 1982 104 4934. 73 G. Grue-Sorensen R. White and I. Spencer J. Am. Chem. SOC. 1986 108 146. 74 (a) K. Tazuya C. Azumi K. Yamada and H. Kumaoka Biochem. Mol. Biol. Int. 1994 33 769; (b) K. Tazuya K. Yamada and H. Kumaoka Biochem. Mol. Biol. Znt. 1993 30,893. 75 K. Tazuya K. Yamada and H.Kumaoka Biochim. Biophys. Acta 1989 990 73. 76 Y. Kawasaki J. Bacteriol. 1993 175 5153. 77 This enzyme has previously been called thiamin phosphate pyrophosphorylase reflecting the apparent reversibility of the reaction. As the reaction catalysed by the E. coli coupling enzyme (ThiE) is not reversible we propose to name the coupling activity thiamin phosphate synthase. 78 G. Brown Methods Enzymol. 1970 Ma 203. 79 K. Nosaka H. Nishimura Y. Kawasaki T. Tsujihara and A. Iwashima J,Bid. Chem. 1994 269 30510. 80 (a) K. Nosaka Biochim. Biophys. Acta 1990,1037 147; (b) M. E. Schweingruber R. Fluri K. Maundrell A. M. Schweingruber and E. Dumermuth J. Biol. Chem. 1986 261 15877. 81 K. Nosaka. Y. Kaneko H. Nishimura and A. Iwashima J. Biol. Chem.1993 268 17440. 82 K. Nosaka Y. Kaneko H. Nishimura and A. Iwashima J. Biol. Chem. 1993 268 17440. 83 K. Nosaka H. Nishimura Y. Kawasaki T. Tsujihara and A. Iwashima J. Biol. Chem. 1994 269 30510. 84 U. M. Praekelt K. Byrne and P. A. Meacock Yeast 1994 10 481. 85 W. Bajwa B. Meyhack H. Rudolph A. M. Schweingruber and A. Hinnen Nucleic Acids Res. 1984 12 7721. 86 (a) H. Nishimura Y. Kawasaki Y. Kaneko K. Nosaka and I. Iwashima J. Bacteriol. 1992 174 4701; (b) H. Nishimura Y. Kawasakia Y. Kaneko K. Nosaka and A. Iwashima FEBS Lett. 1992 297 155. 87 (a) H. Frankhauser and M. Schweingruber Gene 1994,147 141 ; (b) C. S. Tang A. Bueno and P. Russell J. Biol. Chem. 1994,269 11921. 88 (a) A. Zurlinden and M. Schweingruber Gene 1992,117 141 ;(b) A.G. Manetti M. Rosetto and K. G. Maundrell Yeast 1994 10 1075. 89 K. Maundrell J. Biol. Chem. 1990 265 10857. 90 A. Zurlinden and M. Schweingruber J. Bacteriol. 1994 176 663 1. 91 J. Yang and M. E. Schweingruber Curr. Genet. 1990 18 269. 92 A. M. Schweingruber J. Dlugonski E. Edenharter and M. E. Schweingruber Curr Genet 199 1 19 249. 93 (a) C. Evans Vitam. Horm. (N.Y.) 1975 33 467; (b) A. Fujita Adv. Enzymol. 1954 15 389. 94 (a) J. W. Earl and B. V. McCleary Nature (London) 1994 368 683; (b) P. Duffy H. Morris and G. Neilson Am. J. Clin. Nutr. 1981 34 1584; (c) A. Fujita J. Vitaminol. 1972 18 67; (d) R. Hayashi Nutrition Rev. 1957 15 65; (e) K. Murata Ann. N.Y. Acad. Sci. 1982 378 146. 95 It has been proposed that thiaminase I1 may play a biosynthetic role in yeast Y.Kimura and A. Iwashima Experientia 1987,43 888. 96 (a) J. Wittliff and R. Airth Biochemistry 1968 7 736; (b) H. Douthit and R. Airth Arch. Biochem. Biophys. 1966,113,331;(c) J. Wittliff and R. Airth Methods Enzymol. 1970 18a 229. 97 M. Abe S. Ito M. Kimoto R. Hayashi and T. Nishimune Biochim. Biophys. Acta. 1987 909 213. 98 C. Costello N. Kelleher M. Abe F. W. McLafferty and T. P. Begley J. Biol. Chem. 1996 271 3445. 99 N. Campobasso C. A. Costello T. P. Begley and S. Ealick un- published data. 100 (a) S. Puzach Z. Gorbach M. Yu and Y. Ostrovskii Biochemistry (USSR) 1984 49 1178; (b) G. Lienhard Biochemistry 1970 9 301 1. 101 J. A. Hutter and J. T. Slama Biochemistry 1987 26 1969.102 (a) N. Kelleher C. Costello T. P. Begley and F. W. McLafferty J. Am. SOC. Mass Spectrom. 1995 6 981 ; (b) C. Costello N. Kelleher M. Abe F. W. McLafferty and T. P. Begley J. Biol. Chem. 1996 271 3445. 103 (a) R. Nicewonger A. Rammelsberg C. Costello and T. P. Begley Bioorg. Chem. 1995 23 512; (b) R. Nicewonger C. Costello and T. P. Begley J. Org. Chem. in the press.

ISSN:0265-0568    

DOI:10.1039/NP9961300177

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Pyrrolizidine Alkaloids J. Richard Liddell Birch Tree Cottage Alderholt Road Sandleheath Hampshire SP6 I PT UK Reviewing the literature published between July 1994 and June 1995 (Continuing the coverage of literature in Natural Product Reports 1995 Vol. 12 p. 41 3) 1 The Synthesis of Necines 2 The Synthesis of Necic Acids 3 Alkaloids of the Asteraceae (Compositae) 4 Alkaloids of the Boraginaceae 5 Alkaloids of the Casuarinaceae 6 Alkaloids of the Liliaceae 7 Alkaloids from Animals 8 General Studies 9 Pharmacological and Biological Studies 10 References 1 The Synthesis of Necines The potential usefulness of tandem [4+2]/[3 +21 cycloaddition reactions of nitroalkenes for the synthesis of a wide variety of necines has been described by Denmark et al.and illustrated by the synthesis of (-)-hastanecine (6) (Scheme 1).l Cyclo- addition of nitroalkene (1) to vinyl ether (2) in the presence of a catalyst provided nitronate (3) with high selectivity. Cyclo- addition of dimethyl maleate to nitronate (3) afforded the key nitroso acetal (4) as a single diastereoisomer which was reduced under carefully optimised conditions to lactam (5) in good yield and 98% enantiomeric purity. Removal of the unwanted hydroxy group followed by reduction gave the required ( -)-hastanecine (6) the relative configuration of which was confirmed by X-ray analysis of a derivative of lactam (5). Using a similar strategy the same group has synthesised (-)-rosmarinecine (12) (Scheme 2). The key intermediate is the nitroso acetal (9) which was synthesised by a tandem cycloaddition of nitroalkene (7) with the optically active vinyl ether (8).Selective reduction of the nitroso acetal(9) followed by hydrogenolysis gave the lactam-lactol (10) in which all stereocentres except the eventual C-2 have the correct geometry. Protection of the lactol as a methyl acetal and inversion of the stereochemistry at C-2 by a Mitsunobu reaction gave (11). Deprotection of the acetal and reduction of the resulting lactol afforded (-)-rosmarinecine (12). 1ii iii 0 Phn 0' \\ HY dKPh 0 (3) 0 PhKO @-M:H iii c- 0 (5) 1iv-vi &50H (6) Reagents :i Ti(OPr'),Cl,,CH,Cl, -90 -+ -78 "C; ii dimethyl maleate benzene 25 "C;iii H (260 psi) Raney Ni MeOH; iv PhCSCl DMAP pyridine; v Bu,SnH AIBN; vi LiAlH Scheme 1 187 1vi vii (12) Reagents i methylaluminium bis(2,6-diphenoxide) (MAPh) -78 "C CH,Cl,; ii Li(Bu'),BH -78 "C THF; iii H (160 psi) Raney Ni; iv CH(OCH,), MeOH/TsOH reflux 5 h; v 4-N0,C6H,COOH Ph,P DEAD THF rt; vi 90% TFA rt 20 h; vii Red-Al THF reflux 3 h Scheme 2 Bowman et al.have used tandem cyclisation of aminyl radicals to synthesise a variety of structures containing the pyrrolizidine ring system (Scheme 3).3 Initial cyclisation of an aminyl radical (1 4),generated from a sulfenamide (1 3) provided the key intermediate radical (15) which rapidly cyclised to bicyclic radical (16) and was then trapped by hydrogen abstraction from tributyltin hydride. Some trapping of the intermediate (1 5) by the tributyltin hydride also occurred but was minimised by using very low concentrations of the hydride.Structures (1 7)-(22) were produced using this methodology. -&.' -3 SPh Bu3Sn-SPh R2 R2 (13) (14) 5-ex0 cyclisation R' R' Bu3Sn' 4 R' Ph4% Radical cyclisation methodologies have also been used by Smith and Keusenkothen in their syntheses of heliotridane (27) trachelanthamidine (29) and isoretronecanol (39 (Schemes 4 and 5). Lactam (23) was alkylated the resultant ester side- chain reduced and the resultant alcohol (24) was converted I OH I (24) / (2;; (33 (27) Reagents i BrCH,CO,Et KOH THF; ii NaBH,; iii MsC1 NEt,; iv NaI acetone; v AIBN Bu,SnH benzene; vi LiAIH,; vii (Bu,Sn), hv EtI; viii EtC0,Cs Scheme 4 NATURAL PRODUCT REPORTS 1996 into iodide (25) by mesylation followed by Finkelstein exchange (Scheme 4).Using different radical cyclisation conditions iodide (25) was transformed to (-)-heliotridane (27) via pyrrolizidinone (26) or alternatively to (-)-trachelanthamidine (29) via pyrrolizidinone (28). Synthesis of (-)-isoretronecanol (35) was achieved by a modified pathway (Scheme 5). Alkynyl lactam (31) was obtained from vinyl lactam (30) and then converted into iodide (32) which on radical cyclisation afforded bicycle (33). This on desilylation gave the pyrrolizidinone (34) and on reduction (-)-isoretronecanol (35). me351 vii viii c- Reagents i Br,; ii ButOK THF -78 "C; iii BrCH,CH,CI KOH Bu,NI; iv BuLi Me,SiCl; v NaI acetone; vi AIBN Bu,SnH benzene reflux 6 h; vii p-TsOH MeCN 48 h; viii AcOH CH,CI, NEt, DMAP 3 h; ix BH,.THF Scheme 5 An asymmetric route to trachelanthamidine (29) has also been reported by Proctor et al.using an N-acyl anion cyclisation approach (Scheme 6).5 Using a hindered base to generate an 4. /v vi /OH (29) Reagents i (Me,Si),NLi THF -78 "C; ii NaBH, EtOH 24 h; iii MsC1 Et,N CH,Cl, 0 "C 5 h; iv NaCN DMSO 90 "C 3 h; v HCl (gas) MeOH 0 OC 24 h; vi LiAlH, THF reflux 18 h Scheme 6 NATURAL PRODUCT REPORTS 1996-5.R. LIDDELL 4-N3 acyl anion the key amide (36) prepared from N-acetyl proline TESO was cyclised to the pyrrolizidin- 1,3-dione (37) and then reduced --I $co2Me ii iii to a 95:5 mixture of em and endo alcohols (38) and (39).Mesylation of the mixture gave only mesylate (40) in very high C02Me <C02Me optical purity which was transformed into the nitrile (41) and not as expected the isomer (42). Methanolysis of the nitrile (45) (41) and reduction of the resultant ester provided (*)-trac helan thamidine (29). IN H H v OH TESO 4 -Q vii viii -c-. v vi i-N -. -Me0 -N n 0 0 'copi 'C02Me CI 0 (52) i t t;lr cb (49) 0 Reagents i SmI,; ii aq. AcOH THF; iii (PhO),P(O)N, Ph,P (27) DEAD; iv Mg MeOH 0 "C 3 h; v 0, -78 "C then Ph,P; VI MeOCH,PH,+ C1- BuLi; vii aq. AcOH THF 80 "C 1 h; viii TFA Reagents i PhCO,H DEAD Ph,P 0 "C; ii K,CO, MeOH; iii HCl Me,SiH (gas); iv Me,SiCl imidazole DMF Scheme 7 Scheme 8 0 oqoT Boc' BOC/ -Bod OX0 OX0 Oq-OH O?.-OHH0 H0 030.H' 0 H' 5 H MsO bMs MsO 'OMS MsO OMS MsO OMS PMs -OMS OMS -OMS OMS OH Reagents i SnCI, Et,O -85 "C;ii BF,.Et,O Et,O -85 "C; iii Et,,N DMAP CH,Cl, rt; iv H, THF NaOAc Pd/C then 6 M HCl; v MeSO,CI pyridine; vi BH,.Me,S THF rt then DBU benzene reflux; vii 6% Na/Hg Et,O Pr'OH rt; viii Bu,N+BzO- toluene reflux; ix NaOMe MeOH rt Scheme 9 Formal syntheses of heliotridane (27) and pseudoheliotridane (49) have been reported by Honda et al. (Schemes 7 and 8).6 In both syntheses the key step involved a samarium iodide promoted regioselective cleavage of a y-halo ester. Thus in the synthesis of pseudoheliotridane (49) (Scheme 7) the y-halo ester (43) obtainable from (-)-carvone was ring-opened to alkene ester (44).This was converted into the azide (45) which on reduction cyclised to the lactam (46). Modification of the side-chain by ozonolysis and a Wittig reaction provided enol ether (47) as a 1 :1 mixture of E/Z isomers. Cyclisation under acidic conditions followed by reduction of the resultant hydroxylactam provided lactam (48) which had previously been converted into pseudoheliotridane (49). Similarly heliotridane was produced in an identical manner from y-halo ester (51) (Scheme 8). Hydroxy ester (50) obtainable from (+)-carvone was esterified and the stereo- chemistry of the hydroxy group inverted by a Mitsunobu reaction. Addition of hydrogen chloride and protection of the alcohol gave the key ester (51).Thereafter the procedures of Scheme 7 provided lactam (52) from which heliotridane (27) had previously been synthesised. The stereoselective synthesis of all four isomers of cis-1,2-dihydroxypyrrolizidine has been reported by Casiraghi et al. (Scheme 9).' Condensation of optically pure acetonide (53) or its enantiomer (54) with pyrrole (55) selectively afforded the four lactams (56a-d) whose absolute stereochemistries were confirmed by X-ray analyses. Using parallel and identical reactions the lactams were hydrogenated converted into the corresponding mesylates (57a-d) and then cyclised and de- protected via either of two pathways to provide the pyrro- lizidines (58a-d). Transformation of lactams (56a) and (56d) to lactams (56b) and (56c) respectively was also possible thus allowing access to any of the four pyrrolizidines (58a-d) from either of the starting acetonides (53) or (54).A concise regio- and stereo-specific synthesis of pyrrolizidines has been reported by Mann et al. (Scheme Irradiation of a mixture of optically active butenolide (59) and pyrrolidine (60) afforded an intermediate thought to be (61) which cyclised to pyrrolizidinone (62). This has the same ring skeleton and stereochemistry as the alkaloid lindelofidine (63). rOTBDMS 1 OTBDMS TMS 1 &OH 0 CQ (63) = lindelofidine (62) Reagents i hv (350 nm) Ph,CO 1-2 h; ii ButOK THF Scheme 10 A series of reports discussing the a-cyclisation of tertiary amines to generate pyrrolizidines and other bicyclic compounds has been published by Viehe and co-workers (Scheme 1 l).9-11 Heating enamines of general structure (64) with dimethyl acetylene dicarboxylate (DMAD) and DMSO in the presence of molecular sieves provided the bicyclic compounds (67) via a [2 +21 cycloaddition intermediate (65)and aminodiene (66).NATURAL PRODUCT REPORTS. 1996 Me02C Meo&)" ~ n= 1,2,3,4 E = Code COgt R R = H Me Ph (67) Reagents i DMAD DMSO 4A molecular sieves 135 "C 24 h Scheme 11 2 The Synthesis of Necic Acids The first synthesis of senecionine (75) has been reported by Niwa and co-workers (Scheme 12).12 Lactone (68) available from earlier work,13 was isomerised to the (2)-lactone (69) and then converted first into the required protected diacid (70) and then into the anhydride (71).Coupling of the anhydride with the stannoxane (72) available from earlier work,13 gave seco acid (73) regioselectively. This was cyclised under Keck's conditions to provide a mixture of macrocycle (74) and its geometric isomer which were separated. (74) was then de- protected to afford the desired senecionine (75). (69) 1 ii-iv OMTM OMTM -v,vi e C 0 2 M e \ 0 OMe /-f$ 000 Reagents i hv Ph,CO; ii aq. Ba(OH), reflux 1 h; iii CH,N, Et,O; iv DMSO Ac,O 40 "C 24 h; v KOH MeOH H,O reflux 2.5 h; vi DCC CH,Cl,; vii benzene reflux 23 h; viii DCC CSA DMAP rt 2 d; ix Ph3C+BF4- CH,Cl, rt 6.5 h Scheme 12 NATURAL PRODUCT REPORTS 1996J. R.LIDDELL The same group has also carried out the first synthesis of the 12-membered macrocycle ( +)-yamatairnine (80) using in part a similar approach (Scheme 13).14 The key lactone ester (79) was obtained by alkylation of keto ester (76) followed by a Baeyer-Villiger oxidation of the major product giving lactones (77) and (78) in a 1:1 ratio which were separated chromato- graphically. Introduction of an ethylidene group into lactone (78) and reduction of the resultant alkene provided lactone (79) with the desired stereochemistry. Thereafter conversion of lactone (79) into yamataimine (80) was similar to the route followed in Scheme 12. 0 (76) (77) \f iikvi (78' Me02C ' Reagents i MeI K,CO,; ii 80% MCPBA CH2C12 reflux 4 d; iii LDA HMPT CH,CHO -78 "C then -40 "C,3 h; iv Ac,O Et,N DMAP rt 14 h; v DBU rt 2 d; vi H, 10% Pd/C rt 16 h Scheme 13 3 Alkaloids of the Asteraceae (Compositae) The aerial parts of Syneilesis aconitifolia used in Chinese folk medicine have been shown to contain the known alkaloids syneilesine and acetylsyneilesine and the spectroscopic data for these alkaloids have been impr0~ed.l~ Iphiona aucheri Boiss.was investigated for the presence of pyrrolizidine alkaloids following the deaths of racing camels with histological symptoms typical of pyrrolizidine alkaloids.16 However only the non-toxic pyrrolizidine isotussilagine was isolated and further investigation led to the isolation of two toxic terpenoids atractyloside and carboxyatractyloside.4 Alkaloids of the Boraginaceae Two new alkaloids lithosenine (81) and acetyllithosenine (82) have been isolated from Lithosperum oficinale a plant which is used medicinally." On the basis of their structures both new alkaloids are presumed to be toxic. A new alkaloid 7-acetyleuropine (83) has been isolated from Heliotropium bovei and its structure determined by one-and two-dimensional NMR spectroscopy.1s Also present were the known alkaloids lasiocarpine 5'-acetyllasiocarpine their N-oxides and europine. Europine was also found to have both antifungal and insect an ti feedan t activity . An extreme variation in the alkaloid content of the leaves of Cynoglossum oficinale has been observed. l9 The youngest leaves in plants contained pyrrolizidine concentrations up to 190 times higher than the levels found in older leaves while dead leaves had negligible amounts of alkaloids.In the light of these findings the authors of the paper stress the desirability to report findings for the various plant parts rather than for the total biomass. Gas chromatography / matrix isolation / Fourier transform infrared spectroscopy has been applied to the identification of the alkaloids in comfrey (Symphytum oficinale L.) and the results compared against known standards.20 Other workers have reported a method for the extraction solid phase concentration and capillary GC detection of the alkaloids and N-oxides in commercial comfrey products. 21 Alkaloid levels were highest in bulk comfrey root and lowest in mixtures of comfrey leaf with other materials.Another22 TLC method of detecting and quantifying alkaloids in borage (Borago oficin-ah) seed oil has been rep~rted.,~ The major alkaloid found was amabiline with lesser amounts of supinine 7-acetylintermedine and 7-ace ty llycopsamine. 5 Alkaloids of the Casuarinaceae A new highly oxygenated alkaloid casuarine (84) obtained from Casuarina equisetifolia L. has been reported.24 The structure was elucidated by spectroscopic methods and con- firmed by X-ray crystallography. In addition to casuarine a glycoside of the alkaloid was isolated the structure deter- mination of which is in progress. The plant is used medicinally in Western Samoa. 6 Alkaloids of the Liliaceae A novel cage-type alkaloid asparagamine A (85) has been isolated from Asparagus racemosus Willd.and its N-oxide synthesi~ed.~~. 26 The structure of asparagamine A was eluci- dated by spectroscopic chemical and X-ray analyses. This is the first report of pyrrolizidine alkaloids from the Liliaceae. 7 Alkaloids from Animals 14-Deoxyparsonsianidine-N-oxide(86) has been isolated from adults of the danaine butterfly Idea leuconoe and is thought to (81) R=H have been incorporated directly from the host plant Parsonsia (82)R=Ac laevigata during the insect's larval ~tage.~' A detailed study of the chemicals including pyrrolizidines exuded from the hair-pencils of African milkweed butterflies has been carried out.28 In all 214 compounds from a total of 14 different classes were identified.Tracer studies of the bio- synthesis of the insect-specific alkaloid callimorphine present in Tyria jacobaea has revealed that retronecine acquired at any time during the larval stages forms the necine base while isoleucine is specifically incorporated into the necic acid portion of callimorphine and that the alkaloid itself is formed during the early stages of pupation.2g Both male and to a lesser extent female butterflies of the genus Mechanitis polymnia convert the ingested alkaloids intermedine rinderine and echinatine into lycop~amine.~~ Numerous alkaloids have been found in Madagascan frogs of the genus Mantella including four pairs of diastereoisomeric pyrrolizidines (87k(90).31 The same group have shown that some amphibian alkaloids including oxime (91) are derived from dietary source^.^^.^^ (87) R = H (88) R =OH (89) R’ = H; R2=OH (90) R’ R2 = 0 8 General Studies Surveillance of natural toxicants in the United Kingdom food supply has indicated that comfrey-containing products are the most important sources of pyrrolizidine alkaloids with esti- mated intakes of 36 mg per day for root-based infusions and less than 0.2 mg per day for leaf-based infusions.34 A number of reviews relating to pyrrolizidine alkaloids have been published.These include details of the occurrence of pyrrolizidine alkaloids in European medicinal plants with an overview of pyrrolizidine alkaloid chemistry and biochemistry ;35 the for- mation of pyrrolizidines and other ornithine-derived alka- loids ;36 the role of pyrrolizidine alkaloids and other secondary plant metabolites in plant-insect interactions ;37 the detection isolation and identification of alkaloids found in grasses infected by Acremonium species in which the loline group of pyrro- lizidine alkaloids appear to be specific to grasses infected by A.coenophialum ;38 and lastly the chemoecological and biological aspects of pyrrolizidines particularly plant-insect inter-action~.~~ Also included is an alternative classification of structural types to that used else~here,~~~~~ and a most useful NATURAL PRODUCT REPORTS 1996 updating of plant sources of the alkaloids. Both putrescine (92) and spermidine (93) are incorporated into homospermidine (94) a precursor in the biosynthesis of retr~necine.~~ Spermidine is not incorporated in the absence of putrescine.H2N N NH2 H2N-NH2 H (92) (93) 9 Pharmacological and Biological Studies A biological cost/ benefit analysis of pyrrolizidine alkaloids in Senecio jacobaea showed a slight benefit from a decrease in herbivory with increased alkaloid c~ncentration.~~ The alka- loids of Cynoglossum oficinale act as feeding deterrents against generalist herbivores but not against specialist herbivores.44 Young leaves with the highest levels of alkaloids were significantly less damaged than older leaves. In a related study insect-inflicted damage to Cynoglossum oficinale resulted in higher levels of alkaloids in the affected leaves with lower levels in slightly damaged or undamaged leaves.45 A range of concentrations of monocrotaline in the nectar supplied to lepidoptera had no significant deterrent effect on their feeding beha~our.~~ Work by Huxtable and Yan has shown that hepatic glutathione levels regulate the metabolism of mono- crotaline and dehydromonocrotaline in rat 1ive1-s.~~ High glutathione levels are induced by the alkaloids and glutathione binding to the alkaloid metabolites is a major factor in reducing the toxic effects of the alkal~id.~~.~~ A significant synergistic liver toxicity of copper and retrorsine in rats has been observed .50 Feeding trials with rodents have shown riddelliine to be both genotoxic and carcinogenic and it may also be crossing the placental barrier and/or be present in milk causing de- velopmen tal toxicity .The alkaloids monocro taline otosenine retrorsine senecionine seneciphylline and senkirkine proved to be acutely toxic towards Saccharomyes cerevisiae in the ‘yeast test’ and hence the yeast test may be superior to bacterial systems in toxicity studies.s2 An overview of the DNA adducts of pyrrolizidine alkaloids nitroimidazoles and aristolochic acid has been p~b1ished.j~ Senecionine but not senecionine-N-oxide has been shown to be embryotoxic using the chick embryotoxicity screening test and theoretical calculations indicate that senecionine embryotoxicity for mammals ranges between 10-100 mg kg-’ maternal body weight.s4 Segall et al. have shown that the rat and guinea pig glutathione-jacobine conjugates are identical and the rapid formation of the guinea pig conjugate is suggested to account for the resistance of the animal to pyrrolizidine poisoning.j5 Bovine endothelial cells exposed to monocrotaline pyrrole in vitro do not produce changes that would account for the thrombosis observed in viv~.~~ Exposure of cultured rat pulmonary endothelium cells to monocrotaline pyrrole resulted in delayed and progressive damage similar to that observed in in vivo experiment^.^' 10 References 1 S.E. Denmark and A. Thorarensen J. Org. Chem. 1994 59 5672. 2 S. E. Denmark A. Thorarensen and D. S. Middleton J. Org. Chem. 1995 60 3574. 3 W. B. Bowman D. N. Cook and R. J. Marmon Tetrahedron 1994 50 1295.4 M. B. Smith and P. F. Keusenkothen J. Chem. Soc. Perkin Trans. I 1994 2485. 5 G. R. Proctor A. Murray and P. J. Murray Tetrahedron Lett. 1995 36 29 1. NATURAL PRODUCT REPORTS 1996-J. R. LIDDELL 6 T. Honda S. Yamane K. Naito and Y. Suzuki Heterocycles 1995 40. 301. 7 G. Casiraghi. P. Spanu. G. Rassu L. Pinna and F. Ulgheri J. Org. Chem. 1994 59 2906. 8 J. Mann and E. S. de Alvarenga J. Chem. Soc. Perkin Trans. 1 1993 2141. 9 H. G. Viehe. S. Jiang and Z. Janousek Tetrahedron Lett. 1994 35 1185. 10 H. G. Viehe S. Jiang and Z. Janousek Bull. Soc. Chim. Belg. 1993 102 663. 11 H. G. Viehe B. De Boeck S. Jiang and Z. Janousek Tetrahedron 1994 50 7075. 12 H. Niwa T. Sakata and K. Yamada Bull. Chem. Soc.Jpn. 1994 67 1990. 13 H. Niwa. Y. Miyachi 0.Uosaki A. Kuroda H. Ishiwata and K. Yamada. Tctrahedron 1992 48 393. 14 H. Niwa K. Kunitani T. Nagoya and K. Yamada Bull. Chem. Sue. Jpn. 1994 67 3094. 15 E. Roeder H. Wiedenfeld K. Liu and R. Kroger Planta Med. 1995 61 97. 16 E. Roeder T. Bourauel U. Meier and H. Wiedenfeld Phyto-chemurrj- 1994 37 353. 17 E. Roeder L. Krenn and H. Wiedenfeld Phytochemistry 1994 37 275. 18 M. Riena. A. H. Mericli R. Cabrera and A. Gonzalez-Coloma Ph.vtochemiytrj>,1995 30 355. 19 N. M. van Dam R. Verpoorte and E. van der Meijden Pli~tocheriii.vtr?.,1994 37 1013. 20 S. W. Page M. M. Mossoba H. S. Lin D. Andrzejewski J. A. Sphon J. M. Betz L. J. Miller R. M. Eppley and M. W. Trucksess J. AOAC lnt.1994 77 1167. 21 D. Andrzejewski J. M. Betz R. M. Eppley and W. C. Taylor J. Phurm. Sci.. 1994 83 649. 22 D. J. Robins Nar. Prod. Rep. 1995 12 413 and ref. 37 therein. 23 H. J. Mierendorff. Fett Wiss. Technol. 1995 97 33. 24 R. J. Nash P. I. Thomas R. D. Waigh G. W. J. Fleet M. R. Wormald P. M. de Q. Lilley and D. J. Watkin Tetrahedron Lett. 1994 35 7849. 25 T. Sekine F. Ikegami N. Fukasawa Y. Kashiwagi T. Aizawa Y. Fujii N. Ruangrungsi and I. Murakoshi J. Chem. Soc. Perkin Trans I 1995 391. 26 T. Sekine N. Fukasawa Y. Kashiwagi N. Ruangrungsi and I. Murakoshi Cheni. Pharm. Bull. 1994 42 1360. 27 C. S. Kim R. Nishida F. Abe T. Yamauchi and H. Fukami Biosci. Biorrchnol. Biochem. 1994 58 980. 28 S. Schulz M. Boppre and R. I. Vane-Wright Philos.Trans. R. Soe. London. B. 1993 342 161. 29 T. Hartmann and A. Biller Ser. Entomol. 1992,49 (Proc. 8th Int. Symp. Insect- Plant Relationships 1992) 83. 30 J. R. Trigo L. E. S. Barata and K. S. Brown J. Chem. Ecol. 1994 20 2883. 31 J. W. Daly H. M. Garraffo J. Caceres T. F. Spande N. R. Andriamaharavo and M. Andriantsiferana J. Nut. Prod. 1993 56 1016. 32 J. W. Daly H. M. Garraffo T. F. Spande C.Jaramillo and A. S. Rand J. Chem. Ecol. 1994 20 943. 33 J. W. Daly Proc. Natl. Acad. Sci. USA 1995 92 9. 34 Ministry of Agriculture Fisheries and Food (UK) Food Surveil. Pap. 1994 42 68. 35 E. Roeder Pharmazie 1995 50 83. 36 H-R. Schuette Prog. Bot. 1994 55 96. 37 M. Wink Bioforum 1993 16 360. 38 J. K. Porter J. Anim.Sci. 1995 73 871. 39 T. Hartmann and L. Witte in Alkaloids Chemical and Biological Perspectives ed. S. W. Pelletier Elsevier Amsterdam 1995 vol. 9 p. 155. 40 E. Roeder Phytochemistry 1990 29 11. 41 C. G. Logie M. R. Grue and J. R. Liddell Phqitochemistry 1994 37 43. 42 T. Hartmann F. Bottcher and D. Ober Can. J. Chem. 1994 72 80. 43 K. Vrieling and C. A. M. van Wijk Oikos 1994 70 449. 44 N. M. van Dam L. W. M. Vuister. C. Bergshoeff H. de Vos and E. van der Meijden J. Chem. Ecol. 1995 21 507. 45 N. M. van Dam and S. K. Bhairo-Marhk Ser. Entomol. 1992,49 (Proc. 8th Int. Symp. Insect-Plant Relationships 1992) 79. 46 P J. Landolt and B. Lenczewski Flu. Entomol. 1993 76 556. 47 R. J. Huxtable and C.C. Yan Toxicol. Appl. Pharmacol.1995 130 132. 48 R. J. Huxtable and C. C. Yan Toxicon 1995 33 627. 49 R. J. Huxtable and C. C. Yan Toxicol. Appl. Pharmacol. 1995 130,l. 50 P. Morris D. O’Neill and S. Tanner J. Hepatol. 1994 21 735. 51 P. C. Chan J. Mahler J. R. Bucher G. S. Travlos and J. B. Reid Toxicon 1994 32 891. 52 H. P. Koch K. Plobner and M. Trojan Pharmazie 1994,49,934. 53 M. Wiessler in DNA Adducts IdentiJcation and Biological SignzJicance ed. K. Hemminki A. Dipple D. E. G. Shuker F. F. Kadlubar D. Segerback and H. Bartsch IARC Scientific Publications no. 125 Oxford University Press Oxford 1994 165. 54 M. Peterka S. Sarin E. Roeder H. Wiedenfeld and M. HalaSkova Funct. Dev. Morphol. 1994 4 89. 55 H. J. Segall S. R. Dueker M. W. Lame A. D. Jones and D. Morin Biochem. Biophys. Res. Commun. 1994 198 5 16. 56 R. A. Roth and A. E. Schultze Toxicol. Appl. Pharmacol. 1993 122 7. 57 R. A. Roth C. M. Hoorn and J. G. Wagner Toxicol. Appl. Pharmacol. 1993 120 281.

ISSN:0265-0568    

DOI:10.1039/NP9961300187

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Monoterpenoids David H. Grayson University Chemical Laboratory Trinity College Dublin 2 Ireland Reviewing the literature published in 1991 1992 and part of 1993 (Continuing the coverage of literature in Natural Product Reports 1994 Vol. 11 p. 225) 1 Introduction 2 2,6-Dimethyloctanes 3 Artemisyl Santolinyl and Chrysanthemyl Systems 4 Cineol Derivatives 5 Menthanes 6 Pinanes 7 Camphanes and Isocamphanes 8 Caranes 9 Fenc hanes 10 Thujanes 11 Ionone Derivatives 12 Iridanes 13 Cannabinoids 14 References 1 Introduction This article provides a somewhat selective review of the developments in monoterpenoid chemistry whch were reported during 1991 1992 and part of 1993 and follows on from the previous article in the series.' A further article (in preparation) will review advances made during the latter part of 1993 1994 and most of 1995.The recent resurgence of interest in this field stimulated by continuing improvements in analytical meth- odology and by the ongoing quest for a 'perfect' chiral auxiliary shows no sign of abating. Much useful data on known monoterpenoids has been catalogued,2 and more recent aspects of the chemistries of a~yclic,~ monocyclic3 and bicyclic4 members of the series have been collated. Croteau has summarised5 the results obtained from a long series of investigations into monoterpenoid biosynthesis. The effects exerted by azide ion on the hydrolysis of some monoterpenoid diphosphates have been reported.6 The meta- bolic fates of various monoterpenoids which occur in Mentha spp.have been reviewed,7 and seasonal and environmentally- induced variations in the monoterpenoid content of Origanum syriacum have been described.8 The occurrence and properties of monoterpenoid glycosides has been ~urveyed.~ Global concern about reactive gaseous species (or lack of them) in the upper atmosphere is reflected in the increasing number of studies of plant volatiles with respect to their atmospheric fates. The general subject has been reviewed,l" as more specifically has the light-dependent emission of isoprene from plants.l1 The velvet bean (Muncuna sp.) emits isoprene (1) from its leaves at a rate which increases 125-fold as the leaves develop and then declines again as they age. Photo- synthetic competence develops before isoprene emission begins to occur.12 The leaves of Populus tremuloides contain a novel enzyme which catalyses the Mg2+-dependent conversion of dimethylallyl diphosphate into isoprene in a reaction which may be generally responsible for its production in most isoprene-emitting species.13 Ecological aspects of fragrant terpenoids produced by angiosperms have been reviewed,14 as has the ecological impact of monoterpenoids in genera115 and their allelopathic properties in particular.16 The oil from Tanacetum vulgare contains monoterpenoids which repel females of the grapevine moth Lobesia botrana,17 and the 2-O-P-~-glucoside of angelicoidenol which is found in Pinus sylvestris deters moose from feeding on the young plants.18 Certain oils from Mentha species have been found to be strongly active as fungistatic agents against some dermatophytes.l9 The use of essential oils as sources of natural aroma coinpounds,20 and the employment of microbial cultures for the preparation of odorous monoterpenoids2' have both been reviewed as has the production of monoterpenoids from root cultures of Mentha species.22 The use of plant cell cultures to facilitate biotransformations of monoterpenoids has also been reviewed.23A survey of the terpenoids which occur in coniferous species has been provided,24 and geographical variations in the monoterpenoid content of Pinus albicaulii have been recorded.25 Reviews on Thymus oilsz6 and on the extraction and com- position of Citrus oils2' have been published.The use of rapid microwave techniques for the extraction of plant oils has been shown to afford products which are almost identical to those obtained via conventional steam distillation.28 Interesting new plant monoterpenoids which have been isolated during the period under review include the isoprenoid glycosides (2) and (3) which have been obtained from the roots of Rhodiola ~renulata~~ and from Ornithogalum montanum3" respectively. Also new are arnebinone (4) arnebifuranone (5) and the novel ansa-compound (6) all of which have been obtained from Arnebia e~chroma.~~. 32 R' R2 (1) R'=R2=H (7)R' = OEt; R2= H (2)R = P-D-GIc (8) R= H Me0 Me0 0 (4) (5) 195 Table 1 Sources of monoterpenoids Species Libanotis laticalycina Shan et Sheh.Liquidambar orientalis Mill. Litsea pungens Hemsl. Lonicera japonica Thunb. Magnolia coco (Lour) DC. Melaleuca spp. Melaleuca uncinata Melissa par vif ora Michelia alba DC. Micromeria brownei var. pilosiuscula Micromeria fruticosa Druce ssp. barbata NATURAL PRODUCT REPORTS 1996 Comment Reference Abies chensiensis Van Tiegh Achillea biebersteinii Afan. Achillea grandifora Achillea millefolium Achillea millefolium ssp. millefolium Agastache spp. Alpinia galanga Willd. Alpinia oxyphilia Allosyncarpia ternata S. T. Blake Artemisia lacinata chemotypes Artemisia molinieri Artemisia moorcroftiana Wall. Artemisia persica Artemisia pallens Buddleia asiatica Lour. Calamintha arkansana (Nutt.) Shinners Calamintha nepeta ssp.glandulosa Chaerophyllum bulbosum Chamaecyparis Iawsoniana Chamaecyparis pisifera Chromolaena odorata Cinnamomum glaucescens Cinnamomum longepaniculatum Cinnamomum migao H. W. Li Cistus ladanifer Citrus aurantifolia Cleonia lusitanica Conyza pinnata Crithmum maritimum Cryptomeria japonica Cunninghamia lanceolata Cymbopogon coloratus Cymbopogon distans Cym bopogon t ra vanco rensis Egletes viscosa Erigeron canadensis Eucalyptus bicostata Eucalyptus brassiana S. T. Blake Eucalypt us bridgesian a Eucalyptus camaldulensis Eucalyptus dealbata Eucalyptus delg up ta Eucalyptus torelliana Eupatorium adenophorum Spring. Ferulago sylvatica (Besser) Reichenb. Foeniculum vulgare Forsythia spp. Gardenia jasminoides Geranium robertianum Grindelia robusta Nutt.Grindelia squarrosa Dun. Hedychium coronarium Hedychium coronarium Koenig Hedychium odoratissimum Helichrysum picardii Heteropyxis natalensis Hjwopus oficinalis Juniperus sabina Kaunea longipetolia Lanata camara Lepechinia urbanii (Briq.) Epling Lepidophyllum quadrangulare (Meyen) Benth. and Hook. Pinenes limonene 66 Cineol camphor 67 Camphor thujones 68 Ascaridole 69 70 Cineol sabinene 71 72 Myrcene 73 74 Pinenes limonene 75 (a) cis-Chrysanthemyl acetate artemisia 76 ketone; (b) Piperitone Ascaridole 77 78 79 80 Citronellol 81 Pulegone menthone 82 Limonene piperitone oxides 83 84 85 Bornyl acetate 3-carene 85 Bornyl acetate 86 Cineol a-terpineol 87 88 Cineol limonene sabinene a-terpineol 89 a-Pinene isopinocamphone camphene 90 91 a-Pinene limonene 92 (a-P-Ocimene 93 y-Terpinene sabinene methyl thymol 94 Hydrocarbons (45 YO),alcohols (10 YO) 95 Terpinyl acetate terpinolene 96 97 a-Terpinene piperitone 98 99 P-Pinene trans-pinocarveyl acetate 100 Limonene camphene 101 Cineol 102 Cineol a-pinene 103 Cineol 104 Cineol p-cymene 105 Cineol cryptone 106 a-Pinene a-terpinene p-cymene 102 a-Pinene P-pinene 102 p-Cymene bornyl acetate 107 a-Pinene 108 Limonene 109 Geraniol geranial linalool a-terpineol 110 Linalool carveol 111 Linalool y-terpineol 112 a-Pinene bornyl acetate 113 a-Pinene 113 Cineol P-pinene 114 p-Ionone 115 a-Pinene 116 3-Carene 117 /I-Ocimene linalool myrcene 118 Pinocamphone camphor 6-pinene 119 Sabinene sabinyl acetate 120 Geranyl acetate 121 Iridoids 122 3-Carene P-phellandrene 123 a-Pinene P-pinene 124 P-Pinene 125 126 Cineol 127 Linalool geraniol 128 P-Terpinene 4-terpineol a-pinene lin- 129 alool Cineol 130 Terpinen-4-01 130 131 132 Pulegone menthone neomenthol 133 Pulegone 134 NATURAL PRODUCT REPORTS 1996-D.H. GRAYSON Table 1 (cont.) Species Comment Reference Micromeria fruticosa Druce ssp. brachy-Pulegone 135 calyx P. H. Davis Micromeria fruticosa ssp. Pulegone piperitenone piperitenone 136 oxide Monarda didyma cv. 'Cambridge Scarlet ' Linalool 137 Myrtus communis Cineol myrtenyl acetate 138 Nidorella resedifolia DC. Hydrocarbons lavandulyl esters 139 Nothopanax delavayi P-Phellandrene myrcene a-pinene 140 Notopterygium incisum a-Thujene 141 Osbornia octodonta F.Muell a-Pinene cineol a-terpineol 142 Pelargonium spp. 143 Pelargonium quercifolium 144 Pelargonium vitifolium Citronellic acid 145 Peristeria elata Cineol 146 Pimenta racemosa (Miller) J. Moore 147 Pistacia integerrima Pinenes phellandrene 3-carene 148 Polyalthia suaveolens Myrcene 149 Rosmarinus ojficinalis Myrcene cineol camphor a-pinene 150 Sabina vulgaris Sabinene 151 Salvia spp. 152 Santolina chamaecyparissus Artemisia ketone myrcene 153 Satureja grandiyora Pulegone isomenthone menthol neo- 154 isomenthol Schinus latifolia Engl. a-Pinene P-pinene sabinene 155 Seriphidium brevifolium cz-Thuj one P-thujone 156 Sider it is dichotoma a-Pinene /I-pinene 157 Sideritis germanicopolitana subsp.Bornm. Myrcene 158 Sideritis scardica 159 Strobilanthes callosus Nees. 160 Syzygium cuminii Skeel Myrcene a-pinene /I-pinene 161 Tagetes argentina (2)-and (E)-ocimenones 162 Thuja occidentalis 163 Thuja orientalis 163 Thymus riatarurn a-Terpinene carvacrol p-cymene 164 Tirhonia diversifolia (Hemsl.) A. Gray (Z)-P-Ocimene 165 Vitex trifolia Cineol terpinyl acetate sabinene 166 Vitex trifolia var. simplicifolia 166 Zhumeria majdae Rech. Linalool camphor 167 Ziziphora clinopodioides Lam. Cineol pulegone 168 The electron impact mass spectra of 19 monoterpenoids The chromatography of lemon peel oils on silica gel has been exhibit normal fragmentation patterns when obtained at 70 eV shown to lead to the formation of small quantities of oxygenated and 500 K but give simpler spectra especially at low m/z monoterpenoids and this effect can be reduced (but not values at 12 eV and 350 K.33A detailed study has been made eliminated) by operating the column at 3 OC4 of the mass spectra of a number of C,,H, monoterpenes and The acid-catalysed aqueous reactions of many important evidence for significant contributions to their fragmentation monoterpenes have been reviewed and the effects that the pathways by a protonated cycloheptatriene structure has been presence of sodium dodecyl sulfate micelles have on most of The I3C NMR spectra of very many mono-these processes have been The hydration reactions of terpenoids have been collected together in a book,35 and vicinal various monoterpene hydrocarbons in the presence of synthetic 13C-13CJ values for a range of bicyclic monoterpenoids have zeolites has attracted some attenti~n,*~s~~ as has the addition of been measured and their dependence on dihedral angle noted.36 C,-C aliphatic alcohols to them under the same condition^.^^ The use of coupled GC-MS methods for essential oil analysis The zeolite-catalysed reactions of monoterpenoids have been has been reviewed,3i as has the application of supercritical fluid reviewed.51 chromatography for the same purpose.38 There has been a The useful isoprenoid synthon (7) (see page 195) has been flurry of publications (and a review3g) on the use of chiral GC prepared,52 and reaction of the alcohol (8) with oxalic acid has (and HPLC) methods for the enantioselective analysis of been shown to yield isoprene (1) (40%) together with a monoterpenoids.Enantioselective multidimensional GC tech- pleasantly fragrant mixture of 25 identified cyclic and acyclic niques permit the simultaneous separation and stereoanalysis monoterpen~ids.~~ of essential oil components with a view to authenticating their The marmelo oxides A (9) and B (10) have been synthesised natural origins.". *l All of the important unsaturated mono-via palladium-catalysed cyclisation reactions,54 and another terpene hydrocarbons which occur in natural oils can be synthesis of these oxides together with the corresponding enantioselectively separated using dual GC capillary columns coated with heptakis(6-O-methyl-2,3-di-O-pentyl)-P-cyclo-dextrin and octakis(6-O-methyl-2,3-di-O-pentyl)-y-cyclo-de~trin.,~T he preparations of these two modified cyclodextrin stationary phases have been described together with that of the related octakis(2,6-di-O-methyl-3-O-pentyl)-y-cyclodext~n (9)R' =Me; R2=H ;R3= H2 which may be utilised for the enantioselective separation of (10) R1=H; R2= Me; R3= H2 monoterpenoid Two reports on the enantioselective (11) R' =Me; R2=H; R3=0 analysis of Mentha piperita oils using chiral phase GC have (12) R1=H; R2= Me; R3=0 appeared.44.45 (7)and (8) are with (1) and (2) NATURAL PRODUCT REPORTS 1996 lactones (I 1) and (12)has been de~cribed.~~ An enantioselective synthesis of (R)-mevalonolactone (13)has been reported,56 and (+)-cis-rose oxide (14)has been obtained via the lactone (15).57 Lineatin (16) a pheromone of Trypodendron lineaturn has again been synthesised in racemic form,58 and both enantiomers of (16) have been prepared from the intermediate (17) which was resolved via its diastereoisomeric esters with (-)-cam- phanic acid.59 Progress towards a synthesis of paeoniflorin has been reported.60 A route to angustione (18) has been pub- lished,60 and both (+)-and (-)-karahana ethers (19) have been obtained via radical-induced 6-exo-dig cyclisation of the alkyne (20).61Both enantiomers of grandisol (21) have been synthesised via the sensitised photocycloaddition of ethene to the menthyloxy butenolide (22) followed by separation of the diastereoisomeric adduck6* In a transformation which is likely to prove useful elsewhere the campholenic aldehyde (23) can be decarbonylated using Rh-Al,O to give (24) with only a slight amount of racemi~ation.~~ Methods for the stereoselective synthesis of acyclic monoterpenoids have been reviewed.64 Ph (23) R =CHO (+)-(25) (24) R = H Some of the new monoterpenoids discovered during the period under review have been mentioned above and other noteworthy findings are discussed under the appropriate headings later in this article.Table 1 on pages 196-197 collects together in a convenient format references to the results of a wide selection of investigations which have been carried out into plant species where known compounds have been detected quantified and identified. 2 2,6-Dimethyloctanes The a-~-arabinofuranosyl-(l-6)-~-~-glycopyranoside of (S)-(+)-halo01 (25)has been isolated from a methanol extract of raspberry and the three new geranyl derivatives (26)-(28) have been from the leaves of Rapanea umbellata.The novel epoxides (29)and (30)have been in Jasonia montana and the glycosylated aldehydes (31) and (32) the related alcohol (33) and various derived acetylated sugar derivatives have been extra~tedl'~ from Hymenoxys nesiana. The unusual bridged compound lonitoside (34) has been discovered173 in Lonicera nitida and the fruits of Cydonia oblonga provide the glycoside (35) which is a biosynthetic precursor for the isomeric marmelo oxides (9)and (10).17*New compounds isolated175 from Artemisia salsoloides include the spiro-bis(dihydrofuran) (36) and the dienone (37).The role of divalent metal ions in the biosynthesis of cyclic monoterpenoids has been further probed by an examination of Ho2cw (29) R = H (30) R = OH R'% R2 (31) R' = H; R2=0 (34) (32) R' =OH; R2= 0 (33)R'=H; R2=H,0H OH (35) NATURAL PRODUCT REPORTS 1996-D. H. GRAYSON the 31P and 13C NMR spectra of geranyl diphosphate (38) in the presence and absence of Mg2+. The results obtained indicate that magnesium ions bind in a 1 :1 ratio with the diphosphate groups with the metal ion being equidistant from each phosphorus atom.176 The non-enzymic cyclisation reactions of geranyl neryl and linalyl diphosphates in the presence of divalent metal ions have been A y-terpinene synthase from the leaves of Thymus vulgaris which acts on geranyl diphosphate (38) has been purified and ~haracterised.~~~ Geranyl N-phenylcarbamate (39) is biotransformed by Aspergillus niger to the 6,7-epoxide (40) which then undergoes a further enzyme-catalysed transformation at pH 6-7 to give the (6R)-di0l (41).If the epoxide (40) is subjected instead to acid-catalysed hydrolysis at pH 2 then the product is the (651- diol (42). 17’ The N-phenylcarbamates of (3R)-citronellol (43) and of its enantiomer (44) behave similarly with the same stereochemical outcome at C-6 regardless of the configuration at C-3.180 Racemic citronellol can be esterified by oleic acid in a lipase-catalysed reaction which takes place in supercritical CO,. A partial kinetic resolution is possible since the (33- alcohol (44) reacts more rapidly than does its enantiomer.lsl Hydroxylation of myrcene cyclic sulfone (45) by cultures of Sebekia benihana NRRL- 1 1 1 1 1 provides modest yields of the allylic alcohol (46) which can be converted into ipsdienol (47).The hydroxylation of the related ocimene derivative (48) has also been investigated.ls2 A synthesis of (3R)-( -)-[8,8,8-2H3]- linalool (49) potentially useful in probing biochemical and other mechanisms has been reported.ls3 The toxicity of 6,7-dihydrogeraniol (50) has been reviewed and the compound is not recommended for incorporation into fragrance compositions. (38) R = m (39)R = OCONHPh (41) (6R)-OH (42) (6s)-OH (5ij R=OH (68) R = Qpalmitoyl (72) R=OAC (75) R=OMe (78) R=CI (85) R = SH (43)R’ = H; R2 = Me (44)R’ =Me; R2=H (45)R = H (46)R =OH (47) (50) (52) (53) R = H (54) R = CH2CH2C02Me (51) is with (38) P-Cyclodextrin which has been modified with methyl red exhibits colour changes when it hosts geraniol (51) or nerol (52) with a 1.7-fold greater response towards the (E)-isomer (5l).lS5Two reports describe methods for authentication of the natural origin of oils containing linalool (25).One of these involves the use of multidimensional enantioselective GC to determine optical purity,ls6 whilst the other employs 13C and 2H NMR techniques which are also applicable to linalyl acetate.ls7 GC analysis using the chiral stationary phase heptakis(2,3,6-tri-O-methyl)-~-cyclodextrinhas been used to resolve all four stereoisomers of linalyl oxide.lS8 (R)-Citronella1 (53) has been converted via its enamine into the Michael adduct (54) which undergoes a Lewis acid-catalysed intramolecular ene cyclisation to give (55) a degra- dation product of the anti-malarial quinghaosu together with isomeric In a reaction which is a valuable addition to the repertoire the pyrrolidine enamine of (53) reacts sequentially with 9-BBN and then with methanol to yield ,8-citronelladiene (56).Enamines derived from ketones react analogously.lS0 Metallation of isoprene (1) by KDA and then reaction with 3-methylbutanal or with 3-methylbut-2-enal leads to ipsenol (57) or to ipsdienol (47) in poor yields.1s1 (3-( -)-Ipsenol (57) has been synthesised from (3-lactic acid,lS2 and new routes to both enantiomers of ipsdienol (47) have been described.lS3 Both enantiomers of the bicyclic alcohol (58) a key intermediate for the synthesis of grandisol (21) have been synthesised from the enantiomeric linalools (43) and (44).lS4 A synthesis of a-acaridial (59) has been described,lQ5 and citral (E/Z)-(60) has been efficiently converted into @-ionone (61) via condensation with acetone in the presence of KF-Al20,.lQ6 The selective hydrogenation of citral (60) to yield the allylic alcohols geraniol(51) and nerol(52) has been achieved by using Ru or Rh complexes of sulfonated phosphines in an aqueous- organic two-phase solvent system.The regioselectivity depends strongly upon the metal with Ru being prefe~red.’’~ Citral(60) has also been hydrogenated to geraniol and nerol with a tin- modified silica-supported Rh catalyst this time with 96 YO selectivity for reduction of the carbonyl group at 100% substrate conversion.1s8 Hydrogenation of geranial (E)-(60) to give (+)-citronella1 (53) of 62 % ee has been carried out using a catalyst generated in situ from [Rh(CO),acac] and (-)-DIOP.Neral (2)-(60) similarly yields (-)-citronella1 ent-(53) of 55 Oh ee under the same Nerol(52) has been converted into the epoxide (62) of 66 % ee via reaction with Ph,C(Me)OOH-Ti(OPr’) in the presence of the salicylidene-(3-valine (63).200 The same epoxide (62) obtained by an alternative route has been used as a synthon for (R)-mevalonolactone (1 3).201 The kinetic resolution of the epoxides rac-(62) and rac-(64) using chiral Lewis acid catalysts such as the complex formed from the hydroxy-sulfonamide (65) FHO I I !n A NATURAL PRODUCT REPORTS 1996 and Ti(OPri) has been studied.202 Epoxidation of geraniol(51) by monoperoxyphthalic acid in aqueous sodium hydrogen carbonate in the presence of a surfactant leads to the formation of a mixture of the three products (64) (28 YO),(66) (35 YO)and (67) (24YO).,O3 Epoxidation of geraniol (51) by the same peroxyacid in water alone is pH-dependent giving good yields of (66) at pH 8.3 and excellent yields of (64) at pH 12.5.204 Epoxidation of geranyl palmitate (68) using m-chloroperoxy- benzoic acid in dichloromethane leads initially to the derived 2,3-epoxide which is then further oxidised at the 6,7-double bond.205 Isomerisation of dihydromyrcene epoxide (69) to give (70) and/or (71) has been investigated.,06 In a process which is general for 1,5-dienes geranyl acetate (72) undergoes heterogeneous oxidation in the presence of potassium permanganate and catalytic copper(I1) sulfate in aqueous CH2C1 to give the lactones (73) (59%) and (74) (10 %).207 Geranyl methyl ether (75) (and the neryl analogue) reacts208 regioselectively with ethoxycarbonylnitrene to give the 6,7-adduct (76).Geranylbarium (77) which can be obtained209 by reacting geranyl chloride (78) with equirnolar Reike barium in tetrahydrofuran at -78 "C can be coupled with the geraniol- derived bromide (79) to yield geranylgeraniol (80) without disturbance of alkene geometry.210 After appropriate chemistry the sequence can be repeated to synthesise higher homologues.(74) (76) (68) (72) (75) (78) & (85)are with (38) Citronella1 (53) reacts rapidly with diethanolamine to give (81) which undergoes hydration and then hydrolysis in the presence of sulfuric acid to give the hydroxy-aldehyde (82) without significant competing cyclisation.211 Reaction of (R)-citronellyl acetate (83) with thionyl chloride at -20 "C in the presence of catalytic Et2A1C1 and then with methanol yields the rearranged allylic sulfinate ester (84) via an ene-type process. Geranyl and linalyl acetates behave analogously.212 Linalool (25) reacts with thiourea in the presence of hydrohalic acids to give geranyl thiol(85) after basic hydrolysis of the thiouronium salt which is formed.213 The cyclisation reactions of acyclic monoterpenoids continue to attract the attention of various groups.The dehydrolinalool derivatives (86) undergo thermal cyclisation to give the cyclopentanes (87) in 16-93 % yield.214 When (R)-citronella1 (53) on silica gel is pressurised to 15 kbar (1 bar = lo5 Pa) isopulegol (88) is formed in high yield via an ene-like reaction. The same cyclisation can as expected be effected using conventional Lewis acid catalysts such as ZnBr or Me,A1C1.215 Dihydromyrcene (89) reacts in the presence of HSZ-620-HOA zeolite-Al(OH),-H,O to give mainly the tetrahydrocarveol (90).216 (R)-Citronella1 (53) has been converted into the useful chiral synthons (91) and (92).,17 The sulfoxide (93) undergoes an asymmetric ene-cyclisation in the presence of for example catalytic Et,AICl to yield the diastereoisomeric products (94) (66-97 YOde) and (95).The former thermolyses to give the (-)-unsaturated nitrile (96) whilst the latter yields the enantiomeric product (97).,l8. 219 H A (86) R = H C02Me or SiMe3 (87)R = H C02Meor SiMe (94) a-P< (95)p-P+ (96) a-Pf (97)pPr' 0 Electrolysis of linalool(25) in methanolic sodium methoxide yields a mixture of diastereoisomers of the tetrahydrofurans (98) and (99).220 The Diels-Alder reaction between myrcene (100) and (E)-3-methylpent-3-en-2-one which is catalysed by AlCl on layered graphite yields the odiferous compound Ambralux (101).,,l The effectiveness of various Lewis acids which catalyse the Diels-Alder reaction between myrcene (100) and methyl NATURAL PRODUCT REPORTS 1996-D.H. GRAYSON propenoate has been studied,222 and ZnCl has been found to provide optimum yields. The structures of the four isomeric Diels-Alder adducts whch are obtained by reaction of the triene (102) with methacrolein have been determined,223 and geranic acid (103) yields the expected cycloaddition product when it is reacted with ~yclopentadiene.~~~ Reaction of citral E/Z-60 with aniline under mild conditions followed by brief treatment with acid at 0 "C affords a-cyclocitral (104) in 60 YOyield.225 The diene 6-pyronene (103 obtained from myrcene (loo) can be regioselectively epoxidised using m-chloroperoxybenzoic acid to give the mono-epoxide (106) (75%) together with some of the di-epoxide (107) (25 %).226 Treatment of (106) with magnesium bromide converts it into a mixture which is largely y-cyclocitral (108) whilst rearrangement using triflic acid gives mainly /3-cyclocitral (109).The alternative mono-epoxide (1 10) can be obtained from 6-pyronene (105) via its reaction with N-bromo-succinimide to give a bromohydrin which is then cyclised using potassium carbonate.226 P-Cyclocitral(lO9) has been converted into the (2)-dienoic acid (1 1 1) under Perkin condition^,^^' and into the nor-ketol(ll2) by reaction with a peroxy acid followed by hydrolysis.228 The epoxy ether (113) rearranges in the presence of BF Et20 to yield the unexpected dihydropyran (114) together with only traces of the anticipated ketone (1 15).229 &Ho 2H H& 0 Reaction of P-cyclogeranyl bromide (1 16) with excess lithium di-isopropylamide affords the coupling product (1 17) together with the acetone derivative (1 18).230 The authors presume the source of the three additional carbon atoms to be the rearranged lithio-derivative (1 19).201 3 Artemisyl Santolinyl and Ch rysant hemyl Systems The laevorotatory nor-monoterpenyl alcohol (120) has been from Arternisia schimperi together with artemisyl acetate (121) and lyratryl acetate (122) and the novel diastereoisomeric hydroperoxides (1 23) and (124) have been from Artemisia lancea which also contains the sesquiterpenoid antimalarial peroxide quinghaosu.The new chrysanthemyl compounds (125) and (126) have been isolated from Artemisiu tridentatu cana and their structures confirmed by OAC I Ifi (125) R = vinyl (126) R = Pr' Three-bond 13C-'H J values have been measured for a series of cis-and trans-chrysanthemic acid derivatives and these provide useful correlations for the assignment of stereo-chemistry.234 More than 228 strains of various microorganisms have been screened for their ability to enantioselectively hydrolyse ethyl chrysanthemate (127) and the most effective has been found to be Arthrobacter globiformis IFA- 12958 which is capable of providing optically pure chrysanthemic acid (1 28).235 Racemic hotrienol (129) has been synthesised utilising hydroalumination chemistry,236 and yomogi alcohol (130) has been efficiently prepared233$ via the syn-carboindation of 3- methylbutyn-3-01 by (Me,C=CHCH,),In,Br,.Lavandulol (1 3 1) has been synthesised in 70 YOyield in a two-pot sequence where the lithiated sulfide (132) reacts with prenyl bromide to give (1 33) which is then converted into the alkyltitanium (1 34) and thence to lavandul01.~~~ (127) R =Et (128) R=H SPh SPh The chrysanthemum nitrile (1 35) has been synthesised via asymmetric epoxidation of the alcohol (136) to yield (137) the silyl ether of which undergoes Stork cyclisation to give (138) which is a precursor of (135).23g,240 The addition of bromine to the (E)-and (a-isomers of the vinylic chloride (1 39) affords the derived (1 R,2R)-and (1 S,2S)-dibromides respectively the structures of which were determined using NMR with the aid of lanthanide shift reagents.241 The enantioselective synthesis of chrysanthemic acid and its derivatives has been reviewed.242 4 Cineol Derivatives The biotransformations of 1,4-cineol(140) by Aspergillus niger have been extensively and the structures of the four hydroxylated derivatives (14 1H 144) which are produced have been established.1,8-Cineol (145) photo-oxidation to give the keto-cineols (146) and (147) when it is irradiated at 280 nm in the presence of oxygen and catalytic amounts of (Bu,N),W,oO,,. ‘sx.. R2 (140) R’ = R2= R3 = R4= H (145) R’ = R2= H2 (141) R’ =OH; R2 = R3= R4= H (146) R’ = 0; R2 = H2 (142) R’ = R3 = R4= H; R2 = OH (147) R’ = H,; R2 = 0 (143) R’ = R2 = R4 = H; R3 =OH (144) R’=R2=R3=H; R4=OH cO-P-D-Glc I 5 Menthanes The new glycoside perilloside-A (148) has been isolated“* from Perilla frutescens and the nor-monoterpenoid tetrahydro- furanone lepalox (149) has been from Ledum palustre.The novel diol (150) and the related epoxide (151) have both been in the aerial parts of Mikania saltensis (+)-1,2-epoxypulegone (lippione) has been isolated251 from Acrocephalus indicus and the interesting peroxyhemiacetal (1 52) for whch no absolute configuration has been determined New is a constituent of Adenosma caer~leurn.~~~ aromatic monoterpenoids which have been discovered include plucheo- NATURAL PRODUCT REPORTS 1996 side-C (153) the roots of Pluchea indica the thymol derivative (1 54) from254Calea nelsonii and espintanol (1 55) which exhibits trypanicidal and leishmanicidal activities and which has been isolated255 from Oxandra espintana together with its methyl ether (156).0-P-D-Glc%Api Me0 OMe OAc (153) (1 54) (155) R =H (156) R=Me A limonene cyclase for which the substrate is geranyl diphosphate (38) has been isolated256 from the fruits of Citrofortunella mitis and has been purified by ion exchange chromatography. An article which reviews the various bio- transformations of limonene (157) which can be carried out using micro-organisms has been The biosynthesis of ( -)-mintlactone (158) and of (-)-isomintlactone (1 59) in Mentha piperita has been examined.258 The biotransformation of (-)-menthol (160) by Aspergillus niger leads to a mixture of its I- 2- 6- 7- 8-and 9-hydroxy derivatives whilst the same fungus (+)-menthol en?-(160) into its 7-hydroxy derivative (1 6 1).(+)-Menthone (1 62) is converted26o into the lactone (163) by an Acetobacter sp. The major product obtained when racemic piperitone rac-(164) is metabolised by Rhizoctonia solani is the (-)-ketol (165) whose absolute configuration was determined via its Mosher ester.261 Evidence has been obtained that pulegone (166) covalently binds to the prosthetic haem group of cytochrome P450,and that this binding is responsible for loss of biological activity.262 When (+)-pulegone (166) is metabolised by Botrytis allii the major product is the ketol (167) which is formed263 together with some piperitenone (168).264 The latter may arise via dehydration of the alternative ketol (169) which is formed as the major product when (-)-(158) a-H (-)-(159) (+)-(212) P-H (164) R=H (165) R =OH NATURAL PRODUCT REPORTS 1996-D.H. GRAYSON pulegone (166) is metabolised by Aspergillus sp. by Mucor plumbeus CBS- 110- 16 or by Mortierella isabellina MMP- Racemic trans-sobrerol (1 70) has been effectively resolved by the action of Lipase-PS supported on Celite in tert- amyl alcohol as solvent and with vinyl acetate as donor. Using this system the (-)-diol and the (+)-monoacetate are each formed in 100 'YO ee at 50 'YO conversion.266 Coupled chiral and non-chiral CGC columns have been used to carry out an enantioselective analysis which can be employed to determine the authenticity of citrus (mandarin) oils via measurement of the optical purity of the limonene (157) which is The enantioselective analysis of limonene can also be achieved by utilising a GC column coated with a solution of a-cyclodextrin in dimethylformamide as stationary phase,268 whilst /3-cyclodextrin stationary phases have been employed for determination of the contents of (9-( +)-terpinen4-01(171) in lavender and of the flavoursome keto thiols (172) and ent-(172) [synthesised from (-)-and (+)-pulegone (166) respectively] which occur in buchu leaf The cor-responding thiol acetates (1 73) have also been synthesised and have been enantioselectively analysed by similar methods.271 All eight diastereoisomers of the menthyl alcohol series (160) can be observed in the same I9FNMR spectrum obtained at 188.3 MHz when their mixture is esterified with the acid (174) which is obtained from an appropriate ester of lactic acid via a Mitsunobu reaction with fluor~phenol.~~~ A study of the mass spectrometric fragmentation of the 180-labelled mucoactive trio1 (1 75) has indicated that loss of H,O from its molecular ion involves only the tertiary hydroxy group.273 (172) R=H (173) R=Ac F The mechanism of the process whereby the heteropolyanion [PV,MO,,O,~]~- catalyses the aerobic oxidative dehydro-genation of a-terpinene (176) to p-cymene (177) has been investigated.274 When (+)-limonene (157) is reacted with a primary aromatic amine in the presence of HgO-HBF it is converted into the useful chiral diamines (1 78),275 whereas reaction of (1 57) with a nucleophile in the presence of Hg(BF,) followed by reduction of the organomercury intermediate using NaBH leads276 regioselectively to the products (1 79).Acetoxyl- ation of limonene (1 57) with acetic acid in a reaction whch is catalysed by PdCl in the presence of either CuC1 or Cu(OAc) leads mainly to the allylic acetate (180) whereas acetoxylation using Pd(OAc) alone an approximately equal mixture of (180) and the exo-methylene compound (181). Limonene (1 57) can be regioselectively hydrocarbonylated to give the aldehyde (182); isopulegol (88) and its acetate behave similarly.278 The cyclopropanation of limonene (1 57) at either or both of its double bonds by various reagents and solvent combinations has been and the 8,9-epoxylimonene (183) and its diastereoisomer have been prepared in pure form.The limonene hydrochloride (1 84) reacts with zinc thiocyanate to yield a mixture containing the thiocyanate (185) (53 %) and the isothiocyanate (186) (22 and in a reaction of general applicability the allylic phosphate (1 87) is converted into the methylated derivative (188) when it is treated with methylmagnesium chloride in the presence of CuCN * 2LiC1.282 The addition and cycloaddition reactions which limonene (1 57) undergoes at the 8,9-double bond have been reviewed,283 as have methods for the conversion of limonene into carvone (1 89).284 The thermal and photochemical reactions of various p-menthadienes and p-menthatrienes have been AA.A (176) (177) R=H (1 78) (190) R =OH LJ XA (179) R =OH OMe OAc (180) NH2 NHAc or N3 (184) R=CI (185) R = SCN (186) R = NCS Ah h The conversion of thymol (190) into all-cis neoisomenthol rac-(191) by hydrogenation over a defined supported Pt catalyst has been shown286 to proceed via the initial formation of isomenthone rue( 192).In a very convenient reaction (-)-menthol (160) has been converted into the lactone ent-(163) in 95 % yield by oxidation with m-chloroperoxybenzoic acid in the presence of a catalytic amount of the cyclic chromate ester derived from 2,4-dimethylpentan-2,4-diol. Isopulegol (88) 287 undergoes radical chlorination to yield (1 93) when it is reacted either with chlorine or with sulfuryl chloride.288 The optically pure selenonium ylid (194) has been obtained as a stable crystalline solid via fractional recrystallisation of a diastereoisomeric mixture.The absolute configuration of (1 94) was determined by X-ray methods.289* The reductive amination of menthone (162) and of iso- menthone (192) using ethanolic ammonia and a range of metal catalysts has been and it has been shown that Pd catalysts give the best results. Similar mixtures of neo-menthylamine isomenthylamine and menthylamine are formed from each of the ketones (162) and (192) suggesting that imine- enamine tautomerism intervenes during the reaction. No secondary amines are formed in either instance.NATURAL PRODUCT REPORTS 1996 (+)-Pulegone (166) is a major constituent of Turkish-grown Ziziphora tenuior composing ca. 87% of the derived Reduction of pulegone by the combination R,SnH-Et,B yields menth~nes,~~, and the pulegone hydrochloride (195) can be converted into the useful synthons (196) in a single-step process.294 Reaction of ( +)-pulegone (166) with [(thf),Mo(CO),] or with [(EtCN),W(CO),] affords the derived metal carbonyl complexes (197) as single ~tereoi~omer~.~~~ The 8 8 OH 4 HP OH OH 0 OH (203) (204) (205) (20) structure of the tungsten complex has been determined by X-ray methods. The allylic alcohol (198) derived from pulegone (166) has been cyclised to the cyclopentadiene (199) using [Pd(Ph,P),] in acetic A good heterogeneous catalyst for the selective hydrogenation of the conjugated double bond of carvone (189) to give the dihydro derivative (200) is Cu-Al,O which is active at 90 "C in toluene under one atmosphere of hydrogen.297 The alternative selective heterogeneous hydro- genation of the 8,9-double bond of carvone (189) to give the menthenone (201) is best carried out using Rh supported on ~g0.298 I MeP0 (1 94) (195) $+ (196) R = H alkyl or ally1 (197) M = Mo or W (1 98) n New synthetic routes to (sometimes old) monoterpenoids continue to be reported.The diene (+)-P-phellandrene (202) which occurs in the liverwort Conocephalum conicum has been synthesi~ed,~~~ and (s)-(-)-limonene ent-( 157) has been con- verted300 into the diastereoisomers of quinghaosu D (203) via the hydroxy aldehyde (204).The terpinolene epoxide (205) reacts under mild conditions in the presence of montmorillonite K-10 to give karahanaenone (206) in 82% yield.301 A new synthesis of (+)-menthofuran (207) proceeds via a [3 +24 intramolecular cyclisation of the nitrile oxide (208) which gives the intermediate adduct (210).3029 Menthofuran has also been synthesised from 4-methylcyclohexanone.304 The related nitrile oxide (209) cyclises to yield the adduct (211) which has been converted305 into (-)-mintlactone (1 58) and into ( +)-isomintlactone (212). The two mintlactones (-)-( 158) and (+)-(212) have also been synthesised via radical chemistry,306* ,07 and the racemate of (158) has been cleverly obtained308 by the dihydroxylation of ester (2 13) followed by one-pot lactonisation and dehydration of the resulting diol.Cc-9 Qo $N CO2Et (+)-(207) (208) R = CH20Ac (210) R = CH20Ac (213) (209) R = C02Et (21 1) R = C02Et (212) is with (158) Fluoride ion-induced cyclisation of the aldehydo-silane (2 14) leads to a mixture of cis- and trans-isopiperitols (215). The related secondary allylic silane (2 16) cyclises more rapidly and with better stereoselectivity under these conditions.309 The more heavily functionalised silane (217) cyclises when it is treated with TiCI to give mainly the cis-isomer of the hydroxy ester (218). Cyclisation using BF;Et,O yields a mixture of the cis- and trans-isomers of (218) and both of these hydroxy esters are readily lact~nised.~~~ The Wittig product (219) derived from citronella1 (53) reacts with ozone at 0 "C to form an intermediate carbonyl oxide which undergoes intramolecular addition to the 6,7-double bond yielding the diastereoisomeric peroxides (220) and (221).These are converted by catalytic hydrogenation into the p-menthane diols (222) and (223).,1° The vinylic silyl ether (224) also obtained from ctironellal(53) reacts with ozone at -78 "C to give only the peroxide (225) but if (225) is reacted with ozone at 0 "C and the resulting mixture then hydrogenated the isomeric cyclopentyl diols (226) and (227) are obtained in 10 1 ratio.311 The chloride (193) obtained from isopulegol (88) can be coupled with prenylmagnesium chloride in the presence of CuI to yield the sesquiterpenol (228).,12 6, boMe &C02E1 (218) (219) (220) a-configuration (222) a-OH (221) P-configuration (223) P-OH 1 poTBs 4( (224) (225) (226) p-Me (227) a-Me NATURAL PRODUCT REPORTS 1996D.H. GRAYSON The unsaturated bicyclic ether (229) unexpectedly gives the rare trans-3-hydroxyphellandral(230) when it is reacted with chlorosulfonylisocyanate. A mechanism for this transformation has been A synthesis of robinal(231) produced by the mite Rhizoglyphus robini has been (-)-Camone (189) has been converted into paeonilactones A (232) and B (233) and into (7R)-paeonimetabolin (234) and its (7$)-diastereoisomer thus establishing the absolute configur- ations of these (-)-Carvone (189) has also been utilised as a chiral starting material in syntheses of (+)-grandisol (2 1) which was prepared316 via the intermediates (235) and (236) of (-)-patchouli and of 4a(H)- eudesmane (237).318 The Diels-Alder reactions which are catalysed by EtAlCl of (+)-carvone ent-(l89) with various trimethylsiloxy- 1,3-dienes have been studied in the context of sesquiterpenoid CHO CHO Homo 0 .0 Oq0 As alluded to in the Introduction the utilisation of monoterpenoid derivatives as chiral auxiliaries and as reagents for asymmetric synthesis continues to expand.Whitesell has reviewed320 the ways in which derivatives of (-)-8-phenyl- menthol (238) can be exploited in this context. The (1R)-menthoxymethyl ether function is a chiral protecting group for hydroxy functions that allows measurement of ee values to be carried out by NMR at each step of a synthetic reaction sequence.These ethers are prepared via reaction of chloro- methylmenthyl ether (239) with an alcohol in the presence of Pr',NEt and can be cleaved by zinc bromide in CH2C1,.321 An improved route to 8-phenylmenthyl isocyanoacetate (240) which proceeds via the chloroacetate (241) and the azide (242) has been Menthyl cyanoformate (243) in com- bination with hydrogen peroxide epoxidises 2-methyl-5- phenylbut-2-ene to yield product (244) of undetermined absolute configuration and of 20 O/O ee.323 Racemic 1,3-alkanediols can be kinetically enantio-differentiated by acetalisation with for example (-)-menthone ent-( 162).3249 325 The unsaturated acetal (245) formed from (+)-menthone reacts with 9-BBN to afford the equatorial borane (246) which can then be coupled with alkenyl or aryl halides to give products (247).These can be further processed to yield optically active The menthyl derivative (248) can be converted into the fluoroester (249) of 98 YOee by treatment with elemental fluorine in acetonitrile and then with methanolic potassium carbonate.327 The related non-crystalline diastereoisomeric acetoacetate derivatives (250) and (25 1) have been prepared from (+)-menthone (162) by its reaction with tert-butyl 2-methyl-3-oxobutanoate in the presence of Ac,O-H,SO, and their structures have been determined by NMR.328 /CPh A (238) R=H (239) R = CH2CI (240) R = COCH2NC (243) R = COCN (241) R = COCH&I (252) R = COCH=CH2 (242) R = COCHZN3 (258) R zz COCl (256) R = COCH=CH2 (262) R = COCOPh or COCOMe 1 1 (244) (245) (246) R= B3 (247) R = alkenyl or aryl (-)-Menthy1 acrylate (252) undergoes y-alumina-catalysed Diels-Alder cycloaddition with cyclopentadiene to give the endo-adduct in good diastereoisomeric excess.329.330 A study has been made of the effect of variations in solvent on the rate exolendo ratio and diastereoselectivity of the same reaction.331 The unsaturated menthyloxy lactone (253)62 has been developed as a chiral dienophile affording adducts of up to 99% de.332 The compound (253) is also a Michael acceptor reacting with thiols or with secondary amines to give the adducts (254).Reduction of (254) (X = S) using lithium aluminium hydride yields diols (255).333 Both (-)-menth1 acrylate (252) and the corresponding 8-phenylmenthyl derivative (256) undergo Baylis-Hillman ad-dition with aldehydes to yield adducts (257) of 14-100% de. Best results were obtained when benzalde h yde was reacted with the menthyl derivative (252) in the presence of DABCO at a pressure of 7.5 kbar.334 _.. (253) (254) R' = SR2 or NR2* (255) (252) (256) & (258) are with (239) (257) R' = (-)-menthy1 or (-)-8-phenylmenthyl; R2= alkyl or aryl Menthyl chloroformate (258) reacts with the lithium enolate of methyl a-methylphenylacetate to give the malonate derivative (259) of good de,335 and the xanthate (260) which is derived from 8-phenylmenthol can be reduced using Bu,SnH-AIBN to give a 63 :37 mixture of the (R)-and (9-diastereoisomers of the ester (261).Reductive cleavage of (261) using lithium aluminium hydride affords the corresponding phenylpr~panol.~~~ I A C02Me (259) The menthyl glyoxylates (262) are diastereoselectively re- duced by LiAl(OR,)H at -78 "C in THF to give the derived hydroxy The methylated (-)-8-phenylmenthyl aceto-acetate (263) is fluorinated by 1-fluoro-2,4,6-trimethyl-pyridinium triflate in the presence of excess lithium hexa- methyldisilazide to give a 3.8 1 mixture of the (R)-and (9-fluoroesters (264) but the (5')-diastereoisomer of (265) is the major product when the desmethyl acetoacetate (266) is fluorinated.33s The tautomerism of the menthyl /I-keto esters (267) has been investigated by NMR methods and the cyclopentanone derivative which undergoes a crystallisation-induced asym- metric transformation has been found (X-ray) to possess the (R)-co&guration at C-2 of its five-membered ring.339 (+)-Dihydrocarvone ent-(200) undergoes electroreductive coupling with acetonitrile to give the imino alcohol (268) which has been further transformed into the /I-amino alcohol ligand (269).The latter catalyses the enantioselective addition of diethyl zinc to aldehydes.340 The Strecker-derived a-amino acid toluenesulfonamide (270) forms a complex with borane which at a concentration of 0.2 mol% catalyses the enantioselective condensation of terminal silyl enol ethers with aldehydes to give aldols (271) of 81-93% ee.341 (263) R=Me (264) R=Me (266) R =H (265) R=H A (267) n=1,3 NATURAL PRODUCT REPORTS 1996 6 Pinanes The three new diols (272H274) have been obtained from the roots of Urtica di~ica.,~ (+)-cis-3-Pinen-2-01 (275) has been found to act as a pheromone for males of the beetle Monocampus alternatus The enantiomers of a-pinene (276) and of P-pinene (277) can be resolved by CGC using an a-cyclodextrin stationary phase.268 The vibrational CD spectra of both a-and /I-pinene have been measured and analy~ed,~~~ and quantitative comparisons of the scattered and incident circular polarisation Raman optical activities of (-)-a-pinene ent-(276) (-)-P-pinene ent-(277) (-)-cis-pinane (278) and (-)-trans-pinane (279) have been made.345 In a useful study the 'H and I3CNMR spectra of 22 pinane derivatives have been measured and assigned.346 The isomeric pinanes (278) and (279) are oxidised by 0 at 100 "C to give the hydroperoxide (280) and the peroxy- hydroperoxide (28 1).The cis-alkane is oxidised most rapidly and the products can be reduced to the corresponding Permethylated P-cyclodextrin which is linked to a Fe3+ or Mn3+porphyrin species catalyses the enantioselective oxidation of racemic a-pinene rac-(276) by oxygen in the presence of visible light to give a mixture of epoxypinane pinenols and pine none^.^^^ Racemic a-pinene rac-(276) under- goes a kinetic resolution via double stereodifferentiation to give product of up to 65% ee when it is hydrogenated in the presence of chirally-modified Rh (+)-(276) R =H (282) R=OAc (283) R =OCOEt The acyloxylation reactions of a-pinene (276) with Pb(OAc), Pb(OCOEt), Hg(OAc) or PhI(OAc) have been carefully investigated and large scale routes to the allylic acetate (282) and to the propionate (283) have been devised.350 Competing ring-opening reactions can be largely avoided by working in neutral media.a-Pinene (276) undergoes regiospecific hydro- carbonylation to yield the aldehyde (284) and P-pinene (277) behaves similarly to yield the 10-formyl derivative (285).27s The aldehyde (286) derived from a-pinene (276) undergoes McMurry coupling to give the alkene (287) which can be dihydroxylated to yield the diastereoisomeric C,-s ymmetrical diols (288) and (289).351 (+)-(277) (-)-(278) (-)-(279) (280) (284) (285) (286) (288) a-OH (282) &(283) are with (276) (289) P-OH NATURAL PRODUCT REPORTS 1996D.H. GRAYSON The use of biphenyl as sensitiser enhances the yields of the pinenol(290) which is obtained via singlet oxygen oxidation of P-pinene (277).352 An improved route to crystalline 6-terpineol (291) from p-pinene has been and the kinetics of the AlC1,-catalysed ene-reaction which takes place between p- pinene and methyl propenoate have been measured as a function of solvent polarity.354 The results suggest that the reaction may proceed via a transition state which possesses zwitterionic character.Reaction of the allylic bromide (292) with aldehydes in aqueous THF in the presence of Zn-NH,Cl leads to alcohols (293) whose relative configurations at C-1 1 were determined by assuming that reduction of the derived ketones proceeded according to Cram's (290)R=OH (292)R=Br (307)R = OOH The epoxypinane (294) reacts with HS0,F-FS0,Cl and then with methanol to give the acetal (295) (60%) together with other and with ZnBr or ZnC1 to give largely the campholenic aldehyde (23).357 Reduction of the epoxide (294) with lithium in ethylenediamine is claimed358 to yield the isomeric pinanols (296) and (297) but the stereochemistry attributed to the secondary alcohol seems doubtful. Pyrolysis of ent-(294) over synthetic zeolites which have been exchanged with Zn2+ or with Cu2+ affords a-campholenic aldehyde (23) whereas treatment of the epoxide (298) derived from P-pinene (277) yields cis-myrtanal (299).359 Both diastereoisomers of the epoxide (298) react with Me,SiCN-ZnI to yield the array of products (300H304).360 (298) (299) /OTMS QC 4 OTMSc NC &iTMS (304) 207 The hydroperoxide (305) reacts with CuS0,-NH to give (290) and (306)-(309) but gives only the cyclobutane (310) (94%) when it is exposed to FeCl;Et,O in the absence of a proton trap.361 The equilibrium mixture of isopinocamphone (3 1 1) and pinocamphone (3 12) undergoes Baeyer-Villiger oxidation to give the ketol (313) and the lactone (314) respectively in poor overall yield.362 cis-Verbanone (3 15) reacts with phenyllithium to give the derived tertiary benzylic alcohol.This then suffers a Ritter reaction when it is reacted with RCN-H,SO in a 1.O 0.1 molar ratio yielding the amide (316). When RCN-H2S0 in 1.O :0.1 molar ratio is used instead the azabicyclononene (3 17) is formed.363 Reaction of (E)-cis-verbanone oxime (3 18) with H,SO yields the Beckmann lactam (3 19) but the benzeneamine (320) is obtained when (318) is treated with HCl.364 0 (305)R = OOH (308) (309) (306) = OH (307)is with (290) (311)R = P-Me (314) (315)R=O (312) R=a-Me (318)R = NOH RCONH Aph N& &)= H 0 ( +)-Nopinone (321) has been converted into several 4,4- disubstituted derivatives which are useful synthons for sesqui- terpenoid and is the precursor of the vinylic sulfide (322) which is an intermediate in syntheses of (+)-vernolepin and of (-)-ve~nomenin.~~~ The anion of the related sulfone (323) undergoes y-alkylation with e.g.ally1 bromide to yield mainly the diastereoisomer (324),367 and this has been converted into the sesquiterpene ( -)-kanshone A (325).368 Synthetic applications of the sulfide (326) and of the sulfone (323) have been reviewed.369 The closely-related ester (327) undergoes Diels-Alder cycloaddition with buta- 1,3-diene or with isoprene (1) to give exclusively the adducts (328).,'O (+)-Nopinone (321) (+)-(321) (322)R' = SPh; R2 = Me (323)R' = SORh; R2 = Et (326)R' = SPh; R2 = H (327)R' = C02Me;R2 = H 0 OH R (325) (328)R = H or Me has been converted into (A)-(-)-cryptone (329) and into the (9-( +)-dienone (330).371 Borane derivatives based upon the pinane skeleton continue to attract much attention as chiral reagents and auxiliaries.A one-pot procedure for the conversion of a-pinene (276) into di- isopinocampheylchloroborane which obviates the necessity to isolate this air-and moisture-sensitive reagent has been des~ribed.~'~ The Purdue group have found that chiral B-allylditerpenylboranes react rapidly with aldehydes at temper- atures as low as -100 "C provided that magnesium salts formed during preparation of the reagents are The homodiisopinocampheylchloroborane (33 1) reduces 2,2-di-methylcyclopentanone to the corresponding (R)-alcohol of greater than 99% ee and also reduces benzylideneacetone to the unsaturated (R)-al~ohol.~~~ The chiral conjugated enone (332) has been synthesised via (333) which was derived from the unsymmetrical borane (334).375 The principal disadvantage associated with the utilisation of terpenyl boranes for asym- metric synthesis has always been the loss of the terpenoid auxiliary and the necessity for separation of at least molar equivalents of the derived monoterpenoid alcohol from the desired reaction product.The Brown group have now described three effective methods which permit recycling of these chiral auxiliaries. These methods include treatment with 2-methyl- propanal and one equivalent of BF * Et,O treatment with ethanolamine or treatment with 8-hydro~yquinoline.~~~ The boronate (335) has been prepared and reduces but-1-yn-3-one to give alcohol of 39% ee.377 NATURAL PRODUCT REPORTS 1996 (336)R=OCH2Ph (339) (338) R=NEtPh 0 (341)R= H (343) (342)R = OH 7 Camphanes and lsocamphanes Vulgarole (344) of 100% ee has been isolated from Artemisia vulgaris.383 Simple europium-based lanthanide shift reagents have been found to aid the low-field NMR analysis of mixtures of borneol (345) and isoborneol (346).The Eu3+ ion preferentially complexes to the less hindered exo-hydroxy group of (346) and by enhancing the rate of hydroxy proton exchange also sharpens the a-carbinyl proton resonances in each case.384 Solvent effects which are exerted on the n-n* carbonyl transitions of camphor (347) and of 9,lO-dibromocamphor 0 !! (348) have been investigated and the results indicate that camphor derivatives can induce chiral solvation structures about them even when the solvent molecules involved are achiral.,*j The mass spectral fragmentation patterns and the 2H NMR spectra of the thioacetals (349)-(351) and of some of their bromo derivatives have been determined and analy~ed.~~~ / !O eBU R?io R2 Ho& AcO pJ2BC' ! OEt :H (333) (334) (335) The origins of the stereoselectivity observed in aldol reactions of chiral boron enolates especially of (2)-enol diisopino- campheyl borinates have been investigated with the aid of computational methods.378 A series of boronates (336k(338) has been prepared and the amino derivative (338) reduces acetophenone to (9-a-methyl- benzyl alcohol of 77 YOee.379 The optically-active amine-boryl radical (339) enantioselectively abstracts the benzylic hydrogen from racemic methyl a-methylphenylacetate (340) permitting a catalytic partial kinetic resolution of the ester.The (3-enantiomer of (340) of 22% ee is obtained after 41 % of the racemate has reacted.,*O The phenyl derivative (341) and both diastereoisomers of the pinenol (342) have been prepared with a view to their possible use as chiral auxiliaries,381 and the new auxiliary (343) has been synthesi~ed.,~~ Enantioselective separations of racemic borneol (345) and racemic isoborneol(346) can be achieved by capillary GC when a permethylated P-cyclodextrin is used as stationary phase,387 and the enantiomers of camphene (352) can be resolved over a-cyclodextrin by the same 388 The catabolism of (+)-camphor (347) by Salvia oficinalis leads inter alia to its 6-hydroxy and 6-0x0 derivatives,38g and cells of the Acinetobacter sp.NCIB-9871 reduce racemic camphorquinone rac-(353) to a pair of diastereoisomeric exo-hydroxy ketones.390 NATURAL PRODUCT REPORTS 199CD. H. GRAYSON Camphene (352) reacts with formaldehyde in the presence of a calcined ,&zeolite to afford the rearranged ethers (354) and (355),391 and reacts with apalkanediols in the presence of H-Mordenite to give a series of hydroxy ethers (356).392 Photoaddition of methyl 3-oxobutanoate to camphene (352) affords adducts which undergo mild acid-catalysed retro- benzylic acid rearrangement to yield (357) or (358).393 The hydroalumination of camphene (352) by LiAIH * 3AlBr in toluene leads to the novel Lewis acid (359).394 An experimental and computational study of the equilibria involved in the formylation of camphene by formic acid has been carried and reaction of the methylated p-menthadiene (360) with 97 Oh formic acid has been shown to lead to the camphene derivative (361) together with the alkenes (362) and (363) and the tricyclene (364).396 0 ?F (354) (355) (364) (365)R = OAc C02Me etc.The enthalpies of complexation of BF in CH,Cl with the carbonyl groups of various camphor derivatives (365) have been determined and have been shown to correlate well with the corresponding polar substituent The Lewis acid complexes at both sites when the substituent is acetoxy but only at the ketonic carbonyl group when it is carbomethoxy.(+)-Camphor (347) has been converted into the ally1 vinyl ether (366) which undergoes a [2,3]-Wittig rearrangement to yield a 70:30 mixture of (R)-(367) and (S)-(368).398 The silyloxy aldehyde (369) derived from ( +)-camphor (347) undergoes acyloin rearrangement to give a mixture of the stable ketol (370) and the alternative ketol (371) which suffers facile aerial oxidation to yield homocamphoric anhydride.399 Anodic oxidation of (+)-camphor in acetonitrile with 1 mol dm- H,SO as the supporting electrolyte delivers the lactone (372) in up to 96 YOyield. This undergoes further electrochemical trans- formation in more strongly acidic media yielding the butanolide (373).400 Treatment of the lithium enolate of (+)-camphor (347) with 1 equiv.of chlorodiphenylphosphine affords a mixture of the em-and endu-keto phosphines (374) of which the endo-isomer is the more thermodynamically If the lithium enolate of camphor is treated instead with only 0.5 equiv. of Ph,PCl then the salt (375) is formed and this can be converted into the Pd and Pt complexes (376). 209 V (369) (373) (374) (375) (376)M = Pd or Pt When the nitroimines (377) are exposed to 60Co y-radiation they form radical anions which can be studied by ESR.,02 (+)-9-Bromocamphor (378) has been utilised as a chiral starting material in syntheses of the sponge metabolites (-)-furodysin (379) and (-)-furodysinin (380).,03 The mechanism of the reaction of endo-3-bromocamphor (381) with N,N-dimethylaniline at 200 "C which gives camphor (347) has been investigated.404 The same result can be achieved at much lower temperatures by using Et,Ndi-tert-butyl peroxide in aceto- nitrile.The bromocamphor (38 1) does not undergo Ritter-style reaction with nitriles in the presence of acids but exo-3- bromoisocamphor (382) reacts satisfactorily to yield the bis- amides (383).405 The 3,9-dibromo derivatives (384) fragment to yield monocyclic products of stereochemistries which depend upon that at the 2-position in the starting Thus the endo-acetate (384) gives (385) when it is treated with the radical anion sodium dimethylamino(naphtha1enide) whereas the isomeric exo-acetate affords (386).Both of these allylic acetates have been converted into the derived a,P-unsaturated ketone. If the 3-bromo substituent of (384) is replaced by hydrogen then the exo-methanesulfonate is the only derivative which undergoes the fragmentation reaction. .. (377)R = H or CI (379) (380) (378)is with (347) NHCOR &Br NHCOR @' @Br (384)R = Ac PO(OEt)Z (385)P-OAC COCF3or S02Me (386)a-OAc lhe reduction of (+)-camphorquinone (353) by zinc in acetic acid affords a mixture of the isomeric endo-hydroxy ketones (387) and (388). In a reaction which was first reported in 1902 the former reacts with HCl in dry methanol to give the symmetrical dimeric acetal(389) whose structure has now been unequivocally determined.407 The reversibility of the thermal oxy-Cope rearrangement is clearly demonstrated when the borneol derivative (390) is heated in refluxing toluene to yield an equilibrium mixture with the ketone (391).408 -OTBS OTBS \/ The P-chiral mixed anhydride (392) and its diastereoisomer have been prepared from the silver salt of camphorsulfonic acid (393) via its reaction with Ph(tert-B~)IP=0.~~~ The utilisation of camphor derivatives as reagents and auxiliaries for asymmetric synthesis continues to be developed and the subject has been re~iewed,*~~.~~~ as have the myriad applications of camphors~ltams.~~~ The enantiomeric purities of the (R)-and (5')-camphors which are available from the chiral pool have been critically evaluated.413 Ltkr"-" so2 (394)R=Ac (397)R = COCH=CH2 (395) (396)R = Ph Me etc.The acylated sultam (394) has been converted into the silyl enol ether (395) which in a Mukaiyama-type reaction affords diastereoisomerically pure aldols (396) when it is treated with an aldehyde in the presence of TiC14.414 These can be cleaved to yield either P-hydroxy esters or ,8-hydroxy acids. The N-acryloyl sultam (397) undergoes 1,3-dipolar cycloaddition with nitronates RCH=N+(O)OSiMe to yield adducts (398) of good de which are converted into the 2-isoxazoline derivatives (399) when they are treated with toluene-p-sulfonic NATURAL PRODUCT REPORTS 1996 A series of 3,3-dihalogenated camphorsulfonyloxaziridines (400) have been prepared and the dichloro derivative is the best for the enantioselective oxidation of sulfides to sulfoxides (often greater than 95% ee).416 Details of a large-scale preparation of both enantiomers of the oxaziridine (400) (R = Cl) have been published together with those of an efficient route to the parent compound (401).417 The diastereoisomeric sulfoxides (402) prepared from 10- sulfanylisoborneol (403) are good dienophiles reacting with cyclopentadiene and with furan to give adducts of high de.418 (398) (399) (400)R = CI Br or F (402)R = Me Ph or PhCH2 (401) R=H The conjugate addition of butylcopper species to the bornyl crotonates (404) has been studied and the composition of the reagent has been found to exert a profound effect upon the stereochemistry of the newly introduced asymmetric centre.Thus addition of LiBu,Cu leads to (9-products of up to 57 YO de whilst addition of Li,Bu,Cu affords (R)-products of up to 90% de.419 The pyridyl imine (405) which is derived from (+)-camphor (347) forms a lithium salt which can be alkylated to give compounds (406) of mainly (R)-stereochemistry and of 6-67 YO de.420 This diastereoselectivity is enhanced if (405) is first converted into a metal complex (407) and an X-ray crystal structure of the Pd complex has been The glycinate imine (408) can be alkylated to give ultimately (5')-alanine of good optical purity and the effect of the double asymmetric induction resulting from the presence of the menthyl ester compares favourably with the results which are obtained using the alternative tert-butyl ester.422 (404)R = Me Ph or l-naphthyl (405) R = H (406)R=alkyl 4NY &N70J5 Cl-Y---N \ OA CI (407) (408) NATURAL PRODUCT REPORTS 1996-D.H. GRAYSON The isoborneol derivative (409) affords a nitrene (410) which exhibits no asymmetric induction in its (inefficient) aziridination reaction with styrene. In the absence of alkene (410) is converted into the chiral auxiliary (411) which is useful in a variety of reactions including alkylation acylation and aldol condensations. The oxazolidinone (41 1) is more conveniently obtained via thermolysis of the acyl azide (412).423 A route to the isomeric oxazolidinone (413) commences with (+)-camphorquinone (353) which is sequentially oximated at C-3 reduced with NaBH and then hydrogenated over Pt to yield the amino alcohol (414).The N-propionyl derivative of (413) affords the lithium enolate (41 5) which reacts with aldehydes to give mainly the aldol diastereoisomers (416).424 The oxa-zolidinone (41 7) can be acylated and its propionyl derivative can then converted into the enolate (418) which is alkylated to give products (419) of good to excellent de.425 Ethyl ketopinate (420) has been converted into the oxazinone (421) and thence to the propionyl derivative (422) which reacts with aldehydes in the presence of TiC1 to give aldols (423) of very good de.426 The pinacolone enol acetal (424) derived from (+)-camphor- quinone (353) reacts with aryl aldehydes under the same conditions to yield aldols with reasonable de.427 (409) R = NHOS02CeH&’-N02 (410) R=N (412) R=N3 ’ (415) ’ (416) (421) R=H (422) R = COZEt ?” (423) R = $-CO+ ,R (+)-Camphorquinone (353) is also the precursor of the chiral auxiliaries (425) and (426).The derived glyoxylate (427) for example can be diastereoselectively reduced to yield the hydroxy ester (428) and this can be hydrolysed using LiOH in aqueous THF to give the corresponding a-hydroxy The bornene (429) has been converted into the silanol (430) and thence to the chlorosilane (43 1). Replacement of chlorine with 21 1 a suitable allylic function affords the Si-substituted compounds (432) which can be diastereoselectively epoxidised and the epoxides then fragmented using Bu,NF to give allylic alcohols (433) of 49-70% de.429The two new chiral lactams (434) and (435) have been prepared and some cycloaddition reactions of their crotonyl and methacryloyl derivatives have been investi- gated.430 A series of novel camphorsultam-based 2,2-bipyridyl and 9,lO-phenanthrolyl ligands (436)-(440) have been synthesised and the X-ray crystal structure of (436) has been determined.431 The benzylidenecamphor derivative (44 1) affords a mixture of alcohols when it is reduced using Na-EtOH and the useful pure diastereoisomer (442) can be obtained from this via fractional recrystallisation of its p-nitroben~oate.~~~ The acetal (443) derived from (+)-camphorqwinone (353) has been converted into the epichlorohydrin enantiomer (444).433 An X-ray crystal structure and an NMR spectrum of the bis(iodomethy1)zinc complex (445) have been (425) R’ = NHSOAr; R2 = OH (426) R’ = OH; R2 = NHS02Ar (427) R’ = NHSOfir; R2 = OCOCOR (430) R’ = H; R2 = Ph (433) (434) (435) (431) R’ = CH2Ph; RZ= CI (432) R’ = CH,Ph; R2 = \efl R’ R’ (436)R’ = R2 = CAMSOfl (439) R’ = R2= CAMS02N (437) R’ = H; R2 = CAMS02N (440) R’ = OH; R2 = CAMSOZN (438) R’ = R2 = CH2CAMS02N ,-a &YC1 0 OH Me (443) (444) (445) 8 Caranes Long-range l3C-lH J values for (+)-car-3-ene (446) have been and a combined NMR and molecular mechanics investigation has led to the conclusion that the six-membered ring of (446) is practically planar.436 Good agreement has been obtained between the calculated and experimental dipole moments of the keto sulfide (447) and the results suggest that the C-S bond is axially orientated and that it is parallel to the carbonyl group.437 The conformation of the amino oxime (448) has been studied and an X-ray crystal structure has been Fuel blends containing (+)-car-3-ene (446) combust effici- ently under rocket conditions when red fuming nitric acid is utilised as The organoborane derived from carene (446) has been carbonylated to yield the 4a-aldehyde (449),440 and oxidation NATURAL PRODUCT REPORTS 1996 (PhO),Al it is converted in 80% yield into the ether (463).446 (+)-Car-2-ene (464) has been converted into the iron carbonyl complex (465) and this reacts with CO to yield the ketones (466) and (467).447 The same complex (465) affords the lactones (468) and (469) when it is treated with CO in the presence of cerium(1v) ammonium nitrate and these lactones are also formed together with the cycloheptadienyl ester (470) when methanol is additionally present.of (446) under Gif conditions has been ~ho~n~~~,~~~ to afford the well-known enones (450) and (451) together with the rn-menthadienol (452). When (+)-car-3-ene (446) is reacted with Pb(OAc) in acetic acid it is converted into a mixture containing the ketone (453) the p-menthadienol (454) and the two p-menthenediols (455) and (456). An X-ray crystal structure of the diacetate of (456) has been (+)-Car-3-ene (446) has been into the allylic amines (457) and (458). Reaction of carene (446) with PhS0,NSO yields the car-2-ene derivative (459) which is converted into the dimeric cyclo- heptatrienyl disulfide (460) when it is treated with base.Reaction of (459) with 4 equiv. of RMgX in the presence of 5 mol % CuBr * Me$ affords the cycloheptatrienyl sulfide (461) but the allylic displacement product (462) is obtained when 1 equiv. of PhMgBr is used under the same conditions.445 When (+)-car-3-ene (446) is reacted with phenol in the presence of (+)-(446) (447)R' =SPh; R2= 0 (449) (448) R' = NMe2; R2= NOH (450)R'=H2; R2=0 (453) (454) (451) R' =O; R2= H2 I I (455) (457) R=NH2 (458) (462) R=Ph The 3a,4a-epoxycarane (47 1) has been converted into the azido alcohols (472) and (473) and the 3P,4P-epoxycarane (474) affords the corresponding azido alcohols (475) and (476).448 Reaction of the a-epoxide (471) with thiourea in ethanol leads to the allylic 10-disulfide (477) but the hydroxy disulfide (478) is formed if EtONa is also The alternative disulfide (479) is formed from the P-epoxycarane (474) under the same conditions.When the a-epoxide (471) is treated with HS0,F-FS0,Cl at -110 "C and then with methanol it is converted into a mixture of the acetal (480) the ethers (481x482) and the unsaturated ketone (483),450 The gem-dimethylcyclopropyl function of the carene skeleton makes it an attractive starting material for the synthesis of pyrethroids and a review on this subject has been (+)-Car-3-ene (446) has been converted into the lactones (484) (+)-(471) (472) R' = Ng; R2=Me; R3=H; R4=OH (474) (473) R' =Me; R2= OH; R3 = N3; R4 = H (475) R' =Me; R2= N,; R3=OH; R4=H (476) R' =OH; R2= Me; R3= H ; R4 = N3 (487) R' = R4=OH; R2= Me; R3= H (477) (478) R' =Me; R2 = OH; p-S (479) R' =OH; R2= Me; a-S NATURAL PRODUCT REPORTS 1996-D.H. GRAYSON and (485) either of which can be further processed to yield cis-chrysanthemic acid (486),452 and the diol(487) easily obtained from ( +)-3a,4a-epoxycarane (47 l) is oxidised by 0,-Co(AcO) to give a mixture which consists of the useful keto acid synthon (488) (50-80 %).453 The corresponding nitrile (489) has been converted into (1R)-cis-chrysanthemylamine (490),454 and into the p-dicarbonyl derivative (49 1).455 The biotransformation of (+)-car-3-ene by Mycobacterium smegmatis DSM-4306 1 leads to (+)-chaminic acid (492) together with the enone (450) and the m-menthadienol (452).456 Biotransformation of (+)-car-2-ene (464) by the same micro- organism leads to (-)-isochaminic acid (493) and car-2-en-4- one (494).(485) (486) R=CO2H (488) R=C02H (491) (490) R=CH2NH2 (489) R=CN (487) is with (472) (4-(493) (494) (495) R = NSPh (496) R = 0 (497) (499) R = Me Et or OMe The S-phenylsulfenylimine (495) has been prepared from the corresponding cyclobutanone (496) and undergoes a radical- initiated reaction in the presence of Bu,SnH to give the nitrile (497) in high yield.457 trans-Caran-2-one (498) undergoes Michael addition reactions with various acceptors to give products (499) which are useful intermediates in sesquiterpenoid 9 Fenchanes Enantiomerically pure (+)-fenchone (500) has been detected in wild Foeniculum vulgare and enantiomerically pure (-)-fenchone ent-(500) has been found in wormwood tansy and cedarleaf oils.459 The lH 13Cand l70NMR spectra of fenchone oxime (501) and of its various 5- 6- 7- 8- and 9-chloro derivatives have been measured and analy~ed.~~~ X-ray crystal structures of the anti-7-chloro oxime and of the 8-chloro oxime have been Irradiation of fenchone oxime (501) in methanol solution affords in poor yield a 1 :1 mixture of the two lactams (502) and (503).462Fenchone (500) has been converted into fenchelylamine (504) which is the precursor of the acyl aminoxyl radicals (505).These have been demonstrated to cause very slightly enantioselective oxidation of racemic 2-methyl-phenylpropanol and the optical activity of unreacted alcohol was determined using a HPLC-based diode-laser polarimetric detector.463 @ %:. %O (+)-(5~) R = 0 (502) (503) (501) R= NOH PNH2 QYAAr 0 0' I0 Thujanes The new nor-monoterpenoid lebaicone (506) has been obtained from the oil of Ledumpalustre together with the aldehyde (507) and a-thujone (508).464 Both a-and P-thujone (508) and (509) respectively are found in the oil from young plants of Artemisia absinthurn but cis-chrysanthemol predominates after flowering has The oil from Artemisia afra Jacq.which contains the thujones (508) and (509) is utilised in African traditional medicine and is active against a wide range of bacterial species.466 The enzyme-catalysed conversion of geranyl diphosphate into (+)-sabinene (510) has been re~iewed.~" The oil of Salvia lavandufolia contains sabinyl acetate (51 l) and a study of the potential teratogenicity of this compound suggests that there is significant risk associated with the uncontrolled use of this Salvia oil for aromatherapeutic purposes.46s The quadrupole and ion-trap mass spectra of the cis-and trans-sabinene hydrates (5 12) have been measured.46g 0 CHO (507) (+)-(508) a-Me (509) p-Me L II (513) OR 0 I I lonone Derivatives The novel a-ionol disaccharide 9-O-a-~-arabinofuranosyl-(1-6)-~-~-glucopyranoside (5 13) has been isolated from fruits of the raspberry Rubus idaeus,*'O as have the 4-0-w~-arabinofuranosyl-( 1-6)-~-~-glucopyranoside of (4s)-4-hydroxy-P-ionone (5 14)471and the simpler P-D-glucopyranoside (5 1 5).169 Other glycosides which have been discovered include (516) from Epimedium grandiflorum var.thunbergian~m,~'~ icariside B9 (5 17) from Epimedium ~agittatum,~'~ the glucosides (518) and (519) from Meliu too~endan,~~~ compounds (520)and the (521) from Dendrathema shiwogik~,~~~related ketone ampelopsisonoside (522) from Ampelopsis brevipendunculata (Maxim.) Tra~tv.,~'~ and (523) and the epoxide (524) from Prunus ~pinosa.~''The acetals (525) and (526) have been obtained from Cydonia oblongata Mil. and their structures have been confirmed by ~ynthesis.~'~ HO-(51 7) NATURAL PRODUCT REPORTS 1996 (532) and (533) respectively is CU/A~,O,.~~~ Photo-oxidation of a-ionone (532) affords the a-and p-isomers of the hydroperoxide (536) in 23 :77 ratio.The former reacts in the presence of Ti(Pr'O) to give the corresponding alcohol (537) but the p-isomer yields mainly the epoxide (538) when it is treated with the same reagent.4a6 Oxidation of either a-or p-ionone (532) and (533) respectively by I,-cerium(Iv) ammonium nitrate in aqueous or alcoholic media leads to a mixture containing the allylic alcohol or ether (539) together with the ketone (540).487 The same ketone (540) is obtained in 98 2 ratio with the partially saturated analogue (541) when p-ionone (533) is treated with VO(OEt)Cl in ethanolic solution under an oxygen atmosphere but this ratio becomes 64:36 when the reaction is conducted under nitr~gen."~ R 0'' WR I p-~-Glc (518) R' = ~D-GIc;R2 = H (520) R=H,OH (519) R' = H; R2= PO-Glc (521) R =O 0p I p-~-Glc (523) 0 0 (526) (527) R=OAc (528) R=a-OH (533) R = H (539) R = OH or OR The acetate (527) can be resolved using a lipase and the resulting 4-hydroxy-P-ionone (528) has been converted into 6-hydroxy-a-ionone (529) which is an intermediate in a synthesis of some abscisic acid analogues.479 The biotransformations of a-damascone (530) by various strains of Botrytis cinerea have been investigated,4a0 and the conformations of the isomeric cis-and trans-3-hydroxy-a-damascones (531)which are metabolites of the parent compound have been investigated by NMR methods.481 The individual enantiomers of a-damascone (530) have been converted into the (R)-and (3-a-ionones (532) via a novel enone transposition sequence which proceeds without ra-cemi~ation,~~~ and the reverse transpositions wherein a-ionone (532) yields a-damascone (530) and p-ionone (533) affords p-damascone (534)have also been reported.4a3 Thujone (508) has been converted into the damascones (530),484and stereo-controlled total syntheses of (+)-cis-a-irone (535) and of its enantiomer have been A useful heterogeneous catalyst for the selective hydro- genation of the conjugated double bonds of a-and p-ionone (530)R = H (R)-(532) P-configuration (534) (531) R = OH (S)-(532) cc-configuration (536) R =OOH (538) (537) =a-oH (539) is with (527) yp 0 0 12 lridanes Recent developments in the chemistry pharmacology and occurrence of iridoids have been and the distribution of iridoids in members of the Hamamelidae has been Aucubin (542) which has been isolated494 from Buddleia americana has been found to act as an antidote against the toxins of the poisonous mushroom Amanita virosa preventing hepatic damage by suppressing mRNA biosynthesis in the liver.495 Oxidative allylic rearrangement of the cyclopentanol (543) affords the aldehyde (544) which is a useful synthon for various iridane~.~~~ Syntheses of racemic dihydronepetalactone (545),497* and of racemic isodihydronepetalactone (546)498 498 have been reported and geniposide (547) has been converted HO RO@ (542) R0-Hp-~-Glc = (592)R=Ac ' %%f (543) (544) 0 HO (545) p-Me (547) (546) cc-Me NATURAL PRODUCT REPORTS 199GD.H. GRAYSON into nepetalactone (548) isodihydronepetalactone (546) and iridomyrmecin (549).499Zirconium-catalysed cyclisation of the (8-enyne (550) leads after further processing to the ketone (55 1) which has been converted into (+)-iridomyrmecin (549),500and an iron-catalysed cyclisation of the silyloxytriene (552) affords the alcohol (553) which has been converted into (+)-isoiridomyrmecin (554) and into (-)-isodihydronepeta-lactone (546).501Intramolecular Michael reaction of the amido ester (555) leads to (556) which can then be converted into iridomyrmecin (549).502Racemic loganin rac-(557) has been synthesised via rn-chloroperoxybenzoic acid oxidation of the symmetrical diketone (558) followed by further trans-formations of the product lactone (559).503In a sequence which (557)R=H (559) (549)R = p-Me (554) R = a-Me Table 2 Sources of iridoids Species Compound( s) Reference Ajuga repens Ajureptoside (562) 505 Argylia radiata Radiatoside E (563) Radiatoside F (564) 506 Buddleia davidii Biridoside (565) 507 Buddleia japonica Buddlejosides A,-& 508 Cassinopsis madagascarensis 7-Caffeoylloganin (566) 509 Castilleja sessilij?ora 6-0-Acetylmelittoside (567) 510 Coleospermum billardieri 10-Hydroxyloganin derivatives 51 1 Cornus oficinalis Sieb.et Zucc. (568) 512 Cydonia oblongata Mill.P-D-Gentobioside 513 Duranta repens Repenoside (569) 514 Fraxinus chinensis Frachinoside (570) 515 Fraxinus formosana Fraxiformoside (571) 516 Hedyotis dijfusa (572)-(574) 517 Jasm in um amp les ica ule Jasamplexosides 1-111(575)-(577) 518 Jasminum mesnyi (578) and (579) 519 Lamiophlomis rotata Lamiophlomiol C (580) 520 Lamium album Alboside-A (581) and Alboside-B (582) 52 1 Linaria genist;folium Genistifolin (583) 522 Linaria vulgaris (584) and (585) 523 Nepeta leucophylla Iridodials and (586) 524 Nepeta tuberom 5,9-Dehydronepetalactonedimer (587) 525 Nyctanthes arbor-tristis (588) and (589) 526 Oldenlandia corymbosa Asperulosidic acid and scandoside esters 527 Or thocarpus attenattus 8-Deoxylaminol and 5,8-bisdeoxylaminol 528 Orthocarpus purpurascens 6/3-Hydroxyboschnaloside 528 Pedicularis lasiophrys Pedicularioside (590) 529 Pedicularis longiflora 530 Pedicularis nordmanniana (59 1) 531 Plantago carinata Schrad.10-Acetylaucubin (592) 532 Plantago major Majoroside (593) 533 Premna japonica Catalpol derivatives 534 Pseudocalymma elegans Pseudocalymmoside (594) 535 Rehmannia glutinosa var. (595) 536 purpurea Rogeria adenophylla (596) 537 Scrophularia canina (591) 538 Scrophularia koelzii Koelzioside (597) 539 Siphonostegia chinensis Siphonostegiol (598) 540 Stachys macrantha Macranthoside (599) 541 Strychnos ligustrina Ligustrinoside (600) 542 Swertia angustlfolia Angustiamarin (601) 543 Tabebuia avellanedae Ajugol derivatives (602)-(604) 544 Triplostegia grandljlora Triplostoside-A (605) 545 Veronica anagallis aquatica var.Anagalloside (606) 546 anagalloides Villarsia exaltata 547 216 NATURAL PRODUCT REPORTS 1996 proceeds in the reverse direction hexa-acetyl catalpol(560) has been converted into (+)-cyclosarcomycin (561).504 The number and complexity of novel iridoids and seco-iridoids which are isolated from plant sources continues to grow. In this Report for the sake of brevity these are listed by source in alphabetical order in Table 2 on page 215 and structural formulae are provided where appropriate. AcO HO O-P-D-GIC 0 ,PZD-GIc (5711 No Go OAc Acoi O-p-D-Gk(OAc)4 0 (560) (561) (562) OMe R HO (575)R = H; n=2 (576)R = H; n=3 (577)R=OH; n=2 A O-~D-GIC (578)R= H HO & (579)R = $-55 (565) (566)is with (557) A O-O-DGIC ' O-P-D-GIC O-P-D-GIC (584)R = (€)-pcoumafyl (585)R = (2')-pcoumatyl R20*oMe (587) C02MeHr@o0-cellobiosidyl R3 o-P-D-GIc OH (588)R' = R2 = PhCO; R3 = OH (590) (569) (570) (589)R' = (€)-pcinnamoyl;R2 = R3 = H NATURAL PRODUCT REPORTS 1996.D.H. GRAYSON CQMe jp H ogo HO 0-P-D-Glc (591) (593) (592)is with (542) I0 OH CQMe HO JiJ OH (594) (595) (596)R = (Z)-pcinnamoyl OMe fOYO R2 702Me (602)R’ = Me; R2 = H (603)R’ = Me; R2 = OMe (604)R’ = R2 = H Two new tetrahydroisoquinoline-monoterpene glucosides have been isolated from Alangium platanif~lium,~** and a synthesis of oxerine (608) obtained from Oxera morieri has been Isocantleyine (609) has been found in Siphonostegia ~hinensis.~~’ Geniposide (547) is metabolised to genipinine (610) by human intestinal bacteria and gardenoside (61 1) is converted into gardenine (612) under the same conditions.551 A synthesis of racemic tecomanine (613) has been reported.552 HO C02Me HO LQ Me HO/ O-P-D-G~C 13 Cannabinoids The IH NMR spectra of the racemic and optically active forms of the nor-ketone (6 14) are non-superimposable! Non-racemic mixtures of the enantiomers of (614) exhibit two sets of signals for their aromatic protons in ratios which reflect the com- position of the mixtures.This self-induced non-equivalence appears to be caused by diastereoisomeric solute-solute interactions and it is therefore possible to use NMR to determine the ee of a sample of (614) without employing a chiral shift reagent.553 Most of the (chemical) activity in this area has focused on synthesis.Citronella1 (53) reacts with phenols in refluxing quinoline to yield hexahydrocannabinoids (6 15) via inter-mediate quinone methides (61 6).554 Activated phenols can be (614)R = CH3 (623)R = CD3 h xp NATURAL PRODUCT REPORTS 1996 reacted under the milder conditions of boric acid in acetic A similar route has been employed in a synthesis of ( -)-trans-hexahydrocannabinol (617),556The derivative (61 8) undergoes a related intramolecular reaction to yield 9-nor-9- hydroxyhexahydrocannabinol (6 1 9).j5’ Apoverbenone (620) has been converted into the racemic 11- nor-9-carboxy - Ag-tetrahydrocanna bin01 carboxylic acid (62 1) which is the principle human metabolite of Ag-tetrahydro- cannabinol (622).558 The labelled nor-ketone (623) and the labelled ester (624) have been synthesised from the related apo- bromoverbenone (625).559 Reaction of 3,9-dibromocamphor with the aryllithium (626) in the presence of Cul affords (627) which has been converted into (-)-cannibadiol (628) and the corresponding dimethyl ether.560 The intermediate (629) for a synthesis of A9-tetrahydrocannabinol (622) is obtained in crystalline form when the p-menthendiol (630) is reacted with the phenol (631).561 The thioacetal (632) has been converted into the THC-acid (621) by related means.562 Protection of the phenolic hydroxy group of the aldehyde (633) by silylation permits oxidation at C-9 using NaC10,-Na,PO,-ButOH thus providing another route to the acid (621).563 New routes to cis-A9-tetrahydrocannabinol and to trans-A*-tetrahydrocannabinol (634) the main active ingredients of hashish have been f? OH HOL YHO I The diacetate (635) reacts with Me3SiBr in the presence of catalytic ZnBr to give the rearranged allylic bromide (636) and the isomeric acetate (637) provides the rearranged As-bromide (638) under the same Cannabidiol(628) and the As-tetrahydrocannabinol (634) are both selectively halogenated in their aryl rings by LiCl or NaBr in the presence of [181-crown-6 and m-chloroperoxybenzoic acid.566 The two rotationally-restricted tetrahydrocannabinol ethers (639) and (640) have been synthesised with a view to testing theories of psychopharmacological a~tivity.~~’ H $?I$- (617) R=Me (619) R=OH OMOM (620) R= H (625) R = Br R Code I (621) R=C02H (622) R=Me Me0 Me0 (628) R’ = H; R2 = H or Me (629) R‘=OH; R2=H “‘O.-od__ 7 0 ‘ (637) 14 References 1 D.H. Grayson Nat. Prod. Rep. 1994 11 225. 2 Dictionary of Terpenoids,ed. J. D. Connolly and R. A. Hill vol. 1 Chapman and Hall 1991. 3 D. H. 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ISSN:0265-0568    

DOI:10.1039/NP9961300195

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Steroids Reactions and Partial Synthesis James R. Hanson School of Molecular Sciences University of Sussex Brighton Sussex BN I 9QJ,UK Reviewing the literature published in 1994 (Continuing the coverage of literature in Natural Product Reports 1995 Vol. 12 p. 567) 1 Introduction 2 The Spectroscopy and Physical Properties of Steroids 3 Reactions 3.1 Alcohols 3.2 Epoxides 3.3 Alkenes 3.4 Carbonyl Compounds 3.5 Remote Functionalization 3.6 Rearrangement Reactions 3.7 Photochemical Reactions 4 Partial Synthesis 4.1 Estranes 4.2 Androgens 4.3 Pregnanes 4.4 Bile Acids 4.5 Cholestanes 4.6 Brassinosteroids and Ecdysteroids 4.7 Sapogenins 4.8 Cephalostatins 4.9 Vitamin D 5 References 1 Introduction This review covers the literature published between January and December 1994 and follows a similar pattern to its predecessor.1 Interest continues in aromatase inhibitors which have been reviewed,2 and in potential inhibitors of testosterone 5a-reductase.There has also been a great deal of work on the synthesis of vitamin D analogues. Recent progress on the chemistry of the steroids3 and the withanolide lactones’ has been reviewed. 2 The Spectroscopy and Physical Properties of Steroids A strategy for assigning overlapping lH NMR signals based on proton detected 2D-heteronuclear shift correlation spectro- scopy has been illustrated5 with steroid examples. Steric effects observed in the 29Si NMR chemical shifts of the trimethyl- silyloxy steroids have been correlated6 with the accessibility by the solvent to the oxygen atom.The lH and 13C NMR chemical shifts of some cholic acid derivatives determined in aqueous solution are reported’ to show a concentration dependence associated with micelle formation. The lH and 13C NMR spectra of the C-23 and C-24 diastereoisomers of the geo- chemical biomarkers of the Scz-dinosterone series have been assigned.* Examination9 of the NMR spectra of the vinyl- stannane (1) has provided evidence for HO-Sn coordination. The influence of the fluorine atom on the mass spectra of various 3-0x0- 10P-fluoroestra- 1,4-dienes [e.g. (2)] has been investigated.1° The electrospray tandem mass spectra of a-and /I-ecdysone have been reportedll as an aid to the structural characterization of the ecdysteroids that are involved in the moulting cycle of crabs.The crystal structures of a number of steroids have been reported including the 8a-hydroxy steroid (3),12 the unusual 8,9-seco steroid (4),13 and some neuromuscular blocking agents including chandonium dibromide (5)14 and 1lcc-hydroxy-progesterone (6).15 Ph3Sn Me Me Me The X-ray structure of the bis-(cholesteryldiethyl-phosphinite)dichloropalladium(iI) complex (7) has revealed16 that the cholesteryl substituents are folded back in the same direction leaving one axial site of the palladium relatively exposed and the other hindered by the cholesteryl moiety thus providing some interesting catalytic possibilities.X-Ray crystal- lographic studies have been used1’ to explain the formation of the solid-state UV photodecomposition products of mife- pristone (8) in terms of the packing in the crystal. An ENDOR study has been reported1* of the radicals that were formed on y-irradiation of crystals of 17a,21 -dihydroxyprogesterone. Me cholest P-Et 0’ ‘-* The inclusion compounds formed by cholic acid with various organic substances have been examined by X-ray crystallo- graphic st~dies.l~-~~ A comparison of the inclusion compounds formed between cholic acid and aniline or 3-fluoroaniline has 227 shownz1 that the fluorine substituent alters the channel and hydrogen bonding pattern. A bile acid based semi-rigid 'molecular tweezer' (9) derived from methyl deoxycholate and pyrene-3-carboxylic acid has been to bind 1,3,5-trinitrobenzene in solution.The mesomorphic behaviour of various cholesteryl fatty acid esters has also been examined.24. 25 3 Reactions 3.1 Alcohols The preparation of unsymmetrical dialkylcarbonates of ster- oidal alcohols by reaction with an alkyl halide and silver carbonate in dimethylformamide has been described.26 The adverse effect of a trialkylsilyl protecting group in decreasing the quantum yield of the photolytic opening of the diene ring of la-hydroxyprovitamin D has been noted.27 Cholic acid and cholesteryl esters have been used as chiral auxiliaries in the formation of chiral a-hydroxyacids.2sv 29 Thus reaction of the phenylglyoxylate ester (10) with ethylzinc chloride followed by hydrolysis gave the hydroxy acid (1 1) in high optical purity.Further improvements to the procedure for the preparation of cholest-2-ene from the toluene-p-sulfonate of cholestan-3P- 01 have been rec~rded.~~ Steroids bearing a tertiary 17a-hydroxy group lose this on derivatization with perfluoroacyl anhydrides and undergo rearrangement to give 17P-methyl- 18- nor-1 3( 14)-enes. This complicates their analysis by GC-MS.31 The 7cc-hydroxy group in the metabolites of the novel corticosteroid tipredane (12) has been to facilitate the elimination of the 9a-fluorine atom and the formation of a 9,ll-P-epoxide. NATURAL PRODUCT REPORTS 1996 and a catalytic amount of osmium tetroxide yielded36 the corresponding ap-unsaturated ketone.The fragmentation reactions of the alkoxyl radicals derived from variously substituted Sa-hydroxy steroids using (diacet- 0xyiodo)benzene and iodine have been st~died.~~-~~ Thus the fragmentation reaction of (13) gave products such as (14) (15) and (16). The tandem fragmentation of cyclopropane rings driven by the generation of an adjacent carbon radical as in the oxidative fragmentation of (1 7) afforded the highly functional- ized 11-membered ring in (18).39 In some instances ortho-acetate esters have been formed [e.g. (20) from (19)].40 0.' -MeS 3.2 Epoxides The oxirane-ally1 alcohol isomerization (21)-(22) has been Hod applied to the synthesis41 of 16-dehydro-20-oxopregnenes from 17a,20-epoxy-23,24-dinorcholan-22-oicacids (2 1H23).The stereochemical limitations of the syn-stereocontrol in the epoxidation of cyclic allylic alcohols has been explored4* revealing a number of hindered situations in which trans-addition takes place. Me \,C02H ZCOpH r-n I v-" Methods for the direct oxidation of steroidal 5-en-3P-01s to 4-en-3,6-diones have been described.33 34 o-Iodoxybenzoic acid (IBX) has been to smoothly oxidize some steroidal primary and secondary alcohols to aldehydes and ketones respectively. 1,2-Diols were converted to a-ketols or a-diketones without any oxidative cleavage of the glycol C-C bond. The oxidation of steroidal allylic 6-and 7-alcohols with ButOOH NATURAL PRODUCT REPORTS 1996-5.R. HANSON 3.3 Alkenes A comparison of the products of osmylation of A4-and A5-enes in the presence or absence of a complexing amine has been reported4 and the results have been interpreted in terms of a stepwise osmylation. The reaction of 3P-acetoxyandrost-5-en-17-one (24) and some of its relatives with mercury(r1) trifluoro- acetate in dichloromethane has been to give the A4-6P-hydroxy compound (25) and the As-6-chloromercury derivative (26). AcO (25) + AgCl (26) The epoxidation of As-cholesteryl 3-esters on the p-face using molecular oxygen molybdenum acetonylacetonate and iso- butyraldehyde has been However the catalytic epoxidation of 17-ethylidene-androstane by oxygen in the presence of dioxoruthenium tetramesitylporphyrinate was not ~tereoselective.~~ Whilst epoxidation of 16-methylene- 17P- alcohols with rn-chloroperbonzoic acid did not display much stereoselectivity the Sharpless system was highly stereo-selective.The nitration of 3/3,17P-diacetoxy-7-norandrost-5-ene (27) afforded4* the 5P-nitroxy-6a-nitro steroid (28) and the re-arranged product (29). The formation of these was rationalized in terms of a Markovnikov directed diaxial (SP76a)-addition to the A5-double bond of the B-nor steroid in contrast to the 5a76P-diaxial addition found in the normal steroid series. The 5-chloro-6-nitro derivatives of As-enes are formed4' from chlorotrimethylsilane and sodium nitrite. I n' I An interesting series of insertion and rearrangement products have been obtainedso from the reaction of dibromo- and dichloro-carbene with A5(l0)-steroids.The synthesis of 19-hydroxy-5P,19-cycloandrostan-3,17-dione(31) by reductive cyclization of the 19-aldehyde (30) with zinc in aqueous acetic acid has been rep~rted.~' The 19R-epimer isomerized to the 19s-epimer through an intermediate 3-hydro~y-3~5-cyclo-steroid. The oxidation of A7.9(11)-~ter~idal dienes (e.g. (32)] with ruthenium tetroxide has been explored.52 There was some preferential reactivity of the 9(1 1)-double bond affording 9a- hydroxy-1 1-keto and 9a 1la-dihydroxy derivatives (33). The oxidation of 7-dehydrocholesteryl acetate with ruthenium tetroxide has leds3 to the isolation of the first bis-5a,6a-cyclic ruthenium(v1) dies ter . -..AcO OAc (32) (33) The vinylation of unsaturated steroidal 2-enyl and 3,Sdienyl triflates in the presence of a palladium catalyst has been examined.54 In the presence of carbon monoxide insertion of CO took place with the formation of unsaturated ketones. 17a- Ethynyl- 17P-hydroxy steroids (34) have been selectively trans- formeds5 into esters (35) by reaction with carboxylic acids in the presence of the catalyst [Ru(y-0,CH) (CO) (PPh,),]. The reaction proceeded with retention of configuration at C-17. (34) (35) The preparation of a number of organometallic derivatives of steroids has been rep~rted.~~-~~ Compounds such as the estradiol derivative (36) which are stable in biological media have been showns7 to have a high affinity for the estradiol receptor and are consequently of interest in the treatment of breast cancer.3-Methoxyestra-1,3,5( lO)-trien-16-one has been converted60 via the corresponding fulvene to the bis-cyclo- pentadienyl zirconium derivative (37). This complex was used as a homogeneous Ziegler type catalyst for stereoselective propene polymerization. (37) The intramolecular ene reaction of 5-(prop-2-enyl)-2-hydroxy-5a-cholestan-3-one(38) has been examined.61 The major product was the 2,5-ethano-acyloin (39) which underwent further rearrangement to the 3,5-ethano-isomer (40). 3.4 Carbonyl Compounds A mild method for the conversion of 6-nitro-A5-steroids to the corresponding 6-ketones involved their reduction with tin(I1) iodide and a catalytic amount of concentrated hydrochloric acid.62 The addition of alkyl Grignard reagents to the sterically hindered 17-ketones was significantly enhanced using an-hydrous cerium(II1) ~hloride.~~ This was used in the preparation of 17a-propyl-17p-hydroxyandrost-4-en-3-one,a potent an-drogen receptor antagonist.The oxidative aromatization of 19-nor-A4-3-keto steroids with iodine and ammonium cerium(1v) nitrate in methanol or copper(r1) bromide in acetonitrile has been Steroidal 1,4-dien-3-0nes have been to afford either la,2a- or 4P,Sp-epoxides on treatment with dimethyldioxirane. The presence of an 1 1-carbonyl group favours the formation of the la,2a-epoxides. Sa-Fluorocholestan-3-onehas been prepared66 by the ad- dition of fluorine to cholestenone followed by reductive defluorination with triphenyltin hydride and azobisisobutyro- nitrile.The bromofluorination of C-1 phenylsulfides [e.g.(41)] with N-bromosuccinimidelHF or N-bromosuccinimidel diethylaminosulfur trifluoride afforded6$ the C-1 fluoro steroids [e.g.(42)]. In the course of studies on the selectivity of the androgen receptor the selective dehalogenation of steroidal chlorofluoroacetyl derivatives [e.g.(43)] has been carried out with sodium formaldehydesulfoxylate (Rongalit@).6s 0 0 CIFCH. C II H 0 (43) The intramolecular Michael condensation of 3a- and 3p- acetoacetoxy-cholest-4-en-6-one [e.g.(44)] has been to lead stereoselectively to the derivatives (45) and (46). The Vilsmeier-Haack formylation of aza-steroids for example to form (47) has been described.'O HO" OAc NATURAL PRODUCT REPORTS 1996 A series of heterocyclic steroids have been prepa~ed'~-'~ from steroidal ketones.These include the triazole derivative (48) and the pyrimidine (49). The former was obtained via the 4-hydroxy-A4-3-ketone and the latter via the condensation product of the 17-ketone and an aromatic aldehyde. The pentafluorothiophenyl activating group has been used in amide formation with steroidal 22-carboxylic The reaction of 17a-hydroxy- 17-carboxylic acids with carbo-diimides has been to lead to spirocyclic oxazo-lidinones or N-acylurease depending on the reaction condi- tions. Although the N-alkylation of 17-azasteroids [e.g.(50)] with iodomethane or iodoethane proceeded smoothly the reaction was subject to steric hindrance with more highly substituted alkyl halide^.'^ 3.5 Remote Functionalization Extensively perdeuteriated steroids have been produced" by platinum catalysed exchange reactions.The direct oxy-functionalization of 5P-steroids by perfluorodialkyloxaziridines to give Sp-hydroxy steroids has been shown7* to proceed in the presence of a wide range of other substituents. 3.6 Rearrangement Reactions Further evidence has been pre~ented'~ for the diminished homoallylic participation of the CS-C6 double bond in the solvolytic and halogenation reactions of C-3 derivatives in the B-nor steroids. The corner opening of the cyclopropane ring of i-steroids [e.g.(5 l)] by mercury(I1) and thallium(II1) salts has been shownso to afford organometallic compounds such as (52).The further reaction of the organomercurial derivative with molybdenum(v) pentachloride has been reporteda1 to afford cholesteryl chloride (53) and some alkenes. NATURAL PRODUCT REPORTS 1996-5.R. HANSON Cetyltrimethylammonium permanganate has been showns2 to bring about an oxidative rearrangement of ring D of 16-dehydroprogesterone (54) to afford the compounds (55) and (56). Further investigations of the D-homoannular rearrange- ments of cortical steroids have been mades3 using triamcinolone (57). In the presence of aqueous base the major product was (58) whilst the 16a-epimer of (58) was formed in the presence of certain metal ions. 17-Hydroxy-20-keto-steroids have been showns4 to undergo D-homoannulation in the solid state in the presence of gaseous hydrogen chloride to afford 16-chloro-16- methyl- 17-oxo-D-homo steroids.The regioselectivity of some acyloin rearrangements of 3- acetyl-3-hydroxy-A-norsteroids[e.g. (59-60)] have been rationalizeds5 in conformational terms. Me 0&c=o (54) OH 0 3.7 Photochemical Reactions The photochemically induced mercuric oxide :iodine oxidation of cholest-5-en-3a-01 (6 1) and the corresponding 3/3-alcohol has been showns6 to afford products which include the ethers (62) and (63) as well as the 5,6-epoxides. 23 1 0 (65) "OH (64) &H 4 Partial Synthesis 4.1 Estranes 2-Methoxyestradiol (69) a metabolite of estradiol which inhibits tubulin polymerization has been obtaineds8 from estra- diol (67) via Baeyer-Villiger oxidation of the dibenzylether of 2-formylestradiol (68).Some 2-hydroxyalkyl- and aminoalkyl- estradiol derivatives e.g. (70) have been prepareds9 for use in a study of estrogen receptor affinities. A 7a-methyl group increases the binding affinity of estradiol for the estrogen receptor. 7a-Methylestratrienes labelled with lsF at C-16 have been preparedg0 as positron emission tomography imaging agents for breast tumours. A new stereoselective approach to C-7 alkylated derivatives based on the conjugate addition of organolithium reagents to 6-phenylsulfonylestra- 1,3,5( 10),6- tetraenes (71) has been de~eloped.~~ Some 6- and 7-aza-estrane lactams e.g.(72) have been prepareds2 from 3-methoxyestrone.OAc (67) R= H (68)R=CHO (69) R=OMe (70) R = CH&H@H Me0& \ 0 H (72) Some 13a-isoestranes e.g. (73) have been prepareds3 as potential progesterone antagonists. A synthesis of C14-Cl5 methylene bridged equilenin derivatives has been reported.94 The a-bridged compounds were obtained by stereochemically HO'* &'-&+*' .. I,:' I directed cyclopropanation using a 17a-hydroxy group. The allylic a-oriented cyclopropanes (74) with a trans C/D ring &=CH2 & The photolysis of steroidal ap-unsaturated oximes has been examined.87 There is a contrast between the outcome of photochemical rearrangements and ground state Beckmann \ rearrangements.Thus the oxime (64) gave (65) under photo- Me0 Me0 \ chemical conditions and (66) under Beckmann conditions. (73) (74) junction underwent a facile isomerization to the 8-oriented cyclopropane (75) with a cis ring junction. Hydrolysis of the product (77) of the cycloaddition of 2-acetoxyacrylonitrile to estra- 1,3,5( lo) 14,16-pentaen- 17-yl acet- ate (76) gaves5 a ketone (78). Rearrangement of the cor-responding diol (80) afforded the ketone (79). Fragmentation of (81) formed by cycloaddition of acrolein to (76) pro- ~ided~~.~' a route to 148-allylestrone (82) and thence via condensation of the aldehyde (83) to 14a 17a-ethano-estra- 1,3,5(10)-trien-3,178-triol(84),an analogue of estriol. The 148- formyl analogue of (83) has been prepared via cleavage of a cycloadduct with methyl propiolate.Me0&0 (75) OAc QAc AcO (77) i OH OAc OH The oxidation of ring B and C-1 1 of a 14a,l7a-ethano bridged estratriene with ammonium cerium(1v) nitrate has been reportedss to form (85). The stereochemistry of the introduction of alkyl groups at C-15 by oxy-Cope rearrangements and by conjugate addition to Al5-l 7-ketones has been explored.ss A number of 16-spiro steroids [e.g. (86)] have been pre- paredloo in this series. The anomalous formation of 16-spiro compounds was also notedlol during an attempted Wittig reaction at C-17. Estradiol has been coupledlo2 via the 17- succinate to tetracycline to afford a bone seeking estrogen pro- drug. OAc NATURAL PRODUCT REPORTS 1996 4.2 Androgens An efficient route for the conversion of 38-acetoxy-19-hydroxyandrost-5-en- 17-one (87) to estrone via the acetate (88) has been described.lo3 An interesting route to new 19-substituted androstenedione analogues of interest as aromatase inhibitors the sigmatropic rearrangement of 1 1 -substituted estradiendione derivatives.This was exemplified by the conversion of the 1 18-hydroxy steroid (89) to (90) and (91). AcO 0-\c/ 0 0 & 0 A number of variations on the underlying androstane skeleton such as the 3-pyridyl N-oxide (92)lo5 and the 6-aza steroid (93)lo6 have been synthesized in the search for inhibitors of testosterone 5cc-reductase. Other compounds that have been reported in this context include the B-nor-4-aza-5-androstane (94),lo7 the 6-aza steroid (95)loa and the B-homo-6-aza steroid (9 6).O9 CONHCHPhp OJ &HcHph20& O YH H H (94) (95) 0 233 NATURAL PRODUCT REPORTS 1996-5.R. HANSON A series of 6-alkyl and 6-arylandrost-4-en-3,17-diones have been Synthesizedl'O as aromatase inhibitors to gain insight into structure :activity relationships. A range of androst-5-en-7- ones bearing different substituents at C-19 have also been examinedlll as inhibitors of aromatase. Comparison with the corresponding 7-deoxy compounds showed that the presence of a 7-ketone deactivated the enzyme. The synthesis of some A2-and A3-3-deoxy-5a-androgens bearing various C- 19 sub-stituents has been reported.l12 These were used in model reactions relating to the oxidative steps in the aromatase reaction.The synthesis of fluorescent 4,6,8( 14)-trien-3-ones by de- hydrogenation of the 3-alkoxy-3,5,7-trienes has provided113 some useful probes for steroid-protein interactions. The introduction of a 7a-hydroxy group into testosterone has been achieved114 by the conjugate addition of the silylcuprate reagent (PhMe,Si),CuLi to 4,6-dien-3-ones. 7a- Iodo-5a-dihydrotestosterone has been prepared115 as a potential radioligand for the androgen receptor. 7a-Keto-B-homo-testosterone (97) and the corresponding 17a-isomer have been prepared116 by enlargement of ring B using the reaction of a 7- ketone with diazomethane in the presence of a Lewis acid. The preparation of epitestosterone (1 7a-hydroxytestosterone) ana- logues is not straightforward and some routes circumventing the problems have been described.l17 These compounds are plausible metabolites of their 17P-hydroxy relatives.The isomerization of 17-androstanones to their 13a-isomers in refluxing acetic acid containing 1 ,Zphenylenediamine has been reported .I1 A number of 1 1-substituted androstanes e.g. (98),'l9 (99)lB0 and ( have been prepared as analogues of RU 486 and as potential anti-progestins. Desogestrel (102) is a powerful progestogen and is widely used as an oral contraceptive. An alternative synthesis of desogestrel and its major metabolite the 3-0XO derivative from the readily available synthetic steroid (101) has been reported.122 Benzylic oxidation at C-9 with dimethyldioxirane followed by dehydration proved to be the method of choice for introducing a A9(")-double bond and thence the 11-substituent.0Loo (97) NMe2 I OH MeO.. 0 Some D-homo aza steroids e.g. (103) in which ring D has as been converted to a lactam have been ~ynthesizedl~~ potential 'inverted' inhibitors of testosterone Sa-reductase. A series of analogues e.g. (104) of chandonium iodide have been prepared124 and evaluated as potential neuromuscular blocking agents. The biquaternary compounds had greater activity than those in which ring A contained only an unsaturated ketone. Methods for appending peptide side chains onto steroids have been re~0rted.l~~ Some steroid based amphotericin mimics have been examined126 in which androst-5-en-3P 17P-diol has been condensed as its bischloroformate with hexaethylene glycol derivatives.Me 4.3 Pregnanes A series of 6a- and 6P-hydroxylated 11-deoxycortisol cortico- sterone and 11-dehydrocortocosterone derivatives have been preparedlZ7 and ring A reduced to afford the 501-and 5p-epimers. The 1251-labelled iodovinyl steroid (105) has been prepared128 by iododestannylation of the corresponding tri- butyltin derivative using 1251-~~di~m iodide and iron(xI1) sulfate. The iodo compound is a ligand with an affinity for the progesterone receptor. The pregnane side chain has been added129 to the 14P- androst-5-ene series to afford 14p-pregnenolone (106). 17a- Fluoroprogesterone and some derivatives e.g.(109) have been prepared130 via (108) by the reaction of 2O-metho~y-A'~'~~)- unsaturated compounds e.g. (107) with DAST. Compound (109) showed a very strong affinity for the progesterone receptor. The hydrogenolysis of C-17 and C-20 allylic carbon- ates e.g. (1 lo) usingpalladium and triethylammonium formate generated13' the natural stereochemistry at these centres. Me MeO-CH20H 1 Some 14P-hydroxy-5P-pregnane derivatives of oubain have been prepared132 which bind to the digitalis receptor. Both 20a-and 20P-hydroxy- 17a,21 -cyclopregn-4-en-3-ones (1 11) have been prepared133 by Simmons-Smith methylenation of the corresponding 17,20-enol TBDMS ether as potential inhibitors of the C-20 oxosteroid oxidoreductase system.4.4 Bile Acids Cholic acid has been fun~tionalizedl~~ at the C-3 and C-24 positions with quinoline and quinoxaline as intercalating derivatives to afford compounds which show activity against mouse leukaemia cells. Bile acid dimers linked between C-24 and C-3’ by an ethanolamine unit have been prepared135 as specific inhibitors of ileal bile acid transport. The synthesis and incubation of radiolabelled 3a,7a-di-hydroxy-5~-cholestanoic acid with a rat liver preparation has led136 to the identification of (24E)-3a,7a-dihydroxy-5/3-cholest-24-enoic acid and (24R,25S)-3a,7a,24-trihydroxy-5P-cholestanoic acid as intermediates in the formation of cheno- deoxycholic acid. The syn elimination of the 24-pro-R and 25- hydrogen atoms in the dehydrogenation of 3a,7a 12a-tri- hydroxy-5~-cholestan-26-oyl CoA during cholic acid biosyn- thesis has been estab1ishedl3’ through the synthesis of the relevant C-24 deuteriated epimer and its incubation with a rat liver system.The steroidal nitroxide (1 12) spin label has been prepared138 as a spin probe for model membranes that can be used to study alterations to permeability induced by various drugs. Com- pounds such as (1 13) have been synthe~izedl~~ as potential inhibitors of HMG CoA reductase. The rigid concave shape of the cholic acids makes them ideal building blocks for synthetic host molecules. A steroidal cyclopeptide cyclo-[3a-(phenylalaninylamino)-5~-cholanate]2 has been from lithocholic acid and (S)-phenylalanine. The nature of the cavity that it encloses has been explored by NMR methods.The synthesis of some steroidal boranes e.g. (114) from methyl deoxycholate has been reported.141 Their use in asymmetric catalysis has been explored. HOYYO 0 \fo NATURAL PRODUCT REPORTS 1996 4.5 Cholestanes The cholestane derivative cosalane (1 15) has to be a potent inhibitor of HIV and apparently affects a number of events in the viral replication cycle. A steroidal ester (116) of AZT has been in order to improve the pharmaco- kinetic properties of the latter. OH A number of oxygenated sterols including 1/3,3P,Sa-tri- hydroxycholestan-6-one (1 19) have been ~ynthesizedl~~ as structural mimics of part of the phorbol ester tumour promoters (1 17) and (1 18). The steroid target molecules were designed by arranging the hydrogen bonding functional groups of the phorbol moiety over rings A and B of the steroid.The products possessed some weak phorbol-like activity. The synthesis of a [2,3-d]isothiazole (120) from chol-estanone has been reported. 145 An intramolecular Diels-Alder reaction involving the intermediate (121) has been to prepare a 1-epibaccatin-111-steroid hybrid (122) from cholest- 1-en-3-one. The synthesis and structure-activity relationships of some cytotoxic 7a-hydroxy sterols e.g. (123) have been reported. 14i Hoe-H NATURAL PRODUCT REPORTS 1996J. R. HANSON I The synthesis of the steroidal antibiotic squalamine (125) from 3P-acetyoxy-A5-cholenic acid via the amino alcohol (124) has been reported.14' A number of C-19 functionalized cholesterol derivatives including 19-amin0 19-thio and 19-thiomethyl derivatives have been prepared14' from 19-hydroxy- cholesteryl acetate.Epoxidation of the A16-alkene (126) afforded15' a 16a,17a-epoxide (127) which was reduced with lithium aluminium hydride to the 17-alcohol. Oxidation and dehydration gave 17a-hydroxycholest-4-en-3-one(128). Acid catalysed rearrangement of the 164 17a-epoxide (1 27) gave the A13-l 6a-alcohol (1 30). I OS03-I "O Y OH Improvements have been reported15' in the synthesis of (25R)-3P,26-dihydroxy-5a-cholest-8( 14)-en-1 5-one (13l) a compound of value in studies on the inhibition of sterol biosynthesis. The synthesis of 3P-hydroxy-5a-cholestan-15-one from 3~-acetoxy-5a-choIest-8( 14)-ene and its effect on the level of HMG CoA reductase has been described.152 Tritium labelled 26-hydroxycholesterol of high specific activity has been prepared153 by catalytic reduction of (222 25R)-6~-methoxy-3a,5-cyclocholest-22-en-26-01 (132) with tri- tium gas followed by hydrolysis.When the reduction was carried out with deuterium 2H and 13C NMR spectroscopy showed that most of the label was at C-22 and C-23. 25- Fluorocholesterol has been prepared154 from 25-hydroxy-cholesterol by treatment with hydrogen fluoride in pyridine. However it did not have a significant effect on HMG CoA reductase at concentrations at which 25-hydroxycholesterol was inhibitory. -CHzOH ' &$Jo H O Y (131) &H20H OMe (132) The synthesis of [2 1-13C]cholesterol (1 34) has been de- The label was introduced by reacting the 17P-cyano steroid (133) with [13C]methyl magnesium iodide to afford [21- 13C]pregnenolone.The stereochemistry of the biosynthetic addition of hydrogen to C-25 of desmosterol has been e~tablishedl~~ using [26-13C]- and [27-13C]-labelled desmosterol. The key step in the preparation of the [27-13C]-2abelled desmosterol was a Wittig reaction between the aldehyde (135) and the phosphonium salt (136) which gave the (24E) isomer (137) as the major product. TBDMSO WCH0 THPO (135) -7 \r\/\\/C02Me 0L2y-l H:&-oH Syntheses of some phenanthrene steroid-biomarkers e.g. (138) have been ~ep0rted.l~' The syntheses of some similar aromatic steroid hydrocarbons bearing a methyl group at the positions C-2 C-3 and C-6 starting from pregnenolone cholesterol or stigmasterol have also been reported15* in connection with the identification of these compounds in various sediments.4.6 Brassinolides and Ecdysteroids A stereoselective synthesis of (22R,23R,24S)-3P,22,23-trihydroxy-24-methylcholest-5-ene(139) which contains the four chiral centres of the brassinolide side chain has been re~0rted.l~~ The Baeyer-Villiger oxidation of 6-ketones using trifluoroperoxyacetic acid to give the brassinolide ring B lactones has been examined.lG0 HOH (139) Some 7-0x0-7a-oxa-brassino steroids e.g. (140) with a cholestane side chain have been synthesized.lG1These com- pound$ exhibit weak brassinolide activity. New methods have been describedlG2 for constructing the brassinosteroid side chain applicable to 23-aryl analogues e.g. (141). These involve Heck coupling of a 22(23)-ene with an aryl iodide and asymmetric osmylation. 2,24-Diepicasasterone (142) which possesses a trans-2,3-diol has been obtainedlG3 from ergosterol. HO NATURAL PRODUCT REPORTS 1996 ones have been preparedlG4 and shown to be converted by hairy root cultures of Ajuga reptans into 20-hydroxyecdysone indicating their role in the biosynthesis of the phytoecdysteroids. A Lewis acid promoted carbonyl-ene reaction has been developedlG5 which can afford either the (22R)- or (22s)-hydroxy product [(144) or (145)] from the alkene (143).The hydroxylation of 20-isoxazolyl steroids has been exploredlG6 as a method for introducing the 22,23-diol. A number of cholesterol derivatives containing a 22,23-acetylene have been synthesizedlG7 as inhibitors of the C-22 hydroxylation in ecdysone biosynthesis. The base catalysed autoxidation of 20-hydroxyecdysone has given16* the unusual ecdysteroid calony- sterone (146) and 9,20-dihydroxyecdysone. \ I OMe 4.7 Sapogenins The oxidation of sapogenins with dimethyldioxirane has been describedlas as a simple means of opening the spiroketal and generating steroids with a functionalized side chain. 4.8 Cephalostatins The cephalostatins (147) are dimeric steroidal pyrazines which 171 because of their high have attracted synthetic intere~t"~ activity in a substantial proportion of the National Cancer H (147) 20-Hydroxyecdysone is the moulting hormone of many arthropods.[~cx-~H] and [5-2H]3P-Hydroxy-5P-cholest-7-en-6- NATURAL PRODUCT REPORTS 1996J. R. HANSON Institute screens. Studies have been on the stability and possible interconversion of the spiroketal rings of the steroidal ‘North’ 5,5-ring spiroketal and the ‘South’ 6,5-ring spiroketal. Hecogenin has been to an intermediate (148) suitable for conversion to both halves of cephalostatin 7. Some symmetrical pyrazines have been synthesized. CHO \/ 4.9 Vitamin D There has been considerable activity devoted at the total synthesis of vitamin D and its analogues. This is however outside the scope of this review.However some of the synthons required for the C/D portion may be derived by the degradation of other steroids. Thus ozonolysis of a steroidal 5-ene (149) and photoelimination of ring A from (1 50) afforded174 a route to the C/D unit (151). R R J R The NMR spectra of 11-fluoro-la-hydroxyvitaminD have been examined175 in an investigation into the folding of vitamin D in solution. The syntheses of sterically hindered cis-7,8-geometric isomers (152) and (153) of la,25-dihydroxyvitamin D have been re~0rted.l~~ These isomers bind far less effectively to the chick intestinal receptor compared to the natural isomers. The (7R)-epoxides of (5E)- and (5Z)-10-oxo- 19-norcalciferol have been prepared.l’$ HO‘* kH The syntheses of the (10R)-and (lOS)-isomers of la,25- dihydroxy- 10,19-dihydrovitamin D and the conformational analysis of ring A have been described.178 There were marked differences in their biological activity.The 14-epi isomers of 25- hydroxy- and 1 a,25-dihydroxyvitamin D have also been ~ynthesized.”~ They were devoid of biological activity in terms of their effect on calcium metabolism although 14-epi-25- hydroxyvitamin D bound quite effectively to the human serum vitamin D binding protein. Some 20-oxapregnacalciferols e.g. (154) have been synthesizedlso and their binding to the progesterone receptor has been examined. The synthesis of some postulated metabolites of la,25-dihydroxy-22-oxavitamin D, e.g. (1 55) has been reported.lsl Other syntheses of vitamin D analogues with modified side chaida2 include the 24,24-dihomo- lcc,25-dihydroxyvitamin D,.lS3 The 11a-(4’-carboxybutyryloxy)-derivative of (24R)- 24,25-dihydroxyvitamin D has been preparedls4,lE5 as a haptenic derivative in order to obtain antibodies for the development of immunoassays in this area.Me I g! HO HO‘ 5 References 1 J. R. Hanson Nut. Prod. Rep. 1995 12 567. 2 A. M. H. Brodie and R. J. Santon Breast Cancer Research and Treatment 1994 30 1 ; R. W. Brueggemeier Breast Cancer Research and Treatment 1994 30,31; M. Dowsett and R. C. Coombes Breast Cancer Research and Treatment 1994 30 81. 3 F. J. Zeelen in Rodd’s Chemistry of Carbon Compounds ed. M. Sainsbury Elsevier Amsterdam 2nd edn 2nd suppl.Pt. B-E 1994 p. 461. 4 A. B. Ray and M. Gupta Prog. Chem. Org. Nut. Prod. 1994,63 1. 5 P. Bigler and C. Mueller Spectrochim. 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Org.Chem. 1994 59,5439. 104 D. Lesuisse F. Canu and B. Tric. Tetrahedron 1994 50,8491. 105 C. Haffner Tetrahedron Lett. 1994 35 1349. 106 S.V. Frye C. Haffner P. R. Maloney R. A. Mook G. F. Dorsey R. N. Hiner C. M. Cribbs T. N. Wheeler and J. A. Ray J. Med. Chem. 1994 37,2352. 107 K.Ishibashi H. Kurata K. Kojima and H. Horikoshi Bioorg. Med. Chem. Lett. 1994 4 729. 108 T. G. Back D. L. Baron and J. W. Morzycki Heterocycles 1994 38 1053. 109 P. R. Maloney and F. G. Fang Tetrahedron Lett. 1994,35 2823. NATURAL PRODUCT REPORTS 1996-5. R. HANSON 110 M. Numazawa and M. Oshibe J. Med. Chem. 1994 37 1312. 111 M. Numazawa A. Mutsumi M. Tschibana and K. Hos,ii J. Med. Chem. 1994 37 2198. 1 12 S. S. Oh and C. H. Robinson J. Chem. Soc.Perkin Trans. I 1994 2237. 113 R. M. Boehme and M. A. Kempfle Steroids 1994 59 265. 114 D. Garside. D. N. Kirk and N. M. Waldron Steroids 1994 59 702. 115 R. M. Hoyte K. Borderon K. Bryson R. Allen R. B. Hochberg and T. J. Brown J. Med. Chem. 1994 37 1224. 116 L. Kohout and A. Kasal Collect. Czech. Chem. Commun. 1994 59 649. 11 7 H. Chodounska B. Slavikova and A. Kasal Collect. Czech. Chem. Commun. 1994 59 435. 118 F. G. Yaremenko and A. V. Khvat Mendeleev Commun. 1994 187. 119 W. Schwede A. Cleve G. Neef E. Ottow K. Stoeckemann and R. Wiechert Steroids 1994 59 176. 120 E. Ottow S. Beier W. Elger K.-H. Fritzemeier G. Neef and R. Wiechert Steroids 1994 59 185. 121 Q. Zhao and Z. Li Steroids 1994 59 190. 122 S. Schwarz S.Ring G. Weber G. Teichmuller H. J. Palme C. Pfeiffer B. Undeutsch B. Erhart and D. Grawe Tetrahedron 1994 50. 10709. 123 I. A. McDonald P. L. Nyce D. M. Muench C. A. Gates T. R. Blohm M. E. Laughlin and P. M. Weintraub Bioorg. Med. Chem. Lett. 1994 4 847. 124 A. K. Verma C. Y. Lee S. Habtemariam A. L. Harvey and D. P. Jindal Eur. J. Med. Chem. 1994 29 331 (Chem. Abstr. 1994 121 256 112). 125 D. C. Horwell I. C. Lennon and E. Roberts Tetrahedron 1994 50 4225. 126 E. Stadler P. Dedek K. Yamashita and S. L. Regen J. Am. Chem. Soc. 1994 116 6677. 127 G. P. B. Kraan J. Hartstra B. G. Wolthers J. C. van der Molen G. T. Nagel N. M. Drayer R. W. J. Zijlstra and W. H. Kruizinga J. Steroid Biochem. 1994 49 233. 128 K. M. Damodaran M.W. Epperly K. M. R. Pillai and W. D. Bloomer J. Labelled Compd. Radiopharm. 1994 34 17. 129 I. Cerny M. Budesinsky P. Drasar and V. Pouzar Collect. Czech. Chem. Commun. 1994 59 2691. 130 G. Neef G. Ast G. Michl W. Schwede and H. Vierhufe Tetrahedron Lett. 1994 35 8587. 131 T. Mandai T. Matsumoto M. Kawada and J. Tsuji Tetrahedron 1994 50 475. 132 J. F. Templeton Y. Ling T. H. Zeglam K. Marat and F. S. LaBella Eur. J. Med. Chem. 1994 29 799 (Chem. Abstr. 1994 122 240129). 133 J. C. Orr J. F. Templeton H. Majgier-Baranowska and K. Marat J. Chem. Soc. Perkin Trans. I 1994 2667. 134 C. L. Brown M. M. Harding J. R. Kalman C. E. Marjo S. Rainone and L. K. Webster Bioorg. Med. Chem. Lett. 1994,4 1253. 135 G. Wess W. Kramer A. Enhsen H.Glombik K.-H. Baringhaus G. Boeger M. Urmann K. 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Coburn and S. J. Danishefsky Tetrahedron Lett. 1994 35 6603. 147 C. E. Heltzel L. A. A. Gunatilaka D. G. I. Kingston G. A. Hof- mann and R. K. Johnson J. Nut. Prod. 1994 57 620. 148 R. M. Moriarty S. M. Tuladhar L. Guo and S. Wehrli Tetra-hedron Lett. 1994 35 8103. 149 M. S. Mathai and R. A. Pascal Steroids 1994 59 244. 150 H. Velgova A. Kasal and M. Budesinsky Steroids 1994,59 335. 151 A. U. Siddiqui W. K. Wilson and G.J. Schroepfer Chem. Phys. Lipids 1994 71 205. 152 A. U. Siddiqui W. K. Wilson E. J. Parish N. Gerst F. D. Pinkerton and G. J. Schroepfer Chem. Phys. Lipids 1994 74 1. 153 Y. Ni A. Kisic W. K. Wilson and G. J. Schroepfer J. Lipid Res. 1994 35 546. 154 W. K. Wilson S. Swaminathan F. D. Pinkerton N. Gerst and G. J. Schroepfer Steroids 1994 59 310. 155 G. M. Caballero and E. G. Gros J. Labelled Compd. Radio- pharm. 1994 34 127. 156 T. Yagi N. Kobayashi M. Morisaki N. Hara and Y. Fujimoto Chem. Pharm. Bull. 1994 42 680. 157 I.Stoilov R. Shetty J. St. Pyrek S. L. Smith W. J. Layton D. S. Watt R. M. Carlson and J. M. Moldowan J. Org. Chem. 1994 59 926. 158 E. Lechtfouse and P. Albrecht Tetrahedron 1994 50 1731. 159 B. G. Hazra P. L.Joshi B. B. Bahule N. P. Argade V. S. Pore and M. D. Chordia Tetrahedron 1994 50 2523. 160 K. Kohout Collect. Czech. Chem. Commun. 1994 59 457. 161 L. Kohout Collect. Czech. Chem. Commun. 1994 59 1219. 162 L.-F. Huang and W. S. Zhou J. Chem. Soc. Perkin Trans. 1 1994 3579. 163 E. E. Levinson N. A. Kuznetsova N. Y. Podkhalyuzina and V. F. Traven Mendeleev Commun. 1994 96. 164 M. Nagakari T. Kushiro T. Yagi N. Tanaka T. Matsumoto K. Kakinuma and Y. Fujimoto J. Chem. SOC.,Chem. Commun. 1994 1761. 165 K. Mikami and H. Kishino J. Chem. Soc. Chem. Commun. 1994 495. 166 R. P. Litvinovskaya S. V. Drach and V. A. Khripach Zh. Org. Khim. 1994 30 304 (Chem. Abstr. 1994 122 240136). 167 A. Mauvais A. Burger J. P. Roussel C. Hetru and B. Luu Bioorg.Chem. 1994 22 36. 168 A. Suksamrarn P. Ganpinyo and C. Sommechai Tetrahedron Lett. 1994 35 4445. 169 P. Bovicelli P. Lupattelli D. Fracassi and E. Mincione Tetra-hedron Lett. 1994 35 935. 170 G. R. Pettit J. P. Xu M. D. Williams N. D. Christie D. L. Doubek J. M. Schmidt and M. R. Boyd J. Nat. Prod. 1994 57 52. 171 J. U. Jeong and P. L. Fuchs J. Am. Chem. Soc. 1994 116 773. 172 J. U. Jeong and P. L. Fuchs Tetrahedron Lett. 1994 35 5385. 173 S. Kim and P. L. Fuchs Tetrahedron Lett. 1994 35 7163. 174 W. G. Dauben R. R. Ollmann and S. C. Wu Tetrahedron Lett. 1994 35 2149. 175 G. D. Zhu D. Van Haver H. Jurriaans and P. J. De Clercq Tetrahedron 1994 50 7049. 176 E. M. Van Alstyne A. W. Norman and W. H. Okamura J. Am. Chem.Soc. 1994 116 6207. 177 W. Reischl Monatsh. Chem. 1994 125 85. 178 R. R. Sicinski and H. F. DeLuca Bioorg. Chem. 1994 22 150. 179 D. F. Maynard W. G. Trankle A. W. Norman and W. H. Okamura J. Med. Chem. 1994 37 2387. 180 K. L. Perlman H. M. Darwish and H. F. DeLuca Tetrahedron Lett. 1994 35 2295. 181 N. Kubodera and H. Watanabe Bioorg. Med. Chem. Lett. 1994 4 753. 182 J. Perez-Sestelo J. L. Mascarenas L. Castedo and A. Mourino Tetrahedron Lett. 1994 35 275. 183 Y. Tachibana Chem. Pharm. Bull. 1994 42 2349. 184 N. Kobayashi T. Higashi and K. Shimada J. Chem. SOC.,Perkin Trans. I 1994 269. 185 N. Kobayashi J. Kitahori H. Mano and K. Shimada J. Chem. SOC., Perkin Trans. I 1994 1809.

ISSN:0265-0568    

DOI:10.1039/NP9961300227

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Recent Progress in the Chemistry of Non-monoterpenoid lndole Alkaloids Masataka lhara and Keiichiro Fukumoto Pharmaceutical Institute Tohoku University Aoba yama Sendai 980-77 Japan Reviewing the literature published between July 1994 and June 1995 (Continuing the coverage of the literature in Natural Product Reports 1995 Vol. 12 p. 277) 1 2 2.1 2.2 3 3.1 4 Introduction Simple Alkaloids Non-tryptamines Non-isoprenoid Tryptamines Isoprenoid Indole Alkaloids Ergot Alkaloids Bisindole Alkaloids have been determined on the basis of spectroscopic data and chemical reactions.' The new alkaloids bruceollines D (1la) E (1 lb) and F (12) have been isolated from the root wood of Brucea mollis var. tonkinensis.' Quindolinone (1 3) has been found in the West African plant Cryptolepis ~anguinolenta.~ 0 5 References H H (8) Murrayaculatine (9) Brassitin IIntroduction This report follows essentially the pattern of its predecessor and provides selective coverage of the advances in the chemistry of the non-monoterpenoid indole alkaloids.2 Simple Alkaloids 2.1 Non-tryptamines (lOa) R' = OMe; R2 = H (lla) Bruceolline D X = H2 In addition to N-acetylindoline and N-formylindoline a new (lob) R'=H; R2=OH (1 1 b) Bruceolline E X = 0 alkaloid 4-hydroxy-2-(N-indolinyl)butane(1) has been isolated after incubation with various fungal strains.l From the edible mushroom Pleurotus salmoneostramineus a new natural product indolone (2) has been obtained as a pink pigment.2 Convolutamydines A (3),3 B (4) C (5) and D (6)4 possessing OH a dibromohydroxyindole moiety have been found in the Floridian bryozoan Amathia convoluta and the structures have been elucidated on the basis of spectroscopic data.Con- HO OH 0 volutamydines A and B exhibit a biological activity in the (12) BruceollineF (13) Quindolinone differentiation of HL-60 cells. Pamburus missionis roots con- tains a new alkaloid 3-(3-methyl- 1-oxobut-2-eny1)indole (7).5 The reaction of the unsaturated ester (1 5) with carbethoxy- formonitrile oxide followed by saponification and reduction gives mainly the racemate of the natural sweetener monatin (14) (Scheme 1). Attempts to adapt the 1,3-dipolar cyclo- addition to a chiral synthesis of monatin are also reported.I0 (3) ConvolutamydineA (4) Convolutamydine B (5) Convolutamydine C (6) Convolutamydine D (7) Murrayaculatine (8) has been isolated from the fresh flower of Murraya paniculata.6 Three brassinin-related stress metabo- H lites brassitin (9) N-methoxyspirobrassinol methyl ether (10a) (14) Monatin and N-methoxyspirobrassinol (lob) have been obtained from the Japanese radish 'Daikon ' Raphanus sativus var.hortensis Reagents i KOH then H'; ii Na-Hg EtOH then AcOH after incubation with Pseudomonas cichorii. Their structures Scheme 1 24 1 Camalexin (16) having antifungal activity has been synthe- sized by low-valent titanium induced reductive coupling of the 0x0-amide (1 7) which was prepared by two methods (Scheme 2)? (17) (16) Carnalexin Reagents i TiCl, Zn dust; ii EDTA.2Na salt H,O Scheme 2 A short account of synthesis of carbazole alkaloids has been published by Moody.12 The non-cyclized possible biogenetic precursors (1 8) and (19) of girinimbine and mahanimbine have been isolated from the stem bark of Murraya koenigii.The structures have been established by cyclization to dihydro- girinimbine (20) and bicyclomahanimbiline (2 I) re~pective1y.l~ A new carbazole alkaloid designated as clausenal(22) has been obtained from the leaves of Clausena heptuphyllu. The alkaloid is found to be active against both Gram-positive and Gram- negative bacteria and fungi.' Clausenaquinone A (23) has been isolated from the stem bark of Clausena excuvuta. The structure was established from spectral data and total synthesis. The compound (23) shows potent activity as an inhibitor of rabbit platelet aggregation as well as being cytotoxic.15 QyqMe OH (18) R=H (20) Dihydrogirinimbine (19) R = (CH2)&H=CMe2 ti OMe (22) Clausenal NATURAL PRODUCT REPORTS 1996 iii-vii 1 G7H15 (28) 1 ix-xii ayqoH Me -(24) Carazostatin Reagents and conditions i 1-decyne PdC12(PPh,), CuI Et,N; ii Na EtOH ;iii N,N-dimethylmethyleneammoniumchloride; iv Me1 ;v NaCN DMF; vi NaBH, CoCl -6H,O; vii ethyl ethoxymethylene- acetoacetate; viii Ac,O AcOH heat; ix DIBAL; x Dess-Martin periodinane; xi MCPBA KF; xii LiAlH Scheme 3 The indole 2,3-dienolate (30) derived by deprotonation of 1,Zdimethylindole-3-carboxaldehyde(29) has been shown to be a useful 1,6dipole synthon which undergoes facile cycloaddition to a wide range of dienophiles affording substituted carbozoles (3 1) in high yields after treatment with pyridinium tosylate (PPTS) (Scheme 4).17 L the J (30) I ii 0 ""$7g-nMe OH L (31) 0 (23) Clausenaquinone A A novel synthesis of the naturally occurring free radical scavenger carazostatin (24) has been developed by employing two aromatic annulation reactions as key steps." The acetylene (25) was subjected to the first aromatic annulation step to give the indole derivative (26) (Scheme 3).After conversion into the conjugated enamine (27) treatment of (27) with acetic anhydride in hot acetic acid causes the second aromatic annulation accompanied by the elimination of the ethenylamine moiety to provide the carbazole (28) which was then transformed into carazostatin (24).Reagents i LDA; ii R-5-X; iii PPTS Scheme 4 Electrophilic aromatic substitution of 4-methoxyarylamines (33) by the tricarbonyliron-complexed cyclohexadienylium cations (32) leads to the iron complexes (34) (Scheme 5). Chemoselective oxidation of the arylamine moiety of (34) followed by iron-mediated quinone imine cyclization using appropriate oxidizing reagents produces the tricyclic iron complex (35). Demetalation with trimethylamine N-oxide provides a broad access to the 3-hydroxy-9H-carbazoles (36).18 243 NATURAL PRODUCT REPORTS 1996M. IHARA AND K. FUKUMOTO (36) (35) Reagents i MnO,; ii Me,Nf-O-Scheme 5 (+)-cis-'l'rikentrin A (37) has been synthesized by way of an intramolecular Heck coupling (Scheme 6).19 The cyclization of the triflate (39) derived from the phenol (38) was carried out with palladium(0) in the presence of water to give a mixture of (40) and (41).The latter (41) was transformed via treatment with excess vinylmagnesium bromide into (& )-cis-trikentrin A (37). Ivi f f (37)cisTrikentrinA Reagents i AcCl CF,SO,H; ii CH,=CHCH,MgCl; iii Et,SiH TFA; iv. 65 '/o HNO,; v (CF,SO,),O 2,4,6-collidine; vi Pd(OAc), PPh, Et,NCl Et,N H,O; vii CH,=CHMgBr; viii H, Pd-C Scheme 6 The first total synthesis of the marine antitumor grossularine- 2 (42) has been achieved by Hibino and coworkers (Scheme 7).20 The palladium catalysed cross-coupling reaction of the stannane (43) with the iodide (44) provides the imidazolylindole (45).Hydrolysis of the ester (45) followed by Curtius rearrangement with diphenylphosphoryl azide (DPPA) and the subsequent thermal electrocyclic reaction gave the desired tetracyclic compound (46). Synthesis of grossularine-2 (42) was then accomplished via a palladium-catalysed carbonylative H (45) NMe2 iii,iv N4 I H OH (46) (42) Grossularine-2 NMe2 N4 (47)Grossularine-1 Reagents and conditions i Bu'Li Bu,SnCl; ii Pd(PPh,), DMF; iii aq. Na,CO,; iv DPPA Et,N then heat; v (CF,SO,),O pyridine; vi 4-methoxy-methyloxyphenylboronic acid CO PdCl,(PPh,), K,CO, LiCl; vii aq. HCl Scheme 7 As an approach to the marine alkaloid hinckdentine A (48) indolo[ 1,2-~]quinazoline (49) has been synthesized and some attempts to employ it as a synthon for the construction of the pentacyclic skeleton of the alkaloid have been carried out.22 Syntheses of mitosene analogues have been reported by three groups the synthesis of (50) by a copper-catalysed intra- molecular carbon-hydrogen insertion reaction of a diazo ester,23 the construction of (51) via a criss-cross annulation reaction24 and the preparation of (52) through acid-catalysed indole formation reaction.25 (48) HinckdentineA (49) OHCATGAG cross-coupling reaction.A similar approach toward to grossul- VNHAG arines-1 (47) and -2 has been reported by a French group.21 (52) NATURAL PRODUCT REPORTS 1996 2.2 Non-isoprenoid Tryptamines Konbamidin (53) has been found in the Okinawan marine Q-PNH2 a-cNMe2 I sponge Ircinia sp.and the structure determined by spectral data and its synthesis.26 Furthermore two new tryptophan- derived alkaloids isoplysin A (54) and 6-bromohypaphorine (55) have been isolated from the Okinawan marine sponge Aplysina sp. and their structures elucidated by spectral and chemical mean^.^' An indole alkaloid bearing an oxazole moiety almazole C (56) and its putative biogenetic peptidic precursor prealmazole C (57) have been found in a Senegalese delesseriacean seaweed.28 Me H H H (53) Konbarnidin (54)IsoplysinA OMe OMe (62) Lespedarnine (64) li H OMe OMe (65) 1 ii iii H /N\ Q)Tp0%OMe H OMe NMe2 Br ' N H H (55) 6-Bromohypaphorine (56) Almazole C H (57) Prealmazole C The oxazolylindole alkaloids pimprinine (58) pimprinethine (59) and WS-30581A (60) have been readily synthesized in two steps by rhodium(I1) catalysed reactions of the 3-diazoacetyl- indole (61) with the appropriate nitriles followed by removal of the protecting groups (Scheme 8).29 H (58) Pimprinine R = Me (59) Pimprinethine R = Et (60) WS-3058lA R = Pr 1 ii I Boc Reagents i RCN Rh,L,; ii NaOMe Scheme 8 Lespedamine (62) has been synthesized by a route based on 1-hydroxyindole chemistry.30a Chelonin A (63) has been prepared by the application of 1 -hydroxyindole chemistry (Scheme 9).Reaction of the 1-methoxyindole (64) with 3,4,5- trimethoxystyrene oxide gives (65) and its regioisomer.Acid cyclization of (65) followed by catalytic hydrogenation produces (+)-chelonin A (63).30b OMe (63) (k)-Chelonin A Reagents i 3,4,5-trimethoxystyrene oxide; ii 2 M HCI; iii H, 10% Pd-C Scheme 9 A synthesis of (-)-horsfiline (66) a metabolite isolated form Horsfieldia superba has been reported (Scheme The diastereofacial selectivity of the oxidative rearrangement of chiral tetrahydro-P-carboline into oxindoles has been examined and found to depend on the substitution pattern of the aliphatic amino group. Thus (68) derived from serotonin (67) was treated with NBS in acetic acid to afford the oxindole (69) as a main product which was converted into (-)-horsfiline (66) via the nitrile (70).HOD 0 pC02H-i-iv MeOnNpCO&e I ' NH2 I ' NBoc 'N (70) R=CN xC(66)R = H (-)-Horsfiline Reagents i CH,O; ii TMSI MeOH; iii (Boc),O Et,N; iv TMS-CHN, PriNEt; v NBS AcOH; vi TMSCl MeOH; vii CH,O NaBH,CN AcOH; viii NH,; ix TFAA pyridine; x NaBH, pyridine Scheme 10 Full details about the synthesis of the pyrroloquinoline alkaloids makaluvamines A (71) B (73) C (72) D (74) and E (75) have been A new synthetic route to pyrrolo- quinoline alkaloids has been developed (Scheme 1 1),33 in which the indole derivative (78) was prepared in four steps starting with 2,4,5-trimethoxybenzaldehyde(77). Conversion of (78) into (79) followed by treatment with trifluoroacetic acid yields 245 NATURAL PRODUCT REPORTS 1996-M. IHARA AND K.FUKUMOTO (71) Makaluvamine A R’ = H; R2 = Me (73) Makaluvamine 8 (72) Makaluvamine C R’ = Me; R2 = H 0 (74) Makaluvamine D R = H (76) Discorhabdin C (75) Makaluvamine E R = Me the tricyclic quinonimine salt (80) which was transformed into makaluvamine D (74). Discorhabdin C (76) had been previously synthesized from (80). Pyrroloquinoline alkaloids have been alternatively synthe- sized through quinoline derivatives (Scheme 12).34,35 3,4- Dimethoxyaniline (81) was converted into the quinoline derivative (82). Exposure of (82) to trimethyloxonium tetra- fluoroborate followed by reduction produced the indole (83) which was transformed into the ortho-quinone (84) a inter- mediate in the synthesis of diamirones A (85) and B (86).34 OMe OMe Me0 Me0 C02Me OMe OMe (77) liii iv OMe OMe ‘ ‘ NBn2 MeO Me0 OMe Ts OMe ix-xi I (79) (80) 1xiii3 xiv (74) Makaluvamine D Reagents and conditions i N,CH,CO,Me NaOMe; ii heat; iii NaOH ;iv Ba(OH), heat ;v (COCl) ;vi Bn,NH ;vii LiAIH ;viii Ts,O NaH; ix Pd HCO,NH, HC0,H; x (Boc),O Et,N DMAP; xi CAN Bu,NHSO,; xii TFA; xiii tyramine; xiv TFA Scheme 11 (82) I iv v Me0@ ~ 0 OR OMe Me0 Me (84) R = TS (83) (85) Diamirone A R = Me (86) Diamirone B R = H Reagents i CH,=CHCOMe FeCI, AcOH; ii HNO,; iii I, ButI FeCI, TFA DMSO; iv Me,O+ BF,; v NaBH, NiCl,; vi TsCl NaOH Bu,NHSO,; vii BBr then air Scheme 12 (-)-Indolactam V (87) is the structural core common to the teleocidin family of phorboids which have an effect on specific protein kinase C (PKC) isotypes.Optically active indolactam V (87) has been synthesized via the alkylation of the amine (89) with a triflate derived from D-valine (Scheme 13).36A method for the C-alkylation of 4-nitroindole at the C(5) and C(7) positions by an alkyl Grignard reagent has been developed. The 4-nitro-7-octylindole thus prepared was converted into ( - )-7-octylindolactam V (88) using the same method.37 x MeNH MeN C02Bn I H (89) -““.“I NOH ii Y Me?I*CO2Bn (87) Indolactam V R = H (88) R = (CH&Me Reagents i 2,6-lutidine; ii Na,CO,; iii AI-Hg; iv H, Pd-C (+)-camphorsulfonic acid ; v HOBT BDP N-methylmorpholine ; vi LiBH Scheme 13 Tumour-promoting teleocidins are known to exist in an equilibrium between two conformations the twist and the sofa form in solution.It has been revealed that indolactam V (87) takes the fold form in solution and in the crystal indicating that the conformation of the nine-membered lactam ring of indolactams is influenced by the nature of the group at the 13 position.3sA review about structure-activity relationships and conformational analysis of teleocidins has been published.39 Harman (90) has been isolated from Ophiorrhiza a~uminata.~~ Two new 1-acetyl-P-carboline alkaloids stellarines A (9 1) and B (92) have been obtained from Stellaria dichotoma var. lanceo-lata.41 Homolytic acetylation of 3-ethoxycarbonyl-~-carboline and harman occurs at the C(1) position (Scheme 14).Better yields were obtained by generation of the acetyl radical from acetaldehyde than by oxidative decarboxylation of pyruvic 0 (90) Harman (91) Stellarine A R = H (92) StellarineB R = -CH=CHCOfle (cis) R = C02Et or H Scheme 14 A new alkaloid lissoclin C (93) has been isolated from Lissoclinum A novel /3-carboline alkaloid deshydroxy- methylflazin (94) has been found in Ribes nigr~m.~~ The /3-carboline alkaloid infractin (95) has been synthesized by Heck olefination of the triflate (96) followed by catalytic hydrogenation (Scheme 1 5).45 (93) Lissoclin C (94) Deshydroxymethylflazin 1 C02Me (95) lnfractin Reagents i CH,=CHCO,Me Pd(OAc), P(o-Tol) ; ii H, Pd-C Scheme 15 Reactions of the dimetalated P-carboline (99) prepared from 1-bromo-P-carboline (98) with electrophiles could be key steps in the syntheses of various ,8-carboline alkaloids.Transmetal- ation of (99) with zinc chloride followed by palladium- catalysed cross coupling with 2-chloroquinoline has given the alkaloid nitramarine (97) (Scheme 16).46 ._ Ar (97)Nitramarine Reagents i KH; ii ButLi; iii ZnC1,; iv 2-chloroquinoline Pd(PPh,) Scheme 16 NATURAL PRODUCT REPORTS. 1996 Full details of asymmetric steering of the Pictet-Spengler reaction by means of amino acid esters as chiral auxiliary groups have been published.,’ Similar approaches have been further reported by two groups. The Pictet-Spengler reaction of (100) with acetaldehyde gave (101) as a major product which was transformed into ( -)-l-methyl-l,2,3,4-tetrahydro-/3-carboline (102) (Scheme 17).48 Although the selectivity is low (-)-I ,2,3,4-tetrahydroroeharmine(103) has been synthe- sized by a similar strategy.,’ (1 03) (-)-1,2,3,4te! rahydroroeharrnine (-)+ 02) Reagents i MeCHO TFA; ii H, Pd-C Scheme 17 6-Azacyclodeca[5,4-b]indol-1-amine (1 04) which was first postulated as the structure of nazlinin has been prepared.50 (-)-Nazlinin (105) itself has been synthesized via the enantio- selective reduction of the imine (106) (Scheme 18).51 (105) (-)-Nazlinin 1 i ii Reagents i (S)-N-benzoxycarbonylprolinate-borane complex ; MeNH, K,CO Scheme 18 Three new canthin-6-one alkaloids bruceollines A (107) B (108) and 1 1-hydroxycanthin-6-one-N-oxide (109) have been isolated from Brucea mollis var.tonkinensis (Chinese name Dao guo ya dan zi) together with two known alkaloids canthin-6-one and canthin-6-0ne-N-oxide.~~ 2-Methoxycan-thin-&one (1 10) has been found in Quassia~rnara.~~ &$/ R’ (107) Bruceolline A R’ = H; R2 = O-Glc(G+l)Glc (108) BruceollineB R’ = 0-Glc(6+1 )Glc; R2 = H NATURAL PRODUCT REPORTS 1996-M. IHARA AND K. FUKUMOTO Ailanindole (1 11) has been isolated from Ailanthus mala- barica along with canthin-6-one canthin-6-one-3-N-oxide, 1-hydroxycan thin-6-one 1-ethyl-P-carboline 1-ethyl-4-methoxy-P-carboline and P-carboline- 1 -propionic The NMR spectrum of (1 11) is very similar to that of canthin-6-one. The effect of plant growth regulators on the production of canthin- 6-one alkaloids has been studied using cell suspension cultures of Brucea javanica.j5 An approach to canthine derivatives using the intramolecular Pictet-Spengler reaction has been re~0rted.j~ A new tryptophan derived alkaloid cuscutamine (1 12) has been obtained from a 50 YOmethanol extract of Cuscuta chinen~is.~’ OH i __c I Mom Mom (1 18) ii-ivI (117) Fascaplysin Reagents and conditions i o-NO,C,H,COCHO heat; ii LiOH; iii 0 H, PtO,; iv NaNO, HC1 (109) 1 1 -Hydroxycanthin-6-one-N-oxide Scheme 20 Two new cyclic peptides microsclerodermins A (120) and B Q-soMe a-JNH2 N\’ (121) have been isolated from a deep water sponge of the genus Microscleroderma.61 Their structures were determined by / 0 0 (1 10) 2-Methoxycanthin-6-one (111) Ailanindole (1 12) Cuscutamine (1 13) 7-Hydroxyrutaecafpine A new quinazolinocarboline alkaloid 7-hydroxyrutaecarpine (113) has been isolated from the heartwood of Tetradium glabrifolium and the fruit of T.ruti~arpum.~~ A formal synthesis of nauclefine (114) has been reported (Scheme 19).59 The amidine (1 16) is prepared in three steps from the enolate (1 15) of (3-cyanopyridin-4-y1)acetaldehyde.The conversion of (1 16) into nauclifine (1 14) had been previously recorded. (1 14) Nauclepe (1 16) Reagents i tryptamine HCI; ii HCl iii silica gel Scheme 19 Facile synthesis of fascaplysin (1 17) isolated from the Fijian sponge Fascaplypsinopsis Berquist sp. has been reported (Scheme 20).60 Reaction of the iminophosphorane (1 18) with an arylglyoxal causes the aza Wittig-electrocyclic ring closure to afford the 1-aroyl-P-carboline (1 19) which is converted into fascaplysin (1 17) in three steps.Nitramarine (97) has been synthesized by a similar key reaction.60 interpretation of spectral data. Both compounds inhibit the growth of Candida albicans. (120) Microsclerodermin A R = OH (121) Microsclerodermin B R = H (122) Phakellistatin 10 A novel tryptophan derivative phakellistatin 10 (122) has been found from a marine sponge Phakellia The natural product inhibits the growth of the murine P-388 lymphocytic leukemia and human cancer cell lines. Three tryptophan derivatives halicylindramides A (123) B (124) and C (125) have been obtained from the Japanese marine sponge HaZichondria ~ylindrata.~~ Their total structures including absolute stereo- chemistry have been established by a combination of spectral and chemical methods.Halicylindramides A-C are antifungal NATURAL PRODUCT REPORTS 1996 Br' (123) HalicylindramideA R' = H; R2 = Me (124) Halicylindramide B R' = Me; R2 = H (125) Halicylindrarnide C R' = R2 = Me (126) Keramamide F against Mortierella ramanniana and cytotoxic against P-388 murine leukemia cells. A study directed towards the synthesis of keramamide F (126) isolated from the Theonella sponge has been Details about a total synthesis of (+)-jasplakinolide (jaspamide) (127) have been published.65 A facile solid-phase route to the spider toxins based on the orthogonally N-protected key component (128) has been developed.This intermediate (128) was coupled via the aspartyl- Fmoc-N 0 (128) Fmoc =9-fluorenylmethyloxycarbonyl OH I (1 27) Jasplakinolide P-carbonyl group to a solid support and the complete assembly of a wide range of polyamine peptides was achieved using continuous-flow solid-phase methodology. Two natural nephila- toxins NPTX-9 (129) and 11 (130) have been synthesized by this procedure.66 Two new ,!?-carboline alkaloids xestomanzamines A (1 3 1) and B (132) and a new manzamine-type alkaloid manzamine X (133) have been isolated as cytotoxic constituents from an NH-Dde Dde = "1 -(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl] NH2 (129) NPTX-9 NH2 (130) NPTX-11 NATURAL PRODUCT REPORTS 1996M.IHARA AND K. FUKUMOTO Okinawan marine sponge of Xestospongia sp. Another new their structures elucidated on the basis of extensive 2D NMR These compounds (138) and (139) manzamine-type alkaloid manzamine Y (134) has been found and chemical correlation~.~~ in an Okinawan marine sponge of Huliclona sp. The structures are the first examples possessing opposite absolute configur-of these alkaloids were elucidated on the basis of 2D NMR and ations to those of manzamine alkaloid^.^^ X-ray analy~es.~'Manzamine Y (6-hydroxymanzamine A) U (134) has also been isolated from an Okinawan marine sponge of the genus Amphimedon in addition to the novel manzamine-type alkaloid 3,4-dihydromanzamine A (135).6s HO N+ Q-N Me (131) Xestomanzamine A 3,4-dehydro (133) Manzarnine X (132) Xestomanzamine B 3,4dihydro HO 0 'N H (134) (135) ManzamineY (6-HydroxyrnanzamineA) 3,4-DihydromanzarnineA Two new manzamine-type alkaloids (136) and (137) have been further isolated from Papua New Guinea sponges of the genera Petrosiu and Cribochulina which are in different families of the order Haplos~lerida.~~ Two new manzamine-related alkaloids ircinols A (138) and B (139) have been isolated from an Okinawan marine sponge of the genus Amphimedon and Baldwin and Whitehead have proposed that the central tetracyclic ring system of manzamines could be biosynthesized via an intramolecular Diels-Alder reaction of the tricycle (140) wherein the diene component is a dihydropyridine and the dienophile a conjugated iminium An approach to the manzamine alkaloids based on this putative biogenesis has been investigated using a simple model system (Scheme 21) and the key cycloaddition step giving (141) was effected in moderate yield.73 fiN + __c +0 i __c ii p- LcF3c02-&\ (141) Reagents and conditions i TFAA; ii pH 8.3 then NaBH Scheme 21 The AD part (144) of manzamines has been synthesized by the cyclization of the iodide (143) derived from (142) (Scheme 221.74 OTHP R (142) ToH ~ iii-iv YES crl OTHP (136) R=Me (138) lrcinolA (137) R=H I 1v-vii Boc (144) R = (CH2)40Me Reagents and conditions i BuLi HC-C(CH,),OTHP; ii Ph,P DEAD SESNHBoc; iii Bu,NF; iv p-TsOH; v NaIO then heat; v H, Pd-BaSO, quinoline; vi MsC1 Et,N; vii NaI; viii KOBut (139) lrcinol B Scheme 22 NATURAL PRODUCT REPORTS 1996 An enantioselective synthesis of the CE ring system (146) in It has been demonstrated that flustrarine B (153) is manzamines has been reported (Scheme 23).75 The key step quantitativelj ,,nverted into flustramine B N-1-oxide (1 54) by in the route to (146) is the intramolecular generation and treatment with acid and the reverse reaction is effected by rearrangement of the spiro-fused bicyclic ylide (145) from a treatment of (154) with base (Scheme 25)." copper carbenoid./ iii 08-(146) (145) Reagents and conditions i H,NNH, KOH ; ii Br(CH,),COCHN, Et,N; iii Cu(acac), heat Scheme 23 The ABC ring system (148) of manzamines has been constructed by a tandem sulfolene SO extrusion-intramolec-ular Diels-Alder reaction starting with (147) (Scheme 24).76 I CO2Et (147) Scheme 24 A new alkaloid flustramine E (149) has been isolated from the marine bryozoan Flustru foliuceu along with debromo- flustramine B (150).The structure (149) of flustramine E which shows inhibitory activity towards Rhizotoniu soluni and Botrytis cinereu has been established spectroscopically.77 Penicillium verrucosurn var. cyclopium isolated from ground cassava collected in Burundi produces a new mycotoxin roquefortine C (1 5 1) and a new structurally related metabolite (152).7s Y (149) Flustramine E (150) DebromoflustramineB -$ (151) Roquefortine C R = H (152) R=CHO (153) Flustrarine B (154) Flustramine B K1-oxide Scheme 25 (+)-Esermethole (155) has been prepared by reduction of (1 56) with sodium bis(2-methoxyethoxy)aluminium hydride (Scheme 26).80 The synthesis of the cyanide (158) a precursor for (& )-physostigmine (1 57a) has been carried out (Scheme 27).81Another synthesis of (+)-physostigmine (157a) and (+)-physovenine (1 57b) has been reported.@ Meo~-~CONHMe I Me (156) / NaAIH2(0CH2CH20Me)2 Me Me Me (155) (k)-Esermethole Scheme 26 CN qN COaEt 1 iiiv he (157a) (k)-Physostgmine X = NMe (157b) (&)-Physovenine X = 0 Reagents and conditions i CrO, aq.AcOH; ii MeMgI; iii Na,Cr,O, H,SO,; iv NaCN H,O DMSO heat; v K,CO, Me,SO Scheme 27 Optically active pseudophrynaminol (1 59) has been synthe- sized through an asymmetric nitroolefination by Fuji and co- workers (Scheme 28).83 Reaction of the lithium enolate of (160) with (161) gives (162) in high yield with high optical purity.( -)-Pseudophrynaminol (1 59) was then synthesized from (162). NATURAL PRODUCT REPORTS 199&-M. IHARA AND K. FUKUMOTO 251 The synthesis involves radical bromination of (1 63) followed by allylation of the resulting bromide (1 66) with allyltributyltin giving (167). The ally1 group is then converted into the prenyl group by oxidative cleavage and Wittig reaction. After removal of the carboxyl group of (1 68) the product (1 69)is transformed into the (+)-enantiomer (1 65).85 The above intermediate (167) is further converted into the unnatural enantiomer of (-)-pseudophrynaminol (1 59).86 The cyclic tryptophan tautomer (163) has been shown -(161) further to be a useful intermediate in the preparation of jig iii optically pure substituted derivatives of trypt~phan.~’~~~ A synthesis of (+)-debromoflustramine B (150) has been re-TOH corded.89 3 lsoprenoid lndole Alkaloids The structure and relative stereochemistry of a new type of indoloditerpenoid designated as emindole PA (1 70) isolated (159) (-)-Pseudophtynarninol from the mycelium of Emericella purpurea have been confirmed by chemical and spectroscopic investigati~n.~~ The novel Reagents i BuLi; ii 1 M HCl; iii SeO, ButOOH; iv TiCl, NH,OAc; Penicillium metabolites penitremones A (171) B (172) and C v MeNH, MgSO then LiAlH (173)have been characterized by spectral data as 1 O-keto- 1 1,33- Scheme 28 dihydro-variants of the penitrem indole-isoprenoid skeleton.” Four new anti-insect alkaloids schearinines A (174) B (175), Conformations of substituted hexahydropyrrolo[2,3-b]in-C (176) and a paxilline related compound (177) have been doles cyclic tautomers (163) and (164) of tryptophan have isolated from organic extracts of the sclerotioid ascostromata been studied in both solution and solid A diastereo-of Eupenicillium shearii.selective synthesis of the unnatural (+)-enantiomer (1 65) of the marine alkaloid (-)-debromoflustramine B (1 50) has been carried out from one (163) of cyclic tautomers (Scheme 29).H H c&-.!.!-OH (170) Emindole PA li d Br IHl PhS02 C02Me PhS02 C02Me (167) iii-v 1 II (171) Penitrernone A R = H (172) Penitremone B R = OH PhS02 C02Me (173) Penitrernone c H A khe (1 65) (+)-enf-DebromoflustramineB Reagents and conditions i NBS; ii CH,=CHCH,SnBu,; iii NaIO, OsO,; iv Ph,P=CMe,; v KOH; vi Barton’s reductive decar- bonylation; vii KOH; viii NaBH,CN CH,O; ix Na NH,; x I Me,C=CHCH,Br Scheme 29 (1 74) Schearinine A NATURAL PRODUCT REPORTS 1996 py+oH 0 A0 (175) Schearinine B (1 76) Schearinine C These extracts also afford five known related metabolites (1 78H180) (1 82) and (1 83).92These compounds were isolated from fractions displaying activity in dietary assays against the corn earworm Helicoverpa zea and the dried fruit beetle Carpophilus hemipterus and most of the compounds show potent activity in these assays.Shearinine B (175) causes significant mortality in a leaf disk assay against the fall armyworm Spodoptera frugiperda. Three metabolites (1 79) (181) and (1 84) have been isolated from Penicillium paxilli and Acremonium l~lii.~~ (177) R' =CH2CH=CMe2; R2 =OH; R3 =H (178) Paxilline R' =R3 =H; R2 =OH (179) R' =R2 =H; R3 =OH (180) 13-Dehydroxypaxilline R' =R2 =R3 =H (181) 7a-Hydroxypaxilline R' =H; R2 =R3 =OH H 0 H V'O/ 0 (1 83) Paspalinine 3.1 Ergot Alkaloids Ergot alkaloids have been reviewed from the pharmacological point of view.94 A proline-free ergopeptine-type alkaloid ergobalansinine (185) has been isolated from the seeds of Ipomoea piurensi~.~~ The structure of semisynthetic ergot derivative nicergoline (1 86) including its absolute configuration has been determined by X-ray 0 -H (1 85) Ergobalansinine (186) Nicergoline Two series of (5R,8R,10R)-s7 and (5R,8S,10R)-98 ergoline derivatives have been synthesized and their antihypertensive and dopaminergic activities have been evaluated in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra respectively.Some (5R,8R,10R)-derivatives show potent dop- aminergic activity while none of (5R,8S,10R) ones exhibit potent dopaminergic activity.Bovine p-1,4-galactosyltrans-ferase mediates the transfer of galactose from uridine 5'-diphosphogalactose and also the transfer of glucose from uridine 5'-diphosphoglucose to (1 87) yielding the respective diglycosides (188) and (189) (Scheme 30).99 1Galactosykransferase (188) R =axial OH -H (1 89) R =equatorial OH Scheme 30 Facile synthesis of Uhle's ketone (191) has been developed. In the presence of a large amount of oxocarbonium ion species generated from chloroacetyl chloride and aluminium chloride the acid chloride (190) reacts regioselectively to give a pivaloyl derivative of Uhle's ketone (191) (Scheme 31).'0° 253 NATURAL PRODUCT REPORTS 1996-M. IHARA AND K. FUKUMOTO 0 0-C-H 5a r H COCMe3 (190) (1911 Reagents i SOCl,; ii AlCl, ClCH,COCl; iii NaOMe Scheme 31 A possible synthetic intermediate (194) for ergot alkaloids has been synthesized from 4-carbomethoxyindole (1 92), (Scheme 32).lo1 The key step involves an intramolecular cyclization involving the ally1 cation derived from (193).C02Me C02Me 6- I I- i,ii &-JH~cI I t II H (192) Y S02Ph iii-viiI OMe CHO OMe I I S02Ph S02Ph (193) 1 ix -0Me S02Ph (194) Reagents 1 PhSO,Cl KOH Bu,NHSO,; ii Hg(OAc), AcOH HClO, NaCl; iii CH,=CHCH,Br Li,PdCl,; iv OsO, NMO then NaJO,; v Ph,P=CHOMe; vi DIBAL; vii MnO,; viii TMSCH,CBr=CH, Mg ;ix TiCl, N-methylaniline Scheme 32 A potential synthetic intermediate (1 98) for ergot alkaloids has been also synthesized by Padwa and co-workers (Scheme 33).lo2 The diazo imide (196) prepared from (195) was subjected to the intramolecular isomiinchone cycloaddition catalysed by rhodium(I1) perfluorobutyrate.The cycloadduct (197) obtained in excellent yield was converted into (198). However the desired isomerization of the double bond of (198) failed. Co-cyclization of 4-ethynyl-3-indoleacetonitrile(200) with an alkyne in the presence of CpCo(CO) afforded the ergoline derivative (201) in low yield which was transformed into racemic LSD (199) (Scheme 34).lo3 The total enantioselective synthesis of (-)-chanoclavine I (202) has been accomplished starting with indole-4-carbox- aldehyde (203) (Scheme 35).lo4 The key step from (204) to (205) which involves the formation of the C ring is catalysed by a chiral palladium(0) complexes.The chiral ergoline synthon (205) is produced with an excellent diastereo- and enantio-selectivity. 8-&-nH i-iii “BZ Y (195) &-: Me\ % ‘2 Y BZ (196) 1ix 0 Me02C.. BZ iv-vi 1 vii viii -c-Y BZ 0 H h H x-xii M*2cgH - \ Bz \ Bz (197) (198) Reagents and conditions i 0 then NaBH .ii MnO ;iii Ph,P=CH,; iv H,CrO,; v Im,CO; vi MeNH,; Zi ClCOCH,CO,Me; viii MsN, Et,N; ix Rh,(pfb),; x,BF +OEt,;xi PhOCSCl; xii Bu,SnH AIBN heat Scheme 33 Et2NOC H H ‘N H (200) (2011 (199) (k)-LSD Reagents i TMS-CEC-CONEt, CpCo(CO) ; ii CF,SO,Me ;iii NaBH CHO HO Scheme 34 AcOb (204)1vi NHMe c- H ‘ N H H (202) (-)-Chanoclavine I (205) Reagents i (MeO),POCH,CO,Me K,CO ; ii DIBAL; iii Ac,O NEt,; iv Me,NCH=CHNO, TFA; v NaBH,; vi Pd(OAc), (S)-(-)-BINAP K,CO,; vii Zn-Hg HC1; viii (Boc),O DMAP; ix OsO, NMO then NaIO,; x Ph,P=C(Me)CO,Me; xi LiAlH Scheme 35 An efficient synthesis of claviciptic acid (206) has been achieved via palladium catalysed reactions (Scheme 36).lo5 The vinylation of the bromide (207) in the presence of a stoi-chiometric amount of palladium(1r) gave selectively the alkene (208).The asymmetric reduction of (208) followed by the Heck reaction in the presence of Ag,CO provided (209) which was transformed into trans- and cis-claviciptic acids (206). v vi I H I1 H (206) Claviciptic Acid Reagents i Pd(OAc), NaHCO, 0,; ii Rh(cod),BF, DIPAMP H,; iii CH,=CHC(OH)Me, PdC12(PPh3), Ag,CO, Et,N ;iv HCl then Et,N; v Mg MeOH; vi KOH Scheme 36 4 Bisindole Alkaloids New antifungal bisindole alkaloids hamacanthins A (2 10) and B (211) have been isolated from a deep water marine sponge Hamacantha sp.lo6 They are growth inhibitors of Candida albicans and Cryptococcus neoformans.Two new metabolites asterridinone (ARD) (2 12) and ARQ monoacetate (2 13) have been found in mycelium of Aspergillus terreous IF0 6123 producing asterriquinone (ARQ).lo7 Sciodole (2 14) has been (210) Hamacanthin A (21 1) Hamacanthin B NATURAL PRODUCT REPORTS 1996 isolated from fruit bodies of Tricholoma sciodes.lo8 The compound (214) has not been reported as a natural product but is formed when lasicivol the bitter principle of T.lascivum is treated with acid in methanol. A novel antimicrobial substance (2 15) showing a specific inhibition against Bacillus subtilis has been obtained from a strain of the bacterium genus Vibri~.~~~ The ethyl acetate extract of the whole culture medium of Vibrio parahaemolyticus which inhibits the toxic mucus of the box fish Ostracion cubicus afforded a new indole alkaloid vibrindole A (216)."* A new antibiotic indole trimer named trisindoline (217) has been isolated from the culture of a bacterium of Vibrio sp. which is separated from the Okinawan marine sponge Hyrtios altum."' (212) Asterridinone (ARD) (213) ARQ monoacetate Meoh Me 6 (214) Sciodole (215) H H H (216) Vbrindole A (217) Trisindoline NATURAL PRODUCT REPORTS 1994-M.IHARA AND K. FUKUMOTO r 1 The synthesis of eudistomin U (218) has been carried out in five steps (Scheme 37).l12 The key step formation of the p-carboline ring (2 19) involves a tandem aza-Wittig electrocyclic ring closure process. Nortopsentin D (220) has been synthesized by use of a L J successive and regioselective diarylation in which (221) is treated with N-silylated 3-indolylboric acid in the presence of a palladium(0) catalyst (Scheme 38).113 Mom The total synthesis of the cytotoxic marine alkaloid (&)-dragmacidin (222) has been reported (Scheme 39)."* The synthesis proceeds through the reaction of the amine (223) with the acid chloride (224). The product (225) is converted in two steps into an intermediate (226) containing the central diketopiperazine ring which after reduction and deprotection affords the racemic natural product (222) along with its cis-OmJ -QriJ isomer.New cytotoxic epipolysulfanyldioxopiperazinedimers lepto-H Y Mom sins A (227) B (228) C (229) D (230) E (231) F (232),115G (218) Eudistomin U (219) (233) G (234) G (235) H (236),116K (237) K (238) and K (239),117have been isolated from the mycelium of a strain of Reagents and conditions i Bu,P; ii Pd-C xylene heat; iii HC0,H; Leptosphaeria sp. attached to the marine alga Sargassum iv LiOH; v Cu quinoline heat tortile. Leptosins A (227) and C (229) exhibit significant Scheme 37 antitumor activity against Sarcoma 180 ascites. I SEM TBDMS TBDMS H H (220) Nortopsentin D (22 1) Reagents i Pd(PPh,), Na,CO,; ii ButLi then H,O; iii Bu,NF Scheme 38 NHMe I (224) + ii iii __c H (225) t H? Br OH Br H (222) (k)-Dragmacidin Reagents and conditions i Et,N; ii NH,OH H,O, Bu,NHSO,; iii NH,OH heat; iv BH,; v BBr Scheme 39 0 A A (227) Leptosin A x= 4 (230) Leptosin D x= 2 (228) Leptosin B x= 3 (231) Leptosin E x= 3 (229) Leptosin C x= 2 (232) Leptosin F x= 4 A A (233) Leptosin G x= 4; y= 3 (237) Leptosin K x= 2 (234) Leptosin GIx= 3; y= 3 (238) Leptosin K1 x = 3 (235) Leptosin G2 x= 2; y= 3 (239) Leptosin K2 x = 4 (236) Leptosin H x= 2; y = 4 The tetraiodomethane mediated dimerization of an oxindole (241) at the C(3) position to form a benzylic quaternary carbon-carbon bond has been reported (Scheme 40).A radical anion chain mechanism is proposed for the reaction. The dimeric product (242) is transformed into (& )-folicanthine (240) by a series of reductions after amidation.'l8 Me fJ--~c~t i I I Me Me (241) (242) I ii Me Me Me &?? -iii iv / Mec%o CONHMe \ YY Yo Me Me Me (240) (*)-Folicant hine Reagents i NaH CI,; ii Me,Al MeNH,; iii LDA DIBAL; iv NaA1H,(OCH,CH,0Me)2 Scheme 40 NATURAL PRODUCT REPORTS 1996 The stereoselective total synthesis of amauromine (243) has been accomplished by Danishefsky and co-worker~.~'~ Phenyl-selenenylation of (246) followed by treatment of the resulting (247) with methyl triflate and prenyl tributylstannane provided (248).BOP chloride-mediated coupling of (249) with (250) pro- vided the peptide (25 I) readily convertible into amauromine (243) (Scheme 41). The acid (250) was further transformed into ardeemin (244) and 5-N-acetylardeemin (245).'19 Boc Boc Boc (246) (247) 1 ii BOC Boc R " R (250) (248) R=Boc iv L (249) R = H (243) Amauromine (244) Ardeemin R = H (245) 5-NAcetylardeemin R = Ac Reagents i N-phenylselenophthalimide,p-TsOH Na,SO ;ii MeOTf CH,=CHCMe,SnBu, 2,6-di-tert-butylpyridine; iii NaOH ; iv TMSI; V (249) BOP-C1 Et,N Scheme 41 NATURAL PRODUCT REPORTS 1996-M. IHARA AND K. FUKUMOTO Born Born The total synthesis of gypsetin (252) an inhibitor of the I -enzyme acylCoA :cholesterol acyltransferase (ACAT),has been published.120 Introduction of the 'reverse prenyl ' function at the C (2) position of the indole (253) has been achieved by treatments with tert-butyl hypochlorite followed by prenyl-9- BBN (Scheme 42).After conversion of the product (254) into (255) oxidation with dimethyldioxirane provides gypsetin (252) along with two stereoisomers. Oxidation of the phenolic carbazole (256) with di-tert-butyl peroxide yields the parent framework (257) of dimeric carbazole (253) J II 1ii I (252) Gypsetin Reagents i ButOCI Et,N then prenyl-9-BBN; ii dimethyldioxirane Scheme 42 QKyj;:e Et0&"i" (259) Reagents i (ButO),; ii O, PriNH Scheme 43 i,ii I SEM iii Born Born 1v-ix Born I x-xii - xviii-xxi - NHBOC NHMe (260) Staurosporine Reagents and conditions i indole Grignard; ii NaH SEMCl; iii indole Grignard; iv NaH; v Cl,C=S DMAP pyridine C,F,OH; vi Bu,SnH AIBN; vii DDQ; viii Bu,NF; ix hv cat.I, air; x I, PPh,; xi DBU; xii ButOK I,; xiii Bu,SnH AIBN; xiv H, Pd(OH) then NaOMe; xv (Boc),O DMAP; xvi NaH BomCl; xvii Cs,CO,; xviii NaH Me,SO,; xix H, Pd(OH) then NaOMe; xx TFA; xxi NaBH then PhSeH p-TsOH Scheme 44 NATURAL PRODUCT REPORTS 1996 alkaloids (Scheme 43).lZ1 Autoxidation of (258) in the presence of diisopropylamine produces the trichotomine derivative (2 59). The first total synthesis of staurosporine (260) an inhibitor of protein kinase C (PKC) has been accomplished by Danishefsky and co-workers (Scheme 44).lZ3 The key step is the intermolecular indole glycosylation.Thus the reaction of (261) with the epoxide (262) in the presence of sodium hydride produces (263) which is transformed into (264) via photolytic oxidative cyclization. The intramolecular glycosylation is carried out by treatment of the em-glycal with potassium tert-butoxide and iodine forming (265). The final regioselective reduction of the imide derivative is achieved by reduction with sodium borohydride followed by deoxygenation using benz- eneselenol. Several approaches to the staurosporine aglycone arcyria- A flavin A (266) have been e~amined.l~~-'~' route to its analogue (267) possessing an oxazol-2-one heterocycle instead of a maleamide one has been recorded.lZ8 H OQO (266) Arcyriaflavin A 0il,NH Full details on isolation of potent antitumour antibiotics duocarmycins A (268) Cl (269) Bl (270) C2 (271) B2 (272) D (273) and SA (274) have been p~b1ished.l~~ Synthetic and mechanistic studies on duocarmycins by Boger and his group have been re~0rted.l~~ (268) Duocarmycin A (269) Duocarmycin C1 X = CI (270) Doucarmycin B1 X = Br COae -...k 0 (271) Duocarmycin C2 X = CI (272) Doucarmycin 82 X = Br C02Me -*..LO " OMe (273) Duocarmycin D Me02C HNh 0 0&KO H (274) Duocarmycin SA &Me HN 0 OH OMe (275) CC-1065 MQC HNb;j HNN.;j 0 / / OAOBut OAOBu' (276) NBw-DSA (277) NBoc-CPI OAOBut OAOBu' (278) NBoc-CBI (279) N-Boc-CI The doucarmycins and (+)-CC-1065 (275) constitute the parent agents of a class of potent antitumor antibiotics that derive their biological properties through a sequence selective alkylation of DNA.Therefore synthetic study of the alkylating subunits such as (276)-(279) is very attractive. To this end a NATURAL PRODUCT REPORTS 1996M. IHARA AND K. FUKUMOTO synthesis of (28 l) the synthetic precursor of N-Boc-CBI (278) has been developed based on a 5-em-trig aryl radical cyclization of (280) followed by TEMPO trapping (Scheme 45).131 I $ eNB- OBn ii iii I OB" (281) Reagents i Bu,SnH; ii Zn AcOH; iii PPh, CC1 Scheme 45 1 I Scheme 46 I S02Ph (285) (286) R = I C(287) R=OH PhS02 -N&y OH PhS02 -Na .(-Me0 Me0 Reagents i ButLi Cp,ZrMeCI; ii I,; iii BBr,; iv NaH; v Ag,O silica gel; vi Pd(PPh,),; vii CSA Scheme 47 Two research groups have reported a new methodology for the construction of indolines using zirconocene methyl chloride.(Schemes 46 and 47). The key step for the synthesis of compound (284) by Tidwell and Buchwald (Scheme 46)132 involves the generation of a zirconocene-stabilized benzyne complex and a subsequent intramolecular alkene insertion reaction to provide the tricyclic indoline zirconacycle (282). The zirconacyclic intermediate (282) is cleaved with iodine to diiodo indoline (283) which is converted into compound (284). Tietze and Buhr have similarly synthesized the indoline (286) starting with (285).After conversion to the alcohol (287) the Heck reaction of (287) produces a mixture of compounds (288) and (289)133 (Scheme 47). 5 References 1 I. Lacroix D. Buisson M. Philippe and R. Azerad Nut. Prod. Lett. 1995 7 15. 2 S. Takekuma H. Takekuma Y. Matsubara K. Inaba and Z. Yoshida J. Am Chem. Soc. 1994 116 8849. 3 Y. Kamano H.-P. Zhang Y. Ichihara H. Kim K. Komiyama and G. R. Pettit Tetrahedron Lett. 1995 36 2783. 4 H.-P. Zhang Y. Kamano Y. Ichihara H. Kim K. Komiyama H. Itokawa and G. R. Pettit Tetrahedron 1995 51 5523. 5 V. Kumar H. N. K. Bulumulla W. R. Wimalasiri and J. Reisch Phytochernistry 1994 36 879. 6 T.-S. Wu Y.-Y. Chan Y.-L. Leu and S.-C. Huang Phyto-chemistry 1994 37 287. 7 K. Monde M.Takasugi and A. Shirata Phytochemistrv 1995,39 581. 8 Y. Ouyang K. Koike and T. 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ISSN:0265-0568    

DOI:10.1039/NP9961300241

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Book Review Enzyme Catalysis in Organic Synthesis A Comprehensive Handbook By K. Drauz and H. Waldmann VCH Weinheim 1995 2 volumes xxv+ 1050 pp. Price E180 DM 498 ISBN 3527284796 Biotransformations are like swimming. Some people want to do it but don’t seem to get round to it others get by perfectly well without whilst enthusiasts spare no opportunity to promulgate the advantages for health wealth and happiness. Like any new experience sparing time to get started is the most difficult part. Drauz and Waldmann’s Comprehensive Handbook is a magnificent springboard into the murky waters of biotransformations. The 1050 pages are contributed by 53 coauthors and consequently each comparatively short con- tribution retains it freshness. The first volume covers general aspects of biotransformations plus the formation and cleavage of C-0 and C-N bonds.The second volume deals in a similar way with P-0 and C-C bonds plus redox reactions isomerisa- tions catalytic antibodies enzymatic sensors protein en-gineering and extremophiles. I looked first at the section on Baeyer-Villigerases which is my current interest (and to see if I had been cited!). 27 pages exhaustively covered this comparatively minor area and as far as I could tell nothing had been missed. The lipase (or esterase) catalysed cleavage of esters is the most frequently used transformation. No cofactors or special conditions (except pH control) are required and the reactions can be run in water water immiscible organic solvents and mixtures of the two.The chapter on the hydrolysis and formation of C-0 bonds commences with half a page of text followed by five pages of generously spaced diagrams and the recommendation that a continuous flow membrane reactor is useful for large scale synthesis. This part of the chapter is unlikely to make any converts. However the later sections are packed with tables containing literally hundreds of examples. It is difficult to image any alcohol or carboxylic acid from organometallics to complex natural products for which it would not be possible to find a close analogue here. In contrast the following chapter describes the hydrolysis and formation of glycosidic bonds which requires more sophisticated methodology. The complex and expensive nucleo- tide cofactors that are required for the Leloir glycosyl transferases are an almost insurmountable obstruction to stoichiometric synthesis.However many enzymes operate under broadly similar conditions and hence the cofactors can be regenerated in situ by the requisite enzymes. This principle has been utilized in extremely elegant multienzyme multigram- scale syntheses of disaccharides. There is clearly enormous potential for further development of multienzyme systems as shown by Scott’s one-pot synthesis of Vitamin BIZ. The synthesis of complex natural oligo- and poly-saccharides is an area that has lagged well behind that of other biopolymers such as proteins and nucleic acids. On one hand 30-residue polypeptides are routinely made by solid phase synthesis and much longer proteins can be obtained by genetic manipulation.On the other hand abiotic synthesis of polysaccharides with six or more residues can only be achieved by a handful of research groups and manipulation of the biosynthetic pathways is still in its infancy. Isolated enzymes acting on solid phase supported substrates offers one of the best prospects for viable poly- saccharide synthesis. The chapter on nitrile hydrolysis describes acylamide production which is one of the resounding successes of large scale biotransformation. The preferred abiotic manufacturing process is the Raney Copper catalysed hydration of acrylonitrile at a concentration of 300 g lkl whereas the nitrile hydratase 263 from Rhodococcus rhodochrous J 1 catalyses the same reaction at a concentration of 700 g 1-’.The Nitto chemical company in Japan runs this process at 10000 tons per annum against a world production of 200000 tons per annum. The division of any book into chapters inevitably results in some compromises in the way that the work is presented. The use of yeast for the reduction of carbonyl compounds is now virtually commonplace and naturally this work is discussed in the chapter on reductions. However the casual reader will miss the sundry other reactions which yeast catalyse which are located in other chapters. This may result in some surprises in the laboratory ! The impetus for using biotransformations is of course the fact that the reactions are enantioselective in principle if not in practice.It is worthwhile to reflect on where they will find their place within the spectrum of chirotechnology. Classical resolution is still paramount in pharmaceutical development where both enantiomers are required. Moreover as Woodward pointed out the wrong enantiomer provides the perfect model substrate for testing reactions. Chiral pool synthesis from sugars amino acids etc. was used in virtually all the major syntheses of natural products in the eighties. However this strategy requires prolonged molecular surgery or butchery (depending on your point of view) to excise the requisite synthon. Finally abiotic asymmetric synthesis now rivals biotransformations to the extent that artificial enzymes can now be used as catalysts.The fundamental advantage of enzymes is that they have been subjected to evolution and hence are optimized although these adaptations may not be optimal for the biotransformation in the laboratory. Moreover the full force of biotechnology can be brought to bear on their development by site directed random mutagenesis or strain selection cloning and overexpression. These are powerful techniques which are only now being mimicked in asymmetric synthesis although combination chemistry catalytic asym- metric automultiplication (i.e. self catalysis)’ and chiral amplification have the potential to rival them. Prior to the 1980s biotransformations were barely recognized by synthetic organic chemists.2 However the last decade has seen a rich feast of books.Our slim volume Biotransformations in Preparative Organic Chemistry3 was superseded by Biotrans-formations in Organic Chemistry4 and Selective Biocatalysis.’ Last year saw the long awaited Enzymes in Organic Synthesis6 by Wong and Whitesides which is undoubtly the best text to recommend for students. Meanwhile Preparative Biotrans- formations’ continues to produce supplements which are growing into the equivalent of Organic Syntheses. However in this rapidly developing field few books have a worthwhile life span beyond five years. Nevertheless Enzyme Catalysis in Organic Synthesis will last longer than most and should be in the library of any institution where biotransformations are practised. David R. Kelly University of Wales Cardif UK References 1 T.Shibata H. Morioka T. Hayase K. Choji and K. Soai J. Am. Chem. Soc. 1996 118 471. 2 For a notable exception see Klaus Kieslich Microbial Transforma- tions of Non-steroid Cyclic Compounds Georg Thieme Verlag Stuttgart 1976. 3 H. G. Davies R. H. Green D. R. Kelly and S. M. Roberts Biotransformations in Preparative Organic Chemistry Academic Press London 1989. 4 K. Faber Biotransformations in Organic Chemistry Springer-Verlag Heidelberg 1992. 5 L. Poppe and L. Novak Selective Biocatalysis VCH Weinheim 1992. NATURAL PRODUCT REPORTS 1996 6 C.-H. Wong and G. M. Whitesides Enzymes in Organic Chemistry Tetrahedron Organic Chemistry Series no. 12 Pergamon Press Oxford 1994. 7 S. M. Roberts Preparative Biotransformations Wiley Chichester 1993.

ISSN:0265-0568    

DOI:10.1039/NP9961300263

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Hot off the Press Robert A. Hill' and Andrew R. Pitt2 'Department of Chemistry Glasgo w University Glasgow G 12 8QQ,UK.E-mail bobh@chem.gla.ac.uk Department of Pure and Applied Chemistry Strathclyde University Thomas Graham Building 295 Cathedral Street Glasgo w G1 1x1,UK. E-mail a.r.pitt@strath.ac.uk Reviewing the recent literature on natural products and bioorganic chemistry Assufulvenal (1) is an interesting bis-sesquiterpenoid found in Joannesia princeps (H. Achenbach et al. J. Nut. Prod. 1996 59 93). Assufulvenal (1) is formed from a guaiane and patchoulane sesquiterpenoid with the connecting bond forming part of a fulvene system. The structure of assufulvenal (1) was confirmed by X-ray analysis. X-ray analysis was also used to determine the structure of terracinolide A (2) from Euphorbia terracina which has a novel bishomoditerpenoid skeleton formally derived from the jatrophane skeleton by the addition of two carbons to C-17 (J.A. Marco et al. J. Org. Chem. 1996 61 1707). .O VL .K 1-H 'OAc Botryoxanthin A (3) from the green microalga Botryococcus braunii is a new type of metabolite with a ketocarotenoid linked to a tetramethylsqualene derivative (S. Okada et al. Tetra-hedron Lett. 1996 37 1065). A new class of 12-membered ring macrolide amphidinolide Q (4) with a novel carbon skeleton has been isolated from the dinoflagellate Amphidinium sp. (J. Kobayashi et al. Tetrahedron Lett. 1996 37 1499). ($'OMe Broad screening for molecules with TaxolWke activities against microtubule formation has identified (+)-discodenno-lide (5) from Discoderma dissoluta as a significantly more active agent with an IC, of 3.2 pM (TaxoP 23 pM)in some assays (Biochemistry 1996 35 243).A new metabolite L-755,807 (6) has been isolated from an endophytic Microspaeropsis sp. (Y. K. T. Lam et al. Tetrahedron 1996 52 1481). The metabolite L-755,807 (6) is a bradylunin binding inhibitor and has an unusual ring system that may be derived from valine by analogy with tenellin biosynthesis. Tricycloillicinone (7) from IlZicium tashiroi is a prenylated C,-C compound that has been cyclised in an interesting way (Y. Fukuyama et al. Chem. Pharm. Bull. 1995 43 2270). Mimosifolenone (8) from the root wood of Aeschynomene mimosifolia contains an usual cycloheptenone ring which presumably is formed biogenetically by ring enlargement of an aryl ring (F.Fullas et al. J. Nut. Prod. 1996 59 190). A compound (9) with a new bicyclic sesquiterpenoid skeleton has been isolated from Lippia integrifolia (C. A. i\J. Catalan et al. J. Nut. Prod. 1995 58 1713). The new skeleton is probably derived from the co-occurring 1-hydroxylippifolian-5-one(10) by ring opening of the cyclopropane ring together with methyl migration. The absolute configuration of dolabellatrienone (1 1) has been revised on the basis of an enantioselective synthesis and the crystal structure of an intermediate carboxylic acid as an amide with (R)-a-methylbenzylamine (E. J. Corey et al. J. Am. Chem. SOC.,1996,118,1239). This result means that the absolute configuration of several dolabellane diterpenoids should be revised.... 111 NATURAL PRODUCT REPORTS 1996 OYO$N OH 0 OH 0 HO AcO Stoloniolide I (12) from the Okinawan soft coral Clavularia viridis has a 1,lO-cleaved ergostane skeleton (K. Iguchi et al. Chem. Lett. 1995 1109). The authors postulate that stolo- niolide I (12) is derived biogenetically from a co-occurring stoloniferone such as stoloniferone B (13) by nucleophilic attack at the carbonyl followed by ring opening of the epoxide. A deep-water marine sponge Scleritoderma sp. CJpaccardi has been shown to contain the ergost-7-en-3P-01 derivative (14) which contains an unusual naturally-occurring methoxymethyl ether (S. P. Gunasekera et al. J. Nat.Prod. 1996 59 161). W. D. Nes and co-workers have demonstrated the stereo-chemistry of migration of the C-24 hydrogen to C-25 when lanosterol (1 5) is transformed into ergosterol (1 6) (Tetrahedron Lett. 1996 37 1339). T. J. Simpson and co-workers have studied the substrate specificity for the starter unit in norsolorinic acid (17) biosynthesis by cultures of Aspergillus parasiticus (J. Chem. Soc. Chem. Commun. 1996,301). They found that norsolorinic acid synthase would accept N-acetylcysteamine (NAC) thio-esters of the natural hexanoic acid and the unnatural pentanoic and 6-fluorohexanoic acids but not the NAC thioesters of butanoic heptanoic or octanoic acids. The NAC thioester of 2- fluorohexanoic acid was also not incorporated but interestingly it appeared to inhibit the production of norsolorinic acid (1 7).Biosynthetic studies on pyripyropene A (18) are consistent with the biosynthetic pathway involving nicotinic acid acting as a starter unit for the addition of two acetate units and that this is joined to a sesquiterpenoid moiety. (S. Omura et al. J. Org. Chem. 1996 61 882). This is the first report of nicotinic acid being the starter unit in polyketide biosynthesis. Sistodiolynne (19) and sistopyrone (20)are unusual metabo- lites of the wood rot decay fungus Sistotrema raduloides (W. A. Ayer and co-workers Can. J. Chem. 1995 73 21 19). Acetate labelling studies have shown that they are norpentaketides and that the pyrone ring of sistopyrone (20) is probably derived by ring opening of the cyclopentane ring of sistodiolynne (19).Further steps are being taken in the race to engineer a polyketide synthase (PKS) to produce new polyketide anti- biotics. Khosla and Kane report the first comprehensive kinetic study of a fully active modular PKS (6-deoxyerythronolide B synthase) measuring rates buffer effects and affinities for different starter units (Biochemistry 1996 35 2054). Differences in the levels of ($13~ values) have been used to distinguish between carbons derived from the tetrahydrofolate C pool (613~= -2 1.7Oh) and the S-adenosylmethionine C pool (813 < -39 %) (T. Weilacher et al. Phytochemistry 1996 41 1073). The differences are attributed to different isotope effects operating in the two pathways. Baldwin's group have produced evidence for an insertion- N = steroidal nucleus 0 homolysis mechanism for carbon-sulfur bond formation in penicillin biosynthesis by using a series of tripeptides to probe the mechanism of isopenicillin N-synthase (Tetrahedron 1996 52 2515 2537).A. I. Scott and co-workers have provided additional evidence for the existence of two different mechan- isms for the ring contraction in vitamin B, biosynthesis (J. Am. Chem. SOC.,1996 118 1657). The anaerobic route features early insertion of the cobalt and the involvement of the ring A acetate carboxyl group in the ring contraction. In the aerobic route 0 is used to set up the pinacolic ring contraction and cobalt is inserted afterwards. F. J. Leeper and co-worker have demonstrated that 5-amino- 3-thialaevulinic acid (2 1) is a potent inactivator of 5-aminolae- vulinic acid dehydratase (J.Chem. SOC.,Chem. Commun. 1996 303). They have shown using electrospray MS that the enzyme becomes acylated by the 5-amino-3-thialaevulinic acid (21). A kinetic study of the deactivation indicated that two molecules of the inhibitor bind before the inactivation reaction occurs. This suggests that imine formation to 5-aminolaevulic acid (ALA) (22) does not occur until two molecules of ALA are in the active site. \ .S An extensive study of the stereochemical consequences of the carboxylate migration step of tropic acid biosynthesis (Scheme 1) has elucidated the complete mechanism and demonstrated that back migration of the hydrogen does not occur (N.C. J. E. Chesters et al. J. Am. Chem. SOC.,1996,118,925). Labelling studies using N-methylpyrrolidine-2-acetic acid (23) do not support the previous claims that it is a precursor of the tropane alkaloids such as hyoscyamine (24) (M. N. Huang et a/. Phytochemistry 1996 41 767). Scheme 1 NATURAL PRODUCT REPORTS 1996-HOT OFF THE PRESS 0 (24) Acetonedicarboxylic acid was first suggested as a biosynthetic precursor to many alkaloids such as the tropane alkaloids by Sir Robert Robinson in 191 7. However biosynthetic studies have not supported this hypothesis. I. D. Spenser now has the first claim of evidence of direct incorporation of acetonedi- carboxylate into an alkaloid namely lycopodine (25) Cane and Xue have genetically manipulated the sesquiterpene cyclase trichodiene synthase altering amino acids at the active site that may be involved in phosphate binding (J.Am. Chem. Soc. 1996 118 1563). Mutating tyrosine 305 to phenylalanine or tryptophan results in the formation of three new sesqui- terpenes as well as trichodiene (Scheme 2) indicating that it will be possible to generate new natural products by the genetic manipulation of proteins. For the first time a recombinant hydroxynitrile lyase has been expressed in Escherichia coli. The cloned gene product from Manihot esculenta gives enantioselective formation of cyano- hydrins with a range of aldehydes and ketones with ee’s in excess of 85 % in most cases (S. Foster et al. Angew. Chem.Znt. Ed. Engl. 1996 35 437). A novel efficient method for the regeneration of NADPH has been developed by Seebach’s group using a formate dehydrogenase engineered to accept NADPH (Tetrahedron Lett. 1996 37 1377). C. R. Johnson and co-workers have produced a very readable review describing recent advances in enantioselective synthesis through enzymatic asymmetrisation (Tetrahedron 1996 52 3769). They describe the production of enantiopure compounds from prochiral substrates using enzymatic procedures. A. Spatenstein et al. have developed a novel highly active protease inhibitor (26) which is effective against the chymo- trypsin-like activity of porcine endothelial cell derived proteo- somes (Tetrahedron Lett. 1996 37,1343). Based upon an a$-epoxyketone it is effective at nM concentrations.A new twist to the study of C-glycosides as inhibitors of glycosidases has been reported by J.-F. Espinosa et al. NMR has been used to probe the conformations of glycosides bound to ricin B which appears to select different conformers for a pair of 0-and C-glycosides (Angew. Chem. Int. Ed. Engl. 1996 35 303). CBz-He-lie-N trichodiene synthase *w OPP geranyl pyrophosphate trichodiene An iteratively designed 23-residue peptide base on the zinc finger motif has been synthesised. It has a self-assembling defined tertiary structure formed around a hydrophobic core. Y305F Y305W The peptide folds and is stable without the need for metal ions or disulfide bridges (M. J. Struthers et al. Science 1996 271 342). E. Haslam has reviewed the possible use of vegetable tannins as drugs to ameliorate or prevent various diseases (J. Nat. Prod. 1996 59 205). It seems possible that the natural polyphenols may act by complexing with metals acting as antioxidants or by associating with peptides and proteins. However evidence for their remedial effects is based largely on Scheme 2 epidemiological studies rather than scientific observation.

ISSN:0265-0568    

DOI:10.1039/NP996130iiic

出版商:RSC    

年代:1996

数据来源: RSC