摘要:

ISSN 0265-0568 NPRRDF 5(6) 541-663 (1988) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 5 Number 6 CONTENTS 541 Synthesis of Gibberellins and Antheridiogens L. N. Mander Reviewing the literature published to June 1988 581 Natural Products from Plant Tissue Culture B. E. Ellis Reviewing the literature published between January 1979 and December 1986 613 Marine Natural Products D. J. Faulkner Reviewing the literature published between September 1986 and December 1987 Cumulative Contents of Volume 5 Number 1 1 Prostaglandins Thromboxanes Leukotrienes and Related Arachidonic Acid Metabolites (1983 and 1984) T. W. Hart 47 Antibiotics with Antifungal and Antibacterial Activity Against Plant Diseases P.A. Worthington 67 Tropane Alkaloids (July 1985 to December 1986) G. Fodor and R. Dharanipragada 73 The Biosynthesis of Shikimate Metabolites (1986) P. M. Dewick 99 Errata to The Biosynthesis of Triterpenoids and Steroids D. M. Harrison (Vol. 2 No. 6 p. 525) Number 2 101 The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products One-Dimensional Methods I. H. Sadler 129 The Biosynthesis of Penicillins and Cephalosporins J. E. Baldwin and Sir Edward Abraham 147 Steroids Reactions and Partial Syntheses (1985) J. Elks 187 Non-Macrocyclic Trichothecenes (January 1970 to December 1986) J. F. Grove Number 3 21 1 Diterpenoids (1986) J. R. Hanson 229 Naturally Occurring Isocyanides M. S. Edenborough and R. B. Herbert 247 The Biosynthesis of C,-C, Terpenoid Compounds (1986) M.H. Beale and J. MacMillan 265 P-Phenylethylamines and the Isoquinoline Alkaloids (July 1986 to June 1987) K. W. Bentley 293 Quinoline Quinazoline and Acridone Alkaloids (July 1985 to June 1987) M. F. Grundon 309 Book Review Secondary Metabolism (Second Edition) by J. Mann. Reviewed by G. W. Kirby 309 Book Review Biologically Active Natural Products ed. K. Hostettmann and P. J. Lea. Reviewed by A. Pelter Number 4 311 Steroids Reactions and Partial Syntheses (December I985 to October 1986) A. B. Turner 351 Imidazole Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (Jufy 1985 to June 1986) J. R. Lewis 363 Brain Chemistry and Central Nervous System Drugs R. I. Brinkworth E. J. Lloyd and P. R.Andrews 387 The Biosynthesis of Triterpenoids Steroids and Carotenoids (1984 and 1985) D. M. Harrison 41 7 Book Review; Dictionary of Antibiotics and Related Substances ed. B. W. Bycroft. Reviewed by R. B. Herbert Number 5 419 Monoterpenoids (1985 and 1986) D. H. Grayson 465 Trends in Protease Inhibition (November I984 to January 1987) G. Fischer 497 Natural Sesquiterpenoids (1986) B. M. Fraga 523 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (July 1986 to June 1987) R. B. Herbert Articles that will appear in forthcoming issues include Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July 1986 to June 1987) J. E. Saxton Erythrina and Related Alkaloids (July 1985 to June 1987) A. S. Chawla and A. H.Jackson Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids (July 1986 to June 1987) A. R. Pinder The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products Two-Dimensional Methods A. E. Derome Enzyme Inhibitors in Medicine (to December 1987) C. S. J. Walpole and R. Wrigglesworth Amaryllidaceae Alkaloids (Jufy 1985 to June 1987) M. F. Grundon Biosynthetic Studies on Marine Natural Products (to April 1988) M. J. Garson The Biosynthesis of Porphyrins Chlorophylls and Vitamin B, (1986 and 1987) F. J. Leeper Recent Advances in Chemical Ecology (July 1985 to December 1987) J. B. Harborne The Polyether and Macrolide Antibiotics Biogenetic Analysis and Structural Correlations D. O’Hagan Pyrrolizidine Alkaloids (July 1986 to June 1987) D. J. Robins Limonene A. F. Thomas and Y. Bessiere Fatty Acids and Glycerides (1986 and 1987) M. S. F. Lie Ken Jie The Biosynthesis of Shikimate Metabolites (1987) P. M. Dewick Diterpenoids (1987) J. R. Hanson Carotenoids and Polyterpenoids (1986 and 1987) G. Britton Triterpenoids (July 1985 to December 1987) J. D. Connolly and R. A. Hill Muscarine Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (Jufy I986 to June 1987) J. R. Lewis Steroids Physical Methods (mid 1985 to December 1987) D. N. Kirk

ISSN:0265-0568    

DOI:10.1039/NP98805FP013

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年代:1988

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ISSN:0265-0568    

DOI:10.1039/NP98805BP015

出版商:RSC    

年代:1988

数据来源: RSC

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Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor M. I. Page The Polytechnic Huddersfield Professor T. J. Simpson University of Leicester Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products.Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products. Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. ~~~~~~ Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Burlington House London W1 V OBN England. 1988 Annual Subscription Price U.K. f159.00 Rest of World f183.00 U.S.A. $342.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. Second-Class postage paid at Jamaica NY 11431 -9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0The Royal Society of Chemistry 1988 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 1988 U.K. €1 59.00 Overseas €1 83.00 U.S.A. US $342.00 Subscription rates for back issues are (1984) (1985) (1986) (1987) U.K. f120.00 f125.00 f130.00 f142.00 Overseas f1 26.00 f131.OO f143.00 f159.00 U.S.A. US $240.00 US $242.00 US $252.00 US $280.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry 30 Russell Square LONDON WClB 5DT England

ISSN:0265-0568    

DOI:10.1039/NP98805FX017

出版商:RSC    

年代:1988

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ISSN:0265-0568    

DOI:10.1039/NP98805BX019

出版商:RSC    

年代:1988

数据来源: RSC

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Synthesis of Gibberellins and Antheridiogens L. N. Mander Research School of Chemistry Australian National University G.P.0. Box 4 Canberra A. C.T. 260I Australia Reviewing the literature published to June 1988 1 Introduction 2 Characteristic Reactions and Degradation Products of Gibberellins 3 General Procedures for Manipulation and Removal of Functional Groups in Gibberellins 4 Partial Syntheses of C, Gibberellins 4.1 Desoxy-A-ring Gibberellins 4.2 1-Hydroxy- and 1,3-Dihydroxy-gibberellins 4.3 2-Hydroxy- and 2,3-Dihydroxy-gibberellins 4.4 3-Hydroxygibberellins 4.5 12-Hydroxygibberellins 4.6 15P-Hydroxygibberellins 5 Interconversions of C, Gibberellins 6 Interconversions Between C, and C, Gibberellins 7 Conversions of Kaurenoids into C, Gibberellins 7.1 Conversions Based on Kaurenolides 7.2 Conversions Based on Enmein 8 Synthesis of Degradation Products of Gibberellins 9 Total Syntheses of C2,.Gibberellins 9.1 Syntheses of Gibberellin A, 9.2 Total Synthesis of (+)-Gibberellin A, 9.3 Total Synthesis of Gibberellin A, Methyl Ester 10 Total Syntheses of C, Gibberellins 10.1 Aromatic-A-ring-Based Routes to Synthesis of Gibberellins 10.1.1 Synthesis of Gibberellin A Based on Epigibberic Acid 10.1.2 Approaches Based on Birch Reductive Alkylations of Aromatic-A-Ring Acids and Esters -Synthesis of Gibberellic Acid 10.2 B,C,D +A-Ring Approaches 10.2.1 Intramolecular Diels-Alder Route to the Synthesis of Gibberellic Acid 10.2.2 Intramolecular Aldol-Based Approach to Syntheses of (+)-GA, (+)-GA, and Gibberellic Acid 10.3 The C,D +A,B-Ring Approach Synthesis of Gibberellin A5 11 Antheridiogens 1 1.1 Conversions of Gibberellins into Antheridiogens 1 1.2 Total Synthesis of (+)-Antheridic Acid 12 Addendum 13 References 1 Introduction The gibberellins form a group of approximately 70 structurally homogeneous diterpenoids,' many of which have important plant-growth-regulating properties (seed germination breaking of winter dormancy vegetative growth flowering inhibition of senescence e~c.)~ and which are distributed widely throughout the plant Kingdom.One third of the group is based on the gibberellane skeleton with the level of oxidation of C-20 ranging from methyl through to carboxyl.The remainder are derived from the 20-norgibberellane skeleton (2) and but for one exception contain a 19,lO-y-lactone function. In all gibberellins C-7 is a carboxyl group and in the great majority C- 17 is a methylene group. Variations in constitution are largely accounted for by the location and number of hydroxyl groups. These may be attached to C-1 C-2 C-11 C-12 C-15 C- 16 and C-18 but predominantly to C-3 (J!? configuration only) and/or C- 13 ;A1and A olefinic bonds are occasionally present in ring A. Many compounds have been obtained as glucosides or glucosyl esters. Once the structure for a new gibberellin has been established it is given a code name A (abbreviated to GA,).7 Thus gibberellic acid (3) is also known as gibberellin A, or GA,.A summary of the structural differences is given in Tables 1 and 2 for the C, and C, gibberellins respectively. In addition to these derivatives there has been isolated a small number of gibberellin-like compounds which induce the formation of antheridia in fern gametophytes. These substances termed antheridiogen~,~~ e.g. antheridic acid (4),72973 appear to be formed biosynthetically from gibberellins by minor skeletal changes (cf. Section 11). The main pathway for the biogenesis of gibberellins (1) R = Me (2) R = H H H (4) 54 I NATURAL PRODUCT REPORTS 1988 Table 1 Hydroxylation patterns in C, gibberellins" c-11 c-12 C-13 C-15 C-16 C-18 Code No.Refs. 9 899 61 10 62 10 54 11,12 16 13 33 14 55 11,12 57 15 60 10 51 16 40 17,18 34 14 47 19,20 50 21 48 22,23 49 22,23 26 24 8 25 56 11 ? 26 29 27 4 28 7 9,29 35 30 71 31 58 32 30 14 32 33-36 1 37 3 37,38 72 31 63 39 68 40 2 37 ? 26 69 31,41 70 31 31 14 20 42 5 43 67 40 22 44 21 45 45 46 10 47 59 48 6 25 1B lOB-epoxy 19,2-lactone -11 49 GA,. The great majority of derivatives however have been The strained skeleton and the densely functionalized nature Me 12 50 CH20Hb 15 51 CO,H 25 53 CH,OHb 27 24 CO,H 43 54 21 CH,OHb 52 Me 14 55 CO,H 13 60 CHO 23 63 C0,H 28 64 Me 53 65 CH,OHb 44 66 CHO 19 67,68 CO,H 17 69 CH,OHb 64 70 CHO 65 70 CO,H 66 70 Me 42 59 CO,H 41 59 L(9) R = OH scheme 1 C02H C01H C02H a prelude to the Sections on synthesis since a number of the-(13) R = OH 84 Non-aqueous bases effect epimerization at C-3 (a) Parent structure (8); x denotes location of hydroxyl group @denotes hydroxyl group with @configuration adenotes hydroxyl group with a configuration A denotes location of olefinic bond.is outlined in Scheme l.74 They are derived from kaurenoic acid (5) by hydroxylation at C-7 followed by migration of C-8 to C-6 to afford the prototype GA, alde-hyde (6) which may be oxidized to the dicarboxylic acid GA, (7).C-20 is then progressively oxidized and is ultimately lost as CO to form C, gibberellins possessing a 19,lO-y-lactone function. Hydroxylation may occur at several stages but in the most commonly encountered pathways it occurs at C-3 or C-13 in GA, (7),GA, aldehyde (6) or GA (8). The bio- logically most potent gibberellins possess the 19,lO-y-lactone function and a 3/3-hydroxyl ;75-77 the observed activity of many other compounds may be due to metabolism in situ which establishes these features. 78 Gibberellin A (3) is readily available commercially from the large-scale fermentation of the ascomycete Gibberella fujikuroi and a mixture of GA (9) and GA (10) can be obtained from a different strain. Gibberellin A, (1 1) and GA, (1 2) may also be isolated in worthwhile amounts from the mother liquors of isolated in microscopic yields and it has been necessary to confirm tentative structural assignments (sometimes based only on mass-spectrometric fragmentations and chromatographic behaviour) by synthesis from the more readily available fungal compounds; there has also been a considerable demand for the preparation of isotopically labelled intermediates for the elucidation of biosynthetic pathways.In addition to these undertakings there has been a very considerable effort directed towards the total synthesis of gibberellin~,~~-~l presumably as a consequence of the challenge arising from their structural complexity combined with the potential for many of these compounds to effect spectacular changes in various aspects of plant growth.The objective of this article is to provide an overview of the various aspects of this synthetic activity. Material considered to be too specialized or synthetic ap- proaches which did not progress beyond a preliminary stage in a planned total synthesis have been included amongst the references but not described in any detail. NATURAL PRODUCT REPORTS,1988-L. N. MANDER Table 2 Functionality patterns in C,,gibberellins" c-I c-2 c-20 Code No. Refs. CHO 24 52,53 CO,H 46 19,54 CHzOHb 37 56,57 CHO 36 58,59 CO,H 39 22,23 Me 18 61,62 CH,OHb 38 56,57 (a) Parent structure (7); x denotes location of hydroxyl group B denotes location of hydroxyl group with /IConfiguration a denotes location of hydroxyl group with a configuration ; (b) the gibberellin as isolated has the 19,20-lactone structure.(6) R = CHO L(7)COzH R = CO2H (8) R = H of many gibberellins make them reactive towards a wide range of reagents and prone to undergo a variety of rearrangements. H A brief consideration of this chemistry is therefore included as resulting degradation products have served as relay inter- (11) R = C02H mediates for total synthesis as substrates for the preparation of (12) R = CHO the rarer gibberellins and as targets in themselves. 2 Characteristic Reactions and Degradation HO Products of Gibberellins Gibberellic acid (3) and GA (10) are isomerized by very weak aqueous bases or acids to the isomeric lactones (13) and (14) (14) R = H by means of a retrograde aldol/aldol which was NATURAL PRODUCT REPORTS I988 (1 6) Reagents i NaOH; ii H,O+ Scheme 2 Reagents i IM HCl at 60 "C;ii 10 M HCl at 100 "C;iii NH,NH;H,O at 120 "C scheme 3 (23) Reagents i I, NaHCO,; ii NaBH, DMSO Scheme 4 originally observed in the dihydro-derivative GA (1 5) forming (16) (Scheme 2).as The epimerization has even been observed on 3-trimethylsilyl derivatives of these corn pound^.^^.^^ Treatment of GA (3) with a strong acid (Scheme 3) leads to diene acidsa9 which undergo decarboxylative elimination thereby effecting aromatization of ring A and epimerization of C-9 to afford allogibberic acid (1 8).g0*91 Aromatization also occurs at elevated temperatures in hydrazine but largely with retention (or more accurately re-formation) of the B/C-C~S ring-fusion to give epiallogibberic acid (21).92 It is possible with this reagent to interrupt the process and to isolate a moderate yield of the intermediate gibberellenic acid (20).93 More vigorous treatment of (18) with a strong acid induces a Wagner-Meerwein rearrangement to gibberic acid (19),94 while (21) rearranges to epigibberic acid (22).95 The equivalent rearrangement also occurs with GA (15) to form 'gibberellin C' (17),96p97 and is effected even more readily with softer electrophiles such as the halogens. 3 General Procedures for Manipulation and Removal of Functional Groups in Gibberellins In order to facilitate manipulations and isolation procedures and to improve solubility most reactions of gibberellins have been conducted on the derived 7-esters (usually methyl esters) but the final reconstitution of the carboxylic acid is often achieved only with some difficulty.Hydrolysis with hydroxide ion is very slow as a consequence of steric hindrance and prior hydrolysis of the lactone function (in C, gibberellins) which could be presumed to give rise to coulombic repulsion by the 19-carboxylate anion; it is also essential to mask any 3-hydroxyl to avoid epimerization at C-3 (as noted earlier). Except for the simplest analogues e.g. GA (8) hydrolysis by means of cleavage of 0-alkyl bonds is superior and has been achieved by iodide ion,9g but the preferred method is by lithium thiolate in hexamethylphosphoric triamide.loo.lol This has been effective even for the very labile molecule GA (3).lo2 Phenacyl esterslo3 (removed by zinc and acetic acid) have been used to NATURAL PRODUCT REPORTS 1988-L. N. MANDER Reagents i 0,,then Zn HOAc; ii Ph,P=CH scheme 5 good effect as well as p-metho~yphenacyl'~~ (photolabile) and rneth~xymethyl'~~ (removed by trimethylsilyl chloride and methanol). Because GA (3) and GA (10) have been major sources of semi-synthetic gibberellins there has been considerable effort invested into reactions which discriminate between the two olefinic bonds in these molecules especially the selective reduction of the A' olefinic bond. Hydrogenation over a special palladium/ barium carbonate catalyst in the presence of amines has been utilized in order to reduce the double-bond in ring A to avoid concomitant reduction of the methylene group C-17,'06 but the major products are derived from hydrogeno- lysis of the lactone function with migration of the olefinic bond to the position e.g.(23) from GA (3). The lactone func- tion is readily reconstituted through iodolactonization and subsequent removal of the iodine by reduction with sodium borohydride (Scheme 4) however.lo' Olefinic acids which may be more efficiently prepared by reduction with nickel boride,'O* have also been used as important substrates for the partial synthesis of C, gibberellins (cf Section 6). The methylene group C-17 may be preserved by its selective epoxidation (which occurs only very slowly on double-bonds in ring A presumably as a consequence of electron withdrawal by the lactone function as well as the intrinsically low reactivity of disubstituted olefinic bonds of this type) and subsequent re- establishment by deoxygenati~n.'~~+Alternatively this 'lo group may be cleaved (by ozonolysis or by osmium tetraoxide and sodium periodate) to afford the 16-nor-ketone and subsequently re-introduced by means of the Wittig reaction with methylenetriphenylphosphorane-a reaction which has been used extensively for the introduction of isotopic labels."' A useful alternative to the Wittig process is the Lombard0 modification of the non-basic Nozaki-Oshima reaction (di- bromo- or di-iodo-methane with titanium chloride and zinc) (Scheme 5).'12 Conjugate reduction of 1-en-3-ones by various borohydride derivatives is more useful for selectively removing the double- bond in ring A,"~-''~ although reduction of 3-ketones with a borohydride normally affords predominantly the unnatural biologically less potent (and therefore undesired) 3a-hydroxy epimers; e.g.(24) produces (25). The remaining general requirement for modification of the gibberellin molecule is a deoxygenation process which is compatible with the ester function in ring B and the 19,lO- lactone and preferably with the methylene group in ring D as well. This is best satisfied by reduction of halides,106.118 thioe~ters,"~ thioamides,120 methyl oxalate esters,121 or mesyl- ateslZ2 with a stannane. The last two procedures are not completely general but are especially useful for removing the 13-hydroxyl from derivatives of GA (3) which is the cheapest and most plentiful starting material in the gibberellin field.4 Partial Syntheses of C, Gibberellins 4.1 bxy-A-Ring Gibberellins A2-Gibberellins are especially useful intermediates for the preparation of a wide range of A-ring derivatives and as a consequence several methods have been developed for their preparation. Hydrogenolysis of GA methyl ester 3P-mesylate or 3P-tosylate (by H, Pd/CaCO, and pyridine) has been used in an especially direct preparation of the A2 olefin GA methyl ester (26),lo9 but the reaction can be difficult to control and may give a number of by-products. Better yields have been reported from treating the parent alcohol with thionyl chloride to afford the A2-1P-chloride (27) which was then reduced by tri-n- buty1~tannane.l~~ The most reliable method is based on the elimination of the 3-arylsulphonates of GA and GA deriva- tive~.'~~.125 As expected the 3p-derivatives in which the leaving group is axial are more reactive but good yields were also obtained from the 3a-derivatives when tetra-n-butylammonium bromide was added to the reaction mixture (this was presumed to generate a small equilibrium concentration of the 3p-bromide).117 Hydrogenation of the A olefins to A-saturated gibberellin derivatives e.g. GA (8) and GA, (28) can only be achieved satisfactorily if the methylene group C-17 is masked (e.g.as an epoxide) or temporarily removed (to form 17-nor- 16-ones).Access to these gibberellins may therefore be achieved more satisfactorily by reduction of halides or thiocarbonyl derivatives with a stannane (cf Section 3). 4.2 1-Hydroxy- and 1,3Dihydroxy-gibberellins Eight of the known natural gibberellins are hydroxylated at C-1. Hydration of 1-en-3-one derivatives occurs under acidic conditions to afford a 2:3 mixture of la and 1/3 products.126*127 NATURAL PRODUCT REPORTS 1988 R = H or OH ii,iii I AcO HO (29) R = OH (30) R = H Reagents i H,O+; ii Ac,O H+; iii NaBH,; iv PhC(Cl)=NMed C1-; H,S pyridine; v ButSnH azobisisobutyronitrile; vi K,CO Scheme 6 co C02Mo Reagents i HN,; ii NaBH,; iii hv; iv H,O+ scheme 7 0 43% 10% 30% Reagents i KOAc Me,CO (aq.) Scheme 8 These have been utilized in the synthesis of GA, (29) and GA, (30) (Scheme 6).1° A more efficient method is the addition of hydrazoic acid and photolysis of the adducts to form the I-imines which are hydrolysed in situ to the I-ones.These in turn undergo facile elimination to furnish 2-en- 1-one deriva- tives (Scheme 7).128,129 Because these 1-ones are reduced to a -2 1 mixture of la- and la-epimers however the latter isomers are not as readily available by this approach. They are formed with complete stereochemical control by peroxy-carboxylic-acid-induced hydroxy-lactonization of 1 (10)-en-19-oic acids but the reported yields are modest." The most direct method for making l#?-alcohols is simply through solvolysis of a 1-ene-3P-mesylate in buffered aqueous acetone which affords roughly equal amounts of SN2and syn-SN2'products (i.e.l-en-3a-01 and 2-en- la-01 respectively) contaminated with a small amount of the anti-S,2' product 2-en- la-01 (Scheme 8).130 Formation of this last isomer can be suppressed by utilizing a dipolar aprotic medium however (cJ Section 11). NATURAL PRODUCT REPORTS 1988-L. N. MANDER I Reagents i I,. NaHCO ; ii Bu','SnH scheme 9 (33) R = H (34) R = OH on on (35) vi,vii 1 viii 7-co \ C02H Reagents i MeC(O)NHBr LiOAc HOAc; ii KOH; iii 1M H,SO,; iv (Me,Si),NH Me,SiCl; v Ph,P=CH, then H,O'; vi Bu,"SnH; vii NaOH; viii H,CrO,; ix NaBH Scheme 10 4.3 2-Hydroxy- and 2,3-Dihydroxy-gibberellins (stereoselectivity appears to be complete and it is even possible The hydrolysis of GA in dilute aqueous alkali affords direct to achieve moderate chemoselectivity in the presence of the access to the 2a-hydroxy-acid (31) from which the 2a,3p- methylene group in ring D).',' On the other hand acetoxy- dihydroxylated gibberellin GA, (32) has been prepared by bromination (of the 17-nor- 16-one derivatives) is employed in means of an iodolactonization (Scheme 9).11 The more the elaboration of 2a,3p-dihydroxy-derivatives,as in the common approach to functionalization of C-2 however is via preparation of GA, (37) via the epoxide (36) and the simple A2-olefins.The 2/?,3P-dihydroxylation pattern is on the major 2a-hydroxy-analogue GA, (38) by reduction of the 3P-bromo catabolic biosynthetic pathways and is found in ten gibberellin intermediate (35) with tributylstannane (Scheme The 28- derivatives e.g.GA, (33) and GA (34). These are readily epimers e.g. GA, (39) may be prepared (1 :1 mixture with the prepared by oxidation of A2-olefins with osmium tetraoxide 2a-epimers) by reduction of the 2-ketones with sodium NATURAL PRODUCT REPORTS 1988 I Reagents i CBr, Ph,P pyridine acetone; ii Zn HOAc; iii NaHCO, I,; iv Bu,SnH azobisisobutyronitrile; v KOH THF (aq.) Scheme 11 OH OH OH HO OH i ___jt Ac Ac iii-v 1 Ivii,ii OAc OAc Reagents i SeO, Bu'OOH ; ii pyridinium chlorochromate; iii Zn HOAc; iv pyrrolidone *HBr,; v NaBH, MeOCH,CH,OMe; vi Pb(OAc), I, hv; vii K,CO, THF (as.) ;viii Zn(BH4) ;ix Ac,O pyridine ;x MeOC(O)C(O)Cl pyridine; xi BuiSnH azobisisobutyronitrile Scheme 12 borohydride."' The most efficient approach to 2-hydroxy- normally an issue but re-establishment of the 3p stereo-gibberellins however is illustrated in Scheme 11.133 chemistry may be necessary following manipulations in which this part of the molecule is disturbed.Reductions of 3-0x0- gibberellins with metal borohydrides normally afford the 3a- 4.4 3-HydroxygMerellins alcohols and although the 3P-epimers are the major prod- Because the most readily obtained gibberellins all possess a ucts from Meerwein-Pondorf-Verley reductions of 3-oxo-c, 3p-hydroxyl group the introduction of such a function is not gibber ell in^,'^^ this method appears not to be practical for the NATURAL PRODUCT REPORTS 1988-L.N. MANDER 549 o n o n o n i ii - AC AC "0H AC C02CH2COPh COzCHzCOP h CO2CH2COP h Iiii H OH Reagents i SeO, Bu'OOH; ii ClC(O)C(O)Cl DMSO then Et,N; iii Zn HOAc; iv K,CO, MeOH Scheme 13 H Ow HO -C02H COzH (44) more labile C, analogues. Reduction of 3-0x0-7-oic acids de- rived from GA and GA with K-Selectride [KB(CHMeEt),H] however affords predominantly the 3P-epimers. This out- come has been rationalized in terms of steric and coulombic inhibition to the approach of the reagent to the upper face of the substrate by the 6P-carboxylate-boronate complex. 135 4.5 12-Hydroxygibberellins 12-Hydroxygibberellins e.g. GA, (a), GA, (41) and GA, (42) appear to have considerable potential for biological activity but are among the least accessible of the natural gibberellins both in terms of isolation and synthesis.Until recently the only means of gaining access to such compounds (of which there are probably in excess of twenty variants) had been from microbiological transformations of 12-hydroxy-13' ka~renes.'~~.However transannular oxidation of 16a-bromo- 17-hydroxy-derivatives has now made this type of gibberellin freely available (Scheme 12).13* Unfortunately the proscriptions imposed by functionality in the eastern half of the molecule make the elaboration of the required bromohydrin rather convoluted. The pivotal oxidation with lead tetra-acetate and iodine to form the 12p,17-ether (which depends in part for its success on the boat conformation of ring c) gives surprisingly high yields for this type of process as long as the normal tungsten irradiation source is replaced by a medium- pressure mercury lamp (which allows the reaction to be run at room ternperat~re).'~ The incorporation of the bromo sub- (45) stituent allows opening of the ether ring under conditions which are sufficiently mild that the sensitive functionality in ring A is not disturbed.4.6 15fiHydroxygibberellins Oxidation of gibberellins by selenium dioxide and t-butyl hydroper~xide'~~ affords excellent yields of the 15a-hydroxy-derivatives. Although these are prone to undergo lactonization with the neighbouring methoxycarbonyl group they may be manipulated satisfactorily with due care.All nine natural 15- hydroxy-gibberellins have the 15P-configuration,e.g.GA, (43) and are best obtained (Scheme 13) by Swern oxidation followed by reduction with zinc and acetic acid the latter procedure proving to be superior to the more obvious choice of borohydride/lanthanide reagents to avoid or minimize 1,4- reduction.39.40 5 lnterconversions of C, Gibberellins Relatively few interconversions of C, gibberellins have been carried out essentially as a consequence of the limited availability of substrates. Gibberellin A, (11) is the only compound which can be readily obtained in gram quantities and this has been transformed into the methyl esters of GA, (44)and GA, (45) by the same methods as were employed for the C, analogues (Section 4.3).132.141 Gibberellin A, has also NATURAL PRODUCT REPORTS 1988 iii 0 (47) Reagents i H,CrO,; ii NaBH,; iii 135 "C; iv LiBH,; v (Pr'O),Al Pr'OH Scheme 14 40:60 (45%) (9) (11) 1 T ii v-vii AC AC Reagents i Pb(OAc),; ii Ac,O pyridine; iii CH,N,; iv NaOMe; v NaOH; vi I, NaHCO,; vii NaBH, DMSO Scheme 15 (MM= CH~OMO) Reagents 1 MeOCH,Cl PriNEt; ii Li NH (liq.) Bu'OH; iii ClC(O)C(O)Cl then CH,N,; iv Cu C,H, reflux; v KH DMF then 0,; vi 20% NaOH reflux; vii H,O+ Scheme 16 NATURAL PRODUCT REPORTS 1988-L.N. MANDER 55 1 Reagents i H, Pd/C C,H,N; ii Ac,O pyridine; iii ClC(O)C(O)Cl then CH,N,; iv Cu C,H,, reflux; v Li NH (liq.) Bu'OH; vi MeOCH,Cl PriNEt; vii KH DMF then 0,;viii Me,BBr at -70 "C for 2 minutes; ix NaBH Scheme 17 Reagents i H,CrO,; ii NaBH,; iii TsCI pyridine; iv KOH Bu'OH (aq.) Scheme 18 been converted into GA, (Scheme 14).13 The steric in- accessibility of the carboxyl function at C- 10 makes reduction of this group difficult and this was only achieved by harnessing a 3a-hydroxyl in the formation of the lactone (46) which could then be reduced by lithium borohydride.Further manipulations of C-20 are complicated by the ease with which lactonization occurs with the 4-carboxyl group so synthetic access to gibberellins in which C-20 is a methyl group such as GA, (7) has therefore been gained by ring-contraction in kaurenolides (Section 7.1). Gibberellins in which C-20 is formyl e.g. GA, (1 2) have been prepared from C, gibberellins (Section 6).6 lnterconversions Between C, and C Gi bberellins Gibberellin A, (11) has been converted into GA (9) by two closely related approaches in which the key step is the oxidative decarboxylation of the carboxyl group C-20 by lead tetra- acetate (Scheme 15).107* Ig2 Of very much greater utility however is the transformation of the methyl ester of GA (3) into GA, (51) (Scheme 16),14 and into the methyl esters of GA, (12) and GA, (47) (Scheme 17).14 These syntheses depend for their success on an unusual oxidative cleavage mediated by 0,gas on the potassium enolates derived from the products [e.g. (5011 of a selective reduction with lithium in liquid ammonia of the cyclopropyl ketones [e.g.(49)] that can be obtained from an intramolecular cyclopropanation reaction of a A1(lO)gibberellin in which C-19 is a diazoacetyl group e.g.(48). The hydrogenolysis of the 3b-methoxymethyl group in the synthesis of GA, and of the 13-acetate substituent in the preparation of GA, and GA, by the reducing-metal system is also of interest. 7 Conversions of Kaurenoids into C Gibberellins 7.1 Conversions Bad on Kaureoolides The first synthesis of a natural gibberellin145 was (appropriately) that of GA, aldehyde (6) from 7p-hydroxykaurenolide (52) which may be fairly easily obtained by chromatography of the neutral fraction from the fermentation of Gibberella fujikuroi. This transformation (Scheme 18) continues to provide the best NATURAL PRODUCT REPORTS 1988 i-iv TH 0 v,vi I Reagents i dihydropyran H+; ii Cr0;pyridine; iii NaBH,; iv TsCI pyridine; v KOH Bu'OH (aq.); vi H,O+ Scheme 19 VI-VIII -0 (57) Reagents i NaBH,; ii OsO, NaIO,; iii Ac,O; iv SOCI, then NH,; v Pb(OAc), I, hv;vi KOH; vii H,CrO,; viii Ph,P=CH Scheme 20 access to this important gibberellin and its isotopically labelled derivatives.The pivotal step in this sequence is the pinacol-like contraction of ring B [(53)-+(6)] which is best effected by potassium hydroxide in aqueous tertiary butyl and for which it is essential that the nucleofugal tosylate function is aligned anti-periplanar with the migrating C(5)-C(6) bond. Thus it was necessary first to invert the stereochemistry at C-7 in the natural kaurenolide (52) through oxidation followed by reduction.The parent GA, (7) is readily formed by Jones' oxidation and the metholdology was readily extended to the synthesis of GA, aldehyde (55) from 3/3,7,!l-dihydroxy-kaurenolide (54) (Scheme 19)14' and of GA, (57) (Scheme 2O).',' The latter transformation necessitates a transannular functionalization of the methyl group C-20 and this was carried out by oxidation of the amide (56) with lead tetra- acetate but the yield was only 18%. Because the methylene group C-17 underwent isomerization when exposed to the conditions required to form an acyl chloride it was found to be necessary to remove the double-bond (by ozonolysis) and then to reconstitute it (by a Wittig reaction) at a later stage. 7.2 Conversions Based on Enrnein Gibberellins A, (57) and A, (47) have been prepared from degradation products of the diterpenoid enmein (58).Because C-19 is unfunctionalized it is again necessary to carry out a transannular oxidation. In one sequence (Scheme 21)149this was effected by photolysis of the nitrone (59),the first of several NATURAL PRODUCT REPORTS 1988-L. N. MANDER 0 several step -"OTHP OH iii,iv !vii viii,ix L1 O* + OW-C02H CO2H 1:2 (57) (62) Reagents i Na PhMe; ii NH,NH, KOH; iii CrO,; iv NH',OH; v BrN,; vi hv; vii heat; viii HNO,; ix H,CrO,; x NaBH,; xi MsCI pyridine ; xii heat collidine; xiii KOH HOCH,CH,OH scheme 21 554 NATURAL PRODUCT REPORTS 1988 . ' OH 0" 0 (63) (64) vii,viii xi-xiii Me*OMe =H CHO -Me C02Me x,xiv,xv 1 o-0-xviii,x xvi,xix C02Me CO2H (57) x,xvi ,xvi i xx,xix ___t 0 H Reagents i Pb(OAc), I, hv; ii H,O'; iii CH,N, BF;Et,O; iv HClO,; v Cr0;2 pyridine; vi SOCl,; vii ArCO,H NaHCO,; viii BF;Et,O; ix LiAlH,; x H,CrO,; xi NaBH,; xii MsCl pyridine; xiii KOH Bu'OH (aq.); xiv CH,N,; xv HSCH,CH,SH BF;Et,O; xvi Ph,P=CH,; xvii N-chlorosuccinimide; xviii Raney nickel then H, Pt ;xix Pr"SLi HMPA; xx Al(OPr') Scheme 22 remarkable transformations leading to a mixture of acetals (60) 8 Synthesis of Degradation Products of and (61) from which GA, (57) and its A15-isomer (62) were GibberelIins obtained.In a second approach leading to both GA, and The gibberic acids (19) and (22) as well as the allogibberic acids GA, (Scheme 22),150 enmein was degraded by means of a (18) and (21) were popular early targets for total synthesis fourteen-step sequence to the acetal (63) which was then since they served as models for the construction of the right- oxidized by lead tetra-acetate and iodine to the lactone (64).hand half of the gibberellin structure. There was also the Following oxidation at C-7 it was possible to adapt the prospect that they could be utilized as relay intermediates. kaurenolide-based methodology (Section 7.1) in the formation Indeed GA (9) has been reconstructed from epigibberic acid of the ring-contracted aldehyde (65). Racemic (63) was also (22) via gibberellin C (17) (Section 10.1.1). )-Gibberic acid (19) and (i-)-epigibberic acid (22) were prepared by total synthesis (Scheme 23),151which would have (-t established a formal total synthesis of these gibberellins but for prepared independently in the laboratories of Loe~enthal'~~ respectively following the same basic strategy the required optical resolution.and M~ri,'~~ (Scheme 24). This was based on annelation of indanones fol- NATURAL PRODUCT REPORTS 1988-L. N. MANDER vi,vii 1 Vlll OMe f--OMe OMe -Me n x xi xii-xiv CHO Me Me lxv (* 1-(63) Reagents i (MeO),CO NaH then EtC(O)CH,CH,CI; ii H'; iii KOBu' then MeI; iv HOCH,CH,OH H+; v LiAlH,; vi Ac,O pyridine; vii ArC0,H; viii MeOH H'; ix Li NH (liq.) EtOH then H,O+; x HCO,Et NaOMe; xi Bu"SH H'; xii KOBu' then H,C=CHCH,Br; xiii KOH EtOH; xiv O, then Me,S; xv NaOMe MeOH; xvi dihydropyran H'; xvii NH,NH, HOCH,CH,OH Na; xviii SOCl, pyridine; xix B,H, then NaOH H,O Scheme 23 iii NATURAL PRODUCT REPORTS 1988 i-iii Po \ 2 iv '"b0 CO2H 0+O 4 V,Vi vii viii C02Bn -&lH eo I -/ C02Me x,xi I Reagents i CF,CO,H; ii LiAlH,; iii H,CrO,; iv 220 "C; v PhCH,OH; vi CH,N,; vii H, Pd/C; viii Ac,O reflux; ix Zn HOAc reflux; x Ph,P=CH, Bu'OH; xi NaOH MeOH Scheme 25 xi i-x Q-n\ CO2Me -CHO I xii,xiii 1 xvii-xi x I xxiii - (72) xx,xxiv I OTHP xxvii xxv xxvi 0 xviii,xxv T COpH P O C02Mo H P (211 Reagents i CH,(C0,Et)2 R,NH; ii KCN; iii HCl; iv Ac,O; v AlCI,; vi MeOH H'; vii (MeO),CO NaH; viii Ac,O H'; ix H, Pt; x TsOH PhMe; xi butadiene PhH at 190 "C; xii I, NaHCO,; xiii Bu,SnH; xiv MeSO,CH,Li DME; xv H,CrO,; xvi Bu'MgC1; xvii CH,N,; xviii A1 (amalgam); xix H,O+; xx NaBH,; xxi MsCl; xxii collidine heat; xxiii Hg(OAc) or R,BH then NaOH H,O,; xxiv dihydropyran TsOH ; xxv NaOH ; xxvi CrO; 2 pyridine ; xxvii Ph,P = CH Scheme 26 NATURAL PRODUCT REPORTS 1988-L.N. MANDER H i,ii =H CO2Me v-vii I xii,xiiiI vii ii,xiv,xv Q-pL C02H CHo 0 0 (75) (76) Reagents i AcCI pyridine; ii NaBH,; iii B,H, then NaOH H,O,; iv H,CrO,; v Ph,P=CHOAr; vi HClO,; vii Ph,P=CH,; viii N- bromosuccinimide H,O; ix dihydropyran H'; x NaH; xi H,O'; xii Br, HOAc; xiii LiCI DMF; xiv TsCI pyridine; xv KOH Bu'OH Scheme 27 lowed by intramolecular acylation processes to establish ring D. Epiallogibberic acid (21) was first prepared by Mori et al.(Scheme 25)154 by modifying the earlier synthesis of epigibberic acid to form the corresponding nor-ketone (66). Baeyer-Villiger oxidation reduction and oxidation afforded a keto-acid which was then cyclized to the diketone (67) reduction of which afforded the ketol (68). This last step presumably proceeds through a cyclopropanediol and it is of some interest that bond fission leads to the thermodynamically less favoured House et al. approched the synthesis of epiallogibberic acid (21) (Scheme 26)156* by adding ring c in a [4+ 21 cycloaddition 15' to the indene derivative (69) and completing ring D by means of an aldol reaction with the @-keto-sulphoxide (70). The product (71) is somewhat strained and readily reverts to (70).It was concluded that the cyclization depended for its success on chelation with magnesium ion from the t-butylmagnesium chloride which had been employed as the base. Further interesting aspects of this synthesis are the presumed acetoxy- directed functionalization of the 15-ene function in (72) and the use of salt-free ylide for the Wittig reaction. 9 Total Syntheses of Cz0Gibberellins Approaches to the total synthesis of C, gibberellins have drawn heavily from earlier studies on the related kaurenoid diterpenes and Garrya alkaloids. All routes but one begin with a hydrophenanthrene intermediate in which ring c is aromatic. 9.1 Syntheses of Gibberellin A, (7) Gibberellin A, (7) is the simplest of all gibberellins and the biosynthetic prototype.By utilizing the phenanthrene ester (73) which had been an intermediate in an earlier synthesis of rm-kaurenoic acid (5),15* Mori et al. were able to prepare the racemic version of the dioxo-ester (74),159 which had been converted by Cross et a/. into the norkaurenolide (75).145 A formal relay synthesis of GA, aldehyde (6) was then achieved by carrying out a selective Wittig reaction to afford (76). An outline is provided in Scheme 27. NATURAL PRODUCT REPORTS 1988 iii-v 1 vi x,xiii,iv xv-xvii,xi 1 Reagents i AlC1,; ii CrO, HOAc; iii KOH; iv CH,N,; v H,SO, AcOH; vi H, Pd/C; vii CH,COCl AlC1,; viii ArCO,H then NaOH; ix H, RuO,; x H,CrO,; xi Ph,P=CH,; xii B,H, then NaOH H,O,; xiii SOCI,; xiv hv CuSO,; xv HOCH,CH,OH H+; xvi KOH HOCH,CH,OH ;xvii H,O+ Scheme 28 Methyl dehydroabietate (77) is antipodal to the gibberellins at C-5 and C-10 but during a retrograde Friedel-Crafts removal of the isopropyl group inversion occurs at C-10 to afford the ester (78) which thus becomes a feasible enantio- merically pure substrate for the preparation of GA1,.l6O This was completed by Ohtsuka and Tahara as outlined in Scheme 28.lS1 The important steps in this synthesis are the benzilic- acid-type rearrangement on the diketone (79) and the carbenoid insertion into the C(8)-H bond in (81).Stereochemical control is exerted by the 6a-ester function which ensures delivery of hydrogen to the p-face of (80). Once the gibberellin skeleton is complete however base-catalysed epimerization affords the thermodynamically more stable 6P-isomer.9.2 Total Synthesis of (+-)-Gibberellin A, (57) The synthesis of (-+)-GA, (57) by Nagata et al. (Scheme 29)16 was the first genuine total synthesis of a gibberellin and established a significant milestone in the field. It began with the tetracyclic amine (82) which had been utilized in earlier studies on the total synthesis of diterpene alka~ids,'~~. 164 and extended over 35 steps. Unfortunately the choice of (82) as a starting material led to a major inefficiency in the synthesis despite model studies which promised a more encouraging outcome transformation of the piperidine ring at a late stage into the 8-lactone function of the target proceeded without regiochemical control and in only 5% yield.In the early stages of the synthesis standard procedures led via the enone (83) to the B-ring olefin (84) which was subjected to ozonolysis followed by a careful aldol reaction to afford the hydrofluorenone (85). Transformation into the enone (86) and then elaboration of ring D based on 'in house'methodology i.e. 1,4-addition of HCN through the agency of diethylaluminum cyanide,ls5 and homologation of the aldehyde (87) with the carbanion of diethyl cyclohexylaminovinylphosphonate afforded the enal(88) which was further elaborated to the enal (89). Wolff-Kishner reduction of this product proceeded with NATURAL PRODUCT REPORTS 1988-L. N. MANDER - - i ii $OH CHO iii 1 ix-xi NMs CHO CHO -NMs vi HO Me6 xix,xx xxi,xxii xxiv xxiv I 0 1 (91) 0 Reagents i H,C=C(Me)OAc H' then NaBH,; ii 0 then Zn HOAc; iii A1,0,; iv Ac,O pyridine; v Ph,P=CH,; vi K,CO, MeOH; vii H,CrO,; viii Et,AlCN; ix (Pr'O),Al Pr'OH; x BuiAlH then HOAc NaOAc; xi dihydropyran H'; xii C,H,,NHCH =CHP(O)(OEt), NaH; xiii H,O+; xiv TsCl pyridine; xv Ac,O ZnC1,; xvi KOH MeOH; xvii C,H,N then HOAc (as.); xviii Cr0;2 pyridine; xix NH,NH, trigol KOH; xx Li NH (liq.) Bu'OH; xxi (CF,CO),O pyridine; xxii CH,N,; xxiii Pb(OAc),; xxiv NaNO, HOAc; xxv LiI y-collidine Ph,,P Scheme 29 migration of the olefinic bond to furnish the methylene collidine and it was of considerable interest to find that the derivative (90).The last stages followed a methodology racemic GA, (57) had half the activity of the natural material developed by ApSimon,ls7 and afforded the isomeric lactones in the Tanginbozu rice growth bioassay and that the isomeric (91) and (92).Demethylation was effected by lithium. iodide in lactone acid derived from (92) was inactive. 560 NATURAL PRODUCT REPORTS 1 1988 C02Me C02Me (94) (95) v-vii 1 ix -C02Me (97) ii,x1 O\/-. OH OH - X co 0I (98) (99) 1xii OH xiii xiv co xv -H Reagents i CH,Br, Zn TiCI,; ii Me,CHCMe,BH, then H,O, Na,HPO,; iii Cr0;2 pyridine; iv LiNPrh then H,C=CHCH,Br HMPA; v KH PhSeSePh; vi NaBH,; vii H,O, 2,dlutidine; viii (EtCO),O pyridine; ix KH DMF; Et,NH+ OAc-; x pyridinium dichromate; xi K,CO, MeOH; xii (Pr’O),AI Pr’OH; xiii H,O+; xiv Me,SiCI PriNEt; xv Ph,P=CH, PhH (salt-free) Scheme 30 9.3 Total Synthesis of (+)-Gibberellin A Methyl Ester (100) (94) ensured that alkylation of the derived enolate anion took This synthesis (Scheme 30)168 was based on procedures place in the desired way to afford only the aldehyde (95) with developed by Lombard0 in the author’s laboratories from the correct stereogenicity at C-10.methodology originally conceived for the construction of C, gibberellins. It also utilized a common intermediate from this earlier work. Two of the most important steps were the Michael 10 Total Syntheses of C,9 Gibberellins reaction (96) -f (97) and the aldol reaction (98) -+(99) homo- The synthesis of C, gibberellins has attracted far more interest logous variants of processes which had proved to be so effective than that of the C, analogues and has accordingly led to a in total syntheses of (+)-GA, (&)-GA, and GA (Section much greater diversity of approaches and strategies although The absence of the 10.2.2).In the earlier stages of the sequence introduction of C-many have not been ~ompleted.’~’-’~~ 20 by replacement of the 0x0-function in the ketone (93) by a twentieth carbon has encouraged the use of intermediates with carbaldehyde group proved to be a major obstacle. Most an aromatic ring A but only two routes based on such organometallic reagents caused enolization while less basic intermediates (Section 10.1) have been brought to a fruitful reagents e.g. phosphoranes and sulphuranes led to proton conclusion.Following the preparation of this article a synthesis exchange (and therefore epimerization) at pro-C-9. The problem of (_+)-GA (3) based on an intermediate with an aromatic ring was eventually solved by a modification of the Nozaki-Oshima c was disclosed by Yamada the details of which are provided rnethylenation,ll2 following which hydroboration and oxi- in the Addendum. Designs which involve the addition of ring dation afforded the aldehyde (94). The convex upper face of A and lactone functions to B,c,D-tricyclic intermediates have NATURAL PRODUCT REPORTS 1988-L. N. MANDER 56 1 v,vi ___t 0 CO2H vii-x.i 1 -3-xi,xii,i,x vii-x,i @$ -0 0 C02Me xi,xiii,iii,x xiv -H ixv On (9) Reagents i CH,N,; ii HNO, Ac,O; iii H, Pd/C; iv NaNO, H,SO,; v H, Rho,-PtO,; vi H,CrO,; vii HCO,Me NaOMe; viii NaOH KBr,; ix LiBr Li,CO, DMF; x H,O+ heat; xi HOCH,CH,OH H+; xii Ph,CNa then CO, then H,O+; xiii NaBH,; xiv NaOH; xv PCl Scheme 31 proven to be highly successful (Section 10.2) while a C,D + A,B-established the quaternary centre at C-4 with the desired ring sequence has afforded the most direct approach so far stereochemistry following which the A1 olefinic bond and 3-(Section 10.3).one functions were reduced the ester function was hydrolysed and the resulting acid was lactonized to form the 3a-epimer (104) of gibberellin C. Equilibration in base [cf. Scheme 21 10.1 Aromatic-A-Ring-Based Routes to Synthesis of provided a small amount of gibberellin C (1 7) itself which had Gibberellins been converted earlier by Cross et al.into GA methyl ester 10.1.1 Synthesis of Gibberellin A (9) Based on Epigibberic (105) by means of a Wagner-Meerwein rearrangement initiated Acid (22) by treatment of the derived 16-01 with phosphorus penta- The first syntheses of C, gibberellins i.e. GA (9) and its chloride.186 Finally hydrolysis in sodium hydroxide furnished congeners were completed in a formal sense by Mori et al. by GA (9) as a minor component in a mixture with the 3a-utilizing epigibberic acid (22) as a starting This epimer (1 06). compound had been made as the racemate by the same research group but no optical resolution was reported.153 The synthesis is outlined in Scheme 31 and began with hydroxylation of ring 10.1.2 Approaches Based on Birch Reductive Alkylations of A at C-3 by nitration reduction and diazotization to afford the Aromatic- A-Ring Acids and Esters -Synthesis of Gibberellic phenol (1 01).Hydrogenation was followed by re-introduction Acid (3) of double-bonds into the A' and A9 positions by sequential This route to gibberellin synthesis was largely pioneered in the brominations and dehydrobrominations to afford the dienone laboratories of Loewenthal with some valuable inputs by Baker (102). The derived enolate anion was carboxylated and the and House. Lowenthal et al. first established the practicality product converted into the methyl ester (103). C-Methylation of Birch reductive alkylations on 1-naphthoic acids to form NATURAL PRODUCT REPORTS 1988 -iii-v Me Me C02H CO2Me xii-xiv xvii,xviii -(108) (109) Reagents i HCO,Et NaH; ii H,O, Bu'OH; iii Me,SO, NaOH; iv NaOH; v polyphosphoric acid; vi Bu"OC(O)CHO H+; vii H, Pd/CaCO,; viii MeOH H+; ix H,C=CHC(O)Me NaOMe; x (CF,CO),O CF,CO,H; xi H, Pd(OH),/C; xii ArC(S)CI; xiii heat at 230-260 "C for 20 minutes; xiv Pd(OH),/C xylene heat; xv HOCH,CH,OH BF;Et,O; xvi LiNButC,H,, then CO,; xvii CH,N,; xviii NaOMe MeOH Scheme 32 C02Me Pfco2M" i-iii Me0fl$-Me CO2H 0 vi-ix I n n xi,iii,xii Me0/pdQ Me Me0 I OH OH CONHEt C02H xiii,xiv 1 n Reagents i H, PtO,; ii MeOH; iii CH,N,; iv NaOMe PhH; v H,SO, HOAc; vi ClC(O)C(O)Cl; vii AICI, PhH; viii HOCH,CH,OH H+; ix LiAlH,; x Bu"Li then CO,; xi H, Pd/C HCIO,; xii LiNHEt; xiii Bu"Li then CO,; xiv N,O, NaOAc CH,CI,; xv Na NH (liq.) then MeI; xvi 0 Scheme 33 NATURAL PRODUCT REPORTS 1988-L.N. MANDER vi-xi OCOCHpCl OCOCH2CI xii xiii-xv COCHN2 ~-* ___)_ Me xvii xviii -t-I CO2H CO2Et CO2H C02Me xxiii,xxiv i Reagents i Bu"Li then (MeO),CO; ii CIC0,Me; iii NaI Me,CO; iv Li NH (liq.); v polyphosphoric acid; vi HCN NaCN; vii HCI MeOH; viii NaOH; ix (ClCH,CO),O; x ClC(O)C(O)Cl DMF; xi CH,N,; xii CF,CO,H; xiii Na,CO,; xiv HOCH,CH,OH H'; xv MeOCH,CI PriNEt; xvi Bu"Li CO,; xvii H, Pd/C; xviii KOBu' K NH (liq.) MeI; xix MeCHN,; xx Hg(NO,), MeCN; xxi NaBH,; xxii PhCOCI pyridine xxiii KBr, KHCO ; xxiv BuiSnH ; xxv 1,8-diazabicyclo(5.4.OJundec-7-ene; xxvi NaOH ; xxvii CH,N Scheme 34 intermediates which could be readily converted into the ring A/ y-lactone moiety in all C, gibber ell in^.^^' A possible substrate (log) for the synthesis of GA (9) was then constructed from (107) as outlined in Scheme 32; although the work was never completed the development of the benzylic metallation/ carboxylation sequence that was utilized in the preparation of (109) from (1 08) provided a further major methodological contribution.188 In an independent study Baker and Goudie arrived at a similar intermediate (Scheme 33) but found the product of the reductive alkylation (1 10) to be very unstable undergoing oxidative decarboxylation to the toluene derivative (1 I Apart from these difficulties however it seems un- likely that either (109) or (110) would have been a suitable intermediate since House et al.established in model substrates that in order to achieve the desired stereochemistry from alkylation at C-4 it would probably be necessary to carry out the reductive alkylation on the 6a-epime~s.'~~ Indeed this expectation was confirmed when the formal total synthesis of GA (3) along these general lines was completed in the author's laboratories.101 In this synthesis (Scheme 34) the assembly of a suitable hydrofluorene precursor began with the reductive alkylation of 2,5-dimethoxybenzoic acid (1 13) by the benzylic iodide (1 I2), the adduct from which smoothly cyclized in polyphosphoric acid with concomitant decarboxylation to form (I 14). Building on earlier studies (114) was converted into the diazo-ketone (1 13 which underwent acid-catalysed cyclization to form the tetracyclic ketone (1 16).After protection of the functionality in NATURAL PRODUCT REPORTS 1988 HO/ 0Ao7 iii I vii,viii 1 x,xi xiv-xvi t H CO H O P xii \-xiii //CO-H 1 '-//CO=H I HeHe HO -C02Me C02Me "CO2H (3) (MEM =MeOCH2CH20CH2) Reagents i Bu"Li then (E)-ClCH=CHC(O)Cl; ii PhH 1,2-epoxypropane at 160 "C; iii LiN(Pr')C,H,!I. then MeI; iv ZnBr,; v C(O)CI, 4-dimethylaminopyridine then (-)-(QPhCHMeNH,; vi Et,N C1,SiH; vii Na,RuO, NaOH; viii Et,N TsCI then MeOH; ix rn-CIC,H,CO,H; x NaOH; xi I, NaHCO,; xii (CF,CO),O pyridine then Zn then NaHCO,; xiii Pr"SNa HMPT; xiv CH,N,; xv TsCI pyridine; xvi NaBr HMPT; xvii Zn EtOH Scheme 35 ring D the benzylic position C-6 was carboxylated by means of 10.2 B,C,D +A-Ring Approaches the Loewenthal methodology the 9-11 olefinic bond was reduced and the Birch reductive alkylation at C-4was executed 10.2.1 Intramolecular Diels-Alder Route to the Synthesis of with complete diastereoselectivity to afford (1 17).Once the Gibberellic Acid (3) lactone function was in place it was possible to correct the The first synthesis of this challenging molecule was completed and depended for its success on an stereochemistry at C-6 in (118) by equilibration to the by Corey and co-worker~'~~ thermodynamically more stable 6P-epimer (1 19). Hydrolysis intramolecular Diels-Alder reaction for the addition of ring A and re-esterification then afforded (1 20) which had earlier been to a vinyl ethano-indene substrate.A number of approaches converted into GA (3) (Section 10.3). developed largely in the laboratories of Corey but also in those NATURAL PRODUCT REPORTS 1988-L. N. MANDER HO BnO HO' LOB" ix,iv,x-xii H H xvi xvii xiii-xv -H THPO xviii-xx Reagents i heat at 230 "C; ii NaH MeOCH,CH,OCH,Cl; iii OsO, NaIO,; iv NaBH,; v NaH PhCH,Cl; vi CF,CO,H; vii 0, salcomine DMF; viii (a-H,C= CHCH =CHCH,OH PhH heat; ix dihydropyran H+; x PrhNEt MeOCH,Cl; xi LiAIH,; xii MsCl Et,N H,O NaHCO,; xiii H, Rh/C; xiv Li NH (liq.) Bu'OH; xv Cr0;2 pyridine; xvi K TiCI,; xvii DMSO (Cl,CCO),O Et,N; xviii PrLNEt MeOCH,CH,OCH,Cl ; xix OsO, N-methylmorpholine N-oxide; xx Pb(OAc) ;xxi (PhCH,),NHb CF,CO; xxii P$P= CH, HMPA ;xxiii AcOH Scheme 36 of Stork converged on the key alcohol (121) which was converted into the P-chloroacrylate ester (122) and thence the pentacyclic lactone (123) by heating to 160 "C in benzene with propylene oxide as an acid scavenger (Scheme 35).The intramolecularity of the process guaranteed the development of the correct stereogenicity at C-5,which because of the convexity this imposed on the upper face of the enolate anion derived from the lactone ensured that C-methylation at C-4 would subsequently take place in the desired stereochemical sense as well to furnish (124). The methoxyethoxymethyl (MEM) protecting group was removed from this material to allow derivatization with ( -)-a-phenethylamine furnishing a mixture of diastereomeric carbamates (126) which could be separated chromatographically thereby effecting an optical resolution of the ( f)-carbin01 (1 25).Conversion into the half-ester (1 27) completed the formal total synthesis of GA (3),lg2 since (127) had previously been obtained as a degradation product from GA and reconstitutedlol as indicated in the remainder of the Scheme. The synthesis of the vinyl carbinol(l21) was first carried out by means of a 23-step sequence from anisole as outlined in Scheme 36.1g3 The most important step was the Diels-Alder reaction (128) -f (129) which established the correct relative stereochemistry between pro-C-6 C-8 and C-9. It also located a double-bond in ring B where it could be subsequently cleaved. Re-closure by means of a carefully controlled aldol condensation established a suitably functionalized five- membered ring.The a@-unsaturated aldehyde (13I) thus obtained was converted into the triene (132) by means of a double Wittig methylenation and then hydrolysed to the target carbinol (121). A further feature of this synthesis was the pinacol reduction of the keto-aldehyde (130) to form ring D with incorporation of the bridgehead hydroxyl a reaction which was extensively investigated in model NATURAL PRODUCT REPORTS,1988 x,iv H H Gixlxx 0==?m I xix,xxi + OEt iv-viii xv,xvi I H oq H -cIqo xvii,xviii '"'0MEM '"'0MEM (133) \H xxii xxiii '0H '0H Reagents i H,C=CHMgBr Cu,I,; ii OsO, NaIO,; iii NaOH EtOH; iv HOCH,CH,OH (EtO),CH H+ v B(CHMeEt),H NaOH H,O,; vi MsCl Et,N; vii H, Pd/C; viii pyridinium chlorochromate;ix KOBut; x MeLi MeOH (repeat 3 times); xi 0,,Me$; xii NaOH EtOH ;xiii 3,5-(NO,),C,H,CO,H Na,CO, 4,4'-thiobis(6-t-butyl-3-methylphenol);xiv NaOH MeOH ; xv DMSO (Cl,CCO),O Et,N ; xvi MeOCH,CH,OCH,CI PriNEt; xvii Ph,P=CH, HMPA; xviii AcOH H,O; xix EtOCHO NaH; xx KOBu' Mel; xxi NaH Na(MeOCH,CH,O),AlH, NH,Cl ;xxii Na(MeOCH,CH,O),AlH, (CO,H) ; xxiii Ph,P =CH, THF Scheme 37 In an attempt to improve upon the preparation of (121) further syntheses were undertaken by Corey and his co-workers.The first of these is outlined in Scheme 37,1g5 and although it proved to be more protracted than the previous one the elaboration of the tricyclic skeleton from a spiro- cyclohexane precursor (which had precedent in a study reported by TrostlE3) is an interesting departure from more traditional routes.The strategy employing an intramolecular aldol reaction to construct ring D and a subsequent Baeyer-Villiger oxidation to introduce the bridgehead hydroxyl had been followed earlier in a synthesis of the diterpene hibaene.Ig6 A subsequent approach to (121) converging on the ketone (133) (Scheme 38),19' however proved to be remarkably direct saving nine steps over the original synthesis (Scheme 36). The pivotal step in this new route was the oxy-Cope rearrangement of the norbornene derivative (134) to afford the cis-fused indene (135). This product was transformed into the dione (136) which then underwent selective intramolecular cyclization to the desired ethanohydrindanone (1 37) a result which had been predicted from molecular-mechanics calculations to be 2 kcal mol-I more favourable than the alternative cyclization onto the cyclopentanone carbonyl group.The tricyclic ketone (1 37) was also prepared very efficiently by Stork et al. from three approaches (Scheme 39),l9* all of NATURAL PRODUCT REPORTS 1988-L. N. MANDER + 2-isomer (2:l) vi -It (135) vii,viii Reagents i BuLi H,C =C(Br)CH,Br ; ii 1,8-diazabicyclo[5.4.O]undec-7-ene;iii H,C =C(COMe)CO,Me BF .Et,O; iv Me,SiOSO,CF, Et,N; v heat toluene 1,Zepoxypropane ;vi NaC1 wet DMSO; vii 9-borabicyclo[3.3. llnonane H,O, NaOH ;viii pyridinium dichromate; ix BuiCuLi NH,Cl ; x MeOCH20CH,CH,0CH,Cl PrkNEt Scheme 38 iv-vi vii-ix 1 i H xvii,xx xii xxi xvi-xviii T 0 H xxii,xxiii v Reagents i KN(SiMe,), PhH; ii BuiAIH then HOAc; iii LiC CH; iv MsCI pyridine; v NaAl(OCH,CH,OMe),H,; vi LiNPr;; vii LiNPrh then BrCH,C(OMe) =CHCO,Me; viii MeCH =CHCH,MgBr; ix HCIO,; x NaOMe; xi NaCl wet DMSO; xii HOCH,CH,OH H+;xiii KOBu' DMSO; xiv 0,,then Me$; xv Ph,P=CHCI; xvi LiNPri then H,C=C(OMe)CH,Br; xvii H,O+; xviii KOH EtOH; xix Li NH (liq.); xx NaBH,; xxi Cr0;2 pyridine; xxii K NH (liq.) (NH,),SO,; xxiii HOAc (aq.) Scheme 39 NATURAI PRODUCT REPORTS 1988 A (3) -0 0 0 i,ii iii iv,v,ii Reagents i CH,N,; ii MnO,; iii NaOH; iv CICO,Me Et,N; v NaBH,; vi NaOEt scheme 40 R 0 H+ @ -N2 (141) R = H (143) R = H (142) R = OCOCC13 scheme 41 (144) R = OCOCCI OMe dOMe H t C02CH2P h vii cl+co2H OMe 'CH (C02Me)2 lx OPh xi xii-xiv xv-xvii :III OCOP h xviii-xx f----""0C0 Ph OMOM OMOM OMOM (1 45) Reagents i Bu"Li Me,NCH,NMe, CO,; ii Li NH (liq.) ButOH; iii DMF POCl, then H,O; iv PhCH,Br K,CO, DMF; v H,C=CHMgBr; vi SOCl,; vii CH,(CO,Me), NaH DMF HMPA; viii H, Pd/C; ix ClC(O)C(O)Cl then CH,N,; x CF,CO,H; xi PhCH,NMei OMe- PhH; xii NaBH,; xiii PhCOCl pyridine; xiv Pr"SLi HMPA; xv H,SO, CHCl,; xvi H,CrO,; xvii MeOCH,Cl PriNEt; xviii K,CO, MeOH; xix H,CrO,; xx 2,4,6-tri-isopropylphenylsulphonylazide PhH 66 % KOH 18-crown-6 Bu;N+ C1-; xxi hv,THF (aq.) NaHCO Scheme 42 NATURAL PRODUCT REPORTS 1988-L.N. MANDER i ____) ‘0 H iii I v,vi vii,viii I OMOM OMOM OMOM C02Me C02Me C02Me (1 46) (147) xii,viii! Xlll xiii,xiv oc 0 PhC02 C02H CO2Me Reagents i KBuiBH; ii HCO,Me NaOMe; iii TsN, Et,N MeCN; iv hv THF (aq.) NaHCO then CH,N,; v MeOCH2C1 PriNEt; vi B2HG then Na,HPO, H,O,; vii PhSeSePh KH then 30% H,O,; viii Cr0;2 pyridine; ix (H,C=CHCH,),Al; x (EtCO),O 4-dimethylaminopyridine Et,N; xi KH DMF then Et,NH’ OAc-; xii (Me,CHCHMe),BH then Na,HPO, H,O ;xiii K,CO, MeOH ;xiv PhCOCl pyridine; xv Ph,P=CH, ButOH; xvi Pr’OH; xvi Pr”SLi HMPA Scheme 43 which led via the reductive cyclization of the acetylenic ketone forming the C(3)-C(4) bond by an aldol ,01 and this (138).This elegant tactic for the assembly of the methylene- was confirmed by Stork and Singh on a degradation product of carbinol moiety of ring D had also been employed earlier GA as outlined in Scheme 40.85 in the synthesis of the isomeric ketal (139)18’ and of the Two further key elements in the success of these approaches ethanofluorene (1 40).lg9 were the discovery that ring D could be built very efficiently by the intramolecular ipso-alkylation of aromatic rings by a protonated diazoacetyl function e.g. (141) +(143) (Scheme 10.2.2 Intramolecular Aldol-Based Approach to Syntheses of 41).202-204This process affords the additional benefit of (+)-GA (9),(f)-GA (IS),and Gibberellic Acid (3) liberating the latent functionality in the anisole ring and with This approach was inspired by the observation of the this type of dienone in hand it was natural to arrive at the stereochemical inversion at C-3 in GA (15) to give (16) concept of utilizing an intramolecular conjugate reaction to (Scheme 2) a transformation which had been rationalized in add on the elements of ring A.These ideas were translated terms of a retrograde aldol reaction followed by re-closure to initially into the synthesis of the gibberellane (145) outlined in the thermodynamically more stable equatorial 3a-e~imer.~~Scheme 42205-207 and then into the syntheses of (+)-GA (9),08 Studies of model compounds by Dolby et al. established the and (+)-GA (15)87 as outlined in Schemes 43 and 44 feasibility of completing ring A of GA (3) and GA (15) by respectively. The first of these approaches inevitably suffered NATURAL PRODUCT REPORTS 1988 OH OH -iii (144) iv/ OH OH OH c;"' 0 V "Oal -vi C02Me N2 vii,viii OH OH n A\ OH xii,xiii I OH (9) (149) 3P (150) 3a) ':' Reagents i Na,CO,; ii HOCH,CH,OH Dowex 50wX8 4 A sieves ; iii K-Selectride [KB(CHMeEt),H] THF EtOH ; iv 2,4,6-tri- isopropylphenylsulphonyl azide PhH 66 YOKOH 18-crown-6; B$N+ C1-; v hv NaHCO, CH,N,; vi Pr'Me,CBH, H,O, Na,HPO,; vii PhSeSePh KH DMF THF H,O,; viii MnO,; ix (H,C=CHCH,),Al; x (EtCO),O 4-dimethylaminopyridine ; xi KH DMF Et,NH+ OAc-; xii (Pr'MeHC),BH H,O, Na,HPO,; xiii Cr0;2 pyridine; xiv K,CO, MeOH; xv H,O+; xvi Me,SiCl PriNEt; xvii Ph,P=CH, Bu'OH; xviii Pr"SLi DMF then H,O+ Scheme 44 Scheme 45 NATURAL PRODUCT REPORTS 198%-L.N. MANDER 571 0 HOW iii 0 ,- ,OSiMe3 0 0 I- v,vi iv PhC02 PhC02 (153) :O2Me \kii 1" 7 PhC029.vii V Reagents i OsO, N-methylmorpholine N-oxide ; ii PhCHO H+ ; N-bromosuccinimide hv; iv 1,5-diazabicycl0[4.3.O]non-5-ene, DMF ; v H,O+; vi Me,SiCI PriNEt; vii Ph,P=CH, Bu'OH; viii K,CO, MeOH then H,O+; ix,Pr"SLi HMPA. Scheme 46 from lack of stereochemical control because of the number of sp2centres involved but the latter sequences featured excellent stereoselectivity in the elaboration of the stereocentres C-4 C-5 C-9 and C-10 crucial aspects of which were the utilization of the unusual intramolecular Michael addition reaction of the propionate ester (147) and of its GA analogue. Both syntheses suffer from the reactivity of the ketones (146) and (148) towards electrophiles severely proscribing the choice of a suitable precursor synthon for addition of the C(lFC(3) fragment (a problem which was eventually solved by the addition of triallylalane).As expected the final aldol process was effective in completing ring A although with poor stereochemical control at C-3. For the purpose of synthesizing GA (3) this last aspect was of little consequence since the plan (Scheme 45) called for epoxidation of the A2 olefinic ketal (151). This was prepared equally well from either (149) or (150) by elimination of a 3- phenylsulphonate function. Before proceeding however (1 51) was subjected to a Pirkle resolution [c$ (125) ~(126)].209 Unfortunately the double-bond in this molecule was low in reactivity towards peroxycarboxylic acids and forcing con- ditions were required to effect reaction.210 The main problem was nevertheless a lack of stereoselectivity and a 2:3 mixture of 2j3,3P- and 2a73a-stereoisomers was formed.The approach outlined in Scheme 46 was therefore followed.87 This sequence proceeded very smoothly until the Wittig reaction (1 53) + (1 54) was attempted. The product from this reaction was often the triene (155) (ironically the first direct evidence for the intervention of the retro-aldol reactions of 3-hydroxygib-berellins!); the desired outcome was only achieved with enormous care and only then with variable reliability. The problem was solved by the addition of (2-ch1oroethoxy)-trimethylsilane which serves to 'buffer' the t-butoxide base in equilibrium with the phosphonium ylide.88 10.3 The C,D + A,B-Ring Approach Synthesis of Gibberellin A (159) De Clercq and his co-workers have made especially effective use of intramolecular Diels-Alder reactions of furans in the construction of several natural products,211 a strategy which has afforded the most direct approach yet to the total synthesis of gibberellins.Thus the preparation of (-k)-GA (159) in only sixteen steps from 3-methoxybenzoic acid that is outlined in 22 NPR 5 NATURAL PRODUCT REPORTS 1988 iv-vi "\ (1 59) Me0 Me0 Reagents i (2-fury1)magnesium iodide then BrCH,C(Br)=CH ; ii H,O+; iii BuzCuLi ;iv LiAIH,; v ClC(O)C(O)Cl DMSO then Et,N; vi LiC -CCO,Et; vii P-cyclodextrin H,O at 65 "C; viii H (1 equivalent) Pd/CaCO,; ix NaBH, EtOH; x MeOCH,CH,0CH2C1 PrkNEt; xi MeOCH,PPh,+ C1- Am'OK PhH ;xii LiNPr'C,H,, then Me1 ;xiii pyridinium tosylate ButOH; xiv NaCIO, NaH,PO, Me,C =CHMe Scheme 47 Scheme 47212hinges on the high-yield conversion of (156) into (157).At high temperatures (1 57) tended to isomerize to (1 58) but this could be avoided by conducting the reaction at 65 "C in an aqueous medium in the presence of P-cyclodextrin. 11 Antheridiogens Following the discovery of an antheridium-inducing factor in gametophytes of the bracken fern (Pteridium ~quilinum),~'~ several similar substances for which the term antheridiogen has been coined have been isolated from a range of fern species.214The antheridiogens from the Schizaeaceae have been shown to have gibberellin-like properties and the major antheridiogen isolated from Lygodium juponicum to be GA methyl ester (160).215 A less abundant (34 nanograms per litre of culture filtrate) but very much more potent substance has also been isolated from this species and has been shown by synthesis to be the 9,ll-didehydro-analogue (161).216 Of rather Very recently a very small amount more interest has been the structure of the antheridiogen of the genus Anemia.217.218 isolated from Anemia phyllitidis which was deduced initially to (< 50 micrograms) of a new antheridiogen has been isolated be (162)72but for which the structure was subsequently revised from gametophytes of Anemia mexicana.21s From a com-to the 3a-epimer (4).73 It has been given the trivial name bination of spectroscopic and synthetic studies it has been antheridic acid and has been isolated from several other species possible to determine that it has the constitution (163).,,O NATURAL PRODUCT REPORTS 1988-L.N. MANDER AcO"" Scheme 48 i-iv ____t H I vi t 0 I // I 0 0 xi,xii xiii ___)c M MOM I xiv-xvi xviii xix xvii -HO\\'\ OH MOMO\\'\ MoMo"" Reagents i CH,N,; ii pyridinium dichromate; iii NaBH,; iv MeOCH,Cl PrhNEt; v NH,NH;H,O DMF at 120 "C; vi KI, K,CO,; vii O, pyridine then Me,S; viii KH; ix LiOH; x KI,; xi (CF,CO),O pyridine; xii Zn KI; xiii 1,8-diazabicyclo[5.4.0]undec-7-ene; xiv H, Rh/Al,O,; xv Ph,P=CH,; xvi LiN(Pr')C,H,, then Et,NH' C1-(3 cycles); xvii SeO, Bu'OOH; xviii Me,BBr; xix LiOH MeOCH,CH,OMe Scheme 49 1 1.1 Conversions of Gibberellins into Antheridiogens In most cases the prospect of accumulating sufficient quantities of these antheridium-inducing factors from natural sources in order to carry out full chemical and biological studies appears to be remote.The structural similarities with the standard gibberellin molecule however not only indicate a close biosynthetic relationship but also present an opportunity to gain access to these intriguing molecules synthetically. An attempt to do this by means of an epoxide-initiated Wagner- Meerwein rearrangement i.e. (1 64) +(I 65) (Scheme 48) failed but the route outlined in Scheme 49 proved to be satisfac-tory.221 The pivotal steps in this transformation are the intra- molecular alkylation (1 66) 3(1 67) and the controlled frag- mentation (1 68) +(1 69) initiated by enolization of the 7-ester function.The basic strategy had ironically been inspired by a much earlier study designed to provide access to the gib- berellane skeleton.222 An unanticipated bonus of this study was the provision of structural data which allowed the structure of the antheridiogen of Anemia mexicana to be deduced as (163). This was then NATURAL PRODUCT REPORTS. 1988 iv,v H (171) viii V ix,x xi-xiii H0$$do C02Me C02Me Ms Reagents i CH,N,; ii MeOCH,Cl PriNEt; iii NH,NH;H,O DMF at 120 "C; iv KI, K,CO,; v 0, pyridine then Me,S; vi KH; vii Ph,BBr; viii MsC1 Et,N; ix LiOAc HMPT; x K,CO, MeOH; xi H, Rh/Al,O,; xii CH,Br, TIC], Zn; xiii Pr"SLi HMPT Scheme 50 confirmed through synthesis by adapting the methodology that had been developed for the preparation of (4)(Scheme 50).223 The chemistry in this sequence was on the whole straight- forward except for the reinstatement of the methylene group C-17 into (172).The adduct between this compound and methylenetriphenylphosphorane was surprisingly stable and difficulty was experienced in forcing the Wittig reaction to proceed to completion. Fortunately the Lombard0 methylen- ation procedure afforded excellent yields.l12 A further inter- esting feature of the conversion was the contrathermodynamic [cf. (3)+(13)] isomerization of the allylic lactone system in (170) to give (171) during the deprotection of the 3-oxy function by diphenylboron 11.2 Total Synthesis of (fFAntheridic Acid (4) The bicyclo[2.2.2]octene moiety in antheridic acid (4)inevitably invites serious consideration of a Diels-Alder- based approach to the total synthesis of this molecule.It comes as no surprise therefore that once again this most powerful of synthetic procudures features in the Corey-Myers synthesis outlined in Scheme 51.73 The full sequence is rich in chemistry and features the intramolecular cyclopropanation (1 73) +(1 74) (again an echo of early studies on gibberellin synthesis),222 followed by the Lewis-acid-catalysed vinylcyclopropane rearrangement (175)+(176). An important outcome of this work was the provision of both 3-epimers of this type of molecule which enabled the assignment of the correct structure as (4),rather than as (162).226 NATURAL PRODUCT REPORTS 1988-L.N. MANDER ii,iii Meq' 0-CO2Me C02Me C02Me iv-vii - - ix,x viii TB DMS TBDMS TBDMS '0 '0 CH2OCOCHNr (175) ixi- (173) xiii TBDMS TBDMS rH z -\oA'o lxiv 0 v2 xvii,xviii xv,xvi TBDMS TBDMS EHO "zMe xix,xx xxi,xxii xxiii,xxiv ___t TBDMS TBDMS xxiv,xxv xxiii,xxvi (TBDMS = Bu'MeZSi) ____)_ Reagents i (n-cyclohexenyl),Ni,Br, DMF; ii Na NH (liq.) Bu'OH then MeI; iii H,O+; iv Zn(BH,),; v Bu'Me,SiOSO,CF, 2,6-lutidine; vi BuhAIH CH,CI,; vii CIC(0)CH =NHNTs then Et,N; viii bis(N-t-butylsalicylaldiminato)copper(rr) PhMe at 1 10 "C; ix Br, CCI,; x I ,8-diazabicyclo[5.4.O]undec-7-ene; xi Et,AICI ;xii MeCO,,H ;xiii LiNEt ;xiv H,C =CHNO, N,N-dibornylamine ;xv KOH then Na,RuO ; xvi CH,N ; xvii (CF,CO),O pyridine ; xviii I ,8-diazabicyclo[5.4.O]undec-7-ene; xix NaClO, Bu'J)H (aq.) NaH,PO, Me,C =CHMe; xx CF,CH,OH 2,6-lutidine; xxi Me,SiCI Et,N LiNPr;; xxii PrhNEt propylene oxide Mel Me,N=CH I-; xxiii NaBH, MeOH; xxiv pyridine .HF MeCN ;xxv pyridinium dichromate ;xxvi LiOH MeOCH,CH,OMe Scheme 51 NATURAL PRODUCT REPORTS 1988 i-iii iv O7 SEMO 0IMe xii i-xvi ii vi-xii SEMO SEMO xx xxi-xxiv __t COzMe __t CH20MOM CH20MOM CH~OMOM CH20MOM CH2OM0M XXV-xxxii i XI-xlii xxxviii,xxxix __t H -H Jzp COlH ‘OzH H0 (SEM = Me3SiCH2CH20CH2) Reagents i EtO,C(Me)C=C(CN),; ii NaOH EtOH; iii Ac,O; iv AlCl,; v rn-ClC,H,CO,H; vi Me,SiCl imidazole; vii Me,S+ I- Bu”Li; viii BF;OEt,; ix NaBH,; x MeOCH,Cl PrhNEt; xi BuiN+ F-;xii Me,SiCH,CH,OCH,Cl PrhNEt; xiii H, Pd/BaSO,; xiv LiAlH,; xv MeOCH,Cl PrhNEt; xvi Na NH (liq.) EtOH; xvii AcOH (aq.); xviii K,CO, MeOH; xix H,C=C=CH, hv; xx 0, MeOH NaHCO, then Me$; xxi K,NH (liq.) (NH,),SO,; xxii ClC(O)C(O)Cl DMSO then Et,N; xxiii MeOCH,Cl PrhNEt; xxiv MePh,P+ I- Bu”Li;xxv BuiN+ F-;xxvi MsCl pyridine; xxvii 1,8-diazabicyclo[5.4.O]undec-7-ene; xxviii conc.HCl MeOH ;xxix ClC(O)C(O)Cl DMSO then Et,N; xxx NaClO,; xxxi MeOCH,CI Pr’,NEt ;xxxii KOH (aq.) ; xxxiii I, NaHCO,; xxxiv 1,8-diazabicyclo[5.4.0]undec-7-ene; xxxv MeOCH,Cl Prl,NEt ; xxxvi LiNPrl, THF; xxxvii rn-ClC,H,CO,H; xxxviii THF (aq.) pyridine; xxxix LiNPrl, then Li NH (liq.) ; xl I, NaHCO,; xli conc.HCl MeOH ;xlii 1,8-diazabicyclo[5.4.O]undec-7-ene Scheme 52 12 Addendum A total synthesis of (+)-GA has recently been disclosed by 13 References Nagaoka el al. (Scheme 52). The earlier stages involving a 1 ‘Phytohomones and Related Compounds -A Comprehensive [4+2] cycloaddition approach to the elaboration of the tri- Treatise’ Vol. I and 11 ed. D. S. Letham P.B. Goodwin and T. J. V. 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Cossey L. Lombardo and L. N. Mander Tetrahedron Lett. 1980 21 4383. 209 W. H. Pirkle and J. R. Hauske J. Org. Chem. 1977 42 2781. 210 Y. Kishi M. Aratani T. Fukuyama F. Nakatsubo T. Goto S. Inoue H. Tanino S. Sugiura and H. Kakoi J. Am. Chem. SOC. 1972 94 9217. 21 1 L. A. Van Royen R. Mijngheer and P. J. De Clercq Bull. SOC. Chim. Belges 1984 93 1019. 212 W. M. Grootaert and P. J. De Clercq Tetrahedron Lett. 1986,27 1731. 213 W. Dopp Ber. Dtsch.Bot. Ges. 1959 63 139. 214 U. Naf K. Nakanishi and M. Endo Bot. Rev. 1975 41 315. 215 H. Yamane N. Takahashi K. Takeno and M. Furuya Planta 1979 47 215. 216 H. Yamane Y. Satoh K. Nohara M. Nakayama N. Murofushi N. Takahashi K. Takeno M. Furuya M. Furber and L. N. Mander Tetrahedron Lett. 1988 29 3959. 217 R. P. Zanno M. Endo K. Nakanishi U. Naf and C. Stein Naturwissenschaften 1972 59 512. 218 H. Yamane K. Nohara N. Takahashi and H. Schraudolf Plant Cell Physiol. 1987 28 1203. 219 J. E.Nester S. Veysey and R. C. Coolbaugh Planta 1987 170 26. 220 M. Furber L. N. Mander J. E. Nester N. Takahashi and H. Yamane Phytochemistry accepted for publication. 221 M. Furber and L. N. Mander J. Am. Chem. SOC. 1987 109 6389. 222 D. J. Beames J.A. Halleday and L. N. Mander Aust. J. Chem. 1972 25 137. 223 M. Furber and L. N. Mander J. Am. Chem. SOC.,1988,110,4084. 224 Y. Guindon C. Yoakim and H. E. Morton J. Org. Chem. 1984 49 3912. 225 H. 0.House and C. J. Blankley J. Org. Chem. 1968 33,47. 226 E. J. Corey A. G. Myers N. Takahashi and H. Schraudolf Tetra-hedron Lett. 1986 27 5083. 227 H. Nagaoka M. Shimano and Y. Yamada 108th Annual Meet- ing of the Pharmaceutical Society of Japan Hiroshima April 1988 Abstract 55. 228 C’ R. W. Guthrie 2. Valenta and K. Wiesner Tetrahedron Lett. 1966 4645. 229 CJ I. F. Cook and J. R. Knox Tetrahedron Lett. 1970 4091.

ISSN:0265-0568    

DOI:10.1039/NP9880500541

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Natural Products from Plant Tissue Culture B. E. Ellis Department of Chemistry and Biochemistry University of Guelph Guelph Ontario NIG 2WI Canada Reviewing the literature published between January 197.9 and December 1986 1 Introduction 2 Quinones 2.I Ant hraquinones 2.2 Naph thoquinones 3 Phen ylpropanoids 3.1 An thocyanins 3.2 Tannins and Proanthocyanidins 3.3 Flavonoids and Isoflavonoids 3.4 Stilbenes and Dihydrostilbenes 3.5 Phenalenones 3.6 Lignans 3.7 Coumarins 3.8 Dopa and Betalains 3.9 Hydroxycinnamic Acid Derivatives 4 Isoprenoids 4.1 Monoterpenes 4.2 Sesqui terpenes 4.3 Di terpenes 4.4 Triterpenes 4.5 Carotenoids 5 Alkaloids 5.1 Indole Alkaloids 5.2 Furoquinoline and Acridone Alkaloids 5.3 Harringtonine Alkaloids 5.4 Isoquinoline Alkaloids 5.5 Quinolizidine Alkaloids 5.6 Tropane Alkaloids 5.7 Pyridine Alkaloids 5.8 Purine Alkaloids 6 Other Compounds 6.1 Aldoxime Derivatives 6.2 Amino Acid Derivatives 6.3 Volatiles 6.4 Polyacetylenes and Thiophenes 6.5 Organic Acids 6.6 Polyketides 7 References 1 Introduction Culture of plant tissues on defined media under controlled aseptic conditions enables many facets of plant biology to be experimentally manipulated with relative ease.Since one of the striking chemical attributes of plants is the range of natural products (secondary metabolites) which is formed throughout the plant Kingdom it is not surprising that the possibility of this chemical virtuosity being expressed within culture systems quickly attracted attention.Three decades of experience has tempered the initial optimism concerning the potential for industrial exploitation of plant cell cultures but scientific opportunities still abound as reflected in the continuing growth and increasing sophistication of the literature. Detailed exam- ination of optimization of the culture medium identification of the full range of metabolites produced comparison of effects of genotype and the origin of tissues study of the stability of production levels and profiles definition of biosynthetic pathways and the isolation of enzymes have become common themes.The present Report does not cover all of this work in detail. New reports of the accumulation of properly charac- terized natural products have been given first priority since these expand the range of problems which can be addressed in culture systems. Observations on treatments which enhance the productivity of previously reported systems are also important as are manipulations of cultures which lead to reproducible alterations in the pattern of accumulated natural products. These can provide crucial insights into the regulatory mech- anisms which govern the timing and level of expression of those genes responsible for synthesis of natural products. The choice of a time-frame for this Report has taken irlto consideration the comprehensive coverage of the earlier literature provided in reference 1 as well as a number of other authoritative reviews which appeared at about the same time.2-7 In a recent historical perspective,8 Staba was able to identify 27 review articles which appeared between 1965 and 1983 on the general theme of the accumulation of secondary metabolites in cell cultures and this flood continues ~nabated.~-~~ Discussions of more specific aspects of the production of secondary metabolites such as the use of cultures to study bio~ynthesis,~~ the accumulation of metabo- lites in pro top last^,'^^^^ the impact of stress on secondary metabolism in cultured cells,17 methodologies for screening and election,'^.23 regulation of enzymes in secondary metab- oli~m,~.~~ and genetic engineering of the synthesis of natural products,27 have also appeared. Finally the Proceedings of the 1982 and 1986 Congresses of the International Association of Plant Tissue Cult~re~~+~~ should be consulted directly by interested readers since the present Report deals only with refereed publications appearing in the review period. The Report has been broadly organized according to chemical class with major sections for quinones phenylpro- panoids isoprenoids and alkaloids. Section 6 includes the relatively few examples of compounds which do not fall within the first four classes. Excluded from the Report are studies dealing exclusively with compounds (e.g. amino acids vita- mins and enzymes) which do not fit the generally accepted definition of a secondary metabolite.2 Quinones The accumulation of naphthoquinone and anthraquinone derivatives in cultured cells is easily recognized because of the resulting colour. In addition to attracting attention to this expression of secondary metabolism the pigmentation can facilitate the direct selection of high-producing clones. 2.1 Anthraquinones Since the original observation that calli of Cinchona fedgeriana accumulated alizarin (I) alizarin 1-methyl ether (2) rubiadin (3) 1-hydroxy-2-hydroxymethylanthraquinone (4) and 1,8-dihydroxyanthraquinone (5),32 the members of this genus have been the focus of several reports. A more detailed examination 58 1 NATURAI PRODUCT REPORTS 1988 R3 (1) R'=R2=OH.R3=R4=H (2) R1=OMe,R2=OH.R3=R4=H (3) R'=R3=OH.R2=CH3.R4=H (4)R' =OH,R2=CH,0H,R3=R4=H (5) R' =R4=OH,R2=R3=H R5a \R R32 0 R4 (6)R'=R2=R4=OH. R3=R5= R6=H ( 7) R1= R2=OMe ,R3= OH R4 = R =R6= H (8) R1= R3=OMe. R2=OH R4= R5=R6=H (9) R1=OH R2=Me R3= R4= R5=R6=H (10) ~1 =R5= OH R2=Me,R3=R4= H ,R6=OMe (11) R1=OH,R4=H or R1=H,R4=OH; R2=CH20H,R3=H or R2=H,R3=CH20H; R5=R6=0Me (12) R1=R4=R6=0H; R2=Me ,R3=H or R2= H R3=Me; R5= OMe (13) R1=R3=R4=OMe; RZ=OH;R5=R6=H (14) R1=R3=R5=OH ; R2 = R6= H ;R4= OMe (15) R1=R4=OMe;R2R3=OCH20; R5=R6=H (16)Rl=R3=OH;R2=R5=R6=H;R4=OMe (17) Rl=R3=0H; R2=R5 =OMe; R4=R6=H (18) R1=R4=R5=OH;R2=OH,R3=OMeor R2=OMe,R3=OH; R6=H (26) R1=R4= R5= OH; RZ=Me ;R3= R6= H (27) R1=R5=OMe; R2R3=OCH20; R4=R6=H (28) R1=R2=R5=R6= OMe ; R3=R 4= H (29) R' =R3= OMe ; R = R4= R6= OH ;R5=H (30) R1=R3=R4=R6=H;R2=Me;R5=OH R7&R2 R6 R5 of the anthraquinone profile in calli of C.ledgeriana failed to detect alizarin alizarin 1-methyl ether or 1,8-dihydroxyanthra- quinone but did confirm the presence of rubiadin (3) and 1-hydroxy-2-hydroxymethylanthraquinone (4).33 In addition a further thirteen anthraquinone derivatives were identified including eight novel structures. The known compounds included purpurin (6) anthragallol 1,2-dimethyl ether (7) anthragallol 1,3-dimethyl ether (8) 1-hydroxy-2-methylanthra-quinone (9) and 1,7-dihydroxy-8-methoxy-2-methylan thra-quinone (10).The new structures were reported to be 1-(or 4-)hydroxy-2-(or -3-)hydroxymethyl-5,6-dimethoxyanthraqui-none (1 I) 1,4,6-trihydroxy-5-methoxy-2-(or -3-)methylanthra-quinone (1 2) 2-hydroxy- 1,3,4-trimethoxyanthraquinone (1 3) 1,3,5-trihydroxy-4-methoxyanthraquinone(14) 1,4-dimeth-oxy-2,3-methylenedioxyanthraquinone(15) 1,3-dihydroxy-4-methoxyanthraquinone (1 6) 1,3-dihydroxy-2,5-dimethoxy-R3 R4 anthraquinone (1 7) and 2,5-(or 3,5-)dihydroxy- 1,3,4-(or -1,2,4-)trimethoxyanthraquinone(1 8).33 The quantities that accumulated were not reported. In a parallel study calli of Cinchona pubescens Vahl (syn. C.succirubra Paron et Klotzsch) were shown to contain alizarin alizarin 1-methyl ether rubiadin 1,8-dihydroxyanthraquinone,and 1-hydroxy-2-hy-dro~ymethylanthraquinone,~~ this profile being very similar to that of C.fhdgeriana.In a more extensive examination of calli of C.pubescens twelve anthraquinones were detected including the five new compounds 2-hydroxy- 1,3,4,6-(or 1,3,4,7-)tetra- methoxyanthraquinone (19) 1,6-(or 1,7-)dihydroxy-2-methyl-anthraquinone (20) 5-hydroxypurpurin 1-methyl ether (21) 4,6-(or 4,7-)dihydroxy-2,7-(or -2,6-)dimethoxyanthraquinone (22) and 6,7-dihydroxy-1-methoxy-2-methylanthraquinone (23). The known anthraquinones were purpurin (6) anthra- gallol 1,2-dimethyl ether (7) 1-hydroxy-2-hydroxymethyl- NATURAL PRODUCT REPORTS 1988-B. E. ELLIS an thraquinone (4) 2-hydroxy- 1,3,4- trimethox yanthraquinone (1 3) 2,5-(or 3,S)dihydroxy- 1,3,4-(or -1,2,4-)trimethoxy-anthraquinone (1 8) purpurin 1 -methyl ether (24) and alizarin 2-methyl ether (25).35 The total content of anthraquinones in cultures of C.ledgeriana could be increased to 1.5% of the dry weight by treatment with sterilized mycelium of the fungi Phytophthora cinnamomi or Aspergillus niger.36 When suspension cultures of C. ledgeriana were recently analysed in detail fifteen different aglycons were identified including five new anthraquinone derivatives these were 1,4,5-trihydroxy-2-methylanthraquinone (26) 1,Sdimethoxy- 2,3-methylenedioxyanthraquinone (27) 1,2,5,6-tetramethoxy- anthraquinone (28) 2,4,6-tri hydroxy- 1,3-dimethoxyanthra- quinone (29) and 5-hydroxy-2-methylanthraquinone(30).,' The bulk of the anthraquinone complement (90 YO)was released into the medium; this pattern was exploited by incorporating beads of hydrophobic resin into the culture medium.Adsorp- tion of the anthraquinones onto the beads reduced their effective concentrations and apparently released the bio-synthetic pathway from some feedback-inhibitory influence. As a result the production of anthraquinones increased fifteen- fold reaching 530 mg dm- over a culture period of 28 days.,* Optimization of culture conditions was also examined and maximal anthraquinone content was found to be associated with lower concentrations of auxins growth in the dark and either elevated NO,-supply or an elevated supply of 40 Suspension cultures of C. pubescens contained similar overall levels of anthraquinones to those in C.ledgeriana ;the main aglycons that were detected were alizarin and emodin (31).'l Suspension cultures of Morinda citrifolia had earlier been extensively studied in one of the first thorough attempts to optimize the synthesis of natural products through manipu- lation of a medium.42 A full characterization of the anthra- quinone profile was undertaken later and eleven derivatives were positively identified including rubiadin (3) lucidin (32) morindone (33) lucidin 3-0-P-primeveroside (34) and morin- done 6-0-P-primeveroside (35) all of which were already known from this and from other Rubiaceous species. In addition 3 -h ydroxymorindone (36) 5,6-di h ydroxy lucidin (37) 3,5,6-trihydroxy-2-methylanthraquinone(38) and three glyco- sides i.e.the 6-0-P-primeverosides of (36) and (38) and the 3- 0-P-primeveroside of (37) were isolated and characterized all for the first time.43 An earlier report of the presence of alizarin and n~rdamnacanthal~~ could not be confirmed. Suspension cultures of Morinda lucida which can readily be switched from photoautotrophic growth to sucrose-supported heterotrophic growth have provided a striking example of induction and repression of pathways to specific secondary metabolite^.'^ The photoautotrophic cells were found to produce an array of lipoquinones that were typical qualitatively and quantitatively of the intact leaf but they did not produce anthraquinone glycosides. Upon transfer to dark growth conditions in the presence of sucrose synthesis of chlorophyll and lipoquinones ceased and substantial quantities of anthra- quinones accumulated.The profile of anthraquinones changed during the first passages in the heterotrophic environment with lucidin primeveroside and morindone primeveroside making early appearances but being replaced by two more-polar unidentified quinones by the third passage. The anthraquinone spectrum in the fully heterotrophic cultures differed greatly from that of root tissue of M. l~cida.~~ Suspension cultures of Rubia cordifolia have also proven to be a rich source of anthraquinones. Lucidin ethyl ether (39) pseudopurpurin (40) alizarin purpurin and ruberythric acid (41) (a glycoside of alizarin) have been detected.Manipulation of the culture medium showed that as with Cinchona cultures white light was inhibitory to the synthesis of anthraquinones while naphthaleneacetic acid (NAA) was a more effective auxin than was 2,4-D.46,47 In contrast to Morinda cultures however there was no striking sensitivity of the production of anthra- quinones in cells of Rubia cordifolia to modifying the (32) R1=R3=OH,RZ=CH20H,R4=R5=H (33) R1=R4= R5=OH Rz=CHj,R3=H (34) R1=OH,RZ=CH20H,R3=0 -primeverosyl,R4=R5=H (35) R'= R4.s OH,R2=CH3,R3= H R5= 0 -primeverosyl (36) R'=R3=R4=R5=0H,R2=CH3 (37) R1=R3=R4=R5=OH,R2= CHtOH (38) R' = HI R2 =CH3 R3= R4 = R5= OH (39) R' = CH OH R2 = OEt ,R3 = H (40) R' = COzH R2= R3=OH (41) R' = 0-primeverosyl ,R2= R3= H (43) macronutrient composition of the medium.46 Cultures of Rubia fruticosa on the other hand produced maximal levels of anthraquinones (not identified) in a medium that contained 12% In the same study it was demonstrated that various species of Galium Rubia Sherardia and Asperula all produced anthraquinones in suspension cultures although with a wide variation in productivity and in responses to modification of the medium.Suspension cultures of Galium mollugo were found to contain in addition to an array of anthraquinones typical of members of the Rubiaceae a small amount (0.01 YOof the dry weight) of the diglucoside of 1,4- dihydroxy-3-prenyl-2-naphthoicacid methyl ester (42) whose free acid aglycon is a putative biosynthetic intermediate in the formation of an thraquinones.4s By using very protective extraction protocols (inert atmos- phere low temperatures) it has been possible to demonstrate that in addition to the typical anthraquinones (e.g. emodin and chrysophanol) callus cultures of Rumex alpinus Rhamnus frangula and Rhamnus purshiana also contained related labile anthrone and dianthrone derivatives such as chrysophanoldian- throne (43) physcionanthrone and chrysophanolphyscion- dianthr~ne.~~,~' Although the bark of the plants from which the cultures of the Rhamnus species were derived contained closely related anthrone and anthraquinone glycosides the patterns of culture metabolites and bark metabolites were clearly different.50 The calli of Rumex alpinus also contained naphtha- NATURAL PRODUCT REPORTS 1988 (44) R (49) R =H (52) R =OAC YO 0 lene- 1 8-diols [e.g.nepodin (44)]and 2-acetylresorcinol.These studies highlight the problem of determining the forms of some secondary metabolites in situ especially if isolation protocols are employed that include acid hydrolysis heating and/or treatments which permit autolysis in crude homogenates. 2.2 Naphthoquinones The reports of production of naphthoquinones during the period of coverage of this Report have been dominated by the programme directed at formation of shikonin in cultures of Lithospermum erythrorhizon. Since the original visual selection and isolation of high-producing callus clones that are capable of synthesizing approximately 0.6% of their dry weight of shikonin (45)52 (cf.1.2% of the dry weight in roots) much higher-producing (-12YO of the dry weight) suspension cultures have been established. The composition of the culture medium proved to be a major factor in achieving high production. Ammonium nitrogen was a strong inhibitor of shikonin ~ynthesis,~~ although this inhibition could be countered in part by the inclusion in the medium of 0.2% (w/v) of a specific agaropectin fraction.54 Production (but not growth) was also inhibited by the presence of 2,4-D and by gibberellin A (ID5, = lo-'" mol dm-3),5s while it was enhanced by elevated concentrations of Cu2+ (saturating at 1.2 pmol dm-3).56 Cloning protoplasts did not result in any lines with a substantially greater shikonin production5' but combining a q OH (53) 0 'production' medium with larger size of inoculum did raise the yield from 1.4 to 2.3 grams of shikonin per litre.5s The high-producing lines of L.erythrorhizon normally produced a spectrum of naphthoquinone derivatives very similar to that extracted from the medicinal preparations of the plant roots. The major components were the acetylshikonin (46) the isobutyrylshikonin (47) the (J-hydroxyisovalery1)shi-konin (48) and isovalerylshikonin or a-methyl-n-butyrylshiko-nin.59 When the production of naphthoquinones was suppressed by various agents however a different array of metabolites accumulated. These included rosmarinic acid and lithospermic acid (see Section 3.9) 4-hydroxybenzoic acid and its 4-0-p- glucoside (up to 2% of the dry weight of the latter),60 and the benzoquinone derivative echinofuran B (49).61 Echinofuran B also accumulated in cells of L.erythrorhizon that were grown in a production medium and treated with the protein-translation inhibitor puromycin.62 Addition of activated charcoal (1-16 g dm-3) to the medium not only blocked formation of shikonin but led to production of >2 YOof the dry weight of echinofuran B.'jl By contrast a related metabolite 3-geranyl-4-hydroxyben- zoic acid (50) could be detected in non-shikonin-producing cultures only by radioisotope dilution analysis.63 Aside from rosmarinic and lithospermic acids all of these compounds are presumed to be either biosynthetic precursors of shikonin or the products of side reactions taking place on accumulated precursors.The ability to intervene in the biosynthetic pathway to shikonin by simple manipulation of the growth conditions NATURAL PRODUCT REPORTS 1988-8. E. ELLIS offers exciting possibilities for clarifying the enzymology and the regulation of synthesis and accumulation within this group of naph thoquinones. The closely related species Echium lycopsis also formed naphthoquinone derivatives in culture. In addition to small amounts of echjnone (51) and echinofuran (52) large amounts of side-chain-esterified shikonin and alkannin (53) accumulated (-12O/O of the dry weight; cf. 0.03 YO in roots).64.65 While this pattern was similar to that seen in Lithospermum cultures and the production was also reduced by adding 2,4-D or by illumination with white light it differed in the relative proportions of the (R)[shikonin] and (S) [alkannin] isomers that formed.While Lithospermum cells formed predominantly (R) esters Echium cells produced substantially more of the (S) forms although the exact ratio of epimers varied among the individual Finally primary calli of Catalpa ovata were reported to contain low levels of numerous quinones which were identified by gas chromatography-mass spectrometry. These included catalpalactone (54) a-lapachone (59 and a series of a-lapachone derivatives dominated by 8-hydroxydehydroiso- a-lapachone (56) (0.0005 YOof the fresh weight).66 3 Phenylpropanoids The products considered in this section are all non-alkaloidal metabolites that are derived biogenetically from the phenylpro- pane aromatic amino acids most commonly from phenyl- alanine.The majority of reports concern flavonoids but an interesting array of other structural types has also been detected in specific cultures. 3.1 Anthocyanins Cultures of Daucus carota have long been known to accumulate anthocyanin pigments under appropriate growth conditions and this trait together with the good growth characteristics of suspension cultures of D. carota continues to make this a popular system for studies of regulation of the synthesls of anthocyanins. This process has been examined in nutrient- limited chemostat and in various semi-continuous fermentation systems68.69 where relationships between growth rate nutrient supply and accumulation of pigments were explored in detail. A connection between the morphogenetic state of the cultured cells and accumulation of anthocyanins has also been reported in two instances; smaller aggregates of cells in suspension cultures of D. carota accumulated more anthocyanins than did larger while from within a population of small (30-80 pm) aggregates it was possible to recover two sub-populations which differed in their buoyancy in density gradients and in their competence in production of an tho cyan in^.^'. 72 Clonal propagation of cell lines of D.carota that had been selected for high or low production of anthocyanins revealed an intrinsic instability in production values73 similar to that which has been observed in other systems (notably the production of indole alkaloids in cultures of Catharanthus roseus).Manipulation of the culture medium for higher production of anthocyanins in suspensions of D. carota showed that withdrawal of 2,4-D greatly enhanced the accumulation of pigments ; a sharp optimum ( mol dm-3) for the concentration of a cytokinin (zeatin) was also identified.74 The inclusion of gibberellin A in the medium strongly inhibited the accumulation of an tho cyan in^,^^ an effect noted previously in betalain-producing cultures of Beta vulgari~.~~ Despite this interest in regulation of the production of anthocyanins in cultures of Daucus carota little attention was paid to the identity of the pigments involved.In an early report four anthocyanins were identified from suspension-cultured cells these were cyanidin 3-0-glucogalactoside cyanidin 3,5-di-0-galactoside cyanidin 3-O-glucoside and cyanidin 3-0- gala~toside.~~ This pigment profile differed from that of the intact plant and during a subsequent careful re-examination of OH Gal -Glc -Xyl V sinapyl (57) -Glc -Rha p-coumaryl (58) R = H (59) R =Me cultured cells a single major pigment species cyanidin 3-0- (sinapoylxylosylglucosylgalactoside)(57) was detected. This is the same anthocyanin as is found in the plant.78 Another member of the same Family Bupleurum falcatum also produced anthocyanins in culture in this case malvidin glucosides which were not further characterized.79 The antho- cyanins that can be induced to accumulate in cultures of Catharanthus roseus particularly under conditions of illumina- tion high sucrose and low nitrogen and phosphate were shown to be mainly glycosides of petunidin and rnalvidha0 Hirsutidin which is the main aglycon of floral tissue of C. roseus was only a minor component of the culture pigments. While the total level of anthocyanin that accumulated was not exceptional microspectrophotometric examination of individual cells re- vealed that some highly pigmented cells in the culture contained internal concentrations of pigment as high as those in the differentiated plant tissue.81 Calk of both Euphorbia millii and E.tirucalli produce cyanidin-based anthocyanins and it has been reported that stable high-producing lines of E. millii cells can be obtained by repeated visual 83 Cultures of Strobilanthes dyeriana resembled those of Daucus carota in synthesizing the same anthocyanins as are found in the leaves of the source plant (i.e. cyanidin 3,5-di-O-glucoside and peonidin 3,5-di-O-gl~coside).*~ A similar correspondence was noted for cultures of Matthiola incana which accumulated relatively low levels of cyanidin glyco~ides,~~ and for calli of Callistephus chinensis,s6 except that in the latter the cyanidin-based culture pigments resembled those of the plant stem rather than the flower. Other reports of the production of anthocyanins include Vitis vinifera (peonidin 3-O-glucoside cyanidin 3-0-glucoside and peonidin 3,5-di-0- gl~coside),~~ Petunia hybrida [petunidin 3-0-(p-coumaroyl)ruti- noside 5-0-glucoside (58) and malvidin 3-0-(p-coumaroyl)ruti- noside 5-0-glucoside (59)],88 and Ipomoea batatas (unidentified an tho cyan in^).^^ While the production of pigments in Petunia and Ipomoea cultures was reported to be light-dependent as in most other systems the Vitis cultures attained concentrations of 250pg of anthocyanin per gram of fresh weight in the dark.3.2 Tannins and Proanthocyanidins There have been sporadic reports of tannins from plant cultures usually following their histochemical or colorimetric NATURAL PRODUCT REPORTS. I988 R2 (61) R1=OMe,RZ=R3=H (62) R'=H,R2=R3=OH (63) R'=R2=H,R3=OH R HO (70) R=OH (71) R =H flavanone glucosides dihydrowogonin 7-0-glucoside (6 1) erio-dictyol 7-0-glucoside (62) and naringenin 7-0-glucoside [prunin] (63)." Up to 35 mg of prunin per gram of dry weight could be obtained through optimizing the composition of the culture medium.A quercetin derivative that was originally identified as a quercetin arabinosidegs but for which the structure was later corrected to quercetin 3-O-/?-~-glucuronide (64)gg was synthe- sized in suspension cultures of Anethum graveolens in response to irradiation of the cells with ultraviolet B light. The 7-0- glucuronides of wogonin and baicalein (65) as well as the aglycons were accumulated (-8 YO of the dry weight) (64)R1=R3=R5=HIRz= R6= R7=OH,R4= 0-glucuronyl ( 65) R1=R4=R5=R6=R7=HIR2= 0-glucuronyl ,R3= OH (6 6) R1= R2= OMe,R3= R4= R5= R6= R7= H (6 7) R1=R2= OMe ,R3=R4= R 6= R7= H R 5= OH (68) R1= R2= R5= OMe,R3=R4= R6=R7 H (69) R1= R3=HIR2= R6= R7= OH,R4=OMe,R5= assessment.It is only recently that h.p.1.c. technology has begun to simplify the fractionation and the quantitative analysis of this difficult group of compounds. This capability is reflected in a number of detailed studies. The phenolics which accumulate in long-established suspension cultures of Rosa cv. Paul's Scarlet have now been identified as a procyanidin dimer [(-)-epicatechin4+)-catechin C(4)€(8)-linked] (60) and gallic acid.90 More recently established cultures by contrast con- tained in addition to the above epigallocatechin gallate epicatechin gallate and ferulic acid this pattern being similar to that in stem tissue.Suspension cultures and calli of Cryptomeria japonica produced high levels of proanthocyani- The constitutively in calli of Scutellaria baicalensis.loO Unidentified dins reaching 26% of the dry weight in the ~alli.~~,~~ monomeric components (catechin and epicatechin) were accom- panied by a range of dimeric and polymeric forms. Suspension cultures of Pseudotsuga menziesii contained one of the highest levels of secondary metabolites yet reported for cell cultures -up to 40% of the dry weight as pro cyan id in^.^^ This would seem to be surpassed only by cultures of Ginkgo biloba which are reported to accumulate 50@-600 mg per gram of dry weight as procyanidins and pr~delphinidins.~~ The relative proportions of prodelphinidins and procyanidins in cultures of G.biloba P. menziesii and Ribes sanguineum varied with the age of the culture and the source of the tissue. The major 2,3- cis-flavan-3-01 in leaves of the Ginkgo and the Ribes species disappeared during culturing of the tissue leaving 2,3-trans-products (e.g. gallocatechin) as the dominant structural type among the culture metabolite^.^^ The tannins that occur in calli of the legumes Onobrychis viciifolia and Lotus corniculatusg5 have not been identified or quantified. 3.3 Flavonoids and Isoflavonoids Common plant flavonols such as quercetin also occur in cultured cells although they have seldom been fully character- ized or quantified.Calli of Eucalyptus tereticornis accumulated up to 8Opg of a kaempferol glycoside per gram of fresh while callus tissue of Prunus avium contained the derivatives of quercetin and kaempferol have been detected in calli of Peganum harrnala,lo1 this species being better known for its production of indole alkaloids in culture. Three new flavones (66)-(68) appeared in calli of Andro-graphis paniculata six weeks after they had been placed on a root-differentiating medium.lo2 The structures closely resemble but differ from those of known flavones from the plant and seem to represent another example of the expression of normally cryptic biosynthetic capacity during the culturing of this species.Other novel flavonoid structures have been recorded for physiologically active components of suspension cultures of Podophyllum versipelle where podoverines A (69) B (70) and (C) (71) comprised 0.45 YO, 0.2 YO,and 1YO,respectively of the dry weight of the culture.103 Cultured cells of Glycyrrhiza echinatalo4 and G. uralensis105 have proven to contain a complex of related chalcones retro- chalcones isoflavonoids and flavones. The retro-chalcone echinatin (72) which normally makes up -0.0003 YOof the fresh weight of a culture was accompanied by licodione (73) which is a biosynthetic precursor of echinatin,lo6,lo' as well as licoflavone A (74) and 4',7-dihydroxy-8-prenylflavone (75).Various treatments have been found to elevate the production of echinatin including elicitation with a yeast extract or by calcium alginate beads.10s.109 Production levels of 0.7 mg of echinatin per gram of fresh weight could be achieved in alginate-immobilized cells under which conditions a new NATURAL PRODUCT REPORTS 1988-B. E. ELLIS 587 Me0 \OH HoQ++Q HowoH R 0 0 0 0 (74)R' =H,R2= (77) (78) (79) (I R2 (80) (81) R' =HIR2= (82) R' -t\=( R*= H Ho% Ho% / OMe / OH metabolite 5'-prenyl-licodione (76) was detected in the Aavonoid profile.lO* The ability of legume species to produce isoflavonoid phytoalexins when they are stressed is a trait that is also expressed in their cell cultures. The most extensively studied species have been Glycine max (soybean) and Phaseolus vulgaris (french bean).Suspension cultures of P. vulgaris produced phaseollin (77) (ca. 0.5 mg per gram of fresh weight) and smaller amounts of phaseollidin (78) phaseollinisoflavan (79) and kievitone (80)110* upon treatment with hypocotyl extract or with denatured foreign proteins. Cultures of G. max accumulated predominantly glyceollin after they had been challenged with ultraviolet B radiation112 or with biotic elicitor^.^'^^ 114 Minor contributors to the phytoalexin profile have been identified as 2-and 4-prenyl-3,6a,9- trihydroxy- pterocarpan [(8 1) and (82)].'15 Medicarpin (83) was identified in a range of legume cultures (of Canavalia Medicago and Trifolium species) that had been treated with HgCl2,lI6 while treatment of cell suspensions of Vigna angularis with the transcription inhibitor actinomycin D resulted in a striking increase in accumulation of daidzin (84) daidzein 4',7-di-O-P- D-glucoside (85) and 2'-hydroxydaidzein 4',7-di-O-P-~-glu- coside (86).Calli and suspensions of Pueraria Iobata also produced the isoflavonoids that are typical of the species; i.e. puerarin (87) daidzin daidzein genistein (88) and coumestrol (89).11* NATURAL PRODUCT REPORTS 1988 OMe *qJ& ' OMe OMe (90) OMe OH 0 %IOH (96) R=H (98) (99) Members of another class of isoflavonoids the rotenoids have been reported from two culture systems. Cultures of Derris elliptica rapidly lost their ability to accumulate rotenoids but a low (1 60 pg per gram of dry weight) level of production resumed when root differentiation was ind~ced."~ Both rotenone (90) and deguelin (91) could be identified.By comparison main roots in the plant accumulate >8 mg of rotenoids per gram of dry weight. Calli of Crotaluriu burhia on the other hand were reported to accumulate 13 mg of rotenoids per gram of dry weight.lz0 The array of compounds identified included deguelin rotenone elliptone (92) toxicarol (93) sumatrol (94) and tephrosin (95). 3.4 Stilbenes and Dihydrostilbenes The synthesis of stilbenes has been reported as a constitutive trait in calli of Picea excelsu (spruce) which produced resveratrol [3,4'-dihydroxy-5-methoxystilbene] (96).lZ1 The main foliar stilbene by contrast is piceatannol [3,3',4',5- tetrahydroxystilbene].Resveratrol accompanied by 4-prenyl- resveratrol (97) was also found in calli of Arachis hypogaea (peanut) but only after they had been irradiated with ultraviolet C light.lzZ Lunularic acid (98) (a dihydrostilbene derivative unique to liverwort species) was found in suspension cultures of Marchan-\ /OR OH (100)R = H (101) R = Me tia polyrnorphu where the extractable levels reached 1.4 YOof the dry weight under phosphate-deficient growth ~0nditions.l~~ Lower levels were also detected in cultures of Jungermannia subulatu Lophocolea heterophyllu and Calypogeiu tosana. More recent work has revealed that the major compound that accumulates in vivo is actually the unstable pre-aromatic compound prelunularic acid (99) which is rapidly converted into lunularic acid during extraction.L24 lz6 3.5 Phenalenones These unusual phenylalanine-derived pigments have been shown to accumulate in stolon-derived calli of Lachnanthes tinctoria where 2,5,6-trihydroxy-9-phenylphenalenone(1 00) and 2,6-dihydroxy-5-methoxy-9-phenylphenalenone( 101) com-prised up to 28% of the dry weight of the callus.127 NATURAL PRODUCT REPORTS 1988-B. E. ELLIS Me0 OOMe OR^ (102) R1=H.R2= a-OH,R3= Me (103) R'=OH ,R2=R3=H (104) R1=OH,R2=H R3=Me (107) R1=OMe,R2=ct-OH,R3=Me R1 (109) R' =RZ=H (110)R1=OMe ,Rz=H (111) R1=H.RZ=OMe 3.6 Lignans Calli of Podophyllum peltatum produced the same array of lignans [podophyllotoxin (102) a-peltatin (103) and P-peltatin (104)] as the plant rhizome reaching an overall content of 1.5% of the dry weight.128~129 Screening of culture extracts for anti-inflammatory activity led to the identification of dehydrodiconiferyl alcohol 4-0-p-D- glucoside (1 05) and the y-0-P-D-glucoside (1 06) in suspension cultures of Plagiorhegma d~bium.'~~ Together these lignans accounted for 0.38% of the dry weight of the culture.Interestingly lignans have also been identified in cell cultures of plant species for which no previous record exists of the occurrence of lignans. Root organ cultures of Linum fIavum have been found to yield very cytotoxic extracts and the toxicity was traced to a high (>1 YOof the dry weight) content of 5-methoxypodophyllotoxin(1 07) (originally reported as the methyl ether of P-peltatin A).131The native form of the lignan is apparently the 4-O-glucoside which is hydrolysed by a very active glucosidase during its A new lignan (+)-(1R,2S,5R ,6S)-2,6-di-(4 -hydro x y p h e n y 1)-3,7-dioxa b i c y c1o-[3.3.0]octane (108) was one of the minor metabolites synthesized in cell suspensions of Vigna angularis following their treatment with actinomycin D."' Levels of 3.5pg per gram of fresh weight were reported.3.7 Coumarins Scopoletin [7-hydroxy-6-methoxycoumarin]and scopolin [scopoletin 7-O-glucoside] are known constituents of Nicotiana tissue and have been detected in both callus133 and suspension cultures of Nicotiana taba~urn.'~~ 135 The synthesis and release into the medium of scopolin was stimulated five-fold by (105) R' = GIC ,~2 = H (106) R' =H,R2=Glc 0 supplementing the medium with 0.3 YOof L-phenylalanine plus 0.3YOof casein hydr01ysate.l~~ Suspension cultures of Petroselinum hortense and P.crispum contained only traces of the furanocoumarins for which members of the Umbelliferae are noted until the cells were challenged by preparations of fungal 13' Cells of P. hortense responded with a rapid increase in the levels of linear furanocoumarins [psoralen (109) bergapten (1 lo) and xantho- toxin (1 11) and the related 0x0-furan derivative graveolone (1 12)].136 The relative amounts of the coumarins in this mixture were profoundly altered when different species of fungi were used as the source of the elicitor. 3.8 Dopa and Betalains The first report of the accumulation of 3,4-dihydroxy-~-phenylalanine in cell cultures resulted from examination of calli of Stizolobium hassjoo which is a legume that is noted for its high dopa content (33pmol per gram of fresh weight in seedlings).The cultured tissue contained only 0.1 pmol of dopa per gram of fresh weight although radio-tracer studies suggested a rate of synthesis equivalent to that measured in whole ~eedlings.'~~ Suspension cultures of Mucuna pruriens (a species closely related to S. hassjoo) by contrast produced remarkably high levels of L-dopa (up to 9% of the dry Normally the amino acid is retained within the cells but alginate-immobilized cells converted exogenous tyrosine into dopa and released virtually all of the dopa into the medium.140 Endogenous synthesis of dopa was enhanced by limiting the supply of phosphate and by growing cultures in the light.141 Dopa could also be detected in betalain-producing callus NATURAL PRODUCT REPORTS 1988 Ho2cY-C02H 0 N It B HC H02C .# COzH H (113) R =Glc (116) R = glucuronyl-glucosyl (117) R = glucuronyl -glucosyl I I ferulyl p -coumaryl 0 HO (118) R =H (119) R =Me OH 0 II H o W C m O H HO H02C OH OH (122) cultures of Portulaca grandzjlora where it was accompanied by its decarboxylation product doparnine.l4* The main betalain that is produced has been reported to be betanin (I 1 3).143 Calli of Beta vulgaris accumulated 1.3 mg of betanin per gram of dry weight of the callus and 3.4 mg of vulgaxanthin (114) per gram.lg4 These pigments were accompanied by lower levels of the dopa ring-cleavage product betalamic acid (1 15).Hairy-root cultures of B. vulgaris (transformed by transfer of the Ri plasmid from Agrobacterium rhizogenes) showed a lower level and a different pattern of pigmentation accumulating 1.3 mg of betaxanthin per gram of fresh weight and 0.7 mg of betacyanin. lg5High levels of betalains were produced by light- grown suspension cultures of Chenopodium rubrum which were found to contain amaranthin (1 16) betanin celosianin (1 17) and vulgaxanthins I and II.146s lg7 Unidentified betalains have also been reported to be synthesized by dark-grown suspension cultures of Phytolacca americana14* and by calli of Gomphrena globosa .Ig9 3.9 Hydroxycinnamic Acid Derivatives The literature on this group of phenylpropanoid metabolites is dominated by the detailed studies of the accumulation of hydroxycinnamylputrescine in cell cultures of Nicotiana taba- cum.Selection for resistance to the toxic effects of the phenyl- alanine and tyrosine analogue 4-fluoro-~~-phenylalanine in suspension cultures of N. tabacum and N. glauca resulted in the isolation of several cell lines that contained elevated levels (5-10% of the dry weight) of caffeyl- and ferulyl-putrescine [(118) and (1 19)].I5O9 151Other selection agents (L-phenylalanine or L-ornithine) were also effective for the recovery of high- producing lines of N. tabac~m.'~~ Limitation of phosphate in the medium of wild-type cells resulted in a similar accumulation of caffeyl- and ferulyl-putrescine whose levels increased five- to ten-fold.153-156 Supplementing the medium with L-phenylalanine has also been observed to enhance the production of hydroxy- cinnamyl conjugates.157. 158 Although chlorogenic acid [3-0-caffeylquinic acid] (120) is widespread in the plant Kingdom it has only rarely been reported from plant cell cultures. Cell suspensions of Nicotiana tabacum however in addition to accumulating caffeylputre- scine have been observed to contain chlorogenic acid; the content of the latter was elevated about five-fold in photo- heterotrophic cells as compared to heterotrophically grown rnate~ial.'~' Suspension cultures of Pyrus malus have also been shown to contain chlorogenic acid accompanied by the related p-coumaryl ferulyl and sinapyl derivatives.160 Another widespread conjugate rosmarinic acid [a-0-caffeyl- 3,4-dihydroxyphenyl-lacticacid] (1 2 l) reached levels as high as 20% of the dry weight in cell suspension cultures of Coleus blurnei,l6l Anchusa oficinali~,'~~-~~~ Rosmarinus oficinalis Salvia oficinalis and Salvia triloba. 165 Although ultraviolet microspectrophotometry showed that individual cells of the Coleus and the Anchusa species differed greatly in their ability to accumulate rosmarinic acid,166 attempts to clone single cells were not successful in recovering higher-producing lines. 16' Cultures of Lithospermum erythrorhizon which are noted more for their ability to produce shikonin naphthoquinone deriva- tives under appropriate growth conditions were recently found to accumulate 0.5% of their dry weight as rosmarinic acid when grown under conditions which suppressed the synthesis of shikonin.16s The caffeyl ester was accompanied by smaller amounts of lithospermic acid (122) and 4-hydroxybenzoic acid as well as large amounts of 4-hydroxybenzoic acid 4-0- glucoside.6o Uncharacterized caffeic acid derivatives accumulated at levels of up to 9% of the dry weight (as caffeic acid) in suspension cultures of Perilla frutescens ; this species is phylogenetically related to species of Lirhospermum and Coleus and to other rosmarinic-acid-producing species.16'.170 Several NATURAL PRODUCT REPORTS 1988-B.E. ELLIS 59 1 0 II (123) (1 29) reports have dealt with the production by calli and suspension cultures of Lavandula Vera of an intensely blue pigment which is released into the growth medium. Sulphur-containing compounds (notably 0.4 mmol dmP3 of cysteine) greatly stimu- lated the release of this pigment,17' which could be prolonged by immobilizing the cells in various gel mat rice^.'^^.'^^ The chemical identity of the pigment from cultures of L. Vera has yet to be determined but a recent study of the formation of a blue pigment in callus cultures of L. angustifolia (syn. L. Vera) established that in this case the pigment consisted of the iron chelation product of a novel caffeyl ester (123) in which the ester bond stabilizes the enol form of 3,4-dihydroxyphenyl- acetaldehyde.174 This compound was not detectable in whole plants of L. angustifolia but has been reported from the (124) R1= H R2 = caffeyl R3=Rha,R4=OH (125) R'=R*=R3=R4=H ( 126) R1 = Rha R2 = caffeyl ,R3=HIR4= OH (127) R1= H,R2= caffeyl ,R3=Glc,R4= OH fOR1 (132) (133) 4 lsoprenoids 4.1 Monoterpenes The volatility of monoterpene hydrocarbons requires that they be either sequestered in specialized impermeable storage sites in plant tissues or biochemically stabilized by the formation of less-volatile derivatives (e.g. glycosides). The absence of such leaves of Plectranthus caninus Roth (syn. Coleus ~picatus).'~~ morphological differentiation in most long-term cell cultures is an additional factor that could mitigate against the synthesis The calli produced up to 0.2YOof the fresh weight of the tissue of this chelation complex.More elaborate caffeic acid derivatives are formed by cultures of other species within the Tubiflorae. Suspension cultures of Syringa vulgaris produced 12-16% of their dry weight as verbascoside [ = acteoside] (124) where it was accompanied by ca. 3 YOof the dry weight of the simpler 4-hydroxyphenylethanol glucoside salidroside (1 25). 176 Although Forsythia plants pro- duce forsythioside (126),177 cell cultures of Forsythia x intermedia were found to accumulate verbascoside 178 suggesting that a specific glycosyl-transferase activity was not being expressed in the cell cultures.Cultures of Rehmannia glutinosa on the other hand produced verbascoside forsythioside purpureoside B and purpureoside A (127) in a ratio of 4:3 :2 1 Relatively few reports exist of other hydroxy-cinnamyl derivatives from cell cultures which makes the remarkably high levels of these specific caffeyl derivatives of interest from the standpoint of metabolic regulation. Cultures of Chenopodium rubrum accumulate betalain~l~~ but 1-0-p-coumaryl and ferulyl esters of glucose could also be detected. Coniferaldehyde which is normally produced in trace quantities by suspension cultures of the crown galls of Matricaria chamomilla and released into the medium could be recovered at 60-fold higher levels (0.6 mg per gram of fresh weight) by incorporating an activated charcoal adsorbent into the medium.lso Tobacco callus cultures have been reported to contain both the corresponding alcohol (coniferyl alcohol) and the related sinapyl alcohol (40-70 pg per gram of dry weight together) as the free and accumulation of volatile natural products.This idea has been supported by the recent observation that the inclusion of a hydrophobic second phase in the medium of suspension cultures of Thuja occidentalis led to a doubling of the yield of monoterpenes. 181 The main monoterpenes that were recovered were terpinolene (I 28) terpinen-4-o1,2-methoxy-p-cymen-8-o1 and a-thujaplicin (129). The same cultures had earlier been shown to produce low levels of these and several other mono- terpenes including camphor a-terpineol and carvacrol.lE2 Suspension cultures of Valeriana wallichii also produced a range of valepotriate monoterpenoid esters based on (1 30) and the corresponding dihydro-nucleus (1 3 l) acylated at one or more of the three hydroxyl groups by valeryl isovaleryl or p-acetoxyisovaleryl. Five other species of Valeriana were also shown to produce valepotriates in culture while one (V. oficinalis) did In the V. wallichii system the use of a hydrophobic adsorption phase enhanced the overall production of these monoterpene~.'~~ Cell lines that had been selected for resistance to the leucine analogue 5,5,5-trifluoro-~~-leucine were found to over-produce branched-chain amino acids but did not channel any of this carbon pool into production of valepotriate~.'~~ Treatment with colchicine on the other hand did result in enhanced accumulation of the diene class of valepotriates in suspension cultures of V.wallichii.186 Callus cultures of Perilla frutescens var. crispa produced up to 2 mg of volatile oil per gram of fresh weight the composition of the oil reflecting that of the parent plant [perilla ketone (1 32), limonene and isoegomaketone (1 33)].lE7 Suspension cultures (134) f-""-Q HO -od?YoAc (139) OH HO" OH OH (143) (144) produced 20-fold lower levels. Calli of Pinus radiata produced monoterpenes at about the same level as found in foliar tissue but the major component in the culture profile was a-pinene rather than the /3-pinene of the plant.lss Other species that are noted for their distinctive monoterpene products (Rosmarinus oficinalis Lavandula angustifolia Anethum graveolens Ocimum basilicum and Tanacetum vulgare) failed to produce detectable levels of these compounds in culture.189 Cultures of and Rosa darnas~ena'~~ Jasminum ofi~inale'~~ accumulated very low levels of monoterpenes although the enzymes of isoprenoid biosynthesis were shown to be active in these tissues.Rapid turnover of the monoterpene products was proposed as one explanation for this pattern. Suspension cultures of Pelargonium fragrans have recently been found to display an interesting dependency on photoperiod in their production of volatile While dark-grown cultures were able to produce approximately 1 YOof the parental levels of oils those grown under a regime of 18 hours of light and 6 hours dark produced three-fold higher levels.In both cases the profile of components of the essential oil resembled that of the parental tissue. Use of a 12 hour/l2 hour photoperiod however completely suppressed the production of volatiles. Immobilization of the cells greatly enhanced oil production (to 20% of the values for parental tissue) but the profile was skewed with limonene now comprising 90% of the oil. The commercial importance of the pyrethrin class of monoterpenes as well as the unusual structural patterns has repeatedly attracted the attention of tissue culturists but Chrysanthemum cinerariaefolium (syn. Tanacetum cinerariifo- hm) has proven to be very intractable in culture.No pyrethrins could be detected in undifferentiated calli even with sensitive analysis by gas chromatography-mass spectrometry although very low levels of the chrysanthemic acid moiety (134) were found.192lS5 Re-differentiated shoots but not roots regained the ability to synthesize pyrethrins but the levels were still three orders of magnitude below those in floral ti~sue.'~~~'~~ NATURAL PRODUCT REPORTS 1988 0 II Ho*?i 0 R (140) (141) R =H (142)R =OH OH (145) The less volatile iridoid monoterpenes have been detected in suspension cultures of Gardenia jasminoides where a screening programme yielded a line that produced approximately 0.6 mg of iridoid glycosides per gram of fresh weight.lS7 The main components were tarennoside (135) and gardenoside (136) with smaller amounts of geniposide and geniposidic acid.By contrast cultures of Galium mollugo Lonicera tatarica a species of Weigela a species of Hydrangea and a species of Symphoricarp~s'~~~ lv9 all failed to produce detectable levels of iridoid glycosides even though the parent plants are rich sources of these compounds. It should be noted that alkaloids of the indole-isoprenoid type have been reported frequently from plant cell cultures indicating that the synthesis of the monoterpenoid intermediate secologanin must be proceeding in those tissues in vitro (see Section 5.1). Similarly the mixed polyketide-isoprenoid skeleton of A1(6)-tetrahydrocannabinol [=A8-tetrahydrocannabinol] (1 37) has been shown to be synthesized in calli of Cannabis sativa although the products that actually accumulate in the tissue are presumed to be the labile 2-and/or 4-carboxylated precursors.2oo 4.2 Sesquiterpenes The induction of production of sesquiterpenoid phytoalexins in cell cultures has continued to attract interest particularly in species of the Solanaceae.Calli of Solanum tuberosurn that were challenged with homogenized mycelium of the fungal pathogen Phytophthora infestans responded by producing rishitin (1 38) and lower levels of phytuberin (139) but no lubimin (140).201 Cell suspensions of S. tuberosum by contrast responded to co- cultivation with P. infestans by synthesizing rishitin lubimin and solavetivone (141) and releasing most of the sesquiterpene mixture into the medium.202 In yet another study it was reported that while rishitin lubimin and solavetivone were accumulated in challenged suspension-cultured cells of S.tuberusum the major sesquiterpenoid phytoalexin present was NATURAL PRODUCT REPORTS 1988-B. E. ELLIS 1 I\ /\ 0 0 (147) (149) HI UI 0 TH -o.o actually the hydroxysolavetivone derivative ( 142).203The latter was also found to be the major product in cultures of Papaver somniferum and a species of Rosa and was accompanied in all cases by the dihydroxy-derivative ( 143).203In this study suspension cultures of Nicotiana tabacum were found to produce rishitin and lubimin as their main sesquiterpene derivatives,203 but this is not the pattern that has been reported from other studies.Calli or suspension cultures of N. tabacum that were challenged with cellulase from Trichoderma viride or with Pseudomonas sofanacearum consistently produced phytuberol and phytuberin as their main phytoalexin~,~~~-~~~ accompanied in one case by capsidiol(l44) and debneyol ( 145).205Production of capsidiol was also elicited in suspension cultures of Capsicum annuum by exposing them to fungal hydrolases or to extracts of fungi.207 Suspension cultures of Gossypium hirsutum (cotton) produced substantial amounts (0.2% of the dry weight) of gossypol (146) during normal growth,208but this was increased dra-matically by challenging them with conidia or with extractives from the wilt pathogen Verticilfium d~hfiae.~~~ Similarly unchallenged suspension cultures of Ipomoea batatas produced significant quantities of the furanosesquiterpenes ipomea-marone (147) dehydroipomeamarone (1 48) and related com-pounds although the inclusion of a yeast extract in the culture medium could well have served as a form of elicitation.210 A detailed examination of the alcohol-soluble metabolites from heterotrophic suspension cultures of Ruta graveofens by gas chromatography-mass spectrometry showed the major components to include the degraded sesquiterpene hydro-carbons geijerene (149) and pregeijerene (150) at levels of 0.5 and 1.O mg per kilogram of fresh weight respectively.211 CH II 0 The liverwort Cafypogeia granufata when grown in sus-pension culture yielded 2-370 of the fresh weight of the tissue as an essential oil whose main component was the trinorsesquiterpene 1,4-dimethylazulene (151).212 Minor components were bicyclogermacrene tetrahydro-1,4-dimethyl-azulene and the new compound trinoranastreptene (I 52).213 Labile biosynthetic intermediates of (151) were also recovered namely 3,lO-dihydro-1,4-dimethylazulene (153) and 3,7-di-methylindene-Scarbaldehyde(154).214Low levels of the ses-quiterpene lactone artemisinin (155) were found in callus tissue of Artemisia annua after it had been transferred to liquid while calli of Parthenium argentatum (guayule) contained approximately 4% of the parental tissue levels of guayulin A (156) and guayulin B.216Suspension cultures of Matricaria chamomifla released a-bisabolol (1 57) into the medium when grown in the presence of a hydrophobic second phase,217whereas calli that had been initiated from stems and flowerheads produced a small amount (0.2 YOof the dry weight) of essential oil which contained chamomillol(l58) and trans-p-farnesene as the main sesquiterpenes.21sp-Bisabolene was the major sesquiterpene in the oil that could be recovered from calli and suspension cultures of Pimpinelfa anisum; again the absolute quantities were rather low especially in cell suspensions.219 4.3 Diterpenes Relatively few cases of production of diterpenes in plant cell cultures have been described during the period of coverage of this Report.Four species in the Cupressaceae (Thujopsis dolabrata Chamaecyp,.ris obtusa Chamaecyparis pisifera and NATURAL PRODUCT REPORTS 1988 0 (159) (160) +OH 0 (162) R=OH (165) R Scinnamyl (163) R=H (166) R =benzoyl H (169) R = -OH (170) R =a-OH Platycladus orientalis) were all capable of producing abietane- type diterpenes in culture as exemplified by totarol (159) and ferruginol (1 60).220 Interestingly the spectrum of compounds that was produced in culture was very similar in each of the four species but was quite different from that of each of the parent plants.These results suggest that a basic response was being invoked in these gymnosperm species which overrides the differences between individual species. Ferruginol was also the major diterpene that was accumulated by dark-grown suspen- sion cultures of Safvia miltiorrhiza (1.3 % of the dry weight) where it was accompanied by somewhat lower levels of the closely related compound cryptotanshinone (1 61)221 The syn- thesis of ferruginol was depressed if the cultures were grown in the light 222 but strongly enhanced (1 3.7 YOof the dry weight) by omitting iron-EDTA from the growth medium.223 These levels were more than ten-fold higher than the levels that were produced in the plant.Immobilization of the cells of S. miltiorrhiza in alginate beads led to the release of most (61 %) of the cryptotanshinone into the medium.224 Ferruginol on the other hand remained in the cells suggesting that there is a differential mode of compartmentation of these two similar di terpenes.Examination of the isoprenoid complement of suspension cultures of Tripterygium wilfordii showed that low levels (0.016Y0 of the dry weight) of the cytotoxic diterpenes tripdiolide (162) and triptolide (163) were present.225 These were accompanied by dehydroabietic acid (164). Similar levels of tripdiolide were found in calli of T. wilfordii in a different laboratory.226Similar to many other systems a higher degree of differentiation of tissues was found to result in higher levels of production of tripdi~lide.~~' The macrocyclic lathyrane-type diterpene esters jolkinol A (165) and jolkinol A' (166) were detected in callus cultures of Euphorbia fathyrus.228 A total of 9.5 mg was recovered from 118 gram of freeze-dried tissue.4.4 Triterpenes A wide range of common and more unusual triterpene derivatives have been recovered from plant cell cultures. The reports of occurrence of the better known plant triterpenes have been summarized in Table 1. Aside from the almost universal occurrence of p-sitosterol there is no clear trend in the types of triterpenes reported. As in other groups of natural products the triterpene class seems to be generally represented within cell cultures but taxonomically restricted (specialized) derivatives are often not formed. Calli of Cucurbita maxima for example failed to produce cucurbitacins although they did contain a-amyrin P-amyrin and (167).231Similarly long-term NATURAL PRODUCT REPORTS. 1988-B. E. ELLIS Table 1Occurrence of common triterpenes in plant cell cultures Species A B C D E F G H I J K L M N Reference Akebia quinata Chamaecyparis obtusa Chamaecypafis pisifera Chenopodium quinoa Cucurbita maxima X X X X x x X X 229 220 220 230 23 1 Daucus carota X X X 232 Delphinium ajacis Eucalyptus tereticornis Euphorbia pulcherrima Euphorbia tirucalli Maytenus buchananii Perilla frutescens X X X X X X X x X x x x X X 233 234 235 82 236 237 238 Platy cladus orient alis Rabdosia japonica Rubus fruticosus X X X x x x x x 220 239-241 242-246 Saponar ia oficinalis Solanum aviculare X x x x X X 247 248 249 Solanum dulcamara X x x x x x x 250 Solanum laciniatum X X X 25 1 Solanum mammosum X X X 252 Thujopsis dolabrata Trigonella foenum- X X 220 253 Tripterygium wivordii graecum X x x 225 Key A sitosterol ; B stigmasterol ;C fucosterol; D isofucosterol ;E campesterol ;F cholesterol ;G cycloartenol ; H 24-methylenecycloartenol ; I cycloartanol ;J spinasterol; K polpunonic acid; L oleanolic acid; M ursolic acid; N betulinic acid.undifferentiated cultures of cardenolide-producing species (of Digitali~~~~-~~l and of Thevetia262)have failed to accumulate significant levels of cardenolides. Modest levels of synthesis of digitoxin were only restored in Digitalis cultures by invoking developmental programmes which led to somatic embryo- genesis,256. 259 261 o~ganogenesis,~~’* and/or shoot forma-tion.255.258 On the other hand uncommon triterpenes have been found in a number of systems. Calli of Akebia quinata produced mesembryanthemoidigenic acid (1 68) as well as three new triterpenes (169) (170) and (171).229 Both tirucallol (172) and euphol were formed at significant levels (ca.0.1 YOof the dry weight) in calli of Euphorbia tirucalli; compared to the parental tissue the mixture of sterols from cultured cells had a much higher relative content of tirucall01.~~~ One of the minor components of the triterpene fraction that was isolated from suspension cultures of Tripterygium wivordii was shown to be celastrol (173),225 while the two other ‘quinone methide’ sterols tingenone (1 74) and 22P-hydroxytingenone (1 75) formed minor components of the triterpenes from cell cultures of Maytenus b~chananii.~~’ In calli of Solanum dulcamara the better known (173) R’ =C02H,R2=H2,R3=H sterols were accompanied by 24,25-dihydrolanosterol 24-methylenecycloartanal and 24-methylenecholesterol.250 A de-(174) R’ = RZ=H.RZ=O tailed examination of the triterpenes of calli of Delphinium (175) R’=H,RZ=0.R3=OH ajacis revealed that cultures formed far higher (ten- to twenty- fold) levels of these compounds than did the parental The major components (stigmastanol 24-ethylidenelophenol and 7,8-didehydrostigmastanol)of the triterpene fraction from cultured cells made only minor contributions to the fraction from whole plants. Calli of Isodon japonicus Hara (syn. Rabdosia japonica Hara) yielded 2a-hydroxyursolic acid (176) as the main triterpene accompanied by 3-epi-maslinic acid (1 77) and much smaller amounts of maslinic In an extensive series of studies with suspension cultures of Rubus fruticosus specific inhibitors of sterol metabolism have been employed to demonstrate just how plastic this facet of isoprenoid metabolism can be.242-246 Selection of lines that are resistant to various inhibitors resulted in apparently healthy (176) ~1~ P-OH ,R2 = a-OH,R3=Me,R4= H suspension cultures whose sterol profile changed from one that (177) R’ =R* = a-OH R3= H,R4= Me was dominated by the usual plant A5-sterols (sitosterol NATURAL PRODUCT REPORTS 1988 (178) Rha \ Glc0 / Rha ( 181) campesterol and fucosterol together making up 96% of the sterol fraction) to one consisting predominantly of 14a-methyl- A*-~terols,~~~ eight-carbon side-chain or 9/3,19-cyclopropyl-sterols.246 In some cases this resulted from a greatly enhanced accumulation of a previously minor metabo- lite whereas in others the predominant sterols in the resistant lines were not detectable in the sensitive parental cell line [e.g.24-methylenepollinastanol (178) in tridemorph-resistant cul-ture~].~~~ The ability of plant cells to accommodate such drastic shifts in triterpene composition while maintaining key cellular functions such as growth division transport and oxidative metabolism provides an important perspective on the question of whether the usual plant triterpenes represent unique and essential components of the cell membranes of plants. The importance of the diosgenin skeleton (1 79) as a starting point for commercial synthesis of steroid pharmaceuticals has stimulated an ongoing search for cell culture systems that are capable of high levels of accumulation of this and related triterpenes.Not all of the plants that are capable of forming this type of triterpene express the ability in culture; calli of Solanum mammo~um~~~ and calli and suspension cultures of S.avicul~re~~~ both failed to produce diosgenin. The cultures of S. mammosum also contained no solasodine (1 80) but cultures HOw RZ -\ R’ (183) R’ =a-OH R2= p-OH,R3=HIR4=H2 (184) R’ =a-OH,R2=R3= p-OH,R4 = H2 (185) R’= p-OH,R2=a-OH.R = H,R4= H2 (186) R’= p-OH,R2=R3=H R4=0 (187)R’=p-OH,R2=R3=H,R4= H2 it has been demonstrated that the native saponins in cultures of D. deltoidea are actually the furostanol glycoside (1 81) and the spirostanol derivative dioscin (182).283Both of these compounds are converted into diosgenin by the standard treatment with an acid.of S. nigr~m,~~~ 265 268 S. khu~ianum,~~~~~~~ S. la~iniatum,~~‘. S. Other species of Dioscorea have also proven to be capable of j~sminoides,~~~* produced this steroidal 272 and S. d~lcamara~~~ alkaloid at levels from 0.01 to 5% of the dry weight. Higher levels sometimes appeared to be correlated with some degree of tissue differentiation,266* 269 but this was not always the case.264.273 In the cultures of S.jasminoides and S. laciniutum solasodine was accompanied by diosgenin (to 0.16 YOof the dry eight),^^^,^^^,^^^ but in general the highest levels of saponins have been obtained in suspension cultures of Dioscorea deltoidea.Extensive studies of the effects of v;.-ying the composition of the growth medium have enabled the original levels of 0.2-2.0 YOof diosgenin to be increased to 7-8 YOof the dry 277 Treatment with inhibitors of isoprenoid metab~lisrn~~*~ 281 279 or with preparations of fungal elici tors28o. can modify this production pattern with increases of up to 72% in diosgenin content being induced by autoclaved mycelium from various non-host-specific fungal pathogens. The inhibitor studies have also allowed the identification of a glycoside (181) that is believed to represent an intermediate in the biosynthesis of di~sgenin.~”- 282 The diosgenin content in all of these studies has normally been assessed after the tissue extracts have been hydrolysed with an acid.In a recent report producing saponins in culture. Calli of D.JEoribundu contained 1.3YO of their dry weight as di~sgenin,~~~ while suspension cultures of D. tokoro produced diosgenin yonogenin (183) and tokorogenin (184) accompanied by small amounts of the related epimeric furostanol glucosides protoyonogenin and protoneoyonogenin. 285 Saponins have also been found in suspen- sion cultures of Trigonella foenum-gruecum (gitogenin and di~sgenin)~~~ and Agave wightii [gitogenin (1 85) hecogenin (186) and ticogenin (187)]286 as well as in calli of Tribulus terrestris (hecogenin and io~genin).~~~ The physiological properties of the ginseng saponins have motivated a number of studies of the production of ginsenoside in cultures of Punux ginseng.The same array of eleven saponins that is found in ginseng roots has been observed in root- differentiated and undifferentiated cultures and on a dry-weight basis the saponin content of the cultures exceeded that of roots.28* Treatment with 25 mg of thiosemicarbazide per litre of culture redirected triterpene metabolism in cultures of P. ginseng away from the production of phytosterols and into the synthesis of sap on in^.^*^ In auxin-habituated cultures the production of ginsenoside was markedly lower which is NATURAL PRODUCT REPORTS 1981~~. E. ELLIS 597 OH OH / (193) QJ7-HR COzMe (198) R1ZH,R2= Me (197) (199) R1=Me R2= H consistent with the observation that exogenous indole-3-acetic acid depressed ginsenoside levels in non-habituated Unlike many other systems the best auxin for stimulation of ginsenoside was 2,4-D.Cultures of P.ginseng that were grown on a scale of 30 dm3 in an optimized medium yielded 0.7% of their dry weight as ginsenoside~.~~~ Finally a few examples of the formation of highly oxygenated and modified triterpenes have been reported. Ecdysterone (1 88) made up as much as 0.03% of the dry weight of calli of Trianthema portulacastrum this value being four-fold higher than that of the parental Calli of Physalis minima produced levels of physalin B (1 89) physalin D (1 90) and 5,6- epoxyphysalin B (191) which were of the same order as those seen in the plant.293.294 Interestingly while all of these compounds were produced in cultures that originated from triploid tissue explants only physalin D was formed in calli from diploid material.293 Callus and suspension cultures of Picrasma quassioides that were grown on an optimized 'production' medium (whose major novelty was the use of 2 g of galactose per litre as the carbon source) were shown to produce up to 0.3% of their dry weight as quassin (192). This surpassed the content of even the quassin-rich tissues of the parental explants (0.1 14.16 4.5 Carotenoids A sixty-fold increase in the accumulation of carotenoids in dark- grown cultures of Lycopersicon esculentum could be induced by (189) H H4* H MeOzC (195) 602Me ( 200) R = H,R~= OH OH (201) R' =OMe,R2=OH (203) 16s (202) RLRLH (204) 168 treating them with the inhibitor [2-(4-~hlorophenylthio)ethyl]-diethylamine.296 The major component of the increase was lycopene.5 Alkaloids 5.1 Indole Alkaloids Work on this class of alkaloids has been dominated by studies on cultures of Catharanthus roseus; this species is best known for its ability to produce the antineoplastic dimeric indole alkaloids vincristine and vinblastine. One major theme has been the identification of the numerous alkaloids which can appear in cultured cells of C. roseus. From these studies it is clear that the alkaloid profiles vary greatly from one cell line to another. The extent to which such profiles in individual cell lines are stable and reproducible is still a matter of debate but several compounds appear to be frequent if not universal components of the alkaloid profile of C.roseus. These include ajmalicine (193) vallesiachotamine (194) catharanthine (199 strictosidine lactam (196) (presumed to be an artefactual product derived from strictosidine) akuammicine (197), vindolinine (1 98) 19-epi-vindolinine (199) horhammeri-cine (200) horhammerinine (20 l) lochnericine (202) and isositsirikine (203).297-310 Others have been reported less frequently although given the complexity of the alkaloid spectra and the generally low concentration of the minor alkaloids this may be as much a reflection of the separation technology that was used in any experiment and the amount of NATURAL PRODUCT REPORTS 1988 -I-.H*-il COzMe H MeOzC** I (205) R = H OH OH (206) R =OH (207) (208) (209) (214) RLH, R~=AC ( 215) R'= R*= H ( 216) R' =OH,RLH .* R'O OR I C02Me (219) R1=Me.R2=Ac Me02C MeO2Cql II (220) R~=H,R~=AC (222) R =P-H (221) R1=Me,R2=H (223) R =a-H (224) tissue that was analysed as it is a statement about the synthetic capabilities of any given culture. Included in this group would be tabersonine (205),298. 310 20-hydroxytabersonine (206),304 3049 yohimbine (207),299* 303 308 tetrahydroalstonine (208),304* 3019 sitsirikine (209),308dihydrositsirikine (210)3083-iso-ajmalicine (21 1),304 308 minovincinine (213),304 310 pleiocarpamine (212),3049 akuammiline (214),304 desacetylakuammiline (215),313 10-hydroxydesacetylakuammiline (216),310serpentine (217),29820-(225) epi-vindolinine N-oxide (218),30419-acetoxy-11-methoxytaber-sonine (219),299*301 19-acetoxy-11-hydroxytabersonine (220),301 19-hydroxy-11-methoxytabersonine (22l),299.301 3-iso-19-epi-ajmalicine (222),308akuammigine(223),304. 308 antirhine (224),308 and vinervine (225).298In a major study of 458 individually derived lines 312 proved to be able to accumulate at least 0.1 % of their dry weight in indole alkaloids when transferred to a 'production ' medium.300Among these producing lines both OAc limited and complex alkaloid profiles were observed including corynanthe strychnos and/or aspidosperma-type indole alk-HI aloids. Other lines failed to produce any of the alkaloids that MeOzC are normally found in cultures of C.r~seus,~" and none of the lines in this or in any other study has been found to contain vindoline (226) even though it is along with catharanthine a NATURAL PRODUCT REPORTS 1988-B. E. ELLIS (227) (228) (229) AcO H (230) R=OH (232) R =H (233) R =OGlc major component of the alkaloids of aerial tissue of C. r~seus.~O~ It is also worth noting that no reproducible report of the production of vincristine or of vinblastine in cultured cells of C. roseus has appeared. Virtually all of the alkaloids that have been reported from cultures of C. roseus were already known from plants of this or other species but two novel structures have also been found ; these are (16R)-(19E/Z)-isositsirikine (204) and 2 1-hydroxycyclolochnerine (227).312 The levels of total alkaloids in suspension cultures of Catharanthus roseus are low (< 1% of the dry weight) and this has generated many attempts to enhance the production of alkaloids; various approaches have been used.The results have generally been evaluated either in terms of total alkaloids or more commonly in terms of the levels of ajmalicine and serpentine. Manipulation of the composition of the growth medium has been shown markedly to increase the accumulation of ajmalicine and of serpentine the levels reaching 0.5 mg of ajmalicine and 0.05 mg of serpentine per gram of fresh weight (1.5 mg of total alkaloids).314 The relationship between changes in the level of each alkaloid and the nutrient status of the cultures has been studied in some detai1315-319 and it is clear that the accumulation of ajmalicine and that of serpentine respond differently to changes in the cell environment (such as phosphate deprivation the NH:/NO ratio and the population density).The influence of light was particularly striking with growth in the dark favouring the formation of ajmali~ine.~~~.~~~ The rate of accumulation of biomass was directly correlated with extent of accumulation of serpentine when a culture was transferred to 'production ' medium,321 but this relationship no longer held if the temperature was altered.322 Maximal accumulation of biomass occurred at 35 "C whereas production of alkaloids virtually ceased at this temperature.The need for a 'production medium ' (typically high sucrose low phosphate and low auxin) has been questioned recently since replacing 2,4-D with naphthalene- 1-acetic acid in the usual growth medium allowed a sustained production of serpentine of approximately 0.6 YOof the dry Inhibitors of isoprenoid metabolism have also been reported to increase the ajmalicine content of C. roseus cultures two-to fi~e-fold.~~~.~~~ The levels of both ajmalicine and serpentine in suspension cultures of C. roseus were enhanced by supplementing the culture medium with secologanin which is the precursor of the non-indole portion of Synthesis of the latter was also induced in C. roseus lines that had been selected for resistance to the tryptophan analogue 4-methyltrypt~phan.~~~ The cellular levels of tryptamine were simultaneously elevated.The origin of the many different alkaloid profiles that have been reported for cultures of C. roseus remains obscure. When a large array of culture lines was established from protoplasts that had been obtained from a single (presumably genetically homogeneous) leaf a range of alkaloid profiles was still The range however was distinctly narrower then that obtained in the earlier study300 of lines that had been derived from anthers of numerous parent plants. This difference could indicate a measure of genetic control over the expression of alkaloid production in cultures of C. roseus an idea which receives further support from a study in which it was shown that cultures that had been derived from regenerated shoots had essentially the same alkaloid profile as the parental cells.330 A contrary view holding that these traits are intrinsically unstable has been bolstered by observations of the consistent loss over time of specifically selected characteristics of alkaloid production during continuous This behaviour obviously places a serious constraint on any possibilities of commercial exploitation of cultures of C.roseus for production of alkaloids; whether the problem is restricted to this species or to this class of natural products will only be resolved by further study. The production of indole alkaloids is by no means restricted to cultures of Catharanthus roseus. Suspension cultures of the related species Catharanthus ovalis have been reported to contain an array of alkaloids similar to that found in cultures of C.rose~s.~~~ In addition apparicine (228) and alstonine (229) could be detected. The alkaloids that are formed in suspension cultures of Rauwolfia serpentina have been examined in detail. The major component was vomilenine (230) (0.2 O/O of the dry weight) which was accompanied by smaller amounts of ajmaline and reserpine and there were traces of ajmalicine (193) serpentine (21 7) yohimbine (207) 3-iso-ajmalicine (21 I) alstonine (229) sarpagine (23 l) vinorine (232) 17-0-acetylaj- maline and 17-O-a~etylnorajmaline.~~~~ 333 Far higher levels of glycosidically bound vomilenine were present (1.6 YOof the dry This compound which was originally identified as raucaffricine (vomilenine P-D-galactoside) was shown to have these alkaloids but supplying L-tryptophan had no effect.326 been assigned an incorrect structure ;raucaffricine therefore is Immobilization of the cells with an alginate and the use of a low actually vomilenine P-D-glucoside (233).335 Shoot cultures of R.phosphate/low auxin growth-limiting medium resulted in a serpentina contained more alkaloids than plant leaves (0.7 YOof the dry weight versus 0.5%) and the profile which was prolonged and somewhat elevated production of ajmali~ine.~~~ NATURAL PRODUCT REPORTS 1988 HO h02Me (238) (239) R =C02Me (241) R' =OMe,R2=H,R3=C0zMe ( 242) R1= OMe R2=0H R3=COzMe ( 243) R1 = HI R2=OH R3= C02Me Me0 HR COzMe dominated by yohimbine (206) ajmaline (234) and ajmalidine (235) differed from that of any plant part or of undifferentiated The reserpine content of the latter has been raised to 0.07 % of the dry weight by selection of stress-tolerant lines and optimization of the composition of the culture medium.337 Suspension cultures of Tubernuemontunu divuricutu produced small amounts of apparicine conoflorine (236) coronaridine (237) tubotaiwine (238) catharanthine and vinervine (225) while cultures of T.ibogu had a much simpler alkaloid spectrum consisting of (238) and (236).":lH Calli of T. efeguns (240) R = COzMe C02Me I (245) (248) R =C02Me on the other hand contained primarily apparicine (228) vobasine (239) and tabernaemontanine (240).339 Minor compo- nents included isositsirikine (203) (238) isovoacangine (241) (3RS)-3-hydroxyisovoacangine (242) (3RS)-3-hydroxycorona- ridine (243) geissoschizol (244) vobasinol (245) 16-hydroxy- I6,22-dihydroapparicine (3RS)-3-hydroxyconodurine (246) and the dimeric product monogagaine (247) all of which are typical of this genus.Small amounts of a new compound 3-oxoisovoacangine (248) were also found in the alkaloid profile.:j3!' NATURAL PRODUCT REPORTS 1988-B. E. ELLIS 1 Q-- \ ” 0AJ Cultures of Stemmadenia tomentosa var. palmeri have been reported to contain a complex array of typical Apocynaceae alkaloids including tabersonine (205) minovincinine (2 13) vinervine (225) (236) (237) (238) condylocarpine (249) and vincanine (250).340 During the same study it was shown that cultures of Voacanga africana produce a much simpler pattern of alkaloids [lochnericine (202) (205) and (213)] all of the Aspidosperma type.340 What is unusual in this case is that plants of V.africana are known mainly for production of the Iboga class of alkaloids. Two minor dimeric alkaloids that were recovered from cultures of V. africana that had grown in an optimized medium have proven to be new; voafrine A (251) and voafrine B (252) together accounted for 0.02% of the dry weight of the Under these growth conditions the tabersonine content reached 0.6% of the dry weight. Calli of the related species V. thouarsii have been found to contain < 0.001 YOof tabers~nine.~~~ The main alkaloids in cultures of Ochrosia elliptica were ellipticine (253) and 9-methoxyellipticine which reflected the pattern of alkaloids in leaves.343.344 In another study apparicine (228) was also detected and a new alkaloid of the apparicine type epchrosine (254).345 Bioassay screening of suspension cultures of Picralima nitida led to the isolation of another new alkaloid pericine (255) which was accompanied by pericalline (256).34s /3-Carboline alkaloids were produced in cultures of Ailanthus altissima where canthin-6-one (257) and 1-methoxycanthin-6-one reached levels of 0.1-1.3 YOof the dry eight.^^',^^^ They were accompanied by small amounts of related 3-oxide 601 H H (258) R =Me (259) R = Me (260) R = H (261) R =H derivatives the I- 2- 4- and 5-hydroxy forms of canthin-6- one P-carboline- 1-propionic acid 4-methoxy-P-carboline- 1-carboxylic acid methyl ester and 4,5-dihydrocanthin-6-one some of which represent first Heterotrophic cultures of Peganum harmala accumulated about 0.1 % of their dry weight as the /3-carboline alkaloids harmine (258) harmaline (259) harmol (260) and harmalol (261).349 The levels were considerably reduced in photomixotrophic cultures while photoautotrophic cells contained no harman alkaloids.Rever- sion from photoautotrophy to heterotrophic growth restored the production of alkaloids.349 By selection and optimization of the culture medium it was possible to increase the alkaloid content of the heterotrophic cultures to 1-270 of the dry weight ; serotonin (5-hydroxytryptamine) comprised another 2 %.350 Low-producing lines if supplied with exogenous tryptamine readily incorporated it into their serotonin pools but this input did not increase the levels of harman alkaloids.351 The formation of harman and norharman was also observed in suspension cultures of Cinchona ledgeriana after they had been transferred to a ‘production’ medium containing 2.4 mmol dm-3 of L-tryptophan but this proved to be an artefact related to cell lysis in the presence of the tryptophan.352 The main interest in Cinchona relates however to the production of quinine and quinidine by C.ledgeriana and C. succirubra. Earlier attempts to develop undifferentiated cultures which contained these alkaloids were not successful although leaf organ cultures produced 0.04-0.06 YOof both.353 Manipu- lation of the phytohormone composition of the medium did NATURAL PRODUCT REPORTS 1988 H R’@ R’P N N (265) R’ =P-OH,R2=p-H (266) R’ = a-OH R2=a- H HO-H.N .+y 4 (268) R =H (267) ( 269) R =OMe qoqo Me Me OMe OMe p&T+oH Me (270) (271) R=H (274) R = H (272) R =OMe (275) R = OH 0 qo Me OMe Me OH (276) (278) allow small amounts of quinine (262) quinidine (263) and of the total alkaloid production in suspension cultures of C. dihydroquinidine (264) to be produced in calli and suspension ledgerianu was apparently released into the culture medium.364 cultures of C. succirubra but the main alkaloids were cinchonidine (265) and cinchonine (266).354-356 A similar result During another 5.2 Furoquinoline and Acridone Alkaloids was obtained with calli of C.ledgeri~na.~~’ examination of calli of C. succirubra Paron et Klotzsch (syn. C. Two genera of the Rutaceae have been examined for production pubescens Vahl.) dihydrocinchonine (267) cinchonamine of these anthranilate-derived alkaloids in vitro. Calli and (268) and 10-methoxycinchonamine (269) were identified as suspension cultures of Choisyu ternata accumulated 0.01 YOof the main indole alkaloids.358 Supplementation of the medium their dry weight as furoquinoline derivatives (twenty-fold lower with L-tryptophan has been successful in increasing the alkaloid than in the plant) with kokusaginine (270) as the main levels in suspension cultures of C.and in compound. Traces of skimmianine were also 366 On suspension356 and root organ cultures360 of C. ledgerianu but the other hand the cultures contained twice the levels of levels of quinine remained < 10pg per gram of fresh weight. dihydrofuroquinoline alkaloids that were formed in plants The responses of alkaloid production to manipulation of mainly platydesminium (271) with lesser amounts of balfouro- concentrations of individual components of the medium have dinium (272).366 Considerable variation in the relative and been examined in several 364 it appears that the absolute amounts of (271) and (272) was observed between biosynthesis of the indole alkaloids responds to such changes independently derived cell lines.367 independently from that of the quinolines.”’ As much as 70 YO Calli and suspension cultures of Ruta graveolens have been NATURAL PRODUCT REPORTS 1988-B.E. ELLIS 603 (2841 MeOzC7; Meoq*,Me HO ‘ Me0 / (285) Me0 / H°FMe shown to produce the acridine derivatives rutacridone (273) rutacridone epoxide (274) and hydroxyrutacridone epoxide (280) (275) at levels of ca. 1 YOof the dry eight.^^^.^^^ Co-cultivation of the cultures with various fungi or filtrates from fungal cultures resulted in as much as fifty-fold specific increases in the content of acridone epoxide over a period of three day^.^^^.^^^ In other studies of this species further alkaloids including ribaline (276),372 gravacridinol (277),373 and the new structure rutagravine (278),373have been identified.5.3 Harringtonine Alkaloids Calli of Cephalotaxus harringtonia have been re-examined for alkaloid production and nine unidentified alkaloids were detected none of which corresponded to the known Cephalo-taxus alkaloids.374 Possible traces of harringtonine (279) and homoharringtonine were reported from another study but no characterization was carried 5.4 Isoquinoline Alkaloids The presence of the pharmacologically important morphinan alkaloids in the genus Papaver has continued to attract attention with most studies focussing on cultures of P. somniferum and P. bracteatum. The results of this work can be summarized by saying that except for one isolated (and as yet unrepeated) report to the neither species appears to produce measurable amounts of morphine or codeine in culture unless extensive shoot differentiation is ind~ced.~~’-~~l Ro ot organ cultures of P.bracteatum have been found to accumulate 0.03 % of their fresh weight as thebaine.382 Radiotracer studies have suggested that the failure of Papaver cultures to accumulate the morphinans may be due more to high turnover in cultured cells than to an inability to synthesize them.383 The early steps in isoquinoline biosynthesis are clearly present since an array of alkaloids can be found in calli and suspensions of both species. These include isothebaine (280),384* 386 orien-talidine (28 385 protopine (282),385 cryptopine (283),386 and usually as the main product sanguinarine (284).384+385 Treat-ment of suspension cultures of P.sornnjferurn with a homo- genate of a fungus of the genus Botrytis increased the sanguina- rine content as much as 150-fold with levels of 2.9 % of the dry weight being attained.387-388 Sanguinarine was also the main alkaloid in calli of Corydalis ophiocarpa where it was accompanied by protopine and a new alkaloid of the corypalline type (285).389 Jatrorrhizine (286) was found as the main alkaloid (0.4% of the dry weight) in calli of Dioscoreophyllum 23 NPR 5 604 NATURAL PRODUCT REPORTS 1988 R3 Me HO / Me0 ' ( 286) R1= R4= R5= Me R2= R3= H (287) (288) R1=R2=R4=R5=Me,R3=H (289) R'R2=CHt,R3=H,R4=R5=Me (290) R1=R3=H R2= R4= R5=Me (291) R1R2 =R4R5= CH2 R3= H (292) R1R2=CH2,R3=R5= H,R4=Me (293) R'RZ = CH2 R3= OH R4=Me,R5=H Me0 / HOm' NMe Me0 ' OH (295) (2961 (297) ""oy?""' HO BOH R4 OR' (301) R1R2= CH2,R3= OMe R4= H (302) R'R*= CHz,R3= R4 = H (303)R1R2= CH2,R3= R4=OMe (304) R' = R2= Me R3= R4=H cumminsii [accompanied by magnoflorine (287) and palmatine (288)],,@Oas an anti-inflammatory factor in suspension cultures of Plagiorhegma dubium (0.01 YOof the dry weight),,@l and in high concentrations (10% of the dry weight) in cultures of Berberis ~toloniferu.~~~ Much smaller amounts of berberine (289) columbamine (290) and palmatine were also found in the alkaloid fraction of B.stofonifera. Berberine however was the major product in other systems.Suspension cultures of Coptis juponica produced large amounts (8 YOof the dry weight) of berberine following selection of clones and optimization of the 394 Smaller amounts of jatrorrhizine and coptisine (291) were also formed. In calli and suspension cultures of Thalictrum minus a complex mixture of alkaloids was formed dominated by berberine. The minor components included (286) (287) (288) (290) thalifendine (292) thalida-stine (293) and desoxythalidastine (294).395The berberine that was produced in the suspension cultures was largely released into the medium where it crystallized as berbe-rine -HNO or berberine -HCl.396 Cytokinins were essential for highest production which reached the equivalent of 10 YOof the dry Calli of Nandina domestica have also been found to secrete berberine gradually into the medium during long-term Quite a different profile of isoquinoline alkaloids was observed in suspension cultures of Fumaria cupreofutu where the major components were protopine magnoflorine and (+)-reticuline (295).399Smaller amounts of (-)-scoulerine (296) coptisine ( +)-isoboldine (297) N-methylcoclaurine (298) ( -)-pallidine (299) and dehydrocheilanthifoline (300) were also detected.Suspension cultures of Eschscholtziu cufifornicu produced up to 1.7% of their dry weight as benzophenan- thridine alkaloids mainly dihydrochelirubine (301) dihydro-sanguinarine (302) dihydromacarpine (303) and dihydro-chelerythrine (304)."0° Suspension cultures of Macleaya NATURAL PRODUCT REPORTS 1988-B.E. ELLIS HO ' (305) ( 3061 Me Me (309) microcarpa have been reported to secrete sanguinarine and protopine into the culture medium but no quantities were given.401 In the general vein of phenylpropane-based alkaloids calli of Ephedra gerardiana have been shown to contain up to 0.6 YOof ephedrine (305) when grown on an optimized L-phenylalanine- containing medium,402 while calli of Stizolobium hassjoo yielded small amounts of ~-3-carboxy-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline (306) and the 1-methyl derivative.lo3 5.5 Quinolizidine Alkaloids A series of legume species have been extensively examined for their ability to produce quinolizidine alkaloids in culture. Although each species (species of Lupinus three species of Cytisus Laburnum alpinum Baptisia australis Sarothamnus scoparius) displayed a characteristic alkaloid profile in its aerial tissues only very low levels (< 0.05 YOof the dry weight) were produced in culture and this consisted almost exclusively of lupanine (307).404-407 In addition traces of sparteine (308) 13- angelo ylox ylupanine 13-tigloyloxylupanine and I 3-cinnamoyl-oxylupanine were detected by g.c.-m.s.analysis of suspension cultures of Lupinus polyphyll~s.~~~ Organogenesis in cultures of Sarothamnus scoparius has been shown to lead to increased levels of accumulation of alkaloids and the appearance of relatively more sparteine than lu~anine.~~~ A requirement for differentiation has also been observed in cultures of Heimia salicifolia which produced no quinolizidine alkaloids while in the undifferentiated state.110 Various environmental stresses have been reported to cause a transient increase in the quinolizidine alkaloid content of cultures of L. polyphyllu~.~" This response is consistent with the behaviour of many other cell culture systems but curiously a wide phylogenetic range of other cultures were also found to produce traces of quinolizidine alkaloids when subjected to the same While this may indicate the existence of the genes for quinolizidine biosynthesis in plant species for which that capacity has never previously been recognized corrobora- tion of such a potentially important concept must await exploration of the plant genome with appropriate molecular probes.It is interesting to note that among the cultures which responded to stress by forming quinolizidines was Symphytum oficinale a species noted for its synthesis of pyrrolizidine alkaloids. The latter trait was shown to disappear from S. oficinale tissues after two months in 5.6 Tropane Alkaloids The pharmacological importance of tropane derivatives and the responsiveness of Solanaceous species in culture have made 605 0 (308) n the study of this group of alkaloids a popular theme. In most cases however the levels of production have been extremely low. Neither differentiated nor undifferentiated calli of Duboisia leichhardtii contained any tropane alkaloids,413 while suspen- sion cultures of Datura innoxia contained at most 0.0016 YOof their dry weight as scopolamine (309).414 Screening of cell lines of Hyoscyamus niger for alkaloids identified one line which contained 0.01-0.02Y0 of its dry weight as hyoscyamine (3 While production was maintained in suspension culture the latter consisted of very large (8-20 mm) cell aggregates.A similar correlation between organization (cyto- differentiation) and accumulation of alkaloids has been reported for a wide range of related species in culture.416 One means of exploiting this connection is to develop root organ cultures. In the case of Hyoscyamus niger these were shown to accumulate levels of scopolamine (> 0.2 YOof the dry weight) in excess of those found in either plant roots or 1ea~es.l~~ Cultures of Duboisia lei~hhardtii,~~~.420 419 D. myoporoide~,~~~. D. hop~oodii,~~~ H. niger H. albu~,~~~ Hyoscyamus mutic~s,~~~ and A tropa belladonna423 all showed an alkaloid-production response as a result of root differentiation. The content of scopolamine in root cultures of D. leichhardtii reached 1.1 YOof the dry Ploidy levels in callus cultures of H. muticus also apparently influence the production of tropane alkaloids ; haploid-derived clones contained three-fold higher levels of scopolamine than did diploid rnate~ia1.l~~ This is in contrast to an earlier study in which it was found that haploid and diploid specimens of Atropa belladonna contain the same levels of tropane alkaloids.425 'Hairy root ' cultures (induced by the transformation of Atropa belladonna with Agrobacterium rhizogenes) have recently been found to contain up to 0.37 YOof their dry weight as atropine (racemic hyoscyamine) these levels being comparable to those of field-grown plants.426 5.7 Pyridine Alkaloids The production of nicotine in Nicotiana and related genera has been examined in numerous studies.In general it has not been difficult to find modest levels of nicotine (311) in cell cultures of N. tabacum and this can be increased by screening and by optimization of the The genotype of the parental tissue is important as was shown by a comparison of near-isogenic lines of N. tabacum. Of particular interest is the observation that genetic backgrounds which conditioned low production of alkaloids in whole plants did not necessarily condition similar low production of alkaloids when the corresponding tissues were cultured in ~itro.~~~ A number of attempts have been made to enhance the production of pyridine alkaloids by manipulating the culture medium.Replacement of nitrate with urea increased the 23-2 NATURAL PRODUCT REPORTS 1988 (31 2) (313) (314) aco2H Me (315) (316) R =Me (317) R=H <OH Ls-sl HO OH (318) (319) 0 \ (320) nicotine content of calli of N. tabacum by ~OYO,~~O while using a low phosphate/high sucrose combination yielded 2 YOnicotine production being released into the medium. Applying a saline stress and growing the cultures in the light enabled this low production to be increased 90-fold reaching levels of 475 mg of alkaloid per litre of suspension The enhanced production was largely caffeine rather than theobromine.6 Other Compounds 6.1 Aldoxime Derivatives Many plant species convert selected amino acids into aldoximes which serve as biosynthetic precursors to cyanogenic glycosides or to glucosinolates. Neither of these classes of natural products has been convincingly demonstrated to accumulate in the corresponding cell cultures however. Suspension cultures of Eschscholtzia californica failed to produce the expected tyrosine- derived cyanogenic glycosides dhurrin or triglochinin but were found to contain an unidentified glucosidase-sensitive cyanogenic compound. 441 Labelled tyrosine was converted into 1-(4-hydroxyphenyl)-2-nitroethane (3 18) by microsomal pre- parations from the E.californica While no glucosinolates were detected in calli of Descurainia sophia and Alyssum minimum low levels of the glucosinolate hydrolysis products ally1 isothiocyanate and but-3-enyl isothio- cyanate were 443 6.2 Amino Acid Derivatives Acid-hydrolysed callus tissues of Helianthus annuus yielded 1 YO of their dry weight as histamine this level being two- to ten-fold higher than those of parental Radiotracer studies established the ability of primary calli of Idesia polycarpa to synthesize ~-(cyclopent-2-enyl)glycine,~~~ while minute amounts of the cytotoxic cyclic peptide maytansine have been reported to be present in suspensions of Putterlickia verru~osa.~~~ Finally cultures of Nicotiana tabacum that had been transformed with a nopaline Ti plasmid from Agrobacterium tumefaciens secreted a high-molecular-weight partially characterized opine (agro- cinopine A) which could only be taken up from the medium by plasmid-bearing bacteria.447 (on Provision of biosynthetic precursors on the other hand depressed synthesis of nicotine while increasing the concen- tration of another alkaloid anatabine (3 12).432 The highest yield of nicotine that has been reported thus far (5.3% of the dry weight) was obtained in a photomixotrophic suspension culture of N.tabacum at the end of an optimized three-stage protocol of manipulating the medium.433 When transferred to a 20-litre-scale batch fermentor however the process yielded a much more modest 1 YOof nicotine.Differentiated cultures of species of Duboisia have been found to contain nicotine in addition to the tropane alkaloids. Root cultures of D. lei~hhardtii,~~~. 420 419 D.myoporoide~,~~~. and D. hopwoodii4l8all produced 0.2-0.9 YOof their dry weight as nicotine with cultures of D.myoporoides also being reported to contain anabasine (3 13) and nornicotine (314).41y 'Hairy root ' cultures of Nicotiana rustica have recently been shown to produce modest levels of nicotine and anatabine,434 releasing part of this product to the surrounding medium.435 Trigonelline (315) has been shown to occur widely in suspension cultures of gymnosperms and Nicotinic acid autotrophic cultures of Phaseolus aureus con-tained approximately 0.03 pmol of trigonelline per gram of fresh but far higher levels (4% of the dry weight) were produced by suspension cultures of Trigonella foenum-g~aecurn.~~' 5.8 Purine Alkaloids Cell cultures of Cofiea arabica accumulated low levels of caffeine (316)436.439 and theobromine (317),438 with part of the 6.3 Volatiles a dry-weight basis) in suspensions of N.tabac~m.~~~ These often complex and partially characterized mixtures are important as organoleptic factors in food plants and as chemical signals between organisms. While monoterpenes are often major components of such volatile oils hydrocarbons and esters are also important. The main constituent of the volatile oil that was recovered from photomixotrophic suspen- sion cultures of Ruta graveolens for instance was found to be undecan-2-0ne.~~~ Suspension cultures of Solanurn tuberosum yielded ethyl valerate pentan- 1-01 hexan- 1-01 and ethyl benzoate while the not-too-distant relative Lycopersicon esculentum yielded predominantly 2-methylpent-2-enal and methyl sali~ylate.~~' Solanum +Lycopersicon somatic hybrid cultures interestingly yielded some novel volatile components that were not seen in the profile of either parent.449 Suspension cultures of Ricinus communis formed 0.08 YOof the dry weight as the unusual sulphur derivative diethylene glycol disulphide (319)' a compound which has apparently never been reported before in a biological The main flavour components of celery (Apium graveolens) consist of phthalide derivatives whose production ceases in undifferentiated cultures but re-appears as differentiation is induced.451 Aggregation of cells and restoration of photosyn- thetic competence both seem to be positively correlated with the production of phthalides [e.g.3-isobutylidene-3a,4-di-hydrophthalide (320)]and monoterpenes (e.g. Iim~nene).~~~ Much of the phthalide fraction is released into the medium. Calli and regenerating shoot cultures of Allium sativum (garlic) were reported to yield pyruvate values of 2-5 ,ug per mg of protein in an assay for akin (321) (a major flavour component of garlic). 454 NATURAL PRODUCT REPORTS 1988-B. E. ELLIS (326) Me02C HO&y& (327) (328) -0 OH 0 (329) 6.4 Polyacetylenes and Thiophenes Callus cultures of Bidens pilosa which normally produced no detectable polyacetylenes were induced to form 1-phenylhepta-1,3,5-triyne (322) by treatment with culture filtrate from the fungus Pythium aphanidermatum .455 Part of the production of polyacetylenes appeared in the culture medium.A similar response was elicited in suspension cultures of Carthamus tinctorius by cell-wall fractions from the pathogens Phytoph-thora megasperma fsp. glycinea or Alternaria carthami. The main polyacetylenes were tentatively identified as safynol (323) and dehydr~safynol.~~~ Cultures of Bidens pilosa and B. albu that had been transformed with the Ti plasmid of Agrobacterium tumefaciens were found to constitutively produce a root-type profile of polyacetylenes dominated by 7-phenylhept-2-ene-4,6- diyn-1-yl acetate (324).“’ Similarly organized root cultures of B.alba displayed constitutive production of polyacetylenes consisting primarily of (324) and trideca-2,12-diene-4,6,8,10-tetrayn-1-yl acetate (325).458 Calli of Tugetes patula produced low levels of the thiophene 5-(4-acetoxybut-1-ynyl)-2,2’-bithienyl (326).459 While some Agrobacterium-tumefaciens-transformed cell lines initially showed far higher levels (-5 pmol per gram of fresh weight) of accumulation of thiophenes this over-production declined to the levels that are seen in untransformed lines as subculturing continued.459 6.5 Organic Acids Suspension cultures of Amaranthus tricolor accumulated oxalic acid much of which was released to the medium when the cells were immobilized in chitosan gels.46o Alginate gel however did not stimulate such a release.l-cEC-CSC-crC-crcFOAc 6.6 Polyketides Calli and suspension cultures of Cassia torosa accumulated the related polyketides germichrysone (327) and pinselin (328).461 Up to 1.9 mg of germichrysone per gram of fresh weight was reported for callus cultures. Suspension cultures of Daucus carota that had been challenged with a live fungus (Chaetomium globosum) produced and released 6-methoxymellein (329) whose concentration reached a maximum (55 ,ug per 120 cm3 of medium) about 48 hours po~t-challenge.~~~ Heavy-metal salts or fungal extractives failed to trigger the synthesis of 6-methoxymellein in these 463 but fungal cell-wall fractions did stimulate the accumulation of polyphenols and the browning of The induction of 6-methoxymellein formation was shown to be mediated by a cell-wall fraction that could be released from the carrot cells by a fungal glycan lyase a~tivity.~~~.~~~ Acknowledgements The expert assistance of K.Hladun and her colleagues in the typing of this manuscript is greatly appreciated as is the patience and understanding of my students and family. 7 References 1 ‘Plant Tissue Culture as a Source of Biochemicals’ ed. E. J. Staba CRC Press Boca Raton Florida 1980. 2 D. K. Dougall in ‘Cell Substrates’ ed. J. C. 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Uomori S. Seo K. Tori and Y. Tomita Phytochemistry 1983 22 203. 286 0.P. Sharma and P. Khanna J. Nat. Prod. 1980 43,459. 287 W. 0.Erhun and A. Sofowora J. Plant Physiol. 1986 123 181. 288 T. Furuya T. Yoshikawa Y. Orihara and H. Oda Planta Med. 1983 48 83. 289 T. Furuya T. Yoshikawa T. Ishii and K. Kajii Planta Med. 1983 47 200. 290 T. Furuya T. Yoshikawa T. Ishii and K. Kajii Planta Med. 1983 47 183. 291 T. Furuya T. Yoshikawa Y. Orihara and H. Oda J. Nat. Prod. 1984 47 70. 292 G. A. Ravishankar and A. R. Mehta J. Nat. Prod. 1979 42 152. NATURAL PRODUCT REPORTS 1988-B.E. ELLIS 293 A. T. Sipahimalani V. A. Bapat P. S. Rao and M. S. Chadha J. Nut. Prod. 1981 44,114. 294 B. D. Benjamin and N. B. Mulchandani Planta Med. 1979 36 88. 295 A. H. Scragg and E. J. Allan Plant Cell Rep. 1986 5 356. 296 D. E. Fosket and D. N. Radin Plant Sci. Lett. 1983 30,165. 297 A. I. Scott H. Mizukami T. Hirata and S.-L. Lee Phytochemis-try 1950 19 488. 298 J. Stockigt and H. J. Soll Planta Med. 1980 40,22. 299 W. G. W. Kurz K. B. Chatson and F. Constabel Helv. Chim. Acta 1980 63 1891. 300 W. G. W. Kurz K. B. Chatson F. Constabel J. P. Kutney L. S. L. Choi P. Kolodziejczyk S. K. Sleigh K. L. Stuart and B. R. Worth Phytochemistry 1980 19 2583. 301 J. P. Kutney L. S. L. Choi P. Kolodziejczyk S. K. Sleigh K.L. Stuart B. R. Worth W. G. W. Kurz K. B. Chatson and F. Constabel Phytochemistry 1980 19 2589. 302 J. P. Kutney L. S. L. Choi P. Kolodziejczyk S. K. Sleigh K. L. Stuart B. R. Worth W. G. W. Kurz K. B. Chatson and F. Constabel Heterocycles 1980 14 765. 303 J. P. Kutney L. S. L. Choi P. Kolodziejczyk S. K. Sleigh K. L. Stuart B. R. Worth W. G. W. Kurz K. B. Chatson and F. Constabel J. Nut. Prod. 1981 44 536. 304 W. Kohl B. Witte and G. Hofle 2. Naturforsch. Teil B 1981 36 1153. 305 W. G. W. Kurz K. B. Chatson F. Constabel J. P. Kutney L. S. L. Choi P. Kolodziejczyk S. K. Sleigh K. L. Stuart and B. R. Worth Planta Med. 1981 42 22. 306 W. G. W. Kurz K. B. Chatson and F. Constabel in ref. 22 p. 143. 307 J. P. Kutney L. S. L. Choi P. Kolodziejczyk S.K. Sleigh K. L. Stuart B. R. Worth W. G. W. Kurz K. B. Chatson and F. Constabel Helv. Chim. Acta 1981 64 1837. 308 W. Kohl B. Witte and G. Hofle Z. Naturforsch. Teil B 1982 37 1346. 309 W. Kohl B. Witte and G. Hofle Planta Med. 1983 47 177. 310 F. Gueritte N. Langlois and V. Petiard J. Nut. Prod. 1983 46 144. 31 1 J. P. Kutney B. Aweryn L. S. L. Choi P. Kolodziejczyk W. G. W. Kurz K. B. Chatson and F. Constabel Helv. Chim. Acta 1982 65 1271. 312 W. Kohl B. Witte W. S. Sheldrick and G. Hofle Planta Med. 1984 242. 313 K.-H. Knobloch and J. Berlin 2. Naturforsch. Sect. C 1980,35 551. 314 K.-H. Knobloch B. Hansen and J. Berlin 2.Naturforsch. Sect. C 1981 36 40. 315 J. Merillon J.-C. Chenieux and M. Rideau Planta Med. 1983 47 169.316 K.-H. Knobloch G. Bast and J. Berlin Phytochemistry 1982,21 591. 317 K.-H. Knobloch and J. Berlin Plant Cell Tissue Organ Cult. 1983 2 333. 3 18 A. Pareilleux and R. Vinas Appl. Microbiol. Biotechnol. 1984 19 316. 319 J. M. Merillon M. Rideau and J.-C. Chenieux Planta Med. 1984 497. 320 P. Morris Planta Med. 1986 127. 321 A. Stafford L. Smith and M. W. Fowler Plant Cell Tissue Organ Cult. 1985 4 83. 322 P. Morris Plant Cell Rep. 1986 5 427. 323 P. Morris Planta Med. 1986 121. 324 S.-L. Lee K.-D. Cheng and A. I. Scott Phytochemistry 1981,20 1841. 325 J. P. Kutney B. Aweryn K. B. Chatson L. S. L. Choi and W. G. W. Kurz Plant Cell Rep. 1985 4 259. 326 J. Merillon P. Doireau A. Guillot J.-C. Chenieux and M. Rideau Plant Cell Rep.1986 5 23. 327 F. Majerus and A. Pareilleux Plant Cell Rep. 1986 5 302. 328 F. Sasse M. Buchholz and J. Berlin Z. Naturforsch. Sect. C 1983 38 916. 329 F. Constabel S. Rambold K. B. Chatson W. G. W. Kurz and J. P. Kutney Plant Cell Rep. 1981 1 3. 330 F. Constabel P. Gaudet-Laprairie W. G. W. Kurz and J. P. Kutney Plant Cell Rep. 1982 1 139. 331 B. Deus-Neumann and M. H. Zenk Planta Med. 1984,427. 332 J. Stockigt A. Pfitzner and J. Firl Plant Cell Rep. 1981 1 36. 333 S. Uesato S. Matsuda A. Iida H. Inouye and M. H. Zenk Chem. Pharm. Bull. 1984 32 3764. 334 H. Schubel and J. Stockigt Plant Cell Rep. 1984 3 72. 611 335 H. Schiibel A. Treiber and J. Stockigt Helv. Chim. Acta 1984 67 2078. 336 P. C. Roja B. D. Benjamin M. R.Heble and M. S. Chadha Planta Med. 1985 73. 337 0.Yamamoto and Y. Yamada Plant Cell Rep. 1986 5 50. 338 K.-H. Pawelka and J. Stockigt Plant Cell Rep. 1983 2 105. 339 R. van der Heijden R. L. Brouwer R. Verpoorte R.Wijnsma T. A. van Beek P. A. A. Harkes and A. Baerheim Svendsen Phytochernistry 1986 25 843. 340 J. Stockigt K.-H. Pawelka A. Rother and B. Deus Z. Natur-forsch. Sect. C 1982 37 857. 341 J. Stockigt K.-H. Pawelka T. Tanakashi B. Danieli and W. E. Hull Helv. Chim. Acta 1983 66 2525. 342 M. Ferchal D. Courtois and V. Petiard Planta Med. 1983 47 125. 343 K. Kouadio J.-C. Chenieux M. Rideau and C. Viel J. Nut. Prod. 1984 47 872. 344 K. Kouadio J. Creche J.-C. Chenieux M. Rideau and C. Viel J. Plant Physiol. 1985 118 277. 345 K.-H.Pawelka J. Stockigt and B. Danieli Plant Cell Rep. 1986 5 147. 346 H. Arens H. 0. Borbe B. Ulbrich and J. Stockigt Planta Med. 1982 46 210. 347 L. A. Anderson A. Harris and J. D. Phillipson J. Nut. Prod. 1983 46 374. 348 N. Crespi-Perellino A. Guicciardi G. Malyszkov E. Arlandini M. Ballabio and A. Minghetti J. Nut. Prod. 1986 49 1010. 349 W. Barz H. Herzbeck W. Hiisemann G. Schneiders and H. K. Mangold PIanta Med. 1980 40,137. 350 F. Sasse U. Heckenberg and J. Berlin Hunt Physiol. 1982 69 400. 351 F. Sasse U. Heckenberg and J. Berlin Z. PJlanzenphysiol. 1982 105 315. 352 P. A. A. Harkes P. DeJong R. Wijnsma R. Verpoorte and T. van der Leer Plant Sci. 1986 47 71. 353 E. J. Staba and A. C. Chung Phytochemistry 1981 20 2495. 354 T.Mulder-Krieger R. Verpoorte Y.P. de Graaf M. van der Kreek and A. Baerheim Svendsen Planta Med. 1982 46 15. 355 L. A. Anderson A. T. Keene and J. D. Phillipson Planta Med. 1982 46 25. 356 H. Koblitz D. Koblitz H.-P. Schmauder and D. Groger Plant Cell Rep. 1983 2 122. 357 T. Mulder-Krieger R. Verpoorte A. de Water M. van Gessel B. C. J. A. van Oeveren and A. Baerheim Svendsen Planta Med. 1982 46 19. 358 T. Mulder-Krieger R. Verpoorte M. van der Kreek and A. Baerheim Svendsen Planta Med. 1984 50 17. 359 H.-P. Schmauder D. Groger H. Koblitz and D. Koblitz Plant Cell Rep. 1985 4 233. 360 C. Hay L. Anderson M. Roberts and J. Phillipson Plant Cell Rep. 1986 5 1. 361 P. A. A. Harkes L. Krijbolder K. R. Libbenga R. Wijnsma T. S. Aremge and R.Verpoorte Plant Cell Tissue Organ Cult. 1985 4 199. 362 R. Wijnsma R. Verpoorte P. A. A. Harkes T. B. van Vliet H. J. G. ten Hoopen and A. Baerheim Svendsen Plant Cell Tissue Organ Cult. 1986 7 21. 363 M. J. C. Rhodes J. Payne and R. J. Robins Planta Med. 1986 226. 364 R. J. Robins J. Payne and M. J. C. Rhodes Planta Med. 1986 220. 365 M. Montagu-Bourin M. Rideau P. Levillain and J.-C. Chenieux Planta Med. 1980 38 50. 366 M. Sejourne C. Viel J. Bruneton M. Rideau and J.-C. Chenieux Phytochemistry 198 1 20 353. 367 M. Gras J. Creche J.-C. Chenieux and M. Rideau Planta Med. 1982 46,231. 368 B. Wolters and U. Eilert Planta Med. 1981 43 166. 369 A. Baumet I. N. Kuzovkina G. Krauss M.Hieke and D. Groger Plant Cell Rep. 1982 1 168. 370 B.Wolters and U. Eilert Z. Naturforsch. Sect. C 1982 37 575. 371 U. Eilert A. Ehmke and B. Wolters Planta Med. 1984 508. 372 K. G. Ramawat M. Rideau and J.-C. Chenieux Phytochemistry 1985 24 441. 373 A. Nahrstedt V. Wray B. Engel and E. Reinhard Planta Med. 1985 517. 374 N. E. Delfel Planta Med. 1980 39 168. 375 M. Misawa M. Hayashi and S. Takayama Planta Med. 1983 49 115. 376 W. H. J. Tam F. Constabel and W. G. W. Kurz Phytochemistry 1980 19 486. 377 K. K. Kamo W. Kimoto A.-F. Hsu P. G. Mahlberg and D. D. Bills Phytochemistry 1982 21 219. 378 R. Schuchmann and E. Wellmann Plant Cell Rep. 1983 2 88. 379 T. M. Kutchan S. Ayabe R. J. Krueger E. M. Coscia and C. J. Coscia Plant Cell Rep. 1983 2 281. 380 T. Yoshikawa and T.Furuya Planta Med. 1985 110. 381 C. C. Hodges and H. Rapoport J. Nut. Prod. 1982 45 481. 382 S. W. Zit0 and E. J. Staba Planta Med. 1982 45 53. 383 A.-F. Hsu J. Nut. Prod. 1981 44 408. 384 G. B. Lockwood Phytochemistry 1981 20 1463. 385 G. B. Lockwood Z. PJanzenphysiol. 1984 114 361. 386 E. J. Staba S. Zito and M. Amin J. Nut. Prod. 1982 45 256. 387 U. Eilert W. G. Kurz and F. Constabel J. Plant Physiol. 1985 119 65. 388 U. Eilert and F. Constabel J. Plant Physiol. 1986 125 167. 389 K. Iwasa and N. Takao Phytochemistry 1982 21 611. 390 T. Furuya T. Yoshikawa and H. Kiyohara Phytochemistry 1983 22 1671. 391 H. Arens H. Fischer S. Leyck A. Romer and B. Ulbrich Planta Med. 1985 52. 392 H. Hinz and M. H. Zenk Naturwissenschaften 1981 68 620.393 Y. Yamada and F. Sato Phytochemistry 1981 20 545. 394 F. Sato and Y. Yamada Phytochemistry 1984 23 281. 395 A. Ikuta and H. Itokawa Phytochemistry 1982 21 1419. 396 K. Nakagawa A. Konagai H. Fukui and M. Tabata Plant Cell Rep. 1984 3 254. 397 K. Nakagawa H. Fukui and M. Tabata Plant Cell Rep. 1986,5 69. 398 J. H. Gould and T. Murashige Plant Cell Tissue Organ Cult. 1985 4 29. 399 T. Tanahashi and M. H. Zenk Plant Cell Rep. 1985 4 96. 400 J. Berlin E. Forche V. Wray J. Hammer and W. Hosel Z. Naturforsch. Sect. C 1983 38 346. 401 J. Franke and H. Bohm Biochem. Physiol. PJanzen 1982 177 501. 402 K. G. Ramawat and H. C. Arya Phytochemistry 1979 18 484. 403 K. Saito H. Obata-Sasamoto S.-I. Hatanaka H. Noguchi U. Sankawa and A.Komamine Phytochemistry 1982 21 474. 404 M. Wink L. Witte H.-M. Schiebel and T. Hartmann Planta Med. 1980 38 238. 405 M. Wink and T. Hartmann Planta Med. 1980 40 149. 406 M. Wink T. Hartmann L. Witte and H. Schiebel J. Nut. Prod. 1981 44 14. 407 M. Wink L. Witte T. Hartmann C. Theuring and V. Volz Planta Med. 1983 48 253. 408 M. Wink H. M. Schiebel L. Witte and T. Hartmann Planta Med. 1982 44 15. 409 M. Wink L. Witte and T. Hartmann Planta Med. 1981 43 342. 410 A. Rother J. Nut. Prod. 1985 48 33. 411 M. Wink and L. Witte FEBS Lett. 1983 159 196. 412 H. J. Huizing E. C. Pfauth T. M. Malingre and J. H. Sietsma Plant Cell Tissue Organ Cult. 1983 2 227. 413 W. J. Griffin Naturwissenschaften 1979 66 58. 414 R. Kibler and K.-H. Neumann Planta Med.1979 35 354. 415 Y. Yamada and T. Hashimoto Plant Cell Rep. 1982 1 101. 416 K. Lindsey and M. M. Yeoman J. Exp. Bot. 1983 34 1055. 417 T. Hashimoto and Y. Yamada Planta Med. 1983 47 195. 418 Y. Yamada and T. Endo Plant Cell Rep. 1984 3 186. 419 T. Endo and Y. Yamada Phytochemistry 1985 24 1233. 420 Y. Kitamura H. Miura. and M. Sugii Chem. Pharm. Bull. 1985 33 5445. 421 S. Koul A. Ahuja and S. Grewal Planta Med. 1983 47 11. 422 T. Hashimoto Y. Yukimune and Y. Yamada J. Plant. Physiol. 1986 124 61. 423 T. Hartmann L. Witte F. Oprach and G. Toppel Planta Med. 1986 390. 424 K.-M. Oksman-Caldentey and A. Strauss Planta Med. 1986 6. NATURAL PRODUCT REPORTS 1988 425 S. Eapen T. S. Rangan M. S. Chadha and M. R. Heble Plant Sci. tett.1978 13 83. 426 H. Kamada N. Okamura M. Satake H. Harada and K. Shimo- mura Plant Cell Rep. 1986 5 239. 427 T. Ogino N. Hiraoka and M. Tabata Phytochemistry 1978 17 1907. 428 S. Ohta 0.Matsui and M. Yatazawa Agric. Biol. Chem. 1978 42 1245. 429 A. M. Kinnersley and D. K. Dougall Planta 1980 149 205. 430 G. A. Ravishankar and A. R. Mehta Can. J. Bot. 1982 60 237 1. 431 S. H. Mantell D. W. Pearson L. P. Hazell and H. Smith Plant Cell Rep. 1983 2 73. 432 G. B. Lockwood and A. K. Essa Plant Cell Rep. 1984 3 109. 433 W. Roper M. Schulz E. Chaouiche and K. A. Meloh J. Plant Physiol. 1985 118 463. 434 J. D. Hamill A. J. Parr R. J. Robins and M. J. C. Rhodes Plant Cell Rep. 1986 5 11 1. 435 M. J. C. Rhodes M. Hilton A. J. Parr J. D. Hamill and R.J. Robins Biotechnol. Lett. 1986 8 415. 436 U. Willeke V. Heeger M. Meise H. Neuhann I. Schindelmeiser K. Vordemfelde and W. Barz Phytochemistry 1979 18 105. 437 S. S. Radwan and C. K. Kokate Planta 1980 147 340. 438 P. M. Frischknecht and T. W. Baumann Planta Med. 1980 40 245. 439 G. R. Waller C. D. MacVean and T. Suzuki Plant Cell Rep. 1983 2 109. 440 P. M. Frischknecht and T. W. Baumann Phytochemistry 1985 24 2255. 441 W. Hosel J. Berlin T. N. Hanzlik and E. E. Conn Planta 1985 166 176. 442 S. Afsharypuor and G. B. Lockwood Plant Cell Rep. 1985 4 341. 443 G. B. Lockwood and S. Afsharypuor J. Chromatogr. 1986 356 438. 444 R. Kamal and P. Khanna Planta Med. 1979 36 181. 445 I. Tober and F. Spener Plant Cell Rep. 1982 1 193.446 M. Misawa M. Hayashi and S. Takayama Planta Med. 1983 49 115. 447 E. Messens A. Lenaerts R. W. Hedges and M. van Montagu EMBO J. 1985 4 571. 448 F. Drawert R. G. Berger R. Godelmann S. Collin and W. Barz Z. Naturforsch. Sect. C 1984 39 525. 449 H. Ninnemann and F. Juttner Z. PJanzenphysiol. 1981 103 95. 450 Y. Gafni and I. Shechter Phytochemistry 1981 20 2477. 451 S. Al-Abta I. J. Galpin and H. A. Collin Plant Sci. Lett. 1979 16 129. 452 M. J. Watts I. J. Galpin and H. A. Collin New Phytol. 1985 loo 45. 453 M. J. Watts I. J. Galpin and H. A. Collin New Phytol. 1984,98 583. 454 N. Malpathak and S. David Plant Cell Rep. 1986 5 446. 455 F. DiCosmo R. Norton and G. H. N. Towers Naturwissenschaf-ten 1982 69 550. 456 K. G.Tietjen and U. Matern Arch. Biochem. Biophys. 1984,229 136. 457 R. A. Norton and G. H. N. Towers J. Plant Physiol. 1985 120 273. 458 R. A. Norton and G. H. N. Towers J. Plant Physiol. 1986 122 41. 459 R. A. Norton A. J. Finlayson and G. H. N. Towers Phytochem-istry 1985 24 719. 460 D. Knorr and R. A. Teutonico J. Agric. Food Chem. 1986 34 96. 461 H. Noguchi and U. Sankawa Phytochemistry 1982 21 319. 462 F. Kurosaki and A. Nishi Phytochemistry 1983 22 669. 463 F. Kurosaki and A. Nishi Physiol. Plant Pathol. 1984 24 169. 464 F. Kurosaki Y. Tsurusawa and A. Nishi Phytochemistry 1985 24 1479. 465 F. Kurosaki M. Amin and A. Nishi Physiol. Mol. Plant Pathol. 1986 28 359.

ISSN:0265-0568    

DOI:10.1039/NP9880500581

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Marine Natural Products D. J. Faulkner Scripps Institution of Oceanography A-Ol2F University of California San Diego La Jolla CA 92093 USA ~~~~ ~~~~ ~ ~ Reviewing the literature published between September 1986 and December 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 539) 1 Introduction 2 Marine Micro-organisms and Phytoplankton 2 Marine Micro-organisms and 3 Blue-Green Algae (Cyanobacteria) Phytoplankton 4 Green Algae Tetrodotoxin (I) the compound responsible for pufferfish 5 Brown Algae poisoning has been detected in the culture broths of marine 6 Red Algae bacteria that have been identified as species of Pseudomona~,~ 7 Sponges Alteromonas,'O and Vibrio." A bacterium of the genus 8 Coelenterates Pseudomonas was isolated from the skin of the pufferfish Fugu 9 Bryozoans [= Takifugu] poecifonot~s.~ The discovery that symbiotic 10 Marine Molluscs bacteria produce tetrodotoxin (1) and its derivatives explains I1 Tunicates why these toxins have been isolated from so many unrelated 12 Echinoderms host species.I3 Miscellaneous Leptosphaerin (2) is a metabolite of the marine ascomycete 14 References Leptosphaeria oraemaris. Although leptosphaerin (2) is a relatively simple molecule its structural elucidation was complicated by ambiguity over the location of the amide nitrogen. A combination of an X-ray-crystallographic study 1 Introduction and the synthesis of both potential candidate structures allowed This Report is a review of the literature of marine natural both the structure and the absolute configuration of lepto- l3 A short biomimetic synthesis product chemistry that was received in La Jolla during the sphaerin (2) to be confirmed.12~ period 1 September 1986 to 1 December 1987.This is the fifth of leptosphaerin (2) was subsequently reported. l4 Gliovictin in a series of reviews published in Natural Product Reports. The (3) which is a known fungal metabolite was isolated from the earlier cover the period from 1977 to September marine deuteromycete Asteromyces cruciatus.l5 A deep-sea 1987. bacterium of the genus Bacillus produces the known anti- (4).16 A review entitled 'Recent Developments in the Field of microbial agent 3-amino-3-deoxy-~-glucose Marine Natural Products with Emphasis on Biologically Active Compounds ' has provided an excellent coverage of the field by including over 1000 structures and J60 reference^.^ 0- More detailed reviews of 'The Structure of Palytoxin'' and 'Sesterterpenes an Emerging Group of Metabolites from Marine and Terrestrial Organisms " have also appeared.Although the research effort devoted to the structural elucidation of marine natural products has remained almost constant there has been a considerable expansion of research in areas that are directly influenced by marine natural product chemistry. Much of the peripheral literature has been difficult to track and some papers have been judged to be beyond the scope of this review. In general only papers pertaining directly to specific marine natural products will be included.In the area of synthetic organic chemistry reports of the total synthesis of marine natural products are included but papers dealing with methodology that is directed toward the synthesis of a marine metabolite are omitted. Studies of the chemical ecology of marine organisms are included only if research was performed using pure compounds. Pharmacological studies using marine natural products are rapidly increasing in number and scope. While every effort will be made to record the pharmacological OH (2) activity of new metabolites studies of mechanisms of action and reports of basic pharmacology in which marine natural products were used as biochemical probes will be reviewed only when they report a significant change in the biomedical status CH,OH of a compound.The patent literature will not be reviewed in I detail due to its relative inaccessibility but it is known that an It)-.. increasing number of marine natural products have been HO patented as potential pharmaceuticals and in one case as a potential sunscreen.* Chemotaxonomic studies will be reported when they result in a significant revision of the systematic status OH of organisms. 613 H02 C The diatoms Skefetonema costatum and Lithodesmium undufatumproduce ectocarpene (5),17 which is a pheromone of brown algae.'* Although the production of ectocarpene appears to coincide with the development of female gametes there is no direct proof that ectocarpene acts as a pheromone in diatoms. An X-ray-crystallographic study of a chiral dioxolane derivative (6) of brevetoxin B has unequivocally established the absolute configuration of the brevet ox in^.^^ Two studies of the biosynthesis of brevetoxin B (7) during both of which the incorporation of 13C-labelled precursors was assessed by using n.m.r.techniques have resulted in a novel hypothesis to explain the unexpected labelling patterns that have been observed.20* 21 A report that the structure of brevetoxin A (8) can be derived ex post facto from n.m.r. and mass-spectral data was less than satisfactory because it lacked evidence for some NATURAL PRODUCT REPORTS 1988 'R 'CHO 0 of the stereochemical features that had been determined by X-ray crystallography.22 Amphidinolide-A (9) is a twenty-membered macrolide that is produced by a species of dinoflagellate of the genus Amphi-dinium which was isolated from a flatworm (Amphiscofops species).23 The stereochemistry of amphidinolide-A (9) which shows antineoplastic activity has yet to be determined.The same species of Amphidinium has yielded a second antineoplastic macrolide amphidinolide-B ( Amphidinolide-B (lo) which contains a 26-membered ring is lo4 times as active as amphidinolide-A (9). The causative toxin of diarrhetic shellfish poisoning in Europe is okadaic acid (1 1),25 which was previously isolated from the sponge Hafichondria okadaP and from the dino- flagellate Prorocentrum fima.27The observed toxicity of mussels NATURAL PRODUCT REPORTS 1988-D.J. FAULKNER HO Go (12) (13) R = H - (14) R = AC OMe I CO2H C7H1!j 0 (15) Q)-($oN -/ H ROZC (18) R=Me (19) R =H bAC OAc in France and the Netherlands coincided with increases in the dinoflagellate Dinophysis acuminata and in Norway with that of D. acuta.25 3 Blue-Green Algae (Cyanobacteria) Both marine and terrestrial cyanophytes continue to yield interesting biologically active metabolites. During this reporting period the terrestrial cyanophytes have produced the more unusual metabolites while research on marine cyanophytes appears to have been limited to studies of Lyngbya majuscula. Specimens of L. majuscula from Puerto Rico have yielded (-)-(S)-3,4-dihydroxybutanoic acid y-lactone (12)28 and two metabolites called malyngamide D (1 3) and malyngamide D acetate (14).29 Unfortunately the name malyngamide D had previously been assigned to a related and the authors have therefore proposed that the new metabolites be renamed malyngamide F (13) and malyngamide F acetate (14).31 The new malyngamide (13) is mildly cytotoxic to KB cells and the corresponding acetate (14) shows slight anti- microbial activity against Staphylococcus aureus.The major antimicrobial constituents of the Puerto Rican specimens of L. majuscula are elemental sulphur and ( -)-(4E,7S)-7-meth-oxytetradec-4-enoic acid (1 5). OR CHO C HO (23) The absolute stereochemistry of lyngbyatoxin-A (1 6) which is a potent tumour promoter that can be isolated from L. majuscul~,~~ was determined by chemical degradati~n.~~ Lyngbyatoxin-A (16) and a related metabolite have been synthesized in a non-stereoselective synthesis that nonetheless produced optically pure A synthesis of (-)-malyn- golide (1 7) and three stereoisomers employed an enantio-selective Sharpless epoxidation to produce optically active intermediates.35 4 Green Algae Both caulerpin (18) which is a prominent red pigment from many green algae of the genus Caulerpa and the corresponding diacid (19) were shown to promote root growth in lettuce seedlings.3s The activity is similar to that of indoleacetic acid.The distribution of caulerpin (18) in various species of Caulerpa has been de~cribed.~' Six new sesquiterpenes (20)-(25) have been isolated from specimens of Caulerpa ashmeadii that had been collected in Florida.38 The sesquiterpenes (20)--(23) were toxic to dam- selfish and showed antimicrobial activity.When compared with eleven other species of Caulerpa C. ashmeadii was the most strongly avoided by reef fish. The distasteful qualities of the 616 CH20H I CH-OH OH OH (26) (27) (341 (35) (38) R = Et Ac 0 (39) R = n-C5H, (40) (44) alga correlate with the presence of the sesquiterpenoids. This research extends previous studies of chemical defence in tropical green algae of the Order Caulerpale~.~~ The tropical green alga A vrainvilleu nigricans contains 5’- hydroxyisoavrainvilleol (26) as well as the known compounds avrainvilleol (27) and 3-bromo-4,5-dihydroxybenzyl One additional brominated hydroquinone (28) which is a hydrated derivative of cymopolone (29) has been isolated from a specimen of Cymopolia barbata from the Canary Islands.41 5 Brown Algae The volatile constituents of Dictyopteris profifera consisted of the familiar C, hydrocarbons dictyopterene A (30) and dictyopterene B (31)42 together with the new metabolites dictyoprolene (32) and neodictyoprolene (33).43 The structures of dictyoprolene (32) and neodictyoprolene (33) were confirmed by synthesis.The isolation of the acetates (32) and (33) is of biosynthetic significance because the corresponding alcohols were proposed to be the precursors of hydrocarbons (30) and (3 The volatile constituents of Dictyopteris membranacea consisted predominantly of known C, hydrocarbons.Two new hydrocarbons (34) and (35) were identified by gas chromatography-mass spectrometry and the structures con- firmed by ~ynthesis.~~ The volatile constituents of Gzfordia mitchellae are dominated by a complex mixture of stereo- isomeric undeca-2,4,6,8-tetraenes,of which giffordene [(22 NATURAL PRODUCT REPORTS 1988 H PAC H PAC (32) (33) (36) (371 R’o\ R20 OR2 (41) R’ = R2 = H (42) R’ = R2 = Ac (43) R’ = AC R2 = H (451 42,6E,8Z)-undeca-2,4,6,8-tetraene](36) is the major con-stit~ent.~~ Eight stereoisomers of undeca-2,4,6,8-tetraene were synthesized but none of the isomers attract male gametes of G. mi~chellue.~~ Aucantene (37) which is a metabolite of Cutleria rn~ltiJida,~?has been synthesized in three steps to yield racemic material in 63 YOoverall yield.48 Fucoserratene (38) which is a pheromone of Fucusserrat~s,~’and (3E,SZ)-undeca- 1,3,5-triene (39) (a constituent of the essential oils of species of Dictyopteri~)~~ have both been synthesized from a common intermediate in high isomeric purity and on a preparative scale.51 Chromophycadiol monoacetate (40) which is a diterpene that possesses a new carbon skeleton was isolated from a species of Dictyota that had been collected in the Canary Islands.52 The structure of chromophycadiol monoacetate was determined by X-ray analysis.Pachytriol (41) is a minor metabolite of Dictyota dichotoma collected in the Canary The structure of pachytriol (41) was elucidated by interpretation of spectral data and by its conversion into the same triacetate (42) as was formed by acetylation of the corresponding monoacetate (43) that had previously been isolated from Puchydictyon c~riaceum.~~ Dic-tyota dichotoma from Japan is the source of a novel bicyclic diterpene called dictymal (44).55The structure of dictymal (44) was determined by analysis of spectral data.It has been proposed that dictymal (44) results from ring cleavage of epoxydictymene (45),56with which it co-occurs. Examination NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER C H,OAc HI qy HO (461 (47) R'= RL= H (50) (48) R'= OAc R2 = H (49) R' = H,R~=OH ;H PH I \ OAc HO I I Rb I li 12 (51) R = R = H 2 (521 R 1 = H R = AC (53) R1= R 2=Ac (61) of specimens of the brown alga Dictyota dichotoma var.implexa from the North Adriatic Sea revealed the presence of a new diterpene dictyol I acetate (46) together with the familiar metabolites pachydictyol A (47) and dictyol B acetate (48).57 Dictyol E (49) and a new xenicane-type diterpene dilophic acid (50) were isolated from Dilophus guineensis collected at Puerto Ri~o.~~ Dictyotriol A (51) and dictyotriol A monoacetate (52) were isolated from Glossophora kuntii from Chile59 and the structures were elucidated by analysis of spectral data and by their interconversion with dictyotriol A diacetate (53) which is a metabolite of Dictyota binghamiae.60 A new spatane diterpenoid (5R)-19-acetoxy- 15,16-epoxy-5- hydroxyspata- 13( 14) 17-diene (54) has been isolated from Stoechospermum marginatum from India.61 Specimens of Dictyota cervicornis from Brazil contained seven previously described dolastane-type and three secodolastane-type diter- penes two of which are new compounds (see also ref.4 p. 544). The structures of isolinearol (55) and isolinearol acetate (56) were elucidated by analysis of spectral data.62 The carbon skeleton of dolastane has been synthesized from a 6-6-6 CHO (62) tricyclic intermediate using a photochemical rearrangement of an epoxy-ketone to obtain the required 6-7-5 ring-system. Unfortunately the introduction of oxygen at C-4 produced the 'wrong ' stereoisomer 4a/3,10/3-doladiol acetate [or 7P-acetoxy- 14/3-hydroxydolasta- 1(15),8-diene] (57).63 A synthesis of 14a- hydroxydolasta- I( 15),7,9-triene (58) which was isolated from a mixed collection of Dictyota divaricata and D.lineari~,~~ has been accomplished by using a novel annulation sequence.65 A highly stereocontrolled total synthesis has confirmed the structure of sanadaol(59) [= /3-~renulal],~~ which is a metabolite of both Pachydictyon coriaceums7 and Dictyota crenulata.6s (+)-Taonianone (60) which is an unusual metabolite of Taonia at~maria,'~ has been synthesized by two research groups both of which used a strategy involving ring-contraction of a derivative of (-)-(R)-carv~ne.'~* 71 The molluscicidal and anti- fungal activities of a number of algal diterpenes predominantly of the dolabellane series have been rep~rted.'~ Two new linear diterpenes eleganonal (61) and iso-ele- ganonal (62) were isolated from Cystoseira baleari~a.~~ Two varieties of Cystoseira stricta from Sicily have been studied.Six NATURAL PRODUCT REPORTS 1988 (63) R = H (65) (64) R =Me OH Me6 OH (75) new tetraprenylated quinols [(63) (64) and (67)-(70)] have been isolated from C. stricta var. arnentacea and five new metabolites [(65) and (71)-(74)] of similar structure were isolated from C. stricta var. stricta. The structures of amentol (63) amentol methyl ether (64) and strictaepoxide (65) were defined by using extensive two-dimensional n.m.r. experiments and chemical interconversion~.~~ Similarities in the lH n.m.r.spectra (though not in the I3Cn.m.r. spectra) of amentol (63) and cystoseirol D (66) suggest that these materials should be directly compared particularly in the light of the unusual ring system that has been assigned to cystoseirol D (66).75 Amentadione (67) may be regarded as a biosynthetic precursor OH OH (68) R = H (70) (69) R = Me OH (72) (73) 0 (76) of the (2E)bifurcarenone (68) that was found together with the corresponding methyl ether (69) and amentaepoxide (70) in C. stricta var. arnenta~ea.’~ Isocystoketal (71) strictaketal (72) isostrictaketal(73) and isobalearone (74) were all isolated from C. ~tricta.’~, 78 The different absolute configurations that have been indicated for members of this series do not appear to have any significance.Sargahydroquinone (75) and yezoquinolide (76) are two new plastoquinones that were isolated as minor constituents of Sargassurn sagamianurn var. yez~ense.’~ Four arsenic-containing ribofuranosides (77)-(80) together with inorganic arsenic have been isolated from Hizikia fusiforrne which is eaten in Japan under the name ‘hijiki’.80 NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER 619 OH OH (771 R' = OH R2 = OS03H (78) R' = OH R2 = S0,H (79) R' = OH R2 = OPOCH2CH(OH)CH20H 19 I U (80) R' = NH?,R~= S~H (81) R' = R2 = OH (84) (86) Br The structures were elucidated predominantly from 'H n.m.r. data. A similar array of compounds [i.e. (78) (79) and (Sl)] were isolated from the edible seaweed Laminaria japonica.81 6 Red Algae The temperate red alga Ptilota jilicina contains (52,7E 9E 142,17Z)-icosa-5,7,9,14,17-pentaenoic acid (82) and (5E 7E,9E 142,17Z)-icosa-5,7,9,14,17-pentaenoicacid (83) both of which were isolated as the corresponding methyl esters.82 The four new acetylenic hydrocarbons laurencenyne (84) neolaurencenyne (85) trans-laurencenyne (86) and trans-neolaurencenyne (87) which are considered to be potential biosynthetic precursors of halogenated C, enynes have been isolated as minor metabolites of Laurencia okam~rai.~~ The hco2H 182) (85) (87) 4Br Br structures of hydrocarbons (84>-(87) were confirmed by synthesis.The absolute configuration of (32)-isoprelaurefucin (88) which is a metabolite of Laurencia nipponica was determined by chemical correlation with related metabolites of known absolute stereochemistry.84 A new halogenated C, enyne called elatenyne (89) has been isolated from L. elata and its structure was elucidated by interpretation of spectral data.85 The structure of epoxy-trans-isodihydrorhodophytin (90) which is a new metabolite of L. obtusa was determined by X-ray analysis.ss The major metabolite of Ptilonia magellanica from the Kerguelen Islands (in the southern Indian Ocean) was shown to be 4-acetoxy- l,l-dibromoheptan-2-01 (91).87 Two new macrocyclic y-pyrones (92) and (93) together with two novel a-pyrones (94) and (95) were found in Phacelocarpus lubillardieri NATURAL PRODUCT REPORTS 1988 HB%e#c, 0' (96) R = Br (97) R = H Bf (98) R = OH (99) Ho=%cl I 0 J3kC' OH (100) Meo2c% (103) Br CI (104) (105) I OH Or% I ' on Br' ,p&/Br -Br* Br a / OH 6r Ar from Australia.86 The structures were elucidated by comparison of their spectral data with those of known metabolites from this alga.Although no new polyhalogenated monoterpenes have recently been isolated from red algae a structural analysis of cyclic polyhalogenated monoterpenes from a species of Plocamium has revealed that steric interactions involving the halogen atoms distort the expected geometry of the mole- cule~.~~ Hence the 13C n.m.r. chemical shifts that are calcu- lated by using additive effects derived from simple modelsg0 should not be used in the structural elucidation of poly- halogenated cyclic monoterpenes.A biogeographic study of polyhalogenated cyclic monoterpenes from specimens of Plocamium cartilagineum that had been collected at six locations along the Chilean coast has revealed significant ~ariability.~~ The structure of isoaplysin (96) which is a metabolite of Laurencia okamurai has been confirmed by chemical inter- conversion with debromoaplysin (97) and debromoaplysinol (98).92A second X-ray-crystallographic study of pacifenol(99) which was originally isolated from Laurencia pa~$ca,'~ has been reported.B4 Two new halogenated chamigrenes have been isolated from a Jamaican variety of Laurencia obtusa. The structures of 2-chloro-3-hydroxy-a-chamigren-9-one (100) and the related tricyclic ether (101)were assigned by inter- pretation of spectral data and by chemical interconversion with elatol (102) which is the major metabolite of the alga.95 Two new trinorsesquiterpenes (103)and (104)were isolated as minor metabolites of Laurencia caespitosa and the structures were determined by X-ray analysis.96 The absolute configuration of furocaespitane (105) was determined by chemical inter-conversion with the keto-ester (103).96 Several naturally occurring chamigrenes particularly (+)-(2S,6R)-2-bromo-P-chamigrene (106) (from a species of Laurencia)," (-)-(2R 6S,8S,9S)-2,8-dibromo-9-hydroxy-a-chamigrene (107) (from Laurencia nipponi~a),~~ and (2S,6R,8R,9R)-2,8-dibromo-9-hydroxy-a-chamigrene (108)and (2S,6R,8R,9R)-2,8-dibromo-9-hydroxy-/3-chamigrene (109y9 have been synthesized by an enantioselective route.loO Two syntheses of brasilenol (1 lo), which is a metabolite of both Laurencia obtusa and the sea hare Aplysia brasiliana,'O' have been reported.lo2* lo3 The second synthetic route gave racemic brasilenol (1 10) in seven steps (in Oh 31 overall yield) and allowed the natural isomer (+)- NATURAL PRODUCT REPORTS 1988-D..I.FAULKNER 621 OH 0m-A (110) (111) OH OH 9 I 1 $.& '.Br I A i\ Br (114) R = H (115) (116) R = OH I (117) 0r #' Br ' -P-$OH (120) brasilenol to be synthesized thereby defining the absolute configuration of the natural product.lo3 The stereospecific synthesis of ( & )-perforenone (1 1 I) which is a metabolite of Laurencia perforata,lo4 has been accomplished by using a new annulation reaction.lo5 A most unusual tetracyclic polyketal (1 12) was isolated from Laurencia chilensis and its structure was determined by X-ray analysis.'06 The red alga Sphaerococcus coronopifolius continues to provide interesting new brominated diterpenes.Bromotetra- sphaerol (113) is thought to be derived biosynthetically by further cyclization of bromosphaerol (I 14) this being the major metabolite of S. coronopifofius.107 The four new diterpenes (1 2s)- 12-hydroxybromosphaerodiol (1 1 5) (1 2R)- '. Br (119) 5)' Hd HO' (122) (123) 12-hydroxysphaerol (116) isosphaerodiene- 1 (1 17) and iso- sphaerodiene-2 (1 18) were all obtained in small amounts and were identified on the basis of spectral and chemical evi- dence.lo8 Another minor metabolite is the unusual dinor-diterpene norsphaerol (1 19).log It had previously been reported that the proposed structure of the Laurencia metabolite isoconcinndiol (1 20) was incor- rect."O The revised structure of isoconcinndiol (121) was con- firmed by its total synthesis."' Both prepinnaterpene (122) which is the least complex of the brominated diterpenes from Laurencia pinnata,'12 and oppositol (123) which was isolated from L.subopp~sita,~'~ have been synthesized in racemic f01-1n.l~~ H +oyH mR OH (126) R= fOAc OH (127) R = OAC (128) R= OAc "\fOAc I n OAc I (130) R = M OH (131) R = OH (132) R = OH Venustatriol (124) is a new tetracyclic triterpene ether from Laurencia venusta.Venustatriol (124) thyrsiferol (129 and thyrsiferyl 23-acetate (1 26) all displayed significant antiviral activity.'15 The discrepancy between the structures drawn in this review and those depicted previously is due to the fact that the relative configurations at C-14 C-15 C-19 and C-22 had been mistranscribed from the X-ray view of thyrsiferyl 18- acetate (127)? The five new cytotoxic triterpenoids 15(28)- anhydrothyrsiferyl diacetate [ 15,28-didehydro- 15-deoxythyrsi- feryl diacetate] (I 28) 15-anhydrothyrsiferyl diacetate [ I5,16-didehydro- 15-deoxythyrsiferyl diacetate] (1 29) magireol-A (1 30) magireol-B (1 3I) and magireol-C (1 32) have been isolated from Japanese specimens of Laurencia obtusa.11' The new structures were elucidated primarily from spectral data.The structural elucidation and synthesis of ( + )-(IOR,1 1R)-squalene l0,ll-epoxide (133) from L. okamurai has been reported in a full paper.118 Three new insecticidal amino acids namely isodomoic acid A (134) isodomoic acid B (135) and isodomoic acid C (136) NATURAL PRODUCT REPORTS 1988 (133) I HO2C MC02H H02C HNp\ HNP' H0,C C02H 1134) .Q:; C02H (140) Q--cHo H t 141) were isolated from the red alga Chondria armata.llQThese metabolites are slightly less active than the parent compound domoic acid (1 37) when injected subcutaneously into cock- roaches.Two inactive metabolites domoilactones A (138) and B (139) were also isolated from Chondria armata.120The structures of these metabolites were all elucidated by spec- troscopic analysis. An enantiospecific total synthesis of ( -)-a-kainic acid (140) which is a compound from Digenea simplex that has neuroexcitatory properties employs an interesting Claisen rearrangement as its key step.'21 Indole-3-carbaldehyde (141) has been isolated in low yield from the alga Botryocladia lep topoda . 22 NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER mm SCN [CH21n NCS (145) n = 8-15 (146) n = E HCEC-CH-CH=CH[I CH219CH=CH OH (148) OH OH (149) OH (151) (153) 7 Sponges The three glycerol alkyl monoethers (2s)- 1-(hexadecy1oxy)- propane-2,3-diol (142) (23- 1-(16-methylheptadecy1oxy)prop-ane-2,3-diol (143) and (2s)- 1-(15-methylheptadecy1oxy)prop-ane-2,3-diol (144) were obtained in the free form from Tethya a~ran1ia.l~~ A series of eighteen long-chain aliphatic a,o-bis- isothiocyanates (145) and (146) and three a-isothiocyano-o- formyl analogues (147) have been isolated from a Fijian species of Pse~daxinyssa.~~~ The major constituents (145; n = 14) (146; n = 16) and (147; n = 15) all have the same length (i.e.C18)of aliphatic chain. Unlike the terpenoid isothiocyanates rnSCN [ CHZln-CHO 9-10 (1471 n = 9,15,and 16 E [ CH2]9 C H=CH-C H-C-CHI OH OH I bH (1521 this series of isothiocyanates was not accompanied by the cor- responding isocyanides or formamides which suggests that they are formed by a different biosynthetic pathway.A symmetrical acetylenic lipid duryne (148) was isolated as the cytotoxic agent from specimens of Cribrochaha dura that had been collected in the Bahamas.125 Duryne (148) inhibits the growth of P388 murine leukaemia and of colon lung and mammary human tumour cell lines. Petrosynol (149) and petrosynone (1 50) are two polyacetylenic constituents of Japanese species of Petrosia.126Petrosynol (150) was previously reported,12’ with- out a common name from a species of ‘Tetrosia’ which should be corrected to Petrosia. The structure of petrosynol (1 50) which is both antimicrobial and active in the starfish egg assay was determined previously and the absolute configuration has now been established by the exciton chirality method.The absolute configurations of the gastric H+/K+-transporting ATPase inhibitors siphonodiol (1 5 l) dihydrosiphonodiol (1 52) and tetrahydrosiphonodiol (1 53) which were obtained NATURAL PRODUCT REPORTS 1988 Br C0,H Br (154) (155) HO 'OiOH (168) 0 bC02Me'0 (171) OMe tCH2110 + (174) (?Me Rv. /CO 2 Me from Siphonochalina truncata have been determined by the exciton chirality method.12* Six brominated acetylenic acids (1 54)-( 159) were isolated as the corresponding methyl esters from a species of Xestospongia that had been collected in the Red Sea.129 The major metabolite (154) had previously been isolated from Xestospongia testudinaria from near Townsville Australia.130 The structures of the methyl esters were elucidated by interpretation of spectral data. Both Raspailia pumila and R. ramosa contain a mixture of the eleven raspailynes (1 60)-(1 70)13' that includes raspailyne A (1 60) which was previ-ously reported from R. p~mila.'~~ The oxidative cleavage of the enol ether moiety in the raspailynes by aerial oxygen (but not by singlet oxygen) has been A Fijian sponge of the genus Xestospongia has yielded the two cytotoxic cyclic peroxides xestin A (171) and xestin B (172) together with (5R)-2-0~0-2,5-dihydrofuran-5-acetic acid methyl ester (1 73).134 The structure and relative stereochemistry of xestins A and B were proposed on the basis of interpretation of spectral data particularly 'H n.m.r.coupling constants. By analogy with xestin B (172) chondrillin (174) (which is a metabolite of a species of Ch~ndrilla'~~) has the 3S*,6R* stereochemistry. Chondrillin (1 74) and four new cytotoxic cyclic peroxides i.e. methyl (3S*,6S*)-3,6-epidioxy-6-methoxyoctadec-4-enoate NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER Me0 Hp 0 (179) (100) OHC Me OMe 0 Me0 1 Hb OMe (181) (184) (173 methyl (3S*,6S* 16E)-3,6-epidioxy-6-methoxyoctadeca-4,16-dienoate (1 76) methyl (3S*,6S* 14E 16E)-3,6-epidioxy-6- methoxyoctadeca-4,14,16-trienoate(177) and methyl (3S* 6S*,16E,18E)-3,6-epidioxy-6-methoxyicosa-4,16,18-trienoate (1 78) were isolated from the Okinawan sponge Plakortis lita and all exhibited significant antileukaemic activity.136 The stereochemistry of chondrillin (174) was shown to be 3S*,6R* by interpretation of n.0.e.experiments in agreement with the study cited above. A new macrolide (179) with anti-tumour properties has been isolated from a species of Theonella from Okinawa. 13' The structure of misakinolide-A (179) which is now known to be incorrect was elucidated by interpretation of spectral data and comparison of the data with those of swinholide-A (from Theonella swinhoei13*). As part of a study of structure-activity relationships several reactions of latrunculin B (180) (which is obtained from Latrunculia magnijica) were reported but the biological activities of the products have yet to be Full details of the total synthesis of okadaic acid (1 l) which is a toxin from Halichondria okadai and H.melanodocia have been reported in a series of papers.140 Kabiramide B and kabiramide C (18I) previously isolated from egg-masses of an unknown mollusc (possibly Hexa-branchus ~anguineus),'~' are the major metabolites of species of Halichondria collected in Palau. 142 A species of Halichondria from Kwajelein Island contained a new macrolide hali-chondramide (1 82) that possesses significant antifungal ac-tivity. The structure of halichondramide (1 82) was elucidated by interpretation of spectral data but the stereochemistry remains to be determined. The 'sarains' are a group of three unique pentacyclic alkaloids from the Mediterranean sponge Reniera sarai. 143 The structures of sarain- 1 (1 83) and sarain-2 (1 84)were proposed on NATURAL PRODUCT REPORTS.1988 0 0 (187) (192) R = C(0)CMeFCHMe I (196) R = H (193) the basis of interpretation of spectral data particularly the two- dimensional n.m.r. spectra recorded at 500 MHz. An almost complete structure of sarain-3 was also proposed. The sarains appear to act as phase-transfer catalysts similar to crown ethers. The structure of manzamine A hydrochloride (1 85) which is a unique anti-tumour alkaloid from a species of Haliclona was determined by X-ray ana1~sis.l~~ The structure of manzamine A is identical to that of keramamine-A (1 85) which was isolated [together with keramamine-B (1 86)] from a species of Pellina.145 The structure of keramamine-A (185) was also determined by X-ray analysis and that of keramamine-B (186) by interpretation of spectral data.The keramamines were both reported to be antimicrobial. The name manzamine A has precedence over keramamine-A and should therefore be adopted. A highly cytotoxic pigment discorhabdin C (187) was obtained from a species of Latrunculia from New Zealand and was identified by X-ray ana1~sis.l~~ A similar compound prianosin A (188) is a potent antileukaemic agent from the Okinawan sponge Prianos me la no^.'^' The structure of pri- anosin A (188) was also determined by X-ray analysis. In addition to the known metabolite aaptamine (189),14* the sponge Aaptos auptos contains demethylaaptamine (1 90) and demethyloxyaaptamine (191) both of which are cytotoxic and have antimicrobial activity.14' The structures were elucidated by spectral analysis and by chemical degradation. Both aaptamine (1 89) and demethyloxyaaptamine (1 91) have been synthesized in good overall yield^.'^^.'^^ Three metabolites of a Pacific species of Reniera,15' namely renierone (192) N-formyl- 1,2-dihydrorenierone (193) and the isoquinolinequinone (194). RO OMe HN& H 0 (200) R = -CHzC(O)NHz were synthesized in good yields by using a method that enabled replacement of the angelate ester by many other ester groups. 153 The Fijian sponge Xestospongia caycedoi contains the known metabolite mimosamycin (195) and a new quinone renierol (196) that lacks the angelate ester group of renierone (192).154 Mimosamycin (195) has been synthesized in two steps by a route that involves a Diels-Alder cyc10addition.l~~ NATURAL PRODUCT REPORTS 1988-D.J. FAULKNER &TI I \ \ \ (203) HO~\ N H (206) R' = R2 = H (207) R' = OH R2 = H (208)R1 = OH.R2 = Br 0 Br H 0 (213) (214) X (215) X 0 Me N5- NMe HN A N 'N' Me (219) Bengamides A (197) and B (198) are novel heterocyclic metabolites from a member of the Family Jaspidae that are cytotoxic and antimicrobial and possess anthelmintic proper- ties.156 The structures of the bengamides were determined by spectral analysis. Both Dysidea etheria and Ulosa ruetzleri produce a new plant growth regulator 3-hydroxy- 1-(indol-3-y1)-pentane- 1,4-dione (1 99).15' Dysidea etheria also contains indole-3-acetamide (200) and indole-3-carbaldehyde (141). The three novel indole derivatives cis-trikentrin A (201) trans- trikentrin A (202) and trans-trikentrin B (203) together with an inseparable 3:2 mixture of cis-trikentrin B (204) and iso- trans-trikentrin B (205) were obtained from the Northern NHR ~ ~ HO m \O <Mm Oe H (212) R = H OH HN 0 0 H\ = I = Br (216) Australian sponge Trikentrion flabellforme. 15* All trikentrins possess antimicrobial activity and were identified by detailed spectroscopic analysis. Three new bis-indole alkaloids namely topsentin-A (206) topsentin-Bl (207) and topsentin-B2 (208) were isolated from the Mediterranean sponge Topsentia genitrix and identified by interpretation of spectroscopic data.159 The topsentins which are mildly toxic to fish exist as two tautomeric imidazoles only one of which is illustrated. Four new imidazole alkaloids (209)-(212) have been isolated from the calcareous sponge Leucetta chagosensis.160 The structures of naamidine- A (209) naamine-A (210) isonaamidine-A (21 l) and iso- naamine-A (212) were established by spectral methods. Both the (E)-and the (2)-isomer of the proposed structure (213) of barettin which is a metabolite of Geodia buretti,161 were synthesized and were shown to have completely different spectral data from barettin.162 Geodiamolides A (214) and B (215) are novel cyclic depsipeptides from a Caribbean species of Geodi~.'~~ The X-ray structural determinations of geo-diamolides A and B revealed that they contain the same twelve- carbon polypropionate unit that was found in jaspamide (21 6).164.165 Like jaspamide which was recently reported as a metabolite of Juspis johnstoni from New Guinea,'66 the geodiamolides exhibit antifungal activity. Two novel cytotoxic metabolites niphatyne A (217) and niphatyne B (21 8) were isolated from a Fijian species of nip hate^.'^^ The niphatynes are isomers that differ only in the position of the acetylenic bond in the alkyl chain. A new purine 1,3,7-trimethylguanine (2 19) was isolated from Lutrunculia brevis and was identified A by interpretation ofspectral data particularly the mass-spectral fragmentation pattern. 18* A new member of the 'oroidin' family of compounds called hymenin (220) has been isolated from an Okinawan species of Hymenia~idon.'~~ Like aaptamine (189) hymenin (220) is an a-adrenoceptor-blocking agent ;in the isolated rabbit aorta it blocks the contractile response to norepinephrine but does not affect the action of potassium chloride or serotonin.The parent compound oroidin (22 l) which was originally isolated from Agefas oroides,17' has been prepared by two routes both of which employed 4(5)-hydroxymethylimidazole.171A 3 :1 mix- ture of two new dibromo-nitriles (222) and (223) has been isolated from Apfysina faevis. The dibromo-nitriles (222) and (223) were identified by spectral analysis and were synthesized again as a 3 1 mixture by hydrolysis of aeroplysinin-1 (224) which is the major brominated constituent of A.fae~is.'~' There have been three reports of the dimeric disulphide (225). The disulphide was first isolated from an unidentified sponge from Guam and the structure was elucidated by analysis of spectral data.173 The (E,E) stereochemistry of the disulphide (225) was defined by comparing the 13Cn.m.r. data with those of the (E,Z)-isomer (226) that was obtained as an unstable minor product together with 3-bromo-4-hydroxyphenylacetonitrile (227).173 The same major disulphide (225) was isolated from a species of Psammapfysiffaand was called psammaplin A.174 Psammaplin A (225) was isolated from Thorectopsamma xana which was also collected in the same location in Guam together with a minor dimeric metabolite bisaprasin (228).'75A NATURAL PRODUCT REPORTS 1988 CN CN dN (2221 (22 3) (224) Lk BrcTcN HO \ OH (227) Br (230) new dibromotyrosine derivative ianthelline (229) has been obtained from Iantheffa ardis collected in the Bahamas.176 Ianthelline (229) shows modest antimicrobial activity against Staphylococcus aureus and Candida afbicans. An unusual di bromotyrosine derivative named aplysinadiene (230) was obtained from a specimen of Apfysina aerophoba from the Canary 1~lands.l'~ The structure of aplysinadiene (230) was determined by spectroscopic methods and confirmed by total synthesis. A preliminary report of great current interest is that avarol (231) and avarone (232) both of which are metabolites of Dysidea av~ra,~~~ can inhibit human immunodeficiency virus (HIV) in ~itt-0.'~~ The burrowing sponge Siphonodictyon coraffiphagum and closely related species of Siphonodictyon contain a series of sesquiterpene hydroquinones.180 The NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER 629 CHO CHO I (233) Na0,SO CH2 OH $+--f+cH Na03s0P !OH HO \OH CO2H (236) (237) (238) HO OH @3coH qoH Me0 0 I (2431 (244) (240) (241) (242) n activity against Staphylococcus aureus and Bacillus subtilis was recorded for siphonodictyals B (233) C (234) and D (235) and for siphonodictyols G (237) and H (238). The absolute configuration of ilimaquinone (240) which is a metabolite of Hippospongia metachromia,lsl was revisedls2 after it had been chemically interconverted with aureol (24I) the absolute OH configuration of which had been determined by X-ray anal- ‘COzMe ysis of a brominated derivative.lS3 The known184 cytotoxic metabolite puupehenone (242) was isolated from Strongylo-OH phora hartmani that had been collected in deep water off the (245) (246) (247) Bahamas.ls5 Herbacin (243) is a new furanosesquiterpene that is the major metabolite of Dysidea herbacea collected in India.la6 structure of siphonodictyal B has been revised to (233) and six Dictyodendrilla cavernosa from New Zealand also contains a new metabolites namely siphonodictyals C (234) D (235) and new furanosesquiterpene pallescensone (244).la7Both of the E (236) siphonodictyols G (237) and H (238) and siph- structures (243) and (244) were proposed on the basis of onodictyoic acid (239) were described.The structure of spectral data. The known terrestrial toxins picrotoxinin (245) siphonodictyal B (233) was revised on the basis of ‘H n.m.r. picrotin (246) and the methanolysis product methyl picrotoxate NOEDS measurements. The structure of siphonodictyal D (247) were isolated from the sponge Spirastrella inconstans.lS8 (235) was determined by X-ray analysis and the remaining Although the picrotoxins have been extracted from terrestrial structures were elucidated by spectral analysis. Antimicrobial plants and used as fish poisons the practice is now illegal and NATURAL PRODUCT REPORTS 1988 H H (248) (249) (2501 (253) (254) (255) R q q&q k CN (256) R = -NC (259) R = -NC (262) R = -NC (257) R = -NCS (260) R = -NCS (263) R = -NCS (2651 (266) R =-NC (258) R = -NHCHO (261) R = -NHCHO (264) R = -NHCHO (267) R = OH (268) R = -NHCHO (269) R = -NC the authors believe that the toxins originated in the sponge.Several sponge sesquiterpenes have recently been synthesized. The synthesis of (+)-euryfuran (248) from (+)-confertifoline (249)la9 allowed assignment of the absolute configurations of the samples of euryfuran that had been isolated from a species of E~ryspongia'~~ and from Dysidea herbacea.lgl A second synthesis of (+)-euryfuran (248) from manool confirmed this assignment.lg2The synthesis of the isomeric furan pallescensin A (250) was accomplished using a cyclization reaction of a triene as the key step.lg3 Both furodysin (251) and furodysinin (252) which are metabolites of an Australian species of Dysidea,Ig4 have been synthesized as racemates.lg5 Both (+)-cavernosine (253)lg6 and its threo-isomer were synthesized in good yield from dihydro-P-i~none.'~~ (+)-Curcudiol (254) and (+)-curcupheno1 (255) which is the optical enantiomer of a metabolite of the soft coral Pseudopterogorgia rigida,lg8 were isolated from Didiscus flavus.lg9 Two new isocyanide-isothiocyanate-formamide trios have been isolated as minor metabolites of Axinella cannabina.200 Compounds (256)-(258) are based on the epi-eudesmane skeleton and (259)-(26 1) are related to alloaromadendrene. An additional trio of cis-eudesmane derivatives (262)-(264) has been found in A.cannabina while the same isocyanide (262) and isothiocyanate (263) were obtained in higher yield from AcantheIIa acuta201 An ichthyotoxic fraction from Acanthella acuta contained a 2:3 mixture of axisonitrile-3 (265) and 1-isocyanoaromadendrane (266) the stereochemistry of which was based on its chemical interconversion with palustrol (270) (267).202 Axamide- 1 (268) and axisonitrile- 1 (269) which are sesquiterpenes from Axinella ~annabina,~O~ have been syn- thesized in racemic form together with the corresponding c-10 epimer~.~O~ A deep-sea specimen of a species of Stylotella from New Caledonia contained stylotelline (270) which was con- verted into (+)-b~elinene.~O~ Two epimeric series of 7-aminobisabolene derivatives have been described from three sponge species.(6R,7S)-7-Amino- 7,8-dihydro-ct-bisabolene(27 1) was isolated from a species of Halichondria206 and a species of The~nella,~~~ and the iso- mer (6R,7R)-7-amino-7,8-dihydro-a-bisabolene hydrochloride (272) was obtained from a species of Ciocalypta.208 The Halichondria species also contained the corresponding hydro- chloride salt (273) isothiocyanate (274) and symmetrical bis- substituted urea (275) the structure of which was determined by single-crystal X-ray analysis.2o6 Both the amine (271) and the hydrochloride salt (273) showed antibacterial and antifungal activity in vitro and the amine was mildly cytotoxic. An unrelated hydrocarbon guaia-1(5),6-diene (276) was also obtained from the species of Halichondria.206 The species of Ciocalypta [previously reported as a species of Hyrneniacidon that is the source of the isocyanopupukeananes (277) and (278)209] contained the amine hydrochloride (272) together with the corresponding isocyanate (279) and isocyanide (280).208 The structure of the amine hydrochloride (272) was determined by X-ray analysis of the p-bromobenzylurea derivative.In the Okinawan species of Theonella the amine (271) was accom- panied by aminobisabolenol (281) isoaminobisabolenol-a NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER 631 y v I I R’ VH I (277) R’ = -NC R2 = H (281) (278) R’ = H,R2 = -NC (284) (285) R = AC (286) R = H 0 H-RO#’Yo AcO” AcO OAc (288) R = Prn (290) (289) R = AC (282) and isoaminobisabolenol-b (283).207The structure of the amine (271) was determined by X-ray analysis of the corre- sponding N-bromoacetate.The structures of the alcohols (28 1)-(283) were elucidated by interpretation of spectral data and chemical interconversion and the configurations of (282) and (283) at C-12 were determined by using the allylic benzoate chirality method. Three new nor-diterpenes [spongionellin (284) gracilin E (291) (285) and gracilin F (286)210]and two new dinor-diterpenes [gracilin C (287) and gracilin D (288)211]have been reported as metabolites of Spongionellu gracilis. The structure of gracilin B (289) has been revised from (290)212on the basis of additional n.0.e.measurements.211 The structures of this group of 0 metabolites were all proposed on the basis of spectral analysis. I Spongiolactone (29I) which contains a p-lactone ring is the most unusual metabolite to be obtained from Spongionellu gr~cilis.~~~ A second X-ray structure determination of aplyvi- olene (292) from CheIonuplysillu violacea has been reported. 214 0 Re-investigation of a species of Darwinell~,~~~ previously re- (2921 ferred to as Aplysillu roseu from the South Pacific has yielded NATURAL PRODUCT REPORTS 1988 0 (293) (294) (295) Ac I @2‘ PAC OAc 0 0 .*H 587 (296) (297) k’ (299) R1 = H R2 = OC(0)Prn (305) R = OAC CO2 Me (300) R’ = H R2 = OAC (306) R = H (301) R1 = 0H.R’ = OC(0)Prn (302) R’ = OAc,R2 = OC(0)Prn (303) R’ = OC(0)Prn,R2 = OH (304) R’ = OC(O)Pr” R2 = OAc (308) R’ = R2 = H (310) R = H (309) R’ = R2 = OAC (311) R = OH (314) = H,RZ = OH (316) (315) R’ = OH,RZ = H the known metabolites ambliofuran (293)216 and aplysulphurin 4 (302) -5 (303) and -6 (304) the lactones (305) and (306) (294)217 and a new metabolite tetrahydroaplysulphurin-1 and hexahydroambliofuran (307) were identified by inter-(295) but no trace of aplysillin (296) which was previously pretation of spectral data.21g The specimens of Dendrilla rosea reported as a metabolite from A.rosea.21s The New Zealand from New Zealand contained most of the known aplyroseols sponge Darwinella oxeata contains aplysulphurin (294) tetra- together with aplyrose01-7~~~ and dendrillol- 1 (308) -2 (309) hydroaplysulphurin-1 (295) and trace amounts of tetra-3 (310) and -4 (311).215 The chemotaxonomy of diterpene-hydroaplysulphurins-2 (297) and -3 (298).215 Twelve spon- producing sponges is discussed in some detail because both giane derivatives have been isolated from Aplysilla rmea dendroceratid and dictyoceratid sponges are reported to Barrois from Aplyroseol-1 (299) and aplyroseol-2 produce spongiane-derived diterpenes.The Antarctic sponge (300) had previously been found in the Caribbean sponge Dendrilla membranosa has been found to contain 9,ll-Igernella notabilis220 and aplyroseol-3 (30 I) had been reported dihydrogracilin A (3 12) as the major product and membranolide from an Australian species of Aplysi11a,221but the compounds (3 13) as the minor dite~pene.?~~ Some closely related diterpenes had not previously been assigned trivial names.The new have been found in spongivorous nudibranchs (see Section 10). metabolites from the Australian A. ruseu namely aplyroseol- Spongiadiol (3 14) epispongiadiol (3 19 and isospongiadiol NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER [x= A (323) R1 = NC,R2 = Me,R3 = CI R4 = H E (326) R1 = NC.R2 = Me,R3 = H,R4 = CI X (331) R1 = Me,R2 = NCS,R3 = C?R4 = H Y (332) R' R2 = CHz,R3 = CI. R4 = H 2 (333) R1= Me R2= NC.R3 = CI.R4 = H q$ NC I \ NC (334) (316) are three antiviral and cytotoxic diterpenes from a deep- water (>200 m) Caribbean species of S~ongia.~~~ The structure of isospongiadiol (316) was elucidated by comparison of its spectral data with those of the known metabolites.Both spongiadiol(314) and epispongiadiol(3 15) had previously been isolated from an Australian species of S~ongia~~~ that has been reclassified as Rhopaloeides odorabile. A series of transplant experiments were used to demonstrate that there is environ- mentally induced variation in the diterpene composition of R. odorabile.226 A full paper on the structural elucidation of the agelasines (3 17)-(322) from Agelas nakamurai has been published in B (324) R' = R2 = NC.R3= Cl.R4 = Me C (325) R' = R2 = NC,R3R4 = CH2 F (327) R' = R2 = R3 = NC,R4 = Me D (328) R' = R3 = NC R2 = CI R4 = Me G (329) R' = R2 = NC,R3 = NCS,R4 = Me H (330) R' = NCS,R2 = R3 = NC.R4 = Me which there are revised 13Cn.m.r.data for agelasine-A (317) and agelasine-B (3 1 8).227The kalihinols are a series of diterpene isocyanides that have been isolated from two specimens of Acanthella.228The detailed data for five known metabolites (323)-(327) were reported together with the structural eluci- dation of six new compounds (328)-(333). Kalihinols D (328) G (329) and H (330) are trace components of a species of Acanthella from Guam and kalihinols X (331) Y (332) and Z (333) were obtained from a Fijian species of Acanthella. All kalihinols inhibited the growth of Bacillus subtilis Staphylo- coccus aureus and Candida albicans. The total synthesis of 7,20-di-isocyanoadociane(334) which was isolated from a species of Amphimedon that was originally called a species of Ado~ia,~~' allowed assignment of the absolute configuration.230 The tetracyclic skeleton was constructed from (-)-menthol and both isocyanide groups were introduced simultaneously by a non-stereoselective displacement of trifluoroacetate with trimethylsilyl cyanide in the presence of titanium tetra-The three new diterpene isocyanides (3S*,4R* 7S*,8R*,I 1 S*,12R*,13S*)-7-isocyano-l5,20-cycloamphilect-1- 634 20&I NATURAL PRODUCT REPORTS 1988 Hqlyqjlj! I kc r Nc i Nc (3351 (3361 (337) (3381 (339) C02R I (340) R = H (342) R = Me (344) R = H (346) R = Me (350) ene (335) (1 S*,3S*,4R*,7S*,8R* 13R*)-7-isocyano- 15,20- cycloamphilect-11 -ene (336) and 8-isocyanoamphilecta- 10 14-diene (337) were isolated from a Palauan species of Hali-chondri~.'~~ The major metabolite of this sponge was (3S* 4R*,7S*,8S* 1 1S*,13R*)-8-isocyano- 15,20-cycloamphilect- l(12)-ene (338) that had previously been isolated from a species of Amphimedon and assigned an incorrect structure (339).232 The structures of (333 (336) and (338) were determined by X-ray analysis.Trunculins A (340) and B (341) are norsesterterpene cyclic peroxides with a new carbon skeleton that have been isolated together with the corresponding methyl esters (342) and (343) from the Northern Australian sponge Latruncufia brevi~.~~~ The structures of the methyl esters (342) and (343) were both determined by X-ray analyses and their absolute configurations were proposed on the basis of application of the Horeau method.Only the acids (340) and (342) show significant H (341) R = H (343) R = Me OH antimicrobial activity. Two additional norsesterterpenes (344) and (345) have been isolated from Mycale ancorina as the corresponding methyl esters (346) and (347) and the structures of the methyl esters were elucidated by interpretation of spectral data. 234 Two new furanosesterterpenes okinonellins A (348) and B (349) have been isolated from a species of Sp~ngionelfa.'~~ Okinonellin A (348) was subsequently reported under the name hippospongin from a species of Hippo~pongia.~~~ The com- pounds appear to be the same but the stereochemistry was not defined in either paper and there are differences in both the published optical rotations and the 13Cn.m.r.signals associ- ated with the butenolide ring. The okinonellins (348) and (349) inhibit the development of fertilized starfish eggs235 and hippospongin (348) was reported to be antimicrobial and to possess antispasmodic A new furano-sesterterpene ircinic acid (350) was obtained from the same NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER 1 HO 0 HO (353) (3541 OH OH 1 CHO (355) AcO (360) R’ = H,R2 = OAC (362) R’ = H,R2 = OH (361) R’ = OAC R2 = H (365) R’ = 0H.R’ = H Ircinia species that produced ~uvanine.~~~ Ircinin-1 (351) and ircinin-2 (352) previously obtained as a mixture,238 were separated and the structures assigned from spectral properties. A mixture of ircinin-1 (351) and ircinin-2 (352) reduces motility in sea-urchin sperm.237 There is continued interest in the chemistry and phar- macology of manoalide (353) which is a major metabolite of Luflariella variabili~.~~~ Some specimens of L.variabilis con- tained luffariellin A (354) and luffariellin B (355) in place of manoalide (353) and secomanoalide (356) but the change in the alkyl portion of the molecules did not affect the anti-inflammatory Luffariellolide (357) is a sester-terpene from a Palauan species of L~flariella.~~~ Whereas manoalide (353) is an irreversible inhibitor of the enzyme CHO (356) 0-4O CH~OH (358) Me0 ‘OMe OMe (363) (364) phospholipase A, luffariellolide (357) is a slightly less potent but partially reversible inhibitor of the same Studies of the reaction of manoalide with lysine polymers suggest that the irreversible inactivation of phospholipase A by manoalide may involve an ordered reaction with a peptide sequence of the enzyme that contains two lysine residues situated in a 1,4 arrangement.242-244 A second synthesis of manoalide (353) has been reported2a5 and the related natural product (E)-neo- manoalide (358) has also been prepared.2a6 Palauolide (359) which is a metabolite of an unidentified Palauan sponge,247 has been synthesized in a seventeen-step sequence of reactions.248 Five new scalarins namely heteronemin acetate (360) 12-epi-heteronemin acetate (361) 12-deacetyl- 1Zepi-scalaradial (362) and two dimethyl acetals (363) and (364) that could well NPR 5 NATURAL PRODUCT REPORTS 1988 (366) R' = CH0.R' = OAC (368) (367) R' = C02H.R2 = OH R (372) R = D (373) R = b (374) R = c (379I be artifacts have been reported as minor metabolites of Hyrtios e~ecta.~~~ The known metabolite 12-deacetylscalaradial (365) was isolated from Spongia o~eania.~~" Three homosesterterpenes (366) (367) and (368) from an association of species of dictyoceratid and halichondrid sponges cause inhibition of aggregation of blood platelets and possess antimicrobial properties.The structures (366)-(368) were proposed on the basis of spectral data.251 Two halogenated sesterterpene phenols 6'-chlorodisidein triacetate (369) and 6'-bromodisidein triacetate (370) were isolated from Disidea [Dysidea] palfescens and the structure of 6'-bromodisidein triacetate (370) was R (375) R = c (376) R = d (377) R = e (378) R = f d= =j+ Y I 6SOjNa (380) determined by X-ray analysis.252 The triacetates (369) and (370) were synthesized from disidein (37 I) thereby establishing the structure and absolute stereochemistry of the known253 metabolite.Three new A7-3P,6a-dihydroxy-5a-sterols (372)-(374) and four new A7-3/?,Sa,6P-trihydroxy-sterols(375)-(378) have been isolated from Spongionella gra~ifis.~~~. 255 A new sterol disulphate (379) and a new sterol trisulphate (380) both closely related to halistan01,~~~ have been found in a species of Halich ondr ia 57 and in Trach yopsis halic hondr ioides 56 respectively.NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER (381) R = H (382) R = Me c$ OH A (365) (386) ( 3901 (393) (394) The tridecapeptide theonellamine B (381) from a species of The~nella,~~@ has previously been reported under the name theonellapeptolide ld.260 The most recent paper reports that the peptide inhibits the activity of Na+/K+-transporting ATPase. A newly described metabolite of Theonella is theo- nellapeptolide le (382) which is an N-methyl derivative of theonellapeptolide ld.261 5-Thio-~-mannose (383) which is the first example of a naturally occurring 5-thio-sugar has been isolated from Clathriu pyramida.262 8 Coelenterates A stereoselective synthesis of clavularin A (384) which is one of the two isomeric cytotoxins from the soft coral Clavularia k~ellikeri,~~~ has confirmed the revised structure proposed for this compound.264 The five sesquiterpenes ent-oplopanone (385) nephthenol (386) nephtheoxydiol (387) nephthediol (388) and nephthene (389) were isolated from an Okinawan (384) J$JOH I A OH A (387) (388 1 (391) (3921 (395) (396) species of Nephthe~.~~~ The structures of the sesquiterpenes are based on interpretation of spectral data and chemical inter- conversions. However the stereochemistry that has been proposed for nephthediol (388) and nephthenol (386) differs from that proposed previously for similar compounds,266+ 267 despite the fact that the stereochemical assignments are based on almost identical spectral data and chemical interconversions.For example the 'Moffatt oxidation' of nephthediol (388) to anhydro-ent-oplopanone (390) is in fact the same dehydration reaction as was used to relate the diol (391) from Laurenciu subopposita to anhydro-oplopanone (392) ;266 the two papers propose different stereochemical mechanisms for the inter- conversions. It would be interesting to see these rival claims resolved by an A'-ray-crystallographic study. Three new sesquiterpenes coralloidins-C (393) -D (394) and -E (393 have been isolated from Alcyonium corulloides.26s The new coralloidins are all eudesmane derivatives and differ little from coralloidin-A (396).269A specimen of Xenia crassa from Rib 24-2 NATURAL PRODUCT REPORTS 1988 (397) R..W I R (401) R = OH (403) R = OH (402) R = H (404)R = H (407) (409) (410) R = H (411) R = AC I OH (4131 (414) Reef Australia contained 1,2-epoxy-a-muurolene (397) while the alcohol (398) and the epoxy-acetate (399) were obtained from Sinularia mayi that had been collected at Hook Reef.270 The structures of the sesquiterpenes were elucidated by interpretation of spectral data and by chemical inter-conversions.A new sesquiterpene alcohol (400) was isolated from Xenia novae-britanniae collected at Broadhurst Reef and its structure was determined by X-ray analy~is.~" A new capnellane sesquiterpene capnell-9( 1 2)-ene-2a 5,8,8a, lo#?-tetra01 (401) has been isolated from Capnella imbri- cata272and the structure of capnell-9( 12)-ene-8a 10,8-diol(402) has been confirmed by X-ray analysis.273 These structures (401) and (402) are drawn with the opposite absolute configuration to that adopted previously.The first synthesis of capnell-9( 12)- ene-3B,8#? lOa,l4-tetraol (403) and an improved synthesis of capnell-9(12)-ene-3/3,8fl,lOa-triol(404) both of which are now considered to be artifacts from Capnella imbri~ata,~?~ have been accomplished by extending previous synthetic Cap-nell-9(12)-ene (405) has been synthesized by a short and efficient route that features a titanium-induced cyclization of an (399) (400) w q 'H (405) (406) (408) (412) (415) oxo-e~ter.~~~ A synthesis of (f)-precapnelladiene (406) uses the unusual strategy of forming the 5-8 bicyclic ring-system from a 5-5-5 tricyclic ~ing-system.~~~ Sinularene (407) which is a metabolite of Sinularia ma~i,~'~ and 5-epi-sinularene have been synthesized by using an intramolecular Diels-Alder ap- pr~ach.~~~ Full details of a second synthesis of ( f)-sinularene have been reported.280 Lemnalol (408) which is an antitumour agent from Lemnalia tenuis,28L has been synthesized by a route that involved an intramolecular [2 +21 cycloaddition of the ketene that was formed by treatment of farnesoyl chloride with a base.282 During the mass spawning behaviour of soft corals the sea becomes so thick with gametes that the eggs can be collected.3,4-Epoxynephthenol (409) which is the major metabolite of the eggs from Lobophytum microiobulatum is absent in the post-spawning tissue of the soft Both the eggs and the tissue of the coral contained significant amounts of the isomeric metabolite decaryiol (410) and a new cembranoid decaryiol acetate (4 11).Lobophytum microlobuiatum also contained fuscol (412) (which was previously found in the gorgonian NATURAL PRODUCT REPORTS,1988-D. J. FAULKNER pj-y 'OH A (419) (420) (421) HO ;&Lyy HO' (422) (423) (4 24) HO '' (425) (427) (428) R1 = OH,R2 = H (429) R' H.RZ= OH and Eunzcea jiu~ca)~~~isofuscol (413) together with the corresponding germacrene derivatives (414) and (413,a germacrenediol(416) and two eudesmane derivatives (4 17) and (418). Chemical studies of several species of Lobophytum from the Townsville region of Australia have been reviewed and in the process three new diterpenes (419) (420) and (421) were described.283 The germacrene derivative germacrexeniolone (422) was isolated from an Okinawan species of Xenia.285 Germacrexeniolone (422) was gradually oxidized by air to the previously described286 diterpenes xeniolone (423) and iso- xeniolone (424) and in aqueous acetone solution it gave hydratoxeniolone (425) and hydratoisoxeniolone (426) all of which were isolated from the same soft coral in smaller quantities.The structures of the diterpenes (422)-(426) were HO'1 (4261 elucidated by interpretation of spectral data and by chemical interconversions. The observation that some colonies of Lobophytum pauci- florum were overgrown by algae while others were unaffected may possibly result from the difference in chemical content of the colonies.The overgrown colonies contained (2R,7S,8S)- sarcophytoxide (427) while the epiphyte-free colonies contained 14-hydroxycembra-1,3,7,1l-tetraene(428) and 1S-hydroxy-cembra-l,3,7,ll-tetraene(429).287 Both Sarcophyton cf. birk-landi from Australia and S. gZaucum from Guam contained the known metabolite (2R 11R 12R)-isosarcophytoxide (430) and a new isomer (2S 11R,12R)-isosarcophytoxide (43 l) the struc- ture of which was determined by X-ray analysis. The sarcophytoxides and isosarcophytoxides were chemically inter- (432) (433) (436) 40 (4381 (439) A A cOk *OAC 0@-0 AC (442) related.287 Two new cembranoid diols [sinulariol A (432) and sinulariol B (433)] were isolated together with seven known cembranoid methyl lactones from Sinuluriu mayi and their structures were proposed on the basis of spectral data.288 Coralloidolides A (434) and B (435) are two cembranoids which were isolated from the Mediterranean soft coral Alcyonium corulloides.28s The structures (434) and (435) were deduced from spectral properties.The stereoselective total synthesis of isolobophytolide (436) which is a metabolite of Lobophytum crus~um,~~~ has confirmed the trans lactone ring- junction.2s1 A synthesis of the cembranolide (437) from Lobophytum michuelae2s2 has also been reported. 283 Both NATURAL PRODUCT REPORTS 1988 OH OH 0 (437) (440) (441) ,*OAC ov Ac 0 (443) cembrane and pseudopterane diterpenes have been isolated from the soft coral Gersemiu r~biformis.~~~ The structure of gersemolide (438) was determined by X-ray analysis and the structures of rubifolide (439) and epilophodione (440) were inferred from spectral data.Subsequently a novel diterpene with a new rearranged skeleton was isolated from G. rubi-formis the structure of gersolide (441) was determined by X-ray analysis.2s5 Two new xenicane derivatives havannahine (442) and deoxyhavannahine (443) have been collected from Xeniu The membrunuce~.~~~ structure of havannahine (442) was determined by X-ray analysis and that of deoxyhavannahine (443) was proposed on the basis of spectroscopic analysis.A NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER 641 AcO" qc, HHO'... 0 RO' 'CI 0 0 (447)R = Ac (451) (448)R = H AcQ ?H . 0 0 (4521 (453) (4541 HO OH I (4591 I (455)R' = OAC,R~= 'rn I I I I (457) R' = H R2 = / / (4601 (4611 (458) R' = 0Ac.R' = genus StyZat~Za.~~~ The structures and relative stereochemistry of the minabeins (444H453) were determined by inter-pretation of spectral data. series of ten new diterpenes minabein- 1 to -10 [(444)-(453)] Four new polyhydroxylated sterols xeniasterols-a (459 -b that have the briarein skeleton that is generally associated with (456) -c (457) and -d (458) were obtained from an Okinawan sea pens and gorgonians have been obtained from a Pacific soft species of Xenia that also contained the known sesquiterpenes coral of the genus Mina6ea,2e7together with the diterpene (454) germacrene-c (459) the guaiane-type alcohol (460) and the that was previously isolated from a species of sea pen of the diol (461).2e9 The polyhydroxylated sterol sartortuosterol A NATURAL PRODUCT REPORTS 1988 HO’ (462 HO (4671 @;GOR3 A (470) R’ = 8 (471) R’ = C (472) R’ = D (473) R’ = CO2 Me (465) (468) (469) OR R2 = R3 = H Ac.R2 = R3 = H R3 = H,R2 = AC R2 = H,R3 = AC (462) was isolated from Sarcophyton tortuosum from China and the structure was proposed on the basis of spectral and chemical data.300 Some constituents of the arachidonic acid cascade including the methyl and ethyl esters of prostaglandin A (463) and prostaglandin B (464) were identified as A (474)R1 = R2 = R3 = H B (475)R1 = Ac.R2 = R3 = H C (476)R’ = R3 = H,R2 = AC D (477) R’ = R2 = H,R3 = AC pterosins A-D (470)-(473) are a new class of diterpene pentosides that were isolated from the gorgonian coral Pseudopterogorgia eli~abethae.~~~ X-ray-crystallographic An study together with degradation to obtain D-xylose gave the structure of pseudopterosin C (472) to which pseudopterosins constituents of the lipid extract of Lobophytum ~arnatum.~~~ A (470) B (471) and D (473) were related by chemical Pseudopterosin A (470) inhibits cell division Punaglandin-4 (465) which is a metabolite of Telesto rii~ei,~~ interconversi~n.~~~ has been synthesized in racemic form.3o3 The prostanoid preclavulone-A (466) which is biosynthesized by both Cla-vularia viridis from Okinawa and Pseudoplexaura porosa from Florida has been proposed as a key intermediate in the biosynthesis of marine pro~tanoids.~~~ A gorgonian of the genus Acalycigorgia contains 2,3-dihydrolinderazulene (467) which exhibits antitumour and antifungal properties as well as the known compounds linderazulene (468) and guaiazulene (469).305 The pseudo- in fertilized sea-urchin eggs with an IC, of 25 pmol dm-3.307 The pseudopterosins (470)-(473) also possess anti-inflam- matory and analgesic properties that exceed in certain assays the potencies of existing drugs such as indometha~in.~~~ The seco-pseudopterosins A-D (474)-(477) were isolated from a new species of P~eudopterogorgia~~~ and the structures of these compounds which also possess anti-inflammatory and anal- gesic properties were proposed on the basis of spectral analyses and chemical transformations.Two novel steroidal NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER OH (478)R1 = OH,R2 = H (479) R1 = H,R2 = AC (484)R = H (485) R = AC (486) R = C(0)Et 0 (4881 R = Ac [E(45111 (4891 R = C(0)Et (4901 R = C (01Prn glycosides dimorphosides A (478) and B (479) from the gorgonian Anthoplexaura dimorpha inhibit the development of fertilized sea-urchin eggs.31o The structures of dimorphosides A (478) and B (479) were elucidated by using chemical and spectroscopic met hods.Bissetone (480) is an antimicrobial pyrone from Briareum polyanthes that appears to be unrelated to any other metabolites The from coelenterate~.~~~ structure of bissetone was de-termined by X-ray analysis of the corresponding p-bromo- acetate. Five new briarane diterpenes have been isolated OH (480) AcO I (491) spectroscopic methods. The diterpene (483) is identical to minabein-1 (444),297,314but this is not obvious due to the alternative style of structural diagram used. Ptilosarcenone (482) was toxic to larvae of tobacco hornworm (Munduca sexta) at 250 ~.p.m.~l~ The renillafoulins A4 (488)-(490) are briarane diterpenes from the sea pansy Renilla reniformis that inhibit larval settlement in the barnacle Balanus amphitrite amphitrite (EC, = 0.02-0.2 pg cm-3).315 The structure of renillafoulin C (490) was determined by X-ray analysis and the structures of the related compounds renillafoulin A (488) and during a re-investigation of the sea pen Ptilosarcus g~rneyi.~~~ renillafoulin B (489) were elucidated by analysis of spectral The complete stereochemistry of the known metabolites313 data.The structure of renillafoulin A (488) is identical to that ptilosarcone (48 1) and ptilosarcenone (482) and the structures of minabein-8 (451); the latter name has precedence. A new of the five new metabolites (483)-(487) were elucidated by briarane diterpene verecynarmin A (491) has been found in NATURAL PRODUCT REPORTS 1988 p A c0pJ R (492) R = H (4941 (495) (493) R = OAC C02H HOWo> Qp$ I 0 (5001 the Pennatulacean Veretillum cynomorium and its structure was elucidated by interpretation of spectral data and application of the Horeau method to obtain the absolute c~nfiguration.~’~ The three new sesquiterpene furans tubipofuran (492) 15- acetoxytubipofuran (493) and spirotubipolide (494) together with the known metabolite furanodiene (499 were obtained from the stolonifer Tubipora musi~a.~~~.318 The structures of (492)-(494) were proposed on the basis of spectral and chemical evidence. Spirotubipolide (494) has a new carbon Both (492) and (493) are ichthyotoxic toward the killifish Orizias latipes while only (493) is cytotoxic against B- 16 melanoma cells (IC5,,= 33 pg The Mediterranean stolonifer Sarcodictyon roseum contains in low yield the reduced tetraprenylquinone sarcodictyenone (496) the struc- ture of which was proposed on the basis of spectral data.319 There have been three reports concerning metabolites of scleractinian corals.Japanese specimens of Tubastrea aurea 0 (501) contained aplysinopsin (497),320 which was originally found in and tubastrine (498) which is a novel antiviral metabolite.323 The structure of tubastrine (498) was deduced from spectral data.323 Specimens of T. micrantha from Palau contained high concentrations of 3-bromobenzoic acid (499) together with 1,8-dihydroxyanthraquinone(500) 7-hydroxy- 1,8-dimethoxy-2,3-rnethylenedioxyanthraquinone (50I) 2-bromo-4-carboxy-1-hydroxyanthraquinone (502) and 2’-hy- droxy-2,4,4’-trimethoxychalcone(503) as minor The hydroid Garveia annulata has yielded thirteen new anthracenone derivatives most of which are minor metabolites.The structure of the degraded anthracene annulin A (504) was determined by X-ray diffraction analysis and the proposed structure of annulin B (505) was inferred from spectral data.325 Garvalones A (506) and B (507) garvins A (508) and B (509) garveatin D (5 lo) garveatin A quinone (5 1 I) 2-hydroxy-garveatins A (512) and B (513) 2-hydroxygarvin B (514) and NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER CO Me \ /OMe (504) (505) (506) HO HO (509) (507) (508) HOW 0 (512) X = 0 (5131 X = H2 HO (514) -(515) (516) 2 0-P -OCH,CH,NR + (519) R’ = C,6H33,R2 = Me (520) R1 = C,4H29,R2 = Me (521)R’ = CH=CHC~~H~~,R~ = H the dimeric artifacts (515) and (516) were all identified from spectral and chemical data.326 Two additional polyhydroxyl- ated sterols 2a,16@,18-triacetoxycholest-5-en-3a-ol(5 17) and 7@,15@,18-triacetoxycholest-5-en-3a-ol (5 18) have been iso-(522) lated from the Mediterranean hydroid Eudendrium glomer- atum.327 The Japanese hydroid Solanderia secunda contained NHMe three phospholipids (519)-(521) that possess haemolytic properties.328 A novel purine derivative caissarone (522) that was obtained from the sea anemone Bunodosoma caissarum has been identified by means of an X-ray-crystallographic study of the hydrochloride Another new purine 3-methyl-6-methyl- (5231 amino-2-methylimino-9H-purine(523) was isolated from the NATURAL PRODUCT REPORTS 1988 1524) (525) 1526) k (5301 R' = CI R2 = Br R3 = H (531) R' = CI R2 = R3 = H 1527) R = 0 (520) (532) R' = OMe.R2 = R3 = Br (529) R = H2 (533) R' = CI R2 = R3 = Br (534) R = CH(OH)CH3 (535) R = Me 'C02Me 1536) R = Et (537) R = CH=CHZ (538) R' = Ac R2 = OC(0)Pr" (539) R' = C(0) BJ R2 = H (540) R' = Ac R2= H (541) R' = C(O)Pr" R2 = 0C[0)wC3H7 (542) R' = C(O)Pr" R2 = H sea anemone Sagartia troglodytes and its structure was 9 Bryozoans determined by X-ray analysis.33o Calliactine is a pigment from Two new indole alkaloids flustramide B (527) and flustrarine B the sea anemone Calliactis parasitica that was first reported in (528) have been isolated from the bryozoan Flustra foli~cea.~~~ 1940.331 The structure of calliactine is still uncertain but a The structures were elucidated by using spectroscopic studies preferred structure (524) has been suggested on the basis of and that of flustrarine B (528) was confirmed by oxidation of chemical and spectral The Mediterranean anthozoan flustramine B (529).Three new /3-lactam indole alkaloids Astroides calycularis which was previously reported to contain chartellines B (530) and C (531) and methoxydechloro-aplysin~psins,~~~found to contain 3-methyl-~-erythro-chartelline A (532) have been isolated from Chartella papyr- was biopterin (525) which was synthesized from ~-biopterin.~~~ ace^.^^' The structures of the new chartellines (530)-(532) were 3-Methyl-L-erythro-biopterin(525) inhibited the growth of 3T3 elucidated by comparison of their spectral data with those of and CEF cell lines.The species-specific symbiotic relationships chartelline A (533) the structure of which has been between sea anemones and anemone fish are a fascinating determined by X-ray analysis.338 Methoxydechlorochartelline phenomenon.335 Amphikuemin (526) is a novel pyridinium A (532) is thought to be an artifact of the isolation procedure. metabolite produced by the sea anemone Radianthus kueken- A new /3-carboline alkaloid (9-1-(1-hydroxyethyl)-/3-carboline thali that attracts the anemone fish Amphiprion perideraion. (534) was isolated together with the known compounds Aplysinopsins [e.g. (49711 and dihydroaplysinopsins are also harman (535) 1-ethyl-/3-carboline (536) and pavettine (537) implicated in chemical control of the symbiotic relationship.from samples of Costaticella has tat^.^^^ Tyramine and tryptamine are metabolites of the sea anemone Five new bryostatins have been obtained in very low yields Stoichactis kenti that cause behavioural responses in Amphi- from Bugula neritin~.~~O-~~~ Bryostatins-9 (538) and -12 (541) prion ocellaris but these two common amines cannot alone be differ from the previous members of the series only in the responsible for the activity of the crude extracts of the sea identity of the ester side-chains but bryostatins-10 (539) -1 1 (540) and -13 (542) all lack functionality at C-20 and have NATURAL PRODUCT REPORTS 1988-D. J. FAULKNER Br 00 fl-:c' (545) (549) (552) (553) various ester side-chains at C-7.Although the bryostatins were first studied because of their cytotoxicity and antineoplastic activity and indeed remain among the more highly promising candidates for cancer chemotherapy studies of the mechanism of action of bryostatins have revealed that they mimic the phorbol esters which are known to be tumour promoters and bind to the phorbol ester receptor.343.344 Bryostatin-1 activates protein kinase C and prevents phorbol-ester-induced differen-tiation in HL-60 cells.345 Although both bryostatins and phorbol esters activate protein kinase C the cellular responses are not the same.346 10 Marine Molluscs The majority of metabolites that can be isolated from marine molluscs are derived from dietary sources and it is therefore difficult to decide where to place these reports in a review.Although the pectenotoxins which were isolated from the scallop Putinopecten yessoensis are thought to be produced by a dinoflagellate they are probably best reviewed as mollusc metabolites until their exact source is identified. Pectenotoxin-3 (543) a diarrhetic shellfish toxin from P. yessoensis was shown to be an aldehyde347 that is closely related to pectenotoxin-1 (544).348 CI Br' fk.y (547) (5481 OH OH OH (550) (551) ,CO,Me 0 AcO / '0 1482) R = Ac (554) (555)R = C(0)Pr" Four new polyhalogenated monoterpenes aplysiapyranoids A (549 B (546) C (547) and D (548) were isolated from the midgut (digestive) gland of Aplysiu k~rodai.~~~* 350 The structure of aplysiapyranoid B (546) was determined by X-ray analysis349 and the remaining structures were deduced from spectral data.Aplysiapyranoids A (545) and B (546) are conformationally mobile in solution and exhibit only ambiguous n.m.r. sig-nal~.~~~ A total synthesis of debromoaplysiatoxin (549) which is a tumour promoter351from the sea hare Steilocheilus longi-caud~,~~~ has been outlined.353The synthesis is quite flexible and has allowed the preparation of all possible C-29 and C-30 stereoisomers. Bursatellin (550) which was originally iso-lated from Bursutellu leachii~leii,~~~ has recently been found in two Mediterranean sea hares B. leachii leuchii and B. leachii s~vignyunu.~~~ The structure of bursatellin (550) was revised from (551) as the result of a re-interpretation of superior spectral data.The dendronotid nudibranch Tochuinu tetruquetru concen-trates metabolites from the coelenterates that it eats and stores them in its Animals collected at Port Hardy British Columbia contained tochuinyl acetate (552),dihydrotochuinyl acetate (553) rubifolide (439) and pukalide (554) while animals from Bamfield contained ptilosarcenone (482) and a butanoate analogue (555).356 Tochuinyl acetate (552) di- NATURAL PRODUCT REPORTS 1988 (556) (557) PO (561) R =Me (562) (5671 R = H H Br &Jo& Br H q (564) R1 = Br,RZ= H (565) (566) R' = H R2= Br NH? OH (570) hydrotochuinyl acetate (553) and rubifolide (439) were found in the soft coral Gersemia r~biformis~@~ and ptilosarcenone (482) is a metabolite of the sea pen Ptilosarcus g~rneyi.~'~ The Mediterranean nudibranch Armina macufata contained vere-cynarmin A (491) which it obtained from Veretilfum cyno- morium (seep.644).316 The Australian mollusc Planaxis sulcafus contains metabolites that are considered to be obtained from coelenterates. The new cembranoid 3,ll -diacetoxy- 15,16-di- dehydrocembran-6-one (556) which was identified by using n.m.r. and the two known cembranoids dihydro- sinularin (557) and 11-epi-sinularin(558) have been reported as metabolites of P. sul~atus.~~~ The dorid nudibranch Diaulula sundieguensis from British Columbia did not contain any of the chlorinated acetylenes (5581 H OH (563) H (566) (569) that had previously been found in specimens of the same species that had been collected in California.35@ Two new steroids diaulusterols A (559) and B (560) were isolated from the skin extracts of D.sandieguensisand were identified by interpretation of spectral data. 360 The dorid nudibranch Chromodoris funerea collected in Palau appears to oxidize sponge furans to a variety of products that can be produced synthetically by oxidation of the furans with singlet oxygen.361 When extracted with methanol C. funerea yielded 0-methylfurodysinin lactone (561) and furodysinin hydroperoxide (562) both being oxi- dation products of furodysinin (563) (which was shown to be a major metabolite of one species of Dysidea) together with 3,4,5- tri bromo-2-(2,4-di bromophenox y)phenol (564) which was found in Dysidea herb ace^.^^^ A second collection of C.funerea that was extracted with acetone contained furodysi- nin (563) furodysin (565) and 4,6-dibromo-2-(2,4-dibromo-phenoxy)phenol (566) as major metabolites and furodysinin lactone (567) the y-hydroxybutenolide (568) and an epoxy- lactone (569) as minor metabolites.Additional unstable oxidation products of furodysinin (563) were detected by 'H n.m.r. spectroscopy but could not be isolated from extracts of the nudibranch although they could be prepared by oxidation of furodysinin (563) with singlet oxygen.36' Extracts of the digestive gland of the dorid nudibranch Doris verrucosa contained the unusual xyloside 9-(5-deoxy-5-methylthio-/?-~-xylofuranosy1)adenine (570) which was identified by com- NATURAL PRODUCT REPORTS 1988-D.J. FAULKNER @0 C02Me ,/ OAC H (573) R = AC (574) R = C(0)Pr" (579) HoLF+ 0 (582) foH (583) R'= R2 = H (584) R'= OAc R2 = Ac (575) (576) R = OAc (577) R = OC(0) Pr" (578) R = H Oligoceras hemorrhages365) was obtained from both Chrorno-doris lochi and the sponge Spongia mycoJijien~is.~~~ Nine spongiane diterpenes have been isolated from Ceratosorna brevicaudatum from Australia and were identified by detailed spectroscopic analysis.367 Three of the compounds namely aplyroseol-1 (299) aplyroseol-2 (300) and dendrillol- 1 (308) had previously been reported as metabolites of Aplysilla rosea and Dendrilla ro~ea.~l~ The structures of the remaining six metabolites (573)-(578) were determined by interpretation of spectral data.367 The three new rearranged spongiane diterpenes macfarlandin C (579) macfarlandin D (580) and macfarlandin E (58 1) were isolated from the Californian nudibranch Chromodoris ma~farlandi.~~~ The structure of macfarlandin C (579) was determined by X-ray analysis and those of mac- farlandins D (580) and E (581) were elucidated from spectral data.Comparison of the spectral data with those of den- drillolide A369 indicated that the proposed structure of dendrillolide A is incorrect. The pulmonate mollusc Siphonaria normalis from Fiji has provided an unusual tricyclic polypropionate-derived com-pound called muamvatin (582)."'O The structure of muamvatin (582) was elucidated by interpretation of spectral data but the stereochemistry at the chiral centres of the side-chain re- mains to be determined.371Trimusculus reticulatus is unique among pulmonate molluscs because it contains diterpenoids.The structures of 6~-isovaleryloxylabda-8,13-dien-7~, 15-diol (583) and 2ol,7a-diacetoxy-6~-isovaleryloxylabda-8,13-dien-15-01 (584) were elucidated by analysis of spectral data. The diter- pene (583) was found in the mucus of T. reticulatus that was reported to repel predatory ~ea-stars.~~~ parison with synthetic material.363 The unusual combination of the known metabolites latrunculin A (571) (which was originally described from the sponge Latrunculia rnagniji~a.~~~) and dendrolasin (572) (which has been found in the sponge NATURAL PRODUCT REPORTS 1988 0 \N (585) (586) (587) (588\ k (592 1 R (5901 (5911 OH OH ‘GH13-’ H ‘ .’ ONH2 C6H13v H (593 1 (594) The sesquiterpene furan (+)-dihydropallescensin-2 (585) Dolastatin-10 (588) is believed to be the most potent anti- which was first isolated from the dorid nudibranch Cadlina neoplastic agent presently known.The structure of dola- l~teomarginata~~~ statin-10 (588) was proposed on the basis of spectral studies. and later from the sponge Dysidea fragili~,~~~ has been synthesized by using an asymmetric aza-Claisen rearrangement that allowed stereoselective formation of the (S) c~nfiguration.~~~ The major trail-breaking pheromone of the 11 Tunicates carnivorous opisthobranch Navanax inermis navenone A The verapliquinones are diprenylquinones from a species of (586),376 has been synthesized; an arsonium salt was used in Aplidium that was collected in Brittany.384 High-performance place of the usual Wittig reagent to create the polyene chain.377 liquid chromatography yielded a 4 1 mixture of the geometrical Three reports378-381 of synthetic research efforts directed isomers verapliquinone A (589) and verapliquinone B (590) and toward the synthesis of possible components of dolastatin-3 a 4 1 mixture of verapliquinones C (591) and D (592) as minor failed to shed any light on the correct structure of the cytotoxic constituents.The structures of the verapliquinones were However the re- inferred from spectral properties of the mixtures.cyclic peptide from Dolabella auri~ularia.~~~ isolation of dolastatin-3 (587) allowed the correct sequence of The tunicate Pseudodistoma kanoko produces two novel amino acids in the cyclic pentapeptide to be determined by antineoplastic piperidine alkaloids that have calmodulin-n.m.r. studies and the new structure was confirmed by syn- antagonistic The structures of pseudodistomins A A second and more remarkable pentapeptide dola- (593) and B (594) were elucidated by interpretation of spectral data. Full details of a synthesis of the 2,3-erythro-isomer (595a) statin- 10 (588) has been isolated from D. a~ricularia.~~~ NATURAL PRODUCT REPORTS 1988-D.J. FAULKNER OH I OH (595a) R' O(5991 R'= Br R2 = OH R3 = H H(600) R' N(603) R' = R3 = H R2= Br I (601) R' O(604) R' = R2 = H R3= 8r Q (60% R' (616) R' = R3= Br R2= OH G(611) R' P(612) R' C(606) 'R' = R4= H R2 = OH R3 = Br E(607) R' = Br R2 = OH R3 = R4= H F(608) R' = H R2= OH R3 = Br R4= CpP2 K(609) R1 = R2 = R4= H R3 = Br L(610) R'= R3 =R4=H R2= Br and the 2,3-threo-isomer (595b) of aplidiasphingosine which is an anti-tumour agent from a species of Aplidi~rn,~~~ have been 2-Bromoleptoclinidinone (596) is a cytotoxic constituent of a species of Leptoclinides from Truk Lagoon.388 The structure of the novel pentacyclic alkaloid (596) was eludicated by using long-range proton-carbon coupling data. The structure of citorellamine (597) which is a cytotoxic and antimicrobial constituent of Polycitorella rnaric~e,~~~ has been revised from (598).390 Syntheses of both (597) and (598) have been described.The eudistomins are an extensive series of antimicrobial and antiviral alkaloids from the Caribbean tunicate Eudistoma oliva~eum.~~' The syntheses of eudistomins D (599) H (600) I (601) M (602) N (603) 0 (604) and Q (605) were reported 651 OH (595 b) HoQz@N H = Br R2 = H (602) = R2= H = OH R2 = H = H Rz =Br = OH R2 =OH R(613) R'= H R2= Br S (614) R1 = Br.R2= H T (615) R1 = R2 = H together with results from an extensive programme of screen- ing.391 It has been proposed that the stereochemistry of eudisto- mins C (606) E (607) F (608) K (609) and L (610) should be revised on the basis of a detailed NOEDS study of eu-distomin K (609) that was obtained from the New Zealand tunicate Ritterella sigillin~ides.~~~ Two synthetic approaches to the latter group of eudistomins have been pre~ented.~~~~~~~ Eudistoma olivaceum from Bermuda has yielded the known eu- distomins G (61 l) H (600) I (601) and P (612) and three new 16-carbolines which are eudistomins R (613) S (614) and T (615).395 A synthetic eudistomin 7-bromoeudistomin D (616) induces a contraction of chemically skinned muscle fibres and causes release of calcium ion from fragmented sarcoplasmic NATURAL PRODUCT REPORTS 1988 (617) R' = Me R2= 6us R3 = Pri 1618) R1 = H,R2= BuS,R3 = Pri (619) R1 = Me R2 = Bus R3 =CH2Ph (620) R1 =Me R2 = Pri ,R3 =CH2Ph NH "N / Ph 0 OCHO I B 0 HN Me R' "1 Y 6Me (626) R = H 0 V (627) R = CH3kH(OH)C-$ II An X-ray-crystallographic study of ascidiacyclarnide (6 17) which is a cytotoxic cyclic peptide from an unidentified ascid- ian,397 has revealed the conformation of the molecule in the solid The structures of several metabolites from Lisso-clinum patella have been revised as a result of synthetic and spectral The spectral data of the patellamides A-C (618)-(620) have been re-assigned and the new assign- ments were used to elucidate the structures of the three new meta- bolites prelissoclinamide-2 (62 l) prepatellamide-B formate (622) and preulicyclamide (623).Ulicyclamide (624) has been synthesized in high yield by the solid-phase method.400 (62 1) The didemnins are a series of cyclic depsipeptides from a Caribbean didemnid tunicate.401. 402 They possess significant anti-tumour and antiviral activity and didemnin B (625) is currently entering Phase 2 clinical The structures of didemnins A (626) B (625) and C (627) have been corrected by replacement of the (3S,4R)-statine residue which was the subject of a fruitless synthetic effort,405 by a (3S,4R,5S)-isostatine residue.40s The structures of the didemnins (625)- (627) were confirmed by 12 Echinoderms Many starfish are known to elicit an escape response in normally sessile marine invertebrates. The sea anemone Stomphia coccinea responds to contact with the starfish Dermasterias imbricata by releasing its basal disc from the substratum and 'swimming' away.By using a bioassay-directed fractionation it was determined that the benzyltetra-hydroisoquinoline alkaloid imbricatine (628) can elicit the swimming response.4o7 The structure of imbricatine (628) was determined by interpretation of spectral data. Imbricatine (628) is also active in the L-1210 (ED, -=1 pg ~m-~) and P388 (T/C 139 at 0.5 mg per kg) antineoplastic assays. The amino-acid residue in imbricatine (628) is related to a family of thiol- containing amino acids ovothiols A (629) B (630) and C (631) that have been obtained from the starfish Evasterias troschelii the scallop Chlamys hastata and the eggs of the sea- urchin Strongylocentrotus purpuratus respectively.408 Sixteen steroidal glycosides and three sulphated poly-hydroxylated sterols were isolated from the Mediterranean starfish Coscinasterias tenuispin~.~~~ Seven of the saponins had been described previously.The new saponins tenuispinosides A (632) B (633) and C (634) and coscinasterosides A (635) NATURAL PRODUCT REPORTS,1988-D. J. FAULKNER SH CH,R4 H OH OH OH OS03Na OH (635) NATURAL PRODUCT REPORTS 1988 HO 9 OS03Na (636) (637) R’ = H R2= OH R3 = xj+8&oH (638) R’ = H R2= OH R3 = <\&&OH OS03Na OH (640) R’ = OH (641) R = “;6”-r.. (643) R = B (636) C (637) D (638) E (639) and F (640) were identified by using spectroscopic methods. The sulphated polyhydr- oxy-steroids were shown to be (25S)-Sa-cholestane-3P,4P,-6a,8,15P 16P,26-heptaol 3-sulphate (641) (22E)-Sa-cholest- 22-ene-3,8,6P,8,15a,24-pentaol 15-sulphate (642) and (22E)- 5a-cholest-22-ene-3P,4P,6a,8,1 5,8 I6,3,24-heptaol 3-sulphate (643).Two new steroidal glycosides pectinioside A (644) and pectinioside B (645) were isolated from Asterina pectinifera from Japan and the structures were proposed on the basis of chemical and spectroscopic evidence.410 Three steroidal glyco- sides named Co-ARIS I (646) Co-ARIS I1 (647) and Co-ARIS I11 (648) which are essential for inducing the acrosome reaction were isolated from the egg jelly of the starfish ASterias amurensis and their structures were determined by chemical and spectral rneth~ds.~” It was shown that Co-ARIS I (646) and Co-ARIS I11 (648)were identical to ovarian asterosaponin- 1(OA- 1)412 and OA-4,413 respectively while Co-ARIS I1 (647) is OH,R2= H R3 = OH OH (6421 [structures (644) to (650) are with (63211 novel.The complete structures of forbeside A (649) and forbeside B (650) from Asterias forbesi were deduced by using n.m.r. methods414 and were found to be identical to versicoside A415 and versicoside B,416 respectively which are known metabolites of Asterias amurensis. Only known metabolites were isolated from the two Pacific starfish Nardoa novae-caledonia and N. g~mphia.~~’ In addition to known saponins and polyhydroxylated sterols the Pacific starfish Pentaceraster alveolatus has been found to contain a new steroidal glycoside 6-epi-nodososide (65 1).418 Three closely related saponins all of which possess 2,4-di-U- methyl-D-xylose as the terminal sugar have been isolated from Culcita novaeguineae 420 the structures of culcitosides C (652) C (653) and C (654) were determined by chemical degradation.The starfish Astropecten indicus contains a steroidal 5-U-methyl-~-~-galactofuranoside, called indicoside A (655) that was identified by spectroscopic methods.421 NATURAL PRODUCT REPORTS. 1988-D. J. FAULKNER 655 HZOH HO4 HOqowc OMc ! OH OMc I OH H HO I OH OH HOm-'OH OMe 7 HO OH 1 OH OH OH (659) (653) R = OH &OH OH (654) R = H OH The starfish Sphaerodiscus placenta contains the glycosides 22,23-didehydrohalityloside E (656) 22,23-didehydro-halityloside D (657) and plantoside A (658) as well as the known glycosides halitylosides A B and E,422 which had previously been isolated from Halityle reg~1uri.s.~~~ Three polyhydroxylated steroids (659)-(661) were also obtained bH from S.pl~centa.~~~ Continuing previous studies on Crossaster (655) papposu~,~~~ the three new minor glycosides crossasteroside B NATURAL PRODUCT REPORTS,1988 (6621 I?’=H R2= HO I ao I OH OH (664) R’= OH R2= HO OH NaOF” dH (665) OS03Na I II I Na$SO’* OH (666) Na4S0°’ 1 (668) OS03Na .-0SO No i N a0,SO (670) (662) C (663) and D (664) have been isolated and identified using spectral The new steroidal glycoside reported from Porania pulvillus is identical to 22,23-didehydrohalityloside E (656).426 The major polar steroid from the Pacific ophiuroids Ophiocoma dentata Ophiarthrum elegans and Ophiarachna incrassata is S/?-cholestane-3a,4a,1lp,Zl-tetraol 3,21-di-sulphate (665).The minor steroids were found to be disulphates (666) and (667) from Ophiocoma dentata the disulphate (668) from Ophiarthrum elegans and the trisulphates (669) and (670) from Ophiarachna incra~sata.~~’ The major glycoside of the holothurian Neothyonidium magnum is a sulphated saponin called neothyonidioside (671).428 The structure of neothyonidioside (671) was proposed on the basis of interpretation of spectral data. A non-sulphated saponin called caudinoside A (672) which was isolated from Paracaudina ran~onetii,~~’ lacks only the sulphate groups of psolusoside A (673) from Psolus fabri~ii.~~~ NATURAL PRODUCT REPORTS 1988-D.J. FAULKNER CH I C H20R OH HO OH Q-OH (6711 R' = S03Na R2 = R3 = H (672) R' = R3 = H Rz = CH20H (673) R' = H R2 = CH20S03Na R3 = S03Na 0 Br Br \ Br@;" OAc H (6791 R = H (674) 1675) (676) (677) (678) (680) R = Br OH Br (6811 (68 21 (683) OAc epoxycyclohex-2-enone (677) and the corresponding deacetyl- derivative (678).432 The structures of (674) (676) and (677) were determined by X-ray analysis and the remaining com- pounds were identified by analysis of spectral data. The epoxide (677) shows activity against P388 (IC5, = 10 ng ~m-~) in vitro.4,6-Dibromoindole (679) which is a metabolite of a species of Gl~ssobalanus,~~~ and 3,4,6-tribromoindole (680) which was found in Balanoglossus carnos~s,~~~ have been synthesized from The 13 Miscellaneous 3,5-dibromonitroben~ene.~~~hexabrominated diphenyl A survey of ten species of marine worms from soft sediments in ether (68 1) from Ptychodera frava laysanica43e has been South Carolina and Washington state indicated the presence of synthesized by anodic oxidation of 2,3,5-tribromo-4-methoxy-brominated phenols in Saccoglossus kowalewskyi (a hemi- chordate) and Arenicola cristata (an annelid) brominated Very low concentrations of an insect juvenile hormone i.e.JH pyrroles in S. kowalewskyi and bromobenzyl alcohols in I11 (682) and methyl farnesoate (683) have been detected in the Thelepus crispus (an annelid) but the proposed structures are haemolymph of the spider crab Libinia emarginata and it has not adequately defined.431 A new species of Ptychodera (an been suggested that these and similar compounds have acorn worm) has yielded five new brominated metabolites regulatory roles in these being (4S,5R,6S)-4-acetoxy-2,6-dibromo-5-hydroxy-The known boxfish toxin pahutoxin (684) and a new cyclohex-2-enone (674) the corresponding (4S,SR,6S)-epimer homologue homopahutoxin (685) have been isolated from the (675) (3S,4R,5S,6R)-3-acetoxy-1,5-dibrom0-4,6-dihydroxy-mucus that is secreted by the Japanese boxfish Ostracion cyclohexene (676) and (4S,SR,6R)-4-acetoxy-2-brorno-5,6-irnma~ulatus.~~~ The same preluciferin Watasenia preluciferyl 658 C02H I (I' Ph (6861 P-D-glucopyranosiduronic acid (686) has been found in the liver of Neoscopelus rnicrochir and in the nasal photophores of Diaphus el~cens.~~' 14 References 1 D.J. 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ISSN:0265-0568    

DOI:10.1039/NP9880500613

出版商:RSC    

年代:1988

数据来源: RSC