摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Nottingham Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis and chemistry of the major groups of natural products-alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. Many reviews provide details of biological activity and wider aspects of bioorganic chemistry including developments in enzymology genetics and structural spectroscopic and chromatographic methods of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1993 Annual Subscription Price E.C. f242.00 Overseas f266.00 U.S.A. $532.00 Canada f279.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Second-Class postage paid at Jamaica NY 11431-9998. Afl other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1993 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 1993 E.C. f242.00 Overseas f266.00 U.S.A. US $532.00 Subscription rates for back issues are (1988) (1989) (1 990) (1991) (1 992) U.K. €1 59.00 f169.00 f177.00 f198.00 f222.00 Overseas f 183.00 f194.00 f204.00 f228.00 f250.00 U.S.A. US $342.00 US $388.00 US $398.00 US $467.00 US$474.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99310FX013

出版商:RSC    

年代:1993

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99310BX015

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

ISSN 0265-0568 NPRRDF 1O(4) 311-428 (1993) Natural Product Reports A journal of current developments in bio-organic chemistry Volume 10 Number 4 CONTENTS 311 Obituary David N. Kirk 1929-1992 313 Steroid Reactions and Partial Synthesis J. R. Hanson Reviewing the literature published in 1991 327 Advances in Chemical Ecology J. B. Harborne Reviewing the literature published between January 1988 and June 1992 349 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites J. E. Saxton Reviewing the literature published between July 1991 and June 1992 397 Natural Sesquiterpenoids B. M. Fraga Reviewing the literature published during 1991 42I Arsenic Compounds from Marine Organisms J. S. Edmonds K. A. Francesconi and R. V. Stick Reviewing the literature published up until October 1992 22 NPR 10 Cumulative Contents of Volume 10 Number 1 1 Lignans Neolignans and Related Compounds (January 1989 and December 1991) R.S. Ward 29 Muscarine Oxazole Imidazole Thiazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1990 and June 1991) J. R. Lewis 5 1 Indolizidine and Quinolizidine Alkaloids (July 1990 and June 1991) J. P. Michael 71 Microbial Pyran-2-ones and Dihydropyran-2-ones (up to December 2991) J. M. Dickinson Number 2 99 Quinoline Quinazoline and Acridone Alkaloids (July 1990 and June 1991) J. P. Michael 109 The Chemistry of Azadirachtin S. V. Ley A. A. Denholm and A. Wood 159 Diterpenoids (1992) J. R. Hanson 175 Chemical and Biochemical Manipulations of Nucleic Acids M.J. McPherson and J. H. Parish 199 Tropane Alkaloids (January and December 1992) G. Fodor and R. Dharanipragada Number 3 207 NMR of Proteins M. P. Williamson 233 The Biosynthesis of Shikimate Metabolites (1991) P. M. Dewick 265 Biological Variation of Microbial Metabolites by Precursor-directed Biosynthesis R. Thiericke and J. Rohr 291 Amaryllidaceae and Sceletium Alkaloids (1992) J. R. Lewis 301 Stevioside and Related Sweet Diterpenoid Glycosides (up to May 2992) J. R. Hanson and B. H. De Oliveira Articles that will appear in forthcoming issues include Pyrrolizidine Alkaloids (July I991 and June 1992) D. J. Robins Marine Natural Products (1992) D. J. Faulkner Macrocyclic Trichothecenes (up to December 2991) J. F. Grove /I-Phenylethylamines and the Isoquinoline Alkaloids (July 1991 and June 1992) K.W. Bentley Diterpenoid Alkaloids (December 1989 to January 1992) M. S. Yunusov Pigments of Fungi (Macromycetes) (July 1986 and August 1992) M. Gill HMG-CoA Reductase Inhibitors A. Endo and K. Hasumi The Strobilurins Oudemansins and Myxothiazols Fungicidal Derivatives of P-Methoxyacrylic Acid J. M. Clough A Survey of Natural Products which Abstract Hydrogen Atoms from Nucleic Acids J. A. Murphy and J. Griffiths The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (1991) R. B. Herbert The Biosynthesis of Fatty Acid and Polyketide Metabolites (mid 2991 to mid 2992) D. O’Hagan Plant Polyphenols E. Haslam Recent Advances in the use of Enzyme-catalysed Reactions in Organic Synthesis (July 1988 to December 1992) N. J. Turner Triterpenoids (January 1988 and December 1989) J. D. Connolly R. A. Hill and B. T. Ngadju

ISSN:0265-0568    

DOI:10.1039/NP99310FP017

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Professor David N. Kirk (1929-1992) The death of Professor David Kirk on the 7th October 1992 from a heart attack at the age of 63 has deprived steroid chemistry of one of its leaders. David Kirk had an international reputation. He had been a contributor to Natural Product Reports and to its predecessor the Terpenoids and Steroids Specialist Periodical Report for many years. His articles on steroid reactions and latterly on the application of physical methods to the study of the steroids were scholarly com- prehensive and well-written reviews and what is more the manuscripts were produced on time. David Kirk graduated from the South-West Essex Technical College with a first-class honours degree of London University. His early researches with Vladimir Petrow at B.D.H.laid the foundation of his work on the chemistry of the steroids. Subsequently he collaborated with Michael Hartshorn at Christchurch in New Zealand in this area of chemistry before returning to England in 1965 as a lecturer at Westfield College in Professor Klyne’s department. He was promoted to Reader and then in 1976 to Professor. When the teaching of chemistry in London University was re-organized he moved to Queen Mary College. Throughout this period his work involved the chemistry of the steroids their chiroptical and their spec- troscopic properties. His publications were concerned with their separation partial synthesis and more recently microbio- logical transformation. Much of this work was directed at the preparation of compounds for the MRC Reference Collection of Steroids of which he was curator.His collaboration with Michael Hartshorn led to the publication of their book ‘Steroid Reaction Mechanisms ’. Whereas the books by Fieser and by Shoppee on the steroids provided descriptive historical accounts of the development of steroid chemistry Kirk and Hartshorn made a major con-tribution towards the rationalization of the vast body of experimental work on the steroids in terms of conformation and reaction mechanism. Even though this book is now twenty- five years old it still provides one of the best accounts of these features which dominate steroid chemistry. More recently David Kirk was one of the editors of the comprehensive and useful ‘Dictionary of Steroids ’. David Kirk was a careful researcher with a thorough understanding of organic chemistry which he was willing to share with others. He was a quiet kindly man and he will be sorely missed. We extend our sympathy to his wife and family. J. R.Hanson 311

ISSN:0265-0568    

DOI:10.1039/NP9931000311

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Steroid Reactions and Partial Synthesis J. R. Hanson School of Molecular Sciences University of Sussex Brighfon Sussex BN I 9QJ Reviewing the literature published in 1991 (Continuing the coverage of literature in Natural Product Reports Vol. 9 p. 581 ) 1 2 3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 5 Introduction NMR Spectroscopy of Steroids Reactions Alcohols Ethers and Epoxides Thia-steroids and their Relatives Alkenes Aromatic Steroids Carbonyl Compounds Rearrangement Reactions Remote Functionalization of Steroids Photochemical Reactions of Steroids Partial Synthesis The Partial Synthesis of Labelled Steroids Estranes Androstanes Pregnanes and Corticosteroids Cholanes Ecdysteroids Brassinolides and Withanolides Vitamin D Inhibitors of Steroid Metabolism Miscellaneous Partial Syntheses References I Introduction This report follows the pattern of its predecessor and provides a selective coverage of the advances in the chemistry of the steroids published during 1991.A Dictionary of Steroids has been produced and provides a valuable source of data and references1 The first of a series of handbooks of natural product data covers the diterpenoid and steroidal alkaloids. 2 NMR Spectroscopy of Steroids The application3 of ol-decoupled proton homonuclear shift correlated NMR spectroscopy (COSYDEC) allows cross peak recognition at 250 MHz with a facility normally associated only with operation at 500 MHz.The conformation of ring A of 19-functionalized 4-en-3-ones4 and of steroids containing a spirocyclopropane at C-2 (e.g. 1)5 has been examined by NMR methods. A simple lH NMR method based on the changes in the chemical shift of the angular methyl groups induced by acylation with trichloroacetyl isocyanate has been used6 to assign the stereochemistry of hydroxyl groups at C-5 and C-14. 'H NMR and molecular mechanics studies have been reported7 on the epimeric ethyl esters of 20(R,S)-hydroxy-23-nor-cholanoic acids. Other studies have been described8 on the stereochemical influence of C-3 substituents in derivatives of cholic acid. Predictive models for the simulation of the 13C NMR spectra of keto-steroids have been e~aluated.~ A collection of data has been presented'O on the effect of vicinal oxygen functions at C-16 and C-17 on the 13C NMR signals of ring D.Further discussion of the y-gauche effects on the NMR signals of 17p- substituted androstenones has appeared.'l The 13C NMR spectra of polyfunctional bile acid derivatives have been 0 assigned.12A re-examination of the 13C NMR spectrum of 2- methylpentan-3-01 has led13 to the correction of some previous assignments of the signals of the side chain of some sterols and consequently a re-interpretation of some results in the biosynthesis of poriferasterol in Ochromonas malhamensis. The magnitude of the proton-carbon- 13 spin :spin coupling constants for axial and equatorial protons on carbons adjacent to a carbonyl group is a reflection of their stereochemistry.14 Analysis of the NMR spectra of some fluorinated cortico- steroids has led15 to the detection of some long-range proton- fluorine couplings.The fluorine- 19 and deuterium NMR spectra of fluorocolestanols have been reported16 in the context of the role of the sterols in membranes and high-density lipo-protein. The phosphorus-3 1 NMR spectra of a phosphatidylcholine- cholesterol complex has been examined17 in the light of the conformational changes that occur as cholesterol is involved in the packing of lipid bilayers. 3 Reactions 3.1 Alcohols Conditions have been described1* for the protection of 3a- alcohols as their benzyl ethers in the A/B cis series. The solvolysis of the epimeric 3-methoxyestra- I ,3,5( lO)-trien-6a- and 6p-yl sulfates (2) in 180-water has been shown1g to lead to the same mixture of 6a-and 6P-alcohols with the incorporation of oxygen- 18.The formation of the reactive benzylic carbonium ion in this situation has been linked to the carcinogenicity of these metabolites. Thermolysis20 of the four isomeric 3- methoxy -16-methylestra -1,3,5 (10) -trien -17-ylazidoformates gave products arising from the insertion of a nitrene. Thus the azido-formate (3) gave the tetrahydroxazinone (4) whilst the epimer (5) gave both the tetrahydroxazinone (6) and the oxazolidinone (7). NATURAL PRODUCT REPORTS 1993 (3) f 0 BzOT OS02Me The efficient C-21 deoxygenation of 21-alkoxy-20-keto steroids by trimethylsilyl iodide in the presence of methanol has been reported.21 Treatment of the 6P-methanesulfonate (8) with silver acetate in pyridine afforded22 the A-homo-B-nor steroid (9) possibly with participation of the 9-ene.Although the 9-ene is resistant to hydrogenation reduction of the exocyclic double bond in (9) leads to some epimerization of C- 5. Solvolysis of the p-nitrobenzoate (10) led23 to the cyclized product (1 1) through transannular double-bond participation. 3.2 Ethers and Epoxides The conversion of 2a,3a-epoxides to 2P,3a-halohydrins using the resin Dowex-50 and sodium halides has been Neighbouring group participation has been in the chromium trioxide oxidation of steroidal 4,5-epoxides. For example oxidation of (12) afforded the rearrangement product (1 3).Oxidation of the epimeric epoxide (14) on the other hand gave the 4-ketone (1 5). Whereas treatment of 2a,3a-epoxy-5a- hydroxyandrostanes (e.g. 16) with hydrobromic acid in glacial acetic acid gave an aromatic steroid (18) via a dienol benzene rearrangement the 5a,6a-diol (17) gave the ketone (19).26 The acid-catalysed cleavage of some 3-substituted 5a,6a-epoxy-~- norandrostan- 17-ones (e.g. 20) has been inve~tigated.~' The products (21)-(23) are compatible with the epoxide opening to give either a C-5 or a C-6 carbocation. An X-ray crystallographic study of 5a,8a-epidioxy-5a-cholest-6-en-3P-acetate has been reported.2s 3.3 Thia-steroids and their Relatives Reaction of 3a,17P-diacetoxy- 1a,5a-epidithioandrostane(24) with sulfuryl chloride has been to afford a mixture of both 34 17P-diacetoxy- 1a-(chlorodithio)androst-5-ene (25) and 34 17~-diacetoxy-4~-chloro- 1a,5a-dithioandrostane (26).These in turn react with a variety of nucleophiles facilitated in some instances by the formation of a thiiranium ion (27). This 0 YH .CH2 + (7) BzO@0 (9) OAc OAc OAc (13) AcO n work was extended30 to the preparation of some thiocortico- steroid analogues such as la,9a-epidithio-1 lP 17a,21- trihydroxy-16P-rnethylpregn-4-ene-3,20-dione (28). The prep- aration of some methylsulfides (e.g. 30) by reaction of the NATURAL PRODUCT REPORTS 1993-5. R. HANSON 315 0 cl 0 HO R (16)R = H (17) R=OH Ac0'-Br@ 0 (19) ___c AcO" (24)J ACO'.AcO" Cl (26) alkenes (29) with trimethylsilyl chloride and dimethylsulfoxide in acetonitrile has been de~cribed.~' Further oxidation with m-chloroperbenzoic acid gave the sulfone (3 1). Steroidal sulfones have also been by reaction of the alkene with sodium toluene-p-sulfinate and iodine. The reductive desulfonylation of steroidal phenylsulfones by samarium(I1) iodide-hexamethylphosphoric triamide has been X-ray crystallographic studies of a single diastereoisomer of phenyl epiandrosterone sulfite and of the benzyl epi- androsterone sulfite derived from it by nucleophilic sub- NATURAL PRODUCT REPORTS 1993 OTBDMS OTBDMS Me0&-Me0 \ &H \ (39) stitution at sulfur have estal~ished~~ that tLle reaction proceec S with inversion of configuration at sulfur.3.4 Alkenes The catalytic effect of hydrogen chloride on the boron trichloride isomerization of A2-and A3-5a- and 5P-cholestenes has been noted.35 The epoxidation of cholesterol and its acetate by dioxiranes generated in situ from a ketone such as acetone and potassium monopersulfate gave36 a :P ratios closer to 1 1 rather than the 4:l found with peracid epoxidation. Some insertion of oxygen at C-3 and C-7 was also observed. A re-investigation of the oxymercuration-demercuration reaction of A5-steroidal alkenes3’ and a study of the reaction of lead tetra-acetate with steroidal bromonitro-olefins has been reported.38 The Lewis acid (dimethylaluminium chloride) catalysed Prins reaction with paraformaldehyde has to be a valuable method for introducing substituents at C-701- and C-801- in the estrogens (32)+(33); (34)-+(35).This sequence has been extended to the formation of 1-1 1 -methano bridged steroids (36)-+(37).40A dimethylaluminium chloride catalysed ene reaction of a-chloroacetaldehyde has been used to add the 20(S),22(R)-hydroxy side chain of steroids (38)+(39).41 The crystal structure of the adduct (41) of dichloroketene and 3p-acetoxy-20a-homopregna-5,20-diene (40) has been described.42 Various novel conditions for the allylic oxidation of A5-steroids have been reported including the use of t-butylhydro- OTBDMS Me0 (43) R = a-H,f3-OH (44) R =O peroxide and potassium ~ermanganate.~~ On the other hand oxidation of cholesterol with silver chromate and iodine gave44 the unsaturated 6-ketone (42)+(43) whilst tetrapropyl-ammoniumperruthenate and N-methylmorpholine N-oxide the A4-3,6-dione (44).Studies with a ruthenium tetramethylporphyrin catalyst have also been The reaction of 7-norandrost-5-enes (e.g.45) with bromine and silver acetate afforded4’ the fragmentation product (46) as well as the allylic substitution products (47) and (48). Some further studies on the application of the method to normal A5-steroids have been des~ribed.~~ The cycloaddition of phenylvinylsulfolene to the ring D diene of 3-methoxy- 16-methylestra- 1,3,5( 10),14,16-pentaen- 17-yl acetate (49) and some transformations of the products have been described.49 The major products (50) and (51) arise from 317 NATURAL PRODUCT REPORTS 1993-5.R. HANSON HO&-O (45) OAc (52) (53) HO Rpy k (54) R' = R2 = H (55)R' =SePh R2= H (56)R' = halogen R2 = H (57)R' = H R2 = Br (58)R' = R2 = 8r addition to the p-face. Removal of the sulfone and modification of the residual alkene permitted the synthesis of some 14a- and 17a-substituted steroids. These studies have been extended50 to the synthesis of some 14,17-heterobridged steroids [e.g. (52) and (53)]. The influence of the bridgehead group on the reactions of the 14a 17a-ethano-steroids has been 3.5 Aromatic Steroids The selective aromatization of ring A of testosterone by demethylation with pentamethylcyclopentadienylruthenium has been described.52 The characterization and stereochemistry of some ruthenium complexes of estradiol have also been The selective substitution of the aromatic ring of estrogens continues to attract interest.Thus the reaction of estrone (54) with benzeneselenenyl chloride leads to 2-H C ! + Rlo@ OR2 (46) (47) R' = H R2 = AC (48) R' = Ac R2= H 0 (59) CNvTos phenylselenylestrone (55) which reacts with iodine chloride iodine bromide or iodine to give the corresponding 2-halo- steroids (56).54 Routes to halogenated derivatives of 17a-ethynylestradiol have been described.55 4-Bromoestrone (57) has been by the palladium catalysed debromin- ation of 2,4-dibromoestrone (58). The bromination of 3,17~-diacetoxy-6-oxoestra- 1,3,5( 10)-triene with N-bromo-succinimide has been described in connection with the preparation of labelled material.56 A 9P-azido group has been introduced5' into estrone methyl ether using hydrazoic acid and DDQ to give (59).3.6 Carbonyl Compounds The ready availability of androst-4-en-3,17-dione by the microbiological degradation of sterols has provided the stimulus for the development of methods for adding C-20 and C-21 of the pregnane skeleton. The synthesis of I7-(isocyanotoluene-p- sulfonylmethy1ene)-steroids (60) from the corresponding 3-methyl enol ether has been examined in this conte~t.~~~~~ Derivatives of 5a-androstan-301- and 3p-01(e.g. 61) with an acrylonitrile side chain have been prepared60 by condensation of the (2-20 aldehydes with diethylcyanomethylphosphonate.NATURAL PRODUCT REPORTS 1993 THPOJ3P CBH17 H (64) The condensation of the THP ether of pregnenolone with the organolithium derivative of dihydropyran or dihydrofuran has been usedG1 in the synthesis of side chain analogues of cholesterol via (62). The reductive amination of 3-ketones has been employedG2 in the synthesis of 301- and 3P-amino-SP-cholanic acids. The structure of the adducts of primary amines with 16a-hydroxy- 17-ketones has been investigatedG3 in connection with the binding of these derivatives to biological material. The 19-(0- carboxymethy1)-oxime grouping has been examined as a potentially useful immunogen and the preparation of these derivatives (e.g.63) of progesterone and androstanolone has been rep~rted.~~,~~ The oxidation of steroidal ketones with benzeneseleninic anhydride continues to attract attention. The reaction of A-nor- 5a-cholestan-2-one (64) has been shown66 to produce inter alia the lactone (65) and the anhydride (66). Nitration of the enolacetates of ketones with trifluoroacetyl nitrate in methylene chloride has affordedG7 a route to nitroketones such as the 2a- nitro-3-ketones. The isomerization of aldosterone in dilute alkali has been examined.68 Diiodosilane has provedG9 to be a useful reagent for the direct reduction of acetals in the presence of unprotected carbonyl groups allowing the partial reduction of steroidal ketones (e.g. 67+68).The 20,20-dimethylacetal group pro- vided70 protection for the pregnane side chain in the bio- transformation of pregnenolone derivatives to their progester- one analogues. The isomerization of androst-5-en-3,17-dione to androst-4- en-3,17-dione has continued to attract attention with studies being reported on the catalysis by acetate ions.71 The outcome of the vanadium catalysed oxidation of steroidal y-hydroxy- @-unsaturated ketones by t-butylhydroperoxide has been shown to be dependent on the stereochemistry of the hydroxyl group. Equatorial hydroxyl groups give enediones whilst axial hydroxyl groups gave 2,3-epoxy-4-hydroxy- 1 -ketones. The selenium dioxide oxidation of steroidal 1,4-dien-3-ones pro- ~ided~~ a simple route to 6-hydroxycorticosteroids in which the stereochemistry of the 6-hydroxyl group was related to that of the C-9 substituent.The products from the oxidation of progesterone (69) with aqueous hydrogen peroxide in the presence of ferric chloride and picolinic acid in pyridine:acetic acid (the GoAgg 111 conditions) have been examined. 74 The major products were two triketones pregn-4-ene-3,6,20-trione (70) and pregn-4-ene- 3,12,20-trione (71) together with the unstable 5a-formyL~-H H 0 0 (69) R’ = R2 = H H (70) R’ = 0,R2 = H H (71) R’ =H~=R~=o (73) (74) norpregnane-3,20-dione (72). Selective hydrogenations of ster- oidal unsaturated ketones have been achieved75 with a copper- alumina catalyst. Reduction of 4-en-3-ones gave a high yield of the SP-3-ketone.The products of addition of ethyl acetoacetate to some steroidal unsaturated ketones have been reported.76 Silica gel has to be an efficient catalyst for the NATURAL PRODUCT REPORTS 1993-5. R. HANSON OTf 0 0 0JJgLo& CI &'-P~'O~C fragmentation of the toluene-p-sulfonylhydrazides of ap-epoxyketones to acetylenic ketones (73)+(74). The synthesis of 5a-androst- 16-ene-3,7-dione has been achieved78 by conversion of the 17-ketone via the hydrazone to the 17-iodo- 16-ene and hydrogenolysis of the iodine. The palladium catalysed coupling of steroidal vinyl iodides and triflates has been a fruitful area with reports on the coupling of 4-pentynoic acids with the C-17 vinyltriflate (75)-+(76),79 the coupling of vinyl iodides or triflates with vinyltributyltin (77)-+(78),80and the coupling of buten-1,4-diols with (79) to form the hemiacetal (80) and thence on oxidation the y-butyrolactone (8 1).81 Pr'02C-C c,&'II 0 3.7 Rearrangement Reactions The reaction of 19-hydroxyandrost-4-en-3,17-dione (82) with diethylaminosulfur trifluoride has been showne2 to lead to the rearrangement product (83).The rearrangement of 1,2-dehydroprogesterone to aromatic steroids has been further examined.83 The thermal rearrangement of a-chloroglycidic esters (e.g. 84) to chloroketo-esters (85) has been exploreda4 with derivatives of cholestan-3-one. Rearrangement of the toluene-p-sulfonylhydrazone(86) of 3p-hydroxy-3a-acetyl- 14a- methyl-4-nor-5a-cholest-8-ene under Bamford-Stevens con-ditions resulted in the formation of 4a,14a-dimethyl-5a-cholest-8-en-3-one (87) and a mixture of 3,14a-dimethyl-4-oxosteroids.NATURAL PRODUCT REPORTS 1993 ?pY ’J NH J Product (89)-$p ? c=o 6- I (94) R=H (95) R=CI The unusual non-Beckmann rearrangement of the ketoxime (88) to the heterocyclic derivative (89) has been observed.86 The rearrangement proceeds via hydride transfer (90) and cyclization (91)+(92)+(93). 3.8 Remote Functionalization of Steroids The site-directed formation of carbon-bromine bonds by tandem radical chain reactions has been explored.*’ Thus irradiation of the 3a-iodobenzoate (94) in the presence of p-nitrophenyliodosodichloride alone gave the 9a-chloro com-pound (95) whilst with the addition of carbon tetrabromide the 9a-bromo compound was formed.The site-selective hydroxyl- ation of steroids using oxometalloporphinates attached to the C-1701- or C-17P-positions led to the insertion of hydroxyl groups at the C-9a or C-12P positions. 3.9 Photochemical Reactions of Steroids A photochemical double-ring contraction with the extrusion of carbon monoxide has been observeda9 in the conversion of 4a-homo-5a-cholest-3-en- l-one (96) to the cyclobutane (97). The H (97) photosensitized oxidation of the enol of the ring A diketone (98) has been shown to affordg0 the lactol (99). Studies on the photochemical reactivity of the methyl ether of 8,9-didehydro- estrone towards singlet oxygen have been reported.g1 The photochemical radical fragmentation of the hemi-acetal (1 00) in the presence of diacetoxyiodobenzene has providedg2 a convenient synthesis of medium-sized lactones (101) and (102).A further fragmentation has been observedg3 in the photo- oxygenation of some steroidal isoxazolidines. The photo- cyclization of some unsaturated 5,l O-seco-steroidal ketones has been explored.94 Thus the (E)-5,1O-secocholestenone(103) has been shown to afford the (2) isomer and the cyclization product (104). 4 Partial Synthesis 4.1 The Partial Synthesis of Labelled Steroids [1,2-3H]-3a-Hydroxy-5a-pregnan-20-one has been preparedg5 by the incubation of [1 ,2-3H]-progesterone with a homogenate of rat brain tissue. A convenient and highly stereoselective synthesis of 4a-labelled cholesterol (106) involved the palladium (0) catalysed reduction of the cyclic carbonate (105) with labelled sodium b~rohydride.~~ Reduction of the cyclic car- bonate of [4a-3H]-cholest-5-ene-3/3,4P-diol with sodium borohydride and a palladium (0) catalyst resulted in [4P-3H]- cholesterol.The synthesis of [9a 1la 1201 12P-2H,]-cortisol has been reportedg7 in connection with the study of its metabolism. The preparation of the iodinated steroid (107) has been NATURAL PRODUCT REPORTS 1993-5. R. HANSON 321 + & 0 0 c8H17 describedg8 as a potential radio-iodinated ligand for androgen ethynylestradiol have been catalysed by a crown ether :copper receptors. A series of 7a- and 1lp-substituted [21 -1251]-~ter~id~ (I) iodide complex.1o4 Other 17a-substituted analogues of (108) have been synthesizede9 for estrogen receptor studies.In estradiol have been examinedlo5 as potential fluorescent each case the iodovinyl group was prepared by adding a estrogen receptor ligands. The aromatic sulfonic acid derivative tributylstannyl residue to the ethynyl steroid followed by (110) has been reported106 as an inhibitor of testosterone 5a-iododestannylation. The synthesis of [20,2 1-13C2]-pr~ge~ter~nereduc tase. from androst-4-en-3,l 7-dionelo0 and of the [1,2-3H,]-labelled 3-dehydroecdysteroid (1 O9)lo1 have been reported. 4.2 Estranes The synthesis and receptor binding affinity of a series of 7a- and 17a-substituted 2- and 4-chloroestradiol derivatives has been recorded.lo2 Substitution at the 2-and 4-positions of the aromatic ring is known to give products with enhanced in vivo stability due to their decreased rate of metabolism.The 4- chloroestradiol derivatives were obtained by chlorination of the corresponding 19-nortestosterone with sulfuryl chloride fol- lowed by aromatization. Some 17a-alkynylamide derivatives of estradiol have been preparedlo3 to assess their antiestrogenic activity. Nucleophilic additions to the ethynyl group of 4.3 Androstanes The synthesis and androgen receptor affinity of some steroidal ring A furans and thiopenes has been described.Io7 The bridged steroids exemplified by (113) have been shown to possess antiandrogenic properties. This system was preparedlo* from testosterone propionate via reduction of the enol-lactone (1 11) with lithium tri-t-butoxyaluminium hydride and an internal aldol condensation of the resultant keto-aldehyde to form (112).A series of 1I/?-allenic and alkenyIestra-4,9-dien-3,17-diones have been prepared and converted to spirolactone analogues.lo9 The 1Ip-allenes undergo an acid-catalysed isomerization to form the 11-alkenes.'l0 The transformation of NATURAL PRODUCT REPORTS 1993 16a 17a-epoxy- 17P-ethynylandrostanes into some lactones in the presence of cobaltcarbonyl has been described.lll 4.4 Pregnanes and Corticosteroids Methods continue to be described for the elaboration of corticosteroids from androstanes such as androsta-4,9-diene- 3,17-dione.112 The degradation of digitoxin and digitoxigenin derivatives has been explored113 as a route to pregnanes such as 3P,14P-dihydroxy-5P-pregnan-20-one as part of a study on the interaction of such pregnanes with the digitalis receptor of heart muscle.The method involved controlled ozonolysis of the unsaturated lactone (1 14) followed by zinc-acetic acid reduction and hydrolysis to afford (1 15). The modification of pregnanes has incl~dedl'~ the addition of a further ring (1 16) by Diels-Alder reactions with the 16-en- 20-ketones. The synthesis of a further range of corticosteroid 17a-esters in which the ester bears a further functional group has been reported115 as part of the search for topical anti- inflammatory agents. The stereochemistry of free-radical reactions at C-20 in the pregnane series has been examined.l16 The metabolism of cortisol in humans involves various transformations including reduction of the A4-3-ketone to form 3a-hydroxy products in both the 501-H and 5P-H series together with oxidation at C-11 and reduction at C-20.Many of the metabolites are excreted as conjugates with glucuronic acid. In order to assist in the characterization of these metabolites the synthesis of the 3-glucuronides of 5a-cortol and 5a-cortolone has been described. 11' Various steroidal haptens for the radio-immunoassay of pregnanes have been described including steroids substituted with thioether or ester linkages at C-211* and ll-hemi-~uccinates.~~~ A C-21 thioether of dexamethasone has been reported as an affinity label for glucocorticoid receptors.120 4.5 Cholanes The syntheses of the stereoisomeric 3,6,12a-trihydroxy-S/?- cholanic acids from deoxycholic acid have been reported. 121 These compounds were considered to be potential bile acid metabolites. A separate synthesis of methyl 3a,6P-dihydroxy-5- cholanoate has also been recorded.122 Routes for the prep- aration of 2P-hydroxylated bile acids (e.g. 117) have also been described in the context of the synthesis of potential bile acid metabolites. 123 Cholic acids have played a role as components of macrocyclic systems in steroid-capped porphyrins and in cholaphanes. lZ5 124v Cholic acid inclusion crystals have also been used to resolve racemic lactones.126 4.6 Ecdysteroids Brassinolides and Withanolides New routes for the partial synthesis of ecdysteroids continue to attract attention.The regio and stereoselective hydro-boronation of the ring B diene (1 18) affords (1 19) in a key step in one synthesis.12' The elaboration of the side chain from appropriately substituted pregnanes (e.g. 120) has also been U 0 (121) R = **.rq""" further examined.128 26-Iodoponasterone (121) is a very active ecdysteroid which was prepared from inoko~terone.~~~ Both the labelled iodo compound and the 26-p-azidophenylacetate have been prepared for ecdysteroid receptor studies. The acetylene (122) is an inhibitor of ecdysone biosynthe~is.'~~ A volume in the A.C.S. Symposium series contains a number of papers on the brassinosteroids including contributions on their synthesis.131 The synthesis of ring B modified brassino- steroids has attracted attention.132,133 There have been a number of reports of new approaches to the construction of the side-chain of the brassinolides.134-138 The steroids of the brassinolide and a-ecdysone series each have a hydroxyl group at the C-22 position but they differ in its stereochemistry the brassinolides are 22(R) and the a-ecdysones are 22(S). Consideration has therefore been given to developing enantio- NATURAL PRODUCT REPORTS 1993-5. R. HANSON 323 OTHP 0 0 divergent syntheses based on a Cram type addition to the C-22 aldehyde which would generate the brassinolide series and the 'anti-Cram ' addition which would form the a-ecdysone series.The cleavage of acetals has been examined in this context. Other methods involve the Sharpless chiral epoxidation or hydroxylation of alkene~.l~"l~~ In the light of anti-tumour activity of withanolide E (124) and 4P-hydroxywithanolide E some studies have been made on the modification of withanolides with an a-orientated side chain.13' 4.7 Vitamin D Syntheses in the vitamin D area and in particular of 1,25- dihydroxyvitamin D, have attracted a great deal of attention in the light of its role in the regulation of cell differentiation and proliferation as well as calcium balance. Radical methods140 for the formation of ring A and various improvements to existing methodology for the introduction of the C-1 substituent have been re~0rted.l~~.142 A number of routes have been described to vitamin D rnetabolite~'~~ and to its analogues144 including 23- oxa analogues,145 homologues 146 and aromatic side chain ana10gues.l~' Strategies based on cleaving the ring A from the C/D portion separately modifying them and then recombining the fragments have been developed.148 The effect of ring size and substituents on the provitamin D-vitamin D equilibrium has been examined. 14' The synthesis and thermal rearrangement of the 7(Z)-isomer of vitamin D has been reported. 150 4.8 Inhibitors of Steroid Metabolism Mechanistic studies on a placental aromatase model (124) have suggested151 that its conversion by hydrogen peroxide to an estrogen involves a 19-hydroperoxyhemiacetal.The substrate was prepared from 19-hydroxydehydroisoandrosterone.A number of 19-substituted androst-4-enes (e.g.125) have been HC Some aldosterone antagonists including the 6,6-ethylene- 15,16-methylene- 17-spirolactone (127)155 and some 18-sub-stituted androst-4-en-3-ones (e.g.1 28)156 have been synthesized. 4.9 Miscellaneous Partial Syntheses A novel approach to digitoxigenin from 3P-acetoxyandrost-5- en- 17-one included15' the stereoselective free radical substi- tution of a C-17 iodide by a nitrile as a key step. A biogenetic synthesis of halosterol from desmosterol has been reported. 158 The synthesis of some metabolites of norethidrone have been re~0rded.l~~ The conversion of testosterone acetate to the unusual salamander alkaloid samanine (1 29) has been de- scribed.5 References 1 'Dictionary of Steroids' R. A. Hill D. N. Kirk H. L. J. Makin and G. M. Murphy Chapman and Hall London 1991. 2 'Handbook of Natural Products Data Vol. 1 Diterpenoid and Steroidal Alkaloids ' ed. Atta-ur-Rahman Elsevier Amsterdam 1991. 3 D. N. Kirk and H. C. Toms Steroids 1991 56 195. 4 U. R. Desai and G. K. Trivedi J. Org. Chem. 1991 56 4625. 5 U. R. Desai and G. K. Trivedi Magn. Reson. Chem. 1991 29 148. 6 M. Budesinsky A. Kasal Z. Prochazka K. T. Huynh S. Vasikova and P. Kocovsky Collect. Czech. Chem. Commun. 1991 56 1512. 7 M. S. Maier A. M. Seldes and E. G. Gros Magn. Reson. Chem. 1991 29 137. 8 U. Wollborn and D. Leibfritz Liebigs Ann. Chem. 1991 1237. 9 G.P. Sutton L. S. Anker and P. C. Jurs Anal. Chem. 1991 63 443. 10 D. Doller and E. G. Gros Steroids 1991 56 168. 11 P. E. Hammann H. Kluge and G. G. Habermehl Magn. Reson. Chem. 1991 29 133. 12 E. C. Blossey W. T. Ford and M. Periyasamy Magn. Reson. Chem. 1991 29 190. prepared as inhibitors of human placental aromata~e.~~~* 13 D. Colombo F. Ronchetti G. Russo and L. Toma J. Chem. 153 SOC. Perkin Trans. I 1991 962. The inhibition of aromatase by homologated 19-oxiranyl and 14 A. E. Aliev and R. G. Kostyanovski Zh. Org. Khim. 1991 27, 19-thiiranyl steroids (e.g. 126) has been ~ep0rted.I~~ The 214. thiiranes were more potent and the activity depended on the 15 D. W. Hughes A. D. Bain and V. J. Robinson Magn. Reson. stereochemistry of the sulfur.Chem. 1991 29 387. 16 D. G. Reid L. K. MacLashlan K. E. Suckling A. Gee S. Cresswell and C. J. Suckling Lipids 1991 58 175. 17 W. G. Wu and L. M. Chi J. Am. Chem. Soc. 1991 113 4683. 18 S. Banerjee U. R. Desai and G. K. Trivedi Synth. Commun. 1991 21 757. 19 H. Takagi K. Kamatsu and I. Yoshizawa Steroids 1991 56 173. 20 G. Schneider L. Hackler J. Szanyi and P. Sohar J. Chem. Soc. Perkin Trans. 1 1991 37. 21 M. Nagaoka Y. Kunitama and M. Numazawa J. Org. Chem. 1991 56 334. 22 A. Kasal J. Podlaha and J. Zajicek Collect. Czech. Chem. Commun. 1991 56 1070. 23 L. Lorenc M. Rajkovic A. Milovanovic M. Bjelakovic and M. L. Mihailovic J. Serb. Chem. Soc. 1991 56 691 (Chem. Abstr. 1992 116 194669). 24 G. M. Singhal S. S.Zaman and R. P. Sharma Chem. Ind. (London) 1991 687. 25 N. Flaih J. R. Hanson and P. B. Hitchcock J. Chem. Soc. Perkin Trans. 1 1991 1085. 26 N. Flaih J. R. Hanson and P. B. Hitchcock J. Chem. Soc. Perkin Trans. 1 1991 2177. 27 N. Flaih J. R. Hanson P. B. Hitchcock and V. Thangavelu J. Chem. SOC. Perkin Trans. I 1991 1497. 28 K. Takahashi Y. Yamaguchi and A. Hayashi Acta Crystallogr. Sect. C 1991 47 2581. 29 D. H. R. Barton R. M. Hesse S. D. Lindell and M. M. Pechet J. Chem. Soc. Perkin Trans. 1 1991 2845. 30 D. H. R. Barton R. M. Hesse S. D. Lindell and M. M. Pechet J. Chem. SOC. Perkin Trans. 1 1991 2855. 31 Shafiullah P. R. Dun R. C. Srimal and S. A. Ansari Steroids 1991 56 562. 32 Shafiullah I. H. Siddiqui and S. A. Ansari Indian J.Chem. Sect. B 1991 30 1058. 33 H. Kuenzer M. Stahnke G. Sauer and R. Wiechert Tetrahedron Lett. 1991 32 1949. 34 C. L. L. Chai V. Humpbreys K. Prout and G. Lowe J. Chem. SOC. Chem. Commun. 1991 1597. 35 J. M. Hawkins S. D. Loren and Y. K. Kim Tetrahedron Lett. 1991 32 1635. 36 B. A. Marples J. P. Muxworthy and K. H. Baggaley Tetrahedron Lett. 1991 32 533. 37 M. S. Ahmad and T. M. Ayad Indian J. Chem. Sect. B. 1991,30 763. 38 Shafiullah S. A. Ansari and I. H. Siddiqui Indian J. Chem. Sect B 1991 30 702. 39 H. Kuenzer G. Sauer and R. Wiechert Tetrahedron Lett. 1991 32 743. 40 H. Kuenzer G. Sauer and R. Wiechert Tetrahedron Lett. 1991 32 3673. 41 K. Mikami T. P. Loh and T. Nakai J. Chem. Soc. Chem. Commun. 1991 77.42 K. Blaszczyk E. Tykarska and Z. Paryzek J. Chem. Soc. Perkin Trans. 2 1991 257. 43 R. Prousa and B. Schoenecker J. Prakt. Chem. 1991 333 775. 44 Shamsuzzaman S. Ahmad B. Z. Khan and Shafiullah J. Org. Chem. 1991 56 1936. 45 M. J. S. Moreno M. L. Melo and A. S. Campos-Neves Tetra-hedron Lett. 1991 32 3201. 46 M. Tavares R. Ramasseul J. C. Marchon and M. Maumy Catalyst Lett. 1991 8 245. 47 J. R. Hanson and V. Thangavelu J. Chem. Res. (S) 1991 280. 48 U. R. Desai M. H. A. Baig and G. K. Trivedi Indian J. Chem. Sect. B 1991 30 1085. 49 J. R. Bull and K. Bischofberger J. Chem. SOC. Perkin Trans. I 1991 2859. 50 J. R. Bull and L. M. Steer Tetrahedron 1991 47 7377. 51 J. R. Bull and R. I. Thomson S. Afr. J. Chem. 1991 44 87 (Chem.Abstr. 1991 116 21 307). 52 F. Urbanes J. Fernandez-Baeza and B. Chaudret J. Chem. Soc. Chem. Commun. 1991 1739. 53 D. Vichard M. Gruselle H. El Amouri and G. Jaouen J. Chem. Soc. Chem. Commun. 1991 46. 54 H. Ali and J. E. Van Lier J. Chem. Soc. Perkin Trans. 1 1991 269. 55 P. C.Bulman-Page F. Hussain N. M. Bonham P. Morgan J. L. Maggs and B. K. Park Tetrahedron 1991 47 2871. 56 Z. Szendi G. Dombi and I. Vincze Steroids 1991 56 392. 57 A. Guy J. Dousset and M. Lemaire Synthesis 1991 460. NATURAL PRODUCT REPORTS 1993 58 D. Van Leuson and A. M. Van Leusen Recl. Trav. Chim. Pays- Bas 1991 110 393. 59 D. Van Leusen and A. M. Van Leusen Synthesis 1991 531. 60 V. Pouzar H. Chodounska I. Cerny and P. Drasar Collect. Czech.Chem. Commun. 1991 56 2906. 61 Z. Szendi and F. Sweet Steroids 1991 56 458. 62 A. M. Bellini E. Mencini M. P. Quaglio M. Guarneri and A. Fino Steroids 1991 56 395. 63 S. Miyairi T. Ichikawa and T. Nambara Steroids 1991,56 361. 64 J. Fajkos V. Pouzar and K. Veres Collect. Czech. Chem. Commun. 1991 56 1087. 65 J. Fajkos and V. Pouzar Collect. Czech. Chem. Commun. 1991 56 2884. 66 J. W. Morzycki and J. Obidzinska Can. J. Chem. 1991 69 790. 67 W. Rank Tetrahedron Lett. 1991 32 5353. 68 W. L. Daux and J. F. Griffin Chirality 1991 3 71. 69 E. Keinan M. Sahai and R. Shvily Synthesis 1991 641. 70 A. M. Turuta A. V. Kamernitskii N. E. Voishvillo N. V. Dzhlantiashvili A. P. Krymov and N. V. Domrachev Mendeleev Commun. 1991 113. 71 B.Zheng and R. M. Pollack J. Am. Chem. Soc. 1991,113 3838. 72 E. Glotter and M. Mendelovici J. Chem. Res. (S) 1991 214. 73 T. Terasawa and T. Okada Synth. Commun. 1991 21 307. 74 D. H. R. Barton and D. Doller Collect. Czech. Chem. Commun. 1991 56 984. 75 N. Ravasio and M. Rossi J. Org. Chem. 1991 56 4329. 76 M. S. Ahmed and F. El. Ebbar Indian J. Chem. Sect. B 1991,30 658. 77 A. Abad C. Agullo M. Arno A. C. Cunat and R. J. Zaragoza SYNLETT. 1991 787. 78 A. B. Turner and P. T. Van Leersum Chem. Ind. (London) 1991 52. 79 A. Arcadi S. Cacchi M. Delmastro and F. Marinella SYNLETT. 1991 409. 80 R. Skoda-Foldes L. Kollar B. Heil G. Galik Z. Tuba and A. Arcadi Tetrahedron Asymmetry 1991 2 633. 81 A. Arcadi E. Bernocchi S. Cacchi and F.Marinelli Tetrahedron 1991 47 1525. 82 S. Ino H. Oinuma R. Yamakado M. Morisaki Y. Furukawa and T. Hata Chem. Pharm. Bull. (Japan) 1991 39 3335. 83 D. De M. Selh and A. P. Bhaduri Steroids 1991 56 189. 84 J. Ames and B. Castro Bull. Soc. Chim. (France) 1991 550. 85 Z. Paryzek and J. Martynow J. Chem. SOC. Perkin Trans. I 1991 243. 86 G. Neef and G. Michl Tetrahedron Lett. 1991 32 5071. 87 D. Wiedenfeld and R. Breslow J. Am. Chem. Soc. 1991 113 8977. 88 T. L. Stuk P. A. Grieco and M. M. Marsh J. Org. Chem. 1991 56 2957. 89 H. Suginome M. Takemura N. Shimoyama and K. Orito J. Chem. Soc. Perkin Trans. 1 1991 2721. 90 A. A. Frimer S. Ripstos V. Marks G. Aljadeff J. Hameiri-Buch and P. Gilinsky-Sharon Tetrahedron 1991 47 836 1.91 C. Malet A. Planas C. Brosa J. F. Piniella and J. Rius Helv. Chim. Actu 1991 74 1412. 92 M. T. Arenciba R. Freire A. Perales M. S. Rodriguez and E. Suarez J. Chem. Soc. Perkin Trans. I 1991 3349. 93 L. B. Lorenc I. 0.Juranic M. M. Dabovic and M. L. Mihailovic Tetrahedron 1991 47 6389. 94 L. Lorenc V. Pavlovic M. L. Mihailovic J. Kalvoda and H. Fuhrer Helv. Chim. Acta 1991 74 1459. 95 W. M. Mok and N. R. Krieger Steroids 1991 56 544. 96 M. H. Rabinowitz Tetrahedron Lett. 1991 32 6081. 97 L. Linberg J. Z. Wang B. H. Arison and S. Ulick J. Steroid Biochem. 1991 38 351. 98 M. Salman and G. C. Chamness J. Med. Chem. 1991 34 1019. 99 H. Ali J. Rousseau M. A. Ghaffari and J. E. Van Lier J. Med. Chem. 1991 34 854. 100 G. M. Caballero and E.G. Gros J. Labelled Compd. Radiopharm. I99 1 29 805. 101 F. Dolle C. Hetru J. P. Rowel B. Rousseau F. Sobrio B. Luu and J. A. Hoffmann Tetrahedron 1991 47 7067. 102 H. Ali and J. E. Van Lier J. Chem. Soc. Perkin Trans. 1 1991 248 5. 103 D. Poirier C. Labrie Y. Merand and F. Labrie J. Steroid Biochem. 1991 38 759. 104 S. Chen G. Luo X. Chang and H. Zhao Steroids 1991 56 533. 105 M. Salman B. R. Reddy P. Delgado P. L. Stotter L. C.Fulcher and G. C. Chamness Steroids 1991 56 375. NATURAL PRODUCT REPORTS 1993-J. R. HANSON 106 D. A. Holt H. J. Oh M. A. Levy and B. W. Metcalf Steroids 1991 56 4. 107 V. Kumar S. J. Daum M. R. Bell M. A. Alexander R. G. Christiansen J. H. Ackerman M. E. Krolski G. M. Pilling and J.L. Herrmann Tetrahedron 1991 47,5099. 108 J. Polman and A. Kasal J. Chem. SOC. Perkin Trans. 1 1991 127. 109 H. Faraj A. Aumelas M. Claire A. Rondot and G. Auzov Steroids 1991 56 558. 1 10 H. Faraj A. Aumelas and G. Auzov J. Chem. Res. (9,1991,263. 11 I A. M. Turuta A. V. Kamernitskii D. H. Lu and T. M. Fadeeva Izv. Akad. Nauk. SSSR Ser. Khim. 1991 1180 (Chem. Abstr. 1991 115 114860). 112 A. M. Turuta T. M. Fadeeva and M. V. Kamernitskii Izv. Akad. Nauk. SSSR Ser. Khim. 1991 1709. 113 J. F. Templeton Y. Ling J. Jin M. A. Boehmer T. H. Zeglam and F. S. La Bella J. Chem. SOC. Perkin Trans. 1 1991 823. 114 J. Polman and A. Kasal Collect. Czech. Chem. Commun. 1991 56 2892. 115 H. Ueno A. Maruyama M. Miyake E. Nakao K. Nakao K. Umezu and I.Nitta J. Med. Chem. 1991 34,2468. 116 D. J. Hart and R. Krishnamurthy SYNLETT. 1991 412. I17 H. Hosoda K. Osanai and T. Nambara Chem. Pharm. Bull. (Japan) 1991 39,3283. 118 U. R. Desai and G. K. Trivedi Steroids 1991 56 185. 119 A. Kasal J. Pokorna and J. Zajicek Collect. Czech. Chem. Commun. 1991 56 1340. 120 S. Lopez and S. S. Simons J. Med. Chem. 1991 34 1762. 121 T. Iida T. Tamaru F. C. Chang J. Goto and T. Nambara J. Lipid. Res. 1991 32,649. 122 D. Medakovic D. Miljkovic and T. Hranisarljevic Croat. Chim. Acta 1991 64 59. 123 T. Iida I. Komatsubara F. C. Chang J. Goto and T. Nambara Steroids 1991 56 114. 124 R. P. Bonar-Law and J. K. M. Sanders J. Chem. SOC. Chem. Commun. 1991 574. 125 A. P. Davis M. G. Orchard A.M. Z. Slawin and D. J. Williams J. Chem. SOC. Chem. Commun. 1991 612. 126 K. Miki N. Kasai M. Shibikami K. Takemoto and M. Miyata J. Chem. SOC. Chem. Commun. 1991 1757. 127 F. Dolle C. Hetru and B. Luu Tetrahedron 1991 47,7059. 128 U. Hedtmann R. Klintz K. Hobert J. Frelek I. Vlakhov and P. Welzel Tetrahedron 1991 47,3753. 129 S.S. Lee K. Nakanishi and P. Cherbas J. Chem. SOC. Chem. Commun. 1991 51. 130 A. Mauvais C. Hetru and Luu-Bang Tetrahedron Lett. 1991,32 5171. 131 A. C. S. Symposium Series 1991 vol. 474. 132 N. V. Kovganko and T. N. Netesova Zh. Org. Khim. 1991 27 100. 133 N. V. Kovganko and S. K. Ananich Zh. Org. Khim. 1991 27 103. 134 W. Zhou and Z. Shen Chin. Chem. Lett. 1991 2 111 (Chem. Abstr. 1991 115 114880).135 Y. Yamamoto H. Abe S. Nishii and J. Yamada J. Chem. SOC. Perkin Trans. I 1991 3253. 136 T. G. Back P. G. Blazecka and M. V. Krishna Tetrahedron Lett. 1991 32 4817. 137 W. Zhou L. Huang L. Sun and X. Pan Tetrahedron Lett. 1991 32,6745. 138 L. Sun W. Zhou and X. Pan Tetrahedron Asymmetry 1991 2 973. 139 E. Glotter S. Kumar M. Sahai A. Goldman I. Kirson and M. Mendelovia J. Chem. SOC. Perkin Trans. 1 1991 739. 140 D. Batty and D. Crich J. Chem. SOC. Perkin Trans. 1 1991,2894. 141 S. S. Toh T. L. Ngiam L. S. C. Wan and S. L. Leung Steroids 1991 56 30. 142 W. Nerinck P. J. De Clerq C. Couwenhoven W. R. Overbeek and S. J. Halkes Tetrahedron 1991 47,9419. 143 J. L. Mascarenas J. Perez-Sestelo L. Castedo and A. Mourino Tetrahedron Lett.1991 32,28 13. 144 M. Kabat J. Kiegiel N. Cohen K. Toth P. M. Wovkulich and M. R. Uskokovic Tetrahedron Lett. 1991 32,2343. 145 G.Neef and A. Steinmeyer Tetrahedron Lett. 1991 32,5073. 146 M. Chodynski and A. Kutner Steroids 1991 56 31 1. 147 B. Figadere A. W. Norman H. L. Henry H. P. Koeffler J. Y. Zhou and W. H. Okamura J. Med. Chem. 1991 34,2452. 148 J. Kiegiel P. M. Wovkulich and M. R. Uskokovic Tetrahedron Lett. 1991 32,6057. 149 J. D. Enas G. Y. Shen and W. H. Okamura J. Am. Chem. Soc. 1991 113 3873. 150 M. A. Maestro F. J. Sardina L. Castedo and A. Mourino J. Org. Chem. 1991 56 3582. 151 P. A. Cole and C. H. Robinson J. Am. Chem. Soc. 1991 113 8 130. 152 M. Numazawa A. Mutsumi K. Hoshi M. Oshibe E. Ishikawa and H.Kigawa J. Med. Chem. 1991 34,2496. 153 J. P. Burkhart N. P. Peet C. L. Wright and J. O’Neal Johnston J. Med. Chem. 1991 34 1748. 154 W. E. Childers J. V. Silverton J. T. Kellis L. E. Vickery and C. H. Robinson J. Med. Chem. 1991 34 1344. 155 K. Nickisch S. Beier D. Bittler W. Elger H. Laurent W. Losert Y. Nishino E. Schillinger and R. Wiechert J. Med. Chem. 1991 34 2464. 156 A. Viger S. Coustal P. Schambel and A. Marquet Tetrahedron 1991 47,7309. 157 A. R. Daniewski M. M. Kabat M. Masnyk W. Wojciechowska and J. Wicha Collect. Czech. Chem. Commun. 1991 56 1064. 158 K. Maruoka R. Bureau and H. Yamamoto SYNLETT. 1991 363. 159 S. W. Curts D. L. Wren and G. F. Cooper Steroids 1991 56 8. 160 W. A. Cristofoli and M. Benn J. Chem.Soc. Perkin Trans. 1 ” 1991 1825. NPR 10

ISSN:0265-0568    

DOI:10.1039/NP9931000313

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Advances in Chemical Ecology J. B. Harborne Plant Science Laboratories University of Reading Reading RG6 2AS ~~ Reviewing the literature published between January 1988 and June 1992 (Continuing the coverage of literature of Natural Product Reports 1989 Vol. 6 p. 85) 1 Introduction 2 Animal-Animal Interactions 2.1 Animal Toxins of Plant Origin 2.1.1 Evolutionary Origin of Toxin Sequestration 2.1.2 Alkaloids 2.1.3 Iridoids 2.1.4 Other Secondary Metabolites 2.2 Chemical Defence in Animals 2.3 Pheromones 3 Plant-Animal Interactions 3.1 Constitutive Chemical Defence 3.1.1 Phenolics and Tannins 3.1.2 Terpenoids 3.1.3 Alkaloids 3.1.4 Glucosinolates 3.1.5 Furanocoumarins 3.1.6 Plant Lectins 3.1.7 Cyanogenic Glycosides 3.1.8 The Cost of Chemical Defence 3.2 Induced Chemical Defence 3.3 Hormonal Interactions 3.4 Insect Antifeedants 3.5 Oviposition Stimulants and Deterrents 4 Plant-Plant Interactions 4.1 Allelopathic Agents 4.2 Plant-Parasite Interactions 5 Plant-Microbe Interactions 5.1 Mycotoxins 5.2 Phytotoxins 5.3 Constitutive Antimicrobial Defence 5.4 The Phytoalexin Response 6 References 1 Introduction Most research in chemical ecology continues to be devoted to well worn themes providing further details of pheromone mixtures in insects or discovering new examples of the sequestration and storage of plant toxins.Philosophical aspects of coevolution have received considerable attention. Ecologists have stressed the importance of studying plant-animal inter-actions at the tritrophic level e.g. a plant feeding attractant may also attract an insect parasitoid to the site of feeding so that the plant chemical might eventually be deleterious to that insect's survival. Many experiments have been conducted to see whether herbivory can induce chemical changes in plants and a book of essays has appeared on this t0pic.l Certain plant and animal species have received more than their fair share of attention in recent years. Thus papers on the feeding behaviour of the snowshoe hare Lepidus americanus continue to appear very regularly (see section 3.1).Leaves of poplar and other Populus species are frequently being chosen for herbivory experiments but this is partly related to the relatively rapid rate of growth of these trees. Another advantage is that their toxins are largely phenolic in character and are thus easily monitored ;the number of chemical structures present in the leaf is also relatively small. 327 In plant-microbe interactions most developments have concerned macromolecules and much of the research falls into the category of plant molecular biology. However a number of interesting new phytoalexins have been characterized and research on phytotoxins continues to reveal new structures capable of extensively damaging plant systems (see section 5.2). A new journal devoted to the chemistry of plant-animal interactions has been started.2 A book on plant-ant interactions has appeared3 and at least two on plant-insect relationship^.^.A major text on the chemistry of herbivore feeding has now appeared in a second edition in two volumes.6 The first book on the chemoecology of plant-mammalian interactions has been published.' The ecological biochemistry of terpenoids has been reviewed.8 Other new books and review articles will be mentioned under specific topics. 2 Ani ma I-An imal Interactions 2.1 Animal Toxins of Plant Origin 2.1.1 Evolutionary Origin of Toxin Sequestration The origin of sequestration of secondary metabolites has been explored by Jones et al.' by restricting the diet of a generalist herbivore.They chose the lubber grasshopper Romafeaguttata which normally feeds widely on many herbaceous species. Its metathoracic defence secretion is based on p-benzoquinone hydroquinone phenol and catechol synthesized within its body. When it was made to feed only on wild onion Aflium canadense this grasshopper sequestered sulfur volatiles and stored them in the defensive secretion. Included were isopropyl sulfide isopropyl disulfide propane thiol and 2,Sdimethyl- thiophene. These novel defensive secretions were significantly more deterrent by an order of magnitude to two species of ant predators despite a reduction in the concentration of the phenolic defense agents. Thus sequestration of plant chemicals can increase defensive efficacy when diet breadth is reduced.This model experiment may explain how under conditions of specialization a proportion of insect herbivores develop the ability to sequester and store bioactive plant chemicals. Such a process does not necessarily require specific adaptation in the insect or even coevolution with a toxic host plant. A further experimentlo was carried out in which the same grasshopper was left to feed exclusively on catnip Nepeta cataria. There were no obvious adverse effects of this enforced monophagy. Furthermore the grasshopper now sequestered terpenoid lactones characteristic of catnip or their metabolites. Again the defensive secretions became more repellent but in this instance the production of phenols and quinones remained unchanged. Thus the synthesis of phenols and quinones in the animal body was not depressed as occurred in the wild onion feeding experiment.An important new discovery has been made about the site of storage of the toxic cardiac glycosides of dietary origin in the adult monarch butterflies Danaus p1exippus.l' There is up to a 15-fold higher concentration in the cuticle than in the body tissues of the insect and about half the toxin is present in the wings. While this pattern of storage allows the insect to avoid self-poisoning it also means it is more vulnerable to predation especially when the predator is able to selectively feed on the different body tissues. Earlier experiments have shown that in the winter resting sites in Mexico the monarch butterfly is predated upon by two of about 37 local bird species namely the black-headed grosbeak Pheucticus melanocephalus and the black- backed oriole Zcterus galbula abeillei.l2New experiments now show that some of the local mouse species are also able to adapt to feed on these otherwise very poisonous butterflies. At this stage in the life cycle the butterflies have considerable amounts of lipids stored in their bodies so this makes them a particularly valuable food so~rce.'~ Again only one of three common mouse species Peromyscus melanotis eat the How it is able to cope with the poison present is not yet clear but it does have the ability to reject the cardiac glycoside laden cuticular tissues. Also artificial diet experiments with two other mouse species which do not feed on the butterflies showed that rejection was based mainly on the bitter taste of the cardenolides.Up to now most analyses of cardiac glycosides in monarchs and their food plants have been carried out by TLC see for example Ref. 11. A rapid quantitative HPLC system has now been developed and applied to Asclepias fruticosa and the butterflies feeding on it. The method employs a C, reversed phase column with an acetonitrile-water gradient solvent mixture and ultraviolet detection at 220 nm.15 The ability to sequester and store cardiac glycosides is present in many Danaus species and includes the queen butterfly Danaus gilippus. One of the classic examples of Batesian mimicry is the viceroy butterfly which mimics the colour and pattern of the poisonous queen butterfly and yet escapes predation although it is supposedly palatable.Recent experiments on these butterflies indicate that the roles of model and mimic may have to be reversed in some instances. Thus the queen butterfly in Florida feeds on the asclepiadaceous vine Sarcostemma clausum which is a very poor source of cardenolide. Furthermore the queens reared on this diet lack cardenolide and were eaten by red-winged blackbirds. Wild- caught queens which had access in the adult state to pyrrolizidine alkaloids were also relatively palatable and were again eaten although in smaller numbers. By contrast the apparently innocuous viceroy butterfly has been found to be moderately unpalatable in fact more so than the queens.It is possible that these queen butterflies in Florida may be 'automimics 'of populations feeding on high-cardenolide larval food plants e.g. A. curassavica and which are protected by cardenolides.l6 2.1.2 Alkaloids The pyrrolizidines were the first group of plant alkaloids to be found in insects; their role is at least twofold as defences against predators and in the Lepidoptera as precursors for male pheromone production. A well-known example is the cinnabar moth Tyria jacobaeae which feed on ragwort Senecio jacobaea and related plants and stores the plant alkaloids in its tissues for protection against birds. Another specialist insect feeding on ragwort is the aphid Aphis jacobaeae and Witte et ~1.'~ have discovered not only that this aphid can protect itself by absorbing the pyrrolizidine alkaloid as the N-oxide from the phloem but also that ladybirds (Coccinella septempunctata) feeding on these aphids also contain these alkaloids.Thus the alkaloids are passed along the food chain protecting in turn two successive consumers from predators. The up to eight alkaloids present in ragwort e.g. senecionine (l) are taken up unchanged by the aphid and the ladybird the relative proportions remaining approximately the same. The amounts of alkaloids stored by the aphid ranged from 0.8 to 3.5 mg g-' fresh weight and by the ladybird from 0.3 to 4.9 mg 8-l fresh weight. Ladybirds do have their own alkaloids (coccinellines) as deterrents at levels of 10.5 mg 8-l fresh weight so that the pyrrolizidines can make a significant additional contribution to the ladybird defence system.The concentrations of pyrrolizidine alkaloids in ragwort natural populations may vary ten-fold and this variation can be related to whether the plants are defended NATURAL PRODUCT REPORTS 1993 0 (3) (4) by ants Lasius niger or not. Ants defend aphid-infested plants from the cinnabar moth larvae and such plants have significantly lower pyrrolizidine alkaloid content than other- wise.l8 Whereas the aphid is a passive feeder on the ragwort taking in the alkaloids in the phloem as they occur in the plant the larvae of the cinnabar moth actually process the alkaloids before storage. Like the plants the insects store the alkaloids as N-oxides and it is clear that the larvae as well as the pupae are able to N-oxidize any tertiary pyrrolizidine.Furthermore Emke et al.19 have found that the larvae hydrolyse esters of retronecine present in the diet and re-esterify with a necic acid produced by the insect. Hence callimorphine (2) and isocallimorphine (3) make up some 45% of the total pyrrolizidine alkaloids found in the cinnabar moth. This transformation was confirmed by feeding the larvae with [14C]retronecine and isolating [14C]callimorphine N-oxide from the pupae. This ability to modify dietary alkaloids extends to other arctiid moths. Thus it occurs in the moth Creanotos transiens which feeds on Gynura scandens in the Compositae.20 Here the re-esterification takes place on retronecine mainly with (2S,3S)-2-hydroxy-3-methylpentanoicacid with the production of creatonotine although some callimorphine is also made.The time course of the transformation in C. transiens has been monitored and it has been shown to take place within 48 hours of feeding.21 In the female adult some 50-80 YOof the alkaloid is transferred to the eggs while in the male 10.3 YOis transferred to the scent organ the coremata and converted to the male pheromone 7(R)-hydroxydanaidal (4). There is also circum- stantial evidence that the arctiid moth Gnophaela latipennis when it feeds in the larval stage on the borage plant Hackelia californica also processes its dietary alkaloids since callimorphine is tk major alkaloid of the insect whereas other retronecine esters occur in the food plant.22 The moth Utetheisa ornatrix obtains its protective pyrrolizidine alkaloids from a legume host plant Crotalaria rather than from a borage or a Composite.Otherwise this insect is similar to Creanotos in using the alkaloid to protect the eggs as well as the larvae pupae and imagines. In laboratory cultivation the larvae can cannibalize their own eggs par- ticularly if they are deficient of alkaloid. They choose alkaloid- laden rather than alkaloid-free eggs. Thus an egg with high alkaloid content will be protected from predation but will also be more vulnerable to cannibalism. Under natural conditions cannibalism is probably opportunistic rather than a regular event. Nevertheless the alkaloids such as monocrotaline are a NATURAL PRODUCT REPORTS 1993-5.B. HARBORNE 329 OH OH (5) (7) phagostimulant to the larvae at the very low concentration of 10-4 yo.23 Evolutionary aspects of the sequestration and utilization of pyrrolizidine alkaloids by Lepidoptera have been explored by Brown and Fran~ini.~~ They propose that the storage or processing of larval-derived alkaloid is widespread and primi- tive; the use of defensive alkaloids only in the adult stage is intermediate; and the rejection of plant toxin and de novo synthesis of protective chemicals the most advanced feature. They support this hypothesis with reference to the American Composite-feeding Acraeinae butterflies which absorb pyrrolizidine alkaloids from nectars mainly for pheromone synthesis but do not take up alkaloids in the larval stage.These authors show that two genera of these butterflies Actinote and Altinote are cyanogenic by de novo synthesis and not from dietary feeding. The first report of pyrrolizidine alkaloids in the defensive glands of a leaf-feeding beetle has appeared.z5 This is in the chrysomelid beetle Oreana cacaliae which sequesters N-oxides from its food plants Adenostyles alliariae and Senecio fuchsii. An average of 11.4 % of total radioactivity was taken up by beetles receiving [14C]senecionine N-oxide with their food eight days before. An average of 29% of the ingested radioactivity was recovered from the defensive secretions at eight days but the transfer from the body to the glands seems to take some time since more 14Cremained in the body at this time.A second species 0. speciosissima feeding on the same food plant as 0. cacaliae also took up radioactive alkaloid with the same efficiency. Neither species however had the ability to take in the free alkaloid instead of the N-oxide or move it into the defensive gland. A third species 0.bqrons which specializes on Chaerophyllum hirsutum (Umbelliferae) by contrast rejected leaf samples treated with low pyrrolizidine alkaloid con-centrations. A second group of plant alkaloids known to be sequestered from food plants by insects are the quinolizidine alkaloids such as cytisine and sparteine. Larvae of the pyralid moth Uresiphitu reversalis sequester such quinolizidine alkaloids from their legume host plant Genista monspessulana and store it in their cuticle which contains up to 2.5YOdry weight in the last larval instar.This alkaloid protection is reinforced by warning colouration. Experiments in which the innocuous larvae of the potato tuber moth Phthorimaea operculella were artificially treated with surface extracts of U. reversalis or with pure alkaloid solutions confirmed the protective value of alkaloid storage at the surface against an ant and a wasp predator.26 It is advantageous for larvae to store toxin in the cuticle since this avoids problems of toxicity within the animal body. It means that relatively small amounts of toxin are needed and that toxicity is immediately apparent to the predator. Such a system operates in other Lepidoptera which store plant toxins e.g.in the monarch larvae which contain cardiac glycosides (see above) and in the larvae of Zygaena trifolii which have been shown to store cyanogenic glycosides in cuticular cavitie~.~' Work on the sequestration by insects of two other groups of plant alkaloid the pyrrolidines and the pyrazines deserves brief mention. Adults pupae and eggs of the neotropical moth Urania fulgens contain a-homonojirimycin (5) and 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (6) sequestered from the larval food plant Omphalea diandra (Euphorbiaceae). Adult males contained about ten times the level (as a percentage dry weight of alkaloid present) in the food plant so that the concentration present does appear to provide protection from insect-feeding birds.Both the nocturnal cryptically coloured uraniine moth Lyssa macleayi and the diurnal aposematic Alcides metaurus accumulate (5) and (6) from their respective Euphorbiaceous food plants so that the expected correlation between toxicity and aposematism is not complete among these insects.29 Sequestration of 2-methoxy-3-alkylpyrazines,e.g. (7) by insects from food plants has been surveyed by GC-MS.30 Positive results were obtained for 58 YOof adult aposematic insect species 33% of aposematic mimics 42 % qf host plants and 44% of well known toxic plants screened. These data indicate that aposematic and phytophagous insects probably sequester the pyrazines from their host plants whereas predating species manufacture them de novo.The main function of these pyrazines is as alerting signals which warn predators off since most pyrazine-containing insects have other toxins as well. 2.1.3 Iridoids The sequestration of iridoids by insects has been re~iewed~l-~~ and several listing further insect species able to sequester and store these bitter plant toxins have appeared. According to Rim~ler,~~ at least 10 species from 3 Lepidopteran families as well as aphids leaf beetles flies and grasshoppers have been shown to contain plant-derived iridoids. As a result of recent experiments it is apparent that iridoids can undergo processing by the sequestering insects as do pyrrolizidine alkaloids (see above). Thus the main iridoids of Besseya pluntaginea are aromatic esters of catalpol(8) but larvae of the butterfly Euphydryas anicia feeding on this plant only store catalpol.The esters must therefore undergo hydrolysis in vivo and indeed two aromatic acids (benzoic and cinnamic) were recovered from the larval fra~s.~~ There is however no indication of re-esterification as occurs with the pyrrolizidine alkaloids. The protective role of sequestered iridoids not only prevents bird attack but also attack by ants beetles and other insects. It is normally the bitter taste which repels predators but in at least one instance a volatile breakdown product methylmercaptan is repellent. Thus the Rubiaceae-feeding aphid Acyrthrosiphon niponicus is protected from the ladybird beetle Harmonia oxyridis by the iridoid paederoside (9) which occurs in the cornicle secretion to 2 % of the intact body weight.This is sequestered from the food plant Paederia scandens which contains other iridoids such as asperuloside (10) which are not sequestered. The activity against the ladybird is due to the release of the unpleasantly smelling methylmercaptan formed on hydrolysis of (9).37 NATURAL PRODUCT REPORTS 1993 kc oo (11) R’ = CHZOH R2 = H (12) R’ = H R2= CH20H 2.1.4 Other Secondary Metabolites Aliphatic lactones can now be added to the list of plant toxins sequestered by insects. Two butenolides siphonidin (1 1) and isosiphonidin (1 2) have been isolated from fifth-instar larvae of the small ermine moth Yponomenta cagnagellus.They are also present in the host plant the spindle tree Euonymus europaeus and hence are probably dietarily derived. These lactones are also present in several other related moths which do not feed on the spindle tree and in such cases would appear to be synthesized by the insect.38 The repellent taste of these ermine moths was originally thought to be due to cardenolides but they do not in fact occur in these moths. It is likely therefore that the lactones are the bitter agents repelling predators. Another new sequestered toxin is fluoroacetate CH,FCO,H which is accumulated by the larvae of the moth Sindris albimaculata which feeds on the flowers fruits and young leaves of the fluoroacetate-containing Dichapetalum cymosum. The caterpillar is protected from the toxin because it can degrade fluoracetate to fluoride and C0,.39 Yet another novel plant toxin found in the female turnip sawfly is the diterpenoid clerodendron D (13) which occurs in Clerodendrum trichotomum.It is sequestered by the female (8 ,ug per fly) is bitter tasting and presumably protective. This compound is also a feeding stimulant to the fly.40 Plant flavonoids well known to be sequestered and stored by some 10% of butterfly species have now been identified in grasshoppers. Hopkins and Ahmad41 showed that six North American species accumulate quercetin and its 3-glucoside chiefly in the wing cuticle. The concentration in the Carolina grasshopper Dissostera carolina makes up to 2% of the live weight. A fat body UDP-glucosyl transferase preferentially catalyses glucosylation at the 3-hydroxyl of quercetin and it is assumed that this flavonol is absorbed by the larvae from the food plant although this has not yet been established experimentally.The adult grasshopper Schistocerca americana has also been shown to deposit rutin in the cuticle when fed on a diet containing this flavon~id.~, How widespread the phenomenon of quercetin accumulation by grasshoppers is has yet to be determined and yet to be explained is the dietary source of quercetin since this flavonol has a restricted distribution in grasses the main food plants of grasshoppers. 2.2 Chemical Defence in Animals The first major survey of defense chemicals from abdominal glands of 13 rove beetle species of the subtribe Staphylinina has been carried out by Huth and Dettne~-;~~ 41 different volatiles were characterized.The major component in most beetles is the iridoid dialdehyde iridodial with variable amounts of iridoid lactones including nepetalactone several monoterpenoids and short chain ketones. The typical defense system of these beetles is based on a primary fixative agent (e.g. iridodial) with repellents such as the terpenes which are effective against ants. Other groups of beetle are defended by toxic quinones. A typical quinone defended beetle is Diploptera punctata a Pacific islands cockroach. It discharges a fine aerosol of p-benzo- quinone ethyl-p-benzoquinone and methyl-p-benzoquinone. A fine aerosol of these three compounds is released from a pair of tracheal glands in response to disturbance.Baldwin et ~1.~~ have examined the dynamics of benzoquinone production in this beetle with time. They appear to retain 11 YOof their lifetime total benzoquinone content even after repeated discharges. They rapidly fill their glands after moulting at the rate of 18 ,ug of quinone per day but after discharging refill at a much slower rate. Clearly this is a costly defensive system and there may be competition for precursor aromatic amino acid which is also required for cuticular production. Another beetle protected by quinones is Galeruca tanaceti a chrysomelid leaf beetle living on Tanacetum vulgare or Achillea millefolium as food plants. Hilker and Sch~lz~~ have identified two simple anthraquinones chrysophanol and chrysazin in over-wintering eggs larvae and in the ovaries and haemolymph of gravid females.These quinones are probably formed by symbiotic micro-organisms resident within the beetle body. These anthraquinones were shown to be effective defence for the eggs against predation by the ant Myrmica ruginodis. The same two anthraquinones have previously been found to protect the larvae of the unrelated elm leaf beetle Pyrrhalta luteola from predator attack.46 Ever since Wray in the 18th century showed that ants secrete formic acid for defense acid mixtures have been detected in the defensive glands of many different arthropods. The latest report is of the carotid beetle Pasimachus subsulcatus which has a concentrated solution of seven aliphatic acids making up 1 YO of the body weight.The acids were identified as methacrylic tiglic angelic isobutyric 2-methylbutyric isovaleric and sene~ioic.~’ In a single population of this largely flightless beetle the relative ratio of acids was found to be remarkably constant from individual to individual. Diterpenoid resin acids are well known defense agents of the pine sawfly caterpillar Neodiprion sertifer. These acids are secreted from the food plant and then discharged as a poisonous vapour at an ant attacker e.g. Formica polyctema. Bjorkman and Lars~on~~ have found that the Scots pine bark can vary in resin acid content from 1.5 to 5.2% dry weight. As a result caterpillars on a pine with low resin acid content are more susceptible to ant attack than those that feed on high resin acid trees.However feeding on a high concentration pine has a side effect of reducing the growth rate. Therefore the larvae have to choose between being well defended and growing slowly and lacking defense and growing more quickly. Alkaloids synthesized de novo are recognized as defense agents variously in millipedes ladybirds water beetles and fire ants. Two new alkaloids have been recognized in the venom of an Australian fire ant Monomorium sp. namely the pyrrolidines (14) and (15). These alkaloids are highly effective against termites not only by being toxic but they also cause in-stantaneous paralysis even in small doses.49 Some rare tricyclic alkaloids have been reported in the venom of a neo-guinean pseudomyrmecine ant species in the genus Tetraponera.Eight related structures tetraponerines 1-8 differing only in the nature of the side chain (e.g. 16) are present. The ant smears this mixture upon its enemies as a contact poison with deterring and toxic effects.50 2.3 Pheromones Reviews have appeared on the chemical ecology of the pheromonal systems in aphids,51 and pine bark beetles.53 As usual a variety of new pheromones have been reported during the period under consideration. They will be NATURAL PRODUCT REPORTS 1993-5. B. HARBORNE 8 OH discussed here according to whether they are involved in sex aggregation recruitment trail-laying or attack. A unique sex pheromone has been identified in the browntail moth Euproctis chrysorrhoea which feeds in the larval stage on plum and cherry leaves.It has the highest molecular weight (388) so far recorded for a sex attractant and has been identified as Z,Z,Z,Z-7,13,16,19-docosatetraen-1-01 isobutyrate. It is exceptional among Lepidopteran pheromones in having the additional isolated double bond near the ester end of the chain and it is terminated by an alcohol esterified with isobutyric An analysis of the pheromone blends of the neotropical moth Mocis megas indicates a surprisingly close similarity in chemistry in the male and female constituents. Thus the female produces 55 YO(Z,Z,Z)-3,6,9-heneicosatriene and 45 YO(2,Z)-3,6-cis-9S,10(R)-epoxyheneicosadiene,while the male produces 24 ?LOof the first compound 64YOof (2,2)-6,9-heneicosadiene and 12% of related C19 C20,and C, homologue~.~~ The production of female sex pheromones in some moths is sometimes triggered by a chemical signal from the host plant.This happens in the corn budworm Heliothis zea where the female delays reproduction until a suitable host plant is reached on which to deposit its eggs. Perception of volatile signals from the corn silk sets off the synthesis of the female sex pheromone and its subsequent release leads to mating. The triggering signal appears to be partly the presence of the ripening hormone ethylene together with some more specific corn volatile~.~~ In this connection it should be mentioned that an earlier report by Riddiford that pheromone synthesis in the polyphemous moth Antherea polyphemus is induced by the green leaf volatile trans-2-hexenal has not been confirmed by more recent ~tudies.~' The female sex pheromone in the alfalfa blotch leaf miner Agromyza frontella has been identified as 3,7-dimethylnonadecane.58 3-Day-old virgin females contain about 54ng whereas it is completely absent from the males. This compound is important for mating behaviour although the presence of the host plant is also needed. The first known sex pheromone in the family Miridae has been identified in the mullein bug Campylomma verbasci a pest of the apple crop in North America. The female releases a 16 1 mixture of butylbutyrate and (a-crotylbutyrate which comprises an effective attractant for male bugs.59 The first report of a plant nematode pheromone is of a female sex pheromone in the soyabean cyst nematode Heterodera glycines.'O The compound in vanillic acid and it required 24000 females to produce 350 ng of pheromone.It may be noted that vanillin the related aldehyde was earlier reported as a sex pheromone of the bug Eurygaster integriceps.61 A new pheromone identified in the sexual females of the damson-hop aphid Phorodon humuli,62 is closely related in structure to the vetch aphid pheromone. While the vetch aphid has a syner- gistic mixture of (-)-I(R),4a(S),7(S),7a(R)-nepetalactol and (+)-4a(S),7(5'),7a(R)-nepetalactone the damson hop aphid contains a different stereoisomer of the lactol (17) i.e. the all cis-[4a(R),7(s),7a(~]-compound.Seducin the male sex pheromone blend of the cockroach Nauphoeta cinerea has been identified as a mixture of 3-hydroxy-2-butanone 2-methylthiazolidine and 4-ethyl-2-methoxyphenol. These three compounds in the respective ratio of 4:4 1 elicit a maximal response by receptive females. This is the first male sex pheromone identified in a cockroach which attracts the females from a distance.63 33 1 kOH The presence in flies of anti-aphrodisiac pheromones (called abstinones) which are deposited on females by males during mating and turn off other males from later mating is a somewhat controversial subject since the physical masking of active sex pheromones by inactive compounds has also been proposed. Carlson and S~hlein~~ present good evidence that in the tsetse fly Glossina morsitans-morsitans such an abstinone is present.The compound turns out to be an unusual long chain alkene 19,23-dimethyltritriacont-1-ene. It is present at a concentration of 1-2 pg per male fly and is partially transferred to the female during mating. A dose-dependent anti-aphrodisiac effect was seen in exposed male flies with 2-4 pg causing 80 YO loss of copulatory attempts. A novel series of macrolide aggregation pheromones have been uncovered in cucujid grain beetles. For example the saw- toothed grain beetle Oryzaephilus surinamensis a major pest of stored products produces (Z,Z)-3,6-dodecandienolide(18) which synergizes with aliphatics e.g. (R)-1-octen-3-01 or octanol in eliciting beetle aggregati~n.~~ (E)-myrcenol(l9) is an aggregation pheromone new to bark beetles.Males of the Eurasian bark beetle Ips duplicatus when feeding on Norway spruce produce and release ipsdienol and (19) which synergize together to stimulate aggregation.66 Verbenone (20) an anti- aggregation pheromone in some Ips species has been discovered to be released from injured infested trees of Pinus sylvestris. Its odour is picked up in flight by the pine shoot beetle Tomicus piniperda which then avoids landing at that site. The natural release of verbenone from forest trees may well inhibit the attraction of host monoterpenes to these beetle A monoterpenoid related to (E)-myrcenol namely cis-isogeraniol (21) has been recognized as an important re-cruitment pheromone of the ant Leptogenys diminuta.68 While geraniol is well known to be a trail pheromone of the honey bee this is the first time that an isogeraniol derivative has been recognized as having ecological activity.Another ant species the pheromones of which have been investigated recently is the myrmicine Messor bou~ieri.~~ A trail pheromone 3-ethyl-2,5- dimethylpyrazine (22) has been identified in the poison gland of workers in a concentration of 9 ng where it occurs together with the alkaloids anabasine (3 pg per gland) and anabaseine (40 ng per gland). Trail following is elicited in this ant by the release of both this pyrazine from the poison gland and of linear alkanes from the Dufour gland secretion. Finally some account is necessary in this review of recent investigations on the pheromones of the hive bee.One notable discovery is the paralysing effect that the nest allomones of the fire bee Trigona mellicolor have on honey bees Apis mellifera. These fire bees when attacking honey bee nests release two simple diketones (@-3-heptene-2,5-dione and (@-3-nonene-2,5- dione and the honey bees remain motionless on the comb and NATURAL PRODUCT REPORTS 1993 OH (23)R = H (24) R=COPh are completely put out of action. Because of their intense distaste for these ketones it is possible they could be used to control hive bees during swarming. 70 Comparison of European and Africanized honey bees show that the more active defensive behaviour (measured in number of stings) of the latter so-called 'killer bees' is correlated with the release of larger amounts of alarm pheromone.This applies to nine of the 12 pheromonal components. For example the nonan-2-01 levels increase from 0.33 to 1.40 ,ug per bee. By contrast the major sting pheromone isopentenyl acetate does not differ in amount in the two races of bee.71 The queen mandibular pheromone which has such a central role in maintaining the dominance of the queen over the worker bees has been reinvestigated and found to contain aromatic as well as fatty acid components. The most abundant component is the well known (E)-9-keto-2-decenoic acid which occurs with the two optical isomers (R,E)-(-) and (S,E)-(+)9-hydroxy-2-decenoic acids. The two aromatic components present in minor amounts are methylp-hydroxybenzoate and 4-hydroxy-3-methoxyphenylethanol.New results on the dis- tribution of this pheromonal mixture within the colony are described.72 3 Plant-Animal Interactions 3.1 Constitutive Chemical Defence 3.1.I Phenolics and Tannins Recent research has indicated that individual low molecular weight phenols can have decidedly adverse affects on animal feeding.In particular one or more components within the phenolic mixtures present in poplar or willow leaves have been shown to be toxic or antifeedant to herbivores. Thus the two phenolic glycosides salicortin (23) and tremulacin (24) in the leaves of several Populus spp. can severely limit feeding by the gypsy moth Lymantria dispar larvae.The response is however variable within moth populations due to the fact that the larvae differ in their susceptibility to phenolic glycosides. There is variation in esterase-mediated detoxification metabolism with more effective detoxification occurring in the more successful moth population^.^^ Similar effects have also been noted in the butterfly Papilio glaucus the larvae of which feed on the quaking aspen Populus tremuloides in which tremulacin is the major toxic agent.74 Salicortin is also toxic to the larvae of the large willow beetle Phratora vulgati~sima.~~ When larvae are fed on Salix viminalis leaves (normally low in salicortin) which have been treated with 1.52% fresh weight salicortin they fail to pupate. By contrast the relatively high levels of proanthocyanidins present constitutively in S.viminalis leaves have no effect on larval performance. Salicortin varies in concentration in different SaIix spp. A measurement of its content could provide a useful indication of which species are likely to resist willow beetle attack. Yet again salicortin is a major phenolic of the Alaskan balsam poplar Populus balsamifera and Reichardt et have found that during feeding by the snowshoe hare this is hydrolysed to 6-hydroxycyclohexenone (25) which is the major antifeedant together with salicylaldehyde of the plant inter- nodes. The buds of the balsam poplar are protected from snowshoe hare by three other antifeedant compounds cineole benzyl alcohol and (+)-a-bisabolol.The avoidance of feeding on internodes and buds is probably related to the long term Me0 '0H o b CH= CHCH20COPh effects these dietary components have (e.g. antimicrobial properties) on digestion and absorption of food by the hare. Another phenolic of the quaking aspen Populus tremuloides besides salicortin is coniferylbenzoate (26) which occurs in the staminate flower buds and catkins. These tissues are a major food resource of the ruffed grouse Bonasa umbellus and (26) is a feeding deterrent in that the grouse will only feed on the quaking aspen when the levels of (26) are relatively low. The substance produces a burning sensation in the human palate and presumably this could be perceived by the grouse when the concentration in its food is above a certain Birch trees as well as aspen may be protected from browsing .~~ by phenolic constituents.Thus Sunnerheim et ~1have shown that platyphylloside (27) a major phenolic in the buds and internodes inhibits the digestion of ruminants (e.g. the goat) in vitro when present below the natural concentration (0.8 YOdry weight) in the birch. Related phenols present in the bud had no effect in this system. These authors suggest that (27) may restrict the grazing on birch by moose and hare so that they only feed on tissues other than the buds. Gymnosperm as well as angiosperm trees have protective phenolics in their tissues. The meadow vole Microtus pennsyl- vanicus reduces the phenolic toxicity of the conifers it feeds on by cutting the branches off the tree and leaving them to stand in the winter snow for two or three days before eating.During this time the phenolics and tannins reduce in concentration. For example in Picea glauca the phenolic levels drop from 2.8 to 1.5 YOdry weight and there is a 68 YOloss of tannin content.79 The choice of food plant by this vole is initially determined by the level of terpene constituents in the bark and some trees such as Pinus strobus are never grazed upon because of the high content of myrcene and bornyl acetate.80 Even elephants appear to avoid grazing on plants if the phenolic and/or tannin content is too high. Other secondary metabolites e.g. steroidal saponins and a high lignin content also may deter feeding. Jachmann" in a study of plants eaten by elephants noted that immature leaves of many species were regularly rejected.He suggests that the destructive feeding behaviour of elephants on trees represents an attempt to feed on the more palatable leaves higher up the trunk which have a lower phenolic content. Some animals may be forced to feed on plants with high phenolic content in the absence of others which are both nutritious and low in phenols. This applies to the wood rat Neotoma lepida which lives in the Mohave Desert and during the winter has only the creosote bush Larrea tridentata to provide it with food. It generally avoids the antinutritional effects of the phenolic resin in this plant by consistently feeding on low resin plants. When the rat is provided with 12% resin in an artificial diet it continues to feed but it declines in body weight and may die.Here the herbivore is making the most of a relatively unpalatable plant by selecting out the less well NATURAL PRODUCT REPORTS 1993-5. B. HARBORNE OH Meow=ph OM 0 defended members of the population. On the other hand natural selection will be operating in the plant population to increase the levels of defensive Flavonoids may occasionally protect plants from herbivory both the water soluble glycosides and the lipophilic aglycones. .~~ For example Hedin et ~1 record that the 8-rhamnoside and the 8-glucoside of gossypetin present in the flower buds of the Asiatic cotton plant Gossypium arboreum are a source of resistance to the tobacco budworm Hefiothis virescens and are toxic at concentrations as low as 0.007 and 0.024YO.Likewise Janzen et report that various prenylated flavanones e.g.(28) present in Lonchocarpus seeds are toxic to the predating mouse Liomys safvini. In captivity these mice prefer to starve rather than feed on these seeds. Other toxins including non- protein amino acids and pyrrolidine alkaloids present in the seed probably restrict Bruchid beetle feeding but have no deterrent effects whatsoever on the mice. Although low molecular weight phenolics have a role in plant defence against herbivory it is the higher molecular weight tannins which provide the most effective barrier in woody plants against animal feeding. A second edition of the standard work on vegetable tannins has appeared,s5 as well as the proceedings of an international symposium on the condensed tannims6 The best methods of analysing plant material for tannins in ecological experiments have been evaluated.87 Cork and Krockenberger" recommend aqueous acetone over aqueous ethanol for extracting tannins from Eucalyptus leaves.Peng and Jay-Allemand8' were able to improve the yield of tannin from walnut leaves by 30-75 YOby adding an antioxidant (5.5 mM ascorbic acid) to the extractant. Perhaps the most unexpected finding about tannins is the recent report that leaf-cutting ants are deterred from taking tannin-containing plants if the concentration is high enough.'O Nichols-Orians has shown that leaf material of the tropical legume Inga oerstediana is rejected if there is too much tannin present.Protein content was not correlated with acceptance nor was the protein-tannin ratio. Low tannin leaves were preferentially selected and used and it is apparent that a constitutive phenolase activity in the fungal colony of the ant is needed to inactivate the tannin of these leaves. The ability of mammals to defend themselves from the effect of dietary tannin by the manufacture in the saliva of so-called PR (proline-rich) proteins with a high affinity for tannin- binding was described in the last report.g1 A survey of mammals for PR salivary proteins has revealed their presence in marsupials namely in the koala bear for the first time.92 This survey indicated that the best defended animals are rats hares and rabbits while cows and sheep have a much more limited defence system.Even hares however can be choosy about which tannins they will ingest. Thus snowshoe hares in Alaska show a threefold preference for bitterbrush Purshia tridentata tannin compared to that of blackbrush Cofeogne ramosissima. Although both these plants belong to the same family (Rosaceae) they have procyanidins with differing stereochemistries ; in blackbrush the polymers are based on epicatechin units while in bitterbrush they are based on a one to one ratio of catechin and epicatechin units. The deterrent effect on feeding is probably not a direct one but related to the adverse affects of flavans liberated in the gut following ingestion and depolymerization of the tannin^.'^ Fish appear to be unprotected against angiosperm tannins since Balza et aI.'* isolated proanthocyanidins from the 3 Thailand plant species Mammea siamensis Pofygonum stagninum and Diospyros diepenhorstii used by the native people as fish poisons.The pure compounds were piscicidal (50% kill in 24 hours) at very low concentrations (0.24.3 ppm). In moths and butterflies dietary tannins are well known to lower the growth rate but generally speaking only plants with more than average tannin concentrations actually deter feeding. This also appears to be true for aphids. Experiments with Aphis craccivora a pest of the groundnut Arachis hypogaea show that it is deterred from feeding when the procyanidin content in the phloem of the petiole reaches more than 0.3YOfresh weight.Aphids left to feed on cultivars with high tannin content showed a twofold decline in reproductive rates.95 Interestingly tannin production in the peanut appears to be channelled towards resisting aphid attack since other organs and tissues are essentially tannin-free. Even the procyanidin precursor catechin can act as a deterrent to aphid feeding; this is not so for the peanut aphid but it is true in the case of the rose aphid Macrosiphum rosae 96 Although the chemical ecology of condensed tannins has received considerable attention that of the hydrolysable tannins has barely been considered. And yet an increasing number over 600 of hydrolysable tannins have now been characterized in ~1ant.s.'~ One such example is P-punicalagin (29) recently characterized in the leaves of the bushy tree Terminafiu obf~ngutu.'~ Eating the leaves of this plant by cattle and sheep produces yellow-wood poisoning caused by liver damage.The tannin is responsible for these toxic effects and the hydrolysable tannins in leaves of the oak and of Thifoa gfaucocarpa have similarly been identified as being toxic to farm animals.99. loo Unlike farm animals insects can adapt themselves to eating oak leaves and most oak trees have a well developed larval fauna. One particular moth Nemoria arizonaria uses the presence of tannin in the leaves to determine which of two larval forms it will adopt. Thus larvae born in the spring feed on the oak catkins which are low in tannin and are yellow in colour mimicking the catkins in colour and form.Those born in the summer eat the leaves which are rich in tannin and are green-grey resembling in shape the twigs of the tree. The triggering role of the tannin was demonstrated in laboratory feeding experiments when 94 O/O of larvae raised on catkins plus tannins developed into the twig form while 94% of larvae raised on catkins alone took up the catkin form.lol 3 34 Table 1 Mortality (%) on 24 h exposure to Monoterpenes Animal and life role on spruce Mortality* Dendroctonus micans ;solitary colonizer Larvae 0% Adults 5-10 Yo Oh Ips typographus gregarious tree killer Adults 7-20 associated with Ceratocystis fungus Rhizophagus grandis ; specific predator 0 Yo on D.micans Rhizophagus dispar ; occasional predator 100Oh on Ips Formica rupa ant control 100% Tenebrio molito beetle control 4s100Yo * Results of separate tests with a-and j7-pinene 3-carene limonene myrcene a-terpinene and camphene. %& H" 3.1.2 Terpenoids The ecological importance of terpenoids in plant defence is well established,102 and new examples involving several classes of terpene have appeared in the period under review. The toxicity of Norway spruce monoterpenes to two bark beetles and their associates has been surveyed by Everaerts et al.lo3with the results shown in Table 1. The beetle Dendroctonus micans has developed considerable resistance to the terpenes because it cannot fly far and has to feed where it lands.By contrast Ips typographus has not evolved high resistance because it only suffers low exposure to the host monoterpenes. The Colorado beetle avoids feeding on the wild tomato Lycopersicon hirsutum f. hirsutum because of the high content of the sesquiterpene zingiberene (30) in the glandular trichomes. This hydrocarbon originally found in the ginger plant occurs in the leaflets of this tomato at a concentration of 160-250 pg 2 sq cm-I. It killed beetle larvae when 12-25 ,ug were applied to each larva. This sesquiterpene replaces in L. hirsutum the more familiar trichome toxin 2-tridecanone which is found in most other tomato species.1o4 lo5 Terpenoids as well as phenolics (see sections 3.1.1) protect trees and shrubs growing in the harsh environment of the Alaskan winter from grazing by the snowshoe hare.Juvenile tissues of the white spruce Picea glauca contain four times more camphor than mature tissues and this is an important factor limiting grazing to the older plants. A second terpenoid present bornyl acetate had no antifeedant activity on the hare.lo6 In the Labrador tea plant Ledum groenlandicum the protective agent against the browsing hare is the sesquiterpene ketone germacrone (31). This is a slow growing evergreen shrub which needs full protection and the concentrations in the leaves (0.5 % dry weight) and internodes (0.03 %) are sufficient to defend the plant. The ursolic acid and tannins present probably act as a secondary defense.lo7 In the temperate zones of North America the leaves of the ivy Ilex opaca are well defended from herbivory by the tough glabrous epidermis and rigid spines at the leaf margins.Young foliage rich in nutrients lack these physical defences so it is not surprising that Potter and Kimmerer108 have found high concentrations of saponins in these tissues. The fall off in saponin content with leaf age is quite dramatic with 135 mg 8-l dry weight on 30 April 70 mg on 21 May and 40 mg on 1 I June. Feeding tests with the Eastern caterpillar Malacosoma americanurn confirmed the general unpalatability of the young saponin-rich leaves to herbivores. NATURAL PRODUCT REPORTS 1993 I ONM* Me (35) While one plant strategy for protection might involve chemical protection concentrated in young vulnerable leaves another strategy might be based on altering the chemistry as the plant develops.This would make it difficult for an insect to 'home in' on a recognizable host plant. Such a strategy appears to be adopted by the Composite plant Ageratum adenophora. The first leaves on this plant (nodes 1-8) contain the insecticidal chromenes encecalin (32) and two of its derivatives while the older leaves (nodes 9 and above) switch to the synthesis of chlorogenic acid and a new sesquiterpene (33). The latter was shown to be toxic to Noctuid 3.1.3 Alkaloids Although the defensive role of plant alkaloids against mam- malian herbivores is well documented with many examples the protection these bases provide plants against insect attack is less investigated.Recent results obtained on this topic are therefore very welcome. The defensive role of ergot alkaloids has been explored in relation to their production by fungal endophytes in infected grasses. Five of six alkaloids [the exception being lysergol (34)] at concentrations of 70-100 mg I-' in corn leaf discs reduced feeding in the fall armyworm Spodoptera frugiperda.l1° A related study of these alkaloids as they occur constitutively in the higher plant Ipomoea parasitica showed that there was a high concentration in the young seedlings and also in the plant during flowering. Feeding experiments with the larvae of the moth Heliothus uirescens showed that the alkaloids were deterrent to feeding and also reduced fertility.Lysergol (34) one of the four main alkaloids present was less active as an antifeedant than the crude alkaloid mixture. 111 Similar experiments with the p-carboline alkaloids harman and harmine tested against the beet armyworm Spodoptera exigua showed antifeedant activity. Harman (35) was active when added to the diet at 0.03 YOwet weight and it also prolonged the maturation time of the insect.112 Again feeding the lupin alkaloids lupinane and sparteine to the armyworm S. eridania reduced growth and survivorship.113 The beet army worm Spodoptera exigua has also been used as a test insect for the alkaloids of the Cinchona plant. Significantly the indole alkaloids present in high concentration in the young leaflets e.g. cinchophyllamine (36) significantly reduced growth and development and also led to mortality in the larvae.By contrast the quinoline alkaloids which occur in the Cinchona roots had little effect on the armyw~rm."~ The indole alkaloids were also protective against slug feeding when NATURAL PRODUCT REPORTS 1993-5. B. HARBORNE yJoXoH NO I OH (37)R = OMe (38)R = H tested at the same concentrations actually present in the seedlings.115 The hydroxamic acid dimboa (37) is well known to occur in wheat and maize plants where it provides resistance to aphid attack. Aphids feeding on wheat sometimes ingest it during probing before moving off to other plants.'lG In cultivated barley the alkaloid gramine replaces dimboa as the major factor for aphid resistance.New experiments with wild barley Hordeum lechleri show the presence of the related diboa (38) which is toxic to the aphid Rhopalosiphum padi when given to it in an artificial diet. Also there was a good correlation between diboa levels in wild barley and the performance of R. padi on these ~1ants.l~' 3.1.4 Glucosinolates The ecological strategy in the mustard plant Sinapis alba is to protect the vulnerable young tissues with sinalbin (p-hydroxy- benzylglucosinolate). The high concentrations in young cotyledons (20 mM) and young leaves (up to 10 mM) effectively deter both a specialist insect (the flea beetle Phyllotreta crucijerae) and a generalist (the armyworm Marnestra configurata). As the plant grows the concentration drops so that older leaves have 2-3 mM.At these levels there may be some stimulation of feeding to the flea beetle. However such concentrations still deter the more generalist feeder.'18 The feeding behaviour of the flea beetle on mustard also operates in the case of the desert locust Schistocerca gregaria feeding on the wild crucifer Schouwia purpurea. Low concentrations (21 pmol 8-l dry weight) are phagostimulant whereas high concentrations (214 pmol g-1 dry weight) are repulsive. As a result the locust tends to feed on dried senescing leaves rather than fresh green ones. 119 The resistance of a crucifer to insect attack may lie not only in glucosinolate production but also in surface wax which may discourage feeding even before the glucosinolates have been located.This appears to be true for larvae of the diamond back moth Plutella xylostella when offered a resistant cabbage with glossy leaves or a susceptible one with normal wax bloom. The difference in wax constituents includes the presence of a-and P-amyrin in the resistant cultivar.120 3.1.5 Furanocoumarins Berenbaum et a1.121 have tried to answer the question why should a plant produce a mixture of related toxins rather than a single compound? The test plant was the edible parsnip R HCN + 'C=O H' rhdanese/ c"--q p-cyanoalanine synthase \ NCCHZCH( NH2)C02H Pathway of cyanogenic glycoside breakdown and detoxification (R = alkyl or aryl; S = sugar). Scheme 1 Pastinaca sativa the fruits of which contain six related furanocoumarins.Toxicological studies were conducted on Heliothis zea in the presence and absence of UV light since some of the six furanocoumarins of parsnip are phototoxins. In fact UV treatment had little effect on the results which showed that a mixture is indeed more toxic to the insect than an equimolecular amount of one of the compounds xanthotoxin. Parsnip plants respond to shading in the glasshouse by increasing the proportion of non-phototoxic to phototoxic furanocoumarins. The authors concluded that the synthesis of a mixture of related toxins is advantageous in maintaining plant toxicity under a variety of environmental conditions. The toxicity in insects and photodermatitis in man caused by plant furanocoumarins depends to a considerable extent on their localization near or at the plant surface.Zobel and Brown122 have found that psoralen bergapten and xanthotoxin are indeed mainly at the leaf surface in 8 species of Rutaceae and Umbelliferae. In Ruta graveolens the concentration at the leaf surface could be up to 56% of the total wet leaf weight. Expectably younger leaves have much higher concentrations than older leaves. 3.1.6 Plant Lectins The effectiveness of lectins as plant protectants has been studied by Huesing et al.123 Three isolectin homodimers of wheat germ agglutinin were bioassayed against cowpea weevil Callosobruchus maculatus and were found to be equally detrimental to growth and development of the insect. Thus any of the three B genes controlling production could be transferred to cowpea to provide bruchid resistance.A rice lectin had similar activity to wheat germ agglutinin in its toxicity to the cowpea weevil. A stinging nettle lectin a poor agglutinin was found to be 24 times less active.124 Some earlier experiments of Janzen et al.125indicated that the phytohaemagglutinin (PHA) of the common bean Phaseolus vulgaris was toxic to cowpea weevil at a concentration of 1 YOdry weight. It has now been found that commercial PHA is contaminated with an a-amylase inhibitor and it is this inhibitor which is actually the toxic protein.126 The inhibitor is active at 0.2 YOw/w and has a molecular range of 15000. 3.1.7 Cyanogenic Glycosides The enzymology of cyanogenic glycoside breakdown and detoxification has been further investigated and the defensive role of the various products of breakdown and detoxification re-evaluated (see Scheme 1).The hydrolytic glycosidases which NATURAL PRODUCT REPORTS 1993 accompany the glycosides are highly specific for their substrates. A disaccharide may be removed in a single step as occurs with the arabinosylglucoside vicianin in Vicia angustifolia or it may undergo stepwise hydrolysis as happens with the gentiobioside amygdalin in Prunus serotina. Although the decomposition of the intermediate cyanohydrin can occur non-enzymically it is clear that in vivo the presence of hydroxynitrile lyase not only speeds up the process but also this reaction is ecologically important. The compartmentation of enzymes and substrates may vary but generally both are liable to be located in epidermal cells of leaves.In sorghum dhurrin occurs in the epidermal cells while the hydrolytic enzymes are in the mesophyll cells and tissue disruption is needed for hydrolysis. In Phaseolus lunatus leaves enzymes and substrates are both present in the epidermal ~e1ls.l~~ Although it has often been assumed that the hydrocyanic acid released on hydrolysis is the main toxin of cyanogenesis it is now clear that the aldehyde or ketone also released may be equally deterrent to herbivores. 128 129 Benzaldehyde formed by hydrolysis of prunasin present in many Rosaceae plants has an LD, of 0.1 Yo weight basis in the rat and is highly irritant to aphids moths ants and millipedes.Likewise acetone formed from linamarin a widespread cyanogen has an LD, of 0.05 YO weight basis in the rat and is damaging to insects since it will denature the flexible cuticular tissues.128 Test experiments with slugs (3 spp.) have shown that aldehydes and ketones are more repellent to feeding than HCN in the order 4-hydroxybenzaldehyde > benzaldehyde > butanone > acetone > HCN.12’ 3.1.8 The Cost of Chemical Defence The resource availability hypothesis proposes that mature leaves of inherently slowly growing species adapted to resource- limited habitats have much more effective chemical defences and suffer less herbivory than mature leaves of rapidly growing species adapted to productive habitats. Evidence in support of this hypothesis has been obtained by Bryant et al.130 in a study of herbivory by Kudu and Impala in a South African savanna ecosystem.The relative costs of secondary plant metabolism have been assessed by Baas131 and a modified carbon-nutrient cycle theory put forward to explain the differing roles of ‘ quantitative’ toxins (e.g. tannins) and signal molecules mainly terpenoids and phenolics. It has often been assumed that most of the secondary compounds of defence undergo metabolic turnover thus adding to the relative costs of protection from herbivory. In particular monoterpenes in plants such as mint and sage have been regarded as undergoing rapid turnover through loss from the leaf trichomes. Earlier experiments with detached plants confirmed such ideas.132 However new experiments by Mihaliak et ~1.l~~ demonstrate that intact Mentha x piperita plants retain their synthesized monoterpenes for significant periods of growth and that there is minimal turnover.3.2 Induced Chemical Defence Much research continues on how plants respond if at all to herbivory; this may be real with larval feeding or simulated by mechanical damage. A book on the subject has appeared,l as well as several re~iews.l~~-l~~ Some of the results have been contradictory; also results of earlier experiments have been shown to need revision in the light of later knowledge. The discovery of Farmer and Ryan137 that Artemisia tridentata when placed in a closed chamber with tomato plants can trigger off the synthesis of defensive proteinase inhibitors in that plant through the release of methyl jasmonate (39) has led to a flurry of experiments using this signal molecule in other systems.One problem is that negative results are not often reported so that it is still not clear what percentage of plants can respond to herbivory by ‘upgrading’ their chemical defences. In this discussion work on the PIIF system will be 0 0&co2H C02Me 0&C02H e (39) (40) briefly reviewed before outlining the results obtained with secondary metabolites. Work on the PIIF system by which two proteinase inhibitors harmful to the digestion of herbivorous insects are produced de novo by certain plants has mainly concentrated on the signalling system and its ecological importance awaits further in-vestigation.Present data suggest the possibility of multiple A ~igna1ling.l~~ very active polypeptide inducer has been characterized from tomato plants. It is called systemin has 18 amino acids in its sequence and is 10000 times more active than the oligosaccharins which also have the ability to trigger the plant This might be the first signal which is then passed on by methyl jasmonate or jasmonic acid. These are both highly effective at inducing proteinase inhibitors in tomato either when the volatile vapour of (39) is placed near the plant or when the non-volatile jasmonic acid is applied directly to the 1ea~es.l~~ The plant hormone abscisic acid (40) has also been implicated as a signal for setting off this defence process,139 although it appears to be active in some plants (e.g.the potato) and not Other workers have suggested that changes in the electric potential between plant cells may be sufficient to set off the a1arm.140 Finally mention should be made of salicylic acid which at very low concentrations is a systemic signal for acquired resistance in cucumber141 and sets off the synthesis of pathogenesis-related proteins in tobac~0.l~~ Most other research on induced resistance has concentrated on determining whether increases in toxic chemicals occur in ‘triggered’ plants and if so whether these increases are of ecological significance and are sufficient to turn an otherwise palatable leaf into one that is henceforth unpalatable.The most convincing positive evidence comes from the studies of Bald~inl~~ on the responses of the wild tobacco plant Nicotiana sylvestris to real and simulated herbivory. The two major alkaloids present are nicotine and nornicotine. Larval feeding induced a 220 Oh increase in alkaloid content throughout the plant over a period of 5-10 days. Mechanical damage which avoids cutting the secondary veins produced a smaller response (170 %). In fact the tobacco hornworm Manduca sexta when feeding on the tobacco leaf avoids cutting through the secondary veins. It thus avoids triggering off the fullest response in the leaf which can be as much as 400% of the control if the simulated damage includes damaging the vein. The nicotine alkaloids are synthesized in the roots and transported up into the leaf and this fact was elegantly demonstrated by Bald~inl~~ by experiments in which pot-bound plants with confined roots failed to show any significant alkaloid increase after mechanical damage.Similar experiments with the tropane alkaloids in leaves of Atropa acurninata showed a maximum increase of 153-1 64 O/O over the control 8 days after mechanical damage or slug feeding. Repeated mechanical damage at 11 day intervals initially increased the response to 186 YOof the control but this effect fell off with time.145 Further experiments showed that only 9 YOof the leaf area needed to be removed mechanically or by animal feeding to produce the maximum response.146 Another well investigated example of induced chemical defence is the wild parsnip Pastinaca sativa which produces five furanocoumarins in the leaves.Artificial damage increased furanocoumarin synthesis to 162YO of the control while feeding by the generalist insect Trichoplusia ni increased it to 215%. Furthermore larvae of T. ni grew very slowly on induced leaves while larvae on an artificial diet supplemented with furanocoumarins were similarly affected.147 NATURAL PRODUCT REPORTS 1993-5. B. HARBORNE -...-HO oH response is determined by a number of environmental and/or 0 physiological factors which have yet to be fully identified. An even more interesting and remarkable plant-animal interaction involving induced chemical changes has been In observed by Dicke and his co-w~rkers.'~~ response to herbivory some plants have developed the means to release volatile chemicals which are particularly attractive to parasitoids of their herbivores which then visit the plant and destroy the herbivores.As Dicke puts it plants may 'cry for help' when attacked by spider mites and predatory mites come HO to the rescue. Much research has been conducted on the Howo* (44) The response of oil seed rape Brassica napus to insect infestation or leaf damage is quite distinctive and involves the massive accumulation of indole glucosinolates which are barely detectable in the control. There is a corresponding reduction in the amounts of the aliphatic glucosinolates of the plant but the total titre of glucosinolate does appear to increase under these treatments.14* Other examples where induced changes in protective chem- istry have been recorded include dimboa synthesis in wheat following aphid attack ;149 increased monoterpenes in Euca-lyptus melliodora after feeding by the Christmas beetle Anoplognathus montanus;150 increased trichome density in Alnus incana induced by the chrysomelid beetle Agelastica alni;l5l increased mineral deposition in injured leaves of the water lily Victoria amazonica ;152 and increases in the phenolic glycosides salicortin and tremulacin in PopuIus tremuloides in response to simulated herbivory. 153 Against these positive results one must set a number of failures to confirm earlier reports of chemical increases and a number of cases where no detectable change in chemistry occurs.The reports in the early 1980s of increases in phenolic (and/or tannin) levels in birch Betula pubescens red oak Quercus rubra and red alder Alnus rubra after insect attack must now be regarded as of doubtful validity since attempts to repeat these experiments in trees have sometimes failed (see for example Ref. 154). Also the methodology of analysing tannins has much improved in the interim155 and the methods then employed are now considered unreliable. In our laboratory we have tried to induce increases in the phenolic chlorogenic acid by mechanical damage in the plant Ipomoea parasitica over a 3 day period but without any success.156 One of the most thorough attempts to induce chemical changes in a tree has been by Leather et al.who defoliated lodgepole pine Pinus contorta in order to see if it would affect the growth and survival of the pine beauty moth Panolis flammea. Tannins as well as terpenes were monitored in the pine needles and positive results were reported for 2-year-old However a report of the same experiments with 10-year-old trees failed to show any measurable changes in leaf chemistry.15* In general therefore it would seem that increases in secondary metabolites may occur in plants in response to either real or simulated herbivory but that the extent of the predatory mite Phytoseiulus persimilis the spider mite Tetranychus urticae and its host plants. The chemicals released seem to be plant species-specific. Cucumber plants infested by the spider mite release (E)-P-ocimene and (E)-4,8-dimethyl- 1,3,7-nonatriene (41) and are only moderately attractive to the predatory mites while Lima beans release a cocktail of linalool (E)-P-ocimene (41) and methyl salicylate which is highly attractive.A further advantage to the plant world is that the volatile released may alert uninfested neighbouring plants so that they become better protected from spider mite attack. Thus cotton seedlings when infected by these mites release volatile cues which both attract predatory mites and also alert neighbouring plants to withstand herbivore attack. 160 The systemic release of volatile chemicals which mediate in plant-herbivore-predator interactions has been observed in at least three other plant systems.Turlings and Tumlinson161 have recorded that corn (Zea mays) seedlings respond to beet armyworm (Spodoptera exigua) attack by releasing volatiles which attract parasitic wasps Cotesia marginiventris to attack the herbivore. The response occurs throughout the plant and not only at the site of damage. The chemicals released included linalool (41) and (3E,7E)-4,8,12-trimethyl-1,3,7,1l-trideca-tetraene (42). At 0-1 h the release of linalool is at the rate of 1 ng h-l while at 5-6 h it rises to 110 ng h-l. Corn seedlings attacked by noctuid caterpillars respond in exactly the same way.162 A similar tritrophic system exists in the case of the soya bean plant the soya bean looper Pseudoplusia ineludens and its parasitoid Microplitis demolitor.Here the volatiles again include linalool but the more important attractants are guaiacol and 3-octanone. These latter compounds do not appear to be released in appreciable amounts from the plant but are released from the insect frass and are formed within the larvae from dietary sources.163 In other plants such as cotton and cowpea the release of green leaf volatiles (e.g. (Q-2-hexenal and (E)-2- hexen- 1-01) appears to be sufficient to attract parasitic wasps to attack leaf-feeding ~aterpi1lars.l~~ 3.3 Hormonal Interactions Precocene 1 (43) makes up 11 % of the total oil of Platostoma africanum (Labiatae). This is the first report of this anti-juvenile hormone from a plant outside the Compo~itae.'~~ Two new juvabione analogues have been characterized in the wood of Abies sachalinensis.166 About 105 phytoecdysteroids have been found in plants and their interaction with insects has been reviewed.167 Among new structures reported are carthamo- sterone (44) and 5-deoxykaladasterone (45) from Rhaponticum NATURAL PRODUCT REPORTS.1993 OCOPh HO 0 (46) carthamoides (Compositae),168 viticosterone E 22-benzoate (46) from Silene wallichiana (Cary~phylaceae)~~~ and vitexirone (47) from Vitex Jisherii (Verbenaceae).170 Three glycosides have been obtained from the roots of Pfafia iresinoides (Amaranthaceae) 20-hydroxyecdysone 25-glucoside podec- dysone B 25-glucoside and pterosterone 24-glu~oside.~~~ The stems of Diploclisia gluucescens (Menispermaceae) are an unusually rich source (3.2% dry weight) of 20-hydroxy-ecdysone which has an LD, against the groundnut aphid of 1.8 mg kg-1.172 The harmful effects of various ecdysteroids on insects continue to be monitored.166 The brassinolides or brassinosteroids are a group of plant hormones with close structural similarities to ecdysteroids.Not surprisingly they have been shown to have anti-ecdysteroid activity upsetting metamorphosis in the cockroach Periplanata americana and in the blowfly Callophora vi~ina.l~~ 3.4 Insect Antifeedants The natural occurrence in plants of insect antifeedants suggests that such compounds have a defensive role against herbivory. These antifeedants often have other effects on phytophagous insects including growth inhibition delay in maturation reduction in reproductive capacity and direct toxicity.Such compounds may prove to be useful insecticides and this is true of the best known antifeedant azadirachtin from the neem tree. The successful application of azadirachtin in plant protection in the USA and other countries has encouraged the continued search for active compounds. A range of new diterpenoid antifeedants have been described although attempts to relate diterpenoid structure to antifeedant activity have not yet been completely successful. Nineteen clerodane diterpenoids from Teucrium spp. (Labiatae) were assayed against Spodoptera littoralis and Heliothis armigera by Simmonds et The compound 6,19- diacetylteumassilin (48) proved to be the best antifeedant and the presence of epoxide and C-5 methylacetoxy groups were important for activity.Some neoclerodanes from Scutellaria galericulata were also tested and of those jodrellin B (49) was the most potent.175 A grayanoid diterpene from flowers of Rhododendron molle rhodojaponin I11 (50) proved to be antifeedant to larvae of the Colorado beetle Leptinotarsa decernline~ta.~~~ Diterpenes from the Euphorbiaceae which are notorious for their co-carcinogenic effects in Man have also OH HO HO 0 o.loH 0$0 HO OH been shown to be antifeedant. Thus cis-dehydrocrotonin (5I) from Croton cajucara is growth inhibitory to Heliothis vire~cens,~~~ compound (52) from Croton Iinearis is while neurotoxic to Cylas formicarius a pest of the sweet p0tat0.l~~ Various other terpenoid structures have also been reported to have deleterious effects on insect feeders.7-Deacetyl- 17p- hydroxyazadiradione (53) a limonoid from Azadirachta indica reduces the growth of Heliothis vire~cens.l~~ A limonoid with a novel structure (54) from Khaya ivorensis seed is active against the Lepidopteran Agrotis segetum and causes 56 % reduction in growth when fed at 100ppm in an artificial diet.Iso The triterpenoid quassin (55) is an antifeedant at a concentration of 0.05% to the generalist aphid Myzus persicae.lal The sesquiterpenoids ( +)-and (-)-polygodial are also antifeedant to aphids.182 The lactone encelin (56) from Encelia spp. is antifeedant and toxic to Spodoptera litteralis and the LD, was determined to be 60pg per larva.ls3 A comparison of sesquiterpenes (e.g.bisabolangelone) with phenolics (e.g. podophyllotoxin) by Nawrot et al.ls4 as antifeedants to polyphagous lepidopterans indicated greater activity for the sesquiterpenes. Relatively few flavonoids have been recorded as antifeedants so that it is interesting that ermanin (kaempferol7,4'-dimethyl ether) isolated from PassiJora foetida resin is a feeding deterrent to larvae of Dione juno at 40 pprn.la5 Prenylated chalcones and flavanones from seeds of Lonchocarpus and Tephrosia spp. have also proved to be antifeedant when tested against two armyworm species by Simmonds et al.ls6 The most novel antifeedant to be reported for some time from plant sources must be dithyreanitrile (57) which occurs in the seeds of Dithyrea wislizenii (Cruciferae).This is an indole derivative with the two position substituted with the carbon linked to cyanide and to two S-methyl groups. It inhibits feeding in the fall armyworm Spodoptera frugiperda and is strongly deterrent at 1 % level in leaf disc experiment^.^^^ 3.5 Oviposition Stimulants and Deterrents The most widely studied oviposition stimulation is that of the cabbage white butterfly on crucifers where ally1 glucosinolate (sinigrin) has been assumed to be the main elicitor. New experiments with Pieris rapae reared on Brassica campestrislss show that glucobrassicin (3-indolylmethyl glucosinolate) is more potent than sinigrin. Solutions of glucobrassicin at M NATURAL PRODUCT REPORTS 1993-5.B. HARBORNE 0 0@o . 0 O& (55) (56! were as effective as those of sinigrin at M. A mixture of the two in solution is effective at M. These results fit in with the discovery that indole- based glucosinolates occur in larger amounts in crucifer foliage than the better known aliphatic glucosinolates. The oviposition stimulants of the Aristolochiaceae-feeding swallowtail butterfly Atrophaneura alcinous on the leaves of Aristolochia debilis are a mixture of four aristolochic acids (e.g. 58) and seq~oyitol.'~~ The butterfly uses these chemicals for defence against tree sparrows obtaining them through larval feeding and they are also important as feeding cues to the larvae.lgo The oviposition stimulants of the female pipevine swallowtail Battus philenor which lays its eggs on leaves of Aristolochia macrophylla are also aristolochic acids but D-( +)-pinitol replaces sequoyitol as the active cyclit01.~~~ Work has continued on the oviposition stimulants in the Papilionid butterfly Papilio protenor.When the female lays her eggs on Citrus natsudaidai or Citrus unshiu stachydrine quinic acid proline and synephrine together with the flavanones naringin and hesperidin are stimulatory. When it lays on Fagara ailanthoides chlorogenic acid replaces the two flavanones in the synergistic attractant mixture in the leaves.lg2 The butterfly Papilio xuthus is sympatric with P. protenor and feeds on the same citrus plants. Different bases are stimulatory namely adenosine and 5-hydroxy-N-methyltryptamine.lg3 To these two bases should be added bufotenin (5-hydroxy-N,N- dimethyltryptamine) but not its 5-glucoside which also occurs in citrus leaves.lg4 The iridoids aucubin and catalpol which occur in the host plant Plantago lanceolata act as oviposition cues to the Buckeye butterfly Junonia coenia.lg5 The female can discriminate between solutions containing 0.25 and 1 % concentrations of these iridoids and they choose the higher concentrations. Larvae use the iridoids for protection but not the adults. Cardenolides are oviposition stimulants to the monarch butterfly Danaus plexippus. Experiments with plant populations of Asclepias humistrata show that most oviposition occurs on plants where the cardenolide levels are between 200 and 500 pg g-' wet weight.Low or high cardenolide containing plants were generally rejected. Rejection of the high cardenolide plants fits in with the fact that the larvae placed on such plants suffer some physiological strain and do not survive so well at the first instar stage.lg6 The lesser mulberry pyralid feeds on mulberry leaf like the silkworm and the female adult is stimulated to lay her eggs on the leaf by the presence of the benzofuran moracin C (59)previously recorded as a phytoalexin of fungal-infected mulberry shoots. lg7 HO co OCOPr (53) (54) -OMe OH Y (59) Oviposition deterrents in non-host plants are just as important as the attractants in host plants in guiding the female butterfly towards its preferred oviposition site.Deterrents of Erysimum cheiranthoides (Cruciferae) to oviposition by the cabbage butterfly Pieris rapae is mimicked by the cardenolide cymarin. This is a very specific effect and other closely related cardenolides are inactive.lg8 The cardenolides of this plant have been characterized and there are two deterrents erysimoside and erychroside which are two strophanthidin glycosides with an inner sugar of 2,6-dideoxyhexose and an outer sugar attached to C-4.1g9Erychroside is also present in Cheiranthus allioni and deters oviposition by both the large white butterfly P. brassicae2Ooand the small white P. rapae.201 Oviposition deterrents in the swallowtail butterfly Papilio xuthus can be produced by a very small change in structure of the flavonol glycoside present in the leaves of potential host plants.Thus the insect is stimulated to oviposit on Citrus plants by the presence of rutin (quercetin 3-rutinoside) among others. It is deterred from oviposition on a non-host Rutaceae plant Orixa japonica because the leaves contain quercetin 3-(2c- xylosylrutinoside). Thus the simple addition of an extra sugar (xylose) turns rutin from an attractant to a repellent. Other water soluble compounds in Orixa may synergize the rejection of the leaf for oviposition.202 The plum volatile I-nonanol has been identified as an oviposition deterrent to the coddling moth.203 4 Plant-Plant Interactions 4.1 Allelopathic Agents One of the few new studies of allelopathy in the field has been an investigation of autotoxic factors in the roots of Asparagus oficinalis.The results obtained indicate the importance of keeping as closely as possible to in vivo conditions in these types of experiment. Thus fractionation of the dried root gave NATURAL PRODUCT REPORTS 1993 OH several expectable acids (caffeic ferulic isoferulic malic citric fumaric) of moderate activity. However extraction of lyophilized fresh root gave the previously undetectable 3,4- methylenedioxycinnamic acid which was one order of mag- nitude more toxic to Asparagus than the other acids. It also caused severe inhibition of curly cress growth at 25 ppm.204 Weidenhamer et suggest that the allelopathic effects of plant root exudates (e.g.of juglone from walnut) may get diluted out if many neighbouring plants share the phytotoxicity and receive the toxin at sub-lethal doses. Dramatic allelopathic effects are therefore likely to be restricted to habitats (e.g. scrubland) where plant density is low. One such case is the shrub Polygonella myriaphylla which exudes phenolics from its roots and harms the growth of native grasses.2o6 One major problem with this and other examples in extrapolating these data to the field situation is the lack of knowledge about the microbial turnover of the allelochemicals. There is still uncertainty about the turnover of juglone in the soil around walnut even though a bacterium capable of detoxifying juglone has been described from the The assumption of allelopathic effects where a plant is known to exude a potent phytotoxin must always be treated with suspicion unless the right experiments have been carried out.Choesin and Boerner208 investigated the potential allelo- pathic effects of allylisothiocyanate which is released from Brassica napus and other crucifer crops and they could find no evidence of allelopathy. They grew Medicago sativa in soil contaminated with mustard oil but there were no negative effects. Measurement of allylisothiocyanate in soils under a variety of conditions showed that the levels released from Brassica never reached toxic concentrations (see also Ref. 209). Similar studies of quinoline alkaloid released from roots of the Cinchona plant showed that while the roots contained as much as 10m~alkaloid the surrounding soil only had around 0.02 mM levels.Seed of potential competitor species sown close to the Cinchona plant showed 100% germination although in the laboratory there were strong inhibitions of seed germination by the alkaloids.210 In laboratory experiments Fischer et have compared the inhibitory effects of 6 sesquiterpene lactones on the seed germination of 16 monocot and 9 dicot plant species. They observed inhibition at concentrations as low as 1 ,UM and hypothesized that plants releasing these sesquiterpene lactones into the soil might have some harmful effects on neighbouring species. A series of volatile aliphatic alcohols and ketones which are released from Amaranthus palmeri residues were tested for the effects on seed germination and growth.The activity was in the order 2-octanone 2-nonanone > 2-undecanone > 2-heptanone > 2-hexanone and was related to the volatility and hydrophilicity of the ketones. The cor-responding alcohols were also inhibitory. 212 The effects of heterocyclic compounds on lettuce seed germination have been compared. 213 Ferulic acid is recorded as a common allelopathic agent released from many plants and much work has been done on its inhibitory effects in vitro on plant 4.2 Plan t-Par asite Interact ions Seeds of the parasitic witchweed Striga asiatica depend upon a chemical stimulant exuded from the host grass plant to trigger off the process by which its seeds are able to germinate and the seedling attaches itself to the host.The first such stimulant to be characterized was the sesquiterpene lactone strigol(60). This was an artificial compound in the sense it was isolated from the roots of the non-host cotton plant although it was highly effective at stimulating the seeds to germinate. A new stimulant sorgolactone (61) has now been characterized from a genuine host plant Sorghum bicolor and it turns out to be closely related to strig01.~~~ An unstable quinol had earlier been obtained from sorghum roots as a Striga seed ~timulant.~~ However the stable quinone formed from it by oxidation called sorgoleone has now been assigned a different function as an allelopathic agent of Sorghum.216 The strigol model has been used to determine which related sesquiterpene lactones are capable of mimicking this ger- mination activity.The testing of four readily available sesquiterpene lactones showed that one of them dihydroparthenolide (62) was very active. It induced 70 YO germination of witchweed seed across a concentration range of lo-’ to 10-9~.217 A later survey of 24 natural and synthetic lactones showed that the key structural feature for activity is a germacrane-eudesmane skeleton in conjunction with a five- membered lactone ring and that this activity is independent of the presence of any specific functional group. Indeed a mixture of two eudesmanolides santamarin (63) and reynosine (64) gave an activity almost identical to that of strigol.218 A distinctive feature of some plant-parasite interactions is the transfer of certain secondary metabolites from host to parasite.This might have significant ecological benefits to the parasite protecting it from herbivory without having the metabolic costs of toxin synthesis. Such a transfer of alkaloids has now been recognized in the case of two plant genera Castilleja and Pedicularis which are hemi-parasites on various legume and Composite species. Thus species of Castilleja can NATURAL PRODUCT REPORTS. 1993-5. B. HARBORNE 341 CHO grow as root parasites on Senecio atratus when they obtained pyrrolizidines such as senecionine and on Lupinus and Thermopsis species when they obtain quinolizidines such as N-methyl~ytisine.~~~ The transfer is selective in that not all the alkaloids of the host appear in the parasite.It is also variable at the population level and some Castilleja plants may have large quantities and others none. Species of the hemiparasitic Pedicularis also live on legume and Composite plants and similar transfers of quinolizidine and pyrrolizidine alkaloids respectively have been observed. 220 Pedicularis bracteosa is distinctive in parasitizing Engelmann spruce Picea engelmanni. In this case it obtains the pyrrolidine alkaloid pinidinol (65) from its host.220 The holoparasite Cuscuta palaestina is found attached to the shrub Genista acanthocluda. Three of the 20 alkaloids present in Gensista namely lupanine cytisine and anagyrine can be detected in C~tscutu.The total alkaloid content of Cuscuta is only a sixth of that present in Genista so that a very selective uptake is operating.221 5 Plant-Microbe Interactions 5.1 Mycotoxins A symposium proceedings222 and a tetrahedron symposium-in- print223have been devoted to mycotoxin research.Several years ago the Brazilian shrub Buccharis megapotarnica (Compositae) was found to uniquely contain a series of macrocyclic mycotoxins. These trichothecins (e.g. 66) had previously been detected only in soil fungi Fusarium and Myrotheceum species and it was assumed therefore that their presence in higher plant tissue was due to a symbiotic fungal infection. Indeed experiments which included feeding roridin A to the roots of Buccharis plants and isolating the 8-hydroxy derivative baccharinoid B7 from the leaves supported this hypothesis.Buccharis megapotarnica is unusual in being dioecious i.e. in having separate male and female plants. One odd feature of the distribution of the trichothecins was a complete absence from the male plants. A reinvestigation of the distribution of these mycotoxins in B. megapotarnica and a second species containing them B. coridifoliu has now shown unambiguously that they are true higher plant products and are not produced in the plant as a result of fungal infection of the The principal evidence showing this to be so is the restriction of toxin to the female plant and in these plants to the seeds. There are small amounts in the carpel and pappus but the seed may contain from 1000-16000 ppm and this is concentrated entirely in the seed coat.Thus through a quite remarkable parallel evolution these highly advanced Composite plants have developed the ability to synthesize a series of toxins otherwise known only in OH microbes. The principal purpose is one of protection from herbivory and this is reflected in the fact that cattle poisoning occurs in South American pastures where Baccharis plants The seed coat toxins may also protect the seed from insect attack and microbial infection and there is some evidence also that they are involved in the regulation of reproduction and seed germination.225 A survey of 19 other Buccharis species for trichothecenes showed that they are confined to only the two species mentioned above.226 5.2 Phytotoxins In almost every plant disease it is possible to detect metabolites produced by the pathogen in culture or produced in the infected plant which are damaging to the host and which are responsible for the symptoms of disease.These phytotoxins vary immensely in their structures and biosynthetic origins from polyketides and terpenoids to peptides and quinones. Research carried out in the period since 1987 has uncovered a further range of novel structures. Work has also continued on known phytotoxins and such studies have sometimes revealed the presence of further toxins to those already identified. Indeed it is not uncommon to find more than one type of toxin being produced by a pathogen and examples will be given below. The most recent novel structure to be encountered as a phytotoxin must be eutypine (67) a phenolic compound with an acetylenic sidechain.This is the causal agent of the dying arm disease of the grapevine Vitis vinifera and the toxin was detected in both culture filtrates of the organism Eutype lata and in diseased vines.227 A more expectable phenolic toxin is phomazin a derivative (68) of 2,4-dihydroxybenzoic acid and the causal agent of stem canker Phomopsis helianthi in sunflowers. It is highly phytotoxic; 5 pg cause a brown lesion on sunflower leaf within 24 h while 20 pg produces large necrotic areas and chlorotic halos.228 The ester substitution (68) is possibly not necessary for activity since 4-hydroxybenzoic acid is able to produce brown necrotic spots when injected into rice leaves.This simple acid is reported to be a phytotoxin produced by Rhizoctonia oryzae a fungal disease of rice.224 Another simple phenolic phytotoxin is the diphenyl ether cyperine (69) which is synthesized by the fungal pathogen Ascochytu cypericola when it infects the weedy purple nutsedge Cyperus rotund~s.~~~ It is relatively ?on-selective in its activity producing a necrotic action in several non-sedge plants. This non-selectivity is also true of di-0-methyldiaporthin (70) an isocoumarin phytotoxin of Drechslera succans a pathogen of oats and rye grass. Indeed this compound isolated from the culture filtrate is relatively inactive against the host plants but produces necrotic lesions on other plants at the 1 pg Yet another new phenolic phytotoxin is 2,4,8-trihydroxytetralone (7 I) produced by Mycosphuerellu Jijiensis a pathogen causing ‘black sigatoka’ disease in bananas.This compound induces necrotic lesions on sensitive banana cultivars at a concentration of 5 pg ml-l in less than 12 h.232 Four other toxins were isolated juglone 2-carboxy-3-hydroxycinnamic acid iso-ochracinic acid (a phthalide) and 3,4,6,8-tetrahydroxytetralone. These five compounds appear to be major shunt-pathway metabolites formed as by-products of melanin biosynthesis melanin production being another feature NPR 10 of the ‘black sigatoka’ disease. A sixth toxin fijiensin (72) which produces both necrosis and chlorosis in banana plants is presumably of polyketide In the spiciferones A-C (73)-(75) from Cochliobolus spicifer a pathogen on wheat it is the 2-C-methyl substitution in the pyrone ring which contributes to phytotoxicity.Thus both spiciferone A and C are very toxic to wheat while spiciferone B has low activity. A fourth phytotoxin spiciferinone (76) with both a C-methyl and C-ethyl substitution at C-2 is even more toxic than (73).234 Two related lactones oxysporone (77) and pestalopyrone (78) may be mentioned here as phytotoxins produced by Pestalotiopsis oenotherae a pathogen of the evening primrose. The first compound (77) is active down to a concentration of 1 pg ml-l especially on the host plant.235 Turning now to phytotoxins of amino acid origin the simplest is 2s-dihydrophenylalanine (79) which induces necrosis in pear cell cultures and which is formed by the fire- blight pathogen Erwinia amylovora.It is able to upset the redox potential of the plant cell and may be a trigger in plants for the suppression of the hypersensitive response. 236 Another simple nitrogen-based phytotoxin is tenuazonic acid (80) a known product of Pyricularia oryzae which inhibits the growth of rice plants by interfering with protein synthesis on the ribosome. Testing various synthetic analogues with different substitutions at C-3 and C5 showed that the natural compound is the optimal structure for phytotoxi~ity.~~’ Assay of 15 strains of P. oryzae from different geographical areas showed that pro- duction of (80) could vary from 0.05 to 0.8 mM in liquid culture.238 A good example of a pathogen capable of synthesizing more than one class of phytotoxin is AZternaria porri which causes black spot disease of leek and onion.Tentoxin a cyclic peptide and zinniol of polyketide origin have been isolated previously from cultures of A. porri. An even more toxic compound porritoxin (81) has now been isolated and this is capable of inhibiting seedling growth in lettuce at 10ppm. It has a nitrogen substitution in the 8-membered ring fused to benzene NATURAL PRODUCT REPORTS 1993 0 R’ (73)R’ = R2 = Me (74) R’ = CH20H R2= Me (75) R’ = Me R2 = CH@H and is a benzoxazocine derivative.239 A more complex series of nitrogen-based phytotoxins are the diketopiperazines such as sirodesmin H (82).These are produced by the black leg fungus Phoma Zigam which attacks rape seed and other Brassica crops.240 Undoubtedly the best known terpenoid-based phytotoxin is fusicoccin from Fusicoccum amygdali which is non-host-specific in its activity and can cause wilting in most higher plant species. A ‘H NMR conformational study of this toxin and six related structures attempted to relate molecular conformation with biological activity but was not entirely succe~sfu1.~~~ A novel feature of the pimarane diterpenes recently detected as phytotoxins of Hypoxylon mammatum a pathogen on poplar is the presence of sulfate groups in some of them e.g. in hymatoxin A (83).242 A new phytotoxic sesquiterpene seiricardine A (84) has been obtained from cultures of Seiridium cupressi the cause of canker disease in Cypress.243 Besides producing sesquiterpenes this fungus also synthesizes butenolide and macrolide toxins.244 Another class of phytotoxin not so far mentioned are the perylenequinones. Examination of the cultures of Alternaria cassiae gave four known derivatives stemphyperylenol stemphyltoxin 11 alterperylenol and altertoxin I.245 Similar examination of culture extracts of A. alternata a pathogen of the spotted knapweed gave two known and two new perylenequinones alterlosins I (85) and I1 (86).246 One final group of new phytotoxins that deserve mention are the peptides. Ustiloxin (87) with a 13-mernbered ether-linked ring based on 4amino acids is newly reported from false smut balls on rice panicles.It is a product of the fungus Ustilaginoidea ~irens.~~’ Eight new phytotoxins from Pseudomonas syringae pv syringae are the syringostatins which are cyclic nonapeptides with a hydroxy fatty acid sidechain linked to the nitrogen of a serine residue.248 Several new malformins cyclic pentapeptides from Aspergillus niger have also been reported. 249,250 A larger straight chain peptide (or small protein) fimbriaton has been isolated as the toxin of CeratocystisJimbriata,the canker stain NATURAL PRODUCT REPORTS 1993-5. B. HARBORNE HO 0 0 OH NH2 OH M\e,CH2Me I HO&-C-CH2-e-CH2-S A A >=/ 0-c HC-CONHCH2C02H HO HO--CH \ NH I -H -H OH OH OH 0 HO 0 (87) 0 (93) (94) of the plane tree Platanus acerifolia.It has a similar molecular weight (18000) to ceratoulmin the well known phytotoxin of Dutch Elm disease.251 5.3 Constitutive Antimicrobial Defence New structures with antifungal activity continue to be reported from plant tissues but there is rarely supporting evidence showing that these substances provide resistance in vivo. The presence of hydroxylated stilbenes in the heartwood of many trees has long been associated with resistance to decay but recent experiments setting out to establish an in vivo role have not been entirely successful. While several stilbenes were active against two brown rot fungi they showed no activity against the white rot Coriolus versicolor. Furthermore no synergism was observed with mixtures of stilbenes or mixtures with their dihydro derivatives the biben~yls.~~~ More promising evidence for an in vivo role for constitutive antifungal agents has been obtained in the case of the cucurbitacins the characteristic bitter principles of the cu-cumber family.When cucurbitacin I was applied to cucumber roots or plants prior to inoculation with a Botrytis cinerea it prevented the infection spreading. Moreover the protective effect was not due to the localized increase in lignification which could be observed but was due to the ability of the cucurbitacin to inhibit the induction of the enzyme laccase. Formation of this enzyme in Botrytis cinerea is associated with tissue damage and the spread of the infection.253 Three long chain alcohols (88) to (90) have been characterized as constitutive antifungal agents in immature avocado fruit peel.On ripening these compounds disappear from the peel and natural infection then ensues. There is therefore some circumstantial evidence in this case of a protective role during the ripening process. 254 Another example where there is reasonable evidence of an in vivo role is the occurrence of high levels of procyanidin in the flush shoot tissue of the cocoa plant Theobroma cacao. Here the quantities present are well above those required to inhibit the germination of the spores of the witches’ broom pathogen Crinipellis perniciosa in vitro. Furthermore preliminary data suggest that resistant cocoa lines have more procyanidin present than susceptible lines.255 Seven related antimicrobial diterpenes including oryzalide A (91) have been identified in the healthy leaves of rice cultivars which are resistant to leaf blight.Again there is an association between occurrence and natural resistance.256 However no such association exists in the case of (-)-jasmonic acid recently reported as an antifungal agent in the wild rice species Oryza ofi~inalis.~~~ Although jasmonic acid is weakly antifungal in vitro against Pyricularia oryzae the rice blast organism the concentration present (4.5 mg isolated from 22 kg of rice leaves) must preclude any in vivo role. 5.4 The Phytoalexin Response The process of elicitor recognition and signal transduction in the phytoalexin response in plants has been The fungal glucan polytran L has been shown to be an efficient elicitor of phytoalexin synthesis in soyabeans pepper and pea.259 Cryptogein an extracellular protein of Phytophthora cryptogea elicits the hypersensitive response and capsidiol synthesis in tobacco leaves.26o Another protein harpin produced by Erwinia amylovora elicits the hypersensitive response in tobacco without inducing phytoalexin synthesis.It causes tobacco leaf lamella to collapse and local death of the epidermal cells occurs.261 Snyder and Nicholson262 by following the elicitation of the anthocyanin phytoalexins in sorghum have shown that synthesis occurs in subcellular inclusions within the host epidermal cells and is restricted to the first cells that come under fungal attack. The phytoalexins of woody plants mainly phenolics and terpenoids have been reviewed.263 Phytoalexin formation within the tribe Phaseoleae and within the genus Vigna has been 265 Crombie and Mi~try~~~ have shown by synthesis that the phytoalexins of oat leaves are not benzoxazin- 4-ones but the corresponding amides.Thus the structure of avenalumin I has been corrected to (92). Niemann et a1.268 have reported that the phytoalexins of carnation undergo conversion from benzoxazinone (e.g. 93) to N-aroylanthranilate (e.g. 94) during isolation. The complicated chemistry of defence in the carnation to fungal invasion has been reviewed by Niemann.269 Benzoxazinones which occur constitutively in many cereals have been implicated as possible phytoalexins in wheat in response to stem rust Puccinia graminis infection.270 H&=CH(CH2)1 lCHOHCH2CHOHCHflH (88) %Me CH EC( C H2) 11CHOHCH2CHOHCHfl R (89) R = H 0 ‘* H (90)R = Ac (91) NATURAL PRODUCT REPORTS 1993 HO NHC-SMe QT-$::Me H H k a 0 (102) R= H (103) R=OMe The characterization of five novel sulfur-containing indoles as phytoalexins of Brassica campestris and Raphanus sativus was mentioned in the last report.At least seven new structures have since been described. Cyclobrassinin sulfoxide (95) is a phytoalexin of Brassica j~ncea.~~l Infection of B. campestris with Pseudomonas cichorii has led to the synthesis of three aldehydes brassicanals A-C (96)-(98) the thioketone dioxi- brassinin (99) and the N-methoxy derivatives (100) and (101).272,273 Two further structures camalexin (102) and its methoxy derivative (103) have been isolated as phytoalexins in the leaves of Camalina sativa another member of the Cr~ciferae.'~~ Camalexin is remarkably similar in structure to the synthetic systemic fungicide thiabendazole (1 04) showing that nature has long ago arrived at the synthesis of a thiopyrrole structure to ward off fungal infection.Onion like cabbage produces constitutive sulfur compounds but unlike cabbage the phytoalexins of onion Allium cepa are sulfur-free. Two simple cyclopenta- 1,3-diones (105) and (106) have been characterized. 75 The biphenyl (107) has been reported as a phytoalexin in beech leaves although it is also produced in leaves treated with ozone or which have been stressed in other ways.276 Two further biphenyls 4-methoxyaucuparin (108) and rhaphiolepsin (109) are newly reported as phytoalexins from the rosaceous Rhaphiolepsis umbellata.27 These compounds inhibit spore germination in the three fungi tested at 10 ,ug ml-'.The most important phytoalexin of sugar cane is the known stilbene piceatannol. It is formed in response to infection by the red rot disease of sugar cane Colletotrichum fal~atum.~~~ It is claimed to be more fungitoxic than the red pigment luteolinidin earlier isolated as a phytoalexin in this plant. Another anthocyanin pigment apigenidin 5-caffeoylarabinoside is reported to be a phytoalexin of the related cereal plant Sorghum bi~olor.~~~ A different red pigment -an aurone -has been described as a phytoalexin of Cephalocereus senilis (Cactaceae) based on its induction in cell culture after treatment with chitin.It is called cephalocerone (1 10) and is toxic to the cactus rot Erwinia sp.280 Earlier research has shown that the sesquiterpene lactones lettucenin A and costunolide are formed as phytoalexins in certain members of the Compositae notably in the chicory plant Cichorium intybus. A further guaianolide lactone cichoralexin (1 11) has been found in tissues of chicory infected ,CH2N=C(SMe '12 Qp-JCON= I OMe (100) (105) R = (CH2)5Me (107) (106) R = (CH2)7Me \ OR (108) R=Me (109) R=H OMe 1 Q (111) by Pseudomonas cichorii. 281 It is structurally related to the constitutive sesquiterpene lactones of chicory e.g.lactucin and 8-deoxylactucin. Finally two structurally novel phytoalexins deserve mention here. First there is yurinelide a 3-benzylidene- 1,4-benzodioxin-2-0ne (1 12) from bulbs of Lilium maximowczii infected with Fusariurn oxysporum.282 Second there is the odd ether-substituted chromone (1 13) which is a phytoalexin of Cassia obt~sifolia.~~~ The reason why these and other phytoalexins are fungitoxic is not entirely clear. In the case of the isoflavonoid phytoalexins of legume plants structure-activity relationships suggest a function as uncouplers of oxidative phosphorylation in the fungal cell. The relative acidity and the number of phenolic groups then determine the antifungal potency.284 The importance of phytoalexin detoxification for fungal pathogenicity has been stressed by van Etten et a1.285 The tolerance of Gibberella pulicaris to the furanocoumarin NATURAL PRODUCT REPORTS 1993-J.B. HARBORNE OMe (114) c-qco2H OH 6 References 1 2 3 4 5 6 7 8 9 10 ’Phytochemical Induction by Herbivores’ ed. D. W. 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Deane Bowers J. Chem. Ecol. 1988,14,917. 196 M. P. Zalucki L. P. Brower and S. B. Malcolm Ecol. Entomol. 1990 15 231. 197 S. Matsuyama Y. Kuwahara S. Nakamura and T. Suzuki Agr. Biol. Chem. 1991 55 1333. 198 J. A. A. Renwick C. D. Radke and K. Sachdev-Gupta J. Chem. Ecol. 1989 15 2161. 199 K. Sachdev-Gupta J. A. A. Renwick and C. D. Radke J. Chern. Ecol. 1990 16 1059. 200 M. Rothschild H. Alborn G. Stenhagen and L. M. Schoonhoven Phytochemistry 1988 27 101. 201 M. B. Dimock J. A. A. Renwick C. D. Radke and K. Sachdev- Gupta J. Chem.Ecol. 1991 17 525. 202 R. Nishida T. Ohsugi H. Fukami and S. Nakujima Agr. Biol. Chem. 1990 54 1265. 203 V. Y. Yokoyama and G. T. Miller Canad. Entomol. 1991 123 711. 204 A. C. Hartung M. G. Nair and A. R. Putnam J. Chem. Ecol. 1990 16 1707. 205 J. D. Weidenhamer D. C. Hartnett and J. T. Romeo J. Appl. Ecol. 1989 26 613. 206 J. D. Weidenhamer and J. T. Romeo J. Chem. Ecol. 1989 15 1957. 207 G. B. Williamson and J. D. Weidenhamer J. Chem. Ecol. 1990 16 1739. 208 D. Choesin and R. E. J. Boerner Am. J. Bot. 1991 78 1083. 209 P. D. Brown M. J. Morra J. P. McCaffrey D. L. Auld and L. Williams J. Chem. Ecol. 1991 17 2021. 210 R. J. Aerts W. Snoeijer E. van der Meijden and R. Verpoorte Phytochemistry 1991 30 2947. 21 I N. H.Fischer J. D. Weidenhamer and J. M. Bradow J. Chem. Ecol. 1989 15 1785. 212 J. M. Bradow and W. J. Connick J. Chem. Ecol. 1988,14 1617; 1633. 213 T. Reynolds J. Exp. Bot. 1989 40,391. 214 U. Blum and J. Rebbeck J. Chem. Ecol. 1989 15 917. 215 C. Hauck S. Muller and H. Schildknecht J. Plant Physiol. 1992 139 474. 216 F. A. Einhellig and I. F. Souza J. Chem. Ecol. 1992 18 1. 217 N. H. Fischer J. D. Weidenhamer and J. M. Bradow Phytochemistry 1989 28 23 15. 218 N. H. Fischer J. D. Weidenhamer J. L. Riopel L. Quijanos and M. A. Menelaou Phytochemistry 1990 29 2479. 219 F. R. Stermitz and G. H. Harris J. Chem. Ecol. 1987 13 1917. 220 M. J. Schneider and F. R. Stermitz Phytochemistry 1990 29 1811. 221 M. Wink and L. Witte J. Chem.Ecol. 1993 19 441. 222 ‘Mycotoxins and Phycotoxins ‘88’ ed. S. Natori K. Hashimoto and Y. Ueno Elsevier Amsterdam 1989. 348 223 ' Mycotoxins Symposia-in-print no. 37 ' Tetrahedron 1989 45 2237-2560. 224 B. B. Jarvis J. 0.Midiwo G. A. Bean M. B. Abdoul-Nasr and C. S. Barras J. Nat. Prod. 1988 51 736. 225 J. 0. Kuti B. B. Jarvis N. M. Rejali and G. A. Bean J. Chem. Ecol. 1990 16 344. 226 B. B. Jarvis N. M. Rejali E. P. Sehenkel C. S. Barros and N. I. Matzenbacher Phytochemistry 1991 30 789. 227 P. Tey-Rulh I. Phillipe J. M. Reynaud G. Tsoupras P. de Angelis J. Fallot and R. Tabaschi Phytochemistry 1991,30,471. 228 C. Mazars M. Rossignol P. Auriol and A. Klaebe Phytochemistry 1990 29 344 1. 229 R. Adachi and K. Inagaki Agric.Biol. Chem. 1988 52,2625. 230 A. Stierle R. Upadhyay and G. Strobel Phytochemistry 1991 30 2191. 231 Y. F. Hallock J. Clardy D. S. Kenfield and G. Strobel Phytochemistry 1988 27 3 123. 232 A. Stierle R. Upadhyay J. Hershenhorn G. A. Strobel and G. Molina Experientia 199 1 47 853. 233 R. K. Upadhyay G. A. Strobel S. J. Coval and J. Clardy Experientia 1990 46,982. 234 H. Nakajima T. Hamasaki. M.A. Kohno and Y. Kimura Phytochemistry 1991 30 2363. 235 P. Venkatasubbaiah C. G. van Dyke and W. S. Chilton Phytochemistry 1991 30 1471. 236 G. J. Feistner Phytochemistry 1988 27 3417. 237 M. H. Lebrun L. Nicolas M. Banton F. Gaudiemer S. Ranemsujanahary and A. Gaudemer Phytochemistry 1988 27 77. 238 M. H. Lebrun F. Dutfoy F. Gaudemer G. Kunesch and A.Gaudemer Phytochemistry 1990 29 3777. 239 R. Suemitsu K. Ohnishi M. Horinchi A. Kitaguchi and K. Odamura Phytochemistry 1992 31 2335. 240 M. S. C. Pedras G. S. Swartz and S. R. Abrams Phytochemistry 1990 29 777. 241 A. Ballio S. Castellano S. Cerrini A. Evidente G. Randazzo and A. L. Segre Phytochemistry 1991 30 137. 242 K. Borgschulte S. Rebuffat W. Trowotz D. Schomburg J. Pinau and B. Bedo Tetrahedron 1991 47 8351. 243 A. Ballio M. A. C. Morelli A. Evidente A. Graniti G. Randazzo and L. Sparapano Phytochemistry 199 1 30 13 1. 244 A. Ballio A. Evidente A. Graniti G. Randazzo and L. Sparapano Phytochemistry 1988 27 31 17. 245 C. M. Hradil Y. F. Hallak J. Clardy D. S. Kenfield and G. Strobel Phytochemistry 1989 28 73. 246 A. C.Stierle J. H. Cardellina andG. Strobel J. Nut. Prod. 1989 52 42. 247 Y. Koiso M. Natori S. Iwacki and S. Sato Tetrahedron Lett. 1992 33 4157. 248 N. Fukuchi A. Isogai J. Nakayama S. Takayama S. Yamashita K. Suyama and A. Suzuki J. Chem. Soc. Perkin Trans. I 1992 875. 249 F. Sugawara K. W. Klim J. Uzawa S. Yoshida N. Takahashi and R. W. Curtis Tetrahedron Lett. 1990 31 4337. 250 K. W. Kim F. Sugawara J. Uzawa S. Yoshida and R. W. Curtis Tetrahedron Lett. 1991 32 6715. 251 S. Saki H. Darbon L. Grillet and C. Lambert Phytochemistry 1992 31 1199. 252 T. P. Schulz Q. Cheng. W. D. Boldin T. F. Hubbard L. Jin T. H. Fisher and D. P. Nicholas Phytochemistry 1991 30 2939. 253 N. Bar-Nun and A. M. Meyer Phytochemistry 1990 29 787. 254 N. K.B. Adikaran D. F. Ewing A. M. Karunaratne and E. M. K. Wijeratne Phytochemistry 1992 31 93. 255 H. E. Brownlee A. R. McEuen J. Hedger and I. M. Scott Physiol. Mol. Plant Path. 1990 36 39. NATURAL PRODUCT REPORTS 1993 256 M. Watanabe Y. Kono J. Uzawa and M. Teraguchi Biosc. Biotech. Biochem. 1992 56 113. 257 G. C. Neto Y. Kono H. Hyakutaki M. Watanabe Y. Suzuki and A. Sakurai Agr. Biol. Chem. 1991 55 3097. 258 D. Scheel and J. E. Parker Z. Naturforsch. Teil C 1990 45 564. 259 I. S. Bhandal and J. D. Paxton J. Agr. Food Chem. 1991 39 2156. 260 M. L. Milat P. Ricci P. Bonnet and J. P. Blein Phytochemistry 1991 30 2171. 261 Z. M. Wei R. J. Laby C. H. Zamoff D. W. Bauer S. Y. Ho A. Collmer and S. V. Beer Science 1992 257 85. 262 B. A. Snyder and R.L. Nicholson Science 1990 248 1637. 263 D. Gottstein and D. Gross Trees 1992 6 55. 264 J. L. Ingham Biochem. Syst. Ecol. 1990 18 329. 265 J. L. Ingham S. Tahara S. Shibaki and J. Mizutani Z. Naturforsch. Teil C 1989 44,905. 266 G. I. 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ISSN:0265-0568    

DOI:10.1039/NP9931000327

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Recent Progress in the Chemistry of lndole Alkaloids and Mould Metabolites J. E. Saxton School of Chemistry University of Leeds Leeds LS2 9JT ~ Reviewing the literature published between July 1991 and June 1992 (Continuing the coverage of the literature in Natural Product Reports 1992 Vol. 9 p. 393) 1 General 2 Simple Alkaloids 2.1 Non- tryptamines 2.2 Non-isoprenoid Tryptamines 3 Isoprenoid Tryptamines 3.1 4 Ergot Alkaloids Monoterpenoid Alkaloids (1) BrassicanalC (2) Dioxibrassinin 4.1 Alkaloids Containing an Unrearranged 4.2 Monoterpenoid Unit Corynantheine -Heteroyohimbine -Yohimbine R Group and Related Oxindoles 4.3 Sarpagine -Ajmaline -Picraline Group 4.4 Strychnine Group 4.5 Ellipticine -Uleine -Apparicine Group 4.6 4.7 5 6 Aspidospermine -Vincamine Group Catharanthine -Ibogamine Group Bisindole Alkaloids Biogenetically Related Quinoline Alkaloids (4) MethoxybrasseninA R = H H (5) MethoxybrasseninB R = 0 6.1 Cinchona Group 6.2 7 Camptothecin References 0- I General The two chapters in Volume 40 of the Manske-Brossi series of alkaloid monographs are concerned with plant biotechnology OMe for the production of alkaloids,l" and with alkaloids obtained (54 from mushrooms;1b while Volume 41 edited by Brossi and Cordell contains accounts of alkaloids from the plants of Thailand,2" and marine alkaloids ;2b all four chapters contain copious references to indole alkaloids.Another review of heterocyclic compounds derived from marine organisms is exclusively devoted to indole derivatives3 In a survey with a rather different emphasis some of the milestones in Swiss alkaloid research that have been published in Helvetica during the last 75 years have been summarized; these include notable (6) Melochicorine contributions on ergot curare Aspidosperma and Aristotelia alkaloid^.^ plants (Brassica oleracea var.capitata) inoculated with The NMR spectra of indole alkaloids have again been Pseudomonas cichorii.* Dioxindole (2) was readily synthesized disc~ssed.~" from isatin and the lithium derivative of acetonitrile. The use of capillary gas chromatography coupled with mass Methoxybrassenins A and B two phytoalexins isolated from spectrometry for the identification of a wide range of indole Chinese cabbage (B. campestris ssp. pekinen~is),~ prove to have alkaloids has been investigated and the method applied to the the structures (4) and (5).The former of these was prepared by analysis of alkaloids produced by cell suspension cultures of the S-methylation of methoxybrassinin.Interestingly the latter Tabernaemontana divari~ata.~~ (5) exhibits only one signal (6H) for the two methylthio groups Reviews of more restricted topics include a third one on the presumably owing to syn-anti topomerization which indicates carbazole alkaloids,6a an account of synthetic work on the a substantial contribution to the overall structure from the Aristotelia alkaloids,6* a survey of the synthesis of hetero- zwitterionic form (5a); in contrast methoxybrassenin A (4) yohimbine and yohimbine alkaloids by the reductive exhibits two 3H signals owing to the two S-methyl groups.and photocyclization of enamide~,~~ progress towards the The synthesis of glucobrassicin and its 4- and 5-methoxy synthesis of ~uanzine.~~ derivatives,loa and a second synthesis of methoxybrassinin lob have been reported. Syntheses have also been reported of the phytoalexins camalexin and 6-methoxycamalexin and 2 Simple Alkaloids of the methyl ester of the broad spectrum antibiotic, 2.1 Non-tryptamines chuangxinmycin. Brassicanal C (l) a new sulfur-containing phytoalexin and Melochicorine isolated from the aerial parts of Meiochia two dioxindoles (2) and (3) have been isolated from cabbage corchori folia L. is an indoxyl derivative of structure (6).12 349 NATURAL PRODUCT REPORTS 1993 (7) Gomphrenin I R=H (8) Gomphrenin I1 R= HO (9) Gomphrenin I11 R= HO*co- Me0 0 0 H H I 0 Q-i QTW H H The use of NMR spectroscopy and ion spray mass spectroscopy in combination with tandem mass spectroscopy in the elucidation of the structure of the betacyanins has been illustrated by the application of these techniques to the known betacyanins gomphrenins I -I11 (7)-(9) (from Gomphrena globosa L.flowers) betanin (from Beta vulgaris L. ssp. vulgaris var. conditiva Alef. roots) and lampranthin I1 [betanidin 5-0- (6'-0-E-feruloyl-/3-glucoside)] which were obtained from cell suspension cultures of B. vulgaris.l3 Of the eight aromatic compounds isolated from the sponge Tedania ignis Duchassaing and Michelotti collected from Bermudan waters four (1 OF( 13) are simple indole derivatives and a fifth is 1-methylcarbaz01e.l~ Since acetone was used in the extraction process it is not inconceivable that indoles (1 1) and (12) may be artefacts.Two new carbazole alkaloids glycozolicine and glycosinine have been isolated together with 3-formylcarbazole (previously reported) from the roots of Glycosmis pentaphyllu. 15' Glycozolicine was identified as 5-methoxy-3-methylcarbazole and glycosinine as 2-methoxy-3-formylcarbazole. The stem bark of Taiwanese Clausena excavata a shrub which finds use in folk medicine in the treatment of snakebite and abdominal pain has yielded two new alkaloids clausine D (14a) and clausine F (14b) which exhibit significant anti- platelet aggregation activity.15' This is the first report of such activity among the carbazole alkaloids.Another Taiwanese plant Murraya euchrestifolia Hayata has already yielded an impressive range of carbazole alkaloids and several new ones have been reported during the last year. Twelve monomeric alkaloids have been isolated from the stem bark collected in May ;these are pyrayafolines B (1 5) C (1 6a) D (16b),16" and E (17),160 euchrestines A (18) B (19) C (20) D (14a) Clausine D R=CHO (15) Pyrayafoline B (14b) Clausine F R=C02Me R' (16a) Pyrayafoline C R=H (1 6b) Pyrayafoline D R=prenyl Me OH H (17) Pyrayafoline E (21),16" and E (22),16' murrayalines B (23) C (24) and D (25) and murrayaquinone E (26).16' Two bis-carbazole alkaloids were also obtained (q.v.).lSbThe structure of pyrayafoline B (14) was established by synthesis of its 0-methyl ether.16" The root bark of this plant contains two relatively simple monomeric alkaloids which were identified as 3-formyl-7-hydroxy-carbazole and N-methoxy-3-hydroxymethylcarbazole,17 while the fruits yielded murrayamine C (27) in addition to several known alkaloids (murrayafoline A murrayanine mukoeic acid and girinimbine).ls Structure (27) now attributed to murrayamine C has already been assigned to mahanimboline an alkaloid of the root bark of Murraya koenigii Spreng,19 but the two alkaloids are stated to be different in which case the structure of the latter may have to be re-examined.The X-ray crystal structure of N-allylgirinimbine has been determined.20 Syntheses of the antibiotic carbazomycinal [carbazomycin E (28)] (Scheme 1)21 and the free radical scavenger carazostatin (29) a constituent of Streptomyces chromofuscus (Scheme 2),22 have been reported.Carazostatin is claimed to be a superior radical scavenger to butylated hydroxytoluene (BHT). The total assignment of the proton and carbon NMR spectra of cryptolepine in d,-DMSO has been achieved23 by means of heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond correlation experiments (HMBC) and confirmed by a relatively new technique selective inverse multiple bond analysis (SIMBA).23a The same group have performed a similar complete analysis of the NMR spectra of quindoline (norcryptolepine) ;in this case HQMC-TOCSY spectra were used in preference to COSY spectra because of congestion in the proton Inevitably the chemical shifts reported for the protons in cryptolepine in DMSO differ significantly from those reported recently for cryptolepine in deuteriochloroform solution.24 Several anti-insectan indole-diterpene metabolites have re- cently been isolated from two Aspergillus species.The first of these aspernomine (30) a constituent of A. norniu~,~~ contains NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 35 1 ~30 OH ~3 0 OH H H (18) Euchrestine A R' (19)EuchrestineB R' (20)Euchrestine C R' (21)EuchrestineD R' HO = R3 = H R2 = prenyl = H2Cw, = H R2 = geranyl R3 = Me (22)Euchrestine E R' = Me R2 R3=H = R3 = H R2= geranyl = geranyl R2 = R3 = H (23)MurrayalineB R' = R3 = Me R2= CHO (24)Murrayaline C R' = R2 = CHO R3 = Me (25) MurrayalineD R' = CHO R2 = geranyl R3 = Me 0 Me (26)Murrayaquinone E (27)Murrayamine C iiiv L(c0)3FeDD.@OMe ___) a,P"Me \ 'Me H2N Me CHO CHO CHO (28)Carbazornycinal Reagents i MeCN 25 "C; ii Ac,O py DMAP CH,Cl, 25 "C; iii very active MnO, PhMe 25 "C;iv NaOH H,O heat Scheme 1 iii-vii Q~Q" i \o ii \ ~ Q7-7~02" a7qo o7qsiMe3 'C02Et Me H H H H C7H15 C7H15 C7H15 (29)Carazostatin Reagents i (C,H,,CO),O BF; Et,O; ii Me,SiC-CCO,Et PhBr heat; iii LiAIH, dioxan heat; iv Hg(OAc), AcOH; v BF;THF; vi H,O, NaOH H,O; vii HC1 H,O Scheme 2 (30)Aspernornine (31)Nominine a tetrahydroquinoline ring but since it occurs in association with nominine (31) it is almost certainly derived from tryptophan and a diterpene unit.The same group of research workers have isolated a family of indole-diterpene metabolites from the sclerotia of A. sulphureus (Fres.) Thom. and Church.26 The structure of radarin A (32) was deduced by extensive 2D Me Me I (32)RadarinA R = OH (33)Radarin B R =OH (34)RadarinC R=H (35)Radarin D R = H NMR experiments and the structures of radarins B-D (33)-(35) by analysis of NMR data and spectral comparison.26a In accordance with these structures radarin A (32) could be reduced to radarin B (33) by L-selectride. The CD spectra of radarins A (32) and C (34) are consistent with the absolute configurations depicted.H (36) SulpinineA 0 (38) Sulpinine C -0T.t HH (40) Pennigritrem Four other metabolites obtained from this source together with the known penitrem B are sulpinines A-C (36)-(38) and secopenitrem B (39).26b Again the structures were determined by extensive use of NMR spectroscopy and also by comparison with the structurally related penitrems e.g. penitrem B which has a very similar structure to (39) but with a C-16-oxygen to C-18 bond. The previously unknown ring system of sulpinine C (38) is presumably derived by oxidative fission of the indole ring in a suitable precursor e.g. sulpinine A (36). Since the absolute configuration of penitrem B is known it seems highly likely that (39) represents the absolute configuration of secopenitrem B and (36)-(38) represent the absolute stereochemistry of sulpinines A-C.26b Of these metabolites aspernomine (30),25 radarins A and C (32) and (34),26u sulpinines A and B (36) and (37) and secopenitrem B (39)26*exhibit activity against the lepidopteran crop pest the corn earworm Helicoverpa zea.In addition as~ernomine,~~ radarins A and B,26u and sulpinine A26b exhibit cytotoxicity against three human solid tumour lines viz. the A- 549 lung carcinoma MCF-7 breast adenocarcinoma and HT- 29 colon adenocarcinoma cell lines. The optimum conditions for the production of penitrem B by Penicillium aurantiogriseum have been investigated. 27 P. nigricans an important source of the penitrems has now yielded a new tremorgenic mycotoxin pennigritrem (40) which contains an oxetane ring formed by cyclization of the C-25 hydroxy-group of penitrem A on to C-37 of the neighbouring isopropenyl group a structural feature which has not previously been encountered among the indole-diterpenoid fungal metabolites.28 Pennigritrem is much less active as a tremorgen than penitrem A and shows a similar activity on the molar basis to that exhibited by paspalinine.Details of the total synthesis of (+)-paspalicine and (+)-paspalinine by Smith and his collaborators have been NATURAL PRODUCT REPORTS I993 H OH H (37)Sulpinine B (39) Secopenitrem B 0 0 (42a) Nephilatoxin-11 R = H y42 !YH (42b) Nephilatoxin-9 R = COCH(CH2)3NH CNH2 publi~hed.~~ The preparation of the ketone (41) a potential intermediate in an alternative approach to paspalinine has also been reported.30 2.2 Non-isoprenoid Tryptamines The bark of Mimosa scabrella Benth.contains tryptamine N,-methyl tryp tamine N N-dimethyl tryp tamine and Nb-meth yl-1,2,3,4-tetrahydro-,&carboline.31 A Japanese group has completed the first syntheses of four of the neurotoxins nephilatoxins 9-12 (42a b) and (43a b) of the Joro spider Nephila ~lavata.~~ The seeds of Zpomoea obscura (L.) Ker. Gawl. (Convolvulaceae) have yielded three tryptophan-derived metabolites ipobscurines A-C.33a-c Ipobscurine A is simply N,-p-coumaroylserotonin 33u which has been isolated previously from safflower seeds Carthamus tinctorius (Asteraceae) to- gether with Nb-coumaroyltryptamine N,-feruloyltryptamine and serotobenin (44) whose structure was elucidated by X-ray crystal structure analysis.33d (-)-Ipobscurine B has the struc- ture (49 and was shown by synthesis to be the erythro isomer.33b Ipobscurine C (46) has the same skeleton as ipobscurine B but has an additional ether linkage which results in a 21-membered ring.33c Horsfiline (47a) a new oxindole alkaloid has been found in NATURAL PRODUCT REPORTS 1993-5.E. SAXTON n 0 0 (43a) Nephilatoxin-12 R = H H y2 !YH (43b) Nephilatoxin-10 R = COCH(CH2)3NHCNH2 (44) Serotobenine Meo*Me \ N O (45) lpobscurine B (46) lpobscurine C (47b) Nazlinine (48) Chelonin A (49) Chelonin B R = H (50) Bromochelonin B R = Br (53) Citreoindole the leaves of Horsjieldiu superbu a small tree indigenous to Malaysia.34a By use of a bioassay-guided fractionation of the aerial parts of Nitruriu schoberi L.those constituents that exhibited serotonergic activity were isolated and shown to contain tryptamine serotonin and a new alkaloid nazlinine which has the structure (47b).34b Three of the four alkaloids isolated from a purple dendritic sponge Chelonuplysillu species collected from a marine lake on Kaibaku Island Palau are indole derivatives and are clearly composed of tryptamine and tyrosine Of these three alkaloids which have the structures (48)-(50) chelonin A is the first known natural compound to contain a 2,6-disubstituted morpholine part-structure ; chelonin C the fourth alkaloid also contains this structural feature but it does not contain an indole ring and may well be derived from two tyrosine precursors.Compounds (48)--(50) exhibited antimicrobial activity against Bacillus subtilis and chelonin A (48) further showed anti-inflammatory activity in vivo in the mouse. (54) R' = H2 R2 = H (55) R' = 0 R2 = H (56)R' = 0 R2 = H 6,7-P-epoxide (57) R' = H2 R2 = H 6,7-P-epoxide (58)R' = 0 R2 = OH 6,7-&epoxide (ChaetoglobosinA) Details of the of (+)-prosurugatoxin and its conversion into surugatoxin have been p~blished.~' Syntheses of the two indolylimidazole alkaloids (51) and (52) from marine organisms have also been reported.38 Citreoindole (53) is a new dioxopiperazine derivative which has been from a hybrid strain KO 0052 produced by cell fusion technique from Penicillium citreo-viride B.IF0 6200 and 4692. Citreoindole is said to exhibit cytotoxicity against HeLa cells. The isolation of four prochaetoglobosins (54)-(57) which xe presumably precursors of chaetoglobosin A (58) from Chuetomium subufine inoculated with specific cytochrome P- NATURAL PRODUCT REPORTS 1993-5. E. SAXTON Meoy7J;<-i ii CO2Et Me Me (59) (62) (61) Reagents i TMSCl/THF/Et,O/hexanes/Ar then BuLi/- 100 "C; ii NH,Cl. H,O; iii NaH MeI 0 "C; iv LiAlH, THF 0 "C;v NaOH MeOH; vi HCI H,O; vii NaH THF; viii LiBEt,H Scheme 3 Me H Me Me H Me NHCO2Et (65) Esermethole R = Me (66) Physostigmine R = CONHMe Reagents i Br, KOBut; ii KOBu' DMSO; iii H, PtO,; iv CIC0,Et; v LiAIH,; vi NBS; vii NaOMe CuI Scheme 4 450 inhibitor throws some light on the probable later stages of the biosynthesis of chaetoglobosin A.40 A new short synthesis of the alkaloids of the Calabar bean which gives rise to physovenine esermethole and physostigmine in high overall yield has been developed (Scheme 3).41 Cyclization of the amide (59) prepared by acylation of 2- iodo-4-methoxy-N-methylaniline with the acid chloride from monoethyl fumarate by an internal Michael reaction initiated by lithium-iodine exchange gave the oxindole derivative (60).Obvious stages then led to the intermediates (61) and (62) which have previously been converted into physovenine esermethole and physostigmine. A second formal ~ynthesis,~ which has the potential to produce (-)-physostigmine in high enantiomeric excess makes use of the chiral nitro-olefin derivative (63) previously prepared.43 Allylic bromination of (63) followed by aromatization and reduction stages gave the aniline derivative (64) which was converted into (-)-esermethole (65) by unexceptional methods (Scheme 4).This has previously been converted into (-)-physostigmine (66). Takano and his collaborators have another enantio-controlled synthesis of (-)-physovenine and (-)-physostigmine in which chirality was introduced by use of the optically active ketone (67) previously prepared in four stages from cyclopentadiene dimer (Scheme 5). This was converted by conventional steps into the ketone (68) which on pyrolysis gave the chiral cyclopentenone derivative (69).Ozonolysis of (69) followed by reduction gave a triol which on periodate cleavage gave the hemiacetal (70). Removal of the N-acetyl group followed by cyclization then gave the important intermediate (71) which on dealkylation and urethane formation gave (-)-physovenine. This is claimed to be the first enantiocontrolled synthesis of this alkaloid. Alternatively oxidation of the hemiacetal(70) gave a lactone (72) which with aqueous methylamine at high temperature gave the lactam (73). Removal of the N-acetyl group by partial reduction to the carbinolamine stage and loss of acetaldehyde followed by cyclization and further reduction gave (-)-esermethole which as noted above has earlier been converted into (-)-phy~ostigmine.~~ Harman has been found in the stem bark of Simiru mexicana (Bullock) Steyerma~ck~~ and in both the arborescent form and the liana form of Strychnos u~umburensis.~~ 1-Acetyl-P-carboline is one of eight aromatic constituents of the sponge Teduniu ign is.Bioactivity-directed separation of the alkaloidal constituents of the New Zealand marine bryozoan Cribriceha cribruriu has enabled the major cytotoxic component 1 -vinyl-8-hydroxy- P-carboline (74) a new alkaloid to be is~lated.~' A second new alkaloid has the novel sulfone structure (75). In addition 355 NATURAL PRODUCT REPORTS 1993-5. E. SAXTON Ac (67) R = H (69) R = Me v i-vii i I &MeO~ AT M e 0 6 9 OH 0 0 NMe Me H Me ?Me I AC AC Ac (65) (-)-Esermethole R = Me (66) (-)-Physostigmine R = CONHMe (73) (72) (70) Jix MeoyJ- Me H (71) Reagents i LDA MeI THF -30 "C; ii MeO.C,H;pNHNH;HCl py H,O heat; iii Ac,O py; iv NaH MeI DMF THF; v o-C,H,CI, heat ;vi 0,,MeOH -78 "C ;vii NaBH, -78 "C+rt then HCl (neutralize) ;viii NaIO ;ix MeOH HCl (cat.) heat; x Ag,CO, Celite C,H, heat; xi MeNH, H,O 180 "C (sealed tube); xii BuiAIH CH,Cl, -78 "C then NH,OH; xiii LiAlH, THF heat Scheme 5 R3 carbony1-4-methoxy-~-carboline,50 and asymmetric syntheses of S-( -)-tetrahydroharman51 and tr~pargine.~ Two of the three compounds isolated from the marine tunicate Eudistoma album namely eudistomin E already known to possess potent antiviral activity and eudistalbin A (77) have been shown to exhibit cytotoxic activity in vitro against KB human nasopharyngeal carcinoma cells ;a third p-(74) R' = CH=CH2 R2 = OH R3= H carboline derivative eudistalbin B (78) was inactive.53 (75) R' = Et R2 = H R3= S02Me A new synthesis of (-)-woodinine (79)54a.and eudistomins (76) R' = CH=CH2 R2 = R3 = H I (80) and H (81)54a makes use of the Pictet-Spengler reaction between the appropriate tryptamine and N-protected L-prolinal for the formation of the tetrahydro-P-carboline ring (Scheme 6). Methoxycarbonylation of (82) followed by reduction and separation of diastereoisomers then gave (-)-~oodinine.~~~* Alternatively dehydrogenation of (83) followed by deprotection gave dihydroeudistomin I (84) which has pre- Br Br H viously been converted by mild oxidation into eudistomin I (80) H and thence by bromination into eudistomin H (81).54a A neat application of the aza-Wittig reaction has led to a new synthesis of rutaecarpine (85).55 Thus reaction of the amide A A (86) prepared from 1-oxo-1,2,3,4-tetrahydro-P-carboline and (77) Eudistalbin A 2-azidobenzoyl chloride with tributylphosphine gave (78) EudistalbinB rutaecarpine (85) directly (Scheme 7).Tryptanthrin (87) was prepared in exactly analogous fashion from i~atin.~~ A second new synthesis of r~taecarpine~~ is essentially a harman 1-ethyl-P-carboline and pavettine (76) were obtained. development of an earlier one5' of rutaecarpine and Cytotoxicity and antimicrobial activity data for these and a vasicolinone in which the intermediacy of the spirocyclic number of other synthetic P-carbolines were also reported.,' indolenine (88) was implicated.In the new synthesis (Scheme 8) Hairy root cultures of Peganurn harmala genetically this indolenine was deliberately prepared from deoxyvasicinone transformed by Agrobacteriurn rhizagenes strain A-4 produce (89) which contains a preformed five-membered ring c. much higher levels of harmine and harmalol than normal Thermal Fischer indolization of the phenylhydrazone (90) gave suspension cultures; the yield of alkaloids may be as high as the desired spirocyclic indolenine (88) which spontaneously 1.0-1.5 % of the dry rearranged to give rutaecarpine (85). Interestingly the use of Synthetic work in this area includes new syntheses of acid conditions for the indolization of (90) gave only a trace of ~renatine,,~ and l-methoxy-rutaecarpine ;the major product was the pyrroloquinazolinone l-acetyl-4-methoxy-~-carboline NATURAL PRODUCT REPORTS 1993 R = H or Br (82) R = Br (84) Dihydroeudistomin I (83) R = H I ii (onR = Br) I Jvi (80) Eudistomin I R = H (79) (-)-Woodinine (81) Eudistomin H R = Br Reagents i N-Boc-L-prolinal CH,Cl, TFA -78 "C Ih then 18 "C 2h; ii ClCO,Me NEt, CH,Cl,; iii LiAlH, THF heat; iv flash chromatography on silica gel; v Pd xylene heat; vi TFA CH,Cl Scheme 6 O-QNH N H 0 (86) (85) Rutaecarpine i -(87) Tryptanthrim Reagents i 2-azidobenzoyl chloride NEt,; ii PBu Scheme 7 (9l) presumably formed by retroaldol cleavage of protonated non-aromatic portion of the skeleton is almost complete (88).Deformylation of (9 I) followed by N-methylation together with the required stereochemistry. A redox reaction on afforded a new synthesis of vasicolinone (92).56 (98) followed by hydrolytic fission of the immonium ion so In the manzamine group full details of the of formed gives an aldehyde (99) which can condense with manzamine C and its geometrical isomer have been tryptophan to give after decarboxylation and aromatization published.59a the /I-carboline derivative (100). Epoxidation then gives In pursuance of their synthetic approaches to manzamine A manzamine B (IOI) from which manzamine A (95) can be Martin and his collaborators have reported the preparation of formed by trans-eliminative opening of the epoxide function the pyrroloquinoline derivative (93) by an intramolecular allylic oxidation of a double bond and ring closure by Diels-Alder reaction on (94) (Scheme 9).59b formation of the N,C-34 bond.Although at first sight the biosynthesis of manzamines A (95) The validity of Baldwin's ingenious proposal at least in its and B may seem puzzling BaldwinG0 has shown that the later stages is amply illustrated by the isolation of four skeletons of these compounds can be dissected into four simple cytotoxic bases ircinals A (102) and B (103) together with components i.e. the dialdehyde (96) ammonia acrolein and manzamines H (104) and J (105) from the Okinawan marine The structures were deduced from tryptophan the biochemical equivalents of which could sponge Ircina SP.~~ combine in unexceptional fashion to form the manzamines spectroscopic data and confirmed by the conversion of ircinal (Scheme 10).Initial condensation to form a bis-dihydropyridine A (102) into manzamine A (95) by condensation with derivative (97) followed by protonation and an intramolecular tryptamine followed by aromatization (Scheme 11). In anal- Diels-Alder reaction give an intermediate (98) in which the ogous fashion ircinal B gave manzamine H (104) initially then NATURAL PRODUCT REPORTS 1993-5. E. SAXTON CHNMe2 CH=NNHPh 0 0 0 (89) (90) 0 0 (85) Rutaecarpine (92) Vasicolinone (911 Reagents POCl, DMF; ii PhNHNH, EtOH heat; iii Dowtherm A 160-190 "C; iv EtOH HCl DMF; v HCl HOCH,CH,OH 160-180 "C; vi HCl MeOH rt; vii CH,O H,O NaBH,CN MeCN Scheme 8 PhCH2N PhCH2N @-i m 0 \/NC02Et NCO2Et m (93) (94) Reagent i mesitylene heat Scheme 9 (102) lrcinal A the corresponding /3-carboline derivative manzamine J (105) which was also formed from manzamine B (101) by trans-/?-eliminative fission of the epoxide function.61 Full details of the synthesis5* of fascaplysin and homofascaplysins B and C have been published.62 Four canthin-6-one and two p-carboline derivatives have been isolated from the roots of Eurycorna longifolia Jack from Kalimantan Indonesia ; these roots are apparently much used in traditional medicine for the treatment of dysentery persistent fever and tertian malaria.63a The four canthinones isolated all of which show cytotoxic activity against a number of human cancer cell types are 9-hydroxycanthin-6-one (106) 9-methoxycanthin-6-one (107) and their N,-oxides.The two p-carbolines are the 1-propionic acid (108) and its 7-methoxy (95) Manzamine A derivative (109); of these the latter shows significant antimalarial activity. 9-Hydroxycanthin-6-one (106) and 9-methoxycanthin-6-one (107) and its N,-oxide are also constituents of the stem bark of Picrolernma granatensis (Simaroubaceae) from the Colombian Amazon.63b4,5-Dimethoxycanthin-6-onewas also extracted from this source together with a new alkaloid which was identified as 8-hydroxy-9-methoxycanthin-6-one (1 10). Four new alkaloids have also been obtained from Aerva lanata;64these are aervine [IO-hydroxycanthin-6-one, (1 1 1a)] its O-p-D-glUCOSYl derivative (1 1 1 b) methylaervine [10-methoxycanthin-6-one (1 12)] and aervolanine [6-methoxy-P- carboline- 1-propionic acid (1 13)].Canthin-6-one and p-carboline- 1-propionic acid (108) were also isolated. NPR 10 NATURAL PRODUCT REPORTS 1993 (97) J (99) 1 (101) Manzamine B (95) Manzamine A Scheme 10 ( 103) lrcinal B (104) Manzamine H (105) Manzamine J (101) Manzamine B Reagents i tryptamine TFA; ii DDQ; iii NaH DMF Scheme 11 Wakayin (1 14) a new cytotoxic pyrroloiminoquinone Two syntheses of discorhabdin C (1 15) have been reported Both syntheses involve the derivative isolated from a CZuveZina species collected from recently (Schemes 12 and 13).66*67 shallow reef waters off Wakaya Island in the Fiji group is the construction of a sensitive indolequinone imine (1 16a) or first representative of this structural group to be obtained from (1 16b) on to which is attached a 3,5-dibromotyramine residue.Wakayin is superficially related to the The spirocyclic dienone system is then formed by oxidation of a marine a~cidian.~~ discorhabdins and presumably arises from tryptophan and the product (1 17) either by anodic oxidation66 or by means of tyrosine. a hypervalent iodine ~eagent.~’ Discorhabdin C (1 15) is formed 359 NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 0A/ KNW H (106) R’ =OH R2 = H (108) R’ = R2 = H (1 14) Wakayin (107) R’ =OMe R2= H (109) R’ = OMe R2 = H (1 1 la) Aervine R’ = HI R2= OH (113) R’ = H R2 = OMe (11lb) R’ = HI R2 = P-D-GkO (112) R’=H R2=OMe 0 CHO NHC02(CH&TMS i-vii viii 4~~2 ix-xi Et 4 ___F ___F Me0x$ Me0 NHCbz NHCH2Ph Me0 Me0 CH2Ph OMe OMe OMe OMe xii xiii 0 OH J _xv BrqB@ ~ xiv I I Me0J@ N N H H H H 0 0 0 (1 15) Discorhabdin C (117) (116a) Reagents i Jones oxidation; ii Im,CO THF then NaN,; iii PhMe heat; iv TMSCH,CH,OH; v H, Pd/C; vi PhCHO AcOH; vii NaBH,CN; viii ClCH,COCH,CO,Et EtOH heat; ix H, Pd AcOH HC10,; x KOH H,O MeOH then HCI; xi DCC THF; xii BH;Me,S; xiii ceric ammonium nitrate ; xiv 3,5-dibromotyramine7 NaHCO, EtOH ; xv anodic oxidation Ar Scheme 12 in both oxidations but in the anodic process66 some ring enlargement of ring B is also observed.Three new metabolites presumably derived from tryptophan and related to the tryptoquivalines have been isolated from a strain of Aspergillus fumigatus found in the intestinal tract of the saltwater fish Pseudolabrus japonicus.68a Fumiquinazolines A and B have the epimeric structures (1 18a) and (1 18b) and fumiquinazoline C has structure (1 18c) according to X-ray crystal structure analysis. Since hydrogenation of fumiquinazoline C gives fumiquinazoline A (1 18a) the struc- tures of (118a) and (118b) are confirmed. All three fumiquinazolines are reported to exhibit moderate cytotoxicity against cultured P-388 lymphocytic leukaemia cells. The tryptoquivalines isolated earlieP* from Aspergillus fumigatus were not encountered in this investigation presumably because the strain of the micro-organism isolated from the saltwater fish was different from that investigated by the earlier workers.68a Glyantrypine (1 18d) which may be regarded as the parent of this group of tryptophan-anthranilic acid derived metabolites has very recently been obtained from a Yugoslavian strain of Aspergillus clavatus ;68c tryptoquivaline and nortryptoquivalone were also isolated.Finally a number of macrocyclic polypeptides which contain a tryptophan or substituted tryptophan component have been isolated from marine sponges of the Theonella genus collected off Okinawa (K~nbu,~~~ io) and Japan and Kerama Islands69b* (Hachijo-jima Island).i1 Konbamide (119) which exhibits calmodulin antagonistic activity,68 contains a 2- bromo-5- hydroxy-N-methyltryptophan unit and a ureido group and keramamide A (120) contains a 6-chloro-5-hydroxy-N-methyl tryptophan unit and a ureido group.69 These are the first known compounds from a marine organism to contain a ureido group.Keramamides B-D (1 2 1)-( 123)’O and orbiculamide (1 24)i1 are also bioactive this last exhibiting cytotoxicity against P-388 murine leukaemia cells. All four cyclopeptides contain an oxazole ring and a 2-bromo-5-hydroxytryptophan residue. 3 lsoprenoid Tryptamines It has been reported perhaps surprisingly that echinulin is a constituent of the roots and stems of Veratrum nigrum L. var. ussuriense Nakai.i2 Penicillium expansum elaborates roquefortine and 3,12-dihydroroquefortine.73 The highest yield of roquefortine was obtained by surface cultivation of the fungus on a complex medium containing glucose peptone and soybean flour whereas submerged culture in the same medium resulted in almost complete inhibition of roquefortine formation.Paraherquamide (125) has been isolated together with three new analogues (1 26)-( 128) from an unidentified Penicilliunz species obtained from a soil sample from Kemer Turkey.i4 The constituents of this fungus appear to be identical to those isolated recently from P. ~harlesii,~~ i.e. metabolite VM 54159 (126) is identical with paraherquamide E and VM 55594 (127) 25-2 NATURAL PRODUCT REPORTS. 1993 OCH2Ph 6''. b2 v-viii i-iv ___) &frCN Me0 Me0 CO2H Me0 H HI ix-xii MeO@Ts xiii.xiv t 0 Me0&flH 0 0 H CO,(CH2)2TMS (1 16b) ?H 0 -0-xvi xvii ___t II N H H H H 0 0 (117) (1 15) Discorhabdin C Reagents i PhCH,Br K,CO, EtOH heat; ii N,CH*CO,Et NaOEt EtOH; iii xylene heat; iv KOH EtOH heat; v copper chromite quinoline 215 "C; vi CH = N+Me,I-; vii MeI 0 "C; viii NaCN H,O 80 "C; ix H, Ni NH, EtOH; x O,N-C6~,-p-OCO,(CH2),TMS,NaOEt EtOH; xi H, Pd/C; xii Fremy's salt KH,PO,; xiii Ts-Cl ButOK THF; xiv TsOH MeCN NaHCO, 3A mol sieves; xv 3,5-dibromotyramine NaHCO, EtOH heat; xvi MeCH = C(0Me)OTMS; xvii PhI(OCOCF,) rt Scheme 13 R2 R' Me 1 0 NH 0aMe 0-Me (1 18d) Glyantrypine (1 18a) Fumiquinazoline A R' = Me R2 = H (1 18c) Fumiquinazoline C (1 18b) Fumiquinazoline B R' = H R2 = Me /CHMe2 /CHMe2 Me ..PhH2C-.\ HoyJ--Ndo N Br NHCONHyHCO2H H CH2CHMe2 O~NH I (1 19) Konbamide PhH2C-%O2H (120) Keramamide A NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 36 1 OH (121) Keramamide B R' = R2 = Et (122) Keramamide C R' = Et R2= Me (123) Keramamide D R' = R2= Me 0; (1 24) Orbiculamide A (125) Paraherquamide R = OH (126) VM 54159 R = H (130) Methylpendolmycin (1 27) VM 55594 R = H (129) Cycloechinulin (128) VM54158 R=OH and VM 541 58 (128) are identical with paraherquamides F and G respectively. Cycloechinulin (129) so named because of its obvious structural resemblance to echinulin is one of three new metabolites isolated from the sclerotia of Aspergillus ochraceous Wilhelm.76 Cycloechinulin is reported to exhibit moderate activity against the corn earworm Helicoverpa zea.Methylpendolmycin (1 30) the homologue of pendolmycin containing an isoleucine unit instead of valine in the nine- membered ring has been isolated together with pendolmycin from a strain of No~ardiopsis.~~ Full details of the synthesis of indolactam V by Moody and his c011aborators~~~ Details are also have been p~blished.'~ available of the 75 79 of lyngbyatoxin A teleocidin A2 pendolmycin (13 1),80Q*dihydroteleocidin B teleocidin B3 and teleocidin B4,80cby Natsume and his collaborators who have also contributed a second-generation synthesis of pendolmycin.81 The disadvantage of the first synthesis75 was NATURAL PRODUCT REPORTS 1993 OAc OAc (133) ( 1 34) OHC \v-vii Boc I \ XH MeN C02Bu' MeNAC02Bu' OH I 2 xi xii I I xiii / I (137) (1 31 ) Pendolmycin Reagents i Bu"Li THF; ii (132); iii Ac,O py; iv TsOH MeCOMe; v Bu"Li (135); vi MnO, benzene Ar; vii H, Pd/C; viii Me,C = CH-CH,Br Mg; ix Mg NH,Cl MeOH; x NaBH,CN CSA THF MeOH Ar; xi Lawesson's reagent C,H, Ar; xii Lawesson's reagent THF heat Ar; xiii o-BrCH,C,H ,CO,Me DMF Me,C = CHMe heat; xiv TFA rt; xv (EtO),POCN Scheme 14 that there was no control over the stereochemistry at C-9 and the final product was therefore a 1 :1 mixture of pendolmycin (131) and 9-epipendolmycin.In the new synthesis (Scheme 14) the correct chirality at the future C-9 as assured by starting with the protected chiral aminoaldehyde (1 32) which was condensed with the anion derived by lithium-halogen exchange on the ethylene acetal of 4-bromo-2-formyl-N-phenylsulfonylpyrrole.The product of this reaction which was a mixture of epimers (133) was elaborated as shown; the second asymmetric centre being introduced by condensation of the aldehyde (134) with the lithium derivative of the chiral acetylene (1 35) prepared from t-butyl-N-methylvaline and propiolic acid. Later stages of interest include the use of Lawesson's reagent to dehydrate the tertiary alcohol (136) followed by more vigorous reaction with the same reagent to give the thioamide (137) and the use of methyl-2-bromomethylbenzoate as the appropriate alkylating agent to increase the efficacy of the leaving group in the indole- forming cyclization.Deprotection of the product which was a mixture of indoles (138) and (139) followed by formation of the nine-membered ring finally gave (-)-pendolmycin (1 3 1).81 The nine analogues of indolactam V which contain various aminoacids in place of L-valine and which were prepared earlier75 by microbial synthesis from the appropriate trypto- phanol have been examined using two biological tests related NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 363 R I R2 1 CH20H 1 13@Me/ #Me 14 ‘ N 2 HH OR’R4 ‘ HN 0 (141) R = C02Me(140) Indolactam-lle (143a) R’ = Et R2 = CO,Me R3= R4= CI (142) = CH20H (14%) R’= Et R2 = C02Me R3= CI R4 = H (14%) R’= Me R2 = CH20H R3= R4= CI (143d) R’ = Me R2 = CHgH R3= CI R4= H (14%) R’ = Et R2 = CHZOH R3= R3= CI (143f) R’ = Et R2 = CH20H R3= CI R4= H (1439) R’= Me R2 = CHSH R3= R4= Br iii iv A (1 45) Agroclavine (1 47) Setoclavine (1 48) Lysergene (1 46) Lysergol Reagents i K,Cr,O, H,SO, MeCOMe 70 “C; ii Woelm A1,0, ClCH,CH,Cl heat ; iii 9BBN.THF heat; iv NaOH H,O Scheme 15 &f ‘N (149) Ambiguine A R’= H R2 = CI (152) Ambiguine D (150) Ambiguine B R’ = OH R2= CI (151) Arnbiguine C R’ = OH R2 = H to tumour promotion.82 The most active of these proved to be (-)-indolactam-Ile (140) in which the L-valine unit of indolactam V is replaced by L-isoleucine. 3.1 Ergot Alkaloids A new book devoted to the chemistry and biochemistry of the ergot alkaloids has been published.s3 Pencillium palitans and P.oxalicum have been shown to contain fumigaclavines A and B pyroclavine festuclavine and chanoclavine I.84 The bromination of a-and /3-ergocryptines by means of phenyltrimethylammonium perbromide is reported to give a 70 YOyield of 2-brornoergo~ryptines.~~ The electrochemical oxidation of 9,lO-dihydrolysergic acid methyl ester (141) and 9,lO-dihydrolysergol (142) in aqueous alcohol in the presence of hydrochloric or hydrobromic acid gives a range of oxindole derivatives (143a)-(143g) in which halogen has been introduced into positions 12 and 14 of the aromatic ring.86 At lower voltages in the presence of hydro- bromic acid the 2,13-dibromo derivative (144) is formed from dihydrolysergol (142). This curious result is not discussed in any detail and is not mentioned in the experimental section.An efficient conversion87 of agroclavine (145) into lysergol (146) makes use of the known oxidation of agroclavine to setoclavine (147) in the first stage. Dehydration by means of Woelm alumina in 1,2-dichloroethane at reflux then gives lysergene (148) which on anti-Markovnikov hydration by hydroboration-oxidation gives lysergol (146) (Scheme 15). The N-6 oxides of a series of ergolines and ergolenes have been prepared and their stereochemistry at the N-oxide function has been elucidated by proton NMR analysis.88 The factors governing the stereochemical course of the oxidation have been discussed. Full details of earlier syntheses7’ of (f)-chanoclavine I and ( +_)-isochanoclavine I by the enamide photocyclization route have been p~blished.~’ 4 Monoterpenoid Alkaloids 4.1 Alkaloids Containing an Unrearranged Monoterpenoid Unit As a result of the examination of several species of blue-green algae belonging to the Stigonemataceae for fungicidal activity Smitka et aLgOhave isolated hapalindoles G and H and a new series of related fungicidal alkaloids ambiguines A-F (149)+154) from Fischerella ambigua (Nageli) Gomont (UTEX 1903).Ambiguines A and E were also isolated from Hapalosiphon hibernicus W. and G.S. West (UH isolate BZ-3-1). and ambiguines D and E from Westiellopsis prolijica Janet (UH isolate EN -3-1). The ambiguines possess the same ring system as the hapalindoles but contain an additional (reversed) isoprene unit attached to C-2 of the indole ring.In ambiguines NATURAL PRODUCT REPORTS 1993 CI CI (1 53) Ambiguine E (154) Ambiguine F (155) Fischerindole L CHO I (168) (162) R= H ii (on 156) (163)Jiii iiit~7- -= vii 07~ocH2c6H3F2(2sr (1 64) (-)-Allohobartine SO& S02Ar iv v / ~ ix iiic- ArS02N& (161) Alloaristoteline (166) Ar= M e O e (1 57) Aristolasicone Reagents i 4A mol. sieves CHCl,; ii HC0,H; iii Na/Hg MeOH; iv lithium 4,4’-di(t-butyl)biphenyl THF v PCC A1,0, CH,Cl,; BF;Et,O CH,Cl,; vii TsOH C,H,; vii 20% HCl; ix H, Pt Scheme 16 D-F (152)-(154) this additional unit is attached also to the accessible by condensation of the protected terpinylamine carbon atom which carries the isonitrile group. derivative (1 56) with N-protected indole 2-acetaldehyde (1 58).Fischer indole L (155) is another new fungicidal indole The course of the ~ynthesis,’~ executed as envisaged is outlined derivative which was found in the terrestrial cyanophyte in Scheme 16. Condensation of (1 56) with (1 58) gave the cyclic Fischerella rnuscicola (Thuret) Gomont (UTEX 1829).” intermediate (159). Deprotection of both oxygen and indole Fischerindole L contains the same alicyclic skeleton as nitrogen followed by oxidation of the released allylic alcohol hapalindole L and has the same relative stereochemistry but function then gave an unsaturated ketone (160) which on has C- 16 attached to C-2 of the indole ring system rather than further Lewis acid catalysed cyclization gave ( )-aristolasicone to C-4 as it is in hapalindole L.(157). Borschberg has taken his synthetic contributions on the The first attempts3 to synthesize alloaristoteline (16 1) Aristotelia alkaloids a stage further by completing syntheses of involved the condensation of (-)-p-rnenth- 1-en-8-amine (162) (& )-aristolasicone and ( & )-alloarist~teline.~~~ s3 An earlier with the N-protected indole 2-acetaldehyde (1 58). The product ~ynthesis’~ of ( )-arktotelin- 19-one used as starting material (163) on deprotection of the indole nitrogen atom gave (-)-the protected terpinylamine derivative (1 56) and an N-protected allohobartine (1 64) but all attempts to cyclize this compound indole 3-acetaldehyde. Since aristolasicone (1 57) has a reversed to alloaristoteline failed. However the racemic product (159) indole ring attachment to the monoterpenoid unit relative to prepared as described above cyclized via the corresponding aristotelinone the desired skeleton of aristolasicone should be allylic carbonium ion when it was treated with boron trifluoride NATURAL PRODUCT REPORTS 1993-5.E. SAXTON HO (169a) 10-Hydroxystrictosamide R’ = OH R2 = H (1 70a) 10-Hydroxyangustine (1 70b) 3,14-Dihydroangustoline (169b) 6’-O-Acetylstrictosamide R’ = H R2 = Ac MeO2C**V OH OH (171) Glabratine (1 72a) 10-Methoxy-yohimbine ( 172b) 10-Methoxy-4-methylgeissoschizol etherate to give the base (165) together with a small amount of its deprotected analogue (166) and N-protected allosorelline (167) from which allosorelline (168) could be obtained by removal of the p-methoxyphenylsulfonyl protecting group.Alternatively the base (166) could be obtained directly in good yield by the cyclization of (159) by hot mineral acid; hydrogenation of (1 66) then gave ( +)-alloaristoteline (1 61) (Scheme 16).93 4.2 Corynantheine -Heteroyohimbine-Yohimbine Group and Related Oxindoles Strictosamide has been isolated from the stem bark of Simira me~icana,~~ and two new glycosides derived from stric- tosamide namely 10-hydroxystrictosamide (1 69a) and 6’-0-acetylstrictosamide (1 69b) have been found together with strictosamide and vincosamide in the leaves of Nauclea ~rientalis,~~~ which are used together with the bark by villagers in Papua New Guinea in the treatment of abdominal pains and animal bites.When ammonia was used in the extraction process the presence of these glycosides could not be detected and there was a significant increase in the content of angustine- type alkaloids. 94b Altogether nine such alkaloids were isolated ; these included three new ones which were identified as 10- hydroxyangustine (1 70a) and two diastereoisomers (probably C-19 epimers) of 3,14-dihydroangustoline (170b). These alkaloids were shown to exhibit antiproliferative activity in vitro against human bladder carcinoma T-24 cell line and against EGF (epidermal growth factor)-dependent mouse epidermal keratinocytes. 94b The six known alkaloids simul- taneously isolated are angustine 18,19-dihydroangustine nauclefine angustoline 3,14-dihydroangustine and 3,14,18,19- tetrahydroangustine.Glabratine (1 7 1) is a new glucosidic alkaloid which has been extracted from the bark of Uncaria glabrata DC a woody climber from West Sumatra which is used in traditional medicine as a remedy for food poisoning.95 The gross structure (171) was deduced from the spectroscopic data; the stereo- chemistry depicted is tentatively proposed on the basis of its obvious biogenetic relationship to strictosidine. Thirty-three alkaloids including seven new ones have been R’ (1 73a) Isogambirine R’ = H R2 = OH R3 = Et (173b) Gambireine R’ = OH R2 = H R3 = CH=CH2 isolated from the leaves and root bark of Ervatamia hirta (Hook. f)King and Gamble a Malaysian tree that finds use in the preparation of poisoned arrows and in traditional medicine in the treatment of ulcerations of the nose.96 All the alkaloids encountered that belong to this group are already known ;these are (a-16-epi-isositsirikine isositsirikine 19,20- dihydroisositsirikine antirhine yohimbine P-yohimbine 19,20-dehydro-P-yohimbine P-yohimbine pseudoindoxyl and P-yohimbine oxindole.It is noteworthy that this is the first report of the occurrence of alkaloids of the yohimbine group in the Ervatamia genus. The nine alkaloids foundg7” in the bark of Brazilian Aspidosperma pruinosum Mgf. include from this group two new ones 10-methoxyyohimbine (1 72a) and lO-methoxy-N,- methylgeissoschizol (1 72b) in addition to yohimbine P-yohimbine 1O-methoxygeissoschizol 1O-methoxydihydro-corynantheol and 3,4,5,6-tetradehydrositsirikine.10-Hydroxy-N,-methylcorynantheolis one of the quaternary alkaloids of the stem bark of Strychnos usambarensis (liana form) from the Ivory Coast.46 The alkaloid content of eight Malaysian Uncaria species has been investigated and the alkaloid distribution During the course of this investigation two new alkaloids were found in the leaves of U. calophylla; these are isogambirine (1 73a) which is 10-hydroxydihydrocorynantheine and gambireine (1 73b) which is 9-hydroxycorynantheine. Known NATURAL PRODUCT REPORTS 1993 HO H (1 74) 3-Epi-P-yohimbine (175) Ophiorrhizine X = CI Me 0 (176) Amsosinine (1 77) Magniflorine Me H'' 0 \ Me02C (1 79a) C/D cis (180) (1 78a) a-C02Me (179b) C/D trans (178b) P-C02Me Reagents i DBU DMSO 120 "C Scheme 17 alkaloids obtained for the first time from this species include rotundifoline yohimbine pseudoyohimbine a-yohimbine and P-yohimbine.Gambirine and dihydrocorynantheine also isolated had previously been reported to be the major alkaloids. The isolation of isogambirine (173a) is noteworthy since it is the first 10-hydroxy derivative of a heteroyohimbine alkaloid to be found in the Uncaria genus ;all previous hydroxy derivatives encountered have the hydroxyl group at C-9. In this same investigati~n~'~ the constituents of Uncaria borneensis were examined for the first time. Rhynchophylline isorhynchophylline corynoxeine and isocorynoxeine were shown to be the major alkaloids in the leaves together with minor amounts of alloyohimbine pseudoyohimbine and 3-epi- P-yohimbine (174); this last alkaloid is new.The isolation of several yohimbine isomers from U. calophylla and U. borneensis is also noteworthy since previously only one isomer pseudo- yohimbine had been found in the Uncaria genus i.e. in U. calophylla and U. attenu~ta.~~~ Pleiocarpamine is the one representative of this group among the nine alkaloids isolated from the stem bark of Alstonia undulifolia Kochummen and Wong a new species of Alstonia native to the Malay Peninsula.gs Extraction of the aerial parts of Ophiorrhiza major Ridl. a small shrub from West Sumatra has yielded a new quaternary alkaloid ophiorrhizine (175) which was isolated as its chloride.99 Although this shrub is not commonly found it is used in traditional medicine in the region as a component of a poultice applied for the treatment of skin disorders.Fourteen alkaloids have so far been ObtainedlOO from Amsonia sinensis Tsiang et P. T. Li; these include /I-yohimbine tetrahydroalstonine and a new alkaloid amsosinine which according to X-ray crystal structure analysis hydroxy- 16,17-dihydromayumbine. lol (-)-Tetrahydroalstonine has also been isolated from the aerial parts of Ophiorrhiza which like 0.major are used as a poultice for skin infections. Magniflorine (1 77) a new alkaloid isolated from the fruits of Costa Rican Hamelia magniJlora Wernha a species not previously investigated appears to be the lactone derived from 14a-hydroxyajmalicine.lo3 It has again been recorded that reserpine is a constituent of the root bark of Rauwo& littor~lis.~~~ The synthesis of indoloquinolizidines continues to attract considerable attention,lo5-l14 with a view to increasing the scope of alkaloid synthesis.In this connection particular emphasis has been placed in some contributions on the stereochemical course of indoloquinolizidine ring formation. In the last paper in this group114 a new synthesis is described in which the critical stage involved the decarboxylation and recyclization of a tetrahydro- 1,3-0xazine-2-one derivative (1 78a/b) (Scheme 17). The three products (1 79a) (1 79b) and (180) are important intermediates in the synthesis of vindorosine by Langlois et a1.115 A new synthesis of ( + )-deplancheine (1 81)116 proceeds via the formation of the tetracyclic diketone (182) by condensation of 3,4-dihydro-/I-carboline with hydroxymethyleneacetyl-acetone.Preferential removal of the carbonyl group in ring D via the thioacetal (183) gave the known vinylogous amide which on reduction gave ( f)-E-deplancheine (1 81) exclusively (Scheme 18). Reduction of the carbonyl group in (183) NATURAL PRODUCT REPORTS 1993-5. E. SAXTON \ CMe (181) Deplancheine (184) Flavopereirine Reagents i MeOH 28 "C; ii HSCH,CH,SH C,H, TsOH heat; iii Ni EtOH; iv NaBH, ButOH MeOH heat; v NaBH,CN AcOH; vi POCl, py 80 "C; vii DDQ AcOH HClO Scheme 18 H He' H I C02Bu' m. '...M Me**$"U C02Me AcO H I\ OQT% V0 &vii viii v vi IQT'+ H Ha' H I H He' H I C02Me C02Me (185a) E isomer (185b) 2isomer Reagents i LDA THF -78 "C+O "C; ii HBr C,H, pH 6.5 0 "C; iii NaOMe MeOH; iv Ac,O py Ar; v DBU PhMe 115 "C; vi 1M HCl MeOH; vii LiAlH, THF 0 "C; viii MnO, CH,Cl Scheme 19 followed by dehydration thioacetal hydrogenolysis and as shown gave (+)-vallesiachotamine (185a) and (-)-aromatization afforded also a new synthesis of flavopereirine isovallesiachotamine (1 85b).(184). A new chiral synthesislls of (-)-antirhine (189) uses as The first enantioselective synthesisll' of (+)-essential starting material the mannose-derived pyranose-vallesiachotamine (1 85a) and (-)-isovallesiachotamine (185b) lactone (190),119 which was condensed with tryptamine to give is an adaptation of Wenkert's one-pot procedure for the lactam (191).The synthesis was then pursued as illustrated indoloquinolizidine synthesis. Addition of the anion derived in Scheme 20 the desired C-20 epimer (192) being identified by from the chiral lactone-acetal(l86) to the pyridinium salt (187) comparison of the undesired C-20 epimer of (192) with a diol of gave the indoloquinolizidine derivative (1 88) regiospecifically known stereochemistry prepared independently from the and with an extremely high degree of stereoselectivity (> 95 YO) Wadsworth-Emmons product (193). Regioselective selenation (Scheme 19). Methanolysis of (188) exposed the corresponding of (192) followed by oxidative elimination then gave (-)-hydroxy-ester which on acetylation and further transformation antirhine (189)."* NATURAL PRODUCT REPORTS 1993 -i ii iii H 1_ ( 193) iv v ~ 7 viii,ix H H HO (189) Antirhine (192) Reagents:i C,H, heat; ii SO, py DMSO NEt,; iii Wadsworth-Emmons; iv PhMe AcOH heat; v separation of epimers; vi H, Pd/C; vii LiAlH, THF heat ; iii o-O,NC,H,SeCN PBu, THF heat; ix m-CPBA CH,Cl Scheme 20 *‘Et H-’ \CO,Et (195) OSiMe2Bu‘ H (194) Reagents i HS(CH,),SH BF,Et,O; ii tryptamine heat; iii ButMe,SiC1 NEt, DMAP Scheme 21 The preparation of the amide (194) from the previously prepared3,* cyclic acetal(l95) and tryptamine constitutes a new formal synthesis of (f)-dihydroantirhine (Scheme 21).lZ0 The synthesis of dihydrocorynantheol (200a) and 3-epidihydrocoryantheol by Ziegler and SweenylZ1 has been re- examined and extended with the aim of establishing the stereochemical integrity of the Claisen rearrangement.Whereas the earlier workers used the diastereoisomeric mixture of allylic alcohols (196a) and (196b) Lounasmaa and his collaborators used the single diastereoisomers in parallel syntheses (Scheme 22). Thus reaction of (196a) with dimethylacetamide dimethyl acetal followed by Claisen rearrangement gave exclusively the amide (197a) ;methanolysis then gave deformyl-2-geissoschizine (198a) which was reduced to 2-geissoschizol (199a). The diastereoisomer (196b) on similar treatment gave the corresponding 3 P-H epimers (1 97b)-( 199b). Evidently the Claisen rearrangement proceeds with a very high degree of stereoselectivity.It was further shown that deformyl-2-geissoschizine (198a) and its 3-epimer (198b) could be obtained directly from the allylic alcohols (196a) and (196b) by means of trimethyl orthoacetate followed by thermal Claisen rearrangement. The hydrogenation of compounds (198a/b) and (199a/b) was also studied. As expected 2-geissoschizol (199a) gave normal and all0 products i.e. dihydrocorynantheol (200a) and corynantheidol (200b). However 3-epi-2-geissoschizol (1 99b) gave mainly the pseudo isomer 3-epidihydrocorynantheol (200c) together with some normal isomer (200a) by epimerization at C-3 under the conditions of the reaction. Deformyl-2-geissoschizine (1 98a) and deforrnyl-3-epi-Z-geissoschizine (198b) behaved in an exactly analogous manner.The condensation of 3,4-dihydro-P-carboline with 2-0x0- 2H-pyran-6-ylcarbonyl choride (20 1) in the presence of allyltributyltin gives a tetrahydro-P-carboline derivative which when heated in toluene undergoes an intramolecular Diels-Alder reaction followed by loss of carbon dioxide to give the pentacyclic intermediate (202). Hydrogenation of (202) followed by reduction affords a new synthesis of (+)-pseudoyohimbane (203a) and (f)-epialloyohimbane (203b) while dehydrogenation of (202) gives norketoyobyrine (204) (Scheme 23).lZ3 (+)-Normalindine (205) has been prepared in a highly stereoselective process by reaction of dihydronauclefine (206) previously synthesized36b with methyl-lithium followed by reduction of the mixture of products (207a/b) obtained (Scheme 24).124 Apparently in the reduction process whether chemical or catalytic no norisomalindine was detected.The first synthesis of (+)-3-isorauniticine (208) constitutes an impressive example of the application of sultam-directed asymmetric alkylations and the value of palladium-catalysed carbonylation reactions (Scheme 25).125 Asymmetric allylation of the heavily-protected commercially available chiral glycine NATURAL PRODUCT REPORTS 1993-5. E. SAXTON QITCLa&&-\ 0* Ha* (196a) 3a-H (196b) 3p-H OH C02Me (1 98a) Deformyl-Z-geissoschizine3a-H OH (1 98b) Deformyl-3-epi-Z-geissoschizine3P-H (1 gga) Z-Geiswschizol 3a-~ (1 99b) 3-Epi-Z-GeissoschizoI3p-H CONMe2 (197a) 3a-H (197b) 3p-H (200b) Corynantheidol p-Et OH (200a) Dihydrocorynantheol a-Et Reagents i MeC(OMe),NMe, dioxan heat; ii KOH EtOH Ar heat; iii MeCOC1 MeOH 0 "C Ar; iv MeC(OMe), AcOH dioxan heat; v LiAIH, THF; vi H, PtO, MeOH Scheme 22 H bSnBu3 / COCl 0J$ (204) Norketoyobyrine 20 TH H (203a) Pseudoyohimbane 20P-H (203b) 3-Epialloyohimbane 20a-H Reagents i mol.sieves 4A,CH,CI,; ii PhMe heat; iii H, PtO,; iv LiAIH,; v DDQ Scheme 23 derivative (209) followed by replacement of the thioacetal protecting group on nitrogen by a mesitylsulfonyl group gave the sulfonamide (2lo) which was alkylated on nitrogen by means of 2-1-bromo-4-methoxycarbonyloxy-2-butene.The product (21 1) was conveniently constructed to allow palladium- catalysed carbonylation-cyclization to give the methylene- cyclopentanone derivative (2 12) which on stereoselective hydrogenation followed by Baeyer-Villiger oxidation gave the bicyclic lactone (21 3) with obvious potential as the precursor of the D/E ring system of isorauniticine.At this point it became necessary to remove the protecting groups from the carboxyl group at the future C-3 and N without destroying the lactone function. The first of these was achieved by transesterification of the acyl sultam grouping in (213) by lithium p-nitrobenzyloxide and the second (removal of the N-sulfonamide grouping) by means of hydrogen fluoride in pyridine. N-Alkylation by tryptophyl bromide followed by hydrogenolysis of the p-nitrobenzyl ester then a Rapoport decarboxylative cyclization gave the complete pentacyclic framework (214) of the target molecule.Familiar stages (formylation then acid-catalysed methanolysis and recyclization) then gave 3-isorauniticine (208) (Scheme 25).lZ5 New transformations reported in this group include the conversion of yohimbine (215) into its N,-methoxyoxindole analogues (216a) and (216b) by oxidation of the corresponding 2,7-dihydroderivatives by means of hydrogen peroxide and NATURAL PRODUCT REPORTS 1993 + H (206) Dihydronauclefine (207a) I (207b) or iii ii t q O TH H' N'f-HMe (205) Normalindine Reagents i MeLi THF -78 "C- -10 "C; ii H, Pd/C; iii NaBH,CN AcOH 5 "C Scheme 24 Me>=/ vi vii t S02Ar ix x vi -Me 0 0 Jxi 0 xii xiii 0 (208) (+)-3-lsorauniticine (214) Reagents i CH = CH*CH,I Bu,NHSO, LiOH CH,Cl, H,O ultrasound; ii HCl THF H,O; iii Me,C,H,SO,Cl py CH,Cl, heat; iv Z-BrCH,CH = CHCH,OCO,Me NaH DMF 0 "C; v Pd(dba), PBu, CO AcOH 80 "C; vi H, Pd/C; vii rn-CPBA NaHCO, CH,Cl,; viii p-O,NC,H,CH,OH Bu"Li THF hexane -30 "C+ -10 "C; ix py HF PhOMe; x tryptophyl bromide NaHCO, MeCN 80 "C; xi PhPOCl, 105 "C then IM.HCl/H,O; xii NaHMDS THF -78 "C then HC0,Me; xiii HC1 MeOH CH,Cl, 120 "C then TsOH CH,Cl, heat Scheme 25 sodium tungstate (Scheme 26),126 and the conversion of hirsutine (217) into 19,20-P-dihydro- 16-epi-pleiocarpamine (219a) and the isopleiocarpamine derivative (219b) (Scheme 27).12' The difference in behaviour of the epimers (218a) and (218b) is striking; whereas the 3R epimer (218a) cyclizes between C-3 and N, with reformation of the indoloquinoliz- idine ring system present in (219a) the 3s epimer (21 8b) cyclizes presumably on to a C-7-protonated indoleninium ion with formation of the gem.-diamino system of (219b).I2' Several syntheses which came to fruition in earlier years and NATURAL PRODUCT REPORTS 1993-5.E. SAXTON 37 1 H OH (215) Yohimbine $i.iii -I Me02C" I I OH OH (216b) (216a) Reagents i NaBH, TFA; ii Na2W0;2H,O H,O,; iii CH,N,; iv ButOC1 MgO H,O THF Scheme 26 i-v __t vi ___) vii viii I Et Me02C4CHOMe Me02C4CHOH Me02C~CH~CI b02Me H (218a) 3R (217) Hirsutine H C02Me H C02Me H (21 9a) 19,20P-Dihydro-l6-epi-pIeiocarpamine (219b) Reagents i HCl AcOH; ii ButMe,SiC1 NEt, CH,Cl,; iii MgO BrCN MeOH THF; iv 1M .NaOH MeOH 0 "C Ar; v separation of 3R and 3s epimers; vi ButOC1 NEt, CH,Cl,; vii NaH DMSO 90 "C; viii CH,N, MeOH Et,O; ix NH,OAc 5% AcOH-H,O heat Scheme 27 (-)-yohimbane (-)-alloyohimbane and (+)-3-epiallo-yohimbane.133 A detailed analysis of the proton and 13C NMR spectra of Me0 the Mitrugynu inermis alkaloids mitraphylline isomitra-Me H; phylline speciophylline and pteropodine by two-dimensional techniques has been reported and complete assignments have been made.134 Finally yohimbine hydrochloride is now recommended as a (220) 1 1 -Methoxyvincamedine cure for snoring !135 have already been reported in brief have now been recorded in 4.3 Sarpagine -Ajmaline -Picraline Group detail ; these include syntheses of oxogambirtannine and Deacetylpicraline has been isolated from Alstoniu scholaris 136 naucleficine,128 methyl epielen~late,~~~~ 130 methyl elenolate and and from Melodinus fusiformis.13' Picrinine occurs together the heteroyohimbine alkaloids aricine,130 reserpinine,130 tetra- with strictamine in Amsoniu sinensis,lOO and together with ajmali~ine,~~~ hydroal~tonine,'~~-'~~ oxogambirtannine geisso- vincorine 11-methoxy- 17-epivincamajine 18-hydroxy-schizine cathenamine pteropodine and isopteropodine and cabucraline and 1I-methoxyvincamedine (220) in the leaves of NATURAL PRODUCT REPORTS 1993 R2 OH H*- (221) Methyl 12-hydroxyakuammila-17-oate (1 2-Hydroxystrictamine (222) E-16-Epinormacusine B R’ = R3 = H R2 = CH20H (223) Affinisine Nb-oxide R’ = Me R2 = H R3 = CH20H Nb-oxide (224) 16-Epiaffinisine R’ = Me R2 = CH20H R3 = H (225) GAcetyl-16-epiaffinisine R’ = Me R2 = CH20Ac R3 = H H p“ H6 (226) Dehydro-16-epiaffinisine (227) Demethoxyalstonamide R = H (228) Alstonamide R = OMe (229) Alstoumerine Tonduza pittieri Donn.Sm. [Alstonia pittieri (Donn. Sm.) A. Gentry];138 this last alkaloid is new. Methyl 12-hydroxy-akuammilan- 17-oate [12-hydroxystrictamine (22 l)] is another new alkaloid which was found in the leaves of RauwolJia sumatrana Jack a large evergreen tree from Western A decoction of the leaves of this plant is used in the local native medicine as a specific remedy for fever. The four alkaloids obtained from the leaves of Tabernae-montana subglobosa Merr.belong to the 2-acylindole group ; they were identified as vobasine dregamine tabernaemontanine and ervatamine. 140 Thirty-one of the 33 alkaloids isolated from the leaves and root bark of Ervatamia hirta (Hook. f) King and Gamble occur in the root bark and include ten alkaloids from this group.96 Of these five are new and proved to be E-16-epinormacusine B (222) affinisine N,-oxide (223) 16-epiaffinisine (224) O-acetyl- 16-epiaffinisine (225) and dehydro- 16-epiaffinisine (226) ; the five known bases are normacusine B affinisine vobasine dregamine and tabernaemontanine. Normacusine B has also been found in the bark of Aspidosperma pr~inos~m,~~~ and in the root bark of Strychnos mostue~ides.~~~ Echitamine and norechitamine have been obtained from the root bark of Alstonia undulifolia Kochummen and Wongg8 and a group of three new alkaloids (227)-(229) from the leaves of A.macrophylla of Sri Lankan origin. 141 Demethoxyalston-amide (227) differs from vincorine only in having an Na-formyl group instead of an Na-methyl group while alstonamide (228) carries an additional methoxy-group at (2-11. The third alkaloid alstoumerine (229) is an allylic alcohol based on the sarpagine skeleton ;the &-configuration at C-19 was established by application of Horeau’s procedure. The indole alkaloid content (ajmaline serpentine and reserpine) of RauwolJia serpentina roots from regenerated plants (from stem and root-callus cultures) is lower than that observed in the parental stock.However raucaffricine was found in all samples which demonstrates for the first time that raucaffricine occurs normally in R. serpentina roots.143u In cell suspension cultures of R. serpentina raucaffricine is the major alkaloid and occurs to an extent approximately 67 times greater than that observed in the roots. Under these conditions raucaffricine is synthesized from vomilenine and uridine 5’-diphosphateglucose in the presence of microsomal-bound glucosyltransferase enzyme. 1436 Me ’ OH (230) 19S-H ydrox y-Nb-methylrau macline A new alkaloid 19(S)-hydroxy-N,,-methylraumacline(230) has been isolated from cell suspension cultures of R.serpentina following the addition of ajmaline (23 1). The structure of (230) was deduced from its spectroscopic data and confirmed by synthesis from ajmaline (Scheme 28).144 Complete unambiguous assignments have been made of the proton and 13C NMR spectra of polyneuridine isolated from Rhazya orientalis A.DC and of 19Z-akuammidine 16-epivoacarpine and koumidine isolated from Gelsemium elegans (Gardn. and Champ.) Benth.145 The mass spectra of epimeric indole alkaloids can not normally be distinguished by conventional mass spectroscopy. However it has recently been observed that under low energy (10 e.V.) collision conditions the recorded CAD (collision-activated dissociation) spectra of protonated epimers e.g. protonated dregamine and tabernaemontanine generated by FAB displayed characteristic fingerprints. Most fragment ions were the same in the two spectra but the spectrum of dregamine exhibited an ion of significant intensity at m/z 252 which was not present in the spectrum of tabernaemontanine.146 and the Full details of the total of sua~eoline,~~~ partial ~ynthesis’~of koumidine 19Z-taberpsychine and tetraphyllicine from ajmaline have been published. 148 This latter paper also describes the conversion of koumidine (232) into N-demethoxyrankinidine (233) (Scheme 29) analogous to the earlier reportedi9 conversion of gardnerine into Na-demethoxyhumantenirine which thus serves to establish the absolute configuration of N,-demethoxyrankinidine. Other synthetic work reported recently includes a of 20-desethylsilicine (234) by a four-stage process from indole which exemplifies a new approach to the ervatamine group of alkaloids (Scheme 30) and a synthesis of 16-demethylene- NATURAL PRODUCT REPORTS 1993-5.E. SAXTON 373 Et CH20SiBu'Ph2 I (231) Ajmaline OHd xBr I viii ix I OH Me Me H' Me OH OH xi xii (230) 1 9s-Hydroxy-Nb-methylraumacline Reagents i Me,N.NH, H,SO (cat.) EtOH 31% mol. sieves then ClCO,CH,Ph lM.NaOH CH,Cl,; ii CuCl, THF H,O phosphate buffer; iii ButMe,SiOTf NEt, CH,Cl,; iv NBS THF; v DBU DMF; vi NaBH,; vii ButPh,SiC1 NEt, DMAP CH,Cl,; viii BH; Me,S THF then 3M NaOH H,O,; ix ButNF THF; x Pb(OAc), CH,Cl,; xi H, Pd/C MeOH; xii CH,O H,O AcOH (cat) NaBH,CN Scheme 28 (232) Koumidine Jii HO \ (233) NDemethoxyrankinidine Reagents i ClCO,CH,CCl, MgO H,O THF; ii OsO, py THF; iii TsOH py THF H.C(OMe),; iv Ac,O; v 1M NaOH MeOH; vi Zn AcOH Scheme 29 Ncp & 4 Me i Me Me Me QTmMe __t L __F L II ' ' N NC OAc OAc OAc CN CN 'I CN H QT~ Me -I Me iii,iv \ ii Q\ ~rnMe \ H H H H 0 Me02C C02Me (234) Desethylsilicine Reagents i indole ZnC1,; ii AgBF, NaCH(CO,Me), THF; iii H, Pd/C; iv PPA Sche2e 30 NPR 10 NATURAL PRODUCT REPORTS.1993 ._ \ C02Me 6O2Me J (235) 16-Demethyleneervitsine \C02Me Reagents i LDA THF -30 "C;ii 4M HCI; iii NaBH,; iv MnO Scheme 31 H '0Ac (236a) (236b) Reagents i Mn"' Cu" Scheme 32 Br-t. ,Me aN,& &*= &=. ii Koumine -0 (238) Reagents i CH,Br, EtOAc heat; ii 10% NaOH heat Scheme 33 ervitsine (235) (Scheme 3 1),150 which constitutes an advance on the same group's earlier of the 19-Z isomer of (235).The synthesis of the 16-oxo-A19-sarpagan derivative (236a) by a radical cyclization process (Scheme 32),151a and the enantiospecific synthesis of the tetracyclic base (236b) which is a pivotal intermediate in the synthesis of the macroline group of alkaloids,151b have also been reported. An attempt to break open the cage-like ring system of koumine by the modified Hofmann degradation failed -the major product being the 21 -hydroxymethyl derivative (237) (Scheme 33),152 whose structure was established by the X-ray method. This result is most logically explained by an ylid mechanism via the aziridinium ion (238). In the course of extracting Gelsemium elegans plants as a source of koumine Zhang et al.obtained some 1,2-dihydrokoumine ; this appears to be the first time that this compound has been isolated from a natural source although it has previously been prepared in the laboratory. The proton and 13C NMR data of akuammine (239) and the so-called dihydroakuammine (240) have been recorded and assigned and the pharmacology of these two alkaloids has been discussed. 153 4.4 Strychnine Group Norfluorocurarine and its N,-oxide and 12-hydroxy-norfluorocurarine are among the 33 alkaloids found in the leaves and root bark of Ervatamia hirta. 96 Fluorocurarine 3 (239) Akuammine (240) Dihydroakuammine occurs in the stem bark of the liana form of Strychnos usambarensis from the Ivory Coast,46 tubotaiwine in Melodinus f~siforrnis,~~' vincanidine in Amsonia sinensis,loO akuammicine echitamidine and 20-epi- 19-c-echitamidine in the stem bark of Alstonia undulif~lia,~~ and compactinervine in the bark of Aspidosperma pruinosum.97a Although Strychnos henningsii has been examined on many previous occasions a number of new alkaloids have recently been encountered among the 17 alkaloids isolated from the leaves stem and root barks of a Tanzanian specimen.154 The known alkaloids are holstiine splendoline retuline and spermostrychnine (241). The new alkaloids are the derivatives (242)-(245) of spermostrychnine the henningsiine group (246)-(250) which are related to 16,17-dehydrospermo-strychnine the henningsamide group (25 1)-(253) which are 3,7-seco derivatives of henningsiine and cyclostrychnine (254) which is at present sui generis.lj4 NATURAL PRODUCT REPORTS 1993-5.E. SAXTON R (241) Spermostrychnine R = H 19a-H (242) 23-Hydroxyspermostrychnine R = OH 19a-H (243) 23-Hydroxysperrnostrychnine R = OH 19P-H (244) 23-Hydroxyspermostrychnine Nb-oxide R = OH 19a-H Nb-oxide (246) Henningsiine R’ = COCH20H R2 = H (247) Dehydroxyacetylhenningsiine R’ = R2 = H (248) 0-Acetylhenningsiine R’ = COCH20Ac R2= H (249) 3-Hydroxyhenningsiine R’ = COCH20H R2 = OH (250) Henningsiine &,-oxide R’ = COCH20H R2 = H &,-oxide (255) Malagashine (254) Cyclostrychnine AH Hd (245) 17,23-Dihydroxyspermostrychnine (251) Henningsamide R = COCH20H (252) 0-Acetylhenningsamide R = COCH20Ac (253) Dehydroxyacetylhenningsamide R = H .-\O*Me (256) Malagashanine 0 / H H (258) Condylocarpine (259) HO (257) Strychnochromine Scheme 34 The root bark of Strychnos mostueoides which is used in Madagascar as a tonic and in the treatment of malaria has so far yielded eight alkaloids of which seven belong to this group.155 The known bases are the Wieland-Gumlich aldehyde strychnofendlerine spermostrychnine strychnobrasiline and deacetylstrychnobrasiline and the remaining two are new.Malagashine (255) belongs to the N-methyl-sec.-pseudo-strychnine group and has the same structure as tabascanine but without the aromatic methoxy-groups. Malagashanine has been assigned the structure (256) but the position and configuration of the methoxy-group have yet to be firmly established.155 Strychnochromine a relatively new alkaloid from Strychnos gossweileri Exell for which a dihydroindole structure was tentatively is now known by virtue of an X-ray crystal structure determination of its p-bromobenzoate to have the tetrahydroquinoline structure (257).156 This ring system has not previously been encountered but it could conceivably arise from condylocarpine (258) by hydrolysis and decarboxylation to the indolenine (259) followed by hydrolysis to the corresponding aminoketone oxidation at C-18 then formation of the N to C-20 bond with allylic displacement of the C-18 substituent and hydration as outlined in Scheme 34.In any assessment of progress in indole alkaloid chemistry during the past year the formal total ~ynthesis’~’ of strychnine (260) by Magnus and his collaborators the first since Woodward’s epoch-making synthesis of 1954 must be given pride of place.The synthesis essentially starts with the previously prepared tetracyclic base (26 1),158 which was converted as outlined in Scheme 35 into the relay compound (262). This sequence of reactions was initiated by the C/D ring-opening of (261) by a Hobson reaction then N,-protection NATURAL PRODUCT REPORTS 1993 C02Me (283) viii Me02C H 'H I? I m xv xvi-xvii i -c C02Me xxv-xxviii xvi xix xx 1 1 xxxii Ixxix-xxxi ___)_ P H (260) Strychnine (267) Wieland-Gumlich aldehyde Reagents i CICO,CH,CCI, CH,CI,; ii NaOMe MeOH; iii CICO,Me NaOH H,O CH,Cl, PTC; iv Zn AcOH THF; v PhSCH,CO,H BOPCl NEt, CH,Cl,; vi m-CPBA*CH,CI, 0 "C; vii NaH THF; viii (CF,CO),O 2,6-But,-4-Mepyridine; ix HgO CdCO, THF H,O; x BrCH,CH,OH DBU PhMe; xi BH;THF; xii Na,CO, MeOH heat; xiii Hg(OAc), AcOH; xiv Zn H,SO, MeOH; xv NaOMe MeOH; xvi p-MeOC,H,SO,Cl EtNPr'; DMAP CH,CI ;xvii LiBH, THF HN(CH,CH,OH) ;xviii HCIO ;xix OsO (cat.) N-methylmorpholine N-oxide THF ButOH H,O; xx LiBH, THF xxi H,IO, TFA MeOH H,O; xxii PriSiOTf DBU CH,CI,; xxiii (EtO),P(O)CH,CN KHMDS THF; xxiv separation of geometrical isomers; xxv DIBAL; CH,Cl,; xxvi NaBH, MeOH; xxvii 2M HCI MeOH xxviii ButMe,SiOTf DBU CH,CI, -20 "C; xxix SO;py DMSO NEt,; xxx py HF; xxxi Na anthracenide; xxxii CH,(CO,H), NaOAc Ac,O (Ref.159) Scheme 35 NATURAL PRODUCT REPORTS 1993-5. E. SAXTON Me (271) Undulifoline (272) Precondylocarpine (273) 0 Me ii iii Me (274) Ellipticine iv iii SEt I "CH20H CH-SEt .. .. Me Me (278) (277) Reagents i MeLi THF -100 "C then H,O then conc. acid to pH 2; ii MeLi THF; iii NaBH, EtOH heat; iv LiCH(SEt),; iv PhI(CF,CO,), H,O MeCN; v NaBH,CN TFA (cat.) EtOH Scheme 36 replacement of the N,-substituent by a phenylthioacetyl group oxidation to the sulfoxide level of oxidation and formation of the six-membered ring D by an internal Michael reaction which gave the tetracyclic intermediate (263). A Pummerer reaction on (263) followed by mercury-ion assisted hydrolysis intro- duced a carbonyl group to the future C-20 which was protected as its acetal the amide carbonyl group was then removed by reduction and the 3,7-bond was formed by oxidation of the intermediate amine (264) the reaction proceeding via the preferred (and desired !)iminium ion to give the anilinoacrylate derivative (265).Reduction of the 2,16 bond in (265) gave an aminoester (266) whose structure and stereochemistry were confirmed by X-ray crystal structure analysis of its N-acetyl derivative. Epimerization of (266) followed by N,-protection reduction and release of the C-20 carbonyl group then gave the relay compound (262) which was prepared again as shown from strychnine via the Wieland-Gumlich aldehyde (267). The relay compound (262) was then reconverted into (267) by a series of relatively conventional steps.Since strychnine has already been prepared from the Wieland-Gumlich aldehyde 159 this constitutes a formal total synthesis of strychnine. Other synthetic work reported recently includes the prep- aration of the azabicyclononanones (268a) and (268b) which are potential intermediates in the synthesis of tubifoline and condyfoline respectively ;Is0 the synthesis of the azocino [4,3-b] indole derivative (269)Is1 by a new approach and the preparation of the isodasycarpidone derivative (270) which may prove useful in the synthesis of strychnopivotine.162 4.5 Ellipticine -Uleine -Apparicine Group 3,14-Dihydroellipticine and apparicine are two of the 31 alkaloids found in the root bark of Ervatamia hirt~,~~ and a new alkaloid undulifoline (27 I) which contains a uleine skeleton has been isolated from the stem bark of Alstonia undulifolia Kochummen and W~ng.~* In contrast to uleine undulifoline has retained the methoxycarbonyl group and the C-17 oxygen atom which has formed an ether bridge with an oxidized C-18.The absolute configuration implied in (271) is based on the assumption of a biogenetic derivation from precondylocarpine (272). A second route for the conversion of uleine into the quaternary alkaloid (273) has been developed. 163 The low-frequency near-infrared FT Raman spectra of ellipticine and its and the surface-enhanced Raman spectra of ellipticines and their complexes with DNA adsorbed on silver colloids have been studied.16" A recent synthesiP5 of ellipticine (274) proceeds from the Saulnier-Gribble lactam (275) via the lactone (276) (Scheme 36). An analogous synthesis from (276) using the lithium NATURAL PRODUCT REPORTS 1993 (283) (284) lvi U C02C H2P h ~y-i~~~ ~ viiorviii X 0 (279) Dasycarpidone R = Me X = 0 (280) Nordasycarpidone R = H X = (281) Dasycarpidol R = Me X = a-OH P-H (286) Uleine R = Me X = CH2 Reagents i (Boc),O NaOH H,O Bu,NHSO, PhMe; ii rn-CPBA CH,Cl, then (CF,CO),O -15 "C then KCN H,O NaOAc pH 4-5; iii AcOH H,O dioxan 90 "C; iv H, Pd(OH), MeOH; v ClCO,CH,Ph K,CO, CH,Cl,; vi SeO, dioxan 80 "C; vii H, Pd/C MeOH CH,O H,O; viii BF;Et,O Me$ CH,Cl,; ix NaBH, MeOH Scheme 37 (287) 1 1,19R-Dihydroxytabersonine (288) 1 1-Hydroxy-l4,15a-epoxytabersonine (289) Suaveolenine 0 p)-.--Et 'N 8 C02Me Et Et H (290) Vincoline (291) Voaharine (292) Aspidochibine (293) 3-0x0-14,15 -dehydror hazini lam derivative of acetaldehyde dithioacetal gave the thioacetal previously been converted into uleine (286) this synthesis also (277) which proved remarkably resistant to hydrolysis.It was constitutes a formal total synthesis of uleine. eventually hydrolysed by means of bis(trifluoroacetoxy)-iodobenzene; reduction of the released aldehyde then gave 18- hydroxyellipticine (278),165 an alkaloid of Strychnos 4.6 Aspidospermine -Vincamine Group dinklagei.166 Vincadifformine tabersonine lochnericine minovincinine iso- Other synthetic work reported during the last year includes eburnamine A14-isoeburnamine and rhazimine are among the 21 -fluoroellipticine fourteen alkaloids found in Amsonia sinensis Tsiang et P.T. syntheses of 10 12-dimetho~yellipticine~~~~ (by a new convergent approach),168 and several 19-alkylamino Li.lo0 Of these the only new one is A14-isoeburnamine whose derivatives of 1O-methoxy- 19-demethylellipticine. 169 structure was confirmed by the X-ray method. Melodinus A stereoselective of dasycarpidone (279) and fusifovrnis a plant which is used in Chinese folk medicine for nordasycarpidone (280) and the first synthesis of dasycarpidol the treatment of rheumatic heart disease and invigorating the (28 1) starts essentially from the cis-piperidine derivative (282) circulation has so far yielded fifteen alkaloids all but two of which was converted into its 2-cyano derivative and cyclized which belong to this group.13' Three are new and were shown under equilibrating acidic conditions to the dasycarpidan to be 1 1,19R-dihydroxytabersonine(287) 1 1-hydroxy- 14,15a- derivative (283) having the required relative stereochemistry at epoxytabersonine (288) and scandine N,-oxide.The ten known C-20. Replacement of the N-benzyl group by the more alkaloids are vindoline tabersonine 1 1-methoxytabersonine protective benzyloxycarbonyl group gave (284) which was 11-hydroxytabersonine venalstonine kopsinine 1Sa-hydroxy-oxidized at C-16 to the 2-acylindole derivative (285). De- kopsinine scandine 10- hydroxyscandine and meloscandine. protection methylation and reduction stages then gave (*)-Melodinus suaveolens Champ.ex Benth. is another plant which dasycarpidone (279) (+)-nordasycarpidone (280) and (A )-finds use in Chinese folk medicine; this one is used for the dasycarpidol (28 1) (Scheme 37).170 Since dasycarpidone has treatment of hernia infantile malnutrition dyspepsia and NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 379 14 C02Me (294) Lapidilectine A (295) Lapidilectine B (296) Venalstonine 0 Me02C /C02Me OH (297) A'4-Kopsijasm ini lam (298) (-)-Eburnaminol (299) (+)-Larutensine testitis. The trunk of this species contains fourteen alkaloids all of which belong to this group.171 The sole new alkaloid suaveolenine has the structure (289) according to X-ray crystal structure analysis ;it is clearly closely related structurally (but not stereochemically ?) to vincoline (290) with which it occurs in M.suaveolens. The other known alkaloids are vinca-difformine 1 1 -methoxyvincadifformine hazuntine catho-valinine tabersonine 11 -hydroxytabersonine 11 -methoxy- tabersonine 19l?-hydroxytabersonine 1 1,19l?-dihydroxytaber- sonine (287) I 1-methoxy- 19R-hydroxytabersonine vindo-linine and A14-vincine.171 Voaphylline and N,-methylvoaphylline are the major alkaloids of the leaves of Malaysian Tabernaemontana divaricata. Minor alkaloids include a new bisindole alkaloid conophylline (4.v.) and voaharine also new whose structure is amine but elimination of water has created an ether bridge between C-16 and C-18. The four known alkaloids are (+)-eburnamonine (-)-eburnamine ( +)-isoeburnamine and (-)-kopsinine.It is reported that the ultraviolet irradiation (at 370 nm) of multiple shoot cultures of Catharanthus roseus results in a decrease of the vindoline and catharanthine content and a corresponding increase in the production of leurosine. 176 The X-ray crystal structure of 18R-18-methoxycarbonyl- 17- oxo-l-(p-toluenesulfonyl)aspidofractinine79has been deter-mined. 77 The anilinoacrylate bases of the vincadifformine group are extremely difficult to quaternize at N,. In fact attempts to form the N,-methiodide from 2,16-dihydrotabersonine (300) result in the formation of the N,-methyl derivative and the N,-(291) according Voaharine is presumably derived by oxidation and re-arrangement of voaphylline and is the first known Tabernae-montana alkaloid to contain a 3-quinolone rather than an indole ring system.Another alkaloid containing a novel skeleton is aspidochibine (292) which was obtained together with 3-0x0- 1415- dehydrorhazinilam [(293) also new] from cell suspension cultures of Aspidosperma quebrachoblanco S~h1echt.I~~ Struc-ture (292) indicates the relative stereochemistry of aspidochibine; the absolute configuration of both (292) and (293) is at present unknown. Yet another novel skeleton has been encountered recently in lapidilectine A (294) and lapidilectine B (295) two new alkaloids from the bark (294) and leaves (295) of Malaysian Kopsia Iapidilecta Van der Sleesen. 174 If the relative stereochemistry deduced for lapidilectine A (294) from extensive NMR data is correct it could arise by oxidative fission of the 20,21 and Nb,21 bonds in a stereoisomer of venalstonine (296) followed by formation of the Nb,20 bond.Lapidilectine B (295) appears to be the result of further oxidation at C-7 involving the loss of C-21 and lactone formation. These alkaloids may also be derived from a stereoisomer of A14-kopsijasminilam (297) which lacks the Nb,20 bond but already contains the five- membered lactam ring. Note that derivation of (294) from venalstonine (296) itself (or A-14kopsijasminilam) would require transposition of the 18,19 and 16,17 bridges. The same workers have isolated two new alkaloids and four known ones from the stems and bark of the Malaysian tree Kopsia larutensis King and Gamble.175 The new alkaloids are (-)-eburnaminol (298) which is 18-hydroxyeburnamine and (+)-larutensine (299) which has the same skeleton as 18-hydroxyisoeburn-to X-ray crystal structure ana1~sis.l~~trifluoroacetyl derivative of (300) fails to react with methyl iodide in methanol.Interestingly when 2,16-dihydro-tabersonine is a~ylatedl~~ with a large excess of trifluoroacetic anhydride N-acylation is accompanied by oxidation and C- acylation with formation of the compound (30 1). Similarly tabersonine (302) itself gives the analogous product (303). These reactions must involve Nb,C-3 oxidation to give an iminium ion (304a) which then gives a 3,14-enamine (304b) by capture of a nucleophile; enamine acylation followed by hydrolysis of the C-15 acyloxy group during work-up then gives (301) and (303) (Scheme 38).Similarly vincadifformine (305) which lacks the 14,15 double bond gives a product (306) resulting from oxidation to the 5,6-enamine via the appropriate N,,C-5 iminium ion and acy1ati0n.l~~The N,,,3 or N,,,5 iminium cations can also be generated by the 9,10-dicyano- anthracene-sensitized photo-oxygenation of tabersonine (302) or vincadifformine (305) respectively ; these can be efficiently trapped by trimethylsilyl cyanide with formation of the a-aminonitriles (307) and (308) products which may prove useful in interconversions in this alkaloid series. 179 In an earlier studylsoa the flow thermolysis of I ,2-dehydro-aspidospermidine (309) at 580 "C was reported to give vincane (3 lo) the rearrangement presumably involving two 1,5-sigmatropic shifts via the transient intermediate (3 11) (Scheme 39) formed by the shift of C-21 to C-2; the shift of C-16 to nitrogen then gives vincane (310).In principle the shift of C-6 to C-2 in (309) is equally possible to give the intermediate (312); the subsequent shift of C-16 to C-7 then affords the indolenine (3 13). Several other 1,5-sigmatropic shifts are feasible in this system as outlined in Scheme 39. In a thorough reinvestigation of the flow thermolysis of 1,2-dehydro-aspidospermidine Lkvy and his have estab- NATURAL PRODUCT REPORTS 1993 (300) 2,16-Dihydrotabersonine (304a) (302) Tabersonine A2-16 (305) Vincadifformine A2*16 i (on 305)J COCFB O - F O H*‘Et ‘ N I I CF3CO C02Me (301) A2’16 (303) Reagent i (CF,CO),O Scheme 38 - C-16-Na Et Et (314) NATURAL PRODUCT REPORTS 1993-5.E. SAXTON lished that all the sigmatropic shifts illustrated can occur. At 580 "C the only product appears to be vincane (310) but at 620-630 "C all four products the indolenines (313) and (314) and the indoles (310 vincane) and (315 isovincane) are obtained. At higher temperatures (670-680 "C)only the indoles (310) and (315) were isolated together with some unchanged (309). The ring systems represented by compounds (3 13F(3 15) have not yet been encountered in nature but it is of interest to note that those possessed by the intermediates (31 1) and (312) are found in vallesamidine and melonine respectively.The electrochemical (anodic) oxidation of tabersonine (302) X xt13H \ Et C02Me (316) X = H H (317) X = 0 vii -!h (324) 053 \ IH 38 I or 3-oxotabersonine gives dimeric products (3 16) and (3 17) respectively.lsl In the oxidation of 3-oxotabersonine the dimer (317) (68 %) was the sole product but in the oxidation of tabersonine (302) itself some symmetrical 10,lO'-dimer (5 "0) was also obtained together with a trimer (2%) and several other minor unidentified products. A new short synthesislg2 of N-benzylaspidospermidine(318) starts from the enaminoketone (3 19) which is subjected to two alkylations and the hexahydrocarbazolone ring closed by photocyclization. The product (320) is a mixture of epimers containing a trans B/C ring junction but alkylation of the derived anion by means of nitroethylene gives exclusively the desired product (321) as an inseparable mixture of nitroketones containing a cis B/C ring junction (Scheme 40).Reductive cyclization then gives a mixture of imines (322a) (322b) of which the one with the desired stereochemistry (322b) cyclizes spontaneously to give the iminium salt (323). Stereoselective hydrogenation of (323) then gives N-benzylaspidospermidine (318).ls2 The synthesis of alkaloids of the aspidofractinine group developed by Gramain and his collaboratorsi5 has been improvedls3 by the adoption of a convergent approach in which ring E is added to the tricyclic aminoketone (324) by reaction with the iodoacetamide derivative (325).The product (326) is a single diastereoisomer with the correct stereochemistry at the B/C and C/E ring junctions. Dehydration of (326) then gives the tricyclic amine (327) which already contains the three-carbon unit attached to N, and is therefore conveniently set up to provide ring D of the aspidofractinine frame-work (Scheme 40). This approach avoids the N,-protection4eprotection sequence which was found to be necessary in the earlier synthesis. Ph (327) (323) Reagents i LDA EtI THF -78 "C; ii LDA I(CH,),Cl THF -78 "C; iii hv C,H, Ar; iv LDA CH = CHNO, THF -78 "C; v HCOONH, 10% Pd/C MeOH 65 "C; vi H, Pt/Al,O, EtOH 3 atm; vii ICH,CONH(CH,),OCH,CH = CH (325); vii CSA CH,Cl Scheme 40 NATURAL PRODUCT REPORTS 1993 I_ Me Me02C I A- 0-(331) (328) (332) 1ii (329) (330) Reagents i MeSOCH,Li THF DMSO; ii TsOH THF H,O Scheme 41 C02Et Me0 Et (333) The racemization that is observed during the course of the vindorosine synthesis by Langlois et u/.115-184a has earlier been postulated to occur during the rearrangement of the p-ketosulfoxide (328) to the pentacyclic base (329) i.e.via a reverse Mannich reaction on the sulfonium ion (330). However it has now been established that the P-ketosulfoxide (328) itself is race mi^,'^^^ in spite of the fact that it is prepared from the optically pure indoloquinolizidine ester (33 1). It is apparent therefore that the reverse Mannich fission of ring D operates in the P-ketosulfoxide (328) [328)*(332)] and therefore the racemization occurs during the preparation of (328).In contrast esters of type (33 1) or the P-ketoester analogue of (328) appear to be configurationally stable (Scheme 41).lS4* The preparation of an advanced intermediate (333) in a projected synthesis of alalakine has been reported. 185 The epimers of 14-hydroxydesethylvincadifforminehave been synthesized and the 14a-hydroxy epimer has been converted by oxidative rearrangement into 14a-hydroxydesethyl-vincamine (334) and its C-16 epirner.la6 19-Ethoxycarbonyl- 19- demethylvincadifformine (333 prepared earlier,1s7a has also been subjected to oxidative rearrangement in this case via the 16-chloroindolenine derivative the product being 19-ethoxy- carbonyl- 19-demethylapovincamine (336) (Scheme 42).18'0 The synthesis of vincamine (337) from Wenkert's enamine via indoloquinolizidine propionic ester derivatives e.g.(338) has been re-examined and an improved preparation of the oximino-ester (339) has been reported.ls8 Removal of the oximino group from the hydrochloride of (339) under acidic conditions at elevated temperatures gave apovincamine (340) but less vigorous treatment of (339) itself with sodium metabisulfite in aqueous acetic acid gave vincamine (337) together with some 16-epivincamine (Scheme 43). Since apovincamine is relatively easily synthesized and is often obtained in projected syntheses of vincamine if the last (335) Reagent i NCS TFA rt 4h then heat 3 h N Scheme 42 H (on 339,HCI) MeO2CC-CH2W Et Et (338) X = H H (340) Apovincamine (339) X = NOH iv I (337) Vincamine Reagents:i ButONO KOBut PhMe DMF MeOH ;ii TsOH PhMe heat; iii Na S,O, AcOH H,O 90 "C; iv conc.HC1 then NaNO, H,O; v H, Pd/C NEt, K,CO, MeOH Scheme 43 stage involves vigorous (particularly acidic) conditions the reconversion of apovincamine into vincamine is of considerable importance. Three methods of achieving this conversion are already available but none is entirely satisfactory on the basis of efficiency or convenience. Szantay's new method189 is a simple and efficient two-stage process in which apovincamine (340) is dissolved in concentrated hydrochloric acid and treated with aqueous sodium nitrite. The product somewhat surprisingly is the chloroester (34 l) whose structure and NATURAL PRODUCT REPORTS 1993-5.E. SAXTON H HO NOH NH2 (344) (342) (343) Reagents i LiAlH, THF heat; ii NaIO, H,O CH,Cl,; iii Ac,O 100 "C Scheme 44 OMe 0 OMe Me0 Me0 iii I iv or v and vi \ OThp i xii xiii vii ~ H OMe R Me0 Me0 Me0 R = OMe or SMe 0 OH Ixiv Me0 LO LO C02Me xviii xii xix OMe Me02C OHCNH (345) Cuanzine Reagents i LiAlH, THF heat; ii KMnO, Me,CO 0 "C; iii CH = CH-CH = CH.CO,Me; iv Me,OBF, CH,Cl,; v Lawesson's reagent THF heat; vi MeI K2C0, THF; vii CH = CH.COCH,CO,Me TsOH MeOH; viii H, PtO,; ix Ac,O KOAc 100 "C; x LDA THF HMPA -70 "C; xi ICH,CH,OThp -40 "C; xii Ac,O py; xiii TsOH MeOH; xiv I, KIO, AcOH H,O dioxan; xv K,CO, MeOH H,O; xvi (COCI), NEt, DMSO CH,Cl, -70 "C; xvii LiHMDS NC .CH,CO,Me THF -15 "C ;xviii HCl H,O EtOH ;xix DBU THF 80 "C ; xx MeOH HCI heat Scheme 45 stereochemistry were confirmed by the X-ray method.The mechanism of formation of (341) is at present obscure; it is probably not the result of direct addition of hypochlorous acid to apovincamine. Hydrogenolysis of (341) then gives vincamine (337).189 Szantay and his collaborators have also completed the synthesis of decarbomethoxyapocuanzine (342).lS0The later stages of this synthesis involved the intermediate oximino-ester (343) which was prepared earlier during the synthesis of desmethoxycuanzine.75 Reduction of (343) to the related aminoalcohol periodate fission to the aldehyde which cyclized to the carbinolamine form [(344),mixture of epimers] followed by dehydration gave decarbomethoxyapocuanzine (342) (Scheme 44).ls0 The synthesis of cuanzine (345) (Scheme 45) by Ortuno and Langloi~~~l follows identical lines to the same workers' earlier SynthesiP of desmethoxycuanzine.The partial synthesis of (-)-criocerine (346) from (+)- NATURAL PRODUCT REPORTS 1993 (337) (+)-Vincamine R = H (349) (+)-Vincine R = OMe J R (346) (-)-Criocerine R = H (347) (348) (-)-Craspidospermine R = OMe Reagents i I, NaHCO, CHCl, H,O; ii HCO,H Pd/C N Scheme 46 vincamine (337) simply involves the iodination of vincamine with an excess of iodine in the presence of saturated aqueous sodium bicarbonate. 192a The product presumably obtained by iodoether formation from the initially formed tetradehydro- vincamine is 14-iodocriocerine (347); removal of the iodine then gives (-)-criocerine (346) (Scheme 46).(-)-Craspido- spermine (348) can be obtained in an exactly similar manner from (+)-vincine (349).192b 4.7 Catharanthine -Ibogamine Group Ibogaine iboxygaine iboxygaine hydroxyindolenine ibol-uteine and voacristine occur in the root bark of Ervatamia hirta,96and 3S-hydroxyvoacangine (350) a base not previously found in nature is the major alkaloid produced in callus tissue cultures of Tabernaemontana pandacaqui Poir.lg3 The X-ray crystal structure determination of isovoacangine has been reported. lg4 The tetracyclic acetals (35 I) prepared earlier5* during the course of the synthesis of iboxyphylline (352) have proved to be extremely versatile intermediates for the synthesis of alkaloids of this group and the vinblastine group.Whereas [(351) ‘versatiline ’3 is prepared by Kuehne’s ingenious bio- to mimetic route its further manip~lation’~~ afford new syntheses of pseudotabersonine (353) pseudovincadifformine (3 54) coronaridine (3 55) ibogamine (3 56) iboxyphylline (3 52) and ibophyllidine (357) (Scheme 47) largely employs familiar methods few of which require specific comment. However it may be noted that the enamine (358) which had previously been converted somewhat inefficiently into coronaridine (355) by reduction followed by re-oxidation with mercuric acetate was quantitatively and stereoselectively converted into racemic coronaridine on storage under vacuum for several days.Removal of the ester function then gave ibogamine (356). For the synthesis of pseudotabersonine (353) and pseudo- vincadifformine (354) it was necessary to change the trans stereochemistry of the D/E ring junction in the pentacyclic base (359) obtained by deprotection of (35 1) followed by cyclization. This was achieved by dehydrogenation of (359) by means of dibenzoyl peroxide followed by reduction (NaBH,) of the didehydropseudotabersonine (360) so produced. It was similarly necessary to ensure the cis stereochemistry of the D/E ring junctions in iboxyphylline (352) and ibophyllidine (357). This was achieved by reversible acid-catalysed fission of the 3,7 bond in the tetracyclic intermediates (361) and (362); the resulting epimerization appears not to be possible in compounds containing a preformed ring D e.g.in enamine (359) (Scheme 47).Ig5 5 Bisindole Alkaloids A new brominated bisindole derivative 2,2’,6,6’-tetrabromo- 3,3’-bisindole (363) has been isolated together with two known bisindoles 2,3‘,5,5’-tetrabromo- 7’-methoxy- 3,4’- bisindole and 2,2’,3,4’,5,5’-hexabromo-l,3’-bisindole, from an Australian cyanobacterium Rivularia firma Womersley col- lected at Flinders (Victoria).lg6 Two cytotoxic bisindoleamides chondriamides A (364) and B (365) have been extracted from a red alga Chondria sp. collected intertidally at Miramar Buenos Aires. 19’ Some 3- indole acryloyltryptophan (366) was also obtained together with indole 3-aldehyde N-formyl 3-indoleacrylamide indole 3-acrylic acid and 7-hydroxyindole 3-acrylic acid which are presumably oxidation or hydrolysis products of (364)-(366).Two new red pigments (367) and (368) together with caulerpin have been extracted from the green alga Caulerpa racemosa (Forsk.) J. Agardh found off the coast of Visakhapatnam (India). lg8 Several other non-indolic metabolites were also isolated. A new general approach to the synthesis of yuehchukene has been described,lgga and the results of bioassays on the synthetic compound (369) prepared from 1(R)-(+)-camphor and its enantiomer are interpreted as indicating that the bioactive constituent of yuehchukene which is racemic is the 6(R) enantiomer (37O).lggb Details of earlier 79 of yuehchukene by Bergman200 and Kutney201 have been published.The synthesis of staurosporine aglycone by Moody and his collaborators ’j has also been reported in A Streptomyces sp. RK286 produces a novel inhibitor of protein kinase C which is designated RK286D. Closely related to staurosporine RK286D (371) is regarded as a shunt metabolite in the biosynthesis of staur~sporine.~~~ A series of fifteen indolocarbazoles named tjipanazoles A 1 A2 B C1 C2 C3 C4 D E F1 F2 G1 G2 I and J (372)-(386) have been isolated from the blue-green alga Tolypothrix tjipanasensis De Wild (strain DB- 1 -1),,04 found in a soil sample collected at Vero Beach Florida. These metabolites are responsible for the moderate fungicidal activity of the lipophilic extracts of this alga.Their structures were NATURAL PRODUCT REPORTS 1993-5 E. SAXTON yH2Ph Et HI C02Me (351) Et ii vi vii (major C-16 epimer) J \ \ H H Q;q .. (356) lbogamine (355) Coronaridine C02Me (359a) viii I Et 0-q \ HI H C02Me C02Me C02Me (360) (353) Pseudotabersonine (354) Pseudovincadifformine Et H Me H -Et @.K) xi xii xiii-xv \ II 1L ' \ \ N N H H H H C02Me C02Me C02Me C02Me (352) lboxyphylline (3611 (362) (357) lbophyllidine Reagents i NaBH, AcOH 90 "C; ii H, Pd/C; iii HCI MeOH; iv 5 days in vacuo;v N,H, EtOH; vi HC1 H,O; vii H+ 110 "C; viii (PhCO,),; ix NaBH,; x O, CHCI, hv;xi (CH,OH), BF;Et,O C,H,; xii NaOMe; xiii CH,O H+; xiv H30+;xv Selectride Scheme 47 R (364) Chrondriamide A R = H (366) 3-Indoleacryloyltryptophan (365) Chrondriamide B R = OH QT& H ;H Me 0-0-j C02H H OH H H H (367) R = H (368) R=Me (369) (370) 6R-Yuehchu kene (371) RK 286 D NATURAL PRODUCT REPORTS 1993 (372) Tjipanazole A1 R' (373) Tjipanazole A2 R' (374) Tjipanazole C1 R' (375) Tjipanazole C2 R' (376) Tjipanazole C3 R' (377) Tjipanazole C4 R' (378) Tjipanazole G1 R' (379) Tjipanazole G2 R' = R2= CI R3 = Me R4 = H = R2 = CI R3 = H R4 = Me = CI R2= R4 = H R3 = Me = R4 = H R2 = CI R3 = Me = CI R2 = R3 = H R4 = Me = R3 = H R2 = CI R4 = Me = R2 = R4 = H R3 = Me = R2 = R3 = H R4 = Me (384) Tjipanazole D R' = R2 = CI (385) Tjipanazole I R' =CI R2 = H -CI iii-v N H HO OH OH (381) Tjipanazole E R' OH Tjipanazole B R' = R2 = CI R3 = H Tjipanazole E R' = R2 = CI R3 = CHgH Tjipanazole F1 R' = CI R2 = R3 = H Tjipanazole F2 R' = R3 = H R2 = CI H OyNyOH H H (386) TjipanazoleJ H H (384) Tjipanazole D Reagents i conc.HzSO, EtOH 65 "C; ii AcOH 100 "C; iii NaH MeCN; iv 2,3,4,6-tetra-acetylglucopyranosylbromide; v NH, MeOH Scheme 48 determined by spectroscopic methods chemical degradation and synthesis (tjipanazoles D and E) (Scheme 48). In connection with the anti-tumour activity of duocarmycin A which may be related to the irreversible alkylation of DNA it is of interest to note that the duocarmycin A-adenine adduct (387) has been preparedzo5 by the duocarmycin A alkylation of calf thymus DNA.New bis-carbazole alkaloids found16b in the stem bark of Murraya euchrestifoliu include bismurrayafoline C (388) which is derived from two murrayafoline B units and bismurrayafoline D (389) which is a dimethyl ether of (388). Chrestifoline D from the root bark has the structure (390) and can be obtained by the oxidation of bismurrayafoline A (39 1) by means of 2,3-dichloro-5,6-dicyano-1,4-benzo-q~in0ne.l~ Murranimbine (392) also from the root bark is an unsymmetrical dimer of girinimbine. Its structure was deduced from a study of its COSY and HMBC spectra.206 This appears to be the first dimer of girinimbine to be isolated from a natural source. Okaramine C is a new insecticidal metabolite derived from two tryptamine units and two isoprenyl fragments which has been found in Pencillium simplicissimum AHU 8402,207 together with okaramines A and B whose structures were elucidated 79 Okaramine C (393) differs structurally from okaramine A only in the absence of a bond between N-3' and C-4' and a double bond between C-1' and C-2'.Since the insecticidal activity of okaramine C against silkworm larvae is comparable with that of okaramine A it appears that the presence of an azocine ring is not essential for activity. NATURAL PRODUCT REPORTS 1993-5. E. SAXTON OR RO HO H (387) OMe OMe (388) Bismurrayafoline C R = H (389) Bismurrayafoline D R = Me QLyq OMe (390) Chrestifoline D R = CHO (391) Bismurrayafoline A R = Me Me (392) Murranim bine (393) Okaramine C (394) R = H (395) R= Me Me H ‘ (396) lsocalycanthine (397) Psycholeine Two of the three anti-insectan dioxopiperazine metabolites found re~ently’~ in the sclerotia of Aspergillus ochraceous prove to be closely related to amauromine.One of these (394) is isomeric with amauromine and has the same gross structure; it differs from amauromine in the stereochemistry at positions 2 and 3 and is therefore named epiamauromine. The second metabolite is N-methylepiamauromine (395). Both caused moderate reduction in weight gain in assays against the crop pest Helicoverpa z~u.’~ ( -)-Calycanthine mesochimonanthine and a new alkaloid isocalycanthine (396) have been isolated from Psychotria forsteriana A.Gray grown in Vanuatu.208 This appears to be the first time that N-methyltryptamine dimers have been obtained from this genus. More characteristic are trimers and tetramers of N-methyltryptamine a fact which is reinforced by the recent that the leaves of Psychotria oleides (Baill.) Schltr. from New Caledonia contain a new tetrameric alkaloid psycholeine for which the structure and stereo-chemistry expressed in (397) were deduced ; quadrigemine C and hodgkinsine were also isolated in this bioactivity-guided extraction procedure (these alkaloids affect the release of the (398) Quadrigemine C 3aR 3a‘R 3a“S 3a”’R main pituitary hormones). On the basis of its proton NMR spectrum and its CD spectrum the stereochemistry of quad- rigemine C (398) which was previously unknown was deduced and in accordance with these conclusions it was established that quadrigemine C could be isomerized to psycholeine in the presence of acid; in view of this it may well be that psycholeine is an artefact of the extraction procedure.Strychnos usambarensis Gilg. which occurs in an arborescent form in East and South Africa and as a liana in Central Africa has been subjected to further The roots and leaves of the arborescent form are used as the main ingredient of the arrow poison concocted by the Banyambo hunters of Rwanda but it was the stem bark of this form collected in Tanzania that was extracted in the most recent investigation. Aside from harman all the alkaloids obtained were bisindole alkaloids and included usambarensine dihydrousambarensine strychno- foline isostrychnofoline 10-hydroxyusambarine 11 -hydroxy- usambarine and strychnopentamine.The stem bark of the liana form from the Ivory Coast yielded dihydro-usambarensine usambarine dihydrousam barine 10-hydroxy-usambarine and N,-methyl-10-hydro~yusambarine.~~ Of 388 NATURAL PRODUCT REPORTS 1993 OH OH OH OH (399) CallophyllineA (400) Callophylline B C02Me/ Me0 HOP p:H*’Et ‘ (401) R’ = H R2 = OH (402) R’=OH R2= H Me0 ‘ N OMe H C02Me H I C02Me (403)R’ = OAC R2 = H (404) Conophylline (405) Scandomelidine Me 3 (406) Ci micidu phyti ne these strychnopentamine and 3’,4’-dihydrousambarensine were shown to exhibit potent activity against Plasmodium falciparum in vitro.210 Callophyllines A (399) and B (400) are two new bisindole constituents of Malaysian Uncaria callophylla which are composed of gambirine (9-hydroxydihydrocorynantheine) and 3-epi-P-yohimbine (399) or 9-hydroxypseudoyohimbine (400) 211 In callophylline A (399) the attachment is between C- 10 of gambirine and C-21’ of 3-epi-P-yohimbine whereas in callophylline B it is between C-1 1 of gambirine and C-21’ of the pseudoyohimbine component.In both alkaloids the C-21’ substituent is P and equatorial to ring D’. Of the nine alkaloids obtained from the leaves of Tonduzia pittieri Donn. Sm. four are bisindole alkaloid^,'^^ which are the known cabufiline and three new ones composed of vincorine and vincamedine-derived units. These were identified as 1 1-[lo- (1 1-methoxy-17-epivincamajinyl)]-vincorine (40 l) 1 1 -[lo-( 1 1 -methoxyvincamajinyl)]-vincorine (402) and its 17-O-acetate 11 -[lo-( 1 1 -methoxyvincamedinyl)]-vincorine(403).The plant from which these alkaloids were obtained is also known as Alstonia pittieri (Donn. Sm.)A. Gentry. In view of its .= H Et (407) 16-Decarbomethoxy-voacamine pseudoindoxyl alkaloid content the authors of Reference 138 believe that there is no justification in separating the Tonduzia and Alstonia genera. Decarbomethoxytetrahydrosecamine is the only bisindole alkaloid found among the fourteen alkaloids of Arnsonia sinensis.loo New alkaloids composed of Aspidosperma- type units include conophylline scandomelidine and cimiciduphytine. Conophylline a constituent of the leaves of Tabernae-montana divaricata,172 is composed of highly oxygenated tabersonine units and has the structure (404) in which one of the units possibly derived from 10-hydroxy- 1 1,12-dimethoxy- tabersonine is also the precursor of one of the components of pandicine.NATURAL PRODUCT REPORTS 1993-5. E. SAXTON Me0 OAC MeH : C02Me Vindoline (410) / (41 1) 1OV = 10-vindolinyl vii J "H-Me0 OAc t'-we n" '6 C02Me (408) Vinamidine (409) Vinblastine Reagents i ButOCl; ii AgBF, HBF,; iii KBH, AcOH; iv H, Pd/C; v HCl MeOH; vi O, hv,CHCl,; vii 0,,Fe3+,then NaBH Scheme 49 Scandomelidine was obtained in 1974 from the leaves and stems of Melodinus scandens Forst. together with scando- melonine scandomeline and their C-19 epimers.212" The structures of these last four alkaloids were elucidated and it has now been shown212c that scandomelidine (405) the rarest of the four alkaloids is composed of pachysiphine (tabersonine P-epoxide) and venalstonine units the attachment being from C-3 of pachysiphine to C-10 of venalstonine.In common with the other bisindole alkaloids of Haplophyton cimicidum cimiciduphytine is derived from monomeric com- ponents of a less familiar type.213 Like its congener cimilo- phytine cimiciduphytine (406) contains an unrearranged canthiphytine unit but in the latter it is dehydrated. The second component in (406) is derived from dehydroisocimicidine rather than dehydrocimicidine and the double bond is at the 16,17 rather than the 14,15 position as it is in cimilophytine.The four bisindole alkaloids isolated from the root bark of Ervatamia hirta are dihydrotchibangensine 16-decarbo-methoxyvoacamine 19,2O-dihydro- 16-decarbomethoxyvo- acamine and 16-decarbomethoxyvoacaminepseudoindox yl (407) which is new.96 The production of leurosine in multiple shoot cultures of Catharanthus roseus is reported to be stimulated by irradiation at 370 nm.17s Cell suspension cultures of C. roseus convert vinblastine into vincristine (as sole product) after two days' in~ubation.~'~ In the vinblastine group the X-ray crystal structure of 16'- epivinblastine has been determined,215 and the mechanism of the formation of anhydrovinblastine by the oxidative coupling of catharanthine and vindoline by means of the Potier-Polonovski reaction has been thoroughly investigated.216 This study has served to confirm the main features of the accepted mechanism of anhydrovinblastine formation postulated earlier by Potier and by Kutney and their co-workers.The conformation of vinblastine in aqueous (D20) solution at pD4.8-6.6 has been determined by 2D proton and 13C NMR A new synthesis of vinamidine (408) and vinblastine (409) by Kuehne and Bornmannlg5 employs the common intermediate versatiline (351) that was used in the synthesis of coronaridine and other members of the ibogamine group (v. supra). Coupling of the 16-chloroindolenine derived from (35 1) with vindoline gave a bisindole derivative (410) in which the 3',7'- bond could be cleaved reductively; hydrolysis of the acetal function by acid followed by recyclization then gave the important intermediate (41 1).Photochemical oxidation of (41 1) afforded vinamidine (408) and oxidation in the presence of ferric ion followed by reduction (NaBH,) gave vinblastine (409) (Scheme 49). The synthesis of vinblastine (409) by Magnus and his collaborators has been improved by the development of a stereospecific synthesis of the base (412) (Scheme 50).218 A series of aminophosphonic acid derivatives of vinblastine have been prepared from deacetylvinblastine azide for testing for anti-tumour activity.21g One of these (413) proved to be very active against cancer cell lines in vivo and in vitro. NPR 10 NATURAL PRODUCT REPORTS I993 OH-pt-,STOH -% iv-vi OHCX0&- I Et PhS<oo* Et Et Et -viii ix lx Reagents i Ti(OPr'), BU'OOH (-)-diethy1 tartrate CH,Cl, -20 "C; ii PhSH 0.1M NaOH-HzO dioxan; iii Hi,I-methoxycyclohexene; iv rn-CPBA; v Ac,O NjfOAc; vi KzCO, MeOH heat; vii Sn(OTf), N-ethylpiperidine THF; viii Ts,O NEt,; ix DBU CH,Cl,; x Raney Ni (deact.); xi H, Pd/C Scheme 50 Me0 The cephalosporin derivative (414) substituted at position (2-3' with deacetylvinblastine hydrazide has been synthesized (Scheme 51) as a potential prodrug for the treatment of solid tumours.220 In the presence of the P99 p-lactamase enzyme isolated from Enterobacter cloacae 265A the prodrug (414) is efficiently cleaved to deacetylvinvlastine hydrazide.It is hoped that in uivo a p-lactamase enzyme covalently attached to a monoclonal antibody prelocalized at the tumour site will react similarly with release of the cytotoxic vinblastine derivative. Finally the present state of knowledge concerning the metabolism and mechanism of action of vinblastine vincristine and leurosine has been reviewed in some detail and evidence has been presented which indicates that these alkaloids are selective reversible inhibitors of monoamine oxidase B.221 6. Biogenetica Ily Related Quino1ine Alkaloids 6.1 Cinchona Group Details have been publishedzz2" of the synthesis222b of 20S-20-hydroxyquinidine (415 biogenetic numbering) the major metabolite of quinidine in man. The full paper also describes Me H oGC-NH-F;H-CHM~~ P-0 EtO' gEt the X-ray crystal structure determination of the methane- sulfonate of (415) together with the preparation of (415) by microbial oxidation of quinidine by means of Cunninghamella verticillata.2z2a The X-ray crystal structure determination of the 5,5'-dinitro- 2,2'-diphenic acid salt of quinidine has also been reported.z23 A new synthesis of the advanced intermediates (416a) and (416b) the debenzyl derivatives of which have previously been converted into Cinchona alkaloids has been The conversion of the acetal (195) into the piperidine derivative (417) constitutes yet another route to dihydro-cinchonine and dihydrocinchonidine.12' An improved preparation of (+)-N-benzylcinchonine chlor- ide which is useful as a phase-transfer catalyst by the quaternization of cinchonine with benzyl chloride in DMF at 80 "C has been described.2z5 The hydrogenation of ethyl pyruvate by means of hydrogen in the presence of platinum on alumina 18,19-dihydro-0- methylcinchonidine and a catalytic amount of acetic acid is stated to give ethyl lactate with 95 % enantioselectivity.226This is claimed to be the highest enantioselectivity yet reported for any chiral heterogeneous catalyst.NATURAL PRODUCT REPORTS 1993-5. E. SAXTON 391 NO2 + C 02C HPh2 Me0 Me H i ii CONHNHZ I H02C (414) Reagents i pyridine PriNEt; ii TFA Et,SiH CH,Cl, 0 "C Scheme 51 OAc 0 (415) (416a) R=H (416b) R = OMe Et prepared for the purpose of evaluation as anti-tumour agents.These include derivatives in which the quinoline ring is modified,228u derivatives of 7-ethyl- 1 O-hydroxycampto- thecin,228b ring A substituted derivatives,228b and ring E modified derivatives.229 Of these 7-ethyl-10-hydroxycamptothecin (41 8)228band the organic ammonium salts of its 0-sulfate and 0-phosphate,228c and (RS)-20-deoxy- 20-amino-7-ethyl-10-methoxycamptothecin (419)229 showed significant anti-tumour activity. In particular compound (4 19) was found to be more active than (+)-camptothecin in an in vivo assay. 10-Hydroxycamptothecin (420) has been prepared in 73.5 % yield by the lead tetra-acetate oxidation of 1,2,6,7-6.2 Camptothecin tetrahydrocamptothecin (42 1) in trifluoroacetic acid (Scheme For the Japanese reader the synthesis and anti-tumour activity 52).228b of camptothecin analogues have been reviewed.227 Finally the proton and 13C NMR spectra of camptothecin Numerous derivatives of camptothecin have recently been 9-and 12-nitrocamptothecin and 10,ll -methylenedioxy- 27-2 392 Camptothecin -“O-0Ei Reagents i H, PtO,; ii Pb(OAc), TFA Scheme 52 camptothecin have been completely assigned from one- and two-dimensional NMR data.230 24 7 References 25 1 (a) R. Verpoorte R. van der Heijden W. M. Van Gulik and 26 H. J. G. ten Hoopen in ‘The Alkaloids’ ed. A. Brossi Academic Press New York 1991 40 Chapter 1; (b) R. Antkowiak and 27 W. Z. Antkowiak ibid. Chapter 2. 2 (a) B. Tantisewie and S. Ruchirawat in ‘The Alkaloids’ ed.A. 28 Brossi and G. A. Cordell Academic Press New York 1992 41 Chapter 1 ;(6) J. Kobayashi and M. Ishibashi ibid. Chapter 2. 29 3 M. Alvarez M. Salas and J. A. Joule Heterocycles 1991 32 1391. 30 4 A. Guggisberg and M. Hesse Helv. Chim. Acta 1992 75 647. 5 (a) R. Verpoorte in ‘Studies in Natural Product Chemistry’ ed. 31 Atta-ur-Rahman Elsevier Amsterdam 1992 Vol. 9; (6) D. Dagnino J. Schripsema A. Peltenburgh R. Verpoorte and K. Teunis J. Nut. Prod. 1991 54 1558. 32 6 (a) D. P. Chakraborty and S. Roy in ‘Progress in the Chemistry of Natural Products’ 1991 57 71 ;(b) H. J. Borschberg Chimia 1991 45 329. 7 (a)I. Ninomiya J. Nut. Prod. 1992,55 541 ;(b)F. Soti M. Incze Z. Kardos-Balogh and Cs. Szantay in ‘Studies in Natural 33 Product Chemistry ’ ed.Atta-ur-Rahman Elsevier Amsterdam 1991 8 283. 8 K. Monde K. Sasaki A. Shirata and M. Takasugi Phytochemistry 1991 30 29 15. 9 K. Monde K. Sasaki A. Shirata and M. 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V. Iribe J. Crystallogr. Spectroscop. Res. 1991 21 681. 195 W. G. Bornmann and M. E. Kuehne J. Org. Chem. 1992 57 1752. 196 A. R. Hodder and R. J. Capon J. Nat. Prod. 1991 54 1661. 197 J. A. Palermo P. B. Flower and A. M. Seldes Tetrahedron Lett. 1992 33 3097. 198 (a) A. S. R. Anjaneyulu C. V. S. Prakash and U. V. Mallavadhani Phytochemistry 1991 30 3041 ; (b) A. S. R. Anjaneyulu C. V. S. Prakash K. V. S. Raju and U. V. Mallavadhani J. Nat. Prod. 1992 55 496. 199 (a)K.-F. Cheng,. K.-P. Chan and T. F. Lai J. Chem. Soc. Perkin Trans. 1 1991 2461; (b) K.-F. Cheng K.-P. Chan Y.-C. Kong and D.-D. Ho ibid. p. 2955. 200 J. Bergman and L. Venemalm Tetrahedron 1992 48 759. 201 J. P. Kutney F. J. Lopez S.-P. Huang H. Kurobe R. Flogaus K.Piotrowska and S. J. Rettig Can. J. Chem. 1991 69 949. 202 C. J. Moody K. F. Rahimtoola B. Porter and B. C. Ross J. Org. Chem. 1992 57 2105. 203 H. Osada M. Satake H. Koshino R. Onose and K. Isono J. Antobiot. 1992 45 278. 204 R. Bonjouklian T. A. Smitka L. E. Doolin R. M. Molloy M. Debono S. A. Shaffer R. E. Moore J. B. Stewart and G. M. L. Patterson Tetrahedron 1991 47 7739. 205 D. L. Boger T. Ishizaki and H. Zarrinmayeh J. Am. Chem. Soc. 1991 113 6645. 206 C. Ito and H. Furukawa Chem. Pharm. Bull. 1991 39 1355. 207 H. Hayashi T. Fujiwara S. Murao and M. Arai Agric. Biol. Chem. 1991 55 3143. 208 Y. Adjibade B. Weniger J. C. Quirion B. Kuballa P. Cabalion and R. Anton Phytochemistry 1992 31 317. 209 F. Gueritte-Voegelein T. Sevenet J.Pusset M.-T. Adeline B. Gillet J.-C. Beloeil D. Guenard P. Potier R. Rasolonjanahary and C. Kordon J. Nut. Prod. 1992 55 923. 210 C. W. Wright D. H. Bray M. J. O’Neill D. C. Warhurst J. D. Phillipson J. Quetin-Leclerq and L. Angenot Planta Med. 1991 57 337. 21 1 T.-S. Kam K.-H. Lee and S.-H. Goh Phytochemistry 1991 30 3441. 212 (a)H. Mehri and M. Plat Plant. Med. Phytother. 1974,2 143; (b) M. Daudon H. Mehri M. Plat E. W. Hagaman and E. Wenkert J. Org. Chem. 1976 41 3275; (c) H. Mehri and M. Plat J. Nat. Prod. 1992 55 241. 213 A. A. Adesomoju M. B. Lakshmikantham and M. P. Cava Heterocycles 199 1 32 146 1. 214 H. Hamada and K. Nakazawa Biotechnol. Lett. 1991 13 805. 215 V. M. Lynch A. Stamford P. Magnus and B. E. Davis Acta Crystallogr.Sect. C 1991 47 1563. 216 R. J. Sundberg K. G. Gadamasetti and P. J. Hunt Tetrahedron 1992 48 277. 217 E. Gaggelli G. Valensin N. J. Stolowich H. J. Williams and A. I. Scott J. Nut. Prod. 1992 55 285. 218 P. Magnus and J. Mendoza Tetrahedron Lett. 1992 33 899. 219 G. Lavielle P. Hautefaye C. Schaeffer J. A. Boutin C. A. Cudennec and A. Pierre J. Med. Chem. 1991 34 1998. 220 L. N. Jungheim T. A. Shepherd and D. L. Meyer J. Org. Chem. 1992 57 2334. 221 J. P. N. Rosazza M. W. Duffel S. El-Marakby and S. H. Ahn J. Nut. Prod. 1992 55 269. 222 (a) F. I. Carroll P. Abraham K. Gaetano S. W. Mascarella R. A. Wohl J. Lind and K. Petzoldt J. Chem. Soc. Perkin Trans. I 1991 3017; (b) F. I. Carroll A. Philip and M. C. Coleman Tetrahedron Lett.1976 1757. 223 M. Kubicki T. Borowiak and M. Gawron J. Crystallogr. Spectroscop. Res. 1992 22 205. 224 S. R. Wilson and M. J. Di Grandi J. Org. Chem. 1991,56,4766. 225 R. Bao W. Huang and B. He Huaxue Shiji 1992,13,383(Chem. Abstr. 1992 116 214759). 226 H. U. Blaser H. P. Jalett and J. Wiehl J. Mol. Cat. 1991 68 215. 227 H. Terasawa A. Ejima and M. Sugimori Yuki Gosei Kagaku Kyokaishi 1991 49 1013. 228 (a) S. Sawada K. Nokata T. Furuta T. Yokokura and T. Miyasaka Chem. Pharm. Bull. 1991 39 2574; (b) S. Sawada S. Matsuoka K. Nokata H. Nagata T. Furuta T. Yokokura and T. Miyasaka ibid. p. 3183; (c) T. Yaegashi K. Nokata S. Sawada T. Furuta T. Yokokura and T. Miyasaki ibid. 1992,40 131. 229 A. Ejima H. Terasawa M. Sugimori S. Ohsuki. K.Matsumoto Y. Kawato M. Yasuoka and H. Tagawa Chem. Pharm. Bull. 1992 40 683. 230 E. L. Ezell and L. L. Smith J. Nut. Prod. 1991 54 1645.

ISSN:0265-0568    

DOI:10.1039/NP9931000349

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Natural Sesquiterpenoids B. M. Fraga lnstituto de Productos Naturales y Agrobiologia CSlC La Laguna 38206-Tenerife Canary Islands Spain Reviewing the literature published during 1991 (Continuing the coverage of literature in Natural Products Reports 1992 Vol. 9 p. 557) 1 Farnesane 2 Mono- and Bi-cyclofarnesanes 2 Mono- and Bi-cyclofarnesanes The new sesquiterpenes (lo)-( 12) and have been isolated from 3 Bisabolane Artemisia barrelieri12 and Artemisia ~antolinifolia,'~ respectively. 4 a-Santalane The novel ionone glucosides icariside B (13) and icariside B, 5 Cuparane Herbertane Gymnomitrane and Trichothecane 6 Chamigrane OH 7 Carotane Acorane and Anisatin Group 4 8 Cadinane Oplopanane Copaane and Picrotoxane 9 Himachalane Longipinane and Longicyclane 10 Caryophyllane Modhephane and Silphiperfolane I1 Humulane Integrifoliane Lippifoliane Protoilludane (2)R=(CO)Pr' Illudane Hirsutane Lactarane Sterpurane (3) R=Mebu Fomannosane and Marasmane (4) R = Prop 12 Germacrane 13 Elemane 14 Eudesmane and Oppositane 0 15 Eremophilane Bakkane and Chiloscyphane 16 Guaiane Pseudoguaiane Patchoulane and Trixane 17 Aromadendrane Gorgonane Nardosinane and Brasilane 18 Pinguisane (5) 19 Miscellaneous Sesquiterpenoids 20 References 1 Farnesane The new sesquiterpene (1) has been obtained from Caulerpa racemosa.Three new esters of 9-hydroxy-nerolidol (2)-(4) have been isolated from hula viscosa.2 Novel acyclic sesqui- terpene glycosides have been found in Gaillardia aestivali~,~ Polyachyrus ~phaerocephalus,~ and Sapindus delavayi.5 The sesquiterpenes (5) and (6) have been obtained from Athanasia pinnata6 The essential oil of Artemisia pallens contains more than 50 components one of which was identified as the new nerolidol derivative (7).' The structure of smenochromene A has been shown to be (8) by X-ray analysis.This unusual macrocyclic chromene can be derived by cyclization of farnesyl hydroquinone and it has been obtained together with its double bond isomers smenochromenes B-D from a Seychelles sponge of the genus Smenospongia.* Two farnesylcoumarins have been isolated from the roots of Ferula cornmuni~.~ The synthesis of the difuransesquiterpene athanasin (9) has enabled its absolute configuration to be established.lo Stereochemical studies on the biosynthesis of homoterpenes derived from nerolidol and geranyllinalool together with mechanistic phylogenetic and ecological aspects have been reported with higher plants1 0 C02H 397 398 NATURAL PRODUCT REPORTS 1993 0 = /b \? \qo\% %,,..; Cinn = %-Prop ; Ang = ; Epang = ; Meacr = ; Mebu = 0 OMe OH (15) R’=Glc R2=H (17) A6(’) (16) R’=H R2=Glc (18) (14) have been found in Epimedium sagittatum,14 and Epimedium grand~JIorum,~~ respectively whilst meliaionoside A (15) and meliaionoside B (16) have been obtained from Melia toosendan.16Another compound of this type has been identified as a component of the stems of Ampelopsis brevipedunculata. l7 The preparation of optically active 4-hydroxy-P-ionone and its transformation into (S)-6-hydroxy-a-ionone using a lipase in the transesterification of the corresponding racemate in the key step has been reported.18 The lH and 13C NMR spectra of a-ionone have been assigned.l9 The novel halogenated sesquiterpenes (17b(19) have been obtained from the red alga Laurencia caespitosa.2o Although there is now more evidence that the biosynthesis of abscisic acid occurs via carotenoids,21 the chemistry and occurrence of this plant growth regulator is reviewed here. A review on recent investigations on the biochemistry of ABA has been published.22 This phytohormone has been detected in the cultures of ten species of both saprophytic and parasitic fungi.23 The preparation of stably deuteriated abscisic acid phaseic acid and related compounds has been reported,24 and the total syntheses of (+) and (-)-forms of 7’-hydroxyabscisic acid have been carried A flavonoid glycoside acylated with dihydrophaseic acid has been obtained from the seeds of Astragalus complanatus.26 Cyclonerodiol has now been obtained from the fungus Trichoderma koningii and it has been shown to inhibit the growth of etiolated wheat coleoptile~.~~ This compound has also been isolated from corn infested by Fusarium moniliforme and its ‘H and 13CNMR spectra have been assigned.28 The structure of the nor-drimane sesquiterpene (20) has been resolved by X-ray analysis. This compound has been found in two varieties of Acacia a~2eut-a.~~ The known sesquiterpene HH HO (21) R= H (23) (22) R = OH OH OH HO gre O (25) polygodial has been isolated from the flower heads of Spilanthes acmella.30 The fungus Ganoderma neo-japonicus contains two new drimane sesquiterpenes cryptoporic acid H (21) and cryptoporic acid I (22).The latter compound has also been isolated from another fungus Cryptoporus volv~tus.~~ Several new avarol and avarone derivatives have been obtained from the Red Sea sponge Dysidea cinerea. Some of these compounds are cytotoxic show anti-microbial properties and have anti- HIV-1 activitie~.~~ The sesquiterpenes strongylin A (23) mamanuthaquinone (24) and cyanopuupehenol (25) have been found in the marine sponges Strongylophora h~rtmani,~~ f‘asciospongia SP.,~~ and a species of the order Ver~ngida,~~ respectively.These three metabolites of mixed biogenesis show different biological properties. The reactivity of avarone and related sesquiterpenes with NADH model compounds has been The structure of stagninol a drimane sesquiterpene which is a constituent of Persicaria stagnina has been shown to be (26).37 NATURAL PRODUCT REPORTS 1993-B. M. FRAGA HO. gp 0 OHC R’ =OH R2 = Me R’=Me R2=OH C02Me C02Me RPOH C02Me A (34)R=a-H (35)R = P-H (36)R = P-OOH (37)R = a-00H P pflc C02Me R A OH OOH k (39) (40)R = a-OH (43) (41)R=P-OH HO.. OH (44) (45) The synthesis of drimane sesquiterpenes has been reviewed.38 three new isomeric sesquiterpenes whose structures (39)-(41) The stereospecific transformation of uvidin A into (-)-have been elucidated by spectroscopic methods.4* a-Bisabonol A novel and enantio- is the main constituent of the essential oil obtained from young cinnamosmolide has been a~hieved.~’ selective synthesis of drimane sesquiterpenes has been devised.40 leaf buds of Populus deltoide~.~’ The new sesquiterpene (42) The synthesis of (+)-fragolide and (-)-pereniporin B have has been isolated from the Philippine nudibranchs Phyllidia been carried The enantioselective synthesis of the two postulosa and Phyllidia varicosa.This compound has also been The sesquiterpenes (27) and (28) starting from the diterpene (+)-found in the Palauan sponge Halichondria lender~feldi.~~ royleanone has been achieved showing that this is the absolute dimerization of a bisabolane sesquiterpene produces an unusual stereochemistry of two sesquiterpenes which have been found dimeric compound named bacchopetiolone (43).This metab- in Aspergillus oryzae [See Nut. Prod. Rep. 1985 2 p. 148].42 olite has been obtained from the aerial parts of Baccharis Terpenoid coumarins have been obtained from the roots of petiolata which was collected in Chile.51 The basidiomycete Ferula li~skyi,~~ and Ligularia per~ica.~~ Lepistra irina cultivated in liquid cultures produces the new Ferula gummo~a,~~ bisabolane derivative lepistirone (44).52The synthesis structure and configuration of sesquiterpenes derived from 1 -bisabolone 3 Bisabolane have been reviewed.53 The total synthesis of (+)-yingzhaosu A The bisabolane derivatives (29)-(3 1) have been obtained from (49 an antimalarial sesquiterpenoid which has been isolated whilst (32)has been found as a constituent from Artabotrys uncinatus has been carried Polyachyrus f~scus,~ of Athanasia pinnata.6 Several sesquiterpenes with this skeleton bisaborosaol A (33) bisaborosaol B (34) bisaborosaol B (33 bisaborosaol C (36) bisaborosaol C (37) and bisaborosaol D 4 a-Santalane (38) have been isolated from the leaves of Rosa r~gosa.~~,~’ An a-santalene derivative (46) which has been named a-A species of Australian marine sponge Arenochalina sp.contains santalone has been obtained from Polygonum jlaccid~m.~~ NATURAL PRODUCT REPORTS 1993 Me Me HO --q-& HO OHHO OH (47) HO6 br (54) R (59) R=CHO (61) (60) R=C02Me 5 Cuparane Herbertane Gymnomitrane and Trichothecane The structure of microbiotol a new sesquiterpene which has been obtained from needles of Microbiota decussata has been shown to be (47).56 Four novel dimeric herbertane sesquiterpenes mastigophorene A (48) its atropisomer at the biphenyl axis mastigophorene B mastigophorene C (49) mastigophorene D (50),the new herbertane derivative (51) and P-herbertenol have been isolated from Mastigophora diclados a primitive liverwort collected in Borneo.Some of these A compounds show neurotrophic propertie~.~',~* gymno-mitrane sesquiterpene (52) has been obtained from in vitro cultures of the liverwort Reboulia hemi~phaerica.~~ Jarvis et al.have studied twenty-one species of the genus Baccharis to establish their content of macrocyclic tri-chothecenes but only two species Baccharis cordifolia and Baccharis megupotamica were found to contain these types of compounds.6o Two new trichothecenes 8-n-pentanoyl-neosolaniol and 8-n-hexanoyl-neosolaniol, have been isolated from Fusarium sporotrichioides.61 The structure of myrotoxin B has been determined by X-ray analysis.62 In the biosynthesis of the trichothecenes the oxygenation steps after the formation of trichodiene have been studied in cultures of Fusarium culmorum treated with ancymidol as an inhibit~r.~~ The structure of gramilaurone a metabolite found in Fusarium graminearum has been determined as (53) by spectral and chemical methods.64 The biotransformation of the trichothecene T-2 toxin by the fungi Mucor mucedo and Aspergillus niger has been studied.65 U (49) 0 II I OHh ' '0 H (57) (58) I HO (64) a-epoxy (65) P-epoxy -+12 (66) R=CHO (67) R = CHO (68) R = C02H 6 Chamigrane Two new halogenated chamigrene sesquiterpenes pinnatifenol (54) and pinnatifinone (55) have been found in the red alga Laurencia pinnatzjida.66*'' Another species of this genus Laurencia obtusa contains the new chamigrene derivatives hurgadol (56) and P-snyderil acetate.68 The conformational analysis of marine polyhalogenated P-chamigrene sesqui-terpenes has been studied.6g 7 Carotane Acorane and Anisatin Group An intermediate (57) in the autoxidation of carota- 1,4-dien- 14- a1 (58) into rugosal A (59) has also been identified in Rosa rugosa,'O and several carotane sesqui terpenes (60)+74) and one acorane sesquiterpene (75) have been obtained from the NATURAL PRODUCT REPORTS 1993-B.M. FRAGA 401 (70) R’ = CHO R2 = H (74) (75) (71) R’ =C02H R2= H (72) R’ = CHO R2 = OH HO HO HO HO I\HO OR1 (77) (78) R’ = (CO)(C&)OMe R2= H2 R3 = OH (79) R’ = R3 = H R2= 0 (80) R1= (CO)(C&&)OH R2 = 0 R3= H (81) R’ = R3=Ang R2=0 0 0 *O R’ eR2 >O 0 0 (84) R‘ = a-OH,H R2= OH R3= H (88) R =a-Me (85) R’ = 0,R2= R3 = H (89) R=P-Me (86) R’ = H2 R2 = R3 = OH (87) R’ = HP R2 = H R3 = OH (91) (92) R=CH20H (94) (93) R = CHO leaves of this Seven new sesquiterpenes (76)-(82) have been found in a reinvestigation of the roots of Ferula sinai~a.~~ A novel carotane ester lasidiol p-methoxybenzoate has been isolated from Xanthium catharticum.74 The structures of two sesquiterpene lactones which have been obtained from the seeds and the pericarps of Illicium anisatum have been elucidated as (83) and (84).75 Another species of this genus Illicium major contains five new neoanisatin derivatives (85)-(89).76 The syntheses of (-)-ne~anisatin’~ have been achieved. and (-)-norani~atin~~ 8 Cadinane Oplopanane Copaane and Picrotoxane A cadinane derivative (90) has been found in the aerial parts of Artemisiu crithmif~lia.’~ The essential oil obtained from the wood of Juniperus oxycedrus contains three new sesquiterpenes which were identified as (91)-(93) by spectral methods.80 The sesquiterpene (+)-T-cadinol has been shown to be a pharmaco- logically active constituent of scented myrrh the resin of A Commiphora guidottzX8’ The production and properties of the sesquiterpene (+)-torreyo1 in several strains of the genus Stereum have been studied.82 The structure of halipanicina a bioactive marine natural product which has been isolated from the Okinawan marine sponge Halicondria panicea has been determined as (94) by spectroscopic Several sesqui- terpenes with the relative stereochemistry (95)-(97) and with anthelmintic properties have been obtained from the Fijian sponge Axinyssafenestratus.84The sesquiterpene isonitrile (98) has been isolated from the nudibranch Phyllidia pust~losa.~~ A NATURAL PRODUCT REPORTS 1993 A OH (99) R2qo R’ (105)R’ = P-H R2 = CHO (106)R’ = a-H R2 = CHO (107)R’ = P-H R2 = CH20H 0 (108)R’ = a-H R2=CH20H (109) (110)R’=H R2=OH (111)R’=OH R~=H (1 15) (116)R’ = a-Me R2 = a-H (120)R = a-Me (122) (123) (1 17) R’ = a-Me R2 = P-OH (121)R = P-Me (1 18) R’ = P-Me R2 = a-OH (1 19) R’ = P-Me R2 = P-H hydrogen transfer to the methine carbon of the isopropyl side chain of cadalene sesquiterpenes has been observed during biosynthetic studies carried out in cotton (Gossypium hirsutum).86 A laboratory method for obtaining a high yield of artemisinin from Artemisia annua has been rep~rted.~’ The ‘H and 13C NMR assignments for arteannuin B have shown that it is identical to arteannuin C.88The circular dichroism of qinghaosu and sixteen derivatives has been studied.89 Several derivatives of artemisic acid have shown anti-tumour proper- ties.go The cadinane derivative (99) and the oplopanane derivative (100) have been obtained from Senecio aden~phyllus.~~ Four new copaene sesquiterpenes (1 01)-( 104) have been isolated from the essential oil of Ocimun ~mericanum.~~ The bark of Brachylaena hutchinsii contains the antibacterial sesquiterpenes (105)-( 109).g3 Three new picrotoxane sesquiterpenes picro- dendrin E (1 lo) picrodendrin F (1 1 l) and picrodendrin I (112) have been found in a bark extract of Picrodendron baccatum.94 9 Himachalane Longipinane and LongicycIa ne A new isomer of himachalane with the structure (1 13) has been identified in a stem-bark extract of Cedrus de~dora.~~ The structure and absolute configuration of the himachalane derivative (1 14) has been determined by X-ray analysis.96 Studies on HPLC and NMR of several longipinene derivatives have been carried out.These studies have been applied to the structural determination of a new sesquiterpene 7-senecioate-9-angelate of 7P,9a-dihydroxylongipin-2-en-3-one which has been obtained from Stevia subpubescens. 97 The complete assignment of the lH NMR spectrum of the hydrocarbon longicyclene has been achieved. 98 10 Caryophyllane Modhephane and Silphiperfolane The caryophyllane derivative (1 15) has been identified as a component of the aerial parts of Polyachyrus ~USCUS.~ The synthesis absolute configuration and specific rotation of (+)-and ( -)-modhephene has been reported.99 The silphiperfolene derivatives (1 16)-( 121) have been isolated from the essential oil of Artemisia laciniata.lo0 11 Humulane Integrifoliane Lippifoliane ProtoiIludane IIIudane Hi rsutane Lactara ne Sterpurane Fomannosane and Marasmane The hydrolysis of humulene diepoxide A a flavouring compound obtained from hops has been studied.lol The rearrangement of an epoxyderivative of terrecyclic acid A gave the compound (122) as the sole product.lo2 The revised stereochemistry (1 23) has been assigned to integrifolian- 1,s- dione a sesquiterpene isolated from Lippia integrifolia.During this study a revised structure (124) for africanone also obtained from this plant (see Nat. Prod. Rep. 1986 3 279) has been established. Africanone has been renamed lippifoli- 1(6)-en-5-one.lo3 The new sesquiterpene esters armillasin (125) armillatin NATURAL PRODUCT REPORTS 1993-B. M. FRAGA Me w0 \ \ OH OH OH (124) (125) R=H (128) R=H (126) R = CO-(CH2)14-Me (129) R=OH (130) R = H (131) R=OH (126),lo4 armillarizin (127),lo5 armillaritin (128) and armillarivin (1 29) lo6 have been obtained from the fungus Armillaria mellea. Illudin A (130) illudin B (131) and illudalenol (1 32) are three novel sesquiterpenes which have been isolated from cultures of Clitocybe illudens.lo7The liquid cultures of this fungus also contain a fommosane OH sesquiterpene named illudosin to which the structure (1 33) has been assigned using one-and two-dimensional NMR (1 40) (141) R'=OH R2=H techniques.lo8 Dennstoside A a new sesquiterpene glycoside (142) R' = H R2= OTig analogue of ptaquiloside has been found in Dennstaedtia ~cabra.~~~ The enantioselective total synthesis of the triquinane sesquiterpene (-)-ceratopicanol (134) has been carried out."O The structure of incarnal (135) a novel antibacterial sesquiterpene which has been found in cultures of Gloeostereum incarnatum has been determined by X-ray analysis."' The sesquiterpenes (136) and (137) have been found in an ethanol extract of Lactarius vellereus.112,113 The bioconversion of sesquiterpenes in injured fruit-bodies of Lactarius vellereus has (143) R' = R3 = H R2 = OSen been studied and an intermediate (138) in the transformation (144) R' = Ac R2= OSen R3 = H of stearoylvelutinal into isovelleral has been proposed.114 (145) R' = R3 = H R2 = OTig Lactarofurin A and lactarofurin E have been related by (146) R1 =Ac R2=OTig R3= H chemical methods.115 A comparison of the antimicrobial and (147) R' = R2 = H R3 = OH (or OAc) cytotoxic activities of twenty sesquiterpene dialdehydes which were obtained from plants and mushrooms has been carried out. The most active compounds were isovelleral isoisovelleral velleral and methylmarasmate. 116 12 Germacrane The germacrane derivatives (1 39) and (1 40) have been found in extracts of the aerial parts of Polyachyrus ~phaerocephalus~ and Conyza bonu~iensis,~~' respectively.The sesquiterpenes (148) la lO&epoxy R = OH (142)-(146) have been isolated from the roots of Lugularia (149) lp 1001-epoxy R = OH persica.l18 The new germacranes (141) (147)-(149) and (150) lp lOa-epoxy R = H (1 SO) have been obtained from Santolina chamaecypariss~s'~~ NATURAL PRODUCT REPORTS 1993 R2 HO Rq (156)R=OH (158)R' = H R2= OH (157)R = H (159)R' = R2 = OH (160)R' = H R2= OAC (161)R' = R2= H f\'<\r-'"" AcO* rn OMe 0 * 0 Rqqc02H Ac0*c02H (1 62) R = a-OAc (1 63) R = P-OAC 0% 0 9 0 (179)R= H (1 80) R = Ac 9a,lOp-epoxy AcO** OR (182)R=Ac (183)R = H H /OH (170)R' = (CO)Pr' R2= OH R3 = Me (175)R' = R2= H (171)R' = Meacr R2 = OH R3 = Me (176)R' =OH R2=H (172)R' = (CO)Pr' R2 = H R3 = CH20H (177)R' = H R2= OH (173)R' = (CO)Pr' R2 = H R3 = CHO (1 74) R' = (CO)Pr' R2 = OH R3 = CH20H and Pallenis spinosa,lZ0 respectively.The structures (1 5 I)-( 154) have been assigned for four epoxy-germacranes which have been isolated from Curcuma wenyujin. The last substance (1 54) has been named wenjine.121.122 The new sesquiterpene (155) has been identified as a constituent of Senecio philippicus. 123 Another species of this genus Senecio adenophyllus contains the germacrane derivatives (156)-(161).g1 Another three metabolites of this type (162)-(164) have been identified as components of an extract of the aerial parts of Haeckeria punctulata.124 A conformational analysis of periplanone ana- logues by molecular mechanics calculations has been carried out.125 The biotransformation of three germacrane sesqui-terpenes by the fungus Aspergillus niger has been studied.126 A sesquiterpene ketal (165) has been obtained from Bunium paucifolium. 12' Many new germacrane lactones have been isolated from natural sources during 1991 (see Table 1). The structures (1 66)-( 184) represent the new germacranolides whilst the structures (1 85E( 19 1) have been assigned to the heliangolides (192)-(200) to the melampolides and (201)-(211) to the cis,cis-germ acrano li de s. NATURAL PRODUCT REPORTS 1993-B. M. FRAGA R rn(C0)Pr' Table 1 Source of germacrane lactones Source Germacranolides !+&$ Achillea crithmifolia'" Ant hemis cupaniana '29 R' 0 Ho-m Artemisia ludovi~iana'~~ \\ \ Artemisia r~tifolia'~' OH 0 Blumea arfakiana'=' (186) R' = H R2= various (188) R = H or OH Hymenoxys ive~iana'~~ (187) R' = OH R2 = (C0)Pr' Hymenoxys linearifoli~m'~~ Neolitsea bui~anensis'~~ Siegesbeckia orien talis' 36 Stevia grisebachiana'37 OMe 0 Source Bothr iocline amplifolia ' a Cronquistia ringl lei'^^ Helian th opsis sagas t eguiil " Helianthus tuberosuP' Vernonia acutifolia14' Vernon ia jugalis ' Vernon ia stee tziana ' Source Artemisia barrelieri'' Artem isia ludo viciana '3o Junirea lept~lobal~~ Siegesbeckia orien talis '36 Source Bothr io cline amplifolial a Jun irea lep t oloba '44 Vernonia hol~tii'~~ Vernonia zan~ibarensis'~~ (191) R = H Ac or Me &O( CO)Pr' -0 H -0 R Hh.A OH (192) A'('') R = a-OOH (194) R = H (197).(198) R = Ang . (193) R = P-OOH (195) R=OH (199) R = Meacr (196) R = OAC (200) R = Ang(50H) 0 0 CHO I ,-OAng OH (202)R= 0 (203 R = Meacr R' 0 0 fOH ,-OAng o::& OAc :&ok (207) R' = CH20H R2 = Ang (210) 2a 3a-epoxy (208) R' = CHzOH R2 = Meacr (211) 2a-OAc (206) (209) R' = CHO R2 = Ang 28 NPR 10 0 OH OH (221) R=O (222) R = P-OH H There are several points to note in relation to these lactones We have included the brachycalyxolides and related lactones amongst the cis,cis-germacranolides.Four new germacrane lactones (212)-(215) have been isolated from the liverwort Porella acutifolia. 146 The sesquiterpene jugalinone (2 16) has been obtained from Vernoniajugalis.This metabolite is formed in this plant by rearrangement of the same precursor which leads to the hirsutinolide (19 1).142 The novel germacranolide dimer (217) has been isolated from Artemisia barrelieri.l2 A novel germacranolide-amino acid dimeric adduct (2 18) has been obtained from Centaurea aspera.14' Parthenolide the main lactone in Tanacetum parthenium (feverfew) has been quantified by an HPLC method; this was then applied to species from different countries. 14* The NMR spectra of tatridin A and other related sesquiterpene lactones which have been isolated from Tanacetum vulgare have been studied.149 The structure of the cytotoxic heliangolide euparhombin has been revised to (219) as a result of an X-ray analysis.15oKnown germacrane lactones have been isolated from Scierocarpus ses~ilifolius.~~~ A study using molecular mechanics calculation has confirmed the existence of four stable conformers of A1(lo)s4-E,E-germacranolides.152 A stereoselective total synthesis of the complex molecule (+)-eremantholide A has been reported. This synthesis has enabled the absolute configuration of this lactone to be confirmed. It had previously been assigned on the basis of biogenetic considerations. 153 13 Elemane The Composite Centaurea aspera contains the new elemanolide (220),154and another two lactones of this type (221) and (222) NATURAL PRODUCT REPORTS 1993 OH 0 Me R (214) R = a-OOH (215) R = P-OOH R (223) R =O (225) R = 0 (226) R = P-OH H have been obtained from Jurinea leptoloba.144 The synthesis of ,8-elemene derivatives with anti-tumour properties has been rep0~ted.l~~ 14 Eudesmane and Oppositane The new sesquiterpenes jatamol A (223) and jatamol B (224) are two constituents of the roots of Nardostachys jataman~i.~~~ Two eudesmane derivatives (225) and (226) have been obtained from agarwood (Aquilaria agollo~ha),'~~ and another two compounds of this type (227) and (228) have been found in an ethanol extract of SaIvia palaefolia.15* The sesquiterpenes pluchecin (229) and odonticin (230) have been isolated from Pluchea arguta,15' whilst plucheol A (231) plucheol B (232) and plucheoside E (233) have been obtained from Pluchea indica.160 The aerial parts of Artemisia vuIgarislsl and Artemisia rutifolia131contain the new eudesmane acids (234) (235) and (236) respectively.Other compounds of this type (237)-(238) and (239)-(242) have been identified as constituents of hula viscosa,2 and Haeckeria p~nctulata,'~~ respectively. The sesquiterpenes (243)-(249) have been obtained from the aerial parts of Polyachirus sphaero~ephalus.~ Ainsliaside C (250) ainsliaside D (251) and ainsliaside E (252) are three sesquiterpene glycosides which have been obtained from Ainsliaea cordifolia.162Another compound of this type has been found as a constituent of Jurinea lept~loba.~*~ The unusual sesquiterpene piccolamine (253) and its oxidation product (254) have been found in the Senegalese gorgonian Leptogorgia piccola.The first of these metabolites exhibited fungistatic and antibacterial properties,163 and the second is an isomer of codonolactone (255) which has been isolated from 'tangshen' NATURAL PRODUCT REPORTS 1993-B. M. FRAGA OAc R' OH OH (228) (229) R' = P-OAng R2 = OOH (231) R' = H R2 = R3 = OH (232) R' = R3 = OH R2 = H (230) R' = a-O(C0) R2=oH (233) R1 =OGlc R2 = R3= H RJ$4c02H OR (238) A2(3) (239) 3P-OAc (241) R = P-OAC (242) R = a-OAc (243) R = H (244) R=Ac (240) 3~t-OAc OR' OR2 I( 3qq *-4 15 (245) A3(4) R' = R2 = H (246) A3'4) R' (247) R' (248) A4(15) R' (249) A4(15) R' OH 3%OH -* = H R2 = AC = R2 = H = H R2 = AC = Ac R2 = H ,5 OGlc (250) A3(4) (251) A4(15) (252) 4-OH (Codonopsis pilo~ula).'~~The bioconversion of several eudesmane deiivatives with the fungi Rhizopus nigricans and Curvularia lunata has been studied.165,166 The sesquiterpene 12-carboxyeudesma-3,11(13)-diene and the xanthanolide tomentosin are the main compounds responsible for the ichthyotoxicity shown by Dittrichia graveo1ens.167 The structure of the new sesquiterpene ester kupiengester (256)has been established by spectroscopic methods.168 Other I OH 15 (254) A4(5) (253) (255) A4(15) 0 OBz P-agarofuran derivatives have been isolated from Celastrus angulat~s,'~~-'~~, Celastrus glaucophyll~s,'~~ Celastrus gemmatus,173-17 Celastrus paniculatus,176-178 Celastrus ros-Evonymus bungean~s,'~~ thornianu~,'~~-~~~ and Tripterygium wilf~rdii.l~~-l~~ Another compound of this type has been obtained from Salvia palaefolia (Lamiaceae).la6However a re- examination of this species should be carried out because the occurrence of this group of sesquiterpene esters is normally restricted to the Celastraceae.NOE and 2D NMR studies for the assignment of 'H and 13C chemical shifts in P-agarofuran derivatives have been carried The structure of euonine has been determined by X-ray analysis. lE8The stereoselective synthesis of dehydrobaimuxinol and isobaimuxinol starting from (-)-carvone has been described.lE9 Many new eudesmanolides have been isolated from plant 408 R' R2rnR3 U (257) R' = P-OH R2 = H R3 = CH3 (258) R' = P-OH R2 = OAc R3 = P-Me H (259) R' = a-OH R2= OAc R3 = P-Me H (260) R' = P-OH R2= OH R3 = a-Me H (261) R' = f3-OH R2 = OH R3 = P-Me H OH OH q+ 0 (262) OAc OAC 0 0 (267) R=a-Me (268) R = P-Me sources (see Table 2) and their structures have been shown to be (257)-(289).A dimeric eudesmanolide hydroxy-bis-dihydroencelin (290) has been found as a component of the aerial parts of Montanoa speciosa.lS8 The novel dimeric spiroterpenoids (291) and (292) have been isolated from the Panamanian liverwort Plagiochila rnorit~iana.~~~ The seco- and nor-sesquiterpene lactones (267)-(273) possess new carbon skeletons which are probably derived from the eudesmanolide (266).These lactones have been isolated from the aerial parts of Artemisia santoEinifolia.l3 The synthesis of 8-epi-ivangustin and 8-epi-isoivangustin starting from santonin has been carried out.200 The sesquiterpene lactone costunolide has been used in an efficient partial synthesis of several eudesmanolides. 201 The synthesis of (+)-colartin (+)-arbusculin and their C-4epimers has been devised and the plant growth regulating activity of these lactones has been studied.202 A new oppositane sesquiterpene (293) has been obtained from the liverwort Chiloscyphus pallescens. 203 NATURAL PRODUCT REPORTS 1993 0 '0 (270) R = a-Me (271) R =f3-Me OH '0 (272) R = a-Me (274) A3(4) (273) R = P-Me (275) A4(15) R'*q& OH R2 '0 (276) R' = CH2 R2 = (278) R'=OH R2=H (279) R' = H R2 = OH (277) R' = a-Me H R2= H OAc (280) R' = H R2 = OMe OH OkbU Table 2 Source of eudesmanolides Source Eudesmanolides A rtem isia jiagrans ' Artemisia herba-alba's' Artemisia sant olinifolia' Artemisia splenden~'~~ Artemisia xeroph y t ica's3 Athanasia calva6 Blumea arfakianala2 Centaurea a~pera'~~ Guizotia scabraI3'j Pulicar ia undulata s4 Ratibida latipalearis's5 Sal via palae folia ' Senecio ch rysan themoides s6 Sphaeranthus indicu~'~~ Spilanthes acmella3' NATURAL PRODUCT REPORTS 1993-B.M. FRAGA OR’ o::* OAc 0dDo \ (286) R’ =Ac R2= H (287) R’ = R2 = H (288) R‘ = H R2 =OH (285) R0 0* (294) R’= H2 R2 = P-OAC H R3 = H (295) R’ = H2 R2 = 0 R3 = H (296) R’ = R2 = H2 R3 = Oh (297) R’ = P-OAC,H R2 = H2 R3 = H (298) R’ = 0,R2 = a-OH H R3 = H (299) R’ = 0,R2 = P-OAC,H R3 = H (300) R’ = P-OH R2 = OAc (301) R’ = P-OOH R2= OAC (302) R’ = P-OH R2 = H (303) R’ = P-OOH R2= H (304) R’ = a-OH R2 = H (305) R’ = H R2 = P-OAc H (306) R’ = H R2 = 0 (307) R‘ =OAc R2=0 (3081 R’ = OAC.R2= H-.r L C02H HO 0 (309) (310) 9P lO&epoxy (311) 9a 10a-epoxy %OH (314) R = Glucosyl derivative 15 Eremophilane Bakkane and Chiloscyphane The eremophilane derivatives (294)-(313) have been found in the aerial parts of species of Haeckeria. 124 Flue-cured tobacco leaves contain the new acetylated glucoside (314).204 A phytotoxic eremophilane ether hypodoratoxide (3 13 has been isolated from the ascomycete Hypomyces odoratus.205 C02H “O2;& C02H (316) R = OH or OOH The genus Senecio is a good source of eremophilane sesquiterpenes. The novel sesquiterpene (3 16) has been found -~ in -the -aerial parts of Senecio desfontainei.206 A new furanoeremophilane (3 17) has been obtained from Senecio chiZensis and Senecio patagonic~s.~~~ results of the The phytochemical studies of further Chilean Senecio species have also been reported. In this way the furoeremophilane NATURAL PRODUCT REPORTS 1993 R'O OR2 (318) R' = Ac R2 = Prop (319) R' = Ac R2= Val' (322) R=Ang (323) R = Tig (324) R=Ang (325) R =Tig (320) R' = Ac R2 = (C0)Pr' (321) R' = H R2 = Val' OH OR2 HO" 13 wo @?OAng (327) A7(") R' = 0 (330) R' =OH R2 = Tig (333) (328) R' = 0 (331) R' = OMe R2= Ang (329) A"('3) R' = U-OH H (334) (335) R =a-H (336) R =a-OH (337) R=P-H 0 (3411 (342) R' = (CO)Pr' R2 = P-OMe (343) R' = (CO)Pr' R2 = a-OMe (344) R' = Prop R2 = P-OMe (345) R' = Prop R2 = a-OMe sesquiterpenes (3 18)-(321) and (322)-(325) have been isolated from Senecio subumbellatus and Senecio portalesianus re-spectively.123 Other Chilean Senecio species which have been studied include Senecio almeydae (326)-(330) Senecio cachinalensis (33 l) Senecio candollii (332) Senecio dryophyllus (333) Senecio glaber (334)-(337) Senecio reicheanus (3 16) and Senecio serratifolius (338)-(340).91 Another species of this genus Senecio pachyphyllos contains the new sesquiterpene (341) and two pairs of epimeric acetals (342)-(345).208 The eremophilane derivatives (335H336) and (346)-(353) have and been isolated from Senecio toluc~anus~~~ Senecio zoellneri,210 respectively. The sesquiterpenes (354)-(367) and (368)-(370) have been obtained from Euryops jacksonii and Euryops algoensis respectively,211 whilst the compounds (37 1) and (372) have been found in the roots of Roldana sessilifolia.212 Another two substances of this type (373) and (374) have been isolated The from a methanol extract of Hertia ~hirifolia.~~~new benzofuranosesquiterpenes (375) and (376) and two known furanoeremophilanes have been obtained from the rhizomes of Ligularia ~irgaurea.~l* The structure of an amyrinol derivative (338) R = a-H or P-H (339) R'= H R2=OAc (340) R' = OAc R2 = H wo OR' (346) R = (C0)Pr' (348) R' = (CO)Pr' R2= H (347) R = Ang (349) R' = (CO)Pr' R2= Me (350) R' = Ang R2 = Me CHO OH (351) R = (C0)Pr' (353) (352) R=Ang has been determined by X-ray analysis.215 The synthesis of the eremophilane derivatives (+)-gigantenone (+)-phomenone and (+)-phaseolinone have been achieved in a few steps starting from (+)-sporogen A0 (1 3-deo~yphornenone).~'~ A metal catalysed conversion of valencene to nootkatone has been devised.217 A stereoselective synthesis of the bakkane sesquiterpene homogynolide A has been reported.This compound has been isolated from Homogyne alpina and it has been antifeedant properties.218 A revision of the absolute configurations of (-)- NATURAL PRODUCT REPORTS 1992-B.M. FRAGA 411 (354)R' = OAng R2 = H (358) (360)R=H2 (355)R' = OSen R~= H (359)lp lop-epoxy (361)R = 0 (356)R' = R2 = H (362)R =OH H (357)R' = H R2 = Me (365) (366)R = various (368) R' = H R2 = various (371)R=H (367)A2(3) R = various (369) R',R2 = various (372)R=OH OH R' (373)R' = R3 = H R2= OAg (374)R' = R3 = OMe R2 = H OH (379) (380)R' (381)R' (382)R' (370) 11,13-epoxy R' = H R2 = various OH (375) (376)R = H or Me (377) (378) = HP R2= CHO (385) (386) (387) = H2 R2 = CHgH = H2 R2 = C02H = H2 R2= C02Me (383)R' (384)R' = 0,R2 = Me chiloscyphone (377) and (+)-chiloscypholone (378) based on X-ray studies has been described.219 Taking into consideration this work the absolute configuration of the new sesquiterpene 11,12-epoxychiloscypholone,which has been isolated from the liverwort Chifoscyphus palfescens 203 must be represented by HOq Ho-$q 16 Guaiane Pseudoguaiane Patchoulane and (379)-Trixane (388) (389) A new metabolite with a guaiane skeleton (380) has been found in Aquilaria agaffocha (agarwood) 15' and seven sesquiterpenes of this type (381)-(387) have been obtained in a further study of this plant.220 The roots of Curcuma aeruginosa221 and Vaferiana wofgensis222 contain the guaiane sesquiterpenes 3% QR aerugidiol(388) and valerol(389) respectively.Two insecticidal dienols which have been isolated from the resin of OH Diptereocarpus kerri have been identified as (390) and (391).223 The guaiane esters (392)-(394) have been obtained from Thapsia viflosa.The structure of the last has been resolved by (390)A3(4' (391)4a-OH (392)R=Sen (393)R = Ferul (394)R = Coum X-ray analysis.224 The synthesis of (-)-kessane starting from ( +)-aromadendrene has been carried Many new guaianolides have been obtained from different Table 3 Sources of guaianolides Source Achillea millefolium226~ 227 228 Acroptilon repensZz9 Anthemis hydr~ntina'~' A r temisia ludoviciana13' A r temisia mesat lan ticaZ3'*"' Artemisia rutifolia'31* 233 Artemisia xerophyti~a'~~ Brachylaena ~errieri'~~ Brickellia ~alifornica'~~ Centaurea sol~titialis'~~~ 237 Cicerbita alpinaZ3' Cronquistia pringEeil3' Cyathocline purp~rea'~~ Ferula oopodaZ4' Helianthopsis sagast eguii' Hymenoxys i~esiana'~~ Hymenoxys linearifoli~m'~~ Lactuca salignaZ4' Mon tanoa tomen tosaZ4 Saussurea jap~nica'~~ Stevia eupatoriaZ4" Stevia gri~ebachiana'~~ Thaps ia gargan ica 24 Xan thium spinosum 246 -OR .--0 Egelolide derivatives (438) R = Ac or Ang R'O" Ac&o R2 (440) R' = H R2 = P-Me H (441) R' = Glc(2Ac) R2 = CH2 Saussurea lip~hitzii.'~'The NATURAL PRODUCT REPORTS 1993 R'Q2 0 (448) R' = P-OH R2 = OH (451) (449) R' = a-OH R2 = H (450) R' = P-OH R2 = H 0 0 (454) Opofersin (455) R = H or Glc $?+ 0 (439) R' &$ (442) R' (443) R' (444) R' (445) R' (446) R' (447) R' 0 = a-OAc R2 = H = P-OAC R2= H = a-OMe R2 = H = H R2= OH = a-OH R2 = OH = P-OH R2= OH 0 (456) Nortrilobolide QR 0 (457) R=CH2 (458) R = a-Me H Q-OAng 0 (459) stereochemistry of argablin a cytotoxic guaianolide which has been obtained from Artemisia myriantha.has been assessed by 2D NMR The plants (see Table 3). Table 4 shows the novel guaian-6a,l2- olides which have been isolated whilst other lactones of this and badkhysinZ5O have been series are depicted by the structures (438)-(456). structures of 8-epi-i~olipidiol~~~ The new lactones (457) and (458) have been obtained from established by X-ray analysis. After taking these data into the liverwort Porella acutifolia. 146 A 13-norguaianolide has consideration the structure of the last lactone has been revised been found in the aerial parts of Pulicaria undulata.lS4 Known to (459).A study of the conformations of several guaianolides guaianolides have been isolated from the Mongolian species using molecular mechanics calculations has been Two new pseudoguaianolide esters arrivacin A (460) and arrivacin B (461) have been obtained from Ambrosia psilostachia. These compounds show potent binding to NATURAL PRODUCT REPORTS 1993-B. M. FRAGA Table 4 Novel guaian-6a7 12-olides OH 0 'OH 0 Position of Name double bond(s) Substituents and configurations References Bishopsolicepolide der. 2-3 9-10 11-13 la-OH 4a-OH 8a-OH 130 Bishopsolicepolide der. 2-3 10-14 11-13 la-OH 4a-OH 131 a-Perox yachi folid 2-3 11-13 la74a-dioxi 9a-OH 10a-Tig 226 227 P-Peroxy achifolid 2-3 11-13 1/3,4P-dioxi 9a-Tig 1Oa-OH 226 227 Bishopsolicepolide der.2-3 11-13 1a-OH 4a-OH 1Oa-OH 131 Kauniolide deriv. 34 9-10 11-13 la-OH 14-OH 193 Kauniolide deriv. 34 10-1 11-13 14-OH 193 Kauniolide deriv. 34 10-1 11-13 9a-OH 14-OH 193 Lactucin deriv. 34 10-1 11-13 2-0x0 Sa-OAc 15-OGlc 238 Leucodin deriv. 34 l&l 11-13 2-OX0 137 Zuubergenin deriv. 34 10-1 11-13 8P-OR1 235 Zuubergenin deriv. 34 10-1 11-13 8P-OR2 139 Zuubergenin deriv. 34 l&l 11-13 8P-OR3 139 Lactucopicrin deriv. 3410-1 2-0x0 8a-O(CO)CH2(C,H,)OH 1 la 15-OH 24 1 Zoapatanolide F 34,10-1 4a-OH 8a-OAc 9P-OAng 1la 242 Ligustrin deriv. 34 1&14 11-13 8P-OR1 139 Ligustrin deriv.34 1&14 11-13 8P-OR4 244 Hydruntinolide A 3-4 11-13 ~P-OAC,~E-OAC,10a-OH 230 Hydruntinolide B 34 11-13 2P-OAc 8a-O(CO)Pri 9a-OAc 10a-OH 230 Hydruntinolide C 34 11-13 2P-OAc 8a-OTig 9a-OAc 10a-OH 230 Lactucin deriv. 34 11-13 1a,1Oa-epoxy 2a-OH 8a-OH 130 Lactucin deriv. 34 11-13 la,lOa-epoxy 2P-OH 8a-OH 130 Cumambrin deriv. 34 11-13 2-0x0 10P-OH 137 Arbiglovin deriv. 34 11-13 2-0x0 5a-OH ~cz-OAC 10a-OH 193 Desacyleuparotin deriv. 34 11-13 h-OH 1Om-OH 131 Cumambrin deriv. 34 11-13 8/3-OR1 10a-OH 235 Desacylcynaropicrin der. 4-15 10-14 11-13 3P-OR5 &-OH 234 Desacylcynaropicrin der. 415 10-14 11-13 3P-OR5 8a-OR5 234 Solstitial A deriv. 4-15 10-14 ~P-OAC,I 1a-OH 13-OH 236 Solstitial A deriv. 415 10-14 ~P-OAC,1la-OH 13-OAc 237 Mesantilantin A 54 11-13 1 ,2-epoxy 3,4-epoxy 10-OH 231 232 Picrolide A 10-14 11-13 3/3-OH 4a-OH 8a-OR5 l5-O(C0)(C,H4)OH 229 Ligustrin deriv.lG14 11-13 3-0X0 SP-OR' 401 235 Estafietin deriv. 1&14 11-13 3a,4a-epoxy 8P-OR' 139 Estafietin deriv. 1Ck14 11-13 3a-OH 4P-OH 137 Cynaropicrin deriv. 10-14 11-13 3/3-OH 4a-OH 137 Cynaropicrin deriv. 10-14 3P-OH7 4a-OH 1lP 137 Estafietin deriv. 10-14 3a-OH 4P-OH 1lp 137 Artecanhydrate deriv. 11-13 Ia-OH 2a-OH 3a-OH 4a-OH 10a-OH 233 Artecanhydrate deriv. 11-13 la-OH 2a-OH 3a-OH 4P-OH 10a-OH 233 Cynaropicrin deriv. 11-13 ~U-OH,4P-OH7 1OP-OH 137 Cumambrin deriv. 11-13 3P,4P-epoxy 1OP-OH 137 Cumambrin deriv. 11-13 3a,4a-epoxy 10P-OH 137 (460) 2P-OH (461) A2(3) 0 angiotensin I1 receptors in bovine adrenal membranes.252 Other lactones of this type (462) (466) (467) (469)-(471) and (462)-(466) (468) have been identified as components of Hymenoxys ivesi~nal~~and Hymenoxys linearifolium,134 re-spectively. The sesquiterpene lactone-monoterpene adduct (472) has been isolated from Gaillurdia aestivulis. This compound is a Diels-Alder adduct of multigilin and 8-hydroxy-a-phellan-drene.3 The structures of pulchellin C and inuchinenolide C have been determined by X-ray analysis. These lactones have now been isolated from Znula c~spica.~~~The microbiological transformation of parthenin by the fungi Bauberia bassiuna and Sporotrichum pulverulentum has been described. 254 A formal synthesis of (-)-patchouli alcohol starting from (-)-carvone has been devised.255 The preparation of the 29 NPR 10 414 NATURAL PRODUCT REPORTS 1993 HO ’ OH HO OAc 0 OMebu 0 I RO (462) R’,R2 = various R3 = CH2 (465) (466) R’,R2 = various R3 = CH (468) R=Mebu (469) R=Ang (463) R’ = Ang R2 = H R3= p-Me H (467) R’ = Sen R2= Ac R3 = P-Me H (464) R’ = Mebu R2 = H R3 = P-Me H .I H qo p-$o Angd RO / .. I OAc Y ‘r”J (470) R = Ang or Sen (471) R = Ang or Sen (472) (473) (474) R’ = Ang R2 = H (475) R’ = Epang R2= H (476) R’ = Epang R2 = various OHC (477) (478) R =O (479) R = a-OH H (483) (485) R=NC (489) (486) R = NH-CHO (487) R = NCS sesquiterpene alkaloid (-)-patchoulipyridine (473) has been have been obtained from the leafy liverwort Myfia taylorii.260 reported.256Several trixane derivatives (474)-(476) have been The complete assignment of the lH and 13CNMR spectra of obtained from the aerial parts of Acourtia nan~.~~’ some aromadendrane derivatives have been carried out.A metabolite with phytotoxic antimicrobial and plant growth regulating properties has been isolated from Magnofia 17 Aromadendrane Gorgonane Nardosinane grandzjlora and identified with cyclocolorenone (484).262 The and Brasilane hydrocarbon (+)-aromadendrene has been transformed to the Three new secoaromadendrane sesquiterpenes plagiochilal B sesquiterpenes (-)-globulol (-)-epiglobulol (-)-ledol and (477) plagiochiline J (478) and plagiochiline K (479) have ( +)-viridiflor~l.~~~ been isolated from the liverwort Piagiochifa fruticosa. The first The Philippine nudibranchs Phyffidiapustufosa and Phyflidia of these metabolites shows neurotrophic varicosa contain three new gorgonene sesquiterpenes Tanzanene (480) is a spiro benzopyranyl sesquiterpene which (485)-(487).50A stereocontrolled synthesis of the nardosinane The sesquiterpene (-)-kanshone A has been reported.264The has been found in the rootbark of Uvaria tan~aniae.~~’ structures of three novel dimeric sesquiterpenes myltaylorione synthesis of a racemic form of this compound has also been A myltaylorione B and bytaylorione have been determined as described.265 The brasilane sesquiterpenes with the relative (481)-(483) by spectroscopic methods.These compounds configurations (488) and (489) have been found in the NATURAL PRODUCT REPORTS 1993-B. M. FRAGA "O O w AoH (490) (495) (496) R2@' (499) (500)R'=SCN R2=H (501) R' = H R2 = SCN Australian red alga Laurencia implicata,266 whilst the latter (489) and two further compounds with this skeleton (490) and (491) have been isolated from Laurencia obtusa collected in Sicily.267 18 Pinguisane The new sesquiterpene (492) has been isolated from the pungent liverwort Porella acutifolia.146 A chemosystematic study of several bryophytes has shown that PlagiocheZla alternans is a very unusual member of the Plagiochilaceae because it produces pinguisane sesquiterpenes as the main component.268 19 Miscellaneous Sesquiterpenoids The Himalayan species Artemisia rupestris contains a novel sesquiterpene isorupestonic acid (493).269 From the essential oil of another species of this genus Artemisia salsoloides the sesquiterpene salsolone oxide (494) has been structure assigned to versicolactone which has been isolated from the roots of Aristolochia versicolor,271 is similar to that given to manshurolide which has been obtained Aristolochia manshuriensis (see Nut.Prod. Rep. 1992 9 p. 575). The synthesis and absolute configuration of the mossy odorous sesquiterpene tamariscol(495) has been geographical study of the distribution of this pacifigorgiane- type sesquiterpene in the liverwort Frullania tamarisci and related species has been Another liverwort Bazzania japonica contains the new tetracyclic sesquiterpene cyclomyltaylan-3-01 (496) and the corresponding caffeate. 274 The synthesis and the determination of the relative configuration of conocephalenol a sesquiterpene alcohol which has been obtained from the European liverwort Conocephalum conicum has been carried Seiricardine A (497) is a phytotoxic sesquiterpene which has been isolated from three C02H 0 (497) (498) '0 IQNC (502) (503) (504) R=a-H (505) R =P-H Seiridium species which are pathogenic on the cypress (Cupressus ~empervirens).~~~ The isolation and structure de- termination of doremone A (498) a new spiro-sesquiterpene chroman-2,4-dione which has been found in the resin of Dorema ammoniacum (ammoniac gum) has been described.277 The structure of laurobtusol a new rearranged sesquiterpene from the Mediterranean red alga Laurencia obtusa has been determined as (499).This metabolite has a novel carbon skeleton which is probably derived from a-h~mulene.~~~ Two new sesquiterpene thiocyanates (500) and (501) have been isolated from two sponges collected in Pohnpei (unidentified) and Okinawa (Phycopsis terpyli~),~~~ whilst another novel metabolite 2-isocyanoallopupukeaneane (502) has been ob- tained from the nudibranch Phyllidia pust~losa.~~ The soft coral Paralemnalia thyrsoides contains a rare nor-sesquiterpenoid (503) which has been named pathylactone. 280 The first total synthesis of a natural thapsane has been reported.281 The synthesis and the absolute configuration of the antiparasi tic sesqui terpenes (-)-furodysin and (-)-furodysinin The have been achieved.282 The enantioselective syntheses of clavukerin A (504) and its epimer (505) have been carried out.This study has confirmed that clavukerin A which has been from isolated from Clavularia koellikeri and a trinorsesquiterpene obtained from a species of the genus Cespitularia are The absolute configuration of isoclavukerin A has been determined by application of circular dichroism methods to an A autoxidation product. 284 20 References 1 A. 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ISSN:0265-0568    

DOI:10.1039/NP9931000397

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Arsenic Compounds from Marine Organisms J. S. Edmonds,’ K. A. Francesconi,’ and R. V. Stick2 ’W.A. Marine Research Laboratories P.O. Box 20 North Beach Western Australia 6020 Department of Chemistry The University of Western Australia Nedlands Western Australia 6009 Reviewing the literature published up until October 1992 1 Introduction 2 Marine Animals 2.1 Early Work 2.2 Arsenobetaine 2.3 Other Compounds 3 Marine Algae 3.1 Early Work 3.2 Dimethylarsinoylribosides and Related Compounds 4 Chaemotaxonomy 5 Biogenesis of Arsenobetaine 6 Synthesis 7 References 1 Introduction This paper reviews reports of the natural occurrence of organic arsenic compounds in marine organisms up to October 1992. Before 1977 it was known that marine animals contained high levels of arsenic compared with their freshwater counterparts or with terrestrial animals but no compound contributing to this arsenic burden had been identified.Similarly there was considerable information on high levels of arsenic in marine algae but apart form methylarsonic acid (1) and dimethylarsinic acid (2) which were suspected of being the degradation products of more complex arsenicals no compound had been identified before 1981. The identification of arsenobetaine (3) in the western rock lobster’ in 1977 and of arsenic-containing carbohydrates (10) and (11) in a brown alga2 in 1981 has stimulated moderate interest. Work on marine animals in Australia Europe and in particular Japan has confirmed the widespread occurrence of arsenobetaine (3) in marine animals and has revealed the presence of other organic arsenic compounds of simple structure.Studies of algal arsenic compounds have been continued almost entirely by our group in Western Australia and by Morita and co-workers in Japan. The number of algae that have been examined is still small and there is great similarity among many of the compounds that have been isolated. It is not clear if these compounds have any physiological significance or whether they merely represent stages in a sequence of detoxification and elimination. Work to date is probably adequate to allow the toxicological studies necessary to reassure the consumers of seafoods ; further extensive study might well depend on the discovery of some physiological or biochemical role for the arsenic compounds in the organisms that accumulate them.Because this is the first Natural Product Report dealing with arsenic compounds from marine organisms the historical background will be rather fully covered in what follows. 2 Marine Animals 2.1 Early Work Forensic aspects of a traditional criminal use of arsenic (in the form of arsenous oxide or ‘white’ arsenic) required methods for its accurate estimation and a knowledge of what might be considered normal levels in the human body and its excreta. This led to the observation of elevated levels of arsenic in the 42 I (3) Me4As’ Me3As-0 urine of persons on fish diets and consequently to the discovery of high levels of arsenic in fish and ~hellfish.~ A thorough survey revealing considerable levels of arsenic in marine animals collected around the British coast led Chapman4 to carry out some preliminary experiments in an attempt to identify the arsenic compounds present.He was unsuccessful but could say that the arsenic compound (or compounds) was water and ethanol soluble and was resistant to the effects of acid and alkali. In 1935 the publication5 of a study on the metabolism by rats of arsenic contained in shrimps confirmed earlier notions particularly those of Chapman of the non-toxic and meta- bolically inert nature of ‘shrimp’ arsenic when compared to arsenous oxide. There matters rested until the 1970s when papers were published6 ’ describing the methylated cationic nature of the arsenic present in some marine animals without fully characterizing the compound or compounds involved.2.2 Arsenobetaine In 1977 the arsenic compound isolated from the western rock lobster Panulirus cygnus was shown,l by single crystal X-ray analysis to be arsenobetaine [trimethylarsonioacetate (3)]. Although not known previously as a natural product arseno- betaine (3) had been synthesized in the 1930s for phar- macological studies on arsenic analogues of simple nitrogen metabolite^.^^^ Since its discovery in the western rock lobster arsenobetaine (3) has been identified in representatives of such diverse taxa as sponges coelenterates echinoderms bivalve gastropod and cephalopod molluscs crustaceans and in both teleost fishes and sharks.lO l1 Although arsenobetaine (3) was the major arsenical in virtually all of the marine animals that were examined other arsenicals have been found also.ll 2.3 Other compounds The tetramethylarsonium ion (4) (as the chloride salt) has been isolated from two species of gastropod mollusc12 l3 and has been shown to be present in a range of bivalve mollusc^.'^ In some animals and tissues the ion (4) was the major arsenical but arsenobetaine (3) was also present in all case^.^^^'^ Any biogenetic or metabolic connexion between arsenobetaine (3) and tetramethylarsonium ion (4) remained unresolved.A mass fragmentographic technique was used to show the presence of trimethylarsine oxide (5) in a range of teleost fishes from the Baltic Sea.15 All specimens also contained arseno- betaine (3) but apparently individual fish that had been in frozen storage longest contained the greatest proportion of trimethylarsine oxide (5).The authors concluded that it was probably derived from decomposition of arsenobetaine (3). Some support for this supposition may have been provided by studies demonstrating the conversion of arsenobetaine (3) to trimethylarsine oxide (5) by bacteria contained in sediments. l6 On the other hand the estuary catfish Cnidoglanis macrocephalus was shown to naturally contain part of its arsenic burden as trimethylarsine oxide (5) and the proportion [relative to arsenobetaine (3)] could be increased by lacing its food with sodium arsenate.l7 School whiting Sillago bassensis also contained trimethylarsine oxide (5) as well as natural levels of arsenobetaine (3) after receiving arsenate with food. The conclusion reached was that arsenate was being methylated to trimethylarsine oxide (5) by the bacterial flora of the gut tract and the naturally occurring material in the catfish resulted from arsenate contained in sediments being ingested with f00d.l~ As for the tetramethylarsonium ion (4)in molluscs no metabolic connexion was demonstrated between trimethylarsine oxide (5) and arsenobetaine (3) but in this case it could be concluded that they were accumulated independently. As part of an investigation into off-flavours that affected marketability trimethylarsine (6) was detected by headspace- GC-MS at very low @g kg-') levels in some species of deep-sea crustaceans.l8 Possibly the trimethylarsine (6) resulted from reduction of trimethylarsine oxide (5) that might have been present as a result of one of the reasons discussed above.claim^^^,^^ that arsenocholine (7) the likely immediate bio- genetic precursor of arsenobetaine (3) occurs in certain prawns have been queried.'l In one case a re-examination of the same organism failed to find any arsenocholine (7),21 and in the other case the purification method used could not have resulted in the isolation of arsenocholine (7) as reported. The apparent absence of arsenocholine (7) in marine animals was possibly explained by feeding experiments in which a range of arsenic compounds was supplied to fish through their diet^.^^,^^ Administered arsenocholine (7) was rapidly converted to and retained as arsenobetaine (3).22 Arsenocholine (7) was not detected but a small quantity (-4% of administered As) was converted to phosphatidylarsenocholine (8) and to glycerylphosphoryl-arsenocholine (9) ; the former being identified after hydrolysis to the latter.Subsequent to this phosphatidylarsenocholine (8) was shown by HPLC-ICP-MS examination of hydrolysates to be a natural trace component of the western rock lobster digestive gland.24 This observation may be taken to suggest that the lobster is indeed exposed to a source of arsenocholine (7). Most of the compounds of arsenic that have been found in marine animals have been identified following their isolation usually by ion-exchange chromatography and TLC ; phosphatidylarsenocholine (8) in the rock lobster digestive glandz4 was an exception.There have been other exceptions where arsenical components have been identified by HPLC coupled with sensitive element-specific detection (ICP-AES or ICP-MS).21.25 These techniques can facilitate the identification of arsenic compounds present in trace amounts even when a major arsenic compound e.g. arsenobetaine (3) predominates. Such compounds are unlikely to be toxicologically significant because of their low concentrations but might offer clues to the metabolism and origin of major arsenic compounds. Standard materials must be available. Arsenic compounds likely to be of algal origin have been identified in bivalve molluscs by HPLC- ICP-AES.21 3 Marine Algae 3.1 Early Work The early work of Jonesz6 revealing high concentrations of arsenic in marine algae collected from the British coast was NATURAL PRODUCT REPORTS 1993 Me3isCH2CH20P0 ? CH2CHCH20COR' 0-OCOR I I Me3isCH2CH20POCH2CHOHCH20H ! I 0- (9) held ambivalence about arsenic inasmuch as he suggested that the reputation algae possessed as medicinal agents might be due at least in part to their arsenic content.Early studies on the characterization of arsenic in algae were chiefly concerned with the proportions of organically bound and inorganic arsenic and/or the relative contributions of lipid-soluble and water-soluble arsenic compounds to the total arsenic load.27-30 Because of the importance of marine algae in the Japanese diet the majority of studies of this type have originated in Japan and have concentrated on the edible seaweeds of that country. Hizikia fusiforme has received the most attention probably because an early report31 that it contained inorganic arsenic generated toxicological intere~t.~~.~~ indicated Later report~~~,~~ that aqueous extracts of Hizika contained methylarsonic acid (1) and dimethylarsinic acid (2) in addition to inorganic arsenic. Subsequent publication~~~-~~ reported that Hizikia contained approximately half of its arsenic burden as inorganic arsenic with the balance as unknown organic compounds. Limited work on other members of the Sargassaceae produced similar Studies of similar type directed at Laminaria japonica indicated that the bulk of its arsenic was present as unknown organic 36,39*40 A few studies attempted further characterization of the arsenic compounds elaborated by algae.These studies have with one exception involved the growth of algae (usually phytoplankton) in media containing radio-labelled arsenate. A study41 of the arsenic accumulated in the polar lipid (phospholipid) fraction of extracts of the microalga Tetraselmis chuii followed large-scale production of the alga in a medium enriched in unlabelled arsenate. Examination by TLC revealed an arsenic compound migrating with phosphatidylethanol- amine. Hydrolysis of this product with phospholipase led the authors to speculate that there might have been an arseno- choline moiety in the lipid.This tentative conclusion seemed unlikely in the light of work published42 one year later examining the products of subjecting phytoplankton (Chaetoceros concavicornis) to radio-labelled arsenate. The authors claimed to have identified an arsenolipid in extracts of the alga that was based upon the previously unreported trimethylarsoniolactate i.e. trimethylarsoniolactate substituted for choline in for example lecithin.42 Their identification was based upon chromatographic and electrophoretic coordinates and a comparison of these with trimethylarsonolactate apparently obtained by synthesis. The results were particularly persuasive as the authors claimed to be able to convert their confirmed by later studies for example by those of L~nde.~~ compound to arsenobetaine (3) by simple chemical means.A Jones examined algae such as Fucus spp. and Irish moss link between arsenic compounds biosynthesized by algae and (Chondrus crisp) that were traditionally used for those accumulated by marine animals was thus apparently pharmaceutical purposes or as food. His report on the high forged. However an authentic of trimethyl-levels of arsenic that they contained reflected the commonly arsoniolactate resulted in the retra~tion~~~~~ of the work and it NATURAL PRODUCT REPORTS 1993-5. S. EDMONDS K. A. FRANCESCONI AND R. V. STICK 0 -0 Reductive H -0 deamination t Mefis-CO2H Taurine Me&-#S03H 0 26 then C NH2 (28) t I Dimethylarsinoylribosides 2e- then A J X-+ OH OH SAdenosylmethionine (AdoMet) Trimethylarsonioribosides Proposed pathways for the biogenesis of arsenic compounds in marine algae Scheme 1 must be concluded that there is no evidence at all for the natural occurrence of trimethylarsoniolactate or compounds based upon it.Other studies involving the subjection of marine phyt~plankton~~ to radio-labelled arsenate and mar~oalgae~~ produced an abundance of arsenic compounds most at only trace concentrations but apart from methylarsonic acid (1) and dimethylarsinic acid (2) none was identified. 3.2 Dimethylarsinoylribosides and Related Compounds The above studies which might be thought of as the first phase of work on the nature of arsenic compounds in marine algae concentrated on brown algae and phytoplankton.The latter because the nature of the work required organisms that could be easily cultured; the former because brown algae (Phaeophyta) naturally contain more arsenic than red algae (Rhodophyta) or green algae (Chlorophyta) and because brown algae form the bulk of what is eaten by humans (in terms of total weight rather than number of species48). The report2 in 1981 of the isolation of two arsenic-containing carbohydrates from the brown alga Ecklonia radiata and their identification [compounds (10) and (1 l)] by means of NMR spectroscopy as dimethylarsinoyl-/3-ribosides of the simple algal metabolites glycerol and 2,3-dihydroxypropanesulfonicacid initiated a second phase of study.The structures of these compounds were unexpected ; they were more complex than the few arsenic-containing natural products of animal origin that had been identified hitherto and although it was thought that algal arsenic compounds would ultimately be metabolized within food-chains to those compounds such as arsenobetaine (3) found in animals any relationship between the arsenic-containing ribosides and arsenobetaine (3) was not obvious. Extraction of a second batch of Ecklonia yielded the phosphoric acid diester (12) together with compound (10). such a clear-cut difference between the results of the two extractions was not fully determined. The suggestion was made49 that arsenate absorbed by algae was being methylated by mechanisms analogous to those proposed by challenge^-^^*^^ for the methylation of inorganic arsenic by bread cultures of the mould Scopulariopsis brevicaulis and involving sequential reduction and oxidative methylation of the arsenic atom.Cant~ni~~.~~ identified S-adenosylmethionine (AdoMet ; Scheme 1) as the activated methyl donor in a number of enzymatic systems and Challenger54 considered it to be the likely source of methyl groups in the microbial methylation of arsenic. Further evidence that AdoMet was involved in the case of algae was available if it was accepted that AdoMet also provided the /3-ribo system by transfer of an adenosyl group to the arsenic atom. Indeed Cantoni predicted55 that AdoMet would be found to function as an adenosyl donor to suitable acceptors.It followed that the ribose system in the dimethylarsinoylribosides had the D-configuration although nothing could be said of the con-figuration of the aglycones. The NMR spectra suggested stereochemical homogeneity for all three Sub-sequent synthesis of compound (1 1)56 confirmed the stereo- chemistry of the ribose (D) and revealed the configuration of the aglycone as 2(R) [compound (1 la)]. A survey5' of the nature of arsenic compounds in some organisms from the Great Barrier Reef of north-eastern Australia revealed high concentrations of arsenic (-1000 mg kg-l dry weight) in the kidney of the giant clam Tridacna maxima. This mollusc contains symbiotic unicellular green algae5* and possibly its large accumulatory kidney receives products of the metabolism and senescence of these symbionts as well as from other microalgae obtained from filter-feeding.The arsenic compounds present were erroneously identified57 as being based upon the ficticious trimethyl-arsonolactate. A separate of Tridacna kidneys yielded Compound (1 1) was absent from this second extra~tion.~~ compound (1 1 a) previously isolated from Ecklonia and the Although it is evident that hydrolysis of compound (12) will sulfuric acid ester (13). The structure of the latter was yield compound (11) and presumably such a hydrolysis determined by NMR spectroscopy and by X-ray crystallo- occurred in processing the first extract precisely why there was graphy which confirmed the D assignment for the ribose system NATURAL PRODUCT REPORTS 1993 0 t Me2AswR OH OH (13) R = VOSO3H OH (13a)R = y0S03H OH (11) R=TOH OH (21) R= Me (25) R = qco2H OH + Me3*swR OHOH (llb)R= voH and revealed that the aglycone had the 2'(S) configuration (1 3a).The major dimethylarsinoylriboside in Hizikia fusiforme an alga that had been subjected to extensive but largely un-rewarding early studies was the sulfuric acid ester (1 3a).60 This OHOH compound previously isolated from Tridacna kidney accounted for almost 50 % of total arsenic in Hizikia but small quantities of the phosphoric acid diester (12) and hydroxy- sulfonic acid (10) were also present. Also found were the novel aminosulfonic acid (14) and a further arsinoylriboside very similar to the hydroxysulfonic acid (10).Confirmation that this compound was a C-2 diastereoisomer of hydroxysulfonic acid (10) was provided by the synthesisG1 of (2R)-and (28-2-hydroxy-3-~-~-~bofuranosyloxypropanesulfon~c acid sodium salt [compounds (15) and (16)] as models for 'H NMR hydrolyses had been carried out) is arsinoylriboside (1 1) rather spectroscopic analysis (see later). This work established the than trimethylarsoniolactate the results of chemical and stereochemistry of the hydroxysulfonic acid (1 0) [compound enzymatic manipulations suggest that a major arsenic lipid (lOa)] and its C-2 diastereoisomer (17). No other arsinoyl- produced by Chaetoceros concavicornis was compound (19). riboside from Hizikia or indeed from E~klonia~~ or Trid~cna~~Just such a compound was later isolated from the lipid fraction exhibited stereochemical multiplicity but examination62 of another Japanese edible alga Laminaria japonica revealed the C-2 diastereoisomers (loa) and (17) as major arsenic compounds.Phosphoric acid diester (12) and its hydrolysis product (1 1) were also present. Subsequent Japanese work has naturally tended to con-centrate on other edible species of that country and has examined examples of red and green macroalgae as well as brown. Species examined and the arsenic compounds they contained are summarized in Table 1. The sulfuric acid ester (1 3a) predominated in extracts of Sargassum thunbergii but the novel trimethylarsonioriboside (18) was isolated also.66 Although present in low concentration (< 1YOof total arsenic) this compound is of interest because of a possible role in the biogenesis of arsenobetaine (3) (see later).The commercially important brown alga Undaria pinnatzfida contained a sub-stantial amount of arsenic (25 %) in lipid forms. The identification of arsinoylribosides in algae also allowed a reinterpretation68 of some earlier work on arsenic lipids produced by cultured micro-algae subjected to radio-labelled ar~enate.~~ If the assumption is made that the basis of the compounds (i.e. the compound remaining after all enzymatic of an extract of Undaria pinnatrfida. The dipalmitoyl derivative (20) of phosphoric acid diester (12) was identified by NMR spectroscopy and GC-MS.69 More recent work has concentrated on two particularly rich sources of arsenic with the object of identifying compounds possibly of biogenetic or biochemical significance that might be present at very low concentrations.Thus a study61 of Sargassum lacerifolium (Phaeophyta Sargassaceae) and a further examination of Tridacna kidney'O yielded nine novel organic arsenic compounds all except one having the arsenic atom bonded directly to the C-5 of a P-ribose system and thus resembling previously isolated compounds. Several compounds already known from other algal sources were also isolated from Sargassum lacerifolium and are listed in Table 1. An X-ray crystallographic analysis of the aminosulfonic acid (14) established that the aglycone had the 2(S) configuration if the reasonable assumption was made that the ribose had the D-configuration [compound (14a)].61 Of the three new compounds found in Sargassum lacerifolium two the methylriboside (2 1) (possibly an artefact as methanol was the solvent of first extraction) and the ribosylmannitol (22) were of a trivial nature.The third compound (23) was more interesting. NATURAL PRODUCT REPORTS 1993-J. S. EDMONDS K. A. FRANCESCONI AND R. V. STICK Table 1 Arsenic compounds isolated from marine algae and Tridacna kidney Arsenic concentration Source Location fresh weight) (mi2 ks- Compounds (approx. YOof total extractable arsenic) Ref. Brown macroalgae Ecklonia Australia 10 lOa(60 YO),1 la(20 YO) 2 radiata Hizikia fusiforme Laminaria Japan Japan 10 10 4* lOa(50 YO),12a(20YO) Arsenate(5OYO),13a(45YO),10a(1 YO) 12a(0.8YO),14a(0.6%) 17(0.3 YO) 10a(50%) 17(30%) 12a(17%) lla(3 YO) 49 60 62 japon ica Sphaero trichia divaricata Undaria pinnat$da Sargassum Japan Japan Japan 2 2.8* 4.5* 4* 1la(50 YO),12a( 11 %) IOa(9 Oh) 14a(5YO) 'ether-soluble' (25 %) ~O(UPto 25%) 10a(70%) 12a(18%) 11a(12%) 13a(40YO),18a(0.2YO) 65 69 67 66 thunbergii Sargassum lacerlfolium Australia 40 13a(7&85 YO),12a(10%) lOa(5 %) 1la(5 YO),14a(0.5%) 2(0.2YO) 61 21(0.2 %) 22(0.1Yo),23(0.I Yo) Green macroalga Codium Japan 0.6 lOa(50YO),12a( 10 YO),2(5 YO) 63 fragile Red macroalga Porphyru Japan 1.3 13a(70%) 12a(28Oh) arsenate( 1.5 YO) 64 tenera 2(0.2%) Other source Tridacna kidney Australia 200 13a(50YO),1la(30 YO),25(3 YO) 26(2 YO),27(2 YO),lOa(2 YO) 59 70 17(0.5 YO),18a(0.4YO),28(0.2 Yo),29(0.4 Yo) * These values have been estimated from the reported quantity of extractable arsenic Me OH C02H Me OH OH Although isolated in very low yield (0.1 YOtotal arsenic) it offered the possibility of the presence of another arsenic lipid in algae.The acylated trimethylated nitrogen analogue (24) of the arsenic compound (23) has been identified as an important membrane lipid in several marine algae71-72 and the functional presence of the acylated arsenic compound in algae cannot yet be discounted. NMR spectra indicated that compound (23) was a mixture (1 1) of diastereoisomers but the exact nature of this diastereoisomerism was uncertain.Possibly the two compounds differed only in the configuration at the methine attached to the carboxy group.61 When considering the presence of arsenic lipids in algae it is noteworthy that the phosphoric acid diester (12) has been found in all algae so far investigated. It was absent from Tridacnu kidney but this may merely reflect utilization of a greater opportunity for degradation and a need for Tridacna to conserve phosphorus. Compound (1 1 a) probably produced by hydrolysis of phosphoric acid diester (12) represented about NH2 n 0 30% of the arsenic found in Tridacna kidney. On the other hand compound (12) has also been detected by HPLC techniques in a range of bivalve and gastropod molluscsz1 and in trace quantities in rock lobster digestive gland.24 Its widespread occurrence and possibly also that of diacylated analogues for example compound (20),69suggests that it too may possibly have some role in cellular processes.The re-examination of extracts of Tridacna kidney yielded the novel hydroxycarboxylic acids (25) and (26) and the novel oxycarbonylglycine derivative (27).70 The extraction of a second batch of material afforded besides the above the previously unknown N-[4-(dimethylarsinoyl)butanoyl]taurine (28) and the nucleoside (29).70 The former was the first organic arsenic compound apart from dimethylarsinic acid (2) isolated from 'algal ' sources that lacked the P-rib0 nucleus. The nucleoside (29) had been predicted as an intermediate in the formation of arsinoylribosides from oceanic arsenate.Its discovery offered considerable support for the proposed biogenic pathway (Scheme 1). In addition the presence of the nucleoside (29) and the amide (28) in Tridacna kidney may represent the first example of donation by AdoMet of all three of its alkyl groups to a single acceptor (arsenic) within one organism70 (Scheme 1). NATURAL PRODUCT REPORTS. 1993 0 Oxidation t Me2As4COOH Methylation 0 t (31) Dimethylarsinoylacetic acid Anaerobic Decomposition 0 t Me3As+,,COO- (3) Arsenobetaine OH OH (30) Dimethylarsinoylethanol Dimethylarsinoylribosides t Methylation Oxidation (7) Arsenocholine Scheme 2 Me3Asq0R Anaerobic Decomposition + x-Oxidation + -Me3Ase -Me3As,,COO-OH OH OH (7) Arsenocholine (3)Arsenobetaine Trimethylarsonioribosides Scheme 3 4 Chaemotaxonomy The arsenic compounds from representatives of only three of the twelve or so orders constituting marine brown algae have so far been examined.Three species of the order Fucales three of the Laminariales and a single representative of the Chordariales have been investigated. The three species of Fucales namely Hizikia fusiforrne6O Sargassum thunbergii,66 and S. lacerifolium61 each contained the sulfuric acid ester (1 3a) as the major arsenic compound. The three representatives of the order Laminariales on the other hand each contained the hydroxysulfonic acid (loa) as the most abundant arsenic compound but (13a) was absent.49-62.67 Sphaerotrichia divaricata the single member of the Chordariales studied to date presented a rather different picture ; the hydroxysulfonic acid (1Oa) was present but accounted for only about 10% of total arsenic whereas the sulfuric acid ester (13a) was absent.65 Possibly then the nature of the aglycone portion of arsinoylribosides may be related to taxonomy.However the single representatives of the Rhodophyta and Chlorophyta that have been examined Porphyra tenerd4 and Codium fragile,63 each contained only the phosphoric acid ester (12) and compound (1 la). Probably it is too early to say whether the nature of arsenic compounds in algae has any useful chaemotaxonomic significance. 5 Biogenesis of Arsenobetaine A number of studies have suggested that marine animals acquire their burden of arsenic [chiefly arsenobetaine (3)] through their diet rather than from ambient ~ater.’~-’~ The hypothesis that marine algae are absorbing oceanic arsenate which is transformed and passed along food chains received an apparent setback when it was discovered that marine algae convert the arsenate into relatively complex carbohydrate derivatives apparently unrelated to arsenobetaine (3).Never-theless when algal dimethylarsinoylribosides were allowed to decompose in contact with anaerobic marine sediments in laboratory experiments they were quantitatively converted to 2-dimethylarsinoylethan01(30) a compound which appeared to be a likely precursor to arsenobetaine (3).76 However com- pound (30) has never been found as a natural product and its conversion to arsenobetaine (3) has not been achieved in 0 0 t t Me2AsCH2CH20H Me2AsCH2C02H laboratory experiments designed to replicate natural conditions.Consequently the pathway(s) of biogenesis outlined in Scheme 2 while still plausible are yet to be proven. The discovery of the trimethylarsonioriboside (18) in Sargassum thunbergiP and in Tridacna kidney70 offered an alternative route to arsenobetaine (3). Anaerobic decompo- sition of compound (1 8) in laboratory experiments yielded arsenocholine (7) in a manner analogous to the production of compound (30) from the dimethy1arsinoy1ribosides.’’ That marine organisms rapidly oxidized arsenocholine (7) to arsenobetaine (3) had already been demonstrated.22 However trimethylarsonioriboside (18) represented a very small pro- portion of the total arsenic content of the organisms in which it has been found.66.’O Other trimethylarsonioribosides may have been present at even lower concentrations. There must be some doubt as to whether the levels of trimethylarsonioribosides would be adequate to account for all arsenobetaine (3) accumulated in marine animals. This alternative pathway for the biogenesis of arsenobetaine (3) is shown in Scheme 3. 6 Synthesis During the course of the isolation work it became apparent that structure elucidation of the various arsenicals especially with respect to relative and absolute stereochemistry could be aided by total or partial synthesis. Indeed arsenobetaine (3) was simply available by treatment of trimethylarsine with ethyl bromoacetate followed by basic hydroly~is.’~ Other simple arsenicals easily followed arsenocholine (7) by the treatment of trimethylarsine with 2-bromoethan01’~ (and subsequent anion-exchange to give the non-hygroscopic iodide) dimethylarsinoylethanol (30) and dimethylarsinoylacetic acid (31) by the generation of bis(dimethy1arsenic) oxide from iodomethylarsine and then subsequent treatment with NATURAL PRODUCT REPORTS 1993-5.S. EDMONDS K. A. FRANCESCONI AND R. V. STICK + f Me3AsCH2CH20POCH2 CH-CH2 Cr II HOT OPh OK0 BzO O'<P"h"" I (32) (33) Bz=COPh (34) OH (42) R = V B r (49) R = Me X- OH HoTiR OHOH (43) R =qo (44) R =+s03H OH either 2-bromoethan01~~ or sodium chloroacetate.22 Glyceryl- phosphorylarsenocholine (9) was obtained by the classical treatment of phenylphosphoryl dichloride with 1,2-0-isopropylideneglycerol then arsenocholine (7) to provide initially the triester (32); removal of the protecting groups then gave the desired diester (9).23 The first synthesis of an arsenic-containing riboside namely (1 la) was reported in 1987.56 The readily accessible orthoester (33) was combined with the alcohol (34) to provide the p-D-riboside (35) and removal of the ester protecting groups gave the trio1 (36).Isopropylidination of (36) gave the alcohol (37) which was then converted into the chloride (38). Treatment of (38) with dimethylarsinosodium then gave the crucial intermediate arsine (39) which without purification was oxidized to the arsine oxide (40).A brief treatment of (40) with aqeous acid gave the desired (1 la) identical in all respects with the natural product from Ecklonia radiata and confirming the relative and absolute configuration of the molecule. A similar synthesis employing the enantiomer of (34) gave a diastereoisomer of (1 la) namely (1 1 b) at present not known as a natural product. Partial hydrolysis of the synthetic intermediate (40) gave the diol (41) and this could be selectively oxidized to the carboxylic acid ; further hydrolysis then yielded (25) recently isolated together with the diastereoisomer (26) from the kidney of Tridacna maxima. A related synthesis of (26) was from selective oxidation of the tetrol (1 1b).Although none of the naturally occurring arsenic-containing (41) R = T H ,R' = Me2As -0 OH sulfonic acids have been synthesized two model compounds have been prepared. Thus selective hydrolysis of (35) gave a diol which was converted into the bromide (42). Base treatment then gave the epoxide (43) from which the model sulfonic acid (44)was easily obtained with aqueous sodium sulfite. The diastereoisomer (45) was prepared in a related sequence from the enantiomer of (34).61 The main reasons for the synthesis of the model compounds (44) and (45) was to make available NMR data which may be useful in the assignment of the stereochemistry at C-2 in the aglycone chain of the various natural products. Thus in the 'H NMR (300 MHz) spectrum of (44) the two hydrogens attached to C-3 of the aglycone appeared as the AB part of an ABX pattern (6 3.64 3.79) with geminal and vicinal (to H2) coupling constants of 10.5 Hz and 3.3 and 5.8 Hz respectively and with the more downfield proton (6 3.79) exhibiting the larger vicinal coupling constant (5.8 Hz).The comparable spectrum of (45) showed similar chemical shifts (6 3.56 3.86) and value for the germinal coupling constant (10.8 Hz) but the more downfield proton (6 3.88) now exhibited the smaller vicinal coupling constant (3.5 versus 6.4 Hz).~~ These data for the model compounds (44) and (45) were used to assign the stereochemistry at C-2 in the natural sulfonic acids (loa) and (17) (2(S) and 2(R)) the aminosulfonic acid (14a) (2(S)) the tetrol (1 1 a) (2'(R)) the phosphoric acid diester (1 2a) (2'(S)) and the sulfuric acid ester (13a) (2'(S)).61 These assignments were in agreement with those determined by synthesis (1 la)56 and X-ray crystallography (13a and 14a).59161 As the frequency of occurrence and importance of the trimethylarsonio-P-D-ribosides increased it seemed necessary to have a method for their preparation from the more common dimethylarsinoyl compounds.Thus according to some earlier work by Cullen,so the arsine oxide was reduced with 2,3- dimercaptopropanol (British Anti-Lewisite) and the resulting arsine treated with methyl iodide to yield the arsonium species. In such a way the trimethylarsonio compounds (18a),61 (46)-(49)*' were prepared from naturally occurring dimethyl- arsinoyl-P-D-ribosides namely (1 3a) (I 2a) (10a) and (1 1a) and the single synthetic glycoside (21).Only compound (1 8a) is a natural pr~duct,"~~~ and was prepared originally from the dimethylarsinoyl-P-D-riboside (1 3a) in a related reduction/ alkylation sequence.66 Finally two other interesting and natural arsenicals have been synthesized. The taurine derivative (28) was prepared by treatment of 4-dimethylarsinoylbutanoic acid (prepared conventionally from ethyl 4-bromobutanoate and dimethyl- arsinosodium) with taurine in the presence of ethyl (38)R= T O ,R' =CI (46) -0,p R = TO''\OTOH O+ 1 1 OH OH BzO OBz (47) (48) R = Y R = Y S O i O H X-OH R' = Me,As -0 chlor~forrnate.~~ The novel nucleoside (29) was obtained by subjecting 5’-chloro-5’-deoxyadenosineto excess dimethyl-arsinosodium followed by conventional oxidation and pro- tracted workup.’O 7 References 1 J. S. 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ISSN:0265-0568    

DOI:10.1039/NP9931000421

出版商:RSC    

年代:1993

数据来源: RSC