摘要:

ISSN 0265-0568 NPRRDF 5(3) 211-310 (1988) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 5 Number 3 CONTENTS 21 1 Diterpenoids J. R. Hanson Reviewing the literature published during 1986 229 Naturally Occurring Isocyanides M. S. Edenborough and R. B. Herbert 247 The Biosynthesis of C,-C, Terpenoid Compounds M. H. Beale and J. MacMillan Reviewing the literature published during 1986 265 P-Phenylethylamines and the Isoquinoline Alkaloids K. W. Bentley Reviewing the literature published between July 1986 and June 1987 293 Quinoline Quinazoline and Acridone Alkaloids M. F. Grundon Reviewing the literature published between July 1985 and June 1987 309 Book Review Secondary Metabolism (Second Edition) by J.Mann Reviewed by G. W. Kirby 309 Book Review Biologically Active Natural Products ed. K. Hostettmann and P. J. Lea Reviewed by A. Pelter Cumulative Contents of Volume 5 Number 1 1 Prostaglandins Thromboxanes Leukotrienes and Related Arachidonic Acid Metabolites (I983 and 1984) T. W. Hart 47 Antibiotics with Antifungal and Antibacterial Activity Against Plant Diseases P. A. Worthington 67 Tropane Alkaloids (July I985 to December 1986) G. Fodor and R. Dharanipragada 73 The Biosynthesis of Shikimate Metabolites (1986) P. M. Dewick 99 Errata to The Biosynthesis of Triterpenoids and Steroids D. M. Harrison (Vol. 2 No. 6 p. 525) Number 2 101 The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products One-Dimensional Methods I.H. Sadler 129 The Biosynthesis of Penicillins and Cephalosporins J. E. Baldwin and Sir Edward Abraham 147 Steroids Reactions and Partial Syntheses (1985) J. Elks 187 Non-Macrocyclic Trichothecenes (January I970 to December 1986) J. F. Grove Articles that will appear in forthcoming issues include Steroids Reactions and Partial Syntheses (December I985 to October 1986) A. B. Turner Imidazole Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July I985 to June 1986) J. R. Lewis Monoterpenoids (I985 and 1986) D. H. Grayson Natural Sesquiterpenoids (1986) B. M. Fraga Brain Chemistry and Central Nervous System Drugs R. I. Brinkworth E. J. Lloyd and P. R. Andrews Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July I986 to June 1987) J.E. Saxton Synthesis of Gibberellins and Antheridiogens (to December 1987) L. N. Mander Trends in Protease Inhibition (November I984 to January 1987) G. Fischer The Biosynthesis of Triterpenoids Steroids and Carotenoids (I984 and 1985) D. M. Harrison The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (July I986 to June 1987) R. B. Herbert Natural Products from Plant Tissue Culture (January I979 to December 1986) B. E. Ellis Marine Natural Products (September I986 to December 1987) D. J. Faulkner Erythrina and Related Alkaloids (July I985 to June 1987) A. S. Chawla and A. H. Jackson Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids (July I986 to June 1987) A. R. Pinder The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products Two-Dimensional Methods A. E. Derome Enzyme Inhibitors in Medicine (to December 1987) C. S. J. Walpole and R. Wrigglesworth Amaryllidaceae Alkaloids (July I985 to June 1987) M. F. Grundon

ISSN:0265-0568    

DOI:10.1039/NP98805FP007

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Natural Product Reports Editoriaf 6oard Professor G. Pattenden (Chairman) University of Notting ham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor M. I. Page The Polytechnic Huddersfield Dr T. J. Simpson University of Edinburgh Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products.Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products. Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Burlington House London W1V OBN England. 1988 Annual Subscription Price U.K. f159.00 Rest of World f183.00 U.S.A. $342.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 lHN 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. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. ~ ~ ~~~~~~ 0The Royal Society of Chemistry 1988 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1988 U.K. €159.00 Overseas f183.00 U.S.A. US $342.00 Subscription rates for back issues are (I 984) (1985) (1986) (1987) U.K. f 120.00 f 125.00 f 130.00 f 142.00 Overseas f 126.00 f 131.OO f 143.00 f 159.00 U.S.A. US $240.00 US $242.00 US $252.00 US $280.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry 30 Russell Square LONDON WClB 5DT England

ISSN:0265-0568    

DOI:10.1039/NP98805FX009

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

ANIIWORTMT NEW BOOK FOR CHRO2MATOGRAPWERS... SUPERCRITICAL FLUID CHROMATOGRAPHY Edited by Roger M.Smith Loughborough University of Technology Supercritical Fluid Chromatography is part of an important new series from the Royal Society of Chemistry entitled ’RSC Chromatography Monographs’ and is the first book devoted entirely to this rapidly expanding analytical technique. SFC is the current focus of attention in the Chromatography world and promises to revolutionise analytical procedures in the petroleum pharmaceutical food agrochemical and biotechnology industries. This new publication will provide practising chromatographers in both industry and academia with a perspective on its principles practice and potential applications. The book discusses the origins and development of SFC the instrumentation that has been used and the technique’s growth from the related methodologies of GLC and HPLC.It also covers in great detail the way in which the separations in SFC can be altered to increase selectivity compares the roles of packed and capillary columns and covers the coupling of SFC to mass spectrometry. Written by a team of acknowledged experts in the field Supercritical Fluid Chromatography will prove invaluable to all scientists from government industry and academia with an interest in SFC. ISBN 0 85186 577 1 Hardcover 250pp. Publication date April 1988 f27.50 ($59.00) RSC Members price f18.50 Discount price for this title for customers wishing to place a standing order is f20.00 ($43.00) Dont’be without this important publication.orderyour copy talay! Payment by credit card is now accepted -ACCESS/MASTERCARD/EUROCARD/VISA ROYAL Non-RSC Members should order from SOCIETY OF Royal Society of Chemistry Distribution Centre CHEMISTRY Blackhorse Road Letchworth Herts SG6 1HN. United Kingdom. & RSC Members s ould order from Membership Manager Rc jal Society of Chemistry lnformation b-30 Russell Square London WC1 B 5DT United Kingdom Services L L NEW BOOKS FROM THE ROYAL SOCIETY OF CHEMISTRY rn rn Amino Acids and Peptides VOI. 19 ‘I. . . its utility to the group of readers for whom it is intended is unquestionable.” -Medical Book News reviewing Vol. 18. This series was previously entitled ‘Amino Acids Peptides and Proteins’.The latest volume in the series covers the literature published on the subject during 1986. Brief Contents Amino Acids; Peptide Synthesis; Analogue and Conformational Studies on PeDtide Hormones and Other Biologically Active Peptides; Cyclic Modifled and Conjugated Peptides; &Lactam Antibiotic Senior Reporter J.H. Jones Chemistry; Metal Complexes of Amino Acids and Peptides. University of Oxford Specialist Periodical Report (1987) Hardcover 345pp ISBN 0 85186 174 1 Price f69.50 ($136.00) Carbohydrate Chemistry VoI. 19 Part I “We can wholeheartedly support this series and recommend both this volume and the series as a whole as an essential part of the library of all practical carbohydrate workers.Our laboratories would find it difficult to review the whole of this field without the aid of this series.” -British Polymer Journal reviewing Vol. 18 Part 1. From Vol. 14 onwards ‘Carbohydrate Chemistry’ has been split into two parts Part I Mono Di and Tri saccharides and Their Derivatives Part II Macromolecules. Since Vol. 19 Part I has been renamed Monosaccharides Disaccharides and Specific Oligosaccharides. This volume is a review of the literature published during 1985 Brief Contents Senior Reporter N.R. Williams Free Sugars Glycosides and Disaccharides; Oligosaccharides; University of 1ondon Ethers and Anhydro-sugars; Acetals; Esters; Halogeno-sugars; Specialist Periodical Report Amino-sugars; Miscellaneous Nitrogen Derivatives; Thio-and Seleno-sugars; Deoxy-sugars; Unsaturated Derivatives; Branched- (I 987) chain Sugars; Aldosuloses and Dialdoses; Sugar Acids and Lactones; Hardcover 305pp Inorganic Derivatives; Alditols and Cyclitols; Antibiotics; Nucleosides; ISBN 0 85186 222 5 N.M.R.Spectroscopy and Conformational Features; Other Physical Price f60.00 ($1 16.00) Methods; Separatory and Analytical Methods; Synthesis of Enantiomerically Pure Non-carbohydrate Compounds. To order or for further information please write to Royal Society of Chemistry Distribution Centre Blackhorse Road Letchworth Herts SG61 HN UK. or telephone (0462)672555quoting your credit catd details. We now accept AccessNisa/MasterCard/EuroCard. RSC Members are entitled to a discount on most RSC publications and should write to The Membership Manager Royal Society of Chemistry 30 Russell Square London WC1B 5DT UK. PRINTED IN GREAT BRITAIN BY THE UNIVERSITY PRESS CAMBRIDGE

ISSN:0265-0568    

DOI:10.1039/NP98805BX011

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Diterpenoids J. R. Hanson School of Molecular Sciences University of Sussex Brighton Sussex BN I 9QJ Reviewing the literature published during 1986 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 399) 1 2 3 3.1 3.2 3.3 4 4.1 4.2 4.3 4.4 5 5.1 5.2 5.3 5.4 5.5 6 6.1 6.2 6.3 7 8 Introduction Acyclic and Related Diterpenoids Bicyclic Diterpenoids La bdanes trans-Clerodanes cis-Clerodanes Tricyclic Diterpenoids New Natural Products Pimaranes A bietanes Vouacapanes and Cleistanthanes Chemistry of the Tricyclic Diterpenoids Tetracyclic Diterpenoids Kauranes Beyeranes Aphidicolanes Grayanotoxins Gibberellins Macrocyclic Di terpenoids Cembranes Lathyranes and Related Natural Products Taxanes Miscellaneous Diterpenoids References 1 Introduction This Report follows the pattern of its predecessors' and reviews the period between January and December 1986.Many new diterpenoids have been reported as a result of various phytochemical surveys. However in some cases evidence is not presented to define the absolute stereochemistry of these compounds and thus a potentially important phytochemical parameter is ignored. The power of the various two-dimensional n.m.r. techniques continues to be displayed in the elucidation of the structures of new diterpenoids particularly those derived from marine organisms. Several diterpenoids have attracted interest because of their potential medicinal value.Some particularly in the clerodane series have antifeedant activity. 2 Acyclic and Related Diterpenoids Amongst the acyclic diterpenoids that were reported during the year were (12s)-12-hydroxygeranylgeraniol which was ob-tained2 from the brown alga Bifurcaria bifurcata and the tetraol (l) which was isolated3 from Viguiera gilliesii (Com- positae). Attention has continued to be paid to Montanoa tomentosa (zoaptle) because of its biological activity and a further oxepane diterpenoid tomentanol (2) has been isolated from it.4 The synthesis of some naturally occurring geranylgeraniol derivatives such as mikanifuran using sulphone methodology has been described. The cyclization of geranylgeraniol deriv- atives with various Lewis-acid catalysts to form spongiane and labdane terpenoids has been Mercury(I1) trifluoro- methanesulphonate-N,N-dimethylaniline complex appears to be an efficient catalyst for these biomimetic cyclizations.CH,OH (1 1 OH kHO OR (3) (5) 3 Bicyclic Diterpenoids 3.1 Labdanes The diterpenoids of Salvia species have continued to attract interest. 6P-Hydroxysclareol(3) has been obtainedQ from Salvia moorcruftiana. Several diterpene glycosides (4;R = glycosyl) in which (4;R = H) formed the aglycon have been isolated'O from the aerial parts of Gutierrezia sphaerocephalu (Compositae). Further chemosystematic studies on the Compositae have afforded" some new ent-labdanes e.g. (9 and the endo- peroxide (6) from G.spathulata together with some grindelanes 21 1 9-2 e.g.(7) from Haplopappus species and Grindelia species. ent-Labdanes such as (8) were obtained12 from another member of the Compositae Austrobrickellia patens. Labdane diterpenoids are also common constituents of the Cistaceae. Compounds such as (9) have been reportedI3 from Halimium viscosum whilst (I 0) (laurifolic acid) was obtained14 from Cistus laurifolius. The resinous desert plant NoIana rostrata (Nolanaceae) contains15 the diterpene (1 1) and some of its relatives. The principal component of the extract of the leaves of Brickellia vernicosa (Compositae) id6 3a-hydroxycativic acid and the trio1 (12) whilst discoidic acid (I 3) and both cordobic acid (14) and its 7-epimer were obtainedl73 l8 from Grindelia discoidea (Com-positae).The X-ray crystal structure of the nor-diterpene (1 5) obtained from Austroeupatorium inulaefolium has been re-ported.19 Extracts of Stevia rebaudiana (Compositae) which contain the ent-kaurene glycoside stevioside are used as a sweetening agent. The plant also contains some antihyperglycaemic constituents. In the search for these some bisnorditerpenoids the sterebins A-D [e.g. (16) and (17)] were isolated.20 A nor-diterpene (18) has been obtained2I from Isocoma coronopifolia (Compositae). The pre-furan preleosibirin (19) has been found22 in Ballota nigra subsp. foetida (Labiatae). Plants of the genus Sideritis (Labiatae) have been a source of both ent-labdanes and ent-kaurenes. In a continuation of workz3 on the species of the genus that are endemic to the Canary Islands sidnutol (20) gomerol (2 1) and its 13-epimer7 and 3a-hydroxygomeric acid were obtained from Sideritis nutans.Some variants on the manoyl oxide skeleton the scapanins A (22) and B (23) were isolated24 from the liverwort Scapania undulata. A pungent taste is often associated with dialdehydes. Galanal A (24) and its 15-epimer (galanal B) have been isolated,25 ,,CH2 C02Ara A CH,OH (11) (12) R NATURAL PRODUCT REPORTS 1988 together with the epoxy-labdane (25) from AIpinia galanga (Zingiberaceae). This plant is used for flavouring purposes. It is possible that the tricyclic compounds might arise by rearrange- ment of the epoxide followed by an internal aldol condensation.Conformation-odour relationships in the Ambrox analogues (26) and (27) have been explored.26 Because of its hypotensive and other medicinal properties forskolin (coleonol) (28) has continued to attract attention. A thorough lH-13C n.m.r. study has been reported2' whilst there has been some synthetic work.28 The oxidation of grindelic acid to form the spiro-ketal system that is found in grindelistrictic acid (29) has been e~amined.'~ 3.2 trans-Clerodanes Over 400 clerodane diterpenoids are now known. They can be divided into two main classes i.e. those with a trans fusion and those with a cis fusion of rings A and B. Attention has been directed at these compounds because of the insect antifeedant activity shown by some of them particularly relatives of ajugarin 1 (30).The subject has been revie~ed~~,~~ and a total synthesis of ajugarin 1 has been reported32 in full together with a description of some structural modifications of clerodin. Phytochemical investigations of a number of members of the genus Baccharis (Compositae) have afforded some new clero- dane diterpenoids. These include bincatriol (3 1)33 and com- pounds (32) and (33)34 from B. incarum (34) from B. sar~throides,~~ compounds (35) and (36) from B. rhomb~idalis,~~ and bacchasmacranone (37) and its 2P-hydroxy-derivative (38) from B. ma~raei.~~ In a paper in which the isolation of clerodane glycosides from various Baccharis species is described there is a discussion of the chemotaxonomy of the various Sections of the genus.38 OH CH,OH CH~OH (13) (14) #ill2 0R' HO CH~OAC Sterebin A (16a)R' =R2 = H Sterebin 6 (16b)R' =Ac R2 = H Sterebin 0 (17) (15) Sterebin C (16~)R' = HI R2 = Ac NATURAL PRODUCT REPORTS 1988-5.R. HANSON 213 I HO I 0 I I CHO '0H CHO OH (25) @y OH OAc OH (26) CH,OH / ODoMe 0 CHZOH I' AcOCH (30) (33) 00 Me'0 R &/ I 0-.' \ HoYtJ'O CH,OH HO,C I CH,OH 0 0 HOCH, -& H (34) (35) (36) (37) R (38) R = OH The clerodanes portulides A-D [(39)-(42)] have been from Portulaca species in continuation of an examination of these species for plant growth regulators related to portulal. Some further compounds i.e. portulene (43) portulenone (44) and portulenol (43 which bear a formal relationship to possible biosynthetic precursors of portulal have been obtainedg0 from Portulaca grandijlora.The genus Salvia is the largest genus of the Labiatae. It consists of about 900 species amongst which are several medicinal hallucinogenic and culinary herbs. Examination of a Mexican species Salvia lineata has affordedg1 the 8-lactones (46H48) ;these are related to salviarin. Epoxysalviacoccin (49) has been obtainedg2 from Salvia plebeia whilst semiatrin (50) was obtainedg3 from another Mexican species S. semiatratha. I OH Portulide A (39) R' = CH,OH R2 = H (43) Portulide B (40) R' = Me R2 = H Portulide C (41) R'= Me R2 =OH Portulide 0 (42)R' = CHO R2=H H.@ 0 & \ 0 0 0 (4611,lO -d i d e hyd r o (48) (47)lac loor -epoxide Q H (511 NATURAL PRODUCT REPORTS 1988 Another genus of the Labiatae to have attracted considerable interest as a source of clerodanes is Teucrium.The con-figurations at C-12 and at C-20 of many of these diterpenoids have recently been clarifiedg4 by using nuclear Overhauser enhancement studies in the lH n.m.r. spectrum. Recent isolates include teugnaphalodin (5 1) from Teucrium gnaphalode~,~~ 7,8-didehydroeriocephalin (52) teulanigerin (53) the orthoacetate teulanigeridin (54) teulanigin and its 20-epimer (59 and teulanigeral (56) from Teucrium laniger~m,~~ picropolinol (57) 7-deacetylcapitatin (58) and 20-epi-isoeriocephalin (59) from Teucrium poli~m,~' the teusalvins A-F [(60)-(65)] from Teuc- rium salvia~trum,~~ teupyrins A (66) and B (67) from Teucrium pyrenaic~m,~~ 19-acetylteupolin IV (68) from Teucrium poli~m,~" 19-deacetylteuscorodol (69) and teubotrin (70) from 0$-$ \ -O I HO OH OH (44) (45) 0 0 0&o (49) H AcO ~H~OA~ (53) (54)R = OAc NATURAL PRODUCT REPORTS 1988-5.R. HANSON 215 Q H+O 0'flH I CH2 I OAc OAc OAc OAc (55) (56) (57) (58) OH (59) R = OAC (60)R = 0 (62) R = H2 (61) R = a-H 0-OH (63)R = a-H,O-OH;12-epi HO HOCH2 OH (64) (65) (66) (67) HOH2C i OH OH (69) Teucrium botry~,~l teulepicin (7l) 19-acetylteulepicin (72) and teulepicephin (73) from Teucrium lepi~ephalum,~~ and 2p-hydroxyteucvidin (74) from Teucrium webbianum.53 Extraction of the bark of the Brazilian tree Aparisthmium cordatum (Euphorbiaceae) afforded54 the rearranged clerodane aparisthman (79 the structure of which was established by X-ray crystallography. 3.3 cis-Clerodanes Some errors have been made in the past in assigning the stereochemistry of the A/B junction to the cis-clerodane solidagolactones. A detailed analysis of the 13C n.m.r. spectra has been to be of value in determining the stereo- chemistry of these compounds. 18-Deoxysagittariol (76) was from Sagittaria sagittifolia (Alismataceae) whilst an X-ray crystal structure determination has been carried out5' on a compound (77) that was obtained from Gutierrezia texana. The cis-clerodane structure (78) has been assigned5* to the epoxide chiliomarin which was isolated from Chiliotrichum rosmarinifolium.(71) R = H (72)R = AC (77) HO. ..& $5 \ 'H NATURAL PRODUCT REPORTS 1988 The structure of fibraurin (79) from Fibraurea chloroleuca (Menispermaceae) was in doubt after there had been a revision of the stereochemistry of the bitter principles of Colombo root. The structure has now been e~tablished~~ by X-ray crystal- lography. Some further glycosides in this series including tinophylloloside (80) have been obtained from the Chinese medicinal plant Fibraurea tinctoria60 Tinospora cordifolia (Menispermaceae) (' Guduchi ') has been used in Ayurvedic medicine for the treatment of jaundice. Extraction of the stems of this plant has afforded6I the cis-clerodane (81).Borapetol B (82) and its C-6 glucoside borapetoside B have been obtained62 from T. tuberculata another medicinal plant of this genus. The X-ray crystal structure of jateorin (2,3-epoxycolumbin) (83) has been described.63 Palmatoside A is a palmarin glucoside that has been from Jateorhiza palmata (Colombo root) whilst 8-hydroxycolumbin (84) has been isolated65 from the bark of the African medicinal plant Chasmanthera dependens (Menispermaceae). Biosynthetic enrichment studies involving the feeding of [5-'3C]mevalonolactone and sodium [2-13C]acetate to a species of Kitasatosporia have been reported66 for the anti-tumour antibiotic terpentecin (85). HO Me0,C I OH (75) (76) .H I! NATURAL PRODUCT REPORTS 1988-5.R. HANSON Rzedowskia tolantonguensis were established by a combination 4 Tricyclic Diterpenoids of spectroscopic and X-ray studies. Some 19-norditerpenes 4.1 New Natural Products Pimaranes [(97) and (98)] and their C-7 alcohols were also isolated from The tree Dacrydium biforme is endemic to New Zealand and the same source. The pimaric acid derivative (99) has been possesses markedly contrasting forms of juvenile and adult reported74 from Lycopus europaeus. Maximol (100) and the foliage. Whereas 8a-isopimara-9( 1l) 15-diene is a characteristic corresponding acid maximic acid are unusual ent-rosane hydrocarbon of the juvenile foliage the tetracyclic diterpene derivatives in which ring A is aromatic. They have been phyllocladene is in the adult foliage.The isopimara- isolated75 from the fronds of the fern Arachniodes maximowiczii. diene derivatives (86)-(88) have been obtained6* from the The structure (100) was established by X-ray crystallography. Mexican plant Salvia greggii (Labiatae) whilst linifolioside (89) is a con~tituent~~ the medicinal plant Leucas linifolia of (Labiatae). Several A9(l1)-pirnaradiene derivatives including 4.2 Abietanes (90)-(92) have been obtained70 from Mikania triangularis Several highly oxidized abietane derivatives have been obtained (Compositae). The structure and stereochemistry of viguiepinol from members of the genus Salvia (Labiatae). 7p,15-(93) [from Viguiera pinnatilobata (Compositae)] have been Dihydroxyabietatriene (101) has been from aerial established7' by X-ray crystallography.The isopimaradiene parts of Salvia sapinae. The roots of Salvia canariensis which from Lepechinia is endemic to the Canary Islands afforded77 deoxycarnosol 12- derivatives (88) and (94) have been ~btained'~ glomerata (Labiatae). The structures of the isopimaradiene (95) methyl ether (102) salvicanol (103) (which contains a seven- and its relative (96) both of which have been from membered ring) and 601-hydroxydemethylcryptojaponol (1 04). (86 ) R' = OH R2 = CO H R3 = H (87) R1= H R2 = CO,H R3=OH (88) R' = H R2 = CH OH R3 =OH HO CH,OH CH,OH (94) (95) R = CH,OH (97)R = H (96) R = CO,H (98)R = OH 'OAc C H,OH CO H (99) (100) (101) OMe . OH OH (1021 (103) Although 7a-ethoxyroyleanone (105) has been obtained7* from the roots of Salvia luvendulaefolia since the ethoxy-group is very rarely found as a substituent in abietanes this could be an artefact arising from the addition of ethanol to a quinone- methide followed by aerial oxidation.A quinone-methide (106) has been ~btained’~ from Salvia moorcraftiuna whilst methyl carnosoate (107) has been isolated from Salvia lanigera. A group of highly oxidized 20-norabietanes and rearranged diterpenoids namely (1 R)-1-hydroxymiltirone (1 OS) arucadiol (109) and 1-ketoaethiopinone (1 lo) has been extracted from the roots of Salvia argenteaaO whilst the tanshinlactone (1 11) was a minor constituent of Salvia miltiorrhiza.al The fruticulins A (1 12) and B (1 13) are quinonoid products of the Mexican species Salvia fruticulosa.82 The unusual structure of fruticulin A was confirmed by an X-ray analysis.The biosynthesis of cryptotanshinone in tissue cultures of S. miltiorrhiza has been examined.83 Evidence for the structure and absolute configuration of pisiferdiol (1 14) (from Charnaecyparis pisifera) has been reported in full84 whilst the antibiotic and anti-tumour activities of pisiferic acid have been examined.85 Extracts of Euphorbia acaulis are used in the treatment of inflammatory diseases in some folk medicines. The X-ray structure of caudicifolin (1 I5) which can be obtained from the plant has been described.86 The leaf glands of members of the genus Plectrunthus (Labiatae) contain a large number of highly oxidized diter- penoids.(1 6R)-Plectrinone (1 16) has been obtained8’ from Plectranthus barbatus whilst plectranthrone A (1 17) is an example of more than twenty compounds that have been OH I 8 ..O Et NATURAL PRODUCT REPORTS 1988 extracteda8 from a Plectranthus species which was obtained from Rwanda. The stereochemistry of opening of the cyclo- propane ring of the lanugones [e.g. (1 1S)] to afford an n-propyl side-chain [e.g. as in (119)] has been examined.as 4.3 Vouacapanes and Cleistanthanes The shrub Caesulpinia pulcherrima (Leguminosae) is used in folk medicine ;several diterpenoids including (1 20)-( 122) have been isolatedso from its roots. Pulcherralpin (123) which has the cassane skeleton was obtained from the same plant.s1 Caesalpin F (1 24) was obtaineds2 from Caesalpinia bonducella.The absolute configuration of some cleistanthane diterpenoids from members of the Velloziaceae has been establisheds3 by measurements of circular dichroism. 4.4 Chemistry of the Tricyclic Diterpenoids The mass spectra of some substituted derivatives of dehydro- abietic acid have been reported.s4 The oxidation of tricyclic diterpenes with thallium triacetate’j and with iodine and lead tetra-acetates6 has been examined. The reaction of abietic acid methyl ester with m-chloroperoxybenzoic acid leadss7 to initial attack on the 13-14 double-bond predominantly from the B-face. Subsequent hydrolysis gives the 7a,13p-A8(I4)- and 13p, 14a-A7(a)-diols. The reactions of the formaldehyde-levopimaric acid adduct (125) have been re-e~amined.’~ The structure of a 7-7’ dimer of abietic acid that is formed under acid-catalysed conditions has been establi~hed.~~ 0 (105) (106) (108) 0 (112) (113) NATURAL PRODUCT REPORTS 1988-5.R. HANSON (114) (115) OH 0$ \ (116) (117) &. I R2 OH OH R' OR' CO H (124) (1 25) 5 Tetracyclic Diterpenoids 5.1 Kauranes Some new ent-kaurenes including (126) have been isolatedloO from Helianthus divaricatus H. resinosus and H. salicifolius (Compositae). This formed part of a systematic survey of the North American sunflowers. In another study the acids (127) and (I 28) were obtained from Helianthus heterophyllus.lO' ent- 15a-Angeloyloxykaur- 16-en-3/3-01 and its 16p 17-epoxide have been isolatedlo2 from the roots of Elaeoselinurn tenuifolium whilst some esters of ent-7a-hydroxykaur- 16-en- 19-oic acid (129) were foundlo3 in E.foetidurn. Investigations into the diterpenoids of the genus Sideritis (Labiatae) have been continued; there is a report on the constituents of Sideritis infernalis. Io4 These include sinfernol (1 30) ent- 15/3 16P-epoxy- 15,16-dihydrosinfernol (1 3 l) sinfernal (1 32) and 7-epi-sinfernal. The structure of plecostonol (1 33) from Plectranthus (126) (127) R = H (128) R = 0 'OH HOCH (131 1 (134) R = 0 (136) (135)R = a-OH O-H NATURAL PRODUCT REPORTS 1988 coesta (Labiatae) has been establishedlOj by X-ray analysis. Several highly oxidized seco-kaurenes and their relatives have been isolated from medicinal herbs of the genus Rabdosia (Labiatae).These include the sculponeatins A-C [(134)-( 136)] from Rabdosia sculponeata,'06 rabdophyllin H (1 37)"' (the structure of which was established by X-ray analysis'os) and jiuhanin A (1 38) from Rabdosia macrocaly.~,'~~ macrocalyxo-formins B (139) C (140) and E (141)"O from the same plant the reniformins A-C [(142)-( 144)] from Rabdosia latifolia var. rert$orrnis and rabdoserrin D (145) from Rabdosia serra. 111 Many of these compounds possess anti-tumour activity. The importance of the oxidation of ring B in the metabolism af ent-kaurene provided the impetus for finding a method'12 of hydroxylation,of ring B. This is based on the introduction of a hydroxymethyl group at C- 15 followed by a radical cyclization.The transfer of the methyl group at C-10 to C-9 has been brought about'13 by brominating the 9-1 1 double-bond of the CH,OH HOCH,fl I *'OH COZH (129) (130) (133) OAc (1 38) OH -0 dH (142)R' = H R2 = 6-OH R3= CH,OAc (143) R' = OH R2 = a-OAc R3 = CH (139) (140) (141 1 (145)R' = H R2 = O-OH R3 = CH,OH NATURAL PRODUCT REPORTS 1988-5. R. HANSON grandiflorenic acid derivative (146) which rearranges to (147). The stereochemistry of the formation of the 16,17-methylene during the biosynthesis of kaurene has been carefully exam- ined.,' The microbiological transformation of ent-15p,18-dihydroxykaur- 16-ene (candidiol) by Gibberella fujikuroi affords115 the 1 1 P-hydroxy-derivative (148).The transformation of tetracyclic diterpenes by Aspergillus niger has been exam- ined.'16 5.2 Beyeranes Effects of substituents and of stereochemistry on the 13C chemical shifts in the n.m.r. spectra of a series of ent-beyerene diterpenoids have been reported.l17 5.3 Aphidicolanes Aphidicolin has attracted a large amount of biological interest because of its selective action on DNA polymerase a. Some aspects of its chemistry have been examined,11s including the rearrangement of (149) to (150). A new aphidicolin derivative (151) has been reported119 as a metabolite of Nigrospova sacchari. 5.4 Grayanotoxins The seco-derivative (I 52) has been obtained120 from Leucothoe grayana which is the source of the majority of the gray- anotoxins.C0,Me (146) HO (150) OGlc (154) (1 53) 22 1 5.5 Gibberellins High-performance liquid chromatography (h.p.1.c.) provides a major analytical tool for the gibberellins. Maturing seeds of Sechium edule contain high levels of gibberellins and an examination of these has led to the isolation121 of the 7-0- glucoside (1 53) of a GA, derivative. Conjugates of gibberellin A have been detected,, by h.p.1.c. in Phaseolus coccineus whilst gibberellins A, A, A,, and A, were identified123 in immature seeds of Pithecellobium microcarpurn (Leguminosae). A quantitative relationship has been established', between the presence of gibberellin A and the internodal growth in Pisum sativum suggesting that in this species it is gibberellin A that is the primary gibberellin in promoting stem growth.Metabolic studies have continued to provide the stimulus for the partial synthesis of labelled gibberellins and methods have been developed for the stereospecific deuteriation of ring A.~~~. lZ6 A simple route to 2-hydroxy-gibberellins via iodo-lactonization of the diene (154) [to form (155)] has been rep~rted.,~'The X-ray crystal structure of I/?-azidogibberellin A has been described.128 The partial synthesis of 6-epi-GA13 and GA, through the formation of 7-20 anhydrides has been described.12' It has been shown that the biosynthetic pathway from mevalonic acid to gibberellin A, 7-aldehyde is the same in immature seeds of Phaseolus coccineus as in other species.130 Some improvements in the enzymatic synthesis of labelled gibberellin A, 7-aldehyde have been reported.131 The metabolic route between gibberellin A, 7-aldehyde and gibberellins A and A in immature seeds of Phaseolus vulgaris has been delineated.13 The loss of C-20 as CO during the biosynthesis of the C, gibberellins by Pisum sativum has been established,133 paralleling earlier work with Gibberella fujikuroi. 9 \ OH CO Me HOCH (147) (148) 'CH,OH (151) 0 (1 55) 6 Macrocyclic Diterpenoids 6.1 Cembranes Soft corals continue to be a rich source of these diterpenoids. The composition of the constituents of specimens of Clavularia koellikeri that have been collected at the same place and during the same month nevertheless seems to vary with the year of collection.In previous years sesquiterpenes and dolabellane diterpenes have been reported. Further investigations have afforded135 five new cytotoxic cembrenolides the kericem- brenolides A-E [(156H16O)l. Examination of Sinufaria lepto- clados afforded (I 6 1)136 whilst the structure of the epoxide (1 62) which was from the coral Eflatounaria variabilis was established by chemical correlation and by X-ray crystallography. A stereoisomer was obtained from a related member of the same genus. The X-ray crystal structures of cueunicin acetate (163),13s from Eunicea mammosa and sarcophinone (1 64),139 from Sarcophyton decaryi have been reported. The tobacco plant (Nicotiana tabacum) contains a large number of cembranolides (for a review see Nat.Prod. Rep. 1987 4 237). The hydroperoxide (165) isolated from the flowers has indolylacetic-acid-inhibitory activity.140 Some further studies on the acid-catalysed cyclization of the cembrane diterpenoids have been described.141 R’ --OOH 0 @ R2 R’ R2 R3 HO (156) OAc H H 0 (157) H OAc H (161) (158) OAc H OAc (159) OAc H OH (160) OH H OH (164) 0 H I NATURAL PRODUCT REPORTS 1988 A variety of approaches to the synthesis of the cembranes have been explored including the use of the [2,3]-Wittig ring- contraction of cyclic propargylic ethers ; for example (1 66) produces (167).142 Asperdiol (168) and its relatives have been particular target^.^^^^'^^ Agrostistachin (I 69) is a cytotoxic constituent of Agrostistachys hookeri (Euphorbiaceae).145 6.2 Lathyranes and Related Natural Products The structures of the two new lathyranes curculathyrane A (170) and curculathyrane B (1 7I) which were obtained from Jatropha curcus (Euphorbiaceae) have been e~tablishedl~~ by spectroscopic and by X-ray methods. These compounds may be biosynthetic precursors of the tricyclic curcusones [e.g. (1 72)] which were were also isolated147 from this plant. A synthesis of (-)-bertyadionol (I 73) starting from (-)-cis-chrysanthemic acid has been ~ep0rted.l~~ Soft corals of the genus Cespitufaria afford diterpenes of the dolabellane and cembrane skeleta. E~amination’~~ of a further unidentified species has afforded the two cembrane cyclization products (174) (for which the structure was established by X-ray crystallography) and (1 75) and a neodolabellane relative (1 76).The biological activity of the numerous phorbol esters continues to attract attention. Fluorescent esters have been prepared150 to facilitate these studies. oe. \ 1 0 p-& II (162) (163) (166) (167) (168) NATURAL PRODUCT REPORTS 1988-5. R. HANSON 6.3 Taxanes The complex diterpenoid taxol (1 77) is an important cytotoxic and antileukaemic constituent of Taxus brevifolia. Because of its promising anti-cancer activity taxol has been the subject of some careful chemical 152 whilst some new members of the series have also been is01ated.l~~ A 13Cn.m.r.study of taxine B from Taxus baccata has been reported.lS4 There have also been some further synthetic endeavours in this area.155.15s 7 Miscellaneous Diterpenoids Marine organisms continue to provide a wide variety of novel skeletal types. The renillafoulins [e.g. renillafoulin A (178)15’] have an interesting biological activity in preventing the settlement of barnacle larvae on the sea pansy (Renilla reniformis). The related briarene diterpenoids [e.g. ptilo-sarcenone (179) which has been from the sea pen Ptilosarcus gurneyi] have insecticidal activity. The widespread brown marine alga Dictyota dichotoma has been the subject of numerous studies which have afforded a variety of different diterpenoids. A new series of dolabellanes of which (180) is an example has been from collections of this alga from the Indian Ocean.The crenulacetals e.g. (181) are epimeric derivatives that have been obtained from a Japanese collection.lsO Examination of other members of the genus has revealed further structural variations. Thus cervicol (182) was obtained,161 along with a dole~tane,~~~ from 0 (172) (173) Ho,* 0 0’ (1711 + OH (1 74) YHBz ph&co2 -I I mo OH HO 062 HI OAc (177) HO SJq OH A (1751 (176) OAc OAc 0 0 0 (178) (179) \ 7 Me0 OMe ‘OH (180) (181) (182) NATURAL PRODUCT REPORTS 1988 (183) (184) R = H (185) R = OH 0 0 (1881 (189) II0 (1 91) AcO HI OH (1 94) (195) H CO,H &\ H’* @ &-.OH 00 *’ A I -CH20Ac HO*’ H I I OH (198) R = H (200) (196) (197) (199) R = Ac OH HO 6H OH (202) NATURAL PRODUCT REPORTS 1988-J.R. HANSON Dictyota cervicornis whilst the tricyclic compound amijitrienol (1 83) and 14-deoxyisoamijiol (1 84) were from Dictyota linearis. The total synthesis of isoamijiol(1 85) utilizing free-radical cyclization procedures has been reported. 164 Other annulation procedures have also been reported in this The fascioladienal (186) has been obtained166 from the brown alga Dilophus fasciola. Marine sponges have also provided some unusual structures. Gracilin C from Spongionella gracilis has been assigned167 the structure (1 87). Several rearranged spongiane diterpenes [e.g.macfarlandin C (188)168] and aromatic nor-diterpenes [e.g. macfarlandin A (1 89)169] have been obtained from Chromodoris macfarlandi. These structures led to a re-appraisal of the structures that had previously been assigned to dendrillolides A and B. A further spongiane lactone (190) has been from a species of Aplysilla whilst the structure of aplyviolene (191) (obtained’” from the sponge Chelonuplysilla violacea) bears some resemblance to this series. A full paper on the structure of bromotetrasphaerol (192) has appeared.172 A number of new diterpenoids possess prenylated sesquiter- penoid structures. Thus some germacrane diterpenoids e.g. acetoxypachydiol (1 93) have been isolated173 from the alga Pachydictyon coriaceum whilst the hydroazulene derivatives (194)174 and (195)175were obtained from Dictyota dichotoma.Various serrulatane diterpenes e.g. (196) have been ob- tair~ed”~ from Eremophila drummondii (Myoporaceae) and re- lated species. The synthesis has been reported177 of the hydro- carbon biflora-4,1 O( 19) 15-triene (1 97) which forms part of the defensive secretions of termite soldiers. Some new trinervitanes e.g. (198) and (199) have been obtained17* from some New Guinean termites. The verrucosane derivative (200) is a of the liverwort Mylia taylorii. The brown marine algae of the genus Cystoseira produce a number of aromatic compounds that contain diterpenoid substituents. 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Perales Phytochemistry 1986 25 1235. 116 A. Garcia-Granados A. Martinez M. E. Onorato and J. M. Arias J. Nut. Prod. 1986 49 126. 117 A. Garcia-Granados A. Martinez M. E. Onorato and J. San- toro Magn. Reson. Chem. 1986 24 853. 118 J. R. Hanson P. B. Hitchcock and B. L. Yeoh J. Chem. Soc.Perkin Trans. I 1986 639. 119 Y. Ebizuka T. Hakamatsuka E. R. Woo H. Noguchi U. San-kawa S. Seo and A. Itai Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 27th 1985 474 (Chem. Abstr. 1986 104 126 276). 120 M. Katai and H. Meguri Nippon Kagaku Kaishi 1986 1122 (Chem. Abstr. 1987 106 135 218). 121 R. Lorenzi and N. Ceccarelli Phytochemistry 1986 25 817. 122 C. G. N. Turnbull A. Crozier and G. Schneider Phytochemistry 1986 25 1823. I23 M. Koshioka J. Kanazawa and Y. Murakami Agric. Biol. Chem. 1986 50 1899. 124 T. J. Ingram J. B. Reid and J. MacMillan Planta 1986 168 414. 125 J. MacMillan and C. L. Willis J. Chem. SOC. Perkin Trans. I 1986 309. 126 K. S. Albone J. MacMillan A. R. Pitt and C. L. Willis Tetra-hedron 1986 42 3203.127 M. H. Beale J. MacMillan and 1. K. Makinson Tetrahedron Lett. 1986 27 1109. 128 L. Kutschabsky B. Voigt and G. Adam Cryst. Res. Techno/. 1985 20 1157 (Chem. Abstr. 1986 105 227 052). 129 B. M. Fraga M. G. Hernandez and F. G. Tellado J. Chem. SOC. Perkin Trans. I 1986 21. 130 C. G. N. Turnbull A. Crozier L. Schwenen and J. E. Graebe Phytochemistry 1986 25 97. 131 P. R. Birnberg S. L. Maki M. L. Brenner G. C. Davia and M. G. Carnes Anal. Biochem. 1986 153 1. 132 M. Takahashi Y. Kamiya N. Takahashi and J. E. Graebe Planta 1986 168 190. 133 Y. Kamiya N. Takahashi and J. E. Graebe Pfanta 1986 169 524. 134 B. Dockerill R. Evans and J. R. Hanson J. Chem. Soc. Chem. Commun. 1977 919. 135 M. Kobayashi B. W. Son Y. Kyogoku and I.Kitagawa Chem. Pharm. Bull. 1986 34 2306. NATURAL PRODUCT REPORTS 1988-J. R. HANSON 136 V. Lakshmi and F. J. Schmitz J. Nat. Prod. 1986 49 728. 137 B. F. Bowden J. C. Coll. L. Engelhardt G. V. Meehan G. G. Pegg D. M. Tapiolas A. H. White and R. H. Willis Aust. J. Chem. 1986 39 123. 138 P. K. Sen Gupta M. B. Hossain and D. van der Helm Acta Crystallogr. Sect. C 1986 42 434. 139 Y. X. Liu L. M. Zeng and K. M. Trueblood Acta Crystallogr. Sect. C 1986 42 373. 140 K. Koseki F. Saito N. Kawashima and M. Noma Agric. Biol. Chem. 1986 50 1917. 141 V. A. Raldugin S. A. Shevtsov and V. A. Pentegova Zzv. Sib. Otd. Akad. Nauk. SSSR Ser. Khim. Nauk 1985 No. 5 p. 89. 142 J. A. Marshall T. M. Jensen and B. S. Delloff J. Org. Chem. 1986 51 4316.143 J. A. Marshall and D. G. Cleary J. Org. Chem. 1986 51 858. 144 M. A. Tius and A. Fauq J. Am. Chem. Soc. 1986 108 1035 6389. 145 Y.-H. Choi J. Kim J. M. Pezzuto A. D. Kinghorn N. R. Farns- worth. H. Lotter and H. Wagner Tetrahedron Lett. 1986 27 5795. 146 W. Naengchomnong Y. Thebtaranonth P. Wiriyachitra K. T. Okamoto and J. Clardy Tetrahedron Lett. 1986 27 5675. 147 W. Naengchomnong Y. Thebtaranonth P. Wiriyachitra K. T. Okamoto and J. Clardy Tetrahedron Lett. 1986 27 2439. 148 A. B. Smith B. D. Dorsay M. Visnick T. Maeda and M. S. Malamas J. Am. Chem. Soc. 1986 108 3110. 149 B. F. Bowden J. C. Coll. J. M. Gulbis M. F. Mackay and R. H. Willis Aust. J. Chem. 1986 39 803. 150 P. L. Tran M. J. Brienne J. Malthete and L.Lacombe Tetra-hedron Lett. 1986 27 2371. 151 N. F. Magri and D. G. I. Kingston J. Org. Chem. 1986 51 797. 152 D. G. I. Kingston C. Jitrangsri and T. Piccariello J. Org. Chem. 1986 51 3239. 153 C. H. 0.Huang D. G. I. Kingston N. F. Magri G. Samaran-ayaki and F. E. Boettner J. Nat. Prod. 1986 49 665. 154 E. Graf S. Weinandy B. Koch and E. Breitmaier Liebigs Ann. Chem. 1986 1147. 155 A. S. Kende S. Johnson P. Sanfilippo J. C. Hodges and L. N. Jungheim J. Am. Chem. Soc. 1986 108 3513. 156 C. S. Swindel and S. F. Britcher J. Org. Chem. 1986 51 793. 157 P. A. Keifer K. L. Rinehart and I. R. Hooper J. Org. Chem. 1986 51 4450. 158 R. L. Hendrickson and J. H. Cardellina Tetrahedron 1986 42 6565. 159 C. B. Rao R. K. Surapaneni B.W. Sullivan K. F. Albizati D. J. Faulkner C.-H. He and J. Clardy J. Org. Chem. 1986 51 2736. 160 T. Kusumi D. Muanza-Nkongolo M. Goya M. Ishitsuka T. Iwashita and H. Kakisawa J. Org. Chem. 1986 51 384. 161 V. L. Teixeira T. Tomassini and A. Kelecom Bull. Soc. Chim. Belg. 1986 95 263. 162 V. L. Teixeira T. Tomassini B. G. Fleury and A. Kelecom J. Nut. Prod. 1986 49 570. 163 M. Ochi I. Miura and K. Shibata Bull. Chem. Soc. Jpn. 1986 59 661. 164 G. Pattenden and G. M. Robertson Tetrahedron Lett. 1986 27 399. 165 E. Piers and R. W. Friesen J. Org. Chem. 1986 51 3405. 166 C. Tringali M. Piattelli and G. Nicolosi J. Nat. Prod. 1986 49 236. 167 L. Mayol V. Piccialli and D. Sica J. Nat. Prod. 1986 49 823. 168 T. F. Molinski D.J. Faulkner and J. Clardy J. Org. Chem. 1986 51 4564. 169 T. F. Molinski and D. J. Faulkner J. Org. Chem. 1986 51 260 1. 170 T. F. Molinski and D. J. Faulkner J. Org. Chem. 1986 51 11 14. 171 T. W. Hambley A. Poiner and W. C. Taylor Tetrahedron Lett. 1986 27 3281. 172 F. Cafieri E. Fattorusso L. Mayol and C. Santacroce Tetra-hedron 1986 42 4273. 173 M. Ishitsuka T. Kusumi H. Kakisawa Y. Nagai and T. Sato Tetrahedron Lett. 1986 27 2639. 174 S. de Rosa S. de Stefano and N. Zavodnik Phytochemistry 1986 25 2179. 175 T. Kusumi D. Muanza-Nkongolo M. Ishitsuka Y. Inouye and H. Kakisawa Chem. Lett. 1986 1241. 176 P. G. Forster E. L. Ghisalberti P. R. Jefferies V. M. Poletti and N. J. Whiteside Phytochemistry 1986 25 1377. 177 K.A. Parker and J. G. Farmer J. Org. Chem. 1986 51 4023. 178 J. C. Braekman D. Daloze J. M. Pasteels and Y. Roisin Bull. Soc. Chim. Belg. 1986 95 915. 179 L. J. Harrison M. Tori and Y. Asakawa J. Chem. Res. (3,1986 212. 180 C. Francisco B. Banaigs M. Rakba J. Teste and A. Cave J. Org. Chem. 1986 51 2707. 181 C. Francisco B. Banaigs J. Teste and A. Cave J. Org. Chem. 1986 51 1115.

ISSN:0265-0568    

DOI:10.1039/NP9880500211

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Naturally Occurring lsocyanides M. S. Edenborough Dyson Perrins Laboratory University of Oxford Oxford OX 1 3QY" R. B. Herbert Department of Organic Chemistry University of Leeds Leeds LS2 9JT 1 General Introduction 2 Non-Marine Isocyanides 2.1 Introduction 2.2 Xanthocillin-Type Isocyanides 2.3 Cyclopentyl Isocyanides 2.4 Remaining Non-Marine Isocyanides 2.5 Biosynthesis 3 Marine Isocyanides 3.1 Introduction 3.2 Occurrence Structure and Synthesis 3.3 Biosynthesis 4 References 1 General Introduction The first isocyanides were prepared accidentally. For example Lieke in 1859 treated ally1 iodide with silver cyanide expecting to obtain the corresponding cyanide which he wanted to hydrolyse to crotonic acid.However he obtained product (l) with a 'penetrating and vile odour' which after acid hydrolysis gave formic acid (Scheme l).' This unexpected result was explained by Gautier,2 who recognized that isocyanides belonged to a separate class isomeric to nitriles. It is now accepted that the best structural representation for the isocyanide group is structure (2),3 as originally proposed by Lindemann and Wiegrebe in 1930.4 Isocyanides have been the subject of an excellent compre- hensive review. Isocyanides continued to be little more than a curiosity because they were most unpleasant to handle and few methods existed for their effective synthesis. However as advances were made it became possible to synthesize isocyanides more easily and coupled with improvements in manipulation this enabled the fascinating chemistry of the group to be exploited.The isocyanides are unique in that they form the only class of organic compounds which contain a stable formally mono- co-ordinated carbon cf. carbon monoxide. The latter shows particular similarities with isocyanide chemistry in the field of co-ordination complexes. Recently a silicon analogue of the isocyanide group has been prepared5 (Scheme 2). The isocyanide group displays dual nucleophilic/electrophilic character which is often exploited in synthetic applications e.g. a-addition multi-component condensation reaction^,^+'^ in the synthesis of peptides,l' in co-ordination chemistry,l2 l4 organometallic reactions,15 and in carbohydrate chemistry.l6 The unusual character of the isocyanide carbon atom is also reflected in its extreme Lewis ba~icity.~','~ This property was demonstrated when isocyanides provided the first example of a CH-C hydrogen- bond between phenyl isocyanide and phenyl- acetylene.Evidence for the presence of an isocyanide functionality in a compound may come from a variety of spectroscopic and chemi- cal sources e.g. from infrared,20-21 from proton n.m.r.22-24 * Present address :Department of Biochemistry University of Oxford Oxford OX1 3QU. 229 and from carbon- 13 n.m.r. spectr~scopy,~~~~~ from electron- impact mass spectrometry,"~ 28 and from X-ray diffraction.29 The malodorous nature of isocyanides is well known and forms the basis of the Hofmann test for primary amines (Scheme 3).It is possible to hydrolyse isocyanides to forma- mides by using mild acid; it is also sometimes possible to isomerize isocyanides thermally to nitriles without degrading the rest of the molecule. Nickel(I1) chloride forms brown polymers with i~ocyanides,~~ and thus may be used as a developer in thin-layer chromatography as may iodine. There is a sensitive colour test for isocyanide~~~*~~ which has a well- known modification for nitriles. In this manner as little as 0.1 pg of n-butyl isocyanide may be detected. There is a quantitative method for the determination of isocyanides by ultraviolet spectrophotometry.33 Here the isocyanide is hydrolysed to formic acid which after distillation is reduced to formaldehyde and it is the latter which is determined spectrophotometrically.The lower limit for accu- rate determinations is about 20pg of formic acid. The characteristic infrared absorption may be used for quantitative measurements by comparing the isocyanide peak with the C-H stretching band of the solvent (2393 cm-l) in chloroform Isocyanides may also be titrated quantitatively against poly~ulphides~~ or a concentrated aqueous solution of oxalic With respect to nomenclature although 'isocyano' is used as a prefix in IUPAC substitutive nomenclature and in Chemical Abstracts and 'isocyanide ' is used in radicofunctional nomen- clat~re,~~ the name 'isonitrile' has been used sometimes as a generic term by those engaged in research in this field.3 (1 1 Reagents i AgCN; ii H,O+ Scheme 1 + - R-NEC (2 1 PhSiCI I -PhSi(N,),[-R,SiCII T> 700 "C _______)[-4 N21 PhNSi Reagents i R,SiN, AICI Scheme 2 +-RNH A [R-N=CCI,] R-NNC Reagents i KOH CHCI Scheme 3 2 Non-Marine lsocyanides 2.1 Introduction The isocyanides which have been isolated from non-marine natural sources fall into three groups.The first group consists of those isocyanides related to xanthocillin X (3). The members of this group vary in the substitution pattern on the aromatic rings; one compound xanthocillin 2 is of unknown but presumably related structure. The second group is based on the cyclopentyl structures (5) and (6). This group varies in the overall oxidation level of the compounds and the degree of hydration.One metabolite is a spiro-lactone. The last group comprises the remaining non-marine iso- cyanides. One is a modified sugar; another is based on the indole skeleton and the hazimycins are coupled derivatives of tyrosine. 2.2 Xanthocillin-Type Isocyanides In 1948 Rothe isolated the first isocyanide metabolite which was called xanthocillin from a culture of Pencillium notatum We~tling.~* It became apparent however that the xanthocillin antibiotic which was isolated from the mycelia was a complex mixture comprising xanthocillins X Y1 Y2 and Z. The xanthocillin complex has a wide spectrum of antibiotic activity against both Gram-positive and -negative bacteria pathogenic fungi and yeasts.39 The induced resistance of micro-organisms to antibiotics such as the penicillins and sulphonamides was not observed when testing with xanth~cillin.~~ Also xanthocillin was effective against micro-organisms which had experimentally or clinically acquired resistance to penicillins or to sulphon- amides.As xanthocillin is poorly absorbed in the mammalian gut the antibiotic is best applied externally as an ointment to the surface of a wound. Xanthocillin has synergic activity with tyrothri~in.~~ However contrary to tyrothricin xanthocillin has no haemolytic effects. When given in lethal doses it is a neurotoxin. NATURAL PRODUCT REPORTS 1988 The xanthocillin complex could be separated by chromato- graphy on alumina into the X and the Y components.Only traces of xanthocillin Z were ever The precise ratio of the various xanthocillins was quite In order to separate the xanthocillins Y 1 and Y2 polyamide had to be used as the ads~rbant.~~ The structure of xanthocillin X was established as (3) on the basis of degradative studies on the dimethyl ether (4).45,46 Hydrolysis of (4) gave two molecules of formic acid and ammonia (which provided initial evidence for the presence of the isocyanide groups) and the diketone (7). Oxidation of (4) with hydrogen peroxide in acetic acid afforded anisic acid (8) and the imidazole (9). These results and others led solidly through much interesting chemistry to the structure (3) for xanthocillin X which was confirmed by an X-ray analysis of the antibi~tic.~’ Notably the stereochemistry of the double- bonds was secured by this means.Synthesis of (4) was initially attempted48 via the monomer (lo) itself prepared from (1 1). Difficulties in preparing (10) and its instability prevented attempts at dimerizing it.48 An alternative strategy via (1 l) which involved its dimeri~ation~~ with bromine or iodine and alkali was successful (Scheme 4).48.50 The remaining metabolites of the xanthocillin complex in P. notatum are xanthocillins Y1 Y2 and Z. Methylation of xanthocillins Y1 and Y2 gave products the mass spectra of which were similar to (4),which suggested that there is a close structural relationship between X Y 1 and Y2. The presence of isocyanide (rather than cyanide) groups was indicated by infrared spectra and the results of oxidative degradation allowed the structures (12) and (1 3) respectively to be proposed for Y1 and YL51 Mass-spectral analysis of the products obtained from Y1 and Y2 on treatment with diazoethane established that the metabolites isolated from the cultures were free phenols and were not methylated prior to treatment with diazome thane.Xanthocillin Z has appeared only in small amounts if at all. Its structure has not been determined but it may be hypothesized WNCTNC (5) (6) O2kC O NvN H Me0o”1.c Me0 uCozH (9) 0 ii-iv * (4) (1 1) Reagents i KOBu‘ Br or 1,; ii NaBH,; iii POCl, pyridine; iv KOH pyridine Scheme 4 NATURAL PRODUCT REPORTS 1988-M.S. EDENBOROUGH AND R. B. HERBERT 23 I that it is a derivative of xanthocillin X containing extra hydroxyl groups. The xanthocillins (4),(14) and (15) have been isolated from species of Aspergillu.~~~ and (4) has been isolated (along with unrelated metabolites) from Aspergillus cla~atus.~~ Xanthocillin X monomethyl ether (14) has been obtained also from both Dichotomomyces alb~s~~ Dichotomomyces ~ejpii;~~ and this metabolite inhibits the synthesis of prostaglandin H from arachidonic The metabolites (4) (14) and (15) were found to be active against a number of vir~ses.~~,~~ A minor variation in the xanthocillin pattern of structures is found in xanthoascin (16) which was isolated from Aspergillus c~ndidus.~’Xanthoascin was found to exhibit hepato- and cardio-toxicity and teratogenicity in experimental animals.Most curiously a dicyano analogue of the xanthocillins occurs naturally it is emerin (17) which has been isolated from Aspergillus nid~lans.~* The structure for the metabolite followed chiefly from spectroscopic analysis5* and was confirmed by synthesis by following a published routejg which involves base- catalysed condensation of 4-methoxybenzaldehyde with 1,3- dicyanoethane. 2.3 Cyclopentyl Isocyanides The first cyclopentenyl isocyanide to be discovered was dermadin (18). This antibiotic initially called U-21963 was isolated from a soil fungus Trichoderma viride Pers. ex Fries (strain UC 4785).60 The initially colourless crystals of dermadin rapidly darkened on the surface presumably due to polymer- ization or oxidation.The ultraviolet spectrum of dermadin suggested the presence HO NC R (12) R = H (13) R = OH of a double bond conjugated with a triple bond. This was supported by the infrared absorption at 2120 cm-’ which was assigned to an acetylenic group. The metabolite was unstable to acid or base as shown by the irreversible change of its optical rotation under these conditions. It was suggested that dermadin was a monobasic acid (pK 5.05) with molecular formula C,H,N03 and that it possessed an acetylenic group.6L Antibiotic activity could be demonstrated against Gram- positive and -negative bacteria and also against a wide variety of fungi. Dermadin had no activity in vivo against Klebsiella pneumoniae or against Staphylococcus aureus when adminis- tered subcutaneously into mice.However it did inhibit KB tumour cells in vitro.60 The name dermadin was applied first in the patent of 197 I 62 by Coats Meyer and Pyke. The productive strain that was lodged with the patent has the accession number NRRL 3153. Tamura et al. have isolated dermadin and trichoviridin (see below) from strain TK- 1 of Trichoderma k~ningii.~~ After extraction and purification trichoviridin (65 mg dm-3) and dermadin (3 mg dm-3) were isolated. The infrared and ultra- violet spectra were superimposable on those previously reported.60* 61 The structure for dermadin in which an isocyanide group is present was proposed from X-ray studies of the methyl ester.64 The free acid was obtained from Trichoderma hamatum (Bon.) Bain.aggr. (HLX 1360).65 The synthesis of the racemic methyl ester of (18) was achieved by Fukuyama and Yung (Scheme 5);66 this confirmed that the functional group which gives rise to the infrared absorption at 2120 cm-‘ in dermadin is an isocy anide. Dermadin is usually derivatized with diazomethane to form (14) R’ = R2 = H (15) R1 = Me R2 = OMe (16 1 (17) L+hH I Ts C0,Me CH,CO,Me C H2C02Me C H $02Me HO.. HO,\ VI VII CN -o”cNJ+ H COZMe H C02Me C02H C02Me (1 8) Reagents i LiCH,CO,Me; ii NaBH,CN CF,CO,H; iii HCO,H Ac,O pyridine; iv rn-chloroperoxybenzoic acid; v ButOK;vi MsCI Et,N; vii COCl Scheme 5 232 NATURAL PRODUCT REPORTS 1988 the more stable methyl ester.However on standing with excess quality crystal the structure was determined by X-ray analysis diazomethane a dipolar 1,3-addition may take place leading and agreed with that proposed previously. to artefactP7 (see Scheme 6; stereochemistry unknown). This Isonitrin B (21) [cJ trichoviridin (19)] was i~olated'~ from reaction is noticeably faster in the presence of '270' (see below) two strains IMRL 3200 and 3201 which were later identified another isocyanide metabolite often produced by the same as Trichoderma hamatum (Bon.) Bain. aggr. and Trichoderma organism. koningii Oudem. respectively. The LD, for intraperitoneal Interestingly the methyl ester of dermadin loses its methyl injections into mice was greater than 300 mg per kg.The group during electron-impact mass spectroscopy. This was compound inhibits Gram-positive and -negative bacteria and confirmed with the deuteriated ester formed from diazo- its structure was determined by X-ray crystallography. 74 methane and the deuteriated acid.68 Arai et ~1.~~ have recently isolated an isomer of (21) as a Yamano et ~ 1 . ~ ~isolated trichoviridin (19)70 from Tricho- colourless oil from Trichoderma harzianum SANK 12 680 derma viride IF0 8951. This compound was active against (FERM-P 5769). The proton n.m.r. spectrum indicated the Escherichia coli and Trichophyton asteroides. The antibiotic was structural elements of (21) yet the infrared and ultraviolet destroyed by acid or base or by heat. Trichoviridin was also spectra were clearly distinguishable from it ;the new compound isolated63 from T.koningii (strain TK-1). The infrared was called dermanin but no structure was proposed. absorption at 2150 cm-I was assigned to a nitrile group. Another cyclopentyl isocyanide has been reported73 which Nobuhara et aL71 isolated a compound they called 142B was less polar than (21) it has been named compound B (22). from a Trichoderma species; they subsequently identified it as The LD, in mice was 20 mg per kg. Otherwise its biological trichoviridin. Trichoviridin reacted quickly with NaIO ;under activity was similar to (21). The infrared spectrum of compound acidic conditions the reaction proceeded further to give a B matches that given by Fujiwara et al. in a later paper,74 when compound with only two resonances in the proton n.m.r.spectrum viz. 6 = 3.8 and 6 = 8.1 which were both singlets; they assigned this spectrum to a compound called isonitrinic acid F. They gave three possible structures [(23),(24) and (25); the degradation product was suggested to be (20). Several no stereochemistry was implied in the paper] for isonitrinic acid alternative structures for trichoviridin were possible from the F all different from that assigned to compound B (22). The available spectroscopic evidence and so the structure was proton n.m.r. spectrum in the patent73 could be interpreted as determined by X-ray analysis. The absolute configuration was being for the free acid form of the metabolite described by also determined it was found to be structure (19). Brewer et ~l.,~~ in which the structure was assigned as the Ollis et al.isolated trichoviridin during the course of screening methyl ester of one of the three structures proposed by for antibiotic compounds in fungi.72 Eventually using a low- Fujiwara et al. for isonitrinic acid F viz. structure (24). This I - (18) I iii Reagents i CH,N (2 equivalents); ii CH,N (1 equivalent); iii SiO Scheme 6 H H H% NC H02C q N C " O h N C CHO b8' (19) (20) (21) Ho2c-crNc (22) (23) (25) Ho2cWNC H02CdNC (27) (2 8) NATURAL PRODUCT REPORTS 1988-M. S. EDENBOROUGH AND R. B. HERBERT compound has been given the trivial name '270' from the wavelength of the absorption maximum in its ultraviolet $02CH3 spectrum in ether. In all there are two possible exocyclic structures [(24) and (25)] and five endocyclic structures [(22) (23) (26) (27) and (28)] for this compound.Structures (23) (27) and (28) may be eliminated because they do not have a linear chromophore and hence would have a shorter A,, than that observed. Selective n.0.e. experiments (Figure 1)76 provided support for the exocyclic structure (24). Compound '270' has been synthesized (Schemes 7 and 8).77*78 Only +/ CEN Fujiwara et al." seem to have been able to crystallize the '270' acid easily; the methyl ester is not crystalline. However Taylor Figure 1 Numbers refer to n.0.e. enhancements in 'H n.m.r. et aLso have recently formed a stable crystalline derivative of Reagents i N-bromosuccinimide CH,Cl, at 0 "C in the dark ; ii azobisisobutyronitrile (Bu,Sn), heat toluene Bu,SnCH=CHCO,Et ;iii THF H,O AcOH at 25 "C; iv TsCI Me,N CH,Cl, at 0 "C; v 1,8-diazabicyclo[5.4 .O]undec-7-ene CH,Cl,; vi C,D, I,; vii LiOH THF at 20 "C; vii 0.1M HCl added until pH is 34 Scheme 7 0 S H b-%s (ip NHCHO IV (24) "I' "I' C02Me Reagents i BuLi 1,3-dithian HMPA; ii HgCl,; iii Ph,P=CHCO,Me; iv H,NCHO; v COCl, Et,N; vi LiOH THF at 20 "C; vii O.1M HCI added until pH is 34 Scheme 8 NATURAL PRODUCT REPORTS 1988 Ci4'1 -..isonitrin D was deduced from spectroscopic data. Seventy-five strains of Trichoderma species have been examined and a high correlation between the production pattern of isonitrile metabolites and morphological and physiological character- istics has been found.7g Metabolites of Trichoderma species seem to be involved in the aetiology of the widespread root-rot disease caused by the soil-borne fungus Phytophthora cinnamorni Rands.'* This fungus is capable of great variation and hence it may adapt to a wide variety of soils and climates; this makes it extremely important commercially as it may endanger a wide range of crops.Pratt et al. have shown that volatile metabolites from some Figure 2 The structure of the adduct of the methyl ester of '270' strains of Trichoderma koningii induce the production of with bis(~5-pentamethylcyclopentadienyl)bis-~-thiocyanato-~,~-oospores in Phytophthora cinnamorni of the A2 mating type via bis(thiocyanat0-S)dirhodium(m). the methyl ester of '270' with a rhodium complex which was shown by X-ray analysis to have the structure in Figure 2.Two new compounds have recently been found in the culture broth of Trichoderma hamatum HLX 1379.81 The ultraviolet spectrum of the first compound indicated that it was an a/?-unsaturated y-disubstituted lactone and the spiro-lactone structure (29) was proposed for the metabolite. This was confirmed by the synthesis of the same compound (Scheme 9)? The second compound gave a M+-15 peak at m/z 194 (CgH8N04)which was attributed to the loss of a methyl group from an ester (cf-dermadin above). The compound was assigned the structure (30). It was shown that the compound (30) was not derived from (18) during the extraction procedure. Brewer and Taylor have long been concerned with ovine ill thrift,82-85a disease which sheep contract.Grazing on seemingly rich pasture the sheep nevertheless do not thrive. They discovered that in pasture where this disease is common there is a large amount of a Trichoderma species. The secretion of bioactive metabolites from Trichoderma species was well known.86 A detailed study led to the discovery of the presence of the cyclopentyl isocyanides dermadin (18) trichoviridin (19) and '270' (24). These metabolites inhibit the growth of the cellulose-digesting bacteria in the rumen of the sheep and hence are likely to be the cause of ovine ill thrift.87.88 Two other cyclopentyl isocyanides have been isolated74 which are called isonitrin A (31)89 and isonitrin D (32). Isonitrin A was isolated from Trichoderma harzianum Rifai IMI 3208 and from T.hamatum (Bon.) Bain. IMI 3198. The structure of isonitrin A was determined by X-ray analysis while that of a homothallic pathway.'l Rickards et aLg2have identified the volatile metabolites of Trichoderma koningii as homothallin I (33) and homothallin I1 (34). Sakata and Rickardsg3 have synthesized homothallin I1 (Scheme 10). They also found the related amine and the N-formyl derivative in the culture broth; these were suggested to be degradation products as opposed to biosynthetic precursors. There is a possibility that Fujiwara et al. have mis-assigned the structure of isonitrin D (32),74 and it should be the same as homothallin I1 (34). Brasier has also demonstrated the ability of gaseous products of Trichoderma viride Pers.ex S. F. Gray to stimulate some A2 (but not A') isolates of P. cinnamomi to produce homothallic oo~pores,'~ but as yet these products are unidentified. Taylor believes that there is some evidence for the existence of a metabolite that is closely related to the spiro-lactone (29). He has tentatively assigned the structure (35) to this com- pound. 95 Ohsugi et al. have isolated a compound related to dermadin from Penicillium rugosum FERM BP- 142. They assigned the structure (36) to this new which they called Antibiotic No. 2188. 2.4 Remaining Non-Marine Isocyanides There are five remaining non-marine isocyanides that have been isolated from natural sources phenyl isocyanide A32390A B371 and hazimycin factors 5 and 6.The first appears to be an artefact derived during the distillation of denatured rape oils. Aniline and an organic acid reacted to form an amide which then underwent a radical fragmentation to give the isocyanate. This was subsequently deoxygenated by aniline to give phenyl i~ocyanide.'~ In the course of screening of micro-organisms that produce CI NHCHO NC NC I I I Q' CN (29) Reagents i HCI (gas) at -78 "C; ii NH, MeOH at -78 "C then NaOH; iii HC0,Et; iv MeCO,H CHCI,; v COCl, Me,N at 0 "C; vi KOBu' THF at -78 "C; vii pyridinium chlorochromate CH,Cl, at 0 "C; viii (Z)-LiCH=CHCO,Li Et,O at -78 "C then acidify to pH 4.6; ix dicyclohexylcarbodi-imide,EtOAc Scheme 9 OH -HO' '\ HO 0 (30) (311 (32) (331 (34) NATURAL PRODUCT REPORTS 1988-M.S. EDENBOROUGH AND R. B. HERBERT inhibitors for dopamine p-hydroxylase [dopamine p-mono- toxicity are important because amphotericin B which is used oxygenase; E.C. 1.14.17.11 an organism (NRRL 5786) clinically to treat fungal diseases has been reported to have belonging to the genus Pyrenochaeta was identified which some adverse side effects. produced several compounds that inhibited the en~yme.~~,~~ An indoleacryloisocyanide was isolated from Pseudomonas One of these compounds was A32390A which was assigned the structure (37) on the basis of its infrared and n.m.r. spectra and its hydrolysis with methanolic potassium carbonate to yield N- formylvaline and D-mannitol (identified as its hexa-a~etate).~~ The antibiotic (37) has been synthesized via its tetra-0-formyl derivative (38) beginning with N-formyldehydrovaline (39).loo Antibiotic A32390A inhibits dopamine P-hydroxylase non- competitively; its in vitro is 1.7pg ~m-~.A dose-dependent reduction in the norepinephrine levels of the heart and adrenal tissue could be detected in rats after intraperitoneal or subcutaneous administration of A32390A. The antibiotic was also effective at lowering the blood pressure in hypertensive rats when administered parenterally as it lowers the level of catecholamine in the heart and the adrenals. However oral administration was ineffective. Antibiotic A32390A showed activity against a wide spectrum of Gram-positive bacteria. The LD, was greater than 1000 mg per kg (ip.in mice). Antibiotic A32390A is fungistatic in vitro towards the patho- gen Candida albicans.'O' The activity in vivo was affected by poor absorption although its absorption could be greatly improved by forming a solid dispersion with poly(viny1-pyrrolidone) which led to the same activity but from lower doses of A32390A. However the absolute activity could not be raised. The activity in vivo against C. albicans and the low acute .~~~ NCIB 11237 by Evans et ~ 1while screening for antibiotic compounds produced by bacteria. Its production and puri- fication were monitored by assessing its activity against Staphylococcus aureus Oxford H strain VI. After chromato- graphy the active fractions were stored as a methanolic solution because the activity was lost when the solution was taken to dryness.The n.m.r. spectrum of this antibiotic showed the presence of a cis double-bond with one of the vinyl protons interestingly showing a further coupling that has tentatively been attributed to long-range 14N-H coupling with the isocyanide group. The antibiotic called B37 1 was assigned the structure (4O).lo2 B37 1 which is very unstable has been elegantly synthesizedlo3 through the condensation in a key step of indole-3-carbaldehyde (41) with (42) in the presence of sodium bis(trimethylsily1)amide (2 equivalents) as base. This base gave a 3:2 mixture of the (E)-and (Z)-isomers of (40) whereas lithium di-isopropylamide gave the (E)-isomer with only traces of the (2)-isomer (40).Several analogues of B371 have been synthesized.lo3 The antimicrobial activities of these compound^'^^ and of 2-i~ocyanoacrylate~'~~~ lo4(based on A32390A) have been exam- ined. Formylamino-derivatives were inactive so the presence of the isdcyanide group is essential for biological activity. A P-aryl (or heteroaryl) substituent is likewise essential for activity & -fif-(34) t viii vii f--ix vi OHCN OHCN SePh SePh Me0 SePh HZN H H Reagents :i LiNPr', THF HMPA then MeCHO; ii MsCl Et,N; iii 1,5-diazabicyclo[4.3.O]non-5-ene, benzene heat ;iv m-chloroperoxybenzoic acid; v PhSe-; vi NH, EtOH; vii AcOCHO; viii 30% H,O, THF; ix COCl Scheme 10 HO,C INCH0 H O W N C OH (37) R = H (39) (35) (36) (38) R = CHO 0 O\ T C N C QJ-fCHO I1 CN-CH,-P(OEt), H H (40) (411 (42) which is in some cases considerable.Generally compounds with (Z)-geometry of the double-bond are more active than those with (E)-geometry. lo3,lo4 A new class of broad-spectrum antibiotics has been isolated from Micromonospora echinospora var. challisensis SCC 1411.lo5 From a complex of at least six compounds two components were isolated and purified to give hazimycin factors 5 and 6. The structure of factor 5 was determined by X-ray diffraction. Factor 5 has the (R,R)-and (S,S)-stereo- chemistry (43) i.e. it is a racemate. Factor 6 has the (R,S)-configuration (44). These two factors are interconvertible in the presence of water. The hazimycins have been the subject of two syntheses.The first used an enzyme to effect the ortho-coupling of two tyrosine derivatives (Scheme 11). The other started from a commercially available coupled compound and then the side- chains were elaborated (Scheme 12).lo6 2.5 Biosynthesis Inspection of the structures (3) (37) (40) and (43) of the naturally occurring isocyanides discussed thus far leads readily to the hypothesis that they are each derived from the metabolism of amino acids. Such a derivation is obscure for the cyclopentyl isocyanides e.g. (24) but as we shall see they are elaborated from an amino acid tyrosine. It is notable that with the exception of the hazimycins [(43) and (44)] and some cyclopentyl isocyanides all of the isocyanide functions in the metabolites are each conjugated to at least one double-bond.Emerin (1 7) is interesting in that its structure so closely resembles those of the xanthocillins e.g. (4). Whether or not there is any biosynthetic relationship between emerin and the xanthocillins is unknown. ~~-[2-'"C]Tyrosine served as an excellent precursor for xanthocillin X (3) in Penicillium notatum and the activity was confined to the butadiene portion of (3),lo7 By contrast a negligible amount of label was incorporated into (3) when DL-[l-14C]tyrosine was used as the precursor from which it follows that the amino acid is decarboxylated en routeto the xanthocillin and C-1 of tyrosine does not become the isocyanide functions NATURAL PRODUCT REPORTS 1988 OH ~HCHO NHCHO NHCHO 11 iii 1.. AcO OAc +N/ 4 -C Reagents i horseradish peroxidase H,O,; ii Ac,O Et,N ;iii POCI, Et,N; iv NH, MeOH Scheme 11 EtO OEt OHC CHO J of (3).Neither [14C]formate nor ~-[methyl-~~C]methionine which are obvious candidates to provide the isocyanide carbon atoms was significantly incorporated. Label from [1-W]acet-ate was insignificantly incorporated. Although a substantial amount of radioactivity was incorporated from [2-14C]acetate none of the label was present in the isocyanide groups. Streptomyces amakusaensis elaborates tuberin (45) the structure of which resembles those of the xanthocillins [as [(3)]; a similar compound WF-5239 (46) is produced by Aspergillus fumigatus No. 5239.loX It has been shown that the two C units (the N-formyl and the 0-methyl group) in tuberin (45) derive in an orthodox manner by way of C,-tetrahydrofolate metab-olism both C units were labelled by labelled glycine and serine and methyl-labelled methionine labelled the 0-methyl group.109*110 Xanthocillin X monomethyl ether (14) is produced inter alia by Dichotomomyces ~ejpii.~~ The 0-methyl group provides a secure internal check on the incorporation of C,-tetra-hydrofolate intermediates.[2-13C 2-14C]Glycine was well Et /COZEt OHCHN H H NHCHO HO OH OHCHN NHCHO (43)+ (44) Reagents i BBt, CH,CI,; ii PhCH,Br K,CO,; iii CNCH,CO,Et NaH; iv H, Pd EtOH Scheme 12 NHCHO (45) (46) NATURAL PRODUCT REPORTS 1988-M. S. EDENBOROUGH AND R. B. HERBERT eNH2 #OH HO HO \ NHCHO (47) (481 incorporated into (14) but label appeared only in the 0-methyl group as did label from [methyl-13C]methionine (as expected).Neither radioactive formate nor [3-14C]serine labelled the isocyanide groups in (14).l1° It is clear from these results that the isocyanide groups in (14) do not originate from +tetra- hydrofolate metabolism in the fungus D. cejpii. Different results have been obtained for the hazimycins which are produced by a bacterium (see below). Several other compounds were examined as sources for the isocyanide groups in (14) but insignificant incorporations were obtained the compounds were [14C]carbamoyl phosphate [~reido-'~C]citrulline,and potassium [14C]cyanate.1'1 Similar results were obtained with the Trichoderma isonitrile (24) (see below).The origin of the isocyanide groups in di-isocyanoadociane (see Section 3.3) appears to be cyanide ion in a sponge of the genus Amphimedon. With (14) in Dichotomomyces cejpii insignificant incorportions into the isocyanide groups were observed with labelled potassium cyanide with 2-hydroxy-4- methylvaleronitrile (a representative compound for metabolism of amino acids to cyanogenic glycosides or simply a 'protected' form of cyanide ion) and with [2-14C]methionine (C-2 of this amino acid becomes cyanide in the course of biosynthesis of ethylene).'l1 What the origin of the isocyanide groups in the xanthocillins is remains a mystery but it is now well established that the nitrogen atoms like the rest of the carbon framework arise from tyrosine.Results have been obtained for xanthocillin X (3) in Peniciflium notatum112 and for its monomethyl ether (14) in Dichofomomyces cejpii.'" In the latter case comparison was made with the incorporation of 15N from ~~-['~N]tyrosine L-[arnid~-'~N]glutamine, and [15N]ammonium sulphate tyrosine was clearly the best precursor. In the study on the incorporation of [15N]tyrosine into (3) a greater than statistical amount of dilabelled xanthocillin was formed which was taken (with other results) to indicate that (3) is not formed from two identical halves.ll' There is however another possible ex-planation for the non-statistical labelling pattern; it may arise from the manner in which the feeding is carried By use of tyrosine precursors that were chirally deuteriated at C-p it has been that in the formation of the double- bond in (14) the /3(pro-PS)-proton is lost.By contrast in a tuberin (49 which has the opposite geometry of the double- bond the P(pro-PR)-proton is lost [the protons at C-a and the P(pro-PS)-proton are retained in this case so formation of the double-bond occurs by a formal antiperiplanar elimination of a proton and a carboxyl group]. Since 3H-labelled octopamine (47) in contrast to tyrosine was an insignificant precursor for (4) in Aspergilfus clavatus it seems unlikely that hydroxylation of the side-chain is associated with formation of a double-bond in the biosynthesis of the xanth~cillins."~ The diformamide (48) has been isolated from cultures of Penicilfum notatum that produce xanthocillin X (3).l15 The latter compound is not readily hydrolysed to (48) in the cultures; the diformamide appears in the cultures before the di-isocyanide and seems to increase the production of (3) when added to the cultures.This is a tantalizing result which does not tie up with the foregoing discussion; nor does all that has been discovered about the biosynthesis of the hazimycins. As expected hazimycin factor 5 (43) and hazimycin factor 6 (44) are derived from tyrosine."' ~~-~-''C]Tyrosine was well incorporated into the hazimycin metabolites [as (43)] in cultures of Micromonospora echinospora var. chaffisensis and the label was found at C-3' and C-3. [rnethyf-L3C]Methionine was also incorporated if consider-ably less well than tyrosine.Carbon- 13 n.m.r. analysis indicated that the isocyanide groups were labelled (cf. the xanthocillins where C,-tetrahydrofolate intermediates were excluded). This result implies that N-methyltyrosine should be a biosynthetic intermediate but no label from N-["C]methyl-~~-tyrosinewas incorporated into the hazimycins. Further [14C]formaldehyde was not incorporated. The cyclopentyl isocyanides e.g. (24) could a priori arise along a polyketide route that involves ring-contraction of aromatic polyphenols along a route that involves ring-contraction of a derivative of an aromatic amino acid or along a route that involves the modification of a monoterpene. In the event both [2-I4C]- and [1-l4C]-acetate were very poor precur- sors for (24) in Trichoderma hamaturn whereas ~-[U-'~C]tyro- sine was an excellent precursor and was significantly better utilized than was ~-[carboxyf-'~C]phenylalanine or L-[carboxyf- 14C]DOPA; ~-[carboxyf-~~C]tyrosine was also an excellent precursor showing that the carboxyl group of the amino acid is retained in the metabolite."' Incorporation of ~~-[carboxyl-"C]- DL-[P-"C]- ~~-[2,3- 13C2]- and ~~-[3,4,5-'~C,]-tyrosine into (24) and analysis by 13C n.m.r.unambiguously revealed the labelling pattern in the metabolite and the course of biosynthesis that are illustrated in Scheme 13. The cleavage of the aromatic ring seen here has been observed also in the biosynthesis of a number of other diversely different metabolites by metabolism of tyrosine or D0PA.l'' Results of independent experiment~l'~ with 14C- and 'H-labelled tyrosine precursors in T.hamaturn gave (24) that was Tyros ine HO,C I (24) Scheme 13 T 4 HO,C Tyros ine (24) Scheme 14 labelled as shown in Scheme 14 (the two labelled sites that are shown in brackets are probable but were not positively proved). The two sets of labelling results are then in complete agreement. Formally the C,-C metabolites (5) and the C,-C metabolites (6) [E(24)] could be interconverted within their own group by oxidation and hydrolysis. It is possible that the C,-C skeleton is derived from the C,-C skeleton plausibly by decarboxylation of a compound like (24). Alternatively loss of this C unit leading to C,-C2 metabolites may occur following the cleavage of the aromatic ring in tyrosine (cf.Scheme 13); for these metabolites two C units are lost from tyrosine during biosynthesis. The origin of the nitrogen atom in the isocyanide group of (24) was explored in a number of experiments with 15N-labelled compounds (DL-tyrosine N-formyl-DL-tyrosine DL-DOPA N-formyl-DL-DOPA and glycine). In no case was incorporation detected which raises the possibility of a nitrogen-free inter- mediate in bio~ynthesis.~' Several other labelled compounds have been te~ted~'.'~~ as precursors for the isocyanide group in (24); all except [U-14C]glycerol(0.81 YOincorporation ; cf. 5-6 YOfor tyrosine) were incorporated to an insignificant extent barium and sodium [14C]carbonate sodium [14C]cyanide sodium [1-14C]-and [2-14C]-acetate [2-14C]- and [U-14C]-glycine L-[~-'~C]- and ~-[U-'~C]-serine ~-[rnethyl-'~C]methionine ~-[U-l~]lysine ~-[guanido-~~C]arginine, N5-[14C]methyltetrahydrofolate,~-[2-14C]histidine ~-[U-l~C]glutamine L-[U-~-[U-l~C]aspartate 14C]cysteine and ~-[U-~~C]glucose.The biosynthesis of neither the indolic isocyanide B371 (40) nor A32390A (37) has been studied but by inspection the former originates in tryptophan and the latter is formed from valine and D-mannitol. If mannitol was used as the major carbohydrate source when producing A32390A about 25-30% less growth and significantly lower titres of the antibiotic complex resulted. The highest production of A32390A was achieved by using a mixture of glucose and sucrose which may act as a source for ~-mannitol.~~ Ester derivatives of 2-cyano-3-methylcrotonate enhanced produc- tion ;however interconversion to isocyano-substituents or the biosynthesis of any new cyano metabolites (which were not detected) may have occurred.3 Marine Isocyanides 3.1 Introduction The isocyanides that are elaborated by marine organisms form the largest group of naturally occurring isocyanides some two dozen being currently known. The isocyanides are often found as members of triads with the corresponding isothiocyanate and formamide. Where either of the latter two types of compound has been isolated but not the corresponding isocyanide further research should reveal the presence of the isocyanide too since the biosynthetic evidence (Section 3.3) is that the formamides and isothiocyanates derive in vivo from isocyanides.3.2 Occurrence Structure and Synthesis During studies on the metabolites of sponges a series of sesquiterpenoid compounds were isolated from the marine sponge Axinella cannabina. Fresh material was extracted with NATURAL PRODUCT REPORTS 1988 acetone and the ether-soluble fraction gave four series of compounds after extensive chromatography. Each series of compounds contained the isocyanide the isothiocyanate and the N-formyl analogue of the basic skeleton. The series present in the greatest amount was based on axisonitrile-1 (49).121 This was the first marine isocyanide to be reported. Later this structure was confirmed by single-crystal X-ray diffraction studies performed on a derivative of axiso- thiocyanate-1 (50),122the isothiocyanate being a metabolite that was present in small amounts in the original extraction.The derivative was formed by the reaction of axisothiocyanate- 1 (50) with p-bromoaniline. However as only poor-quality crystals could be grown only the relative stereochemistry could be deduced. Yet it was possible to prepare a keto-derivative which was suitable for measurements of its circular dichroism. The ketone was deduced to have the configurations lR 8R,9R and IOS and and the same configurations follow for axiso- nitrile-1. The structural relationship between axisonitrile- 1 and axisothiocyanate-1 was confirmed by the conversion of axiso- nitrile-1 (49) into axisothiocyanate- 1 by treating (49) with sulphur at 120 "C.The corresponding formamide axamide- 1 (51) was isolated in very small am0~nts.l~~ Its structure was deduced from spectroscopic data and confirmed by hydration of axisonitrile- 1 which gave an N-formyl derivative identical to axamide-1 (5 1). Axisonitrile-1 (49) was the first member to be discovered of a new group of sesquiterpenes having the so-called axane skeleton. Since then oppositol a metabolite of the marine red alga Laurencia subopposita has been shown to have the same skeleton.124 A second triad of sesquiterpenes has also been isolated from Axinella cannabina. 123. 125 The spectroscopic evidence indicated that one of the compounds axisonitrile-2 is a sesquiterpenoid isocyanide and that it possesses a tricyclic ~ke1eton.l~~ Reduc-tion of axisonitrile-2 with sodium in liquid ammonia gave a product (56) which was spectroscopically and chromato-graphically identical with the product of hydrogenation of the tricyclic sesquiterpene aromadendrene.However by using g.1.c. it was possible to distinguish two reduction products derived from axisonitrile-2 and from aromadendrene which in each case were evidently epimeric at C-10. It was deduced from this that the isocyanide group is located at C-10 in axisonitrile- 2 which was then assigned structure (52). It is possible that the compounds that can be derived from the reduction of the isocyanide are enantiomers of those derived from catalytic hydrogenation of aromadendrene because the relative ratios of the two epimers were different in the two reactions.Axisothiocyanate-2 (53) could not be isolated pure but only as part of a mixture of at least four components. However after allowing the mixture to react with dimethylamine and further purification it was possible to isolate a thiourea derivative. Spectroscopic evidence was used to deduce the structure of this compound as (55). A synthetic sample of (53) was then shown to be identical (by g.1.c.) with one of the components of the original Axamide-2 (54) was also isolated and was shown to be identical with the hydration product of axisonitrile- 2.123 (49) R =NC (52) R = NC (56) (50)R =NCS (53)R = NCS (51) R =NHCHO (54)R = NHCHO (55) R = NHCNMe2 II S NATURAL PRODUCT REPORTS 1988-M.S. EDENBOROUGH AND R. B. HERBERT A further triad was found to be present in Axinella cannabina in relatively small amounts. A combination of chemical spectroscopic and X-ray evidence led to the structures of these compounds as axisonitrile-3 (57) axisothiocyanate-3 (58) and axamide-3 (59). All are based on the novel 'spiroxane' skeleton. lZ6 (-)-Axisonitrile-3 (57) has been synthesized from (+)-dihydrocarvone by a route which involved reductive (using Li and EtNH,) ring-opening of the vinylcyclopropane (60) to give exclusively (61) as the The natural and the synthetic materials were found to be of opposite rotation from which it follows that the absolute stereochemistry of the natural triad is opposite to that shown in structures (57)-(59).A triad of compounds has been found to be a present in Axinella cannabina in very small amounts that is based upon the dehydroaxane skeleton.128 Axisonitrile-4 (62) had a strong spectroscopic resemblance to axisonitrile- 1 with the notable exceptions of peaks for two new vinylic methyl groups which replaced those of the isopropyl group. The existence of the isothiocyanate-4 (63) present in a complex mixture was demonstrated through the formation of its methylamine adduct. Also a synthetic sample was made from the isocyanide which was identical with one component of the original mixture. The N-formyl compound (64) could not be isolated pure yet its presence was inferred from the fact that synthetic N-formyl compound was identical by g.1.c.with one component of the mixture. Several isocyano-sesquiterpenes have been identified as present in Acanthella acuta (the genera Acanthella and Axinella both belong to the Order Axinellida). The major component acanthellin-I of the mixture obtained by extraction of the sponge showed antimicrobial activity. Its structure was deduced to be (65),with a 4-epi-eudesmane skeleton. The structure (65) was deduced chiefly by lH n.m.r. spectroscopy and by direct comparison of a reduction product (using Li and EtNH,) with the epimeric products obtained by hydrogenation of p-eudesmene.lZ9 Recently acanthellin- 1 has been isolated from Axinella cannabina along with five other related compounds ;130 these form two triads of isonitriles isothiocyanates and formamides.Proton spin-decoupling experiments and an analysis of the coupling constants suggested the structure (68) for the new isocyanide. The stereochemistry of the ring junction was deduced from a n.0.e. experiment. The proton n.m.r. spectrum revealed that the proton at C-6 was a double doublet (J = 11.5 and 5.0 Hz) each line being further split into a 1 :1 :1 triplet (J = 2.5 Hz) by the 14N. Further evidence in support of the structure was achieved by dehydrogenation over palladized charcoal which gave eudalene. The isothiocyanate (66) showed a close relationship with acanthellin-1 (65) from a comparison of their spectroscopic data. This was confirmed by treating acanthellin- 1 with sulphur at 120 "C to give a synthetic isothiocyanate identical to the natural compound.The structure of the isothiocyanate (69) was confirmed in a similar manner. The splitting of the proton at C-6 by the I4N in the isothiocyanate was totally absent leading to a sharp double doublet (6 = 4.09; J = 11.5 and 5.0 Hz). The corresponding formamides were isolated as pure compounds. Acanthellin-1 formamide (67) existed as two rotamers about the formamide group the ratio of cis to trans rotamers being 5:2. The proton n.m.r. data for the cis rotamer were S = 7.99 (d; J = 2.2 Hz) and 8 = 4.88 (bs) and those for the trans rotamer were 6 = 7.77 (d; J = 12.4 Hz) and S = 5.13 (bs) confirmed by spin-decoupling experiments. The form- amide (70) existed almost exclusively in the cis form 6 = 8.08 (d; J = 1.5 Hz) and 6 = 5.30 (bs).The structure of each was confirmed by hydrating the corresponding isocyanide which gave the N-formyl compound identical with the natural product. A richly functionalized tricyclic isocyanoditerpene kali-fractions derived from the extracts of this sponge. Although spectral data were obtained for kalihinol-A its structure could only be solved by X-ray analysis. The 10-methyl group in (71) gave rise to a 1 :1:1 triplet (6 = 1.29; J = 2 Hz) in the n.m.r. spectrum of kalihinol-A due to long-range lH-14N coupling to the isocyanide group. The infrared spectrum showed two isocyanide frequencies at 21 35 and 2100 cm-l. Kalihinol-A exhibited activity in vitro against Bacillus subtilis Staphylo- coccus aureus and Candida albicans but was inactive against Escherichia coli.The activity against C. albicans was used to monitor the purification of kalihinol-A. The second impure fraction was resolved by h.p.1.c. to give kalihinol-E (72) which is epimeric at C- 14 with kalihinol- A and an unprecedented tri-isocyanide kalihinol-F (73).132 Kali- hinol-F showed activity in vitro against B. subtilis S. aureus and C. albicans. Its structure was determined chiefly by X-ray analysis. Two more isocyanides namely kalihinol-B (74) and kalihinol-C (79 were isolated from the mother liquors after HO I (57) R = NC (60) (61) (58) R = NCS (59) R = NHCHO (62 R = NC (65) R NC (68) R = NC (63 R NCS (66) R = NCS (69) R = NCS (64 R = NHCHO (67) R = NHCHO (70) R = NHCHO hinol-A (71) has been isolated from a species of A~anthella.~~~ It was obtained from one of two bioactive chromatographic crystallization of kalihinol-A.Their structures were suggested by comparison of their spectroscopic properties with those of the other three kalihin01s.l~~ In the course of a screening programme directed at the isolation of antimicrobial metabolites from marine sponges the triads (76)-(78) and (79)-(81) have been isolated from ex- tracts of Halichondria species. 133 134 Non-functionalized hydro- carbons were also isolated. The relationships between the members of each triad were provided by interconverting the isocyanides and the formamides and by transforming the iso- cyanides into the corresponding isothiocyanates by heating them with sulphur.The structures for the triad of sesquiterpenes (76>-(78) were established by a combination of spectroscopic techniques and degradative procedures. Two key degradative compounds were obtained namely cadalene (83) (which established the carbon framework) and the ketone (82). The stereochemistry of the latter compound followed from its circular dichroism and its lH n.m.r. spectrum. The formamide (78) could not be obtained pure and was thus purified as its N-methylamino-derivative,prepared by reduction of (78) with lithium aluminium hydride. The isothiocyanates (77) and (80) were obtained as a mixture. The reaction of the mixture with aniline left the severely hindered sesquiterpene (77) unaltered after which separation could be achieved.The structures of the diterpenes followed chiefly from lH n.m.r. analysis of the isocyanide (79). An isocyanodi terpene di-isocyanoadociane (84) has been isolated from a species of Adocia (the sponge is unrelated to those of the Order Halichondrida). The structure was estab- lished chiefly by X-ray analysis.29 It has recently been the subiect of an enantioselective synthesis one outcome of which was to permit the assignment -of absolute stereochemistry as that shown in structure (84).135 The synthesis began with (-)-(1R,2S,SR)-menthol which afforded (91) in three steps. Conventional ketalization of (91) to (92) failed and a new method involving an intermediate P-(phenylse1eno)ethylene ketal was used.Michael addition in the conversion of (92) into Several steps then give the transform this compound isomer. (93) proceeded to served to threo-isomer as the major (93) into (94) which underwent stereospecific internal Diels-Alder reaction to give the trans-fused adduct (95). This compound was then converted into (96) which underwent an internal Diels-Alder reaction and yielded (97) as the major product. This material was then elaborated to (84),which was one of four diastereoisomeric di-isocyanides which were obtained in the last step (Scheme 15). In addition to (84) a further six isocyanides have been isolated as minor components from the same Adocia species.136 The structures of three of these compounds namely (85) (88) and (89) were suggested by spectroscopic data and confirmed by X-ray analysis while the structures for the other three [(86) (87) and (90)] were proposed on the basis of spectral com- parison with (84) (85) (88) and (89).The compound (84) and the mixture of (85H90) had marked activity in vitro against Gram-positive bacteria but no activity in vivo other than marked t0xi~ity.l~~ Another di-isocyanide related to the foregoing compounds namely 8,15-di-isocyanoamphilect-1l(20)-ene (100) (the parent hydrocarbon is amphilectane) has been isolated from Hymeni- acidon amphilecta (Order Halichondrida). Its structure was de- duced chiefly through an X-ray analysis. 13’ The formamide (101) was also isolated; both (100) and (101) gave the same diformamide (102) when they were hydrated and both (100) and (101) inhibited the growth of Staphylococcus aureus Bacillus subtilis and Candida albicans.Isocyanides have provided the answer to a puzzle that has been posed by marine biologists since the early 1960’s. Nudibranchs which are a type of mollusc are often brightly coloured and delicately shaped and all lack an external shell for protection. However they are rarely eaten by predatory fish; their only common predators are other carnivorous NATURAL PRODUCT REPORTS 1988 HI A (76) R= NC (77) R =NCS (78) R = NHCHO R (79) R = NC (80)R = NCS (81) R =NHCHO -* A (82) (83) H r;C l7 \*NC (84) (85) R = CH=CMe (86) R = CH2C(Me)=CH2 (87) R = CH2C(-NC)Me2 a 1 r;c i (88) (89) H (90) NATURAL PRODUCT REPORTS 1988-M.S. EDENBOROUGH AND R. B. HERBERT 24 1 n %02Me %OSi Me2But X (95) X = CH,OSi Me,Bu' (94) (93) (96)X = BzOW n* 0 II - iii iv Bz0 00 I I H Me M H H Me Reagents i LiNPr', at -78 "C; ii methyl (Q-crotonate; iii MeLi (4.8 equivalents) CeC1 (5 equivalents); iv (CF,CO,),O pyridine; v Me,SiCN (1 5 equivalents) TiCl (20 equivalents) Scheme 15 R2 (100) R' = R2 = NC (101) R' = NC R2 = NHCHO (102) R' = R2 = NHCHO opisthobranchs. Thompson138 proposed that there must be some biological mechanism of protection such as undischarged nematocysts or acidic mucus; yet he also found that the skin secretions of some organisms were non-acidic.Further work concerning these non-acidic secretions was done by Johan- ne~,'~~ who showed that a 2% solution of the mucus from the nudibranch Phyllidia varicosa Lamarck 1801 in an aquarium was able to kill several crustaceans when they were placed therein. The mucus was characterized as a volatile relatively heat-stable tasteless material of neutral pH possessing an unusual smell Scheuer and co-workers found that the active principle of the mucus could be milked from the organism by gently squeezing it; however only the first milking produced any significant quantities of the biologically active com-Then by a chance observation the nudibranch was observed feeding upon a species of sponge of the genus Hymeniacidon which after extraction with ethanol yielded the active component in large amounts.141 The active ingredient was isolated.Its infrared spectrum revealed only a strong band at 2120 cm-' which was assigned to an isocyanide group. This assignment of structure was confirmed by the thermal isomerization of the active ingredient to a nitrile (A,, 2250 cm-I) and its acid hydrolysis to a formamide (A,, 1685 cm-l). NPR 5 The ketone derivative (103) could be made from the isocyanide. It did not match any known sesquiterpene ketone however. Recourse was therefore had to an X-ray-crystallo- graphic analysis which was carried out on the derivative (104). The structure (105) was assigned to the isocyanide named 9-isocyanopupukeanane.This metabolite has a novel sesquiter- pene ring system which has been given the euphonic name pupukeanane after the place where the mollusc and the sponge were collected. The isocyanide that was initially isolated by chromatography was a binary mixture (both the proton and the carbon n.m.r. spectrum showed some doubling of signa1s).lg2 However while this mixture proved inseparable by chromatography or com- plexation the derivatives that could be obtained from it consisted of only a single compound. Thus the other compound was being destroyed or it isomerized or was inert. Fortunately after prolonged standing the unknown isomer crystallized from the mother liquor. Its structure was deduced to be (106) following X-ray-crystallographic analysis; that is to say it is the C-2 isomer of the other isocyanide (105).This isomer only underwent two reactions readily ;defunctionalization to form a hydrocarbon and hydrolysis to the formamide. A plausible reason for the extreme inertness of the C-2 isomer is that it is sterically a bisneopentyl derivative. The ketone (103) derived from the C-9 isomer allowed circular dichroism measurements to be taken which showed that the absolute configuration is 1R,3S,5R,6S,7S. It followed that the absolute configurations of the isocyanide groups in (105) and (106) are 9R and 2R respectively. The sponge but not the mollusc contained varying amounts of the two active ingredients and other sesquiterpenoids. Both isomers have been the target of a number of ~yntheses.'~~-'~~ Faulkner et al.,lg8working on the chemical defence of the nudibranch Cadlina luteomarginata reported a series of compounds one of which was an isocyanide Cl,H2,N.On the basis of its spectroscopic data it was assigned the structure (107). The isocyanide could be hydrated to the corresponding formamide the X-ray-crystallographic analysis of which al- lowed the structure (107) for the parent isocyanide to be confirmed. The corresponding isothiocyanate (1 08) was also naturally occurring its structure being deduced from the close similarity of its 'H n.m.r. spectrum to that of (107). Two other isocyanides and two further isothiocyanates of unknown structure were isolated. All six compounds were found not only in this nudibranch but also in the sponge on which it fed which was a species of Axinella.Mixtures of the three isocyanides and of the isothiocyanates were found to be effective as antifeedants against goldfish (1Opg per mg in a food pellet). A novel sesquiterpene theonellin (109) has been isolated from the Okinawan sponge Theonella cf. swinhoei of the Class Demospongia.lg9 The isothiocyanate (1 11) and the formamide (1 12) were also isolated but not the corresponding isocyanide (1 lo) which on biogenetic grounds (see Section 3.3) would be expected to be present. It has however been found to be present in a species of nudibranch of the genus Phyllidia.'50 Further bisabolene derivatives have been found in a species of Ci~calypta'~'and in a Halichondria species,151 these sponges belonging to the Order Halichondrida.The compounds isolated from the former are (1 13)-(115) and a bis(dihydrobisabo1ene)urea and from the latter the C-7 antipodal series (1 16) the isocyanate (1 17) (which is unpre- cedented) and (118). Both (1 10) and (1 18) were found to inhibit the growth of Bacillus subtilis in vitro. Farnesyl isothiocyanate (I I9) but not the corresponding isocyanide has been isolated from the sponge Pseudaxinyssa pitys.152 Five isothiocyanates (epipolasins A-E) together with two thiourea derivatives have been isolated from the sponge Epipolasis kushimotoensis. 153 The structure (120) was deduced for epipolasin B which apart from stereochemistry is that proposed for axisothiocyanate-2 (53). On the basis of differences NATURAL PRODUCT REPORTS 1988 in optical rotation it was suggested that the two compounds are stereoisomers.Similarly the structure (108) was assigned to epipolasin A which has also been assigned to an isothiocyanate isolated from the nudibranch Cadlina lute~rnarginata'~~ (see above). Marked differences in optical rotation indicate that the two metabolites are diastereoisomers; only one can have the stereochemistry shown in (108). (103) R' R2 =O (104)R' = NMeCNHPh R2= ti II S (105) R' = NC R2 = H (106) (107) R = NC (108) R = NCS JJAA k (109) (110) R = NC (111) R NCS (112) R = NHCHO (113) R = &H,CI-(116) R = NC (114) R = NH (117)R =NCO (118) R = NH,CI-+ (115)R = NCS (119) (120) NATURAL PRODUCT REPORTS 1988-M.S. EDENBOROUGH AND R. B. HERBERT 3.3 Biosynthesis The isocyanides which are derived from marine organisms account for just over half of the naturally occurring isocyanides. So far all are either sesquiterpenes or diterpenes. Most of the marine isocyanides are functionalized only by the presence of the isocyanide group (or the related isothiocyanate and formamide groups). The kalihinol group [(71)-(75)] is ex-ceptional in being highly functionalized. As marine isocyanides often occur together with the corresponding isothiocyanates and formamides it is reasonable to conclude that there is a biosynthetic relationship between them. In some cases the corresponding amine e.g.(1 14) is also found naturally and these compounds may also be related biosynthetically.154 It is further reasonable to hypothesize that the isocyanide functionality is derived in vivo by dehydration of an N-formyl group. Clear evidence has been obtained however that this does not occur. Axamide-1 (51) that was labelled with 14C on the N-formyl carbon atom was synthesized and fed to the sponge Axinella cannabina which was maintained in well-aerated sea water.’55 The metabolites were isolated and assayed for radioactivity. Up to I5 % of the activity was recovered in the axamide-1 (51). Some radioactivity was found in the free fatty-acid fraction which indicated that the precursor was taken up by the sponge and metabolized. This also suggests that formamides are genuine metabolites and not artefacts of the extraction procedures.No radioactivity was found in axisonitrile- 1 (49) from which it was concluded that the isocyanide is probably the precursor for the formamide and not the other way round. Samples of 2-isocyanopupukeanane (106) and the corres- ponding isothiocyanate and formamide each with a 13C label on the C,-N substituent were synthesized. They were fed alongside [13C]formate (in gelatine capsules) to a Hyrneniacidon species growing in its natural habitat (this involved SCUBA diving in Shark’s Cove Oahu Hawaii -some people have all the The results showed that no formamide or isothiocyanate was transformed into 2-isocyanopupukeanane (106) and that [13C]formate was not used by the sponge for the biosynthesis of the isocyanide group of (106).On the other hand it could clearly be demonstrated that the isocyanide is the precursor for the formamide and for the isothiocyanate. It seems probable that this is a finding which will be general in marine organisms. The biosynthetic focus moves then to the question of the origin of the isocyanide groups in vivo. Although some of the marine isocyanides bear their isocyanide groups on secondary carbon atoms some have these substituents on tertiary centres. Given that the skeletons of all of them are terpenoid the isocyanide nitrogen must be incorporated at some point from a pathway other than that which leads to the skeleton. Substitution at tertiary centres [particularly and unambiguously for e.g. the isocyanide group at C-7 in di-isocyanoadociane (84)] excludes incorporation by transamination onto a keto- function.It is reasonable then to hypothesize that cyanide is the source of both atoms of the isocyanide groups its incorporation being either by displacement of halogen [cf. the structures of the kalihinols (73) and (74)] or by quenching of a formal carbonium ion which in many cases is formed during the course of the cyclization reactions that lead to the terpenoid skeleton. The correctness of the hypothesis that cyanide ion may be the source for marine isocyanides has been demonstrated very nicely and with experimental aplomb for di-isocyanoadociane (84) in a sponge of the genus Amphimedon.15’ Sodium [14C]cy- anide was found to be specifically incorporated into the isocyanide groups of (84) (1.83 % incorporation after incu- bation for thirty-four days) (cf.non-marine isocyanides Section 2.5). [2-14C]Acetate was not in~orporated’~’ into (84) which is consistent with the report that sponges are incapable of the synthesis of terpenes de novo from acetate.158 There are many novel terpenoid ~keletons’~~ among the Scheme 16 NCCI CI (121) (NCc‘z I I OH (122) (123) NCCIz (124) (125) marine isocyanides. The adociane skeleton in (84) and also in (89) lacks any angular methyl groups. It has been suggested that this formally arises from a single methyl shift associated with a unique cyclization of geranylgeranyl diphosphate (Scheme 16).29The structure of the co-occurring metabolite (88) supports this view’36 and both the metabolite (85) for example and (88) may be taken to represent intermediates on the pathway to metabolites with the skeleton seen in (84).Several carbonimidic dichlorides (1 2 1)-( 125) have been iso- lated from marine natural sources by Faulkner et al.1529159,160 The authors suggest that these arise from the isocyanide by a chlorination reaction. They have found no biological activity for these dichlorides but the corresponding isocyanides do have activity. It may be hypothesized that the chlorination is a protection in vivo of the isocyanide group which may then be readily unmasked to give the active compound when needed. 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Herbert Tetrahedron Lett. 1987 28 4101 ; J. Chem. Soc. Perkin Trans. I 1987 1593. 110 R. B. Herbert and J. Mann J. Chem. Soc. Chem. Commun. 1984 1474. 11 1 K. M. Cable R. B. Herbert and J. Mann Tetrahedron Lett. 1987 28 3159. 112 H. Grisebach and F. Konig Chem. Ber. 1972 105 784. 113 A. Romer and R. B. Herbert Z. Naturforsch. Sect. C 1982 37 1070; R. B. Herbert J. Mann and A. Romer ibid. p. 159. 114 R. B. Herbert and J. Mann Tetrahedron Lett. 1984 25 4263. 115 S. Pfeifer H. Bar and J. Zarnack Pharmazie 1972 27 536.1 16 M. S. Puar H. Munayyer V. Hegde B. K. Lee and J. A. Waitz J. Antibiot. 1985 38,530. 117 J. E. Baldwin A. E. Derome L. D. Field P. T. Gallagher A. A. Taha V. Thaller D. Brewer and A. Taylor J. Chem. SOC. Chem. Commun. 1981 1227; J. E. Baldwin H. S. Bansal J. Chond- rogianni L. D. Field A. A. Taha V. Thaller D. Brewer and A. Taylor Tetrahedron 1985 41 1931. 118 R. B. Herbert ‘The Biosynthesis of Secondary Metabolites’ Chapman and Hall London 1981. 119 R. J. Parry and H. P. Buu Tetrahedron Lett. 1982 23 1435. 120 M. S. Edenborough University of Oxford unpublished work. 121 F. Cafieri E. Fattorusso S. Magno C. Santacroce and D. Sica Tetrahedron 1973 29 4259. 122 M. Adinolfi L. De Napoli B. Di Blasio A. Iengo C. Pedone and C.Santacroce Tetrahedron Lett. 1977 281 5. 123 E. Fattorusso S. Magno L. Mayol C. Santacroce and D. Sica Tetrahedron. 1975 31 269. 124 S. S. Hall D. J. Faulkner J. Fayos and J. Clardy J. Am. Chem. SOC.,1973 95. 7187. 125 E. Fattorusso S. Magno L. Mayol C. Santacroce and D. Sica Tetruhedron 1974 30 391 1. 126 B. Di Blasio E. Fattorusso S. Magno L. Mayol C. Pedone C. Santacroce and D. Sica Tetrahedron 1976 32 473. 127 D. Caine and H. Deutsch J. Am. Chem. Soc. 1978 100 8030. 128 A. Iengo L. Mayol and C. Santacroce Experientiu 1977 33 11. 129 L. Minale R. Riccio and G. Sodano Tetrahedron 1974 30 1341. 130 P. Ciminiello E. Fattorusso S. Magno and L. Mayol J. Org. Chem. 1984 49 3949. 131 C. W. J. Chang A. Patra D. M. Roll P. J. Scheuer G.K. Mat- sumoto and J. Clardy J. Am. Chem. Soc. 1984 106 4644. 132 A. Patra C. W. J. Chang P. J. Scheuer G. D. van Duyne G. K. Matsumoto and J. Clardy J. Am. Chem. Soc. 1984 106 798 I. 133 B. J. Burreson C. Christophersen and P. J. Scheuer J. Am. Chem. Sac. 1975 97 201 ; B. J. Burreson and P. J. Scheuer J. Chem. Soc. Chem. Commun. 1974 1035. 134 B. J. Burreson C. Christophersen and P. J. Scheuer Tetrahedron 1975 31 2015. 135 E. J. Corey and P. A. Magriotis J. Am. Chem. Soc. 1987 109 287. 136 R. Kazlauskas P. T. Murphy R. J. Wells and J. F. Blount Tetra-hedron Lett. 1980 21 315. 137 S. J. Wratten D. J. Faulkner K. Hirotsu and J. Clardy Tetra-hedron Lett. 1978 4345. 138 T. E. Thompson J. Mar. Biol. Assoc. U.K. 1960 39 123. 139 R.E. Johannes Veliger 1963 5 104. 140 G. R. Schulte and P. J. Scheuer Tetrahedron 1982 38 1857. 141 B. J. Burreson P. J. Scheuer J. Finer and J. Clardy J. Am. Chem. Soc. 1975 97 4763. 142 M. R. Hagadone B. J. Burreson P. J. Scheuer J. S. Finer and J. Clardy Helv. Chim. Acta 1979 62 2484. 143 E. J. Corey M. Behforouz and M. Ishiguro J. Am. Chem. Soc. 1979 101 1608. 144 H. Yamamoto and H. L. Sham J. Am. Chem. Soc. 1979 101 1609. 145 G. A. Schiehser and J. D. White J. Org. Chem. 1980 45 1864. 146 E. J. Corey and M. Ishiguro Tetrahedron Lett. 1979 2745. 147 G. Frater and J. Wenger Helv. Chim. Acta 1984 67 1702. 148 J. E. Thompson R. P. Walker S. J. Wratten and D. J. Faulk- ner Tetrahedron 1982 38 1865. 149 H. Nakamura J. Kobayashi Y.Ohizumi and Y. Hirata Tetra-hedron Lett. 1984 25 5401. 150 N. K. Gulavita E. D. de Silva M. R. Hagadone P. Karuso P. J. Scheuer G. D. van Duyne and J. Clardy J. Org. Chem. 1986,51 5136. 151 B. W. Sullivan D. J. Faulkner K. T. Okamoto M. H. M. Chen and J. Clardy J. Org. Chem. 1986 51 5134. 152 S. J. Wratten D. J. Faulkner D. van Engen and J. Clardy Tetrahedron Lett. 1978 1391. 153 H. Tada and F. Yasuda Chem. Phurm. Bull. 1985 33 1941. 154 cf. D. J. Faulkner Tetrahedron 1977 33 1421; Nat. Prod Rep. 1986 3 1; ibid. 1984 1 251 and p. 551. 155 A. Iengo S. Santacroce and G. Sodano Experientia 1979 35 10. 156 M. R. Hagadone P. J. Scheuer and A. Holm J. Am. Chem. Soc. 1984 106 2447. 157 M. J. Garson J. Chem. Soc. Chem. Commun. 1986 35.158 L. Minale in ‘Marine Natural Products Chemical and Biological Perspectives’ ed. P. J. Scheuer Academic Press London 1978 Vol. 1 p. 204. 159 S. J. Wratten and D. J. Faulkner J. Am. Chem. Soc. 1977 99 7367. 160 S. J. Wratten and D. J. Faulkner Tetrahedron Lett. 1978 1395.

ISSN:0265-0568    

DOI:10.1039/NP9880500229

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

The Biosynthesis of C,-C, Terpenoid Compounds M. H. Beale and J. MacMillan Department of Chemistry University of Bristol CantockS Close Bristol BS8 1TS Reviewing the literature published during 1986 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 157) 1 Introduction 2 Mevalonic Acid 3 Hemiterpenoids 4 Monoterpenoids 5 Sesquiterpenoids 6 Diterpenoids 7 References 1 Introduction The format of this year's review has been changed slightly from that of the past few years. An increasing volume of work concerning the enzymes of mevalonic acid biosynthesis is appearing. Most of this concerns the enzymes 3-hydroxy-3- methylglutaryl-CoA synthetase [hydroxymethylglutaryl-CoA synthase ;E.C. 4.1 .3.5] and reductase [hydroxymethylglutaryl- CoA reductase (NADPH); E.C.1.1.1.341 in which there is intense medical and pharmaceutical interest. This work and other aspects of mevalonate biosynthesis is now grouped under the heading mevalonic acid. Even so only papers dealing with enzyme purification enzyme mechanism and the genes coding for these enzymes are reported in detail. There are many clinical- type papers relating enzyme activity to steroid levels. These have not been included. Previous Reports in this series have included separate sections for plant tissue culture genetics biotransformations and chemotaxonomy. These have now been omitted. Where a plant tissue culture was used or the genetics of the biosynthetic step have been examined these aspects are covered in discussion of the biosynthesis of the compound concerned under the relevant section of the classical divisions (C5 Cl0 C15 or C20).The outstanding feature of this year's output is the increased use of purified enzymes in the study of key biosynthetic reactions. The isolation of an enzyme allows rapid progress to be made in the understanding of the stereo- or regio-specificity of the particular step without inputs from other enzymes which may interfere with the analysis of experimental data. As shown in the work on the 3-hydroxy-3-methylglutaryl-CoA enzymes a pure enzyme can now lead rapidly to the gene although in this case the speed of progress has been fuelled by possible medical applications. A cautionary note published by Brown et al.' should be of interest to workers who use deuterium-labelled compounds in their biosynthetic studies.It was shown that deuterium-labelled compounds may separate from their 'H counterparts on both normal and reverse-phase h.p.l.c. and the extent of separation increases with the number of 2H atoms in the compound. Thus to ensure correct 2H:'H ratios the whole h.p.1.c. peak must be collected and analysed. The same effect has been observed on g.l.c. and care must be taken when measuring incorporations of isotopes by gas chromatography-mass spectrometry. 2 Mevalonic Acid Efficient chemical syntheses of (2R)- and (2S)-[2-2H,]mevalonic acid lactone and of (4R)-and (4S)-[4-2H,]mevalonic acid lactone in optical purity of 80-90% and suitable for the preparation of gram quantities have been described.2 Investigation of the biosynthesis of lipids in the aerobic archaebacteria Halobacterium cutirubrum and H.halobium by I3C n.m.r. indicated that not all carbons in phytanyl chains It originated from a~etate.~ was shown that the branch methine-methyl carbon pairs in phytanyl chains and the olefin-methyl pairs in squalene were derived from amino acids particularly lysine whereas the other carbons are from acetate. This led to the conclusions that mevalonate is biosynthesized in these bacteria by condensation of two acetate units and one two-carbon unit from lysine as shown in (1). There has been rapid progress in the molecular biology of 3- hydroxy-3-methylglutaryl-coenzyme-A synthetase (HMG-CoA synthase; E.C.4.1.3.5); this is the enzyme which catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA as shown in Scheme 1. A cDNA for the enzyme was isolated from a line of hamster ovary cells that are resistant to compactin which is an inhibitor of HMG-CoA reductases. These cells produce large amounts of mRNA for both HMG-CoA synthase and HMG-CoA reductase (NADPH). The cDNA (3.3 kilobase) was sequenced; its identity was confirmed by comparison of the N-terminal amino-acid sequence (predicted from the nucleotide sequence) with that of purified enz~rne.~ A peptide was synthesized in which the amino-acid sequence matched that predicted by the cDNA. The antibodies that were raised against this peptide were shown to precipitate HMG-CoA synthase from liver cytoplasm.In a second paper,5 the 32P-labelled cDNA was used to probe for the gene for hamster HMG-CoA synthase. This gene which spans 20 kilobases was isolated and characterized. In studies with rats HMG-CoA synthase was purified to Br/J ::oA ( 1 1 0 from lysine from acetate 0 II CH3C-CoA + I P; C0,t -I 0 0 A&\ \ CH,CCH,C II-CoA u SCoA II 7 "5 CozH HO Enzymes i hydroxymethylglutaryl-CoA synthase ;ii hydroxymethyl-glutaryl-CoA reductase (NADPH) Scheme 1 247 homogeneity from liver cytoplasm.6 The enzyme which is a dimer with a subunit mass of 53000 was partially sequenced from the N-terminus. Antibodies to the enzyme were used to screen for cDNA clones; these were isolated and used to localize the human HMG-CoA synthase gene to chromosome 5..~ Leonard et ~ 1 have also localized this gene to chromosome 5 i.e. the same chromosome as carries the gene for HMG-CoA reductase (NADPH). The use of a cDNA clone encoding hamster HMG-CoA reductase (NADPH) led to the isolation of two genes from baker's yeast (Succhuromyces cerevisiue).8 These genes HMGl and HMG2 encode proteins with sequence homology to the C-terminal half of the hamster protein. It was shown by analysis of enzyme activity in hmgl-and hmg2-mutants of baker's yeast that at least 83% of the activity was contributed by HMGl in the wild-type yeast. Dugan and Katiyar' have inactivated both yeast and rat HMG-CoA reductase (NADPH) by affinity labelling with (4-bromo-2,3-dioxobutyl)-CoA (2).Inactivation was attributed to the reaction of (2) with a cysteine residue in the active site. An active-site histidine residue was also inferred but the involvement of an arginine or a serine residue was ruled out. Hydroxymethylglutaryl-CoAreductase (NADPH) has now '~~~~ been purified from plant sources. Bach et ~ 1 . solubilized the enzyme from a heavy membrane fraction that had been obtained from homogenates of radish seedlings. It was purified (350-fold) by chromatography on DEAE-Sephadex A-50 and on blue dextran-agarose and affinity chromatography on HMG-CoA-hexane-agarose. The apparent molecular weight of 180 000 was made up of subunits of mass 45 000. Interestingly antibodies to yeast or to rat liver enzyme failed to bind to the radish enzyme or to inactivate it.The apparent K,, for (8-HMG-CoA was 1.5 pmol dm-3 and for NADPH was 27 pmol dm-3. Other data indicated that the mechanism involves binding of HMG-CoA before NADPH. Purification of HMG-CoA reductase (NADPH) from potato tubers has also been reported.12 This was also achieved by affinity chromatography on HMG-CoA-hexane-agarose. The molecular weight was estimated to be 110000 with a subunit of 55000 and the apparent values of K of 16.4 pmol dmP3 for (9-HMG-CoA and 25 pmol dmP3 for NADPH are similar to those of the radish enzyme. A partial purification of this enzyme from the leaves of Parthenium argentatum has been described.13 In this case the enzyme from the cytosol and that from chloroplasts were different in that K for cytosolic enzyme was 250pmol dm-3 while that of chloroplastic enzyme was 18 pmol dm-3.The values for NADPH were 310 pmol dm-3 for cytosolic and 420 pmol dm-3for chloroplastic enzyme. Other investi- gations of HMG-CoA reductase activity have been carried out for Halobacterium h~lobium'~ and the alga Ochromonas malhamensis.l5 New inhibitors of HMG-CoA reductase (NADPH) that were reported during the year include methylcyc1ohexanolsl6 and numerous synthetic analogues of c~mpactin.l~-~~ The rat liver enzyme was thought to be modulated by cholesterol 7a-mono-oxygenase. However evidence has now been presented against this.21,22 There are many more papers dealing with modulation and inhibition of HMG-CoA reductase (NADPH) by known inhibitors and even by insulin and ascorbate.These are beyond the scope of this review. 3 Hemiterpenoids The conversion of mevalonate 5-diphosphate (MVAPP) (3) into isopentenyl diphosphate (IPP) (4) by mevalonate- 5- diphosphate decarboxylase [diphosphomevalonate decarboxyl- ase; E.C. 4.1.1.3.31 utilizes ATP and produces ADP and inorganic phosphate. It is known that the oxygen atom at C-3 of MVAPP ends up in this inorganic phosphate. This conversion has been studied by Iyengar et uZ.,~~who used the enzyme from chicken liver and stereospecifically labelled adenosine (SJ-5'- O-(y-thio[P,y-,u-"O, y-l7Ol,y-1801]triphosphate) (5) in place of ATP. They found that the inorganic [1701 l8Ol]-NATURAL PRODUCT REPORTS.1988 thiophosphate that was produced had the (R,) configuration corresponding to overall inversion at phosphorus (see Scheme 2). This indicates that there is a direct enzyme-mediated reaction between the oxygen at C-3 of MVAPP and ATP rather than the alternative mechanism (involving initial transfer of phosphate from ATP to the enzyme and then on to MVAPP which would lead to retention of configuration at phosphorus). Isopentenyl-diphosphate A-isomerase which catalyses the interconversion of IPP (4) and dimethylallyl diphosphate (DMAPP) (6) has been to 90% homogeneity from the fungus Claviceps SD58. The enzyme which has a molecular weight of 35000 (cf. 22000 for hog liver enzyme) was purified by chromatography on blue trisacryl DEAE-cellulose Sepha- dex G-100 and DEAE-trisacryl and has a requirement for Mg2+ and a pH optimum of 6.0-8.5.It is inhibited by inorganic diphosphate and by alkyl diphosphates such as farnesyl di- phosphate and geranyl diphosphate indicating that the diphosphate group is important in substrate binding. Most bacterial cells including Escherichia coli do not appear to take up mevalonate or isopentenyl diphosphate. However .~~ Fujisaki et ~ 1 have reported that re-hydration of lyophilized E. coli cells with phosphate buffer that contained 14C-labelled IPP resulted in 14C label appearing in ubiquinones and polyprenols. The uptake and the incorporation of 14C-labelled IPP were increased when either geranyl diphosphate or farnesyl diphosphate was included in the re-hydration buffer.The compartmentation of synthesis of IPP in plant cells has been reviewed.26 The activities of several enzymes including a dimethyallyltransferase in soybean roots that had been infected with zoospores of Phytophthora megusperma have been mea~ured.~' The activity of this enzyme which is specific for the biosynthesis of the phytoalexin glyceollin was shown to increase considerably if the plant was infected with incompatible strains of the fungus whereas infection with compatible strains had no effect on enzyme levels. Suga et aL2* have extended their earlier work on the S 17 ADP-0-P II ADPJ70-H + II 16 P-0 (6) r 1 'OH -'n (7) NATURAL PRODUCT REPORTS 1988-M. +CH,,@ I fOH H.BEALE AND J. MACMILLAN process requires loss of tritium from C-1 of geranyl diphosphate. The three allylic diphosphates were also shown to interconvert in cell-free extracts of Mentha spicata by a non-redox process without loss of tritium from C- 1. In competition experiments the incorporation of 3H-labelled linalyl diphosphate (14) was directly compared with that of 14C-labelled geranyl diphosphate and [14C]neryl diphosphate. In both intact plants and cell-free systems linalyl diphosphate was incorporated faster than neryl diphosphate which itself was converted faster than geranyl CH,O@ 6 stereochemistry of the elimination of the prochiral hydrogens at C-4 of mevalonate during the formation of the (a-and (2)-prenyl chains in malloprenols [tritrans,polycis-polyprenols](7).Their results obtained with (4R)- and (4S)-[2-14C 4-3Hl]- mevalonate and with (2,s)- and (2R)-[4-14C 2-3H,]isopentenyl diphosphate clearly show that the 4(pro-4S)-hydrogen of mevalonate [ =2@ro-2R)-hydrogenof IPP] is eliminated during the formation of both the E-and the 2-double-bond of the polyprenol chain. The authors claimed in their earlier paper (in 1983) that this was the first example of the formation of a 2-double-bond by loss of a mevalonoid 4(pro-4S)-hydrogen. This claim now appears to have been dropped in the light of protestations from Banthorpe et al.29 However the authors are continuing to discuss their results in relation to a 'rule ' that loss of the 4(pro-4S)-hydrogen leads to E and of the 4(pro-4R)- hydrogen leads to 2 configuration.As pointed out in reference 29 there is no obligatory correlation between the prochirality of loss of a proton at C-4 and the geometry of the double-bond that is formed. 4 Monoterpenoids The biosynthesis of irregular monoterpenes such as chrysan- themyl alcohol (8) and artemisia ketone (9) has been the subject of much debate. Boulton et aL30 have tested the hypothesis that homoallylic alcohols such as (10) may be involved in the biosynthesis of (8) and (9). They synthesized "C-labelled samples of the alcohols (10) and (1 1) and incubated them with an enzyme preparation from Arternisia annua; this system is known to produce artemisia ketone (9) from IPP via chrysan-themyl alcohol (8).Neither (10) nor (1 1) was incorporated into artemisia ketone. Thus neither was converted into trans-chrysanthemyl alcohol and there is no support from these results for a homoallylic mechanism for the formation of a cyclopropane. The nature of the acyclic allylic diphosphate precursor to cyclic monoterpenoids has also been extensively researched. This and other aspects of the biosynthesis of cyclic monoterpenoids in particular enzymology has been re-viewed.31 Suga et al.32 have continued their investigations of the interconversion and cyclizations of geranyl diphosphate (1 2) neryl diphosphate (1 3) and linalyl diphosphate (14) in intact plants and in cell-free extracts. Feeding (4R)- and (4S)-[2-14C 4-3H,]me~alonate to several plants and analysis of the 3H:14C ratios confirmed that the 4(pro-4S)-hydrogen is eliminated in diphosphate.Thus further confirmation of the involvement of teriary allylic diphosphates in the biosynthesis of cyclic terpenoids was obtained. OH Croteau et al.33 used partially purified enzyme preparations (11) (12 1 when they examined the cyclization of geranyl diphosphate to (+)-bornyl diphosphate (15) in Salvia oficinalis and to (-)-O@ bornyl diphosphate (16) in Tanaceturn vulgare. The hypothesis I \/ that these cyclizations proceed via the respective (-)-(3R)- and (+)-(3S)-linalyl diphosphate (as shown in Scheme 3) has been Salvia Tanocet urn O@ O@ I I ( -1 -( 3R 1-L PP (+)-(3S)- LPP 1 1 @0- 1 1 -0@ & 3 @O 1 & -$@1 III H A the condensation of IPP and DMAPP.There was no loss of tritium from [2-14C 5-3Hl]mevalonate or from [ l-"C l-3H,]-neryl diphosphate or -1inalyl diphosphate when these were incorporated into cyclic monoterpenoids. This indicated a non- redox process in the biosynthesis. A previously proposed redox Scheme 3 (16) tested. A mixture of (3R)-[8,9-14C]linaly1 diphosphate and (1 E,3RS)-[ l-3Hl]linalyl diphosphate (3H:14C= 5.2 :1) was in- cubated with the two cyclase preparations. The borneol that was isolated from the T. vulgare system had a 3H 14C ratio of > 31 :1 indicating that there had been almost exclusive use of the 3H-labelled (3S)-enantiomer as predicted. The borneol from the S. oficinalis system had a 3H:14C ratio of 4.16 :1 indicating a preference for the 14C-labelled (3R)-enantiomer but also an ability to utilize the 3H-labelled (39-enantiomer.In separate incubations with T. vulgare (3S)-linalyl diphosphate geranyl diphosphate and neryl diphosphate all gave optically pure (-)-( 1S,4S)-bornyl diphosphate (16) ;(3S)-linalyl diphosphate was the best substrate (yel/Km= 224) followed by geranyl diphosphate (V,,,/K = 100) and neryl diphosphate (V,el/Km= 26). In a similar experiment with S. oficinalis the best substrate was (3R)-linalyl diphosphate (V,,JK = 487) to give (+)-(1 R,4R)-bornyl diphosphate (1 5). However this preparation could also convert (3S)-linalyl diphosphate (V,,,/K = 25) into (-)-( 1S74S)-bornyl diphosphate (16). Thus although the cyclase from T. vulgare is enantioselective that from S.oficinalis can catalyse the cyclization of both enantiomers of linalyl diphosphate. In an attempt to uncouple the isomerization and the cyclization of geranyl diphosphate by the cyclase of S. oficinalis Wheeler and Crotea~~~ studied the metabolism of the non-cyclizable analogue 6,7-dihydrogeranyl diphosphate (17). The products of the incubation were acyclic terpene olefins and alcohols and were qualitatively similar to the products of chemical solvolysis of 6,7-dihydrolinalyl diphos- phate although the enzymic product contained more olefins. In terms of pH optimum requirement for metal ions and other characteristics the enzymic reaction of the analogue resembled that of the normal substrate. It was concluded that the analogue was first isomerized as normal to the linalyl diphosphate analogue which after ionization of the diphos- phate group could not cyclize.Therefore the cation was either captured by water or deprotonated. Croteau has also that 2-fluorogeranyl diphosphate (1 8) and 2-fluorolinalyl diphosphate (19) are competitive inhibitors of the cyclization of geranyl diphosphate by several different cyclases in S.oficinalis. The rate of conversion of (18) and (19) was at least two orders of magnitude less than the rate of cyclization of geranyl diphosphate. The inhibition was shown not to be the result of irreversible inactivation of the enzyme. It was suggested that the electron-withdrawing fluorine atom suppresses ionization of the allylic diphosphate group.In a similar study,"' the sulphonium analogues of the presumptive carbo-cations (20) and (21) were shown to be inhibitors of S. oficinalis cyclases. The observed inhibition was more effective with increasing substrate concentrations and also in the presence of inorganic diphosphate. In another noteworthy publication the (-)-a-pinene cyclase of s. oficinalis has been to catalyse the conversion of geranyl diphosphate into a-pinene camphene limonene and myrcene in a medium consisting of hexane with a minimal amount of water (0.1 to 10 YO).The enzyme showed the same characteristics in this solvent as it does in water and was in fact more stable with respect to temperature and time. The biosynthesis of (+)-pulegone (25) from (-)-isopiper- itenone (22) could occur via piperitenone (23) or (+)-cis-isopulegone (24) as shown in Scheme 4.Croteau and Venkata~halam~' have used both leaf discs and enzyme preparations of Mentha piperita to show that the pathway through (+)-cis-isopulegone (24) is the correct one. The enzyme responsible for the reduction of the enone double-bond of (23) was partially purified and had a M of 60000. Enzyme activities for the isomerization of (22) to (23) and of (24) to (25) were not separable by gel-filtration chromatography although (24) isomerized faster than (22). Several papers dealing with the biosynthesis of the iridoid glucosides have appeared during the year. in which 10-hydroxy[1-3H]geraniol (26) and 9,1O-dihydroxy[ 1-3H]- geraniol (27) were fed to several species indicated that the NATURAL PRODUCT REPORTS 1988 pathway to iridotrial (30) and hence to loganin (31) proceeded via iridodial (28) rather than the alternative route via (29) as shown in Scheme 5.Using cell cultures of Gardenia jasminoides the biosynthesis of tarennoside (32) and gardenoside (33) was to occur via 8-epi-iridodial (34) 8-epi-iridotrial (33 and 7,8-didehydroiridotrial glucoside (36). The involvement of iridodial (28) or 8-epi-iridodial (34) in the biosynthesis of iridoid glucosides seems to be dependent on plant type. In Galium mollugo G. spurium and Deutzia crenata deoxyloganic acid (37) has been shown40 to be a precursor of various iridoid glycosides. Using suitably labelled mevalonate Akhila41 has shown that citronella1 (40) is biosynthesized in Cymbopogon winterianus from geraniol (38) via citronellol (39).A detailed study of the regioselectivity and deuterium isotope effects in the 8-hydroxylation of geraniol (38) to give 8-hydroxygeraniol (41) by a cytochrome P-450 mono-oxygenase from Catharanthus roseus has been published.42 Using a preparation of microsomes from etiolated seedlings a 35 YO conversion of (38) into (41) as a single product was achieved. Incubation of [9-13C]geraniol with the enzyme gave (41) and the [9-13C]geraniol that was recovered contained no 13C at C-8 Me I 2 (23) A ( 24) Scheme 4 NATURAL PRODUCT REPOXTS 1988-M. H. BEALE AND J. MACMILLAN 251 '" +OH (26) OH (281 J (29) Scheme 5 HO CHO HI HO C0 MeHI OGlc @OH OGLc ~ OGIc (32) (33) (34) R=CH3 (371 I104r0H5 (35) R=CHO 9 8 OH (38) (39)RtCH20H 9 8 (LO) RrCHO ( .= '3c ) Scheme 6 demonstrating that there was no scrambling of carbons 8 and a mixture of [9-13C 8,8,8-2H,]geraniol and [9-13C]geraniol with 9 during the enzymic hydroxylation.The intramolecular isotope the enzyme was surprisingly k,/k = 0.5 at low conversion. It effect for abstraction of hydrogen [(k,/k,)i,,,] was calculated was suggested that this inverse isotope effect indicated the to be 8.0 by incubating [9-13C 8,8-2H2]geraniol with the enzyme existence of other rate-contributing steps before the first and determining the ratio of [9-I3C 8,8-2H,]-(41) to [9-13C 8-irreversible isotope-sensitive reaction (hydrogen abstraction).2H,]-(41) by n.m.r. spectrometry (see Scheme 6).However the Further investigations of the genetic control of the formation intermolecular isotope effect that was measured by incubating of monoterpenes and the composition of those terpenes have been published. Analysis of the ratios of perillaketone (42) to isoegomaketone (43) in plants that had been produced by intercrossing two chemotypes of Perilla frutescens led to the conclusion that levels of (43) are controlled by an inhibitor gene that suppresses the isomerization of egomaketone (44) to (43).43In a wider study of the same species the chemical genetics of several groups of monoterpenes and also phenyl- propanoids was It was concluded that chemical composition is controlled by multiple alleles (GI G, and g) and an independent pair of alleles (H and h).The presence of either G or G is essential for the biosynthesis of monoterpenoids while the homozygous recessive (gg) plants produce phenyl- propanoids. Lincoln et aL4 have examined monoterpenoids in Mentha citrata x M. aquatica hybrids. The dominant gene Is was shown to prevent almost entirely the formation of 2-or 3-substituted p-menthones and a general scheme was presented to hypothesize the position of action of gene Is and the other genes that control the formation of monoterpenoids in Mentha species. Many plants when grown in tissue culture do not produce secondary metabolites. Banthorpe et have examined ~1.~~9~’ callus and suspension cultures of several species which produced negligible amounts of monoterpenes.Cell-free extracts of callus or suspensions were shown to convert mevalonate and isopentenyl diphosphate into geranyl neryl and farnesyl diphosphates at rates up to 400-fold greater than those in enzyme extracts from parent plants. Possible explanations’ for the non-accumulation of terpenes in cultures which appear to have the necessary enzymes were discussed. The rapid oxidative metabolism of geraniol by cultures of Rosa damascena indica-ted4’ that the terpene precursors could be degraded as soon as they were produced possibly because of the absence of storage structures within the undifferentiated tissue. The plant growth regulators Phosfon D and Cycocel were 0 CO H \ CO H (45) NATURAL PRODUCT REPORTS 1988 shown to increase the yield of essential oils of Saivia oflcinalis and Mentha ~iperita.~’ Some changes in the composition of the oils were also observed as a result of these treatments.Leucoplasts of Citrofortuneila mitis and Citrus unshiu have been prepared and shown to produce geranyl diphosphate and monoterpene hydrocarbons when supplied with isopentenyl diphosphate and dimethylaliyl diphosphate in the presence of Mn2+49 The bio transformation of monoterpenoids by Pseudomonas species has been reviewed.,O The biotransformation of 3,333-tetramethyl-limonene and of p-menth-I -ene by Gibberella cyanea and other and of trans-sobrenol in ratss3 has been reported. Enantioselective hydrolysis of bornyl acetate by cell cultures of Nicotiana tabacum has been demon~trated.,~ 5 Sesquiterpenoids Weinstein et al., have used cultured chick liver cells to show that the C, side-chain of haem a (45) is formed from mevalonate via the isoprene pathway.This had previously eluded experi- mental confirmation for a variety of reasons including difficulties in the separation of haem a from its immediate tetrapyrrole precursor protohaem (46). If a reverse-phase h.p.1.c. system was used (45) and (46) were cleanly separated. 5-Amin0[4-~~C]laevulinicacid was incorporated into both protohaem and haem a but [2-14C]mevalonic acid was incorporated only into haem a demonstrating that mevalonic acid is utilized intact in the biosynthesis of the side-chain. Some key papers concerning the isomerizationxyclization of farnesyl diphosphate (FPP) (47) to trichodiene (49) which is the parent hydrocarbon of the trichothecanes have appeared.Cane and Ha,,‘ using an enzyme preparation from Tricho-thecium roseum have demonstrated for the first time the conversion of nerolidyl diphosphate (48) into trichodiene. They (44) CO H \ CO,H (46) FPP (L7) (481 (49) NATURAL PRODUCT REPORTS 1988-M. H. BEALE AND J. MACMILLAN (47) H H (L9) Scheme 7 CH,OA c 15 (50) R = OC(0)CH2CHMe2 (51) Rs H describe the synthesis of (la-[ 12,l3-14C2 I-3Hl]nerolidyl diphosphate and have shown (by degradative methods) that when it is incorporated into trichodiene the tritium is located at the 1lp-position.In an elegant experiment that was designed to show that nerolidyl diphosphate is a true intermediate between farnesyl diphosphate and trichodiene the authors carried out a competition experiment feeding 3H-labelled FPP and 14C- labelled nerolidyl diphosphate. By measuring the 3H/14C ratios in trichodiene and also in the farnesol and the nerolidol that were recovered in aliquots that were taken at intervals from the incubation mixture it was concluded that the two allylic diphosphates compete for the same cyclase with negligible release of free intermediates. Interpretation of the results is hampered by the presence in this cell-free system of an isomerase which catalyses the conversion of FPP into nerolidyl diphosphate. However calculation of the ratio of apparent values of VmaX/K,,,revealed that for the cyclase nerolidyl diphosphate was some 1.5 to 2.0 times better as a substrate than FPP.It was concluded that the formation of trichodiene from FPP involves isomerization to (3R)-nerolidyl diphosphate which cyclizes via an anti-boat conformation as depicted in Scheme 7. This enzyme trichodiene cyclase has now been purified by Hohn and VanMiddle~worth,~’ to greater than 95 O/O homogeneity from Fusarium sporotrichioides. This was achieved by a combination of hydrophobic-interaction anion- exchange and gel-filtration chromatography. The enzyme is a dimer with a subunit of M 45000 and requires Mg2+. Maximum activity was observed between pH 6.75 and 7.75 with K, for FPP of 0.065 pmol dm-3.This accomplishment will now enable comparative kinetic experiments with FPP and nerolidyl diphosphate of the type described above to be made without the interference of other enzymes. In another paper from the same laboratory an investigation of the oxidative elaboration of trichodiene to T-2 toxin (50),using cultures of F. sporotrichioides that had grown in the presence of H2180 or 1802 is described. It was shown by mass spectrometry that the oxygen atom at position 1 and those in the 12,13-epoxy-group and the hydroxyl groups at C-3 C-4 C-8 and C-15 were all derived from molecular oxygen.5s In a useful application of the cytochrome P-450 mono-oxygenase inhibitor ancymidol Van- Middlesworth et al.59 have suppressed the biosynthesis of the diacetoxyscirpenol (51) in Gibberella pulicaris with the con- comitant accumulation of trichodiene which is normally only ( 531 present in trace amounts.When the fungus was grown in solid culture on converted rice in the presence of ancymidol trichodiene was obtained in a yield of 202 mg per kilogram of rice. The essential oil of Arternisia pallens contains the furanoid sequiterpenes davanone (52) and artemone (53). Feeding studies in intact plants have been carried out with [2-14C,5,5-3H2]- and [2-14C,2,2-3H2]-mevalonic acid.60 Davanone (52) retained all six tritium atoms arising from C-5 of mevalonate but lost one of those arising from C-2. Another tritium atom from C-2 of mevalonate was located at C-7 of davanone by base-catalysed exchange.The authors accounted for these observations in a biogenetic pathway via nerolidyl diphosphate and invoked an X-group mechanism for the formation of davanone (Scheme 8). No evidence for this mechanism was presented. A more FPP 1 03 X Enz Enz A i T T (T=tritium atom from C-2 of mevalonatel Scheme 8 plausible mechanism not considered by the authors is via a 6,7-epoxide (54) the oxygen of which then becomes part of the furan ring. The irregular sesquiterpene artemone (53) similarly retained all mevalonoid 5-hydrogens and lost one of those arising from C-2. These results ruled out the (very unlikely) route involving shifts of the two methyl groups at C-1 1 in nerolidyl diphosphate to C-9. Instead they proposed a novel route (Scheme 9) involving the condensation of isopentenyl diphosphate with dimethylvinylcarbinol diphosphate (55); this led to (56) which then underwent the same X-group trans- formations as proposed for davanone.However it was conceded that the isotope ratios that were observed could be equally accommodated in a scheme that involves the formation of the cyclopropyl intermediate (57) thereby obviating the need to involve dimethylvinylcarbinol diphosphate. -9 DMA PP (55) DMAPP J. 1 + (56) (531 Scheme 9 NATURAL PRODUCT REPORTS. 1988 Investigations into the biosynthesis of the tetracyclic ses-quiterpene quadrone (58) and the related terrecyclic acid (59) in cultures of Aspergillus terreus have continued.Cane et aL6' have reported results of feeding [ 1-13C]acetate [13C,]acetate and [3,4-13C,]mevalonate to the fungus. It was confirmed that the cyclization of FPP to yield ultimately quadrone involved the cleavage of the farnesyl 6-7 double-bond (derived from a 3-4 bond in mevalonate). To account for these observations and those made recently by other groups the cyclization mechanism in Scheme 10 was proposed. The regulation of the enzymes that are involved in the biosynthesis of pentaleno- lactone (60) in Streptomyces arenae has been examined.62 Activities of HMG-CoA reductase isopentenyl-diphosphate A-isomerase dimethylallyl- and geranyl-transferases and farn- esyl-diphosphate cyclase were assayed in cell-free solutions that had been prepared from cultures at different stages of production of pentalenolactone.Of the enzymes that were tested only farnesyl-diphosphate cyclase controlled the levels of pentalenolactone. End-product inhibition of this enzyme by pentalenolactone and its derivatives but not by pentalenone or humulene was also demonstrated. The biosynthesis of gossypof (6 1) in Gossypiurn arboreum has been re-investigated using [13C,]acetate.63 The labelling pattern in apogossypol (62) which was prepared chemically from the 0 H0,C A. @O P-$j$ 1 t + I I * NATURAL PRODUCT REPORTS 1988-M. H. BEALE AND J. MACMILLAN mixture of gossypol and its methyl ethers that was produced in The biogenesis of rishitin (65) which is the noreudesmane the biosynthetic experiment can only be rationalized in a phytoalexin of potato is now known to occur by a double pathway that involves 2-cis,6-trans-farnesyl diphosphate (or rearrangement of the eudesmane cation (63) through the nerolidyl diphosphate) and not from 2-cis,6-cis-farnesyl vetispirane hydroxylubimin (64) as shown in Scheme 12.diphosphate (as previously proposed) ;see Scheme 1 1. Stoessl and StotherP4have examined the possibility of a similar *:02H 0 0 (60) - 13. 13.CH3=CO2 - + 0 2-cis ,6 -trans -FPP OMe met hylat i on (61) Me0 HO 2 (62) Scheme 11 2 -frans 6 -trans -FPP + 12 A (65) Scheme 12 NATURAL PRODUCT REPORTS 1988 route for the biosynthesis of aubergenone (66) and other related eudesmanes in the eggplant (Solanurn rnelongena).If [1-13C,2H3]acetate was fed to the plant there would be ‘H at C-5 of the eudesmane cation (63) if a similar route is followed. The intermediacy of a vetispirane requires a shift of this deuterium to C-4. In the event the incorporation of label into aubergenone (66) was too low for its position to be investigated by 2H or I3C n.m.r. spectrometry. However a new metabolite aubergenol (67) was identified and characterized. The 2H n.m.r. spectrum of (67) revealed that deuterium atoms were present at C-3 and C-5 but absent from C-4. Thus it appears that aubergenol (67) and aubergenone (66) are normal eudesmanes and are not produced via vetispirane inter-mediates. Rishitin (65) is metabolized in vivo to the side-chain- hydroxylated compounds rishitin M-1 (68) and rishitin M-2 (69).Murai et al.65 have prepared and fed (-)-[12,12-2H2]- rishitin to Solanurn tuberosurn x S.dernissurn and have used 2H n.m.r. spectroscopy to examine the samples of (68) and (69) that were produced. It was shown that while (68) arose from direct hydroxylation of (65) (69) retained one 2H atom at C-12 but the other was located at C-11. This unprecedented stereospecific 1,2-shift of a hydrogen atom on an isolated double-bond did not occur via the epoxide (70) which was isolated and re-fed to the plant; the diols (71) were produced. The fungus Marasmius alliaceus produces the sesqui terpene lactone alliacolide (72). Avent et have prepared 14C-labelled specimens of the 4-deoxy-compound alliacide (73) and fed them to the fungus.They demonstrated that alliacide is incorporated into (72) in 38% yield and also into .12- hydroxyalliacolide (74) in 9 % yield. Thus the 4-hydroxyl group of alliacolide is introduced by direct hydroxylation rather than by a route that involves the intermolecular opening of a 4,Sepoxide by a 13-carboxylate. Cantharidin (75) is a poisonous defensive substance in blister beetles (Cantharidus obtectus) and although apparently a monoterpene is produced by degradation of a farnesyl skeleton. CH2 ( 68 ) R = CD7L (72) R’=OH R*=H (73) R’=R~=H (74 I R’=R*= OH CDZOH Very little is known about the conversion of the C, precursor into cantharidin. McCormick et ~1.~’ have now shown (by labelling studies using leg2and H2180) that the tetra-hydrofuranyl oxygen and two of the anhydride oxygens are derived from molecular oxygen and the third anhydride oxygen is derived from H,O.It was postulated that the biosynthesis of cantharidin from farnesoic acid or methyl farnesoate may involve juvenile hormone I11 (76d) which was suggested to be a juvenile hormone in these beetles. 31-Fluoromevalonate is known to inhibit the biosynthesis of juvenile hormones in Lepidoptera. Therefore male blister beetles were fed 3l-fluoromevalonate and the cantharidin content was shown68 to be much lower in treated beetles than in untreated or mevalonate- treated controls. The term ‘chemical disarmament ’ was introduced to describe this effect. A similar study of the effect of insect growth regulators (juvenile hormone agonists and antagonists) including 31-fluoromevalonate on the levels of juvenile hormones in Manduca sexta has been carried Jones et al.” have completed a detailed kinetic analysis of juvenile hormone esterase which is an important regulator of the levels of juvenile hormones in the moth Trichoplusia ni.They concluded that at least two forms of active sites existed in the esterase. The site with the higher affinity had K in the range 42-85 nmol dm-3 for JH I (76 b) JH I1 (76c) and JH I11 (76d) while the K of the lower-affinity site for these three substances was in the range 400-760 nmol dm-3. These results may require a re-evaluation of the current single-site model for juvenile hormone esterase in this and other insects.Proposals on the nomenclature and revision of the numbering system of (+)-(5‘)-abscisic acid (ABA) and its metabolites have been published.’l The new numbering system is shown in structure (77). The biosynthesis and metabolism,i2-i3 the biological activity,i3 and factors effecting the molecular recognition7‘ of ABA have been reviewed. A remarkable of the presence of ABA in brains of pig and rat awaits confirmation. In two studies of the biosynthesis of ABA in R3 R2 R’ V R’ JH 0 (76a) Et JH I (76b)Me R2 Et Et R3 Et Et JHII(76c) Me Me Et JH IU(76d) Me Me Me (75) OH (77) (79) NATURAL PRODUCT REPORTS 1988-M. H. BEALE AND J. MACMILLAN fungal systems there have been attempts to inhibit its production by adding plant growth regulators.Hirai et uI.,~~ working with Botrytis cinerea found that maleic hydrazide (2-chloroethy1)- trimethylammonium chloride (CCC) and zeatin inhibited the production of ABA while AMO- 161 8 and 4-ethoxy- I-(p-toly1)- s-triazine-2,6-dione (TA) stimulated it. No accumulated meta- bolites were identified in inhibited cultures. However the l ’,4’-trans-diol (78) was isolated from untreated cultures and shown to be incorporated efficiently into ABA when re-fed in labelled form. Norman et using Cercospora rosicola found that the plant growth regulators paclobutrazol ancymidol and decylimidazole all inhibited the production of ABA. Experi- ments with 14C-labelled farnesyl diphosphate led to the conclusion that ancymidol blocked the biosynthesis of ABA before FPP and paclobutrazol and decylimidazole blocked it after FPP.However no build-up of radioactive intermediates between FPP and ABA was detected. In higher plants where the indirect pathway via the breakdown of xanthophylls (C,,) is currently favoured new studies have adopted a similar approach in that blockage of the biosynthesis of carotenoids should lead to a deficiency of ABA. Neil1 et have measured the levels of carotenoids and ABA in wild-type and viviparous (vp) mutants of Zea mays. Mutants vp-2 vp-5 vp-7 and vp-9 were deficient in both xanthophylls and ABA. However vp-8 had normal carotenoid content but reduced levels of ABA. Although the absence of carotenoids was apparently linked to reduced levels of ABA it was concluded that ABA deficiency could be associated with abnormal development of plastids because chlorophyll levels were also low in the carotenoid- deficient mutants.Gamble and Mullet7s have achieved caro- tenoid deficiency without any effect on plastids by treating barley seedlings with fluridone which inhibits the desaturation of phytoene. Treated plants when water-stressed accumulated very little ABA compared to controls. This suggested that there is a direct link between carotenoid content and the ability of a plant to produce ABA. A decrease in the levels of anthera- xanthin violaxanthin and neoxanthin that accompanies an increase in levels of ABA in dehydrated fluridone-treated plants was consistent with these xanthophylls being precursors to ABA.In studies on the metabolism of racemic (&)-ABA by leaves of Xanthium strumarium Boyer and Zeevaartso have identified a new metabolite as ( -)-( 1’R)-7’-hydroxyabscisic acid (79). This compound results from the metabolism of the unnatural (-)-(1’R)-isomer of ABA. It was suggested that this 7’-hydroxylation of (1’R)-ABA is catalysed by the same oxygenase that converts natural (1 ’5‘)-ABA into 8’-hydroxy- abscisic acid (80) and hence into phaseic acid. Another study of the metabolism of (+)-ABA has concerned its biotrans- formation by cell suspensions of Lycopersicon esculentum.81 An analysis of the intracellular distribution of 14C-labelled (+)-ABA and its metabolites showed that its P-D-glucopyranosyl ester and other glucosides were located only in the vacuoles whereas the other acidic metabolites were extravacuolar.The promising antimalarial compound artemisinin (qing- haosu) (8 1) is arousing some biosynthetic interest although no definitive investigations of the pathway have yet been .~~ published. Liersch et ~1have analysed specimens of Artemisia annua from several sources. The levels of artemisinin varied from 0 to 0.1 YO.Artemisia apiacea was also found to contain this compound (0.08 YO).Treatment of plants with the growth regulator chloromequat was found to increase the levels in A. annua by 30%. Tissue cultures of A. annua have been repor- teda3 to produce artemisinin ;cell suspensions yielded 8 mg dm- in the culture filtrate.It has been ~uggested,~ on the basis of a biomimetic photo-oxygenation that quinghao acid (82) may be a biogenetic precursor of (8 1). Halogenated chamigrene sesquiterpenes are found in algae of the genus Laurencia and in the sea hares which feed on them. Sakai et ds5have isolated and characterized (by X-ray crystallography) several new examples of these compounds from the sea hare Aplysia dactylomela. Two of the compounds [(83) and (84)] are remarkable in that they are enantiomeric to HI II 0 (81) HI $x 0 (8R I 9R) (63)R=H (el)R=OAc those previously isolated. Consequently a new biogenetic pathway (Scheme 13) has been proposed involving the cyclization of FPP to a cyclohexenyl cation with either the S or R configuration at the junction of the cyclohexene ring with the aliphatic chain.These cations are then fixed to the enzyme surface by either their si or their re face thus giving four possible configurations. The naturally occurring enantiomeric structures can now all be accounted for by further elaboration of ring A and chlorobromination of the 8-9 double-bond in the appropriate conformer as shown in Scheme 13. There are reports in other papers of the g.c.-m.s. analysis of sesquiterpene hydrocarbons that have been obtained by feeding [31,31,31-2H,]me~alonate to callus tissue of Perilla species,86 the effect of light on the accumulation of sesquiterpenes in sunflower seedling^,^' and biotransformations of guaiane-6,12-diol (85) to (86) by Phaseolus aureuss8 and of several sesquiterpenes by hydroxylation in rabbits.8s Investigations into the biosynthesis of meroterpenoids which arise from a mixed polyketide-terpenoid pathway have continued.Scott et dS0 described the synthesis of ethyl 3,s- dimethylorsellinate (87) that was doubly labelled with 13C and l80at the carbonyl group C-7 and both C-6 and its attached hydroxyl group. Incorporation of (87) into the meroterpenoid austin (88) in Asper-gillus ustus was examined by 13C n.m.r. which showed isotope shifts for C-6’ and C-8’. This indicates their derivation from 3,5-dimethylorsellinate. Similar experi- ments with (87) and also with 1802 and [l-13C 1802]acetate in Aspergillus variecolor revealed the origins of all of the oxygen atoms in andilesin A (89).s1 6 Diterpenoids A marine sponge of the genus Amphimedon elaborates the novel tetracyclic diterpene di-isocyanoadociane (90).Garsong2 has shown that the carbon atoms of both isocyanide groups arise from cyanide ion. This is in contrast to other known biosyntheses of isocyanides from the corresponding amine and a C fragment that is derived from for example methionine. It was suggested that the isocyanide groups were introduced by capture of cyanide ion by the carbonium ions that form during the cyclization of geranylgeranyl diphosphate (GGPP). 14C-Labelled acetate was not incorporated into (90) as has been observed for terpenes that are produced by other marine sponges. It is thought that sponges are incapable of synthesis of terpenes de novo from acetate but do elaborate precursors that are transferred at a C or C level to them from symbiotic bacteria and algae.Two further papers regarding the enzymology of biosynthesis of casbene (91) (Scheme 14) in castor bean (Ricinus communis) NATURAL PRODUCT REPORTS 1988 / / or S R I C1 Me (€1 Scheme 13 H H Q Q OH co CH,OH OH a. OH 0K (87) -(88) (89) from orsellinate * )t from 0 A A from CH,CO,- NATURAL PRODUCT REPORTS. 1988-M. H. BEALE AND J. MACMILLAN CGN 5% (90) MVA-5-PP & IPP ,-$+ DMAPP GGPP &ai IV (91) Enzymes i diphosphomevalonate decarboxylase ; ii isopentenyl-di- phosphate A-isomerase ; iii geranyltranstransferase ; iv farnesyl- transtransferase ;v casbene synthetase Scheme 14 have been published by West and co-workers.In the first paper,93 activities of mevalonate-5-diphosphate decarboxylase farnesyl-diphosphate synthase [geranyltranstransferase; E.C. 2.5.1 . lo] geranylgeranyl-diphosphate synthase [farnesyl-transtransferase ; E.C. 2.5.1 .29] and casbene synthetase were measured in cell-free extracts of castor bean seedlings both in controls and in those that had been infected with the fungus Rhizopus stolonifer. It was found that the rate of conversion of mevalonate into isopentenyl diphosphate was not altered by fungal infection. However the activities of farnesyl-diphos- I GG PP T phate and geranylgeranyl-diphosphate synthases and casbene synthetase were considerably increased in infected plants.Subcellular localization of these enzymes identified FPP synthase and isopentenyl-diphosphate A-isomerase in pro- plastids of both infected and control cells. Geranylgeranyl- diphosphate synthase and casbene synthetase were only detected in proplastids of infected cells. It was concluded that these last two steps of casbene biosynthesis are induced by fungal infection and that the enzymes responsible are located in the proplastids. In the second paper,94 geranylgeranyl-diphos- phate synthase was purified (400-fold) from infected seedlings. The enzyme which was obtained by fractional precipitation with ammonium sulphate and chromatography on Sephadex- DEAE A-25 and then on hydroxyapatite has a molecular weight of ca 72000; it requires Mg2+ and has a pH optimum of 8-9.The best substrates were farnesyl diphosphate (K 0.5 pmol dm-3) but the enzyme would also accept geranyl diphosphate (K 24 pmol dm-3) with isopentenyl diphosphate. Dimethylallyl diphosphate was not a substrate contrary to other (less well characterised) prenyltransferases from higher plants. The eluate from the Sephadex-DEAE A-25 column contained one peak of geranylgeranyl-diphosphate synthase activity well separated from two peaks of farnesyl-diphosphate synthase activity indicating that the syntheses of FPP and GGPP are catalysed by different proteins. The stereochemistry of the formation of the exocyclic methylene function in ent-kaurene (92) has been examined by Coates et ~l.,~~ who used mevalonate that contained a chirally labelled methyl group.The chemical synthesis of phenyl (R)-and (,!+acetate that contained a chiral methyl group (CHDT) and from then (3lR)- and (31S)-[31-2H1,31-3H1]mevalonate, is described. The incorporation of both (3lR)- and (31S)-[31-2H, 31-3H,]mevalonate into ent-kaurene (92) in a cell-free extract from seeds of Marah macrocarpus has been examined (Scheme 15). Chemical degradation of the 16-17 bond of the kaurene product yielded samples of chiral acetate which were examined by an enzyme chirality assay and compared with acetate that had been obtained by hydrolysis of the starting phenyl (R)-and (S)-[2Hl,3Hl]acetate. Although there was some loss of optical purity there was overall retention of configuration indicating that the methyl-methylene elimination had occurred with an endo orientation as indicated in Scheme 15.Two reviews of the chemistry biosynthesis and metabolism of the gibberellin plant hormones (GAS) have been published. One contains some useful tabulations of physical and analytical data.96 The other summarizes the current situation regarding the biosynthesis enzymology and mode of action of gibber- ell in^.^' The biosynthesis of gibberellins in vegetative shoots of Pisum sativum (pea) and of Zea mays (maize) and probably in * (92) Scheme 15 many other higher plants is shown in Scheme 16. It is believed that gibberellin A (GA,) is the only compound of this pathway that has intrinsic biological activity (i.e.causes stem elonga- tion). Precursors to GA show activity because they are metabolized to GA within the plant. Gibberellins A, and A and their catabolites are inactive. These conclusions are based on extensive metabolic and bioassay studies in which a range of single-gene dwarf mutants of pea and maize were used. This work in maize has been reviewed recently by Phinney et ul.98.99 The biosynthesis of gibberellins beyond gibberellin A, aldehyde has also been summarized by Graebe.lo0 As a consequence efforts in this field are now concentrated on investigating the operation and control of this pathway and its relationship to plant growth. As the levels of gibberellins in plants are very low (nanograms per gram of plant tissue) it is thought that immunological methods will be of use in the investigation of the biochemistry of this pathway.With this in mind several groups have begun programmes to prepare monoclonal antibodies to various gibberellins. Eberle et ~1.'~' have described a monoclonal antibody which recognizes gibberellin A,. However this antibody in common with other polyclonal antibodies to gibberellins that have been prepared by this group and by other groups requires esterification of the carboxyl group C-7 for binding (for numbering see GA in Scheme 16). Knox et dlo2 have overcome this problem by preparing antigenic gibberellin-protein complexes that are linked through C-3 or C-17. Using these conjugates a panel of monoclonal antibodies which recognize different structural MVA __j GGPP + fl @ \\ t \ OH CHO CO H CO,H L GA, aldehyde 1 20 4 + @ GdH CO H CO H C0,H GA 53 NATURAL PRODUCT REPORTS 1988 features of the gibberellin molecule including the free carboxyl group (C-7) have been prepared.These antibodies are useful for the radioimmunoassay of gibberellins but their future application in the immunoaffinity purification of metabolities on a physiological scale should be rewarding. Using similar chemistry at C-17 probes for studying the biosynthesis of gibberellins and their mode of action have been prepared.Io3 These include photoaffinity labels and Sepharose-linked gibber- ellins for the isolation and investigation of enzymes and receptors. The partial purification by classical methods of a gibberellin 2P-hydroxylase activity from seeds of Pisum sativum has been described.lo4 This enzyme which converts the active compound GA into the inactive gibberellin A (Scheme 16) is a dioxygenase and requires 2-oxoglutarate Fe2+,and ascorbate.It has a molecular weight of 44000 and a pH optimum of 7.4-7.8. The rate of 2P-hydroxylation by the enzyme purified by chromatography on DEAE-cellulose and by gel-filtration chromatography was different for gibberellin A (V,, = 6.95 pmol h-' mg ')and gibberellin A,o( V,,, = 24.8 pmol h mg-l). Some evidence indicating that these conversions are catalysed by two different proteins was presented along with a discussion of the role of this enzyme(s) in the maintenance of steady-state levels of bioactive GA,.Chung and Coolbaugh'Oj have examined the conversion of [2-14C]mevalonate into ent-kaurene in cell-free extracts from different parts of both normal and dwarf pea seedlings. Their results indicated that the biosynthesis of ent-kaurene was at a ( -Kaurene ( 92) 1 C02H 20 GA 19 GA20 GA 29 1 -0H GA 8 Scheme 16 NATURAL PRODUCT REPORTS 1988-M. H. BEALE AND J. MACMILLAN 26 1 maximum in young expanding tissue. This is consistent with previous reports that shoot tips and young leaves are the primary sites of biosynthesis of gibberellins. The biosynthesis of kaurene in elongating internodes was greater in normal than in dwarf plants but the levels in young leaves were greater in the dwarfs.The mechanism of the loss of C-20 in the formation of the C,,-gibberellins is not known. Kamiya et a1.1°6 have examined this problem by feeding GA, aldehyde that was labelled at C- 20 with "C to a cell-free system from Pisum sativum. They showed that "CO was formed at an equivalent rate to the C,,- gibberellins. Neither [14C]formic acid nor [14C]formaldehyde was detected. In control experiments [14C]formic acid released '.'CO at much lower rates than those observed from GA, aldehyde leading to the conclusion that C-20 is lost directly as CO, and not as HC0,H which subsequently decomposes to CO,. In discussion the authors point out that any mechanism now has to account for this and for several other previous observations viz. (i) the immediate precursor of the lactonic C, compounds is the C-20 aldehyde not the C-20 carboxylic acid; (ii) both oxygen atoms of the lactone arise from the carboxyl group C- 19; and (iii) no loss of hydrogen occurs from c-1.The biosynthesis of gibberellins in a cell-free system from seeds of Phaseolus vulgaris has been in~estigated,'~' using gibberellins that were labelled with radioisotopes and with stable isotopes. The conversions that were observed are shown in Scheme 17 and contain two primary pathways these being the 13-hydroxy pathway (Scheme 16) and the non-hydroxy pathway to gibberellin A,. 13-Hydroxylation could occur at any step of the pathway to GA although it was pointed out that this may not be the case in vivo. No 2P-hydroxylating activity was found in these preparations.This was surprising as intact seeds and cotyledons from germinating seeds contain a 2P-hydroxylase. A similar cell-free system from seeds of Phaseolus coccineus has been shown1os to operate the early part of the pathway (Scheme 16) from mevalonate to gibberellin A, aldehyde. Metabolism of ,H-labelled gibberellin A in seedlings of the same plant gavelo9 GA, GA, and GA glucosyl ester and the glucosyl ethers of GA, GA,, and GA,. Ingram et al.ll* have studied the quantitative relationship between the conversion of GA, into GA and internode growth in plants of Pisum sativum that contain the dwarfing genes nu and le (which block the biosynthesis of gibberellins). The le mutation is at the conversion of GA, into GA while the nu mutation blocks the biosynthesis of gibberellins at an early step.In plants that contain the na Le genotype gibberellin A, was converted into gibberellin A thirty times faster than in those of the na le genotype. The le mutation is 'leaky' in that low levels of gibberellin A and its metabolites were detected from gibberellin A, that had been fed to the plants. Measurement of levels of gibberellin A (which is the immediate metabolite of gibberellin A,) in feeds of GA, to both genotypes showed that there is a linear relationship between internode growth and the log of the concentration of gibberellin A,. Thus growth appears to be directly related to the levels of GA, confirming that GA is the only gibberellin that is active per se in stem elongation.Reid and Potts"' have described three further internode-length mutants of pea. Two of these (lh and Is) appear to possess reduced gibberellin biosynthesis whereas the other (lk)is a gibberellin-insensitive mutant. Another interesting aspect of the control of the biosynthetic pathway to gibberellins (and hence of internode growth) is the effect of light. Sponse1112 has examined stem elongation in tall (Le Le) and dwarf (le le) forms of P. sativum in darkness and in continuous red light. Internode length in both the le le and Le Le form was the same in the dark indicating that the le mutation does not operate in the dark. This was confirmed by bioassay and by feeding gibberellin A, to the plants which caused stem elongation of the le le form in the dark but not in red light.Gibberellin A, was metabolized to GA, GA, GA2, and their catabolites when both tall and dwarf plants were grown in darkness. In the light 3P-hydroxylation of GA, was observed in tall but not in dwarf lines. Campell and Banner" have carried out similar experiments with the same cultivars and came to the conclusion that the deficiency in 38-hydroxylation of GA, to GA in le le genotypes is due to phytochrome-induced suppression of gibberellin 3P-hydroxyl- ase. Spinach (Spinacia oleracea) grows as a rosette plant if exposed to short days but it grows a stem when it is transferred to a regime of long days. It is known that on transfer to long days the level of GA, decreases suggesting that photoperiod regulates the conversion of GA, into the C,,-gibberellins (see Scheme 16).Gilmour et ~1.l'~ have examined the biosynthesis of gibberellins in cell-free extracts from leaves of spinach plants that were grown under long and short days. Under long days the pathway GA, +GA, -+ GA, -+GA, (Scheme 16) was found to operate. The enzymes that carry out these conversions require 0, Fez+ 2-oxoglutarate and ascorbate. It was found that the activities of the enzymes that catalyse the conversions GA, +GA, and GA, -+GA, are increased in long days and decreased in short days. The conversion of GA, into GA, was uninfluenced by photoperiod. The G genetic line of Pisum sativum undergoes senescence when transferred from short to long days. Davies et al.115examined the metabolism of "C-labelled GA, aldehyde in shoots of long- or short-day plants.The metabolites were identified by their retention time on h.p.1.c. It was concluded that photoperiod alters the rate of production of gibberellin A, from gibberellin A, aldehyde. Much work on the biosynthesis of gibberellins utilizes radiolabelled GA, aldehyde which is the first compound of the pathway with the gibberellin carbon skeleton. Although available at low specific activity by chemical synthesis it is commonly prepared enzymically from 14C-labelled mevalonate in cell-free systems from Cucurbita maxima. Birnberg et a1.'16 have described improvements to this method that result in a higher yield and easier isolation of 14C-labelled GA, aldehyde. Other studies of metabolism of gibberellins this year have been f f -1 1 liA3g-l-,..23 17GA,--*GA8 I I GA aldehyde +GAS3+ GAL-GA,,+ GA 20--+GA,, 53 I I I 9 A GA1-7 GAS GA6 Scheme 17 c 4 (95) Scheme 18 OH n (98) R=H (99) R=OH of GA, aldehyde in soybean of GA in maize,'18 and of GA in apple.llg A book on diterpene esters of members of the Euphorbiaceae contains chapters on daphnane ingenane and phorbol esters and their tumour-promoting activities and includes a chapter of biosynthetic speculation.120 Isshiki et a/.121have examined the biosynthesis of the clerodane terpentecin (93) in Kita-satosporia species by feeding [5-'3C]mevalonate and [2-13C]-acetate.The labelling pattern supported a route that involves backbone rearrangement of copalyl diphosphate (94).Ohsaki et ~1.l~~ have suggested a common cyclopropyl intermediate (95) to account for the biosynthesis of clerodane and portulal in Portulaca grandzjlora as shown in Scheme 18. Two papers NATURAL PRODUCT REPORTS 1988 deal with the production of ferruginol (96) and crypto-tanshinone (97). A two-stage plant cell suspension culture method is described in the while their production by immobilized cells is reported in the Fraga et have examined the metabolism of candidiol (98) by Gibberella fujikuroi. Interestingly the 1lp-hydroxylated product (99) was not oxidized at C-19 which is a normal process in G. fujikuroi. The transformation of ent-18-acetoxykaur- 16-ene-3,7-dione (100) into 16- and 17-hydroxy-compounds by Aspergillus niger has been described.126 7 References 1 B.H. Brown S. J. Neill and R. Horgan Planfa 1986 167 421. 2 J. A. Schneider and K. Yoshihara J. Org. Chem. 1986 51 1077. 3 I. Ekiel G. D. Sprott and I. C. P. Smith J. Bacferiol. 1986 166 559. 4 G. Gill J. L. Goldstein C. A. Slaughter and M. S. Brown J. Biol. Chem. 1986 261 3710. 5 G. Gil M. S. Brown and J. L. Goldstein J. Biol. Chem. 1986 261 3717. 6 M. Mehrabian K. A. Callaway C. F. Clarke R. D. Tanaka M. Greenspan A. J. Lusis R. S. Sparkes T. Mohandas J. Edmond A. M. Fogelman and P. A. Edwards J. Biol. Chem. 1986 261 16249. 7 S. Leonard D. Arbogast D. Geyer C. Jones and M. Sinensky Proc. Natl. Acad. Sci. USA 1986 83 2187. 8 M.E. Basson M. Thorsness and J. Rine Pruc. Natl. Acad. Sci. USA 1986 83 5563. 9 R. E. Dugan and S. S. Katiyar Biochem. Biophys. Res. Cummun. 1986 141 278. 10 T. J. Bach D. H. Rogers and H. Rudney Eur. J. Biuchem. 1986 154 103. 11 T. J. Bach Lipids 1986 21 82. 12 K. Kondo and K. Oba J. Biochem. (Tokyo) 1986 100 967. 13 A. R. Reddy and V. S. R. Das Phytochemistry 1986 25 2471. 14 J. A. Cabrera J. Bolds P. E. Shields C. M. Havel and J. A. Watson J. Biol. Chem. 1986 261 3578. 15 K. Maurey F. Wolf and J. Golbeck Plant Physiol. 1986 82 523. 16 A. Miciak D. A. White and B. Middleton Biuchem. Pharmacol. 1986 35 3489. 17 W. F. Hoffman A. W. Alberts E. J. Cragoe A. A. Deana B. E. Evans J. L. Gilfillan N. P. Gould J. W. Huff F. C. Novello J.D. Prugh K. E. Rittle R. L. Smith G. E. Stokker and A. K. Willard J. Med. Chem. 1986 29 159. I 18 G. E. Stokker A. W. Alberts P. S. Anderson E. J. Cragoe A. A. Deana J. L. Gilfillan J. Hishfield W. J. Holtz W. F. Hoffman 1. W. Huff T. J. Lee F. C. Novello J. D. Prugh C. S. Rooney R. L. Smith and A. K. Willard J. Med. Chem. 1986 29 170. 19 W. F. Hoffman A. W. Alberts P. S. Anderson J. S. Chen R. L. Smith and A. K. Willard J. Med. Chem. 1986 29 849. 20 IG. E. Stokker A. W. Alberts J. L. Gilfillan J. W. Huff and R. L. Smith J. Med. Chem. 1986 29 852. 21 [.Bjorkhem Biochim. Biophys. Acfa 1986 877 43. 22 L. Berglund I. Bjorkhem B. Angelin and K. Einarsson Acfa Chem. Scand. Ser. B 1986 40,457. 23 R. Iyengar E. Cardemil and P. A. Frey Biochemistry 1986 25 4693.24 E. Bruenger L. Chayet,andH. C. Rilling Arch. Biuchem. Biophys. 1986 248 620. 25 S. Fujisaki T. Nishino and H. Katsuki J. Biochem. (Tokyo) 1986 99 1137. 26 B. Liedvogel J. Plant Physiol. 1986 124 211. 27 A. Bonhoff R. Loyal K. Feller J. Ebel and H. Grisebach Biol. Chem. Huppe-Seyler 1986 367 797 28 T. Suga T. Hirata T. Aoki and T. Kataoka J. Am. Chem. Soc. 1986 108 2366. 29 D. V. Banthorpe C. A. Bunton 0.Cori and M. J. 0.Francis Phytochemistry 1985 24 251. 30 K. Boulton I. Shirley I. H. Smith and D. A. Whiting J. Chem. Soc. Perkin Trans. I 1986 1817. 31 R. Croteau in 'Biogeneration of Aromas' (ACS Symposium No. 317) ed. T. H. Parliament and R. Croteau The American Chemi- cal Society Washington D.C.1986 p. 134. 32 T. Suga T. Hirata T. Aoki and T. Shishibori Phytochemistry 1986 25 2769. NATURAL PRODUCT REPORTS 1988-M. H. BEALE AND J. MACMILLAN 33 R. Croteau D. M. Satterwhite D. E. Cane and C. C. Chang J. Biol. Chem. 1986 261 13438. 34 C. J. Wheeler and R. Croteau Arch. Biochem. Biophys. 1986 246,733. 35 (a) R. Croteau Arch. Biochem. Biophys. 1986 251 777; (b) R. Croteau C. J. Wheeler R. Aksela and A. C. Oehlschlager J. Biol. Chem. 1986 261 7257. 36 C. J. Wheeler and R. Croteau Arch. Biochem. Biophys. 1986,248 429. 37 R. Croteau and K. V. Venkatachalam Arch. Biochem. Biophys. 1986 249 306. 38 S. Uesato S. Kanomi A. Iida H. Inouye and M H. Zenk Phyto-chemistry 1986 25 839. 39 S. Uesato S. Ueda K. Kobayashi M.Miyauchi H. Itoh and H. Inouye Phytochemistry 1986 25 2309. 40 S. Uesato M. Miyauchi H. Itoh and H. Inouye Phytochemistry 1986 25 2515. 41 A. Akhila Phytochemistry 1986 25 421. 42 H. Fretz and W. D. Woggon Helv. Chim. Acta 1986 69 1959. 43 Y. Koezuka G. Honda and M. Tabata Phytochemistry 1986 25 2656. 44 Y. Koezuka G. Honda and M. Tabata Phytochemistry 1986 25 859. 45 D. E. Lincoln M. J. Murray and B. M. Lawrence Phyto-chemistry 1986 25 1857. 46 D. V. Banthorpe S. A. Branch V. C. 0.Njar M. G. Osborne and D. G. Watson Phytochemistry 1986 25 629. 47 D. V. Banthorpe T. J. Grey I. Poots and W. D. Fordham Phyto-chemistry 1986 25 2321. 48 N. E. El-Keltawi and R. Croteau Phytochemistry 1986 25 1603. 49 G. Pauly L. Bellingheri A.Marpeau and M. Gleizes Plant Cell Rep. 1986 5 19. 50 P. W. Trudgill in ‘The Bacteria’ Vol. X (The Biology of Pseudomonas) ed. J. R. Sokatch Academic Press London 1986 p. 483. 51 W. R. Abraham B. Stumpf K. Kieslich S. Reif and H. M. R. Hoffmann Appl. Microbiol. Biotechnol. 1986 24 31. 52 W. Abraham B. Stumpf and K. Kieslich Appl. Microbiol. Biotechnol. 1986 24 24. 53 P. Ventura R. Pellegata M. Schiavi and S. Serafini Xenobiotica 1986 16 317. 54 T. Suga T. Hirata and S. Izumi Phytochemistry 1986 25 279 1. 55 J. D. Weinstein R. Branchaud S. I. Beale W. J. Bement and P. R. Sinclair Arch. Biochem. Biophys. 1986 245 44. 56 D. E. Cane and H.-J. Ha J. Am. Chem. SOC. 1986 108 3097. 57 T. M. Hohn and F. VanMiddlesworth Arch. Biochem.Biophys. 1986 251 756. 58 A. E. Desjardins R. D. Plattner and F. VanMiddlesworth Appl. Environ. Microbiol. 1986 51 493. 59 F. VanMiddlesworth A. E. Desjardins S. L. Taylor and R. D. Plattner J. Chem. SOC. Chem. Commun. 1986 1156. 60 A. Akhila P. K. Sharma and R. S. Thakur Tetrahedron Lett. 1986 27 5885. 61 D. E. Cane Y. G. Whittle andT. C. Liang Bio-org. Chem. 1986 14 417. 62 K. H. Maurer and D. Mecke J. Antibiot. 1986 39 267. 63 R. D. Stipanovic A. Stoessl J. B. Stothers D. W. Altman A. A. Bell and P. Heinstein J. Chem. SOC. Chem. Commun. 1986 100. 64 A. Stoessl and J. B. Stothers Can. J. Chem. 1986 64 1. 65 A. Murai Y. Yoshizawa M. Ikura N. Katsui and T. Masamune J. Chem. SOC. Chem. Commun. 1986 891. 66 A. G. Avent J.R. Hanson and B. L. Yeoh J. Chem. Res. (S) 1986 422. 67 J. P. McCormick J. E. Carrel and J. P. Doom J. Am. Chem. SOC.,1986 108 8071. 68 J. E. Careel J. P. Doom and J. P. McCormick Experientia 1986 42 853. 69 F. C. Baker C. A. Miller L. W. Tsai G. C. Jamieson D. C. Cerf and D. A. Schooley Insect Biochem. 1986 16 741. 70 D. Jones G. Jones A. Click M. Rudnicka and S. Sreekrishna Comp. Biochem. Physiol. B. 1986 85 773. 71 G. L. Boyer B. V. Milborrow P. F. Wareing and J. A. D. Zee-vaart in ‘Plant Growth Substances 1985’ ed. M. Bopp Springer Verlag Heidelberg 1986 p. 99. 72 J. A. D. Zeevaart G. L. Boyer K. Cornish and R. A. Creelman in ref. 71 p. 101. 73 N. Hirai in ‘Chemistry of Plant Hormones’ ed. N. Takahashi CRC Press Boca Raton Florida 1986 p.201. 74 B. V. Milborrow in ref. 71 p. 108. 75 M. T. H. Le Page-Degivry J.-N. Bidard E. Rouvier C. Bulard and M. Lazdunski Proc. Natl. Acad. Sci. USA 1986 83 1155. 76 N. Hirai M. Okamoto and K. Koshimizu Phytochemistry 1986 25 1865. 77 S. M. Norman R. D. Bennett S. M. Poling V. P. Maier and M. D. Nelson Plant Physiol. 1986 80 122. 78 S. J. Neill R. Hogan and A. D. Parry Planta 1986 169 87. 79 P. E. Gamble and J. E. Mullet Eur. J. Biochem. 1986 160 117. 80 G. L. Boyer and J. A. D. Zeevaart Phytochemistry 1986 25 1103. 81 H. Lehmann and K. Glund Planta 1986 168 559. 82 R. Liersch H. Soicke C. Stehr and H. U. Tullner Planta Med. 1986 387. 83 M. S. R. Nair N. Acton D. L. Klayman K. Kendrick D. V. Basile and S. Mante J.Nat. Prod. 1986 49 504. 84 F. S. El-Feraly I. A. Al-Meshal M. A. Al-Yahya and M. S. Hifnawy Phytochemistry 1986 25 2777. 85 R. Sakai T. Higa C. W. Jefford and G. Bernardinelli Helv. Chim. Acta 1986 69 91. 86 K. Nabeta T. Oda and H. Sugisawa Agric. Biol. Chem. 1986 50 2915. 87 0.Spring T. Priester and A. Hager J. Plant Physiol. 1986 123 79. 88 K. K. Talwar and P. S. Kalsi Phytochemistry 1986 25 262. 89 Y. Asakawa T. Ishida M. Toyota and T. Takemoto Xeno-biotica 1986 16 753. 90 F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. SOC. Chem. Commun. 1986 214. 91 C. R. McIntyre F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. SOC. Chem. Commun. 1986 501. 92 M. J. Garson J. Chem. SOC. Chem. Commun.1986 35. 93 M. W. Dudley M. T. Dueber and C. A. West Plant Physiol. 1986 81 335. 94 M. W. Dudley T. R. Green and C. A. West Plant Physiol. 1986 81 343. 95 R. M. Coates S. C. Koch and S. Hegde J. Am. Chem. SOC. 1986 108 2762. 96 N. Takahashi I. Yamaguchi and H. Yamane in ref. 73 p. 57. 97 J. MacMillan in ‘Current Topics in Plant Biochemistry and Physiology’ University of Missouri-Columbia 1985 Vol. 4 p. 53. 98 B. 0.Phinney M. Freeling D. S. Robertson C. R. Spray and J. Silverthorne in ref. 71 p. 55. 99 B. 0.Phinney and C. R. Spray in ref. 97 p. 67. 100 J. E. Graebe in ref. 71 p. 74. 101 J. Eberle I. Yamaguchi R. Nakagawa N. Takahashi and E. W. Weiler FEBS. Lett. 1986 202 27. 102 J. P. Knox M. H. Beale G. W. Butcher and J. MacMillan Planta 1987 170 86.103 M. H. Beale R. Hooley and J. MacMillan in ref. 71 p. 65. 104 V. A. Smith and J. MacMillan Planta 1986 167 9. 105 C. H. Chung and R. C. Coolbaugh Plant Physiol. 1986 80 544. 106 Y. Kamiya N. Takahashi and J. E. Graebe Planta 1986 169 524. 107 M. Takahashi Y. Kamiya N. Takahashi and J. E. Graebe Planta 1986 168 190. 108 C. G. N. Turnbull A. Crozier L. Schwenen and J. E. Graebe Phytochemistry 1986 25 97. 109 C. G. N. Turnbull A. Crozier and G. Schneider Phytochemistry 1986 25 1823. 110 T. J. Ingram J. B. Reid and J. MacMillan Planta 1986 168 414. 111 J. B. Reid and W. C. Potts Physiol. Plant 1986 66 417. 112 V. M. Sponsel Planta 1986 168 119. 113 B. R. Campell and B. A. Bonner Plant Physiol.1986 82 909. 114 S. J. Gilmour J. A. D. Zeevaart L. Schwenen and J. E. Graebe Plant Physiol. 1986 82 190. 115 P. J. Davies P. R. Birnberg S. L. Maki and M. L. Brenner Plant Physiol. 1986 81 991. 116 P. R. Birnberg S. L. Maki M. L. Brenner G. C. Davies and M. G. Carnes Anal. Biochem. 1986 153 1. 117 P. R. Birnberg M. L. Brenner M. C. Mardaus H. Abe and R. P. Pharis Plant Physiol. 1986 82 241. 118 S. B. Rood Can. J. Bot. 1986 64 2160. 119 D. Richards W. K. Thompson and R. P. Pharis Plant Physiol. 1986 82 1090. NATURAL PRODUCT REPORTS. 1988 120 ‘Naturally Occurring Phorbol Esters’ ed. F. J. Evans CRC 124 H. Miyasaka M. Nasu T. Yamamoto Y. Endo and K. Yoneda Press Boca Raton Florida 1986. Phytochemistry 1986 25 1621. 121 K.Isshiki T. Tamamura T. Sawa H. Naganawa T. Takeuchi 125 B. M. Fraga P. Gonzalez M. G. Hernandez F. G. Tellado and and H. Umezawa J.Anribiot. 1986 39 1634. A. Perales Phytochemistry 1986 25 1235. 122 A. Ohsaki K. Shibata T. Tokoroyama T. Kubota and H. 126 A. Garcia-Granados A. Martinez M. E. Onorato and J. M. Naoki Chem. Lett. 1986 1585. Arias J. Nat. Prod. 1986 49 126. 123 H. Miyasaka M. Nasu T. Yamamoto Y. Endo and K. Yoneda Phytochemistry 1986 25 637.

ISSN:0265-0568    

DOI:10.1039/NP9880500247

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

p-Phenylethylamines and the lsoquinoline Alkaloids K.W. Bentley Department of Chemistry Loughborough University of Technology Loughborough Leicestershire LEl 7 3TU Reviewing the literature published between July 1986 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 677) 1 P-Phenylethylamines 2 Isoquinolines 3 Benzylisoquinolines 4 Bisbenzylisoquinolines 5 Cularines 6 Pavines and Isopavines 7 Berberines and Tetrahydroberberines 8 Secoberberines 9 Azaberberines 10 Protopines 11 Phthalide-isoquinolines 12 Spirobenzylisoquinolines 13 Isoindolobenzazepines 14 Rhoeadines 15 Emetine and Related Alkaloids 16 Benzophenanthridines 17 Aporphinoid Alkaloids 17.1 Proaporphines 17.2 Aporphines 17.3 Dimeric Aporphines 17.4 Oxoaporphines 17.5 Dioxoaporphines 17.6 Phenanthrenes 17.7 Benzylisoquinoline-Aporphine Dimers 17.8 Aristolochic Acids and Aristolactams 17.9 Oxoisoaporphines 17.10 Other Aporphinoid Alkaloids 18 Morphine Alkaloids 19 Phenethylisoquinolines 20 Colchicine 21 Other Alkaloids 22 References 1 j?-Phenylethylamines Hordenine tyramine N-methyltyramine and NN-dimethyl- dopamine have been isolated from Mammillaria microcarpa,' candicine has been isolated from Fagaropsis glabra,2 and N-formylnorephedrine has been isolated from Catha ed~lis.~ Derivatives of ephedrine of structures (1 ;R = H) and (1 ;R = Me) have been prepared for pharmacological studies4 and X-ray-crystallographic studies have been made of derivatives of ephedrine with N-acetyl-L-valine and N-benzyloxycarbony1-L- le~cine.~ A method for the determination of ephedra bases has been described.8 The effects of ephedrine on the heart,' on the cough reflex,a and on metabolic rate9 and of mescaline on behaviour'O and on locomotor activity" have been studied.Me 2 Isoquinolines The occurrence and properties of simple isoquinoline alkaloids have been reviewed.12 A new alkaloid isopycnarrhine (2) has been isolated from Popowia pisocarpa its structure being confirmed by its reduction with sodium borohydride to isocorypalline.l3 Thalifoline has been isolated from Berberis brandisiana.l4 Quinocarmycin [a metabolite of Streptomyces melanovinace~s,~~ and assigned the structure (3)16] has been shown to be an effective anti-tumour agent in vitro and in vivo; it inhibits the formation of RNA and DNA in P388 leukaemia cells and shows good activity against human mammary tumour MX-1.17 Some reactions of cotarnine have been re-examined.With hydroxylamine the base yields the oxime (4; R = OH)'* and with phenylhydrazine it gives (4; R = NHPh) which is in equilibrium with the cyclic form (5; R = NHPh),19 whereas with aniline and with urea it gives only the cyclic bases (5 ;R = Ph) and (5; R = CONH,) respectively.'' With acetophenone the cyclic base (6) is formed whereas N-acetylcotarnine (7) and the so-called cyclic 0-acetylcotarnine [identified as the cinnamic acid derivative (8)] are formed when cotarnine reacts with COZH u? (q 0 HMe Me0 'NR NHR (4 1 (5) Ph (6 1 (7) 265 acetic anhydride.2o Similar reactions have been observed for hydrastinine. Both the resolvable bishydrocotarnine (9; R = Me) and its meso-isomer have been prepared and these have been converted into (9; R = CO,Et) (9; R = CO,CH,CCl,) (9; R = H) and (10) and their meso-isomers.21 A highly efficient asymmetric hydrogenation of the enamide (1 1) in the presence of A-($)-[2,2’-bis(diphenylphosphino)-1,l’-binaphthyllruthenium(11)diacetate to give N-acetyl-(8-salsoli- dine has been achieved., The A-(R)-and the A-($)-form of this catalyst have been used in asymmetric syntheses of benzyliso- quinoline alkaloids (see Section 3).(_+)-Salsolidine has been synthesized by treatment of the pyrylium salt (12) with benzylamine followed by complete reduction of the resulting N- benzylisoquinolinium salt., Full details of the synthesis of (-)-(R)-calycotomine (-)-(9-carnegine and O-methylcory- palline by Pictet-Spengler cyclization of (+)-(R)-glyceralde-hyde and dopamine followed by other processes (described in the previous Report) have been published.24 The amine (13; R’=OBz R2= H) prepared from 4-benzyloxystyrene oxide and N-(3-benzyloxy-4-met hoxybenzy1)- N-methylamine has been cyclized and debenzylated in acid to the alkaloid cherylline (14; R’=OH R2= H).25 The isomeric amine prepared by conventional processes from [2-hydroxy-2- (4-hydroxypheny1)ethyllamineand 6-bromoisovanillin has been cyclized to the isomeric base latifine (14; R1 = H R2 = OH).26 A patent has been published covering the debenzylation of 00-dibenzyl-latifine.27 The naphthylisoquinoline alkaloids ancistrocladine (1 8) and its rotational isomer hamatine have been synthesized from the ester (1 5) which was cyclized to the lactone (16) and its rotamer (in a 3 1 ratio) by hydrogenation in the presence of a homogeneous palladium catalyst. Reduction of the lactone with lithium aluminium hydride gave the phenolic alcohol (1 7) which was further reduced to ancistrocladine. By similar processes the rotamer of (16) gave hamatine.28 (0 T Me0 N r o (9) (10) NATURAL PRODUCT REPORTS 1988 Me0 OMe Me0 OMe 8r Me Me (15) (1 6) Me0 OMe Me0 OMe WCH20H @Me Me Me (1 7) (1 8) 3 Benzyl isoquinolines Benzylisoquinoline alkaloids have been isolated from the following plant species the eight marked with an asterisk being new A rgemone albifolia 29 reticuline Argemone ochrole~ca~~ reticuline Berberis actinacantha30 berbitine* (19 ;R’R’ = CH,) and dihydrotaxilamine* (19; R’= R2= Me) Berberis brandi~iana’~ reticuline Corydalis bulleyana31 norjuziphine Corydalis cla~iculata~~ viguine* (20) Erythrina herbacea3 nororientaline Guat ter ia sago t iana34 armepavine and N-methy lcoclaurine Leontice leon topetalum 35 Meorno+ Me0 Me0 \ juziphine norjuziphine magnocurarine ch,aride MeoqNAc I Me ClOl oblongine chloride petaline chloride and reticuline Nelumbo n~cifera,~ armepavine and N-methyl-4’-0-methylcoclaurine*(21) (11) (12) Papaver pseudo- orien tale37 pseudorine iodide* (22) Popowia piso~arpa’~ armepavine coclaurine and N-methylpseudolaudanine OBz Pseudoxandra sclero~arpa~~ luxandrim* (23) Roemeria ~arica~~ roemecarhe* (24) and its N-oxide* Rollinia emarginata4O MeO&qH NMe re ticuline Thalictrum cultratum4’ R’ \ reticuline In addition the starfish Dermasterias imbricata has been found (13) (141 to excrete imbricatine which produces a dramatic swimming response in some sea anemones; it was assigned the structure NATURAL PRODUCT REPORTS.1988-K. W. BENTLEY (25) on the basis of its spectra and its cleavage by Raney nickel to methylhistidine and the residual benzyltetrahydroisoquino-linecarboxylic 6,7-Dimethoxy-2-methyltetrahydroisoquinoline- 1,3,4,trione and veratryl alcohol have been obtained from the products of heating laudanosine N-oxide with acetic anhydride.43 (2)-Enamides of general structure (26) undergo efficient asymmetric hydrogenation in the presence of A-(R)and A-(S) isomers of [2,2’-bis(dipheny1phosphino)-1,l’-binaphthyllruth-enium(I1) diacetate to give respectively the (R)and (S) isomers of the 1-benzyltetrahydroisoquinolines; (&)-tetrahydropap-averine (R)-laudanosine and (R)-reticuline of high optical purity have been prepared in this way.The isomeric (a-enamides are resistant to hydrogenation with these catalysts.22 The aldehyde (27) which is an intermediate in the previously reported synthesis of (-)-(R)-calycotomine and (-)-(5‘)-carne-gine from- dopamine and glyceraldehyde has been converted R20 ”OWN OH boMe OMe (1 9) Me0 \ (22) HOcIgH OH (25) 267 into laudanosine by treatment with 3,4-dimethoxyphenyl-lithium [to give the threo-compound (28) only] followed by treatment successively with thionyl chloride and lithium aluminium hydride.25 The negative-ion mass spectra of some brominated benzyliso- quinoline alkaloids have been shown to exhibit peaks attribu- table to ap~rphines.~~ Chromatographic methods of separating benzylisoquinoline alkaloids in opium have been described.45 46 The effects of papaverine on the metabolism of amines in brain,47 on the renal transport of adenosine,48 and on electrically induced seizures,49 of laudanosine on the cardio-vascular system50 and on ~etabolism,~~ of higenamine on synovial fluid,62 on a-adrenore~eptors,~~ on dopamine receptor^,^^ on asthmatic attacks,55 on cytochrome enzymes,56 and on mem- brane p~tential,~’ and the general pharmacological properties of atrac~rium~~ -64 and of papaverine errh hen ate^^ have been studied.““TNMe HO DOMe OMe (21) Me0 T\ NMe “ H‘ (24) OR^ OR^ (26) CHO OMe OMe (27) (28) NATURAL PRODUCT REPORTS 1988 4 Bisbenzylisoquinolines e Bisbenzylisoquinoline alkaloids have been isolated from the MH'eN/% 0 3 following species the forty marked by an asterisk being new alkaloids Berberis brandi~iana,'~ berbamine berbamine 2'/3-oxide* and isotetrandrine \ OH / Berberis oblonga66 berbamine 2'-me th yliso tetrandrine* and oxy acant hine (30) Caryomene 01ivascens~~ caryolivine* (29) 2-norlimacine,* 2-norlimacusine 1,2- didehydro-2-norlimacusine,* and NN-dimethyl- lindholdamine Muhonia uquifolium68 '* aquifoline* (30) aromoline baluchistine berbamine isotetrandrine obamegine and oxyacanthine Nelumbo n~cifera~~ isoliensinine and neferine Popowia pisocurpa7' dauricine (31 ; R' = R2 = R3= Me R4= H) 0-methyldauricine (31 ; R' = R2 = R3= R4 = Me) 0-(31 1 methyldauricine 2-oxide,* 0-methyldauricine 2'-oxide,* dauricoline (31 ; R' = R2 = R4= H R3= Me) popkine* (31 ; R' = R2 = R4 = Me R3 = H) popidine* (31 ; R' = H R2 = R3= R4 = Me) popisidine* (31 ; R' = R3= R4 = Me R2 = H) popisonine* (31 ; R' = R2 = H R" = R' = Me) popisopine* (31 ; R' = R3 = H R2= R1= Me) pisopowine* (32; R' = R2 = R3= R4 = R5 = Me) pisopowidine* (32; R' = R3 = R4 = R5 = Me R2 = H) pisopowiarine* (32; R' = R4 = R" = Me R2 = R3= H) pisopowetine* (32; R' = R2 = R3 = M el R4= R5 = H) pisopowiaridine* (32; R' = R4= Me R2 = R3= R5 = H) pisopowamine* (32; R' = R4= R5 = (32) H R2 = R3 = Me) 2'-norpisopowiaridine* (32; R1= R2 = R3 = R5= H R4 = Me) Pseudoxandra lucida oxandrine* (33; R = H) oxandrinine* (33; R = Me) pseudoxandrine* (34 ; R = H) and pseudoxandrinine* (34; R = Me) Pseudoxandra sclerocarpu73 berbamunine homoaromoline secolucidine* (35) and y7J-p thaligrisine* (36) \ OMe RO Stephania suber~sa~~ cepharanthine cepharanthine 2/3-oxide,* 2-nor- (33) cepharanthine,* stephasubine* (37; R = Me) norstephasubine* (37 ; R = H) and stephasubimine* (38) 75 Thalictrum c~ltratum~~ M e N\ !OMe oMe0g/ ; e revolutinone thalcultrimine* (39) 0-methylthalicberine thalictrine thalidasine 2-northalidasine1 5-hydroxy- thalidasine* (40) thaliphylline thalmiculine* (41 ; H R = Me) thalmiculimine* (42; R' = OH R2 = Me) 0 \ thalmiculatimine* (42; R' = R2= H) thalmine 2-northalmine 5-hydroxythalmine* (41 ; R = H) \ OH Me0 / thaligosine (thalisopine) thalrugosaminine thalrugosidine thalrugosinone and thalsivasine (34) Tiliacora triandra76 78 dinklacorine tiliacorine tiliacorinine 2-nortiliacorinine tiliangine* (43; R' = OH R2 = H R3 = Me) yanangcorinine* (43 ; R1= R2= H R3 = Me) and yanangine* (43; R' = OH R2= Me R3= H) NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY The structures of the new alkaloids were determined by spectroscopic methods. Tiliangine and yanangine are 5-hydroxy-yanangcorinine and 5-hydroxytiliacorinine7 respec- tively. The four new alkaloids that have been isolated from Pseudoxandra lucida are the first monoketo-bisbenzylisoquino-line alkaloids to be identified and the seven biphenyl alkaloids of structure (32) are the first bisbenzylisoquinolines to be discovered that contain no diphenyl ether linkage. Secolucidine is the enantiomer of secotiliacorine which can be prepared by the oxidation of tiliacorine. The correction of the structures of thalrugosinone and thalpindione (reported in the previous review) has been re-affirmed.41 Syntheses of fangchinoline (44) by conventional methods79 and of phaeantharine by Bischler-Napieralsky cyclization of the diamide (45),with simultaneous loss of methanol,8o have been achieved.The effects of berbamine on the hearts1~s2 and on immune function,x3 of 0-(4-ethoxybutyl)berbamine as a calmodulin antagoni~t,~~ of dauricine of cepharanthine on nasal allergie~,'~ on the aggregation of platelets,s6 on inflamrnati~n,~~ and on the cardio-vascular system,s* of tetrandrine on neutrophils and monocytesB9 and on calcium metab~lism,~~ of trilobine on inflammation,91 of dimethyltrilobine iodide on neuromuscular transmission 92 of tubocurarine on neuromuscular trans-mission,.59 93-95 on the release of acetylch~line,~~ and on levels of histamine in plasma,97 the anti-mitotic cytotoxic activity of g~attegaumerine,'~ and the metabolism of cepharanthineg9 have been studied.OMe (38) (39) OH n (411 (44) OMe OMe 0 AC MeO-OMe (461 (47) Me0 OMe (48) 5 Cularines Recent work on the cularine alkaloids has been reviewed.loO Three new alkaloids of this group have been discovered. Henderine (46) has been isolated from Corydalis hendersonii Hemsl. (= C. nepalensis Kitamura)'O' and dioxocularine (47) and norsecocularine (48) have been isolated from Corydalis clavi~ulata.~~ Henderine is the third cularine-like alkaloid to have a 6,7,8-oxygenation pattern in the isoquinoline system the two previously known bases of this type being linaresine and dihydrolinaresine.lo2 The selective demethylation of cula- rine derivatives has been achieved under acidic and nucleophilic conditions; hydrogen bromide in acetic acid demethylates cularine to c~lacorine.~~~ 6 Pavines and lsopavines Alkaloids of this group have been isolated from the following species that marked with an asterisk being new Argemone albalo4 0-methylplatycerine Argemone hybridalo4 0-methylplatycerine Argemone mexicanalo4 0-methylplatycerine Argemone platy~eras~~~ 0-methylplatycerine Eschscholtzia californ ica lo5 lo6 9 californidine caryachine eschscholtzine eschscholtzine N-oxide,* norargemonine isonorargemonine and bisnorargemonine Eschscholtzia douglasii1Q5 caryachine N-methylcaryachinium iodide norargemonine isonorargemonine and bisnorargemonine Eschscholtzia glaucalo5 californidine caryachine eschscholtzine norargemonine isonorargemonine and bisnorargemonine Thalictrum cultratum 41 thalisopavine 7 Berberines and Tetrahydroberberines Alkaloids of this group have been isolated from the following species the four marked with an asterisk being new Argemone albifoliaZ9 berberine and scoulerine Argemone mexicanalo7 berberine and coptisine Argemone OC~YO~~UC~~~ berberine cheilanthifoline and scoulerine NATURAL PRODUCT REPORTS.1988 Artabotrys venustus1OB artavenustine* (49) discretamine and 10-0-demethyldiscretine Berberis amurensislog berberine and palmatine Berberis brandi~iana'~ berberine and palmatine Berberis heterobotry~'~~ berberine and palmatine Berberis heteropodalog berberine ja tro rr hizine and palma t ine Berberis oblonga66 Io9 berberine columbamine and palmatine Berberis ottawensislo9 berberine oxyberberine and palmatine Berberis regelianal" berberine Berberis vulgarislog berberine and palmatine Caryomene olivascens67 pseudopalmatine Corydalis ambigual10 cavidine corybulbine and corydaline Corydalis bulleyana31 cheilanthifoline scoulerine and stylopine Corydalis cavalll coptisine corysamine and stylopine Corydalis rutifolia112 coptisine and corydaline Corydalis turtschaninovii f.yanhu~uo"~. 114 tetrahydroberberine columbamine tetrahydrocolumbamine coptisine tetrahydrocoptisine corybulbine corydaline dehydrocorydaline palmatine tetrahydropalmatine and yuanhunine* (50) Corydalis yanhu~uo"~ coptisine tetrahydrocoptisine corydaline palmatine and tetrahydropalmatine Fumaria asepala116 scoulerine and stylopine Fumaria densifloral" cheilanthifoline and scoulerine Glaucium grandijIorum1ls corypalmine and tetrahydropalmatine Guatteria our ego^"^ coreximine Mahonia aquifolia68v 69 berberine oxyberberine jatrorrhizine and palmatine Papaver a tlan t icum scoulerine stylopine and 13P-hydroxy-N- methylstylopinium iodide Papaver glaucum12(' coptisine Papaver oreophilum l2 mecambridine Papa ver orien taleIz2 alborine mecambridine and orientalidine Papaver p~eudo-orientale~~ alborine coptisine mecambridine orientalidine and palmatine Parabaena sagittatalZ3 berberine tetrahydropalmatine thaicanine* (51 ; R = H) and 0-methylthaicanine* (51 ; R = Me) Popowia pisocarpa13 stepharanine Stephania suc~ifera'~~ tetrahydropalmatine Thalictrum cultratum41 berberine Thalictrum faurieilZ5 dehydrodiscretine and thalifaurine Recent work on the alkaloids of this group has been re-viewed.126 NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY 27 1 An X-ray-crystallographic determination of the structure of A novel synthesis of (&)-stylopine has been achieved by the (-)-canadinium (+)-10-camphorsulphonate has been re-photocyclization of the dihydroisoquinolinium salt (56) pre-Canadine has been found to give a complex (52) with sumably by sequential electron-transfer desilylation and inter- ~0rted.l~' chromium tricarbonyl in which one face of the molecule is nal pairing of a diradical.In the same way (&)-xylopinine has shielded from attack and this complex can be converted into been synthesized from the appropriately substituted analogue the 11-trimethylsilyl compound which on treatment with of the salt (56).132 A regioselective synthesis of 13-substituted butyl-lithium and methyl iodide followed by removal of the tetrahydroberberines has been developed which involves the trimethylsilyl group and the chromium gives (-)-(8R)-8-cyclo-addition of dimethoxy- or methylenedioxy-arynes to keto-methylcanadine (53). In contrast treatment of berberine lactams such as (57); for example (f)-corydaline has been chloride with methylmagnesium iodide and reduction of the prepared by the reduction of the oxyberberine (59) that results product affords only 9 % of (f)-(8R)-8-methylcanadine and from the addition of the appropriate dimethoxyaryne to the Patents cover the preparation lactam (57).The process probably proceeds through the 91 % of the (+)-(8S)-i~omer.'~* of 13-allyl- and 13-propyl-berberinelZ9 and of 6-Q-tolyl)-intermediate (58) which then loses carbon monoxide and is The quinone acetal(54) obtained from discretine not applicable to the production of 13-unsubstituted alkaloids xy10pinine.l~~ has been converted (by acetic anhydride in sulphuric acid) into since the C-demethyl analogue of (58) loses carbon monoxide 4-acetoxy-O-acetyldiscretine(59 which gives 4-methoxyxylo- but reacts with a second mole of aryne to give 13-aryl- pinine on hydrolysis and methy1ati0n.l~~ oxyberberines.133 OMe HO (49) (501 (51) OMe (52) (53) (54) OAc MC3SiTx9 OMe (55) (56) (57) Me Me0 (58) (59) The phthalimidin-2-ylacetic acid (60) prepared from glycine and the appropriate tetramethoxybenzylidene phthalide has been cyclized to the isoindolobenzazepine (61); this has been converted (by simple processes) into the quaternary salt (62).Rearrangement of this salt in aqueous potassium hydroxide affords the tetrahydropalmatinium salt the acetate (63) of which on pyrolysis hydrolysis and then reduction with borane yields (f)-tetrahydropalmatine.134 5-Hydroxy-8-methylxylopinine (65) has been synthesized by cyclization of the aldehyde (64; R = CH,CHO) which was obtained from (64;R = H) by way of [64; R = CH2CH(OH)CH20H].135 The spirobenzylisoquinoline (66; R' = OMe R2 = H) has been rearranged to the berberine system by photolysis in the presence of vitamin C (to suppress oxidation); the product after reduction with sodium borohydride yielded tetrahydro- palmatine. In the same way (66; R' = H R2 = OMe) has been (60) Me0 Me0 OMe OMe Me0 (64) NATURAL PRODUCT REPORTS 1988 converted into xy10pinine.l~~ Protopine on treatment with ethyl chloroformate followed by hydrolysis has been shown to give dihydrocoptisine (67); if protopine was treated with iodine and sodium acetate followed by pyrolysis it was converted into the coptisine betaine (68)137 These processes suggest that the structure (69) makes a contribution to the normal state of protopine.The antifibrillatory effects of berberine,13* the general pharmacology of 13-propylberberine 139 and the analgesic'4o* and anti pyre ti^'^^ effects of stepholidine have been studied as have the effects of stepholidine tetrahydroberberine corydal- mine tetrahydropalmatine and scoulerine on dopamine recep- tors in brain,142-144 of stepholidine on monoamine oxidases in brain,145 and of tetrahydropalmatine on the metabolism of d~paminel~~ and on the effects of dihydroetorphine. 147 OMe OH Me0 (65) (66) NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY 8 Secoberberines Secoberberine alkaloids have been isolated from the following species the eight marked with an asterisk being new Corydalis bulleyana3' corydamine (70; R = H) and acetylcorydamine (70; R = Ac) Corydalis rutifolia112 bilitsine* (71) Hypecoum proc~rnbens'~~ (76) (77) formylcorydamine (70; R = CHO) and hypecurnine* (70; R = Me) Papaver f~gax'~~ narcotine hemiacetal* (72) and papaveroxine* (73 ; R = OAC) Papaver p~eudo-orientale'~~ macrantaldehyde* (73; R = H) macrantaline (74; R = H) macrantoridine narcotinediol* (74; R = OH) narcotine hemiacetal (72) narcotolinol* (79 and papaveroxinoline* (74; R = OAc) The new alkaloids from Papaver fugax and P. pseudo-orientale have been related by chemical interconversions.Bilitsine is clearly the product of cyclization of a secoberberine possibly a precursor of hypecorinine. 9 Azaberberines A new azaberberine alkaloid isolated from Alangium lamarckii alamaridine (78) has been synthesized by the cyclization of the dihydroisoquinolinium salt (76) to the enamine (77) followed by reduction with sodium cyanoborohydride the diastereoiso- meric base being produced at the same time. The relative dispositions of the hydrogen atoms at the two asymmetric centres was determined by comparison of n.m.r. spectra of the compounds with those of 8-methyltetrahydroberberines. I5O HO (701 (71) Me0 ,,.' (0 q N M e CHO (78) 10 Protopines Alkaloids of the protopine group have been isolated from the following species Argemone albifolia2' protopine Argemone mexicana'O' allocryptopine and protopine Argemone ochroleu~a~~ allocryptopine and protopine Corydalis bulleyana3I allocryptopine corycavamine and protopine Corydalis cava"' protopine Corydalis hendersonii"' allocryptopine and protopine Corydalis rutifolia'12 allocryptopine and protopine Corydalis turtschaninovii f.yanhu~uol'~ allocryptopine and protopine Eschscholtzia ~alifornica'~~ allocryptopine and protopine Eschscholtzia dougla~ii~~~ allocryptopine and protopine Eschscholtzia g1auca'O5 allocryptopine and protopine Fumaria asepalal" cryptopine and protopine Fumaria bracteosa l5' protopine Fumaria denszjIora1" cryptopine and protopine Glaucium grandiJlorum"* allocryptopine and protopine Hypecoum procumben~'~~ hunnemanine and 13-oxoprotopine (72) (73) Papaver atlan t icurnlzQ cryptopine muramine and protopine Papaver glaucurnlz0 allocryptopine cryptopine and protopine Papaver oreophilum 21 Papaver pavoninum152 allocryptopine and protopine (741 OMe (75) / OMe OMe allocryptopine and protopine allocryptopine and protopine Papaver p~eudo-orientale~~ Bromination and nitration of protopine to the 12-bromo- and 12-nitro-compounds has been effected137 and the spectra of protopine and allocryptopine have been studied.153 11 NPR 5 274 11 Phthalide-isoquinolines Alkaloids of this group have been isolated from the following species the three marked by an asterisk being new Corydalis cava'l' adlumidiceine and capnoidine Corydalis ru tifolia' coryrutine* (79) and N-methylhydrasteine (8 1) Fumaria asepalall6 bicuculline Fumaria bracteo~a'~' adlumine bicuculline and a-hydrastine Fumaria den~ijlora"~~ 154 adlumidine bicuculline fumadensine* (SO) a-hydrastine and N-methylhydrasteine (8 1) Papaver f~gax'~~ narcotine Papaver p~eudo-orientale~~.149 narcotine and pseudoronine* [(82; R' = H R2= Me) or (82; R' = Me R2= H)] Fumadensine (SO) which is a racemic base is dehydrated by trifluoroacetic acid to a mixture of the (2)-and (E)-stilbenes ;it can be synthesized from N-methylhydrasteine (81) and p-phen~lethylamine'~~ and it is conceivable that it is an artifact NATURAL PRODUCT REPORTS 1988 being formed from these bases during isolation although /3-phenylethylamine has not been reported to occur in F.denszjlora. Pseudoronine (82) may be a decarboxylated ana- logue of bicucullinidine (83) or a product of oxidation and demethylation of pseudorine iodide (22) which has been isolated from P. p~eudo-orientale,~~ in which case it would not be assignable to this group. Nornarceine imide (84; R= H) has been prepared from nornarceine by fusion with urea; an attempt to prepare it by the N-demethylation of narceine imide (84; R = Me) afforded the keto-amide (85).155Quaternization of narcotine with 3-bromo- propanal followed by Hofmann degradation has yielded N-(3-hydroxypropyl)nornarceine which has been cyclized to the macrolide (86).156 The conformations of bicuc~lline'~~ and other phthalide-isoquinoline alkaloids158 have been studied by n.m.r . spectroscopy. Chroma tograp hic met hods of separating narcotine from other opium alkaloids have been described.45 The excretion of narcotine in human milk'59 and the effects of bicuculline on the analgesic properties of morphine,160 on the sedative effects of pentobarbita1,l6l and on behaviour162 have been studied. The general pharmacology of tritoqualine which is a synthetic analogue of narcotine has been st~died'~~-'~* and other analogues of narcotine and hydrastine have been synthesized as potential anti-allergy agent~.'~~,'~~ OMe OMe (79) (80) Me0Ho WN\ Me Me0 Me 0R' H0,C O-f (82 1 (83) Me (1 q N Me OMe 0 (85) NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY 275 dehydrated to the tetracyclic compound (92); this was 12 Spirobenzyl isoqu ino1ines catalytically reduced to lennoxamine the lactam ring of which Alkaloids of this group have been isolated from the following was further reduced to give chilenamine.180 species the three marked with an asterisk being new The base chileninone recently isolated from three Berberis Corydalis solida' species and assigned the isoindolobenzazepine structure (94),18' corpaine and (& )-corysolidine* (87) has been shown to be identical with berberrubine (95),'82which Fumaria densijIora1l7 has been isolated from Berberis species and may itself be an fumaridine fumariline fumaritine parfumidine and artifact of the isolation procedure.It is normally reported to h par fumine accompanied by berberine and it has been found that if Rupicapnos a frkana'a berberine is treated with ammonium hydroxide and chloroform africanine* (89) and isoparfumine* (88) (which are generally used in isolating alkaloids) berberine- The pharmacological properties of fumariline have been chloroform (96; R1R2= CH,) is formed and that this is studied.179 converted (in part) on a silica column into berberrubine and oxyberberine.182 It has further been shown that if the analogous palmatine-chloroform (96; R1= R2= Me) is subjected to slow 13 lsoindolobenzazepines column chromatography on silica approximately 25 YOof it is Lennoxamine (93; X = 0)and chilenamine (93; X = H,) have converted into the isoquinolinobenzazepine alkaloid saulatine been synthesized from the benzylidene phthalide (90).Conden-(101 ; R1= R2= Me) which could arise via the intermediates sation of this with amino-acetal afforded the lactam (91) (97)-(loo) the oxidation of (97) to (98) being effected by which after catalytic reduction was hydrolysed and cyclo- atmospheric oxygen. This makes it very probable that saulatine HO HO Me0 Me0 Me0 HO %H c,\ OMe Me0 OMe <qoMe \ OMe OMe 0Me (91) (921 (95 1 11-2 and the related compound puntarenine (101 ;R1R2= CH,) are artifacts of isolation.la2 The isoindolobenzazocine magal- lanesine (1O7)la3 is also probably an artifact arising from the reaction of berberine with chloroform and oxygen to give (1 02) followed by rearrangement through the intermediates (103)-( 106).la2 14 Rhoeadines Alkaloids of this group have been isolated from Papaver species as follows Papaver a tlan t icum 2o rhoeadine rhoeagenine and papaverrubines A B D and E Papaver glaucum120 papaverrubines B C D and H Papaver pseudo-orientale3' papaverrubine D Recent chemistry of the alkaloids has been reviewed.la4 ..? A.0-1 Me OMe 0 NATURAL PRODUCT REPORTS 1988 15 Emetine and Related Alkaloids The (*)-and (-)-form of the acid (108) prepared by conventional methods have been hydrogenolysed to (k)-and (-)-alancine the (-)-form of which was identified with the natural alkaloid from Alangium 1amar~kii.l~~ The acids (109; R1 = Bz R2 = Me) and (109; R' = Me R2= Bz) have been used to synthesize 9-0-demethyl and 1 0-0-demethyl isomers respectively of cephaleine186 and of tubul~sine'~~~ laa by Bischler-Napieralsky cyclization of their amides with [p-(3-benzyloxy-4-methoxyphenyl]ethyl]amine and 5-(benzy1oxy)-tryptamine followed by removal of the benzyl groups.The ester of the acid (109; R1 = R2 = Me) has been prepared by internal Michael condensation of the keto-ester (1 lo) followed by reduction of the keto-group; the product was reduced to protoemetinol. la9 The effects of emetine on phagocytic processes have been studied.lgO 0 0 CI 0-(105) (106) 062 Me0 Me0 Me0 Me0 q; CO H ?\Me 0 CO Et (109) (110) R3 0 (11 2) NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY 16 Benzophenanthridines Benzophenanthridine alkaloids have been isolated from the following species the six marked with an asterisk being new Argemone mexicanalo7 chelerythrine and sanguinarine Argemone o~hroleuca~~ sanguinarine Corydalis bulleyana3' bulleyanaline* (1 11 ; R1= CH2Ac R2 = H R3 = OH) bulleyanine* (1 12) consperine (1 1 1;R' = CH2Ac R2 = Ac R3 = H) corynoline (1 11 ; R' = R2 = R3 = H) 0-acetylcorynoline (1 11 ; R' = R3 = H R2 = Ac) 6-acetonylcorynoline* (1 1 1 ; R' = CH2Ac R2 = R3 = H) 12-formyloxycorynoline* (1 11 ; R' = R2 = H R3 = OCHO) 12-hydroxycorynoline* (1 11; R1= R2 = H R3 = OH) O-acetyl-6-oxocorynoline* (1 13) corynoloxine isocorynoline 0-acetylisocorynoline and di h ydrosanguinarine Corydalis rutifolia1I2 dih ydrosanguinarine Corydalis yanhusu~'~~ dehydronantenine and dihydrosanguinarine Eschscholtzia californicalo5 chelerythrine chelilutine chelirubine macarpine and sanguinarine Eschscholtzia glaucalo5 chelerythrine chelilutine chelirubine macarpine and sanguinarine Fagaropsis glabra2 chelerythrine norchelerythrine dihydrochelerythrine and 6-acetonyldihydrochelerythrine Fumaria asepala'16 sanguinarine Glaucium grandijiorumlls di hydroc helerythrine 6-ace tonyldi hydrochelerythrine and norchelidonine Papaver atlanticum120 sanguinarine Papaver glaucum'2Q sanguinarine Of the new alkaloids 6-acetonylcorynoline has been prepared from corynoline and 12-hydroxycorynoline has been obtained by dehydration of corynoline epoxidation of the resulting olefin and subsequent opening of the epoxide ring with an alkali.Acetyl-6-oxocorynoline has been prepared by the oxidation of 0-acetylcorynoline. 31 The quaternary alkaloids chelerythrine chelilutine cheli- rubine sanguinarine sanguilutine and sanguirubine have been reduced to their dihydro-compounds by NADH and NADPH.lS2 The I -(ferrocenyl)-2-methylpropylgroup has been used to induce asymmetric syntheses of these alkaloids. The (&form of the imine (114) reacts with the appropriate homophthalic anhydride to give 81 YOof the lactam acid (1 15) together with 10YOof the oppositely configured isomer. Treatment of (1 15) with trifluoroacetic and thioglycollic acids afforded the acid (1 16) which was converted [through the diazo-ketone (1 17)] into the ketone (1 18); reduction of this gave (-)-corynoline (1 11; R' = R2 = R3 = H).The minor isomer of (115) in similar fashion afforded (+)-corynoline.lS3Avicine nitidine 6-methylnitidine 7-methoxynitidine 10-methoxynitidine and 7-met h oxy -2,3 ;9,lO-bi s(me t h y 1ened i ox y )be nzo [c]p hen- anthridinium chloride have been synthesized by processes previously described for the synthesis of sanguirubine ; the products together with chelerythrine chelirubine chelilutine sanguinarine sanguilutine and sanguirubine have been eval- uated as anti-tumour agents.ls4 By processes analogous to those that were described in the previous Report for the conversion of berberine into homochelidonine coptisine has been converted [via the betaine (1 19)] into the cis-fused olefin (120) which has been converted into (i-)-chelidonine (+)-chelamine (1 2a-hydroxychelidonine) sanguinarine and di-hydrosanguinarine.lS5 The toxicity of sang~inarine'~~ and the complexation of benzophenanthridine alkaloids with DNAlg7 have been studied. (11 4) (115) (116) (117) (118) LO (119) (120) 17 Aporphinoid Alkaloids 17.1 Proaporphines Known proaporphine alkaloids have been isolated from the following species Berberis brandi~iana'~ apoglaziovine Caryomene olivascenss7 pronuciferine Guat ter ia sagot iana34 glaziovine Photoirradiation of orientalinone (121 ; R = H) results in its rearrangement to (+)-isoboldine (122; R = H) together with (+)-isothebaine (123; R = H) as a minor product whereas under the same conditions roemerialinone (121 ; R = Me) affords 0-methylisothebaine (123; R = Me) as the main product together with a small amount of 0-methylisoboldine (122; R = Me).The formation of these products has been rationalized as involving the intermediates (124) and (123 each produced by two photorearrangements steric hindrance favouring the formation of (124) when R is H and (125) when R is Me. The exclusive formation of lumipakistanine with retention of the benzyltetrahydroquinoline unit on photo-rearrangement of pakistanamine indicates that pakistanamine has the stereochemistry shown in (126).Ig8 17.2 Aporphines Aporphine alkaloids have been isolated from the following species the sixteen marked with an asterisk being new Argemone alba'04 corydine and isocorydine Argemone hybridalQ4 corydine and isocorydine Argemone rnexicana'O4 corydine and isocorydine Argemone platy~eras'~~ corydine and isocorydine Aristolochia c~ntorta'~~ magnoflorine Artabotrys venustus'08 anonaine asimilobine lirinidine norcorydine nuciferine nornuciferine norstephalagine and norushinsunine Berberis brandi~iana'~ is0 boldine Cary omene olivascens6 stepharine and N-formylstepharine Corydalis cava'" bulbocapnine domesticine isoboldine and predicentrine Corydalis turtschaninovii f.yanhus~o"~, 2oo glaucine dehydroglaucine N-methyl-laurotetanine and nantenine Corydalis yan husuo 'l5 glaucine Desmos dasymachalus2"' dasymachaline* (127) Eschscholtzia californica'Q5 corydine isocorydine corytuberine N-methyl- laurotetanine and magnoflorine Eschscholtzia dougla~ii'~~ corydine isocorydine corytuberine and magnoflorine Eschscholtzia glaucalQ5 corydine isocorydine corytuberine and N-methyl- lauro te tanine Glaucium jimbrilligerum202 glaufinine* (1 28) Guatteria our ego^^'^ formouregine* (129 ;R = OMe) dehydroformouregine,* isopiline (1 30) 0-methylisopiline,* N-methylisopiline,* 0-methyldehydroisopiline,* lirindine lirinine O-methyl- lirinine nuciferine nornuciferine N-formyl- NATURAL PRODUCT REPORTS 1988 nornuciferine* (1 29 ; R = H) 3-hydroxynornuciferine dehydronornuciferine oureguattine* (13 I) and pentouregine Guatteria ~agotiana~~ anolobine dehydroroemerine dehydrostephalagine* (1 32) duguespixine elmerillicine N-methylelmerillicine* (1 33) guatterine guatterine N-oxide lirinidine norlaureline noroliveroline nuciferidine* (134) nornuciferine 3-hydroxynornuciferine obovamine oliveroline oliveroline N-oxide pachyconfine pukateine 0-methylpukateine puterine roemerine trichoguattine* (135) and xylopine Hedycarya ang~stifolia~~~ boldine corydine glaucine isosevanine* (1 36) laureline 6,6a-didehydronorlaureline*(1 37) and laurotetanine Liriodendron t~lipifera~~~ N-methyl-laurotetanine Papa ver at lan ticum '2Q corytuberine isothebaine and magnoflorine Papaver glaucum'2Q corydine isocorydine corytuberine glaucamine glaudine and magnoflorine Papaver orien tale is0 thebaine Papa ver pseudo- orien tale3 bracteoline corytuberine isothebaine N-methylisothebaine iodide magnoflorine and nuciferine Popowia pi~ocarpa'~ asimilobine corydine norcorydine nornuciferine norushinsunine pancoridine thaliporphine wilsonirine and 4-hydroxywiIsonirine* (1 38) Pseudoxandra scler ocarpa ushinsunine Rollinia emarginata4' anonaine and asimilobine Step han ia epigeae 2Q5 cass ythicine Step han ia su ccifera 24 asimilobine crebanine crebanine N-oxide dehydrocrebanine and schefferine Thalictrum cultratum4' thalicsimidine Thalictrum fa~rieil~~ corydine isocorydine magnoflorine and onconovine An X-ray-crystallographic examination of isocorydine methio- dide has been reported206 and the Cope degradation of several alkaloid N-oxides to phenanthrenes has been studied.2Q7 ':p;e MeO OH NATURAL PRODUCT REPORTS 1988-K. W. BENTLEY 0-Me (1 25) (126) Me0 OMe (128) (129) (130) M eMe0 (1311 o R M eH (132)(lpCHO \ / (133) (134) (135) OH H -1 HO Me0 (136 1 (138) Treatment of the tetrahydroisoquinoline (1 39) with 3,4- dimethoxybenzyl bromide and t-butyl-lithium followed by N-methylation of the product gave 4-methoxyromneine with high enantiomeric specificity ; oxidation of this with thallium(rn) trifluoroacetate yielded ochoteine (140).,08 The 6’-bromobenzyl- isoquinolines (141) (142; R1= H R2= OH) and (142; R1= OH R2= H) have been photo-cyclized to 4-hydroxycreban- ine,209 ushinsunine,210 and oliverine,210 respectively.The effects of bulbocapnine on dopamine receptors,211 of corydine on mouse vas deferens,,12 of isocorydine on ventricular NATURAL PRODUCT REPORTS 1988 ?H (:y:e \ / OMe OMe muscles,213 and of apomorphine on beha~iour,~l~-~~~on appetite,225on the release of histamine,226 on foetal lambs,227 on (141) (142) spinal reflexes,228 on the metabolism of d~pamine,~~~.230 on levels of tetrahydr~biopterin,~~~on phago~ytosis,~~~ and on the effects of morphine,233 ~lonidine,,~~ and haloperid01~~~ have been studied. 17.3 Dimeric Aporphines Two dimeric aporphines representing a new class of alkaloid have been isolated from Popowia pisocarpa.13 The structures of bipowine (143) and bipowinone (144) were deduced from their spectra and from the easy aerial oxidation of the former to the latter.Since bipowine is 7,7’-bis(6a,7-didehydrowilsonirine) an attempt was made to prepare it by the oxidation of wilsonirine with N-chlorosuccinimide followed by sodium ethoxide which afforded principally pancoridine (145) with a small quantity of its dimer bipowinone. Dehydronorglaucine can be dimerized by sodium ethoxide to 7,7’-bis(dehydr0-norglaucine) identical with 0,O’-dimethylbipowine. l3 17.4 Oxoaporphines Oxoaporphine alkaloids have been isolated from the following species that marked with an asterisk being new Desmos dasymachalus201 dicen trinone Fissist igma glaucescens 23 kuafumine* (1 46) Guatteria ouregoullg lysicamine 0-methylmoschatoline and subsessiline Guatteria ~agotiana~~ liriodenine oxoanolobine oxolaureline and oxoputerine Popowia pisocarpa13 liriodenine Sapran thus ~alanga~~~ liriodenine Ring-opening of aporphine alkaloids with ethyl chloroformate to phenanthrenes followed by hydrolysis of the N-carbethoxy- compounds to secondary bases and then oxidation affords the phenanthraquinones (1 47) which yield oxoaporphines when they are treated with a base in the presence of oxygen.In this way secoglaucine (147; R1= R2 = Me R3 = R4= OMe) affords 0-methylatheroline (148; R’ = R2 = Me R3 = R4= OMe) and secoroemerine (147; R1R2= CH, R3= R4= H) affords liriodenine (148; R1R2= CH, R3= R4= H).238 OMe (145) OMe (146) NATURAL PRODUCT REPORTS. 1988-K. W. BENTLEY 28 I 17.5 Dioxoaporphines Dioxoaporphines have been isolated from the following species the two marked with an asterisk being new Guatteria ouregou' '' norcepharadione-B (149; R' =R2 = Me R3 =H) and ouregidione* (149; R' = R2 =Me R3 =OMe) norcepharadione-A* (149; R1R2 =CH, R3 =H) Oncodostigma mono~perma~~' O-methylmoschatoline and ouregidione Pseuduvaria ma~rophylla~~~ (1511 17.6 Phenanthrenes A new phenanthrene alkaloid isouvariopsine (1 50) has been isolated from Hedycurya ang~stifolia,~~~ argentinine has been isolated from Popowia pisocarpa l3 and thalflavidine and thaliglucine have been isolated from Thalictrum cultratum.41 17.7 BenzylisoquinolineAporphine Dimers Dimeric alkaloids of this group have been isolated from Thalictrum species as follows the seven marked with asterisks being new 'soJT Me0 Thalictrum cultratum4'* 241 adiantifoline thalibulamine* (15l) thalifaramine* (152; R = H) thalifaronine* (152; R =Me) (152) thalifaracine* (153; R' =R3 = R4=Me R2 =R5 = H) thalifarazine* (153; R' =H R2 = R3 =R4 = R5 =Me) thalifaberine (153; R1 = R2 = R3 = R4 =R5=M el thalifaretine* (153; R' = R3 =R4 = R5 =Me R2 =H) thalifarapine (thalifaroline) (153; R' = R2 =R4 = R5 = Me R3 = H) thalilutine thalmelatidine and thalmineline oR3 Thalictrum faberi242 thalifalandine* (153; R1 =R2 =R3 =R5 =Me R4 =H) Thalifaroline was claimed to be a new alkal~id,~' but the 3-0- demethylthalifaberine structure that has been assigned to it is the same as that of thalifara~ine.,~~ The structures of the new alkaloids were determined by spectroscopic methods.'0 17.8 Aristolochic Acids and Aristolactams 153) Aristolochic acid and the new aristolochic acid E (154) have been isolated from Aristolochiu contorta. l'' Six new aristo- lactams have been isolated namely enterocarpam-I (1 55 ;R = OMe) and enterocarpam-I1 (355; R =H) from Orophea enter~carpa,~~and the lactams (1 56 ;R' =OMe R2=CH,OH R3 =H) (156; R' =OMe R2 =CH,OH R3 =OMe) (156; R1 =OH R2 =CO,H R3 =H) and (156; R1 =OH R2 = CO,H R3 =OMe) which have not been given simple names from A ris tolochia argent ina. 245 17.9 Oxoisoaporphines OMe Menisporphine (157 ;R =OMe) has been catalytically reduced to bianfugecine (157; R =H) with loss of the methoxy-group at position 1 in a process analogous to the reduction of the oxoaporphine O-methylatheroline to 2,9,1 O-trimethoxyoxo- (154) (155) ap~rphine.~~~ OMe 12 NPR 5 17.10 Other Aporphinoid Alkaloids The azahomoaporphines dragabine (158; R = Me) and nor- dragabine (158; R = H) which represent novel alkaloid structures have been isolated from Guatteria ~agotiana~~ 247 and Meiogyne ~irgata,,~~ respectively.Their structures were determined spectroscopically. 1,6-Diazafluoranthene (1 59) has been isolated from Cananga odorata and given the name ~ampangine.,~~ This base was previously isolated from Eupomatia laurina as eupolauridine the structure of which was confirmed by synthesis;249 it was assumed to be a modified aporphine. 18 Morphine Alkaloids Alkaloids of this group have been isolated from the following species the two marked with asterisks being new Fumaria densfloral" isosalutaridine Papaver pse~do-orientale~~* 149 salutaridine and thebaine Sapran thus ~alanga~~' se biferine Stephania epigeae205 sinoacutine and sinomenine Step han ia japonica 50 prostephanaberine* (1 60) and stephanaberine* (1 6 1) Thalictrum fa~riei',~ ocho bo trine Thebaine has been isolated from callus cell cultures of Papaver bracteatum.251 \/ Me0 NF Me0 (164) Me0 / 0r (167) NATURAL PRODUCT REPORTS 1988 The structures of the new alkaloids were determined by n.m.r.spectroscopy and by the conversion of prostephanaberine into stephanaberine by hydrochloric Some recent work on the morphine alkaloids has been reviewed.252 Cleavage of the nitrogen-containing ring of thebaine with ethyl chloroformate has been and this process has been adapted to provide an easy route from thebaine to neopinone.If treated with P-trimethylsilylethyl chloroformate and potassium carbonate thebaine gives the dienone (162; R = Me,SiCH,CH,OCO) which can be hydro- lysed by trifluoroacetic acid to the salt of the secondary base (162; R = H). This when neutralized with sodium bicarbonate suffers addition of the free base to the dienone to give neopinone (163) and codeinone (164) in a 6 1 ratio. A third base which may be (1 65) is formed in small quantity. Thebaine reacts with toluene-p-sulphonyl bromide to afford (162; R = SO,C,H,Me) which resists hydrolysis to (162; R = H).254 Another report of the conversion of thebaine into codeinone and codeine by previously described methods has been published.255 Dihydrocodeinone and dihydromorphinone have been found to react with 2-nitrobenzaldehyde to give the indoxyl derivatives (166; R = Me) and (166; R = H) rather than the 2-nitrobenzylidene ketones.256 Diels-Alder addition of 2-thiolen-4-one 1,l -dioxide to thebaine affords (167) which isomerized to (1 68) if treated with cold sodium methoxide and which is rearranged by hot sodium methoxide to (169) analogous to the product of rearrangement of dihydrothebainequinone.Boiling sodium bicarbonate in methanol converts (1 67) into (1 70) presumably by degradation to the @-unsaturated ketone followed by addition of methanol to give a P-methoxy-ketone which can then rearrange in the --NMe ' 'NMe R / 0 (165) (166) M eO MeoQHO 'Me OMe OA Me (169) (170) NATURAL PRODUCT REPORTS 1988-K.W. BENTLEY same way as the adduct of thebaine and methyl vinyl ketone. Thermally induced rearrangement of the adduct (1 67) to (1 7 1) has been reported but this must involve oxidation since the two bases differ in Benzylidene derivatives of (167) (168) and (171) have been obtained starting from the benzylidene derivative of the dien~phile.~~' Attempts to hydrogenate the ester (172) which had pre- viously been prepared from thebaine and methyl propiolate afforded the rearranged product (173) the structure of which was determined crystallographically. 258 Details of the preparation of the following have been given norcodeine and its N-alkyl and other N-substituted deriva- tive~,~~~ N-[2-(4-azidophenyl)ethyl]dihydronormorphine and its 7,8-di tri tiated analogue 260 [N-methyl-13C] thebaine 26 pure (+)-salutaridine and (-)-thebaine (from 6-0-demethylsalu- taridine),261 /3-dihydrothebaine and 6-demethoxy-/3-dihydro- thebaine,262 6-demethoxythebaine and its 6-chloro- and 6-bromo-deri~atives,~~~ 3-0-acyl derivatives of a range of 3- hydroxy-compounds (as potential pro-drug~),~~~ 3-0-( 1,2-dichlorovinyl)morphine,265 14-chloro-and 14-bromo-6-0-tosylcodeine,26614-hydroxydihydronormorphinoneand its N-and O-substituted derivatives,267 14-hydroxy- and 14-meth-oxy-dihydrothebainone and their derivatives,268 6-N-methyl- 283 a variety of derivatives of naltrexamine of structure (174) in which R is NMeCH2CH2C1,271.272 NCS,272 NHC(0)CH21,272 [NHC(0)CH2]l-,N(CH2CH2Cl)2,273 or mHC(O)CH,],_,NHC- (0)CH=CHC02Et273 and bimolecular amides of naltrexamine in which two basic (174) units are linked by the system [NHC(O)CH,],_,NHC(O)CH :CHC(0)NH[CH2C(O)NH]l_,274 or ~HC(0)CH2]l-3NHC(O)CH2NH[CH2CH2C(O)NH]l-3,275 the bimolecular pyrroles (175; R = H) and (175; R = Me),276 b~prenorphine~~~ l'c-labelled buprenor~hine,~~~ and the pyrrolidinocodeine (1 76),263 phenylethyldihydrothebaine (asocain~l),~~~ 11-0-2-chloro- and 2-bromo-apo~odeine,~~~ methyl-N-propylnorapomorphine,281and the endu-etheno-compounds of general structure (177) in which R1is H NCS or NHC(O)CH,Br and R2 is ally1 or cyclopropylmethyl.282 The preferred conformations of some morphine derivatives have been determined by analysing their spin-lattice relaxation and the mass spectra of alkaloids of the hasu- banonine group have been The metabolism of norcodeine to normorphine has been dem~nstrated.~~~ A new synthesis of codeinone and neopinone has been achieved.The dibromo-compound (1 78) was cyclized by butyl- lithium to (179) which was oxidized to the aldehyde (180); this was converted (through the N-methylimine) into (1 8 1; other ester analogues of funaltre~amine,~~~ funaltre~amine,~~~ R = CH2CH2SiMe3). Oxidation of this to the ketone R C02Me C0,Me HO Me0 I k' (175) (176) (177) 9 SO,Ph H0' Me%cHo SO*Ph HO' HO'' (179) (180) 12-2 284 NATURAL PRODUCT REPORTS 1988 followed by conversion into the enol ether gave (182; R = 14-O-chloroacetylnaltrexone,506 f~naltrexarnine,~~O-~~~ N-CH2CH2SiMe3),which in the presence of potassium t-butoxide cyclopropylmethyl-7a-(2-hydroxy-5-methylhex-2-~1)-6,1 4-endo-phenylethyldihydrothebaine suffered elimination to give the dienol ether (183; R = ethenotetrahydron~roripavine,~~~ CH2CH2SiMe3).Bromination and hydrolysis of this diene (as~cainol),~~~ and ~inomenine.~~~ afforded the dienone (162; R = OCOCH2CH2SiMe3),whose preparation from thebaine and conversion into neopinone and codeinone is described above.286 A novel synthesis of salutaridine (186) has been achieved from the tetrahydroisoquinoline (184) by cyclization with stannic chloride to the dienone (185) followed by dehydro-genation with 2,3-dichloro-5,6-dicyanobenzoquinone.287 A syn-thesis of the ketone (191 ;R1R2= 0)which constitutes a formal synthesis of O-methylpallidinine has been achieved from (187).This on reduction with sodium borohydride and cyclization with formic acid gave (188) which was converted into the aldehyde (189). This resisted cyclization but epimerization afforded (190) which was easily cyclized and converted via the alcohol (19 1;R' = H R2 = OH) into the ketone (19 1;R1R2= O).288O-Methylflavinantine has been obtained by the electro-lytic oxidation of laudanosine tetrafluoroborate under very Me0 simple conditions.289 Methods for the detection and estimation of morph-ine,45.290-296 codeine,45.291,294,297.298 heroin 298-305 thebaine,45 7 307 dihydrom~rphinone,~~~ dihydroc~deinone,~~~~ 14-hydroxy-But MezSi0 dihydromorphin~ne,~~~ 310 and etorph-6-O-a~etylmorphine,~~~ ine311have been reported and a reagent for the production of fluorescent derivatives of ketonic alkaloids of the group has been described.312 Me0 The analge~ic~l~-~~~ prop-and the psychopharmac~logical~~~ erties the pharmac~kinetics,~~~-~~~ 346 and the metabolism345-of morphine and the effects of this alkaloid on the brain,347-355 on the gastro-on behavio~r,~~~-~~l cardio-va~cular,~~~-~~~ inte~tinal,~~~-~~~ systems on re~piration,~~~-~~~ and nervous388-395 on the immune respon~e,~~~.~~~ on the spinal ~~rd,~~~,~~~ on body temperature,406on the bladder,407on the production OMe of urine,408on haemorrhagic on locomotor "'"o\ on muscle rigidity,410on the electrophysiological properties of HO muscles,411on phagocytic function,412on the production of antibodies,413on the synthesis of DNA,414on the synthesis of proteins in brain on the intake of sugar,416on tests ofliver on the growth ofmetastatic turn our^,^^^ on the production of gonadotr~phin,~~~ of lutein-of prola~tin,~~~-~~~ izing 424 of the atrial natriuretic of cyclic 0 AMP,426and of cortico~terone,~~~ on the activity of adenylate cycla~e~~~ and and of ATP~s~,~'~on the effects of clonid-(186) (187) 29v ine 430 hal~peridol,~~ erap pa mil,^^^ yohimbine,433 pheno-have thi~pental,"~and apom~rphine~~~ been studied as has the relationship between morphine addiction 437 and diabetes mellitu~.~~~.OMe OMe The morphine antagonist properfie~~~~-~~~ and the pharma-cokinetic~~~~ of naloxone have been studied as have the effects of this base on the brain,449-451on the cardio-vascular 452-460 on the gastro-intestinal 378 383 on H CO on haemorrhagic ~ho~k,~~~-~~~ beha~iour,~~l-~~~ endotoxin Bzo8 ~ho~k,~~~+~~~ on muscle NCOZBZ and anaphylactic on synapatic on hyp~thermia,~~~ on intake I of and of water,479on the production of growth horm-CHO of luteinizing hormone,423.424.481 of peptides that are derived from pr~dynorphin,~~~ of neutrophil ~uperoxide,~~~ (188) (189) and of cyclic AMP,484on the activity of ~-aminopeptidase,~~~ and on the physiological effects of anaesthetics,486dextro-meth~rphan,~~~ergot alkaloids,488 chlordiazepoxide,489'490 s~lpiride,~'~valproic acid,490and turpentine.492 The pharmacological and physiological effects of the fol- Me0 Me0 OMe lowing have also been studied dihydrom~rphine,~~~14- hydroxydihydromorphinone 493 6-azidodeoxymorphine,494 495-500 bupren~rphine,~~~.365*501 et~rphine,~~l-~~~di-hydr~etorphine,'~~.147 16-methyl~yprenorphine,~~~14-bromo- C0,Bz acetamid~morphine,~~~nal~rphine,~~~nalorphine 7,8p-ep~xide,~~~nalb~fine,~~~.508-510 nalmefene,511.512 naloxone BzO methobr~mide,~~~.513 naloxona~ine,~~~*514* 515 naltrex- one,332,444,446.462.481.493.516 519 naltrexone methobr~mide,~~~ (190) (191) NATURAL PRODUCT REPORTS.1988-K. W. BENTLEY 285 tetrahydrocolchicide (1 97) and derivatives which have been 19 Phenet hylisoqu ino1 ines oxidized to colchi~ides.~~~ Full details of the synthesis of Two new homoproaporphine alkaloids have been discovered.deacetamidocolchicine from the a-pyrone (198) that was Isoregecoline (192; R1 = OH R2 = H) isolated from Col-described in the previous Report have been published.534 chicum kesselringii is an epimer of regecoline (192; R1 = H The effects of colchicine on the brain,535 on the ovaries,536 R2= OH) ;528 collutine isolated from CoZchicum Zuteum has and on the development of have been studied. been assigned the structure (193).529 On spectroscopic evidence the structure of luteidine has been amended to (194),529and an X-ray study indicates that the structure should be (195) for U-21 Other Alkaloids methylkesselringine rneth~bromide.~~~ Full details of one of the syntheses of aaptamine (199) that were described in the previous Report have been published538 and the synthesis has been adapted to prepare demethyloxy-20 Colchicine aaptamine (204) which occurs together with aaptamine.Re- Convenient racemization of colchicine and several of its duction and cyclization of the nitro-ester (200) yields the derivatives by acetic anhydride has been achieved and resolution lactam from which (201 ; R' = H R2= But) (201 ; R' = Bz of the racemates has afforded quantities of derivatives of (+)-R2= But) and (202) were successively prepared. Reduction of colchicine for pharmacological evaluation.531 Isocolchicine has the lactam (202) gave the amine (203) which yielded (204) on been converted into 1 1 -methylthioisocolchicine (196) ;532 thio-dehydrogenation over palladium.538 colchicine and its derivatives have been converted into Necatorin first isolated from the fungus Lactarius necator Me MeO.a: N#Me R' N Me0Me0 M e\o q N H A c Me0 \ ::ZMq \' MeS 0 0 HO 0 (195) (196) (198) Xvco2R2 Et 0,C / 0 (200) (201) "'OWNHMeowNH BzO \ BzO Me'.0 HNvJ HN$ 0 (2021 (203) (204) NATURAL PRODUCT REPORTS 1988 15 16 17 18 19 (2051 (206) 20 21 22 23 24 25 OMe OH 26 (207) (2081 27 28 29 30 31 32 33 (2 09) 34 35 and originally assigned the structure of a coumarocinnoline 539 has been shown to be identical with necatorone which was 36 isolated from the same source and assigned the structure (205) [which bears obvious similarities to (204)] on spectroscopic 37 This structure has been confirmed by synthesis.Bischler-Napieralsky cyclization of the amide (206) afforded 38 the dihydroisoquinoline (207) which was oxidized and de- 39 methylated to (208; R = NO,). 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ISSN:0265-0568    

DOI:10.1039/NP9880500265

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Quinol i ne Qui nazol ine and Acridone Alkaloids M. F. Grundon Department of Chemistry The University of Ulster Coleraine Northern Ireland B 152 ISA Reviewing the literature published between July 1985 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 225) 1 1.1 1.2 1.3 1.4 1.5 2 2.1 2.2 3 3.1 3.2 3.3 4 Quinoline Alkaloids Occurrence Non-terpenoid Quinolines Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids Furoquinoline Alkaloids Dimeric Quinolinone Alkaloids Quinazoline Alkaloids Quinazolin-4-ones Py rroloquinazolines Acridone Alkaloids Occurrence and Structural Studies Synthesis Polymeric Acridones References R' R4 OMe OE t OMe OMe H (2) 0 Me (6 R Me OH / 1 Mester' has published a valuable account of the occurrence of alkaloids in the Rutales ;quinoline quinazoline and acridone alkaloids are included and the review covers the literature up to 1982.1 Quinoline Alkaloids 1.1 Occurrence Sixteen new quinoline and quinolinone alkaloids have been reported during the period of coverage of this review and are included with known alkaloids that have been obtained from new sources in Table 1.1-21 A study of the alkaloid content of Agathosma species2 showed that five contain the furoquinoline alkaloid skimmianine ; the trimethoxyquinolin-2-one halford-amine (2) which was obtained prr'ously only from HalJbrdia scleroxyla was also isolated from three members of this group.A 4-ethoxyquinolin-2-one structure was proposed for an alkaloid that has been found in Glycosmis pentaphylla6 and three 4-ethoxyfuroquinolines (3) which are believed not to be artefacts of the isolation procedure were isolated from Dic-tamnus da~ycarpus.~ Five species of Haplophyllum were investi- gated mainly by Bessonova Yunusov and their co-workers ; quinoline alkaloids were obtained from H. glabrinumg and from H. IeptomerumlO for the first time. In H. acutfolium the content of a 2-nonadienyl- and 2-nonyl-quinolin-4-one and of the 2,2-dimethylpyranoquinolinehaplamine (5; R' = OMe R2 = R3= H) was highest during the formation of flower buds but in general the site of growth affected the alkaloid composition in this plant more than the season.' Variability of the production of quaternary dihydrofuroquinoline alkaloids in tissue cultures of Choisya terncta has been studied.22 1.2 Non-terpenoid Quinolines The methyl ether of the 3-methoxyquinolin-2-one alkaloid swietenidin A was synthesized earlier (cf.ref. 23a) and a synthesis of the alkaloid itself has now been described by CoppolaZ4 (Scheme 1). The reaction of 8-methoxy-N-methyl- isatoic anhydride (8) with the lithium enolate of ethyl methoxyacetate followed by thermal cyclization of the product gave swietenidin A (9) in 71 YOyield. The structure of the new alkaloid leptornerine N-methyl-2- (3) (5) 0 (8) \ 0 Reagents i MeOCH,CO,Et LiNPr', THF at -78 "C ; ii PhMe reflux Scheme 1 293 NATURAL PRODUCT REPORTS 1988 Table 1 Isolation of quinoline alkaloids Species Aga t hosma bisulca Agathosma capensis Agathosma peglerae Agathosma sp.nov. Agathosma thymifolia Dictamnus dasycarpus Echinops ech inatus Geijera balansae Gly cosm is pen taph y Ila Haplophy llum acu tifo lium Haplophyllum foliosum Haplophyllum glabrinum Haplophyllum leptomerum Haplophyllum obtusifolium Haplophyllum perforatum Helietta parvifolia Melicope confusa Ruta chalepensis Sarcomelicope argyrophylla Sarcomelicope glauca Alkaloid (Structure) Ref. Halfordamine (2) Skimmianine (1 ; R’ = R2 = H R3 = R4= OMe) Skimmianine 2 Halfordamine Skimmianine *( -)-cis-3’,4’-Dihydroxy-3’,4’-dihydroflindersine (44) y-Fagarine (1 ; R’ = R2 = R3 = H R4 = OMe) Flindersine (5; R’ = R2 = R3 = H) *4’-Hydroxy-3’,4’-dihydroflindersine (42) 4-Methoxy- 1 -methylquinolin-2-one (+)-Platydesmine Evodine [I ; R‘ = R2 = H R3 = OCH,CH(OH)C(=CH,)Me R4 = OMe] Evoxine [l ;R’ = R2 = H R3 = CH,CH(OH)C(OH)Me, R4 = OMe] y-Fagarine Flindersine Haplophydine (1 ; R’ = R2 = R3 = H R4 = OCH,CH=CMe,) .7-Isopentenyloxy-y-fagarine(1 ; R’ = R2 = H R3= OCH,CH=CMe, Methylevoxine [I ; R’ = R2 = H R3 = OCH,CH(OH)C(OMe)Me, R4 Perfamine (61) y-Fagarine *Leptomerine (6;n = 2) N-Methyl-2-phenylquinolin-4-one Skimmianine Dictamnine y-Fagarine *Haplobine (58) Robustine (I ; R’ = R2 = R3 = H R4 = OH) *Haplafine (33) Maculine (1 ; R’ = R4 = H R2R3 = OCH,O) Heliparvifoline (1 ;R’ = R4 = H R2 = OMe R3 $ 9 R4 = OMe) = OMe] 12 13 14 15 17 = OH) *3’-Hydroxygraveoline (10) Acronycidine (1 ;R’ = R3 = Dictamnine Evolitrine (1 ; R’ = R2= R4 Dictamnine Evolitrine R4 = OMe R2 = H) = H R3 = OMe) Haplopine (1 ;R’ = R2 = H R3 = OH R4 = OMe) *7-Hydroxy-8-(3-methylbut-Zenyl)-Cmethoxyfuro[2,3-b]quinoline (59) Kokusaginine (1 ; R1 = R4 = H R2 = R3 = OMe) 4-Methoxy- 1 -methylquinolin-2-one N-Methylflindersine (5; R1 = R2 = H R3= Me) Skimmianine NATURAL PRODUCT REPORTS 1988-M.F. GRUNDON Table 1 (continued) Species Alkaloid (Structure) Skimmia reevesiana Evodine Evoxine Haplopine 7-Isopentenyloxy-y-fagarine *Reevesianine-A (13) *Reevesianine-B (14) Skimmianine Tinospora malabarica Kokusaginine Zanthoxylum acanthopodium Skimmianine Zanthoxylum tessmannii Skimmianine * New alkaloids 0 *#YO’ OH (1 0) 0 (11) R’ = R2 = H (12) R1 = OMe R2 = H Reevesianine-A (13) R’ = H R2 =OH Reevesianine-B (14) R’ = OMe R2 = OH propylquinolin-4-one (6 ; n = 2) from fiaplophyllum lepto- merum was determined by spectroscopic studies1” Three new 2- arylquinolin-4-ones have been reported.The structure of 3’- hydroxygraveoline (lo) which was isolated from Ruta chale- pensis,15 was established mainly by its IH n.m.r. spectrum which is similar to that of graveoline (1 7) except for doublets at 6.90 and 6.87 p.p.m. These have been attributed to meta- coupled protons at C-2’ and C-6’; graveoline is also a constituent of the plant.Reevesianine-A (1 3) and reevesianine- B (14) were found in Skimmia reevesiana.18 The structures of both alkaloids were determined by spectroscopy. The presence of a quinolin-4-one carbonyl group in reevesianine-A was indicated by an infrared absorption at 1610 cm-I by a high- field IH n.m.r. resonance at 8.28 p.p.m. (5-H) and by a resonance at 176.8 p.p.m. in the 13C n.m.r. spectrum of 0-acetylreevesianine-A; the 13Cn.m.r. data for the two alkaloids were compared with those for the related compounds (1 1) and (12). New approaches to the synthesis of 2-arylquinoline alkaloids have been reported. Thus Terashima and co-workersZ5 allowed the boron derivative (15) to react with l-bromo-3,4- methylenedioxybenzene in the presence of a PdO catalyst under phase-transfer conditions to give the alkaloid dubamine (16) in Ref.19 20 21 42 % yield (Scheme 2); subsequent methylation and oxidation furnished the quinolin-4-one alkaloid graveoline (1 7). The styryl derivative (18) was obtained from the reaction between the boroquinoline (15) and the vinyl bromide (19) in 50% yield ; catalytic reduction followed by methylation then fur- nished the alkaloid cuspareine (22) in good yield. Kametani et a1.26prepared dubamine (16) in very poor yield by the reaction of the Schiff base (20) with ethyl vinyl ether and a Lewis-acid catalyst but the application of this procedure to compound (21) (prepared from aniline and 3,4-dimethoxycinnamaIdehyde) provided an alternative route to the styryl derivative (18) also in 50% yield (Scheme 2).Buchi et al.27 have reported a new six-step synthesis of the bacterial coenzyme methoxatin (30) (see Scheme 3) from the indole derivative (23) the benzyl derivative of which is commercially available. The Michael reaction of the dehydro- derivative (24) with the protected amino acid (25) gave the intermediate (26) which was converted into a mixture of the chlorinated oxidation product (27) and its tetrahydro- derivative ; the latter was oxidized to the former with mangan- ese dioxide or nickel oxide. Compound (28) was obtained by treating (27) with acid and when (28) was heated it was converted into the methoxatin triester (29) in good yield probably via the ally1 derivative (31) and the corresponding imine followed by electrocyclic ring-closure and elimination of hydrochloric acid.Hydrolysis of the triester with lithium hydroxide furnished methoxatin (30). A full account has now been published of the synthesis of methoxatin by Rees and co-workersz8 (cf. ref. 23a). 1.3 Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids The N-methyl-U-prenylquinolin-2-one ravenine (32) is believed to be a precursor of 1,I-and 1,2-dimethylallylquinoline alkaloids with which it co-occurs in Ravenia spectabilis and now the compound without a N-methyl group has been isolated from Haplophyllum perforaturn and named haplafine (33). The structure of haplafine was determined mainly by spectroscopic studies.12 Grundon and Ramachandran recently carried out the synthesis and interconversion (by a Claisen rearrangement) of the C,O-diprenylquinolinone (34) and the 3- (1,l-dimethylallyl)-3-(3,3-dimethylallyl)quinolinone alkaloid buchapine (35) (cf.ref. 23 b). Bellino and Vent~rella~~ have now reported a similar synthesis of buchapine. A new alkaloid folidine was isolated from Haplophyllum foliosum and shown to be the 8-(3-methyl-2-oxobutoxy)quinolin-2-one (36).* The structure was indicated by infrared absorptions at 1730 (ketonic C=O) and 1640 cm-I (quinolin-2-one carbonyl group) by the ‘H n.m.r. spectrum and by the cleavage of the molecule in the mass spectrometer between C-1’ and C-2’ to give fragment ions of rn/z71 (Me,CHCO) and of m/z218 (CH,OAr); the conversion of folidine into folifidine (37) by fusing it with an NATURAL PRODUCT REPORTS 1988 Iiii 0 (19) (18) v ii t Reagents i BuLi Et,O at -70 “C; ii 9-methoxy-9-borabicyclo[3.3.llnonane ; iii l-bromo-3,4-methylenedioxybenzene,KOH Bun,NBr (PPh,),Pd PhH reflux; iv CF,SO,Me at 50 “C; v K,[Fe(CN),] 20% NaOH; vi KOH Bu”,NBr (PPh,),Pd PhH reflux; vii EtOCH =CH, BF .Et,O CH,Cl,; viii H, Pt EtOH; ix NaH THF then Me1 Scheme 2 alkali confirmed that the prenyloxy side-chain is located at dihydrodimethylpyranoquinolinone derivative^.^ One of these C-8. alkaloids is (42) which can be regarded as a hydrate of A prenylquinolin-2-one alkaloid that has been isolated from flindersine (52; R = H) with which it co-occurs; the gross the root-bark of Gfycosrnis pentaphylfa was named homo- structure was apparent from its spectral characteristics glycosolone and assigned structure (38) mainly on the basis of especially the lH n.m.r.spectrum which resembles that of the infrared and lH n.m.r. spectroscopy although the latter N-methyl analogue (43) that is a constituent of Euxylophora technique does not establish the presence of an ethoxy-group in paraensis (cf ref. 30a). The absolute configuration of (42) has the alkaloid.‘j The reaction of homo-glycosolone with an acid not yet been determined. The second alkaloid was shown to be gives a product that has been formulated as an isopropyl-cis-3’,4’-dihydroxy-3’,4’-dihydroflindersine(44) by spectro-furoquinolinone (39) instead of a dimethyldihydropyrano-scopic and chemical studies.In the ‘H n.m.r. spectrum doublets quinoline that would be expected from cyclization of a at 5.61 (J = 3 Hz) and 4.80p.p.m. (J = 5 Hz) were attributed to 3-prenylquinolin-2-one. Further work on the structure of hydroxyl groups at C-4’ and C-3’ respectively and if D,O was homoglycosolone is promised and will be awaited with interest. added to the sample resonances at 4.74 (4’-H) and 3.65 p.p.m. The structure (41) which was proposed for the dihydro- (3’-H) were changed to an AX system (J = 6 Hz). The latter dimethylpyranoquinolinone alkaloid ravesilone on rather in- coupling constant excluded a trans-diaxial configuration for the secure evidence (cf. ref. 23c) has now been confirmed by protons at C-4’and C-3’ but did not distinguish between a synthesis.29 Thus N-methylation of the 8-methoxyquinolin-2- trans-diequatorial and a cis-axial-equatorial arrangement.This one (40) followed by reaction with hydrobromic acid gave the ambiguity was resolved by chemical means. The reaction of 8-hydroxy-N-methylquinolinone(4I) identical with the alka- flindersine (52; R = H) with chromic acid in acetic acid (as loid (Scheme 4). Two new optically active alkaloids that have described by Brown et af.31) gave ( )-trans-4’-acetoxy-3’-been obtained from Geijera balansae were also shown to be hydroxy-3’,4’-dihydroflindersine (45) which with sodium 297 NATURAL PRODUCT REPORTS 1988-M. F. GRUNDON OH II 0 Et 0,C (23) (24) NHCbz + OH (26) R = C0,Me (25) I iii Et 0,C HO 0 (31) (28) R = C0,Me (27) R = C02Me + t et ra hydr 0 -der i vat ive (Cbz = CO,CH,Ph) Reagents i MeCN KH,PO, H,O at 20 "C;ii Et,N THF ;iii N-chlorosuccinimide Et,N CH,Cl, then 2,3-dichloro-5,6-dicyanobenzoquinone or MnO,; iv MnO or NiO Et,N CH,Cl, v CF,CO,H; vi PhC1 at 131 "C Scheme 3 0 (32)R = Me (34) (35) Haplafine (33)R = H Me O--+ (If 0 HO Me Folidine (36) (3 7) Homo-glycosolone (38) (39) NATURAL PRODUCT REPORTS 1988 (40) (411 Reagents i MeI K,C03 Me,CO reflux; ii HBr AcOH reflux Scheme 4 (42)R = H (43)R =Me (44) (45)R = Ac (46)R = H methoxide in methanol was converted into the corresponding ( f)-trans-3',4'-dihydroxy-derivative(46) ; the 'H n.m.r.spec- trum of the latter compound was clearly different from that of the natural diol and the coupling constant [J(3',4') = 5 Hz] indicated that the protons at C-3' and C-4' had a diequatorial arrangement in the synthetic product.The cis structure (44) of the alkaloid was confirmed by synthesizing the racemate by the reaction of flindersine with osmium tetraoxide in pyridine although the absolute stereochemistry was not established. As expected for a cis-1,2-dio17 compound (44) was converted into an acetonide by its reaction with acetone and sulphuric acid. The dimethylpyranoquinolinone alkaloids flindersine (52 ; R = H) and its 8-methoxy-derivative were prepared some years ago from thallous salts of 4-hydroxyquinolin-2-onesand 3- chloro-3-methylprop-1-yne.32 new investigation by Reisch A and co-w~rkers,~~~ 34 who used a phase-transfer catalyst resulted in the synthesis of flindersine (52; R = H) and N-methyl- flindersine (52; R = Me) (Scheme 5).The furoquinolinones (47) and (48) and the dimer (49) were identified as minor products. The reaction mechanisms which may involve the formation and rearrangement of 4-ethers (50) and the dienone (51) were discussed. The first synthesis of the alkaloid haplophylline (53) was carried out by allowing flindersine to react with the chloromethyl ester of 3-methylbut-2-enoic A new synthesis of 4-hydroxyquinolin-2-ones is applic- able to quinoline alkaloids.35 For example the ketene imine (54) which was prepared from the phosphonate (55) and phenyl isocyanate cyclized thermally to the 4-hydroxy-3-prenyl derivative (56); reaction with 2,3-dichloro-5,6-dicyano-benzoquinone then gave the 2-ethoxypyranoquinoline (57) (Scheme 6).1.4 Furoquinoline Alkaloids A new chlorine-containing furoquinoline haplobine was isolated from the root of Haplophyllum obtusifolium and assigned structure (58) on the basis of the 'H n.m.r. and the mass spectrum and its hydrolysis to 7-hydroxy-8-methoxy- dictamnine (haplopine) (1 ; R' = R2= H R3 = OH R4= OMe)." A new furoquinoline alkaloid of Sarcomelicope glauca was shown by spectroscopic and chemical studies to have the unusual structure (59) in which a 3-methylbut-2-enyl group is adjacent to a phenolic hydroxyl group;17 the diprenyl-furoquinoline (60) had been synthesized earlier and was converted into alkaloid (59) by its reaction with hydrogen bromide in methanol at ambient temperature.The alkaloid perfamine (6 1) and related furoquinolines that contain partly reduced homocyclic rings were obtained pre- viously only from Haplophyllum perforatum but Reisch and co-workersg have now isolated perfamine and the new alkaloid 5,6-dihydroperfamine (62) from the roots of Haplophyllum glabrinum. The spectroscopic properties of dihydroperfamine are similar to those of perfamine except that a four-proton multiplet is present at 2.5-3.3 p.p.m. (protons at C-5 and at C-6) in the 'H n.m.r. spectrum. The structure of dihydroperfamine was determined by X-ray analysis. This result combined with the spectroscopic data also confirms the constitution of perfamine (cf refs.30a and 236). The alkaloid taifine from Ruta chalepensis was assigned the N-ethyl-7-methoxyquinolin-4-one structure (63) rather than the isomeric 7-ethoxy-N-methyl derivative on the basis of a comparison of its 'H n.m.r. spectra in neutral and in acidic solvents (cf ref. 30 b). The N-ethylquinolin-4-one derivative (63) now has been ~ynthesized~~ by the modified procedure of Tuppy and Bohm (Scheme 7). Ethylation of the ketone (65) gave a mixture of the N-ethylquinolin-4-one (66) and the 0-ethylquinoline (67) which were converted into compounds (63) and (64) respectively. The N-ethylfuroquinolinone (63) (m.pt. 178 "C) was clearly not identical with taifine. (m.pt. I10 "C). Although the 4-ethoxyfuroquinolinone (64) has the same melting point as taifine and the lH n.m.r.data are close to those recorded for the alkaloid the final choice of structure must await direct comparison of samples. 1.5 Dimeris Quinolinone Alkaloids This subject has been re~iewed.~'.~~ A new dimeric quinolinone alkaloid C,,H,,N,O, isolated from Geijera balansae was given the name geijedimerine and assigned structure (68) principally on the basis of its spectro- scopic proper tie^.^ In the 'H n.m.r. spectrum in DMSO resonances at 7.83 and 7.92 p.p.m. were attributed to protons attached to C-5 in a quinolin-2-one ring and to C-5' in a quinolin-4-one ring respectively. Geijedimerine appears to have the same stereochemistry as paraensidimerin F (73) which is one of the alkaloids of Euxylophora paraensis (cf.ref. 234 since the resonances and the coupliing constants associated with the protons of rings A B and c are similar in the 'H n.m.r. spectra of the two alkaloids. Methylation of geijedimerine with methyl iodide and potassium carbonate gave the dimethyl derivative (69). The tetramethoxy dimeric quinolinone alkaloids vepridi- merine A (74) vepridimerine B (73 and vepridimerine C (70) are constituents of Vepris louisii and vepridimerines B C and D (71) were obtained from Oricia renieri (cf. ref. 30c). Ayafor et al.39 have reported a synthesis of the four dimeric alkaloids by pyrolysis of the dimethylpyranoquinolinone veprisine (76). A fifth isomeric product has not been obtained from natural sources and was given the name vepridimerine E and assigned structure (72) as a result of spectroscopic studies.There is no evidence that the quinolin-4-one moiety is on the 'left-hand side' of the molecule except by analogy with vepridimerines C and D (cf. ref. 234 but now that geijedimerine has been NATURAL PRODUCT REPORTS 1988-M. F. GRUNDON r 1 K -Q)yH [R = Me or HI Q&o R L R 0 1-(50) (52) 1 .1 ii [R =HI [R= Hor Me1 [R=HI OH NMe R I CH20C(0)CH=CMe2 (47) (48) (49) (53) Reagents i ClMe,CC CH Bu",NBr PhMe aq. NaOH ; ii ClCH,- OC(0)CH =CMe, THF NaH Scheme 5 0 II (EtO),P CH C0,Et I CHZCH =CMe iii/ (57) Reagents i NaH PhH or THF; ii heat at 180 "C; iii 2,3-dichloro-5,6-dicyanobenzoquinone,PhH reflux Scheme 6 0Me OMe A Haplobine (58) (59) R = H Perfamine (61) Dihydroperfamine (62) (60)R = CH2CH=CMe2 NATURAL PRODUCT REPORTS 1988 H H (65) A 0 Et (661 (671 iii iv iii v I 1 OEt Me0& Me0 \ Et (631 (641 Reagents i PhOPh at 240-256 “C;ii Et,SO, K,CO, DMF; iii NaBH, MeOH; iv fused KHSO, dioxane reflux; v conc.HCl Scheme 7 R’ R2 R” R2 5’ R2w Geijedimerine (68) R1= R2 = H; O -Hd a-He (69) R’ = Me R2 = H; O-H, a-He Vepridimerine c (70) R’ = Me R* =OMe; a-Hd a-H Vepridimerine D (71) R’ = Me R* =OMe; a-Hd O-H VepridimerineE (72)R’ = Me R2 =OMe; 0-H, a-He Paraensidimerin F (73)R = H; O-Hd a-He Vepridimerine A (74) R = OMe; oc-Hd a-He Vepridimerine B (75) R = OMe; a-H,,O-He .r Me (76) (77) gy+ NO Me (78) discovered the close correspondence between the lH n.m.r.spectra of vepridimerine E (72) and NN-dimethylgeijedimerine (69) is worth noting. The formation of the vepridimerines is regarded as occurring by thermal heteroelectrocyclic ring- opening of veprisine (76) to give a quinolinone quinone methide (77) leading to the diene (78) followed by Diels-Alder dimerization and then ring-closure to form pyranoquino-hones; the pericyclic reactions are in accord with Wood- ward-Hofmann rules. 2 Quinazoline Alkaloids 2.1 Quinazolin-4-ones A new quinazolin-4-one alkaloid echinozolinone which was isolated from Echinops echinat~s,~ was shown by spectroscopic studies to have structure (79). The nature of the side-chain was indicated by triplets in its ‘H n.m.r.spectrum at 4.12 (N-CH,) and 3.20 p.p.m. (CH,OH) and the presence of a carbonyl group at C-4 was apparent from a resonance at 8.00 p.p.m. (H-5). In the mass spectrum the base peak occurred at m/z 172 (M+-H,O); the absence of a fragmentation peak at m/z 163 which would be expected to arise (by retro-Diels-Alder cleavage of the heterocyclic ring) if a substituent is at N-1 confirmed that the side-chain was attached to N-3. Echinozolinone which had been synthesized before its isolation is the first quinazolin- 4-one alkaloid to be obtained from a species of the Compositae. 0 Ec hinozolinone (79 1 OH Vasicine (80)R = H Vasicinol (81) R=OH NATURAL PRODUCT REPORTS 1988-M.F. GRUNDON 30 1 + H,NCH2CH2CHCH(OEt)2 \ I Me0 NH2 OH aCHO \ Ill QLQ -Me0EqOH Me0 OH Adhavasinone (83) (82) Reagents i H,O at pH 2; ii H, Pd/BaSO, aq. MeOH; iii 30% HZO2 Scheme 8 0 0 &,Q-Qy-.q 0 (90)R' = Me R2 = OAc (91 1 R' = OH R2 = Me (92)~~ = OH RZ = H 0 H Me (93) OH Br Vasicinone (85) a1 dn "2 (84) 0 0 w P h vi ____) dAo H (86) (major) (87) Reagents i pyrrolidin-2-one CO [Pd(OAc),(PPh,)] K,CO, at 110 "C; ii N-bromosuccinimide; iii AgOAc; iv KOH; v (2-phenylethyl)amine CO [Pd(OAc),(PPh,)] K,CO, at 110 "C; vi ClCO,Et then KOH Scheme 9 Deoxyvosicinone (88) R = H (89) R =Me 2.2 Pyrroloquinazolines Vasicine (80) vasicinone (85) and deoxyvasicinone (88) were shown to be constituents of Adhatoda bedd~mei.~~ The antifertility and antifeedant activity against insects of extracts of Adhatoda vasica is due to the major alkaloids vasicine (80) vasicinone (85) and especially vasicinol (81); the latter has severe antifertility effects against Dysdercus koenigii and Tribolium castaneum and the alkaloids show feeding deterrence against Aulacophora foveicollis and Epilachna vig- intioctopunctata.41 Adhatoda vasica was shown by Chowdhury and Bhatta- ~haryya~~.43 to contain two new optically inactive pyrrolo- quinazoline alkaloids. Structure (82) was assigned to one alkaloid on the basis of its infrared absorptions at 3470 (OH) and 1630 cm-' (C=N) of the lH n.m.r. spectrum and of the mass spectrum in which there were fragmentation peaks at m/z 203 (M+-15) and 199 (M+-1-18); the compound had been prepared earlier but was synthesized by a different method from the diethyl acetal of 4-amino-2-hydroxybutan-1-a1 (Scheme 8).42Structure (83) for the second alkaloid which was given the name adhavasinone was also determined by spectroscopic studies and confirmed by its formation from the synthetic compound (82) by its oxidation with 30 YOhydrogen peroxide.43 New syntheses of quinazolinones involving palladium- catalysed carbonylation have been reported (Scheme 9).44 Thus the catalysed reaction of o-iodoaniline with 2-pyrrolidone and carbon monoxide gave the pyrroloquinazolinone (84) [in 52% yield] which was converted into vasicinone (85) by a modification of Onaka's method (cf.ref. 45). A similar reaction of o-iodoaniline with 2-phenylethylamine afforded the amide (86) as the major product (65 YOyield); this with ethyl chloro- formate followed by treatment with potassium hydroxide gave the quinazoline-2,4-dione (87). Dunn and co-w~rkers~~ have continued to study the reactions of deoxyvasicinone (88) (cf. ref. 23h). The reaction of the enol acetate (90) with sodium methoxide gave a 3-acetyl derivative which appears to exist as the enol (91) in the solid state. Reduction of the 3-hydroxymethylene derivative (92) with sodium borohydride gave a mixture of the 3-methyl derivative (89) and the amine (93) perhaps by formation of a hydroxy- methyl derivative and then dehydration to a methylene com- pound and subsequent reduction.3 Acridone Alkaloids 3.1 Occurrence and Structural Studies Nine new alkaloids have been isolated since the last Report and together with alkaloids that have been obtained from new sources are recorded in Table 2.l3,I6* 17947-55 Of the three new simple acridone alkaloids one was isolated from the leaves of Atalantia ceylanica by Bowen and Pate14s and shown by spectroscopic studies to be 1,5-dihydroxy-3- methoxy-N-methylacridone (95). The authors point out that this compound represents one half of the dimeric alkaloid atalanine while 1 1 -hydroxynoracronycine (108) which was also found in the leaves constitutes one half of the other dimeric acridone alkaloid ataline ; the dimeric alkaloids that were present in the bark of A.ceylanica were not detected in its leaves. Another new alkaloid is 1,6-dihydroxy-2,3,5- trimethoxy-N-methylacridone(97) which has been found by Bowen and Pate153 in the stem of Pleiospermium datum. The structure was determined by comparison of its spectroscopic properties with those of 5-hydroxyarborinine (100) (also a constituent of P. datum) and 1,5-dihydroxy-3-rnethoxy-N-methylacridone (95). The Chinese drug tung-feng-jie which is obtained from the roots of Atalantia buxifolia was shown to contain a new acridone alkaloid. This was given the name atalafoline and assigned the structure 1,3-dihydroxy-2,5,6-trimethoxy-N-methylacridone (98) ;47 it is therefore isomeric with the new alkaloid of P. datum. Two new prenylacridones have been isolated from Citrus species.Thus the 4-prenylacridone derivative (1 06) (baiyumine- B) was isolated from Citrus grandis by Wu4’ and its structure was determined by spectroscopic means and by its formation from grandisinine (105) if this was treated with diazomethane. The structure of the 2-prenylacridone junosine (107) which was isolated from Citrus junos by Furukawa and co-w~rkers,~’ was also established by spectroscopy. In the 13C n.m.r. spectra of prenylacridones that bear oxygen substituents at both C-1 and C-3 the chemical shifts of methylene groups are 21.1-22.5 Table 2 Isolation of acridone alkaloids NATURAL PRODUCT REPORTS 1988 p.p.m. when a prenyl group is at C-2 and 26.0-27.1 p.p.m. when the group is at C-4 (cf.ref. 23e);this observation was of value in confirming the structures of junosine (107) and baiyumine-B (106) for which the requisite resonances occurred at 22.25 and 26.1 p.p.m. respectively. 1 1 -Hydroxynoracronycine (1 08) (formerly named 5-hy-droxynoracronycine) has now been isolated from the new sources Citrus nat~udaidai~~ The new and Poncirus trifoli~ta.~~ alkaloid 1 -methoxynoracronycine (1 09) (baiyumine- A) is a constituent of Citrus grandis4’ and Citrus j~nos;~l its structure was established by spectroscopy and by its formation from Il- hydroxynoracronycine by methylation. The structure of the new dimethylpyranoacridone honyumine (1 1l) which was obtained from the root bark of Citrus grandis was determined by spectroscopic The ultraviolet spectrum of the alkaloid was like those of the other linear pyranoacridones pyranofoline (1 12) and glycofoline (1 13) ; the linear arrangement of the four rings of honyumine was apparent from measurements of nuclear Overhauser effects in the lH n.m.r.spectrum [in which irradiation at 3.98 p.p.m. (N-Me) produced enhancement (23 %) only at 6.28 p.p.m. (proton at C-4)] and from the 13C n.m.r. spectrum [in which there were resonances at 39.1 (N-Me) and at 116.0 p.p.m. (C-4)] (cf. ref. 23e). Two new optically active alkaloids of Sarcomelicope glauca were shown to be cis-1,2-dihydroxy- 1,2-dihydro- acronycine (1 14) and its trans-isomer (1 15) by methods similar to those that have been described earlier in this Report for the dihydroxydihydroflindersine derivatives (44) and (46).17 Thus compound (1 14) clearly has a cis arrangement of hydroxyl groups from the coupling constant of J = 4.5 Hz for 1-H and 2-H in the ‘H n.m.r.spectrum and because it can be prepared from acronycine (1 10) by its reaction with osmium tetraoxide. In the case of trans-isomer (1 15) the corresponding coupling constant is 8 Hz and the alkaloid was synthesized by the reaction of acronycine with chromic acid in acetic acid to give the acetate (116) followed by its hydrolysis with sodium methoxide in methanol.” Species Alkaloid (Structure) Ref. Atalantia buxifolia *Atalafoline (98) 47 A talan tia cey lanica *1,5-Dihydroxy-3-methoxy-N-methylacridone(95) 48 Citrus grandis Cilrus junos * 11 -Methoxynoracronycine (baiyumine-A) (1.09) *Baiyumine-B (1 06) *Honyumine (1 1 1) *Junosine (I 07) 1 -Methoxynoracronycine } 49 1 51 50 Citrus natsudaidai 1-Hydroxynoracronycine (108) 52 Helietta parviJolia 1-Hydroxy-3-methoxy-N-methylacridone (94) 13 Pleiospermium alatum Poncirus trifoliata Sarcomelicope argyrophylla 5-Hydroxyarborinine (100) 1 1 -Hydroxynoracronycine Acronycine (1 10) Melicopicine (102) Melicopidine (103) 1,2,3-Trimethoxy-N-rnethylacridone(101) * 1,6-Dihydroxy-2,3,5-trimethoxy-N-rnethylacridone(97) } 53 54 1 l6 Sarcomelicope glauca Acronycine (1 10) *cis-l,2-Dihydroxy- 1,2-dihydroacronycine (1 14) *trans-1,2-Dihydroxy- 1 ,2-dihydroacronycine (1 15) Melicopicine (1 02) Melicopidine (103) il7 Zanthoxylum leprieurii Arborinine (99) 1-Hydroxy-3-methoxy-N-methylacridone (94) Xanthoxoline (104) *New alkaloids NATURAL PRODUCT REPORTS 1988-M.F. GRUNDON O...H 0 R Me R Me (94)R =H (97) R'= H R2=Me Arbor inine (99)R= H (951R =OH Atalafoline (98) R' =Me R2 =H (100) R = OH (96)R =OMe O..*H'O Me H (101)R = H Meli cop id ine (103) Xant hoxoline (104) Melicopicine (102)R =OMe Grandisinine (105)R = H Junosine (107) Baiyumine-B(l06)R =Me o.% O...H'O 10 04 Me Me Me0 2' 11-Hydroxynoracronycine (108)R =H Acronycine (110) Honyumine (111) 11-Methoxynoracronycine (109)R =Me (Baiyumine -A) Me Me % HO" RO' OH I OH Pyranofoline (112) R' = OMe R2- (114) (115) R = H Glycofoline (113) R' = P CMe (116) R =Ac NATURAL PRODUCT REPORTS 1988 (124) 11 -H yd r ox yac r onyc ine (125) $ vi iii ~\ o vH PhCH20 H (117 1 (122) Atalaphyllidine (123) H ..,.. WOH -11 Ill PhCH,O Glycocitrine-I (120) 1 N-Met h y latalaphy IIi ne (1211 Reagents i H,C=CHC(OH)Me, BF; Et,O dioxane; ii MeI K,CO, Me,CO reflux; iii H, Pd/C NaOEt EtOH; iv PhCH,Cl Nal K,CO, Me,CO reflux; v Me,C(OH)CH,CH(OMe), pyridine reflux; vi MeI K,CO, Me,CO reflux then separate the products Scheme 10 NATURAL PRODUCT REPORTS. 1988-M. F. GRUNDON 3.2 Synthesis 5-Benzyloxy- 1,3-dihydroxyacridone (1 17) which was prepared by benzylation of 1,3,5-trihydroxyacridone,was used by Ramesh and Ka~i1~~ to synthesize a number of acridone alkaloids (Scheme 10). Prenylation of (1 17) with 2-methylbut- 3-en-2-01 gave a mixture of monoprenyl (1 18) and diprenyl derivatives (1 19) ;methylation and then hydrogenolysis of the former product gave glycocitrine-I (1 20) while benzylation of the diprenylacridone and subsequent methylation and hydro- genolysis afforded N-methylatalaphylline (1 2 1).The benzyl- oxypyranoacridone (122) was obtained by the reaction of compound (1 17) with 3-hydroxy-3-methylbutanaldimethyl acetal and (122) lost the benzyl group to give atalaphyllidine (123); methylation of the pyranoacridone (122) gave a mixture of N-methyl and N,O-dimethyl derivatives which on hydro- genolysis were converted into 1 1-hydroxynoracronycine (1 24 ; R = OH) and 11-hydroxyacronycine (125) respectively. 3.3 Polymeric Acridones Funayama and Cordell have continued their interesting investigations of the polymers that can be obtained from noracronycine (124; R = H) (cf.refs. 23b and 23g). Improved synthetic procedures using methanolic hydrochloric acid or methanolic sulphuric acid for the formation of dimers of noracronycine were described and a new linear-angular-angular trimer (126) was obtained from the reaction of the dimer AB-2 (127) with 1,2-dihydronoracronycine(128).57 The presence of three resonances that could be attributed to N-methyl groups and of one aromatic singlet in the ‘H n.m.r. spectrum indicated that the new product was a trimer. Other features of the spectrum [e.g. the presence of only one higher- field doublet (1 1’-H) apparently caused by shielding of the A’ ring by the A“ ring] confirmed the arrangement of the units.Previously a linear-angular-angular-angular tetramer AB-5B and an all-angular pentamer AB-5A were prepared. Treatment 0 (128) + of noracronycine with 98 YOsulphuric acid-methanol (9 :1) at ambient temperature has now been shown to give a mixture of polymers from which a tetramer AB-4 (9 YO),was separated; the new tetramer was shown (by ‘H n.m.r. spectroscopy) to be the all-angular compound (130).58 From the reaction mixture that could be obtained by refluxing a solution of noracronycine in aqueous methanolic hydrochloric acid the pentamer AB- 6A (132) and the all-angular pentamer AB-6B (131) were separated. The all-angular structure (13 1) was also assigned to a pentamer AB-5A (cf.ref. 23g); the two compounds differ in their chromatographic properties and in details of the ‘H n.m.r. spectra and it has been suggested that they may not have the same stereo~hemistry.~~ An earlier proposal that the dimer AB-1 (129) is formed by protonation at C-2 of noracronycine (124; R = H) followed by electrophilic aromatic substitution at C-5 of a second unit (cf. ref. 23b) has been supported by carrying out the reaction with 98 YOD,SO, which gave noracronycine that was labelled with 2H at C-2 and at C-5 and AB-1 (129) in which 2Hwas present in the methylene group C-2 and the methine groups C-5 and c-2t.59 When a 1 :10 mixture of noracronycine and 1,2-dihydro- noracronycine (1 28) was refluxed with methanolic hydrochloric acid 1’,2’-dihydro-AB-2 [cf.(127)] was obtained (86 YO). If the reaction was allowed to take place with deuteriated reagents dihydronoracronycine (128) was recovered that was labelled at C-5 and lt,2’-dihydro-AB-2 [cf. (127)] was produced in which the methylene group C-3 and the methyl groups at C-2 were fully deuteriated. This result is consistent with a mechanism that involves the formation of 1’,2’-dihydro-AB-1 (1 33) and then rearrangement to 1’,2’-dihydro-AB-2 [cf. (127)] (Scheme ll) but there is some evidence that ring-opening in 1’,2’-dihydro-AB-2 may also occur.59 The rearrangement of 1,2-dihydronoracronycine(1 28) with 98% sulphuric acid to give the linear 3,4-dihydro-norisoacronycine (1 35) and 1,3-dihydroxy-N-methyIacridone (cf. ref. 23g) has been studied further.60 A third product was Me 0 I 2‘ ‘ AB-2 (127) NATURAL PRODUCT REPORTS 1988 Me AD-1 (129) n =O AB -6A (132) AB-4(130) n =2 AB-SA AB-6B (131) n =3 Me Me 6""' l' 2'-Dihydro-AB-2 [cf.(127)1 Me l',2'-Di hydro -AB-1 (133) Scheme 11 &'OR Me (136) R =H (137) R =Me identified as the angular compound (1 36) by spectroscopy and by its conversion into the known methoxyacridone derivative (137).The formation of the pentacyclic compound (138) when the reaction was carried out for a shorter time suggested that an intermolecular reaction perhaps through an intermediate (134) occurred during the rearrangement of 1,2-dihydro-(138) noracronycine (128) into 3,4-dihydronorisoacronycine (1 35) (Scheme 12).In labelling studies incorporation of deuterium at C-3 C-12 and the geminal methyl groups of 3,4-dihydro- norisoacronycine (135) was observed and the failure of compound (139) to react emphasized the importance of the geminal methyl groups in the rearrangement. NATURAL PRODUCT REPORTS 1988-M. F. GRUNDON 307 -0 i It 1 0 Me [R =Me1 Me ++ o& R R 1 Me (135) (128) R = Me (139) R = H (134) Scheme 12 4 References 1 I. Mester in ‘Chemistry and Chemical Taxonomy of the Rutales’ 29 A. Bellino and P. Venturella Heterocycles 1986 24 1821. ed. P. G. Waterman and M. F. Grundon Academic Press Lon-30 M. F. Grundon in ‘The Alkaloids’ ed. M. F. Grundon. (Spec-don 1983 p. 31. ialist Periodical Reports) The Royal Society of Chemistry 2 W.E. Campbell K. P. Finch P. A. Bean and N. Finkelstein London (a) 1983 Vol. 13 p. 109; (b) 1983 Vol. 13 p. 111; (c) Phytochemistry 1987 26 433. 1983 Vol. 13 p. 113. 3 T. P. Lin and B. Shieh Hua Hsueh 1986 44 96 (Chem. Abstr. 31 R. F. C. Brown J. J. Hobbs G. K. Hughes and E. Ritchie Aust. 1987 106 30033). J. Chem. 1954 7 348. 4 P. K. Chaudhuri Phytochemistry 1987 26 587. 32 J. W. Huffman and T. M. Hsu Tetrahedron Lett. 1972 141. 5 S. Mitaku A. L. Skaltsounis F. Tillequin M. Koch J. Pusset 33 J. Reisch A. Bathe and R. A. Salehi-Artimani Arch. Pharm. and G. Chauviere J. Nat. Prod. 1985 48 772. (Weinheim Cer.) 1986 319 720. 6 F. Kumar B. P. Das and S. K. P. Sinha Chem. Znd. (London) 34 J. Reisch A. Bathe B.H. W. Rosenthal and R. A. Salehi-Arti-1986 669. mani J. Heterocycl. Chem. 1987 24 869. 7 D. M. Razakova I. A. Bessonova and S. Yu. Yunusov Khim. 35 J. Motoyoshiya A. Takagi K. Hirakawa and T. Kakurai J. Prir. Soedin. 1986 384 (Chem. Abstr. 1986 105 149 739). Heterocycl. Chem. 1986 23 597. 8 V. I. Akhmedzhanova I. A. Bessonova and S. Yu. Yunusov 36 S. C. Kuo T. P. Lin S. S. Chang C. H. Wu B. Shieh and T. C. Khim. Prir. Soedin. 1985 823. Chou J. Nat. Prod. 1986 49 48. 9 Z. Rozsa M. Rabik K. Szendrei A. Kalman G. Argay I. 37 M. F. Grundon in ref. 1 p. 21. Pelczer M. Aynechi I. Mester and J. Reisch Phytochemistry 38 P. G. Waterman in ‘Alkaloids Chemical and Biological Pers-1986 25 2005. pectives’ ed. S. W. Pelletier Wiley New York 1986 Vol. 4. 10 V. I. Akhmedzhanova 1.A. Bessonova and S. Yu. Yunusov p. 331 Khim. Prir. Soedin. 1986 84. 39 J. F. Ayafor B. L. Sondengam J. D. Connolly and D. S. Ry-11 1. A. Bessonova and S. Yu. Yunusov Khim. Prir. Soedin. 1986 croft Tetrahedron Lett. 1985 26 4529. 736 (Chem. Abstr. 1987 106 153 117). 40 M. P. Jain and T. N. Srivastava Fitoterapia 1986 57 297. 12 I. A. Bessonova and S. Yu. Yunusov Khim. Prir. Soedin. 1986 41 B. P. Saxena K. Tikku C. K. Atal and 0.Koul Insect Sci. Its 654 (Chem. Abstr. 1987 106 153024). Appl. 1986 7 489 (Chem. Abstr. 1987 106 1794). 13 X. A. Dominguez R. Franco S. Garcia A. Merijanian G. Espin-42 B. K. Chowdhury and P. Bhattacharyya Phytochemistry 1985 oza S. Tamez R. and A. B. Zilli Rev. Latinoam. Quim. 1986,17 24 3080. 60 (Chem. Abstr. 1986 105 75983).43 B. K. Chowdhury and P. Bhattacharyya Chem. Znd. (London) 14 S. S. Kang and W. S. Woo Arch. Pharmacol. Res. 1986 9 11. 1987 35. 15 A. Ulubelen B. Terem E. Tuzlaci K. F. Cheng andY. C. Kong 44 M. Mori H. Kobayashi M. Kimura and Y. Ban Heterocycles Phytochemistry 1986 25 2692. 1985 23 2803. 16 M. Brum-Bouquet F. Tillequin M. Koch and T. Sevenet 45 V. A. Snieckus in ‘The Alkaloids’ ed. J. E. Saxton (Specialist Planta Med. 1985 536. Periodical Reports) The Chemical Society London 1973 Vol. 3 17 S. Mitaku A. L. Skaltsounis F. Tillequin M. Koch J. Pusset p. 104 (see p. 113). and G. Chauviere J. Nat. Prod. 1986 49 1091. 46 A. D. Dunn K. E. Kinnear R. Norrie N. Ringan and D. 18 T. S. Wu Phytochemistry 1987 26 873. Martin J. Heterocycl. Chem. 1987 24 175. 19 I.H. Bowen and M. M. Motawa Planta Med. 1985 529. 47 D.-K. Qin Yaoxue Xuebao 1986 21 683 (Chem. Abstr. 1987 20 L.-J. Ren F.-Z. Xie and Z. Xue Zhongcaoyao 1986 17 193 106 135228). (Chem. Abstr. 1986 105 94500). 48 I. H. Bowen and Y. N. Patel Planta Med. 1987 53 73. 21 S. K. Adesina and D. D. Akinwusi HRC CC J. High Resolut. 49 T.-S. Wu Phytochemistry 1987 26 871. Chromatogr. Commun. 1986 9 412. 50 T.-S. Wu S.-C. Huang T.-T. Jong J.-S. Lai and H. Furukawa 22 J. Creche J. Guiller F. Andreu M. Gras J.-C. Chenieux and Heterocycles 1986 24 41. M. Rideau Phytochemistry 1987 26 1947. 51 M. Juichi M. Inoue K. Aoki and H. Furukawa Heterocyles 23 M. F. Grundon Nat. Prod. Rep. (a) 1985,2,393; (6) 1987,4,228; 1986 24 1595. (c) 1985,2,394; (d) 1984,1 198; (e) 1985,2,397; (f) 1985,2,398; 52 Cited in ref.50. (g) 1987 4 235; (h) 1981 4 232. 53 I. H. Bowen and Y. N. Patel Phytochemistry 1986 25 429. 24 G. M. Coppola J. Heterocycl. Chem. 1985 22 1087. 54 T. S. Wu R. J. Cheng S. C. Huang and H. Furukawa J. Nat. 25 M. Ishikura T. Mano I. Oda and M. Terashima Heterocycles Prod. 1986 49 1154. 1984 22 2471; M. Ishikura I. Oda and M. Terashima ibid. 55 J. Reisch S. K. Adesina and D. Bergenthal Pharmazie 1985,40 1985 23 2375. 811. 26 T. Kametani H. Takeda Y. Suzuki H. Kasai and T. Honda 56 K. Ramesh and R. S. Kapil Indian J. Chem. Sect. B. 1986 25 Heterocycles 1986 24 3385. 684. 27 G. Buchi T. H. Botkin G. C. M. Lee and K. Yakushijin J. Am. 57 S. Funayama and G. A. Cordell J. Nat. Prod. 1985 48 536. Chem. Soc. 1985 107 5555.58 S. Funayama and G. A. Cordell J. Nat. Prod. 1986 49 210. 28 A. R. MacKenzie C. J. Moody and C. W. Rees Tetrahedron 59 S. Funayama and G. A. Cordell J. Nat. Prod, 1985 48 547. 1986 42 3259. 60 S. Funayama and G. A. Cordell J. Nat. Prod. 1985 48 938.

ISSN:0265-0568    

DOI:10.1039/NP9880500293

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Book Reviews Secondary Metabolism [Oxford Chemistry Series No. 331 (2nd edition) J. Mann; 1987; Oxford University Press Oxford; xv+374 pp; f35.00 (hardback); ISBN 0-1 9-855530-X; or f15.95 (paperback) ; ISBN 0-1 9-855529-6 The publication in 1978 as part of the Oxford Chemistry Series of the first edition of Mann’s book along with its companion volume by Staunton on Primary Metabolism was welcomed by natural product chemists engaged in the investi- gation or teaching of biosynthetic pathways. Together they provided concise up-to-date surveys of the fundamental ideas and experimental findings needed for a newcomer to the field to initiate research or plan advanced lecture courses. The appearance of a second edition of Mann’s book some nine years later is timely in that the subject has continued to grow in size and importance especially with the current increasing interest in plant biochemistry.The structure of the book follows that of the first edition. An introduction to primary and secondary metabolism including a brief account of enzymic catalysis and experimental methods is followed by chapters on the major biosynthetic pathways leading successively to fatty acids and polyketides to isoprenoids to shikimic acid metabolites to metabolites of amino acids and to metabolites of mixed biosynthetic origin. A final chapter on secondary metabolism and ecology is especially welcome and should convince animal biochemists that secon- dary plant metabolites can no longer be dismissed merely as exotic excretion products.Each chapter concludes with problems that test the reader’s comprehension and impor- tantly extend the exemplification of natural product structures while providing references to the research literature. Solutions to the problems some with additional references to related research are given at the end of the book. An extensive bibliography of texts and reviews is followed by a valuable new feature of this edition a list of over 100 research references divided according to chapters and given with their titles for ease of identification. The book concludes with a reliable index largely devoted to the names of natural products and their classes. Readers of the 1978 edition will rediscover much familiar material and will welcome its retention.However this edition is much more than a corrected reprinting enlivened with a few recent examples. Its length (374 pages) is substantially greater in the same format than that of the first edition (316 pages). Space has been created in the main text for new material by moving selected examples of natural products into the problem sections. Nevertheless recent developments in biosynthetic research demanded and have received an increase in length in most of the chapters notably the one dealing with polyketides. Although biosynthetic research has not exactly been ‘revolu-tionized’ during the nine years between the two editions the widespread use of advanced n.m.r. techniques employing 13C 2H and l80,has greatly increased the speed and level of detail of metabolic studies.The author wisely has not devoted a separate chapter to the new methods but rather has illustrated their scope with examples in the relevant chapters. Again an account of the new recombinant genetic techniques would have been too specialized and possibly premature for a book at this level. The inclusion of answers to problems will increase the value of the book in teaching and the new list of research references the majority dating from 1980 onwards will appeal greatly to postgraduate research workers (and their super- visors !). Again a short new preface on stereochemical nomenclature should aid the undergraduate reader. Regular users of the first edition will have discovered the dual value of the general index (an author index is not provided) as a guide to biosynthetic processes and as a convenient ‘shortlist’ of key natural product structures.The new edition displays structures for over 500 natural products including those given in the problems. Repeated testing of the index confirmed its reliability indeed only one compound fusarubin (p. 93) was found to have escaped listing. The opportunity has been taken to correct errors in the first edition for example the wayward arrows associated with IPP-isomerase have been disciplined on pages 99 and 100 and overall the book is very well produced for a work of such complexity. Some attention to points of detail would improve the presentation. For example stereochemical prefixes are incon- sistently written with or without italics and within or without brackets as 2(R) or (2R) but 2(2) and 2-2.Again the use of double brackets of the same type and deutero and deuterated does not conform to common practice. However these minor points do not affect comprehension of the text. The level of Mann’s book is best suited to postgraduate students or to experienced organic chemists wishing to begin research into secondary metabolism. Lecturers at all levels will appreciate its value in constructing courses in natural product chemistry. An undergraduate unfamiliar with the subject would probably benefit more from a less demanding treatment for example that provided by R. B. Herbert’s 1981 text. Nevertheless Mann’s book will provide excellent ‘further reading ’for an undergraduate course on biosynthesis especially since sets of problems and answers are included.All engaged in biosynthetic research should have personal copies of ‘Secon-dary Metabolism’ to hand and libraries should place this second edition alongside the first. G. W. Kirby Biologically Active Natural Products (Annual Proceedings of the Phytochemical Society of Europe; No. 27) ed. K. Hostettmann and P. J. Lea; 1987; Clarendon Press Oxford; xi+283 pp.; f35.00; ISBN 0-19-854196-1 This volume reports the proceedings of the annual meeting of the Phytochemical Society of Europe held in September 1986 and is therefore mainly devoted to natural products from higher plants. In the past plant natural products have been examined by the organic chemist from a variety of viewpoints.There has been the ‘stamp-collectors ’approach which has been valuable in first defining whole new classes of natural product. There would seem to be less and less justification for this approach as the establishment of structures becomes less intellectually demanding and also as it becomes clear that almost every variation on any one theme is likely to be encountered sooner or later. There has been an interest in obvious plant characteristics such as colour odour waxiness production of oils of economic value etc. In particular plants which produce compounds such as morphine mescaline or strychnine which 309 directly affect the human system have been investigated as have those which produce compounds reputed to be of therapeutic use.Again plants that produce natural products that may affect those organisms that compete with man for his food crop have received much attention. Structural studies have always gone hand in hand with synthetic studies and a large proportion of the known synthetic methodology has originated in natural product synthesis. The biosynthesis of natural products has also been extensively investigated. Rather more rarely has the organic chemist in collaboration with biologists asked meaningful questions about the function of natural products why they are there at all and what roles they play in the economy of the organism. Again the mode of action of physiologically active natural products is a difficult field demanding an inter-disciplinary approach.At the moment there seems little reason to characterize a natural product unless it is physiologically active is suspected of having an unusual structure or is part of a phytochemical survey. The volume under review touches on all the topics raised above and indeed goes beyond them. Thus the intriguing discussion by Suffness on methodology for the discovery of anti-tumour agents raises the question of the relationship of the screens being used to the nature of the type of tumour which responds. It would seem that a major re-testing programme is required for slow-growing tumours and that no broad-spectrum cancer drugs can be expected. Close attention to assay methodology is also evident in the survey of the liver- protective activity of medicinal plants.The results obtained when organic chemists undertake to answer ‘functional ’ questions are impressive. The investigation of the cross-linking of DNA by mitomycin uses a complete armoury of techniques including computer molecular modelling this being an im- portant technique hardly mentioned elsewhere. The survey of the chemical defences of ‘oat-roots’ also combines ‘state of the art ’ structure determination with thought-provoking biological results. Many of the papers are ‘target-oriented’ e.g. to insect control to liver protection or to antineoplastic activity. Others are oriented to examining particular groups of compounds for any activity present these in turn being the basis for new leads.A particularly interesting paper involves a new look at old drugs by natural product chemists and pharmacologists. The differences particularly with flavonoids between activity in vitro and inactivity in vivo point to selective drug delivery as a clear target for the utilization of many natural products. Other reports are directed to triterpenoid saponins and cyanogenic glycosides. Synthesis receives little attention in this volume but it does contain an excellent review of syntheses of medium and large ring compounds by ‘zip reactions’. All in all this reasonably priced volume provides a broad introduction to an enormous field. It is entertaining and informative reading and it demonstrates how the subject of ‘natural products ’ is evolving. Vlietinck’s comment on page 44 provides a suitable note on which to end. ‘Whether such compounds will ever play a significant role in the development of new drugs as templates for synthesis or semi-synthesis and as biochemical tools depends on a variety of factors not least the dedication of natural product chemists and pharma-cologists provided they co-operate closely. ’ A. Pelter

ISSN:0265-0568    

DOI:10.1039/NP9880500309

出版商:RSC    

年代:1988

数据来源: RSC