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Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) Dr J. R. Hanson Dr R. B. Herbert Professor J. Mann Professor D. J. Robins Dr C. J. Schofield Dr D. A. Whiting Editorial Staff Dr Sheila R. Buxton Managing Editor Miss Nicole Brooks Deputy Editor Miss Nicola P. Coward Production Editor Dr Anthony P. Breen Mr Michael J. Francis Tech n ica I Editors Miss Daphne E. Houston Miss Karen L. White Edito ria I Secretaries University of Bristol University of Sussex University of Leeds University of Reading University of Glasgow U n ive rs ity of Oxf ord University of Nottingham Editorial Office The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cam bridge UK CB4 4WF Telephone +44 (0)1223 420066 Facsimile +44 (0)1223 420247 E-mail rscl@rsc.org RSC Server http://c hem ist ry.rsc.org/rsc/ Natural Product Reports is a bimonthly journal of critical reviews.It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis biological activity and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. This is augmented by frequent reviews of the wider context of bioorganic chemistry including developments in enzymology nucleic acids genetics chemical ecology primary and secondary metabolism and isolation and analytical techniques which will be of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568)is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. 1996Annual Subscription Price EEA f325.00,USA $615.00,Rest of World f333.00.Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. UK SG6 1HN. Air Freight and mailing in the USA by Publications Expediting Service Inc.200 Meacham Avenue Elmont NY 11003.US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003.Periodicals postage paid at Jamaica NY 11431-9998.All other despatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the UK. Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. 0 The Royal Society of Chemistry 1996 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1996 EEA f 325.00 USA $615.00 Rest of World f333.00

ISSN:0265-0568    

DOI:10.1039/NP99613FX017

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99613BX019

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

ISSN 0265-0568 NPRRDF 13(5) 365-468 (1996) Natural Product Reports A journal of current developments in bioorganic chemistry Volume 13 Number 5 CONTENTS ... 111 Hot off the Press Robert A. Hill and Andrew R. Pitt Reviewing the recent literature on natural products and bioorganic chemistry 365 Decanolides 10-membered Lactones of Natural Origin Gerald Drager Andreas Kirschning Ralf Thiericke and Marion Zerlin Reviewing the literature published between 1975 and 1995 377 Natural Guanidine Derivatives Roberto G. S. Berlinck Reviewing the literature published in 1994 and 1995 41 1 Oligomeric Proanthocyanidins Naturally Occurring 0-Heterocycles Daneel Ferreira and Riaan Bekker Reviewing the literature published between January 1992 and December 1995 435 Muscarine Imidazole Oxazole Thiazole and Peptide Alkaloids and Other Miscellaneous Alkaloids John R.Lewis Reviewing the literature published between July 1993 and June 1994 Cumulative Contents of Volume 13 Number 1 1 Modern Bioassays using Metal Chelates as Luminescent Probes Peter G. Sammes and Gokhan Yahioglu 29 The DAP Pathway to Lysine as a Target for Antimicrobial Agents (up to September 1995) Russell J. Cox 45 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (1994) Richard B. Herbert 59 Diterpenoids (1994) James R. Hanson 73 Book Reviews Anticancer Drugsfrom Animals Plants and Microorganisms by George R. Pettit Fiona H. Pierson and Cherry L. Herald (reviewed by John Mann); Oxidative Stress and Antioxidant Defenses in Biology ed.S. Ahmad (reviewed by David J. Robins); Advances in Nitrogen Heterocycles (Volume I),ed. C. J. Moody (reviewed by Joseph P. Michael) Number 2 75 Marine Natural Products (1994) D. John Faulkner 127 P-Phenylethylamines and the Isoquinoline Alkaloids (July 1994 to June 1995) K. W. Bentley 151 Triterpenoids (1994) Joseph D. Connolly and Robert A. Hill 171 Amaryllidaceae and Sceletium Alkaloids (1994) John R. Lewis Number 3 177 The Biosynthesis and Degradation of Thiamin (Vitamin B,) (January 1986 to January 1996) Tadhg P. Begley 187 Pyrrolizidine Alkaloids (July 1994 to June 1995) J. Richard Liddell 195 Monoterpenoids (1991 1992 and part of 1993) David H. Grayson 227 Steroids Reactions and Partial Synthesis (1994) James R.Hanson 241 Recent Progress in the Chemistry of Non-monoterpenoid Indole Alkaloids (July 1994 to June 1995) Masataka Ihara and Keiichiro Fukumoto 263 Book Review Enzyme Catalysis in Organic Synthesis A Comprehensive Handbook by K. Drauz and H. Waldmann (reviewed by David R. Kelly) Number 4 265 Dietary Antioxidants in Disease Prevention Michael H. Gordon 275 Recent Advances in Annonaceous Acetogenins (up to January 1996) Lu Zeng Qing Ye Nicholas H. Oberlies Guoen Shi Zhe-Ming Gu Kan He and Jerry L. McLaughlin 307 Natural Sesquiterpenoids (1994) Braulio M. Fraga 327 Recent Progress in the Chemistry of the Monoterpenoid Indole Alkaloids (July 1994 lo December 1995) J. Edwin Saxton Number 5 365 Decanolides 10-membered Lactones of Natural Origin (1975 to 1995) Gerald Drager Andreas Kirschning Ralf Thiericke and Marion Zerlin 377 Natural Guanidine Derivatives (1994 and 1995) Roberto G.S. Berlinck 41 1 Oligomeric Proanthocyanidins Naturally Occurring 0-Heterocycles (January 1992 to December 1995) Daneel Ferreira and Riaan Bekker 435 Muscarine Imidazole Oxazole Thiazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1993 to June 1994) John R. Lewis Articles that will appear in forthcoming issues include The Glycopeptide Story -How to Kill the Deadly ‘Superbugs’ Dudley H. Williams Catalytic Antibodies -Reaching Adolescence? (up to the end of February 1996) Neil R. Thomas Pigments of Fungi (Macromycetes) (September 1992 to February 1996) Melvyn Gill The Sesterterpenoids (November 1991 to March 1996) James R. Hanson Cyclopeptide Alkaloids (January 1985 to December 1995) D. C. Gournelis G. G. Laskaris and Robert Verpoorte Brassinosteroids Shozo Fujioka and Akira Sakurai Lignans Neolignans and Related Compounds (January 1994 to December 1995) Robert S. Ward Quinoline Quinazoline and Acridone Alkaloids (July 1994 to June 1995) Joseph P. Michael Indolizidine and Quinolizidine Alkaloids (July 1994 to June 1995) Joseph P.Michael Recent Advances in Chemical Ecology (July 1992 to December 1995) J. B. Harborne The Role of Carbohydrates in Biologically Active Natural Products Alexander C. Weymouth-Wilson The Biosynthesis of C,-C, Terpenoid Compounds (1993-1995) Paul M. Dewick

ISSN:0265-0568    

DOI:10.1039/NP99613FP021

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99613BP023

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Decanolides 10-membered Lactones of Natural Origin Gerald Drager," Andreas Kirschning," Ralf Thierickeb and Marion Zerlin" a lnstitut fur Organische Chemie Technische Universitat Clausthal LeibnizstraQe 6 D -38678 Clausthal-Zellerfeld Germany Hans- Knoll-lnstitut fur Naturstoff- Forschung e. V. BeutenbergstraQe I I 0-07745 Jena Germany Arbeitsgruppe 'Signalubertragung von Wachstumsfaktoren 'der Max- Planck- Gesellscha ft DrackendorfstraQe I D -07747 Jena Germany Reviewing the literature published between 1975 and 1995 1 Introduction encountered y-and 6-lactones the classical and non-classical 2 Screening Programmes and Occurrence in Nature macrolides polyene antibiotics spiro-macrolides and macro- 3 Naturally Occurring Decanolides 4 Biosynthesis 5 Chemistry 5.1 Strategies for Synthesis of 10-membered Lactone Rings 5.1.1 Oxidative Fragmentation of Annulated Decanolides 5.1.2 Ring Closure by C-C Bond Forming Processes 5.1.3 Ring Closure by Macrolactonization 5.1.4 Miscellaneous Strategies 5.2 Approaches to Total Synthesis 5.3 Derivatization 6 Biological Properties 7 References I Introduction The present article is intended to provide an overview of the group of naturally occurring 10-membered lactones the decanolides.As depicted in Table 1 these medium-sized lactones can be integrated into a range of various secondary metabolites from natural origin bearing lactone moieties :l the few examples of p-lactones followed by the more often Table 1 Lactones from natural sources Ring size Examples 4 Lipstatin obafluorin oxazolomycin curromycin 5 A-Factor patulin penicillic acid acetomycin 6 Mevinolin 10 Diplodialide decarestrictine achaetolide 12-16 Erythromycin oleandomycin leucomycin 12-24 Soraphen brefeldin zearalenone FK 506 2W4 Nystatin amphotericin filipin rapamycin 1626 Avermectin milbemycin oligom ycin 18 Concanamycin, bafilomycin 9 Elaiophylin colletodiol antimycin nonactin 3248 Oasomycin primycin copiamycin monazom ycin 32-60 Quinolidomicin Classification b-Lactones y-Lactones &-Lactones Decanolides Classical macrolides Non-classical macrolides Polyenes Spiro-macrolides Plecomacrolides Macrodiolides and macrotetrolides Marginolactones Macrolactones Reference 141-155 156160 161 162 2 17 18 29 60 61 1 163 1 164-170 1 169-172 173-1 76 1 177 1 178 179 1 180-183 1 184 lactones of the macrodiolide macrotetrolide and margino- lactone type.Important pharmaceutical drugs have been obtained in most of these lactone-containing subgroups for example lipstatin (orlistat) mevinolin (lovastatin) erythro- mycin A FK 506 nystatin amphotericin B rapamycin and avermectin (ivermec) among others. However medium sized lactones especially the 10-membered representatives (decano- lides) have drawn little attention to date. The first examples of decanolides to be discovered the diplodialides A-D 1-4 were reported by Ishida and Wada in 1975 (Table 2).2 These metabolites of microbial origin exhibit biological properties as steroid-hydroxylase inhibitors.In the past five years an increasing number of articles have appeared in the literature revealing numerous new members of the decanolide family and their biological properties. Further- more novel synthetic strategies for constructing medium-sized lactones have been developed recently. The aim of this review is to summarize the various decanolides in terms of their structure synthetic availability pharmacological potency and biogenesis. 2 Screening Programmes and Occurrence in Nature Naturally occurring 10-membered lactones were discovered more or less randomly by different screening method^.^ The structurally more complex decanolides like nargenicin A antibiotic U-61732 5,5nodusmicin 76 and coloradocin 8lgo (Table 4) were obtained via biological assays focussing on antibacterial activities whereas antifungal activity was the marker that led to the isolation of the pyrenolides P-ll.7*s The diplodialides were found as steroid- 1 1 -hydroxylase inhibitors2 and ascidiatrienolide A 12 via a phospholipase A,-inhibition assay (although the purified metabolite 12 appeared to be lo inacti~e).~.More strikingly tuckolide 18 was discovered during ethno-botanical investigations as a constituent of the fungus Polyporus tuberaster commonly known as 'Canadian tuckahoe'.,' On the other hand chemical screening12-'j of a variety of Fungi imperfecti strains resulted in the discovery of the decarestrictines 13-27 (Table 2) as metabolites of Penicillium simplicissimum.16-1s However a number of decanolides were found by analysis and isolation of the metabolite patterns produced from organisms of biological interest such as marine tunicates (the didemnilactones 28-3019- 2o and ascidiatrienolide A 1193'0) or the Eucalypt longicorn beetle (e.g.the phor- acantholides I and J 32 33).21322 To date about fifty different decanolides have been reported (Figure 1) from a wide variety of organisms. It is remarkable that 10-membered lactones were isolated as secondary meta- bolites of microorganisms (41 metabolites) plants (1 j and animals (7). Therefore it can be assumed that the decanolides are widespread natural compounds which play diverse bio- logical roles in the different producing organisms.The bicyclic 365 NATURAL PRODUCT REPORTS 1996 Table 2 Simple decanolides with methyl and oxygen-containing substituents v=oH R7QFi Me 0 'Ho-s~ Me 0 13:mo -R6 R5 R4 R3 R3 R2 0 Me 0 P I1 35 thiobiscephalosporolideA'-24 27 decarestrictineIbs Compound R' R2 R3 R4 R5 R6 R7 Remarks Ref. Formula1 32 phoracantholide I HHHHHHH C 21,22 - 34 (R,E)-4-decen-9-olide HH -HH C 21,22 H-9 Dvrenolide A -=O - -0-C 7 -10 birenolide B - -0 -H H C 8 -11 pyrenolideC -=O -OH H b (at C-7) 8 - 1 diplodialide A H =O HH H C 2 2 diplodialide B H --OH - HH H C 185,186 3 diplodialide C H --OH HHHH H C 185 4 diplodialide 0 H -OH H=O H H H b 185 187 47 cephalosporolide C H --OH 4OH H =O H H C 188 48 cephalosporolide G H --OH --OH- H =O H H C 186 13 decarestrictineA H -OH -0-H a 16,17 14 decarestrictineA2 H --OH - -0-H a 16,17 15 decarestrictineB H =O H --OH 40-H C 16,17 -16 decarestrictine C H --OH --OH H H a 16,17 17 decarestrictineC2 H -OH --OH H H a 16,17 18 decarestrictine D (tuckolide) H --OH 4OH -OH H a 11 14 16 17 19 decarestridine E H =O --0Me 40-H a 18 H - 20 decarestrictine F H =O 40-H a 18 21 decarestrictine G H =O H -OH - -OH H H a 18 22 decarestrictineH H =O H -OH H b 18 23 decarestrictineJ H =O H H -OH H a 18 H -24 decarestrictineK H =O H -OH -'i b 18 25 decarestrictine N H -OH --OH -OH I.a 31 - 26 decarestrictine 0 H --OH --OH 4OH H a 31 107 humicolactone --o-- =O --OH H a 191 Formula I1 33 phoracantholide J H - HH C 21,22 49 cephalosporolide B --OH -OH H =O H C 188 ~~ a relativeconfigurationreported no relativeconfigurationreported 'absolute configurationreported Actinomycetes Fungi Marine Terrestrial Plants organisms organisms Microorganisms Animals Plants Figure 1 Number and sources of decanolides isolated to date NATURAL PRODUCT REPORTS 1996-G.DRAGER A. KIRSCHNING R. THIERICKE AND M. ZERLIN Table 3 Decanolides with extended alkyl chains III IV 50 achaetolide A 29 Configurationat Compound R’ R2 C8-OH C9/10 C10/11 C12/13 C14/15 Remarks Ref. -__-__ cis Formula 111 28 didemnilactone A = trans trans c 19 20 29 didemnilactone B = ---cis trans cis a 20 H -30 neodidemnilactone H ---cis trans trans a 19,20 12 ascidiatrienolideA H H -----trans cis cis a 9,lO ~~~ ~ ~ ~ Configurationat Compound R’ R2 R3 R4 C2-OH C9/10 Remarks Ref.- -OH --OH --.---. a Formula IV 45 lethaloxin 189 41 pinolidoxin - -OH -OH -b 137 -42 7-epjpino1idoxin -OH -OH -b 136 43 dihydropinolidoxin H H -OH -OH -b 136 44 epoxypinolidoxin -0-OH -OH -b 136 a relative configurationreported rx) relative configurationreported absolute configurationreported Table 4 Structurally complex decanolides with additional rings V 46 M-5032lX 31 8 colorado~in’~~~ compound R’ R2 R3 R4 R5 Remarks Ref. FormulaV 6 nargenicinA H A -0Me OH H a 4,27 36 18-deoxynargenicinAl H A -0Me H H a 4 37 nargenicinB1 OMe A --OH OH OMe a 133,134 38 nargenicin82 OMe A --OH H OH a 133,134 39 nargenicinB3 H A --OH OH OMe a 133,134 40 nargeniunC OMe A -0Me OH OMe a 4 5 U-61732 H A --0Me H H C 5 7 nodusmicin H OH -0Me OH H a 6 a relatwe configuratm reported no relativeConfigurationreported reiativeconflgurationnot proven ketolactone 31 isolated from the oil of Jusmium grund$orum is 32 metabolites being isolated from fungi.It should be noted the only example of a decanolide found so far in In that the eukaryotic fungi predominantly form simple 10-addition 10-membered lactones have been identified in both membered lactones with alkyl and oxygen substituents as marine and terrestrial animals. The marine tunicates Didemnum depicted in Table 2 (with the exception of the dimeric sulfur-moseleyi and D.candidum are able to biosynthesize the containing thiobiscephalosporolide A 35 from a mutant strain while the prokaryotic actino-didemnilactones A and B 28 and 29 neodidemnilactone 3019*20 of Cephalosporium aphidicoZa2*)) and ascidiatrienolide A 129.10(Table 3) while the phoracan-mycetes produce more complex decanolides (Table 4). tholides I and J 32 and 33 as well as 4-decen-9-olide 34 are constituents of the metasternal gland secretion of the terrestrial Eucalypt longicorn beetle (Choleoptera Ceramby-3 Naturally Occurring Decanolides However most of the decanolides were found as In this review article the 10-memberedlactone moiety has been cide).21$22 secondary metabolites of microorganisms with the majority used as the characteristic structural element.Although many 368 classification systems are based on the biogenetic or biosynthetic origin of natural prod~cts,~~*~~ we have had to neglect this method due to the lack of biosynthetic studies on most of the decanolides. Therefore we decided to classify the decanolide group of metabolites according to the following criteria (i) simple decanolides with methyl and oxygen substituents (Table 2) (ii) decanolides with extended alkyl chains (Table 3) (iii) structurally complex decanolides with additional rings (Table 4) Most of the 10-membered lactones described can be classified as simple decanolides which exhibit methyl (usually located at C-9) and oxygen substituents on the lactone ring (Table 2).Simple decanolides contain double bonds and oxygen sub- stituents in the form of hydroxy epoxy and keto groups in nearly all possible combinations. It should be noted that decarestrictine D 1817 is identical with tucko1ide.l' The peculiarity of thiobiscephalosporolide A 35 lies in the formation of a symmetric decanolide dimer in which two 10-membered lactones are connected via a thioether linkage. With the exception of pyrenolide B 10 diplodialide D 4 and the decarestrictines H 22 and K 24 configuration data are available for all of the simple decanolides (see remarks in Table 2). The absolute configuration of the centres of chirality have been determined for the phoracantholides pyrenolides diplodialides and cephalosporolides by both NMR spectroscopy and syn- thetic approaches.X-Ray structural analysis has been reported for decarestrictine D 1816 and thiobiscephalosporolide A 35 resulting in the elucidation of the relative configuration for all stereogenic centres. The X-ray data obtained from crystals of 5-0-(3'-bromobenzoyl)-decarestrictine B and 3-0-methane-sulfonyl-cephalosporolide B led to absolute stereochemical information.16 Decanolides with extended alkyl chains (3-1 1 carbon atoms) are summarized in Table 3. They usually bear the same additional functionalities in the lactone ring as described for the simple decanolides. Carbon side chains are typically located at C-9 of the lactone ring. The absolute configuration of didemnilactone A 28 was elucidated from NMR spectroscopic investigations in combination with synthetic methods.20 Stereo- chemical information is not available for the pinolidoxins 41-44.Finally all structurally complex decanolides containing additional annulated rings were discovered in the culture broth of Actinomycete strains (Table 4) or as constituents of plant material (jasmine oil component 31). Although the nargenicins A to C 6 36-40; (note that nargenicin A 6 is identical with antibiotic CP-47,44427) nodusmicin 7 and antibiotic U-61732 5 exhibit 10-membered lactone moieties their chemical structures are dominated by characteristic tricyclic ring systems with an ether bridge between C-8 and C-13. The latter structural feature is unique in microbial secondary metabolism. However all members of this subgroup show close structural similarities.Variation is restricted to their oxygenation pattern (including methoxy groups) in the ethyl side chain (R4,R5),in a hydroxy or methoxy group at C-2 in the oxidation state at C-20 and in the case of nodusmicin 7 in the absence of the 2-pyrrolo- carboxylate residue. The relative configurations of nargenicin A 627 and nodusmicin 76 were concluded from NMR spectroscopic studies for the former and unambiguously confirmed by X-ray crystallography for the latter decanolide. 4 Biosynthesis The first biosynthetic studies on 10-membered lactones were attempted in 1983 by feeding 13C-labelled acetates to the organism producing achaetolide A 50 showing that the carbon skeleton was assembled via the polyketide pathway28 from eight acetate building However detailed biosynthetic investigations on simple decanolides (Table 2) have only been NATURAL PRODUCT REPORTS 1996 15 decarestridineB 18 decarestrictine D Figure 2 reported for the decarestri~tines.~~* 31 Feeding experiments using 13C-labelled acetates and malonic acid to Penicillium simplicissimum confirmed the polyketide origin of the 10-membered lactones of the decarestrictines (Figure 2).The oxygenation pattern was investigated by incorporating l*O-labelled precursors resulting in a detailed biosynthetic analysis of the main products decarestrictine B 15 and D 18. The whole family of decarestrictines seem to arise from a common pentaketide percursor which undergoes subsequent post-polyketide modifications.In combination with the product profiles during fermentation pH-static fermentation and in vitro investigations with the isolated decarestrictines their biosynthetic relationships can be described as shown in Figure 3. In addition to enzymatically catalysed reactions an unex- pected non-enzymatic conversion was found to be a key step in the biosynthetic sequence leading to decarestrictine D 18.31 It is reasonable to conclude that this type of polyketide biosynthesis using acetate and malonate building blocks to form 10-membered lactone skeletons may also be found in other fungal decanolides such as the diplodialides 1-4 the pyrenolides 9-11 cephalosporolide B 49 or lethaloxin 45 and the pinolidoxins 41-44. In contrast the marine metabolites didemnilactone A and B 28 and 29 neodidemnilactone 30 and ascidiatrienolide A 12 as representatives of eicosapolyenes seem to arise from C-20 fatty acid precursors.28 In an analogous fashion the phoracantholides 32 and 33 should also be derived from fatty acid metabolism.Biosynthetic investigations on complex decanolides (see Table 4) from actinomyces which bear a characteristic cis-fused octalin ring system were reported for nodusrnicin 732and nargenicin A 6.33Feeding experiments with 13C- and I4C- labelled precursors established the acetate (five building blocks) and propionate origin (four building blocks) of their carbon frameworks whereas the pyrrole carboxy moiety derives from a-ketoglutarate via proline (Figure 4).From the incorporation of 13C,180-labelled acetate and propionate and 1802,34 the origin of all the oxygen atoms in nargenicin A 6 has been established. Lactonization and an intramolecular Diels-Alder mechanism of the linear nonaketide precursor was proposed for the generation of the bicyclic octalin ring in nargenicin A 6 followed by oxidation at the appropriate sites and attachment of the pyrrole carboxylate (Figure 5). This hypothesis was further supported by the intact incorporation of doubly labelled NAC-thioesters of the pre- sumptive di- tri- tetra- and penta-ketide 52 prec~rsors.~~ The pentaketide substrate 52 bearing four stereogenic centres and a conjugated E,E-diene is the most complex polyketide in- termediate to be successfully incorporated into a target metabolite so far.In conclusion these experiments illuminate new mechanistic aspects of polyketide synthases showing that the oxidation level and stereochemistry of polyketide chains are adjusted prior to each step of chain elongation. Subsequent hydroxyl- ations methylation and glycosylation steps as well as further modifications of the carbon skeleton or non-enzymatic reac- tions finally generate the bioactive metabolites. NATURAL PRODUCT REPORTS 1996G. DaGER A. KIRSCHNING R. THIERICKE AND M. ZERLIN 369 Me 0 Me 0 0 hypothetical precursor 20 decarestrictineF decarestrictine B related metabolites /\decarestridineD related metabolites Me 0 Me 0 0 DOH O -HOG 0 26 decarestrictine 0 13,14 decarestrictine Al A2 15 decarestrictine B 27 decarestridineI I Me y-t5 Hd 25 decarestridine N 18 decarestrictineD 19 decarestriitine E 51 decarestriitine M Figure 3 Biosynthetic relationships between various decanolides 5 Chemistry 5.1 Strategies for Synthesis of 10-membered Lactone Rings In principle 10-membered lactone rings can be generated by cyclization of a corresponding acyclic percursor or by cleavage of internal bonds in annulated systems mostly in decalin However cyclization of 9-to 11-membered deri~atives.~~-~~ lactones is an entropically disfavoured process and therefore the formation of dimers or even trimers by intermolecular coupling is often difficult to 39-45 Depending upon the type of bond either cleaved or formed in the key reaction synthetic approaches to 10-membered lactones can be classified as follows :(i) oxidative fragmentation of annulated decalins (Schemes 1-3) (ii) ring closure by C-C bond formation (Schemes4-6) (iii) ring closure by macrolactonization (Scheme 7) and (iv) miscellaneous strategies (Schemes 8 9).6 nargenicinA1 Figure 4 5.1.I Oxidative Fragmentation of Annulated Decanolides The first synthetic approach to decanolides relied on m-chloroperbenzoic acid (MCPBA) promoted oxidative cleavage of bicyclic enol ethers 53 affording 10-membered ketolactones 54.46This method proved p~pular~',~* and was later improved with the employment of MCPBA/lead tetraa~etate,~' chromic or ozone followed by reductive ~ork-up~~. 50-52 and other ~xidants~~-~~ (Scheme 1).However only MCPBA/lead tetra- acetate4' and pyridinium chlorochr~mate~~ displayed the desired chemoselectivity when an additional olefinic double bond was present. In analogous fashion 55 yields the corresponding diketolactone under ozonolytic reaction con- ditions.s' Medo 53 n=1,2; m=2,3 54 6 55 Figure 5 Hypothesized biosynthesis of nargenicin A 6 Scheme 1 In addition oxabicycloalkenones 56 have been reported to be potent precursors for decanolide formation.58 Regioselective addition of hypochloric acid gave lactol 57 which in the presence of base was converted via retro-aldol cleavage into a ketolactone. Alternatively the acetylenic lactone was obtained when the corresponding tosylhydrazone 58 was oxidized with aqueous NBS followed by reductive elimination (Scheme 2).Scheme 2 In a related fragmentation strategy the a-bridging bond in bicyclic ether 59 was cleaved (Scheme 3). Thus lead tetraacetate is the reagent of choice for the transformation of diol59a into the corresponding keto lactone 60a. Enol ether 53 can serve as starting material for 59a.50-59-62 In a related study it was demonstrated that in the presence of potassium permanganate the acetyl ester of 1-cycloheptyl- 1 '-enyl-2-me thylpropan-2-01 cyclizes to a bicyclic intermediate which is further oxidized by analogy with Scheme 3.63 The nitro-containing compound 59b is also directly converted into lactone 60b with 2-aminoethanol or catalytic amounts of tetrabutylammonium fluoride or sodium h~dride.~~-@ Key precursors in this context are hemiacetals 59c d and 61a b which were transformed into the corresponding lactones 60 or 62.Thus fragmentation of lactol59c d gave 6-iodo lactone 60c d by treatment with either or iodobenzene dia~etate,~~-$l the reagent system mer-cury(r~)oxide/iodine/pyridine~~-~~ followed by irradiation in the presence of iodine. Furthermore 59c can also directly be converted into 60a by chromium trioxide-promoted oxidation (Scheme l).46.75 As an extension of this approach the oxidative fragmentation of y-hydroxy stannanes 61b by lead tetraacetate or iodobenzene diacetate afforded 62 in up to 91 % yield.76-s0In this context Schreiber et al. treated hydroperoxide 61c with ferrous sulfate and cupric acetate to furnish 62 as a single product in good ~ield.~'-~~ Finally the elegant fragmentation of the tricyclic acetal 100 directly leads to 10-membered lactones (see Scheme 12).84.85 &-Q R1 R2 R' R2 59a X=Y=OH 60a Z'Z2 = 0 59b X = OH; Y = NO2 60b Z1 = N02; Z2 = H 59c X=OH; Y=H 60c Z' = I; Z2 = H 59d X=OH; Y=Me 60d Z' =I; Z2 = Me Y R' -R mR2 m62 R 2 61a X=OH; Y=H 61b X = OH; Y = SnBua 61c X=OOH; Y=H Scheme 3 NATURAL PRODUCT REPORTS 1996 5.1.2 Ring Closure by C-C Bond Forming Processes C-C Bond formation can serve as a powerful tool for the construction of decanolides.Palladium-catalysed cross coup- ling of allylic acetate 63a and potassium hexamethyldisilazane induced cyclization of allylic chloride 63b leads to lactone 64 in 88 and 71 YOyields respectively (Scheme 4),s6-ss whereas the Stille reaction of 65 proved troublesome furnishing 66 in only 15YOyield.3g However the same product was obtained in yields of 31 % by base-promoted cyclization of the bromo p-ketosulfone 67 followed by elimination of sulfinic acid with DBU.s9 Me 0 Me 0 6% X = OAC; R = Swh 64 63b X = CI; R = SPh 0 6 0 65 66 i.K2COa ii. DBU I 0 y S O 2 P h 0 67 Scheme 4 In an elegant reaction the Sm12-g0 or Et2A1C1/Zn-inducedg1 Reformatzky reaction has been used for the ring closure of aldehyde 68a resulting in 69 (Scheme 5). In contrast the intramolecular Wittig reaction of phosphorane 68b proceeded sluggishly to give 70 in poor yield whilst the formation of dimers and trimers prevailed."+ 92 y,&Unsaturated lactone 72 has been obtained from a Lewis acid promoted cyclization of allyl silane 71.93 The high reactivity of radicals was exploited in intramolecular addition reactions to olefinic double bonds (Scheme 6).For example allyl stannane 7394995 forms 74 when treated with tin hydrides and a,a'-di- or tri-chloroesters 75 give di- and tri-chlorodecanolides 76 in the presence of copper(1) ~hloride.'~ As an extension of this approach iodoacrylate 77 cyclizes to the corresponding lactone 78 in high yieldsg7 A n + I route to decanolides utilizes carbon monoxide as the C unit in -0 68a X=Br; R'=HorMe; R2=HorMe 69 68b X = PPh3Br; R' = R2 = H or 70 Me 0 flOJQ2 Lewls acid ____) SiMe 71 72 Scheme 5 NATURAL PRODUCT REPORTS 1996-G.DRAGER A. KIRSCHNING R. THIERICKE AND M. ZERLIN 37 1 SePh 73 74 0 0 R' R' I c1 X= H,C1 75 76 0 i 77 78 0 0 79 80 Scheme 6 a tris( trimethylsily1)silane-promotedmacrocyclization of acrylic ester 79 to afford the ring-enlarged y-keto-decanolide 5.1.3 Ring Closure by Mucroluctonizution Macrolactonization of o-hydroxy carboxylic acids is an important strategy for constructing 12-to 18-membered macrolide antibiotics and has also been utilized for the synthesis of decanolides. This has been systematically studied by Bartra and Vilarrasa (Scheme 7).41 High-dilution techniques have 0 0 R<X dO -R -R<='=" OH 81 82 Scheme 7 proved to be beneficial for preventing dimer and trimer formation.Mixed anhydrides obtained from trifluoroacetic anhydride4199 and p-trifluoromethylbenzoic anhydride (X = p-trifluoromethylbenzoate; Y = OH)loO and in a variation of Yamaguchi's method (X = 2,4,6-trichlorobenzoate; Y = OH)lO,19.20.11.101-104 have widely been employed in the cycliz- ation step. Macrolactonization can also be forced by tem- porarily activating the carboxyl group in 81 (X = Y = OH) with N-methylpyridinium salts the Mukaiyama method,41.105-108 with the reagents DCC/4-DMAP,41 cyanuric log or by employing anhydrous acidic reaction conditions.lo4 Furthermore thiol esters (X = SR; Y = OH) like Corey's pyridinethiolate (X = Spy) were reported to be efficiently transformed into 10-membered lac tone^.^^.110-118 Wasserman et al. took advantage of the fact that photo- oxygenation of trisubstituted oxazoles easily afford the cor- responding triacyl amines [X = N(OCPh),; Y = OH] which upon activation with collidinium toluene-p-sulfonate (CPTS) form the corresponding decan~lide.~~."~.'~~ In addition it was demonstrated that w-hydroxy ketenes 82 which are accessible by thermolysis of the corresponding ethyl alkynyl or dioxo1enones,'21 spontaneously form macrolactones. Alter-natively cyclization can be effected by intramolecular attack of the carboxylic acid onto the activated hydroxy group. Typically the alcohol was transformed into a mesylate or bromide prior to ring closure.41 122 5.1.4 Miscellaneous Strategies Apart from the straightforward methods described in Schemes 1-7 a few ring expansion and contraction strategies leading to decanolides have appeared in the 1iterat~re.l~~ Thus Baeyer- Villiger oxidation of 9-membered ketones 83 directly gave the corresponding lactones 84 (Scheme 8).124-127 In contrast ring enlargement of the cyclic ally1 ether 85 forms lactone 86.Even thioethers could be used as starting materia1.12* Alterna- tively ring expansion was achieved by chlorocarbene addition onto cyclic ketene acetal 87 furnishing 88 via a highly reactive tetrasubstituted cyclopr~pane.~~~~~~~ 83 04 Me Me Me 'Me 85 86 87 88 Scheme 8 Ireland and co-workers applied the Eschenmoser sulfide contraction onto thioamide 89 resulting in the 1 1-membered macrocycle 90 through initial carbon-sulfur bond formation.The sulfide was then readily converted into 91 (Scheme 9).45 -NMe2 1-MeKO 0 89 0 MeKO 0 91 Scheme 9 5.2 Approaches to Total Synthesis Various members of the decanolide family have been synthesized and reported in combination with methodological studies (see Section 5.1). Here four examples are highlighted in order to demonstrate the diverse synthetic chemistry that has flourished around the decanolides. Holmes and co-workers described an efficient synthetic approach to ascidiatrienolide A 12,1° thereby revising the initial structural assignment (Scheme lo).' Starting with 2-deoxy-~-ribose methyl furanoside 92 was obtained by standard methods in three steps.Demethylation NATURAL PRODUCT REPORTS 1996 ated and oxidized to furnish ketone 98. Epoxidation of the olefinic bond leads to an oxirane intermediate which spon- taneously affords the tricyclic acetal 99 as the main product. TBDPS~ Treatment of 99 with methyllithium followed by reduction of OH 92 the methyl ketone led to (R)-alcohol 100 as the major stereoisomer. In the presence of silica gel the corresponding mesylate underwent the stereoelectronically favoured frag- mentation to lactone 101. Finally the alcohol and ethylidene groups were removed by a set of standard reactions to give the OTBDPS OH target molecule 32. -GDPS 8 94 0 12 Scheme 10 furnished the corresponding lactol which was transformed into the (2)-olefinic acid 93 by a Wittig reaction.Yamaguchi 1actonizationlOl of 93 gave the 10-membered lactone 94 in excellent yields. Finally the side chain was elaborated by using the sequence of regioselective desilylation Swern oxidation two Wittig reactions Stille coupling and deprotection to afford 12. Recently Katsuki published an enantioselective synthesis of (R)-phoracantholide I 32 (Scheme 1l).lo3 Homoprop-2-ynylic alcohol 95 is the key intermediate in this approach and was prepared in 83% ee by Pd(0)-catalysed coupling of (2)-1- bromoprop- 1-ene and metallated hex-l-yne followed by enantioselective epoxidation and regioselective reductive ring opening. Base-promoted alkyne migration was followed by crystallization of the corresponding p-nitrobenzoate to give the enantiomerically pure terminal alkyne 96.This was converted into the ethyl ester 97 in two steps. Hydrogenation of 97 was followed by desilylation and hydrolysis to give the seco acid which then was cyclized to (R)-phoracantholide I32 using the Yamaguchi method. MLBr + BrMg+C4H9 Me 9s 97 96 32 Scheme 11 An alternate synthesis of 32 by Sakai and co-workers is based on the stereocontrolled cleavage of an internal acetal (Scheme 12).84 Enzymatically prepared (1R,2S) ethyl 2-hydroxycyclohexane-1-carboxylate was stereoselectively alkyl- 98 100 11 L ___) 32 HP Me 101 Scheme 12 Decanolide 32 can also be derived from (-)-4-(l-nitro-2- oxocyclohexyl)butan-2-one 102.65Asymmetric reduction of the side chain carbonyl group and further treatment with amino- ethanol furnished the desired ring-enlarged nitrolactone 103 (Scheme 13).However under neutral reaction conditions bicyclic lactol 104 can be isolated. The sequence is terminated by radical denitration and formation of enantiomerically enriched 32 (47% ee). &.Me -32 __D No 102 103 104 Scheme 13 5.3 Derivatization Over the past decades synthetic modification of naturally important compounds have become an important tool in altering their pharmacological profile and potency. Exchange of hydrogen with fluorine is a well established strategy and was realized in the preparation of both enantiomers of 10-fluorodecane-9-olide 105 via lipase-catalysed enantioselective esterification of p-fluoro alcohols (Figure 6).lo29lg2 NATURAL PRODUCT REPORTS 199GG.DRAGER A. KIRSCHNING R. THIERICKE AND M. ZERLIN 105 106 Figure 6 In order to modulate the antibacterial activity of nodusmicin 7 several 9-O-esters such as pyrrole-2’-carbonyl esters (nargenicin A 6) pyrrole-3’-carbonyl esters benzoyl esters and others have been prepared and biologically tested.132 An alternate approach uses decarestrictine D 18 as an aglycon for the formation of glyco-conjugates employing structural and pharmaceutical analogies to macrolide anti- biotics. These structural hybrides combine the features of a fungal derived decanolide with a sugar building block usually known from bacterial sources.For this purpose the 2,3,6- trideoxyhexose L-rhodinose typically found in many glycosylated antimicrobial active drugs was chemically coupled with 18 to give among others glycoside 106.13’ 6 Biological Properties It is apparent from the diverse chemical structures and the variable substitution patterns found among the decanolides that their biological activity can not be restricted to a common mode of biological action. The nodusmicin-type decanolides shown in Table 4 (nodusmicin 7 the nargenicins A to C 6 3640 and the antibiotic U-61732 5)show antibacterial activity especially against Gram-positive bacteria (e.g. Micrococcus luteus Staphylococcus au~eus).~-~ Obviously the annu- 133 lated tricyclic structural element is correlated to the antibacterial properties obtained.For the subgroup of simple 10-membered lactones no antibacterial activity was described. Antifungal activities of decanolides have been reported for the pyrenolides A to C 9-11 which inhibit the growth of hyphae of the phytopathogenic fungus CochIiobolous lunata (irregularly swol- len due to the application of 9-11).7-8Weak toxicity was observed for antibiotic M 5032 46 (50 mg kg-l i.p. in mice),135 7-epi-pinolidoxin and epoxypinolidoxin 42,44 (50 pg ml-l brine shrimp).136 Humicolactone 107 possesses cytotoxic activity towards L1210 cells (ICs0= 2.5 pg mF1).lgl Assayed on pea and bean leaves 7-epi-pinolidoxin and dihydropinolidoxin 42 and 43 caused necrotic lesions whereas epoxypinolidoxin 44 was 13’ Activity on plants was also observed for achaetolide A 50,29shown by the increased transpiration of cut barley leaves (Bittner’s Moderate enzyme inhibitory effects were discovered for the didemnilactones A and B 28 and 29 neodidemnilactone 30 and its corresponding diol acids against 5-lipoxygenase (IC0 = 2.9 to > 10 pmol dm-3) and 15-lipoxygenase (IC0 = 4.9-41 pmol dm-3) of human polymorphonuclear leukocyte^.'^^ 2o In addition didemnilactone A 28 and neodidemnilactone 30 showed weak binding activity towards leukotriene B receptors of human polymorphonuclear leukocyte membrane fractions (IC5, = 38 and 50 pmol dm-3 respecti~ely).’~~~~ Diplodialide A 1 inhibits 11-hydroxylase of progesterone in vegetable cell cultures of Rhisopus stolonifer at 125 ppm.2 With the exception of decarestrictine G 21 and K 24 the decarestrictines showed activity in cell line tests with HEP-G2 liver cells13g.140 by inhibition of cholestrol biosynthesis (at lo-’ mol dm-3 :inhibitory effects are 18-66 %).16-18 In normolipemic rats after oral application of 10 mg kg-’ daily for a total of 7 days the most potent metabolite decarestrictine D 18 showed a hypolipidemic activity equivalent to that elicited by daily application of 100 mg kg-’ of the commercial product clo- fibrate. 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ISSN:0265-0568    

DOI:10.1039/NP9961300365

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Natu ra I Guanidine Derivatives Reviewing the literature published in 1994 and 1995 [Continuing the coverage of literature in Progress in the Chemistry of Organic Natural Products (Fortschritte der Chemie Organischer Naturstoffe) 1995 vol. 66 p. 11 91 1 Introduction 2 Natural Guanidines from Microorganisms 3 Natural Guanidine Derivatives from Marine and Freshwater Organisms 3.1 Marine and Freshwater Microorganisms 3.2 Marine Algae 3.3 Marine Sponges 3.4 Other Marine Invertebrates 4 Natural Guanidine Derivatives from Higher Plants 5 Natural Guanidine Derivatives from Terrestrial Invertebrates 6 Vertebrates 7 Conclusion 8 References 1 Introduction Ths report is an update of the author’s review recently published1 dealing with guanidine natural products.The present review attempts to cover the literature concerning such compounds published during 1994 and 1995. Previously uncovered literature will also be discussed. The topics include the isolation structure determination synthesis and bio-synthesis of natural compounds bearing a guanidine function and some related compounds. Most 2-aminoimidazoles pteridines 2-aminopyrimidines and other ‘guanidine-like’ derivatives are omitted with a few exceptions. Natural and synthetic guanidine derivatives have presented much interest mainly due to their pronounced biological activities,2-8 but also as cataly~ts,~-l~ as enantioselective and/or substrate-specific oxoanion host~,’~-~~ in peptide mimetic^*^ and in DNA-drug interaction^.^^ Recently several new methods of guanidine synthesis have been de~eloped,~~-~’ and the synthesis of several natural guanidine compounds have been accomplished.Also 15N NMR studies at natural abun- dance with synthetic guanidines have recently been performed.60.61 While the biogenetic pathway of some arginine- derived guanidine compounds has been established that of natural guanidines originating from free or alkylated guanidines have been poorly studied. Many well-known compounds such as bleomycins tetrodotoxin saxitoxin and their derivatives as well as neurotoxins isolated from spiders continue to provide impressive results concerning their utilization mainly as pharmacological and biochemical tools. An extensive coverage of such compounds is beyond the scope of this review and only selected topics on these molecules will be discussed here.2 Natural Guanidines from Microorganisms In the continuing studies on the biosynthesis of blasticidin S 1 Gould et al.62 fed cultures of Streptomycin griseochromogenes with different labelled precursors but several of them showed poor or no incorporation into blasticidin S [1-14C]arginine [l-14C]glucose and [l’-2H]cytosylglucose. Based on these nega- tive results the authors selected various potential inhibitors of blasticidin S biosynthesis with the aim to block potential biosynthetic steps the transaminase inhibitors aminooxyacetic acid 2 and 2-methylglutamate 3 and amidotransferase in- hibitors azaserine 4 and 6-diazo-5-oxo-~-norleucine 5 which blocks transamination; the L-a-arginine biosynthetic inhibitors 2-methylglutamate 3 and L-arginine hydroxamate 6; and a blocker of N-methylation L-ethionine 7 a methyltransferase inhibitor.n 1 R=Me 8 R=H H02C-xco2H H2NOVC02H Me NH2 2 3 0 0 4 5 When aminooxyacetic acid 2 or L-arginine hydroxamate 6 were fed on S. griseochromogenes the production of cytosyl metabolites and demethylblasticidin S 8 was stimulated but the biosynthesis of blasticidin S 1 was inhibited by half. The amidotransferase inhibitors 4 and 5 showed a mild effect on the inhibition of blasticidin S 1 and demethylblasticidin S 8 biosynthesis. 2-Methylglutamate 3 had a similar effect to aminooxyacetic acid 2 on the biosynthesis of 1.The time- dependent inhibitory effect of L-ethionine 7 confirmed the proposal that N-methylation is the last step in the biosynthesis of blasticidin S. Moreover several new biosynthetic inter- mediates 9-13 of blasticidin S have been isolated and identified during these experiments,62’ 63 providing an intimate view of the biochemical steps leading to blasticidin S. Amycins A 14 and B 15 are further members of the macrocyclic lactone group with an alkyl guanidine side chain,l which possess broad antimicrobial activity. Amycins A and B have been isolated from the Streptomyces strain (DSM 38 16).64 The structures of amycins A 14 and B 15 were established by analysis of spectroscopic data mainly FABMS and I3C NMR. The position of the malonyl group in amycin A could not be definitively established due to the overlapping of signals of the malonyl group in 2D-NMR contour plots and also due to 377 NATURAL PRODUCT REPORTS 1996 p2+ H xGyyNH2 OH N/ 9 x=o 10 X=NOH 17 "-y-%JNH2 HON H2NYNNH N/ OH 11 oHOfiIF NH Me HNp# A Me HO A Me 12 y2 OH &OF ' OH OANH2 H NOH NH 13 degradation reactions observed in alkaline media.Results of biological tests carried out with the natural compounds and with the products of alkaline degradation suggested that those compounds which have the malonyl monoester group are less active. Moreover it seems that amycin A 14 is the original fermentation product which is cleaved by the action of nucleophiles in the extraction media giving amycin I3 15 and niphimycin 16.65-67 New analogues of netropsin 17 containing a carborane moiety have been synthesized for the containing studies of DNA-netropsin binding interactions6' The bleomycins and its congeners including the bleomycins B 18a is the same as for bleomycin A Me the more active B Ma B 18c and the phleomycins D 18b and D (or member of this group of compounds.L-Arginyl-D-threonyl-L-phenylalanine phleomycin E) 18d have been the subject of recent re~iews~~~'~ 19 an antifungal tri- on the mechanism of interaction with DNA and RNA. peptide was isolated from the dermatophyte Keratinophyton Phleomycins D and D (E) cleave DNA as efficiently as terreum.'l The tripeptide 19 was identified by gas chomato- bleomycin A 18e and it appears that a positive charge at the graphy mass spectrometry and by synthesis.The analogue L-extremity of the molecule increases the strength of binding to Arginyl-L-threonyl-L-phenylalaninedid not show antifungal DNA. Moreover it seems that the site of action for bleomycin activity. Me IH HNKN NH NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK NH 0 19 _-20 The hexapeptide substance-I (arginyl-glycyl-prolyl-Tremerogen A-13 21 a tridecapeptide linked to a farnesyl phenylalanyl-prolyl-isoleucine) 20 isolated from the yeast group through the terminal cystine sulfur is a peptidal sex Saccharomyces cerevisiae is an inducer of sexual agglutinability. hormone of the basidiomycete Tremella rne~enterica.'~Its The hexapeptide was identified by mass spectrometry analysis structure was established by Edman and enzymatic degrad- and synthesis.72 ations as well as by 'H NMR and mass spectrometric analysis.'* OVOH H ,Nlr" HO OH 21 OH 23 It co-occurs with tremerogen A-10 22 an analogue which also has sexual hormone activity but a different amino acid sequence.75, 76 Some analogues of these peptidal sex hormones were synthesized and the results showed that those containing four or five isoprenyl groups were the most active peptide hormones. 78 '3 A related polypeptide rhodotorucine A 23 has been isolated from cultured Rhodosporidium tor~loides.'~ Rhodotorucine A 23 induces mating tube formation during the sexual process of R.toruloides. The structure was established by acid hydrolysis Edman and enzymatic degradations and by spectroscopic analysis mainly 'H NMR and mass spectrometry. Moreover rhodotorudine A was synthesized using L-amino acids,79 and the synthetic compound showed the same activity as the natural product. Spergualin trihydrochloride 24 has been isolated from the bacterial strain BMG 162-aF2 closely related to Bacillus laterosporus.80* It exhibited strong inhibition against mouse 81 tumours and against several microorganisms,80 while it also showed low toxicity to mice (LD, = 150 mg kg-'). The structure of spergualin was established by 'H and 13C NMR analysis chemical degradation and by a convergent total synthesis. (Schemes la and 1b).81,82 NH2 0 a L25 2 H Ardt-Eistert homologationa3 27?/0 1 NH UCO S 2H 26 01 pyridine-H2GEbN (10:lO:l) 4a% NHCbz UCO2H 27 1 7% NHCbz 28 85% NHCbz OH 0 29 NH UCONH 30 OM9 i i.02N.NANH NaOH MeOH ii. H2 Pd-C MeOH-H2C-AcOH (2:2:1) 64% H I NATURAL PRODUCT REPORTS 1996 In this synthesis (S)-3,7-diaminoheptanoicacid 26 obtained from L-lysine 25 via Arndt-Eistert homol~gation,~~ was converted in to (S)-7-benzyloxycarbonylamino-3-hydroxy-heptanoic acid 28 through sodium nitrite oxidation of the p-amino group of selectively protected 27. The acid 28 was then converted to the amide 29 which was subsequently deprotected to 30 the direct precursor of 31 a degradation product of spergualin (Scheme la).72.73 The spermidine moiety of spergualine was obtained as follows (Scheme lb) the fully protected triamine 34 was prepared from 3-aminopropan- 1-0132 through the substitution of the tosylate 33 with the suitably protected nucleophile 4-benzyloxycarbonylaminobutylamine.The benzyloxycarbonyl group of triamine 34 was selectively removed in order to HOMNH2 32 33 0 LiBr DMF 34 i. H2 Pd-BaC03 ii.p I 79% OH DCC EMAc 0 I 35 i. 0.1N HCI dioxane (5:2) ii. 0.2 N NaOH HOq' N NH22HCI 0 36 +-H I Scheme la NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK introduce an acetal-containing group giving 36 after removal of the remaining protective groups. The dihydrochloride 36 was then coupled to 31 in mild conditions to give natural (-)-spergualine trihydrochloride 24 and its enantiomer after final purification by HPLC.In the search for more active antitumour compounds several analogues and derivatives of spergualin were synthesized.sk86 Mer-N5075A 37,isolated from Streptomyces chromofuscus is a new antiviral agent that inhibits HIV-1 protease.87 Its structure was elucidated by analysis of spectroscopic data mainly FABMS 'H and 13C NMR. The absolute configuration of phenylalaninol residue was established as S by chiral HPLC analysis. Mer-N5075A 37is related to a-MAP1 38and /I-MAP1 39,protease inhibitors which have been previously isolated from Streptomyces nigrescens.88.8s a-MAP1 38 is the most potent HIV- 1 protease inhibitor in this series; thus the absolute configuration and the aldehyde function seem to be crucial for the expression of HIV-1 protease inhibition.H 37 R = CHZOH *S 38 R = CHO *S 39 R = CHO 'R Two new muscarinic receptor antagonists 40 and 41 have been isolated from an actinomycete strain (Streptomyces SCC 2268).s0 Structures of 40and 41were proposed by spectroscopic analysis and chemical degradations. Both compounds inhibited the binding of quinuclidinyl benzilate to the muscarinic m, m and m4 receptors with IC, at the level of nM for 40and p~ for 41. 0 XNX H2N H HN-0 H2NKLuVd NH 40 0 H2NXNwvvJ$nP H HNKMe 0 41 3 Natural Guanidine Derivatives from Marine and Freshwater Organisms Faulkner's comprehensive reviews on marine natural products includes all guanidines and related derivatives (2-amino- imidazoles pteridines among others) originating from marine organi~ms.~' Moreover a review on marine alkaloids by Kobayashi and Ishibashi' also includes the majority of guanidines and their derivatives isolated from the same sources.The synthesis of several guanidine derivatives of marine origin has been recently 3.1 Marine and Freshwater Microorganisms Analytical methods for detecting paralytic shellfish poisoning promoted by saxitoxin 42and some of its derivatives as well as 381 by other seafood marine toxins were reviewed in 1988.94 Further a new and highly sensitive method for the analysis of saxitoxin 42 tetrodotoxin 44 and microcystin-LR 56 by capillary zone laser induced electrophoresis has been reporteds5 as well as an undergraduate laboratory procedure for detecting saxitoxin 42 and its derivative^.^^ A series of bioassays with natural (+)saxitoxin 42,(+)-decarbamoylsaxitoxin 43and the unnatural (-) antipodes as well as with several other analogues have shown that only natural (+) stereoisomers displayed the sodium channel blocking acti~ity.~' Moreover it appears that substituents at C-6 show a marked influence on the binding constants with the sodium channel suggesting a role for the groups attached at C-6 in blocking the sodium channel activity probably through hydrogen bonding.On the other hand changes in the substituents at C-12 were shown to have little influence on this activity.0 43 R=OH Tetrodotoxin 44not only occurs in living organisms but also in marine sediments. It has been isolated from the marine sediment off the coast of Japan.gs Tetrodotoxin was also found in extracts obtained from the skin of Atelopus subornatus A. peruensis and A. oxyrhynchus Bufonidae New tetro- dotoxin derivatives have been isolated from different species of puffer fish. The first one (6S)-11-nortetrodotoxin-6-o145, has been isolated from Arothron nigropunctatus.lOO The structure of 45was established by analysis of spectral data and by synthesis from tetrodotoxin (H5106 oxidation in [,H,] HOAc/D,O followed by NaBH,CN reduction in 0.2 M HOAc). The second 5,6,1l-trideoxytetrodotoxin46 and its respective and more abundant epimer at C-4 47,was isolated from Fugu poecilo- notu~.'~'The structures of both epimers were determined by analysis of spectroscopic data including 'H-lH COSY HOHAHA HMQC HMBC and NOE NMR experiments as well as circular dichroism analysis which indicated the configuration at C-9 as depicted.Based on these findings and previous assumption^,^^^^^^^ the authors proposed a new route for the biosynthesis of tetrodotoxin in which it is suggested that the 2-aminotetrahydropyrimidinecyclic moiety of tetrodotoxin may arise from the condensation of guanidine with 2-deoxy-3- 0x0-D-pentose. 0-0 OH 44 R = CH20H 46 R' =H; R*=OH 45 R=H 47 R' =OH; R~=H A new route to an asymmetric synthesis of tetrodotoxin 44 has been developedlo4 (Scheme 2).The chiral allylic alcohol 48 synthesized from levoglucosenone was converted to the trichloroacetamide 50 through a procedure involving an Overman rearrangement as the key step. After the conversion of the amide 50 into the protected carbodiimide 52,this latter product was transformed into the dibenzylguanidine 53.This Cl3CCN - NaH Me &H \ 48 EtpO Me 49 xylene reflux 52% (2 steps)I Me NapC03 DMF 80°c Me 51 75% 50 97% 52 i. TFA-HeMeOH ii. HIO4 HpO-MeOH I 78% (2 steps) Ph /Ph I Ph Me Me 54 Scheme 2 transformation was performed by Lewis acid catalysis employing either scandium or ytterbium triflates Sc(OTf) or Yb(OTf), at low temperatures in order to preserve the nucleophilicity of benzylamine.Finally the dibenzylguanidine 53 was converted to the dichloromethane-soluble cyclic guanidine 54 which has the same basic skeleton and stereo-chemistry of (-)-tetrodotoxin. Several polypeptide toxins are produced by the freshwater bloom-forming cyanobacterium Microcystis aeruginosa,'05 among them cyanogenosin-RR5S06and microcystin-LR56.1°7 Cyanogenosin-RR55 was isolated from a Japanese strain of M. aeruginosa and its structure was proposed by analysis of spectral data and by chemical and enzymatic degradation.lo6 H fNXNH2 55 NATURAL PRODUCT REPORTS 1996 The biosynthesis of some amino acids of the potent hepatotoxin microcystin-LR 56 was elucidated.los In the (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl- 10-phenyl-deca-4,6-dienoicacid (Adda) residue the C-6 and C-8 methyl groups are methionine-derived while the C-2 methyl group appears to originate from propionate.The C-3to C-8segment is acetate-derived,while the aromatic residue is phenylalanine-derived. The iso-linked (2R,3S)-3-methylasparticacid (Masp) residue seems to be synthesized from condensation of acetyl-CoA and pyruvic acid to 2-hydroxy-2-methylsuccinic acid. This latter compound is further convertedto Masp via isomerization oxidation and transamination. u1 Masp 56 C03R3 Me 0 57 [D-Asp3]microcystin-LRX = L-Leu; R' = R3 = H; R2 = Me; R4 = CH;! 58 microcystin-HiIR X = X'; R' = R2= Me; R3 = H; R4 = CH2 59 [~-MeLan']microcystin-LR X = L-Leu; R' = R2 = Me; R3 = H; R4 = H Z (R,R) 60 H-Adda-D-GluLMdha-D-Ala-L-Leu-D-MeAsprnL-Arg-OH 61 H-L-Leu-MeAspLi-Arg-Adda-D-GIu Mdha-D-Ala-OH L 62 H-L-Phe-MeAspLL-Arg-Adda-D-Glu'LMdha-D-Ala-OH Ph D-Glu Mdha-D-Ala-OH L H2N 0 0 63 NATURAL PRODUCT REPORTS 1996-R.G. S. BERLINCK Microcystin-LR is also a potent inhibitor of protein phosphatase~,~~~ and has potent insecticidal activity against third instar diamond-backed moth (Pluteffaxylosteffa),house fly (Musca domestica) and against third instar cotton leafwonn (Spodoptera lit toralis). 110 Recently a series of new microcystins 57-63 have been isolated from Microcystis aeruginosa collected from Homer Lake (I1linois)'l1 together with previously known compounds. The structures of these new microcystins 57-63 have been established by extensive mass spectrometry (FABMS/CID/MS) and by IH NMR analysis.Other new polypeptides have been isolated from M. aeruginosa. The structure of aeruginosin 298-A 64 isolated from the strain NIES-298,'12 contains the unusual arginine- derived amino alcohol argininol (argol) and was established by analysis of spectroscopic data. Aeruginosin 298-A inhibits the enzymatic activity of thrombin and trypsin. Aeruginosins 98-A 65 and -B 66 have been isolated from the strain NIES-98.ll3 The structures were established by analysis of spectroscopic data of both the natural products and the acetylated derivative of aeruginosin 98-A 65. Aeruginosins 98-A and 98-B inhibited the activities of trypsin plasmin and thrombin.Micropeptin 90 67 was also isolated from a strain (NIES-90) of M. ~eruginosa.'~~ Its structure was elucidated by analysis of spectroscopic data. Micropeptin 90 67 showed inhibition of the enzymatic activity of plasmin and trypsin. Interestingly the 3-amino-6-hydroxy-2-piperidoneresidue in the structure of micropeptin 90 has been previously found in dolastatin 13 from the sea hare Dolabeflu auricularia,l15 and in other polypeptides originating in blue-green algae,'14 suggesting that dolastatin 13 has a microbial origin. [~-Asp~,Dhb~]microcystin-RR 68 has been isolated from Osciffatoria agardhii. 116 The structure was established by extensive NMR analysis in order to distinguish it from desmethylmicrocystin-RR. The finding of dehydrobutyramine (Dhb) residue in a microcystin is unusual the occurrence of N-methyldehydroalanine (Mdha) being normally observed.[~-Asp~~,Dhb~]microcystin-RR 68 presented acute toxicity to mice at the level of 400 pg kg-l. Cylindrospermosin 69 a hepatotoxin isolated from the cyanobacterium Cylidrospermopsis raciborskii,117g 11* has been the subject of a synthetic approach leading to a model bicyclic guanidine which has the same relative stereochemistry of the tricyclic moiety of cylindrosperm~sin.~~~ Cyclidrospermosin was recently isolated from the cyanobacterium Umesakia natans.120v 121 In the synthesis of the cylindrospermosin bicyclic model (Scheme 3) (E)-l,3-dibromobut-2-ene 70 was converted into the protected amine 71 which was condensed with cro-tonaldehyde deprotected and reprotected with tert-butoxycarbonyl anhydride to give the alcohol 72.After oxidation the unsaturated ketone 73 was converted into the 4-ketopiperidine derivative 74 which presented the desired stereochemistry (by 'H NMR). The latter product 74 was reduced to the axial alcohol 75 which was subsequently deprotected to 76 and treated with an N-protected iso-thiocyanate generated in situ to give the thiourea 77. After cyclization to the bicyclic guanidine 78 and N-deprotection the axial hydroxyl group was converted to the sulfate 80 a suitable precursor for the synthesis of cylidrospennosin. 3.2 Marine Algae A new synthesis of the cyclopropane arginine-derived amino acid carnosadine 81 isolated from the red alga GrateZoupia carnosa122has been reported (Scheme 4).lZ3The sequence of reactions utilized revealed to be optimal for large-scale preparation of 2,3-methanoamino acids suitable for their incorporation into peptidomimetics.The lactone 82 previously obtained by the same authors,12* was converted into the alcohol 83 by ammonolysis acetylation of the alcohol Hofmann Hd 64 Hd 65 R=CI 66 R=H H03SO OH 67 68 69 NATURAL PRODUCT REPORTS 1996 NH40H NH4CI ii. MeOH NHBoc 86% NHBw MeOH 67OC. 16 h 55% 70 71 44% 72 73 74 L-slectride 188% -S=C=N ,CqCH2CC13 TFA CH2CI2 H36 BocHN OH OH 78 77 76 75 79 80 NH 81 i. NH40H(aq.) 25% ii. Ac20 cat. DMAP + iii. PWOAC)~, BU'OH,reflux iv. K2C03 MeOH 70 "C 82 59% I.i. HP. PM EtOAc NTs NTs 85 61YO NH, AgN03 Et3N MeCN 98% I II NTs 86 NMtr 88 Scheme 4 Scheme 3 3.3 Marine Sponges Two new approaches to the synthesis of aplysinopsin-like guanidine alkaloids have been developed. The first one is based on the condensation of S-benzylisothiouronium chloride with unsaturated 2-0xazolin-5-ones.~~~ The second involves aza- Wittig type reactions of an iminophosphoranes (derived from Bu'O~C NHBoc ethyl a-azido-P-(3-indolyl)propeonates and triphenylphos-phine) with methyl isocyanate and carbon dioxide or carbon disulfide followed by further cyclization by the action of 83 84 87 nitrogenous reagents.lz6'lZ7 Recently a new aplysinopsin derivative isoaplysin 89 has been isolated from the sponge ApEysina sp.lZ8 The structure of isoaplysin 89 was determined by analysis of spectroscopic data and chemical degradation.Mauritamide 90 a new guanidine derivative related to oroidin 91 has been isolated from AgeEas rn~uritiana'~~ together with the known dibromophakellin 92130 131 and midcapamide 93. The structure of mauritamide 90 was established by spectroscopic analysis including HMBC and ROESY experiments. O-JQJC-.N H H 89 Br rearrangement on the primary amide and methanolysis of the acetylated alcohol. The product 83 was converted into the azide 84 through the mesylate without any purification. After reduction of the azide to the corresponding amine this was coupled with S,S-dime thyl-N-(6me thy1 benzenesulfony1)- carbonimidodithioate in order to obtain the protected guani- dine 86 after treatment with ammonia.Finally the acid and a- amino functions of 86 were deprotected but the a-amino reprotected giving the desired product 87in 2.6-6.0 % overall yield depending on the scale of the reactions. Alternatively Fmoc-2-cyclo-Arg (Mtr) 88 was prepared in a slightly lower yield. The two other stereoisomers of carnosadine were also 0 prepared in an analogous way. 93 NATURAL PRODUCT REPORTS 1996R. G. S. BERLINCK A new diketopiperazine cyclo(-L-Arg-dehydrotyrosine-)94 has been isolated together with new pipecolate derivatives from the marine sponge Anthosigmella aff. raromi~rosclera.'~~ The structure of 94 has been established by analysis of spectral data.Hymenialdisine 95 and debromohymenialdisine 96 pre-viously isolated from various Agelasidae sponges (Hymeniacidon Acanthella Axinella Pseudaxinyssa and Phakellia') have been ~ynthesized'~~ based on the treatment of the p,yunsaturated-a-methanesulfonyloxy esters 102a and 102b with guanidine via stereospecific isomerization of the C9-C10 double bond into the ClO-Cll conjugated system (Scheme 5). A different approach to debromohymenialdisine 96 has been tentatively deve10ped.l~~. 135 94 H2N x4 0 95 X=Br 96 X=H i. SOC12 cat. DMF toluene 60°C ' Hymenialdisine 95 debromohymenialdisine 96 and dibromophakellin 103 have been re-isolated from the sponge Axinella carteri (previously Acanthella carter9 together with a new guanidine derivative 3-bromohymenialdisine 104 and the related known 2-aminoimidazole compounds hymenidin and 0r0idin.l~~ In this study these compounds have been isolated from specimens of A.carteri collected from different locations 1500-2000 km distant one from another Java (Indonesia) Sumatra (Indonesia) and Mindoro (Phillipines). The com-position of the different specimens were shown to be remarkably similar suggesting de novo synthesis either by the sponge itself or by symbiotic microorganisms. Moreover hymenialdisine 95 and debromohymenialdisine 96 showed insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis. 136 H2NLN 103 104 A series of styloguanidines 105 106 and 107 remarkable complex polycyclic bis-guanidine alkaloids related to Palau'amine 108,13'have been isolated from the marine sponge Stylotella a~rantium.'~~ The four compounds were isolated by charcoal bio-gel and RPHPLC chromatography and the structures of styloguanidines 105-107 have been established by extensive analysis of NMR data and by comparison with NMR data of palau'amine 108 phakellin 109139and isophakellin l10130*131.The styloguanidines 105 106 and 107 showed inhibitory activity against the chitinase of Schwanella sp. at the level of 2.5 pg disk-'. HZN(CH~)~CQM~* ($co*HH ii. Et3N CHpClz rt X~ ~~O$vk 63% i. 10% aq. NaOH MeOH (2:1)*rt 97 56% (SEMCI). NaH SEM' L0,Cl DMF*rt 0 SEM iv. silica gel chromatography 99a X=H 23% 99b X=Br f /C02Et -) 0 100a X=H i.guanidine DMF 50°C 5 h x / \ KHMDS. THF -78°C 4 ii. 5% HCI-MeOH (1:1) 80°C 2 h ii. MsCI EbN CHzC12. 0°C SEd 0 SEM 95 X = Br (29%,2 steps) 102a X = H (72% 2 steps) 96 X = H (39%,2 steps) 102b X = Br (78%,2 steps) 0 SEM 101a X=H 101b X=Br Scheme 5 NATURAL PRODUCT REPORTS 1996 H2NqN$ N H 109 110 111 Agelasidine A 111 previously isolated from two different specimens of Agela~,l~@l~~ has been synthesized through a biomimetic pathway (Scheme 6).144 The acetoxysulfinate 113 was required for the [2,3]-sigmatropic rearrangement carried out in dilute medium in order to avoid by side products arising from [1,3]-sigmatropic rearrangement. The sulfone 114 was converted into agelasidine A 111by elimination of the acetoxy group followed by conjugate addition of guanidine free base on the vinyl sulfone intermediate.The unstable agelasidine A 111 was characterized as its 4,6-dimethylpyrimidin-2-y1 derivative. 112 ACO-~O 113 50-79% DMF. 140%. 35 min (conc. 5.5 x lo-* M) I 111 Scheme 6 115 Agelasidine C 115 also isolated from Agelas was synthesized through the coupling of the diterpene bromide 116 previously prepared by the same authors with the protected mercaptan 117. The product of coupling 118 was oxidized with m-chloroperbenzoic acid deprotected and treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate giving agelasidine C 115 in 26% overall yield (Scheme 7).146 116 117 0 118 0 119 I i.H2NNH2 EtOH 93% 115 Scheme 7 Eight new onnamide A 120 congeners 13-des-0-methyl- onnamide A 121 dihydroonnamide A 122 onnamide B 123 17-oxoonnamide B 124 onnamide C 125 onnamide D 126 onnamide E 127 and pseudoonnamide A 128 have been isolated from two Theonella specimen^.'^' Further three new onnamide A derivatives 6,7-dihydro- 11-oxoonnamide A 129 11-0x0-onnamide A 130 and 42-onnamide A 131 have been isolated from another specimen of Theonella sp.14* All these compounds have an arginine residue linked to an acetate derived polyfunctionalized carbon skeleton and the structures were determined by analysis of spectroscopic data. Potent cytotoxic and antiviral activities have been reported149 for 'onnamides' and other pederin-like 132 compounds such as rny~alamides'~~ (e.g.mycalamide A 133) and more recently the theopederins.150 Ptilomycalin A 134 a polycyclic guanidine alkaloid isolated from PtilocauZis spiculifer and Hemimycale sp.,151-153 has been the subject of several synthetic approache~.'~~-'~~ Snider and Shi154, 155 developed a biomimetic route to ptilomycalin A. Initially a model study leading to the central tricyclic moiety of ptilomycalin A was carried out (Scheme 8).154 The diketone 139 obtained through four steps from the alkyne 135 was coupled with 0-methylisourea giving a 1:3 mixture of the cis and trans stereoisomes 140 and 141. The NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK 0 0 II 121 0 II 123 0 0 “OMe 0 I1 125 OMe II 126 0 0 Me0 0” “OMe 127 128 0 0 0 0 I1 130 NATURAL PRODUCT REPORTS 1996 MeOK HOJ II 132 II 133 relative stereochemistry of both isomers separated by flash reconverted quantitatively into animal 143a in MeOH at room chromatography was established by ROESY NMR temperature over four hours.the convergent synthesis of the pentacyclic experiments. Heating the 1 :3 mixture of 140 and 141 with an S~bsequently,'~~ excess of ammonium acetate in methanol saturated with nucleus of ptilomycalin A was achieved (Schemes 9a-9c). ammonia gave 143a as the only product despite the N,O-Skalemic keto aldehyde 152 was prepared (Scheme 9a) from the alkylidene relative stereochemistry. The same product was same starting synthon 135 as that previously utilized in the obtained by reaction of separated stereoisomers 140 and 141 in synthesis of the tricyclic central moiety of ptilomycalin A.The the same conditions. Flash chromatography of 143a gave the skalemic P-keto ester 157 was obtained from (R)-3-hemiaminal 143b. Similar hydrolysis was obtained on treating hydroxybutyric acid 153 in five steps (Scheme 9b). The coupling the product 143a with 50 YOaqueous THF. Hemiaminal143b is of 152 and 157 through Knoevenagel condensation was more -Buli LiAIH4 THF Me(CH&CHO // -OH \I\ reflux 5 h 135 92% bi 96% OH 136 137 94% 0 -CO2Me 0 a 0 C02Me 0 139 H 138 89% Me0 m5H1 Ro H 1 -C7H15 wc5H11 NH40Ac b NH3 MeOH C7H15 N CO9Me 140 142 -1 14% R=Me COQMe NH40Ac t NH3 MeOH 143b R=H 0 c 7 H 1 5 w C5H11 C02Me 141 Scheme 8 NATURAL PRODUCT REPORTS 1996-R.G. S. BERLINCK -I BuLi DMPU THF -vOOsi= MeCH2CH0,-78% 135 94% 1 44 91% 145 9-BBN a-pinene rt 30 hI 95%,93%ee TBDPSiCl Y H2 Lindlar catalyst - rt 1 h CH2C12 rt 20 h 98% 93% 148 147 1 46 Ph I. Swern oxidation 5 -OH - ii. 136 BuLi DMPU THF. -78°C 149 92X 150 151 (COCI)2 EbN OMSOI 96% 152 Scheme 9a Ph ,Ph Ph ,Ph OH TBDPSiCl DlBAL i. TsCI pyridine. -2OOC 12 h 153 LCQEt 85%rt 3 h imiciazob DMF 'LcOgt154 66%hemne -m%,12 h' 155 ii. NaI acetone refux 1 h 91% 1 56 Ph ,Ph 157 I ,Ph cat. piperiiine CH&& o,si. Ph 0 -78"C+-20"C,20h > a6% 158a R = TBDPSI E 152 158b R = TBDPSi,Z Scheme 9b difficult than in the preceding model studies and required careful control of the reaction temperature.Also the addition of 0-methylisourea to the mixture of stereoisomers 158a and 158b was achieved after several trials with a variety of bases in different solvents by treating the mixture of 158a and 158b with 0-methylisourea sulfate and diisopropylethylamine in dimethyl sulfoxide (Scheme 9c). The stereochemistry of the products 159a and 159b was assigned by comparison with the previously synthesized 140 and 141. The direct precursor of the central pentacyclic moiety of ptilomycalin A 165 was obtained after the treatment of the mixture 159a and 159b with ammonia-ammonium acetate in tert-butyl alcohol followed by deprotection and simultaneous cyclization of the heptacyclic ring with aqueous hydrofluoric acid-acetonitrile.The precursor 161 was finally cyclized to a mixture of diastereomers 162 and 163 with triethylamine in methanol and the products were separated by flash chromatography. The stereochemistry of both 162 and 163 was established by direct comparison of NMR data with that of natural ptilomycalin A and also by analysis of 2D-ROESY spectra. As NATURAL PRODUCT REPORTS 1996 NH3 NH~OAC c 3u'OH 60°C 40 h 72% 52% 1:1 16Oa/160b 4:l 159d159b Me0& 158a R = TBDPSI,E 158b R = TBDPSi,Z 159a R = TBDPSi; H10,H13 trans 159b R = TBDPSi; Hlo,Hl cis 160a R = TBDPSi; H10,H13 cis p 160b R = TBDPSi;Hlo,H13cis a 3:7HF-MeCN 1-3O"C 3 d Et3N.MeOH 60% 20 h 602Me 162+ 78Xfrom 160a and 160b4 13 H2CMeOH 161 60C 16 h H 1 63 d Scheme 9c HN3 DEAD Ph3P LiAIH, THF 0°C 425% 15 ht 0°C +25% HO 1 64 (Miitsunobu reaction) 165 75% from 164,94% ee 166 HCI KNCO H20,80°C 8c-90%I + H o qOYNH2.OH 03. MeOH MeO I 1 69 60% 1 70 50% from 168 1 OAcO-H2 168 -7B"C Me2S ca. l0OX 167 HO 20 h 95% COAe 171a p-H 171b ocH pTsOH CHCI,. 172 23"C ca. 100%1 HO 174 1 73 Scheme 10 NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK 391 NH i. KOCN HCI 70% i::i:Ly' HOLCSHQ MeOzC& Ph3P- ii. @ MeOH,61Yo -78OC 175 72% - 176 HO 177 MeO&,) 0 VTBDMS NaH BuLi - R02C& OTBDMS morpholine HOAc EtOH Na2S04,70°C 1 78 73% 179 R=Me 61% 180 R = (CH2)15C02CH&H=CH2 OH II OF J 0 cq pH II i.PPTS MeOH 50°C 4 ii.pTsOH,CHCl3 23 "C 96% TBDMSO C02(CH2)15C02CH$H=CHz CQ(CH2)1&0&H2CH=CH2 182 181 i. Swern oxidation ii.R3N MeOTf. CH2C12,23°C 0 1 67% ii. Swem oxidation 58% 1 83 184 i. TBAF 1ii. NH3,NHdOAc 51% i.Pd(PPh3)4,pyrrolidine,MeCN 23°C (75%) .. B~~HN-NH 'I. B~~HN 134 EDCI DMAP CH2C12.23% (60%) iii.EtaN MeOH 65°C (50%) iv. HCQH 23°C (100%) Scheme 11 185 in the synthesis of the acyl moiety of crambescin B,162 161 162 achieved the total synthesis of ptilomycalin A (Scheme 1l).15' and 163 appear to be an equilibrium mixture in which the ratio The (S)-ureido aldehyde 177 prepared in four steps and 44% of the compounds change if treated with MeOH-Et,N [7:5 :8 yield from the chiral synthon 175 was condensed through the of 161 162 and 163 respectively] or if treated with 50% Biginelli reaction with (R)-P-ketoester 180 giving the aqueous MeOH in which the tautomer 161 is more stable.By hexahydro- 1 -oxopyrrolo[ 1,2-~]-pyrimidine 181 in 61 O/O yield. heating a mixture of 162 and 163with Et,N in 1 :1 MeOH-H,O The spirocyclization of 181 into 182 was achieved by initial the resulting product is a mixture of 50 70161 and 25 YOof both deprotection of the TBDMS group. The stereochemistry of 182 recovered 162 and 163. was verified by analysis of lH NMR spectrum. In order to Overman and Rabinowitz have developed a route to an prepare the substrate for condensation with the remaining advanced intermediate for the synthesis of ptilomycalin A carbon chain 182 was oxidized and the urea group through a tethered Biginelli condensation (Scheme 1O).156 In protected/activated for subsequent guanidine formation.Con- this synthesis the (R)-urea 168 was obtained from (S)-3-densation of the product 183 obtained with 2 equiv. of the hydroxy-7-methyloct-6-enoicacid 164 in four steps. The (R)-Grignard reagent derived from 7-(tert-butyldimethyl-urea 168 was then condensed by the Biginelli reaction with siloxy)hept-4-yn-3-one and further oxidation furnished the the protected methylester of (S)-3-keto-7-(tert-butyldimethyl ketone 184 in 58 Oh overall yield. Cyclization to the pentacyclic si1oxy)octanoic acid 170 this latter compound having been core of ptilomycalin A was achieved in similar conditions of prepared from methyl acetoacetate and (S)-1-iodo-3-(tert-that employed by Snider and Shi (Scheme 8),154providing a butyldimethylsi1oxy)butane 169.The condensation provided a single product 185 after purification by flash chromatography. mixture of stereoisomers 171a and 171b from which 171a was Remotion of the ally1 ester group coupling with bis-Boc- separated and deprotected to give the bicyclic alcohol 172. protected spermidine epimerization in triethylamine-methanol Catalytic acid cyclization of 172 furnished the undesired and remotion of Boc protecting groups gave (-)-ptilomycalin spiroaminal 173 in almost quantitative yield. The stereo-A 134 identical to the natural product. chemistry of 173 was assigned by analysis of 1D-and 2D-NMR Another synthetic approach towards ptilomycalin A is that spectra.Epimarization of the P-carbomethoxy group with of Murphy Williams and collaborator^,^^^^ 159 which initially toluene-p-sulfonic acid in methanol gave a 1 :2 mixture of 173 led to a tricyclic and a tetracyclic model of the pentacyclic core and 174. The stereochemistry of 174 was proposed by NMR of ptilomycalin A. The synthesis of the tricyclic model was analysis and confirmed by single-crystal X-ray analysis. based on previous observations that guanidine free base Following the same approach these authors have recently undergoes a double Michael addition and subsequent NATURAL PRODUCT REPORTS 1996 Q-HO-00 0&120 HH 1 92 1 93 I 186 - 0- I o--p-imidamle TBDMSiCl t 2 w.EtO&CH=PPh3 Et02C / CO*Et DMF '0 78% c OH 98% OH 188 195 1 94 187 PCC CH2C12 1celite 78x + -Si-I O--Tf-0 196 i. guanidine DMF ii. MeOH HCI 0% 1 ? + T O H sat. aq. HBF4 c 198 + 1:2 CHCl3-CC4 crystallization 197 80% overall from 196 Scheme 12 Scheme 13 U 199 2 q.H2C=PPh3 TBSCI, ooTHF,-78'C H o T P P h 3 imidazole DMF 0 0 200 201 202 THF,48h I ow '0 I 45% overall from 200 YOTBS i. H2C=PPh3 THF -78°C ii. TBSCI imidazole DMF a P P h 3 78% 203 204 206 i. gwnidine DMF ii. HCI MeOH 0°C +rt 24 h iii. sat. aq. NaSF4 0 iv. crystallization 25% over 4 steps ? OTBS 0 208 i. guanidine DMF ii. HCI MeOH 0°C -+ tt,24 h iii. sat. aq. NaBF4 iv. crystallization 20Kover 4 steps 1 205 209 Scheme 14 NATURAL PRODUCT REPORTS 1996-R.G. S. BERLINCK cyclisation with methyl acrylate to give pyrimido[ 1,2-a]- pyrimidine-dione 186. The tricyclic model was then prepared from succinaldehyde 187 in three steps (Scheme 12) as a 1 :2 mixture of stereoisomers 190 and 191. The tetracyclic model of ptilomycalin A was synthesized15* from 2,3-dihydropyran 192 in six steps as outlined in Scheme 13. Cyclization of the dioll97 resulted in an 1 :1 mixture of 198 and 199 from which 199 was separated by crystallization in 1 :2 chloroform-tetrachloromethane. Both structures 198 and 199 were assigned by X-ray crystallographic analysis. Subsequently two pentacyclic models of ptilomycalin A were synthesized based on the same approach (Scheme 14).159 The pentacyclic model 205 was obtained from valerolactone 200 via a double Wittig reaction of protected phosphorane 202 with succinaldehyde giving the aldehyde 203 and the dienone 204.The dienone 204 was then treated as in the previous conditions for introducing guanidine and cyclization giving 205. The authors observed that 205 is preferentially obtained over a stereoisomer at the methine carbons in cyclic junctions of the pyrrolidine nucleus. The synthesis of the second pentacyclic model 209 was achieved by condensing the aldehyde 203 with the protected phosphorane 207 followed by cyclization. The 3-hydroxyspermidine moiety of ptilomycalin A has been preparedl6O as well as the first analogue of ptilomycalin A.161 The absolute stereochemistry at the carbons of the pentacyclic core of crambescidins 800 210 816 211 830 212 844 213 and isocramescidin 800 214 all isolated from Crambe ramb be,'^^^ 164 was e~tab1ished.l~~ Ozonolysis of crambescidin 816 211 and isocrambescidin 800 214 followed by H,O oxidation acid 219 i.LDA -78°C. THF ii. TBDMSCI rt 12 h 58% Cbz IH hydrolysis and methylation gave a mixture containing methyl 2-hydroxybutanoate. Analysis by chiral GC-MS indicated the absolute stereochemistry of the ester as being 2S establishing the absolute stereochemistry of the pentacyclic moiety of 210-213 as being 3S 8S lOS 13S 14R 15s and 19R. In compound 214 the stereochemistry at C-13 C-14and C-15 is reversed. Recently crambescidin 800 210 has been isolated from a Brazilian specimen of Monanchora arbuscula.166 210 R=H; n=13 211 R=OH; n= 13 212 R=OH; n= 14 213 R=OH; n=15 f rrr 1 OH 214 n=13 HO-N 'Cbz Cbz NH -Si-221 * TBDMSO&O-NKN.cbz 00 I DMAP benzene,b LdJOMe 220 53% NH 222 MHphridine CH&l2 " 1 82% OMe HO OMe i.HpNANH NaHCq DMF ii.50% aq. HF MeCN H 82% 224 NH 223 NH~OAC, NH3 MeOH A 1 H NH2 O O i. MsCI Et3N ii. EtaN CHC13 A b iii. Hz Pd H 215a 37% L+R2 225b 34% NH NH 225a R'=H; R2=Cbz 215 225b R1 = Cbz; R2 = H Scheme 15 NATURAL PRODUCT REPORTS. 1996 Cbz H OTBDMS I HO-N KN%bz -Si-226 NH Cbz H LJUolile DMAP benzene A 0 O-')("Cbz NH 220 227 dH piperdine,CH2C12 NH2 OMe TBDMSO i.H2N ANH TBDMSO NaHCO3 DMF ii. NH40Ac,NH3 t- MeOH,A b$("Cbz NH 229 228 50%aq. HF MeCN 230a 31% 230b 50% 1 NH2 NH2 4:: ~~~~HCl3, A+ OH ~'KN-R' l%+NH2 NH NH 230a R' = H; R2= Cbz 216 230b R' = Cbz; R2 = H Scheme 16 The total syntheses of racemic crambescins A 215 B 216 Cl NH 217 and C2 218 bis-guanidine alkaloids which have been isolated from the marine sponge Cvambe crambe,16'3168 have been accomplished. Following the same approach as previously described for the synthesis of the acyl moieties of crambescins A and B,162 Snider and ShP9 have synthesized different homologues of crambescins A B C1 and C2. Herein we will discuss the syntheses of the natural compounds.In the synthesis of crambescin A 215 (Scheme 15),16' ester NH2 exchange between the protected methyl ester of 6-hydroxy-3- 21 5 0x0-hexanoic acid 220 and diprotected 4-guanidinobutan- 1-01 221 afforded the guanidino protected alkyl ester 222. After NH condensation of 222 with dodecanal followed by addition of 0-methylisourea alcohol deprotection and 0-methylisourea conversion into guanidine two different protected alkyl guanidines were obtained 225a and 225b. Both 225a and 225b were used in the final steps of the synthesis of crambescin A 215 cyclization in basic conditions through the alcohol mesylate followed by alkyl guanidine deprotection. The synthesis of crambescin B 216169follows the same 216 approach (Scheme 16). N-Protected 7-guanidinoheptan- 1-01 226 was prepared from 7-aminoheptan- 1-01 and S-methyl- isothiourea.The synthesis of the bicyclic moiety of crambescin B is identical to that described to crambescin A except that the ammonolysis was carried out on the silyl ether 228 and the product of this reaction 229 was deprotected with HF in MeCN giving 230a and 230b both of which were cyclized to crambescin B 216. Based on this synthesis Snider and Shi established the correct structure of crambescin B 216 which was confirmed by Jares-Erijman et al."O cr The syntheses of crambescins C1 217 and C2 21816' were ij~~ accomplished by hydrogenolysis (Pd-C aq. HC1 CHC1,) of 217 n=7;m=4 the corresponding monocyclic intermediates 230a plus 230b for 218 n=9;m=l NATURAL PRODUCT REPORTS 1996R.G. S. BERLINCK crambescin C1 and 225a plus 225b for crambescin C2 with appropriate guanidino and alkyl side chains. The correct structure of crambescin C1 217 was also established after its synthesis. A series of new polycyclic guanidine alkaloids have been isolated from the marine sponge Batzella sp,171 which is apparently the same species earlier identified as Ptilocaulis spiculifer from which Kashman et a1.151-153 have isolated ptilomycalin A 134. The batzelladines A-E 233-237 were isolated together with the methyl ester 231 ptilocaulin 232 crambescin A 215 crambescidin 800 210 crambescidin 816 211 and an exceptional amount of ptilomycalin A 134. All compounds were identified by analysis of spectroscopic data and chemical degradations.Batzelladine A 233 and batzelladine B 234 inhibit the binding of the gp120 domain of HIV-envelope gp160 glycoprotein to the CD4 receptor on the surface of the human T cell. This binding is the first stage of HIV-host cell binding after which HIV penetrates into the host cell in order to repli~ate.'~' A first attempt on the synthesis of the tricyclic moiety of batzelladine A 233 has appeared.172 H 232 NH 233 n= 1 (major) 2,3 YN-N9 234 n= 1 (major),2,3 A new ptilocaulin analogue 8b-hydroxyptilocaulin 238 has been isolated from the marine sponge Monanchora arbuscula originating from the Brazilian coast and from Be1i~e.l~~ 8b-hydroxyptilocaulin was identified by analysis of spectroscopic data.The authors also discussed the taxonomy of Ptilocaulis aff. spiculifer from which ptilocaulin 232 and isoptilocaulin 239 have been previously isolated,174 and suggested that classification must be revised to the Batzella genus closely related to Crarnbe and Monanchora. Various polypeptides have been isolated from marine sponges several of them with an arginine or a modified arginine residue. Discodermins A-D 240a-240d were the first polypeptides which have been isolated from a marine sponge (Discoderrnia kiieylsi~~~~-~'~). Recently a series of new discodermins E-H 240e-240h have been isolated from the same sponge D. and the structure of discodermins A-D have been revised.17g The structures of discodermins were established by extensive chemical degradations and analysis of spectroscopic data.Discodermins A-H 240a-240h presented a broad range of antimicrobial activity. 235 236 n = 1 (major) 2,3 H 237 NH 238 NH II Me H 239 NATURAL PRODUCT REPORTS 1996 H NH 240a discodermin A R' = R2= H; R3 = R4 = Me; R5 = X 240b discodermin B R' = R2 = R3 = H; R4= Me; R5 = X 240c discodermin C R' = R2 = R4 = H; R3 = Me; R5 = X 240d discodermin D R' = R2 = R3 = R4 = H; R5 = X 2408 discodermin E R' = R2 = H; R3 = R4= Me; R5 = Y 240f discodermin F R' = R2 = H; R3 = Me; R4 = Et; R5 = X 2409 discodermin G R' = R3 = R4 = Me; R2 = H; R5 = X 240h discodermin H R' = H; R2 = OH; R3 = R4 = Me; R5 = X 24 1 Polydiscamide A 241 is a depsipeptide closely related to discodermins but it has a 3-methylisoleucine replacing a tert-leucine and the lactone cycle of polydiscamide A 241 has five amino acids instead of six.lg0 Polydiscamide A has been isolated from the sponge Discodermia sp.,and the structure was determined by analysis of spectroscopic data and chemical degradation.The absolute stereochemistry of cyclotheonamides A 242 and B 243 was revised during the synthesis of different stereoisomers. The absolute configuration of the arginine- derived residue is (S) and that of the vinyltyrosine residue is (S).lS1 The (S,R)respective analogue of cyclotheonamide B has a potent inhibition of thrombin activity. The synthesis of cyclotheonamide B (Scheme 17) was accomplished by the same authors.lB1 The vinylogous tyrosine derivative 244 was prepared from a protected tyrosine deriv- 242 R =H 243 R=Me NATURAL PRODUCT REPORTS 1996-R.G. S. BERLINCK 397 ative and cc-hydroxy-~-N-tert-butoxycarbonyl-N3-guanido-4-group with p-TsOH showed the utility of a novel guanidin- methoxy-2,5,6- trimethylbenzenesulfonyl-N -guanido-tert-but-ium protecting group strategy. The ammonium p-toluene- oxycarbonylhomoarginine 245 was prepared from a protected sulfonate thus obtained was neutralized with Hiining's base and amide derivative of arginine. Zinc-acid catalysed removal treated with 4-(N,N-dimethylamino)pyridine(DMAP) to give of the phenacyl protected group of proline in 247 was fol- the cyclic peptide 249. This compound was finally oxidised and lowed by pentafluorophenyl ester formation at the C-terminus.the protecting groups were removed with trifluoroacetic acid Careful and selective removal of the N-terminal Boc protecting and thioanisole giving cyclotheonamide B 243. H "OMe Ie BocHN 0 i. LiAIH4 THF ii. LiAIH4. THF ii. Ph3P=CHC02Et (89% 2 steps) iii. HC(SMe)3 Bu"Li (48X 2 steps) iii. LiOH MeOH H@ iv. HgO HgC12 H20 dioxane 89% iv. DCC C6F50H. CH&l2 100% V. LDH H20 lOO?! t H MtrHNKN7 B*xw6F5 0 NBoc b BocHN 0H 244 OH 245 Mtr = dmethoxy-2,5,6-tnmethylbenzenesunonyl i. L-Pro-OMe,HOBT DCC (86%) ii. H2 W-C iii. Ac20 iv. LiOH v. PacBr CsC03 (7% 4 steps) H *i. Dess-Martin oxidation CHpCl2 74% ii. TFA. C&SMe rt 3 h 58% Pac = phenacyl \-Ph 0 Mtr = 4-methoxy-2,5,6-trimthylbenzenesulfonyl Scheme 17 NATURAL PRODUCT REPORTS 1996 i.NMM cico2t3J i. TIPSCI imidazole DMAP CH2CI2(88Yo) ii. MeNHOMe Et3N ii. LiAIH4,THF -5OOC 92% -BocHNP O H iii. (Et0)2P(0)CH2C0$iMe3 BuLi THF H30+(66%) 250 N Me' 'OMe Br-+H3N 251 702Me 253 4 NHCbz HN THPO MtrHNAN Cbz POT"" 255 i. LiOH MeOH H?O ii. NMM CIC02Bu' THF -50°C iii. o-Phe-OMe I Me02C '&% H! THPO ii. LOH MeOH H20 i. Boc20 DMAP CH2C12 (86%) 254 HN THPO + iii. DHP PPTS CH2C12 (79%) MtrHNKNd iv. H2 Pd-C MeOH (lOOYo) MtrHNKN I H Boc I. Pd(PPh& dimedone THF rt (87%) 256 257 1iii. 257(76%) i. 0.05 N HCI Et2GCH2CI2 8 ii. C$50H DCC CH2C12 (80%) iii. sat. HCI Et20-CH2Cl2 iv.NMM CH2C12 (53%) 4 v. Dess-Martin periodinane,MeCN 80°C 1 h (83Y0) vi. HF-pyridine THF vii. TFA thioanisole (36%) BocNKNHMtr NH 242 258 Scheme 18 Other syntheses of cyclotheonamide B 243 and some Finally removal of the protecting groups gave synthetic derivativeswere developedlszusing diethylphosphonocyanidate cyclotheonamide A 242 in 30% yield. [(EtO),P(O)CN DEPC] and pentafluorophenyldiphenyl-Another synthesis of cyclotheonamides A and B have been phosphinate [Ph,P(O)OC,F, FDPP] as coupling reagents in recently reported.186 Cyclotheonamide A 242 was first the formation of the peptide bonds. synthesizedthrough a convergent [3 +21 fragment condensation Cyclotheonamide A 242 has been synthesized through a approach. The first fragment was obtained as follows (Scheme convergent route (Scheme 18).183-185The vinylogous amino 19a) N-2-carboxybenzyl-N"-tosyldiprotected arginine 259 acid 252 was synthesized from L-Boc-tyrosine via the Weinreb was converted via its imidazoline derivative into the cor-amide 251.Coupling of the unsaturated amino acid 252 with responding aldehyde and subsequently to a mixture of hydrobromide 253 was achieved by activation of the acid diastereomers of the cyanohydrin 260. After hydrolysis of the function of 252 with diphenylphosphinic chloride. After nitrile function the a-hydroxycarboxyl group of 261 was condensation of the arginine extended residue 255 with D-protected giving 262. This latter compound was coupled with phenylalanine methyl ester change of N,protective group of D-PheO-Butto give the dipeptide 263 which was converted into the guanidine 256 improved the condensation of the two 264 after hydrogenolysis of the N-carboxybenzyl protecting cyclotheonamide A moieties.C-terminal deprotection of group condensation with Fmoc protected proline and tri-tripeptide 254 with PdO in the presence of dimedone followed fluoroacetic acid removal of the tert-butyl ester group. by segment condensation with dipeptide 257 furnished the The second fragment was synthesized in the following complete framework of cyclotheonamide A. After macro-manner (Scheme 19b) methyl tyrosine 265 was diprotected on lactamization the a-hydroxyamide function was oxidized with its hydroxy and amino groups reduced to the corresponding an excess of Dess-Martin periodinane at high temperature.aldehyde and condensed with a suitable phosphorane to give NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK 0 CN poH Ho~NHcbz NHCbz i. a) (Im)$O b) DIBAL-H I c I Hfl *C02Me J ii. KCN J 265 i. Fmoc-CI K2CO3 ii. TBDMS-CI iii. DIBAL-H iv. PhaP=CHC02Bd (73%,4 steps) i. HCI MeOH (-78 to 0°C) ii. NaHC03 V. TFA (sly') iii. HOAc (pH 4) C02H C02Me NHCbz NHCbz + cNH2 i. SEM-CI lutidine But0.&.' NPht ii. LOH imOC 35% from 259 "3 Ho7 HN HN 266 267 72% EDC,HOBt I 262 261 OSiMe2But I HN NPht Fmoc 268 HO i. H2 Pd(OH)2 0 ii. Fmoc-Pro,DCC C iii. TFA OSiMe2But I 00 Scheme 19b ButMe2Si0 Ph I.../ codi AH Fmoc HO BOP-CI - 0 0 Et3N 65% PhtN3 CQBu' 269 270 i.TFA 41% ii. Et2NH iii. DCC HOBt I i. HC02Et (88%) ii. Dess-Martin oxidation iii. HF PhOMe cyclotheonamideA 242 cyclotheonamideB 243 HN I ii. Dess-Martin oxidation iii. HF PhOMe 30% Scheme 19c the fully protected vinyltyrosine amino acid 266 after treatment with trifluoroacetic acid. The acid 266 was further coupled with the amine 267 obtained from ~-2,3-diaminopropanoic acid through a multistep procedure in order to furnish the dipeptide 269 after removal of the N-Fmoc protecting group of the vinyltyrosine residue. The [3 + 21 coupling was achieved in 65 % yield (Scheme 19c). Macrocyclic lactam formation was effected under high-dilution conditions (0.001 M in CH,Cl,) to give 271 in 41 % yield.Removal of the phthalimide protecting group was rather troublesome but it was achieved by reacting 271 with hydrazine in the presence of an olefin scavenger in order to avoid reduction of the vinyltyrosine double bond by a possible diimide arising from hydrazine. The crude product 272 was subsequently acylated oxidized with an excess of Dess-Martin periodinane and finally deprotected with anhydrous HF to give cyclotheonamide A 242. Alternatively the amine 272 was selectively acetylated oxidized and deprotected to give cyclo- theonamide B 243. A detailed discussion of the thrombin inhibition activity of cyclotheonamides A and B was presented in this report.le6 Wipf recently reviewed the chemistry of biologically active marine cyclopeptides including a detailed discussion on the various syntheses of cyclothe~namides.~~~ Further a similar synthetic approach to that of Maryanoff et UI.'~~ was employed by Bastiaans et towards the synthesis of cyclotheonamide B.Two proline-rich cyclic heptapeptides hymenamides A 273 and B 274 have been isolated from Hyrneniacidon sp,le9 but only hymenamide A 273 has an arginine residue. The structure of both polypeptides were established by hydrolysis and spectroscopic analysis The absolute configurations of the amino acids were established by chiral HPLC and chiral GC analyses. 2D NMR conformation studies in solution were performed for both compounds. 273 274 A series of new polypeptides have been isolated from a Cymbastela sp.sponge collected in Papua New Guinea,lgo among them the criamides A 275 and B 276. The structure of criamide A 275 was proposed by analysis of spectroscopic data and also by chemical degradations in order to confirm the presence of the L-arginine residue. The structure of criamide B 276 was established by comparison to that of criamide A. NATURAL PRODUCT REPORTS 1996 Criamide B is a potent cytotoxic compound against a series of different tumour cell lines such as murine leukaemia P388 (ED, 7.3 ng ml-l) human breast cancer MCF7 (ED, 6.8 pglml-l) human glioblastoma/astrocytoma U373 (ED, 0.27 pg ml-l) human ovarian carcinoma HEY (ED, 0.19 pg ml-l) human colon LOVO (ED, 0.15 pg ml-l) and human lung A549 (ED, 0.29 pg ml-l).275 R=H 276 R = Me A series of new phloeodictines Al-A7 277-283 and Cl-C2 284-285 have been isolated as mixtures of homologues from the New Caledonian sponge Phloeodictyon sp.lgl The compounds exhibited in vitro antibacterial activities and showed moderate cytotoxicity against KB cells. The structures of these compounds were established by analysis of spectroscopic data mainly the fragmentation by B/E collisionally activated dissociation (CAD) FAB mass spectrometry and by chemical derivatization with pentane-2,4-dione. 2TI phloeodictine A1 n= 4; R = CH2CH=CH2 278 phloeodictine A3 n= 2; R = CH2CH=CH2 279 phloeodictine A5 n= 1; R = CH2CH=CH2 280 phloeodctine A6 n= 5; R = CHMe2 281 phloeodictine A2 n= 4; R = CH2CH=CH2 282 phloeodictine A4 n = 2; R = CH2CH=CH2 283 phloeodictine A7 n = 5; R = CHMe2 284 phloeodictine C1 n= 2 285 phloeodictine C2 n= 1 Leucettamine B 286 previously isolated from Leucettu mi~roruphis,'~~ has been synthesized (Scheme 20).lg3 Reaction of the aldehyde 287 with ethyl azidoacetate gave the azide 288 which was converted to the iminophosphorane 289 with triphenylphosphine.Aza-Wittig type reaction of imino- NATURAL PRODUCT REPORTS 1996R. G. S. BERLINCK NH3 sealed tube 145°C 80% NH2 291 AH2 286 Scheme 20 phosphorane 289 with methyl isocyanate yielded the carbodiimide 290.Treatment of 290 with ammonia furnished leucettamine B 286 through the substituted guanidine in- termediate 291 in 49% overall yield.Four new dimeric peptide alkaloids anchmopeptolides B-D 292-294 and cycloanchinopeptolide C 296,have been isolated from the marine sponge Achinue tenuciur.lg4 The structures were established by comparison of spectral data with that of anchinopeptolide A 295 previously isolated from the same sponge.lg5 SOH 293 R’ = H; R2= Me 294 R’ = R2 = H 295 R’ = R2= Me -OH HNYNH2 401 Variolin A 297 variolin B 298 and 3’-methyltetra-hydrovariolin 299are pyridopyrrolopyrimidine alkaloids which have been isolated from the Antarctic sponge Kirkpatrickia vuriulosu.196~197 The structure of variolin B 298 was initially elucidated by X-ray diffraction analysis and the structures of variolin A 297 and 3’-methyltetrahydrovariolin 299 were elucidated by spectroscopic and X-ray diffraction analysis.3’-Methyltetrahydrovariolin 299 is the only ‘true ’ guanidine derivative in this series. All these compounds have similar mild cytotoxic and antifungal activities. y42 y2 297 298 OH 299 Narains 300and 301 are further examples of natural products with an N,N-dimethylguanidinium counter ion. The two narains 300 and 301 have been isolated from a sponge of the genus J~spis,’~~ and the structures have been established by analysis of spectroscopic data. Both narains as well as the anions only are metamorphosis inducers of the larvae of the ascidian Halucynthiu ruretzi. Interestingly the narains are closely related to tubastrine 302 which has been isolated from the coral 300 OS03-HOxp-H2N Me OH Hd Me 301 NH HO OH OH 296 302 Tubastrea aurea.lgg A related derivative 303 has been isolated from a Spongosorites sp.sponge from Australia.200 The structure 303 was established by analysis of spectroscopic data and confirmed by transformation into the 1,2-dihydro-pyrimidinyl derivative 304. Similar reactivity was presented by tubastrine 302 which did not react with pentane-2,4-dione as did its dihydro derivative.lg9 Compound 303 produced modest growth inhibition against Staphylococcus aureus and Escherichia coli. 303 H 304 A guanidine bromotyrosine derivative has been recently isolated from Aplysina cauliformis.201 Aplysinamisine I1 305 has been isolated together with other bromotyrosine derived compounds which are characteristic of the sponges of the order Verongida.The structure of aplysinamisine I1 305 was established by analysis of its spectral data and by derivatisation with pentane-2,4-dione. Aplysinamisine I1 305 exhibited mar- ginal antimicrobial activity against Staphylococcus aureus Pseudomonas aeruginosa and Escherichia coli mild in vitro antitumour activity against the human breast (MCF-7) and T cell leukemia (CCRF-CEM) cell lines and selective activity against the human colon (HCT 116) solid tumour cell line.2o1 Although not a 'true guanidine' zarzissine 306 which is a cytotoxic 2-aminoimidazopyridazine has been isolated from the mediterranean sponge Anchinoe paupertas.202 Zarzissine 306 exhibited positive reaction to the Sakaguchi reagent and its structure was determined by analysis of spectroscopic data.OMe 305 H 306 307 NATURAL PRODUCT REPORTS 1996 Two agmatine fatty acid derivatives aplysillamides A 307 and B 308 have been isolated from the sponge Psammaplysilla p~rea.~O~ Both compounds were identified by analysis of spectroscopic data while only aplysillamide B has been synthesized in order to establish the (S) absolute stereo-chemistry at the chiral carbon (Scheme 21). BOMoAOH 309 ii. Ph3PCeH13Br,BuLi,THF rt 12 h BOMOL 310 Raney-Ni Hp EtOH rt 66 h 1 HOL 31 1 ii. NaCN DMSO 7OoC 1 h Nc+ /-d 312 NaOH H202 EtOH reflux 22 h 1 313 i. N-hydroxysuccinimide DCC dioxane doc 20 h ii. Agmatine sulfate THF-H20 rt 44 h I 308 Scheme 21 3.4 Other Marine Invertebrates Eusynstyelamide 314 has been isolated from the tunicate Eusynstyela mi~akiensis.~~~ The structure of eusynstyelamide 314 was established by analysis of spectroscopic data.Fuscusine 315 a tetrahydroisoquinoline alkaloid has been isolated from the seastar Perknaster fuscus antar~ticus.~'~ The structure of fuscusine 315 which is racemic also was established by analysis of its spectral data. H H 31 4 308 315 NATURAL PRODUCT REPORTS 1996-R. G. S. BERLINCK Ptilomycalin A 134 crambescidin 800 210 and two new related polycyclic guanidine alkaloids celeromycalin 316 and fromiamyacalin 317 have been isolated from the starfishes Fromia monilis and Ceferina heflermani.206 The structures of the two new compounds were established by analysis of FABMS and NMR data.The stereochemistry at the pentacyclic nucleus of both compounds were assigned by NOE difference spectra and by comparison with data previously reported for ptilomycalin A and the crambescidins. Moreover the (R) absolute stereochemistry of the carbinol carbon C-36 of celeromycalin 316 was established by the Mosher's method and the absolute stereochemistry of the pentacyclic moiety of 316 was proposed as shown by comparison to that previously established for the crambescidin~.~~~ Both celeromycalin 316 and fromiomycalin 317 displayed anti-HIV activity on CEM 4 cells infected by HIV-1 at the concentrations of 0.32 pg ml-I and 0.11 pg ml-l respectively.The authors also reported the isolation of the hydroxyspermidine w-hydroxy fatty acid moiety 318 which showed a weaker cytotoxicity in this assay suggesting that the activity could be mostly due to the pentacyclic guanidine 'vessel ' portions of these compounds. 206 316 317 HomN-NH2 0 318 319 Leucylarginine 319 is a pheromone which stimulates the liberation of mature eggs by the female of the crab Rhitropanopeus harrisii. At the moment of hatching the eggs the female of R. harrisii stands up on her walking legs and flexes her abdomen back and forth in a pumping action. This physically breaks unhatched eggs and brings about nearly simultaneous release of all the larvae. Hatched eggs produce leucylarginine 319 which acts at the threshold of 43 pg ml-l to stimulate this physical action by the female of R.harrisii."' Polyandrocarpidines A-D 320a-320d isolated earlier from the ascidian tunicate Polyandrocarpa sp.,208 '09 are feeding deterrent compounds.21o The mixture of naturally occurring 320a-320d significantly reduced the consumption of treated food by the hermit crab Cfibanarius digueti (to the extent of -lOO%) the marine snails Cassipira pluto (-79 YO)and Tegula rugosu (-82 as well as the hermit crab Pagurus O/O) granosimanus ( -56 YO). 403 320a polyandrocarpidineA n = 4 32Oc polyandrocarpidineC n = 3 0 H '(CH$,-N HN +42 320b polyandrocarpidine B n = 4 32Od polyandrocarpidine D n = 3 Q 321 A new cyclic guanidine derivative caledonin 321 has been isolated from the tunicate Didemnum rodriguesi collected at new Caledonia."l The structure of caledonin 321 was proposed by analysis of spectroscopic data and by chemical degradation.The absolute stereochemistry of the primary amino group was established as (S) by derivatization with (R)-and (S)-methoxyphenylacetic acid and analysis of the 'H NMR spectrum after separation by HPLC. Caledonin 321 complexed by ZnC1 to give a caledonin-Zn" complex which was characterized by FABMS and NMR spectroscopy. 4 Natural Guanidine Derivatives from Higher Plants Several guanidine derivatives isolated from various Leguminosae and Tephrosieae such as Millettia Mundufeu Tephrosia Derris Leptoderris Lonchocarpus and Piscidia genera212-213 were not covered in the previous review.l The compounds isolated comprise enduracididine 322 previously isolated from Streptomyces fungicidu~,~~~ 2-[2-amino-2-imidazolin-4-yl]acetic acid 323 and the well known homoarginine y-hydroxyarginine and canavanine.Other unidentified guanidine derivatives have been isolated from these plants.212 Interestingly 2-aminoimidazole 324 was isolated from Mundufeu sericea.216 2-Aminoimidazole has been previously isolated from the marine sponge Reniera cratera217 and from Streptomyces eurocidicus.21s .... 322 323 324 Me 0 I II 325 326 Two new 2-aminopyrimidine alkaloids 5a,9a-dihydro-5a- hydroxymillaurine 325 and milletonine 326 assigned as guanidine derivatives have been isolated from Milletia laurentii (Legumin~sae).~~~~ 220 The structures of these compounds were established by analysis of spectral data.Martinelline 327 and martinellic acid 328 are new G-protein linked receptor antagonists which have been isolated from Martinella iquitosensis (Bignoniaceae).22f Both compounds were isolated by reverse phase chromatography and RPHPLC and the structures were established by analysis of spectroscopic data. Radioligand binding studies revealed that martinelline 327 interacts with bradikinin (BK) B and B, a,-adrenergic and muscarinic receptors. Moreover martinelline is also a competitive blocker of [des-Argg]-BK of norepinephrine and histamine-stimulated contractions of rabbit thoracic aorta and carbachol-induced contractions of guinea pig ileum.Martinelline 327 also displayed modest Gram-positive and Gram-negative antibiotic activity. The combined effects of analgesia antimicrobial activity and reduction of inflammation may explain the folklore use of M. iquitosensi for eye ailments mainly conjunctivitis. Three further prenylated guanidines nitensidines A 329 B 330 and C 331 have been isolated from Pterogyne nitens.222 The structures of nitensidines A B and C were established by analysis of spectroscopic data including HMBC for nitensidine C 331. All nitensidines displayed moderate activity towards the mutant strain RS 321 of Saccharornyces cerevisiae used in a mechanism-based anticancer bioassay suggesting their po- tential as DNA-modifying agents.222 NATURAL PRODUCT REPORTS 1996 5 Natural Guanidine Derivatives from Terrestrial Invertebrates Neurotoxic polyamines originating from spiders have been the subject of research as biochemical tools.In this sense the compounds continue to be surveyed by many authors. Usherwood and Blagbro~gh~~~. 224 have extensively reviewed this subject with an emphasis on pharmacology. Scott Sutton and Dolphin225 have discussed the interaction of the polyamines with neuronal ion channels. Nakanishi et a1,226 presented a brief review concerning structure-activity relationships of the natural polyamine neurotoxins and a variety of analogues already synthesized by these authors. Other authors have not only reviewed this subject thoro~ghly,~~' but also synthesized a variety of new analogues of po1yamine.22s Other reviews on this subject have also been rep~rted.~~~,~~~ Blagbrough et al.also have synthesized some of the naturally occurring compounds and a variety of new analog~es.~~~-~~~ A variety of new acylpolyamine toxins originating from various spiders have been isolated but none of these have an arginine The nephilatoxins-9 332 and -1 1 333 as well as a new analogue 334 have been synthesized by a new solid-phase which involves the preparation of an orthogonally N-protected Na-(Fmoc-L-Asp)-Ne-Dde-cadaver-ine as the key intermediate. Recently a new polyamine toxin called FTX has been isolated from the venom of Agelenopsis aperta Holonina curta and Calilena spiders. FTX blocks the action of the voltage sensitive calcium channels in marnmal~.~~"~~O Llinas and HHNyN-y+ HHNyNy 327 328 329 330 331 332 333 P 334 NATURAL PRODUCT REPORTS 1996-R.G. S. BERLINCK proposed the structure 335 for FTX based on the synthesis and Ca2+ channel-blocking activity of various polyamines. Nevertheless Blagbrough and Moya2,, 256 have synthesized FTX 335 (also called FTX-3.3) as well as the analogue sFTX 336 and showed that synthetic FTX 335 has different spectroscopic data than those reported for natural FTX.248 Hence the structure of natural FTX remains un- determined. Interestingly whle FTX 335 inhibits the action of 2513 P-type calcium 252 sFTX 336 reversibly inhibits low voltage-activated T-type calcium current^.^^^.^,^ 335 336 337 338 Also recently a pharmacologically and biologically inactive polyamine Plt-I 337 has been isolated from the venom of the primitive hunting spider Plectreurys tri~tis.~~' The structure of Plt-I 337 was established by spectroscopic analysis of the degradation products and also by synthesis from dimethyl oxalate and agmatine sulfate in alkaline media.A new synthesis of hirudonine 338 isolated from the leech Hirudo medicinulis L.,258has been reported25e with a new strategy for protecting and deprotecting the amino groups of the polyamines (Scheme 22). 6 Vertebrates Trypargine 345 has been isolated from the skin of the African rhacophorid frog Kussinu senegulensis,260* 265 and presents acute toxicity to mice at the level of LD, 16.9 mg kg-l.The structure was established by spectroscopic analysis chemical degradation and confirmed by synthe~is.~~l-~~~ An asymmetric synthesis of trypargine 345 established the absolute stereochemistry at C- 1 as being (S) (Scheme 23).264 345 405 ? H2N-N-NH2 339 CF3CO#t H20 MeCN,reflux 7 h 89% J H I CFaCONH-N-NHCOCF3 340 t OY0DN3 I CF3CoNH-N-NHCmCF 341 NH3 MeOH I dark rt 6d MeqMe 1 MeOH,81X dark rt 3 d 343 dfihiothreitol Et3N MeOH H20. It 4 h I 50% H H I H2NyN-N-N H "02 344 H, 10% Pd-C HC02H HS rt 3 h J H H I HzNKN-NwN H NH .-.. 338 Scheme 22 Condensation of D-tryptophan 346 with benzaldehyde followed by reduction gave N,-benzylidenetryptophan methyl ester 347 in good yield.The methyl ester 347 was submitted to the Pictet-Spengler condensation in the presence of a-ketoglutaric acid in anhydrous medium giving a mixture of (348a and 348b) and (349a and 349b) diastereomers. After separation by chromatography the mixture of diastereomers 349 was methylated giving the mixture (-)-350a and (-)-350b from which (-)-350a was obtained in 78% yield after separation by silica-gel chromatography. By ammonolysis this latter compound was converted to a mixture of the diamide (-)-352 and the monoamide (-)-351. The stereochemistry of (+)-348a (-)-349a (-)-349b (-)-350a and (-)-351 was established by chemical correlations analysis of lH and 13C NMR spectra as well as by X-ray crystallographic analysis of (-)-350a which indicated a 1S,3R configuration for this latter NATURAL PRODUCT REPORTS 1996 .,C02H i.PhCHO benzene ..C02Me ii. NaBH4 MeOH (81%) OTflNHCHPh 1:1 HW c H or benzene-dioxane 8 h. reflux 070NH2 H2 Pd-C PhCHO EtOH (82%) H 346 347 (+)-348a C-1-aH (5%) (+)-348b C-1-pH (3%) + ,.CO2Me CH2N2 ayqH silica gel chromatography “CHZPh \I C02Me C02H (-)-350a C-1-aH (78%) (-)-349a C-1-d-I (-)-350b C-1-f4-I (7%) 76% { (-)-349b C-1-pH NH3 MeOH silica gel chromatography I 0 /c*N ~~~~~~~ + .-*LN; ayTH$h POCl3 ay7T =H _____c DMF-pyridine 92X 0 NH2 0 NH2 N (-)-351 (1 2%) (-)-352 (86%) (-)-353 it NaBh EOH (70%) ii. LiAIH., Et20 (95%) 4 i. 10% Pd-C SMe H2 EtOH HCI (95%) aycH2Ph ayq ii.H2NANH 55% NH2 (-)-345 (-)-354 Scheme 23 compound. Subsequently the diamide (-)-352 was converted 3 P. P. De Deyn B. Marescau V. Stalon and I. A. Quereshi to the dinitrile (-)-353 which was subjected to reductive Guanidino Compounds in Biology and Medicine John Libbey and decyanation at C-3 and reduction of the remaining nitrile to Co London 1992. give (-)-354. After remotion of the benzyl protecting group 4 C. R. Ganellin in Medicinal Chemistry ed. C. R. Ganellin and the free base was reacted with S-methylisothiourea sulfate S. M. Roberts Academic Press London 1993 2nd edn pp. 228-256. giving the natural enantiomer of trypargine 345. 5 M. Chandler M. J. Bamford R. Conroy B. Lamont B. Patel V. K. Patel I.P. Steeples R. Storer N. G. Weir M. Wright and C. Williamson J. Chem. SOC. Perkin Trans. 1 1995 1173. 7 Conclusion 6 M. J. Bamford J. C. Pichel W. Husman B. Patel R. Storer and Although the isolation of natural guanidine derivatives seems N. G. Wier J. Chem. SOC. Perkin Trans. I 1995 1181. to be rather fortuitous these compounds are of widespread 7 M. Chandler R. Conroy A. W. J. Cooper R. B. Lamont J. J. occurrence in nature and very often present unusual structural Sciciski J. E. Smart R. Storer N. G. Weir R. D. Wilson and P. G. Wyatt J. Chem SOC.,Perkin Trans. I 1995 1189. features as well as remarkable biological activities. We believe 8 S. Ciccosto and M. von Itzstein Tetrahedron Lett. 1995 36, that further work in this field will clarify many aspects of 5405.biological activities deriving from the structural motifs of 9 V. Alcazar J. R. Moran and J. de Mendoza Tetrahedron Lett. natural guanidines. It will be also desirable to perform 1995 36 3941. biosynthetic studies in view of new insights about arginine 10 R. Chinchilla C. Najera and P. Sanchez-Agullo Tetrahedron metabolism and the incorporation of free or alkylated guanidine Asymmetry 1994 5 1393. into natural products. 11 V. Jubian R. P. Dixon and A. D. Hamilton J. Am. Chem. SOC. 1992 114 1120. Acknowledgments. The author is gratefully indebted to Dr 12 V. Jubian A. Veronese R. P. Dixon and A. D. Hamilton Angew. 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ISSN:0265-0568    

DOI:10.1039/NP9961300377

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Oligomeric Proanthocyanidins Naturally Occurring O-Heterocycles Daneel Ferreira and Riaan Bekker Department of Chemistry University of the Orange Free State PO Box 339,Bloemfontein 9300South Africa Reviewing the literature published between January 1992 and December 1995 1 Introduction fla~an-3,4-diol,~ to a nucleophilic flavanyl moiety often a 2 Flavan-3-01s and Flavan-3,4-diols flavan-3-01. However the limits between the biflavonoids and 2.1 Flavan-3-01s the proanthocyanidins have become somewhat arbitrary since 2.2 Flavan-3,4-diols an increasing number of ‘mixed’ dimers e.g. flavan-3-01- 3 A-type Proanthocyanidins dihydroflavonol and ‘non-proanthocyanidins ’ comprising 4 B-type Proanthocyanidins oxidatively coupled flavan-3-ols have lately been identified.’ 4.1 Procyanidins (3,5,7,3’,4’-Pen tahydroxylation) The oligomeric proanthocyanidins and compounds possessing 4.2 Prodelphinidins (3,5,7,3’,4’,5’-Hexahydroxylation) at least one flavan or flavan-3-01 constituent unit will be dealt 4.3 Propelargonidins (3,5,7,4’-Te trahydroxy lation) with in this Report.The nomenclature system proposed by 4.4 Profisetinidins (3,7,3’,4’-Tetrahydroxylation) Hemingway4 is applied consistently. 4.5 Proro binetinidins (3,7,3’,4’ 5’-Pentahydroxylation) 4.6 Pro teracacinidins (3,7,8,4’-Te trahydroxyla tion) 5 Non-moanthocvanidins with Flavan or Flavan-3-01 2 Flavan-3-01s and Flavan-3,4-diols Consiituent units Owing to the purported role of the flavan-3-01s as nucleophilic 6 ‘Complex Tannins’ chain-terminating units and of flavan-3,4-diols (leucoantho- 7 Conformation of Proanthocyanidins cyanidins) as electrophilic chain-extender units in the biosynthe- 8 Astringency sis of the pro an tho cyan id in^,^ these two classes of compounds 9 References are also discussed.2.1 Fiavan-3-ois Besides the identification of the novel epirobinetinidol 1 from I Introduction commercial wattle bark extract, a considerable number of new The oligomeric and polymeric proanthocyanidins represent a derivatives of known flavan-3-01s have been reported. These major group of phenolic constituents in woody and some include a rutinoside [a-L-rhamnopyranosyl-( 1 +0 +~)-P-D-herbaceous p1ants.l Together with the biflavonoids they glucopyranosyl] derivative 27 and a 3’-O-methyl-7-O-P-~-represent the two main classes of complex C,-C3-C secondary glucopyranosyl derivative 38of catechin the galloyl esters 49 metabolites.The bi-and tri-flavonoids2 are products of and Soof epigallocatechin epigallocatechin-3-O-(4-hydroxy-oxidative coupling of flavones flavonols dihydroflavonols benzoate) 6,l1 4’- O-methyl-en t-gallocatechin 7 its enantiomer flavanones isoflavones aurones and chalcones and thus 4’-O-rnethylgallocate~hin,~~ afzelechin-3-O-a-~-rhamnopyran- consistently possess a carbonyl function at C(4) or its equivalent oside 8,14 afzelechin-4’-O-P-~-glucopyranoside 9,154-P-car-in every constituent flavanyl unit. In contrast the proantho- boxymethylepiafzelechin 10,15 epiafzelechin-3-O-P-~-allpy-cyanidins usually originate by coupling at C(4) (C-ring) of an ranoside 1l,l6 epicatechin-5-O-P-~-glucopyranoside 12” and electrophilic flavanyl unit generated from a flavan-4-oll or a the tri-O-methylether 13,18 two epicatechin derivatives,lg ”OR’ 1 2 R’ = P-D-glucopyranosyl-Oa-L-rhamnopyranosyl; R2 = R3 = H 4 R’ = 3,4,5-tri-OH-benzoyl(galloyl);R2= R3 = H 3 R’ = H; R2= P-D-glucopyranosyl; R3 = Me 5 R’ = galloyl; R2= R3= Me 6 R’ = 4-OH-benzoyl; R2 = R3 = H R20w.*a::3 HO Ho~o DOR2 Rl *’OH *‘OR’ “OH \ Ho9 ’ OH OH OH R2 OR’ 7 8 R’ = a-L-hamnopyranosyl; R2 = H 10 R’ = H;R2 = CH2C02H 12 R’ = p-D-glUCOpyBnoSyl; R2 = R3= H 9 R1= H; R2= P-D-glucopyranosyl 11 R’ = B-Pallopyranosyl; R2= H 13 R‘ = R2 = R3 = Me 41 1 NATURAL PRODUCT REPORTS 1996 HO OH OH OH HO OMe 14/15 16 davalliosides A* 14 and B* 15 the 3’,4’-methylenedioxy analogue 16 of epicatechin,18 gallocatechin 3’- and 4‘-0-gallates20 17 and 18 and gallocatechin 3’,7- and 4’,7-di-0- gallates2019 and 20 which occurred in almost racemic form.The rare series of naturally occurring flavan-3-01s with an additional pyran ring1 was extended by identification of two epicatechin derivativesz1 21 and 22 as well as four phenyl- propanoid-substituted catechins22 23-26 of the cinchonain type. The structures of the latter four compounds including their stereochemistry were elucidated on the basis of spec-troscopic evidence and also by the synthesis of analogues 25 and 26 via acid catalysed condensation of catechin and caffeic acid. Comparison of the CD data of compounds 23-26 with those of cinchonains Ia-Id has led to revision of previous structures not only for Ia-Idz3 but also of the related proanthocyanidins cinchonains IIa and IIb,24 and kandelins A-1 A-2 and B-1 -B-4.25The co-occurrence of 4’-0-methyl- epigallocatechin 27 and the peltogynoid-type analogue 28 in Cassine papillosa was demonstratedz6 and their biogenetic relationship established by transformation of 27 into 28 using acetone and toluene-p-sulfonic acid a reaction that occurs readily at room temperature proceeds with retention of the configuration at C(2) and C(3) and which is general for a variety of flavan-3-0ls.~’ In the 5-deoxy (A-ring) series of oligoflavanoids with their exceptionally stable interflavanyl bonds and in the A-type proanthocyanidins (vide infra) where chemical degradation into the constituent flavanyl units is not permitted estab- lishment of the absolute configuration at the stereocentres of the chain-terminating flavan-3-01 DEF moiety in e.g.the fisetinidol-(4a -+ 8)-catechin biflavanoid 29 still represents a major obstacle in this field. This problem has recently been addressed by application of a modified Moshers’ method2*. 29 to a series of flavan-3-01s as models for representative classes of oligomeric proantho- cyan id in^.^^ Thus conversion of the permethylaryl ethers of Ho% OH .a:; 6““’ Ho-;c&)...aoH OH \ *‘OH \ *‘OH OH OH *‘OH 21 22 OH 27 OH OH OH OH 23 I (P-aryl) 28 24 {= (a-aryl) 0 25 I = (P-atyl) I 26 a = i (a-atyl) * Overlooked in a previous comprehensive review.’ NATURAL PRODUCT REPORTS 1996-D.FERREIRA AND R. BEKKER catechin 30 and epicatechin 33 into the a-methoxy-ol-trifluoro- methylphenyl acetic acid [R-(+)-and S-(-)-MTPA] esters 31 32 and 34 35 respectively and subsequent 'H NMR analysis permitted the construction of configuration correlation models 36 and 37 for the R-(+)-and S-( -)-MTPA esters 31 and 32 of a flavan-3-01 with 3s absolute configuration and 38 and 39 for Mosher esters 34 and 35 of a flavan-3-01 with 3R absolute stereochemistry. In the model for correlating lH NMR shifts and absolute stereochemistry of the R-(+)-and S-(-)-MTPA esters the a-trifluoromethyl group carbonyl and carbinyl hydrogen are approximately eclipsed hence leading to dia- magnetic shielding of the protons of the substituent which are eclipsed by the phenyl ring of the acyl functionality e.g.in conformation 36. A similar approach but with 4-arylflavan-3-01s provided a model for the establishment of the absolute configuration of the C-ring stereocentres of the phlobatannin class of oligomeric flavanoids.30 This approach has subsequently also been applied to assessing the absolute configuration of the A-type proantho- cyanidins3I where the Horeau method has been used to achieve the same goal32 (see also Section 5). Essentially all the biological significance (e.g. the protection of plants from insects diseases and herbivores) and most of the current uses (e.g.leather manufacture) and promising new uses (e.g. as pharmaceuticals or wood preservatives) of the polymeric proanthocyanidins rest on their complexation with other biopolymers e.g. proteins and carbohydrates or metal ions.33 34 Increasing attention is thus now being directed to understanding the conformation and conformational mobility of both the flavan-3-01s as models for the oligomers and of the oligo- flavanoids. This aspect will be discussed in Section 7. 2.2 Flavan-3,4-diols The only four new flavan-3,4-diols 40-43 to be identified were isolated from the seeds of Musa ~apienturn.~~ These were claimed to be the leucoguibourtinidins ent-epiguibourtinidol- 4a-0140 en t-gui bourtinidol-4a-0141 (-)-2S,3R,4R-2,3-trans-3,4-cis-4'-hydroxyflavan-3,4-diol 42 hitherto the first flavan- 3,4-diol devoid of hydroxylation at the A-ring and the leucopelargonidin ent-epiafzelechin-4a-01 43.Compound 42 could then be dubbed a leucosapienidin and following the suggestions by Porter,' named ent-sapienidol-4a-01. The relative 2,3-trans-3,4-cis configuration for compounds 41 and 42 (3J2 = 10.5 3J3,4 = 3.1 Hz and 3J2,3= 10.5 3J3,4= 2.5 Hz re-spectively) was convincingly deduced from lH NMR data of the per-0-acetyl derivatives but the proposed 2,3-cis-3,4-trans configuration of the 0-acetyl derivatives of diols 40 and 43 was definitely NOT supported by coupling constants (3J2,3= 3.5 3J3,4= 10.5 Hz and 3J2,3= 3.5 3J3,4= 9.5 Hz for the deriva- tives of 40 and 43 respectively). A further feature that casts some doubt on the validity of the structural claims is the apparent stability of the leucopelargonidin 43 in contrast to the well established reactivity of flavan-3,4-diols with 5,7-dihydroxyl- ated A-rings.OMe Me0 OMe 31 36 OMe 32 37 Me0 34 3a Me0 Me0 35 39 R&OH H O M O H \ I OH \ OH &I 40 1E 1 (3P-OH); R = OH OH& 43 41 { = i (3a-OH); R =OH 42 1I (3a-OH); R = H HO& ..DO" The rare series of flavan-3,4-diols where 0-methylation had occurred at one of the hydroxyl functions of a pyrogallol-type *'OH A-ring was extended by identification of 8-0-methylepioritin- bH 4a-01 44 in the heartwood of Acacia ~aflra.~~ 44 NATURAL PRODUCT REPORTS 1996 \ 46 QOH OH 45 -OH 47 The enzymatic conversion of a variety of dihydroflavonols via stereospecific reduction to cis-flavan-3,4-diols using flower extracts of Dianthus caryophyllus L.was also dem~nstrated.~' 3 A-type Proanthocyanidins In contrast to proanthocyanidins of the B-type where the constituent flavanyl units are linked via only one bond analogues of the A-class possess an unusual second ether linkage to C(2) of the T-unit. This feature introduces a high degree of conformational stability which culminates in high- quality and unequivocal NMR spectra conspicuously free of the effects of dynamic rotational isomerism hence making it an attractive area of research. Compounds of this class are readily recognizable from the characteristic AB-doublet (3J3 = 3-4 Hz) of C-ring protons in the heterocyclic region of their lH NMR spectra and may possess either (2q4tc)- or (2p,4p)- double interflavanyl linkages.As a consequence of these favourable structural features and because of their considerable biological a variety of additional analogues have been described. The recently proposed system of nomenclature for the A-type pro an tho cyan id in^^^ will be used leading in some instances to a change of published names as far as the a,@-designations are concerned. In a paper40 that was conspicuously overlooked in previous reviews the identification of proanthocyanidins A-6 46 [epicate-chin-(2P -+ 7 4p -+ 6)-epicatechin] and A-7 47 [epicatechin-(2P + 5 4P + 6)-epicatechin] from the seed shells of Aesculus hippocastanum L.was described. Their structures were un- equivocally confirmed by oxidative conversion of procyanidin B-5 45 and these were the first A-type compounds possessing (4 -+ 6)-interflavanyl linkages. Proanthocyanidin A-7 47 repre-sented the first example of a dimeric A-type with a 5-ether linkage and was later also obtained from the seeds of Theobroma cacao.41 The same paper40 also dealt with a series of trimeric proanthocyanidins which will be discussed below. Additional dimeric analogues included pavetannin A-2 4842 [ent-epicatechin-(2a -+ 7 4a-,8)-catechin] epiafzelechin-(2,8 + 7 4,8 + 8)-ent-afzelechin 49,31 7-O-methylepiafzelechin-(2P -+ 7 4p -+ 8)-epiafzelechin 5043and 7-0-methylepiafzelechin-(2p -,7 4p -,8)-ent-afzelechin51,43the latter two compounds representing the first naturally occurring 0-methylated A-type proanthocyanidins.Besides a multitude of dimeric proanthocyanidins of the A- and B-types as well as two B-type trimer~,~~ the seed shells of A. OH HO HO 40 hippocastanum the horse chestnut tree contain seven additional oligomeric proanthocyanidins possessing A-type These have been named aesculitannins A-G and comprised four trimers (aesculitannins A-D) and three tetramers (aesculi-tannins E-G). Their structures were elucidated by utilization of the full range of lH and 13C NMR techniques mass spectrometry thiolytic degradation using phenylmethanethiol in acidic medium oxidative formation of the ether linkage when the carbon-hydrogen bond at C(2) and the 4-flavanyl substituent are cofacial using hydrogen peroxide-sodium hydrogen carbonate and transformation of thermodynamically less stable 2,3-cis-flavan-3-01 units into 2,3-trans moieties via base-catalysed epimerization at C(2).Aesculitannins A 52 and B were accordingly identified as epicatechin-(4/3+ 8)-epicatechin-(2/3-+ 7 4p 4 8)-epicatechin and epicatechin-(2P + 7 4p + 8)-ent-catechin-(4P-+8)-epi-catechin* respectively. Aesculitannins C 53 [epicatechin-(2P+ 7 4,8 4 8)-epicatechin-(2,8+ 7 4p + 8)-epicatechin] and D 54 were unique since they represented the first A-type oligo- flavanoids possessing two doubly-bonded interflavanoid link- ages in each molecule. Analogues A 52 C 53 and D 54 are used to demonstrate the aforementioned chemical manipulations (Scheme 1).* In the original paper40 aesculitannin B was named epicatechin-(2B -+ 7,4p -+ 8)-ent-catechin-(4a + 8)-epicatechin. NATURAL PRODUCT REPORTS 1996D. FERREIRA AND R. BEKKER 415 HO H2Q NaHC03 EtOH 7-OH (D-ring) +C-2 (C-ring) c HO OH 52 53 K2C03 Me2C0 epirnerizationat C-2 (I-ring) OH 54 Interconversion of aesculitannins A 52 C 53 and D 54. Scheme 1 56 PhCH2SH H' OH 55 57 Thiolytic degradation of aesculitannin G 55 and desulphurization of benzyl thioether 56. Scheme 2 The tetrameric aesculitannins E and F each contain a single doubly-bonded moiety and were identified as epicatechin-(2P +7 4P +8)-epicatechin-(4P +8)-epicatechin-(4P +8)-epi-catechin and epicatechin-(2/3 -+ 7 4P +8)-ent-catechin-(4/3-+ 8)-epicatechin-(4P+8)-epicatechin respectively while aesculi- tannin G possesses two A-type moieties and was named epicatechin-(2/?-+ 7 4P -+ 8)-epicatechin-(4P-+ 8)-epicatechin-(2p +7 4P +8)-epicatechin 55.Confirmation of the structure of the latter complex molecule was simply effected by acid- catalysed thiolytic cleavage of the central 4,8-interflavanyl bond in 55 to afford the 4-P-benzylthioether 56 of pro-anthocyanidin A-2 and proanthocyanidin A-z4' 57 (Scheme 2). The latter compound also formed when the benzylthioether 56 was desulfurized with Raney Ni. The stem bark of Pavetta owariensis has proven to be an extremely productive source of A-type proanthocyanidins and has thus far afforded a remarkable number of new entries that were dubbed the pave tannin^.^^ 44-47 Since the reconciliation of name and structure is now well established only the names of the dimeric trimeric tetrameric and pentameric pavetannins are listed below.The structures were again elucidated by using physical techniques especially lH and 13CNMR spectroscopy and where sample quantities were sufficient thiolytic cleavage of B-type bonds and subsequent desulfurization of 4-benzyl thioethers. The NMR spectra of most of these analogues were complicated due to the adverse effects of dynamic rotational isomerism about the B-type interflavanyl bonds. The interpre- tational skills of the relevant authors permitted in some instances structural corroboration even on mixtures of two compounds.These and other papers32’ 48 contain comprehensive lH- and 13C-NMR data and should thus feature as key references for future work in this field. Besides proantho- ,447 cyanidins A-2 and A-4,4’ pavetannin A- 1 45 cinnamtannins B-142 and B-2,46 and aesculitannin F,47the following novel A- type proanthocyanidins were thus far identified in P. owariensis Pavetannin A-2 ent-epicatechin-(2a -+ 7 4a -+ 8)-~atechin~~ Pavetannin B-1 epicatechin-(2P-+ 7 4P -+ 8)-epicatechin-(4a -,8)-ent-epi~atechin~~ Pavetannin B-2 epicatechin-(2/3-+ 7 4P -,8)-epicatechin-(4a -+ 8)-epi~atechin~~ Pavetannin B-3 epicatechin-(2P-+ 7 4P -+ 6)-epicatechin-(4a -+ 8)-epicate~hin~~, 45 Pavetannin B-4 epicatechin-(2/3-+ 7,4P -+ ti)-en~-epicatechin-(4p -+ 8)-epi~atechin~~ Pavetannin B-5 epicatechin-(2P-+ 7 4P -+ 6)-catechin-(4a -+ 8)-epicate~hin~~? 45 Pavetannin B-6 epicatechin-(2P-+ 7 4P -+ 8)-epicatechin-(4a -+ 8)-cate~hin~~~~~ Pavetannin B-7 epicatechin-(2/?-+ 7,4P -+ 8)-ent-epicatechin-(201 -+ 7 401 -+ 8)-ent-epi~atechin~~ Pavetannin B-8 epicatechin-(2P-+ 7 4P -+ 8)-epicatechin-(2/3 -+ 7 4P -+ 8)-ent-~atechin~~ Pavetannin C-1 epicatechin-(4,8-,6)-epicatechin-(2P-+ 7 4P -,8)-epicatechin-(4P+ 8)-epi~atechin~~, 49 Pavetannin C-2 epicatechin-(2/3-+ 7,4p -+ 8)-ent-epicatechin-(4 a -,8)-ent -epicatechin -(4 a -,8)-epicate-Pavetannin C-3 epiafzelechin-(2P-+ 7 4p -+ 8)-epicatechin-(4p -+ 8)-epicatechin-(4P-,8)-epi~atechin~~ Pavetannin C-4 epiafzelechin-(2P-+ 7 4P -+ 8)-ent-afze-lechin-(4a-+ 8)-ent-epicatechin-(2a + 7 4a -+ 8)-ent-catechin4’ Pavetannin C-5 epiafzelechin-(2P -+ 7 4P -,8)-ent-catechin-(4a -,8)-ent-epicatechin-(2a-+ 7 401 -+ 8)-ent-cate~hin~~ The work on P.owariensis also led to revision of the structure of cinnamtannin B- 149 [epicatechin-(2/3-,7 4P -+ 8)-epicatechin-(4a -+ 8)-epi~atechin]~~ and of the name of cinnam- tannin B-249 [epicatechin-(4P-+ 8)-epicatechin-(2P-+ 7 4P -+ 8)-epicatechin-(4P-+ 8)-epi~atechin.~~ Two additional novel trimeric proanthocyanidins of the A-type epicatechin-(2P -+ 7 4P -+ 8)-catechin-(4P-+ 8)-epica-techin and epicatechin-(4a -,8)-epicatechin-(2P-+ 7 4P -+ 8)-epicatechin were recently identified50 in the seed shells of A. hippocastanurn while the highly sweet selligueain A51 [epia- fzelechin-(2,8 -+ 7 4P -+ 8)-epiafzelechin-(4P-+ 8)-afzelechin] and selligueain B15 [epiafzelechin-(2/3 + 7 4P -+ 8)-epiafze-lechin-(4p -+ 8)-3’-deoxydryopteric acid methyl ester zz epiafzelechin-(2P+ 7 4P -+ 8)-epiafzelechin-(4P-+ 8)-epiafze-lechin-4P-acetic acid methyl ester] were obtained from the rhizomes of Selliguea feei.NATURAL PRODUCT REPORTS 1996 4 B-type Proanthocyanidins Proanthocyanidins of the B-type are characterized by singly linked flavanyl units usually between C(4) of the flavan-3-01 chain-extender unit and C(6) or C(8) of the chain-terminating moiety. They are classified according to the hydroxylation pattern of the chain-extender units’ and the classes which were augmented during the review period include the procyanidins prodelphinidins propelargonidins profisetinidins prorobineti- nidins and the proteracacinidins.A considerable number of novel compounds have been added such a sustained research effort being motivated by the growing realization of the importance of these secondary metabolites in health food agriculture and various other industrial applications. Infor- mation in this regard may be found in the cited references. A significant number of the new entries are derivatized via e.g. 3,4,5-trihydroxybenzoylation(galloylation) and glycosylation hence stressing the relevance of the flavan-3-01s exhibiting similar derivatization (Section 2.1). 4.1 Procyanidins (3,5,7,3’,4’-Pentahydroxylation) The procyanidins maintained their position as a dominant and ubiquitous group of naturally occurring proanthocyanidins.New entries include the following analogues catechin-(4a -+ 8)-gallocatechin 58,9 catechin-(4a -+ 8)-epigallocatechin 59,52 catechin-(4a + 8)-catechin-3-O-P-~-glucopyranoside,~ the ‘ mixed ’ procyanidin-prodelphinidin trimer catechin-(4a -+ 8)-gallocatechin-(4a -+ 8)-gallocatechin 6052and the ‘mixed ’ pro-cyanidin-propelargonidin tetramer davallin 61”-54 [epicate-chin-(4P -+ 6)-epiafzelechin-(4/3-+ 8)-epicatechin-(4P -+ 6)-epi-catechin]. The constitution and sequence of flavanyl units of the latter complex product were effected via acid-catalysed aoH HOWOH OH HOH iOW &OH OH 6\ OH OH 58 1= I @-OH) 59 ifi (a-OH) -OH AH 60 NATURAL PRODUCT REPORTS 1996D.FERREIRA AND R. BEKKER Hov-h OH OH i OH OH HO OH Hi?H HO'* OH OH QOH OH 61 thiolytic degradation and the extensive use of 2D NMR techniques. Both the 'H and I3C NMR spectra in methan~l-[~H,] 62 R' = galloyl; R2 = H 66 63 R' = H; R2=galloyl 64 R' = R~ = galioyt 6s R'=R*=H showed complicated spin patterns due to the presence of at least two conformers as a result of restricted rotation about the interflavanyl bonds. In methan~l-[~H,]-D,O (2 1) as a solvent however a single conformer was evident which subsequently permitted full assignment of both lH- and 13C-spectra. The rare series of procyanidins with ent-epicatechin con- stituent units' was considerably extended by the isolation55 of four dimers and two trimers from the stem bark of Byrsonirna crassfolia (Malpighiaceae) which is used medicinally by the Mixe Indians.Amongst the dimers were 3-0-galloyl-ent-epicatechin-(4a-+ 8)-ent-epicatechin 62 ent-epicatechin-(4a -+ 8)-3-O-galloyl-ent-epicatechin 63 3-0-galloyl-ent-epicatechin-(4a +8)-3-0-galloyl-ent-epicatechin 64 and ent-epicatechin- (4a -+6)-ent-epicatechin 66 while the trimers comprised of 3- O-galloyl-ent-epicatechin-(4cc+8)-3-O-galloyl-ent-epicatechin-(4a -+ 8)-ent-epicatechin (compound 66 with an enantio-meric ABC moiety) and 3-O-galloyl-epicatechin-(4P-+ 8)-3-0-galloyl-ent-epicatechin-(4cr.+8)-ent-epicatechin67. These com- pounds were accompanied by the known ent-epicatechin-(4cr.-+ 8)-ent-epicatechin 65 eat-epicatechin 3-0-galloyl-ent- epicatechin and catechin.The enantiomeric purity of ent-epicatechin and the dimers 65 and ent-epicatechin-(4a -+ 6)-ent-epicatechin 66 was assessed by HPLC on a chiral cyclo- dextrin column. The bark of Bruguieragymnorrhiza (tancang) a commercially important mangrove species in the estuaries of Indonesia contains a mixture of procyanidin and prodelphinidin poly- mer~.~~ I3C-NMR spectra of the water-soluble polymer indi- cated a mixture of the latter proanthocyanidins mainly of 2,3- cis stereochemistry and the presence of bound carbohydrates of which a C(6)-deoxy glycoside was a major component. Subsequent acid-catalysed cleavage of the 'purified ' isolates in the presence of phloroglucinol as a capture nucleophile gave in addition to the anticipated procyanidin-phloroglucinol and prodelphinidin-phloroglucinol adducts 3-O-a-~-rhamnopyra- nosylcatechin-(4a -+ 2)-phloroglucinol68 hence providing evi- dence for covalently bonded glycoside moieties in the chain- extender units of mangrove bark tannins.The acid-catalysed thiolytic cleavage of the interflavanyl bond(s) in the 5-oxygenated (A-ring) proanthocyanidins using thiols as capture nucleophiles and yielding flavan-3-01 4-thioethers from the extender units and flavan-3-01s from the terminal unit has played a crucial role in the structure elucidation of these complex natural products. Application5* of OH 67 R = galloyl OH 68 thiolytic cleavage to gain insight into the structure of the polymeric proanthocyanidins from pecan nut pith known to be comprised of epigallocatechin gallocatechin and epicatechin extender units in the approximate ratios of 5 :2 :1 with either catechin or gallocatechin as terminal ~nits,~' consistently afforded significant amounts of phloroglucinol and a mixture of 1,3-dithiobenzyl-2,4,5,6-tetrahydroxyindane diastereomers 75.NATURAL PRODUCT REPORTS 1996 OH OH How. & .6 OH OH PhCH2SH H+ How OH "OH =-"OH * OH Flavanyl OH SCHZPh L 72 71 PH PhCH2SHc PhCHS$-Ho SCH2Ph 75 Proposed route to the formation of phloroglucinol and indane diastereomers 74 during thiolysis of a prodelphinidin. Scheme 3 Such a conversion is demonstrated in Scheme 3 for a typical prodelphinidin 69 with 2,3-cis configuration of the chain- extender units.Thiolytic cleavage of the prodelphinidin 69 gives the 4P-thiobenzyl ether 70 which is protonated at the electron-rich phloroglucinol A-ring to afford intermediate 71 with a labile C(4)-C(1) bond which then ruptures under the influence of the electron-donating thiobenzyl group. This process represents the equivalent of the cleaving of the interflavanyl bond under acidic conditions but under the influence of an external sulfur nucleophile. Rearrangement of the intermediate sulfonium ion 72leads to the formation of the indane diastereomeric mixture 73 with its labile benzylic ether linkage which is cleaved with the release of phloroglucinol to carbocation 74. Reaction of the latter with the capture nucleophile benzyl thiol affords the mixture of 1,3-dithio- benzyl-2,4,5,6-tetrahydroxyindane diastereomers 75.These re- sults invalidate the use of extended thiolysis to provide meaningful estimates of molecular weight of polymeric pro- anthocyanidins.It also calls to question the use of thiolysis as a means of obtaining 'quantitative' information on the composition of mixed proanthocyanidin polymers. 4.2 Prodelphinidins (3,5,7,3',4',5'-Hexahydroxylation) Besides the 'mixed ' procyanidin-prodelphinidin trimer5z 60 (vide supra) a large number of novel prodelphinidins have lately been reported. Dimeric analogous include gallocatechin- (4a +6)-gallocatechin76,9gallocatechin-(4a +6)-epigallocate-chin 77,52gallocatechin-(4a +8)-epi~atechin,~~ epigallocate-chin-(4P +8)-epigal1ocatechinl1 and prodelphinidin B- I [epi-gallocatechin-(4,8+8)-gallocatechin] that was obtained inde- pendently from Psidium guaj~va~~ and Pithecellobium lobatum.60 A variety of dimers galloylated at the secondary hydroxy group of the heterocycle were also described i.e.3-0-galloyl-epigallocatechin-(4P+6)-gall0catechin,~' 3-0-galloyl-epigallo- catechin-(4P -+S)-gallocatechin,61 3-0-galloyl-epigallocate-chin-(4fl+ 8)-epigallo~atechin'~ and epigallocatechin-(4P 46)- OH OH 1 HO OH 3-0-galloyl-epigallocatechin. In addition the 13C NMR data of dodecaacetylprodelphinidin B-3 were described.6z Two unique dimeric compounds samarangenin A 78 and samarangenin B 79,that are related to the prodelphinidins were recently in the leaves of Syzygium samarangens and S.aqueum. These compounds are presumably composed of two basic epigallocatechin moieties possessing the characteristic C-D-ring linkage of B-type proanthocyanidins as well as a C-0 bond between a B-ring carbon and an oxygen function of the pyrogallol-type ring of the 3-0-galloyl moiety at the DEF- unit. Accordingly they represent the first doubly-bonded proanthocyanidins which possess interflavanyl bonds orig- inating from both two-electron (the 4-8 bond) and one-electron (the carbon -+ oxygen bond) processes. The close NATURAL PRODUCT REPORTS 1996-D. FERREIRA AND R. BEKKER OH OH 'AU 78 R=H 79 R = galloyl structural resemblance of the two compounds was confirmed by partial hydrolysis of 79with tannase which afforded 78 and gallic acid.Unequivocal proof for the proposed absolute configurations could however not be provided. The novel trimeric prodelphinidins gallocatechin-(4a+ 8)- gallocatechin-(4a .+8)-epigallo~atechin~~ and gallocatechin-(4a -+ 8)-gallocatechin-(4a -+ 8)-gallo~atechin~~ were identified in blackcurrant leaves Ribes nigrum L. and the blood-red sap of the bark of Croton Zechleri respectively two plant species possessing considerable ethnopharmacological reputation. 4.3 Propelargonidins (3,5,7,4'-Tetrahydroxylation) In addition to the 'mixed ' procyanidin-propelargonidin tetra-mer davallin 6153,54 (vide supra) a single new oligomeric propelargonidin the trimeric epiafzelechin-(4P -+ 8)-epiafzele-chin-(4P +8)-4'-0-methylepigallocatechin from the stem bark of Heisteria pallida Engl.reputed for its antiphlogistic effect was recently reported. This compound represents the first naturally occurring trimeric propelargonidin with a 4-0- methylepigallocatechin chain-terminating unit. The structure of the terminal unit of ouratea proanthocyanidin A the DEF-GHI moiety of compound 80 was only recently established using 'H-NMR NOE experiments.26 4.4 Profisetinidins (3,7,3',4'-Tetrahydroxylation) The profisetinidins are the most important polyflavanoids of commerce making up the major constituents of wattle and quebracho tannins. It is thus surprising that just one new dimeric analogue fisetinidol-(4a -+8)-6-methylcatechin 81 has recently been identified in the first comprehensive investigation of commercial wattle bark extract.6 Since this compound was identified as the permethylaryl ether diacetate the methyl group might well have originated from diazomethane used to effect methylation.The readily occurring cleavage of the interflavanyl bond in proanthocyanidins which exhibit C-5 oxygenation of the A- ring of their chain-extender units with sulfur nucleophiles under acid catalysis plays a crucial role in the structure elucidation of this complex group of natural products (vide supra). In the 5-deoxy series of compounds e.g. the fisetinidol- (4 -+ 8)-and -(4 -+ 6)-catechin profisetinidins 82,83and 84 this C(sp3)-C(sp2) bond is remarkably stable under a variety of conditions and has hitherto resisted all afforts at cleavage in a controlled fashion.Such a stable interflavanyl bond has adversely affected both the structural investigation of the polymeric proanthocyanidins in black wattle bark and of those from other commercial sources as well as the establishment of the absolute configuration of the chain-terminating flavan-3-01 moiety in the 5-deoxyoligoflavanoids. It has recently66 been demonstrated that the interflavanyl bond in the proantho- cyanidins including the 5-deoxy analogues and their per- methylaryl ethers is readily subject to reductive cleavage with "OY! &I 80 OH 81 I HOP . QOH AH 84 sodium cyanoboranuide [Na(CN)BH,] in trifluoroacetic acid (TFA) at 0 "C. Treatment of fisetinido1-(4a -+ 8)-catechin 82,representing a typical tannin unit of commercial wattle bark extract with Na(CN)BH in TFA gave conversion into a mixture comprising the starting material 82(24 % recovery) catechin 30(15 %) and the (2R)- 1-(2,4-dihydroxypheny1)-3-(3,4-dihydroxyphenyl)pro- NATURAL PRODUCT REPORTS 1996 OR 30 R=H 87 R=Me R 85 R=OH 86 R=OMe L -I 88 J w+90+ OMe “0~ ’OR’ R1 93 R’=H 94 R’ = D Proposed route to the cleavage of the interflavanyl bond and of the C-ring in profisetinidin 82.Scheme 4 pan-2-01 89 (16 Oh). Similar treatment of the fisetinidol-(4P -+ 8)- and -(4a -+ 6)-catechin profisetinidins 83 and 84 with their respective more and less labile interflavanyl bonds compared with the C(4)-C(8) bond in compound 82 under acidic condition^,^' also afforded a mixture consisting of starting material (83 and 84; 16 and 12% recovery respectively) catechin (30; 17 and 4% respectively) and the (2R)-1,3- diarylpropan-2-01 (89; 18 and 4 O/O respectively).Similar conditions also effected cleavage of the interflavanyl bond in the permethylaryl ether of biflavanoid 82 to afford tetra-0- methylcatechin 87 the 1,3-diarylpropan-2-01 90 and tri-0- methylfisetinidol93. Such ‘liberation ’ of the chain-terminating flavan-3-01 unit 30 irrespective of whether the phenol 82or its methyl ether is used provides a powerful probe towards addressing the hitherto unsolved problem of defining the absolute configuration at the stereocentres of this moiety in naturally occurring proanthocyanidins that are often syn- thetically inaccessible due to the unavailability of the flavan- 3,4-diol and/or flavan-3-01 precursors.Whereas the heterocyclic ring of the DEF moiety of the biflavanoid invariably remains intact during the reductive process cleavage of both the (4 +6)- and (4-+8)kterflavanyl bonds in the free phenolic profisetinidins 82-84 is apparently associated with the simultaneous opening of the C-ring of the chain-extender unit. Protonation of the electron-rich phloro- glucinol D-ring in profisetinidin 82(Scheme4),and concomitant delivery of the equivalent of a hydride ion at C(2) of the C-ring of intermediate 85 effects the concurrent rupture of the pyran C-ring and of the C(4)-C(8) bond to give catechin 30 and the o-quinone methide intermediate 88 which is subsequently reduced to the 1,3-diarylpropan-2-01 89.This mechanism for cleavage of the interflavanyl bond in the profisetinidin biflavanoid was confirmed using Na(CN)BD in TFA. Under these conditions biflavanoid 82was converted into catechin 30 and the dideuterio- 1,3-diarylpropan-2-01 91 while the per- methylaryl ethers of 82and 83both gave tetra-0-methylcatechin 87,the dideuterio-l,3-diarylpropan-2-0192 and the 4P-deuterio- fisetinidol derivative 94. The mild conditions effecting simple cleavage of the strong interflavanyl bonds in the profisetinidins 82-84 also cause rupture of the same bonds in procyanidins B-1 and B-3 and of their permethylaryl ethers without the concomitant ‘opening ’ of the C-ring and of other profisetinidins with different C-ring stereochemistry.The collective consideration of these results indicated that the hydride ion is consistently delivered at C-4 from the side opposite to the 2-aryl group of the C-ring. This presumably indicates that delivery of the hydride ion occurs from a complex between the reducing agent and the C-ring heterocyclic oxygen lone pair trans to the 2-aryl group such transfer being most readily facilitated in an A-conformer68 95 (see also Section 7). Q& -H H i-l; 95 4.5 Prorobinetinidins (3,7,3’,4’,5’-Pentahydroxylation) The prorobinetinidins also feature prominently in wattle bark extract. The recent investigation of the commercial product had led to the identification of robinetinidol-(4P + 8)-catechin 96 and robinetinidol-(4P -+ 8)-gallocatechin 97 the first pro- robinetinidins with a 3,4-cis C-ring configuration as well as a novel series of functionalized prorobinetinidin-type tetra-hydropyrano[2,3-flchromenes 98-101 and the ‘isomerization intermediate’ 102.Compounds 98-102 all exhibit the charac- teristic structural features that are essential for the use of ‘Mimosa ’ extract in cold-setting adhesives and leather-tanning application^.^^ They form readily from the ‘conventional’ bi- and tri-flavanoids by rearrangement of the pyran heterocyclic NATURAL PRODUCT REPORTS 1996-D.FERREIRA AND R. BEKKER 42 1 OH OH OH 96 R=H 97 R=OH HO OH &I 102 ring under mild basic conditions.The mechanisms explaining their intricate genesis were recently reviewed.70 71 Such a susceptibility of the constituent flavanyl units of proanthocyanidins to intramolecular rearrangement via B-ring quinone methides under basic condition^^^^ ‘l was also demon- ~trated~~in an unusual dimerization-rearrangement reaction of OH catechin 30 at pH 12 and 40 “C (Scheme 5). Deprotonation of the 4’-OH of catechin 30 leads to an intermediate B-ring quinone methide 103 which is intermolecularly trapped by the powerful nucleoplulic C(8) of catechin in a highly stereoselective fashion to give the ‘dimeric’ intermediate 104. This compound is transformed by base into the F-ring quinone methide 105 OH 101 which then stereoselectively recyclizes to compound 106 i.e.the l-(3,4-dihydroxyphenyl)-3-(2,4,6-trihydroxyphenyl)pro-pan-2-01 substituted at C(1) with a catechinic acid moiety. A novel series of nine prorobinetinidins was recently isolated from the heartwood of the locust tree Robiniu pseud~cucia.~~In this natural source the flavan-3,4-diol leucorobinetinidin 30 +Re-faceat C-2 - -0” OH OH 30 103 OH C-5 (Pring) + C-2 (Re-face) - OH OH OH 106 105 Proposed route to the dimerization-rearrangement of catechin 30 at pH 12 and 40 “C. Scheme 5 NATURAL PRODUCT REPORTS 1996 OH OH HO HO OH OH OH 107 108 1 = I(0-OH) 109 1= i (a-OH) OH OH OH 110 1= 1 @-OH) 111 i (a-OH) (robinetinidol-4a-01) 107 as the incipient electrophile for prorobinetinidin biosynthesis co-exists which a variety of monomeric flavonoids invariably possessing C(4) oxygenation hence reducing the nucleophilicity of their A-rings compared to that of the corresponding functionality in the C(4) deoxy compounds e.g.catechin. The locust tree therefore represents a rare metabolic pool where oligomer formation has to occur via the action of the very potent electrophile 10774on chain- terminating units apparently lacking the nucleophilicity that is associated with natural sources in which oligomeric proantho- cyanidin formation is paramount. The novel prorobinetinidins are the robinetinidol-(4/3 -+ 6)- and (4a -,2')-robinetinidol-4-01s 108-111 robinetinidol-(4a -+ 2')- (4p -+ 6)- and (4a -+ 8)-dihydrorobinetins* 112-114 robinetinidol-(4cc+2')-robine-tin* 115 and the robinetinidol-(4p +2')-7,3',4',5'-tetra-hydroxyflavone 116.Analogues 108-1 11 not only complement the rare series of oligoflavanoids with a flavan-3,4-diol chain- terminating DEF unit1,S5 and of those with a C +E-ring interflavanyl bond1 (110 lll),but represent the first entries into these classes that are exclusively based on leuco-robinetinidin precursors of type 107. Compounds 112 113 and 114 similarly represent the first natural prorobinetinidins with a dihydroflavonol constituent DEF unit and 115 and 116 with respectively a flavonol and flavone terminal units. The diversity regarding the oxidation level of the chain-terminating moieties suggests that the biflavanoids in R. pseudacacia may be interrelated via oxidation-reduction of these units.A conspicuous feature of the 'H NMR spectra of the permethylaryl ether acetates of the prorobinetinidins 108 109 * Dihydrorobinetin is (2R,3R)-2,3-trans-3,7,3',4',5'-pentahydroxyflavanone and robinetin the corresponding flavonol. OH b"" OH "mOH OH 0 112 HO OH HO OH OH 0 113 114 OH HO OH 0 115 111; R=OH 112,113 and 114 employed for purification and identification is the absence of the effects of dynamic rotational isomerism about the interflavanyl bonds at ambient temperature. Such single sets of sharp resonances have previously invariably been ascribed to 'fast' rotation on the NMR tirne~cale.~~ However prominent NOE associations of 5-H(D) with 2-H(C) and 5-H(A) and the conspicuous absence of associations between 7-OMe(D) and the latter protons in the methyl ether acetates of 108 and 109 are presumably reminiscent of the preponderance of a conformation 117 of the interflavanyl bond in which the 10-C(A) 4-C(C) 6-C(D) 7-C(D) dihedral angle approximates +90".A significant preference for this orientation may then explain the absence of signal duplication or broadened resonances in their 'H NMR spectra. In the 'H NMR spectrum of the methyl ether acetate of analogue 112 the selective NOE association of 3-OMe(E) with 3-H(C) but not with 4-H(C) presumably again indicates NATURAL PRODUCT REPORTS 1996-D. FERREIRA AND R. BEKKER preference for an interflavanyl conformation 118 in which the lO-C(A) 4-C(C) 2-C(E) 3-C(E) dihedral angle approximates +90".This conformation and the phenomenon of a pre-dominant preference for a specific orientation are additionally supported by the observed NOE between 3-H(F) and 4-H(C) and the conspicuous absence of association between the former proton and 3-H(C) that could be anticipated if 'free rotation' had occurred. The selective NOE between 2-H(F) and 6-H(E) presumably indicates a 1-C(E) 2-C(F) orientation in which repulsion of the bulky 3-OAc(C) and 3-OMe(F) is minimized. The significant shielding of 3-OMe(E) in the NMR spectrum of the derivative of 112 does not only support the orientation depicted in structure 118 but is presumably also reminiscent of an attractive n-alkyl interaction between the n-system of the A- ring and the methyl group.The NOE association of 5-H(D) with 2-H(C) and the marked absence of an NOE between the latter proton and 7-OMe(D) similarly points towards a preferred interflavanyl conformation with a 10-C(A)4-C(Ct6- C(D)-7-C(D) dihedral angle approximating + 90" for the derivative of compound 113. In the derivative of the (4,8)- prorobinetinidin 114,the NOE association of 7-OMe(D) with 4-H(C) but not with 3-H(C) and of both 7-OMe(A) and 8-H(A) with 2-and 6-H(E) exemplifies a conspicuous preference for the more crowded conformation 119.The conformational itinerary of the interflavanyl bond is presumably controlled by complex forces such as n-n and n-alkyl inte~actions,~~*~~ and the tendency to minimize the surface area of the molecule and hence solute-solvent c~ntact.'~ ,OMe 'OMe 117 OMe 118 OMe 0 119 4.6 Proteracacinidins(3,7,8,4'-Tetrahydroxylation) In contrast to the large number of oligomeric proantho- cyanidins with resorcinol- or phloroglucinol-type A-rings of the chain-extender units,' 75 those possessing pyrogallol-type A-rings are extremely rare and are hitherto restricted to only two examples of the promelacacinidin (3,7,8,3',4'-penta-hydroxylation) class in the heartwoods of Prosopis glandu- 81 losasO~ and Acacia pylelanoxylon.82 The first four pro-teracacinidin analogues were recently isolated from the heart- woods of Acacia galpinii and Acacia caflra.These compounds were the dimeric epioritin-(4/3 -,6)-epioritin-4a-o1 120 and its C(4) (F-ring) epimer 121,83the doubly-linked ent-oritin-(4,8 - 7 5 - 6)-epioritin-4a-ol 122,84and ent-oritin-(4P -+ 5)-epi-oritin-4/3-01 123.36The structures of dimers 120 and 121 were unequivocally confirmed by the acid-catalysed self-conden- sation of their apparent biogenetic flavan-3,4-diol precursor epioritin-4a-01 which co-occurs in the heartwood of A.galpinii.Besides samarangenins A 78 and B 79,63the doubly-linked proteracacinidin-type compound 122 represents only the third proanthocyanidin where the interflavanyl linkages are pre- sumably established by a combined one-electron (5 + 6 bond) and two-electron (7-0 -+ 4 bond) process. HO HO.. OH Q I OH OH 120 1 i (4a-OH) 122 121 1= I(4P-OH) HO 123 5 Non-proanthocyanidins with Flavan or Flavan-3-01 Constituent Units In addition to the extensive range of dimeric and trimeric oligoflavanoids with rearranged C-rings dubbed phlobatan- nins1,6v70,71 (see Section 4.9 daphnodorins A B and C and larixinol were earlier reported as rearranged biflavanoid metabolites comprising either flavan or flavan-3-01 and 2',4,4',6'-tetrahydroxychalcone (chalconaringenin) constituent units.’ 75 Three spirobiflavonoids dubbed genkwanol A 124,85 B 12586,s7 and C 12688were recently isolated from the buds and roots of Daphne genkwa Sieb.et Succ. and their structures and absolute configurations were established by the collective utilization of lH and 13C NMR data X-ray analysis and the modified Moshers’ method as was outlined in Section 2.The basic carbon framework of an afzelechin moiety coupled at C(8) to the a-carbon of a chalconaringenin unit is evident in the structures of all three genkwanols. 6I-l 124 HO 0 125 8 126 OH OH 127 R =OH 128 R=H Two related but non-rearranged compounds comprising 5,7,4‘-trihydroxyflavoneand afzelechin constituent units the (3 +8)-coupled atropisomeric wikstrols A 127and B were iso- lated from the roots of Wikstroemia ~ikokiana.~~ They were shown to arise by acid-catalysed rearrangement of daphnodorin B 129 via the intermediate ketal 131. Daphnodorin A 130 NATURAL PRODUCT REPORTS 1996 OH OH 129 R =OH 130 R=H 1 HO R OH -131 R=OH 132 R=H I 127 +wikstrol B 128 + daphnodorin D-2 OH 133 (hi 134 the flavan analogue of daphnodorin B 129,is similarly trans- formed by acid into the atropisomeric 5,7,4‘-trihydroxyflavone-(3 4 8)-(2S)-5,7,4’-trihydroxyflavans,daphnodorins D- 1 128 and D-2.89 Daphnodorins A B C D-1 and D-2 are accompanied in the roots of Daphne odora Thumb.by daphnodorins E 133 and F lM.’OTheir 2s absolute configurations were assumed while the 2”R 3”R and 2”S 3”sabsolute configurations for 133 and 134 respectively were deduced by application of the dibenzoate rule to the splitting of the Cotton effects in their CD spectra. NATURAL PRODUCT REPORTS 1996D. FERREIRA AND R. BEKKER The dragon’s blood tree Dracaena cinnabari Balf. fil. contains two unique ‘non-proanthocyanidins ’ the biflavonoid cinna- barone 13591 comprising a retro-dihydrochalcone and a deoxotetrahydrochalcone constituent unit and the triflavanoid damalachawin 13692 comprising a flavan and two deoxo-tetrahydrochalcone moieties.Definition of the absolute con- figuration at the stereocentres of both 135 and 136 was however not attempted. The same natural source also gave the novel (2S)-7,3‘-dihydroxy-4’-metho~yflavan.~~ 0 OH 135 6I-l 136 Three novel fermentation products theogallinin 137 com-prising a theogallin unit linked through a pyrogallol ring to a similar ring of epigallocatechin-3-O-gallate theaflavonin 138 and desgalloyl theaflavonin 139 were obtained from black tea.94 The latter two compounds are B,B’-linked bisflavanoids formed presumably via oxidative coupling of the flavonol glucoside isomyricitrin and 3-O-galloylepigallocatechin and epigallo- catechin respectively.The Rabsolute configuration of the atropisomeric biphenyl linkage of theogallinin 137 was es- tablished by comparison of its CD data with those of theasinensins C and E having Rand S chirality respectively. Similar comparison of the CD data of compounds 138 and 139 established the Rconfiguration of their biphenyl bonds. The same authorsg4 also proposed an informative schematic representation of the enzymatic conversion of the polyphenols in tea leaves. 6 ‘Complex Tannins‘ The term ‘complex tannin’ appears to be established as descriptor for the class of polyphenols in which a flavan-3-01 unit representing a constituent unit of the condensed tannins (polymeric proanthocyanidins) is connected to a hydrolysable (gallo- or ellagi-) tannin through a carbon-carbon linkage.Since the first demonstration of their natural occ~rrence,~~ a considerable number of these unique secondary metabolites have been identified.1,75 Recent additions to this series of compounds came exclusively from the groups of Nonaka and Nishioka and Okuda and Yoshida in Japan. Malabathrins A 140 E 141 and F 142 which are composed of a C-glucosidic ellagitannin and a C-C coupled epicatechin moiety were isolated from the dried leaves of Melastoma malabatri~urn.~~ The S chirality for both the hexahydroxy- OH0 137 R = salW 1s R’ = ga~loyl;R* = pD-glucopyranosyI 139 R’ = H; R2= Po-glucopyranosyl diphenoyl (HHDP) (hexahydroxybiphenyldicarbonyloxy) groups in compound 140 was deduced from its CD curve which exhibited positive and negative Cotton effects at 233 and 262 nm respectively and the structure was unequivocally confirmed by acid-catalysed condensation of the ellagitannin casuarinin and 3-O-galloepicatechin.Structure elucidation of malabathrins E 141 and of its regiomer malabathrin F 142 was performed by comparison of lH and 13C NMR data with those of mongolicain A which also possesses a cyclopentenone moiety linked to glucose C( 1). The S absolute configuration of the HHDP-group in malabathrin E 141 was established by methanolysis of its permethylaryl ether which gave dimethyl hexamethoxydiphenate with an [a],value of -27”.Comparison of the CD data of malabathrin F 142 with those of 141 confirmed the same S chirality for the HHDP moiety in the former compound.The cyclopentenone moiety in e.g. com-pound 141 is regarded as the product of oxidative conversion of the HHDP-group at 0(2)-0(3) of glucose in e.g. compound 140g6(see also Scheme 6). Six additional complex tannins named guajavins A 143 and B 145 psidinins A 147 B 149 and C 151 and psiguavin 153 all consisting of a gallocatechin unit and a C-glycosidic ellagitannin moiety have been isolated from the bark of Psidium guajava L.97 The lH NMR spectrum of guajavin A 143 at room temperature was complicated due to the effects of conforma- tional isomerism a feature that was commonly observed in ‘complex tannins’ where the C(8) position of the flavan-3-01 unit is substit~ted.~~ Structure elucidation of guajavins A 143 and B 145 was affected by comparison of their 13C NMR data with those of the related catechin analogues stenophyllanin A 144 and acutissimin B 146 respectively and by synthesis via acid-catalysed condensation of gallocatechin with the ellagitan- nins stachyurin and vescalagin respe~tively.~? The lH and 13C NMR spectra of psidinins A 147 B 149 and C 151 similarly resembled those of their catechin analogues mongolicains A 148 and B 150 and stenophyllinin A 152 respectively thus readily facilitating the structure elucidation of the former three compounds.The novel psiguavin 153 in which the B-ring of the flavan-3- 01 unit is extensively rearranged is considered to be derived biosynthetically from eugenigrandin A (partial structure 154) by successive oxidation of the pyrogallol B-ring benzylic acid- type rearrangement and decarboxylation followed by oxidative coupling as is indicated in Scheme 6.97 Strobilanin 155 isolated from the fruits and bark of Platycarya strobilacea Sieb.et ZUCC.,’~ with its C(8) substituted gallocatechin moiety was related as above to its catechin- ellagitannin analogue stenophyllanin C.98 The leaves and fruits of Camellia japonica afforded five novel analogues camelliatannins C 156,looD 157,1°1 E 158,loo F 159” and G 160.99Camelliatannins C 156 D 157 and E 158 possess structural features that are unique among the ‘complex tannin’ group of natural products.Compounds 156 and 158 with their C(6) and C(8) substituted epicatechin moieties NATURAL PRODUCT REPORTS 1996 HO HO OH OH OH HO HO OH OH OH 140 141 HO OH OH How \ / OH co co 142 143 R= OH 144 R=H How \/ OH HO HO OH OH 145 R =OH 147 R =OH 146 R=H 148 R=H respectively represent the first examples lacking a C-C bond between C(l) of glucose and the HHDP-group at O(2)of the glucose unit. These bonds could however be readily formed by treatment of analogues 156 and 158 with polyphosphoric acid hence transforming them into camelliatannins B and A respectively.loOCamelliatannins C 156 and E 158 may thus be considered as precursors to the ‘normal’ type of ‘complex tannins’ and may be anticipated to co-occur in the plant sources containing the latter class of metabolites.Camellia- tannin D 157 a new inhibitor of bone resorption represents the NATURAL PRODUCT REPORTS 1996-D. FERREIRA AND R. BEKKER HO HO OH OH 149 R=OH 151 R=OH 150 R=H 152 R=H OH 0 154 Possible biosynthetic pathway of psiguavin 153 from eugenigrandin A 154. Scheme 6 How \ / OH HO HO HO OH OH 155 156 R = 6-epicatechin 158 R = 8-epicatechin NATURAL PRODUCT REPORTS 1996 HO co-0 HO OH HOW0 OH HO HO OH OH HO HO OH 157 HO OH 0 OH co-0 He HO 159 first example of a 'complex tannin' composed of dimeric hydrolysable tannin and flavan-3-01 constituent units. Based upon the chemical conversion of camelliatannin A into camelliatannin F 159 in ethanolic acetic acid,99 the former compound was suggested as a biogenetic precursor to both camelliatannins F 159 and G 160.Stachyuranins A 161 B 162 and C 163 were isolatedlo2 from the leaves of Stachyurus praecox Sieb. et Succ. Compounds 161 and 162 like camelliatannins C 156 and E 158 lack the C-C linkage between C( 1) of the glucose moiety and the aroyl group OH 160 at the glucose O(2). When dissolved in aqueous methanol (1 1) at room temperature stachyuranin A 161 is gradually converted into stenophyllanin Ag5which presumably suggests that the latter compound is produced non-enzymatically from 161 in plants. 161 R' = 8-catechin; R2 = galloyl 162 R' = 6-catechin; R2 = H 163 NATURAL PRODUCT REPORTS 1996D.FERREIRA AND R. BEKKER C(2)-sofa Half-chair C(3)-sofa Figure 1 Ground-state energy conformations of the flavan heterocycle. 7 Conformation of Proanthocyanidins Conformational analysis of proanthocyanidin oligomers is in principle concerned with the conformation of the pyran heterocycle and with the phenomenon of conformational isomerism due to restricted rotation about the interflavanyl linkage(s). Realization of the fact that the conformational itinerary of the heterocyclic rings involves a dynamic equi- librium between E-and A-conformers68 had a huge impact in this field'O and has led to an increased utilization of relevant molecular modelling calculations in an effort to address some of the many unexplained phenomena that still exist.The conformational equilibration of the C-ring of flavan-3- 01s may be described by the following equilibrium C(Z)-Sofa === Boat C(3)-Sofa Half-chair Half-chair 11 C(3)-Sofa -C(2)-Sofa (E-conformers) -(A-conformers) Figure 168 depicts the ground-state energy conformations which may be adopted by the flavan heterocycle with the hatched line indicating the projection of the A-ring. Figure 268 gives the relative stereochemistry of groups at C(2) and C(3) for the E- and A-conformations of catechin (164 and 165) and epicatechin (166 and 167). The conformations are viewed in the sense indicated by the arrow in Figure 2 and the solid line in 164-167 represents the A-ring plane. The boat conformation represents the high-energy transition state for the inter-conversion of E- and A-conformers.An unequal conforma- tional energy of these conformers is manifested by an unequal population of the two states the one with the lower energy being populated to a greater extent. It was suggested that substitution at C-4 of catechin or epicatechin by a hydroxy or aryl substituent would strongly favour the E-conformation due to the tendency to minimize 1,3-diaxial interactions and the pseudo-allylic or A( 1,3)-strain effect.68 In derivatives of 4-resorcyl-5-oxyflavan-3-ols however coupling constants of heterocyclic protons for analogues with a 2,4-cis arrangement of B- and D-rings e.g.the 2,3-trans-3,4- trans-and 2,3-cis-3,4-cis-compounds168 and 169 are not reconcilable with dihedral angles.lo3 Such conformational behaviour also results in reversal of the Cotton effects in the 220-250 nm region of their CD spectra predicted by the aromatic quadrant rule.Io3 The effect of A-strain on the 2,4-cis E-conformers'*~lo*is reflected in a tendency of the pyran ring towards a C(2)-sofa conformation hence decreasing both the C(3)-C(4) -C( 10)-C(9) torsion angle and the out-of-plane distance of C(3).The latter represents an effective increase in the torsion angle between 5-OMe(A) and the 4-resorcyl group and therefore alleviation of the A-strain. This effect is absent for E-conformers of 4-resorcyl-5-oxyflavan-3-ols with 2,4-trans B-and D-rings culminating in a tendency towards a C(3)-sofa A+ ff OY 'TOH Ar 164 i= I (3B-OH) 165 1 = 1 (3p-OH) oyfoH OH Ar 166 i= i (3a-OH) 167 1 = (&-OH) Figure 2 Relative stereochemistry of the E-and A-conformations of catechin and epicatechin.conformation for the C-ring and the absence of irregularities regarding their IH NMR and CD data. Maximum relief from A-strain however is achieved for the aforementioned 2,4-cis isomers by inversion of the pyran ring to an A-c~nformer.'~ While 1,3-diaxial arrangements are Io4 commonly avoided on energetic grounds in terms of a classical stereochemical approach A-conformers 170 as opposed to E-conformers 171 for these isomers appear to be an exception by virtue of the aromaticity and associated geometry of the 1,3- diaxial2,4-biphenyl substituents which are stacked parallFl to the O(lw(2) bond at an interplanar distance of -3.5 A by MMXP (Figure 3).Even though this geometry is achieved by MMXP principally via van der Waals and electrostatic interactions it also conforms with an offset face-to-face arrangement 172 required for n-stacking (stabilizing n-g attra~tion).'~ This is probably further reinforced by a n-CH interactionlo5 between 3-OMe(B) and the n-system of the A- ring (see 172). It was recently demonstrated106 that crystalline tetra-0- methylcatechin exists in two different conformations. The substituents of the pyran ring attain equatorial orientations in both of these conformations having different orientations of the C(3)-O-H and C(4tO-Me bonds and which results from optimization of intermolecular hydrogen bonding.In solution however the A- and E-conformations are present in approxi- mately 40 60 relative populations hence mutating the het- erocyclic proton dihedral angles which roughly explains the observed 3J2,3lH NMR value of 8.1 Hz. A GMMX con- formational search routine on the contrary gives an ensemble of conformations that reflects the Boltzmann-averaged het- NATURAL PRODUCT REPORTS 1996 OMe VMe OMe OMe 168 169 170 171 172 Figure 3 Newman projections of the 2,4-cis-4-resorcyl-5-oxyflavan-4-ols illustrating an E-conformer 171 viewed along the C(2FO( I)/ C(4)-C( 10) bonds with the A-ring depicted horizontally; the analogous A-conformer 170; and the A-conformer viewed along the C(3)-C(4) bond showing the offset face-to-face arrangement of the B-and D-rings and the 7r-n and n-alkyl interactions.Substituents have been omitted for clarity. erocyclic ring conformations of tetra-O-methyl~atechin.~~' This approach leads to the prediction of all three coupling constants of heterocyclic protons of this compound with a remarkable degree of accuracy (Observed J2,3= 8.1 J3,4eq 5.5 J3,4ax = = 9.0 Hz. Calculated J2 = 8.15 J3,4eq = 5.25 and J3,4ax = 9.84 Hz). This method thus possesses obvious advantages compared to the approach that assumes a distribution of time spent between A- and E-conformer idealized states. The presence or absence of a C(5)-hydroxy group at the A- ring has a profound influence on the reactivity of the C(6) and C(8) positions of flavan-3-01s with electrophiles as well as the stability of the interflavanyl bond in oligomeric proantho- cyanidin.In a recent investigationlog the crystal structure conformational analyses and charge density distributions of ent-epifisetinidol 173 were studied as a model for the pro- fisetinidin class of oligomeric proanthocyanidins and the results compared with those obtained for epicatechin. Molecular modelling and molecular orbital analyses of compound 173 gave good predictions of the approximate 'reverse half-chair ' conformation found for the crystal structure. MNDO and AM 1 analyses of HOMO electron densities permitted the same authors to explain for the first time the remarkable degree of regioselectivity at C(6) of the A-ring which is observed when 5- deoxyflavan-3-01s are treated with electr~philes.'~~ The C(5) hydroxy group of the A-ring also influences the fluorescence properties of the procyanidin monomers and dimers compared to those of analogous compounds of the profisetinidin series."O There is a measurable heterogeneity in the fluorescence of fisetinidol (5-deoxy) in contrast to the OH 1M simpler fluorescence of the procyanidin monomers catechin and epicatechin.This heterogeneity is attributed to differences in the photophysical properties of the aromatic A-and B-rings in fisetinidol which are larger in the latter compound than in catechin and epicatechin. In the absence of a conformational constraint that forces the occupation of a single rotational isomer at the interflavanyl bond dimeric procyanidins and profisetinidins exhibit heterogeneous decay of the fluorescence which can be used to assign the populations of the two rotamers at the interflavanyl bond in the procyanidins but not in the profisetinidin series of compounds.The conformation of the heterocyclic rings in the upper and lower flavan-3-01 units and the conformations of major and minor rotational isomers about the interflavanyl linkages were recently assessed for a series of methyl ether acetate derivatives of dimeric profisetinidin diastereomers by application of COSY and NOE experiments."' These results indicate that the eight fisetinidol- and ent-fisetinidol-(4 -+ 6)- and (4 -,8)-catechins were present in two rotameric forms.They are depicted by formulations 174 and 175 for the fisetinidol-(4cc +8)-catechins and by 176 and 177 for the fisetinidol-(4a -+ 6)-catechins OMe 174 bOMe .' OMe 175 Me0QF::: Mp e 0 AGO 8 Q-Me0J$ ' We OMe bMe 176 177 NATURAL PRODUCT REPORTS 1996D. FERREIRA AND R. BEKKER 431 conformations 174 and 177 being the more crowded or more compact conformations. A conspicuous preference of all compounds for these compressed conformations was observed presumably to minimize the surface area of the molecule and hence solute-solvent c~ntact.’~ The heterocyclic ring in the upper chain-extender unit was predominantly in an E-conformation 178 rather than an A-conformation 179 i.e.half-chair in the 2R,3S isomers and a ‘reverse’ half-chair in the 2S,3R isomers while the pyran ring conformation of the terminal catechin unit although mostly in an E-conformation was often represented by significant proportions of A-conformers. -OH ’H HO HO 178 HO. OH OH 179 8 Astringency Polyphenolic compounds including the oligomeric proantho- cyanidins have a harsh astringent taste and produce in the palate a feeling of roughness dryness and constriction.l12 These substances thus contribute significantly if not uniquely to the astringency of wines fruits and fruit juices teas and other beverages. The primary reaction whereby astringency develops is via precipitation of proteins and mucopolysaccharides in the mucous secretion~.’~~ Mammalian herbivores produce unique proline rich salivary proteins (PRPs) which have a high affinity for p01yphenols.l’~ In humans these PRPs appear to be essential and are present in amounts which reflect the approximate levels of polyphenols and related phenolics in the normal diet.It has thus been suggested that the PRPs constitute the first line of defence against polyphenols in the digestive tract.’14 This has led to intensive investigations of the action of polysaccharides and proline-rich peptides in the moderation of astringent response. The current status of knowledge in this regard is summarized in ref. 113. A recent paper115 discussing the trypsin inhibitor activity of the proanthocyanidins from Vicia faba L.(faba beans) is also informative. The fruits of astringent Japanese persimmon cultivars idiospyros kaki are edible after artificial removal of the astringency by treatment with ethanol vapour carbon dioxide gas or warm water.ll6 During these anaerobic treatments acetaldehyde accumulates and concomitantly the water-soluble oligoflavanoids are gradually changed chemically via the formation of 1,l-ethylidene bridges into insoluble forms to decrease the astringency. This phenomenon was recently115 firmly confirmed by ‘removal’ of the astringency from persimmon fruit using ethanol and the subsequent thiol-promoted (HSCH,CH,OH/H+) degradation of the insolu- bilized proanthocyanidin polymers to give 4/3-(2-hydroxy- methylsulfany1)-6-and 8-[1-(2-hydroxyethylsulfanyl)ethyl]-flavan-3-ols e.g.the 8-substituted epigallocatechin derivative 180. 180 9 References 1 L. J. Porter in The Flavonoids Advances in Research since 1986 ed. J. B. Harborne Chapman and Hall London 1994 p. 23 and references cited therein. 2 H. 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ISSN:0265-0568    

DOI:10.1039/NP9961300411

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Muscarine Imidazole Oxazole Thiazole and Peptide Alkaloids and Other Miscellaneous Alkaloids John R. Lewis Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen AB9 2UE UK ~ ~~~ Reviewing the literature published between July 1993 and June 1994 (Continuing the coverage of literature in Natural Product Reports 1995 vol. 12,p. 135) 1 Muscarine Imidazole Oxazole and Thiazole Alkaloids 2 Peptide Alkaloids 3 Miscellaneous Alkaloids 4 References 1 Muscarine Imidazole Oxazole and Thiazole Alkaloids 3-Hydroxymuscarines can be synthesized from L-rhamnose 1. No protection is needed if (3R)-3-hydroxymuscarine 9 is made but for (3S)-3-hydroxymuscarine 15 a silyl ether protecting group was necessary (Scheme l).’ The primary step in this synthesis was the ring contraction of the pyranose to a furan.Two pathways via either a y-or b-lactone could be identified when an oxidation of rhamnose with bromine in aqueous barium carbonate was carried out 1 +2 +5. Equilibration with aqueous trifluoroacetic acid gave the more stable y-lactone whence selective triflication gave 3 which on treatment with methanolic pyridine produced tetrahydrofuran 4. The &lactone 5 on treatment with triflic anhydride followed by methanol gave 4 directly. Reduction of 4 with lithium aluminium hydride gave alcohol 7 which tosylated selectively to 8 so as to allow introduction of the trimethylamine substituent thus giving (3R)-3-hydroxymuscarine 9. If ester 4 was protected reduced tosylated and triflated to give 13 it was thus possible to invert configuration at C-3 to yield 14 which after disilylation proceeded to (3S)-3-hydroxymuscarine 15.?H HO 1 Three new imidazole alkaloids have been isolated from a sponge of the Leucetta family found off Australia in the Great Barrier Reef. Naamidine E 16 and naamidine F 17 are related to the polycyclic alkaloid kealiiquinone 18 found in a Guan OMe 16 OH OMe OMe 17 18 H0..LoJOSiPh2Bu vii ___L MeO&”’ 10 1 iv iv t HO..-/OSiPh2Bu Reagents i Br, BaCO, H,O; ii (CF,SO,),O py THF; iii MeOH py; iv LiAlH, THF; v p-MeC,H,SO,Cl DMAP py; vi Me,N MeOH; vii ButPh,SiC1 imidazole DMF; viii CF,COONa DMF then MeOH AcOH; ix Bu,NF THF Scheme 1 435 Leucetta3 while the third imidazole is clathridine C 19a.A predator nudibranch (Notodoris garineri) found in the vicinity of these sponges when extracted contained clathridine 19b which is thought to be a metabolic product resulting from the predator’s assimilation of the ~ponge.~ 0 R’ -Q R2 19a R’ =H; R~=OH b R’ = R2 = -0CHzO-The imidazole moiety has also been found in one of the three alkaloids obtained from the Caribbean sponge Aplysina caul if or mi^.^ Aplysinamisine I has structure 20 while its companion aplysinamisine I1 is the closely related guianine 21. Both alkaloids contain the isoxazole ring which is derived by oxidative cyclization of a dibromotyrosine precursor. The third component found in this sponge was the bistyrosine derived alkaloid aplysinamisine 111 22.OMe 20 21 OMe 22 The isoxazole metabolite hemifistularin 3 also obtained from a sponge of the Aplysinellidae family has structure 23. Co-occurring in this sponge are 19-deoxyfistularin 3 24a and 19-deoxy-1 1 -0xofistularin 3 24b. Currently the authors are undecided as to whether 23 is a biogenetic precursor or a degraded peptide of 1l-oxofistularin 24c which incidently was also isolated from the same e~tract.~ NATURAL PRODUCT REPORTS 1996 OMe OMe OMe 24a R’=OH; R2=R3=H b R’ + R2 = 0; R3 = H c R~+R~=o; R~=OH Related to the fistularins are the three alkaloids agelorin A 25a,agelorin B 25b and 1 l-epifistularin 26 which were found in the tropical sponge Agelas oroides.G Phthoxazoline A 27 produced by the strain Streptomyces OM-5714 has been found to be a specific inhibitor of cellulose biosynthesis.’ The gliding bacterium Myxococcus stipitatus contains rhizopodin 28 which inhibits the growth of a number of animal cell cultures without killing them.8 Consequently it and its derivatives have been ~atented.~ OMe 25a R1 = H; R2 = Br b R1=Br; R2=H OMe OMe H .i&-d +4 0 26 27 OMe OH Me0 Me 28 NATURAL PRODUCT REPORTS 1996-5.R. LEWIS Trehalimine 29a is the aglycone of trehazolin 29b which is obtained by acid hydrolysis D-glucose being liberated in the process. Cultures of two micro-organisms Micrornonosporu sp. SANK 62390 and Amycolatopsis sp. SANK 60791 which produce the glycoside have also been found to contain the aglycone.lo OMe 29a R = H 33 b R = glUcOSe A one step synthesis (Scheme 2) of the oxazolealkaloid 0-methylhalfordinol 32 has been achieved by the reaction of 4- methoxyphenacyl azide 30 with nicotinoyl chloride 31 mediated by triphenylphosphine." If 3,4-dimethoxycinnanoyl chloride instead of 31 is used annulotine 33 is produced.30 N2 >Ph3p*Meoqb \ N 32 31 Scheme 2 Serraticochelin 34 is a new catecholate siderophore isolated from the culture medium of Serratia rnurcescens T.W. when it is grown on an iron deficient medium. Its structure was confirmed by synthesis." A new variation in the arrangement of the bis-oxazole core of bengazol alkaloids has been found.13 An inseparable mixture of bengazole alkaloids obtained from the choristid marine sponge Jaspis cf.coricea when hydrolysed produced the new bisoxazole core benzazol 2 35. Myristic and 13-methylmyristic acids were the co-isolates. Variation in structure of the alkaloids is associated with the location of the two esterifying acid groups. HO 34 Three new cytotoxic macrolides namely Jaspisamides A to C obtained from an Okinawan sponge of the Jaspis family contain three oxazole rings linked to each other.14 Jaspisamide A has structure 36 while jaspisamide B is 37a and C 37c. Three other tris-oxazoles halichondramide dihydrohalichondramide and isohalichondramide were also present in the extract. NCHO Me 36 0 OMe 37a R' =OH; R~=H b R'=H; R2-M -e A novel cytotoxic metabolite obtained from the mycelium of the fungus Streptomyces sp.517-02 is the benzoxazole dimer UK-1 38.15 Although it possesses potent cytotoxic activity against HeLa P388 and B.16 tumour cells it does not have antimicrobial properties.16 The total synthesis of (-)-tantazole B 39b" and the closely followed publication of a revision of the structures of tantazole A 39a and tantazole B 39b based on the incorporation of I3C and 15N amino acids followed by Marfey analysis of the hydrolysates,l8 has firmly established the nature of this oxazole-tetrathiazoline metabolite. The difference in structure is the orientation of the terminal thiazoline methyl group* now being assigned the a-configuration for tantazole A. 38 39a R = H 39b R=Me 438 NATURAL PRODUCT REPORTS 1996 A species of gliding bacteria Polyangium P1 3007 has been shown to produce the antibiotic thiangazole.Its production antimicrobial activity and methanism of action have been describedlg and its absolute configuration 40 determined by X-ray measurements. 2o The molecular conformation of patellamide A has been determined by X-ray crystal analysis. This cytotoxic cyclic peptide was obtained from the ascidian Lissochinum patella21 and the X-ray data were obtained from crystals grown from aqueous methanol and then sealed in a glass capillary containing some mother liquor so as to prevent loss of solvent molecules during measurements. Consequently to was found that the peptide adopts a saddle shaped rectangular form 41 and is wrapped around water and methanol solvent molecules.The novel oxazole alkaloid obtained from the Okinawan marine sponge Theonella theonezolida A 42 is the first member of a new class of polyketide natural products which contain both an oxazole and a thiazole grouping.22 42 The structure of the antibiotic A 10255 complex obtained from strains Streptomyces gardineri NPRL 15537 or 18260 is based on the oxazole-thiazole macrolide ring system e.g. Factor B is 43. All eight factors C-J are bacteriocides and feed utilization efficiency enhancer^.^^ Thiazole and thiazolium rings are frequently associated with a number of marine organisms. Curacin A 44has antimitotic and antiproliferative properties and is a metabolite of the blue-green cyanobacterium Lyngbya majuscule.24 It possesses only one thiazoline ring which is presumably derived from a polyketide attached to a decarboxylated cysteine.A related fungicide myxothiazol 4525,26 has been synthesized through a combination of three prime structural components a P-methoxyacrylamide unit a thiazole unit and a heptadienyl unit which possesses a thioamide terminus thus allowing creation of the first thiazole unit (Scheme 3).27 (R)-Methyl 3-hydroxy-2-methylpropionate46 was first protected as its 1-ethoxyethyl derivative 47 and then converted into aldehyde 48 which upon Wittig reaction with 49 gave two dienes the E,E-isomer predominating (4 1 ratio). Upon deprotection of this mixture 50 the resulting alcohol mixture could be irradiated in the presence of iodine to give exclusively the E,E-isomer 51.Functional group manipulation through ester and amide allowed thioamide 52 to be prepared. Two routes allowed this thioamide 52 to be converted into the bis-thiazole ester. Using the Hantzsch reaction with ethyl bromopyruvate 53 was produced which upon conversion to its thioamide 54 enabled a second Hantzsch to give the bis-thiazole 55a. Alternatively and more productively thioamide 52 was reacted with 2,4-disubstituted thiazole bromoketone 56 to give 55 directly and thence to the Wittig reagent 58. The P-methoxyacrylamide synthon was synthesized by condensing first cinnamaldehyde with the dianion derived from methyl 3-oxopentanoate 59 to give a I 1 mixture of syn- and anti-2H-pyran-2-one methyl ether 60.Ring opening and methylation gave a diene ester mixture which was chromatographically separated to give the required syn-diastereoisomer 61. Its methyl ether 62 could be converted into amide 63 which upon oxidative cleavage via its vicinal diol gave without any epimerization of the chiral centres an unstable sensitive aldehyde amide 64.Finally Wittig reaction of this aldehyde amide 64 and phosphoranylide 58 gave an E-stereoselective product i.e. 7S 18SR 19RS- myxothiazole 45 identical spectroscopically with the natural product. 43 OMe 44 Me OMe 0 JyyY*& NH2 ?I 45 439 NATURAL PRODUCT REPORTS 199GJ. R. LEWIS v vi -Royo + +pph3+-(Et0)MeCHOd RO-C02Me IV -HO -Br 746 R=H 48 49 50 47 R = CHMeOEt 52 xiv c55a R = C02Me 55b R = CH20H xvc57 R=CH21 x xi xvi 58 R = CH2PPh3+ I-t x xi 7 54 53 OMe OR OMe OMe OMe OMe -o .Po ___) 58 W P h XXI pF'h XXIII N_ 45 xvlll Me0& 59 60 61 R=H 62 R = OMe NH2 64 63 R = NH2 Reagents i LiH THF EtOCH(Me)CI rt 3 h; ii LiAIH, Et,O; iii Dess-Martin periodinane CH,Cl,; iv BuLi Et,O -10 "C; v HCI THF/H,O; vi I (cat) Et,O hv; vii NaCIO, NaH,PO, ButOH Me,C =CHMe; viii (COCI), DMF (cat) CH,Cl then NH, Et,O; ix P4Sl0 PhH; x Br CH,COCO,Et KHCO, THF 6 "C; xi TFAA py; xii NH, EtOH; xiii Lawesson's reagent PhH heat; xiv DIBAL THF -88 to 0 "C; xv PPh, imidazole I,; xvi PPh, PhH; xvii NaH BuLi THF 0 "C then PhCH=CH-CHO then H30+; xviii Me,SO, K,CO, acetone heat; xix KOH H,O then H,O+; xx CH,N,; xxi MeI Ag,O Et,O; xxii Me,AlNH, CH,Cl, heat; xxiii OsO, NMMO Me,CO/H,O then NaIO, THF/H,O ; xxiv lithium hexamethyldisilazide THF 0 "C Scheme 3 A patent describes a group of funcigidal antibiotics called The molecular structure of lienamycin 67 was determined by epothilones.Variations in their structure 65 includes sub- X-ray analysis using a single crystal which was ultimately stitution on oxygen with alkyl and acyl groupings.28 produced after 300 combinations of various solvents. This The blue to blue-grey encrusting sponge Dysidea herbacea antitumour antibiotic produced by a Streptomyces species found in shallow waters contains three highly chlorinated contains a 1,3-diox0-1,2-dithiolanefeature which is new.3o thiazole peptides.Two contain two trichloromethyl terminii i.e. 66a is called dysideathiazole while 66b is N-methyl-dysideathiazole.29 OR2 0 65 68 69 76 75 73 1 vi H2Nf7 Eto~h N+S N+S n 78 79 IViiiOEt Reagents i Lithium diisopropylamide THF DMPU -90 "C then MeI; ii HCl/MeOH; iii MeOH HCl rt 1 h; iv Et,N CH,Cl, rt 3 d; v MeOH aq. NH,; vi Lawesson's reagent THF rt; vii Ethyl bromopyruvate EtOH heat ;viii Et,O+ PF,- CH,Cl, heat; ix 74 CH,Cl, rt; x AcCH,Cl EtOH heat Scheme 4 Mollamide is a cyclic heptapeptide possessing cytotoxic properties produced by the Australian Ascidian Didernnum rn01k3* Its structure 68was first determined by a combination of one-and two-dimensional NMR measurements. Con-firmation and relative stereochemistry were obtained by X-ray measurements and its absolute stereochemistry by deriva-tization of the amino acids present (all had L-configurations).A linear fused bis(thiazo1ine-thiazole) arrangement is present in the cytotoxic alkaloid (-)-didehydromirabazole A 69. Its synthesis3 based on biomimetic considerations required an ample supply of (R)-2-methylcysteine and 4-methyl-2-thiazoline (Scheme 4). Using a modification of Seebach's 'self-regulation of chirality ' procedure the N-formyl-derivative of thiazolidine adduct 70 [derived from (R)-cysteine methyl ester HC1 and pivalaldehyde] upon treatment with base followed by methyl- ation gave the methylated thiazole 71which on hydrolysis to 72 followed by methylation gave the required synthon (R)-2- NATURAL PRODUCT REPORTS 1996 methylcysteine methyl ester 73 in good yield.Coupling of 73 with iminoether 74 (derived from isobutyronitrile) in the presence of triethylamine led to thiazole 75 which through its amide 76 and thioamide 77 gave the bisthiazole 78. Repeating the procedure 79-80 with reintroduction of 74 gave the tristhiazole 81 and then the tetratriazole 82 and finally the dihydromirabazole A 69. Aeruginol is a new fluorescent secondary metabolite obtained from Pseudornonas aeruginosa On the basis of its spectral properties and the reversible blue shift in the UV upon addition of 6 mol dm-3 NaOH aeruginol was given structure 2- (2'-hydroxypheny1)-4- h ydroxymethylthiazol 83. a3 When synthon (S)-2-methylcysteine hydrochloride 84 produced by a procedure related to the synthesis of its enantiomer (ref.51) is heated with 2-cyano-3-hydroxypyridine 85 in the presence of triethylamine (9-desferrithiocin 86 was generated in 97% yield (Scheme 5).34 84 as 86 Scheme 5 Interest in topoisomerases arises due to their ability to modify DNA; thus inhibitors to this enzyme system could lead to potential anticancer agents. Topoisomerase 1I inhibitor BE 10988 is an indolequinone possessing a thiazole car-boxamide at the 3-position 87; it was first reported in 1991.35 Two syntheses of this heterocycle have appeared confirming its structure. The first (Scheme 6) started with readily available 4-benzyloxy-5-methoxyindole-2-carboxalde-hyde 88 which on decarboxylation with a rhodium catalyst gave indole 89.N-Methylation 90 and introduction of an N-chlorosulfonylamide substituent 91 using highly electrophilic chlorosulfonyl isocyanate (CSI) was followed by radical decomposition to give amide 92. Using the well established ester-to-thiazoline Hantzsch procedure (cf. Scheme 4) thiazole 94 was produced where concommitant debenzylation had also occurred thus allowing Fremy's salt oxidation to give ester quinone 94. Finally ester to amide transformation gave the inhibitor 87. 441 NATURAL PRODUCT REPORTS 1996-5. R. LEWIS OBn OBn 89 R=H 88 iiK 90 R=Me I iii OBn R OBn 0 Me Me 92 R=O 91 VC 93 R=S I vi vii viii -87 Reagents i (Ph,P),RhCO(Cl) Ph,P(CH,),PPh, mesitylene; ii KH MeI DMF; iii CSI Et,O; iv Bu,SnH AlBN PhH; v Lawesson's reagent PhH; vi BrCH,COCO,Et EtOH reflux; vii Fremy's salt acetone NaH,PO buffer; viii liq.NH Scheme 6 The second synthesis of topoisomerase 11 inhibitor BE 10988 started with commercially available Fast Blue RR 95 which contained the appropriate functionalities necessary to generate the indole 98(Scheme 7). Introduction of the thioester OMe OMe bMe OMe 95 96 1ii OMe OMe Me Me OMe OMe 98 97 99 R=C02Et 101 vii viii .C100 R=H 1 87 Reagents i (CH,O) NaOMe NaBH,; ii (EtO),CHCH,Br K,CO, MeO(CH,),OH; iii ZnCI, DMF; iv Et0,CN =C =S toluene; v KOH EtOH; vi BrCH,COCONH,; vii CAN MeOH; viii NH,OH MeOH Scheme 7 at position 3 in 99 was achieved using ethoxycarbonyl- isotluocyanate which then allowed a modified Hantzsch reaction with bromopyruvamide to give thiazole 101.Demethyl-ation with CAN and hydrolysis of the protecting group gave the natural product 87.36 2 Peptide Alkaloids 0-Methylcinnamide 102 produced by Streptomyces griseo- luteus has been found to inhibit cancer invasion and metastasis several other cinnamoyl derivatives also being effe~tive.~' Three sulfur containing amides have been isolated from the leaf All extracts of Glycusmis ma~ritiana.~~ possess antifungal properties and they have been designated illukumbin B 103 methylillukumbin B 103b and methylillukumbin A 104.A series of iron-chelating amino acids have been isolated from graminaceous plants. These phytosiderophores promote the uptake and transport of iron required for chlorophyll biosynthesis.Two typical ones are mugineic acid 105 and distichonic acid A 106.Both have now been ~ynthesized.~~~~~ A 102 1O3a R=H b R=Me 104 105 106 common feature of both acids is a /3-hydroxyhomoserine system which was synthesized from (25',35')-2,3-epoxycinnamyl alcohol 107 through conversion into azide 108 which upon reduction gave amine 109. Protection of this amino group (2,2,2-trichloroethylchlorocarbonate,TrocC1) followed by 0-acetylation gave the fully protected phenylamine 110 which enabled oxidative decomposition of the phenyl ring with ruthenium chloride-sodium metaperiodate to give the protected /3-hydroxyhomoserine which was stabilized as its tert-butyl ester 111.Conversion into the required synthon 112 followed the usual deprotection and reprotection procedures. The right hand constituent was synthesized starting with (2R,3R)-2,3-epoxycinnamyl alcohol 113which by a similar reaction sequence gave diacetate ester 114 which was used to generate aldehyde 115.(S)-Azetidine-2-carboxylic acid 116 was converted into its tert-butyl ester and thence to its acetic acid salt 117to complete the third synthon comp~nent.~~ Combination of synthons 117 and 112required 112to be first oxidized under Swern conditions to allow its reductive N-alkylation with 117to take place giving 118.Removal of the nitrogen protecting Troc group allowed synthon 115to be incorporated creating the triester 120whence removal of all the protecting groups gave mugineic acid 105 (Scheme 8).Distichomic A 106 required synthon 112 to be coupled to the acetic acid salt of glycine tert-butyl ester followed by synthon 115under the same procedures as described earlier. Deprotection then giving the natural 106. It took two years to collect enough of the Tasmanian bryozoan Amathia convoluta for an investigation of its metabolic products. An alkaloid of the amathamide group was 442 NATURAL PRODUCT REPORTS 1996 H HO+Ph Y Ph OH 2HO)\rN Ph OH -HO+NH2 Ph OAc %AcC)~NHTroc C02f3u' NHTroc 5HOGZ~roc OAc OMOM -rAcO 107 108 109 110 111 112 xi xii v vi vii viii xiii xiv HOdPh -2:; H AcO 113 114 115 118 R=Troc 120 117 xix C 119 R=H Reagents i NaN, NH,C1 MeOH H,O 70 "C 10 h; ii 10% Pd/C HCO,NH, MeOH rt 1 h; iii TrocC1 KHCO, EtOAc H,O rt 1 h; iv Ac,O DMAP pyridine CH,Cl, rt 19 h; v RuCl, NaIO, EtOAc CH,CN H,O rt 24 h; vi O-tert-butyl-N,N'-diisopropylisourea, ButOH CH,CI, 50 "C 6 h; vii Et,N MeOH H, -20 "C 3 h then 0 "C 2 h; viii TBSCI DMAP Et,N CH,CI, rt 20 h; ix MOMC1 Pr',NEt CH,Cl, reflux 1 h; x Ac,O H,O rt 24 h; xi Red-Al DME 0 "C 0.5 h then rt 4.5 h; xii Ac,O DMAP Et,N CH,CI, rt 6 h; xiii Ac,O THF H,O (9 1 :2) rt 20 h; xiv (COCI), DMSO Et,N CH,Cl, -78 to 0 "C; xv ZC1 NaHCO, dioxane H,O rt 16 h; xvi O-tert-butyl-N,N'-diisopropylisourea,CH,Cl, reflux 8 h; xvii 10 YoPd-C H, EtOAc rt 1 h then AcOH (1 eq); xviii 112 1 M NaBH,CN THF MeOH 0 "C 16 h; xix Zn HOAc THF rt 4 h; xx 115 1 M NaBH,CN THF AcOH 1 eq MeOH 0 "C 16 h; xxi constant boiling HCl anisole THF rt 40 h; xxii Dowex 509WX4 (H,O then 15% aq.pyridine); xxiii ODs silica gel H,O followed by recryst. H,O-EtOH. Scheme 8 found and identified as 121 (R = OMe) and being new was designated amathamide G.,l In a small one off collection of Amathia pinnata the known amathamide C 121 was found. Studies involving 5-aminolevulinic acid 122 have established its role in the biosynthesis of reductiomycin 123. It undergoes an intramolecular cyclisation mediated by pyridoxyl to give the C,N moiety necessary for subsequent polyketide elaboration to the antibiotic., Dehydroodorin 124 is a cytotoxic diamide obtained from the leaves of Aglaia formsosana; it displays significant activity against A-549 human lung adenocarcin~ma.~~ Br Me Br 121 R=H 122 Alkaloids 1 127a 2 127b and 3 127c were obtained from a brown-purple coloured ascidian belonging to the Aplidium family.Agelasphins are novel a-galactosylceramides isolated from the marine sponge Agelas mouritianus. Four closely related metabolites named agelaspin 7a 9a 9b and 11 are 128a 123 124 A group of some 40 or more antioxidants are known to be present in oat grains. Two new ones avenanthramide 1 125a and arenanthraimide 2 125b are typical of this type of cinnamoyl-anthranilic acid derived amide.44 Mn-2 is a tunichrome 126a produced by the iron-accumu- lating tunicate Molgular manhattensis. The stoichiometry of the Fe complex is about 2.5 :1. Protection of the catechol hydroxy groups as tert-butyldimethylsilyl derivatives 126b removed completely the complexing capability of the t~nichrome.~~ Three novel iodinated peptide alkaloids have been identified as having two iodotyrosine derivatives coupled to cadaverine.125a R = H b R=OMe H2NYY OR RO 126a R=H b R = SiMe3 Me$$ \ I R' OMe be 127a R' = H; R2 = Me b R'=I; R2=Me c R'=R2=H NATURAL PRODUCT REPORTS 1996-J. R. LEWIS 128a R = C12H25 b R=C13H27 c R = (CHdI1CHMe2 d R = (CH2),,CH(Me)Et b c d re~pectively.~'The synthesis of agelasphin 9b 12% confirmed its absolute stereochemistry as 2S 3S 4R 2'R (Scheme 9). Formic ester aldehyde 129 was condensed with Wittig reagent 130 to give a mixture which on mesylation with OBn 130 12' li,ii BnO A OBn 131 iii.iv I HO A OH 132 I v-vii TO A OBz 133 viii.02NC&l@COCH(OAc)(CH2)21 Me 134 I OAC Ov(CH2)21Me NH ?Bz Hov(CH&l ,CHMe2 OBz 135 OAC 136 x xi I 128~R = (CHdl1CHMe2 Reagents i BuLi THF rt 15 h; ii MsCl py rt 15 h; iii H, Pd (black) THF rt 15 h; iv NaN, DMF 100 "C 15 h; v TrCI py 50 "C 15 h; vi BzCl DMAP py rt 15 h; vii TsOH CH,CI, MeOH rt 15 h; viii THF rt 15 h; ix Tetrabenzylgalactosyl fluoride SnCl, AgClO, 4 A MS THF rt ;x H, Pd (black) AcOEt rt 15 h; xi NaOMe MeOH rt 1 h Scheme 9 131 reduction of the double bonds followed by treatment with sodium azide gave 132. Protection of the primary and secondary alcohol groups allowed azide reduction to give amine 133 which after detritylation was condensed with (R)-2-acetoxytetra-cosanoic ester 134 to give a protected ceramide 135.Intro-duction of the galactosyl group via its benzylated fluoride gave an a-galactoside 136 which upon debenzylation gave agelasphin 9b 128~.~~ A nerve growth factor promoter produced by Penicillium fellutan~m,*~ has been identified as the tripeptide 137. Neonenactins are a series of antifungal agents produced by Streptomyces roseoviridis which all contain an L-serine-hydroxamic acid The first total and unequivocal synthesis of two members of this group namely neoenactin A 149 and its N-deshydroxy analogue 150 has been described. The synthetic strategy involved ring opening of a cyclooctene with ruthenium chloride-periodate reagent to give an 8-keto acid (Scheme 10).Cyclooctanone 138 reacted with the Grignard reagent from 1-bromohexane 139 to give a tertiary alcohol which dehydrated to give alkene mixture 140. Oxidative ring opening gave moderate yields (48 %) of 8-oxotetradecanoic acid 141 thus indicating that the alkene mixture was predominantly the endo-isomer. Conversion of the acid to the vinyldiketone 142 was achieved using oxalyl chloride followed by vinyl tributylstannane catalysed by trans-benzyl(ch1oro)- bistriphenylphosphinepalladium11. Michael addition of either serine hydroxamate 143 or benzyl protected serine hydroxamate 144 gave the corresponding 8-oxotetradecanyl serine hydroxa- mate 145 or 146. Removal of the benzyl protecting groups from 145 or 146 resulted in 0-debenzylation and N-deoxybenzy- lation i.e.147 and 148. The monobenzylated compound 146 gave 148 unequivically. N-Boc-neoenactin 147 was deprotected with trifluoroacetic acid to give neoenactin A 149 while N-deshydroxyneoenactin A 150 was obtained from 148; both were isolated as their sulfate salts through addition of dilute sulfuric acid. Tan-1057 A B C 'and D are new antibiotics with potent activity against methicillin resistant Staphylococcus aureus. These quinone containing peptides e.g. Tan- 1057A 151 were obtained from two gram negative bacteria of the Flexibacter family designated strain PK-74 and PK-176. They also possessed gram-negative and gram-positive antibacterial a~tivity.~' NH H 2 N A ! m ' y 1 NH2 00 N' NHCONH 151 A total synthesis of (f)-polyoxin J 176 starts with myo- inositol 15252through first protecting all but one of its hydroxy groups 153 which allowed a Bayer-Villiger reaction to create two lactones 155 and 165 which in turn led to the appropriate nucleoside portion 163 or to the a-methylfuranoside section of the natural product 171 (Scheme 11).Introduction of the pyrimidine moiety 172 gave after reduction of the azide group to amine the amino acid synthon 173 which was hydrolysed NATURAL PRODUCT REPORTS 1996 d r-iii 140 141 142 139 143 R=H 144 R=Bn - Bc=HNJY+ ~CHNJY&‘ OR HHO’ 2‘ NR J Y 4 viii HO’ ‘ R vii RO’ 149 R=OH 150 R=H 148 R=H 147 R=OH * vii 14‘ R=BnJ146 R=H Reagents i Mg THF Ar rt 18 h; ii TsOH (cat) benzene reflux; iii RuCl,xH,O (cat) NaIO,; iv (COCI), reflux 2 h; v Bu,Sn-CH =CH, (Bn)PdCl(PPh,), benzene reflux; vi 143 or 144 toluene KOBut (cat) Ar reflux 9 h; vii H, PdCI EtOH; viii TFA THF/CH,CI (1 :I) rt 1 h then H,SO (0.2 M) Scheme 10 NH H2NAim’yx several steps NH2 0 MPMO 0 N’ NHCONH2 OH * Ba&~O(OAc)P~ 151 OMPM 152 153 i,xvi BnO O BnPn v v BnOp __c 0 OBz MPMO‘.*‘OBz MPMO’. OMPM OMPM OMPM MPMO ‘OBz 155 R = OBZ 154 164 165 156 R=OH 1 157 R=O xvii Me02C 1 vi ~-~ y ~ Me02C z ~ +xviii BzoqOyOMe ~ ~ MPMO OBn AcO’ *’*-OBn RO-‘OBn vii 168 7166 R = MPM O -1 iv. xix xx ixL167 R=H OBn R2 MPMO 158 159 R’ = Code; R2 = N3 viiiK160= CH20H; R2= NHZ R’ xxii x.OH OBn /ix-xi / + MeaSidKNOSiMe3 AcO” *‘OAc 0 169 X=OH; Y=H 171 172 xxi C170 X=H; Y=N3 Z o&C02H OBn NH2 I I xxiv I 163 xxv-xxvii -Hd’ Acd‘ ‘OAc 174 173 Hd” ‘OH 175 R=Bn xxix C 176 R=H Scheme 11 (for reagents see facing page) NATURAL PRODUCT REPORTS 1996-5. R. LEWIS 177 8' 0 0 / OH 181 and the amino acid groups 174 set up for peptide linking to acid 163 under Shioriri conditions. This gave the protected pyrimidinyl amide 175 which upon deprotection gave (*)-polyoxin J 176. Using a bioassay directed purification an extract of the leaves of Verbesina caracasana yielded a metabolite with hypotensive activity. Caracasanamide 177 is a mixture of Z-and E-isomers of the cinnamoyl group which is coupled to guianidine and a diaminobutane.A synthesis of ths structure realised the E-isomer which confirmed their geometrical relationship.53 Three bromine containing metabolites derived from tyrosine have been isolated from the sponge Psammaphysilla purpurea called aplysamine 3 4 and 5. They have structures 178a b and 179 respectively.54 The marine gastropod mollusc Monodonta labio contains three alkaloids monodontamide A B and C; all contain a putrescene coupled to malonic acid. Thus A is 180a B is 180b and C is 180~.~~ Thiomarinol 181 is a new hybrid antimicrobial antibiotic produced by the marine bacterium Alteromonas rava sp. NOV.SANK 73390. Having both gram-positive and gram- negative activity it was found to be more effective than its component parts namely pseudomoic acid and pyrr~thine.~~ A stereoselective synthesis of bengamide E 182 differs from that of previous syntheses of bengamide A B and C in that the carbohydrate elongation procedure involves an ally1 stannane thus directly introducing an E-double bond (Scheme 12).57 8' 178a R=H b R=Br )&#qL..&OH OH 0 182 Thus allylstanane 184 was prepared from enal 183 which underwent isomerization to the y-alkoxyallylic stannane 185 on treatment with BF etherate.To this racemic stannane was added meso-tartaric acid derivative 186 as it was anticipated that this reaction in the presence of MgBr would become chelation controlled so that the S-enantiomer (stannane) would preferentially react.This did in fact take place and the predominant products hydroxy ester 187 and its lactone 188 were both generated (89% yield). This mixture was coupled with (S)-2-aminocaprolactam 189 to give the benzylated natural product 190 which on deprotection gave bengamide E 182. A synthesis ofhomaline 191 either as its (+)-or its (S,S)-(-)-form which is the naturally occurring configuration uses a novel versatile amination and transamidative ring expansion procedure carried out in liquid ammonia to create the homochiral eight-membered ring in 191. Its key step was a ring expansion of N-chloropropylazetidinone 196 to the required azalactam 19757(Scheme 13). R-(-)-Phenylglycine 192 was converted into (a-P-phenyl-P-alanine 193 which gave (9-P-lactam 194.Alkylation of this azetinone with l-bromo-3-chloropropane 195 gave the chloride 196 which on amination and ring expansion in liquid ammonia for 3 days produced demethyl azalactam 196. Coupling of two of these units 197 with 1,4-dibromobutane gave homochiral didemethylhomaline 198 in 54 YOyield. Reductive methylation using formaldehyde and sodium cyanoborohydride gave without racemisation (S,S)-homaline 191. Reagents i BzCI DMAP pyridine rt; ii MeSO,Cl pyridine 50°C; iii NaN, DMF 80°C; iv MeONa MeOH; v DMSO DCC TFA pyridine benzene rt; vi MCPBA KHCO, (CH,Cl), 0 "C; vii NaBH, MeONa MeOH 0 "C; viii LiAlH, Et,O then ZC1 NaHCO, THF- H,O; ix CH,(OMe), TsOH DMF; x Ac,O pyridine; xi DDQ CH,Cl, H,O; xii Pb(OAc), benzene rt then NaBH, MeOH; xiii 4-Nitrophenylchloroformate then NH,-MeOH CH,CI,; xiv TsOH MeOH rt; xv Jones reagent acetone 0 "C; xvi PDC 4A MS CH,CI,; xvii TsOH HC(OMe), MeOH rt then MeI NaHCO, DMF; xviii (CF,SO,),O TF,O pyridine CH, 0 "C then AcOK DMF 5 "C; xix H, Pd(OH), EtOH; xx MeC(OMe), TsOH DMF rt; xxi Tf,O pyridine CH,CI, 0 "C then NaN, DMF rt; xxii Dowex 50WX8 MeOH rt; xxiii Ac,O H,SO, CH,Cl, AcOH; xxiv pyrimidine 172 Me,SiOSO,CF, CH,Cl, rt; xxv H, 5% Pd-BaSO, dioxane H,O then 1 M Ba(OH), H,Gdioxane rt ;xxvi Di-fert-butylcarbonate K,CO, dioxane-H,O then BnBr NaHCO, DMF rt ;xxvii TFA EtOAc 0 "C;xxvii (EtO),P(O)CN Et,N DMF rt; xxix H, 10% Pd-C MeOH-H,O Scheme 11 (facing page) NATURAL PRODUCT REPORTS 1996 %fH 0 183 i ii 1 SnBu3 OBOM 1 84 I iii e t H T C02Me h Bu3Sn OBOM SBn 1 85 186 I liv m;O2Me I BOMO OBn BOMO OB" 187 188 t 189 vi-;; R=Bn Scheme 12 191 Using the same azetidine to azalactam synthetic strategy hoprimine 199a hoprominol 199b and hopromalinol 199c the unsymmetrical alkaloids found in the leaves of Homalium pronyense were also synthe~ized.~~ A detailed study of this transamidative ring expansion of N-o-halgenoalkyl-P-lactams60 has opened up a synthetic pro- cedure for the synthesis of 7- 8-and 9-membered azalactams but not for 13- 15-and 17-membered rings as they are unstable 192 193 Ph-"Po LCI 196 198 R=H XC191 R=Me Reagents i BuO,CCl N-methylmorpholine THF; ii CH,N2; iii AgOCOPh MeOH; iv Pd-C H,; v 10% aq NaOH ion exchange; vi 2,2'-dithiopyridine PPh, MeCN ; vii Br(CH,),Cl KOH DMSO; viii liqNH, 3 d 20 "C; ix Br(CH,),Br KOH Me,SO; x CH,O NaBH,CN MeCN AcOH Scheme 13 in liquid ammonia.Using this procedure (+)-dihydro-periphylline 200 and (&)-celabenzine 201 have been prepared. Balanol 202 is a potent inhibitor of protein kinase C an enzyme which is involved in a key role in cell growth metabolism and differentiation. The fungus which produces this metabolite was found in a collection of decaying pine needles.61 0 H 200 201 H 202 0 0 HOfEbEALN Me Me(CH2)6 NH2 203 NATURAL PRODUCT REPORTS 1996J. R. LEWIS Onnamides are metabolites of marine sponges belonging to the Theoneffafamily. First reported in 1986 these macrocyclic lactones have been found to have potent antiviral a~tivity.~ Three new congened3 have been isolated which only show structural modification at the central C( 11) to C(5) portion of the molecule.Thus 6,7-dihydro- 11-0x0-onnamide is 204a 11-0x0-onnamide is 204b and 4-(2)-onnamide is the geometric isomer 204 of onnamide A. A dimeric peptide alkaloid of a completely new type has been found in the marine sponge Anchinoe tenacior. Its terminus has a styrylamino grouping connected to a L-alanylpentanoyl guanidino system 205 which dimerises to create the natural An unidentified sponge contained a fungus belonging to the Streptomyces group which when grown on an artificial medium produced antibiotics uranchimycin A 206a and uranchimycin B 206b.These are the first antimycin antibiotics to possess a branched alkyl side chain.65 0 204a R’ + R2 = 0; a,b saturated b R’ + R2 = 0; a,b unsaturated c R’ = OH; R2 = H; a,b unsaturated H NH 0 205 HOCHN OH 0 I 206a R’ = Me; R2 = H b R’=H; R2=Me An enantiomeric total synthesis of lankacidin C 207 makes this acid/base unstable alkaloid now available in quantity. A study of its substantial in vivo antitumour activity is thus now possible.66 The stereochemical aspects of the phenyl valeryl section of neoantimycin 208 a metabolite of Streptoverticiffinin orinoci has been established using labelled methionine pro- pionate and a~etate.~’ Exceptional antischistosomiasis activity has been found in the latex of the common Brazilian ornamental plant Eupharbia mifii var.hisfopii.68A bioassay-guided fractionation yielded a terpene component mixture based on eugenol. Its most active constituent was milliamine L 209 having an activity of 4n~ (2.5 ,ug 1-’). HO-OH 207 NHCHO f! COHN 208 NH2 COHN-209 Monumycin type antibiotics are produced by Streptomyces. Their variation in structure can be accounted for by polyketide modification during their biosynthesis; a study of the meta- bolites produced by Streptomyces paevufus confirms the polyketide interrelationship between monoumycin A 210 and those of B C and D.6gNisamycin 211 produced by strain K106,’O has been patented twice by the same group. c. HN aoH 0 210 448 Asukamycin 212a,the metabolite from Streptomyces nodosus subsp.asukaenosis has now been completely ~haracterized,~~ its dienoid relative is alisamycin 212b.72Two total syntheses of aranorsin 213 have established its hitherto unknown chirality at C-6' as R.73374 Lactobicillus helveticus produces a number of cyclo-tetrapeptides which can incorporate Group I1 metals such as Zn Cu Mn Mg Ca and Fe.75 It is suggested that these ionopheres could be useful as sedatives microbiocides anti- hypertensives tyrosinase inhibitors melanin formation inhibitors etc. (!). One of these tetrapeptides 214 was patented earlier as being specific for melanin inhibiti~n.~~ 212a n=3 b n=2 213 or$ N-... M-.... IH Q OH 214 215 A bicyclic depsipeptide designated FR90 1228 has been obtained from the bacterium Chromobacterium violaceum strain No.968. Its structure 215 was determined by spectroscopic analysis coupled to X-ray ~rystallography.~~ The sea hare Dolabella auricularia produces a number of peptide alkaloids named do last in^.^ Since a number of these compounds show powerful antineoplastic activity interest in this marine creature continues unabated. Dolastin C 21678and dolastin D 21779have been isolated and synthesized while dolastin 10 218 and its cogeners have been synthesized and tested for activity.80 The backleg fungus Phoma lingam is a plant pathogen especially virulent to canola oilseed crops. When grown on an artificial medium it produced firstly phomalide 219 and later sirodesmin PL 220.24-60 hour old cultures were optimal for 219 production while 220 was the metabolite from 52+ hour old cultures.81 NATURAL PRODUCT REPORTS 1996 Me2N 0 0 216 217 Metarhizium anisophiae is an entornopathogenic fungus which produces destr~xins.~ Four new oness2 are the cyclic depsipeptides destruxin A3 221a,destruxin F 221b,desmethyl-destruxin A 221c and desmethyldestruxin C 221d.Respiranin is an insecticidal antibiotics3 possessing a cyclodepsipeptide structure 222;it is produced in the mycelia of Streptomyces species No. 4403. 221a R' = CH&H=CH2; R2 = Me b R' = CH2CH(OH)Me; R2 = Me c R' = CH2CH=CH2; R2 = H d R' = CH2CH(Me)CH20H; R2 = H 222 NATURAL PRODUCT REPORTS 1996-J. R. LEWIS The soap-fish Diploprion bifasciatum produces lipogram- mistin-A 223 which is a lipophilic ichthyotoxin and it is used by its host as a defence substance against predators.s4 A cyclic pentapeptide has been obtained from the dried roots of Aster tatari~us.~~ Spectral analysis revealed it to possess two chlorine atoms as depicted in structure 224.In a separate investigation on the same plants6 two mono-chlorinated pentapeptides astin D 225a and astin E 225b were identified. H 223 n CI 224 22% R=H b R=OH A novel lactam has been extracted from the leaves of Clausena excavata;s7 called clausen-lactam it has structure 226. The transamidative ring expansion of N-w-halogenoalkyl-P- lactams reported earlier in this section has been used to synthesise nine-membered (f)-dihydroperiphylline 227 and 13-membered celabenzine 22tXEs Buchnerine and N'-(2)-p-methoxycinnamoylbucherine are two spermidine macrocyclic alkaloids found in the leaves of CZerodendrum buchneri.Their structures 229a b were confirmed by synthesks9 I H COCH=CHPh 226 227 0 Ph L-h H 228 0 229a R=H b R = COCH=CHC6H40Me 7-Hydroxypleurocorine 230 is a new alkaloid isolated from the leaves of Pleurostyllia opposita and it represents a new type of spermidine derivative incorporating a pyrrolidinone ring.90 Two cyclopeptide alkaloids obtained from the dried root bark of Zizypus lotus have been designated as lotusine A 231a and lotusine D 231b.g1 The leaves and terminal branches of Antidesma montana are a source for two other cyclopeptide alkaloids designated AM 1 and AB2.Careful reexamination of the spectroscopic data for AM1 confirmed that it was identical with myrianthine B 232b in which the isoleucine moiety has the L-configuration. AM2 is thought to be similar to aralionine B 232b.92 230 R2 23la R =Me 232a R' =CHMe; R2=Me b R=H b R1 =Phi R2=H Rubia cordifolia is the source for a series of bicyclic heptapeptides designated as the FUseries. Interest in these alkaloids is promoted by their ability to inhibit protein synthesis by binding to eukaryotic 805 ribosomes much like the bouvardin~.~~ The most important of these RAs is VII 233a which has been patenteds4 along with Further examination of the root bark of this plantg6 has produced two more alkaloids RA-XV 233b and RA-XVI 22%.Structure-activity relationships have established that a large size substituent on the a-side of the peptide ring inhibits the ribosomal binding.97 Solution NMR spectroscopy has also identified the conformation of the bicyclic heptapeptide which shows the greater binding effect. 2% R1 =Me; R2= H b R' = p-D-glucose; R2 = H c R~ = C-acetyI-pD-gIuwse; R~ = OAC A water soluble toxin has been obtained from smut ballsgs growing parasitically on rice plants. It can induce abnormal swelling in seedling roots and structurally it is similar to phomopsin A. It is however a unique tetrapeptide containing an ether linkage 234. However cultivation of the parasite of Ustilaginoidea vireus on panicles of rice plants produces false smut balls and water extraction yields ustiloxin A and B 235 which can be esterified to give its dimethylester dihydro- chloride.99 The parent compounds are active against stomach and breast cancers and have been patented.The structures quoted in these two papers are however not compatible. 234 R2 R102C CONHCH2C02R1 HO MeHN 235 A novel bastadin has been isolated from a sponge of the Ianthella group.1oo It has been designated bastadin 15 and its structure 236a was ellucidated by NMR measurements on the natural product and on its permethyl ether 236b. Also present in this extract were bastadins 8 and 12 which were fully characterized through their more soluble permethylated deriva- tives. From the same sponge genus a sulfated bastadin 237 has been obtained in which the 34-phenolic grouping was modified dilute acidic hydrolysis liberating bastadin 13.lo’ “J NOR 236a R=H b R=Me 237 NATURAL PRODUCT REPORTS 1996 Nairaimides A and B containing a novel diproline hepta- peptide ring system were found in an ascidian Lissoclinum bistratum and were identified as 238a b respectively.lo2 An unidentified non-spore forming filamentous micro-organism PF1022 in culture produces three anthelmintic cyclic depsipeptides.lo3 All contain the depsipeptide arrangement 239 with alkyl-aryl modifications at R. Two depsipeptides were isolated from a marine Streptomycete found on the surface of the jellyfish Cassiopeia xamachana.lo4 Both salinamide A and salinamide B have anti-inflammatory properties and have the unusual bicyclic arrangement as depicted in 240a b.238a R=Me b R=Et 240a R’ = a-OH; R2 = P-CHzCI 0 b R’+R2=A Toxins produced by certain cyanobacteria manifest them- selves in acute liver failure. Four depsipeptides aerugino- peptides 1 to 4 have been isolated from Microcystis aeruginosa TAC95 and M228,1°5 and they like dolastin 13 possess a depsipeptide structure 241 where one or two threonine units are incorporated at X and Y. NATURAL PRODUCT REPORTS 1996-5. R. LEWIS 45 1 241 I R' oTNvo Hd 242a R' =CH@H; R2 =CI 243 b R' = Me; R2 = CI A soil sample from Cochin in India produced a micro-method gave the desired dipeptide 246 in 88% yield which organism of the Microbiospora family.lo6 It SPMA6857 condensed with imino acid 247 to give tripeptide 248 and 249 produced in culture two cyclic depsipeptides cochinmycin IV upon deprotection.This enabled a third coupling process with 242a and cochinmycin V 242b. theonyl proline 250 in DMF and diethylphosphoryl cyanide Echinocandin D 243 has been synthesized (Scheme 14).lo7 (DEPC) to give pentapeptide 251 which upon deprotection Starting with 0-protected L-threonine 244 coupling with the gave amino acid 252. Further condensation with N-lino-thiol ester of peptide 245 using the 1 -(trimethylsilyl)imidazole leylornithine 253 gave 254 which on total deprotection gave TBsx: 244 + SPY 246 245 OH R2 243 254 R' = OMe; R2 = NHBoc; R3 = TBS 251 R' = OMe; R2 =Z v.vi 255 R' = OH; R2 = NH2; R3 = H 'K252 R'=OMe; R2=H Reagents i ButMe,SiCl imidazole DMF N, 0 "C to rt 14 h; ii DEPC Et3N; iii DL-camphorsulfonic acid MeOH rt 20 h then in vacuo then TFA CH,Cl, rt 20 min then in vacuo,then 1 M HC1 THF rt 14 h; iv H, Pd-C MeOH; v 0.5 M NaOH THF 0 "C 19 h then 0.5 M NaOH rt 8 h; vi TFA CH,CI, rt 15 min; vii DPPA Et,N Scheme 14 NATURAL PRODUCT REPORTS 1996 H02C H 256a R' = tyrosyl; R2 = H; R3 = OH b R1=8indoline; R2=H; R3=OH c R' = tyrosyl; R2 = benzyl; R3 = OH -d R' = tyrosyl; R2 = H; R3 = (Me)Et 257 9 9 i,ii -iii-v vi vii "NHCHO HN HN HN Boc BOC Boc /' C02H I I C02H CON(Me)OMe 260 261 262 258 259 xiii i Tu Ph !FCOR~ C02Me 0 NHR~ viii i THpo7NHz o-Phe-OMe * ZN 264 THpo? )cNH NH Mtr NHR' 263 265 R' = Mtr; R2 =Z; R3 = OMe xiv xv 269 R' = BOC; R2 =THP 266 R' = Boc; R2 = Z; R3 = OMe K270 R' = BOC; R2 = CGFSO 267 R' =Boc; R2=Z; R3=OTHP xvi xvii 1 xii ix't-268 R' = BOC;R2= H; R3 =OTHP YYoT'ps xviii xix xx 257 4 Reagents i NNM ClC0,Bu'; ii MeNH(OMe) Et,N; iii TIPS-Cl imidazole DMAP CH,Cl,; iv LAH THF -50 "C; v (EtO),P(O)CH,CO,Si(Me), BuLi THF H,O/H+; vi Ph,P(O)Cl NMM THF; vii Et,N CH,Cl ; viii LiOH MeOH H,O; ix (Boc),O DMAP CH,Cl,; x LiOH MeOH H,O; xi DHP PPTS CH,Cl,; xii H, Pd-C MeOH; xiii Pd(PPh,), dimedone THF rt; xiv 0.05 M HCl Et20/CH,Cl,; xv F,C,OH DCC CH,Cl,; xvi sat.HCl Et,O/CH,Cl,; xvii NMM CH,Cl,; xviii Dess-Martin periodinane MeCN 80 OC 1 h; xix HF/pyridine THF ;xx CF,CO,H thioanisole Scheme 15 NATURAL PRODUCT REPORTS 1996-5.R. LEWIS amino acid 255. Intramolecular cyclization occurred with diphenylphosphoryl azide (DPPA) to give echinocandin D 243. The oriental crude drug Lycii Radicis Cortex is prepared from the dried root bark of Lyciurn Chinese. A detailed examination of the water soluble components of both the drug and fresh plants has identified four new cyclic peptides.lo8 These are lyciumins A 256a,lyciumins B 256b,lyciumins C 256c and lyciumins D 256d. Cyclotheonamide A and B reported in 1993,1°9 are novel 19-membered cyclic peptides which possess antithrombotic properties. A 257 has now been synthesized in a convergent strategy from D-phenylalanine vinylogous L-tyrosine L-diaminopropanoic acid L-proline and a hydroxy derivative of L-arginine."O The synthesis (Scheme 15) starts with protected L-tyrosine 258 which with isobutyl chloroformate and N- methylmorpholine was converted into the Weinreb amide 259.Elaboration of the side chain to unsaturated amino acid 260 enabled mixed anhydride condensation with pyrrolidine hydro- bromide 261 to give the right hand side of the natural product 262.The preparation of the left hand side of cyclotheonamide was achieved by condensation of chain extended arginine derivative 263 with D-phenylalanine methyl ester 264 which when followed by a change of protecting groups allowed amine 268 to be prepared. C-Terminal deprotection of tripeptide 262 with PdO in the presence of dimedone allowed segment condensation with 268 to give an acid sensitive pentapeptide 269.Removal of the THP group and reactivation via its pentafluorophenyl ester 270 was followed by amine depro- tection which gave 271 allowing macrolactamization to be achieved with NMM creating cyclopeptide 272.Oxidation of the secondary hydroxy group was possible using the Dess- Martin periodinane reagent in hot acetonitrile which when followed by deprotection gave cyclotheonamide 257. A sponge harvested in the Western Indian ocean and identified as Phakellia carteri contains two isomeric cyclo- heptapeptides. Named phakellistin-3 and isophakellistin-3 they represent a new type of cyclopeptide where a tryptophan unit has been photooxidised resulting in ring juncture reversal.Isophakellistin 3 crystallized from acetone and its structure 273 was confirmed as having a cis P-ring junction. Phakellistin had the cis a-oriented ring junction."l Cyclothialidine is a novel DNA gyrase inhibitor obtained from the culture fluid of Streptornyces~fipinensis.'l2 Its unique 12-membered lactone-peptide is represented by structure 274.A bioassay involving trypsin inhibition located two active principles micropeptin A and micropeptin B in the fresh water blue-green coloured alga Microcystis aer~ginosa."~ They differed only in having the side chain based on hexanoic or octanoic acid 275. ( -)-Sandramycin has a decadepsipeptide structure 276 containing a two-fold axis of symmetry and two pendant heteroaromatic chromophores.These pendants are thought to be the units capable of incalation into the developing chain of DNA. The synthesis of this antitumour antibiotic has been carried out starting with protected glycylsarcosine 277 and 273 'bH 274 H-OH 275 0,N-dimethyl valine 278; protected L-pipecolinic acid benzyl ester 281 and N-SES serine 282.Coupling of these intermediates as indicated in Scheme 16 led to 280 and 283 which on combination gave 284. Deprotection gave the linear decadepsideptide 286 which combined with 284in the presence of EDCL to give 287. Deprotection and treatment with diphenyl phosphorazidate gave cyclisation to 290.Release of 276 NATURAL PRODUCT REPORTS 1996 290 R = SES 291 R=Boc 292 R=H Reagents :i DCC (1 eq) Et,N DMAP (cat) CH,Cl, 25 "C 24 h ;ii LiOH (3 eq) THF MeOH-H,O (3 :1:l) 25 "C 3 h; iii BOPCl(l.3 eq) Et,N CH,Cl, 0 "C 10 h; iv DCC (1 eq) DMAP (1 eq) CH,CI, 0 "C 24 h; v 3 M HC1 EtOAc 25 "C 30 min; vi H, Pd-C MeOH 25 "C 12 h; vii EDCl(1 eq) HOBt (1 eq) NaHCO (2.2 eq) CH,CI, 25 "C 24 h; viii DPPA (4 eq) NaHCO (10 eq) 0.003 M DMF 0 "C 48 h; ix B I,NF (Boc),O (29 eq) THF 25 "C 48 h; x quinoline 293 EDCl(4.2 eq) HOBt (5.5 eq) Et,N DMF 25 "C 48 h; xi H, Pd-C EtOAc 25 "C 12 h Scheme 16 the peripheral amino groups 292 enabled 3-benzyloxyquinoline 2-carboxylic acid 293 to couple to give (-)-O-benzyloxy- sandramycin 294.Final deprotection resulted in (-)- sandramycin 276 identical to the natural product.l14 Ascomycin 295a FK-506 295b and rapamycin 298 have some common structural features but all possess good immuno- repressive properties as a result of their ability to bind to the FK506-binding protein.It was thought that a conformational change took place to enable this linking to occur but now aqueous solution spectral studies on FK-506 show that this is not ~0."~A closely related analogue FK90052 296 has recently 0 been isolated from novel Streptomyces lavendulae strain (ATCC No. 55230);'16 the hemi-ketal grouping is of particular interest. Synthetic studies in this field have at one stage or another required lactone and hemiacetal formation. The former had presented little problem but not so the final ketal ring closure. The use of isopropoxytitanium trichloride as a prom~ter'~' to generate the enolate at position 27 of 297 was a great 295a R = Et b R =ally1 OMe C>Me 296 improvement (33 % yield) on previous procedures e.g.for the synthesis of 298. Further investigation into the nature of the NATURAL PRODUCT REPORTS 1996-5. R. LEWIS 297 298 metabolites alterobactin A and alterobactin B first isolated in 1991 from an open ocean micro-organism Ateromonas luteo-violacea has established a ring structure 299 for A and open chain structure for B 300. This difference is manifest in that A has a remarkably high ferric iron affinity constant1l8 but B does not. Hymenamides A and B are two proline rich cyclic hepta- peptides obtained from the Okinawan marine sponge belonging to the Hymeniacidon family. Extensive spectral analyses suggest I yNH 299 45 5 that the conformation of A is 301 while that of B is 302.’19 The same source has produced three additional proline rich heptapeptides called hymenamides C D and E.120 Structure identification was obtained by extensive NMR measurements identifying C as 303a D as 303b and E 303c.The total synthesis of cyclic lactones jaspamide 304 and geodiamolide D 305 also involved a macrolactamisation step which in the case of the jaspamide precursor ring-closed in 22% yield using DCC DMAP DMAPTFA in boiling chloroform. The geodiamolide D precursor however only gave the natural product in 7% yield under the same conditions.121 U 301 ‘Ph 302 02 303a R’ = CH2CO&l; R2 = CHMe; R3 = Sindolyl; R4 = CH2Ph; R5 = H b R’ = CHMe2; R2 = H; R3 = CH(Me)Et; R4 = 4-hydroxyphenyl; R5 = CHSQH c R’ = dhydroxyphenyl; R2 = R3 = phenyl; R4 = OH(Me); R5 = CH(0H)Me A OH 304 305 456 NATURAL PRODUCT REPORTS 1996 0 A fresh water blue-green alga Microcystis aeruginosa contains two metabolites that have plasmin and typsin inhibitor properties.Called micropeptin A and B their structures 306a and 306b respectively were determined by chemical degradation and 2D NMR measurements.122 The absolute configuration of d 306a R=Et b R=H majusculamide C the metabolite obtained from the sponge Ptidocaulis trachys has been determined by X-ray crystal- lography thus establishing the absolute stereochemistry of the 2-methyl-3-aminopentanoicacid residue in 307 as (2S,3R).lZ3 A new family of pigments the myxochromides have been isolated from gliding bacterium Myxococcus virescens.Typical of these antibiotic substances is myxochromide A 3O8.lz4 A new topoisomerase I1 inhibitor called BE-22179 309 has been produced by fermentation of Streptomyces sp. A22179. It does not inhibit topoisomerase 1 but it has potent antitumour 307 HO 308 309 BOC-L-I~-312 BOCN RHN 313 314 315 R=Boc 'K316 R=Hy I\/CO~BU' I IN"H Bn 317 vi. iii,vii ___) + viii ix c319 R' = But; R2 = H COTce 320 R' = H; R2 = Bn 318 Reagents i MeN+H,(OMe)Cl Pr'NEt DCC DMAP CH,C12 0 "C;ii vinylmagnesium bromide THF -13 "C to rt ;iii N-Ac-L-CYS py DMF rt; iv Et,O phenyldiazomethane THF rt; v 4 M HCl dioxane rt; vi DEPC Et,N DMF 0 "C to rt; vii (COCI), bz 50 "C N-ethylmorpholine THF -15 "C to rt ;viii Zn 1 M NH,OAc aq THF rt ;ix H,+NOBnCl- DEPC Et,N THF DMF (10 :3) -15 "C ; x TFA CH,Cl, rt; xi DEPC Et,N 0 "C to rt; xii Pd (black) MeOH rt Scheme 17 NATURAL PRODUCT REPORTS 1996-5.R. LEWIS 1 310 c..-. 311 322 activity against several tumour cell lines.lZ5 The cyclopeptide 310 produced by Strachybotrys chartarium No. 19392 has excellent immunosuppressant properties.126 The total synthesis of matlystatin A a piperazic acid derivative 311 produced by Actinomadura atramentaria has established its absolute stereo- hemi is try.'^' First (Scheme 17) protected L-isoleucine 312 was condensed with N,O-dimethylhydroxylamine HCl and the resulting amide 313 alkylated with vinyl magnesium bromide to give ketone 314 which upon Michael reaction with N-actyl-L- cystine gave thioether 315.The piperazic acid component was synthesized by first coupling piperazic acid 317 with 2R- trichloroethoxy carbonyl hepatonic acid 31812' and then modifying the protecting group 318-320 to allow condensation with 316. The resulting combination was the protected natural product 321 which on deprotection gave matlystatin A 311. In much the same way matlystatin B 322was synthesized.12s The piperazine ring is also present in the hexadepsipeptide 323 produced by Streptomyces strain MJ202-72F3. 129 0 then 328 323 325 326a R' = H; R2 = OH b R1+R2=0 3 Miscellaneous Alkaloids An expeditious synthesis of cispentacin i.e. (-)-( 1R,2S)-2-aminocyclopentane-1-carboxylic acid 324 has been achieved by a highly stereoselective conjugated addition reaction of lithium (9-(a-methy1benzene)benzylamide to tert-butylcyclo- pentene-1-carboxylate which when followed by hydrogenation and hydrolysis gave the natural The culture medium of Penicillium chrysogenum contains 2- [(2-hydroxypropionyl)amino]benzamide325; this is the first report of its isolation as a naturally occurring The use of a regioselective oxidation procedure for p-hydroxy azo compounds has led to the synthesis of hydroxy- azoxy This in turn has been applied to the synthesis of maniwamycin A 326a and maniwamycin B 326b (Scheme 18).Starting with butyl methyl ketone 327 introduction of the azo group using dibenzylazoadicarboxylate 328 gave diazoketone 329; reduction with sodium borohydride gave alcohol 330 which was protected as its trimethyl tert-butylsilyl ether 331.Lithiation of 331 allowed alkylation with cyclic sulfate 332 which after hydrolysis gave 333. Four steps generated the epimeric alcohol mixture 335 which was 327 330 R=H 329 vi C Bn02CN= NC02Bn 331 R=TBS 328 + 333 R=H x-xii ix C334 R=Ac -OAc 332 Reagents i LDA then 328; ii H+; iii H, Pd-C; iv Aw Cu(OAc),; v NaBH,; vi TBSOTf Et,N CH,Cl, 0 "C,40 min; vii BuLi HMPA THF -78 "C 10 min then 332 THF rt 2 d; viii H,SO (5 mol YO),dioxane rt 20 min; ix A1,0 DMAP py 40 "C 1 d; x 2 YOHCl MeOH rt 0.5 h; xi H, PdC AcOH-EtOH rt 2 h; xii air Cu(OAc) (10 mol%) AcOH-H,O-EtOH rt 40 min; xiii 3.63 M ButOOH toluene VO(acac) (40 mol%) CH,Cl, 0 "C 20 min; xiv MsCl DCC py TFA ether rt 1.5 h; xv DBU toluene 40 "C 100 min; xvi K,CO, MeOH rt 1 h; xvii Me,SO DCC py TFA ether rt 15 h; xviii PhCO,H PPh, DEAD THF 0 OC 40 min; xix K,CO, MeOH rt 3.5 h Scheme 18 458 peroxidated and dehydrated to give epimaniwamycin B 337.Its oxidation gave maniwamycin A 326a while Mitsunobu reaction gave maniwamycin B 326b. Many tropical cnidarins which live in shallow waters contain a class of UV-absorbing compounds which are amino acids. These mycrosporine-like amino acids are thought to protect against the effect of solar UV. Two new compounds with UV absorbing properties have been isolated from the sea anemone Arithopleura el~gentissima,'~~ they are mycosporine-taurine 338a and mycosporine-glycine 338b.Acrodontiolamide 339 is a chlorofungal metabolite found in the cell free culture of micro- organism Acrodontium salmonenin ; it possesses antifungal activity .134 R2 338a R' =CH2S03H; R2=0 339 b R' = COpH; R2 = NCH2C02H Hb bH H&HcoR 340a R' = NHC(=S)OMe; R2 = H 341a R = (CH2)5CHMe b R' = NHC(=S)OEt; R2= H b R = (CH,),CHMeEt c R' = NHC(=S)OEt; R2 = AC NATURAL PRODUCT REPORTS 1996 Br SPr -t Me0 CHO Me0 CHO 344 345 3461vi SPr SPr vii viii Me0 Me0 NO 349 350 n=l; R=TEDC 351 n= 3; R = TEDC xi K 343 (TFAsalt) Reagents i Br, HOAc; ii MeI aq K,CO, NBuNI THF; iii Br, HOAc 60 "C; iv CuSPr quinoline-py 160 "C; v (MeO),SO, aq K,CO, BuNI CH,Cl, H,O; vi MeNO, NH,OAc-HOAc; vii LiAlH, THF reflux; viii p-02NC,H,0C0,CH2CH,SiMe, Et,N CH,Cl,; ix Na NH,; x S,Cl, THF; xi TFA CHCl Scheme 19 Enediynes have been of interest in recent years because of their ability to cleave DNA., 92.log* 139 A typical component of OMe these antitumour antibiotics is the chromophore of neo-carzinostatin 352 which is stabilised in situ by association with 0 its apoprotein (133 amino acids). A full structural determination of this complex in solution has now been determined by 2D Meo9(s-sb S'S NMR;140 consequently an explanation of its stability and of its reactivity with thiols causing aromatization of the enediyne ring OH H NH2 342 R = Me CH(OH)Me etc. 343 The first naturally occurring thiocarbonates have been isolated from fresh leaves of Moringa 01eifera.l~~ All five possess hypotensive activity and have been separated into four components niazinin A 340a its rotamer niazinin B niazimicin 4 340b and the rotamer mixture niaziminin A +B 34Oc.Two new caprolactams have been isolated from an unidentified gram-positive bacterium found in a deep ocean sediment. Caprolactin A 341a and caprolactin B 341b were both found to have cytotoxic and anti-viral acti~ities.'~~ A careful search of the culture fluid of Streptomyces viridiochromogenes has revealed several more minor com-ponents which belong to the obscurolide complex. Differences in structure can be accounted for by polyketide modification 342.13' The unique dopamine related benzopentathiepin metabolite varacin 343 isolated from Lissochinum vareau,log has been synthesised in eleven steps starting with vanillin 344 (Scheme 19).Thus its bromination and methylation gave dibromo- veratraldehyde 345 which was converted to the dipropyl sulfide 346 and thence via nitrostyrene 347 to protected phenyl- ethylamine 348.Depropylation generated the dithioylate 349 which combined with sulfur dichloride to give two thiepin derivatives namely tri- and penta-thianes 350 and 351. Amine deprotection gave the natural product 343 as its trifluoroacetate salt.138 3524355 +356) has been formulated (Scheme 20).141 Fusarium fateritium is important as a biofungicide and as a bioherbicide ; it is particularly effective against the plant pathogen Enypa armeviiaceae. A bioassay guided isolation for the metabolites isolated from this micro-organism resulted in the identification of two novel alkaloids 2-(1-hydroxyethyl)-4-(3H)-quinazolinone357a and 2-acetyl-4- (3H)-quinazolinone 357b.Also isolated were three peptide alkaloids enniatin B B and A, all containing a cyclo-depsipeptide Lagunamycin 358 is a novel 5-lipoxygenone inhibitor isolated from the culture broth of Streptomyces strain AA0310.l4 On reductive acetylation a triacetate 359 was obtained which also possessed the same inhibitor 0 &N2\N 0 0 357a R = CH(0H)Me 358 b R=COMe NATURAL PRODUCT REPORTS 1996-5.R. LEWIS 459 0 0 OK OK0 (-1 = sugar0 \ OMe Y OAc OAc 359 360 Dragmacidin 360 was originally isolated from a Pacific sponge belonging to the Hexadella family.It contains a bis- indolylpiperazine ring system which has now been syn-thesi~ed'l~~ 361 starting with 1,4-dimethylpiperazine-2,5-dione (Scheme 21). Bromination gave a labile dibromo derivative 362 which without isolation reacted with two moles of 6-bromoindole 363 giving bis-indolyl 2,5diketopiperazine 364. Removal of oxygen with borane gave the natural product 360. The diketopiperazine ring has been found in two alkaloids isolated from the culture fluid of the fungus Tolypocladiurn. Designated Sch54794 365a and Sch54796 365b they are classed as cis- and trans-isomers re~pective1y.l~~ 361 362 OY" "OH 353 355 0 354 356 Scheme 20 365a R'=H; R2=SMe 366a R=Br b R = CH2CH(Me)CHMe2 b R' = SMe; R2 = H c R =CH&H(Me)CH2Me Njl"' \N %OR 367a R=H b R=Ac The mandibular gland of the ant Dinoponera australis secretes eleven pyrazines as well as other Three of these pyrazines are tetra-alkylated and are namely 366a b c.Millaurine 367a and its acetate 367b have been isolated from the seeds of Millettia l~urentii.'~~ They both contain a new alkaloid skeleton which was fully characterized by X-ray crystal analysis. Hypodemapyrazine is a new alkaloid with the novel structure 368 obtained from the fern Hypodematium sinense. 149 Atherosclerosis inflammation Parkinson's disease and stroke amongst others are instigated by oxygen derived free radicals and as such are ameliorated or overcome by substances which exert free radical scavenging activities.A screen for these types of scavengers in microbes has located two benthocyanin B 369 and benthocyanin C 370 were found MqNuBr 360- Br a-fi"" A H 364 Reagents i NBS AIBN CCl,; ii DMF; iii BH, THF A Scheme 21 369 370 NATURAL PRODUCT REPORTS 1996 380. Removal of the protecting group on the isoquinoline enabled an intramolecular cyclisation to give the tetracyclic alcohol 381. Conversion to cyanide 382 and N-deprotection allowed N-methylation giving 383 which on further deprotection allowed the hydroxymethyl group to create the required carboxyl functionality 384. Hydrolysis gave the cynanide 385 which was known to convert to the natural product 372. The culture fluid of Streptomyces tauricus produces furan macrocycles with a dimethylamino appendage and generalized structure 386.Several individual furans have been isolated and 372 identified typically R = H Me Et; n = 2 3 or 4.153 371 These compounds individually and collectively are vasodilators. The sponge Neosiphonia superites contains four macrolides in the mycelium obtained from culturing Streptomyces pruni-three of which are new and all possess high cytotoxicity against CO~O~.~~~ A third scavenger benthophoenin 371 has also been various human carcinoma cells. Sphinxolide 387a is the known obtained on further examination from the same m~celia.'~' metabolite while the new ones are sphinxolide B 387b The secondary metabolite (-)-quinocarin 372 produced by sphinxolide C 387c and sphinxolide D 387d.'54 Streptomyces mehnovinaceus has notable antitumour a~tivity.,~ The total synthesis of (-)-papuamine 389 the antipode of It can be ring opened at C-7 to give a cyano-cogener which can the natural product has been achieved using an intramolecular revert to its parent by treatment with hydrochloric acid or silver Pd* catalysed coupling reaction whereby a diazadiene 388 is nitrate.A total synthesis of 372 has now been which ring ~1osed.l~~ involves three key steps (Scheme 22). The synthesis of ketone The macrocyclic piperazine alkaloid piperazinomycin 390 374 in four steps from 2-bromo-3-methoxytoluene 373 followed a minor metabolite of Streptomyces olivoreliculi subsp. by its condensation with pyrrolidine aldehyde 375 gave ketol neoenacticus contains a 14-membered para-and meta-376 which on Jones oxidation produced diketone 377 thus cyclophane diary1 ether structural subunit -which also occurs enabling a ring closure to isoquinoline 378 through its treatment in bouvardiang2 and other natural products such as RA-1-X with ammonia in THF.Reduction to piperidine 379 and OF4949-1 and K-13,25 all of which possess considerable modification of its threose side chain gave pyrrolidinoketone cytotoxic activity. A concise total synthesis of 390 has been rOMOM OMe ?Me vii __c b"' d:x -rzx Me ' Me + V %OBn CH20MOM CH~OMOM 373 374 .yR' =OH; R~= 375 H 378 377 R' + R2 = 0 viii " 1 rOMOM OMe foAc OMe I xvi ix-xv +-%iOC?OBn H CH20MOM CH2OMOM 383 381 R=OH 380 379 382 R=CN ,OH xxii -372 *Me R 384 R=CHzOH nic385 R = C02H Reagents BuLi Et,O -78 "C 4-O-benzyl-isopropylidene-~-threose,78 "C; ii Collins oxidation; iii H, Pd(OH), MeOH rt; iv MOMCI -Pr',EtN CH,Cl, rt; v LDA THF -78 "C TMEDA then 395 -78 "C; vi Jones oxidation; vii 14M NH, THF rt; viii NaBH,CN 01 M HCI MeOH 0 "C; ix TrocC1 py rt; x FeC1,-SiO, CHCl, rt; xi NaIO, MeOH H,O rt; xii NaBH, MeOH H, rt; xiii Ac,O DMAP py rt; xiv H, 10% Pd-C EtOAc rt; xv (COCI), Me,SO CH,Cl -78 "C Et,N; xvi Zn THF HOAc H,O rt; xvii TMSCN ZnCI, CH,CI, rt; xviii TFA CH,Cl, rt; xix Mel Pr',NH MeCN 38 "C; xx 1 M NaOH MeOH rt; xxi Jones oxidation; xxii AgNO, MeOH rt Scheme 2 2 NATURAL PRODUCT REPORTS.1996-5. R. LEWIS 46 I 386 R' Me0 I H 391 Ii OMe CHO cy-tQ+ 387a R' = OMe; R2 = H iii -H b R1=R2=H c R1 =OMe; R2= Me d R'=H; R2=Me N R' H,* N H H 392 R' = 0; R2 = Me 390 iiK393 R' = H; R2 = Me Reagents i NaH (4 eq) DMF 0 "C Ar 20 min CuBr-SMe (10 eq) 25 "C 1 h then 170 "C 48 h; ii BH, THF (15 eq) THF 25 "C Ar 1 h then 45-50 "C for 72 h; iii HBr (48 YO), HOAc 25 "C then reflux lh Scheme 23 pme OH AH achieved through an improved Ullmann macrocyclisation An rea~ti0n.l~~ earlier synthesis used a phenol oxidation 394a R' = p-OH; R2 = 0 395a R =a-OH b R'=a-OH; R2=0 b R=D-OH procedure for this ring closure but only a 19% yield could be c R' = P-OH; R2 = a-OH obtained.In this synthesis the iodophenol 391 was converted d R' = R2 = a-OH into diketopiperazinomycin 392 using first sodium hydride followed by CuBr-SMe in boiling DMF under moderately dilute reaction conditions; a 53 % yield of diphenyl ether being obtained.Reduction with diborane gave O-methylpiperazino- OR2 OR' 0 mycin 393 which could be demethylated to the natural product by hydrogen bromide in acetic acid (Scheme 23). YNH2 Fungal plant pathogens chemically infect their host plants with secondary metabolites. Drechsfera tritici-repentis which is also called Pyrenophoria triticipentis is such a plant pathogen and when cultured produced six related spirocyclic lactams called tritocone~.'~' X-Ray studies on the first two lactams triticone A 394a and tritcon B 394b established their structures. OHC(Me)N4 Their four cogeners are C 394c D 394 E 395a and F 39513.Aplyronine A 396a is a potent antitumour macrolide obtained 396a R' = COCH(NMe2)CH20Me;R2 = H from the sea hare Aplysia kurodai as are cogeners aplycomine b R' = H; R2 = COCH(NMe2)CH20Me c R' = R2= H B 39613 and aplyronine C 396~'~~ Two new pseurotins A and D have been isolated from the microorganism Aspergillus furnigat~s.'~~ These closely related Bi! OH Bz apomorphine antagonists 397 and 398 have been patented *rH hopefully for use in the treatment of psychiatric disorders. The Et OH same company has also patented pseurotins F1 and F2160 for 0 OH OMe 0 OH OMe having the same pharmacological properties. 397 398 Ecteinascidins are potent anticancer agents isolated from the Caribbean tunicate Ecteinascidia turbinata.161An X-ray analysis of the W2-formyl derivative of one of these metabolites Et-729 399a and the ',N-oxide has established their stereochemistry. A bisguanidine alkaloid produced by the sponge Stylotella agminata possesses cytoxic and immunosuppressive activity. Water soluble palan amine 400 was identified by spectral analysis. ?Me 399a R' = Me; R2 = CHO 400 b R' = H; R2= (0)Me Cryptospirolepine 401 is a unique spiro-nonacyclic alkaloid isolated from the powdered root of Cryptolepis sang~inolenta.'~~ Also present in minor amounts was cryptolepine 402;there is possibly a biogenetic relationship between these two alkaloids. Crambines are the polycyclic guanidine alkaloids produced by the sponge Ptilocaulis spic~lifer.'~~ Typical of this group is crambine A 403 which has been synthesised by a biomimetic procedure (Scheme 24) starting with the protected keto- ester 404 which underwent a Taber ester exchange with guanido alcohol 405 giving ester 406.Piperidine catalysed Knoevenagel condensation with dodecanal gave 407 which with 0-methylisourea 408 followed by aminolysis gave guanidine 409 deprotection and ring closure then giving carabine A 403. A synthesis of crambine B resulted in a structural revision to 412 for the natural product and the structure of crambine C1 413 is also revised.164 A complementary publication also revised the structure of these guanidine containing alkaloids and suggested a new trivial name crambescins to avoid confusion with a 25-year old protein called ~rarnbine.'~~ NATURAL PRODUCT REPORTS 1996 00 TBDMSO&OMe + HO(CH,)4N(Z)C(=NH)NHZ 404 li 405 406 L 1 ii NH TBDMSO 407 NH OMe ZHN/'*NH 409 R=TBDMS iv K 410 R=H 7 1' y2 C02(CH2)4NHCNHZ MH 411 Reagents i DMAP bz reflux 24 h; ii C,,H,,CHO piperidine rt N, 1 h; iii 408 DMF NaHCO, 55 "C 3 h; iv HF/H,O (1 l) MsCl,min; vi 5"C,10NH,OAc,ButOH,NH,,v,h; 1; MeCN rt Phloedictines are also guanidine alkaloids with cytotoxic activity which are found in a sponge of the Phloedictyon family.166 Seven of the nine so far isolated namely A1 to A7 possess the basic structure 414 with variation of the side chains length (n:m= 4:9).The remaining two C(1) and C(2) atoms Pd-C aq HCl (37'/0 1 drop) CHCI, 3 h * Et,N CH,CI, 0 "C 15 min; vii CHCI, Et,N reflux 24 h; viii H, Scheme 24 have an additional thio-ether functionality 415.hip OH NH2 C10H21 'QCloH21 Me CO2(CH2),,NH(C=NH)NH2 C02(CH2),NH(C=NH)NH2 412 413 401 414 402 403 415 NATURAL PRODUCT REPORTS 1996J. R. LEWIS 0 416 M 424 OMe 425 426 427 428 The biosynthesis of tetraponerine-8 416 the defense alkaloid excreted by the ant Tetraponera has been established by first developing a degradative procedure for the alkaloid. Sufficient quantities of alkaloid material were obtained by synthesis and as a result the pyrrolidine ring was found to be created from L-glutamic acid via L-ornithine and putresine. The 12 carbon side chain arises from six acetate A new synthesis of lavendamycin methyl ester 417 is reported to be practical and short with an overall yield of 33% from known starting materials.'68 In the preparation of one of the intermediates quinolinedione 421 an aza Diels-Alder reaction was effected with siloxy-activated 1-azadiene 419 and bromo- quinone 418 to give 420 in 66 YOyield.Its oxidation to aldehyde 421 enabled a Pictet-Spengler condensation with /3-methyl- tryptophan 422 to give 423 which on acid hydrolysis gave lavendamycin methyl ester 417 (Scheme 25). Hispidospermidine 424 is a novel phospholipase C inhibitor produced by Chactosphaeronema hispid~fum.'~~ Cultivation of a species of Streptomyces designated RK88-1409B (FERMP-11952) by an aerobic shake culture has produced an antibiotic (RK 1409B)425 which inhibits protein kinase C.As such it 425 may be useful as an anticancer and antiinflaminatory agent.170 An alkaloid isolated from the seeds of Daphniphyffum ~afycinum"~ is reported to have structure 426. Cfavefina cyfindrica is an ascidian not previously investigated for its metabolic constituents. A dichloromethane extract of freeze dried material has been found to contain two new alkaloids with the new pyrido-[2,1 -j]-quinoline ring Spectroscopic analysis which was supported by X-ray single 0 0 AcHN AcHN R 0 0 41 8 419 iiK420 R=Me 421 R=CHO h V RHN 422 423 R = AC IVC417 R=H Reagents i chlorobenzene reflux Ar 22 h; ii SeO, dioxane H,O Ar reflux 9 h; iii xylene Ar reflux 19 h; iv H,SO,-H,O (4:3) Ar 60 "C 4 h Scheme 25 429 crystal studies established structure 427 for cylindricine A and 428 for cylindricine B.A phenanthrene alkaloid has been obtained from the leaves of Annona m~ntana;'?~ named annoretine it possesses the novel tetrahydropyridophenanthrene structure 429. __c __c OMe t>Me 431 432 R=H 430 433 R=Br 434 R=CN 435 R=C@H vi 436 R=C02Me Reagents :i PhB(OH), Pd(PPh,), Na,CO, EtOH benzene reflux; ii Fe AcOH EtOH; iii Br,CHCOOH CHCl, 0°C; iv CuCN HMPA 140-150 "C N,; v KOH H,O EtOH reflux N,; vi CH,N, ether; vii NaNO, H,O HC1; viii NaN, ix xylene reflux Scheme 26 The synthesis (Scheme 26) of norsegoline 430 the pyridoacridine alkaloid produced by a marine tunicate of the Eudistoma group started with 4-chloroquinoline 431 which when cross coupled Suzuki fashion with phenylboronic acid gave the 4-phenyl product 432.Its bromination to 433 allowed introduction of the cyano group 434 which was followed by hydrolysis 435 and esterification 436. Diazotization and conversion into the azide enable a thermolysis in xylene to give norgseline 430.17 Hematopodine 437 is a pyrrolepyridine type alkaloid isolated from Mycena haematop~s."~ A cytotoxic pigment green-black in colour has been isolated from an undescribed species of a Histodermella Called makaluvamine C its structure 438 was determined by extensive HMQC and DEPT NMR measurements; it is probably derived biogenetically from typtamine and tyramine. Agelastatin A 439 was obtained from the Axinellid sponge Agelas dendromorpha found in the Coral Sea off New Caledonia.Its structure suggests that it may be derived from a hymenidin- like precursor 440 which has also been found in this sponge family.17' The ladybird beetle Chilocorus cacti contains a heptacyclic alkaloid which has been named chilocorine. Its structure 441 suggests that it is derived from azaphenylene and azaacenaphthylene moieties,178 both of which have been cited in another dimeric type alkaloid exochromine 442. A two-stem biomimetic synthesis of ascididemin 443 can also be applied to make its derivatives (Scheme 27).179Thus kynuramine 444 after protection to 445 and when mixed under oxidative conditions with quinolinequinone 446 afforded adduct 447 which with acid or base cyclised to dihydroascididemin 448; aerial oxidation occurred in situ to create natural product 443.Kynuramine 444 has also been used (as its trifluoroacetyl derivative 445) in a condensation with catechol under oxidation conditions to generate eilatin 449. This procedure is also regarded as being biomimetic.180 0gH 0 437 438 0 0 439 440 H H 441 442 Pantherinine 450 is a tetracyclic aromatic alkaloid obtained from the ascidian Aplidium paritherinum. This purple coloured metabolite showed mild cytotoxic properties against P388 murine leukaemia cells.1s1 The biosynthesis of sharmilamine B 451 a metabolite found in the tunicate seems to involve tryptophan dopamine and cysteine. Feeding experiments were carried out on both intact tunicates and on cell free extracts,162 the latter being more efficient in label uptake.NATURAL PRODUCT REPORTS 1996 NHCOCF3 I 444 R=H 446 447 445 R = COCF3 I 0 0 443 448 Scheme 27 Antitumour and antibiotic properties are associated with RK-1409 452 which is produced by culturing Streptomyces sp. RK-1409 aerobi~a1ly.l~~ Two new polycyclic aromatic alkaloids biemnadin 453 and 8,9-dihydro-11-hydroxy-ascididemin 454 have been isolated from a sponge of the Biemna family.164 X-Ray crystallographic measurements on the hydrochloride salt of biemnadin established its unique skeletal arrangement 453. Br 449 450 (-&JO H NHAc 451 452 453 454 4 References 1 S.J. Mantell P. S. Ford D. J. Watkin G. W. J. Fleet and D. Brown Tetrahedron 1993 49 3343. 2 A. H. Carroll B. F. Bowden and J. C. Coll Aust. J. Chem. 1993 46,1229. 3 J. R. Lewis Nat. Prod. Rep. 1992 9 81. 4 A. D. Rodriguez and I. C. Pina J. Nat. Prod, 1993 56 907. 5 I. Mancini G. Guella P. 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ISSN:0265-0568    

DOI:10.1039/NP9961300435

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Hot off the Press Robert A. Hill’ and Andrew R. Pitt2 ’Department of Chemistry Glasgow University Glasgow G 72 8QQ,UK. E-mail bobh@chem.gla.ac.uk Department of Pure and Applied Chemistry Strathclyde University Thomas Graham Building 295 Cathedral Street Glasgow G I 7x1 UK. E-mail a.r.pitt@strath.ac.uk Reviewing the recent literature on natural products and bioorganic chemistry The marine sponge Halichondria okadai contains the spiro- alkaloid halichlorine 1 (Y. Uemura and co-workers Tetra-hedron Lett. 1996 37 3867). The same group have isolated related spiroalkaloids pinnaic acid 2 and tauropinnaic acid 3 from the Okinawan bivalve Pinna muricata (Tetrahedron Lett. 1996 37 387 1). The spiroalkaloids are clearly biosynthetically related. Nakamurol A 4 from the Okinawan sponge Agelas nakamurai has a 19(4 -+ 5)-abeolabdane skeleton (N.Shoji et al. J. Nat. Prod. 1996 59 448). This diterpenoid skeleton is named thelepogane after the structurally-related diterpene alkaloid thelepogine. A forward-looking review of marine natural product research has been published (G. M. Konig and A. D. Wright Planta Med. 1996 62 193). H I OH 2R=OH 3 R = NHCH2CH2SOsH 1 4 W.-Y. Tsui and G. D. Brown have isolated an endoperoxide 5 together with a cyclopentenone 6 from Baeckea frutescens (Tetrahedron 1996 52 9735). The authors suggest that the cyclopentenone 6 arises from a ring contraction of the endoperoxide 5. Papyracillic acid 7 a metabolite of Lachnum papyraceurn is related to penicillic acid 8 (0.Sterner and co- workers Tetrahedron 1996 52 10249).Papyracillic acid 7 is presumably formed by ring cleavage of a quinone such as 9 by analogy to penicillic acid 8 biosynthesis. 0 Me0w 7 8 9 Agrocybenine 10 is a representative of a new class of alkaloids from the Korean mushroom Agrocybe cylindracea (H. Koshina et al. Tetrahedron Lett. 1996,37,4549). A bicylic triterpenoid preoleanatetraene 11 with a new carbon skeleton has been isolated from the fern Polypodiodes formosana (Y. Arai et al. Tetrahedron Lett. 1996,37,4381).The authors suggest that this compound may be a precursor to oleananes by an alternative pathway in ferns. Two C, terpenoids such as 12 with a new apiane skeleton have been isolated from Salvia apiana (J. G. Luis et al.Tetrahedron Lett. 1996 37 4213). The structure of 12 was confirmed by X-ray diffraction analysis. The apiane skeleton probably arises from a rearranged abietane coupled to a three carbon unit. Rearranged abietanes are common in Salvia species. Although garcinielliptin oxide 13 from Garcinia subelliptica has 30 carbons it is clearly not a triterpenoid contrary to the authors’ suggestion (C.-N. Lin et al. Chem. Commun. 1996 1315). Garcinielliptin oxide 13 is apparently a prenylated perhydroindane derivative. 10 11 /O 12 13 Schmidt and Wenbrenner have reported (Angew. Chem. Int. Ed. Engl. 1996 35 1336) that a revision is needed to the structure of konbamide from Theonella sp. They synthesised the proposed structure and an analogue which both differed 5 6 from the natural product.They were not able to identify the 111 problem although it may be that the natural konbamide is a different diastereomer. M. E. Bunnage and K. C. Nicolaou have reported a neat use of a low temperature retro Diels-Alder reaction to generate an enediyne nucleus (Angew. Chem. In?. Ed. Engl. 1996 35 11 10) (Scheme 1). ii. retro Diels-Aldc 25OC W Scheme 1 Labelling studies have indicated that the algal pheromone homosirene 14 is formed by degradation of eicosa-5,8,11,14,17- pentaenoic acid 15 by the diatom Gomphonema parvulum (G. Pohnert and W. Boland Tetrahedron 1996,52,10073) (Scheme 2). Nine novel lactonised oxylipin docosanoids the solande- lactones e.g. 16 have been isolated from Solanderia secunda and fully characterised (Y.Seo et al. Tetrahedron 1996 52 10583). They differ in their hydroxylation pattern and in that some contain a 43- or a 19,20-double bond. The paper also suggests a possible biogenetic pathway. COOH 15 OOH COOH I \m 10 \-+HWCOOH I 14 Scheme 2 16 R' R2 R3 = OH or H Studies on the biosynthesis of vitamins B 18 (thiamin) and B 19 (pyridoxol) have shown that the intact C5 chain of [2,3-13C,]- 1-deoxy-D-xyulose 17 is incorporated concurrently into the thiazole of vitamin B 18 and the pyridine of pyridoxol 19 respectively using an Escherichia coli mutant (I. D. Spencer and co-workers Chem. Commun. 1996 1 187). Labelling studies have established that indole 20 is a precursor of DIMBOA 21 the defensive metabolite of young maize and wheat plants (W.S. Chilton and co-workers Chem. Commun. 1996 1321). NATURAL PRODUCT REPORTS 1996 (OH OH 17 18 19 m-Meoa:xoH 0 H I OH 20 21 E. I. Graziani and R. J. Andersen have reported a technique for studying the biosynthesis of sesquiterpenoids in the dorid nudibranch Acanthodoris nanaimoensis using [1,2-13C,]acetate (J. Am. Chem. SOC.,1996 128,4701). This is the first successful use of stable isotope detection by NMR to study the biosynthesis of terpenoid skeletons by a marine invertebrate. Analysis of the results has revealed that an unusual arrangement occurs in the biosynthetic route to isoacanthodoral 22. YCHO p 22 Studies on the biosynthesis of coloradocin 23 using numerous feeding experiments has determined the source of all but four of the carbons (J.B. McAlpine et al. Tetrahedron 1996 52 10327). The upper portion is polyketide derived from a mixture of acetate and propionate units but the lower portion is non- polyketide coming from acetate and succinate (Scheme 3). The source of the remaining four carbon unit is unknown. A compact review of some chemical and biochemical aspects of the biosynthesis of ethene has been published (L. Stella et al. Bull. SOC.Chim. Fr. 1996 133 441). -from I3cacetate 0 7 from I3cpropionate from I3csuccinate HO/\ (less one carbon) \A 23 Scheme 3 NATURAL PRODUCT REPORTS 1996HOT OFF THE PRESS Determination of the TcmO gene sequence that is responsible for the O-methylation of tetracenomycin B3 to give tetra- cenomycin E in tetracenomycin biosynthesis (Scheme 4) has allowed the gene to be inserted into Streptomyces coelicolor together with the actinorhodin polyketide synthase which pro- duces a new product 24 O-methylated at the 3-hydroxy group (H.Fu et al. Biochemistry 1996,35,6527). The overexpression of the gene has also allowed Khosla’s group to study the sub- strate specification which has shown that the adjacent carboxyl is essential for recognition. Scheme 4 24 An ingenious method for the measurement of carbon isotope effects has been reported for formate dehydrogenase that should be applicable to many enzymes (H. Xue et al. J. Am. Chem. Soc. 1996 118 5804).Using a continuous-flow stirred- tank reactor a steady state concentration of reactants and products was set up using spectroscopic monitoring. Switching to a 13C labelled substrate causes a drop in rate and the increase in flow needed to restore the system to the previous state allows the relative kcat’sto be determined. An improvement in the activity of two lipases and subtilisin of over 300-fold has been reported in low water organic solvents as a result of crosslinking the crystalline form and drying using surfactants (M. Khalaf et a/. J. Am. Chem. SOC.,1996 118 5494). A model for pyruvate oxidase 25 containing the flavin and thiazole prosthetic groups arranged close to a well-defined cyclophane derived binding site has been constructed by P.Mattei and F. Diederich (Angew.Chem.,Int. Ed. Engl. 1996,35 1341). The catalyst converts 2-naphthaldehyde to methyl 2- naphthoate in MeOH-Et,N with high efficiency and complete chemoselectivity. O-Alkyl hydroxamates can be used as analogues of enzyme-bound enolate equivalents in hydroxy acid dehydrogenases (M. C. Pirrung et a!. J. Org. Chem. 1996 61 4527). The best of these 26 inhibits the Escherichia coZi isocitrate dehydrogenase with a Kiof 30n~ and is uncom- petitive with respect to isocitrate. A useful review of inhibitors of the carbohydrate processing enzymes based on sugar shaped heterocycles has been published by B. Ganem (Ace. Chem. Res. 1996 29 1340). It covers a broad range from the classic inhibitors from aza-sugars to the amidines and beyond.N KN,C4H9 C4H9\,5A0 I 25 H -0 -6.. . .Mg2+ 26 JoAnne Stubbe’s group have shown that the nucleotide lphosphate analogue (E)-2’-fluoromethylene-2’-deoxycytidine-5’-diphosphate 27 is a mechanism based inhibitor of ribo- nucleotide reductase (W. A. van der Donk et al. Biochemistry 1996,35,8381). Their studies have indicated that 27 is able both to quench the tyrosyl radical of one of the homodimeric subunits R2 and to irreversibly inactivate the enzyme by alkylating the other homodimeric subunit R1 by forming the enone product. They suggested that this is the mode of action for the cytotoxic activity of the compounds. Steven Benner’s group have synthesised a non-ionic form of DNA 28 with a dhnethylenesulfone bridge in place of the phosphate (C.Reichert et al. J. Am. Chem. Soc. 1996 118 4518). Using a thiol as a nucleophile and then oxidising to the sulfone they were able to construct an octamer and study its properties which suggest that the role of the phosphate charge is far more complex than previously thought. The preparation of a parallel stranded DNA triple helix with a polyether tethered minor groove binding Hoechst 33258 analogue has been reported (J. Robles et al. J. Am. Chem. SOC.,1996,118 5820). The results show the stabilisation of the complex by both major and minor groove interactions. HO KH k0S 27 28 D. Seebach et al. have made another important contribution to the field of /?-peptides (Helv. Chim.Acta 1996 79 913). Using Arndt-Eistert homologation of a-amino acids and concomitant peptide coupling they have made a number of short /?-peptides and studied their properties by NMR CD and X-ray crystallography. They adopt a /&sheet co&gura@on in the solid state and a compact 3 left-handed helix of 5 A pitch in solution. Surprisingly these secondary structures appeared to be more stable than the a-amino acid equivalents. They are not substrates for pepsin. Seebach continues to muse on the possibility of a parallel @-amino acid world.

ISSN:0265-0568    

DOI:10.1039/NP996130iiie

出版商:RSC    

年代:1996

数据来源: RSC