摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Nottingham Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis and chemistry of the major groups of natural products-alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. Many reviews provide details of biological activity and wider aspects of bioorganic chemistry including developments in enzymology genetics and structural spectroscopic and chromatographic methods of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1993 Annual Subscription Price E.C. f242.00 Overseas f266.00 U.S.A. $532.00 Canada f279.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Second-Class postage paid at Jamaica NY 11431-9998. Afl other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1993 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1993 E.C. f242.00 Overseas f266.00 U.S.A. US $532.00 Subscription rates for back issues are (1988) (1989) (1 990) (1991) (1 992) U.K. €1 59.00 f169.00 f177.00 f198.00 f222.00 Overseas f 183.00 f194.00 f204.00 f228.00 f250.00 U.S.A. US $342.00 US $388.00 US $398.00 US $467.00 US$474.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99310FX017

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

N P R 10 Cumulative Contents of Volume 10 Number 1 1 Lignans Neolignans and Related Compounds (January 1989 and December 1991) R. S. Ward 29 Muscarine Oxazole Jmidazole Thiazole and Peptide Alkaloids and Other Miscellaneous Alkaloids (July 1990 and June 1991) J. R. Lewis 51 Indolizidine and Quinolizidine Alkaloids (July 1990 and June 1991) J. P. Michael 7 1 Microbial Pyran-2-ones and Dihydropyran-2-ones (up to December 1991) J. M. Dickinson Number 2 99 Quinoline Quinazoline and Acridone Alkaloids (July 1990 and June 1991) J. P. Michael 109 The Chemistry of Azadirachtin S. V. Ley A. A. Denholm and A. Wood 159 Diterpenoids (1991) J. R. Hanson 175 Chemical and Biochemical Manipulations of Nucleic Acids M. J. McPherson and J. H. Parish 199 Tropane Alkaloids (January and December 1991) G.Fodor and R. Dharanipragada Number 3 207 NMR of Proteins M. P. Williamson 233 The Biosynthesis of Shikimate Metabolites (1991) P. M. Dewick 265 Biological Variation of Microbial Metabolites by Precursor-directed Biosynthesis R. Thiericke and J. Rohr 291 Amaryllidaceae and Sceletium Alkaloids (1991) J. R. Lewis 301 Stevioside and Related Sweet Diterpenoid Glycosides (up to May 1992) J. R. Hanson and B. H. De Oliveira Number 4 311 Obituary David N. Kirk 1929-1992 313 Steroid Reactions and Partial Synthesis (1991) J. R. Hanson 327 Advances in Chemical Ecology (January 1988 and June 1992) J. B. Harborne 349 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites (July 1991 and June 1992) J. E. Saxton 397 Natural Sesquiterpenoids (1991) B.M. Fraga 421 Arsenic Compounds from Marine Organisms (up co October 1992) J. S. Edmonds K. A. Francesconi and R. V. Stick Articles that will appear in forthcoming issues include Pigments of Fungi (Macromycetes) (July 1986 and August 1992) M. Gill HMG-CoA Reductase Inhibitors A. Endo and K. Hasumi The Strobilurins Oudemansins and Myxothiazols Fungicidal Derivatives of /3-Methoxyacrylic Acid J. M. Clough A Survey of Natural Products which Abstract Hydrogen Atoms from Nucleic Acids J. A. Murphy and J. Griffiths The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites (1991) R. B. Herbert The Biosynthesis of Fatty Acid and Polyketide Metabolites (mid 1991 to mid 1992) D. O’Hagan Plant Polyphenols E. Haslam Recent Advances in the use of Enzyme-catalysed Reactions in Organic Synthesis (July 1988 to December 1992) N. J. Turner Triterpenoids (January 1988 and December 1989) J. D. Connolly R. A. Hill and B. T. Ngadju Indolizidine and Quinolizidine Alkaloids (July 1991 and June 1992) J. P. Michael Novel Constituents of Uvaria Species (1968 and February 1993) V. S. Parmar et al. Quinoline Quinazoline and Acridone Alkaloids (July 1991 and June 1992) J. P. Michael The Biosynthesis of Shikimate Metabolites (1992) P. M. Dewick The Fluorinated Natural Products D. B. Harper and D. O’Hagan Deoxynojirimycin Synthesis and Biological Activity (up to December 1992) A. B. Hughes and A. J. Rudge Isoprenoid-substituted Phenolic Compounds of Moraceous Plants T. Nomura and Y. Hano

ISSN:0265-0568    

DOI:10.1039/NP99310FP019

出版商:RSC    

年代:1993

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99310BP021

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Macrocycl ic Trichothecenes J. F. Grove 3 Homestead Court Welwyn Garden City Herts. AL7 4LY -~~ Reviewing the literature to December 1991 1 Introduction and Nomenclature 2 Historical Background 3 Naturally Occurring Compounds 3.1 Verrucarins 3.2 Roridins 3.3 Baccharinoids 4 Biosynthesis 4.1 Biosynthesis in Fungi 4.2 Biosynthesis in Baccharis sp. 5 Unnatural Macrocyclic Trichothecenes 6 Chemistry 6.1 Ethylenic Double Bonds 6.1.1 Isomerization 6.1.2 Catalytic Reduction 6.1.3 Electrophilic Addition Reactions (i> Epoxidation (ii) Hydration and Hypobromination 6.1.4 Reactions at the a-Carbon Atom 6.2 Hydroxyl Groups 6.2.1 Regioselective Esterification 6.2.2 Regioselective Oxidation 6.2.3 Deoxygenation 6.2.4 Selective Nucleophilic Substitution 6.3 Keto Groups 6.3.1 Stereospecific Reduction 6.3.2 Reactions at the &-Carbon Atom 6.4 Epoxide Functions 6.4.1 Acid-catalysed Rearrangements 0) 12,13-Epoxide (a) The Trichothecene -,10,13-Cyclotrichothecane Rearrangement (b) The Trichothecene -+ Apotrichothecene Rearrangement (ii) 6’,7’-Epoxide (iii) 7’,8’-Epoxide 6.4.2 Base-catalysed Rearrangements (0 12,13-Epoxide (ii) 2’,3’-Epoxide 7 Spectroscopy 7.1 Ultraviolet Spectra 7.2 Nuclear Magnetic Resonance Spectra 7.2.1 lH Spectra 7.2.2 13C Spectra 7.3 Mass Spectra 8 References 1 Introduction and Nomenclature The macrocyclic trichothecene mycotoxins are esters of sesquiterpene alcohols derived from a common tricyclic skeleton trichothecane (I) numbered as shown.’ The ester groups involved in forming the macrolide ring are attached at positions 4/3 and 15 of the trichothecene verrucarol (2) or a substituted verrucarol giving the tetracyclic skeletons (3) or (4) which contain an 18-atom macrolide.With three exceptions verrucarin K (1 2,13-deoxyverrucarin A) (5) which has a 12- ene,’ and miophytocen A (6) and B (7) which are 10,13-cyclo- c~mpounds,~ all the macrocyclic trichothecenes* have a 12,13- epoxide group. * Sometimes herein called ‘macrocycles ’. 429 (3) 172 Trichothecenes have been isolated from natural sources of which 67 are macrocycles.Whilst the non-macrocyclic trichothecenest~~ are without exception metabolic products of fungi particularly Fusarium and Trichothecium sp. 28 macro- cyclic trichothecenes (42 %) the baccharinoids have been isolated only from plants of the genus Baccharis. The remaining macrocycles are fungal products from Myrothecium and Stachybotrys sp. and one species each of Cylindrocarpon Verticinimonosporium and Phomopsis. Among this group verrucarins A and J and roridins A D and E have also been obtained from Baccharis sp. The fungal macrocycles are classified as roridins [skeleton (3)] mainly C, compounds or verrucarins [skeleton (4)] mainly C, compounds. For convenience the baccharinoids are treated separately but of the 28 members of this class only baccharinoid B25 has the verrucarin skeleton the remaining baccharinoids have the roridin skeleton.Both systems (4A) and (4B) have been used to number the verrucarin skeleton. Although Chemical Abstracts uses the system (4C) this review uses the numbering system (4) which is directly comparable with the numbering (3) of the roridin skeleton. The skeleton (8) of the myrotoxins can formally be constructed from the verrucarin skeleton (4) by the formation of a C6’-C12’ bond (see Section 3) and this group of macrocycles is classified with the verrucarins. Likewise the skeletons of the satratoxins (9) (lo) roritoxins (1 1)-(13) mytoxins (14) (15) and vertisporin (16) which also contain a tetrahydropyranyl ring can be obtained from the roridin skeleton (3) by C6’-C12’ bond f~rmation,~ and these groups of compounds are classified with the roridins.Initially,6 the names verrucarin and roridin followed by a capital letter were assigned respectively to any metabolic t Sometimes herein called ‘simple trichothecenes’. '0 CC.c'O 5' II Me 0 12' (5A) (9) product of M. verrucaria and M. roridum. Later on the names came to have the implications outlined above. By convention the 9(10)-ene is implied in the name trichothecene. Valency bonds to atoms above (p) and below (a) the plane of a ring are indicated by wedges and broken lines respectively and for the macrolide ring this applies to the conformation illustrated by structure (3).Planar representation of the conformation of the macrolide ring is far from easy and molecules containing a 2',3'-ene have frequently been repre- sented by structure (3). However in examples where the structure has been investigated by X-ray diffraction the 2'- eneoate chromophore is in the syn-periplanar orientation with the C3'-C12' bond and l'C=O eclipsed and approximately at right angles to the plane of the 7'-dieneoate chromophore (C7'-C11'). This arrangement of atoms is more correctly represented by (3A) than by the anti-periplanar rotamer (3) which is nevertheless used in this review. When the 2',3'-ene is reduced as in structure (5),the C2'-C6' portion of the ring is flexible and can adopt several conform- ations.Other conformations (e.g.5A) can be drawn in addition to (5) and can produce different apparent configurations of substituents at C2'-C4'. The conformation (5) is a convention adopted in this review because it brings out certain relationships NATURAL PRODUCT REPORTS 1993 5' II 0 I Me-C-OH A H (6) 0 between 2',3'-enes (3) and their reduction products it is not necessarily the conformation present when the molecule is in the crystalline state. Indeed where this is known (see Section 3.3) the conformation of these reduced macrocycles is sometimes close to (5A) with the 12'-methyl group p. Likewise in this review C14' is placed as in structure (3) where it is in position to form a bond (through oxygen) to C12' even though the rotamer (3B) is usually that found in the crystal.To avoid any possible confusion the absolute configuration of each asymmetric centre of the macrolide is given in Tables 4-6 in Section 3. It must be remembered however that the macrocyclic trichothecenes along with many other groups of natural products suffer from the well-known disadvantage of the Cahn-Ingold-Prelog system (sequence rule) which does not necessarily reveal correlation of configuration in a group of analogues particularly when atoms adjacent to the asymmetric centre under consideration are substituted by oxygen. 2 Historical Background The antifungal antibiotic glutino~in,~.~ isolated in 1946 at the Butterwick (later Akers) Laboratories of Imperial Chemical Industries Ltd.from a fungus wrongly identified as NATURAL PRODUCT REPORTS 1993-5. F. GROVE e COMe OH (16) Metarrhizium glutinosum but laterg recognized as Myrothecium verrucaria was the first material consisting of macrocyclic trichothecenes to be described in the literature it was subsequently shownlo to be a mixture of verrucarins A and B. In 1962 the isolation in pure form from Myrotheciurn cultures of verrucarins A and B and roridin A at the Sandoz laboratories6 resulted from the operation of a screen for cytostatic compounds and heralded the start of a 30-year investigation by Tamm and his collaborators into the isolation structure synthesis and biosynthesis of the macrocyclic trichothecenes. This investigation laid the foundations of our knowledge of this group of compounds.At about the same time many strains of Myrothecium sp. were examined by several groups of workers and a number of metabolic products shown subsequently to consist of macro- cyclic trichothecenes were obtained. Of these myrothecin,". l2 like glutinosin was a mixture of verrucarins A and B; a myrothecin co-metabolite m.p. 204-205 "C and antibiotic X37913 were identical with roridin A; and muconomycin A14 and antibiotic Y37913 consisted essentially of verrucarin A. l5 The soil fungus Dendrodochium toxicum16 is now considered" to be Myrothecium verrucaria and its metabolic products the dendrodochin(e)s include verrucarin A18 and roridin A.19 Necroticin described in 1965,20 is also likely to have been a mixture of macrocycles.The search for the toxin responsible for equine Stachybotryo- toxicosis,21 a problem first noticed in the Ukraine in 1931 but now recognized to be of general occurrence when fodder is infected with Stachybotrys sp. ended in 1973 with the isolation of the satratoxins from cultures of this genus.22 The satratoxins were shown5 to contain a tetrahydropyranyl ring as part of the macrolide but this feature was first demonstrated in the antibiotic vertisp~rin.~~. 24 The next important development occurred in 1976 with the of a macrocyclic trichothecene baccharin (bac-charinoid B5) from the Brazilian shrub B. megapotamica which had been included in a screen for potential tumour 43 1 inhibitors. Baccharin was the forerunner of a large group of roridin-related compounds to be isolated from this plant.Similar compounds including roridins A and E were sub- sequently found in the related species B. coridifolia.26 Initially there was much circumstantial evidence that the baccharinoids were products of a plant-fungus interaction in which fungal macrocyclic trichothecenes were taken up by the plant and modified further. More recently however the baccharinoids have been shown to be authentic plant products (see Section 4). The exceptional activity shown by some baccharinoids against P388 leukemia in mice stimulated a major on-going investigation by Jarvis and his collaborators into the structure chemistry and biosynthesis of these macrocycles and related roridins.3 Naturally Occurring Compounds The naturally occurring macrocyclic trichothecenes classified as fungal verrucarins and roridins and baccharinoids are listed in Tables 1-3 together with their sources synonyms and structures. The configuration at each substituted position of the macrocycle is not always readily discernible by inspection of planar structural formulae and is therefore set out in Tables 4-6. These Tables are based on the common skeleton (1 7) and give an overview of each class the macrocycles are listed in the same order as they are listed in Tables 1-3. In drawing up Tables 1-3 S. atra S. alternans and S. chartarum are taken to be S. atra is used but only because of the association with the name satratoxin. Within each class and group of macrocycles it is frequently possible to discern sub-groups in which the (E)-2'-ene of structure (17) is formally either intact hydrogenated a-epoxidized or hydrated.The sub-groups arise from and represent a series of steps in the biosynthetic transformation of a mevalonate-derived six-carbon unit. There are only two compounds PD113225 and roridin J where the 2'-ene is known to have the alternative relative configuration. However X-ray crystallographic determinations28*29 of the structures of the myrotoxins reveal that the tetrahydropyran ring has the configuration and conformation shown in (8). This configur- ation implies formation (Scheme 1)28 from a precursor in which C 1' and C12' are trans related [(Z)-2'-ene if the precursor has an ethylenic double bond at this position as in structure (18)].According to the rules of chemical nomenclature the formation of a C6'-C12' bond in structure (19) changes a 2'- ene from 2 in the putative precursor (18) to E in the product (19). 3.1 Verrucarins (Tables 1 and 4) Including the 4 myrotoxins which have the tetrahydropyran ring as part of the macrolide there are 12 compounds with the verrucarin skeleton. The myrotoxins do not possess the cis trans-muconic ester group of the verrucarins but instead have a 6',7'-ene and are macrodiolides. The verrucarins are macrotriolides. In the verrucarin series none of the missing members verrucarins C-I is a trichothecene. Verrucarin 130 is said to be an analogue of verrucarin E which is a pyrrole:31 verrucarins F and G also contain Verrucarin H33 was reclassified as a roridin (Table 2).Verrucarins C and D were incompletely characterized. In the four examples where the verrucarol nucleus is substituted further this has occurred at the 8a position a common oxygen substitution in the simple trich~thecenes.~ In the macrolide ring the 2',3'-epoxide present in the myrotoxins and in verrucarin B has the a-configuration as is the case in the roridins (Table 5) and baccharinoids (Table 6). Dehydro- verrucarin A is the only macrocycle to contain a keto group at C2'. In compounds where the 2'-ene is hydrated (verrucarins A and K) and in dehydroverrucarin A the configuration at C3' is R. NATURAL PRODUCT REPORTS. 1993 Table 1 Sources of Verrucarins and Myrotoxins Trivial Name Formula (Synonym) Structure Source? Ref.C2,H3,0 Verrucarin J (20; R = H) M. roridum verrucaria 66 33 (Muconomycin B ref. 68. S. atra kampalensis 67 69 Satratoxin C ref. 5) S. albipes microspora 69 70 B. coridifolia 71 2'-Dehydroverrucarin A (21 ; R'R2=0) M. roridum 39 Myrotoxin A (8; R' = R2 = H R3 = OH) M. roridum 72 Myrotoxin C (8; R1 = R3 = H R2 = OH) M. roridum 28 PD113325" (22) M. roridum 66 Verrucarin B (23) M. roridum verrucaria 6 6 Verrucarin L (20; R = OH) M. verrucaria 42 Verrucarin Kb (5) M. verrucaria 2 Verrucarin A (21 ; R' = H R2 = OH) M. roridum verrucaria 6 6 (Antibiotic Y379 ref. 13 M. leucotrichum 73 Muconomycin A ref. 14) B. coridifolia 71 Acetylverrucarin L (20; R = OAC) M.verrucaria 42 Myrotoxin B (8; R1 = OAC R2 = H R3 = OH) M. roridum 72 Myrotoxin D (8; R' = OAC R2 =OH R3 = H) M. roridum 28 f M = Myrothecium; S = Stachybotrys; B = Baccharis. * Originally," incorrectly named 12'-hydroxyverrucarin J. bAnearliers4 bearer of this name was renamed Roridin E." Table 2 Sources of Roridins and Relatives Trivial Name Formula (Synonym) Structure Source? Ref. C29H3201 1 Roritoxin D (12; R1R2=0) M. roridum 74 C29H32012 Roritoxin C (13) M. roridum 74 C29H3409 7/3,8P-Epoxyroridin H (27; R'R2=0) Cylindrocarpon sp. 54 C29H34010 Diepoxyroridin H (28) Cylindrocarpon sp. 54 C29H34010 Roritoxin A (11) M. roridum 74 C29H34010 Satratoxin F (10; R = COMe) S. atra kampalensis 75 69 C29H34011 Roritoxin B (12; R'R2 = H OH) M.roridum 74 C29H3608 Roridin Ha (27; R' = R2 = H) M. verrucaria 33 Cylindrocarpon sp. 54 C29H3609 7/3,8P-Epoxyisororidin E (29; R'R2=0) Cylindrocarpon sp. 54 C29H3609 Mytoxin B (14) M. roridum 28 C29H3609 Roridin J (30) M. verrucaria 56 C29H3609 Satratoxin H (9; R' = H R2 = OH) S. atra kampalensis 5 69 S. microspora 70 C29H3609 PD 113326 (9; R' = H R2= OH) M. roridum 66 (isosatratoxin H ref. 76) C29H3609 Satratoxin H (9; R' = OH R2 = H) S. atra 67 diastereoisomer 2 9 36 9 Satratoxin H (9; R' = OH R2 = H) S. atra 57 diastereoisomer C29H36010 Mytoxin A (15; R' = H R2= OH) M. roridum 28 C29H36010 Mytoxin C (15; R' = OH R2 = H) M. roridum 28 C29H36010 Satratoxin G (10; R = CH(OH).Me) S. atra kampalensis 75 69 C29H36010 Vertisporin (16) V.diflractum 23 C29H3808 Roridin E (26; R = H) M. roridum verrucaria 77 33 (Satratoxin D ref. 22) S. atra kampalensis 67 69 S. microspora 70 B. coridifolia 26 B. megapotamica 78 C29H3808 Roridin E-2 M. verrucaria 79 C29H3808 isoRoridin E (29; R' = R2= H) M. verrucaria 80 Cylindrocarpon sp. 54 '2gH38'9 8/3-Hydroxyroridin E (26; R = OH) Myrothecium sp. 81 C29H3809 Roridin D (25) M. roridum 33 B. coridifolia 3 B. megapotamica 78 C29H4009 Roridin A (24; R = /3-H) M. roridum verrucaria 6 6 (Antibiotic X379 Ref. 13) B. coridifolia 26 B. megapotamica 82 P. leptostromiformis 83 C29H40O9 isoRoridin A (24; R = n-H) M. verrucaria 50 C31H40010 Acetylroridin K (31) M. verrucaria 80 t M = Myrothecium; S = Stachybotrys; B = Baccharis; V = Verticinimonosporium;P = Phomopsis.Previously Verrucarin H.33 NATURAL PRODUCT REPORTS 1993-5. F. GROVE 43 3 H27 oec.o Osc'fiH 'CH H e HHC;'CH 0.1 ,CH ? Me0 'OH Me0 'OH 0 H H H (23) (25) (27) Table 3 Sources of Baccharinoids Trivial Name Formula (Synonym) Structure Sourcef-Ref. C, H3,0 Baccharinoid 825 (33)" B. megapotamica 60 C,,H36010 Baccharinoid B27 (34) B. megapotamica 60 C,,H,,O Miophytocen A (6) B. coridifolia 3 C,,H3,08 Miophytocen B (7) B. coridifolia 3 C,,H,,O Miotoxin A (35) B. coridifolia 62 C,,H3,0 Miotoxin B (36; R' = R2 = R3 = R6 = H R4R5=0) B. corid$olia 64 C29H38010 Baccharinoid B9 (37; R =PH) B. megapotamica 60 C,,H3,01 Baccharinoid B10 (37; R = aH) B. megapotamica 60 C,,H,,O, Baccharinoid B12 (38; R' = PH R2 = R3 = H R4 = OH) B.megapotamica 60 C,,H,,O, Baccharinoid B13 (39; R' = PH R2 = H R3 = OH) B. megapotamica 60 C,,H,,O, Baccharinoid B14 (39; R1= aH,R2 = H R3 = OH) B. megapotamica 60 C,,H3,0, Baccharinoid B 16 (39; R' = aH R2 = OH R3 = H) B. megapotamica 60 C29H3,0, Baccharinoid B 17 (40; R1 = PH R2 = H) B. megapotamica 60 C,,H,,O, Baccharinoid B21 (38; R' = PH R2 = R4 = H R3 = OH) B. megapotamica 60 C2,H3,011 Baccharinoid B4 (38; R1 = aH R2= R3 = OH R4 = H) B. megapotamica 63 (Baccharinol) C,,H,,O, Baccharinoid B5 (40; R1 = PH R2 = OH) B. megapotamica 25 (Baccharin) B. coridifolia (?) 86 C,,H,,O, Baccharinoid B6 (38; R' = PH R2 = R3 = OH R4 = H) B. megapotamica 63 (isoBaccharino1) C,,H3,011 Baccharinoid B8 (40; R' = aH R2 = OH) B.megapotamica 63 (isoBaccharin) C29H4009 Miotoxin D (36; R1= R3 = PH R2 = R5 = R6 = H R4 = OH) B. coridifolia 87 C,,H,,O isoMiotoxin D (36; R' = R3 = PH R2 = R5 = R6 = H R4 = OH) B. coridifolia 87 C,,H4,01 Baccharinoid B1 (41; R' = PH R2 = R4 = OH R3 = H) B. megapotamica 61 C29H40010 Baccharinoid B2 (41;R1=aH,R2=R4=OH,R3=H) B. megapotamica 61 C,,H,,Ol Baccharinoid B3 (41 ; R1 = aH R2 = H R3 = R4 = OH) B. megapotamica 61 (Baccharisol) B. coridifolia 71 C2,H4,010 Baccharinoid B7 B. megapotamica 61 (isoBacchariso1) B. coridifolia 71 C,,H4001 Baccharinoid B20 (42) B. megapotamica 60 C29H40010 Baccharinoid B 23 (43; R = PH) B. megapotamica 60 C,,H,,O, Baccharinoid B 24 (43; R = aH) B. megapotamica 60 C3,H,,O1 Miotoxin C (36; R' = R3 = PH R2= Ac R4R5= H OH R6= OH) B.coridifolia 64 "No evidence is presented6' for an (E)-2'-ene. The chemical shift for C-12' is consistent with the (Z)configuration (see section 7.2.2). t B. = Baccharis NATURAL PRODUCT REPORTS 1993 R' I Me'c 'OH H (29) Me'T'OH H (32) (33) ....OQ H w H29 H29 I II I Me' '0 R2 MeOtxOH R' R (37) ...Of H2C\ O\ O,c'O 0""CH I I Me'? 'OH Me'Y'OH R' R' (40) (41) and B35were elucidated The structures of verrucarin A34.15 by chemical degradation and confirmed by X-ray crystal- l~graphy,~~,~',~~ which also established the absolute configur- ation. Verrucarin A was converted to 2'-dehydroverrucarin A by o~idation.~~ Chemical degradation was used to establish the structure of verrucarin K2and the gross structure of verrucarin J.40 The configuration of the 2'-ene in verrucarin J was subsequently changed from Z to E on spectroscopic evidence.41 The structure of verrucarin L was assigned42 by spectroscopic comparison with the revised structure for verrucarin J.The 0 O,c'O fiHoQc H Y HHfi'CH HO 0.1 ,CH7 MeOc'OH Me' 'OH H H (34) (35) I Me' 7'OH MeO$'OH R' R' (38) (39) U Me' ?'OH R (41A) (42) (43) structures of the mvrotoxins were obtained by X-ray crys- tall~graphy.~~,~~,~~ Verrucarins A,44+45 and J47.48 have been synthesized. B,46 3.2 Roridins (Tables 2 and 5) There are 27 fungal macrocycles based on the roridin skeleton of which 14 the satratoxins roritoxins mytoxins and vertisporin have the tetrahydropyran ring as part of the macrodiolide.In vertisporin and the mytoxins the 7',8'-ene of NATURAL PRODUCT REPORTS 1993-J. F. GROVE 435 Table 4 Substitution and Configuration in the Verrucarins and Myrotoxins [(17) (C13’ and C14’ absent)] Trivial Name 8 12 2‘ 3‘ 6’ 7‘ 8’ 12‘ Verrucarin J =O 2’-Dehydroverrucarin A =O R-PH =O Myrotoxin A S-a-0 R-a-0 -12’ 6’,7’-ene H S-a-OH -6 Myrotoxin C S-a-0 R-a-0 -12‘ 6’,7’-ene H R-p-OH -6’ PD 113325 a a =O OH Verrucarin B S-a-0 R-a-0 =O Verrucarin L a-OH =O Verrucarin K =CH S-a-OH R-P-H =O Verrucarin A S-a-OH R-p-H =O Acetylverrucarin L a-OAc =O Myrotoxin B u-OAC s-a-0 R-a-0 -12‘ 6‘,7’-ene H S-a-OH -6’ Myrotoxin D CX-OAC S-a-0 R-a-0 -12‘ 6’,7’-ene H R-P-OH -6’ “The 2’-ene has the same relative geometry as 2’-(Z)-verrucarin J but substitution by OH at C12’ changes the designation from Z to E.Table 5 Substitution and Configuration in the Roridins and Relatives (17) Trivial Name 7 8 9 10 2’ 3‘ 4’ 5’ 6’ 7’ 8’ 12‘ 13‘ 14‘ Roritoxin D S-a-0 R-a-0 S R-a-0-14’ ? OH =O 0-12’ Roritoxin C p-0 p-0 S-a-0 R-a-0 S R-a-0-14’ ? OH =O 0-12’ 7p,8/3-Epoxyroridin H p-0 p-0 ?? ? Diepoxyroridin H p-0 p-0 S-a-0 R-a-0 ?? ? Roritoxin A S R-a-0-14’ ? OH ? OH 0-12’ Satratoxin F S-a-0 R-a-0 S R-a-OH =O Roritoxin B S-OC-0 R-a-0 S R-a-0-14’ ? OH ? OH 0-12’ Roridin H ? ?” ?“ 7P,8/?-Epoxyisororidin E p-0 p-0 S S-OH Mytoxin B S H H R-a-OH =O Roridin J z z ?OH ? ? ? Satratoxin H R R-a-OH Sb-OH PD113326 R R-a-OH Re-OH Satratoxin H R S-/3-OH ?d OH diastereoisomers Mytoxin A S-a-0 R-a-0 S H H R-a-OH =O Mytoxin C S-a-0 R-a-0 S H H S-/3-OH =O Satratoxin G S-a-0 R-a-0 R R-a-OH ? OH Vertisporin S H H R-a-0-14‘ R-p-OH R-a-OH 0-12’ Roridin E R-OH Roridin E2 ?“ ?“ ? OH isoRoridin E S-OH 8p-Hydroxyroridin E /3-OH R-OH Roridin D S-u-0 R-a-0 R-OH Roridin A S-a-OH R-p-H R-OH isoRoridin A S-a-OH R-/3-H S-OH Acetylroridin K a-OAc ? OH “H-6’and H-13’ are cis related.53 bSee Section 7.2.2.13’-epimer of satratoxin H.” Likely to be epimeric at C-13’. Rep~rted‘~ to be Z at a time when the 2‘-ene in roridin E was believed to be Z. ? Configuration not known. a tetrahydrofuran ring fused to the macrolide tetrahydropyran. An ether linkage between C13’ and C5’ of the roridin skeleton gives a cyclic acetal system in roridin H and its derivatives and in roridin J.Of the missing members of the series roridin B was identified as and roridin C is identical with the simple trichothecene trichodermol.* Roridin L2 (32 biosynthetic numbering) though closely related to roridin E is also a simple tri~hothecene.~’ Roridin K is known in nature only as the 801-acetyl derivative. The names roridin F G,and I have not been assigned. The conformation of the tetrahydropyran ring and the configuration of the substituents in vertisporin and in the satratoxins was determined by NMR analysis augmented by NOE measurements. The conclusions agree with the results of skeleton (1 7) is reduced mytoxin A is 7’,8’-dihydrosatratoxin X-ray diffraction studies on the myrotoxins.F. In vertisporin and the roritoxins the two-carbon side chain All roridins with the tetrahydropyranyl ring in the macrolide at position 6’ of the roridin skeleton becomes as a result of the have the same relative configuration at C6’ but following formation of an ether linkage between C14’ and C12’ part of application of the sequence rule this may be designated either NATURAL PRODUCT REPORTS 1993 Table 6 Substitution and Configuration in the Baccharinoids (1 7) Trivial Name 3 8 9 10 16 2' 3' 4' 6' 13' Baccharinoid B25 P-OH ? OH =O Baccharinoid B27 =O ? OH R S-OH Miophytocen A Miophytocen B Miotoxin A a a a a a a R-a-OHb R R R R-OH R-OH R-OH Miotoxin B H ?H =O ? ? OH Baccharinoid B9 P-0 P-0 ? OH R R-OH Baccharinoid B 10 Baccharinoid B 1 1 " a-OH P-0 P-0 S-a-0 R-a-0 ? OH R R S-OH SOH Baccharinoid B 12 a-OH S-a-0 R-a-0 R R-OH Baccharinoid B 13 P-OH ? OH R R-OH Baccharinoid B 14 P-OH ? OH R S-OH Baccharinoid B 15" OH ? OH R R-OH Baccharinoid B 16 OH ? OH R S-OH Baccharinoid B 17 Baccharinoid B 18" Baccharinoid B21 Baccharinoid B4 P-OH P-OH P-0 P-0 0-0 P-0 s-a-0 s-a-0 S-a-0s-a-0 R-a-0 R-a-0 R-a-0 R-a-0 S-a-OH R R R R R-OH S-OH R-OH S-OH Baccharinoid B5 Baccharinoid B6 P-OH P-0 P-0 S-a-0 s-a-0 R-a-0 R-a-0 S-a-OH S-a-OH R R R-OH R-OH Baccharinoid B8 P-0 P-0 s-a-0 R-a-0 S-a-OH R S-OH Miotoxin Dd H ?H R-a-OH" R R-OH isoMiotoxin Dd H ?H R-a-OH" R R-OH Baccharinoid B1 P-OH H S-P-H R-a-OH R R-OH Baccharinoid B2 P-OH H S-P-H R-&-OH R S-OH Baccharinoid B3 P-OH R-P-OH R-P-H R SOH Baccharinoid B7 P-OH R-P-OH R-P-H R R-OH Baccharinoid B 19" P-0 P-0 H H OH R R-OH Baccharinoid B20 P-0 P-0 H ?H ? OH R S-CIIi Baccharinoid B23 OH H ?H ? OH R R-OH Baccharinoid B24 OH H ?H ? OH R S-OH Miotoxin C H ? OH ? OH R R-OAC aSee structures (6) and (7).bSho~ns3 as /3 but this is incorrect. 'Not isolated. dMiotoxin D and isomiotoxin D are epimeric at position 3'. 'By analogy with miotoxin A. ? Configuration not known. oxidation procedure (see Section 6.3.2) for removing the two- carbon side chain at position 6' allowed the conversion of roridin A and isororidin A to verrucarin A; and roridin D to verrucarin B.50 By the same procedure roridin E and isororidin E were both converted to verrucarin J confirming the presence of the (E)-2'-ene in these macro cycle^.^^ The 2'-ene in roridins E52and H53 was originally assigned the Z configuration but (34 (18) (19) this was changed to E following NOE mea~urements.~~.~~ Formation of the tetrahydropyranyl ring in the macrolide.Spectroscopic correlation was used to confirm the configuration Scheme 1 at positions 6' and 13' in isororidin E.55 Roridin E2 is a stereoisomer of roridin E. The hydrogens at positions 6' and 13' in roridin H are cis related,53 but the absolute configuration at R or S. Thus the 3 satratoxins (F-H) have the same relative these centres and at position 5' is unknown. The gross structure configuration at this position but with the assignation being R of roridin J was determined by spectroscopic comparison with in satratoxins G and H and S in satratoxin F following roridin H NOE measurements showed the presence of a (2)-conversion of the -CH(OH)Me side chain to -COMe.2'-ene.56 The configuration at positions 4' 5' 6' and 13' in Roridin A and isororidin A differ only in the configuration roridin J and at 6' and 13' in acetylroridin K is unknown. at C13' and together with satratoxin H and PDll326 are the The structures assigned to vertisporin the roritoxins the only known pairs of 13'-diasteroisomers among the fungal mytoxins and the satratoxins rest on interpretation of the roridins. Roridin E and isororidin E differ not only at this NMR spectra. The two isomers of satratoxin H obtained from centre but also at position 6' where isororidin E has the S S.atra are different and differ from PD113236.57 The configuration. relationship of one of the two isomers and of PDll3236 to 8P-Hydroxyroridin E and roritoxin C are of interest because satratoxin H has very recently been el~cidated.~* If satratoxin 8P-hydroxylation and 9P,1 OP-epoxidation rare in fungal H and its three isomers differ only in configuration at C12' and trichothecenes are commonly found in the baccharinoids. C13' the structure of the second S. atra isomer can be deduced. 7P,8P-Epoxidation present in two derivatives of roridin H The name 'isosatratoxin H' has been used both for PDll3326 occurs in the simple trichothecene cr~tocin.~ and for the isomers from S. atra. In the macrolide ring the 2',3'-epoxide present in the Roridin E has been ~ynthesized.~~ roritoxins some mytoxins and satratoxins and in roridin D and diepoxyroridin H has the a-configuration as is found in the verrucarins and baccharinoids with this feature.Roridin A 3.3 Baccharinoids (Tables 3 and 6) like verrucarin A has a 3'R centre. The nomenclature of the 28 baccharinoids (the miotoxins are X-Ray structure determinations have been carried out on included) contains some inconsistencies. Initially (B 1-B8) roridin A50 and isororidin E.51The development of a standard numbers were based on the chronology of isolation,6o though NATURAL PRODUCT REPORTS 1993-5. F. GROVE View from 3‘-2‘ 4’-3’ 5’-4‘ C2‘ c 3’ :*: H Roridin A H+: C4’ Me H c5’ C2’ Baccharinoid 87 c4w’=$:: HO Me H O+ H Me CS C2‘ C3’ Baccharinoid (triacetate)82 c4$ Me Newman projections viewed as indicated of the conformations at C2’-C5’in crystals of roridin A and baccharinoids B7 and B2 (triacetate).Macrolide skeletal bonds are indicated by -lines. Scheme 2 not apparently of publication (baccharin the first bac- charinoid to be described in the literature25 is B5). Thereafter when it became evident that the baccharinoids were often present as pairs of diastereoisomers epimeric at position 13’ the pairs appear in sequence e.g. B9 and B10.60 This somewhat over-ambitious scheme has some drawbacks. Seven members of the series Bll B15 B18 B19 B22 B26 and B28 have not yet been isolated though only four of these names Bl 1,B15 B18 and B19 were actually assigned to structures.When both 13’- epimers have been isolated e.g. B9 and B10 the first (odd) number is usually allocated to the compound with the 13’-R configuration and the second (even) number has 13’4 but this scheme is reversed with baccharinoids B11 and B12 and baccharinoid B27 has the 13‘-S configuration. Baccharinoids B3 (1 3’4) and B7 (13’-R) from the initial scheme are also in the reverse order. The baccharinoids are essentially roridins which have undergone further hydroxylation and/or epoxidation giving a substitution pattern found only rarely in the fungal macrocyclic trichothecenes. Thus 3a-hydroxylation in baccharinoid B 12 though of common occurrence in the simple trich~thecenes,~ is unknown in other macrocycles.8P-Hydroxylation occurs in ten baccharinoids but in only two fungal products one macrocycle and one simple trichothecene. Baccharinoid B27 is the only macrocycle to have an 8-0x0 group a common feature among simple trich~thecenes.~9p lop-Epoxidation occurs in six baccharinoids but otherwise only in the fungal roridin roritoxin C. 16-Hydroxylation occurs in three baccharinoids but other- wise only in non-macrocyclic Myrothecium product^.^ Inter-estingly there are no compounds with both 9,lO-epoxidation and 8p-or 16-hydroxylation. Most baccharinoids are hydroxylated at position 4’whereas roridin J is the only fungal macrocycle to show this feature. Where known the configuration of the 4’-OH is a. Miotoxin B is the only macrocycle with a 4’-oxo group and miotoxin C is the only member to have an acetoxyl group at C13’.In miotoxin C the mevalonate-derived macrolide unit has been hydroxylated at C4’ but is otherwise unmodified. Seven baccharinoids have a 2’,3’-epoxide which has the a-configuration as in the fungal verrucarins and roridins. By contrast the 2’-OH in baccharinoids B3 and B7 has the opposite relative configuration (,8) to that found in the verrucarins and roridins. The configuration at C6’ is R in all cases where it has been determined (i.e. all members with the roridin skeleton with the exception of miotoxin B). The possibility that the miophytocens are artefacts produced from roridin E during work-up cannot be e~cluded.~ When the metabolic products of the two trichothecene-producing Baccharis sp.are compared it is seen that although there is significant overlap B. megapotamica mainly affords baccharinoids whereas B. coridifolia mainly produces roridins. The structures of the baccharinoids are as well founded as those of the verrucarins and roridins. X-Ray diffraction was used to determine the structures of baccharinoids B2,61 B5,25 B7,61 and B12,60 and miotoxin A.62 A standard procedure was worked out whereby pairs of baccharinoids epimeric at C13’ were first selectively reduced to the 7’,8’,9’ 10’-tetrahydro- derivatives and then selectively oxidized to the same 13’-0xo compound. This procedure established the structures of baccharinoids B1,61 B3,61 and B8,63 and the relationship between baccharinoids B4 and B6.63 The ‘H and 13C NMR of the ~pectra~~.~~13’-epimers are also characteristic (see Section 7) and provide a reliable method of assigning configuration at C6’ and C13’.This spectroscopic evidence was usedGo to relate baccharinoids B9 and B10 B13 and B14 and B23 and B24; and to establish the C13’ configuration in baccharinoids B16 B20 and B27. The structures of bac-charinoids B4 B6 B9 B10 B13 B14 B16 B20 B23 B24 B25 and B27 and miotoxins B C and D were determined by spectroscopic comparison with baccharinoids of known struc- ture. Baccharinoids B17 and B21 were obtained by chemical transformation of roridin D.60The original structure assigned to miotoxin C64 was amended.65 Baccharinoid B5 has been synthe~ized.~~ Although roridin A crystallizes in a conformation close to that indicated by structure (24) crystalline baccharinoid B7 approximates to that indicated by structure (41A; R2= H R3 = OH).Newman projections shown in Scheme 2 illustrate the variety of conformations in the flexible portion C2’-C5’ adopted by crystalline roridin A and baccharinoids B7 and B2 (triacetate) with trans forms by no means predominant. Scheme 3 shows Newman projections of the C6’ side chain in crystals of various macrocycles with the roridin skeleton. 4 Biosynthesis The biosynthesis in Myrothecium spp. of the sesquiterpene (simple trichothecene) moiety and of the stable tetrahydro- roridinic acid (44),derived from the macrolide portion of the roridin skeleton has been reviewed in some detai14-32.88 and is not dealt with here.Because for nearly ten years the baccharinoids were believed to be plant-modified fungal metabolites no work has been done on the early stages of the biosynthesis of the macrocyclic trichothecenes in Baccharisspp. This may not necessarily take precisely the same course as biosynthesis in fungi. NATURAL PRODUCT REPORTS 1993 H&OH 0 C7’ H:@e C7’ C7‘ C7’ ;$$C7’ OH HIClMe Ac;CIH H Me H H Me Roridin A Miotoxin A 87 82(triacetate) isoRoridin E (UR, 13‘R) (6’R 13’R) (6’R,13’R) (WR 13’5) (65,13’S) Newman projections viewed from C13’ of the conformation at C6’ and C13’ in crystals of various roridins and baccharinoids. Scheme 3 H*Me HHfiHcH H II H2C HO,k,CH H0.t ,CH C6” 6“ 1-I HOH2C h7” MeOi‘OH Me0 :‘OH MeOirbH MeO:‘OH H (44) 4.1 Biosynthesis in Fungi Only classical methods have been used to study the biosynthesis of the macrolide portion no enzymology or genetics have been employed.A key development was the isolation8’ from a M. verrucaria culture of the simple trichothecenes the verrucarol diesters trichoverrin A (45) (6”-S 7”S) and B (45A) (6”-S 7”-R),and the demonstration (TLC evidence) that 14C-labelled trichoverrin was incorporated by M. verrucaria into a number of its macrocyclic trichothecene metabolic products inclpding roridin A and verrucarin A. This demonstration was supported by the results of a preparative experiment with unlabelled material. The mechanism of the ring closure step is not as straightforward as it appears to be at first sight.Whereas the formation of diastereoisomeric pairs of baccharinoids (6’-R 13’-SR) by closure of the trichoverrins (6”-S 7”-SR) is readily understood,8o both the natural occurrence of isororidin E (6’3) and the production of roridin A (13’-R) from both trichoverrins A and B70have still to be explained. In the former case the intervention of a 6”,7”-epoxide could be responsible; the simple trichothecene tri~hodermadiene,~ a known metabolic product of M. verrucaria has just such a grouping. In the latter case an unspecified common intermediate has been and a compound with a 13’-oxo group is a possibility. A 13’-0x0 group is present in satratoxin F and in the mytoxins. As well as the trichoverrins 12,13-deoxytrichoverrinshave been isolated from M.verrucariaso but whether these 12-enes are precursors of verrucarin K or whether deoxygenation takes place at a late stage of the biosynthetic pathway after the formation of the macrolide is unknown. Additional analogues of the trichoverrins occur as fungal metabolites4 These show minor variations in the acetate-derived ester side chain attached at position 4,*O but no variation in the mevalonate-derived 5-hydroxy-3-methyl-pentenoyl side chain attached at position 15. Trichoverrin A and B have also been isolated from S. at~a:~l thus both genera containing the principal sources of the fungal macrocyclic trichothecenes also produce the trichoverrins. Although the trichoverrins have not been isolated from Baccharis the related trichoverrol A and B (46) have been obtained from B.megaputamica.60 Inspection of the structural formulae suggests the sequence shown in Scheme 4to be a possible biosynthetic pathway to the H Verrucarol -Trichoverrin -Roridin -Baccharinoid Myrotoxin *---Verrucarin ---* Satratoxin/relatives Possible biosynthetic pathway to the macrocyclic trichothecenes. Scheme 4 macrocyclic trichothecenes. The scheme assumes that the pathway in Baccharis is essentially the same as that in Myrothecium and that all the fungal producers of macrocyclic trichothecenes use the same pathway. In Scheme 4,a roridin skeleton possibly that of roridin E (26; R = H) occupies a central position oxidative removal of the two-carbon side chain at position 6’ gives the verrucarin skeleton; formation of a C6’-C12’ bond gives the tetrahydro- pyranyl compounds e.g.the satratoxins as outlined in Scheme 1 above; and further hydroxylation and/or epoxidation of both the verrucarol nucleus and the macrolide ring yields the baccharinoids. The biosynthetic origin of the myrotoxins is uncertain. Formal proof of this attractive scheme using specifically labelled materials has still to be obtained but there is some circumstantial supporting evidence. Thus verrucarins A B J and L could be derived from roridins A D E and K respectively. There is abundant evidence that with the possible exception of 3a-hydroxylation oxygenation of the simple trichothecene skeleton takes place at a very late stage in the biosynthetic pathway.It follows that if the formation of the macrolide ring precedes these oxygenation steps the nature of this ring may determine the pattern of oxygenation. This could go some way towards explaining the difference in substitution pattern between verrucarin and roridin-based macrocycles though biosynthetic specificity associated with the producing organism is obviously important. Only one studys2 has been made of further microbial oxygenation of the macrocyclic trichothecenes. Rhizopus arrhizus was found to convert verrucarin A to 16-hydroxyverrucarin A and verrucarin B into a mixture of 16- hydroxyverrucarin B and 3’-hydroxyverrucarin A. The action of this organism on simple trichothecenes is unknown. NATURAL PRODUCT REPORTS 1993-5.F. GROVE "~C-CHri II (47) Me 0 I (48) (49) ! \ 4.2 Biosynthesis in Baccharis sp. A bewildering sequence of 71,65 has been advanced concerning the occurrence of macrocyclic trichothecenes in Baccharis spp. It is not unusual to find that complex secondary metabolic products of higher plants are also made by micro- organisms. For example the natural plant growth regulators indole-3-acetic acid gibberellic acid and abscisic acid are all made by fungi as is the carrot phytoalexin 6-methoxymellein and numerous simple polyketides. Despite this background it was initially believed78 that the baccharinoids were products of a plant-fungus interaction in which fungal macrocyclic tri- chothecenes were taken up by the plant and further modified.This hypothesis has now been ~ithdrawn,'~ but initially there was a considerable weight of circumstantial evidence in its favour. Signifi~antly,~~ B. megapotamica plants grown from seed in Maryland USA were found not to contain baccharinoids and this result was attributed to the absence of the trichothecene- producing soil fungus assumed to be present in Brazilian soil. Incidentally a completely satisfactory explanation of this result in the light of the current hyp~thesis,~~ is still required it has been attributedg3 to a failure of the plants to flower but suitable controls are lacking. However B. coridifolia plants grown also from seed in Maryland came into flower and macrocycles were subsequently detected in the seeds.Although M. verruc~ria~~~~ and M. roriduma6were isolated from Brazilian soil associated with B. ~oridifolia~,~~ and B. megapotamica,86 none of the isolates was a good producer of macrocyclic trichothecenes in the laboratory,86 and many unusually were non-producers. Likewise a Cylindrocarpon SP.~~ isolated from the same environment and Fusarium s~p.~~ failed to produce macrocyclic trichothe~enes,~~ though some F. oxysporum and F. sporotrichioides strains produced a normal spectrum4 of simple trichothecenes. An examination by electron microscopy of the tissues of B. cordifolia plants for fungal symbionts gave negative results.71 Following the failure to demonstrate any fungal involvement it was concluded71 that Brazilian Baccharis synthesized macro- cyclic trichothecenes de novo.This conclusion is consistent with an earlier claim96 (TLC evidence only) to have produced baccharin from B. megapotamica by tissue culture. The initial survey of Baccharis SP.~~ appeared to show that the macrocycles were restricted to the flowering female plant this conclusion which resulted from the use of an insensitive analytical procedure is erroneous and has been ~ithdrawn.~~ In a more recent survey,65 twenty-one species of Baccharis (out of a total of approx. 500 described) were analysed for macrocyclic trichothecenes but only B. coridifolia and B. megapotamica were found to contain them. Macrocyclic trichothecenes were still present in herbarium samples of seeds of these species of which one B.coridifolia dated back to the mid-19th century. Thus not only are the macrocyclic trichothecenes stable over this period of time but their accumulation in Baccharis is not a recent event. Substantial differences in distribution were found between and within male and female B. coridifolia plants but not between male and female B. megapotamica. Male B. coridifolia plants and plants not in flower contained macrocyclic trichothecenes but at levels an order of magnitude lower than those commonly found in flowering female plants. The highest concentrations were found in the seeds and particularly in the seed coat. Roridin A fed to B. megapotamica plants which did not contain or produce (in a control experiment) baccharinoids was converted in the course of one week78 to baccharinoid B7 as well as to 8P-hydroxyroridin A.Thus B. megapotamica not only P-hydroxylates C8 but also epimerizes the C2' centre. Whether this conversion proceeds through a 2'-0xo inter-mediate (the only known 2'-0xo macrocycle is of fungal origin) is a matter for speculation. A mixture of trichoverrins A and B fed to B. coridifolia plants which did not contain trichoverrins or roridin E was taken up translocated and partly converted to roridin E." This transformation was also carried out by B. sarothroides a Baccharis sp. which does not produce macrocyclic trich- othecenes. Baccharis spp. are therefore capable of carrying out two steps of the generalized Scheme 4. Diacetylverrucarol a known metabolic product of M.verrucaria may also have been obtained from B. ~oridifolia.~~,~ 5 Unnatural Macrocyclic Trichothecenes A number of analogues of the naturally occurring macrocyclic trichothecenes have been synthesized. 3a-Hydroxyverrucarin A (50) was prepared45 from diacetoxyscirpenol (47) before the isolation of baccharinoid B 12 revealed that 3a-hydroxy-macrocycles occurred naturally. In the synthesis of 3-isoverrucarin A (5 l) the 4P-acetoxy group of diacetoxy-scirpenol was first removed by the Barton deoxygenation procedure and the muconic acid portion of the macrolide was then esterified with the 3a-hydroxy group.98 Cyclization of the intermediate seco-acid (48) yielded 3-isoverrucarin A together with the novel macrocycles verrucene (49) and verrucinol(52).4-Epiverrucarin A has been prepared from 4-epiverrucarol by standard pr~cedures.~~ Some crown ether analogues of the macrocyclic tri-chothecenes have been preparedloo,lol from suitable OH-protected derivatives of T-2 tetraol (54). The macrolide was attached at positions 8 15 (53; n = 1 and 2) and 3:4 (53 as well as 4 15 (56; n = 1 and 2) and (57). The 4:15-bridged compounds (56) and (57) together with the 8 15-bridged compounds (53) have 17-crown-5 or 20-crown-6 rings com- pared with the naturally occurring trichothecenes which have 18-membered macrolides. Only the 3 :4-bridged compound (55) has an 18-crown-6 ring but this is distorted compared with the ionophore 18-crown-6 (58) by the trans fusion at positions 3 and 4.This work on the synthesis of unnatural macrocycles together with earlier synthetic work directed at the naturally occurring macrocycles has been reviewed.lo23 lo3 6 Chemistry The most important feature of the chemistry of the macrocyclic trichothecenes is hydrolytic fission with methanolic potassium hydroxide or carbonate to a simple trichothecene e.g. verrucarol(2) and a fragment or fragments derived from the macrolide ring (Scheme 5). From the verrucarins these fragments consist of (2 E)-muconic acid (59) and from verrucarin J (20; R = H) anhydromevalonic acid (60).40 Verrucarins in which the 2’-ene is hydrated or otherwise modified yield the corresponding derivative of anhydro-mevalonic acid e.g. verrucarinolactone (61) from verrucarin A (21; R1= H R2 = OH).34,15From the roridins the corre-sponding fragments are 2-anhydrororidinic acid (62) from roridin E (26; R = roridinic acid (63) from roridin A (24; R = PH),lo4 and 2,3-epoxy-2-anhydrororidinicacid from roridin D (25).lo5 The chemistry of these fragments has been revie~ed.~~.*~ Preferential fission of the muconic acid fragment has been achieved using very dilute potassium carbonate.40 Macrocycles mainly baccharinoids in which the trichothecene moiety is substituted yield the corresponding substituted verrucarols or derivatives thereof e.g.the 10/3-hydroxy-l5 + 9-ether (64) from baccharinoid B5 (40; R1= PH R2 = OH).63 This review deals only with the chemistry of the intact macrocycle and like the earlier account4 of the simple NATURAL PRODUCT REPORTS 1993 HO’ W (55) trichothecenes is arranged in terms of the reactivity of functional groups.In general the chemistry of the trichothecene nucleus is altered little by the presence of the macrolide. However the bulky macrolide ring makes the a-face of the trichothecene nucleus less accessible to reagents than is the case in most simple trichothecenes. Particularly affected in theory are verrucarins related to Group 114of the simple trichothecenes with substituents at the 8a-position. In these compounds the normal half-chair conformation of ring A might be expected to be modified. Whereas this may well be true in solution as exemplified in myrotoxin chemistry and in the reactions described in Section 6.1.1 there is virtually no difference in the conformations adopted in the crystalline state by myrotoxin A (8; R1 = R2 = H R3 = OH)28and myrotoxin B (8; R1= OAc R2= H R3= OH).43 So far as can be ascertained from NMR spectra albeit in non-polar solvents the conformation of the macrolide ring in solution agrees closely with that in the solid state as determined by X-ray crystallography.Surprisingly no transannular reactions have been reported. 6.1 Ethylenic Double-Bonds 6.1.1 Isomerization The (E E)-isomer (65) of verrucarin J (20; R = H) when treated with I in benzene at room temperature gave verrucarin J (61 %) together with the (E 2)-isomer (66) (31 %).48 Potassium t-butoxide in isopropanol caused conjugation of the 3’,4’-ene with the ester group in the analogue (67) to give roridin E (26; R = H).59 [3,3]-Sigmatropic rearrangement in boiling toluene of the thionocarbonate (69; R = CSOPh) of baccharinoid B4 to the 8,9-ene regioisomer (70) occurred,lo6 but in unsatisfactory yield and was accompanied by formation of the diene (71).Only the diene (71) was obtained from the attempted rearrangement of the 8a-epimer a result which may arise from the effect of 8a 15-diaxial interaction on the conformation of ring A. Other attempted allylic rearrangements failed as did attempts to isomerize the 6’,7’-ene in myrotoxin B (8; R’ = OAc R2= H R3 = OH) to the 7’,8’-po~ition.~~~ 6.1.2 Catalytic Reduction The use of palladized charcoal in ethanol allowed regiospecific 441 NATURAL PRODUCT REPORTS 1993-5.F. GROVE Verrucarin J (20; R = H) -Verrucarin A OH-(2) (21; R~ = H R~ = OH) OH- Roridin E -(2) (26; R = H) __c Roridin A OH-(2) (24; R = PH) Hydrolytic fission of the macrocyclic trichothecenes. Scheme 5 II \,O.?EH c C Roridin E (26; R = H) 1-BuOK/ 0 ....o* 0 H26\ H2C\ 4 4 o,c’o I osc‘$H rnCPBA o,c’o ~ I Osc\EH HC/cH M;< HHE.cH 0.1 ,EH O,l,CH MeL H 5 H -‘ 7 Me + (59) + + H02C + I hydrogenation (2 mols. H upta-e) of the 7’,8’ 9’,10’-diene in roridin A (24; R = PH)lo4 and in several baccharinoid~,~~.~~ leaving the 9-ene intact. In other cases e.g.myrotoxin B,lo6the 9-ene was reduced. Adams’ platinum oxide catalyst in acetic acid gave complete hydrogenation of all double bonds in verrucarins A (21; R1= H R2= OH)34and B (23),35 and in roridin A,104 and also in the 2’,3’-enes verrucarin J (20; R = H)40and roridins E (26; R = H)52and H (27; R1= R2= H),53with the formation of one product only in each and every case.Hydrogenation of all these macrocycles is therefore stereoselective from the p-face for the 9-ene and from the a-face for the 2’-ene. 6.1.3. Electrophilic Addition Reactions (i) Epoxidution. With peroxybenzoic acid and its 3-chloro- derivative epoxidation is usually confined to the 9-ene though MeOi<OH MeOy<OH some epoxidation of the 7’-ene occurred in r~ridins.~~’,~~‘’ H H Exceptionally some 9P lop :2’a,3’a-diepoxide (9p,1 OP-epoxy- (67) (68) verrucarin B) was obtained as a minor product (0.8 %) from the NATURAL PRODUCT REPORTS 1993 (73) epoxidation of verrucarin J (20; R = H);loS and epoxidation of roridin E (26; R = H) is stated to give baccharinoid B17 (40; R’ = PH R2 = H).60 Epoxidation of the 9-ene was not wholly stereospecific and some a-epoxide was obtained as a minor product (5-6%) from acetylverrucarin A (21 ;R1 = H R2 = OAc),lo9 verrucarin A,110 verrucarin J,lo8 and the diacetyl derivatives of roridin A (24; R = PH)lo7 and roridin H (27; R’ = R2 = H).lo8 The major product from all these reactions was the 9/3,1OP-epoxide.Epoxidation of the 8P-and 16-hydroxy derivatives of both verrucarin A and roridin A gave the 9P 10P-epoxy-derivatives exclusively.log The 9-ene is deactivated to some extent by 8-oxygenation and although no problems were encountered with baccharinoid B4 (38; R1 aH,R2 = R3 = OH R4 = H) (8p-OH),lo6 myrotoxin B (8; R’ = OAc R2 = H R3 = OH) yielded only the ester (73) which did not react further.However myrotoxin A hydrate (72; R = H) was only epoxidized in poor yield. The 2’-ene is likewise deactivated by 4’-oxygenation and the dieneoate system was preferentially attacked by the peracid in bac- charinoids B9 and B10 (37; R = H) and in baccharinoid B13 (39; R’ = PH R2 = H R3 = OH).60 Epoxidation of baccharinoid B5 (40; R1 = PH R2 = OH) gave a mixture of 7’P,8’P- and 7’a,8’a-epoxides in the ratio 2 1.ll1 Epoxidation of the 3’-ene (67) gave one product the 9P lop 3’P,4’P-diepoxide (68).59 (ii) Hydration and Hypobromination.The 6’,7’-enol ether linkage in the myrotoxins readily adds the elements of water or hypobromous acid to give from myrotoxin B (8; R1 = OAc, R2= H R3 = OH) the hydrate (72; R = OAc) and bromo- hydrin (74; see Scheme 7) respectively.ll2-lo6 The con-figurations assigned to the products are based on the assumption that the electrophile approaches from the less hindered a-face of the enol. Myrotoxins C and D when allowed to stand in acetone-chloroform at room temperature for several weeks were transformed into the corresponding hydrates.43 6.1.4 Reactions at the a-Carbon Atom Allylic oxidation of verrucarin A (21 ; R’ = H R2 = OH) with selenium dioxidellO took the same course as similar oxidations of simple trichothecenes113* ‘14 giving the 8P-hydroxy derivative as the main product (40-50%) together with some 16-hydroxylation (10 %).Similar results were obtained with roridins A (24; R = PH)lo8 and D (25),60and also with the 2‘- ene verrucarin J (20; R = H).lo8 6.2 Hydroxyl Groups 6.2.1 Regioselective EsteriJication Hydroxyl groups at positions 2‘ 4’ 12’ and 13’ are all readily acylated and little work aimed at regioselective esterification has been attempted. The 6’ (hemiaceta1)-OH of myrotoxin B hydrate (72; R = OAc) was not acetylated by acetic anhydride- H% H HCO‘H II 0.1 ,CH HO C Cl (75) pyridine at room temperature,lo6 but the 14’ (hemiaceta1)-OH of roritoxins A (1 1) and B (12; R’ = R2 = H OH) was acetylated under these conditions in the presence of 4-(dimethy1amino)pyridine.74 The 13’-OH group in baccharinoid B5 (40; R1 = PH R2 = OH) was selectively silylated with t-butyldimethylsilyl ch1oride.l” The derivative after acetylation at position 4’ and depro tection facilitated the preparation of 4’-acetyl bac- charinoid B5.Reaction of baccharinoid B4 (38; R1 = aH R2 = R3 = OH R4 = H) with phenylchlorothionoformate at 0 “C selectively gave the 8P-thionocarbonate (69; R = CSOPh),lo6 but pro- tection of the hydroxyls at positions 4’ and 13’ was necessary before preparation of the 8a-epimer. 6.2.2 Regioselective Oxidation The 13’-OH in roridins is more readily oxidized than a hydroxyl at position 2’. With the chromic oxide-sulphuric acid reagent in acetone at room temperature the 7’,8’,9’ 10’- tetrahydro derivative of roridin A (24; R = PH) gave the 13’- 0x0 compound but the 2’ 13’-dioxo derivative was obtainedlo4 on further oxidation under the same conditions.These conditions yielded the 2’-0xo derivative of verrucarin A (21 ; R1 = H R2 = OH)15 but the 13’-oxo derivative of roridin A.lo3 Pyridinium chlorochromate also gave the I 3’-0xo derivative of tetrahydrororidin A; but roridin A yielded a complex mixture of The allylic OH groups in both 8P-and 16-hydroxyverrucarin A gave the corresponding 8-and 16-0x0 derivatives with Collins reagent (chromic oxide-pyridine in dichloromethane) without the 2’-OH being affected.’1° Baccharinoids provide much greater scope for regioselective oxidation since in addition to variable hydroxylation of the trichothecene nucleus at positions 3,8 and 16 most possess OH substituents at both positions 4’ and 13’.In baccharinoids B9 and BlO B13 and B14 B16 B25 and B27 and in miotoxin A the 4’-OH is allylic but this feature has yet to be exploited. The allylic 8P-OH of baccharinoid B4 (38; R1 = aH R2 = R3 = OH R4 = H) was oxidized to the 8-ketone with pyridinium chlorochromate without the OH groups at positions 4’ and 13’ being affected,63 but the 13’-OH of 7’,8’,9’ 10’-tetrahydro- baccharinoid B4 was oxidized under similar condition^.^^ 8,13’-Diketones were also obtained with pyridinium chloro-chromate from the 7’,8’,9’ 10’-tetrahydro derivatives of baccharinoids B3 and B7 (41; R’ = R2= H R3= R4 = OH) (2’P-OH unaffected) and baccharinoids B1 and B2 (41 ; R’ = R3 = H R2 = R4 = OH) (4’-OH unaffected).61 In attempts to prepare the 8/3,9P-epoxide from baccharinoid B4 by the action of N-bromosuccinimide-pyridine in aceto- nitri1e,lo6 the only product isolated was the 8-ketone.The 14’- hemiacetal group of roritoxin B (12; R’R2 = H,OH) was oxidized to the lactone [roritoxin D (12; R1R2 = O)] in boiling toluene by silver carbonate on Celite.74 NATURAL PRODUCT REPORTS 1993-5. F. GROVE H+ -(76) (77) iH+ (40; R'=PH R2=OH) 6.2.3 Deoxygenation Hydrogenolysis of 16-mesyloxyverrucarin A with sodium borohydride in a buffered system with a phase transfer catalyst yielded verrucarin A.115 This reaction was used to prepare 116- 3H]-verrucarin A. Hydrogenolysis of the 8a-acetoxy group of myrotoxin B (8 ;R1 = OAc R2= H R3 = OH) occurred during the course of hydrogenation with a palladium catalyst.'06 6.2.4 Selective Nucleophilic Substitution With the 13'-OH protected as the t-butyldimethylsilyl ether inversion at the 4'-position in the diepoxide (75) was achieved using the Mitsunobu116 procedure giving after deprotection baccharinoid B5 (40; R1 = PH R2= OH),59 6.3 Keto Groups Keto groups are uncommon in the macrocyclic trichothecenes and when they do occur or are created in the macrolide at positions 2' 4' and 13' their reactions have not been studied.8-0x0 groups a common feature in the simple trichothecenes also occur relatively rarely and then by oxidation of naturally occurring 8/3-hydroxy-compounds.6.3.1 Stereospecijic Reduction Reduction of the 8-0x0 derivative of verrucarin A (21 ;R1 = H, R2= OH) to the 8a-hydroxy analogue with sodium boro- hydride at 0 "C was accompanied by reduction of the 9-ene.llO This complication was eliminated when the reaction was carried out at -35 "C. 9-Ene hydrogenation was also encountered as a side reaction in the reduction of 8-0x0- baccharinoid B4.1°6 6.3.2 Reactions at the a-Carbon Atom In the standard procedure50 for the conversion of the roridin to the verrucarin skeleton with pyridinium dichromate in dimethylformamide at 25 "C(see Section 3.2) the intermediacy is assumed of the 13'-0x0 compound which then undergoes fission of the two-carbon unit. The yield was poor and sometimes the oxidative cleavage failed completely in the presence of a 4'-OH group (most baccharinoids)."l Better yieids from baccharinoid B5 (40; R1= PH R2 = OH) of the u + yq$-J ACOH~ -H Me' H verrucarin analogue were obtained using tetra-n-butyl-ammonium dichromate in dimethylformamide at 60 "C.The cleavage with pyridinium dichromate occurred satisfactorily when the 4'-OH was protected. No explanation of these facts has been advanced. 6.4 Epoxide Functions The 12,13-epoxide is of prime importance in the chemistry of the simple trich~thecenes.~ Macrocyclic trichothecenes often have additional epoxide functions at the 2'a,3'a-,7,8,8,8- and 9/3,lOP-positions. 7',8'-Epoxides of the roridin skeleton are also known. 6.4.1 Acid-catalysed Rearrangements (i) 12,13-Epoxide (a) The Trichothecene -+I0,13-Cyclotrichothecane Rear-rangement.This reaction which involves a conformational change in ring A,4 occurred readily with diacetylverrucarol (76),'17 giving the 10 -+ 13-cyclo-products (77) and (78) but failed with verrucarin A.ll* Miophytocens A (6) and B (7) are 10 -,13 -cyclo compounds corresponding to roridin E (26; R = H) but their preparation via this rearrangement has yet to be achieved. (b) The Trichothecene -+Apotrichothecene Rearrangement. This rearrangement exemplified by the conversion of diacetyl- verrucarol (76) to the apo-compounds (79; R1 = R2 = Ac, R3= C1 or OH) appeared to be unaffected by the presence of the macrolide ring and proceeded normally with verrucarin A and hydrogen chloride at room ternperature,lls giving the apotri- chothecene (79; R'R2 = macrolide R3= Cl).Somewhat more stringent conditions than normal were required for the reaction with dilute sulfuric acid in dioxan,llg giving from verrucarins A and J (20; R = H) and from roridin A (24; R = BH) the corresponding apo-compounds (79 ; R1R2= macrolide R3 = OH). (ii) 6',7'-Epoxide. Treatment of myrotoxin B (8; R' = OAc R2 = H R3= OH) with 3-chloroperoxybenzoic acid in the presence or absence of sodium hydrogen carbonate led only to the formation of the 3-chlorobenzoate (73),lo6 formed presumably from the ready opening of the intermediate 6',7'-epoxide under the conditions of the reaction. (iii) 7',8'-Epoxide. In the epoxidation of baccharinoid B5 (40; NPR 10 NATURAL PRODUCT REPORTS 1993 AcO” 0 - DBU 0 -OH OH 0 \OH \ OH (72; R = OAC) DBU c- T O0 H qo0 Rearrangement of myrotoxin B hydrate (72; R = OAc).Scheme 6 R1 = PH R2 = OH) with 3,5-dinitroperoxybenzoicacid,ll’ the major product was not the expected 7’P78’P-epoxide (80) but the tetrahydrofuran (8 l) resulting from the intramolecular opening of the epoxide by the 13’-OH group. 6.4.2 Base-catalysed Rearrangements (i) 12,13-Epoxide. The mild conditions (2 Oh potassium car-bonate in methanol at room temperature) used to hydrolyse the 4- and 15-ester groups in 7/3,8/3-epoxyisororidin E (29; R1R2 = 0) induced rearrangement of the trichothecene moiety the crotocol analogue (82) to the 7,13 :8,15-diepoxytrichothecene (83).j5 (ii) 2’,3’-Epoxide.Opening of the 2’,3’-epoxide of myrotoxin B hydrate (72; R = OAc) with 178-diazabicyclo[5. 4.OIundec-7- ene (DBU) in tetrahydrofuran at room temperature gave the isomer (84)112 according to the sequence outlined in Scheme 6. Under the same conditions the 2’,3’-epoxide in myrotoxin B bromohydrin (74) was unaffected and the desired 7’,8’ 9’ 10’- diene was not formed. The product was the ketone (85) believed to arise from the reaction sequence set out in Scheme 7. 7 Spectroscopy 7.1 Ultraviolet Spectra In general with the increase in availability of high-field NMR spectrometers the usage of UV spectroscopy in natural product chemistry has declined during the past ten years. UV absorption is nevertheless a useful tool when applied to the macrocyclic trichothecenes.The macrolide dieneoate chromophore A,, 260-263 nm and the 2’,3’-eneoate chromophore Amax 218-223 nm absorb independently and have diagnostic value. The trichothecene 9-en-8-one chromophore A,, 220 nm overlaps the latter but is uncommon in macrocycles. The presence of two eneoate chromophores in e.g. vertisporin (16) can usually be deduced from the value of the molecular extinction coefficient. Complications exist and sometimes it has been necessary to postulate out of plane distortion of the dieneoate chromophore in order to explain the results e.g. satratoxins G (10; R = CH(0H)Me) and H (9; R’= H R2= OH) A,, 255-256 nm;22 and the product (87) A,,, 250 nm of the action of 1,8-diazabicyclo[5.4.O]undec-7-ene on the iodoazide (86).lo6 7.2 Nuclear Magnetic Resonance Spectra 7.2.1 ‘H Spectra Because of the number of overlapping signals from methine- oxygen groups acetylation of the macrocycle is advisable before interpretation of the spectrum is attempted.Chemical shifts and coupling constants for the trichothecene moiety have been tabulated4 and are little changed by the presence of the macrolide ring. Three features of the macro- cycles infrequently encountered in simple trichothecenes are the 9P7lOP-epoxide and the SP-and 16-OH groups. The first gives rise to H-10 6 3.1 d J,,,,,= 6 Hz; the second to H-Scr 6 5.2 (after acetylation) dd JEa,8= 10 Hz J8a,a= 5-6 Hz; and the last to a singlet at 6 3.7 (6 4.5 after acetylation).In the macrolide H-2’ is seen at 6 5.2 in 2’-enes and at 6 3.4 in 2’,3’-epoxides. The dieneoate grouping gives a characteristic pattern of peaks. In verrucarins H-7’ and H-10’ are seen as doublets at 6 5.8-6.2 with J,.,,,= 16 Hz and Js.,lo.11 Hz = H-9‘ is a triplet at 6 6.5-6.6 JE,,9, = 11 Hz whilst H-8’ appears as a double doublet at 6 8.1. This H-8’ signal moves upfield to 67.4-7.7 in roridins and to 66.8-7.3 in the satratoxins. The latter value may result from diminished de-shielding by the 11’- C=O group in the out of plane satratoxin dieneoate chromo- phore (see Section 7.1). This distortion changes H-9’ to a double doublet with J8r,sr = 7.5 Hz in satratoxin G and 6 Hz in satratoxin F.’j A similar value for J8,.s, is found in compound (8 7).O6 In roridins the configuration at C-6’ determines the value of J6,,,,. This is 6 Hz in compounds where C-6’ is S and 2 Hz when C-6’ is R.55 13-Acetoxy-(6’R)-roridinswith 13’3 show an eight- line pattern (dq J13,,14 = = 6.5 Hz J6r,13.3.5 Hz) for H-13’ at -6 5 whilst those with 13’-R show a five-line pattern (J13r,14r = = J6.,13. 6.5 Hz).~ Additionally €3-13’ chemical shifts are consistently though only marginally higher in the 13’-R NATURAL PRODUCT REPORTS 1993-5. F. GROVE HH AcO‘ Ad‘. 0 0 OH OH (8; R’=OAc R2=H R3=OH) (74) (85) Base-catalysed transformation of myrotoxin B bromohydrin (74). Scheme 7 HWi OH N3 I series.6oIt follows that in a baccharinoid (6’-R) of unknown structure the lH NMR spectrum can be used to determine the configuration at C-13’.A Me group at position 14’ is seen at S 1.2 and a Me at 12’ at 62.3 in 2’-enes or S 1.4in 2’,3’-epoxides. The configuration at C-12’ in macrocycles containing the tetrahydropyran ring can be correlated with the chemical shift of H-2’.28 The nuclear Overhauser effect or its absence has been useful in establishing the relative configuration of the 2’-H and the 12’-Me group in compounds with a 2’-ene;55,56the configuration of the 12’-substituent in satratoxin H5 and other macrocycles containing the tetrahydropyran ring ;28 and the relative con-figuration of H-7’ and H-12’ in myrotoxin A.28 7.2.2 13CSpectra 13CSpectra of most of the macrocycles isolated since 1970 have been recorded.The chemical shifts for carbons in the trichothecene moiety are very similar to those found for diacetylverr~carol.~The introduction into the verrucarol nucleus of uncommon substituents produces the chemical shifts expected e.g. 57.5 ppm for C-9 and C-10 in 9,lO-epoxides. Chemical shifts reported in ppm downfield from an internal reference of tetramethylsilane for carbon atoms in the macrolide portion of representative macrocycles are given in Table 7. In (6’-R)-roridins the chemical shifts for C-13’ are at consistently higher frequencies (1-2 ppm) in the 13’-R series compared with diastereoisomers with 13’-S (cf. baccharinoids B13 and B14).60 This correlation has contributed to the assignment of the 13’-configuration in several pairs of 13’-epimeric baccharinoids.If it is also valid for satratoxins then satratoxin H and PD113326 have 13/43and 13’-R respectively. The chemical shift for C-12’ in 4’-hydroxyroridins with an (E)-2’-ene falls within the range 15.5-19 ppm but roridin J is exceptional (13.1 ppm) and this has been correlated with the presence of the (Z)-2’-ene.80If this is a valid correlation and holds for verrucarins baccharinoid B25 (13.9 ppm) could also have a (Z)-2’-ene. 7.3 Mass Spectra Unlike the simple trichothecenes the macrocycles are not normally contaminants of grain and grain products. Conse-quently there has not been the same pressure to develop methods for their detection and estimation though the analysis of fodder and bedding straw for the metabolic products of Stachybotrys sp.has received considerable attention com-mensurate with its practical importance. The identification of roridins and baccharinoids in extracts of Baccharis sp. has also been studied but more as an academic exercise because of the large number of isomers involved (see Tables 2 and 3). There are for example eight C2,H3,010 compounds and seven C,,H,,O, compounds amongst the known baccharinoids. Electron-impact mass spectra of pure specimens of the macrocycles are readily obtained by direct insertion and more sophisticated and more sensitive tandem mass spectroscopic techniques have recently been employed. Chemical ionization (CI) in the presence of ammonia followed by collisionally activated dissociation (CAD) using 446 NATURAL PRODUCT REPORTS 1993 Table 7 Macrolide Ring 13C NMR Spectra of some Macrocyclic Trichothecenes Cpd.Ref. 1’ 2’ 3’ 4‘ 5’ 6’ 7’ 8’ 9‘ 10’ 11’ 12’ 13’ 14’ 1 41 165.6 118.5 156.3 40.0 60.2 165.8 127.7 138.9 139.9 125.3 165.3 17.0 2 120 174.3 73.8 32.9 31.9 60.8 165.8 127.2 138.6 138.6 125.5 165.1 9.8 3 120 167.4 58.0 61.1 36.9 60.4 165.8 127.2 138.0 138.0 125.6 164.9 15.8 4 60 165.8 116.8 158.3 74.3 63.7 165.1 126.5 139.1 139.7 125.9 165.8 13.9 5 55 165.8 119.0 159.0 41.3 69.8 83.8 138.1 126.6 143.7 117.2 166.4 20.2 70.5 18.3 6 120 174.5 75.3 36.7 33.0 69.5 83.7 139.0 126.0 143.6 117.2 166.3 14.4 70.4 18.0 7 120 167.8 57.9 62.9 39.4 67.3 85.3 138.1 126.2 142.9 117.8 166.1 17.2 70.5 17.9 8 60 166.3 121.2 160.5 74.3 73.6 84.0 137.6 126.8 143.5 115.0 165.9 18.9 70.8 16.0 9 60 166.3 121.1 161.2 74.8 73.1 82.7 137.2 126.9 143.5 114.9 166.3 19.0 68.5 15.9 10 75 166.2 119.0 155.1 25.3 60.4 81.4 132.2 134.2 143.0 120.4 167.0 73.7 69.7 15.7 11 66 165.4 118.2 154.9 25.5 51.0 78.7 133.6 134.1 142.3 121.1 166.7 75.4 74.7 15.8 Uncertain assignments in italics approx.chemical shift only. 1 Verrucarin J 2 Verrucarin A 3 Verrucarin B 4 Baccharinoid B25 5 Roridin E 6 Roridin A 7 Roridin D. 8 Baccharinoid B13 9Baccharinoid B14 10Satratoxin H 11 PDI 13326. argon of the MNH adducts has been employed for the 7 P. W. Brian and J. C. McGowan Nature (London) 1946 157 simultaneous analysis of 50-1 50 pg quantities of the roridins 334. (and two baccharinoids) present in extracts of Baccharis 8 P.W. Brian P. J. Curtis and H. G. Hemming Proc. R. Soc. plants.121 This procedure was subsequently applied using London Ser. B 1947 135 106. thermospray ionization conditions to aqueous solutions of an 9 P. W. Brian H. G. Hemming and E. G. Jefferys Mycologia 1948 40 363. extended range of baccharinoids.12’ Negative ion (NI) CI 10 J. F. Grove J. Chem. Soc. (C) 1968 810 coupled to the CAD technique was effective in the detection of 11 M. Kocor A. Nespiak and A. Siewinski Bull. Acad. Polon. Sci. 1-2 ng quantities of a number of verrucarins and roridinslZ3 Ser. Sci. Chim. 1961 9 207. and 5 pg of satratoxins G and H.124 12 A. Nespiak M. Kocor and A. Siewinski Nature (London) 1961 In GCMS systems derivatization of simple trichothecenes 192 138. was found to be necessary in order to overcome an inherent 13 A.N. Kishaba D. L. Shankland R. W. Curtis and M. C. lack of volatility. This is doubly true of the macrocycles which Wilson J. Econ. Entomol. 1962 55 21 1. are in general more polar and less volatile than the simple 14 B. M. Vittimberga J. Org. Chem. 1963 28 1786. 15 J. Gutzwiller and C. Tamm Helv. Chim. Actu 1965 48,157. trichothecenes.125 Additionally the macrolide ester linkages are 16 V. I. Bilai A. A. Mikhailovnina and F. N. Stepanov Dokl. Acad. thermally unstable and recovery from the GC step is poor. Nauk SSSR 1962 144 105. Notwithstanding these disadvantages the mass spectra at the 17 M. Tulloch Commonwealth Mycological Institute Mvcological 1-10 ng level of trimethylsilyl derivatives of some members of Papers 1972 130 3.all three classes of macrocycles have been obtained by sample 18 K. Panozishvili N. Y. Zolnikova and A. V. Vorovkov Chem. introduction by GC on a short capillary column with on-Nut. Compd. (Eng. Transl.) 1972 8 244. column injection.126 19 K. Panozishvili and A. V. Borovkov Chem. Nut. Compd. (Eng. In a different developed from an earlier Transl.) 1974 10 408. procedure for the detection and identification of verrucar01,~~ 20 V. H. Pawar P. V. Deshmuk and M. J. Thirumalachar Hindustan Antibiot. Bull. 1965 8 59 (Chem. Abstr. 1966 84 14633). the sample containing baccharinoids was hydrolysed and the 21 J. Forgacs in ‘Micobial Toxins Vol. VIII Fungal Toxins’ ed. S. resulting cleaned up mixture of substituted verrucarols was Kadis A. Ciegler and C. J. Ajl Academic Press New York 1972 analysed by GCMS under NICI conditions.This procedure p. 95. only provided information on the relative amounts of macro- 22 R. M. Eppley and W. J. Bailey Science 1973 181 758. cycles with different verrucarol moieties. 23 H. Minato T. Katayama and K. Tori Tetrahedron Lett. 1975 More promising results were obtained using HPLC-MS. 16 2579. HPLC has been used successfully to separate mixtures of 24 S. Hayakawa E. Kondo Y. Wakisaka H. Minato and K. roridins,i8 satratoxins G and H,12R.91 Katagiri J. Antibiot. 1975 28 550. and baccharinoid~.~~~~~~~~ After separation in methanol-0.1 M ammonium acetate on a 25 S. M. Kupchan B. B. Jarvis R. G. Dailey W. Bright R. F. Bryan and Y. Shizuri J. Amer. Chem. Soc. 1976 98 7092. reversed-phase HPLC column a number of roridins and 26 L.Busam and G. G. Habermehl Naturwissenschaften 1982 69, baccharinoids were ionized at a thermospray interface and the 392. CI spectra were recorded. Using selective ion monitoring the 27 E.-L. Hintikka in ‘Mycotoxic Fungi Mycotoxins Mycotoxicoses unambiguous identification and estimation of some isomeric Vol. l’ ed. T. D. Wyllie and L. G. Morehouse Dekker New baccharinoids was achieved and the method was applied York 1977 p. 91. satisfactorily at the 5 ng level to extracts of Baccharis ~1ants.l~’ 28 B. B. Jarvis F. T. Comezoglu Y.-W. Lee J. L. Flippen-Anderson Capillary column supercritical fluid chromatography coupled R. D. Gilardi and C. F. George Bull. Soc. Chim. Belg. 1986,85 to ammonia CI mass spectrometry has also been used with 681.George, limited success.13o 29 C. R. Gilardi and J. L. Flippen-Anderson Acta Crystallogr. Sect. C 1991 47 218. 30 Chem. Abstr. 1979 91 134123. 8 References 31 E. Fetz and C. Tamm Helv. Chim. Acra 1966 49 349; P. F. Pfaffli and C. Tamm Helv. Chim. Acta 1969 52 191 I. 1 W. 0.Godtfredsen J. F. Grove and C. Tamm Helv. Chim. Acta 32 C. Tamm Fortschr. Chem. Org. Naturst. 1974 31 63. 1967 50 1666. 33 B. Bohner E. Fertz E. Harri H. P. Sigg C. Stoll and C. Tamm 2 W. Breitenstein and C. Tamm Helv. Chim. Acta 1977 60 1522. Helv. Chim. Acta 1965 48 1079. 3 G. G. Habermehl L. Busam P. Heydel D. Mebs C. H. Tokarnia 34 C. Tamm and J. Gutzwiller Helv. Chim. Acta 1962 45 1726. J. Dobreiner and M. Spraul Toxicon 1985 23 731. 35 J. Gutzwiller and C.Tamm Helv. Chim. Acta 1965 48 177. 4 J. F. Grove Nut. Prod. Rep. 1988 5 187. 36 A. T. McPhail and G. A. Sim Chem. Commun. 1965 350. 5 R. M. Eppley E. P. Mazzola R. J. Highet and W. J. Bailey 37 A. T. McPhail and G. A. Sim J. Chem. Soc. (C) 1966 1394. J. Org. Chem. 1977 42 240. 38 W. Breitenstein C. Tamm E. V. Arnold and J. Clardy Helv. 6 E. Harri W. Loeffler H. P. Sigg H. Stahelin C. Stoll C. Tamm Chim. Acta 1979 62 2699. and D. Wiesinger Helv. Chim. Actu 1962 45 839. 39 W. Zurcher and C. Tamm Helv. Chim. Acta 1966 49 2594. NATURAL PRODUCT REPORTS 1993-3. F. GROVE 40 E. Fetz B. Bohner and C. Tamm Helv. Chim. Acta 1965 48 1669. 41 W. Breitenstein and C. Tamm Heh. Chim. Acta. 1978 61 1975. 42 B. B. Jarvis J. 0. Midiwo T. DeSilva and E. P. Mazzola J.Antibiot. 1981 34 120. 43 B. B. Jarvis F. T. Comezoglu S. Wang and H. L. Ammon Mycotoxin Res. 1991 7 73. 44 W. C. Still and H. Ohmizu J. Org. Chem. 1981 46 5242. 45 P. Mohr M. Tori P. Grossen P. Herold and C. Tamm Helv. Chim. Acta 1982 65 1412. 46 W. R. Roush and T. A. Blizzard J. Org. Chem. 1984 49 4332. 47 R. Esmond B. Frazer-Reid and B. B. Jarvis J. Org. Chem. 1982 47 3358. 48 W. R. Roush and T. A. Blizzard J. Org. Chem. 1983 48 758; 1984 49 1772. 49 R. J. Bloem T. A. Smitka R. H. Bunge J. C. French and E. P. Mazzola Tetrahedron Lett. 1983 24 249. 50 B B. Jarvis J. 0. Midiwo J. L. Flippen-Anderson and E. P. Mazzola J. Nat. Prod. 1982 45 440. 51 J. L. Flippen-Anderson and R. Gilardi Acta Crj,stallogr. Sect. C 1986 42 1184.52 P. Traxler W. Zurcher and C. Tamm Helv. Chim. Acta 1970,53 2071. 53 P. Trdxler and C. Tamm Helv. Chim. Acta 1970 53 1846. 54 M. Matsumoto H. Minato H. Uotani K. Matsumoto and E. Kondo J. Antibiot. 1977 30 681. 55 M. Matsumoto H. Minato K. Tori and M. Ueyama Tetrahedron Lett. 1977 18 4093. 56 B. B. Jarvis G. P. Stahly G. Pavanasasivam and E. P. Mazzola J. Antibiot. 1980 33 256. 57 A. Bata B. Harrach K. Ujszaszi A. Kis-Tamas and R. Lasztity Appl. Environ. Microbiol. 1985 49 678. 58 Chem. Abstr. 1991 115 88909. 59 W. C. Still J. Gennari J. A. Noguez. and D. A. Pearson J. Amer. Chem. Soc. 1984 106 260. 60 B. B. Jarvis S. N. Comezoglu M. M. Rao N. B. Pena F. E. Boettner W. M. Tara G. Forsyth and B. Epling J. Org. Chem.1987 52 45. 61 B. B. Jarvis S. N. Comezoglu H. L. Ammon C. K. Breedlove R. W. Miller M. K. Woode D. R. Streelman A. T. Sneden R. G. Dailey and S. M. Kupchan J. Nat. Prod. 1987 50 815. 62 G. G. Habermehl L. Busam and J. Stegemann Z. Naturforsch. Teil C 1984 39 212. 63 S. M. Kupchan D. R. Streelman B. B. Jarvis R. G. Dailey and A. T. Sneden J. Org. Chem. 1977 42 4221. 64 G. G. Habermehl and L. Busam Liebigs Ann. Chem. 1984 1746. 65 B. B. Jarvis N. Mokhtari-Rejali E. P. Shenkel C. S. Barros and N. I. Matzenbacher Phytochemistry 1991 30 789. 66 T. A. Smitka R. H. Bunge R. J. Bloem and J. C. French J. Antibiotics 1984 37 823. 67 B. Harrach C. J. Mirocha S. V. Pathre and M. Palyusik Appl. Environ. Microbiol. 1981 41 1428. 68 J. S.Vittimberga and B. M. Vittimberga J. Org. Chem. 1965 30 746. 69 0.M. 0. El-Maghraby G. A. Bean B. B. Jarvis and M. B. Aboul-Nasr Mycopathologia 1991 113 109. 70 1. A. El-Kady and M. H. Moubasher Expt. Mycol. 1982 6 25. 71 B. B. Jarvis J. 0. Midiwo G. A. Bean M. B. Aboul-Nasr and C. S. Barros J. Nut. Prod. 1988 51 736. 72 B. B. Jarvis Y.-W. Lee T. Comezoglu S. N. Comezoglu and G. A. Bean Tetrahedron Lett. 1985 26 4859. 73 E. P. White P. H. Mortimer and M. E. diMenna in ‘Mycotoxic Fungi Mycotoxins Mycotoxicoses Vol. 1 ’ ed. T. D. Wyllie and L. G. Morehouse Dekker New York 1977 p. 465. 74 B. B. Jarvis and C. S. Yatawara J. Org. Chem. 1986 51 2906. 75 R. M. Eppley E. P. Mazzola M. E. Stack and P. A. Dreifus J. Org. Chem. 1980 45 2522. 76 Chem.Abstr. 1984 101 5555. 77 G. A. Bean T. Fernando B. B. Jarvis and B. Bruton J. Nat. Prod. 1984 47 727. 78 B. B. Jarvis J. 0.Midiwo D. Tuthill and G. A. Bean Science 1981 214 460. 79 Chem. Abstr. 1984 100 137375. 80 B. B. Jarvis G. P. Stahly G. Pavanasasivam J. 0. Midiwo T. DeSilva C. E. Holmlund E. P. Mazzola and R. F. Geoghegan J. Org. Chem. 1982 47 1117. 81 A. Kobayashi Y. Nakai T. Kawasaki and K. Kawazu Agric. Biol. Chem. 1989 53,585. 82 B. B. Jarvis N. B. Pena M. M. Rao N. S. Comezoglu T. F. Comezoglu and N. B. Mandava in ‘The Chemistry of Allelo-pathy’ ed. A. C. Thompson A.C.S. Symposium Ser. 268 1985 p. 149. 83 Chem. Abstr. 1984 100 186974. 84 Chem. Abstr. 1965 62 8947; 1968 68 67750. 85 C. Tamm personal communication.86 B. B. Jarvis K. M. Wells Y.-W. Lee G. A. Bean T. Kommedahl C. S. Barros and S. S. Barros Phytopathology 1987 77 980. 87 G. G. Habermehl L. Busam and M. Spraul Liebigs Ann. Chem 1985 633. 88 C. Tamm and W. Breitenstein in ‘The Biosynthesis of Mycotoxins’ ed. P. S. Steyn Academic Press London 1980 p. 69. 89 B. B. Jarvis G. Pavanasasivam C. E. Holmlund T. DeSilva G. P. Stahly and E. P. Mazzola 1.Amer. Chem. Soc. 1981 103 472. 90 B. B. Jarvis J. 0. Midiwo and M.-D. Guo J. Nut. Prod. 1989 52 663. 91 B. B. Jarvis Y.-W. Lee S. N. Comezoglu and C. S. Yatawara Appl. Environ. Microbiol. 1986 51 915. 92 G. Pavanasasivam and B. B. Jarvis Appl. Environ. Microbiol. 1983 46 480. 93 B. B. Jarvis G. A. Bean J. 0. Midiwo M. B. Aboul-Nasr J.Kuti and N. Mokhtari in ‘Mycotoxins and Phycotoxins Vol lo’ ed. S. Natori K. Hashimoto and Y. Ueno Elsevier Amsterdam 1989 p. 197. 94 T. Kommedahl H. K. Abbas C. J. Mirocha G. A. Bean B. B. Jarvis and M. Guo Phytopathology 1987 77 584. 95 C. J. Mirocha H. K. Abbas T. Kommedahl and B. B. Jarvis Appl. Environ. Microbiol. 1989 55 254. 96 M. Misawa M. Hayashi and S. Takayama in ‘Proc. 5th. Int. Congr. Plant Tissue Cell Cult.’ ed. A. Fujiwara Maruzen. Tokyo 1982 p. 279. (Chem. Abstr. 1983 99 155364.) 97 G. Habermehl Pure Appl. Chem. 1989 61 377. 98 N. Jeker and C. Tamm Helv. Chim. Acta 1988 71 1895. 99 N. Jeker and C. Tamm Helv. Chim. Acta 1988 71 1904. 100 D. W. Anderson R. M. Black D. A. Leigh and J. F. Stoddart Tetrahedron Lett.1987 28 2653. 101 D. W. Anderson R. M. Black D. A. Leigh and J. F. Stoddart Tetrahedron Lett. 1987 28 2657. 102 P. G. McDougal and N. R. Schmuff Fortschr. Chem. Org. Naturst. 1984 47 153. 103 C. Tamm and N. Jeker Tetrahedron 1989 45 2385. 104 B. Bohner and C. Tamm Helv. Chim. Acta 1966 49 2527. 105 B. Bohner and C. Tamm Helv. Chim. Acta 1966 49 2547. 106 B. B. Jarvis R. 0. Kollah and M. Zeng Quim Nova 1990 13 315. 107 R. Achini and C. Tamm Helv. Chim. Acta 1968 51 1712. 108 B. B. Jarvis J. 0. Midiwo and E. P. Mazzola J. Med. Chem. 1984 27 239. 109 W. Zurcher J. Gutzwiller and C. Tamm Hclv. Chim. Acta 1965 48 840. 110 B. B. Jarvis G. P. Stahly G. Pavanasasivam and E. P. Mazzola J. Med. Chem. 1980 23 1054. 111 B. B.Jarvis S. N. Comezoglu and M. E. Alvarez J. Org. Chem. 1988 53 1918. 112 B. B. Jarvis M. Zeng and E. P. Mazzola Tetrahedron Lett. 1990 31 4401. 113 B. Muller R. Achini and C. Tamm Helv. Chim. Acta 1975 58 471. 1 14 J. F. Grove J. Chem. Soc. Perkin Trans. I 1990 1 199. 115 B. Yagen and B. B. Jarvis J. Lab. Cpds Radiopharm. 1989 27 675. 116 0. Mitsunobu Synthesis 1981 1. 117 J. Gutzwiller R. Mauli H. P. Sigg and C. Tamm Helv. Chim. Acta 1964 47 2234 118 J. F. Grove J. Chem. Soc. Perkin Trans. I 1986 647. 119 N. Jeker and C. Tamm Tetrahedron Lett. 1989 30 6001. 120 W. Breitenstein and C. Tamm Helv. Chim. Acta 1975 58 1172. 121 T. Krishnamurthy and E. W. Sarver Anal. Chem. 1987 59 1274. 122 T. Krishnamurthy D. J. Beck and R.K. Isensee Biomed. Environ. Mass Spectrom. 1989 18 287. 123 T. Krishnamurthy and E. W. Sarver Biomed. Environ. Mass Spectrom. 1988 15 13. 124 T. Krishnamurthy and E. W. Sarver Biomed. Environ. Mass Spectrom. 1988 15 185. 125 H. M. Stahr M. Domoto W. Hyde andP. J. Martin Microchem. J. 1985 32 266. 126 J. D. Rosen R. T. Rosen and T. G. Hartman J. Chromatogr. 1986 355 241. 127 T. Krishnamurthy E. W. Sarver S. L. Greene and B. B. Jarvis J. Assoc. Of. Analyt. Chem. 1987 70 132. NATURAL PRODUCT REPORTS 1993 128 M. E. Stack and R. M. Eppley J. Assoc. Of. Analyr. Chem. 1980 63 1278. 129 T. Krishnamurthy D. J. Beck R. K. Isensee and B. B. Jarvis J. Chromatogr. 1989 469 209. 130 R. D. Smith H. R. Udseth and B. W. Wright J.Chromatogr. Sci. 1985 23 192.

ISSN:0265-0568    

DOI:10.1039/NP9931000429

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

P-Phenylethylamines and the lsoquinoline Alkaloids K. W. Bentley Marrview Tiffybirloch Midmar Aberdeenshire AB5 7 7PS Reviewing the literature published between July 1991 and June 1992 (Continuing the coverage of literature in Natural Product Reports 1992 Vol. 9 p. 365) 1 /3-Phenylethylamines 2 Isoquinolines 3 Naphthylisoquinolines 4 Benzylisoquinolines 5 Bisbenzylisoquinolines 6 Cularines 7 Pavines and Isopavines 8 Benzop yrrocolines 9 Berberines and Te trahydro berberines 10 Secoberberines 11 Pro to pines 12 Phthalide-isoquinolines 13 Spirobenzylisoquinolines 14 Rhoeadines 15 Other Modified Berberines 16 Einetine and Related Alkaloids 17 Benzop henan thridines 18 Aporphinoid Alkaloids 18.1 Proaporphines 18.2 Aporp hines 18.3 Aporphine-Benzylisoquinoline Dimers 18.4 Phenanthrenes 18.5 0x0-aporphines 18.6 Dioxo-aporphines 18.7 Aristolochic Acids and Aristolactams 18.8 Other Aporphinoid Alkaloids 19 Morphine Alkaloids 20 Homoaporphinoid Alkaloids 21 Colchicine and its Analogues 22 Erythrina and Related Alkaloids 22.1 Erq'rhrina Alkaloids 22.2 Homoerythrina Alkaloids 23 Other Isoquinoline Alkaloids 24 References 1 p-Phenylethylamines Ephedrine has been isolated from Hamelia patens' (this is the first reported finding of the alkaloid in the Rubiaceae) and N-trans-feruloyltyramine (1) has been isolated as a new alkaloid from Monocylcanthus vignei.2 A review of the occurrence of alkaloids of this and other groups in crop plants has been p~blished.~ Methods for the identification of ephedrine methylephedrine norephedrine and their pseudoephedrine analogues in Chinese Ephedra species have been publi~hed.~ Studies of the physiological effects of /3-phenylethylamine,5 e~hedrine,~.~ and norephedrine* and of the effects of ephedrine on the actions of aspiring have been reported.2 lsoquinolines Simple isoquinoline alkaloids have been isolated from the following plant species Cardiope talum calop hy llum dehydro-N-methylcorydaldine (2-methyl-6,7-dimethoxy-isoquinoline) Thalictrum foetidumll thalictamine Thalictrum minus12 thalictamine Xylopia vieillardi'3 backbergine and pycnarrhine The oxidation of salsolinol(2) in solution under physiological conditions has been shown to give the ortho-quinone (3) = (4) in the first instance with later production of the cis and trans forms of 4-hydroxysalsolinol (5) and finally the fully aromatic compound (6).14 In syntheses within this group the amide (7) has been converted by heating with acetic anhydride into the acetoxy- sulfoxide (8) which has been cyciized by acid to the tetrahydro- isoquinolone (9) and this has been desulfurized to N-methylcorydaldine (10) and degraded to N-methyldehydro-corydaldine (1 The E and Z isomers of the unsaturated sulfoxide (12) have been stereospecifically cyclized to tetra- hydroisoquinolines and the (R)-isomer (1 3) obtained in this way has -been desulfurized 'and N-rnethylated to (R)-(+)-carnegine (14)P A synthesis of salsolidine (1 5 R' = Me R2= H) has been achieved by conversion of the ester (15 R' = H R2 = OCOCMe,) into the anion with t-butyllithium and methylation of this to (15 R' = Me R2 = OCOMe,) fol-lowed by acid-catalysed hydr01ysis.l~ (9-( -)-Carnegine (1 5 Ph OH 0s' AcO SOPh Ho@~ Meo&)Me HO Me0 Me0 0 (7) 449 NATURAL PRODUCT REPORTS 1993 NH Me0 MeomNH Meow Me0 SO NO2 NO2 'SO Me R' '0 (14) (15) IVIGU I Me HNq Meh OH OMe Me "OWN OH Me R1= Me R2 = H) has been obtained in 66.6% excess over the (R)isomer by the reduction of the cation (16) with Mosher's reagent ;less stereoselective reduction was achieved with other reducing agents.Is Treatment of the acetoxyhemiquinone (17) with allyltrimethylsilane and boron trifluoride in dichloro-methane and trifluoroacetic acid yields 8-allylcorypalline (18 R1 = CH,CH =CH, R2 = H) whereas in acetonitrile the product is 4-allylcorypalline (18 R' = H R2 = CH,CH= CH2).19A review of the synthesis of lemaireocereine by the Claisen rearrangement of arylpropargyl ethers has been published.,O The metabolism of salsolinol in tissue cultures of Pupuver species has been studied.,' 3 Naphthylisoquinolines Alkaloids of this group all being new alkaloids have been isolated from the following plants species Ancistrocludus ubbreviutus22* 23 N-methyldioncophylline A (19) its atropisomer N-methyl-7-epi-dioncophyllineA michellamine A (20) and its atropisomer michellamine B Triphyophyllum peltat~m~~.25 dioncolactone A (2 l) dioncopeltine A (22) and dionco-phylline B (23) The structures of the new alkaloids were determined principally by spectroscopic methods and also by an X-ray crystallographic study of dioncopeltine A by the conversion of dioncopeltine A into the known 0-methyldioncopeltine A by the oxidation of dioncopeltine A to D-alanine and (R)-3-aminobutyric acid by the reduction of dioncolactone A to dioncopeltine A with lithium aluminium hydride and by the preparation of N-methyldioncophylline A and its 7-epi-isomer fi mMeqJMe HoHf Me HO e Me0 0 Me0 mMe OH Me0 OMf3 Me OMe Me0 (23) (24) by the methylation of the corresponding known secondary bases.Dioncophylline B (23) is the first alkaloid of this group to be discovered with a 7,6'-coupling of the isoquinoline and naphthalene units and it is also the first in which the diphenyl linkage is insufficiently hindered to prevent free rotation with the result that only one isomer of the alkaloid exists. The structure previously assigned to dioncophylline A has been confirmed by an X-ray crystallographic study.26A chemical method for the unambiguous assignment of axial chirality to rotational isomers of alkaloids of this group has been developed in which reactive groups on opposite sides of the stereogenic axis are connected. For example only one isomer of the ester-amide (24) is free from strain the rotamer being too highly strained to be Michellamines A and B clearly products of phenol oxidative coupling of incompletely methylated ancistrocladine and hamatine have been found to give complete protection from the cytopathic effects of Human Immunodeficiency Virus-I on human lymphoblastoid cells in vitro and michellamine B gives similar protection against the effects of HIV-II.23 Full details of the synthesis of bisdehydroancistrocladisine (25) and of 0-methylancistrocladine (26) from isoxazoles of general structure (28) and the Grignard reagents (29 R' = H R2 = MgBr R3= Me) and (29 R1= MgBr R' = H R3= Me) recorded in earlier reports,28have been publi~hed.~~*~~ The processes used for synthesizing the second of these alkaloids have been modified by substituting the Grignard reagent (29 R1 = H R2 = MgBr R3= CH,Ph) for its methoxy analogue and omission of the reduction of the dihydroisoquinoline after the Bischler-Napieralsky cyclization to effect a synthesis of NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY 451 OMe OMe HN5'dL02H 0 H02C' S Me0pMe OMe Me M$$$,&re' HO OMe Me Me0 \ OMe OMe OMe OMe Ph OMe Me '-OMe (27) (28) Me0+0R3 R2 oAo u (29) HO HO HO OH HO (33) (-)-ancistrocladinine (27) the first phenolic alkaloid of the group to be ~ynthesized.~~.~~ Attempts have been made to clarify the factors controlling the preferential production of diastereoisomers in the reactions of Grignard reagents with isoxazoles (28) which are essential steps in these ~yntheses.~~ Details of the preparation of N- benzyl-O-methyldioncolactone A (21 OH = OMe NH = NCH,Ph) an intermediate in a previously reported synthesis of dioncophylline A have also been published.33 ''%OH OH 0 (34) Me I Me0 CO2Et MeO% OMe ' OMe (35) 4 Benzylisoqu inol ines Benzylisoquinoline alkaloids have been isolated from the following plant species Anona ~alzrnanii~~ reticuline Guatteria go~dotianu~~ juziphine and reticuline Illigera parv@or~~~ reticuline Monocyclanthus vignei2 reticuline Neolitsea koni~hii~~ reticuline Papaver ~omniferurn~~ papaverine Plumula nel~mbensis~~ lotusine Sarcocapnos saetabensis4" crassifoline and N-methylviguine Xylopia vieill~rdi'~ N-methylcoclaurine and reticuline The electrolytic oxidation of tetrahydropapaveroline (30 R1= R2 = R3= H) has been shown to give initially the quinone (3 I) which in the absence of nucleophiles undergoes internal addition of the secondary amine to the quinone system to give the benzopyrrocoline (32) which is the product of enzymic oxidation.The quinone (3 1) will however react with any nucleophiles that may be present during the oxidation; for example in the presence of glutathione the isoquinoline (33) is formed and this can be further oxidized to the 6,7-quinone which reacts further with glutathione to give (34) and its 8,6'- disubstituted isomer.41 The methylation of (R)-and (S)-3-hydroxycoclaurine (30 R1= Me R2 = R3= H) with (9-adenosyl-L-methionine in the presence of mammalian catechol 0-methyltransferase has been found to give almost equal amounts of norreticuline (30 R1= R3 = M e R2 = H) and nororientaline (30, R1= R2 = Me R3 = H).Under the same conditions (R)-N-methyl-3-hydroxycoclaurinebehaves in the same way giving equal amounts of (R)-reticuline and (R)-orientaline but its (S) enantiomer gives largely (q-~rientaline.~~ (-)-Laudanosine has been stereospecifically ring opened by ethyl chloroformate to the optically active compound (35).43 NATURAL PRODUCT REPORTS 1993 Me0 OMe OH "eo*NH Me0 Me0 RO RO HOWR HOWR BoR OMe HowR OMe ' OMe OMe (36) (37) (38) (39) <mNMe Me0 m N Me BF3 M Me0e o m N -(-)S-phenylrnenthyl Me0 (40) (43) Me0 Me0 MeoTR HO Me0 Me0 ao> 0 ' OMe '0 (44) (45) (47) CI-Me0 cI-OMe Me0PC-(O-O$NP 3 OMe O OMe Me0 q '9-OMe OMe One of the side reactions in the Pomeranz-Fritsch synthesis published4' and the preparation of (R) and (S)forms of the of isoquinolines is formation of pavines and isopavines from base (44 R = Br) by resolution of the 0-benzyl ether with di- The 4-acetyl- the intermediate dihydroisoquinolines under the acidic condi- p-toluoyl-D-tartaric acid has been rep~rted.~' tions of the cyclization.It has been found that the formation of isoquinoline (45 R = H) has been synthesized by conventional these compounds can be largely avoided by effecting the methods and converted into the nitrile (45 R = CH,CN) cyclizations with benzoyl chloride in pyridine.In this way the careful reduction of which involved cyclization of the keto- acetals (36 R =Me) and (36 R = CH,Ph) have been suc- amine to the imine (46). This was reduced by a modified +)-normacrostomine (47 R = H), cessfully converted in good yield into the bases (37 R = Me) Iwakuma's reagent to (R)-( +)-(38 R = Me) (37 R = CH,Ph) and (38 R = CH,Ph). De- which was converted through (47 R = CHO) into (R)-( hydration of these bases gives papaverine (39 R = Me) and its macrostomine (47 R = Me).50A review of methods of synthesis analogue (39 R = CH,Ph).44 of benzylisoquinoline alkaloids has been published.51 Formation of an anion from N-methyl-6,7-dimethoxytetra-The rate of decay of atracurium (48) to laudanosine in vivo hydroisoquinoline involves loss of a proton from C-4 but the has been as have the physiological effects of this of laudano~ine,~~~~~ of ethaverine,62 cation (40) readily loses a proton from C-1 to give the ylid ~alt,~,-~' of pa~averine,~~-~l and of tetrahydropapaveroline.63 which reacts with 3,4-dimethoxybenzyl bromide to give of isocras~ifoline,~~ laudano~ine.~~ Similarly the anion of the methylenedioxy analogue of (40) with piperonal yields two isomers of the hydroxy compound (41).46 Loss of a proton from C-1 is also 5 Bisbenzyl isoquinol ines observed with (15 R1= H R2= CO,CMe,) and treatment of Bisbenzylisoquinoline alkaloids have been isolated from the the resulting ylid with dimethoxybenzyl bromide followed by following plant species the two marked with asterisks being reduction with lithium aluminium hydride gives 1audanosine.l' new alkaloids Modification of the Pictet-Spengler synthesis using the chiral Berberis poirettiP4 amide (42) and the masked aldehyde (43) affords a pre-berbamine dominantly stereospecific synthesis of (-)-la~danosine.~~ Cardiopetalum calophylluml* A patent for the synthesis of reticuline (44 R = OH) has been dauricine NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY OMe OH HO Ha-CI- OMe ' OH R Me0 OMe Me0 (53) (54) Cocculus trilobus65 isotrilobine isotrilobine-2-N-oxide* (49) trilobine and nortrilobine Dehaasia incrassataG6 oxyacanthine Menispermum d~uricum~~ dauriciline* (50) Plumula nelumbensi~~~ liensinine Thalictrum foetidum" hernandezine 0-methylthalicberine thalidezine and thaligosine Thalictrum fargesP thalfoetidine thalidasine thaligosinine and thaliso-pidine Thalictrum gland~losissimum~~ hernandezine and thalidezine Thalictrum minus70 obaberine oxyacanthine thalicberine O-methylthalic- berine and thaligosine In addition cepharanthine cycleanine and tetrandrine have atjehenine77 and the mass spectra of dauricine and daurisoline have been st~died.'~ A review detailing the botanical sources physicochemical and spectroscopic data and pharmacological properties of 122 bisbenzylisoquinoline alkaloids discovered in the years 19861989 has been published.79 Dauricine (55)has been synthesized by conventional methods involving Bischler-Napieralski ring closures of the isoquinoline units and the products have been resolved to give all four stereoisomers.80 Patents have appeared giving methods of preparation and claiming use as anti-tumour agents of ethers and esters of bisbenzylisoquinoline alkaloids specific deriv- atives of berbamine,81 cepharanoline,82 and isoliensinineR3 being cited as examples.The physiological and pharmacological effects of berb-amine,s4-88~epharanthine,"~~~ O,@-diacetyldaur-da~ricine,~~*~* is~line,~~ tetrandrine,85.88 96-99 trilobine,loO N,N'-dimethyltri- lobine iodide,'O' and tubocurarinelo2 have been studied. 6 Cularines Alkaloids of the cularine group have been isolated from the berbamine isotetrandrine and oxyacanthine have been isolated from unspecified varieties of Berberis Epimedium Mahonia Nandina and Podophyllum species,72 and N,N-di(chloromethy1)tetrandrine dichloride (5 1) has been isolated as an artefact from Stephania tetrandra during extraction of alkaloids with dichl~romethane.~~ A patent for the extraction of dauricine from Menispermum dauricum has been p~blished.'~ The absolute stereochemistry of pseudorepanduline has been assigned as in (52 R' = H R2= OMe) as a result of I3CNMR studies of this base and of repanduline (52 R1R2= OCH20)75 and similar studies have led to the assignment of the structures (53 R = OMe) and (53 R = H) to N-methyltiliamosine and tiliaresine respe~tively.~~ An X-ray crystallographic study has confirmed the structure (54) previously assigned to cyclo-been isolated from nine unspecified varieties of Ste~hania;~~following plant species Corydalis solidalo3 oxocularine and oxosarcocapnine Sarcocapnos ~aetabensis~~ celtine cularine isonoyaine oxocularine oxosarco-capnidine and sarcocapnidine The physiological effects of celtisine cularine and cularidine have been studied.59 7 Pavines and lsopavines Argemonine-N-oxide has been isolated from Thalictrum foeti- dum.'l The reduction of eschschlotzine (56) with sodium and liquid ammonia has been shown to give a mixture of the diphenols (57 R' = OH R2 = H) and (57 R' = H R2 = OH).104 Me0 Meo%OMe Me ' OMe 8 Benzopyrrocolines The conversion of tetrahydropapaveroline through the quinone (31) into the benzopyrrocoline (32) during electrochemical and enzymic oxidations4l is described in Section 4.9 Berberines and Tetrahydroberberines Alkaloids of the berberine group have been isolated from the following plant species the four marked with asterisks being new alkaloids Acangelisia gusanlunglo5 berberine gusanlung A* (58 R = H) gusanlung B* (58 R = Me) and jatrorrhizine Berberis poire t tii 64 berberine jatrorrhizine and palmatine Chelidonum majus106 berberine coptisine and tetrahydrocoptisine Corydalis caucasialo7 cheilanthifoline scoulerine and stylopine Corydalis esquiroliiloB cavidine isocorypalmine tetrahydrocoptisine and tetrahydrocorysamine Corydalis hsuchowensi~~~~ cheilanthifoline scoulerine and stylopine Corydalis omeiensisllO tetrahydrocolumbamine Corydalis solidalo3 berberine canadine corybrachylobine* (59) corydal-dine corydalidzine corydalmine dehydrocorydaline 13-methylcolumbamine ophiocarpine scoulerine and sinactine Corydalis stewartiilll cheilanthifoline scoulerine and stylopine Corydalis thyrsifolia1l2 cavidine sinactine and tetrahydrocoptisine Fagara chalybea113 jatrorrhizine Glaucium arabicum114 berberine coptisine jatrorrhizine oxyberberine pal- matine and thalifendine Papaver macrantha115 orientalidine Papaver orientale116 coptisine palmatine and scoulerine Ranunculus ~erbicus~~' berberine columbamine and palmatine Sarcocapnos saetabensis4" scoulerine NATURAL PRODUCT REPORTS 1993 OH 0 OMe Stylophorus lasiocarpum'18 berberine coptisine corysamine scoulerine stylopine and cis-and trans-N-methylstylopiniumhydroxide Thalictrum glandulosissimum68 berberrubine and 8-oxocoptisine Thalictrum minus69 berberine Xylopia vieillardi13 coreximine corydalmine corypalmine corytenchirine dehydrocorytenchirine* (60) dehydrodiscretine dis-cretine 1l-demethyldiscretine pseudopalmatine tetra- hydropalmatine and xylopinine In addition stepholidine has been isolated from nine unspecified varieties of Stephania71and both berberine and palmatine have been isolated from unspecified varieties of Berberis Epimedium Mahonia Nandina and Podophyllum specie^.'^ Oxidation of caseamine (61 R1 = R2 = H) caseadine (61, R1= H R2 = Me) and O-methylcaseadine (61 R1 = R2 = Me) with iodine has been shown to give the hemiquinone (62 R = H) from caseamine and caseadine and its ether (62 R = Me) from O-methylcaseadine whereas the oxidation of the isomeric phenols (63 R1= R2= H) (63 R1 = H R2 = Me) and (63 R1= R2 = Me) in the same way affords the protoberberinium salts (64 R1 = R2 = H) (64 R1 = H R2 = Me) and (64 R1 = R2 = Me) respe~tively."~ Photolysis of berberine phenol betaine (65) has yielded the pentacyclic ketone (66) which with ethyl chloroformate suffered ring fission to (67 R1 = C02Et R2= Cl) and this on conversion into (67 R1= R2= H) followed by further irradiation gave the lactam (68).N-Methylation of this gave the quaternary salt which on an ion- exchange column afforded some of the olefin (69).12" Trans- formation of a berberine analogue into a benzophenanthridine has been used in the synthesis of the alkaloid ambinine -see Section 17.A synthesis of the 13-methylberbine system with no cisltrans stereoselectivity has been achieved by the cyclization of the silane (70)I2l and 13-alkyl-8-oxotetrahydroxylopinines(72) have been prepared in good yields by the photochemical NATURAL PRODUCT REPORTS 1993-K. W. BENTLEY OMe (69) Me0 OMe OMe cyclization of olefins of structure (71).122Improved yields of 8-oxotetrahydroberberines have been obtained by modification of previousIy reported procedures.122 A review covering some methods of synthesis of alkaloids of the group has been published .51 The physiological and pharmacological effects of berber- ine,123-131tetrahydr~berberine,~~~.~~~ benzyl-berberr~bine,~~~ tetrahydr~palmatine,'~~ have been stud- and ~tepholidinel~~-'~~ ied.A method for estimating berberine in body fluids has been described.13g 10 Secoberberines A new secoberberine alkaloid coryximine (73 R = CO,H) has been isolated from Corydalis hsuchowensis. Its structure deduced from its spectra was confirmed by its reduction with lithium aluminium hydride to (+)-corydalisol (73 R = CH20H).'Og Narcotine diol(74 R = H) has been selectively acetylated to give papaveroxinoline (74,R = C0CH3).l4O 11 Protopines Alkaloids of the protopine group have been isolated from the following plant species Chelidonum majus104. 141 protopine Corydulis cau~asia'~~ allocryptopine and pro topine Corydalis esquiroliil O8 cryptopine muramine and protopine Corydalis hsuchowensi~~~~ pro to pine Corydulis omeiensisl'O allocryptopine cryptopine muramine and protopine Corydulis solidalo3 allocryptopine and protopine rnN\Cr OMe (71) OMe Corydulis stewurtiil'l cryptopine Corydalis thyrsifolial pro topine Gallium a~arinel~~ pro to pine Glaucium urabicuml allocryptopine and protopine Sarcocapnos saetabensis40 protopine Stylophorum lasiocarpuml l8 allocryptopine and cryptopine Thalictrum foetidumll pro topine Thalictrum glandulosissimum68 cryptopine and protopine Dihydrocryptopine (75 R1 = R2 = H) on treatment with chromium tricarbonyl gives a single coordination complex (76 R1 = R2 = H) the structure and stereochemistry of which were determined by X-ray crystallographic examination.Methyl- ation of this complex gave the methyl ether (76 R' = Me R2 = H) obtained also directly from (75 R' = Me R2 = H). Deprotonation of (76 R' = Me R2 = H) followed by alkyl- ation and removal of the chromium yielded the bases (75, R1= R2 = Me) and (75 R1 = Me R2= CH2NMe2). Crypto- pine also reacts readily with chromium tricarbonyl but a mixture of products is obtained consisting of the ketone analogue of (76 R1= R2 = H) (32%) the isomeric complex (77) (1 1 %) and the di-coordinated complex of uncertain stereochemistry (78) (3 12 Phthalide-isoquinolines Phthalide-isoquinoline alkaloids have been isolated from the following plant species Corydulis caucasialo7 adlumidine bicuculline and /I-hydrastine NATURAL PRODUCT REPORTS 1993 Me0 OHC bMe (79) <%o) C02H '0 (84) OMe '%OMe ' OMe \ OMe (89) (90) Corydulis esquiroliilos bicuculline and corlumine Corydulis hsuchowensi~'~~ adlumine bicuculline and humosine A Corydulis omeiensis' lo bicuculline and corlumine Corydalis solidu'03 bicuculline and a-hydrastine Corydulis thyrs$oliu1l2 adlumidine bicuculline corlumine and fumaramine Pupuver ~omniferurn~~ narcotine The confusion of nomenclature in the literature between (+)-and (-)-bicuculline has been ~1arified.l~~ An X-ray crystallographic study of the conformation of capnoidine has been reported.145 Dihydronarceone imide (79) has been cyclized to the tetracyclic compound (80).146 Treatment of the ylid resulting from the removal of a proton from (40) with the aldehydo-esters (81 R1= R2 = Me) and (81 R1R2= CH,) has resulted in the synthesis of cordrastine (82 R' = R2 = Me) and corlumine (82 R1R2= CH,) with an erythro threo ratio of 5 1.45 Similarly the ylid from the methylenedioxy analogue of (40) on treatment with the dialdehyde (81 R1R2= CH, CO,Et = CHO) yielded a mixture of erythro and threo alkaloids corytensine and egenine (83).46Oxidation of the olefin (84)has afforded adlumidiceine (85) its two enol lactones (86) and (87) and bicucullinine (88).147Bicucullinine has been converted into fumaramine.'12 Some amino-substituted analogues of hydrastine and nar- cotine have been synthesized as potential pharmaceutical The mutagenic effects of narcotine have been st~died.'~' 13 Spi ro benzy I isoquino1ines Spirobenzylisoquinoline alkaloids have been isolated from the following plant species Corydalis hsucho~ensis~~~ sibiricine OR2 OR2 OMe OMe OMe Corydulis solidalo3 corpaine fumariline fumaritine fumarophycine parfu- mine and sibiricine Corydulis stewartii' ' yenhusomidine Corydulis thyrsifolia112 ochotensine and sibiricine The conversion of berberine into certain spiro-compounds is described in Section 9.14 Rhoeadines Papaverrubines A B C D and G have been isolated from Pupuver orientule.'l6 A method for the isolation and estimation of isorhoeadine and rhoeagenine from petals of Pupuver rhoeus has been described.150 15 Other Modified Berberines Two new alkaloids that can be regarded as modified berberines namely dehydropuntarenine (89 R'R2 = CH,) and dehydro- saulatine (89 R' = R2= Me) have been isolated from Berberis actinu~unthal~~ and an alkaloid that was not fully characterized but may be puntarenine has been isolated from Thulictrum glundulosissimum.68 Base-catalysed condensation of hydrastinine with dimethoxy- phthalide yields 1 3-hydroxy-8-oxotetrahydroberberine(90) and this has been oxidized to the 8,13-dioxo-compound and finally to the hydroxydione (9 1) which following a previously reported procedure has been rearranged by aqueous ammonia to chilenine (92) thus providing a convenient short synthesis of this alka10id.l~~ 16 Emetine and Related Alkaloids The known alkaloids alangiside ipecoside (93 R1= OH R2 = R3= H R4 = Me) neoipecoside (93 R1= R2 = H R3 = OH R4= Me) and 7-0-methylneoipecoside (93 R1= H R2= R4 = Me R3= OH) and the four new alkaloids 6-0-methyl- NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY 0 CHpOH (93) Me0 Me0 0 ipecoside (93 R1 = OMe R2 = R3 = H R4 = Me) ipecosidic acid (93 R' = OH R2 = R3= R4 = H) demethylalangiside (94) and 3,4-dehydroneoipecoside (95) have been isolated from Cephaelis ipe~acuanha.'~~ The structures of these new alkaloids were determined by spectroscopic methods and confirmed by interconversions with known alkaloids of the group. A chirally predominant synthesis of (97) an intermediate in the synthesis of emetine and its analogues has been achieved from (96) following previously reported prin~ip1es.l~~ A review of the cardiotoxicity of emetine and its analogues has been ~ub1ished.l~~ 17 Benzophenanthridines Benzophenanthridine alkaloids have been isolated from the following plant species the two marked with asterisks being new alkaloids Bocconia integrifolia156 dihydrochelerythrine 12-methoxydihydrochelery-thrine* (98) dihydrochelirubine and dihydro-sanguinarine o+=OH CHpOH (94) Chelidonum majus106.14' chelidonine homochelidonine 6-methoxydihydro-chelerythrine 6-methoxydihydrosanguinarine and sanguinarine Corydalis solidalo3 chelidimerine and norsanguinarine Corydalis thyrsifolia' 8-acetonylsanguinarine and dihydrosanguinarine Corydalis tra~hycarpal~~ corynoline 8-acetylcorynoline and 8-oxocorynoline Fagara chalybea113 chelerythrine and dihydrochelerythrine Glaucium ~rabicuml'~ norchelidonine Sarcocapnos saetabensi~~~ chelamine chelidonine and ( +)-14-epichelidonine*(99) Stylophorum lasiocarpum chelerythrine chelidonine chelilutine chelirubine macarpine and sanguinarine Zanthoxylum budrunga15' dihydroavicine In addition sanguinarine has been isolated as the major alkaloid of a complex mixture of isoquinoline alkaloids produced in callus cell cultures of Chelidonum maj~s.'~~ The alkaloids isolated from Chelidonum majus have been claimed to be dependent upon the mode of fixation and digestion of the plant material.160 A patent for methods of purification of extracts of benzophenanthridine alkaloids has been pub-lished.The crystal structure of chelidonine has been determined162 and the I3CNMR spectrum of chelidimerine has been In syntheses within the group Diels-Alder addition of dimethoxybenzyne to the isocyanate (100) has afforded the lactam (lOl) which has been successively reduced and dehydrogenated to nornitidine (102).1640-Methylfagaronine chloride (105) has been synthesized from the olefin (103) by hydroboration and oxidation to give (104) followed by cyclization reduction of the lactam system and dehydro- genati011.l~~ A first synthesis of ambinine (109) has been achieved from the synthetic dihydroberberinium salt (106).Hofmann degradation of this gave the olefin (107) which was converted by hydroboration and oxidation into the aldehyde (1OS) isolated as the dimethyl ketal. Acid-catalysed cyclization of the ketal yielded the cis-fused alkaloid (109).'66Nitration of ethoxydihydrosanguinarine in methanol yields the nitro-methoxy-dihydro base (1 10 R = NO,) and this on reduction to the amine (1 10 R = NH,) and diazotization yields a diazonium salt that on warming with methanol gives the bocconine analogue (1 10 R = OMe).167A review of methods of synthesis of chelerythrine has been published.20 The physiological effects of sanguinarine have been stud- ied168.169 and patents have been published covering the use of benzophenanthridine alkaloids as anti-tumour agent^.'^^^^^^ 18 Aporphinoid Alkaloids 18.1 Proaporphines Proaporphine alkaloids have been isolated from the following plant species Neolitsea konishiF glaziovine and stepharine Plumula nel~mbensis~~ pronuciferine 18.2 Aporphines Aporphine alkaloids have been isolated from the following plant species the four marked with asterisks being new alkaloids Anona salzmaniP4 anonaine isoboldine and laurelliptine Aristolochia ~lematitis'~~ magno florine Cardiopetalum calophyllumlO anonaine asimilobine isoboldine and norushinsunine Corydalis caucasia'O bulbocapnine isoboldine N-methyllaurotetanine and norisocorydine Corydalis hsuchowensi~'~~ bul bocapnine Corydalis solidalo3 bulbocapnine and isoboldine Dehaasia incrassata66 isocorydine and norisocorydine NATURAL PRODUCT REPORTS 1993 Glaucium arabicum114 isoboldine magnoflorine and thaliporphine Guatteria g~udotiana~~ anolobine corytuberine dehydronantenine dehydro- neolitsine* (1 1l) goudotianine* (1 12 IX1 = H R2 = Me) 3-hydroxynornuciferine isol=Adine isodomes- ticine norisodomesticine laurotetanine N-methyl-laurotetanine and neolitsine Illigera parvijlora36 actinodap hnine hernovine and li tsiferine Lindera megaphylla'73s 17* dicentrine Liriodendron t~1ipifei-a'~~ glaucine N-methyllaurotetanine lirioferine and lirio- tulipiferine Monocyclanthus vignei asimilobine and N-methylasimilobine Nectandra sinua ta' nordomesticine 3-methoxynordomesticine* (1 13) nor- lirioferine and 3-methoxynornantenine Neolitsea konishii 37 actinodaphnine boldine corytuberine isoboldine laurolitsine laurotetanine N-methyllaurotetanine and nornuci ferine Papaver macran tha' l5 isothebaine Papaver orientale116 bracteoline isoboldine N-methylisothebaine hydroxide and magnoflorine Platycapnos ~picata'~~ glaucine and nantenine Platycapnos ten~iloba'~~ glaucine and nantenine Plumula nelumben~is~~ nuciferine Ranunculus serbicus' l7 magnoflorine Sarcocapnos saetabensis40 dehydroglaucine glaucine isocorydine and O-methyl- atheroline Stylophorum lasiocarpumlls corytuberine isoboldine and magnoflorine Thalic trum minus6' magnoflorine Xylop ia vie illa rdi' anolobine calycinine corytuberine isoboldine magno- florine norglaucine nornantenine xylopine and de- hydroxylopine* (1 14) NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY 0 0 QcoNprL OMe OMe OMe OMe MeogH2 OMe Me0 Ho Me0 CONPrL Meo~ Me0 CONPrh \ \ 'OMe 'OMe OMe OMe In addition crebanine dicentrine and isocorydine have been isolated from unspecified varieties of Stephania71 and magno- Aorine has been found in unspecified varieties of Berberis Epimedium Mahonia Nandina and Podophyllum species.72 The structure of goudotianine was confirmed by the synthesis of the two isomeric bases (1 12 R1 = H R2 = Me) and (I 12 R'= Me R2 = H) the former being identical with the alkaloid.35 An X-ray crystallographic study of nanteni~~el~~ and a study of the 13C NMR spectrum of glaucine hydrofluoro- borate17' have been reported.The preparation of N-methyl- N-propyl- and N-allyl-3-chloro- and 3-bromonorapocodeines from the corresponding derivatives of 7-chloro and 7-bromo-6- demethoxythebaine has been described.lso A review of methods of synthesis of aporphine alkaloids has been published .51 The pharmacological and physiological effects of apo-Monocyclanthus vignei 7-oxodehydroasimilobine Xylopia vieillardi'3 lanuginosine and oxoglaucine 18.6 Dioxo-aporphines 4,5-Dioxodehydroasimilobine and the new alkaloid 1. demethoxy-4,5-dioxoasimilobine(115) have been isolated from Monocyclanthus vignei the structure of the new base being deduced from its 13CNMR spectrum.2 18.7 Aristolochic Acids and Aristolactams Aristolochic acids and aristolactams have been isolated from the following plant species the acid (1 16) being a new alkaloid N-propylnorapomorphine,laa b~ldine,'~~-~~~ morphine,6*181-'a7 Aristolochia clematiti~l~~ lS2glaucine,'26* di~entrine,~~~.175*lS3 isocorydine,lS4 liri~ferine,'~~ aristolochic acids I and I1 and aristolactam N-P-D-liri~tulipiferine,'~~ and stephaninelS5 N-methylla~rotetanine,~'~ have been studied. 18.3 Aporphine-Benzylisoquinoline Dimers Adiantifoline thalmelatine and 0-methylthalmelatine have been isolated from Thalictrum minus.69 18.4 Phenanthrenes Phenanthrene alkaloids belonging to the aporphinoid group have been isolated from the following plant species Guatteria g~udotiana~~ argentinine Monocyclanthus vignei2 argentinine stephanthrine stephanthrine-N-oxide 8-hydroxystephanthrine and 8-hydroxystephanthrine-N-oxide Platy capnos sp ica tal ' thalicthuberine Platycapnos tenuil~ba''~ thalicthuberine 18.5 0x0-aporphines 0x0-aporphine alkaloids have been isolated from the following plant species Cardiopetalum calophyllumlo liriodenine glucoside Aristolochia pontic~m''~ aristolochic acids I and 11 9-methoxyaristolochic acid I1 (116) aristolactams I and 11 and 9-methoxy- aristolactam I Monocyclanthus vignei aristolactam A I1 18.8 Other Aporphinoid Alkaloids A new synthesis of the amide (1 17) previously converted into the aza-aristolactam eupolauramine (1 18) has been reported.l" Condensation of the bromo-aldehyde (1 19) with the arylboric acid (120) affords the aldehyde (1 2 I) which has been converted by condensation with nitromethane and reduction into the amine (122).Bischler-Napieralski ring closure of this followed by dehydrogenation has given the alkaloid imelutine (I 23) which is regarded as a degraded aporphine.lga 19 Morphine Alkaloids Alkaloids of the morphine group have been isolated from the following plant species the N-oxide (124)being a new alkaloid Alseodaphne perakensi~'~' 0-methylflavinantine-N-oxide(1 24) Cardiopetalum calophyllum'O pallidine Corydalis stewartii"' sinoacu tine NPR 10 Me0 N-C02Me N-C02Me Me0 HO N-C02Me 0 HO HO Meo-Gua t ter ia goudo tiana35 pallidine Neolitsea koni~hii~~ pallidine Papaver macran t ha’ ’ oripavine and thebaine Papaver orientale’ ’ti N-me t h yl thebaine hydroxide Papaver somniferum3* codeine morphine and thebaine Platycapnos saxicola’ 77 sinoacutine Sarcocapnos saetabensis40 0-methylpallidine and salutaridine A review of low codeine yielding varieties of Papaver somniferum200and a method for the estimation and isolation of morphine codeine and thebaine from ‘poppy straw’201 have been published.N-Methoxycarbonylnorcodeinone (1 25) has been photo-chemically rearranged in aqueous tetrahydrofuran with mi- gration of the aromatic nucleus to the unsaturated keto-alcohol (126 R = H) the methyl ether of this (126 R = Me) being the product of rearrangement in methanol. Reduction of these products with lithium aluminium hydride leads to the N-methyl saturated ketones (127 R = H) and (127 R = Me) respectively the sterically hindered keto group being unaf- fected.,02 Photolysis of 5-methylcodeinone (128 R = Me) in methanol yields the cyclic ether (129 R = Me) whereas under the same conditions photolysis of the N-carbomethoxy analogue (128 R = C0,Me) affords a mixture of (129 R = C0,Me) and the olefin (130).The olefin (130) is however the sole product of photolysis of (128 R = C0,Me) in benzene and is completely converted by an internal Michael addition into the cyclic ether (129 R = C0,Me) under the influence of base.202In complete contrast with these reactions the photolysis of (1 25) in the presence of oxalic acid affords the chiral enamide NATURAL PRODUCT REPORTS 1993 NR NR 0 Me0 9@?Me0 0-.Me HO (131) which has been reduced with lithium hydride to 6-0- demethylneodihydrothebaine (1 32).,03 The 4-nitrobenzoyl ester of 14-chlorocodeine (133 R = C1) suffers inversion on hydrolysis to give 14-chloroisocodeine (134) whereas the ester of the related 14-bromocodeine (133 R = Br) suffers allylic rearrangement as well as inversion to give 7P-bromoisoneopine (1 35).,04 Hofmann degradation of 14-hydroxycodeinone (1 36 R = OH) gives the methine base (137) which when heated with methyl iodide and potassium hydroxide in dimethyl sulfoxide affords 6-methoxymorphenol (139 R = Me) rather than the 14-vinyl compound which would be the normal product of Hofmann degradation.,05 This reviewer feels obliged to record that this work is not original.In 1980 he supplied the first named author of this paper,2o5 then his research student with suggestions for further work including full details of this work as accomplished in 1974 by Dr G. D. Khandelwal to whom no credit is now given. The work was not published in 1974 since it appeared that 6-methoxymorphenol had already been prepared by a probably related process. Fleischhacker and ViebockZo6 report the reduction of the compound to thebaol (141 R = H) and refer to its preparation by Klintz207 in 1944 from the dimethyl ketal of 14-bromocodeinone (136 R = Br). Formation of the compound from the base (137) presumably proceeds by quaternization and enolization towards C-5 which involves little ring strain once the nitrogen-containing ring has been opened followed by the E2‘ elimination of hydroxyl ion as shown in (1 38 R = OH).This process is essentially similar to that involved in the production of acetylthebaol(l41 R = Ac) during the acetolysis of thebaine methiodide through (140). Clearly the initial product of this elimination must be 6- hydroxymorphenol (1 39 R = H) and this must be methylated by quaternary salt to (139 R = Me) and it may be noted that Khandelwal found conditions under which this phenol (1 39 R = H) is the principal product. Details of Klintz’s preparation of 6-methoxymorphenol are not readily available but it may be NATURAL PRODUCT REPORTS 1993-K. W. BENTLEY 461 SR SR (146) (147) Me0 Me0 Me0 Me0 0 0 Me0 Me0 Me0 Me 0 assumed that a similar process is involved with elimination of bromide ion from the dimethyl ketal or enol methyl ether of (138 R = Br) or the mechanistically equivalent elimination shown in (142) in all of which cases the product would be the methoxy-compound (139 R = Me) and not the phenol (139 R = H).Northebaine has been converted through the bromoketal (143) into the aziridine (144) which yielded the chloroketone (145) on treatment with hydrochloric acid.208 Diels-Alder addition of thebaine to various substituted p-benzoquinones has afforded the adducts (146 R = CH,OH) (146 R = CH,CO,H) (146 R = CH,CO,Me) and (146 R = CH,CH(NH,)CO,H) which have been rearranged in acid RS (148) (149) to the correspondingly substituted quinols (147) and these on thermal rearrangement have furnished the correspondingly substituted benzofurans (148).,09 Diels-Alder addition of thebaine to trifluoroacetaldehyde and to pentafluoropropion- aldehyde yields the adducts (149 R = CF,) and (149 R = CF,CF,) which have been hydrolysed to the 14-substituted codeinones (150 R = CF,) and (150 R = CF,CF,) and these have been reduced to the correspondingly substituted codeines (151).210 In contrast with these additions the Diels-Alder addition of thebaine to ethyl thioformate proceeds in the opposite sense giving as primary adduct the C-14-sulfur linked base (152) which can be isomerized by base to (153) and rearranged by heat first to (1 54) and finally to the 4,6-linked cyclic ether (1 55).Treatment of (152) with 2-oxopropanethiol yields the ketone (156) an analogue of the adduct of thebaine and methyl vinyl ketone which with n-propylmagnesium iodide gives the alcohol (1 57) and this is an analgesic considerably less potent than 3-O-methyletorphine.211 Diels-Alder additions of 5-methyl-6-demethoxythebaine (158) proceed with the formation of both 6,14-endo and 6,14- exo compounds the products with methyl vinyl ketone being (1 59 R = Me) and (1 60 R = Me) with ethyl acrylate they are (159 R = OEt) and (160 R = OEt) and with maleic anhydride they are (161) and (162).,12 Heating of the toluenesulfonates (163 R1 = OMe R2 = Me) and (163 R1 = OMe R2 = H) and their analogues in which R' = H and in which R' = Cl with sodium azide affords principally the aziridines (1 64 R' = OMe R2= Me) and (1 64 R' = OMe R2 = H) and their analogues in which R1 = H and C1 together with smaller quantities of the correspondingly substituted azides (165) and in the cases where R2 = H the olefins (166 R = OMe) (166 R = Cl) and (166 R = H).,13 The demethylation of thebaine to oripavine in vivo has been The bonding of water in hydrates of 14-hydroxy-dihydromorphinone and 14- hydroxydihydrocodeinone has been studied by NMR An X-ray crystallo- graphic study of naltrexone has been made2I6 and details of the preparations of the following have been reported 3-0-acetyl-a-isomorphine,21 3-O-acetylis~codeine,~~~ 14-methoxy-N-cyclopropylmethyl-3-demethoxy-tetrahydrodeoxycodeine, 218 the bimolecular bases (167 R = H) (167 R = Me) and (168),219 the bimolecular hydrazones (169 X = CH,) and (169 X = CH2CH,0CH,),220 the amino acid esters (170 rn = 1 n = 7) (170 rn = 1 n = ll) (170 rn = 1 n = 17) (170 rn = 2 n = 7) and (170 rn = 2 n = 1l),,,l the spirohydantoins (171 R1= R2 = H R3 = Me) (171 R1 = R3 = Me R2 = OH) (171 R' = H R2 = OH R3 = CH,CH=CH,) and (171 R' = H R2= OH R3 = CH2C3H5),222 the sulfate esters (172 R = CH,CH=CH,) (172 R = CH2CH=CMe2) and (172 R = CH,C3H5),223the thiogycolic acid derivative (1 73),224 and 3-chloro and 3-bromo-apocodeines and the N-propyl and N-NATURAL PRODUCT REPORTS 1993 Me0 Me leOJA -.. (174) ally1 derivatives of the corresponding norapocodeines.180 In addition patents have been published covering the preparation and pharmaceutical uses of 3-0-eth~lmorphine,~~~ esters of naloxone and naltrexone,226 N-cyclopropylmethyl-6-thio-4,5-deoxynor-a-isomorphine and its analogues,227 N-alkyl N-cycloalkyl and N-ally1 derivatives of 14-hydroxydi-hydrodeoxynorrnorphine,228n~rbinaltorphimine,~~~ and ( +)-etorphine.230 Methods for the detection and estimation of m~rphine,~~l-~~~ norm~rphine,~~~ 6-0-a~etylmorphine,~~~ codeine,231 nor-codeine,231 14-hydroxydihydrocodeinone, 234 nal trexone 235 236 6P-naltrex01,~~~ have been published.and ~inomenine~~~ The analge~ic~~~-~~~ and electrophysiologica1263 effects of morphine its pharmacokineti~s~~~-~~~ and pharmaco-dynamic^,^^^.^^^ and the binding of the alkaloid to receptors270 have been studied as have the effects of morphine on behavio~r,~~l-,~~ on the on the cardio-vascular System,245,285-289 on respiration,286$290,291 on the immune re- sponse ~ystem,~~~-~~~ on the gastro-intestinal tract,295 on the liver,296 on the and thyroid297 glands on the on the new-b~rn,~~~ hippocampu~,~~~ on the spinal 301 on renal on spleen cells,3o3 on the growth of metastatic cancer cells,3o4 on the general metabolism of pigs,3o5 on temperature,306 on locomotor on the cough on the release of histamine,309 of luteinizing hor- mone306 and of ~ubstance-P,~~~ on the production of milk310 and of lymph~kinase,~~' on the replication of human immuno- NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY Me0 HCHO '*% R'O Me0 10 R2 OMe (177) OAc MeO 20 Homoaporphinoid Alkaloids Alkaloids of Colchicum autumnale with special reference to the homoproaporphines (175 R = H) and (175 R = Me) have been evaluated as inhibitors of choline-estera~e.~~~ 0 21 Colchicine and its Analogues Alkaloids related to colchicine have been isolated from the following plant species the four marked by asterisks being new alkaloids Colchicum aut~mnale~~~ deficiency virus,312p313 on the hydroxylation of N-acetoacetyl-N-deacetylcolchicine 2-0-demethylco-on the activity of adenylcyclase315 and the levels of cyclic- chifoline P-lumicolchicine y-lumicolchicine and N-AMP316,317and on the effects of ovarian of acetoacety 1-N-deacety 1-y-lumicolchicine n~radrenalin,~'~ of NMDA-antagoni~ts,~~'and of apo-Colchicum morphine.321 The metabolic glucuronidation of androbiphenylline 3-0-demethyl-N-deacetyl-N-formyl-and the effects of ephedrine on the toxicity of morphine7 have P-lumicolchicine" (1 76) jerusaelemine* (1 77 R1= H also been studied.R2 = OH R3 = OMe) salimine* (177 R' = Me The morphine antagonist properties of na10xone238.323.324 R2 = C02H R3 = OMe) and suhailamine* (177 have been studied as have the effects of this compound on R' = Me R2= H R3 = C0,Me) on behavio~r,~~'-~~~ pain,325.326 on the cardio-vascular sys-Sanderson ia auran tica402 tem,335-337 on on the brain,339 on the spinal colchicine on the activity of enzymes,34o on haemorrhagic The chemical structures and absolute stereochemistry of the ~~rd,~~~.~~~ shock,341 on convulsions resulting from electric on alkaloids of this group have been reviewed403 and a method for amygdaloid kindling,343 on ischaemically damaged intestine,344 estimating colchicine has been described.404 The glycosides on the secretion of luteinizing horm~ne~~~*~~~ colchicoside and thiocolchicoside have been enzymatically and of pro-on the self-administration of cocaine,347 and on the acetylated in the glucose unit with excellent regioselectivity for la~tin,~~~ effects of amphetamine348 and of chlordia~epoxide.~~~ the CH,OH group.4o5 The pharmacological properties and physiological The pharmacological properties and physiological actions of and N-deacetylc~lchicine~~~ effects of the following have also been studied (+)-~01chicine~~~~~~ have been studied.6-0-a~etylrnorphine,~~~~~~~ 3,6-di-O-acetylmor-phine (her~in),~~~.~~~,~~~ mor-morphine 3-glu~uronide,~~~,~~~ phine-6-gluc~ronide,~~~* 315 354-358 codeine,270,308,350.351.35!&362 6-22 Erythrina and Related Alkaloids 0-met hy lmorp hine (he terocodeine) 27 O 3,6- 0,O-dime thyl- 22.1 Erythrina Alkaloids 3-0-(2-morpholino-Erysotramidine erysotrine-N-oxide erythratine and the new 3-0-ethylm0rphine,~~~*~~~ ethy1)morphine (phol~odine),~~~ 14-hydroxydihydro-alkaloid erythristemine-N-oxide (1 78) have been isolated from 364 codeinone,260 3-0-acetyl-N-cyclopropylmethyldihydronor-Erythrina bidwillii. The structure of the new alkaloid has been naltre~one,~~~ naloxone 6-spiro-confirmed by its preparation from erythristemine by oxidation m~rphinone,~~~ 366-372 hydan toin nal bup hine nal trexamine nal trexhydra- with m-chloroperbenzoic ~ine,~~ 37 na1mefene,344 norbinaltror- Oxidation of erysotramidine in acetonitrile and acetic acid p-funal t~examine,~~~.has afforded the acetoxy-compound (1 79) which on reduction phimine,368,378-380 eto~phine,~~' dihydroet~rphine,~~',~~~ b~prenorphine,~~~. 1 6-me thylcyprenorp hine 368 and with lithium aluminium hydride affords the alcohol (1 80, 383-391 ~inomenine.~~~ R = H) and the acetyl ester of this (180 R = COCH,) is not Patents have been published covering the use of bupre- identical with erythrascine to which this structure was norphine in the treatment of cocaine abuse393 and the use of the previously assigned.413 The chemistry of the alkaloids of the complex pyrroles (174) in which R1is alkyl cycloalkyl or aryl group has been reviewed.414 and R2is H or OH as inhibitors of the necrosis of brain cells.394 In syntheses within this group the ester (181) previously Reviews have been published of the use of opium alkaloids as reported on treatment with phenylselenium chloride has yielded receptor-affinity labels,395 of opioid analgesics,396 and of opioid a mixture of (182 R' = H R2 = SePh) (182 R1= C1 R2 = receptor antagonists derived from naltrex~ne.~~~ SePh) and (183 R = SePh).The first of these products on 464 Me0 Me0 Me0 MeO *' C02Et Me0 \r/-0 OR (184) Me0 0 Me0 OH CO2Et 0 (193) hydrolysis gave the ketone (183 R = H) the second was converted through (183 R = C1) and (182 R' = R2= OMe) into the same ketone (1 83 R = H) and the third gave (1 84) on treatment with sodium sulfide in methanol.Of these compounds the ketal (182 R1= R2= OMe) on reduction yielded (185 R = H) and this was converted into the methyldithiocarbonate ester (185 R = CS-SMe) which on treatment with butyltin suffered opening of the three-membered ring to give (186). It was found that the ethyl ester series resisted hydrolysis and decarboxylation but the corresponding methyl ester was easily converted into the enol ether (187) which on hydrolysis and decarboxylation yielded (1 88). Reduction of this gave the alcohol (189 R = H) the methyl ether of which (189 R = Me) was converted into (190) by treatment with phenylselenium chloride.Oxidative elimination of (190) yielded the doubly unsaturated keto-amide (191) from which erysotramidine (192 X = 0)and erysotrine (192 X = H H) have previously been prepared.415 Internal aldol condensation of the diketone (193) affords the ketol (194) which is rearranged by polyphosphoric acid presumably through (195) to the keto-ester (196) thus blocking further progress. Diels-Alder addition of 1-methoxy-4-tri-methylsilyloxybutadiene to the enone (197) yields (198) which is rearranged by heat to (199) and this has been converted into (200).416 The stereochemistry of reductions of 7-ketones of general structure (201) has been studied. Sodium borohydride in ethanol/tetrahydrofuran yields mainly the 7P-hydroxy-com- pound whereas the 7a-isomer is the principal product of reduction with tetrabutylammonium borohydride in methanol ; the isomeric excess is not more than 3 1 with any reagent.417 NATURAL PRODUCT REPORTS 1993 Me0 Me0 Me0 Me0 Me0 OH OEt CO2Et -V (195) OSiMe3 (199) The stereochemistry of the phenylselenation of the olefins (202) in methanol has been examined.The ester (202 R = C0,Et) suffers attack on the least hindered face to give (203 R = CO,Et) whereas (202 R = H) is attacked on the opposite face which is also the least hindered in this compound the selenium becoming attached at C-3 in each case. The structures of the products were confirmed by X-ray studies of the elimination products e.g.(204).41s 22.2 Homoerythrina Alkaloids The alkaloids (205 R1= R2 = Me) (205 R1R2= CH,) 3-0- methylrobustidine (206 R1R2= CH, R3 = OH R4 = H) comosivine (206 R1 = R2 = Me R3 = H R4 = OMe) and the two new alkaloids 201-hydroxycomosivine (206 R' = R2= Me R3 = OH R4 = OMe) and 2a-hydroxydyshomoerythrine (206 R1R2= CH, R3 = OH R4 = OMe) have been isolated from Phelline c~mosa.~~~ The structures of the new alkaloids were determined by comparison of their spectra with those of known alkaloids of the group especially those of 3-epi-2,18-dimethoxy- schelhammericine cited as a new alkaloid in the previous review which is 2a-methoxydyshomoerythrine (206 R1R2= CH, R3 = R4 = OMe). A review of the homoerythrina alkaloids has been and the metabolism of homoharringtonine has been 23 Other lsoquinoline Alkaloids The novel alkaloid enkleine (207) has been isolated from Enkleia siarnensi~.~ Hirsutine also a new alkaloid has been isolated from 465 NATURAL PRODUCT REPORTS 1993-K.W. BENTLEY OSOZMe OS02Me Me0 Me0 PhSe'.. OMe OMe R4 OMe 0-0 0 Q Meoa 0 HODC' \ '*OMe N\ Me0A N AO O* NH Me MeOq Me0 0 Ph-N e ' X O MOMe Me0 PhH2c-N-fo OMe 0LN,CH2Ph Cocculus hirsutus and assigned the structure (208) on the basis of the identity of its methyl ether with the product of reduction of jamtine-N-~xide.~~~ Also obtained from Cocculus hirsutus are the two new alkaloids cohirsinine (209 R' = Me R2 = H)424and shaheenine (209 R1 = R2 = H),425both of which on O-methylation yield cohirsine (R' = R2 = Me).The assignment of structure to cohirsinine is based on detailed spectroscopic studies which appear to rule out the isomeric structure (209 R1 = H R2= Me).424 The antibiotic A,-1 18D a metabolite of Actinornyces A,-118D has been identified as lysolipin Two novel alkaloids that are complex derivatives of isoquinoline namely eudistone A (21 1) and eudistone B (212) have been isolated from a dark green tunicate of the Eudistorna species; the structures are based on spectroscopic studies and on the production of eudistone B by the aerial oxidation of eudistone A.427 In an attempt to synthesize saframycin B (213) the diketopiperazine (214) was condensed with 2,3,4,5-tetra-methoxybenzaldehyde to give the Schiff base (2 15).Reduction of this followed by treatment successively with lithium OMe 0 OMe q-$ OMe OMe aluminium hydride and trifluoroacetic acid gave the base (216 R1 = R2 = CH,Ph) which was converted into (216 R' = Me R2 = H) epimeric with an intermediate in a previous synthesis of (213) but inversion at the asymmetric centre was not achieved.428 The cleavage of DNA by quinocarmycin (217) has been 24 References 1 P. 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ISSN:0265-0568    

DOI:10.1039/NP9931000449

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Diterpenoid Alkaloids M. S. Yunusov Institute of Organic Chemistry Ural Department of the Russian Academy of Science Russia 450054 Ufa Reviewing the literature published between the end of 1989 and the beginning of 1992 (Continuing the coverage of literature in Natural Product Reports 1991 Vol. 8 p. 499) 1 Introduction 4.8 On the Structure of 14-U-acetylnudicauline 2 Phytochemical Studies 4.9 Reactions of Denudatine with NBS-Acetic Acid and 2.1 Alkaloids of Aconitum species of Mongolia HCl 2.2 Alkaloids of Aconitum alboviolaceum Kom. 4.10 Deoxygenation of Pseudokobusine to Kobusine 2.3 Alkaloids of Aconitum austroyunanense 5 Chromatographic Studies 2.4 Alkaloids of Aconitum barbetum var. Hispidum Ledeb. 6 Pharmacology 2.5 Alkaloids of Aconitum campylorrhynchum 7 References 2.6 Alkaloids of Aconitum carmichaeli Debx.2.7 Alkaloids of Aconitum contortum Finet et Gagnep 2.8 Alkaloids of Aconitum coreanum (Levl.) Rapaics 2.9 Alkaloids of Aconitum dolichorhynchum (Wang var. 1 Introduction subglabratum T. L. Ming) In this review as proposed by Pelletier Cls-diterpenoid 2.10 Alkaloids of Aconitum fukutomei Hay alkaloids are sometimes named norditerpenoid alkaloids and 2.1 1 Alkaloids of Aconitum jaluense Komarov C,,-alkaloids called diterpenoid alkaloids. 2.12 Alkaloids of Aconitum karakolicum Rapaics In this review period the bulk of the publications relate 2.13 Alkaloids of Aconitum kirinense Nakai to phytochemical studies of plants of genera Aconitum and 2.14 Alkaloids of Aconitum kongboense var.villosum Delphinium ; one could hardly find a publication reporting 2.15 Alkaloids of Aconitum kusnezo$i Reichb. investigations of plant material from Consolida Spiraea etc. 2.16 Alkaloids of Aconitum liangshanium W. Z. Wang Only one synthesis which is on the asymmetric total synthesis 2.17 Alkaloids of Aconitum orientale Mill. of atisine (1) via intramolecular double Michael reaction has 2.18 Alkaloids of Aconitum palmatum Don. been pub1ished.l 2.19 Alkaloids of Aconitum rubricundum Fisch. Chinese researchers have reviewed the chemical structures 2.20 Alkaloids of Aconitum sczukini Turcz. spectral characteristics and distribution of the natural C2,,- 2.21 Alkaloids of Aconitum tanguticum (Maxim.) Stapf.diterpenoid alkaloids.2 A review of some phytochemical studies W. T. Wang of the genera Aconitum L. Delphinium L. and Consolida (DS) 2.22 Alkaloids of Aconitum vilmorinianum var. patentipilum S. F. Gray has been published by Fuente and Reina. The 2.23 Alkaloids of Aconitum yesoense var. macroyesoense alkaloid content structural types and oxygenation patterns are (Nakai) Tamura discussed with respect to related specie^.^ Some unpublished 2.24 Alkaloids of Delphinium ajacis L. results on the alkaloid content of Aconitum burnatii Gayer A. 2.25 Alkaloids of Delphinium barbeyi compactum Reicheng Delphinium montanum DC and D. 2.26 Alkaloids of Delphinium bulleyanum (Forrest ex Diels) requienii DC have been included.Two of the alkaloids 1,6,14- 2.27 Alkaloids of Delphinium cardiopetalum D.C. tribenzoylsenbusin A (2) and 8-0-ethyl-3,14,15-tribenzoyl- 2.28 Alkaloids of Delphinium elatum L. aconine (3) are probably new. It was also noted that D. 2.29 Alkaloids of Delphinium gracile D.C. montanum is the first species from which Cl,-diterpenoids 2.30 Alkaloids of Delphinium gyalanum Marq. et Shaw. which are as functionalized as the aconines have been obtained 2.3 1 Alkaloids of Delphinium kamaonense var. glabrescens and D. verdunense and D. gracile are the only species of 2.32 Alkaloids of Delphinium menziesii D.C. 2.33 Alkaloids of Delphinium nuttallianum (Pritz.) 2.34 Alkaloids of Delphinium staphisagria L.2.35 Alkaloids of Delphinium tatsienense Franch. 2.36 Alkaloids of Delphinium vestitum Wall 2.37 Alkaloids of Delphinium winklerianum Muth. 2.38 Alkaloids of Consolida regalis Gray 2.39 Alkaloids of Spiraea japonica L. 3 Spectral Studies 4 General Studies 4.1 Reaction of Lycoctonine Alkaloids with Sodium in Liquid Ammonia 4.2 Acid-catalysed Isomerization of Isoatisine OH 4.3 Epimerization of the 1 -a-OH group of Norditerpenoid Alkaloids 4.4 Demethylation of Norditerpenoid Alkaloids 4.5 The Structures and NMR Spectra of some Non- naturally-occurring Cls-diterpenoid Alkaloids 4.6 Preparation of 7,l 7-seco-Cls-diterpenoid Alkaloids via Pyrolysis of their N-oxides 4.7 Reaction of Lycoctonine Alkaloids with Acetic Anhydride and p-toluenesulfonic acid (3) 47 1 NATURAL PRODUCT REPORTS 1993 OR2 R 0CH3 H3C0 (5) R'=R2=R4=Ac R3=H (6) R1=R2=R3=R4=Ac (7) R1=R2=Ac R3=R4=H (8) R' = R2= R3 = R4= Ac C14-OAc (4) OH ' 1 0CH3 H3C0 (9) OR' I OAc H3C0 0CH3 AN:; (20) R' = R2 = COCH (21) R' = R2 = C~CC,H~ (10) R = Ac CB-OAC CQ-OAC (22) R' = CH3 R2= COC& (11) R=CH3 0(12) R =C4-0-CO H35 H3C (13) R =Bz (14) R = COC6H4-2-OCHs (15) R = COC6H44-OCH3 (16) R = COCeH2-3,4,5-(OCH3)3 (1 7) R = COC6H44-NO2 (18) R = COC(C6H5)3 (19) R = COCH=C(CH3)2 Delphinium to afford C,,-diterpenoid alkaloids without a C-16 f~nctionality.~ It has been shown that a principal insecticidal toxin of several Delphinium species having a long history of use as an insecticide is methyllycaconitine (4).The compound has a high affinity for the insect cholinergic re~eptor.~ In order to study insect mortality and housefly nicotinic receptor inhibition activity new derivatives of aconitine (5)-(8) delphonine (9) N-deacetyllappaconitine (lo)-( 1 9),5 delphinine (20)-(22) and lycoctonine (23)-(3 1)6 have been synthesized. Katz reported that the aphids Brachycaudus napelli (Schrk. lSOl) which feed on Aconitum napellus L. and A. paniculatum Lam. ssp. paniculatum accumulated 0.67 % of aconitine (32) and 0.34 % of talatisamine (33) and 14-0-acetyltalatisamine (34) with reference to the dry weight of the aphids.It was inferred that B. napelli is a phloem feeder and hence that the alkaloids (32)-(34) are transported in the phloem.' Beshitaishvili studied the extraction process using several different electrolytes of alkaloids from Aconitum orientale.' It was shown that the more expedient extraction procedures are (23) R = COC6H44-OCH3 (24) R = COC6H4-2-OCH3 (25) R = COC6H44-NO2 (26) R = COC~H2-3,4,5-(0CH3)3 (27) R = CO(CH2)16-CH3 (28) R = CO(CH2)1&H3 (29) R = CO(CH2)7-CH=CH-CH2-CH=CH-(CH2)rCH3 (30) R = CH&eH4-4-C6H5 (31) R=CH&H3 OH kH3 H3CO H3C0 (33) R = OH (34) R =Ac those using 2% H,SO or 5% CH,COOH when the yield of the total alkaloids reached 96 O/O.A list of new diterpenoid alkaloids is given in Table 1. 2 Phytochemical Studies 2.1 Alkaloids of Aconitum species of Mongolia Batbajar and co-workers have surveyed the alkaloids of the aerial parts of three species growing in Mongolia. Plants were collected during the fruit-bearing stage. A. baikalense Turczg contained 0.30% total alkaloids from which the known alkaloids aconitine songorine and napelline were isolated. Aconitine and napelline were also isolated from A. vollubile PaLL ex Koelleg that contained 0.60 % total alkaloids. A new diterpenoid alkaloid 1 1 -acetyl- 1,19-epoxydenudatine (35) was isolated from the above-ground parts of A. barbatum.loa Its structure was elucidated by spectroscopic methods.The known alkaloids delsoline lepenine and lepetine were also isolated.lob Plants of A. altaicum Steinb.g yielded 0.13 YOof total alkaloids. Only napelline was isolated from this species. 2.2 Alkaloids of Aconitum alboviolaceum Kom. From the whole plant of A. alboviolaceum collected in Liaoning Province in China a new diterpenoid alkaloid named albovionitine (36) and four known diterpenoid alkaloids ajacine avadharidine lycoctonine and lycaconitine were isolated. The structure of the new alkaloid including the relative stereochemistry was elucidated by spectral analysis. Albovionitine is the first C,,-diterpenoid alkaloid bearing a hydroxyl group at C-18 and seco N-20 functionality." 2.3 Alkaloids of Aconitum austroyunanense Chinese researchers continuing their study of alkaloids of this plant have isolated the known alkaloids talatizidine con-delphine and yunaconitine and a new alkaloid austroconitine B (37).The structure of (37) was established by spectroscopic methods and correlation with vilmorrianine A (38) through NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV Table 1 New diterpenoid plant alkaloids Plant Alkaloid A. alboviolaceum Albovionitine A. austroyunanense B Austroconitine A. barbatum A. barbetum A. camphylorrhvn-chum A. carmichaeli A. contorrum A. coreanum A. dolichorhyn-chum A. fukutomei A. karakolicum A. kirinense A. kongboense A. liangshanium A. orientale A. palmatum A. sczukini A.tanguticum A. vilmorinianum A. yesoense D. ajacis D. barbeyi D. bulleyanum D. cardiopetalum D. elatum D. gracile D. gyalanum D. kamaonense D. menziesii D. montanum D. nuttallianum D. staphisagria 1 1 -acetyl- 1,19- epox ydenudatine Hispaconitine 8-acet yldol-aconi tine Chuanfumine Conturtumine Conaconitine Corifine Corifidine Dolichotine A Dolichotine B Dolichotine C Dolichotine D Dolichotine E 10-Hydroxyneoline 14-Acetyl- 10- h ydrox yneoline Karakomine 8-Acetylexcelsine Kongboenine 12-epi-Lucidusculine 12-epi- 19-Dehydro- napelline 12-epi-19-Dehydro-lucidusculine Liangshanine Liangshanone Orgetine Vakhmatine Va khmadine Sczukinine Sczukidine Sczukitine Tungutisine Patentine Vilmorrianone Yesodine Yesoensine 19-Oxoanthrano yl-1ycoctonine 19-Oxodelphatine Ajadelphine Ajadelphinine Barbisine Bulleyanitine A Bulleyanitine B Bulleyanitine C Cardionine Elanine 1 1 -Acetylcardionine Gyalanine A Gyalanine B Glabredelphinine Delmenzine 1,6,14-Tribenzoylsen-busine A 8-0-Ethyl-3,14,15-tri-benzo ylaconine Desacet yl-6-epi-pu- bescenine 6-epi-Neolinine-14-0-acetate Nuttallianidine Bicolorine- 14-0- acetate Delectinine-14-0-acetate Staphisadrine Staphisadrinine Pyrodelphinine 14-Acetyl- 1 -epi- neoline Ref.11 12 10 13 16 17 21 22 23 23a 27 27 27 27 27 28 28 32 33 34 35 35 35 35 35 3 7a 38 38 41 41 41 42 48 49a,b 50 50 50a 50a 50b 50b 51 52,53 52,53 52 53 54 54 54 57 57 58 59 3 3 60a 60a 60a 60a 60a 61 61 61 61 Table 1-cont.Plant Alkaloid Structure Ref. D. tatsienense Tatsirine (1 22) 62 Tatsidine (124) 63 D. vestitum Isodelectine (125) 64 D. winklerianum Winkleriline (127) 65 Winkleridine (1 28) 65 (37)R = H (An= anisoyl) (39) (38)R=Ac Et H reaction of both compounds with Ac,O/TsOH to give the same product. 2.4 Alkaloids of Aconitum barbetum var. Hispidum Ledeb. From the alcohol extracts of the roots of A. barbeturn Chinese and Japanese researchers have isolated the new C,,-diterpenoid alkaloid hispaconitine (39) along with four known alkaloids tuguaconitine delsoline 14-acetyldelcosine and de1c0sine.l~ The structure of hispaconitine was elucidated by 2D NMR spectroscopic analysis; and from its mass spectrum the acetoxyl group was deduced to be at C-8 on the basis of a peak at rn/z 435 (M -CH,COOH)+ (base peak).However such a situation is usually observed when the acetoxyl group is attached at the C-4 p0siti0n.l~ The presence of the acetoxyl group at C-8 as a rule results in easy elimination of acetic acid under MS measurement conditions but it is not the base peak (M -AcOH)+.15 The lH-'H COSY lH-13C COSY and IH-13C long range COSY spectrum of tuguaconitine (40) indicated that the assignments for C-5 and C-10 described in the literature should be revised to C-9 and C-13 re~pectively.'~ 2.5 Alkaloids of Aconitum campylorrhynchum Six compounds were isolated from the roots of this plant.One of them is a new alkaloid. It has been deduced to be 8- acetyldolaconine (41) by means of IR mass spectroscopy lH 474 NATURAL PRODUCT REPORTS 1993 Et (43) R' = R2 = H (45) R' = H R2 =An (44) R' = R2= OH (46) R'=CH3 R2=H (47) R' = R2= H OH / 0 CH2 N-CH3 AcO 1 AcO. Scheme 1 and 13C NMR (with DEPT and CH-COSY techniques) and on the basis of its saponification to aconosine. The other five compounds were dolaconine aconosine P-sitosterol palmitic acid and p-coumaric acid.16 2.6 Alkaloids of Aconitum carmichaefi Debx.The reinvestigation of the roots of this plant a famous Chinese traditional medicine afforded a new water-soluble C,,-diter- penoid alkaloid chuanfumine (42). Its structure was proposed on the basis of MS 1D and 2D NMR spectral data NOE tests and chemical evidence.17 It is necessary to note however that the authors in comparing (42) with dictizine (43)lS referred to its incorrect ~tructure.'~ Dictizine as well as macrocentrine (44),O are atisine type alkaloids and have a P-oxymethylene group at C-16. 2.7 Alkaloids of Aconitum contortum Finet et Gagnep Chinese and Japanese researchers have isolated the new diterpenoid alkaloids contortumine (45),l and conaconitine (46),22 along with the known alkaloids delavaconitine delava- conine aconosine dolaconine delavaconitine C episco-palidine and commaconine,21 from the roots of A.contortum. The structures of the new alkaloids were determined on the basis of spectral data and hydrolysis of contortumine to delavaconine (47). 2.8 Alkaloids of Aconitum coreanum (Levl.) Rapaics Continuing the study of alkaloids of the aerial parts of this plant the new C,,-diterpenoid alkaloids corifine (48) and corifidine (48a)23a have been isolated. The structures of these alkaloids were deduced on the basis of spectral data and confirmed for corifine by X-ray analysis of its perchlorate (49).23A plausible pathway of biosynthesis for corifine type alkaloids (50),from the zeraconine type (51) via an intermediate Claisen rearrangement product (52) has been proposed (Scheme l).23 Corifine and corifidine are a new type of C2,- diterpenoid alkaloid and contain a 2,3,3a,7a,6,7,-hexahydro-N-methylindol-6-onic fragment characteristic of alkaloids of the Sceletium genus.The structure of the C,,-diterpenoid alkaloid guan-fu base A (53),24isolated from the roots of A. coreanum has been confirmed by Chinese researchers using spectral data and X-ray diffraction analysis.25 A known C,?-diterpenoid alkaloid 2-isobutyryl- 13-acetyl- 14-hydroxyhetisine (guan-fu base F) was also isolated from the aerial parts of this plant.26 NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV 47 5 H3CO (54)R' = An (anisoyl) (57) R' = COC15H31,R2 =An R3 = H (55)R' = Vr(veratroy1) (58)R' = COC15H3, R2 =An R3 = OH (56)R' = CO-CH=CH-Ph (59)R' = R2 = R3 = H (60)R' = R2 = H R3 = OH Et-H33($F3 -N OR H3C0 OCH3 (65)R= Et (66)R=Ac OR2 OH (67)R'=R2=H R3=Ac (68)R= H (70)R1= CH3 R2 = R3 = H (69)R =Ac (72)R1 = R2 = R3 = H (73)R' = TBS,R2 = R3 = H 0 (74)R1= TBS R2= R3 = Bz (75) R1 = H R2= R3=Bz (76)R' = CH3 R2 = R3= Bz 2.9 Alkaloids of Aconitum dolichovhynchum (Wang var.subglabvatum T. L. Ming) From the roots of this plant five new minor alkaloids dolichotine A (54) dolichotine B (59 dolichotine C (56) dolichotine D (57) and dolichotine E (58) as well as the six known alkaloids yunaconitine 8-deacetylyunaconitine7 crassi- cauline A talatisamine columbidine and cammaconine have been isolated.The structures of the new alkaloids were determined with the aid of spectral data and hydrolysis of (54) and (55) to talatisamine (33) (57) to chasmanine (59) and (58) to bikhaconine (60).27 2.10 Alkaloids of Aconitum fukutomei Hay Chemical investigation of the roots of A.fukutornei,collected in Taiwan resulted in the isolation of two new norditerpenoid alkaloids 10-hydroxyneoline (61) (16.5 O/O based on the crude base) and 14-0-acetyl- 10-hydroxyneoline (62) (0.3 YO),along with seven known compounds neoline (1 1 YO),14-acetylneoline (0.7 Yo) 15-a-hydroxyneoline (0.3 YO),senbusine A (0.2 %) isotalatizidine (0.03 YO),mesaconitine (0.07 Yo) and lassio- carpine (0.3 YO)."The structures of the two new alkaloids were H3CO (61) R= H (62)R = AC determined by spectroscopic analysis (2D lH-13C COSY and COLOC) and chemical reactions.The placement of the tertiary hydroxy group at the C-10 position in (61) and (62) was established from the downfield shift of /3-H-14 in their 'H NMR and from those at C-9 C-11 and C-12 in the 13C-NMR spectra. The regioselective acetylation of (61) with trifluoroacetic acid in glacial HOAc at 80-90 "C for 6 h gave (62) in 62% yield. 2.11 Alkaloids of Aconitum jaluense Komarov From the root of this plant 11 alkaloids were isolated and characterized. These include deoxyaconitine hypaconitine aconitine mesaconitine acetyltalatisamine talatisamine neo- line and benzoylmesa~onine.~~~ 31 Three new alkaloids jaluen- sine and 2 bultasan bases were characterized by their mass spectra.2.12 Alkaloids of Aconitum karakolicum Rapaics The continuation of work on the constituents of roots of the plant has led to isolation of a new amorphous C,,-diterpenoid alkaloid karakomine (63) and two known compounds songorine and ne01ine.~~ The structure of the new alkaloid was determined from spectral data. 2.13 Alkaloids of Aconitum kirinense Nakai From the aerial parts of this plant collected during the fruit- bearing stage (1.9 YOof total alkaloids) a new C,,-diterpenoid alkaloid 8-acetylexcelsine (64) was isolated.33 The structure of (64) was determined from spectroscopic and chemical data. 2.14 Alkaloids of Aconitum kongboense var. villosurn Chinese researchers have investigated the constituents of this plant and in addition to the known alkaloids chasmaconitine and talatisamine isolated the new base kongboenine (65).34 The structure of kongboenine was determined on the basis of spectral data and chemical correlation with chasmaconitine (66) by heating an ethanolic solution of the latter in a sealed tube at 130-135 "C.Using methanol for extraction the authors showed that kongboenine is a genuine plant alkaloid. 2.15 Alkaloids of Aconitum kusnezofii Reichb. The diterpenoid alkaloids aconitine deoxyaconitine hypa- conitine mesaconitine and beiwutine were isolated from the roots of A. kusnezojii and the known diterpenoid alkaloids lepenine and denudatine were isolated from the aerial parts of this plant collected in Mongolia.34b 2.16 Alkaloids of Aconitum liangshanium W.Z. Wang Five new C,,-diterpenoid alkaloids having the napelline-type skeleton 12-epi-lucidusculine (67) 12-epi- 19-dehydronapelline (68) 12-epi- 19-dehydrolucidusculine (69) liangshanine (70), and liangshanone (71) along with six known alkaloids 12-NPR 10 NATURAL PRODUCT REPORTS. 1993 0 AcC? . Ad)..& H3C-N H2 Ad)'. CH3 O epinapelline songorine aconitine aconine neoline and sen- busine A have been isolated from the roots of A. liang~hanium.~~ (81) R' =Ac R2 = H (85) R' = Ac R2 = BZ (82)R' = R~ = H (86) R' = R2= H (83) R' = COCH(CH3)CH&H3 R2 = AC derivatives (79) and (80). Vakhmadine was isolated in the form of a quaternary base and the C-6 keto group was masked in both crystalline form and solution; but on acetylation the C-6 keto group was restored i.e.the triacetyl derivative (80) was obtained.38 The early literature assignments of a 8 value of 62.9 to C-5 and 8 58.2 to C-14 for dia~etylhetidine~~ have been inter- changed. 2.19 Alkaloids of Aconitum rubricundum Fisch. The known alkaloids isolappaconitine 9-deoxylappaconitine lycaconitine puberaconitine lycoctonine runaconitine ajacine and septentriodine have been isolated from aerial parts Senbusine A and 12-epinapelline are the main bases of this plant. The structures of the new alkaloids were elucidated by spectroscopic analysis and chemical reactions. On hydrolysis with 5% KOH-aq. MeOH (67) gave 12-epinapelline (72) which on treatment with N-bromosuccinimide in dry benzene at 90 "C for 3 h gave (68) in 56% yield.Liangshanine (70) was synthesized from (72). The reaction of (72) with t-butyldimethyl- silyl (TBDMS) chloride in CH,Cl, in the presence of triethyl amine at 0 "C for 2 h provided the C,-OTBDMS derivative (73) in 57% yield. Benzoylation followed by removal of the silyl protective group in (74) yielded the alcohol (75). The methylation of the free hydroxyl group at C-1 in (75) and finally hydrolysis of the benzoyl esters in (76) furnished 1-0- methyl- 12-epi-napelline which is identical with natural liang- shanine (70). Reduction of liangshanone (71) with LiAlH in THF at room temperature gave two epimeric alcohols (70) and 1-0-methyl-napelline in I6 YO and 45 O/O yield respectively. Liangshanine (70) and liangshanone (71) are the second and third examples of C,,-diterpenoid alkaloids bearing a methoxy group in their structures.The methoxy group had been previously found in le~edine,~~ an alkaloid from A. pseudo-huiliense. 2.17 Alkaloids of Aconitum orientale Mill. From the aerial parts of this plant (total alkaloids 0.55%) collected in the pre-budding stage in the North Caucausus the known norditerpenoid alkaloids lappaconitine lappaconine gigaktonine d-deacetyllappaconitine and lycoctonine and the known aporphine alkaloid corydine have been isolated. Lappaconitine was the major alkaloid (25% of the total alkaloid^).^^ The new diterpenoid alkaloid orgetine (76a) was also isolated from A. ~rientale.~"Its structure was assigned from spectral data.2.18 Alkaloids of Aconitum palmatum Don. Two new water-soluble diterpenoid alkaloids designated as vakhmatine (77) and vakhmadine (78) as well as the known alkaloids atisine and hetisine have been isolated from the roots of A. palmatum. The structures of the new alkaloids were established by 2DNMR and NOE studies on their acetyl of A. rubricundum collected during the fruit-bearing stage (2.9 YOof total alkaloid^).^^ 2.20 Alkaloids of Aconitum sczukini Turcz. A study of the alkaloids of A. sczukini has led to the isolation of three new C,,-diterpenoid alkaloids sczukinine (8I) sczukidine (82) and sczukitine (83) whose structures have been established on the basis of their various spectral data (IR MS 'H and 13C NMR 2D NMR) as well as chemical rnethods.,l 2.21 Alkaloids of Aconitum tanguticum (Maxim.) Stapf.W. T. Wang The continued study of whole plants of this species has led to the isolation of a new C,,-diterpenoid alkaloid tangutisine (84).42 Its structure has been determined on the basis of homonuclear 'H COSY HETCOR two dimensional NOE 'H-13C long range correlations (FLOCK) and selective INEPT NMR techniques. Five alkaloids guan-fu base A,43. 44 guan-fu base G,43,45 guan-fu base guan-fu base Y,44guan-fu base Z,44-47 B46-47 which are acylated derivatives of tangutisine have been isolated from A. bullatofolium and A. coreanum. 2.22 Alkaloids of Aconitum vilmorinianum var. patentipilum Five diterpenoid alkaloids have been isolated from an ethanol extract of the roots of this plant.Among them is a new amorphous compound named at en tine,^ whose structure has been elucidated as (85) on the basis of spectral evidence and by its saponification to foresticine (86). The other three alkaloids were identified as indaconitine yunaconitine and talatis- amine.48 None of these compounds has been found in this plant previously. The structure of the new minor diterpenoid alkaloid vilmorrianone (87) also isolated from this species was elucidated by spectral data and confirmed by X-ray diffraction analysis.49a.6 2.23 Alkaloids of Aconitum yesoense var. macroyesoense (Nakai) Tamura. Continuing investigations on the constituents of the rhizoma of this plant resulted in the isolation of two new amorphous NATURAL PRODUCT REPORTS 1993-M.S. YUNUSOV (88) R = CO-C-C~HS (90) R = H H HO (91a) R = anthranoyl (91c) R1 = R2 = H R3 = Ac (91b) R=OCH3 (91d) R' + R2= CH2 R3 = H V 1 &NH-g-CH2-yH-fi-NH2 CH3 0 (93) Ci-P-OCH3 (96) Ci-a-OCH3 diterpenoid alkaloids yesodine (88) and yesoensine (89) together with two known alkaloids macrocentridine and subcusine isolated from this plant for the first time.50 The structures of the new alkaloids were determined on the basis of their spectra and by the synthesis of (88) from pseudokobusine (90) through the intermediate 6,11-di-p-nitrobenzoate, and 15-[(S)-2-methylbutyryl1-6,11-di-p-ni tro benzo ylpseudono busine and (89) by oxidation of 14-dehydrodelcosine (91) with potassium permanganate in acetone-H,O.2.24 Alkaloids of Delphinium ajacis L. In a continuation of studies on the alkaloids of D.ajacis (syn. = Consolida ambigua (L) P. W. Ball and Heyw.) Pelletier and co-workers isolated from the stems two new norditer- penoid alkaloids 19-oxoanthranoyllycoctonine (91a) and 19- oxodelphatine (9 1 b) ; six known alkaloids delectine 14-deacetylambiguine deltatsine gigactonine takaosamine and 18-methyoxygadesine; and five previously reported from the seeds of D. ajacis anthranoyllycoctonine browniine delcosine delphatine and delsoline. From the leaves of this plant three of the isolated alkaloids delsoline delcosine and anthranoyl- lycoctonine were previously reported and deltaline delpheline and gigactonine are new to this plant.50u Two new norditerpenoid alkaloids ajadelphine (9 lc) and ajadelphinine (91d) together with six known ones delsoline delsoline deltaline gigactonine 18-methoxygadesine and delphisine were isolated from the roots of D.ajaci~.~'* The co NH-g-FH-CHZ-G-NH2 (94) R= 0 & 0 CH3 Ci-P-OCH3 co Ci-P-OCH3 (97) R =as in (94) C1-a-OCH3 (98) R = as in (95) C1-a-OCH3 structures of the new alkaloids were determined with the aid of 'H and 13C NMR spectroscopy and by synthesis of 19- oxoanthranoyllycoctonine from ajacine and anthranoyl-lycoctonine. 19-Oxodelphatine was prepared earlier by KMnO oxidation of del~hatine.~~~ Delphisine is the first aconitine-type alkaloid found in this plant and alkaloids bearing the 7,s-methylenedioxy group deltaline and delpheline appeared to be absent in the stems or seeds of this plant.Ajadelphine is the first lycoctonine-type norditerpenoid alkaloid to have a methoxyl group at C-8 and an 18-OH group and ajadelphinine is the first one having a C-7-C-8 methylenedioxy group and a C-18 hydroxyl group. 2.25 Alkaloid of Delphinium barbeyi Pelletier and co-workers have isolated a new alkaloid barbisine (92) -the third representative of an N-C(19)-seco C20-diterpenoid alkaloid from D. barbe~i.~'The structure and stereochemistry of barbisine were deduced by a combination of NMR spectroscopy and a single-crystal X-ray diffraction analysis. 2.26 Alkaloids of Delphinium bulleyanum (Forrest ex Diels) Chinese researchers have obtained three new diterpenoid alkaloids named bulleyanitine A B and C and three known alkaloids methyllycaconitine ajacine and delsemine from the roots of D.bulleyanum.On the basis of spectroscopic and chemical evidence the structures of the new alkaloids were established as (93) (94) and (95) re~pectively.~~ However Pelletier and Joshi on the basis of analysis of 13C NMR shift data of C-1 in C,,-diterpenoid alkaloids showed that these can be used as a diagnostic tool for the assignment of configuration of the oxygen function at C-1 and corrected the structures (93)-(95) to C-la-methoxyl compounds (96)-(98) respect-33-2 NATURAL PRODUCT REPORTS 1993 U I (102) R' = R2= H (103) R' =R~=AC (105) R' = H R2= AC (100) R=H (101) R=CH3 y3 R = CO-C-C~HS &N5cH3 H i~ely.~~ The change of configuration of C-1-/3-OMe groups to C 1-a-OMe was also carried out for anhweidelphinine (99) puberaconitine (100) and puberaconitidine (101).53 2.27 Alkaloids of Delphinium cardiopetalum D.C.The structure of the new alkaloid cardionine (102) isolated from the above-ground parts of plants of D.cardiopetal~rn,~~ was deduced from spectroscopic data and confirmed by acetylation of the alkaloid with acetic anhydride in pyridine which afforded the same diacetates (103) and (104) as did 11- acetylcardionine (105) isolated from D. 2.28 Alkaloids of Delphinium elatum L. In a continuation of the search for diterpenoid alkaloids from the seeds of this plant Pelletier and co-workers have isolated a new norditerpenoid alkaloid elanine (106) together with two known norditerpenoid alkaloids pacinine and delectinine and the known diterpenoid alkaloid aja~onine.~~ The known norditerpenoid alkaloid nudicaulidine was isolated from the aerial parts of D.el~turn.~~~ The structure of the new alkaloid has been determined on the basis of its spectral data and alkaline hydrolysis to delectinine. 13C NMR chemical shifts assigned to C-3 C-6 C-12 and C-18 of ajaconine (107)56 have been revised on the basis of DEPT 13C NMR measurements. 2.29 Alkaloids of Delphinium gracile D.C. A new diterpenoid alkaloid 11-acetylcardionine (109 was isolated from the aerial parts of plants of D. gracile.54 Its structure was established through chemical and spectroscopic evidence obtained from decoupling NOE difference DEPT HETCORR 2D and INEPT 1D NMR experiments.2.30 Alkaloids of Delphinium gyalanum Marq. et Shaw From the roots of this plant native to China a pair of new regioisomeric diterpenoid alkaloids were isolated as a mixture and named gyalanine A (108) and gyalanine B (109).57 The known diterpenoid alkaloids delsemine A and B methyl-lycaconitine and lycoctonine were also isolated. 0 R2= CH3 2.31 Alkaloids of Delphinium kamaonense var. glabrescens A new diterpenoid alkaloid and the known alkaloid tatsiensine were isolated from the roots of this plant. The structure of the new alkaloid named glabredelphinine (1 lo) was established as 2(3)-dehydro-6-demethyl-18-demethoxydelcosine from IR MS and lH and 13C NMR spectral data.5s 2.32 Alkaloids of Delphinium menziesii D.C.From the air-dried epigeal parts of D.menziesii Canadian researchers isolated eleven norditerpenoid alkaloids of which ten were known anhweidelphinine browniine delcosine deltatsine desacetyl-6-epi-pubescenine (1 12),60 methyllyca-conitine nudicauline takaosamine virescenine and umbro- sine and one named delmenzine (1 1l) was new. The structure of the last alkaloid was determined by application of a variety of NMR meas~rements.~~ 2.33 Alkaloids of Delphinium nuttallianum (Pritz.) Further fractionation of the minor bases of this plant resulted in the separation of thirteen components. Eight were identified as alkaloids which had been described before :N-acetyldelectine bicolorine 2-dehydrohetisine delectinine hetisine hetisine- 1 1,13-di-O-acetate lycoctonine and takaosamine.Structures of the other five new alkaloids desacetyl-6-epi-pubescenine (1 12) 6-epi-neolinine- 14-0-acetate (1 13) nuttallianidine (1 14) (nuttalline) bicolorine- 14-0-acetate (1 19 delectinine- 14-0- acetate (1 16) were deduced by spectroscopic methods and by saponification of 6-epi-pubescenine (1 17) to (1 12) (1 13) to 6- epi-neolinine (1 15) to bicolorine (1 16) to delectinine.'jO" A known norditerpenoid alkaloid anhweidelphinine was also isolated from D.nuttallianum.60b 2.34 Alkaloids of Delphinium stuphisagria L. Two novel norditerpenoid alkaloids staphisadrine (118) and staphisadrinine (1 19) have been isolated from the seeds of plants of this species.61 Structures (118) and (119) were determined from physical and spectroscopic data including DEPT and NOE difference experiments.Staphisadrine is the NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV (110) R' = R2 = H A2 (112) R' = R6 = H R2 = OCH, R3= p-OH R4= OH R5 = CH3 (1f 8) (1 11) R' + R2= CH2 (113) R' = R4= R5 = H R2 = OH R3 = P-OCH3 R6 = AC (114) R' = CH3 R2 = OH R3 = P-OCH3 R4= R5= R6 = H (115) R1=R2=R4=R5=H R3=P-OH R6=Ac (116) R' = CH3 R2 = R4 = OH R3 = P-OCH3 R5 = H R6 = AC (117) R' = H R2= OCH3 R3=P-OH R4 =OH R5=CH3 R6=Ac (119) C,-a-OH R=H C-16=0 (1 20) (121) R=Ac Et ..-I &H2 (125) R' = R2= H (126) R' = H R2 = CH3 (1 26a) first example of an aconitine type alkaloid bearing a formyl group on C-4.Staphisadrinine is the first norditerpenoid alkaloid to possess a carbonyl function on C-16. Two alkaloids pyrodelphinine (1 20) and 14-acetyl- 1 -epi-neoline (1 2I) were also isolated and have not been previously reported as natural products. 2.35 Alkaloids of Delphinium tatsienense Franch. In continuing studies on alkaloids of the roots of D. tatsienense collected during the flowering stage in China three bases were obtained. One of these has been identified as the known diterpenoid alkaloid dictizine.62 The other new diterpenoid alkaloid designated as tatsirine has been assigned structure (122).62 This structure was established on the basis of homonuclear lH COSY fixed-evolution HETCOR two-dimensional NOE and selective INEPT studies on (123).The latter was obtained by the facile isomerization of the exocyclic double bond of tatsirine (122) in CDC1,-solution followed by chromatography on alumina The authors explained this process by the formation of a carbonium ion (with traces of HC1 from CDC1,) which is stabilized with the suitably placed p-hydroxyl group to form an oxitane. On alumina the more stable isomer (123) is readily formed by loss of a proton from C-15. There are very few examples of hetisine type diterpenoid alkaloids in which a hydroxyl group at C-13 is located in a p-43 Et-position (equatorial hydroxyl in the boat conformation of ring formed by carbons 8,9 11 12 13 14). The structure of a third new diterpenoid alkaloid named tatsidine (1 24) was derived on the basis of spectroscopic data.63 2.36 Alkaloids of Delphinium vestitum Wall Further studies of the aerial parts of this species led to the isolation of the new amorphous alkaloid isodelectine (125) and the known alkaloid anthranoyllycoctonine which has not been previously reported from this plant.64 The structure of the new alkaloid has been deduced from spectroscopic data and was confirmed by demethylation of delvestine (126) to (125) with 3M H,SO,.2.37 Alkaloids of Delphinium winklerianum Muth. Five diterpenoid alkaloids have been isolated from an ethanol extract of the whole herb of D. winklerianum. Two are new compounds named winkleriline (127) and winkleridine (128). The other three were identified as methyllycaconitine lycoc- tonine and lappa~onitine.~~ Structures of the new alkaloids were elucidated on the basis of chemical and spectral evidence.But there is a doubt about signal assignments in the 13C NMR spectrum of (1 28) for example for C-16 (6 89.4) and C- 16-OCH3 (658.6). Perhaps the possibility of C-6-OCH3 instead of C-16- OCH is worth discussing. 2.38 Alkaloids of Consolida regalis Gray From the whole plant of this species collected in Czecho- slovakia Slavik and co-workers isolated in the form of its NATURAL PRODUCT REPORTS 1993 I R' (132) R' = H R2= OH (133) Ce-P-OH R' = H R2 = OH 6""" (136) R'=OCH3 R2=H (131) (137) CG-P-OH R' = OCH, R2= H (134) R=OH (138) R'=OH R2=H ( 1 39) (141) R' + R2= CH2 (143) R' = CH3 R2 = H (135) R = H (140) R' + R2 = 0 iodide a quaternary alkaloid with probable composition C,,H,,NO,.From its IR spectrum the presence of a carbonyl group (1760 cm-l) could be deduced.66 One of the possible structures for this alkaloid is that of cuauchichicine iodide (129).67 Aporphine alkaloids magnoflorine and corytuberine were also detected.66 2.39 Alkaloids of Spiraea japonica L. In continuing studies on the alkaloids of this plant four diterpenoid alkaloids spiramine A spiramine B spiramine C and spiramine D have been isolated and identified.68s69 A full communication on the isolation and structure determination of the earlier reported70 diterpenoid alkaloid spirasine I11 has been published.71 3 Spectral Studies Rashkes and co-worker showed that measurement of the ratio of metastable and parent ion peak heights (A),and of metastable transition energy allowed distinction between the different modes of cleavage of the same fragments in C, and C, diterpenoid alkaloid^.^ In common with the previously used metastable defocusing (MD) data7 the B/E linked scan technique was employed and the appropriate spectra of M+ (M -15)+ and (M -OR,)+* ions of twenty lycoctonine bases were st~died.'~ The spectra generally and the A values appeared to be characteristic of similar fragmentation reactions.The A values obtained by the MD and B/E linked scan technique have the same order and in most cases do not differ by more than 30 %.73,74 Studying the B/E spectra helped in the determination of alternative breakdown processes of identical particles.74 The mass spectra of five hetisine type alkaloids with an OH group at C-14 have been studied.A mechanism for the main processes of forming the base fragments was Pelletier and co-workers have published lH- and 13C-NMR studies on the diterpenoid alkaloids delpheline (1 30) 8,9-methylenedioxylappaconitine (1 3 l) and dictizine (43).75 Un- ambiguous 'H-and 13C-NMR assignments for all three alkaloids were accomplished through detailed analysis using DEPT COSY fixed evolution HETCOR NOESY and * OR -substituent at C,; R,= H Me Ac. (142) R' = CHB R2 = OH (144) R' = H R2 = CH3 selective INEPT techniques. This work corrected previous assignments for (1 30) (1 3 l) and (43).The results of the NMR studies revealed that for all three alkaloids the A ring adopts a chair conformation and the D ring a boat conformation. Molecular mechanics modelling (QUANTA/CHARMm) studies were in agreement with these results. The structure and stereochemistry of the norditerpenoid alkaloid delvestine (126) was confirmed by X-ray crystallo- graphic The X-ray diffraction analysis of the diterpenoid alkaloids hetisine hydrochloride talatisine 2-isobutyryl- 13-acetyl- 14- hydroxyhetisine N-oxide and the new alkaloid tadzhaconine (126a)76cwas carried Pelletier and Joshi have reviewed the carbon-13 and proton NMR shift assignments and physical constants of norditer- penoid alkaloids. 4 General Studies 4.1 Reaction of Lycoctonine Alkaloids with Sodium in Liquid Ammonia One of the problems in the chemistry of the C,,-diterpenoid alkaloids is the elimination of oxygen functions and the passage from alkaloids of the lycoctonine-type (7,s-oxygen functions) to alkaloids of the aconitine-type (8-oxygen function only).Narzullaev and co-workers reported that reaction of 6-keto- derivatives of diterpenoid alkaloids containing a 7,8-methylenedioxy group with sodium in liquid ammonia gives as the main products the 7-deoxy compounds. The reaction with 6-dehydroeldelidine (132) gave eldelidine (1 33) and two other products -(1 34) and (1 35).78 The structure (1 34) was confirmed by X-ray analysis.79 The reaction with 6-dehydrodelcorine (1 36) resulted in delcorine (1 37) and products (1 38) (1 39) and (140).78 It is worth noting that so far only one method for passing from lycoctonine to aconitine alkaloids has been described in the literature.,O Features of fragmentation of the derived compounds under electron impact were 4.2 Acid-catalysed Isomerization of Isoatisine An acid-catalysed isomerization of isoatisine (141) in ca.7 YO aqueous HC1 for 7 days at room temperature gave a hydrate (142) in a yield of 50% as well as a mixture of the methyl ketones (143) and (144).,l A plausible mechanism for the NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV 481 (145) (147) Scheme 2 (1 48) R' = CZ-OH,R2 = R3 = H (149) R' = j3-OH R2 = CH3 R3 = H (150) R' = a-OH R2 = R3 = Ac (151) R' =P-OH R2= H R3=Ac Et ' / ATU Scheme 3 1 OCH3 H3CO (1 56) Scheme 4 isomerizations involves protonation of the exocyclic double bond of isoatisine (141) to generate a carbocation (145).At room temperature this intermediate is attacked by H,O to give (146) which upon the basic workup affords the diol(l42) as a major product. However under refluxing conditions inter- mediate (145) undergoes exclusively a pinacol- type hydride shift from the a face to give (147) (Scheme 2) which upon epimerization via an enol in acidic medium and basic workup gives the two methyl ketones (143) and (144). 4.3 Epimerization of the l-a-OH Group of Norditerpenoid Alkaloids It is known that methanolysis of norditerpenoid alkaloids with an 8-O-acetyl group such as aconitine (32) leads to facile replacement of the 8-OAc group by a methoxyl function.82 Pelletier and co-workers have now reported that methanolysis or hydrolysis of such alkaloids which also have an a-OH at C- 1 results in the replacement of the 8-OAc group by a methoxyl or hydroxyl function and C-1 epimeri~ation.~~ Thus refluxing a methanolic solution of 8-O-acetylneoline (148) for two days gave 8-O-methyl-l-epi-neoline (149) in 95 % yield.Similarly refluxing a suspension of delphisine (1 50) in water for 24 h gave 14-O-acetyl-1-epi-neoline (1 51) in > 95 % yield. On the basis of experiments with H2180 two plausible mechanisms for the epimerization were proposed. One of them is based on intermediates (1 52)-( 155) and another on (152) (1 56) and (155) (Schemes 3 and 4).MM2 calculations revealed that (1 50) has an energy 1.34 kcal mol-' higher than its C-l-epimer. This energy difference should parallel that of two epimeric inter- mediates (1 52) and (1 59 suggesting a ratio of (1 52) to (1 55) of ca. 9 to 91.83 OH . 1 OCH~ H3C0 (163) R' = R3 = OH R2 = H (164) R' = R3 = H R2 = AC 4.4 Demethylation of Norditerpenoid Alkaloids Pelletier and co-workers have investigated the reaction of norditerpenoid alkaloids with HBr-AcOH in glacial acetic acid. This reaction proceeds by partial demethylation and then acetylation of the hydroxyl groups formed during the demethyl- ation. Although there is little specificity in the demethylation the C- 16 methoxyl group is demethylated in all cases ;the C- 18 methoxyl is demethylated in the two aconitine-type alkaloids which possess an a-methoxyl group at the C-6 position delphisine (150) and delphinine (157); the C-18 methoxyl is not demethylated in delsoline (1 58) a lycoctonine-type alkaloid which has a /3-methoxyl group at C-6.In all the alkaloids the C-1 and C-6 methoxyl groups do not appear to undergo demethylation with this reagent.84 4.5 The Structures and NMR Spectra of some Non-naturally- occurring C,,-diterpenoid Alkaloids Sixteen non-naturally-occurring norditerpenoid alkaloids (1 59)-( 174) were obtained by Wang and Pelletier in studies on the diterpenoid alkaloids. Their structures were established on the basis of spectral analysis.85 It was shown that N-oxide (166) reacts with acetyl chloride to form the N-desethyl compound (173) under mild conditions (-5 "C 2 days) by a probable mechanism shown in Scheme 5.4.6 Preparation of 7,17-seco-C,,-diterpnoid Alkaloids via Pyrolysis of their N-oxides Wang and Pelletier have reported the preparation of the 7,17- seco compounds (175) and (176) via pyrolysis (at 140 "C for 2 h) of yunaconitine N-oxide (1 77) and crassicauline A N-oxide (178) in anhydrous diglyme in 30% and 15% yields respectively.86 A probable mechanism for the formation of (175) and (176) from the N-oxides (177) and (178) was proposed first the oxygen atom in the N-0 bond in (177) or (1 78) acts as an internal nucleophile resulting in the cleavage of the C(17)-C(7) bond with formation of an intermediate NATURAL PRODUCT REPORTS.1993 R4 (167) R' = H R2 = OH (1 69) R' = R2 = OAC 0-H O-COCH3 4 AcCl <H3-iO-N -,NH \ Et-N+ -kq-CH24-/\ /\ 0 I' Scheme 5 oxazidium ion (179) and the loss of the acetyl group at C-8; second the AcO- ion attacks C-17 to give the N-oxide of the acetyl ester (180) followed by the imine (181). The latter may be reduced by hydride to form the desired compound (1 75) or (176). One of the probable sources of hydride may be the methyl group in CH,(D,)CO; as shown in Scheme 6.86 4.7 Reaction of Lycoctonine Alkaloids with Acetic Anhydride and p-Toluenesulfonic Acid The reaction of the norditerpenoid alkaloids lycoctonine (1 82) browniine (1 83) and dihydromonticoline (1 84) with acetic anhydride and p-toluenesulfonic acid have been studied.In this way lycoctonine gave triacetyllycoctonine (1 85) (base product) and the anhydro product (188) but browniine and dihydro- monticoline gave with small yield anhydro products (186) and (187) respe~tively.~' NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV OH OCH3 -(177) R=OH (178) R=H OH (175) R=OH (176) R= H Scheme 6 Et-Et-(182) R' = R3 = R4 = OCH3 R2 = CH20ti (186) R' = R3 = OCH3 R2 = CH2OCH3 R4 = OH (189) R' = CH3 R2 = H R3 = AC (183) R' = R3 = OCH3 R2 = CH2OCH3 R4 = OH (1 87) R' = R2 = OAc R3 = H R4 = OCH (190) R' = R2 = H R3 = CH3 (184) R' = R2 = OH R3 = H R4 = OCH (188) R' = R3 = R4 = OCH3 R2 = CH20H (191) R' = CH, R2 = R3 = H .. (185) R' = R3 = R4 = OCH3 R2 = CH~OAC C-7-OAc C-8-OAc (192) R' =R2=R3=CH3 OAc (201) R' = OAc R2= Br (202) R' = Br R~= OAC (193) R =H (1 94) 9-P-CHO (200) R = AC (195) Q-a-CHO 4.9 Reactions of Denudatine with NBS-Acetic Acid and HCl It is known that treatment of C,,-diterpenoid alkaloids possessing the allylic secondary alcohol system e.g.,atisine (l) with acids usually leads to rearrangement to 16 P-methyl ketone derivatives.Chinese researchers have shown that treatment of denudatine (193) having the same allylic alcohol system with 10% HCI solution at 45-50 "C for 3 days afforded unusual products i.e. epimers (194) and (195) in 72 YO yield.89 Another rearrangement product (196) in 10 YO yield along with the pair of epimers (194) and (195) was obtained on (1 96) 1 1-a-OH 1 1 -P-H using 10% HCl solution at 30-40 "C for 1 day.Reaction of (197) 1 1 -a-OEt 11-P-H (198) 11-a-H 11-P-OEt denudatine with 10% HCl containing a little EtOH at 30-40 "C led to only a pair of epimers (1 97) and (1 98) in 48% yield besides the starting material.90 The treatment of denuda- tine (193) with NBS-5 YOHOAc solution resulted in C( 11)- 4.8 On the Structure of 14-0-Acetylnudicaulidine C(12) bond cleavage and afforded mainly (199) under very The earlier published structure of 14-0-acetylnudicaulidine mild conditions in 80 % yield. Under similar conditions (1 89) was confirmed by chemical transformations. The methyl- diacetyldenudatine (200) afforded (201) without C( 11)-C( 12) ation of demethylendelpheline (1 90) and nudicaulidine (1 9 1) bond cleavage.It was found that treatment of (201) with with CH,I and NaH in dioxane gave the same product (192).88 Ac,O-Py (9 "C 36 h) gives (2OQS1 A possible mechanism for NATURAL PRODUCT REPORTS 1993 1- -(197) + (198) (199) X=Br (203) X = H Scheme 7 (204) R = H S (205) R = O-E-Nq LN OH . 1 OCH3 H3C0 (207) R' = H OH R2 = CH3 Et R3 = OBz OAn R4 =a-or P-OCH3 (208) R' = OH R2= Et R3 = OBz R4 = a-OCH3 (209) R' =OH R2 = Et R3 = OBz R4 = P-OCH3 these rearrangements involves initial formation of (203) (Scheme 7). 89-91 4.10 Deoxygenation of Pseudokobusine to Kobusine The chemical conversion of a bridgehead hydroxy group at C-6 in C,,-diterpenoid alkaloids into H at-C-6 is difficult. Japanese researchers have worked out a short conversion of pseudokobusine (90) into kobusine (204).92 Treatment of (90) with N,N'-thiocarbonyldiimidazole in methylene chloride at room temperature gave 6-0-imidazoylthiocarbonylpseudo-kobusine (205) in 94 YOyield.The latter was treated with tri-n- butyltin hydride in methylene chloride to give kobusine in 89 YO yield. 5 Chromatographic Studies Chinese researchers have used TLC (silica gel GF,,,) for the determination of yunaconitine and talatisamine in Aconitum species (A. taipeicum A. legendri A. sungpanenese A. vilmorin- ianum A. episcopale A. transsectum A. crassicaule A. hemsleyanum A. austroyunanense and A. staptianum). The developing solvent was cyclohexane-EtOAc-diethylamine (8 1:1). The proportion of yunaconitine was in the range 0.06-0.47 YOand of talatisamine 0-0.46 Monitoring the quality of the preparation of allapinin an effective antiarrhythmic agent by high performance liquid chromatography has been carried out.It was shown that allapinin contains in addition to the C,,-diterpenoid alkaloid lappaconitine N-deacetyllappaconitine and three compounds of unestablished ~tructure.~~ Determination of the alkaloids in the dimethyl ether extract of Aconitum franchetii has been carried out using HPLC with a ZORAX column. The mobile phase was MeOH-H,O-I co &NHAc CHC1,triethylamine (70 :30 1 :0. I). A dried powder sample contained 3.3I % indaconitine 0.017 YO talatisamine and 0.029 YOcha~rnaconitine.~~ An HPLC method for the separation and quantification of lappaconitine and its metabolites in rat urine using a p-Bondapak C, column has been developed.The methodology uses ammonium acetate-methanol-acetonitrile as mobile phase an amperometric detector and/or a UV detector at 252 nm.96 Determination of the diterpenoid alkaloids avadkharidine lappaconitine and deacetyllappaconitine in Aconitum orientale has been carried out using TLC and HPLC. The content of lappaconitine was 0.08-0.10% of the dry weight of plant material.97 6 Pharmacology Japanese researchers have investigated the structure-activity relationship of aconitine alkaloids to elucidate the relation between their analgesic properties and their toxicity. The researchers concentrated on jesaconitine (206) (which has the most potent analgesic and toxic activities among aconitine alkaloids) and studied the role of the oxygen-function attached to positions C-3 and C-8 of (206) and its derivatives in connection with the induction of toxicity and analgesia.The results indicate that the C-3 hydroxy function of (206) participates in the induction of toxicity rather than of analgesia and the C-8 function is important to the induction of analgesia and toxicity and also that this function participates differently in the induction of the analgesia and Aconitine derivatives (207) have been prepared as analgesic and anti-inflammatory agents. The heating of aconitine (32) at 200 "C 2-2.5 mmHg gave (208) and (209). These compounds showed EDBosof 1.70 and 1.10 mg/kg s.c.respectively in mice in a writhing test and both of them also inhibited carrageenan- induced edema at 3 mg/kg orally in mice.99 In the tail pinch hot plate and acetic acid-induced writhing tests in mice lappaconitine (210) and morphine injected in tracerebroventricularl y (i.c. v. ) in traci sternally (i.cist .) and intrathecally (i. t.) produced dose-dependent antinociception. In the tail pinch and acetic acid-induced writhing tests both compounds were more potent by i.t. than i.c.v. or i.cist. The NATURAL PRODUCT REPORTS 1993-M. S. YUNUSOV antinociceptive action of lappaconitine was less potent than that of morphine. This action of morphine was antagonized by naloxone whereas that of lappaconitine was not except for antinociception in the tail pinch test which was partially antagonized by naloxone.loo To investigate structure-activity relationships Narzullaev and Matveev have prepared heteratisine derivatives (211).lo1 7 References 1 M.Ihara M. Suzuki K. Fukumoto and C. Kabuto J. Am. Chem. SOC. 1990 112 1164. 2 (a)L. Ding and Y. Chen Tianran Chanwu Yanjiu Yu Kaifa 1990 2,74; (b)L. Ding and W. Chen Tianran Chanwu Yanjiu Yu Kaifa 1989 1 6. 3 G. De la Fuente and M. Reina Collect. Bot. (Barcelona) 1990,19 129. 4 K. R. Jennings D. G. Brown and D. P. Wright Jr. Experientia 1986 42 61 1. 5 S. A. Ross and S. W. Pelletier Heterocycles 1991 32 1307. 6 S. W. Pelletier and S. A. Ross Heterocycles 1990 31 671. 7 A Katz J. Nat Prod. 1990 53 204. 8 L. V.Beshitaishvili Khim. Prir. Soedin. 1991 816. 9 N. Batbajar D. Batsuren and M. N. Sultankhodzhaev Khim. Prir. Soedin. 1990 559. 10 (a)B. Proksa D. Uhrin D. 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ISSN:0265-0568    

DOI:10.1039/NP9931000471

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Pyrrolizidine Alkaloids D. J. Robins Department of Chemistry University of Glasgow Glasgow G 12 8QQ Reviewing the literature published between July 1991 and June 1992 (Continuing the coverage of literature in Natural Product Reports 1992 Vol. 9 p. 313) 1 The Synthesis of Necines 2 The Synthesis of Necic Acids 3 The Synthesis of Pyrrolizidine Alkaloids and Analogues 4 Alkaloids of the Asteraceae (Compositae) 5 Alkaloids of the Boraginaceae 6 Alkaloids of the Fabaceae (Leguminosae) 7 Alkaloids of the Graminae 8 Alkaloids in Insects 9 General Studies 10 X-Ray Studies 1 1 Pharmacological and Biological Studies 12 References 1 The Synthesis of Necines A new route to optically active forms of heliotridane (7) and isoretronecanol (8) has been established by Knight and Ley using a n-allyltricarbonyliron lactam complex to form the C-2 to C-3 bond in (8).l The methyl ketone (1) was prepared from (S)-N-t-butoxycarbonylproline(Scheme 1).Wittig reaction on this ketone (1) followed by allylic oxidation generated the allylic alcohol (2). Deprotection of the carbamate was carried out in order to prepare the cyclic carbamate (3). Treatment of this material (3) with di-iron nonacarbonyl in benzene with ultrasonication gave the key n-allyltricarbonyliron lactam complex (4) in almost quantitative yield. Conversion of the complex (4)into the corresponding lactam (5) could be achieved by oxidation with ceric ammonium nitrate in acetonitrile or better by exhaustive carbonylation under forcing conditions.Hydrogenation of the lactam (5) gave the amide (6) and a diastereoisomer in a 7 :2 ratio. Compound (6)can be converted into (-)-heliotridane (7). Reduction of lactam (5) and hydration of the double bond yielded (-)-isoretronecanol (8). Extension of this work to other necines is feasible. Formation of the diastereoisomeric necine (-)-trachelan-thamidine (12) from (S)-proline is reported by Seijas et a1.l This route relies on the formation of the C-1 to C-2 bond in (-)-trachelanthamidine by a 5-ex0 trig radical cyclization. The desired precursor (1 0) was prepared from (9-N-carbobenzyl- oxyproline (9) in several steps (Scheme 2). The radical was generated by heating the trichloro compound (10) in acetonitrile in a sealed tube at 150 "C using copper (I) chloride as a catalyst.Homolysis of the C-C1 bond was followed by cyclization to give the pyrrolizidinone (1 1) as a single diastereoisomer in 93 % yield. Reductive removal of the geminal chlorine atoms in (1 1) was followed by conversion of the remaining chloride into an alcohol and reduction of the amide to afford (-)-trachelan- thamidine (12). i-iv (-y (-&v vi c& ~ N C02H N C02Bn C02Bn COCCI (12) 0 0 (11) Reagents i ClCO,Et Et,N; ii NaBH,; iii Swern oxidation; iv Ph,P=CH,; v HBr AcOH; vi Cl,CCOCI DMAP; vii CuCl MeCN 150 "C; viii H,-Pd/C or Bu,SnH; ix NaI; x AgOAc; xi LiAlH Scheme 2 x or xi 1 xii a-4 4-xiii 1 c-xiv H&1 2 N N3 0 0 Reagents i N,W-carbonyldiimidazole THF; ii MeONHMe.HCl; iii MeMgC1 THF; iv Ph3P=CH2 Et,O ;v SeO, ButOOH CH,CI ;vi HCI CHCl,; vii MeOCOCI Et,N CH,CI,; viii NaH PhMe; ix Fe,(CO), PhH; x Ce(NH,),(NO,), MeCN; xi CO 305 atm. C,H, 105 "C; xii H, 10% Pd/C EtOAc; xii LiAlH,; xiv BH, THF; NaOH H,02; HCl Scheme 1 487 NATURAL PRODUCT REPORTS 1993 ii iii vi vii 4. -{NH iv v -&OH /%OH SH 0 viii ix t &-@ CH20H 2&$o&$o+)\sph 0 (21) (20) HOH2C” YO*-0 \\ SPh (17) (19) (18) Reagents i Et,N; ii NCS; iii 3-butyn-1-01 Ph,P; diethylazodicarboxylate; iv mCBPA; v cyclopentadiene ZnC1,; vi NaBH, HCI MeOH; vii SmI, ButOH HMPA ;viii pyridinium p-toluenesulfonate MeOH ;ix (PhS), lithium hexamethyldisilazide; x HCO,H ;xi NaBH, MeOH ;xii FVP 500 “C; xiii H,-PtO, EtOH; xiv LiAIH Scheme 3 A lengthy but enantio- and diastereoselective route to (+)-trachelanthamidine (21) has been described by Arai et aL3 The optically active succinimide (1 3) was prepared from maleimide and the chiral auxiliary 1O-mercaptoisoborneol as outlined in Scheme 3.The maleimide (14) was reformed by a chlorination- dehydrochlorination sequence and N-alkylation was achieved under Mitsunobu conditions. Diels-Alder reaction of the maleimide (14) with cyclopentadiene gave the adduct (1 5) with 96 % diastereoisomeric excess. The reduction of the imide (15) was regioselective leading to the tricyclic lactam (16) as a mixture of diastereoisomers. This mixture was converted into the phenylsulfide (17) which was obtained as a single diastereoisomer.Treatment of the phenylsulfide (1 7) with formic acid generated an acyliminium ion which underwent nucleophilic addition on the convex face due to the steric constraint imposed by the fused bicyclic system. The tricyclic product (18) was reduced to the alcohol (19) which was subjected to flash vacuum pyrolysis to afford the unsaturated pyrrolizidinone (20) by a retro Diels-Alder reaction. Reduction steps then yielded (+)-trachelanthamidine (2 1). A synthesis of (-)-supinidine (32) utilizing the Sharpless asymmetric oxidation has been devised by Takahata et ~21.~ The starting material was racemic N-protected 3-hydroxy-4-pentenylamine (22) which was treated with t-butyl hydro- peroxide and D-( -)-diisopropyl tartrate in the presence of molecular sieves to yield optically active alkene (23) epoxide (24) and pyrrolidine (25) (Scheme 4).Routes to supinidine were devi;ed from all three products (23)-(25) and the one involving he alkene (23) is shown in Scheme 5. Formation of the aldeh. de (26) was achieved after stereoselective intra- molecular midomercuration of alkene (23). Horner-Emmons reaction o the aldehyde (26) enabled the additional two carbon ato is to be incorporated to give the unsaturated ester (27). Hydrc ;enation conditions served to saturate the double bond and rc nove the N-protecting group and the intermediate ester (28) w s cyclized to afford the pyrrolizidinone (29). The protected hydroxy compound (29) was converted into the phenylthio derivative (30). The amide (30) was reduced and the sulfoxide was prepared so that the hydroxymethyl group could be introduced to yield pyrrolizidine (31).The double bond was generated by thermal elimination of the sulfoxide and depro- tection gave (-)-supinidine (32). Curassanecine (38) was previously isolated from Helio-tropium curass~vicum.~ As this is the first necine containing a 1-hydroxy-group I suggested that confirmation of this structure PH OH LNHCBZ \NHCBZ ‘NHC~Z ?BZ by synthesis would be desirable.6u Gramain et al. have now responded to this challenge and have carried out the first synthesis of this necine.’ The ketoester (33) was obtained by condensation of methyl oxalate with the anion derived from N-acetylpyrrolidine (Scheme 6). Photocyclization of the ketoester (33) yielded a mixture of hydroxyesters (34) and (35) in a 1 :1 ratio which was separated by flash chromatography.Reduction of the esters afforded curassanecine (38) and its diastereoisomer (39). The assignment of relative configuration in curassanecine (38) was carried out by solvent effect experiments in ‘H NMR spectroscopy on the esters (34) and (35) and by comparison of the spectra with those of model compounds (36) and (37). An X-ray crystal structure determination on pyrrolizidinone (37) confirmed these assignments although final proof by con-version of (37) into (35) could not be achieved. The N-substituted Geissman-Waiss lactone (42) is a useful intermediate in the preparation of a number of necines. A new route to this compound has been reported by Sakai and co- workers (Scheme 7).8 The bislactone (40) was converted by known steps into the unsaturated lactone (41).The tosylate (41) was treated with azide and the product was hydrogenated in the presence of a Lindlar catalyst. Alkylation of the product afforded the desired derivative (42). Attempts to make lactone (42) in optically active form via optically active compound (41) failed presumably due to the facile racemization of the y-substituted a$-unsaturated lactone. Xenovenine (44) is the only known example of a 33-dialkylpyrrolizidine. It is produced by the cryptic thief ant Solenopsis xenovenenum and may form part of the ant’s defensive system. A synthesis of xenovenine by Hesse and co- workers uses 5-nitropentadecane-2,8-dione(43) as the key intermediate.s This was prepared by a Michael reaction from nitromethane methylvinylketone and dec-l-en-3-one (Scheme 8).Reduction of the nitro compound (43) gave a mixture of 33- dialkylpyrrolizidines. The best yield (88 %) of xenovenine (44) was obtained under carefully defined conditions. NATURAL PRODUCT REPORTS 1993-D. J. ROBINS OTBDMS OTBDMS OTBDMS OTBDMS (23) z+ ''CHO CBZ vi QYH=CHC02Me Q*.CH2CH2CO2Me CBZ H 0 &CH20H &SOPh CH20Bn ' @SPh xiv xv xt-xiii -c-. 0 Reagents i Hg(OAc),; ii NaHCO, NaBr; iii TBDMSC1 imidazole DMF; iv 0, NaBH, DMF; v Py-SO, DMSO Et,N; vi (EtO),POCH,CO,Me NaH; vii H,/Pd(OH),; viii AlMe then H+; ix MsCl py; x NaSPh DMF; xi LiAlH,; xii mCBPA; xiii LDA BnOCH,Cl; xiv 150 "C; xv Na/NH Scheme 5 (33) (34) R=COzMe (35) R=C02Me (36) R = Ph (37) R = Ph iii iii J aCH2OH &OH CH20H OH Reagents i (CO,Me), LDA; ii hv; iii LiAlH Scheme 6 0-0 -oc CH~TS Reagents i NaN, HMPA; ii H, Lindlar catalyst; iii BrCH,CO,Et Scheme 7 (43) Reagents i PBu,; ii NH,OAc KOH MeOH NaBH,CN; iii NaBH (44) Scheme 8 NATURAL PRODUCT REPORTS 1993 (53) (50)R' = (CH2)30H R2 = H (51)R' = H R2 = (CH2)sOH Reagents i MeOH SOC1,; ii NaBH,; iii TsCl Et,N; iv Nal; v H,/PtO,; vi Me,SO,; vii 2-acetylbutyrolactone Ni(acac),; viii 3~ HCl 60 "C; ix BnOCOC1 NaHCO,; x PCC; xi n-C,H,,MgBr; xii H,-Pd/BaSO Scheme 9 K K K K 2*OTr 40 iii iv v ?P vi vii 4P __c (45) -POTr?P O N -P O T r -HOpOTr HO-pr Boc ON 0 Boc NHBoc NHBoc NHBoc HO TBDMSO (54) (55) (56) (57) (58) viii J xiv xv 9KP xi xii ix ?% ix x 0x9 HO Hq --OH -MOMO..F "yp TBDh4SO/'"&OTr N CH20H CH20H Bn -Boc Boc (64) (63) OH (59) (62) (60) (61) epimer at * Reagents i OsO, N-methylmorpholine N-oxide ;ii 2,2-dimethoxypropane p-TsOH ;iii vinyl magnesium bromide ;iv NaBH, CeCl,; v 0 then NaBH,; vi TBDMSC1 imidazole DMF; vii Swern oxidation then NaBH,; viii MsCl Et,N then ButOK; ix Bu,N+F-; x Swern oxidation then allylmagnesium chloride ;xi ClCH,OMe N,N-diethylaniline ;xii TBDMS triflate 2,6-lutidine ;xiii BnBr K,CO ; xiv MsCl Et,N ;xv H,-10% Pd/C Scheme 10 Asymmetric syntheses of xenovenine (44) have been reported glycosidases.(9-Pyroglutamic acid (45) was converted into the previously.6"d Another route to the (3S,SR,SS)-isomer (44) protected trio1 (55) via the unsaturated lactam (54).Grignard has been devised by Lhommet and co-workers (Scheme ,).lo reaction on the protected lactam (55) yielded the ring opened The starting material was (9-pyroglutamic acid (45). This acid compound (56). Reduction of the unsaturated ketone (56) was esterified in order to carry out the transformations followed by ozonolysis generated epimeric diols (57). The necessary to produce the methyl group in (46). The amide (46) unwanted isomer could be separated then oxidized and reduced was converted into the lactam ether (47) which was condensed leading also to the desired protected compound (58). Ring with 2-acetylbutyrolactone to afford the P-enaminolactone closure led to the pyrrolidine (59).The additional carbon atoms (48). Under acidic conditions hydrolysis and decarboxylation required were added by diastereoselective alkylation to give the of the unsaturated lactone (48) occurred to give the imino- alkene (60) and the diastereoisomer (61) in a 2.5 1 ratio after alcohol (49). Reduction of this imine (49) gave a mixture of removal of the silyl protecting group and oxidation of the pyrrolidines (50) and (51). Separation of these compounds was alcohol to an aldehyde. Further transformations of (60) led to achieved by treatment of the mixture with benzyl chloroformate the protected alcohol (62). Mesylation of the alcohol (62) when only the carbamate of the cis-isomer (51) was formed at followed by removal of the protecting groups afforded 1,7a- 0 "C.The unreacted amine (50) was readily separated and diepialexine (63). A parallel series of reactions served to converted into the carbamate (52) at 80 "C. Elongation of the produce 1,7,7a-triepiaIexine (64) from alkene (61). carbon side chain of (52) was carried out by Grignard reaction Synthesis of alexines (63) and (64) has also been reported (after oxidation of the alcohol to the aldehyde) to afford the from heptonolactones by Fleet and co-workers.12 All of the secondary alcohol (53). Oxidation of this alcohol and hydro- chiral centres required for the synthesis of 1,7a-diepialexine genation over a partially poisoned catalyst yielded (+)-(63) are present in the readily available lactone diacetonide (65) (3S,5R,8 S)-xenovenine (44).(Scheme 11). The azide (65) was transformed into the nitrile (9-Pyroglutamic acid (45) has also been used as the starting (66) in nine steps. Cyclization of the nitrile (66) afforded the material in a synthesis of the naturally occurring 1,7a-pyrrolizidinone (67) which was reduced and treated with diepialexine (63) and the non-natural 1,7,7a-triepialexine (64) trifluoroacetic acid to yield 1,7,7a-triepialexine (64). Alternat- by Ikota (Scheme 10).l1 Alexines are polyhydroxylated pyrro- ively oxidation of alcohol (67) followed by reduction from the lizidine alkaloids with a hydroxymethyl group at C-3 rather least hindered face gave alcohol (68). A parallel sequence of than C-1. Some of them have inhibitory activity towards reactions then led to 1,7a-diepialexine (63).NATURAL PRODUCT REPORTS 1993-D. J. ROBINS 49 1 (67) (66) ii iii 1 (64) Reagents i NH,Cl NH, 100 "C; ii THF. BH,; iii 50% aq. CF,CO,H; iv PCC; v NaBH Scheme 11 BnO BnO L-xylose BnO OH -BnO BnO BnO BnOi BnOj (69) (70) (711 (72) HO (H$ Hwn vi vii -OBn --OBn + BnO &OH N3 CH20Bn CH20Bn BnOj BnOi (75) (74) (73) viii viii 1 1 (77) (76) Reagents i Ph,P+CH,Br- BuLi; ii Tf,O py; Bu,",; iii 0 then Me,S; iv Ph,P+(CH,),OH Br ,KN(SiMe,),; Me,SiCl; HCl; v mCPBA; vi TsCl py DMAP; vii 5 wt YOH,-lOYo Pd/C 15 h; K,CO,; viii 300 wt % H,-10% Pd/C 48 h Scheme 12 alcohol (70) was converted into the azide and ozonolysis of the double bond gave the aldehyde (71). Another Wittig reaction HCgC02Et + was carried out and the alkene (72) was converted into the OCOCOMe epoxide (73) as a mixture of diastereoisomers.Tosylation of the I (78) mixture followed by hydrogenolysis led to a 2 :1 mixture of the Ph 1 pyrrolizidines (74) and (75). These were separated by flash chromatography and debenzylation afforded 7,7a-diepialexine ii (76) and 7-epialexine (77) respectively. R= n Yo 2 The Synthesis of Necic Acids + Fang and Hong previously described the synthesis of crobar- RCO RCO batic acid (83).14 Attempts to modify this synthesis in order to produce optically active material failed. Use of the (-)-8- (82) (811 phenylmenthoxy group as a chiral auxiliary did however lead (83) R = OH to successful preparation of an ester (82) of crobarbatic acid by Reagents i LDA MgC1,; ii Me,CuLi; iii H,-Pd/C Chen and Fang (Scheme 13).15 Nucleophilic addition of the Scheme 13 alkynyllithium generated from ethyl propiolate (78) to ( -)-8-phenylmenthyl pyruvate (79) occurred stereoselectively to give mainly the (2S)-alcohol (80) (70%) with a little (loo/,) of the Pearson and Hines have developed a route to naturally (2R)-isomer.Treatment of the alkynoate (80) with lithium occurring 7,7a-diepialexine (76) and the non-natural epimer dimethylcuprate yielded the unsaturated lactone (8 l) and (77) starting from L-xylose (Scheme 12).13 The protected hydrogenation of (8 1) afforded the crobarbatate ester (82). The xylofuranose (69) was prepared in three steps from L-xylose (2&3R)-absolute configuration of (82) was established by 'H and subjected to Wittig olefination to give (70).The unsaturated NMR spectroscopy and confirmed by X-ray crystallography. NPR 10 NATURAL PRODUCT REPORTS 1993 (86) R = Me (87) R=CHZOH HO + v-vii viii __t ___c H02C C02H N Me02C C02Me (84) Reagents i CH,N ;ii HS(CH,),SH BF .Et,O; iii NaOH ;iv Ac,O; v DME; vi Ph,P 2,2'-dipyridyldisulfide; vii HgCl,; viii HO,CCH,ONH Scheme 14 3 The Synthesis of Pyrrolizidine Alkaloids and Analogues H i,ii A full account of the synthesis of (+)-integerrimhe (86) by ("7 -Niwa et al. has appeared.16 This involves synthesis of (+)-HO2C C02H retronecine (84) and the acid portion.6e Coupling of the two portions was achieved via a cyclic stannoxane (85).6e Full details" are now available of two routes to (+)-integerrimine I iii-v (86) by White and co-workers.6e,.f (+)-Usaramine (87) was also t prepared.COC H2C H2CO2H Kurth et al. have devised routes to two new types of pyrrolizidine alkaloid analogues (92) and (96).lg These are f designed to provide a point of attachment (-C0,H) to a protein and as macrocyclic dilactones it is suggested that they may retain the conformation of natural 1 1-membered alkaloids (ester carbonyl groups are usually cis and directed below the plane of the ring). Ketodiacid (88) was esterified and the (96) (95) carbonyl group was protected to give the dithiane (89). The anhydride (90) was prepared and coupled with (+)-retronecine Reagents i ButOCO,N=C(C,H,)CN Et,N; ii DCC; iii DME; iv (84) by the Corey-Nicolaou method to give the ketone (91).Ph,P 2,2'-dipyridyldisulfide; v HCl ;vi succinic anhydride This ketone was converted into its carboxymethyloxime derivative (92) (Scheme 14). Unfortunately lack of stereocontrol Scheme 15 in the synthesis led to the formation of four diastereoisomers. The second analogue (96) was designed to avoid these stereochemical problems and the synthetic route used is shown The major alkaloidal constituent of Senecio adonidifolius in Scheme 15.1g Iminodiacetic acid (93) was converted into the adonifoline was previously assigned the structure (102).6qAn anhydride (94) and coupled with (+)-retronecine (84) as before alkaloid with almost identical NMR spectra had also been to give the macrocyclic dilactone (95).Finally reaction of the isolated from S. dolichodovyius and the structure (103) was secondary amine with succinic anhydride yielded the pyrro- proposed.6h Re-investigation of S. adonidifolius by Witte et al. lizidine alkaloid analogue (96). has led to a reassignment of the structure of the alkaloid to the pentacyclic arrangement (104) on the basis of detailed NMR spectroscopic studies.21 Stereochemical details could not be 4 Alkaloids of the Asteraceae (Compositae) deduced. Eupatorium fortunei is a traditional Chinese medicine used to Four pyrrolizidine alkaloids and six secopyrrolizidine alka- treat many diseases. Liu et al. have isolated supinine (97) loids were previously reported from Senecio anonymus Wood rinderine (98) and 7-0-acetylrinderine (99) from this plant.lg by Zalkow and co-workers.6i A minor component of this 7-0-Acetylrinderine is a new alkaloid.All three alkaloids have species has now been shown to be acetylanonamine (105) by the structural features necessary to exhibit hepatotoxicity. comparison of its spectra with anonamine (106) and by Two new alkaloids have been isolated from Senecio racemosus conversion of the alcohol (106) into the ester (105).22 by Malik and co-workers.20 Structures (100) and (101) were 7-Epidesacetylsenaetnine (107) and 7-episenaetnine (1 08) are assigned to racemocine and racemonine on the basis of detailed reported to be constituents of Chilean Senecio portale~ianus.~~ NMR spectroscopic studies. On alkaline hydrolysis both S.nebrodensis L. is a perennial plant found in the Spanish alkaloids gave a new necine named racemonecine. mountains. It contains the N-oxides of senecionine integer- NATURAL PRODUCT REPORTS 1993-D. J. ROBINS OH (97) R=H (98)R = OH (100) R= kMe (99) R = OAC Me (101) R= kw OCOEt Me @ 0 (105) R=Ac (107) R =H (106) R =H (108)R=Ac rimine (86) retrorsine and sarracine together with the free bases of the first two alkaloids mentioned.24 S.jacobaea L. was introduced into Canada in the 1950s. It thrives in cool wet areas on the west and east coasts. It can be controlled by herbicides or the cinnabar moth (Tyria jac~baea).~~ A study of more than 100 populations of S. jacobaea from different locations in Europe revealed that there are two chemotypes.26 One chemotype produces mainly jacobine and its derivatives whereas erucifoline and it 0-acetyl derivative predominate in the other.A similar situation exists in 25 populations of S. erucifolius which were studied.26 One chemotype also produces erucifoline and its 0-acetyl derivative and the other contains mainly eruciflorine (109) (21 -hydroxyintegerrimine) which is a new pyrrolizidine alkaloid. Tussilago farfara (coltsfoot) is a frequently used medicinal plant. GC analysis showed that 30-54% of the senkirkine present in the leaves was found in aqueous preparation^.^^ Echinatine and supinine were isolated from Eupatorium cannabinum var. syriacum.28 Lycopsamine and echinatine are present in the medicinal herb Ageratum conyzoides from Kenya.29 This is the first report of pyrrolizidine alkaloids from this genus.5 Alkaloids of the Boraginaceae The distribution of pyrrolizidine alkaloids within the genus Amsinckia has been studied using GC-MS by Kelley and Seiber.30 From 55 samples 28 different pyrrolizidine alkaloids were identified in 12 of the 14 known species. The chemo- systematic significance of the results was discussed. Two new alkaloids were identified -tessellatine (1 10) from A. tessellata var. gloriosa populations and 3',7-diacetylintermedine (111) from one A. menziesii var. intermedia sample.31 Roeder et al. have isolated seven alkaloids from Echium pininana Webb et Berth. which is endemic to the Canary Known alkaloids were myoscorpine hydroxymyo- scorpine echimidine and acetylintermedine.Three new alka- loids were identified by spectroscopic methods as echiupinine (7-senecioyl-9-(+)-trachelanthoylretronecine) (1 12) together with its N-oxide and the N-oxide (113) of myoscorpine. Echinatine rinderine and heliotrine together with their N- oxides are constituents of Cynoglossum nervosum Benth. ex Hook.33 Echinatine and heliosupine are mainly present as their N-oxides in C. rnacrostylum B~nge.~* 6 Alkaloids of the Fabaceae (Leguminosae) Madurensine and a new pyrrolizidine alkaloid trans-anacrotine (1 14) were isolated from seeds of South African Crotalaria capensis by Verdoorn and van Wyk.35 Pyrrolizidine alkaloids were detected in the graft hybrid Laburnocytisus adamii by GC-MS methods.36 Pereira et al.have identified a new alexine from Alexa grandz~7ora.~~ The structure (1 15) was proposed for 7a-epialexaflorine on the basis of spectroscopic evidence. Con- firmation of the structure and stereochemistry was obtained by X-ray crystallography. This is the first example of a naturally occurring pyrrolizidine-3-carboxylic acid. YH(0H)Me Y(0H)Et CHzOCO ?HI 0- 7 Alkaloids of the Graminae Loline alkaloids are present in tall fescue (Festuca arundinacea) infected with the endophytic fungus Acremonium coenophialum. Separation of these alkaloids from ergot types of F. arundinacea has been achieved by high speed countercurrent chromat-ograph~.~~ Acremonium fungus was shown to be present on meadow fescue (Festuca pratensis) by microscopic examination.A GC-MS study of an extract indicated the presence of N- formyl- and N-acetyl-loline. The lolines were only produced in the presence of the fungus at elevated temperature^.^' The aphids Rhopalosiphum padi are sensitive to the presence of loline alkaloids in tall fescue infected with the endophytic fungus. They survive longer on loline-free tall 8 Alkaloids in Insects Pyrrolizidine alkaloids are sequestered by the danaine butterfly Idea leuconoe. Two new metabolites were identified from adult forms feeding on plants from the Ap~cynaceae.~~ Ideamine A (116) is related to lycopsamine N-oxide and ideamine B (1 17) is similar to parsonsine N-oxide. Both alkaloid N-oxides were also present in I.leuconoe. Aposematic queen butterflies (Danaus gilippus) with a low pyrrolizidine alkaloid content were readily eaten by predator^.*^ Specialist herbivores (mono- phagous) are adapted to a qualitative chemical defence by pyrrolizidine alkaloids whereas generalists (polyphagous) are not.43 Interactions between ants (Lasius niger) aphids (Aphis jacobaea Shrank) moths (Tyria jacobaea L.) and Senecio jacobaea can explain the genetic variations observed in NATURAL PRODUCT REPORTS 1993 The ‘H and 13C NMR spectra of retronecine (84),heliotridine crotanecine otonecine together with their hydrochloride salts and N-oxides have been recorded.53 10 X-Ray Studies An X-ray crystal structure of latifoline (1 18) as the hydro- bromide by Culvenor and Mackay has confirmed the absolute configuration of latifolic acid as 2R,3S,4S.54Latifoline is a constituent of Cynoglossum latifolium.11 Pharmacological and Biological Studies The toxicity of pyrrolizidine alkaloids has been reviewed.55 Comfrey (Symphytum spp.) is widely grown as a garden herb and is consumed by humans for medicinal purposes as a salad ingredient and as a herbal tea. The toxicity of comfrey has been All of the pyrrolizidine alkaloids from Russian comfrey (Symphytumx uplandicum) caused liver damage in rats and it is clear that the safety of comfrey for human consumption requires further When 3H-seneciphylline was fed to dairy cows radioactivity appeared in the milk mainly in the first 24 hours and reached a concentration of 0.1 pg ml-l.Only 0.16% of the dose was extracted in the milk. Seneciphylline retronecine and their N-oxides were detected in the milk.58 The occurrence of pyrrolizidine alkaloids in milk and their potential effects on humans have been reviewed.59 The toxicity of five species of Senecio has been studied in pyrrolizidine alkaloid concentrations in Senecio j~cobaea.~~ cattle and chicks.6o Six calves fed dried Cynoglossum oficinale Larvae of the arctiid moth Utethesia ornatrix are unpalatable to the wolf spider (Lycosa ceratiola) when they contain pyrrolizidine alkaloids sequestered from their food plants.45 Larvae which are deficient in pyrrolizidine alkaloids cannibalize eggs rich in the alkaloid^.^^ However pyrrolizidine alkaloids in the eggs of U.ornatrix did not protect against fungal infection.47 Some pyrrolizidine alkaloids are converted into pheromones such as hydroxydanaidal by U.ornatrix. This compound was found to stimulate the olfactory receptor neurons in U.ornatrix females.48 Chrysomalid beetles were able to sequester injected showed typical damaging effects on their livers.61 Three ponies in the Pacific north-west of the USA were diagnosed with liver failure probably due to pyrrolizidine alkaloid poisoning. 62 Severe losses of yaks in the eastern region of Bhutan were due to ingestion of pyrrolizidine alkaloids. This was confirmed by recovery of the toxic pyrrolic metabolites from liver Vascular injuries induced by monocrotaline pyrrole may be caused by interactions of metals with vascular cells.64 The role of glutathione as a trapping agent for pyrrolic metabolites of senecionine has been in~estigated.~~ The best tests for pyrro- 14C-senecionine N-oxide in their exocrine defensive ~ecretion.~~ lizidine alkaloid intoxication are liver biopsy and determination 9 General Studies Ofline supercritical fluid extraction with methanol and carbon dioxide provided quicker extraction simpler work up and higher recovery of pyrrolizidine alkaloids than Soxhlet ex- traction.50 A two step enzyme-linked immunosorbent assay (ELISA) has been developed for the detection of pyrrolizidine alkaloids in vitro in the ppb range.51 The two haptens were synthesized by modification of retronecine (84) and pyrrolizidine alkaloids were detected after hydrolysis to retronecine.There was no cross reactivity with the indolizidine alkaloid swainsonine nor with the quinolizidine alkaloid lupinine. A method for the separation of platyphylline and seneci- phylline without using organic solvents by precipitation out of aqueous solution at different pH values has been patented.52 of enzyme activities in the liver serum.66 A flavin-containing monooxygenase is a major detoxifying enzyme for senecionine in guinea pig tissue leading to N-oxide formation.67 Guinea pigs are less susceptible to pyrrolizidine alkaloid poisoning than mice hamsters or rats.68 The mutagenicity of pyrrolizidine alkaloids in several Italian Senecio species has been e~aluated.~~ 16 pyrrolizidine All alkaloids tested were genotoxic except a C-9 monoester of ~upinidine.~~ Eight bifunctional pyrrolizidine alkaloids all generated cross links in DNA in cultured bovine kidney epithelial cells.71 The cytotoxic effect of integerrimine (86) from Senecio brasiliensis Less.var. tripartitus depended on the alkaloidal concentration and the DNA repair capacity of the strains of Saccharomyces cerevisiae The alkaloids isolated from Doronicum austriacum inhibited the growth of mouse fibroblasts in vitro and the growth of mouse mammary carcinomas in viv~.~~ NATURAL PRODUCT REPORTS 1993-D. J. ROBINS 25 J. F. Bain Can. J. Plant Sci. 1991 71 127. 26 L. Witte L. Ernst H. Adam and T. Hartmann Phytochemistry 1992 31 559. . .. HoQnC' Meo' -'. NHAc 27 H. Miething and R.A. Steinbach PZ Wiss. 1990 135 253. 28 F. Pagani Boll. Chim. Farm. 1990 129 281 (Chem. Abstr. 1991 115 228 434). iii iv 29 H. Wiedenfeld and E. Roeder Planta Med. 1991 57 578. 30 R. B. Kelley and J. N. Seiber Phytochemistry 1992 31 2369. 31 R. B. Kelley and J. N. Seiber Phytochemistry 1992 31 2513. 32 E. Roeder K. Liu and T. Bourauel Phytochemistry 1991 30 3107. 33 D. B. Hagan and D. J. Robins Fitoterapia 1991 62 186. 34 H. A. Kelly and D. J. Robins Fitoterapia 1992 63 91. (119) 35 G. H. Verdoorn and B.-E. van Wyk Phytochemistry 1992 31 Reagents i Phthalimide Ph,P DEAD; ii NH,NH,; iii CDI; iv 369. KOH 36 R. Greinwald M. Wink L. Witte and F. C. Czygan Biochem. Scheme 16 Physiol. Pjlanz. 1991 187 385. 37 A. C. de S. Pereira M. A.C. Kaplan J. G. S. Maia 0.R. Gottlieb R. J. Nash G. Fleet L. Pearce D. J. Watkin and A. M. Scofield Tetrahedron 1991 47 5637. No cost was detected in terms of reproductive output in the 38 R. J. Petroski and R. G. Powell ACS Symp. Ser. 1991,449 426. production of pyrrolizidine alkaloids by Senecio jacobaea L.74 39 H. J. Huizing W. Van der Molen W. Kloek A. P. M. Den Nijs Grass Forage Sci. 1991 46 441. An argument has been put forward for the deaths of livestock 40 H. Eichenseer D. L. Dahlman and L. P. Buch Entomol. Exp. from industrial pollution rather than pyrrolizidine alkaloid Appl. 1991 60 29. poisoning as previously ~uggested.~~ 41 R. Nishida C. S. Kim H. Fukami and R. Irie Agric. Biol. Chem.. Flynn and co-workers have synthesized pyrrolizidine deriv- 1991 55 1787.atives which are more potent and selective at the newly 42 D. B. Ritland J. Chem. Ecol. 1991 17 1593. described serotonin 5-HT4 receptor site than known gastro- 43 K. Vrieling L. L. Soldaat and W. Smit Neth. J. Zool. 1991 41 intestinal agents such as meto~lopramide.~~ The most active 228. compound was amide (1 19) prepared from (-)-trachel-44 K. Vrieling W. Smit and E. Van der Meijden Oecologia (Heidelb.) 1991 86 177. anthamidine (12) as shown in Scheme 16. 45 T. Eisner and M. Eisner Psyche (Camb.) 1991 98 11 1. 46 F. Bogner and T. Eisner Experientia 1991 48 97; idem. J. Chem. Ecol. 1991 17 2063. 12 References 47 G. K. Storey D. J. Aneshansley and T. Eisner J. Chem. Ecol. 1 J. G. Knight and S. V. Ley Tetrahedron Lett. 1991 32 71 19.1991 17 686. 2 J. A. Seijas M. P. Vazquez-Tato L. Castedo R. J. Estevez M. G. 48 F. Bogner A. J. Grant and R. J. O'Connell J. Chem. Ecol. 1992 Onega and M. Ruiz Tetrahedron 1992 48 1637. 18 427. 3 Y. Arai T. Kontani and T. Koizumi Chem. Lett. 1991 2135. 49 A. Ehmke M. Rowell-Rahier J. M. Pasteels and T. Hartmann 4 H. Takahata Y. Banba and T. Momose Tetrahedron 1991 47 J. Chem. Ecol. 1991 17 2367. 7635. 50 C. Bicchi P. Rubiolo C. Frattini P. Sandra and F. 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Bras. 1990 100 63. 17 J. D. White J. C. Amedio S. Gut and L. R. Jayasinghe J. Org. 61 D. C. Baker J. A. Pfister R. J. Molyneux and P. Kechele Chem. 1992 57 2270. J. Comp. Pathol. 1991 104 403. 18 M. J. Kurth L. A. Milco and R. B. Miller Tetrahedron 1992,48 62 E. G. Pearson J. Am. Vet. Med. Assoc. 1991 198 1651. 1407. 63 H. Winter A. A. Seawright J. Hrdlicka U. Tshewang and B. J. 19 K. Liu E. Roeder H. L. Chen and X. J. Xiu Phytochemistry Gurung Res. Vet. Sci. 1992 52 187. 1992 31 2573. 64 J. F. Reindel C. M. Hoorn J. G. Wagner and R. A. Roth Am. 20 W. Ahmed Z. Ahmed A. Malik F. Ergun and B. Sener 1. Physiol. 1991 261 L406.Heterocycles 1991 32 1729. 65 D. R. Buhler C. L. Miranda B. Kedzierski and R. L. Reed Adv. 21 L. Witte L. Ernst V. Wray and T. Hartmann Phytochemistry Exp. Med. Biol. 1991 283 597. 1992 31 1027. 66 A. M. Craig E. G. Pearson C. Meyer and J. A. Schmidz Am. J. 22 C. F. Asibal L. H. Zalkow and L. T. Gelbaum J. Nut. Prod. Vet. Res. 1991 52 1969. 1991 54 1425. 67 C. L. Miranda W. Chung R. E. Reed X. Zhao M. C. Henderson 23 J. Jakupovic M. Grenz F. Bohlmann and H. M. Niemeyer J. L. Wang D. E. Williams and D. R. Buhler Biochem. Biophys. Phytochemistry 199 1 30 269 1. Res. Commun. 1991 178 546. 24 A. F. Barreiro E. J. Alvarez-Manzaneda Roldan and R. Alvarez- 68 P.-S. Chu and H. J. Segall Comp. Biochem. Physiol. C Comp. Manzaneda Roldan An. Quim. 1991 87 386. Pharmacol.Toxicol. 1991 100 683. 69 P. Rubiolo L. Pieters M. Calomme C. Bicchi A. Vlietinck and D. Vanden Berghe Mutat. Res. 1992 281 143. 70 H. Frei J. Luethy J. Brauchli U. Zweifel F. E. Wuergler and C. Schlatter Chem.-Biol. Interact. 1992 83 1. 71 J. R. Hincks H. Y. Kim H. J. Segall R. J. Molyneux F. R. Stermitz and R. A. Coulombe Toxicol. Appl. Pharmacol. 1991 111 90. 72 A. L. L. Paula-Ramos C. B. Querol E. K. Marques and J. A. P. Henriques Rev. Bras. Genet. 1991 14 897. NATURAL PRODUCT REPORTS 1993 73 J. Petricic M. Osmak M. Hadzija Z. Kalodera and M. Slijepcevic Acta Pharm. Jugosl. 1991 41 169. 74 K. Vrieling,Meded. Fac. Landbouwwet. Rijksuniv. Gent. 1991,56 781. 75 0.L. Lloyd M. M. Lloyd F. L. R. Williams A. McKenzie and A.Hay Sci. Total Environ. 1991 106 83. 76 D. L. Flynn D. L. Zabrowski D. P. Becker R. Nosal C. I. Villamil G. W. Gullikson C. Moummi and D.-C. Yang J. Med. Chem. 1992 35 1486.

ISSN:0265-0568    

DOI:10.1039/NP9931000487

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Marine Natural Products D. J. Faulkner Scripps Institution of Oceanography University of California San Diego La Jolla CA 92093-0212 USA Reviewing the literature published during 1991 (Continuing the coverage of literature in Natural Product Reports 1992 Vol. 9 p. 323) 1 Introduction 2 Marine Micro-organisms and Phytoplankton 3 Blue-Green Algae (Cyanobacteria) 4 Green Algae 5 Brown Algae 6 Red Algae 7 Sponges 8 Coelenterates 9 Bryozoans 10 Molluscs 11 Tunicates 12 Echinoderms 13 Miscellaneous 14 References 1 Introduction This Report is a review of the literature of marine natural product chemistry for 1991 and is the ninth in a series of reviews published in Natural Product Reports. The earlier reports cover the period from 1977 to December 1990.'-s The format for this review is identical to that of the previous reports.The review does not provide a comprehensive coverage of all research involving chemicals from marine organisms but concentrates on reports of novel marine natural products with interesting biological and pharmaceutical properties. Bio-chemical studies involving marine organisms and reports of primary metabolites are specifically omitted. Research on the biosynthesis of marine natural products has in the past been reviewed in detailg and is not included in this report. Wherever possible the biological and pharmacological properties of new marine natural products have been reported but papers detailing the pharmacological studies have been omitted.In the area of synthetic organic chemistry reports of the total synthesis of marine natural products or close analogues are included but papers dealing with methodology directed towards the synthesis of marine natural products have not been covered. No attempt has been made to review the patent literature or conference abstracts. Several interesting and timely reviews appeared during 199 1. A very concise review of 'Bioactive Compounds from Algae ' has drawn together nearly 450 references concerning the potential pharmaceutical and agricultural uses of algal metabo- lites.'' A comprehensive coverage of 'Marine and more specialized reviews of 'Sponge Sterols Origin and Biosynthesis '12 and 'Sponge Phospholipids '13 have appeared. Two reviews on different classes of marine nitrogenous heterocycles have appeared.l4 l5 An essay on 'Unraveling the Chemistry of Tunichromes ' has provided a very insightful picture of progress in this difficult but fascinating research area.16 A similar review of 'The Bryostatins ' provides an extensive overview of the chemistry and pharmacology of this promising group of anti-tumour agents." A summary report of presentations at the 1990 United States-Japan Seminar on Bioorganic Marine Chemistry provides a useful overview of research in both countries.18 The proceedings of a 1989 Conference in Goa India on 'Bioactive Compounds from Marine Organisms' contains a number of papers on marine natural products.l 2 Marine Micro-organisms and Phytoplankton During the last year there has been a significant increase in interest in the secondary metabolites of marine bacteria and we are now beginning to see the results from research programs that were initiated several years ago.Oncorhyncolide (1) was isolated from the culture medium of a gram negative marine bacterium (isolate no. 157) that was obtained from a surface water sample taken near a chinook salmon net-pen farming operation in British Columbia. The structure of oncorhyncolide (1) was elucidated by spectroscopic analysis.2o The actinomycete strain CNB-228 which was isolated from sediments in the Bahamas Islands produces (1 'R,2S,4S)-2-( 1'-hydroxy-6'- me thyl hep ty1)-4- h ydr oxyme thyl bu tanolide (2). The structure of butanolide (2) was assigned by analysis of spectral data and the absolute configuration was determined by synthesis.21 The octalactins (3) and (4) are cytotoxic lactones from a Stvepto-myces species (isolate PG- 19) from the surface of a gorgonian of the genus Pucijigorgia from the Sea of Cortez Mexico.The structures of octalactins A (3) and B (4) were determined by 0 OH 0 497 498 Br Br single crystal X-ray analysis and interpretation of spectral data.22 A marine bacterium of the order Actinomycetales (isolate no. CNB-032) from Bodega Bay California has yielded the 24-membered macrolide glycoside maduralide (5) the structure of which was elucidated by spectroscopic methods.23 In one of the most important and controversial papers of the year it was reported that the phenol (6) incorrectly named 3,5-dibromo-2-(3’ 5’-dibromo-2’-methoxyphenoxy)phenol,24 which had previously been regarded as a sponge metabolite was produced by a bacterium of the genus Vibrio that had been isolated from the sponge Dysidea The controversial aspect of this paper concerns the very low yield of phenol (6) detected in the bacterial culture versus the high yields typically obtained from the sponge.26 Four benzothiazoles (7)-( 10) have been obtained from cultures of a Micrococcus species that was isolated from tissues of the sponge Tedania ignis.2’ The structures of benzothiazoles (7)-(lo) all of which were known compounds were elucidated by analysis of spectral data.A structure-activity study revealed that the antimicrobial activity of pentabromopseudilin (1 l) which is produced by Alteromonas luteoviolaceus,28g 29 is absent in isopentabromopseudilin (1 2) and some related synthetic analogues.3o Leptosphaerolide (13) and a 10:9 mixture of two isomeric diketones (14) which are assumed to be derived by addition of the solvent acetone to leptosphaerodione (1 5) were isolated from the marine fungus Leptosphaeria oreamaris collected in the Bay of Naples.The structures of (1 3)-( 15) were deduced by analysis of spectral data.31 Phomactin A (16) is a PAF (platelet activating factor) antagonist from the culture medium of the marine fungus Phoma sp. that was isolated from the shell of a crab. The unusual bridged tetracyclic ring system of phomactin A (16) was revealed by X-ray analysis.32 The fungus Penicillium fellutanurn isolated from the gastrointestinal tract of a marine fish Apogon endekataenia has yielded two cytotoxic pep tide^.^^ The structures of fellutamides A (1 7) and B (1 8) were elucidated by interpretation of spectral data.Three new cytotoxic macrolides amphidinolides F (19) G (20) and H (21) have been isolated from the cultured dinoflagellate Aphidinium sp. and identified by interpretation of spectral data.34. 35 The stereochemistry of amphidinolide A (22) NATURAL PRODUCT REPORTS 1993 Me HO (7) R = SH (8) R= Me (9) R = OH y42 U 0 (17) R =OH (18) R=H 0 the first member of the series was inferred by interpretation of NOESY data.36 The complete proton and carbon NMR assignments for okadaic acid (23) which was originally reported as a sponge metabolite3’ but which is now recognized as a dinoflagellate toxin,3s- 39 have been reported.40 The cultured dinoflagellate Amphidinium klebsii produces amphidinol (24) which is a polyhydroxypolyene sulfate that exhibits antifungal activity.The structure of amphidinol (24) was deduced by interpretation of NMR and mass spectral data.41 The circadian clock in the dinoflagellate Gonyaulax polyedra is accelerated by gonyauline (25) which was isolated from the cells themselve~.~~ The structure of gonyauline (25) was elucidated by interpret- ation of spectral data42 and confirmed by synthesis.43 3 Blue-Green Algae (Cyanobacteria) A shallow water species of Lyngbya from Victoria Australia produces an unusual 2-bromopropenyl ester (26) of 2,5-dimethyldodecanoic acid which was previously described44 from L.ae~tuarii.~~ A reinvestigation of Rivularia jirma has yielded an additional brominated biindole (27) together with known Oscillatoriolide (28) which inhibits the development of fertilized echinoderm eggs is a novel macrolide from a Japanese Oscillatoria specie^.^' The proposed structure of oscillatoriolide which lacks stereochemical definition was based on interpretation of spectral data. A new synthesis of NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER OH "OH (23) OH OH OH OH OH Br Br OH Br H COOR' /H H (32) R' = R2 = H (33) R'=Me R2=H (34) R' = R2 = Me CHO q C O O H 0 (35) 4 Green Algae (-)-malyngolide (29) which is a metabolite of Lyngbya The green alga Caulerpa racemosa has yielded a sesquiterpene acid (31) and two new red pigments caulerpinic acid (32) and rnaju~cula,~~ involves an epoxyketone rear~angement.~~the corresponding monomethyl ester (33) together with the Lyngbyatoxin A (30) which is a tumour promoter isolated from familiar pigment caulerpin (34).52 A new diterpene acetate L.rnaj~scula,~~ has been synthesized together with related halitunal(33 which was identified by interpretation of spectral data has been isolated from HaZimedu tuna from the Bahamas.53 NATURAL PRODUCT REPORTS 1993 0 0 0 0 )OH \ \ \ 0 5 Brown Algae Six new C, lipids (36)-(41) one of which (36) is 0-acylated by arachidonic acid were isolated from the brown alga Notheia anomala and identified by spectroscopic analysis and chemical degradati~n.~~ By using a bioassay-directed fractionation 6- acetoxylinoleic acid (42) was identified as a pollen germination and growth inhibitor from Spatoglossum pa~lJicum.~~ Synthesis of the dictyopterenes which are gamete attractants of brown algae,56 requires stereospecific synthesis of cyclopropanes.The synthesis of (+)-dictyopterene B (43) employed a biosynthetically-inspired dehydration The synthesis of (+)-dictyopterene A (44) and (-)-dictyopterene C’ (45) required enzymatic resolution of a cyclopropane intermediate.58 An enantioselective synthesis of ( + )-kjellmanianone (46) which is an antibiotic from Sargassum kjellrnanian~m,~~ has been reported.60 In addition to the known metabolites elegandiol (47)61 and 0 00 0 0 eleganolone (48),62 five new cyclic diterpenes (49)-(53) all of which contain a furan or lactone ring were isolated from Bifurcaria bifur~ata.~~.64 A reinvestigation of the metabolites of Dictyota pardalis f.pseudohamata from the Great Barrier Reef resulted in the crystallization of the known dolabellane (54)65 and the isolation of two new metabolites (55) and (56). The structures of (1 R*,3S*,7S* 11R*,4Z)-dolabella-4,8( 17) 12( 18)- triene-3,7-diol (54) and (1 R*,3S*,4S*,7S*,8S*,l lR*,14R* 12E)-3 4,7 8-diepoxydolabella- 12-ene- 14,18-diol (55) were determined by X-ray analysis and the structure of the unusual nor-diterpene (56) was elucidated by analysis of spectral data.66 As a result of the X-ray analysis of (53 the authors propose that the structures of (57) isolated previously from the same alga,65 and (58) from a North Queensland specimen of Dictyopteris deli~ulata~~ be revised to (59) and (60) respec- tively.66A study of the metabolites of an Indian Ocean specimen of Dictyota divaricata resulted in the isolation of one known NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 501 (55) OR / (65) R =H (66) R = AC (71) R’=OH R2=Me (74) (75) R=OH (72) R’=H R2=CH20H (76) R = H (73) R’ = OH R2 = CH20H diterpene (59) and eleven new diterpenes of which four are dolabellanes six are dolastanes and one is a novel aromatic isodolastane.68 The structures of (lR*,3E,6S*,7E 1 1S*)-6- hydroxydolabella-3,7,12-triene (6 l) (1 S*,3S*,4R*,6S*,7E 11S*)-3,4-epoxy-6-hydroxydolabella-7,12-diene(62) (1R* 32,7E 1 1 S*,12S*)-12-hydroxydolabella-3,7-dien-2-one(63), (1 R*,32,72,11 S*,12S*)-12-hydroxydolabella-3,7-dien-2-one (64) (1 S*,11S*)-3:4,7 :8-diepoxy-18-hydroxydolabella-l2-ene HO 0 HO-’ / c 8 (77) Amijiol (71) and three new dolastanes dictinol (72) dictindiol (73) and dictintriol (74) were isolated from an Arabian Sea specimen of Dictyota indica and identified by interpretation of spectral data.69 Two investigations of an Australian collection of Dictyota divaricata have resulted in the isolation of diterpenes of several different structural classes.Initially the structures of (2R,3R,4S,6E,9E,lOR)-4,17-dihydroxyxenic-6,9,13-trien-l-al-18-oic acid lactone (75) (2R,3R,6E,9E 10R)- 17-hydroxyxenic- (revised to 59 see above) (5S*,8S*,9S*,12R*,13R*,14R*)-9,13-dihydroxydolasta- 1,3-diene (65) (5S*,8S*,9S*,12R* 6,9,13-trien- 1 -al- 18-oic acid lactone (76) (2R,3R,4S76R,7R 1,3-diene (66) 9E 10R)-4,17-dihydroxy-6,7-epoxyxenic-9,13-dien-13R* 14R*)- 13-acetoxy-9-hydroxydolasta-1 -al- 18-oic (5R*,8S* ,9S* 12R* 14S*)-9-hydroxydolasta-l,3-dien-13-oneacid lactone (77) (2R,3R,4S,6E,9E 10R)-17-acetoxy-4- (67) (5R*,8S*,9S* 12R* 13S* 14S*)-9,13-dihydroxydolasta-hydroxyxenic-6,9,13-trien-1,2-dial (78) 17-acetoxy-4a- 1,3-diene (68) and (8S*,9S* 12R*)-9-hydroxyisodolasta-1,3 5( 14)-trien- 13-one (69) were established by interpretation of spectral data and chemical interconversions.Two isomers of (8S*,9S* 12S*)-9-hydroxydolasta- 1,3-diene (70) were isolated but their stereochemistries could not be completely elucidated.68 hydroxycrenulide (79) deacetoxydictyol H (80) and 2-hydroxydictyoxide (8 1) were assigned by analysis of spectral data.70 The same research group subsequently reported7‘ the structural elucidations of (2R*,3R*,6E,9E,lOR*,18S*)-17,18:18,19-bisepoxy-19-rnethoxyxenic-6,9,13-triene(82) and NATURAL PRODUCT REPORTS 1993 (83) R = OH (84)R = H (88)R’=OH R2=H (90) (91) (92) (89)R’ = H R2 =OH H PH 0 OH (93) (94) (95) (96) (97) @+ \ Me0 OMe I 0 OH HO OMf3 OMe 3P-hydroxydilophol (83) and the isolation and further spec- troscopic characterization of the known diterpenes dilophol (84) from Dilophus ligat~s,~~ and (lR*,2E,4R*,7E,llS*,12R*)-18-hydroxy-2,7-dolabelladiene(85) which was first isolated from the sea hare Dolabella ~alifornica~~ and then from the alga Glossophora galap~gensis.~~ The structure of 9-epi-dictyol B R HO li0voH I (86) isolated from Glossophora kuntii was elucidated by 0 OH spectral and chemical The absolute configuration of 9-epi-dictyol B (86) was determined using the CD exciton (105)R =H chirality method and a reinterpretation of previous CD (106)R=OH experiments on dictyotadiol (87),76a compound first isolated from Dictyota dichotom~,~~ has resulted in revision of the absolute configurations of dictyotriols C (88) D (89) and E (90) dictyol B (91) and dictyotadiol (87).75 intramolecular addition of an allylsilane to a conjugated The total syntheses of Full details of the syntheses of (+)-stoechospermol (92) dienone as the key transformati~n.~~ 5(R) 15(R) 18-trihydroxyspata-l3,16(E)-diene (93) and (+)-(+)-isoamijiol(96) which is the optical antipode of a diterpene and ( +)-dolasta- 1,(15),7,9-trien-l4-01 spatol (94) which are diterpenes from Stoechospermum from Dictyota lineari~,~~ marginat~m,~~ and S.howleii,80 (97) the optical antipode of a metabolite from a mixture of D. Spatoglossum s~hmittii,~~*~~ have been described.86 have been described in two consecutive papers.s1~82 The linearis and D.divaricat~,~~ stereoselective synthesis of racemic 14-deoxyisoamijiol (95) A bioassay-guided fractionation of extracts of Landsburgia from Dictyota lineariss3 has been accomplished using an quercifolia resulted in the isolation of deoxylapachol (98) NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 503 OH ?H HOfJoyp;&oq;&oH OH OH OH OH OH OH OH OH OH oToH OH OH (I iSj ?H OH OH OH (116) R1=H R2=b b= 'TOH OH (117) R'=a R2=H (118) R'=a R2=b OH previously found in teak wood from the tree Tectona grandi~,~~ deoxystypoldione (105) which is a very close analogue of as the major cytotoxic component together with 1,4-dimethoxy- 2-(3-methyl-2-butenyl)naphthalene (99) 2,3-dihydro-2,2-bis(3-methyl-2-butenyl)-1,4-naphthalenedione (loo) and 2-(3-methyl-2-butenyl)-2,3-epoxy- 1,4-naphthalenedione 4,4-di- methoxy ketal (101).86 Fractionation of the extracts of Cystoseira mediterranea using the crown-gall potato disc assay resulted in the isolation of mediterraneone (102) as the active component.The structure of mediterraneone (102) was de- termined by interpretation of spectral data.89 A very unusual structure has been proposed for mediterraneol E (103) a metabolite of C. mediterranea on the basis of interpretation of two-dimensional NMR experirnent~.~~ The complete 'H and 13CNMR assignments of balearone (104) from C. strictagl have been reported.92 A biomimetic synthesis of the spiro- benzofuran ring system has enabled the synthesis of 14-stypoldione (1 06),93 94 a cytotoxic ortho-quinone from Stypo-podium ona ale.^^ A series of three papers describe new phlorotanins polymers of phloroglucinol that are isolated as peracetyl derivatives from Carpophyllum maschalocarpum from New Zealand.The first describes 20 phlorotanins that consist of phloroglucinol units joined exclusively by ether linkages seven of these 1,2,3,5-tetrahydroxybenzene (107) tetrafuhalol D (IOS) hydroxypentaphlorethol (109) deshydroxypentafuhalol A (1 lo) hydroxypentafuhalol A (1 1 l) hydroxyhexaphlorethol (112) and hexafuhalol B (113) have not been described previo~sly.~~ The second paper describes the peracetates of diphloethohydroxycarmalol (1 14) triphloethohydroxy-carmalol(l15) phlorethopentafuhalol A (1 16) phlorethopenta- fuhalol B (1 17) and diphlorethopentafuhalol A (118).97In the NATURAL PRODUCT REPORTS.1993 OH HO HO HO OH OH (119) OH 0 OH 0 f OH HO OH HO (122) R = OMe (1 23) R = O-mannitol (124) R = 0yS03H NH2 HO OH WoMe yCrnMe AcO-W COOMe Ad)& OAc 0 (131) R=H (132) R=Ac third paper the peracetates of hydroxyfucodiphlorethol(l19) eicosanoids from red algae is driven by the importance of this hydroxybisfucotriphlorethol (1 20) terfucopentaphlorethol group of compounds in biomedical research. Gracilariopsis (121) and three similar but even larger polymers terfuco- lemaneiformis from the Oregon coast has yielded a number of hexaphlorethol hydroxyterfucohexaphlorethol and quater- known eicoanoids together with three new compounds all fucononaphlorethol were reported.98 In addition to several of which were isolated as the peracetate methyl esters.’O0 known members of the series three new arsenic-containing The isolated derivatives were methyl 10(S*)-acetoxy-ribosides methyl 5-deoxy-5-(dimethylarsinoyl)-P-~-riboside 6(Z),8(E) 12(Z) 15(Z)-octadecatetraenoate (126) methyl 12-acetoxy-5(Z),8(E) 10(E)-dodecatrienoate (127) and methyl (1 22) 1-O-[5’-deoxy-5’-(dimethylarsinoyl)-~-~-ribosyl]man-nitol (123) and the dimethylarsonio-P-D-riboside(124) were 12(R*),13(S*)-diacetoxy-18-keto-5(Z),8(Z),lO(E),14(Z),16(E)-The structures of eicosapentaenoate (128).The isolation of these metabolites isolated from Sargassum lacerif~lium.~~ (1 22)-(124) were elucidated by spectral and chemical methods indicates the presence of a suite of oxidative enzymes with and that of 2-amino-3-[5’-deoxy-5’-(dimethylarsinoyl)-different positional specificities.Aqueous extracts of Bossiella ribosyloxy]propane-1-sulfonic acid (125) was determined by orbigniana catalyse the enzymatic oxidation of arachidonic acid X-ray analysis. to bosseopentaenoic acid (129) [5(2),8(2) lo(@ 12(E) 14(2)- eicosapentaenoic acid] which was also isolated together with other eicosanoids from extracts of the alga.lol 6 Red Algae Although it is very unusual to find compounds of algal origin Research on red algae is again dominated by the discovery of in sponges three C, acetogenins (130H132) were found in new halogenated metabolites but it is somewhat disappointing both Laurencia microcladia and the sponge Spongia zimocca.’02 that biological and pharmacological properties are so seldom The structures of regioleneynes A (130) B (131) and C (132) reported for these compounds.In contrast the research on were based on interpretation of physical and chemical data. NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER 505 (134) 3(€) R = AC (137) 3(Z) R = H (135) 3(Z) R = H (138) 3(€) R = H (136) 3(€) R = H (139) 3(Z) R = AC (140) 3(€) R =Ac Br Br (145) CI X (149) (150) X=Br (151) X=H Br ' ./i Br. .. (155) -CI isolaureatin (147),lo6 and laurallene (148),lo7 has been isolated from L. nipponica.los There is an extensive discussion of the & 4.. biosynthesis of C, acetogenins from L.nipponica in a paper OMe OH R' (165) (166) R'=OH R2=OMe (167) R' = OMe R2 = OH The absolute configurations of okamurallene (133) and related congeners which are metabolites of Laurenciu intricata,lo3 were established by X-ray crystallography and by analysis of chemical and spectral evidence.lo4 Seven new C, acetogenins (1 34)-(140) were isolated from L.pinnatiJidu and their structures were assigned on the basis of spectroscopic methods and chemical The absolute configurations of (a-and (a-pinnatifidienynes (141) and (142) were reassigned as the result of an X-ray analysis. It is not clear whether isomers (143) and (144) are also new compounds.105 Prelaureatin (145) which is a proposed biosynthetic precursor of laureatin (146),lo6 that describes the isolation of notoryne (149) a compound that contains two tetrahydrofuran rings.log 10-Bromoobtusallene (1 50) which is a new metabolite from a Turkish specimen of L.obtusa was identified by comparison of spectral data with those of obtusallene (15l).ll0 Kasallene (l52),l1l the allene (1 53),112 and obtusallene I1 (1 54)ll1 were also isolated from collections of L. obtusu from Kas in Turkey. Two new C, acetogenins (1 55) and (1 56) were isolated from a Great Barrier Reef specimen of L. imp1i~ata.l~~ The total synthesis of (+)-trans-kumausyne (1 57) which is a metabolite of Laurenciu nipponica from Hokkaido Japan,l14 was accomplished in 13 steps and > 5% overall yield.l15 The insecticidal and acaricidal activities of four new polyhalogenated monoterpenes (158)-( 161) from Chilean speci- mens of Plocumium cartilagineum have been reported.'16 A new polyhalogenated monoterpene (1 62) was also isolated from an Antarctic sample of P.~arti1agineum.l~' Five new monoterpenes (1 63)-( 167) were obtained from Portieria (= Chondrococcus) NATURAL PRODUCT REPORTS 1993 A OH OH 0 Br (177) (179) Br OH Br OH OH (183) R=Me (184) R=H hornemannii and were identified by interpretation of spectral data.118 Three new sesquiterpenes (1 68)-( 170) of the brasilinane family were isolated from a Mediterranean specimen of Laurencia obtusa.'lg The structures of 4-hydroxy-5-brasilene (1 68) epi-5,9-dihydroxybrasil-1(1 6)-en-7-one (169) and 9-hydroxybrasil- 1 (1 6),4-dien-7-one (1 70) were determined by interpretation of spectral data.Although drawn as the opposite optical isomer 4-hydroxy-5-brasilene (168) having the same negative sign of rotation was isolated together with 10-hydroxy-4-brasilene (1 7 1) from the Great Barrier Reef specimen of L. implicata that also contained (1 55) and (1 56) and 10 other known metabolite^.^'^ The structure and relative configuration of laurobtusol (172) which is a tricyclic sesquiterpene from a Mediterranean specimen of L. obtusa was determined by interpretation of spectral data and molecular mechanics calculations.120 Cycloeudesmol (1 73) which is a metabolite of Chondria oppositiclada121 and Laurencia nipponica,122 has been synthesized by employing organo-tin chemistry.123 Three halogenated monocyclofarnesane derivatives (1 74)- (1 76) were isolated from Laurencia caespitosa from the Canary Islands and their structures and absolute configurations albeit without the relative stereochemistry in the side chain were elucidated by spectral analysis and CD methods.124 Two new halogenated sesquiterpenes pinnatifenol (1 77) and pinnati- finone (178) have been isolated from L.pinnatiJida from the Karachi coast :the structures were established by interpretation of spectroscopic data.125. 126 The conformational analysis of several polyhalogenated P-chamigrenes by using temperature dependent NMR methods has been described.127 A total 0 HOWBr Br OH OH OH (181) a Ph / synthesis of (f)-(9Z)-bromomethylene-1,5,5-trimethylspiro-[5.5]undeca- 1,7-diene-3-0ne (1 79) from L.majuscula128involves a spiroannelation ~eacti0n.l~~ The total synthesis of teurilene (180) which is a triterpene polyether from L. obtu.~a,l~~ has been accomplished using two vanadium(v)-catalysed oxidation<yclization reactions with different stereo-chernistries.l3l Vidalols A (181) and B (1 82) were isolated from the Caribbean red alga Vidalia obtusaloba and were identified by interpretation of spectral data. The vidalols (181) and (182) are anti-inflammatory agents that act through inhibition of phospho- lipase A,. 13 The Oregon red alga Gracilariopsis lemaneiformis contains N-(2-hydroxypropyl)-2-(2-hydroxyl)-acetopyrrole (183) and N-(2-hydroxyethyl)-2-(2-hydroxyl)-acetopyrrole (184) which were isolated and identified as the diacetate derivatives.133Acantaphora spicifera from Goa contained the known dipeptide aurantiamide acetate (185)134 and a new diastereoisomer dia-aurantiamide acetate (1 86).135 A total synthesis of (+)-allokainic acid (187) which is a neuro-excitatory agent from Diginea simplex,136 incorporates two allylsilane N-acyliminium ion ~eacti0ns.l~~ 7 Sponges Although they must strictly be regarded as primary metabolites some unusual fatty acids have been isolated from Erylus formo~us,'~~ Amphimedon ~ornplanata,'~~and Geodia gibbero~a.'~~ Two sphingosine-derived azetidines penaresidins A (188) and B (189) were isolated as potent actomyosin ATPase activators from an Okinawan species of Penares and NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER OH (188) R' = OH R2= H (189) R'=H R2=OH 0 w.4>OH 0 0 (1 92) (193) 0 OH (194) (198) R = -Cj3H27 (199) R = -C~HI~CH~CH-CCH~~ OSteryl OSteryl (197) their structures were elucidated on the basis of spectral data.14' ethylcholesta-5,7,22-trien-3P-01. The structures of the cor-The structure and absolute configuration of a cerebroside (190) responding methyl esters were elucidated by analysis of spectral from Chondropsis sp. that inhibits histidine decarb~xylasel~~ data.lq8 Eleven alkyl and alkenyl resorcinols (198)-(208) three have been confirmed by ~ynthesis.'~~ The stereochemistry of neohalicholactone (19 l) which is an eicosanoid from Hali- chondria okadai,14* was determined by X-ray crystallogra- The absolute configurations of bretonin A (192) and isobretonin A (193) which are unusual glyceryl ethers from an unidentified demosponge from the coast of Brittany,146 have been determined by ~ynthesis.'~' A new isomer bretonin B (194) has also been described.Three furan fatty acid steryl esters (1994197) that possess significant anti-inflammatory activity were isolated from the Mediterranean sponge Dicty-onellu incisa.14* The sterols involved were cholesta-5,7,22-trien-3P-01 24-rnethylcholesta-5,7,22-trien-3~-01, and 24-of which (198)-(200) were known compounds have been isolated from an Australian species of Haliclona and identified by analysis of spectral data.149 Callydiyne (209) is a symmetrical bis-enyne from Callyspongia flarnrnea from Papua New Guinea that was identified by spectral methods.lso Two new brominated acetylenic esters (210) and (21 1) have been isolated as minor constituents of Xestospongia tesfudinaria and identified by comparison of spectral data with those of known acetylenic acids.51 A number of cytotoxic five-and six-membered cyclic peroxides have been isolated from a Plakortis species from Fiji. The structures of the five-membered cyclic peroxides plakinic NPR 10 NATURAL PRODUCT REPORTS 1993 COOH COOH (212) R = a-Me (213) R=a-Me (214) R = p-Me (215) R=p-Me OMe a*.. . I OMe (218) acids C (2 12) and D (2 13) and epiplakinic acids C (2 14) and D (219 which were isolated as the more stable methyl esters were elucidated by interpretation of spectral data.152 The structure of plakortolide (216) which has the same side chain as plakinic acid D (213) was based on interpretation of spectral data and the stereochemistry about the peroxide ring was assigned as the result of a ROESY experiment.153 An unusual perlactone (2 17) was isolated from the Caribbean sponge Plakortis angulospiculatus and identified by interpretation of spectral data.154 In all three of the studies above the stereochemistry of the secondary methyl groups on the side chain was not assigned.Although the yields of macrolides obtained from sponges are relatively low the compounds are of great interest due to their complex structures and cytotoxic properties.Four new macrolides of the bistheonellide series bistheonellide C (2 18) isobistheonellide A (219) and bistheonellic acids A (220) and B (221) have been isolated from an Okinawan specimen of Theonella sp.155 A different specimen of Theonella from Okinawa has yielded swinholides D (222) E (223) F (224) and G (225) as well as a monomeric seco acid (226) of swinholide A (227).156 The structures of these minor macrolides were elucidated by spectral and chemical methods. The absolute configuration and molecular conformation of swinholide A (227) which was originally isolated from T. swinhoei15' and the structure elucidated by spectral methods,158 were determined by X-ray analysis of a di-p-bromobenzylated diketone de- ri~ative.'~~ Two new cytotoxic metabolites 13-deoxytedanolide (228) and hiburipyranone (229) have been isolated from Mycale adhaerens and identified by spectroscopic analysis.16o Discodermide (230) is a very unusual pentacyclic metabolite from Discodermia dissoluta that shows antifungal and cytotoxic activities.The structure and most of the stereochemistry of discodermide (230) were elucidated by spectroscopic +.% OMe yvo.... OH OHV-'OH OH /-0Me 1 A0 0 methods.lG1 Four additional inhibitors of protein phosphatases 1 and 2A were isolated from D. calyx. The structures of calyculins E (231) F (232) G (233) and H (234) were assigned on the basis of spectral data.162 The absolute configurations of the calyculins were determined by CD measurements on a degradation and calyclins E (23 1) and F (232) were shown to be in~ecticida1.l~~ Pateamine (235) is a potent cytotoxin from a New Zealand species of Mycale that was identified by analysis of spectral data.165 Aurantosides A (236) and B (237) are cytotoxic tetramic acid glycosides from a Japanese species of Theonella.166 The structures of these NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 509 OH Hoot* OH Hd HO..Ho$J OH 0 R3 OMe (221) OMe I (231) R’ = CN R2 = R3 = H (232) R’ = R3 = H R2 = CN (233) R’=CN R2=H R3=Me (234) R’=H R2=CN R3=Me I OMe (222) R’ = R3 = H H2= Me (223) R’ = R2 = Me R3 = OH (224) R’ = R2 = Me R3 = H AT= 2 (225) R’ = Me R2 = R3 = H (227) R’ = R2 = Me R3 = H HOOC-0 “O+ OH OH OMe (236) R = Me O-Q--R’ (237) R= H RO* OH &:** (238) R’ =OH R2= Me (239) R’ =OH R2 = Et (240) R’ =OH R2 = Bun (241) R’ = H R2= Me OH 0 0 interesting chlorinated metabolites were elucidated by spec- troscopic analysis and chemical degradation.The structures of hennoxazoles A (238) B (239) C (240) and D (241) from an Okinawan species of Polyfibrospongia were deduced by analysis OH 0 of spectral data.167 Hennoxazole A (238) is antiviral and (229) displays peripheral analgesic activity. . A ‘total synthesis of 35-2 NATURAL PRODUCT REPORTS 1993 HO'.? HO" (247) onnamide A (242) which is an antiviral agent from an Okinawan species of Theonellu,168has been described.169 Two syntheses of bengamide E (243) and one of bengamide B (244) which are anthelminthics from an undescribed Fijian species of Ju~pis,l~~ have been reported.One synthesis of bengamide E (243) uses the abundant cyclitol L-querbrachitol as starting material,171 while the second synthetic route to both (243) and (244) starts from ~-glucose.l~~ A convergent synthesis of (+)-jasplakinolide ( = jaspamide) (245) which is an antifungal 174 metabolite of Juspis SP.,~'~ was accomplished in 6.6 % overall yield. 175 A cytotoxicity-guided fractionation of the extracts of an Axinellu species from Palau resulted in the isolation of the known cytotoxins homohalichondrin B (246) and halichondrin B (247),176, 17' together with a new cyclic heptapeptide axinastatin 1 (248) that was identified by spectral and chemical methods.178 Nazumamide A (249) is a thrombin-inhibitory tetrapeptide from the same specimen of Theonella sp.179 that contained the cyclotheonamides.The structure of nazumamide A (249) was assigned on the basis of spectroscopic and chemical methods.lso The same Theonella sp. also contained the cytotoxic cyclic peptide orbiculamide A (250) which contains several unusual amino acid residues including 2-bromo-5-hydroxy- tryptamine that could be identified from spectroscopic data.lsl An Okinawan specimen of Theonella sp. contained konbamide (251) which is a calmodulin antagonist that also contains a 2- bromo-5-hydroxytryptamine residue.lS2 Keramamide A (252) HO 'R2 (243)R' = R2 = H (244)R' = Me R2 = OCOC13H2 OH JN H is a new cyclic hexapeptide from a different specimen of Theonella sp.from Okinawa.ls3 Keramamides B (253) C (254) and D (255) are minor metabolites of the same specimen of Theonellasp. that have structures similar to that of orbiculamide A (25O).ls4 The structures of konbamide (251) and the keramamides (252F(255) were elucidated by interpretation of spectroscopic data. The structures of the tridecapeptide lactones theonellapeptolides Ia (256) Ib (257) Ic (258) Id (259) and Ie (260) from T. swinhoei were elucidated by chemical degradation (amino acid analysis) and spectroscopic methods.185* lE6 Eight simple aromatic compounds (261t(268) some of which may result from condensation with the extraction solvent have been isolated from Teduniu igni~.l*~ Of greater interest is the unusual sulfur-containing diketopiperazine (269) from the NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 511 A0 HOOC 0 PhAlKNH 0 II H (253) R' = R2= Et (256) R' = R3 = H R2 = R4= Me (254) R' = Et R2=Me (257) R' = R2 = H R3 = R4= Me (255) R' = R2= Me (258) R' = R4= H R2 = R3= Me (259) R'=H R2=R3=R4=Me (260) R' = R2= R3= R4= Me QL&3 o-fioH R H PhCHzCONH2 (261) (262) R=COCH3 (264) (263) R=CH3 (271) X=H (273) X=CI same sponge.1s8 Neamphine (270) is a most unexpected sulfur- containing alkaloid from Neamphius huxleyi from Papua New Guinea. The structure of neamphine (270) was determined by X-ray cry~tallography.~~~ Dysidamides B (271) and C (272) are additional minor polychlorinated amino-acid derivatives re- (274) X= H lated to dysidamide (273),lgo from an Ethiopian specimen of (275) X=Br Dysidea herba~ea.'~~ The structures of the dysidamides were elucidated by interpretation of spectral data.New metabolites of the oroidin class continue to be discovered. Clathrodin (274) is a non-brominated derivative of oroidin (275) that was obtained from Agelas ~lathrodes.~~~ A possible biosynthetic precursor of oroidin (275),lg3 3-amino- 1-(2-aminoimidazolyl)-prop-1-ene (276) has been obtained from both Teichaxinella morchella and Ptilocaulis walpersi. lg4 Girol-line (277) which is an anti-tumour agent from Pseudaxinyssa NATURAL PRODUCT REPORTS 1993 II *2 AcOH (278) X=Br (279) X=Y=H (283) X = Y = H (282) X= H (280) X = H Y = Br (284) X = Br Y = H (281) X=Y =Br (285) X = Y = Br (286) R = H (289) R = Et (287) R = OH (290) R = H 0 H Br &NH2 H2NJohi 7 H H HO" MeOKNmS'SbN 0 H N 0 H (291) X=-S)2 (292) X=-SCN (293) X = -S02NH2 0 (294) X=-S-S -NKOMe H OMe cantharella,lg5has been subjected to both diastereoselective and (293) and D (294) and prepsammaplin A (295) which may enantioselective lg7Oxysceptrin (278) is a potent provide insight into the biosynthesis of this group.2o5 Of these actomyosin ATPase activator from Agelas cf.nemoechinata metabolites all of which were identified by interpretation of from Okinawa.lSa Oxysceptrin (278) was among the metabolites spectral data only psammaplin D (294) showed antimicrobial of the Caribbean sponge Agelas conifera which also contained activity and mild tyrosine kinase inhibition.The purealidins debromosceptrin (279) sceptrin (28O),lg9 dibromosceptrin (296)-(298) are three new bromotyrosine-derived alkaloids (28 l) debromooxysceptrin (282) ageliferin (283),200 bromo- from Psammaplysilla purea (= P. . purpurea?) from 207 The structures of purealidin A (296),206 which ageliferin (284),200 and dibromoageliferin (285),200 all of which Okinawa.206. were isolated as acetate salts.201 The structures of compounds is cytotoxic purealidin B (297),207 which is antimicrobial and (278)-(285) were elucidated by spectroscopic methods and an purealidin C (298),207 which shows antifungal and antineo- abundance of bioactivity data is presented.Manzacidins A-C plastic activities were elucidated by spectroscopic analysis. (286)-(288) are novel tetrahydropyrimidine alkaloids from a Both 14-debromoaraplysillin I (299) and its presumed bio- species of Hymeniacidon from Okinawa that were identified by synthetic precursor 14-debromoprearaplysillin I (300) were analysis of spectral data.202 isolated from Druinella ( = Psammaplysilla) purpurea from the The Caribbean sponge Pseudoceratina crassa contains two Seychelles together with the known2O8 metabolite araplysillin relatively simple dibromotyrosine derivatives ethyl 33-(301).209 In addition to known compounds in the bastadin dibromo-4-(3'N,N-dimethylaminopropyloxy)-cinnamate (289) series bastadin 12 (302) and hemibastadins 1 (303) and 2 (304) which possessed antimicrobial activity as well as genotoxicity were identified by spectroscopic methods as minor metabolites and cytotoxicity in the E.coli PQ37 SOSchromotest and the of lanthella basta.210 The verongiaquinols exemplified corresponding acid (290) which is inactive. The structures of by 4-acetamido-2,6-dibromo-4-hydroxycyclohexa-2,5-dienone (289) and (290) were elucidated by interpretation of spectral (305),211 can be conveniently prepared by anodic oxidation of data and confirmed by In addition to the major the corresponding phenol (e.g. 4-acetamido-2,6-dibromo-metabolite psammaplin A (29 1),204 Psammaplysilla purpurea phenol).212 has yielded four minor metabolites psammaplins B (292) C The deep-water sponge Discodermia polydiscus contains the NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 0 (299) R= H (301) R=Br (300) Br Me0 BrpBr0 fibNH2 a dNWBr Br~ II H / "OMe 'OMe HO II H X 'N N \ OH \ N Br H X CONH;! H (303) X =H (307) X = H (304) X=Br (305) (306) (308) X=Br (309) X' = X2 = Br a X=O (312) anion of a (310) X' = Br X2 = H b X=H2 (313) anion of b (311) X' = H X2 = Br \ (314) anion of b (31 5) anion of a (316) anion of b H f"7 OMe Br H (321) X=H (323) X=Br Me0 COOMe OHC cytotoxic tryptophan derivative discodermindole (306) the structure of which was assigned from spectroscopic data.213 In addition to the known compounds topsentin (307) and bromo topsentin (308) l4 the deep-water sponge Spongosorites ruetzleri contains nortopsentins A (309) B (310) and C (31 l) which show cytotoxicity and antifungal The struc- tures of the new compounds were deduced from spectral properties.Fuscuplysinopsis reticulutu contains an interesting mixture of alkaloids and sesterterpenes some of which co- occur as salts.216,217 The structures of reticulatines A (312) and B (313) fascaplysins A (314) and B (315) homofascaplysins A (316) B (317) and C (318) and secofascaplysin A (319) were assigned from spectral and chemical studies. Four aromatic alkaloids chelonins A (320) B (321) and C (322) and bromochelonin B (323) were isolated from a Palauan species of Chelonuplysillu and identified by interpretation of spectral data and chemical interconversions.218 Chelonin A (320) which shows in vivo anti-inflammatory activity and chelonin C (322) are the first examples of naturally-occurring 2,6-disubstituted morpholines.OH If employed with caution it appears that chemotaxonomy will assist the classical taxonomist in classifying sponges at the OMe Me0 HN/\ $3 0@ “@ HN 0 *HCI 0 R’ 0 Me (324) (325) R’ = R2= Me (327) (326) R’ = H R2= Me Br 0 0 (333) (334) (340) R=d (341) R=a c = -(CH2),,N(OMe)Me (344) R =a (342) R=c (345) R = b (343) R=d d = -(CHdlsN(OMe)Me family level. The discovery of aaptamine (324) originally obtained from Aaptos a~ptos,~~~ in an Australian species of Suberites has resulted in the reassignment of the genus Aaptos from the family Tethyiidae to the family Suberitidae.220 The structures of two new pyrroloquinone alkaloids damirones A (325) and B (326) from a Palauan species of Damiria were assigned by comparison of their spectral data with those of the batzellines.221 The tricyclic indole alkaloids batzelline C (327) and isobatzelline C (328) from Batzeffa sp.,222.223 have been synthesized.224 The spectral data of prianosins C and D from Prianos mefanos are identical to those of 2-hydroxydiscorhabdin D and discorhabdin D from Latruncufia bre~is,~~~ 226 and the structures were therefore revised from (329) to (330) for prianosin C and (331) to (332) for prianosin D.227A total synthesis of discorhabdin C (333) a cytotoxin from Latrunculia SP.,~~* has been accomplished by using an electrochemical phenol oxidation to create the spiro ring junction.229 A simple synthesis of amphimedine (334) which is an alkaloid from Amphimedon sp.,230 was reported.231 A series of antiviral and cytotoxic alkaloids have been isolated from the Mediterranean sponge Crambe crambe. The structures of crambescidins 816 (335) 830 (336) 844 (337) and 800 (338) were assigned on the basis of spectroscopic analysis.232 The pyridinium alkaloids xestamines D (339) E (340) and F (341) and an inseparable mixture of xestamines G (342) and H (343) together with the known xestamines A (344) and B (345) from Xestospongia ~iedenmayeri,~~~ were isolated from Calyx podatypa from the The pyridinium salts (341)-(343) show pronounced antimicrobial activity but lack the cytotoxicity of the corresponding pyridines (344) (339) and (340).Theonelladins A-D (346>(349) from an Okinawan specimen of Theoneffa s~inhoei,~~~ have been synthesized in a stereospecific manner.236 A stereoselective total synthesis of ( & )-ptilocaulin (350) which was isolated as the (+)-enantiomer from Ptilocaufis aff. P. spic~llfer,~~~ and its 7-epimer was based on the use of an intramolecular nitrile oxide olefin cycloaddition reaction.238 A five step synthesis of (&)-cis-and (&)-trans-NATURAL PRODUCT REPORTS 1993 (328) 0 0 (329) R=OH (330) R=OH (331) R =H (332) R = H f (335) R = OH n= 13 (336) R = OH n= 14 (337) R= OH n= 15 (338) R=H n=13 (346) R = H (348) R = H (347) R=Me (349) R=Me & & H H (350) (351) Meo$$N \ -Me Me 0 (352) (353) trikentrin A (351) and (352) which are indole alkaloids from Trikentrionflabeflif~rme,~~~ employs an interesting Diels-Alder reaction of heteroaromatic a~adienes.~~~ A one-pot synthesis of 6-methoxy-2,5-dimethyl-2H-isoindol-4,7-dione (353) which is a metabolite of Reniera employs a 1,3-dipolar cyclo- addition reaction.242 Although several groups have reported progress toward synthesis of the more complex manzamines only the most simple of the manzamine alkaloids from an Okinawan species of H~ficfona,~~~ manzamine C (354) has been synthe~ized.”~ A total synthesis of corallistin A (355) which is a free porphyrin from a Coral Sea species of Coralfistes species,245 has been achieved using an a,c-biladiene route.246 There is continued interest in meroterpenoids of the avarol family.An Australian species of Dysidea contains both avarol (356) and the exocyclic double bond isomer isoavarol (357).247 Dysidea cinevea from the Red Sea is the source of six new meroterpenoids 3’-hydroxyavarone (358) 3’,6’-dihydroxy- NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER 0 OH I 0 w COOMe (357) (354) (355) (356) R= H (358) R' = OH R'= R3 = H (360) R=OH (359)R' = R3 = OH R2 = H (361) R=OAc (362) R' = R2 = H R3 = OAc HoeoMe (363) R' = H R2 = OMe R3 = OH ?H &OH @ (364) (365) (370) (371) "'Q (373) (374) (375) (379) R =-NC (380) R =-NC (381) R = -NHCHO (382) R = -NHCHO avarone (359) 6'-hydroxyavarol (360) 6'-acetoxyavarol (361) 6'-acetoxyavarone (362) and 6'-hydroxy-4'-methoxyavarone (363)."* The absolute configurations of (358)-(363) were shown to be the same as that of avarol (356) and the cytotoxicity antimicrobial activity and anti-HIV- 1 reverse transcriptase activities of the new compounds were reported.Strongylin A (364) is a new meroterpenoid from the deep-water Caribbean sponge Stronglophora hartrnani that shows in vitro cytotoxicity and antiviral Mamanuthaquinone (365) is an antimicrobial and cytotoxic metabolite of a Fijian species of Fascio~pongia.~~~ From a chemotaxonomic viewpoint it is very (367) OH COOMe Me0 Ho% (372) HO Hop (376) (377) (378) epimers at * unexpected that a meroterpenoid such as the antiviral agent cyanopuupehenol (366) should be isolated from a Verongid sponge.251 A species of Smenospongia from the Seychelles produces four unusual macrocyclic sesquiterpene hydroquinone derivatives smenochromenes A (367) B (368) C (369) and D (370) together with smenodiol (371).252 The structure of smenochromene A (367) was determined by X-ray analysis while all other meroterpenoids reported above were identified by interpretation of spectral data.It should be noted that the unusual geometry of the smenochromenes (367)-(370) results in unusual 'H NMR data.252 A species of Fasciospongia from New Caledonia contained an unusual meroditerpenoid (372).253 A formal total synthesis of xestoquinone (373) which was isolated from Xestospongia ~apra,~~~ has been accomplished using a furan ring transfer Along with the known major metabolites ( +)-curcupheno1 (374) and (+)-curcudiol (375),256*257 three new aromatic sesquiterpenes (376)-(378) have been isolated as minor metabo- lites from an Australian species of Aren~chalina.'~~ A Philippine species of Halichondria cf.lendenfeldi contained 3-isocyano- theonellin (379),259 3-isocyanobisabolane-8,lO-diene(380) and the corresponding formamides (38 l)260 and (382).261 516 I SCN (383) R' = H,R2=-SCN (384) R' =-SCN R2= H (386) H A A Two isomeric sesquiterpene thiocyanates 2-thiocyanatoneo- pupukaenane (383) and 4-thiocyanatoneopupukaenane (384) were isolated from an unidentified sponge from Pohnpei and from Phycopsis terpnis from Okinawa.262 More recent research has shown the proposed stereochemistry of 2-thiocyanato- neopupukaenane to be A sesquiterpene isothio- cyanate halipanicine (385) was obtained from an Okinawan specimen of Halichondria pan ice^.^^^ Three new antiparasitic sesqui terpene is0 thiocyanates (1R*,4S* ,6R* ,7S*)-4-isothio-cyanato-9-amorphene (386) 10-isothiocyanato-4,6-amorpha-diene (387) and (4S* lOS*)-lO-isothiocyanato-5-amorphen-4-01 (388) were isolated together with the known compound (1 R,6S,7S 10s)- 10-isothiocyanato-4-amorphene (389),265 from a Fijian specimen of Axinyssafenestratus and were identified by interpretation of spectral data.266 3-Isocyanotheonellin (= theonellin isocyanide) (379) which is a metabolite of Ciocalypta sp.,229was synthesized in a biomimetic manner.267 An interesting synthesis of euryfuran (390) which has been isolated from several sponges including a Euryspongia species,268 and the dorid nudibranchs that feed upon them involves two sequential furan ring transfer reactions.269 The syntheses of (-)-furodysin (391) and (-)-furodysinin (392) from has allowed the assignment of absolute configurations to the natural products that occur as both (+) and (-) enantiomers in different Dysidea species.2i' Two new diterpene isothiocyanates kalihinols I (393) and J (394) together with the known kalihinols X (395) and Y (396),2i2 were obtained from a specimen of Acanthella cavernosa from Thailand.266 Four new spongian diterpenes (397)-(400) NATURAL PRODUCT REPORTS 1993 J$Is H Ho CI Hd "% "(2-Cl (392) (393) R = -NCS (396) (394) R = -NHCHO (395) R =-NC have been identified by spectral methods from a Great Barrier Reef species of Sp~ngia.~~~ Among nine diterpenes isolated from a Pohnpeian Chelonaplysilla species only three were undescribed.The structures of chelonaplysins A (401) B (402) and C (403) were elucidated by interpretation of spectral data and chemical correlation with known The structure of cheloviolacene (404) from Chelonaplysilla violacea was determined by an X-ray crystallographic Aplysilla glacialis from British Columbia contained five new diterpenoids cadlinolides A (405) and B (406) aplysillolides A (407) and B (408) and marginatone (409). The structure of cadlinolide A (405) was determined by X-ray analysis and the remaining compounds (406)-(409) were identified by spectroscopic and chemical Isoreiswigin (410) is a minor constituent of Epipolasis reiswigi that has a carbon skeleton related to that of reiswigin A (411)277 by a 1,3-migration of the side chain.278 The furanoditerpene dehydroambliol A (41 2) which was isolated from Dysidea arnbli~,~~~ has been synthesized by a straightforward route that also produced the undesired 72 isomer.28o Dendrillol 1 (413) which is a metabolite of Dendrilla rosea,281has been synthesized from (+)-podocarp-8( 14)-en-1 3-one of known absolute configuration.282 A norditerpene acid (414) and its methyl ester (415) and a norsesterterpene acid (416) and its methyl ester (41 7) were isolated from an Australian specimen of Latrunculia brevis that was devoid of the cyclic peroxides283 normally found in related sponges.284 Three new sesterterpene peroxides trunculin C methyl ester (418) trunculin D methyl ester (419) and trunculin E (420) were isolated from an Australian Latrunculia species.285 NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER OH 0 COOR & 6 // MeOOCe COOR // I I / (414) R=H (416) R = H (415) R=Me (417) R=Me HOOC -11 I (423) R = n-C3H7 (425) (424) R=CH3 OH CI OH 0 The structure of trunculin C methyl ester (418) was determined by X-ray analysis and the remaining structures were established by interpretation of spectral data chemical interconversions and biosynthetic considerations.An Australian specimen of Mycale (Carmia) cf. spongiosa has provided two new nor-sesterterpene peroxides (421) and (422) for which the stereo- chemistry was partially determined by analysis of spectroscopic data.286 Kimbasines A (423) and B (424) are norsesterterpene alkaloids from Igernella notabilis from Bermuda that were identified by interpretation of spectral data.,*’ /”. R 0 (429) R = CHZCOOH (430) R=CHO In addition to the known sesterterpene furospinulosin 1 (425),288an undescribed species of Thorecta from New Zealand contained 22-deoxyvariabilin (426) the structure of which was incorrectly drawn as a tetrahydrofuran and which was identified by analysis of spectral data.289 There are two reports of degraded sesterterpenes from an unidentified sponge collected in Senegal.Konakhin (427) is a chlorinated norsesterterpene that is related to the known290 sesterterpene fasciculatin (428).291 The same sponge also contained the corresponding C, acid (429) and C, aldehyde (430) that could be prepared from NATURAL PRODUCT REPORTS 1993 0 (431) (432) q C O OCOOH H (433) (434) @x; .-lo 0 0 (435) (436) epimers at * (437) 0 COOH fasciculatin (428) by oxidation with hydrogen peroxide in the presence of basic alumina.292 The Caribbean sponge Thorecta horridus contained the linear sesterterpenes (43 1) and (432) but only (43 1) exhibited anti-inflammatory Along with the P-carbolium salts (3 12H3 19) reported above Fascaply-sinopsis reticulata from Fiji also contained isodehydro-luffariellolide (433) and dehydroluffariellolide diacid (434) both of which were identified by analysis of spectral data.217 Three new sesterterpenes aplysolides A (435) and B (436) and aplyolide A (437) which were characterized by interpretation of NMR data have been isolated from Aplysinopsis cf.elegans from Fiji.294 Three new 24-methylscalaranes 12/3,168,22- trihydroxy-24-methylscalaran-25,24-olide(438) 12p 16P- dihydroxy-24-methylscalaran-25,24-olide (439) and 12/3,16P 22-trihydroxy-24-methyl-24-oxo-25-norscalarane(440) were obtained from an Indian Ocean specimen of PhylZospongia de~zdyi.~'~ A South China Sea specimen of Phyllospongia (syn. Carteriospongia) foliascens has yielded three bishomo-scalaranes phyllofenone B (44 1) phyllofolactone A (442) and (438)R=OH (440) (439)R = H AcQ (443)R = H (445) (444)R=Ac OH (448) (449) phyllofolactone B (443) one of which phyllofenone B (441) shows cytotoxicity against the P-388 cell A specimen of Carteriospongia (= Phyllospongia) foliascens from the Great Barrier Reef contained 12a-acetoxy-20,24~-dimethylscalar-17-en-25,24-lactone (444) the acetate of phyllofolactone B (443).297 The structures of the sesterterpenes (438)-(444) were all deduced by interpretation of spectroscopic data.The structure of heteronemin (449 which is a metabolite of Hyrtios has (= Heteronema) ere~ta,~~* been confirmed by X-ray The absolute configuration of (+)-dysideapalaunic acid (446) which is an unpublished aldose reductase inhibitor from a Palauan species of Dy~idea,~"has been determined by means of an eight step total A mixed collection of Rhaphisia sp.and an unidentified Axinellid sponge contained two mildly cytotoxic triterpenoids naurols A (447) and B (448) the structures of which were elucidated from spectroscopic data.302 The absolute con-figuration of sipholenol A (449) from Siphonochalina ~iphonella~~~ has been determined by application of Mosher's NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER (450) (451) R=H (455) R=Ac OH (457) R-a (458) R’ = b R2 = a (459) R’ = H R2=c HOq a= 0 OH HO-1 OH (463) R = a Me0 H Me0 H (464) method.304 The structure of raspacionin (450) from the Mediterranean sponge Raspaciond ac~leata~~~ has been de- termined by X-ray crystallographic analysis.3o6 Six new anti- neoplastic isomalabaracanes stelliferins A-F (451)-(456) have been isolated from an Okinawan specimen of Jaspis stellifera and identified by spectroscopic analyses.3o7 Seven new tri-terpenoid glycosides isoxestovanin A (457) xestovanin B (458) xestovanin C (459) dehydroxestovanin A (460) epidehydroxestovanin A (461) dehydroxestovanin C (462) and secodehydroxestovanin A (463) have been obtained from the Northeastern Pacific sponge Xestospongia vanilla.308 The (452) R = H (456) R=Ac (460) R = a (461) R=a (462) R=c HOq 0 C= I 0 ‘r \ HO H‘ OH (465) (466) structures of the glycosides were elucidated by spectral analysis and chemical degradation.Some most unusual modified sterols have been isolated from sponges. The structures of jereisterols A (464) and B (465) which were isolated from the New Caledonian sponge Jereicopsis graphidiophora were elucidated by analysis of spectral data.309 A specimen of Spongia oficinalis from the Bay of Naples contained 3P,6a-dihydroxy-9-0~0-9,11 -seco-Sa-cholest-7-en-l l -a1 (466).310 3P,Sa,6/?-trihydroxy sterols were obtained from Cliona c~piosa~~~ and from Dysidea herbacea. lgl Three antiviral sterol disulfate orthoesters orthoesterol NATURAL PRODUCT REPORTS 1993 (467) R =/' 4 (468) R = /4 (469) R = #4 OR2 (473) R' = CH20H R2 = a (476) R' = H R2=a (479) R' = R2 = H disulfates A (467) B (468) and C (469) were obtained from Petrosia weinbergi and their structures were defined by analysis of spectroscopic data.,, Weinbersterol disulfates A (470) and B (471) are also antiviral metabolites from P.~einbergi.~, An unusual sterol ester (472) has been isolated from a deep water species of Xestospongia from the Caribbean.314 The structures of sarasinosides A (473) A (474) A (475) B (476) B (477) B (478) C (479) C (480) and C (481) from the Palauan sponge Asteropus sarasinosum were elucidated on the basis of their spectral data.315 8 Coelenterates Although some very exciting pharmacological properties have been reported for metabolites of coelenterates the number of papers describing new natural products from gorgonians and soft corals appears to be declining.For example few new sesquiterpenes were reported in 199 1. A single paper reported a new sesquiterpene furan (482) the corresponding y-hydroxybutenolide (483) piccolamine (484) and piccolamine N-oxide (485) from the Senegalese gorgonian Leptogorgia pi~cola.~~~ The structures of (482)-(485) were elucidated by interpretation of spectral data. Despite the paucity of new structures synthetic studies continue to appear. The total syntheses of (_+)-neolemnanyl acetate (486) and (+)-neolemnane (487) which are sesquiterpenes from the Pacific soft coral LemnaZia africana that contain a cyclooctane ring,,,' are based on an intramolecular allylsilane addition reaction to (470) R'=H R2=OH (471) R' =OH R2= H 0 (472) CH90H 6' NHAc HO OR2 (474) R' = CH20H R2 = a (477) R' = H R2= a (480) R' = R' = H HO@-?@qo NHAc OH HO 0R2 Ho NHAc d (475) R' = CH,OH R2 = a (478) R' = H R2= a (481) R' = R2 = H CH2OA fQ a= HO OH NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 52 1 (482) R = H (488) (486) R = AC (484) R = CH2NMe2 (487) R = H (485) R = CH2NMe2 .) 0 (496) 10a (498) lop (497) lop (499) 1Oa @J$. 0 OR OR (504) R = H (506) R = AC (505)R= H (507)R=Ac A speciesof Sarcophyton from Thailand contained form the eight-membered ring.31a A9(12)-Capnellene (488) a mamrno~a.~~~ continues to a new diterpene ether (495) that possesses unspecified anti- metabolite of the soft coral Capnella imbricataY3l9 be a target molecule for those interested in the synthesis of fouling Seven new diterpenoids calyculones D fused cyclopentane rings.A formal synthesis of ( -)-A9(l2)-(496) E (497) F (498)’ and G (499) (lE,3E,llE)-l,3,11- capnellene (488) and its antipode involves a photochemical cembratrien-6-one (500)’ (12,32,11E)-l,3,11-cembratrien-6-rearrangement of ( +)-A3-carene as the key ~tep.~~~,~~~ (501) and (1E,32,1 lE)-l,3,1l-cembratrien-6-one(502)’ A second one synthesis of ( )-A9(12)-capnellene (488) involves an intra-molecular Diels-Alder reaction as the key Clavukerin A (489) and clavularin A (490) are two trisnorsesquiterpenes from Clavularia keollikeri that are related biogenetically by oxidative cleavage of a double bond.323,324 A synthesis of (-)-clavukerin A (489) that has confirmed its absolute stereo- and a synthesis of (+)-clavukerin A (489) together with its biomimetic conversion into ( + )-clavularin A (490),326 have been reported.Diterpenes continue to be the major group of compounds isolated from both soft corals and gorgonians. A new dihydrofuranocembranoid sarcophytonin E (49 l) was ob-tained from an Okinawan species of Sarcophyton but attempts to determine the absolute stereochemistry by using Mosher’s method were unsuccessful.327 An anomaly in the application of the modified Mosher’s method prevents its being used to determine the absolute configuration of cembranoids with sterically-hindered secondary ( -)-Sarcophytol A (492) the antipode of a known metabolite of the Indo-Pacific soft coral Sarcophyton gl~ucum,~~~ and ( + )-marasol(493) were isolated from the Caribbean gorgonian Plexaura flexuosa and were identified by analysis of spectral data.330 Eupalmerin (494) is a minor constituent of the Caribbean gorgonian Eunicea from the gorgonian Eunicea calyculata were identified by spectroscopic The cembratriene (500) could be converted into the calyculones (496)-(499) by a photochemical 1,3-acyl migration.The conformations of diterpenes (496)- (502) in solution are The autoxidation of dihydrofuranocembranoids such as 16-deoxysarcophine (503) a reaction that has previously been employed in structural elucidation,334 has been studied in A reinvestigation of the relative and absolute configurations of lobophytol and lobophytol acetate which are metabolites of the soft coral Lobophytum pau~zjlorum,~~~ resulted in revision of the structure of lobophytol from (504) to (505) and lobophytol acetate from (506) to (507).337 The absolute configuration of methyl sarcophytoate (508) which is a dimeric diterpene from Sarcophyton glau~um,~~~ elucidated by difference CD was spectroscopy using a lanthanide reagent.339 Methyl sarcoate (509) which is one of the presumed biosynthetic precursors of the dimer (508) was isolated as a minor constituent of S.gla~curn.~~O The synthesis of the cembranolide (510) which is a metabolite of Lobophytum mi~haelae~~l and Sinularia has been achieved by using organo-tin chemistry to accomplish the key cyclization reaction.343 Two collections of Pseudopterogorgia acerosa from Tobago NATURAL PRODUCT REPORTS 1993 COOMe y-& )q-& Jy-yO; 0 0 COOMe COOMe $-..(0 0 “0 -_ OH AcO’.H 0 0 R OAc (517)R=OH (518)R=OMe (520)R = -)NH p. OH (527) / OAc (531) (532) (533) yielded mixtures of acids that were esterified with diazo-methane to obtain acerosolide (511) and deoxypseudopterolide (512) in March and tobagolide (513) in July.344The structure of an additional pseudopterane diepoxygorgiacerone (514) from P. acerosa was determined by X-ray analysis.345 Six more pseudopteranoids pseudopterolide-methanol adduct (515),346 gorgiacerone (516) gorgiacerodiol (5 17) methoxygorgiacerol (518) isogorgiacerodiol (519) and bis(gorgiacero1)amine (520) have also been isolated from P.acerosa and identified by interpretation of spectral data.347Two cladiellane diterpenoids calicophirins A (521) and B (522) that inhibit insect growth have been isolated from a species of Cali~ogorgia.~~~ Lito-phynins F (523) G (524) and H (525) are novel diterpenes from the soft coral Litophyton sp. that were identified from spectroscopic and chemical The aglycones (526) and (527) of the pseudopterosins and secopseudopterosins which are metabolites of Pseudopterogorgia 351 have 353 been synthesized in a stereoselective Five new dolabellane diterpenes (1S*,11R*)-18-hydroxydolabella-3(E),7(E) 12(E)-triene (528) (1S*,11R*)-dolabella-3(E),7(E),12( 18)-triene (529) (lS*,4S*,llR*)-dolabella-7(E) 12(18)-diene-2,13-dione (530) (1S*,4S*,11R* 12S*)-dolabella-7(E)-ene-2,13-dione (53l) and (lS*,7R* 1lR*)-7-acetoxydolabella-3(E),8(17),12( 18)-triene-l3-one(532) have been isolated from the Caribbean gorgonian Eunicea 0 R \ OH (513)R = NMe2 (515)R = OMe (519)R=OH 0 0 (514) 0 OAc (522) (523)R1 = OH R2 = R3 = H (524)R1R2= 0,R3 = H (525)R’ = R3 = OH R2 = H 0 0 (534)R=OH (536) (535)R = H la~iniata.~~~ The structures of (528)-(532) were elucidated by interpretation of spectroscopic data and in doing so it was established that the structure of palominol a metabolite obtained from E.calyculata and E. la~iniata,~~~ should be revised from (533) to (528).354Five dolabellane lactones clavirolides A (534) B (539 C (536) D (537) and E (538) and a dolabellane clavudiol A (539) were isolated from the Chinese soft coral Clavularia viridi~.~~~, 357 The structure of clavudiol A (539) was determined by X-ray analysis356and those of the clavirolides (534)-(538) were elucidated by analysis of spectral data including CD.Fuscosides A (540) B (541) C (542) and D (543) are anti-inflammatory diterpene glycosides from the Caribbean gorgonian Euniceafusca that were identified on the basis of chemical and spectral Fuscosides A (540) and B (541) inhibit chemically-induced inflammation in the mouse ear assay and fuscoside B (541) inhibits leukotriene synthesis. The known briarane diterpenes erythrolides A (544) and B (545),359and seven new erythrolides (546)-(552) were isolated from the Caribbean gorgonian Erythropodium ca~ibaeorum.~~~ In addition a species of Briareum from Puerto Rico which was identified as either B.asbestinum or B. polyunthes contained nine new briarane diterpenes which were named briareolides A-I (553)-(561). The structure and absolute configuration of briareolide B (554) was determined by X-ray crystallographic NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER 523 / '' 'OH OH OH 0 0 (537) (538) (539) (540) (542) (543) RRor SSat * (2 bis epimers) (544) (545) (546) R = AC (548) R = AC (550) (553) R = COPr (554) R=Ac (547) R = -COCH20Ac (549)R = COCHzOAc (552) R = COCH20H (555) R = COPr (557) R=COPr (559) (556) R=Ac (558) R=Ac OH 0 ct Aco.sv S OH S ,OH AcO * *XI ACO'*~:.*TI OH AcO'. . . AcO HO'* 0:. *, s:. G HO'; 0 0 0: '0 Acd ,, ..-* AcO ,, *o 0 (566) R = AC (567) R = H anti-inflammatory activity in the mouse ear assay. The structure of brianolide (562) which is an anti-inflammatory diterpenoid from a Japanese species of Briareurn was determined by X-ray cry~tallography.~~~ Six new diterpenoids of the briarane class gemmacolides A-F (563)-(568) were obtained from Junceella gemmacea from Pohnpei and their structures and relative configurations were assigned on the basis of spectroscopic 0 (562) yfg .CH3 _--0 0 (563) R = OAC (564) R = OCOCH&H(CH3)2 (565) R = H q$ -.-0 A specimen of Briareurn asbestinurn from Puerto Rico yielded four new asbestinane diterpenoids 4-deoxy- asbestinin A (569) 1 1-acetoxy-4-deoxyasbestininB (570) 4- deoxyasbestinin C (57l) and 1 1-acetoxy-4-deoxyasbestininD (572).363 The structures of the new asbestinins were elucidated by using extensive NMR experiments.NPR 10 (569) R =COPr (571) R = COPr (570) R = AC (572) R = AC analysis and the structures of the remaining briareolides and of erythrolides C-I (546)-(552) were elucidated by interpretation of spectroscopic data.360 Briareolides A-E (553)-(557) exhibited NATURAL PRODUCT REPORTS 1993 (576) R = 0 HO'. HO (577) R= (578) R = OH OH (579) R = .Mp HO OH (585) R=OAc (583) (584) (586) R = H OH OH AcO A# (592) (593) Two unusual secosterols calicoferols A (573) and B (574) have been isolated from the Japanese gorgonian Calicogorgia sp.The calicoferols which are toxic to brine shrimp were identified on the basis of chemical and spectroscopic evidence.364 The structure of verrucoside (573 which is a cytotoxic glycoside from the gorgonian Eunicellu verrucosa that was collected near Cadiz Spain was elucidated by spectroscopic A series of four 3P,7a-dihydroxy-5a,6a-epoxy-A8-steroids melithasterols A-D (576)-(579) from the Okinawan gorgonian Melithaea ocracea were identified by interpretation of spectral data and chemical interconversions. 366 Two specimens of Sclerophytum sp. from the Andaman and Nicobar Islands contain a series of polyhydroxy sterols that include andaman- sterol (580),nicobarsterol(58 I) and five new polyhydroxylated sterols (582)-(586).3673 368 An Indian soft coral of the genus Nephthea is the source of R3 (594) R' = CH=CH2 R2= OH,R3 = H (595) R' = Et R2= H R3 = S(02)Me (596) R' = Me R2= R3= H (597) R' = Et R2 = R3= H (598) R' = CH=CH2 R2= R3 = H meso-1,3-diphenyl- 1,3-propanediol (587).369 A dimer (588) and trimer (589) of acetone (+ammonia) have been reported as metabolites of an Indian specimen of Lobophytum strictum that was extracted with acetone.370 The total syntheses of clavulones I-IV (590)-(593) which are prostanoids from the soft coral Clavularia viridi~,~~~ have been 9 Bryozoans A study of the cytotoxic constituents of Cribricellina cribraria from New Zealand resulted in the isolation of l-vinyl-8- NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER 525 MeOOCMoAc 0 a= 0 b = pbromobenzoate c = COC(Me)3 d=& OH ‘COOMe (599) R’ =Ac R2=a (600) R’ = H R2=a (601) R’ = b R2= a (605) R’ = c R2 = H (606) R‘ = Ac R2= d HO 0 HO 0 (603) R = a Br@*=. hydroxy-/3-carboline (594) as the major cytotoxic component together with 1-ethyl-4-methylsulfone-/3-carboline (595) and the known compounds harman (596) 1-ethyl-/3-carboline (597) and pavettine (598).3i3 The structures were assigned on the basis of spectral data and extensive antimicrobial antiviral and cytotoxicity data were recorded. An interesting study of the distribution of the amathamide alkaloids within single colonies of Amathia wifsoni revealed that the alkaloids were localized primarily in the tips of the There is considerable interest in the bryostatins from Bugufa neritina because they show cytostatic effects bind to and activate protein kinase C stimulate haematopoietic progenitor cells activate T cells and have immunomodulating proper- ties.li.3i5 The large scale isolation of bryostatin 1 (599) has been undertaken in order to provide material for clinical In addition bryostatin 2 (600) has been converted into bryo- statin 1 (599) by a route involving selective protection and depr~tection.~’~ The absolute configuration of bryostatins 1 (599) and 2 (600) was determined by an X-ray crystallographic study of the p-bromobenzoate (601).3ii The ‘H and 13CNMR assignments of bryostatin 1 (599) have been revised.3i8 A new metabolite bryostatin 3 26-ketone (602) has been isolated from B.neritina and a reinvestigation of bryostatin 3 using 2D NMR spectroscopy has resulted in revision of the structure from (603) (602) R=COMe (604) R =$-( OH flBr OAc HO o% CI Yo-0 / to (604).3i9 Two additional minor metabolites bryostatins 14 (605) and 15 (606) have been reported380 and the first member of a new family of macrocycles neristatin 1 (607) was isolated and shown to be mildly active against the P-388 cell line.381 10 Molluscs There has been very little recent research describing new metabolites from opisthobranch molluscs or sea hares. Two new sesquiterpenoids 9-acetoxy-3-chloro-4,l O-dibromo-a- chamigrene (608) and laurenisol acetate (609) were obtained from Easter Island specimens of Apfysia dactylomefa that feed upon the red alga Laurencia cfavif~rmis.~~~ A second paper reports the X-ray structure determination of an unusual brominated diterpene lactone angasiol acetate (610) which is undoubtedly of red algal origin from specimens of Apfysia juliana that were collected on the Karachi coast of the Arabian Sea.383 A new synthesis of (+)-aplysin (611) which is a metabolite of A.k~rodai,~~~ is based on the rearrangement of arylo~imes.~~~ An efficient total synthesis of aplysiapyranoid D (612) which is a cytotoxin from A. k~t-odai,~~~ has been accomplished by using a brominative cyclization reaction.38i A formal synthesis of aplysiatoxin (613) which is a metabolite of the sea hare Stylocheilus fongi~auda,~~~ has been described.389 36-2 NATURAL PRODUCT REPORTS 1993 -Ph OH HO 1 (620) R' = R2= Me (621) R'=SMe R2=H 0 Me0 II 0 R " (625) R = Me (626) R= H Dolastatin 10 (614) which is an antineoplastic agent from the sea hare Dolabella auric~laria,~~~ has been synthesized by two research groups.3s1 392 A second antineoplastic agent from D.auricularia dolastatin 15 (61 5),393has also been synthesized.394 A synthesis of (-)-bursatellin (616) which is a metabolite of the sea hare Bursatella employs a selective benzylic In the opisthobranch mollusc Tethysfimbria it has been demonstrated that prostaglandins are converted into the corresponding 1,15-1actones that are then accumulated in the dorso-lateral appendages.When molested the dorso-lateral appendages detach and an in vivo conversion of the 1,15- lactones back to the prostaglandins occurs.3s7 Thus the prostaglandins may be stored and released when needed. In addition to the previously reported prostaglandin lactones of the E series,3s8PGF,,-1,15-1actone 1 1 -acetate (6 17) PGF3,-1,15-1actone 1 1-acetate (6 1 8) and PGE,-1,15-1actone1 1 -acetate (619) were identified as constituents of the mantle and cerata of T.Jimbria.3ssThe egg masses of T.Jimbria contain a complex mixture of prostaglandin 1,lSlactone fatty acid The absolute configuration of umbraculumins A (620) and C (621) which are ichthyotoxic constituents of Umbraculum mediter- raneuy~1,~~~ have been determined by total Three new polypropionates (622)-(624) were isolated from Siphonaria lessoni from the coast of Chile and the structures were proposed on the basis of spectral data.402 The cyercenes are polypropionate pyrones that are biosynthesized de novo by Cyerce cristallina an ascoglossan mollusc that when attacked sheds its cerata and secretes large amounts of a supposedly toxic mucous The structures of the ichthyotoxic AcO' AcO' 0 0 OMe 0 +R 0";-.(627) R=Me (630) R=Me (628) R = Et. (631) R=Et (629) R=Pr' polypropionates cyercenes A (625) and B (626) and cyercenes 1-5 (627)-(63 1) were elucidated by means of Cyercenes 1 (627) 2 (628) and 3 (629) were found only in the mantle tissue and the mucus contained all cyercenes except cyercene A (625) which occurs as the only polypropionate in regenerating The stereoselective total syntheses of denticulatins A (632) and B (633) which are polypropionates 407 from Siphonaria denti~ulata,~~~ have been Nudibranchs of the genus Phyllidia appear to feed prefer- entially if not exclusively on sponges that produce terpene isonitriles.Two specimens of Phyllidia pustulosa from Japan contained surprisingly large quantities of 9-isocyanopupu- keanane (634),408 9-epi-9-isocyanopupukeanane (635),409 3- isocyanotheonellin (379),25s 7-isocyano-7,8-dihydro-a-bisabo-lene (636),259 axisonitrile-2 (637),410 and two new compounds 2-isocyanoallopupukeanane (638) and 4a-isocyano-9-amor-phene (639) [~f.(386)].~~' Specimens of P.pustulosa from the Philippines contained the known compounds 11 -isocyano-7P- H-eudesm-5-ene (640),412 11-isothiocyano-7P-H-eudesm-5-ene (641),410 and (6R,7S)-7-isothiocyanato-7,8-dihydro-a-bisabo-lene (642),413 together with 4a-isocyanogorgon- 1 1 -ene (643) 4a-formamidogorgon- 1 1 -ene (644) 4a-isothiocyanogorgon- 1 1-ene (645) and 3-isocyanobisabolane-8,lO-diene(380).261 Speci- mens of P.varicosa from the Philippines yielded 4a-isocyanogorgon-11-ene (643) and 4a-formamidogorgon- 1 1-ene (644).261 All new isonitriles isothiocyanates and formamides were identified by interpretation of spectral data. Five diterpenoic acid glycerides (646)-(650) were isolated from a single specimen of the Antarctic nudibranch Austrodoris kerguelensis and were identified by interpretation of spectral 527 NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER ‘r r OH / (379) (632)R = p-Me (634)R’ = H R2= NC (633)R= a-Me (635) R’=NC R2=H TcooR (640) R=NC (643) R=NC (646)R = -CH,CH(OAc)CH,OH (641)R = NCS (644)R = NHCHO (647)R = -CH~CH(OH)CH~OAC (645) R=NCS a ’ ‘H bAc (648)R’ =Ac R2= H (649) R’=H R‘=Ac OAc R’ OAc I. I (lp&p 0 H (653) (654)R = H (656)R’ = OAC,R2= H (655)R=OAc (657)R‘=H R2=OAc (658)R’ = R2= OAC 0 OAc 0 (661)R=H (665) R= H (662) R=OAc (666)R=Ac and chemical data.414 The skin extracts of Chromodoris cavae (66 1),420 and lactone (662).421 The new metabolites (655) (657) from Sri Lanka is the source of two new diterpenoids and (658) were identified by spectroscopic analysis.422 Skin chromodorolides A (651) and B (652) that have highly extracts of the Pacific nudibranch Cadlina luteomarginata that rearranged carbon Also from Sri Lanka C.gleniei were found on the sponge Aplysilla glacialis contained the contained dendrillolide A (653),416 12-desacetoxyshahamin C sponge metabolites glaciolide (663),423 cadlinolide A (405) and (654),416 and shahamin K (655) C. geminus contained tetrahydroaplysulphurin 1 (664). 276 12/3,15a 16a-triacetoxyspongian (656),417 601,154 16a-triacet- When molested the cephalaspidean mollusc Haminoea oxyspongian (657) and 6a 12/3 15a 16a-tetraacetoxyspongian navicula secretes a mixture of haminols A (665) and B (666) that (658) C.annulata contained shahamin F (659),41s and C. induces an alarm response in trail-following con specific^.^^^ inopinata contained aplyroseol2 (660),419 spongian- 16-one The structures of haminols A (665) and B (666) were elucidated NATURAL PRODUCT REPORTS. 1993 bOH Me (670) OH HOO’OEt (673) I OMf3 (679) (680) R = H (681) R=Me OR z. 0 Jf 0 I Meo+ zfln Br (683) R=Me (686) R=Z=H X=Y=Br (692) 2 = H (684) R= H (687) R = H X = Y = Br 2 = CI (693) 2 = CI (688) R=Y=Z=H X=Br (689) R = X = Z = H Y = Br (690) R=X=Y=Z=H i691j R = Me by interpretation of spectral data. The known p-hydroxy- claim was immediately refuted when the spectral data were benzoate esters kelletinin I (667)425 and kelletinin A (668),426 recognized to be those of 1-ethoxyethyl hydroperoxide (673) isolated from Buccinulum corneum were shown to be inhibitors which is familiar as an explosive oxidation product formed of eukaryotic DNA polymerase Three specimens of the when ether is stored in clear bottles and it was noted that the Indo-Pacific nudibranch Notodoris gardineri yielded isonaamine same compound had been reported from However the A (669) a known metabolite from the sponge Leucetta claim that a hydroperoxide of ether is a natural product cannot chagosensi~,~~~ and dorimidazole (670) the structure of which be dismissed entirely because of the absence of ether in the was identified by analysis of spectral data and confirmed by isolation process.Didemnilactone (674) and neodidemnilactone An arsenic-containing nucleoside 5’-deoxy-5’- (675) which were isolated from a Japanese specimen of dimethylarsinyladenosine (67 l) has been isolated from the Didemnum moseleyi and identified by spectral analysis are the kidney of the giant clam Tridacna maxima.430 first eicosanoid lactones to be found in a t~nicate.~~~ The principal cytotoxic and antifungal constituents of Pseudo-distoma novaezelandiae from New Zealand were identified as 11 Tunicates the simple amines (676)-(679).434 Two new antineoplastic 24- Tunicates continue to yield some of the more unusual and membered macrolide sulfates iejimalides C (680) and D (681) bioactive marine natural products.Among the most unusual were isolated from Eudistoma cf. rigida and identified on the was the hydroperoxide (672) that was claimed to be a natural basis of spectral data.435 product from four solitary ascidians Phallusia mammillata The structure of lissoclinotoxin the antimicrobial constituent Ascidia ahodori Styela pricata and Halocynthia roret~i.~~~ of Lissoclinum perforatum from France was reported to be a This NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER H (694) (695) (697) R = Et (698) R = CHSH2Ph (699) R = H (700) R = CH&H(Me)2 OMe Me0 H SMe SMe NH C HH H M Me Me (703) (704) R = H (705) R= Br (707) R’ = X R2 =OH (708) R’ = Y R2=OH (709) R’ = X R2= OMe (710) R‘ = Y R2=OMe (711) R’ = X R2= OCO(CH,)+2H=CH(CH2)+2H3 (712) R’ = Y R2= OCO(CH2)&H=CH(CH2)&H (713) R’ = X R2= H (714) R’ = Y R2= H / N RO (717) R=OH (718) R = H 172,3-trithiane derivative (682) on the basis of analysis of spectral data.436 A very closely related cytotoxin from a Fijian specimen of L.vareau is varacin (683) for which a benzopen- tathiepin structure was proposed by interpretation of spectral data.437 As might be expected these compounds are indeed very closely related and it is now known that lissoclinotoxin is the corresponding pentasulfide (684).438 The structure of a very simple aromatic sulfate polyclinal (685) that was isolated from a California specimen of Polyclinum planum was determined by X-ray analysis.439 Rubrolides A-H (686)-(693) are a series of antimicrobial halogenated phenolics that were isolated from the Northeastern Pacific colonial tunicate Ritterella rubra and identified by chemical and spectral methods.44o Two specimens of Didemnum candidum from the Gulf of California contain 6-bromotryptamine derivatives.One speci- men contained 6-bromotryptamine (694) a compound that had previously been synthesized,441 and the other specimen yielded 2,2-bis(6’-bromo-3’-indoyl)ethylamine (695) and 2,5-bis(6’-bromo-3’-indoyl)piperazine (696) both of which were identified by analysis of spectral data.442 The ichthyodeterrent metabolites tambjamines E (697) and F (698) together with the known bryozoan metabolites tambjamines A (699) and C (700),443 and the blue pigment (701),444* 445 were isolated from a Philippine species of Atapazoa and from several nembrothid nudibranchs that feed upon the a~cidian.~~~ The structures of the new tambjamines (697) and (698) were elucidated by interpretation of spectral data and both the tambjamines (697)-(700) and the blue pigment (701) were shown to be localized in the granular amebocyte blood cells.Eudistomidins E (702) and F (703) are two new P-carboline alkaloids from an Okinawan specimen of Eudistoma glaucus that were identified by spectroscopic means.447 A biomimetic synthesis of eudistomins H (704) and I (705) which are metabolites of E. oliv~ceum,~~~ and woodinine (706) from E. frag~m,~~’ employs a Pictet-Spengler type reaction.45o The minor cytotoxic constituents of the Okinawan tunicate Cystodytes dellechiajei were isolated as a 3.5 1 mixture of cystodytins D (707) and E (708) a 3.5 1 mixture of cystodytins F (709) and G (710) and a 3.5 1 mixture ofcystodytins H (71 1) and I (712).451 The individual cystodytins A (713) and B (714) which were also isolated as an inseparable 3.5 1 mixture,452 have been synthesized by an efficient total synthesis that includes a photochemical nitrene insertion reaction.453 The structure of meridine (71 5) which is a cytotoxic alkaloid from Amphicarpa meridiana from South Australia was determined by X-ray crystallographic analysis while that of a stable tautomer (716) was elucidated by spectral analysis.454 A specimen of Leptoclinides sp.from Truk contained 11-hydroxyascididemin (7 17).4s4 Although the known alkaloid ascididemin (718)455 was the major bioactive component of a species of Eudistoma from the Seychelles two octacylic NATURAL PRODUCT REPORTS 1993 H \ (" (725) 0 Me * (731) R=\ 53 MeH (732) R =\?*' bH alkaloids eudistones A (719) and B (720) were isolated as minor metabolites and their structures were spectral analysis and chemical intercon~ersion.~~~ Wakayin (721) which was isolated from a Fijian species of Cluvelinu is the first example of a pyrroloiminoquinone alkaloid from an a~cidian.~~' The structure of this DNA-damaging cytotoxin was elucidated from its spectral properties.The quinolizidine alkaloids clavepictines A (722) and B (723) are the cytotoxic constituents of C.pictu from Bermuda. The structure of clavepictine B (723) was determined by X-ray analysis and that of clavepictine A (722) by analysis of spectral data.4s8 A Venezuelan specimen of C.picta contained pictamine (724) which is a lower homologue of claveyictine B (723).459 Lepadin A (725) is a decahydroquinoline alkaloid from a North Sea specimen of C. lepudiformis that was identified by spectroscopic (722) R = Ac n=4 (723) R = H n= 4 (724) R = H /I= 2 = H R2 =\ w (726) R' (728) R = CH2CH(Me)2 NH2 (729) R = Pr' (727) R'=Br R2=H (730) R = CH2Ph 0 A (735) R = COCH3 (736) R=\ UCoOMe OVo analysis.46o The structures of two most interesting cytotoxic cyclic peptides diazonamides A (726) and B (727) which were isolated from the Philippine ascidian Diazona chinensis were proposed by correlation of the spectral data with those of a derivative the structure of which was determined by X-ray (734) analysis.461 Three cyclotetrapeptides (728k(730) were isolated from a Mediterranean specimen of Cystodytes della chiujei (or delluchiujei?).The structures of cyclo(L-Pro-L-Leu-L-Pro-L-Leu) (728) cyclo(L-Pro-L-Val-L-Pro-L-Val) (729) and cyclo(L- Pro-L-Phe-L-Pro-L-Phe) (730) were established by interpret- elucidated by ation of spectral data and confirmed by A delayed publication has reported syntheses of didemnins A-C (73 1)-(733) which are cytotoxic and immunosuppressive constituents of Trididemnum ~olidum,~~~ that are appropriate for the synthesis of multi-gram quantities.464 Terpenes are rarely encountered as metabolites of ascidians. Dichlorolissoclimide (734) is a cytotoxic labdane derivative from a New Caledonia specimen of Lissoclinum voeltzkowi that was identified by interpretation of spectroscopic data.465 Two terpenoid HIV-1 protease inhibitors didemnaketals A (735) and B (736) were isolated as minor constituents of a species of Didemnum from pa la^.^^^ The structures of the didemnaketals (735) and (736) were elucidated by analysis of spectral data but the stereochemisty at many centres remains to be determined.NATURAL PRODUCT REPORTS 1993-D. J. FAULKNER 531 (737) R = H (738) R=Me OH HO OH (739) R' = C13H27 R2= -(CH2)zCH2)7CH (740) R' = Cj4H29 R2 = -(CH2)5CH,),CH3 m (741) R' = CIdHa R2 =-.(CH2)3 (CH2)11CH3 HO 0 HO HO 0 OH 0 OH OH 0 (748) R' = R2 = Br (749) R' = H R2= Br or R' = Br R2= H HO 0 HO HO OH 0 OH OH (752) 12 Echinoderms The sea cucumber Cucumaria frondosa contains 2,6-dimethylnonane-1-sodium sulfate (737) and 2,4,6-trimethyl- nonane- 1-sodium sulfate (738) the structures of which lacking stereochemical details were proposed on the basis of spec- troscopic data.467 Six new cerebrosides asteriacerebrosides A-F (739)-(744) have been isolated together with the known astrocerebroside A (745)468 and acanthacerebroside C (746),469 from the sea star Asterias amurensis ~ersicolov.~~~ Full details of the structural elucidation and partial synthesis of imbricatine (747) which is a cytotoxic constituent of the starfish Der-Me HO HO 0 HO OH OH 0 OH Na03SO HO HO OH (753) masterias imbricata that is responsible for eliciting the 'swimming response' in the sea anemones Stomphia coccinea and S.didem~n,~~l have been The deep-water stalked crinoid Gymnocrinus richeri contained five very unusual pigments gymnochromes A-D (748)-(75 1) and isogymno- chrome D (752).473 The gymnochromes (748)-(752) have a helical chirality and the presence of chiral atoms in the side chains gives rise to diastereoisomers. The complete structure of the saponin forbeside D (753) from the sea star Asteriasforbesi was deduced from NMR data.474A. forbesi also contained four new polyhydroxylated NPR 10 NATURAL PRODUCT REPORTS 1993 OMe OMe (754) R = H (756) OH HOY MeEO-O MeO-o@ HO OH OM&0H f p To / OH OH HO?HO/ R OH (758) R= H OMe OH OR (757) (760) R = H (759) R=OH (761) R = S03Na OH R’ OH (767) ..R= I (764) R’ = S03Na R2 = H .MT (762) R‘ = H R2 = HO (765) R’ = R2= H OH (CWH (766) R’ = S03Na R2 = H-OH (768) R = **-m JVT HOQ0 0 OMe (763) R’ =OH R2=H glycosides forbesides I (754) J (755) K (756) and L (757) that identified by interpretation of spectral data.482 An Indian were identified by spectroscopic methods.475 A reinvestigation specimen of Actinopyga mauritiana has yielded echinoside B of the starfish Cuicita novaeguineae from Okina~a~~~,~~’ has led (778) which was previously isolated from A. e~hinites,,~~.as to the isolation of five new steroidal glycosides culcitosides C the major toxic constituent.485 The Far Eastern holothurian (758) C (759) C (760) C (761) and C (762) and a new Duasmodactyia kuriiensis is the source of two new saponins polyhydroxysteroid (763) all of which were identified by kurilosides A (779) and C (780) that were identified by interpretation of spectral data.478 Seven novel polyhydroxylated spectroscopic analysis.486 Cucumarioside G (78 1) is a minor steroids (764)-(770) and a new steroidal glycoside myxodermo- triterpene glycoside from the holothurian Eupentacta fraudatrix side A (771) have been isolated from the starfish Myxoderma that contains a novel triterpenoid component.487 As part of a platyacanthum and identified by interpretation of spectral data comparative study of the triterpene oligoglycosides from ten side and the synthesis of the A22E-27-nor-24-methyl-26-carboxy species of Okinawan holothurians a new example 24-chain.479 The stereochemistry of the side chain of 26-dehydroechinoside B (782) was isolated from Actinopyga homothornasterol B (772) which is an aglycone of pectinioside ma~ritiana.~, C from A~terinapectinifera,~~~ has been determined by synthesis and X-ray crystallographic analysis.4s1 The holothurinosides A (773) B (774) C (779 and D (776) 13 Miscellaneous and desholothurin A (777) are cytotoxic and antiviral triterpene Three additional lumazines 6~-methoxypropionyl-3-methyl-glycosides from the sea cucumber Holothuria forskalii that were lumazine (783) 6~-methoxypropionyl-1,3-dimethyllumazine NATURAL PRODUCT REPORTS 1993-D.J. FAULKNER OH 1-4 1-3 I Gal-Xyl -Qui t 1-2 (772) = yo* Qui (771) Glu = glucose Qui = quinovose Gal = galactose Xyl = xylose all sugars are in the P-pyranose form -OH 0 Na03S0 w HO OH OH RO OH (778) (782) 24A CHzOH (779) R= @-HO OH (780) R = H (784) and 6~-hydroxypropionyl-3-methyllumazine (785) have been isolated from the polychaete worm Odontosyllis un-decirnd~nta.~~' The dimethyl ester (786) of bonellin which is the green sex-differentiating pigment of Bonellia vi~idis,~~" has been synthesized by a highly convergent pathway.491 Two new ciguatoxins CTX-2 and CTX-3 have been isolated from the moray eel Lycodontis javanicus but the structures were not completely characterized.49 14 References HO (LJ 1 D.J. Faulkner Nat. Prod. Rep. 1984 1 251. OH 2 D. J. Faulkner Nat. Prod. Rep. 1984 1 551. OH 3 D. J. Faulkner Nat. Prod. Rep. 1986 3 1. 4 D. J. Faulkner Nat. Prod. Rep. 1987 4 539. 5 D. J. Faulkner Nat. Prod. Rep. 1988 5 613. 6 D. J. Faulkner Nat. Prod. Rep. 1990 7 269. 7 D. J. 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ISSN:0265-0568    

DOI:10.1039/NP9931000497

出版商:RSC    

年代:1993

数据来源: RSC