ISSN:0265-0568    

DOI:10.1039/a802hopy

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Marine natural products D. John Faulkner Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA Covering: 1996 Previous review: 1997, 14, 259 1 Introduction 2 Marine microorganisms and phytoplankton 3 Green algae 4 Brown algae 5 Red algae 6 Sponges 7 Coelenterates 8 Bryozoans 9 Molluscs 10 Tunicates (ascidians) 11 Echinoderms 12 Miscellaneous 13 References 1 Introduction This report is a review of the literature of marine natural product chemistry for 1996.Earlier reports published in this journal cover the period from 1977 to December 1995.1 Over the past two years, marine natural product chemistry has graduated from an expanding to a mature field. Approximately the same number of new compounds have been described but more marine natural products are being selected for synthesis and for in-depth investigations of their biological properties, both from the biomedical and ecological (biofouling) viewpoints.The format for this review is identical to that of its immediate predecessor. 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. Biochemical studies involving marine organisms, studies of the biosynthesis of marine natural products, and reports of primary metabolites are specifically omitted. Wherever possible, the biological and pharmacological properties of new marine natural products have been reported but papers detailing pharmacological studies are considered to be beyond the scope of this review.In the area of synthetic organic chemistry, the review focuses on reports of the total synthesis of marine natural products that confirm or redefine chemical structures. No attempt has been made to review the patent literature or conference abstracts, although recent experience has shown that these sources are probably the most important for those seeking new structures for synthesis.Nearly all of the reviews involving marine natural product chemistry that were published during 1996 are of quite limited scope, often reviewing primarily the research from a single research group. Notable exceptions to this trend are the two critical reviews ‘3-Alkylpiperidine alkaloids isolated from marine sponges in the order Haplosclerida’2 and ‘‚-Carboline and isoquinoline alkaloids from marine organisms’.3 In the biomedical arena, there are reviews on ‘Antimalarial activity: the search for marine-derived natural products with selective antimalarial activity’,4 ‘Naturally occurring somatostatin and vasoactive intestinal peptide inhibitors.Isolation of alkaloids from two marine sponges’,5 and ‘Sphingosine-related marine alkaloids: cyclic amino alcohols’.6 The rationales for studying marine bacteria, marine microalgae and both marine and terrestrial cyanobacteria were made in reviews entitled ‘Marine bacterial diversity as a resource for novel microbial products’,7 ‘Microalgal metabolites: a new perspective’,8 and ‘Cyclic peptides and depsipeptides from cyanobacteria: a review’.9 The marine ecologists’ view of marine natural product chemistry is expressed in articles entitled ‘Marine chemical ecology: what’s known and what’s next’10 and ‘Chemical ecology and marine biodiversity: insights and products from the sea’.11 The biomedical and industrial contributions of marine natural product chemistry have been discussed in reviews on ‘Marine biodiversity and the medicine cabinet.The status of new drugs from marine organisms’,12 ‘Biomedical potential of marine natural products’,13 ‘Marine natural products for industrial applications’,14 and ‘Marine natural products research: current directions and future potential’.15 In addition, a series of short reviews in the general area of marine toxins have appeared.16–22 2 Marine microorganisms and phytoplankton The importance of marine bacteria as producers of bioactive marine natural products has been powerfully demonstrated by the discovery that an antifungal cyclic peptide and the cytotoxin swinholide 1, previously isolated from the sponge Theonella swinhoei,23 were localized in, and presumably produced by, symbiotic filamentous bacteria and unicellular bacteria, respectively.24 Thus the sources of marine bacterial cultures gain additional significance.An actinomycete (CNB- 984) from a shallow water marine sediment in southern California produced the cytotoxic lagunapyrones A–C 2–4, that are a homologous family of polyketides.25 It should be noted that the stereochemistry proposed for the lagunapyrones is not completely secure, as explained in the publication. A O OMe OH O O HO HO OMe HO O O OMe HO O O HO HO MeO HO O 1 Faulkner: Marine natural products 113Streptomyces sp.designated BD-26T(20), isolated from a shallow water sediment in Hawaii, contained wailupemycins A–C 5–7 and 3-epideoxyenterocin 8.26 Cyclo(L-Arg-D-Pro) (aka CI-4) 9 was identified as a chitinase inhibitor produced by a cultured Pseudomonas sp. IZ208.27 A novel glycolipid, 1,2- diacyl-3-·-D-glucuronopyranosyl-sn-glycerol taurineamide 10, has been isolated from Hyphomonas jannaschiana.28 The structure and stereochemistry of (")-macrolactin A 11, an antiviral metabolite from an unidentified deep-sea bacterium,29 has been confirmed by total synthesis.30 Moiramide B 12, which is an antimicrobial agent from Pseudomonas fluorescens,31 has been synthesized in a diastereoselective manner.32 Marine bacteria are often isolated from the surface of marine algae and invertebrates.A strain of Pseudomonas aeruginosa isolated from the Antarctic sponge Isodictya setifera contained a series of six diketopiperazines that included one new example, cyclo(L-Pro-D-Met) 13, and two known phenazine alkaloids.33 Aburatubolactam A 14 is an inhibitor of superoxide anion generation that was isolated from a Streptomyces sp.(SCRC-A20) found on an unidentified marine mollusc.34 A Bacillus sp. (MK-PNG-276A) isolated from the tissues of an unidentified tube worm from Papua New Guinea produced an antimicrobial cyclic peptide, loloatin B 15, that has some structural features in common with the tyrocinidines.35 Studies of marine fungi have recently provided some interesting contributions to marine natural product chemistry.The Penicillium strain BM923 that was isolated from a marine sediment from oVshore Japan produced acetophthalidin 16, a metabolite that arrested the cell cycle in the G2 phase.36 It is interesting that the compound eventually isolated from the fungus was an inactive metabolite, 3,4,6-trihydroxymelleine 17, which was reconverted into the original active metabolite 16 by treatment with boiling aqueous acid.36 The structure of the sesquiterpene isoculmorin 18, which was isolated from Kallichroma tethys, was determined by X-ray crystallography. 37 An isolate of Chaetomium sp. from the reef at the Yap Islands contained chaetoglobosin A 19 that showed antifungal activity and weakly inhibited microtubule assembly. 38 Penochalasins A 20, B 21 and C 22 are cytotoxic metabolites from a Penicillium sp. that was isolated from the O R O OH HO OH 2 R = Me 3 R = Pr n 4 R = Bu n O Ph O O OH HO HO O MeO O O O O Ph HO O OMe O O HO Ph O O O OMe O O OH O Ph O O MeO HO OH H N NH O O NH NH2 NH 6 5 9 7 8 O OH O OH HO OCOC17H33 OCOC15H31 NH HO3S O NH O O Ph NH O NH O O O O HO OH HO 10 11 12 N NH O O H H H O N HN O O OH OH H Et Me SMe N O O HN NH NH HN HN NH HN NH O O O O O O O O HN HOOC H2NOC Ph Ph CH2NH2 OH NH 14 15 13 HO CH2OH O HO OH O OH OH HO OH O O O 16 17 18 114 Natural Product Reports, 1998alga Enteromorpha intestinalis.39 The same Penicillium sp., cultivated on a diVerent medium, produced penostatins A–D 23–26, three of which 23–25 exhibited cytotoxicity against P338 cells.40 Microsphaeropsis olivacea, which was isolated from an unidentified Florida sponge, produced an unusual fatty acid 27, the corresponding glyceride 28 and the cerebroside 29.41, 42 A trimeric antibiotic, exophilin A 30, was obtained from the mycelia of Exophiala pisciphila NI10102 that was isolated from the sponge Mycale adhaerens, which the little dragon sculpin Blepsias cirrhosus uses as a spawning bed.43 Chlorocarolides A 31 and B 32 are chlorinated polyketides that were obtained from Aspergillus cf.ochraceus that had been isolated from the sponge Jaspis cf. coriacea.44 An unidentified fungal strain (951014) isolated from the Indo-Pacific sponge Spirastrella vagabunda produced the antimicrobial agent secocurvularin 33.45 A strain of Microascus longirostris (SF-73) isolated from an unidentified New Zealand sponge produced the potent inhibitors of cysteine proteases, cathestatins A–C 34–36.46 The structure of phomactin D 37, which is a platelet activating factor (PAF) antagonist from Phoma sp.(SANK 11468),47 has been confirmed by total synthesis.48 A specimen of the cyanobacterium Lyngbya majuscula from Guam contained ypaoamide 38, which was shown to be a broad-acting feeding deterrent.49 Laingolide 39 is a 15-membered macrolide from L. bouillonii from Laing Island in Papua New Guinea that was isolated by following brine O NH H HN O O O OH NH H O NH HN O NH H O NH HN O OH OH 19 21 22 O NH H O NH HN O 20 O C7H15 O R1 R2 H H H O C7H15 O H H H O C7H15 OH H H H HO C8H17 COOR O OH O OH HO HN OH HO C14H29 O OH C9H19 O O OH HOOC OH OH OH C5H11 C5H11 C5H11 O O 23 R1 = OH; R2 = H 24 R1 = H; R2 = OH 25 26 27 R = H 28 R = CH2CH(OH)CH2OH 29 30 Cl OH O O OH COOEt HO OH O 31 7 R*,8 R* 32 7 S*,8 S* 7 8 33 NH HN R2 O HOOC O R1 O O O CHO 34 R1 = H; R2 = NH2 35 R1 = OH; R2 = NH2 36 R1 = OH; R2 = CH2NH2 37 O OMe HN O N O HO OMe N O Me Ph N S N O O O Me 40 39 38 Faulkner: Marine natural products 115shrimp toxicity.50 Barbamide 40 is molluscicidal lipopeptide that was obtained from the same collection of L.majuscula from Curaçao that produced curacin A 41.51 The structure of curacin A 41, which is a potent antimitotic agent,52 has been confirmed by several syntheses.53–58 The absolute stereochemistry of microcolin A 42, which is an immunosuppressive agent from L.majuscula from Venezuela,59 was determined by total synthesis.60 Two additional syntheses of (")-malyngolide 43 and one of the acid 44, both of which were isolated from L. majuscula, have been reported.61–63 Nakienone B 45, which was isolated from Synechocystis sp.,64 has been synthesized to illustrate a palladium-catalyzed coupling reaction.65 Amphidinolide Q 46 is a moderately cytotoxic macrolide from the dinoflagellate Amphidinium sp. that is a symbiont of OH Me OSO3Na OH Me OH Me Me OH O O O O O O OH OH O OH OH Me Me O O O O O O OH O O O HO O O O O O O O O O O O O O O O O Me Me Me Me Me Me Me Me OH NaO3SO OH OH HO OH OH OH OH OH OH Me HO Me Me Me Me OH HO OH H H H H H HO OH H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H OH OH Me Me Cl O O O O O OH O HO HO OH HO OH HO Cl O HO HO OH O O O O O O OH OH O O Cl OH HO HO O OH OH OH OH Me H2N H H H H H H H H H H H H H H H H H H H H H H H H H H H H 48 49 N HN O Me O N O OAc Me O N OH O N O OMe N S H H COOH OMe O O C9H19 OH OH O OH O O O HO 42 N OH O OH OH OH O O O O OH OH HO 46 45 43 44 41 OSO3H OH 47 116 Natural Product Reports, 1998the flatworm Amphiscolops sp.66 The tropical dinoflagellate Prorocentrum maculosum produces a fast-acting toxin, prorocentrolide B 47, the structure of which was established with limited stereochemical assignments by interpretation of NMR and mass spectral data.67 The complete relative and absolute stereochemistry of maitotoxin 48, which is a toxin from Gambierdiscus toxicus that acts on voltage-sensitive Ca2+ channels,68 have been determined by synthetic methods combined with NMR analyses.69–71 Prymnesin-2 49, which is a potent ichthyotoxic and hemolytic polyether glycoside that is terminated by acetylenic lipid chains, was isolated from the red tide organism Prymnesium parvum that poses a serious threat to fish farming in brackish waters. The structure of prymnesin-2 49 was elucidated by interpretation of spectral data,72 with some stereochemical information being derived from NOE measurements and a computational study of the molecule.73 Hemibrevetoxin B 50, which is a metabolite of Gymnodinium breve,74 has been synthesized in a stereoselective manner.75 Various strains of the marine ciliate Euplotes rariseta, collected from a number of coastal locations worldwide, contained rarisetenolide 51, epoxyrarisetenolide 52 and epirarisetonolide 53, which are weakly toxic to other ciliates.76 Epoxyfocardin 54 and its putative biosynthetic precursor focardin 55 were obtained from the Antarctic ciliate Euplotes focardii.77 3 Green algae The ceramide erythro-sphinga-4,8-dien-N-palmitate 56 was isolated as an antiviral constituent of Ulva fasciata from India.78 A specimen of Dictyosphaeria sericea from southern Australia yielded the bicyclic lipid dictyosphaerin 57.79 Kahalalides A 58, B 59, F 60 and G 61 were isolated from a Bryopsis O O O O OH Me H H H OHC OH Me H H 50 O OH H H O O OH H H H H O H H O H O H H O H O O H H O H 54 55 51 52 53 COOH OH C9H19 OH NHCOC15H31 OH 57 56 O NH O O HN O HN O N O NH HN O HO Ph NH O O OH 58 59 O NH O O HN O HN Ph O NH O NH HN O HO HO NH O O Ph HN HN NH O HN O NH HN O O O O O O HN O NH O NH2 N O HN O NH O HN O HN O OH Ph 60 HN HN NH HN O NH HN O O O O O HN O NH O NH2 N O HN O NH O HN O HN O OH Ph COOH HO 61 Faulkner: Marine natural products 117sp.on which the ascoglossan mollusc Elysia rufescens, the original source of the kahalalides, was feeding (see p. 33). Only kahilalide G 61, a linear peptide that is a possible precursor of kahalalide F 60,80 was unique to Bryopsis sp.81 Both enantiomers of halitunal 62, which is an antiviral agent from Halimeda tuna,82 have been synthesized from the iridoid monoterpene (+)-genepin 63 but, despite using a chiral starting material, the absolute stereochemistry of the natural product remains unknown.83 4 Brown algae In 1996, there was an unusual decline in the number of papers reporting new metabolites from brown algae.The spermatozoid-releasing pheromone from Laminaria digitata has been defined as a mixture of (1*S,2*R,6S)-lamoxirene 64 (71&6%) and (1*S,2*R,6R)-lamoxirene 65.84 The algal pheromones (+)-multifidene 66 from Cutleria multifida85 and (+)- viridiene 67 from Desmarestia viridis86 were synthesized using a chemoenzymatic methodology.87 The autofluorescent substance found in the posterior flagellum of flagellated reproductive cells of Scytosiphon lomentaria has been identified as 4*,5*-cyclic FMN (riboflavin-4*,5*-cyclic phosphate) 68.88 Cyclozonarone 69 is a sesquiterpene quinone from Dictyopteris undulata from Japan that inhibited the feeding of young abalone Haliotis discus.89 A specimen of Cystoseira amentacea var.stricta from the French Riviera coast yielded two additional cystoketal derivatives, demethoxy cystoketal chromane 70 and cystoketal quinone 71.90 (")-Stypoldione 72, which is a microtubule polymerization inhibitor from Stypopodium zonale,91 has been synthesized in a stereocontrolled manner from (+)-carvone.92 Acutilol A 73, acutilol A acetate 74 and acutilol B 75 from a Hawaiian specimen of Dictyota acutiloba are potent feeding deterrents against temperate and tropical fishes and sea urchins.93 Acetoxycrenulide 76, which is a metabolite of D.crenulata,94 has been synthesized in an enantioselective manner.95 5 Red algae The antibacterial pyrone microthecin 77, which is biosynthesized from 1,5-anhydro-D-fructose, has been isolated from Gracilariopsis lemaneiformis.96 Laurencione 78, which is a labile dihydrofuranone from Laurencia spectabilis,97 has been synthesized in a straight-forward manner.98 An allelopathic substance from Neodilsea yendoana that inhibits growth of the green alga Monostroma oxyspermum was identified as (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoic acid 79.99 Agardhilactone 80 is an oxylipin from Agardhiella subulata from Massachusetts that was characterized by spectroscopic methods.100 Constanolactone E 81, which is an oxylipin from Constantinea simplex,101 has been synthesized by a stereospecific route.102 (2E)-Tridecylheptadec-2-enal 82, which was isolated from Laurencia spp.,103 has been synthesized in a straightforward manner.104 Two new halogenated C15 acetogenins, pannosallene 83 from L.pannosa from Vietnam and neoisoprelaurefucin 84 from L.nipponica from Japan have been described.105, 106 Pantofuranoids A–F 85–90 are an unusual family of halogenated monoterpenes from the Antarctic red alga Pantoneura plocamioides that were identified by using spectroscopic methods.107 In addition to known metabolites, two new 62 63 O OHC OAc O HOH2C COOMe H H OH N N NH N O O O P O O– O OH HO O O 64 65 66 68 67 O O HO O O O O O H H HO H O O O 71 69 70 72 RO H O H HO H H O O AcO O O OH OH O O O OH COOH O H H HO HO O O O O OH 73 R = H 74 R = Ac 75 76 78 77 80 79 81 118 Natural Product Reports, 1998acyclic halogenated monoterpenes, (3Z,7E)-5,8-dibromo-2,6- dichloro-2,6-dimethylocta-3,7-dien-1-al 91 and (E)-2,8- dibromo-2,7-dichloro-2,6-dimethyloct-5-ene 92, were isolated from Plocamium cartilagineum from the Portuguese coast.108 Benkarlaol 93 is a sesquiterpene from a Chinese specimen of Laurencia karlae that possesses a new carbon skeleton.109 Six additional parguerane derivatives 94–99 were isolated, together with known sesquiterpenes, from a collection of L.filiformis from southern Australia.110 L. viridis from Tenerife, Canary Islands, has yielded two non-halogenated diterpenes, viridiols A 100 and B 101, that were identified by interpretation of spectroscopic data.111 Isodehydrothyrsiferol 102 and 10-epidehydrothyrsiferol 103 were isolated as antitumour agents from L. viridis sp. nov from Macaronesia in the Canary Islands.112 Three new cytotoxic sterols, peroxides 104 and 105 and epoxide 106, were isolated from Galaxaura marginata from Taiwan.113 Somalenone 107 is a C26 sterol from Melanothamnus somalensis from the Arabian Sea.114 Almazole D 108 is an antibacterial oxazole dipeptide from a new collection of delesseriacean seaweed (Haraldiophyllum sp.?) collected in Senegal that previously yielded related dipeptides.115 Addition syntheses of (")-·-kainic acid 109, which is a metabolite of Digenea simplex,116 have been reported.117, 118 6 Sponges Once again, research on sponges dominates the marine natural product literature in 1996.Most sponge metabolites have been studied because of their biomedical properties but there have also been some studies of their ecological functions. Bioassayguided fractionation led to the identification of lyso-plateletactivating factor 110 as the active constituent of the Australian sponge Crella incrustans that inhibits ascidian, barnacle, R4 R2 R1 R3 H H Br H OH H H Br OH OH OH OH OH O O O Br H H H O HO OH H H O O O Br H H H O OH OH OOH HO HO OOH O O OH O O N O Ph NH O NMe2 HO NH COOH COOH 94 R1 = R3 = R4 = OAc; R2 = OH 95 R1 = R3 = OAc; R2 = H; R4 = OH 96 R1 = OAc; R2 = R3 = H; R4 = OH 97 R1 = R2 = R3 = H; R4 = OH 99 98 103 104 102 100 101 105 106 107 108 109 C14H29 C13H27 OHC O O Br Br O Br Br O H H H O R1 Br R2 R3 H O R Br OH H Br Br Cl OHC Cl Br Cl Br Cl 82 84 85 R1 = Br; R2 = OH; R3 = Me 86 R1 = Br; R2 = Me; R3 = OH 88 R1 = R3 = OH; R2 = Me 89 R1 = R2 = OH; R3 = Me 83 87 R = Br 90 R = OH 91 92 OH 93 Faulkner: Marine natural products 119bryozoan and algal settling.119 Three additional glycolipids, erylusamine TA 111, erylusine 112 and erylusidine 113, were isolated from a cytotoxic extract of a Red Sea sponge that was tentatively identified as Erylus cf.lendenfeldi.120 A tetraglycosylated sphingolipid 114 was obtained from the polar extracts of Agelas longissima from the Bahamas,121 and a novel triglycosylceramide 115 was isolated as the major component of the glycosphingolipid mixture from A.dispar.122 The Mediterranean sponge Clathrina coriacea contains coriacenins A–D 116–119, a series of long-chain amino alcohols that were characterized as their peracetyl derivatives.123 The penaramides 120 are a group of polyamines from Penares aV. incrustans that inhibit binding of ¢-conotoxin GVIA to N-type Ca2+ channels. The structure of the simplest component, penaramide A 121, was confirmed by total synthesis.124 The absolute stereochemistry of penaresidins A 122 and B 123, which were isolated from a Penares species from Okinawa,125 was determined by application of Mosher’s method.126 Two enantiomers of penazetidine A, which is an alkaloid from P.sollasi that inhibits protein kinase C,127 have been synthesized and the absolute stereochemistry of the natural product has been established as either (2S,3R,4S,12*R)- or (2S,3R,4S,12*S)-124.128 Many of the polyacetylenic compounds from marine sponges exhibit cytotoxicity.A Haliclona sp. from Palau yielded three relatively simple acetylenic metabolites 125–127 whose structural assignments were complicated by having a methyl substituent on the alkyl chain.129 Vasculyne 128 is a H2C H2C H HO O O P O O O– C16H33 CH2 R2 NH C5H11 O O OR3 O O O O O O HO OH CH2OH OH HO HOH2C OH OH OH R1O O O HO OH HO O R2 NH O R1 OH O HO O O AcHN HO HO O HO HO O OH HO OH OH OH O OH NH OH O OH O O O HO O O HO HO HO AcHN HO OH OH HO OH R1 R2 H2N HN OH CnH2( n–1) NH OH NH2 H2N HN OH (CH2)9 NH OH NH2 H2N HN OH NH OH NH2 (CH2)7 R1 N N HN NH N O Me Me Me Me Me N R2 O Me NH HO HO OH 110 n m 111 R1 = Ac; R2 = (CH2)5NMe2; R3 = H; n = 8, m = 2 112 R1 = Ac; R2 = (CH2)3NMe(CH2)5NMe2; R3 = H; n = 8, m = 2 113 R1 = H; R2 = (CH2)4NHC=NH(NH2); R3 = COCH2CHMe2; n = 8, m = 3 NH HO HO OH 115 R1 = C19H39 to C21H43; R2 = C11H23 to C16H33 116 117 n = 9 118 n = 11 C10H21 (CH2)7CHMe2 (CH2)6CHMeEt (CH2)2CHMeC6H13 CH2CHMeC7H15 120 R1,R2 = NH HO HO Cl– 119 121 R1 = R2 = C10H21 C6H13 122 114 R1 = C17H35 to C21H43; R2 = C13H27 to C16H33 Cl– 123 CH2 NMe3 + 124 + + 120 Natural Product Reports, 1998cytotoxic bis-acetylene from Cribrochalina vasculum from the Caribbean130 and fulvinol 129 is a slightly more complex cytotoxin from a Spanish specimen of Reniera fulva.131 Pellina triangulata from Truk in Micronesia contained triangulynes A–H 130–137 and triangulynic acid 138, which are a series of cytotoxic polyacetylenes that are most active against leukemia and colon tumour lines.132 The absolute configurations of 130, 131, 135, 137 and 138 were determined by application of Mosher’s method.Adociacetylenes A–D 139–142 are cytotoxic constituents of an Okinawan Adocia sp. that exhibit activity in an in vitro endothelial cell–neutrophil leukocyte adhesion assay.133 The most unusual of the polyacetylenes are callyspongins A 143 and B 144 from a Japanese specimen of Callyspongia truncata. Callyspongins A 143 and B 144 are sulfated metabolites that inhibit fertilization of starfish (Asterias amurensis) gametes.134 The structure of carduusyne A 145, which is a metabolite of Phakellia carduus,135 has been confirmed by a stereocontrolled synthesis.136 The synthesis of (+)-(4E,15E)-docosa-4,15-dien-1-yn-3-ol 146 from Cribrochalina vasculum137 has been accomplished using a chemoenzymatic strategy.138 (+)-Isobretonin A 147, from an unidentified sponge from Britanny,139 has been synthesized in an enantioselective manner.140 Using a bioassay that measured activation of cardiac SR-Ca2+-pumping ATPase, three cyclic peroxides, plakortides F–H 148–150, the related bicyclic lactones, plakortones A–D 151–154, and an acid, plakortide E 155, have been isolated from a Jamaican specimen of Plakortis halichondrioides.141, 142 The absolute configuration of (2Z,6R,8R,9E)-3,6-epoxy-4,6,8- triethyl-2,4,9-dodecatrienoate 156 from P.halichondrioides has been determined using a strategy that might be of general use to determine the stereochemistry of allylic alkyl substituents on the side chains of similar Plakortis metabolites.143 The proposed stereostructures of two cyclic peroxides, manadic acids A and B, isolated from a Plakortis sp. from Indonesia, were subsequently revised from 157 and 158 to 159 and 160, respectively.144 X-Ray analyses were used to confirm the structures and determine the absolute configurations of latrunculin A 161, originally isolated from Latrunculia magnifica,145 and laulimalide 162 from Hyatella sp.146 (or fijianolide B from Spongia mycofijiensis),147 now obtained from an Okinawan specimen of Fasciospongia rimosa.148 The same sponge contained two new cytotoxic macrolides, latrunculin S 163 and neolaulimalide 164.149 A diVerent specimen of F.rimosa from Okinawa produced an additional cytotoxic macrolide, zampanolide 165.150 The alkaloidal macrolide halichlorine 166, which is an inhibitor of vasicular cell adhesion molecule-1 (VCAM-1) induction, was obtained in very low yield from Halichondria okadai.151 Leucascandrolide A 167 is an antifungal and cytotoxic macrolide from the calcareous sponge Leucascandra caveolata from New Caledonia.152 A shallow water lithistid sponge of the genus Callipelta contained a fascinating cytotoxic macrolide, callipeltoside A 168, that incorporates an unusual chlorocyclopropyl group and an amino-sugar.153 The complete stereochemistry and absolute configuration of phorboxazoles A 169 and B 170, which are cytotoxic macrolides from Phorbas sp.,154 have been determined by using spectroscopic methods and by partial synthesis.155, 156 The absolute stereostructures of altohyrtins A–C 171–173 and 5-desacetylaltohyrtin A 174, which are potent cytotoxic macrolides from Hyrtios altum,157 were elucidated by interpretation of spectroscopic data.158 Total syntheses of swinholide A 1 and preswinholide A 175, which are metabolites of lithistid sponges of the genus Theonella,159, 160 have been reported.161–163 Pallidin 176 is an interesting diketopiperazine alkaloid from Rhaphisia pallida from Hainin Island, China.164 The structure of hemiasterlin 177, which is a tripeptide from Hemiasterella minor,165 was confirmed by X-ray analysis of the corresponding methyl ester.166 Two additional peptides, halicylindramide D 178, which is antifungal and cytotoxic, and halicylindramide E 179, were obtained from Halichondria cylindrica from Japan.167 An Okinawan species of Hymeniacidon contains an additional proline-rich cyclic heptapeptide, hymenamide F 180, that was identified by interpretation of the spectral data of the corresponding sulfoxide.168 Even more proline residues are found in the cyclic hexapeptide waiakeamide 181 from an Indonesian collection of Ircinia dendroides.169 Kapakahines A–D 182–185 are a very unusual group of moderately cytotoxic cyclic peptides that were isolated in low yield from Cribrochalina olmeda from Pohnpei.170 The Callipelta sp.from New Caledonia that was the source of callipeltoside A 168 (see above) has also yielded three cyclic peptides, callipeltins A–C (CH2)3 OH (CH2)8 (CH2)8 (CH2)3 OH OH (CH2)m OH (CH2) n OH HOH2C OH HO HOH2C R HO HOH2C OH HO (CH2)7 HOOC (CH2)10 OH m n n 10 10 9 125 126 n 7 12– n 3 129 127 128 m + n = 31 130 m = 6, n = 9 131 m = 7, n = 9 132 m = 7, n = 7 133 m = 13, n = 11 134 R = OH; m = 5, n = 8 135 R = OH; m = 7, n = 8 136 R = H; m = 7, n = 8 137 138 m Faulkner: Marine natural products 121186–188.Callipeltin A 186 protects cells infected with HIV and callipeltins A 186 and B 187 show significant cytotoxicity. 171, 172 Aciculitins A–C 189–191 are a homologous series of antifungal and cytotoxic bicyclic peptides that were isolated from Aciculites orientalis from the Philippines.173 Aciculitin B 190 undergoes an interesting and facile photooxidation reaction on the imidazole ring.173 A number of cyclic peptides from sponges have been targeted for total synthesis.The proposed structure of konbamide 192, which is a calmodulin antagonist from an Okinawan O OH OH OH OH OH OAc OH OH OH OH OH O O O 139 140 141 142 OSO3Na OR 143 R = SO3Na 144 R = H COOH OH O O HO O OH 145 146 147 H2)8 C6H13 (C O O Et Et Et COOMe O O Et Et Et COOMe O O Et Et Et COOMe 148 149 150 O O Et H Et R Et O O O Et H Et R Et O O O Et Me Et COOH Et 153 R = Me 154 R = H 151 R = Et 152 R = Me 155 O COOMe Et Et Et 156 O O R OMe COOH O O R OMe COOH 157 R = Me 158 R = Et 159 R = Me 160 R = Et 122 Natural Product Reports, 1998specimen of Theonella sp.,174 has been synthesized but the synthetic and natural materials were not identical.175 Cyclotheonamide B 193 from Theonella sp.176 has been synthesized via guanidation of an ornithine residue.177 Axinastatins 2–5 194–197, which are cytotoxic cyclic peptides from Axinella species from the Comoros and Palau,178–180 were synthesized by one research group, who found that the synthetic compounds had only a fraction of the cytotoxicity claimed for the natural products,181 and axinastatins 2 194 and 3 195 by another group.182 The structure of stylopeptide 1 198, which is a minor metabolite of Stylotella aurantium,183 has been confirmed by total synthesis.184 Five additional bisoxazole alkaloids, bengazoles C–G 199– 203, were isolated from a Great Barrier Reef specimen of Jaspis sp.and the absolute stereochemistry at C-10 of the bengazoles was determined by Mosher’s method and by CD measurements.185 The unusual alkaloid clathyrimine 204 was obtained from only one of five diVerent collections of Clathria basilana from Indonesia and Papua New Guinea.186 The structure of xestospongin D 205, which was first isolated from Xestospongia exigua,187 was confirmed by X-ray analysis of a crystal obtained from a Niphates sp.from Singapore.188 Xestospongins A 206 and C 207, which are also from X. exigua,187 have been synthesized using macrocyclic dimerization reactions.189 Hyrtiomanzamine 208, which was isolated from a Red Sea specimen of Hyrtios erecta, is a ‚-carboline alkaloid that shows immunosuppressive activity.190 The 5-alkylpyrrole-2-carboxaldehydes 209 and 210, first isolated from Laxosuberites sp.,191 have been reported from Mycalecarmia monanchrorata and Mycale mytilorum from India.192 An enantioselective synthesis of cis-trikentrin B 211 from Trikentrion flabelliforme,193 has been described.194 (+)- Papuamine, the antipode of the natural product 212 from Haliclona sp.,195 has been synthesized by a stereoselective route.196 In an accompanying paper, the syntheses of both (")-papuamine 212 and (")-haliclonadiamine 213, which is from the same Haliclona sp.,197 were reported.198 An Okinawan specimen of Callyspongia sp.contained three nitroalkyl pyridine alkaloids, untenines A 214, B 215 and C 216, that inhibited microfouling.199 Both enantiomers of the antineoplastic alkaloid niphatesine D 217 from Niphates sp.200 were synthesized.201 Cyclostellettamine C 218, which is one of a series of homologous cyclic pyridinium alkaloids from Stelletta maxima,202 has been synthesized using a stepwise ring closure strategy.203 Three additional cytotoxic alkaloids in the halicyclamine series have been reported.Haliclonacyclamines A 219 and B 220 were isolated from a Haliclona sp. from the Great Barrier Reef and the structure of haliclonacyclamine A 219 was determined by X-ray analysis.204 The structure of halicyclamine B 221 from an Indonesian Xestospongia sp. was also determined by X-ray analysis.205 After chiral resolution, 206 the absolute stereochemistry of (+)-keramaphidin B 222, which is the major enantiomer of a mixture of enantiomeric alkaloids from Amphimedon sp.,207 was determined by the use of Mosher’s method on a derivative.208 An additional manzamine alkaloid, manzamine L 223, was isolated from the O O O HN S O OH H O O O O OH O H H H HO H O O OH HN S O H O O H H H HO H OH OH O O O O O O O NH O HO N O O H Cl Me HO O O O O OMe O O N O HN MeOOC O O O MeO OH O O NH O O MeO Cl Br O OMe OH OH O N O O O N O O O R2 R1 161 162 163 164 165 OMe 166 167 168 169 R1 = OH, R2 = H 170 R1 = H, R2 = OH Faulkner: Marine natural products 123same Amphimedon sp.from Okinawa and the absolute con- figurations at C-1 of manzamines D 224 and H 225 were determined.206 Four new manzamine alkaloids 226–229, three of which are N-oxides of known alkaloids, were obtained from Xestospongia ashmorica from the Philippines.209 The structures and stereochemistry of saraines B 230 and C 231 and the absolute configuration of saraine A 232, which are alkaloids from Reniera sarai from the Mediterranean,210 have been defined by spectroscopic methods.211 A second paper reports the absolute stereochemistry of saraines-1 233 and -2 234, which are also metabolites of R.serai,212 and the structural elucidations of saraine-3 235 and isosaraine-3 236.213 Makaluvic acids A 237 and B 238 were isolated, in addition to known makaluvamines, from Zyzzya fuliginosus from Chuuk (Truk) Atoll and were identified by interpretation of spectral data.214 An unidentified spinach-green coloured deep water sponge from the South Indian Ocean yielded four new pyrroloiminoquinone alkaloids, epinardins A–D 239–242, that possess useful cytotoxicity.215 An undescribed latrunculid sponge from South Africa contained tsitsikammamines A 243 and B 244, 14-bromodiscorhabdin C 245 and 14-bromodihydrodiscorhabdin C 246.216 Sagitol 247 is a pyridoacridine alkaloid from Oceanapia sagittaria in which the aromatic system is disrupted. Although sagitol 247 can be obtained by singlet oxygen oxidation of dercitin 248, its CD spectrum suggests that it is not entirely an artifact.217 Amphimedine 249, a pyridoacridine alkaloid from Amphimedon sp.,218 has been synthesized using hetero-Diels–Alder reactions.219 Permethylation of nortopsentin D 250, which is a new alkaloid from the deep water Indo-Pacific sponge Dragmacidon sp., produced a highly cytotoxic product from an inactive natural product.220 Nortopsentins A–C 251–253, which are antifungal alkaloids obtained from Spongosorites ruetzleri,221 and a non-brominated derivative 254, also called nortopsentin D, have been synthesized.222 Deoxytopsentin 255, topsentin 256 and bromotopsentin 257, which are ichthyotoxic alkaloids from Topsentia genitrix,223 have been synthesized using a three-component coupling scheme.224 An eYcient synthesis of homofascaplysin C 258 from Fascaplysinopsis reticulata225 has been described.226 Storniamides A–D 259–262 are antimicrobial pyrrole alkaloids from a Cliona sp from Patagonia.227 Arenochalina mirabilis from southern Australia contained six tricyclic alkaloids, mirabilins A–F 263–268, that were isolated as monoacetyl or diacetyl derivatives.228 The stereochemistries of batzelladines A and D, which are metabolites of a Caribbean Batzella sp.,229 were revised from 269 to 270 and from 271 to 272, respectively, as the result of the synthesis of hydrolysis products and analysis of NOESY data.230 A short synthesis of (+)-ptilocaulin 273, which is an alkaloid from O O OAc O O O O O O O OH R1 HO OH OH OH HO OMe R2O HO H O OMe OH OH O HO HO OMe HO COOH NH N COOMe N Me NHMe Me O O HN NH HN NH HN NH N NH O O NHCHO O O O O O O NH OSO3Na NH H2N HN O O O HN MeN HN NH Ph O O O CONH2 H2NOC HN NH HN NH HN N HN CONH2 NH N NH O O NHCHO O O O O O O O O NH OSO3Na Me OH NH H2N HN CONH2 Ph Br Br 171 R1 = Cl, R2 = Ac 172 R1 = Br, R2 = Ac 173 R1 = H, R2 = Ac 174 R1 = Cl, R2 = H 175 177 178 179 N HN NH O O COOH 176 124 Natural Product Reports, 1998Ptilocaulis aV. P.spiculifera,231 has been reported.232 An undescribed Xestospongia sp. from the Philippines contained a derivative of renierone 274 that was probably an artifact formed by condensation of the extraction solvent acetone to the known N-formyl derivative 275.233 In a paper discussing the tautomerism of hymenialdisine and debromohymenialdisine, the corresponding 10E isomers, (10E)-hymenialdisine 276 and (10E)-debromohymenialdisine 277, were reported as minor metabolites of Stylotella aurantium from Palau.234 Hymenin 278, which is a metabolite of Hymeniacidon sp.,235 has been converted into stevensine 279, a metabolite from an unidentified sponge,236 by a route that involved bromination/dehydrobromination.237 Pseudoceratidine 280 is an antifouling spermidine derivative from Pseudoceratina purpurea that inhibited settlement and metamorphosis of barnacle larvae.238 The synthesis of pseudoceratidine 280 was reported shortly after the structural elucidation appeared.239 Dispacamide 281 and monobromodispacamide 282, which were isolated from four Caribbean species of Agelas (A.conifera, A. clathrodes, A. dispar and A. longissima), show selective antihistamine activity in the guinea pig ileum.240 A. clathrodes also contained the mildly antifungal agents, clathramides A 283 and B 284.241 Mauritiamine 285 is a ‘dimeric’ oroidin derivative from A. mauritiana that inhibited the metamorphosis of barnacle larvae.242 Seven N-methylated ageliferins 286–292 were isolated from the sclerosponge Astrosclera willeyana, thereby supporting taxonomic evidence that A.willeyana is related to Agelas species.243 Along with several known metabolites, three additional bromotyrosine alkaloids, pseudoceratinines A–C 293–295, have been isolated from two specimens of Pseudoceratina verrucosa from New Caledonia.244 Ceratinamine 296 is a cytotoxic cyanoformamide from a Japanese specimen of P.purpurea that is toxic toward barnacle cyprid larvae.245 The same sponge also contained ceratinamides A 297 and B 298, which inhibited settlement and metamorphosis of barnacle larvae.246 Only one new bromotyrosine derivative 299 was among the ten related metabolites isolated from a Caribbean specimen of Aplysina archeri.247 Three new bastadin analogues, bastadin 20 300, 15,34-O-disulfatobastadin 7 301 NH N N O O O NH NH HN O O O HN O MeS HN H2N NH O N NH O NH O N N HN S N O O O S Me O S Me O Ph O O N O NH O N HN HN O NH NH2 N N N O O O H OH NH N N O Ph O H HN O O NH O NH2 NH N Ph O 180 181 182 183 O O N O NH O N HN HN O NH NH N N N O O O H H OH OH O O N O NH O N HN HN O NH NH N N N O O O H H OH OH 185 184 NH HN NH NH OH O O O O N O NH N NH O HN O Me O O O HN O O OH OH H2NOC OH NH2 Me CONH2 HO OMe HN NH2 NH HN NH HN NH O O O N O NH N NH O HN O Me O O O OH HN NH NH2 Me CONH2 NH O HO OMe 187 186 Faulkner: Marine natural products 125and 10-O-sulfatobastadin 3 302, which were isolated from Ianthella basta from Exmouth Gulf, Western Australia, showed moderate diVerential activity as SR-Ca2+-channel agonists of the Ry1R FKBP12 complex.248 Hemibastadinols 1–3 303–305, monomethyl ethers 306 and 307 of hemibastadins 1 and 2,249 and the oxalic acid amide 308 were isolated as minor metabolites of I.basta from Papua New Guinea.250 Two additional tetrabrominated diphenyl ethers 309 and 310 have been reported from an undescribed Dysidea sp.from Chuuk, Micronesia and from an Indian specimen of D. herbacea, respectively.251, 252 A Senegalese specimen of Ptilocaulis spiculifer contained an iodinated tyrosine derivative, dakaramine 311, with an unusual alkyl sulfate counterion 312.253 The meroditerpenoid 2-(4-hydroxy-3-tetraprenyl-phenyl)- acetic acid 313 was isolated as a topoisomerase II inhibitor from Ircinia muscarum.254 A southern Australian species of Euryspongia contained deoxyspongiaquinone 314, deoxyspongiaquinol 315, (E)-chlorodeoxyspongiaquinone 316 and (E)-chlorodeoxyspongiaquinol 317.255 The absolute stereochemistry of puupehenone 318, which was first isolated from Chondrosia chucalla, has been determined using a sample from NH HN NH NH OH O O O HO N O NH N NH O HN Me O O O HN O O OH OH CONH2 OH NH2 Me CONH2 HO OMe HN NH2 NH HN NH HOOC OH N HN NH O HN O NH O NH NH O O HN NH O HN O H2NOC CONH2 OH OH HN O O H N O O R HO O OH OH OH NH O N O NH HN O O HN O Me NH NH O COOH 188 NH Br HO 189 R = C5H11 190 R = C6H13 191 R = C7H15 192 N NH O O NH O H2NOC N HN O O NH HN O O Ph R HN NH HN O O HN O O N NHAc O NH NH O OH NH2 194 R = Me 195 R = Et 193 N N HN O O O O NH O NH HN O NH O O N OH N NH O O NH O OH N HN O O NH HN O O NH NH N O O N O HN NH O NH O O NH O Ph OH 197 196 198 126 Natural Product Reports, 1998Dysidea sp.from southern Australia.256 Dipuupehedione 319 is a mildly cytotoxic red coloured dimer of puupehenone from a New Caledonian Hyrtios sp.257 (+)-Avarol 320 and (+)- avarone 321, which are metabolites of Dysidea avara,258 have been synthesized, together with related metabolites, by two groups.259, 260 The synthesis of (+)-xestoquinone 322, which is a merosesquiterpene from Xestospongia sapra,261 has been accomplished in 68% enantiomeric excess.262 Stellettadine A 323, which was isolated from a Japanese Stelletta sp., is a bisguanidinium alkaloid incorporating a norsesquiterpene residue that induces larval metamorphosis in ascidians.263 Five additional drimane sesquiterpenes 324–328 have been isolated from Dysidea fusca from New Caledonia.264 The stereochemistry of a known drimane sesquiterpene, previously isolated from a Dysidea sp.from southern Australia,265 has been revised from 329 to 330.264 As part of a study of the sponges of the Lagoon of Venice, two „-hydroxybutenolides 331 and 332 were isolated from D. fragilis.266 Pallescensone 333, which is a metabolite of Dictyodendrilla cavernosa,267 has been synthesized in an enantioselective manner to determine the absolute configuration of the natural product.268 The absolute configuration of (")-microcionin 2 334, which was first isolated from Microciona toxystila,269 was confirmed by total synthesis.270 (")-Furodysin 335 from Dysidea tupha271 OH OH OH OH O N OR N O N Ph COOH N O (CH2)5 (CH2)5 N O H H N O (CH2)5 (CH2)5 N O H H R N NH O N N Me SMe Me OH NH OHC R NH Et HN HN H H H H HN HN H H H H 199 R = COC12H25 200 R = CO(CH2)10CHMe2 201 R = COC14H29 202 R = CO(CH2)11CHMeEt 203 R = COC15H31 N NO2 204 206 N 205 R = OH 207 R = H N NO2 209 R = C15H31 210 R = C16H33 211 NO2 208 212 213 214 215 216 N NH2 217 + + N N N N H H N N H H N N H N N N NH HN OH H NH R N NH N OH H NH H H 222 10 219 218 220 221 223 R = a-H 225 R = b-H 10 224 + + Faulkner: Marine natural products 127and D.herbacea,272 the enantiomer of herbasolide 336, which was isolated from a Papua New Guinea specimen of D.herbacea,273 and tavacpallescensin 337 from a mixture of D. avara and Pleraplysilla spinifera,271 have all been synthesized by the same research group.274–276 Syntheses of (&)- halipanicine 338 from Halichondria panicea277 and both (&)- axisonitrile-1 339 and (&)-axamide-1 340 from Axinella cannabina278 were also reported.279, 280 A Japanese specimen of Acanthella cavernosa contained fourteen terpenoids, six of which had not been described previously, that inhibited the settlement and metamorphosis of barnacle larvae.The structures of the sesquiterpene isothiocyanate 341, a diterpene hydrocarbon, biflora-4,9,15-triene 342, and four kalihinane diterpenes, 10‚-formamidokalihinol- A 343, 10‚ -formamido-5-cyanatokalihinol-A 344, 10‚ - formamido-5‚-isothiocyanatokalihinol-A 345 and 10‚- formamidokalihinol-E 346, were assigned by interpretation of spectral data.281 A second specimen of A.cavernosa contained kalihipyrans A 347 and B 348, which can also act as antifouling agents.282 Twelve additional diterpenes 349–360 bearing isocyanate, isothiocyanate or isonitrile groups have been isolated from Cymbastela hooperi from the Great Barrier Reef.283 The structures and relative stereochemistry of four diterpene isonitriles, 353, 355, 358 and 361, from C. hooperi were determined by low temperature X-ray crystallographic studies.284 Nakamurols A–D 362–365 are four additional diterpenoids, one of which contains a pyrrole-2- carboxaldehyde residue, from an Okinawan species of Agelas nakamurai.285 Full details of the total syntheses of (&)- agelasimines A 366 and B 367, which are alkaloids from A.mauritiana,286 have been reported.287 The purino-diterpene 368 that had previously been isolated from A. mauritiana after acetylation of the crude alkaloid fraction,288 was obtained by acetylation of agelasimine B 367.287 Several syntheses of spongian diterpenes have been reported.(&)-Isospongiadiol 369, which was obtained from the deep water sponge Spongia linnaeus,289 was constructed using an intramolecular radical cascade approach.290 Both (+)-isoagatholactone 370 and (")- spongia-13(16),14-diene 371, which are diterpenes from two diVerent collections of S. oYcinalis,291, 292 were synthesized starting from a podocarpane derivative.293 A concise synthesis of spongian-16-one 372, which has been reported from both Dictyodendrilla cavernosa294 and Chelonaplysilla violacea,295 employs three consecutive radical cyclization steps.296 N N N OH H NH O N N HN OH H NH O N N N OH H NH O N N O HO HO N N O HO HO N N O HO HO N N O H H N N O H H N N O H H N N COOH O R1 R2 N HN O HN OH N HN O HN OH HO Br Br 3 N HN O HN OH 4 227 228 D3,4 229 232 226 Br Br 231 230 236 17 18 233 D17,18 234 235 237 R1 = H; R2 = Me 238 R1 = Me; R2 = H 239 240 241 N HN O HN OH Br Br + OMe 242 NH O N NH HN O HN Br Br NH HN O HN OH Br Br HN OH R O 246 243 R = H 244 R = Me 245 Br Br + + + 128 Natural Product Reports, 1998Isonitenin 373 is an additional C21 difuranoterpene from a Spanish collection of Spongia oYcinalis.297 A C21 difuranoterpene 374 from a Spanish specimen of S.virgultosa was found to be the enantiomer of (")-untenospongin B from a Japanese Hippospongia sp.298, 299 Comparison of spectral data suggested that the structure of tetradehydrofurospongin-1 from an Australian Spongia sp.300 be revised from 375 to 374.299 The absolute configuration of the C21 difuranoterpene 376, isolated from Fasciospongia cavernosa from the Arabian Sea,301 has been determined by synthesis of its enantiomer.302 An additional norsesterterpene peroxide, hurghaperoxide 377, was isolated from an undescribed haplosclerid sponge N N N S HO NHCOEt N NH HN NH N O NH Me NH2 Br Br NH N N N N S NHCOEt N O O Me N NH NH HN R1 R2 N NH HN R1 O HN R2 N HN CHO N HN HN O O HO OH R1 OH R3 OH HO HO HO R2 OH N N NH2 C3H7 N N NH2 N N NH2 C3H7 C4H9 N HN NH2 C3H7 N HN NH2 N HN NH2 C4H9 OH OH H H H H H H H H H H N NH O O NH O H N NH2 O N N NH C9H19 NH H N NH O O NH O H N NH2 O N N NH C9H19 NH 258 250 259 R1 = OH; R2 = R3 = H 260 R1 = R3 = OH; R2 = H 261 R1 = H; R2 = R3 = OH 262 R1 = R2 = R3 = OH 249 266 247 248 251 R1 = R2 = Br 252 R1 = H; R2 = Br 253 R1 = Br; R2 = H 254 R1 = R2 = H 263 H 255 R1 = R2 = H 256 R1 = H; R2 = OH 257 R1 = Br; R2 = OH H H H H 264 265 268 267 269 270 O O N N NH C9H19 O O N N NH C9H19 H H H H HN H2N NH HN H2N NH N O O O O O MeO N O O O O CHO MeO NH HN NH H H H 272 275 271 274 273 Faulkner: Marine natural products 129from the Red Sea but the stereochemistry was not completely determined.303 Four unstable sulfate esters 378–381 of known furanosesterterpenes were obtained from Ircinia variabilis and I.oros from the northern Adriatic Sea.304 Hippospongins A–F 382–387 are furanosesteterpenes and truncated furanosesterterpenes, some of which are amides that incorporate diaminoethane, from Hippospongia sp.from southern Australian waters.305 Rhopaloic acid A 388 is an unusual cytotoxic norsesterterpene from a Japanese specimen of Rhopaloeides sp. that also inhibits gastrulation of starfish embryos.306 A New Caledonian specimen of Hyrtios sp. contained thorectolide monoacetate 389, which is a cytotoxic sesterterpene of the manoalide family.307 Palauolol 390 is an additional antiinflammatory sesterterpene from a Fascaplysinopsis sp. from Palau.The absolute configurations of both palauolol 390 and paluolide 391, which had previously been isolated from a mixed sample of sponges,308 were determined.309 NH NH NH N Br Br O H2N NH NH NH N Br Br O H2N NH NH NH N O O NH2 R HN NH NH O NH Br Br O HN Br Br 279 276 R = Br 277 R = H 278 280 NH HN O Br R N HN O NH2 NH HN O Br N HN Me Me R1 R2 283 R1 = H; R2 = COO- 284 R1 = COO-; R2 = H 281 R = Br 282 R = H + NH HN O Br Br N NH O NH2 NH HN O Br Br NH N NH2 NH HN HN HN O O NR N Me NH2 Br X3 X1 X2 NH HN NH2 286 R = X1 = X2 = H; X3 = Br 287 R = Me; X1 = X2 = H; X3 = Br 288 R = X1 = X3 = H; X2 = Br 289 R = Me; X1 = X3 = H; X2 = Br 290 R = X2 = H; X1 = X3 = Br 291 R = X1 = H; R = Me; X2 = X3 = Br 292 R = H; X1 = X2 = X3 = Br 285 + + + + O N HO HN NH N NH2 O Br OMe Br HN NH N NH2 O Me3N MeO Br Br O N HO HN NH N NH2 O Br OMe Br H N O O Br Br NH2 293 294 H N O Br Br NH2 NC O 295 296 + + O N O NH O Br MeO Br O NHR HO Br Br 297 R = CHO 298 R = CO(CH2)11CHMe2 O N HN NH O Br O O O N O O Br Br Br HO OH 299 130 Natural Product Reports, 1998HN O Br OSO3Na NOH O O Br NH NOH O NaO3SO Br Br HN O OH NOH O HO Br O NH O Br Br Br NOH HN Br OH NOH O NaO3SO Br NH NOH O HO Br Br HO 300 301 302 HN O Y OH Br X HO Br OH HN O X OMe Br HO Br NOH HN NH2 O HO Br O O Br Br OR Br X O I I OSO3 – NMe2 NMe2 303 X = Y = H 304 X = H; Y = Br 305 X = Br; Y = H 306 X = H 307 X = Br 308 311 312 Y 309 R = Y =H; X = Br 310 R = Me; X =H; Y = Br H OH COOH O OMe O Cl O O OMe H H HO OMe OH Cl OH HO OMe H H O O H O H H H O O O O OH O HO OH O O O O O O 4 313 314 316 317 315 318 320 319 321 322 NH NH O NH HN NH2 NH O H O H H HO CH2OAc CH2OAc H CHO COOH HO O O H O OH O O HO O HO O HO H H O H O OH 325 323 324 326 330 327 328 332 329 331 Faulkner: Marine natural products 131Dysidea etheria from the Caribbean contained the novel sesterterpene, dysidiolide 392, that inhibited the cdc25A protein phosphatase.The structure of dysidiolide 392 was determined by single crystal X-ray diVraction.310 Three additional cytotoxic sesterterpenes, 16-O-deacetyl-16-episcalarobutenolide 393, 12-O-acetyl-16-O-deacetyl-16-episcalarobutenolide 394 and 12-deacetoxy-21-acetoxyscalarin 395, were obtained from a Japanese specimen of Hyrtios cf. erectus (=erecta?).311 Two additional homoscalarins, phyllactones H and I, which are C-24 isomers of the bis-homoscalarane 396, have been isolated from a Chinese species of Phyllospongia.312 The X-ray crystallographic data for a previously reported313 sesterterpene lactone 397 from Petrosaspongia nigra sp.nov. has been published.314 Lintenolides C–E 398–400 are additional sesterterpenes from Cacospongia cf. linteiformis from the Caribbean that inhibit fish feeding.315 (")-12-Deacetoxyscalaradial 401, which is a O O O 333 334 O H H O O O O O SCN H H R 336 337 338 335 339 R = NC 340 R = NHCHO H SCN H H O Cl HO NHCHO H H R O Cl HO NHCHO H H NC 346 341 342 343 R = NC 344 R = NCO 345 R = NCS O NHCHO H H O NHCHO H H Cl 347 348 H H R1 H R2 H H H H H NCS H H H H NC H H H H H H NC H H H H H NC H H H H NC H H H H NC H H H H NC H NCS H H NCS H OH H NC H H 349 353 350 R1 = NC; R2 = NCS 351 R1 = NC; R2 = NCO 352 R1 = NCO; R2 = NC 354 356 357 358 H H NC H H 359 360 361 355 OH H O HO H O HO H HO O O HN 362 363 364 365 132 Natural Product Reports, 1998metabolite of C.mollior,316 has been synthesized from manool.317 A Japanese Hippospongia sp.contained hippospongic acid A 402, which is a triterpenoid that inhibits gastrulation of starfish embryos. However, the proposed strucure 402 is not based on a regular triterpene (squalene) skeleton.318 Four cytotoxic isomalabaracane triterpenes, globostellatic acids A–D 403– 406, were isolated from Stelletta globostellata from Japan,319 and an additional four related compounds, stellettins C–F 407–410, were obtained from a Stelletta sp. from northern Australia.320 Jaspiferals A–G 411–417 are cytotoxic OH R H N N N N Me NHMe NMe N N N Me NH N N N N Me O 366 R = 367 R = 368 R = O O HO H H HO O H H O H H O O H H O 369 370 372 371 O O O O O O OH O O OH O O 373 374 375 376 OH O O COOMe H 377 O O OSO3K O O O OSO3K O O O OSO3K O O O OSO3K O O O 378 379 380 381 O O O COOH O O O COOH O O O NH O NH2 O O O 382 383 O 384 O O O NH O NHR 386 R = H 387 R = Ac 385 O O O AcO HO O COOH 388 389 Faulkner: Marine natural products 133isomalabaracane-type nortriterpenoids from an Okinawan specimen of Jaspis stellifera, that are probably formed by oxidative cleavage of side chain double bonds.321 (22E)-24·-Methylcholest-4,8(9),22-triene-3·,7‚-diol 418 was among the sterols isolated from an Indian specimen of H O H OH H O O HO H 390 391 O O OH HO O OH R O O CH2OAc HO O O O OH 392 396 393 R = OH 394 R = OAc 395 O O O OAc O H H O O O HO OH O O O H H H H H H H H OH OH O O O H H H OH CHO CHO 399 398 397 401 400 O COOH 402 2 NaOOC AcO O H H O OH NaOOC AcO O H H OH NaOOC RO O H H OH OMe OMe 405 R = Ac 406 R = H 403 404 O AcO H H O AcO H H O AcO H H O H H O 407 409 408 410 O O COOH O O COOH 134 Natural Product Reports, 1998Suberites carnosus.322 A rather unusual 3-methoxymethyl ether of a ƒ7-sterol 419 was obtained from a deep-water Caribbean sponge Scleritoderma sp.cf. paccardi.323 An A-nor sterol 420 with rare ring D unsaturation was isolated from Axinella proliferans from Réunion Island in the Indian Ocean.324 A new cyclopropane containing sterol 421 was isolated from Rhizochalina incrustata.325 Aragusteroketals A 422 and C 423, which are dimethoxy ketals of known ketones,326, 327 are additional cytotoxic sterols from a Xestospongia sp.from Okinawa.328 A stereoselective synthesis of petrosterol 424, which was obtained from Petrosia ficiformis,329 and a formal synthesis of aragusterols have been described.330 A new epoxy sterol 425 was described from an Indian specimen of Ircinia fasciculata331 and an aromatic polyhydroxygenated sterol, geodisterol 426, was found in a Geodia sp.from Papua New Guinea.332 The polyoxygenated sterols incrusterols A 427 and B 428 from Dysidea incrustans333 have been synthesized in a straightforward manner.334 The structure of mycalone 429, which is an unusual sterone from a Mycale sp. from southern Australia, was determined by single crystal X-ray diVraction analysis.335 Polymastiamides B–F 430–434 are additional amino acid conjugates of steroids that were isolated from Polymastia boletiformis from Norway.336 Halistanol disulfate B 435 is a sulfated sterol from Pachastrella sp.that inhibits endothelin converting enzyme.337 7 Coelenterates As always, the chemistry of coelenterates is dominated by terpenes, particularly diterpenes, but there are several reports of bioactive compounds belonging to other classes.Two relatively simple amides 436 and 437 that were isolated from the octocoral Telesto riisei collected at Chuuk (Truk) Atoll HOOC HO O H H CHO HOOC HO O CHO H H HOOC HO O CHO H H HOOC HO O H H CHO 411 (13 Z) 412 (13 E) 415 (13 Z) 416 (13 E) 417 413 (13 Z) 414 (13 E) 13 13 13 O O HO OH OH HOH2C HO 418 419 420 421 HO MeO MeO O OH HO MeO MeO OH OH HO Cl HO O OH 424 422 423 425 HO OH O HO OH HO O O HO OH O O O H H OAc 427 428 429 HO OH OH H H H 426 Faulkner: Marine natural products 135were mildly cytotoxic.338 A mixture of sphingosines having N-palmitoyl-2-amino-1,3-dihydroxyoctadeca-4,8-diene 438 as the major constituent was obtained from both Sinularia conferta and a Lobophytum sp.from the Andaman and Nicobar Islands.339 The Okinawan soft coral Clavularia viridis contained two additional prostanoids 439 and 440 that are salts that might be derived by hydrolysis of the known „-lactones, clavulolactones II and III.340 (11R)-Hydroxyeicosatetraenoic acid 441, a proposed intermediate on the pathway to prostanoids in coelenterates, has been found in the gorgonian Plexaurella dichotoma.341 Solandelactones A–I 442–450 are cyclopropane-containing docosanoids from the Korean hydroid Solanderia secunda. Solandelactones C 444, D 445 and G 448 inhibit farnesyl protein transferase.342 Two cytotoxic diacetylenic acids, montiporic acids A 451 and B 452, were found in the eggs of the scleractinian coral Montipora digitata.343 (+)-Ancepsenolide 453, which is a metabolite of Pterogorgia anceps,344 has been synthesized using a two-directional strategy.345 Four tetraprenyltoluquinols have been obtained from South African soft corals.The ketal sindurol 454 was isolated from a specimen of Sinularia dura while nephthoside 455, its aglycone 456 and nephthoside acetate 457 were obtained from a species of Nephthea.346 NaO3SO NH R2 COOH O NaO3SO NH R2 COOH O R1 R1 HO3SO HO3SO 432 R1 = Me; R2 = OMe 433 R1 = H; R2 = OMe 434 R1 = Me; R2 = H 435 430 R1 = H; R2 = OMe 431 R1 = Me; R2 = H Ph NH C7H15 O O Ph NH C7H15 O OH C9H9 OH NHCOC15H31 HO 436 438 437 COOH OH COONa C5H11 O OH OH C5H11 O OH COONa HO 441 439 440 C5H11 R2 R1 O O H H H R2 R1 O O H H H HO HO C5H11 R2 R1 O O H H H R2 R1 O O H H H HO HO O O H H H HO C5H11 OH 442 R1 = OH; R2 = H 443 R1 = H; R2 = OH 446 R1 = OH; R2 = H 447 R1 = H; R2 = OH 444 R1 = OH; R2 = H 445 R1 = H; R2 = OH 448 R1 = OH; R2 = H 449 R1 = H; R2 = OH 450 COOH O COOH O O O O O 451 452 453 136 Natural Product Reports, 1998The soft coral Lobophytum catalai from India contained a new sesquiterpene epoxide 458 in which the normal sesquiterpene skeleton has undergone a rearrangement.347 Two practical syntheses of the antiinflammatory sesquiterpene furan 459, which is a metabolite of Sinularia spp.,348 both employ a strategy based on the Claisen rearrangement.349 Clavulinin 460, from a Chinese specimen of the soft coral Clavularia inflata, contains an unusual lactam ring.350 The gorgonian Subergorgia suberosa contained suberosenone 461, which is a relatively potent cytotoxic sesquiterpene of the quadrone class.351 The Caribbean gorgonian Pseudopterogorgia americana contained five highly oxidized guanolides, americanolides A–C 462–464 and two methyl ethers 465 and 466 that are considered to be artifacts derived by reaction of hemiketals 462 and 463 with the extraction solvent.352 An additional guaiazulene pigment that possesses mild antimicrobial activity, 2,2*- biguaiazulenyl 467, has been isolated together with known pigments from a Korean specimen of the gorgonian Calicogorgia granulosa.353 Isovalerenenol 468, which is a metabolite of Xenia sp.,354 has been synthesized in racemic form.355 Two primnatriene-type sesquiterpenes 469 and 470, which had been isolated from the New Zealand soft coral Primnoides sp.,356 were synthesized by using a route in which all the stereochemistry of the starting material is lost.357 Two additional syntheses of (")-ƒ9(12)-capnellene 471 from Capnella imbricata358 have been reported359, 360 as have additional syntheses of the perennial favourites (")-clavukerin A 472361 and (")- isoclavukerin A 473362 from Clavularia koellikeri.363, 364 Four new cytotoxic cembranoids, (1E,3E,7E)-11,12- epoxycembratrien-15-ol 474, (1E ,7E)-3,4:11,12-diepoxy-15- methoxycembradiene 475, (1E ,3E,7E,11E)-cembratetraene- 14,15-diol 476 and (1E,7E,11E)-3,14-epoxycembratrien-4,15- diol 477, were obtained from Sinularia gibberosa and one, 7‚,8·-dihydroxydeepoxysarcophine 478, from Sarcophyton trocheliophorum, both of which were collected in Taiwan.365 An Okinawan soft coral of the genus Sarcophyton contained 3,4-epoxysarcophytonin 479 and sarcodiol 480, the structure O O OAc OH OH OAc HO OH OH H OH O H O OH OR OH 454 4 456 4 455 R = H 457 R = Ac O O O H H O HOOC HN COOMe O HO O H 461 459 458 460 O O O O R O O O O R 462 R = OH 464 R = H 465 R = OMe 463 R = OH 466 R = OMe OH H H 467 468 O X MeO H H H H H 469 X = O 470 X = H2 471 472 473 O OH OMe O O OH OH O OH 474 475 477 O O HO HO 476 OH 478 Faulkner: Marine natural products 137of which was determined by X-ray analysis of the corresponding di-p-bromobenzoate.366 In addition to known sesquiterpenes and diterpenes, a number of cembranoids have been isolated from soft corals from the Andaman and Nicobar Islands. Sinularia hirta contained mayol acetate 481 and the lactone 482,367 S.conferta produced the lactone 483 and a methyl ether 484, which may well be an artifact of the isolation procedure,368 and flexibilolide 485 and dihydroflexibilolide 486 were isolated from S. flexibilis.369 Ten additional cembranoids, sartol A 487, 4-O-methylsartol A 488, sartones A–D 489–492, 4-O-methylsartone B 493, epoxysartone A 494, 6‚-hydroxysarcotol acetate 495 and 4-O-methylsarcotol 496, some of which were found to be ichthyotoxic, were isolated from a Japanese species of Sarcophyton.370 Two cembranoids from Sinularia mayi,371, 372 (+)-sinulariol-D 497 and (RR/SS)- sinulariol-B 498, and three isomeric cembratrienones 499–501 from the gorgonian Eunicea calyculata,373 have been synthesized by the same research group.374–377 Singardin 502 is an unusual cytotoxic norcembranoid dimer containing a 10-membered bis-lactone ring that was isolated from the Red Sea soft coral Sinularia gardineri.378 An Okinawan specimen of Sinularia sp.contained sinulariadiolide 503 which is a norditerpene dilactone with a new carbon skeleton.379 In addition to several known diterpenes, five additional lobane derivatives 504–508 were isolated from two specimens of the soft coral Lobophytum microlobulatum from the Andaman and Nicobar Islands.380, 381 Sarcophyton glaucum from South Africa contained the cytotoxic diterpene sarcoglane 509, which possesses an unprecedented tricyclic carbon skeleton.382 The absolute configuration of dolabellatrienone, which is a diterpene from the Caribbean gorgonian Eunicea calyculata,383 has been revised to 510 as the result of a total synthesis.384 Of the five new diterpenes of the eunicellan class, labiatamides A 511 and B 512 and labiatins A–C 513–515, that were isolated from the Senegalese gorgonian Eunicella labiata, only labiatin B 514 was cytotoxic.385 Two diterpenoid glycosides, eleuthosides A 516 and B 517 were isolated from the South African soft coral Eleutherobia aurea.386 Aceropterine 518, which was isolated from the Caribbean gorgonian Pseudopterogorgia acerosa, is an unusual O O OH HO O O 480 479 OH MeO O O OH OH O OH O OH OH O OH O OH OH 484 O O 483 OAc 486 OH 485 481 482 OR OH OH O O OH OH O O O OH O O CH2OAc HO OMe O CH2OH 495 494 492 491 490 R = H 493 R = Me 487 R = H 488 R = Me 489 496 OR OH OH OH OH O O O O O O O O O O O O O O O 497 498 500 502 499 501 138 Natural Product Reports, 1998dimethylamino-containing pseudopterane in which the lactone ring has been transposed from its usual position.387 Five additional pseudopteranes, pseudopteradiene 519, pseudopteradienoic acid 520, 11-pseudopteranol 521, pseudopteranoic acid 522 and diepoxygorgiacerodiol 523, and a very unusual norditerpene, alanolide 524, in which the furan ring of the pseudopterane ring system has been opened and decarboxylated, were all obtained from the same specimen of P.acerosa.388, 389 The enantiomer of kallolide B 525, which is O COOMe HO Me2N O O O O O COOR O O O COOMe O O O COOH O OH O O COOMe O OH O O OH O O O O O O O O O Me2N H AcO OH OH RO HO OH OH RO AcO OH C17H35COO HO HO OH OH RO O HO O OH C17H35COO O 518 522 521 523 519 R = Me 520 R = H 524 532 535 530 R = COC17H35 531 R = COC15H31 533 R = COC17H35 534 R = COC15H31 525 526 R = COC17H35 527 R = COC15H31 528 R = COC18H37 529 R = COC19H39 O O O OH H O OH OH O O O OH OH OH OH OH OH 505 507 508 506 504 503 COOMe COOH O H OH H H O H 510 509 O N OAc H H H H R AcO Ac Me O OAc H H H H AcO AcO H H AcO O OH OAc H H H H AcO AcO O O OAc OAc O 511 R = OAc 512 R = H 513 514 515 O O OH O N N O O OAc OR1 R2O H H Me 516 R1 = Ac; R2 = H 517 R1 = H; R2 = Ac Faulkner: Marine natural products 139a pseudopterane diterpene from the Caribbean gorgonian P.kallos,390 has been synthesized from (S)-(")-perillyl alcohol.391 A total of twenty xenicane diterpenoids have been isolated from two Japanese collections of soft corals of the genus Xenia.Azamilides A–J 526–535 are aliphatic esters of ringopened xeniolides, xeniaethers C–H 536–541 are additional members of that series, azamials A 542 and B 543 were obtained as an inseparable mixture, isoxeniatine C 544 is a geometrical isomer of a known metabolite, and xenicinedial 545 is a ring-opened oxidation product.392–394 Ten additional briarane diterpenoids, briareins C–L 546–555, were reported from a Puerto Rican specimen of Briareum asbestinum,395 while a specimen of B.asbestinum from Tobago contained O O OH RO O OH RO O OH O HO O O CHO CHO AcO OAc AcO OHC O O HO 536 R = H 537 R = COC17H35 538 R = COC15H31 539 R = COC17H35 540 R = COC15H31 541 R = COC18H37 12 544 545 4 542 543 4(12) E AcO O OAc OAc O H C3H7COO HO OH Cl AcO O OAc OAc O H R1O R2O OH Cl O AcO O OAc OAc O H R1O R2O OH AcO O OAc OAc O H AcO HO OH Cl O 547 R1 = R2 = Ac 548 R1 = Ac; R2 = H 549 R1 = COC3H7; R2 = Ac 551 R1 = Ac; R2 = H; R3 = OAc 552 R1 = Ac; R2 = H; OCOC7H15 553 R1 = Ac; R2 = H; R3 = Cl 554 R1 = COC7H15; R2 = H; OCOC3H7 555 R1 = COC3H7; R2 = R3 = OAc OH 546 R3 550 AcO O OCOC3H7 H RO O COOMe AcO O OCOC3H7 H HO COOMe AcO H AcO O OCOC3H7 O OCOC3H7 H O O COOMe AcO O OH OCOC3H7 O H AcO O O OCOC3H7 O H OH 556 R = H 557 R = Ac 558 R = COC3H7 E or Z 559 560 562 563 561 AcO O O O OH OAc O AcO O OH OAc O HO R H H 565 R = H 566 R = OAc 564 AcO AcO OAc AcO O CH2Cl OH O O OAc Cl AcO O OH O AcO AcO OAc Cl AcO O OH O O AcO AcO OAc Cl AcO O OH O HO AcO HO 567 568 570 569 140 Natural Product Reports, 1998briareolate esters D–I 556–561 and briareolides J 562 and K 563.396 The structure of briareolate ester D 556 was determined by X-ray analysis.396 Three cytotoxic briarane diterpenes, 2‚-acetoxy-2-(debutyryloxy)stecholide E 564, 9-deacetylstylatulide lactone 565 and 4‚-acetoxy-9- deacetylstylatulide lactone 566, have been isolated from a Korean species of Briareum.397 In addition to known compounds previously isolated from Junceella species, four briarane diterpenoids, nuiinoalides A–D 567–570, were isolated from two unidentified gorgonians from Pohnpei.398 HO OH HO OR H HO OH HO HO HO OH HO HO R HO OH HO O R O COOH COOMe COOMe COOMe OH COOMe OH O O AcO H H H O O AcO H H H AcO O O AcO H H H RO O O AcO H H H HO O O AcO H H H HO O O HO OH H N SMe SMe HO SMe HO N SMe HO S N SMe NH N N N H2N NH2 571 R = H 572 R = Ac 573 574 575 R = 576 R = 577 R = 578 R = 6 583 R = ; D6,7 579 R = O 580 R = O O HO 582 R = 581 R = 22 HO 584 D22,23 585 OH O 22 OH 589 R = H;D22,23 590 R = H O OH HO OH 592 D1,2;4,5 593 D1,2 594 D4,5 595 1 4 588 O 591 O OH HO OH 600 601 602 603 OH HO H OH OH H OH 22 586 D22,23 587 O HO 596 597 599 598 Faulkner: Marine natural products 141Polyhydroxylated sterols are commonly found in coelenterates.The octocoral Telesto riisei contained cholestane- 3‚,5·,6‚,26-tetrol 571 and the corresponding 26-acetate 572.338 Sarcoaldesterols A 573 and B 574 are 3‚,5·,6‚, 12·-tetrahydroxysterols from an Okinawan soft coral of the genus Sarcophyton.399 Three 7·,8·-epoxy-3‚,5·,6·-trihydroxy sterols 575–577 were obtained from the Korean gorgonian Acabaria undulata and a fourth polyhydroxylated sterol 578 was isolated as its 3,6-diacetate derivative.400 Sterols 575–577 exhibited mild cytotoxicity while 576 and 578 inhibited phospholipase A2.400 Five new 3-keto steroids 579–583 of the cholic acid class and three previously-known steroids were isolated from the deep-water scleractinian coral Deltocyathus magnificus from the Loyalty Islands.401 Eight new sterols 584–591, two of which, 584 and 585, were cytotoxic, were isolated from the Okinawan soft coral Clavularia viridis and the structure of 587 was determined by an X-ray crystallographic analysis.402 The steroidal hemiacetals anastomosacetals A–D 592–595 were isolated from the Korean gorgonian Euplexaura anastomosans but were not responsible for the bioactivity of the crude extract.403 The cytotoxic component of the New Caledonian gorgonian Ctenocella sp.is a mixture of isomeric hemiacetals 596 that were identified by spectroscopic analysis of the 18‚-acetate.404 The stereochemistry of gerardiasterone 597, which is an ecdysone analog from the Mediterranean zoanthid Gerardia savaglia,405 was established by synthesis.406 Two steroidal glycosides 598 and 599 were isolated from Andaman and Nicobar Island specimens of Sinularia grandilobata and S.gibberosa, respectively.407, 408 The marine hydroid Tridentata marginata contained the unusual aromatic alkaloids tridentatols A–C 600–602, only one of which, tridentatol A 600, inhibited feeding by the planehead filefish.409 The structure of tridentatol C 602 was established by a single crystal X-ray diVraction study.409 Parazoanthoxanthin A 603, which is a fluorescent pigment from Parazoanthus sp.,410 has been synthesized by a route involving oxidative dimerization.411 8 Bryozoans The bryozoans have attracted only a very small following among marine natural product researchers, which is somewhat surprising considering the interesting structures that bryozoans produce.The structures of six halogenated indole alkaloids NH N Cl HN N Br O R N N HN N O O R Cl NH HN Cl HN N Br O R N HN Br Br MeO Me O N HN B r Br MeO Me O N R Me N Br Br MeO Me N HN Br Br MeO Me O NMe2 O NMe2 Br OMe OMe Br 604 R = H 605 R = Br 606 R = Br 607 R = H 608 R = H 609 R = Br 610 611 R = H 612 R = Me 613 614 N N Me Br 615 O O O O MeOOC O COOMe O OH OH O HO O O O O MeOOC O O OH OH O HO MeOOC O O O O MeOOC O O OH OH O HO OH MeOOC O O O O MeOOC O O OH OH O HO OH COOMe 616 618 617 619 142 Natural Product Reports, 1998from Securiflustra securifrons from the North Sea, securamines A–D 604–607 and securines A 608 and B 609, have been determined by interpretation of spectral data.Securines A 608 and B 609 are in equilibrium with securamines A 604 and B 605.412 Amathia convoluta from the North Carolina coast has yielded five aromatic alkaloids, volutamides A–E 610–614, several of which deter feeding by potential predators and are toxic toward the larvae of a cooccurring hydroid.413 The structure of flustramine C 615, which is a prenylated indole alkaloid from Flustra foliacea,414 has been confirmed by total synthesis.415 Bryostatin 1 from Bugula neritina is now in phase II clinical trials.Three additional antileukemic macrolides, bryostatins 16 616, 17 617 and 18 618, were isolated in trace quantities from B. neritina from the Gulf of Mexico.416 Some preliminary biosynthetic studies of the bryostatins have been reported417 and a conformational study of bryostatin 10 619 has established a well defined conformation in solution.418 9 Molluscs Studies of the sea hare Dolabella auricularia have yielded a number of cytotoxic metabolites but the dietary sources of these metabolites, if any, are unknown.The cytotoxic polypropionates auripyrones A 620 and B 621, which are similar in many respects to the polypropionates from Siphonaria species, were isolated as cytotoxic constituents of D. auricularia from Japan.419 Aurisides A 622 and B 623 are cytotoxic macrolide glycosides from the same specimens of D. auricularia.420 An enantioselective synthesis of aplyronine 624, which is a cytotoxic macrolide from Aplysia kurodai that inhibited polymerization of G-actin to F-actin,421 has been achieved using a convergent approach.422 The synthesis of dactylyne 625 and isodactylyne 626, which are metabolites of A.dactylomela, 423, 424 has been described in detail.425 A concise synthesis of dactylol 627, which was also isolated from A. dactylomela,426 has been reported.427 The structures of dolastatin H 628 and isodolastatin H 629, which are very minor but highly cytotoxic linear peptides from Dolabella auricularia, were elucidated by interpretation of spectroscopic data and confirmed by total synthesis.428 The cytotoxic cyclic depsipeptides dolastatin G 630 and nordolastatin G 631 were isolated from D.auricularia429 and were subsequently synthesized.430 Aurilide 632 is another cytotoxic cyclic depsipeptide from D. auricularia that contains a new lipid component.431 Philinopsis speciosa is a carnivorous cephalaspidean mollusc from which the cytotoxic cyclic peptide kulolide 633 was isolated.432 It is suggested that P.speciosa obtained the linear peptide pupukeamide 634 by consuming the sea hare Stylochilus longicauda, which had in turn been feeding on cyanobacteria such as Lyngbya majuscula.433 Five additional cyclic peptides, kahalalides A–E 58, 59, 635, 636 and 637 were isolated from the ascoglossan mollusc Elysia rufescens that eats the green alga Bryopsis sp. (see p. 4).81 Keenamide A 638 is a cytotoxic cyclic hexapeptide from the notaspidean mollusc Pleurobranchus forskalii, which is known to feed upon ascidians.434 The pulmonate mollusc Onchidium sp.from New Caledonia contains the cytotoxic cyclic depsipeptide onchidin B 639, the asymmetry of which is due to the diVerent chirality of the two proline residues, as shown by synthesis.435 Two prenyl chromanols 640 and 641 and the acid 642 have been isolated from the aeolid mollusc Cratena peregrina which O O O O OR O 620 R = COCH2CHMe2 621 R = COCH(Me)Et O O O Br O OH H O O MeO OMe O O MeO OH OMe O O O Br O OH H O O MeO OMe OCONH2 623 622 O OH OMe O O O O NMe2 O Me2N OMe OMe OH AcO N CHO Me 624 O Cl Br Et O Cl Br Br Br Et H OH 625 627 626 Me2N HN N N O O OMe O MeO COOR Me Ph OH OH Ph 629 R = 628 R = Faulkner: Marine natural products 143feeds on the hydroid Eudendrium racemosum.436 Studies of the antifouling substances from four nudibranchs, Phyllidia ocelata, P.varicosa, P. pustulosa and Phillidiopsis krempfi, led to the isolation of three new sesquiterpene isonitriles, 10- epi-axisonitrile-3 643, 10-isocyano-4-cadinene 644 and 2- isocyanotrachyopsane 645, as well as the peroxide, 1,7- epidioxy-5-cadinene 646, and several known sesquiterpene isonitriles.437 Nanaimoal 647 but not acanthodoral 648, both of which are sesquiterpenes from the nudibranch Acanthodoris nanaimoensis,438 was synthesized by a cationic cyclization route.439 Seven cytotoxic spongian diterpenoids, dorisenones A–D 649–652, 7·-hydroxyspongian-16-one 653, 15· ,16·- diacetoxy-11,12‚-epoxyspongian 654, and 7·-acetoxydendrillol- 3 655, were isolated from the Japanese nudibranch Chromodoris obsoleta.440 As part of a study of the defensive role of diterpenes produced by marine pulmonate molluscs of the genus Trimusculus, a polyacetylated sterol 656 and an additional diterpene 657 were isolated from the New Zealand pulmonate T.conica.441 Four new labdane diterpenoids 658– 661 were isolated from T.peruvianus from Chile.442 The structure of 6‚-isovaleroxylabda-8,13-diene-7·,15-diol 662, a defensive metabolite of T. reticulatus,441, 443 was confirmed N Me O N Me N N Me N O O N O O O O O MeO OMe O O OH Me N Me O N Me N N Me N O O N O O O O O MeO O O O OH Me O O OH O HN O O N N NH Me O Me O N O O Me 630 631 632 O O HN O N O O HN O O N O Me HN O Ph C3H7 N HN N O Me O O O N Me COOH Me OMe O NH O O HN HN HN O HN O Ph HN O O NH NH2 NH OH OH N NH HN O HN O O NH O O N S O N O O N O N O O O O O O N O O O O O O O 638 634 635 639 C3H7 O 633 NH NH O O HN O N O O NH NH O O O NH 637 O HN N O O HN O O HN NH2 NH NH 636 144 Natural Product Reports, 1998by total synthesis.444 The diterpene glyceride 663, which was isolated from Archidoris montereyensis,445 has been synthesized from sclareol.446 An additional polypropionate, tridachiahydropyrone 664, has been isolated from a Venezuelan collection of the ascoglossan mollusc Tridachia crispata.447 Dolabriferol 665 is the first polypropionate to be reported from a Cuban collection of the anaspidean mollusc Dolabrifera dolabrifera.448 (")- Denticulatins A 666 and B 667, which are isomeric polypropionates from the pulmonate mollusc Siphonaria denticulata,449 have been synthesized in relatively high overall yields.450 The stereoselective synthesis of (+)-siphonienone 668, which is a metabolite of S.grisea,451 was accomplished using asymmetric alkylation controlled by a chiral auxiliary.452 The stereochemistry proposed for vallartanone B from S.maura453 has been revised from 669 to 670 as the result of a stereoselective synthesis.454, 455 The cephalaspidean mollusc Smaragdinella calyculata from Hawaii contained a cytotoxic polypropionate of unknown stereochemistry, nalodionol 671, and an amino alkyl pyridine, naloamine 672.456 649 R1 = OAc; R2 = OH 650 R1 = H; R2 = OH 652 R1 = OAc; R2 = H 651 653 655 654 OH COOH CN H NC H CN O O CHO CHO H 640 R = H 641 R = OMe 642 643 647 645 644 646 648 O HO R O R1 AcO O O OAc AcO O O OH H H R2 O OAc H H O OAc OAc COOMe O O AcO HO OAc AcO AcO OR1 R2 OR3 OH O OH O H O H OH O OH H 656 658 R1 = H; R2 = OAc; R3 = Ac 659 R1 = R3 = Ac; R2 = OAc 660 R1 = Ac; R2 = OAc; R3 = H 661 R1 = Ac; R2 = R3 = H 662 663 O O COOH OAc 657 O MeO O O O OH Et O O OH N NH2 O O OH HO Cl OH HN R O H H Et O O Et R O O R O O OH OH O 664 665 672 671 673 R = OH 674 R = NHCH2CH2SO3H O 666 R = a-Me 667 R = b-Me 669 R = b-Me 670 R = a-Me 668 Faulkner: Marine natural products 145Two cytosolic phospholipase A2 inhibitors, pinnaic acid 673 and tauropinnaic acid 674, were isolated from the Okinawan bivalve Pinna muricata (pen shell) and their structures and stereochemistry at all but one center were elucidated by interpretation of spectroscopic data.457 The relative stereochemistry of pinnatoxin A 675, a potent shell- fish toxin from P.muricata,458 has been determined and a new toxin, pinnatoxin D 676, has been described.459, 460 Spirolides E 677 and F 678 are biologically inactive metabolites from the mussel Mytilus edulis and the scallop Placopecten magellanicus that have helped to define the pharmacophore of the spirolides.461 The relative and absolute stereochemistry of yessotoxin 679, which is a toxin from the Japanese scallop Patinopecten yessoensis that causes diarrhetic shellfish poisoning, have been determined and the structures of two new analogues, 45-hydroxyyessotoxin 680 and 45,46,47-trinoryessotoxin 681, have been elucidated.462, 463 O O O O HN O COO– OH HO O O O O HN O HO O COO– OH H H O O HO O OH O O O H2N O O O O O O O O O O O R NaO3SO NaO3SO H H H H H H H H H H H H H H H H H H HO OH OH + 675 676 677 D2,3 678 2 679 R = 680 R = 681 R = + O Ph O O HO OH OH O R O OMe O HO NaO3SO OSO3Na O O HO NaO3SO OSO3Na O NHCOOMe HO O MeSSS O O O O HO HN OMe O MeS O MeS OH HO N H RO C6H13 NH OH NH2 NH OH NH2 NH OH NH2 N NR HO OMe Me H S O O NH2 OAc Me MeO OH OH N N HO OMe Me H S O O O OAc Me OH O O N N HO OMe Me H S O O O OAc Me MeO OH OH Me Me N N Me OMe HO AcO Me H OH NH S O O O O HO MeO Me 683 R = OH 684 R = H 685 R = OCOC21H43 686 R = OCOC19H39 682 687 688 R = Ac 689 R = H 690 691 692 693 R = Me 694 R = H 695 696 697 146 Natural Product Reports, 199810 Tunicates (ascidians) The in vitro anti-HIV activity of Didemnum molle from Pohnpei is associated with the sulfated mannose polysaccharide kakelokelose 682.464 A Didemnum sp.from Western Australia contained the well-known microbial metabolite enterocin 683, as well as 5-deoxyenterocin 684, enterocin-5- behenate 685 and enterocin-5-arachidate 686.465 In what is probably the most unexpected discovery of 1996, an enediyne antitumour antibiotic, namenamicin 687, was isolated from Polysyncraton lithostrotum from Fiji.466 The absolute stereochemistries of clavepictines A 688 and B 689, which are cytotoxic alkaloids from Clavelina picta,467 have been determined by total synthesis.468 The structure and stereochemistry of pseudodistomin C 690, which is a piperidine alkaloid from the Okinawan tunicate Pseudodistoma kanoko,469 have been confirmed by a synthesis from D-serine.470 It is becoming diYcult to follow the literature regarding the structural revisions for pseudistomins A and B, which are also from P. kanoko.471 As a result of synthetic studies, the structures of pseudistomins A and B were proposed to be 691 and 692, respectively,472 but these proposals still need to be confirmed because other authors have suggested the reverse assignments. 470 Ecteinascidins 597 693, 583 694, 594 695 and 596 696 are putative biosynthetic precursors of the ecteinascidins described previously473, 474 from Ecteinascidia turbinata from the Caribbean.475 An elegant enantioselective synthesis of ecteinascidin 743 697, which is now in phase 1 clinical trials as an anticancer agent, was communicated.476 The cytotoxic dimeric disulfide alkaloid, polycarpine 698, the corresponding dihydrochloride, and three related monomers 699–701 were isolated from Polycarpa clavata from Western Australia.477 The same alkaloid, polycarpine 698, was isolated together with the monomers 699 and 702 and N,Ndidesmethylgrossularine- 1 703 from P.aurata from Chuuk.478 The 13C NMR assignments for grossularines-1 704 and -2 705, which are alkaloids from Dendrodoa grossularia from Brittany,479 have been revised.480 An additional synthesis of rigidin 706, which is an alkaloid from Eudistoma cf.rigida,481 has been reported.482 The structure of 5,6-dihydrolamellarin H 707 from a Didemnum sp. was elucidated as a demonstration of the 1,1-ADEQUATE NMR experiment.483 Lamellarin-S 708 is an aromatic alkaloid from a south-eastern Australian tunicate of the genus Didemnum.484 A Western Australian Eudistoma sp. contained 19-bromoisoeudistomin U 709 in addition to isoeoudistomin U 710, which had been incorrectly NH N O X Me R MeO N N S S N N MeO OMe Me NH2 Me H2N NH N NH N O NH NR2 MeO O S NHMe NH N HN NH NH O NH N O OH OH NMe2 OH O O 699 R = OMe; X = S 700 R = OH; X = S 701 R = OMe; X = O 703 R = H 704 R = Me 698 702 705 706 O N HO HO O OH RO HO HO NH N NH R NH N Ph O R NH H N NH2 O COOH NH HO NH H N NH2 O COOH NH NH NH R O COOH NH Br NH HN NH H NH N H N NH2 NH HN NH N O O S N HN NH HN O O Ph S N Ph Ph 707 R = H 708 R = Me HN NH HN O O Ph Ph S N 709 R = Br 710 R = H 711 R = H 712 R = Br Ph 717 R = 715 R = 716 R = 713 714 718 719 720 Faulkner: Marine natural products 147identified earlier.485 Two related metabolites, eudistomins S 711 and T 712 from E.olivaceum486 have been synthesized.487 Five unusual amino acid derivatives 713–717 were isolated from the cytotoxic extracts of Leptoclinides dubius but no bioactivity data was presented for the pure compounds.488 The mildly cytotoxic linear peptides, virenamides A–C 718– 720, were isolated from Diplosoma virens from the Great Barrier Reef.489 A specimen of Lissoclinum patella from the Fiji contained the cyclic peptides, patellins 1–5 721–725, while a Lissoclinum sp.from the Great Barrier Reef yielded patellins 3 723, 5 725 and 6 726 and trunkamide A 727, all of which were identified by interpretation of spectroscopic data and by use of Marfey’s method to determine the absolute O N O O HN NH O NH O NH O O S N O HN O O HN N O NH O NH O O S N N S HN NH NH N N O O O NH O NH O O O O O N S HN NH NH N N O O O NH O NH O O O O O N S HN NH NH N N O O O NH O NH O O O Ph O O N S HN NH NH N N O O O NH O NH O O Ph O O O N S NH N HN O O HN O NH NH O O O O O Ph N O NH N O 723 725 NH N S NH O Ph O O S N 721 722 724 NH N S O N O HN O N S NH O N Ph O 726 727 Ph 729 728 O HO O HO O Cl Cl OH NH OH O O H N N O O O O OH HO OH O HO H H H H H H H H 733 730 732 731 OH N N N NH2 R O Me HO OH N N N N O Me RO Me Et Me Me HOOC 734 R = H 735 R = Br 736 R = various acyl groups Ni 148 Natural Product Reports, 1998N N OH HO NH HN O O O O O C7H15 O HN OH R OH O OH OH HO HO O O HN R OH O OH OH HO HO (CH2) nCHMe2 OH HO O O HN R1 OH O OH OH HO HO R2 OH HO HO OH HO OH OSO3Na OH OH HO OH HO OH OSO3Na OH OH OH HOOC C11H23 737 741 R = C20H41; n = 10 742 R = C22H45; n = 11 738 R = C20H41 739 R = C21H43 740 R = C22H45 743 R1 = C20H41; R2 = C12H25 744 R1 = C20H41; R2 = (CH2)10CHMe2 745 R1 = C22H45; R2 = (CH2)11CHMe2 747 748 746 NaSO3O H OSO3Na HO HO NaO3SO OH OH OH OH HO 749 750 HO OH R OH HO OH R OH OH OH OH OH OH OH OH OH OH a 25 S b 25 R c e d 751 R = a 752 R = b 753 R = c 754 R = d 755 R = e 756 R = a 757 R = b 758 R = c 759 R = d HO O OH OH OH HO OH OH OH OH NaO3SO OH O OH 762 761 763 764 HO OH OH OH OH OH HO OH OH OH OH OH 760 Faulkner: Marine natural products 149stereochemistry of the constituent amino acids.490 The stereochemistry of lissoclinamide 7 728, which is a cytotoxic cyclic peptide from a Great Barrier Reef specimen of L.patella,491 has been determined by a synthesis that used the Burgess reagent to form the oxazoline and thiazoline rings without scrambling adjacent chiral centers.492 Total synthesis of the proposed structure of cyclodidemnamide 729, which was isolated from a Philippines specimen of Didemnum molle,493 gave a product that did not have identical spectral data to those of the natural product, which is now thought to be a stereoisomer.494 Two chromenols 730 and 731 were obtained from Aplidium solidum from southern Australia and the absolute stereochemistry of 730 was determined by chemical degradation.495 The absolute configuration of dichlorolissoclimide 732, which is a cytotoxic diterpene from Lissoclinum voeltzkowi,496 was determined by single crystal X-ray diVraction analysis.497 The orientation of the steroidal units in ritterazine A 733, which is a cytotoxic metabolite of Ritterella tokioka,498 was determined using 15NHMBC spectroscopy.499 The nucleosides 5*-deoxytubercidin 734 and 5*-deoxy-3- bromotubercidin 735 were isolated together with two known HO OH R OH OH OH O O OMe HO OH O O O OH OH O HO MeO OMe O O HO OH R1 OH O O OMe HO OR1 O O O OH R1 O HO HO OMe OH O O HO OH OH HO HO OSO3Na OH OH OH O O OMe OH HO OSO3Na OH OH OH O O OH O HO MeO OMe OH OH OH OH O NaO3SO R O O O O O Me HO HO OH HO O Me HO Me HO O O O O OH HO HO OH OH HO O O Me OH HO OH O O O OH OH OH NaO3SO O O O O O Me HO HO OH HO O Me HO Me HO O O OH 777 R1 O O OH R2 HO O OH HO HO Me a b c d e R3 f 765 R = a; 25 S 766 R = a; 25 R 767 R = b; 25 S 768 R = b; 25 R 769 R = c; R1 = H 770 R = c; R1 = CH2OH 771 R = d; R1 = SO3Na 772 R = d; R1 = H 773 R = e; R1 = CH2OH 774 R = e; R1 = H 775 R = f 776 781 R1 = R2 = OH; R3 = H 782 R1 = R2 = H; R3 = OH 779 R = 780 R = 778 R = 150 Natural Product Reports, 1998R NaO3SO O O OH OSO3Na OH H OH OH NaO3SO O O OH OSO3Na OH H O O NaO3SO O O OH OSO3Na OH H O O O COONa HO HO OH OH H R1 R2 OSO3Na HO O O COONa HO HO OH OSO3Na R O R1 R2 OH R O 783 R = 784 R = 785 786 787 R1 = Me; R2 = H 788 R1 = H; R2 = Me 789 R = a; R1 = R2 = H 790 R = a; R1 = H; R2 = Me 791 R = a; R1 = OH; R2 = Me 792 R = b; R = H 793 R = b; R = Me a b O O COONa HO HO OH OSO3Na OH O O HO HO OMe OH OH OH OH OH 796 D9,11 797 798 O O COONa HO HO O OSO3Na O R O OH OH OH 794 R = H 795 R = Me O O HO OH O O O HO O OAc R1 R2 O O O HO HO OH Me OH NaO3SO O O O HO OH OH Me HO HO 799 800 801 R1 = R2 = O 802 R1 = O; R2 = b-OH, a-H 803 R1 = R2 = b-OH, a-H Faulkner: Marine natural products 151tubercidin analogues from Didemnum voeltzkowi from the Philippines.500 A series of acyl tunichlorins 736, which represent a new class of nickel chlorins, have been isolated from Trididemnum solidum from the Caribbean.501 11 Echinoderms Once again the majority of secondary metabolites reported from echinoderms are saponins or polyhydroxylated sterols, but there are some interesting exceptions.An unusual dimeric dipeptide 737 was isolated from the seastar Pentaceraster regulus from India and was identified by interpretation of spectral data.502 Eight cerebrosides 738–745 of three molecular classes were obtained from a Japanese specimen of the seastar Stellaster equestris.503 The Caribbean sea cucumber Holothuria mexicana contains (6Z)-7-methyloctadec-6-enoic acid 746 among the fatty acids that are found in the phospholipid fraction.504 Two additional polyhydroxysteroidal sulfates, (22E,24R, 25R)-24-ethyl-5·-cholest-22-en-3‚,5,6‚,8,15·,25,26-heptol 26- sulfate 747 and (24R,25R)-24-ethyl-5·-cholestane-3‚,5,6‚,15·, 16‚,25,26-heptol 26-sulfate 748, were isolated from the deep water seastar Styracaster caroli from New Caledonia and the stereochemistry of their side chains was determined by synthesis of model compounds and comparison of spectral data.505 The ophiuroid Ophioplocus januarii from Argentina contained one new antiviral steroidal sulfate, (22E)-24-nor-5‚- cholest-22-en-3·,4·,11‚,21-tetrol 3,21-disulfate 749, together with three known ophiuroid metabolites.506 One new polyhydroxysteroidal sulfate, 5·-cholestane-3‚,5,6‚,15·,16‚,26- hexol 3-sulfate 750, and four known metabolites were isolated from the seastars Luidia quinaria and Distolasterias elegans from the Sea of Okhotsk.507 Studies of an Antarctic seastar of the family Echinasteridae resulted in the isolation of fourteen polyhydroxylated sterols 751–764, one of which 764 was sulfated, thirteen polyhydroxylated steroidal oligoglycosides, antarctinosides D–M 765–777, and five new asterosaponins, antacticosides A 778, B 779 and C 780, 24- methylbrasiliensoside 781, and 24-methylpectinioside A 782, some of which showed moderate cytotoxicity.508, 509 The Japanese seastar Asteropecten latespinosus produced four steroidal glycoside disulfates, latespinosides A–D 783–786, two of which, 785 and 786, showed weak cytotoxicity, that diVer only in the composition of the steroidal side chain.510 In addition to nine known glycosides, eleven new steroidal glycosides, downeysides A–L 787–797 and desulfated 26- norechinasteroside A 798, were isolated from Henricia downeyae from the northern Gulf of Mexico and their structures were elucidated by interpretation of spectral data.511 One new triterpene glycoside 799 has been isolated together with several known metabolites from an Indian specimen of the sea cucumber Holothuria atra.512 Neothyoside B 800 is an antifungal triterpene diglycoside from the Gulf of California holothurian Neothyone gibbosa.513 Cucumariaxanthins A–C 801–803 are unusual di-(Z)-carotenoids from the sea cucumber Cucumaria japonica.514 12 Miscellaneous The structure of (S)-2-methyl-1,5-bis(1,3-dimethyllumazin-6- yl)penta-1,5-dione 804, which is an additional dimeric luminescent pigment from the Japanese polychaete worm Odontosyllis undecimdonta, was confirmed by total synthesis.515 The first report of marine natural products from brachiopods described the isolation of four long-chained glycerol ethers 805–808 from Gryphus vitreus.516 Scaritoxin or ciguatoxin-4A 809 is a new ciguatoxin precursor that was isolated from the parrotfish Scarus gibbus and from cultures of the dinoflagellate Gambierdiscus toxicus.517 13 References 1 D.J. 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ISSN:0265-0568    

DOI:10.1039/a815113y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Mycosporines: are they nature’s sunscreens? Wickramasinghe M. Bandaranayake* Australian Institute of Marine Science, Cape Ferguson, PMB No. 3, Townsville, M.C., Queensland, 4810, Australia Covering: 1960 to 1997 1 Introduction 2 Distribution 3 Structures of mycosporines and MAAs 4 Isolation and identification 5 Properties of mycosporines and MAAs 6 Biosynthesis of mycosporines and MAAs 7 Synthesis of mycosporines, MAAs and analogues 8 The role of mycosporines and MAAs in nature 8.1 Role of mycosporines in fungi 8.2 Role of MAAs in marine organisms 8.3 Role of related compounds 9 Development of a commercial sunscreen 10 Conclusion 11 References 1.Introduction Light decisively aVects the life of fungi, and is an absolute requirement for the formation of their reproductive organs.1 Ultraviolet (UV) light has been shown to induce sporulation in a number of fungi, with the formation of substances that absorb specifically at 240 and 310 nm.1–5 These substances were absent in non-sporulating colonies grown in the dark.The majority of these compounds have UV absorption maxima at 310 nm and are conventionally called ‘P310’.4–8 They were first isolated from the fungus Ascochyta pisi.4,5 However, in investigations of marine organisms, Wittenberg in 19609 noted the presence of a strong UV absorbance at 305 nm in the extracts of the gas glands of the coelenterate, the Portuguese man-of-war Physalia physalis, and the substance responsible was isolated from the floats and ampullae of the organism.A molecular weight of approximately 1200 was assigned to the metabolite and reported to contain ‚-alanine, p-aminobutyric acid and probably tryptophan.10 In 1968, Bon et al.11 demonstrated the existence in lenses of fishes, amphibians and cephalopods of components characterised by their strong absorbance in the region 320–360 nm, while Shibata in 196912 observed that some corals contain chemicals (S320) that were transparent to visible light but had similar broad UV absorption maxima in the region of 320 nm.The exact UV maxima of these compounds varied amongst the samples from 315–323 nm, suggesting the presence of a group of spectrally similar compounds. Since 1965, many examples of compounds with high UV absorbance have been isolated and characterised. This review describes the physio-chemical properties, distribution, and role played by this unique class of metabolites among both terrestrial and marine sources and their potential use to man. 2 Distribution There seem to be few major taxonomic boundaries to the presence of these UV-absorbing metabolites.13 They appear widespread among the fungal classes Zygomycetes,5 Deuteromycetes,1,4,5,14–21 Ascomycetes,4,5,22–26 and Basidiomycetes, 1,5,7,18,27–32 Bacillariophyta33,34 and Aphyllophorales33 but absent in Agaricales,24,35 and in the only protozoan investigated.33 These metabolites are also found on the surfaces of apples exposed to solar radiation36–38 and have now been isolated from a broad array of marine species ranging from a marine heterotrophic bacterium,39 cyanobacteria (bluegreen algae, prokaryotes),12,13,33,40–45 all of the major divisions of marine algae,13,33,46–66 tissues of an arthropod13 and other invertebrates with,13,32,67–74 or without,10,32,75–80 symbionts.Such symbionts include dinoflagellate algae (zooxanthellae, eukaryotes) in association with scleractinian corals13,33,81–85 and anemones,33,51,86–93 cyanobacteria in association with sponges13,33,94 and ascidians,95 vertebrates,33,96 the ovaries and eggs of sea urchins,97,98 embryos of shrimp,99 starfish100 and fish,96,101 lens tissues of fish102 and in the mucus covering the external surfaces of samples of Fungiidae103 and other marine organisms.104 They have not been detected in members of the genus Ctenophora and certain holothurians.33 Mycosporinelike amino acids (MAAs) range from temperate and tropical latitudes to the frozen oceans of Antarctica.12,13,33,84,105–107 3 Structures of mycosporines and MAAs These UV absorbing compounds contain one of two cyclic units; an aminocyclohexenone or an aminocyclohexenimine (Figs. 1 and 2). Fungal metabolites with UV absorption at 310 or 320 nm, possess exclusively the aminocyclohexenone ring system and are collectively referred to by the generic name mycosporines (sometimes spelled as mycosporins), a name that reflects their origin.Mycosporines can be considered to be SchiV bases (enamino ketones), which possess a common cyclohexenone (C6–C1) ring system linked with an amino acid or an amino alcohol. Two chromophores have been described, diVerentiating mycosporines (2-OMe, UV Îmax at 310 nm) from nor-mycosporines (2-OH, UV Îmax 320 nm).5,26,108 Within both groups, the structures vary according to the amino moiety. In fungal mycosporines, with the exception of mycosporine-alanine isolated from the conidial mucilage of Colletotrichum graminicola,109 the only amino acids involved are serine, and its corresponding ·-amino alcohol serinol, and the related pairs glutamine–glutaminol and glutamic acid– glutamicol.5 The first chemical structure of this class of metabolite, mycosporine-1 (mycosporine serinol) 1, isolated from the carpophores of Basidiomycetes Stereum hirutum, was elucidated in 197627,29 and is characterised by a cyclohexenone ring bound to a reduced serine moiety.Mycosporine-2 4,10 from Botrytis cinera16 possesses a derivative of glutamic acid and appears to be the most widespread among fungi and exists in the open chain 4 and ring forms 10. Mycosporine-2 occurs in vivo mainly as the glycoside 11 and predominantly in the ring form, and the mycosporine-glycosides so far are reported only from fungi.5,20,26,108,110,111 Nor-mycosporine-glutamine 13,5,20,26,108,110,111 the only nor-mycosporine, is reported as the major UV absorbing substance in the fungus Pyronema omphalodes.In contrast, and with only two exceptions, UV absorbing metabolites of marine organisms and algae are imine derivatives of mycosporines (enamino imines) which contain aminocyclohexenimine ring systems, with UV absorption maxima between 310 and 360 nm and these compounds have become known as mycosporine-like amino acids (MAAs). Glycine is the most common amino acid present in all MAAs. *E-mail: banda@aims.gov.au Bandaranayake: Mycosporines: are they nature’s sunscreens? 159An exception to this is the imino-MAA, mycosporinemethylamine- threonine 30, isolated from the reef building corals Pocillopora damicornis and Stylophora pistillata, where glycine has been replaced by methylamine.112 Other exceptions include the two mycosporine sulfate esters 31 and 32, characterised from the coral Stylophora pistillata,85 where glycine is replaced by threonine and serine, respectively, and the sea anemone Anthopleura eleggantissima which contains mycosporine-taurine 15.113 Mycosporine-glycine (mycosporine-Gly) 14, the first MAA to be characterised,72 and mycosporine-taurine 15,113 (both with Îmax 310 nm) are the only known aminocyclohexenone MAAs from marine sources.Usujirene 22 is an algal iminomycosporine.51,55,59 Substitution with diVerent amino acids and alcohols or other amino functionalities at C-3 of mycosporine-Gly determines the specific absorption maximum of each imino-MAAs which range from 320–360 nm.To date, 17 diVerent aminocyclohexenimines and 15 aminocyclohexenones have been identified from marine and terrestrial organisms (Figs. 1 and 2). Fig. 1 Fungal mycosporines OMe O HO OH NH R OMe NR HO OH NH COOH 14 mycosporine-Gly R = CH2COOH lmax 310 nm e 28800 (Refs. 13,33,51,71,72,76,77,80–82,93,95,96,100,247,250) 15 mycosporine-taurine R = CH2CH2SO3H lmax 310 nm (Ref. 113) 16 palythine R = H lmax 320 nm e 36200 (Refs. 13,33,51,53,72,74,76,78,80–82,93,96,100,102,106,115,250) 17 palythinol R = CH(Me)CH2OH lmax 332 nm e 43500 (Refs. 13,33,72,73,77,80–83,102) 18 asterina R = CH2CH2OH 330 lmax 330 nm e 43800 (Refs. 13,33,51,55,74,75,80,93,96,99,102,100,115) 19 shinorine (mytilin A) R = CH(COOH)CH2OH lmax 334 nm (Refs. 13,33,46,51,55,74,76,77,80,97,113) OMe NR HO OH NHMe NH2 OMe NH HO –O3SO OH Me COOH HO –O3SO OMe NH NH2 OH COOH H 30 R = CH(COOH)CH(Me)OH mycosporine-methylamine-Thr lmax 330 nm e 33000 (Ref. 112) 32 palythine-Ser-sulfate lmax 320 nm (Ref. 85) 31 palythine-Thr-sulfate lmax 320 nm (Ref. 85) + + Fig. 2 Mycosporine-like amino acids (MAAs) from marine organisms and algae 160 Natural Product Reports, 1998UV inducible substances with Îmax 312 and 335 nm have been described covalently linked to oligosaccharides in the terrestrial cyanobacterium Nostoc commune.42,114 Although the precise chemical nature of these water soluble pigments is as yet unknown, these compounds are reminiscent of MAAs in their physio-chemical traits.Spectrally similar water soluble compounds have also been isolated from another strain of cyanobacteria. Mycosporine-like amino acids, when present in marine invertebrates having symbiotic algae (e.g. Pacific staghorn coral Acropora formosa and the giant clam Tridachna formosa) are freely diVusible (i.e. soluble but not associated with any protein species) whereas, in invertebrates without symbiotic algae (e.g. Crown-of-Thorns starfish, Acanthaster planci and teleostean fish) the MAAs are protein ‘associated’.In these invertebrates, protein associated MAAs are concentrated on the outer epidermal tissues, and in the case of teleostean fish, in the eye lens as well.102 Asterina 330 1876 and gadusol 33 (3,5,6-trihydroxy-5-hydroxymethyl-2- methoxycyclohex-2-en-1-one),13,98–101 structurally related to MAAs, exist in association with soluble proteins in fish lenses. The major component of the highly unstable complexes with absorption Îmax 330 when dissociated, yielded asterina 330 (Îmax 330) and a protein of MW 80–100 kDa (Îmax 280 nm).The second, relatively ‘stable’ minor complex of Îmax 323 nm, under similar conditions, yielded gadusol (Îmax 268) and a protein of MW 20–30 kDa (Îmax 280 nm).115 The molecular weights of these two proteins are characteristic of ‚- and „-crystallins, respectively, which are two of the three major soluble crystallin proteins present in fish lenses.116,117 The association of gadusol with „-crystallin is similar in nature to the visual pigment rhodopsin (Îmax 498), a SchiV base which contains 11-cis-retinal (Îmax 382) as the prosthetic group and a lipoprotein opsin (Îmax 280 nm).118 The compound with UV absorption at 310 nm isolated from Physalia physalis, has been found to be a mixture, and the major component has now been characterised as mycosporine-Gly 14 (Îmax 310 nm).119 The UV-absorbing compounds from marine fish eye lens tissues have been found to be a mixture of iminomycosporines, palythine 16, palythinol 17, asterina 330 18 and palythene 21.102 The ‘S320’ compounds from Acropora spp.and Pocillopora spp. are a mixture of mycosporine-Gly 14, palythine 16 and palythinol 17.81 The structure elucidation of these compounds has been variously achieved by chemical degradation and spectroscopic techniques. Ring 13C NMR shifts previously reported as interchangeable between C-1–C-6 and C-3–C-4 have now been assigned.112 The crystal and molecular structures and the absolute configuration of palythine 16,73,74 the most abundant aminocyclohexinimine MAA, and that of palythene 21120 have been unambiguously determined.121,122 These two metabolites are represented as resonance hybrids between two canonical forms, and X-ray analysis suggests that positive and negative charges in the inner salt prefer to exist at close sites.Palythine, for example, exists as a zwitterion in the crystal which is stabilised by resonance between the two nearly equivalent structures 34 and 35 and the actual structure is visualised as a resonance hybrid of the stable vinylogues of amidine 36.Supportive evidence for this postulate is provided by the IR spectra of palythinol, palythene and palythine. In addition, it can be deduced from the NMR spectral data that delocalisation of the positive charges on C-1 and C-3 is more eVective in palythine hydrochloride and its methyl ester than in palythine itself and conversion of the carboxylate to carboxylic acid or its methyl ester causes remarkable delocalisation of the positive charges.The X-ray structure indicates that palythine and water molecules are connected by 12 types of hydrogen bonds, forming a 3-dimensional hydrogen bonded structure. In mass spectrometry, the highest mass of most natural mycosporines and MMAs corresponds to the dehydration of molecular ions and the MH ion of the dehydrated product.24,79,110 4 Isolation and identification Chromatographic techniques involving gel permeation,48,71,73, 84,109,115,120 ion exchange resins,13,20,32,46,48,50,71,73,76,77,81,84,93, 94,96–100,119–124, norite A,48 carbon46,124 and cellulose101 columns, and preparative TLC on silica gel120 have all been used in diVerent combinations in the purification of aqueous methanolic or ethanolic extracts of fresh or freeze dried samples.Purification on Dowex 50W is the most convenient method and gives the best results.94,96,100,119 Elution with H2O, EtOH, dilute HCl and various buVers yielded mycosporines and MAAs as oils, amorphous powders or crystals.However, preparative reverse-phase isocratic high-performance liquid chromatography (HPLC)5,13,27–29,85,112 with UV detection appears to be the most popular method employed in the separation and quantification of these metabolites. Water containing approximately 0.1% acetic acid is used as the mobile phase to separate less polar compounds, while this mobile phase containing methanol is used for more polar components.13 In the HPLC analysis, known mycosporines and MAAs have been identified by cochromatography with authentic standards and/or comparison with published UV spectral data and HPLC retention times.33,81,93,97,101,102 Such characterisation of these metabolites should be treated with caution.94 Thus, mycosporine-glutamic acid-glycine (mycosporine-Glu-Gly) 24, identified from the sponge Dysidea herbacea and the mycosporine, asterina-33076 18, obtained from eye lens tissues of coral trout Plectropomus leopardus, displayed identical UV absorption maxima, similar extinction coeYcients and identical retention times on HPLC in two diVerent solvent systems.Hence, agreement of these parameters may not necessarily establish the identity of the mycosporine. The chemical structures of unknown MAAs were determined by HPLC fractionation, alkaline hydrolysis and identification of the hydrolysed amino acid or amino functionality by derivatisation with phthalaldehyde.123 It has often been assumed that an unknown and a known MAA possess the same chromophore and ring substituents based on UV measurements.This assumption may at times be misleading. For example, palythine-Thr-sulfate 31, palythine- Ser-sulfate 32 and palythine 16 have identical UV absorption maxima (320 nm), yet they diVer in having diVerent functionalities at the stereogenic centre of the ring.74,85 OH O HO HO HO OMe 33 NHCH2COO– OMe NH2 HO HO NHCH2COO– OMe NH2 HO HO NHCH2COO– OMe NH2 HO HO + + + 34 35 36 Bandaranayake: Mycosporines: are they nature’s sunscreens? 1615 Properties of mycosporines and MAAs Mycosporines, N-substituted amino acid derivatives of 6-deoxygadusol 37, (3,5-dihydroxy-5-hydroxymethyl-2-methoxycyclohex- 2-en-1-one) and MAAs (iminomycosporines) are hydrophilic, optically active and highly unstable substances.Once extracted from their cytosolic origins, they undergo dehydration and aromatisation, as well as hydrolysis.Some of these unstable MAAs could be converted to more stable methyl esters or acetates.71,73,120 Methylation with CH2N2 and acetylation with acetic anhydride in pyridine invariably led to the production of aromatised methyl esters or acetates, respectively.72,73,79 In some instances esterification with methanolic HCl resulted in the expected methyl ester.74 Some mycosporines are remarkably susceptible to hydrolysis.When heated with water, mycosporine-Gly, for example, gave glycine and the ‚-diketone, 6-deoxygadusol 37,72,73 the proposed biosynthetic precursor of the mycosporine ring system. Hydrolysis with alkali under varying reaction conditions yielded the amino acid or amine subunit and diVerent cyclohexenone derivatives or aminophenols.74,124,125 Palythine for example, when treated with ammonium hydroxide at room temperature aVorded glycine and compounds 38, 39 and 40.74 Free amino acids were released from MAAs by treatment with bromine, water or with horseradish peroxidase acting as an iodide peroxidase.99 Under aerobic conditions and in the presence of photosensitisers such as flavin and DABCO (1,4- diazabicyclo[2.2.2]octane), light causes the photolysis of mycosporines.126 Thus, this temperature dependent reaction yielded the aminocyclohexenone and 2-hydroxyglutaric acid 41 from mycosporine-glutamine 8.126 6 Biosynthesis of mycosporines and MAAs Although the biogenesis of mycosporines and MAAs is unproven, reasonable hypotheses73,127 are illustrated in Scheme 1.It has been demonstrated that the basic unit, a ‚-diketone, originated from the first step of the shikimate pathway.128 In the deuteromycete Trichothecium roseum, the production level of mycosporine-glutaminol 6 was improved when glucose was substituted by quinic acid in the culture medium. Data from the incorporation of [1-14C]acetic acid, [1-14C]glyceric acid and [U-14C]-3-dehydroquinic acid (3-DHQ) 42 are in good agreement with the hypothesis that 3-dehydroquinic acid, a metabolite of the shikimate pathway, acts as the precursor for the C6–C1 unit of fungal mycosporines.127 It is also the precursor of acetate via the ketoadipate pathway (Scheme 1) which can be incorporated into the amino acid derived unit.Thus, a reasonable intermediate for the production of mycosporines and MAAs could include 3-dehydroquinic acid 42.A probable relationship between mycosporine and nor-mycosporine could be expected, and it is tempting to imagine a relationship between normycosporine and 5-dehydroquinic acid. The occurrence in fungi of an association between a shikimic pathway product and glutamine residue is already known.129,130 Subsequent biological transformations would involve the incorporation of the amino acid unit, followed by oxidation, reduction and methylation (Schemes 1 and 2). Introduction of a second nitrogen-containing functionality into an enamino-type compound may proceed through activated intermediates such as 43 and 44.73 For example, compound 48 was obtained in vitro from dimedone 45 in three steps through 47.131 This reaction sequence was in fact used to synthesise analogous iminomycosporines. 131 The biogenetic interrelationships of some MAAs are illustrated in Scheme 2.73 The shikimic acid biogenetic pathway defines the configuration of the stereogenic centre in the ring to be S.The fungus Pyronema omphalodes grown in culture contained nor-mycosporine-glutamine 13, mycosporine-glutamine 8 and the mycosporine-glutaminolglucoside 7.26 Nor-mycosporine-glutamine was found in the primordia but absent in the spores, but its concentration decreased as the culture ripened, with simultaneous increase of mycosporine-glutaminol-glucoside in the spores. It may be that 2-O-methylation of the nor-mycosporine occurred during ascospore formation giving rise to 8, which could undergo reduction to give 6.Reduction of the ·-COOH of the glutamine occurs, which is an uncommon reaction (although reduction of alanine to alaninol in bacteria has been reported),132 followed by glycosylation to give 7. This last step has been demonstrated by Pittet et al.133 using the soluble enzymatic fraction from conidia of Ascochyta fabae. A. fabae, a phytopathogenic Deuteromycete parasite of the broad bean, produces mycosporine-2 4 during reproduction which is accumulated in spores as glucoside derivatives in a similar manner to the accumulation of flavonoid glucoside in higher plants.134 Studies conducted to ascertain the enzyme properties of a soluble uridine-5-diphosphate (UDP) glucose:mycosporine-2- glucosyltransferase from spores of A.fabae, showed that its kinetic parameters were very similar to those of the flavonoid specific glucosyltransferase and in both cases glucosylation of the compounds appears to be the ultimate step in the biosynthesis.135 Light induced perithecial development and mycosporine biosynthesis have been correlated with high ratios of an enzyme of the tricarboxylic acid cycle (NADP&isocitrate dehydrogenase) and one from the glyoxylate cycle (isocitrate lyase).When mycosporine was added to the nutrient medium, with incubation in the darkness, the fertility of the fungus was partially increased and the activity of the isocitrate lyase was significantly reduced.135 In the absence of mycosporine, and in the dark, high isocitrate lyase activity was associated with vegetative growth of the fungi. 7 Synthesis of mycosporines, MAAs and analogues Mycosporine-Gly 14 and mycosporine-1 1 have been synthesised from D-(")-quinic acid 49.136 The synthetic strategy illustrates a novel application of the Staudinger reaction137,138 of an iminophosphorane for introducing the appropriate mycosporine side chain (Scheme 3).The intermediate 51, synthesised from D-(")-quinic acid 49 via 50, when subjected to a Staudinger reaction with triphenylphosphine yielded the stable iminophosphorane 52. This intermediate was then converted into mycosporine-Gly 14 and mycosporine-1 1 by reacting with appropriate substrates. Thus, the amine 53, obtained by reacting 52 with benzylglyoxylate, on reduction OH O HO HO OMe 37 O OMe NH2 HO HO OMe NH2 NH2 OH NHCH2COOH OMe NH2 OH 38 39 40 HO CH COOH CH2CH2COOH 41 162 Natural Product Reports, 1998with sodium cyanoborohydride and cleavage of the acetonide with trifluroacetic acid followed by hydrogenolysis aVorded mycosporine-Gly 14.The methyl ester of both natural and synthetic mycosporine-Gly possessed identical negative optical rotation, thereby defining the ring stereogenic centre of mycosporine-Gly as S, in agreement with the proposed biosynthesis of mycosporines via the shikimate pathway. The intermediate 52 was reacted with diethyl ketomalonate and the intermediate imine 54 reduced as before.Direct reduction of the ·-amino diester moiety followed by unmasking of the acetonide produced mycosporine-1 1. Final confirmation of identity was made by converting both natural and synthetic compounds to the same bis-acetonide 55. Attempts to prepare iminomycosporines by direct condensation of mycosporine- Gly with various amines were unsuccessful.136 However, ‘analogous iminomycosporines’ have been synthesised.131 Hydrogenation of pyrogallol yielded dihydropyrogallol,139 which on methylation with dimethyl sulfate140 yielded 3-hydroxy-2-methoxycyclohex-1-one.Direct reaction of this 1,3-dione with primary and secondary amines in an aromatic solvent, such as benzene, and in the presence of an acid catalyst and with azeotropic removal of water,141,142 resulted in the enamino ketones. The enaminones involving amino acid esters were prepared by refluxing it with the 1,3-diones in alcohol, in the presence of a strong acid.143 The enamino ketones on refluxing with methyl iodide produced the activated intermediates 47, which then react with primary or secondary amines and amino acid esters to give the analogous iminomycosporine iodides. 8 The role of mycosporines and MAAs in nature The ubiquitous presence of mycosporines and MAAs in terrestrial and marine organisms suggests they play an important, albeit not fully clarified, role in biological systems.Many hypotheses have been formulated. These natural products have been considered to be energy traps or transducers of UV wavelengths10,54 to wavelengths utilisable for photosynthesis54,144 or biosynthetic precursors for other compounds or pigments.10,12 It is proposed that mycosporine-Gly 14 may function as a biological antioxidant in marine organisms.145 In a study conducted to understand the biochemical variability in morphologically and physiologically distinct colonies (morphotypes) of a coral species, it was found that the profiles of UV absorbing compounds can be used as distinct chemical signatures in identifying colonies as members of a particular genotype (morphotype).146–149 However, two major functions attributed to MAAs are their capacity to act as photoprotective UV filters in various marine12,49,54,65,67,68,81,88–90,105,144,150–152 and terrestrial36–38 organisms or to exercise a regulatory eVect on sporulation.4,5 Whilst evidence supporting the photoprotective role in marine organisms is mainly circumstantial,153 COOH OH COOH OH HO HO OH HO OH O Me O O HOOC R HO OH OH COOH COOH O O Succinate + Acetate O Quinate Protocatechuate 3-DHQ R = CH2OH A Shikimate Aromatics CO2 Pathways : COOH CHOH CH2O~P Mycosporines 42 COOH CHO~P CH2OH Ketoadipate pathway C6–C1 unit R = CH2OH B Glucose Me–COO– (A) 3-P-Glycerate Erythrose-4-P P-Enolpyruvate Glutamate Amine unit DAHP 3-DHQ / Shikimate Acetate (B) Scheme 1 Possible biosynthetic pathways for the formation of the C6–C1 unit of mycosporines; DAHP: 3-deoxy-D-arabinoheptulosonate-7- phosphate, 3-DHQ: 3-dehydroquinic acid (Ref. 128) Bandaranayake: Mycosporines: are they nature’s sunscreens? 163and limited in the fungi,36–38 it appears that sporogenic activity has been well demonstrated for fungal mycosporines. 1,4,5,31,154–157 8.1 Role of mycosporines in fungi In many species of fungi, light is an absolute requirement for the formation of reproductive organs.5 The relationship between UV radiation and mycosporines (‘P310’) has been the subject of studies by Leach,2–4,6 Vargas and Wilcoxon,17 van den Ende and Cornelis,24 Hite,14 Tan and Epton,15 Arpin et al.,155 Favre-Bonvin,156 and Dehorter and Bernillon.154 Literature references to ‘P310’ are often ambiguous, since this designation actually refers to three substances, ‘P310’ A, B and C which have been characterised as mycosporine-1, -3 and -2, respectively.They each absorb diVerently at shorter wavelengths than the 310 nm maximum and contain several amino acids5 and possibly other significant contaminants.Thus interpretation of experimental observations must be made with caution. The three forms of ‘P310’ diVer in their sporogenic activity.5 Several other mycosporines have now been isolated from diVerent classes of fungi (Fig. 1). Mycosporine-2 (4, 10), the most abundant fungal mycosporine, exists in the ring 10 and open chain 4 forms,16,158,159 the former being the main and active compound in vivo.Buscot and Bernillon isolated an unknown metabolite called ‘P295’ (because of its UV absorption maximum) from mycelia of Morchella esculenta.160 The spectral and chromatographic properties of this compound are reminiscent of the aminocyclohexenone 38.100,125 Mycosporines or their biochemical precursors have always been associated with sporulating mycelia5 and were considered as biochemical markers for reproductive states of fungi.Only in a few instances have they been assigned a photoprotective role.36–38 It has been demonstrated that the synthesis of these metabolites is regulated by the light intensity present during growth. Changes in irradiance from ‘low’ to ‘high’ light intensity induce a rapid response, which has been interpreted as an adaptive mechanism that confers upon these organisms a competitive advantage at high light intensity and short wavelengths. 161 Besides light intensity, their synthesis is highly dependent on the spectral composition of the light source.14,30 The following observations in in vivo and in vitro experiments strongly suggest a reproductive functional role for these metabolites in diVerent fungi.(i) Non-diVerentiated mycelia and rhizomorphs, nonsporulating mycelia or sporulating mycelia grown in darkness did not contain any mycosporines or related compounds but were found in sporulating mycelia and sclerotia. The synthesis and the occurrence of mycosporines appeared to be linked strictly to the sporulation process and accumulated in the ascocarps and the sporulating hymenium.160 (ii) Mycosporines were produced when mycelia were induced with near-UV radiation and absent in irradiated mycelia and sclerotia from which near-UV rays have been filtered.114 (iii) Light is required solely to initiate the process of production of ‘P310’ and once stimulated, the production of ‘P310’ continued in the dark as in the presence of light.However, when light was an absolute requirement for sporogenesis, mycosporines were not produced in the dark.31,36,158 (iv) The rate of production of ‘P310’ varied with wavelength of irradiation, period of irradiation, light intensity and nutritional conditions of the culture.30,31,154,157 The formation of ascospores and of mycosporines requires similar light conditions23,154 and mycelia producing both conidia and perithecia, elaborate the same mycosporine but in higher amounts with conidia than with perithecia developed in the dark.(v) Addition of purified ‘P310’ to dark grown conidia prolonged the survival of conidia under irradiation indicating that they were photomimetic.154 (vi) Mycosporines were at all times present in the thallus. However, the concentrations were highest in the conidiogenous thallus, intermediate in the perithecial thallus and lowest in the vegetative mycelium. In conidiogenous thallus, both macro- and micro-conidia are sites of mycosporine accumulation.In the perithecal thallus, mycosporine levels were not higher in perithecia than in mycelia, even during their O OMe OH HO HO OMe OMe NR HO HO O NR OMe HO HO NH2 OMe NHCH2COO– HO HO NHCH=CHMe OMe NHCH2COO– HO HO OMe NHCH2COO– HO HO OMe NHCH2COO– HO HO OMe NHCH2COO– HO HO OMe NHCH2COOH O HO HO HNCH(Me)CH2OH HNCH(COOH)CH(Me)OH HNCH(Me)COOH OH O OMe HO HO OMe O HO HO X Na+ + + + + + Na+ 37 44 NH2 43 38 27 14 21 17 25 37 16 Scheme 2 Biosynthetic relationships of some MAAs; solid arrows indicate chemically feasible steps (Ref. 73) O O MeO NH2 NH HN NH2 O 45 Dimedone 47 Activated intermediate I– + CH3I 48 Iminomycosporine 46 Enamino ketone + O O I– 164 Natural Product Reports, 1998maturation period. The quantitative variation of mycosporines during the thallus development and their accumulation inside conidia suggest translocation from sites of synthesis towards reproductive cells.158 (vii) Some fungi contained nor-mycosporine 13, mycosporine 8 and mycosporine glucoside 7.20,26,110 The normycosporine was found in the primordia but not in the spores and its concentration decreased as the culture ripened and the concentration of the glucoside increased and was accumulated in the spores.It is reasonable to postulate for mycosporines an order of biogenetic advancement, which is symbolised by their progressive chemical stability as they progressed from the unstable nor-mycosporine to the stable glycoside. (viii) Because of their photomimetic role in sexual diVerentiation and regulation of intermediate metabolism, mycosporines appear to be a biochemical transmitter of light energy required for the transformation of ascocarp.154 (ix) The relationship between the nature and content of free sterols and diVerent degrees of sexual morphogenesis, induced either by light or by mycosporines, has been demonstrated. 31,162 These in vitro experiments suggest that mycosporines may be a biochemical intermediate between light and sexual morphogenesis.The data available so far suggest that mycosporines cannot fundamentally be considered as direct photoproducts but appear to be products from a type of metabolism that occurs at a very low level during mycelial growth which increases its activity during reproductive morphogenesis,161 and that mycosporines may be participating in biochemical events such as the modification of sterol metabolism. These observations provide strong evidence for their sporogenic activity and establish a relationship between photoinduction, synthesis and reproduction. Young and Patterson38 were the first to demonstrate that mycosporines were present in the mucilage that surrounds conidia of some fungi and there was no evidence of their presence inside the conidia.This was later corroborated by Leite and Nicholson,109 and by Brook.36,37 These authors postulated that at least in some fungi, mycosporines either performed a photoprotective function or they protected the conidia from untimely germination. 8.2 Role of MAAs in marine organisms Biologically important solar UV radiations (UVR) UV-A and particularly UV-B radiation, have deleterious eVects due to their actinic nature, manifested genetically, physiologically and photosynthetically, and are potentially damaging to many forms of life including marine organisms.63,163–175 Their eVects have been detected in a variety of ecosystems spanning alpine regions,168 terrestrial environments and aquatic ecosystems, and geographically from Antarctica to temperate and tropical environments.52,70,81,177–179 Tropical ecosystems have an evolutionary history of exposure to high flux of UVR.180 Due to the transparency of tropical waters to UV radiation84,181–184 and the thinness of the ozone layer in the equatorial area, the reef population in tropical shallow waters such as coral reefs and temperate intertidal zones are exposed to the eVects of UV light from 285–400 nm.There is growing evidence that solar UV-B radiation is a stress agent.67,85,89,90,185–190 In the marine environment, deleterious eVects of UVR have been detected sometimes in organisms inhabiting depths as deep as 20–30 m,63 and include both the direct eVects of UV-B and the indirect eVects of UV-A mediated damage.191 In addition to an increase in temperature,186,192–197 UVR has been implicated in the bleaching of microalgal–invertebrate symbiosis.66,85,170,198–200 The eVects of high levels of solar radiation include: inhibition of growth,68,152,192,201 coral calcification,202,203 skeletal growth,68 photosynthesis,204–210 reduced motility,211–213 motality200 and survival,214,215 reduction in the concentration of photosynthetic pigments and their destruction,210,216,217 photoinhibition,218,219 decrease in carbon fixation210 and nitrogen uptake,220 decreased reproductive potential,221 and impaired development,221 and protein inactivation and DNA damage.221,222 At certain times of the year, large areas of the reef are exposed to atmospheric conditions including UV radiation, for several hours each day.However, the abundance of algae and diversity of invertebrates and the jumbled profusion of life in these regions suggests that protective or defence adaptations have evolved against the harmful eVects of UV radiation. Corals that flourish in shallow areas obviously tolerate extremely high levels of solar radiation, and it cannot be assumed that UV is innocuous to these organisms.Aquatic organisms generally must expend energy in order to cope with UVR in the upper euphotic zone. On the other hand, UVR is CO2H OH HO HO OH PhSO2 OMe N3 OMe O Ph3P=N OMe O O O OMe NH EtO2C EtO2C O OMe OMe O NH NH OMe HO OH O NH OMe HO OH O O O O O O O O O O O O NH BnO O 52 53 55 14 1 50 54 O 49 51 HO O CH2 CH2 HO HO Scheme 3 Synthesis of mycosporine-Gly and mycosporine-1 (Ref. 136) Bandaranayake: Mycosporines: are they nature’s sunscreens? 165a very important environmental factor for reef organisms. The notable success of corals and other invertebrates might be attributed to their ability to tolerate UVR and derive a benefit from solar radiation, and under normal conditions one seldom finds a ‘sunburned’ coral.223 Several protective mechanisms may mitigate UV toxicity. These include behavioural (e.g. migration),92,166,215,219,224 bathymetric and morphological adaptations,70 contraction of body tissues,92,225–227 biochemical modifications including DNA repair mechanisms,33,227 or chemicals that scavenge photochemically-produced harmful substances,210 presence of pigments that reflect UV or fluoresce energy into the visible portion of the spectrum, 173,175,190,228–230 presence of small molecule antioxidants145,231 and enzymic antioxidants,93,173,210 shielding by external tissues or objects,189,190,232,233 extracellular structural adaptations and presence of protective sheaths or mucus with UV absorbing compounds,103,104 processes other than screening mechanisms such as changes in species composition, selection of UV-resistant strains or preadaptation during their evolution, and the production of UV-absorbing compounds with absorption in the UV-A and UV-B regions.MAAs are widely thought to be such a class of metabolites. 12,84,89,103,152,234 Nature is replete with symbiotic systems.From human societies to nature’s ecosystems, collaboration enhances eY- ciency for survival, and the creatures of the reef live by this essential rule of life. Symbiosis is one of the most eYcient biological systems operating on the reef and occurs in a wide range of marine invertebrates, ranging from a single cell protozoan to the giant clam Tridacna maxima.235,236 They are either eucaryotic symbionts (endosymbiotic dinoflagellates, zooxanthellae, Symbiodinium microadriaticum) or prokaryotic symbionts (the filamentous cyanophytes, blue-green algae).Scleractinian corals contain zooxanthellae which are important contributors to photosynthetic reef production in nutrientpoor tropical waters receiving high solar irradiance. Researchers have suggested that the symbionts are responsible for the synthesis by MAAs in these associations12,52,71,81 (some holothurians are exceptions),113 on the basis that the biosynthesis of MAAs uses the first steps of the shikimic acid pathway,127,237 a biogenetic process present only in algae, fungi and bacteria and absent in metazoans.DiVerent species of zooxanthellae diVer in their capacity to synthesise, accumulate and translocate MAAs.86,113,188,238 The origin of these compounds in non-symbiotic species is proposed to be dietary.75,80,84,86,113 A close concordance of the MAA complements of marine organisms and their potential diets in the field is taken as indirect evidence for their bioaccumulation, as no biosynthetic pathways for these compounds have been discovered in invertebrates and vertebrates. It is feasible that heterotrophic bacteria present in some of these organisms are capable of de novo synthesis of MAA precursors and being the provider of these metabolites.94 Despite some exceptions to the foregoing relationships,89,90,95,113,239 a photoprotective function of these compounds has been inferred from the following observations.(i) High concentrations in coral reef-dwelling species,12,81 very high molar extinction coeYcients in the range of environmentally relevant UVR,10,12,81 together with a lack of evidence for any other physiological function. (ii) Decrease in concentration and UV tolerance in different species as well as in conspecifics as depth increases.63,70,84,89,90,103,151,239–241 (iii) UV radiation can trigger their production, and accumulation, and can modulate their concentrations.Corals grown in full spectrum of the solar radiation produce higher concentrations of MAAs than those screened from UV radiation,52,93 and a positive correlation between UVB absorption maxima with natural levels of UV has been demonstrated.114 (iv) MAAs are prominent, especially in tegumentary or other peripheral tissues in multicellular organisms.80 This is regarded as a way of optimising the eVectiveness of the sunscreen, in the fashion of other known natural sunscreens, such as melanin,175,242 plant phenylpropanoids243 and cyanobacterial scytonemin.40,244–246 (v) The presence of several MAAs with diVerent absorption maxima within the organism. It is proposed that the cumulative eVect of having several MAAs with diVerent absorption maxima between 285–360 nm is that the filtering capability is broadened, thus increasing protection across a large range of wavelengths.50,51,81,84 In most cases, however, there was one compound that clearly accounted for most of the absorbance, while other MAAs were relatively minor.(vi) Photopigment destruction did not occur, nor was there an increase in UV-absorbing substances, when the UV component of sunlight was selectively removed by UV filters. Under unfiltered, natural UV-containing sunlight, photopigment destruction occurs and the concentration of UV-absorbing compounds increased.113 (vii) A photoprotective role of MAAs in sea urchin eggs has been demostrated. Owing to their small size and short optical pathlengths, most marine invertebrate embryos that occur in shallow waters are at risk of damage by UV radiation.97 Accumulating MAAs in the eggs may protect them from UV damage during their planktonic development.Sperm of sea urchin97 and other invertebrates75,80,101,107 need to remain viable in seawater only long enough to fertilise the eggs, so the duration of their exposure to UV is far less than that of eggs and embryos.75 This was considered to be the reason for the lack of accumulation of MAAs in sperm of sea urchins97 and invertebrates.75,80,107 The embryos displayed a significant inverse logarithmic relationship between MAA concentration and percentage cleavage delay, so that the greater the MAA concentration in the eggs, the less they were aVected by UV radiation.97 These results suggest that the organisms detect and respond to UV light.(viii) One compound for which a sunscreen role has been established is the extracellular, lipid soluble, sheath pigment scytonemin 56 with an in vivo maximum at Îmax 370 nm, present in some species of cyanobacteria.40,244–246 In cyanobacteria significant protection from UV damage could be gained from the possession of both MAAs and scytonemin.41 More direct evidence for a UV-protective role of MAAs in marine organisms is scarce. Shick et al.80 have observed that UV exposure is not the sole determinant of MAA concentration in holothurians which do not harbour algal symbionts.Most marine organisms contain a complex mixture of MAAs, where some MAAs increase in concentration during exposure to UV radiation, while others do not. It was proposed that the increase in the concentration of some MAAs was not a direct response to UV radiation, but represents accumulation due to seasonal changes, reproductive state or diet.113 The observations that the MAA, mytilin A (shinorine) 19 and B (porphyra 334) 2077 have a blocking eVect on the development of sea urchin embryo by inhibiting the cell fission, without causing cellular lysis,78 and the presence of MAAs in developing cysts of the brine shrimp Artemia,99 and in fish96,101 and starfish eggs,100 suggests that at least some MAAs may act as N O OH N HO O H H 56 166 Natural Product Reports, 1998development control regulators in the reproductive stages.Researchers have observed that in some tropical marine organisms there was a tendency for concentrations of MAAs to be higher prior to spawning than at other seasons.71 Antarctic algae Palmaria decipiens contain a range of UV-absorbing pigments106 and their profile changed as the alga underwent its annual cycle of growth.Maximum concentrations and complexity of the MAA profile occurred in the mature fronds in the summer, and their concentration was not increased any further by exposure to an enhanced ratio of UVB radiation to visible light. Three iminomycosporines with absorption maxima at 320, 330 and 334 nm, present in the MAA rich diet, were also present in the eggs and other tissues of the sea cucumber Strongylocentrotus droebachiensis.75 However, mycosporine-Gly 14, absent in the MAA rich diet or in the sea cucumber prior to the feeding experiment, was present in the eggs and gut tissues, and its concentration in the ovaries increased significantly prior to spawning.It was proposed that mycosporine-Gly was produced from the major iminomycosporine, by the bacteria present either in the organism or the ingested algal diet.In some Holothurian species collected in the field, the gonads contained only mycosporine-Gly (Îmax 310 nm), either in detectable or large quantities, and the imino-MAAs present in the epidermal tissues or in the diet were absent or present in trace quantities in the gonads.80 Similar observations have been made in the echinoderm Holothuria atra which has no endosymbiotic algae and feeds mainly on organic contents of sand, calcareous fragments of corals and detritus.247 The organism transformed all the imino-MAAs present in the diet into mycosporine-Gly and was stored in the ovaries and eggs.However, the other tissues, especially the epidermal tissues, contained the MAAs present in the diet. The iminomycosporines present in the diet and epidermal tissues covering the UV range approximately 310 to 340 nm certainly can function as a broad spectrum UV absorber and there is no necessity for the organism to dissipate its energy to produce another MAA, especially one with a narrower absorption band, to perform the same function.Dunlap and Yamamoto145 have proposed that mycosporine- Gly, but not imino-MAAs (e.g. palythine) has antioxidant activity. Mycosporine-Gly (Îmax 310 nm) and palythine (Îmax 320 nm) are the most predominant MAAs in most zooxanthellate marine organisms on the Great Barrier reef,248 and on Caribbean reefs.249 The production of mycosporine-Gly by the sea urchin and Holothurian spp.and its presence in other marine organisms in these oxygenic photoautotropic environments may be taken as indirect evidence for its antioxidant function, and along with palythine, may provide additional defence against direct UV-B radiation. The presence of MAAs in apozooxanthellate and azooxanthellate sea anemone113,238 and non-symbiotic metazoans such as fish,33,96,101 mussels,77 brine shrimp99 and certain echinoderms,80,100,247 indicate that these compounds may have another provenance, at least in some organisms.The variation of the concentrations of the individual and total MAAs content in relation to photon-flux density, air, and water temperature has been monitored in the tropical sponge Dysidea herbacea in the field.250 The results clearly showed that the concentrations of total MAAs followed the photon irradiance profile indicating that they have some role relating to light intensity, i.e.photoprotectivity. However, the concentration of the individual MAAs did not mirror the rise and fall of photon-flux density. Quantisation of MAAs in the sponge suggests that while some MAAs (aminocyclohexenones) may serve as UV protectants, others (iminomycosporines) are intrinsically involved in the reproductive process. The study demonstrated that the presence or absence of some MAAs is not a direct response to UV radiation, but is a reflection of the reproductive state of the organism.Larval rearing experiments carried out with Crown-of-Thorn starfish Acanthaster planci100 living in the tropical waters, demonstrated that the concentration of the most abundant imino- MAA was highest in the ovaries and eggs of gravid females and peaked closer to spawning (summer; December) and they were absent or present in trace quantities in the testes and sperms. Most of the larvae from females with the highest ovarian concentrations of the MAA, survived much longer than those obtained from lower ovarian MAA content and there was a gradual decline in the MAA content as the larvae developed .Similar trends have been observed with sea urchin eggs where the MAA concentration was significantly lower in the 5 days old pluteii.97 The MAAs concentrations in the mature ovaries of starfish and sea urchins were very much lower than in the spawned eggs which indicate that the MAAs are sequestrated in the eggs rather than in supporting cells in the ovaries.97,100 The occurrence of UV-A absorbing imino- MAAs of absorption 330–360 nm, showed considerable taxonomic80,84,93,144,241,250 and seasonal100,250 variations and there has been little consideration of these as potential sunscreens.The rapid reaction of MAAs with an iodide peroxidase results in the release of free amino acids. The same reaction is catalysed by an iodide peroxidase that has been purified from the cysts and nauplii of Artemia.99 Irrespective of the reaction mechanism, it appears that mycosporines are decomposed or utilised during early stages of embryonic development, and the function of the enzymic reaction may be to increase the pool of free amino acids available to the embryo.99 The presence of a UV absorbing compound is not a satisfactory criterion for invoking its role as a UV protectant.153 Possibly, the most crucial condition that should be met by a sunscreen compound is that the compound should absorb a fraction of the incident light radiation high enough to provide a meaningful benefit to the organism.153 This function is the ‘sun protection factor’ (SPF)251 The function of MAAs in ocular tissues of fish is unclear.Results presented so far indicate that it is not an obligate adaptation to protect fish eye lens from UV damage. Regardless of whether the UV protective properties of MAAs are a primary or secondary function, or whether they are synthesised or bioaccumulated, the presence of these compounds within cells of organisms may shield internal organs and organelles from deleterious eVects of UV radiation and provide some degree of biochemical protection from physiologically harmful UV-B radiation.Mycosporines and MAAs may well be natural sunscreens. However, it may not be their only function. Evidence available so far suggests that some of these MAAs appear to be secondary metabolites appearing as products from a type of metabolism aided by light, that occurs at low level during the early stages of growth of the organisms and increases their concentration as it approaches reproductive maturity, indicating that they are linked to the reproductive process, which is very similar to the formation and function of mycosporines in fungi. 8.3 Role of related compounds Gadusol 33 occurs in the unfertilised mature eggs of several marine fish,96,98,101,252,253 starfish100 and sea urchins,98 developing bipinnaria of A.planci,100 in the developing cysts and motile nauplii of the brine shrimp Artemia,99 and fish eye lenses.102,115 This optically active metabolite cooccured with imino-MAAs in varying proportions in these tissues and was absent in testes and sperms.98,99,100 6-Deoxygadusol 37, structurally related to gadusol, was absent or present in trace quantities in these tissues except in the ripe eggs of Holothuria atra which contained only 6-deoxygadusol and mycosporine- Gly 14.247 6-Deoxygadusol has also been characterised from carpospores of fungi125 and gadusol, isomeric with spinulosin quinol-hydrate 57, a secondary metabolic product of fungal metabolism isolated from Aspergillus fumigatus,254 so far has not been reported as a fungal metabolite. Gadusol has some properties similar to ascorbic acid.253 Specific assays have shown that the concentration of gadusol in the roes of marine fish are several times greater than those of ascorbic acid and its high concentration in the eggs suggests a functional role in Bandaranayake: Mycosporines: are they nature’s sunscreens? 167embryonic development.Early embryological development in Artemia99 and A. planci100 results in the utilisation or the ‘decomposition’ of MAAs with subsequent formation of gadusol or 6-deoxygadusol suggesting the existence of a biological relationship between MAAs, gadusol and 6-deoxygadusol. In solution this tautomeric compound exists essentially in the enol form.253 With an increase in pH the enolate is formed, resulting in a bathochromic shift in the absorption maximum and an increase in the molar absorption coeYcient, typical of 1,3-diketones, and also exhibited by ascorbic acid and spinulosin quinol-hydrate.This chemical behaviour was often used to detect the presence of gadusol and 6-deoxygadusol in crude or partially purified extracts of marine organisms.94,96,100,119,250 Gadusol and 6-deoxygadusol, with a UV maximum of 264 nm, are unlikely to have a UV protective function but have the potential to act as antioxidants. 9 Development of a commercial sunscreen ‘Sunburned’ corals among marine organisms are rare.223 The unusual tolerance of the living tissues of coral reef invertebrates to withstand long term exposure to the potentially damaging eVects of tropical UV light and the high eYcacy of their UV-absorbing compounds (MAAs), suggest potential commercial application in suncare products for skin protection and protection of non-biological materials as photostabilising additives in the plastic, paint and varnish industries.255–257 A large number of synthetic analogues of aminocyclohexenones and aminocyclohexenimines using 2,3-dihydroxycyclohex- 2-en-1-one 58, 3-hydroxy-2-methoxycyclohex-2-en-1-one 59,130 3-hydroxycyclohex-2-en-1-one 60, 2-alkyl-3-hydroxycyclohex- 2-en-1-one 61, 5,5-dimethyl-cyclohexane-1,3-dione 45 and acyclic 1,3-diketones,255,258,259 were prepared to compare their chemical properties and physical attributes.The amino acid or the amino alcohol functions in the MAAs were replaced by alkyl amino groups to reduce their hydrophilic properties. Reacting the above substrates with primary and secondary amines produced aminocyclohexenones with Îmax 290–315 nm and aminocyclohexenimines with Îmax 318– 330 nm. Due to the high instability and non-conformity to requirements of sunscreen products, these derivatives were deemed unsuitable for commercial application. However, tetrahydropyridine derivatives 64 and 65 with Îmax 305–311 nm, with extremely high absorptivity (Â 32 000), were prepared from 3-alkanoyl-1,4,5,6-tetrahydropyridines 62 and 63,260–264 suf- ficiently stable for commercial considerations as skin care products.This class of compounds with the 4,4-dimethyl structure 65 were the most promising candidates. The gem-dimethyl group (also present in vitamin A and retinal) prevents radical processes at the ·-ring position of the chromophore, thereby preventing oxidative decomposition of the compound, and also restricts free rotation of the alkanoyl group, hence increasing the Îmax of the derivatives.Commercial activities are presently in progress in partnership with international cosmetic manufacturers. Patent applications for the use of enamino ketones of 1,2-diketones as suncare products265 and manufacture of mycosporine-like amino acids from a culture have been lodged.266 10 Conclusion Despite many studies to evaluate the complex question of the role of MAAs in biological systems, there are many questions yet to be addressed.The evolutionary implications of the distribution of MAAs and their absence in certain organisms remain yet to be investigated.33 Few studies have been conducted to evaluate the interaction between the host and symbionts as a function of exposure to UVR. It would be useful to study the photoacclamatory or photoadaptive abilities of dinoflagellates and the eVects of long-term exposure to solar radiation on growth, motility and mortality.The biogenesis of MAAs and their localisation in the tissues should be resolved. Qualitative eVects of UVR on coral reef organisms have been documented usually in experiments comparing the biological responses to the presence or absence of UVR. Most studies have not distinguished between the eVects of UV-B and UV-A, although in the context of global change in stratospheric ozone loss, it is the latter wavelengths that are relevant. 267,268 The lack of data on species-specific responses to increased UV-B is a primary limitation to the quantitative evaluation of the ecological impact of ozone depletion.269,270 So far researchers have pursued the photoprotective role of MAAs in organisms at great length and alternative mechanisms have not been explored.271 For example, organisms have evolved a variety of enzymes that detoxify photochemicals or toxicants.272,273 Searches for such processes, and chemicals with antioxidant properties,231,274,275 new UV absorbing compounds or compensatory changes in other factors possibly aVecting UV resistance276 should be explored.For example, the ovothiols A, 66, B 67 and C 68, a redox active family of aromatic thiols of the parent amino acid L-histidine-5-thiol 69, found in sea urchin and octopus eggs, possess unique antioxidant properties.274,275,277,278 Three novel sulfur-containing metabolites with strong UV-A and UV-B absorption have been characterised.One metabolite was found in the animals only during the reproductive season,279 and the other two compounds are mycosporine sulfate esters 31 and 32.85 Other natural products present in marine organisms absorb UVR to varying extent, but there has been little consideration of these as potential sunscreens. For example, the role of OH OH OH O MeO OH Me 57 R OH O 58 R = OH 59 R = OMe 60 R = H 61 R = Alkyl 1-Alkyl-3-alkanoyl-1,4,5,6-tetrahydropyridines N N R2 R3 O O R3 R1 R1 NH NH R2 R3 O O R3 R1,R2, R3 = Alkyl R1,R2, R3 = Alkyl 64 65 3-Alkanoyl-1,4,5,6-tetrahydropyridines 62 63 168 Natural Product Reports, 1998UV-absorbing compounds such as the alkaloids isolated from the sponges of the orders Poecilosclerida, Axinellida and Halichondria,280–282 (e.g.hymenialdisines 70, 71 and axinohydantoin 72) and the carotenoids in colourful corals warrant study. The photoprotective and antioxidant properties of carotenoids are well documented.283–285 For example, the major carotenoids present in the dorsal skin of holothurians were also present in their ripe eggs and may well have a functional role in these organisms.247,286 There is a need to develop action spectra for species containing UV-absorbing compounds and to compare with the absorption spectra of the compounds involved52,287 Gadusol and/or 6-deoxygadusol along with MAAs present in the ovaries and eggs may have a role in the organisms. 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ISSN:0265-0568    

DOI:10.1039/a815159y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

The synthesis of O-glucuronides Andrew V. Stachulski and Gareth N. Jenkins Salford Ultrafine Chemicals and Research, Synergy House, Guildhall Close, Manchester Science Park, Manchester, UK M15 6SY Covering: From 1987 to March 1997 Previous review: Xenobiotica, 1987, 17, 1451 1 Introduction 2 Occurrence and relation to other carbohydrates 2.1 Classification of O-glucuronides 2.2 General synthetic remarks 3 Alkyl and aryl glucuronides 3.1 Ester series. Preparation of fundamental intermediates 3.1.1 Bromo sugar couplings.Koenigs–Knorr and other methods 3.1.2 Perester couplings 3.1.3 1-Hydroxy sugar couplings 3.1.4 Trichloroacetimidate method 3.1.5 Other methods using acyl protection 3.1.6 Higher acyl derivatives 3.1.7 Hydrolysis of ester-protected glucuronides 3.2 Ether series. Preparation of intermediates 3.2.1 1-Halo and 1-hydroxy sugars, ether series 3.2.2 Ether trichloroacetimidates 4 Acyl and carbamoyl glucuronides 4.1 Acyl glucuronides 4.2 Carbamoyl glucuronides 5 Other synthetic methods 6 Furanose forms 7 Dehydroglucuronides and other modified glucuronides 8 Enzymic methods of glucuronidation 8.1 UDP-glucuronosyl transferase 8.2 Exploitation 8.2.1 Purified UDPGTs 8.2.1.1 Isolation and purification 8.2.1.2 Immobilisation 8.2.2 Liver microsomes 8.2.2.1 Immobilised artificial membranes 9 References 1 Introduction The days when glucuronides could be dismissed as biological waste products of little interest are now over.Increased understanding of metabolic processes has led to a growing appreciation of the role and significance of ‘phase 2’ metabolites, glucuronides in particular.As well as being frequently the final form of a drug or xenobiotic eliminated from the body, often performing an important detoxification role, glucuronides may have significant biological activity in their own right. This point is illustrated later with regard to morphine-6-glucuronide (Section 3.1.6). Analysts, in addition, demand authentic high-purity samples of glucuronides for assay purposes, while potential new drugs are frequently found as their glucuronides during toxicological investigations or clinical trials.Regulatory bodies are now demanding that the glucuronide (or other metabolite) should be tested thoroughly in its own right before acceptance of the parent drug. For all these reasons, eYcient methods of glucuronide synthesis are of considerable importance. The last significant review of this area was by Kaspersen and van Boeckel (1987)1 who covered in a thorough manner the synthesis of both sulfate and glucuronide (C, O, N and S) conjugates. Since then there have been a number of new developments and, inevitably, some reappraisal of older methods.This article will cover only the synthesis of O-glucuronides, the largest and most important class and the one subjected to most chemical investigation. For completeness this review includes the most significant references prior to 1987 along with a detailed analysis of the literature since then.While the layout and main thrust of the article is founded on synthesis, where relevant the biological significance of the examples presented is mentioned. 2 Occurrence and relation to other carbohydrates 2.1 Classification of O-glucuronides O-Glucuronides may conveniently be divided into three classes, as typified by paracetamol glucuronide (aryl) 1, 11·- hydroxyprogesterone glucuronide (alkyl) 2 and valproic acid glucuronide (acyl) 3.In general, it may be said that the same synthetic methods are likely to be viable for both aryl and alkyl glucuronides: both classes are naturally abundant. Aryl glucuronides are especially common, indeed it is unusual for a reasonably lipophilic, phenolic drug not to yield at least some glucuronide conjugate in humans. Both classes are generally of good chemical stability. Acyl glucuronides are also widespread but of low chemical stability, being readily hydrolysed either side of pH 7 and subject to facile rearrangement.Only recently has there been much progress in convenient synthesis of appreciable quantities of this class of metabolite. 2.2 General synthetic remarks Naturally, most of the methods for glucuronide synthesis have their parallel in glucoside synthesis but even the commendable recent monograph by Collins and Ferrier2 dismisses glucuronides in a few pages. Glucuronides have their own distinctive chemistry, however, and are usually more diYcult to prepare than the corresponding glucopyranosides. Schmidt and coworkers3 have in fact drawn up a glycosidation ‘league table’, in increasing ease of glycosyl donation: glycuronates<aldoses< deoxy sugars<ketoses<3-deoxy-2-glyculosonates.That is, of all common sugars, glycuronates require the highest activation for a given aglycone. In view of this, it is surprising that the imidate method for glucuronidation has been relatively slow to O O HO2C HO OH NHCOCH3 HO O O HO2C HO OH HO O O O HO2C HO OH HO O O CH( n-C3H7)2 1 2 3 Stachulski and Jenkins: The synthesis of O-glucuronides 173gain acceptance.Mechanistically, the electron-withdrawing 5-alkoxycarbonyl group has a destabilising eVect on an incipient C-1 cation. Provided that the aglycone portion is compatible with hydrolytic (usually base-catalysed) removal of ester groups, the readily accessible acyl glucuronate intermediates are fully satisfactory and are indeed the most commonly used.Generally the participating C-2 substituent in this case leads predominantly to the ‚-configuration of the glucuronide which is almost invariably the natural configuration. Exceptions occur, however, particularly with couplings of the 1-hydroxy sugar (Section 3.1.3). By contrast, ether intermediates will typically yield ·/‚ mixtures, though varying degrees of stereochemical control are possible. Several steps are required to prepare the activated intermediates: benzyl ethers have been most commonly used.On the credit side, non-hydrolytic removal of protecting groups may be essential for some aglycones, and the intermediates are more reactive than the sluggish acyl intermediates. Among other protecting groups, only allyl (removed by Pd0 reagents) has gained significant acceptance. 3 Alkyl and aryl glucuronides 3.1 Ester series. Preparation of fundamental intermediates A clear majority of all glucuronides have been synthesised via acyl-protected intermediates: the preparations of those most often used for coupling are summarised in Scheme 1, starting with the commercially available D-glucurono-6,3-lactone (‘glucurone’) 4.The first reaction yields an ·/‚ mixture4 from which the ‚-anomer 5 is easily separated by crystallisation; in fact the anomeric mixture may be converted without separation to the bromo sugar 6. Both 55 and 66 are suitable precursors of the 1-hydroxy sugar 7, which exists as a ca. 5:1 ·:‚ mixture (NMR in CDCl3). This hemiacetal is itself a useful glycosyl donor, or it may be converted as shown to the trichloroacetimidate 8.7 Further details of these preparations will be given in the appropriate sections. 3.1.1 Bromo sugar couplings. Koenigs–Knorr and other methods The 1·-bromo sugar 64,8 is probably still the most popular glucuronidation intermediate and is commercially available. Its ‘highly unstable’ reputation is not entirely justified, but it must be kept dry: under desiccation at "20 )C it may be stored for extended periods.The Koenigs–Knorr method remains the most popular for the synthesis of a wide range of alkyl and aryl glucuronides. Catalysts used are typically AgI salts, especially Ag2CO3, Hg(CN)2 or CdCO3. For easy reference, Table 1 lists glucuronides prepared by this method according to aglycone type, including some leading references from the earlier review.Steroidal examples are especially numerous.9–40 The most common solvents used have been benzene, toluene and quinoline; removal of any water produced (molecular sieves, azeotropic distillation) is important. Additional base may be necessary to destroy the HBr formed. In general the method appears rather more suitable for alkyl than for aryl glucuronides, though it is interesting that the conjugate 9 from methyl salicylate was satisfactorily produced only from 6 and Ag2CO3;40 acid-catalysed methods using tetraester 5 (Section 3.1.2), often good for phenols, proved quite unsuccessful.Strong intramolecular H-bonding is doubtless a factor here since steric hindrance, even in 2,6-disubstituted phenols, is not in itself a barrier. The by-products that may occur with the Koenigs–Knorr method are well illustrated by glycyrrhetic acid benzyl ester 10.25 Reaction with 6 using Ag2CO3 catalysis gave the desired conjugate 11 (46%) and ortho ester 12 (12%); with Hg(CN)2, only 25% of 11 was produced together with acetate 13 (15%).The latter, ‘acyl transfer’ product, is commonly observed and results from rearrangement of an ortho ester.41 With Hg(CN)2 a more profound rearrangement, leading to ring-A contracted product 14 (20%), was also observed. In this example ·-glucuronide formation was not reported, though it is often observed, usually not exceeding 5%. Significant variations may occur with diVerent catalyst batches, however.Included among the steroidal examples are both deuterium and tritium-labelled examples. A critique13 of a synthesis of O OH OH HO O O O MeO2C AcO OAc AcO OAc O MeO2C AcO AcO AcO Br O MeO2C AcO AcO AcO O O MeO2C AcO AcO AcO NH Cl3C OH 4 5 6 7 8 i ii iv iii v Scheme 1. Intermediates for glucuronidation, ester series. Reagents: i, NaOMe, MeOH then Ac2O, Py; ii, HBr–AcOH; iii, Bun 3–SnOMe; iv, Ag2CO3, H2O; v, Cl3CCN, base O MeO2C AcO AcO AcO CO2Me O O CO2Bn RO O MeO2C AcO AcO AcO O MeO2C AcO AcO O O Me O CO2Bn 9 10 R = H 11 R = 12 R = 13 R = Ac 14 174 Natural Product Reports, 1998an androst-9(11)-ene-17-glucuronide (for tritiation)12 was adequately answered by published corrigenda.14 When specific glucuronides of polyhydroxylated steroids are required, protection of other hydroxy groups is not always needed.For instance, the deuterated androstane-3·,17‚-diol 15 was specifically glucuronidated at position 17 on a small scale.10 By contrast, the tertiary 17·-OH in the cortisone series does not compete with a 3·-OH.An 11‚-OH is also less reactive, e.g. the cortoic acid 16 was specifically glucuronidated at position 3.15 The case of estriol 17 is interesting.20 Synthesis of the 16·-glucuronide required protection of both the phenolic (3-) and the 17‚-OH, but no phenolic protection was necessary to obtain the 17‚-glucuronide (CdCO3 catalysis). Further chemistry may sometimes be performed on the glucuronide ester conjugates prior to deprotection. For instance, the alkali-sensitive ketol C-17 side-chain of the cortisol derivative 18 was protected19 by semicarbazone formation prior to hydrolysis. Reductions of steroidal ketones using NaBD4 21 or tert-butylamine·BH3 22 without aVecting a protected glucuronide moiety have also been reported.Of other catalysts, silver trifluoromethanesulfonate (triflate) has been less used for glucuronidation but it gave a markedly better yield27 than Ag2CO3 in a synthesis of retinyl glucuronide.The use of silver carbonate on Celite was recommended31 for the preparation of the important metabolite morphine-6- glucuronide 21 though any improvement over Yoshimura’s original synthesis42 appears slight (see also Section 3.1.6). Continuing interest in opiates and their metabolism is evinced by another synthesis of codeine-6-glucuronide32 and one of 3-O-ethylmorphine-6-glucuronide.33 Another known morphine metabolite is normorphine, formed by cytochrome P450 mediated oxidative de-N-methylation, and its Table 1 Glucuronidations using the Koenigs–Knorr procedure Aglycone (Site of attachment of glucuronide) Catalyst Yield (%) Comments Refs.O-Alkyl, steroids 5·-Androstane-3·,17‚-diol (3,17) Ag2CO3 34,38 On 3·-, 17‚-acetates; also Sections 3.1.3, 3.1.4 9 5·-[16,16,17-2H3]Androstane-3·,17‚-diol (17) 15 Ag2CO3 On unprotected 3,17-diol; see text 10 1·-Hydroxy-5·-androstane-3·,17‚-diol (17) Ag2CO3 32 Positions 3, 11 both protected 11 5·-Androst-9(11)-en-3·,17‚-diol (17) and the [9·, 11·-3H2] adduct Ag2CO3 ca. 40 Much orthoester also formed. On 3·-acetate, see text 12–14 Cortoic acid 3-glucuronides 16 Ag2CO3 Both 11‚-OH and 11-oxo; both 20-epimers (4 cmpds.) 15 Cortol and cortolone (3) Ag2CO3 In ref. 1 16 5·-Cortol and 5·-cortolone (3) Ag2CO3 22–34 Both 11‚-OH and 11-oxo; both 20-epimers (4 cmpds.) 17 Allotetrahydrocortisol and allotetrahydrocortisone (3,21) Ag2CO3 28–54 Both 3- and 21-products in 11‚-OH and 11-oxo series (4 cmpds.) 18 Allotetrahydro-11-deoxycortisol (3,21) 18 Ag2CO3 See text 19 Estriol (16,17) 17 CdCO3 47–80 Selective protection (acetyl, silyl); see text 20 [2H6]Estriol (16) Ag2CO3 66 Via 17-ketone 21 Hyodeoxycholic acid (3,6) CdCO3 32–57 On 3-(6-)oxo Me esters 22 2,2,3,4,4-[2H5]Pregnanediol (3) Ag2O 63 On 20-TBDMS ether 23 16,16,17-[2H3]Testosterone and -epitestosterone (17) CdCO3 50–60 24 O-Alkyl, non-steroids Glycyrrhetic acid (3) Ag2CO3 or Hg(CN)2 46,25 On benzyl ester; see text for by-products 25 All-trans-retinol 19 Ag2CO3 AgOTf 15 72 Yield after hydrolysis Collidine as base; "40 )C 26 27 All-trans-[11-3H]retinol Ag2CO3 For metabolic study 28 Dihydroartemisinin and hydroxy-analogues (various) Ag2CO3 Some antimalarial activity retained; see also section 3.1.3 29 Carazolol (2) 20 Ag2CO3 82 Via 3-N-Boc derivative 30 Morphine (6) 21 Ag2CO3–celite 45 Also applied to codeine; see text 31 Codeine (6) Ag2CO3 32 3-Ethylmorphine (6) Ag2CO3 35 No enone seen 33 Normorphine (6) Ag2CO3 0.6 On N,O(3)-bis-Z derivative; yield after hydrolysis 34 2-Phenylpropan-1-ol Ag2CO3–celite 50 35 Ethanol Ag2CO3 35 36 O-Aryl Various phenols Ag2CO3 31 Yield on phenol itself 4 Steroidal phenols (six) CdCO3 46–71 Estrone and equilin series 37 Paracetamol CdCO3 25 Earlier prep.via 4-nitrophenyl glucuronide, ref. 39 38 Salicylic acid (2) Ag2O 57 On Me ester; see text 40 HO H D D OH D CHOAc MeO2C OH HO H HO HO OH OH 3 17 3 11 17 15 16 17 17 16 Stachulski and Jenkins: The synthesis of O-glucuronides 1756-glucuronide has been obtained in low yield34 after appropriate protection and deprotection steps.Nalorphine-6- glucuronide was noted previously.43 By comparison with alcohols, phenols may react poorly or not at all under Koenigs–Knorr conditions, though simple phenols have long been known to give acceptable yields.4 Cadmium carbonate was introduced specifically to give better access to steroidal aryl glucuronides;37 ortho esters and ·-anomers may still result, however, and the C-glucuronide 22 was also observed (14%) from reaction of 6 with equilenin.It is noteworthy that the 1·-chloro analogue of 6 may be used with CdCO3; with other catalysts, its reactivity is generally insuYcient.8 An extra possibility with phenols is to react 6 with the alkali metal phenolate. Marginally the best procedure appears to be to use the lithium salt in methanol and morphine-3- glucuronide 23, the major human metabolite of morphine (cf. 19), has been obtained in 53% yield in this way.44 Other phenolic glucuronides of morphine analogues34,42,43 have been prepared using the sodium salts in aqueous acetone, but yields in these cases were less than 10%. More recently 7- hydroxycoumarin was reacted with 6 using benzyltriethylammonium bromide as a phase-transfer catalyst45 on the Na salt and the conjugate 24 was produced in 11% yield. A persistent by-product46 from such reactions is the ‘glycoseen’ or 2-acetoxyglycal 25, formed by HBr elimination.The O-2 glucuronide of 5-fluorocytosine 26, an antifungal agent, and the protected bis-O-2, O-4 glucuronide of the antitumor agent 5-fluorouracil 27 have been obtained47 via the pyrimidine silver salts. Under these conditions only O-glucuronides were seen, however when SnCl4 was used as catalyst, ·/‚ mixtures of O-glucuronides were produced together with the N-1 and N-3 ‚-glucuronides.Finally, 6 has been employed in some oligosaccharide syntheses, exemplified by the aldobiuronic acid 28 (Ag2O)8 and a repeating unit of chondroitin 4-(6-)sulfate (AgOTf).48 Interestingly, in the latter case the author preferred this method to the imidate method (Section 3.1.4) in view of a better yield and reduced ortho ester formation. 3.1.2 Perester couplings An obvious saving results if the tetraacetate methyl ester 5 may be satisfactorily coupled to the aglycone. Many aryl glucuronides have been made in this way, e.g.fusion of phenol with 5 using toluene-4-sulfonic acid or zinc chloride4 is probably the simplest preparation of adduct 29 in up to 55% yield, essentially as in the original Helferich procedure. Paracetamol glucuronide 1 has been made similarly38 (28%, cf. Section 3.1.1) as has the 6-O-glucuronide of the antidiabetic drug CS-045 30.49 Interestingly, the latter glucuronide retained most of the parent drug’s activity. The reaction is stereochemically reliable, giving only ‚-anomers of the conjugates.The use of 1‚-ester 5 is essential, the 1·-anomer 314,8,50 giving very little or no product. With more acidic phenols, e.g. 4-nitro or 2-chloro, no product was obtained.4 With the more powerful Lewis acid SnCl4, heating is unnecessary and reaction may proceed satisfactorily at 0 )C.51 This procedure works very satisfactorily for the O-aryl glucuronide of estrone1 and is also feasible for more acidic phenols; aryl ‚-glucuronides are the sole or greatly favoured products, e.g.the 16,17-diacetate of 17 gave a ‚:· ratio of 8:1 OH H O CH2OAc O MeO2C AcO AcO AcO O HO O PriHN OH N H 18 19 20 O O CO2H HO HO OH O NMe HO H O HO O MeO2C OAc AcO OAc 22 21 O O CO2H HO HO OH O NMe H HO O O CO2Me AcO AcO OAc O O O CO2Me AcO AcO AcO 23 24 25 N N HO F NH2 N N O F O H H O HO HO O O HO2C HO HO OH OH 26 27 28 O O CO2Me AcO AcO OAc Ph O HO O CO2Me AcO AcO OAc AcO 30 31 6 Me Me Me 29 176 Natural Product Reports, 1998(yield, 50%).It was easily shown that SnCl4 cannot equilibrate the anomers. Primary alcohols are less stereoselective, however, and at 20 )C or above the ·-glucuronide was the major product when 5 reacted with 4-nitrobenzyl alcohol or 2,2,2-trichloroethanol. A more recent example, again showing regioselective glucuronidation of a polyol, involved the small-scale glucuronidation of the bile alcohols 32 using 5 and SnCl4. The 3-glucuronides were obtained as 1:1 ·:‚ mixtures which were separated by preparative TLC.52 In contrast to the glucose series, the use of other Lewis acids has not yet been reported for this type of coupling. 3.1.3 1-Hydroxy sugar couplings The use of intermediate 7 is becoming more popular, not least because it admits of more than one coupling method to the aglycone. As shown in Scheme 1, either the ‚-tetraacetate 5 or the bromo sugar 6 are suitable precursors. Treatment of 5 with Bun 3SnOMe in THF at reflux5 aVorded a 78% isolated yield of crystalline 7; the paper summarises other reagents, notably nitrogen nucleophiles, used for this purpose.The ‚-ester 5 reacted much faster than ·-ester 31; complexation as shown in 33 was proposed to account for the diVerence. The more circuitous route to 7 calls for the Ag2CO3 catalysed hydrolysis of 6 for which a 98% yield has been claimed.6 It was possible to obtain some O-aryl glucuronides directly by the Mitsunobu coupling of 7 to the appropriate phenol.For more acidic phenols (4-Br, 4-NO2) a 40–50% yield of conjugate was obtained, but phenols of low acidity, e.g. p-cresol, required prior complexation to Cr(CO)3 to obtain useful yields. Signifi- cant amounts of ortho ester and some ·-glucuronide were also obtained.53 O-Alkyl glucuronides have not been obtained in this manner. More often, however, Lewis acid-catalysed coupling of 7 has been used, particularly employing trimethylsilyl trifluoromethanesulfonate (TMSOTf).7 Both alcohols and phenols have been glucuronidated in this way, and the first intermediate is believed to be the silyl ether 34 or its O-1 protonated form (note that 7 exists as a roughly 5:1 ·:‚ mixture).The final stereochemical outcome then depends on a delicate balance of factors. Relatively nucleophilic aglycones (low-acidity phenols, primary alcohols) yield almost entirely the ‚-glucuronide, either by direct displacement on 34 or via participation of the 2-acetate, thence the stabilised cation 35.When the aglycone can form a stabilised cation (e.g. Ph2CHOH), 7 or 34 may become the nucleophile, resulting in predominant or exclusive ·-glucuronide formation. Phenols of pKa<9 do not react under these conditions, so that the Mitsunobu procedure has useful complementarity. Tietze and Seele54 have obtained both anomers of 34 separately via the 1‚-benzyl glucuronide (hydrogenation, prompt silylation and isomerisation), and had earlier established the value of such intermediates in glycosidation.55 In the artemisinin series29 (cf.Table 1, Section 3.1.1) the ‚-glucuronide of ‚-dihydroartemisinin 36 was obtained (17%) only by using 7 in conjunction with BF3 · Et2O catalysis; minor amounts of the ·-glucuronide and the 11-epimer also resulted. Here the Koenigs–Knorr procedure had aVorded only a low yield of the 10·-OH aglycone plus ·-glucuronides, and couplings of 5 failed completely. The method has been little used with steroidal alcohols. When applied9 to the monoacetates of 5·-androstane-3·,17‚- diol (15, undeuterated) only ·-glucuronides were formed in 40 and 52% yield. 3.1.4 Trichloroacetimidate method Schmidt’s pioneering studies on glycosidation using trichloroacetimidates56 have led to an increasing number of applications to glucuronidation. The relatively mild catalysis required and very high ‚-stereoselectivity make 8 an attractive intermediate. Reaction of Cl3CCN with 7 was earlier performed using sodium hydride7 or DBU48 but in fact sodium or potassium carbonate in CH2Cl2 are suYciently basic and deliver 8 in excellent yield.57 Only the ·-imidate was reported in the earlier literature but we have recently isolated the ‚-anomer 37 (cf.the glucose series).56 Crystalline 8 may be stored at "20 )C under desiccation for several weeks with little decomposition. The value of the method is seen clearly in the reaction of 8 with 4-nitrophenol using BF3. Et2 O catalysis, aVording the ‚-conjugate in 85% yield;7 as noted above, 7 fails to couple in this case and the Mitsunobu procedure gives a 50% yield (Section 3.1.3).In these laboratories we similarly obtained 24 from 8 in 61% yield57 which was a great improvement on an R HO H HO OH 3 32 R = (CH2) nCMe2OH ( n = 2,3) O O MeO2C AcO AcO OAc Sn OMe Bun 3 O 33 O CO2Me AcO AcO OAc OSiMe3 O CO2Me AcO AcO +O O Me 34 35 O O O O H H OH 11 12 36 O CO2Me AcO AcO AcO O CCl3 NH 37 Stachulski and Jenkins: The synthesis of O-glucuronides 177earlier synthesis (Section 3.1.1), and a further O-aryl glucuronide example was aVorded by the antiinflammatory drug DUP 697 38 which gave a 33% yield of the conjugate.58 The catalyst used is almost invariably BF3·Et2O, or occasionally TMSOTf. Schmidt et al.59 have successfully used chloral as a non-acidic catalyst for glycosidation using glucose imidates, but this has not been studied in the glucuronic acid series.For O-alkyl glucuronides, the method may not be quite so reliable.Thus, returning to the monoacetates of undeuterated 15,9 the 3-glucuronide ester was obtained from 8 in 40% yield, slightly superior to the Koenigs–Knorr method, but the 17- glucuronide ester in only 8% yield; both products were stereospecifically ‚. The disaccharide units 39 related to chondroitin were mentioned in Section 3.1.1; the author preferred48 TMSOTf when coupling 8 to the galactosyl acceptor, and obtained both adducts as single ‚-anomers in over 70% yield, although some regulation of catalyst quantity was needed to suppress ortho ester formation.A preliminary report has appeared60 on the successful glucuronidation of iliparcil, a thio-xylopyranoside of 4-ethyl-7-hydroxycoumarin and an antithrombotic agent, using 8; no glucuronidation was obtained with 6. The propensity of the tetrahydrocannabinol system to give C-glucuronidation1 was again shown in the reaction of ƒ6- tetrahydrocannabinol with 8 under BF3 catalysis, giving 40 in 44% yield;61 7 similarly gave 26% of 40. 3.1.5 Other methods using acyl protection Glycosyl fluorides were developed extensively as eYcient glycosylating agents in the 1980s, notably through the work of Nicolaou and Noyori, but the glucuronic acid analogues have been studied very little. The 1‚-fluoro sugar 4162 was obtained by kinetic halogen exchange63 on 6 and in BF3-mediated couplings to three aryl trimethylsilyl ethers, including the coumarins 42, gave the conjugates in 60–80% yields.Similar remarks apply to glycosyl phosphites, which have been used very eYciently in the sialic acid series. The glucuronyl phosphite 43 was obtained64 as a 1:1 anomeric mixture from 7 by reaction with dibenzyl N,Ndiethylphosphoramidate and was used to prepare the disaccharide 44, a protected form of a key unit of hyaluronic acid. In the glucose series, 1‚-thioglycosides are useful glycosyl donors but the corresponding acetylated glucuronic acid derivatives are too unreactive.Garegg et al. have described65 the interesting mixed acyl/benzyl protected analogues 45; the presence of two activating benzyl groups makes these viable glucuronyl donors on activation with dimethyl (methylthio)sulfonium triflate. The most useful compound was the 2-benzoyl (R=Ph), from which disaccharides were obtained in 70–85% yield, the 2-acyl group still guaranteeing exclusive ‚-linkage. From a practical point of view, the lengthy sequence required to prepare 45 is a drawback, cf.Section 3.2. 3.1.6 Higher acyl derivatives With the sole exception of intermediates 45, a very special case, all the glucuronic acid derivatives mentioned to date have employed acetyl protection. Two persistent problems with these derivatives, namely relative instability and tendency towards ortho ester formation, may be countered at least in part by using higher acyl derivatives; to this end Vlahov and Snatzke66 prepared the pivaloyl compounds 46a,b. The bromo sugar 46b gave 70–95% yields on Koenigs–Knorr condensation with various alcohols, and predictably is considerably more stable than 6.However, the preparation of 46a is a very slow reaction and the final hydrolytic removal of protecting groups is also sluggish, limiting the usefulness of the method. O-Aryl glucuronides of the tramadol metabolites 47 were obtained67 in 10–22% yields (after hydrolysis) by reaction of 46b with the phenolate salts, without interference from the tertiary alcohol and, notably, in the presence of non-tertiary amines.The use of isobutyryl derivatives has also been disclosed, notably of the imidate 4868 which gave the highest-yielding synthesis of paracetamol glucuronide 1 yet reported69 (cf. Sections 3.1.1, 3.1.2). As noted previously, morphine-6-glucuronide 21 is a very significant human metabolite of morphine. Not only is its analgesic activity superior to that of morphine, but it shows markedly reduced side-eVects (toxicity, nausea, respiratory depression and addiction) compared to the parent.The use of 48 in a synthesis68 of 21 was criticised as being poorly reproducible,31 but this claim was subsequently rebutted70 and the value of 48 was further illustrated in a synthesis of the hapten 49. In general, BF3-catalysed couplings of 48 to 3-acylmorphines have given 50–69% yields of the desired conjugates in our laboratories. The 1-OH intermediate S HO SO2Me F Br O MeO2C AcO AcO OAc O O R1O OR2 N3 OMe O O AcO AcO OAc CO2Me OH C5H11 38 39 R1 = Bn; R2 = Ac or vice versa 40 O CO2Me AcO AcO AcO F O HO R O O MeO2C AcO AcO OAc O P OBn OBn O O MeO2C AcO AcO OAc O HO OTBDPS NHAc O O CO2Me BnO BnO OCOR SEt 41 42 R = Me or CF3 43 44 45 R = various O MeO2C PivO PivO OPiv R HO OH NR1R2 46a R = b-OPiv b R = a-Br Piv = Me3CCO 47 R1,R2 = H,Me 178 Natural Product Reports, 1998required to prepare 48 is obtained by selective hydrolysis of the corresponding ‚-tetraester using ammonia.68 As with the pivaloyl intermediates, transacylation products are much reduced, but the coupling reactions are significantly faster. 3.1.7 Hydrolysis of ester-protected glucuronides Normally the final glucuronide is obtained by simple hydrolysis of the ester-protected conjugate using KOH or NaOH in aqueous alcohols. This is especially convenient if the alkali metal salt of the glucuronide is desired (e.g. ref. 37). If the free glucuronic acid is required, it may be useful to deacetylate by the Zemplen procedure,42 possibly using a basic ionexchange resin,71 followed by Ba(OH)2 hydrolysis of the methyl glucuronate and precipitation of BaSO4 with sulfuric acid.Milder base may be quite adequate, even preferable, e.g. ester 24 was hydrolysed in good yield using Na2CO3 without any opening of the coumarin lactone.57 Enzymic deacetylation may also be considered, e.g. acetylated furan[3,2-b]furan-2-one 50 was fully deprotected by an Aspergillus lipase,72 but ‘normal’ glucuronide esters do not appear to have been hydrolysed in this way. 3.2 Ether series. Preparation of intermediates While the ease of preparation and deprotection of acyl glucuronide conjugates bring many advantages, there are numerous occasions when they are not suitable, as noted in Section 2.2. The necessary activated intermediates in the benzyl ether series have generally been obtained by oxidation of appropriate glucose derivatives, as shown in Scheme 2.Thus, oxidation of primary alcohol 51,73 itself available74 from glucose, followed by esterification aVorded the fully protected glucuronic acid derivative 52. Hydrolysis of the glycosidic linkage aVorded the key 1-hydroxy sugar 53 which could be transformed into the halo sugars73 54a,b or the imidate 55.75 Closely similar sequences have been used to prepare similar intermediates with diVerent esters. 3.2.1 1-Halo and 1-hydroxy sugars, ether series While treatment of the 1-hydroxy sugar 53 with PBr3 aVorded exclusively the 1·-bromo sugar 54a, either anomer of the chloro sugar 54b could be isolated after SOCl2 treatment.73 Schmidt and Ruecker found that reaction of any of these halo intermediates with various aglycones using silver perchlorate in acetonitrile led very largely to the ·-glucuronides at "15 )C.The common intermediate is believed to be the nitrilium conjugate 56 (associated with further solvent molecules); other solvents gave diVerent results.The 1-hydroxy sugar 53 has also been used in glucuronide synthesis, along with the corresponding benzyl ester;76 both these compounds could be obtained by alternative routes from ester 5. Condensation of 53 with various glucose acceptor species using a 4-nitrobenzenesulfonyl chloride, AgOTf and triethylamine mixture in CH2Cl2 aVorded the ·-glucuronides 57 in all cases; only with the primary alcohol acceptor (1–6 link) was the amount of ‚-glucuronide significant.A glucuronide-containing trisaccharide was also made by this method. 3.2.2 Ether trichloroacetimidates Reaction of imidate 55 with a range of alcohol and phenol acceptors75,77 using BF3 in CH2Cl2 at "15 to "30 )C aVorded stereoselectively O-alkyl and O-aryl ‚-glucuronides; the products were readily isomerised to the ·-anomers with BF3 at +20 )C. Schmidt noted that other acid catalysts (toluene-4-sulfonic acid, TMSOTf) were not suitable for obtaining the ‚-products.The use of 55 to obtain the aryl glucuronides of the hydroxy metabolites 58 and 59 of the antidepressant drug mianserin and its 6-aza analogue, Org 3770,78 was reported in the earlier review.1 N-Trifluoroacetyl protection was used and the desired ‚-glucuronides were preferentially formed. Various methods using bromo sugars or a perester coupling failed here, but the acyl imidate 8 was apparently not tried. Reaction of ·-imidates with mono- and di-esters of phosphoric acid aVords a general synthesis of sugar phosphates; the O MeO2C PriCO2 PriCO2 O NH CCl3 PriCO2 O HO2C HO HO OH O O N HO H NH2 48 49 O O O OAc OAc OAc 50 O BnO BnO HO OBn OMe O BnO BnO CO2Me OBn OMe O BnO BnO CO2Me OBn OH O BnO BnO CO2Me OBn O BnO BnO CO2Me BnO X O NH CCl3 a-Me-D-glucoside i, ii iii, iv v 52 vi 53 54a X = a-Br b X = a/b-Cl 51 55 Scheme 2 Intermediates for glucuronidation, ether series.Reagents: i, CrO3, H2SO4; ii, CH2N2; iii, AcOH, Ac2O; iv, NaOMe, MeOH; v, PBr3 or SOCl2; vi, Cl3CCN, NaH, CH2Cl2 O BnO BnO CO2Me BnO N C Me O BnO BnO CO2R BnO OG 56 57 R = Me, Bn; G = glucose residue + Stachulski and Jenkins: The synthesis of O-glucuronides 179glucuronic acid examples 60 have been recorded.79 Here again, acid-catalysed isomerisation leads to the thermodynamically more stable 1·-phosphates.Carboxylic acids similarly yield protected O-acyl glucuronides. 4 Acyl and carbamoyl glucuronides There has been a considerable growth of interest lately in the synthesis of these classes of metabolites, which are conveniently grouped together.As noted in the introduction, O-acyl glucuronides show very low hydrolytic stability and conventionally protected derivatives, especially of the acyl series, are liable to be of very limited use. O-Carbamoyl derivatives are significantly more stable. Here base-catalysed deprotection, if mild, has a fair chance of success. Ether protection has been used for both classes, though there has been a growing tendency to develop new protective methods, or even to use unprotected sugars.Compernolle’s pioneering syntheses80,81 of bilirubin and biliverdin O-acyl glucuronides, cited in the Kaspersen and Van Boeckel review,1 employed ·-ethoxyethyl ethers (removable by mild acid) but these have not been employed subsequently. 4.1 Acyl glucuronides Considering first acyl-protected sugars, it has long been known6 that acylation of 1-hydroxy sugar 7 with carboxylic acids using N,N* -dicyclohexylcarbodiimide aVorded ·/‚ mixtures of fully protected O-acyl glucuronides.Varying ·/‚ ratios were reported with diVerent classes of acid and no attempts at deprotection were reported. A number of syntheses of retinoyl glucuronides have been reported, the interest stemming from the high biological activity (cell growth control, teratogenicity) of retinoids. The polyene conjugation of the retinoyl moiety improves its hydrolytic stability, so that Zemplen deacylation of the conjugate 61 was possible, leaving the methyl ester 62;27 61 was obtained in high yield by coupling the silver salt of all-trans retinoic acid to bromo sugar 6.Allyl- and allyloxy-carbonyl groups are removable under very mild conditions using Pd0 reagents and are therefore suitable for acyl glucuronide synthesis. The ester tricarbonate 63 was prepared82 by a lengthy sequence from 6 and used to prepare the O-acyl glucuronide of the analgesic acid 64 (Mitsunobu coupling).The corresponding tri-O-benzyl ether conjugate, prepared from a known intermediate,83 could not be deprotected without reducing the ketone function. Very recently the allyl ester of D-glucuronic acid has been successfully coupled to a range of carboxylic acids, again using Mitsunobu conditions, to aVord conjugates 6584 which were deprotected by Pd0 in the presence of pyrrolidine to aVord good yields of the O-acyl ‚-glucuronides.Preparative highperformance liquid chromatography (HPLC) was required to obtain the desired ‚-adducts 65 in good purity (25–40%), but hundreds of milligrams of product were conveniently made in this way. Benzyl ester/ether protection was successfully applied to the synthesis of the O-acyl glucuronide of lithocholic acid 66;85 protection of the 3-OH was unnecessary in the Mitsunobu coupling step. The product was shown to be identical with an enzymatic glucuronidation product.Silyl protection has also been investigated. Thus the trichloroethyl ester, tris-silyl ether 67 was obtained86 in six steps from 6 via the 1-benzyl ether.6,54 The intermediate was used to prepare the O-acyl glucuronide of acid 68 after phenolic protection; it was necessary to use HF in MeCN, rather than tetrabutylammonium fluoride, for deprotection to preserve the anomeric acyl linkage. A number of syntheses of retinoyl glucuronide (v. s.) have been reported which dispose altogether with protecting groups: compared to retinoic acid, the glucuronide (viz.free acid form of 62) is considerably less cytotoxic and has attracted attention as a possible anticancer, or at least prophylactic, agent. Retinoyl fluoride 69, on reaction with glucuronolactone 4 in mildly basic solution, gave a mixture of lactones (cf. Sections 5, 6) from which the desired O-acyl ‚-glucuronide could be isolated87 by cautious hydrolysis and preparative HPLC. The product peak was assayed using ‚-glucuronidase.Glucuronic acid (Gla) itself, or its sodium salt, has been similarly coupled X N N HO H O BnO BnO CO2Me BnO O P OX OR O 58 X = CH 59 X = N 60 R = alkyl; X = H or alkyl O RO RO MeO2C RO O O 4 13 9 61 R = Ac 62 R = H O AocO AocO BnO2C AocO OH HO2C HO O O HO HO HO O R O O O 63 Aoc = allyloxycarbonyl 64 65 R = various CO2H HO H O RO RO Cl3CCH2O2C RO OH OH OMe CO2H R O N N 3 66 67 R = TBDMS 68 69 R = F 70 R = 180 Natural Product Reports, 1998to 69 and the 11-3H-labelled analogue of the glucuronide has been prepared as a metabolic probe.27,88 The yield of retinoyl glucuronide has been improved to 68–79% in a recent modifi- cation whereby the tetra-n-butylammonium salt of Gla was reacted with the acyl imidazolide 70.89 Finally, a number of analogues of 62 free acid have been prepared90 containing 9Eor 13E-double bonds with or without a 4-oxo group, using the sodium salt of Gla plus the appropriate fluoro-analogues of 69. 4.2 Carbamoyl glucuronides Amino groups in drugs and other xenobiotics are often metabolised directly as N-glucuronides, but it has been established relatively recently that carbamoyl glucuronides may also be formed. Thus the structure 71 was firmly established91 as a metabolite of the antidepressant Org 3770 (cf. 59). Its synthesis was achieved by reacting the benzyl ester corresponding to 53 with the appropriate acyl imidazolide; the desired ‚-anomer was separated by preparative HPLC after removal of benzyl groups.Anthracyclines such as daunomycin are of great value as anticancer agents. In a recent study92 various daunomycin derivatives, including a carbamoyl glucuronide, were synthesised as prodrugs. As hoped, this glucuronide was appreciably less toxic (1:2000) than the parent drug. Its synthesis was achieved from the ‚-anomer of silyl ether 3454 by desilylation and rapid acylation to give the mixed carbonate 72 as the single ‚-anomer. Base-catalysed reaction of 72 with daunomycinone · HCl followed by mild hydrolysis aVorded the desired prodrug.Isocyanates have also been used as precursors of carbamoyl glucuronides. Thus reaction of RNCO with the 1-hydroxy sugar 7 aVorded adducts 73, the best ‚-stereoselectivity (>98%) resulting from a combination of toluene and triethylamine. 93 The isocyanates were generated in situ from azides via Curtius rearrangement (85 )C). 5 Other synthetic methods Since, as noted above, glucosides are often easier to prepare than glucuronides, selective oxidation of a preformed glucoside oVers a logical glucuronide synthesis. Thus the oxidation of several O-aryl ‚-D-glucopyranosides to the corresponding glucuronides using platinum black and oxygen at pH 8–1094 proceeded in 17–39% yield; product isolation was assisted by in situ conversion to the benzyl esters. A recent synthesis of a glucuronic acid-containing pentasaccharide95 involved at a late stage the two-step oxidation of a glucoside precursor (Swern oxidation with oxalyl chloride, then sodium chlorite).In another recent variant96 the n-octyl glucuronide methyl ester 74 was obtained from the corresponding unprotected octyl glucoside in 67% yield by oxidation with sodium hypochlorite and a catalytic amount of 2,2,6,6-tetramethylpiperidinyloxy free radical (TEMPO). Other manipulations of existing glucuronides are possible. Thus hydrogenolysis of fully protected 4-nitrophenyl glucuronide aVorded the amine 7597 which was acylated with retinoyl chloride to give another retinoyl derivative of potential interest in cancer therapy (cf.Section 4.1). Enzymic synthetic methods will be considered in Section 8, but an interesting selective enzyme hydrolysis is worth recording here. Thus treatment of morphine-3,6-diglucuronide 7668 with a variety of ‚-glucuronidases gave another synthesis of morphine-6-glucuronide 21 by preferential cleavage of the O-aryl glucuronide.The most eYcient enzyme was that derived from limpets Patella vulgata.98 6 Furanose forms Glucurono-6,3-lactone 4 is itself a furanose form, and while this review is primarily concerned with the ‘normal’ pyranose forms, glucofuranosidurono-6,3-lactones will be briefly discussed here. The generally higher reactivity of furano sugars applies in the uronic acid series also, and the ·/‚ methyl uronosides 77 are obtained simply by heating 4 with methanol in the presence of a cationic exchange resin.99 The anomeric triacetates 78 have long been known and are easily separated;100 they are both readily substituted at the anomeric centre by various aglycones with Lewis acid catalysis.More recently, furano glucuronides analogous to 77 were prepared by treating 4 (or Gla itself) with various long-chain primary alcohols and BF3·Et2O in THF at reflux. Saponifi- cation gave the ‚-D-glucofuranosidic acids 79.101 If this result is correct, one may query whether the retinoyl glucuronide obtained in Barua and Olson’s original synthesis87 (using 4) might also have been a furanose form (Section 4.1).Acetylated structures such as 80 are very base-labile, and give complex mixtures on saponification (cf. Section 7). Mild 73 R = various 72 N N N O O O HO2C HO HO OH 71 O MeO2C AcO AcO AcO O O O N O O O MeO2C AcO AcO AcO O O NHR 74 76 75 O MeO2C AcO AcO AcO OC8H18- n O MeO2C AcO AcO AcO O NH2 O HO2C HO HO HO O O HO2C HO HO HO O O NMe H 77 5 78 R = a/b-OAc 80 R = a/b-OMe 79 R = n-C8H18 etc.O O OMe OH OH O O O R OAc OAc O O HO OR OH HO2C OH Stachulski and Jenkins: The synthesis of O-glucuronides 181non-aqueous base (Et3N in CHCl3) treatment of 80 aVords one way of achieving isomerisation at C-5, entering the L-iduronic acid series.102 7 Dehydroglucuronides and other modified glucuronides A detailed discussion of the chemistry of glucuronides is beyond the scope of this review, but some of the more significant and easily obtained modified structures will be mentioned here.Among these, ƒ4,5-glucuronides (referred to herein as ‘dehydroglucuronides’) are particularly relevant as they may be formed in trace or even significant amounts during glucuronide synthesis. Adamczyk et al.103 noted that HPLC analysis of both commercial and synthetic estriol 16·-glucuronide revealed two components. The minor component was tentatively assigned as a dehydroglucuronide, and indeed when the precursor ester was treated with DBU in THF the ·‚-unsaturated ester 81 resulted in 79% yield; hydrolysis aVorded the fullycharacterised dehydroglucuronide, identical with the HPLC impurity. It is clear that any basic hydrolysis is liable to give traces of dehydroglucuronides (cf.Section 3.1.7); small amounts of such derivatives were probably overlooked in earlier work, or removed by crystallisation. The mechanism of this elimination is of interest. Clearly the C-4 and C-5 substituents are not disposed for classical trans E2 elimination, even after conformational change, and indeed evidence for an E1cB mechanism has been presented,104 a C-5 anion being stabilised by the neighbouring ester group.Predictably the ‚-D-galacturonic acid derivative 82, perfectly disposed for E2 elimination, lost the elements of MeOH much more readily than its 4·-OMe (gluco) epimer. Similar results were obtained by Tajima105 who showed that the elimination was also facilitated by a 1‚-substituent.Thus the free C-5 acid corresponding to 5 on treatment with triethylamine and acetic anhydride at 50 )C readily lost two molecules of AcOH, giving mainly comanic acid 83 in high yield. Under the same conditions, the 1·-acetate gave mainly 84. It may be noted that treatment of a free glucuronide in the chrysine series with acetic anhydride and NaOAc did not yield elimination products but the lactone 85 as cited in the earlier review.1,106 Another intriguing product, the cyclopentanone 86, obtained from the methyl ester of 84 on treatment with triethylamine in methanol107 is a useful perfumery and pharmaceutical intermediate.Naturally, hydrogenation of dehydroglucuronides aVords an entry to 4-deoxyuronic acid derivatives.108 The sense of addition is controlled by the 1-substituent. Thus hydrogenation of the 1·-methylglycoside 87 aVorded mainly the 4-deoxy-L-ido (5·-CO2Me) product. This result was discussed in terms of both conformational and steric factors.In general, inversion of the D-gluco to the L-ido series is of value, since L-iduronic acid is a constituent of some important natural products (heparin, dermatan sulfate) but commercially very expensive. The isomerisation of a furanose form was noted above (Section 6) and other L-iduronic acid syntheses have been described109 from isopropylidene-protected furanose forms of glucose or glucuronolactone, e.g. 88 by inversion of the tosylate-bearing carbon via an epoxide.An ingenious approach by Sinay, leading directly to a protected form of L-iduronic acid useful in synthesis, again takes advantage of the distinctive C-5 reactivity of glucuronic acid derivatives. In addition to the stabilisation of a C-5 anion, C-5 radicals are stabilised through the captodative eVect. Thus bromination of ester 5, using N-bromosuccinimide110 or (better) bromine and a heat lamp,111 aVords the fairly stable 5·-bromo derivative 89 in up to 89% yield.Elimination reactions from 89 give other routes to dehydroglucuronides (4-H or 4-acetoxy). Radical reduction of 89 using tri-n-butyl tin hydride112 aVords a mixture of 5 (63%) and the desired ido-product 90 (27%); though the yield of 90 is modest, it may readily be separated on a multigram scale. When these reactions were repeated in the 4-deoxy series, radical reduction of the much less stable 5·-Br compound almost entirely regenerated the 5‚-CO2Me series, but the 5·-CO2Me derivative 91 was the major product on zinc–AcOH reduction (not possible on the 4·-OAc compound 89 because of ‚-elimination).Clearly the ‚-CO bond profoundly aVects the radical chemistry. ‚-Glucuronidases are commonly used as analytical tools as it is generally assumed that they will hydrolyse any suspected glucuronide metabolite to the aglycone. Therefore there is some interest in more deeply modified structures which could be substrates for, or inhibitors of, ‚-glucuronidases. The phosphono 92 and tetrazolyl 93 analogues of 4-methylumbelliferyl glucuronide were obtained by lengthy sequences from glucose and glucuronolactone precursors, respectively.113 Compound 92 was a moderate substrate for an E.coli ‚-glucuronidase, but neither 92 nor 93 was hydrolysed by a bovine liver-derived enzyme. Also the oximino structures 94 and 95 were prepared by analogy with a known ‚-glucuronidase inhibitor and tested. The carboxylate 94 HO OH O AcO AcO CO2Me O CO2Me OMe MeO MeO OMe O 81 82 O O CO2H O CO2H AcO AcO OAc O OAc OAc O O O O O OAc Ph MeO OH CO2Me OMe O 86 83 84 85 O O O HO OH TsO O CO2Me HO HO OMe 87 88 O CO2Me AcO AcO AcO OAc Br O R AcO AcO OAc CO2Me 89 90 R = OAc 91 R = H 182 Natural Product Reports, 1998proved quite a potent inhibitor of both enzymes but the phosphonate 95 was a very weak inhibitor only of the bovine liver enzyme. 8. Enzymic methods of glucuronidation 8.1 UDP-glucuronosyl transferase The enzymes involved in the glucuronidation of xenobiotics are known as UDP-glucuronosyltransferases (UDPGTs; EC 2.4.1.17).These are located in the endoplasmic reticulum of cells from a number of tissues but usually have a greater abundance in the liver. Whole families of UDPGTs have evolved to specifically metabolise a variety of endogenous and various food chemicals114 and dozens of isoforms have been characterised in rat115,116 and humans117,118 by conventional purification techniques and cDNA cloning.117 All of these UDPGTs also randomly catalyse the glucuronidation of drugs, pesticides, carcinogens and other man-made substrates (Table 2).Multiple forms of UDPGTs have been observed in most species (Table 3) with individual isoforms of UDPGT exhibiting higher specificity for particular endogenous substrates.119 These isoforms are often trivially named after their selectivity towards this endogenous substrate. The work of Burchell et al. on the cloning of the Human cDNAs that express UDPGTs has produced a systematic nomenclature based on an assessment of the similarity of the amino acid sequence of the enzyme.118 The enzymes are thought to be anchored into the endoplasmic reticulum membrane.From studies of the topology of the protein sequence using protein and antibody studies120 or by computer simulation121 of UDPGT sequences, it is likely that the carboxy terminal end, which is highly charged, is exposed to the cytoplasmic surface of the membrane.A short transmembrane region then leads to the majority of the protein, which includes the active site, being located in the lumen (Fig. 1). Comparisons between diVerent UDPGTs on an amino acid level has shown good conservation in the transmembrane and UDPGA binding domains. It is the substrate binding domain that shows the majority of the variability between diVerent UDPGTs. The catalytic cycle involved in the glucuronidation of substrates is outlined in Fig. 2. The UDPGT enzymes require UDP-glucuronic acid [UDPGA] as cosubstrate. This in turn is synthesised from UDP-glucose by UDP-glucose dehydrogenase which coexists in the same tissues as UDPGT and is often induced by increases in UDPGT levels.122 8.2 Exploitation The isolation of this class of enzymes and their subsequent exploitation to provide convenient catalysts for industrial or even laboratory glucuronidation is fraught with diYculties. As membrane anchored enzymes, they are phospholipid dependant and this instability has delayed the isolation and purifi- cation of many of the UDPGTs.Their use can be divided into two camps—isolated purified enzymes or liver microsomes. 8.2.1 Purified UDPGTs 8.2.1.1 Isolation and purification The isolation and purification of UDPGTs has been continuously improving123 since early attempts in the 1950s.124 Earliest protocols were long and this had a marked, detrimental eVect on the activity of the enzyme extract.125 The phospholipid dependancy and inherent instability makes the eYciency and conditions of any isolation technique very crucial in determining the success.The use of high amounts of detergent to release the enzyme from the reticulum can be problematical but good results have been observed with Lubrol 12AU114 or Emulgen 911.115 This solubilisation of the enzyme is often followed by anion exchange chromatography to remove the detergent and then use of UDP-hexanolamine Sepharose aYnity chromatography can eVect the isolation of UDPGTs.The presence of many isoforms of UDPGT means Table 2 Substrates that react with multiple forms of rat UDPGT 4-Nitrophenol (4 forms) 4-Methylumbelliferone (4 forms) 1-Naphthol (3 forms) ·-Naphthylamine (3 forms) ‚-Naphthylamine (3 forms) Testosterone (2 forms) Estradiol (2 forms) 4-Hydroxybiphenyl (2 forms) O R HO HO HO O O O Me N N NH N O R HO HO HO N O NHPh O 92 R = PO(ONa)2 93 R = 94 R = CO2Na 95 R = PO(ONa)2 Table 3 Example of liver UDPGTs from diVerent animals Rat 4-Nitrophenol UDPGT (2 forms) 17‚-Hydroxy steroid UDPGT (2 forms) 3·-Hydroxy steroid UDPGT Morphine UDPGT (2 forms) Digitoxigenin UDPGT Bilirubin UDPGT Estrone UDPGT 4-Hydroxybiphenyl UDPGT Rabbit 4-Nitrophenol UDPGT (2 forms) Estrone UDPGT Morphine UDPGT Mouse pI 8.5 UDPGT pI 6.7 UDPGT Pig 4-Nitrophenol UDPGT (2 forms) Human pI 7.4 UDPGT (estriol) pI 6.2 UDPGT Bilirubin UDPGT Morphine UDPGT (2 forms) 6-Hydroxy bile acid UDPGT Tertiary amine UDPGT Phenol UDPGT (2 forms) H3N COO– Cytoplasm UDPGA binding conserved + Lumen Endoplasmic reticulum Substrate binding region variable Fig. 1 Location of UDPGT Stachulski and Jenkins: The synthesis of O-glucuronides 183that further techniques such as column isoelectric focusing have become widespread if single isoforms are required.115,126 8.2.1.2 Immobilisation The first reported immobilisation in the mid 1970s solved two of the problems inherent in using isolated UDPGT.127 The technique employed was condensed into 8 hours, increasing the final activity of the enzyme preparation and the immobilisation onto Sepharose, using a standard CNBr methodology, greatly increased the stability, increasing the half-life of the enzyme from 10 days to 45 days. Further studies128 demonstrated that the immobilised enzyme could still glucuronidate a variety of substrates including the glucuronidation of propafenone 96 and 5-hydroxypropafenone 97.This later study129 demonstrated that it was possible to determine kinetic parameters for diVerent substrates quantitatively (5-hydroxypropafenone is 10 times a better substrate than propafenone). Purification and immobilisation of the UDPGTs has met with limited success, with losses of up to 80% of the enzymic activity.130 The increase in genetic engineering techniques has now begun to produce techniques for the cloning of the cDNA reponsible for the various families of UDPGTs.118 This has allowed greater expression of the enzymes.131 This approach is still technically challenging. 8.2.2 Liver microsomes To overcome the diYculties of isolating purified enzymes and maintaining their viability, many workers use crude liver microsomes in their investigations.Liver microsomes are prepared by homogenising fresh liver and collecting the microsomes by centrifugation. They have the advantages of being relatively stable and also possess the UDP-glucose dehydrogenase which potentially can be used for generating the required UDPGA from UDP-glucose. Many of these applications have been concerned with establishing the glucuronidation pathway of various drugs and their metabolites which were only required in small quantities for detection in HPLC and mass spectrometry assays.However, production of larger amounts of glucuronides is diYcult to achieve by this method. 8.2.2.1 Immobilised artificial membranes An approach to increasing the throughput of enzymic glucuronidation systems involving liver microsomes relies on hollow fibres that contain lipid membranes.These are known as immobilised artificial membrane (IAM) supports and form microsomal immobilised enzyme reactors (MIER). To prevent problems of product inhibition, continuous dialysis is often employed. These approaches have been used in both batchwise and continuous flow modes which can produce up to 10 mmol of glucuronide per hour and mg of protein.As crude liver extracts can be used, advantage can be taken of the presence of UDP-glucose dehydrogenase to generate UDPGA in situ as demonstrated by Gygax et al.132 In this system a chamber with a semi-permeable membrane that retains all material of >10 kDa is charged with crude liver extract. The substrate 98 (at 5 mM) is passed through the chamber at 6 ml h"1 over a period of 20 h, showing up to 95% conversion (determined by radioactivity scanning) with an isolated yield of 37 mg (50%) after reverse phase HPLC.The high conversion rates of some substrates has led to the development of a precolumn cartridge for HPLC analysis of glucuronides.133 A commercially available immobilised artificial membrane cartridge (IAM.PC) is loaded with nonsolubilised rat liver microsomes. This was then placed in line with another IAM.PC, used to chromatographically separate the mixture of glucuronides formed when a substrate was injected into the flow.To increase the glucuronidation observed, the flow was stopped for 20 min. This was repeated over the course of 8 days to demonstrate that the specific activity of the UDPGTs decreased from 96 pmol 4-methylumbelliferone min"1 mg"1 protein to 7.8. This report showed that it is possible to set up an in-line glucuronidation system for analysis by HPLC, which would be useful for one week. The use of liver microsomes is far from ideal. Although more stable than the isolated enzymes there are reported diYculties in obtaining reproducible glucuronidation activities.This arises due to the latency of the enzymes which often require some form of induction to switch on the activity. However, many of the substrates used to induce the enzymes can disrupt the membranes. Although this increases activity of glucuronidation (possibly by increasing the transport of UDP-GA from inside the cell to the binding site of the UDPGT) it increases the instability of the enzyme and reduces the turnover.In conclusion, the area of glucuronidation by the use of UDP-glucuronosyl transferase has remained the province of the pharmacologists and biochemists. Today there are well documented techniques for isolating either liver preparations or purified UDPGT enzyme which are being exploited by some companies and researchers to probe the products of drug O HO HO HO OUDP HO O HO HO HO OUDP HO O O HO HO HO HO O O R O HO HO HO OPO3 2– HO 2 NAD+ UDP UTP PPi I II III phosphoenolpyruvate pyruvate UDP-glucose UDP-glucuronic acid substrate b-D-glucuronide glucose-1-phosphate I UDP-glucuronosyl transferase II UDP-glucose dehydrogenase III UDP-glucose pyrophosphorylase IV pyruvate kinase Enzymes involved: 2 NADH HO—R IV Fig. 2 UDPGT cycle O O OH NH R 96 R = H 97 R = OH N HO NH 98 184 Natural Product Reports, 1998metabolism. The extensive work by the Dundee group led by Burchell is making over-expression of many diVerent human UDPGT enzymes possible and as our understanding of the nature of these enzymes increases, so too will their applications to the synthesis of unusual glucuronides. 9 References 1 F.M.Kaspersen and C. A. 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ISSN:0265-0568    

DOI:10.1039/a815173y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Recent advances in the chemistry of caryophyllene Isidro G. Collado,a James R. Hansonb and Antonio J. Macías-Sáncheza aDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Apartado 40, 11510, Puerto Real, Cádiz, Spain bThe School of Chemistry, Physics and Environmental Science, University of Sussex, Brighton, Sussex, UK BN1 9QJ Covering: Up to June 1997 1 Introduction 2 The conformations of caryophyllene 3 Cyclization reactions of trans-caryophyllene 3.1 Cyclizations in acidic media 3.2 Mercuration–demercuration 3.3 Cyclizations in super-acid media 4 Isocaryophyllene 5 Caryophyllene oxides 5.1 Cyclization in an acidic medium 5.2 Mercuration–demercuration 5.3 Cyclization in a super-acid medium 6 Solvolytic reaction of caryophyllenols 7 Thermal rearrangements of trans-caryophyllene 8 Radical rearrangements of trans-caryophyllene 9 Reaction of the epoxides in alkali 10 Oxidation and reduction of caryophyllene 11 The rearrangements of clovene, neoclovene and caryolan-1-ol in acidic and super-acidic media 12 Conclusions 13 References 1 Introduction (")-trans-Caryophyllene [(")‚-caryophyllene] 1 plays an important role in the chemistry of the sesquiterpenoids.Caryophyllene 1 and its hydroxylation products are found in many plants and fungi.1 The most abundant source of caryophyllene 1 is the clove tree Eugenia caryophyllata (Syzygium caromaticum). Caryophyllene 1 is a biogenetic relative of humulene 2,2 with which it cooccurs.The unusual structure of caryophyllene involving a cyclobutane ring fused in a trans manner to a nine-membered ring containing a 1,5-diene, provides the basis for a variety of transformations leading to tricyclic sesquiterpenoids. 3 An understanding of the chemistry and conformational aspects of these cyclizations is important in rationalizing the biosynthesis of these families of polycyclic sesquiterpenes. Since caryophyllene 1 is readily available, these cyclizations may provide useful access to rarer sesquiterpenoids in suY- cient quantities for the chemical and microbiological synthesis of biologically interesting sesquiterpenoids. The object of this review is to describe recent advances in the chemistry of caryophyllene 1 in the light of its conformational mobility and cyclizations. Caryophyllene 1 has been known since 1834, although the material obtained in the initial studies on oil of cloves was a mixture of cis-caryophyllene 3 and trans-caryophyllene 1 with humulene 2.In 1892, Wallach and Walker4 obtained its crystalline nitrosite (1,2-nitro-nitroso derivative) and were able to characterize trans-caryophyllene 1. Extensive degradative studies over the following 60 years led to the structure of caryophyllene. Oxidative degradation of caryophyllene aVorded three cyclobutane dicarboxylic acids, norcaryophyllenic acid 4, caryophyllenic acid 5 and homocaryophyllenic acid 6, which have been synthesized,5 thus establishing the presence of the four-membered ring.The nature of the second ring was a matter of doubt for some years but it was eventually clarified by the degradation of caryophyllene oxide.6 This led to the realization that caryophyllene possessed a ninemembered ring. Studies on the acid-catalysed cyclization of caryophyllene and caryophyllene oxide7,8 revealed the formation of two series of cyclization products possessing the caryolane and clovane skeleta and exemplified by the alcohol caryolan-1-ol 7a and the unsaturated hydrocarbon clov-2- ene 8.The elucidation of the structures of these cyclization H H 1 3 5 7 1 9 2 15 10 12 14 13 CO2H (CH2) nCO2H R H H H H H H 2 6 6 11 12 13 14 3 9 9 11 12 13 14 15 15 3 4 n = 0 5 n = 1 6 n = 2 8a 7a R = OH 7b R = Cl ba aa bb ab (Kcal mol–1) % (MM1) % (13C NMR) 14.78 3.37 – 13.69 21.22 25 12.94 75.33 75 16.94 0.09 – D H Scheme 1 O H H 9 Collado et al.: Recent advances in the chemistry of caryophyllene 187products in 1953,9 together with an X-ray structure of caryolanyl chloride 7b10 and studies on the absolute stereochemistry of these alcohols,11 led to the establishment of the complete stereochemistry of (")-trans-caryophyllene 1 and its cis isomer, called isocaryophyllene 3.This work has been summarized in previous reviews.12 Two general features emerged from this earlier work. The first was that the endocyclic 4,5-double bond of transcaryophyllene 1 was more reactive than the exocyclic 8(13)- double bond and the second was the propensity of the system to undergo cyclization reactions.The first synthesis of trans-caryophyllene 1 and isocaryophyllene 3 was reported in 196313 and a number of other successful syntheses have subsequently been reported.14–19 2 The conformations of caryophyllene Molecular mechanics calculations and 13C NMR20,21 studies have shown that there are four possible conformations of (")-trans-caryophyllene 1 distinguished by the relative Scheme 2 H H H H H H H H H H H 1 3 7 9 6 1 1 9 8 8 4 1 9 10 a-Neoclovene 11 b-Neoclovene 12 a-Panasinsene 13 14 15 16 H HO H H H H OH H H H H H H H HO 9 2 1 1 8 4 5 7a 3a 17 18 19 20 21 22 Panasinsan-8b-ol 24 Clovan-2b-ol 23 Isocaryolan-8-ol + H+ – H+ + H+ – H+ + H+ – H+ 3, 17 H H H + + + + 1-ba A B 19, 20, 21 Scheme 3 H H H H H H H H H H H H H + H+ – H+ + + + + 15 16 17 14 3 1 + H+ – H+ + H+ – H+ + H+ – H+ + H+ – H+ + H+ + H+ – H+ + H+ – H+ + H+ – H+ + H+ – H+ – H+ Scheme 4 188 Natural Product Reports, 1998disposition of the exocyclic methylene and olefinic methyl groups.The predicted and experimentally determined populations of these conformations are shown (Scheme 1). NMR spectroscopic studies indicate that there is a low inversion barrier (ƒG1=16.25&0.11 or 16.1&0.3 kcal mol"1) between the ‚·- and ‚‚-conformers. The relative population of these conformers is reflected to a certain extent in the ratios of products of various reactions of caryophyllene such as epoxidation, hydroboration and photooxidation.20 A similar ratio of conformers (80:20) has been found for the nor-ketone 9.22 The conformers of the cis isomer, isocaryophyllene 3 (Scheme 2), diVer far less in their stability23,24 and there is a lower inversion barrier between them.25 3 Cyclization reactions of trans-caryophyllene The cyclizations of trans-caryophyllene 1, initiated by electrophilic attack on one of the two double bonds may be considered under three headings: (i) cyclizations in acidic media such as sulfuric acid–diethyl ether; (ii) mercuration and reductive demercuration with sodium borohydride; and (iii) reactions in super-acid media. 3.1 Cyclizations in acidic media When trans-caryophyllene 1 is treated with three equivalents of concentrated sulfuric acid in diethyl ether at 0–20 )C for 30 min, a mixture containing at least 14 hydrocarbons and 4 alcohols is formed. After three days this mixture is simplified to 3 hydrocarbons and 3 alcohols.The products that are formed after 30 min are: clov-2-ene 8a,9 caryolan-1-ol 7a,9 ·-neoclovene 10,26 ‚-neoclovene 11,26 ·-panasinsene 12,27 13,28 isocaryophyllene 3,9,29 14,30 15,30 16,30 17,3b 18,3b 19,3b 20,3b 21,3b panasinsan-8‚-ol (panasinsanol B) 22,3b isocaryolan-8-ol 2331 and clovan-2‚-ol 2432. The major products that are found after three days are caryolan-1-ol 7a, clov-2-ene 8a and ·-neoclovene 10.Protonation of the exocyclic double bond of the major ‚·-conformer of 1, generates the carbocation A which has the correct geometry to cyclize, with the formation of 19, 20 and Table 1 Major cyclization products of caryophyllene with diVerent reagents Starting material Product Reagent(s) Refs. 1 7 Chloroacetic acids (mono-, di- and tri-) AcOH–cationic exchange resins 36,37 38 1 8 Lewis acids (e.g. AlCl3) AcOH–cationic exchange resins 39 38 1 26 Synthetic zeolites 40 1 27 Chloroacetic acids (mono-, di- and tri-) AcOH–cationic exchange resins 36,37 38 1 28 HCO2H 41,42 1 29 Chloroacetic acids (mono-, di- and tri-) AcOH–cationic exchange resins Synthetic zeolites 36,37 38 40 1 30 Chloroacetic acids (mono-, di- and tri-) 36,37 1 31 Lewis acids (e.g.AlCl3) 39 1 33a HCO2H 41,42 1 32 ClSO2N=C=Ob 43 aCompound 33=caryolan-1-yl formate, bchlorosulfonyl isocyanate. H X X H X H H X H HO H H H H H H X H X X ba aa bb ab 8a X = H 8b X = 2H 7a X = H 7b X = 2H + X+ – X+ + X+ – X+ + H2O X – H+ – H+ + + + + + + Scheme 5 Table 2 Examples of natural products related to caryophyllene cyclization products Source Compound(s) Refs.Panax ginseng ·-Panasinsene 12 44 ‚-Panasinsene 34 ·-Neoclovene 10 ‚-Neoclovene 11 Panasinsanol A 35 Panasinsanol B 22 Naematoloma fasciculare Naematolin C 36 45 Naematolin G 37 Dipterocarpus pilosus Clov-2‚-9·-diol 38 66 Magnolia ovobata Clovanemagnolol 39 46 Caryolanemagnolol 40 Collybia confluens Collybial 41 47 Panax ginseng Ginsenol 42 109 Oil of hops and cloves Triphyllenol 43 74 Collado et al.: Recent advances in the chemistry of caryophyllene 18921 (Scheme 3).Alternatively the isocaryophyllene carbocation B may be formed and undergo further elimination to form the isocaryophyllene series. These cyclizations and rearrangements are reversible and eventually lead to the more stable isomers. Protonation of the endocyclic double bond and elimination leads to a further series of isomers 14–17 (Scheme 4).These alkenes may also be obtained by dehydrochlorination (AgNO3–DMSO) of trans-caryophyllene 1 or isocaryophyllene dihydrochloride.33 The diVerent tricyclic skeleta that are formed, reflect the major conformers that are present (Scheme 5). The ··-conformer undergoes a cyclization on the lower face of the molecule generating the clovane skeleton, after expansion of the four-membered ring. When the ‚‚-conformer is involved, H H H H OH H H H H 1 25 23 + H2O – H+ – H+ + H+ + H+ – H+ + H+ – H+ + + + Scheme 6 H H H HCOO H H H H H H H HN H H R1 R2 OH OH O 29 32 33 31 30 26 R1 = R2 = OH 27 R1 = OH; R2 = H 28 R1 = OCHO; R2 = H 14 13 14, 17 12 18 22 10, 11 – H+ + H+ + H+ – H+ a b b – H+ + H+ + + + + + + – H+ a – H+ + H+ + H+ + + + + H+ – H+ – H+, + H2O + H+, – H2O Scheme 7 H H H H H H H H H CHO H H HO H H OH H O H O OH OH O OH OH HO O OH OH R 34 b-Panasinsene 35 Panasinsanol A 36 Naematolin C (R = a-OAc) 37 Naematolin G (R = b-OAc) 39 Clovanemagnolol 40 Caryolanemagnolol 41 Collybial 42 Ginsenol 43 Triphyllenol 190 Natural Product Reports, 1998cyclization takes place on the ‚-face of the molecule, to yield caryolan-1-ol 7a.These cyclizations have been carried out in deuteriated sulfuric acid to aVord [9‚-2H]caryolan-1-ol 7b and [9·-2H]clov-2-ene 8b.34 The diVering stereochemistry of the deuterium confirms that these compounds originate from the diVerent conformations of trans-caryophyllene 1. The isocaryolan-8-ol 23 may be formed via the isomerization of the endocyclic alkene to an exocyclic position.Protonation of the 8(13)-alkene 25 and cyclization aVords 23 (Scheme 6). This compound has been formed by the reaction of 1 on acidic alumina,35 whilst the exocyclic alkene has been obtained through the hydrochlorination–dehydrochlorination of trans-caryophyllene 1.30 The formation of double bond isomers of transcaryophyllene 1, particularly 14 and 17, and their subsequent cyclization, may generate the neoclovane skeleton (compounds 10 and 11), the panasinsane skeleton (compounds 12 and 22) and the compounds 13 and 18 (Scheme 7).The formation of some of these compounds is favored by other acidic media. These are listed in Table 1. Some related natural products are listed in Table 2. The dimeric structure 21, obtained by heating trans-caryophyllene 1 in toluene at 120 )C in the presence of Lewis catalyst is interesting in that it represents a trapped form of one of the initial cyclization products of caryophyllene prior to their rearrangement and thus provides evidence for the formation of such carbocations.H H HgOAc HgOAc H HgOAc H HgOAc H H HgOAc H OH H H H H HgOAc H H HgOAc OH H H HgOAc OH AcOHg O H H H H O H H HgOAc OH AcOHg H H O OH OH HgOAc HgOAc HgOAc 1 8 34 46 44 45 47 + + NaBH4 Hg(OAc)2 – H+ Hg(OAc)2 7 i. H2O ii. NaBH4 H2O NaBH4 Hg(OAc)2 H2O i. – H+ ii. NaBH4 ii. NaBH4 i. –H+ ii. NaBH4 i. – H+ Hg(OAc)2 i.– H+ ii. NaBH4 Hg(OAc)2 Scheme 8 H H H H H H H H Hg H OAc Hg AcO Hg OAc AcO R1 Hg AcO HgOAc R2 OH H 1-ba 51 50 48 R1 = H; R2 = OAc 49 R1 = OAc; R2 = H Hg(OAc)2 NaBH4 i. NaBH4 ii. [O] ii. AcO– Hg(OAc)2 – AcOH i. NaBH4 + Scheme 9 ba aa bb aa bb ab – 50 °C – 120 °C % (MM3) 29 44 26 – ab ba Scheme 10 Collado et al.: Recent advances in the chemistry of caryophyllene 1913.2 Mercuration–demercuration The mercuration–reductive demercuration reaction in THF gives three series of compounds:48 (i) a non-polar fraction comprising ‚-panasinsene49 34 and clov-2-ene 8; (ii) an oxide fraction comprising the epimeric caryophyllene-4,8- oxides 44 and 45, and (iii) a more polar fraction comprising caryolan-1-ol 7 and the caryophyllen-4-ols 46 and 47 (Scheme 8).When the mercuration takes place in acetic acid, the products have the 1,4,4-trimethyltricyclo-12·-methylen[6,3,1,02,5] dodecane skeleton (compounds 48–51) (Scheme 9).50 The generation of this, including the formation of the anti-Bredt alkenes 50 and 51, may arise through a transannular migration of the mercuric acetate in the course of the cyclization. 3.3 Cyclizations in super-acid media The distribution of the products obtained from the rearrangement of trans-caryophyllene 1 in a super-acid medium diVers considerably from that obtained in normal acidic media. At the temperatures used for super-acid cyclization the various conformers of caryophyllene 1 are not rapidly interconverting. Examination of the low temperature ("124 )C) 13C NMR spectrum of trans-caryophyllene 1 in SO2FCl provided evidence for a significant transition barrier between the ‚‚- and ··-conformations.25 These studies provide experimental support for the results of population predictions based on MM351 calculations, suggesting proportions of 44, 29 and 26% for ··-, ·‚- and ‚‚-conformations, respectively (Scheme 10.Scheme 1 for MM1 predictions).3b The implication of this is that in the absence of interconversion between the conformers that give rise to caryolan-1-ol 7 and clovene 8, the cyclization products obtained from transcaryophyllene 1 in super-acid medium are the sum of the products obtained separately from 7 and 8 (Scheme 11).These are discussed later under the cyclization of 7 and 8. 4 Isocaryophyllene Although there have not been extensive studies on the acidcatalysed cyclization of isocaryophyllene 3, the principal products are known.When isocaryophyllene was treated with concentrated sulfuric acid in diethyl ether at 0 )C, ·-neoclovene 10 and 52 were obtained.28b,52 The latter, which had not been detected in the cyclization of trans-caryophyllene 1, may be formed as in Scheme 12. It is the 11-epimer of the H H H R H H H + + + + 1-aa 1-bb H2O – H+ 8 7 R = OH H+ H+ Scheme 11 H H H H H H H H H H H H + + 8 + 3 H+ 52 – H+ Scheme 12 H H H H H H H H H H H H H H RO H + + + 14, 15 3 ROH H+ HSO3F, SO2FCl 52a R = H 52b R = Me HSO3F, SO2FCl Scheme 13 H H H H HO H OH H H + + + + H2SO4 Et2O 10 42 53 – H+ + H2O – H+ + H2O Scheme 14 192 Natural Product Reports, 1998botrylane sesquiterpenoids, formed by the fungus Botrytis cinerea.53 The transformations which the other double-bond isomers of trans-caryophyllene 1 undergo, have been described previously but their behavior in super-acid medium is again diVerent and can be summarized in Scheme 13. Interestingly they also aVord the 11-epibotrylane skeleta.54 Recently, the acid-catalysed cyclization of isocaryophyllene 3 has been reexamined.55 In addition to the known compounds caryolan-1-ol 7, ·-neoclovene 10 and 52, the compounds ginsenol 42 and 53 were obtained.Ginsenol 42 is the alcohol derived from a carbocation proposed in the formation of ·-neoclovene 10 from trans-caryophyllene 1 (Scheme 7). Ginsenol is also a natural product, isolated from Panax ginseng.109 Compound 53 originates from further rearrangement of ·-neoclovene 10 (Scheme 14).Treatment of isocaryophyllene 3 with SiO2–FeCl3 55 yielded compounds 10, 52, 42, 53 and a bicyclic chloro-derivative 54 (Scheme 15). The structure this compound has been confirmed by synthesis.55 5 Caryophyllene oxides trans-Caryophyllene 1 and isocaryophyllene 3 may be epoxidized to form the epimeric endocyclic epoxides (Scheme 16):56 (a) 4‚,5·-epoxycaryophyll-8(13)-ene 55 and 4·,5‚-epoxycaryophyll- 8(13)-ene 56, from 1; (b) 4·,5·-epoxycaryophyll- 8(13)-ene 57 and 4‚,5‚-epoxy-caryophyll-8(13)-ene 58 from 3.The proportions of these epoxides reflect the conformational composition of 1 and 3.56 The most abundant of these epoxides 55 occurs naturally in oil of cloves and is commercially available as caryophyllene oxide 55. H H H Cl H H H H H H Cl H H Cl H + + 1 + H+ – H+ 7 + H+ 6 + Cl– + H+ – H+ 17 52 54 10 a-Neoclovene 3-ba 3-aa Scheme 15 H H H H H H O H H O H H O H H O 1 55 56 3 57 58 (86:14) (50:50) Scheme 16 H H H H H O H O H H H O H H OH H H OH H H OH OMe H H OH H H OH OH O R OH OH H 38 R = OH 59 R = Me 60 61 62 64 66 67 63 65 68 Collado et al.: Recent advances in the chemistry of caryophyllene 1935.1 Cyclization in an acidic medium The major acid-catalysed (sulfuric acid–diethyl ether) cyclization product of caryophyllene oxide 55 is clovan-2‚,9·-ol 38.57,58 Its formation is analogous to that of clovene 8 from trans-caryophyllene 1.Other products 59–68 which have been obtained with diVerent reagents are given in Table 3.Their formation may be rationalized as shown in Scheme 17. Cyclization of 4‚,5·-epoxycaryophyll-8(13)-ene 55 with the mild �-acid catalyst tetracyanoethylene (TCNE) in methanol, gave 2‚-methoxyclovan-9·-ol 59, together with the products of simple methanolysis, 4‚-methoxycaryophyllen-5·-ol 67, and elimination, 64. However, in dipolar aprotic solvents, elimination products were formed.68 5.2 Mercuration–demercuration The cyclic ethers that are obtained by reaction with mercuric acetate in aqueous tetrahydrofuran69 reflect the relative disposition of the exocyclic alkene and the 4,5-epoxide (Scheme 18).In the epoxides derived from isocaryophyllene 3, the 4,5-epoxide may behave as an internal nucleophile forming the ether bridge. On the other hand, in the epoxides derived from trans-caryophyllene 1, hydration of the mercuric acetate adduct leads to a C-8 tertiary alcohol which then attacks the epoxide with the formation of the cyclic ethers 73 and 74.When the reaction is performed in acetic acid,70 the major product is ‚-panasinsen-5·-ol 75 (Scheme 19). This may be formed via an allylic organomercurial derivative. The acetic acid medium favors elimination rather than hydration to discharge the initial carbocation. 5.3 Cyclization in a super-acid medium The products of the reaction of the epoxides of isocaryophyllene 3, with super-acid (HSO3F–SO2FCl),71 which are compounds 57 and 58, are determined by the stereochemistry at C-4.Rear side attack by the exocyclic double bond takes place on the ·-face of 58 and the ‚-face of 57. This leads to the enantiomeric ions A and B and thence to the enantiomeric dienols 77 and 79 (Scheme 20). Under conventional acidic conditions, a clovane 78 and a caryolane 76 derivative are formed. The products from caryophyllene oxide 55 are temperature dependent (Scheme 21). At "100 )C clov-2-en-9·-ol 60 is Table 3 Major cyclization products of caryophyllene oxides with diVerent reagents Starting material Final product Reagent(s) Refs.Starting material Final product Reagent(s) Refs. 55 38 H2SO4–Et2O 57 55 63 Synthetic zeolites 65 AcOH–AcONa (pH 4 buVer) 59 55 64 Solid acidsa 61 55 60 BF3–Et2O 60 AcOH–AcONa (pH 4 buVer) 59 Solid acidsa 61 Activated alumina 64,66 Synthetic zeolites 62 Pyridine – HBr 67 55 61 BF3–Et2O 60 55 65 Solid acidsa 61 Gas chromatography 63 Activated alumina 64 AcOH–AcONa (pH 4 buVer) 59 AcOH–AcONa (pH 4 buVer) 59 55 62 BF3–Et2O 60 55 68 AcOH–AcONa (pH 4 buVer) 59 Activated alumina 64 56 66 Solid acidsa 61 Solid acidsa 61 Activated alumina 66 Synthetic zeolites 62,65 AcOH–AcONa (pH 4 buVer) 59 aLewis acids, e.g.supported on silica or alumina. H O E H O E H O H O E H O E H EO H EO H H OE H H EO H O H + + + + + + + S: a b a b a b 38, 59, 60 63 61 56 55 + E+ + E+ 67 62 + E+ 64 65 a b + E+ 66 Scheme 17 194 Natural Product Reports, 1998formed, but at "80 )C methyl group migration and dehydrogenation takes place.Compound 81, with the selinane skeleton, has been isolated when the reaction was carried out at "130 )C. It is possible that this was formed via a humulene carbocation (Scheme 22). 6 Solvolytic reaction of caryophyllenols Solvolysis of the methanesulfonate 82 derived via caryophyllene oxide, aVorded compounds with the triphyllane skeleton (compounds 43, 83–85).72,73 The parent alcohol 43 is a natural product that is found in cloves and hops.74 Although the methanesulfonate 82 can exist in four diVerent conformations, only one of these 82· has the appropriate geometry for cyclization (Scheme 23).When the epimeric allylic acetates 86 and 89, prepared from the epoxides 55 and 58, respectively, were cyclized by oxymercuration and reduction, the isocaryolanes 87 and 90 were obtained (Scheme 24).50 A reinvestigation of the reaction of caryophyllene oxide 55 with H2SO4–Et2O75 led to the isolation of two ethers, 91 and 92, derived from further reaction on the exocyclic double bond of the isomerization and epoxide opening products, 64 and 88, respectively.Compound 91 was also obtained in the treatment of caryophyllene oxide 55 with TCNE. Compounds 93–95 were also obtained from further reaction on the exocyclic double bond of the caryophyllenols 64 and 65.68,76 Sharpless syn epoxidation of allylic alcohols 64, 65 and 66 led to the formation of the trans epoxy alcohols 96–98.77 The products of the reaction of the epoxy alcohols with TCNE reflected the stereochemistry of the parent epoxide.The 3·,4·- epoxide 96 gave the 1-methoxycaryolan-7·,9‚-diol 99, whilst the 3‚,4‚-epoxide 97 gave the simple methanolysis product 100. On the other hand, the 4‚,12-epoxide 98 aVorded 2‚-methoxyclovan-9·,15-diol 101 accompanied by (4R)-12- hydroxy-5-oxocaryophyll-8(13)-ene 102 (Scheme 26). Formation of trans epoxides by syn epoxidation is a consequence of the conformational flexibility of the nine-membered ring, which places the alcohol at C-5 close to the ·-face of the endo-alkene in 96 and close to the ‚-face in 97 and 98.The epoxy alcohol 96 has also been isolated from an extract of Sindora sumatrana.78 7 Thermal rearrangements of trans-caryophyllene Pyrolysis of caryophyllene at low pressure aVorded isocaryophyllene 3 by a series of [3,3]-sigmatropic rearrangements of the 1,5-diene79 (Scheme 27). When this Cope rearrangement was blocked through epoxidation, a reverse [2+2] reaction involving cleavage of the cyclobutane ring occured at high temperatures with the formation of a series of farnesane epoxides 103–10680 (Scheme 28).O H O O H O H O H HgOAc O AcOHg H H O H HgOAc O H AcOHg O H HO H O OH OH H O H O OH H O OH O H HO + + + + + H2O, – H+ NaBH4 Hg(OAc)2 + H+, – H+ 56 57 55 58 69 70 71 72 73 74 Hg(OAc)2 Hg(OAc)2 Hg(OAc)2 + H2O, – H+ NaBH4 + H2O, – H+ NaBH4 + H2O, – H+ NaBH4 + H+, – H+ Scheme 18 + H O H H O H H OH H H HgOAc O HgOAc Ac HgOAc OH OH + 55 75 Hg(OAc)2 – HOAc + H+ Scheme 19 Collado et al.: Recent advances in the chemistry of caryophyllene 195trans-Caryophyllene 1 will also undergo ene reactions involving the trisubstituted double bond.Adducts with maleic anhydride 10781 and formaldehyde 10882 have been isolated. The unsaturated ketone 109, a C-15 deoxy derivative of compounds found in Pucaria dysenterica83 and Pulicaria arabica,84 has been synthesized from caryophyllene oxide 55 and undergoes an interesting dimerization (Scheme 29). 8 Radical rearrangements of trans-caryophyllene Caryophyllene nitrosite 110, prepared initially in 18924,85 by treating trans-caryophyllene 1 with nitrous acid, absorbs radiation at 270 nm and also in the red region of the spectrum at 670 nm, giving rise to the blue colour of the solid. When the adduct was treated with iodine in chloroform, a stable nitroxide radical 111 was formed.86 When the nitro nitroso adduct 110 was irradiated with red light in chloroform in the absence of air, it decomposed aVording, inter alia, the dimer 11287 (Scheme 30).Various elimination reactions occur in the absence of solvent, leading to the formation of the unsaturated nitro compounds 112, 113 and 114. When compound 110 is irradiated with ultraviolet light, the nitro group absorbs the radiation and generates the cyclization product 115 (Scheme 31). The radical addition of acetaldehyde to trans-caryophyllene 189 takes place by attack on the endocyclic double bond. Cyclization of the tertiary radical at C-4 with C-8 generates compounds possessing the tricyclo[7.2.0.04,8]undecane skeleton (compounds 116–119) (Scheme 32). The punctaporonines, sesquiterpene antibiotics produced by Poronia punctata,90 possess this carbon skeleton.H CF3CO2H B 57 76 77 HSO3F, SO2FCl H2 H O OH OH OH H H O H OH H H O O H H HO H OH O F F F OH O F F F OH OH H OH 78 79 + + + CF3CO2H A 58 HSO3F, SO2FCl H2 + + + Scheme 20 OH OH H OH H H O H OH OH –100 °C –130 °C + 55 80 HSO3F, SO2FCl 60 + + HSO3F, SO2FCl HSO3F, SO2FCl 81 –80 °C 60 Scheme 21 196 Natural Product Reports, 1998Compounds of this type have also been obtained from the epoxides of trans-caryophyllene 1 and isocaryophyllene 3 by reduction with lithium in liquid ammonia.91 The stereochemistry of the products 120–127 (Scheme 33) clearly reflects the preferred conformation of the parent epoxides. 9 Reaction of the epoxides in alkali Caryophyllene oxide 55 is exceptionally stable to base. It is not even attacked by caustic soda at 150 )C.92 The conformation of the nine-membered ring prevents attack by an external O H O H HO H O H OH + + + + 55 81 + H+ + H+ – H+ Scheme 22 H H O H H H H H H H H RO OMs H 55 i. LDA, THF ii. NEt3, MsCl + ROH 82a 43 R = H 83 R = OCHO 84 R = OAc 85 R = OMe pro-1 S,8 Z Scheme 23 H H O H H O R OH H H OAc H H O H H O R OH H H OAc 55 i. Al2O3 ii.Ac2O 65 R = OH 86 R = OAc i. Hg(AcO)2 ii. NaBH4 87 58 i. Al2O3 ii. Ac2O i. Hg(AcO)2 ii. NaBH4 90 88 R = OH 89 R = OAc Scheme 24 H2SO4, Et2O H H H H H H H H H H O OH O H O OH OH OH + + 88 91 92 55 64 Scheme 25 H H H H H H H O MeO OH OH 93 94 95 1-aa 1-bb 3 > 270 °C > 240 °C > 240 °C Scheme 27 Collado et al.: Recent advances in the chemistry of caryophyllene 197nucleophile on the rear-face of the epoxide. However, the nor-ketone kobusone 128 and its epimers 129 and 130 undergo intramolecular cyclization,93 with the formation of compounds of the panasinsane skeleton (Scheme 34).Where the epoxide stereochemistry precludes this, as in 130, a cyclopropane ring is formed. The structure of the product 132 from 128 has recently been revised to 138.94 The hydroxy ketones 133 and 134, are formed by a transannular 1,4-hydride shift. Further epoxidation and hydrolysis of the exocyclic double bond or glycol formation with osmium tetroxide, aVorded a range of 8,13-diols which undergo intramolecular ether formation reactions92 (Scheme 35, Scheme 36, Scheme 37 and Scheme 38).When the bis-epoxides derived from 55 (compounds 140 and 141) are treated with LiAlH4 in THF,95 four possible ethers might be formed, but only two were actually obtained (Scheme 39), compounds 142 and 143. This result is in agreement H H OH H H OH H H OH H H OH H H OH H H OH H H OH MeO H H H H H OH OH O O O O OH MeO OH OH OH MeO H 66 96 99 64 97 100 101 65 98 102 VO(acac)2 ButOOH TCNE MeOH VO(acac)2 ButOOH TCNE MeOH VO(acac)2 ButOOH TCNE MeOH + Scheme 26 H H O H H O O O H H O H H O O O 55 56 103 104 57 58 105 106 Scheme 28 H H H H OH H O O O H 107 108 H H i.NPSP, THF ii. H2O2 i. PD C, CH2Cl2 109 ButOOH ii. TBAF, THF toluene, reflux 55 LDA VO(acac)2 H H O H H OH H H OH O H H OH H H OH OTBDMS OTBDMS H 65 i. TBDMSCl H OTBDMS ii. LDA OH + H H O OH O H H O O Scheme 29 198 Natural Product Reports, 1998with the previously presented results (Scheme 35–38), because it is only from the bis-epoxides of 55 (140 and 141) that it would be possible to obtain ethers involving a tertiary alcohol precursor. 10 Oxidation and reduction of caryophyllene trans-Caryophyllene 1 reacts in most cases initially on the endocyclic double bond substantially reducing the ring strain. Ozonolysis, for example, occurs firstly on the endocyclic double bond.96 Monoepoxidation takes place selectively on the endocyclic double bond.56 If the amount of peracid is raised, and the temperature and time are controlled, then bisepoxidation products 141, 140 or kobusone 128 are obtained.95 Hence, in order to prepare the exocyclic epoxide 144, transcaryophyllene 1 was converted via its epoxide 55 and the nor-ketone kobusone 128, to 9, which was then converted to the epoxide 144 by a Corey–Chaikovsky reaction (Scheme 40).97 H H H H H H N+ H H H H –O I N+ O– NO2 NO2 O2N NO2 NO • • HNO2 I2, CHCl3 CHCl3 red light 1 110 111 112 Scheme 30 H H H H NO2 NO2 H H NO2 112 114 113 O2N NO C C ON NO OHC N+ NO –O O H • • • 110 hn 115 Scheme 31 COMe COMe R2 H H R1 R2 H H R1 1-aa 1-bb CH3C=O CH3C=O 115 R1 = OAc; R2 = H 116 R1 = H; R2 = OAc 118 R1 = OAc; R2 = H 119 R1 = H; R2 = OAc • • Scheme 32 55-aa H H H 56-bb O H OH H H H H H H OH H H H H H OH H H H OH H H H OH OH H H H O O H O H OH OH 57-aa 58-bb 120 121 122 123 124 125 126 127 Li, NH3 Li, NH3 Li, NH3 Li, NH3 + + + + Scheme 33 56 KOH OsO4 O H O H HO HO H HO HO O Scheme 35 Collado et al.: Recent advances in the chemistry of caryophyllene 199trans-Caryophyllene 1 reacted with sulfur in the presence of light to form a 4,5-thiirane.Autoxidation of trans-caryophyllene 1 and isocaryophyllene 3 in the presence of Bengal Red as a photosensitizer, led to a series of allylic alcohols 64, 65, 66, 145, 146 and 147, again derived from reaction of the endocyclic double bond.99 Oxidation of trans-caryophyllene 1 with lead tetraacetate100 aVorded a range of compounds (55, 56, 64, 65, 66, 43, 147, 148, 149, 150, 151 and 152) derived, with one exception 152, from reaction of the endocyclic double bond.Compound 43, with the triphyllane skeleton, may arise by cyclization of one of the allylic alcohols 65. Hydroboration of trans-caryophyllene 1101 took place exclusively on the endocyclic double bond to give the alcohols 153 O O H O O H O OH H H H H H O H HO H O H O H H O OH H H O H OH O OH H O H O H H HO H H O OH H H O H HO HO OH O O H H OH 128 131 132 133 129 134 135 130 136 137 138 + 1,4 H shift + 1,4 H shift RO– RO– RO– Scheme 34 55 OsO4 KOH KOH RCO3H 139 138 O H O H OH O H H O O O H O H HO HO HO HO HO OH HO Scheme 36 OsO4 KOH RCO3H 57 KOH O H O H O O H HO H O OH O H HO HO OH H OH O HO HO Scheme 37 OsO4 KOH RCO3H 58 KOH O O O O O H OH OH O HO HO HO H H H H HO O HO H OH Scheme 38 O O H O H O H O H HO O OH LIAlH4 THF 140 141 142 143 LIAlH4 THF Scheme 39 200 Natural Product Reports, 1998O H H H H H H O H H O O O O3, Me2S 55 128 9 144 Zn, EtOH reflux (Me)3S+ I–, NaH, DMSO 153 154 155 156 157 H H H H H H H H HO H OH H H H OH Scheme 40 i.HSO3F, SO2FCl ii. MeOH, Et2O (–120 °C) 8 158 159 160 161 + + + + H H 162 Scheme 41 152 H H H H H H H H H H H H H H O O OH OH OH OH OH 145 146 147 148 H H 149 150 151 OH X H H H HO H H H H H HO H H H H H MeO H H X H H H OH H OH 15 + + + 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 2 3 4 5 6 8 9 7 10 11 12 13 14 SbF5, SO2FCl H2O, acetone (–30 °C) 7a X = OH 7b X = Cl HSO3F, SO2FCl 163 164 165 166 167 168 SbF5, SO2FCl (–120 °C) –100 °C (–100 °C) MeOH, Et2O SbF5, SO2FCl (–120 °C) H2O, acetone SbF5, SO2FCl –60 °C H2O, acetone SbF5, SO2FCl (–100 °C) (–100 °C) (–100 °C) 7a X = OH 7b X = Cl H2O, acetone SbF5, SO2FCl Scheme 42 Collado et al.: Recent advances in the chemistry of caryophyllene 201and 154 in amounts which reflected the proportions of the diVerent conformers.However, isocaryophyllene 3, with a less reactive endocyclic double bond, aVorded the alcohol 155.The endocyclic double bond of trans-caryophyllene 1 was reduced by diimide (compound 156)101 whilst it was the exocyclic double bond of isocaryophyllene 3 that reacted (compound 157). However, catalytic hydrogenation, reflecting the ease of access of the double bond, reduced the exocyclic double bond of caryophyllene. 11 The rearrangements of clovene, neoclovene and caryolan-1-ol in acidic and super-acidic media As noted previously the products obtained by treatment of trans-caryophyllene 1 with super-acid are the sum of the products from the reaction of clov-2-ene 8 and caryolan-1-ol 7.When clov-2-ene 8 was treated with the super-acid system HSO3F–SO2FCl at "120 )C and the reaction mixture then neutralized with methanol–diethyl ether, the olefins 158, 159, 160, 161 and 162 were obtained.25 On the other hand, when caryolan-1-ol 7a or its chloride were subjected to reaction with super acid, the products varied with the conditions.102 At "120 )C in the presence of SbF5– SO2FCl followed by neutralization with methanol–diethyl ether, the methyl ether 163 was obtained (Scheme 42).At "100 )C rearrangements started to occur and the alcohols 164, 165, 166 and 167 were obtained after the reaction mixture was quenched with water in acetone. Finally at "30 )C the super-acid system HSO3F–SO2FCl gave the diene 168 after neutralization with the methanol–diethyl ether mixture.This compound was the enantiomer of 162, obtained from clov-2-ene 8. The formation of these products may be rationalized in terms of distinct sets of carbocations which cannot interconvert through their parent caryophyllene because of the barrier to conformational inversion under these conditions. The rearrangements of caryolan-1-ol 7 in polyphosphoric acid103 have been examined and the products which were isolated are shown in Scheme 43.The intervention of a diene 173 formed by fragmentation of the cyclobutane ring, may account for the products isoclovene 169,104 pseudoclovene A 170,105 pseudoclovene B 171106 and epiclovene 172.107 Treatment of neoclovene 10 with super-acid108 led to a series of products depending on the temperature. Reaction with HSO3F–SO2FCl at "120 )C and neutralization with water in acetone gave the alcohols 174, 175 and 42. The latter is ginsenol which has been isolated from the roots of Panax ginseng.109 At "70 )C various skeletal rearrangements occur and the products are 176–179.H H HO H H H H H H H H H H + 7 170 169 171 173 + + 172 + H+ Scheme 43 H R2 R1 H 174 R1 = Me; R2 = OH 175 R1 = OH; R2 = Me OH 42 H H H 10 H 177 H H 2 178 O S O 10 176 8 179 7 11 H2O + 1 2 5 4 11 7 1 1 5 6 (–120 °C) HSO3F, SO2FCl + + (–70 °C) HSO3F, SO2FCl + 5 6 1 H + Scheme 44 H H H H H H H + + + + + H2SO4 dioxane 70 °C 10 A 180 – H+ + Scheme 45 181, 182 + HSO3F, SO2FCl H H O O OH 184, 185 183 (–120 °C) Scheme 46 202 Natural Product Reports, 1998In contrast to the reaction with super-acid, treatment of ·-neoclovene 10 with sulfuric acid in dioxane at 70 )C gives exclusively the alkene 180 (Scheme 45).This compound does not appear amongst the products of super-acid treatment. However, the epoxides of neoclovene 10 (181 and 182), when treated with super-acid give the ketone 183 and the rearrangement products 184 and 185 (Scheme 46).110 Compound 53, obtained from the acid-catalysed cyclization of isocaryophyllene 3, and derived from carbocation A, has been correlated with 180,55 supporting the proposed pathway (Scheme 45). 12 Conclusions In conclusion, in this review we have shown that the unique chemistry of caryophyllene is dominated by the flexible conformations of the nine-membered ring and the consequent relative positions of the reactive functional groups. The various cyclizations may lead to other polycyclic naturallyoccurring sesquiterpenoid skeleta, paving the way for partial syntheses and the exploration of the structure–biological activity relationships in these families of natural products. 13 References 1 (a) Dictionary of Organic Compounds, 5th edn., Vol. 1, p. 1012, ref. C-00398; (b) B. M. Fraga, Nat. Prod. 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Org. Chem. USSR (Engl. Transl.), 1991, 27, 516]. 204 Natural Product Reports, 1998

ISSN:0265-0568    

DOI:10.1039/a815187y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Excitatory amino acids Mark G. Moloney Dyson Perrins Laboratory, South Parks Rd, Oxford, UK OX1 3QY Covering: January 1994 to December 1996 1 Excitatory amino acids 2 Ionotropic glutamate receptors 2.1 AMPA 2.2 KA 2.2.1 Synthetic approaches 2.2.2 Medicinal chemistry 2.3 NMDA 3 Metabotropic glutamate receptors 3.1 (1S,3R)-ACPD 3.2 Group I 3.3 Group II 3.4 Group III 4 Conclusion 5 References 1 Excitatory amino acids Excitatory amino acids (EAA) are known to mediate synaptic excitation, and therefore nerve signal transmission, in the mammalian central nervous system by binding to EAA receptors.L-Glutamic acid 1, which is the major excitatory neurotransmitter, is known to act at two classes of receptor.1,2 The first class, called the ionotropic glutamate receptors (iGluRs), are coupled to ion channels which control the flux of sodium, potassium and calcium ions into a nerve cell, and are capable of millisecond or faster response times. These receptors can be selectively activated, and are further characterised, by their agonists, which are known to include (S)-2-amino-3-(3- hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) 2, kainic acid (KA) 3 and N-methyl-D-aspartate (NMDA) 4.In general, the agonists for the iGluRs are isosteric with a folded conformer of glutamate.3,4 Comprehensive reviews of the molecular biology, pharmacological properties and structural analysis of AMPA/kainate receptors, and structure–activity relationships of their agonists and antagonists,5 and of the NMDA receptor,6 have recently appeared.The second class, the metabotropic glutamate receptors (mGluRs) are activated by the selective agonist (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) 5, and are slower responding than the ionotropic receptors, but produce longer lasting changes to nerve cells, and have been implicated in learning and memory functions. They are coupled to eVector proteins through GTP-binding proteins (the so-called G-proteins), and there have been eight sub-types identified, which have been divided into three major groups on the basis of homology of the receptor proteins.Group I mGluRs (mGluR1 and 5) are positively coupled to phosphoinositide hydrolysis, while both Group II (mGluR2 and 3) and Group III mGluRs (mGluR4,6,7 and 8) are negatively coupled to adenylate cyclase. Group I is selectively activated by quisqalic acid QUIS 6, Group II by L-CCG-I 7 while Group III mGluRs are selectively activated by L-2-amino-4- phosphonobutanoic acid (L-AP4) 8a.4,7 Ibotenic acid 9 exhibits non-selective activity at EAA receptors.8 In general, agonists of the mGluRs are (S)-amino acids with a remote acidic (carboxy or phosphate) function in an extended conformation. 3,4 Considerable recent attention has been focused on the mGluRs, and there are some excellent reviews outlining the structures, pharmacology and physiological roles of these receptors.9–14 In particular, eVort has concentrated upon the identification of potent and selective antagonists, which can be used as probes for the biochemical and physiological roles of these important receptors.The EAA receptors play a role in a number of physiological processes concerned with memory and learning (e.g. long term potentiation),9,15,16 and the neuroendocrine regulation of several hormonal systems,17,18 and have been implicated in both acute and chronic neuronal disfunction (e.g.epilepsy, neurolatirism and schizophrenia, ischemia, Huntington’s chorea, and Alzheimer’s and Parkinson’s disease).19,20 Excessive activation of iGluRs can trigger a cascade of events which ultimately cause cell death, and this process has been called excitotoxicity.21 There has been a recent suggestion that the excitotoxicity of EAAs is linked to the production of free radicals in vivo.22 The diverse biological roles and the pharmacological and pharmaceutical significance of this important class of amino acids have recently been comprehensively reviewed5 and a variety of monographs are available.23–29 As more is becoming understood of the biological signifi- cance of these compounds, the demand for eYcient syntheses of both the naturally occurring EAAs and their analogues is CO2H HO2C NH2 CO2H NH2 O N Me OH CO2H HO2C NHMe NH CO2H CO2H 1 (S)-Glu 2 AMPA 4 NMDA 3 KA NH2 CO2H HO2C H O N CO2H NH2 HN O O N O HO CO2H NH2 CO2H H2O3P H H HO2C NH2 CO2H NH2 5 (1 S,3 R)-ACPD 9 (CH2) n 7 L-CCG-I 8a L-AP4 n = 0 8b L-AP5 n = 1 8c L-AP7 n = 3 6 QUIS Moloney: Excitatory amino acids 205growing, for use both as therapeutic agents in their own right and as tools to study the etiology of neurodegenerative disorders.This review covers recent developments in the preparation and activity of agonists and antagonists of the EAA receptors and is sub-divided according to receptor type. It is not restricted merely to amino acids, but includes other reported agonists and antagonists for each of the respective receptors. As many of these compounds are commonly referred to in the specialist literature by abbreviation rather than their full IUPAC name, these abbreviations have been listed with their chemical structure to provide a glossary of terms and structures. 2 Ionotropic glutamate receptors 2.1 AMPA The AMPA receptor is selectively activated by (S)-AMPA 2, (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA) 10, (RS)-2-amino-3-(3-hydroxy-5-bromomethylisoxazol- 4-yl)propionic acid (ABPA) 11 and (S)-2-amino-3- (3-hydroxy-4-bromoisoxazol-5-yl)propionic acid [(S)-BrHIBO] 12.30 Although (S)-AMPA is a highly selective and potent AMPA receptor agonist, its (R)-enantiomer is virtually devoid of activity.The phenyl analogue (RS)-APPA has recently been shown to possess about 60% of the activity of (RS)-AMPA, but the recent resolution of the former compound has allowed pharmacological evaluation of each enantiomer independently. 31 (S)-(+)-APPA 13 and (R)-(")-APPA were obtained in at least 99% ee by chemical resolution using (R)-(+)- and (S)-(")-1-phenylethylamine, respectively, and the absolute stereochemistry of the (R)-enantiomer hydrochloride salt was determined by single crystal X-ray crystallographic analysis.The (S)-enantiomer has full agonist activity at the AMPA receptor, but the (R)-enantiomer has been found to be a competitive antagonist which exhibits preferential blocking of the AMPA receptor.32 This is consistent with earlier reports that only the (S)-enantiomers of AMPA and BrHIBO exhibit full agonistic activity.It has been suggested that both (S)- AMPA and (S)-APPA 13 interact with a high aYnity receptor conformation, while the competitive antagonists (RS)-AMOA 14 and (R)-APPA bind to a low-aYnity AMPA receptor conformation.32 It has recently been shown that it is possible to partially agonise the AMPA receptor by the coadministration of carefully defined molar ratios of AMPA 2 or ATPA 10 as well as a competitive antagonist (such as AMOA 14, NBQX 15c, NMDA 4 and CPP 16).33 A recent report34 claiming that ‚-N-oxalylamino-L-alanine (BOAA) 17 is a mitochondrial NADH dehydrogenase inhibitor at sub-picomolar concentrations has been refuted; it has been suggested that the observed inhibition was caused by neuronal damage due to the excitotoxicity of BOAA 17.The most potent AMPA-selective antagonists are the quinoxalinediones (e.g.DNQX 15a, CNQX 15b, NBQX 15c and YM90K 15d) and the isatin oximes (e.g. NS229 18). Nitro substituents at C-6 and a second polar group (e.g. NO2, CN, SO2NH2) at C-7 are required for maximal activity. Some of these derivatives are anticonvulsants and neuroprotectants, and are of potential therapeutic application to epilepsy and cerebral ischemia. Recently, 3-(sulfonylamino)-2(1H)- quinolones (e.g. S16678 19) have been shown to possess antagonistic activity at the AMPA/kainate receptor, and a range of analogues were prepared by condensation of dimethyl malonate with the required substituted 2-aminobenzaldehyde, followed by manipulation of the C-3 substituent (CO2Me, CN) to give the quinolone derivative 20 (Scheme 1).35 Noteworthy was the unexpected formation of the 3-bromo-2(1H)- quinolone 20 (Y=Br, R1=R2=H, R3=NO2) upon treatment CO2H NH2 O N HO Br CO2H NH2 O N But OH CO2H NH2 O N BrCH2 OH 12 (S)-BrHIBO 10 ATPA 11 ABPA CO2H NH2 O N Ph OH CO2H NH2 O N Me O HO2C 13 (S)-APPA 14 (RS)-AMOA NH HN O O O2N O2N NH HN O O NC O2N NH HN O O O2N H2NO2S NH HN O O N O2N N 15a DNQX 15b CNQX 15c NBQX 15d YM90K 6 7 6 7 6 7 HN N PO3 H2 HO2C HO2C HN CO2H NH2 O 17 BOAA 16 CPP NH O NOH Me2NO2S O2N O2N NH NHSO2CF3 O 19 S16678 18 NS229 R1 R2 R3 CHO NH2 R1 R2 R3 NH Y O N N NH N NH N OH N N O OH Y CO2 Me Y = CO2H, PO3H2, C(O)NHOH, CONH2, SCH2CO2H, NHSO2CF3 , 5 6 , R1 = H, Cl R2 = H, Cl, NO2 R3 = Cl, NO2 20 7 3 , Scheme 1 206 Natural Product Reports, 1998of acid 20 (Y=CO2H, R1=R2=H, R3=NO2) with bromine– pyridine; no aromatic bromination was observed under these conditions.This useful intermediate was used to access a variety of 3-substituted analogues of quinolone 20 (for various R1, R2, R3), either by lithiation followed by an electrophilic quench, or by Heck-type coupling. While carboxylic substituents at C-3 were found to exhibit maximal activity, the order of activity of other acidic groups at this position was established to be PO3H2>1H-tetrazol-5-yl>SCH2CO2H>C(O)NHOH with other heterocyclic bioisosteres being much less active.The receptor selectivity of derivatives of 20 was found to depend upon several factors, including the substituents (nitro groups show greater selectivity than chloro groups for the AMPA receptor), the position of substitution (5,7- more active than 6,7- for NMDA–glycine selectivity) and the length of the C-3 substituent (the greater the separation of the acidic hydrogen of the C-3 substituent and the quinoline ring, the greater the AMPA selectivity).An extensive evaluation of analogues has shown that 6,7-dichloro-2-oxoquinoline-3-phosphonic acid 20 (S17625, R1=H, R2=R3=Cl, Y=PO3H2) is a water soluble compound with comparable in vivo activity to the AMPA antagonist NBQX 15c. The N-alkylquinoxalinediones 21a–d have been shown to be AMPA agonists.36 These compounds were designed and synthesised on the basis of the similarity of the 1,2-dicarbonyl moiety of both the quinoxaline-2,3-diones 15 and BOAA 17; the authors reasoned that the N-alkyl substituent should enhance the activity of compounds 21.These compounds were readily obtained as shown in Scheme 2; thus, N-Boc-Serine 22 (either enantiomer) was converted to lactone 23. Deprotection and conversion to the toluene-psulfonate (tosylate) salt 24, and ring opening with the required 1,2-phenylenediamine and cyclisation with oxalyl chloride, gave the desired substituted ‚-aminoalanines 21a–d in enantiopure form.An investigation of a wide range of substituted quinoxalinediones with fused piperidine rings has identified 25 as a potent AMPA antagonist.37 This class of compounds was in general readily prepared by catalytic reduction of an appropriately substituted nitroisoquinoline; the resulting aminotetrahydroisoquinoline was easily manipulated to the desired quinoxalinedione.Very recently, 6-substituted decahydroisoquinoline-3- carboxylic acids 26 have been shown to possess significant and highly selective AMPA (or NMDA—see below) antagonist activity,38 and could find application for neuroprotection.39 These compounds were prepared from the readily available ketone 27a by manipulation of the C-6 carbonyl function. More recently, an improved synthesis of an alternatively protected form of 27a has appeared which involves an intramolecular Diels–Alder reaction (Scheme 3).40 Dimethyl acetal 28c, obtained from protected aspartic acid 28a via the aldehyde 28b, was transformed into the N-benzyl derivative 28d.N-Acylation, followed by ketone deprotection, Horner– Emmons homologation, and enol ether formation gave the intermediate 29c suitable for an intramolecular Diels–Alder cycloaddition. Reaction under very mild conditions gave the required oxodecahydroisoquinolone 30, with complete control of the cis relative stereochemistry at the ring junction. Protection of the ketone as the dimethyl ketal, lactam reduction and deprotection aVorded the product 27b.An examination of the eVect of changes in stereochemistry at C-3, C-4a, C-6 and C-8a have indicated that the stereochemistry shown for decahydroisoquinoline 26 displays the optimal activity. SAR analysis has shown that an ethylene spacer (n=2) at C-6 of decahydroisoquinoline 26 gives optimum activity, that heteroatom substitution (O or N) within this spacer reduced AMPA antagonist activity, and that incorporation of a methyl or phenyl substituent on the side chain had little eVect on activity.Modification of the C-6 pendant tetrazolyl unit with a variety of isosteres HO CO2H NHBoc O O NHBoc O O NH3 +TsO– N HN O O R1 R2 NH2·HCl CO2H NH2 NH2 R1 R2 , iv ii, iii i 22 23 24 v ( S)-21a R1 = R2 = Me ( S)-21b R1 = R2 = H ( R)-21c R1 = R2 = Me ( R)-21d R1= R2 = H Scheme 2 Reagents: i, DEAD, Ph3P, THF; ii, CF3CO2H; iii, TSOH; iv, DMF; v, ClCOCOCl O2N HN NH O O Me N 25 R1 CO2Me NHR2 R CO2Me NCH2Ph O NCH2Ph CO2Me H H H O O 28a R1 = CO2H; R2 = Z 28b R1 = CHO; R2 = Z 28c R1 = CH(OMe)2; R2 = Z 28d R1 = CH(OMe)2; R2 = CH2Ph 29a R = CHO 29b R = CH=CHC(O)Me 29c R = CH=CHC(OTES)=CH2 30 i–iv v, vi Scheme 3 Reagents: i, CH2=CHCOCl, Et3N; ii, 10% aq.HCl, CH3CN; iii, (EtO)2POCH2C(O)CH3, NaH, THF, iv, Et3SiOTf, Et3N, room temp; v, KF, MeOH; vi, BH3vMe2S, THF then HCl, reflux Moloney: Excitatory amino acids 207generally led to reduced activity, although the triazolylsulfonyl derivative 31 (X=1,2,4-triazolyl, Y–Z=SO2CH2) was found to be an especially potent and selective antagonist.41 The selectivity of these compounds for the AMPA and NMDA receptors was found to depend on the side chain length. Thus, compound 32a with direct attachment of the tetrazole to the bicyclic ring gave dual AMPA–NMDA activity, but the derivatives 32b and 32c with one- and two-carbon tethers exhibited NMDA and AMPA selectivity, respectively.Some of these were shown to be active by intraperitoneal administration in mice.41 The two enantiomers of homoibotenic acid 37 (HIBO) have been synthesised using a resolution procedure (Scheme 4).42 Racemic isoxazole 33, prepared by bromination of 34 followed by displacement with diethyl acetamidomalonate, was converted to the diastereomeric amides 35a,b with (S)-Bocphenylalanine. Although these compounds were nonseparable, deprotection allowed the amine 36a to be obtained after preparative layer chromatography.Edman degradation, followed by hydrolysis, gave (R)-HIBO 37. A similar procedure gave the (S)-enantiomer, although in this case facile hydrolysis of the ester 36b was noted upon chromatographic separation. The optical purity was demonstrated by chiral HPLC analysis. The (R)-enantiomer was found to be an AMPA agonist, and the (S)-enantiomer displayed very weak NMDA agonist activity. 2.2 KA The kainoid amino acids all possess a trisubstituted ring with three contiguous stereocentres, and are typified by the parent structure of kainic acid 38a. In all known naturally occurring examples, the C-2 substituent is a carboxy substituent and the C-3 substituent is a carboxymethyl residue, but the nature of that at C-4 varies widely although always possesses some �-electron density. The C-3–C-4 cis relative stereochemistry is by far the most common, although epimers at C-4 are known (e.g. allokainic acid).Kainic acid is isolated from the seaweed Digenea simplex, domoic acid 38b from the red algae Chondria armata and the acromelic acids (e.g. A 38c and B 38d) from the poisonous mushroom Clitocybe acromelalga. Recent reports detail the distribution of NMDA, KA and domoic acid in marine algae43 and of the isolation of new domoic acid analogues.44 These compounds all exhibit potent neuroexcitatory activity, and this is particularly true of domoic acid 38b, which has been responsible for a number of fatalities.Maximal biological activity is observed only for compounds with the KA relative stereochemistry, and for compounds with �-electron density at the C-4 substituent. These compounds are believed to function as a conformationally restricted form of glutamic acid.3 The potent biological activity of these compounds has pted considerable eVorts to both develop convenient synthetic approaches and to elucidate their pharmacology.Five kainate receptors have been identified (GluR5, 6 and 7, KA and KA1).45,46 2.2.1 Synthetic approaches A recent very comprehensive review on synthetic approaches to the kainoid amino acids has appeared which covers the literature up to November 1995.47 The development of new methodologies has none the less continued unabated, and the strategies which are used involve either construction of the pyrrolidine ring, or more commonly, modification of a pre-existing ring.The former strategy has been used for the preparation of the simple kainic acid analogue 39 (Scheme 5).48 D-Serine was elaborated in 7 steps to the oxazolidine 40, which upon radical cyclisation gave the lactam 41 with high regio- and diastereocontrol. This product was then converted to the analogue 39 in a further 4 steps, a compound which had previously been used in the synthesis of the kainic acid analogue 38 (R=H). (&)-Kainic acid has been prepared from isonitrile 42.49,50 Thus, radical ring closure (EtSH, AIBN, toluene, 60 )C) to dihydropyrrole 43 was achieved in 77% yield, which was then converted to the proline 44 (56% over 4 steps).Oxidation to the sulfone followed by intramolecular alkylation gave the bicyclic derivative 45 in high overall yield, which was then converted to kainic acid 38a in 3 steps (49% yield) (Scheme 6). NH CO2H H H H Z H Y X N N N NH NH O N O HO N N NH 31 Y–Z = CH2CH2, SCH2; SO2CH2 X = MeSO2NHCO–; PhSO2NHCO– 3 4a 6 8a , , NH CO2H N N N NH 32a n = 0 32b n = 1 32c n = 2 (CH2) n N O OEt N O OEt EtO2C NH N O OEt NH Ph NHBoc O R2 R1 N O OEt NH Ph NH2 O R2 R1 N O OH NH HO2C H Cl– 34 33 35a R1 = CO2Et; R2 = H 35b R1 = H; R2 = CO2Et 37 36a R1 = H; R2 = CO2Et 36b R1 = CO2Et; R2 = H + Scheme 4 NH CO2H CH2CO2H R Me Me HN HN Me HO2C O CO2H O HO2C R = a 38 c b d 2 3 4 208 Natural Product Reports, 1998The compound 46a and its conformationally constrained relative 46b have been prepared in an 11 step sequence from the readily available Diels–Alder adducts 47a,b.The key steps of the sequence involved an oxidative C=C cleavage to the required diacid functionality, introduction of the lactam nitrogen by treatment of the intermediate anhydride with benzylamine, and introduction of the C-2 carboxylic acid via cyanide addition to the corresponding imine.51 These compounds, however, were not tested for biological activity, although they are close analogues of the triacid 48 which is known to possess substantial activity at the KA receptor.Hanessian and Ninkovic have reported the preparation of (")-·-kainic acid and (+)-·-allokainic acid in 2 and 3% overall yields, respectively, in routes in which the key step is a trimethylstannyl radical carbocyclisation reaction (Scheme 7).52 Using the same strategy, these authors have also prepared the 4,5-methano analogues 49a,b and 50a,b, but these exhibited very low binding aYnites for the NMDA and kainate receptors.53 The elaboration of an existing ring is a popular alternative strategy for the synthesis of the kainoids, and the ready availability of KA itself has enabled its use as a convenient starting material.The preparation of the protected KA analogues 51a–g using standard peptide methodology, and an NMR investigation of their conformational structure, has been reported.54 The derivative 51d was prepared as a methotrexate analogue. The inclusion of some of these KA derivatives in short peptide chains, exemplified by the synthesis of substance P analogues (Fig. 1), has been reported by the same group.55 Some of the most useful methodology for the construction of kainoids and their analogues has made use of pyroglutamic acid or hydroxyproline as chiral starting materials. A group from Lilly56,57 has developed a route to allokainoids using pyroglutamate 52; conversion to the unsaturated ester 53 can be achieved in 3 steps and 48% overall yield.This compound readily undergoes conjugate additions with a variety of carbon nucleophiles (e.g. enolates derived from ‚-dicarbonyls or O N SPh O Cl Me Me CO2But O N SPh Me Me H CO2But O N CO2Me CH2OH CH2CO2But O Bu3SnH AIBN 39 steps 40 41 Scheme 5 Me CN SEt OTBDMS CO2But N CO2But OTBDMS EtS N Boc CO2But OTs S Cl CO2Me N Boc CO2But S O O CO2Me Me Cl H H 38a 42 43 44 45 Scheme 6 NH CO2H CH2CO2H HO2CH2C NH CO2H H H H H HO2C CO2H O H H O O O H H O O CH 2 NH CO2H CH2CO2H HO2C 46a 47a 47b 48 46b N O CO2But O H N O CO2But O H Me3Sn Me3SnCl, NaCNBH3, AIBN Scheme 7 NH CO2H R CO2H NH 50a R = H 50b R = CH2=CH CO2H R CO2H 49a R = H 49b R = CH2=CH NR CO2Me NHMe O Y X a R = Fmoc; X = O; Y = OMe b R = Boc; X = O; Y = OMe c R = CPh3; X = O; Y = OMe e R = H; X = O; Y = NH2 f R = H; X = O; Y = OCH2Ph g R = H; X = H2; Y = OCH2Ph 51 ; X = O; Y = OMe d R = NH CO2H Y X Kan X = O; Y = NH2 Kai(Bzl) X = O; Y = OBn Kol(Bzl) X = H2; Y = OBn KanGlnPhePheGlyLeuMetNH2 GlpKanPhePheGlyLeuMetNH2 KanPhePheGlyLeuMetNH2 GlpGluPhePheGlyLeuKai(Bzl)NH2 GlpGluPhePheGlyLeuKol(Bzl)NH2 Fig. 1 Oligopeptide analogues of substance P Moloney: Excitatory amino acids 209esters, and organocuprates) giving the product 54 with all trans stereochemistry exclusively, and in moderate to excellent yields. Thus, although the C-2 stereochemistry of pyroglutamate 52 is lost upon conversion to 53, it is completely returned after the addition which forms 54 but in an opposite absolute sense; the observed all trans stereochemistry is dictated by the (4R)-centre.Deprotection with 6 M HCl at reflux gives the allokainoids 55 in 44–72% yields (Scheme 8). Furthermore, the unsaturated compound 53 has also been converted to the 4-benzyl-2,3-methanoproline derivative 56 by treatment with (dimethylamino)phenyloxosulfonium methylide. However, some of the most direct and versatile routes so far developed use hydroxyproline as a starting material.58 Considerable eVort has been made to develop practical routes to 4-arylkainoids, since some of these have particularly high biological activity. Baldwin et al.59 have improved the cis stereoselectivity of their earlier reported route60 by converting enamine 57 to the hydroxymethyl derivative 58 with excess sodium borohydride.Stereoselective reduction to give the cis C-3–C-4 relative stereochemistry, oxidation and then deprotection provides the 4-aryl kainoids 59 in good yield (Scheme 9).This approach is particularly attractive for its versatility and applicability to the synthesis of a wide range of C-4 kainoid analogues. Horikawa and Shirahama61 have reported an alternative elegant approach to this important series of compounds. After protection and oxidation of 4-hydroxyproline 60 to the corresponding ketone, organometallic addition followed by elimination gave the ƒ3,4 proline 61 (along with the ƒ4,5 isomer in a 6:1 ratio). Radical addition of monomethyl malonate at elevated temperature gave only the lactone 62, which could be easily manipulated to the phenyl kainoid 63 in 4 steps and 55% overall yield (Scheme 10).Because of the exceptional biological activity of 4-aryl kainoids, these two routes are of particular significance, oVering convenience, simplicity and generality, and are potentially applicable to a wide range of analogues. A related strategy to both of these approaches has been developed by Young and co-workers, who introduced the C-3 side chain by alkylation of 4-oxoproline derivatives, thereby providing access to a range of kainoid analogues.62 Shirahama and co-workers have established a simple and readily applicable method for the stereochemical assignment of kainoid amino acids, based upon the H-2 and H-4 chemical shifts in D2O (for pD 3–8); the diVerence in chemical shifts is assumed to arise from the anisotropy of the substituents at these positions.63 The binding of kainic acid to chiral 1,1*-binaphthyl molecular clefts has recently been investigated using NMR techniques.64 2.2.2 Medicinal chemistry The importance of the conformation of KA for binding and activity has received considerable attention.By using the analogues 64a–c prepared from a Pd-mediated coupling of N O CO2Et CO2Me N CO2Et CO2Me Ph N CO2Et CO2Me Ph Nu NH CO2H Ph R 52 53 54 4 Nu– ·HCl HCl (6 M) reflux 3 steps, 48% yield 55 R = CH2CO2H, CH2COCH3, Me, Ph Scheme 8 NH CO2H Ph H 56 ·HCl N COPh CO2Me Ar CO2But N COPh Ar CO2But OH N COPh CO2Me Ar CO2But ii–iv i 57 58 Ar = Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 59 Scheme 9 Reagents: i, excess NaBH4; ii, H2 (1 atm), Pd black; iii, RuO4; iv, CH2N2 NH CO2H HO NH CO2H CH2CO2H Ph N Boc CO2Me O N Boc CO2Me Ph N Boc CO2Me O O Ph H 62 63 i–iii iv, v vi vii–x 60 61 Scheme 10 Reagents: i, Boc2O, Et3N; ii, CH2N2; iii, PDC, 4Ar mol.sieves; iv, PhLi, CeCl3, THF; v, MsCl, Et3N; vi, MeO2CCH2CO2H, Mn(OAc)3, AcOH, 90 )C; vii, 10% Pd(OH)2, EtOAc; viii, CH2N2; ix, aq.KOH, MeOH; x, TFA N O OAc TMS CO2But O H NH CO2H H H CO2H NH CO2H H H CO2H NH CO2H H H CO2H NH CO2H O OH 66 64a 64c 64b 65 210 Natural Product Reports, 1998diene 65, Shirahama and co-workers showed that �-systems which are essentially coplanar with the pyrrolidine ring are up to 100 times less active than KA; it would appear that an orthogonal relationship between these two units is necessary for high activity.65 Molecular modelling has suggested that the ground state conformation of KA 66 is the most active, and that the C-4 isopropenyl substituent plays a crucial role in maintaining this conformation.66 Modification in the nature of this substituent aVects not only binding at the KA receptor, but aYnity for other EAA receptors, thereby providing the possibility for selective activation.66 The ‚-benzyl- and ‚-methallyl-glutamates 67a,b have been stereospecifically (all 4 stereoisomers for each) prepared from either lactam 68 or lactone 69; however, only the (2S,3R)-diastereomers displayed more depolarising activity than L-Glu, but both were substantially lower than KA.67 Thus, the pyrrolidine ring seems to be crucial for a good fit at the KA receptor.An exhaustive study by Ohfune and co-workers3 of some conformationally restricted glutamates (CCG 7 and MCG 70 as their various stereoisomers) has led to a postulate for the preferred conformational requirements for GluRs.The required compounds were either accessed by literature methodology or by the route shown in Scheme 11. Thus, the Garner aldehyde 71 was readily converted to amide 72 by standard procedures. Diazotisation (NaNO2, 5% citric acid) and palladium(II)-mediated carbene insertion generated the lactam derivative 73 as a single diastereomer in 61% yield. This compound was elaborated directly to various stereoisomers of MCG by simple deprotection and oxidation. Alternatively, a range of epimers were accessible via the cyclopropyl derivative 74, which was itself readily available from lactam 73 by alcoholysis (LiOH–MeOH).Selective manipulation of the C-3* hydroxymethyl substituent and the C-2* carboxy group, or epimerisation at these positions, allowed synthesis of a range of diastereomers of MCG 70. It would appear that the anti-anti conformation 75a of L-Glu is required for binding to the mGluRs, but the g(+)g(+) rotamer 75b for binding to the NMDA–kainate receptors.3 A synthesis of (2S,4R)-4-methylglutamic acid 76, which is applicable to the gram scale, has recently been reported (Scheme 12).68 The diastereoselective alkylation of the lactam enolate of 77 with methyl iodide gave a 1:6 cis:trans mixture of products.The desired trans compound was readily obtained in pure form by chromatography, which was then converted to 76 in 4 steps. This compound was found to inhibit [3H]KA binding to cortical membranes (IC50=35 nM) without signifi- cant interaction with either the AMPA or NMDA receptors (IC50>7 mM).Using a modification of an earlier synthesis, a Lilly group45 have prepared a wide range of C-4-modified kainoid analogues. These were readily available from the ketone 78 by aryl Grignard addition, and elimination to the lactam 79 (Scheme 13). Subsequent elaboration gave the compounds 80a–c N Boc OTBS O O O BocHN H2N CO2H CO2H RCH2 HO2C NH2 OMe CO2H H H 70 68 69 67a R = Ph 67b R = CH2=C(Me) 3' 2 1' 2' N O O H H H TBSO H O BocN OHC Me Me O N Me Me TBDMSO O H2N 72 73 MeO2C NHBoc OTBDMS CH2OTBDMS H H 2' 1' 3' 9 74 71 Scheme 11 H H H CO2 – NH H –O2C H H H NH H CO2 – CO2 – H H 75a 75b aa g+g+ + + N Boc O OTBDPS N Boc O OTBDPS Me HO2C CO2 H Me NH2 77 4 steps 76 i Scheme 12 Reagents: i, LiHMDS, THF, "78 )C, then MeI N H H CO2Et O CO2Bn N H H CO2Et Ar CO2Bn NH CO2H CH2CO2H R1 R2 R3 R4 Me R3 R4 R3 R4 80a R1 = 80b R1 = 80c R1 = H; R2 = ; R2 = H ; R2 = H i, ii steps 79 78 Scheme 13 Reagents: i, ArMgBr, TiCl4; ii, TsOH, toluene Moloney: Excitatory amino acids 211(R3=H, alkyl, halo, alkoxy; R4=H, Me, F).Of those tested, kainoid 80 [R1=CH2=C(Ph), R2=H] was found to have high aYnity and agonist potency at the GluR6 receptor. Using kainoid 81a prepared with his earlier methodology, Shirahama and co-workers69 has obtained the derivatives 81b–d, but these displayed only very weak depolarising activities, possibly due to electronic modification of the C-4 aromatic ring, or steric or conformational changes brought about by the additional ring substituents. A photolabile o-nitrobenzyl-substituted kainoid 82 has been prepared by modification of kainic acid, and used to probe the kinetics of the KA receptor in the milli- to micro-second timescale.70 Alternatively, the azidophenyl kainoid derivatives 83a,b in which the photoactivable group is attached to the isopropenyl side-chain have been prepared in a synthesis in which the key step is a palladium-catalysed allylic amination of the C-4 substituent of protected kainic acid 84a to give the protected amine 85; deprotection and acylation is used to introduce the p-azidobenzoyl unit.The amide 86 has been prepared by coupling of lactam 84b with 2-(4- azidobenzamido)ethylamine, followed by acidic deprotection. Preliminary pharmacological investigations indicated that 83 but not 86 is a strong inhibitor of KA binding, and therefore the former could be of value for photoaYnity studies.71–73 2.3 NMDA NMDA 4 is a selective agonist for the NMDA receptor, as are (RS)-2-amino-2-(3-hydroxy-5-methyl-isoxazol-4-yl)acetic acid (AMMA) 87a, (RS)-2-N-methylamino-2-(3-hydroxy-5- methyl-isoxazol-4-yl)acetic acid (N-Me-AMMA) 87b and quinolinic acid 88.[(RS)-3-(2-Carboxy-piperazin-4-yl)prop- 1-yl]phosphonic acid (CPP) 16 and (R)-2-amino-5- phosphonopentanoic acid (D-AP5) ent-8b are selective competitive antagonists. This receptor also contains binding sites for the cotransmitter glycine and the non-competitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (MK-801) 89.30 A series of racemic analogues based on the AMAA template have been prepared (by modification of an appropriately substituted isoxazole) and investigated for NMDA receptor activity.30 The substituted isoxazoles 90a,b displayed potent antagonist and agonist activities at the NMDA receptor, respectively, and molecular modelling of isoxazole 90a suggested that this could be due to a substantial restriction in conformational mobility.In contrast, the compounds 90c,d, prepared as mimics of quinolinic acid with its weakly basic nitrogen, were essentially devoid of activity. The tritiated racemic analogue 90e has been prepared in a short sequence, but attempts to develop a radioligand binding assay were unsuccessful.74 Racemic tetrazol-5-ylglycine 91 has been shown to be a very selective NMDA agonist at the nanomolar range, and its application as a probe for NMDA-mediated excitotoxic activity has been proposed.75 Enantiopure AMAA 87a (both enantiomers) have been prepared and their activity evaluated.76a Although the intermediates 92 were readily available via a four-component Ugi condensation, subsequent deprotection occurred with substantial racemisation.An alternative approach, using the previously reported isoxazole 93,76b which involved a resolution with cinchonidine, aVorded AMAA in enantiopure form.The NH CO2Me CH2CO2Me OH NH CO2H CH2CO2H OR X 81b R = H; X = I 81c R = OMe; X = I 81d R = CO2H; X = H 81a NR 3 CO2R2 CO2R1 N Fmoc CO2Me CO2Me NHCH( p-MeOC6H4) N Fmoc CO2Me CO2Me NH N3 N Boc CO2CHPh2 O HN NH O N3 R R NH CO2H O O CO2H O2N 86 83a R = H 83b R = 3H 84a R1= Me; R2= Me; R3= Fmoc 84b R1= H; R2= CHPh2; R3= Boc 85 82 N O Me OH R CO2H N CO2H CO2H NH Me 89 MK-801 87a R = NH2 (AMMA) 87b R = NHMe ( N-Me-AMMA) 88 Quinolinic acid N O R1 OH R2 CO2H NH N N N NH2 CO2H 90a R1 = Bu t; R2 =NH2 90b R1 = CH2OH; R2 = NH2 90c R1 = Me; R2 =SMe 90d R1 = Me; R2 = OMe 90e R1 = 3HH2C; R2 =NH2 91 N O Me OCH2Ph ButN O N Ph Ph Me O N O Me OMe EtO2C NH2·HBr 92 93 212 Natural Product Reports, 1998(R)-enantiomer displayed greater activity at the NMDA receptor than the (S)-enantiomer, although neither exhibited any kainate activity. 6-Substituted decahydroisoquinoline-3-carboxylic acids (e.g. compound 94a,b) have been shown to be highly potent and selective NMDA antagonists38 and were readily obtained from ketone 27a, a compound which has also been used for the preparation of AMPA antagonists and mentioned earlier.40 LY246492 94c has been prepared from the aldehyde 9577 and found to possess both NMDA and AMPA antagonist activity; the (")-enantiomer has been found to be responsible for this activity.78 The synthesis of the four stereoisomers of 3-(4- chlorophenyl)glutamic acid 96 has been reported which makes use of a modification of literature methodology.79 It has been proposed that L-homocysteic acid (L-HCA) 97 has excitatory activity, and the attenuation of its activity by the administration of each of the diastereomers of 96 was examined; of these, the (2S,3S)-isomer was the most potent, and the (2R,3S)-isomer was found to be a weak NMDA antagonist.79 A conformationally constrained analogue of L-Glu, L-trans- 2,3-pyrrolidine dicarboxylate (trans-2,2-PDC) 98, whose synthesis has been achieved via a Rapoport-type alkylation of aspartic acid followed by ring closure,80 has been shown to possess similar excitotoxic activity to NMDA, activity which could be attenuated by the coadministration of MK-801 89.81 An enantiospecific synthesis of L-687,414 99 has recently been reported.82 The bromo derivative 100 (Scheme 14), readily prepared from a ‚-lactam starting material in 5 steps, was converted to the pyrrolidine 101 by reaction with N-Boc-Obenzylhydroxylamine followed by deprotection (TFA) and concomitant cyclisation, and thence to the product 99 by hydrogenolytic deprotection.The synthesis of cis- and trans-(2S,3S)-2,3-dicarboxypiperidines 102a,b, cyclic analogues of NMDA, has recently been reported. The key intermediate 103, prepared from (2S)-phenylglycinol in 2 steps, was hydrogenated with either 5% Pd/C catalyst, giving the cis addition product 104a, or 5% Pd/C catalyst in the presence of sodium carbonate, giving the trans product 104c (Scheme 15).Diborane reduction of the lactam carbonyl to 104b,d respectively, followed by hydrogenolysis and acidic hydrolysis then gave the enantiomerically pure products cis-102a and trans-102b.83 These enantiopure materials were not, however, tested for biological activity. 14C Labelled CGS 19755 105 has been prepared from the commercially available pyridine derivative 106.84 After conversion to the pyridine N-oxide derivative 107, treatment with dimethylsulfate followed by K14CN gave nitrile 108 directly.Hydrolysis followed by hydrogenation gave the cis-piperidine 109, which upon further hydrolysis and neutralisation, gave the product 105, which was obtained in greater than 99.6% radiochemical purity by HPLC. Conantokin-G 110, a 17-mer polypeptide, has been found to act as an NMDA antagonist.85 Interestingly, Conantokin-G possesses five „-carboxyglutamate residues, and has a high degree of helicity in aqueous media.It has been found that Gla at positions 3 and 4, but not at 7, 10 and 14 are essential for NCO2Me H H CO2Et OHC NH H H CO2H R NH N N N NH N N N 95 94c R = 94a R = 94b R = H2O3PCH2 6 SO3H CO2H H2N CO2H CO2H H2N Cl NH CO2H HO2C trans-2,3-PDC 96 97 98 L-HCA N O ZHN Me Br NHZ CO2But Me N OH O H2N Me OBn i, ii iii 100 101 99 Scheme 14 Reagents: i, BocNHOBn, K2CO3, KI; ii, TFA; iii, Pd(OH)2/C, H2, MeOH N O O CO2Me O Ph N O X CO2Me O Ph N O X CO2Me O Ph H H N CO2H N CO2H CO2H CO2H 103 102a 102b 104c X = O 104d X = H2 104a X = O 104b X = H2 i v iii, iv iii, iv ii ii Scheme 15 Reagents: i, H2, Pd/C, EtOH; ii, BH3vMe2S; iii, H2, Pd(OH)2/C, EtOH; iv, 3 M HCl; v, H2, Pd/C, Na2CO3, EtOH; vi, BH3vTHF N PO3Et2 N PO3Et2 O– N PO3Et2 14CN NH PO3Et2 CONH2 NH PO3H2 CO2H 14 14 106 107 109 108 105 + ·H3PO4 Moloney: Excitatory amino acids 213antagonist activity.The data is consistent with the suggestion that Conantokin-G 110 acts at a unique polyamine-associated site on the NMDA receptor.The synthesis of phosphonate substituted amino acids and analogues has attracted considerable attention, principally as analogues of the AP derivatives 8. The NMDA antagonist CGS 19755 111 (cis-4-phosphonomethyl-piperidine-2- carboxylic acid) has been prepared from ethyl isonicotinate 112. Subjection of 112 to the Minisci conditions (HCONH2, H2O2, FeSO4) gave the amide 113, which was converted to the ester 114 in a 4 step sequence.Catalytic reduction and deprotection then gave the desired product in an 11% overall yield on a multigram scale.86 A wide range of 4-phosphonoalkylquinoline derivatives have been prepared, and evaluated for NMDA receptor activity. Of the compounds studied, 115 and 116a both showed antagonism at the CNQX and glycine regulatory sites of the NMDA receptor, and the dichloro derivative 116b was the most active.87 The synthesis of phosphonomethylpyrrolidines from hydroxyproline have been reported.88 Thus, phosphonate 117, readily available from trans-4-hydroxy-L-proline, was reacted under Bucherer– Bergs conditions [(NH4)2CO3–KCN] to give an 84:16 diastereomeric mixture of the spirohydantoins 118.A 2 step deprotection sequence then provided the diastereomeric phosphonomethylpyrrolidines 119 (Scheme 16). No biological activity data for these compounds was, however, provided, although they are conformationally restricted forms of 2-amino-5-phosphonopentanoic acid (AP-5) 8b.A synthesis of (R)-4-oxo-5-phosphononorvaline 120, from protected (R)- aspartic acid in 4 steps and applicable to the gram scale has been described (Scheme 17).89 The fully protected aspartate 121 was treated with an ·-lithiomethylphosphonate to give the intermediate ketone 122; deprotection then gave the product 120. Recent developments are not, however, solely restricted to amino acids and their analogues. An asymmetric synthesis of the NMDA antagonist Eliprodil 123 has been reported (Scheme 18).The diol 124, obtained by Sharpless’ asymmetric dihydroxylation of chlorostyrene with AD-mix-‚, was converted to the epoxide 125. Ring opening with 4-(4- fluorobenzyl)piperidine 126 gave the product 123, whose optical purity was demonstrated by NMR analysis of the MTPA ester. The opposite enantiomer was also prepared and pharmacological studies suggested that the observed neuroprotective activity resides predominantly in the (")-(R)- enantiomer.90 The piperidine propanols 127, readily prepared from the appropriately substituted propiophenone and piperidine subunits, are analogues of the antihypertensive agent Ifenprodil, and have been examined for NMDA antagonist activity.91 Of the compounds examined, chloro derivative 127 (X=Cl, R=Ph) is a selective and highly active antagonist, and displays substantial neuroprotective activity.Analogues of 3-hydroxy-1H-1-benzazepine-2,5-dione 128 (HBAD) have been synthesised and examined for NMDA receptor activity.Substitution at the 8-position resulted in greatest activity, Gly-Glu-Gla-Gla-Leu-Glu-Gla-Asn-Glu-Gla-Leu-Ile-Arg-Gla-Lys-Ser-AsnNH2 110 N CO2Et N CONH2 CO2Et N CO2Bui CH2PO3Et2 NH CO2H CH2PO3H2 112 113 114 111 N PO3H2 CO2H Cl NH PO3H2 O R2 R1 115 116a R1 = H; R2 = Cl 116b R1 = R2 = Cl N Bn O PO3Pri 2 N Bn PO3Pri 2 NH HN O O NH PO3H2 R2 R1 117 118 ii,iii 119a R1 = CO2H; R2 = NH2 119b R1 = NH2; R2 = CO2H i Scheme 16 Reagents: i, (NH4)2CO3–KCN; ii, 6 M HCl; iii, H2, Pd(OH2)/C TrHN CO2Me CO2Me TrHN CO2Me PO3Me2 O H2N CO2H PO3H2 O i ii,iii 121 122 120 Scheme 17 Reagents: i, (MeO)2P(O)CH2CH2Li; ii, 5 M HCl; iii, propylene oxide, MeOH Cl OH OH Cl O Cl OH N F 123 125 124 Scheme 18 N OH Me OH R X HN F 127 X = OH, Cl, F R = Ph, PhCH2, p-ClC6H4, p-Cl6H4, 126 214 Natural Product Reports, 1998with the methyl-, chloro- and bromo-derivatives being the most active.92 Some analogues of PCP 129, the ciscyclohexylpiperidines 130 have been reported to have been prepared from methylcyclohexanone.Thus, aryllithium (2-furyl, 2-thienyl) addition to ·-methylcyclohexanone 131 gave a diastereomeric mixture of alcohols 132, which upon displacement with azide and thermodynamic equilibration followed by reduction gave predominantly the cis diastereomers of amine 133. Piperidine ring formation with 1,5- dibromopentane then gave racemic 130 (X=O or S). The cis relative stereochemistry was shown by 13C NMR analysis. These compounds were resolved with ditolyltartaric acid, and stereochemical assignment made on the basis of an X-ray crystallographic analysis of (1S,2R)-130 (X=S).The (1S,2R)- isomers of methylcyclohexane 130 were shown to possess a substantially higher aYnity for the PCP receptor site than their enantiomers.93 An unusual series of non-competitive NMDA antagonists 134, which are analogues of MK-801 89, have been suggested as possible neuroprotective agents since they do not possess the psychomimetic side eVects exhibited by other PCPs.94 An investigation of a wide range of substituted quinoxalinediones with fused piperidines has identified PNQX 135 as a compound with considerable aYnity for the glycine binding site of the NMDA receptor.37 3 Metabotropic glutamate receptors 3.1 (1S,3R)-ACPD All mGluRs are selectively activated by ACPD 5.Recently, each enantiomer for the two diastereomers of the aza analogue APDC 136a,b, were prepared and pharmacologically evaluated. 95 Using D-trans-4-hydroxyproline 137, the ketone 138 could be prepared by standard protection and oxidation procedures. Conversion to the hydantoin 139 (NH4CO2NH2, KCN, EtOH, H2O) gave an epimeric mixture of products which was hydrolysed and esterified to give the pyrrolidines 140a,b as an 80:20 mixture. Separation of these compounds, followed by deprotection using standard methodology, gave the products 136a,b. The enantiomers of these two compounds were prepared using a similar sequence, but starting from L-trans-4-hydroxyproline.The stereochemical assignment of the products was made by a comprehensive series of NOE experiments. Pharmacological investigations indicated that (2R,4R)-APDC was a selective agonist of the mGluR receptors, which displayed in vivo anticonvulsant eVects. The 1-aminoindandicarboxylic acids 141a–c have been prepared by Bucherer–Bergs reaction of the corresponding indanones.None of these showed iGluR activity but 141b was a potent agonist at mGluR1, and it has been proposed that this is because it is a conformationally constrained form of M4CPG 142.96 The stereoselective synthesis of (S)-(+)-M4CPG 143, a selective mGluR antagonist, has been reported.97 (R)-4- Hydroxyphenylglycine 144, after protection, was converted to the imidazolide 145a and alkylated to give the methyl derivative 145b. This compound was obtained as a single diastereomer, whose configuration was assigned by literature precedent on the basis of Seebach’s ‘Principle of Self Regeneration of Stereocentres’.98 Benzyl deprotection and palladium-catalysed carbonylation of the intermediate trifluoromethanesulphonate (triflate) gave 145c, acidic deprotection of which gave the glycine derivative 143.The synthesis of racemic and enantiomerically pure 4-methyleneglutamic acid 146 has been reported,99 by alkylation of the glycine ester derivatives 147a,b with methyl 2-bromomethyl acrylate, respectively to give 148, followed by standard deprotection procedures. The L-enantiomer (absolute configuration not specified) is reported to have activity at mGluRs.Me N X NH O O OH R1 R2 R3 R4 Ph N 128 8 130 X = O,S 129 PCP Me OH X Me NH2 X 133 X = O,S 132 X = O,S O Me 131 N+ X Y R2 R2 R1 R1 NH HN Me N O O O2N R1 = OEt; R2=H, Me X = S, NR (R = aryl, alkyl) Y = CH, N Cl– 135 PNQX 134 NH HO CO2H NR 1 O CO2Et N Bn CO2Et NH HN O O N Bn CO2Et NH2 EtO2C N Bn CO2Et CO2Et H2N NH CO2H NH2 HO2C NH CO2H CO2H H2N 137 138 136a 140a 140b 136b 139 H2N CO2H R1 R2 R3 CO2H CO2H H2N Me 142 M4CPG 141a R1 = CO2H; R2 = R3 = H 141b R1 = R3 = H; R2 = CO2H 141c R1 = R2 = H; R3 = CO2H Moloney: Excitatory amino acids 2153.2 Group I Although these receptors are selectively activated by QUIS 6, it has recently been found that 3,5-DHPG 149 is also a selective agonist.It has been suggested that (S)-BrHIBO 12 may weakly interact with phosphoinositide-coupled glutamate receptors.100 A novel class of highly potent antagonists 150a–c for the mGluR1 receptor based on the cyclopropanechromene nucleus have recently been reported (Scheme 19).101 These compounds are readily available by the cyclopropanation of the 4-oxo-4Hbenzopyran- 2-carboxylic acid derivatives 151a–c to give 152a–c followed by conversion to the oxime 150a–c. These compounds were found to be significantly more potent than M4CPG 142, which is currently used as a reference standard for mGluR1 antagonists. 3.3 Group II L-CCG-I 7 is a highly selective agonist for Group II receptors. The neurotoxicity of DCG-IV 153 has been investigated, possibly by activation of both the NMDA and mGluR receptors.102 The phenyl-substituted derivative 154 has been found to be a potent and selective antagonist at mGluR2.103 This compound, along with its 15 other possible stereoisomers, were synthesised and pharmacologically characterised in a meticulous study.104 The required library of compounds was prepared by copper-catalysed cyclopropanation of either the E- or Z-cinnamoyldiazoester 155 to give the diastereomeric cyclopropanes 156.Elaboration of these compounds gave the four aldehydes 157a–d, each as a racemate, which were individually subjected to diastereoselective Strecker reaction with either (R)- or (S)-phenylglycinol. The diastereomers obtained from this reaction for each aldehyde were separated by HPLC, and each one then cleaved (Pb(OAc)4) and hydrolysed, to give the required stereoisomeric amino acids PCCG 158.The absolute stereochemistry was assigned where possible by single crystal X-ray analysis, or by unambiguous chemical enantioselective synthesis. Another class of functionalised CCG derivatives, cis- and trans- MCG-I 159, displayed pharmacological similarities to the phosphonate-containing analogues of glutamate L-AP4 and L-AP6.105 A detailed examination of the conformationally restricted amino acid trans-azetidine-2,4-dicarboxylic acid ADA 160 (both enantiomers)106 has indicated that the (2S,4S)- compound exhibits weak activity at the mGluR2 receptor and is essentially inactive at mGluR1,4 and 5.107 The racemic phenylglycine analogues 161a–f, prepared by Bucherer–Bergs reaction on the appropriately substituted acetophenone, have been shown to selectively activate Group II and III receptors.108 In a detailed structure–activity study, it has earlier been shown that a variety of substituted phenylglycines exhibit pronounced activity at these receptors.108–112 CO2H HO NH2 NMe PhCON But O R2 R1 CO2H HO2C NH2 Me 145a R1 = H; R2= p-BnOC6H4 145b R1 = p-BnOC6H4; R2= Me 145c R1 = p-(EtO2C)C6H4; R2= Me 144 143 HO2C CO2 H NH2 R CO2 Me R CO2 Me CO2Me Me OH N 148 147a R = Ph2C=N 147b R = 146 HO2C NH2 HO OH 149 3,5-DHPG O O COR O O COR O NOH COR a R = OEt b R = NHPh c R = NMePh 151 152 150 i ii Scheme 19 Reagents: i, Me3S+OI", NaOH, DMF; ii, NH2OH, py H H HO2C NH2 CO2H CO2H H H HO2C NH2 CO2H Ph 154 PCCG-IV 153 DCG-IV Ph O O N2 O O Ph Ph CHO O N O Ph CHO O N O Ph CHO O N O Ph CHO O N O OMe HO2C NH2 CO2H Ph HO2C NH2 CO2H 158 PCCG 157a 157b 157c 157d 159 MCG-I 155 156 H 216 Natural Product Reports, 19983.4 Group III These receptors are sensitive to L-AP4 8a.An extensive study of phosphate substituted amino acids at mGluR4 has identified the novel agonists 162–164.113 A recent report has described that (RS)-a-cyclopropyl-4-phosphonophenylglycine (CPPG) 165 and (S)-·-ethylglutamate (EGLU) 166 are potent antagonists at presynaptic mGluRs, although not at postsynaptic ones.114 The synthetic details for these two compounds are to be disclosed later.(S)-2-Amino-2-methyl-4-phosphonobutyric acid (MAP4) 167 has been found to be a potent mGluR agonist in adult rat brain cerebrocortical slices, but a potent antagonist in neonatal rat spinal cord, as well as exhibiting a range of eVects in other systems.115 The selective activation of the phenylglycine derivatives 161a–f has already been mentioned.108 Other phenylsubstituted amino acid derivatives 168 and 169 have also been reported to exhibit antagonistic activity at these receptors, and indicate that these receptors are responsible for neuroprotective activity against excitotoxic neuronal death.116 Homo-AMPA 170, prepared from heterocycle 171 by bromination, displacement with acetamidomalonate and decarboxylation and deprotection, has been shown to be a specific antagonist for mGluR6.In contrast, AMPA and the next higher homologue 172 of 170 were shown to have only weak agonistic activity at mGluR6.117 4 Conclusion The declaration of the 1990s as the Decade of the Brain has focused international attention on all aspects of the mechanisms of brain function. There is now a real prospect that brain injury and disease will ultimately be treatable, with stroke and Alzheimers disease being key targets in this regard.Chemists, academic and industrial, have played no small role in this work, as is evidenced by the work in this necessarily brief review. Despite their apparent simplicity, there is still however, a real need to develop new methodology for the synthesis of not only naturally occurring amino acids, but also their analogues and related drug candidates. The control of stereochemistry, both relative and absolute, is a crucial issue. 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Moloney: Excitatory amino acids 219

ISSN:0265-0568    

DOI:10.1039/a815205y

出版商:RSC    

年代:1998

数据来源: RSC