Diterpenoids James R. Hanson School of Chemistry, Physics and Environmental Science, University of Sussex, Brighton, Sussex, UK BN1 9QJ Covering: 1996 Previous review: 1997, 14, 245 1 Introduction 2 Acyclic and related diterpenoids 3 Bicyclic diterpenoids 3.1 Labdanes 3.2 Clerodanes 4 Tricyclic diterpenoids 4.1 Pimaranes 4.2 Abietanes and related diterpenoids 5 Tetracyclic diterpenoids 5.1 Kaurenes 5.2 Beyerenes, atiserenes and aphidicolanes 5.3 Gibberellins 6 Macrocyclic diterpenoids and their cyclization products 6.1 Taxanes 6.2 Cembranes and other cyclization products 7 Miscellaneous diterpenoids 8 References 1 Introduction This review continues the pattern of coverage of its predecessors. 1 The period under review has again been dominated by publications on the taxanes and their biological activity.The number of known gibberellin plant hormones now exceeds 100. Diterpenoids continue to be associated with the biological activity of many plant extracts. 2 Acyclic and related diterpenoids Analysis of the labial gland secretion of the cuckoo-bumblebee (Psithyrus vestalis) males revealed2 that geranylcitronellyl acetate was a major component. These secretions play an important role as territorial marking pheromones. The unusual geometry of the aldehydic dicarboxylic acid 1 obtained from an Eremophila species, was established3 by X-ray crystallography of its semicarbazone. Some glycosides based on 20-hydroxygeranyllinalool have been found4 in Nicotiana tabacum. The epimeric viridiols A and B 2 were isolated5 from the marine red alga Laurencia viridis. 3 Bicyclic diterpenoids 3.1 Labdanes Copaiba oil, which is a mixture of oleoresins extracted from Copaifera species and used for medicinal and cosmetic purposes, has been shown6 to contain the norlabdane 3 and a clerodane 7·-acetoxybacchotricuneatin D 4. Extraction of the leaves of Guarea trichilioides (Meliaceae) gave7 the labdane 5 and the simple clerodane 6, whilst 7 together with ent-13- epimanool have been obtained8 from the liverwort Jungermannia vulcanicola.The seeds of Alpinia zerumbet (Zingiberaceae), which are used in Chinese medicine for stomach problems, have been shown9 to contain zerumin A 8. Investigation into the larvicidal activity of the diterpenes produced by the marine pulmonate Trimusculus reticulatus have shown10 that 6‚-isovaleroxylabda-8,13-dien-7·,15-diol was responsible for the biological activity. Examination of the bark of Juniperus formosana (Cupressaceae), indigenous to Taiwan, revealed11 the presence of the known dicarboxylic acid, ent-oliveric acid, and (13S)-15-hydroxylabd-8(17)-en-19-oic acid 9 together with some 15-esters. The oxidative degradation of the labdane side chain to provide ambergris odorants and starting materials for diterpenoid partial synthesis, has continued to attract attention with HO2C H O CO2H OH OH 1 2 O HO H H HO H H OH OH H HO2C H H CH2OH CHO H H CO2H H HOCH2 OAc H OH 3 4 5 6 7 8 9 O Hanson: Diterpenoids 93work being reported on larixol 10,12,13 including some microbiological studies, and on sclareol14 and copalic acid.15 Some relatives of andrographolide including 11 (wightional) have been obtained16 from Andrographis wightiana (Acanthaceae), a medicinal herb found in the Annamalais Hills of India.Leopersin C 12 was among17 the furanoid and secolabdanoid diterpenes of Leonurus persicus (Labiatae). The insect antifeedant properties of compounds of the grindelic acid series has stimulated interest in the biotransformation of grindelic acid 13.18 Microbiological hydroxylation by Cunninghamella echinulata occurred at the 2‚,3‚ and 6· positions.The X-ray crystal structure of tarapacol 15-acetate 14, from Grindelia tarapacana (Asteraceae), has been published. 19 The resinous wood of Excoecaria agallocha (Euphorbiaceae) has been used as incense (Okinawa-jinko). The constituents of the wood include20,21 ent-13-epimanoyl oxide and its 3·-alcohol (ribenol), and 3-ketone (ribenone), the 11·-hydroxy derivative of ribenone and some ent-8·,13:14,15- diepoxides known as the excoecarins A–C and exemplified by 15.Forskolin activates adenylyl cyclase and although it is widely used as a biochemical probe for characterizing adenylyl cyclase coupled biological responses, therapeutic application is limited due to its poor solubility. A series of carbamate esters have been examined22 in an eVort to overcome these problems.The known labdanes, vulgarol and marrubiin have been found23 in Marrubium anisodon (Labiatae) whilst an X-ray structure has been published24 of leonotinin 16 which was obtained from Leonotis nepetaefolia (Labiatae), a plant used for treating skin infections. Extraction of the Egyptian herb Leucas neufliseana (Labiatae) gave25 3-oxomarrubiin and the prefuran 17. Continuing investigations of diVerent chemotypes of Halimium viscosum have given26 some isofregenedane diterpenoids including the diol 18.This skeleton may be obtained27 by iodine catalysed rearrangement of labdane diterpenes, e.g. 20]19. The unusual structure of saudinolide 21, obtained from Cluytia richardiana, may be derived28 by cleavage of the 6,7-bond of a labdane and recyclization. A norfriedo-labdane 22 has been isolated29 from a Brazilian collection of Vellozia stipitata. 3.2 Clerodanes The triol 23 has been isolated30 from two varieties of Viguiera tucumanensis (Asteraceae) in the course of a chemotaxonomic study of this genus.Soulidiol 24 was obtained31 from Aster souliei, whilst the lactone 25 and a perhydroazulenoid rearrangement product 26 of a clerodane were isolated32 from a Chilean collection of Baccharis linearis (Asteraceae), a medicinal herb known locally as romerillo and used for the treatment of rheumatism. The clerodane 27 has been isolated33 from the toxic bark of the Madagascan tree Croton hovarum (Euphorbiaceae).The glucoside, amarisolide 28, was obtained34 from a Mexican collection of Salvia amarissima (Labiatae). The aglycone was recovered by incubation of the glucoside with the fungus Fusarium monoliforme. The absolute stereochemistry of tanabalin 29, an insect antifeedant from the bitter tasting Brazilian plant Tanacetum balsamita (Compositae), catinga-de-mulata, was established35 by a combination of X-ray crystallography and a modified Mosher’s method.Extraction of Teucrium sandrasicum (Labiatae), a plant used in folk medicine in Turkey in the treatment of diabetes, gave36 the clerodane, sandrasin A 30, whilst teucrasiatin 31 was obtained37 from a Spanish collection of Teucrium asiaticum. Several studies have been reported on Ajuga species, including A. decumbens,38 A. lupulina, which aVorded lupulin A 32,39 and A. parviflora.40 The latter, which occurs in the H H OH OH CHO H H HOCH2 CH2OH OH H O O 10 11 12 O O OH O H O CO2H O O O OAc OH H H O H H H 13 R 14 15 CO O H CO O H O O O OH O O O O OR OAc O O O O O OH OAc H H RO AcO H OH 16 17 18 R = H 19 R = Ac HO2C CO2H H 20 21 22 94 Natural Product Reports, 1998Himalayas, aVorded two groups of clerodanes exemplified by deoxyajugarin 1 33 and 3‚-acetoxyclerodinin C 34.The neoclerodane diterpenoids which have been isolated from Scutellaria (Labiatae) species, are of interest because of their biological activity as insect antifeedants and antifungal agents.Two separate studies41,42 on S. altissima have aVorded the lactol, scutaltisin 36, whilst S. albida gave scutalbin 37.42 The dibenzoate ester 38 was obtained from S. balcalensis,43 whilst the nicotinic acid derivative, scutebarbatine A 39, was isolated44 from S. barbata. Other new compounds that have been isolated include scutecyprol A 35 from S. cypria,45 the 15-ethoxyclerodin 34 and some relatives of jodrellin and scutaltisin from the Nepalese drug S. discolor,46 scutegalin C 40 from S.galericulata47 and scutorientalin A 41 from S. orientalis.48 8-Hydroxysalviarin 42 was obtained49 from Salvia reflexa whilst the unusual 5,10-secoclerodane structure 43 was assigned50 to tonalensin, from S. tonalensis, on the basis of a HO OH O O O O HO2C HO HO OH O O O O O R2 CHO HO CHO HO HO H OH H H H HO H R1 H 25 23 24 26 27 28 R1 = OGlu; R2 = H 29 R 1 = H; R2 = OAc O OAc O O O O O OAc O O O O CH2 OAc O O MeO OAc HO OH H OAc HO OH H H EtCH Me O C 30 31 32 OAc OAc H O OH OAc H O OAc OAc H O O OAc H O O O O O O O O OH O O H R H H H H H H H H H C O 33 36 37 34 R = OEt 35 R = OH CHEt Me O H OR OR O H OTig OAc O O O O O O OCOCHMe2 OAc O O O O O O O O O O H H H OH OH H OH OTig O O CC6H5 O CC5H4N 38 R = 39 R = 40 41 42 43 Hanson: Diterpenoids 95crystallographic study.The eVect of the clerodanes isolated from Salvia species on the feeding behaviour of Spodoptera littoralis has been examined.51 Chemosystematic studies on liverworts have continued to reveal the presence of clerodanes. Heteroscypholide A 44 was obtained52 from cell cultures of Heteroscyphus planus, whilst the 3,4-secohalimane 45 was isolated53 from H.coalitus. Some chemical transformations of the clerodanes have been reported including the cleavage of ring A of eriocephalin and capitatin,54 and the selective reduction55 and the basecatalysed rearrangement56 of teucvidin 46 to the ketone 47. The latter has potent insect antifeedant activity against the larvae of Leucania separata. The X-ray crystal structure of the 18-chloro-4·-hydroxy derivative 48 of 19-acetylteupolin has been reported.57 A number of A/B cis-clerodanes have been examined.The synthesis of the cis-clerodane acid 49 has been reported58 but the product diVered from the natural product suggesting that the structure of the latter requires revision. Nakamurol A 50 has been obtained59 from the Okinawan sponge Agelas nakamurai. The glucoside, rumphioside 51 has been isolated60 from the Philippine medicinal plant Tinospora rumphii (Menispermaceae), whilst the amphiacrolides, e.g. 52, are lactones which were extracted61,62 from Amphiachyris dracunuloides. Extraction of the bark of Casearia tremula (Flacourtiaceae) gave63 the cis-clerodane 53, whilst the relative 54 was obtained64 from Laetia procera (Flacourtiaceae). Both plants came from Costa Rica. 4 Tricyclic diterpenoids 4.1 Pimaranes A phytotoxic pimarane, sphaeropsidin A 55, has been isolated65 from the cypress canker fungus Sphaeropsis sapinea var.cupressi. The structure is the same as that previously assigned to an Aspergillus metabolite. The zythiostromic acids, e.g. 56, are antifungal metabolites of a Zythiostroma species associated with the aspen tree.66 The plant growth regulatory O O OAc OAc O H MeO2C O C O O O H 44 45 O O O O O H HO2C O O O O H H H H O O O H HO Cl OAc H O OAc 46 47 48 O CO2H OH MeO2C O O OGlu O O O O O C O EtCH Me O O CH2OH H H HO H EtO OH H OR2 AcO OAc HO H AcO OAc OR1 OMe O H 49 50 51 52 53 54 CO O OH H OH HO OH H H H OH CO2H O MeO2C OH H H O OH H H O OH HO AcO AcO 55 56 57 58 96 Natural Product Reports, 1998activity of the vouacapanes of Pterodon polygalaeflorus has been examined.67 Extraction of the Indonesian medicinal plant Caesalpinia major (Fabaceae), known as ‘dekar’ and used as an anthelmintic, has aVorded68 the caesaldekarins, e.g. 57, whilst the cassane derivative 58 was obtained69 from C.bonduc. The betonicosides A–D, e.g. 59, are similar compounds which have been isolated70 from the roots of Stachys oYcinalis (Labiatae). The swartziarboreols are cassane derivatives which have been isolated71 from Swartzia arborescens. The X-ray crystal structure of trinervinol 60 has been published.72 During studies on the partial synthesis of gibberellin analogues, the base-catalysed cyclization of 61 has been shown73 to give the unexpected spiro-diketone 62.The cytotoxic spongian diterpene 63 has been isolated74 from the nudibranch Chromodoris obsoleta. 4.2 Abietanes and related diterpenoids 19-Hydroxy-abieta-8(9),15-diene 64 has been isolated75 from Vellozia flavicans (Velloziaceae) in a continuation of studies on this species. Extraction of the bark of Juniperus formosana var. concolor (Cupressaceae) gave76 totarol and a number of abietanes including dehydrosugiol 65. 6‚-Hydroxyferruginol 66 together with some 6·,7‚-dimeric ethers have been obtained77 from the heartwood of J.formosana. In this work it has been suggested that the 6‚-hydroxyferruginol which had been previously isolated78 from Cryptomeria japonica, may in fact be the 6·-isomer. The ortho-quinone 67, obtained79 from the bark of J. procera, has strong antibacterial action. Evidence has been presented80 indicating that the yellow colour of buddlejone 68, obtained from the roots of Buddleja albiflora (Loganiaceae), arises from the presence of the enol tautomer 69.The widely distributed Japanese cedar, sugi, Cryptomeria japonica (Taxodiaceae), has been the source of many diterpenoids. Recent isolates included81 the ketol 70. The quinonemethide 72 and the phenol 73 have been isolated82 as antimicrobial constituents from Plectranthus elegans (Labiatae). The diketone forskalinone 71, which possessed antimicrobial activity, was isolated83 from the roots of Salvia forskohlei. Euphorbia calyptrata (Euphorbiaceae) is a poisonous shrub growing in the Sahara which produces a series of lactones, the helioscopinolides that have CNS activity.Cell culture lines have been established84 to produce quantities of these lactones including some novel members of the series such as helioscopinolide F 74.85 The rearranged abietane 75, possessing moderate antibacterial activity, has been isolated86 from Plectranthus hereroensis (Labiatae), whilst examination of Caryopteris incana gave87 incanone 76 and Coleus scutellarioides yielded88 scutequinone 77.Some ring A cleavage products, including limbinal 78 and a compound with the rather surprising structure 79, have been isolated89,90 from Salvia limbata. Salvibretol 80 from S. montbretii, represents91 a further unusual modification of the basic abietane skeleton. The roots of S. miltiorrhiza (Tan-shen) have continued92 to yield novel diterpenoids including tanshinketolactone 81. A survey of the tanshinone diterpenoids from the roots of some Salvia species have been reported.93 The Californian white sage, S.apiana, has been used as a medicinal herb. Examination of this species has yielded two unusual O O O O HO CH2OH OH OH OH OH CO2Me MeO2C O O AcO H H H CO2Me O H H HO 59 60 61 62 63 HO OH O OH O O H H H OH OH 64 65 66 67 OH O O OH H H 68 69 O R2 O R1 HO OMe O HO HO OMe O O H H H OH H H H H 70 R1 = H; R2 = a-OH, b-H 71 R1 = OH; R2 = O 72 73 74 Hanson: Diterpenoids 97families of C23 terpenoids, known as the apiananes94 and hassananes95 and exemplified by 82 and 83, respectively.The rearrangement of ring B of abietanes has been observed96 in the structure 84 of taiwaniaquinone D, which was obtained from the leaves of Taiwania cryptomerioides (Taxodiaceae). [4+2] Cycloaddition products of the quinone with ‚-myrcene and with trans-ozic were also isolated. The chemistry of the readily available tricyclic diterpenoids has continued to attract interest. Studies have been reported97 on the photosensitized oxidation of diterpenoids.The partial synthesis of umbrosone 85 from dehydroabietic acid has been reported.98 The conversion of abietic acid into methyl (13S)- 13-hydroxy isoatisiren-18-oate 87 via the unsaturated ketone 86 has been described.99 This also represented a formal synthesis of methyl trachyloban-18-oate. Methyl 11,12-di-Omethyl- 6,7-didehydrocarnosate 88, obtained from carnosol, has been shown100 to undergo an interesting rearrangement when treated with potassium tert-butoxide in dimethyl sulfoxide involving rearrangement of the C-20 carboxy group to C-7 resulting in the formation of 89.This rearrangement facilitated a partial synthesis of the potent benzodiazepine agonist, miltirone 90. NMR methods have been used101 to examine the temperature-dependence of conformational changes involving hydrogen bonding to the carboxamide group in 91. The organometallic chemistry of the ring C aromatic diterpenoids has continued to be explored102 with reports on their ruthenium catalysed alkylation. Dimers of podocarpic acid derivatives have been produced103 by thallium(III) trifluoroacetate oxidation. 5 Tetracyclic diterpenoids 5.1 Kaurenes In further studies on Yugoslavian species of Achillea (Asteraceae), examination of A. clypeolata gave104 3·-acetoxyent- kauran-16,17-epoxide 92. 17-O-‚-D-Glucopyranosyl-16‚- H-ent-kauran-19-oic acid 93 has been isolated105 from Inula britannica (Compositae), a Chinese medicinal plant used in the treatment of inflammation. A series of ent-kaur-16-en-15-ones, O O OH OH OH HO OH O OH O O OH CHO O O OH HO HO O OH H OH H OMe HO AcO OH 75 76 77 78 79 80 O O O O O O O O HO O O CO O CHO O O OH H OMe OH OMe H H 81 82 83 84 O O OH O HO MeO2C H H MeO2C H H 85 86 87 MeO OMe MeO OMe O O H MeO2C 88 89 90 CO2H KOBut OMe CONEt2 OH H MeOCH2 91 98 Natural Product Reports, 1998exemplified by 94, have been found106 in the liverwort Jungermannia truncata.The acid 95 was obtained107 from Adenostemma brasilianum (Compositae). ent-16‚,17- Dihydroxykauran-19-oic acid was identified108 as an anti-HIV principle in Annona squamosa whilst annosquamosin A was shown to be 96. Some further bioactive kaurenes have been detected109 in A. senegalensis. ent-3‚,7·,18-Triacetoxykaur-16- ene (triacetoxyfoliol) has been found110 in Turkish Sideritis huber-morathic. More highly oxygenated kaurenes, such as exsertifolin B 97 and some 7–11 dimers based on the seco ring B ent-kaurene 98, have been isolated111 from the liverwort Jungermannia exsertifolia subsp.cordifolia. Some glycosides closely related to atractyloside have been isolated from the toxic plant Xanthium spinosum (Compositae).112 Examination of Isodon ternifolius aVorded113 the isodoternifolins A 99 and B. The ease with which the ·,‚-unsaturated ketone of the enmein and oridonin series reacts with methanethiol has been noted.114 The 8,9-secokaurene 100 has been identified115 as a cytotoxic constituent of the New Zealand liverwort Lepidolaena taylorii.The partial purification of the enzyme system from Stevia rebaudiana which mediates the conversion of ent-kauren-19-oic acid to steviol has been reported.116 The microbiological hydroxylation of isosteviol at C-7· and C-12‚ by Fusarium verticolloides has been described.117 The formation of ent-11·,16·-epoxykaurane from kauranol by Gibberella fujikuroi has been reported.118 The biotransformation of 3,15- oxygenated kauranes by G.fujikuroi has also been shown119 to lead to the formation of ent-11·,16·-ethers exemplified by the conversion of 101 to 102. The stereospecificity of the microbiological reduction of ·,‚-unsaturated ketones by G. fujikuroi has been examined.120 The 13C NMR spectra of some phyllocladene diterpenoids have been assigned,121 whilst the unusual phyllocladene (13‚- kaurene) stereochemistry has been assigned to 103 which was obtained122 from Plectranthus ambiguus. 5.2 Beyerenes, atiserenes and aphidicolanes The ruthenium-catalysed rearrangement of ent-14- (benzoyloxy)-15,16-epoxybeyerane to compounds of the kaurene series has been explored.123 The atiserene skeleton has been assigned124 to the lactone spiramilactone 104, obtained from Spirea japonica. The production of scopadulcic acid 105 by tissue cultures of Scoparia dulcis (Scrophulariaceae) and its inhibitory eVect on bone resorption as well as its antiviral and antitumour activity have been examined.125,126 5.3 Gibberellins Over 100 gibberellin plant hormones are now known and those reported during 1996 are mentioned here.GA95 106 was detected127 in Prunus cereus (sour cherry) seed and the 19–2 isolactone was also found. GA96 107 was identified128 as a minor antheridiogen in the ferns Lygodium circinnatum and L. flexuosum. GA97 108, GA98 109 and GA99 110 were obtained129 from spinach Spinacia oleracea.Authentic samples were synthesized130 from gibberellic acid. Gibberellins A100– A102 111–113 were isolated131 from Helianthus annuus (sunflower). The structure elucidation and synthesis of these three 13,15‚-dihydroxygibberellins which diVer in the oxidation level of C-20, involved the conversion of gibberellic acid to gibberellin A19 and thence to the new gibberellins. The gibberellins that are present in the Japanese cherry Prunus spachiana, have been identified132 by GC–MS.A major review of gibberellin biosynthesis has appeared133 covering not only O AcO CO2H CH2OGlu H H H 92 93 H H H CO2H H H CHO H H H H OH O O O O O O AcO OH AcO O OH HO OH OH H H CH2OAc OAc OAc H O OH O O OR 94 95 96 97 98 99 100 H H H H O HO HO OH OH 101 102 H H C O OH Me2C CH AcO O OH 103 H H O OH OH O O H OBz HO2C H 104 105 Hanson: Diterpenoids 99the formation of the carbon skeleton but also the relationship between the variously hydroxylated gibberellins found in higher plants and recent studies on the enzymology of the gibberellins.The partial synthesis of GA32 114, one of the rare but biologically potent gibberellins, from gibberellic acid has been reported.134 An interesting aspect of this work was the utilization of the 7-carboxy group to assist the reduction of the C-15 ketone. GA53 115 and its 17-2H2-labelled derivative have also been synthesized135 from gibberellic acid for metabolic studies. An unexpected C-arylation at C-10 has been observed136 in the course of a thionocarbonate radical deoxygenation.Thus treatment of the phenylthionocarbonate 116 with tributyltin hydride and AIBN in benzene, gave the aryl derivative 117. The synthesis of the glucosyl conjugates of [17-2H2]GA34 118 for metabolic studies has been described.137 Further studies have been reported138 on the decomposition of gibberellic acid in aqueous solution. 6 Macrocyclic diterpenoids and their cyclization products 6.1 Taxanes A review of the naturally occurring oxetane group of taxanes has appeared.139 A particularly diYcult step in the isolation of paclitaxel (Taxol>) from Taxus brevifolia is its separation from the closely related cephalomannine.Improved methods have been described140,141 for achieving this. A number of new taxanes have been described. Immunological methods have been used142 in the detection of a new taxoid from Taxus baccata stem bark whilst some new Taxus alkaloids have been obtained143 from the needles.Teixidol 119 is an abeotaxane which was obtained144 from this source whilst 120 was obtained145 as a minor product during the large scale extraction of paclitaxel from T. brevifolia. The production of paclitaxel and cephalomannine in cell cultures of T. brevifolia has been investigated146 using very sensitive HPLC and tandem mass spectrometric methods of separation and detection. Two new abeotaxanes, the taxchinins L 122 and M 123, have been isolated147 from T.chinensis var. mairei. Further investigations148–151 of the Japanese yew T. cuspidata have led to the isolation of a series of taxanes and abeotaxanes known as the taxuspines K–W and exemplified by taxuspine K 124, the seco derivative U 125 and the 2(3–20)-abeotaxane W 126. Examination of the Taiwanese species, T. mairei, has aVorded152 the taxane 127 and the taxumairols, e.g. 128,153 whilst the abeotaxane 121 was obtained154,155 from the Himalayan yew T.wallichiana. The C-14 oxygenated taxane 129 was isolated156 from T. yunnanensis cell culture. The same species has yielded157 an 11,12-epoxide 131 and some 11(15–1)- abeotaxanes158 whilst a 2(3–20)-abeotaxane identical to taxuspine W 126, has also been found159 in the needles of a Taxus x media cultivar. The biotransformation of the taxane 130, the parent alcohol of which was obtained in high yield from cell cultures of T. yunnanensis, using the fungi Cunninghamella elegans and C.echinulata has been described.160 The mechanism of action CO2H O CO2H CO2H R CO H CO2H O CO H HO2C R OH OH HO2C OH H H H H HO OH H OH 106 107 108 R = Me 109 R = CH2OH (19®20-lactone) 110 R = CHO 111 R = Me 112 R = CH2OH (19®20-lactone) 113 R = CHO HO2C O CO H CO2H OH OH OH HO2C H H OH H HO 114 115 H H ArOC S C O O O O O Ar 116 117 O CO CO2H O CO HO GluO 118 119 120 R = H 121 R = Ac AcO OAc H OAc AcO OH HO OAc H OH BzO OH OR O OAc OH 122 R = H 123 R = Ac 124 125 126 RO OAc H OBz HO OH OAc O OAc OAc AcO O AcO H OAc OAc OH HO O HO AcO AcO H CH2OH OAc OAc OH OAc OH OAc OH OAc 100 Natural Product Reports, 1998of taxadiene synthase, a diterpene cyclase which catalyses the initial stages in Taxol biosynthesis from geranylgeranyl pyrophosphate, has been examined,161 Structure–activity studies have shown that the 2*-hydroxy group in the side chain is very important for biological activity.Combined NMR and molecular modelling studies of paclitaxel have revealed two predominant conformations – one in nonpolar and the other in polar solution.Taxol 2*-acetate displays no significant in vitro microtubule polymerization activity. NMR studies have shown162 that the presence of the acetate does not modify the side chain conformation implying that the hydroxy group may be interacting directly with a protein residue in the Taxol–microtubule complex possibly as a hydrogen bond donor. The X-ray crystal structure of the 7-methanesulfonate of paclitaxel has revealed163 a further side chain conformation whilst the ‘hydrophobic collapse’ conformation has been observed164 in the crystal structure of 10-deacetyl-7-epitaxol.The taxane skeleton undergoes a number of rearrangements. The conditions have been explored for the formation of 11(15–1)-abeotaxanes. Toluene-p-sulfonic acid catalysis brings165 about the rearrangement of 132 to 133, whilst 9,10-dioxotaxanes in the presence of trichloroacetic acid also undergo166 a ring-contraction reaction (134 to 135).The taxanes form167 an unusually stable enol 136 on reduction of the unsaturated ketone with zinc and acetic acid. However 11,12-dihydro derivatives are biologically inactive168 and 2-epipaclitaxel also shows a significantly reduced biological activity.169 The synthesis of azetidine taxanes in which the oxetane ring has been replaced by a nitrogen ring, and the synthesis of 7,9-pyrazoline adducts, have been reported.170,171 The partial synthesis of some 7-deoxypaclitaxel analogues has also been described.172 A new method based on using thioesters has been developed173 for introducing C-13 side chain.The synthesis, conformational analysis and biological evaluation of paclitaxel analogues containing heteroaromatic rings on the side chain has been reported.174 These include derivatives which show a biological activity comparable to paclitaxel. 2*-Phosphonoxy methyl ethers have been prepared175 as water soluble paclitaxel pro-drugs. The preparation of phenolic paclitaxel metabolites has been reported.176 6.2 Cembranes and other cyclization products Marine organisms have continued to provide the source of cembrane and related diterpenoids.The cembranolide, sartol A 137 has been found177 as an ichthyotoxic metabolite of a Sarcophyton species. A number of cytotoxic cembranoids such as 138 have been isolated178 from the soft corals Sinularia gibberosa and Sarcophyton trocheliophorum, whilst 3,4- epoxysarcophytonin 139 was obtained179 from an Okinawan Sarcophyton species. Some norcembranoids were obtained180 from the Red Sea soft coral Sinularia gardineri.Various collections of the gorgonian octocoral Briareum asbestinum have yielded novel briareolides such as 140,181 141182 and 142.183 The carbon skeleton of sarcoglane 143 isolated184 from the soft coral Sarcophyton glaucum, may arise via a cembrane 127 128 129 R = H 130 R = Ac 131 OAc AcO OH CH2OBz AcO H OH OAc OAc H OH AcO OAc H OAc O C O MeCH Et RO OR H OAc RO OAc AcO OAc H OH H H OAc O O MeO OBz H OH HO OH OH OH HO OH AcO OBz AcO H OAc OH O HO OH 132 133 HO HO C OH OAc HO O O OBz HO H OAc OH O HO OBz O O OH 134 135 O AcO OBz HO H OAc OTES O HO 136 O O O OH O O OH OMe 137 138 139 Hanson: Diterpenoids 101or a xeniaphyllane.The labiatamides A and B, e.g. 144, are eunicellane diterpenoids which have been obtained185 from a deep water gorgonian Eunicella labiata.Members of the Euphorbiaceae produce a number of groups of toxic and irritant diterpenoids. A new lathyrane 145 has been obtained186 from Euphorbia portulacoides whilst 19-acetoxyingenol was found187 in the latex of E. poisonii. The latter was also the source of a new tigliane 146 possessing a 9,10-methyleneundecanoate ester.188 The aleppicatines A 147 and B were isolated189 from the Turkish shrub E. aleppica. Two unusual bishomoditerpenes, the terracinolides A 148 and B, have been obtained190 from E.terracina. A number of phorbol analogues which bind to protein kinase C have been prepared.191 7 Miscellaneous diterpenoids The pseudopteradienoic acid 149 has been isolated192 from the Caribbean sea plume Pseudopterogorgia acerosa. The dimethylamino derivatives, aceropterine 150193 and its relative alanolide,194 were obtained from the same species. Sinulariadiolide 151 is a norditerpenoid which has been found195 in an Okinawan Sinularia species of soft coral.The Xenia species of soft corals have been a rich source of diterpenoids containing the nine-membered xenicane ring and exemplified in the current report by the azamilides, e.g. 152,196–198 whch are esterified with long chain fatty acids. Examination of Mulinum crassifolium (Umbelliferae) which is a Chilean plant used in folk medicine for the treatment of diabetes and bronchial disorders, has aVorded199 mulinolic acid 153, whilst other mulinanes were obtained200 from M.spinosum. The erinacines are a group of diterpenoid xylosides possessing a cyathan skeleton which have been isolated from the mycelium of Hericium erinaceum. They have attracted interest as stimulators of nerve growth factor synthesis with potential O O O O MeO2C O O PrC O O O O N Ac Me O H H HO AcO H AcO AcO Cl AcO AcO H AcO OAc OH Cl H OH OAc H H AcO H H AcO OAc OAc O H 140 141 142 143 144 O CPr O H AcO H OAc OAc O AcO O CH2OH C(CH2)7 O AcO H O OAc OH O H TigO AcO H H AcO HO H CH CHCH3 CH2 O O OCOCHMe2 O H AcO AcO OAc AcO OAc OAc 145 146 147 148 O O O CO2H O O CO2Me O HO Me2N O H O O OH O MeO2C O O C17H35C O OH AcO H OH H H H OH 149 150 151 152 CO2H H OH 153 102 Natural Product Reports, 1998application in the treatment of degenerative neuronal disorders such as Alzheimer’s disease.Recent examples that have been described201,202 include the erinacines D–G, exemplified by 154. The Basidiomycete Lepista sordida, has aVorded lepistal 155 which has been found203 to induce the diVerentiation of human leukaemic cells. Chemotaxonomic studies of the liverworts have yielded204 some 13-epineoverrucosane diterpenoids, e.g. 156, which was isolated from a New Zealand collection of Jamesoniella tasmanica. The sphenolobane 157 was isolated205 from Anastrophyllum donianum, the sacculatane 158206 from Porella platyphylla and infuscatrienol 159207 from Jungermannia infusca. The lobane derivative 160 has been obtained208 from the soft coral, Lobophytum microlobulatum whilst the 2-epicedrene isoprenologue 161 was isolated209 from the resin of the desert adapted species Eremophila pungens (Myoporaceae).The kalihinane derivative 162, extracted from the marine sponge Acanthella cavernosa, has been shown210 to have antifouling activity against barnacle larvae. A futher secotrinervitane 163 has been isolated211 from soldiers of the Madagascan termite Nasutitermes canaliculatus. The amphilectane and isocycloamphilectane isonitrile and isocyanate derivatives, e.g. 164, which have been found212,213 in the tropical marine sponge Cymbastela hooperi, have attracted interest because they show significant in vitro antimalarial activity. Leaf extracts of Ginko biloba (the maiden-hair tree) are widely used as a medicinal drug. The ginkolides are potent platelet-activating factor antagonists and their stereochemistry at C-1 has now been confirmed by an NMR study.214 Ryanodine is a potent regulator of the calcium release channel of mammalian muscle and a series of structure:activity studies have been reported.215,216 The neovibsanines A 165 and B have been found217 in Viburnum awabuki, a poisonous plant used for catching fish.Compounds of this structural type were obtained by the photochemical rearrangement of vibsanine B 166 which had been obtained previously from this plant. 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