Diterpenoids of terrestrial origin

This report covering the period January to December, 2015, follows the pattern of its predecessors and includes the identication and chemistry of diterpenoids of terrestrial as opposed to marine origin. The latter are covered in the articles on marine natural products. Traditional Chinese medicines have continued to be a treasure trove of novel diterpenoids. Many of these warrant a further examination of their structure– biological activity relationships in order to identify the pharmacophores. There are a number of diterpenoids that are sufficiently abundant to provide suitable starting materials for partial synthesis. Several studies in this context have been reported during the year including work on the abietane diterpenoids. This has been reviewed. Advances in the synthesis of multi-functionalized decalins, the bicyclo[3,2,l]-octane system of the ent-kauranoids, the atisane diterpenoids, the neodolastanes, the pseudopterosin aglycones, and vinigrol, together with the use of dehydrogenation to access diterpenoid degradation products that are found in the environment, have all been reviewed. Other


Introduction
This report covering the period January to December, 2015, follows the pattern of its predecessors 1,2 and includes the identication and chemistry of diterpenoids of terrestrial as opposed to marine origin.The latter are covered in the articles on marine natural products. 3Traditional Chinese medicines have continued to be a treasure trove of novel diterpenoids.Many of these warrant a further examination of their structurebiological activity relationships in order to identify the pharmacophores.There are a number of diterpenoids that are sufficiently abundant to provide suitable starting materials for partial synthesis.Several studies in this context have been reported during the year including work on the abietane diterpenoids.This has been reviewed. 4,5dvances in the synthesis of multi-functionalized decalins, 6 the bicyclo[3,2,l]-octane system of the ent-kauranoids, 7,8 the atisane diterpenoids, 9 the neodolastanes, 10 the pseudopterosin aglycones, 11 and vinigrol, 12 together with the use of dehydrogenation to access diterpenoid degradation products that are found in the environment, 13 have all been reviewed.Other articles on the diterpenoid composition of Pinus sibirica 14 and various aspects of the diterpene biosynthetic synthases including their genetics, have appeared. 15,16Genetic studies have led to the identication of diterpene gene clusters 17 and of silent pathways that can be activated to produce diterpenoids. 18Acyclic and related diterpenoids The syntheses of C-8, C-9 and C-10 deuteriated geranylgeraniols have been reported. 19Bicyclic diterpenoids

Labdanes
Labdanolic acids have been identied as biomarkers for the botanical origin of French ambers 20 whilst copalic acid and its relatives have been associated 21 with the biological activity of the resins from Copaifera species.The lanceolatanols, including some rare hydroperoxides such as the 12-hydroperoxide 1, have been isolated 22 from the Chinese r, Cunninghamia lanceolata (Cupressaceae) which is grown in plantations for timber production.The lanceolatins A-G (e.g.A, 2) are a group of labdanes and abietanes which were obtained 23 from Cephalotaxus lanceolata (Cephalotaxaceae).Some of the abietanes described in this paper were formulated without comment, as a dienone tautomer of a phenol.
A number of the labdanes which have been found in members of the Zingiberaceae, e.g.Alpinia japonica, 24 Curcuma longa 25 and Hedychium longipetalum 26 such as the hedylongnoids A-C (e.g.A, 3), inhibit the production of nitric oxide.The paraguhenryisins A-D (e.g.C, 4) which were isolated 27 from the capitate glandula trichomes of Paragutzlaffi henryi (Acanthaceae), have phytotoxic properties and may provide a defensive measure against other invasive plants.The absolute conguration at C-14 of the labdanes from Physalis nicandroides (Solanaceae) has been established. 28bdane glycosides have been reported 29 as constituents of Diplopterygium rufopilosum (Gleicheniaceae) whilst examination of the seeds and leaves of Colophospermum mopane [Fabaceae (Leguminosae)] 30 and Leonotis leonurus (Lamiaceae) 31 has yielded some further labdanes and clerodanes.Continued examination of Leonurus japonicus gave leojaponin D 32 whilst the macranthins (e.g.A, 5) were anti-inammatory labdanes which were obtained 33 from L. macranthus.Further studies on white horehound (Marrubium vulgare, Lamiaceae) afforded 34 12(S)hydroxymarrubiin.The structure 6 has been assigned 35 to cinereanoid A which was isolated from Roylea cinerea (Lamiaceae) whilst the vitexolides A-E were similar anti-bacterial g-hydroxyab-unsaturated 15/16-lactones which were obtained 36 from Vitex vestita (Lamiaceae).
Isodon species (Lamiaceae) are renowned for the tetracyclic diterpenoid constituents of their leaves.However examination of the roots of I. adenantha afforded 37 the labdanes, adenanthic acids A and B (e.g.A, 7) and the adenanthosides A-C whilst two other labdanes were obtained 38 from I. yuennanensis.
A large number of labdanes have been detected in Chinese liverworts including the haplomintrins (e.g.A, 8) from Haplomitrium minioides 39 in which a cyclobutane ring has been formed by the possible photochemical addition of a side-chain furan across the double bond of a 7,8-en-6-one.Other examples of labdanes which have been isolated include the ptychantins P and R from Ptychanthus striatus 40 and the scapairrins A-Q from Scapania irrigua. 41rious methods for the recovery of useful compounds from Stevia rebaudiana (Asteraceae) have been reviewed. 42The fermentation of S. rebaudiana with the yeast Saccharomyces cerevisiae has led 43 to the formation of some modied sterebins arising from the selective epoxidation and hydration of the 14,15-double bond.Examination of the Taiwanese shrub, Callicarpa randaiensis (Verbenaceae) in the search for anti-inammatory agents afforded 44 the randainins A-D.As an alternative to the biosynthesis suggested in the original paper, their structures (e.g.A, 9) may arise by the oxidative cleavage of a 5,10double bond of a halimane followed by aldol condensations of the 5,10-diketone to form the trans 7/5 and 5/7 ring systems of these diterpenoids.
The cleavage of ring A has been encountered in a number of diterpenoids including labdanes.A 3-nor-2,3-secolabdane structure 10 has been assigned 45 to penioxalicin which was obtained from the fungus, Penicillium oxalicum and to paecilomycine A from an insect pathogenic fungus, Paecilomyces sp. 46urther examination 47 of the stems of the highly poisonous mangrove plant, Excoecaria agallocha (Euphorbiaceae) gave excolide 11 in a study which also led to a revision of the structure of rhizophorin A. The structure of the spiro-ketal, leonuketal 12 obtained 48 from Leonurus japonicus, may be derived by a retro-Prins cleavage of the 8 : 9-bond in a 7,9-dihydroxylabdane followed by a cyclization involving the 3-hydroxyl group, the 9-ketone and C-15.
Derivatives of the readily available labdanes such as polyalthic acid 49 and copalic acid 50 have been evaluated for the treatment of various diseases.The merosesquiterpenes, neopterosiquinones A and B have been synthesized 51 from transcommunic acid.The anti-fungal activity of sclareol 52 and some derivatives 53 has been examined.Sclareol has been used 54 as the starting material for the synthesis of the sesterterpenes, luffarin L and 16-epiluffarin and for a biomimetic synthesis of two salmahyrtisanes. 55Work has continued [56][57][58] to prepare derivatives of andrographolide in order to study structure-biological activity relationships.The enzyme systems responsible for the biosynthesis of 13(R)-manoyl oxide have been transferred 59 from Sitka spruce to a cyanobacterium, Synechocystis sp.
The clerodane pyrrole 14 was amongst 63 the anti-plasmodial constituents of Polyalthia longifolia var n .pendula(Annonaceae), the bark of which is used in West African folk medicine for the treatment of malaria.2b-Acetoxyhardwickiic acid and a number of other clerodanes were anti-bacterial constituents of Salvia adenophora (Lamiaceae) 64 and S. buchananii. 65Further structural modications of salvinorin have been made 66 including some 2-alkyl-2-methoxymethyl ethers in order to examine its structure-activity relationships as a selective k-opioid receptor agonist.ent-2b,18,19-Trihydroxycleroda-3,13-dien-15,16-olide has been obtained 67 from Crassocephalum bauchiense (Asteraceae) which is a herb that is used in Cameroon folk medicine.The dichrocephnoids A-E (e.g.A, 15) which possess anti-HIV integrase activity, were isolated 68 from Dichrocephala benthamii (Asteraceae).Further examination of the Chinese medicinal herb, Scutellaria barbata (Lamiaceae) has led to the isolation of the anti-viral scutolides A-L (e.g.A, 16) 69 and the scutebatins A-C 70 which inhibit NO production.The scutefolides (e.g.A, 17) were obtained 71 from S. coleifolia whilst the teufruintins A-G (e.g.A, 18) were obtained 72 from the aerial parts of the herb, Teucrium fruticans (Lamiaceae) which had been cultivated in China.Examination of Isodon scoparius (Lamiaceae) afforded 73 the scopariusicides A 19 and B which were unusual cyclobutane derivatives which were formed by the cycloaddition of an ester of 4-hydroxycinnamic acid to the clerodane side chain.The unusual spirocyclic ring system 20 which may be derived from a clerodane, has been assigned 74 to teotihuacanin, which was obtained from the Mexican plant, Salvia amarissima.It has shown activity against multi-drug resistance in cancer cells.
A number of new cis-clerodanes have been isolated including linarenone A from Linaria japonica (Plantaginaceae), 75 the crotocurins A-C from Croton europhyllus (Euphorbiaceae) 76 and the graveopenes A-J (e.g.A, 21) from Casearia graveolens (Flacourtiaceae). 77The latter were shown to stimulate NGF-mediated neurite out-growth which is of interest in the context of neuron degeneration in Alzheimer's disease.The related caseagrewifolins were obtained 78 from C. grewifolia.Further examination of Tinospora sagittata (Menispermaceae) gave 79 tinosporin A and B.

Pimaranes
The arabinofuranoside of isopimara-7,15-dien-19-ol has been identied 80 amongst the anti-fungal constituents of Sagittaria latifolia (Alismataceae).A series of isopimaranes known as the kaempulchraols A-I have been obtained [81][82][83] from the rhizomes of Kaempferia pulchra (Zingiberaceae).Some constituents of the roots of Oryza sativa (rice) including momilactone D 22 have been shown 84 to inhibit the production of NO.Further studies [85][86][87] on the tubers of the Nigerian herbal medicine Icacina trichantha (Icacinaceae) have revealed the presence of more 9b-H-pimaranes and some aromatic 17-norpimaranes, the icacinlactones A-H (e.g.A, 23).The xylabisboeins A and B were anti-bacterial pimarane 14,16-ethers which were isolated 88 from an endophytic Xylaria sp.obtained from the leaves of Bisboeckiera microcephala.Isopimaranes (e.g.24) were amongst 89 the anti-inammatory constituents of Dysoxylum gotadhora.A group of 16-norditerpenoids have been obtained 90 from the aerial parts of Flickingeria mbriata (Orchidaceae) whilst some pentahydroxypimaranes were isolated 91 from Aerva lanata (Amaranthaceae), a plant which is used in Ayurvedic medicine.The dienone 25 and the corresponding 11,14-a-and b-epidioxides and diols were isolated 92 from the stems of Croton insularis which was found in the Australian rain forest.A group of rosanes, e.g.stachyrosane I 26 have been reported [93][94][95] as constituents of Stachys parviora (Lamiaceae).

Abietanes
The intervention of quinone methides in the anti-oxidant activity of the phenolic diterpenoids ferruginol 96 and carnosic acid 97 has been described.The anti-fungal activity of some abietic acid esters in the context of their use as wood preservatives 98 and the antiviral activity of podocarpic acid derivatives 99   31).These include some modied abietanes arising from the cleavage of ring C. The quinone, caryopterone A possesses a methylcyclopropane ring in place of the isopropyl group of the abietanes.It was isolated 107 from the roots of Caryopteris mongolica (Lamiaceae).Some of the abietanes from this plant showed 108 cholinesterase inhibitory activity.The macrophypenes A-E, obtained 109 from Callicarpa macrophylla (Verbenaceae) included some rearranged abietanes (e.g.A, 32).
The constituents of the genus Chloranthus have been reviewed. 110 Further studies on the traditional Chinese medicine Tripterygium wilfordii (Celastraceae) have afforded more highly oxidized 18(4/3)-abeo-abietanoid derivatives including the triptergulides A and B (e.g.B, 35), 114 the wilfordosides A and B, 115 and the tripterlides A-F (e.g.A, 36) 116 in which ring C has also undergone rearrangement.A range of abietanes, pimaranes and kauranes have been isolated 117 from T. hypoglaucom.
Examination of the anti-proliferative constituents of Ethiopean Podocarpus falcatus led 118 to the isolation of 16-hydroxynagilactone F and a revision of the stereochemistry of 2a-hydroxynagilactone F to the 2b-epimer.The botryosphaerins G and H (e.g.G, 37) which were obtained 119 from a Botryospbaeria endophyte of Huperzia serrata, have a seco ring C structure or they may be tetranorlabdanes.Some further icetexanes have been isolated 120 from Perovskia atriplicifoiia (Lamiaceae).The hispidanols A and B (e.g.B, 38) were sempervirane relatives which were obtained 121 from the rhizomes of Isodon hispida.The roots of Pygmacopremna herbacea (Verbenaceae), which have been used in Ayurvedic medicine as an anti-inammatory agent, yielded a quinone which was assigned 122 the somewhat unusual structure 39 in which ring B has been expanded but the C-20 methyl group has been retained.Another unusual structure 40 involving a curious biosynthesis, has been assigned 123 to plebeianiol A which was obtained from Salvia plebeia.Neoboutomannin A 41 isolated 124 from the West African Neoboutonia macrocalyx (Euphorbiaceae) may be a degraded abietane.

Cassanes
Cassane diterpenoids are characteristic constituents of the Caesalpiniaceae.Further examination of Caesalpinia bonducella has yielded 125 the bonducellpins H-P whilst C. crista afforded 126 the phangininoxys D and E. The echinalides H-U were obtained 127 from C. echinata.Many of these compounds have been shown to possess anti-inammatory and anti-oxidative properties.The cassanes from several studies [128][129][130] of C. minax have been examined in this context.These included the caesalmins I-M 128 and a seco ring A compound neocaesalminin A 42. 130 The caesalsappanins A-L (e.g.A, 43) which were isolated 131 from C. sappan, have been studied for their anti-malarial and anti-proliferative activity.Other cassanes have been isolated from Erythrophleum suaveolens 132 and Swartzia simplex. 133The activation by epigenetic mining of a silent biosynthetic pathway in the fungus Calcarisporium arbuscula led to the isolation 18 of arbusculic acid A 44.A new phytoalexin phytocassane F 45 has been identied 134 in rice leaves that had been subjected to UV radiation.
The cleistanthanes phyllanembloids A-F (e.g.A, 46) have been obtained 135 from the roots of Phyllanthus emblica which are used in Chinese traditional medicine.

Tetracyclic diterpenoids
The ent-kauranes which have been obtained 136 from the fruits of Annona glabra (Annonaceae) as part of a study of their anti-inammatory activity, include 7b,16a,17-trihydroxy-ent-kauran-19oic acid.4b,16a,17,19-Tetrahydroxy-18-nor-ent-kaurane has been isolated 137 from Wedelia trilobata (Asteraceae) whilst some entkaurenoic acid glycosides have been found 138 in Ageratina cylindrica (Asteraceae).It has been estimated that over a thousand diterpenoids, many of which possess interesting biological activity, have been detected in Isodon (Lamiaceae) species.Further examples include the neolaxiorins I-Y 139 and the unusual laxiorol A 47 140 from I. eriocalyx var n .laxiora.Extraction of I. excisoides, 141 I. parvifolius 142 and I. scoparius 143 provided other examples.The 7,20azakaurenes, kaurines A and B (e.g.A, 48) were isolated 144 from I. rubescens together with a compound containing an unusual 17succinimide moiety.Xerophilusin B has been shown 145 to induce cell cycle arrest and apoptosis in esophageal squamosus cell carcinoma.The total synthesis of maoecrystal V has been described. 146e helikaurolides A-D which were obtained from Helianthus annuus var n .arianna,have been assigned 147 structures based on a combination of a sesquiterpene lactone (helivypolide L) and an ent-kauranoic acid.
The steviol glycosides from Stevisa rebaudiana have continued to attract attention particularly in the food industry.The relationship between the conformation of rebaudioside A in solution and its sweetness 148 and molecular modeling studies of the docking of rebaudioside A with the human sweet taste receptor 149 have been reported.Dereplication of the NMR proles of mixed steviol glycosides 150 and the application of new separation techniques 151 have been described.15a-Hydroxyrebaudioside M has been isolated 152 from S. rebaudiana.4][155][156] The X-ray crystal structure of a dimeric isosteviol sulte has been described. 157he prinsosides A-C which were isolated 158 from Prinsepia utilis (Rosaceae) included the seco-ring B ent-kaurane (C, 49).Two glycosides, ranunculosides A and B that were isolated 159 from Ranunculus muricatus (Ranunculaceae), were described as ent-kaurane glycosides but were drawn with an ent-phyllocladene structure 50.
Cafestol has been shown 160 to stimulate insulin production and it has been suggested that cafestol may contribute to the effect of coffee on reducing type 2 diabetes.The known furanokaurane, mozambioside 51 has been identied 161 as a bitter tasting glycoside that is specic to Coffea arabica as opposed to C. robusta.The tricalysins A-H that were found 162 in Tricalysia fruticosa (Rubiaceae), have been shown to be cafestol relatives and to have anti-inammatory properties.The frutilactones A and B (e.g.A, 52) were 2,3-seco-cafestol relatives that were isolated 163 from the same plant.
The gastroprotective activity of some derivatives of 18-hydroxybeyerenes has been described. 1642b,12b-Dihydroxygibberellin A 12 has been isolated 165 from the leaves of Scheffiera sessiliora (Araliaceae) in a surprisingly high amount for a gibberellin.The synthesis of pharbinilic acid 53 starting from gibberellic acid has been described. 166This is an allogibberic acid relative which had been obtained from Morning Glory (Pharbitis nil).
Further grayane diterpenoids have been obtained from the leaves of Rhododendron micranthum (Ericaceae) 167 and R. molle 168 both of which are used in Chinese traditional medicine.The total synthesis of atisane diterpenoids has been reported. 169The biological activity of scopadulciol has been examined. 170Macrocyclic diterpenoids and their cyclization products Diterpenoids with the cembrane skeleton have been found in various resins.Thus the resin of the North American Bursera microphylla (Burseraceae) afforded 171 microphyllanin 54 whilst the frankincense from Boswellia carterii (Burseraceae) yielded 172 a further group of cembranoids including the boscartins.The regioselective oxidation of the tobacco component, b-cembranediol at C-9 and C-10 using cytochrome P 450 variants has been studied. 173Some casbanes, e.g.pekinenin G 55 have been isolated 174 from Euphorbia pekinensis.A relative, sapidisin A was obtained 175 from Sapium discolor (Euphorbiaceae).
Preparative methods have been described 176 for the isolation of paclitaxel (taxol®) and of further taxanes from Taxus chinensis (T.wallichiana var n .mairei). 177The modication of the structure of ring D-seco-taxanes in the context of microtubule interactions has been examined. 178Further synthetic studies directed at paclitaxel continue to be reported. 179 large number of esters of jatrophanes, lathyranes, myrsinanes, daphnanes, tiglianes and ingenanes have been isolated, particularly from members of the Euphorbiaceae and Thymelaeaceae.Care must be taken in the separation of these compounds to avoid conditions that may lead to acyl migration and transesterication.The juxtaposition and consequent interactions between functional groups provide ample opportunities for these reactions in this closely related series of compounds and indeed may contribute to their biological activity.Molecular modeling and advanced NMR methods have been used in locating esters in the jatrophanes of Euphorbia amydaloides. 180Some cytotoxic lathyranes including lathyranlactone and jatrocurcusenone A have been isolated 181 from Jatropha curcas cv.nigroviens rugosus whilst further jatrophane and myrsinane esters have been obtained from E. connata, 182 E. dracunculoides, 183-185 E. exigua. 186E. osyridea, 187 E. prolifera, 188 and E. wallichii. 189A 12,17-cyclojatrophane, euphowelwitschine A 56 was isolated 190 from E. weiwitschii.Venenatin 57 which had been obtained from Excoecaria venenta (Euphorbiaceae), showed 191 inhibitory effects on human leukaemia cells.Further daphnane esters have been isolated from Trigonostemon xyphophylloides (Euphorbiaceae), 192 Daphne genkwa (Thymelaeaceae), 193 Gnidia polycephela (Thymelaeaceae), 194 and Stellera chamaejasme (Thymelaeaceae) 195 whilst some more tigliane (phorbol) esters with cytotoxic and anti-viral activity were obtained from Croton tiglium (Euphorbiaceae), 196,197 Daphne aurantica, 198 and Stillingia lineata (Euphorbiaceae). 199The anti-viral activity of these compounds (e.g.58) against the chikungunya virus was examined.The evaluation of epoxylathyrol derivatives in combating multi-drug resistance 200 and the anti-viral activity of a number of phorbol and ingenol esters 201 has been reported.Some synthetic studies directed towards jatrophanes have been described. 202he synthesis of the 5,6,7-ring system of the mulinane diterpenoids has been achieved. 203A number of new cyathane diterpenoids have been isolated including the striatoids A-F (e.g.A, 59) from the basidiomycetes, Cyathus striatus, 204 and from C. africanus 205 and Hericium erinaceus. 206The total synthesis of the guanacastepenes N and O, 207 dolestatrienol, 208 and the trichoaurantiolides C and D 209 have been reported.Further derivatives of pleuromutilin have been prepared 210 in the context of their potential anti-tubercular activity.
Dehydrovibsanin G has been isolated 211 from Viburnum odoratissimum and a total synthesis of vibsanin which unambiguously denes its stereochemistry has been reported. 2128-Hydroxyserrulat-14-en-19-oic acid 60 (R ¼ CO 2 H) which was isolated from the Australian medicinal plant, Eremophila neglecta (Scrophulariaceae) has been shown 213 to break-up and disperse bacterial biolms with the potential for use in wound management.A number of modied serrulatanes have been synthesized 214 from leubethanol 60 (R ¼ Me) and examined for activity against Mycobacterium tuberculosis.
have been examined.The action of a visible light LED on the N-chlorosulfonamide of dehydroabietylamine afforded 100 a 6a-chloro compound.Dehydroabietic acid has been shown 101 to regulate liver glucose levels which may be linked to the use of Abies balsamea in a folk medicine treatment for type 2 diabetes.The brevistylumsides A and B, obtained from Illicium brevistylus have been identied 102 as glycosides of dehydroabietic acid.The structure 27 has been assigned 103 to the o-quinone teuvisone which was obtained from Teucrium viscidum.The dimeric biteuvisones A and B arose by addition of the corresponding o-catechol across the 8,9-bond.Further examples of diterpenoids in which ring A has been cleaved have been isolated from Salvia species.Thus salviaprione 29 was isolated 104 as a racemate from S. prionitis.It may be formed by the cyclization of salvisyrianone 28.1-Ketoethiopinone 30 was obtained 105 from the roots of S. sahendica.The diacetate of dihydroethiopinone inhibits the growth of breast cancer cells.The roots of S. grandifolia yielded 106 the grandifolias A-F (e.g.A, ent-Abietanes have been obtained 111 from C. henryi whilst the chlorabietols A-C isolated 112 from C. oldhamii included an unusual phloroglucinol-abietane adduct (A, 33).Rings B and C have been cleaved in the formation of various sessilifols A-N (e.g.C, 34) obtained 113 from C. sessilifolius.