Diterpenoids

Contents

• 1 Introduction

• 2 Acyclic and related diterpenoids

• 3 Bicyclic diterpenoids
  • 3.1 Labdanes
  • 3.2 Clerodanes

• 4 Tricyclic diterpenoids

• 5 Tetracyclic diterpenoids

• 6 Macrocyclic diterpenoids and their cyclization products
  • 6.1 Taxanes

• 7 Miscellaneous diterpenoids

• References

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Abstract

Covering: 1999. Previous review: Nat. Prod. Rep., 2000, 17, 165.

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1 Introduction

This report follows the pattern of its predecessors.¹ The isolation and chemistry of the taxoids has again dominated the area. A number of studies have been reported on the chemotaxonomy of Taxus species. There have also been further studies on the structure–activity relationships of clerodanes as insect antifeedants. The diversity of the diterpenoid structures obtained from marine organisms and their biological activity has continued to attract interest.

2 Acyclic and related diterpenoids

Geranylgeraniol and some oxygenated derivatives have been obtained ² from the brown alga Bifurcaria bifurcata. Miriamin 1 has been identified ³ as a defensive diterpenoid produced by the eggs of a land slug of the Arion species. It has been shown to provide antifeedant protective action against predation by various species of beetle. The meroterpenoid chrysochlamic acid 2 from Chrysochlamys ulei has been reported ⁴ to inhibit DNA polymerase β. The antifungal agent, methoxybifuracerenone 3, which was previously reported as a constituent of Cystoseira amentacea, has been isolated ⁵ from C. tamariscifolia.

3 Bicyclic diterpenoids

3.1 Labdanes

The dinorlabdane 4 has been found ⁶ in Copaiba oil. The triene, juniperexcelsic acid 5, has been shown ⁷ to be a cytotoxic constituent of the berries of Juniperus excelsa. The furanolabdadienoic acid 6 was amongst the diterpenoid constituents of Baccharis pingraea.⁸ Further investigations of Vitex rotundifolia have afforded ⁹ the spiro-ether 7.

Labdanes have continued to be obtained from Croton species including Croton oblongifolius.¹⁰ Crotonadiol 8 was isolated ¹¹ from the stems of C. zambesicus. The highly oxygenated 6,7-secolabdane, 2β-hydroxysaudinolide 9, was obtained ¹² from Clutia richardiana. A number of bis-diterpenoids have been reported including moldenin 10 from Moldenhawera nutans.¹³ Further studies on the excoecarins from the wood of Excoecaria agalocha have been reported.¹⁴

Studies on the partial synthesis of labdanes have included the synthesis of limonidilactone 11 from zamuranic acid.¹⁵

3.2 Clerodanes

The full ¹H and ¹³C NMR assignments for stephalic acid 12 have been reported.¹⁶ Conyzalactone 13 has been obtained ¹⁷ from Conyza blinii. Examination of the Mexican plant Onoseris alata has afforded ¹⁸ some derivatives of 14. Further investigations of Teucrium polium, which has been used in Turkish folk medicine for the treatment of stomach complaints, has yielded ¹⁹ teululin A 15. Clerodendrin I 16, which is a feeding stimulant for the turnip sawfly, has been isolated ²⁰ from Clerodendron trichotomum. The insect antifeedant activity of scutecyprol B, obtained from Scutelaria rubicunda and of some other compounds derived by modification of fruticolone and scutelagin B, has been examined.^21,22

A rearranged (4→2)-abeo-clerodane 17 has been obtained ²³ from Aristolochia chamissonis. The cis languidulane carbon skeleton of salvimexicanolide 18, isolated from Salvia mexicana, may be derived from a clerodane.²⁴ Jamesoniellide H 19 is a seco-clerodane which was obtained ²⁵ from axenic cultures of the liverwort Jamesoniella autumnalis. Other cis clerodanes were isolated from the liverwort, Scapania nemorea.

The photochemical transformation of clerodanes including fruticolone has been examined.²⁶ The structures of the products has led to the suggestion that some clerodanes may be photochemical artefacts. The photoxidation of the furan ring of hardwickiic acid to form a butenolide has been used in the clarification of the structure of some clerodanes.

4 Tricyclic diterpenoids

11α-Hydroxyabietadiene has been obtained ²⁷ from Cryptomeria japonica (sugi). The structure 20 has been assigned ²⁸ to gaultheric acid which was isolated from the roots of Gaultheria yunnanensis. A study ²⁹ of the immunosuppressive constituents of Tripterygium wilfordii led to the isolation of triptobenzene L 21 whilst the cyclic peroxide 22 was obtained ³⁰ from the heartwood.

Mandarone A 23 was amongst the abietane diterpenoids isolated ³¹ from Clerodendron mandarinorum whilst the royleanone, bungone A 24, was detected ³² in the stems of C. bungei. Another royleanone 25 was obtained ³³ from the roots of Salvia nutans whilst further investigations yielded similar compounds from the roots of S. glutinosa, S. austriaca, S. tomentosa and S. verticillata. Kronenquinone 26 is a constituent of S. kronenburgii.³⁴ Trials have been reported ³⁵ on salvicine, a modified diterpenoid quinone, as a tumour inhibitor. Examination of the Chinese medicinal plant, Euphorbia fischeriana (Lang Du), has led ³⁶ to the isolation of langduin B 27, the structure of which was established by X-ray crystallography.

A number of rearranged abietanes have been reported including standishinal 28 from Thuja standishii,³⁷ dichroanal A 29 from Salvia dichroantha ³⁸ and the dimeric diterpene, grandione 30 from Torreya grandis.³⁹ The oidiolactones including 31 have been isolated ⁴⁰ from the fungus, Oidiodendron truncata. Some of these tetranorditerpene lactones have shown activity against pathogenic yeasts.⁴¹

Some rearranged pimaranes have been obtained from Orthosiphon species including neoorthosiphol A 32 from O. aristatus,⁴² and staminol A 33 and the staminolactones (e.g. A, 34) from O. stamineus.^43,44

The bromination of methyl dehydroabietate in the presence of montmorillonite K10 ⁴⁵ and the ozonolysis of methyl abietate ⁴⁶ have been studied. Some modifications of rings B and C of podocarpic acid, directed at the synthesis of quassinoids, have been reported.⁴⁷

5 Tetracyclic diterpenoids

The crystal structure of linearol, ent-18-acetoxy-3β,7α-dihydroxykaurene, has been reported.⁴⁸ The biotransformation of isosteviol and kaurenoic acid by Rhizopus species has been shown ⁴⁹ to give the 7β- and 12-hydroxy derivatives. Steviol and some relatives have been isolated ⁵⁰ from the rootbark of the marine mangrove tree, Bruguiera gymnorrhiza. The production of ent-kaurane-3,15-dione by cell cultures of the liverwort Jungermannia subulata and of carboxyatractyloside by cell suspension cultures of Atractylis gummifera have been reported.^51,52

Further investigations of Isodon (Rabdosia) species have led to the isolation of more hydroxylated kaurenoids including glabcensin V 35 from I. angustifoliusvarn. glabrescens,⁵³ eriocalyxin C 36 from I. eriocalyx,⁵⁴ rabdosianone I 37 from I. japonicus,⁵⁵ lungshengenin G 38 from I. lungshengensis,⁵⁶ and melissoidesin E 39 from I. melissoides.⁵⁷ Some cytotoxic 11-oxygenated 8,9-secokauranes have been isolated ⁵⁸ from a New Zealand liverwort, Lepidolaeria taylorii.

The total synthesis of the tetracyclic aphidicolane stemodane diterpenoids has been reviewed.⁵⁹ A number of intermediates in the biosynthesis of aphidicolin have been isolated ⁶⁰ from fermentations of Phoma betae treated with cytochrome P450 inhibitors. Studies on the biosynthesis of the gibberellins in maize ⁶¹ and on the metabolism of kaurenoids and gibberellins in some mutants of the fungus Gibberella fujikuroi ⁶² have been reported.

6 Macrocyclic diterpenoids and their cyclization products

Further investigation of Croton oblongifolius has led ⁶³ to the isolation of neocrotocembranal 40. The number of cembranes that have been obtained from marine organisms continues to rise. Cembranes that have been described include sartol acetate B 41 from a Sarcophyton species,⁶⁴ brassicolide 42 from the coral, Nephthea brassica,⁶⁵ sethukarailin 43 from Sinularia maxima,⁶⁶ and further cembranolides from Pseudopterogorgia bipinnata.⁶⁷

Investigations of the latex of the Euphorbiaceae have continued to yield diterpenes with the lathyrane, jatrophane and phorbol skeleta. These include euforboetol 44 which was isolated as its 3,5,17-triacetate from the irritant latex of a Portugese collection of Euphorbia boetica,⁶⁸ some further jatrophanes from E. peplus,⁶⁹ ingol esters from E. lactea,⁷⁰ lathyranes from E. lathyris,⁷¹ and tumour promoting ingenol esters (milliamines) from E. leuconeura.⁷² The latter is a succulent plant which is sometimes used as an indoor decorative plant. Maprouneacin 45 is a daphnane with antihyperglycemic activity which was isolated ⁷³ from Maprounea africana.

6.1 Taxanes

A comprehensive review of the naturally occurring taxanes has appeared.⁷⁴ Recent advances in the medicinal chemistry of the taxanes has also been reviewed.⁷⁵ The constituents of various members of the yew family have been reviewed. The distinction between the various Taxus species is difficult. The chemotaxonomy of Taxus species has been examined ⁷⁶ in the light of their taxane content. The results of the analysis allowed a distinction to be made between the North American and Eurasian species. The occurrence of paclitaxel in Podocarpus gracilior (African fern pine) has been reported.⁷⁷ A study of the seasonal variation of neutral and basic taxoids in the European yew, Taxus baccata, has revealed ⁷⁸ a dependency on the location of the plant rather than the season.

A number of novel taxoids have been isolated. These include 46 from T. canadensis needles,⁷⁹ 1-hydroxytaxuspine C 47,⁸⁰ taxezopidine J 48 ⁸¹ and the rearranged taxane 49 ⁸² from T. cuspidata. There have been a number of investigations into the taxanes of the Chinese yew, T. mairei. These have led to the isolation of the bicyclic compounds 50 ⁸³ and 51 ⁸⁴ and taxamain A 52.⁸⁵ Further reports ^86–90 on this species have included ⁹¹ the isolation of a 2(3→20)abeo-taxane 53. Other paclitaxel and brevifoliol analogues (e.g.54) have been obtained from T. media,⁹² and T. wallichiana.⁹³

A conformational study of the phenylisoserine side chain of paclitaxel has been reported.⁹⁴ Further methods for the modification of the side chain have been described ^95,96 together with a number of side chain variants.⁹⁷ The synthesis and structure–activity relationships of taxoids possessing different substituents on the C-2 benzoyl group have been reported.⁹⁸

The use of enzymatic methods in the structure modification of taxoids has been described.⁹⁹ Some water soluble taxoids have been prepared.¹⁰⁰ The modulation of multi-drug resistance in tumour cells by taxinine derivatives has been examined.¹⁰¹ The synthesis of 7-deoxy-6-hydroxypaclitaxel ¹⁰² and 10-deacetoxypaclitaxel ¹⁰³ have been reported. The structures of some rearrangement products of taxanes under various mineral and Lewis acid catalysed conditions have been elucidated.^104–106 Other modifications of paclitaxel ¹⁰⁷ and the synthesis of photoaffinity analogues ¹⁰⁸ have been described.

7 Miscellaneous diterpenoids

The absolute configuration of the marine diterpenoid kalihinol A has been established by applying the exciton chirality methods to the p-bromobenzamide derivative 55.¹⁰⁹ A number of spongiane and related diterpenoids have been described. A modified spongiane skeleton has been assigned ¹¹⁰ to the antibacterial diterpenoid, noscomin 56, which was isolated from Nostoc commune. The absolute stereochemistry has been determined ¹¹¹ of anisodorin 5 57. This compound was obtained from the nudibranch, Anisodoris fontaini. Examination ¹¹² of the Antarctic nudibranch, Austrodoris kerguelenensis, led to the isolation of the austrodorins A 58 and B. Spongiabutenolide A 59 was obtained ¹¹³ from a Phillippines marine sponge.

An antibacterial acid 60 with a mulinane skeleton has been isolated ¹¹⁴ from Azorella compacta. Examination of the brown alga Stoechospermum marginatum has led ¹¹⁵ to the isolation of a further spatane 61 whilst a number of secospatanes such as secospatacetal A 62 ¹¹⁶ and dilkamural 63 ¹¹⁷ have been found in the brown alga, Dilophus okamurai.

The total synthesis and chemical biology of the cytotoxic sarcodictyins have been reviewed.¹¹⁸ Massileunicellin A 64, which was obtained ¹¹⁹ from the gorgonian coral, Eunicella cavolinii, has an unusual structure with two ether bridges. Labiatin D 65 was obtained ¹²⁰ from E. labiata. Examination of the gorgonian coral Briareum excavatum has led to the identification of a range of briarane diterpenoids known as the excavatolides ¹²¹ or briaexcavatolides. A number of these show cytotoxic activity. These include briaexcavatolide A 66,¹²² briaexcavatolide G 67,¹²³ and briaexcavatolide U 68.¹²⁴ The violides, e.g.69, were isolated ¹²⁵ from another Briareum species whilst further briarane diterpenoids have been obtained ¹²⁶ from the gorgonian octacoral, Erythropodium caribaeurum. The malayenolides A–D, e.g. A, 70, were isolated ¹²⁷ from an Indonesian sea pen, Veretillum malayense. Xeniaol 71 is a xenicane diterpenoid which was obtained ¹²⁸ from an Okinawan Xenia species of coral. Investigation of the West Indian sea whip, Pseudopterogorgia elisabethae, has afforded a number of diterpenoids including the sandresolides A 72 and B ¹²⁹ and the amphilectanes, elisabatins A 73 and B.¹³⁰ The oxazole pseudopteroxazole 1, 74, from the same species, was found ¹³¹ to be a potent inhibitor of Mycobaterium tuberculosis. The isocyanide 75 was obtained ¹³² from a Cribochalina species of sponge.

Extraction of the rhizomes of Eurphorbia fischeriana afforded ¹³³ the norditerpene, fischeria A 76. The aldovibsanines A 77 and B were obtained ¹³⁴ from Viburnum odoratissimum whilst the unusual macrocyclic endoperoxide structure 78 was assigned ¹³⁵ to neovibsanin C which was obtained from V. aurabuki. Hatcherenone 79 which was isolated ¹³⁶ from the German liverwort, Barbilophozia hatcheri, has a novel diterpenoid structure.

The fungus Alternariabrassicicola, which is responsible for a black spot disease of canola, has been shown ¹³⁷ to produce the phytotoxin brassicicene A 80. The atranones, e.g.81, have been identified ¹³⁸ as metabolites of the toxigenic mould, Stachybotrys atra. Some further ryanoids have been isolated ¹³⁹ from the insecticidal plant, Ryania speciosa.

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