Of tetracyclic diterpenoids

Naturally Occurring Substances.—Beyeria (Euphorbiaceae) species have been the source of a number of tetracyclic diterpenoids. Some of these were new or poorly defined species and their classification has now been clarified. " The presence of enf-kaurenal has again been recorded in Fusarium monoliforme, whilst ent-kaur-16-en-19-oic acid (72) has been isolated from Mikania hirsutissima (Composi-tae). Microbiological hydro xylation of ent-kaur-16-en-19-oic acid by... 

A group of tetracyclic diterpenoids, the grayanotoxins, extracted from the leaves of plants of the family Ericaceae have similar actions to BTX. The general structure is given in Figure 1.11 [129—132]. Again, these toxins act when applied to the inner or the outer surface of excitable membranes, are antagonised by low sodium or TTX, but differ from BTX in that they are reversible and can be washed out of the tissue [133]. 

Scheme 102.6 The biosynthesis of tetracyclic diterpenoids based on (a) ent-kaurene and (b) phorbol skeletons...

The Lewis-acid-promoted formal intramolecular 3 + 2-cycloaddition of cyclopropane 1,1-diesters with allenes (25) produced [4.3.0]nonanes (26) and [3.2.1]octanes (27) by parallel-cycloaddition and cross-cycloaddition, respectively (Scheme 8). Similarly, the Lewis-acid-catalysed formal intramolecular 3 + 2-cycloaddition reactions of cyclopropane 1,1-diesters with alkenes produced bridged[n.2.1]carbocyclic compounds with excellent stereo- and regio-selectivity under mild conditions. This reaction has been successfully applied to the total synthesis of tetracyclic diterpenoids phallocladanol and phallocladene. ... 

Of the isomeric group of tetracyclic diterpenoids originating from the isopi-marenyl cation (Fig. 8.1.24), only two types have been encountered so far. Isohi-baene (451) from Chamaecyparis nootkatensis (93) has already been mentioned. The other type is represented by phyllocladene, known since 1910 (350), but correctly characterized only in 1959. (H-)-Phyllocladanol (462) from the wood of Cryptomeria japonica is an appropriate example for the present discussion (64). Only a few compounds in each class are known at present, and all of these belong to the normal series. 

The synthetic potential provided by the intramolecular variant of the Diels-Alder reaction is further illustrated in key steps in the synthesis of tetracyclic diterpenoids possessing bridged bicyclic [3,2,l]octane units, (127) (128), and... 

Vlad, P.F., N.D. Ungur, and M.N. Koltsa Cyclization and rearrangements of diterpenoids. I. Synthesis of tetracyclic diterpenoids with a new carbon skeleton from labdanes. Tetrahedron 39, 3947 (1983). 

Ruthenium-catalyzed intramolecular [2 -b 2 -b 2] alkyne cyclotrimerizations also found applications in total synthesis, as demonstrated by the synthesis of tetracyclic diterpenoide cryptoacetalide 42 isolated from the Chinese medical plant Salvia mil-tiorrhiza (Lamiaceae) (Scheme 7.9) [16]. 

It has been shown" that isomerization of the exocyclic allylic system of the five-membered ring D of kaurenols depends on the orientation of the C(15) hydroxyl group. The total synthesis of methyl atis-16-en-19-oate, a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane skeleton, has been accomplished" using a homoallyl-homoallyl radical rearrangement process of methyl 12-hydroxykaur-16-en-19-oate monothioimid-azolide (280) as the pivotal step. Two plausible mechanisms have been presented" ... 

Chemistry of the Tetracyclic Diterpenoids.—The transannular hypoiodite reactions of 6-hydroxy-17-norkauranes have been studied with the object of functionalizing the methyl groups of ring A. Whereas the 6a-alcohols afford the 6—20 ethers, the 6/3-alcohols produce substitution at C-19. 

Aphidicolin, a tetracyclic diterpenoid, is a potent inhibitor of mammalian nuclear DNA polymerases, It does not affect mitochondrial DNA polymerase. 

The construction of the tetracyclic diterpenoids has continued to attract attention. The intramolecular alkylation of an olefin by the acid-catalysed reaction of y5-unsaturated diazo-ketones has been used ° to generate ring D in the step (194)->(195) -i- (196). A benzocyclobutane route based on the thermal cyclization of (197) to (198) has been developed for the synthesis of the beyerane skeleton. A stereoselective synthesis of stachenone, based on a series of... 

The Chemistry of the Tetracyclic Diterpenoids.—The reaction of cnt-kaur-16-ene with thallium(lli) nitrate affords cnt-kaur-16-en-15j8-ol nitrate which undergoes a ready [3,3] sigmatropic rearrangement to cnt-kaur-15-en-17-ol nitrate. The reactions of phyllocladene and of labda-8(17)-en-13-ol with sodium azide and iodine chloride have been examined. ° The synthesis of 13-hydroxylated cnt-kaur-16-ene derivatives such as steviol using an acyloin-like cyclization of keto-esters has been developed. A detailed analysis was made of the products arising from the use of sodium in liquid ammonia in this reaction. 

The crystal structure of 18-hydroxydecipia-2(4),14-dien-l-oic acid (98) has been published. The structure and absolute stereochemistry of a novel tetracyclic diterpenoid, stemarin (99), has been described. Eremantholide A(IOO) is a tumour-inhibitory compound which has been obtained from Eremanthus eleagnus (Compositae) and is possibly a nor-diterpenoid. The structure of colletotrichin (formerly known as acetylcolletotrichin) (101), which has been determined by an... 

Dalziel W, Hesp B, Stevenson KM, Jarvis JAJ. The structure and absolute configuration of the antibiotic aphidicolin a tetracyclic diterpenoid containing a new ring system. J Chem Soc Perkin Trans I 2841-2451, 1973. 

A further group of trinervitene (126) diterpenoids have been isolated from the frontal glands of a termite soldier, Nasutitermes rippertii. These include the 9/8-mono-ol, the 2/8,3a-diol and its acetates, the 2/3,3a,9o -triol and its triacetate, the 2j8,3a,13a-triol and its triacetate, and the 13-oxotrinervi-j8,3a-diol and its diacetate. Isotrinervi-2jS-ol has been obtained from the defensive secretions of T. gratiosus. Kempene-1 (127) and kempene-2 (128) are tetracyclic diterpenoids of a related type which were obtained from another Nasutitermes species. The structure (128) was established by A-ray analysis. 

Furthermore, possible biosynthetic pathway of scopadulan type and related tetracyclic diterpenoids in S. dulcis was proposed. 

BIOSYNTHESIS OF SCOPADULAN-TYPE AND RELATED TETRACYCLIC DITERPENOIDS... 

Generally, terpenoids have been believed to be biosynthesized via acetate-mevalonate pathway. Aphidicolin, a tetracyclic diterpenoid isolated from moulds, Cephalosporium aphidicola [47] and Nigrospora sphaerica [48], was also proved to be biosynthesized from mevanonic acid [49]. In this pathway, isopentenyl pyrophosphate (IPP), geranylgeranyl diphosphate (GGPP), labdane-type and pimarane-type diterpenoids were proposed to be intermediate precursors of aphidicolin [50]. 

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