Tetracyclic Diterpenoids

Triterpenoids (C30 compounds) are the most ubiquitous of the terpenoids and are found in both terrestrial and marine flora and fauna (Mahato et al., 1992). Diterpenoids and triterpenoids rarely occur together in the same tissue. In higher plants, triterpenoid resins are found in numerous genera of broad-leaved trees, predominantly but not exclusively tropical (Mills and White, 1994 105). They show considerable diversity in the carbon skeleton (both tetracyclic and pentacyclic structures are found) which occur in nature either in the free state or as glycosides, although many have either a keto or a hydroxyl group at C-3, with possible further functional groups and/or double bonds in the side-chains. 

Another tetracyclic carbon skeleton, named cumbiane, has been isolated from Pseudopterogorgia elisahethae. Its representatives are the diterpenoids cumbiasin A (33) and B (34) [20] their structures and relative configurations were elucidated by interpretation of a combination of spectral data. The six-membered ring D was formed by connecting CIO and C16 of an elisabethane carbon skeleton. The carbocyclic skeleton of the cumbiasins is unprecedented and represents a new class of C20 rearranged diterpenes. The tricyclic seco-cumbiane skeleton is derived from the cumbiasins by cleavage of the C15-C16 bond. Due to intramolecular cyclizations two additional oxo-heterocycles are present in cumbiasin C (35) [20] (Fig. 7). 

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" ... 

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... 

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. 

The synthesis of the tetracyclic amide 437 has been reported by Meyer and co-workers (196) in work directed toward a general diterpenoid synthesis. The enantiomer of this amide has been prepared earlier by Tahara and colleagues (197) and converted to atisine, veatchine, and garryine. 

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

Deprotection of a dimethyl acetal at a late stage in a synthesis of the unusual diterpenoid tropone Hainanolido was not a problem.123 What was a problem was the fate of the aldehyde released because under most conditions, the aide-hyde underwent a very easy Prins-like reaction with the cycloheptatriene ring to give the tetracyclic product 573 [Scheme 2.57], This reaction could not be suppressed completely, but it was minimised by using zinc bromide to deprotect the dimethyl acetal 57.1. The desired aldehyde 573 was obtained in 61 % yield together with 16% of the unwanted 573. 

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 diterpenoids, which contain 20 carbon atoms, are represented by acyclic, monocyclic, bicyclic, tricyclic, and tetracyclic structures. Over 5,000 naturally occurring diterpenoids, many of which frequently occur in plant families Araliaceae, Aster-aceae, Cistaceae, Cupressaceae, Euphorbiaceae, Leguminosae, Labiatae, and Pinaceae, are known (32). The acyclic diterpenoid... 

We ve classified more than 550 diteipenoids (listed in Table 3 whith corresponding sources) from all the reported Salvia species which we ve divided into 2 categories. The first one contains the monocyclic and bicyclic diterpenoids including labdanes and clerodanes and related diterpenes. The second category concerns tricyclic and tetracyclic diterpenes including pimaranes and abietanes and related diterpenes. The clerodane type diterpenes are mainly represented by american species while abietane type are found in european and asian species. 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

J. R. Hanson, The Tetracyclic Diterpenoids , Pergamon Press, Oxford, 1968 more recent refs, to this area are given in J. R. Hanson, Nat. Prod. Rep., 1989, 6, 347, and previous reports. 

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... 

---