SYNTHESIS OF ELEUTHESIDES

Abstract

The review is devoted to research in the field of "marine" diterpene metabolites of the 4,7-oxaeunicellan type, which have a taxol-like mechanism of cytotoxic action. The known most effective chemical syntheses are presented, as well as the results of our own research, on the basis of which, based on (+)-δ-cadinol, the formal synthesis of eleuthesides was realized, and the synthesis of analogs of sorcrdictyin A and eleutherobin was carried out from the Diels-Alder adduct of levogluclsenone and piperylene. In the course of the research, the features of the chemical behavior of the little-studied sesquiterpene (+)-δ-cadinol, isolated from the resin of the Siberian cedar Pinus sibirica R.Mayer, were revealed, which caused certain difficulties at the initial stage of research when developing a scheme for the synthesis of eleuthesides. Thus, the ozonolytic cleavage of the double bond, regardless of the reaction conditions, was accompanied by α-ketol rearrangement and aldol cyclization. Both problems were solved by protecting the aldehyde group into dimethyl acetal, and the hydroxyl groups by intramolecular oxacyclization into 1,4-epoxide. After the construction of the "upper" and "lower" side chains, the reverse transition from the 1,4-epoxide to the linear structure was carried out by the action of BF3·Et2O-Ac2O to obtain a diacetate derivative corresponding to the key synthon of the synthesis scheme of Nicolau et al., which completed the formal synthesis of eleuthesides. Based on the analysis of literature data on the properties of N-methylurocanoic acid and its role in sarcodictyins, an assumption was made about the manifestation of cytotoxic properties by more accessible esters of the little-studied N-methylurocanoic acid. In this regard, methods have been developed for obtaining esters of urocanic acid from histidine and glucose and its N-methylation. Then, esters of N-methylurocanoic acid were synthesized with a number of alcohols, including those of natural origin. Using a similar strategy, a scheme was developed for the synthesis of the structural core of an eleutheside analog with a 14-methylcyclohexene ring A starting from the Diels-Alder adduct of levoglucosenone and piperylene. The key step of the scheme is the intramolecular acetylenealdehyde cyclization into a 10-membered carbocycle, which completes the construction of the eleutheside core. Trichloroacetimidate, a glycosylation agent in the synthesis of eleutherobin, was obtained. Synthetic studies have been completed by obtaining analogs of sarcodictin A with a 14-methylcyclohexene ring A and an analog of eleutherobin with a similar ring A and an orthoester arabinose substituent.