Abstract
AbstractThis thesis reports on the formal total synthesis of (±)-acutifolone A, a novel and highly effective ring closure approach to highly substituted bicyclic systems possessing a methylenecyclopentanyl system, and the utility of the aforementioned methodology in a study towards the total synthesis of (±)-elisabethin C.Towards the formal total synthesis of (±)-acutifolone A, 4-methyl- cyclo-hexanone (18) was carbomethoxylated and oxidized to furnish β- ketoester 30. Addition of a methyl group in a 1,4-fashion gave β-ketoester 28 which was oxidized to yield enone 19 and subsequently allowed the formation of ketoester 27. Zinc iodide mediated cyclization of ketoester 27 gave bicyclic ketoester 26, the trimethylsilyl moiety of which was removed in the presence of TBAF to furnish ketoester 21, an advance intermediate in a previous total synthesis of (±)-acutifolone A.Towards the realization of the aforementioned methodology, 2-cyano- cycloalkenones, readily obtained from commercially available dinitriles, were treated with the lithium enolate of ester 80 to furnish 3-substituted 2-cyanocycloakanones in good to excellent yields. The ring closing process as mediated by palladium acetate in the presence of copper acetate led to the formation of highly substituted bicyclic systems bearing a methylenecyclopentane system and 3 contiguous stereogenic centers.Towards the total synthesis of (±)-elisabethin C, the aforementioned methodology was used to rapidly and effectively construct the perhydroindene core bearing 3 of the 5 stereogenic centers found in the targeted natural product (i.e. compound 113). Protection of the ketone moiety found in compound 113 was followed by complete reduction of the remaining ethyl ester and installation of the isopropenyl group to result in bicyclic compound 159. All that remain is to unmask the protected carbonyl group followed by a facial selective alkylation to install the final stereogenic center which will complete the total synthesis of (±)-elisabethin C.