An Asymmetric Synthesis of the Tricyclic Core and a Formal Total Synthesis of Roseophilin via an Enyne Metathesis

Abstract

A formal synthesis of roseophilin, a novel pentacyclic structure possessing significant antitumor activity, starting from 3-cycloundecenylcarboxylic acid has been completed. The acid was converted diastereoselectively to the corresponding menthol ester via the ketene which, in turn, provided (S)-3-cycloundecenylcarboxaldehyde. Diastereoselective propargylation with propargyltriphenylstannane promoted by an asymmetric boron reagent prepared in situ from boron tribromide and the bis-p-toluenesulfonamide of (S,S)-stilbenediamine gave (1S,1‘R)-1-cycloundec-2‘-enylbut-3-yn-1-ol which set the stage for the key metathesis reaction. Platinum-catalyzed enyne metathesis via a formal [2 + 2] cycloaddition to a cyclobutene followed by conrotatory ring opening created the corresponding bicyclo[10.2.1]pentadeca-1(15),2-diene. Regioselective epoxidation of the less reactive double bond of the 1,3-diene was accomplished by 1,4-bromohydrin formation followed by base. Cuprate opening regio- and stereospecifically installed the isopropyl substituent. Standard procedures converted this intermediate to (1R,12R,13R,15R)-13-(tert-butyldimethylsiloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-dione. This diketone was converted to the corresponding unstable pyrrole by condensation with ammonium acetate, and the pyrrole nitrogen immediately alkylated with SEM-chloride. The formal synthesis was completed by conversion of the siloxy group to the corresponding ketone which previously had been condensed with the heterocyclic side chain to complete a synthesis of roseophilin. By having access to the tricyclic core asymmetrically for the first time, this route provides the opportunity to establish the absolute configuration of the natural product.