Chrolactomycin and okilactomycin are structurally related novel antitumor antibiotic polyketides produced by Streptomyces species. Both metabolites have demonstrated significant cytotoxicity in vitro towards several cell lines and okilactomycin was shown to exhibit antitumor activity in vivo against Ehrlich ascites carcinoma. Novel architectural features of these molecules include a 13-membered macrocycle with an intraether bridge forming a 2,6 cis-substituted tetrahydropyranone and a gamma-lactone and cyclohexene fused by a spirocarbon. The purpose of this study is to provide a synthetic approach for the rapid construction of these potent antitumor natural products and establish their absolute configuration, since only their relative stereochemistry is known. The designed synthesis is flexible to access the correct structure of the natural product, and includes a novel extension of tandem anionic oxy-Cope enolate oxygenation processes to form the heavily functionalized cyclohexane unit. An extension of the Petasis-Ferrier rearrangement will be employed to construct the tetrahydropyranone core.
| Smith 3rd, Amos B; Bosanac, Todd; Basu, Kallol (2009) Evolution of the total synthesis of (-)-okilactomycin exploiting a tandem oxy-cope rearrangement/oxidation, a Petasis-Ferrier union/rearrangement, and ring-closing metathesis. J Am Chem Soc 131:2348-58 |
| Smith 3rd, Amos B; Basu, Kallol; Bosanac, Todd (2007) Total synthesis of (-)-okilactomycin. J Am Chem Soc 129:14872-4 |
