Fostriecin, a structurally novel antibiotic isolated from the fermentation broth of Streptomyces pulveraceus, shows significant in vivo and in vitro activity against leukemia (IC50 0.46 microM), lung, breast, and ovarian cancer. Clinical trials were conducted on fostriecin, but the molecule was unstable for prolonged periods. Since fostriecin is so biologically active, the development of versatile synthetic methods are warranted to construct stable derivatives for clinical use and to elucidate the pharmacophore. The proposed synthesis of fostriecin breaks the molecule into a triene fragment and a chiral lactone fragment. The lactone is constructed using olefin metathesis after the contiguous stereocenters are set using the dihydroxylation of a chiral alphaacetoxy-sulfone. A Takai reaction will install the sensitive triene moiety and a mild reduction controlled by the orientation of the C9 hydroxyl group will establish the anti-relationship needed between the C9 and C11 hydroxyl groups. Incorporating the phosphate ester selectively onto the C9 hydroxyl group and global deprotection will complete the synthesis.
