DESCRIPTION: (Applicant's Description) Salicylihalamide A is the first member of a novel class of complex macrocyclic salicylates and displays a unique differential cytotoxicity profile in the National Cancer Institute's 60-cell line human tumor assay. Since their initial discovery in 1997, a growing number of structurally related metabolites have been isolated, including lobatamides A-F, apicularen A, oximidines I-II, CJ 12,950 and SCH351448. The observation that each one of them seems to induce a unique response in mammalian cells, and as such represent unique new leads for the development of therapeutic agents, warrants the development of synthetic chemistry in this area. Building on an efficient synthesis of the salicylihalamide and apicularen macrocyclic cores, part of the proposed research is intended to provide synthetic materials, otherwise not accessible, for structure-activity and mode-of-action studies. Synthetic substitutes for their common, but labile enamide side-chain will be explored in addition to the synthesis of photoaffinity, radiolabeled, and biotinylated probes. The remainder of the proposed research deals with chemistry related to oximidine, CJ- 12,950 and SCH 351448. To achieve a total synthesis of oximidine, a variety of cross- coupling approaches will be explored to install a highly unusual conjugated E,Z,Z-triene subunit embedded within a 1 2-membered benzolactone. For the determination of the relative and absolute stereochemistry of CJ-12,950, which remains unknown, an efficient synthesis of a selected stereoisomer of the benzolactone core is proposed, serving as a platform for rapid stereoisomer interconversion via Mitsunobu chemistry. NMR spectroscopy will be the tool to correlate spectroscopic fingerprints of these advanced intermediates with CJ-12,950. Finally, a short, highly convergent synthesis of SCH351448, a macrocyclic polyketide bis-lactone composed of two identical acids, is proposed using a novel tandem inter-/intramolecular olefin metathesis strategy. Ultimately, the proposed studies will provide small-molecule probes for discovery biology in addition to new therapeutic leads.