DESCRIPTION: (Principal Investigator's Abstract) Explicit goals of this research include: 1. To complete a highly convergent, relatively short total synthesis of the anticancer agent halichondrin B, which is potently active against several resistant human solid tumor xenografts, but is limited by scarcity from further advancement in NCI preclinical studies. 2. To further develop a powerful synthesis of 6,8-dioxabicyclo(3.2.1)octanes by intermolecular acetalization/intramolecular diene metathesis, for application to sialic acid syntheses (KDN, N-acetylneuraminic acid (Neu5Ac), and KDO). The last of these targets will require development of a means to distinguish between enantiotopic vinyl groups in the metathesis desymmetrization. 3. To explore the conversion of bridged 6,8-dioxabicyclo(3.2.1)octane derivatives to 1,7-dioxaspiro(5.5)decane spiroketals, which are ubiquitous structural components in insect pheromones, anticancer and antibiotic natural products. 4. To develop a new synthetic approach to the annonaceous acetogenins using catalytic ring closing metathesis to construct the bis(tetrahydrofuran) core, exemplified by a total synthesis of squamotacin. Quick access to the enantiomerically pure, C2-symmetric core will provide ready access to several additional potent antitumor agents in this class, which show potency ten to the 8th power to ten to the 10th power times that of adriamycin against several tumor cell lines. 5. To exploit, at the strategic level, symmetry and novel strategies for symmetry-breaking to simplify complex targets and to provide short and efficient syntheses thereof.