This proposal is directed at the design and development of general synthetic methodology and the application of this methodology to the synthesis of the potent tumor promoters and inhibitors of the tigliane, ingenane, and daphnane families. These efforts and supporting structure activity studies are intended to establish new chemistry and to contribute to our understanding of tumor promotion, a potentially significant factor in the multifactorial etiology of human cancer. The syntheses of the targets and their analogues are to be realized through the use of a divinylcyclopropane strategy, an intramolecular Diels-Alder strategy, and an intramolecular arene olefin cycloaddition strategy. The viability of intramolecular [6 + 4] and [5 + 2] cycloadditions for the elaboration of the target skeleta are also proposed. Degradation and partial syntheses are proposed to support these synthesis studies and to provide analogues for structure activity investigations. The latter effort will be conducted, in part, using computer modelling. These studies are intended to contribute to our understanding of tumor promotion, its role in cancer, and how it can be suppressed or inhibited. A synthesis of the anti-leukemic agent quadrone is also proposed based on the intramolecular arene olefin cycloaddition, a fundamentally new methodology for total synthesis.
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