Total Synthesis of Bioactive Natural Products

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DESCRIPTION (provided by applicant): The goal of this program is to define new strategies and methods for the synthesis of bioactive natural products that contain a seven-membered ring. The molecules we make will provide tools to study many biological processes and may ultimately be used to develop new therapeutics, especially for cancer. Specifically, we intend to develop a general strategy for the synthesis of the rearranged steroidal compounds cortistatin A and alkaloids in the Lycopodium family. The cortistatins are potent angiogenesis inhibitors and should find use in combating tumor cell metastasis. We present a strategy to synthesize these natural products using cycloheptadiene precursors. These cycloheptadienes are in turn generated from novel metal-mediated methods. It is our expectation that these new methodological developments for seven-membered ring formation will streamline the synthesis of complex molecules. The total synthesis of the cortistatins and Lycopodium alkaloids will drive new developments, which will in turn, be applied to the synthesis of other molecules of biological and structural interest. These contributions will aid advances in human medicine and chemical biology using small molecules. PUBLIC HEALTH RELEVANCE: Finding new and more efficient ways to construct small organic molecules is an important pursuit that will provide new tools for chemical biology as well as medicine and lead to improvements in human health. Our goals are to develop new strategies and methods that efficiently build small molecules including natural products that are of pharmaceutical importance. In this regard, we are especially interested in new seven- membered ring forming reactions using transition metals.