This application proposes to develop new organometallic chemistry that will allow compounds with important pharmacological properties to be prepared in sufficient quantities for detailed biological studies. The proposed development of powerful new organic synthesis methodology is the primary health significance of the research proposed in this application. It is our aim to provide versatile new organic synthesis tools to enable the development of new chemical agents for treating disease. A secondary health significance of the proposed research derives from the proposed collaborative biological studies of our total synthesis targets and analogs. During the current project period we demonstrated that insertions of aryl- and alkenyl-palladium intermediates into tethered alkenes (intramolecular Heck reactions) proceed with exceptional efficacy for constructing congested quaternary carbon centers, often the most difficult centers to form in the synthesis of complex organic molecules. The studies proposed for the project years aim at further developing and exploiting the power of intramolecular Heck reactions. Proposed exploratory investigations focus heavily on the catalytic asymmetric synthesis of quaternary carbon centers. In the total synthesis area: (a) sequential intramolecular Heck reactions will be developed for the asymmetric total synthesis of scopadulan diterpenes (powerful inhibitors of H+, K+-ATPase) and pentacyclic opiates, (b) intramolecular Heck cyclization of a highly oxidized enol triflate will be explored as the key step in a projected total synthesis of complex cardenolides such as ouabain (an endogenous ligand for Na+, K+-ATPase), (c) an asymmetric Heck cyclization will be employed to forge the two contiguous quaternary centers of the MDR- inhibitor 5-N-acetylardeemin, and (d) double asymmetric Heck cyclizations will be investigated for the synthesis of the growth hormone stimulant psycholeine. The targets of total synthesis for these project years display unusually promising pharmacological activities with a range of potential therapeutic uses: e.g., for reversing multidrug resistance in cancer chemotherapy, treating Alzheimer's disease, treating peptic ulcer and related diseases, as stimulants of growth hormone release and as analgesics.
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