The present NIH-sponsored research program on alkaloid synthesis is to be continued and focused in the next granting period on the total synthesis of the following indole alkaloids: vallesiachotamine, antirhine, geissoschizine, corynantheine, 19-dehydroyohimbine, deserpideine, pleiocarpamine, vincaridine, akuammicine, stemmadenine, tabersonine, and venalstonine. The syntheses are to be achieved by building on the PI's two general alkaloid synthesis schemes,--reduction/cyclization and nucleophile interaction/cyclization of N-substituted Beta-acylpyridines,--as well as on discoveries of the present granting period,--radical chemistry in the nucleophile-pyridine interaction, photocyclization of N-dienylindoleacetamides, and indole Beta-carbon trapping in an Aspidosperma skeleton-forming cyclization. The main significance of the proposed research is the development of new bioorganic chemistry of an synthetic pathways toward potentially pharmacologically active organic compounds. The research will open new, efficient routes to structurally complex natural products and synthetic intermediates, which can form the basis of future studies of structure-activity relationships. The research program is oriented toward indole alkaloids in view of the high preponderance of such bases among drugs used in current medical practice (e.g.: vincamine, a European antisenility agent; vincaleukoblastine, an anticancer drug, reserpine, a hypotensive factor) and the consequent high probability of finding more pharmacologically important agents in the indole alkaloid field.
