This proposal focuses on the application of pericyclic reactions in new methodology for the synthesis of several important classes of carbocyclic and heterocyclic organic compounds. Part I describes the development of new strategies for the efficient synthesis of several classes of carbocyclic and heterocyclic compounds. Intramolecular [4 + 2] cycloaddition reactions of conjugated enynes will be investigated and employed in new routes to aromatic, dihydroaromatic, and seven-membered ring containing compounds. Heterocyclic variants of this process will be developed leading to five- and six-membered nitrogen and oxygen heterocycles. The application of this chemistry to the synthesis of pentacyclic polyketide marine natural products with protein tyrosine kinase inhibitory activity, the antitumor agent clavepictine A, and to the synthesis of quinolizidine and indolizidine alkaloids that are noncompetitive blockers for nicotinic receptor-channels will also be examined. Part II of the proposal describes the development of a tandem strategy in which a new ynamide-based benzannulation reaction is employed in conjunction with various heterocyclization processes to provide efficient access to polycyclic benzo-fused heteroaromatic systems including indoles, dihydroquinolines, and benzazocines. Applications of this chemistry to the synthesis of the antitumor agents ascochlorin and FR900482, the redox cofactor PQQ (methoxatin), and the alkaloid herbindole C are described. The new methods developed in this program will provide researchers with powerful new tools for the efficient chemical synthesis of several classes of organic compounds known to possess activity as pharmaceuticals. This research will thus benefit the development of new antimicrobial agents as well as drugs for the treatment of cancer, cardiovascular disease, and other disorders.
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