TRANSITION METAL CATALYZED C-C BONDING FORMING REACTION

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DESCRIPTION: (Applicant's Abstract) Synthetic organic chemistry continues to play a dominant role in optimizing the therapeutic-activity of biologically active structures. Research in my group is directed toward the development of novel catalytic transition-metal-mediated carbon-carbon bond forming reactions applied to the carbocyclization of unsaturated substrates. Our goal is to provide novel cyclization methodologies for organic synthesis that utilize common organic functional groups and proceed catalytic in metal. To date our approach has been to address both mechanistic aspects of the cyclizations as well as very simple synthetic applications of the new methods. The prior funding period marked a transition away from methodology and toward synthetic applications. This competitive renewal application continues that move. On the basis of the discovery and developmental work that was completed under prior NIH support there is a good survey of the accessible rings systems, functionalities tolerated and the stereochemical control in both the iron-catalyzed enediene carbocyclizations and the palladium-catalyzed bisdiene carbocyclizations. We now focus more targeted problems in the synthesis of pharmaceutically relevant molecules. The specific aim of the proposal is to demonstrate the viability of these novel bond constructions as strategy-level reactions for complex molecule total synthesis. The targets include A80577, prostanoids, brefeldin, and steroids. Their syntheses are designed to exploit the unique structure and reactivity of organometal intermediates to control the stereochemical and regiochemical course of carbon-carbon bond construction, but are not simply applications of chemistry we now know. Each application is designed to push the limits of the metal-mediated cyclization methodology, and as such will require targeted developmental work to be successful.