Palladium-Catalyzed Reactions Using C-C Bond Activation of Strained Tertiary Alcohols and their Applications in Complex Molecule Synthesis

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Our research aims to develop innovative and efficient syntheses of complex small molecules that are of high value in pharmaceutical discovery. A key design element in our work is the use of palladium-catalyzed carbon-carbon bond activation of strained tertiary alcohols. Palladium-catalyzed cross-coupling reactions have revolutionized the way in which synthesis is conducted, particularly in medicinal chemistry research. Most of these reactions are effective at forging new carbon-carbon bonds between sp2-hybridized carbons, and generally do not impart new stereochemical information in the products. It has been suggested that an over-reliance on these methods has inadvertently resulted in limited exploration of chemical space, and negatively impacts drug discovery efforts. All of the reactions we will develop using strained tertiary alcohols result in the formation of at least one stereogenic carbon atom in the cyclic products and, in the context of pharmaceutical discovery, this added stereochemical information will facilitate a broader exploration of chemical space. While some of these reactions are diastereoselective, many are enantioselective and are also amenable to the preparation of small-molecule libraries through variation of the cross-coupling partners. In addition to these practical applications, our work also entails exploration of new reactivity and addresses some long-standing problems in organic synthesis and palladium catalysis, and will therefore result in advancement of fundamental knowledge. Finally, the proposed research program will also serve as an excellent training tool for highly qualified personnel, and will provide them with a host of valuable skills for future work in chemistry and science related areas.