Catalytic Generation of Nucleophiles at Main Group Centres for Stereoselective Transformations

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Summary of Proposal Organic synthesis raises our quality of life by providing means to prepare fine chemicals used in medicine, materials and agriculture. Transformations in organic chemistry are often complicated by a lack of generality, or accompanied by the formation of undesired side products, consequently the development of new catalysts for fine chemical transformations continues to be an area of active investigation. My new research group at Dalhousie University is developing methodology employing catalysts synthesized from earth abundant main group elements to make synthesis cheaper, safer, and to make currently unknown transformations accessible, by providing complementary reactivity to catalysts derived from transition metals. We are exploring two promising themes, both of which develop new classes of nucleophiles based on main group centres with different and improved reactivity profiles to current technologies. One theme involves the hypothesis that borenium cations supported by bis(amino)cyclopropylidene (BAC) carbenes will display greater reactivity than known borenium cations because of the diminished steric bulk of BAC carbenes. We have already demonstrated that BAC carbene borenium cations are capable of hydrogenating substrates that are inaccessible to previously reported borenium cations. We will investigate the synthesis of chiral BAC carbene-supported borenium cations for asymmetric catalysis, including hydrogenation, aldol, and Diels- Alder reactions, all of vital importance in the synthesis of fine chemicals including pharmaceuticals. Our second theme involves the hypothesis that complexation of a heteroatom to a diazaphospholene raises the heteroatom's nucleophilicity. We have demonstrated that diazaphospholene alkoxides can catalyze imine reduction and conjugate reduction reactions. We will synthesize chiral diazaphospholenes with diverse architectures, and explore their ability to conduct catalytic activation and addition of nucleophiles other than hydride to conjugate acceptors and carbonyl compounds. The lack of Lewis acidity of diazaphospholenes renders them compatible with protic functional groups and Lewis basic functional groups, reducing the need for protecting groups, and potentially allowing the development of new strategies for functionalized molecule synthesis. The concepts we will develop from both themes will result in major impacts in synthetic chemistry through discovery of new reactivity. Catalysts such as those being developed in my group, that exhibit enhanced functional group tolerance, or allow transformations that are not currently accessible, allow steps to be cut in fine chemical synthesis. This streamlining will result in major environmental and financial savings, since fine chemical synthesis, especially pharmaceuticals, represent an industry worth hundreds of billions of dollars per year.