Enabling Triplet-Energy Transfer via NHC Catalysis

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PROJECT SUMMARY: Stereoselective synthesis is critical for the assessment of drug candidates. Over the last century, the community understanding of stereocontrol of thermal reactions has matured significantly. By contrast, strategies for controlling the stereochemistry of photochemical transformations remain underdeveloped, despite the growing importance of synthetic organic photochemistry. Integral to overcoming this limitation is a deeper understanding of photoactivation mechanisms and how the photophysical properties of organic molecules and catalysts can be harnessed to promote enantioselective pathways. This proposal outlines a means by which photoexcitation of inexpensive alkenes can be accomplished with a carbene catalyst, photosensitizer, and visible light. This will allow chemical feedstocks to be directly engaged in enantioselective photocycloadditions to generate cyclobutanes containing medicinally relevant functional groups. In the first of two Specific Aims, the concept of this proposal will be developed through an assessment of the mechanism and of the physical properties of the key reactive intermediate and the features that enable photoexcitation. These fundamental studies will lay the groundwork to advance asymmetric catalysis of the cycloaddition reactions. Upon establishment of the viability of the approach, scope and limitations will be defined. In the second Specific Aim, a first-principles design of new catalysts will be performed to elicit reactivity from previously inert classes of alkyl-substituted substrates. The fruition of this proposal will directly benefit the drug discovery process by establishing a powerful new tool to construct biologically active molecules in new areas of chemical space and a basis to assess the factors that drive selectivity in a new mode of photocatalysis.