Visible Light-Enabled Synthesis of Heterocycles through Energy Transfer

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Project Summary/Abstract Azetidines, azetines, and oxetanes are four-membered heterocycles that exhibit desirable pharmacokinetic effects and represent important building blocks in current medicinal chemistry. Cycloaddition reactions between alkenes and imines or carbonyls, also referred to as (aza) Paternò-Büchi reactions, represent the most direct synthetic approach to access these compounds, however the current utility of these transformations is highly restricted due to the stringent requirement of UV-light and competing reaction paths accessible upon photochemical excitation. Thus, the ability to incorporate functionalized azetidines, azetines, and oxetanes into pharmaceutical lead structures is currently severely limited due to a lack of efficient synthetic methods. To date, no visible light-based platform of general synthetic utility for cycloadditions between alkenes and imines or carbonyls exists. The objective of the proposed research program is to identify and develop chemical strategies that enable efficient cycloadditions between these functional groups to access azetidines, azetines, and oxetanes based on energy transfer catalysis facilitated by visible light. These new synthetic methods will provide general and modular protocols for the synthesis of a large variety of heterocyclic motifs that are highly desirable in current medicinal chemistry. Additionally, the strategies described will enable cycloaddition reactions between alkenes and imines or carbonyls under mild reaction conditions with high functional group tolerance as they forego the requirement of UV-light. The utility of the accessible 4-membered heterocycles as building blocks will be demonstrated in secondary modifications and by enabling the synthesis of biologically active target structures from commercially available starting materials. The compounds prepared within this research program will be incorporated into the compound library maintained by the Center for Chemical Genomics (CCG) at the University of Michigan and become part of high-throughput screening (HTS) approaches for biological research and new drug discovery projects. In summary, the research described will enable general, catalytic strategies for aza Paternò-Büchi and Paternò-Büchi reactions relying on energy transfer upon excitation with visible light. These new transformations represent desirable synthetic tools that will enable direct access to functionalized azetidines, azetines, and oxetanes, and are expected to have broad implications in the area of medicinal chemistry.