Photoactivation of Supramolecular Hosts: Novel Chemical Reactivity Through Photocatalytic Formation of High-Energy Intermediates in Host Microenvironments - Project Summary Organic synthesis is a rate-limiting factor in drug discovery, and the chemical space that can be accessed by medicinal chemists is limited by the synthetic methods available to access targets of interest. The development of novel synthetic methods for constructing organic molecules with distinct architectures has the potential to enhance human health by enabling the synthesis and discovery of new small molecule drugs. Supramolecular host catalysis has proven to be a unique synthetic approach which can enable novel chemical reactions that are not observed in bulk solution. In this approach, substrates encapsulated within supramolecular hosts can engage in host-guest binding interactions that induce distinct reactivity and product selectivity in both intra- and intermolecular transformations. Significantly, supramolecular host-guest binding has been found to promote size-, site-, regio-, and enantioselective reactions. Building off work by the Toste, Raymond, and Bergman groups studying the reactivity of supramolecular host assemblies, the objective of this proposal is to design and develop supramolecular hosts that function as photocatalysts to induce novel photochemical reactions that afford access to oxygen- and nitrogen-containing heterocycles in a highly selective manner. Prior work by the Toste lab has established that stoichiometric quantities of a dodecanionic GaIII-centered tetrahedral host assembly can engage in photoinduced single-electron transfer events with encapsulated substrates to enable a radical rearrangement reaction. This established photoactivity of tetrahedral host assemblies will be explored in two orthogonal approaches for the development of new host-catalyzed photochemical reactions. The first approach develops supramolecular photocatalysts that perform single-electron transfer to encapsulated substrates. Through the design of supramolecular assemblies with modulated redox potentials and tailored microenvironments, new supramolecular hosts will be developed and applied as photocatalysts to facilitate radical cyclization reactions that afford oxygen- and nitrogen-based heterocycles. The second application will apply pyrene-based supramolecular hosts as photocatalysts to perform triplet energy transfer to azides, generating encapsulated triplet nitrene intermediates. Through coencapsulation of triplet nitrenes with suitable coupling partners, these hosts will be applied to promote intermolecular reactions of nitrenes to afford nitrogen- based heterocycles and other nitrogenated molecules with chemoselectivity and site selectivity. As nitrogen- and oxygen-based heterocycles are privileged scaffolds in medicinal chemistry, it is expected that these proposed methods will have a positive impact on human health by aiding chemists in the synthesis of new small molecules for drug discovery efforts.
