Catalytic Redox Reactions for Pharmaceutical Synthesis

University Of Wisconsin-Madison, Madison WI

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Abstract

PROJECT SUMMARY Redox reactions are among the most important synthetic methods in organic chemistry, playing a crucial role in the preparation of pharmaceuticals, natural products, and other bioactive compounds. Advances in catalytic oxidation and reduction reactions targeted in this project will have broad impact across the drug discovery and development pipeline. Many existing catalytic redox methods face challenges in their efficiency and selectivity, including chemo-, regio- and stereoselectivity, limiting their use in both small- and large-scale applications. The proposed research will further develop oxidation, reduction, and coupling methods that form carbon-carbon and carbon-heteroatom bonds. New C(sp3)–H functionalization/diversification reactions will streamline the discovery of new bioactive molecules with diverse three-dimensional architectures, addressing key challenges in medicinal chemistry and drug discovery, while others will provide the basis for streamlined process-scale synthesis of pharmaceuticals. Four complementary project directions are highlighted in this proposal. The first focuses on the synthesis and functionalization of “synthetic linchpins” derived from C(sp3)–H bonds to enable rapid access to pharmaceutically relevant compounds. New methods will be developed to access versatile synthetic linchpins, especially those that may be integrated with Ni-catalyzed cross-electrophile coupling to form C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds. The second project will develop new electrosynthetic methods, including both oxidation and reduction reactions. These efforts will build upon our use of electrochemical mediators to facilitate new oxygenation, cross-electrophile coupling, deoxygenation, dehydration, radical chain, and biocatalytic reactions. We will use our expertise to develop electroanalytical methods that support optimization of catalysts and conditions for these reactions. The third project will apply chemistry developed in the first two projects to the synthesis of drug metabolites, in addition to developing new nucleophilic oxidation methods that mimic aldehyde oxidase metabolism. Development of a ‘metabolite synthesis toolbox’ will address a major bottleneck in drug development. Finally, we will develop heterogeneous catalysts for aerobic oxidation and oxidative coupling reactions that address unmet synthetic challenges, such as formation of N–N and N–O bonds, and provide opportunities for practical application in large-scale synthesis of pharmaceutical intermediates and APIs. Close interactions and collaborations with multiple academic groups and pharmaceutical companies in all phases of this project will play an important role in ensuring the broadest possible impact of our efforts.