Synthetic Methods based on Biphilic Phosphorus Catalysts

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PROJECT SUMMARY/ABSTRACT Advances in catalytic science and technology enable the preparation of pharmaceutical agents used to treat human disease. This project has the long-term goal of developing a broad class of inexpensive nonmetal catalysts that promote catalytic transformations via formal oxidation state cycling in qualitative analogy to transition metal catalysis. Within this overarching goal, the primary focus of this proposal is the design and application of phosphorus-based catalysts that function in the P(III)⇌P(V) redox couple. While phosphines are well-established in catalysis as spectator ligands for transition metal catalysis and as nucleophilic catalysts, this research describes innovative phosphorus-based catalysts of novel com- position and structure that explore the structural and electronic conditions required to enable new catalyt- ically-relevant reactivity via reversible P(III)⇌P(V) oxidation state cycling. The first major effort is the de- velopment of new methods for activation of amides and stable oxoanions for direct functionalization via P(III)⇌P(V) redox reactivity. The second major effort is the development of phosphine-catalyzed O-atom transfer methods that result in reductive transformations of nitroarene compounds to furnish functional- ized anilines through the formation of new carbon-nitrogen bonds. The third major effort involves the de- velopment of P(III)⇌P(V)-catalyzed O-atom transfer methods that result in reductive N-functionalization of nitroalkanes, including new phosphacyclic structures that express biphilic P(III)⇌P(V) redox reactivity. The proposed research is expected to yield new practical catalytic methods for the construction of phar- macologically-relevant small molecules that meet the challenges of sustainable synthesis, and an im- proved fundamental understanding the interplay between structure and reactivity in the p-block that will underpin future development of nonmetals for atom transfer, bond activation, and catalysis. Taken to- gether, these outcomes will advance nonmetal-based redox catalysis as a powerful modality in pharma- ceutical synthesis.