Innovative Tools for Chemical Synthesis: Cyclase-inspired Catalysis, Shuttle Catalysis , and Tandem Catalysis

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Principle Investigator/Program Director (Last, first, middle): Dong, Vy, M Project Summary/Abstract The construction of amide bonds is a widely used chemical transformation across many disparate disciplines of chemistry and is one of the most frequently employed disconnections in the pharmaceutical industry. As such, efforts to improve and expand the synthetic utility of amide bond formation remain integral for multidisciplinary reaction development and drug discovery campaigns within academic and industrial sectors. The coupling of sterically hindered amino acids, such as therapeutically valuable α,α-disubstituted α-amino acids and derivatives thereof, represents an underdeveloped yet promising area for amide bond formation that can be improved. Although methods to construct difficult amide bonds are available, waste generated from either stoichiometric or super-stoichiometric reagent use as well as possible deleterious reaction byproducts produced using conventional approaches imposes the need to develop more sustainable protocols. Previous work from Xie and coworkers have shown that acyl radical peptide precursors can be generated under photoredox conditions via a P(V)/P(III) cycle, however is limited to nitroarene and nitroalkane coupling partners. Therefore, our goal is to broaden the scope of accessing sterically hindered amide bonds catalytically by employing an umpolung approach using a phosphorus catalyst to generate nucleophilic acyl radical amino acid partners to form hindered secondary and tertiary amide bonds with readily accessible, electrophilic hydroxylamine esters. If successful, this methodology could enable a more facile approach towards sterically hindered peptides that may be extended towards additional challenging amide structural motifs.