Development of a photoinduced, copper-catalyzed, enantioconvergent synthesis of unnatural amino acids

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ABSTRACT β,β-Disubstituted-α-amino acids and α-aminoboronic acids are two classes of unnatural α-amino acids that are present in pharmaceuticals used to treat conditions ranging from diabetes to cancer. There is considerable room for improvement on existing methods for the preparation of these two classes of unnatural amino acids, as they are largely dependent on diastereoselective synthesis with a stoichiometric amount of a chiral auxiliary. This proposal outlines a research plan to develop a new asymmetric, photoinduced, copper-catalyzed methodology to synthesize β,β-disubstituted-α-amino acids and α-aminoboronic acids from racemic of α-malonyl and α-boryl NHP esters, respectively. Here, the chiral copper catalyst in combination with blue-LED irradiation will mediate the decarboxylation of NHP esters and their subsequent enantioselective Csp3-N cross-coupling with phthalimide, efficiently used as the source of protected amine. The proposed reaction will not generate any stoichiometric waste, other than CO2, in the reaction itself, and will not require an exogenous precious metal photocatalyst to initiate the reaction. The utility of this method will be explored through the synthesis of an array of hindered unnatural α-amino acids and alkyl substituted α-aminoboronic acids, including new variants that have never been synthesized before.