Visible Light-Mediated Enantioselective Alkylation Using a Deaminative Approach: Access to Unnatural Amino Acids and Peptides.
TL;DR
A visible light-driven enantioselective deaminative alkylation of glycine derivatives enabled by an in situ-generated chiral copper complex is reported, demonstrating its utility and robustness in asymmetric synthesis.
Abstract
Unnatural amino acids (UAAs) have become essential assets in the development of peptide- and peptidomimetic-based medications to enhance target selectivity and optimize physicochemical characteristics. The creation of peptides with drug-like qualities is still difficult, despite evidence that they may control receptor and alter disease processes. Herein, we report a visible light-driven enantioselective deaminative alkylation of glycine derivatives enabled by an in situ-generated chiral copper complex. The photoactive copper catalyst mediates single-electron reduction of Katritzky salts to generate alkyl radicals, which undergo stereocontrolled C(sp3)-C(sp3) bond formation. While deamination strategies are well explored, asymmetric variants remain underdeveloped. This methodology addresses that gap, delivering high enantioselectivity across a broad substrate scope, including natural product-derived and conformationally constrained scaffolds. The protocol is further applied to the synthesis of unnatural amino acid analogues and polypeptides without a loss of enantiopurity, demonstrating its utility and robustness in asymmetric synthesis.