Iron Photocatalysis Towards Site-Selective C(sp3)-H Alkylation of Glycines and Peptides

Utilizing iron-mediated ligand-to-metal charge transfer (LMCT) photocatalysis provides a sustainable platform for generating carbon-centered radicals. This study presents the use of abundant and inexpensive iron as a photocatalyst to easily activate aliphatic carboxylic acids, producing Csp3 radicals for site-selective C(sp3)-H alkylation of glycines and peptides. The method exhibits broad applicability, cost-effectiveness, and excellent tolerance to various functional groups. It is a flexible and efficient approach applicable to the synthesis of various unnatural α-amino acids and enables peptide drug bioconjugation. In addition to secondary and tertiary radicals, the iron-LMCT system enables access to primary radicals and the highly unstable methyl radical, derived from acetic acid, facilitating the production of methylated glycine derivatives. Preliminary mechanistic studies suggest a reaction pathway involving an Fe(III)-Fe(II)-Fe(III) redox cycle and radical-radical cross-coupling.