Late-Stage, Stereoretentive, and Site-Selective Modification of Synthetic Peptides by Using Photoredox Catalysis

Late-stage functionalisation is an attractive method to generate peptide analogues containing non-natural residues. It is shown that cysteine residues can be activated as Crich-type thioethers, either by alkylation of a synthetic cysteine-continuing peptide or by incorporation of a modified cysteine unit into solid phase or solution phase peptide synthesis. Photoredox catalysed reaction of the thioether generates an alanyl radical intermediate in a stereoretentive and site-selective manner, even in the presence of free cysteine residues. The radical can react with non-activated alkenes to form non-natural residues bearing aliphatic, hydrophobic units. A method to avoid unwanted alkylation of amine residues was identified and the process was applied to the functionalization of both linear and cyclic synthetic peptides.