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

Abstract

AbstractLate‐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.