Electrochemistry Enables O-Arylation of Tyrosine with Aminoisoxazoles: Late-Stage Diversification of Peptides and Pharmaceuticals

We report a metal-free electrochemical strategy enabling the formation of direct O-C(sp²) bonds between tyrosine and electron-deficient heteroaromatics. The method achieves site-specific O-heteroarylation of tyrosine-containing drug derivatives and peptides under mild conditions, providing the general platform for constructing tyrosine-electron-deficient heteroaromatic ether linkages. Mechanistic investigations, which included cyclic voltammetry (CV) and radical inhibition experiments, provide support for the proposed mechanism involving electrochemical generation of radical intermediates followed by radical-radical coupling.