Mild and Selective Trifluoromethylation of Peptides at Tryptophane Residues by a Water‐Soluble Copper Complex with Redox‐Active Ligands

Selective functionalization of aminoacids is a key endeavor in chemical biology. Radical manifolds offer interesting possibilities but can suffer from limited control over radical processes, resulting in a lack of selectivity in product distribution. A water-soluble copper complex with redox-active ligands has been developed and performs trifluoromethylation of tryptophane residues with high selectivity. This method displays both inter- and intramolecular selectivity and its synthetic relevance is demonstrated by the selective conversion of a 13-residue peptidic sequence and an endomorphine analogue in good yields.

Abstract

Selective chemical modifications of biomolecules are in high demand for the development and implementation of chemical biology strategies. Methods involving radicals have emerged as powerful options yet potentially generate side reactivities when involving harsh reaction conditions. We report the development of a mild catalytic method for the selective functionalization of tryptophane residues in peptides with a trifluoromethyl group using a water-soluble copper complex with redox-active ligands. This method displays both inter- and intramolecular selectivity for tryptophane residues and its synthetic relevance is demonstrated by the selective conversion of a 13-residue peptidic sequence and an endomorphine analogue in good yields.

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