Bioinspired Methionine-Selective Desulfurization Editing of Peptides via the Photocatalysis Strategy

<i>S</i>-Adenosylmethionine (SAM) frequently functions as a cofactor or precursor for enzymes, initiating an array of radical reactions in biological systems. In contrast with the conventional 5'-deoxyadenosyl (dAdo) radical pathway, which proceeds via homolytic cleavage of the S-C(5') bond of SAM, the Dph2 enzyme provides an alternative 3-amino-3-carboxypropyl (ACP) radical pathway through breaking the S-C(γ) bond. Inspired by this distinctive bond cleavage mode, we have developed a chemically induced pathway to generate an ACP-type radical intermediate on methionine-based sulfonium. This strategy presents a novel desulfurization conjugation mode for methionine modification, diverging from previous approaches that conjugate onto the sulfur atom or the adjacent methyl group of methionine. The versatility of this strategy is demonstrated by the efficient functionalization of various peptides and peptide macrocyclizations. Density Functional Theory (DFT) calculations provide further insights into the mechanism of this desulfurization reaction, explaining the exceptional selectivity of homolytic cleavage of the S-C(γ) bond of methionine-based sulfonium. The successful implementation of this novel desulfurization strategy represents a substantial advancement in the understanding of sulfonium-based intramolecular radical substitution reactions and provides new opportunities for the functionalization of biomolecules, thereby fostering progress in interdisciplinary research.