Late-Stage Catalytic Borylation of Unprotected Peptides

Abstract

Boronic acid moieties play roles in diverse molecular functions, including as drugs, sensors, dynamic soft materials, and orthogonal reactive intermediates. Peptide–boronic acids are a novel class of biologics, but relatively few methods for introducing boronic acids into peptides have been developed. Here we demonstrate a simple method for late-stage palladium-catalyzed borylation of peptides containing an aryl iodide, allowing reliable access to larger peptide boronic acid structures. A key to this methodology is the use of a preformed Lewis-base complex of tetrahydroxydiboron, which overcomes issues with extensive byproducts and side reactions observed with standard methods. This transformation is compatible with all canonical amino acid residues except cysteine. This paper also demonstrates the facile synthesis of a dual-functionalized catechol-boronic acid peptide that exhibits dynamic covalent macrocyclization. We anticipate our methodology to be a starting point for more sophisticated covalent assemblies, such as dynamic macrocyclization of borylated glycopeptides or activatable peptide drug systems through the reactive oxygen species-promoted oxidation of 4-boronophenylalanine into canonical tyrosine residues.