Heterogeneous Catalysis Expands the Toolbox for Chemoselective Peptide Derivatization and Labeling.

The ability to chemoselectively modify either the peptide backbone or specific side chains is critical to advance the fields of bioconjugation and peptide pharmaceuticals. Transition-metal catalysis has been widely used in peptide and protein derivatization but mostly under homogeneous conditions. Herein, we present a first-in-class heterogeneous catalytic approach for the site-selective functionalization of histidine-containing peptides with aryl and alkenyl moieties bearing fluorescent and affinity tags, lipids, and conjugation handles. This heterogeneous derivatization strategy employs a copper(II) hexacyanometallate to catalyze the Chan-Lam reaction with boronic acids at either the backbone or the histidine imidazole, thus providing novel results that differ from those previously reported for the homogeneous Cu(OAc)-mediated coupling procedure. A correlation was established between the structural and electronic properties of the copper(II) hexacyanometalate with its ability to catalyze this oxidative cross-coupling. This report expands the toolbox for late-stage peptide derivatization and labeling by unlocking the reactivity of the histidine side chain rather than merely acting as a directing group, thus boosting applications of heterogeneous catalysis in drug discovery and development.