Copper-Mediated Cross-Coupling\nSelective for Pyroglutamate\nPost-Translational Modifications

Pyroglutamate is a cyclic <i>N</i>-terminal\npost-translational\nmodification that occurs in both proteins and peptide hormones. The\nprevalence and biological roles of pyroglutamate are little understood,\nin part due to limited tools to identify, quantify, and manipulate\nits pyrrolidinone structure. Selective modification of pyroglutamate\nresidues in complex polypeptides may provide unique tools to better\nunderstand its biological roles and to allow late-stage diversification\nof biologically active pyroglutamate-containing sequences. This work\ndescribes a copper-catalyzed N–H cross-coupling of unprotected\npeptides that is selective for <i>N</i>-terminal pyroglutamate\nresidues. The reaction is operationally simple under mild conditions\nand tolerates all canonical residues. Mechanistic studies point to\na key role for a multidentate copper-binding mode of the extended\npolypeptide structure in delivering the observed reactivity. The reaction\nallows for direct labeling and identification of a pyroglutamate hormone\npresent in porcine intestinal extracts.