Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers

Abstract

AbstractCopper‐mediated coupling between alkynes to generate a structurally rigid, linear 1,3‐diyne linkage has been known for over a century. However, the mechanistic requirement to simultaneously maintain CuI and an oxidant has limited its practical utility, especially for complex functional molecules in aqueous solution. We find that addition of a specific bpy‐diol ligand protects unprotected peptides from CuII‐mediated oxidative damage through the formation of an insoluble CuII gel which solves the critical challenge of applying Glaser coupling to substrates that are degraded by CuII. The generality of this method is illustrated through the conjugation of a series of polar and nonpolar labels onto a fully unprotected GLP‐1R agonist through a linear 7 Å diynyl linker.