Microwave-Assisted Thioester-Empowered Toolkit for Modular Glycopeptide Synthesis

Glycopeptides and glycoproteins with structural precision are valuable for functional studies and applications. Conventional couplings of glycosyl amino acids are slow, wasteful, and impractical for broad use. To address the fundamental synthetic challenges, the current work presents a new paradigm for glycopeptide synthesis, featuring a key component (thioester-functionalized glycosyl amino acid) and a comprehensive reaction system (AgSbF₆ for activation, Oxyma as an additive, DIPEA as a base, under microwave irradiation). The reaction offers rapid and clean on-resin conversion (10 min), economical reagent use (1 equiv), broad effectiveness across varied glycan structures and multiple peptide coupling sites (27 examples), and readiness to automation. Moreover, it seamlessly integrates with enzymatic glycan elaboration and protein ligation strategies, furnishing glycopeptides and glycoproteins with an increased structural complexity. Taken together, this robust and versatile platform broadens access to complex glycopeptides and glycoproteins, thereby offering a powerful entry point for functional glycoscience and biomedical discovery.