Thiocarbonyl fluoride ligation for bioconjugation

Abstract

Click chemistry has emerged as a transformative technology for molecular linkage, enabling the streamlined construction of functional chemical architectures essential for life science and drug discovery. Groundbreaking achievement has been established through two generations of click chemistry, copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur(VI) fluoride exchange (SuFEx). Near-perfect reactions are always with great demand for ‘reactivity-availability-functionality’ trilogy. Herein, we developed a thiocarbonyl fluoride exchange protocol for thiocarbonyl-functionalized bioconjugations. Pivotal CF2= S-derived connective hubs were strategically designed via facile coupling between elemental sulfur (S8) and difluorocarbene generated in situ. This bilateral relay fluoride exchange enabled ligation across diverse S- N-, and O-nucleophiles with precise chemo- and regio-selectivity, facilitating modular assembly for drug-, peptide- and protein-scaffolds.