Expeditious Synthesis of 2-Deoxy-2-perfluoroalkyl Glycosides

In carbohydrate-based drug discovery, fluorine-containing substituents are widely used to enhance pharmacodynamic and pharmacokinetic profiles. However, the precise incorporation of C(sp³)-perfluoroalkyl moieties at the C2 position of sugar scaffolds remains a significant synthetic challenge. In this study, we report a highly efficient and cost-effective protocol for the synthesis of 2-deoxy-2-perfluoroalkyl glycosides from readily available glycals. This protocol demonstrates exceptional substrate generality, encompassing glucal, galactal, rhamnal, sialic acid, and arabinofuranose derivatives. More importantly, this platform enables the efficient synthesis of diverse C-, N-, and O-glycosides (over 50 examples) under gold(I)-catalyzed conditions, including the synthesis of previously inaccessible 2-deoxy-2-CF₃-substituted nucleoside analogues. Additionally, photocatalytically generated 2-deoxy-2-CF₃ glycosyl anomeric radicals readily undergo Giese-type additions to alkenes, affording alkylated glycosides, or engage in cross-coupling with aryl bromides to deliver antidiabetic drug candidates. Preliminary biological evaluations indicate that 2-deoxy-2-CF₃-modified glycosides exhibit enhanced pharmacological properties, underscoring the translational potential of this synthetic technique for advancing carbohydrate-based therapeutics.