Stereoselective Assembly of 2-Deoxy-2-fluoroglycosides Enabled by Pyridinium Catalysis

2-Deoxy-2-fluoroglycosides are versatile chemical entities in glycoscience, functioning as enzyme probes, inhibitors, and valuable building blocks for bioactive glycomimetics. However, their efficient and stereoselective synthesis remains challenging. Herein, we report a pyridinium-salt-catalyzed highly stereoselective addition of an O-type glycosyl acceptor to 2-fluoroglycals, providing efficient access to a structurally diverse library of 2-fluoroglycosides. The excellent stereoselectivity favoring <i>syn</i>-addition and deuterated experimental results suggest a concerted mechanism. NMR titrations combined with DFT calculations demonstrate the presence of product inhibition and shed light on the reduced efficiency observed in the reactions involving electron-deficient phenols as well as alcoholic substrates.