Stereospecific Synthesis of 2-Deoxy-2-fluoroglycosides via S _<i>N</i> 2 Glycosylation

A directing-group-on-leaving-group strategy (DGLG) was applied to stereospecific synthesis of 2-deoxy-2-fluoroglycosides via S _<i>N</i> 2 glycosylation. This strategy utilized 2-deoxy-2-fluoroglycosyl donors featuring a chromenone-based leaving group, which is activated rapidly under exceedingly mild conditions to achieve complete stereochemical inversion at the donor anomeric position. This method readily applies to 2-deoxy-2-fluoroglucose, 2-deoxy-2-fluorogalactose, 2,6-dideoxy-2-fluoroglucose, 2-deoxy-2-fluoroarabinose, and 2-deoxy-2-fluororibose, delivering high yields and complete stereochemical inversion, despite the presence of a neighboring deactivating fluoro group and the potential adverse fluorine directing effect. This method addresses the unmet challenges in constructing 1,2-<i>cis</i> glycosidic linkages in 2-deoxy-2-fluorosugars with stereospecificity. It also represents a major advance by enabling stereospecific synthesis of 2-deoxo-2-fluoroarabinofuranosides and 2-deoxy-2-fluororibofuranosides with either an α or a β anomeric configuration, showcasing the versatility of the DGLG approach. It offers by far the only stereospecific construction of these fluorinated glycosides of significant interest in glycoscience research. With the employment of excess donors permitted, this approach can be readily adopted to multistep sequential glycosylations, enabling streamlined and stereospecific access to complex fluorinated glycans.