S _<i>N</i> 2 Glycosylation Enabled by a Directing-Group-on-Leaving-Group Strategy: Highly Stereoselective Synthesis of Glycosyl Carboxylates

By employing a directing-group-on-leaving-group (DGLG) strategy, we have implemented an S_<i>N</i>2 glycosylation of carboxylic acids with mostly complete stereochemical inversion at the anomeric position and largely near quantitative yields. This chemistry is based on a 4<i>H</i>-chromen-4-one core in the donor leaving group, which links its sugar moiety and a diisopropylphosphinoyl directing group, and is achieved under stoichiometric activation. A range of sugar types, including glucose, galactose, mannose, alluronate, fucose, rhamnose, and 2-deoxyglucose, is tolerated, and the conversion of α-donors to β-products and vice versa is readily accommodated. DFT calculation suggests that both carboxylic acid oxygens can be the nucleophilic atom, but the HO oxygen attack is preferred over the typically more nucleophilic carbonyl oxygen under this directed glycosylation paradigm.