Cooperative Stereocontrol in Glycosylation: Dissecting the α-Directing Effects of 4 <i>-O-</i> Acyl and 4 <i>-O-</i> Pentafluorobenzoyl Groups and the Role of 6 <i>-O-</i> Substituents in Glucosyl and Galactosyl Donors

Despite significant progress in carbohydrate chemistry, the stereoselective synthesis of 1,2-<i>cis</i>-glycosides remains a long-standing challenge. To address this issue, glycosyl donors-bearing acyl substituents remote from the anomeric center are increasingly employed. Yet the origin of their stereochemical influence remains unresolved, being alternately interpreted in the literature as arising from remote participation or, more rarely, from intrinsic electron-withdrawing effects. Here we show that the electron-withdrawing 4-<i>O</i>-pentafluorobenzoyl (PFB) group exerts a strong α-directing effect in both galactosyl and glucosyl donors, irrespective of the configuration at C-4. This behavior demonstrates that the observed α-selectivity arises not from remote participation but from the electron-withdrawing nature of the PFB substituent. Comparative studies with less electron-withdrawing acyl groups (Ac, Bz, pMeOBz) confirmed that 4-<i>O</i>-PFB possesses the strongest α-directing ability. In galactosyl donors, the 6-<i>O</i>-benzoyl group alone favored β-glycoside formation, yet in combination with a 4-<i>O</i>-PFB substituent, it acted cooperatively, thereby providing complete α-selectivity. This cooperative action of 4-<i>O</i>-PFB and 6-<i>O</i>-substituents was further demonstrated in the stereoselective synthesis of a penta-α-(1→6)-d-galactoside structurally related to the α-(1→6)-d-galactan main chain of <i>Cryptococcus neoformans</i> galactoxylomannan.