Role of ion pairs in model glycosylation reactions of permethylated glucosyl and xylosyl triflates

Elucidating the molecular mechanisms of chemical O-glycosylation remains a significant challenge in glycochemistry. This study examines the mechanism of the nucleophilic substitution reaction between glycosyl triflates, which are extensively used in studies of glycosylation mechanisms, and several acceptor alcohols. The investigation was conducted through a comparative analysis of permethylated glucosyl triflate GTf and its xylosyl counterpart XTf. The glycosylation reactions, conducted in dichloromethane using GTf and XTf with EtOH, tBuOH, and CF₃CH₂OH, exhibited diverse α/β selectivities depending on the types of donor and acceptor molecules used. Identifying a unified mechanism to explain this range of selectivities proved challenging. Notably, we observed a distinct trend wherein the addition of excess triflate salt (Bu₄NOTf) had a more pronounced effect on the α/β selectivity in glycosylation reactions utilizing XTf compared to those using GTf. Quantum chemical calculations performed at the SCS-MP2//DFT(M06-2X) level, with explicit inclusion of five solvent molecules, showed that contact ion pairs arising from XTf were significantly more stable than those from GTf. These experimental and computational results strongly suggest that ion pairs play a more crucial role in the glycosylation process involving XTf than GTf. Additionally, our quantum chemical analyses clarified that the enhanced stability of the ion pairs from XTf was attributed not to the strength of the C-1−OTf bond within XTf but to the flexibility in the conformational changes of XTf's pyranosyl ring.