Modeling of the Carbohydrate Oxacarbenium Ionic Intermediates of Glycosylation Reactions with Explicit Account for Protective Group Effects.

O-Protected oxacarbenium ions are key intermediates of glycosylation reactions. The knowledge of their conformational preferences is crucial for choosing the correct blocking group pattern to achieve the required stereochemical outcome. This article describes a computational study of several glucosyl oxacarbenium cations. The primary aim was to address the challenge of modeling oxacarbenium structures with all explicit O-blocking groups present instead of their simplified models. There exists no physical method to directly measure the energy of such structures. Therefore, the DLPNO-CCSD(T) method was used as a reference, which is considered to give the most exact results, however, without the possibility of geometry optimizations. Three DFT methods were tried to compare their values to those computed with DLPNO-CCSD(T). Finally, the B3LYP-D3 combination is suggested as the best recommendation for future studies of complex carbohydrate reaction intermediates with explicit protective groups. Possible reasons for the relative stability of different conformers of glycosyl cations are discussed in terms of SCF and electron correlation energies. The results of the B3LYP-D3 method show a good correlation with several model glycosylation reactions.