Plausible transition states for glycosylation reactions

[Display omitted] ► First attempt at including donor, acceptor, promoter, and solvent in glycoside formation modeling. ► Long range (2.725Ǻ) interactions of acceptor oxygens with donor C-1 during ionization identified. ► Promoter in TS and is the most strongly solvated molecule. ► SSIP-like Transition States identified for α- or β- attack on β- or α-triflates. ► Orientation of the nucleophile identified as key determinant of stereospecificity. The Transition State (TS) for any chemical glycosylation reaction is not known with certainty. Both experimental and computational approaches have been limited due to the complexity of the problem. This work describes a preliminary computational ionization approach using density functional theory calculations to arrive at hypothetical TSs. The new TSs contain the glycosyl donor as anomeric triflates, the acceptor as methanol, some CH2Cl2 molecules, and a Li+ ion promoter. In this computational approach all glycosylations are disassociative in that the C-1–OTf bond length is greater then 2Å before any nucleophilic attack. All nucleophilic attack requires some preassociation of the nucleophile with examples of the pre-attack complexation to donor oxygens. These hypothetical models are intended to guide both experimental and computational approaches to finding TSs for glycosylation reactions that can be used to optimize stereoselectivity of glycosylation.