Beyond the two-conformer model: boat conformers provide stereoselectivity in S(N)1-type glycosylations of manno-type donors.

Oxocarbenium ions play a central role in shaping the stereochemical outcome of S1-type glycosylation reactions. Generally, glycosylations involving -like glycosyl cations proceed with α-selectivity, whereas those involving -like cations furnish β-products, reflecting favorable chair-like transition states. While this analysis holds for many glycosyl cations, it breaks down for mannosyl donors. Although the mannosyl cation is significantly more stable than its counterpart, addition of weak carbon nucleophiles predominantly yields α-products. To elucidate the origin of this deviation from the predictive two-conformer model, we examined -allylation reactions of nucleophiles spanning three orders of magnitude in reactivity with a series of glucosyl and mannosyl-type donors (mannose, rhamnose, and mannuronic acid). Quantum chemical calculations of the competing reaction pathways show that, for mannose, glycosylation proceeds under Curtin-Hammett control α-attack on a -like (boat) oxocarbenium ion through an -type transition state that avoids the severe steric (Pauli) repulsion present along the β- trajectory. Activation-strain and energy-decomposition analyses quantify the steric and electronic effects and explain why rhamnose, with reduced C6 steric demand, provides slightly more β-selective glycosylation reactions and mannuronic acid, of which the is exceptionally favorable, shows β-selectivity. The mechanistic framework provides a quantitative basis for understanding and designing stereoselective S1-type glycosylations.