Beyond the Two-Conformer Model: The Role of Boat Conformers in the Stereoselectivity of SN1-Type Glycosylations

Abstract

Oxocarbenium ions play a central role in shaping the stereochemical outcome of SN1-type glycosylation reactions. Generally, glycosylations involving 4 H3-like glycosyl cations proceed with α-selectivity, whereas those involving 3 H4-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 3 H4 cation is significantly more stable than its 4 H3 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 C-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 via α-attack on a B2,5-like (boat) oxocarbenium ion through an OS2-type transition state that avoids the severe steric (Pauli) repulsion present along the β-1 C4 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 3 H4 is exceptionally favorable, shows β-selectivity. The mechanistic framework provides a quantitative basis for understanding and designing stereoselective SN1-type glycosylations.