The Stereoselectivity of Neighboring Group-Directed Glycosylation Is Concentration-Dependent

Abstract

The formation of 1,2-trans-glycosides taking advantage of neighboring group participation by stereodirecting esters at the 2-position of glycosyl donors is widely held to be a robust and reliable protocol. Examples abound, however, of cases in which less-than-perfect selectivity is obtained, causing practitioners to survey different esters or resort to alternative strategies in the quest for optimal selectivities and yields. Consideration of the mechanism of neighboring group participation and in particular of the competing process of S_N2-like glycosylation with activated covalent donors leads to the hypothesis that in cases of imperfect selectivity, more careful attention to reaction concentration and stoichiometry may be beneficial. Three case studies are presented to demonstrate the concentration dependence of neighboring group-directed glycosylation reactions targeting the formation of both 1,2-trans-equatorial and 1,2-trans-axial glycosides. Higher concentrations, whether achieved through increased acceptor:donor stoichiometry or through increased concentration at a fixed stoichiometry, mostly lead to erosion of 1,2-trans-selectivity as the competing S_N2-like reaction with the covalent donors becomes increasingly important. These observations underline the importance of a rational, mechanism-based approach to glycosylation in general and more importantly suggest a simple approach to enhancing 1,2-trans-selectivity in neighboring group-directed glycosylation reactions displaying less-than-perfect 1,2-trans-selectivity, namely, moving to a different concentration regime.

Scheme 1. Classical Mechanism for Neighboring Group-Directed Glycosylation Illustrated for the Formation of a 1,2-trans-Equatorial Glycopyranoside

Scheme 2. (a) Classical and (b) Non-classical Equilibria in Neighboring Group-Directed Glycosylation

Scheme 3. Protecting Group and Temperature-Dependent Nature of the Glycosyl Triflate–Dioxalenium Ion Equilibrium

Scheme 4. Glycosylation of the D-Acceptor 18 by the D- and L-Donors 19 and 20

Scheme 5. Revised Mechanism for Neighboring Group-Directed Glycosylation Accounting for Concentration Dependence, Illustrated for the Formation of a 1,2-trans-equatorial Glycoside

Orthoester donors and products are omitted for clarity.

Scheme 6. Abbreviated Mechanism for 1,2-trans-Axial Glycoside (β-D-Mannopyranoside) Formation with Neighboring Group Participation