Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex

Abstract

The mechanism of solvent effects on the stereoselectivity of glycosylation reactions is investigated using quantum-mechanical (QM) calculations and molecular dynamics (MD) simulations, considering a methyl-protected glucopyranoside triflate as a glycosyl donor equivalent and the solvents acetonitrile, ether, dioxane, or toluene, as well as gas-phase conditions (vacuum). The QM calculations on oxacarbenium-solvent complexes do not provide support to the usual solvent-coordination hypothesis, suggesting that an experimentally observed β-selectivity (α-selectivity) is caused by the preferential coordination of a solvent molecule to the reactive cation on the α-side (β-side) of the anomeric carbon. Instead, explicit-solvent MD simulations of the oxacarbenium-counterion (triflate ion) complex (along with corresponding QM calculations) are compatible with an alternative mechanism, termed here the conformer and counterion distribution hypothesis. This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, (1) the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the α or β face, and (2) the preferential coordination of the counterion to the oxacarbenium cation on one side of the anomeric carbon, hindering a nucleophilic attack from this side. For example, in acetonitrile, the calculations suggest a dominant B2,5 ring conformation of the cation with preferential coordination of the counterion on the α side, both factors leading to the experimentally observed β selectivity. Conversely, in dioxane, they suggest a dominant (4)H3 ring conformation with preferential counterion coordination on the β side, both factors leading to the experimentally observed α selectivity.

The intriguing dual-directing effect of 2-cyanobenzyl ether for a highly stereospecific glycosylation reaction

“…However, we were surprised to observe a complete reversal of anomeric preference when TFE (2,2,2-trifluoroethanol) was used as the acceptor. Under b-optimized condition, a-3h was obtained as the major product with an a:b ratio of 417:1 ( 34 and/or solvent influence [5][6][7] .…”

“…One of the earliest and yet very effective way to acquire the desired anomeric stereoselectivity was through employment of participating solvents, notably nitrile-type 5,6 (for example, acetonitrile) or ether-type 7 (for example, diethyl ether) for the preferential formation of b-D-and a-D-glucosides, respectively. On the other hand, neighbouring hydroxyl groups of the donor could show influence on the anomeric preference through their protecting substituents, many of which were routinely exploited in various glycosylation methods, such as 2-O-ester-type [8][9][10] or 2-O-picolyl-type [11][12][13] for 1,2-trans glycosylation, and several sulfide auxiliaries [14][15][16][17][18] as well as intramolecular aglycon delivery IAD-type 19,20 for 1,2-cis glycosylation reactions.…”

The dielectric continuum solvent model adapted for treating preferential solvation effects

“…Many molecular simulations for ion pairs, mainly in water and alcohols, have been reported in the literature [22][23][24][25][26][27][28][29][30][31][32][33][34]. Few of them deal with binary mixtures of water and organic solvents.…”

Computational Chemistry on Chemical Glycosylations

“…The nature of the solvent is known to be a key factor in the stereoselectivity of glycosylation reactions (49,(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). For glucopyranosides, for example, the 1,2-cis-glucoside (α linkage) is predominantly formed in diethyl ether or in 1,4-dioxane, whereas the 1,2-trans-glucoside (β linkage) is predominantly formed in acetonitrile (Fig.…”