Absence of Reverse Anomeric Effect in Glycosylimidazoles

Abstract

The so-called reverse anomeric effect is the preference of cationic substituents for the equatorial position on a pyranose ring, but it is not consistent with theories of molecular structure. To reinvestigate this, we have measured the N-protonation-induced shifts of the anomeric equilibrium in N-(glycopyranosyl)imidazoles and their tetra-O-acetyl derivatives 1−3 with high precision through an NMR titration method that is applicable to a mixture of α and β anomers. We find a ΔΔG°β→α that is almost always negative, corresponding to a greater preference for the axial position of a protonated imidazolyl group than of an unprotonated group. This preference counters a small steric effect, arising from hindrance to ionic solvation, that has been measured independently in N-(4-tert-butylcyclohexyl)imidazoles 4. These results are exactly opposite to what is expected from the reverse anomeric effect. We conclude that there is no firm evidence for this effect.