A number of models are used to study the structure and energetics of the axial and equatorial anomers of 4,6-dimethyl-2-methoxytetrahydropyran in aqueous solution, to understand the observed preferential solvation of the equatorial form. Both quantum mechanical continuum and supermolecule treatments predict this effect qualitatively, but lead to its underestimation, suggesting the need for both long-range interactions and explicit solvent. A reference interaction site model, which includes both effects and uses a classical potential, is successful in quantitatively predicting such differential solvation, the result being less satisfactory when the solute is modeled quantum mechanically.