Nucleophilic substitution reactions of monosubstituted tetrahydropyran acetals give opposite selectivities when a remote alkyl or alkoxy substituent is present at C-4. Coupled with earlier computational reports on the intermediates of glycosylation reactions, these results are consistent with the preference for the oxocarbenium ion intermediate derived from alkoxy-substituted tetrahydropyran acetals to occupy a pseudoaxial conformation. Theoretical, spectroscopic, and X-ray crystallographic evidence of this conformational preference in an analogous and more stable dioxocarbenium ion are provided. This contrasteric preference for an axial orientation of an alkoxy substituent likely derives from the electronically favored pseudoaxial orientation of remote electronegative substituents in neutral six-membered rings possessing electron-deficient carbon atoms.