Modulating Conformational Preferences by Allylic Strain toward Improved Physical Properties and Binding Interactions

[Image: see text] The preference of the axial over the equatorial orientation of 2-substitutent for both phenyl-1-piperidines and N-acylpiperidines is studied at the M06-2X level of theory. For phenyl-1-piperidines, the axial 2-substituent is modestly favored over the equatorial one. In contrast, the pseudoallylic strain in N-acylpiperidines dictates the axial orientation of 2-substituent with a ΔG up to −3.2 kcal/mol. The calculations agree well with the statistics from both the Cambridge Structural Database of small-molecule organic crystal structures and the Protein Data Bank. The equilibrium between the twist-boat and chair conformations for N-acylpiperidines with a 2-substituent was further investigated. The twist-boat conformation is found to be around 1.5 kcal/mol less favorable. Finally, the three-dimensionality in shape resulting from minimization of the pseudoallylic strain is characterized, and its implication in protein–ligand interactions is briefly reviewed.