Conformational Preference and Cis−Trans Isomerization of 4(R)-Substituted Proline Residues

We report here the conformational preference and prolyl cis−trans isomerization of 4(R)-substituted proline dipeptides, N-acetyl-N‘-methylamides of 4(R)-hydroxy-l-proline and 4(R)-fluoro-l-proline (Ac-Hyp-NHMe and Ac-Flp-NHMe, respectively), studied at the HF/6-31+G(d), B3LYP/6-31+G(d), and B3LYP/6-311++G(d,p) levels of theory. The 4(R)-substitution by electron-withdrawing groups did not result in significant changes in backbone torsion angles as well as endocyclic torsion angles of the prolyl ring. However, the small changes in backbone torsion angles φ and ψ and the decrease of bond lengths r(Cβ−Cγ) or r(Cγ−Cδ) appear to induce the increase of the relative stability of the trans up-puckered conformation and to alter the relative stabilities of transition states for prolyl cis−trans isomerization. Solvation free energies of local minima and transition states in chloroform and water were calculated using the conductor-like polarizable continuum model at the HF/6-31+G(d) level of theory. The population of trans up-puckered conformations increases in the order Ac-Pro-NHMe < Ac-Hyp-NHMe < Ac-Flp-NHMe in chloroform and water. The increase in population for trans up-puckered conformations in solution is attributed to the increase in population for the polyproline-II-like conformations with up puckering. The barriers ΔG ct ⧧ to prolyl cis-to-trans isomerization for Ac-Hyp-NHMe and Ac-Flp-NHMe increase as the solvent polarity increases, as seen for Ac-Pro-NHMe. In particular, it was identified that the cis−trans isomerization proceeds through the clockwise rotation about the prolyl peptide bond for Ac-Hyp-NHMe and Ac-Flp-NHMe in chloroform and water, as seen for Ac-Pro-NHMe.