Influence of side chain restriction and NH···π interaction on the β-turn folding modes of dipeptides incorporating phenylalanine cyclohexane derivatives

Abstract

We have synthesized the model dipeptides Piv-l-Pro-c6Phe-NHiPr, incorporating each of the two cis cyclohexane analogues of phenylalanine: (S,S)- and (R,R)-1-amino-2-phenylcyclohexanecarboxylic acid. Their structural analysis has been carried out in solution by 1H NMR and FTIR absorption spectroscopy and in the solid state by X-ray diffraction. In weakly polar chlorinated solvents, the (S,S)c6Phe-containing dipeptide mainly accommodates a type I β-turn, whereas the (R,R) residue shows a greater propensity to βII-folding. This behavior does not differ significantly from that exhibited by the analogous dipeptides containing l- and d-Phe. However, the l-Pro-l-Phe sequence has been shown to undergo a βI-to-βII transition in the presence of a strong solvating medium, such as DMSO, or in the crystalline state. Interestingly, Piv-l-Pro-(S,S)c6Phe-NHiPr, incorporating its cyclohexane analogue with χ1 fixed at +60°, retains the βI-folded structure under these conditions. Theoretical calculations, supported by the experimental data, indicate that a c6Phe-NH to aromatic π-orbitals interaction has an important influence on the observed β-folding preferences.