Influence of Side Chain Restriction and NH···π Interaction on the β-Turn Folding Modes of Dipeptides Incorporating Phenylalanine Cyclohexane Derivatives

We have synthesized the model dipeptides Piv- l -Pro-c 6 Phe-NH i Pr, 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 1 H NMR and FTIR absorption spectroscopy and in the solid state by X-ray diffraction. In weakly polar chlorinated solvents, the ( S, S )c 6 Phe-containing dipeptide mainly accommodates a type I β -turn, whereas the ( R, R ) residue shows a greater propensity to β II-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 β I-to- β II transition in the presence of a strong solvating medium, such as DMSO, or in the crystalline state. Interestingly, Piv- l -Pro-( S, S )c 6 Phe-NH i Pr, incorporating its cyclohexane analogue with χ 1 fixed at +60°, retains the β I-folded structure under these conditions. Theoretical calculations, supported by the experimental data, indicate that a c 6 Phe- NH to aromatic π -orbitals interaction has an important influence on the observed β -folding preferences.