Cyclopropane amino acids that mimic two χ1-conformations of phenylalanine

Abstract

A highly constrained analogue of phenylalanine was prepared in optically pure form. This disubstituted cyclopropane amino acid, DiFi, realises two χ1 values of the phenylalanine side chain. Unlike monosubstituted analogues, amino acids of this type impart very specific perturbations at the N and C termini simultaneously. Model studies were performed to elucidate the intrinsic conformational biases of this amino acid and its isomeric analogue FiFi. These derivatives were incorporated into a simple model to determine the propensity of these compounds for γ-turn (or inverse γ-turn) conformations. Three other phenylalanine derivatives (1-3) were also prepared for comparison purposes. Structural biases were assessed by CD, IR, and NMR spectrsocopy, X-ray crystal structure analysis, and molecular simulations. CD and IR spectra indicated that the two disubstituted derivatives DiFi and FiFi contain secondary structural elements that appear to be absent in the other analogues. Molecular simulation protocols that involved grid-search routines were used to explore the conformational space accessible to derivatives 1-5. These indicated, that the FiFi derivative 5 was the most rigid of the analogues and that both the inverse γ-turn and the left-handed α-helix appear to be accessible conformations.