Cyclopropane amino acids that mimic two chi(1)-conformations of phenylalanine

A highly constrained analogue of phenylalanine was prepared in optically pu re form. This disubstituted cyclopropane amino acid, DiFi, realises two chi (1) values of the phenylalanine side chain. Unlike monosubstituted analogue s, amino acids of this type impart very specific perturbations at the N and C termini simultaneously. Model studies were performed to elucidate the in trinsic 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 gamma-turn (or inverse gamma-turn) co nformations. Three other phenylalanine derivatives (1--3) were also prepare d for comparison purposes. Structural biases were assessed by CD, IR, and N MR spectrsocopy, X-ray crystal structure analysis, and molecular simulation s. 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-sear ch routines were used to explore the conformational space accessible to der ivatives 1-5. These indicated that the FiFi derivative 5 was the most rigid of the analogues and that both the inverse gamma-turn and the left-handed alpha-helix appear to be accessible conformations.