Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine

Terminally blocked, homopeptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c(3)diPhe), a chiral member of the family of C(alpha)-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-C(3)diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where C(3)diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that CAPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)- helix conformations. However, when C(3)diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed.