First observation of a helical peptide containing chiral α-monosubstituted residues without a preferred screw sense

Abstract

We report the detailed X-ray structure of the fully blocked tetrapeptide Z-D-Val-(Aib)₂-L-Phe-OMe. The compound crystallizes in the space group P2₁ with four independent tetrapeptide molecules aligned in a parallel arrangement along the c axis. There is a regular alternation of right- and left-handed 3₁₀-helices hydrogen bonded head-to-tail along this axis. Pairs of molecules with the same handedness differ in the conformation of the side chains and of the N- and C-terminal blocking groups. This is the first observation, to the best of our knowledge, of a helical peptide containing chiral α-monosubstituted α-amino acids without a preferred screw sense. Conformational energy computations confirmed that those helices with different handedness have comparable stabilities. This work is a part of our studies on fully protected tetrapeptides containing homo and hetero chiral residues at N- and C-termini spaced by an achiral dipeptide segment, in order to understand the structural features responsible for the diastereoselective separation by reversed-phase HPLC.