Crystal state conformation of three azapeptides containing the Azaproline residue, a β-turn regulator

The molecular structure of three protected AzaPro‐containing peptides have been determined by x‐ray diffraction: Z‐AzaPro‐NHiPr (1; Z: benzyloxycarbonyl), Z‐AzaPro‐L‐Ala‐NHiPr (2), and Boc‐L‐Ala‐AzaPro‐NHiPr (3; Boc: tert‐butyloxycarbonyl). Starting from the key synthon benzyl‐azaprolinate, compounds 1, 2, and 3 have been prepared by combined use of liquid phase peptide synthesis method and adequate isocyanates. In all peptides, the following geometric characteristics are retained: (a) pyramidal character of the two nitrogen atoms of the pyrazolidine ring; (b) pseudo cis conformation of the urethane (1, 2) or tertiary amide (3) function preceding the AzaPro residue; (c) identical absolute values of the Azaproline residue torsion angles “ϕ, ψ” respectively 111° and 23°. In compound 2, the two nitrogen atoms of the pyrazolidine ring are R, R but the opposite S, S absolute configurations are observed in compound 3. In the crystal, compound 3 adopts a folded structure similar to a type VI β‐turn with a weak intramolecular i + 3 → i hydrogen bond, while an extended structure is observed in compound 2. In the light of our findings, in a peptide chain and contrary to the Pro residue, an AzaPro residue should prevent the formation of any type of any type of β‐turn with the residue following it but could accommodate a folded structure with a pseudo type VI βturn with the preceding residue. If confirmed, this would be of tremendous importance in the design of biologically active peptides and drugs. © 1993 John Wiley & Sons, Inc.