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 “?, 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.