Influence of N ‐terminal residue stereochemistry on the prolyl amide geometry and the conformation of 5‐ tert ‐butylproline type VI β‐turn mimics

The effects of N ‐terminal amino acid stereochemistry on prolyl amide geometry and peptide turn conformation were investigated by coupling both ‐ and ‐amino acids to (2 S , 5 R )‐5‐ tert ‐butylproline and ‐proline to generate, respectively, N ‐(acetyl)dipeptide N ′‐methylamides 1 and 2 . Prolyl amide cis ‐ and trans ‐isomers were, respectively, favored for peptides 1 and 2 as observed by proton NMR spectroscopy in water, DMSO and chloroform. The influence of solvent composition on amide proton chemical shift indicated an intramolecular hydrogen bond between the N ′‐methylamide proton and the acetamide carbonyl for the major conformer of dipeptides ( S )‐ 1 , that became less favorable in ( R )‐ 1 and 2 . The coupling constant ( 3 J NH,α ) values for the cis ‐isomer of ( R )‐ 1 indicated a ϕ 2 dihedral angle value characteristic of a type VIb β‐turn conformation in solution. X‐ray crystallographic analysis of N ‐acetyl‐‐leucyl‐5‐ tert ‐butylproline N ′‐methylamide ( R )‐ 1b showed the prolyl residue in a type VIb β‐turn geometry possessing an amide cis ‐isomer and ψ 3 ‐dihedral angle having a value of 157°, which precluded an intramolecular hydrogen bond. Intermolecular hydrogen bonding between the leucyl residues of two turn structures within the unit cell positioned the N ‐terminal residue in a geometry where their ϕ 2 and ψ 2 dihedral angle values were not characteristic of an ideal type VIb turn. The circular dichroism spectra of tert ‐butylprolyl peptides ( S )‐ and ( R )‐ 1b were found not to be influenced by changes in solvent composition from water to acetonitrile. The type B spectrum exhibited by ( S )‐ 1b has been previously assigned to a type VIa β‐turn conformation [Halab L, Lubell WD. J. Org. Chem. 1999; 64 : 3312–3321]. The type C spectrum exhibited by the ( R )‐ 1b has previously been associated with type II′ β‐turn and α‐helical conformations in solution and appears now to be also characteristic for a type VIb geometry. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.