Use of Steric Interactions To Control Peptide Turn Geometry. Synthesis of Type VI beta-Turn Mimics with 5-tert-Butylproline.

Abstract

The influences of steric interactions on peptide geometry were studied to develop a novel means for generating type VIa beta-turn mimics. (2S,5R)-5-tert-Butylproline and L-proline were respectively introduced at the C-terminal residue of N-(acetyl)dipeptide N'-methylamides 1 and 2. The relative populations of prolyl cis- and trans-amide isomers in dipeptides 1 and 2 were measured in chloroform, DMSO, and water by proton NMR spectroscopy. Although the trans-amide isomer was favored in prolyl peptide 2, the Xaa-Pro peptide bond adopted preferably the cis-amide isomer in the case of 5-tert-butylprolyl peptide 1. Measurements of the influence of solvent and temperature on the chemical shift values for the amide proton signals of 1 in the cis-amide conformer indicated that the N'-methylamide was engaged in a hydrogen bond with the acetamide carbonyl in a type VIa beta-turn conformation. Analysis of N-(acetyl)leucyl-5-tert-butylproline N'-methylamide (1d) in the solid state by X-ray diffraction showed the cis-amide conformer which adopted a geometry characteristic of the central, i + 1 and i + 2 residues of an ideal type VIa beta-turn. In contrast to prolyl peptides 2b and 2d, N-(acetyl)alanyl- and N-(acetyl)leucyl-5-tert-butylproline N'-methylamides (1b and 1d) maintained ordered beta-turn conformations in solution that were shown to be independent of solvent composition by a comparison of their circular dichroism spectra obtained in water and acetonitrile. The NMR, X-ray, and CD data all confirm that the steric interactions of the 5-tert-butylprolyl residue induced dipeptide 1 to adopt a type VIa beta-turn conformation.