Peptides Constrained to Type VI beta-Turns. 1. Evidence for an Exceptionally Stable Intramolecular Hydrogen Bond

The synthesis and conformational analysis of conjugates of amino acids with a type VI beta-turn dipeptide mimic (1) is described. The mimic possessed high structural similarity to the central two residues of the turn and was constrained from rotation about two of the four single bonds. Coupling of amino acids to the carboxyl group of the mimic afforded conjugates that were capable of forming intramolecular hydrogen bonds. In nonpolar solvents, IR and NMR spectra of the conjugates indicated that the amide hydrogen of the amino acid residue was hydrogen bonded to the carbonyl group of the N-terminal carbamate functionality, as in typical beta-turns. In the hydrogen-bonding solvent DMSO, the intramolecular hydrogen bond was still present, according to the temperature dependence of the chemical shift. The presence of the i, i + 3 hydrogen bond in the conjugates of mimic 1 was substantiated by the spectral properties of conjugates of the isomeric mimic 3, which showed no evidence for the presence of an intramolecular hydrogen bond. The results from these studies suggest that the intramolecularly hydrogen-bonded type VIa turn is an inherently more stable conformation for a peptide than the non-hydrogen-bonded type VIb conformation, in the absence of other structural constraints.