Chirality-Driven Folding of Short β-Lactam Pseudopeptides

Novel enantiopure pseudopeptide models containing a central -(beta-lactam)-(Aa)- scaffold characterized by the combined presence of an alpha-alkyl-alpha-amino-beta-lactam (i +1) residue and a alpha-substituted (i + 2) amino acid have been readily synthesized from alpha-alkyl serines. The conformational analysis of such beta-lactam pseudopeptides conducted in CDCl3 and DMSO-d(6) solutions using 1D- and 2D-NMR techniques revealed an equilibrium between beta-II turn and gamma-turn conformers, which was ultimately modulated by the relative configuration of the -(beta-lactam)-(Aa)- residues. Long-range chiral effects on the alpha-lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(beta-lactam)-(Aib)- segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a beta-II turn conformer, whereas homochiral corner residues stabilized an overlapped beta-II/beta-I double turn motif. No beta-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, beta-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(beta-lactam)-(i + 2)- segment was proposed to account for the observed chiral effects.