Chirality-Driven Folding of Short β‑Lactam Pseudopeptides

Novel enantiopure pseudopeptide models containing a central
-(β-lactam)-(Aa)-
scaffold characterized by the combined presence of an α-alkyl-α-amino-β-lactam
(i+1) residue and a α-substituted (i + 2) amino acid have been readily synthesized from α-alkyl
serines. The conformational analysis of such β-lactam pseudopeptides
conducted in CDCl3 and DMSO-d6 solutions using 1D- and 2D-NMR techniques revealed an equilibrium
between β-II turn and γ-turn conformers, which was ultimately
modulated by the relative configuration of the -(β-lactam)-(Aa)-
residues. Long-range chiral effects on the α-lactam pseudopeptide
conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a
central -(β-lactam)-(Aib)- segment. In such mimetics, heterochiral
(i) and (i + 3) residues reinforced
a β-II turn conformer, whereas homochiral corner residues stabilized
an overlapped β-II/ β-I double turn motif. No β-hairpin
nucleation was observed in any instance. In good agreement with the
conformers found in solution, β-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 -(β-lactam)-(i + 2)- segment was proposed to account for the observed
chiral effects.