Chirality-Driven Folding of Short β‑Lactam Pseudopeptides

• Published in: Journal of organic chemistry 2013-01, Vol.78 (2), p.224-237
• Main Authors: Aizpurua, Jesus M, Palomo, Claudio, Balentová, Eva, Jimenez, Azucena, Andreieff, Elena, Sagartzazu-Aizpurua, Maialen, Miranda, José Ignacio, Linden, Anthony
• Format: Article
• Language: English
• Subjects: beta-Lactams - chemistry; Crystallography, X-Ray; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Peptides - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo302368y

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-d 6 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.