title: Chirality-driven folding of short β-lactam pseudopeptides.
abstract: 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 CDCl(3) 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.
authors.affiliation: Departamento de Química Orgánica-I, Facultad de Química, Universidad del País Vasco UPV/EHU, Paseo Manuel Lardizabal-3, 20018 San Sebastian, Spain. jesusmaria.aizpurua@ehu.es
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Aizpurua
authors.forename: Claudio
authors.initials: C
authors.lastname: Palomo
authors.forename: Eva
authors.initials: E
authors.lastname: Balentová
authors.forename: Azucena
authors.initials: A
authors.lastname: Jimenez
authors.forename: Elena
authors.initials: E
authors.lastname: Andreieff
authors.forename: Maialen
authors.initials: M
authors.lastname: Sagartzazu-Aizpurua
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Miranda
authors.forename: Anthony
authors.initials: A
authors.lastname: Linden
mesh_terms: D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D013237:Stereoisomerism; D047090:beta-Lactams / Q000737:chemistry*
chemical_list: D010455:Peptides; D047090:beta-Lactams