Chirality-Driven Folding of Short 尾-Lactam Pseudopeptides

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• 作者：Jesus M. Aizpurua ; Claudio Palomo ; Eva Balentov谩 ; Azucena Jimenez ; Elena Andreieff ; Maialen Sagartzazu-Aizpurua ; Jos茅 Ignacio Miranda ; Anthony Linden
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：January 18, 2013
• 年：2013
• 卷：78
• 期：2
• 页码：224-237
• 全文大小：620K
• 年卷期：v.78,no.2(January 18, 2013)
• ISSN：1520-6904

文摘

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