Peptoids that are oligomers of N-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the cis and trans conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-cis polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (n → π*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1-naphthylethyl (1npe) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered α-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (S)-N-(1-tert-butylethyl)glycine (Ns1tbe) peptoid homo-oligomers. The X-ray crystal structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only α-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of NtBu and Ns1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(tBu)₂-(s1tbe)₄-(tBu)₂-COOtBu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence.

中文翻译：

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具有非芳香族α-手性侧链的类肽的均质且坚固的多脯氨酸I型螺旋

作为N-取代的甘氨酸的低聚物的类肽代表了一类肽模拟物，其在从药物化学到生物材料科学的领域中都具有巨大的潜力。控制其主链酰胺的顺式和反式构象之间的平衡是构建离散折叠结构，特别是开发全顺式聚脯氨酸I型（PPI）螺旋（作为调节生物学功能的工具）所要克服的主要障碍。骨架对侧链电子相互作用（n →π*）和侧链蓬松度在促进顺式反应中的突出作用本质上研究了类肽芳族侧链的α-酰胺，其中手性1-萘乙基（1npe）基团产生了最好的结果。我们首次探索了在空间上受阻的α-手性脂肪族侧链实现类似性能的可能性。在此，我们在合成和一系列（的详细构象分析报告小号- ）ñ - （1-叔-butylethyl）甘氨酸（Ñ s1tbe）类肽均-寡聚物。N s1tbe五聚体的X射线晶体结构显示出全顺式PPI螺旋，N的CD曲线寡聚体也类似于PPI肽螺旋的寡聚体。有趣的是，这里报道的CD数据是仅包含α-手性脂族侧链的任何构象均一的螺旋类肽的首个数据。最后，我们还合成并分析了由Nt Bu和N s1tbe单体组成的两种混合低聚物。令人惊讶的是，混合的低聚物Ac-（t Bu）_2-（s1tbe）_4-（t Bu）₂ -COO t Bu的固态结构是任何线性拟肽中最长的待解决的问题，显示出PPI螺旋的规则性非常强尽管序列中仅存在50％的手性侧链。