Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α‑Chiral Side Chains

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.

作为N-取代甘氨酸低聚物的类肽（peptoids），是一类极具应用潜力的肽模拟物，其应用场景覆盖从药物化学到生物材料科学等诸多领域。调控其主链酰胺的顺式与反式构象平衡，是构建离散折叠结构的核心难题，尤其对于开发全顺式聚脯氨酸I型（polyproline type I, PPI）螺旋以作为调控生物功能的工具而言，这一难题更为突出。主链-侧链电子相互作用（n→π*）与侧链体积位阻在促进顺式酰胺形成中的关键作用，此前主要通过芳香族侧链类肽开展研究，其中手性1-萘乙基（1-naphthylethyl, 1npe）侧链取得了最优效果。本研究首次探索了利用位阻受阻的α-手性脂肪族侧链实现类似效果的可能性。本文报道了一系列(S)-N-(1-叔丁基乙基)甘氨酸（Ns1tbe）类肽均低聚物的合成与详细构象分析。Ns1tbe五聚体的X射线晶体结构显示其呈现全顺式PPI螺旋，且Ns1tbe低聚物的圆二色谱（circular dichroism, CD）曲线也与PPI肽螺旋的曲线高度相似。值得注意的是，本文报道的CD数据，是首个针对仅含α-手性脂肪族侧链的构象均一螺旋类肽的相关数据。最后，本研究还合成并分析了两种由N-叔丁基甘氨酸（NtBu）与Ns1tbe单体组成的混合低聚物。令人惊讶的是，混合低聚物Ac-(tBu)2-(s1tbe)4-(tBu)2-COOtBu的固态结构呈现出高度规整的PPI螺旋——这是目前已解析的最长线性类肽结构——尽管其序列中仅含有50%的手性侧链。