Gorske Benjamin C, Blackwell Helen E
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706-1322, USA.
J Am Chem Soc. 2006 Nov 8;128(44):14378-87. doi: 10.1021/ja065248o.
Peptoids, or oligomers of N-substituted glycine, are an important class of non-native polymers whose close structural similarity to natural alpha-peptides and ease of synthesis offer significant advantages for the study of biomolecular interactions and the development of biomimetics. Peptoids that are N-substituted with alpha-chiral aromatic side chains have been shown to adopt either helical or "threaded loop" conformations, depending upon solvent and oligomer length. Elucidation of the factors that impact peptoid conformation is essential for the development of general rules for the design of peptoids with discrete and novel structures. Here, we report the first study of the effects of pentafluoroaromatic functionality on the conformational profiles of peptoids. This work was enabled by the synthesis of a new, alpha-chiral amine building block, (S)-1-(pentafluorophenyl)ethylamine (S-2), which was found to be highly compatible with peptoid synthesis (delivering (S)-N-(1-(pentafluorophenyl)ethyl)glycine oligomers). The incorporation of this fluorinated monomer unit allowed us to probe both the potential for pi-stacking interactions along the faces of peptoid helices and the role of side chain electrostatics in peptoid folding. A series of homo- and heteropeptoids derived from S-2 and non-fluorinated, alpha-chiral aromatic amide side chains were synthesized and characterized by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Enhancement of pi-stacking by quadrupolar interactions did not appear to play a significant role in stabilizing the conformations of heteropeptoids with alternating fluorinated and non-fluorinated side chains. However, incorporation of (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomers enforced helicity in peptoids that typically exhibit threaded loop conformations. Moreover, we found that the incorporation of a single (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomer could be used to selectively promote looped or helical structure in this important peptoid class by tuning the electronics of nearby heteroatoms. The strategic installation of this monomer unit represents a new approach for the manipulation of canonical peptoid structure and the construction of novel peptoid architectures.
类肽，即N-取代甘氨酸的低聚物，是一类重要的非天然聚合物，其与天然α-肽的结构相似性以及易于合成的特点，为生物分子相互作用的研究和仿生学的发展提供了显著优势。已表明，用α-手性芳香侧链进行N-取代的类肽会根据溶剂和低聚物长度采取螺旋或“穿线环”构象。阐明影响类肽构象的因素对于制定具有离散和新颖结构的类肽设计通用规则至关重要。在此，我们报告了关于五氟芳香族官能团对类肽构象分布影响的首次研究。这项工作得益于一种新型α-手性胺构建单元（S）-1-（五氟苯基）乙胺（S-2）的合成，发现它与类肽合成具有高度兼容性（可得到（S）-N-（1-（五氟苯基）乙基）甘氨酸低聚物）。这种含氟单体单元的引入使我们能够探究沿类肽螺旋表面的π-堆积相互作用的可能性以及侧链静电在类肽折叠中的作用。合成了一系列由S-2和非氟化α-手性芳香酰胺侧链衍生的同肽和杂肽，并通过圆二色性（CD）和核磁共振（NMR）光谱进行了表征。通过四极相互作用增强π-堆积似乎在稳定具有交替氟化和非氟化侧链的杂肽构象方面不起重要作用。然而，（S）-N-（1-（五氟苯基）乙基）甘氨酸单体的引入使通常呈现穿线环构象的类肽具有螺旋性。此外，我们发现通过调节附近杂原子的电子性质，引入单个（S）-N-（1-（五氟苯基）乙基）甘氨酸单体可用于选择性地促进这类重要类肽的环状或螺旋结构。该单体单元的策略性引入代表了一种操纵经典类肽结构和构建新型类肽结构的新方法。
