Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK_a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C⁴-exo conformation of the pyrrolidine ring.

中文翻译：

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4-氟-和4-（三氟甲基）脯氨酸的极性效应。

脯氨酸的含氟类似物在肽和蛋白质的工程和NMR光谱研究中是有价值的工具。它们的使用依赖于对氨基酸残基的取代基和主链基团之间相互作用的基本理解。这项研究旨在展示分子模型中官能团之间相互作用产生的极性相关效应。检查了非对映体4-氟脯氨酸，4-（三氟甲基）脯氨酸和1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸盐的性质，例如构象，酸碱过渡和酰胺键异构性。脯氨酸环上的优选构象源自对单个氟原子的优先轴向定位，以及对于三氟甲基或二氟亚甲基的赤道定位。K _a值，亲脂性和酰胺键旋转的动力学。该研究还提供了一组证据，表明肽基-脯氨酰胺中酰胺键旋转的过渡态有利于吡咯烷环的C ⁴ - exo构象。