Polarity effects in 4-fluoro-and 4-(trifluoromethyl)prolines
Polarity effects in 4-fluoro-and 4-(trifluoromethyl)prolines
复制标题
DOI：
10.3762/bjoc.16.151
复制
发表时间：
2020-07-23
影响因子：
2.7
通讯作者：
Kubyshkin, Vladimir
中科院分区：
文献类型：
--
作者：
Kubyshkin, Vladimir
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。本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。研究了双立体异构体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-羧酸酯的构象、酸碱转换和酰胺键异构性等性质。脯氨酸环上的优选构象起源于单个氟原子的优先轴向定位和三氟甲基或二氟亚甲基的赤道定位。这种取向的取代基解释了所观察到的趋势的pKa值，亲油性，和动力学的酰胺键旋转。该研究还提供了一组证据表明，在肽基脯氨酰的酰胺键旋转的过渡态有利于吡咯烷环的C4-exo构象。
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 dia-stereomeric 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 posi-tioning for a trifluoromethyl-or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pKa 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.