Silva Ana Flávia Candida, Martins Francisco A, Freitas Matheus P
Department of Chemistry, Institute of Natural Sciences, Federal University of Lavras, 37200-900, Lavras, MG, Brazil.
Department of Chemistry, University of Houston, Houston, TX, USA.
Beilstein J Org Chem. 2024 Jul 12;20:1572-1579. doi: 10.3762/bjoc.20.140. eCollection 2024.
Selective fluorination of the pyrrolidine ring in proline motifs has been found to induce significant conformational changes that impact the structure and biological roles of modified peptides and proteins. Vicinal difluorination of fluoroproline, for example, in (3,4)-3,4-difluoroproline, serves to mitigate the inherent conformational bias of the pyrrolidine ring by inducing stereoelectronic effects that attenuate this conformational bias. In this investigation, we present a quantumchemical analysis of the conformational equilibrium and effects that are induced in difluorinated pyrrolidines, with a particular focus on exploring the impact of and anomeric effects on the conformer stabilities of different stereo- and regioisomers. Initially, we conducted a benchmark assessment comparing the optimal density functional theory method with coupled cluster with single and double excitations (CCSD) calculations and crystallographic data using the 3-fluoropyrrolidinium cation and 3-fluoropyrrolidine. Subsequently, we explored the relative energy of all favored conformations of all different stereoisomers of 2,3-, 2,4-, and 3,4-difluoropyrrolidines at the B3LYP-D3BJ/6-311++G** level. A generalized anomeric effect, arising from n→σ* electron delocalization, is particularly important in modulating the energetics of the α-fluoro isomers and imparts a strong conformational bias. In contrast, the fluorine effect assumes a secondary role, as it is overshadowed by steric and electrostatic interactions, referred to as Lewis interactions from a natural bond orbital perspective.
脯氨酸基序中吡咯烷环的选择性氟化已被发现会引发显著的构象变化，这些变化会影响修饰后的肽和蛋白质的结构及生物学作用。例如，氟代脯氨酸（如（3,4）-3,4-二氟脯氨酸）的邻位二氟化通过诱导立体电子效应来减轻吡咯烷环固有的构象偏向，这种效应会减弱这种构象偏向。在本研究中，我们对二氟化吡咯烷的构象平衡及诱导效应进行了量子化学分析，特别关注探索β效应和异头效应对不同立体异构体和区域异构体构象稳定性的影响。最初，我们进行了一项基准评估，将最优密度泛函理论方法与含单双激发的耦合簇（CCSD）计算以及使用3-氟吡咯烷鎓阳离子和3-氟吡咯烷的晶体学数据进行比较。随后，我们在B3LYP-D3BJ/6-311++G*水平上探索了2,3-、2,4-和3,4-二氟吡咯烷所有不同立体异构体的所有有利构象的相对能量。由n→σ电子离域产生的广义异头效应在调节α-氟异构体的能量方面尤为重要，并赋予强烈的构象偏向。相比之下，氟效应起次要作用，因为它被空间和静电相互作用（从自然键轨道角度称为路易斯相互作用）所掩盖。
