Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción, Chile.
Org Biomol Chem. 2022 Nov 16;20(44):8662-8671. doi: 10.1039/d2ob00989g.
Hydride transfer reactions involving 1,4-dihydropyridines play a central role in bioorganic chemistry as they represent an important share of redox metabolism. For this class of reactions, direct hydride transfer is the commonly accepted mechanism; however, an Alder-Ene-like pathway has been proposed as a plausible alternative. The reaction between 1,4-ditrimethylsilyl-1,4-dihydropyridine and α,β-unsaturated nitriles is a solid candidate for this latter pathway. In this work, we perform high level and density functional theory computations to characterize the mechanism of this reaction, taking into account diverse reaction paths, and evaluating the effect of solvent polarity and variations in the chemical structure. Our analysis explains the stereochemical aspects of the reaction, characterizing the up to now unresolved spatial configurations of the predominant products, and may contribute to the understanding of enzymatic reactions involving NADP(H). The reactions are found to proceed in an asynchronous fashion, with transition states that display significant aromatic features. With this observation in mind, Alder-Ene and direct hydride transfer pathways can be understood as two extremes of a continuous mechanistic spectrum for this kind of reaction, with the analyzed systems located approximately equidistant from both ends.
涉及 1,4-二氢吡啶的氢化物转移反应在生物有机化学中起着核心作用，因为它们代表了氧化还原代谢的重要组成部分。对于这一类反应，直接氢化物转移是公认的机制；然而，Alder-Ene 型途径已被提出作为一种合理的替代途径。1,4-二三甲硅基-1,4-二氢吡啶与α,β-不饱和腈之间的反应就是这种后一种途径的一个很好的候选反应。在这项工作中，我们通过高级和密度泛函理论计算来描述该反应的机理，考虑了不同的反应路径，并评估了溶剂极性和化学结构变化的影响。我们的分析解释了反应的立体化学方面，对目前尚未解决的主要产物的空间构型进行了特征化，并且可能有助于理解涉及 NADP(H)的酶反应。反应以异步的方式进行，过渡态显示出显著的芳香特征。考虑到这一观察结果，Alder-Ene 和直接氢化物转移途径可以被理解为这种反应的连续机制谱的两个极端，所分析的体系大致位于两个极端之间。
