Huang Gou-Tao, Yu Jen-Shiang K
Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu City 300, Taiwan.
Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu City 300, Taiwan.
Phys Chem Chem Phys. 2024 Apr 17;26(15):11833-11853. doi: 10.1039/d3cp06051a.
The intramolecular Stetter reaction catalyzed by a carbene is investigated by density functional theory (DFT) calculations and kinetic simulations. Catalyst 1 first reacts with aldehyde 2 to give the primary adduct (PA). The PA undergoes the intramolecular oxa-Michael reaction to irreversibly generate enol ether intermediate 9. The conversion of the enol ether to the Breslow intermediate (BI) requires the assistance of a base such as the PA. The next step involves formation of a carbon-carbon bond through the Michael addition, and expulsion of the catalyst generates the Stetter product 7. Calculations show that the catalytic cycle is composed of two irreversible processes: the first one involves the exergonic formation of the enol ether intermediate, while the second one is the conversion of the enol ether to the final product. Kinetic simulations using initial concentrations of [1] = 0.005 M and [2] = 0.025 M demonstrate that under a steady-state condition, 35% of the catalyst rests on the state of the enol ether (0.0018 M). The catalyst resting state therefore consists of the unbound form (the free catalyst) and its bound form (the enol ether species). According to variable time normalization analysis, the reaction exhibits a second-order dependence (first order in catalyst and first order in substrate), which agrees with experiments. The oxa-Michael reaction to form the enol ether is identified to be turnover limiting in the intramolecular Stetter reaction, which rationalizes the observed electronic effect of the Michael acceptor on the reactivity, as well as the measured isotope effect with respect to the aldehydic proton/deuteron. The base that participates in the BI formation has a significant effect on the build-up of the resting state 9 and the active catalyst concentration. In addition, the thermodynamic stability of the enol ether is found to depend on the tether length between the aromatic aldehyde and the Michael acceptor, as well as the chemical nature of the carbene catalyst. The favorability for the oxa-Michael reaction is therefore suggested to govern the reactivity of the intramolecular Stetter transformation.
通过密度泛函理论（DFT）计算和动力学模拟研究了卡宾催化的分子内施泰特反应。催化剂1首先与醛2反应生成初级加合物（PA）。PA发生分子内氧杂迈克尔反应，不可逆地生成烯醇醚中间体9。烯醇醚转化为布雷斯洛中间体（BI）需要碱（如PA）的协助。下一步涉及通过迈克尔加成形成碳-碳键，催化剂的排出生成施泰特产物7。计算表明，催化循环由两个不可逆过程组成：第一个过程涉及烯醇醚中间体的放能形成，而第二个过程是烯醇醚转化为最终产物。使用初始浓度[1]=0.005 M和[2]=0.025 M的动力学模拟表明，在稳态条件下，35%的催化剂处于烯醇醚状态（0.0018 M）。因此，催化剂的静止状态由未结合形式（游离催化剂）及其结合形式（烯醇醚物种）组成。根据可变时间归一化分析，该反应表现出二级依赖性（对催化剂为一级，对底物为一级），这与实验结果一致。形成烯醇醚的氧杂迈克尔反应被确定为分子内施泰特反应中的周转限制步骤，这解释了观察到的迈克尔受体对反应性的电子效应，以及相对于醛基质子/氘核的测量同位素效应。参与BI形成的碱对静止状态9的积累和活性催化剂浓度有显著影响。此外，发现烯醇醚的热力学稳定性取决于芳族醛与迈克尔受体之间的连接链长度以及卡宾催化剂的化学性质。因此，氧杂迈克尔反应的有利性被认为决定了分子内施泰特转化的反应性。
