DFT perspective toward [3 + 2] annulation reaction of enals with α-ketoamides through NHC and Brønsted acid cooperative catalysis: mechanism, stereoselectivity, and role of NHC
DFT perspective toward [3 + 2] annulation reaction of enals with α-ketoamides through NHC and Brønsted acid cooperative catalysis: mechanism, stereoselectivity, and role of NHC
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DOI：
10.1039/c5qo00338e
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发表时间：
2016-01
影响因子：
5.4
通讯作者：
Yang Wang;Bohua Wu;Linjie Zheng;D. Wei;M. Tang
中科院分区：
文献类型：
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作者：
Yang Wang;Bohua Wu;Linjie Zheng;D. Wei;M. Tang
采用密度泛函理论（DFT）方法对N-杂环卡宾（NHC）催化烯醛与α-酮酰胺的[3 + 2]成环反应的可能机理和立体选择性进行了系统的理论研究.计算结果表明，有利的路径包括七个步骤，即，催化剂的加入、Breslow中间体的形成、烯醇化物中间体的形成、C-C键形成步骤、质子转移过程、闭环过程和催化剂的再生。对于质子转移过程，除了直接质子转移机制外，还研究了碱TMEDA和原位生成的Bronsted酸TMEDA·H+介导的质子转移机制，发现显式引入Bronsted酸TMEDA·H+显著降低了关键质子转移步骤的自由能.计算结果表明，C-C键形成步骤是立体选择性的决定步骤，在该步骤中形成了两个与偶合碳原子相对应的手性中心，主要产物为RR构型的非对映体，这与实验结果吻合较好.已经进行了全局反应指数（GRI）分析以证实NHC主要起刘易斯碱催化剂的作用。此外，畸变/相互作用，NCI，和NBO分析表明，强相互作用和电子离域的反应活性部位决定的立体选择性，与RR配置的产品被优先生成。在本研究中获得的机理的见解应该是有价值的合理设计的一个有效的有机催化剂，这种反应具有高立体选择性。
A systematic theoretical study has been carried out to understand the possible mechanisms and stereoselectivity of the N-heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation reaction of enals with α-ketoamides using density functional theory (DFT) calculations. The calculated results reveal that the favorable pathway comprises of seven steps, i.e., addition of the catalyst, formation of the Breslow intermediate, formation of the enolate intermediate, the C–C bond formation step, the proton transfer process, the ring-closure process and the regeneration of the catalyst. For the proton transfer process, apart from the direct proton transfer mechanism, the base TMEDA and the in situ generated Bronsted acid TMEDA·H+ mediated proton transfer mechanisms are also investigated; the free energy for the crucial proton transfer steps is found to be significantly lowered by explicit inclusion of the Bronsted acid TMEDA·H+. The computational results show that the C–C bond formation step is the stereoselectivity-determining step, in which two chirality centers assigned to the coupling carbon atoms are formed, and the RR-configured diastereomer is the predominant product, which is in good agreement with the experimental observations. Global reaction index (GRI) analysis has been performed to confirm that NHC mainly plays a role of a Lewis base catalyst. In addition, the distortion/interaction, NCI, and NBO analyses show that the strong interaction and electron delocalization of the reaction active site determine the stereoselectivity, with the RR-configured product being generated preferentially. The mechanistic insights obtained in the present study should be valuable for the rational design of an effective organocatalyst for this kind of reaction with high stereoselectivity.