期刊
JOURNAL OF ORGANIC CHEMISTRY
卷 77, 期 21, 页码 9813-9825出版社
AMER CHEMICAL SOC
DOI: 10.1021/jo302133n
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资金
- National Natural Science Foundation of China [20933009, 20972064]
- Key Grant Project of Chinese Ministry of Education [309028]
- 111 Project
In-depth understanding of the activation mechanism in asymmetric organocatalysis is of great importance for rational development of highly efficient catalytic systems. In this Article, the mechanism for the direct vinylogous Michael reaction of alpha,beta-unsaturated gamma-butyrolactam (Nu) and chalcone (EI) catalyzed by the bifunctional cinchona alkaloid thiourea organocatalyst (Cat) was studied with a combination of experimental (NMR) and theoretical (DFT) approaches, through which a new dual activation pathway was found. The key feature of this new dual activation mechanism (Pathway C) is that one N-H-A of the thiourea moiety and the N-H of the protonated amine in Cat simultaneously activate Nu, while the other N-H-B of the thiourea moiety activates EI. Both the NMR measurement and the DFT calculation identified that the interaction of Cat with Nu is stronger than that with EI in the catalyst-substrate complexes. Kinetic studies via variable temperature NMR measurements indicated that, with the experimental activation energy E-a of 10.2 kcal/mol, the reaction is all first order in Nu, El, and Cat The DFT calculation further revealed that the C-C bond formation is both the rate determining and the stereoselectivity-controlling steps. In agreement with the experimental data, the energy barrier for the rate determining step along Pathway C was calculated as 8.8 kcal/mol. The validity of Pathway C was further evidenced by the calculated enantioselectivity (100% ee) and diastereoselectivity (60:1 dr), which are in excellent match with the experimental data (98% ee and > 30:1 dr, respectively). Mechanistic study on the Michael addition of nitromethane to chalcone catalyzed by the Catalyst I further identified the generality of this new dual activation mechanism in cinchona alkaloid thiourea organocatalysis.
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