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Insights into the NHC-catalyzed cascade Michael/aldol/lactamization reaction: mechanism and origin of stereoselectivity

Abstract

The detailed mechanism and origin of stereoselectivity on the N-heterocyclic carbene (NHC)-catalyzed cascade Michael/aldol/lactamization reaction of enals and indole-derived enones have been investigated in theory. Based on the computational results, the reaction contains eight steps, including the nucleophilic addition of NHC to enal, the intramolecular proton transfer for the formation of Breslow intermediate, the intermolecular Michael addition reaction of indole-derived α,β-unsaturated ketone with Breslow intermediate, the subsequent [1,6]-proton transfer to afford the enolate intermediate, the intramolecular aldol reaction coupled with the proton transfer process, the intramolecular lactamization reaction, and the release of NHC catalyst from the product. Moreover, the C-C bond formation step involved in the intermolecular Michael addition reaction was identified to be the stereoselectivity-determining step, and the RS-configured product was generated preferentially. In addition, the NCI analysis indicates that the more effective C-H•••π and π•••π interactions are contributed significantly to the stability of RS-configured transition state. The mechanistic insights obtained in this study should open the door for rational design on effective construction of the functional heterocyclic molecules through a sequential strategy under the NHC organocatalysis.

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Publication details

The article was received on 18 Apr 2018, accepted on 14 May 2018 and first published on 14 May 2018


Article type: Research Article
DOI: 10.1039/C8QO00398J
Citation: Org. Chem. Front., 2018, Accepted Manuscript
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    Insights into the NHC-catalyzed cascade Michael/aldol/lactamization reaction: mechanism and origin of stereoselectivity

    Y. Wang, S. Zhang, Y. Wang, L. Qu and D. Wei, Org. Chem. Front., 2018, Accepted Manuscript , DOI: 10.1039/C8QO00398J

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