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Mechanism, Chemoselectivity, and Stereoselectivity of NHC‐Catalyzed Asymmetric Desymmetrization of Enal‐Tethered Cyclohexadienones
Author(s) -
Xiao Yang,
Zhao Jimin,
Zhao Miao,
Chong Ruifeng,
Li Xin,
Qiao Yan
Publication year - 2020
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202000477
Subject(s) - chemoselectivity , chemistry , desymmetrization , stereoselectivity , protonation , transition state , carbene , nucleophile , catalysis , stereochemistry , computational chemistry , medicinal chemistry , enantioselective synthesis , organic chemistry , ion
Density functional theory calculations were performed to study the mechanism, chemoselectivity, and stereoselectivity for the N ‐heterocyclic carbene (NHC)‐catalyzed asymmetric desymmetrization of enal‐tethered cyclohexadienones. The results showed that the whole reaction includes nucleophilic addition, homoenolate intermediate generation, Michael addition, protonation, esterification, and catalyst elimination. Protonation and esterification were demonstrated to be mediated by AcOH/AcO – , in stark contrast to the experimental speculation that MeOH provided the proton. The Michael addition step determined the chemoselectivity and stereoselectivity. The observed β‐chemoselectivity was attributed to the hydrogen‐bond and favorable π–π interaction in the β‐addition transition states. Moreover, the β‐addition transition state with ( S,R,S )‐configuration was most stable, in agreement with the experimental results that the product derived from this structure was preferentially generated. Further noncovalent interaction analysis showed that stronger π–π interaction between cyclohexadienones and the NHC catalyst, as well as C–H ··· π interactions, made the ( S,R,S )‐configuration transition state the most energetically favored.