Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones

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Abstract

We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.

Original languageEnglish
Pages (from-to)4396-4401
Number of pages6
JournalJournal of Organic Chemistry
Volume82
Issue number8
Early online date20 Mar 2017
DOIs
Publication statusPublished - 21 Apr 2017

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Cinchona
Stereoselectivity
Thiourea
Hydrogen bonds
Nucleophiles
Catalysts
Amines
Density functional theory
Chemical activation
Geometry

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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title = "Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones",
abstract = "We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of So{\'o}s' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.",
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N2 - We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.

AB - We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.

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