An Asymmetric SN2 Dynamic Kinetic Resolution

Nomaan M. Rezayee; Valdemar J. Enemærke; Sif T. Linde; Johannes N. Lamhauge; Gabriel J. Reyes-Rodríguez; Karl Anker Jørgensen; Chenxi Lu; K. N. Houk

doi:10.1021/jacs.1c02193

An Asymmetric S_N2 Dynamic Kinetic Resolution

Nomaan M. Rezayee, Valdemar J. Enemærke, Sif T. Linde, Johannes N. Lamhauge, Gabriel J. Reyes-Rodríguez, Karl Anker Jørgensen^*, Chenxi Lu, K. N. Houk^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

2 Citations (Scopus)

Abstract

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Original language	English
Journal	Journal of the American Chemical Society
Volume	143
Issue	19
Pages (from-to)	7509-7520
Number of pages	12
ISSN	0002-7863
DOIs	https://doi.org/10.1021/jacs.1c02193
Publication status	Published - May 2021

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@article{5c36825d46ac40db8069b46c79457bef,

title = "An Asymmetric SN2 Dynamic Kinetic Resolution",

abstract = "The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions. ",

author = "Rezayee, {Nomaan M.} and Enem{\ae}rke, {Valdemar J.} and Linde, {Sif T.} and Lamhauge, {Johannes N.} and Reyes-Rodr{\'i}guez, {Gabriel J.} and J{\o}rgensen, {Karl Anker} and Chenxi Lu and Houk, {K. N.}",

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year = "2021",

month = may,

doi = "10.1021/jacs.1c02193",

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T1 - An Asymmetric SN2 Dynamic Kinetic Resolution

AU - Rezayee, Nomaan M.

AU - Enemærke, Valdemar J.

AU - Linde, Sif T.

AU - Lamhauge, Johannes N.

AU - Reyes-Rodríguez, Gabriel J.

AU - Jørgensen, Karl Anker

AU - Lu, Chenxi

AU - Houk, K. N.

PY - 2021/5

Y1 - 2021/5

N2 - The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

AB - The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

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M3 - Journal article

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AN - SCOPUS:85106353004

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VL - 143

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JO - Journal of the American Chemical Society

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ER -

An Asymmetric S_N2 Dynamic Kinetic Resolution

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