An Asymmetric SN2 Dynamic Kinetic Resolution

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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.

OriginalsprogEngelsk
TidsskriftJournal of the American Chemical Society
Vol/bind143
Nummer19
Sider (fra-til)7509-7520
Antal sider12
ISSN0002-7863
DOI
StatusUdgivet - maj 2021

Bibliografisk note

Funding Information:
K.A.J. thanks Villum Investigator grant (no. 25867), the Carlsberg Foundation “Semper Ardens”, and Aarhus University. We also thank Mathias Kirk Thøgersen for elucidation of the X-ray structure of 4bb . Access to instruments at the Danish Center for Ultrahigh-Field NMR Spectroscopy funded by the Danish Ministry of Higher Education and Science (AU-2010-612-181) is acknowledged. Computations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575). We are grateful for financial support of the UCLA work from the National Science Foundation (CHE-1764328 to K.N.H.).

Publisher Copyright:
© 2021 American Chemical Society.

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