An Asymmetric S_N2 Dynamic Kinetic Resolution

The S_N2 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 S_N2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an S_N2 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 S_N2 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 S_N2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric S_N2 dynamic kinetic resolution to be used for a variety of future reactions.