An Asymmetric S_N2 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.

Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)–N Bonds

“…Recent related studies have disclosed an S N 2 substitution as the rate determining step of the oxidative umpolung reaction. 34 S N 2-type reactions have classically demonstrated enhanced reaction rates in polar, aprotic solvents. 40 Consequently, an evaluation of solvents was undertaken in the substitution step.…”

Organocatalyzed Cross-Nucleophile Couplings: Umpolung of Catalytic Enamines

“…Knowing that the reaction proceeds via a quinone adduct, we envisioned two different resolution strategies to introduce enantioselectivity: (1) an aminocatalyzed stereoselective oxidation followed by substitution with chirality transfer (Scheme 8b, left) or (2) a non-stereoselective oxidation followed by a kinetic resolution manifested by the catalyst- ■ ASYMMETRIC S N 2-DKR Identification of the substitutionally labile quinone adduct prompted a re-evaluation of the mechanistic working model. 3 Isolation of the quinone adduct unambiguously affirmed a two-electron oxidation prior to substitution. While the thiolcoupling methodology leveraged the formation of the quinone adduct into a two-step protocol, prior methodologies employing indole as the nucleophile operated in a single step and furnished quaternary carbon stereocenters in >50% yield of a single enantiomer.…”

“…Identification of the substitutionally labile quinone adduct prompted a re-evaluation of the mechanistic working model . Isolation of the quinone adduct unambiguously affirmed a two-electron oxidation prior to substitution.…”

Organocatalytic asymmetric azidation of sulfoxonium ylides: mild synthesis of enantioenriched α-azido ketones bearing a labile tertiary stereocenter

“…This result may also suggest that the catalyst functions prior to the enantiodetermining substitution step (dynamic interconversion). 27 Finally, the product ee value showed a linear relation to the catalyst ee, suggesting only one catalyst molecule operates in the enantiodetermining transition state (Scheme 5d). 26d Based on the above results and the typical HBD activation modes as well as DFT computations (Scheme 5e and Fig.…”