The bimolecular nucleophilic substitution (SN2) reaction is a well-known mechanism taught in every introductory organic chemistry course. It is distinguished by three key features. Firstly, it exhibits first order kinetic dependence on both nucleophile and electrophile. Secondly, it is a stereospecific reaction resulting in Walden inversion of any stereocenters undergoing substitution. Thirdly, highly substituted carbon-centers are very unlikely to react through this mechanism due to the highly ordered and congested transition state. Development of the organocatalytic oxidative coupling of alpha-branched aldehydes with indoles are presented. Extensive mechanistic studies (both experimental and computational) led to the elucidation of an exemplar Curtin-Hammett scenario in which an SN2 reaction of an all-carbon stereocenter is the rate determining step. Knowledge of the mechanistic details led to improvements of the methodology: the scope of aldehydes was broadened to include previously incompatible electron-neutral and -poor species. Racemic aldehydes were used as starting materials giving highly enantioenriched products in moderate to high yields providing evidence for an operating dynamic kinetic resolution.

Organocatalytic deracemisation of quarternary carbon stereocenters via an SN2 reaction

ACS Spring 2022

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