Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles

Carbonyl groups that bear an a stereocenter are commonly found in bioactive compounds, and intense effort has therefore been dedicated to the pursuit of stereoselective methods for constructing this motif. While the chiral auxiliary-enabled coupling of enolates with alkyl electrophiles represented groundbreaking progress in addressing this challenge, the next advance in the evolution of this enolate-alkylation approach would be to use a chiral catalyst to control stereochemistry. Herein we describe the achievement of this objective, demonstrating that a nickel catalyst can accomplish enantioselective intermolecular alkylations of racemic Reformatsky reagents with unactivated electrophiles; the resulting alpha-alkylated carbonyl compounds can be converted in one additional step into a diverse array of ubiquitous families of chiral molecules. Applying a broad spectrum of mechanistic tools, we have gained insight into key intermediates (including the alkylnickel(II) resting state) and elementary steps of the catalytic cycle.

Automated summary

This study achieved the objective of using a nickel catalyst to perform enantioselective intermolecular alkylations of racemic Reformatsky reagents, resulting in α-alkylated carbonyl compounds. The importance of chiral catalysts in constructing carbonyl compounds with an α stereocenter was further demonstrated. Additionally, detailed mechanistic studies provided insights into key intermediates and elementary steps of the catalytic cycle.