Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 32, Pages 14856-14863Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c06154
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Funding
- National Institutes of Health (National Institute of General Medical Sciences) [R01-GM62871, R35-GM145315]
- Alexander von Humboldt Foundation
- Beckman Institute
- Gordon and Betty Moore Foundation
- Dow Next-Generation Educator Fund
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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.
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.
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