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Published August 17, 2022 | Accepted + Supplementary
Journal Article Open

Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles

  • 1. ROR icon California Institute of Technology

Abstract

Carbonyl groups that bear an α 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 α-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.

Additional Information

© 2022 American Chemical Society. Received 10 June 2022. Published online 4 August 2022. This work is dedicated to the memory of Prof. David A. Evans. We thank Dr. Haohua Huo, Arianna Ayonon, and Dr. Zhaobin Wang for preliminary experiments, and we acknowledge Robert L. Anderson, Dr. Caiyou Chen, Hyungdo Cho, Dr. Dylan J. Freas, Dr. Lawrence M. Henling, Zachary P. Ifkovits, Dr. Mona Shahgholi, Dr. Michael K. Takase, Dr. David G. Vander Velde, Dr. Zepeng Yang, and Wendy Zhang for assistance and helpful discussions. Funding: Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, Grants R01-GM62871 and R35-GM145315), the Alexander von Humboldt Foundation (research fellowship for F.S.), the Beckman Institute (support of the Center for Catalysis and Chemical Synthesis, the EPR facility, the Molecular Materials Research Center, and the X-ray crystallography facility), the Gordon and Betty Moore Foundation (support of the Center for Catalysis and Chemical Synthesis), and the Dow Next-Generation Educator Fund (grant to the California Institute of Technology). Author Contributions. X.T. and F S. contributed equally. The authors declare no competing financial interest. Accession Codes: CCDC 2150649−2150650 and 2150652−2150653 contain the supplementary crystallographic data for this paper.

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Supplemental Material - ja2c06154_si_001.pdf

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Additional details

Created:
September 29, 2023
Modified:
January 18, 2024