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Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles

Tong, Xiaoyu and Schneck, Felix and Fu, Gregory C. (2022) Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles. Journal of the American Chemical Society, 144 (32). pp. 14856-14863. ISSN 0002-7863. doi:10.1021/jacs.2c06154.

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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.

Item Type:Article
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URLURL TypeDescription
Tong, Xiaoyu0000-0002-1343-6335
Schneck, Felix0000-0002-0947-518X
Fu, Gregory C.0000-0002-0927-680X
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.
Funding AgencyGrant Number
Alexander von Humboldt FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Dow Next Generation Educator FundUNSPECIFIED
Subject Keywords:Alkyls, Carbonyls, Catalysts, Electrophiles, Reagents
Issue or Number:32
Record Number:CaltechAUTHORS:20220805-758034000
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Official Citation:Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles Xiaoyu Tong, Felix Schneck, and Gregory C. Fu Journal of the American Chemical Society Article ASAP DOI: 10.1021/jacs.2c06154
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:116148
Deposited By: George Porter
Deposited On:09 Aug 2022 17:46
Last Modified:29 Aug 2022 23:51

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