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The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions

Yang, Ze-Peng and Freas, Dylan J. and Fu, Gregory C. (2021) The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions. Journal of the American Chemical Society, 143 (7). pp. 2930-2937. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20210211-151616006

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Abstract

Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH₂R versus CH₂R¹). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1–1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.0c13034DOIArticle
ORCID:
AuthorORCID
Yang, Ze-Peng0000-0003-0248-1963
Freas, Dylan J.0000-0003-0611-7907
Fu, Gregory C.0000-0002-0927-680X
Additional Information:© 2021 American Chemical Society. Received: December 16, 2020; Published: February 10, 2021. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences; grant R01-GM062871), the National Science Foundation Graduate Research Fellowship Program (grant DGE-1745301 to D. J. F.), and the Dow Next-Generation Educator Fund (grant to Caltech). We thank Dr. Haohua Huo for important early contributions to this project, and we thank Nicholas J. Fastuca, Lawrence M. Henling and Dr. Michael K. Takase (Caltech X-Ray Crystallography Facility), Dr. Paul H. Oyala (Caltech EPR Facility), Dr. Felix Schneck, Xiaoyu Tong, Dr. David G. VanderVelde (Caltech NMR Facility), Dr. Scott C. Virgil (Caltech Center for Catalysis and Chemical Synthesis), and Wanji Zhang for assistance and helpful discussions. Author Contributions. Z.-P.Y. and D.J.F. contributed equally. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
NIHR01-GM062871
NSF Graduate Research FellowshipDGE-1745301
Dow Next Generation Educator FundUNSPECIFIED
Subject Keywords:Coupling reactions, Organic compounds, Alkyls, Substitution reactions, Enantioselective synthesis
Issue or Number:7
Record Number:CaltechAUTHORS:20210211-151616006
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210211-151616006
Official Citation:The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions. Ze-Peng Yang, Dylan J. Freas, and Gregory C. Fu. Journal of the American Chemical Society 2021 143 (7), 2930-2937; DOI: 10.1021/jacs.0c13034
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108014
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:11 Feb 2021 23:37
Last Modified:26 Feb 2021 17:27

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