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Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling

Yang, Ze-Peng and Freas, Dylan J. and Fu, Gregory C. (2021) Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling. Journal of the American Chemical Society, 143 (23). pp. 8614-8618. ISSN 0002-7863. PMCID PMC8351905. doi:10.1021/jacs.1c03903. https://resolver.caltech.edu/CaltechAUTHORS:20210604-111535270

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Abstract

Interest in unnatural α-amino acids has increased rapidly in recent years in areas ranging from protein design to medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their enantioselective synthesis is an important objective in reaction development. In this report, we establish that a chiral catalyst based on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a wide variety of alkylzinc reagents (1:1.1 ratio) to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling, which proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups, complements earlier approaches to the catalytic asymmetric synthesis of this valuable family of molecules. We have applied our new method to the generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c03903DOIArticle
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: April 14, 2021; Published: June 3, 2021. This paper is dedicated to Professor David A. Evans on the occasion of his 80th birthday. 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), and the Dow Next-Generation Educator Fund (grant to Caltech). We thank Lawrence M. Henling and Dr. Michael K. Takase (Caltech X-Ray Crystallography Facility), Dr. Asik Hossain, Dr. Paul H. Oyala (Caltech EPR Facility), Dr. Felix Schneck, Dr. David G. VanderVelde (Caltech NMR Facility), and Dr. Scott C. Virgil (Caltech Center for Catalysis and Chemical Synthesis) for assistance and helpful discussions. Author Contributions. Z.-P.Y. and D.J.F. contributed equally. The authors declare no competing financial interest. Accession Codes. CCDC 2072620 contains the supplementary crystallographic data for this paper.
Funders:
Funding AgencyGrant Number
NIHR01-GM062871
NSF Graduate Research FellowshipDGE-1745301
Dow Next Generation Educator FundUNSPECIFIED
Subject Keywords:Reagents, Enantioselective synthesis, Electrophiles, Alkyls, Cross coupling reaction
Issue or Number:23
PubMed Central ID:PMC8351905
DOI:10.1021/jacs.1c03903
Record Number:CaltechAUTHORS:20210604-111535270
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210604-111535270
Official Citation:Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling. Ze-Peng Yang, Dylan J. Freas, and Gregory C. Fu. Journal of the American Chemical Society 2021 143 (23), 8614-8618; DOI: 10.1021/jacs.1c03903
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109385
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:07 Jun 2021 15:38
Last Modified:02 Sep 2021 22:34

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