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Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity

Chen, Caiyou and Peters, Jonas C. and Fu, Gregory C. (2021) Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity. Nature, 596 (7871). pp. 250-256. ISSN 0028-0836. PMCID PMC8363576. doi:10.1038/s41586-021-03730-w.

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The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Whereas substantial progress has been reported in recent years in exploiting transition-metal catalysis to dramatically expand the scope of nucleophilic substitution reactions using carbon nucleophiles, there has been limited progress in corresponding reactions with nitrogen nucleophiles. Furthermore, for many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide, through the use of a photoinduced catalyst system based on copper, an earth-abundant metal. This process for asymmetric N-alkylation relies upon three distinct ligands: a bisphosphine, a phenoxide and a chiral diamine, that assemble, in situ, a copper/bisphosphine/phenoxide complex that serves as a photocatalyst and a chiral copper/diamine complex that catalyzes enantioselective C–N bond formation. This study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp²-hybridized substituent on the carbon undergoing substitution) to include unactivated electrophiles.

Item Type:Article
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URLURL TypeDescription ReadCube access InC&EN -- Science Concentrates
Chen, Caiyou0000-0001-7536-7139
Peters, Jonas C.0000-0002-6610-4414
Fu, Gregory C.0000-0002-0927-680X
Alternate Title:Photoinduced Cu-catalysed asymmetric amidation via ligand cooperativity
Additional Information:© The Author(s), under exclusive licence to Springer Nature Limited 2021. Received 21 February 2021; Accepted 16 June 2021; Published 28 June 2021. This manuscript is dedicated to the memory of Gregory P. Harlow. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, R01-GM109194), the Beckman Institute (support of the Laser Resource Center, as well as the Center for Catalysis and Chemical Synthesis, the EPR facility, and the X-ray crystallography facility), the Gordon and Betty Moore Foundation (support for the Center for Catalysis and Chemical Synthesis), the Dow Next-Generation Educator Fund (grant to Caltech) and Boehringer–Ingelheim Pharmaceuticals. We thank C. Citek, T. M. Donnell, J. Dørfler, P. Garrido Barros, L. M. Henling, P. H. Oyala, F. Schneck, M. Shahgoli, D. VanderVelde and J. R. Winkler for assistance and discussions. Data availability: The data that support the findings of this study are available within the paper, its Supplementary Information (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (; crystallographic data are available free of charge under CCDC reference numbers CCDC 2055329–2055338). Author Contributions: C.C. performed all experiments. C.C., J.C.P. and G.C.F. wrote the manuscript. All authors contributed to the analysis and the interpretation of the results. The authors declare no competing interests. Peer review information: Nature thanks the anonymous reviewers for their contribution to the peer review of this work.
Funding AgencyGrant Number
Caltech Beckman InstituteUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Dow Next Generation Educator FundUNSPECIFIED
Boehringer-Ingelheim PharmaceuticalsUNSPECIFIED
Subject Keywords:Asymmetric catalysis; Asymmetric synthesis; Catalytic mechanisms; Synthetic chemistry methodology; Photocatalysis
Issue or Number:7871
PubMed Central ID:PMC8363576
Record Number:CaltechAUTHORS:20210527-133944938
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Official Citation:Chen, C., Peters, J.C. & Fu, G.C. Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity. Nature 596, 250–256 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109283
Deposited By: George Porter
Deposited On:28 Jun 2021 17:40
Last Modified:26 Aug 2021 18:43

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