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Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity

Nature volume 596, pages 250–256 (2021)Cite this article

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Abstract

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. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles1,2,3,4, there has been limited progress in corresponding reactions with nitrogen nucleophiles5,6,7,8. 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. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands—a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C–N bond formation. Our 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)8,9,10,11,12,13 to include unactivated electrophiles.

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Fig. 1: Chiral secondary amides.
Fig. 2: An array of amides that serve as nucleophilic coupling partners.
Fig. 3: An array of alkyl bromides that serve as electrophilic coupling partners.
Fig. 4: Mechanism.

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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 (https://www.ccdc.cam.ac.uk/structures; crystallographic data are available free of charge under CCDC reference numbers CCDC 2055329–2055338).

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Acknowledgements

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.

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Authors and Affiliations

  1. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

    Caiyou Chen, Jonas C. Peters & Gregory C. Fu

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  1. Caiyou Chen
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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.

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Correspondence to Jonas C. Peters or Gregory C. Fu.

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The authors declare no competing interests.

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Peer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Continued scope of alkyl bromides serving as electrophilic coupling partners.

Couplings were generally conducted using 0.5 mmol of the amide, and N1* was used as the diamine, unless otherwise noted. All data represent the average of two experiments. The per cent yield represents purified product. aElectrophile (1.5 equiv.), Cu(CH3CN)4PF6 (15 mol%), P (5 mol%), N1* (20 mol%), K3PO4 ∙ H2O (1.5 equiv.; in place of Cs2CO3), 10 °C. Ar1, p-(F3C)C6H4.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Tables 1-2, Supplementary Figures 1-31 and NMR Spectra Data - see contents page for details.

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Chen, C., Peters, J.C. & Fu, G.C. Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity. Nature 596, 250–256 (2021). https://doi.org/10.1038/s41586-021-03730-w

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