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Nickel-catalysed asymmetric hydrogenation of oximes

Abstract

Chiral hydroxylamines are vital substances in bioscience and versatile subunits in the preparation of a variety of functional molecules. However, asymmetric and non-asymmetric synthetic approaches to these compounds are far from satisfactory. Although atom-economic metal-catalysed asymmetric hydrogenations have been studied for over 50 years, the asymmetric hydrogenation of oximes to the corresponding chiral hydroxylamines remains challenging because of the labile N–O bond and inert C=N bond. Here we report an environmentally friendly, earth-abundant, transition-metal nickel-catalysed asymmetric hydrogenation of oximes, affording the corresponding chiral hydroxylamines with up to 99% yield, 99% e.e. and with a substrate/catalyst ratio of 1,000. Computational results indicate that the weak interactions between the catalyst and substrate play crucial roles not only in the transition states, but also during the approach of the substrate to the catalyst, by selectively reducing the reaction barriers and thus improving the reaction efficiency and securing the generation of chirality.

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Fig. 1: Reduction of oximes to chiral hydroxylamines.
Fig. 2: Synthetic applications.
Fig. 3: Theoretical calculations of the approach of the substrate to the catalyst.
Fig. 4: Computed mechanism.

Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. For the experimental procedures, data for the NMR and HPLC analyses and cartesian coordinates of the optimized structures, see the Supplementary Methods in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 2059388 (1a) and 2059391 (2a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We dedicate this work to Professor Tsuneo Imamoto for his 80th birthday. We thank the National Key R&D Program of China (no. 2018YFE0126800, W.Z.), National Natural Science Foundation of China (nos. 21620102003, W.Z.; 21991112, W.Z.; 21772119, J.C.; 21702134, J.C.) and Shanghai Municipal Education Commission (no. 201701070002E00030, W.Z.) for financial support. We thank the Instrumental Analysis Center of SJTU for characterization.

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Authors and Affiliations

Authors

Contributions

W.Z. directed the project. B.L. conducted most of the synthetic experiments. D.L. conducted some of the synthetic experiments. I.D.G. conducted the density functional theory computational study. J.C., B.L., W.Z. and I.D.G. wrote the original draft of the manuscript. J.C., W.Z., B.L. and I.D.G. reviewed and edited the manuscript.

Corresponding author

Correspondence to Wanbin Zhang.

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The authors declare no competing interests.

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Nature Chemistry thanks Tomas Smeijkal, Jianrong Zhou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7 and Tables 1–8. Synthesis and characterization data, supplementary discussion, computational and procedural details, crystallographic data, NMR spectra, HPLC traces.

Supplementary Data 1

Crystallographic data for compound 1a; CCDC reference 2059388

Supplementary Data 2

Crystallographic data for compound 2a; CCDC reference 2059391

Supplementary Data 3

Contains the Cartesian coordinates of computational structures

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Li, B., Chen, J., Liu, D. et al. Nickel-catalysed asymmetric hydrogenation of oximes. Nat. Chem. 14, 920–927 (2022). https://doi.org/10.1038/s41557-022-00971-8

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