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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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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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.
The authors declare no competing interests.
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Supplementary Figs. 1–7 and Tables 1–8. Synthesis and characterization data, supplementary discussion, computational and procedural details, crystallographic data, NMR spectra, HPLC traces.
Crystallographic data for compound 1a; CCDC reference 2059388
Crystallographic data for compound 2a; CCDC reference 2059391
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