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Cu-catalysed intramolecular radical enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones

Nature Catalysis volume 3, pages 539–546 (2020)Cite this article

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Abstract

In contrast to the wealth of enantioselective prochiral C(sp3)–H functionalization that is transition-metal-catalysed, the enantioconvergent transformation of racemic tertiary C(sp3)–H bonds (pKa > 25) still represents a vastly uncharted domain. The mechanistic limitation is partial or complete chirality retention, which is inherent to developed enantioselective C–H functionalization catalysis and poses the major challenge in establishing such a process. To this end, we herein describe the combination of decoupled hydrogen atom abstraction with asymmetric copper catalysis for enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones. This method, when allied with follow-up transformations, provides facile access to a range of enantioenriched compounds featuring quaternary stereocentres. We anticipate that this work will inspire the future design of generally efficient catalysts for enantioconvergent transformations of racemic tertiary C(sp3)–H bonds.

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Fig. 1: Design of catalytic enantioconvergent tertiary C(sp3)–H functionalization.
Fig. 2: Substrate scope of the N-sulfonylhydrazone moiety.
Fig. 3: Scope of the tertiary C(sp3)–H moiety, synthetic practicality and applications.
Fig. 4: Mechanistic studies and proposal.

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Data availability

The findings of this study are available within the paper and its Supplementary Information. Crystallographic parameters for compounds 14 and 62 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1923926 (14) and 1923927 (62). All data are available from the authors upon reasonable request.

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Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (nos. 21722203, 21702093, 21831002 and 21801116), Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002), Guangdong Innovative Program (no. 2019BT02Y335), Guangdong Basic and Applied Basic Research Foundation (no. 2019A1515110822), Shenzhen Special Funds (nos. JCYJ20170412152435366, JCYJ20180302180235837 and JCYJ20180302174416591), Shenzhen Nobel Prize Scientists Laboratory Project (no. C17783101), and SUSTech Special Fund for the Construction of High-Level Universities (no. G02216303).

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Author notes

  1. These authors contributed equally: Chang-Jiang Yang, Chi Zhang, Qiang-Shuai Gu.

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Chang-Jiang Yang, Chi Zhang, Jia-Heng Fang, Yan Sun, Yu Tian & Xin-Yuan Liu

  2. Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Qiang-Shuai Gu, Liu Ye & Zhong-Liang Li

  3. Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, China

    Xiao-Long Su

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  1. Chang-Jiang Yang
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Contributions

C.-J.Y., C.Z. and Q.-S.G. designed the experiments and analysed the data. C.-J.Y., C.Z., J.-H.F., X.-L.S., L.Y., Y.S., Y.T. and Z.-L.L. performed the experiments. All authors participated in writing the manuscript. X.-Y.L. conceived and supervised the project.

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Correspondence to Xin-Yuan Liu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–4, Tables 1–4, Methods, NMR spectra, HPLC spectra and references.

Crystallographic Data 1

Crystallographic data for compound 14

Crystallographic Data 2

Crystallographic data for compound 62

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Yang, CJ., Zhang, C., Gu, QS. et al. Cu-catalysed intramolecular radical enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones. Nat Catal 3, 539–546 (2020). https://doi.org/10.1038/s41929-020-0460-y

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