Abstract
Although α-chiral C(sp3)–S bonds are of enormous importance in organic synthesis and related areas, the transition-metal-catalysed enantioselective C(sp3)–S bond construction still represents an underdeveloped domain probably due to the difficult heterolytic metal–sulfur bond cleavage and notorious catalyst-poisoning capability of sulfur nucleophiles. Here we demonstrate the use of chiral tridentate anionic ligands in combination with Cu(I) catalysts to enable a biomimetic enantioconvergent radical C(sp3)–S cross-coupling reaction of both racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles. This protocol not only exhibits a broad substrate scope with high enantioselectivity but also provides universal access to a range of useful α-chiral alkyl organosulfur compounds with different sulfur oxidation states, thus providing a complementary approach to known asymmetric C(sp3)–S bond formation methods. Mechanistic results support a biomimetic radical homolytic substitution pathway for the critical C(sp3)–S bond formation step.
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Data availability
Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, DFT calculations, HPLC spectra, NMR spectra, and mass spectrometry are available in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2212974 (1), 2213037 (52) and 2213038 (83). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
The authors highly appreciate the help of C. Yu and S. Chen from SUSTech in preparing the image of protein CteB in Fig. 1a and the assistance of SUSTech Core Research Facilities. Financial support from the National Natural Science Foundation of China (22025103, 92256301 and 21831002), the National Key R&D Program of China (2021YFF0701604 and 2021YFF0701704), Guangdong Innovative Program (2019BT02Y335), Shenzhen Science and Technology Program (KQTD20210811090112004 and JCYJ20220818100604009), and Shenzhen Special Funds (JCYJ20200109141001789) is gratefully acknowledged. We appreciate the assistance of SUSTech Core Research Facilities. Calculations were performed on the high‐performance computing system at the Department of Chemistry, Zhejiang University.
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Y.T., X.-T.L., J.C. and A.G. designed the experiments and analysed the data. Y.T., X.-T.L., J.C., A.G., N.-Y.Y., Z.L., K.-X.G., W.Z. and H.-T.W. performed the experiments. X.H. designed the DFT calculations. J.-R.L. performed the DFT calculations. Y.T., Z.-L.L., Q.-S.G., and X.-Y.L. wrote the manuscript. X.-Y.L. conceived and supervised the project.
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Supplementary Information
Supplementary Figs. 1–17 and Tables 1–13, experimental procedures, synthetic procedures, characterization data, DFT calculations, and mechanistic discussion.
Supplementary Data 1
Crystallographic data for compound 1; CCDC reference 2212974.
Supplementary Data 2
Crystallographic data for compound 52; CCDC reference 2213037.
Supplementary Data 3
Crystallographic data for compound 83; CCDC reference 2213038.
Supplementary Data 4
Tables of energies and coordinates in xyz format.
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Tian, Y., Li, XT., Liu, JR. et al. A general copper-catalysed enantioconvergent C(sp3)–S cross-coupling via biomimetic radical homolytic substitution. Nat. Chem. 16, 466–475 (2024). https://doi.org/10.1038/s41557-023-01385-w
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DOI: https://doi.org/10.1038/s41557-023-01385-w
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