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Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides

Nature Chemistry volume 9, pages 970–976 (2017)Cite this article

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Abstract

The trifluoromethylthio (SCF3) functional group has been of increasing importance in drug design and development as a consequence of its unique electronic properties and high stability coupled with its high lipophilicity. As a result, methods to introduce this highly electronegative functional group have attracted considerable attention in recent years. Although significant progress has been made in the introduction of SCF3 functionality into a variety of molecules, there remain significant challenges regarding the enantioselective synthesis of SCF3-containing compounds. Here, an asymmetric trifluoromethylthiolation that proceeds through the enantioselective [2,3]-sigmatropic rearrangement of a sulfonium ylide generated from a metal carbene and sulfide (Doyle–Kirmse reaction) has been developed using chiral Rh(II) and Cu(I) catalysts. This transformation features mild reaction conditions and excellent enantioselectivities (up to 98% yield and 98% e.e.), thus providing a unique, highly efficient and enantioselective method for the construction of C(sp3)–SCF3 bonds bearing chiral centres.

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Figure 1: Catalytic asymmetric trifluoromethylthiolation.
Figure 2: Assignment of the absolute configuration of the product 3f.
Figure 3: Mechanistic experiments.

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Acknowledgements

The authors acknowledge financial support from the National Basic Research Program of China (973 programme no. 2015CB856600) and Natural Science Foundation of China (grant no. 21332002). We thank Y. Wang and Z. Yu (Peking University) for the discussion on the reaction mechanism. We greatly appreciate W.-X. Zhang and N. Wang (Peking University) for the assistance in obtaining X-ray crystallographic structures.

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Authors and Affiliations

  1. Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, 100871, China

    Zhikun Zhang, Zhe Sheng, Weizhi Yu, Guojiao Wu, Rui Zhang, Wen-Dao Chu, Yan Zhang & Jianbo Wang

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  1. Zhikun Zhang
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Contributions

Z.Z., Z.S., W.Y., G.W. and R.Z. performed the experiments. W.-D.C. and Y.Z. participated in the discussion and helped the measurement of optical purities. J.W. conceived and supervised the project. Z.Z. and J.W. wrote the manuscript.

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Correspondence to Jianbo Wang.

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Supplementary information

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Supplementary information (PDF 9487 kb)

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Crystallographic data for compound 8 (CIF 37 kb)

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Crystallographic data for compound 10j (CIF 36 kb)

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Zhang, Z., Sheng, Z., Yu, W. et al. Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides. Nature Chem 9, 970–976 (2017). https://doi.org/10.1038/nchem.2789

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