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Enantioselective synthesis of tetraarylmethanes through meta-hydroxyl-directed benzylic substitution

Nature Synthesis volume 2, pages 275–285 (2023)Cite this article

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Abstract

Benzylic carbocations bearing an ortho- or para-hydroxyl group can be stabilized by forming quinone methides, which have been explored in enantioselective synthesis. However, those with a meta-hydroxyl group have remained almost unexplored in organic synthesis. The lack of resonance stabilization by a typical quinone methide form renders them not only difficult to generate, but also challenging to control for asymmetric bond formation. Here we report an efficient catalytic enantioselective reaction between meta-hydroxyl triarylmethanols and indoles, via triaryl carbocations, for the synthesis of tetraarylmethanes with excellent enantiocontrol. Control experiments reveal that the meta-hydroxyl group is essential for both reactivity and stereocontrol. Ortho-directing groups (alkoxyl, sulfenyl or fluoro) benefit enantiocontrol through secondary hydrogen-bonding interactions, but are not required for reactivity. The resulting tetraarylmethane products show anticancer activities, through a mechanism distinct from that of classical anticancer drugs.

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Fig. 1: Introduction to QMs and reaction design.
Fig. 2: Gram-scale synthesis and derivatizations.
Fig. 3: Mechanistic experiments and proposed mechanism.
Fig. 4: Anticancer activity of the synthetic compounds and SAR analysis.
Fig. 5: The lead compounds induced necroptosis in LCSCs.

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Data availability

Source Data are provided with this Article. All data generated and analysed during this study are included in this Article, its Supplementary Information and its Source Data. The X-ray crystallographic coordinates of the structure of 8 (a derivative of 3p) have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2142024 and can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (91956114, 22077108 and 21877092), the Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20200109141408054 and JCYJ20210324120004011), the Hong Kong Research Grants Council (16303420, 16309321, 11307419, 11303320 and 11302221) and the Innovation and Technology Commission (ITC-CNERC14SC01). We thank H. H. Y. Sung for help in structure elucidation by X-ray crystallography.

Author information

Author notes

  1. These authors contributed equally: Xuefeng Tan, Zhiqin Deng.

Authors and Affiliations

  1. Department of Chemistry, Institute for Advanced Study and the Hong Kong Branch of Chinese National Engineering Research Centre for Tissue Restoration and Reconstruction, The Hong Kong University of Science and Technology (HKUST), Hong Kong SAR, China

    Xuefeng Tan, Qingli Wang & Jianwei Sun

  2. Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China

    Zhiqin Deng, Shu Chen & Guangyu Zhu

  3. Shenzhen Bay Laboratory, Shenzhen, China

    Qingli Wang

  4. Shenzhen Research Institute, HKUST, Shenzhen, China

    Qingli Wang & Jianwei Sun

  5. City University of Hong Kong Shenzhen Research Institute, Shenzhen, China

    Shu Chen & Guangyu Zhu

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Contributions

X.T. and Q.W. performed the chemical syntheses and wrote the paper. Z.D. and S.C. performed the experiments for the biological study and wrote the paper. G.Z. directed the biological study and wrote the paper. J.S. conceived and directed the project and wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Guangyu Zhu or Jianwei Sun.

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Competing interests

X.T. and J.S. are owners of a Chinese patent application (202210842981.9). The other authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Luca Bernardi, Robert Musiol and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental procedures, characterization data and mechanistic studies, Supplementary Figs. 1–4, Tables 1–5, NMR spectra and HPLC traces.

Reporting Summary

Supplementary Data 1

Crystallographic data for 8; CCDC 2142024.

Source data

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

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Tan, X., Deng, Z., Wang, Q. et al. Enantioselective synthesis of tetraarylmethanes through meta-hydroxyl-directed benzylic substitution. Nat. Synth 2, 275–285 (2023). https://doi.org/10.1038/s44160-022-00211-4

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