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Catalytic enantioselective synthesis of chiral tetraarylmethanes

Nature Catalysis volume 3, pages 1010–1019 (2020)Cite this article

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Abstract

While synthetic chemistry has experienced substantial development in the past century, challenges still remain to fully satisfy the needs in drug development. A bias in sampling linear and disc-shaped molecules in drug discovery over spherical ones has existed due to the lack of efficient access to the latter chemical space. Specifically, efficient strategies to synthesize tetraarylmethanes, a unique family of spherical molecules, has remained scarce. In particular, there has been essentially no efficient asymmetric synthesis of chiral tetraarylmethanes due to the overwhelming steric congestion and challenging stereocontrol encountered in assembly of the all-aryl-substituted quaternary stereocentre. Here we disclose an efficient catalytic synthesis of chiral tetraarylmethanes with high enantioselectivity via a stereoconvergent formal nucleophilic substitution reaction. Control experiments and density functional theory calculations provided strong support on hydrogen bonding interactions as the key elements to successful stereocontrol. The obtained enantioenriched products showed impressive preliminary anticancer activities.

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Fig. 1: Catalytic enantioselective synthesis of CTAMs.
Fig. 2: Control experiments and derivatizations.
Fig. 3: DFT calculations for the formation of CTAM 3a.

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Data availability

All data generated and analysed during this study are included in this Article and its Supplementary Information. They are also available from the authors upon reasonable request. The X-ray crystallographic coordinates for the structures of 3ae′ (derivative of 3ae) and 5a have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 1935077 and CCDC 1935078, respectively, and can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We thank the Research Grants Council of Hong Kong (16302617, 16302318), National Natural Science Foundation of China (91956114, 21877092), Shenzhen Science and Technology Innovation Committee (JCYJ20170818113708560, JCYJ20160229205441091, JCYJ20200109141408054) and the National Science Foundation (CHE-1764328 to K.N.H) for financial support of this work. Calculations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575). We also thank H. H. Y. Sung for help with structure elucidation.

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Author notes

  1. These authors contributed equally: Xingguang Li, Meng Duan, Zhiqin Deng.

Authors and Affiliations

  1. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Xingguang Li, Min Chen & Jianwei Sun

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Meng Duan, Qianzhen Shao & K. N. Houk

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

    Zhiqin Deng & Guangyu Zhu

  4. Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China

    Jianwei Sun

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Contributions

X.L. conceived the project, performed the experiments and wrote the paper. M.D. and Q.S. performed DFT calculations. K.N.H. directed the DFT calculations and mechanism analysis. Z.D. performed the cytotoxicity experiments. G.Z. directed the cytotoxicity study. 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, K. N. Houk or Jianwei Sun.

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Competing interests

J.S. and X.L. are inventors on US patent application no. 62/918,404 submitted by the Hong Kong University of Science and Technology, which covers the catalytic system and its application in synthetic transformations. Other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Methods, Fig.1, Tables 1–29, NMR spectra and HPLC traces.

Reporting Summary

Supplementary Data 1

Crystallographic data for compound 3ae′.

Supplementary Data 2

Crystallographic data for compound 5a.

Supplementary Data 3

The atomic coordinates of DFT-computed structures.

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Li, X., Duan, M., Deng, Z. et al. Catalytic enantioselective synthesis of chiral tetraarylmethanes. Nat Catal 3, 1010–1019 (2020). https://doi.org/10.1038/s41929-020-00535-4

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