Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Catalytic enantioselective synthesis of chiral tetraarylmethanes


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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

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


  1. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Campos, K. R. et al. The importance of synthetic chemistry in the pharmaceutical industry. Science 363, eaat0805 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Franklin, M. R. Induction of rat liver drug-metabolizing enzymes by heterocycle-containing mono-, di-, tri- and tetra-arylmethanes. Biochem. Pharmacol. 46, 683–689 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. El-Kaderi, H. M. et al. Designed synthesis of 3D covalent organic frameworks. Science 316, 268–272 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Ganesan, P. et al. Tetrahedral n-type materials: efficient quenching of the excitation of p-type polymers in amorphous films. J. Am. Chem. Soc. 127, 14530–14531 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Bonardi, F. et al. Probing the SecYEG translocation pore size with preproteins conjugated with sizable rigid spherical molecules. Proc. Natl Acad. Sci. USA 108, 7775–7780 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Huang, X. et al. Self-assembly of morphology-tunable architectures from tetraarylmethane derivatives for targeted drug delivery. Langmuir 29, 3223–3233 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Dong, J., Liu, Y. & Cui, Y. Chiral porous organic frameworks for asymmetric heterogeneous catalysis and gas chromatographic separation. Chem. Commun. 50, 14949–14952 (2014).

    Article  CAS  Google Scholar 

  10. Wu, C. et al. Highly conjugated three-dimensional covalent organic frameworks based on spirobifluorene for perovskite solar cell enhancement. J. Am. Chem. Soc. 140, 10016–10024 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Mercado, R. et al. In silico design of 2D and 3D covalent organic frameworks for methane storage applications. Chem. Mater. 30, 5069–5086 (2018).

    Article  CAS  Google Scholar 

  12. Oniki, J., Moriuchi, T., Kamochi, K., Tobisu, M. & Amaya, T. Linear [3]spirobifluorenylene: an S-shaped molecular geometry of p-oligophenyls. J. Am. Chem. Soc. 141, 18238–18245 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Schoepfle, C. S. & Trepp, S. G. The reaction between triarylmethyl halides and phenylmagnesium bromide. II. J. Am. Chem. Soc. 58, 791–794 (1936).

    Article  CAS  Google Scholar 

  14. Adams, R., Hine, J. & Campbell, J. Triarylpyridylmethanes. J. Am. Chem. Soc. 71, 387–390 (1949).

    Article  CAS  Google Scholar 

  15. Nambo, M., Yar, M., Smith, J. D. & Crudden, C. M. The concise synthesis of unsymmetric triarylacetonitriles via Pd-catalyzed sequential arylation: a new synthetic approach to tri- and tetraarylmethanes. Org. Lett. 17, 50–53 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Nambo, M., Yim, J. C.-H., Gowler, K. G. & Crudden, C. M. Synthesis of tetraarylmethanes by the triflic acid-promoted formal cross-dehydrogenative coupling of triarylmethanes with arenes. Synlett 28, 2936–2940 (2017).

    Article  CAS  Google Scholar 

  17. Zhang, S., Kim, B.-S., Wu, C., Mao, J. & Walsh, P. J. Palladium-catalysed synthesis of triaryl(heteroaryl)methanes. Nat. Commun. 8, 14641 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Griffin, P. J., Fava, M. A., Whittaker, J. T., Kolonko, K. J. & Catino, A. J. Synthesis of tetraarylmethanes via a Friedel-Crafts cyclization/desulfurization strategy. Tetrahedron Lett. 59, 3999–4002 (2018).

    Article  CAS  Google Scholar 

  19. Roy, D. & Panda, G. A dehydrative arylation and thiolation of tertiary alcohols catalyzed by in situ generated triflic acid - viable protocol for C–C and C–S bond formation. Tetrahedron 74, 6270–6277 (2018).

    Article  CAS  Google Scholar 

  20. Palchaudhuri, R., Nesterenko, V. & Hergenrother, P. J. The complex role of the triphenylmethyl motif in anticancer compounds. J. Am. Chem. Soc. 130, 10274–10281 (2018).

    Article  CAS  Google Scholar 

  21. Kshatriya, R., Jejurkar, V. P. & Saha, S. Advances in the catalytic synthesis of triarylmethanes (TRAMs). Eur. J. Org. Chem. 2019, 3818–3841 (2019).

    Article  CAS  Google Scholar 

  22. Matthew, S. C., Glasspoole, B. W., Eisenberger, P. & Crudden, C. M. Synthesis of enantiomerically enriched triarylmethanes by enantiospecific Suzuki–Miyaura cross-coupling reactions. J. Am. Chem. Soc. 136, 5828–5831 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Huang, Y. & Hayashi, T. Asymmetric synthesis of triarylmethanes by rhodium-catalyzed enantioselective arylation of diarylmethylamines with arylboroxines. J. Am. Chem. Soc. 137, 7556–7559 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Pan, T. et al. CuH-catalyzed asymmetric 1,6-conjugate reduction of p-quinone methides: enantioselective synthesis of triarylmethanes and 1,1,2-triarylethanes. Org. Lett. 21, 6397–6402 (2019).

    Article  PubMed  CAS  Google Scholar 

  25. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prakash, J. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).

    Article  CAS  Google Scholar 

  27. Tsuchida, K., Senda, Y., Nakajima, K. & Nishibayashi, Y. Construction of chiral tri- and tetra-arylmethanes bearing quaternary carbon centers: copper-catalyzed enantioselective propargylation of indoles with propargylic esters. Angew. Chem. Int. Ed. 55, 9728–9732 (2016).

    Article  CAS  Google Scholar 

  28. Mahlau, M. & List, B. Asymmetric counteranion-directed catalysis: concept, definition, and applications. Angew. Chem. Int. Ed. 52, 518–533 (2013).

    Article  CAS  Google Scholar 

  29. Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013).

    Article  CAS  Google Scholar 

  30. Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Wang, Z. & Sun, J. Recent advances in catalytic asymmetric reactions of o-quinone methides. Synthesis 47, 3629–3644 (2015).

    Article  CAS  Google Scholar 

  33. Caruana, L., Fochi, M. & Bernardi, L. The emergence of quinone methides in asymmetric organocatalysis. Molecules 20, 11733–11764 (2019).

    Article  CAS  Google Scholar 

  34. Li, W., Xu, X., Zhang, P. & Li, P. Recent advances in the catalytic enantioselective reactions of para-quinone methides. Chem. Asian J. 13, 2350–2359 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. El-Sepelgy, O., Haseloff, S., Alamsetti, S. K. & Schneider, C. Brønsted acid catalyzed, conjugate addition of β-dicarbonyls to in situ generated ortho-quinone methides—enantioselective synthesis of 4-aryl-4H-chromenes. Angew. Chem. Int. Ed. 53, 7923–7927 (2014).

    Article  CAS  Google Scholar 

  36. Wang, Z. et al. Organocatalytic asymmetric synthesis of 1,1-diarylethanes by transfer hydrogenation. J. Am. Chem. Soc. 137, 383–389 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, Z., Wong, Y. F. & Sun, J. Catalytic asymmetric 1,6-conjugate addition of para-quinone methides: formation of all-carbon quaternary stereocenters. Angew. Chem. Int. Ed. 54, 13711–13714 (2015).

    Article  CAS  Google Scholar 

  38. Zhao, J.-J., Sun, S.-B., He, S.-H., Wu, Q. & Shi, F. Catalytic asymmetric inverse-electron-demand oxa-Diels–Alder reaction of in situ generated ortho-quinone methides with 3-methyl-2-vinylindoles. Angew. Chem. Int. Ed. 54, 5460–5464 (2015).

    Article  CAS  Google Scholar 

  39. Xie, Y. & List, B. Catalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho-quinone methides. Angew. Chem. Int. Ed. 56, 4936–4940 (2017).

    Article  CAS  Google Scholar 

  40. Lin, J.-S. et al. Cu/chiral phosphoric acid-catalyzed asymmetric three-component radical-initiated 1,2-dicarbofunctionalization of alkenes. J. Am. Chem. Soc. 141, 1074–1083 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Ma, D., Miao, C.-B. & Sun, J. Catalytic enantioselective House–Meinwald rearrangement: efficient construction of all-carbon quaternary stereocenters. J. Am. Chem. Soc. 141, 13783–13787 (2019).

    Article  CAS  PubMed  Google Scholar 

  42. Zhang, H.-H. et al. Design and enantioselective construction of axially chiral naphthyl-indole skeletons. Angew. Chem. Int. Ed. 56, 116–121 (2017).

    Article  CAS  Google Scholar 

  43. Sundberg, R. J. Indoles (Academic Press, 1996).

  44. Kochanowska-Karamyan, A. J. & Hamann, M. T. Marine indole alkaloids: potential new drug leads for the control of depression and anxiety. Chem. Rev. 110, 4489–4497 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  46. Uraguchi, D. & Terada, M. Chiral Brønsted acid-catalyzed direct Mannich reactions via electrophilic activation. J. Am. Chem. Soc. 126, 5356–5357 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Frisch, M. J. et al. Gaussian 16, Revision A.03 (Gaussian Inc., 2016).

  48. Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 132, 154104 (2010).

    PubMed  Google Scholar 

  49. Grimme, S., Ehrlich, S. & Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 32, 1456–1465 (2011).

    CAS  PubMed  Google Scholar 

  50. Marenich, A. V., Cramer, C. J. & Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 113, 6378–6396 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Zhao, Y. & Truhlar, D. G. Density functionals with broad applicability in chemistry. Acc. Chem. Res. 41, 157–167 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, X., Duan, M., Deng, Z. et al. Catalytic enantioselective synthesis of chiral tetraarylmethanes. Nat Catal 3, 1010–1019 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing