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 atropisomeric biaryls by a cation-directed O-alkylation


Axially chiral biaryls, as exemplified by 1,1′-bi-2-naphthol (BINOL), are key components of catalysts, natural products and medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls by a cation-directed O-alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O-alkylation with e.r. up to 98:2. Oxidation with DDQ gives access to C2-symmetric and non-symmetric BINOL derivatives without compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating atropisomeric enolates, leading to highly atropselective O-alkylation. This dynamic kinetic resolution process offers a general approach to the synthesis of enantioenriched atropisomeric materials.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Strategies for the enantioselective synthesis of biaryls.
Figure 2: Chemoselective derivatization of axially chiral enol ether intermediate and BINOL products.
Figure 3: Proposed mechanism for observed enantioselectivity by variable rates of O-alkylation.


  1. 1

    Clayden, J., Moran, W. J., Edwards, P. J. & LaPlante, S. R. The challenge of atropisomerism in drug discovery. Angew. Chem. Int. Ed. 48, 6398–6401 (2009).

    CAS  Article  Google Scholar 

  2. 2

    Smyth, J. E., Butler, N. M. & Keller, P. A. A twist of nature – the significance of atropisomers in biological systems. Nat. Prod. Rep. 32, 1562–1583 (2015).

    CAS  Article  Google Scholar 

  3. 3

    Zask, A., Murphy, J. & Ellestad, G. A. Biological stereoselectivity of atropisomeric natural products and drugs. Chirality 25, 265–274 (2013).

    CAS  Article  Google Scholar 

  4. 4

    LaPlante, S. R., Edwards, P. J., Fader, L. D., Jakalian, A. & Hucke, O. Revealing atropisomer axial chirality in drug discovery. ChemMedChem. 6, 505–513 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    CAS  Article  Google Scholar 

  6. 6

    Tanaka, K. Transition-metal-catalyzed enantioselective [2+2+2] cycloadditions for the synthesis of axially chiral biaryls. Chem. Asian J. 4, 508–518 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Guo, F., Konkol, L. C. & Thomson, R. J. Enantioselective synthesis of biphenols from 1,4-diketones by traceless central-to-axial chirality exchange. J. Am. Chem. Soc. 133, 18–20 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Kozlowski, M., Morgan, B. J. & Linton, E. C. Total synthesis of chiral biaryl natural products by asymmetric biaryl coupling. Chem. Soc. Rev. 38, 3193–3207 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Wencel-Delord, J., Panossian, A., Leroux, F. R. & Colobert, F. Recent advances and new concepts for the synthesis of axially stereoenriched biaryls. Chem. Soc. Rev. 44, 3418–3430 (2015).

    CAS  Article  Google Scholar 

  10. 10

    Bringmann, G. et al. Atroposelective synthesis of axially chiral biaryl compounds. Angew. Chem. Int. Ed. 44, 5384–5427 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Ma, G. & Sibi, M. P. Catalytic kinetic resolution of biaryl compounds. Chem. Eur. J. 21, 11644–11657 (2015).

    CAS  Article  Google Scholar 

  12. 12

    Li, G.-Q. et al. Organocatalytic aryl–aryl bond formation: an atroposelective [3,3]-rearrangement approach to BINAM derivatives. J. Am. Chem. Soc. 135, 7414–7416 (2013).

    CAS  Article  Google Scholar 

  13. 13

    Bencivenni, G. Organocatalytic strategies for the synthesis of axially chiral compounds. Synlett 26, 1915–1922 (2015).

    CAS  Article  Google Scholar 

  14. 14

    Kanta De, C., Pesciaioli, F. & List, B. Catalytic asymmetric benzidine rearrangement. Angew. Chem. Int. Ed. 52, 9293–9296 (2013).

    Article  Google Scholar 

  15. 15

    Gustafson, J. L., Lim, D. & Miller, S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 328, 1251–1255 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Shirakawa, S., Wu, X. & Maruoka, K. Kinetic resolution of axially chiral 2-amino-1,1′-biaryls by phase-transfer-catalyzed N-allylation. Angew. Chem. Int. Ed. 52, 14200–14203 (2013).

    CAS  Article  Google Scholar 

  17. 17

    Armstrong, R. J. & Smith, M. D. Catalytic enantioselective synthesis of atropisomeric biaryls: a cation-directed nucleophilic aromatic substitution reaction. Angew. Chem. Int. Ed. 53, 12822–12836 (2014).

    CAS  Article  Google Scholar 

  18. 18

    Link, A. & Sparr, C. Organocatalytic atroposelective aldol condensation: synthesis of axially chiral biaryls by arene formation. Angew. Chem. Int. Ed. 53, 5458–5461 (2014).

    CAS  Article  Google Scholar 

  19. 19

    Miyaji, R., Asano, K. & Matsubara, S. Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline N-oxides. J. Am. Chem. Soc. 137, 6766–6769 (2015).

    CAS  Article  Google Scholar 

  20. 20

    Mori, K. et al. Enantioselective synthesis of multisubstituted biaryl skeleton by chiral phosphoric acid catalyzed desymmetrization/kinetic resolution sequence. J. Am. Chem. Soc. 135, 3964–3970 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Lu, S., Bei Poh, S. & Zhao, Y. Kinetic resolution of 1,1′-biaryl-2,2′-diols and amino alcohols through NHC-catalyzed atroposelective acylation. Angew. Chem. Int. Ed. 53, 11041–11045 (2014).

    CAS  Article  Google Scholar 

  22. 22

    Ma, G., Deng, J. & Sibi, M. P . Fluxionally chiral DMAP catalysts: kinetic resolution of axially chiral biaryl compounds. Angew. Chem. Int. Ed. 53, 11818–11821 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Claraz, A., Oudeyer, S. & Levacher, V. Enantioselective desymmetrization of prochiral ketones via an organocatalytic deprotonation process. Tetrahedron Asymm. 24, 764–768 (2013).

    CAS  Article  Google Scholar 

  24. 24

    O’Donnell, M. J., Bennett, W. D. & Wu, S. The stereoselective synthesis of α-amino acids by phase-transfer catalysis. J. Am. Chem. Soc. 111, 2353–2355 (1989).

    Article  Google Scholar 

  25. 25

    O'Donnell, M. J., Boniece, J. M. & Earp, S. E. The synthesis of amino acids by phase-transfer reactions. Tetrahedron Lett. 19, 2641–2644 (1978).

    Article  Google Scholar 

  26. 26

    Wu, Y., Hu, L., Li, Z. & Deng, L. Catalytic asymmetric umpolung reactions of imines. Nature 523, 445–450 (2015).

    CAS  Article  Google Scholar 

  27. 27

    Jones, M. E., Kass, S. R., Filley, J., Barkley, R. M. & Ellison, G. B. Alkylation of enolate ions. J. Am. Chem. Soc. 107, 109–115 (1985).

    CAS  Article  Google Scholar 

  28. 28

    Brickhouse, M. D. & Squires, R. R. Experimental determination of carbon vs. oxygen regioselectivity in reactions of gas-phase enolate ions. J. Phys. Org. Chem. 2, 389–409 (1989).

    CAS  Article  Google Scholar 

  29. 29

    Zhong, M. & Brauman, J. I. Ambident reactivity of enolate anions in the gas phase. Experimental determination of carbon vs oxygen acylation with CF3COCl. J. Am. Chem. Soc. 118, 636–641 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Breugst, M., Zipse, H., Guthrie, J. P. & Mayr, H. Marcus analysis of ambident reactivity. Angew. Chem. Int. Ed. 49, 5165–5169 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Chan, V., Gon Kim, J., Jimeno, C., Carroll, P. J. & Walsh, P. J. Dynamic kinetic resolution of atropisomeric amides. Org. Lett. 6, 2051–2053 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Gao, H. et al. Practical organocatalytic synthesis of functionalized non-C2-symmetrical atropisomeric biaryls. Angew. Chem. Int. Ed. 55, 566–571 (2016).

    CAS  Article  Google Scholar 

  33. 33

    Kočovský, P., Vyskočil, S. & Smrčina, M. Non-symmetrically substituted 1,1′-binaphthyls in enantioselective catalysis. Chem. Rev. 103, 3213–3245 (2003).

    Article  Google Scholar 

  34. 34

    Jensen, B. L. & Slobodzian, S. V. A concise synthesis of 1-substituted-2-tetralones by selective diol dehydration leading to ketone transposition. Tetrahedron Lett. 41, 6029–6033 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Kitamura, M., Shirakawa, S. & Maruoka, K. Powerful chiral phase-transfer catalysts for the asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids. Angew. Chem. Int. Ed. 44, 1549–1551 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Qafisheh, N. et al. Potassium phosphate as a high-performance solid base in phase-transfer-catalyzed alkylation reactions. Ind. Eng. Chem. Res. 46, 3016–3023 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Sharma, K. et al. Cation-controlled enantioselective and diastereoselective synthesis of indolines: an autoinductive phase-transfer initiated 5-endo-trig process. J. Am. Chem. Soc. 137, 13414–13424 (2015).

    CAS  Article  Google Scholar 

  38. 38

    Novacek, J. & Waser, M. Bifunctional chiral quaternary ammonium salt catalysts – a rapidly emerging class of powerful asymmetric catalysts. Eur. J. Org. Chem 637–648 (2013).

  39. 39

    Gao, G. et al. Neighboring lithium-assisted [1,2]-Wittig rearrangement: practical access to diarylmethanol-based 1,4-diols and optically active BINOL derivatives with axial and sp3-central chirality. Chem. Eur. J. 17, 2698–2703 (2011).

    CAS  Article  Google Scholar 

Download references


The European Research Council has provided financial support under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no. 259056. We are grateful to EPSRC for a DTP award (to J.D.J.). We are grateful to J. Wickens and B. Odell (Oxford Chemistry) for their valuable assistance with spectroscopic techniques.

Author information




M.D.S., J.D.J. and R.J.A. conceived and designed the study. J.D.J. and R.J.A. performed the synthetic experiments and analysed data for all compounds. M.D.S., J.D.J. and R.J.A. co-wrote the paper.

Corresponding author

Correspondence to Martin D. Smith.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 12582 kb)

Supplementary information

Crystallographic data for compound 26. (CIF 38 kb)

Supplementary information

Structure factors file for compound 26. (TXT 644 kb)

Supplementary information

Crystallographic data for compound 29. (CIF 24 kb)

Supplementary information

Structure factors file for compound 29. (TXT 281 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jolliffe, J., Armstrong, R. & Smith, M. Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation. Nature Chem 9, 558–562 (2017).

Download citation

Further reading


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