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Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation

Nature Chemistry volume 9, pages 558–562 (2017)Cite this article

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Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK

    John D. Jolliffe, Roly J. Armstrong & Martin D. Smith

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  1. John D. Jolliffe
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  2. Roly J. Armstrong
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Contributions

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.

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Correspondence to Martin D. Smith.

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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)

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Jolliffe, J., Armstrong, R. & Smith, M. Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation. Nature Chem 9, 558–562 (2017). https://doi.org/10.1038/nchem.2710

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