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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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.
The authors declare no competing financial interests.
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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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