Nature Chemistry
Nature Chemistry
5 years ago

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

Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation
John D. Jolliffe, Roly J. Armstrong, Martin D. Smith
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.

Publisher URL: http://dx.doi.org/10.1038/nchem.2710

DOI: 10.1038/nchem.2710

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