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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 C 2 -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. A chiral ammonium salt mediates a dynamic kinetic resolution of racemic α-aryl ketones by atropselective O -alkylation. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives in high yields and with high enantioselectivity.

Atropisomers are molecules whose stereogenicity arises from restricted rotation about a single bond. They are of current importance because of their applications in catalysis, medicine and materials science. The defining feature of atropisomeric molecules is that their stereoisomers are related to one another by bond rotation: as a result, evaluating their configurational stability (i.e., the rate at which their stereoisomers interconvert) is central to any work in this area. Important atropisomeric scaffolds include C–C linked biaryls, such as the ligand BINAP and the drug vancomycin, and C–N linked amine derivatives such as the drug telenzepine. This article focuses on the three most widely used experimental methods that are available to measure the rate of racemization in atropisomers, namely: (i) kinetic analysis of the racemization of an enantioenriched sample, (ii) dynamic HPLC and (iii) variable-temperature NMR. For each technique, an explanation of the theory is set out, followed by a detailed experimental procedure. A discussion is also included of which technique to try when confronted with a new molecular structure whose properties are not yet known. None of the three procedures require complex experimental techniques, and all can be performed by using standard analytical equipment (NMR and HPLC). The time taken to determine a racemization rate depends on which experimental method is required, but for a new compound it is generally possible to measure a racemization rate in <1 d. This protocol describes how to measure the rate of racemization in atropisomers by (i) kinetic analysis of the racemization of an enantioenriched sample, (ii) dynamic HPLC and (iii) variable-temperature NMR. Key points Stereoisomers of atropisomeric molecules interconvert by rotation of a single bond. If the interconversion rate is slow enough, the atropisomers can be separated by HPLC. After enrichment of one isomer, the kinetics of racemization can be determined. At increasing rates of interconversion, analytical HPLC shows two peaks, a ‘Batman’ profile (dynamic HPLC) or a single peak. For molecules with faster interconversion, variable-temperature NMR can be performed.