Atropisomerism is a form of chirality, which differs from normal point chirality in that the chirality is about a bond (i.e. aryl-aryl bonds), hence racemization can spontaneously occur via bond rotation. Our lab has recently exploited this stereochemical phenomenon to increase the target selectivity of small molecule kinase inhibitors. While we have since focused our efforts on the efficient enantioselective synthesis of these kinase inhibitors, we also wanted to explore the atroposelective synthesis of new chiral scaffolds towards the design of unique chiral ligands. The atroposelective synthesis of new chiral ligands from “feedstock” molecules offers an attractive approach towards adding unique scaffolds and geometries (which are currently unavailable) to the arsenal of catalysts used for enantioselective transformations. We have recently focused our efforts toward the synthesis of atropisomerically pure aryl-naphthoquinone analogues. This synthetic strategy allows us to preinstall a variety of functionality proximal to the atropisomeric axis prior to the enantioselective transformation. This allows us to structurally diversify the enantioenriched product towards the synthesis of various chiral catalysts and ligands. Via the nucleophilic addition of thiophenol into a rapidly interconverting aryl-naphthoquinone atropisomer, we have achieved a general Dynamic Kinetic Resolution (DKR) of rapidly racemizing atropisomers. We have found cinchona alkaloid catalysts can efficiently catalyze the nucleophilic addition of thiophenol into the quinone moiety of a rapidly interconverting naphthoquinone-aryl scaffold, affording atropisomerically stable 1,4-dimethoxynaphthatlene scaffolds in high yields and enantiomeric ratios (i.e. 98% yield, 98:2 enantiomeric ratio). This is an unprecedented approach towards the enantioselective synthesis of atropisomers with diverse substitution patterns. This new catalytic methodology holds the potential to increase the efficiency of synthesizing enantiomerically pure atropisomeric ligands, which offer unique catalytic active site geometries and conformations.

Development of a nucleophilic dynamic kinetic resolution of aryl-naphthoquinone atropisomers

255th National Meeting (2018)

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