Atropisomerism is a specific type of chirality that arises from various steric substituents around an axis where the rotational conformers are enantiomers. It differs from the more common point chirality in that racemization can occur over time, depending on the barrier to rotation about the axis of chirality. Consequently, atropisomers can exist as either stable isolable enantiomers or rapidly interconverting mixtures. Many small molecules such as natural products and bioactives in pharmaceuticals exist as rapidly interconverting atropisomers, yet bind to their biological targets in a conformer-specific orientation. Therefore, exploration of new chemical transformations to access pure atropisomeric small molecules is highly desired. Currently, obtaining pure analogs is a major bottleneck when attempting to synthesize and resolve atropisomeric small molecules. While the conformers can be separated by HPLC, the conversion of the desired products in inefficient and modest. An organocatalytic atroposelective methodology would represent a more effective and scalable approach. The literature has focused primarily on the atroposelective resolution of biaryls and binaphthyls, while mostly neglecting other pharmaceutically relevant moieties such as diaryl ethers, a scaffold most notably present in drugs such as Levatinib and Vancomycin. Therefore, a methodology for diaryl ethers would be advantageous. Previous work by Tan et. al. inspired us to attempt an atroposelective dynamic kinetic resolution on a diaryl ether scaffold via nucleophilic addition onto a quinone adjacent to a prochiral axis. To probe feasibility, we chose quaternary ammonium salts derived from quinine to direct the addition of different nucleophiles, settling on nitromethane as a mild alkylating reagent. These conditions provided the methylated product with moderate selectivities, confirming our initial proof of concept. Further catalyst optimization showed addition of hydrogen-bond donating functional groups such as bulky ureas and carbamates increased the enantioselectivity as high at 85:15 e.r. Further catalyst optimization must be done to improve enantioselectivity, as well as expansion of the diaryl ether and nucleophile substrate scope.

Atroposelective dynamic kinetic resolution of diaryl ether naphthoquinones through alkylation

255th National Meeting (2018)

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