Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHCCatalyzed Desymmetrization and Following Resolution.

Abstract

Axially chiral diaryl ethers present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N-heterocyclic carbene-catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2-aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late-stage functionalization, gram-scale synthesis, and diverse enantioretentive transformations. Control experiments and the DFT calculation support the association of NHC-catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity.