Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution

Axially chiral diaryl ethers are 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 DFT calculations support the association of NHC-catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity. The NHC-catalyzed enantioselective synthesis of axially chiral diaryl ethers was developed via desymmetrization of prochiral 2- aryloxyisophthalaldehydes. Mechanistic studies indicate that this process involves NHC-catalyzed desymmetrization followed by kinetic resolution sequence. The utility of this methodology was demonstrated through a broad scope and completed by further late-stage functionalization.image

Automated summary

The N-heterocyclic carbene-catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2-aryloxyisophthalaldehydes has been presented. This method exhibits mild reaction conditions, broad substrate scope, and excellent enantioselectivity. The utility of this methodology has been demonstrated through late-stage functionalization and various enantioretentive transformations.