De novo construction of C-O axial chirality via cobalt-catalyzed atroposelective C-H activation/annulation

Abstract

The catalytic asymmetric synthesis of axially chiral compounds has attracted growing attention over the past decades. C-O axially chiral compounds represent a distinctive class of atropisomers characterized by a unique dual-axial architecture. Their atroposelective construction remains a formidable challenge due to inherent low rotational barriers and high conformational flexibility. Current catalytic approaches rely predominantly on enantioselective desymmetrization of preformed diaryl ethers. Here, we report an unprecedented de novo synthetic strategy, enabling the construction of a new type of C-O axially chiral aryl-heterocyclic ethers. This protocol is achieved by an earth-abundant cobalt-catalyzed atroposelective C-H activation/annulation of arylamides with phenylethynyl ethers, which concurrently builds the heterocycle and the C-O chiral axis in a single step. Notably, a traceless directing group strategy is successfully implemented, featuring smooth in situ cleavage. Furthermore, a series of C-O atropisomers bearing multiple stereogenic elements are prepared with excellent stereoselectivity. Racemization experiments reveal high configurational stability of the products.Derivatization studies afford a versatile library of non-biaryl C-O axially chiral scaffolds, extending the applicability of this strategy.