An Axial-to-Axial Chirality Transfer Strategy for Atroposelective Construction of C–N Axial Chirality

Abstract

Summary C–N axially chiral skeletons are ubiquitous in bioactive natural products, pharmaceuticals, and chiral ligands. However, their atroposelective synthesis remains a formidable challenge because of their innate low configurational stability compared with that of well-developed C–C atropisomers. Herein, we report a general and efficient method for accessing C–N atropisomers through an axial-to-axial chirality transfer strategy based on palladium/chiral norbornene cooperative catalysis. The obtained C–N axial chirality originates from the preformed transient C–C axial chirality with high fidelity. A variety of C–N axially chiral phenanthridinones are obtained in excellent enantioselectivities (44 examples, up to >99% ee). This method can be applied for the construction of two stereogenic axes via double atroposelective C–H arylation or further transformation of the products via axial-to-axial diastereoinduction. Additionally, the reaction mechanism and the chirality transfer process are elucidated by density functional theory calculations.