Enantiodivergent Construction of Oxa-Quaternary Carbon Centers via Desymmetrization Based on Palladium/Chiral Norbornene Cooperative Catalysis.

Oxa-quaternary carbon centers are prevalent in bioactive natural products and pharmaceuticals. However, the development of general and practical methods to construct these oxa-quaternary carbon stereocenters remains a formidable challenge. Herein, we report a desymmetrization strategy for the construction of oxa-quaternary carbon stereocenters based on palladium/chiral norbornene cooperative catalysis. With readily available aryl iodides and prochiral 2'-bromo-aryl-substituted tertiary alcohols as the building blocks, a wide variety of 6H-benzo[c]chromenes bearing an oxa-quaternary carbon stereocenter and a versatile C-Br bond are expediently prepared in a highly enantioselective manner (43 examples, up to 99% e.e.). Notably, both enantiomers can be stereodivergently obtained through a simple switch of the same configurated chiral NBE cocatalysts. The synthetic utility of this method is demonstrated by a successful scale-up experiment and diverse late-stage structural modifications through the facile elaboration of the common C-Br bond of the obtained chiral 6H-benzo[c]chromene products. In addition to the experimental studies, DFT calculations are performed to elucidate the reaction mechanism, the origin of enantiodiscrimination, and enantioselectivity inversion in this desymmetrization process.