Palladium-Catalyzed Enantioselective Synthesis of Cyclic Sulfamidates and Application to a Synthesis of Verubecestat

An enantioselective arylation reaction catalyzed by palladium complexed with substituted phosphinooxazoline (PHOX) ligands is described. Aza-quaternary stereocenters are readily accessible through the arylation reaction between cyclic iminosulfates and a wide variety of arylboronic acids, including electron-poor and ortho-substituted arylboronic acids. This reaction was applied to the preparation of verubecestat, which is currently undergoing clinical evaluation for the treatment of Alzheimer's disease.