Desymmetrization of a Propane-1,3-diol to Introduce the Quaternary Chiral Center of an AMG 176 Drug Substance Intermediate

A chiral Cu(II)-PyBOX complex was prepared and utilized to accomplish desymmetrization of a 1,3-diol en route to AMG 176. An expedient synthesis of the racemic 1,3-diol is described, in addition to efforts for rapid optimization and subsequent kilogram-scale execution of the desymmetrization process to generate material for pre-clinical activities. An overview of the kilogram-scale synthesis of the Cu(II)-PyBOX complex is provided.