Formal Synthesis of HIF-2α Inhibitor Casdatifan (AB521): Stereospecific Copper(I)-Mediated Ring Opening of Chiral 2-Aryl-cyclopropane-1,1-dicarboxylate with Aryl Grignard Reagents

In the development of a cost-effective synthesis of the HIF-2α inhibitor casdatifan (AB521), an alternative formal synthesis was demonstrated containing the following features: (1) preparation of chiral 2-aryl-cyclopropane-1,1-dicarboxylate 10 from readily available chiral 1,2-diols; (2) a novel stereospecific copper(I)-catalyzed cyclopropane opening of 10 with a functionalized aryl Grignard reagent to form intermediate 14 with a stereocenter that is difficult to access; and (3) a late-stage Friedel-Crafts reaction to form the tetralin ring, leading to the key diketone intermediate 7 for the established manufacturing route of casdatifan.