Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.
Patrick B BradyBryan K SorensenRoberto M RisiMichael L CurtinRobert A ManteiAlan S FlorjancicAnthony MastracchioCheng JiAaron R KunzerChunqiu LaiGregory E StorerVincent S ChanRodger F HenryAndrew J SouersMichael R MichaelidesAndrew S JuddT Matthew HansenPublished in: The Journal of organic chemistry (2023)
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.