Gram-scale synthesis of (+)-elacestrant streamlined by iridium-catalyzed dynamic kinetic asymmetric hydrogenation of α-substituted tetralones.

A catalytic protocol for the iridium-catalyzed dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) of α-substituted tetralones to rapidly assemble various enantioenriched tetrahydronaphthols is disclosed. A wide range of enantioenriched tetrahydronaphthols were obtained in high yields and excellent stereoselectivities (up to 99% yield, up to >99.5 : 0.5 er and >20 : 1 dr). And this unique platform exhibited high efficiency for the enantioselective synthesis of (+)-elacestrant, which was approved by the FDA in 2023 for the treatment of metastatic breast cancer. Additionally, palladium-catalyzed amination of aryl chloride assisted in furnishing the gram-scale synthesis of this oral anti-tumor drug within 7 steps in 43% yield.