Asymmetric Synthesis of [3.2.1]Tropane scaffolds via Enantioselective β-H elimi-nation reaction

Tropanes and their related bridged bicyclic systems constitute highly sought-after scaffolds in drug discovery and development. Notably, the enantioselective synthesis of chiral 3-aryltropanes—compounds widely distributed across bioactive pharmaceutical agents—remains underdeveloped. Tropinone is a readily available and cost-effective starting material. By initiating the synthesis from tropinone, it is possible to substantially lower the synthesis costs. Here we describe an enantioselective Pd/Ming-Phos-catalyzed β-H elimination reaction of Tropinone-derived N-arylsulfonylhydrazones and aryl bromides to give chiral tropanes and oxatropanes. Strikingly, this study achieves enantioselective β-H elimination which needs to simultaneously control over both diastereoselectivity during the migratory insertion and enantioselectivity during the β-H elimination. This approach shows broad functional group tolerance, excellent enantiocontrol as well as easy scale-up. Moreover, the synthetic value is further demon-strated by the enantioselective catalytic total synthesis of drugs for treating Alzheimer’s disease and monoamine transporter ligands. Additionally, both the facile elaborations and the preliminary biological activities of the products demonstrate the application potential.