Abstract
N-bridged [3.2.1]octanes (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 which are 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, good enantiocontrol as well as easy scale-up. Moreover, the synthetic value is further demonstrated 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.
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Data availability
The data supporting the findings of this study are available within the article and its Supplementary Information. And all data are available from the corresponding author upon request. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2451377 (3bd). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
The authors gratefully acknowledge the funding support of the National Key R&D Program of China (No. 2021YFF0701600), NSFC (No. 22031004, 22501294), the Shanghai Municipal Education Commission (No. 20212308), and STCSM (No. 23ZR1445600). The authors also particularly thank Dr. Chengbin Yang for his contributions to the evaluation of biological activity.
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C.F. carried out the experimental and data-analysis work. J.A. and Q.W. carried out the experimental work. B.X. carried out data-analysis work and wrote the paper. Z.-M.Z. and J.Z. designed the reaction, directed the project, and wrote the paper.
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Fang, C., Ai, J., Wang, Q. et al. Asymmetric synthesis of Heteroatom-bridged [3.2.1]Octane scaffolds via enantioselective β-H elimination reaction. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69960-6
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DOI: https://doi.org/10.1038/s41467-026-69960-6
