Abstract
Due to the ubiquitous presence of ortho-disubstituted benzenes in pharmaceuticals and agrochemicals, the exploration of their bioisosteres incorporating three-dimensional bridged cyclic scaffolds has attracted significant interest among chemists in recent years. As a result, 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes have recently emerged as promising candidates owing to their enhanced pharmacological potency, improved metabolic stability, and, importantly, superior aqueous solubility. Herein, we report our recent progress on enantioselective synthesis of such compounds via an intramolecular [2 + 2] photocycloaddition enabled by cooperative photoinduced energy transfer (EnT) and chiral Brønsted acid catalysis. A broad range of valuable pyridine-functionalized 2-oxabicyclo[2.1.1]hexane derivatives have been obtained in high yields with good to excellent enantioselectivity and diastereoselectivity. In addition, this transition metal-free approach offers an efficient and modular route to pyridine-based bicyclo[2.1.1]hexanes, which contain a significant yet challenging structural motif—pyridine rings directly attached to the bridgehead carbon atoms. Mechanistic studies demonstrate that the photosensitizer and low reaction temperature are crucial for rendering the chiral catalyst indispensable in facilitating substrate activation to the triplet state, thereby enabling enantiocontrol in this highly reactive transformation.
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Data availability
All data are available from the corresponding author. The authors declare that all data supporting the findings of this study are available in the paper and its Supplementary Information files. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers (CCDC 2496083) (2 g). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
This work was financially supported by the National Science Foundation of China (Nos. 22471064, 22401086, 22301061, 22171072, and 22201068), Central Government Guided Local Science and Technology Development Fund Projects (Z20231811081), and the Key Project of the Henan Provincial Natural Science Foundation (Nos. 252300421286 and 254000510005).
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Z.J. conceived and designed the study. D.T. and C.Q. performed the experiments. D.T., C.Q., S.C., B.Y., X.Z. and J.Z. analyzed and interpreted the data. S.C. carried out the DFT calculations. D.T., J.Z., and Z.J. prepared the Supplementary Information. Z.J. wrote the manuscript. All authors discussed the results and commented on the manuscript.
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Nature Communications thanks Shunxi Dong, liang yi and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Tian, D., Qu, C., Cao, S. et al. Enantioselective Synthesis of 2-Oxabicyclo[2.1.1]hexanes and Bicyclo[2.1.1]hexanes via Catalytic Asymmetric Intramolecular Photocycloadditions. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71590-x
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DOI: https://doi.org/10.1038/s41467-026-71590-x
