Abstract
Bridged frameworks are widely recognized as privileged motifs in natural products and pharmaceuticals, and their distinctive three-dimensional architectures often underpin target recognition and bioactivity. However, their preparation remains a formidable challenge, with most strategies relying on either linear multi-step syntheses or structurally specialized substrates. Here we report a bridged scaffold editing strategy for heterocycles and carbocycles, which employs formaldehyde and ureas in a distinct multicomponent reaction, toward modular and efficient construction of diverse bridged polycycles. Notably, this protocol enables concurrent C(sp²)–H and unactivated C(sp³)–H functionalization, for directly assembling bridged polycyclic products from planar or quasi-planar cyclic substrates through regio- and diastereoselective multiple bond formations. Experimental and computational studies collectively elucidate the plausible reaction pathways underlying these transformations. By offering rapid and general access to three-dimensional polycyclic skeletons, this approach expands the molecular editing toolbox and provides a versatile platform for generating structurally unique compounds with potential applications in drug discovery.
Acknowledgements
We are grateful to Zhenjun Mao (Department of Chemistry, Zhejiang University), Jianyang Pan (Research and Service Center, College of Pharmaceutical Science, Zhejiang University), Jiyong Liu (Department of Chemistry, Zhejiang University) for performing NMR spectrometry, HRMS for structure elucidation and X-ray analysis.
Funding
We are grateful for financial support from the National Natural Science Foundation of China (U24A20801, S.C. (Cui); 22277106, S.C. (Cui); 82504610, J.L.), National Postdoctoral Program for Innovative Talents (BX20240306, J.L.), China Postdoctoral Science Foundation (2025M773535, J.L.), Zhejiang Provincial Natural Science Foundation of China (LR23H300001, S.C. (Cui); LMS25H300001, J.L.), Zhejiang Provincial Key R&D Program (2023C03118, S.C. (Cui)) and the National Program for Support of Top-notch Young Professionals (grant 2022, S.C. (Cui)).
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Li, J., Yang, Y., Dai, Z. et al. Bridged scaffold editing of carbocycles and heterocycles. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73354-z
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DOI: https://doi.org/10.1038/s41467-026-73354-z
