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Catalytic endo-stereoselective [2+2] cycloaddition of norbornadienes with internal alkynes

Nature Chemistry (2026) Cite this article

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Abstract

Facial stereoselective transformations of bicyclic compounds offer streamlined access to conformationally constrained scaffolds that are valuable in catalysis, materials science and drug discovery. Owing to the higher electron density of the highest occupied molecular orbital on the exo-face, norbornadiene (NBD), a typical bicyclic molecule, undergoes most reactions on its more accessible exo-face, whereas reactions on the endo-face remain underdeveloped. Here we report a nickel(0)-catalysed endo-stereoselective [2+2] cycloaddition of NBDs with unactivated internal alkynes, enabled by ligand-mediated facial differentiation of NBDs and nickel-controlled configuration of a key intermediate. This method provides an expedient pathway to important scaffolds, including endo-tricyclononadienes and substituted homocubanes, with excellent atom economy. The utility of this scalable reaction is demonstrated through applications of the products in asymmetric catalysis and in the synthesis of drug analogues.

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Fig. 1: Importances and challenges of the facial stereoselective transformations of bicyclic compounds.
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Fig. 2: Optimization of the nickel(0)-catalysed endo-stereoselective [2+2] cycloaddition of NBD with diphenylacetylene.
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Fig. 3: Nickel(0)-catalysed endo-stereoselective [2+2] cycloaddition of NBDs with internal alkynes.
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Fig. 4: The utility of endo-tricyclononadienes.
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Fig. 5: Pharmaceutical analogues, their pharmacokinetic analysis and bioactivity evaluation.
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Fig. 6: Mechanism for the endo-stereoselective [2+2] cycloaddition and DFT calculations.
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Data availability

The data supporting the findings of this Article are provided in the Supplementary Information, including optimization of reaction conditions, experimental procedures, characterization of compounds, biological evaluations, X-ray data and computational results. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2474825 (I), 2474824 (5), 2474823 [(±)-30], 2526037 [(1R,2S,5R,6S)-65], 2474831 (72’), 2474827 (IV), 2474829 (V) and 2474828 (VI). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.

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Acknowledgements

We thank N. Jiao (Peking University), T. Wang (Beijing University of Chemical Technology), Z. Chen (Emory University) and Q. Zhao (Hokkaido University) for helpful suggestions, X. Wang (Hunan University) for assistance with IR spectroscopy, Y. Liu, L. Liu and L. Xu (Hunan Normal University) for assistance with X-ray crystallographic analysis, B. Yin (Hunan Normal University) for assistance with in situ NMR analysis, C. Liu (Fuzhou University) for assistance with flow-photochemistry, X. Qi (Shanghai University), Y. Li and G. Luo (Anhui University) for assistance with DFT calculations, S. Zhang (Ocean University of China) for assistance with biological evaluation and S. Stewart (The University of Western Australia) for assistance with proofreading. Financial support from the National Natural Science Foundation of China (grant nos. 22071051 to W.Z. and 22571188 to X.L.), the Natural Science Foundation of Hunan Province (grant no. 2024JJ5255 to W.Z.) and Hunan Normal University are greatly appreciated.

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Author notes

  1. These authors contributed equally: Longji Dai, Gufeng Yin, Zekun Tuo, Zhichao Chang

Authors and Affiliations

  1. Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, and Key Laboratory of Phytochemical R&D of Hunan Province, Hunan Normal University, Changsha, China

    Longji Dai  (戴龙吉), Gufeng Yin  (殷谷锋), Zekun Tuo  (庹泽锟), Zhichao Chang  (常智超), Xinye Xia  (夏欣烨), Zhongjin Zuo  (左中晋), Yongchun Hu  (胡永春), Shuangshuang Li  (黎双双), Shugen Kuang  (旷述根), Yunfei Lai  (赖云飞) & Wang Zhou  (周旺)

  2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Tzumei Wang  (王子玫) & Chao Wang  (王超)

  3. Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy and Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, China and Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, China

    Chong Qin  (秦冲)

  4. Department of Chemistry, College of Sciences, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai, China

    Xinyao Li  (郦鑫耀)

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  1. Longji Dai  (戴龙吉)
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Contributions

L.D., G.Y., Z.T., Z.C. and W.Z. conceived and designed the experiments. L.D., G.Y., Z.T., Z.C., Y.H., S.L., S.K. and Y.L. performed main methodology development, scope evaluation, downstream diversifications, diene-rhodium(I) catalysis and muti-decagrams scale synthesis. L.D. and X.X. carried out mechanistic investigation. L.D., Z.C. and Z.Z. conducted the synthesis of pharmaceutical analogues. T.W., C.W. and C.Q. accomplished biological evaluation. X.L. carried out DFT computations. L.D., G.Y., Z.T., Z.C., X.X., Z.Z., T.W., C.W., C.Q., X. L. and W.Z. analysed data. L.D., G.Y., Z.T., Z.C., X.X., Z.Z., C.W., Q.C., X.L. and W.Z. wrote the study. W.Z. directed the research.

Corresponding author

Correspondence to Wang Zhou  (周旺).

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Competing interests

Y.L., G.Y., L.D., Z.T., Z.C., Z.Z. and W.Z. are inventors on pending patents: Methods for the synthesis of endo/exo-type 3,4-disubstituted tricyclic[4.2.1.02,5]non-3,7-diene compounds (CN202311358089.4, China); Synthesis and catalytic performance of diene rhodium, palladium, and iridium catalysts (CN202410619494.5, China); A method for the synthesis of 4,5-disubstituted homocubanes (CN202410619657.X, China). Hunan Normal University is patent applicant of the above-mentioned patents. The other authors declare no competing interests.

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Dai, L., Yin, G., Tuo, Z. et al. Catalytic endo-stereoselective [2+2] cycloaddition of norbornadienes with internal alkynes. Nat. Chem. (2026). https://doi.org/10.1038/s41557-026-02167-w

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