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Palladium-catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes

Nature Synthesis volume 4, pages 124–133 (2025)Cite this article

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Abstract

Cycloaddition reactions of bicyclo[1.1.0]butanes (BCBs) with 2π components are a powerful tool for preparing C(sp3)-rich arene bioisosteres. Despite enormous progress in this field, catalytic enantioselective cycloadditions of BCBs that produce enantioenriched three-dimensional bioisosteres are underdeveloped. Here we report a palladium-catalysed [3 + 2] cycloaddition reaction of vinyl-carbonyl-BCBs with carbonyl compounds, including formaldehyde, activated ketones, and aliphatic and aromatic aldehydes. This approach provides quick access to a wide variety of 2-oxabicyclo[2.1.1]hexanes. Density functional theory calculations indicate that the reaction occurs through a zwitterionic mechanism involving σ-bond cleavage, nucleophilic addition and allylic substitution. When (R,R)-ANDEN-phenyl Trost ligand is used, the stereoselectivity of the addition of palladium-zwitterionic enolates to carbonyl can be controlled to achieve enantioselective [3 + 2] cycloadditions. We further demonstrate the practicality of the method by carrying out several downstream transformations of cycloaddition products.

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Fig. 1: [2σ + 2π] Cycloaddition reactions of BCBs.
Fig. 2: Development of [2σ + 2π] cycloaddition of VC-BCB 1a with paraformaldehyde.
Fig. 3: Substrate scope for palladium-catalysed [2σ + 2π] cycloaddition reaction of VC-BCBs with carbonyl compounds.
Fig. 4: Investigation of the enantioselective [2σ + 2π] cycloaddition of VC-BCBs 1a with benzaldehyde.
Fig. 5: Substrate scope for enantioselective [2σ + 2π] cycloadditions of VC-BCBs with aldehydes.
Fig. 6: Synthetic applications of the cycloaddition reaction.

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Data availability

The authors declare that the data supporting the findings of this study are available within the Article and its Supplementary Information files. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2358250 for (S)-4o and CCDC 2325465 for (R)-4ab. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We gratefully acknowledge funding support from the National Key R&D Program of China (numbers 2022YFA1503700, 2023YFA1506700), the National Natural Science Foundation of China (numbers 22071118, 22271162, 22188101) and the Natural Science Foundation of Tianjin (number 21JCZDJC00350). We thank the Haihe Laboratory of Sustainable Chemical Transformations and Frontiers Science Center for New Organic Matter for financial support. We thank F. Dean Toste for helpful discussions.

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  1. These authors contributed equally: Tianzhu Qin, Mengyang He.

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin, China

    Tianzhu Qin, Mengyang He & Weiwei Zi

  2. Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China

    Weiwei Zi

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  1. Tianzhu Qin
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Contributions

W.Z. conceived and supervised this work. T.Q. and M.H. conducted the studies and prepared the Supplementary Information. All the authors co-wrote the manuscript.

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Correspondence to Weiwei Zi.

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Supplementary information

Supplementary Information

Experimental details, DFT calculations, X-ray crystallographic analysis and NMR spectra.

Supplementary Data 1

Crystallographic data for (S)-4o CCDC 2358250.

Supplementary Data 2

Crystallographic data for (R)-4ab CCDC 2325465.

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Qin, T., He, M. & Zi, W. Palladium-catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes. Nat. Synth 4, 124–133 (2025). https://doi.org/10.1038/s44160-024-00659-6

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