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Enantioselective type II intramolecular [5 + 2] cycloadditions of oxidopyrylium ylides using chiral-phosphoric-acid catalysis

Nature Synthesis volume 4, pages 1223–1231 (2025)Cite this article

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Abstract

Intramolecular [5 + 2] cycloaddition reactions of oxidopyrylium ylides provide rapid access to privileged bridged seven-membered polycyclic structures. In particular, type II variants provide convenient access to highly strained adducts bearing an anti-Bredt double bond. However, enantioselective variants using catalytic methods remain unknown. Here we report an enantioselective method enabled by a non-covalent activation strategy using chiral acid catalysis. The use of a suitable leaving group in the oxidopyrylium precursor and an effective chiral-phosphoric-acid catalyst are crucial to the process. Multiple stereogenic centres can be constructed in one step with high efficiency and excellent enantioselectivity and diastereoselectivity under mild conditions. The products generated from this process are not only structurally intriguing but also represent core structures or advanced intermediates found in natural products. Both mechanistic experiments and computational calculations reveal that enolization is the rate-determining step, whereas the cycloaddition is the enantiodetermining step.

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Fig. 1: Introduction and design of enantioselective type II [5 + 2] cycloaddition reactions using CPA catalysis.
Fig. 2: Enantioselective synthesis of 8-azabicyclo[4.3.1]decanes.
Fig. 3: Enantioselective synthesis of cycloadducts with bicyclo[4.n.1]alkane cores.
Fig. 4: Scaled-up syntheses and product transformations.
Fig. 5: Mechanism experiments.
Fig. 6: DFT calculations.

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Data availability

All data, including experimental details, characterization data, NMR spectra and HLPC traces, are available in the Supplementary Information. The X-ray crystallographic coordinates for structures of 2h′ and 4c have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2340809 and 2340807, respectively, and can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

We thank the National Natural Science Foundation of China (22271242 and 22471232 to J.S.), the Hong Kong Research Grants Council (C6012-21G, 16304322, 16309722 and 16309023 to J.S.) and the Innovation and Technology Commission (ITC-CNERC14SC01 to J.S.) for financial support. L.Y. thanks the Hong Kong Scholars Program for a postdoctoral fellowship. P.C. acknowledges the support of the State Key Laboratory of Synthetic Chemistry. We also thank H. H. Y. Sung for help with structure elucidation.

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Authors and Affiliations

  1. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China

    Liangliang Yang, Ka Lok Chan, Ka Key Cheung, Zhenyang Lin & Jianwei Sun

  2. The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration & Reconstruction, The Hong Kong University of Science and Technology, Hong Kong, China

    Liangliang Yang & Jianwei Sun

  3. Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, China

    Pauline Chiu

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Contributions

J.S. conceived and directed the project. L.Y. designed and performed experiments. Z.L. conceived and directed the computational study. K.L.C. and K.K.C. performed the computational study. P.C. assisted with the mechanism study. All authors discussed the results and commented on the paper.

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Correspondence to Zhenyang Lin or Jianwei Sun.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Experimental details, Supplementary Figs. 1 and 2, and Tables 1–9.

Supplementary Data 1

X-ray crystallographic data for 2h′, CCDC 2340809.

Supplementary Data 2

X-ray crystallographic data for 4c, CCDC 2340807.

Supplementary Data 3 (download TXT )

Coordinates of calculated structures.

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Yang, L., Chan, K.L., Cheung, K.K. et al. Enantioselective type II intramolecular [5 + 2] cycloadditions of oxidopyrylium ylides using chiral-phosphoric-acid catalysis. Nat. Synth 4, 1223–1231 (2025). https://doi.org/10.1038/s44160-025-00803-w

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