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Divergent housane synthesis via intramolecular [2 + 2] cycloaddition of 1,4-dienes

Nature Synthesis (2026)Cite this article

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Abstract

Highly strained rings serve as privileged building blocks for the synthesis of saturated, three-dimensional scaffolds, which are increasingly recognized as critical components in modern drug discovery. Here we disclose a substrate-dependent, divergent strategy to access a broad family of housanes through an intramolecular-energy-transfer-mediated [2 + 2] cycloaddition of 1,4-dienes—a transformation that has long been considered challenging. This method rapidly builds up strain while suppressing the di-π-methane rearrangement, thereby expanding the toolkit for efficient exploration of housane chemical space. Substituent engineering enables switching between single and double energy-transfer pathways to deliver 1,3- and 1,2-disubstituted housanes with excellent stereocontrol and broad functional-group tolerance. Mechanistic studies and density functional theory calculations support an energy-transfer pathway and rationalize the observed selectivity.

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Fig. 1: Overview of housane synthesis and current work.
Fig. 2: Scope for 1,3-disubstituted housanes.
Fig. 3: Scope for 1,2-disubstituted housanes.
Fig. 4: Scale-up experiment and postsynthetic diversification.
Fig. 5: Mechanistic investigations.
Fig. 6: Mechanistic outline.

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Data availability

All data are available in the main text or the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2486494 (2k), 2486495 (2ao), 2486496 (3av) and 2504328 (7). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Computational data (ORCA input and output files) can be accessed in the IOChemBD repository (https://doi.org/10.19061/iochem-bd-6-583).

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Acknowledgements

This work is supported by Muenster University. J.D. acknowledges PhD fellowship funding by the Hans und Ria Messer Stiftung. N.H. acknowledges PhD fellowship funding by the German National Academic Foundation (Studienstiftung des deutschen Volkes). The authors thank D. Rana and L. Schlosser for helpful discussions.

Author information

Author notes

  1. These authors contributed equally: Julius Domack, Niklas Hölter.

Authors and Affiliations

  1. Organisch-Chemisches Institut, University of Münster, Münster, Germany

    Fuhao Zhang, Julius Domack, Niklas Hölter, Constantin G. Daniliuc & Frank Glorius

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  1. Fuhao Zhang
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  2. Julius Domack
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  3. Niklas Hölter
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Contributions

F.G. and F.Z. conceived the project. F.Z. designed all the experiments. F.Z. and J.D. performed synthetic experiments. N.H. conducted computational investigations. All authors analysed the data. C.G.D. analysed X-ray structures. F.G. and F.Z. supervised the research and wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Frank Glorius.

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

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Supplementary information

Supplementary Information

Experimental details, Supplementary sections 1–12, Figs. 1–19 and Tables 1–8.

Supplementary Data 1

Crystallographic data for compound 2ao, CCDC 2486495.

Supplementary Data 2

Crystallographic data for compound 2k, CCDC 2486494.

Supplementary Data 3

Crystallographic data for compound 3av, CCDC 2486496.

Supplementary Data 4

Crystallographic data for compound 7, CCDC 2504328.

Source data

Source Data Fig. 5

Statistical source data for Fig. 5a–c.

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Zhang, F., Domack, J., Hölter, N. et al. Divergent housane synthesis via intramolecular [2 + 2] cycloaddition of 1,4-dienes. Nat. Synth (2026). https://doi.org/10.1038/s44160-026-00997-7

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