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Total synthesis of the Daphniphyllum alkaloid daphenylline

Nature Chemistry volume 5, pages 679–684 (2013)Cite this article

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Abstract

The Daphniphyllum alkaloids are a large class of natural products isolated from a genus of evergreen plants widely used in Chinese herbal medicine. They display a remarkable range of biological activities, including anticancer, antioxidant, and vasorelaxation properties as well as elevation of nerve growth factor. Daphenylline is a structurally unique member among the predominately aliphatic Daphniphyllum alkaloids, and contains a tetrasubstituted arene moiety mounted on a sterically compact hexacyclic scaffold. Herein, we describe the first total synthesis of daphenylline. A gold-catalysed 6-exo-dig cyclization reaction and a subsequent intramolecular Michael addition reaction, inspired by Dixon's seminal work, were exploited to construct the bridged 6,6,5-tricyclic motif of the natural product at an early stage, and the aromatic moiety was forged through a photoinduced olefin isomerization/6π-electrocyclization cascade followed by an oxidative aromatization process.

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Figure 1: Selected natural products that represent major subfamilies of Daphniphyllum alkaloids.
Figure 2: An inspiring synthesis of the tricyclic core of calyciphylline A-type alkaloids by Dixon and co-workers26.
Figure 3: Retrosynthetic analysis of daphenylline.
Figure 4: Construction of the bridged tricycle 9.
Figure 5: Assembly of the pentacyclic intermediate 25.
Figure 6: Completion of the total synthesis of daphenylline.

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Acknowledgements

This paper is dedicated to Dawei Ma for his contributions to China's natural product synthesis on the occasion of his 50th birthday. We thank X-J. Hao for providing an authentic sample of daphenylline, Z-J. Yao for assistance with the cryoprobe NMR facility and D. J. Edmonds and R. Denton for helpful discussions. Financial support was provided by the Ministry of Science & Technology (2013CB836900) and the National Natural Science Foundation of China (21290180, 21172235 and 21222202).

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  1. Zhaoyong Lu and Yong Li: These authors contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, 345 Lingling Road, China

    Zhaoyong Lu, Yong Li, Jun Deng & Ang Li

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Contributions

Z.L. and Y.L. contributed equally to this work. A.L., Z.L. and Y.L. conceived the synthetic route and analysed the results. Z.L., Y.L. and J.D. conducted the experimental work. A.L. directed the project and wrote the manuscript.

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Correspondence to Ang Li.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 9904 kb)

Supplementary information

Crystallographic data for compound 10. (CIF 18 kb)

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Crystallographic data for racemate of compound 27. (CIF 38 kb)

Supplementary information

Crystallographic data for desilylated compound 9a. (CIF 17 kb)

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Lu, Z., Li, Y., Deng, J. et al. Total synthesis of the Daphniphyllum alkaloid daphenylline. Nature Chem 5, 679–684 (2013). https://doi.org/10.1038/nchem.1694

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