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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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).
The authors declare no competing financial interests.
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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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