Abstract
To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (−)-catharanthine.
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Acknowledgements
The authors dedicate this manuscript to Masahiro Hirama on the occasion of his 65th birthday. The authors thank Y. Fujimura (Shionogi & Co.) and T. Matsumoto (Rigaku Corporation) for performing X-ray analyses. This work was supported by JSPS KAKENHI (grant no. 23310156 to H. Oguri) and in part by the Naito Foundation and the Science and Technology Research Partnership for Sustainable Development Program (SATREPS) of the Japan Science and Technology Agency (JST). The authors acknowledge a fellowship for H.M. from the JSPS.
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H.M. carried out the experimental work. H.M. and H. Oguri conceived the projects, analysed the experimental results and wrote the manuscript. H. Oikawa discussed the results and provided oversight.
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Mizoguchi, H., Oikawa, H. & Oguri, H. Biogenetically inspired synthesis and skeletal diversification of indole alkaloids. Nature Chem 6, 57–64 (2014). https://doi.org/10.1038/nchem.1798
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DOI: https://doi.org/10.1038/nchem.1798
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