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An eight-step gram-scale synthesis of (−)-jiadifenolide

Abstract

Development of a biologically active secondary metabolite into a useful medicine requires continuous access to meaningful quantities of material. Although any chemical synthesis is broadly useful for its versatility, identification of a synthesis route that can be economically scaled represents a greater challenge. Here we report a concise synthesis of the neurotrophic trace metabolite (−)-jiadifenolide and its production on a gram-scale. The brevity of the route and the structural similarity of a key intermediate to many potent Illicium terpenes make chemical synthesis the unquestionable method for accessing and modifying these potential therapeutics.

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Figure 1: Retrosynthetic analysis of the lllicium terpene family.
Figure 2: Synthesis of butenolides 8 and 9.
Figure 3: Concise synthesis of (−)-jiadifenolide (1).
Figure 4: Proof of bias.

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Acknowledgements

The authors thank C. Moore and A. Rheingold for crystal X-ray diffraction data and C. Guerrero for help and advice. This work was supported by the National Science Foundation (DGE-1346837, to M.D.M.). The authors acknowledge Amgen, Boehringer Ingelheim, the Baxter Foundation, Bristol-Myers Squibb, Eli Lilly, Novartis and the Sloan Foundation for additional financial support. This work is dedicated to Raymond L. Funk for his many contributions to organic chemistry research and education.

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Authors and Affiliations

Authors

Contributions

All authors conceived and designed the experiments and analysed the data. H-H.L. and M.D.M. performed the experiments. R.A.S. wrote the paper.

Corresponding author

Correspondence to Ryan A. Shenvi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2713 kb)

Supplementary information

Crystallographic data for compound (-)-15 (CIF 723 kb)

Supplementary information

Crystallographic data for compound (+)-7 (CIF 319 kb)

Supplementary information

Crystallographic data for compound 2-epi-15 (CIF 534 kb)

Supplementary information

Crystallographic data for compound 11 (CIF 578 kb)

Supplementary information

Crystallographic data for compound 18 (CIF 1169 kb)

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Lu, HH., Martinez, M. & Shenvi, R. An eight-step gram-scale synthesis of (−)-jiadifenolide. Nature Chem 7, 604–607 (2015). https://doi.org/10.1038/nchem.2283

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