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A 16-step synthesis of the isoryanodane diterpene (+)-perseanol

Abstract

(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica1 and has potent antifeedant and insecticidal properties. It is structurally related to (+)-ryanodine, which is a high-affinity ligand for and modulator of ryanodine receptors—ligand-gated ion channels that are critical for intracellular Ca2+ signalling in most multicellular organisms2. Ryanodine itself modulates ryanodine-receptor-dependent Ca2+ release in many organisms, including mammals; however, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester—such as perseanol—may have selective activity in insects3. Here we report a chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available (R)-pulegone. The synthesis involves a two-step annulation process that rapidly assembles the tetracyclic core from readily accessible cyclopentyl building blocks. This work demonstrates how convergent fragment coupling, when combined with strategic oxidation tactics, can enable the concise synthesis of complex and highly oxidized diterpene natural products.

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Fig. 1: The ryanodane and isoryanodane diterpenes.
Fig. 2: Fragment preparation for the synthesis of (+)-perseanol.
Fig. 3: Sixteen-step synthesis of (+)-perseanol.

Data availability

Characterization data for all compounds produced in this study are available in Supplementary Information or on request from the corresponding author. Metrical parameters for the structures of 32 and S21 are available free of charge from the Cambridge Crystallographic Data Centre (CCDC, https://www.ccdc.cam.ac.uk/) under reference numbers 1909375 and 1914686, respectively.

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Acknowledgements

We acknowledge S. Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment; L. Henling and J. Hofstra for X-ray data collection and data refinement, respectively, for the structures of 32 and S21; Y. Zhang for providing original spectral data of perseanol; and K. Chuang for contributions to the synthetic design. Fellowship support was provided by the National Institutes of Health (NIH; Nos. 5T32GM007616-37 and 1F31GM120821, to A.H.). S.E.R. is a Heritage Medical Research Investigator. Financial support from the NIH (Nos. NIGMS RGM097582-01 and R35GM118191-01), Eli Lilly and Novartis is acknowledged.

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Authors

Contributions

A.H. and S.E.R. conceived this work; A.H., Y.T. and S.E.R. designed the experiments and analysed the data; A.H. and Y.T. conducted the experiments; and A.H. and S.E.R. wrote the manuscript.

Corresponding author

Correspondence to Sarah E. Reisman.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

This file contains: General Procedures; Positional Numbering; Synthetic Scheme of Inoue’s Isoryanodane Approach; Synthetic Procedures; 1H and 13C NMR Comparison Tables for Perseanol; Single Crystal X-Ray Diffraction Data; Supplementary References and 1H and 13C NMR Spectral Data.

Supplementary Data

This zipped file contains checkcif files for compounds 32 and S21.

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Han, A., Tao, Y. & Reisman, S.E. A 16-step synthesis of the isoryanodane diterpene (+)-perseanol. Nature 573, 563–567 (2019). https://doi.org/10.1038/s41586-019-1580-x

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