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

Han, Arthur and Tao, Yujia and Reisman, Sarah E. (2019) A 16-step synthesis of the isoryanodane diterpene (+)-perseanol. Nature, 573 (7775). pp. 563-567. ISSN 0028-0836. PMCID PMC7123484. https://resolver.caltech.edu/CaltechAUTHORS:20190610-080930538

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Abstract

(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica 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 Ca^(2+) signalling in most multicellular organisms. Ryanodine itself modulates ryanodine-receptor-dependent Ca^(2+) 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 insects. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-019-1580-xDOIArticle
https://rdcu.be/bRTaOPublisherFree ReadCube access
https://chemrxiv.org/articles/16-Step_Synthesis_of_the_Isoryanodane_Diterpene_-Perseanol/8100152OrganizationDiscussion Paper
https://pubs.acs.org/doi/10.1021/cen-09738-scicon2Featured InC&EN : Science Concentrates
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123484PubMed CentralArticle
ORCID:
AuthorORCID
Han, Arthur0000-0001-8691-699X
Tao, Yujia0000-0003-4615-6409
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:© 2019 Nature Publishing Group. Received 09 May 2019; Accepted 15 July 2019; Published 25 September 2019. 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. 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. Author 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. Competing interests: The authors declare no competing interests.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
NIH Predoctoral Fellowship5T32GM007616-37
NIH Postdoctoral Fellowship1F31GM120821
Heritage Medical Research InstituteUNSPECIFIED
NIHRGM097582-01
NIHR35GM118191-01
Eli LillyUNSPECIFIED
NovartisUNSPECIFIED
Subject Keywords:perseanol; total synthesis; isoryanodane; Pd-catalyzed
Issue or Number:7775
PubMed Central ID:PMC7123484
Record Number:CaltechAUTHORS:20190610-080930538
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190610-080930538
Official Citation: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
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96224
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Jun 2019 17:42
Last Modified:06 Apr 2020 18:35

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