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A 15-step synthesis of (+)-ryanodol

Chuang, Kangway V. and Xu, Chen and Reisman, Sarah E. (2016) A 15-step synthesis of (+)-ryanodol. Science, 353 (6302). pp. 912-915. ISSN 0036-8075. PMCID PMC5505075. http://resolver.caltech.edu/CaltechAUTHORS:20160630-153826956

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Abstract

(+)-Ryanodine and (+)-ryanodol are complex diterpenoids that modulate intracellular calcium-ion release at ryanodine receptors, ion channels critical for skeletal and cardiac muscle excitation-contraction coupling and synaptic transmission. Chemical derivatization of these diterpenoids has demonstrated that certain peripheral structural modifications can alter binding affinity and selectivity among ryanodine receptor isoforms. Here, we report a short chemical synthesis of (+)-ryanodol that proceeds in only 15 steps from the commercially available terpene (S)-pulegone. The efficiency of the synthesis derives from the use of a Pauson-Khand reaction to rapidly build the carbon framework and a SeO_2-mediated oxidation to install three oxygen atoms in a single step. This work highlights how strategic C–O bond constructions can streamline the synthesis of polyhydroxylated terpenes by minimizing protecting group and redox adjustments.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aag1028DOIArticle
https://www.sciencemag.org/content/353/6302/912/suppl/DC1PublisherSupplemental Materials
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505075PubMed CentralArticle
ORCID:
AuthorORCID
Chuang, Kangway V.0000-0002-0652-8071
Xu, Chen0000-0002-3222-459X
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:© 2016 American Association for the Advancement of Science. 9 May 2016; accepted 25 July 2016. The California Institute of Technology Center for Catalysis and Chemical Synthesis is gratefully acknowledged for access to analytical equipment. We thank S. Virgil and J. Hofstra for assistance in obtaining x-ray–quality crystals and solving the structure of 15, respectively. M. Takase and L. Henling are acknowledged for acquiring the x-ray diffraction data for 15 (CCDC deposition no. 1478621; the data are available free of charge from The Cambridge Crystallographic Data Centre). M. Kieffer is gratefully acknowledged for critical feedback and helpful suggestions. Fellowship support was provided by the National Science Foundation (graduate research fellowship to K.V.C., grant DGE-1144469) and the Shenzhen UV-ChemTech Inc. (postdoctoral fellowship to C.X.). S.E.R. is an American Cancer Society Research Scholar and Heritage Medical Research Institute investigator. Financial support from the NIH (National Institute of General Medical Sciences grant RGM097582-01), Eli Lilly, and Novartis is gratefully acknowledged. The California Institute of Technology has filed a provisional patent on this work (application no. 62/269,760).
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
Shenzhen UV-ChemTech Inc.UNSPECIFIED
American Cancer SocietyUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
NIHRGM097582-01
Eli LillyUNSPECIFIED
NovartisUNSPECIFIED
Issue or Number:6302
PubMed Central ID:PMC5505075
Record Number:CaltechAUTHORS:20160630-153826956
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160630-153826956
Official Citation:A 15-step synthesis of (+)-ryanodol Kangway V. Chuang, Chen Xu, Sarah E. Reisman Science 26 Aug 2016: Vol. 353, Issue 6302, pp. 912-915 DOI: 10.1126/science.aag1028
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:68795
Collection:CaltechAUTHORS
Deposited By: Joy Painter
Deposited On:25 Aug 2016 19:03
Last Modified:17 Sep 2019 18:13

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