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Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine

Xu, Chen and Han, Arthur and Virgil, Scott C. and Reisman, Sarah E. (2017) Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine. ACS Central Science, 3 (4). pp. 278-282. ISSN 2374-7943. PMCID PMC5409222. https://resolver.caltech.edu/CaltechAUTHORS:20170310-084018084

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Abstract

(+)-Ryanodine is a natural product modulator of ryanodine receptors, important intracellular calcium ion channels that play a critical role in signal transduction leading to muscle movement and synaptic transmission. Chemical derivatization of (+)-ryanodine has demonstrated that certain peripheral structural modifications can alter its pharmacology, and that the pyrrole-2-carboxylate ester is critical for high affinity binding to ryanodine receptors. However, the structural variation of available ryanodine analogues has been limited by the challenge of site-specific functionalization of semisynthetic intermediates, such as (+)-ryanodol. Here we report a synthetic strategy that provides access to (+)-ryanodine and the related natural product (+)-20-deoxyspiganthine in 18 and 19 steps, respectively. A key feature of this strategy is the reductive cyclization of an epoxide intermediate that possesses the critical pyrrole-2-carboxylate ester. This approach allows for the direct introduction of this ester in the final stage of the synthesis and provides a framework for the synthesis of previously inaccessible synthetic ryanoids.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acscentsci.6b00361DOIArticle
http://pubs.acs.org/doi/abs/10.1021/acscentsci.6b00361PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/acscentsci.6b00361PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409222PubMed CentralArticle
ORCID:
AuthorORCID
Xu, Chen0000-0002-3222-459X
Han, Arthur0000-0001-8691-699X
Virgil, Scott C.0000-0001-8586-5641
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:© 2017 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: November 22, 2016; Published: March 9, 2017. The Caltech Center for Catalysis and Chemical Synthesis is gratefully acknowledged for access to analytical equipment. We thank Dr. Michael Takase and Larry Henling for acquiring the X-ray diffraction data and Julie Hofstra for solving the structures of compounds 1, 3, 16, and 18. Fellowship support was provided by the Shenzhen UV-ChemTech Inc. (postdoctoral fellowship to C.X.) and the NIH (training grant 5T32GM007616-37 to A.H.). S.E.R. is an American Cancer Society Research Scholar and Heritage Medical Research Institute investigator. Financial support from the NIH (NIGMS RGM097582-01, R35GM118191-01), Eli Lilly, and Novartis is gratefully acknowledged.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Shenzhen UV-ChemTech Inc.UNSPECIFIED
NIH Predoctoral Fellowship5T32GM007616-37
American Cancer SocietyUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
NIHRGM097582-01
NIHR35GM118191-01
Eli LillyUNSPECIFIED
NovartisUNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC5409222
Record Number:CaltechAUTHORS:20170310-084018084
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170310-084018084
Official Citation:Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine Chen Xu, Arthur Han, Scott C. Virgil, and Sarah E. Reisman ACS Central Science 2017 3 (4), 278-282 DOI: 10.1021/acscentsci.6b00361
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75016
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Mar 2017 16:56
Last Modified:03 Oct 2019 16:45

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