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Published August 26, 2016 | Accepted Version + Supplemental Material
Journal Article Open

A 15-step synthesis of (+)-ryanodol

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.

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).

Attached Files

Accepted Version - nihms871737.pdf

Supplemental Material - 24/353.6302.912.DC1/Chuang.SM.pdf

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August 20, 2023
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