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. 2017 Apr 26;3(4):278-282.
doi: 10.1021/acscentsci.6b00361. Epub 2017 Mar 9.

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

Chen Xu  1 , Arthur Han  1 , Scott C Virgil  1 , Sarah E Reisman  1
Affiliations

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

Chen Xu et al. ACS Cent Sci. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Ryanodine, ryanodol, and related natural products.
Figure 2
Figure 2
Synthetic considerations. (A) Oxidation products 7 and 8, each accessible from 6 by modification of the SeO2 reaction conditions, can be elaborated to either (+)-ryanodine (1) or (+)-20-deoxyspiganthine (3), respectively. (B) Retrosynthetic analysis for 1 and 3. Key strategic innovation is to directly incorporate pyrrole-2-carboxylate ester (as in 10) prior to reductive cyclization.
Scheme 1
Scheme 1. Chemical Synthesis of (+)-Ryanodine
Scheme 2
Scheme 2. Chemical Synthesis of (+)-20-Deoxyspiganthine
See this image and copyright information in PMC

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