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A 15-step synthesis of (+)-ryanodol

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Science  26 Aug 2016:
Vol. 353, Issue 6302, pp. 912-915
DOI: 10.1126/science.aag1028

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Rapid ryanodol route

The plant-derived compound ryanodine and its hydrolyzed cousin ryanodol are biochemically interesting for their calcium-regulating capacity and chemically interesting for their dense tangle of carbon rings brimming with oxygen appendages. Chuang et al. report an efficient 15-step asymmetric synthesis of ryanodol from the structurally much simpler terpene pulegone (see the Perspective by Verdaguer). Key steps include a Pauson-Khand cyclization of a tethered alkene and alkyne with carbon monoxide to set the ring motifs, followed by an oxidation using selenium dioxide that delivers three different oxygen substituents in tandem.

Science, this issue p. 912; see also p. 866

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 SeO2-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.

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