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 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.

Fig. 1. Ryanodine and selected ryanoids

(A) Chemical structures of (+)-ryanodine (1), (+)-ryanodol (2), (+)-anhydroryanodol (3), (+)-3-epi-ryanodol (4), and (+)-3-epi-ryanodine (5). (B) Carbon numbering and ring system letter assignment. (C) Retrosynthetic analysis of anhydroryanodol.

Fig. 2. Complete synthetic sequence for the chemical synthesis of (+)-anhydroryanodol and (+)-ryanodol

Reagents and conditions as follows: 1. potassium hexamethyldisilazide (2.5 equiv), THF −78 °C; then 11 (2.4 equiv), 42-50% yield. 2. benzyl chloromethyl ether (5.0 equiv), ⁱPr₂NEt (8.0 equiv), ⁿBu₄NI (2.0 equiv), CH₂Cl₂, 50 °C, 65% yield. 3. Propynylmagnesium bromide, THF, 0 °C, 81% yield, 5:1 dr. 4. O₃,/O₂, CH₂Cl₂/MeOH (4:1), −78 °C; then PPh₃, 91% yield. 5. Ethoxyethynylmagnesium bromide (5.0 equiv), THF, 0 °C, 75% yield. 6. AgOTf (2 mol %), PhMe, 0 °C, 90% yield. 7. CuI (3.0 equiv), vinylmagnesium bromide (6.0 equiv), THF, −78 to −30 °C, 84% yield. 8. [RhCl(CO)₂]₂ (1 mol %), CO (1 atm), m-xylene, 110 °C, 85% yield. 9. SeO₂ (10 equiv), 4Å MS, 1,4-dioxane, 110 °C. 10. Comins' reagent, ⁱPr₂NEt, CH₂Cl₂, −78 to 0 °C, 28% yield, 2-steps. 11. PdCl₂(PPh₃)₂, tributyl(prop-1-en-2-yl)stannane, LiCl, 2-MeTHF, 85 °C, 64% yield. 12. LiBH₄, THF, −15 to −10 °C; then KHF₂/MeOH. 13. H₂, Pd(OH)₂/C, EtOH, 61% yield, 2-steps. 14. Trifluoroacetic anhydride, urea hydrogen peroxide, Na₂HPO₄, 86% yield. 15. Li⁰ wire, NH₃/THF, −78 °C, 38% yield.

Fig. 3. Selenium dioxide-mediated A-ring oxidation

In the presence of water, SeO₂-mediated oxidation of enone 17 provides 21. In the absence of water, further oxidation occurs to deliver 18.