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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
  • 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 to 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.), 4 Å MS, 1,4-dioxane, 110°C. 10. Comins’ reagent, iPr2NEt, CH2Cl2, –78° to 0°C, 28% yield, two 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, two 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.

  • *Reactions conducted on 0.2 mmol scale. THF, tetrahydrofuran; DMSO, dimethylsulfoxide; NMO, N-methylmorpholine N-oxide; DMF, N,N-dimethylformamide. †Determined by 1H-NMR spectroscopy. ‡Isolated yield after purification by silica gel chromatography.

    Supplementary Materials

    • A 15-step synthesis of (+)-ryanodol

      Kangway V. Chuang, Chen Xu, Sarah E. Reisman

      Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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      • Materials and Methods
      • Schemes S1 and S2
      • Tables S1 to S9
      • NMR Spectra
      • Full reference list

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