A 15-step synthesis of (+)-ryanodol by Kangway V. Chuang, Chen Xu, and Sarah E. Reisman Science Volume 353(6302):912-915 August 26, 2016 Published by AAAS

Fig. 1 Ryanodine and selected ryanoids. 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. Kangway V. Chuang et al. Science 2016;353:912-915 Published by AAAS

Fig. 2 Complete synthetic sequence for the chemical synthesis of (+)-anhydroryanodol and (+)-ryanodol. 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. Kangway V. Chuang et al. Science 2016;353:912-915 Published by AAAS

Table 1 Evaluation of Pauson-Khand reaction conditions. Kangway V. Chuang et al. Science 2016;353:912-915 Published by AAAS

Fig. 3 Selenium dioxide-mediated A-ring oxidation. 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. Kangway V. Chuang et al. Science 2016;353:912-915 Published by AAAS