Supporting Information

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1 Supporting Information Wiley-VCH Weinheim, Germany Enantioselective Total Synthesis of ( )-Jiadifenolide** Jing Xu, Lynnie Trzoss, Weng K. Chang, and Emmanuel A. Theodorakis* anie_ _sm_miscellaneous_information.pdf

2 Supporting Information General Procedures. Unless indicated, all commercial available reagents and anhydrous solvents were purchased at the highest commercial quality and were used as received without further purification. All non-aqueous reactions were carried out under argon atmosphere using dry glassware that had been flame-dried under a stream of argon unless otherwise noted. Dry tetrahydrofuran (THF), diethyl ether (Et 2 ), methylene chloride (CH 2 Cl 2 ) and dimethylformamide (DMF) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Flash column chromatography was performed on silica gel (Merck Kieselgel 60, mesh) using hexane-etac or CH 2 Cl 2 -MeH mixtures of increasing polarity. The progress of all the reactions was monitored by thin-layer chromatography (TLC) using glass plates precoated with silica gel-60 F 254 to a thickness of 0.5 mm (Merck). 13 C NMR and 1 H NMR spectra were recorded on either 400 MHz/500 MHz Varian instrument or a 500 MHz JEL instrument. CDCl 3 was treated with flame dried K 2 C 3, chemical shifts (δ) are quoted in parts per million (ppm) referenced to the appropriate residual solvent peak (CHCl 3 or CD 3 D), with the abbreviations s, br s, d, t, q, and m denoting singlet, broad singlet, doublet, triplet, quartet and multiplet respectively. J = coupling constants given in Hertz (Hz). High resolution Mass spectra (HRMS) were recorded on a trisector WG AutoSpecQ spectrometer. ptical rotation data were collected on a Jasco P-1010 polarimeter using HPLC grade CHCl 3 (dried over molecular sieves) or anhydrous MeH. 1

3 13 Compound 13 was synthesized based on reported procedure with modification [1-3] : Allyl palladium chloride dimmer (1.69 g, 4.6 mmol) and 1,2-bis(diphenylphosphino)ethane (9.20 g, 23 mmol) were dissolved in anhydrous THF (1000 ml), then allyl acetate (50.0 ml, 0.46 mol), 1,3-cyclopentadione (12, 45.0 g, 0.46 mol), N,-bis (trimethylsilyl)acetamide (114 ml, 0.46 mol) and sodium acetate (1.10 g, 13.8 mmol) were added successively. This reaction was refluxed for 40 h before it was cooled to RT and quenched with MeH (500 ml). The solvents were removed on the rotavap, and the residue was dissolved in hot EtAc and crystallized to afford the crude product as yellow solid (43.0 g, 70%). A suspension of this yellow solid (43.0 g, 0.31 mol) and methyl vinyl ketone (53.8 ml, 0.62 mol) in a mixture of water (620 ml) and acetic acid (9.20 ml) was refluxed for 4 h. The resulting mixture was cooled down and extracted with EtAc (3 x 500 ml). The combined organic extracts were washed with saturated NaHC 3 solution, dried over Na 2 S 4 and concentrated under reduced pressure. Purification of the residue through column chromatography on silica gel (hexanes:etac = 10:1 to 3:1) afforded 13 (60.5 g, 90%, 63% for 2 steps). All the analytical data are in the agreement with the reported data. [1-3] 11 11: To a solution of 13 (36.0 g, 0.17 mol) in dry MeCN (600 ml) was added D-prolinamide (5.92 g, 52.0 mmol) and pyridinium p- toluenesulfonate (13.0 g, 52.0 mmol). This solution was warmed up to 40 ºC for 14 d before it was cooled to RT and quenched with water (300 ml). The mixture was extracted with EtAc (3 x 500 ml), dried over Na 2 S 4, concentrated and loaded on a short silica pad and washed thoroughly with EtAc and concentrated under reduced pressure to afford 11 as a yellow oil (22.0 g, 74%) in good purity and was used to next step directly. A pure sample of 11 was purified via silica flash column chromatography (hexanes:etac = 20:1 to 1.5:1) to afford a colorless oil. (ee > 90%); R f = 0.38 (silica gel, hexanes:etac = 2:1); [α] 23 D (c 1.00, CHCl 3 ); All the spectroscopic data are in the agreement with the reported data. [3] 1 H NMR (500 MHz, CDCl 3 ) δ 6.00 (br s, 1H), 5.72 (m, 1H), 5.14 (m, 2H), 2.93 (m, 1H), 2.79 (m, 1H), 2.66 (m, 1H), (m, 5H), 2.23 (m, 1H), 1.76 (m, 1H); 13 C NMR 2

4 (125 MHz, CDCl 3 ) δ 215.8, 198.2, 169.1, 131.8, 124.7, 119.8, 52.7, 39.0, 36.2, 32.6, 27.3, 27.3; HRMS (ESI) m/e [M+H + ] calcd for C 12 H : TBS 14 14: The enone 11 (21.0 g, 0.11 mol) was dissolved in absolute ethanol (220 ml), NaBH 4 (1.05 g, 27.6 mmol) was added portionwise at 0 ºC and the reaction was stirred for 30 min. Then this reaction was carefully quenched with saturated NH 4 Cl solution (100 ml) and the solvent was removed under reduced pressure. The mixture was extracted with EtAc (3 x 200 ml), dried over Na 2 S 4 and concentrated. The crude alcohol was then dissolved in dry DMF (220 ml) and was cooled to 0 ºC. To this solution NH 4 N 3 (26.4 g, 0.33 mol) was added followed by TBSCl (33.2 g, 0.22 mol). The reaction was then warmed up to RT for 12 h before it was quenched with saturated NH 4 Cl solution (100 ml). The mixture was extracted with EtAc (3 x 200 ml), dried over Na 2 S 4 and concentrated. The crude product was then purified by silica flash column chromatography (hexanes:etac = 100:1 to 10:1) to afford the product 14 as light yellow solid (31.1 g, 92% over 2 steps). R f = 0.67 (silica gel, hexanes:etac = 4:1); [α] 24 D 72.0 (c 0.76, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 6.01 (m, 1H), 5.82 (br s, 1H), 5.06 (d, J = 14.7 Hz, 1H), 4.99 (d, J = 7.4 Hz, 1H), 3.81 (t, J = 7.8 Hz, 1H), 2.64 (m, 1H), (m, 2H), 2.37 (m, 1H), (m, 3H), 2.00 (m, 1H), 1.84 (m, 1H), 1.69 (m, 1H), 0.91 (s, 9H), 0.06 (s, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 173.6, 136.2, 124.2, 117.0, 82.3, 48.8, 36.4, 33.5, 33.4, 30.0, 27.3, 26.0, 18.1, -4.5, -4.8; HRMS (ESI) m/e [M+H + ] calcd for C 18 H 31 2 Si + : TBS Et 15 15: To a solution of 14 (17.0 g, 55.5 mmol) in anhydrous DMF (110 ml) was added magnesium methyl carbonate (111 ml, 0.22 mol, 2.0 M in DMF). This solution was degassed for 5 min under argon, then immersed in an oil bath which was pre-heated to 130 ºC and stirred for 3 h. The reaction was cooled to 0 ºC and poured in to a mixture of ice/2n HCl (300 ml). Then this mixture was acidified to ph = 2~3 with 2N HCl. Ether (500 ml) was added to form a two-phase clear solution. The aqueous phase was separated and it was re-extracted with ether (2 x 500 ml). The combined 3

5 organic extracts were dried over Na 2 S 4 and concentrated under reduced pressure at 30 ºC. The residue was dried on high-vaccum pump for 1 h to remove the trace of DMF to afford a yellow solid. This solid was dissolved in dry CH 2 Cl 2 (100 ml), triethyloxonium tetrafluoroborate (50.0 ml, 50.0 mmol, 1M in CH 2 Cl 2 ) was added at 0 ºC, then DIPEA (13.1 ml, 75.0 mmol) was added dropwise. After 1 minute, TLC showed that the completion of this reaction. Then this reaction was quenched with saturated NH 4 Cl solution (100 ml), extracted with CH 2 Cl 2 (3 x 100 ml), washed with saturated NaHC 3 solution and brine, dried over Na 2 S 4 and concentrated under reduced pressure. The unstable crude product was passed through a short silica pad (hexanes:etac = 6:1, 2000 ml), concentrated and dried on high-vaccum pump and was used to next step directly. To a solution of this crude ester (20.0 g, ~ 55.5 mmol) in dry CH 2 Cl 2 (200 ml) was added 2,6-lutidine (13.1 ml, 111 mmol) at 0 ºC, followed by addition of TMSTf (13.0 ml, 72.0 mmol) dropwise. After 30 min, the reaction was diluted with hexanes (500 ml), quenched with 5% (not saturated!) NaHC 3 solution (200 ml), extracted with hexanes (3 x 300 ml), the combined organic extracts were dried over Na 2 S 4 and concentrated under reduced pressure. The residue was further dried on high-vacuum pump for 10 min (not longer!). The unstable crude TMS-enol ether was dissolved in dry THF (200 ml), cooled to -78 ºC, methyl iodide (17.0 ml, 0.27 mol) was added in, followed by addition of TBAF solution dropwise (55.5 ml, 55.5 mmol, 1M in THF). This reaction was then allowed to warm to RT slowly over 30 min, and stirred at RT for extra 2 h before it was quenched with saturated NH 4 Cl solution (100 ml). The mixture was extracted with EtAc (3 x 200 ml), the combined organic phase was washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (hexanes:etac = 100:1 to 10:1) to afford 15 as a yellow oil (9.33 g, 43% over 2 steps). R f = 0.70 (silica gel, hexanes:etac = 6:1); [α] 23 D 91.3 (c 1.40, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 5.99 (m, 1H), 5.72 (t, J = 2.3 Hz, 1H), 5.02 (d, J = 16.6 Hz, 1H), 4.96 (d, J = 10.3 Hz, 1H), 4.19 (m, 1H), 4.10 (m, 1H), 4.03 (t, J = 8.7 Hz, 1H), 2.81 (m, 1H), (m, 5H), 2.07 (m, 1H), 1.53 (m, 1H), 1.47 (s, 3H), 1.25 (t, J = 12.5 Hz, 3H), 0.90 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 208.0, 172.0, 145.4, 136.4, 125.9, 116.5, 82.9, 61.9, 58.9, 50.8, 39.8, 36.5, 36.2, 34.4, 26.0, 19.8, 18.2, 14.0, -4.4, -4.8; HRMS (ESI) m/e [M+H + ] calcd for C 22 H 37 4 Si + :

6 TBS TBS 16 16: To a solution of 15 (17 g, 43 mmol) in dry THF (200 ml) was added LiAlH 4 solution (165 ml, 0.32 mol, 2M in THF) at 0 ºC. This reaction was stirred for 30 min before it was carefully quenched with 2N NaH solution (200 ml). The mixture was taken with EtAc (200 ml) and filtrated through Celite and washed thoroughly with EtAc (1000 ml). The organic phase was separated and the aqueous phase was re-extracted with EtAc (2 x 200 ml). The combined organic extracts were washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. The crude diol was used to next step directly. The crude diol was dissolved in CH 2 Cl 2 (200 ml) and was cooled to 0 ºC. Imidazole (5.37 g, 80.0 mmol) was added in followed by the adding of TBS-Cl solution (6.78 g, 45.0 mmol) in CH 2 Cl 2 (20 ml) slowly. After 30 min, this reaction was quenched with saturated NH 4 Cl solution (200 ml), extracted with CH 2 Cl 2 (3 x 200 ml), washed with brine and dried over Na 2 S 4, then concentrated under reduced pressure. The crude mono-tbsether was used to next step directly. The crude mono-tbs-ether was dissolved in dry DMS (200 ml), IBX (33.6 g, 0.12 mol) was added in and this reaction was heated to 80 ºC for 1 h. Upon completion, the reaction was cooled to RT and water (200 ml) was added in and the reaction was filtered through Celite, the filtrates were extracted with EtAc (3 x 200 ml), The combined organic extracts were then washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. The obtained residue was purified via silica flash column chromatography (hexanes:etac = 100:1 to 20:1) to afford 16 as a white solid (17.4 g, 85% over 3 steps). R f = 0.32 (silica gel, hexanes:etac = 20:1); [α] 23 D 22.1 (c 0.82, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 6.04 (m, 1H), 5.51 (br s, 1H), 5.04 (d, J = 18.4 Hz, 1H), 4.95 (d, J = 10.3 Hz, 1H), 4.01 (t, J = 8.6 Hz, 1H), 3.73 (d, J = 9.7 Hz, 1H), 3.65 (d, J = 9.7 Hz, 1H), (m, 3H), 2.32 (m, 3H), 2.00 (m, 1H), 1.17 (s, 3H), 1.16 (m, 1H), 0.91 (s, 9H), 0.85 (s, 9H), 0.05 (s, 6H), 0.01 (s, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 213.3, 149.0, 136.9, 123.7, 116.3, 83.3, 69.6, 55.1, 50.4, 39.7, 36.4, 35.8, 34.0, 26.0, 25.9, 20.7, 18.5, 18.2, -4.5, -4.7, -5.4, -5.4; HRMS (ESI) m/e [M+H + ] calcd for C 26 H 49 3 Si + 2 :

7 TBS 10 10: To a solution of ketone 16 (10.5 g, 22.6 mmol) in dry THF (200 ml) was added in KHMDS (226 ml, 113 mmol, 0.5 M in Toluene) dropwise at 78 ºC and stirred for 30 min. A solution of PhNTf 2 (24.2 g, 67.8 mmol) in THF (50 ml) was added in and the reaction was stirred for 30 min at the same temperature before it was warmed up to RT over 30 min. The reaction was quenched with saturated NH 4 Cl solution (100 ml) and extracted with EtAc (3 x 200 ml). The combined organic phase was washed with brine and dried over Na 2 S 4, concentrated under reduced pressure and purified via silica flash column chromatography (hexanes:etac = 100:1) to afford the vinyl triflate as a white solid (11.5 g, 86%). The vinyl triflate obtained above (11.5 g, 19.4 mmol) was dissolved in DMF/MeH (150 ml/50 ml, 3:1), Pd(PPh 3 ) 4 (224 mg, 0.19 mmol) and triethylamine (8.10 ml, 58.1 mmol) was added. This orange solution was degassed under argon atmosphere for 5 min, followed by bubbling in carbon monoxide for 5 min. This solution was then heated to 50 ºC for 2 h under carbon monoxide atmosphere before it was concentrated under reduced pressure. The residue was passed through a short silica pad (hexanes:etac = 50:1, 2000 ml), concentrated and re-dissolved in dry CH 2 Cl 2 (200 ml), TFA (2.94 ml, 38.4 mmol) was added in and this reaction was stirred at RT for 5 h before it was quenched with saturated NaHC 3 solution (50 ml). The mixture was extracted with CH 2 Cl 2 (3 x 100 ml), the combined organic phase was washed with brine and dried over Na 2 S 4, concentrated under reduced pressure and purified via silica flash column chromatography (hexanes:etac = 100:1 to 10:1) to afford the lactone 10 as a white solid (5.62 g, 80%; 69% over two steps). R f = 0.20 (silica gel, hexanes:etac = 20:1); [α] 23 D 1.8 (c 0.49, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 6.90 (dd, J = 7.9 Hz, 3.0 Hz, 1H), 5.86 (m, 1H), 5.64 (br s, 1H), 4.90 (d, J = 13.2 Hz, 1H), 4.87 (d, J = 19.1 Hz, 1H), 4.13 (d, J = 8.3 Hz, 1H), 4.10 (t, J = 9.8 Hz, 1H), 3.99 (d, J = 8.3 Hz, 1H), 2.56 (dd, J = 15.6 Hz, 7.8 Hz, 1H), 2.47 (m, 1H), 2.36 (m, 1H), 2.19 (m, 2H), 1.95 (dd, J = 16.1 Hz, 3.0 Hz, 1H), 1.32 (s, 3H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 169.7, 147.8, 136.6, 135.0, 134.7, 124.3, 116.6, 82.5, 76.3, 54.8, 41.7, 40.1, 37.0, 35.8, 27.5, 25.9, 18.2, -4.4, -4.7; HRMS (ESI) m/e [M+H + ] calcd for C 21 H 33 3 Si + :

8 TBS 17 17: To a solution of 10 (4.70 g, 13.0 mmol) in MeH (100 ml) was added a pre-mixed solution of 3N NaH (13 ml) and 30% H 2 2 (13 ml) dropwise at 0 ºC. This reaction was warmed up to RT and vigorous stirred for 5 h. The mixture was then diluted with water, acidified with 2N HCl to ph = 1, separated with EtAc/brine (200ml/200ml) and the aqueous phase was extracted with EtAc (2 x 200 ml). The organic phase was combined, dried over Na 2 S 4 and concentrate under reduced pressure to afford 17 (4.86 g, 99%) as a white solid. The obtained epoxide 17 was pure enough to use without further purification. R f = 0.18 (silica gel, hexanes:etac = 20:1); [α] 22 D (c 0.92, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 5.86 (m, 1H), 5.70 (m, 1H), 5.03 (m, 2H), 4.34 (d, J = 8.8 Hz, 1H), 4.17 (d, J = 9.3 Hz, 1H), 3.94 (t, J = 9.8 Hz, 1H), 3.61 (dd, J = 6.3 Hz, 2.4 Hz, 1H), (m, 3H), (m, 2H), 1.39 (m, 1H), 1.38 (s, 3H), 0.91 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 173.2, 143.3, 135.8, 126.3, 117.7, 82.1, 75.6, 61.4, 58.5, 52.5, 40.6, 39.0, 38.2, 37.5, 26.0, 21.8, 18.2, -4.3, -4.7; HRMS (ESI) m/e [M+Na + ] calcd for C 21 H 32 4 SiNa + : TBS 9 H 9: 17 (6.25 g, 16.6 mmol) was dissolved in 1,4-dioxane (180 ml) and water (60 ml). To this solution 2,6-lutidine (3.84 ml, 33.2 mmol), s 4 (1.05 ml, 4% solution in H 2, mmol) was added, then NaI 4 (14.4 g, 66.4 mmol) was added portionwise at 0 ºC. This reaction was then warmed up to RT and stirred for 12 h. The reaction was diluted with water (200 ml) and extracted with CH 2 Cl 2 (3 x 200 ml). The organic phase was dried over Na 2 S 4 and concentrated under reduced pressure to afford the aldehyde as a white solid, which was clean enough to be used for next reaction. To a solution of the aldehyde obtained above (~ 6.2 g, 16.4 mmol) in acetone (400 ml) was added Jones reagent (37.0 ml, 98.4 mmol, 2.67 M) dropwise at 0 ºC, and this reaction was stirred at 0 ºC for 30 min. Ethanol (50 ml) was carefully dropped in to quench this reaction, followed by dropping the saturated NaHC 3 solution (50 ml). The mixture was stirred for 5 min before it was filtrated through Celite, and the filter cake 7

9 was then washed thoroughly with EtAc (1000 ml). The combined organic extracts were dried over Na 2 S 4 and concentrated under reduced pressure. The crude residue was purified via column chromatography (hexanes:ch 2 Cl 2 = 1:1 to 1:3 to 100% CH 2 Cl 2, then CH 2 Cl 2 :MeH = 200:1 to 50:1) afford the product 9 as a white solid (4.58 g, 70% over 2 steps). R f = 0.48 (silica gel, hexanes:etac = 2:1); [α] 22 D 2.6 (c 0.58, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 5.78 (m, 1H), 4.65 (dd, J = 4.4 Hz, 1.5 Hz, 1H), 4.06 (t, J = 7.8 Hz, 1H), 3.97 (d, J = 9.8 Hz, 1H), 3.85 (d, J = 9.8 Hz, 1H), 3.02 (d, J = 19.1 Hz, 1H), (m, 2H), 2.20 (m, 1H), 2.07 (m, 1H), 1.94 (m, 1H), 1.32 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 177.6, 170.2, 144.1, 126.5, 79.3, 79.3, 76.8, 76.3, 45.4, 42.5, 37.6, 36.7, 29.6, 25.9, 21.6, 18.1, -4.3, -4.7; HRMS (ESI) m/e [M+H + ] calcd for C 20 H 31 6 Si + : H H 18 18: To a solution of 9 (3.95 g, 10.0 mmol) in THF (100 ml) was added TBAF solution (20.0 ml, 20.0 mmol, 1 M in THF) dropwise at RT, then this reaction was stirred at RT for 30 min. ph = 7 buffer solution (20 ml) was added to quench this reaction, and the mixture was diluted with EtAc (1000 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (CH 2 Cl 2 :MeH = 100:1 to 20:1) afford the product 18 as a white foam (2.66 g, 95%). R f = 0.70 (silica gel, CH 2 Cl 2 :MeH = 5:1); [α] 23 D 38.1 (c 0.67, MeH); 1 H NMR (500 MHz, CD 3 D) δ 5.85 (m, 1H), 4.70 (dd, J = 4.6 Hz, 1.7 Hz, 1H), 4.02 (t, J = 7.9 Hz, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.72 (d, J = 9.7 Hz, 1H), 2.95 (d, J = 18.9 Hz, 1H), (m, 2H), (m, 2H), 1.91 (m, 1H), 1.29 (s, 3H); 13 C NMR (125 MHz, CD 3 D) δ 177.4, 171.4, 144.6, 126.1, 79.7, 78.3, 76.6, 75.3, 44.8, 42.2, 36.1, 36.0, 29.0, 20.5; HRMS (ESI) m/e [M+H + ] calcd for C 14 H : H 8: To a solution of 18 (870 mg, 3.10 mmol) in THF (30 ml) was added mcpba (3.20 g, 13 mmol, ~ 70%) portionwise and warmed 8 H up to 50 ºC for 3 h. This mixture was then cooled to RT and quenched with saturated NaHC 3 solution/saturated Na 2 S 2 3 solution (10ml/10ml). Then the mixture was diluted with EtAc 8

10 (500 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The afforded crude epoxide was used to next step directly. This crude epoxide (~ 3 mmol) was diluted with acetone (30 ml), sonicated for 10 min, and the Dess-Martin-Periodinane (2.54 g, 6 mmol) was added. This reaction was stirred vigorously (sonication was applied in larger scale) at RT for 2 h and quenched with saturated NaHC 3 solution/saturated Na 2 S 2 3 solution (10ml/10ml). Then the mixture was diluted with EtAc (500 ml), dried over Na 2 S 4 and concentrated under reduced pressure to afford the crude product, which was purified via silica flash column chromatography (CH 2 Cl 2 :MeH = 100:1 to 20:1) afford the product 8 as a white solid (346 mg, 38%). R f = 0.50 (silica gel, CH 2 Cl 2 :MeH = 20:1 x 2 times); [α] 23 D 13.1 (c 0.40, MeH); 1 H NMR (500 MHz, CD 3 D) δ 7.96 (d, J = 5.9 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.49 (d, J = 9.8 Hz, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.69 (dd, J = 9.8 Hz, 3.9 Hz, 1H), 3.21 (d, J = 19.0 Hz, 1H), 2.86 (d, J = 19.1 Hz, 1H), 2.20 (m, 1H), 2.10 (m, 1H), 1.41 (s, 3H); 13 C NMR (125 MHz, CD 3 D) δ 209.1, 177.5, 174.8, 160.5, 136.2, 93.3, 80.1, 74.9, 72.9, 52.1, 49.5, 39.8, 34.1, 19.4; HRMS (ESI) m/e [M+Na + ] calcd for C 14 H 14 7 Na + : : A pressure glass reactor was filled with 8 (294 mg, 1.00 mmol), MeH (5 ml) and palladium (53.0 mg, 5 mol%, 10% on charcoal), TES then this reactor was loaded on a shaking-hydrogenator and was H shaken under hydrogen atmosphere (6 bar) at RT for 24 h. The pressure was released slowly and the mixture was filtered through a 19 short silica pad. The filter pad was washed with MeH (5 x 20 ml), and the combined filtrates were concentrated to afford the corresponding reduced ketone, then it was dissolved in THF (5 ml), 2,6-lutidine (463 µl, 4.00 mmol) was added followed by TESTf (452 µl, 2.00 mmol) at 0 ºC. This reaction was then allowed to warm up to RT and stirred for 30 min before it was quenched with saturated NaHC 3 solution (5 ml). This mixture was diluted with EtAc (200 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (CH 2 Cl 2 :MeH = 200:1 to 50:1) afford the product 19 as a colorless oil (369 mg, 90%). R f = 0.85 (silica gel, CH 2 Cl 2 :MeH = 20:1); [α] 23 D 8.5 (c 1.32, MeH); 1 H NMR (500 9

11 MHz, CD 3 D) δ 4.36 (d, J = 9.8 Hz, 1H), 4.10 (m, 1H), 3.90 (d, J = 8.6 Hz, 1H), 3.51 (d, J = 18.9 Hz, 1H), 2.75 (d, J = 18.9 Hz, 1H), (m, 3H), 2.25 (m, 1H), 1.95 (dd, J = 15.5 Hz, 3.5 Hz, 1H), 1.81 (dd, J = 14.9 Hz, 2.9 Hz, 1H), 1.33 (s, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.65 (q, J = 8.6 Hz, 6H); 13 C NMR (125 MHz, CD 3 D) δ 217.9, 177.6, 174.2, 93.1, 79.3, 72.8, 72.2, 53.6, 47.4, 37.4, 32.8, 28.2, 27.3, 17.2, 5.8, 4.1; HRMS (ESI) m/e [M+Na + ] calcd for C 20 H 30 7 SiNa + : : To a solution of 19 (41.0 mg, 0.10 mmol) in dry THF (600 µl) was added KHMDS (150 µl, 0.15 mmol, 1 M in THF) at 78 ºC and TES H stirred for 30 min, then a solution of Comins reagent (N-(5-chloro- 2-pyridyl)triflimide, 34.2 mg, 0.11 mmol) in THF (200 µl) was added in dropwise and stirred for another 30 min at 78 ºC before it 7 was warmed up to RT and stirred for another 30 min. This reaction was then quenched with saturated NH 4 Cl solution (500 µl), diluted with EtAc (100 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (hexanes:etac = 50:1 to 4:1) to afford the corresponding vinyl triflate as light colorless oil (34.7 mg, 64%). This vinyl triflate (34.7 mg, mmol) was then dissolved in dry THF (300 µl), Pd(PPh 3 ) 4 (37.0 mg, mmol) was added in, followed by a solution of AlMe 3 (640 µl, 1.28 mmol, 2M in hexanes). This reaction was stirred at RT for 2 h before it was carefully quenched with saturated NaHC 3 solution (500 µl). This mixture was diluted with EtAc (100 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (hexanes:etac = 50:1 to 4:1) to afford the 7 as light colorless oil (23.3 mg, 89%; 57% over 2 steps). R f = 0.37 (silica gel, hexanes:etac = 3:1); [α] 23 D (c 1.40, MeH); 1 H NMR (500 MHz, CD 3 D) δ 5.37 (br s, 1H), 4.38 (d, J = 8.6 Hz, 1H), 3.94 (dd, J = 6.9 Hz, 3.5 Hz, 1H), 3.88 (d, J = 9.2 Hz, 1H), 3.23 (d, J = 18.9 Hz, 1H), 2.74 (m, 1H), 2.70 (d, J = 18.9 Hz, 1H), 2.55 (d, J = 17.8 Hz, 1H), 2.07 (dd, J = 14.9 Hz, 6.9 Hz, 1H), 1.78 (dd, J = 14.9 Hz, 3.4 Hz, 1H), 1.69 (br s, 3H), 1.28 (s, 3H), 0.97 (t, J = 8.1 Hz, 9H), 0.64 (q, J = 7.5 Hz, 6H); 13 C NMR (125 MHz, CD 3 D) δ 177.0, 175.8, 142.6, 121.1, 96.0, 79.6, 73.3, 72.8, 54.3, 47.8, 40.8, 37.4, 32.9, 18.1, 10.7, 5.8, 4.2; HRMS (ESI) m/e [M+Na + ] calcd for C 21 H 32 6 SiNa + :

12 H 1 (( )-jiadifenolide): A high pressure steel autoclave equipped with magnetic stir bar was filled with olefin 7 (20.0 mg, mmol), H platinum dioxide (2.2 mg, 9.8 µmol) and MeH (2.0 ml). The autoclave was pressurized to 90 atm with H 2 and the suspension was vigorously stirred at RT for 24 h. The pressure was released slowly 1: jiadifenolide and the mixture was filtered through a short silica pad. The filter pad was washed with MeH (5 x 10 ml), and the combined filtrates were concentrated to afford the crude reduced product with some inseparable impurities. This crude mixture (~ 20 mg, ~ mmol) was then dissolved in dry THF (300 µl) and cooled to 78 ºC, to this solution was added NaHMDS (196 µl, mmol) dropwise and stirred for 15 min, then a solution of (±)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine (64.0 mg, mmol) in THF (100 µl) was added in dropwise and stirred for 30 min before it was warmed up slowly to RT. Then this reaction was quenched with saturated NH 4 Cl solution (1 ml) and diluted with EtAc (200 ml), dried over Na 2 S 4 and concentrated under reduced pressure. Purification via silica flash column chromatography (hexanes:etac = 40:1 to 5:1) afforded the α-hydroxyl lactone 20 (~ 10 mg) with trace of inseparable impurities. This α-hydroxyl lactone 20 (~ 10 mg, ~ mmol) was dissolved in acetone (1 ml) then was added Jones reagent (44 µl, mmol, 2.67 M) at 0 ºC, stirred for 15 min and carefully quenched with MeH (100 µl) followed by saturated NaHC 3 solution (100 µl). This mixture was diluted with EtAc (100 ml), dried over Na 2 S 4 and concentrated under reduced pressure. The residue was purified via silica flash column chromatography (CH 2 Cl 2 :MeH = 200:1 to 20:1) to afford ( )-jiadifenolide (1) as small white crystals (5.10 mg, 33% over 3 steps). R f = 0.23 (silica gel, CH 2 Cl 2 :MeH = 20:1); [α] 23 D 73.7 (c 0.38, MeH); (Reported value for natural 1: [α] 23 D 56.8 (c 1.14, MeH). [4] The optical rotation difference between natural 1 and synthetic 1 is probably due to the different measuring concentrations.) 1 H NMR (500 MHz, CD 3 D) δ 4.61 (d, J = 9.2 Hz, 1H), 4.42 (d, J = 6.3 Hz, 1H), 3.80 (d, J = 9.8 Hz, 1H), 2.47 (dd, J = 13.2 Hz, 5.8 Hz, 1H), 2.22 (m, 1H), 2.09 (d, J = 13.2 Hz, 1H), 2.08 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H), 1.29 (m, 1H), 1.23 (s, 3H), 1.21 (d, J = 7.6 Hz, 3H); 13 C NMR (125 MHz, CD 3 D) δ 178.3, 173.6, 101.9, 97.4, 79.1, 77.6, 74.6, 58.8, 48.1, 41.6, 35.2, 33.0, 32.1, 19.9, 14.7; HRMS (ESI) m/e [M+Na + ] calcd for C 15 H 18 7 Na + :

13 References: [1] P. K. Ruprah, J.-P. Cros, J. E. Pease, W. G. Whittingham, J. M. J. Williams, Eur. J. rg. Chem. 2002, [2] E. Lacoste, E. Vaique, M. Berlande, I. Pianet, J. M. Vincent, Y. Landais, Eur. J. rg. Chem. 2007, [3] X.-M. Zhang, M. Wang, Y.-Q. Tu, C.-A. Fan, Y.-J. Jiang, S.-Y. Zhang, F.-M. Zhang, Synlett 2008, [4] M. Kubo, C. kada, J.-M. Huang, K. Harada, H. Hioki, Y. Fukuyama, rg. Lett. 2009, 11,

14 Table 1. 1 H NMR and 13 C NMR datum comparison of synthetic 1 with natural ( )- jiadifenolide (data reported in ref. 4). Position 1 2α 2β 3α 3β δ 1 H (natural) (CD 3 D, 600MHz) 2.21 (qdd, 12.3, 12.3, 7.1) 1.27 (dddd, 12.3, 12.3, 12.3, 6.0) 1.88 (brdddd, 12.3, 12.3, 12.3, 4.1) 2.08 (ddd, 12.9, 12.3, 6.0) 2.00 (brdd, 12.9, 4.1) δ 1 H (synthetic) (CD 3 D, 500MHz) Δ δ 13 C (natural) δ 13 C (synthetic) 2.22 (m) (m) (m) (m) (m) (d, 5.8) 4.42 (d, 6.3) α 2.09 (d, 12.9) 2.09 (d, 13.2) (dd, 12.9, 2.47 (dd, 13.2, 8β ) 5.8) (s, 3H) 1.23 (s, 3H) α 3.79 (d, 9.3) 3.80 (d, 9.8) β 4.60 (d, 9.3) 4.61 (d, 9.2) H (d, 7.1, 3H) 1.21 (d, 7.6, 3H) H 1: jiadifenolide Δ 13

15 11 14

16 11 15

17 11 16

18 TBS 14 17

19 TBS 14 18

20 TBS 15 Et 19

21 TBS 15 Et 20

22 TBS 16 TBS 21

23 TBS 16 TBS 22

24 TBS 10 23

25 TBS 10 24

26 TBS 17 25

27 TBS 17 26

28 TBS 9 H 27

29 TBS 9 H 28

30 TBS 9 H 29

31 H 18 H 30

32 H 18 H 31

33 8 H H 32

34 8 H H 33

35 8 H H 34

36 19 TES H 35

37 19 TES H 36

38 19 TES H 37

39 7 TES H 38

40 7 TES H 39

41 7 TES H 40

42 H H 1: jiadifenolide 41

43 H H 1: jiadifenolide 42

44 H H 1: jiadifenolide 43

45 H H 1: jiadifenolide 44