Supplementary Information. 1. General Experimental procedures for (+)-omphadiol Comparison table of (+)-omphadiol 11-12

Transcription

1 Synthesis of (+)-Omphadiol and (+)-Pyxidatol C Gowrisankar Parthasarathy, Ulrike Eggert, and Markus Kalesse* Institute for Organic Chemistry and Centre for Biomolecular Drug Research, Leibniz Universität Hannover, Schneiderberg 1B, Hannover, Germany Markus.Kalesse@oci.uni-hannover.de Supplementary Information CONTENTS: Page 1. General Experimental procedures for (+)-omphadiol Comparison table of (+)-omphadiol References Experimental procedures for (+)-pyxidatol C Comparison table of (+)-pyxidatol C References Spectroscopic data of (+)-omphadiol Spectroscopic data of (+)-pyxidatol C 35-45

2 Experimental section General: Unless otherwise indicated, all reactions were carried out under a positive pressure of nitrogen and with ovendried glassware using standard Schlenk techniques. Infrared spectra (IR) were recorded on a Perkin-Elmer FT- IR SPECTRUM ONE spectrometer (diamond ATR Golder Gate sampling). Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on Bruker AMX 300 or 400. Chemical shifts are reported in parts per million (ppm) relative to internal standard (tetramethylsilane, δ H = 0.00; CDCl 3, δ H = 7.26; acetone- d6, δ H = 2.05 and C 6 D 6, δ H = 7.16). Data are presented as follows: chemical shift (δ, ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broad), coupling constant (reported in Hz), assignment. Carbon magnetic resonance ( 13 C NMR) spectra were recorded on Bruker AMX 300 or 400. Chemical shifts are reported in parts per million (ppm) relative to internal standard (tetramethylsilane, δ C = 0.00; CDCl 3, δ C = 77.00). Electron impact (EI) mass spectra were obtained using Varian CH-4 or SM-1 instruments operating at 40 ev and electrospray (ESI) spectra using an Applied Biosystems API 150EX LC/MS system. Product purification by flash column chromatography was performed using Brunschwig silica gel 60 Å (32-63 mesh). Analytical thin layer chromatography (TLC) was carried out using Merck commercial aluminium sheets coated (0.2 mm layer thickness) with Kieselgel 60 F 254, with visualization by ultraviolet. THF was freshly distilled from Na. CH 2 Cl 2 was freshly distilled from CaH 2. Diethyl ether, n-hexane, toluene were purified on Al 2 O 3 columns. Diisopropylamine was distilled over sodium hydride prior to use. Cyclohexane and ethyl acetate for flash chromatography are used without further purification. 2

3 3-Hydroxy-2,2-dimethylpropyl pivalate (A) To a solution of 2,2-methyl-propane-1,3-diol (2.5 g, mmol) in CH 2 Cl 2 (125 ml) at room temperature was added triethylamine (5 ml, mmol) and pivaloyl chloride (3.1 ml, mmol) at room temperature. The resultant mixture was stirred at room temperature for overnight and quenched with brine. The layers were separated and the organic layer was dried (Na 2 SO 4 ), concentrated under vacuum and silica gel flash chromatography (hexanes/ether, 3:1) to give 3-hydroxy-2,2-dimethylpropyl pivalate A (3.6 g, 80%) as a colorless oil. 1 H NMR (200 MHz, CDCl 3 ) δ 3.90 (s, 2H), 3.26 (s, 2H), 1.20 (s, 9H), 0.91 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 179.2, 69.1, 68.1, 38.9, 36.6, 27.2, ,2-Dimethyl-3-oxopropyl pivalate (10) To a solution of oxalyl chloride (2.0 ml, mmol) in CH 2 Cl 2 (40 ml) was added DMSO (2.6 ml, mmol) at 78 o C over a period of 5 mins. After 15 min, a solution of alcohol A (3.0 g, mmol) in CH 2 Cl 2 (15 ml) was added into the above reaction mixture at 78 o C and allowed to stir for additional 1 h and quenched with NEt 3 (11.10 ml, 79.8 mmol) at 78 o C. The turbid solution was allowed to attain room temperature over a period of 1 h. The reaction mixture was diluted with water (50 ml) and extracted with diethyl ether (2x20 ml) followed by brine (20 ml) then dried over (Na 2 SO 4 ). The obtained crude aldehyde 10 was purified by flash chromatography (hexanes/ethyl acetate 5:1) to yield pure compound 10 (2.6 g, 82%). 1 H NMR (200 MHz, CDCl 3 ) δ 9.53 (s, 1H), 4.09 (s, 2H), 1.17 (s, 9H), 1.11 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 203.4, 178.0, 67.7, 46.5, 38.8, 27.0, (R)-3-hydroxy-2,2-dimethyl-3-((2S,3S,3aS,4S,7R,7aS)-1-oxo-3-(prop-1-en-2-yl)-2,3,3a,4,7,7a-hexahydro- 1H-4,7-methanoinden-2-yl)propyl pivalate tert-buli (28.8 ml, 1.6 M in pentane, 46.1 mmol) was added to a solution of 2-bromopropene (2 ml, 21.9 mmol) in anhydrous ether (120 ml) at 78 o C. The resultant solution was stirred at 78 o C for 30 min. and then warmed to 0 o C for 30 min. The above prepared solution was transferred into a suspension of CuI (2.1g,

4 mmol) in ether (10 ml) at 78 o C and warmed to rt for 10 min. The resultant black mixture was cooled to 78 o C and treated with a solution of (-)-KDP enone 9 (1.6 g, mmol) in ether (2 ml). The resultant brown mixture was warmed to 40 o C for 2 h and then aldehyde A (3,3 g, mmol) was added at 78 o C and stirred at 30 o C for 2h, then at 15 o C for another 1 h. The reaction was quenched with a saturated aqueous NH 4 Cl solution (10 ml) at 78 o C and the aqueous layer was extracted with ether (3x20 ml). The combined ether layers were washed with a saturated aqueous NaCl solution and dried over Na 2 SO 4. Silica gel flash chromatography to afford a pure aldol 11 as white solid (3.64 g, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 6.23 (dd, J = 5.7, 2.9 Hz, 1H), 6.15 (dd, J = 5.7, 3.0 Hz, 1H), (m, 1H), 4.83 (s, 1H), 3.96 (d, J = 10.9 Hz, 1H), 3.80 (d, J = 10.9 Hz, 1H), 3.24 (d, J = 1.1 Hz, 2H), 3.14 (bs, 1H), 3.05 (ddd, J = 10.8, 4.3, 2.3 Hz, 1H), 2.99 (bs, 1H), (m, 1H), 2.71 (dd, J = 13.0, 2.4 Hz, 1H), 2.41 (dd, J = 13.0, 8.1 Hz, 1H), 1.80 (s, 3H), 1.65 (dt, J = 8.3, 1.7 Hz, 1H), 1.46 (d, J = 8.4 Hz, 1H), 1.18 (s, 9H), 0.88 (s, 3H), 0.86 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 217.5, 178.2, 144.3, 137.1, 135.5, 113.8, 74.2, 69.9, 54.9, 54.9, 52.4, 51.6, 45.3, 44.0, 43.6, 39.0, 38.9, 27.2, 22.2, 20.6, 18.6; IR (ATR, neat) ν max 3528, 2964, 1720, 1479, 1285, 1174, 883 cm -1 ; HRMS (ESI-TOF): calcd. for C 23 H 35 O 4 (M+1) + m/z found m/z [α] 20 D (c 0.81, CHCl 3 ). (E)-2,2-dimethyl-3-((3R,3aS,4S,7R,7aS)-1-oxo-3-(prop-1-en-2-yl)-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoinden-2-ylidene)propyl pivalate To a solution of Keto1 11 (3.5 g, 9.36 mmol) in THF (320 ml) was added methyl chlorosulfonate (2.2 ml, mmol) and DMAP (5.71 g, 46.8 mmol) at room temperature. The resultant white suspension was heated to reflux for 4 days and concentrated in vacuo to remove the volatiles. The reaction mixture was diluted with water (15 ml) and extracted with diethyl ether (150 ml). The combined organic layer was washed with water (10 ml), brine (10 ml), dried over Na 2 SO 4, and concentrated. The obtained crude product was purified by chromatography on silica gel (hexanes/etoac, 5:1) to afford 3.1 g (93%) of enone 12 as white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 6.40 (d, J = 2.1 Hz, 1H), 6.00 (dd, J = 5.6, 2.9 Hz, 1H), 5.95 (dd, J = 5.6, 2.9 Hz, 1H), (m, 1H), 4.59 (d, J = 0.7 Hz, 1H), 3.89 (d, J = 10.6 Hz, 1H), 3.86 (d, J = 10.6 Hz, 1H), (m, 1H), 3.16 (s, 1H), 3.08 (bs, 1H), 2.95 (dd, J = 8.8, 4.8 Hz, 1H), 2.58 (ddd, J = 8.8, 4.1, 1.6 Hz, 1H), 1.75 (s, 3H), 1.50 (dt, J = 8.3, 1.7 Hz, 1H), 1.41 (d, J = 8.4 Hz, 1H), 1.19 (s, 9H), 1.12 (s, 3H), 1.04 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 209.5, 178.3, 149.5, 143.5, 140.3, 136.3, 133.0, 110.7, 71.9, 52.1, 51.4, 48.2, 47.6, 47.6, 45.6, 38.9, 37.5, 27.2, 23.6, 23.3, 21.3; IR (ATR, neat) ν max 2979, 2926, 1727, 1708, 1627, 1365, 4

5 1291, 1234, 1173, 889 cm -1 ; HRMS (ESI-TOF): calcd. for C 23 H 32 O 3 Na (M+Na) + m/z found m/z ; [α] 20 D (c 1.04, CHCl 3 ). (2R,3S,3aS,4S,7R,7aS)-2-(3-hydroxy-2,2-dimethylpropyl)-3-(prop-1-en-2-yl)-2,3,3a,4,7,7a-hexahydro-1H- 4,7-methanoinden-1-one Lithium metal pieces (250 mg, 35.4 mmol) were added to an anhydrous liquid NH 3 (about 150 ml) at -78 o C under nitrogen atmosphere. The resultant blue solution was treated with a solution of 12 (1.6 g, 5.06 mmol) in THF (100 ml) at 78 o C. The reaction mixture was allowed to stir for 1 h at 78 o C, then quenched with tert. BuOH (50 ml) followed by MeOH (10 ml) at the same temperature, then allowed to attain room temperature. The excess NH 3 was evaporated under the stream of nitrogen flow and allowed to stir at room temperature for another 2h. The resultant white suspension was treated with neat methyl salicylate (4.5 ml, 35.4 mmol) and allowed to stir for 30 mins at the same temperature. The reaction was diluted with saturated aqueous NH 4 Cl (20 ml) and extracted with EtOAc (3 X 40 ml). The combined organic layers were dried Na 2 SO 4 and concentration in vacuo gave crude 14. Flash chromatography on silica gel (hexanes:etoac, 4:1) to afford 960 mg (80 %) of hydroxylketone 14 as single diastereomer. 1 H NMR (400 MHz, CDCl 3 ) δ 6.22 (dd, J = 5.7, 2.5 Hz, 1H), 6.08 (dd, J = 5.8, 3.0 Hz, 1H), (m, 1H), 4.78 (s, 1H), 4.12 (dd, J = 10.3, 4.6 Hz, 1H), (m, 3H), (m, 1H), 2.98 (bs, 1H), (m, 1H), (m, 1H), (m, 1H), 1.82 (s, 3H), (m, 2H), 1.49 (d, J = 8.3 Hz, 1H), 0.94 (s, 3H), 0.75 (d, J = 14.6 Hz, 1H), 0.66 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 220.7, 144.4, 137.3, 135.4, 113.2, 69.4, 54.4, 54.2, 52.5, 51.9, 45.2, 43.9, 43.8, 35.2, 34.2, 26.6, 23.2, 18.6; IR (ATR, neat) ν max 3463, 2954, 2868, 1721, 1449, 1048, 894 cm -1 ; HRMS (ESI-TOF): calcd. for C 18 H 26 O 2 Na (M+Na) + m/z found m/z ; [α] 20 D 2.0 (c 0.85, CHCl 3 ). 5

6 (1R,2R,3S,3aS,4S,7R,7aS)-2-(3-hydroxy-2,2-dimethylpropyl)-1-methyl-3-(prop-1-en-2-yl)-2,3,3a,4,7,7ahexahydro-1H-4,7-methanoinden-1-ol To a flask was added CeCl 3-7H 2 O and heated at 100 o C for 1 h, then at 130 o C for additional 1 h without stirring under high vacuum (0.1 mm/hg). Later, allowed to attain room temperature and flushed with Nitrogen. The obtained anhydrous CeCl 3 was treated with anhydrous THF (40 ml) at 0 o C and stirred at rt for 3 h. The above suspension was cooled to -78 o C and treated with MeLi (10.6 ml, 16.9 mmol), and the resultant yellow color suspension was stirred for 30 mint at the same temperature. A solution of compound 14 (1.16 g, 4.23 mmol) in THF (15 ml) was added into the reaction mixture at 78 o C, and slowly warmed to rt over a period of 3 h. The reaction was quenched with saturated aqueous solution of NH 4 Cl at 0 o C, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over Na 2 SO 4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes/etoac, 1:1) to afford diol 15 (980 mg, 80%) as white solid. 1 H NMR (500 MHz, CDCl 3 ) δ 6.46 (dd, J = 5.5, 3.0 Hz, 1H), 6.15 (dd, J = 5.5, 3.0 Hz, 1H), 4.88 (s, 1H), 4.79 (d, J = 2.0 Hz, 1H), 3.21 (dd, J = 11.1, 3.1 Hz, 1H), 3.12 (dd, J = 10.8, 7.5 Hz, 1H), 2.94 (s, 1H), (m, 1H), 2.68 (s, 1H), 2.62 (dd, J = 10.9, 3.6 Hz, 1H), 1.80 (s, 3H), (m, 2H), 1.63 (t, J = 3.6 Hz, 1H), 1.59 (d, J = 3.9 Hz, 1H), 1.56 (d, J = 4.2 Hz, 1H), 1.52 (dd, J = 12.4, 2.3 Hz, 1H), 1.49 (d, J = 8.0 Hz, 1H), 1.29 (s, 3H), 0.93 (dd, J = 15.3, 3.4 Hz, 1H), 0.86 (s, 3H), 0.78 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 146.5, 137.3, 135.2, 113.7, 78.9, 71.4, 58.1, 56.9, 54.8, 51.7, 48.7, 44.6, 43.6, 34.7, 33.6, 27.7, 25.5, 24.4, 18.9; IR (ATR, neat) ν max 3425, 2961, 2929, 1638, 1473, 1337, 1046, 1032, 881cm -1 ; HRMS (ESI-TOF): calcd. for C 19 H 30 O 2 Na (M+Na) + m/z found m/z [α] 20 D (c 1.04, CHCl 3 ) (1S,4S,5R)-5-(3-hydroxy-2,2-dimethylpropyl)-1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol Compound15 (390 mg, 1.34 mmol) was placed in a quartz tube and connected to a pyrolysis apparatus while other end of the receiver connected to a vacuum pump through a cold trap at -78 o C. Then, the quartz tube was heated to o C at 0.01 mm/hg, while the pyrolysis tube (10 cm long) was kept at 480 o C until the 6

7 starting material had disappeared. The obtained product from cold trap was further purified by flash chromatography (1:1, n-hexanes/ethyl acetate) to give pure compound 6 (230 mg, 75%). 1 H NMR (400 MHz, CDCl 3 ) δ 5.72 (dd, J = 5.7, 2.3 Hz, 1H), 5.68 (dd, J = 5.7, 1.8 Hz, 1H), 4.81 (s, 1H), 4.80 (d, J = 1.4 Hz, 1H), 3.39 (d, J = 11.3 Hz, 1H), 3.22 (d, J = 11.3 Hz, 1H), 3.10 (dt, J = 6.8, 1.9 Hz, 1H), 2.60 (bs, 1H), 1.98 (dd, J = 15.0, 7.1 Hz, 1H), 1.78 (td, J = 7.0, 3.6 Hz, 1H), 1.66 (s, 3H), 1.45 (s, 3H), 1.22 (dd, J = 15.0, 3.6 Hz, 1H), 0.93 (s, 3H), 0.86 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 146.2, 138.0, 136.2, 111.9, 83.2, 70.8, 63.0, 47.2, 37.8, 35.2, 28.4, 26.5, 24.4, 18.9; IR (ATR, neat) ν max 3301, 2956, 2869, 1645, 1473, 1092, 1047, 889 cm -1 ; HRMS (ESI-TOF): calcd. for C 14 H 24 O 2 Na (M+Na) + m/z found m/z ; [α] 20 D (c 0.82, CHCl 3 ) (4aS,5R,7aR)-3,3,7a-trimethyl-5-(prop-1-en-2-yl)-2,3,4,4a,5,7a-hexahydrocyclopenta[b]pyran-2-ol To a stirred solution of compound 6 (200 mg, 0.89 mmol) and Et 3 N (0.62 ml, 4.46 mmol) in CH 2 Cl 2 (10 ml) was added a solution of SO 3 Py (355 mg, 2.23 mmol) in DMSO (0.5 ml) at 0 o C. After being stirred for 1h, the mixture was allowed to stir for additional 1 h at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated in Vacuo. The resultant residue was purified by silica gel flash chromatography (20:1 hexanes:etoac) to give 160 mg compound 5 in 80 % yield an inseparable diastereomeric mixture. 1 H NMR (major isomer) (200 MHz, CDCl 3 ) δ 5.82 (dd, J = 5.7, 2.3 Hz, 1H), 5.75 (dd, J = 5.7, 1.8 Hz, 1H), 4.76 (s, 1H), 4.59 (s, 1H), 4.48 (d, J = 6.7 Hz, 1H), 2.76 (s, 1H), 2.41 (d, J = 10.3 Hz, 1H), 1.96 (dd, J = 15.0, 7.1 Hz, 1H), 1.78 (s, 3H), (m, 2H), 1.33 (s, 3H), 0.86 (s, 3H), 0.51 (s, 3H); 13 C NMR (Major isomer) (101 MHz, CDCl 3 ) δ 146.6, 136.7, 132.2, 110.1, 98.1, 87.2, 58.8, 43.7, 42.1, 36.6, 33.8, 29.3, 25.9, IR (ATR, neat) νmax 3358, 2972, 2931, 1648, 1480, 1443, 1287, 1157, 1083, 1061, 1005, 908 cm -1 ; [α] 20 D (c 0.74, CHCl 3 ) 7

8 (1S,4S,5R)-5-((S)-3-hydroxy-2,2-dimethylpent-4-en-1-yl)-1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol To a solution of lactol 5 (150 mg, 0.67 mmol) in anhydrous benzene (10 ml) was added vinyl magnesium bromide (4.8 ml, 0.7 M in THF) dropwise at 0 o C under nitrogen atmosphere. The mixture was stirred at room temperature for 8 h. The reaction was quenched cautiously with saturated solution of NH 4 Cl at 0 o C and the aqueous layer was extracted with ethyl acetate (3 X 10 ml). The combined organic layers were washed with saturated aqueous NaCl solution (10 ml) and concentrated. The obtained crude product was further purified by flash chromatography on silica gel (2:5 hexane:etoac) to give 135 mg (80 %) of allylic alcohol H NMR (400 MHz, CDCl 3 ) δ 5.93 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.69 (dd, J = 5.7, 2.2 Hz, 1H), 5.65 (dd, J = 5.7, 1.7 Hz, 1H), 5.25 (dt, J = 17.2, 1.6 Hz, 1H), (m, 1H), 4.77 (s, 2H), 3.93 (d, J = 6.3 Hz, 1H), 3.09 (dt, J = 6.6, 1.9 Hz, 1H), 3.05 (bs, 1H), 2.49 (bs, 1H), 2.15 (dd, J = 15.1, 7.7 Hz, 1H), 1.85 (td, J = 7.6, 3.2 Hz, 1H), 1.64 (t, J = 1.0 Hz, 3H), 1.47 (s, 3H), 1.19 (dd, J = 15.1, 3.2 Hz, 1H), 0.86 (s, 3H), 0.85 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 145.7, 137.8, 137.6, 135.7, 116.2, 111.9, 82.9, 78.5, 63.5, 47.0, 39.7, 37.4, 29.1, 23.9, 23.3, 19.1; IR (ATR, neat) ν max 3338, 2967, 2871, 1645, 1450, 1372, 1083, 996, 891 cm -1 ; HRMS (ESI-TOF): calcd. for C 16 H 26 O 2 (M+Na) + m/z found m/z ; [α] 20 D (c 0.68, CHCl 3 ) (1R,3aR,6S,8aS)-1,4,7,7-tetramethyl-1,3a,6,7,8,8a-hexahydroazulene-1,6-diol To a solution of diene 16 (135 mg, 0.54 mmol) in anhydrous toluene (50 ml) was added a solution of Grubbs 2 nd generation catalyst (14 mg, mmol) in toluene (2 ml) at room temperature under nitrogen atmosphere. Then, the reaction mixture was allowed to stir at rt for 15 min, then heated to reflux for 3 h. The reaction allowed to attain room temperature and filtered through a plug of silica gel. The obtained crude material was further purified by flash chromatography to afford compound 17 (100 mg, 80 %) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.02 (dd, J = 5.8, 1.6 Hz, 1H), 5.84 (dd, J = 5.8, 2.9 Hz, 1H), (m, 1H), 3.97 (d, J = 8.8 Hz, 1H), 3.75 (d, J = 7.4 Hz, 1H), 2.14 (t, J = 13.2 Hz, 1H), 1.76 (dd, J = 1.4, 1.0 Hz, 3H), 1.70 (ddd, J = 12.6, 8.9, 2.3 Hz, 2H), (m, 1H), 1.33 (s, 3H), (m, 1H), 1.09 (s, 3H), 0.94 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 144.3, 137.9, 135.2, 125.2, 82.4, 77.0, 50.5, 49.1, 36.4, 8

9 35.7, 30.4, 25.1, 24.9, 22.5; HRMS (ESI-TOF): calcd. for C 14 H 22 O 2 (M+Na)+ m/z found m/z ; IR (ATR, neat) νmax 3386, 2967, 2929, 1656, 1447, 1375, 1253, 1142, 1078, 1017, 933 cm -1 ; [α] 20 D (c 0.75, CHCl 3 ). (1R,3aR,8aS)-1-hydroxy-1,4,7,7-tetramethyl-3a,7,8,8a-tetrahydroazulen-6(1H)-one To a slurry of alcohol 17 (35 mg, 0.16 mmol) and NaHCO 3 (40 mg, 0.48 mmol) in CH 2 Cl 2 (7 ml) at 0 C was added Dess Martin periodinane (90 mg, 0.21 mmol), and the resultant mixture was stirred for 30 min at the same temperature. The reaction mixture was diluted with a saturated aqueous Na 2 SO 3 solution and extracted with CH 2 Cl 2. The organic layer was washed with brine, dried over Na 2 SO 4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give dienone 4 (22 mg, 62%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.14 (dd, J = 5.8, 1.6 Hz, 1H), 5.92 (dd, J = 5.8, 3.1 Hz, 1H), 5.82 (dd, J = 2.9, 1.4 Hz, 1H), (m, 1H), 2.00 (s, 3H), (m, 3H), 1.38 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 208.1, 150.7, 138.2, 134.1, 127.9, 82.4, 54.0, 52.6, 46.8, 37.6, 28.2, 27.0, 25.5, 23.7; IR (ATR, neat) ν max 2969, 2956, 1656, 1453, 1381, 1271, 1140, 1034, 754 cm -1 ; HRMS (ESI-TOF): calcd. for C 14 H 20 O 2 (M+Na) + m/z found m/z ; [α] 20 D 3.65 (c 0.52, CHCl 3 ) (3R,3aS,8aR)-3-hydroxy-3,5,5,8-tetramethyl-2,3,3a,4,5,8a-hexahydroazulen-6(1H)-one To a solution of diene 4 (10 mg, 45 µmol) in MeOH (3 ml) was added 5% Rh on alumina (2 mg) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under hydrogen atmosphere for 4 h. Then, the reaction mixture diluted with EtOAc, filtered through Celite and concentrated in vacuo. The obtained residue was purified by flash chromatography to afford α,β-unsaturated ester 18 (8 mg, 80%) as a viscous material. 1 H NMR (400 MHz, CDCl 3 ) δ 5.80 (s, 1H), 2.70 (dd, J = 12.5, 7.5 Hz, 1H), (m, 1H), 1.89 (s, 3H), (m, 3H), (m, 2H), (m, 2H), 1.29 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 208.9, 153.9, 126.6, 80.2, 52.2, 51.5, 47.4, 38.9, 36.8, 29.3, 9

10 27.7, 26.8, 25.8, 24.6; IR (ATR, neat) ν max 3463, 2959, 1623, 1458, 1381, 1108, 1076, 943 cm -1. HRMS (ESI-TOF): calcd. for C 14 H 22 O 2 (M+Na) + m/z found m/z [α] 20 D 82.2 (c 0.51, CHCl 3 ) (1R,3aR,6R,8aS)-1,4,7,7-tetramethyl-1,2,3,3a,6,7,8,8a-octahydroazulene-1,6-diol To a solution of DIBAL-H (870 μl, 0.95 mmol, 1.1 M solution in toluene) at 0 o C was added tert-buli (500 μl, 0.95 mmol, 1.9 M in pentane) under nitrogen atmosphere and stirred at 0 o C for 30 mins. Then, a solution of enone (10 mg, mmol) in toluene (1.5 ml) was added into the above reaction mixture of DIBAL- H/tBuLi 1 complex in toluene (0.69 M, 260 μl, 0.18 mmol) at -78 o C and stirred for 8 h. The reaction was quenched with MeOH, diluted with CH 2 Cl 2 and 100 μl of 20% NaOH. The reaction was stirred at room temperature for 8h. The obtained white precipitate was removed by filtration through a pad of celite and filtrate was concentrated, further purified by flash chromatography to afford diol 3 as an amorphous solid (7.3 mg, 71%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 4.17 (s, 1H), (m, 1H), (m, 1H), 1.78 (s, 3H), (m, 3H), (m, 3H), (m, 2H), 1.25 (s, 3H), 1.07 (s, 3H), 0.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 138.9, 130.4, 80.7, 77.4, 48.7, 45.8, 42.5, 41.0, 35.7, 29.2, 26.5, 24.6, 22.1, 19.4; IR (ATR, neat) ν max 2963, 2931, 1652, 1459, 1373, 1081, 1017 cm -1 ; HRMS (ESI- TOF): calcd. for C 14 H 24 O 2 (M+Na) + m/z found m/z ; [α] 20 D (c 0.37, CHCl 3 ). (+)-omphadiol (1) To a solution of diol 3 (7 mg, 30 µmol, 1.0 equiv) in CH 2 Cl 2 (2 ml) was added Et 2 Zn (25 μl, 0.31 mmol, 1 M solution in hexane) drop wise at -30 C. After stirring for 10 mins, CH 2 I 2 (0.4 μl, ~0.5 mmol) was added drop wise. The reaction mixture was slowly warmed to 0 C and stirred at this temperature for 2 h. The reaction was then quenched with H 2 O, diluted with EtOAc, washed with 1M NaOH followed by brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography (SiO 2, eluting with 20 to 50% EtOAc/hexanes) to afford (+)-omphadiol 1 as an amorphous solid (5.8 mg, 78%). IR (ATR, neat) ν max 3347, 2948, 2929, 1467, 1373 cm ; [α] D (c 0.36, EtOH); HRMS (ESI-TOF)): calcd. for C 15 H 27 O 2 (M+1) + m/z found m/z ; For 1 H and 13 C NMR, see comparison Tables 1 and 2 below; 10

11 Comparison Table-1: ( 1 H NMR characterization data) 1 H NMR Natural omphadiol 2 (600 MHz, (CD 3 ) 2 CO) Synthetic omphadiol 3 (500 MHz, (CD 3 ) 2 CO) Synthetic omphadiol 4 (400 MHz, (CD 3 ) 2 CO) Our synthetic omphadiol (400 MHz, (CD 3 ) 2 CO) (overlap) 1.45 (m) 1.46 (dd, J = 10.5, 3.6) (m) 3α 0.34 (t, J = 4.4 ) 0.34 (t, J = 4.4 ) 0.34 (t, J = 4.3) 0.36 (t, J = 4.4 Hz) 3β 0.62 (dd, J = 8.2, 4.0) 0.62 (dd, J = 8.5, 4.0) 0.61 (dd, J = 8.1, 3.9) 0.63 (dd, J = 8.2, 3.9 Hz) (m) (m) (m) (m) 5α 3.05 (dd, J = 9.0, 4.2 ) 3.05 (dd, J = 8.5, 4.5 ) 3.03 (dd, J = 8.5, 4.4) 3.06 (dd, J = 8.5, 4.5 Hz) 7α (m) (m) (m) (m) 7β 1.42 (overlap) 1.42 (m) 1.42 (t, J = 3.5) (m) (overlap) 1.59 (m) (m) (m) 10α 1.58 (overlap) 1.58 (m) (m) (m) 10β 1.65 (overlap) 1.65 (m) (m) α 1.64 (overlap) 1.64 (m) (m) β (m) (m) 1.79 (ddd, J = 18.1, (m, 2H) 10.5, 5.0) (s, 3 H) 0.98 (s, 3 H) 0.98 (s, 3 H) 0.99 (s, 3H) (s, 3 H) 0.97 (s, 3 H) 0.97 (s, 3 H) 0.97 (s, 3H) (s, 3 H) 0.94 (s, 3 H) 0.94 (s, 3 H) 0.95 (s, 3H) (s, 3 H) 1.21 (s, 3 H) 1.21 (s, 3 H) 1.23 (s, 6H) 5(OH) 3.40 (d, J = 4.2) 3.41 (d, J = 4.5) 3.40 (d, J = 4.5) 3.40 (d, J = 4.4 Hz) 9(OH) 2.90 (s) 2.90 (s) 2.89 (s) 2.90 (s, 1H) 11

12 Comparison Table-2: ( 13 C NMR characterization data) 13C Natural omphadiol 2 (150 MHz, (CD 3 ) 2 CO) Synthetic omphadiol 3 (125 MHz, (CD 3 ) 2 CO) Synthetic omphadiol 4 (100 MHz, (CD 3 ) 2 CO) Our synthetic omphadiol (100 MHz, (CD 3 ) 2 CO) Δδ References: 1. Bian, J.; Van Wingerden, M.; Ready, J. M., J. Am. Chem. Soc. 2006, 128, Zheng, Y.-B.; Lu, C.-H.; Zheng, Z.-H.; Lin, X.-H.; Su, W. J.; Shen, Y. M. Helv. Chim. Acta 2008, 91, Liu, G.; Romo, D. Angew. Chem. Int. Ed. 2011, 50, Zhou, L.; Yao, Y.; Xu, W.; Liang, G. J. Org. Chem. 2014, 79,

13 (4aR,5R,7aR)-2-(4-methoxyphenyl)-7a-methyl-5-(prop-1-en-2-yl)hexahydrocyclopenta[d] [1,3]dioxine To a solution of diol 23 (1.79 g, 10.5 mmol) in CH 2 Cl 2 (10.5 ml) was added p-anisaldehyde dimethylacetal (1.97 ml, 1.10 eq, 11.6 mmol) and PPTS (265 mg, 0.10 eq, 1.05 mmol) at 0 o C allowed to react at room temperature for 4 h. The mixture was diluted with CH 2 Cl 2, and then washed with sat.aq. NaHCO 3, dried (MgSO 4 ) and concentrated. The obtained residue was purified by flash chromatography (PE:MTBE, 9:1) to afford acetal B as a pale yellow oil (2.53 g, 83%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 5.62 (s, 1H), 4.78 (s, 1H), (m, 1H), 4.09 (dd, J = 11.8, 2.9 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.28 (dd, J = 17.5, 9.8 Hz, 1H), 2.13 (ddd, J = 16.9, 12.7, 8.9 Hz, 1H), 1.98 (ddd, J = 13.3, 8.7, 4.4 Hz, 1H), (m, 1H), 1.72 (s, 3H), (m, 1H), 1.52 (s, 3H), 1.45 (dd, J = 10.4, 1.6 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 159.9, 146.9, 131.9, 127.5, 113.7, 110.5, 95.6, 82.2, 63.9, 55.3, 47.3, 45.9, 41.1, 27.9, 20.8, 19.4; HRMS (ESI-TOF): calcd. for C 18 H 25 O 3 (M+1) + m/z found m/z ; [α] 20 D 97.8 (c 0.95, CHCl 3 ). ((1R,2R,5R)-2-((4-methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)methanol To a solution of above acetal B (1.23 g, 4.28 mmol) in CH 2 Cl 2 (20 ml) was added DIBAL-H (1 M solution in CH 2 Cl 2, 2.50 eq, ml) dropwise at -78 C. The resulting mixture was stirred for 1 h at -78 C and then allowed to reach 0 C. Then the mixture was diluted with MTBE and quenched with sat. aq. Rochelle salt solution carefully. The reaction mixture was stirred for 30 min and the separated organic layer was washed with brine, dried (MgSO 4 ) and evaporated. The crude product was purified by column chromatography (PE:MTBE, 85:15) to yield compound 24 as a colorless oil (2.12 g, 82%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), (m, 1H), (m, 1H), 4.41 (d, J = 10.7 Hz, 1H), 4.34 (d, J = 10.7 Hz, 1H), 3.89 (dt, J = 11.6, 2.9 Hz, 1H), 3.80 (s, 3H), 3.63 (ddd, J = 11.6, 9.0, 5.0 Hz, 1H), 3.18 (dd, J = 9.0, 3.1 Hz, 1H), 2.97 (dd, J = 19.0, 8.6 Hz, 1H), (m, 1H), (m, 1H), 1.72 (s, 3H), (m, 2H), (m, 1H), 1.44 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , 87.38, 64.03, 60.47, 55.25, 54.64, 46.06, 35.67, 28.14, 23.20, HRMS (ESI-TOF): Calcd for C 18 H 26 O 3 (M+Na) + m/z , found m/z ; [α] 20 D 38.6 (c 1.41, CHCl 3 ). 13

14 ((1R,2R,5R)-2-((4-methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)methyl 4- methylbenzenesulfonate To a solution of alcohol 24 (1.45 g, 5.00 mmol) in pyridine (5 ml) was added 4-toluenesulfonyl chloride (1.00 g, 1.05 eq, 5.25 mmol) and the mixture was stirred for 18 h at room temperature. Then reaction was diluted with water and extracted with MTBE (3x10 ml). The combined organic layers were washed with 1 M aq. HCl solution (5 ml), brine and dried (MgSO 4 ). After removal of the solvent, the obtained crude product was purified by column chromatography (PE:MTBE, 9:1) to afford compound 22 as colorless crystals (1.92 g, 86%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), (m, 1H), 4.66 (s, 1H), 4.40 (dd, J = 9.7, 8.6 Hz, 1H), 4.29 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 11.1 Hz, 1H), 3.99 (dd, J = 9.8, 4.2 Hz, 1H), 3.84 (s, 3H), (m, 1H), 2.43 (s, 3H), (m, 2H), (m, 1H), 1.66 (s, 3H), (m, 2H), 1.41 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 158.7, 146.1, 144.3, 133.2, 131.7, 129.6, 128.2, 127.3, 113.6, 111.1, 83.5, 69.5, 63.3, 55.3, 52.3, 48.5, 35.0, 27.8, 22.5, 21.6, 18.8; HRMS (ESI-TOF): m/z Calcd for C 25 H 32 O 5 S(M+ Na) + m/z , found m/z ; [α] 20 D 56.0 (c 0.52, CHCl 3 ). 3-((1S,2R,5R)-2-((4-methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-2,2- dimethylpropanenitrile To a solution of diisopropylamine (350 µl, 2.50 eq, 2.50 mmol) in THF (4 ml) was added n-buli (1.00 ml, 2.50 eq, 2.50 mmol, 2.5 M solution in hexane) at 0 C and stirred for 30 min. Then, isobutyronitrile (224 µl, 2.50 eq, 2.50 mmol) was introduced into the reaction mixture and stirring was continued for 30 min. Later, a solution of tosylate 22 (222 mg, mmol) in THF (2 ml) was added drop wise at 0 o C and the mixture was allowed to reach room temperature for overnight. The reaction was quenched with water, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with and dried (MgSO 4 ). After concentration, the obtained crude product was purified by column chromatography to afford the nitrile C as colorless oil (147 mg, 86%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.78 (d, J = 2.0 Hz, 1H), (m, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.31 (d, J = 11.0 Hz, 1H), 3.81 (s, 3H), 2.59 (td, J = 9.6, 5.8 Hz, 1H), 2.21 (dd, J = 15.1, 4.2 Hz, 1H), (m, 1H), (m, 1H), 1.74 (s, 3H), (m, 1H), (m, 2H), 1.42 (s, 14

15 3H),1.36 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 158.7, 147.2, 132.0, 128.2, 125.9, 113.6, 111.6, 84.8, 63.4, 55.3, 54.2, 50.2, 39.6, 35.1, 32.2, 28.5, 28.0, 27.2, 22.2, 19.0; HRMS (ESI- TOF): Calcd for C 22 H 31 NO 2 (M+ Na) + m/z , found ; [α] 20 D 58.3 (c 0.24, CHCl 3 ). 3-((1S,2R,5R)-2-((4-methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-2,2-dimethylpropanal To a solution of above compound (1.00 g, 2.93 mmol) in CH 2 Cl 2 (29 ml) was added DIBAl-H (8.79 ml, 3.00 eq, 8,79 mmol, 1 M solution in CH 2 Cl 2 ) dropwise at -78 C. The mixture was stirred for 1 h and then allowed to reach 0 C. The reaction was quenched with Sat. aq. Rochelle salt solution followed by addition of MTBE (20 ml) and the mixture was stirred for 30 min. The organic layer was separated, washed with brine and dried over MgSO 4. Column chromatography (PE/MTBE, 95:5) of the crude product afforded aldehyde 21 as colorless oil (1.00 g, 99%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), (m, 1H), 4.72 (dd, J = 2.4, 1.4 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 4.28 (d, J = 11.0 Hz, 1H), 3.81 (s, 3H), 2.49 (dd, J = 17.4, 9.2 Hz, 1H), 2.07 (dd, J = 15.1, 5.5 Hz, 1H), (m, 1H), 1.81 (ddt, J = 15.0, 12.6, 6.0 Hz, 1H), 1.63 (d, J = 0.5 Hz, 3H), (m, 3H), 1.37 (dd, J = 15.1, 4.3 Hz, 1H), 1.27 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 206.7, 158.7, 147.0, 132.0, 128.5, 113.6, 111.8, 84.3, 63.5, 55.3, 55.0, 49.1, 45.5, 36.8, 36.1, 28.0, 23.0, 22.8, 21.8, 18.5; HRMS (ESI- TOF): Calcd for C 22 H 32 O 3 (M+ Na) + m/z , found m/z ; [α] 20 D 61.2 (c 0.50, CHCl 3 ). 4-((1S,2R,5R)-2-((4-methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-3,3-dimethylbutanal To a solution of (methoxymethyl)diphenylphosphine oxide (985 mg, 2.00 eq, 4.00 mmol) in THF (16 ml) was added KHMDS solution (4.00 ml, 2.00 eq, 4.00 mmol, 1 M solution in THF) dropwise 1. The resultant yellow suspension was stirred for 30 min and then aldehyde 21 (689 mg, 2.00 mmol) in THF (4 ml) was added. The reaction mixture was stirred for 16 h and then quenched with sat. aq. NH 4 Cl solution (5 ml). The organic layer was separated, washed with brine, dried (MgSO 4 ) and evaporated. The unreacted Wittig reagent was removed by short column filtration to afford crude enol ether 25 which was dissolved in THF (10 ml) and allowed to react with conc. HCl solution (0.5 ml). After complete consumption of starting material (2 h) by TLC, the reaction was basified with sat. aq. NaHCO 3 solution cautiously. The separated organic layer was washed with brine, dried (MgSO 4 ) and concentrated. Purification by column chromatography (PE:MTBE, 95:5) afforded aldehyde 26 as colorless oil (612 mg, 85%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.82 (t, J = 3.1 Hz, 15

16 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.76 (s, 1H), 4.71 (s, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.31 (d, J = 11.3 Hz, 1H), 3.81 (s, 3H), 2.57 (td, J = 9.5, 5.4 Hz, 1H), (m, 2H), 2.07 (dd, J = 10.2, 7.8 Hz, 1H), 1.99 (dd, J = 15.1, 3.5 Hz, 1H), (m, 1H), 1.71 (s, 3H), (m, 1H), (m, 2H), (m, 1H), 1.25 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 204.3, 158.7, 147.8, 132.2, 128.2, 113.6, 111.4, 85.3, 63.3, 55.6, 55.3, 54.9, 48.9, 41.8, 35.1, 33.1, 28.2, 28.1, 27.9, 22.1, 19.2; HRMS (ESI-TOF): Calcd for C 23 H 35 O 3 (M+1) + m/z , found m/z ; [α] 20 D 56.4 (c 0.50, CHCl 3 ). 1-((((1R,2S,3R)-2-(2,2-dimethylpent-4-en-1-yl)-1-methyl-3-(prop-1-en-2-yl)cyclopentyl)oxy) methoxybenzene methyl)-4- To a suspension of methyltriphenylphosphonium bromide (1.14 g, 2.00 eq, 3.18 mmol) in THF (16 ml) was added KHMDS solution (3.18 ml, 2.00 eq, 3.18 mmol, 1 M solution in THF) dropwise at 0 o C. The resulting yellow solution was stirred for additional 30 min and then treated with a solution of aldehyde 26 (570 mg, 1.59 mmol) in THF (1.6 ml). The reaction mixture was stirred for 1 h and then quenched with sat. aq. NH 4 Cl solution (5 ml). The organic layer was washed with brine, dried (MgSO 4 ) and evaporated. The crude product was purified by column chromatography (PE:MTBE, 99:1) to afford olefin 20 as colorless oil (505 mg, 89%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.84 (ddt, J = 17.6, 10.3, 7.4 Hz, 1H), (m, 2H), 4.76 (d, J = 2.2 Hz, 1H), 4.69 (dd, J = 2.3, 1.3 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 3.81 (s, 3H), (m, 1H), (m, 1H), (m, 4H), 1.71 (s, 3H), 1.60 (ddd, J = 9.0, 5.3, 3.4 Hz, 1H), (m, 2H), 1.30 (s, 3H), 1.18 (dd, J = 15.0, 5.4 Hz, 1H), (m, 2H), 0.81 (s, 3H), 0.78 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 158.6, 148.2, 136.3, 132.5, 128.0, 116.3, 113.6, 110.8, 85.6, 63.1, 55.3, 54.9, 48.9, 47.9, 41.1, 35.0, 32.8, 28.2, 27.2, 27.1, 22.0, 19.3; HRMS (ESI-TOF): Calcd for C 24 H 36 O 2 (M+Na) + m/z , found m/z ; [α] 20 D 49.5 (c 1.31, CHCl 3 ). 16

17 (3R,3aS,8aR)-3-((4-methoxybenzyl)oxy)-3,5,5,8-tetramethyl-1,2,3,3a,4,5,6,8a-octahydroazulene A solution of olefin 20 (481 mg, 1.35 mmol) and Grubbs 2 nd generation (57.3 mg, 67.5 µmol) in toluene (13.5 ml) was stirred for at room temperature 15 min and then heated to reflux for 1 h. After being cooled down to room temperature, the volatiles were removed and the obtained crude product purified by flash chromatography (PE/MTBE, 99:1) to afford compound 27 as colorless oil (361 mg, 81%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), (m, 1H), (m, 2H), 3.81 (s, 3H), 2.93 (dd, J = 17.4, 9.3 Hz, 1H), 2.14 (dd, J = 14.2, 4.8 Hz, 1H), 2.06 (ddd, J = 13.3, 7.6, 3.8 Hz, 1H), (m, 6H), 1.66 (d, J = 12.0 Hz, 1H), 1.58 (dt, J = 13.5, 2.4 Hz 1H), (m, 2H), 1.23 (s, 3H), 0.95 (s, 3H), 0.84 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 158.5, 133.4, 142.1, 128.0, 122.8, 113.6, 84.7, 63.3, 55.3, 50.8, 45.6, 43.3, 40.4, 35.3, 34.0, 31.1, 25.4, 24.8, 22.1, 21.0; HRMS (ESI-TOF): Calcd for C 22 H 32 O 2 (M+Na) + m/z , found m/z ; [α] 20 D 37.7 (c 0.48, CHCl 3 ). (1R,3aR,8aS)-1,4,7,7-tetramethyl-1,2,3,3a,6,7,8,8a-octahydroazulen-1-ol To a solution of compound 27 (296 mg, mmol) in a mixture of CH 2 Cl 2 /ph7 buffer solution (9.9 ml, 10:1) was added DDQ (409 mg, 2.00 eq, 1.80 mmol) at once. The mixture was allowed to stir for 30 min and then quenched with sat. aq. NaHCO 3 solution (2 ml). The reaction mixture was extracted with MTBE and the combined organic layers were washed with brine, dried (MgSO 4 ) and concentrated. The obtained crude product was purified by flash chromatography (PE:MTBE, 9:1) to afford alcohol 19 as colorless oil (133 mg, 71%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 2.79 (dd, J = 16.3, 8.4 Hz, 1H), 2.11 (dd, J = 14.4, 5.4 Hz, 1H), 1.89 (tdd, J = 8.9, 6.5, 3.1 Hz, 1H), 1.79 (ddd, J = 14.4, 8.4, 2.0 Hz, 1H), (m, 6H), 1.55 (dt, J = 12.3, 1.9 Hz, 1H), 1.42 (t, J = 12.2 Hz, 1H), 1.34 (ddd, J = 12.1, 8.0, 2.0 Hz, 1H), 1.22 (s, 3H), 0.96 (s, 3H), 0.84 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 141.5, 122.8, 80.7, 48.7, 45.9, 43.8, 40.9, 40.4, 33.9, 31.1, 26.5, 25.4, 24.9, 22.2; [α] 20 D (c 0.38, CHCl 3 ). 17

18 (1R,3aR,8aS)-4-(hydroxymethyl)-1,7,7-trimethyl-1,2,3,3a,6,7,8,8a-octahydroazulen-1-ol (29) To a suspension of SeO 2 (31.6 mg, 0.5 eq, mmol) in CH 2 Cl 2 was added a solution of t-buooh (215 µl, 2.00 eq, 1.18 mmol, ca. 5.5 M in decane). The reaction mixture was stirred for 30 min and then treated with a solution of compound 19 (123 mg, 590 µmol) in CH 2 Cl 2 (0.9 ml). After complete starting material (30 min, by TLC), the reaction was quenched with sat. aq. Na 2 SO 3 solution (2 ml) and extracted with MTBE (3x5 ml). The combined organic layers were washed with brine and dried (MgSO 4 ). The obtained crude product was purified by column chromatography (PE/MTBE, 1:1) to afford alcohol 29 (29.0 mg, 22%) and aldehyde 28 (46.0 mg, 35%) as colorless oils. The aldehyde 28 was further converted into the alcohol 29 with NaBH 4 in MeOH. Analytical data of alcohol 29; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 4.11 (s, 2H), 2.86 (q, J = 8.3 Hz, 1H), 2.16 (dd, J = 14.3, 5.4 Hz, 1H), (m, 3H), (m, 2H), 1.58 (d, J = 12.4 Hz, 1H), (m, 3H), (m, 1H), 1.22 (s, 3H), 0.99 (s, 3H), 0.86 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 144.7, 126.3, 80.6, 66.7, 49.5, 44.4, 43.7, 40.8, 40.3, 34.0, 30.9, 26.4, 25.2, 23.9; HRMS (ESI-TOF): Calcd for C 14 H 24 O 2 (M+Na) + m/z , found m/z ; [α] 20 D (c 0.43, CHCl 3 ). (+)-Pyxidatol C (2) To a solution of diol 29 (13.2 mg, mmol) in CH 2 Cl 2 (1 ml) was added diethyl zinc (0.590 ml, 10 eq, ml, 1 M solution in hexane) at -30 C and stirred for 10 min. Later, CH 2 I 2 (95.2 µl, 20 eq, 1.18 mmol) was added into the reaction mixture at the same temperature and allowed to reach 0 C for 2 h. Then, the cooling bath was removed and the mixture was stirred at rt for overnight. The reaction was quenched with water and extracted with MTBE. The combined organic layers were washed with 2 N NaOH solution, brine and dried (MgSO 4 ). The obtained crude product after evaporation of solvent was purified by column chromatography (PE:MTBE, 1:1) to afford (+)-pyxidatol C (2) as light yellow oil (4.6 mg, 33%). HRMS 18

19 (ESI-TOF): Calcd for C 15 H 26 O 2 (M+Na) + m/z: , found m/z ; [α] 20 D +8.0 (c 0.20, MeOH); For 1 H and 13 C NMR, see comparison Tables 3 and 4 below. 19

20 Comparison Table-3: ( 1 H NMR characterization data of pyxidatol C (2)) 1 H NMR Natural pyxidatol C 2 (600 MHz, (CD 3 ) 2 CO) Synthetic pyxidatol C 3 (400 MHz, (CD 3 ) 2 CO) Our synthetic pyxidatol C (400 MHz, (CD 3 ) 2 CO) (overlap) (m) (m) 3α 0.14 (t, J = 3.8 Hz) 0.14 (t, J = 4.1 Hz) 0.15 ((t, J = 4.2 Hz) 3β 0.70 (dd, J = 8.5, 3.8 Hz) 0.69 (dd, J = 8.5, 3.7 Hz) 0.69 (dd, J = 8.5, 3.7 Hz) (m) (m) (m) 5α (m) 1.10 (dd, J = 10.1, 4.3 Hz) (m) 5β 1.85 (overlap) (m) (m) 7α (m) (m) (m) 7β (m) (m) 1.44 (dt, J = 13.4, 2.5 Hz) (overlap) (m) (m) 10α (m) (m) (m) 10β 1.72 (overlap) (m) (m) 11α 1.82 (overlap) (m) (m) 11β 1.96 (overlap) (m) (m) 12α 3.49 (dd, J = 11.2, 5.0 Hz) 3.48 (dd, J = 11.1, 5.6 Hz) 3.49 (dd, J = 11.2, 5.8 Hz) 12β 3.61 (dd, J = 11.2, 5.0 Hz) 3.59 (dd, J = 11.1, 4.6 Hz) 3.60 (dd, J = 11.2, 4.8 Hz) (s, 3 H) 1.04 (s, 3 H) 1.03 (s, 3H) (s, 3 H) 0.89 (s, 3 H) 0.90 (s, 3H) (s, 3 H) 1.19 (s, 3 H) 1.19 (s, 3H) 9(OH) 2.80 (s) 2.79 (s) 2.80 (s) 12(OH) 3.42 (t, J = 5.0 Hz) 3.42 (t, J = 5.0 Hz) 3.42 (t, J = 5.0 Hz) 20

21 Comparison Table-4: ( 13 C NMR characterization data of pyxidatol C (2)) 13C Natural pyxidatol C 2 (150 MHz, (CD 3 ) 2 CO) Synthetic pyxidatol C 3 (100 MHz, (CD 3 ) 2 CO) Our synthetic pyxidatol C (100 MHz, (CD 3 ) 2 CO) Δδ Note: The 1 ppm difference is due to different labeling on residual peak for (CD 3 ) 2 CO (the peak they labeled 1 as is very close to the residue peak of (CD 3 ) 2 CO which is referred as 29.8 ppm) References: 1. Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin Trans , 12, Zheng, Y.-B.; Lu, C.-H.; Zheng, Z.-H.; Lin, X.-H.; Su, W. J.; Shen, Y. M. Helv. Chim. Acta 2008, 91, Zhou, L.; Yao, Y.; Xu, W.; Liang, G. J. Org. Chem. 2014, 79,

22 Spectroscopic data 1 H NMR (200 MHz, CDCl 3 ) of compound A 13 C NMR (101 MHz, CDCl 3 ) of compound-a 22

23 1 H NMR (200 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-10 23

24 1 H NMR (400 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-11 24

25 1 H NMR (400 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-12 25

26 1 H NMR (400 MHz, CDCl 3 of compound C NMR (101 MHz, CDCl 3 ) of compound-14 26

27 1 H NMR (500 MHz, CDCl 3 ) of Compound C NMR (101 MHz, CDCl 3 ) of compound-15 27

28 1 H NMR (400 MHz, CDCl 3 ) of compound-6 13 C NMR (101 MHz, CDCl 3 ) of compound-6 28

29 1 H NMR (200 MHz, CDCl 3 ) of compound-5 13 C NMR (101 MHz, CDCl 3 ) of compound-5 29

30 1 H NMR (400 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-16 30

31 1 H NMR (400 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-17 31

32 1 H NMR (400 MHz, CDCl 3 ) of compound-4 13 C NMR (101 MHz, CDCl 3 ) of compound-4 32

33 1 H NMR (400 MHz, CDCl 3 ) of compound C NMR (101 MHz, CDCl 3 ) of compound-18 33

34 1 H NMR (400 MHz, CDCl 3 ) of compound-3 13 C NMR (101 MHz, CDCl 3 ) of compound-3 34

35 1 H NMR (400 MHz, (CD3)2CO) of (+)-omphadiol (1) 13 C NMR (101 MHz, (CD3)2CO) of (+)-omphadiol (1) 35

36 1 H NMR (400 MHz, CDCl 3 ) of compound B APT-NMR (101 MHz, CDCl 3 ) of Compound B 36

37 1 H NMR (400 MHz, CDCl 3 ) of compound 24 APT-NMR (101 MHz, CDCl 3 ) of Compound 24 37

38 1 H NMR (400 MHz, CDCl 3 ) of compound 22 APT-NMR (101 MHz, CDCl 3 ) of Compound 22 38

39 1 H NMR (400 MHz, CDCl 3 ) of compound C APT-NMR (101 MHz, CDCl 3 ) of Compound C 39

40 1 H NMR (400 MHz, CDCl 3 ) of compound 21 APT-NMR (101 MHz, CDCl 3 ) of Compound 21 40

41 1 H NMR (400 MHz, CDCl 3 ) of compound 26 APT-NMR (101 MHz, CDCl 3 ) of Compound 26 41

42 1 H-NMR (400 MHz, CDCl 3 ) of compound 20 APT-NMR (101 MHz, CDCl 3 ) of Compound 20 42

43 1 H NMR (400 MHz, CDCl 3 ) of compound 27 APT-NMR (101 MHz, CDCl 3 ) of Compound 27 43

44 1 H NMR (400 MHz, CDCl 3 ) of compound 19 APT-NMR (101 MHz, CDCl 3 ) of Compound 19 44

45 1 H NMR (400 MHz, CDCl 3 ) of compound 29 APT-NMR (101 MHz, CDCl 3 ) of Compound 29 45

46 1 H NMR (400 MHz, (CD3)2CO) of (+)-Pyxidatol C (2) APT-NMR (101 MHz, (CD3)2CO) of (+)-Pyxidatol C (2) 46