Supporting Information. for. Angew. Chem. Int. Ed. Z Wiley-VCH 2002

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1 Supporting Information for Angew. Chem. Int. Ed. Z50016 Wiley-VCH Weinheim, Germany

2 Total Synthesis of (±)-Wortmannin Takashi Mizutani, Shinobu Honzawa, Shin-ya Tosaki, and Masakatsu Shibasaki* Experimental Section General: NMR spectra were measured in JEOL JNM-LA500 (500MHz). Chemical shifts were reported in the δ scale relative to residual CHCl 3 (7.26 ppm for 1 H and ppm for 13 C) and C 6 H 6 (7.15 ppm for 1 H and ppm for 13 C) as internal references. Infrared (IR) spectra were recorded on JASCO FT/IR-410. Mass spectra (EI, FAB) were measured on JEOL JMS-BU20-Gcmate. ESI mass spectra were measured on Waters- ZQ4000. Column chromatography was performed with silica gel Merck 60 ( mesh ASTM). In general, reactions were carried out in dry solvents (purchased from KANTO CHEMICAL Inc.; Co.) under an argon atmosphere, unless otherwise mentioned, and monitored with analytical TLC (Merck Art. 5715, Silica gel 60 F 254 plates). SEM ether 7 To a stirred solution of 6 (25.0 g, 62.8 mmol ) in CH 2 Cl 2 (200 ml) were added 2,6-lutidin (14.6 ml, mol), tetrabutylammonium iodide (2.32 g, 6.28 mmol) and 2-(trimethylsilyl)ethoxymethyl chrolide (14.4 ml, 81.6 mmol) at 0 C. The reaction mixture was warmed up to 40 C, then stirred at 40 C for 24 hr, poured into water, and extracted with EtOAc. Organic extract was washed with saturated aqueous NaHCO 3 solution and brine, dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:10) to give 7 (29.0 g, 87%) as a colorless oil. IR(neat) 3082, 1670, 1639, 1409, 1210, 1143 cm -1 ; 1 H-NMR (CDCl 3 ) δ: (s, 9H), (ddd, 1H, J = 5.2, 11.6, 13.7 Hz), (ddd, 1H, J = 5.8, 11.3, 13.7 Hz), 1.05 (s, 3H), 1.62 (m, 1H), 1.87 (m, 2H), 2.03 (m, 2H), 2.14 (m, 1H), 2.70 (dd, 1H, J = 6.7, 13.3 Hz), 2.76 (dd, 1H J = 7.1, 13.3 Hz), 3.13 (dd, 1H, J = 5.8, 15.0 Hz), 3.55 (ddd, 1H, J = 5.8, 9.7, 11.3 Hz), 3.82 (brddd, 1H), 3.83 (m, 2H), 3.92 (m, 2H), 4.32 (d, 1H, J = 5.5 Hz), 4.72 (d, 1H, J = 7.3 Hz), 4.82 (d, 1H, J = 7.3 Hz), 5.08 (d, 1H, J = 10.1 Hz), 5.11 (d, 1H, J = 17.0 Hz), 5.72 (m, 1H); 13 C-NMR (CDCl 3 ) δ: -1.50, 14.6, 18.1, 20.9, 32.1, 34.8, 34.9, 44.3, 46.0, 64.5, 65.4, 65.5, 74.2, 96.4, , , 133.2, 133.4, 141.7; EI-MS m/z 528 (M + ), 455 (M + -Si(CH 3 ) 3 ), FAB-HRMS (matrix:peg-600) calcd for C 22 H 35 F 3 O 7 SSi (M + ) , found ([M+H] + ) 1

3 Suzuki coupling product 4 To a stirred solution of 4 (22.5 g, 42.5 mmol) in THF (50 ml) was added a solution of 9-BBN (0.5 M in THF, 102 ml) dropwise at 0 C. The reaction mixture was stirred at rt for 2 hr, quenched by addition of water (1.5 ml). To the residual solution were added K 3 PO 4 3H 2 O (28.3 g, mol), alkenyl iodide 8 (13.5 g, 46.8 mmol) and PdCl 2 (dppf) (933 mg, 1.27 mmol) and DMF (50 ml) at rt. After degassing, the reaction mixture was stirred at 60 C for 17 hr, then cooled down to 0 C and quenched by addition of 3 N aqueous NaOAc solution (20 ml) and 30% aqueous H 2 O 2 solution (20 ml) at 0 C. The quenched reaction mixture was stirred at rt for 10 hr, poured into water, and extracted with EtOAc. Organic extract was successively washed with saturated aqueous NaHCO 3 solution, 10% aqueous Na 2 S 2 O 3 solution and brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:20) to give 4 (18.9 g, 64 %) as a pale yellow oil. IR(neat) 2951, 1407, 1245, 1209, 1143, 1052, 836, 737 cm -1 ; 1H-NMR (CDCl 3 ) δ: 0.03 (s, 9H), 0.89 (ddd, J = 13.8, 11.6, 5.5 Hz, 1H), 0.98 (ddd, J = 13.8, 11.9, 5.8 Hz, 1H), 1.04 (s, 3H), 1.44 (m, 1H), (m, 2H), 1.73 (s, 3H), 1.77 (m, 1H), 1.92 (m, 2H), (m, 4H), 2.15 (ddd. J = 2.8, 11.3, 14.5 Hz, 1H), 2.30 (dt, J = 12.2, 5.5 Hz, 1H), 2.67 (dd, J = 12.4, 7.2 Hz, 1H), 3.54 (ddd, J = 11.6, 9.8, 5.8 Hz, 1H), 3.83 (m, 1H) (m, 4H), 3.98 (d, J = 7.0, 2H), 4.28 (m, 1H), 4.49 (s, 1H), 4.71 (d, J = 7.4, 1H), 4.81 (d, J = 7.4, 1H), 5.44 (t, J = 7.0, 1H), 7.27 (m, 1H), (m, 4H); 13 C- NMR (CDCl 3 ) δ: 1.52, 14.5, 18.1, 21.0, 23.3, 26.3, 27.8, 32.0, 34.8, 34.9, 44.2, 45.8, 64.5, 65.3, 65.5, 66.2, 72.2, 74.2, 96.4, 117.4, 118.5(ddd, coupled with 3F), 122.3, 127.5, 127.8, 128.3, 135.6, 138.4, 139.8, 141.1; ESI-MS m/z 713 [M+Na] +, FAB- HRMS (matrix:peg-600) calcd for C 33 H 49 F 3 O 8 SSi (M + ) , found ([M+H] + ) Heck product 3 After degassing a mixture of the coupling product 4 (18.9 g, 27.3 mmol), K 2 CO 3 (9.44g, 68.3 mmol), tetrabutylammonium bromide (8.80 g, 27.3 mmol), 1,3- bis(diphenylphosphino)propane (2.31 g, 5.60 mmol) and Pd(OAc) 2 (613 mg, 2.73 mmol) in toluene (90 ml), the reaction mixture was stirred at 100 C for 17 hr. After cooling down to rt, the reaction mixture was poured into water, and extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:20) to give 3 (9.60 g, 65%) as a colorless oil. 2

4 IR(neat) 2947, 1648, 1149, 1027, 836, 736, 696 cm -1 ; 1 H-NMR (CDCl 3 ) δ: 0.03 (s, 9H), (m, 2H), 0.97 (s, 3H), 1.26 (s, 3H), (m, 3H), 1.61 (m, 1H), (m, 2H), 1.79 (dd, J = 13..8, 5.8 Hz, 1H), (m, 3H), 2.03 (dt, J = 18.0, 5.2 Hz, 1H), 2.11 (ddd. J = 14.5, 11.3, 2.8 Hz, 1H), 2.34 (dd, J = 12.2, 7.4 Hz, 1H), 3.46 (ddd, J = 11.6, 9.8, 5.8 Hz, 1H), (m, 5H), 4.15 (m, 1H), 4.61 (d, J = 7.2, 1H), 4.65 (d, J = 7.2 Hz, 1H), 4.71 (s, 2H), 4.90 (d, J = 12.8 Hz, 1H), 6.21 (d, J = 12.8 Hz, 1H), 7.29 (m, 1H), (m, 4H); 13 C-NMR (CDCl 3 ) δ: 2.34, 13.7, 17.2, 17.3, 21.3, 25.8, 26.2, 34.2, 35.4, 36.4, 39.2, 43.4, 47.1, 63.6, 64.3, 70.3, 76.3, 95.4, 115.0, 117.9, 126.7, 126.9, 127.5, 132.2, 133.4, 136.4, 144.2; ESI-MS m/z 563 [M+Na] +, FAB- HRMS (matrix:peg-600) calcd for C 32 H 48 O 5 Si (M + ) , found ([M+H] + ) α-oh 9 A mixture of 3 (13.2 g, 24.4 mmol) and anhydrous CsF (18.6 g, 122 mmol) in DMF (70 ml) was stirred at 130 C for 45 hr. After cooling down to rt, the reaction mixture was poured into water, and extracted 3 times with Et 2 O. Organic extract was washed with brine, dried (Na 2 SO 4 ), and concentrated to give crude β-oh. To a solution of crude β-oh in CH 2 Cl 2 (100 ml) were added sodium acetate (40 g, 0.49 mol) and pyridinium dichromate (18.4 g, 48.8 mmol) at rt. The reaction mixture was stirred at rt for 1 hr, diluted with Et 2 O, filtered through Celite pad and the Celite pad was washed with Et 2 O. The filtrate was washed with water and brine, dried (MgSO 4 ), and concentrated to give crude enone. To a stirred solution of crude enone in toluene (100 ml) was added diisobutylaluminum hydride (48.8 ml, 1.0 M solution in toluene, 48.8 mmol) at -78 C. The reaction mixture was stirred at -78 C for 20 min, quenched by addition of water and Rochelle s salt (34g, mol). After being stirred at rt for 3 hr, the quenched reaction mixture was poured into water, and extracted with EtOAc. Organic extract was washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (Et 2 O-hexane = 1:5) to give 9 (more polar, 4.50 g, 45% in 3 steps) as a white solid and the diastereomer (β-oh) (less polar, 4.0g, 40% in 3 steps) IR(KBr) 3516, 2942, 1626, 1147, 1030, 848, 747, 698 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: 0.92 (s, 3H), (m, 4H), 1.38 (s, 3H), (m, 2H), (m, 2H), 1.92 (ddd, J = 14.4, 9.3, 7.2 Hz, 1H), (m, 4H), 2.82 (m, 1H), (m, 4H), 4.42 (s, 2H), 4.67 (m, 1H), 5.09 (d, J = 12.8 Hz, 1H), 6.40 (d, J = 12.8 Hz, 1H), 7.07 (m, 1H), (m, 4H); 13 C-NMR (C 6 D 6 ) δ: 13.7, 17.3, 21.3, 26.1, 26.6, 34.3, 35.6, 39.6, 39.8, 46.4, 63.8, 64.4, 68.2, 70.4, 114.8, 118.0, 126.8, 127.0, 127.7, 132.0, 133.7, 136.9, 3

5 146.6; ESI-MS m/z 433 [M+Na] +, Anal. Calcd for C 26 H 34 O 4 : C, 76.06; H, Found: C, 76.03; H, TBS ether 10 To a stirred solution of 9 (95 mg, mmol) in DMF (0.3 ml) were added imidazole (31.4 mg, mmol) and tert-butyldimethylsilyl chloride (52.2 mg, mmol) at rt. The reaction mixture was stirred at rt for 24 hr, poured into saturated aqueous NaHCO 3 solution and extracted with Et 2 O. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:5) to give 10 (105 mg, 86%) as a white solid. IR(KBr) 2949, 1654, 1046, 862, 769, 696 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: 0.19 (s, 3H), 0.20 (s, 3H), 0.95 (s, 3H), 1.06 (s, 9H), (m, 3H), 1.32 (s, 3H), 1.56 (m, 1H), (m, 3H), 1.91 (ddd, J = 14.4, 9.2, 7.0 Hz, 1H), 1.98 (dd, J = 11.8, 7.1 Hz, 1H), 2.08 (ddd, J = 14.4, 11.3, 2.8 Hz, 1H), 2.14 (dd, J = 11.8, 8.9 Hz, 1H), 2.89 (brdd, 1H), (m, 4H), 4.62 (s, 2H), 4.75 (brdd, 1H), 4.95 (d, J = 12.8 Hz, 1H), 6.46 (d, J = 12.8 Hz, 1H), 7.08 (t, J = 7.4 Hz 1H), 7.17 (brdd, 2H), 7.36 (d, J = 7.0 Hz, 2H); 13 C-NMR (C 6 D 6 ) δ: 5.38, 3.33, 14.1, 17.4, 17.7, 21.2, 25.6, 26.6, 27.1, 34.3, 36.4, 40.0, 41.1, 45.7, 46.8, 63.7, 64.4, 69.4, 69.7, 113.5, 118.1, , , 127.7, 132.3, 134.0, 137.6, 147.0; ESI-MS m/z 547 [M+Na] +, Anal. Calcd for C 32 H 48 O 4 Si: C, 73.24; H, Found: C, 73.05; H, Diol 11 A mixture of 10 (105 mg, mmol), 4-methylmorpholine N-oxide (46.4 mg, mmol), OsO 4 (50 µl of 0.2M tbuoh solution, 9.9 µmol) in acetone (3 ml) and H 2 O (1 ml) was stirred at rt for 65 hr, then poured into 10% aqueous NaHSO 3 solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ) and concentrated to give crude hydroxyaldehyde. To a stirred solution of crude hydroxyaldehyde in THF (1 ml) was added lithium aluminum hydride (9.4mg (80 % purity), mmol) at 40 C. The reaction mixture was stirred at 40 C for 20 min, quenched by addition of water and excess Rochelle s salt. After being stirred at rt for 15 hr, the quenched reaction mixture was poured into water, and extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:4) to give 11 (more polar, 37.5 mg, 42% in 2 steps) as a colorless oil, and the undesired isomer (less polar, 44.5 mg, 50% in 2 steps) was isolated. 4

6 IR(neat) 3384, 2951, 1044, 835, 774 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: 0.15 (s, 3H), 0.21 (s, 3H), 0.86 (s, 3H), (m, 3H), 1.03 (s, 9H), 1.16 (s, 3H), (m, 2H), (m, 2H), (m, 3H), (m, 2H), 2.02 (ddd, J = 14.4, 11.3, 2.8 Hz, 1H), 2.15 (dd, J = 11.9, 8.3 Hz, 1H), 2.40 (d, J = 6.7 Hz, 1H), 2.80 (m, 1H), (m, 4H), 3.66 (t, J = 9.5 Hz, 1H), 3.80 (m, 1H), 4.05 (m, 1H), 4.51 (s, 1H), 4.68 (m, 1H); 13 C-NMR (C 6 D 6 ) δ: 4.56, 3.59, 14.3, 17.4, 18.1, 21.2, 21.6, 25.8, 26.4, 34.5, 39.8, 40.9, 45.7, 47.5, 63.3, 64.0, 64.7, 70.4, 76.0, 118.2, 133.9, 136.2; ESI-MS m/z 475 [M+Na] +, EI-HRMS calcd for C 25 H 44 O 5 Si (M + ) , found At this stage, the undesired diastereomer of 11 (less polar) was recrystallized from acetone and the X-ray crystallographic analysis succeeded in confirming the stereochemistry. Acetate 12 To a stirred solution of 11 (1.73g, 3.82 mmol) in MeI (4.8 ml) was added Ag 2 O (4.43 g, 19.1 mmol) at rt. The reaction mixture was stirred at rt under dark for 15 hr, filtered through Celite pad and the Celite pad was washed with Et 2 O. The filtrate was concentrated to give crude monomethyl ether. To a stirred solution of the crude monomethyl ether in CH 2 Cl 2 (5 ml) were added pyridine (0.92 ml, 11.5 mmol), 4- dimethylaminopyridine (46 mg, 0.38 mmol), and Ac 2 O (0.72 ml, 7,7 mmol) at rt. The reaction mixture was stirred at rt for 20 hr, diluted with EtOAc, poured into saturated aqueous NH 4 Cl solution and extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ) and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:20) to give 12 (1.75 g, 90% in 2 steps) as a colorless oil. IR(neat) 2950, 1742, 1239, 1042, 837, 776 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: 0.25 (s, 3H), 0.51 (s, 3H), 0.91 (s, 3H), 1.08 (m, 1H), 1.12 (s, 9H), 1.20 (s, 3H), 1.37 (qd, J = 12.2, 7.0 Hz, 1H), 1.46 (m, 1H), (m, 2H), (m, 2H), 1.83 (s, 3H), 1.84 (dd, J = 12.5, 6.7 Hz, 1H), 1.92 (ddd, J = 14.3, 9.5, 7.1 Hz, 1H), 2.07 (ddd, J = 14.3, 11.3, 2.8 Hz, 1H), 2.19 (dd, J = 12.5, 6.7 Hz, 1H), 2.25 (ddd, J = 13.8, 4.7, 3.7 Hz, 1H), 2.99 (m, 1H), 3.17 (s, 3H), (m, 5H), 3.83 (dd, J = 9.6, 2.3 Hz, 1H), 4.85 (dt, J = 6.7, 1.6 Hz,1H), 6.00 (dd, J = 9.6, 2.0 Hz, 1H); 13 C-NMR (C 6 D 6 ) δ: 4.37, 4.16, 14.9, 17.6, 19.0, 19.9, 20.7, 25.5, 25.7, 26.8, 32.0, 34.1, 39.3, 40.6, 45.1, 47.2, 57.7, 63.5, 64.2, 5

7 68.2, 73.2, 77.4, 117.7, 132.1, 136.2, 168.9; ESI-MS m/z 531 [M+Na] +, EI-HRMS calcd for C 28 H 48 O 6 Si (M + ) , found Enone 13 To a stirred suspension of chromium trioxide (6.20 g, 51.5 mmol) in CH 2 Cl 2 (20 ml) was added recrystallized 3,5-dimethylpyrazole (4.95 g, 51.5 mmol) in one portion at -20 C. After being stirred vigorously at -20 C for 20 min, a solution of 12 (1.75 g, 3.43 mmol) in CH 2 Cl 2 (8 ml) was added to the mixture at 20 C. The reaction mixture was stirred at -20 C for 30 min, diluted with EtOAc, poured into 1 N aqueous HCl solution, extracted with EtOAc. Organic extract was successively washed with water, saturated aqueous NaHCO 3 solution and brine, dried (MgSO 4 ) and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:5) to give 13 (1.16 g, 65%) as a white solid. IR(neat) 2929, 1746, 1671, 1234, 1045, 833, 776 cm -1 ; 1 H-NMR (CDCl 3 ) δ: 0.17 (s, 3H), 0.24 (s, 3H), 0.79 (s, 3H), 0.93 (s, 9H), 1.28 (s, 3H), 1.32 (m, 1H), 1.67 (td, J = 13.7, 6.4 Hz, 1H), 1.80 (dd, J = 11.8, 9.3Hz, 1H), (m, 3H), 2.12 (s, 3H), 2.25 (ddd, J = 13.7, 5.8, 2.5 Hz, 1H), 2.34 (ddd, J = 19.2, 6.4, 2.5 Hz, 1H), 2.49 (m, 1H), 2.67 (ddd, J = 19.2, 13.7, 5.8 Hz, 1H), 2.80 (ddd, J = 12.8, 7.0, 2.6 Hz, 1H), 3.17 (s, 3H), 3.31 (dd, J = 10.1, 8.4 Hz, 1H), 3.42 (dd, J = 10.1, 2.9 Hz,1H), 3.82 (m,1h), (m, 2H), 3.97 (m,1h), 4.80 (ddd, J = 9.3, 7.0, 2.6 Hz, 1H), 5.60 (dd, J = 8.4, 2.9 Hz, 1H); 13 C-NMR (CDCl 3 ) δ: 4.81, 13.5, 17.2, 19.9, 22.6, 25.0, 25.1, 30.8, 33.4, 33.9, 38.8, 40.4, 41.6, 45.3, 57.7, 63.4, 64.2, 69.2, 71.7, 76.2, 116.8, 136.2, 154,6, 169.6, 198.4; ESI-MS m/z 545 [M+Na] +, EI-HRMS calcd for C 28 H 46 O 7 Si (M + ) , found Allyl ether of diosphenol 14 To a stirred solution of 13 (1.16 g, 2.28 mmol) in CH 2 Cl 2 (15 ml) were added ipr 2 NEt (2.38 ml, 13.7 mmol) and TMSOTf (2.06 ml, 11.4 mmol) at -78 C. The reaction mixture was stirred at -78 C for 2 hr, quenched by addition of saturated aqueous NaHCO 3 solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. To the residual oil was added freshly prepared acetone solution of dimethyldioxirane (excess, ca M) at rt. After being stirred at rt for 5 min, solvent was evaporated. To a stirred solution of the residual oil in MeOH (5 ml) was added pyridinium p-toluenesulfonate (excess) at rt. The reaction mixture was stirred at rt for 10 min, quenched by addition of saturated aqueous NaHCO 3 solution, extracted with CH 2 Cl 2. Organic extract was washed with brine, dried (MgSO 4 ), and 6

8 concentrated to give crude α-hydroxyketone. To a stirred solution of oxalyl chloride (389 µl, 4.56 mmol) in CH 2 Cl 2 (5 ml) was added DMSO (486 µl, 6.84 mmol) at 78 C. After being stirred at 78 C for 15 min, a solution of the crude α-hydroxyketone in CH 2 Cl 2 (5 ml) was added to the mixture at 78 C. The reaction mixture was stirred at 40 C for 50 min. To the stirred reaction mixture was added triethylamine (1.58 ml, 11.4 mmol) at 40 C. The reaction mixture was stirred at 40 C for 15 min, quenched by addition of saturated aqueous NH 4 Cl solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated to give crude diosphenol. To a stirred solution of the crude diosphenol in acetone (20 ml) were added K 2 CO 3 (1.58 g, 11.4 mmol) and allyl bromide (1.0 ml, 11.4 mmol) at rt. The reaction mixture was stirred at 50 C for 40 hr, poured into 1N aqueous NaOH solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:9) to give 14(860 mg, 67% in 5 steps) as a off-white solid. IR(neat) 2933, 1748, 1654, 1230, 1123, 1051, 837, 778 cm -1 ; 1 H-NMR (CDCl 3 ) δ: (s, 3H), (s, 3H), (s, 3H), (s, 9H), 1.34 (s, 3H), 1.58 (m, 1H), 1.83 (dd, J = 12.5, 6.7 Hz, 1H), 1.89 (m, 1H), (m, 2H), 2.14 (s, 3H), 2.59 (m, 1H), 2.97 (ddd, J = 12.9, 7.0, 2.1 Hz, 1H), 3.03 (dd, J = 10.2, 8.9 Hz, 1H), 3.13 (s, 3H), 3.26 (dd, J = 10.2, 3.1 Hz, 1H), (m, 4H), 4.39 (d, J = 5.5 Hz, 2H) 4.86 (m, 1H), 5.28 (dd, J = 10.4, 1.3 Hz, 1H), 5.38 (dd, J = 17.3, 1.3 Hz, 1H), 5.82 (s, 1H), 5.93 (dd, J = 8.9, 3.1 Hz, 1H), 6.03 (ddt, J = 17.3, 10.4, 5.5 Hz, 1H); 13 C-NMR (CDCl 3 ) δ: 3.74, 3.36, 15.8, 18.3, 21.1, 22.7, 23.4, 26.2, 34,7, 39.9, 42.6, 45.1, 47.2, 59.0, 64.4, 65.3, 68.6, 69.7, 71.6, 76.4, 117.8, 118.2, 120.3, 132.7, 137.7, 149.0, 153.0, 170.5, 181.6; ESI-MS m/z 599 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 31 H 48 O 8 Si (M + ) , found ([M+H] + ) Cyclic orthoformate 15 A solution of 14 (199.4 mg, mmol) in xylene (2 ml) was stirred at 200 C for 50 min, then concentrated. To a solution of the residual oil in MeOH (10 ml) was added CeCl 3 7H 2 O (528 mg, 1.38 mmol) at rt. After completely dissolving CeCl 3 7H 2 O, NaBH 4 (762 mg, 20.1 mmol) was added portionwise to the stirred solution at 0 C. The reaction mixture was stirred at 0 C for 1 hr, quenched by addition of acetone and water, and extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. To a stirred solution of the residual oil in HC(OMe) 3 (3 ml) was added pyridinium p-toluenesulfonate (8.9 mg, mmol) at 7

9 rt. The reaction mixture was stirred at rt for 1 hr, quenched by addition of saturated aqueous NaHCO 3 solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:9 to 1:5 to 1:1) to give 15(144 mg, 67% in 3 steps, including several diastereomers) as colorless oil. major diastereomer of 15 IR(neat) 2929, 1742, 1236, 1099, 1045, 839, 777 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: (s, 3H), (s, 3H), (s, 3H), (s, 3H), 1.07 (s, 9H), 1.17 (dd, J = 14.4, 6.1 Hz, 1H), 1.85 (m, 1H), (m, 4H), 2.40 (brt, J = 7.5 Hz, 1H), 2.43 (brt, J = 7.5 Hz, 1H), 2.98 (m, 1H), 3.08 (s, 3H), 3.14 (s, 3H), (m, 2H), (m, 4H), 3.74 (dd, J = 9.8, 2.1 Hz, 1H), 4.19 (dd, J = 9.9, 6.4 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 4.99 (brd, 1H), 5.12 (brd, 1H), 5.27 (dd, J = 7.1, 2.1 Hz, 1H), 5.81 (s, 1H), 5.95 (dd, J = 9.5, 2.1 Hz, 1H) 6.33 (ddt, J = 17.1, 9.5, 7.5 Hz, 1H); 13 C-NMR (C 6 D 6 ) δ: 5.27, 3.49, 16.8, 17.3, 19.1, 19,6, 25.4, 29.0, 32.7, 34.2, 38.7, 39.4, 41.6, 44.6, 49.5, 50.2, 57.6, 63.0, 63.8, 66.4, 70.5, 71.6, 75.5, 75.9, 114.3, 114.5, 116.9, 132.6, 137.9, 141.3, 169.1; ESI-MS m/z 645 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 33 H 54 O 9 Si (M + ) , found ([M+H] + ) Aldehyde 16 To a stirred solution of 15 (144 mg, mmol) in CH 3 CN (1 ml) and H 2 O (0.5 ml) were added 4-methylmorpholine N-oxide (54.2 mg, mmol) and OsO 4 (58 µl of 0.2M solution in tbuoh, 11.6 µmol) at rt. The reaction mixture was stirred at rt for 18 hr, diluted with EtOAc and poured into 10% aqueous NaHSO 3 solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ) and concentrated to give crude diol. To a stirred solution of the crude diol in CHCl 3 (2 ml) was added nbu 4 NIO 4 (300 mg, mmol) at rt. The reaction mixture was stirred at 50 C for 12 hr, then, concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:3 to 1:1) to give 16 (85.5 mg, 59% in 2 steps, including several diastereomers) as colorless oil. major diastereomer of 16 IR(neat) 2930, 1747, 1653, 1230, 1099, 837, 778 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: (s, 3H), (s, 3H), (s, 6H), 1.05 (s, 9H), 1.07 (m, 1H), 1.68 (s, 3H), (m, 4H), 2.31 (ddd, J = 16.8, 9.2, 2.8 Hz, 1H), 2.44 (d, J = 14.7 Hz, 1H), 2.68 (ddd, J = 11.0, 9, Hz, 1H), 3.03 (s, 3H), 3.07 (s, 3H), 3.08 (m, 1H), (m, 2H), 3.49 (dd, J = 13.8, 7.5 Hz, 1H), (m, 2H), 3.62 (dd, J = 9.9, 8.3 Hz, 1H), 3.77 (dd, J 8

10 = 9.8, 2.5 Hz, 1H), 3.82 (dd, J = 11.0, 5.8 Hz, 1H), 4.50 (d, J = 5.8 Hz 1H), 4.91 (brd, J = 5.8 Hz 1H), 5,76 (s, 1H), 5.82 (dd, J = 8.3, 2.5 Hz, 1H), 9.87 (d, J = 2.8 Hz, 1H); 13 C- NMR (C 6 D 6 ) δ: 5.37, 3.36, 15.6, 17.2, 17.7, 18.7, 19.5, 25.4, 34.2, 35.4, 38.5, 41.4, 42.6, 44.2, 49.9, 50.4, 57.6, 62.9, 63.8, 66.0, 70.3, 70.9, 75.1, 76.3, 114.8, 116.8, 133.2, 142.0, 168.9, 199.1; ESI-MS m/z 647 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 32 H 52 O 10 Si (M + ) , found ([M+H] + ) Lactone 2 To a stirred solution of 16 (85.5 mg, mmol) in MeOH (2 ml) was added K 2 CO 3 (94 mg, 0.68 mmol) at rt. The reaction mixture was stirred at rt for 24 hr, poured into water, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated to give crude hemiacetal. To a stirred solution of the crude hemiacetal in CH 2 Cl 2 (2 ml) were added MS4A (68 mg), 4-methylmorpholine N-oxide (15.9 mg, mmol), and tetrapropylammonium perruthenate (TPAP, 4.8 mg, mmol) at rt. The reaction mixture was stirred at rt for 30 min, then concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane =1:5 to 1:3 to 1:1) to give 2 (59.5 mg, 75% in 2 steps, including several diastereomers) as colorless oil. major diastereomer of 2 IR(neat) 2935, 1740, 1119, 1070, 837, 780 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: (s, 3H), (s, 3H), 0.73 (s, 3H), 0.81 (s, 3H), 0.91 (s, 9H), 1.54 (m, 1H), 1.76 (dd, J = 12.5, 6.4 Hz, 1H), 1.88 (m, 1H), (m, 2H), 2.16 (dd, J = 12.5, 8.2 Hz, 1H), 2.35 (dd, J = 18.6, 11.4 Hz, 1H), 2.59 (dt, J = 1.4, 6.4 Hz, 1H), 3.02 (s, 3H), 3.06 (s, 3H), 3.11 (m, 1H), 3.22 (dd, J = 18.6, 6.4 Hz, 1H), (m, 4H), 3.54 (dd, J = 11.0, 4.5 Hz, 1H), 3.63 (dd, J = 11.0, 2.9 Hz, 1H), 3.64 (dd, J = 11.4, 6.4 Hz, 1H), 4.29 (d, J = 6.4 Hz 1H), 4.64 (m, 1H), 5.01 (dd, J = 4.5, 2.9 Hz, 1H), 5.62 (s, 1H); 13 C-NMR (C 6 D 6 ) δ: 4.40, 3.63, 15.0, 17.5, 18.0, 21.2, 25.9, 31.4, 34.4, 45.5, 41.0, , 48.4, 50.8, 58.9, 63.9, 64.7, 69.5, 70.9, 72.9, 74.9, 82.8, 114.9, 117.7, 132.6, 139.3, 168.2; ESI-MS m/z 603 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 30 H 48 O 9 Si (M + ) , found ([M+H] + ) Enol 17 A mixture of 2 (144.0 mg, mmol) and HC(NM 2 ) 3 (0.5 ml) in DMF (1 ml) was stirred at 100 C for 48 hr, then concentrated. The residue was dissolved in 9

11 THF (1 ml), and phosphate buffer (ca 0.2 M KH 2 PO 4 solution) and 0.1M tartaric acid solution was added to adjust the ph of the reaction medium around 4 (checked by universal paper). The reaction mixture was stirred at rt for 6 hr, poured into saturated aqueous NaHCO 3 solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:3 to EtOAc only) to give 17 (109 mg, 72% in 2 steps, including several diastereomers) as a white solid. major diastereomer of 17 IR(neat) 2935, 1659, 1416, 1120, 1068, 837, 779 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: (s, 3H), (s, 3H), 0.71 (s, 3H), 0.82 (s, 3H), 0.93 (s, 9H), 1.54 (m, 1H), 1.73 (dd, J = 12.5, 6.6 Hz, 1H), 1.89 (m, 1H), (m, 2H), 2.19 (dd, J = 12.5, 8.0 Hz, 1H), 2.95 (d, J = 10.7, 1.5 Hz, 1H), 2.98 (s, 3H), 3.00 (s, 3H), 3.12 (m, 1H), 3.39 (dd, J = 10.7, 5.4 Hz, 1H), (m, 4H), 3.66 (dd, J = 10.7, 3.1 Hz, 1H), 3.93 (dd, J = 10.7, 7.0 Hz, 1H), 4.31 (d, J = 7.0 Hz, 1H), 4.61 (m, 1H), 5.03 (dd, J = 5.4, 3.1 Hz 1H), 5.56 (s, 1H), 8.27 (dd, J = 12.2, 1.5 Hz, 1H), 14.0 (d, J = 12.2 Hz, 1H); 13 C-NMR (C 6 D 6 ) δ: 4.43, 3.63, 15.0, 17.9, 18.9, 21.0, 25.8, 34.3, 37.7, 40.8, 41.0, 43.8, 48.4, 50.8, 58.6, 63,8, 64.6, 69.3, 70.8, 72.9, 73.8, 82.7, 100.2, 114.3, 117.5, 132.2, 138.4, 165.1, 171.3; ESI-MS m/z 631 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 31 H 48 O 10 Si (M + ) , found ([M+H] + ) Diol 18 To a stirred solution of 17 (64.7mg, mmol) in acetone (1 ml) were successively added K 2 CO 3 (58.8 mg, mmol) and Me 2 SO 4 (30.1 µl, mmol) at rt. The reaction mixture was stirred at rt for 7hr, quenched by addition of 1N aqueous NaOH solution, extracted with EtOAc. Organic extract was successively washed with 1N aqueous HCl solution, water, and brine, dried (MgSO 4 ), and concentrated. To a solution of the residue in THF (0.5 ml) was added 1N aqueous NaOH solution (0.5 ml) at rt. The reaction mixture was stirred at rt for 15 min, poured into water, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc only to acetone only ) to give 18 (11.7 mg of minor diasterereomer (less polar product), 19%, 36.3 mg of major diastereomer (more polar product), 59%) as a white solid major diastereomer of 18 IR(neat) 3502, 2932, 1712, 1645, 1122, 837, 777 cm -1 ; 1 H-NMR (C 6 D 6 ) δ: (s, 6H), (s, 3H), (s, 9H), 1.17 (s, 3H), 1.49 (m, 1H), 1.83 (dd, J = 11.9, 6.1 Hz, 10

12 1H), (m, 4H), 2.66 (d, J = 4.9 Hz, 1H), 2.94 (ddd, J = 13.2, 7.1, 3.2 Hz, 1H), 3.33 (s, 3H), 3.52 (dd, J = 11.6, 1.2 Hz, 1H), 3.63 (dd, J = 11.0, 2.7 Hz, 1H), 3.74 (dd, J = 11.0, 4.9 Hz, 1H), (m, 3H), (m, 2H), 3.91 (s,3h), 3.97 (t, J = 6.6 Hz 1H), 4.10 (brt, J = 3.8 Hz 1H), 4,70 (m, 1H), 4.97 (dd, J = 4.9, 2.7 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H); 13 C-NMR (C 6 D 6 ) δ: 4.85, 4.19, 14.3, 17.5,18.2, 21.3, 25.3, 34.0, 37.7, 40.5, 42.0, 44.3, 46.3, 58.8, 61.6, 63.9, 64.5, 64.9, 66.6, 70.7, 73.0, 85.6, 106.7, 117.6, 134.0, 134.6, 155.6, 166.9; ESI-MS m/z 603 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 30 H 48 O 9 Si (M + ) , found ([M+H] + ) Enone 19 To a stirred mixture of major diastereomer of 18 (17.3 mg, mmol) and NaOAc (48.9 mg, 0.60 mmol) in CH 2 Cl 2 (1.0 ml) was added pyridinium dichromate (16.8 mg, mmol) at rt. The reaction mixture was stirred at rt for 20 hr, filtered through Celite pad and the Celite pad was washed with acetone. The filtrate was concentrated and the residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:1 to EtOAc only) to give 19 (12.3 mg, 71%) as white solid and recovery of 18 (0.8 mg, 4.6%). IR(KBr) 3431, 2953, 1716, 1672, 1641, 1136, 1117, 841, 779 cm -1 ; 1 H-NMR (CDCl 3 ) δ: 0.163(s, 6H), (s, 3H), 0.911(s, 9H), 1.30 (m, 1H), 1.42 (s, 3H), (m, 4H), 2.45 (m, 1H), 2.89 (ddd, J = 12.8, 7.0, 3.5 Hz, 1H), 3.25 (s, 3H), 3.42 (dd, J = 13.5, 1.5 Hz, 1H), 3.56 (dd, J = 10.7, 4.3 Hz, 1H), 3.59 (dd, J = 10.7, 3.4 Hz, 1H), (m, 5H), 3.89 (s, 3H), 4.45 (dd, J = 13.5, 3.4 Hz 1H), 4.87 (ddd, J = 10.1, 6.4, 3.5 Hz 1H), 5.00 (dd, J = 4.3, 3.4 Hz, 1H) 7.45 (d, J = 1.5 Hz, 1H); 13 C-NMR (CDCl 3 ) δ: 5.07, 4.43, 15.1, 17.4, 18.2, 22.6, 25.3, 33.9, 39.7, 42.3, 42.6, 43.6, 46.4, 58.3, 60.2, 63.4, 64.3, 68.4, 71.0, 73.4, 84.5, 104.0, , 133.5, 153.3, 158.1, 164.9, 198.8; ESI- MS m/z 601 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 30 H 46 O 9 Si (M + ) , found ([M+H] + ) Diosphenol 20 To a stirred solution of oxalyl chloride (5.3 µl, mmol) in CH 2 Cl 2 (0.2 ml) was added DMSO (8.8 µl, mmol) at 78 C. After being stirred at 78 C for 15 min, a solution of 18 (12.0 mg, mmol) in CH 2 Cl 2 (0.3 ml) was added to the mixture at 78 C. After being stirred at 20 C for 1 hr, triethylamine (17.2 µl, mmol) was added to the stirred reaction mixture at 20 C. The reaction mixture 11

13 was stirred at 20 C for 20 min, quenched by the addition of saturated aqueous NH 4 Cl solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by flash silica gel column chromatography (EtOAc-hexane = 1:2) to give 20 (9.0 mg, 75%) as a white solid IR(neat) 3384, 2929, 1747, 1107, 838, 779 cm -1 ; 1 H-NMR (CDCl 3 ) δ: 0.172(s, 3H), (s, 3H), (s, 3H), 0.920(s, 9H), 1.54 (m, 1H), 1.55 (s, 3H), (m, 3H), 2.03 (m, 1H), 2.66 (m, 1H), 2.94 (ddd, J = 12.5, 7.2, 2.8 Hz, 1H), 3.13 (dd, J = 11.0, 5.8 Hz, 1H), 3.14 (s, 3H), 3.31 (dd, J = 11.0, 3.1 Hz, 1H), 3.84 (dd, J = 12.8, 6.4 Hz, 1H), (m, 2H), 3.99 (dd, J = 12.8, 6.1 Hz 1H), 4.02 (s, 3H), 5.00 (td, J = 8.8, 2.8 Hz 1H), 5.47 (dd, J = 5.8, 3.1 Hz, 1H) 6.95 (s, 1H), 7.81 (s, 1H); 13 C-NMR (CDCl 3 ) δ: 5.09, 4.54, 14.0, 17.1, 22.0, 22.4, 24.9, 33.4, 38.9, 41.8, 42.4, 45.6, 58.2, 61.8, 63.5, 64.3, 69.9, 71.3, 81.5, 101.0, 116.5, 120.1, 134.5, 140.6, 153.2, 162.1, 163.9, 179.8; ESI-MS m/z 599 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 30 H 44 O 9 Si (M + ) , found ([M+H] + ) TBS-wortmannin 22 To a stirred solution of 20 (3.5 mg, 6.0 µmol) in CH 2 Cl 2 (0.2 ml) was added Et 2 NH (6.3 µl, 0.06 mmol) at rt. The reaction mixture was stirred at rt for 20 min, then concentrated. To a solution of the residue in THF (0.2 ml) was added 1N aqueous HCl solution (0.2 ml) at rt. The reaction mixture was stirred at rt for 45 hr, poured into water, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by preparative thin layer chromatography (EtOAc-hexane = 1:5) to give 22 (1.8 mg, 60%) as a white solid IR(neat) 2925, 1741, 1674, 1542, 1100, 861, 835 cm -1 ; 1 H-NMR (CDCl 3 ) δ: 0.231(s, 3H), (s, 3H), (s, 3H), (s, 9H), 1.71 (dd, J = 12.5, 9.8 Hz, 1H), 1.75 (s, 3H), 2.01 (m, 1H), 2.22 (dt, J = 19.6, 9.0 Hz, 1H), 2.38 (dd, J = 12.5, 6.7 Hz, 1H), 2.58 (dd, J = 19.6, 8.4 Hz, 1H), 2.87 (ddd, J = 13.0, 5,7, 3.1 Hz, 1H), 3.06 (s, 3H), 3.10 (dd, J = 10.8, 6.0 Hz, 1H), 3.16 (m, 1H), 3.45 (dd, J = 10.8, 2.9 Hz, 1H), 5.11(ddd, J = 9.8, 6.7, 3.1 Hz 1H), 5.34 (dd, J = 6.0, 2.9 Hz 1H), 8.20 (s, 1H); 13 C-NMR (CDCl 3 ) δ: 3.91, 3.02, 14.7, 18.3, 23.1, 25.9, 26.2, 29.7, 35.8, 39.8, 44.2, 49.1, 59.3, 71.0, 72.5, 87.7, 114.7, 137.3, 144.0, 144.9, 149.7, 153.3, 158.5, 173.5, 216.7; ESI-MS m/z 523 [M+Na] +, FAB-HRMS (matrix:peg-600) calcd for C 27 H 36 O 7 Si (M + ) , found ([M+H] + ) 12

14 (±)-wortmannin To a stirred solution of 22 (1.9 mg, 3.8µmol) in THF (0.2 ml) was added 3HF Et 3 N (0.1 ml) at rt. The reaction mixture was stirred at 40 C for 75 hr, then silica gel and CH 2 Cl 2 was added to the reaction mixture. After stirring at rt for 1hr, the reaction mixture was filtrated through Celite pad and the Celite pad was washd with CH 2 Cl 2. The filtrate was washed with 1N aqueous HCl solution, water, and brine, dried (MgSO 4 ), and concentrated. To a stirred solution of the residual oil in pyridine (0.1 ml) was added Ac 2 O (3.6 µl, 38 mol) at rt. The reaction mixture was stirred at rt for 20 hr, poured into 1N aqueous HCl solution, extracted with EtOAc. Organic extract was washed with brine, dried (MgSO 4 ), and concentrated. The residue was purified by preparative thin layer chromatography (EtOAc-hexane = 1:4) to give (±)-wortmannin (0.5 mg, 31% in 2 steps) as white solid and recovery of 22 (0.14 mg, 7.4%). 1 H-NMR (CDCl 3 ) δ: 0.94 (s, 3H), (s, 9H), 1.59 (m, 1H), 1.74 (s, 3H), 2.05 (m, 1H), 2.14 (s, 3H), 2.25 (m, 1H), (m, 2H), 2.88 (ddd, J = 12.5, 6.1, 2.6 Hz, 1H), 3.00 (dd, J = 11.3, 7.0 Hz, 3H), 3.19 (s, 3H), 3.45 (dd, J = 11.3, 1.8 Hz, 1H), 4.76 (dd, J = 7.0, 1.8 Hz 1H), 6.16 (dd, J = 8.8, 2.8 Hz 1H), 8.25 (s, 1H); 13 C-NMR (CDCl 3 ) δ: 13.4, 19.8, 21.7, 25.3, 34.5, 35.0, 39.6, 42.9, 48.0, 58.2, 68.9, 71.7, 87.3, 113.1, 139.2, 141.7, 143.6, 148.3, 148.8, 156.4, 168.3, 171.4, FAB-HRMS (matrix:peg-600) calcd for C 23 H 24 O 8 (M + ) , found ([M+H] + ) 13

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