Total Synthesis of (+) Vicenin-2

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1 Supporting Information Total Synthesis of (+) Vicenin-2 Thanh C. Ho, Haruki Kamimura, Ken Ohmori,* and Keisuke Suzuki* Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo , Japan * *kohmori@chem.titech.ac.jp *ksuzuki@chem.titech.ac.jp Table of Contents General Information and Experimental Procedures...S1 1 H-NMR, 13 C-NMR, and 19 F-NMR spectra......s13

2 General information All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under an atmosphere of dry argon. Ethereal solvents and dichloromethane (anhydrous; Kanto Chemical Co., Inc.) were purified under argon, using an Organic Solvent Pure Unit (Wako Pure Chemical Industries, Ltd.). For thin-layer chromatography (TLC) analysis, Merck pre-coated plates (TLC silica gel 60 F254, Art 5715, 0.25 mm) were used. Silica-gel preparative thin-layer chromatography (PTLC) was performed using plates prepared from Merck Silica gel 60 PF254 (Art 7747). For flash column chromatography, silica gel 60N (Spherical, neutral, μm) from Kanto Chemical was used. Melting point (mp) determinations were performed by using a Mettler Toledo MP-70 melting point system, and are uncorrected. 1 H-, 13 C- and 19 F-NMR were measured on a Bruker DRX-500 (500MHz), a Bruker Advance-600 (600 MHz) or a JEOL JNM ECX-400 (400 MHz) spectrometer in the solvent indicated; Chemical shifts (δ) are expressed in parts per million (ppm) and are referenced to internal standard (hexafluorobenzene for 19 F-NMR), (tetramethylsilane 0.00 for 1 H-NMR) or to the solvent, i.e. 7.26/77.0 for CHCl 3 /CDCl 3 and coupling constants are reported as hertz (Hz). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Infrared (IR) spectra were recorded on a Thermo Fisher Scientific Nicolet is5 FT-IR spectropolarimeter. High-resolution mass spectra (HRMS) were obtained with Bruker Daltonics microtof-q II. High-performance liquid chromatography (HPLC) analyses were performed on a JASCO CO-2060 plus for column thermostat, UV-2077 plus for UV/VIS detector, PU-1580 for HPLC pump. Gelpermeation chromatography preparative isolations were performed on a LC-918 recycling preparative HPLC (Japan Analytical Industry Co., Ltd.), YRU-880 midget plus for RI/UV monitor (SHIMAMURATECH Ltd.). Optical rotations ([α]d) were measured on a JASCO P-3000 polarimeter. S-1

3 Experimental Procedures F OBn OBn BnO BnO O BnO O 4 BnO F n-buli F Et 2 O 78 C 78 C 15 min F 1 h 98% 3 OBn OBn F 6 O OH F (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)-2-(2,4,6-trifluorophenyl)tetrahydro-2H-pyran-2-ol (6) To a solution of 1,3,5-trifluorobenzene (3.86 g, 29.2 mmol) in Et 2 O (50 ml) under argon atmosphere at 78 o C was added a 1.54 M solution of n-buli/hexane (18.0 ml, 27.7 mmol) over 20 min. The mixture was stirred at 78 o C for an additional 1 h. Aryllithium was introduced to a solution of lactone 4 (10.0 g, 18.6 mmol) in Et 2 O (50 ml) at 78 o C via a cannula, and the reaction mixture was stirred at 78 o C for 15 min. Glacial acetic acid (1.8 ml, 32 mmol) was added slowly at 78 o C, and the mixture was stirred for an additional 10 min at this temperature. Saturated aqueous NaHCO 3 (ca. 15 ml) was added slowly, and the mixture was warmed to room temperature. The organic material was extracted with Et 2 O. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (3/7) as eluent to afford ketal 6 (12.0 g, 98% yield) as a white solid. R f 0.57 (EtOAc/hexane = 3/7); mp o C; 1 H NMR (500 MHz, acetone-d 6, 300 K) δ (m, 18H), (m, 2H), 6.78 (dd, 3 J H,F = 9.9, 9.9 Hz, 2H), 5.66 (s, 1H), 4.92 (s, 2H), 4.90 (d, J = 11.2 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.26 (d, J = 11.2 Hz, 1H), (m, 2H), (m, 3H), 3.69 (d, J = 11.2 Hz, 1H); 13 C NMR (126 MHz, acetone-d 6, 300 K) δ (dt, 1 J C,F = 248 Hz, 3 J C,F = 17 Hz), (ddd, 1 J C,F = 253 Hz, 3 J C,F = 15 Hz, 3 J C,F = 9 Hz), 140.4, 140.3, 140.2, 139.3, (12C), (td, 2 J C,F = 13 Hz, 4 J C,F = 5 Hz), (ddd, 2 J C,F = 29 Hz, 2 J C,F = 25 Hz, 4 J C,F = 4 Hz), 99.2 (t, 3 J C,F = 4 Hz), 84.5, 84.2, 79.8, 76.4, 76.1, 75.8, 74.0, 73.2, 70.3; 19 F NMR (565 MHz, acetone-d 6, 300 K) δ (br), 107.9; IR (thin film, cm -1 ): 3550 (br, OH), 3030, 2928, 2867, 1624, 1600, 1496, 1453, 1439, 1362, 1209, 1123, 1090, 843, 737, 698; HRMS (ESI-TOF) m/z Calcd for C 40 H 37 F 3 NaO 6 : [M+Na] , found ; [α] 23 D 9.0 o (c 1.0, CHCl 3 ). S-2

4 (2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-(2,4,6-trifluorophenyl)tetrahydro-2H-pyran (7) To a solution of ketal 6 (12.0 g, 17.9 mmol) in CH 2 Cl 2 (180 ml) under nitrogen atmosphere at 78 o C was added Et 3 SiH (8.55 ml, 53.7 mmol) followed by addition of BF 3 OEt 2 (6.63 ml, 53.7 mmol) over 5 min. After completion of addition, the reaction mixture was stirred at 0 o C for 35 min. Saturated aqueous NaHCO 3 (ca. 30 ml) was added slowly to the reaction mixture under ice-cooling, and the organic material was extracted with CH 2 Cl 2. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (1/9 1/4) as eluent to afford glycoside 7 (9.68 g, 83% yield) as a colorless oil. R f 0.59 (EtOAc/hexane = 1/4); 1 H NMR (600 MHz, acetone-d 6, 300 K) δ (m, 18H, H-Ar), (m, 2H, H- Ar), 6.86 (dd, 3 J H,F = 8.9, 8.9 Hz, 2H, H-4), 5.01 (s, 2H, CH 2 Ph), 4.96 (d, J = 10.9 Hz, 1H, CHPh), 4.78 (d, J = 9.4 Hz, 1H, H-1'), 4.77 (d, J = 10.9 Hz, 1H, CHPh), 4.73 (d, J = 11.2 Hz, 1H, CHPh), 4.67 (d, J = 12.2 Hz, 1H, CHPh), 4.56 (d, J = 12.2 Hz, 1H, CHPh), 4.32 (d, J = 11.2 Hz, 1H, CHPh), 4.04 (dd, J = 8.7, 9.4 Hz, 1H, H-2'), (m, 3H, H-3',4',6'), 3.79 (d, J = 11.2 Hz, 1H, H-6'), (m, 1H, H-5'); 13 C NMR (151 MHz, acetone-d 6, 300 K) δ (dt, 1 J C,F = Hz, 3 J C,F = 15.8 Hz, C-5), (brd, 1 J C,F = 250 Hz, C-1), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (t, 2 J C,F = 17.1 Hz, C-2), (brs, C-4), 88.2 (C-3'), 81.3 (C-2'), 80.9 (C-5'), 79.5 (C-4'), 76.3 (CH 2 Ph), 75.8 (CH 2 Ph), 75.5 (CH 2 Ph), 74.1 (CH 2 Ph), 73.0 (C-1'), 70.2 (C-6'); 19 F NMR (565 MHz, acetone-d 6, 300 K) δ (br), 107.1, (br); IR (thin film, cm -1 ): 3030, 2900, 2865, 1635, 1605, 1497, 1451, 1360, 1208, 1119, 1072, 842, 736, 697; HRMS (ESI-TOF) m/z Calcd for C 40 H 37 F 3 NaO 5 : [M+Na] , found ; [α] 23 D 16.9 o (c 1.0, CHCl 3 ). S-3

5 (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)-2-(2,4,6-trifluoro-3-((2S,3S,4R,5R,6R)-3,4,5- tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2h-pyran-2-yl)phenyl)tetrahydro-2h-pyran-2-ol (8) To a solution of mono-glycoside 7 (8.0 g, mol) in Et 2 O (25 ml) under argon atmosphere at 78 o C was added a 1.65 M solution of t-buli/pentane (8.1 ml, mol) over 20 min. The mixture was stirred at 78 o C for an additional 1 h. Aryllithium was introduced to a solution of lactone 4 (6.6 g, mol) in Et 2 O (25 ml) at 78 o C via a cannula, and the reaction mixture was stirred at 78 o C for 30 min. Glacial acetic acid (0.80 ml, mol) was added slowly at 78 o C, and the mixture was stirred for an additional 10 min at this temperature. Saturated aqueous NaHCO 3 (ca. 7.0 ml) was added slowly, and the mixture was warmed to room temperature. The organic material was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (1/4 3/7) as eluent to afford ketal 8 (12.1 g, 83% yield) as a white foam. R f 0.51 (EtOAc/hexane = 3/7); 1 H NMR (500 MHz, toluene-d 8, 333 K) δ (m, 40H), 6.15 (dd, 3 J H,F = 10.9, 11.0 Hz, 1H), (m, 5H), (m, 3H), 4.66 (d, J = 11.4 Hz, 1H), (m, 3H), (m, 1H), 4.41 (d, J = 12.2 Hz, 2H), (m, 1H), 4.21 (d, J = 11.4 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 3H), (m, 1H), (m, 3H), (m, 1H); 13 C NMR (126 MHz, toluene-d 8, 333 K) δ (brd, 1 J C,F = Hz), (brd, 1 J C,F = Hz), (brd, 1 J C,F = Hz), 139.5, 139.5, 139.4, 139.4, 139.3, 139.2, 138.6, 138.0, (24C), (brs), (dd, 2 J C,F = 16.1 Hz), (brs), 98.6, 87.6, 84.0, 81.1, 80.7, 78.8, 78.8, 75.7, 75.6, 75.5, 75.0, 75.0, 74.8, 73.7, 73.6, 73.6, 73.1, 72.9, 69.7, 69.4; 19 F NMR (376 MHz, toluene-d 8, 333 K) δ (br), (br), (br); IR (thin film, cm -1 ): 3545 (br, OH), 3030, 2911, 2865, 1624, 1603, 1496, 1454, 1361, 1208, 1137, 1092, 736, 697; HRMS (ESI-TOF) m/z Calcd for C 74 H 71 F 3 NaO 11 : [M+Na] , found ; [α] 23 D 7.3 o (c 1.0, CHCl 3 ). S-4

6 (2R,2'R,3R,3'R,4R,4'R,5S,5'S,6S,6'S)-6,6'-(2,4,6-Trifluoro-1,3-phenylene)bis(3,4,5-tris(benzyloxy)-2- ((benzyloxy)methyl)tetrahydro-2h-pyran) (9) To a solution of ketal 8 (6.60 g, 5.53 mmol) in CH 2 Cl 2 (200 ml) under nitrogen atmosphere at 78 o C was added Et 3 SiH (4.4 ml, 28 mmol) followed by addition of BF 3 OEt 2 (3.4 ml, 28 mmol) over 6 min. After completion of addition, the reaction mixture was stirred at 0 o C for 30 min. Saturated aqueous NaHCO 3 (ca. 15 ml) was added slowly to the reaction mixture under ice-cooling, and the organic material was extracted with CH 2 Cl 2. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (3/17 1/4) as eluent to afford bis-c-glycoside 9 (5.31 g, 82% yield) as a white foam. R f 0.40 (EtOAc/hexane = 1/4); 1 H NMR (500 MHz, toluene-d 8, 373 K) δ (m, 40H, H-Ar), 6.23 (t, 3 J H,F = 10.1 Hz, 1H, H-6), 4.84 (d, J = 11.4 Hz, 2H, CHPh), 4.83 (s, 4H, CH 2 Ph), 4.76 (d, J = 9.8 Hz, 2H, H-1'), 4.67 (d, J = 11.4 Hz, 2H, CHPh), 4.55 (d, J = 11.4 Hz, 2H, CHPh), 4.53 (d, J = 12.2, 2H, CHPh), 4.41 (d, J = 12.2 Hz, 2H, CHPh), 4.22 (d, J = 11.4 Hz, 2H), 4.10 (dd, J = 9.2, 9.8 Hz, 2H, H-2'), 3.84 (dd, J = 9.3, 9.4 Hz, 2H, H-4'), 3.77 (dd, J = 11.4, 4.2 Hz, 2H, H- 6'), 3.69 (dd, J = 9.2, 9.3 Hz, 2H, H-3'), 3.65 (dd, J = 11.4 Hz, 1.8 Hz, 2H, H-6'), 3.46 (ddd, J = 9.4, 4.2, 1.8 Hz, 2H, H-5'); 13 C NMR (126 MHz, toluene-d 8, 373 K) δ (ddd, 1 J C,F = 253 Hz, 3 J C,F = 16 Hz, 3 J C,F = 11 Hz, C-1), (brd, 1 J C,F = 253 Hz, C-3), (C-Ar), (C-Ar), (C-Ar), (C-Ar), (12C, C-Ar), (ddd, 2 J C,F = 18 Hz, 2 J C,F = 18 Hz, 4 J C,F = 4 Hz, C-2), (td, 2 J C,F = 28 Hz, 4 J C,F = 2 Hz, C-6), 87.9 (C-3'), 81.6 (C-2'), 81.0 (C-5'), 79.2 (C-4'), 75.7 (CH 2 Ph), 75.2 (CH 2 Ph), 75.0 (CH 2 Ph), 74.0 (CH 2 Ph), 73.2 (C-1'), 70.1 (C-6'); 19 F NMR (376 MHz, toluene-d 8, 373 K) δ (br, 3F); IR (thin film, cm -1 ): 3030, 2908, 2864, 1637, 1609, 1496, 1453, 1360, 1208, 1134, 1095, 735, 697; HRMS (ESI-TOF) m/z Calcd for C 74 H 71 F 3 NaO 10 : [M+Na] , found ; [α] 23 D 14.4 o (c 1.0, CHCl 3 ). S-5

7 (E)-3-(4-(Benzyloxy)phenyl)-1-(2,4,6-trifluoro-3,5-bis((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2h-pyran-2-yl)phenyl)prop-2-en-1-one (2) To a solution of bis-glycoside 9 (4.30 g, 3.65 mmol) in Et 2 O (30 ml) under argon atmosphere at 78 o C was added a 1.65 M solution of t-buli/pentane (2.6 ml, 4.3 mmol) over 10 min. The mixture was stirred at 78 o C for an additional 1h. Aryllithium was introduced to a solution of amide 5 (1.09 g, 3.65 mmol) in THF (50 ml) at 50 o C via a cannula, and the reaction mixture was stirred at 50 o C for 2 h. The reaction was quenched with saturated aqueous NH 4 Cl, and the organic material was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (1/4) as eluent to afford 2 (4.12 g, 80%) as a pale yellow amorphous solid. Bis-glycoside 9 was recovered in 0.68 g (15%). R f 0.28 (EtOAc/hexane = 1/4); mp o C; 1 H NMR (500 MHz, toluene-d 8, 363 K) δ 7.44 (d, J = 16.0 Hz, 1H), (m, 47H), 6.82 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), (m, 8H), 4.72 (s, 2H), 4.67 (d, J = 11.4 Hz, 2H), 4.59 (d, J = 11.3 Hz, 2H), 4.53 (d, J = 12.3 Hz, 2H), 4.42 (d, J = 12.3 Hz, 2H), 4.28 (d, J = 11.3 Hz, 2H), 4.12 (dd, J = 9.1, 9.2 Hz, 2H), 3.85 (dd, J = 9.3, 9.4 Hz, 2H), 3.77 (dd, J = 11.3, 4.1 Hz, 2H), 3.70 (dd, J = 9.1, 9.3 Hz, 2H), 3.66 (dd, J = 11.3, 1.8 Hz, 2H), 3.46 (ddd, J = 9.4, 4.1, 1.8 Hz, 2H); 13 C NMR (126 MHz, toluene-d 8, 363 K) δ 185.1, (brd, 1 J C,F = 259 Hz), 161.7, (brd, 1 J C,F = 256 Hz), 146.0, 139.6, 139.5, 139.4, 138.7, 137.3, 130.8, (16C), 126.0, (brs), 115.9, (t, 2 J C,F = 17 Hz), 87.7, 81.4, 81.0, 79.0, 75.6, 75.1, 75.1, 73.9, 73.2, 70.5, 69.9; 19 F NMR (376 MHz, toluene-d 8, 373 K) δ (br), 110.5; IR (thin film, cm -1 ): 3031, 2914, 2866, 1651 (CO), 1597, 1510, 1497, 1453, 1360, 1265, 1172, 829, 744, 697; HRMS (ESI-TOF) m/z Calcd for C 90 H 84 F 3 O 12 : [M+H] , found ; [α] 23 D 24.2 o (c 1.0, CHCl 3 ). S-6

8 (E)-3-(4-(Benzyloxy)phenyl)-1-(2,4-difluoro-6-hydroxy-3,5-bis((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2h-pyran-2-yl)phenyl)prop-2-en-1-one (10) To a solution of 2 (1.04 g, mmol) and benzaldoxime (182 mg, 1.50 mmol) in THF (25 ml) under nitrogen flush at room temperature was added t-buok (185 mg, 1.65 mmol) in one portion. The reaction mixture was stirred at room temperature for 10 h, quenched with 1 M aqueous HCl until ph ~ 3, and the organic material was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (1/4) as eluent to afford 10 (0.93 g, 90% yield) as a yellow amorphous solid. R f 0.31 (EtOAc/hexane = 1/4); mp o C; 1 H NMR (500 MHz, toluene-d 8, 363 K) δ (brs, OH), 7.89 (d, J = 15.5 Hz, 1H), (m, 48H), 6.75 (d, J = 8.7 Hz, 2H), 5.14 (brs, 1H), (m, 15H), (m, 4H), 4.34 (d, J = 10.9 Hz, 1H), 4.16 (dd, J = 9.3, 9.2 Hz, 1H), (m, 8H), (m, 2H); 13 C NMR (126 MHz, toluene-d 8, 363 K) δ 192.0, (brd, 1 J C,F = 253 Hz), 165.2, (brd, 1 J C,F = 257 Hz), 161.9, 145.9, 139.8, 139.6, 139.6, 139.4, 139.4, 139.3, 139.2, 138.7, 137.1, 130.9, (28C), 123.8, 116.0, (brs), (brs), (dd, 2 J C,F = 19.3, 19.3 Hz), 87.9, 87.6, 81.1, 80.8, 80.7, 79.2, 79.1, 78.9, 75.6, 75.6, 75.1, 75.5, 75.5, 74.8, 73.9, 73.9, 73.3, 73.0, 70.5, 70.1, 70.0 ; 19 F NMR (376 MHz, toluene-d 8, 373 K) δ 97.9 (br), (br); IR (thin film, cm -1 ): 3350 (br, OH), 3030, 2897, 2865, 1633 (CO), 1555, 1510, 1497, 1453, 1358, 1255, 1163, 829, 743, 697; HRMS (ESI-TOF) m/z Calcd for C 90 H 85 F 2 O 13 : [M+H] , found ; [α] 23 D 1.2 o (c 1.0, CHCl 3 ). S-7

9 2H-pyran-2-yl)-4H-chromen-4-one (11) To a solution of 10 (1.42 g, 1.01 mmol) in DMSO (85 ml) under nitrogen atmosphere at room temperature was added I 2 (25 mg, 0.10 mmol) in DMSO (15 ml). The reaction mixture was warmed to 140 o C and stirred for 3 h. After cooled to room temperature, water (50 ml) was added, and the organic material was extracted with EtOAc (3 150 ml). Brine (ca. 3 ml) was added to give a phase separation in extraction. The combined organic extracts were washed with aqueous Na 2 S 2 O 3, brine, dried over MgSO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (3/7) as eluent to afford 11 (1.27 g, 90% yield) as a pale yellow amorphous solid. R f 0.23 (EtOAc/hexane = 3/7); mp o C; 1 H NMR (500 MHz, toluene-d 8, 373 K) δ 7.75 (brs, 2H), (m, 45H), 6.74 (d, J = 6.7 Hz, 2H), 6.35 (s, 1H), 5.02 (brs, 1H), (m, 7H), (m, 3H), 4.70 (d, J = 11.4 Hz, 1H), (m, 2H), (m, 8H), 4.01 (brs, 1H), (m, 4H), (m, 3H), (m, 2H). 13 C NMR (126 MHz, toluene-d 8, 373 K) δ 174.4, (brd, 1 J C,F = Hz), 162.1, 161.9, (brd, 1 J C,F = Hz), (brs), (7C), 138.6, 137.1, (29C), 124.6, 116.0, (brs), (brs), 107.8, 88.5, 87.7, 81.1, 80.9, 80.7, 79.1, 79.0, 78.2, 75.5, 75.5, 75.0, 75.0, 74.9, 74.2, 74.0, 73.9, 73.8, 73.1, 70.6, 70.1, 69.9 ; 19 F NMR (376 MHz, toluene-d 8, 373 K) δ 100.8, 105.9, 107.1; IR (thin film, cm -1 ): 3030, 2932, 2866, 1656 (CO), 1620, 1510, 1453, 1353, 1264, 1178, 1095, 836, 748, 698. HRMS (ESI-TOF) m/z Calcd for C 90 H 83 F 2 O 13 : [M+H] , found [α] 23 D 6.0 o (c 1.0, CHCl 3 ). BnO OBn OBn BnO OBn OBn BnO BnO O BnO H F O H O F O OBn OBn 11 OBn BnOH KOH 1,4-dioxane 88 o C, 2 h 89% BnO BnO O BnO H BnO O H O OBn O OBn OBn 12 OBn 5,7-Difluoro-2-(4-hydroxyphenyl)-6,8-bis((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro- 5,7-Bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-6,8-bis((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2h-pyran-2-yl)-4h-chromen-4-one (12) To a solution of 11 (400 mg, mmol) and benzyl alcohol (600 mg, 5.55 mmol, excess) in 1,4-dioxane (20 ml) under nitrogen flush at room temperature was added KOH (320 mg, 5.70 mmol, excess) in one portion. The heterogeneous reaction mixture was stirred in a preheated oil bath at 88 o C. Upon completion (LC-MS analysis, ca. 2 h), the reaction mixture was cooled to room temperature, quenched with 1M aqueous HCl until ph ~ 3, and the organic material was S-8

10 extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (1/3 3/7) as eluent to afford 12 (401 mg, 89%) as a pale yellow amorphous solid. HPLC ( mm Ph-3, 30% EtOAc in hexane, 1 ml/min, UV detection at 254 nm) 5.81 min and 99.0% pure; R f 0.39 (EtOAc/hexane = 3/7); mp o C; IR (thin film, cm -1 ): 3030, 2932, 2866, 1646 (CO), 1605, 1510, 1497, 1454, 1343, 1263, 1178, 1097, 836, 749, 697; HRMS (ESI-TOF) m/z Calcd for C 104 H 97 O 15 : [M+H] , found ; [α] 23 D o (c 1.0, CHCl 3 ). NMR spectral data of 12 is complicated by the mixture of rotamers (see the NMR spectra below). 5,7-Dihydroxy-2-(4-hydroxyphenyl)-6,8-bis((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2Hpyran-2-yl)-4H-chromen-4-one (1) A mixture of 12 (155 mg, mmol) and ASCA-2 (77 mg, 52% H 2 O, 10% Pd(OH) 2 /C, 2.4 wt%) in EtOH/EtOAc (66 ml, 1/1) was stirred under H 2 atmosphere (balloon) at room temperature. Upon completion (LC-MS analysis, ca. 12 h), the catalyst was removed via filtration (Celite pad), and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (5 ml), neutralized with Amberlite IR-120 (H + ), and filtered, and concentrated under reduced pressure. The residue was absorbed onto Celite, and purified by Cosmosil column chromatography (Cosmosil 75C 18 OPN, Nacalai Tesque, Inc., 150 ml) with MeOH/H 2 O (1/9 3/7) as eluent to afford 1 (54 mg, 92 % yield) as a pale yellow powder. Note: yellow color intensity, solubility in an organic solvent (MeOH or DMSO), and 1 H NMR chemical shifts of hydroxy groups of vicenin-2 vary depending on the ph of the solution. Vicenin-2 in DMSO-d 6 decomposes slowly at 100 o C. HPLC ( mm ODS-3, 85% H 2 O (ph 2.2, H 3 PO 4 ) in CH 3 CN (90% in H 2 O), 0.8 ml/min, UV detection at 200 nm) min and 98.1 % pure; mp 150 o C (decomp); 1 H NMR (500 MHz, DMSO-d 6, 363 K) δ (br, ArOH), 9.96 (br, ArOH), 9.19 (br, ArOH), 7.96 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.69 (s, 1H), 4.91 (d, J = 8.6 Hz, 1H), 4.82 (d, J = 9.7 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 6H); 13 C NMR (126 MHz, DMSO-d 6, 363 K) 182.0, 163.9, 160.9, 160.7, 159.0, 154.5, 128.4, 121.4, 115.8, 107.8, 104.2, 103.6, 102.5, 81.4, 80.9, S-9

11 78.5, 78.2, 73.7 (2C), 71.3 (2C), 70.1, 69.7, 61.0, 60.5; IR (ATR, cm -1 ): 3270 (br), 2923, 1645, 1621, 1610, 1573, 1442, 1356, 1214, 1178, 1077, 1007, 832; HRMS (ESI-TOF) m/z Calcd for C 27 H 31 O 15 : [M+H] , found ; [α] 23 D o (c 0.1, MeOH). Sample of Vicenin-2 from Kanto Chemical Co., Inc., Japan, purchasing from PhytoLab GmbH & Co. KG, Germany on June 17, 2016: HPLC ( mm ODS-3, 85% H 2 O (ph 2.2, H 3 PO 4 ) in CH 3 CN (90% in H 2 O), 0.8 ml/min, UV detection at 200 nm) min and 98.3 % pure; [α] 23 D o (c 0.1, MeOH). * Preparation of lactone 4 (1) (3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (4) To a stirred suspension of NaH (25.0 g, 63 % in oil, mol) in DMF (400 ml) at 0 o C under nitrogen atmosphere was added portion wise methyl-α-d-glucopyranoside 13 (19.4 g, mol). The mixture was vigorously stirred at room temperature for 2 h. TBAI (3.69 g, mol) was added to the mixture, followed by dropwise addition of BnBr (72 ml, 0.60 mol) over 45 min. The reaction mixture was stirred for 18 h. Ice cold water was added, and the organic material was extracted with Et 2 O. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to give crude methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside as a pale yellow oil. To a stirred solution of crude methyl glycoside in glacial acetic acid (585 ml) at 85 o C was added 2 M aqueous HCl (225 ml) dropwise over 45 min. The reaction mixture was stirred at this temperature for an additional 2 h 45 min, cooled to room temperature, and left over night for crystallization of product. The crystals were filtered, washed consecutively with water (3 100 ml), methanol (2 100 ml) and air dried to afford 14 (24.7 g) as a white powder. The filtrated solution was heated again at 85 o C for 3.5 h, and the second crop of crystallization gave additional 6.6 g of 14 (58% overall yield from 13). Note: Acidic hydrolysis of methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside in 7 h continuously gave 14 in 45% yield. The major anomer of 14 can be obtained in pure form (see the NMR spectra below) by recrystallization after further purification of the mixture of anomers 14 by silica gel column chromatography with EtOAc/hexane (1/1) as eluent. R f 0.52 and 0.60 (EtOAc/hexane = 2/3); 1 H NMR (500 MHz, CDCl 3, 300 K) δ (m, 20H), 5.20 (t, J = 3.3 Hz, 1H), (m, 1H), (m, 4H), (m, 3H), (m, 7H); 13 C NMR (126 MHz, CDCl 3, 300 K) δ 138.6, (anomer), (anomer), 138.2, (anomer), 137.8, 137.8, (anomer), (24C), 97.4 (anomer), 91.1, 84.5 (anomer), 83.0 (anomer), 81.7, 79.9, 77.8 (anomer), 77.7, 75.6, 75.6 (anomer), 74.9, 74.9 (anomer), S-10

12 74.6 (anomer), 74.5 (anomer), 73.4 (anomer), 73.4, 73.0, 70.0, 68.9 (anomer), 68.6; IR (thin film, cm -1 ): 3350 (br, OH), 3029, 2916, 2860, 1496, 1451, 1357, 1212, 1147, 1087, 745, 695; HRMS (ESI-TOF) m/z Calcd for C 34 H 36 NaO 6 : [M+Na] , found A solution of hemiacetals 14 (22.4 g, 41.4 mmol) in DMSO (112 ml) was stirred under nitrogen atmosphere at room temperature for 30 min. Acetic acid anhydride (67 ml) was added over 15 min, and the reaction mixture was stirred for 22 h at room temperature. Water (900 ml) was added to dilute, and the organic material was extracted with EtOAc (4 300 ml). The combined organic extracts were washed with ph 7 phosphate buffer, brine, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure at room temperature. The residue was carefully purified by silica gel column chromatography with EtOAc/hexane (3/20 1/4) as eluent to afford gluconolactone 4 (19.9 g, 89% yield) as a colorless oil. R f 0.37 (EtOAc/hexane = 1/4); 1 H NMR (500 MHz, CDCl 3, 300 K) δ (m, 20H), 4.97 (d, J = 11.4 Hz, 1H), (m, 8H), 4.12 (d, J = 6.6 Hz, 1H), (m, 2H), (m, 2H); 13 C NMR (126 MHz, CDCl 3, 300 K) δ 169.2, 137.5, 137.4, 137.4, 136.9, (12C), 80.8, 78.1, 77.3, 76.0, 73.8, 73.6, 73.6, 73.4, 68.2; IR (thin film, cm -1 ): 3030, 2910, 2868, 1756 (CO), 1496, 1453, 1362, 1210, 1164, 1097, 738, 698; HRMS (ESI-TOF) m/z Calcd for C 34 H 35 O 6 : [M+H] , found ; [α] 23 D o (c 1.0, CHCl 3 ). * Preparation of amide 5 (2) (E)-3-(4-(Benzyloxy)phenyl)-N-methoxy-N-methylacrylamide (5) To a suspension of ester 15 (2.01 g, 7.49 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.73g, 17.7 mmol) in THF (20 ml) under argon atmosphere at 20 o C was added a 1.78 M solution of i-prmgcl/thf (20 ml, 36 mmol) dropwise. The reaction mixture was stirred at 0 o C for 1 h. Saturated aqueous NH 4 Cl was added, and the organic material was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/hexane (3/2) as eluent to afford amide 5 (1.96 g, 93% yield) as a white solid. R f 0.53 (EtOAc/hexane = 3/2); mp o C; 1 H NMR (600 MHz, CDCl 3, 300 K) δ 7.69 (d, J = 15.8 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), (m, 4H), 7.32 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 15.8 Hz, 1H), 5.08 (s, 2H), S-11

13 3.74 (s, 3H), 3.29 (s, 3H); 13 C NMR (151 MHz, CDCl 3, 300 K) δ 167.3, 160.1, 143.0, 136.5, 129.6, 128.6, 128.1, 128.0, 127.4, 115.1, 113.4, 70.0, 61.7, 32.5; IR (thin film, cm -1 ): 3035, 2964, 2936, 2871, 1650 (CO), 1612, 1511, 1455, 1423, 1383, 1303, 1241, 1176, 1097, 1004, 829, 739, 698; HRMS (ESI-TOF) m/z Calcd for C 18 H 20 NO 3 : [M+H] , found * Preparation of benzaldehyde oxime (3) To a solution of hydroxylamine hydrochloride (4.20 g, 60.0 mmol) and sodium acetate (4.92 g, 60.0 mmol) in MeOH (165 ml) and water (15 ml) under nitrogen atmosphere at room temperature was added dropwise benzaldehyde (3.0 ml, 0.03 mol) over 10 min, and the reaction mixture was stirred at ambient temperature for 4 h. Solvent was removed under reduced pressure. The organic material was diluted with EtOAc, washed with water (4 times), dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. Benzaldoxime (3.45 g, 95% yield) as a white semisolid at room temperature was used for the next step without further purification. 1 H NMR (600 MHz, CDCl 3, 300 K) δ 9.84 (brs, OH), 8.18 (s, 1H, CH=N), (m, 2H, Ar), (m, 3H, Ar); 13 C NMR (151 MHz, CDCl 3, 300 K) δ (C=N), (C), (CHp), (CHo), (CHm) in good agreement with the literature data; 3b IR (thin film, cm -1 ): 3314 (br, OH), 3028, 2986, 2898, 1700 (C=N), 1633, 1494, 1451, 1304, 1211, 951, 870, 742, 691. References (1) For the preparation of hemiacetals 14, see: (a) Dasari, B.; Jogula, S.; Borhade, R.; Balasubramanian, S.; Chandrasekar, G.; Kitambi, S. S.; Arya, P. Org. Lett. 2013, 15, For the oxidation of 14, see: (b) Li, L.-T.; Zhou, L.-F.; Li, Y.-J.; Huang, J.; Liu, R.-H.; Wang, B.; Wang, P. Bioorg. Med. Chem. Lett. 2012, 22, (c) Zhang, F.; Vasella, A. Carbohydr. Res. 2007, 342, (2) For the preparation of Weinreb amide from the corresponding ester, see: (a) Cusso, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-Fillol, J.; Costas, M. J. Am. Chem. Soc. 2013, 135, Ester 15 was prepared from 4- hydroxybenzaldehyde, see: (b) Nanda, S.; Tetrahedron Lett. 2005, 46, (3) (a) Tamilselvan, P.; Basavaraju, Y. B.; Sampathkumar, E.; Murugesan, R. Catal. Commun. 2009, 10, (b) Sanders, B. C.; Friscourt, F.; Ledin, P. A.; Mbua, N. E.; Arumugam, S.; Gou, J.; Boltje, T. J.; Popik, V. V.; Boons, G. J. J. Am. Chem. Soc. 2011, 133, S-12

14 1 H NMR (500 MHz, acetone d 6, 300 K) NAME nmr EXPNO 42 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Acetone NS 32 DS 2 SWH Hz FIDRES Hz AQ sec RG 18 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-13

15 13 C NMR (126 MHz, acetone d 6, 300 K) NAME nmr EXPNO 46 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Acetone NS 1029 DS 8 SWH Hz FIDRES Hz AQ sec RG DW use DE 6.00 use TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P use PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-14

16 19 F NMR (565 MHz, acetone-d 6, 300 K, C 6 F 6 internal standard) NAME th01.04.no5 EXPNO 11 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG zgflqn TD SOLVENT Acetone NS 128 DS 4 SWH Hz FIDRES Hz AQ sec RG 17.5 DW use DE use TE K D sec TD0 1 ======== CHANNEL f1 ======= SFO MHz NUC1 19F P use PLW W SI SF MHz LB 0.30 Hz PC ppm S-15

17 1 H NMR (600 MHz, acetone d 6, 300 K) NAME th01.05.no7 EXPNO 20 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG zg30 TD SOLVENT Acetone NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 5.45 DW use DE use TE K D sec TD0 1 ======== CHANNEL f1 ======= SFO MHz NUC1 1H P use PLW W SI SF MHz LB 0.30 Hz PC ppm S-16

18 13 C NMR (151 MHz, acetone d 6, 300 K) NAME th01.05.no7 EXPNO 11 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG zgpg30 TD SOLVENT Acetone NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW use DE use TE K D sec D sec TD0 1 ======== CHANNEL f1 ======= SFO MHz NUC1 13C P use PLW W ======== CHANNEL f2 ======= SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-17

19 19 F NMR (565 MHz, acetone d 6, 300 K, C 6 F 6 internal standard) NAME th01.05.no7 EXPNO 22 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG zgflqn TD SOLVENT Acetone NS 16 DS 4 SWH Hz FIDRES Hz AQ sec RG DW use DE use TE K D sec TD0 1 ======== CHANNEL f1 ======= SFO MHz NUC1 19F P use PLW W SI SF MHz LB 0.30 Hz PC ppm S-18

20 COSYGPSW (acetone d 6, 300 K) ppm NAME th01.05.no7 EXPNO 15 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG cosygpppqf TD 2048 SOLVENT Acetone NS 1 DS 8 SWH Hz FIDRES Hz AQ sec RG 4.46 DW usec DE usec TE K D sec D sec D sec D sec D sec D sec IN sec ======== CHANNEL f1 ======== SFO MHz NUC1 1H P usec P usec P usec PLW W PLW W ====== GRADIENT CHANNEL ===== GPNAM[1] SMSQ GPZ % P usec F1 Acquisition parameters TD 128 SFO MHz FIDRES Hz SW ppm FnMODE QF SI 1024 SF MHz WDW QSINE LB 0 Hz PC ppm S-19

21 HMBCGP (acetone d 6, 300 K) ppm NAME th01.05.no7 EXPNO 16 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG hmbcgplpndqf TD 2048 SOLVENT Acetone NS 4 DS 16 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec TE K CNST CNST D sec D sec D sec D sec D sec IN sec ======== CHANNEL f1 ======== SFO MHz NUC1 1H P usec P usec PLW W ======== CHANNEL f2 ======== SFO MHz NUC2 13C P usec PLW W ====== GRADIENT CHANNEL ===== GPNAM[1] SMSQ GPNAM[2] SMSQ GPNAM[3] SMSQ GPZ % GPZ % GPZ % P usec F1 Acquisition parameters TD 128 SFO MHz FIDRES Hz SW ppm FnMODE QF ppm S-20

22 HSQCEDETGPSISP (acetone d 6, 300 K) ppm NAME th01.05.no7 EXPNO 17 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG hsqcedetgpsisp2.3 TD 2048 SOLVENT Acetone NS 4 DS 32 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec TE K CNST CNST D sec D sec D sec D sec D sec D sec D sec IN sec ======== CHANNEL f1 ======== SFO MHz NUC1 1H P usec P usec P28 0 usec PLW W ======== CHANNEL f2 ======== SFO MHz NUC2 13C CPDPRG[2 garp P usec P usec P usec P usec PCPD usec PLW0 0 W PLW W PLW W SPNAM[3] Crp60,0.5,20.1 SPOAL SPOFFS3 0 Hz SPW W SPNAM[7] Crp60comp.4 SPOAL SPOFFS7 0 Hz SPW W SPNAM[18 Crp60_xfilt.2 SPOAL SPOFFS18 0 Hz SPW W ppm S-21

23 13 C DEPT135 (acetone d 6, 300 K) NAME th01.05.no7 EXPNO 12 Date_ Time PROBHD 5 mm CPPBBO BB PULPROG deptsp135 TD SOLVENT Acetone NS 256 DS 4 SWH Hz FIDRES Hz AQ sec RG DW use DE use TE K CNST D sec D sec D sec TD0 1 ======== CHANNEL f1 ======= SFO MHz NUC1 13C P use P use PLW0 0 W PLW W SPNAM[5] Crp60comp.4 SPOAL SPOFFS5 0 Hz SPW W ======== CHANNEL f2 ======= SFO MHz NUC2 1H CPDPRG[2 waltz16 P use P use PCPD use PLW W PLW W ppm S-22

24 1 H NMR (500 MHz, toluene d 8, 333 K) NAME nmr EXPNO 163 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 32 DS 2 SWH Hz FIDRES Hz AQ sec RG 128 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-23

25 13 C NMR (126 MHz, toluene d 8, 333 K) NAME nmr EXPNO 165 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Tol NS DS 8 SWH Hz FIDRES Hz AQ sec RG DW use DE 6.00 use TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P use PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-24

26 abundance 19 F NMR (376 MHz, toluene-d 8, 333 K, C 6 F 6 internal standard) Filename = th01.06.te60oc_fluorine-3- Author = suzuki Experiment = proton.jxp Sample_Id = th01.06 Solvent = TOLUENE-D8 Creation_Time = 1-JUN :41:47 Revision_Time = 1-JUN :45:57 Current_Time = 1-JUN :50:27 Comment = single_pulse Data_Format = 1D COMPLEX Dim_Size = Dim_Title = Fluorine19 Dim_Units = [ppm] Dimensions = X Site = JNM-ECS400 Spectrometer = DELTA2_NMR Field_Strength = [T] (400[MHz]) X_Acq_Duration = [ms] X_Domain = 19F X_Freq = [MHz] X_Offset = 0[ppm] X_Points = X_Prescans = 1 X_Resolution = [Hz] X_Sweep = [kHz] X_Sweep_Clipped = [kHz] Irr_Domain = Fluorine19 Irr_Freq = [MHz] Irr_Offset = 5[ppm] Tri_Domain = Fluorine19 Tri_Freq = [MHz] Tri_Offset = 5[ppm] Clipped = FALSE Scans = 32 Total_Scans = 32 Relaxation_Delay = 5[s] Recvr_Gain = 44 Temp_Get = 60[dC] X_90_Width = 7.12[us] X_Acq_Time = [ms] X_Angle = 45[deg] X_Atn = 2.3[dB] X_Pulse = 3.56[us] Irr_Mode = Off Tri_Mode = Off Dante_Presat = FALSE Initial_Wait = 1[s] Repetition_Time = [s] X : parts per Million : Fluorine S

27 1 H NMR (500 MHz, toluene d 8, 373 K) NAME nmr EXPNO 80 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 22.6 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-26

28 13 C NMR (126 MHz, toluene d 8, 373 K) NAME nmr EXPNO 78 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Tol NS 2175 DS 8 SWH Hz FIDRES Hz AQ sec RG DW use DE 6.00 use TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P use PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-27

29 abundance F NMR (376 MHz, toluene-d 8, 373 K, C 6 F 6 internal standard) Filename = th01.07.te100oc_fluorine-1 Author = suzuki Experiment = proton.jxp Sample_Id = th01.07.te100oc Solvent = TOLUENE-D8 Creation_Time = 19-FEB :28:15 Revision_Time = 19-FEB :36:43 Current_Time = 19-FEB :36:50 Comment = single_pulse Data_Format = 1D COMPLEX Dim_Size = Dim_Title = Fluorine19 Dim_Units = [ppm] Dimensions = X Site = JNM-ECS400 Spectrometer = DELTA2_NMR Field_Strength = [T] (400[MHz]) X_Acq_Duration = [ms] X_Domain = 19F X_Freq = [MHz] X_Offset = 0[ppm] X_Points = X_Prescans = 1 X_Resolution = [Hz] X_Sweep = [kHz] X_Sweep_Clipped = [kHz] Irr_Domain = Fluorine19 Irr_Freq = [MHz] Irr_Offset = 5[ppm] Tri_Domain = Fluorine19 Tri_Freq = [MHz] Tri_Offset = 5[ppm] Clipped = FALSE Scans = 128 Total_Scans = 128 Relaxation_Delay = 5[s] Recvr_Gain = 46 Temp_Get = 100[dC] X_90_Width = 7.12[us] X_Acq_Time = [ms] X_Angle = 45[deg] X_Atn = 2.3[dB] X_Pulse = 3.56[us] Irr_Mode = Off Tri_Mode = Off Dante_Presat = FALSE Initial_Wait = 1[s] Repetition_Time = [s] X : parts per Million : Fluorine S

30 COSY fg (toluene d 8, 373 K) ppm NAME nmr EXPNO 81 Date_ Time INSTRUM PROBHD PULPROG TD SOLVENT NS DS spect 5 mm Multinucl cosygs 2048 Tol 4 2 SWH Hz FIDRES Hz AQ sec RG 90.5 DW usec DE TE 6.00 usec K D sec D sec D sec D sec IN sec ======== CHANNEL f1 ======== NUC1 1H P usec P usec PL db SFO MHz ====== GRADIENT CHANNEL ===== P usec F1 Acquisition parameters TD 256 SFO MHz FIDRES Hz SW ppm FnMODE undefined SI 1024 SF MHz WDW SINE LB 0 Hz PC 1.00 F1 Processing parameters SI 1024 MC2 QF SF MHz WDW SINE LB 0 Hz ppm S-29

31 HMBC FG (toluene d 8, 373 K) ppm NAME nmr EXPNO 170 Date_ Time PROBHD 5 mm Multinucl PULPROG inv4gslplrnd TD 2048 SOLVENT Tol NS 2 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE 6.00usec TE 373.0K D sec D sec D sec D sec D sec D sec IN sec ======== CHANNEL f1 ======== NUC1 1H P usec P usec PL db SFO MHz ======== CHANNEL f2 ======== NUC2 13C P usec PL db SFO MHz ====== GRADIENT CHANNEL ===== P usec F1 Acquisition parameters TD 1024 SFO MHz FIDRES Hz SW ppm FnMODE undefined ppm S-30

32 HMQC (toluene d 8, 373 K) ppm NAME nmr EXPNO 174 F1 Acquisition parameters TD 128 SFO MHz FIDRES Hz SW ppm FnMODE undefined SI 1024 SF MHz WDW QSINE SSB 2 LB 0 Hz PC 1.40 F1 Processing parameters SI 512 MC2 TPPI SF MHz WDW QSINE SSB 2 LB 0 Hz ppm S-31

33 13 C DEPT135 (toluene d 8, 373 K) ppm S-32

34 1 H NMR (500 MHz, toluene d 8, 363 K) NAME nmr EXPNO 11 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 32 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-33

35 13 C NMR (126 MHz, toluene d 8, 363 K) NAME nmr EXPNO 48 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Tol NS 4096 DS 8 SWH Hz FIDRES Hz AQ sec RG DW usec DE 6.00 usec TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P usec PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-34

36 abundance F NMR (376 MHz, toluene-d 8, 373 K, C 6 F 6 internal standard) Filename = th01.10.te100oc_19f-1-7.jd Author = suzuki Experiment = proton.jxp Sample_Id = th01.10.te100oc Solvent = TOLUENE-D8 Creation_Time = 18-FEB :14:39 Revision_Time = 19-FEB :09:20 Current_Time = 19-FEB :09:33 Comment = single_pulse Data_Format = 1D COMPLEX Dim_Size = Dim_Title = Fluorine19 Dim_Units = [ppm] Dimensions = X Site = JNM-ECS400 Spectrometer = DELTA2_NMR Field_Strength = [T] (400[MHz]) X_Acq_Duration = [ms] X_Domain = 19F X_Freq = [MHz] X_Offset = 0[ppm] X_Points = X_Prescans = 1 X_Resolution = [Hz] X_Sweep = [kHz] X_Sweep_Clipped = [kHz] Irr_Domain = Fluorine19 Irr_Freq = [MHz] Irr_Offset = 5[ppm] Tri_Domain = Fluorine19 Tri_Freq = [MHz] Tri_Offset = 5[ppm] Clipped = FALSE Scans = 32 Total_Scans = 32 Relaxation_Delay = 5[s] Recvr_Gain = 46 Temp_Get = 100[dC] X_90_Width = 7.12[us] X_Acq_Time = [ms] X_Angle = 45[deg] X_Atn = 2.3[dB] X_Pulse = 3.56[us] Irr_Mode = Off Tri_Mode = Off Dante_Presat = FALSE Initial_Wait = 1[s] Repetition_Time = [s] X : parts per Million : Fluorine S

37 1 H NMR (500 MHz, toluene d 8, 363 K) NAME nmr EXPNO 35 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 12.7 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-36

38 13 C NMR (126 MHz, toluene d 8, 363 K) NAME nmr EXPNO 124 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Tol NS 2252 DS 8 SWH Hz FIDRES Hz AQ sec RG DW use DE 6.00 use TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P use PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-37

39 19 F NMR (376 MHz, toluene-d 8, 373 K, C 6 F 6 internal standard) Filename = th01.26.te100oc_fluorine-2 Author = suzuki Experiment = proton.jxp Sample_Id = th01.26 Solvent = TOLUENE-D8 Creation_Time = 12-MAY :32:29 Revision_Time = 13-MAY :37:01 Current_Time = 13-MAY :38: abundance Comment = single_pulse Data_Format = 1D COMPLEX Dim_Size = Dim_Title = Fluorine19 Dim_Units = [ppm] Dimensions = X Site = JNM-ECS400 Spectrometer = DELTA2_NMR Field_Strength = [T] (400[MHz]) X_Acq_Duration = [ms] X_Domain = 19F X_Freq = [MHz] X_Offset = 0[ppm] X_Points = X_Prescans = 1 X_Resolution = [Hz] X_Sweep = [kHz] X_Sweep_Clipped = [kHz] Irr_Domain = Fluorine19 Irr_Freq = [MHz] Irr_Offset = 5[ppm] Tri_Domain = Fluorine19 Tri_Freq = [MHz] Tri_Offset = 5[ppm] Clipped = FALSE Scans = 64 Total_Scans = 64 Relaxation_Delay = 5[s] Recvr_Gain = 46 Temp_Get = 100[dC] X_90_Width = 7.12[us] X_Acq_Time = [ms] X_Angle = 45[deg] X_Atn = 2.3[dB] X_Pulse = 3.56[us] Irr_Mode = Off Tri_Mode = Off Dante_Presat = FALSE Initial_Wait = 1[s] Repetition_Time = [s] X : parts per Million : Fluorine S

40 1 H NMR (500 MHz, toluene d 8, 373 K) NAME nmr EXPNO 154 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 32 DS 2 SWH Hz FIDRES Hz AQ sec RG 128 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-39

41 13 C NMR (126 MHz, toluene d 8, 373 K) NAME nmr EXPNO 160 Date_ Time PROBHD 5 mm Multinucl PULPROG zgpg TD SOLVENT Tol NS 3637 DS 8 SWH Hz FIDRES Hz AQ sec RG DW use DE 6.00 use TE K D sec d sec DELTA sec TD0 1 SFO MHz NUC1 13C P use PLW W SFO MHz NUC2 1H CPDPRG[2 waltz16 PCPD use PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm S-40

42 abundance 19 F NMR (376 MHz, toluene-d 8, 373 K, C 6 F 6 internal standard) Filename = th te100oc.fluorine- Author = suzuki Experiment = proton.jxp Sample_Id = th01.36.no4 Solvent = TOLUENE-D8 Creation_Time = 12-MAY :36:02 Revision_Time = 13-MAY :16:31 Current_Time = 13-MAY :20:48 Comment = single_pulse Data_Format = 1D COMPLEX Dim_Size = Dim_Title = Fluorine19 Dim_Units = [ppm] Dimensions = X Site = JNM-ECS400 Spectrometer = DELTA2_NMR Field_Strength = [T] (400[MHz]) X_Acq_Duration = [ms] X_Domain = 19F X_Freq = [MHz] X_Offset = 0[ppm] X_Points = X_Prescans = 1 X_Resolution = [Hz] X_Sweep = [kHz] X_Sweep_Clipped = [kHz] Irr_Domain = Fluorine19 Irr_Freq = [MHz] Irr_Offset = 5[ppm] Tri_Domain = Fluorine19 Tri_Freq = [MHz] Tri_Offset = 5[ppm] Clipped = FALSE Scans = 64 Total_Scans = 64 Relaxation_Delay = 5[s] Recvr_Gain = 46 Temp_Get = 100[dC] X_90_Width = 7.12[us] X_Acq_Time = [ms] X_Angle = 45[deg] X_Atn = 2.3[dB] X_Pulse = 3.56[us] Irr_Mode = Off Tri_Mode = Off Dante_Presat = FALSE Initial_Wait = 1[s] Repetition_Time = [s] X : parts per Million : Fluorine S

43 1 H NMR (500 MHz, toluene d 8, 300 K) NAME nmr EXPNO 168 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 64 DS 2 SWH Hz FIDRES Hz AQ sec RG 64 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-42

44 1 H NMR (500 MHz, toluene d 8, 373 K) NAME nmr EXPNO 104 Date_ Time PROBHD 5 mm Multinucl PULPROG zg TD SOLVENT Tol NS 128 DS 2 SWH Hz FIDRES Hz AQ sec RG 128 DW use DE 6.00 use TE K D sec MCREST 0 sec MCWRK sec ======== CHANNEL f1 ======= NUC1 1H P use PL db SFO MHz SI SF MHz LB 0.20 Hz PC ppm S-43

45 HPLC HPLC ( mm Ph-3, 30% EtOAc in hexane, 1 ml/min, UV detection at 254 nm) 5.81 min and 99.0% pure; R f 0.39 (EtOAc/hexane = 3/7). S-44