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Example 11 [Show Image] Synthesis of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol; Five drops of 1,2-dibromoethane were added to a mixture of magnesium (1.11 g, 45.7 mmol), 2-(5-bromo-2-chlorophenyl)-1,3-dioxolane (9.64 g, 36.5 mmol) and tetrahydrofuran (20 mL) and this mixture was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and tetrahydrofuran (15 mL) of 2,3,4,6-tetra-0-benzyl-5-thio-D-glucono-1,5-lactone (10.14 g, 36.5 mmol) was added dropwise to this solution and stirred at room temperature for 30 minutes. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:1) to obtain a colorless amorphous 2,3,4,6-tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolan-2-yl)phenyl]-5-thio-D-glucopyranose (11.81 g, 87percent). [Show Image] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 3.06 (s, 1H) 3.47 - 3.58 (m, 1H) 3.64 (dd, J=10.0, 2.9 Hz, 1H) 3.83 - 4.21 (m, 9H) 4.48 - 4.56 (m, 3 H) 4.66 (d, J=10.6 Hz, 1 H) 4.82 - 4.97 (m, 3 H) 6.15 (s, 1 H) 6.77 (dd, J=7.9, 1.5 Hz, 2 H) 7.08 - 7.21 (m, 5 H) 7.23 - 7.37 (m, 14 H) 7.55 (dd, J=8.4, 2.5 Hz, 1 H) 7:92 (d, J=2.5 Hz, 1 H). Then, 6M hydrochloric acid (120 mL) was added to a tetrahydrofuran (50 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolane-2-yl)phenyl]-5-thio-D-glucopyranose (6.01 g, 8.12 mmol) while ice-cooled, and stirred at room temperature for two days. The reaction mixture was added with an iced water and extracted with ethyl acetate and the organic phase was washed with a saturated sodium bicarbonate aqueous solution, brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain colorless amorphous 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (4.53 g, 80percent). [Show Image] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 3.14 (s, 1 H) 3.43 - 3.58 (m, 1 H) 3.63 (dd, J=10.0, 2.6 Hz, 1 H) 3.87 - 4.16 (m, 5 H) 4.45 - 4.72 (m, 4 H) 4.80 - 5.05 (m, 3 H) 6.73 (d, J=7.8 Hz, 2 H) 7.02 - 7.43 (m, 19 H) 7.74 (dd, J=8.4, 2.5 Hz, 1 H) 8.06 (d, J=2.5 Hz, 1 H) 10.39 (s, 1 H). Then, 2.6 M n-butylithium hexane solution (1.6 mL) was added to a mixture of <strong>[68155-69-1]1-bromo-4-ethoxy-2-methylbenzene</strong> (0.94 g, 4 . 37 mmol) and tetrahydrofuran (12 mL) at -78°C. After stirred for one hour, the mixture was added with a tetrahydrofuran (10 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose(1.52.g, 2.18 mmol), and, further stirred for 20 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-methylphenyl)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1.72 g, 95percent) as a yellow amorphous diastereomer mixture. Then, an acetonitrile (20 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-methylphenyl)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1.72 g, 2.06 mmol) was added sequentially with Et3SiH (1.98 mL, 12.4 mmol) and BF3*Et2O (1.04 mL, 8.27 mmol) while cooled on ice. After stirred for one hour, the reaction mixture was warmed up to room temperature and stirred for three hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate =5:1) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[4-chloro-3-(4-ethoxy-2-methylbenzyl)phenyl]-1-thio-D-glucitol (1.01 g, 61percent) as a colorless powder. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.40 (t, J=7.0 Hz, 3 H) 2.14 (s, 3 H) 3.01 - 3.12 (m, 1 H) 3.48 (t, J=8.9 Hz, 1 H) 3.65 - 4.06 (m, 10 H) 4.46 - 4.61 (m, 4 H) 4.80 - 4.91 (m, 3 H) 6.58 (dd, J=8.2, 2.5 Hz, 1 H) 6.68 - 6.76 (m, 2 H) 6.81 (d, J=8.4 Hz, 1 H) 6.98 (d, J=2.2 Hz, 1 H) 7.10 - 7.39 (m, 21 H). |
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