2,3,4,6-TETRA-O-BENZYL-D-GLUCONO-1,5-LACTONE

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-1-chlorobenzene (intermediate BI) (123 mg, 0.34 mmol) and (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (362 mg, 0.67 mmol) in anhydrous THF (1.5 mL) under argon and kept at −78° C. was added dropwise a 1.6 M solution of n-butyl lithium in hexane (0.63 mL) over 15 min. The mixture was stirred at −78° C. for 1.5 h. A solution of methanesulfonic acid (0.1 mL) in methanol (1 mL) was added to the reaction mixture and allowed to warm to room temperature over time. The mixture was stirred at room temperature for 21 h. A saturated solution of sodium bicarbonate was slowly added to the reaction mixture to bring the pH to 8. Water (2 mL) was added and the product was extracted into ethyl acetate (3×2 mL), the combined ethyl acetate solution was washed with brine (1.5 mL), dried (Na2SO4), filtered and evaporated. Preparative thin layer chromatography (TLC) using 12:1 hexane:EtOAc gave intermediate BJ (80 mg, yield 28%). LC-ESI-MS (m/z): 807 (M−OMe). kept at −78° C. to warm to room temperature over time The mixture was stirred at room temperature for 21 h the product was extracted into ethyl acetate (3×2 mL) the combined ethyl acetate solution was washed with brine (1.5 mL) dried (Na2SO4) filtered evaporated EtOAc gave intermediate BJ (80 mg, yield 28%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a tetrahydrofuran solution (3 mL) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxymethoxy)ethyl]benzyl]benzene (290 mg, 0.609 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (234 μL, 0.609 mmol), and the mixture was stirred for 5 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) was added dropwise, and the mixture was stirred for an hour at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (124 mg, 22%) as a colorless oily compound. the mixture was stirred for an hour at the same temperature the resulting mixture was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine dried with anhydrous magnesium sulfate The drying agent was filtered off the solvent was evaporated under reduced pressure Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a tetrahydrofuran solution (3 mL) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxymethoxy)ethyl]benzyl]benzene (290 mg, 0.609 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (234 μL, 0.609 mmol), and the mixture was stirred for 5 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) was added dropwise, and the mixture was stirred for an hour at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (124 mg, 22%) as a colorless oily compound. the mixture was stirred for an hour at the same temperature the resulting mixture was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine dried with anhydrous magnesium sulfate The drying agent was filtered off the solvent was evaporated under reduced pressure Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a tetrahydrofuran solution (36 mL) of 2-[4-(benzyloxy)-5-bromo-2-methylphenyl]-1,3-dioxolane (5.82 g, 16.6 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (6.40 mL, 16.6 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (18 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) was added dropwise, and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound (10.7 g, 87%) as a yellow oily compound. the mixture was stirred for 20 minutes at the same temperature the resulting mixture was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine dried with anhydrous magnesium sulfate The drying agent was filtered off the solvent was evaporated under reduced pressure Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a tetrahydrofuran solution (36 mL) of 2-[4-(benzyloxy)-5-bromo-2-methylphenyl]-1,3-dioxolane (5.82 g, 16.6 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (6.40 mL, 16.6 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (18 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) was added dropwise, and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound (10.7 g, 87%) as a yellow oily compound. the mixture was stirred for 20 minutes at the same temperature the resulting mixture was extracted with ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine dried with anhydrous magnesium sulfate The drying agent was filtered off the solvent was evaporated under reduced pressure Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyllithium in n-hexane (1.6M solution, 68.8 ml) was added to a solution of dimethyl methylphosphonate (13.65 g) in tetrahydrofuran (200 ml) in a stream of argon at -70° to -78° C., and then stirred for 30 min. To the solution was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (29.6 g) in tetrahydrofuran (150 ml) at -70° to -78° C. The mixture was stirred for 1 hour at the same temperature. The cooling bath was removed and the mixture was allowed to warm to 0° C. with stirring. Ice-cold 10% ammonium chloride solution (400 ml) was added to the reaction mixture and the resulting oily substances were extracted with ethyl acetate (1.2 l). The ethyl acetate solution was washed with 2N hydrochloric acid and saturated aqueous sodium hydrogen-carbonate, dried with anhydrous sodium sulfate and then evaporated in vacuo. Ethyl ether-petroleum ether (1:3; 400 ml) was added to the residue and the mixture was refrigerated to give 3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (33.1 g) as white crystals; m.p. 112°-113° C.; The mixture was stirred for 1 hour at the same temperature The cooling bath was removed with stirring Ice-cold 10% ammonium chloride solution (400 ml) was added to the reaction mixture the resulting oily substances were extracted with ethyl acetate (1.2 l) The ethyl acetate solution was washed with 2N hydrochloric acid and saturated aqueous sodium hydrogen-carbonate dried with anhydrous sodium sulfate evaporated in vacuo Ethyl ether-petroleum ether (1:3; 400 ml) was added to the residue

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-3-(2-phenylethyl)benzo[b]-thiophene (0.94 g) in tetrahydrofuran (25 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 1.24 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.80 g) in tetrahydrofuran (4 mL), and the mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (1.1 g). stirred for 30 minutes the mixture was extracted with diethyl ether The organic layer was washed with water and brine dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-1-chlorobenzene (intermediate BI) (123 mg, 0.34 mmol) and (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (362 mg, 0.67 mmol) in anhydrous THF (1.5 mL) under argon and kept at −78° C. was added dropwise a 1.6 M solution of n-butyl lithium in hexane (0.63 mL) over 15 min. The mixture was stirred at −78° C. for 1.5 h. A solution of methanesulfonic acid (0.1 mL) in methanol (1 mL) was added to the reaction mixture and allowed to warm to room temperature over time. The mixture was stirred at room temperature for 21 h. A saturated solution of sodium bicarbonate was slowly added to the reaction mixture to bring the pH to 8. Water (2 mL) was added and the product was extracted into ethyl acetate (3×2 mL), the combined ethyl acetate solution was washed with brine (1.5 mL), dried (Na2SO4), filtered and evaporated. Preparative thin layer chromatography (TLC) using 12:1 hexane:EtOAc gave intermediate BJ (80 mg, yield 28%). LC-ESI-MS (m/z): 807 (M−OMe). kept at −78° C. to warm to room temperature over time The mixture was stirred at room temperature for 21 h the product was extracted into ethyl acetate (3×2 mL) the combined ethyl acetate solution was washed with brine (1.5 mL) dried (Na2SO4) filtered evaporated EtOAc gave intermediate BJ (80 mg, yield 28%)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-1-chlorobenzene (intermediate BI) (123 mg, 0.34 mmol) and (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (362 mg, 0.67 mmol) in anhydrous THF (1.5 mL) under argon and kept at −78° C. was added dropwise a 1.6 M solution of n-butyl lithium in hexane (0.63 mL) over 15 min. The mixture was stirred at −78° C. for 1.5 h. A solution of methanesulfonic acid (0.1 mL) in methanol (1 mL) was added to the reaction mixture and allowed to warm to room temperature over time. The mixture was stirred at room temperature for 21 h. A saturated solution of sodium bicarbonate was slowly added to the reaction mixture to bring the pH to 8. Water (2 mL) was added and the product was extracted into ethyl acetate (3×2 mL), the combined ethyl acetate solution was washed with brine (1.5 mL), dried (Na2SO4), filtered and evaporated. Preparative thin layer chromatography (TLC) using 12:1 hexane:EtOAc gave intermediate BJ (80 mg, yield 28%). LC-ESI-MS (m/z): 807 (M−OMe). kept at −78° C. to warm to room temperature over time The mixture was stirred at room temperature for 21 h the product was extracted into ethyl acetate (3×2 mL) the combined ethyl acetate solution was washed with brine (1.5 mL) dried (Na2SO4) filtered evaporated EtOAc gave intermediate BJ (80 mg, yield 28%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7-(4-methylbenzyl)benzo[b]thiophene (0.57 g) in tetrahydrofuran (10 mL) was added n-butyllithium (2.71 mol/L tetrahydrofuran solution, 0.88 mL) at −78° C. under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.2 g) in tetrahydrofuran (5 mL) was added to the mixture. The reaction mixture was warmed to 0° C. and stirred for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.2 g). stirred for 10 minutes the mixture was extracted with diethyl ether The organic layer washed with brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(2-phenylethyl)benzo[b]thiophene (0.4 g) in tetrahydrofuran (15 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 0.69 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.82 g) in tetrahydrofuran (3 mL), and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethylether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2,3,4,6-tetra-O-benzyl-1-[4-(2-phenylethyl)benzo[b]-thiophene-2-yl]-D-glucopyranose (1.02 g). This material was dissolved in acetonitrile (13 mL) and triethylsilane (0.42 mL) was added to the solution. Boron trifluoride diethylether complex (0.18 mL) was added to the solution at −20° C., and the mixture was stirred at room temperature for 1 hour. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give the title compound (0.58 g). the mixture was stirred under ice- cooling for 10 minutes the mixture was extracted with diethylether The extract washed with water and brine dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7-(4-methylbenzyl)benzo[b]thiophene (0.57 g) in tetrahydrofuran (10 mL) was added n-butyllithium (2.71 mol/L tetrahydrofuran solution, 0.88 mL) at −78° C. under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.2 g) in tetrahydrofuran (5 mL) was added to the mixture. The reaction mixture was warmed to 0° C. and stirred for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.2 g). stirred for 10 minutes the mixture was extracted with diethyl ether The organic layer washed with brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1)