(4S)-3-(3-phenylpropanoyl)-4-propan-2-yl-1,3-oxazolidin-2-one

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

Procedure: Add dibutylboron triflate (1 M in dichloromethane, 11.8 mL, 11.8 mmol) to a solution of 4-(S)-isopropyl-3-(3-phenylpropionyl)-oxazolidin-2-one (2.8 g, 10.7 mmol) in dichloromethane (40 mL) at 0° C. Stir 5 min. Add N,N-diisopropylethylamine (2.25 mL, 12.87 mmol) and stir 90 min. Cool to −78° C. and add 4-(R)-fluoro-2-(R)-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.53 g, 11.6 mmol) in dichloromethane (15 mL) over 15 min. Stir 90 min and then warm to room temperature over 18 h. Cool in ice bath and add 0.05 M pH 7 phosphate buffer (15 mL). Extract with dichloromethane and concentrate. Dissolve in methanol (50 mL) and cool in ice bath. Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath. Stir 5 min and concentrate. Extract with ethyl acetate and wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (2.68 g, 52%). Stir 90 min warm to room temperature over 18 h Cool in ice bath Extract with dichloromethane concentrate Dissolve in methanol (50 mL) cool in ice bath Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath Stir 5 min concentrate Extract with ethyl acetate wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with hexanes and ethyl acetate)

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

Procedure: Add dibutylboron triflate (1 M in dichloromethane, 11.8 mL, 11.8 mmol) to a solution of 4-(S)-isopropyl-3-(3-phenylpropionyl)-oxazolidin-2-one (2.8 g, 10.7 mmol) in dichloromethane (40 mL) at 0° C. Stir 5 min. Add N,N-diisopropylethylamine (2.25 mL, 12.87 mmol) and stir 90 min. Cool to −78° C. and add 4-(R)-fluoro-2-(R)-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.53 g, 11.6 mmol) in dichloromethane (15 mL) over 15 min. Stir 90 min and then warm to room temperature over 18 h. Cool in ice bath and add 0.05 M pH 7 phosphate buffer (15 mL). Extract with dichloromethane and concentrate. Dissolve in methanol (50 mL) and cool in ice bath. Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath. Stir 5 min and concentrate. Extract with ethyl acetate and wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (2.68 g, 52%). Stir 90 min warm to room temperature over 18 h Cool in ice bath Extract with dichloromethane concentrate Dissolve in methanol (50 mL) cool in ice bath Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath Stir 5 min concentrate Extract with ethyl acetate wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with hexanes and ethyl acetate)

Conditions: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add n-butyllithium (2.5 M solution in hexanes, 32 mL of, 80 mmol) to a solution of 4-(S)-isopropyloxazolidin-2-one (10.26 g, 79.4 mmol) in THF (250 mL) at −78° C. Stir 30 min. Add 3-phenylpropionyl chloride (13.2 mL, 89 mmol) over 4 min. Stir 2.5 h at −78° C., then warm to −55° C. and stir 2 h. Add saturated aqueous ammonium chloride (75 mL) and warm to room temperature. Extract with dichloromethane and wash extract with 1 N NaOH (200 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate. Add hexanes (50 mL), filter solids and dry under vacuum to give a white solid (18.94 g, 91%). Stir 2.5 h at −78° C. stir 2 h Extract with dichloromethane wash extract with 1 N NaOH (200 mL), saturated aqueous sodium chloride dry (magnesium sulfate) concentrate Add hexanes (50 mL), filter solids dry under vacuum

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

Procedure: 1.55 ml (11 mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.61 g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J.J. Plattner et al., J. Med. Chem. 1988, 31 (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether

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

Procedure: 1.55 ml (11 mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.61 g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J.J. Plattner et al., J. Med. Chem. 1988, 31 (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether

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

Procedure: 8.61 ml (13.8 mmoles) of butyllithium (as a 1.6M hexane solution) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 1.93 ml (13.8 mmoles) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes, and then a solution of 3.00 mg (11.5 mmoles) of 4(S)-isopropyl-3-(3-phenylpropionyl)-2-oxazolidinone (prepared as described in Preparation 16) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred for 1 hour. At the end of this time, 2.99 ml (34.6 mmoles) of allyl bromide were added to the mixture, and the mixture was stirred for 12 hours, whilst allowing it to return gradually to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 5:1 by volume mixture of hexane and ethyl acetate as eluent), to give 2.14 g (yield 62%) of the title compound as a colorless oily substance. the mixture was stirred for 1 hour the mixture was stirred for 12 hours to return gradually to room temperature was then extracted with ethyl acetate The extract was dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure the residue was purified by medium pressure silica gel column chromatography ( by volume mixture of hexane and ethyl acetate as eluent),

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

Procedure: 8.61 ml (13.8 mmoles) of butyllithium (as a 1.6M hexane solution) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 1.93 ml (13.8 mmoles) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes, and then a solution of 3.00 mg (11.5 mmoles) of 4(S)-isopropyl-3-(3-phenylpropionyl)-2-oxazolidinone (prepared as described in Preparation 16) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred for 1 hour. At the end of this time, 2.99 ml (34.6 mmoles) of allyl bromide were added to the mixture, and the mixture was stirred for 12 hours, whilst allowing it to return gradually to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 5:1 by volume mixture of hexane and ethyl acetate as eluent), to give 2.14 g (yield 62%) of the title compound as a colorless oily substance. the mixture was stirred for 1 hour the mixture was stirred for 12 hours to return gradually to room temperature was then extracted with ethyl acetate The extract was dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure the residue was purified by medium pressure silica gel column chromatography ( by volume mixture of hexane and ethyl acetate as eluent),

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

Procedure: 1.55 ml (1l mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml 10 (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.6l g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J. J. Plattner et al., J. Med. Chem. 1988, 3l (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes is then added dropwise to a solution of 2.6l The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether

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

Procedure: 1.55 ml (1l mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml 10 (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.6l g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J. J. Plattner et al., J. Med. Chem. 1988, 3l (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes is then added dropwise to a solution of 2.6l The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether

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

Procedure: 1.55 ml (1l mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml 10 (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.6l g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J. J. Plattner et al., J. Med. Chem. 1988, 3l (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes is then added dropwise to a solution of 2.6l The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether

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

Procedure: 22.50 ml (36.0 mmole) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 5.05 ml (36.0 mmole) of diisopropylamine in 100 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 7.84 g (30.0 mmole) of 4(S)-isopropyl-3-(3-phenyl-1-oxopropyl)-2-oxazolidinone (prepared as described in Preparation 12) in 50 ml of anhydrous tetrahydrofuran was added dropwise to the mixture. The mixture was then stirred for 1 hour, after which 14.26 ml (90.0 mmole) of benzyl bromoacetate were added to it. The mixture was stirred for 6 hours while the temperature of the reaction mixture was permitted to revert to room temperature. At the end of this time, the reaction mixture was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was stripped from it by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 9.05 g (yield 74%) of the title compound as white crystals, melting at 118°-120° C. The mixture was then stirred for 1 hour The mixture was stirred for 6 hours while the temperature of the reaction mixture to revert to room temperature extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate the solvent was stripped from it by distillation under reduced pressure The residue was purified by medium pressure column chromatography through silica gel ( by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether

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

Procedure: 1.55 ml (11 mmol) of diisopropylamine is dissolved in 20 ml of absolute THF under argon and 7.75 ml (12 mmol) of n-butyllithium solution (1.55M in n-hexane, Aldrich) are added at -20° C. with stirring. The mixture is stirred at this temperature for 10 minutes and the freshly prepared solution of lithium diisopropylamide prepared in this way is then added dropwise to a solution of 2.61 g (10 mmol) of (4S)-3-(3-phenylpropionyl)-4-(2-propyl)-oxazolidin-2-one (J.J. Plattner et al., J. Med. Chem. 1988, 31 (12), 2277-2288) cooled to -70° C. in 30 ml of absolute THF. The mixture is subsequently stirred at -70° C. for 30 minutes and 1.32 ml (13 mmol) of benzaldehyde are injected into the mixture via a septum. After one hour at this temperature, the mixture is hydrolyzed by adding 100 ml of saturated ammonium chloride solution and allowed to come to room temperature, and 100 ml of diethyl ether are added. The organic phase is separated off and the aqueous phase is extracted with 100 ml of diethyl ether. The mixture is stirred at this temperature for 10 minutes The mixture is subsequently stirred at -70° C. for 30 minutes to come to room temperature The organic phase is separated off the aqueous phase is extracted with 100 ml of diethyl ether