(4R)-4-benzyl-1,3-oxazolidin-2-one

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

Procedure: To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minute and 0° C. at 1 h. The white solid was filtered off to receive the anhydride in the filtrate which was cooled back to −78° C. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred at −78° C. for 45 min. This metalated chiral auxiliary was cannulated to the anhydride at −78° C. and warmed to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minutes and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to receive 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid. maintaining the internal temperature below −70° C The white solid was filtered off was cooled back to −78° C maintaining the internal temperature below −70° C. stirred at −78° C. for 45 min warmed to 0° C. over 1.5 h The resulting mixture was stirred further at 0° C. for 30 minutes quenched by adding excess saturated aqueous NH4Cl solution The solution was diluted with EtOAc (200 mL) the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL) The solution was dried over MgSO4 the solvent was removed in vacuo The crude material was purified by ISCO silica gel column chromatography

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

Procedure: Flush with nitrogen a 12 L 3-neck round bottom flask equipped with a mechanical stirrer, internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone (250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool in a dry ice/acetone bath until the internal temperature is −74° C. Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol) to the addition funnel via cannula, and add to the oxazolidinone solution at a rate such that the internal temperature does not reach above −65° C. After the addition is complete, allow the reaction to stir in the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585 mol) to the addition funnel and add dropwise to the anion solution over a 25 min period. Stir the reaction for 45 min in the cooling bath. Remove the cooling bath and stir the reaction 18 hr as it slowly reaches room temperature. Dilute the mixture with 1N aqueous hydrochloric acid (1.5 L) and diethyl ether (1 L). Separate the layers and wash the organic phase with water (2×1 L) then brine (1 L). Extract the combined aqueous washes with ether (1 L). Dry the combined organic phases over anhydrous magnesium sulfate, filter, and concentrate to 390 g of a light tan oil. Purify this material by silica gel chromatography using hexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil. Flush with nitrogen a 12 L 3-neck round bottom flask equipped with a mechanical stirrer internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min cool in a dry ice/acetone bath until the internal temperature is −74° C does not reach above −65° C After the addition the reaction Stir the reaction for 45 min in the cooling bath Remove the cooling bath stir the reaction 18 hr as it slowly reaches room temperature Separate the layers wash the organic phase with water (2×1 L) Extract the combined aqueous washes with ether (1 L) Dry the combined organic phases over anhydrous magnesium sulfate filter concentrate to 390 g of a light tan oil Purify this material by silica gel chromatography ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil

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

Procedure: N-Butyllithium (2M in hexanes, 50 ml) was added to a solution of (R)-4-benzyloxazolidin-2-one (17 g) in tetrahydrofuran at −78° C. and the suspension was stirred for 30 minutes, then isovaleryl chloride (12 g) was added dropwise. The solution was stirred for 30 min, allowed to warm to room temperature, and saturated ammonium chloride (200 ml) was added. The mixture was evaporated in vacuo and extracted with diethyl ether (2×100 ml), the solvent washed with water and saturated brine, dried (Na2SO4) and evaporated to give the title compound as a colourless solid (25.0 g, 95%). The solution was stirred for 30 min The mixture was evaporated in vacuo extracted with diethyl ether (2×100 ml) the solvent washed with water and saturated brine dried (Na2SO4) evaporated

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

Procedure: 2-(4-Chloro-3-fluorophenyl)acetic acid (1.00 g, 5.30 mmol) was dissolved in THF (14 mL) at 0° C. and treated with triethylamine (0.81 mL, 5.8 mmol). Pivaloyl chloride (0.69 mL, 5.6 mmol) was then added to the solution, and the mixture was allowed to stir for one hour at 0° C. In a separate flask, (R)-4-benzyloxazolidin-2-one (0.987 g, 5.57 mmol) was dissolved in THF (14 mL) at −78° C. and treated with n-BuLi (2.54 mL, 5.83 mmol). The above anion solution was stirred for 20 minutes and then cannulated into the anhydride at −78° C. The reaction was then allowed to stir for one hour at −78° C., and then warmed to 0° C. for two hours. The mixture was quenched with the addition of saturated NH4Cl solution (20 mL) and concentrated in vacuo. The resulting residue was then partitioned between ethyl acetate and water. The aqueous layer was extracted once with ethyl acetate, and the organic fractions were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (0.95 g, 51%) as an oil, which solidified upon standing. The above anion solution was stirred for 20 minutes to stir for one hour at −78° C. warmed to 0° C. for two hours The mixture was quenched with the addition of saturated NH4Cl solution (20 mL) concentrated in vacuo The resulting residue was then partitioned between ethyl acetate and water The aqueous layer was extracted once with ethyl acetate washed with brine separated dried over MgSO4 filtered concentrated in vacuo The resulting residue was purified by column chromatography (3:1 hexanes:ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Bromophenyl)acetic acid (7.85 g, 36.5 mmol) and (R)-4-benzyloxazolidin-2-one (3.23 g, 18.3 mmol) were combined in toluene (30 mL) and triethylamine (10.2 mL, 73.0 mmol). The solution was then heated to 80° C., and a solution of pivaloyl chloride (4.49 mL, 36.5 mmol) in toluene (7.5 mL) was added slowly. The reaction was heated to 110° C. and stirred overnight. The reaction was then cooled, and the toluene solution was washed with 2N HCl, water, 5% Na2CO3, brine and then dried over Na3SO4. After removal of the solvent, the residue was purified by column chromatography to give (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (5.65 g, 83%) as a solid. The reaction was heated to 110° C. The reaction was then cooled the toluene solution was washed with 2N HCl, water, 5% Na2CO3, brine dried over Na3SO4 After removal of the solvent the residue was purified by column chromatography

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9 L) at −78° C. was added over 30 minutes a 2.5 M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than −55° C. during the addition. The reaction mixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) δ7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm−1; mp 102-104° C. The temperature of the reaction mixture was maintained at less than −55° C. during the addition to warm to 0° C., at which The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L) The aqueous phase was separated extracted with ethyl acetate (3 L) The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L) dried over magnesium sulfate concentrated in vacuo to approximately 2 L of a viscous yellow suspension This slurry was dissolved in ethyl acetate (3 L) concentrated to a solid dissolved in ethyl acetate at 50° C Hexanes (10.7 L) was added the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which The solids were collected by filtration washed with hexanes air-dried at ambient temperature

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9 L) at −78° C. was added over 30 minutes a 2.5 M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than −55° C. during the addition. The reaction mixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) δ7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm−1; mp 102-104° C. The temperature of the reaction mixture was maintained at less than −55° C. during the addition to warm to 0° C., at which The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L) The aqueous phase was separated extracted with ethyl acetate (3 L) The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L) dried over magnesium sulfate concentrated in vacuo to approximately 2 L of a viscous yellow suspension This slurry was dissolved in ethyl acetate (3 L) concentrated to a solid dissolved in ethyl acetate at 50° C Hexanes (10.7 L) was added the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which The solids were collected by filtration washed with hexanes air-dried at ambient temperature

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

Procedure: 3 g of (R)-(+)-2-amino-3-phenylpropanol and 1.8 g of ethylene carbonate in 50 ml toluene in a round bottom flask equipped with a Dean-Stark trap was refluxed for 24 hrs. The reaction mixture was poured into ethyl acetate/water mixture and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated. Kugelrohr distillation at 150°-160° C./0.5 mm Hg provided 2.75 g (75%) of an oil. was refluxed for 24 hrs the aqueous layer was extracted with ethyl acetate The combined organic extracts were washed with water dried concentrated Kugelrohr distillation at 150°-160° C./0.5 mm Hg

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of (2E)-3-[3-(tert-butoxycarbonyl)phenyl]prop-2-enoic acid from the previous step (0.186 g, 0.749 mmol) in THF (3 mL) was added triethylamine (0.110 mL, 0.787 mmol) and the mixture was cooled to −20° C. Pivaloyl chloride (0.0969 mL, 0.787 mmol) was added and then the reaction mixture was stirred at −20° C. for 15 min, warmed to 0° C. and stirred for 40 min. Meanwhile, to a cooled (−78° C.) solution of (R)-4-benzyl-2-oxazolidinone (0.305 g, 1.72 mmol) in THF (5 mL), was added nBuLi (1.1 mL, 1.6M in hexanes) dropwise and the mixture was stirred for 30 min. The slurry was warmed to 0° C. and added via cannula into the anion solution. After one hour, the reaction was quenched by the addition of 10 mL 20% aqueous NH4Cl solution, warmed to room temperature and extracted with 2×50 mL ether. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure, and chromatographed on a 4″ 25 mm SiO2 column using 18% EtOAc:hexanes. The clean fractions were combined and the solvent was removed under reduced pressure to give tert-butyl 3-{(1E)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxoprop-1-enyl}benzoate as an oil (0.273 g, 89%). TLC Rf=0.3 (1:4 EtOAc:hexanes, UV visualization); HPLC RT=2.9 min, method B; M+H=408. warmed to 0° C. stirred for 40 min the mixture was stirred for 30 min The slurry was warmed to 0° C. added via cannula into the anion solution After one hour the reaction was quenched by the addition of 10 mL 20% aqueous NH4Cl solution warmed to room temperature extracted with 2×50 mL ether The organic layer was washed with saturated aqueous NaHCO3 and brine dried over MgSO4 filtered the solvent removed under reduced pressure chromatographed on a 4″ 25 mm SiO2 column the solvent was removed under reduced pressure

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

Procedure: Dissolve (R)-4-Benzyl-2-oxazolidinone (5.906 g, 33.33 mmoles) and 4-Pentenoyl chloride (4.54 g, 38.33 mmoles) in THF (50 mL). Cool the mixture in a dry ice acetone bath, and add n-Butyl Lithium (36.66 mmoles; 14.66 mL; 10.12 g) dropwise at −78° C. Stir the mixture at −78° C. for 30 min and then warm to ambient temperature. Quench the solution with 60 ml of sat. ammonium chloride, and then extract with 60 ml MTBE. Separate the organics and dry over magnesium sulfate. Filter the drying agent and concentrate under vacuum to an oil (6.96 g). LCMS=100% 260 amu (M+1). Cool the mixture in a dry ice acetone bath warm to ambient temperature Quench the solution with 60 ml of sat. ammonium chloride extract with 60 ml MTBE Separate the organics and dry over magnesium sulfate Filter the drying agent concentrate under vacuum to an oil (6.96 g)

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

Procedure: Dissolve (R)-4-Benzyl-2-oxazolidinone (5.906 g, 33.33 mmoles) and 4-Pentenoyl chloride (4.54 g, 38.33 mmoles) in THF (50 mL). Cool the mixture in a dry ice acetone bath, and add n-Butyl Lithium (36.66 mmoles; 14.66 mL; 10.12 g) dropwise at −78° C. Stir the mixture at −78° C. for 30 min and then warm to ambient temperature. Quench the solution with 60 ml of sat. ammonium chloride, and then extract with 60 ml MTBE. Separate the organics and dry over magnesium sulfate. Filter the drying agent and concentrate under vacuum to an oil (6.96 g). LCMS=100% 260 amu (M+1). Cool the mixture in a dry ice acetone bath warm to ambient temperature Quench the solution with 60 ml of sat. ammonium chloride extract with 60 ml MTBE Separate the organics and dry over magnesium sulfate Filter the drying agent concentrate under vacuum to an oil (6.96 g)

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

Procedure: Flush with nitrogen a 12 L 3-neck round bottom flask equipped with mechanical stirrer, internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min, then add (R)-4-benzyl-2-oxazolidinone (250 g, 1.41 mol). Dilute with THF (1.8 L) and cool in a dry ice/acetone bath until the internal temperature is −74° C. Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol) to the addition funnel via cannula, and add to the oxazolidinone solution at a rate such that the internal temperature does not reach above −65° C. After the addition is complete, allow the reaction to stir in the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585 mol) to the addition funnel and add dropwise to the anion solution over a 25 min period. Stir the reaction for 45 min in the cooling bath. Remove the cooling bath and stir the reaction 18 hr as it slowly reaches room temperature. Dilute the mixture with 1N aqueous hydrochloric acid (1.5 L) and diethyl ether (1.0 L). Separate the layers and wash the organic phase with water (2×1 L) then brine (1 L). Extract the combined aqueous washes with ether (1 L). Dry the combined organic phases over anhydrous magnesium sulfate, filter, and concentrate to 390 g of a tan oil. Purify this material by silica gel chromatography using hexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil. Flush with nitrogen a 12 L 3-neck round bottom flask equipped with mechanical stirrer internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min cool in a dry ice/acetone bath until the internal temperature is −74° C does not reach above −65° C After the addition the reaction Stir the reaction for 45 min in the cooling bath Remove the cooling bath stir the reaction 18 hr as it slowly reaches room temperature Separate the layers wash the organic phase with water (2×1 L) Extract the combined aqueous washes with ether (1 L) Dry the combined organic phases over anhydrous magnesium sulfate filter concentrate to 390 g of a tan oil Purify this material by silica gel chromatography ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil