methyl (2S)-1-benzyl-5-oxopyrrolidine-2-carboxylate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl (2S)-5-pyrrolidone-2-carboxylate (80 g) in tetrahydrofuran (900 ml) was added sodium hydride (60% in oil, 23.5 g) by portions. After the addition, the reaction mixture was heated to 60° C., and benzyl bromide (69.8 ml) was added dropwise thereto. After 3 hours, the reaction mixture was cooled to room temperature and water (100 ml) was added dropwise thereto. The reaction mixture was poured into a mixture of ethyl acetate (2 l) and water (800 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V) to give methyl (2S)-1-benzyl-5-pyrrolidone-2-carboxylate (100.8 g). After the addition the reaction mixture was cooled to room temperature The organic layer was separated washed with brine dried over magnesium sulfate Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V)

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

Procedure: Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification. washed with dichloromethane The aqueous layer was evaporated the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml) The mixture was evaporated once more the residue was triturated with dichloromethane the combined dichloromethane fractions were evaporated

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

Procedure: Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification. washed with dichloromethane The aqueous layer was evaporated the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml) The mixture was evaporated once more the residue was triturated with dichloromethane the combined dichloromethane fractions were evaporated

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

Procedure: Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification. washed with dichloromethane The aqueous layer was evaporated the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml) The mixture was evaporated once more the residue was triturated with dichloromethane the combined dichloromethane fractions were evaporated

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

Procedure: A solution of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester (132 g, 0.556 mol) in 600 mL of t-butanol was cooled to ca. 18° C. Sodium borohydride (41 g, 1.12 mol) was added in one portion. To the suspension was added over 45 min 425 mL of methanol. The reaction was kept at 15° C. during the addition, during which time hydrogen gas was evolved. After the addition, the mixture was kept at 20° C. until hydrogen evolution had subsided, and was allowed to stand at room temperature overnight. The solvents were removed on a rotary evaporator, and the residue was dissolved in 1 L of water and acidified to pH 7.5 with 2N HCl. The mixture was extracted with methylene chloride and the combined extracts were washed with 2N HCl and brine, and dried over Na2SO4. Evaporation of the solvent afforded 96.3 g of crude product, which was recrystallized once from toluene to give 89.5 g (77% yield) of (S)-5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone as a white solid, mp 82°-4° C. (toluene). 1H NMR (CDCl3) δ 1.92 and 1.94 (dd, J=6.5 Hz, 1 H, OH), 1.96-2.11 (m, 2 H, CH2), 2.36-2.61 (m, 2 H, COCH2), 3.48-3.78. (m, 3 H, CH2O and CH), 4.29 and 4.81 (AB, Jgem =15 Hz, 2 H, CH2Ph), 7.26-7.35 (m, 5 H, phenyl). [α]25D =+116° (c 1.07, methanol). Anal. Calcd for C12H15NO2 : C, 70.22; H, 7.37; N, 6.75. Found: C, 70.06; H, 7.41; N 6.75. After the addition The solvents were removed on a rotary evaporator the residue was dissolved in 1 L of water The mixture was extracted with methylene chloride the combined extracts were washed with 2N HCl and brine dried over Na2SO4 Evaporation of the solvent afforded 96.3 g of crude product, which was recrystallized once from toluene

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

Procedure: The crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid (160 g, 0.73 mol) was dissolved in 300 mL of toluene and 550 mL of methanol. To the solution was added 9 mL of conc H2SO4 and the solution was heated to reflux overnight. The solution was cooled in an ice bath and neutralized to pH 5 with 25% NaOH, followed by adding 50 mL of saturated sodium bicarbonate to bring the solution to pH 7. The methanol was removed on a rotary evaporator and the residue was diluted with 500 mL of water and extracted with methylene chloride. The combined extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded 132 g of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester as an oil which was >95% pure by NMR. 1H NMR (CDCl3) δ 2.0-2.6 (m,4H,CH2 's), 3.68 (s,3 H,CH3), 3.95 (dd, 1 H,J=4,9 Hz, H-4), 4.02 and 5.03 (AB, 2 H,Jgem =16 Hz, CH2Ph), 7.2-7.4 (m, 5 H, arom). the solution was heated to reflux overnight The solution was cooled in an ice bath The methanol was removed on a rotary evaporator the residue was diluted with 500 mL of water extracted with methylene chloride The combined extracts were washed with brine dried over MgSO4 Evaporation of the solvent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl (2S)-5-pyrrolidone-2-carboxylate (80 g) in tetrahydrofuran (900 ml) was added sodium hydride (60% in oil, 23.5 g) by portions. After the addition, the reaction mixture was heated to 60° C., and benzyl bromide (69.8 ml) was added dropwise thereto. After 3 hours, the reaction mixture was cooled to room temperature and water (100 ml) was added dropwise thereto. The reaction mixture was poured into a mixture of ethyl acetate (2 l) and water (800 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V) to give methyl (2S)-1-benzyl-5-pyrrolidone-2-carboxylate (100.8 g). After the addition the reaction mixture was cooled to room temperature The organic layer was separated washed with brine dried over magnesium sulfate Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V)

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

Procedure: Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification. washed with dichloromethane The aqueous layer was evaporated the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml) The mixture was evaporated once more the residue was triturated with dichloromethane the combined dichloromethane fractions were evaporated