tert-butyl (2S)-5-oxopyrrolidine-2-carboxylate

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

Procedure: To a solution of L-pyroglutamic acid (100 g, 775 mmol) in tert-butyl acetate (1.3 L) was added 70% aqueous perchloric acid (25 mL). After stirring for 18 hours in a 3-liter round bottom flask sealed with a rubber septum, the reaction mixture was poured carefully into saturated aqueous sodium bicarbonate (800 mL) and extracted with ethyl acetate (1 L, then 300 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to provide tert-Butyl L-pyroglutamate (100.5 g, 70% mass recovery). The tert-butyl L-pyroglutamate was dissolved in acetonitrile (1.5 L) with 4-dimethylaminopyridine (6.0 g, 49.1 mmol) and cooled to 0° C. A solution of di-tert-butyl-dicarbonate (154 g, 705 mmol) in acetonitrile (150 mL) was added over 30 min and after an additional 30 min the cooling bath was removed. After stirring at room temperature for 48 hours, the reaction mixture was concentrated. The residue was dissolved in ether (1 L) and hexanes (1 L), then washed with saturated aqueous sodium bicarbonate (2×100 mL) and saturated aqueous sodium chloride. The solution was dried (sodium sulfate), filtered and concentrated to give a yellow oil (140 g). The residue was purified by recrystallization from hexanes (800 ml) and ethyl acetate (25 mL), and the mother liquor was recrystallized from hexanes (300 mL) and ethyl acetate (10 mL) to give two crops of the title compound (122 g, 428 mmol, 55%) as a white solid. NMR data was consistent with previously reported material: R. A. August et al, J. Chem. Soc., Perkin Trans. 1 (1996) 507-514. sealed with a rubber septum extracted with ethyl acetate (1 L The combined organic layers were dried (sodium sulfate) filtered concentrated

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

Procedure: Perchloric acid (70% aqueous, 0.521 cm3, 6.05 mmol) was added dropwise to a stirred suspension of (S)-pyroglutamic acid 9 (1 g, 7.75 mmol) in tent-butyl acetate (12 cm3, 85.5 mmol). The mixture was stirred for 24 h then sodium carbonate (0.80 g, 7.60 mmol) was added cautiously, ether was added and the organic phase washed with saturated sodium hydrogen carbonate solution and brine. The aqueous phase was extracted with ethyl acetate, dried (MgSO4), filtered and the solvent removed to yield an oil to which was added carbon tetrachloride and the solvent evaporated in vacuo to remove traces of acetic acid to give ester 10 (0.81 g, 56%) as a white solid: δH (300 MHz; CDCl3; Me4Si) 1.48 [9H, s, C(CH3)], 2.33-2.45 (4H, m, 3-H2, 4-H2), 4.12-4.16 (1H, m, 5-H) and 6.16 (1H, br s, N—H); δC (75 MHz; CDCl3) 24.7 (CH2, 4-C), 27.8 [CH3, C(CH3)], 29.2 (CH2, 3-C), 55.9 (CH, 5-C), 82.3 [quat., C(CH3)], 170.9 (quat., 5-CO) and 177.7 (quat., 2-C). the organic phase washed with saturated sodium hydrogen carbonate solution and brine The aqueous phase was extracted with ethyl acetate dried (MgSO4) filtered the solvent removed to yield an oil to which the solvent evaporated in vacuo to remove traces of acetic acid

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

Procedure: Perchloric acid (70% aqueous, 0.521 cm3, 6.05 mmol) was added dropwise to a stirred suspension of (S)-pyroglutamic acid 9 (1 g, 7.75 mmol) in tent-butyl acetate (12 cm3, 85.5 mmol). The mixture was stirred for 24 h then sodium carbonate (0.80 g, 7.60 mmol) was added cautiously, ether was added and the organic phase washed with saturated sodium hydrogen carbonate solution and brine. The aqueous phase was extracted with ethyl acetate, dried (MgSO4), filtered and the solvent removed to yield an oil to which was added carbon tetrachloride and the solvent evaporated in vacuo to remove traces of acetic acid to give ester 10 (0.81 g, 56%) as a white solid: δH (300 MHz; CDCl3; Me4Si) 1.48 [9H, s, C(CH3)], 2.33-2.45 (4H, m, 3-H2, 4-H2), 4.12-4.16 (1H, m, 5-H) and 6.16 (1H, br s, N—H); δC (75 MHz; CDCl3) 24.7 (CH2, 4-C), 27.8 [CH3, C(CH3)], 29.2 (CH2, 3-C), 55.9 (CH, 5-C), 82.3 [quat., C(CH3)], 170.9 (quat., 5-CO) and 177.7 (quat., 2-C). the organic phase washed with saturated sodium hydrogen carbonate solution and brine The aqueous phase was extracted with ethyl acetate dried (MgSO4) filtered the solvent removed to yield an oil to which the solvent evaporated in vacuo to remove traces of acetic acid

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

Procedure: 30.0 g of L-pyroglutamic acid 133 (232 mmol) was suspended in 500 ml of tert-butyl acetate and added with 12 ml of 60% perchloric acid. After stirring for 15 h at RT, the resulting clear solution was cooled to 0° C. and adjusted to a pH value of 4-5 by adding 30.0 g of solid NaHCO3. After removing the solid by filtration, the filtrate was concentrated to dryness, thereby obtaining 25.4 g (136 mmol, 58%) of the tert-butyl ester 206 as a white solid that was reacted without further purification. An analytical sample was obtained by column chromatography over silica gel (eluant: EE). the resulting clear solution was cooled to 0° C. After removing the solid by filtration the filtrate was concentrated to dryness

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

Procedure: 30.0 g of L-pyroglutamic acid 133 (232 mmol) was suspended in 500 ml of tert-butyl acetate and added with 12 ml of 60% perchloric acid. After stirring for 15 h at RT, the resulting clear solution was cooled to 0° C. and adjusted to a pH value of 4-5 by adding 30.0 g of solid NaHCO3. After removing the solid by filtration, the filtrate was concentrated to dryness, thereby obtaining 25.4 g (136 mmol, 58%) of the tert-butyl ester 206 as a white solid that was reacted without further purification. An analytical sample was obtained by column chromatography over silica gel (eluant: EE). the resulting clear solution was cooled to 0° C. After removing the solid by filtration the filtrate was concentrated to dryness

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

Procedure: 1,1-dimethylethyl 5-oxo-L-prolinate (2.7 g, 12 mmol, prepared as described in Synth. Comm., 2005, 35(8), 1129) was added to a suspension of sodium hydride (0.428 g (60% suspension in oil), 10.7 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 5 minutes. Ethyl iodide (1.67 g, 10.7 mmol) was then added and the mixture was heated at 40° C. for 2 hrs. A further quantity of sodium hydride (0.24 g) was added and stirring continued overnight at room temperature. An additional quantity of ethyl iodide (0.86 ml) was added to the mixture at this stage and the mixture was left to stand at room temperature over the weekend. Water (˜10 ml) was added to the mixture and this was stirred for 15 minutes. The tetrahydrofuran was evaporated and the remaining aqueous layer was extracted with dichloromethane (2×50 ml) and a 3:1 mixture of chloroform and isopropanol (50 ml). The combined organic layers were filtered through a hydrophobic frit and evaporated to give a yellow oil. Toluene was added to the mixture and then evaporated to a yellow oil once more. This material was purified by automated silica flash-column chromatography (Biotage SP4), eluting with a 15-100% gradient of ethyl acetate in hexane, to give pure 1,1-dimethylethyl 1-ethyl-5-oxo-prolinate. the mixture was heated at 40° C. for 2 hrs stirring continued overnight at room temperature the mixture was left to stand at room temperature over the weekend this was stirred for 15 minutes The tetrahydrofuran was evaporated the remaining aqueous layer was extracted with dichloromethane (2×50 ml) a 3:1 mixture of chloroform and isopropanol (50 ml) The combined organic layers were filtered through a hydrophobic frit evaporated to give a yellow oil evaporated to a yellow oil once more This material was purified by automated silica flash-column chromatography (Biotage SP4) eluting with a 15-100% gradient of ethyl acetate in hexane

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

Procedure: 1,1-dimethylethyl 5-oxo-L-prolinate (2.7 g, 12 mmol, prepared as described in Synth. Comm., 2005, 35(8), 1129) was added to a suspension of sodium hydride (0.428 g (60% suspension in oil), 10.7 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 5 minutes. Ethyl iodide (1.67 g, 10.7 mmol) was then added and the mixture was heated at 40° C. for 2 hrs. A further quantity of sodium hydride (0.24 g) was added and stirring continued overnight at room temperature. An additional quantity of ethyl iodide (0.86 ml) was added to the mixture at this stage and the mixture was left to stand at room temperature over the weekend. Water (˜10 ml) was added to the mixture and this was stirred for 15 minutes. The tetrahydrofuran was evaporated and the remaining aqueous layer was extracted with dichloromethane (2×50 ml) and a 3:1 mixture of chloroform and isopropanol (50 ml). The combined organic layers were filtered through a hydrophobic frit and evaporated to give a yellow oil. Toluene was added to the mixture and then evaporated to a yellow oil once more. This material was purified by automated silica flash-column chromatography (Biotage SP4), eluting with a 15-100% gradient of ethyl acetate in hexane, to give pure 1,1-dimethylethyl 1-ethyl-5-oxo-prolinate. the mixture was heated at 40° C. for 2 hrs stirring continued overnight at room temperature the mixture was left to stand at room temperature over the weekend this was stirred for 15 minutes The tetrahydrofuran was evaporated the remaining aqueous layer was extracted with dichloromethane (2×50 ml) a 3:1 mixture of chloroform and isopropanol (50 ml) The combined organic layers were filtered through a hydrophobic frit evaporated to give a yellow oil evaporated to a yellow oil once more This material was purified by automated silica flash-column chromatography (Biotage SP4) eluting with a 15-100% gradient of ethyl acetate in hexane

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

Procedure: To a solution of 1a (2.00 g, 10.8 mmol) in 50 mL THF at −78° C., was added LiHMDS (1M THF, 11.9 mL, 11.9 mmol). The mixture was stirred at −78° C. for 20 min, then Cbz-Cl was added, dropwise over 5 min. The mixture was stirred at −78° for 20 min, then quenched with sat. NH4Cl. The mixture was diluted with H2O and extracted with EtOAc (3×). The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (30 to 35 to 40% EtOAc/hexanes) to afford 3.12 g (90%) of 8a as a colorless solid. The mixture was stirred at −78° for 20 min quenched with sat. NH4Cl The mixture was diluted with H2O extracted with EtOAc (3×) The organic phase was washed with brine dried (Na2SO4) concentrated The crude product was purified by flash chromatography (30 to 35 to 40% EtOAc/hexanes)

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

Procedure: To a solution of 1a (2.00 g, 10.8 mmol) in 50 mL THF at −78° C., was added LiHMDS (1M THF, 11.9 mL, 11.9 mmol). The mixture was stirred at −78° C. for 20 min, then Cbz-Cl was added, dropwise over 5 min. The mixture was stirred at −78° for 20 min, then quenched with sat. NH4Cl. The mixture was diluted with H2O and extracted with EtOAc (3×). The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (30 to 35 to 40% EtOAc/hexanes) to afford 3.12 g (90%) of 8a as a colorless solid. The mixture was stirred at −78° for 20 min quenched with sat. NH4Cl The mixture was diluted with H2O extracted with EtOAc (3×) The organic phase was washed with brine dried (Na2SO4) concentrated The crude product was purified by flash chromatography (30 to 35 to 40% EtOAc/hexanes)

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

Procedure: To a solution of t-butyl pyroglutamate (1a) (10.12 g, 54.6 mmol) in benzene (250 mL), was added Lawesson's reagent (11.05 g, 27.3 mmol). The mixture was stirred at reflux for 15.5 h, then concentrated. The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3) to afford 10.50 g (95%) of the title compound, 1b. 1H NMR (300 MHz, CDCl3) δ7.27 (br s, 1H), 4.46-4.39 (m, 1H), 3.03-2.84 (m, 2H), 2.58-2.46 (m, 1H), 2.37-2.23 (m, 2H), 1.49 (s, 9H). at reflux for 15.5 h concentrated The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3)

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

Procedure: To a suspension of L-pyroglutamic acid (13.2 g, 102 mmol) in t-butyl acetate (200 mL), was added perchloric acid (70%, 9.7 mL, 113 mmol). The mixture was stirred at rt for 20 h, then poured into sat. NaHCO3. NaHCO3 (s) was added until neutral. The aqueous phase was extracted with EtOAc (6×). The combined organic extract was dried (Na2SO4) and concentrated to afford 13.68 g (72%) of the title compound, 1a. 1H NMR (300 MHz, CDCl3) δ6.17 (br s, 1H), 4.13 (dd, J=7.4, 5.2, 1H), 2.44-2.31 (m, 3H), 2.22-2.15 (m, 1H), 1.47 (s, 9H). The aqueous phase was extracted with EtOAc (6×) The combined organic extract was dried (Na2SO4) concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a pressure tube containing (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (0.5 g, 2.699 mmol), 2-bromo-5-fluoropyridine (0.57 g, 3.239 mmol), cesium carbonate (1.231 g, 3.779 mmol), Xantphos (0.156 g, 0.27 mmol), and tris (dibenzylideneacetone)palladium (0) (0.247 g, 0.27 mmol) is added 13.5 mL degassed anhydrous 1,4-dioxane. The mixture is heated at 120° C. under an atmosphere of Argon overnight. The solution is cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure. The crude material is purified by flash chromatography eluting product with 305 ethyl acetate/heptanes. The product fractions are pooled and concentrated under reduced pressure to afford 45 mg of title compound. Yield 6%. ESI m/z 225=MH+ degassed anhydrous 1,4-dioxane The solution is cooled to room temperature filtered through Celite® concentrated under reduced pressure The crude material is purified by flash chromatography eluting product with 305 ethyl acetate/heptanes concentrated under reduced pressure