1-O-tert-butyl 2-O-methyl (2R)-5-oxopyrrolidine-1,2-dicarboxylate

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

Procedure: To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s). The mixture was heated at reflux for 2 hr at 0° C. for 1 hr the reaction was quenched with 8 mL of 1:1 HOAc/MeOH the mixture diluted with Et2O (40 mL) The organic layers were washed with water and brine dried (Na2SO4) concentrated under vacuum Purification by silica gel chromatography (10–20% EtOAc/hexanes)

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

Procedure: To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s). The mixture was heated at reflux for 2 hr at 0° C. for 1 hr the reaction was quenched with 8 mL of 1:1 HOAc/MeOH the mixture diluted with Et2O (40 mL) The organic layers were washed with water and brine dried (Na2SO4) concentrated under vacuum Purification by silica gel chromatography (10–20% EtOAc/hexanes)

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

Procedure: To a solution of trimethylsilyidiazomethane (1.24 mL of a 2M solution in hexane, 2.5 mmol) in 12 mL of tetrahydrofuran at −100° C. was added n-butyllithium (1.01 mL of a 2.5 M solution in hexane, 2.5 mmol). After stirring for 30 min, the solution was transferred via an insulated cannula to a −100° C. solution of N-BOC (D)-pyroglutamic acid methyl ester (0.50 g, 2.1 mmol) in 21 mL of tetrahydrofuran. After stirring for 20 min, the mixture was poured into saturated aqueous NH4Cl, extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated, affording 0.62 g of 2-tert-butoxycarbonylamino-5-diazo-4-oxo-pentanoic acid methyl ester as a yellow oil. was transferred via an insulated cannula to a −100° C. After stirring for 20 min extracted twice with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated

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

Procedure: To a mixture of 1-bromo-3-fluorobenzene (0.79 g, 4.5 mmol) and magnesium turnings (0.12 g, 5.0 mmol) in anhydrous THF (8 mL) was added a small piece of iodine. The mixture was heated at reflux for 2 hr and no magnesium turnings left. The solution was cooled to 0° C. and transferred into a stirred solution of N-Boc-D-pyroglutamic acid methyl ester (0.80 g, 3.3 mmol) in anhydrous THF (4 mL) at −40° C. under argon atmosphere. After stirring at −40° C. for 1 hr and then at 0° C. for 1 hr, the reaction was quenched with 8 mL of 1:1 HOAc/MeOH and the mixture diluted with Et2O (40 mL). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by silica gel chromatography (10–20% EtOAc/hexanes) gave 0.57 g (51%) of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.82 (1H, d), 7.75 (1H, d), 7.56 (1H, q), 7.38 (1H, t), 5.30 (1H, br.d), 4.50 (1H, br.s), 3.87 (3H, s), 3.20 (2H, m), 2.45 (1H, m), 2.20 (1H, m), 1.54 (9H, s). The mixture was heated at reflux for 2 hr at 0° C. for 1 hr the reaction was quenched with 8 mL of 1:1 HOAc/MeOH the mixture diluted with Et2O (40 mL) The organic layers were washed with water and brine dried (Na2SO4) concentrated under vacuum Purification by silica gel chromatography (10–20% EtOAc/hexanes)