1-O-tert-butyl 2-O-methyl 4-oxopyrrolidine-1,2-dicarboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a stirred solution of N-Boc proline methyl ester (2 .0 g, 8.15 mmol) in CH2Cl2 were added 3 A molecular sieves (2 g) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celiete pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57%) as a colorless oil. 1H-NMR (CDCl3) δ1.46-1.48 (m, 9 H), 2.56-2.61 (m, 1 H), 2.88-3.00 (m, 1 H), 3.77 (s, 3 H), 3.82-3.88 (m, 2 H), 4.71-4.83 (m, 1 H). The mixture was filtered through a Celiete pad the filtrate was evaporated The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent

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

Procedure: To a stirred solution of N-Boc proline methyl ester (2 .0 g, 8.15 mmol) in CH2Cl2 were added 3 A molecular sieves (2 g) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celiete pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57%) as a colorless oil. 1H-NMR (CDCl3) δ 1.46–1.48 (m, 9 H), 2.56–2.61 (m, 1 H), 2.88–3.00 (m, 1 H), 3.77 (s, 3 H), 3.82–3.88 (m, 2 H), 4.71–4.83 (m, 1 H). The mixture was filtered through a Celiete pad the filtrate was evaporated The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent

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

Procedure: To a suspension of methyltriphenylphosphonium iodide (1.25 g, 3.08 mmol) in THF (20 ml) at 0° C., 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (500 mg, 2.05 mmol) and potassium ter-butoxide (460 mg, 4.11 mmol) was added. It was stirred for overnight at room temperature. Water was added and the compound was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography offered 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil (0.23 g, 46%). the compound was extracted with ethyl acetate The ethyl acetate layer was washed with brine dried over sodium sulphate filtered concentrated under vacuum Purification by column chromatography

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

Procedure: To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8 g, 32.65 mmol) in DCM (200 ml), pyridinium dichromate (24.55 g, 65.3 mmol) was added at 0° C. It was stirred at room temperature for overnight. Reaction mixture was filtered through celite pad and DCM layer was concentrated. Purification by column chromatography offered 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a white solid (6 g, 76%). Reaction mixture was filtered through celite pad and DCM layer was concentrated Purification by column chromatography

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

Procedure: To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8 g, 32.65 mmol) in DCM (200 ml), pyridinium dichromate (24.55 g, 65.3 mmol) was added at 0° C. It was stirred at room temperature for overnight. Reaction mixture was filtered through celite pad and DCM layer was concentrated. Purification by column chromatography offered 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a white solid (6 g, 76%). Reaction mixture was filtered through celite pad and DCM layer was concentrated Purification by column chromatography

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

Procedure: To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5 g, 20.4 mmol) in DCM (100 mL), Dess-Martin periodinane (12.97 g, 30.6 mmol) is added. After completion of the reaction as judged by TLC the reaction is quenched with sat NaHCO3, washed with sat sodium thiosulfate and extracted with DCM. The organics are dried and evaporated and used crude in the next step. After completion of the reaction is quenched with sat NaHCO3 washed extracted with DCM The organics are dried evaporated

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

Procedure: To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5 g, 20.4 mmol) in DCM (100 mL), Dess-Martin periodinane (12.97 g, 30.6 mmol) is added. After completion of the reaction as judged by TLC the reaction is quenched with sat NaHCO3, washed with sat sodium thiosulfate and extracted with DCM. The organics are dried and evaporated and used crude in the next step. After completion of the reaction is quenched with sat NaHCO3 washed extracted with DCM The organics are dried evaporated