N-BOC-TRANS-4-HYDROXY-D-PROLINE METHYL ESTER

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%. NMR δ(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.3(m, 1H), 2.5 to 2.8(m, 1H), 3.08(s, 3H), 3.8 to 4.0(m, 5H), 4.3 to 4.6(m, 1H), 5.3(m, 1H). to react for 30 minutes

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 g). Yield: 100%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.2 Hz, 9H), 1.9 to 2.4(m, 2H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 g). Yield: 100%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.2 Hz, 9H), 1.9 to 2.4(m, 2H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).

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

Procedure: To an ice cold solution of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.15 g, 4.69 mmol) and 3-methoxyphenol (0.56 mL, 5.158 mmol) in THF (10 mL) is added triphenylphosphine (1.84 g, 7.03 mmol) followed by the dropwise addition of diisopropyl-azodicarboxylate (1.40 mL, 7.03 mmol). Warm to room temperature and stir for 18 h. Dilute the reaction with ethyl acetate and wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (0.57 g, 34%). Dilute wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride dry (magnesium sulfate) purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures)

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

Procedure: To an ice cold solution of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.15 g, 4.69 mmol) and 3-methoxyphenol (0.56 mL, 5.158 mmol) in THF (10 mL) is added triphenylphosphine (1.84 g, 7.03 mmol) followed by the dropwise addition of diisopropyl-azodicarboxylate (1.40 mL, 7.03 mmol). Warm to room temperature and stir for 18 h. Dilute the reaction with ethyl acetate and wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (0.57 g, 34%). Dilute wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride dry (magnesium sulfate) purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures)

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

Procedure: Add (diethylamino)sulfur trifluoride (10.5 mL, 80 mmol) to a −78° C. cooled solution of 4-(S)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.83 g, 40 mmol) in dichloromethane (60 mL). Stir 2 h, then remove cooling bath and stir 18 h at room temperature. Heat to reflux for 30 min, then cool in ice bath and add saturated aqueous sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25° C.) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) and then concentrate at 120 mbar at 25° C. to give the title compound as an oil (9.09 g, 92%). remove cooling bath stir 18 h at room temperature Heat to reflux for 30 min cool in ice bath add saturated aqueous sodium bicarbonate solution dry (magnesium sulfate) concentrate (350 mbar, 25° C.) purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) concentrate at 120 mbar at 25° C.

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

Procedure: To a solution of (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%. to react for 30 minutes

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 Yield: 100%. Colorless oil.

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

Procedure: tert-Butyldimethylsilyl triflate (1.44 ml) was added to a stirred solution of 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.03 g) and triethylamine (1.76 ml) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours and then the mixture was washed with saturated aqueous potassium hydrogensulfate, dried (Na2SO4), and concentrated in vacuo to give a clear oil. Purification by column chromatography, using 0-30% ethyl acetate in hexane as eluent, gave 1-tert-butyl 2-methyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate as a clear oil (891 mg, 59%); NMR spectrum (CDCl3) 4.43-4.32 (m, 2H), 3.75-3.72 (m, 2H), 3.65-3.56 (m, 1H), 3.43-3.31 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.98 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H), 0.88 (s, 9H), 0.07 (s, 6H). the mixture was washed with saturated aqueous potassium hydrogensulfate dried (Na2SO4) concentrated in vacuo to give a clear oil Purification by column chromatography

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

Procedure: (Trimethylsilyl)diazomethane (2N solution in hexane, 2.9 ml) was added dropwise over 5 minutes to a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline (1.0 g) in DCM (20 ml) and methanol (5 ml) at room temperature until a permanent faint yellow colour persisted. The reaction mixture was concentrated in vacuo and purified by column chromatography, using 0-50% ethyl acetate in hexane as eluent, to give 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate as a clear oil (1.03 g, 97%); NMR spectrum (CDCl3) 4.90-4.37 (m, 2H), 3.73 (s, 3H), 3.64 (dd, 1H), 3.53-3.43 (m, 1H), 2.34-2.27 (m, 1H), 2.12-1.97 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H). The reaction mixture was concentrated in vacuo purified by column chromatography

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%. NMR δ(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.3(m, 1H), 2.5 to 2.8(m, 1H), 3.08(s, 3H), 3.8 to 4.0(m, 5H), 4.3 to 4.6(m, 1H), 5.3(m, 1H). to react for 30 minutes

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

Procedure: To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 g). Yield: 100%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.2 Hz, 9H), 1.9 to 2.4(m, 2H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).