tert-butyl (2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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

Procedure: Add triethylamine (6.6 mL, 47.7 mmol) and sulfurtrioxide-pyridine complex (3.8 g, 23.9 mmol) to an ice cold solution of 4-(R)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g, 11.9 mmol) in DMSO (12 mL). Stir 30 min, then warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that is used in the next step without further purification. stir 30 min wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride dry (magnesium sulfate) concentrate

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

Procedure: Add lithium borohydride (1.03 g, 47.4 mmol) to an ice cold solution of 4-(R)-fluoropyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 31.5 mmol) in THF (100 mL). Let warm to room temperature over 18 h. Cool in ice bath. Slowly add acetic acid (5 mL) and water and extract with ethyl acetate. Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a thick oil (5.56 g, 80%). Cool in ice bath Slowly add acetic acid (5 mL) and water and extract with ethyl acetate Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with hexanes and ethyl acetate)

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

Procedure: Add lithium borohydride (1.03 g, 47.4 mmol) to an ice cold solution of 4-(R)-fluoropyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 31.5 mmol) in THF (100 mL). Let warm to room temperature over 18 h. Cool in ice bath. Slowly add acetic acid (5 mL) and water and extract with ethyl acetate. Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a thick oil (5.56 g, 80%). Cool in ice bath Slowly add acetic acid (5 mL) and water and extract with ethyl acetate Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with hexanes and ethyl acetate)

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

Procedure: Add triethylamine (6.6 mL, 47.7 mmol) and sulfurtrioxide-pyridine complex (3.8 g, 23.9 mmol) to an ice cold solution of 4-(R)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g, 11.9 mmol) in DMSO (12 mL). Stir 30 min, then warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that is used in the next step without further purification. stir 30 min wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride dry (magnesium sulfate) concentrate

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

Procedure: Add lithium borohydride (1.03 g, 47.4 mmol) to an ice cold solution of 4-(R)-fluoropyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 31.5 mmol) in THF (100 mL). Let warm to room temperature over 18 h. Cool in ice bath. Slowly add acetic acid (5 mL) and water and extract with ethyl acetate. Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a thick oil (5.56 g, 80%). Cool in ice bath Slowly add acetic acid (5 mL) and water and extract with ethyl acetate Wash extract with water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with hexanes and ethyl acetate)