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

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

Procedure: To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (4.7 g) in tetrahydrofuran (40 ml), a borane-tetrahydrofuran complex (0.95 M solution in tetrahydrofuran, 31.6 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.2 g). followed by extraction with ethyl acetate The extract was washed with saturated saline dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (4.7 g) in tetrahydrofuran (40 ml), a borane-tetrahydrofuran complex (0.95 M solution in tetrahydrofuran, 31.6 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.2 g). followed by extraction with ethyl acetate The extract was washed with saturated saline dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: A solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (500 mg, 2.14 mmol) in THF (15 mL) was treated with a 1N solution of BH3-THF complex (4.29 mL, 4.29 mmol). The mixture was stirred at ambient temperature for 12 hours then quenched with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound (425 mg, 90%). MS (DCI/NH3) m/z 220 (M+H)+. then quenched with MeOH concentrated under reduced pressure The residue was purified by column chromatography

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

Procedure: N-Boc-cis-4-fluoro-L-proline (2 g, 8.575 mmol) was dissolved in tetrahydrofuran (20 ml), the solution was cooled and boron hydride-tetrahydrofuran complex (1 mol/l, 12.86 ml) was added slowly at 0° C. The reaction mixture warmed slowly to room temperature, after stirring for 3 h it was cooled again to 0° C., water (5 ml) was slowly added dropwise, potassium carbonate (2 g, 14.477 mmol) was added and the mixture was stirred for 30 min. After separation of the phases, the aqueous phase was extracted with diethyl ether (3×20 ml) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with diethyl ether/hexane (4:1). Yield: 1.73 g, 92% the solution was cooled boron hydride-tetrahydrofuran complex (1 mol/l, 12.86 ml) was added slowly at 0° C was cooled again to 0° C. the mixture was stirred for 30 min After separation of the phases the aqueous phase was extracted with diethyl ether (3×20 ml) the combined organic phases were dried over sodium sulfate concentrated in vacuo The crude product was purified by column chromatography (silica gel) with diethyl ether/hexane (4:1)

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

Procedure: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethanol (2.46 g, 11.2 mmol) in THF (100 ml), sodium hydride (60% in oil; 896 mg, 22.4 mmol) was added in portions under stirring at 0° C. in a nitrogen gas stream. After stirring at the same temperature for 20 minutes, a solution of (Z)-4-benzyloxy-1-bromo-2-butene (2.76 g, 11.2 mmol) in THF (100 ml) was added. The reaction mixture was stirred for 5 minutes. To the reaction mixture was added tetra-n-butyl ammonium iodide (100 mg, 0.27 mmol) at 0° C. and the mixture was stirred for 15 minutes. The reaction mixture was stirred further at room temperature for 19 hours. Water (50 ml) was added while stirring the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 120 g), whereby from hexane/ethyl acetate (4/1) eluate fractions, the title compound (3.30 g, 78%) was obtained as a colorless oil. After stirring at the same temperature for 20 minutes The reaction mixture was stirred for 5 minutes the mixture was stirred for 15 minutes The reaction mixture was stirred further at room temperature for 19 hours while stirring the reaction mixture under ice cooling followed by extraction with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate distilled under reduced pressure to remove the solvent The residue was purified by chromatography on a silica gel column (silica gel: 120 g), whereby from hexane/ethyl acetate (4/1) eluate fractions

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

Procedure: To a THF (20 mL) solution of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate (950 mg, 3.9 mmol) at 0° C., 5.8 mL 2M LiBH4 (11.6 mmol, 3 eq) was added slowly. The resulting mixture was left stirring overnight while allowing the temperature to warm up to room temperature. The resulting mixture was left

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

Procedure: To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (4.7 g) in tetrahydrofuran (40 ml), a borane-tetrahydrofuran complex (0.95 M solution in tetrahydrofuran, 31.6 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.2 g). followed by extraction with ethyl acetate The extract was washed with saturated saline dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)