3-(4-chlorophenyl)propanal

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: Intermediate 21 (0.35 g), methylamine (2.07 ml, 2M solution in tetrahydrofuran) were stirred together in tetrahydrofuran (15 ml) for 5 min, before sodium triacetoxyborohydride (1.32 g) was added. The reaction was stirred for 18 h, before water (10 ml) was added, and the tetrahydrofuran was removed in vacuo. The resulting slurry was washed with ethyl acetate (3×50 ml), and then basified to pH 11 using sodium hydroxide (2M). The aqueous was then re-extracted with ethyl acetate (3 ×50 ml). These combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate (1 g), and the solvent removed in vacuo to yield the title compound as a colourless oil (0.13 g). was added was added the tetrahydrofuran was removed in vacuo The resulting slurry was washed with ethyl acetate (3×50 ml) The aqueous was then re-extracted with ethyl acetate (3 ×50 ml) These combined organic extracts were washed with brine (100 ml) dried over magnesium sulphate (1 g) the solvent removed in vacuo

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

Procedure: To a stirred solution of oxalyl chloride (2.04 ml) in dichloromethane (40 ml) at −78° C. was added dimethyl sulphoxide (3.33 ml), and the reaction stirred for 10 min. 3-(4-Chlorophenyl)propanol (2.0 g) in dichloromethane (20 ml) was added and the reaction stirred at −78° C. for 75 min. Triethylamine (11.53 ml) was added, the reaction allowed to warm to room temperature, and stirred for 30 min. Water (150 ml) was added, and the reaction extracted with dichloromethane (2×100 ml). The combined organic extracts were washed with water (3×100 ml), dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield a yellow oil. This was purified by flash chromatography (silica, eluent dichloromethane) to yield the title compound as a pale yellow oil (0.96 g). the reaction stirred at −78° C. for 75 min stirred for 30 min the reaction extracted with dichloromethane (2×100 ml) The combined organic extracts were washed with water (3×100 ml) dried over magnesium sulphate (2 g) the solvent removed in vacuo to yield a yellow oil This was purified by flash chromatography (silica, eluent dichloromethane)

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

Procedure: To a stirred solution of oxalyl chloride (2.04 ml) in dichloromethane (40 ml) at −78° C. was added dimethyl sulphoxide (3.33 ml), and the reaction stirred for 10 min. 3-(4-Chlorophenyl)propanol (2.0 g) in dichloromethane (20 ml) was added and the reaction stirred at −78° C. for 75 min. Triethylamine (11.53 ml) was added, the reaction allowed to warm to room temperature, and stirred for 30 min. Water (150 ml) was added, and the reaction extracted with dichloromethane (2×100 ml). The combined organic extracts were washed with water (3×100 ml), dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield a yellow oil. This was purified by flash chromatography (silica, eluent dichloromethane) to yield the title compound as a pale yellow oil (0.96 g). the reaction stirred at −78° C. for 75 min stirred for 30 min the reaction extracted with dichloromethane (2×100 ml) The combined organic extracts were washed with water (3×100 ml) dried over magnesium sulphate (2 g) the solvent removed in vacuo to yield a yellow oil This was purified by flash chromatography (silica, eluent dichloromethane)

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

Procedure: 79 g (0.79 mol) of 3,3-dimethylbutyraldehyde are added to a solution of 10.5 g of 50% strength by weight aqueous NaOH in 500 ml of methanol, after which 123 g (0.73 mol) of p-chlorodihydrocinnamaldehyde are added dropwise at 34° C. The mixture is stirred for one hour and then neutralized with dilute sulfuric acid, the solution is evaporated down and the residue is then subjected to fractional distillation. the solution is evaporated down the residue is then subjected to fractional distillation

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

Procedure: 79 g (0.79 mol) of 3,3-dimethylbutyraldehyde are added to a solution of 10.5 g of 50% strength by weight aqueous NaOH in 500 ml of methanol, after which 123 g (0.73 mol) of p-chlorodihydrocinnamaldehyde are added dropwise at 34° C. The mixture is stirred for one hour and then neutralized with dilute sulfuric acid, the solution is evaporated down and the residue is then subjected to fractional distillation. the solution is evaporated down the residue is then subjected to fractional distillation

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

Procedure: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and 3-(4-chlorophenyl)propionaldehyde (118 mg, 0.7 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(3-(4-chlorophenyl)propyl)pyrrolidine-3-carboxylic acid (84.3 mg, 38%) as a white powder. NMR (D2O) 7.25 (d, J=8 Hz, 2 H), 7.13 (d, J=8 Hz, 2 H), 3.75-4.10 (m, 2 H), 3.40-3.60 (m, 1 H), 3.10-3.30 (m, 3 H), 2.60 (t, J=7 Hz, 2 H), 2.40-2.55 (m, 1 H), 1.85-2.00 (m, 2 H), 1.50-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 369.1; MS (m−H2O+1): 351.2. stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each) dried (MgSO4) concentrated isolated

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

Procedure: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and 3-(4-chlorophenyl)propionaldehyde (118 mg, 0.7 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(3-(4-chlorophenyl)propyl)pyrrolidine-3-carboxylic acid (84.3 mg, 38%) as a white powder. NMR (D2O) 7.25 (d, J=8 Hz, 2 H), 7.13 (d, J=8 Hz, 2 H), 3.75-4.10 (m, 2 H), 3.40-3.60 (m, 1 H), 3.10-3.30 (m, 3 H), 2.60 (t, J=7 Hz, 2 H), 2.40-2.55 (m, 1 H), 1.85-2.00 (m, 2 H), 1.50-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 369.1; MS (m−H2O+1): 351.2. stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each) dried (MgSO4) concentrated isolated

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

Procedure: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and 3-(4-chlorophenyl)propionaldehyde (118 mg, 0.7 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(3-(4-chlorophenyl)propyl)pyrrolidine-3-carboxylic acid (84.3 mg, 38%) as a white powder. NMR (D2O) 7.25 (d, J=8 Hz, 2 H), 7.13 (d, J=8 Hz, 2 H), 3.75-4.10 (m, 2 H), 3.40-3.60 (m, 1 H), 3.10-3.30 (m, 3 H), 2.60 (t, J=7 Hz, 2 H), 2.40-2.55 (m, 1 H), 1.85-2.00 (m, 2 H), 1.50-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 369.1; MS (m−H2O+1): 351.2. stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each) dried (MgSO4) concentrated isolated

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

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