tert-butyl N-(2-oxocyclopentyl)carbamate

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,6,6-Tetramethylpiperidine-N-oxide (2.2 g, 14.2 mmol) and potassium bromide (8.5 g, 71 mmol) are added to a solution of racemic trans-tert-butyl N-[2-hydroxycyclopentyl]carbamate (75 g, 283 mmol) in dichloromethane (285 mL). The mixture is cooled to 5° C. with stirring. A freshly prepared ice cooled (5° C.) sodium hypochlorite aqueous solution (766 mL, 566 mmol, pH adjusted to 7.5-8 by addition of 10 g of solid potassium carbonate) is added with stirring to the reaction mixture while keeping the temperature below 5° C. The mixture is stirred at 5° C. for an additional 30 min. The reaction mixture is diluted with saturated aqueous sodium chloride solution (150 mL). The organic layer is separated and evaporated. The oily red residue is purified over a silica gel pad, eluting with EtOAc/hexanes (1/3) to obtain the title compound as a cream colored solid (43 g, 76%). 1H-NMR (300 MHz, DMSO-d6) δ 6.99 (d, 1H, NH), 3.76 (q, 1H), 1.63-2.31 (m, 6H), 1.37 (s, 9H). is added with stirring to the reaction mixture the temperature below 5° C The mixture is stirred at 5° C. for an additional 30 min The organic layer is separated evaporated The oily red residue is purified over a silica gel pad eluting with EtOAc/hexanes (1/3)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,6,6-Tetramethylpiperidine-N-oxide (2.2 g, 14.2 mmol) and potassium bromide (8.5 g, 71 mmol) are added to a solution of racemic trans-tert-butyl N-[2-hydroxycyclopentyl]carbamate (75 g, 283 mmol) in dichloromethane (285 mL). The mixture is cooled to 5° C. with stirring. A freshly prepared ice cooled (5° C.) sodium hypochlorite aqueous solution (766 mL, 566 mmol, pH adjusted to 7.5-8 by addition of 10 g of solid potassium carbonate) is added with stirring to the reaction mixture while keeping the temperature below 5° C. The mixture is stirred at 5° C. for an additional 30 min. The reaction mixture is diluted with saturated aqueous sodium chloride solution (150 mL). The organic layer is separated and evaporated. The oily red residue is purified over a silica gel pad, eluting with EtOAc/hexanes (1/3) to obtain the title compound as a cream colored solid (43 g, 76%). 1H-NMR (300 MHz, DMSO-d6) δ 6.99 (d, 1H, NH), 3.76 (q, 1H), 1.63-2.31 (m, 6H), 1.37 (s, 9H). is added with stirring to the reaction mixture the temperature below 5° C The mixture is stirred at 5° C. for an additional 30 min The organic layer is separated evaporated The oily red residue is purified over a silica gel pad eluting with EtOAc/hexanes (1/3)

Conditions: temp:40.01; 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) and 2-(N—BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) 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 brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9. cooled to room temperature 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 brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

Conditions: temp:40.01; 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) and 2-(N—BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) 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 brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9. cooled to room temperature 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 brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,6,6-Tetramethylpiperidine-N-oxide (2.2 g, 14.2 mmol) and potassium bromide (8.5 g, 71 mmol) are added to a solution of racemic trans-tert-butyl N-[2-hydroxycyclopentyl]carbamate (75 g, 283 mmol) in dichloromethane (285 mL). The mixture is cooled to 5° C. with stirring. A freshly prepared ice cooled (5° C.) sodium hypochlorite aqueous solution (766 mL, 566 mmol, pH adjusted to 7.5-8 by addition of 10 g of solid potassium carbonate) is added with stirring to the reaction mixture while keeping the temperature below 5° C. The mixture is stirred at 5° C. for an additional 30 min. The reaction mixture is diluted with saturated aqueous sodium chloride solution (150 mL). The organic layer is separated and evaporated. The oily red residue is purified over a silica gel pad, eluting with EtOAc/hexanes (1/3) to obtain the title compound as a cream colored solid (43 g, 76%). 1H-NMR (300 MHz, DMSO-d6) δ 6.99 (d, 1H, NH), 3.76 (q, 1H), 1.63-2.31 (m, 6H), 1.37 (s, 9H). is added with stirring to the reaction mixture the temperature below 5° C The mixture is stirred at 5° C. for an additional 30 min The organic layer is separated evaporated The oily red residue is purified over a silica gel pad eluting with EtOAc/hexanes (1/3)

Conditions: temp:40.01; 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) and 2-(N-BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) 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 brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9. cooled to room temperature 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 brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

Conditions: temp:40.01; 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) and 2-(N-BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) 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 brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9. cooled to room temperature 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 brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

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

Procedure: To the suspension of diethyl ((5-(trifluoromethyl)pyridin-2-yl)methyl)phosphonate (2.0 g, 6.71 mmol) in THF (50 ml) at 0° C. was added potassium tert-butoxide (1.5 g, 13.42 mmol) and then stirred at room temperature for 30 minutes. To this was then added a solution of tert-butyl N-(2-oxocyclopentyl)carbamate (CAS number 477585-30-1; 1.62 g, 8.05 mmol) in THF (20 ml) and the resulting reaction was stirred at room temperature for 1 hour and then heated at reflux overnight. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-15% ethyl acetate/n-hexane) to afford the title compound. the resulting reaction was stirred at room temperature for 1 hour heated at reflux overnight The reaction was quenched with water (50 ml) extracted with ethyl acetate (3×100 ml) The combined organics were washed with brine dried over sodium sulfate concentrated in vacuo The resulting residue was purified by column chromatography (silica, 0-15% ethyl acetate/n-hexane)

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

Procedure: A 1.6 M ether solution of methyllithium (13.59 mL, 21.75 mmol) was added to a stirred suspension of tert-butyl 2-oxocyclopentylcarbamate (1.97 g, 9.89 mmol, from Step 2) and cerium(III) chloride (5.36 g, 21.75 mmol) in tetrahydrofuran (50 mL) at −78° C. under nitrogen. After 2.5 h at −78° C., the mixture was quenched with saturated ammonium chloride, allowed to warm to room temperature, and filtered through a short bed of Celite to remove insoluble cerium salt. The filter cake was rinsed with ethyl acetate. The filtrated was extracted with ethyl acetate three times. The combined ethyl acetate phase was washed with saturated ammonium chloride and brine respectively, dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl 2-hydroxy-2-methylcyclopentylcarbamate as yellow solid (1.47 g, 82% yield). 1H NMR analysis indicated the presence of approximately a 3:1 diastereomeric mixture. the mixture was quenched with saturated ammonium chloride filtered through a short bed of Celite to remove insoluble cerium salt The filter cake was rinsed with ethyl acetate The filtrated was extracted with ethyl acetate three times The combined ethyl acetate phase was washed with saturated ammonium chloride and brine respectively dried (MgSO4) filtered concentrated Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes

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

Procedure: Dess-Martin periodinane (2.72 g, 6.41 mmol) was added to a stirred solution of tert-butyl 2-hydroxycyclopentylcarbamate (1.23 g, 6.11 mmol, from Step 1) in dichloromethane (30 mL) while the reaction container was placed in a room temperature water bath. After 1.5 h at room temperature, the mixture was quenched with 1 M aqueous sodium thiosulfate. After shaking the mixture vigorously, the dichloromethane phase was separated and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl 2-oxocyclopentylcarbamate as white crystalline solid (824.6 mg, 68% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.03 (1 H, br. s.), 3.90 (1 H, br. s.), 2.56 (1 H, br. s.), 2.38 (1 H, dd, J=19.15, 8.80 Hz), 2.08-2.22 (1 H, m), 1.96-2.08 (1 H, m), 1.73-1.89 (1 H, m), 1.52-1.69 (1 H, m), 1.42 (9 H, s). was placed in a room temperature the mixture was quenched with 1 M aqueous sodium thiosulfate the dichloromethane phase was separated concentrated Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes

Conditions: temp:40.01; 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) and 2-(N—BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) 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 brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9. cooled to room temperature 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 brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,6,6-Tetramethylpiperidine-N-oxide (2.2 g, 14.2 mmol) and potassium bromide (8.5 g, 71 mmol) are added to a solution of racemic trans-tert-butyl N-[2-hydroxycyclopentyl]carbamate (75 g, 283 mmol) in dichloromethane (285 mL). The mixture is cooled to 5° C. with stirring. A freshly prepared ice cooled (5° C.) sodium hypochlorite aqueous solution (766 mL, 566 mmol, pH adjusted to 7.5-8 by addition of 10 g of solid potassium carbonate) is added with stirring to the reaction mixture while keeping the temperature below 5° C. The mixture is stirred at 5° C. for an additional 30 min. The reaction mixture is diluted with saturated aqueous sodium chloride solution (150 mL). The organic layer is separated and evaporated. The oily red residue is purified over a silica gel pad, eluting with EtOAc/hexanes (1/3) to obtain the title compound as a cream colored solid (43 g, 76%). 1H-NMR (300 MHz, DMSO-d6) δ 6.99 (d, 1H, NH), 3.76 (q, 1H), 1.63-2.31 (m, 6H), 1.37 (s, 9H). is added with stirring to the reaction mixture the temperature below 5° C The mixture is stirred at 5° C. for an additional 30 min The organic layer is separated evaporated The oily red residue is purified over a silica gel pad eluting with EtOAc/hexanes (1/3)