methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate

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

Procedure: To a solution of cis-4-hydroxy-L-proline methyl ester (10.0 g, 68.8 mmol), triethylamine (13.9 g, 138 mmol), and CH2Cl2 (200 mL) was added 3-cyanobenzene-1-sulfonyl chloride (13.9 g, 68.8 mmol). After 1 h, the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes) to afford the title compound as a colorless crystalline solid: 1H NMR (500 MHz, CDCl3) δ 8.19-8.18 (m, 1H), 8.13-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.69-7.65 (t, 1H), 4.52-4.50 (m, 1H), 4.44-4.43 (m, 1H), 3.67 (s, 3H), 3.52 (dd, 1H), 3.47-3.41 (m, 1H), 3.1 (d, 1H), 2.33-2.27 (m, 1H), 2.20-2.17 (m, 1H); LRMS (ESI) m/z 311 (311 calcd for C13H14N2O5S, M+H). the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL) The layers were separated the aqueous layer was extracted with CH2Cl2 (3×75 mL) The combined organic layers were dried (MgSO4) filtered concentrated The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes)

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

Procedure: To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036 mol) in 10 mL of DMF cooled at 0° C. was added K2CO3 (0.52 g) (1.1 eq.), then 3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred overnight at RT and the insoluble material removed by filtration. The solution was concentrated under vacuum and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5) to afford the titled compound as a white solid (0.25 g). NMR (CDCl3, 200 MHz): 7.35 (3H, s), 4.45 (1H, m), 4.30 (1H, dd), 4.0 (1H, d), 3.1 (1H, dd), 2.35-2.2 (2H, m), 1.95 (1H, bs, OH). the insoluble material removed by filtration The solution was concentrated under vacuum the residue dissolved in DCM The organic layer was washed with water dried over MgSO4 evaporated under reduced pressure The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5)

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

Procedure: To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036 mol) in 10 mL of DMF cooled at 0° C. was added K2CO3 (0.52 g) (1.1 eq.), then 3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred overnight at RT and the insoluble material removed by filtration. The solution was concentrated under vacuum and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5) to afford the titled compound as a white solid (0.25 g). NMR (CDCl3, 200 MHz): 7.35 (3H, s), 4.45 (1H, m), 4.30 (1H, dd), 4.0 (1H, d), 3.1 (1H, dd), 2.35-2.2 (2H, m), 1.95 (1H, bs, OH). the insoluble material removed by filtration The solution was concentrated under vacuum the residue dissolved in DCM The organic layer was washed with water dried over MgSO4 evaporated under reduced pressure The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5)

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

Procedure: Methyl (4S)-4-hydroxyprolinate (52.0 g, 0.286 mol) was dissolved in 500 mL CH2Cl2 and cooled to 0° C. Triethylamine (83.6 mL, 0.600 mol) was added, followed by 3-cyanobenzenesulfonyl chloride (55.0, 0.273 mol) slowly. The reaction mixture was stirred at room temperature overnight. Water was added, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with 1N HCl, H2O, 1N NaOH, and brine, dried over MgSO4, and concentrated to give a viscous residue. Ethyl acetate (300 mL) was added to completely dissolve the residue. Approximately 100 mL hexanes was added slowly until the solution became slightly cloudy. The mixture was then stirred overnight to allow the product to precipitate. The solid was filtered and rinsed two times with 30% EtOAc/hexanes to give the desired product as an off-white powder (66.2 g, 78%). 1H-NMR (CDCl3, 500 MHz) δ 8.20-8.18 (m, 1H), 8.15-8.12 (m, 1H), 7.92-7.89 (m, 1H), 7.72 (t, 1H), 4.51-4.47 (m, 1H), 4.42 (br s, 1H), 3.74 (s, 3H), 3.53-3.49 (m, 1H), 3.46-3.43 (m, 1H), 3.39 (br s, 1H), 2.29-2.25 (m, 1H), 2.21-2.02 (m, 1H). MS (ESI) calculated for C13H14N2O5S 310.3, observed m/e 311.2 (MH+). the aqueous layer was extracted three times with CH2Cl2 The combined organic layers were washed with 1N HCl, H2O, 1N NaOH, and brine dried over MgSO4 concentrated to give a viscous residue to completely dissolve the residue The mixture was then stirred overnight to precipitate The solid was filtered rinsed two times with 30% EtOAc/hexanes

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

Procedure: Into a flame-dried 100 ml three-necked round-bottomed flask containing 30 ml of distilled THF was placed 3.00 g (16.575 mmol) of (cis)-4-hydroxy-L-proline, methyl ester; the vessel was immersed in an ice/water bath and the suspension was allowed to stir under argon for 5 minutes. At this time, 6.35 ml (36.465 mmol) of diisopropylethylamine was added slowly via syringe; the mixture was allowed to stir for 10 minutes, whereupon 3.64 g (16.576 mmol) of 2-bromobenzoyl chloride was added dropwise via syringe over the course of 10 minutes. The mixture was allowed to stir at 0° for 2 hours then gradually brought to room temperature overnight. The mixture was concentrated under vacuum to a minimal volume, transferred to a separatory funnel, and diluted with 100 ml of ethyl acetate, then washed with 1N HCl (2×30 ml), saturated sodium bicarbonate (2×30 ml), and brine (30 ml). The organic solution was dried over sodium sulfate, filtered, and concentrated under vacuum. Recrystallization from hot ethyl acetate yielded 3.034 g (55.6%) of the title compound, m.p. 145.5°-146.8° C.; a second recrystallization of the mother liquor yielded 1.726 g to bring the net yield to 4.760 g (87.3%). the vessel was immersed in an ice/water bath was added dropwise via syringe over the course of 10 minutes to stir at 0° for 2 hours then gradually brought to room temperature overnight The mixture was concentrated under vacuum to a minimal volume transferred to a separatory funnel diluted with 100 ml of ethyl acetate washed with 1N HCl (2×30 ml), saturated sodium bicarbonate (2×30 ml), and brine (30 ml) The organic solution was dried over sodium sulfate filtered concentrated under vacuum Recrystallization from hot ethyl acetate

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

Procedure: To a solution of cis-4-hydroxy-L-proline methyl ester (10.0 g, 68.8 mmol), triethylamine (13.9 g, 138 mmol), and CH2Cl2 (200 mL) was added 3-cyanobenzene-1-sulfonyl chloride (13.9 g, 68.8 mmol). After 1 h, the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes) to afford the title compound as a colorless crystalline solid: 1H NMR (500 MHz, CDCl3) δ 8.19-8.18 (m, 1H), 8.13-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.69-7.65 (t, 1H), 4.52-4.50 (m, 1H), 4.44-4.43 (m, 1H), 3.67 (s, 3H), 3.52 (dd, 1H), 3.47-3.41 (m, 1H), 3.1 (d, 1H), 2.33-2.27 (m, 1H), 2.20-2.17 (m, 1H); LRMS (ESI) m/z 311 (311 calcd for C13H14N2O5S, M+H). the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL) The layers were separated the aqueous layer was extracted with CH2Cl2 (3×75 mL) The combined organic layers were dried (MgSO4) filtered concentrated The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes)

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

Procedure: To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036 mol) in 10 mL of DMF cooled at 0° C. was added K2CO3 (0.52 g) (1.1 eq.), then 3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred overnight at RT and the insoluble material removed by filtration. The solution was concentrated under vacuum and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5) to afford the titled compound as a white solid (0.25 g). NMR (CDCl3, 200 MHz): 7.35 (3H, s), 4.45 (1H, m), 4.30 (1H, dd), 4.0 (1H, d), 3.1 (1H, dd), 2.35-2.2 (2H, m), 1.95 (1H, bs, OH). the insoluble material removed by filtration The solution was concentrated under vacuum the residue dissolved in DCM The organic layer was washed with water dried over MgSO4 evaporated under reduced pressure The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5)