(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-oxopyrrolidine-2-carboxylic acid

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

Procedure: To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H). re-cooled to 0° C was added over 40 minutes The reaction was warmed to room temperature cooled to 0° C The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) the aqueous layer was separated The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) the combined aqueous layers were filtered through Celite® was acidified with 6 N HCl (2.6 vol) at ambient temperature extracted twice with isopropyl acetate (16 vol The organic phase was dried (MgSO4) the solvent removed The crude product was dissolved in isopropyl acetate (10 vol) extracted with 0.5 M NaOH (10 vol were acidified at ambient temperature with 6 N HCl to pH=3 extracted twice with ethyl acetate (10 vol The combined extracts were dried (Na2SO4) the solvent removed the crude product was recrystallized from cyclohexane (5 vol)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H). A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour stirred for 10 minutes the phases were separated The organic phase was washed with aqueous 5% Na2SO3 (2 vol) brine (1 vol) then dried azeotropically concentrated

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

Procedure: To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H). re-cooled to 0° C was added over 40 minutes The reaction was warmed to room temperature cooled to 0° C The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) the aqueous layer was separated The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) the combined aqueous layers were filtered through Celite® was acidified with 6 N HCl (2.6 vol) at ambient temperature extracted twice with isopropyl acetate (16 vol The organic phase was dried (MgSO4) the solvent removed The crude product was dissolved in isopropyl acetate (10 vol) extracted with 0.5 M NaOH (10 vol were acidified at ambient temperature with 6 N HCl to pH=3 extracted twice with ethyl acetate (10 vol The combined extracts were dried (Na2SO4) the solvent removed the crude product was recrystallized from cyclohexane (5 vol)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H). A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour stirred for 10 minutes the phases were separated The organic phase was washed with aqueous 5% Na2SO3 (2 vol) brine (1 vol) then dried azeotropically concentrated

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); ≈2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H). A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour stirred for 10 minutes the phases were separated The organic phase was washed with aqueous 5% Na2SO3 (2 vol) brine (1 vol) then dried azeotropically concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methylenetriphenyl phosphorane, previously prepared from 37 g (777 mmol, 50% NaH in mineral oil, 4 eq) and 277.6 g (777 mmol, 4 eq) methyltriphenyl-phosphonium bromide in 1.5 l THF by stirring at 50° C. for 4 h, were added 44.5 g (194 mmol, leq) (2S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 300 ml over a period of 30 min at RT. The suspension was stirred at 50° C. over night. After cooling to RT the suspension was added to a 5% NaHCO3 solution, washed with ether, the inorganic phase was acidified and extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated. 32.1 g (72%) (2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were isolated as white solid. The suspension was stirred at 50° C. over night After cooling to RT the suspension washed with ether extracted with EtOAc washed with brine dried over Na2SO4 evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methylenetriphenyl phosphorane, previously prepared from 37 g (777 mmol, 50% NaH in mineral oil, 4 eq) and 277.6 g (777 mmol, 4 eq) methyltriphenyl-phosphonium bromide in 1.5 l THF by stirring at 50° C. for 4 h, were added 44.5 g (194 mmol, leq) (2S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 300 ml over a period of 30 min at RT. The suspension was stirred at 50° C. over night. After cooling to RT the suspension was added to a 5% NaHCO3 solution, washed with ether, the inorganic phase was acidified and extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated. 32.1 g (72%) (2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were isolated as white solid. The suspension was stirred at 50° C. over night After cooling to RT the suspension washed with ether extracted with EtOAc washed with brine dried over Na2SO4 evaporated

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

Procedure: Jones' reagent (3.9 mL, 31.3 mmol) is added dropwise over a period of 5 mins to a solution of Boc-L-hydroxyproline (1 g, 4.3 mmol) in acetone (55 mL). The stirring is continued for an additional 30 minutes. The reaction is quenched with methanol (1 mL) and stirred at room temperature for 10 minutes. The reaction mixture is filtered through Celite® and the filtrate is concentrated under reduced pressure. It was diluted with water and extracted with dichloromethane 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. ESI m/z 130 [M+H+−100]. The reaction is quenched with methanol (1 mL) The reaction mixture is filtered through Celite® the filtrate is concentrated under reduced pressure It was diluted with water extracted with dichloromethane 3 times washed with brine dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methylenetriphenyl phosphorane, previously prepared from 37 g (777 mmol, 50% NaH in mineral oil, 4 eq) and 277.6 g (777 mmol, 4 eq) methyltriphenyl-phosphonium bromide in 1.51 THF by stirring at 50° C. for 4 h, were added 44.5 g (194 mmol, 1 eq) (2S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 300 ml over a period of 30 min at RT. The suspension was stirred at 50° C. over night. After cooling to RT the suspension was added to a 5% NaHCO3 solution, washed with ether, the inorganic phase was acidified and extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated. 32.1 g (72%) (2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were isolated as white solid. The suspension was stirred at 50° C. over night After cooling to RT the suspension washed with ether extracted with EtOAc washed with brine dried over Na2SO4 evaporated

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

Procedure: The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1[(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.

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

Procedure: A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and removal of solvent in vacuo. The desired product (5.9 g, 94%) was isolated as a pale yellow oil. The reaction was heated to reflux for 2.5 h before cooling removal of solvent The residue was dissolved in ethyl acetate washed rapidly with 1.3N HCl (40 ml) The acidic layer was then extracted with ethyl acetate (3×20 ml) the combined organic layers washed with brine before drying over magnesium sulfate filtering removal of solvent in vacuo

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

Procedure: A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and removal of solvent in vacuo. The desired product (5.9 g, 94%) was isolated as a pale yellow oil. The reaction was heated to reflux for 2.5 h before cooling removal of solvent The residue was dissolved in ethyl acetate washed rapidly with 1.3N HCl (40 ml) The acidic layer was then extracted with ethyl acetate (3×20 ml) the combined organic layers washed with brine before drying over magnesium sulfate filtering removal of solvent in vacuo