1-O-叔-丁基2-O-甲基(2S)-4-氧代吡咯烷-1,2-二羧酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Tetrapropylammonium perruthenate (287 mg, 0.82 mmol) was added to a solution of trans-N-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.0 g, 8.15 mmol) and 4-methylmorpholine N-oxide (2.1 g, 17.9 mmol) in dichloromethane (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate. the reaction mixture was concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 3.5 mL (40.2 mmol) of oxalyl chloride in 20 mL of CH2Cl2 was cooled in a −78° C. bath and 3.5 mL (49.3 mmol) of dry DMSO was added. After 30 min, a solution of 5.31 g (23 mmol) of N-(BOC)-4-hydroxy-(L)-proline, methyl ester was added. A precipitate developed during the addition. After 30 min at −78° C., 15 mL (107 mmol) of TEA was added. Another 30 mL of CH2Cl2 was added to the reaction mixture to facilitate stirring and cold bath was removed. After 1.5 hr the solution was partitioned between CH2Cl2 and water. The organic layer was washed with water, 1.2 N HCl, brine then dried over anydrous Na2SO4. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluted with a gradient of 20-40% EtOAc/hexane to yield N-(BOC)-4-oxo-(L)-proline, methyl ester (4.56 g). A precipitate developed during the addition After 30 min at −78° C. cold bath was removed After 1.5 hr the solution was partitioned between CH2Cl2 and water The organic layer was washed with water, 1.2 N HCl, brine then dried over anydrous Na2SO4 The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel eluted with a gradient of 20-40% EtOAc/hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 12.7 g of N-t-butoxycarbonyl-4-hydroxyproline methyl ester and 44.7 g of pyridinium chlorochromate in 150 ml of methylene chloride is stirred at room temperature for 30 hours, diluted with 200 ml of ether and filtered through Florisil washing with ether (500 ml). The solution is evaporated to dryness, the residue is purified by flash chromatography on silica gel using ethyl acetate/hexane (40:60) as eluant to give N-t-butoxycarbonyl-4-oxoproline methyl ester. filtered through Florisil washing with ether (500 ml) The solution is evaporated to dryness the residue is purified by flash chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of N-t-butoxycarbonyl-4-oxo-L-proline methyl ester (1.0 g, 4 mmol) (J. Org. Chem. 2001, 10, 3593), pyrrolidine (0.4 ml, 5 mmol), acetic add (0.3 ml, 5 mmol) in CH2Cl2 (20 ml) was added sodium triacetoxyborohydride (1.0 g, 5 mmol) and the mixture stirred for 2 h. After which time it was washed with saturated sodium hydrogen carbonate, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:MeOH 95:5) afforded the title compound (1.0 g, 81%) as a yellow oil. After which time it was washed with saturated sodium hydrogen carbonate dried (Na2SO4) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to a solution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixture was stirred at between −40° C. and −10° C. for 2 h and then was quenched with amonium chloride solution (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification. was quenched with amonium chloride solution (5 mL) The organic phase was separated the aqueous phase was extracted with ethyl acetate (2×5 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was used directly in the next step without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (2.00 g, 0.00815 mol) was dissolved in acetone (50.0 mL, 0.681 mol) and ether (50 mL). To the solution with stirring, was added a solution of chromium(VI) oxide (1.90 g, 0.0190 mol) in water (5.50 mL, 0.305 mol) and sulfuric acid (1.60 mL, 0.0294 mol) over 15 minutes with the presence of an ice-water bathto maintain the reaction temperature at about room temperature. The mixture was stirred at rt for 10 minutes and then iso-propanol (10 mL) was added. The mixture was stirred for an additional 5 min. The mixture was filtered through a pad of silica gel plus potassium carbonate. The filtrated was concentrated and the residue was purified by Combiflash with ethyl acetate/heaxane (25%) to give the desired product (1.12 g). bathto maintain the reaction temperature at about room temperature The mixture was stirred at rt for 10 minutes The mixture was stirred for an additional 5 min The mixture was filtered through a pad of silica gel plus potassium carbonate The filtrated was concentrated the residue was purified by Combiflash with ethyl acetate/heaxane (25%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (2.00 g, 0.00815 mol) was dissolved in acetone (50.0 mL, 0.681 mol) and ether (50 mL). To the solution with stirring, was added a solution of chromium(VI) oxide (1.90 g, 0.0190 mol) in water (5.50 mL, 0.305 mol) and sulfuric acid (1.60 mL, 0.0294 mol) over 15 minutes with the presence of an ice-water bathto maintain the reaction temperature at about room temperature. The mixture was stirred at rt for 10 minutes and then iso-propanol (10 mL) was added. The mixture was stirred for an additional 5 min. The mixture was filtered through a pad of silica gel plus potassium carbonate. The filtrated was concentrated and the residue was purified by Combiflash with ethyl acetate/heaxane (25%) to give the desired product (1.12 g). bathto maintain the reaction temperature at about room temperature The mixture was stirred at rt for 10 minutes The mixture was stirred for an additional 5 min The mixture was filtered through a pad of silica gel plus potassium carbonate The filtrated was concentrated the residue was purified by Combiflash with ethyl acetate/heaxane (25%)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CH2Cl2 stirred at −78° C. was added a solution of 0.94 mL (13.2 mmol) of methyl sulfoxide in 15 mL of CH2Cl2. The solution was stirred at −78° C. for 30 min. A solution of 1.47 g (6 mmol) of N-Boc-4-hydroxyproline methyl ester in 19 mL of CH2Cl2 was then added dropwise. The mixture was stirred at −78° C. for 1.5 h, and 3.34 mL (24 mmol) of triethylamine was added. The solution was allowed to warm up to room temperature and stirred overnight. It was then diluted with 100 mL of CH2Cl2, washed successively with 100 mL of water, 100 mL of 1N HCl, and 100 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with ethyl acetate/hexanes, 1:3), to afford 1.294 g (89% yield) of N-Boc-4-oxo-proline methyl ester. 1H NMR (500 MHz, CDCl3) δ 1.45 (m, 9H), 2.60 (m, 1H), 2.95 (m, 1H), 3.75 (m, 3H), 3.90 (m, 2H), 4.80 (m, 1H). The mixture was stirred at −78° C. for 1.5 h to warm up to room temperature stirred overnight washed successively with 100 mL of water, 100 mL of 1N HCl, and 100 mL of brine dried (MgSO4) concentrated in vacuo The residue was purified by column chromatography over silica gel (eluted with ethyl acetate/hexanes, 1:3)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) in DCM (100 mL) was cooled to 0° C., then treated portion wise with Dess-Martin periodinane (17.29 g, 40.8 mmol) over 20 min. The reaction was maintained at 0° C. for 1 h, and then the cold bath was removed. After another 3 h at room temperature, the reaction was treated with 300 mL of 1:1 sat. aq. Na2SO3:sat. aq. NaHCO3. The reaction was stirred vigorously overnight at room temperature, then the layers were separated. The organics were washed with water and brine, then dried over magnesium sulfate and concentrated. The resulting mixture was slurried in DCM (20 mL) then filtered over Celite. The organics were concentrated. The crude oil was further purified by direct filtration from grained solids to provide (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (8.53 g, 87% yield). LCMS (m/z): 244.3 (MH+), 0.42 min. the cold bath was removed the reaction was treated with 300 mL of 1:1 sat. aq. Na2SO3 the layers were separated The organics were washed with water and brine dried over magnesium sulfate concentrated then filtered over Celite The organics were concentrated The crude oil was further purified by direct filtration from grained solids

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Ph3PEtBr (84 g, 227 mmol) and KOtBu (76.7 g, 556 mmol) in THF (1100 mL) was stirred at rt under nitrogen atmosphere for 1 h, and then added (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (50 g, 206 mmol) in THF (350 mL) dropwise. The mixture was stirred at room temperature for 4 hs. TLC showed the reaction was completed. The mixture was quenched with NH4Cl aqueous and concentrated to remove THF, and then dissolved in EtOAc and water. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EtOAc=30:1 to 5:1) to afford (S)-1-tert-butyl 2-methyl 4-ethylidenepyrrolidine-1,2-dicarboxylate (18.3 g, 35%) as yellow oil. The mixture was quenched with NH4Cl aqueous concentrated to remove THF dissolved in EtOAc The combined organic layer was washed with water, brine dried over Na2SO4 filtered concentrated The crude product was purified by column chromatography (PE: EtOAc=30:1 to 5:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: CrO3 (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 hs at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aq. NaHCO3, 10% aqueous critic acid, and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81%) as yellow oil. The formed dark solid was decanted washed with DCM The organic phases were washed with aq. NaHCO3, 10% aqueous critic acid, and brine dried over anhydrous Na2SO4 The solvent was removed in vacuo purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to a solution of 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixture was stirred at between −40° C. and −10° C. for 2 h and then was quenched with ammonium chloride solution (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification. was quenched with ammonium chloride solution (5 mL) The organic phase was separated the aqueous phase was extracted with ethyl acetate (2×5 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was used directly in the next step without further purification