1-O-叔-丁基2-O-甲基(2R,4R)-4-羟基吡咯烷-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: To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H). the reaction to an 18 L carboy until precipitation Stir the mixture overnight Filter off the solids concentrate the ether layer Dissolve the oily residue in dichloromethane filter through a silica plug eluting with dichloromethane until no more product Concentrate the dichloromethane layer treat with 5% ethyl acetate in hexanes (4 L) to form Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes collect only the fractions that Concentrate the solution dissolve in 5% ethyl acetate in hexanes (2 L) purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes

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

实验步骤: To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H). the reaction to an 18 L carboy until precipitation Stir the mixture overnight Filter off the solids concentrate the ether layer Dissolve the oily residue in dichloromethane filter through a silica plug eluting with dichloromethane until no more product Concentrate the dichloromethane layer treat with 5% ethyl acetate in hexanes (4 L) to form Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes collect only the fractions that Concentrate the solution dissolve in 5% ethyl acetate in hexanes (2 L) purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes

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

实验步骤: 1.55 g (38.6 mmol) of sodium hydride are added in portions under nitrogen to the solution of 10.3 g (42 mmol) of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate and 36.34 ml (420 mmol) of 3-bromo-1-propene in 100 ml of dimethylformamide (DMF), and the mixture is subsequently stirred at room temperature for 15 minutes. 9.73 g (42 mmol) of silver oxide are then added in portions to the reaction mixture, and the reaction mixture is left to stir at room temperature for a further 12 hours: The reaction mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure, and the residue is taken up in 20 ml of saturated citric acid solution. After the precipitate has been filtered off, the filtrate is extracted twice with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 11.6 g of 1-tert-butyl 2-methyl (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylate as a red-brown oil; ESI 286. the reaction mixture is left to stir at room temperature for a further 12 hours The reaction mixture is then filtered the filtrate is evaporated to dryness under reduced pressure After the precipitate has been filtered off the filtrate is extracted twice with 20 ml of ethyl acetate each time Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent

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

实验步骤: 1.55 g (38.6 mmol) of sodium hydride are added in portions under nitrogen to the solution of 10.3 g (42 mmol) of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate and 36.34 ml (420 mmol) of 3-bromo-1-propene in 100 ml of dimethylformamide (DMF), and the mixture is subsequently stirred at room temperature for 15 minutes. 9.73 g (42 mmol) of silver oxide are then added in portions to the reaction mixture, and the reaction mixture is left to stir at room temperature for a further 12 hours: The reaction mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure, and the residue is taken up in 20 ml of saturated citric acid solution. After the precipitate has been filtered off, the filtrate is extracted twice with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 11.6 g of 1-tert-butyl 2-methyl (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylate as a red-brown oil; ESI 286. the reaction mixture is left to stir at room temperature for a further 12 hours The reaction mixture is then filtered the filtrate is evaporated to dryness under reduced pressure After the precipitate has been filtered off the filtrate is extracted twice with 20 ml of ethyl acetate each time Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent

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

实验步骤: To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (2.45 g: 10 mmole) in tetrahydrofuran (10 ml), formic acid (453 μl: 12 mmole), triphenylphosphine (3.15 g: 12 mmole), and diethyl azodicarboxylate (1.89 ml: 12 mmole) are successively is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 30 minutes at the same temperature to give (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.17 g). Yield: 79%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=7.8 Hz, 9H), 2.1 to 2.6(m, 2H), 3.5 to 3.9(m, 5H), 4.4(m, 1H), 5.4(m, 1H), 8.0(s, 1H).

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

实验步骤: To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%. NMR δ(CDCl3) ppm: 1.46(d, J=9.6 Hz, 9H), 2.5(m, 2H), 3.02(s, 3H), 3.76(s, 3H), 3.8(m, 2H), 4.3 to 4.6(m, 1H), 5.2 to 5.3(m, 1H).

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

实验步骤: To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%. NMR δ(CDCl3) ppm: 1.46(d, J=9.6 Hz, 9H), 2.5(m, 2H), 3.02(s, 3H), 3.76(s, 3H), 3.8(m, 2H), 4.3 to 4.6(m, 1H), 5.2 to 5.3(m, 1H).

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Tert-Butyldimethylsilylchloride (9.36 g) was added to a mixture of O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) and imidazole (9.61 g) in DMF (100 ml). The reaction was stirred at 20° C. for 19 hours and then evaporated to dryness. The residues were slurried in diethyl ether and filtered. The filtrate was evaporated to dryness and the residues purified by flash chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95). Fractions containing the desired product were combined and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxypyrrolidine-1,2-dicarboxylate (10.35 g) as a colourless oil. NMR Spectrum: (DMSOd6) 0.00 (6H, s); 0.80 (9H, s); 1.32-1.38 (9H, m); 1.84-1.89 (1H, m); 2.30-2.35 (1H, m); 3.06-3.10 (1H, m); 3.49 (1H, q); 3.59 (3H, d); 4.22-4.26 (1H, m); 4.37 (1H, d). evaporated to dryness filtered The filtrate was evaporated to dryness the residues purified by flash chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95) Fractions containing the desired product evaporated to dryness

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Iodomethane (4.17 ml) was added to (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (15.00 g) in DMF (100 ml) at 0° C. Caesium carbonate (25.4 g) was added in one portion and the resulting mixture stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (2×150 ml). The combined organics were washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) as a yellow oil. 1 NMR Spectrum: (DMSOd6) 1.32 (9H, s); 1.77-1.85 (1H, m); 2.24-2.38 (1H, m); 3.07-3.15 (1H, m); 3.47 (1H, q); 3.63 (3H, t); 4.16-4.23 (2H, m); 4.92-4.98 (1H, m). extracted with dichloromethane (2×150 ml) The combined organics were washed with brine (100 ml) dried over Magnesium sulphate filtered evaporated to dryness

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Iodomethane (4.17 ml) was added to (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (15.00 g) in DMF (100 ml) at 0° C. Caesium carbonate (25.4 g) was added in one portion and the resulting mixture stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (2×150 ml). The combined organics were washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) as a yellow oil. 1 NMR Spectrum: (DMSOd6) 1.32 (9H, s); 1.77-1.85 (1H, m); 2.24-2.38 (1H, m); 3.07-3.15 (1H, m); 3.47 (1H, q); 3.63 (3H, t); 4.16-4.23 (2H, m); 4.92-4.98 (1H, m). extracted with dichloromethane (2×150 ml) The combined organics were washed with brine (100 ml) dried over Magnesium sulphate filtered evaporated to dryness

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

实验步骤: To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.12 g, 8.65 mmol) and N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) in dichloromethane (30 mL) was added benzyl chloromethyl ether (2.71 g, 17.3 mmol). After stirring at room temperature for 18 h, the mixture was poured into water. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3) to give 2.29 g (72%) of the title compound as a colorless oil. The aqueous layer was extracted with dichloromethane three times The combined organic layers were dried over magnesium sulfate concentrated in vacuo to afford an oil The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3)

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

实验步骤: Add lanthanum triflate (3.6 g, 6.16 mmol) to a solution of 2,2,2-trichloro-acetimidic acid 4-methoxybenzyl ester (52.2 g, 185 mmol) and (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (30.2 g, 123 mmol) in toluene (200 mL). Stir 2.5 h, add methanol and concentrate. Dissolve in 25:75 dichloromethane:hexanes, filter away the insolubles and purify filtrate (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (37.85 g, 84%). concentrate Dissolve in 25:75 dichloromethane hexanes, filter away the insolubles purify filtrate (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures)