diethyl (2R,3R)-2,3-dihydroxybutanedioate

Conditions: temp:-23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 190 ml of dry dichloromethane, 3.3 g of a molecular sieves (powder, 3A) was suspended, and 4.2 ml of isopropyl orthotitanate and 2.9 ml of diethyl L(+)-tartarate were added thereto under stirring at -23° C. The mixture was stirred at the same temperature for 15 minutes. Then, 3 ml of a dry dichloromethane solution of 4.7 g of (E)-4-benzyloxy-2-buten-1-ol was added thereto, and the mixture was stirred at the same temperature for 5 minutes. 11 ml of tert-butylhydroxyperoxide (5.17M dichloromethane solution) was added thereto, and the mixture was stirred for further seven hours. Then, the reaction solution was left to stand at -23° C. overnight. To the reaction solution, 190 ml of diethyl ether and 4.2 ml of a saturated sodium sulfate aqueous solution were added, and the mixture was stirred at room temperature for 4 hours. The insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 240 ml of diethyl ether, and 42 ml of a 1N sodium chloride aqueous solution was added thereto under stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. The diethyl ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 2.9 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol as colorless oily substance. The mixture was stirred at the same temperature for 15 minutes the mixture was stirred at the same temperature for 5 minutes the mixture was stirred for further seven hours Then, the reaction solution was left the mixture was stirred at room temperature for 4 hours The insolubles were removed by filtration the solvent was distilled off under reduced pressure The residue was dissolved in 240 ml of diethyl ether 42 ml of a 1N sodium chloride aqueous solution was added under stirring at 0° C The mixture was stirred at 0° C. for 30 minutes The diethyl ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1)

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

Procedure: To a solution of diethyl L(+)-tartrate (16 ml, 0.094 mole) in dry CH2Cl2 (2.4 L) is added activated 3A° molecular sieve powder (600 g) and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (59 ml, 0.20 mole) followed by t-butyl hydroperoxide (156 ml of 5-6M solution in decane) and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of crude 6b, in CH2Cl2 (200 ml) is added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 140 ml of 30% aq. NaOH solution saturated with NaCl and the mixture is allowed to warm to 10 °C. Added 120 g of MgSO4, 40 g of celite and continued to stir at 10° C. for 30 minutes. The mixture is suction-filtered over celite. To the filtrate toluene (2 L), and 1.5 L of ether re added and insoluble material removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 7c as a light brown oil. stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10 °C to stir at 10° C. for 30 minutes The mixture is suction-filtered over celite To the filtrate toluene (2 L), and 1.5 L of ether re added insoluble material removed by filtration The filtrate is evaporated under reduced pressure

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

Procedure: To a solution of diethyl L(+)-tartrate (8 ml, 0.047 mole) in dry CH2Cl2 (1.2 L) is added activated 3A° molecular sieve powder (300 g) and cooled the mixture to -5 ° C. Added a solution of titanium (IV) isopropoxide (30 ml, 0.10 mole) followed by t-butyl hydroperoxide (78 ml of 5-6M solution in decane) and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of crude 6b, in CH2Cl2 (100 ml) is added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 70 ml of 30% aq. NaOH solution saturated with NaCI and the mixture is allowed to warm to 10° C. Added 60 g of MgSO4, 20 g of celite and continued to stir at 10° C. for 30 minutes. The mixture is suction-filtered over celite. To the filtrate toluene (1 L), and 700 ml of ether are added and insoluble material removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 7c as a light brown oil. stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10° C to stir at 10° C. for 30 minutes The mixture is suction-filtered over celite To the filtrate toluene (1 L), and 700 ml of ether are added insoluble material removed by filtration The filtrate is evaporated under reduced pressure

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

Procedure: To a solution of diethyl L(+)-tartrate (32.2 ml, 0.188 mole) in dry CH2Cl2 (5 L) is added activated 3A° molecular sieve powder (120 g) and cooled the mixture to -5 ° C. Added a solution of titanium (IV) isopropoxide (120 ml, 0.4 mole) followed by t-butyl hydroperoxide (312 ml of 5-6M solution in decane) and continue to stir at -5 ° C. for 25 minutes. To this mixture, a solution of crude 6a in CH2Cl2 (400 ml) is added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 280 ml of 30% aq. NaOH solution saturated with NaCl and the mixture is allowed to warm to 10° C. Added 250 g of MgSO4, 80 g of celite and continued to stir at 10° C. for 30 minutes. The mixture is suction-filtered over celite. To the filtrate toluene (4 L) and 3 L of ether are added and insoluble material removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 7a as oil. stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10° C to stir at 10° C. for 30 minutes The mixture is suction-filtered over celite To the filtrate toluene (4 L) and 3 L of ether are added insoluble material removed by filtration The filtrate is evaporated under reduced pressure

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

Procedure: To a solution of diethyl L(+)-tartrate (161 ml, 0.94 mole) in dry CH2Cl2 (24 L) was added activated 3A° molecular sieve powder (600 g) and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (597 ml, 2.0 mole) followed by t-butyl hydroperoxide (1.56 L of 5-6M solution in decane) and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of crude 6a, (664 g) in CH2Cl2 (2 L) was added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 1.4 L of 30% aq. NaOH solution saturated with NaCl and the mixture was allowed to warm to 10° C. Added 1.2 kg of MgSO4, 400 g of celite and continued to stir at 10° C. for 30 minutes. The mixture was suction-filtered over celite. To the filtrate toluene (20 L), and 15 L of ether were added and insoluble material removed by filtration. The filtrate was evaporated under reduced pressure to give the crude 7a as a light brown oil (740 g). stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10° C to stir at 10° C. for 30 minutes The mixture was suction-filtered over celite To the filtrate toluene (20 L), and 15 L of ether were added insoluble material removed by filtration The filtrate was evaporated under reduced pressure

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

Procedure: To a solution of diethyl L-(+)-tartrate (4.86 g, 0.0236 mole) in 940 ml of dry CH2Cl2 were added 12 g of activated 3A° molecular sieve powder and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (14.4 g, .0506 mole) in 76 ml of CH2Cl2 followed by t-butyl hydroperoxide (22.4 g, 0.248 mole) in 150 ml of CH2Cl2 and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of compound 6b, (2R)-3-(2,4-Difluorophenyl)-3-buten-2-ol, (15 g, 0.0815 moles) in 76 ml of CH2Cl2 was added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 4(0 ml of 30% aq. NaOH solution saturated with NaCl and the mixture was allowed to warm to 10° C. Added 40 g of MgSO4, 12 g of celite and continued to stir at 10° C. for 30 minutes. The mixture was suction-filtered over celite. To the filtrate 560 ml of toluene, 450 ml of ether were added and insoluble material removed by filtration. The filtrate was evaporated in vacuo, the residue was dissolved in 400 ml of ether and suction filtered to remove the insoluble material. The filtrate was passed through a bed of silica gel and washed the pad of silica gel with 40 ml of ether. The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel. Elution with CHCl3 gave title compound 7c as oil (11.9 g, 73%). stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10° C to stir at 10° C. for 30 minutes The mixture was suction-filtered over celite To the filtrate 560 ml of toluene, 450 ml of ether were added insoluble material removed by filtration The filtrate was evaporated in vacuo the residue was dissolved in 400 ml of ether suction filtered to remove the insoluble material washed the pad of silica gel with 40 ml of ether The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel Elution with CHCl3

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

Procedure: To a solution of diethyl L(+)-tartrate (2.43 g, 0.0118 mole) in 470 ml of dry CH2Cl2 were added activated 3A° molecular sieve powder (6 g) and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (7.2 g, 0.0253 mole) in 38 ml of CH2Cl2 followed by t-butyl hydroperoxide (11.2 g, 0.124 mole) in 75 ml of CH2Cl2 and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of compound 6a, (2S)-3-(2,4-Difluorophenyl)-3-buten-2-ol, (7.5 g, 0.041 mole) in 38 ml of CH2Cl2 was added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 20 ml of 30% aq. NaOH solution saturated with NaCl and the mixture was allowed to warm to 10° C. 20 g of MgSO4, 6 g of celite was added to the mixture and continued to stir at 10° C. for 30 minutes. The mixture was suction-filtered over celite. To the filtrate 280 ml of toluene, 225 ml of ether were added and insoluble material removed by filtration. The filtrate was evaporated in vacuo, the residue was dissolved in 200 ml of ether and suction filtered to remove the insoluble material. The filtrate was passed through a bed of silica gel and washed the pad of silica gel with 20 ml of ether. The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel. Elution with CHCl3 gave title compound 7a as an oil (3.5 g, 43%). stirred for 12 hours at 5° C Cooled the reaction mixture to -40° C. to warm to 10° C to stir at 10° C. for 30 minutes The mixture was suction-filtered over celite To the filtrate 280 ml of toluene, 225 ml of ether were added insoluble material removed by filtration The filtrate was evaporated in vacuo the residue was dissolved in 200 ml of ether suction filtered to remove the insoluble material washed the pad of silica gel with 20 ml of ether The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel Elution with CHCl3

Conditions: temp:-23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 190 ml of dry dichloromethane, 3.3 g of a molecular sieves (powder, 3A) was suspended, and 4.2 ml of isopropyl orthotitanate and 2.9 ml of diethyl L(+)-tartarate were added thereto under stirring at -23° C. The mixture was stirred at the same temperature for 15 minutes. then, 3 ml of a dry dichloromethane solution of 4.7 g of (E)-4-benzyloxy-2-buten-1-ol was added thereto, and the mixture was stirred at the same temperature for 5 minutes. 11 ml of tert-butylhydroxyperoxide (5.17M dichloromethane solution) was added thereto, and the mixture was stirred for further seven hours. Then, the reaction solution was left to stand at -23° C. overnight. To the reaction solution, 190 ml of diethyl ether and 4.2 ml of a saturated sodium sulfate aqueous solution were added, and the mixture was stirred at room temperature for 4 hours. The insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 240 ml of diethyl ether, and 42 ml of a 1N sodium chloride aqueous solution was added thereto under stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. The diethyl ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane,/ethyl acetate=1/1) to obtain 2.9 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol as colorless oily substance. The mixture was stirred at the same temperature for 15 minutes the mixture was stirred at the same temperature for 5 minutes the mixture was stirred for further seven hours Then, the reaction solution was left the mixture was stirred at room temperature for 4 hours The insolubles were removed by filtration the solvent was distilled off under reduced pressure The residue was dissolved in 240 ml of diethyl ether 42 ml of a 1N sodium chloride aqueous solution was added under stirring at 0° C The mixture was stirred at 0° C. for 30 minutes The diethyl ether layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (n-hexane,/ethyl acetate=1/1)

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

Procedure: To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at an internal temperature of 10° C. or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10° C. or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50° C. for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound (1.24 g, yield: 60%) was obtained. The reaction solution was stirred at room temperature for 30 minutes by stirring at 50° C. for 3 hours the aqueous layer was extracted with ethyl acetate dried over magnesium sulfate

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

Procedure: To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at the internal temperature of 10° C. or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10° C. or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50° C. for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound was not produced. The condition for HPLC analysis was identical with that for Example 5. The reaction solution was stirred at room temperature for 30 minutes by stirring at 50° C. for 3 hours the aqueous layer was extracted with ethyl acetate dried over magnesium sulfate was not produced

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

Procedure: To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at the internal temperature of 10° C. or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10° C. or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50° C. for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound was not produced. The condition for HPLC analysis was identical with that for Example 5. The reaction solution was stirred at room temperature for 30 minutes by stirring at 50° C. for 3 hours the aqueous layer was extracted with ethyl acetate dried over magnesium sulfate was not produced

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: L-Tartaric acid diethyl ester (50.0 g), acetic acid (900 ml), 1,3-dibromo-5,5-dimethylhydantoin (149.1 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (750 mg) were mixed, and the reaction solution was stirred at 70° C. for 2 hours, followed by stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure until its volume became approximately 300 ml to obtain a solution of diethyl dioxobutanedioate in acetic acid as a yellow liquid. by stirring at room temperature for 16 hours The reaction solution was concentrated under reduced pressure until its volume