dipropan-2-yl (2S,3S)-2,3-dihydroxybutanedioate

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

Procedure: A solution of (2E)-1,1-diethoxybut-2-ene (32.20 g, 223.27 mmol), (−)-diisopropyl D-tartrate (64.64 mL, 245.60 mmol) and pyridinium tosylate (2.24 g, 8.93 mmol) in 100 mL benzene was heated to 95° C. to distill off the solvent and EtOH produced. After 7 h at 95° C., the reaction was cooled to rt and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 35.37 g (55%) of diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate as an orange oil. 1H NMR (CDCl3, 400 MHz) 6.03 (m, 1H); 5.86 (m, 2H); 5.12 (m, 2H); 4.71 (d, J=3.84 Hz, 1H); 4.63 (d, J=3.84 Hz, 1H); 1.78 (m, 3H); 1.30 (d, J=6.23 Hz, 12H); LC/MS [M+H]+=287. to distill off the solvent and EtOH produced concentrated in vacuo Purification by normal phase chromatography (10->30% EtOAc/hexanes)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl D-tartrate (1.690 mL, 8.038 mmol) was dissolved in dichloromethane (500 mL) and cooled to −20° C. Activated powdered 4 Å molecular sieves (3 g), titanium(IV) isopropoxide (1.570 mL, 5.359 mmol) and tert-butyl hydroperoxide (19.49 mL, 107.2 mmol; in decane) were added sequentially, and the mixture was agitated for 1 hour at −20° C. (E)-3-(4-Chloro-3-fluorophenyl)prop-2-en-1-ol (10.0 g, 53.59 mmol) was dissolved in dichloromethane (25 mL) and treated with 4 Å molecular sieves (1.0 g) for 1 hour. This mixture was added to the initial mixture over 20 minutes and agitation was continued for another 3 hours at −20° C. The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% w/v NaOH (3 mL). Ether was added (100 mL), and the mixture was allowed to warm up to 10° C. After agitating for 10 minutes at this temperature, MsSO4 (5 g) and Celite® (2 g) were added, and the mixture was agitated for an additional 15 minutes. The mixture was then allowed to settle and filtered through a pad of Celite®, washing with ether. Solvents were then evaporated, and resulting solid was triturated with hexane to give ((2R,3R)-3-(4-chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol, 97.17% yield) as a solid. were added sequentially treated with 4 Å molecular sieves (1.0 g) for 1 hour The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% Ether was added (100 mL) to warm up to 10° C were added the mixture was agitated for an additional 15 minutes filtered through a pad of Celite® washing with ether Solvents were then evaporated resulting solid was triturated with hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl D-tartrate (1.690 mL, 8.038 mmol) was dissolved in dichloromethane (500 mL) and cooled to −20° C. Activated powdered 4 Å molecular sieves (3 g), titanium(IV) isopropoxide (1.570 mL, 5.359 mmol) and tert-butyl hydroperoxide (19.49 mL, 107.2 mmol; in decane) were added sequentially, and the mixture was agitated for 1 hour at −20° C. (E)-3-(4-Chloro-3-fluorophenyl)prop-2-en-1-ol (10.0 g, 53.59 mmol) was dissolved in dichloromethane (25 mL) and treated with 4 Å molecular sieves (1.0 g) for 1 hour. This mixture was added to the initial mixture over 20 minutes and agitation was continued for another 3 hours at −20° C. The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% w/v NaOH (3 mL). Ether was added (100 mL), and the mixture was allowed to warm up to 10° C. After agitating for 10 minutes at this temperature, MsSO4 (5 g) and Celite® (2 g) were added, and the mixture was agitated for an additional 15 minutes. The mixture was then allowed to settle and filtered through a pad of Celite®, washing with ether. Solvents were then evaporated, and resulting solid was triturated with hexane to give ((2R,3R)-3-(4-chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07 mmol, 97.17% yield) as a solid. were added sequentially treated with 4 Å molecular sieves (1.0 g) for 1 hour The reaction was then quenched by addition of a mixture of a saturated NaCl solution (3 mL) and 50% Ether was added (100 mL) to warm up to 10° C were added the mixture was agitated for an additional 15 minutes filtered through a pad of Celite® washing with ether Solvents were then evaporated resulting solid was triturated with hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried, 3-neck, 2-L round bottom flask fitted with two oven-dried addition funnels and a rubber septum was charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4 Å powdered, activated molecular sieves (40 g) and dry dichloromethane (800 mL) under nitrogen. After being cooled to −25° C., to the reaction mixture was added titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was added at a moderate rate via an addition funnel. The resulting mixture was stirred at −25° C. for 30 minutes. trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise via an addition funnel while maintaining the temperature at −25° C. After the addition, the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours. After the reaction was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was added slowly at −20° C. After diethyl ether (150 mL) was added, the cold bath was removed and the mixture was allowed to warm to ˜5° C. and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 mL). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate:hexane) to give 24.80 g (90%) of [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous, colorless oil. Percent ee: >96.5%. MS (ESI) m/z 169.1 ([M+H]+). oven-dried addition funnels The resulting mixture was stirred at −25° C. for 30 minutes while maintaining the temperature at −25° C After the addition the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours was added slowly at −20° C the cold bath was removed to warm to ˜5° C. stirred for 1 hour Magnesium sulfate (anhydrous, 50 g) was added the mixture was stirred for 20 minutes filtered through a pad of silica gel washed with ether (300 mL) The filtrate was concentrated The residual oil was purified on silica gel (0-30% ethyl acetate:hexane)

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried, 3-neck, 2-L round bottom flask fitted with two oven-dried addition funnels and a rubber septum was charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4 Å powdered, activated molecular sieves (40 g) and dry dichloromethane (800 mL) under nitrogen. After being cooled to −25° C., to the reaction mixture was added titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was added at a moderate rate via an addition funnel. The resulting mixture was stirred at −25° C. for 30 minutes. trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise via an addition funnel while maintaining the temperature at −25° C. After the addition, the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours. After the reaction was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was added slowly at −20° C. After diethyl ether (150 mL) was added, the cold bath was removed and the mixture was allowed to warm to ˜5° C. and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 mL). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate:hexane) to give 24.80 g (90%) of [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous, colorless oil. Percent ee: >96.5%. MS (ESI) m/z 169.1 ([M+H]+). oven-dried addition funnels The resulting mixture was stirred at −25° C. for 30 minutes while maintaining the temperature at −25° C After the addition the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours was added slowly at −20° C the cold bath was removed to warm to ˜5° C. stirred for 1 hour Magnesium sulfate (anhydrous, 50 g) was added the mixture was stirred for 20 minutes filtered through a pad of silica gel washed with ether (300 mL) The filtrate was concentrated The residual oil was purified on silica gel (0-30% ethyl acetate:hexane)

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried, 3-neck, 2-L round bottom flask fitted with two oven-dried addition funnels and a rubber septum was charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4 Å powdered, activated molecular sieves (40 g) and dry dichloromethane (800 mL) under nitrogen. After being cooled to −25° C., to the reaction mixture was added titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was added at a moderate rate via an addition funnel. The resulting mixture was stirred at −25° C. for 30 minutes. trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise via an addition funnel while maintaining the temperature at −25° C. After the addition, the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours. After the reaction was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was added slowly at −20° C. After diethyl ether (150 mL) was added, the cold bath was removed and the mixture was allowed to warm to ˜5° C. and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 mL). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate:hexane) to give 24.80 g (90%) of [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous, colorless oil. Percent ee: >96.5%. MS (ESI) m/z 169.1 ([M+H]+). oven-dried addition funnels The resulting mixture was stirred at −25° C. for 30 minutes while maintaining the temperature at −25° C After the addition the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours was added slowly at −20° C the cold bath was removed to warm to ˜5° C. stirred for 1 hour Magnesium sulfate (anhydrous, 50 g) was added the mixture was stirred for 20 minutes filtered through a pad of silica gel washed with ether (300 mL) The filtrate was concentrated The residual oil was purified on silica gel (0-30% ethyl acetate:hexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to -15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to -15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried, 3-neck, 2-L round bottom flask fitted with two oven-dried addition funnels and a rubber septum was charged with diisopropyl D-tartrate (11.55 g, 49.3 mmol, 0.30 equiv.), 4 Å powdered, activated molecular sieves (40 g) and dry dichloromethane (800 mL) under nitrogen. After being cooled to −25° C., to the reaction mixture was added titanium isopropoxide (9.6 mL, 33 mmol, 0.20 equiv.) slowly via a hypodermic syringe. After stirring for 10 minutes, anhydrous t-butyl hydroperoxide (5.5 M in decane, 75.0 mL, 413 mmol, 2.5 equiv.) was added at a moderate rate via an addition funnel. The resulting mixture was stirred at −25° C. for 30 minutes. trans-3-Fluorocinnamyl alcohol (25.0 g, 164 mmol) in dry dichloromethane (50 mL) was added dropwise via an addition funnel while maintaining the temperature at −25° C. After the addition, the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours. After the reaction was complete, cooled aqueous sodium hydroxide solution (30%, 20 mL) saturated with sodium chloride was added slowly at −20° C. After diethyl ether (150 mL) was added, the cold bath was removed and the mixture was allowed to warm to ˜5° C. and stirred for 1 hour. Magnesium sulfate (anhydrous, 50 g) was added and the mixture was stirred for 20 minutes, then filtered through a pad of silica gel, and washed with ether (300 mL). The filtrate was concentrated and toluene was used to azeotropically remove excess t-butyl hydroperoxide. The residual oil was purified on silica gel (0-30% ethyl acetate:hexane) to give 24.80 g (90%) of [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol as a viscous, colorless oil. Percent ee: >96.5%. MS (ESI) m/z 169.1 ([M+H]+). oven-dried addition funnels The resulting mixture was stirred at −25° C. for 30 minutes while maintaining the temperature at −25° C After the addition the reaction mixture was stirred at −25° C. for 1 hour and at −20° C. for another 3 hours was added slowly at −20° C the cold bath was removed to warm to ˜5° C. stirred for 1 hour Magnesium sulfate (anhydrous, 50 g) was added the mixture was stirred for 20 minutes filtered through a pad of silica gel washed with ether (300 mL) The filtrate was concentrated The residual oil was purified on silica gel (0-30% ethyl acetate:hexane)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon atmosphere, to anhydrous dichloromethane suspension (150 ml) containing 3.4 g of Molecular Sieves 4A were added 3.3 g (14.08 mmol) of diisopropyl D-(−)-tartarate, 3.3 g (11.73 mmol) of titanium tetraisopropoxide and 13.4 g (117.30 mmol) of (trans)-2-heptene-1-ol at −30 to −40° C. and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −60° C., and under stirring, 105 ml of a toluene solution containing 2.23M of t-butylhydroperoxide was added dropwise to the mixture over 20 minutes, and the temperature of the resulting mixture was returned to room temperature over 2 hours. After completion of the reaction, the reaction mixture was added to an aqueous solution (400 ml) containing iron (III) sulfate heptahydrate (80 g) and L-tartaric acid (40 g), and the resulting mixture was extracted with dichloromethane (400 ml). The organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue were added ether (400 ml) and 1N-sodium hydroxide (200 ml), and the mixture was stirred at room temperature for one hour. After completion of the reaction, the organic layer was separated, and the aqueous layer was extracted with ether (50 ml). The organic layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was evaporated under reduced pressure to obtain 11.6 g (Yield: 76.2%) of the title compound. under stirring was added dropwise to the mixture over 20 minutes the temperature of the resulting mixture was returned to room temperature over 2 hours After completion of the reaction the resulting mixture was extracted with dichloromethane (400 ml) The organic layer was washed with a saturated NaCl solution dried over anhydrous sodium sulfate the solvent was removed under reduced pressure To the residue were added ether (400 ml) and 1N-sodium hydroxide (200 ml) the mixture was stirred at room temperature for one hour After completion of the reaction the organic layer was separated the aqueous layer was extracted with ether (50 ml) The organic layer was washed with a saturated NaCl solution dried over anhydrous sodium sulfate the solvent was removed under reduced pressure The residue was evaporated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate