methyl (3S)-3-hydroxybutanoate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4). filtered The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water After drying with anhydrous sodium sulfate the solution was filtered the solvents were removed on a rotovap The resulting solid was purified silica gel and elution with ether/hexane (1:4)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A chemical reference for desired product was prepared as follows. Methyl (S)-(+)-3-hydroxybutyrate (Aldrich) was dissolved in benzyl alcohol and treated with a catalytic amount of titanium tetraisopropoxide. The mixture was aged at 60° C. for 24 hours. Partial concentration on a rotary evaporator and filtration afforded benzyl (S)-(+)-3-hydroxybutyrate and residual benzyl alcohol. Partial concentration on a rotary evaporator and filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4). filtered The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water After drying with anhydrous sodium sulfate the solution was filtered the solvents were removed on a rotovap The resulting solid was purified silica gel and elution with ether/hexane (1:4)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4). filtered The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water After drying with anhydrous sodium sulfate the solution was filtered the solvents were removed on a rotovap The resulting solid was purified silica gel and elution with ether/hexane (1:4)

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Subsequently, in a 50 ml flask were charged 3.3 g (30.0 mmol) of diisopropylamine and 10 ml of tetrahydrofuran, and 16.6 ml (24.9 mmol) of n-butyllithium 1.5M hexane solution was added thereto dropwise on an ice bath in a nitrogen stream. The mixture was then stirred for 1 hour at that temperature. The reaction mixture was further cooled to −40° C., and 1.40 g (11.9 mmol) of methyl (S)-3-hydroxybutyrate prepared as above was added thereto dropwise. After the mixture was stirred for 0.5 hour, 3.00 g (17.5 mmol) of benzyl bromide dissolved in 6 ml of hexamethylphosphoramide was added thereto dropwise at −10° C. or lower temperature. After the addition, the temperature was heated up to 0° C., and the mixture was stirred for 15 min. The resulting mixture was then poured into an ice water, and was extracted with ethyl acetate. The ethyl acetate layer was concentrated to give 3.90 g of a crude product. The crude product was subjected to column chromatography (hexane/ethyl acetate=4/1 by volume) to obtain 1.50 g (61%) of the title compound (anti/syn=98/2). was added as above was added After the mixture was stirred for 0.5 hour was added dropwise at −10° C. After the addition the temperature was heated up to 0° C. the mixture was stirred for 15 min was extracted with ethyl acetate The ethyl acetate layer was concentrated to give 3.90 g of a crude product

反応条件: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (19.93 milliliters (mL), 142 millimoles (mmol)) in anhydrous THF (99 mL) at −50° C. (deficient dry ice/acetone bath) was added n-butyllithium (n-BuLi; 54.3 mL, 130 mmol, 2.5 M in hexanes). This solution was removed from the cold bath for 15 minutes (min), then re-cooled to −50° C. To the lithium diisopropylamide (LDA) was added a solution of (S)-methyl 3-hydroxybutanoate (6.64 ml, 59.3 mmol) in THF (20.0 mL) dropwise over 15 min using a cannula. This solution was allowed to warm to −30° C. over 30 min, stirred at −30° C. for 1 h, and recooled to −78° C. To the enolate was added a solution of 1-bromo-3-methylbut-2-ene (13.7 mL, 119 mmol) in anhydrous 1,2-dimethoxyethane (20.0 mL, 193 mmol) dropwise over 15 min. The cold bath was at −60° C. after 1 h at which time the reaction flask was removed from the bath and stirred without cooling for 1.5 h. The reaction was quenched by the addition of sat. aq. ammonium chloride (NH4Cl; 50 mL), diluted with EtOAc (50 mL), and the phases were separated. The aqueous phase was further extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with sat. aq. sodium chloride (NaCl, brine; 50 mL), dried over sodium sulfate Na2SO4, filtered, and concentrated to dryness. The crude residue was purified by flash column chromatography (120 grams (g) silica gel (SiO2), 0→40% EtOAc/hexanes) to afford the title compound (9.5 g, 51.0 mmol, 86%) as a slightly yellow oil: IR (thin film) 3452, 2971, 2929, 1730, 1437, 1198, 1160 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.11-5.01 (m, 1H), 3.92 (p, J=6.3 Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46-2.28 (m, 3H), 1.69 (d, J=1.4 Hz, 3H), 1.62 (s, 3H), 1.23 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46, 17.64. This solution was removed from the cold bath for 15 minutes (min) to warm to −30° C. over 30 min recooled to −78° C The cold bath was at −60° C. after 1 h at which time the reaction flask was removed from the bath stirred without cooling for 1.5 h The reaction was quenched by the addition of sat. aq. ammonium chloride (NH4Cl; 50 mL) diluted with EtOAc (50 mL) the phases were separated The aqueous phase was further extracted with EtOAc (2×50 mL) the combined organic extracts were washed with sat. aq. sodium chloride (NaCl, brine; 50 mL) dried over sodium sulfate Na2SO4 filtered concentrated to dryness The crude residue was purified by flash column chromatography (120 grams (g) silica gel (SiO2), 0→40% EtOAc/hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl(chloro)diphenylsilane (15.282 g, 55.6 mmol) was added dropwise to an ice-cooled and stirred solution of (S)-3-hydroxybutanoic acid methyl ester (5.473 g, 46.3 mmol) and 1H-imidazole (6.939 g, 102 mmol) and DMAP (0.566 g, 4.63 mmol) in DMF (250 mL). After 10 min., the cloudy reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was taken up in EtOAc, then washed successively with H2O (3×), 1N HCl and a sat. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to give a viscous colourless oil. cooled the cloudy reaction mixture washed successively with H2O (3×), 1N HCl The organic phase was dried (Na2SO4) filtered concentrated to give a viscous colourless oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl (S)-(+)-3-hydroxybutyrate (0.48 g, 4.04 mmol) (Aldrich) was dissolved in dichloromethane (6 mL, dried over molecular sieves). Imidazole (0.39 g, 5.65 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenylsilyl chloride (1.05 mL, 4.04 mmol) was added dropwise and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with additional dichloromethane, washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes) gave (S)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester. (Yield 1.33 g, 92.4%). When all had dissolved washed with water (2×) and brine dried over anhydrous sodium sulfate filtered concentrated Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A chemical reference for desired product was prepared as follows. Methyl (S)-(+)-3-hydroxybutyrate (Aldrich) was dissolved in benzyl alcohol and treated with a catalytic amount of titanium tetraisopropoxide. The mixture was aged at 60° C. for 24 hours. Partial concentration on a rotary evaporator and filtration afforded benzyl (S)-(+)-3-hydroxybutyrate and residual benzyl alcohol. Partial concentration on a rotary evaporator and filtration

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4). filtered The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water After drying with anhydrous sodium sulfate the solution was filtered the solvents were removed on a rotovap The resulting solid was purified silica gel and elution with ether/hexane (1:4)