methyl (3R)-3-hydroxybutanoate

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

Procedure: 9.45 g of methyl (R)-(-)-3-hydroxybutyrate was dissolved in 200 ml of tetrahydrofuran, and 112 ml of a 1.5M cyclohexane solution of lithium diisopropylamide was added thereto with stirring under cooling to -70° C. Then, the temperature was raised to -25° C. Then, 35 ml of a hexamethylphosphoric triamide solution of 21.1 g of 3,4-dichlorobenzyl bromide was dropwise added to this solution under stirring while maintaining the temperature at -25° C. After the dropwise addition, the temperature was raised to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction solution with stirring under cooling with ice. Then, the temperature was raised to room temperature, and ethyl ether and water were added thereto for liquid separation. The organic layer was collected by separation and post-treated by a conventional method. The product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 10.6 g (yield: 48%) of methyl (2R, 3R)-2-(3,4-dichlorobenzyl)-3-hydroxybutyrate. Then, the temperature was raised to -25° C under stirring while maintaining the temperature at -25° C After the dropwise addition the temperature was raised to room temperature with stirring under cooling with ice Then, the temperature was raised to room temperature for liquid separation The organic layer was collected by separation post-treated by a conventional method The product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1)

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

Procedure: This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)-methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127. This compound was prepared

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

Procedure: To a -23° C. solution of PPh3 (40 mmol, 10.48 g) in THF (100 mL) was added diethyl azodicarboxylate (40 mmol, 6.28 mL) dropwise and the mixture was stirred at -23° C. for 16 hours, during which time a white precipitate was obtained. A THF (30 mL) solution of methyl 3(R)-hydroxybutanoate (20 mm, 2.36 g) and thiolacetic acid (20 mmol, 2.85 mL) was slowly added and the mixture was allowed to slowly warm to 25° C. and was stirred 16 h at 250° C. Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles were removed by filtration and the residue was purified by chromatography on silica gel to afford the title compound. [α]D25 =-21° (c=3, CHCl3). was obtained to slowly warm to 25° C. was stirred 16 h at 250° C Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added Insolubles were removed by filtration the residue was purified by chromatography on silica gel

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

Procedure: This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127. This compound was prepared

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

Procedure: To a -23° C. solution of PPh3 (40 mmol, 10.48 g) in THF (100 mL) was added diethyl azodicarboxylate (40 mmol, 6.28 mL) dropwise and the mixture was stirred at -23° C. for 16 hours, during which time a white precipitate was obtained. A THF (30 mL) solution of methyl 3(R)-hydroxybutanoate (20 mm, 2.36 g) and thiolacetic acid (20 mmol, 2.85 mL) was slowly added and the mixture was allowed to slowly warm to 25° C. and was stirred 16 h at 25° C. Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles were removed by filtration and the residue was purified by chromatography on silica gel to afford the title compound. was obtained to slowly warm to 25° C. was stirred 16 h at 25° C Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added Insolubles were removed by filtration the residue was purified by chromatography on silica gel

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 22-L three-necked round-bottomed flask affixed with an overhead mechanical stirrer, thermocouple, nitrogen bubbler, and provision for external cooling was charged dry pyridine (3.0 L, K.F. <0.005%) and methyl (R)-3-hydroxybutyrate (1.14 assay Kg, 9.67 moles, K.F. <0.005 wt %). While maintaining the temperature at <-5° C., p-toluenesulfonyl chloride (2.35 Kg, 98% tech. grade, 12.4 mole) was added to the alcohol/pyridine mixture. (The charge of tosyl chloride should be at least 125 mole % of the alcohol charge and should be adjusted upward, mole for mole, to compensate for the total system water content.) The reaction mixture was stirred for 24 hours at 0° C. or until judged complete by HPLC. Workup commenced by cooling the batch to -16° C. and subsequently adding water (200 mL), dropwise, while maintaining the temperature at <2° C. (It is essential that all tosyl chloride be decomposed with the addition of water while the batch is still homogeneous. If too much water is added initially, the reaction becomes biphasic and the rate of hydrolysis slows dramatically. Tosyl chloride then co-crystallizes with the product.) The batch was then aged with vigorous agitation for 30 minutes at 0°-2° C. An additional 400 mL of water was then added in similar fashion. After 30 minutes, HPLC analysis (see below) showed no remaining tosyl chloride. The batch was then diluted with the slow addition of water (9 L) at 0°-5° C. Product crystallizes spontaneously. After a 2 hour age at 0°-5 ° C. the batch was filtered, the product cake slurry-washed with water at least five times to remove p-toluenesulfonic acid and pyridine, and sucked dry under nitrogen to constant weight. The yield of methyl (R)- 3-(p-toluenesulfonyloxy) butyrate was 2.57 Kg (98%), mp 46°-47.5° C. HPLC Conditions: [Sample preparation: A quantity of 0.1 mL of the above reaction mixture was shaken with 5 mL water, 5 mL ethyl acetate, and 0.1 mL concentrated hydrochloric acid to neutralize and remove the pyridine solvent. The mixture was then separated and the upper ethyl acetate layer diluted 1:10 with acetonitrile for injection. At 254 nm, an area ratio of 1:2 product tosylate:tosyl chloride signifies a complete reaction. Column: C-8 Altex Ultra sphere 5 micron (4.1 mm×25 cm); Eluant: 50:50 A:B isocratic @2.0 mL/min, A=H2O (0.1% H3PO4 v/v), B=CH3CN; Temp: 24° C.; Detector: UV@254 nm; RT tosylate (1) 3.5 min., RT tosyl chloride 5.5 min⟧ Analysis: 1H NMR (CDCl3) 7.79(d,2H,J=8.36 Hz), 7.34(d,2H,J=8.36 Hz), 4.97(m,1H), 3.59(s, 3H), 2.74(dd,1H,J=15.8,J=6.5 Hz), 2.52(dd,1H,J=15.8,J=6.8 Hz), 2.45(s,3H), 1.36(d,3H,J=6.3 Hz); 13C NMR (CDCl3) 169.7(s), 144.8(s), 133.9(s), 129.8(s), 127.7(s), 75.8(s), 51.8(s), 41.2(s), 21.6 (s), 20.9(s); [α]40525 =-16.3 (c=2,toluene); Anal. Calcd. for C12H16O5S: C,52.94; H,5.88; S,11.76. Found: C,52.98; H,5.93; S,11.76. To a 22-L three-necked round-bottomed flask affixed with an overhead mechanical stirrer thermocouple, nitrogen bubbler, and provision for external cooling While maintaining the temperature at <-5° C. charge by cooling the batch to -16° C. the rate of hydrolysis ) The batch was then aged with vigorous agitation for 30 minutes at 0°-2° C After 30 minutes Product crystallizes spontaneously After a 2 hour age at 0°-5 ° C. the batch was filtered the product cake slurry-washed with water at least five times to remove p-toluenesulfonic acid and pyridine sucked dry under nitrogen to constant weight HPLC Conditions: [Sample preparation remove the pyridine solvent The mixture was then separated the upper ethyl acetate layer diluted 1:10 with acetonitrile for injection a complete reaction 24° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 775 ml of 1.6M n-butyllithium solution in n-hexane are added dropwise within a period of 20 minutes at -25° C. to a solution of 1.27 mol of diisopropylamine in 600 ml of tetrahydrofuran. At -70° C., 70.9 g of (R)-3-hydroxybutyric acid methyl ester are then added dropwise within a period of 30 minutes and, after 1 hour, 70.9 g of oxalic acid dimethyl ester are added dropwise within a period of 40 minutes. After a reaction time of two hours at -60° C., the whole is warmed to 0° C. and acidified to pH 2 with 430 ml of 6N hydrochloric acid. The product is isolated by repeated extraction with ethyl acetate and pre-purified by extraction into aqueous bicarbonate solution, acidification with 6N hydrochloric acid to pH 2.5 and extraction once more with ethyl acetate. The solvent is distilled off and the residue is recrystallised from ether/petroleum ether. [α]D20 =+30.0° (3% in CHCl3), m.p. 94°-96° C. pre-purified by extraction into aqueous bicarbonate solution, acidification with 6N hydrochloric acid to pH 2.5 and extraction once more with ethyl acetate The solvent is distilled off the residue is recrystallised from ether/petroleum ether [α]D20 =+30.0° (3% in CHCl3), m.p. 94°-96° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 775 ml of 1.6M n-butyllithium solution in n-hexane are added dropwise within a period of 20 minutes at -25° C. to a solution of 1.27 mol of diisopropylamine in 600 ml of tetrahydrofuran. At -70° C., 70.9 g of (R)-3-hydroxybutyric acid methyl ester are then added dropwise within a period of 30 minutes and, after 1 hour, 70.9 g of oxalic acid dimethyl ester are added dropwise within a period of 40 minutes. After a reaction time of two hours at -60° C., the whole is warmed to 0° C. and acidified to pH 2 with 430 ml of 6N hydrochloric acid. The product is isolated by repeated extraction with ethyl acetate and pre-purified by extraction into aqueous bicarbonate solution, acidification with 6N hydrochloric acid to pH 2.5 and extraction once more with ethyl acetate. The solvent is distilled off and the residue is recrystallised from ether/petroleum ether. [α]D20 =+30.0° (3% in CHCl3), m.p. 94°-96° C. pre-purified by extraction into aqueous bicarbonate solution, acidification with 6N hydrochloric acid to pH 2.5 and extraction once more with ethyl acetate The solvent is distilled off the residue is recrystallised from ether/petroleum ether [α]D20 =+30.0° (3% in CHCl3), m.p. 94°-96° C.

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

Procedure: To a solution of diisopropylamine (47.1 g, 466.1 mmol) in THF (500 mL) cooled to −50.degree. C. is added n-butyllithium (466.1 mmol, 2.5M in hexanes) and the resulting solution is stirred at −50.degree. C. for 0.5 h. The reaction mixture is cooled to −78.degree. C. followed by slow addition of methyl (3R)-3-hydroxybutanoate (25 g, 211.9 mmol). After 0.5 h a solution of cinnamyl bromide (45.9 g, 233.0 mmol) in HMPA (10 mL) is added and the reaction mixture is allowed to warm to 0.degree. C. and stirred for 16 h. The reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate-hexanes) to afford methyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield). The reaction mixture is cooled to −78.degree to warm to 0.degree and stirred for 16 h The reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution is poured into 400 mL of 1 M hydrochloric acid is extracted with two 500 mL portions of ethyl acetate The combined organic layers are dried over magnesium sulfate concentrated in vacuo purified by silica gel chromatography (elution with 25% ethyl acetate-hexanes)

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

Procedure: This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)-methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127. This compound was prepared

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

Procedure: This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)-methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127. This compound was prepared

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

Procedure: To a -23° C. solution of PPh3 (40 mmol, 10.48 g) in THF (100 mL) was added diethyl azodicarboxylate (40 mmol, 6.28 mL) dropwise and the mixture was stirred at -23° C. for 16 hours, during which time a white precipitate was obtained. A THF (30 mL) solution of methyl 3(R)-hydroxybutanoate (20 mm, 2.36 g) and thiolacetic acid (20 mmol, 2.85 mL) was slowly added and the mixture was allowed to slowly warm to 25° C. and was stirred 16 h at 25° C. Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles were removed by filtration and the residue was purified by chromatography on silica gel to afford the title compound. was obtained to slowly warm to 25° C. was stirred 16 h at 25° C Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added Insolubles were removed by filtration the residue was purified by chromatography on silica gel