benzyl 3-methyl-2-oxobutanoate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (122 mg, 1.21 mmol) in anhydrous tetrahydrofuran (2 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (703 μL, 1.11 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min and then at −78° C. for 5 min. A solution of benzyl 2-(tetrahydropyran-4-yl)acetate (250 mg, 1.07 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise over 6 min at the same temperature, and the reaction mixture was further stirred for 15 min. The cold enolate solution thus prepared was added dropwise via a cannula to a solution of benzyl a solution of benzyl 3-methyl-2-ketobutyrate (191 mg, 0.928 mmol) in anhydrous tetrahydrofuran (1 mL) solution having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid and raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases for extraction. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinate as oil in amounts of 115 mg (low polar diastereomer, yield: 29%) and 158 mg (high polar diastereomer, yield: 39%), respectively. the mixture was stirred at 0° C. for 10 min the reaction mixture was further stirred for 15 min After stirring at −78° C. for 1 h raised to room temperature The reaction solvent was evaporated under reduced pressure the residue was diluted with ethyl acetate and water to separate the phases for extraction The aqueous layer was extracted again with ethyl acetate the combined organic layer was concentrated under reduced pressure the residue thus obtained

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (418 mg, 4.15 mmol) in anhydrous tetrahydrofuran (6 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (2.5 mL, 5.4 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min, and then at −78° C. for 5 min. A solution of trans-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexan (1.36 g, 3.76 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise at the same temperature over 7 min, and the reaction mixture was further stirred for 15 min. The cold enolate solution thus prepared was added dropwise via canula to a solution of benzyl 3-methyl-2-ketobutyrate (776 mg, 3.76 mmol) in anhydrous tetrahydrofuran (4 mL) having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid, and the temperature was raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases for extraction. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 20:1) to give dibenzyl 3-(trans-4-t-butyldimethylsilyloxycyclohexyl)-2-hydroxy-2-isopropylsuccinate as oil in amounts of 629 mg (low polar diastereomer, yield: 29%) and 801 mg (high polar diastereomer, yield: 37%), respectively. the mixture was stirred at 0° C. for 10 min the reaction mixture was further stirred for 15 min After stirring at −78° C. for 1 h the temperature was raised to room temperature The reaction solvent was evaporated under reduced pressure the residue was diluted with ethyl acetate and water to separate the phases for extraction The aqueous layer was extracted again with ethyl acetate the combined organic layer was concentrated under reduced pressure the residue thus obtained

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To anhydrous tetrahydrofuran (5 mL) was added diisopropylamine (759 mg, 7.5 mmol) under nitrogen stream, and the mixture was cooled to −78° C. To the solution was added a 1.58 M n-butyl lithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at −78° C. for 5 min, and then at 0° C. for 15 min. The solution of lithium diisopropylamide tetrahydrofuran was cooled to −78° C., and a solution of benzyl propionate (821 mg, 5.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 1 h, and the reaction mixture was further stirred at −78° C. for 1 h. The enolate thus prepared was added via a cannula to a solution of benzyl 3-methyl-2-ketobutyrate (1.24 g, 6.0 mmol) in anhydrous tetrahydrofuran (5 mL) having been cooled to −78° C. After stirring at −78° C. for 2 h, the reaction mixture was diluted with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 1.22 g of dibenzyl 2-isopropyl-2-hydroxy-3-methylsuccinate as oil (yield: 66%) in the form of a diastereomer mixture. To the solution was added a 1.58 M n-butyl lithium-hexane solution (4.3 mL, 6.8 mmol) at 0° C. for 15 min the reaction mixture was further stirred at −78° C. for 1 h having been cooled to −78° C After stirring at −78° C. for 2 h extracted with ethyl acetate The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine dried over anhydrous magnesium sulfate filtered The solvent was evaporated under reduced pressure the residue thus obtained