tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 mL of tetrahydrofuran and 190 mL of methanol under a nitrogen atmosphere. This solution is cooled to -85° C. and 95 mL of a 15% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97° C. and 6.5 9 (0.172 mol) of sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is maintained between -93° C. and -97° C. for 13 hours and allowed to warm to room temperature and stand for 60 hours under a nitrogen atmosphere. The reaction is quenched by the addition of 25 mL (0.395 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 mL methanol, concentrated by vacuum distillation, redissolved with 500 mL methanol and reconcentrated by vacuum distillation to give a dark brown oil. This oil is taken up in 500 mL of ethyl acetate and filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate The solution is evaporated to give 15 g of crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which is used without further purification. The reaction is cooled to -97° C. The reaction is maintained between -93° C. and -97° C. for 13 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue is dissolved with 500 mL methanol concentrated by vacuum distillation redissolved with 500 mL methanol reconcentrated by vacuum distillation to give a dark brown oil filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate The solution is evaporated

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

Procedure: A solution of crude (R)-1,1-dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3oxohexanoate, 43 g (0.126 mol) in 350 mL of tetrahydrofuran is treated with 213 mL of tetrabutylammonium fluoride solution (1.0 M in hexane). The resulting mixture is stirred for five hours, at 25° C. The mixture is treated with 500 mL of water, 300 mL of diethyl ether is added, and the layers separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel with the aid of anhydrous diethyl ether. The solvent is removed under a vacuum to obtain 21 g of crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra. is added the layers separated The organic layer is dried (magnesium sulfate) filtered through a plug of silica gel with the aid of anhydrous diethyl ether The solvent is removed under a vacuum

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (R)-1,1-dimethylethyl 6-cyano-5hydroxy-3-oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 mL of tetrahydrofuran and 190 mL of methanol under a nitrogen atmosphere. This solution is cooled to -85° C. and 95 mL of a 15% solution of methoxydiethyl-borane in tetrahydrofuran is added. The reaction is cooled to -97° C. and 6.5 g (0.172 mol) of sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is maintained between -93° C. and -97° C. for 13 hours and allowed to warm to room temperature and stand for 60 hours under a nitrogen atmosphere. The reaction is quenched by the addition of 25 mL (0.395 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 mL methanol, concentrated by vacuum distillation, redissolved with 500 mL methanol and reconcentrated by vacuum distillation to give a dark brown oil. This oil is taken up in 500 mL of ethyl acetate and filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate. The solution is evaporated to give 15 g of crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which is used without further purification. The reaction is cooled to -97° C. The reaction is maintained between -93° C. and -97° C. for 13 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue is dissolved with 500 mL methanol concentrated by vacuum distillation redissolved with 500 mL methanol reconcentrated by vacuum distillation to give a dark brown oil filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate The solution is evaporated

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

Procedure: A solution of crude (R)-1,1-dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 mL of tetrahydro-furan is treated with 213 mL of tetrabutylammonium fluoride solution (1.0 M in hexane). The resulting mixture is stirred for five hours, at 25° C. The mixture is treated with 500 mL of water, 300 mL of diethyl ether is added, and the layers separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel with the aid of anhydrous diethyl ether. The solvent is removed under a vacuum to obtain 21 g of crude (R)-1,1-dimethyl-ethyl 6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra. is added the layers separated The organic layer is dried (magnesium sulfate) filtered through a plug of silica gel with the aid of anhydrous diethyl ether The solvent is removed under a vacuum

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate (Example 4), approximately 52 mol, was dissolved in 90 L of tetrahydrofuran and 19 L of methanol under a nitrogen atmosphere. This solution was cooled to -85° C. and 24 L of a 50% solution of methoxy-diethylborane in tetrahydrofuran was added. The reaction was cooled to -97° C. and 3.6 kg (126 mol) of sodium borohydride was added in 0.2 kg portions over 3 hours. The reaction was maintained between -93° C. and -85° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction was quenched by the addition of 7.5 L (118.5 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue was dissolved with 40 L of methanol, concentrated by vacuum distillation, redissolved with 44 L of methanol, and reconcentrated by vacuum distillation to give a brown oil. This oil was taken up in 90 L of ethyl acetate and washed with 30 L of deionized water. The ethyl acetate solution was concentrated by vacuum distillation to give the title compound, [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, which was used without further purification. The reaction was cooled to -97° C. The reaction was maintained between -93° C. and -85° C. for 5 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue was dissolved with 40 L of methanol concentrated by vacuum distillation redissolved with 44 L of methanol reconcentrated by vacuum distillation to give a brown oil washed with 30 L of deionized water The ethyl acetate solution was concentrated by vacuum distillation

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate (Example 4), approximately 52 mol, was dissolved in 90 L of tetrahydrofuran and 19 L of methanol under a nitrogen atmosphere. This solution was cooled to -85° C. and 24 L of a 50% solution of methoxy-diethylborane in tetrahydrofuran was added. The reaction was cooled to -97° C. and 3.6 kg (126 mol) of sodium borohydride was added in 0.2 kg portions over 3 hours. The reaction was maintained between -93° C. and -85° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction was quenched by the addition of 7.5 L (118.5 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue was dissolved with 40 L of methanol, concentrated by vacuum distillation, redissolved with 44 L of methanol, and reconcentrated by vacuum distillation to give a brown oil. This oil was taken up in 90 L of ethyl acetate and washed with 30 L of deionized water. The ethyl acetate solution was concentrated by vacuum distillation to give the title compound, [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, which was used without further purification. The reaction was cooled to -97° C. The reaction was maintained between -93° C. and -85° C. for 5 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue was dissolved with 40 L of methanol concentrated by vacuum distillation redissolved with 44 L of methanol reconcentrated by vacuum distillation to give a brown oil washed with 30 L of deionized water The ethyl acetate solution was concentrated by vacuum distillation

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

Procedure: To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane was added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran, and the mixture was stirred to -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Step A) (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran was then added to the previous mixture. The reaction mixture was stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8N aqueous hydrochloric acid solution. The aqueous layer was extracted with 50 kg of ethyl acetate, the aqueous layer was separated and reextracted with 36 kg of ethyl acetate, the extracts are combined, and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which was not isolated. A small sample was purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate. a rinse of 3 kg of tetrahydrofuran The reaction mixture was stirred for 30 minutes at -5° C. to -30° C. transferred to 240 L of 0° C The aqueous layer was extracted with 50 kg of ethyl acetate the aqueous layer was separated concentrated in vacuo

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate (Example 1), approximately 52 mol, is dissolved in 90 L of tetrahydrofuran and 19 L of methanol under a nitrogen atmosphere. This solution is cooled to -85° C. and 24 L of a 50% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97° C. and 3.6 kg (126 mol) of sodium borohydride is added in 0.2 kg portions over 3 hours. The reaction is maintained between -93° C. and -85° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of 7.5 L (118.5 mol) of acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 40 L of methanol, concentrated by vacuum distillation, redissolved with 44 L of methanol and reconcentrated by vacuum distillation to give a brown oil. This oil is taken up in 90 L of ethyl acetate and washed with 30 L of deionized water. The ethyl acetate solution is concentrated by vacuum distillation to give the title compound, [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, which is used without further purification. The reaction is cooled to -97° C. The reaction is maintained between -93° C. and -85° C. for 5 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue is dissolved with 40 L of methanol concentrated by vacuum distillation redissolved with 44 L of methanol reconcentrated by vacuum distillation to give a brown oil washed with 30 L of deionized water The ethyl acetate solution is concentrated by vacuum distillation

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

Procedure: To a stirred -50° C. solution of tertiary-butyl acetate (60 mL, 0.44 mol), (R)-4-cyano-3-hydroxybutyric acid, n-butyl ester (20 g, 0.11 mol) and 150 mL tetrahydrofuran is added lithium diisopropylamide (300 mL of 1.5 M) in tetrahydrofuran over 15 minutes and the mixture is stirred at -45° C. to -50° C. for 90 minutes. To this solution is added 700 mL of 5% aqueous hydrochloric acid solution along with 300 mL of ethyl acetate. The aqueous layer is separated and the remaining top layer washed with aqueous sodium chloride solution. The organic layer is then concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which is not isolated, and is carried on to (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl -1,3-dioxane-4-acetate as described in Example 2. TLC: Rf =0.15 (1:1 ethyl acetate: hexanes) on a Kieselgel 60 F254 0.254 mm silica thin layer plate. The aqueous layer is separated the remaining top layer washed with aqueous sodium chloride solution The organic layer is then concentrated in vacuo

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

Procedure: To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane is added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran and the mixture is stirred at -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8 N aqueous hydrochloric acid solution. The aqueous layer is extracted with 50 kg of ethyl acetate, the aqueous layer is separated and reextracted with 36 kg of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo -hexanoate which is not isolated. A small sample is purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate. 1H--NMR: (CDCl3) 1.48 (9H, s), 2.61 (2H, m), 2.88 (2H, d), 3.43 (2H, s), 3.58 (1H, bs), 4.40 (1H, m). MS:(EI) m/e, (%): 229 (3), 228(26),173(10), 172(100), 154(62), 112(30), 59(50), 57(77). a rinse of 3 kg of tetrahydrofuran The reaction mixture is stirred for 30 minutes at -5° C. to -30° C. transferred to 240 L of 0° C The aqueous layer is extracted with 50 kg of ethyl acetate the aqueous layer is separated concentrated in vacuo

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

Procedure: To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane is added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran and the mixture is stirred at -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8 N aqueous hydrochloric acid solution. The aqueous layer is extracted with 50 kg of ethyl acetate, the aqueous layer is separated and reextracted with 36 kg of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo -hexanoate which is not isolated. A small sample is purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate. 1H--NMR: (CDCl3) 1.48 (9H, s), 2.61 (2H, m), 2.88 (2H, d), 3.43 (2H, s), 3.58 (1H, bs), 4.40 (1H, m). MS:(EI) m/e, (%): 229 (3), 228(26),173(10), 172(100), 154(62), 112(30), 59(50), 57(77). a rinse of 3 kg of tetrahydrofuran The reaction mixture is stirred for 30 minutes at -5° C. to -30° C. transferred to 240 L of 0° C The aqueous layer is extracted with 50 kg of ethyl acetate the aqueous layer is separated concentrated in vacuo

Conditions: temp:-85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 mL of tetrahydrofuran and 190 mL of methanol under a nitrogen atmosphere. This solution is cooled to -85° C. and 95 mL of a 15% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97° C. and 6.5 9 (0.172 mol) of sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is maintained between -93° C. and -97° C. for 13 hours and allowed to warm to room temperature and stand for 60 hours under a nitrogen atmosphere. The reaction is quenched by the addition of 25 mL (0.395 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 mL methanol, concentrated by vacuum distillation, redissolved with 500 mL methanol and reconcentrated by vacuum distillation to give a dark brown oil. This oil is taken up in 500 mL of ethyl acetate and filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate The solution is evaporated to give 15 g of crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which is used without further purification. The reaction is cooled to -97° C. The reaction is maintained between -93° C. and -97° C. for 13 hours to warm to room temperature concentrated by vacuum distillation to an oil The residue is dissolved with 500 mL methanol concentrated by vacuum distillation redissolved with 500 mL methanol reconcentrated by vacuum distillation to give a dark brown oil filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate The solution is evaporated