7-methyl-1,4-dioxaspiro[4.5]decan-8-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a tetrahydrofuran (100 mL) solution of 7-methyl-1,4-dioxa-spiro[4.5]-decan-8-one (Tetrahedron Asymmetry 2001, 12, 1683) (9.50 g), K-Selectride (1.0 mol/L tetrahydrofuran solution, 65 mL) was gradually added at −78° C. After 1 hour, the reaction mixture was warmed to 0° C., and a 1 N aqueous sodium hydroxide solution (120 mL) and 30% aqueous hydrogen peroxide (100 mL) were gradually added thereto. The purified aqueous mixture was stirred overnight, followed by two extractions with dichloromethane. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=4:1→2:1→1:1) to obtain the title compound (8.18 g, 85%) as a colorless oil. followed by two extractions with dichloromethane The organic layer was washed with saturated brine dried over sodium sulfate concentrated The residue was purified by chromatography (hexane/ethyl acetate=4:1→2:1→1:1)

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

Procedure: According to the process described in Tetrahedron, 47, 1991, 3259, a solution of sodium amide (18.5 g) in THF (100 ml) was added to a solution of 1,4-cyclohexanedione monoethylene ketal (18.5 g) in THF (100 ml) under a nitrogen atmosphere while keeping the temperature of the solution at 10-20° C. After stirring at 20° C. for 30 minutes, methyl iodide (41.3 g) was added and the stirring was continued at room temperature for 1 hour. The reaction solution was mixed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with diethyl ether. The diethyl ether layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel and an oily mixture (mixture ratio of 1:1, 15.1 g) of 4,4-ethylenedioxy-2-methyl-1-cyclohexanone and 4,4-ethylenedioxy-2,2-dimethyl-1-cyclohexanone was obtained from the eluates with ethyl acetate-hexane (4:1). To a solution of this mixture (2.0 g) in ethanol (20 ml) was added sodium borohydride (440 mg) under ice cooling. After stirring at room temperature for 2 hours, acetic acid (0.2 ml) was added, and the mixture was evaporated under reduced pressure to remove the solvent. To the residue was added ethyl acetate and the resulting solution was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 4-hydoxy-3-methyl-1-cyclohexanone ethylene ketal (140 mg, 1H NMR (CDCl3) δ: 1.02 (3H, d, J=6.6 Hz), 1.20-2.00 (8H, m), 3.15-3.30 (1H, m), 3.94 (4H, br s)) and 4-hydoxy-3,3-dimethyl-1-cyclohexanone ethylene ketal (470 mg, 1H NMR (CDCl3) δ: 1.00 (3H, s), 1.01 (3H,s), 1.35-1.90 (7H, m), 3.38-3.46 (1H, m), 3.90-4.00 (4H, m)) from the eluates with ethyl acetate-hexane (6:1) as oily substances, respectively. at 10-20° C the stirring was continued at room temperature for 1 hour extracted with diethyl ether The diethyl ether layer was washed with water dried (MgSO4) evaporated under reduced pressure to remove the solvent

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

Procedure: According to the process described in Tetrahedron, 47, 1991, 3259, a solution of sodium amide (18.5 g) in THF (100 ml) was added to a solution of 1,4-cyclohexanedione monoethylene ketal (18.5 g) in THF (100 ml) under a nitrogen atmosphere while keeping the temperature of the solution at 10-20° C. After stirring at 20° C. for 30 minutes, methyl iodide (41.3 g) was added and the stirring was continued at room temperature for 1 hour. The reaction solution was mixed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with diethyl ether. The diethyl ether layer was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel and an oily mixture (mixture ratio of 1:1, 15.1 g) of 4,4-ethylenedioxy-2-methyl-1-cyclohexanone and 4,4-ethylenedioxy-2,2-dimethyl-1-cyclohexanone was obtained from the eluates with ethyl acetate-hexane (4:1). To a solution of this mixture (2.0 g) in ethanol (20 ml) was added sodium borohydride (440 mg) under ice cooling. After stirring at room temperature for 2 hours, acetic acid (0.2 ml) was added, and the mixture was evaporated under reduced pressure to remove the solvent. To the residue was added ethyl acetate and the resulting solution was washed with water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain 4-hydoxy-3-methyl-1-cyclohexanone ethylene ketal (140 mg, 1H NMR (CDCl3) δ: 1.02 (3H, d, J=6.6 Hz), 1.20-2.00 (8H, m), 3.15-3.30 (1H, m), 3.94 (4H, br s)) and 4-hydoxy-3,3-dimethyl-1-cyclohexanone ethylene ketal (470 mg, 1H NMR (CDCl3) δ: 1.00 (3H, s), 1.01 (3H,s), 1.35-1.90 (7H, m), 3.38-3.46 (1H, m), 3.90-4.00 (4H, m)) from the eluates with ethyl acetate-hexane (6:1) as oily substances, respectively. at 10-20° C the stirring was continued at room temperature for 1 hour extracted with diethyl ether The diethyl ether layer was washed with water dried (MgSO4) evaporated under reduced pressure to remove the solvent

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Dissolve 7-methyl-1,4-dioxa-spiro[4.5]decan-8-one (11.45 g, 67.28 mmol) in THF (300 mL) and cool the solution to 0° C. under N2. Add super-hydride (74.0 mL, 74.0 mmol, 1 M in THF) and stir the reaction mixture overnight. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×300 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-50% of EtOAc/Hexane) to give cis-7-Methyl-1,4-dioxa-spiro[4.5]decan-8-ol. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×300 mL) Combine the organic layers and dry with Na2SO4 filter concentrate purify by flash column chromatography (silica gel, 30-50% of EtOAc/Hexane)

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

Procedure: Dissolve 7-methyl-1,4-dioxa-spiro[4.5]decan-8-one (11.45 g, 67.28 mmol) in THF (300 mL) and cool the solution to 0° C. under N2. Add super-hydride (74.0 mL, 74.0 mmol, 1 M in THF) and stir the reaction mixture overnight. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×300 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-50% of EtOAc/Hexane) to give cis-7-Methyl-1,4-dioxa-spiro[4.5]decan-8-ol. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×300 mL) Combine the organic layers and dry with Na2SO4 filter concentrate purify by flash column chromatography (silica gel, 30-50% of EtOAc/Hexane)

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

Procedure: 7-Methyl-1,4-dioxaspiro[4.5]decan-8-one (10.5 g, 62 mmol) was dissolved in methanolic potassium hydroxide solution (10 w/w %, 60 g). To the solution was added dropwise a solution of aqueous formaldehyde solution (37%, 4.6 ml) in methanol (5 ml) under ice-cooling over 20 min, and the mixture was stirred for 30 min. Then, to the reaction mixture were added 1 N hydrochloric acid and saturated aqueous ammonium chloride solution, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.9 g, yield 56%). cooling over 20 min the mixture was extracted three times with chloroform The combined organic layers were dried over magnesium sulfate Magnesium sulfate was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: Under a nitrogen atmosphere, to a solution of lithium bis(trimethylsilyl)amide (1M, 100 ml, 100 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one (15.6 g, 100 mmol) in tetrahydrofuran (50 ml) at −78° C. over about 30 min, and the mixture was stirred for 30 min. Then, methyl iodide (2.5 ml, 120 mmol) was added dropwise over 5 min, and the mixture was stirred at −78° C. for 30 min, and at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (10.6 g, yield 62%). the mixture was stirred at −78° C. for 30 min at room temperature for 2 hr the mixture was extracted three times with diethyl ether The combined organic layers were dried over magnesium sulfate Magnesium sulfate was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography