benzyl N-[(2S)-1-oxopropan-2-yl]carbamate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyltriphenylphosphonium bromide (16.92 g, 47.30 mmol) was taken up in toluene (350 mL). The heterogeneous solution was cooled to 0° C. then KHMDS 0.5M in toluene (90 mL, 45 mmol) was added. The reaction was stirred at 0° C. for 30 min, then cooled to −78° C. and (1-(S)-methyl-2-oxo-ethyl)-carbamic acid benzyl ester (6.11 g, 29.56 mmol) that was dissolved in toluene (45 mL) was added. The solution was warm to rt, stirred at it for 30 min, then quenched with sat NH4Cl(aq) (150 mL). The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over Na2SO4. Solids were removed by filtration and solvent removed under reduced pressure. (1-(S)-methyl-allyl)-carbamic acid benzyl ester (4.90 g, 81%) was isolated by silica gel chromatography as a colorless oil. cooled to −78° C. was added The solution was warm to rt stirred at it for 30 min quenched with sat NH4Cl(aq) (150 mL) The layers were separated the aqueous was washed with EtOAc dried over Na2SO4 Solids were removed by filtration and solvent removed under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H). to warm to room temperature overnight the mixture was extracted with EtOAc (3×50 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to afford the crude product This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient)

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

実験手順: Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to a stirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry CH2Cl2 (12.6 mL) at −78° C. under N2 and the reaction was stirred for 15 min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in dry CH2Cl2 (12.6 mL) was added dropwise by cannula and the mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and was stirred for 2 h. Water (15 mL) was added and the aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated NaHCO3 and brine, then dried (MgSO4) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. Rf=0.75 (50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H). the mixture was stirred at −78° C. for 30 min was stirred for 2 h the aqueous phase was separated extracted with CH2Cl2 (3×15 mL) The combined organic extracts were washed with saturated NaHCO3 and brine dried (MgSO4) concentrated in vacuo

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

実験手順: Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to a stirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry CH2Cl2 (12.6 mL) at −78° C. under N2 and the reaction was stirred for 15 min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in dry CH2Cl2 (12.6 mL) was added dropwise by cannula and the mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and was stirred for 2 h. Water (15 mL) was added and the aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated NaHCO3 and brine, then dried (MgSO4) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. Rf=0.75 (50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H). the mixture was stirred at −78° C. for 30 min was stirred for 2 h the aqueous phase was separated extracted with CH2Cl2 (3×15 mL) The combined organic extracts were washed with saturated NaHCO3 and brine dried (MgSO4) concentrated in vacuo

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

実験手順: According to the method of Example 26, from aldehyde 28 (640 mg, 3.1 mmol) and 1-bromopentadecane (5.0 g, 17.2 mmol), alcohol 90 was obtained as a colorless oil (690 mg, 53% yield).

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

実験手順: To a solution (30 mL) of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (3.0 g) in tetrahydrofuran was added 1.0 mol/L solution (28.8 mL) of allylmagnesium bromide in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate as a colorless oil. To a solution (10 mL) of the obtained benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate in tetrahydrofuran were added 2,6-lutidine (0.629 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.91 mL) and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield: 610 mg). cooling the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diethylalumninum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H). to warm to room temperature overnight the mixture was extracted with EtOAc (3×50 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to afford the crude product This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient)

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

実験手順: Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to a stirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry CH2Cl2 (12.6 mL) at −78° C. under N2 and the reaction was stirred for 15 min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in dry CH2Cl2 (12.6 mL) was added dropwise by cannula and the mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and was stirred for 2 h. Water (15 mL) was added and the aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated NaHCO3 and brine, then dried (MgSO4) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. Rf=0.75 (50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H). the mixture was stirred at −78° C. for 30 min was stirred for 2 h the aqueous phase was separated extracted with CH2Cl2 (3×15 mL) The combined organic extracts were washed with saturated NaHCO3 and brine dried (MgSO4) concentrated in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyltriphenylphosphonium bromide (16.92 g, 47.30 mmol) was taken up in toluene (350 mL). The heterogeneous solution was cooled to 0° C. then KHMDS 0.5M in toluene (90 mL, 45 mmol) was added. The reaction was stirred at 0° C. for 30 min, then cooled to −78° C. and (1-(S)-methyl-2-oxo-ethyl)-carbamic acid benzyl ester (6.11 g, 29.56 mmol) that was dissolved in toluene (45 mL) was added. The solution was warm to rt, stirred at it for 30 min, then quenched with sat NH4Cl(aq) (150 mL). The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over Na2SO4. Solids were removed by filtration and solvent removed under reduced pressure. (1-(S)-methyl-allyl)-carbamic acid benzyl ester (4.90 g, 81%) was isolated by silica gel chromatography as a colorless oil. cooled to −78° C. was added The solution was warm to rt stirred at it for 30 min quenched with sat NH4Cl(aq) (150 mL) The layers were separated the aqueous was washed with EtOAc dried over Na2SO4 Solids were removed by filtration and solvent removed under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H). to warm to room temperature overnight the mixture was extracted with EtOAc (3×50 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to afford the crude product This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient)

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

実験手順: Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to a stirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry CH2Cl2 (12.6 mL) at −78° C. under N2 and the reaction was stirred for 15 min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in dry CH2Cl2 (12.6 mL) was added dropwise by cannula and the mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and was stirred for 2 h. Water (15 mL) was added and the aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated NaHCO3 and brine, then dried (MgSO4) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. Rf=0.75 (50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H). the mixture was stirred at −78° C. for 30 min was stirred for 2 h the aqueous phase was separated extracted with CH2Cl2 (3×15 mL) The combined organic extracts were washed with saturated NaHCO3 and brine dried (MgSO4) concentrated in vacuo

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

実験手順: According to the method of Example 26, from aldehyde 28 (640 mg, 3.1 mmol) and 1-bromopentadecane (5.0 g, 17.2 mmol), alcohol 90 was obtained as a colorless oil (690 mg, 53% yield).