8-oxabicyclo[3.2.1]octan-3-one

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

実験手順: To a solution of 71 mg of 8-oxabicyclo[3.2.1]octan-3-one (which was prepared by the method as described in Bull. Chem. Soc. Jpn., 1978, 51, 2745-2746) in tetrahydrofuran (2 ml), 32 mg of lithium aluminium hydride was added in nitrogen atmosphere at 0° C., and stirred for 30 minutes at the same temperature. To the solution 300 mg of sodium sulfate decahydrate was added, followed by 15 hours' stirring at room temperature. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 72 mg of the title compound. followed by 15 hours ' stirring at room temperature The insoluble matter was removed by filtration the filtrate was concentrated under reduced pressure

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

実験手順: To a solution of 71 mg of 8-oxabicyclo[3.2.1]octan-3-one (which was prepared by the method as described in Bull. Chem. Soc. Jpn., 1978, 51, 2745-2746) in tetrahydrofuran (2 ml), 32 mg of lithium aluminium hydride was added in nitrogen atmosphere at 0° C., and stirred for 30 minutes at the same temperature. To the solution 300 mg of sodium sulfate decahydrate was added, followed by 15 hours' stirring at room temperature. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 72 mg of the title compound. followed by 15 hours ' stirring at room temperature The insoluble matter was removed by filtration the filtrate was concentrated under reduced pressure

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

実験手順: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.

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

実験手順: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.

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

実験手順: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3] cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999, 64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsatured ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

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

実験手順: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3] cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999, 64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsatured ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

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

実験手順: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.

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

実験手順: A solution of sodium bis(trimethylsilyl)amide 1M in THF (24.48 ml, 24.48 mmol) was added drop wise to a suspension of (methoxymethyl)triphenylphosphonium chloride (8.39 g, 24.48 mmol) in THF (98 ml) at −40° C. Stirring was continued for 0.5 h at −40° C. and then the solution of 8-oxa-bicyclo[3.2.1]octan-3-one [CAS #77745-32-5] (1.93 g, 15.3 mmol) in THF (20 ml) was added at −40° C. The suspension was allowed to warm to RT and stirring was continued for 6 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluting with a gradient of heptane-EtOAc 97:3 to 0:100) yielding the title compound as a slightly yellow oil (1.71 g, 11.09 mmol, 72%): 1H-NMR (400 MHz, CDCl3): δ 1.58-2.43 (m, 8H), 3.54 (s, 3H), 4.41 (m, 2H), 5.85 (s, 1H) stirring was continued for 6 h The reaction mixture was quenched with a saturated solution of NH4Cl extracted with EtOAc (2×) The combined organic phases were washed with brine dried over Na2SO4 filtered evaporated to dryness The crude product was purified by silica gel column chromatography ( eluting with a gradient of heptane-EtOAc 97:3 to 0:100)

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

実験手順: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3]cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999,64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsaturated ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

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

実験手順: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3]cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999,64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsaturated ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

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

実験手順: To a solution of 71 mg of 8-oxabicyclo[3.2.1]octan-3-one (which was prepared by the method as described in Bull. Chem. Soc. Jpn., 1978, 51, 2745-2746) in tetrahydrofuran (2 ml), 32 mg of lithium aluminium hydride was added in nitrogen atmosphere at 0° C., and stirred for 30 minutes at the same temperature. To the solution 300 mg of sodium sulfate decahydrate was added, followed by 15 hours' stirring at room temperature. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 72 mg of the title compound. followed by 15 hours ' stirring at room temperature The insoluble matter was removed by filtration the filtrate was concentrated under reduced pressure

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

実験手順: The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.