9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-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:0.00; pressure:0.00; stir:

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

Procedure: A solution of C-1 (18 g, 81 mmol) in 40 mL of water and 14 mL acetic acid was heated to 120° C. for 2 h, cooled to room temperature and diluted with 400 mL of pH 4 buffer (160 mL 0.1 M citric acid and 240 mL 0.1 M K2HPO4). After cooling to 0° C., a preformed solution of 9.54 g (66.4 mmol) benzylamine hydrochloride, 100 mL water, and 31 mL concentrated HCl was added dropwise over 10 minutes, keeping the internal temperature below 5° C. Acetonedicarboxylic acid (23.3 g, 160 mmol) was then added in four equal portions, five minutes apart. The pH of the solution was increased to 4 by adding K2HPO4, and the reaction was allowed to warm to room temperature and stir overnight. Solid citric acid was added to return the pH to 4, and the reaction was stirred at room temperature 48 h more, at which time it was cooled to 0° C. and acidified to pH 2 with HCl, and extracted twice with Et2O. The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH, and extracted three times with CH2Cl2. The combined organic extracts were washed with 0.1 M citric acid, then with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid. Data for C-2: 1H NMR (CDCl3, 500 MHz) δ 7.45-7.2 (m, 5H), 3.9 (s, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.3 (m, 2H) ppm. After cooling to 0° C. the internal temperature below 5° C The pH of the solution was increased to 4 to warm to room temperature the reaction was stirred at room temperature 48 h more at which time it was cooled to 0° C. extracted twice with Et2O The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH extracted three times with CH2Cl2 The combined organic extracts were washed with 0.1 M citric acid with saturated NaHCO3, brine, dried over Na2SO4 concentrated The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid

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

Procedure: A solution of C-1 (18 g, 81 mmol) in 40 mL of water and 14 mL acetic acid was heated to 120° C. for 2 h, cooled to room temperature and diluted with 400 mL of pH 4 buffer (160 mL 0.1 M citric acid and 240 mL 0.1 M K2HPO4). After cooling to 0° C., a preformed solution of 9.54 g (66.4 mmol) benzylamine hydrochloride, 100 mL water, and 31 mL concentrated HCl was added dropwise over 10 minutes, keeping the internal temperature below 5° C. Acetonedicarboxylic acid (23.3 g, 160 mmol) was then added in four equal portions, five minutes apart. The pH of the solution was increased to 4 by adding K2HPO4, and the reaction was allowed to warm to room temperature and stir overnight. Solid citric acid was added to return the pH to 4, and the reaction was stirred at room temperature 48 h more, at which time it was cooled to 0° C. and acidified to pH 2 with HCl, and extracted twice with Et2O. The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH, and extracted three times with CH2Cl2. The combined organic extracts were washed with 0.1 M citric acid, then with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid. Data for C-2: 1H NMR (CDCl3, 500 MHz) δ 7.45-7.2 (m, 5H), 3.9 (s, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.3 (m, 2H) ppm. After cooling to 0° C. the internal temperature below 5° C The pH of the solution was increased to 4 to warm to room temperature the reaction was stirred at room temperature 48 h more at which time it was cooled to 0° C. extracted twice with Et2O The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH extracted three times with CH2Cl2 The combined organic extracts were washed with 0.1 M citric acid with saturated NaHCO3, brine, dried over Na2SO4 concentrated The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid

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

Procedure: To a stirring mixture of 9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (1.1 g, 4.76 mmol) in EtOAc/HOAc (6 mL, 1:1, v/v) was added palladium on carbon (250 mg). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 2 days. The suspension was filtered through Celite and the filtrate was concentrated under vacuum to give a quantitative yield of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a yellow oil. This crude mixture was converted to the corresponding hydrochloric salt by the addition of HCl (3 mL, 1N aqueous HCl). The mixture was concentrated under reduced pressure and this process was repeated twice. Retention time (min)=0.231, Method [1], MS (ESI) 142.2 (M+H). The suspension was filtered through Celite the filtrate was concentrated under vacuum

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

Procedure: To a stirring mixture of 2,5-dihydrofuran (3.5 g, 49.9 mmol) in CH2Cl2/MeOH (10:1) at −78° C. was added NaHCO3 (3.5 g). An excess of ozone was bubbled into this mixture for 45 min. The resulting mixture was then purged with a stream of N2 for 10 min at −78° C. To this reaction mixture was added PPh3 (6.6 g, 25 mmol). The reaction mixture was slowly warmed up to room temperature over 48 h. The reaction mixture was filtered to remove solid NaHCO3 and then concentrated to half of its original volume under reduced pressure. To this crude mixture was added water (10 mL). Acetone-1,3-dicarboxylic acid (3.65 g, 25.0 mmol) and sodium acetate (2.2 g, 26.25 mmol) were added to the crude aldehyde in H2O. Benzylamine (2.68 g, 25.0 mmol) was dissolved in aqueous HCl (3 N, 16 mL) and was subsequently added to the stirring solution of the dialdehyde and the dicarboxylic acid over a 15 min period. The reaction mixture was stirred for 3 days at room temperature after which the pH was adjusted to 8 by the addition of potassium carbonate. The resulting solution was extracted with EtOAc (4×50 mL), the organic extracts dried (MgSO4), filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to give 3.3 g of 9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a yellowish solid. Retention time (min)=0.352 and 0.243, Method [1], MS (ESI) 232.2 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.49-7.27 (m, 5H), 3.91 (s, 2H), 3.84 (d, J=10.44 Hz, 2H), 3.71 (d, J=10.44 Hz, 2H), 3.15 (d, J=5.5 Hz, 2H), 2.74 (dd, J=15.94, 6.05 Hz, 2H), 2.32 (d, J=15.4 Hz, 2H). An excess of ozone was bubbled into this mixture for 45 min The resulting mixture was then purged with a stream of N2 for 10 min at −78° C The reaction mixture was filtered to remove solid NaHCO3 concentrated to half of its original volume under reduced pressure To this crude mixture was added water (10 mL) The resulting solution was extracted with EtOAc (4×50 mL) the organic extracts dried (MgSO4) filtered concentrated under vacuum The resulting residue was purified by silica gel chromatography

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

Procedure: To a stirring mixture of 2,5-dihydrofuran (3.5 g, 49.9 mmol) in CH2Cl2/MeOH (10:1) at −78° C. was added NaHCO3 (3.5 g). An excess of ozone was bubbled into this mixture for 45 min. The resulting mixture was then purged with a stream of N2 for 10 min at −78° C. To this reaction mixture was added PPh3 (6.6 g, 25 mmol). The reaction mixture was slowly warmed up to room temperature over 48 h. The reaction mixture was filtered to remove solid NaHCO3 and then concentrated to half of its original volume under reduced pressure. To this crude mixture was added water (10 mL). Acetone-1,3-dicarboxylic acid (3.65 g, 25.0 mmol) and sodium acetate (2.2 g, 26.25 mmol) were added to the crude aldehyde in H2O. Benzylamine (2.68 g, 25.0 mmol) was dissolved in aqueous HCl (3 N, 16 mL) and was subsequently added to the stirring solution of the dialdehyde and the dicarboxylic acid over a 15 min period. The reaction mixture was stirred for 3 days at room temperature after which the pH was adjusted to 8 by the addition of potassium carbonate. The resulting solution was extracted with EtOAc (4×50 mL), the organic extracts dried (MgSO4), filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to give 3.3 g of 9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a yellowish solid. Retention time (min)=0.352 and 0.243, Method [1], MS (ESI) 232.2 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.49-7.27 (m, 5H), 3.91 (s, 2H), 3.84 (d, J=10.44 Hz, 2H), 3.71 (d, J=10.44 Hz, 2H), 3.15 (d, J=5.5 Hz, 2H), 2.74 (dd, J=15.94, 6.05 Hz, 2H), 2.32 (d, J=15.4 Hz, 2H). An excess of ozone was bubbled into this mixture for 45 min The resulting mixture was then purged with a stream of N2 for 10 min at −78° C The reaction mixture was filtered to remove solid NaHCO3 concentrated to half of its original volume under reduced pressure To this crude mixture was added water (10 mL) The resulting solution was extracted with EtOAc (4×50 mL) the organic extracts dried (MgSO4) filtered concentrated under vacuum The resulting residue was purified by silica gel chromatography

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

Procedure: The mixture of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.5 g, 2.2 mmol), 3-methoxy-3-oxo-propanoic acid (0.44 g, 3.3 mmol), ammonium acetate (0.33 g, 4.4 mmol) in ethanol (5 mL) was refluxed for 3 hours. After removal of solvent, the residue was purified by flash silica gel chromatography to afford ethyl 2-(7-amino-9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 146c. Yield: 5%. MS: calc'd (MH+) 319, measured (MH+) 319. was refluxed for 3 hours After removal of solvent the residue was purified by flash silica gel chromatography

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

Procedure: To a stirred solution of potassium hydroxide (730 mg, 13 mmol) in dry MeOH (50 mL) at 0° C. under nitrogen was added a solution of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (CAS: 81514-40-1, 1 g, 4.3 mmol) in dry MeOH (20 mL) dropwise over 10 min. The reaction mixture was stirred at 0° C. for another 10 min, and PhI(OAc)2 (1.83 g, 5.5 mmol) was added portion wise over 10 min. The reaction mixture was warmed to room temperature, with stirring, overnight. After the starting material disappeared as monitored by TLC, MeOH was removed under reduced pressure and the residue was cooled to 0° C. and 10 ml of 6N HCl was added carefully. The mixture was stirred at room temperature for 2 hours, and then ethyl acetate and water (50 mL, 1:1) were added. The aqueous layer was separated and was added into K2CO3 till the solution was saturated. The mixture was extracted with ethyl acetate (20 mL) three times, dried and concentrated, the residue was purified by silica gel (EA/PE=1:2) to give 9-benzyl-6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 106b as colorless oil, 270 mg, yield: 25%. MS: calc'd (MH+) 248, measured (MH+) 248. The reaction mixture was warmed to room temperature with stirring, overnight was removed under reduced pressure the residue was cooled to 0° C. 10 ml of 6N HCl was added carefully The mixture was stirred at room temperature for 2 hours ethyl acetate and water (50 mL, 1:1) were added The aqueous layer was separated was added into K2CO3 till the solution The mixture was extracted with ethyl acetate (20 mL) three times dried concentrated the residue was purified by silica gel (EA/PE=1:2)

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

Procedure: To a stirring mixture of 9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (1.1 g, 4.76 mmol) in EtOAc/HOAc (6 mL, 1:1, v/v) was added palladium on carbon (250 mg). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 2 days. The suspension was filtered through Celite and the filtrate was concentrated under vacuum to give a quantitative yield of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a yellow oil. This crude mixture was converted to the corresponding hydrochloric salt by the addition of HCl (3 mL, 1N aqueous HCl). The mixture was concentrated under reduced pressure and this process was repeated twice. Retention time (min)=0.231, Method [1], MS(ESI) 142.2 (M+H). The suspension was filtered through Celite the filtrate was concentrated under vacuum