methyl 10-oxospiro[4.5]decane-9-carboxylate

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: In a flask containing methyl 6-oxospiro[4.5]decane-7-carboxylate, 60, (4.10 g, 19.50 mmol) in MeOH (35 mL) was added ammonium acetate (10.52 g, 136.50 mmol) and NaCNBH3 (1.47 g, 23.40 mmol). The mixture was stirred at room temperature for 24 hrs. GCMS showed conversion to product SM (Rt=12.3 min, E+=211), product (Rt=12.6 min, ES+=212 [major] and Rt=12.45 min, ES+=212 [minor]). The solvent was evaporated, HCl (1N) was added and the aqueous phase was extracted with EtOAc. The organic phase was neutralized with NaOH (6N) to pH ˜10. The aqueous phase was extracted three times with EtOAc and twice with dichloromethane, dried over Na2SO4 to yield 1.6 g of product. The solvent was evaporated HCl (1N) was added the aqueous phase was extracted with EtOAc The aqueous phase was extracted three times with EtOAc twice with dichloromethane, dried over Na2SO4

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

Procedure: In a flask containing methyl 6-oxospiro[4.5]decane-7-carboxylate, 60, (4.10 g, 19.50 mmol) in MeOH (35 mL) was added ammonium acetate (10.52 g, 136.50 mmol) and NaCNBH3 (1.47 g, 23.40 mmol). The mixture was stirred at room temperature for 24 hrs. GCMS showed conversion to product SM (Rt=12.3 min, E+=211), product (Rt=12.6 min, ES+=212 [major] and Rt=12.45 min, ES+=212 [minor]). The solvent was evaporated, HCl (1N) was added and the aqueous phase was extracted with EtOAc. The organic phase was neutralized with NaOH (6N) to pH ˜10. The aqueous phase was extracted three times with EtOAc and twice with dichloromethane, dried over Na2SO4 to yield 1.6 g of product. The solvent was evaporated HCl (1N) was added the aqueous phase was extracted with EtOAc The aqueous phase was extracted three times with EtOAc twice with dichloromethane, dried over Na2SO4

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask containing NaH (4.73 g, 118.20 mmol) in THF (30 mL) was added dimethylcarbonate (8.30 mL, 98.52 mmol). The mixture was heated at 80° C. To the mixture was added a solution of spiro[4.5]decan-10-one, 59, (6.00 g, 39.41 mmol) in THF dropwise (25 mL). The reaction was heated for 6 hrs at 80° C. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated and the crude residue was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The reaction was heated for 6 hrs at 80° C The solvent was evaporated the crude residue was diluted with water extracted with EtOAc The organic layer was washed with aqueous saturated NaHCO3 and brine dried over Na2SO4 filtered concentrated in vacuo

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 Example 10B (4.5 g, 21.4 mmol), guanidine hydrochloride (6.13 g, 64.2 mmol), and potassium carbonate (9.46 g, 68.5 mmol) in N,N-dimethylformamide (30 mL) was heated at 105-110° C. for 3 hours. The mixture was then filtered through a layer of diatomaceous earth, and the filter pad was washed with a small amount of N,N-dimethylformamide. Approximately two volumes of water were then added, and the pH of the resulting mixture was adjusted to pH 6-7 with acetic acid. The precipitate was collected, washed with water, and dried under vacuum to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.61 (m, 1H), 5.98-6.08 (m, 2H), 2.20 (t, 2H), 1.95-2.04 (m, 2H), 1.68-1.76 (m, 2H), 1.61-1.68 (m, 2H), 1.48-1.58 (m, 4H), 1.34-1.45 (m, 2H); MS (DCI+) m/z 220 (M+H)+. The mixture was then filtered through a layer of diatomaceous earth the filter pad was washed with a small amount of N,N-dimethylformamide Approximately two volumes of water were then added The precipitate was collected washed with water dried under vacuum

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

Procedure: A solution of Example 10B (4.5 g, 21.4 mmol), guanidine hydrochloride (6.13 g, 64.2 mmol), and potassium carbonate (9.46 g, 68.5 mmol) in N,N-dimethylformamide (30 mL) was heated at 105-110° C. for 3 hours. The mixture was then filtered through a layer of diatomaceous earth, and the filter pad was washed with a small amount of N,N-dimethylformamide. Approximately two volumes of water were then added, and the pH of the resulting mixture was adjusted to pH 6-7 with acetic acid. The precipitate was collected, washed with water, and dried under vacuum to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.61 (m, 1H), 5.98-6.08 (m, 2H), 2.20 (t, 2H), 1.95-2.04 (m, 2H), 1.68-1.76 (m, 2H), 1.61-1.68 (m, 2H), 1.48-1.58 (m, 4H), 1.34-1.45 (m, 2H); MS (DCI+) m/z 220 (M+H)+. The mixture was then filtered through a layer of diatomaceous earth the filter pad was washed with a small amount of N,N-dimethylformamide Approximately two volumes of water were then added The precipitate was collected washed with water dried under vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) was cooled to −78° C. and then was treated slowly with n-butyllithium (16.75 mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes; then this solution was transferred via cannula into a −78° C. solution of Example 10A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirred at this temperature for 30 minutes and then was treated with dimethyl carbonate (23.50 mL, 279 mmol). The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride and diluted with ether (100 mL); then the layers were separated. The aqueous layer was extracted with additional ether, then the organic layers were combined, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (100% hexane to 85:15 ethyl acetate/hexanes, eluant) to provide the title product. 1H NMR (300 MHz, CDCl3) δ 12.40-12.42 (m, 1H), 3.72-3.76 (m, 3H), 2.18-2.26 (m, 2H), 2.00-2.12 (m, 2H), 1.74-1.86 (m, 2H), 1.57-1.62 (m, 2H), 1.54-1.57 (m, 2H), 1.35-1.48 (m, 4H); MS (DCI+) m/z 211 (M+H)+. was transferred via cannula into a −78° C. The mixture was stirred at this temperature for 30 minutes The resulting mixture was warmed to ambient temperature stirred for 16 hours The mixture was quenched with saturated ammonium chloride diluted with ether (100 mL) then the layers were separated The aqueous layer was extracted with additional ether dried with magnesium sulfate concentrated under reduced pressure The residue was chromatographed on silica gel (100% hexane to 85:15 ethyl acetate/hexanes, eluant)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) was cooled to −78° C. and then was treated slowly with n-butyllithium (16.75 mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes; then this solution was transferred via cannula into a −78° C. solution of Example 10A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirred at this temperature for 30 minutes and then was treated with dimethyl carbonate (23.50 mL, 279 mmol). The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride and diluted with ether (100 mL); then the layers were separated. The aqueous layer was extracted with additional ether, then the organic layers were combined, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (100% hexane to 85:15 ethyl acetate/hexanes, eluant) to provide the title product. 1H NMR (300 MHz, CDCl3) δ 12.40-12.42 (m, 1H), 3.72-3.76 (m, 3H), 2.18-2.26 (m, 2H), 2.00-2.12 (m, 2H), 1.74-1.86 (m, 2H), 1.57-1.62 (m, 2H), 1.54-1.57 (m, 2H), 1.35-1.48 (m, 4H); MS (DCI+) m/z 211 (M+H)+. was transferred via cannula into a −78° C. The mixture was stirred at this temperature for 30 minutes The resulting mixture was warmed to ambient temperature stirred for 16 hours The mixture was quenched with saturated ammonium chloride diluted with ether (100 mL) then the layers were separated The aqueous layer was extracted with additional ether dried with magnesium sulfate concentrated under reduced pressure The residue was chromatographed on silica gel (100% hexane to 85:15 ethyl acetate/hexanes, eluant)