1-(2,3-dihydro-1H-inden-2-yl)-2-dimethoxyphosphorylethanone

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 20.4 g (164 mmoles) dimethyl methylphosphonate (Aldrich) in 200 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) methyl indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indany)ethylphsphonate (2i). the reaction temperature less than -70° (20 minutes) After 1.0 hour at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 75 ml portions of methylene chloride (4x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: A solution of 20.4 g (164 mmoles) dimethyl methylphosphonate (Aldrich) in 200 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) methyl indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indany)ethylphsphonate (2i). the reaction temperature less than -70° (20 minutes) After 1.0 hour at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 75 ml portions of methylene chloride (4x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

Procedure: To a stirring mixture consisting of lithium chloride (3.75 g, 88.5 mmol) and triethylamine (4.86 mL) in THF (350 mL) cooled to 0° C. and stirred for 5 minutes at that temperature was added a solution consisting of dimethyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoethylphosphonate (8.61 g) in THF (100 mL). The reaction mixture was stirred for 5 minutes and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-formyl-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step G, 10.31 g) in THF was added slowly. The reaction mixture was stirred as it was allowed to warm to room temperature overnight. The reaction mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (13.4 g, 94%). was added a solution The reaction mixture was stirred for 5 minutes was added slowly The reaction mixture was stirred as it to warm to room temperature overnight extracted with DCM the organic layers were washed twice with brine After drying over sodium sulfate, filtration, and solvent removal under reduced pressure the crude product was purified on silica gel Elution with hexanes-ethyl acetate (9:1)

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

Procedure: To a stirring mixture consisting of lithium chloride (3.75 g, 88.5 mmol) and triethylamine (4.86 mL) in THF (350 mL) cooled to 0° C. and stirred for 5 minutes at that temperature was added a solution consisting of dimethyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoethylphosphonate (8.61 g) in THF (100 mL). The reaction mixture was stirred for 5 minutes and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-formyl-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step G, 10.31 g) in THF was added slowly. The reaction mixture was stirred as it was allowed to warm to room temperature overnight. The reaction mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (13.4 g, 94%). was added a solution The reaction mixture was stirred for 5 minutes was added slowly The reaction mixture was stirred as it to warm to room temperature overnight extracted with DCM the organic layers were washed twice with brine After drying over sodium sulfate, filtration, and solvent removal under reduced pressure the crude product was purified on silica gel Elution with hexanes-ethyl acetate (9:1)

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

Procedure: A solution of 20.4 g (164 mmoles) dimethyl methylphosphonate (Aldrich) in 200 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) methyl indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indany)ethylphsphonate (2i). the reaction temperature less than -70° (20 minutes) After 1.0 hour at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 75 ml portions of methylene chloride (4x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled

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

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

Procedure: To a stirring mixture consisting of lithium chloride (3.75 g, 88.5 mmol) and triethylamine (4.86 mL) in THF (350 mL) cooled to 0° C. and stirred for 5 minutes at that temperature was added a solution consisting of dimethyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoethylphosphonate (8.61 g) in THF (100 mL). The reaction mixture was stirred for 5 minutes and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-formyl-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step G, 10.31 g) in THF was added slowly. The reaction mixture was stirred as it was allowed to warm to room temperature overnight. The reaction mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (13.4 g, 94%). was added a solution The reaction mixture was stirred for 5 minutes was added slowly The reaction mixture was stirred as it to warm to room temperature overnight extracted with DCM the organic layers were washed twice with brine After drying over sodium sulfate, filtration, and solvent removal under reduced pressure the crude product was purified on silica gel Elution with hexanes-ethyl acetate (9:1)

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

Procedure: A solution of 20.4 g (164 mmoles) dimethyl methylphosphonate (Aldrich) in 200 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) methyl indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indany)ethylphsphonate (2i). the reaction temperature less than -70° (20 minutes) After 1.0 hour at -78° the reaction mixture was allowed rotary evaporated to a white gel the aqueous phase extracted with 75 ml portions of methylene chloride (4x) dried (MgSO4) concentrated (water aspirator) to a crude residue distilled