1-dimethoxyphosphorylheptan-2-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:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound. After 1 h at rt was recooled to 0° C. to warm to rt After 17 h at rt the reaction was quenched with acetic acid (50% aqueous, 20 mL) extracted with EtOAc (3×20 mL) The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient)

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

Procedure: Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound. After 50 min at rt was recooled to 0° C. to warm to rt After 18 h at rt the reaction was quenched with acetic acid and water (1:1, 15 mL) extracted with EtOAc (3×40 mL) The combined organic phase was washed with brine (50 mL) dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient)

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

Procedure: Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester. After 1 h at rt was recooled to 0° C. to warm to rt After 18.5 h at rt the reaction was quenched with aqueous acetic acid (50%, 5 mL) extracted with EtOAc (3×10 mL) The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient)

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

Procedure: Sodium hydride (60% dispersion in oil, 7.2 mg, 0.18 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (47 mg, 0.19 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with Example 29, step 5, ˜0.20 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 59 mg (90%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester. After 1 h at rt was recooled to 0° C. to warm to rt After 17 h at rt the reaction was quenched with aqueous acetic acid (50%, 5 mL) extracted with EtOAc (3×10 mL) The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient)

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

Procedure: Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound. After 1 h at rt was recooled to 0° C. to warm to rt After 17 h at rt the reaction was quenched with acetic acid (50% aqueous, 20 mL) extracted with EtOAc (3×20 mL) The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient)

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

Procedure: Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound. After 50 min at rt was recooled to 0° C. to warm to rt After 18 h at rt the reaction was quenched with acetic acid and water (1:1, 15 mL) extracted with EtOAc (3×40 mL) The combined organic phase was washed with brine (50 mL) dried (Na2SO4) filtered concentrated in vacuo Purification of the residue by flash column chromatography on silica gel (10% →50% EtOAc/CH2Cl2, gradient)

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

Procedure: To a suspension of 0.45 g of sodium hydride in 5 ml of anhydrous 1,2-dimethoxy-ethane a solution of 4.12 g of 2-oxoheptylphosphonic acid dimethyl ester in 20 ml of 1,2-dimethoxy-ethane was added under stirring at room temperature. The reaction mixture was stirred for an hour, then a solution of 1 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, R1 = CH3) prepared according to point (e) of Example 2, in 10 ml of 1,2-dimethoxy-ethane was added dropwise, and stirring was continued for 5 hours. After adding dropwise 30 ml of water under ice-cooling to the reaction mixture, it was extracted with 3 × 20 ml of diethyl ether. The extract was dried on over sodium sulphate and evaporated in vacuo. The evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. The yield was 0.81 g of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = CH3) of chromatographic purity. was added The reaction mixture was stirred for an hour was added dropwise stirring cooling to the reaction mixture, it was extracted with 3 × 20 ml of diethyl ether The extract was dried on over sodium sulphate evaporated in vacuo The evaporation residue was purified by preparative thin layer chromatography a mixture of 40 % ethyl acetate and 60 % n-heptane

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

Procedure: A solution of 100 g. of dimethyl methylphosphonate in 670 ml. of anhydrous tetrahydrofuran is cooled to -78°C. under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0.1M solution of n-butyllithium in tetrahydrofuran, maintaining the temperature at -70°C. When the addition is complete the reaction mixture is maintained under the same conditions for 10 additional minutes, a solution of 58 ml. of methyl caproate dissolved in 187 ml. of tetrahydrofuran is then carefully added, maintaining the temperature at -78°C. The reaction mixture is stirred at -78°C. for 2 hours followed by stirring for 4 hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in ether-water (1:1, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distillation, thus obtaining the pure dimethyl 2-oxoheptylphosphonate. To the cold solution are added dropwise When the addition is maintained under the same conditions for 10 additional minutes The reaction mixture is stirred at -78°C. for 2 hours by stirring for 4 hours at room temperature the solvent is evaporated under high vacuo The residue is dissolved in ether-water (1:1, 950 ml each), the ethereal phase is separated washed with water dried over magnesium sulfate The ether is evaporated the residue is purified by vacuum distillation

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

Procedure: To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801 mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate (32.5 mg, 0.775 mmol) was added and the mixture was stirred for two hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12 ml) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane =3:7), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil. the mixed solution was stirred for one hour at room temperature extracted twice with t-butyl methyl ether sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride dried with anhydrous magnesium sulfate After concentration under reduced pressure the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane =3:7)