benzyl 2-dimethoxyphosphorylacetate

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: Potassium tertiary butoxide (2.1 g., 0.0188 mol.) was suspended in dry dimethylformamide (50 mls.). To the suspension was added benzyl dimethylphosphonoethanoate (4.6 g., 0.0187 mol.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. N-(4-Methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-Methylamide (3.0 g., 0.00913 mol) was added portionwise to the reaction mixture over a period of 10 minutes to yield a red solution. The red solution was stirred at room temperature for 4 hours, and then poured into water (500 mls.). The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) and the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.). The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane to yield E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide as a light brown crystalline solid. (m.p. 167°-9° C. Found: C, 68.3; H, 7.1; N, 6.3 %. C25H30N2O5 requires C, 68.5; H, 6.9; N, 6.4%). to yield a red solution The red solution was stirred at room temperature for 4 hours The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) dried over anhydrous magnesium sulfate The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.) The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzyl dimethyl phosphonoacetate (1.94 g, 7.5 mmol) in THF (15 mL) cooled to −78° C. in a dry ice/isopropanol bath was added LHMDS (9.0 mL of a 1 M solution in THF, 9.0 mmol). The reaction was allowed to warm to 10° C. over 30 min, then recooled to −78° C. NBS (1.6 g, 9.0 mmol) was added as a solution in THF (20 mL), and the reaction was allowed to warm to room temperature over 18 h. Saturated ammonium chloride was added to quench any remaining base, and the reaction was concentrated to dryness. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained as a yellow oil and was subsequently purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes to afford the desired product, bromo-(dimethoxy-phosphoryl)-acetic acid benzyl ester, as a pale yellow oil, 1.61 g (63%). 1H NMR (300 MHz, CDCl3): δ 7.36 (m, 5H), 5.24 (s, 2H), 4.44 (d, J=14.1 Hz, 1H), 3.83 (q, J=4.8 Hz, 6H). LC-MS m/z=417 [C11H15O5P+H]+. recooled to −78° C to warm to room temperature over 18 h to quench any remaining base the reaction was concentrated to dryness Ethyl acetate was added the organic layer was washed with water and brine dried over sodium sulfate The crude product was obtained as a yellow oil was subsequently purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes

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

Procedure: To a suspension of hexane-washed sodium hydride (0.42 g of 60% suspension in mineral oil, 10.52 mmol) in 120 mL of THF at 0° C. was added benzyl 2-(dimethoxyphosphoryl)acetate (2.72 g, 10.52 mmol) dropwise in 10 mL of THF. The resulting mixture was stirred 5 min at 0° C. and then was allowed to warm to ambient temperature and stirred for 20 min. To this solution was added methyl 2-formyl-6-(trifluoromethyl)benzoate (2.22 g, 9.56 mmol) dropwise in 10 mL of THF. The resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1N HCl (100 mL) and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.4 g (97%) of the title compound which was sufficiently pure to be used without purification. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.9 Hz), 7.72-7.67 (m, 2H), 7.55 (t, 1H, J=7.9 Hz), 7.38-7.30 (m, 5H), 6.47 (d, 1H, J=15.8 Hz), 5.23 (s, 2H), 3.94 (s, 3H). LRMS (ESI): 387.17 (M+H+Na)+. to warm to ambient temperature stirred for 20 min The resulting solution was stirred at ambient temperature for 1 h The reaction mixture was quenched with 1N HCl (100 mL) extracted with ethyl acetate The organics were washed with sat'd aq NaHCO3 and brine dried (MgSO4) filtered through a pad of silica gel concentrated in vacuo

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

Procedure: A mixture of cyclobutaneone-3-carboxylic acid (5 g, 43.82 mmol), benzyl-2-(dimethoxyphosphoryl)acetate (13.58 g, 52.59 mmol), LiOH (4.20 g, 23.95 mmol) and 3 Å activated molecular sieves (25 g, powder form) in THF (250 ml) was heated to reflux under nitrogen for 4 h. The reaction was allowed to cool to RT and EtOAc (100 ml) followed by HCl (1N, 100 ml) were added. This mixture was filtered through celite. The phases were separated and the aqueous layer was extracted with EtOAc (4×50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield a colorless oil. Dry flash chromatography over SiO2, eluting with Hept:EtOAc from 7:3 to 1:1 gave the desired product as a colorless oil (5.2 g, 39%); MS (ESI+) for C14H14O4 m/z 269.05 [M+Na]+; MS (ESI−) for C14H14O4 m/z 245.15 [M−H]−; HPLC purity 81% (ret. time, 1.85 min); 1H NMR (250 MHz, CHLOROFORM-d) δH ppm 2.95-3.62 (5 H, m), 4.96-5.31 (2 H, m), 5.75 (1 H, t, J=2.21 Hz), 7.27-7.45 (5 H, m). was heated to reflux under nitrogen for 4 h were added This mixture was filtered through celite The phases were separated the aqueous layer was extracted with EtOAc (4×50 ml) The combined organic layers were dried over Na2SO4 filtered concentrated to yield a colorless oil Dry flash chromatography over SiO2 eluting with Hept

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzyl dimethyl phosphonoacetate (1.94 g, 7.5 mmol) in THF (15 mL) cooled to −78° C. in a dry ice/isopropanol bath was added LHMDS (9.0 mL of a 1 M solution in THF, 9.0 mmol). The reaction was allowed to warm to 10° C. over 30 min, then recooled to 78° C. NBS (1.6 g, 9.0 mmol) was added as a solution in THF (20 mL), and the reaction was allowed to warm to room temperature over 18 h. Saturated ammonium chloride was added to quench any remaining base, and the reaction was concentrated to dryness. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained as a yellow oil and was subsequently purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes to afford the desired product, bromo-(dimethoxy-phosphoryl)-acetic acid benzyl ester, as a pale yellow oil, 1.61 g (63%). 1H NMR (300 MHz, CDCl3): δ 7.36 (m, 5H), 5.24 (s, 2H), 4.44 (d, J=14.1 Hz, 1H), 3.83 (q, J=4.8 Hz, 6H). LC-MS m/z=417 [C11H15O5P+H]+. recooled to 78° C to warm to room temperature over 18 h to quench any remaining base the reaction was concentrated to dryness Ethyl acetate was added the organic layer was washed with water and brine dried over sodium sulfate The crude product was obtained as a yellow oil was subsequently purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes

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

Procedure: To a solution of dimethyl(benzyloxycarbonyl)methylphosphonate (2.20 g) in tetrahydrofuran (32.0 mL) was added 55% sodium hydride (406 mg) under ice-cooling, followed by stirring at room temperature for 30 minutes. Subsequently, tert-butyl 3-formylbenzoate (1.60 g) was added thereto, followed by stirring at room temperature for 16 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxopropa-1-en-1-yl]benzoate (1.60 g). cooling by stirring at room temperature for 16 hours the organic layer was extracted The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane-ethyl acetate)

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

Procedure: Potassium tertiary butoxide (2.1 g., 0.0188 mol.) was suspended in dry dimethylformamide (50 mls.). To the suspension was added benzyl dimethylphosphonoethanoate (4.6 g., 0.0187 mol.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. N-(4-Methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-Methylamide (3.0 g., 0.00913 mol) was added portionwise to the reaction mixture over a period of 10 minutes to yield a red solution. The red solution was stirred at room temperature for 4 hours, and then poured into water (500 mls.). The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) and the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.). The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane to yield E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide as a light brown crystalline solid. (m.p. 167°-9° C. Found: C, 68.3; H, 7.1; N, 6.3 %. C25H30N2O5 requires C, 68.5; H, 6.9; N, 6.4%). to yield a red solution The red solution was stirred at room temperature for 4 hours The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) dried over anhydrous magnesium sulfate The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.) The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane