1-dimethoxyphosphoryl-3-methyloct-5-yn-2-one

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

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

Procedure: Under argon atmosphere, to a stirred solution of dimethyl methylphosphonate (7.91 ml, 0.074 mol) in anhydrous THF (150 ml) was added dropwise a solution of n-butyl lithium in hexane (1.71N, 43 ml, 0.074 mol) and the mixture was stirred for 30 min at -78° C. A solution of ethyl 2-methyl-4-heptynoate (5.0 g, 0.03 mol) in anhydrous THF (5 ml) was dropwise added into the mixture, and the resulting mixture was stirred for 30 min. at -78° C. The resulting mixture was allowed to room temperature and 30 min. later, to the solution were then added water (10 ml) and acetic acid (45 ml) under ice-cooling, and concentrated. The residue was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml) and with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give dimethyl 3-methyl-2-oxo-5-octynylphosphonate (6.55 g, 0.027 mol, 88%, B.p.: 118°-121° C./0.35 mmHg). The product was assigned the structure by the following data. the resulting mixture was stirred for 30 min. at -78° C The resulting mixture was allowed to room temperature and 30 min. concentrated The residue was diluted with water (20 ml) extracted with ethyl acetate (50 ml×2) The combined ethyl acetate layers were washed with water (20 ml) and with brine (20 ml) dried over anhydrous sodium sulfate concentrated The residue was distilled

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

Procedure: Methyl 4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate was prepared by the method described in Example 1, Steps A and B, except that (R)-methyl 4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b) was used instead of (R)-methyl 7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a) and (±)-dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate (15bb(i)/15bc(i)) was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.

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

Procedure: Analogously to Example 1(g), 14.2 g of the title compound was synthesized from 9.85 g of 3-methyl-2-oxooct-5-inylphosphonic acid dimethyl ester and 11 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].

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

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

Procedure: 646 ml of a 1.52% butyl lithium solution in hexane is dripped into a solution of 176 g of methane phosphonic acid dimethylester in 2 liters of tetra-hydrofuran at -70° C.; the mixture is stirred for 15 minutes and slowly a solution of 82.5 g of 2-methyl-hept-4-yne acid ethylester in 320 ml of tetrahydrofuran is added. This mixture is stirred for 4 h at -70° C., neutralized with acetic acid and vacuum evaporated. The residue is reacted with 200 ml of water, extracted three times with 600 ml of methylene chloride each time, the organic extract is shaken once with 100 ml of water, dried over magnesium sulfate and vacuum evaporated. The distillation of the residue in a 0.6 torr vacuum and at 120° C. yields 85 g of the title compound in the form of a colorless liquid. This mixture is stirred for 4 h at -70° C. evaporated The residue is reacted with 200 ml of water extracted three times with 600 ml of methylene chloride each time the organic extract is shaken once with 100 ml of water dried over magnesium sulfate and vacuum evaporated The distillation of the residue in a 0.6 torr vacuum

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

Procedure: Analogously to Example 1(g), 14.2 g of the title compound was synthesized from 9.85 g of 3-methyl-2-oxooct-5-inylphosphonic acid dimethyl ester and 11 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].

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

Procedure: Under argon atmosphere, to a stirred solution of dimethyl methylphosphonate (7.91 ml, 0.074 mol) in anhydrous THF (150 ml) was added dropwise a solution of n-butyl lithium in hexane (1.71N, 43 ml, 0.074 mol) and the mixture was stirred for 30 min at -78° C. A solution of ethyl 2-methyl-4-heptynoate (5.0 g, 0.03 mol) in anhydrous THF (5 ml) was dropwise added into the mixture, and the resulting mixture was stirred for 30 min. at -78° C. The resulting mixture was allowed to room temperature and 30 min. later, to the solution were then added water (10 ml) and acetic acid (45 ml) under ice-cooling, and concentrated. The residue was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml) and with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give dimethyl 3-methyl-2-oxo-5-octynylphosphonate (6.55 g, 0.027 mol, 88%, B.p.: 118°-121° C./0.35 mmHg). The product was assigned the structure by the following data. the resulting mixture was stirred for 30 min. at -78° C The resulting mixture was allowed to room temperature and 30 min. concentrated The residue was diluted with water (20 ml) extracted with ethyl acetate (50 ml×2) The combined ethyl acetate layers were washed with water (20 ml) and with brine (20 ml) dried over anhydrous sodium sulfate concentrated The residue was distilled

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

Procedure: Methyl 4-(2-((5R)-3,3-difluoro-5-((E)-3-hydroxy-4-methylnon-1-en-6-yn-1-yl)-2-oxopyrrolidin-1-yl)ethyl)benzoate was prepared by the method described in Example 1, Steps A and B, except that (R)-methyl 4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate (13b) was used instead of (R)-methyl 7-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl) heptanoate (13a) and (±)-dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate (15bb(i)/15bc(i)) was used instead of (±)-dimethyl(3-methyl-2-oxohept-5-yn-1-yl)phosphonate (15ab(i)/15ac(i)) in Step A.

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

Procedure: Analogously to Example 1(g), 14.2 g of the title compound was synthesized from 9.85 g of 3-methyl-2-oxooct-5-inylphosphonic acid dimethyl ester and 11 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].