methyl 3-oxo-4-phenylbutanoate

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 70 ml of methylene chloride was dissolved 36.03 g (0.25 mol) of Meldrum's acid. Pyridine (38.17 g, 0.48 mol) was used as a base. To the solution was added dropwise 42.52 g (0.275 mol) of phenylacetyl chloride in an ice bath while stirring. After the reaction, ice-water and diluted hydrochloric acid were added to wash. Methylene chloride was evaporated, methanol was added, followed by refluxing, and the solvent was evaporated to give 44 g (91.7%) of methyl 4-phenyl-3-oxobutyrate. were added to wash Methylene chloride was evaporated methanol was added by refluxing the solvent was evaporated

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

Procedure: DBU (1.33 ml; 8.90 mmol; 1.10 eq.) was dissolved in DMF (17 ml) and put under nitrogen atmosphere. 3-Oxo-4-phenyl-butyric acid methyl ester (Chemcollect, 1.711 g; 8.90 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.11 g; 8.10 mmol; 1 eq.) in DMF (2 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (30 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×40 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 312.1 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×40 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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

Procedure: Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCl--NH3M/Z: 395 (M+NH4)+. stirring continued overnight The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) the aqueous layer was extracted with diethyl ether The combined organic layers were washed with 1N aqueous hydrochloric acid and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1)

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

Procedure: DBU (1.33 ml; 8.90 mmol; 1.10 eq.) was dissolved in DMF (17 ml) and put under nitrogen atmosphere. 3-Oxo-4-phenyl-butyric acid methyl ester (Chemcollect, 1.711 g; 8.90 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.11 g; 8.10 mmol; 1 eq.) in DMF (2 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (30 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×40 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 312.1 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×40 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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: Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCl--NH3M/Z: 395 (M+NH4)+. stirring continued overnight The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) the aqueous layer was extracted with diethyl ether The combined organic layers were washed with 1N aqueous hydrochloric acid and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1)

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

Procedure: Ru(OAc)2((R)-dm-binap) (0.248 g, 0.260 mmol), methyl 3-oxo-4-phenylbutanoate (10.00 g, 52.0 mmol), ammonium acetate (4.01 g, 52.0 mmol) and methanol (50 mL) were placed in a 200 mL stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature and further stirred under a hydrogen pressure of 3 MPa at 80° C. for 14 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R)-3-amino-4-phenylbutanoate as a crude material (13.01 g). The enantiomeric excess of methyl (3R)-3-amino-4-phenylbutanoate in the crude product was determined to be 94.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)-4-phenylbutanoate. The reaction mixture was cooled down to room temperature further stirred under a hydrogen pressure of 3 MPa at 80° C. for 14 hours After completion of the reaction the solvent was removed by evaporation

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

Procedure: Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCI-NH3M/Z: 395 (M+NH4)+. stirring continued overnight The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) the aqueous layer was extracted with diethyl ether The combined organic layers were washed with 1N aqueous hydrochloric acid and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1)

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

Procedure: In 70 ml of methylene chloride was dissolved 36.03 g (0.25 mol) of Meldrum's acid. Pyridine (38.17 g, 0.48 mol) was used as a base. To the solution was added dropwise 42.52 g (0.275 mol) of phenylacetyl chloride in an ice bath while stirring. After the reaction, ice-water and diluted hydrochloric acid were added to wash. Methylene chloride was evaporated, methanol was added, followed by refluxing, and the solvent was evaporated to give 44 g (91.7%) of methyl 4-phenyl-3-oxobutyrate. were added to wash Methylene chloride was evaporated methanol was added by refluxing the solvent was evaporated