methyl 2-oxo-3-phenylpropanoate

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

Procedure: Following the procedures outlined in Examples 2-6, and replacing L-cyclohexylalanine methyl ester with L-phenylalanine methyl ester in Example 2 and methyl 3-methyl-2-oxobutyrate with methyl 3-phenyl-2-oxopropionate in Example 4 provides the title compound.

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

Procedure: Following the procedures outlined in Examples 2-6, and replacing L-cyclohexylalanine methyl ester with L-phenylalanine methyl ester in Example 2 and methyl 3-methyl-2-oxobutyrate with methyl 3-phenyl-2-oxopropionate in Example 4 provides the title compound.

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

Procedure: In the same manner as in Example 1, methyl 3-phenylpyruvate (35.62 g; 0.2 mol) is dissolved in a mixture of acetonitrile (240 g) and trichlorotrifluoroethane (1.6 L) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the residue is rectified to give methyl 3-phenyl-3-fluoropyruvate (11.8 g). The silyl enol ether obtained by the treatment of the above product with bis-(trimethylsilyl)acetamide (BSA) in methylene chloride shows boiling point 93°-95° C./1 mmHg and 19F NMR (CDCl3), δ (int. C6F6)+31.5 (s).

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

Procedure: Methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-phenylethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group affords 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group

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

Procedure: Methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-phenylethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group affords 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group

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

Procedure: To a solution of methyl 2-oxo-3-phenylpropionate (2.0 g) and 3-benzyloxypropanal (1.84 g) in N,N-dimethylformamide (40 ml) was dropwise added 1,8-diazabicyclo[5.4.0]undecen-7 (1.76 ml) at 0° C. with stirring. The mixture was stirred at the same temperature for 2 hours PG,28 and the solvent was evaporated. The residue was added to diluted hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated in vacuo. The residue was recrystallized from diisopropyl ether to give 3-hydroxy-4-phenyl-5(2-benzyloxyethyl)-2(5H)furanone (2.39 g). at 0° C. The mixture was stirred at the same temperature for 2 hours PG,28 the solvent was evaporated The residue was added to diluted hydrochloric acid extracted with diethyl ether The extract was washed with water dried evaporated in vacuo The residue was recrystallized from diisopropyl ether

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

Procedure: 2-Oxo-3-phenylpropanoic acid (20 g), DMF (100 ml) and DBU (18.2 ml) were combined at 0° C. under N2 atmosphere, and the mixture was stirred at 0° C. for an hour. Then iodomethane (15.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 3 hours, and poured into 1N—HCl. The mixture was extracted with AcOEt (twice). The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/AcOEt (30:1) as an eluent, and triturated with IPE/n-Hexane to give methyl 2-oxo-3-phenylpropanoate (11.2 g) as a pale yellow wax. were combined at 0° C. under N2 atmosphere The reaction mixture was stirred at r.t. for 3 hours The mixture was extracted with AcOEt (twice) The combined organic layer was washed with brine dried over anhydrous MgSO4 concentrated in vacuo The residue was purified by flash column chromatography over silica gel with CHCl3/AcOEt (30:1) as an eluent triturated with IPE/n-Hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 40-mL scintillation vial containing Compound (10-3) (320 mg, 2.0 mmol, 1 eq.), methyl phenylpyruvate (360 mg, 2.2 mmol, 1.1 eq.), and 20% AcOH (20 mL) was stirred at room temperature for 1.5 hours and at 65° C. for 4 hours. The mixture was allowed to cool and the precipitated solid was filtered and washed successively with water (15 mL) and Et2O (2×10 mL). The solid was dried in vacuo to give Compound (10-4) as a yellowish solid. to cool the precipitated solid was filtered washed successively with water (15 mL) and Et2O (2×10 mL) The solid was dried in vacuo

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

Procedure: Following the procedures outlined in Examples 2-6, and replacing L-cylohexylalanine methyl ester with L-phenylalanine methyl ester in Example 2 and methyl 3-methyl-2-oxobutyrate with methyl 3-phenyl-2-oxopropionate in Example 4 provides the title compound.

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

Procedure: Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 30% conversion to methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19methyl) with 85.4% ee as determined by chiral GC analysis. for 6 hours

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

Procedure: Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (R,S)-1f (3.3 mg; 6 μmol; 0.012 equiv) for 6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19=methyl) with 86.0% ee as determined by chiral GC analysis. for 6 hours

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

Procedure: Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for 6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19=methyl) with 83.2% ee as determined by chiral GC analysis. for 6 hours