4-methyl-2-oxopentanoic acid

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:

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

Procedure: Alternatively, for those compounds wherein n=1 and R1 is H, the compounds can be prepared by condensing the ylide 1,1-dimethoxy-2-(triphenylphosphoranylidene) ethane prepared from triphenylphosphine and 1,1-dimethoxy-2-bromoethane with 4-methyl-2-oxopentanoic acid. The product is then hydrogenated to obtain 4,4-dimethoxy-2-isobutylbutanoic acid which is coupled to the moiety R3NHCHR4COX to obtain 4,4-dimethoxy-2-isobutylbutanoyl--NR3CHR4COX. Treatment with aqueous acid yields the aldehyde 2-isobutyl-4-oxobutanoyl--NR3CHR4COX. The oxime is prepared by reaction with hydroxylamine and reduced to the corresponding N-substituted hydroxylamine. Acylation of both the hydroxaminol oxygen and nitrogen followed by hydrolysis of the O-acyl group provides the N-acyl reverse hydroxymates. (Summers, J.B., et al., J Med Chem (1988) 31:1960-1964.)

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:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-methyl-2-oxopentanoic acid (5 g) in acetic acid (40 ml) was added pyridine hydrobromide perbromide (12.3 g) and the mixture stirred at 20° C. for 18 hr, then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with water (100 ml), separated by hydrophobic frit and evaporated. The residue was taken up in ethanol (100 ml) and treated with concentrated sulphuric acid (1 ml) and heated at reflux for 18 h, then concentrated in vacuo to approx 30 ml. The mixture was diluted with water (250 ml) and extracted with diethyl ether (100 ml), dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (5.3 g). the solvent was removed in vacuo The residue was dissolved in DCM (100 ml) washed with water (100 ml) separated by hydrophobic frit evaporated treated with concentrated sulphuric acid (1 ml) heated at reflux for 18 h concentrated in vacuo to approx 30 ml The mixture was diluted with water (250 ml) extracted with diethyl ether (100 ml) dried over sodium sulphate evaporated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-methyl-2-oxopentanoic acid (5 g) in acetic acid (40 ml) was added pyridine hydrobromide perbromide (12.3 g) and the mixture stirred at 20° C. for 18 hr, then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with water (100 ml), separated by hydrophobic frit and evaporated. The residue was taken up in ethanol (100 ml) and treated with concentrated sulphuric acid (1 ml) and heated at reflux for 18 h, then concentrated in vacuo to approx 30 ml. The mixture was diluted with water (250 ml) and extracted with diethyl ether (100 ml), dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (5.3 g). the solvent was removed in vacuo The residue was dissolved in DCM (100 ml) washed with water (100 ml) separated by hydrophobic frit evaporated treated with concentrated sulphuric acid (1 ml) heated at reflux for 18 h concentrated in vacuo to approx 30 ml The mixture was diluted with water (250 ml) extracted with diethyl ether (100 ml) dried over sodium sulphate evaporated

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

Procedure: With reference to reaction Scheme 2, a slurry of 25 g (0.164 mol) of the sodium salt of 4-methyl-2-oxopentanoic acid, sodium salt in anhydrous N,N-dimethylformamide (50 ml) containing 19.6 ml (0.164 mol) of benzyl bromide was agitated at room temperature for 4 days. The solvent was removed in vacuo. The residue was dissolved in 250 ml of hexane and washed with water (3×50 ml) and brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 33.2 g (92% yield) of benzyl 4-methyl-2-oxopentanoate (1a) as a viscous, colorless oil. TLC: Rf 0.70 (ethyl acetate-hexane 1:4); 1H NMR(CDCl3) δ 0.94(d, 6H), 2.18(m, 1H), 2.71(d, 2H), 5.26(s, 2H), 7.37(m, 5H); 13C NMR (CDCl3) δ 22.5, 24.2, 48.1, 67.9, 128.7, 128.8, 128.9, 134.7, 161.3, 194.0. With reference to reaction Scheme 2 The solvent was removed in vacuo The residue was dissolved in 250 ml of hexane washed with water (3×50 ml) and brine (50 ml) After drying over anhydrous magnesium sulfate the solution was filtered concentrated in vacuo

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

Procedure: Alternatively, for those compounds wherein n=1 and R1 is H, the compounds can be prepared by condensing the ylide 1,1-dimethoxy-2-(triphenylphosphoranylidene) ethane prepared from triphenylphosphine and 1,1-dimethoxy-2-bromoethane with 4-methyl-2-oxopentanoic acid. The product is then hydrogenated to obtain 4,4-dimethoxy-2-isobutylbutanoic acid which is coupled to the moiety R3NHCHR4COX to obtain 4,4-dimethoxy-2-isobutyl-butanoyl-NR3CHR4COX. Treatment with aqueous acid yields the aldehyde 2-isobutyl-4-oxobutanoyl-NR3 CHR4COX. The oxime is prepared by reaction with hydroxylamine and reduced to the corresponding N-substituted hydroxylamine. Acylation of both the hydroxaminol oxygen and nitrogen followed by hydrolysis of the O-acyl group provides the N-acyl reverse hydroxymates. (Summers, J. B., et al., J Med Chem (1988) 31:1960-1964.)