ethyl 5-methyl-3-oxohexanoate

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (13.5 ml, 100 mmol) in isobutylmethyl ketone (30 ml, 200 mmol) was added dropwise at room temperature over 20 minutes. The reaction was heated to 60° C. and stirred at this temperature for one hour. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (4×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 5-methyl-3-oxo-hexanoic acid ethyl ester (20 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.70 (1H, brs), 6.27 (1H, s), 4.25-4.32 (2H, quart), 2.26-2.31 (2H, d) (1H, m), 1.29-1.34 (3H, t), 0.89-0.94 (6H, d) ppm. LRMS (thermospray): m/z [M+NH4]+ 218. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) extracted with diethylether (4×200 ml) The combined organic extracts were washed with water dried over MgSO4 concentrated under reduced pressure

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

Procedure: The 5-aminotetrazole (850 mg; 10.0 mmole) is dissolved in hot ethanol (25 ml) with triethylamine (1.8 mmole; 0.25 ml). When all solids are dissolved (about ten minutes of heating at 82° C.), 1-naphthaldehyde (1.36 ml; 10.0 mmole) is added followed by ethyl isopropylacetoacetate (1.60 ml; 10.0 mmole). The clear solution is maintained at reflux for 15 h. The ethanol is removed in vacuo and the residue is dissolved in ethyl acetate. The ethyl acetate phase is added to a separatory funnel and subsequently washed with 1M HCl, water, then brine. The organic phase is dried over MgSO4 and filtered. The organic phase is reduced in volume in vacuo to get an oil. A 1:1 mixture of ethyl acetate and hexanes was added to the viscous oil and stirred with a spatula to provide a precipitate. The solid was filtered to provide the product (0.700 g, 19%) as a white powder. 1H NMR (400 MHz; CDCl3) d 11.0 (bs, 1H); 7.88 (d, 1H, J=8.2 Hz); 7.82 (d, 1H, J=8.2 Hz); 7.70-7.36 (m, 5H); 4.5 (m, 1H); 3.92-3.80 (m, 2H); 1.55 (d, 3H, J=6.7 Hz); 1.40 (d, 3H, J=7.0 Hz); 0.74 (at, 3H, J=7.0 Hz). LC MS shows MH+ at 364 and 2 MH+ at 727. When all solids are dissolved is added The clear solution is maintained at reflux for 15 h The ethanol is removed in vacuo the residue is dissolved in ethyl acetate The ethyl acetate phase is added to a separatory funnel subsequently washed with 1M HCl, water The organic phase is dried over MgSO4 filtered to get an oil was added to the viscous oil to provide a precipitate The solid was filtered

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

Procedure: Compound 9 was dissolved in EtOH (150 mL) and refluxed overnight. The reaction mixture was evaporated to yield product (10.315 g), which was shown by NMR to be pure. 1H NMR (500 MHz, CDCl3): δ 0.93 (d, 6H), 1.28 (t, 3H), 2.16 (m, 1H), 2.42 (d, 2H), 3.41 (2, 2H), 4.20 (q, 2H). refluxed overnight The reaction mixture was evaporated

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

Procedure: Compound 9 was dissolved in EtOH (150 mL) and refluxed overnight. The reaction mixture was evaporated to yield product (10.315 g), which was shown by NMR to be pure. 1H NMR (500 MHz, CDCl3): δ 0.93 (d, 6H), 1.28 (t, 3H), 2.16 (m, 1H), 2.42 (d, 2H), 3.41 (2, 2H), 4.20 (q, 2H). refluxed overnight The reaction mixture was evaporated

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

Procedure: 26 g of acetoacetic acid ethyl ester and 15 g of pyrrolidine were boiled in 70 ml of toluene on a water separator until the theoretical quantity of water was separated. The solution was added drop by drop at -40° C. to a suspension of 8.6 g of sodium amide in 300 ml of liquid ammonia. By heating to room temperature, the ammonia was removed. After the reaction solution had been cooled again to 0° C., isopropyl iodide dissolved in 100 ml of toluene was added at the same temperature. The solution was allowed to react for 3 hours at 0° C. The reaction solution was poured into 200 ml of water. The phases were separated and the toluene of the organic phase was removed using a rotary evaporator. Of the residue, 1.2 g of the first runnings was then distilled off at 1.5 torr (2×102Pa) and up to a still temperature of 60° C., which contained above all 2 -isopropyl acetoacetic acid ethyl ester. The brownish oil remaining behind was dissolved in 70 ml of methylene chloride, and 21 g of concentrated hydrochloric acid was added. The material was hydrolyzed for 1.5 hours at ambient temperature. The two phases were separated. The organic phase was dried, the solvent was removed and the residue was distilled. 28.1 g of 5-methyl-3-oxohexanoic acid ethyl ester (82 percent) was obtained. was separated The solution was added drop by drop at -40° C. to a suspension of 8.6 g of sodium amide in 300 ml of liquid ammonia the ammonia was removed After the reaction solution had been cooled again to 0° C. isopropyl iodide dissolved in 100 ml of toluene was added at the same temperature to react for 3 hours at 0° C The phases were separated the toluene of the organic phase was removed a rotary evaporator Of the residue, 1.2 g of the first runnings was then distilled off at 1.5 torr (2×102Pa) and up to a still temperature of 60° C., which The brownish oil remaining behind was dissolved in 70 ml of methylene chloride 21 g of concentrated hydrochloric acid was added The two phases were separated The organic phase was dried the solvent was removed the residue was distilled

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

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

Procedure: The 5-aminotetrazole (850 mg; 10.0 mmole) is dissolved in hot ethanol (25 ml) with triethylamine (1.8 mmole; 0.25 ml). When all solids are dissolved (about ten minutes of heating at 82° C.), 1-naphthaldehyde (1.36 ml; 10.0 mmole) is added followed by ethyl isopropylacetoacetate (1.60 ml; 10.0 mmole). The clear solution is maintained at reflux for 15 h. The ethanol is removed in vacuo and the residue is dissolved in ethyl acetate. The ethyl acetate phase is added to a separatory funnel and subsequently washed with 1M HCl, water, then brine. The organic phase is dried over MgSO4 and filtered. The organic phase is reduced in volume in vacuo to get an oil. A 1:1 mixture of ethyl acetate and hexanes was added to the viscous oil and stirred with a spatula to provide a precipitate. The solid was filtered to provide the product (0.700 g, 19%) as a white powder. 1H NMR (400 MHz; CDCl3) δ 11.0 (bs, 1H); 7.88 (d, 1H, J=8.2 Hz); 7.82 (d, 1H, J=8.2 Hz); 7.70-7.36 (m, 5H); 4.5 (m, 1H); 3.92-3.80 (m, 2H); 1.55 (d, 3H, J=6.7 Hz); 1.40 (d, 3H, J=7.0 Hz); 0.74 (at, 3H, J=7.0 Hz). LC MS shows MH+ at 364 and 2 MH+ at 727. When all solids are dissolved is added The clear solution is maintained at reflux for 15 h The ethanol is removed in vacuo the residue is dissolved in ethyl acetate The ethyl acetate phase is added to a separatory funnel subsequently washed with 1M HCl, water The organic phase is dried over MgSO4 filtered to get an oil was added to the viscous oil to provide a precipitate The solid was filtered

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

Procedure: Ru(OCOCH3)2((R)-dm-binap)(5.5 mg, 0.058 mmol), ethyl 5-methyl-3-oxo-hexanoate (500 mg, 2.903 mmol), ammonium acetate (224 mg, 2.903 mmol) and ethanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=50/50/5) to give ethyl (−)-3-amino-5-methylhexanoate (175 mg) as a colorless oil in 35.0% yield. The resulting ethyl (−)-3-amino-5-methylhexanoate was converted into ethyl 3-(4-nitrobenzoylamino)-5-methylhexanoate, and the enantiomeric excess of the product was found to be 97.3% ee by HPLC analysis using a CHIRALCEL OD-H column. After completion of the reaction the solvent was removed by evaporation in vacuo the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=50/50/5)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-methyl-3-oxohexanoate (1.20 g, 6.99 mmol, 1.4 eq.) obtained in Example 93a) and 4-azido-N-ethylbenzamide (1.00 g, 4.99 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.49 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 18 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (25 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 45 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (1.45 g, 4.58 mmol, 91.7%). was evaporated The residue was diluted with 2% aqueous sodium carbonate solution (25 ml) the mixture was washed with ethyl acetate-hexane (2:1, 45 ml) The organic layer was extracted with 1% aqueous sodium carbonate solution (15 ml) washed with ethyl acetate-hexane (1:1, 30 ml) extracted with ethyl acetate (40 ml and 30 ml) washed with saturated brine dried over anhydrous sodium sulfate concentrated ethyl acetate was added The precipitate was collected by filtration washed with ethyl acetate and diethyl ether dried

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

Procedure: According to Scheme 1 Step 1: A solution of ethyl 5-methyl-3-oxohexanoate (11.6 mmol, 2.00 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (11.6 mmole, 1.54 mL) in DMF (10 mL) was microwaved for 30 minutes at 120° C. After evaporation of the solvent, 2.64 g (11.6 mmol) of ethyl 2-((dimethylamino)methylene)-5-methyl-3-oxohexanoate as an orange oil were obtained and used without further purification. After evaporation of the solvent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (13.5 ml, 100 mmol) in isobutylmethyl ketone (30 ml, 200 mmol) was added dropwise at room temperature over 20 minutes. The reaction was heated to 60° C. and stirred at this temperature for one hour. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (4×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 5-methyl-3-oxo-hexanoic acid ethyl ester (20 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.70 (1H, brs), 6.27 (1H, s), 4.25-4.32 (2H, quart), 2.26-2.31 (2H, d) (1H, m), 1.29-1.34 (3H, t), 0.89-0.94 (6H, d) ppm. LRMS (thermospray): m/z [M+NH4]+ 218. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) extracted with diethylether (4×200 ml) The combined organic extracts were washed with water dried over MgSO4 concentrated under reduced pressure