(2R)-4-methyl-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pentanoic acid

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

Procedure: 4.4 g of 4-tert.butyl 1-(4-nitrobenzyl) 2(R)-isobutylsuccinate were dissolved in 50 ml of ethyl acetate and hydrogenated for 3.5 hours at room temperature and atmospheric pressure in the presence of 0.6 g of 5% palladium/carbon. The catalyst was removed by filtration and the solution was extracted three times with cold 2N hydrochloric acid. The organic layer was then washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the crude product was purified by chromatography on silica gel using chloroform for the elution. 2.0 g (72%) of 4-tert.butyl hydrogen 2(R)-isobutylsuccinate were obtained in the form of an oil. Rf (System C) 0.65. The catalyst was removed by filtration the solution was extracted three times with cold 2N hydrochloric acid The organic layer was then washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate The solvent was removed by evaporation the crude product was purified by chromatography on silica gel for the elution

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

Procedure: 4.4 g of 4-tert.butyl 1-(4-nitrobenzyl) 2(R)-isobutylsuccinate were dissolved in 50 ml of ethyl acetate and hydrogenated for 3.5 hours at room temperature and atmospheric pressure in the presence of 0.6 g of 5% palladium/carbon. The catalyst was removed by filtration and the solution was extracted three times with cold 2N hydrochloric acid. The organic layer was then washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the crude product was purified by chromatography on silica gel using chloroform for the elution. 2.0 g (72%) of 4-tert.butyl hydrogen 2(R)-isobutylsuccinate were obtained in the form of an oil. Rf (System C) 0.65. The catalyst was removed by filtration the solution was extracted three times with cold 2N hydrochloric acid The organic layer was then washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate The solvent was removed by evaporation the crude product was purified by chromatography on silica gel for the elution

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

Procedure: Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt.H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2 Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%). the next morning the DMF was removed at 35° C. under high vacuum The residue was partitioned between CH2 Cl2 (150 mL)/water (75 mL) the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL) After drying the CH2Cl2 layer over Na2SO4, it was filtered evaporated to dryness Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether)

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

Procedure: Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt-H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%). the next morning the DMF was removed at 35° C. under high vacuum The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL) the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL) After drying the CH2Cl2 layer over Na2SO4, it was filtered evaporated to dryness Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether)

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

Procedure: Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt-H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%). the next morning the DMF was removed at 35° C. under high vacuum The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL) the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL) After drying the CH2Cl2 layer over Na2SO4, it was filtered evaporated to dryness Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether)

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

Procedure: A solution of 5.19 g of 4-tert-butyl hydrogen 2(R)-isobutylsuccinate in 50 ml of dry tetrahydrofuran was cooled to −78° C. while stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 15 minutes. A solution of 5.55 g of cinnamyl bromide in 25 ml of dry tetrahydrofuran was then added dropwise and the mixture was left to come to room temperature gradually. After stirring overnight the tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give an orange oil. This was dissolved in 100 ml of hexane to which 2.35 g of cyclohexylamine were added. The mixture was left to stand for 2 hours and the solid formed was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulphuric acid to give a clear solution. The ethyl acetate solution was washed twice with water and then with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate. After evaporation of the solvent there were obtained 6.41 g of (E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in the form of a pale cream coloured solid. the mixture was stirred at −78° C. for 15 minutes the mixture was left to come to room temperature was evaporated the residue was partitioned between ethyl acetate and 5% citric acid solution The ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution dried over anhydrous magnesium sulphate The solvent was evaporated to give an orange oil were added The mixture was left the solid formed was collected by filtration shaken with two portions of 2M sulphuric acid to give a clear solution The ethyl acetate solution was washed twice with water with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate After evaporation of the solvent there

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

Procedure: 4.4 g of 4-tert.butyl 1-(4-nitrobenzyl) 2(R)-isobutylsuccinate were dissolved in 50 ml of ethyl acetate and hydrogenated for 3.5 hours at room temperature and atmospheric pressure in the presence of 0.6 g of 5% palladium/carbon. The catalyst was removed by filtration and the solution was extracted three times with cold 2N hydrochloric acid. The organic layer was then washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the crude product was purified by chromatography on silica gel using chloroform for the elution. 2.0 g (72%) of 4-tert.butyl hydrogen 2(R)-isobutylsuccinate were obtained in the form of an oil. Rf (System C) 0.65. The catalyst was removed by filtration the solution was extracted three times with cold 2N hydrochloric acid The organic layer was then washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate The solvent was removed by evaporation the crude product was purified by chromatography on silica gel for the elution

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

Procedure: Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt.H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2 Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%). the next morning the DMF was removed at 35° C. under high vacuum The residue was partitioned between CH2 Cl2 (150 mL)/water (75 mL) the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL) After drying the CH2Cl2 layer over Na2SO4, it was filtered evaporated to dryness Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether)

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

Procedure: Alternatively, to a solution of (2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above (2.39 g, 10.4 mmol), HOBt-H2O (2.5 g, 1 eq.), N-methylmorpholine (2.3 mL, 2 eq.), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was stirred overnight, then the next morning the DMF was removed at 35° C. under high vacuum. The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL), then the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL). After drying the CH2Cl2 layer over Na2SO4, it was filtered and evaporated to dryness. Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether) gave (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (3.24 g, 62.7%). the next morning the DMF was removed at 35° C. under high vacuum The residue was partitioned between CH2Cl2 (150 mL)/water (75 mL) the organic layer was washed with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and finally with brine (1×75 mL) After drying the CH2Cl2 layer over Na2SO4, it was filtered evaporated to dryness Purification by column chromatography (petroleum ether to 30% ethyl acetate/petroleum ether)