Benzyl tert-butyl malonate

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

Procedure: A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of 1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of 5.37 g of benzyl 3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in 20 ml of dichloromethane was added dropwise at 0°. The mixture was stirred at 0° for 2 hours and then left to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propane-tricarboxylate as a 1:1 mixture of diastereoisomers in the form of an orange oil. cooled to 0° The mixture was stirred at 0° for 2 hours left to warm to room temperature overnight The solvent was evaporated the residue was dissolved in ethyl acetate The solution was washed with water and saturated sodium chloride solution After drying over anhydrous magnesium sulphate the solvent was evaporated

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

Procedure: Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated sulphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%. was maintained below 10° C to warm to room temperature was cautiously added The reaction mixture was extracted with ethyl acetate (2×100 ml) the ethyl acetate extracts were washed with water (4×) dried (Na2SO4) evaporated

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

Procedure: To a suspension of 66 mg sodium hydride (60% in oil, 1.66 mmol) in N,N-dimethyl-formamide (10 mL) was added a solution of 456 mg benzyl tert-butyl malonate (commercial, 1.82 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred for one hour at room temperature before a solution of 560 mg tert-butyl (2R)-4-bromo-2-[(tert-butoxycarbonyl)amino]butanoate (1.66 mmol) in N,N-dimethylformamide (5 mL) was added. The mixture was stirred for 60 hours at room temperature and was then evaporated in vacuo. The residue was purified by column chromatography on silica gel (1.5→20% ethyl acetate in hexane) to give the title compound (390 mg, 46% yield). was added was then evaporated in vacuo The residue was purified by column chromatography on silica gel (1.5→20% ethyl acetate in hexane)

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

Procedure: Benzyl tert-butyl malonate (24.9 g, 99.6 mmol) was dissolved in DMF (60 ml) and added portion wise with potassium tert-butoxide (13.4 g, 120 mmol) at 0° C. under stirring. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and dropped in 1 hour with the solution of the Example 3-a compound (28.4 g, 99.6 mmol) dissolved in DMF (60 ml). After the reaction mixture was stirred at 5° C. overnight, it was added with AcOEt (2 l) and washed with a saturated aqueous solution of NaCl, 1N-HCl, a saturated aqueous solution of NaHCO3 and then the saturated aqueous solution of NaCl two times respectively. The organic layer was dried over anhydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 750 g, elution with the mixed solvent; n-hexane: AcOEt=20:1), giving the title compound (40.0 g, 89%) of a colorless oil. The mixture was stirred at room temperature for 1 hour After the reaction mixture was stirred at 5° C. overnight washed with a saturated aqueous solution of NaCl, 1N-HCl The organic layer was dried over anhydrous MgSO4 evaporated under reduced pressure purified by column chromatography (silica gel 750 g, elution with the mixed solvent

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

Procedure: To a suspension of NaH (160 mg, 4.0 mmol) in DMF (8 mL) at 0° C. under N2, was added benzyl tert-butyl malonate (1.0 g, 4.0 mmol) in DMF (2 mL). The mixture was stirred for 50 min after which 1-bromoundecane in DMF (2 mL) was added. After an additional hour of stirring the reaction was allowed to warm to room temperature. The reaction was maintained overnight. Et2O (100 mL) and water (20 mL) were added to partition the reaction. The aqueous phase was extracted with Et2O (100 mL), and the combined organics dried over Na2SO4. The solvent was evaporated and the residue purified by flash column (C18 12 g, 40-100% ACN/water+0.1% TFA) to yield the title compound as a colorless oil (1.14 g, 2.82 mmol, 71%): LCMS Method F Rt=1.58 min, M+Na 427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84-0.96 (m, 3H) 1.28 (br. s, 12H) 1.31 (m, J=3.90 Hz, 6H) 1.41 (s, 9H) 1.88 (q, J=7.38 Hz, 2H) 3.29 (t, J=7.58 Hz, 1H) 5.19 (q, J=12.27 Hz, 2H) 7.30-7.42 (m, 5H). was added The reaction was maintained overnight to partition the reaction The aqueous phase was extracted with Et2O (100 mL) the combined organics dried over Na2SO4 The solvent was evaporated the residue purified by flash column (C18 12 g, 40-100% ACN/water+0.1% TFA)

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

Procedure: Carbamoylmethyl-carbamic acid tert-butyl ester (8a; 0.84 g, 4.8 mmol) was dissolved in dichloromethane (10 mL), and added with triethylamine (1.0 mL, 7.2 mmol) and benzyl chloroformate (0.85 g, 0.75 mL, 5.0 mmol) at 0° C. After stirring for 5 min, 4-dimethylaminopyridine (DMAP; 0.32 g, 2.6 mmol) was added slowly with continuous stirring at 0° C. for 1 h. After the reaction is completed, dichloromethane (10 mL) and saturated Na2CO3 solution (10 mL) were added. The organic phase was washed by H2O (10 mL), 1N HCl (20 mL), H2O (20 mL) and saturated NaCl solution (20 mL) separately, and dried over MgSO4 and concentrated under reduced pressure to remove dichloromethane to obtain white solid product 12 (1.15 g; 95%). 1H-NMR (200 MHz) (CDCl3) δ: 7.30˜7.38 (m, 5H, ArH), 5.17 (s, 2H, CO2CH2Ph), 5.02 (br, s, 1H, NHBOC), 3.94 (d, 2H, Gly-H), 1.43 [s, 9H, CO2C(CH3)3] with continuous stirring at 0° C. for 1 h The organic phase was washed by H2O (10 mL), 1N HCl (20 mL), H2O (20 mL) and saturated NaCl solution (20 mL) separately dried over MgSO4 concentrated under reduced pressure to remove dichloromethane

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

Procedure: Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated suphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%. was maintained below 10° C to warm to room temperature was cautiously added The reaction mixture was extracted with ethyl acetate (2×100 ml) the ethyl acetate extracts were washed with water (4×) dried (Na2SO4) evaporated

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

Procedure: Sodium hydride (0.96 g, 50% suspension in mineral oil) was added to a stirred solution of t-butyl benzyl malonate (5 g) in dry dimethylformamide (50 ml), maintained at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes, 2-chloroethyl-methyl sulphide (2.21 g) in dimethylformamide (10 ml) was added dropwise, while the temperature of the reaction was maintained below 10° C. The reaction was allowed to warm to room temperature and stirred for 15 hours when water was cautiously added. The reaction mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts were washed with water (4×), dried (Na2SO4) and evaporated to give 4-methylthio-2-t-butyloxycarbonyl-butanoic acid benzyl ester as an oil (6.4 g). This product was dissolved in trifluoroacetic acid (50 ml) with vigorous stirring at 0° C. under nitrogen. After stirring for 45 minutes, the trifluoroacetic acid was evaporated under reduced pressure at below 35° C. Final traces of trifuoroacetic acid were removed by azeotroping with carbon tetrachloride (3×20 ml), to leave an oily residue, which was dissolved in pyridine (20 ml). To this solution were added piperidine (0.44 ml) and paraformaldehyde (1.47 g), and the mixture heated at 60° C. under nitrogen for 2 hours. The reaction mixture was cautiously poured onto iced water, and the pH adjusted to 1 using concentrated sulphuric acid. The mixture was extracted with ether (2×100 ml), and the ether extracts dried (Na2SO4) and evaporated under reduced pressure to yield the crude product (5.4 g) as an oil. This was chromatographed over silica gel, eluting with a mixture of hexane and ethyl acetate, to yield the title ester as a colourless oil (1.22 g). Found: C,64.69; H,6.55. C13H16O2S (0.25 H2O) requires C,64.85; H,6.91%. was maintained below 10° C to warm to room temperature was cautiously added The reaction mixture was extracted with ethyl acetate (2×100 ml) the ethyl acetate extracts were washed with water (4×) dried (Na2SO4) evaporated

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

Procedure: Benzyl tert-butyl malonate (24.9 g, 99.6 mmol) was dissolved in DMF (60 ml) and added portion wise with potassium tert-butoxide (13.4 g, 120 mmol) at 0° C. under stirring. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C., and dropped in 1 hour with the solution of the Example 3-a compound (28.4 g, 99.6 mmol) dissolved in DMF (60 ml). After the reaction mixture was stirred at 5° C. overnight, it was added with AcOEt (2 l) and washed with a saturated aqueous solution of NaCl, 1N-HCl, a saturated aqueous solution of NaHCO3 and then the saturated aqueous solution of NaCl two times respectively. The organic layer was dried over anhydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 750 g, elution with the mixed solvent; n-hexane:AcOEt=20:1), giving the title compound (40.0 g, 89%) of a colorless oil. The mixture was stirred at room temperature for 1 hour After the reaction mixture was stirred at 5° C. overnight washed with a saturated aqueous solution of NaCl, 1N-HCl The organic layer was dried over anhydrous MgSO4 evaporated under reduced pressure purified by column chromatography (silica gel 750 g, elution with the mixed solvent

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

Procedure: A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of 1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of 5.37 g of benzyl 3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in 20 ml of dichloromethane was added dropwise at 0°. The mixture was stirred at 0° for 2 hours and then left to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propane-tricarboxylate as a 1:1 mixture of diastereoisomers in the form of an orange oil. cooled to 0° The mixture was stirred at 0° for 2 hours left to warm to room temperature overnight The solvent was evaporated the residue was dissolved in ethyl acetate The solution was washed with water and saturated sodium chloride solution After drying over anhydrous magnesium sulphate the solvent was evaporated

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

Procedure: To a suspension of 66 mg sodium hydride (60% in oil, 1.66 mmol) in N,N-dimethyl-formamide (10 mL) was added a solution of 456 mg benzyl tert-butyl malonate (commercial, 1.82 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred for one hour at room temperature before a solution of 560 mg tert-butyl (2R)-4-bromo-2-[(tert-butoxycarbonyl)amino]butanoate (1.66 mmol) in N,N-dimethylformamide (5 mL) was added. The mixture was stirred for 60 hours at room temperature and was then evaporated in vacuo. The residue was purified by column chromatography on silica gel (1.5→20% ethyl acetate in hexane) to give the title compound (390 mg, 46% yield). was added was then evaporated in vacuo The residue was purified by column chromatography on silica gel (1.5→20% ethyl acetate in hexane)