tert-butyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(phenylmethoxycarbonylamino)pentanoate

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

Procedure: Mix N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester (2.0 g, 5.0 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give N-t-butyloxycarbonyl-ornithine, t-butyl ester. at room temperature Filter evaporate the filtrate in vacuo

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

Procedure: Dissolve N5 -benzyloxycarbonyl-ornithine, t-butyl ester (3.22 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3X) dry (MgSO4) and blow to a residue with a stream of nitrogen to give N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester. Add, by dropwise addition at 10° C extract with ether (3X) dry (MgSO4) and blow to a residue with a stream of nitrogen

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

Procedure: Mix N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester (2.0 g, 5.0 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give N-t-butyloxycarbonyl-ornithine, t-butyl ester. at room temperature Filter evaporate the filtrate in vacuo

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

Procedure: Dissolve N5 -benzyloxycarbonyl-ornithine, t-butyl ester (3.22 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3×), dry (MgSO4) and blow to a residue with a stream of nitrogen to give N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester. Add, by dropwise addition at 10° C extract with ether (3×) dry (MgSO4) and blow to a residue with a stream of nitrogen

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

Procedure: Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t,1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H). stirring was continued for 3 additional hours at room temperature The solvent was evaporated at reduced pressure the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) Fractions of approximately 5 ml were collected Chromatographic fractions containing product evaporated to a thick oil by rotary evaporation at reduced pressure

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

Procedure: Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t,1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H). stirring was continued for 3 additional hours at room temperature The solvent was evaporated at reduced pressure the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) Fractions of approximately 5 ml were collected Chromatographic fractions containing product evaporated to a thick oil by rotary evaporation at reduced pressure

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

Procedure: Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ 1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t, 1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H). stirring was continued for 3 additional hours at room temperature The solvent was evaporated at reduced pressure the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) Fractions of approximately 5 ml were collected Chromatographic fractions containing product evaporated to a thick oil by rotary evaporation at reduced pressure

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6.1 g (14.4 mmol) N5-((Benzyloxy)carbonyl)-N2-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester in 100 mL ethyl acetate was added 1.0 g 10% palladium on carbon. The suspension was shaken at 22° C. under 50 psi H2 for 45 minutes in a 500 mL Parr bottle. The catalyst was removed by filtration through celite. The resulting solution was concentrated to yield a crude oil. The oil was dissolved into 50 mL of diethyl ether and added dropwise to a 0° C. stirred solution of 1.52 g (14.3 mmol) of cyanogen bromide in 30 mL ether. The solution was stirred for 2 h, poured into aqueous sodium bicarbonate, and extracted with ether. The ether solution was dried (magnesium sulfate), concentrated, and purified by silica gel chromatography (100 g, 130-400 mesh silica gel). Elution with a gradient of ethyl acetate in hexanes (30%-60%) gave 3.0 g (67% yield) N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester as an oil. The catalyst was removed by filtration through celite The resulting solution was concentrated to yield a crude oil added dropwise to a 0° C. The solution was stirred for 2 h extracted with ether The ether solution was dried (magnesium sulfate) concentrated purified by silica gel chromatography (100 g, 130-400 mesh silica gel) Elution with a gradient of ethyl acetate in hexanes (30%-60%)

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

Procedure: Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t,1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H). stirring was continued for 3 additional hours at room temperature The solvent was evaporated at reduced pressure the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) Fractions of approximately 5 ml were collected Chromatographic fractions containing product evaporated to a thick oil by rotary evaporation at reduced pressure

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

Procedure: Mix N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester (2.0 g, 5.0 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give N-t-butyloxycarbonyl-ornithine, t-butyl ester. at room temperature Filter evaporate the filtrate in vacuo

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

Procedure: Dissolve N5 -benzyloxycarbonyl-ornithine, t-butyl ester (3.22 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3X) dry (MgSO4) and blow to a residue with a stream of nitrogen to give N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester. Add, by dropwise addition at 10° C extract with ether (3X) dry (MgSO4) and blow to a residue with a stream of nitrogen

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

Procedure: Mix N-t-butyloxycarbonyl-N5 -benzyloxycarbonyl-ornithine, t-butyl ester (2.0 g, 5.0 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 mL). Hydrogenate at room temperature at atmospheric pressure. Filter and evaporate the filtrate in vacuo to give N-t-butyloxycarbonyl-ornithine, t-butyl ester. at room temperature Filter evaporate the filtrate in vacuo