tert-butyl N-[(2S)-4-methyl-1-oxopentan-2-yl]carbamate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Weinreb amide of BocLeucine was dissolved in dry Et2O and added by cannula to an Et2O suspension of an equimolar amount of LiAlH4 at 0° C. After stirring for one hour, the reaction flask was removed from 0° C. and allowed to warm to room temperature. After a reaction time of 80 minutes, an aqueous solution of KHSO4, (2 equiv. of KHSO4, 5 ml H2O/mmnol of Weinreb amide) was added slowly while stirring. The aqueous phase was extracted with Et2O and the confined Et2O phases were washed with 3N HCl, saturated NaHCO3, and saturated NaCl. After drying (MgSO4,) and rotary evaporation, the oil was found to contain one compound by thin layer chromatography. the reaction flask was removed from 0° C. while stirring The aqueous phase was extracted with Et2O the confined Et2O phases were washed with 3N HCl, saturated NaHCO3, and saturated NaCl After drying (MgSO4,) and rotary evaporation

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sulfur trioxide pyridine complex (7.8 g, 49.1 mmol, 3.0 equiv) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) was added to a solution of BOC-L-Leucinol (3.56 g, 16.4 mmol. 1 equiv) and Et3N (8 mL) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at 23° C. for 30 min, then poured into ice water (300 mL), and extracted with Et2O (2×200 mL). The combined organic layers were washed with 0.5M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL), then dried over Na2SO4, and concentrated to afford crude BOC-L-Leucinal as pale yellow oil (3.48 g, 99%). This material was used without further purification. 1H NMR (CDCl3) δ 0.92-0.94 (m, 6H), 1.44 (s, 9H), 1.59-1.64 (m, 1H), 1.67-1.85 (m, 2H), (4.21 (m, 1H), 5.12 (s, br, 1H), 9.57 (s, 1H). extracted with Et2O (2×200 mL) The combined organic layers were washed with 0.5M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL) dried over Na2SO4 concentrated

反应条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To diisopropylamine (7.7 g, 0.077 mol) in dry tetrahydrofuran (26 mL) cooled to -20 degrees C. under argon was added dropwise n-butyllithium in hexane (1.46 M, 52.4 mL, 0.077 mol). The solution was stirred 15 min, the temperature lowered to -78 degrees C. and dry ethyl acetate (6.7 g, 0.077 mol) added dropwise while maintaining the temperature below -75 degrees C. The solution was stirred 10 min and a precooled (-78 degrees C.) tetrahydrofuran solution of Boc-L-leucinal (11 g, 0.051 mol) was added. After 30 min, 2 M HCl (40 mL) was added and the mixture was slowly warmed to 10 degrees C. and extracted with ether (3 ×200 mL). The combined ethereal extract was washed with saturated sodium chloride and dried with magnesium sulfate and filtered. Evaporation of the filtrate in vacuo gave 14 g of crude product which was purified by flash chromatography (20% ethyl acetate in hexane) to give 6 g of desired product. lowered to -78 degrees C while maintaining the temperature below -75 degrees C The solution was stirred 10 min After 30 min and extracted with ether (3 ×200 mL) The combined ethereal extract was washed with saturated sodium chloride dried with magnesium sulfate filtered Evaporation of the filtrate in vacuo gave 14 g of crude product which was purified by flash chromatography (20% ethyl acetate in hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAC-66% benzene-4% MeOH, was used as eluant, The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.53 was isolated by preparative plate as a yellow oil (0.27 g) and used in used step. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The 2 layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile) The two diastereomers gave different Rf values on TLC (0.68 and 0.53)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAC-66% benzene-4% MeOH, was used as eluant, The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.53 was isolated by preparative plate as a yellow oil (0.27 g) and used in used step. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The 2 layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile) The two diastereomers gave different Rf values on TLC (0.68 and 0.53)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAc-66% benzene-4% MeOH, was used as eluant. The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.68 was isolated by preparative plate as a yellow oil (0.3 g) and used in used step. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile) The two diastereomers gave different Rf values on TLC (0.68 and 0.53)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAc-66% benzene-4% MeOH, was used as eluant. The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.68 was isolated by preparative plate as a yellow oil (0.3 g) and used in used step. the solution was cooled to 0° C. in an ice-water bath The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. 12 hours at ambient temperature the resulting mixture was stirred for 5 minutes The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) The combined organic solution was dried over Na2SO4 The solution was concentrated in vacuo affording a viscous oil The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile) The two diastereomers gave different Rf values on TLC (0.68 and 0.53)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution consisting of 1.00 g (4.64 mmol) N-tert-butoxycarbonyl-L-leucinal and 1.52 g (4.64 mmol) 2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 2, Step C) in 20 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 0.614 g (9.29 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using 30% to 40% ethyl acetate:hexane to give 735 mg (30%) of [S-(R*,S*)]-(1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a clear foam. was added The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling then extracted with three 50 mL portions of ethyl acetate The combined extracts were washed with 100 mL brine dried over anhydrous sodium sulphate evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution consisting of 1.00 g (4.64 mmol) N-tert-butoxycarbonyl-L-leucinal and 1.52 g (4.64 mmol) 2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 2, Step C) in 20 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 0.614 g (9.29 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using 30% to 40% ethyl acetate:hexane to give 735 mg (30%) of [S-(R*,S*)]-(1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a clear foam. was added The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling then extracted with three 50 mL portions of ethyl acetate The combined extracts were washed with 100 mL brine dried over anhydrous sodium sulphate evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under an argon gas stream, N-(tert-butoxycarbonyl)-L-leucine methyl ester (0.98 g, 4.0 mmol) was dissolved in toluene (7.1 ml), and cooled to -78° C. To the reaction solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 5.0 ml). After stirring at -78° C. for 30 minutes, thereby there was obtained (S)-2-(tert-butoxycarbonylamino)-4-methylpentanal. at -60 to -70° C.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under an argon gas stream, N-(tert-butoxycarbonyl)-L-leucine methyl ester (0.98 g, 4.0 mmol) was dissolved in toluene (7.1 ml), and cooled to -78° C. To the reaction solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 5.0 ml). After stirring at -78° C. for 30 minutes, thereby there was obtained (S)-2-(tert-butoxycarbonylamino)-4-methylpentanal. at -60 to -70° C.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of methyltriphenyl phosphonium bromide (10.97 g, 30.70 mmol) in anhydrous tetrahydrofuran (200 ml) at -78° C. (dry ice/acetone bath) under an argon atmosphere, was added n butyl lithium (19.8 ml of a 1.55M hexane solution) dropwise over the course of 5 minutes. After 10 minutes, the -78° C. bath was replaced with a 0° C. bath for one half hour, at which time the resulting orange solution was cooled again to -78° C. The solution was then added dropwise by cannula to a stirred -78° C. solution of Boc-leucinal (6.00 g, 27.91 mmol) in anhydrous tetrahydrofuran (30 ml) over the course of one-half hour. The mixture was then allowed to warm to room temperature during a 3 hour period after which water (150 ml) was added. Extraction with hexane (4×100 ml) provided a combined organic phase which was washed with brine (100 ml), dried (Na2SO4, and concentrated to give crude 3-t-butyloxycarbonylamino-5-methylhex-1-ene (6.5 g). Chromatography with ether/hexane (1/9) provided pure 3-t-butyloxycarbonyl-amino-5 methylhex-1-ene (3.71 g, 60%). Mass spectrum: EI, M+ -57=156; CI, (M+H)+ =214. the -78° C. bath was replaced with a 0° C. for one half hour was added Extraction with hexane (4×100 ml) provided a combined organic phase which was washed with brine (100 ml) dried (Na2SO4 concentrated