tert-butyl N-[(2S)-3-methyl-1-oxobutan-2-yl]carbamate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Bromosuccinimide (4.60 g, 25.9 mmol) and anhydrous potassium carbonate (8.10 g, 58.8 mmol) are successively added, over a period of 20 minutes, to a solution of (methoxycarbonylmethylene)triphenylphosphorane (PH3P═CH—CO2Me, 7.90 g, 23.5 mmol) in dichloromethane (60 ml) cooled to −20.0° C. The mixture, yellow-brown, is left under stirring for 20 min and freshly prepared N-(Boc)Valinal 2 (4.74 g, 23.5 mmol) dissolved in CH2Cl2 (20 ml) is instilled. The addition completed, the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature. A TLC check indicates the total disappearance of the aldehyde. The mixture is filtered on a fritted disc coated with celite, and the fritted disc is rinsed with ether. After evaporation of the filtrate under a vacuum, the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25). 2.10 g (27%, Rf=0.46 (AcOEt/Hept 1/3)) of pure isomer E, 0.63 g of mixture (7%, Z+E) and 3.2 g (41%, Rf=0.35 (AcOEt/Hept 1/3)) of pure isomer Z are obtained. The mixture, yellow-brown, is left The addition the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature The mixture is filtered on a fritted disc the fritted disc is rinsed with ether After evaporation of the filtrate under a vacuum the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25)

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

Procedure: A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil. directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate The organics were removed the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) treated with trifluoroacetic acid (8 mL) After stirring under nitrogen for 1 h the solvent was removed in vacuo The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform The organic layer was dried with magnesium sulfate filtered concentrated

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Bromosuccinimide (4.60 g, 25.9 mmol) and anhydrous potassium carbonate (8.10 g, 58.8 mmol) are successively added, over a period of 20 minutes, to a solution of (methoxycarbonylmethylene)triphenylphosphorane (PH3P═CH—CO2Me, 7.90 g, 23.5 mmol) in dichloromethane (60 ml) cooled to −20.0° C. The mixture, yellow-brown, is left under stirring for 20 min and freshly prepared N-(Boc)Valinal 2 (4.74 g, 23.5 mmol) dissolved in CH2Cl2 (20 ml) is instilled. The addition completed, the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature. A TLC check indicates the total disappearance of the aldehyde. The mixture is filtered on a fritted disc coated with celite, and the fritted disc is rinsed with ether. After evaporation of the filtrate under a vacuum, the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25). 2.10 g (27%, Rf=0.46 (AcOEt/Hept 1/3)) of pure isomer E, 0.63 g of mixture (7%, Z+E) and 3.2 g (41%, Rf=0.35 (AcOEt/Hept 1/3)) of pure isomer Z are obtained. The mixture, yellow-brown, is left The addition the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature The mixture is filtered on a fritted disc the fritted disc is rinsed with ether After evaporation of the filtrate under a vacuum the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Bromosuccinimide (4.60 g, 25.9 mmol) and anhydrous potassium carbonate (8.10 g, 58.8 mmol) are successively added, over a period of 20 minutes, to a solution of (methoxycarbonylmethylene)triphenylphosphorane (PH3P═CH—CO2Me, 7.90 g, 23.5 mmol) in dichloromethane (60 ml) cooled to −20.0° C. The mixture, yellow-brown, is left under stirring for 20 min and freshly prepared N-(Boc)Valinal 2 (4.74 g, 23.5 mmol) dissolved in CH2Cl2 (20 ml) is instilled. The addition completed, the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature. A TLC check indicates the total disappearance of the aldehyde. The mixture is filtered on a fritted disc coated with celite, and the fritted disc is rinsed with ether. After evaporation of the filtrate under a vacuum, the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25). 2.10 g (27%, Rf=0.46 (AcOEt/Hept 1/3)) of pure isomer E, 0.63 g of mixture (7%, Z+E) and 3.2 g (41%, Rf=0.35 (AcOEt/Hept 1/3)) of pure isomer Z are obtained. The mixture, yellow-brown, is left The addition the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature The mixture is filtered on a fritted disc the fritted disc is rinsed with ether After evaporation of the filtrate under a vacuum the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25)

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

Procedure: A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil. directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate The organics were removed the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) treated with trifluoroacetic acid (8 mL) After stirring under nitrogen for 1 h the solvent was removed in vacuo The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform The organic layer was dried with magnesium sulfate filtered concentrated

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

Procedure: A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil. directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate The organics were removed the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) treated with trifluoroacetic acid (8 mL) After stirring under nitrogen for 1 h the solvent was removed in vacuo The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform The organic layer was dried with magnesium sulfate filtered concentrated

Conditions: temp:22.01; pressure:0.00; stir:

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

Procedure: To a solution of N-tert-butoxycarbonyl-L-valinal (240 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (278 mg) in methanol (10 ml) was added sodium cyanoborohydride (63 mg) at 0° C. and the mixture was stirred at 0° C. for 2 hours and at room temperature for 18 hours. After concentration under reduced pressure, the residue was subjected to flush silica gel column chromatography, followed by elution with ethyl acetate-methanol(20:1). The effective fractions were combined and concentrated under reduced pressure. To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) and the whole was stirred at room temperature for 1 hour. Removal of the organic solvent gave a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (25 mg). After concentration under reduced pressure to flush silica gel column chromatography followed by elution with ethyl acetate-methanol(20:1) concentrated under reduced pressure To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) the whole was stirred at room temperature for 1 hour Removal of the organic solvent gave a residue, which followed by elution with water-acetonitrile concentrated under reduced pressure The residue was recrystallized from methanol-diethylether

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

Procedure: To a solution of N-tert-butoxycarbonyl-L-valinal (240 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (278 mg) in methanol (10 ml) was added sodium cyanoborohydride (63 mg) at 0° C. and the mixture was stirred at 0° C. for 2 hours and at room temperature for 18 hours. After concentration under reduced pressure, the residue was subjected to flush silica gel column chromatography, followed by elution with ethyl acetate-methanol(20:1). The effective fractions were combined and concentrated under reduced pressure. To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) and the whole was stirred at room temperature for 1 hour. Removal of the organic solvent gave a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (25 mg). After concentration under reduced pressure to flush silica gel column chromatography followed by elution with ethyl acetate-methanol(20:1) concentrated under reduced pressure To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) the whole was stirred at room temperature for 1 hour Removal of the organic solvent gave a residue, which followed by elution with water-acetonitrile concentrated under reduced pressure The residue was recrystallized from methanol-diethylether

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

Procedure: Sodium cyanoborohydride (2.0 g, 0.03 mole) was added portionwise (one hour) to a solution of the known compound 2(S)-t-butoxycarbonylamino-3-methylbutyraldehyde (5.8 g, 0.029 mole) and phenylalanine methyl ester hydrochloride (6.1 g, 0.028 mole) in methanol (150 ml) and acetic acid (1.5 ml). The clear reaction mixture was stirred at room temperature under argon for 2 hours and concentrated in vacuo. The residue was cooled in an ice bath, neutralized with saturated NaHCO3 and extracted (3×) with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give a pale yellow residue, which was purified by column chromatography on silica gel using 20% ethyl acetate-hexane. The title compound (8.4 g) was obtained as a pale yellow oil. concentrated in vacuo The residue was cooled in an ice bath extracted (3×) with ethyl acetate The organic phase was dried (Na2SO4) filtered evaporated to give a pale yellow residue, which was purified by column chromatography on silica gel using 20% ethyl acetate-hexane

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Bromosuccinimide (4.60 g, 25.9 mmol) and anhydrous potassium carbonate (8.10 g, 58.8 mmol) are successively added, over a period of 20 minutes, to a solution of (methoxycarbonylmethylene)triphenylphosphorane (PH3P═CH—CO2Me, 7.90 g, 23.5 mmol) in dichloromethane (60 ml) cooled to −20.0° C. The mixture, yellow-brown, is left under stirring for 20 min and freshly prepared N-(Boc)Valinal 2 (4.74 g, 23.5 mmol) dissolved in CH2Cl2 (20 ml) is instilled. The addition completed, the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature. A TLC check indicates the total disappearance of the aldehyde. The mixture is filtered on a fritted disc coated with celite, and the fritted disc is rinsed with ether. After evaporation of the filtrate under a vacuum, the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25). 2.10 g (27%, Rf=0.46 (AcOEt/Hept 1/3)) of pure isomer E, 0.63 g of mixture (7%, Z+E) and 3.2 g (41%, Rf=0.35 (AcOEt/Hept 1/3)) of pure isomer Z are obtained. The mixture, yellow-brown, is left The addition the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature The mixture is filtered on a fritted disc the fritted disc is rinsed with ether After evaporation of the filtrate under a vacuum the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25)

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

Procedure: A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil. directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate The organics were removed the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) treated with trifluoroacetic acid (8 mL) After stirring under nitrogen for 1 h the solvent was removed in vacuo The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform The organic layer was dried with magnesium sulfate filtered concentrated