benzyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate

Conditions: temp:-72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (17.5 ml, 0.127 moles) in 300 ml of dry tetrahydrofuran at -45° C. under argon was treated with 70 ml (0.117 moles) of 1.71 M n-butyllithium (in hexane). After 20 minutes at -45° C., the mixture was cooled to -72° C. and treated with 13.3 g (0.05 moles) of dried N-(t-butoxycarbonyl)glycine, benzyl ester in 60 ml of dry tetrahydrofuran. After 50 minutes, the dark yellow homogeneous solution was treated with 5 ml (5.43 g, 0.0543 moles) of tetrahydro-4-pyranone in 50 ml of tetrahydrofuran and the temperature allowed to rise to 0° C. over 1.5 hours. A solution of 7.2 g (0.12 moles) of glacial acetic acid in 20 ml of tetrahydrofuran was added to the purple solution, and the resulting light yellow turbid mixture was poured into 1 L of water and extracted with ethyl acetate. The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine, dried (sodium sulfate) and evaporated to an oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which solidified on trituration with hexane yielding a total of 10.34 g of product as a white solid, melting point 90°-93° C. After 50 minutes to rise to 0° C. over 1.5 hours extracted with ethyl acetate The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine dried (sodium sulfate) evaporated to an oil Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (9.7 ml, 70 mmoles) in 150 ml of dry tetrahydrofuran at -40° C. under argon was treated with 39 ml (64.5 mmoles) of 1.71N n-butyllithium in hexane and the pale yellow solution stirred at -40° C. for 20 minutes. The solution was cooled to -78° C., and a solution of 7.95 g (30 mmoles) of N-(t-butoxycarbonyl) glycine, benzyl ester in 30 ml of dry tetrahydrofuran was dripped in over 5 minutes, resulting in a dark yellow solution, and, after 20 minutes, a slight turbidity. After 0.5 hours, a solution of 2.42 g (2.0 ml, 34.5 mmoles) of cyclobutanone in 30 ml of tetrahydrofuran was added. The resulting yellow turbid mixture was stirred at -78° C. for 15 minutes, then placed in a 0° C. ice bath for 2 hours. At an internal temperature of -25° C. (1 hour), the solution became clear, and at -15° C. turned dark purple. It was stirred at 0° C. for 0.5 hours, then treated with 3.96 g (66 mmoles) of glacial acetic acid in 15 ml of tetrahydrofuran, giving a turbid, light yellow mixture. This was poured into 500 ml of cold water and extracted twice with ethyl acetate. The extracts were washed with 2% potassium bisulfate, 5% sodium bicarbonate, and brine, dried (sodium sulfate) and evaporated to a thick oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (2:1) and combination of the product fractions (Rf=.29) gave 7.8 g of product as an oil. The solution was cooled to -78° C. was dripped in over 5 minutes resulting in a dark yellow solution after 20 minutes After 0.5 hours was stirred at -78° C. for 15 minutes placed in a 0° C. for 2 hours At an internal temperature of -25° C. (1 hour) at -15° C. It was stirred at 0° C. for 0.5 hours giving a turbid, light yellow mixture extracted twice with ethyl acetate The extracts were washed with 2% potassium bisulfate, 5% sodium bicarbonate, and brine dried (sodium sulfate) evaporated to a thick oil

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (3.77 ml, 23 mmole) in 40 ml of dry tetrahydrofuran under argon was chilled to -40° C. and treated with 13 ml of a 1.71 N n-butyllithium solution (21.5 mmoles). After stirring for 20 minutes, the mixture was cooled to -78° C. and treated with a solution of N-(t-butoxycarbonyl)glycine, benzyl ester (2.65 g, 10 mmole) in 10 ml of tetrahydrofuran. The mixture became darker yellow, but remained clear. After 0.5 hours at -78° C., 0.88 ml (11.5 mmoles) of dried (4 Å sieves) cyclopentanone was added and then after 15 minutes at -78° C., the mixture was warmed over 0.5 hours to -20° C., whereupon the solution darkened to a deep purple. The temperature was raised to 0° C. for 20 minutes, then 1.32 g (22 mmole) of acetic acid in 5 ml of tetrahydrofuran was added, whereupon the color was discharged, leaving a gelatinous precipitate. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane:ethyl acetate, 3:1. Evaporation of product fractions and crystallization from hexane gave, in two crops, 1.68 g of product, melting point 68°-70° C. (Rf=0.77, silica, hexane:ethyl acetate, 3:1). After 0.5 hours at -78° C. 0.88 ml (11.5 mmoles) of dried (4 Å sieves) cyclopentanone was added after 15 minutes at -78° C. the mixture was warmed over 0.5 hours to -20° C., whereupon the solution The temperature was raised to 0° C. for 20 minutes leaving a gelatinous precipitate extracted with ethyl acetate The organic layer was washed with brine dried (sodium sulfate) evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane Evaporation of product fractions and crystallization from hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (3.77 ml, 23 mmole) in 40 ml of dry tetrahydrofuran under argon was chilled to -40° C. and treated with 13 ml of a 1.71 N n-butyllithium solution (21.5 mmoles). After stirring for 20 minutes, the mixture was cooled to -78° C. and treated with a solution of N-(t-butoxycarbonyl)glycine, benzyl ester (2.65 g, 10 mmole) in 10 ml of tetrahydrofuran. The mixture became darker yellow, but remained clear. After 0.5 hours at -78° C., 0.88 ml (11.5 mmoles) of dried (4 Å sieves) cyclopentanone was added and then after 15 minutes at -78° C., the mixture was warmed over 0.5 hours to -20° C., whereupon the solution darkened to a deep purple. The temperature was raised to 0° C. for 20 minutes, then 1.32 g (22 mmole) of acetic acid in 5 ml of tetrahydrofuran was added, whereupon the color was discharged, leaving a gelatinous precipitate. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane:ethyl acetate, 3:1. Evaporation of product fractions and crystallization from hexane gave, in two crops, 1.68 g of product, melting point 68°-70° C. (Rf=0.77, silica, hexane:ethyl acetate, 3:1). After 0.5 hours at -78° C. 0.88 ml (11.5 mmoles) of dried (4 Å sieves) cyclopentanone was added after 15 minutes at -78° C. the mixture was warmed over 0.5 hours to -20° C., whereupon the solution The temperature was raised to 0° C. for 20 minutes leaving a gelatinous precipitate extracted with ethyl acetate The organic layer was washed with brine dried (sodium sulfate) evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane Evaporation of product fractions and crystallization from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(t-Butoxycarbonyl)glycine (8.75 g, 0.05 mole) and benzyl bromide (9.4 g, 0.055 mole) were slurried in 20 ml of dimethylformamide and treated with 6.0 g (0.06 mole) of potassium bicarbonate under argon. After stirring for 38 hours, water was added to give a mass of chunky white solid which was filtered and washed with water. The solid was taken up in ethyl acetate, dried (sodium sulfate), evaporated to a solid, and recrystallized from 600 ml of hot hexane. Cooling to -5° C. for two hours and filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C., in two crops. to give a mass of chunky white solid which was filtered washed with water dried (sodium sulfate) evaporated to a solid recrystallized from 600 ml of hot hexane filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C.

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

Procedure: To a solution of N-Boc-Gly (3.0 g) in methylene chloride (100 ml) was added benzyl alcohol (1.6 ml), EDC (4.4 g) and a catalytic amount of DMAP. After 2 hours, the mixture was poured into 1N HCl and extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to give N-Boc-Gly-OBn (4.5 g). To a solution of N-Boc-Gly-OBn (1.32 g) in THF (10 ml) was added potassium bis(trimethylsilyl)amide (1.19 g) in THF (20 ml) at -78° C. After 30 minutes at -78° C. allyl bromide (0.52 ml) was added to the reaction mixture slowly. The resulting mixture was slowly warmed up to room temperature and stirred for an additional 12 hours. The mixture was poured into 1N HCl and extracted with ether, the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatotron (hexanes/ethyl acetate=10/1) to give desired product (585 mg). ##STR91## extracted with methylene chloride dried over sodium sulfate filtered concentrated

Conditions: temp:-72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (17.5 ml, 0.127 moles) in 300 ml of dry tetrahydrofuran at -45° C. under argon was treated with 70 ml (0.117 moles) of 1.71M n-butyllithium (in hexane). After 20 minutes at -45° C., the mixture was cooled to -72° C. and treated with 13.3 g (0.05 moles) of dried N-(t-butoxycarbonyl)glycine, benzyl ester in 60 ml of dry tetrahydrofuran. After 50 minutes, the dark yellow homogeneous solution was treated with 5 ml (5.43 g, 0.0543 moles) of tetrahydro-4-pyranone in 50 ml of tetrahydrofuran and the temperature allowed to rise to 0° C. over 1.5 hours. A solution of 7.2 g (0.12 moles) of glacial acetic acid in 20 ml of tetrahydrofuran was added to the purple solution, and the resulting light yellow turbid mixture was poured into 1L of water and extracted with ethyl acetate. The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine, dried (sodium sulfate) and evaporated to an oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which solidified on trituration with hexane yielding a total of 10.34 g of product as a white solid, melting point 90°-93° C. After 50 minutes to rise to 0° C. over 1.5 hours extracted with ethyl acetate The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine dried (sodium sulfate) evaporated to an oil Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (9.7 ml, 70 mmoles) in 150 ml of dry tetrahydrofuran at -40° C. under argon was treated with 39 ml (64.5 mmoles) of 1.71N n-butyllithium is hexane and the pale yellow solution stirred at -40° C. for 20 minutes. The solution was cooled to -78° C., and a solution of 7.95 g (30 mmoles) of N-(t-butoxycarbonyl)glycine, benzyl ester in 30 ml of dry tetrahydrofuran was dripped in over 5 minutes, resulting in a dark yellow solution, and, after 20 minutes, a slight turbidity. After 0.5 hours, a solution of 2.42 g (2.0 ml, 34.5 mmoles) of cyclobutanone in 30 ml of tetrahydrofuran was added. The resulting yellow turbid mixture was stirred at -78° C. for 15 minutes, then placed in a 0° C. ice bath for 2 hours. At an internal temperature of -25° C. (1 hour), the solution became clear, and at -15° C. turned dark purple. It was stirred at 0° C. for 0.5 hours, then treated with 3.96 g (66 mmoles) of glacial acetic acid in 15 ml of tetrahydrofuran, giving a turbid, light yellow mixture. This was poured into 500 ml of cold water and extracted twice with ethyl acetate. The extracts were washed with 2% potassium bisulfate, 5% sodium bicarbonate, and brine, dried (sodium sulfate) and evaporated to a thick oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (2:1) and combination of the product fractions (Rf=0.29) gave 7.8 g of product as an oil. The solution was cooled to -78° C. was dripped in over 5 minutes resulting in a dark yellow solution after 20 minutes After 0.5 hours was stirred at -78° C. for 15 minutes placed in a 0° C. for 2 hours At an internal temperature of -25° C. (1 hour) at -15° C. It was stirred at 0° C. for 0.5 hours giving a turbid, light yellow mixture extracted twice with ethyl acetate The extracts were washed with 2% potassium bisulfate, 5% sodium bicarbonate, and brine dried (sodium sulfate) evaporated to a thick oil

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (3.77 ml, 23 mmole) in 40 ml of dry tetrahydrofuran under argon was chilled to -40° C. and treated with 13 ml of a 1.71 N n-butyllithium solution (21.5 mmoles). After stirring for 20 minutes, the mixture was cooled to -78° C. and treated with a solution of N-(t-butoxycarbonyl)glycine, benzyl ester (2.65 g, 10 mmole) in 10 ml of tetrahydrofuran. The mixture became darker yellow, but remained clear. After 0.5 hours at -78° C., 0.88 ml (11.5 mmoles) of dried (4Å sieves) cyclopentanone was added and then after 15 minutes at -78° C., the mixture was warmed over 0.5 hours to -20° C., whereupon the solution darkened to a deep purple. The temperature was raised to 0° C. for 20 minutes, then 1.32 g (22 mmole) of acetic acid in 5 ml of tetrahydrofuran was added, whereupon the color was discharged, leaving a gelatinous precipitate. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane:ethyl acetate, 3:1. Evaporation of product fractions and crystallization from hexane gave, in two crops, 1.68 g of product, melting point 68°-70° C. (Rf=0.77, silica, hexane:ethyl acetate, 3:1). After 0.5 hours at -78° C. 0.88 ml (11.5 mmoles) of dried (4Å sieves) cyclopentanone was added after 15 minutes at -78° C. the mixture was warmed over 0.5 hours to -20° C., whereupon the solution The temperature was raised to 0° C. for 20 minutes leaving a gelatinous precipitate extracted with ethyl acetate The organic layer was washed with brine dried (sodium sulfate) evaporated to an oil which was chromatographed on 900 ml of LPS-1 in hexane Evaporation of product fractions and crystallization from hexane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(t-Butoxycarbonyl)glycine (8.75 g, 0.05 mole) and benzyl bromide (9.4 g, 0.055 mole) were slurried in 20 ml of dimethylformamide and treated with 6.0 g (0.06 mole) of potassium bicarbonate under argon. After stirring for 38 hours, water was added to give a mass of chunky white solid which was filtered and washed with water. The solid was taken up in ethyl acetate, dried (sodium sulfate), evaporated to a solid, and recrystallized from 600 ml of hot hexane. Cooling to -5° C. for two hours and filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C., in two crops. to give a mass of chunky white solid which was filtered washed with water dried (sodium sulfate) evaporated to a solid recrystallized from 600 ml of hot hexane filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C.

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

Procedure: A mixture of benzyl N-Bocglycinate (3 g, 11.3 mmol) and HCl in dioxane (20 mL) was stirred at rt for 2 h. Solvents were evaporated under reduced pressure and was diluted with dioxane (20 mL) and triethylamine (2.24 mL, 16.24 mmol). Then 2-chloro-4,5-dinitrobenzoic acid (2 g, 8.1 mmol) was added and cooled to 5° C. A solution of DCC (5.8 g, 28.1 mmol) in dioxane (20 mL) was added followed by catalytic amount of DMAP. The reaction mixture was stirred at rt for 5 h. Few drops of water was added to the reaction mixture and again stirred for 15 min. Reaction mixture was cooled to 0° C. and filtered. The solid was washed with ether (50 mL) and EtOAc (50 mL). The filtrate was poured into water and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with brine and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:acetone (90:10) as eluents to give the product as a pale yellow color solid (2.5 g, 75%), mp 122-124° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, s), 7.96 (1H, s), 7.39 (5H, s), 6.94 (1H, br s), 5.25 (2H, s), 4.32 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 392 (M−H)−. Solvents were evaporated under reduced pressure cooled to 5° C The reaction mixture was stirred at rt for 5 h again stirred for 15 min Reaction mixture was cooled to 0° C. filtered The solid was washed with ether (50 mL) and EtOAc (50 mL) The filtrate was poured into water the organic layer was separated The aqueous layer was extracted with EtOAc (3×100 mL) the combined organic layer was washed with brine dried over anhyd Na2SO4 The solution was filtered evaporated the solvent The residue was chromatographed over silica gel column

Conditions: temp:-72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (17.5 ml, 0.127 moles) in 300 ml of dry tetrahydrofuran at -45° C. under argon was treated with 70 ml (0.117 moles) of 1.71 M n-butyllithium (in hexane). After 20 minutes at -45° C., the mixture was cooled to -72° C. and treated with 13.3 g (0.05 moles) of dried N-(t-butoxycarbonyl)glycine, benzyl ester in 60 ml of dry tetrahydrofuran. After 50 minutes, the dark yellow homogeneous solution was treated with 5 ml (5.43 g, 0.0543 moles) of tetrahydro-4-pyranone in 50 ml of tetrahydrofuran and the temperature allowed to rise to 0° C. over 1.5 hours. A solution of 7.2 g (0.12 moles) of glacial acetic acid in 20 ml of tetrahydrofuran was added to the purple solution, and the resulting light yellow turbid mixture was poured into 1 L of water and extracted with ethyl acetate. The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine, dried (sodium sulfate) and evaporated to an oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which solidified on trituration with hexane yielding a total of 10.34 g of product as a white solid, melting point 90°-93° C. After 50 minutes to rise to 0° C. over 1.5 hours extracted with ethyl acetate The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine dried (sodium sulfate) evaporated to an oil Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which