5-((tert-Butoxycarbonyl)amino)-4-oxopentanoic acid

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

Procedure: A solution of N,N′-dicyclohexylcarbodiimide (DCC, 3.34 g; 16.2 mmol) in dry dichloromethane (20 mL) was added using a syringe to a stirred mixture of 5-(Boc-amino)-4-oxopentanoic acid (3.70 g; 16.0 mmol), t-butyl 3-hydroxypropanoate (2.31 g; 15.8 mmol), and 4-dimethylaminopyridine (DMAP, 50 mg) in dichloromethane (40 mL) at ambient temperature under argon. The mild exothermic reaction was moderated with an ice-water bath. After stirring 2 days at ambient temperature, the mixture was suction-filtered on a glass-sinter filter. The residue was washed with dichloromethane (3×20 mL). The combined filtrates were evaporated and the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL), collecting 7×50 ml fractions. After evaporation of fractions 2-4, 5.45 g (96%) product was obtained (pale yellow oil). The mild exothermic reaction was moderated with an ice-water bath the mixture was suction-filtered on a glass-sinter filter The residue was washed with dichloromethane (3×20 mL) The combined filtrates were evaporated the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL) collecting 7×50 ml fractions After evaporation of fractions 2-4

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

Procedure: This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (2.0 g; 8.6 mmol), the product of 14a (3.0 g; 8.6 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.1 g; 10.0 mmol), and pyridine (4.0 mL) in dichloromethane (75 mL) using Procedure E. The crude product was purified on a 90×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:3), collecting 13×50 mL fractions. Following evaporation of fractions 6-11, 1.44 g (30%) product was obtained (yellowish oil). The crude product was purified on a 90×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:3) collecting 13×50 mL fractions evaporation of fractions 6-11

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

Procedure: This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.00 g; 4.3 mmol), the product from 12a (1.37 g; 4.3 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 1.03 g; 5.0 mmol), and pyridine (2.0 mL) in dichloromethane (40 mL) using Procedure E. The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2), collecting 16×50 mL fractions. From evaporation of fractions 4-9 gave 1.6 g (71%) product was obtained (yellowish oil). The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) collecting 16×50 mL fractions From evaporation of fractions 4-9

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

Procedure: This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.97 g; 8.5 mmol), the product of 6a (2.35 g; 8.7 mmol), and triethylamine (0.88 g; 8.7 mmol) in ethyl acetate (30 mL) as described in Example 1a. The crude product was purified by flash chromatography on a 65×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (1100 mL) collecting 18×50 mL fractions. After evaporation of fractions 3-8, 2.79 g (78%) product was obtained (amber oil). The crude product was purified by flash chromatography on a 65×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (1100 mL) collecting 18×50 mL fractions After evaporation of fractions 3-8

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

Procedure: Triethylamine (2.22 g; 22.0 mmol) was added dropwise to a stirred solution of 5-(Boc-amino)-4-oxopentanoic acid (4.62 g; 20.0 mmol) and t-butyl bromoacetate (4.30 g; 22.0 mmol) in ethyl acetate (60 mL) under argon at ambient temperature. The mixture (slurry) was refluxed for 17 h, then cooled to ambient temperature, poured into 0.5 M HCl (100 mL) and shaken thoroughly. The aqueous portion was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with saturated NaHCO3 solution (1×20 mL) and saturated NaCl solution (1×20 mL) then dried (MgSO4), filtered and evaporated. Evaporation resulted in an amber oil that was purified by flash chromatography on a 40×55-mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (600 mL), collecting 5×100 mL fractions. Evaporation of fractions 1 and 2 resulted in 6.15 g (89%) product (yellow oil). The mixture (slurry) was refluxed for 17 h The aqueous portion was extracted with ethyl acetate (2×20 mL) The combined organic solutions were washed with saturated NaHCO3 solution (1×20 mL) and saturated NaCl solution (1×20 mL) then dried (MgSO4) filtered evaporated Evaporation resulted in an amber oil that was purified by flash chromatography on a 40×55-mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (600 mL) collecting 5×100 mL fractions Evaporation of fractions 1 and 2

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

Procedure: The compound was prepared as described in Procedures A and B above from 2-chlorobutylbutyrate and 5-(tert-butoxycarbonylamino)-4-oxopentanoic acid. 1H-NMR (300 MHz, CD3OD) ppm δ 0.95+0.96 (two t, J=6.6 Hz, 6H, two Me), 1.65 (m, 6H, CH3CH2CH2CO2+CH3CH2CH2CH), 2.27 (t, J=10.8 Hz, 2H, CH2CH2CH2CO2), 2.70 (“t”, 2H, COCH2CH2CO2), 2.87 (“t”, 2H, COCH2CH2CO2), 4.02 (s, 2H, CH2NH2), 6.72 (t, J=8.4 Hz, 1H, OCHO). The compound was prepared

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

Procedure: The compound was prepared as described in Procedures A and B above from 2-chloroethyloctanoate and 5-(tert-butoxycarbonylamino)-4-oxopentanoic acid. 1H-NMR (300 MHz, CDCl3) ppm δ 0.87 (t, J=7.20 Hz, 3H, CH2Me), 1.27 (m, 8H, (CH2)4CH2CH2CO2), 1.45 (d, J=5.40 Hz, 3H, OCH(CH3)O), 1.58 (sext, J=7.32 Hz, 2H, CH2CH2CH2CO2), 2.28 (t, J=7.30 Hz, 2H, CH2CH2CH2CO2), 2.66 (“t”, 2H, COCH2CH2CO2), 2.94 (“t”, 2H, COCH2CH2CO2), 4.28 (s, 2H, CH2NH2), 6.83 (q, J=5.60 Hz, 1H, OCHO). The compound was prepared