Imidazole → 4-Benzyloxycarbonylamino-5,5-dimethyl-3-oxo hexanoic acid tert-butyl ester

HRID 480208Notes

Reaction equation

HRID 480208 reaction equation
[C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C([Li])CCC.C(NC(C)C)(C)C.[C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:46])[CH3:45].N1C=CN=C1>C1COCC1>[C:48]([O:47][C:44](=[O:46])[CH2:45][C:17](=[O:19])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:51])([CH3:50])[CH3:49]

Participants

8

Reactant 6

HCID 795ImidazoleHCID 7912DiisopropylamineHCID 10908tert-Butyl acetateHCID 682631,1'-CarbonyldiimidazoleHCID 9899995(2S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acidHCID 178418339Butyllithium

Product 1

HCID 538424094-Benzyloxycarbonylamino-5,5-dimethyl-3-oxo hexanoic acid tert-butyl esterYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
23 °C

Procedure

To a solution of CBZ-L-tert-leucine (20.53 g, 77.4 mmol, 1 equiv) in THF (150 mL) was added 1,1′-carbonyldiimidazole (13.81 g, 85.14 mmol, 1.1 equiv) at 23° C. The resulting solution was stirred at 23° C. for 1 h. In a separate flask, n-butyllithium (101.59 mL of a 1.6 M solution in hexanes, 162.54 mmol, 2.1 equiv) was added to a solution of diisopropylamine (22.78 mL, 162.54 mmol, 2.1 equiv) in THF (100 mL) at −78° C. The reaction mixture was stirred for 15 min at −78° C., warmed to 0° C. for 5 min, then cooled back to −78° C. A solution of tert-butyl acetate (21.9 mL, 162.54 mmol, 2.1 equiv) in THF (10 mL) was added via cannula, and the resulting mixture was stirred at −78° C. for 10 min. The above imidazole solution was then added dropwise to the lithium enolate at −78° C. The resulting mixture was stirred at −78° C. for 1 h, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to afford 4-benzyloxycarbonylamino-5,5-dimethyl-3-oxo-hexanoic acid tert-butyl ester as a pale yellow oil (12.06 g, 44%): IR (cm−1) 1717, 1508, 1265, 739; 1H NMR (CDCl3) δ 1.09 (s, 9H), 1.44 (s, 9H), 3.50 (s, 2H), 4.29 (d, 1H, J=9.3), 5.03 (s, 2H), 5.35-5.42 (m, 1H), 7.34 (s, 5H).

Workup

  1. stirringThe reaction mixture was stirred for 15 min at −78° C.
  2. temperaturewarmed to 0° C. for 5 min
  3. temperaturecooled back to −78° C
  4. stirringthe resulting mixture was stirred at −78° C. for 10 min
  5. stirringThe resulting mixture was stirred at −78° C. for 1 h
  6. customquenched with 1 M HCl (100 mL)
  7. extractionextracted with EtOAc (2×100 mL)
  8. washThe combined organic layers were washed with brine (150 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customThe residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes)

Sources & evidence

ORD record
ord-142cfb9526094e03b573975cf613ec67
Source dataset
uspto-grants-2003_11
Patent number
US06649639B2

Reaction notes

Loading…