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

HRID 376455Notes

Reaction equation

HRID 376455 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), fried 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), 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. concentrationconcentrated
  10. customThe residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes)

Sources & evidence

ORD record
ord-b094ccef3d85404f88814962611983b0
Source dataset
uspto-grants-2000_02
Patent number
US06020371

Reaction notes

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