Hydrochloric Acid → (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate

HRID 1056118Notes

Reaction equation

HRID 1056118 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:35]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:36]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10](=[O:12])[CH2:36][C:35]([O:41][CH2:42][CH3:43])=[O:40])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 25232732N-Boc-O-TBDMS-D-threonine

Product 1

HCID 131736417(4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoateYield 65.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (615a) (14.52 g, 43.5 mmol) in THF (100 mL) was treated with 1,1′-carbonyldiimidazole (7.41 g, 45.7 mmol) and stirred at RT for 30 min and then at 60° C. for 2 h. The mixture was cooled to RT and then potassium ethyl malonate (Aldrich) (14.82 g, 87 mmol) and magnesium chloride (Aldrich) (8.29 g, 87 mmol) were added. The resulting suspension was stirred at 50° C. for 20 h. The suspension was concentrated and then extracted into EtOAc (2×100 mL) from saturated aq. brine (500 mL) containing 5 M aq. HCl (40 mL, 200 mmol). The combined organic extracts were washed with saturated aq. NaHCO3 (2×100 mL), dried (Na2SO4), and concentrated to give a pale yellow gum. The crude product was purified by flash chromatography on silica gel (160 g) eluting with DCM to give (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (165) (11.49 g, 28.5 mmol, 65% yield) as a colorless oil. LC-MS m/z 426.0, [M+Na]+.

Workup

  1. waitat 60° C. for 2 h
  2. temperatureThe mixture was cooled to RT
  3. stirringThe resulting suspension was stirred at 50° C. for 20 h
  4. concentrationThe suspension was concentrated
  5. extractionextracted into EtOAc (2×100 mL) from saturated aq. brine (500 mL)
  6. washThe combined organic extracts were washed with saturated aq. NaHCO3 (2×100 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customto give a pale yellow gum
  10. customThe crude product was purified by flash chromatography on silica gel (160 g)
  11. washeluting with DCM

Sources & evidence

ORD record
ord-1e837c933b9c40a59e62f119652ec108
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

Loading…