Acetic Acid → dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinate

HRID 1774395Notes

Reaction equation

HRID 1774395 reaction equation
C(NC(C)C)(C)C.[O:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:9]1.[CH3:25][CH:26]([CH3:39])[C:27](=[O:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(O)(=O)C>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:38][C:27]([CH:26]([CH3:39])[CH3:25])([CH:14]([CH:11]1[CH2:10][CH2:9][O:8][CH2:13][CH2:12]1)[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 7912DiisopropylamineHCID 11160044Benzyl 3-methyl-2-oxobutanoateHCID 59706533Benzyl 2-(tetrahydro-2H-pyran-4-yl)acetate

Product 1

HCID 66648508dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinateYield 29%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of diisopropylamine (122 mg, 1.21 mmol) in anhydrous tetrahydrofuran (2 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (703 μL, 1.11 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min and then at −78° C. for 5 min. A solution of benzyl 2-(tetrahydropyran-4-yl)acetate (250 mg, 1.07 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise over 6 min at the same temperature, and the reaction mixture was further stirred for 15 min. The cold enolate solution thus prepared was added dropwise via a cannula to a solution of benzyl a solution of benzyl 3-methyl-2-ketobutyrate (191 mg, 0.928 mmol) in anhydrous tetrahydrofuran (1 mL) solution having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid and raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases for extraction. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinate as oil in amounts of 115 mg (low polar diastereomer, yield: 29%) and 158 mg (high polar diastereomer, yield: 39%), respectively.

Workup

  1. stirringthe mixture was stirred at 0° C. for 10 min
  2. stirringthe reaction mixture was further stirred for 15 min
  3. stirringAfter stirring at −78° C. for 1 h
  4. temperatureraised to room temperature
  5. customThe reaction solvent was evaporated under reduced pressure
  6. additionthe residue was diluted with ethyl acetate and water
  7. customto separate the phases
  8. extractionfor extraction
  9. extractionThe aqueous layer was extracted again with ethyl acetate
  10. concentrationthe combined organic layer was concentrated under reduced pressure
  11. customthe residue thus obtained

Sources & evidence

ORD record
ord-21e0818ca3364376b5b5a85992033651
Source dataset
uspto-grants-2016_02
Patent number
US09260375B2

Reaction notes

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