4-Methylmorpholine → (E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione

HRID 529439Notes

Reaction equation

HRID 529439 reaction equation
C(Cl)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([OH:17])(=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][C:13]([OH:15])=O.C[N:19]1[CH2:24][CH2:23][O:22][CH2:21]C1.[Li][CH2:26][CH2:27][CH2:28]C.[CH2:30]([C@H:37]1[CH2:41][O:40][C:39](=[O:42])[NH:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C[O:46]CC1>>[CH2:30]([C@H:37]1[CH2:41][O:40][C:39](=[O:42])[N:38]1[C:13](=[O:15])[CH2:12]/[CH:11]=[CH:10]/[CH2:9][C:8]([N:19]1[C@@H:24]([CH2:5][C:2]2[CH:3]=[CH:28][CH:27]=[CH:26][CH:4]=2)[CH2:23][O:22][C:21]1=[O:46])=[O:17])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1

Participants

7

Reactant 6

HCID 79724-MethylmorpholineHCID 8028Tetrahydrofuran2×HCID 62493Pivaloyl chlorideHCID 736225(S)-4-Benzyl-2-oxazolidinoneHCID 5351896trans-beta-Hydromuconic acidHCID 178418339Butyllithium

Product 1

HCID 68292127(E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dioneYield 23.8%

Procedure

Pivaloyl chloride (6.73 gm, 55.8 mmol) was slowly added to a solution of (E)-hex-3-enedioic acid (4.00 gm, 27.8 mmol) and NMM (5.64 gm, 55.8 mmol) in THF (100 mL) at 0° C. The ice bath was removed and the mixture was allowed warm to rt. After 30 min the mixture was cooled back down to 0° C. In a separate vessel, a solution of n-BuLi (2.5 M in hexanes, 22.2 mL, 55.5 mmol) was slowly added to a −78° C. solution of (S)-4-benzyloxazolidin-2-one (Evans chiral auxiliary) (9.84 gm, 55.5 mmol) in THF (100 mL). The mixture was allowed to stir at −78° C. for 45 min. The mixture containing the activated di-acid was cooled to −78° C. and then cannulated into the mixture containing the lithiated Evans chiral auxiliary. Upon addition the reaction mixture turned reddish in color. The dry ice/acetone bath was removed and the mixture was allowed to warm to rt. After 2 hr at rt, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (50 mL). The mixture was partitioned between water and a small amount of EtOAc. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-10% MeOH/DCM to give (E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (3.06 g, 6.62 mmol, 23.8% yield) as a white solid.

Workup

  1. customThe ice bath was removed
  2. temperatureAfter 30 min the mixture was cooled back down to 0° C
  3. temperaturewas cooled to −78° C.
  4. additioncontaining the lithiated Evans chiral auxiliary
  5. additionUpon addition the reaction mixture
  6. customThe dry ice/acetone bath was removed
  7. temperatureto warm to rt
  8. waitAfter 2 hr at rt
  9. customthe reaction mixture was quenched by addition of saturated aqueous NH4Cl (50 mL)
  10. customThe mixture was partitioned between water
  11. customThe aqueous phase was isolated
  12. extractionextracted with EtOAc
  13. washwashed with saturated aqueous NaCl
  14. dry with materialdried over MgSO4
  15. concentrationconcentrated
  16. customThe crude product was purified
  17. washeluting with a gradient of 0-10% MeOH/DCM

Sources & evidence

ORD record
ord-2e11418aee884cca89939bcb0fb1c51d
Source dataset
uspto-grants-2016_05
Patent number
US09346852B2

Reaction notes

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