Lithium Hexamethyldisilazide → (1S,5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl ester

HRID 1917343Notes

Reaction equation

HRID 1917343 reaction equation
[C:1]([O:5][C:6]([C:8]1([CH2:22][CH:23]2[CH2:25][O:24]2)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:22][CH:23]([OH:24])[CH2:25][C@@H:12]1[C:11](=[O:13])[N:10]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH2:9]2)=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

4

Reactant 2

HCID 2733832Lithium HexamethyldisilazideHCID 86664649HCID 86664649, compound

Product 1

HCID 67491063(1S,5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid tert-butyl esterYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

3-(Oxiran-2-ylmethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.2 g, 12.16 mmol) was dissolved in tetrahydrofuran (50 mL). A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (18 mL, 1.5 equivalents) was added in an argon atmosphere at −78° C., and the mixture was gradually heated. When the reaction temperature reached about room temperature, the reaction was quenched with an ammonium chloride solution, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1→1:1→1:2) to give 1.07 g (26%) of the title compound having a single isomer as a colorless oil. 1.0 g (24%) of the raw material was collected. 1.20 g (29%) of a four-membered ring-closed compound as a by-product was obtained as a diastereomer mixture.

Workup

  1. temperaturethe mixture was gradually heated
  2. customreached about room temperature
  3. customthe reaction was quenched with an ammonium chloride solution
  4. extractionfollowed by extraction with ethyl acetate
  5. dry with materialThe extract was dried over magnesium sulfate
  6. filtrationAfter filtration
  7. customthe solvent was evaporated under reduced pressure
  8. customThe resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1→1:1→1:2)

Sources & evidence

ORD record
ord-81ca90c1e9cc449a97ce6729d18a0618
Source dataset
uspto-grants-2013_12
Patent number
US08618094B2

Reaction notes

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