Tetrahydrofuran → (S)-3-((S)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester

HRID 1671391Notes

Reaction equation

HRID 1671391 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH2:19][CH:15]=[CH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH2:22][CH:21]=[CH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 1514343(S)-tert-butyl 3-formylpyrrolidine-1-carboxylateHCID 178455850HCID 178455850, compound

Product 2

HCID 58104609(S)-3-((S)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl esterHCID 66892341(S)-3-((R)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester

Conditions

Temperature
-78 °C

Procedure

(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (1.5 g, 7.5 mmol) was dissolved in THF (15.0 mL, 186 mmol). The reaction mixture and cooled at −78° C., before adding allylmagnesium bromide (1.0M in ether; 11.3 mL, 11.3 mmol) dropwise. The resulting mixture was allowed to warm to room temperature slowly overnight. The reaction was quenched with saturated aqueous NH4Cl (30 mL), added dropwise. The resulting mixture was extracted with EtOAc (2×30 mL), then the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield the crude product, which was then purified by preparative HPLC (10-50% MeCN:H2O; 0.05% TFA; over 80 minutes). Each diastereomer dissolved in EtOAc and free based by adding saturated aqueous NH4CO3. The organics were separated, dried over Na2SO4, and the solvent removed to yield (S)-3-((S)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (105 mg; 1st eluting peak) and (S)-3-((R)-1-hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (90 mg; 2nd eluting peak).

Workup

  1. temperatureto warm to room temperature slowly overnight
  2. customThe reaction was quenched with saturated aqueous NH4Cl (30 mL)
  3. additionadded dropwise
  4. extractionThe resulting mixture was extracted with EtOAc (2×30 mL)
  5. washthe combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL)
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto yield the crude product, which
  10. customwas then purified by preparative HPLC (10-50% MeCN:H2O; 0.05% TFA; over 80 minutes)
  11. dissolutionEach diastereomer dissolved in EtOAc
  12. additionby adding saturated aqueous NH4CO3
  13. customThe organics were separated
  14. dry with materialdried over Na2SO4
  15. customthe solvent removed

Sources & evidence

ORD record
ord-2accfc4eedc040e99333e8cfd9842ae0
Source dataset
uspto-grants-2011_08
Patent number
US07994209B2

Reaction notes

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