Trifluoroacetic acid → (2R,5R)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidine

HRID 243659Notes

Reaction equation

HRID 243659 reaction equation
[Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([NH:25]C(=O)OCC1C=CC(OC)=CC=1)[CH2:11][CH2:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]1[CH2:11][CH2:12][C@@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:25]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:25]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 579074284-methoxybenzyl [(1R)-1-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrophenyl)-4-oxopentyl]carbamate

Product 2

HCID 57907554(2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidineHCID 57907644(2R,5R)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidineYield 26%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of MOZ protected ketone amine (from Step G, 34 g, 56 mmol) in DCM (350 ml) was added TFA (256 ml) and the resulting mixture stirred at room temperature for 1.5 h. The solution was evaporated under vacuum and residue partitioned between DCM and sat. NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in MeOH (750 ml) and cooled to 0° C. via ice/water bath. Sodium cyanoborohydride (21.2 g, 337 mmol) was then added and the resulting mixture was stirred overnight to allow to warm to room temperature. The mixture was quenched by addition of water and the organics removed under vacuum. The aqueous layer was then extracted with EtOAc (x2) and the combined EtOAc layers washed with sat. NaCl, dried over MgSO4, filtered and evaporated under vacuum. The residue was purified by column chromatography on silica (eluent: gradient rising from 100% Hexanes to 35% EtOAc in Hexanes) to give 16.4 g (63.4%) of the first isomer, (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidine, and 3.1 g (12%) of the second isomer (2R,5R)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidine.

Workup

  1. customThe solution was evaporated under vacuum and residue
  2. custompartitioned between DCM and sat. NaHCO3
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customevaporated
  6. dissolutionThe residue was dissolved in MeOH (750 ml)
  7. temperaturecooled to 0° C. via ice/water bath
  8. stirringthe resulting mixture was stirred overnight
  9. temperatureto warm to room temperature
  10. customThe mixture was quenched by addition of water
  11. customthe organics removed under vacuum
  12. extractionThe aqueous layer was then extracted with EtOAc (x2)
  13. washthe combined EtOAc layers washed with sat. NaCl
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. customevaporated under vacuum
  17. customThe residue was purified by column chromatography on silica (eluent: gradient rising from 100% Hexanes to 35% EtOAc in Hexanes)

Sources & evidence

ORD record
ord-9d8f1280130748518d420b44dc2b9f3d
Source dataset
uspto-grants-2014_02
Patent number
US08653260B2

Reaction notes

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