Diisobutylaluminumhydride → (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate

HRID 1945332Notes

Reaction equation

HRID 1945332 reaction equation
[H-].C([Al+]CC(C)C)C(C)C.[CH3:11][CH:12]([C:44](OC)=[O:45])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[OH:45][CH2:44][C@@H:12]([CH3:11])[C@H:13]([NH:24][C:25]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]

Participants

4

Reactant 2

HCID 21225700DiisobutylaluminumhydrideHCID 66648857(2S)-1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate

Product 1

HCID 67176385(2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoateYield 34.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol) was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL) solution of (2S)-1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol) prepared above, and stirred at −78° C. for 20 hr. The reaction mixture was removed from the cooling bath and rapidly poured into ˜1M H3PO4/H2O (250 mL) with stirring, and the mixture was extracted with ether (100 mL, 2×). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. A silica gel mesh of the crude material was prepared and submitted to chromatography (25% EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with benzyl alcohol, as a colorless viscous oil and (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containing the (2S,3R) stereoisomer as an impurity. The later sample was resubmitted to the same column chromatography purification conditions to afford 750 mg of purified material as a white foam. [Note: the (2S,3S) isomer elutes before the (2S,3R) isomer under the above condition]. (2S,3S) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21 (app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), ˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d, J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45; found 464.22. (2S,3R) isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1, 1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8, 3H). LC (Cond. 1): RT=1.92 min; LC/MS: Anal. Calcd. for [M+H]+ C31H30NO3: 464.45; found 464.52.

Workup

  1. customprepared above, and
  2. customThe reaction mixture was removed from the cooling bath
  3. additionrapidly poured into ˜1M H3PO4/H2O (250 mL)
  4. stirringwith stirring
  5. extractionthe mixture was extracted with ether (100 mL, 2×)
  6. washThe combined organic phase was washed with brine
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customA silica gel mesh of the crude material was prepared
  11. washsubmitted to chromatography (25% EtOAc/hexanes; gravity elution)

Sources & evidence

ORD record
ord-b2b914bd8a834c0290dbe23db1bb0dc2
Source dataset
uspto-grants-2013_03
Patent number
US08394968B2

Reaction notes

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