Diisobutylaluminum hydride → (3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one

HRID 417907Notes

Reaction equation

HRID 417907 reaction equation
CC(C[AlH]CC(C)C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O[CH2:21][C@@H:22]([CH3:54])[C@H:23]([NH:34][C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:24]([O:26]CC1C=CC=CC=1)=[O:25]>C1COCC1>[CH3:21][C@@H:22]1[CH2:54][O:26][C:24](=[O:25])[C@H:23]1[NH:34][C:35]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:46]2[C:47]1=[CH:42][CH:43]=[CH:44][CH:45]=2

Participants

5

Reactant 3

HCID 14487Diisobutylaluminum hydrideHCID 2733832Lithium HexamethyldisilazideHCID 67176385(2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate

Product 1

HCID 66648558(3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The relative stereochemical assignments of the DIBAL-reduction products were made based on NOE studies conducted on lactone derivatives prepared from each isomer by employing the following protocol: LiHMDS (50 μL of 1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg, 0.135 mmol), and the reaction mixture was stirred at similar temperature for ˜2 hr. The volatile component was removed in vacuo and the residue was partitioned between CH2Cl2 (30 mL), water (20 mL) and saturated aqueous NH4Cl solution (1 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo, and the resulting crude material was submitted to a Biotage purification (40 g silica gel; 10-15% EtOAc/hexanes) to afford (3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one as a colorless film of solid (28.1 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one. (3S,4S)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.83 (d, J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8, NH), 3.45 (app t, J=9.2, 1H), 2.47 (m, 1H, partially overlapped with solvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1): RT=1.98 min; LC/MS: Anal. Calcd. for [M+Na]+ C24H21NNaO2: 378.15; found 378.42. (3S,4R)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd, J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 11H), 2.96 (d, J=3.0, NH), 2.92 (dd, J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03 min; LC/MS: Anal. Calcd. for [M+Na]− C24H21NNaO2: 378.15; found 378.49.

Workup

  1. customderivatives prepared from each isomer
  2. customThe volatile component was removed in vacuo
  3. customthe residue was partitioned between CH2Cl2 (30 mL), water (20 mL) and saturated aqueous NH4Cl solution (1 mL)
  4. dry with materialThe organic layer was dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customthe resulting crude material was submitted to a Biotage purification (40 g silica gel; 10-15% EtOAc/hexanes)

Sources & evidence

ORD record
ord-001759d94551481f86ab973490a27958
Source dataset
uspto-grants-2012_01
Patent number
US08093243B2

Reaction notes

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