Aluminium lithium hydride → [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester

HRID 420303Notes

Reaction equation

HRID 420303 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:33])[NH:13][C@@H:14]1[C:19](=[O:20])[C@H:18]([CH2:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24]([F:32])[CH:23]=2)[CH2:17][S:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:33])[NH:13][C@@H:14]1[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]2[CH:23]=[C:24]([F:32])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([F:28])[CH:27]=2)[CH2:17][S:16][CH2:15]1)([CH3:10])([CH3:8])[CH3:9]

Participants

4

Reactant 2

HCID 21226445Aluminium lithium hydrideHCID 57386307HCID 57386307, compound

Product 1

HCID 57386308[(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a suspension of LiAlH4 (2.137 g, 53.5 mmol) in anhydrous THF (200 mL) was added under argon a solution of [(3R*,5S*)-5-(3,5-difluoro-4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (19.56 g, 48.6 mmol) in anhydrous THF (300 mL) below −70° C. over a period of 2 h. After stirring for 5 h at −78° C. the reaction was quenched with 4.2 mL H2O at 0° C., 4.2 mL 4N aq. NaOH and after stirring for 30 min an additional 12.6 mL H2O were added. After addition of MgSO4, the reaction mixture was filtered over Celite, and the colorless filtrate was evaporated. The title compound was obtained after two crystallizations from EtOH as a single diastereoisomer. The racemate [(3R*,4S*,5S*)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester was separated by preparative HPLC on Chiralpak AD-I (5×20 cm) with hexane-AcOEt-iPrOH 80:15:5 to yield the (3R,4S,5S)-diastereoisomer with >99% ee (peak 1) and the (3S,4R,5R)-diastereoisomer with >98% ee as light yellow crystalline solid: TLC (hexane-EtOAc 1:1) Rf=0.38; HPLC RtA=2.05 min; ESIMS [M+H-isobutylene]+=349; 1H NMR (400 MHz, CDCl3): δ 6.92 (d, 2H), 5.55 (d, 1H), 4.34 (m, 1H), 3.54 (m, 1H), 3.22 (dd, 1H), 2.91 (m, 1H), 2.75 (m, 1H), 2.46 (dd, 1H), 2.36 (dd, 1H), 2.26 (m, 2H), 2.03 (m, 1H), 1.36 (s, 9H).

Workup

  1. customwas quenched with 4.2 mL H2O at 0° C.
  2. stirring4.2 mL 4N aq. NaOH and after stirring for 30 min an additional 12.6 mL H2O
  3. additionwere added
  4. additionAfter addition of MgSO4
  5. filtrationthe reaction mixture was filtered over Celite
  6. customthe colorless filtrate was evaporated

Sources & evidence

ORD record
ord-127a852a06dc4c7e8fd9f2a33a44a6e5
Source dataset
uspto-grants-2012_01
Patent number
US08093406B2

Reaction notes

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