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

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence