Enantioselective Synthesis of (+)-(S,S)-Reboxetine

Abstract

An efficient enantioselective synthesis leading directly to (+)-(S,S)-reboxetine has been described from commercially available trans-cinnammyl bromide using Sharpless asymmetric dihydroxylation as the key step.

Key words

dihydroxylation - hydrogenation - coupling - reboxetine - trans-cinnamyl bromide

References and Notes

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14

For the measurement of ee, the diol 4 was converted into the epoxide which was further converted into the corresponding (S)-Mosher’s ester by reaction with (R)-(-)-α-methoxy-α-(trifluoromethyl)phenyl acetyl chloride (CH₂Cl₂-DMAP, Et₃N, 0 °C, 4 h, 90% yield). The enantiomeric purity of the diol 4 was estimated to be 95%.

15

(2 R ,3 S )-1-Bromo-3-phenylpropane-2,3-diol ( 4). To a mixture of K₃Fe(CN)₆ (25.05 g, 76.1 mmol), K₂CO₃ (10.5 g, 76.1 mmol), NaHCO₃ (6.39 g, 76.1 mmol) and (DHQ)₂PHAL (197 mg, 1 mol%), in t-BuOH-H₂O (1:1, 126 mL) cooled to 0 °C, was added OsO₄ as a 0.1 M solution in toluene (0.3 mol%) followed by methanesulfonamide (2.4 g, 25.3 mmol). After stirring for 30 min at 0 °C, the trans-cinnamyl bromide (5 g, 25.3 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 24 h and then quenched with solid Na₂SO₃ (40 g). Stirring was continued for 45 min and the solution was extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (PE-EtOAc, 8:2) affording the diol 4 (4.9 g, 84%) as a colorless, syrupy liquid: [α]_D ²⁵ -8.66 (c 1.16, EtOH). IR (CHCl₃): 3368, 3055, 1595, 1452, 1265, 1049, 738, 702 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 3.11-3.19 (dd, J = 5.69 Hz, 1 H), 3.33-3.40 (dd, J = 3.92 Hz, 1 H), 4.25-4.38 (m, 1 H), 4.66-4.69 (d, J = 6.5 Hz, 1 H), 7.36-7.38 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 35.0, 74.5, 75.1, 126.0, 126.4, 127.9, 128.3, 139.5, 139.8. Anal. Calcd for C₉H₁₁BrO₂: C, 46.78; H, 4.80; Br, 34.58. Found: C, 46.66; H, 4.67; Br, 34.36. LCMS: 231.07 [M⁺].