Enantioselective Hydrogenation of β-Ketoesters Using a MeO-PEG-Supported Biphep Ligand under Atmospheric Pressure: A Practical Synthesis of (S)-Fluoxetine

Abstract

The preparation of a novel chiral 2,2′-bis(MeO-PEG-supported)-6,6′-bis(diphenylphosphanyl)biphenyl (MeO-PEG-Biphep) ligand is described. The derived ruthenium complex catalyzes the hydrogenation of β-ketoesters in up to 99% yield and 99% ee under atmospheric pressure. The accelerating effects exerted by the PEG linkage are dramatic when compared to the unsupported analogue, MeO-Biphep-RuBr₂. Furthermore, the catalyst can be recovered easily and the recycled catalysts were shown to maintain their efficiency in two consecutive runs, albeit with declining activity. One of the products, (S)-ethyl-3-hydroxy-3-phenylpropanoate, is useful in the preparation of (S)-fluoxetine.

asymmetric synthesis - supported catalysis - hydrogenation - biphenyl ligands - fluoxetine

References and Notes

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11

This work was first communicated at the 15^th International Symposium on Fine Chemistry and Functional Polymers held at Shanghai during October 2005.

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Preparation of ( R )-3: MeO-PEG-OMs (2.6 g, 1.24 mmol), (6,6′-dihydroxybiphenyl-2,2′-diyl)bis(diphenylphosphine) (2) (0.34 g, 0.62 mmol) and Cs₂CO₃ (0.8 g, 2.44 mmol) were added to rigorously degassed DMF (20 mL). The resulting stirred solution was heated to 65 °C for 18 h. Most of the DMF was removed under reduced pressure. The resulting mixture was cooled to 0 °C, H₂O (20 mL) and HCl (2 M, 2 mL) were added carefully and the mixture was extracted with CH₂Cl₂ (2 × 20 mL). The CH₂Cl₂ extracts were combined and washed with brine (20 mL), dried over MgSO₄ and concentrated (to ˜ 4 mL). Et₂O (400 mL) was added to the solution and the mixture was stirred under 0 °C for 0.5 h. The resulting precipitate was isolated by filtration and washed with cold i-PrOH (30 mL) and Et₂O (100 mL), to give the supported ligand (R)-3 as an off-white solid (2.6 g, 92%). ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.12-7.31 (m, 22 H), 6.82 (d, J = 8.4 Hz, 2 H), 6.57 (d, J = 7.0 Hz, 2 H), 3.2-3.8 (polyethylene glycol peaks, ˜380 H). ³¹P NMR (400 MHz, CDCl₃): δ = -14.05 (s).

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Catalyst Preparation: To a mixture of diphosphine ligand 3 (60 mg, 0.0126 mmol) and bis(2-methylallyl)cycloocta-1,5-diene ruthenium (II) complex (4 mg, 0.0126 mmol) in anhydrous degassed acetone (1.5 mL) was added 0.18 M methanolic HBr (0.14 mL, 0.025 mmol). The amber mixture was stirred at room temperature for 0.5 h and the solvent removed thoroughly in vacuo to leave the active catalyst, which was used immediately as a hydrogenation catalyst.

16 Fan Q.-H. Deng G.-J. Lin C.-C. Chan ASC. Tetrahedron: Asymmetry  2001,  12:  1241 

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Typical Hydrogenation Procedure: The appropriate ketone (0.63 mmol) was dissolved in degassed EtOH (1 mL) and the solution was canulated into a Schlenk tube and degassed by 3 cycles of vacuum/argon. The mixture was added to the in situ generated catalyst (2 mol%) in a glass vessel and placed under argon. The argon atmosphere was replaced with H₂ (1 atm) and the mixture was heated for the period specified in Table [2] . After the reaction was complete, the mixture was cooled to 0 °C and the residue was treated with cooled Et₂O (30 mL). The precipitated polymeric catalyst was collected by filtration for reuse in the next run. Both the yield and the ee value of the alcohol were determined from the filtrate.