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Synlett 2006(15): 2395-2398  
DOI: 10.1055/s-2006-949650
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Liting Chai, Huansheng Chen, Zhiming Li, Quanrui Wang*, Fenggang Tao
Department of Chemistry, Fudan University, 200433 Shanghai, P. R. of China
Fax: +86(21)65641740; e-Mail: qrwang@fudan.edu.cn;
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Publication History

Received 27 March 2006
Publication Date:
08 September 2006 (online)

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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.

Key words

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

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This work was first communicated at the 15th 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.

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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.