Enantioselective Alkylation of α-Fluoro-β-Keto Esters by Asymmetric Phase-Transfer Catalysis

Abstract

Highly enantioselective alkylation of tert-butyl α-fluoro-β-keto esters can be effected by the use of N-spiro chiral quaternary ammonium salt as chiral phase-transfer catalyst, as a complementary approach to the asymmetric fluorination of α-alkyl-β-keto esters.

Key words

phase-transfer catalysis - alkylations - asymmetric catalysis - esters - alkyl halides

References and Notes

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7

Typical Procedure for the Catalytic Asymmetric Alkylation of tert -Butyl 2-Fluoro-3-oxo-3-phenyl-propanoate (2b) under Phase-Transfer Conditions To a solution of phase-transfer catalyst (S,S)-1 (0.001 mmol, 0.9 mg) and 2b (0.10 mmol, 23.6 mg) in mesitylene (2 mL) was added benzyl bromide (0.12 mmol, 14.0 µL), and the mixture was cooled to 0 ˚C. After adding 10% aq CsOH (0.3 mL, ca. 0.2 mmol) to this mixture, the reaction mixture was vigorously stirred until the completion of the reaction. The mixture was then poured into sat. aq NH₄Cl and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on SiO₂ to give tert-butyl 2-benzyl-2-fluoro-3-oxo-3-phenylpropanoate (3b) as a colorless oil [82% (26.8 mg), 85% ee]. Enantiomeric purity was determined by HPLC analysis [Daicel Chiralpak OD, hexane-2-PrOH (300:1), flow rate = 0.5 mL/min, 254 nm, t _R= 18.8 min(minor) and 21.7 min(major)]. ^¹H NMR (400 MHz, CDCl₃): δ = 7.99-8.02 (2 H, m, ArH), 7.53-7.58 (1 H, m, ArH), 7.41-7.44 (2 H, m, ArH), 7.25-7.30 (5 H, m, ArH), 3.46-3.68 (2 H, m, PhCH₂), 1.29 (9 H, s, t-Bu).