N,N,N',N'-Tetramethylethylenediamine → Methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-fluoro-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate

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To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl)methyl ether (D41, 500 mg, 1.67 mmol) and TMEDA (178 mg, 1.53 mmol) in dry THF (7 ml) at −78° C. under nitrogen atmosphere was added n-butyllithium 1.6M solution in hexanes (1 ml, 1.6 mmol) dropwise. The resulting suspension was stirred at −78° C. for 15 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 338 mg, 1.39 mmol) in dry THF (2 ml). The mixture was stirred at −78° C. for 1 h, then it was quenched with a saturated ammonium chloride aqueous solution. The phases were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15) affording the title compound as a white solid (254 mg, 39%); 1H NMR (300 MHz, CDCl3-d) δ (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1H); 7.42-7.25 (m, 1H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1H); 6.75-6.65 (m, 1H); 5.18 (s, 2H); 4.50-4.30 (m, 1H); 3.71 (s, 3H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1H); 2.15-1.90 (m, 1H); 1.40 (s, 9H).

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