Reaction Steps
Under N2, n-butyllithium (56 mL, 2.5 M in hexane, 0.14 mol) is added to the mixture of HMDS (24.2 g, 0.15 mol) in 300 mL dry tetrahydrofuran at −10° C., the resulting mixture is then stirred for 30 min at −10° C. A mixture of (S)-2-biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1=t-butoxycarbonyl) (35.1 g, 0.1 mol) in 50 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., after about 30 min, n-butyllithium (40 mL, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 100 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 24.3 g, 0.3 mol), K2CO3 aqueous solution (27.6 g in 100 mL water, 0.2 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 1.3 g, 5 mmol) are added to the remaining organic phase, and heated to 50° C., and stirred for 2 hours. Then the reaction mixture is diluted with 100 mL brine and stirred for 15 min, stop stirring, and remove the lower aqueous layer. the organic phase is then concentrated in vacuo. ethyl acetate 200 mL is added, filtered and the filtrate concentrated to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=t-butoxycarbonyl). Crude (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=t-butoxycarbonyl) is purified by column chromatography eluting with 3:1 heptane/ethyl acetate. 1HNMR (400 MHz, CDCl3): 1.62 (s, 9H, (CH3)3), 2.56 (m, 1H, 3-CHH), 2.60 (m, 1H, 3CHH), 2.70 (d, 1H, 5-CHH), 3.26 (d, 1H, 5-CHH), 4.43 (m, 1H, 4-CH), 5.45 (d, 1H, C═CHH), 6.17 (d, 1H, C═CHH), 7.20˜7.60 (9H, m, aromatic).; m/z (+ESI) 381 ([MNa]+, 7%), 364 ([MH]+, 12), 308(100), 264 (10). the ratio of intermediate (3S,5S-4, R1=t-butoxycarbonyl, R4=phenyl) to (3R,5S-4, R1=t-butoxycarbonyl, R4=phenyl) is 70:30 as determined by HPLC.
