Reaction Steps
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.02 g, 0.052 mmol, example 1) in DCM (3 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.059 g, 0.272 mmol) followed by DCC (0.032 g, 0.157 mmol) and DMAP (6.39 mg, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (10 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 35% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (27 mg, 79%). LC/MS (Conditions A) RT=2.523 min, (M+H)+=582.2. 1H NMR (400 MHz, methanol-d4) δ 7.36 (d, J=8.5 Hz, 2H), 7.18 (s, 4H), 7.08 (d, J=8.5 Hz, 2H), 4.80-4.59 (m, J=10.0, 10.0, 5.0 Hz, 1H), 4.51 (d, J=15.0 Hz, 1H), 4.39 (d, J=15.0 Hz, 1H), 4.23 (dd, J=8.3, 6.3 Hz, 1H), 3.72 (t, J=8.8 Hz, 1H), 3.56-3.40 (m, 1H), 3.32-3.22 (m, 2H), 2.86-2.61 (m, 2H), 2.47 (td, J=10.0, 5.0 Hz, 1H), 2.34 (s, 3H), 2.32-2.23 (m, 1H), 2.22-2.01 (m, 2H), 1.88 (dd, J=9.5, 4.0 Hz, 2H), 1.74 (dt, J=13.4, 3.8 Hz, 1H), 1.50 (s, 9H), 1.42-1.30 (m, 1H), 1.09 (dd, J=10.0, 7.0 Hz, 6H). 19F NMR (376 MHz, methanol-d4) δ −184.32.
