tert-Butyl((1S)-3-(benzyloxy)-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)carbamate (9)
To a 3 L multinecked flask equipped with an overhead stirrer, nitrogen inlet, and internal thermometer was charged N-(tert-butoxycarbonyl)-3-[(3S)-2-oxopyrrolidin-3-yl]-l-alanine (190 g, 698 mmol) followed by dichloromethane (1100 mL) and the solution was cooled to 0 °C employing an ice/NaCl bath. N,O-Dimethylhydroxylamine hydrochloric acid salt (68 g, 698 mmol) was added followed by N-methylmorpholine (230 mL, 2.09 mol), HOBt.hydrate (106 g, 698 mmol), and EDCI (147 g, 768 mmol), and the mixture was stirred at 0 °C under nitrogen for 6 h before quenching with water (500 mL). The biphasic mixture was transferred to a sep funnel, and the organics were isolated, washed with 1 M hydrochloric acid (2 × 500 mL), water (400 mL), satd. NaHCO3 (2 × 700 mL), and brine (300 mL) and then dried over MgSO4, filtered, and the solvents were evaporated in vacuo to yield tert-butyl ((1S)-2-[methoxy(methyl)amino]-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}ethyl)carbamate as a pale yellow solid, 173 g, 79%. 1H NMR (400 MHz, CDCl3) δ 5.92 (s, 1H), 5.39 (d, J = 8.8 Hz, 1H), 4.66 (td, J = 9.6, 2.8 Hz, 1H), 3.77 (s, 3H), 3.33 (dd, J = 9.3, 4.0 Hz, 2H), 3.19 (s, 2H), 2.41–2.62 (m, 2H), 2.05–2.16 (m, 1H), 1.75–1.95 (m, 1H), 1.67 (m, 1H), 1.41 (s, 9H).
To a 100 mL multinecked flask equipped with a stirrer bar, nitrogen inlet, and internal thermometer were charged magnesium turnings (dried in oven at 100 °C overnight, 1.04 g, 43 mmol) and HgCl2 (774 mg, 2.85 mmol), and the flask was purged with nitrogen for 10 min. THF (50 mL) was added, and the suspension was cooled to −45 °C before adding BOM-Cl (5.94 mL, 43 mmol), and the resulting suspension was stirred for 5 h, the temperature returning to 5 °C. The suspension was recooled to −50 °C, and tert-butyl ((1S)-2-[methoxy(methyl)amino]-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}ethyl)carbamate (1.5 g, 4.76 mmol) was added, and the thick suspension was stirred for 48 h under nitrogen and was allowed to come to an ambient temperature. The reaction was quenched by the careful addition of satd. NH4Cl solution (25 mL), and the mixture was stirred until effervescence ceased and then extracted with ethyl acetate (3 × 120 mL). The combined organics were dried over MgSO4, filtered, and the solvents were evaporated in vacuo to yield a crude orange gum, which was purified by flash chromatography, eluting with 1–3% methanol/dichloromethane to afford the title compound as a clear glass, 900 mg, 50%. 1H NMR (400 MHz, CDCl3) δ 7.21–7.33 (m, 5H), 5.63–5.73 (m, 2H), 4.52 (m, 3H), 4.19 (q, J = 17.4 Hz, 2H), 3.19–3.25 (m, 2H), 2.29–2.42 (m, 2H), 1.68–1.93 (m, 3H), 1.35 (s, 9H); MS (APCI+) for C20H28N2O5m/z 378.1 (M + H)+.