Reaction Steps
tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (0.096 g, 0.22 mmol, 1 equiv), ethyl (2Z)-3-amino-5-(4-fluorophenyl)-2-pentenoate (0.052 g, 0.22 mmol, 1 equiv), 4-carboxy-3-fluorobenzaldehyde (0.037 g, 0.22 mmol, 1 equiv), and piperidine (0.011 mL, 0.11 mmol, 0.5 equiv) were combined in toluene (0.5 mL). After 2 h at 90° C., the reaction was cooled to ambient temp. CAN (0.24 g, 0.44 mmol, 2 equiv) and H2O (0.5 mL) were added. After 0.5 h the layers were separated. The aqueous portion was extracted with EtOAc (2×1 mL) and the combined organic portions were concentrated to a brown oil. The crude oil was then treated with 4 N HCl in dioxane (1.0 mL). After 1 h, the mixture was concentrated to a brown oil. A CH2Cl2 solution (1.0 mL) of this crude oil was treated with Et3N (0.15 mL, 1.10 mmol, 5 equiv). After 8 h, the mixture was concentrated to a brown foam. A solution of the crude foam (0.028 g, 0.06 mmol, 1 equiv) in CH2Cl2 (0.5 mL) was treated with (−)-α-4-(pyridyl)ethylamine (0.015 g, 0.12 mmol, 2 equiv), EDCI (0.013 g, 0.07 mmol, 1.2 equiv), and HOBt (0.009 g, 0.07 mmol, 1.2 equiv). After 12 h at ambient temperature, the reaction was diluted with CH2Cl2 (1.0 mL) and treated with saturated aqueous NaHCO3 (1 mL). The organic portion was the washed with 1N HCl (1 mL) followed by brine (1 mL). Concentration gave a brown oil that was chromatographed radially (SiO2, 1 mm plate, EtOAc) to provide the title compound as a pale yellow foam (0.020 g, 59%): 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, J=5.1 Hz, 2H), 8.08 (t, J=8.2 Hz, 1H), 7.40 (d, J=5.2 Hz, 2H), 7.25–7.21 (m, 2H), 7.17–7.13 (m, 2H), 7.06–7.03 (m, 1H), 6.95 (t, J=8.6 Hz, 2H), 5.33–5.30 (m, 1H), 4.72 (dd, J=10.3, 6.3 Hz, 1H), 4.10–4.02 (m, 2H), 3.74–3.67 (m, 1H), 3.41–3.35 (m, 1H), 3.20–3.02 (m, 4H), 2.50.2.45 (m, 1H), 2.37–2.29 (m, 2H), 1.60 (d, J=7.2 Hz, 3H), 1.43–1.33 (m, 1H), 1.00 (t, J=7.1 Hz, 3H); low resolution MS (ES+) m/e 611 (MH+); RP-HPLC (Dynamax C-18 25 cm×4.1 mm; 50–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=6.37 min, 95% purity.
