Synthesis of Tetracyclic Compounds 217 and 216

Example 183

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To a mixture of LHMDS (1 M, 1.0 mL, 1.5 eq) in THF (3 mL) was added compound 183-1a (143.1 mg, 0.81 mmol, 0.13 mL, 1.2 eq) at 0° C. and stirred for 30 min. Then compound 183-1 (250 mg, 0.67 mmol, 1 eq) in THF (3 mL) was added to the mixture and stirred for 2 hr at 25° C. The reaction mixture was quenched with saturated aq.NH₄Cl (4 mL), extracted with EA (5 mL*3). The combined organic phase was washed with H₂O (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated in vacuum. The crude product was purified by flash silica gel chromatography. Then the product was purified by SFC (column: Phenomenex-Amylose-1 (250 mm*30 mm, 5 um); mobile phase: [0.1% NH₃H₂O ETOH]; B %: 35%-35%, min). Compound 217 (68.81 mg, 0.17 mmol, 25.9% yield) was obtained. Compound 216 (27.0 mg, 67 umol, 10.0% yield) was obtained. Compound 216 LCMS (ESI): RT=0.858 min, mass calcd. For C₂₃H₁₇F₃N₂O, 394.13 m/z found 394.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.94-7.86 (m, 1H), 7.78 (d, J=8.5 Hz, 3H), 7.68-7.59 (m, 3H), 7.52 (dd, J=1.3, 7.0 Hz, 1H), 6.65 (td, J=7.7, 11.0 Hz, 1H), 6.43 (br t, J=5.5 Hz, 1H), 5.46 (d, J=10.8 Hz, 1H), 3.75 (q, J=6.4 Hz, 2H), 2.90-2.75 (m, 2H).