Reaction Steps
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (200 mg, 0.28 mmol) in THF (5 mL) was added 4-fluorophenylmagnesium bromide (4.30 mL, 1.0 M solution in THF, 4.30 mmol) at −30° C. The mixture was stirred under nitrogen for 30 min. The reaction mixture was quenched with water (0.30 mL), the reaction was brought to room temperature and pH was adjusted to 7 with 1N HCl. The reaction mixture was extracted with dichloromethane (3×50 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-methyl 12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate as a diastereomer A (13 mg, 7%) and as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.58-7.55 (m, 2H), 7.53 (s, 1H), 7.13-7.07 (m, 2H), 6.60 (s, 1H), 5.69 (s, 1H), 4.93 (br s, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.58-3.46 (m, 5H), 3.37-3.33 (m, 2H), 3.25-3.21 (m, 1H), 2.92 (t, J=9.0 Hz, 1H), 2.41 (s, 3H), 1.35-1.25 (m, 2H), 1.17 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 794 (M+H); HPLC 95.4% (AUC), tR 13.49 min.
