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Sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added to a solution of (−)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1a) (0.116 g, 0.56 mmol) and 3-phenoxybenzaldehyde (1.15 g, 0.56 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour and then partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography (silica gel, hexane:ethyl acetate) to give (−)-(trans)-ethyl-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate (III-2a) (0.167 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 3H), 7.11 (t, J=7.32 Hz, 2H), 7.02 (m, 1H), 6.99 (d, J=8.60 Hz, 2H), 6.92 (d, J=8.42 Hz, 2H), 6.89 (m, 1H), 6.54 (d, J=8.60 Hz, 2H), 4.19 (s, 2H), 4.17 (q, J=7.14 Hz, 2H), 4.03 (br s, 1H), 2.44 (m, 1H), 1.78 (m, 1H), 1.52 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 388 (MH+). Aqueous sodium hydroxide (1.0 mL of a 25% solution) was added to a solution of III-2a (0.167 g, 0.43 mmol) in 4 mL of methanol and the mixture was heated at reflux for 8 hours. The volatile solvents were removed under vacuum, water was added, and the pH was adjusted to 5 with saturated aqueous sodium bisulfate. The mixture was extracted with dichloromethane, the organic phase was dried over sodium sulfate and concentrated to give 0.192 g of the title compound (III-3a) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.34 (t, J=8.42 Hz, 2H), 7.29 (t, J=7.87 Hz, 1H), 7.10 (m, 2H), 6.98 (s, 1H), 6.93 (d, J=7.68 Hz, 2H), 6.81 (d, J=8.42 Hz, 1H), 6.75 (d, J=8.23 Hz, 2H), 6.42 (d, J=8.42 Hz, 2H), 6.08 (m, 1H), 4.20 (m, 2H), 2.02 (m, 1H), 1.44 (m, 1H), 1.15 (m, 1H), 0.91 (m, 1H). ES-MS m/z 360 (MH+). [α]25,D=−187° (dichloromethane, c=4). Product was determined to be >99% ee by chiral SFC according to Method 1.
