Enantioselective Alkylation of 2-[(4- Chlorobenzyliden)Amino]Propanoic Acid tert-Butyl Ester: Synthesis of (R)-2-Amino-2-Methyl-3-Phenylpropanoic Acid tert-Butyl Ester

摘要

A. 2-[(4-Chlorobenzyliden)amino]propanoic acid tert-butyl ester. A 200-mL, three-necked, round-bottomed flask, equipped with an overhead mechanical stirrer (Note 1), a 10-mL pressure-equalizing dropping funnel (attached to an argon inlet), and a thermometer fitted with a thermometer adapter, is charged with L-alanine tert-butyl ester hydrochloride (5.00 g, 27.5 mmol, 1.05 equiv) (Notes 2 and 3), 4-chlorobenzaldehyde (3.69 g, 26.2 mmol, 1.00 equiv) (Note 4) and toluene (25.0 mL). The mixture is stirred at 400 rpm and triethylamine (4.20 mL, 30.1 mmol, 1.15 equiv) (Note 5) is added dropwise over 5 min through the dropping funnel at ambient temperature (Note 6). The addition funnel is removed and replaced with a reflux condenser fitted with an argon inlet. The reaction mixture is heated to 70 °C in an oil bath and stirred at 400 rpm for 4 h (Note 7). After cooling to ambient temperature, the reaction mixture is diluted by the addition of water (50 mL). The reaction mixture is transferred to a 500-mL separatory funnel and toluene (50 mL) is added. The organic layer is separated and washed with brine (2 × 50 mL). The organic solution is dried over sodium sulfate (20 g), filtered, and concentrated on a rotary evaporator (15 mm Hg, 35 °C). The residue is dried by stirring under reduced pressure (0.2 mm Hg) at 23 °C for 2 h to afford the crude aldimine product (6.66 g,, 95% yield) (Note 8) as an amber oil (Note 9).