SCHEDULED MAINTENANCE
Asymmetric synthesis of optically active phthalides via ortho-lithiation and cyclization of chiral N-monosubstituted benzamides
Abstract
The chiral N-monosubstituted benzamides 1a–d, derived from (S)-(–)-α-phenylethylamine and L-(–)-phenylalanine, gave the ortho-lithiated species on treatment with butyllithium (2.2 equiv.) and TMEDA in THF at 0 °C. The resulting lithio amides reacted smoothly with aldehydes to afford the expected ortho substituted products 2a–d as diastereoisomeric mixtures, which were converted quantitatively into the phthalides 3a, b on acidic hydrolysis. Use of (S)-(–)-N-benzoyl-O-methylphenylalaninol 1c and (S)-(–)-N-(3-methoxybenzoyl)-O-methylphenylalaninol 1d as the amide resulted in consistently high diastereoselectivities. The reaction of the dianions derived from 1c with valeraldehyde gave, after cyclization, (S)-(–)-3-butylphthalide, an essential oil of celery, with 83% e.e.
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