ASYMMETRIC-SYNTHESIS OF OPTICALLY-ACTIVE PHTHALIDES USING THE LITHIATED CHIRAL N-MONOSUBSTITUTED BENZAMIDES

Chiral N-monosubstituted benzamides (1a-f), derived from optically act ive amines and amino acids, caused ortho-lithiation with 2.2 molar amo unt of n-BuLi and TMEDA in THF at 0 degrees C. The resulting ortho-lit hiated benzamides reacted with aldehydes to afford adducts (2a-f) as d iastereoisomeric mixtures, which were converted into phthalides (3) on acidic hydrolysis in high yields. The reaction of benzamides derived from chiral amines with aldehydes exhibited low diastereoselectivity. The optical yields of 3 obtained by the cyclization of 2a-c were also low. The use of benzamides (1d-f) derived from chiral beta-methoxy ami nes remarkably enhanced the diastereoselectivity of 2d-f and the optic al yields of 3. The reaction of the dianion derived from (-)-N-[1-(met hoxymethyl)-2-methyl-propyl]benzamide (le) with pentanal followed by t he cyclization under acidic conditions produced(S)-(-)-3-butylphthalid e, an essential oil of celery, with 78% ee.