Microbial asymmetric syntheses of 3-alkylphthalide derivatives

Phthalide derivatives, almost all of which have an S-configuration, have a wide range of activity and exist in Angerica sinensis Diels and Sligusticum wallichiii Franch. For the first time, optically active (S)-3-methylphthalide derivatives were synthesized using two methods, asymmetric microbial reduction and microbial hydroxylation. For the first method, methyl 2-acetylbenzoate was synthesized as a substrate, which was reduced asymmetrically by Geotrichum candidum IFO 34614 to obtain (S)-3-methylphtalide in 92% yield (99% enantiomeric excess, ee). For the second method, 2-ethylbenzoic acid was employed as a substrate which was hydroxylated asymmetrically at the benzylic position by either Pseudomonas putida ATCC 12633 or Aspergillus niger IFO 6661, whose fermentation was induced by o-toluic acid, to obtain (S)-3-methylphthalide in 80% yield (99% ee). (S)-3-Butylphthalide and (S)-3-octylphthalide were obtained in the same manner in 12% yield (ee=99%) and 10% yield (ee=99%), respectively. (C) 1997 Elsevier Science Ltd.