Optically active (S)-3-methylphthalide was synthesized by the enzymic reduction of 2-iodoacetophenone using baker’s yeast, followed by palladium-catalysed carbonylation under carbon monoxide. With enzymic reduction using baker’s yeast, however, 2-bromo- or 2-iodovarelophenones were not reduced, even after 25 days. On the other hand, the enantioselective hydrolysis of alpha-alkylated 2-halobenzyl acylates using pig liver esterase, horse liver esterase or lipase from Candida rugosa resulted in the formation of (R)-alpha-alkylated 2-halobenzyl alcohol and (S)-acylate, and the following palladium-catalysed carbonylation of the products yielded the (R)- and (S)-3-alkylated phthalides, respectively.