Highly Stereoselective Chemoenzymatic Synthesis of the 3H-Isobenzofuran Skeleton. Access to Enantiopure 3-Methylphthalides

A straightforward synthesis of (S)-3-methylphthalides has been developed, with the key asymmetric step being the bioreduction of 2-acetylbenzonitriles. Enzymatic processes have been found to be highly dependent on the pH value, with acidic conditions being required to avoid undesired side reactions. Baker's yeast was found to be the best biocatalyst acting in a highly stereoselective fashion. The simple treatment of the reaction crudes with aqueous HCl has provided access to enantiopure (S)-3-methylphthalides in moderate to excellent yields.