An Accessible Continuous Flow Procedure for the Enantioselective Desymmetrization of a Key Precursor of Bioactive Myo-Inositol Derivatives

Abstract

We report herein continuous flow conditions for the TL-IM lipase-catalyzed enantioselective desymmetrization of 4,6-di-O-benzyl-myo-inositol, a relevant precursor of bioactive myo-inositol derivatives to the D-1-O-acetyl derivative. This study represents the first example of enantioselective desymmetrization of an inositol under continuous flow conditions. Given the roles of myo-inositol derivatives in cell biology research and medicine, practical, sustainable, and efficient preparative procedures for chiral inositols are highly desirable. Upon testing substrate solutions in vinyl acetate/hexanes at various ratios and passing them through a packed-bed lipase reactor, a home-made assembly, we identified optimal conditions. Reactions conducted in a 1.0:1.5 vinyl acetate/hexanes mixture at 45 °C achieved conversions of 97–95% with residence times of 2.6–1.6 min, respectively. Notably, reactions in a more hydrophobic solvent system (1.0:2.5 vinyl acetate/hexanes) also showed high conversions (95%) at a 1.6-min residence time, highlighting the benefits of increased solvent hydrophobicity. Productivity assessments and reuse experiments confirmed the robustness of the biocatalyst under flow conditions, contrasting with a significant decline in performance under batch conditions.