Chemoenzymatic Synthesis of Optically Active Mandelic Acid Employing Continuous-Flow Resolution of Cyanohydrin as a Key Step

Resumo

Optically active mandelic acid is important to organic synthesis in stereochemical investigations and as a precursor of different pharmaceuticals. Therefore, several synthetic methodologies have been developed for its synthesis, including biocatalytic approaches.  Among the biocatalyzed reactions, lipase-mediated enzymatic kinetic resolution (EKR) reactions are advantageous, since both enantiomers can be achieved. However, limitations are observed in direct EKR of mandelic acid and its ester derivatives, related to enzyme inhibition and structural dependence to achieve high enantioselectivity. Herein, a chemo-enzymatic approach is proposed to achieve optically active mandelic acid from a continuous-flow lipase-mediated resolution of mandelonitrile followed by separation and chemical hydrolysis of nitrile moiety. Using this strategy, both mandelic acid enantiomers were obtained in good isolated yields and high enantiomeric excesses (R enantiomer: 70% yield; e.e. = 94%; S enantiomer: 80% yield; e.e. = 98%).