Kinetic Resolution of Pipecolic Acid Using Partially-Purified Lipase from Aspergillus niger

Article abstract of DOI:10.1021/jo00087a023

Synthesis of biologically active peptides, alkaloids, and immunosuppresants such as FK506 requires enantiomerically-pure pipecolic acid (2-piperidinecarboxylic acid).We report an efficient kinetic resolution of pipecolic acid esters by enzyme-catalyzed hydrolysis.We screened commercially available hydrolases and identified crude lipase from Aspergillus niger (ANL) as the most enantioselective catalyst for the hydrolysis of (+/-)-methyl pipecolate, E=20+/-4 in favor of the (S)-enantiomer at pH 7.Changing of the ester group to n-pentyl or n-octyl did not increase the enantioselectivity, while addition of an N-acetyl group decreased the enantioselectivity.Partial purification of ANL by fractional precipitation with ammonium sulfate (25-45percent saturation) increased the enantioselectivity to >100.A synthetic scale resolution of (+/-)-n-octyl pipecolate using this partially purified ANL gave (S)-(-)-pipecolic acid (93percent ee, 0.89 g) and (R)-(+)-pipecolic acid (97percent ee, 1.20 g).Further purification of ANL confirmed that the lipase (apparent molecular weight of 32 kDa), and not an impurity, was responsible for the enantioselective hydrolysis of octyl pipecolate.