title: Chemoenzymatic Synthesis of Proxyphylline Enantiomers.
abstract: A novel synthetic route for preparation of proxyphylline enantiomers using a kinetic resolution (KR) procedure as the key step is presented. The reactions were catalyzed by immobilized Candida antarctica lipase B in acetonitrile. Three types of reactions were examined: (i) enantioselective transesterification of racemic proxyphylline with vinyl acetate as well as (ii) hydrolysis and (iii) methanolysis of its esters. The influence of reaction conditions on the substrate conversion and enantiomeric purity of the products were investigated. Studies on analytical scale reactions revealed that the titled API enantiomers could be successfully obtained with excellent enantiomeric excess (up to >99% ee). The process was easily conducted on a 5 g scale at 100 g/L. In a preparative-scale reaction, unreacted (S)-(+)-butanoate (97% ee) and (R)-(-)-alcohol (96% ee) were obtained after 2 days in yields of 45% and 46%, respectively. When the reaction time was extended to 6 days, (S)-(+)-butanoate was isolated in >99% ee and acceptable high enantioselectivity (E = 90). Importantly, the KR's products could be conveniently isolated by exploiting varying solubility of the ester/alcohol in acetonitrile at room temperature. In addition, a chiral preference of the CAL-B active site for the R-enantiomer was rationalized by in sillico docking studies.
authors.affiliation: Warsaw University of Technology , Faculty of Chemistry, Institute of Biotechnology, Koszykowa St. 3, 00-664 Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Borowiecki
authors.affiliation: Warsaw University of Technology , Faculty of Chemistry, Institute of Biotechnology, Koszykowa St. 3, 00-664 Warsaw, Poland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Paprocki
authors.affiliation: Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences , Niezapominajek St. 8, 30-239 Cracow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dudzik
authors.affiliation: Warsaw University of Technology , Faculty of Chemistry, Institute of Biotechnology, Koszykowa St. 3, 00-664 Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Plenkiewicz
mesh_terms: D000097:Acetonitriles / Q000737:chemistry*; D002175:Candida / Q000201:enzymology*; D002384:Catalysis; D004800:Enzymes, Immobilized / Q000737:chemistry*; D004952:Esters; D000431:Ethanol / Q000737:chemistry*; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013806:Theophylline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D004800:Enzymes, Immobilized; D004952:Esters; D005656:Fungal Proteins; C003237:proxyphylline; D000431:Ethanol; D013806:Theophylline; D008049:Lipase; C431349:lipase B, Candida antarctica