Chemoenzymatic Synthesis of Proxyphylline Enantiomers
Paweł Borowiecki , Daniel Paprocki , Agnieszka Dudzik , Jan Plenkiewicz
AbstractA novel synthetic route for preparation of proxyphylline enantiomers using a kinetic resolution (KR) procedure as e 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.
|Journal series||Journal of Organic Chemistry, ISSN 0022-3263|
|Publication size in sheets||0.75|
|Keywords in English||Lipase Catalysis; Kinetic Resolution; Proxyphylline; lipase B from Candida antarctica, 1,3-Dimethylxanthines, Docking|
|Score|| = 35.0, 28-11-2017, ArticleFromJournal|
= 40.0, 28-11-2017, ArticleFromJournal
|Publication indicators||: 2016 = 4.849 (2) - 2016=4.425 (5)|
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