Chemoenzymatic Synthesis of Proxyphylline Enantiomers

Paweł Borowiecki , Daniel Paprocki , Agnieszka Dudzik , Jan Plenkiewicz

Abstract

A 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.
Author Paweł Borowiecki ZTiBSL
Paweł Borowiecki,,
- Department Of Drug Technology And Biotechnology
, Daniel Paprocki WCh
Daniel Paprocki,,
- Faculty of Chemistry
, Agnieszka Dudzik
Agnieszka Dudzik,,
-
, Jan Plenkiewicz WCh
Jan Plenkiewicz,,
- Faculty of Chemistry
Journal seriesJournal of Organic Chemistry, ISSN 0022-3263
Issue year2016
Vol81
No2
Pages380-395
Publication size in sheets0.75
Keywords in EnglishLipase Catalysis; Kinetic Resolution; Proxyphylline; lipase B from Candida antarctica, 1,3-Dimethylxanthines, Docking
DOIDOI:10.1021/acs.joc.5b01840
URL http://pubs.acs.org/doi/abs/10.1021/acs.joc.5b01840
Languageen angielski
File
wdpb_publikacje_pliki_plik_publikacja_2720_org.pdf (file archived - login or check accessibility on faculty) wdpb_publikacje_pliki_plik_publikacja_2720_org.pdf 3.46 MB
Score (nominal)40
ScoreMinisterial score = 35.0, 28-11-2017, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 28-11-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 4.849 (2) - 2016=4.425 (5)
Citation count*0
Cite
Share Share



* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
Back