Chemoenzymatic Synthesis of Proxyphylline Enantiomers

Paweł Borowiecki , Daniel Paprocki , Agnieszka Dudzik , Jan Plenkiewicz


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 (FC / IBC / DDTB)
Paweł Borowiecki,,
- Department Of Drug Technology And Biotechnology
, Daniel Paprocki (FC)
Daniel Paprocki,,
- Faculty of Chemistry
, Agnieszka Dudzik - [Institute of Catalysis and Surface Chemistry of the Polish Academy of Sciences]
Agnieszka Dudzik,,
, Jan Plenkiewicz (FC)
Jan Plenkiewicz,,
- Faculty of Chemistry
Journal seriesJournal of Organic Chemistry, ISSN 0022-3263
Issue year2016
Publication size in sheets0.75
Keywords in EnglishLipase Catalysis; Kinetic Resolution; Proxyphylline; lipase B from Candida antarctica, 1,3-Dimethylxanthines, Docking
ASJC Classification1605 Organic Chemistry
Languageen angielski
wdpb_publikacje_pliki_plik_publikacja_2720_org.pdf 3.46 MB
Score (nominal)40
Score sourcejournalList
ScoreMinisterial score = 35.0, 02-02-2020, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 02-02-2020, ArticleFromJournal
Publication indicators Scopus Citations = 10; WoS Citations = 8; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.048; WoS Impact Factor: 2016 = 4.849 (2) - 2016=4.425 (5)
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