Chemoenzymatic enantioselective and stereo-convergent syntheses of lisofylline enantiomers via lipase-catalyzed kinetic resolution and optical inversion approach
Authors:
- Paweł Borowiecki,
- Beata Zdun,
- Maciej Dranka
Abstract
Highly enantioselective enzymatic kinetic resolution (EKR) of racemic lisofylline is presented for the first time. A comprehensive optimization of the key parameters of lipase-catalyzed transesterification of racemic lisofylline revealed that optimal biocatalytic system consisted of immobilized lipase type B from Candida antarctica (Chirazyme L-2, C-3) suspended in a mixture of 3 equiv of vinyl acetate as an acetyl donor and ethyl acetate as a solvent. Under optimal reaction conditions, the 1 g-scale (Chirazyme L-2, C-3)-catalyzed kinetic resolution of racemic lisofylline furnished both the EKR products in a homochiral form (>99 % ee) with the 50 % conv., and the highest possible enantioselectivity. The best results in terms of the reaction yields (47–50 %) and enantiomeric purity of the kinetically-resolved optically active products were achieved when the preparative-scale EKR was carried out for 2 h at 60 °C. In addition, stereoinversion of the less biologically-relevant (S)-lisofylline into its (R)-enantiomer was successfully achieved via acetolysis of the respective optically pure (S)-mesylate by using 2 equiv of ceasium acetate and catalytic amount of 18-Crown-6 in dry toluene, followed by K2CO3-mediated methanolysis of (R)-acetate. The elaborated EKR methodology together with enantioconvergent strategy provided a useful chemoenzymatic protocol for the synthesis of complementary enantiomers of titled API. Moreover, we report on the first single-crystal X-ray diffraction (XRD) analyses performed for the synthesized lisofylline enantiomers. Insight into the source of CAL-B stereoselectivity toward racemic lisofylline was gained by molecular docking experiments. In silico theoretical predictions matched very well with experimental results.
- Record ID
- WUT7bb40c3d48814926bdd478913cc6cf95
- Author
- Journal series
- Molecular Catalysis, ISSN 2468-8231
- Issue year
- 2021
- Vol
- 504
- Pages
- 1-20
- Article number
- 111451
- DOI
- DOI:10.1016/j.mcat.2021.111451 Opening in a new tab
- URL
- https://www.sciencedirect.com/science/article/abs/pii/S2468823121000687 Opening in a new tab
- Language
- (en) English
- File
-
- File: 1
- wdpb_publikacje_pliki_plik_publikacja_4273_org.pdf
-
- Score (nominal)
- 70
- Score source
- journalList
- Score
- = 70.0, 14-12-2021, ArticleFromJournal
- Publication indicators
- = 1; : 2019 (2 years) = 3.687 - 2019 (5 years) =3.690
- Uniform Resource Identifier
- https://repo.pw.edu.pl/info/article/WUT7bb40c3d48814926bdd478913cc6cf95/
- URN
urn:pw-repo:WUT7bb40c3d48814926bdd478913cc6cf95
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or PerishOpening in a new tab system.