Journal
ADVANCED SYNTHESIS & CATALYSIS
Volume 363, Issue 7, Pages 1867-1872Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adsc.202001367
Keywords
Rational design; Electronic effect; Lipase; Diarylmethanols; Kinetic resolution
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Funding
- National Natural Science Foundation of China [91956128]
- Zhejiang Provincial Natural Science Foundation [LY19B020014]
- Ph.D. Scientific Research Starting Foundation of Jiaxing University [CD70519086]
- Scientific Research Starting Foundation of Zhejiang University of Technology [2020105009029]
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Using an electronic effect-guided rational design strategy, significant improvement of enantioselectivity towards bulky pyridyl(phenyl)methanols is achieved in CALB mutants, leading to successful kinetic resolution of various phenyl pyridyl methyl acetates with good yields and ee values.
Herein, we developed an electronic effect-guided rational design strategy to enhance the enantioselectivity of Candida antarctica lipase B (CALB) mutants towards bulky pyridyl(phenyl)methanols. Compared to W104A mutant previously reported with reversed S-stereoselectivity toward sec-alcohols, three mutants (W104C, W104S and W104T) displayed significant improvement of S-enantioselectivity in the kinetic resolution (KR) of various phenyl pyridyl methyl acetates due to the increased electronic effects between pyridyl and polar residues. The electronic effects were also observed when mutating other residues surrounding the stereospecificity pocket of CALB, such as T42A, S47A, A281S or A281C, and can be used to manipulate the stereoselectivity. A series of bulky pyridyl(phenyl) methanols, including S-(4-chlorophenyl)(pyridin-2-yl) methanol (S-CPMA), the intermediate of bepotastine, were obtained in good yields and ee values.
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