The reliable design and prediction of enzyme promiscuity to access transformations not observed in nature remains a long‐standing challenge. Herein, we present the first example of an intramolecular stereoselective Stetter reaction catalyzed by benzaldehyde lyase, guided by the rational structure screening of various ThDP‐dependent enzymes using molecular dynamics (MD) simulations. After optimization, high productivity (up to 99 %) and stereoselectivity (up to 99:1 e.r.) for this novel enzyme function was achieved.
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 Senantioselectivity 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.
The reliable design and prediction of enzyme promiscuity to access transformations not observed in nature remains a long‐standing challenge. Herein, we present the first example of an intramolecular stereoselective Stetter reaction catalyzed by benzaldehyde lyase, guided by the rational structure screening of various ThDP‐dependent enzymes using molecular dynamics (MD) simulations. After optimization, high productivity (up to 99 %) and stereoselectivity (up to 99:1 e.r.) for this novel enzyme function was achieved.
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