Asymmetric whole-cell bioreduction of sterically bulky 2-benzoylpyridine derivatives in aqueous hydrophilic ionic liquid media

The asymmetric reduction of 2-benzoylpyridine derivatives for enantiopure alcohols with excellent enantioselectivity and atom economy is still a challenging synthetic problem due to the coordination effects of 2-pyridine and substituents. In this study, we investigated an alternative cost-effective and green route for the enantioselective bioreduction of prochiral 2-benzoylpyridine derivatives employing a novel biocatalyst Cryptococcus sp. whole-cell to corresponding (S)-alcohols. This biocatalyst was more enantioselective toward the reduction of 2-benzoylpyridine derivatives with a para-substituent on the phenyl group, rather than those with an ortho- or meta-substituent. This property was quite contrary to the cases of known chemical catalysts. Moreover, Cryptococcus sp. whole-cell-catalyzed reduction of (4-chlorophenyl)-(pyridin-2-yl) methanone (CPMK) could proceed with perfect enantioselectivity in aqueous hydrophilic ionic liquid (IL) media, affording the product (S)-(4-chlorophenyl)-(pyridin-2-yl)methanol [(S)-CPMA] with excellent enantioselectivity (99% ee) and good conversion (89%), which is a crucial chiral synthon of new antiallergic drug, Betahistine. To overcome the known toxicity of hydrophilic ILs to cells, a high IL-tolerant mutant of Cryptococcus sp. (M9-3) was adopted in the reaction. The excellent tolerance of the biocatalyst to various hydrophilic ILs enabled the exploration of the positive effects of ILs on the biocatalytic efficiency and enantio-selectivity. In addition, the enzymatic hydrolyzate of bagasse was firstly used as the co-substrate during the asymmetric bioreduction of CPMK, with a higher conversion achieved (92%) than using pure glucose. This is a novel and economical route for the green synthesis of chiral diarylmethanols.