- Reprogramming Epoxide Hydrolase to Improve Enantioconvergence in Hydrolysis of Styrene Oxide Scaffolds
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Enantioconvergent hydrolysis by epoxide hydrolase is a promising method for the synthesis of important vicinal diols. However, the poor regioselectivity of the naturally occurring enzymes results in low enantioconvergence in the enzymatic hydrolysis of styrene oxides. Herein, modulated residue No. 263 was redesigned based on structural information and a smart variant library was constructed by site-directed modification using an “optimized amino acid alphabet” to improve the regioselectivity of epoxide hydrolase from Vigna radiata (VrEH2). The regioselectivity coefficient (r) of variant M263Q for the R-isomer of meta-substituted styrene oxides was improved 40–63-fold, and variant M263V also exhibited higher regioselectivity towards the R-isomer of para-substituted styrene oxides compared with the wild type, which resulted in improved enantioconvergence in hydrolysis of styrene oxide scaffolds. Structural insight showed the crucial role of residue No. 263 in modulating the substrate binding conformation by altering the binding surroundings. Furthermore, increased differences in the attacking distance between nucleophilic residue Asp101 and the two carbon atoms of the epoxide ring provided evidence for improved regioselectivity. Several high-value vicinal diols were readily synthesized (>88% yield, 90%–98% ee) by enantioconvergent hydrolysis using the reprogrammed variants. These findings provide a successful strategy for enhancing the enantioconvergence of native epoxide hydrolases through key single-site mutation and more powerful enzyme tools for the enantioconvergent hydrolysis of styrene oxide scaffolds into single (R)-enantiomers of chiral vicinal diols. (Figure presented.).
- Li, Fu-Long,Qiu, Yan-Yan,Zheng, Yu-Cong,Chen, Fei-Fei,Kong, Xu–Dong,Xu, Jian-He,Yu, Hui-Lei
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p. 4699 - 4706
(2020/09/21)
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- A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors
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The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14α-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV.
- Lepesheva, Galina,Christov, Plamen,Sulikowski, Gary A.,Kim, Kwangho
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supporting information
p. 4248 - 4250
(2017/10/12)
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- Ru-MACHO-Catalyzed Highly Chemoselective Hydrogenation of α-Keto Esters to 1,2-Diols or α-Hydroxy Esters
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A ruthenium pincer catalyst has been shown to be highly effective for the hydrogenation of a wide range of α-keto esters, affording either diols or hydroxy esters depending on the choice of reaction conditions. Strong base, high temperature, and pressure favor the formation of diols whilst the opposite is true for the hydroxy esters.
- Gao, Shaochan,Tang, Weijun,Zhang, Minghui,Wang, Chao,Xiao, Jianliang
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supporting information
p. 1748 - 1752
(2016/07/06)
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