Stereoselective Synthesis of Enantiopure Oxazolidinones via Biocatalytic Asymmetric Aminohydroxylation of Alkenes

Zhou, Xiaoying; Wan, Nan‐Wei; Li, Yingna; Ma, Ran; Cui, Bao‐Dong; Han, Wen‐Yong; Chen, Yong‐Zheng

doi:10.1002/adsc.202100468

Cited by 14 publications

(10 citation statements)

References 44 publications

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“…41,42 In order to solve the problem of low stereoselectivity, a cascade reaction using enantioselective styrene monooxygenase, which provided the enantio-enriched styrene oxides, and IcHheG was constructed, and chiral 4-phenyl-2-oxazolidinone was obtained in 99% ee and 60% yield. 43 Very recently, the newly discovered HHDHamb 44 has catalyzed the kinetic resolution of phenyl epoxide at the α-position by nitrite. When the reaction conditions were set at an unusually low temperature of 0.5 °C, chiral β-nitroalcohol was obtained with 41% yield and 99% ee.…”

Section: ■ Introductionmentioning

confidence: 99%

Flipping the Substrate Creates a Highly Selective Halohydrin Dehalogenase for the Synthesis of Chiral 4-Aryl-2-oxazolidinones from Readily Available Epoxides

Zhou

Chen

et al. 2023

ACS Catal.

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Chiral oxazolidinones are a class of important heterocyclic compounds in pharmaceutical chemistry due to their biological activity. Halohydrin dehalogenase-catalyzed epoxide ring-opening reaction with cyanate offers an attractive approach to the synthesis of chiral oxazolidinones, but the α/β-regioselectivity and stereoselectivity are still un-addressed issues. In this study, a unique halohydrin dehalogenase (AbHheG) was found to have high activity and α/β-regioselectivity toward the ring opening of racemic styrene oxide with cyanate but with poor stereoselectivity (E < 3). By reshaping the substrate-binding site of AbHheG, a variant Y15M/N182S was obtained with excellent α/β-regioselectivity and stereoselectivity. The variant showed E > 200 for 9 of the 13 tested styrene oxides. Since (R)-4-aryl-2-oxazolidinones were easily separated from (R)-styrene oxides, both (R)- and (S)-4-aryl-2-oxazolidinones could be readily prepared. Crystallographic and enzyme–substrate docking analysis showed that flipping of the substrate in the binding site resulted in the R-configuration substrate being away from the catalytic triad in the mutant, which was responsible for the enhanced α/β-regioselectivity and stereoselectivity. This work has demonstrated that halohydrin dehalogenase is a useful biocatalyst for the synthesis of both enantiomers of 4-aryl-2-oxazolidinones from readily available racemic styrene oxides. The structural and computational studies provide a guidance for further engineering of halohydrin dehalogenases to control the α/β-regioselectivity and stereoselectivity for the efficient synthesis of the desired optically pure 4- or 5-substituted 2-oxazolidinones.

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Section: ■ Introductionmentioning

confidence: 99%

Flipping the Substrate Creates a Highly Selective Halohydrin Dehalogenase for the Synthesis of Chiral 4-Aryl-2-oxazolidinones from Readily Available Epoxides

Zhou

Chen

et al. 2023

ACS Catal.

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“…Wan and Chen combined styrene monooxygenases (SMOs) with halohydrin dehydrogenases (HheX) to convert substituted styrenes to chiral oxazolidinones . The enantioselectivity is established in the epoxidation step, which affords ( S )-styrene epoxide 129 (Scheme ).…”

Section: Cascade Biocatalysismentioning

confidence: 99%

Highlights of the Recent Patent Literature─Focus on Biocatalysis Innovation

Hughes¹

2022

Org. Process Res. Dev.

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This review surveys recent advances in biocatalysis, with a primary focus on contributions from the patent literature since 2018, including reductive aminations, nitro reductions, amidations, carbon–carbon bond formation catalyzed by lipases and aldolases, and cascade biocatalysis. Examples of processes that have been designed and developed for the industrial preparation of pharmaceutical intermediates are highlighted.

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“…[18][19][20]24,[32][33][34][35][36][37] Activity towards ortho-substituted SO is limited solely to an o-F (1a) derivative, as observed in this study and previously by others. [36][37][38][39] A larger substituent at this position might not allow placing of a ligand in a productive orientation. This prompted us to probe the activity of HheC towards the substrate bearing another valuable but larger fluorine containing substituent, the trifluoromethyl group at the ortho position.…”

Section: Substrate Scope and Enantioselectivity Of Hhecmentioning

confidence: 99%