Asymmetric reduction of a key intermediate of eslicarbazepine acetate using whole cell biotransformation in a biphasic medium

Singh, Manpreet; Singh, Sawraj; Deshaboina, Sateesh; Krishnen, Hare; Lloyd, Richard C.; Holt-Tiffin, Karen E.; Bhattacharya, Apurba; Bandichhor, Rakeshwar

doi:10.1039/c2cy00537a

Cited by 17 publications

(8 citation statements)

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“…Enzymes generally require aqueous media in which the hydrophobic substrates are poorly soluble and even unstable. A straightforward solution to this issue might be the application of an aqueous organic solvent system [ 28 , 29 ]. There are several documented cases in which organic solvents can affect the enzymatic activity [ 30 – 33 ].…”

Section: Discussionmentioning

confidence: 99%

Efficient biosynthesis of ethyl (R)-4-chloro-3-hydroxybutyrate using a stereoselective carbonyl reductase from Burkholderia gladioli

et al. 2016

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BackgroundEthyl (R)-4-chloro-3-hydroxybutyrate ((R)-CHBE) is a versatile chiral precursor for many pharmaceuticals. Although several biosynthesis strategies have been documented to convert ethyl 4-chloro-3-oxobutanoate (COBE) to (R)-CHBE, the catalytic efficiency and stereoselectivity are still too low to be scaled up for industrial applications. Due to the increasing demand of (R)-CHBE, it is essential to explore more robust biocatalyst capable of preparing (R)-CHBE efficiently.ResultsA stereoselective carbonyl reductase toolbox was constructed and employed into the asymmetric reduction of COBE to (R)-CHBE. A robust enzyme designed as BgADH3 from Burkholderia gladioli CCTCC M 2012379 exhibited excellent activity and enantioselectivity, and was further characterized and investigated in the asymmetric synthesis of (R)-CHBE. An economical and satisfactory enzyme-coupled cofactor recycling system was created using recombinant Escherichia coli cells co-expressing BgADH3 and glucose dehydrogenase genes to regenerate NADPH in situ. In an aqueous/octanol biphasic system, as much as 1200 mmol COBE was completely converted by using substrate fed-batch strategy to afford (R)-CHBE with 99.9 % ee at a space-time yield per gram of biomass of 4.47 mmol∙L−1∙h−1∙g DCW−1.ConclusionsThese data demonstrate the promising of BgADH3 in practical synthesis of (R)-CHBE as a valuable chiral synthon. This study allows for the further application of BgADH3 in the biosynthesis of chiral alcohols, and establishes a preparative scale process for producing (R)-CHBE with excellent enantiopurity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12896-016-0301-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Efficient biosynthesis of ethyl (R)-4-chloro-3-hydroxybutyrate using a stereoselective carbonyl reductase from Burkholderia gladioli

et al. 2016

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“…Substrate solubility is another important issue that can significantly affect these bioreductions. 24 Due to the fact that enzymatic reactions catalyzed by ADHs are generally carried out in an aqueous buffer solution to keep the enzyme stability, and since the majority of ketones of interest are highly hydrophobic, the use of organic cosolvents in biphasic [37][38][39] and monophasic systems [40][41][42] has been proposed. In the standard HT conditions, 5% v/v of 2-PrOH was used as a hydrogen donor and also helped to solubilize the substrates, but under the minimal setup 2% v/v of dimethylsulfoxide (DMSO) was added for solid ketone substrates that did not afford high conversions, to check whether their water-solubility could be an issue that would hamper higher degrees of alcohol formation.…”

Section: Comparison Of Enzymatic Activities and Conversions: Electronmentioning

confidence: 99%

Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones

et al. 2014

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Lactobacillus brevis ADH (LBADH) is an alcohol dehydrogenase that is commonly employed to reduce alkyl or aryl ketones usually bearing a methyl, an ethyl or a chloromethyl as a small ketone substituent to the corresponding (R)-alcohols. Herein we have tested a series of 24 acetophenone derivatives differing in their size and electronic properties for their reduction employing LBADH. After plotting the relative activity against the measured substrate volumes we observed that apart from the substrate size other effects must be responsible for the activity obtained. Compared to acetophenone (100% relative activity), other small substrates such as propiophenone, α,α,α-trifluoroacetophenone, α-hydroxyacetophenone, and benzoylacetonitrile had relative activities lower than 30%, while medium-sized ketones such as α-bromo-, α,α-dichloro-, and α,α-dibromoacetophenone presented relative activities between 70% and 550%. Moreover, the comparison between the enzymatic activity and the obtained final conversions using an excess or just 2.5 equiv. of the hydrogen donor 2-propanol, denoted again deviations between them. These data supported that these hydrogen transfer (HT) transformations are mainly thermodynamically controlled. For instance, bulky α-halogenated derivatives could be quantitatively reduced by LBADH even employing 2.5 equiv. of 2-propanol independently of their kinetic values. Finally, we found good correlations between the IR absorption band of the carbonyl groups and the degrees of conversion obtained in these HT processes, making this simple method a convenient tool to predict the success of these transformations.

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“…This can be considered to be beneficial in respect to retrieving the product. 102 However, it also decreases the extraction efficiency of other compounds in the aqueous phase, 103,104 and a more tedious wastewater treatment is required. 105 Finally, the compound can also be hard to separate from the product.…”

Section: Solvent Choices For Non-conventional Mediamentioning

confidence: 99%

Applied biocatalysis beyond just buffers – from aqueous to unconventional media. Options and guidelines

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Bocola³

et al. 2021

Green Chem.

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Asymmetric reduction of a key intermediate of eslicarbazepine acetate using whole cell biotransformation in a biphasic medium

Cited by 17 publications

References 25 publications

Efficient biosynthesis of ethyl (R)-4-chloro-3-hydroxybutyrate using a stereoselective carbonyl reductase from Burkholderia gladioli

Efficient biosynthesis of ethyl (R)-4-chloro-3-hydroxybutyrate using a stereoselective carbonyl reductase from Burkholderia gladioli

Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones

Applied biocatalysis beyond just buffers – from aqueous to unconventional media. Options and guidelines

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