Biocatalytic Ketone Reduction - A Study on Screening and Effect of Culture Conditions on the Reduction of Selected Ketones (original) (raw)
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Selection of microbial biocatalysts for the reduction of cyclic and heterocyclic ketones
Process Biochemistry, 2017
Biocatalysts for prochiral heterocyclic ketone reduction were selected by screening E. chrysanthemi and M. racemosus almost quantitatively reduced cyclododecanone. E. carotovora produced (S)-N-Boc-3-pyrrolidinol with 87% yield and 99%ee. X. fragariae produced (S)-1-phenylethanol with 100% yield and 79%ee. G. candidum produced (R)-1-phenylethanol with 55% yield and 93%ee.
Preparative Biochemistry & Biotechnology, 2020
Microbial asymmetric reduction of ketone is an efficient tool for the synthesis of chiral alcohols. This research focuses on exploring the soil fungal isolates for their ability toward the keto reduction of acetophenone and its derivatives to their corresponding chiral alcohols using growing cells. Bioreduction of acetophenone, 4-fluoro acetophenone, 4-methyl acetophenone, and 3-hydroxy acetophenone was carried out using different fungal cultures isolated from soil. Among the fungal isolates, Penicillium sp. and Aspergillus sp. showed significant bioconversion with varying enantioselectivity. However, the Penicillium sp. has shown the maximum ability of bioreduction. The potential isolate was characterized using the internal transcribed spacer (ITS) region and found to be Penicillium rubens VIT SS1 (Genbank accession number: MK063869.1), which showed higher conversion and selectivity > 90%. The biocatalyst production and the reaction conditions were optimized using Taguchi analysis. The process conditions such as pH, temperature, media components, cosolvent, and substrate dosing were evaluated for the bioreduction of 3-hydroxy acetophenone, which is a key chiral intermediate of Phenylephrine and Rivastigmine using P. rubens VIT SS1. This study concludes about the potential of fungal cultures for sustainable synthesis of key chiral intermediates of Phenylephrine and Rivastigmine, similarly many aromatic chiral alcohols in simpler, novel, and cost-effective manner.
Enantioselective microbial reduction of substituted acetophenones
Tetrahedron-asymmetry, 2004
The chiral intermediate (S)-1-(2 0 -bromo-4 0 -fluoro phenyl)ethanol 2 was prepared by the enantioselective microbial reduction of 2-bromo-4-fluoro acetophenone 1. Organisms from genus Candida, Hansenula, Pichia, Rhodotorula, Saccharomyces, Sphingomonas and Baker's yeast reduced 1 to 2 in >90% yield and 99% enantiomeric excess (ee). In an alternative approach, the enantioselective microbial reductions of methyl, ethyl, and tert-butyl 4-(2 0 -acetyl-5 0 -fluorophenyl) butanoates 3, 5, and 7, respectively, were demonstrated using strains of Candida and Pichia. Reaction yields of 40-53% and ee's of 90-99% were obtained for the corresponding (S)-hydroxy esters 4, 6, and 8. The reductase, which catalyzed the enantioselective reduction of ketoesters was purified to homogeneity from cell extracts of Pichia methanolica SC 13825. It was cloned and expressed in Escherichia coli with recombinant cultures used for the enantioselective reduction of keto methyl ester 3 to the corresponding (S)-hydroxy methyl ester 4. On a preparative scale, a reaction yield of 98% and an ee of 99% was obtained.
Biotechnology Journal, 2006
The enantioselective bioreduction of acetophenone and its various analogues has been carried out using a new yeast strain, Candida tropicalis MTCC 5158, to obtain the corresponding (S)-aryl ethanols with good yield and almost absolute enantioselectivity. The catalytic ability of this microbial strain for acetophenone reduction has been examined and also various parameters of the bioreduction reaction have been optimized. Studies on the catalytic performance showed that this microorganism is capable of carrying out the reduction in a broad range of pH (3–10) and temperature (25–40°C), making it a more versatile biocatalyst. The preparative scale bioreduction of acetophenone using resting cells of Candida tropicalis yielded S-(–)-1-phenyl ethanol with 43% yield and >99% enantiomeric excess.
Tetrahedron: Asymmetry, 2009
A set of five fungal species, Botrytis cinerea, Trichoderma viride and Eutypa lata, and the endophytic fungi Colletotrichum crassipes and Xylaria sp., was used in screening for microbial biocatalysts to detect monooxygenase and alcohol dehydrogenase activities (for the stereoselective reduction of carbonyl compounds). 4-Ethylcyclohexanone and acetophenone were biotransformed by the fungal set. The main reaction pathways involved reduction and hydroxylations at several positions including tertiary carbons. B. cinerea was very effective in the bioreduction of both substrates leading to the chiral alcohol (S)-1phenylethanol in up to 90% enantiomeric excess, and the cis-trans ratio for 4-ethylcyclohexanol was 0:100. trans-4-Ethyl-1-(1S-hydroxyethyl)cyclohexanol, obtained from biotransformation by means of an acyloin-type reaction, is reported here for the first time. The absolute configurations of the compounds trans-4-ethyl-1-(1S-hydroxyethyl)cyclohexanol and 4-(1S-and 4-(1R-hydroxyethyl)cyclohexanone were determined by NMR analysis of the corresponding Mosher's esters.
Process Biochemistry, 2012
Freely suspended and variously entrapped viable cells of the yeast Metschnikowia koreensis were examined for the asymmetric reduction of prochiral acetophenone. A ketone substrate at 25 mM can be converted (92%) to the corresponding alcohol within 3 h using freely suspended cells [46 mg/mL dry cell weight (DCW)] at pH 9 (Tris buffer, 50 mM), 25 • C, in an agitated reactor (200 rpm). The reaction displayed an excellent stereoselectivity of >99%. Supplementation of the reaction mixture with glucose (20 g/L) greatly enhanced the rate of the bioreduction reaction likely because of improved cofactor recycling in the cells. The cells could successfully reduce various acetophenones substituted with electron withdrawing groups on the phenyl ring, particularly at the para-position compared to ortho-or meta-substituted acetophenones. The ketone reductase of M. koreensis showed Prelog-selectivity as the reaction exclusively yielded (S)-alcohols. The thermostability and the substrate tolerance of the yeast were improved by immobilization in calcium alginate beads. Immobilization reduced the effectiveness factor only slightly.
Rhodotorula mucilaginosa as a new biocatalyst for asymmetric reduction of acetophenone
The biocatalysts for asymmetric reduction of aromatic ketones were successfully screened from soil samples polluted by substituted acetophenones. 12 strains could asymmetrically reduce acetophenone into phenethanol, while only strain YS62 possessed the best performance of reducing acetophenone into (S)-1-phenethanol. It was identified as Rhodotorula mucilaginosa based on phenotypic and genetics characteristics and it was used for further asymmetric reduction experiments of acetophenone as a new biocatalyst. R. mucilaginosa YS62 whole-cells could catalyze the asymmetric reduction of acetophenone (35 mM) into (S)-1-phenethanol (31.4 mM) with a conversion rate of 89.7% and enantiomeric excess (e.e.) of 99.9% under 60 g/L YS62 cell, pH 6.5 , 34°C for 30 h and 2% glucose as a co-substrate. These results have shown that R. mucilaginosa YS62 is a promising biocatalyst for the production of optically active phenylethanol derivatives.
Tetrahedron: Asymmetry, 2011
The versatility of Kluyveromyces marxianus CBS 6556 growing cells in the enantioselective reduction of ketone functionalities to the corresponding alcohols was exploited. In particular, methyl ketones were reduced to (S)-alcohols with ees of up to 96%. Longer chain alkyl ketones afforded, under the same experimental condition, (R)-alcohols with an ee of up to 84%. Interestingly, carbon-carbon double and the triple bonds can also be reduced in the presence of Kluyveromyces marxianus CBS 6556 yeast. A cyclic ketone, such as 2-tetralone, was also quantitatively reduced to its corresponding (S)-alcohol with ee = 76%.
Helvetica Chimica Acta, 2011
The biocatalytic reduction of acetophenone derivatives was exploited by using algal biomass from Bostrychia radicans and B. tenella producing exclusively (S)-2-phenylethanols with high enantiomeric excess (> 99% ee). Bacterial populations associated with algal biomass were identified as the Bacillus genus. This report deals with the first investigations involving the use of marine bacteria associated with B. radicans and B. tenella marine algae for the biocatalytic reduction of acetophenone derivatives.
Biotechnology Letters, 2018
Objective Chiral building blocks [(S)-1-(3-methylphenyl)ethanol, (S)-1-(3,4-dimethylphenyl)ethanol and (S)-1-(2,4,6-trimethylphenyl)ethanol] for drug synthesis were prepared using two green approaches: (1) the yeast Saccharomyces cerevisiae as the biocatalyst and (2) the natural deep eutectic solvents (NADES) as the alternative solvents. Three different NADES with different water contents were prepared and screened for the highest conversion and enantiomeric excess of reduction of 1-(3-methylphenyl)ethanone, 1-(3,4-dimethylphenyl)ethanone (DMPA) and 1-(2,4,6-trimethyphenyl)ethanone by S. cerevisiae. The results were used in the development of eco-friendly procedures on a preparative scale. Results The highest enantioselectivity of bakers yeast was for the bioconversion of DMPA in choline chloride:glycerol with 30% (v/v) of water (ChGly30). This reaction was used for further studies. Parameters such as pre-treatment of biocatalysts and recyclation of solvent were tested for a possible scale-up of this reaction system. Conversion was improved with the ultrasound pre-treatment of the biocatalysts in ChG-ly30. Moreover, the biocatalytic asymmetric reduction of DMPA in ChGly30 was successfully performed on a preparative scale with the efficient recyclation of NADES in two cycles, in which the reduction of DMPA was also successfully performed. Conclusion Three enantioselective reductions in NADES with baker's yeast were successfully conducted. According to the highest enantioselectivity of the biocatalyst, the asymmetric reduction of 1-(3,4dimethylphenyl)ethanone in ChGly30 was also performed on a preparative scale with efficient recyclation and reuse of NADES as a first step towards the implementation of this method on the industrial scale.