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- MakaleYalnız künye2024Scopus SJRQ1Effective biocatalytic synthesis of enentiopure (R)-1,2-diphenylethanol as a pharmaceutical precursor using whole-cell biocatalyst
Çakmak, Fadile; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Optically active alcohols are crucial precursors. 1,2-Diarylethanols and their analogues constitute a significant group of substances of biological significance. The biocatalytic synthesis of (R)-1,2-diphenylethanol ((R)-2), which can be utilized as a precursor to important drugs, is still not at the desired level in terms of substrate amount and production process. This study asymmetrically reduced 1,2-diphenylethanone (1) using the Lactobacillus paracasei BD87E6 biocatalyst and a novel orthogonal quadratic design-embedded optimization approach. The following reaction optimization conditions were determined using the suggested optimization technique: pH = 6, temperature = 31 °C, incubation period = 48 h, and agitation speed=134 rpm. In addition, the reaction conversion was estimated to be 99.38 %, and the product's enantiomeric excess (ee) was estimated to be 99.12 %. Further, (R)-2 was produced with >99 % ee, >99 % conversion, and 98 % yield in the experimental investigation under the established optimum conditions. This study is the first attempt to reduce substrate 1 to (R) or (S)-2 using a mathematical optimization method in the presence of a biocatalyst. Furthermore, on a high-gram scale, 1 (15.70 g) was entirely transformed into (R)-2 (15.54 g, 98 % isolated yield). Notably, this study is also the first to perform the gram-scale production of (R)-2 using a novel optimization approach and a biocatalyst. Finally, the innovative and novel orthogonal quadratic design-embedded optimization technique has been demonstrated as an efficient, cost-effective, and environmentally friendly biocatalytic procedure for synthesizing (R)-2.
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İncele - MakaleAçık Erişim2022Scopus SJRQ2Efficient bioreduction of cyclohexyl phenyl ketone by Leuconostoc pseudomesenteroides N13 biocatalyst using a distance-based design-focused optimization model
Özdemir, Akın; Şahin, Engin
Whole-cell biocatalysts have been a popular method for the preparation of chiral alcohols. Although asymmetric reduction of cyclohexyl(phenyl)methanone (1) by chemical catalysts is common, a biocatalytic asymmetric reduction is extremely rare. In this respect, we report herein that Leuconostoc pseudomesenteroides N13 was successfully employed as a biocatalyst to reduce 1 to (S)-cyclohexyl(phenyl)methanol ((S)-2). Furthermore, the use of a mathematical optimization strategy for asymmetric reduction of substrate 1 is not known in the current literature. The new distance-based design-focused optimization model was used to enhance the conversion of the substrate, enantiomeric excess (ee) of product, and yield. The distance-based design-focused optimization model identified the following optimal bioreduction conditions: pH=6.46, temperature=30°C, incubation period=72 hours, and agitation speed=199 rpm. Then it was stated that under these ideal conditions, (S)-2 may be produced with 99 % ee and 98.46 % conversion rate (cr). (S)-2 was achieved with 99% ee, and 99% cr as a consequence of the experimental reaction carried out under the indicated optimization conditions. It has been shown that Leuconostoc pseudomesenteroides N13 can be utilized as a biocatalyst in asymmetric reduction reactions. This study, in addition to being the first example of a bioreduction of substrate 1 by mathematical optimization, also demonstrates for the first time the distance-based design-focused model can be used in the bioreduction reaction.
AtıfScopus9WoS9OpenAlex8İncele - MakaleAçık Erişim2022Scopus SJRQ3Production of enantiomerically enriched chiral carbinols using whole-cell biocatalyst
Baydaş, Yasemin; Kalay, Erbay; Şahin, Engin
Biocatalytic asymmetric reduction of ketone is an efficient method for the production of chiral carbinols. The study indicates selective bioreduction of different ketones (1–8) to their respective (R)-alcohols (1a–8a) in low to high selectivity (0- >99%) with good yields (11–96%). In this work, whole-cell of Lactobacillus kefiri P2 catalysed enantioselective reduction of various prochiral ketones was investigated. (R)-4-Phenyl-2-butanol 2a, which is used as a precursor to antihypertensive agents and spasmolytics (anti-epileptic agents), was obtained using L kefiri P2 in 99% conversion and 91% enantiomeric excess (ee). Moreover, bioreduction of 2-methyl-1-phenylpropan-1-one substrate 8, containing a branched alkyl chain and difficult to asymmetric reduction with chemical catalysts as an enantioselective, to (R)-2-methyl-1-phenylpropan-1-ol (8a) in enantiomerically pure form was carried out in excellent yield (96%). The gram-scale production was carried out, and 9.70 g of (R)-2-methyl-1-phenylpropan-1-ol (8a) in enantiomerically pure form was obtained in 96% yield. Also especially, the yield and gram scale of (R)-2-methyl-1-phenylpropan-1-ol (8a) synthesised through catalytic asymmetric reduction using the biocatalyst was the highest report so far. The efficiency of L kefiri P2 for the conversion of the substrates and ee of products were markedly influenced by the steric factors of the substrates. This is a cheap, clean and eco-friendly process for production of chiral carbinols compared to chemical processes.
AtıfScopus5WoS5OpenAlex6İncele - MakaleYalnız künye2022Scopus SJRQ3Optimization of asymmetric reduction conditions of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone by Lactobacillus fermentum P1 using D-optimal experimental design-based model
Özdemir, Akın; Dertli, Enes; Şahin, Engin
The biocatalytic asymmetric reduction of prochiral ketones is a significant transformation in organic chemistry as chiral carbinols are biologically active molecules and may be used as precursors of many drugs. In this study, the bioreduction of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone for the production of enantiomerically pure (S)-1-(1,3-benzodioxal-5-yl) ethanol was investigated using freeze-dried whole-cell of Lactobacillus fermentum P1 and the reduction conditions was optimized with a D-optimal experimental design-based optimization methodology. This is the first study using this optimization methodology in a biocatalytic asymmetric reduction. Using D-optimal experimental design-based optimization, optimum reaction conditions were predicted as pH 6.20, temperature 30 °C, incubation time 30 h, and agitation speed 193 rpm. For these operating conditions, it was estimated that the product could be obtained with 94% enantiomeric excess (ee) and 95% conversion rate (cr). Besides, the actual ee and cr were found to be 99% tested under optimized reaction conditions. These findings demonstrated that L. fermentum P1 as an effective biocatalyst to obtain (S)-1-(1,3-benzodioxal-5-yl) ethanol and with the D-optimal experimental design-based optimization, this product could be obtained with the 99% ee and 99% cr. Finally, the proposed mathematical optimization technique showed the applicability of the obtained results for asymmetric reduction reactions.
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İncele - MakaleYalnız künye2021Scopus SJRQ3Regioselective asymmetric bioreduction of trans-4-phenylbut-3-en-2-one by whole-cell of Weissella cibaria N9 biocatalyst
Kalay, Erbay; Şahin, Engin
There is a considerable interest in the asymmetric production of chiral allylic alcohols, the main building blocks of many functional molecules. The asymmetric reduction of α,β-unsaturated ketones is difficult with traditional chemical protocols in a regioselective and stereoselective manner. In this study, the reductive capacity of whole cell of Leuconostoc mesenteroides N6, Weissella paramesenteroides N7, Weissella cibaria N9, and Leuconostoc pseudomesenteroides N13 was investigated as whole-cell biocatalysts in the enantioselective reduction of (E)-4-phenylbut-3-en-2-one (1). The biocatalytic reduction of 1 to (S,E)-4-phenylbut-3-en-2-ol ((S,E)-2) using the whole cell of W. cibaria N9 isolated from Turkish sourdough was developed in a regioselective fashion, occurring with excellent conversion and recovering the product in good yield. In biocatalytic reduction reactions, the conversion of the substrate and the enantiomeric excess (ee) of the product are significantly affected by optimization parameters such as temperature, agitation rate, pH, and incubation time. Effects of these parameters on ee and conversion were investigated comprehensively. In addition, to our knowledge, this is the first report on production of (S,E)-2 using whole-cell biocatalyst in excellent yield, conversion with enantiopure form and at gram scale. These findings pave the way for the use of whole cell of W. cibaria N9 for challenging higher substrate concentrations of different α,β-unsaturated ketones for regioselective reduction at industrial scale.
AtıfScopus21WoS21OpenAlex23İncele - MakaleYalnız künye2021Scopus SJRQ2Asymmetric reduction of aromatic heterocyclic ketones with bio-based catalyst Lactobacillus kefiri P2
Baydaş, Yasemin; Kalay, Erbay; Şahin, Engin
Abstract: Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical intermediates. In this study, Lactobacillus kefiri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asymmetric bioreduction of different prochiral substrates with results up to > 99% enantiomeric excess (ee). (R)-1-(benzofuran-2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale, high yield and enantiomerically pure form using L. kefiri P2 biocatalysts. The gram-scale production was carried out, and 9.70 g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-effective, clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an environmental and economic perspective, this biocatalytic method has great application potential, making it a green and sustainable way of synthesis. Graphical Abstract: [Figure not available: see fulltext.]
AtıfScopus8WoS8OpenAlex9İncele - MakaleAçık Erişim2020Scopus SJRQ3Bio-catalytic asymmetric synthesis of β-adrenergic receptor blocker precursor: (R)-2-bromo-1-(naphthalen-2-yl)ethanol
Taşdemir, Volkan; Kalay, Erbay; Dertli, Enes; Şahin, Engin
Aromatic α-halohydrins, particularly 2-haloethanols as significant precursor of drugs, can easily be converted to chiral β-adrenergic receptor blockers. Eight strains of Lactobacillus curvatus were tested as biocatalysts for asymmetric reduction of 2-bromo-1-(naphthalen-2-yl)ethanone 1 to 2-bromo-1- (naphthalen-2-yl) ethanol 2. The parameters of the bioreduction were optimized using L. curvatus N4, the best biocatalyst found. As a result, (R)-2-bromo-1-(naphthalen-2-yl)ethanol 2, which can be β-adrenergic receptor blocker precursor, was produced for the first time in high yield and enantiomerically pure form using biocatalysts. Moreover, the gram scale synthesis was performed and 7.54 g of (R)-2 was synthesized as enantiopure form (enantiomeric excess >99%) in 48 h. The important advantages of this process are that it produces of (R)-2 for the first time in enantiopure form, in excellent yield and under environmentally friendly and moderate reaction conditions. This system is of the potential to be applied at a commercial scale.
AtıfScopus2WoS2OpenAlex2İncele - MakaleAçık Erişim2020Scopus SJRQ3Synthesis of enantiopure (S)-6-chlorochroman-4-ol using whole-cell Lactobacillus paracasei biotransformation
Şahin, Engin
Chromane, which has a fused cyclic structure, is a significant molecule that can be found in the structure of many important compounds. Lactobacillus paracasei BD101 was demonstrated as whole-cell biocatalyst for the synthesis of (S)-6-chlorochroman-4-ol with immense enantioselectivity. The conditions of asymmetric reduction were optimized one factor by one factor using L paracasei BD101 to achieve enantiomerically pure product and complete conversion. Using these obtained optimization conditions, asymmetric reduction of 6-chlorochroman-4-one was performed under environmentally friendly conditions; 6-chlorochroman-4-one, having a fused cyclic structure as previously noted to be difficult to asymmetric reduction with biocatalysts, was enantiomerically reduced to (S)-6-chlorochroman-4-ol with an enantiomeric excess >99% on a high gram scale. This study is the first example in the literature for the enantiopure synthesis of (S)-6-chlorochroman-4-ol using a biocatalyst. Also notably, the optical purity of (S)-6-chlorochroman-4-ol obtained in this study through asymmetric bioreduction using whole-cell biocatalyst is the highest value in the literature. In this study, (S)-6-chlorochroman-4-ol was produced on a gram scale by an easy, inexpensive, and environmentally friendly method, which has shown the production of valuable chiral precursors for drug synthesis and other industrial applications. This study provides a convenient method for the production of (S)-6-chlorochroman-4-ol, which can meet the industrial green production demand of this chiral secondary alcohol.
AtıfScopus23WoS23OpenAlex24İncele - MakaleAçık Erişim2019Scopus SJRQ3Whole cell application of Lactobacillus paracasei BD101 to produce enantiomerically pure (S)-cyclohexyl(phenyl)methanol
Şahin, Engin; Serencam, Hüseyin; Dertli, Enes
In this study, a total of 10 bacterial strains were screened for their ability to reduce cyclohexyl(phenyl)methanone 1 to its corresponding alcohol. Among these strains, Lactobacillus paracasei BD101 was found to be the most successful biocatalyst to reduce the ketones to the corresponding alcohols. The reaction conditions were systematically optimized for the reducing agent L paracasei BD101, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale asymmetric reduction of cyclohexyl(phenyl)methanone (1) by L paracasei BD101 gave (S)-cyclohexyl(phenyl)methanol (2) with 92% yield and >99% enantiomeric excess. The preparative scale study was carried out, and a total of 5.602 g of (S)-cyclohexyl(phenyl)methanol in high enantiomerically pure form (>99% enantiomeric excess) was produced. L paracasei BD101 has been shown to be an important biocatalyst in asymmetric reduction of bulky substrates. This study demonstrates the first example of the effective synthesis of (S)-cyclohexyl(phenyl)methanol by the L paracasei BD101 as a biocatalyst in preparative scale.
AtıfScopus39WoS37İncele - MakaleAçık Erişim2018Scopus SJRQ2Production of (R)-1-(1,3-benzodioxol-5-yl)ethanol in high enantiomeric purity by Lactobacillus paracasei BD101
Şahin, Engin
Piperonyl ring is found in a number of naturally occurring compounds and possesses enormous biological activities. There are many studies in the literature with compounds containing a piperonyl ring, but there are very few studies on the synthesis of chiral piperonyl carbinol. The objective of this study was to determine the microbial reduction ability of bacterial strains and to reveal the effects of different physicochemical parameters on this reduction ability. A total of 15 bacterial isolates were screened for their ability to reduce 1-(benzo[d][1,3]dioxol-5-yl) ethanone 1 to its corresponding alcohol. Among these isolates Lactobacillus paracasei BD101 was found to be the most successful biocatalyst to reduce the ketone containing piperonyl ring to the corresponding alcohol. The reaction conditions were systematically optimized for the reducing agent L paracasei BD101, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale study was performed, and a total of 3.72 g of (R)-1-(1,3-benzodioxol-5-yl) ethanol in high enantiomeric form (>99% enantiomeric excess) was produced in a mild, cheap, and environment-friendly process. This study demonstrates that L paracasei BD101 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity.
AtıfScopus43WoS42İncele - MakaleAçık Erişim2017Scopus SJRQ2Highly Enantioselective Production of Chiral Secondary Alcohols with Candida zeylanoides as a New Whole Cell Biocatalyst
Şahin, Engin; Dertli, Enes
The increasing demand for biocatalysts in synthesizing enantiomerically pure chiral alcohols results from the outstanding characteristics of biocatalysts in reaction, economic, and ecological issues. Herein, fifteen yeast strains belonging to three food originated yeast species Candida zeylanoides, Pichia fermentans, and Saccharomyces uvarum were tested for their capability for asymmetric reduction of acetophenone to 1-phenylethanol as biocatalysts. Of these strains, C. zeylanoides P1 showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high yields. The preparative scale asymmetric bioreduction of 4-nitroacetophenone (1m) by C. zeylanoides P1 gave (S)-1-(4-nitrophenyl)ethanol (2m) with 89% yield and > 99% enantiomeric excess. Compound 2m has been obtained in an enantiomerically pure and inexpensive form. Additionally, these results indicate that C. zeylanoides P1 is a promising biocatalyst for the synthesis of chiral alcohols in industry.
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