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Öğe Biocatalyzed Enantiomerically Pure Production of (S)?Phenyl(thiophen?2?yl)methanol(The Journal of Heterocyclic Chemistry, 2019) Şahin, Engin; Dertli, EnesChiral aryl heteroaryl methanols are important precursors for the synthesis of pharmaceutically important molecules. The aims of this study were to use a biocatalyst that could efficiently bioreduce phenyl(thiophen‐2‐yl)methanone 1 to (S)‐phenyl(thiophen‐2‐yl)methanol 2, to identify the impact of the physicochemical factors that might affect the bioreduction by the biocatalyst, and to obtain multigram production of aryl heteroaryl secondary alcohol 2 with the biocatalyst under optimized conditions. Over the years, the (S)‐phenyl(thiophen‐2‐yl)methanol was synthesized on a small scale using a chemical catalyst without its enantiomerically pure form. In this study, Lactobacillus paracasei BD101 was used for the asymmetric reduction of phenyl(thiophen‐2‐yl)methanone to (S)‐phenyl(thiophen‐2‐yl)methanol in the large‐scale production. The asymmetric bioreduction conditions were systematically optimized, and the production of 3.77 g of (S)‐phenyl(thiophen‐2‐yl)methanol was carried out in enantiomerically pure form >99% enantiomeric excess (ee), >99% conversion, and 90% yield. This method obtained with this biocatalyst is a process that can be used industrially in terms of conversion, ee, and yield. This study provides guidance for the application of L. paracasei BD101 in the production of optically active aryl heteroaryl alcohols.Öğe Candida zeylanoides as whole-cell biocatalyst to perform asymmetric bioreduction of benzophenone derivatives(Synthetic Communications, 2020) Şahin, EnginCandida zeylanoides P1 was investigated as whole cell biocatalyst for the bioreduction of biaryl prochiral ketones into chiral carbinols, which can be used as pharmaceutical intermediate. Bioreduction of different biaryl ketones was carried out to their corresponding chiral biaryl carbinols such as (S)-(4-chlorophenyl) (phenyl) methanol (2a), which can be used in the synthesis of L-cloperastine drug, with antitussive, antiepidemic activity and bronchial musculature relaxant characteristics, in gram scale, enantiopure form (>99%) and excellent yields. The selectivity of C. zeylanoides P1 in enantioselective reduction of biaryl ketones was not affected by the steric and electronic effects of substrates. The current method demonstrates an encouraging green chemistry approach for the production of biaryl secondary chiral alcohols of pharmaceutical importance in mild, inexpensive and environmentally friendly process. The present study has many benefits since this yeast biocatalyst were successfully applied bioreduction of structurally bulky prochiral substrates, which cannot be reducted by chemical catalysis.Öğe Debaryomyces hansenii as a new biocatalyst in the asymmetric reduction of substituted acetophenones(Biocatalysis and Biotransformation, 2017) Şahin, EnginChiral secondary alcohols are convenient mediator for the synthesis of biologically active compounds and natural products. In this study fifteen yeast strains belonging to three food originated yeast species Debaryomyces hansenii, Saccharomyces cerevisiae and Hanseniaspora guilliermondii were tested for their capability for the asymmetric reduction of acetophenone to 1-phenylethanol as biocatalyst microorganisms. Of these strains, Debaryomyces hansenii P1 strain showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to the corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high conversion rates. This is the first report on the enantioselective reduction of acetophenone by D. hansenii P1 from pastırma, a fermented Turkish meat product. The preparative scale asymmetric bio reduction of 3-methoxy acetophenone 1g by D. hansenii P1 gave (R)-1-(3-methoxyphenyl) ethanol 2g 82% yield, and >99% enantiomeric excess. Compound 2g can be used for the synthesis of (+)-NPS-R-568 [3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenly) ethyl] propan-1-amine] which have a great potential for the treatment of primary and secondary hyper-parathyroidism. In addition, D. hansenii P1 successfully reduced acetophenone derivatives. This study showed that this yeast can be used industrially to produce enantiomerically pure chiral secondary alcohols, which can be easily converted to different functional groups.Öğe First green synthesis of (R)-2-methyl-1-phenylpropan-1-ol using whole-cell Lactobacillus paracasei BD101 biotransformation(Biocatalysis and Biotransformation, 2020) Şahin, EnginGreen chemistry includes a novel process in the production of drugs precursors and biological active molecules using biocatalysts, so reducing the threats for human sanitary and ecological pollutions. Asymmetric bioreduction of prochiral ketones by biocatalysts is one of the best prevalent used methods in synthetic organic chemistry due to the production of enantiopure chiral carbinols. This study emphasizes the application biocatalyst L paracasei BD101 for enantioselective bioreduction of 2-methyl-1-phenylpropan-1-one ketone, which contain branched alkyl chain, to (R)-2-methyl-1-phenylpropan-1-ol ((R)-2) in high yields and excellent enantiomeric excess (>99%). The scale-up production was performed, and 4.61 g of (R)-2 in enantiopure form was synthesized. L paracasei BD101 was proved to be a substantial biocatalyst in asymmetric bioreduction of a ketone which contains a branched alkyl chain. There is not any work in the literature similar to our study. Hence, it is important to work on filling this gap. This study is the first example for an enantiopure synthesis of (R)-2 by a biocatalyst. The new green method was developed for bioreduction of bulky ketones, which contains a branched alkyl chain, and it approves the synthesis of novel chiral carbinols in an easy, cheap, and environmentally friendly condition using L paracasei BD101.Öğe Green synthesis of chiral aromatic alcohols with Lactobacillus kefiri P2 as a novel biocatalyst(Synthetic Communications, 2020) Baydaş, Yasemin; Dertli, Enes; Şahin, EnginBiocatalytic reduction is a very important field of research in synthetic organic chemistry. Herein, three different Lactic Acid Bacteria (LAB) strains were evaluated for their bioreduction potential using acetophenone as a model substrate. Among these strains, Lactobacillus kefiri P2 strain was determined as the best asymmetric reduction biocatalyst. Reaction optimization parameters such as reaction time, temperature, agitation speed and pH were systematically optimized using Lactobacillus kefiri P2 strain and model substrate acetophenone. Under these optimized reaction conditions, secondary chiral alcohols were obtained by bioreduction of various prochiral ketones with results up to 99% enantiomeric excess. In addition, the steric and electronic effects of substituents on enantioselectivity and conversion were evaluated. It has been shown that Lactobacillus kefiri P2 biocatalyst was an effective catalyst for asymmetric reduction. This method provides an environmentally friendly method for the synthesis of optically pure alcohols and an alternative approach to chemical catalysts.Öğe Green synthesis of enantiopure (S)?1?(benzofuran?2?yl)ethanol by whole?cell biocatalyst(Chirality, 2019) Şahin, EnginOptically active aromatic alcohols are valuable chiral building blocks of many natural products and chiral drugs. Lactobacillus paracasei BD87E6, which was isolated from a cereal‐based fermented beverage, was shown as a biocatalyst for the bioreduction of 1‐(benzofuran‐2‐yl) ethanone to (S)‐1‐(benzofuran‐2‐yl) ethanol with highly stereoselectivity. The bioreduction conditions were optimized using L. paracasei BD87E6 to obtain high enantiomeric excess (ee) and conversion. After optimization of the bioreduction conditions, it was shown that the bioreduction of 1‐(benzofuran‐2‐yl)ethanone was performed in mild reaction conditions. The asymmetric bioreduction of the 1‐(benzofuran‐2‐yl)ethanone had reached 92% yield with ee of higher than 99.9% at 6.73 g of substrate. Our study gave the first example for enantiopure production of (S)‐1‐(benzofuran‐2‐yl)ethanol by a biological green method. This process is also scalable and has potential in application. In this study, a basic and novel whole‐cell mediated biocatalytic method was performed for the enantiopure production of (S)‐1‐(benzofuran‐2‐yl)ethanol in the aqueous medium, which empowered the synthesis of a precious chiral intermediary process to be converted into a sophisticated molecule for drug production.Öğe Highly Enantioselective Production of Chiral Secondary Alcohols Using Lactobacillus paracasei BD101 as a New Whole Cell Biocatalyst and Evaluation of Their Antimicrobial Effects(Chemistry Biodiversity, 20017) Yılmaz, Durmuşhan; Şahin, Engin; Dertli, EnesChiral secondary alcohols are valuable intermediates for many important enantiopure pharmaceuticals and biologically active molecules. In this work, we studied asymmetric reduction of aromatic ketones to produce the corresponding chiral secondary alcohols using lactic acid bacteria (LAB) as new biocatalysts. Seven LAB strains were screened for their ability to reduce acetophenones to their corresponding alcohols. Among these strains, Lactobacillus paracasei BD101 was found to be the most successful at reducing the ketones to the corresponding alcohols. The reaction conditions were further systematically optimized for this strain and high enantioselectivity (99%) and very good yields were obtained. These secondary alcohols were further tested for their antimicrobial activities against important pathogens and significant levels of antimicrobial activities were observed although these activities were altered depending on the secondary alcohols as well as their enantiomeric properties. The current methodology demonstrates a promising and alternative green approach for the synthesis of chiral secondary alcohols of biological importance in a cheap, mild, and environmentally useful process.Öğe Highly Enantioselective Production of Chiral Secondary Alcohols with Candida zeylanoides as a New Whole Cell Biocatalyst(Chemistry Biodiversity, 2017) Şahin, Engin; Dertli, EnesThe 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.Öğe Lactobacillus curvatus Suşu ile Asetofenon Türevlerinin Asimetrik İndirgenmesi(2017) Şahin, EnginSekiz farklı Lactobacillus curvatus suşu asetofenon'un 1-fenil etanol'e asimetrik indirgenmesinde biyokatalizör olarak değerlendirildi. Test edilen bu laktik asit bakteri (LAB) suşları arasında Lactobacillus curvatusN5asetofenon'un enantiyoseçici indirgenmesinde en etkili biyokatalizör olarak bulundu. Optimize edilen reaksiyon şartları altında asetofenon türevleri % 99 enantiyomerik fazlalığa kadar ilgili kiral sekonder alkollere dönüştürüldü.Öğe Lactobacillus paracasei biyokatalizörü ile enantiyosaf (S)-1- (4-metoksifenil) etanol üretimi(2021) Şahin, EnginBu çalışmada, 4-metoksiasetofenonun enantiyoseçici indirgenmesinde yedi biyokatalizörün indirgeme kapasitesi tam hücre biyokatalizör olarak araştırılmıştır. Lactobacillus paracasei BD28'in en iyi indirgeme kapasitesine sahip olduğu bulunmuştur. pH, inkübasyon süresi, çalkalama hızı ve sıcaklık gibi farklı parametrelerin enantiyomerik aşırılık ve dönüşüm üzerindeki etkileri araştırıldı. Tam hücre biyokatalizörü Lactobacillus paracasei BD28 kullanılarak, genel alerjik yanıt için tedavi fonksiyonuna sahip sikloalkil [b] indollerin sentezinde kullanılabilen (S)-1-(4-metoksifenil) etanol, gram ölçeğinde, yüksek verimli ve enantiyomerik olarak saf halde üretilmiştir. Gram ölçekli üretim gerçekleştirildi ve % 95 verimle optik olarak saf formda 9,69 g (S)-1-(4-metoksifenil) etanol üretildi. Bu, kimyasal işlemlere kıyasla (S)-1-(4-metoksifenil) etanol üretimi için ucuz, temiz ve çevre dostu bir işlemdir.Öğe Production of (R)?1?(1,3?benzodioxol?5?yl)ethanol in high enantiomeric purity by Lactobacillus paracaseiBD101(Chirality, 2018) Şahin, EnginPiperonyl 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.Öğe Production of enantiomerically enriched chiral carbinols using Weissella paramesenteroides as a novel whole cell biocatalyst(Biocatalysis and Biotransformation, 2019) Tozlu, Caner; Şahin, Engin; Serencam, Hüseyin; Dertli, EnesIn this study, four bacterial strains were tested for their ability to reduce acetophenones to its corresponding alcohol. Among these strains Weissella paramesenteroides N7 was found to be the most successful biocatalyst to reduce the ketones to the corresponding alcohols. The reaction conditions were systematically optimized for W. paramesenteroides N7 that resulted in high enantioselectivity and conversion rates for the bioreduction. The scale-up asymmetric reduction of 1-(4-methoxyphenyl) propan-1-one (1r) by W. paramesenteroides N7 gave (R)-1-(4-methoxyphenyl) propan-1-ol (2r) with 94% yield and >99% enantiomeric excess. This is the first report showing the synthesis of (R)-1-(4-methoxyphenyl) propan-1-ol (2r) in enantiopure form using a biocatalyst on a gram scale. The whole cell catalyzed the reductions of ketone substrates on the preparative scale, demonstrating that W. paramesenteroides N7 would be a valuable biocatalyst for the preparation of chiral aromatic alcohols of pharmaceutical interest as a promising and alternative green approach. Weissella paramesenteroides as a food originated yeast species is capable of bioreduction of prochiral ketones to secondary chiral alcohols in one enantiomeric form.Öğe Production of enantiomerically pure (S)-phenyl(pyridin-2-yl)methanol with Lactobacillus paracasei BD101(Biocatalysis and Biotransformation, 2019) Şahin, Engin; Serencam, Hüseyin; Dertli, EnesAsymmetric reduction studies of heteroaryl ketones, including phenyl(pyridin-2-yl)methanone in enantioselective form with biocatalysts are very few, and chiral heteroaryl alcohols have been synthesized generally in the small scale. In this study, seven bacterial strains have been used to produce the (S)-phenyl(pyridin-2-yl)methanol in high enantiomeric excess and yield. Among the tested strains, Lactobacillus paracasei BD101, was found to be the best biocatalyst for the reducing phenyl(pyridin-2-yl)methanone to the (S)-phenyl(pyridin-2-yl)methanol at gram scale. The asymmetric bioreduction conditions were systematically optimized using L. paracasei BD101, which demonstrated excellent enantioselectivity and high level of conversion for the bioreduction reaction. (S)-phenyl(pyridin-2-yl)methanol, which is an analgesic, was produced enantiomerically pure form in the first time on gram scale using a biocatalyst. In total, 5.857 g of (S)-phenyl(pyridin-2-yl)methanol in enantiomerically pure form (>99% enantiomeric excess) was obtained in 52 h with 93% yield using whole cells of L. paracasei BD101. Enantiomerically pure (S)-phenyl (pyridin-2-yl)methanol, which is an analgesic, was first produced in the gram scale using a biocatalyst with excellent ee (>99%) and yield (93%).Öğe Production of enantiopure chiral aryl heteroaryl carbinols using whole?cell Lactobacillus paracasei biotransformation(Synthetic Communications, 2020) Şahin, EnginAryl and heteroaryl chiral carbinols are useful precursors in the synthesis of drugs. Lactobacillus paracasei BD87E6, which is obtained from a cereal based fermented beverage, was investigated as whole cell biocatalyst for the bioreduction of different ketones (including aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbinols, which can be used as a pharmaceutical intermediate. The study shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone (1-5) to their corresponding chiral carbinols (1a-5a) in excellent enantioselectivity (>99%) with high yields. This study gave the first example for an enantiopure production of (S)-6-chlorochroman-4-ol (3a), which has many antioxidant activity, by a biological method. For asymmetric bioreduction of other prochiral ketones, these results open way to use of L. paracasei BD87E6 as biocatalysts. Also, the present process shows a hopeful and alternative green synthesis for the production of enantiopure carbinols in a mild, inexpensive and environmentally friendly process.Öğe Synthesis and Biological Evaluation of Novel Tricyclic Pyrrolidinyl (R)?Alcohols and Amines(The Journal of Heterocyclic Chemistry, 2019) Şahin, Engin; Kılıç, Hamdullah; Törnük. Fatih; Dertli, EnesThree new tricyclic pyrrolidinyl alcohols and three tricyclic pyrrolidinyl amines were synthesized, and the antibacterial activities of these compounds were tested against Salmonella enterica subsp. enterica serovar Typhimurium, Escherichia coli O157:H7, Staphylococcus aureus, and Listeria monocytogenes. All tested pyrrolidinyl alcohols and amines showed antibacterial activity to the tested pathogens, but this activity was dependent on the final concentration of the tested compound, and the structure of these compounds were also important for this antibacterial activity. Of the tested compounds, (2R)‐2‐(octahydro‐4,8‐ethanocyclohepta[c]pyrrol‐2(1H)‐yl)‐2‐phenylethanamine (2c) was the most effective compound among the tested pyrrolidinyl alcohols and amines. This study shows a good example of finding new antimicrobials in order to control pathogenic bacteria.Öğe Synthesis of Enantiomerically Enriched Drug Precursors by Lactobacillus paracasei BD87E6 as a Biocatalyst(Chemistry Biodiversity, 2018) Öksüz, Selda; Şahin, Engin; Dertli, EnesGlobal sales of single enantiomeric drug products are growing at an alarming rate every year. A total of 7 bacterial strains were screened for their ability to reduce acetophenones to its corresponding alcohol. Among these strains Lactobacillus paracasei BD87E6 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 Lactobacillus paracasei BD87E6, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale asymmetric reduction of 3‐methoxyacetophenone (1h) by Lactobacillus paracasei BD87E6 gave (R)‐1‐(3‐methoxyphenyl)ethanol (2h) with 92% yield and 99% enantiomeric excess. Compound 2h could be used for the synthesis of (S)‐rivastigmine which has a great potential for the treatment of Alzheimer's disease. This study demonstrates that Lactobacillus paracasei BD87E6 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity. The whole cell catalyzed the reductions of ketone substrates on the preparative scale, demonstrating that Lactobacillus paracasei BD87E6 would be a valuable biocatalyst for the preparation of chiral aromatic alcohols of pharmaceutical interest.Öğe Synthesis of enantiopure (S)?6?chlorochroman?4?ol using whole?cell Lactobacillus paracasei biotransformation(Chirality, 2020) Şahin, EnginChromane, 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.Öğe Whole cell application of Lactobacillus paracasei BD101 to produce enantiomerically pure (S)?cyclohexyl(phenyl)methanol(Chirality, 2019) Şahin, Engin; Serencam, Hüseyin; Dertli, EnesIn 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.
