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- MakaleAçık Erişim2024Scopus SJRQ1Efficient bioreduction of 4-phenyl-2-butanone to drug precursor (S)-4-phenyl-2-butanol by a whole-cell biocatalyst using a novel hybrid design technique
Bayhan, Beyzanur; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Asymmetric synthesis is a critical tactic in pharmaceutical industries for creating chiral medications as it allows an enantiomer to be obtained in synthetic chemistry. The asymmetric bioreduction processes by biocatalysts have shown significant potential in producing chiral alcohols. The amount of substrate and the production method of the biocatalytic synthesis of (S)-4-phenyl-2-butanol ((S)-2) are not still desired levels. Furthermore, the biocatalytic asymmetric reduction of 4-phenyl-2-butanone (1) to (R)- or (S)-4-phenyl-2-butanol did not use any mathematical modeling techniques. In this study, the asymmetric bioreduction of 1 was carried out in this work employing Lactobacillus paracasei BD71 biocatalyst and a novel hybrid design-based optimization approach. By using the hybrid design technique, the optimal circumstances were discovered to be pH = 7, temperature = 29 °C, incubation period = 66 h, and agitation speed = 189 rpm. Also, the enantiomeric excess (ee) and conversion could be 99.15 % and 98.19 %, respectively. Next, (S)-2 was acquired to be ee: 99 %, conversion: >99 %, and yield: 97 % from the optimum bioreduction conditions. Furthermore, 14.08 g of 1 under optimal conditions was entirely transformed into (S)-2 (13.84 g, 97 % isolated yield). This study is the first research attempt to use a biocatalyst and an innovative and new hybrid design-based optimization approach to fabricate enantiopure (S)-2 at a high gram scale. This work has successfully demonstrated that the new hybrid design-based optimization technique is applicable to biocatalytic asymmetric reduction processes.
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İncele - MakaleAçık Erişim2024Scopus SJRQ1A Multi-response Nonlinear Programming Model with an Inscribed Design to Optimize Bioreduction Conditions of (S)-phenyl (pyridin-2-yl)methanol by Leuconostoc pseudomesenteroides N13
Özdemir, Akın; Şahin, Engin
Asymmetric bioreductions have the potential to synthesize chiral alcohols when catalyzed by biocatalysts. Nevertheless, the (S)-phenyl (pyridin-2-yl)methanol ((S)-2) analgesic synthesis poses significant challenges concerning unsatisfactory substrate amount and production method. Thus, this study proposes an inscribed design-focused multi-response nonlinear optimization model for the asymmetric reduction of the phenyl(pyridin-2-yl)methanone (1) with Leuconostoc pseudomesenteroides N13 biocatalyst. From the novel inscribed design-focused multi-response nonlinear optimization model, optimization conditions of the reaction, such as pH = 6, temperature = 29 °C, incubation time = 53 h, and agitation speed = 153 rpm, were found. Also, the reaction conversion was predicted to be 99%, and the product of the enantiomeric excess (ee) was 98.4% under the obtained optimization conditions. (S)-2 was obtained with 99% ee, 99% conversion, and 98% yield while performing a validation experiment using the determined optimized conditions. In addition, 1 with the amount of 11.9 g was converted entirely to (S)-2 (11.79 g, 98% isolated yield) on a high gram scale. Also, this study is noted as the first example of the gram-scale production of (S)-2 using an optimization strategy and biocatalyst. Further, the applicability of the inscribed design-focused optimization model in biocatalytic reactions has been demonstrated and provides an effective process for the analgesic synthesis of (S)-2, which is a green, cost-effective method of producing chiral aryl heteroaryl methanol.
AtıfScopus3WoS3OpenAlex3İncele - MakaleAçık Erişim2022Scopus SJRQ1Optimization of Biocatalytic Production of Enantiopure (S)-1-(4-Methoxyphenyl) Ethanol with Lactobacillus senmaizuke Using the Box–Behnken Design-Based Model
Kavi, Mervenur; Özdemir, Akın; Dertli, Enes; Şahin, Engin
Enantiomerically pure (S)-1-(4-methoxyphenyl) ethanol is a significant molecule for the production of various drug intermediates. (S)-1-(4-methoxyphenyl) ethanol was synthesized from 4-methoxyacetophenone using Lactobacillus senmaizuke as a biocatalyst. In addition, optimization of experimental conditions is important to analyze the role of culture parameters for catalytic bioreduction reactions. For this particular purpose, the experimental conditions of pH, incubation period, temperature, and agitation speed were investigated with the Box–Behnken experimental design-based proposed optimization model. (S)-1-(4-methoxyphenyl) ethanol, which can be used for the synthesis of antihistamines, including diphenhydramine hydrochloride and loratadine cycloalkyl [b] indoles that have the treatment function for an allergic response, was obtained in > 99% conversion, > 99% enantiomeric excess and 96% yield with whole cells of L. senmaizukei at this optimization conditions: pH = 5.80, the temperature = 29 °C, incubation period = 50 h, and agitation speed = 155 rpm. The bioreduction of 4-methoxyacetophenone efficiency was importantly affected by the quadratic and linear effects of experimental design parameters. Besides, the results demonstrate the importance of design parameters for catalytic bioreduction reactions. It is also concluded that the results show the effectiveness of the Box–Behnken experimental design-based proposed model to obtain optimum operating conditions of design parameters for catalytic bioreduction reactions.
AtıfScopus4WoS4OpenAlex4İncele - 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.
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