Reduction Of Prochiral Ketones Research Articles

Vigna radiata (mung) as superior natural biobased catalyst for asymmetric reduction of prochiral acetophenone

Asymmetric reduction of prochiral ketone via biocatalysis is one of the most promising and straight forward routes to prepare optically active alcohols. In this work, whole cells of Vigna radiata (also called mung) catalyzed enantioselective reduction of prochiral aromatic ketones was investigated. Effects of various parameters such as co-substrate, temperature, cell loading, substrate concentration on conversion and enantioselectivity were studied in a systematic manner by using acetophenone as the model compound. Glucose was found to be the most effective co-substrate for co-factor regeneration among different co-substrates employed. Whole cells of mung have shown excellent thermostability and high substrate tolerance (up to 200 mM). Under optimum conditions, maximum conversion of 93.44% and enantioselectivity of 98.92% were obtained in 9 h. Good conversion and enantioselectivity were observed with various substituted aromatic ketones. This is a cheap, clean, and eco-friendly process for preparation of chiral secondary alcohols compared to chemical processes.

Enzymatic approach to the synthesis of chiral intermediate of Rodatristat ethyl

Ketoreductases are widely explored for the reduction of prochiral ketones for the preparation of chiral alcohols. Though, the chiral Ir(III) catalyst has been used for the asymmetric reduction of keto intermediate of Rodatristat ethyl, an enzymatic approach for its preparation has not yet been reported. In this regard, we report, for the first time the preparation of enantiopure secondary alcohols (R-3) and (S-3) from 1-(5-chloro-[1,1’-biphenyl]-2-yl)-2,2,2-trifluoroenthan-1-one (2) using commercially available ketoreductases at 30 °C in the presence of 125 mM sodium phosphate buffer pH 6 over 24 h. This enzymatic approach provides the (R)-3 and (S)-3 chiral alcohols in >99% enantiomeric excess (ee) with >99% conversion using KRED-244 and KRED-101 respectively. Furthermore, the KRED-244 and KRED-101 enzymes have been successfully immobilized with sodium alginate, which makes them recyclable and reusable in subsequent reactions. The reusability experiments were carried out over 15 cycles without any apparent loss of activity even after 10 cycles. It is a sustainable approach to the synthesis of enantiopure intermediates of rodatristat ethyl, contributing to the advancement of green chemistry.

Enantioselective Regulation of Short‐Chain Dehydrogenases via Key Sites in its Loop and Adjacent Regions for the Enantiodivergent Reduction of Difficult‐To‐Reduce Ketones

AbstractShort‐chain dehydrogenases (SDRs) are powerful catalysts for the asymmetric reduction of prochiral ketones in pharmaceutical products. Herein, through gene mining and evolutionary analysis, we obtained two major types of SDRs (SDR‐1 and SDR‐2) for the enantioselective complementary reduction of N‐Boc‐piperidone, which gives the corresponding product (R)‐ or (S)‐N‐Boc‐piperidol, an intermediate of the interleukin inhibitor and lymphoma treatment drug (imbruvica), respectively. By integrating multiple sequence alignment, site‐directed mutagenesis and computational modeling, we proposed a “loop regulation” mechanism for the enantioselective control of SDRs, through which residues in the loop region could potentially fine‐tune their enantioselectivity. Further, site‐directed mutagenesis assays showed that two key residues (L201 and F205 for SDR‐1, F92 and H93 for SDR‐2) in the loop and its adjacent region played critical roles in fine‐tuning the enantioselectivity of SDRs. Understanding this mechanism of SDR stereo preference in catalyzing asymmetric reduction, we further switched the enantioselectivity of the homologous enzymes. The obtained enzymes catalyzed the enantiodivergent synthesis of chiral heterocyclic alcohols with different ring sizes and substituents (25–99% conversion and 25–99% ee (R/S)), including piperidols, 4‐hydroxy azepanes, 3‐hydroxy azepanes and pyrrolidinols. These findings could potentially guide future attempts at protein engineering of stereoselective SDRs.

Development of a novel magnetic metal-organic framework for the immobilization of short-chain dehydrogenase for the asymmetric reduction of pro-chiral ketone

Short-chain dehydrogenase/reductase (SDR) acts as a biocatalyst in the synthesis of chiral alcohols with high optical purity. Herein, we achieved immobilization via crosslinking on novel magnetic metal–organic framework nanoparticles with a three-layer shell structure (Fe3O4@PDA@Cu (PABA)). The results of scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and energy dispersive X-ray spectroscopy confirmed the morphology and cross-linking property of immobilized SDR, which was more durable, stable, and reusable and exhibited better kinetic performance than free enzyme. The SDR and glucose dehydrogenase (GDH) were co-immobilized and then used for the asymmetric reduction of COBE and ethyl 2-oxo-4-phenylbutanoate (OPBE). These finding suggest that enzymes immobilized on novel MOF nanoparticles can serve as promising biocatalysts for asymmetric reduction prochiral ketones into chiral alcohols.

Modified distance optimization method for the asymmetric bioreduction conditions of phenyl(thiophen-2-yl)methanone by Weissella paramesenteroides N7

Chirality plays a significant part in life since it is closely linked to carrying out the many metabolic processes that make up a living being. Chiral secondary alcohols such as diaryl-, aryl heteroaryl-, and diheteroaryl are employed in pharmaceuticals as drug intermediates. Although biocatalytic asymmetric reduction of prochiral ketones containing aromatic and heteroaromatic groups is widely known, biocatalytic reduction of heteroaromatic prochiral ketones containing sulfur heteroatoms is rarely known. Very few studies exist in the literature, including the biocatalytic reduction of phenyl(thiophen-2-yl)methanone (1). Moreover, the biocatalytic reduction of 1 with a mathematical modelling and optimization technique is unknown until now. In this study, Weissella paramesenteroides N7 biocatalyst for the asymmetric bioreduction of 1 using a novel modified distance optimization method. Optimization conditions were found as pH = 6.46, temperature = 26 °C, incubation period = 71 h, agitation speed = 200 rpm by the modified distance optimization method, and it was determined that the conversion and enantiomeric excess (ee) under these conditions could be 98.7% and 98%, respectively. Under these proposed optimization conditions, (S)-phenyl(thiophen-2-yl)methanol ((S)-2) was obtained with >99% ee, >99% conversion, and 97% yield. In addition, 11.29 g of 1 was completely converted into (S)-2 (11.07 g, 97% isolated yield) under optimized conditions. This is the first report about the fabrication of enantiopure (S)-2 in high gram scale using a biocatalyst and a novel modified distance optimization technique. In this study, the successful applicability of the new modified distance optimization method in biocatalytic asymmetric reduction reactions has been successfully demonstrated.

Optimization of asymmetric bioreduction conditions of 1-indanone by Leuconostoc mesenteroides N6 using a face-centered design-based multi-objective optimization model

There has been an increasing interest in biocatalysts over the past few decades in order to obtain high efficiency, high yield, and environmentally benign procedures aiming at the manufacture of pharmacologically relevant chemicals. Lactic Acid Bacteria (LAB), a microbial group, can be employed as biocatalysts while performing asymmetric reduction of prochiral ketones. In this study, Leuconostoc mesenteroides N6 was used for the asymmetric bioreduction 1-indanone. And then, a novel and innovative face-centered design-based multi-objective optimization model was used to optimize experimental conditions. Also, the experimental design factors were defined as agitation speed, incubation period, pH, and temperature for optimization to acquire the maximum enantiomeric excess (ee) and conversion rate (cr) values. When using the face-centered design-based multi-objective optimization model, the optimum culture conditions corresponded to 96.34 and 99.42%, ee and cr responses, respectively, were pH = 5.87, incubation temperature = 35 °C, incubation period = 50.88 h, and agitation speed = 152.60 rpm. Notably, the validation experiment under the optimum model conditions confirmed the model results. This study demonstrated the importance of the optimization and the efficiency of the face-centered design-based multi-objective model.

New Strategy for Effective Biosynthesis of Chiral Aryl Alcohols: Co-Cultivation Microbe with Natural Deep-Eutectic Solvent

In this study, a new strategy was developed for efficient synthesis of chiral aryl alcohols mediated by permeabilizing whole-cell catalyzed bioreduction. The permeabilized biocatalyst was prepared via co-cultivation microbial cells with natural deep-eutectic solvent (NADES) in their growth period, and the bioreductive efficiency was significantly enhanced due to the improvement of cell permeability for overcoming mass-transfer limitation in the reduction of prochiral ketones. This approach was successfully employed in the model reaction of 2-chloro-1-(3,4-difluorophenyl)ethanone to (S)-2-chloro-1-(3,4-difluorophenyl)ethanol [(S)-CFPL] with newly isolated Geotrichum candidum ZJPH1907 in a Tween 80-containing buffer system. Compared to the conventional NADES addition in reaction system as co-solvent, a much higher catalytic yield (98.7% vs 62.5%) was achieved with good enantioselectivity via a co-cultivation strategy, in which the permeabilizing biocatalyst was obtained by co-incubation G. candidum cells with 0.5% (w/v) choline chloride/lysine (ChCl/Lys) (molar ratio 1:2). The developed new strategy was concise, feasible, and eco-friendly through the analysis of green chemistry metric, and the catalytic efficiencies were also enhanced in the bioreduction of other aryl ketones. This work provides a new understanding of NADES in biocatalysis and broadens its application.

Bioorganometallic Chemistry at the Interface with Biocatalysis: Chemoselective Reduction of Biomimetic NAD+ Cofactors with [Cp*Rh(bpy)H]+, Tandem Catalysis with 1,4-NADH-Dependent Enzymes, Chiral Synthesis, Organotin Metabolites, and DFT Mechanism Studies

This Review will focus on our studies of the utilization of the [Cp*Rh(bpy)H]+ complex as a biomimetic hydrogenase, regeneration reagent for chemoselective reduction of biomimetic NAD+ cofactors, N-benzylnicotinamide triflate, 1, β-nicotinamide ribose-5′-methyl phosphate, 2, and natural NAD+, 3, in the conversion to their 1,4-NADH analogues, 1,4-dihydro-N-benzylnicotinamide, 4, and β-1,4-dihydronicotinamide-5′-ribose methyl phosphate, 5, and natural 1,4-NADH, 6, respectively. This regeneration reaction with 1,4-NADH biomimetics 4 and 5 was used in tandem with 1,4-NADH-dependent enzymes for organic synthesis. The enzyme examples will encompass horse liver alcohol dehydrogenase (HLADH) reductions of prochiral ketones to chiral S-alcohols; cytochrome P450 enzymes for selective C–H oxidation reactions of organic compounds, and organometallic substrates, tributyltin acetate and cyclohexyltriphenyltin, with 1,4-NAD(P)H; and the biomimetic 1,4-NADH cofactor, 4, with the 2-hydroxybiphenyl-3-monooxygenase enzyme, HbpA, a FAD-containing monooxygenase enzyme, for hydroxylation of ortho-substituted phenols to catechols. This Review also includes discussions on in-depth DFT mechanism studies, and other chemical mechanistic aspects, of all tandem catalytic reactions that demonstrate, utilizing a simplified model of the HLADH-Zn(II)-mediated enzyme, the unprecedented role of Zn(II) in the hydride transfer reaction. Moreover, site-directed mutagenesis with 1,4-NAD(P)H-dependent cytochrome P450 BM-3 improved the molecular recognition process for biomimetic 1,4-NADH cofactors in organic compound C–H oxidation reactions. The 1,4-NADH-dependent cytochrome P450 CAM recognized the biomimetic 1,4-NADH cofactors; however, site-directed mutagenesis of the putidaredoxin reductase (PdR) component increased the kinetics for the C–H oxidation reaction of camphor. Cyclohexyltriphenyltin demonstrated the differences in hydroxylation regioselectivity, when comparing the cytochrome P450 enzyme with biomimetic P450 porphyrin Fe(III) and Mn(III) models. The biomimetic 1,4-NADH cofactor, 1,4-dihydro-N-benzylnicotinamide, 4, was also utilized as a reducing agent, providing the reduced, chemoselective coenzyme, the FADH– anion, that further reacts with O2/H+ to provide the 4α-hydroperoxide flavin, for the HbpA enzymatic oxidative conversion of ortho-substituted phenols to catechols.

New Anti-Prelog Stereospecific Whole-Cell Biocatalyst for Asymmetric Reduction of Prochiral Ketones.

The biocatalytic asymmetric reduction of prochiral ketones for the production of enantiopure alcohols is highly desirable due to its inherent advantages over chemical methods. In this study, a new bacterial strain capable of transforming ketones to corresponding alcohols with high activity and excellent enantioselectivity was discovered in a soil sample. The strain was subsequently identified as Bacillus cereus TQ-2 based on its physiological characteristics and 16S rDNA sequence analysis. Under optimized reaction conditions, the resting cells of B. cereus TQ-2 converted acetophenone to enantioenriched (R)-1-phenylethanol with 99% enantiometric excess following anti-Prelog's rule, which is scarce in biocatalytic ketone reduction. The optimum temperature for the cells was 30 °C, and considerable catalytic activity was observed over a broad pH range from 5.0 to 9.0. The cells showed enhanced catalytic activity in the presence of 15% (v/v) glycerol as a co-substrate. The catalytic activity can also be substantially improved by adding Ca2+ or K+ ions. Moreover, the B. cereus TQ-2 cell was highly active in reducing several structurally diverse ketones and aldehydes to form corresponding alcohols with good to excellent conversion. Our study provides a versatile whole-cell biocatalyst that can be used in the asymmetric reduction of ketones for the production of chiral alcohol, thereby expanding the biocatalytic toolbox for potential practical applications.

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α-haloacetophenones to optically pure (2S, 3S)-ketols and (R)-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols.

Enantioselective 1,4-addition of diarylphosphine oxides to α,β-unsaturated ketones catalyzed by oxazaborolidines

A new application of oxazaborolidines in enantioselective phospha-Michael addition to α,β-unsaturated ketones under mild reaction conditions was developed and the possible mechanism is described.

Engineering ketoreductases for the enantioselective synthesis of chiral alcohols.

The use of engineered ketoreductases (KREDS), both as whole microbial cells and isolated enzymes, in the highly enantiospecific reduction of prochiral ketones is reviewed. The homochiral alcohol products are key intermediates in, for example, pharmaceuticals synthesis. The application of sophisticated protein engineering and enzyme immobilisation techniques to increase industrial viability are discussed.

Ketoreductase Catalyzed (Dynamic) Kinetic Resolution for Biomanufacturing of Chiral Chemicals.

Biocatalyzed asymmetric reduction of ketones is an environmentally friendly approach and one of the most cost-effective routes for producing chiral alcohols. In comparison with the well-studied reduction of prochiral ketones to generate chiral alcohols with one chiral center, resolution of racemates by ketoreductases (KREDs) to produce chiral compounds with at least two chiral centers is also an important strategy in asymmetric synthesis. The development of protein engineering and the combination with chemo-catalysts further enhanced the application of KREDs in the efficient production of chiral alcohols with high stereoselectivity. This review discusses the advances in the research area of KRED catalyzed asymmetric synthesis for biomanufacturing of chiral chemicals with at least two chiral centers through the kinetic resolution (KR) approach and the dynamic kinetic resolution (DKR) approach.

Recent Advances in Organocatalyzed Asymmetric Reduction of Prochiral Ketones: An Update

AbstractChiral alcohols are important synthetic intermediates and building blocks for the synthesis of drugs, agrochemicals, and natural products. Asymmetric reduction of prochiral ketones has been the most investigated method for accessing chiral alcohols. In this regard, organocatalyzed asymmetric reduction, as a complementary method to transition-metal- and enzyme-catalyzed reactions, has attracted tremendous interest in the past decades due to the reactions with such catalysts being metal-free and easy to operate, and principally, the ease of recovery and the ability to reuse the catalysts. Following up on a comprehensive overview on organocatalyzed asymmetric reductions of prochiral ketones in early 2018, this short review is intended to summarize the recent progress in this area from the beginning of 2018 until the end of August 2021.1 Introduction2 Boron-Based Chiral Organocatalysts2.1 Boron-Containing Chiral Schiff Base Catalysts2.2 Chiral Alpine-Borane Catalysts2.3 Boron-Containing Chiral Frustrated Lewis Pair Catalysts2.4 Chiral Borate Ester–Amine Complex Catalysts3 Phosphorus-Based Chiral Organocatalysts3.1 Chiral Phosphoric Acid Organocatalysts3.2 Chiral Phosphinamide and Phosphoramide Organocatalysts4 Chiral Ionic Liquid Organocatalysts5 Chiral-Oxazoline-Based Organocatalysts6 Conclusion and Outlook

Continuous-flow stereoselective reduction of prochiral ketones in a whole cell bioreactor with natural deep eutectic solvents

Immobilized whole cells of Rhodotorula rubra MIM147 were used in a packed bed flow reactor for the enantioselective reduction of β-ketonitriles and for the obtainment of a key building block for the synthesis of the antidepressant drug duloxetine.

Quinone Reduction by Organo-Osmium Half-Sandwich Transfer Hydrogenation Catalysts

Organo-osmium(II) 16-electron complexes [OsII(η6-arene)(R-PhDPEN)] (where η6-arene = para-cymene or biphenyl) can catalyze the reduction of prochiral ketones to optically pure alcohols in the presence of a hydride source. Such complexes can achieve the conversion of pyruvate to unnatural d-lactate in cancer cells. To improve the catalytic performance of these osmium complexes, we have introduced electron-donor and electron-acceptor substituents (R) into the para (R1) or meta (R2) positions of the chiral R-phenyl-sulfonyl-diphenylethylenediamine (R-PhDPEN) ligands and explored the reduction of quinones, potential biological substrates, which play a major role in cellular electron transfer chains. We show that the series of [OsII(η6-arene)(R-PhDPEN)] derivatives exhibit high turnover frequencies, enantioselectivities (>92%), and conversions (>93%) for the asymmetric transfer hydrogenation (ATH) of acetophenone-derived substrates and reduce duroquinone and menadione to their di-alcohol derivatives. Modeling of the catalysis using density functional theory (DFT) calculations suggests a mechanism involving formic acid deprotonation assisted by the catalyst amine groups, phenyl-duroquinone stacking, hydride transfer to OsII, possible CO2 coordination, and tilting of the η6-arene ring, followed by hydride transfer to the quinone. These findings not only reveal subtle differences between Ru(II) and Os(II) catalysts, but also introduce potential biological applications.

Organosilanes in Metal-Catalyzed, Enantioselective Reductions

The growth and development of an extensive range of metals complexed with chiral ligands for the purpose of catalyzing a variety of reactions in an enantioselective manner has been impressive for its scope, chemical yields and high ee values. Chief among the classes of synthetic transformations has been that of the asymmetric reduction of prochiral substrates. These include the asymmetric reduction of prochiral ketones, imines, unsaturated aldehydes, ketones, esters, nitriles and olefins, as well as a number of asymmetric coupling reactions. In concert with these efficient catalyst systems, organosilanes have the ability to carry out any number of organic reductions under a variety of conditions. In these reactions, which in reality are hydrosilylations (hydrosilylation and reduction are considered interchangeable herein) in which the initially resulting silylated product is hydrolyzed to the ultimate desired functionality, the ability to sterically and electronically alter the organosilane reductant can contribute to the overall success of the transformation. In this review, we present a thorough compilation of the literature covering the use of organosilanes in metal-catalyzed asymmetric reductions (hydrosilylations) and coupling reactions.

Altering the Stereoselectivity of Whole-Cell Biotransformations via the Physicochemical Parameters Impacting the Processes

The enantioselective synthesis of organic compounds is one of the great challenges in organic synthetic chemistry due to its importance for the acquisition of biologically active derivatives, e.g., pharmaceuticals, agrochemicals, and others. This is why biological systems are increasingly applied as tools for chiral compounds synthesis or modification. The use of whole cells of “wild-type” microorganisms is one possible approach, especially as some methods allow improving the conversion degrees and controlling the stereoselectivity of the reaction without the need to introduce changes at the genetic level. Simple manipulation of the culture conditions, the form of a biocatalyst, or the appropriate composition of the biotransformation medium makes it possible to obtain optically pure products in a cheap, safe, and environmentally friendly manner. This review contains selected examples of the influence of physicochemical factors on the stereochemistry of the biocatalytic preparation of enantiomerically pure compounds, which is undertaken through kinetically controlled separation of their racemic mixtures or reduction of prochiral ketones and has an effect on the final enantiomeric purity and enantioselectivity of the reaction.

The Development of Organocatalytic Asymmetric Reduction of Carbonyls and Imines Using Silicon Hydrides

AbstractThe asymmetric reduction of prochiral ketones and ketimines represents one of the most important and practical chemical transformations toward the synthesis of valuable chiral alcohols and amines. Among the existing strategies, organocatalyzed asymmetric reduction of carbonyls and imines using silicon hydrides is attractive due to low‐cost, chemical stability, and easy handling in experiments. In this review, we wish to highlight the recent progress made in the past fifteen years in this field. Four catalytic systems of different activation modes are presented and discussed in detail. We aim to help shed light on common features that enable highly enantioselective silicon hydride reductions through organocatalysis and provide the design principles for the development of more effective catalytic systems.

Optimization 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

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.