Asymmetric Reductive Reaction Research Articles

Chiral SPINOL‐Derived Borophosphate‐Catalyzed Asymmetric 1,4‐Reduction of Exocyclic α,β‐Unsaturated Ketones

AbstractAn asymmetric 1,4‐reduction of exocyclic α,β‐unsaturated ketones, yielding diverse optically active α‐substituted tetralones, has been achieved using a chiral SPINOL‐derived borophosphate catalyst. The enantioselectivity‐determining step of the reaction involves the protonation of a highly active boron enolates intermediate. This catalytic reduction system, comprising chiral SPINOL‐derived borophosphate and pinacolborane, has potential for broader application in other asymmetric reduction reactions.

Catalytic Synthesis of (S)-CHBE by Directional Coupling and Immobilization of Carbonyl Reductase and Glucose Dehydrogenase.

Ethyl (S)-4-chloro-3-hydroxybutyrate ((S)-CHBE) is an important chiral intermediate in the synthesis of the cholesterol-lowering drug atorvastatin. Studying the use of SpyTag/SpyCatcher and SnoopTag/SnoopCatcher systems for the asymmetric reduction reaction and directed coupling coenzyme regeneration is practical for efficiently synthesizing (S)-CHBE. In this study, Spy and Snoop systems were used to construct a double-enzyme directed fixation system of carbonyl reductase (BsCR) and glucose dehydrogenase (BsGDH) for converting 4-chloroacetoacetate (COBE) to (S)-CHBE and achieving coenzyme regeneration. We discussed the enzymatic properties of the immobilized enzyme and the optimal catalytic conditions and reusability of the double-enzyme immobilization system. Compared to the free enzyme, the immobilized enzyme showed an improved optimal pH and temperature, maintaining higher relative activity across a wider range. The double-enzyme immobilization system was applied to catalyze the asymmetric reduction reaction of COBE, and the yield of (S)-CHBE reached 60.1% at 30 °C and pH 8.0. In addition, the double-enzyme immobilization system possessed better operational stability than the free enzyme, and maintained about 50% of the initial yield after six cycles. In summary, we show a simple and effective strategy for self-assembling SpyCatcher/SnoopCatcher and SpyTag/SnoopTag fusion proteins, which inspires building more cascade systems at the interface. It provides a new method for facilitating the rapid construction of in vitro immobilized multi-enzyme complexes from crude cell lysate.

Light-driven asymmetric coupling of aromatic aldehydes and aryl iodides using a simple amine reductant

In light of overcoming the sustainability challenge in reduction processes by using a ‘greener’ yet less reactive reductant, a cobalt-catalyzed asymmetric reductive coupling reaction of aromatic aldehydes and aryl iodides has been developed with i-Pr2NEt as the reductant.

DABCO-based ionic salts: synthesis, characterization, and application as organocatalysts in asymmetric reduction reactions

DABCO-based ionic salts: synthesis, characterization, and application as organocatalysts in asymmetric reduction reactions

Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

Piperidines are frequently found in natural products and are of importance to the pharmaceutical industry. A generally useful asymmetric route to enantiomerically enriched 3-substituted piperidines remains elusive. Here we report a cross-coupling approach to enantioenriched 3-piperidines from pyridine- and sp2-hybridized boronic acids. The key step involves a Rh-catalyzed asymmetric reductive Heck reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines in high yield and excellent enantioselectivity with a wide functional group tolerance. A three-step process involving i) partial reduction of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then iii) another reduction provides access to a wide variety of enantioenriched 3-piperidines, including clinically used materials such as Preclamol and Niraparib.

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.

Polymer-supported chiral palladium-based complexes as efficient heterogeneous catalysts for asymmetric reductive Heck reaction

Heterogeneous asymmetric catalysis is an important strategy for the industrial production of chiral compounds. Herein, we reported a polymer-bound Xu-Phos-derived palladium catalyst that shows good performance in heterogeneous asymmetric reductive Heck reaction of allyl aryl ethers. This heterogeneous catalyst was easily prepared by efficient immobilization of the sulfonamide phosphine ligand (Xu-Phos) in the cross-linked polystyrene via copolymerization, and exhibits similar catalytic activity and enantioselectivity to that of the homogeneous catalyst. Moreover, the heterogeneous catalyst system is proved to be easily recovered and reused several times without losing catalytic activity obviously.

Enhancing intracellular NADPH bioavailability through improving pentose phosphate pathway flux and its application in biocatalysis asymmetric reduction reaction

The intracellular NAD(P)H insufficiency is the key factor which limits the reduced product (such as chiral alcohols) synthesis by whole cell biocatalysis or microbial cell factory. In this paper, we reported a novel solution to increase NADPH supply through strengthening the pentose phosphate pathway (PPP) flux with overexpression of extra zwf (gene for glucose 6-phosphatedehydrogenase) and glk (gene for glucokinase) by recombinant Escherichia coli BL21(DE3)/pETDuet-1-glk-zwf and pET28a-bccr containing a carbonyl reductase gene bccr. The amount of intracellular NADPH was significantly increased from 150.3μmol/L to 681.8μmol/L after strengthening the PPP flux, which was 4.5-fold to that of the control. It was applied to improve the asymmetric reduction of 4-chloroacetoacetate to ethyl S-4-chloro-3-hydroxybutylate catalyzed by the BcCR, which increased the reaction yield 2.8-fold to the control. This strategy provides a new way to increase NADPH supply in E.coli cell factories.

Chiral NADH Model: Design, Synthesis, Asymmetric Reduction Reaction, and Fluorescence Characteristics

Abstract: A new type of NADH model compound, which has six asymmetric carbon centers, has been synthesized by an efficient and convenient method. We used NADH models combined with enzymes in the asymmetric reduction. It was the first time that dehydrogenase combined with NADH models instead of inorganic catalysts, such as MgCl2, was used in the asymmetric reduction. Furthermore, the experimental results showed that the new NADH model has the strongest fluorescence emission properties compared to previously reported models.

Efficient bioreduction of cyclohexyl phenyl ketone by Leuconostoc pseudomesenteroides N13 biocatalyst using a distance-based design-focused optimization model

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.

Optimization of asymmetric reduction conditions of 2-bromo-1-(naphthalen-2-yl)ethanone by Enterococcus faecium BY48 biocatalyst with A-optimal design-embedded model.

Aromatic α-halohydrins, especially 2-haloethanols, which are a common pharmacological precursor, may be readily transformed to chiral β-adrenergic receptor blockers. Studies including the synthesis of (S)-2-bromo-1-(naphthalen-2-yl)ethanol ((S)-2), an α-halohydrin, in high conversion, enantiomeric excess (ee), and yield by biocatalytic asymmetric reduction of 2-bromo-1-(naphthalen-2-yl)ethanone (1) are still insufficient. Moreover, asymmetric reduction of substrate 1 using a mathematical optimization method is not explored in the current literature. In this article, the four asymmetric bioreduction conditions, which are (1) pH, (2) temperature, (3) incubation period, and (4) agitation speed, of substrate 1 were optimized to obtain (S)-2 with A-optimal design-embedded model in the presence of Enterococcus faecium BY48. Optimum bioreduction conditions were determined by the A-optimal design-embedded model as follows: pH = 7, temperature = 25°C, incubation period = 24 h, and agitation speed = 200 rpm. And then, it was suggested that (S)-2 could be obtained with 98.88% ee and 100% conversion rate (cr) under these optimum conditions. As a result of the experimental reaction performed under the optimization conditions suggested by the model, (S)-2 was obtained with 99% ee and 100% cr. The study revealed that E.faecium BY48 could be used as a biocatalyst in asymmetric reduction reactions. Also, the A-optimal design-embedded model could have the great potential to obtain the optimum asymmetric bioreduction conditions.

Crystal morphology tuning and green post-synthetic modification of metal organic framework for HPLC enantioseparation

Chiral metal-organic frameworks (CMOFs) served as chiral stationary phases (CSPs) show great potential in enantioseparation field. However, their performance improvement are still hindered by the difficult column packed and high back pressure due to the irregular morphology and broad size scope of CMOF particles. Here, the size and morphology of achiral Co-MOF-74 were effectively adjusted by controlling the synthetic route, temperature, the ratio of reactants and the amount of 2-methylimidazole (2-MI) at first. As a result, the uniformly spherical crystals in size of about 5 μm with good dispersion were obtained. Subsequently, a simple, green post-synthetic modification strategy was proposed for the fabrication of l-tyrosine functionalized Co-MOF-74, namely Co-MOF-74-L-Tyr in H2O by incorporating l-tyrosine into the parent framework of Co-MOF-74 to construct chiral microenvironment. The homochiral Co-MOF-74-L-Tyr CSP gave superior enantioseparation performance for the eight chiral drugs and drug intermediates, such as nitrendipine, nimodipine, benzoin, 2,2′-furoin and bi-2-naphthol to the commercial columns under normal phase condition. The good repeatability and stability of this CSP was verified by the replicate enantioseparation for nimodipine and flavanone. Furthermore, the Co-MOF-74-L-Tyr packed column was successfully applied to detect the product N-1-(1-naphthyl)ethyltosylamide (HR-8) in the asymmetric reductive amination reaction. The size/morphology-controlled synthesis coupled with the green post-synthetic modification approach paves the way to fabricate target chiral MOFs with pre-designed functional groups, which is an effective complement for the preparation of CSPs in chiral chromatography.

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.

Integrated hybrid of graphitic carbon-encapsulated CuxO on multilayered mesoporous carbon from copper MOFs and polyaniline for asymmetric supercapacitor and oxygen reduction reactions

Hybrid electrode materials composed of metal-organic framework (MOF)-derived oxides and conducting polymers have abundant potential for energy applications. The energy storage and conversion phenomena of such materials are due to their high porosity, long stability, good conductivity, low charge transport resistance, and fast charge-discharge rate. Herein, CuxO-C/PANI is synthesized by the in situ polymerization of aniline on multilayered mesoporous CuxO-C from Cu-MOF. Such an integrated hybrid can provide a potential route for electron transfer and improve the kinetics of redox reactions. Subsequently, the CuxO-C/PANI composite demonstrates a maximum specific capacitance of 1308 F g−1 at 1 A g−1 in a 3-electrode system. Additionally, as a fabricated device, CuxO-C/PANI//ZIF-8NPC shows an uppermost energy density of 55.1 W h kg−1 (at a 862.4 W kg−1 power density) and power density of 8668.2 W kg−1 (at a 30.1 W h kg−1 energy density), with 88.3% capacitance retention, even after 10000 cycles. Additionally, CuxO-C/PANI, as an efficient oxygen reduction catalyst, delivers an outstanding onset potential (0.94 V) and half-wave potential (0.76 V) against the reversible hydrogen electrode with good stability. Hence, these results show that the as-fabricated electrode material is an efficient alternative electrocatalyst for energy storage and oxygen reduction applications.

Recent Advances of Catalytic Enantioselective Heck Reactions and Reductive‐Heck Reactions

AbstractHeck reaction is one of the most important carbon‐carbon bond forming reactions with wide applications in organic synthesis. Considerable advances of enantioselective Heck reaction have been achieved in the past decades. This review focuses on recent development of catalytic asymmetric Heck reaction and reductive Heck reaction, which covers intermolecular and intramolecular versions since 2011. The article is organized in terms of the catalysts and olefin substrates.

Electrochemical Asymmetric Reduction of Ketoesters Induced by β‐Cyclodextrin Modified by (1S,2S)‐(+)‐1,2‐Diaminocyclohexane

AbstractChiral cyclohexanediamine was chemically bonded to β‐cyclodextrin as an inducer to induce the asymmetric reduction of ketoesters under electrochemical conditions. The reaction was carried out in an undivided glass cell to form the optically active products. The whole experiment was carried out under mild conditions without high temperature and high pressure. For the electrochemical asymmetric reduction reaction of ethyl benzoylacetate, 63 % yield and 50 % ee value can be obtained.

Chiral cyclometalated iridium complexes for asymmetric reduction reactions.

A series of chiral cyclometalated iridium complexes have been synthesised by cyclometalating chiral 2-aryl-oxazoline and imidazoline ligands with [Cp*IrCl2]2. These iridacycles were studied for asymmetric transfer hydrogenation reactions with formic acid as the hydrogen source and were found to display various activities and enantioselectivities, with the most effective ones affording up to 63% ee in the asymmetric reductive amination of ketones and 77% ee in the reduction of pyridinium ions.

Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel.

Nickel-catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2-cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel

AbstractNickel‐catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2‐cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Design and application of a bi-functional redox biocatalyst through covalent co-immobilization of ene-reductase and glucose dehydrogenase

An immobilized bi-functional redox biocatalyst was designed for the asymmetric reduction of alkenes by nicotinamide-dependent ene-reductases. The biocatalyst, which consists of co-immobilized ene-reductase and glucose dehydrogenase, was implemented in biotransformations in the presence of glucose as source of reducing equivalents and catalytic amounts of the cofactor. Enzyme co-immobilization employing glutaraldehyde activated Relizyme HA403/M as support material was performed directly from the crude cell-free extract obtained after protein overexpression in E. coli and cell lysis, avoiding enzyme purification steps. The resulting optimum catalyst showed excellent level of activity and stereoselectivity in asymmetric reduction reactions using either OYE3 from Saccharomyces cerevisiae or NCR from Zymomonas mobilis in the presence of organic cosolvents in up to 20 vol%. The bi-functional redox biocatalyst, which demonstrated remarkable reusability over several cycles, was applied in preparative-scale synthesis at 50 mM substrate concentration and provided access to three industrially relevant chiral compounds in high enantiopurity (ee up to 97 %) and in up to 42 % isolated yield. The present method highlights the potential of (co-)immobilization of ene-reductases, notorious for their poor scalability, and complements the few existing methods available for increasing productivity in asymmetric bioreduction reactions.