Enantioselective Reduction Of Ketones Research Articles

Preparation of chiral alcohols by enantioselective reduction of prochiral ketones with Sinapis alba seeds as biocatalyst

The objective of this work is to apply yellow mustard seeds in the enzymatic reduction (biocatalysis) of acetophenone and its derivatives, providing a new biocatalyst for this type of reduction. The reaction parameters were optimized from acetophenone, resulting in 1-phenylethanol, with 68.5% conversion yield and 53% enantiomeric excess (e.e.), analyzed by GC and HPLC, respectively. Reactions to acetophenone and its derivatives were conducted in aqueous medium using buffers pH 6.0 and pH 6.5 in the presence of PVP. A polymer that can act as a protector preventing oxidation of peroxidase enzymes. The results for the derivatives presented low yields (4–18%: substances 5, 7 and 8), moderate (28–40%: substances 3, 4 and 6) and optimum (81%: substance 2) yields, with enantiomeric excesses varying from good to excellent results. Meta-substituted derivatives showed inversion of configuration in the presence of PVP. The biocatalyst was also tested in reactions with other carbonyl compounds, presenting moderate results. In this way, this work offers a new perspective of the application of PVP in biocatalysis reactions and a new biocatalyst for future applications.

Enantioselective reduction of azaarene-based ketones via visible light-driven photoredox asymmetric catalysis.

An enantioselective reduction of azaarene-based ketones through photoredox asymmetric catalysis is reported. With a transition metal-free dual catalytic system including a chiral phosphoric acid and a photosensitizer DPZ mediated by visible light, the transformations involved a tandem process involving double single-electron-transfer reductions and enantioselective protonation, providing valuable chiral alcohols in high yields (up to >99%) with good to excellent enantioselectivities (up to 97% ee).

Neutron and X-ray crystal structures of Lactobacillus brevis alcohol dehydrogenase reveal new insights into hydrogen-bonding pathways.

Lactobacillus brevis alcohol dehydrogenase (LbADH) is a well studied homotetrameric enzyme which catalyzes the enantioselective reduction of prochiral ketones to the corresponding secondary alcohols. LbADH is stable and enzymatically active at elevated temperatures and accepts a broad range of substrates, making it a valuable tool in industrial biocatalysis. Here, the expression, purification and crystallization of LbADH to generate large, single crystals with a volume of up to 1 mm3 suitable for neutron diffraction studies are described. Neutron diffraction data were collected from an H/D-exchanged LbADH crystal using the BIODIFF instrument at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany to a resolution dmin of 2.15 Å in 16 days. This allowed the first neutron crystal structure of LbADH to be determined. The neutron structure revealed new details of the hydrogen-bonding network originating from the ion-binding site of LbADH and provided new insights into the reasons why divalent magnesium (Mg2+) or manganese (Mn2+) ions are necessary for its activity. X-ray diffraction data were obtained from the same crystal at the European Synchrotron Radiation Facility (ESRF), Grenoble, France to a resolution dmin of 1.48 Å. The high-resolution X-ray structure suggested partial occupancy of Mn2+ and Mg2+ at the ion-binding site. This is supported by the different binding affinity of Mn2+ and Mg2+ to the tetrameric structure calculated via free-energy molecular-dynamics simulations.

Piano-stool Ru(II)-benzene complexes bearing D/L-alanine derived chiral aroylthiourea ligands for asymmetric transfer hydrogenation of ketones in water

The new water soluble chiral Ru(II)-benzene complexes of the type [ $$\hbox {RuCl}_{2}(\eta ^{6}\hbox {-C}_{6}\hbox {H}_{6})\hbox {L}$$ ] were obtained from the reactions between $$[\hbox {RuCl}_{2}(\eta ^{6}\hbox {-C}_{6}\hbox {H}_{6})]_{2 }$$ and the chiral aroylthiourea ligands (L) derived from unprotected D/L-alanine and characterized. The solid-state structure of representative complexes was confirmed by single crystal X-ray diffraction technique. The Ru(II)-benzene complexes catalyzed the asymmetric transfer hydrogenation (ATH) of aromatic ketones to their enantiopure secondary alcohols. The reactions were carried out in the presence of formic acid–triethylamine mixture in water, and the product alcohols were obtained with excellent conversions (up to 99%) and enantiomeric excesses (up to 99%). The scope of the catalytic system was extended to various aromatic ketones. The catalytic activity of the present water-soluble Ru-benzene complexes toward enantioselective reduction of ketones was considerably higher than that of p-cymene analogues in water. The water-soluble chiral Ru(II)-benzene complexes were produced from the reactions between $$[\hbox {RuCl}_{2}(\eta ^{6}\hbox {-C}_{6}\hbox {H}_{6})]_{2 }$$ and the chiral aroylthiourea ligands derived from unprotected D/L-alanine. The catalytic activity of the Ru(II)-benzene complexes toward enantioselective reduction of ketones was found to be good in water medium.

Highly enantioselective reduction of ketones in air catalyzed by Rh-based macrocycles

The asymmetric transfer hydrogenation (ATH) of ketones catalyzed by Rh-based macrocycles proceeded smoothly in the presence of air with high catalytic activity and enantioselectivity. Even though the S/C ratio (substrate to catalyst molar ratio) was increased up to 2000:1, the ATH of ketone still afforded 92% isolated yield with 92% ee. Notably, the Rh-based macrocycles could be successfully used to catalyze the ATH of ketones without any need of inert atmosphere, which further highlighted its advantage over those generally air-sensitive transition metal catalysts. The addition of NH4I greatly improved both the catalytic activity and enantioselectivity. On the basis of NMR evidence, we postulate that the NH4I significantly enhanced the coordination between chiral macrocyclic ligands and rhodium center.

Practical Enantioselective Reduction of Ketones Using Oxazaborolidine Catalysts Generated In Situ from Chiral Lactam Alcohols.

Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during storage. Therefore, we investigated a more reliable and practical method for the reduction of a variety of ketones including challenging substrates, primary aliphatic ketones, α,β-enones, and trifluoromethyl ketones. This review surveys the developments in borane reduction using oxazaborolidine catalysts generated in situ from chiral lactam alcohols and borane.

Immobilized and Free Cells of Geotrichum candidum for Asymmetric Reduction of Ketones: Stability and Recyclability.

Marine-derived fungus Geotrichum candidum AS 2.361 was previously reported by our group as an active strain for the enantioselective reduction of ketones. Although some other Geotrichum strains were also found from the terrestrial sources, information on their stability and reusability is scarce. Herein, the stabilities—in terms of pH tolerance, thermostability, and storage stability, and reusability—of G. candidum AS 2.361 were described for the asymmetric reduction of a series of aromatic ketones. Two differently immobilized cells (agar immobilization and calcium alginate immobilization) as well as free cells were prepared. For three substrates (1-(3-bromophenyl) ethan-1-one (1b), 1-(2-chlorophenyl) ethan-1-one (1d), and acetophenone (1g)) immobilized cells on agar showed a great improvement in the bioreduction activities compared to the free cells, increasing yields up to 97% with ee values of 99%. Cells immobilized on agar/calcium alginate could maintain more than 90% of the original activities within the assayed pH ranges of 3.5–11, while free cells were highly sensitive to alkaline and acidic conditions. Concerning thermostability, immobilized cells on agar kept 99% of their original activities after incubation at 60 °C for 1 h, while almost no activity was detected for the free cells under the same condition. Immobilized cells were stable at 4 °C for 80 days without any activity loss, while free cells started to decrease the activity after storage at 4 °C for six days. The immobilized cells retained almost 99% activity after four reuse cycles, while free cells lost almost all the activities at on the third cycle.

Expression of engineered carbonyl reductase from Ogataea minuta in Rhodococcus opacus and its application to whole-cell bioconversion in anhydrous solvents

The carbonyl reductase from the methylotrophic yeast Ogataea minuta can catalyze the regio- and enantio-selective reduction of prochiral ketones to chiral alcohols, and is available for industrial manufacturing of statin drugs. We previously conducted a directed evolution experiment of the enzyme, and obtained a mutant (OCR_V166A) with improved tolerance to organic solvents. This expanded the applicability of the enzyme to the bioconversion of water-insoluble compounds (Honda etal., J. Biosci. Bioeng., 123, 673-678, 2017). In the present study, we expressed OCR_V166A in Rhodococcus opacus cells, which have a highly lipophilic surface structure and are dispersible in anhydrous organic solvents, and developed a whole-cell biocatalyst which can function in an organic-solvent-based reaction medium. The secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeADH) was employed as an NADPH-regenerating enzyme and co-expressed with OCR_V166A in R. opacus. The whole-cell bioconversion of 2,2,2-trifluoroacetophenone to α-(trifluoromethyl)benzyl alcohol was performed in organic solvents, including isopropanol, isobutanol, and cyclohexanol, which served both as reaction media and as substrates for TeADH. The type of organic solvents markedly affected not only the product titer but also the enantio-purity of the product. When isobutanol was used as the reaction medium, the whole-cell biocatalyst showed higher stability than the isolated enzyme. Consequently, a high concentration (1M) of the substrate was converted to the product with an overall conversion yield of 81% (mol/mol) in 24h.

Ytterbium-Catalyzed Enantioselective Reduction of Ketones

Ytterbium-Catalyzed Enantioselective Reduction of Ketones

Enantioselective metal-free reduction of ketones by a user-friendly silane with a reusable chiral additive

1-Hydrosilatrane, a safe and easy-to-handle reducing reagent that can be inexpensively accessed, has been shown to reduce prochiral ketones asymmetrically in the presence of chiral 1,2-aminoalcohols with ees ranging from 8% to 86%. The best result was achieved using ephedrine as the source of chirality, which is readily commercially available. The additive can be recovered through extraction and reused without any erosion of enantioselectivity.

Whole Cells as Biocatalysts in Organic Transformations.

Currently, the power and usefulness of biocatalysis in organic synthesis is undeniable, mainly due to the very high enantiomeric excess reached using enzymes, in an attempt to emulate natural processes. However, the use of isolated enzymes has some significant drawbacks, the most important of which is cost. The use of whole cells has emerged as a useful strategy with several advantages over isolated enzymes; for this reason, modern research in this field is increasing, and various reports have been published recently. This review surveys the most recent developments in the enantioselective reduction of carbon-carbon double bonds and prochiral ketones and the oxidation of prochiral sulfides using whole cells as biocatalytic systems.

Enantioselective Reduction of Ketones Catalyzed by Rare-Earth Metals Complexed with Phenoxy Modified Chiral Prolinols.

Enantioselective reduction of ketones and α,β-unsaturated ketones by pinacolborane (HBpin) has been well-established by using chiral rare-earth metal catalysts with phenoxy modified prolinols. A number of highly optically active alcohols were obtained from reduction of simple ketones catalyzed by ytterbium complex 1 [L4Yb(L4H)] (H2L4 = ( S)-2- tert-butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol). Moreover, α,β-unsaturated ketones were selectively reduced to a wide range of chiral allylic alcohols with excellent yields, high enantioselectivity, and complete chemoselectivity, catalyzed by a single component chiral ytterbium complex 2 [L1Yb(L1H)] (H2L1 = ( S)-2,4-di- tert-butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol).

Iridium-Catalyzed Enantioselective Reduction of Heteroaryl Ketones

Iridium-Catalyzed Enantioselective Reduction of Heteroaryl Ketones

Formal Synthesis of Angiopterlactone B via Enantioselective Reduction of Ketone with Daucus Carota Root

AbstractFormal synthesis of angiopterlactone B has been accomplished via. enantioselective reduction of ketone with Daucus carota, Sharpless dihydroxylation and Andos modified Horner‐Wadsworth‐Emmons (HWE) reagent to introduce Z‐olefination. Here we evolved a new path for the synthesis of (S,S)‐osmundalactone and 3–5 dihydroxy γ‐caprolactone. The initial synthetic route for both caprolactone and osmundalcactone build on biocatalytic process while in later case Sharpless dihydroxylation delivered required stereocentres. Z‐selective olefination was utilized to furnish caprolactone which was further recycled in to 1‐(5‐oxotetrahydrofuran‐2yl) ethyl 2‐phenyl acetate. Both synthetic routes found to be applicable for many synthetic reactions.

Synthesis and characterization of novel silica coated magnetic nanoparticles with tags of β-cyclodextrin: application as an eco-friendly and chiral micro-vessel catalyst in the enantioselective reduction of ketones

In this work, we report the synthesis of a novel, green and recoverable organic–inorganic magnetic nanocomposite by grafting β-cyclodextrin on the surface of a silica-coated magnetic nanoparticle, Fe3O4@SiO2/Pr-β-CD. FT-IR spectroscopy, transmission electron microscopy, CHN analysis, thermogravimetric analysis, vibrating sample magnetometer and X-ray diffraction analyses confirmed its structure. The magnetic core–shell structured modified silica microsphere has been successfully used as a chiral micro-vessel catalyst for the enantioselective reduction of ketones by NaBH4. The described catalyst was regenerated and reused without any significant changes in the yield and enantiomeric excess.

Synthesis, characterization, and organocatalytic application of chiral ionic liquids derived from (S,R)-noscapine

ABSTRACT(S,R)-Noscapine, a phthalideisoquinoline alkaloid has been used as precursor for the synthesis of chiral ionic liquids (CILs). Noscapine based CILs have been synthesized from reaction between (S,R)-noscapine and methyl iodide in acetonitrile at room temperature. The synthesized CILs have been characterized by 1H NMR, 13C NMR, EI-MS, and polarimetry techniques. These CILs have been used as organocatalysts in the enantioselective reduction of prochiral ketones to produce optically active secondary alcohols. The optically active secondary alcohols have been obtained with excellent yields and low to moderate enantiomeric excess (ee); also the complete enantiomeric excess (100% ee) has been achieved in some cases.

Enantioselective reduction of aryl and hetero aryl methyl ketones using plant cell suspension cultures of Vigna radiata

Vigna radiata was investigated as whole cell catalyst for the bioreduction of aryl and heteroaryl prochiral ketones into optically active alcohols. The study indicates selective bioreduction of different substituted aryl and heteroaryl ketones (1a–12a) to their respective (S) – chiral alcohols (1b–12b) in good to high enantioselectivity (77.7–97.5%) with very good yields (73–82%). The results obtained confirm that the keto reductase has broad substrate specificity and selectivity in catalyzing both six and five-membered heteroaryl methyl ketones. The current methodology substantiates a promising and alternative green approach for the synthesis of secondary chiral alcohols of biological importance in a mild, cheap and environmentally benign process.

Chiral phosphinites as efficient ligands for enantioselective Ru(II), Rh(I) and Ir(III)-catalyzed transfer hydrogenation reactions

Metal-catalyzed enantioselective transfer reduction of ketones to enantiomerically enriched chiral alcohols has recently attracted attention. Therefore, a series of methyl alkyl or alkyl/aryl ketones have been reduced by using Ru(II), Rh(I) and Ir(III) catalysts based on C 2-symmetric chiral ferrocenyl phosphinite ligands. The corresponding optically active secondary alcohols were obtained in excellent conversions and moderate-to-good enantioselectivities. The best results were obtained with an iridium catalyst, giving up to 98% conversion and 80% ee.

Inducing high activity of a thermophilic enzyme at ambient temperatures by directed evolution.

The long-standing problem of achieving high activity of a thermophilic enzyme at low temperatures and short reaction times with little tradeoff in thermostability has been solved by directed evolution, an alcohol dehydrogenase found in hot springs serving as the catalyst in enantioselective ketone reductions.

1‐Hydrosilatrane: A Locomotive for Efficient Ketone Reductions

An efficient method for the reduction of ketones with 1‐hydrosilatrane is described. In the presence of a Lewis base activator, the resulting secondary alcohols are rapidly formed in good to excellent yields (20 examples, 71–99 % yields). The relative bulkiness of 1‐hydrosilatrane also enables the diastereoselective reduction of (–)‐menthone to (+)‐neomenthol, and the use of a chiral alkoxide activator can lead to the enantioselective reduction of prochiral ketones.