Reduction Of Prochiral Ketones Research Articles

Iron-, Cobalt-, and Nickel-Catalyzed Asymmetric Transfer Hydrogenation and Asymmetric Hydrogenation of Ketones.

Chiral alcohols are important building blocks in the pharmaceutical and fine chemical industries. The enantioselective reduction of prochiral ketones catalyzed by transition metal complexes, especially asymmetric transfer hydrogenation (ATH) and asymmetric hydrogenation (AH), is one of the most efficient and practical methods for producing chiral alcohols. In both academic laboratories and industrial operations, catalysts based on noble metals such as ruthenium, rhodium, and iridium dominated the asymmetric reduction of ketones. However, the limited availability, high price, and toxicity of these critical metals demand their replacement with abundant, nonprecious, and biocommon metals. In this respect, the reactions catalyzed by first-row transition metals, which are more abundant and benign, have attracted more and more attention. As one of the most abundant metals on earth, iron is inexpensive, environmentally benign, and of low toxicity, and as such it is a fascinating alternative to the precious metals for catalysis and sustainable chemical manufacturing. However, iron catalysts have been undeveloped compared to other transition metals. Compared with the examples of iron-catalyzed asymmetric reduction, cobalt- and nickel-catalyzed ATH and AH of ketones are even seldom reported. In early 2004, we reported the first ATH of ketones with catalysts generated in situ from iron cluster complex and chiral PNNP ligand. Since then, we have devoted ourselves to the development of ATH and AH of ketones with iron, cobalt, and nickel catalysts containing novel chiral aminophosphine ligands. In our study, the iron catalyst containing chiral aminophosphine ligands, which are expected to control the stereochemistry at the metal atom, restrict the number of possible diastereoisomers, and effectively transfer chiral information, are successful catalysts for enantioselective reduction of ketones. Among these novel chiral aminophosphine ligands, 22-membered macrocycle P2N4 exhibited extraordinary enantioselectivities when combined with iron(0) cluster Fe3(CO)12. A broad scope of ketones including aromatic, heteroaromatic, and β-ketoesters can be reduced smoothly with excellent enantioselectivities (up to 99% ee) approaching or exceeding those achievable with the noble metal catalysts. Notably, the chiral iron-based catalyst proved to be highly efficient for both ATH as well as AH of various ketones. Until now, such "universal" catalyst is very rare. Preliminary studies suggest that the AH reaction most likely involved iron particles as the active catalytic species. These research results point to a new direction in developing viable effective nonprecious metal catalysts for asymmetric reduction and probably for other asymmetric catalytic reactions as well.

ChemInform Abstract: Synthesis of Several Polyethers Derived from BINOL and Their Application in the Asymmetric Borane Reduction of Prochiral Ketones.

AbstractSeveral novel polyethylene glycol linked BINOL catalysts are prepared and employed to induce the enantioselective borane reduction of prochiral ketones.

Asymmetric Borane Reduction of Prochiral Ketones Catalyzed By Helical Poly[(S)-3-vinyl-2,2'-dihydroxy-1,1'-binaphthyl

The application of helical poly[(S)-3-vinyl-2,2'-dihydroxy-1, 1'-binaphthyl] (L*) in the asymmetric borane reduction of prochiral ketones was studied. The results showed that L* had excellent catalytic activity as well as enantioselectivity, giving up to 96% yield and up to 99% enantiomeric excess (ee) of the corresponding secondary alcohol at 25 °C. Moreover, L* can be easily recovered and reused without loss of catalytic activity.

Biocatalytic anti-Prelog reduction of prochiral ketones with whole cells of a newly isolated strain Empedobacter brevis ZJUY-1401

Robust biocatalysts are in high demand for the reduction of prochiral ketones to anti-Prelog chiral alcohols. A recently isolated bacterial strain ZJUY-1401 exhibited high reduction activity and excellent anti-Prelog stereospecificity toward prochiral ketones. Based on the colony and microscopic morphology, physiological tests, and 16S rDNA sequence, the isolate was identified as Empedobacter brevis. Upon addition of either NADH or NADPH, the whole cells of E. brevis ZJUY-1401 showed enhanced catalytic activity. The activity and stereoselectivity of the biocatalyst toward acetophenone were significantly increased in the presence of 10% (v/v) ethanol as cosubstrate. Important properties concerning the application of E. brevis ZJUY-1401 include the excellent catalytic performance over a broad pH range from 6.0 to 9.5, temperature optimum of 35°C, and noticeable tolerance against ethanol. Under the optimal conditions, E. brevis ZJUY-1401 was highly active for the reduction of acetophenone derivatives, giving corresponding alcohols in excellent enantiomeric purity (>99% ee). These results imply that E. brevis ZJUY-1401 is a promising biocatalyst for the preparation of anti-Prelog chiral alcohols.

Synthesis of several polyethers derived from BINOL and their application in the asymmetric borane reduction of prochiral ketones

Several novel epoxy monomers, (S,S)- or (S,R)-3-(glycidyloxy)methyl-2,2′-bis(methoxymethyloxy)-1,1′-binaphthalene and (S,S)- or (S,R)-6-(glycidyloxy)methyl-2,2′-bis(methoxymethyloxy)-1,1′-binaphthalene, which were derived from chiral BINOL and epichlorohydrin, were synthesized and underwent anionic polymerization and deprotection of the MOM groups to obtain soluble polyethers. These polyethers were used to induce the enantioselective borane reduction of prochiral ketones. The substrates gave up to 98% yield with over 99% ee values. The recovered polyethers could be reused many times to induce the enantioselective reduction of prochiral ketones without losing their enantioselective induction ability.

ChemInform Abstract: A Solar Light‐Driven, Eco‐Friendly Protocol for Highly Enantioselective Synthesis of Chiral Alcohols via Photocatalytic/Biocatalytic Cascades.

AbstractAn asymmetric artificial photosynthesis system that comprises an efficient method of nicotinamide cofactor regeneration under visible light employing a graphene‐based light harvesting photocatalyst and its subsequent utilization in an enzyme‐catalyzed asymmetric reduction of prochiral ketones is described.

Chiral polyethers derived from BINOL and ECH as highly enantioselective and efficient catalysts for the borane reduction of prochiral ketones

Two novel polyethers derived from BINOL were synthesized and used to induce the enantioselective borane reduction of prochiral ketones. The polyethers gave the expected secondary alcohols with up to 98% yields and over 99% ee values. The recovered polyethers could be reused for many times to induce the enantioselective reduction of prochiral ketones without losing their enantioselective induction ability.

Asymmetric reduction of ketones catalyzed by α,α-diphenyl-(L)-prolinol modified with imidazolium ionic liquid and BH3·SMe2 as a recoverable catalyst

The synthesis of α,α-diphenyl-4-trans-hydroxy-(L)-prolinol modified with imidazolium based ionic liquids was carried out with trans-α,α-diphenyl-4-hydroxy-(L)-prolinol, 5-bromovaleric acid or 1,5-dibromopentane and imidazole. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquid was treated with BH3·SMe2 which generate 1,3,2-oxazaborolidine, that acts as a catalyst for asymmetric reduction of prochiral ketones. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquids (PF6 anion) with BH3·SMe2 found to be an efficient catalyst (10mol%) for the reduction of the acetophenone, gave 99% yield and 87–84% ee. The catalytic method has wide applicability for a variety of substrates. 1,3,2-oxazaborolidine containing ether linkage ionic liquid was recovered and reused up to 4 cycles with 99–91% yields and 87–81% ee’s.

Asymmetric reduction of ketones by biocatalysis using clementine mandarin (Citrus reticulata) fruit grown in Annaba or by ruthenium catalysis for access to both enantiomers.

Biocatalytic reduction of prochiral ketones using freshly ripened clementine mandarin (Citrus reticulata) in aqueous medium is reported. High enantioselectivities were observed, especially for the bioreduction of indanone , tetralone , and thiochromanone with respectively 95%, 99%, and 86% enantiomeric excess (ee). Enantioselective bio- and metal-catalyzed reactions were compared. Chiral ruthenium catalysts afforded good asymmetric inductions (>75% ee) in most cases, enantiomeric excesses depending on the nature of substrate and ligand. N-aminoindanol prolinamide was revealed as the best ligand for most ketones. Interestingly, for several substrates both enantiomers could be obtained using either Citrus reticulata or ruthenium complex.

Fruits of the glossy privet (Ligustrum lucidum—Oleaceae) as biocatalysts for producing chiral aromatic alcohols

The screening of four invasive plant species for use as biocatalysts in the stereoselective reduction of ketones is reported. Our studies revealed that fruits of Ligustrum lucidum can be used for the bioreduction of acetophenone to (S)-1-phenylethanol (94% conversion, > 99 enantiomeric excess [ee]%). Using this methodology, 13 substituted (S)-phenylethanols were synthesized with good ee values (> 99.9 to 78%) using a technique which is more environmentally friendly than classical reduction of prochiral ketones. The results reveal the fruits of L. lucidum to be promising biocatalysts for the production of key intermediates.

Whole-cell biotransformation systems for reduction of prochiral carbonyl compounds to chiral alcohol in Escherichia coli.

Lactobacillus brevis alcohol dehydrogenase (Lb-ADH) catalyzes reduction of prochiral carbonyl compounds to chiral alcohol and meanwhile consumes its cofactor NADH into NAD+, while the cofactor regeneration can be catalyzed by Candida boidinii formate dehydrogenase (Cb-FDH). This work presents three different Escherichia coli whole-cell biocatalyst systems expressing recombinant ADH/FDH, FDH-LIN1-ADH and FDH-LIN2-ADH, respectively, all of which display very high efficacies of prochiral carbonyl conversion with respect to conversion rates and enantiomeric excess values. ADH/FDH represents co-expression of Lb-ADH and Cb-FDH under different promoters in a single vector. Fusion of Lb-ADH and Cb-FDH by a linker peptide LIN1 (GGGGS)2 or LIN2 (EAAAK)2 generates the two bifunctional enzymes FDH-LIN1-ADH and FDH-LIN2-ADH, which enable efficient asymmetric reduction of prochiral ketones in whole-cell biotransformation.

ChemInform Abstract: Enantioselective Reduction of Prochiral Ketones with NaBH4/Me2SO4/(S)‐Me‐CBS.

AbstractBorane, generated in situ via reaction of NaBH4 with DMSO, is successfully applied to reduce prochiral ketones.

Biphasic Reaction System Allows for Conversion of Hydrophobic Substrates by Amine Dehydrogenases

A novel amine dehydrogenase, “F-AmDH”, catalyzes the reversible reduction of prochiral ketones to chiral amines. However, many targeted hydrophobic substrates of F-AmDH show little to no solubility in an aqueous medium. The introduction of water-miscible organic solvents was unsuccessful because of AmDH deactivation. In a biphasic aqueous–organic system, F-AmDH, coupled with formate dehydrogenase (FDH), and hydrophilic co-factors are envisioned to remain in the aqueous phase while the hydrophobic substrate partitions between the phases. The advantages include a larger amount of total substrate present in the system, straightforward product removal, and reduced or negligible substrate and product inhibition. We succeeded in generating chiral amines from hydrophobic substrates that were previously unattainable because of the low solubility of the ketone substrate in aqueous medium. The partition coefficient played an important role in establishing optimal reaction conditions. Specific activity was found to be comparable between aqueous and biphasic reaction systems for substrates that showed some solubility. Thus, biphasic reaction conditions widen the range of substrates for the production of chiral amines using amine dehydrogenases.

A solar light-driven, eco-friendly protocol for highly enantioselective synthesis of chiral alcohols via photocatalytic/biocatalytic cascades

The judicious utilization of solar light for the asymmetric synthesis of optically active compounds by imitating natural photosynthesis introduces a new concept that harnesses this renewable energy in vitro for ultimate transformation into chiral chemical bonds. Herein, we present a comprehensive description of such a biomimetic endeavor towards the design and construction of an asymmetric artificial photosynthesis system that comprises an efficient method of nicotinamide cofactor (NADPH) regeneration under visible light employing a graphene-based light harvesting photocatalyst and its subsequent utilization in an enzyme-catalyzed asymmetric reduction of prochiral ketones to expediently furnish the corresponding chiral secondary alcohols. A detailed optimization study revealed a major dependency of the reaction outcome on the amount of cofactor, photocatalyst and enzyme used, as well as the mode of their addition. A series of structurally diverse ketones bearing an array of (hetero)aryl/alkyl substituents proved to be highly suitable to our photocatalytic–biocatalytic cascade approach, providing (R/S)-1-(hetero)aryl/alkylethanols in excellent enantioselectivities (ee ∼ 95–>99.9%) under mild and environmentally benign conditions. To the best of our knowledge, the synthesis of these enantiopure alcohols employing a visible-light-driven nicotinamide cofactor regeneration strategy has been reported for the first time. Such enantioenriched alcohols act as versatile chiral building blocks for the synthesis of compounds having industrial and pharmaceutical relevance. In addition, this solar-to-chiral chemicals prototype appears advantageous from ecological and economical perspectives. We describe mechanistic pathways to demonstrate how the present catalytic synthesis protocol functions through perfect orchestration between visible-light-driven photocatalysis and biocatalysis to be successively applied in inducing asymmetry in an achiral molecule for the ultimate goal of solar energy utilization in the synthesis of valuable chiral fine chemicals. This work highlights the potential advantages of a bioinspired system to the pertinence of solar energy in asymmetric transformations leading to enantioenriched alcohol precursors, and thus opens up a new field of research that might emerge as an important breakthrough with promising implications towards generating a sustainable and non-fossil/non-nuclear energy future.

Enantioselective Reduction of Prochiral Ketones with NaBH4/Me2SO4/(S)-Me-CBS

The enantioselective reduction of prochiral ketones with NaBH4/Me2SO4/(S)-Me-CBS is described. Borane is generated in situ via the reaction of NaBH4 with Me2SO4 in tetrahydrofuran, which is as efficient as the commercial one. Such in situ–generated borane reagent was applied to reduce prochiral ketones in the presence of chiral oxazaborolidine catalyst directly. The corresponding chiral secondary alcohols were obtained with excellent enantiomeric excesses (93–99% ee) and good to excellent yield (80–99%).

Genomic mining-based identification of novel stereospecific aldo-keto reductases toolbox from Candida parapsilosis for highly enantioselective reduction of carbonyl compounds

Abstract Biocatalytic reduction of prochiral ketones offers significant potential in synthesis of optically active alcohols. However, so far the application of aldo-keto reductases (AKRs) in asymmetric reduction has been hampered due to limited availability of AKRs with high enantioselectivity and catalytic efficiency. Based on the genome sequence of Candida parapsilosis, a versatile bioresource for asymmetric reduction, eight open reading frames encoding putative AKRs were discovered and expressed, and the resulted enzymes (CPARs), comprising an AKR toolbox, were evaluated toward various carbonyl substrates. The CPARs were active to the selected substrates, especially 2-hydroxyacetophenone and ethyl 4-chloro-3-oxobutyrate. Additionally, most of them were obviously enantioselective to the substrates and gave alcohol products with optical purity up to 99%e.e. Of the enzymes, CPAR4 was outstanding with excellent enantioselectivity and broad substrate spectrum. All these positive features demonstrate that genomic mining is powerful in searching for novel and efficient biocatalysts of desired reactions for pharmaceuticals and fine chemicals synthesis.

ChemInform Abstract: Catalytic Asymmetric Reduction of Prochiral Ketones with Chiral β‐Amino Alcohol N‐Boranes and the Corresponding Tris(oxazaborolidine)borazines.

AbstractThe catalytic activity of chiral monomeric and trimeric boron catalysts in the asymmetric reduction of prochiral ketones are evaluated.

Asymmetric bioreduction of acetophenones by Baker's yeast and its cell-free extract encapsulated in sol–gel silica materials

Baker's yeast (BY) encapsulated in silica materials was synthesized using a yeast cell suspension and its cell-free extract during a sol–gel reaction of tetramethoxysilane with nitric acid as a catalyst. The synthesized samples were fully characterized using various methods, such as scanning electron microscopy, nitrogen adsorption–desorption, Fourier transform infrared spectroscopy, thermogravimetry, and differential thermal analysis. The BY cells were easily encapsulated inside silica-gel networks, and the ratio of the cells in the silica gel was approximately 75wt%, which indicated that a large volume of BY was trapped with a small amount of silica. The enzyme activity (asymmetric reduction of prochiral ketones) of BY and its cell-free extract encapsulated in silica gel was investigated in detail. The activities and enantioselectivities of free and encapsulated BY were similar to those of acetophenone and its fluorine derivatives, which indicated that the conformation structure of BY enzymes inside silica-gel networks did not change. In addition, the encapsulated BY exhibited considerably better solvent (methanol) stability and recyclability compared to free BY solution. We expect that the development of BY encapsulated in sol–gel silica materials will significantly impact the industrial-scale advancement of high-efficiency and low-cost biocatalysts for the synthesis of valuable chiral alcohols.

ChemInform Abstract: β‐Hydroxyamide Derivatives of Salicylic Acid as Organocatalysts for Enantioselective Reductions of Prochiral Ketones.

AbstractSeven chiral salicylic acid amide derivatives are prepared and tested as catalysts for the asymmetric borane reduction of prochiral ketones.

Structures of Alcohol Dehydrogenases from Ralstonia and Sphingobium spp. Reveal the Molecular Basis for Their Recognition of ‘Bulky–Bulky’ Ketones

Alcohol dehydrogenases (ADHs) are applied in industrial synthetic chemistry for the production of optically active secondary alcohols. However, the substrate spectrum of many ADHs is narrow, and few, for example, are suitable for the reduction of prochiral ketones in which the carbonyl group is bounded by two bulky and/or hydrophobic groups; so-called ‘bulky–bulky’ ketones. Recently two ADHs, RasADH from Ralstonia sp. DSM 6428, and SyADH from Sphingobium yanoikuyae DSM 6900, have been described, which are distinguished by their ability to accept bulky–bulky ketones as substrates. In order to examine the molecular basis of the recognition of these substrates the structures of the native and NADPH complex of RasADH, and the NADPH complex of SyADH have been determined and refined to resolutions of 1.5, 2.9 and 2.5 Å, respectively. The structures reveal hydrophobic active site tunnels near the surface of the enzymes that are well-suited to the recognition of large hydrophobic substrates, as determined by modelling of the bulky–bulky substrate n-pentyl phenyl ketone. The structures also reveal the bases for NADPH specificity and (S)-stereoselectivity in each of the biocatalysts for n-pentyl phenyl ketone and related substrates.