Enantioselective Reduction Of Prochiral Ketones Research Articles

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.

Enantioselective reduction of prochiral ketones promoted by amino amide ruthenium complexes: A DFT study

The origin of enantioselectivity in the reaction of chiral Ru amino amide complexes in the asymmetric transfer hydrogenation of acetophenone was investigated using DFT calculations. For the most stable active catalysts, the full free energy profiles for the reaction were calculated according to the concerted hydrogen transfer mechanism. We succeeded in reproducing the experimentally observed enantioselectivity for the studied Ru amino amide complexes. Our results indicate that the high enantioselectivity can be explained by a stabilizing CH-π interaction existing between the phenyl group of acetophenone and the aromatic substituent of the catalyst, which plays a significant role in selectivity. Finally, our results show that important insights can be obtained with such a theoretical approach not simply to explain the origin of the reaction asymmetry but also to predict the enantiomeric excess. This can help experimentalists to design new enantioselective catalysts.

Recent Advances in Metal‐Catalyzed Asymmetric Hydroboration of Ketones

AbstractMetal‐catalyzed asymmetric reduction of unsaturated functions is a highly useful and fundamental transformation to give diverse chiral synthons. In particular, the enantioselective reduction of prochiral ketones is of great synthetic interest, since it can provide optically active chiral alcohols which have wide applications in organic synthesis, materials science, and pharmaceutical chemistry. Numerous and diverse metal catalytic systems for asymmetric hydrogenation and hydrosilylation of ketones extensively evolved in terms of activity, selectivity, and practicality, while only limited varieties of metal catalysts for the asymmetrichydroborationhad been documented until 2010.Diverseandnewmetal complexes with a range of multi‐dentate chiral ligands have recently emerged as catalysts for the enantioselective ketone hydroboration, which are highly differentiated from the precedence in several aspects. This Minireview summarizes recent examples of the metal catalyst systems for the asymmetric hydroboration of ketones published from 2015 to 2020. Diverse catalytic working modes involved in a process of enantiodifferentiating hydride transfer, are discussed with a strong emphasis on the steric and electronic effects of chiral ligands.

Гидроксипроизводные левоглюкозенона в реакциях энантиоселективного восстановления 1,3-дифенилпропан-1-она

The enantioselective reduction of prochiral ketones is an important method for the preparation of enanti-enriched secondary alcohols, which can serve as starting materials for optically active compounds. Chiral metal hydride reagents, such as lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4), modified with chiral ligands, have been developed to effect enantioselective reduction. However, in most cases, derivatives are used to obtain chiral hydride reagents, which are rare and hardly available. Therefore, the search for more accessible and effective derivatives suitable for the modification of hydride reagents is an urgent task. Levoglucosenone is an optically pure enone of carbohydrate nature, readily available by pyrolysis of any cellulose-containing materials. Levoglucosenone is considered a promising bioplatform for both laboratory synthesis and industrial use. The prospect of the development of chemistry of levoglucosenone and its derivatives in industry makes it possible to pay attention to these compounds from the point of view of studying their possibilities as chiral inducers or auxiliaries. In this work, we studied the possibilities of chiral induction in the reduction reactions of 1,3-diphenylpropan-1-one with hydride reagents obtained by replacing hydrogens in LiAlH4 and NaBH4 with hydroxy derivatives of levoglucosenone. The reduction of 1,3-diphenylpropan-1-one with chiral aluminum hydride reagents proceeded with low enantioselectivity, mainly with a predominance of (S)-1,3-diphenylpropan-1-ol. It was found that the enantiomeric purity of the S-stereomer decreases with an increase in the substitution of hydrogen atoms in LiAlH4 by hydroxy derivatives of levoglucosenone. Reduction of 1,3-diphenylpropan-1-one with reagents obtained by partial neutralization of NaBH4 with hydroxy derivatives of levoglucosenone, on the contrary, predominantly leads to the formation of (R)-1,3-diphenylpropan-1-ol. The addition of AcOH and Bu4NCl to NaBH4 has a positive effect on the optical frequency of the R-alcohol. At the same time, enantioselectivity in the reactions was almost absent upon reduction of 1,3-diphenylpropan-1-one with reagents obtained by partial neutralization of BH3. The best results of enantioselective reduction were shown by unsaturated alcohols: (1S,4S,5R) -6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol and (1S,4S,5R)-4-methyl-6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol, of which (1S,4S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol was the most effective. It is likely that an increase in the enantioselectivity of reactions carried out in the presence of hydroxy derivatives of levoglucosenone is possible by obtaining more bulky chiral ligands, provided that the double bond is retained.

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.

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.

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.

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.

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.

ChemInform Abstract: A Series of Novel β‐Hydroxyamide Based Catalysts for Borane‐Mediated Enantioselective Reductions of Prochiral Ketones.

AbstractSeven catalysts are prepared and tested in the title process.

A series of novel β-hydroxyamide based catalysts for borane-mediated enantioselective reductions of prochiral ketones

The enantioselective reduction of prochiral ketones with borane in the presence of a chiral ligand has received considerable attention. Hydroxylamine-based chiral ligands with amide and hydroxyl functions in the presence of other co-ordinating groups are highly effective in these asymmetric reductions. The current work presents a simple one step synthesis of a series of β-hydroxyamide-based ligands from the reaction between 3-hydroxy-2-naphthoic acid and chiral amino alcohols and their applications as catalysts in asymmetric borane-mediated reductions of aromatic prochiral ketones in THF. The reductions provided the corresponding secondary alcohols with up to 96% ee and in good to excellent yields (89–99%). DFT calculations at B3LYP/6-31+g(d) level offered theoretical models to account for the enantioselectivity imposed by the chiral ligands in the reductions of the ketones.

Ru(ii)-p-cymene complexes containing esters of chiral d/l-phenylalanine derived aroylthiourea ligands for enantioselective reduction of pro-chiral ketones

The chiral Ru(ii)-p-cymene complexes are efficient catalysts for the enantioselective reduction of ketones to chiral alcohols.

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.

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.

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.

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.

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%).

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.

β-Hydroxyamide derivatives of salicylic acid as organocatalysts for enantioselective reductions of prochiral ketones

In order to find the most effective catalyst for the enantioselective reduction of a prochiral ketone, a series of novel β-hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized. Different substituted prochiral ketones have been reduced in high yield (up to 99%) and the corresponding secondary alcohols are formed with good enantiomeric excess (up to 86%). The mechanism of this type of catalyst can be explained by considering the reaction mechanism for the CBS catalyst.

Immobilization of chiral oxazaborolidine catalyst over highly ordered 3D mesoporous silica with Ia3d symmetry for enantioselective reduction of prochiral ketone

Here we demonstrate for the first time the encapsulation of a chiral oxazaborolidine complex in the 3D mesoporous channels of an amine functionalized KIT-6 material via covalent bonding through a post-synthetic approach. The physico-chemical properties of the pure and immobilized KIT-6 catalysts were obtained by various techniques such as XRD, nitrogen adsorption, HRSEM, UV-Vis diffuse reflectance spectroscopy, and FT-IR spectroscopy. It has been found that the structural stability of the KIT-6 was not affected even after the immobilization of a significant amount of chiral ligand inside the mesoporous channels of the support. However, the values of structural parameters such as the specific surface area and the specific pore volume of the KIT-6 support was significantly lower than the pure KIT-6 support. The chemical interaction between the chiral ligand inside the mesochannels and the KIT-6 support was also confirmed by UV-Vis and FT-IR spectroscopy. The chiral catalytic performance of the immobilized catalysts for the enantioselective reduction of aromatic prochiral ketones was demonstrated and the results were compared with chiral catalyst immobilized supports with uni-dimensional porous structures, such as MCM-41 and SBA-15. Among the catalysts studied, chiral catalyst immobilized KIT-6 showed the highest performance with a high product yield and a high enantioselectivity due to its 3D porous structure with two continuous and interpenetrating systems of chiral channels and an interwoven 3D cylindrical type pores of Ia3d symmetry. The catalyst also exhibited much better recycling capability than other chiral catalyst supported mesoporous materials used in the study.