Α-keto Esters Research Articles

Exploiting Cofactor Versatility to Convert a FAD-Dependent Baeyer-Villiger Monooxygenase into a Ketoreductase.

Cyclohexanone monooxygenases (CHMOs) show very high catalytic specificity for natural Baeyer-Villiger (BV) reactions and promiscuous reduction reactions have not been reported to date. Wild-type CHMO from Acinetobacter sp. NCIMB 9871 was found to possess an innate, promiscuous ability to reduce an aromatic α-keto ester, but with poor yield and stereoselectivity. Structure-guided, site-directed mutagenesis drastically improved the catalytic carbonyl-reduction activity (yield up to 99 %) and stereoselectivity (ee up to 99 %), thereby converting this CHMO into a ketoreductase, which can reduce a range of differently substituted aromatic α-keto esters. The improved, promiscuous reduction activity of the mutant enzyme in comparison to the wild-type enzyme results from a decrease in the distance between the carbonyl moiety of the substrate and the hydrogen atom on N5 of the reduced flavin adenine dinucleotide (FAD) cofactor, as confirmed using docking and molecular dynamics simulations.

ZnO nanoparticles: An efficient catalyst for transesterification reaction of α-keto carboxylic esters

• Pure ZnO nanoparticles prepared by a simple and sustainable precipitation method. • ZnO nanoparticles as efficient catalyst for transesterification of α -keto carboxylic esters. • Transesterification reaction of different carboxylic esters with various alcohols. Pure ZnO nanoparticles were synthesized by a sustainable precipitation method using zinc nitrate and sodium hydroxide in aqueous medium at room temperature. They were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM-EDX), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV–vis) spectroscopy and Brunauer-Emmett-Teller (BET) analysis. The XRD patterns indicate the formation of the hexagonal wurtzite phase with high purity and SEM-EDS analysis confirm the purity and a homogenous distribution of the nanostructures. The ZnO nanostructures present plate-like agglomerates, resulting in a quasi-spherical morphology. The catalytic activity of the formed ZnO nanoparticles was evaluated towards the transesterification reaction of different carboxylic esters in the presence of various alcohols. This catalyst is highly selective for the transesterification of α -keto carboxylic ester (methyl benzoylformate) and leads to ca . 97% of product yield within 24 h of reaction time.

Key sites insight on the stereoselectivity of four mined aldo-keto reductases toward α-keto esters and halogen-substituted acetophenones.

Biocatalytic reduction catalyzed by aldo-keto reductases (AKRs) is a valuable approach for asymmetric synthesis of chiral alcohols. In this study, four novel aldo-keto reductases with significant activity and stereoselectivity toward a variety of α-keto esters and halogen-substituted acetophenones were identified by genome mining. Through analysis of the crystal structure and multiple-sequence alignment of the starting AKR YvgN from Bacillus subtilis, residues F25 and W113 were proposed as the key positions that might control the stereoselectivity of YvgN. F25S and F25S/W113F variants of YvgN were able to improve its activity and stereoselectivity toward some α-keto ester compounds and halogen-substituted acetophenone derivatives. In addition, similar enhancement of catalytic activity and stereoselectivity was also found in the other three AKRs with corresponding mutations of starting YvgN.

Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – Scalable approach to novel functionalized pyrimidines

Two protocols for synthesis of series of low-molecular-weight di- and tri-substituted pyrimidines bearing a functional group at the 4th position, which rely on a base-mediated condensation of amidines or guanidines with β-alkoxyvinyl α-keto esters, have been developed. This approach allowed for multigram preparation of novel pyrimidine-4-carboxylates in 21–90% yield. The synthetic utility of these compounds was demonstrated by some standard functional group transformations providing promising building blocks for organic synthesis and drug discovery.

Synthesis of chiral spiro-cyclopentene/cyclopentadiene-oxindoles through an asymmetric [3 + 2] cycloaddition of isatin-derived MBH carbonates and β,γ-unsaturated α-keto esters

A highly stereoselective [3 + 2] cycloaddition for constructing the chiral spiro-cyclopentene/cyclopentadiene-oxindole skeletons is developed. Under the mild reaction conditions, the straightforward cyclization of isatin-derived MBH carbonates and β,γ-unsaturated α-keto esters involving a chiral tertiary amine catalyst provides the corresponding spirooxindole derivatives with an extraordinary level of diastereo- and enantioselectivities. Further synthetic utility of this protocol is demonstrated by the gram-scale experiment and functional transformation of the synthetic compound into other structurally diverse spirooxindole.

Solvent-Dependent Enantiodivergence in anti-Selective Catalytic Asymmetric Nitroaldol Reactions.

anti-Selective catalytic asymmetric nitroaldol reactions of α-keto esters promoted by a heterogeneous Nd/Na heterobimetallic catalyst exhibited a significant, unexpected disparity in enantioselection that was solvent-dependent. This phenomenon exclusively occurred when the stereogenic center of a diamide ligand had the smallest substituent (Me group, derived from l-Ala), which behaved uniquely in comparison with other structurally similar ligands to provide antipodal products under otherwise identical conditions.

Palladium-Catalyzed [3+2] Cycloaddition of Vinylcyclopropane and Ketones

A Pd-catalyzed [3+2] cycloaddition reaction of vinylcyclopropane and trifluoromethyl ketones as well as α-keto esters were developed, affording tetrahydrofurans in high yield.

Novel Effect of Zinc Nitrate/Vanadyl Oxalate for Selective Catalytic Oxidation of α-Hydroxy Esters to α-Keto Esters with Molecular Oxygen: An In Situ ATR-IR Study.

Selective oxidation of α-hydroxy esters is one of the most important methods to prepare high value-added α-keto esters. An efficient catalytic system consisting of Zn(NO3)2/VOC2O4 is reported for catalytic oxidation of α-hydroxy esters with molecular oxygen. Up to 99% conversion of methyl DL-mandelate or methyl lactate could be facilely obtained with high selectivity for its corresponding α-keto ester under mild reaction conditions. Zn(NO3)2 exhibited higher catalytic activity in combination with VOC2O4 compared with Fe(NO3)3 and different nitric oxidative gases were detected by situ attenuated total reflection infrared (ATR-IR) spectroscopy. UV-vis and ATR-IR results indicated that coordination complex formed in Zn(NO3)2 in CH3CN solution was quite different from Fe(NO3)3; it is proposed that the charge-transfer from Zn2+ to coordinated nitrate groups might account for the generation of different nitric oxidative gases. The XPS result indicate that nitric oxidative gas derived from the interaction of Zn(NO3)2 with VOC2O4 could be in favor of oxidizing VOC2O4 to generate active vanadium (V) species. It might account for different catalytic activity of Zn(NO3)2 or Fe(NO3)3 combined with VOC2O4. This work contributes to further development of efficient aerobic oxidation under mild reaction conditions.

Asymmetric Synthesis of α-Amino Acids by Organocatalytic Biomimetic Transamination.

A biomimetic enantioselective transamination of α-keto ester derivatives can be realized under mild conditions by using chiral quaternary ammonium arenecarboxylates in the absence of base additives. The corresponding α-amino acids can be used as versatile intermediates for further synthetic transformations that furnish chiral pyrrolidine and octahydroindolizine derivatives.

Direct Synthesis of β,γ-Unsaturated α-Keto Esters from Aldehydes and Pyruvates

Herein, we describe two practical methods to synthesize β,γ-unsaturated α-keto esters directly from aldehydes and pyruvates promoted by BF3•Et2O in the presence of Ac2O or by Ti(OEt)4 under mild conditions. A variety of aromatic aldehydes was tolerated to afford the desired products in moderate to excellent yield. Moreover, aliphatic aldehydes and Isatin were also employed to give the γ-alkyl β,γ-unsaturated α-keto esters in moderate yield with use of the Ti(OEt)4 system.

Thiourea-catalyzed asymmetric domino Michael-cyclization reaction of 3-isothiocyanato oxindoles with β,γ-unsaturated α-keto esters for the synthesis of spirocyclic oxindoles

A reaction between 3-isothiocyanato oxindoles and β,γ-unsaturated α-keto esters catalyzed by a chiral thiourea organocatalyst via a domino Michael-cyclization process is described, which delivers a range of biologically important 2′-thioxospiro[indoline-3,4′-oxazolidin]-2-one compounds in high yields with good diastereo- and enantioselectivities (up to 99% yield, >99:1 dr, >99% ee). Moreover, two of 2′-thioxospiro[indoline-3,4′-oxazolidin]-2-one compounds were found to significantly behave in anti-inflammatory activities in a preliminary biological evaluation.

Oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters: concise synthesis of clausenamide analogues.

A one-pot oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters at room temperature is reported. The protocol features copper/organo cooperative catalysis and provides densely functionalized pyrrolones in high yields. Subsequent reduction furnished multi-substituted pyrrolidinones which represent the core-structure of the natural product clausenamide, a lead molecule for the treatment of Alzheimer's disease.

Microbial Production of Chiral Hydroxy Esters and Their Analogs: Biocatalytic Reduction of Carbonyl Compounds by Actinobacteria, <i>Agromyces</i> and <i>Gordonia</i> Strains

We screened 15 Agromyces strains from the Microbacteriaceae family and 16 Gordonia strains from the Gordoniaceae family to investigate their biocatalytic ability to reduce carbonyl compounds. Two Agromyces strains (A. soli NBRC109063 and A. humatus NBRC109085) and two Gordonia strains (G. hydrophobica NBRC16057 and G. malaquae NBRC108250) grew well in 230 medium. The stereoselective reduction of various carbonyl compounds using these four strains was investigated. We discovered that these strains can reduce aliphatic and aromatic α-keto esters and an aromatic α-keto amide. On the basis of the conversion rate and stereoselectivity of the alcohols produced, G. hydrophobica NBRC16057 is a potential biocatalyst for the stereoselective reduction of α-keto esters and an aromatic α-keto amide to the corresponding chiral alcohols. Our results also suggest that the reduction of ethyl 2-methylacetoacetate by wet G. hydrophobica NBRC16057 cells in the presence of L-glutamate is useful for the production of chiral ethyl 3-hydroxy-2-methylbutanoate.

Water enables an asymmetric cross reaction of α-keto acids with α-keto esters for the synthesis of quaternary isotetronic acids.

A water promoted asymmetric aldol/lactonization/enolization cascade reaction of α-keto acids and α-keto esters was developed, affording the first general protocol for the construction of chiral quaternary isotetronic acids with excellent enantioselectivity. Theoretical results indicate that intramolecular ionized enamine intermediates stabilized by water generate zwitterionic transition states in a lower activation energy and higher face selectivity, resulting in high activity and chemo- and enantioselectivity.

Formation of Complex α-Imino Esters via Multihetero-Cope Rearrangement­ of α-Keto Ester Derived Nitrones

A sequential benzoylation and multihetero-Cope rearrangement of α-keto ester derived nitrones has been developed. The reaction furnishes a diverse array of complex α-imino ester derivatives. The products can be transformed into amino alcohols via LiAlH4 reduction.

Straightforward Synthesis of Triester-Substituted Pyrrolizidines by a Three-Component Reaction of β,γ-Unsaturated α-Keto Esters, Proline, and Maleates

A three-component reaction of β,γ-unsaturated α-keto esters, proline, and dialkyl maleates has been developed. This reaction provides pyrrolizidine derivatives containing three ester groups and a styrenyl group, as well as a quaternary center, in moderate to good yields and with good to excellent diastereoselectivities.

Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients.

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Organocatalytic Asymmetric Synthesis of 3,3'-Pyrrolidinyl-bispirooxindoles via Michael/ N-Hemiketalization Cascade Reaction between 3-Aminooxindoles and Isatin-Derived β,γ-Unsaturated α-Keto Esters.

A novel strategy for the construction of 3,3'-pyrrolidinyl-bispirooxindoles through a Michael/ N-hemiketalization cascade reaction of 3-aminooxindoles and isatin-derived β,γ-unsaturated α-keto esters was developed. Under mild conditions, a series of 3,3'-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereo- and enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. This work represents the first example using the 3-aminooxindoles for the construction of 3,3'-pyrrolidinyl-bispirooxindoles.

Enantioselective Alkylation of N-Arylhydrazones Derived from α-Keto Esters and Isatin Derivatives through Asymmetric Phase-Transfer Catalysis.

The phase-transfer-catalyzed asymmetric alkylation reactions of N-arylhydrazones derived from α-keto-esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra-substituted carbon stereocenter in good yields with high chemo- and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza-β-lactams without loss of enantiopurity.

Chemoselective P(NMe2)3-Mediated Reductive Epoxidation between Two Different Carbonyl Electrophiles: Synthesis of Highly Functionalized Unsymmetrical Epoxides.

Herein, we report a chemoselective P(NMe2)3-mediated reductive epoxidation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones, leading to an efficient synthesis of a wide range of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. The Kukhtin-Ramirez adduct, which is exclusively generated in situ from an α-dicarbonyl compound and P(NMe2)3, plays a key role in governing the chemoselectivity. It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles and also complements the existing methods of generating epoxides.