Α-keto Esters Research Articles

‘On Water’ Direct Aldol Reaction of Oxindoles with β,γ-Unsaturated α-Keto Esters for the Synthesis of 3-(α-Hydroxy-β-carbonyl)oxindoles

An efficient ‘on water’ direct aldol reaction of oxindoles and β,γ-unsaturated α-keto esters was developed, giving 3-(α-hydroxy-β-carbonyl)oxindoles in high yields (up to 92%) and diastereoselectivities (up to >20:1). Compared with organic solvent, water as the solvent was crucial to the reaction and rate acceleration was observed in water.

Synthesis of Complex Tertiary Glycolates by Enantioconvergent Arylation of Stereochemically Labile α-Keto Esters.

Enantioconvergent arylation reactions of boronic acids and racemic β-stereogenic α-keto esters have been developed. The reactions are catalyzed by a chiral (diene)Rh(I) complex and provide a wide array of β-stereogenic tertiary aryl glycolate derivatives with high levels of diastereo- and enantioselectivity. Racemization studies employing a series of sterically differentiated tertiary amines suggest that the steric nature of the amine base additive exerts a significant influence on the rate of substrate racemization.

Synthesis of Optically Active Oxazolines by an Organocatalytic Isocyanoacetate Aldol Reaction with α-Keto Esters

An enantioselective [3+2] cyclization is reported for the construction of a chiral oxazoline skeleton in moderate yield and up to 97% ee. The reactivity and stereochemical discrimination originate from the noncovalent interaction and orientation of a bifunctional catalyst. The novel combination of an α-keto ester and an α-isocyanoacetate establishes an oxazoline which could be a potential chiral ligand for metal-mediated catalysis, and also could be easily converted into an optically active β-hydroxy-α-amino acid.

Asymmetric Organocatalytic Michael/Michael/Henry Sequence to Construct Cyclohexanes with Six Vicinal Stereogenic Centers

An efficient, asymmetric, catalytic, triple-cascade reaction between α-keto esters and nitroalkenes to construct cyclohexanes with six vicinal stereogenic centers in good yields and with high enantioselectivities has been established. A bifunctional guanidine–amide organocatalyst proved to be useful for the Michael/Michael/Henry sequence through Bronsted base and hydrogen-bonding cooperative catalysis.

Copper-catalyzed TEMPO oxidative cleavage of 1,3-diketones and β-keto esters for the synthesis of 1,2-diketones and α-keto esters.

A copper-catalyzed efficient and practical method has been developed for the synthesis of 1,2-diketones and α-keto esters. TEMPO was used as a radical initiator and scavenger, oxidizing the cleavage of α-methylene of 1,3-diketones and β-keto esters to form 1,2-diketones and α-keto esters. This method provided a general way for the formation of 1,2-dicarbonyl compounds.

Metal-free, direct conversion of α-amino acids into α-keto γ-amino esters for the synthesis of α,γ-peptides.

An efficient, metal-free synthesis of unusual α-keto γ-amino esters from α-amino acids is achieved by a radical scission-oxidation-addition of silyloxy acrylates procedure, where no purification of the reaction intermediates is needed. This protocol can be applied to the selective modification of the C-terminal position in peptides to give α,γ-hybrids.

A Complex Catalytic Reaction Caught in the Act: Intermediates and Products Sampling Online by Liquid μ-Beam Mass Spectrometry and Theoretical Modeling.

Liquid-beam IR-laser desorption mass spectrometry has been used to monitor the reactants, intermediates, and products of a complex organic signature reaction in real time on multiple timescales directly from the liquid phase. The reaction was chosen because it has advantages in medicinal chemistry applications, and the three-component, modular construction provides a means to generate molecular diversity rapidly. Under Lewis acid catalysis, a vinylogous Mannich reaction was monitored as it generated a δ-amino-α-silyloxy-α,β-unsaturated ester, which upon hydrolysis to the corresponding α-keto ester spontaneously reacted in a [3+2] cycloannulation to the final pyrrolo[2,1-b]benzoxazole. The kinetic data were compared with predictions of quantum chemical calculations to elucidate and verify or exclude reaction pathways and mechanisms for a possible rational optimization of the reaction. The simplicity and rapid response of this approach make it a very powerful technique for online characterization of chemical reactions on timescales spanning several orders of magnitude. This enables full control over chemical reactions, thereby maximizing the product yield. This combined experimental and theoretical approach opens up a new route for the study of novel chemistry in liquid-phase reactions.

ChemInform Abstract: Ru‐MACHO‐Catalyzed Highly Chemoselective Hydrogenation of α‐Keto Esters to 1,2‐Diols or α‐Hydroxy Esters.

A ruthenium pincer catalyst has been shown to be highly effective for the hydrogenation of a wide range of α-keto esters, affording either diols or hydroxy esters depending on the choice of reaction conditions. Strong base, high temperature, and pressure favor the formation of diols whilst the opposite is true for the hydroxy esters.

Compositional Effect in AuPd Bimetallic Nanoparticles Towards Product Selectivity during Aerobic Oxidation of α-Hydroxy Esters and Phosphonates

Aerobic oxidation of α-hydroxy esters and phosphonates for direct formation of α-keto esters and α-keto phosphonates was explored using Au nanoparticle based catalytic systems. Alloying Au with Pd resulted in high activity and selectivity for the aerobic oxidation reaction under base and solvent free conditions. The formation of desired α-keto esters and α-keto phosphonates as sole products were highly dependent on the composition of the alloy nanocatalyst. Addition of a secondary oxidizer such as tert-butylhydroperoxide (TBHP) significantly enhanced the yield of the products at shorter reaction time under mild reaction conditions.

Michael Addition-Lactonization of Arylacetyl Phosphonate to β,γ-Unsaturated α-Keto Esters for the Synthesis of Chiral syn-3,4-Dihydropyranones and 5,6-Dihydropyranones.

Catalytic asymmetric Michael addition-lactonization of arylacetyl phosphonates to β,γ-unsaturated α-keto esters by a chiral bifunctional thiourea-tertiary amine was established. Using the developed protocol, a range of optically pure syn-3,4-dihydropyranones were generated in good yields with good to excellent stereoselectivities (up to >20:1 dr and 99% ee). Meanwhile, when stoichiometric diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene were used as the base for the same reaction, a series of 5,6-dihydropyranones could be obtained in moderate to good yields (53-75% yield).

Novel Synthesis of α-Keto Esters and Amides by an sp3 C–H Oxidation of Nitromethyl Aryl Ketones Promoted by Ion-Supported (Diacetoxyiodo)benzene

A simple and efficient method is described for the preparation of α-keto esters or amides from nitromethyl aryl ketones. In the presence of nucleophiles (alcohols or amines), the ion-supported (di­acetoxyiodo)benzene-promoted sp3 C–H oxidation of nitromethyl aryl ketones proceeded efficiently under mild conditions to give the corresponding α-keto esters and amides in moderate to good yields. This is the first reported use of (diacetoxyiodo)benzene in the synthesis of α-keto esters and amides. The reaction is ecofriendly and has the ­advantages of mild conditions, short reaction times, and a recyclable reagent.

ChemInform Abstract: Preparation of 2,3,3‐Triarylacrylic Acid Esters Using Suzuki—Miyaura Coupling Reactions.

We report here a new strategy to produce 2,3,3-triarylacrylic acid esters, a class of 1,2,2-triarylethene compounds with an α,β-unsaturated ester functionality. Our approach requires the preparation of a gem-dibromoalkene precursor from an α-keto ester, followed by the installation of two aryl groups by Suzuki–Miyaura coupling reactions on the two C–Br bonds. Many 2,3,3-triarylacrylic acid esters with one, two, or three different aryl groups were obtained with complete regio- and stereocontrol in most cases.

ChemInform Abstract: Photochemical and Additive‐Free Coupling Reaction of α‐Cumyl α‐Keto Esters via Intermolecular C—H Bond Activation.

We developed a photo-chemical coupling reaction of α-keto esters with several simple alcohols, alkanes, ethers, and amides. Use of tertiary alkyl ester, α-cumyl ester, is the key for avoiding the known photo-degradation process. Intermolecular C–H bond activation and subsequent C–C bond formation were promoted by irradiation with an LED lamp (365 nm) without any additives. Among the coupling partners, reactions with sterically less demanding amides proceeded efficiently to provide unique N-acyl-β-amino-α-hydroxy acid derivatives. In benzene or acetone as a solvent, the reaction with a solid amino acid derivative provided a precursor of tetrahydro-1,4-diazepine-2,5-dione derivatives.

Enantioselective Organocatalyzed Consecutive Synthesis of Alkyl 4,5-Dihydrofuran-2-carboxylates from α-Keto Esters and (Z)-β-Chloro-β-nitrostyrenes

Alkyl 4,5-dihydrofuran-2-carboxylates can be efficiently ob- tained via an enantioselective organocatalyzed consecutive reaction between _-keto esters and (Z)-(2-chloro-2-nitroethenyl)benzenes. The overall sequence combines a (R,R)-TUC-catalyzed Michael addition with a DABCO-promoted intramolecular O-alkylation leading to the title products as single diastereomers with enantiomeric excesses from 86% up to 97%.

A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

Around 2006, our group launched a long-term project on the asymmetric hydrogenation of functionalized ketones by using ruthenium complexes with SunPhos ligands. In this review, we recount the burgeoning and blossoming of this project. At the outset, we attempted some benchmark reactions with an array of monofunctionalized ketones, including α- and β-keto esters/amides, β-keto sulfones, phosphonates, and α-hydroxy ketones. For α-keto esters and amides, we discovered that CeCl3 •7H2 O was an efficient additive for both activity and enantioselectivity. The element iodine was found to be a valid additive for β-keto sulfones. β,γ-Unsaturated α-keto acids and esters were also hydrogenated to the saturated chiral blocks with good enantioselectivity and a high turnover number. For the α-substituted β-keto esters and phosphonates, exceptionally high stereoselectivity was achieved through dynamic kinetic resolution. Based on these incipient successes, we diverted to bifunctionalized ketone substrates, such as γ-heteroatom-substituted β-keto esters and δ-ketal-β-keto esters. For the δ-ketal-β-keto esters, CaCO3 was added to stabilize the δ-ketal groups, which ensured the formation of δ-ketal-β-hydroxy esters in good yields and high ee values. More interestingly, γ-halo-γ,δ-unsaturated-β-keto esters were hydrogenated to afford highly enantiopure chiral allyl alcohols under mild and neutral conditions. The distance effect of the directing groups was investigated in β-, γ-, and δ-keto amides; the last two were hydrogenated with the Ru-SunPhos-diamine system. To implement the pinpoint recognition of two carbonyl groups in similar chemical propinquity, we compared the reaction rates of different β-keto acid derivatives. THF was found to be a helpful coordinative solvent to control the chemo- and enantioselectivity for more challenging polycarbonyl substrates, such as 3-oxo glutaric acid derivatives, β,δ-diketo carboxamides, and γ-heteroatom-substituted β-diketones. The effects of solvents and heteroatoms in these substrates were also studied. Applications of these hydrogenation reactions were also exemplified by the employment of the products for important pharmaceutical syntheses.

Ru-MACHO-Catalyzed Highly Chemoselective Hydrogenation of α-Keto Esters to 1,2-Diols or α-Hydroxy Esters

A ruthenium pincer catalyst has been shown to be highly effective for the hydrogenation of a wide range of α-keto esters, affording either diols or hydroxy esters depending on the choice of reaction conditions. Strong base, high temperature, and pressure favor the formation of diols whilst the opposite is true for the hydroxy esters.

Preparation of 2,3,3-Triarylacrylic Acid Esters Using Suzuki–Miyaura Coupling Reactions

We report here a new strategy to produce 2,3,3-triarylacrylic acid esters, a class of 1,2,2-triarylethene compounds with an α,β-unsaturated ester functionality. Our approach requires the preparation of a gem-dibromoalkene precursor from an α-keto ester, followed by the installation of two aryl groups by Suzuki–Miyaura coupling reactions on the two C–Br bonds. Many 2,3,3-triarylacrylic acid esters with one, two, or three different aryl groups were obtained with complete regio- and stereocontrol in most cases.

Enzyme-catalyzed asymmetric construction of chiral tertiary alcohols via aldol reaction using proteinase

A new enzyme-catalyzed asymmetric construction of chiral tertiary alcohols via asymmetric aldol reactions between β,γ-unsaturated α-keto esters and ketones was reported. Proteinase from Aspergillus melleus (AMP) was used as a sustainable biocatalyst. The best results can be obtained with yields of up to 90%, diastereoselectives of up to 93:7 dr, and enantioselectivities of up to 70% ee. This work not only expands the application of enzymatic promiscuity, but also provides more examples for constructing chiral tertiary alcohols.

ChemInform Abstract: Synthesis of 1,3‐Dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates via Intramolecular Cyclization of 2‐[2‐(Dimethoxymethyl)phenyl]‐2‐hydroxyalkanoates Followed by Oxidation.

A novel and efficient method for the preparation of 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates 4 under mild conditions has been developed. Thus, the reaction of [2-(dimethoxymethyl)phenyl]lithiums, generated easily from 1-bromo-2-(dimethoxymethyl)benzenes 1, with α-keto esters gives the corresponding 2-[2-(dimethoxymethyl)phenyl]-2-hydroxyalkanoates 2. The TsOH-catalyzed cyclization of these hydroxy acetals is followed by the oxidation of the resulting cyclic acetals 3 with PCC to give the desired products in satisfactory yields. The reaction of [2-(dimethoxymethyl)-4,5-dimethoxyphenyl]lithium with (MeOCO)2, followed by treatment with NaBH4 or organolithiums, affords 2-[2-(dimethoxymethyl)-4,5-dimethoxyphenyl]-2-hydroxyalkanoates 6, which can similarly be transformed into the corresponding 1,3-dihydro-3-oxo-2-benzofuran-1-carboxylates 7 in reasonable yields.

A Facile Approach to Optically Active Hydroquinoline-2-carboxylates by a One-Pot Asymmetric Michael/Transamination/Cyclization Process.

An efficient one-pot synthesis of optically active hydroquinoline-2-carboxylates from 1,3-cyclohexanediones, β,γ-unsaturated α-keto ester, and benzylamine in the presence of a chiral base catalyst and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) with good diastereoselectivity and high enantioselectivity is described. The reaction proceeds by a sequential asymmetric Michael/transamination/cyclization process.