Search Results (58)

An efficient stereoselective strategy for the synthesis of chiral bisspiro barbituric acid–oxindole derivatives was developed. The asymmetric Michael addition/cyclization tandem reaction between benzylidene barbituric acids and oxindolylmalonitriles was catalyzed by squaramide catalyst, and the corresponding spirocyclic products were obtained in good-to-high yields (up to 97%) with excellent stereoselectivities (up to >99% ee, >20:1 dr). At the same time, the practicality of the reaction was verified by the gram-scale preparation reaction. Full article

An organocatalytic asymmetric Michael addition reaction of α-azidoindanones with azadienes was developed. A series of optically active benzofuran derivatives containing an azido group was obtained in 32–82% yields with 66:34–>95:5 dr and 53:47–90:10 er. These products demonstrate excellent stability. Furthermore, when the template reaction was scaled up, the reaction efficiency remained consistent. To further assess the practicality of this catalytic asymmetric reaction, two derivative reactions were successfully conducted, affording the corresponding derivative products in good yields and with high stereoselectivities. In addition, a plausible reaction mechanism was also proposed. Full article

Salens are a class of important ligands and have been widely applied in asymmetric catalytic organic reactions. Enlarged salen-like ligands containing flexible chains were synthesized from L-phenylalanine, ethane/propanediamines, and salicylaldehydes, and successfully utilized in the scandium-catalyzed enantioselective Michael addition of indoles and enones (2-cinnamoylpyridine 1-oxides). The catalytic system demonstrates excellent reactivity and stereoselective control over electron-rich indole substrates with up to 99% yield and 99% enantiomeric excess. The enlarged Salen ligands with flexible and rigid combined linkers fit their coordination with large rare earth elements. Their coordination abilities were tuned by the electronic effect of substituents on their salicylaldehyde moiety, facilitating the construction of excellent chiral environments in the scandium(III)-catalyzed asymmetric Michael addition of indoles to 2-cinnamoylpyridine 1-oxides. Full article

The range of chemical databases available has dramatically increased in recent years, but the reliability and quality of their data are often negatively affected by human-error fidelity. The size of chemical databases can make manual data curation/checking of such sets time consuming; thus, automated tools to help this process are highly desirable. Herein, we propose the use of Graph Neural Networks (GNNs) to identifying potential stereochemical misassignments in the primary asymmetric catalysis literature. Our method relies on the use of an ensemble of GNN models to predict the expected stereoselectivity of exemplars for a particular asymmetric reaction. When the majority of these models do not correlate to the reported outcome, the point is labeled as a possible stereochemical misassignment. Such identified cases are few in number and more easily investigated for their cause. We demonstrate the use of this approach to spot potential literature stereochemical misassignments in the ketone products resulting from catalytic asymmetric 1,4-addition of organoboron nucleophiles to Michael acceptors in two different databases, each one using a different family of chiral ligands (bisphosphine and diene ligands). Our results demonstrate that this methodology is useful for curation of medium-sized databases, speeding this process significantly compared to complete manual curation/checking. In the datasets investigated, human expert checking was reduced to 2.2% and 3.5% of the total data exemplars. Full article

Carbon–carbon bond formation represents a key reaction in organic synthesis, resulting in paramount importance for constructing the carbon backbone of organic molecules. However, traditional metal-based catalysis, despite its advantages, often struggles with issues related to efficiency, selectivity, and sustainability. On the other hand, while biocatalysis offers superior selectivity due to an extraordinary recognition process of the substrate, the scope of its applicable reactions remains somewhat limited. In this context, Artificial Metalloenzymes (ArMs) and Metallo Peptides (MPs) offer a promising and not fully explored solution, merging the two fields of transition metal catalysis and biotransformations, by inserting a catalytically active metal cofactor into a customizable protein scaffold or coordinating the metal ion directly to a short and tunable amino acid (Aa) sequence, respectively. As a result, these hybrid catalysts have gained attention as valuable tools for challenging catalytic transformations, providing systems with new-to-nature properties in organic synthesis. This review offers an overview of recent advances in the development of ArMs and MPs, focusing on their application in the asymmetric carbon–carbon bond-forming reactions, such as carbene insertion, Michael additions, Friedel–Crafts and cross-coupling reactions, and cyclopropanation, underscoring the versatility of these systems in synthesizing biologically relevant compounds. Full article

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms. Full article

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at ¹H, ¹³C and ¹⁹F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate. DOSY experiments were employed to evaluate whether the catalyst–substrate ionic adduct was a tight one or not. ROESY experiments were employed to investigate the role of the squaramide unit in the adduct formation. A mechanism of interaction was proposed in accordance with the literature data. Full article

The recovery and reuse of the enantioselective catalysts produced by tedious work are important not only from the perspective of green chemistry, but also from the point of view of productivity. Some of the carbohydrate-based crown ethers prepared in our research group were able to generate significant asymmetric induction in certain cases. However, they were not recoverable after the synthesis. Therefore, we modified the most effective structure with a propargyl group so that it can be attached to a polymer with an azide–alkyne reaction. It was investigated whether the position of the bonding affects the activity of the crown ethers, hence, the propargyl group was introduced either to the side chain, to the anomeric center or to the benzylidene protecting group. To anchor the macrocycles, low molecular weight PVC was modified with azide groups in 4% and 10%, respectively. It was found that glucose-based crown ether bearing the propargyl group on the benzylidene unit and grafted to PVC in 4% has the highest activity regarding the enantioselectivity (77% ee). The catalyst was recoverable in the Michael addition of diethyl acetamidomalonate to nitrostyrene and it could be reused five times without the loss of enantioselectivity. Full article

α-Substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides have emerged as new versatile synthons for various metal-catalyzed and organic-catalyzed asymmetric reactions, which have attracted much attention from chemists. In this review, the progress of research on 7-azaindoline amides in the asymmetric aldol reaction, the Mannich reaction, the conjugate addition, the 1,3-dipole cycloaddition, the Michael/aldol cascade reaction, aminomethylation and the Michael addition-initiated ring-closure reaction is discussed. The α-substituted-7-azaindoline amides, as nucleophiles, are classified according to the type of α-substituted group, whereas the α,β-unsaturated 7-azaindoline amides, as electrophiles, are classified according to the type of reaction. Full article

The preparation of a new class of six bifunctional thiourea organocatalysts having a D-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity. Full article

Regio- and stereoselective switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Ag₂CO₃ plays a key role in the switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles. Ag₂CO₃-free reactions lead to thermodynamically stable (E)-N-carbonylvinylated pyrazoles in excellent yields whereas reactions with Ag₂CO₃ give (Z)-N-carbonylvinylated pyrazoles in good yields. It is noteworthy that (E)- or (Z)-N¹-carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag⁺ acts as coordination guidance. Full article

A Lewis acid-promoted annulation of azadienes and cyclobutamines was developed. This reaction proceeded through Michael addition and ring-expansion cascade, affording the corresponding nitrogen-containing medium-sized rings with a broad scope in moderate to high yields. The catalytic asymmetric version of this reaction has also been explored using a chiral base. Full article

Different Chiral Ionic Liquids (CIL) based on L-proline have been developed. Simple and efficient synthetic methodologies are used, allowing preparation in good yields for twelve novel CILs using L-proline as a cation or anion combined with suitable counter-ions. A detailed physical and chemical characterization of the CILs was performed to evaluate the influence of counter-ions on the final properties. The most promissory CILs were tested as efficient chiral catalysts in IL media for asymmetric Michael addition reactions of ketones and aldehydes to nitro-olefins. Similar or even better conversions and enantioselectivities (ee up to 95%) compared to the original L-proline were achieved. Additionally, a good product extraction performance using supercritical CO₂ processes was obtained. Full article

The preparation and characterization of a new chiral tertiary dibenzylamine are described. These molecules are well known in the literature for their high neuropharmacological potential. The general synthetic pathway is based on asymmetric Aza–Michael addition of chiral (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl cyclohex-1-en-carboxilate obtaining the β-amino ester, followed by carboxylic acid hydrolysis and subsequent Barton descarboxylation. Interestingly, it is a general synthetic procedure of a wide range of chiral amines by careful choice of insaturated esters and alkylation of the chiral enolate in the initial reaction. The new tertiary dibenzylamine molecule is fully characterized by NMR Spectroscopy (¹H and ¹³C), as well by High-Resolution Mass Spectrometry and Infrared Spectroscopy. Full article

Chiral primary α-amino amides, consisting of an adjacent enamine bonding site (Bronsted base site), a hydrogen bonding site (Bronsted acid site), and flexible bulky substituent groups to modify the steric factor, are proving to be extremely valuable bifunctional organocatalysts for a wide range of asymmetric organic transformations. Primary α-amino amides are less expensive alternatives to other primary amino organocatalysts, such as chiral diamines and cinchona-alkaloid-derived primary amines, as they are easy to synthesize, air-stable, and allow for the incorporation of a variety of functional groups. In recent years, we have demonstrated the catalytic use of simple primary α-amino amides and their derivatives as organocatalysts for the aldol reaction, Strecker reaction, Michael tandem reaction, allylation of aldehydes, reduction of N-Aryl mines, opening of epoxides, hydrosilylation, asymmetric hydrogen transfer, and N-specific nitrosobenzene reaction with aldehydes. Full article