Michael Addition Research Articles

Recent Progress on the Synthesis, Biological Activity of Fused Pyrimidines from Azole Amines

AbstractFused pyrimidines are a class of heterocyclic compounds that have gained considerable interest due to their extensive biological activities and potential applications in drug development. This review article aims to provide a comprehensive overview of the latest synthetic approaches to fused pyrimidines, including Michael reactions, multicomponent reactions, metal‐catalyzed reactions, photocatalytic reactions, peroxide‐mediated reactions, and inverse electron demand Diels–Alder reactions. Furthermore, the biological activities of these compounds, such as their ability to combat cancer and microbial infections, are also discussed. This review article summarizes the existing literature on the synthesis and biological activity of fused pyrimidines from 2020 to 2023. We hope this review article will inspire the development of more effective and less toxic fused pyrimidine drugs with well‐designed structures.

Programmable Plasma-Microdroplet Cascade Reactions for Multicomponent Systems.

The concept of programmable cascade reactions in charged microdroplets is introduced using carbon-carbon (C-C) bond formation via uncatalyzed Michael addition in a three-tier study culminating in programmable Hantzsch multicomponent, multistep reactions. In situ generated reactive oxygen species (ROS) from nonthermal plasma discharge are fused with charged water microdroplets (devoid of ROS) in real time for accelerated chemical reactions. This plasma-microdroplet fusion platform utilizing a coaxial spray configuration enabled product selection while avoiding unwanted side reactions. Hydrogen abstraction via ROS facilitated the formation of enolate anions without strong base use. Reaction enhancement factors >103 were calculated for plasma-microdroplet fusion versus microdroplet-only reactions. The platform programmability was showcased through (i) uncatalyzed 1,4-Michael addition of α,β-unsaturated carbonyls, (ii) novel C-C bond formation via the use of pro-electrophilic amine and alcohol substrates─activated through collisions in the microdroplet environment to serve as Michael acceptors, and (iii) selective Hantzsch cascade reaction with cross-coupling products, avoiding side reactions including N-alkylation and self-coupling product formation. Milligram quantity product collection is achieved, showcasing plasma-microdroplet fusion as an effective tool for preparative-scale synthesis. Thus, the controlled generation of ROS via plasma discharge during charged water microdroplet evolution establishes a green synthetic method for uncatalyzed C-C bond formation.

Hybrid Metal Catalysts as Valuable Tools in Organic Synthesis: An Overview of the Recent Advances in Asymmetric C─C Bond Formation Reactions

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.

Evaluation of Potency and Specificity of Cryptophycin-Loaded Antibody-Drug Conjugates.

An enhanced variant of the antimitotic toxin cryptophycin was conjugated to the anti-Her2 monoclonal antibody (mAb) Trastuzumab upon Michael addition. Either antibodies with freed hinge-region cysteines or THIOMAB formats with engineered cysteines in the mAbs light chain were added to a maleimide derivative of cryptophycin. These Antibody-Drug Conjugates (ADCs) showed retained binding to Her2 positive tumor cells and highly efficient cell killing in double-digit pM range on high Her2-expressing SK-BR-3 cells. Two ADCs (DAR6, DAR3) showed superior cell killing of the cell lines JIMT-1 and RT112 with medium receptor expression level in comparison with a DAR6 MMAE ADC serving as reference. The observed cell cytotoxicity is target-dependent since no impact on cell viability was observed for low Her2-expressing MDA-MB468 cells. Particularly the DAR3 ADC in THIOMAB format exhibiting desirable biophysical properties and high potency emerged as a promising candidate for further in vivo investigations.

Development of an efficient biocatalytic three-component reaction for synthesizing pyrrole derivatives

Multi-component reactions (MCRs) enable the development of efficient and atom-economic methods for synthesizing pyrrole derivatives. However, the current MCRs methods for synthesizing pyrrole derivatives in the enzymatic process have been unexploited. Herein, we developed a one-pot three-component enzymatic promiscuous catalytic system with green, efficient, and atom-economic to construct pyrrole derivatives. In this system, amines and 1,3-dicarbonyl compounds formed enamines with subsequent Michael addition with nitroolefins catalyzed by trypsin. A series of pyrrole derivatives were successfully obtained with moderate to good yield (up to 92 %). In addition, molecular simulations were conducted to gain insight into the source of differing tolerance of aromatic amides and fatty amines and the intrinsic effect of solvents in this system. This enzymatic catalytic one-pot three-component system has excellent functional tolerance, simple operation, and application potential for industrial production demonstrated by the gram scale experiment.

Synthesis of Multifunctional Organic Molecules via Michael Addition Reaction to Manage Perovskite Crystallization and Defect

AbstractAdditive engineering plays a pivotal role in achieving high‐quality light‐absorbing layers for high‐performance and stable perovskite solar cells (PSCs). Various functional groups within the additives exert distinct regulatory effects on the perovskite layer. However, few additive molecules can synergistically fulfill the dual functions of regulating crystallization and passivating defects. Here, we custom‐synthesized 2‐ureido‐4‐pyrimidone (UPy) organic small molecules with diverse functional groups as additives to modulate crystallization and defects in perovskite films via the Michael addition reaction. Theoretical and experimental investigations demonstrate that the −OH groups in UPy exhibit significant effects in fixing uncoordinated Pb2+ ions, passivation of lead‐iodide antisite defects, alleviating hysteresis, and reducing non‐radiative recombination. Furthermore, the enhanced C=O and −NH2 motifs interact with the A‐site cation via hydrogen bonding, which relieves residual strain and adjusts crystal orientation. This strategy effectively controls perovskite crystallization and passivates defects, ultimately enhancing the quality of perovskite films. Consequently, the open‐circuit voltage of the UPy‐based p‐i‐n PSCs reaches 1.20 V, and the fill factor surpasses 84 %. The champion device delivers a power conversion efficiency of 25.75 %. Remarkably, the unencapsulated device maintained 96.9 % and 94.5 % of its initial efficiency following 3,360 hours of dark storage and 1,866 hours of 1‐sun illumination, respectively.

Comparative Study on Catalysis Strategies: Friedel-Crafts Alkylation vs. Michael Addition of Indoles to Nitroalkenes

Indoles are critical in natural amalgamation for their flexible jobs in drugs, regular items, and material science, exhibiting huge pharmacological and compound reactivity. Due to their versatility and high reactivity, nitroalkenes are essential electrophilic partners in organic synthesis. While indoles and nitroalkenes are used in both Michael addition and Friedel-Crafts alkylation for producing carbon-carbon bonds, the catalyst types and reactions involved are different. Michael addition employs conjugate addition, whereas Friedel-Crafts alkylation employs electrophilic aromatic substitution. Each technique has a different level of selectivity and distinct synthetic applications. This review aims to examine the advancements and persistent challenges in catalysis, focusing on the comparative methodologies of Friedel-Crafts alkylation and Michael addition involving indoles and nitroalkenes. Emphasizing green chemistry principles, it discusses the potential for sustainable and efficient synthetic processes through the use of innovative catalysts, including photocatalysis and biocatalysis. The integration of computational studies and interdisciplinary collaboration is essential for developing economically viable and environmentally responsible chemical synthesis, ultimately contributing to the creation of advanced materials and pharmaceuticals.

Noncanonical Functions of Ketosynthase Domains in Type I Polyketide Synthases.

Modular type I polyketide synthases (PKSs) are remarkable molecular machines that can synthesize structurally complex polyketide natural products with a wide range of biological activities. In these molecular machines, ketosynthase (KS) domains play a central role, typically by catalyzing decarboxylative Claisen condensation for polyketide chain extension. Noncanonical KS domains with catalytic functions rather than Claisen condensation have increasingly been evidenced, further demonstrating the capability of type I PKSs for structural diversity. This review provides an overview of the reactions involving unusual KS activities, including PKS priming, acyl transfer, Dickmann condensation, Michael addition, aldol-lactonization bicyclization, C-N bond formation and decarbonylation. Insights into these reactions can deepen the understanding of PKS-based assembly line chemistry and guide the efforts for rational engineering of polyketide-related molecules.

Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells.

Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx, was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and β-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.

Preparation and properties of polyamide elastomers by a new synthesis route of Michael addition reaction

At present, the mainstream industrial synthesis method of polyamide is still bulk fusion polymerization, which is not in line with the concept of green synthesis because of the high threshold of reaction conditions and large energy consumption. Based on this, a new synthesis route of polyamide elastomer was studied in this paper. By synthesizing the end-functionalized long carbon chain diacrylamide (DDA) containing amide bonds, the synthesis mechanism was made by the thiol double bond Michael addition reaction. A series of polyamide elastomers with different ratios of hard and soft segments were synthesized by using dimercaptan chain extenders with different molecular weights. The results showed that the new synthesis route successfully prepared DDA and polyamide elastomers. The mechanical properties of the products were excellent, and the strain rate could reach 383 %. Tensile strength up to 23.08 MPa. The synthesis route has the characteristics of simple reaction process, mild reaction conditions and high reaction conversion rate. It provides theoretical guidance for the new synthesis route of polyamide elastomer.

Recent Advances in Scandium(III) Triflate Catalysis: A Review

AbstractOver the past three decades, triflate salts have emerged as crucial Lewis acid catalysts in organic synthesis, playing a significant role in cyclization, C−H bond functionalization, and various other reactions. Among these, rare‐earth triflates have garnered attention due to their water compatibility, environmental friendliness, noncorrosive nature, and reusability. In particular, scandium(III) triflate [Sc(OTf)3] stands out as a water‐resistant Lewis acid with remarkable catalytic activity in aqueous environments. Unlike typical Lewis acids such as AlCl3, BF3, and SnCl4, which are decomposed or deactivated by water, Sc(OTf)3 remains stable and effective. Its exceptional Lewis acidity, resilience against hydrolysis, and recyclability make it a prominent green catalyst. The unique stability of Sc(OTf)3 in water is attributed to the smaller size of scandium ions (Sc3+), enhancing its catalytic efficiency. Sc(OTf)3 has a longstanding history in organic synthesis, facilitating a wide range of reactions including aldol, Michael, allylation, Friedel‐Crafts acylations, Diels‐Alder, Mannich, cycloadditions (including cyclopropanation), and cascade reactions. The increasing utilization of Sc(OTf)3 over the past decade underscores the necessity for updated insights. This review provides a concise overview of the versatility of Sc(OTf)3 as a catalyst, focusing on developments from 2017 to 2024.

Hydrogen-bonded Supramolecular Network Enabled Gentle Reprogramming of Liquid Crystal Elastomer toward Evolutionary Robot.

In nature, many organisms augment chances of survival by reprogramming their structures to evolving environment, among which sea squirts being a prime example. Such reprogramming has been demonstrated in liquid crystal elastomer (LCE) actuator assembled with heat assistance. However, the required temperature being higher than the actuation temperature limits its application. Here, we reported a hydrogen-bonded supramolecular network LCE to construct soft modular and reprogrammable actuator by assembling with a gentle heat treatment. Leveraging the Michael addition reaction, we introduced hydrogen bonding to the LCE matrix with functionalized pyridine monomers. Experimental and molecular dynamics modeling proved the efficient dynamic hydrogen bond exchange at 60°C, significantly lower than the actuating temperature of the LCE. This gave rise to the reversible and robust adhesion of the same collection of LCE modules capable of being built into different bilayers and performing various morphing upon a short thermal stimulation. Therefore, we demonstrated that these comparatively weak cross-links enabled reconfiguration of the LCE actuator. With the developed hydrogen-bonding LCEs, we built proof-of-concept modular reprogrammable robot, performing crawling, sailing, and microcircuit repair tasks. This bioinspired and efficient method for evolutionary LCE robot offers a viable path for further development of intelligent actuators sustainable in complex environments.

Hydrogen‐bonded Supramolecular Network Enabled Gentle Reprogramming of Liquid Crystal Elastomer toward Evolutionary Robot

In nature, many organisms augment chances of survival by reprogramming their structures to evolving environment, among which sea squirts being a prime example. Such reprogramming has been demonstrated in liquid crystal elastomer (LCE) actuator assembled with heat assistance. However, the required temperature being higher than the actuation temperature limits its application. Here, we reported a hydrogen‐bonded supramolecular network LCE to construct soft modular and reprogrammable actuator by assembling with a gentle heat treatment. Leveraging the Michael addition reaction, we introduced hydrogen bonding to the LCE matrix with functionalized pyridine monomers. Experimental and molecular dynamics modeling proved the efficient dynamic hydrogen bond exchange at 60°C, significantly lower than the actuating temperature of the LCE. This gave rise to the reversible and robust adhesion of the same collection of LCE modules capable of being built into different bilayers and performing various morphing upon a short thermal stimulation. Therefore, we demonstrated that these comparatively weak cross‐links enabled reconfiguration of the LCE actuator. With the developed hydrogen‐bonding LCEs, we built proof‐of‐concept modular reprogrammable robot, performing crawling, sailing, and microcircuit repair tasks. This bioinspired and efficient method for evolutionary LCE robot offers a viable path for further development of intelligent actuators sustainable in complex environments.

Design, In Silico, and In vitro Evaluation of Polymer-Based Drug Conjugates Incorporated with Derivative of Cinnamic Acid, Zidovudine, and 4-Aminosalicylic Acid against Pseudo-HIV-1.

The incorporation of anti-HIV drugs into polymer to form polymer-drug conjugates has been reported to result in improved therapeutic activity. Zidovudine, an anti-HIV drug, was explored alone and in combination with known drug molecules using polyamidoaminebased carriers. Polymer-drug conjugates incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid were prepared and evaluated for their potential efficacy in vitro against pseudo- HIV-1. Aqueous Michael addition polymerization reaction was employed to prepare the conjugates. The conjugates were incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid. They were characterized by SEM/EDX, XRD, FTIR, NMR, LC-MS, particle size analysis, in vitro analysis, computational studies, and in silico toxicity predictions. The conjugates displayed spherically shaped morphology. The in vitro findings showed that polymer-drug conjugates, T15 and T16, with a single drug were effective against pseudo- HIV-1 at high concentrations of 111.11 and 333.33 μg/mL, respectively. The molecular docking studies confirmed the in vitro results. The Swiss ADME, ProTox-II, and GUSAR (General Unrestricted Structure-Activity Relationships) revealed that these compounds are promising antiviral compounds. The prepared polymer-drug conjugates with a single drug showed promising effects against the Pseudo-HIV-1, and the conjugates displayed features that make them potential anti- HIV therapeutics that require further studies.

Conjugation of Multiple Proteins Onto the Surface of PLGA/Lipid Hybrid Nanoparticles.

Nanoparticles are increasingly being used in the development of vaccines for disease prevention or treatment. Recent research has demonstrated that conjugating a protein onto the surface of nanoparticles can significantly increase its immunogenicity. Considering various pathogens that threaten human health, multivalent vaccines are often desirable. Up to now, nanoparticle-based vaccines are mostly limited to one protein per nanoparticle. No research has been conducted to explore the possibility of conjugating more than one protein onto the surface of a nanoparticle. Here we developed a specific conjugation strategy to conjugate multiple proteins to the PLGA/lipid hybrid nanoparticle surface. The maleimide-thiol Michael addition, Aizde-DBCO (Dibenzocyclooctyne), and TCO (trans-cycloctene)-Tetrazine click chemistry were employed to conjugate three different proteins, subunit keyhole limpet hemocyanin (sKLH), Ovalbumin (OVA), and cross-reactive material 197 (CRM197), to the surface of PLGA/lipid hybrid nanoparticles (hNPs). The successful results of this study pave the way for developing multivalent vaccines against different pathogens.

Recent Progress on NHC-Catalyzed 1,6-Conjugate Addition Reactions.

As a significant variant of the Michael reaction, the 1,6-addition reaction has undergone considerable development over the past decade. This effective strategy enables the synthesis of a variety of novel and potentially bioactive functional molecules. In this review, we summarize the recent progress in NHC-catalyzed 1,6-addition reactions, highlighting their efficiency in the rapid synthesis of complex functional molecules. We also provide our perspectives on the future development of this dynamic and highly active research area.

An Acid-Activatable Fluorescent Probe for Sulfur Dioxide in Traditional Chinese Medicines and Living Cells.

Excessive sulfur dioxide (SO₂) disturbs physiology of lysosomes causing diseases and threatening human health. A fluorescent probe has been regarded as one of the most attractive approaches, which is compatible with living cells and possesses high sensitivity. However, most of fluorescent probes' reaction sites are activated before they reach the destination. In this work, an acid-activatable fluorescent probe PT1 was synthesized, characterized, and used for SO2 detection. The introduction of oxazolines in PT1 enables the intelligent response of probe to release the activation stie for SO2 derivatives through Michael addition upon exposure to acid. In vitro studies showed a remarkable selectivity of PT1 to SO₂ derivatives than other biothiols with a limit of detection as low as 62 nM. By using this acidic pH-controlled fluorescence responsiveness to SO₂, precise spatiotemporal identification of lysosomal SO2 fluctuations has been successfully performed. Furthermore, probe PT1 can be applied for monitoring SO₂ derivatives in traditional Chinese medicines.

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Domino Reaction for the Synthesis of Substituted Pyrano[3',4':3,4]cyclopenta[1,2-c]chromenes Involving Double Ring Formation.

Herein, we present a green cascade approach for synthesizing a range of chemoselective polysubstituted pyrano[3',4':3,4]cyclopenta[1,2-c]chromenes containing a chiral stereocenter. The strategy involves a metal-free nucleophilic reaction between dialkyl (2E)-2-{2-oxo-3-[(2E)-3-aryl-2-propenoyl]-2H-chromen-4-yl}-2-butenedioates and α,α-dicyanoolefins under reflux conditions in ethanol solvent. Mechanistic studies have shown that the reaction proceeds via a cascade of steps, including Michael addition, intramolecular C- and O-cyclization, intramolecular trans-esterification, [1,2]-H and [1,5]-methoxy- and ethoxy carbonyl shift, and finally aromatization to yield the desired product. In this method, three bonds (2C-C and C-O) form in one pot, simultaneously forming two new cyclopentane and pyrano rings by double cyclization reactions. Other advantages of this method are that it has a simple operation, readily available starting materials, a chemoselective cascade process, transition metal-free, synthetically useful yields, and green conditions by using ethanol as a solvent.

Asymmetric Michael Addition Catalyzed by a Polyisocyanide-Based Porous Polymer

Asymmetric Michael Addition Catalyzed by a Polyisocyanide-Based Porous Polymer