Michael Addition Research Articles

Catalytic Performance of Chiral Tetraaza-Bridged Calix[4]arene[2]triazine Derivatives for Enantioselective Michael Reactions.

Novel chiral tetraaza-bridged calix[4]arene[2]triazine-based organocatalysts were synthesized and used for catalytic asymmetric Michael reaction of acetylacetone to various aromatic nitrostyrenes. Chiral subunits (R)- and (S)-1,2,3,4-tetrahydro-1-naphthylamine were attached to the tetraaza-bridged calix[4]arene[2]triazine platform in both enantiomeric forms. The R configuration of the major enantiomer of the Michael product was obtained when 3a was used as catalyst, and the S configuration was obtained when 3b was used as catalyst. This indicated that the configuration of the Michael product was controlled by the chiral calixarene moiety. The Michael adducts were obtained in excellent yields (91%) and enantioselectivities (98%).

PEGylated β-Cell-Targeting Exosomes from Mesenchymal Stem Cells Improve β Cell Function and Quantity by Suppressing NRF2-Mediated Ferroptosis.

The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness. The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed. We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2-related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting. MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.

Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.

Switchable Enantio- and Diastereoselective Michael Additions of β-Keto Amides to Nitroolefins: Crystallization-Based Inversion of Kinetic Stereocontrol.

Asymmetric catalytic reactions rely on chiral catalysts that induce highly ordered transition states capable of imparting stereoselectivity in the bond-forming step(s). Productive deviations from this paradigm are rare yet hold the potential for accessing different stereoisomers using the same catalyst. Here, we present an enantio- and diastereoselective Michael addition of β-keto amides to nitroolefin electrophiles proceeding via an unusual scenario where the kinetic diastereocontrol imparted by the catalyst may be overridden by crystallization to provide the complementary stereoisomer of the product.

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

Additive 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.

Sequential Synthesis of Alkenylated Quinazolines Through sp3 C−H Functionalization and Their Photophysical Properties

AbstractQuinazolines are biologically potent heterocyclic compounds; however, their synthesis poses high challenges. In this present study, we have developed an inexpensive cobalt metal‐catalyzed acceptorless dehydrogenative pathway for the sequential synthesis of alkenylated quinazolines from benzhydrol via dehydrogenation, cyclization, and subsequent dehydrogenative sp3 C−H functionalization. This transformation holds potential owing to its commercially available key starting materials, good functional tolerance, moderate reaction conditions, environmental friendliness, and applicability for gram‐scale synthesis. Furthermore, the synthetic utility of the synthesized derivatives has been explored through various reactions, including reduction, halogenation, methoxylation, Michael addition, and spiro cyclization. Additionally, the photophysical properties indicate that the nitrogen atom of the synthesized derivatives readily undergoes a reversible protonation, leading to significant changes in colour. This characteristic presents an opportunity for the creation of pH sensors with colourimetric capabilities.

Substituent-Oriented Synthesis of Substituted Pyridines/Pyrido[3,2-C]coumarins via Sequential Reactions of α-H and Me/Aryl Substituted Oxime Acetates and 3-Formylchromones.

A facile one pot sequential and highly chemoselective synthesis of substituted pyridines/pyrido[3,2-c]coumarins has been developed from oxime acetates and 3-formylchromones in the presence of FeCl2. This reaction was oriented by different substituents on the α-position (H, methyl/aryl) of oxime acetates. Mechanistic investigations suggested that substituted pyridines were formed via intramolecular aza-Michael addition followed by ring opening, while pyrido[3,2-c]coumarins were formed via intermolecular Michael addition. Besides, anti-TB activity was screened for some of the synthesized pyridines. Among the tested compounds, 3ga, 3ha, 3ja, 3ma, 3ac, 4pa, 4pb and 4sb were found to have good activity with an MIC of 12.5 μg/mL.

Stable and antibacterial tannic acid-based covalent polymeric hydrogel for highly selective Pb2+ recovery from lead-acid battery industrial wastewater

The resource of trace lead (Pb2+) from wastewater bearing intricate components is imperative for sustainable progression of the lead-acid battery industry. Herein, we fabricated a tannic acid-based covalent polymeric hydrogel (TA@PMAM) with antimicrobial properties and stability via facile Michael addition reaction. The incorporation of tannic acid (TA) through robust covalent bond leads to a stable porous 3D covalent polymer network with almost no loss of mechanical properties even after 20 compression cycles. Batch adsorption experiments of TA@PMAM revealed an extraordinary adsorption capacity of Pb2+(Qe =196.6 mg/g), achieving 87.2 % of Pb2+ adsorption within the first 5 min owing to porous structure, numerous adsorption sites and good hydrophilicity. Moreover, TA@PMAM demonstrated a strong affinity for Pb2+ in the presence of the interfere metal ions (Cu2+, Co2+, Mn2+etc.) due to the carbonyl and phenolic hydroxyl that can specifically pair with Pb2+. Stable adsorption properties of TA@PMAM were confirmed in fixed bed column adsorption experiment using lead-acid batteries wastewater, retaining 79.56 % of initial adsorption capacity even after 10 times’ reuse. Besides, TA@PMAM possesses a broad spectrum of antimicrobial properties. This study sheds novel light on the design and fabrication of adsorbent, which holds great potential for commercialization in recovering lead from battery industrial wastewater.

Base-Mediated Chemodivergent [4 + 1] and [2 + 1] Cycloadditions of N-Alkylpyridiniums and Enones.

Divergent synthesis of structurally different products from the same kinds of starting materials is highly synthetically useful but very challenging. Herein, we reported a base-mediated chemodivergent [4 + 1] and [2 + 1] cycloaddition of N-alkylpyridinium and enone under mild conditions, leading to furan-fused bicycles with high diastereoselectivity and spirobicycles, respectively, from moderate to high yields. N-Alkylpyridinium salts were modular nucleophilic transfer reagents and C1 synthons, which underwent tandem Michael addition to the α,β-unsaturated ketones and cyclization under the base conditions. Late-stage derivatization of 4-propyldicyclohexylanone from an important industrial raw of liquid crystal display (LCD) screens was realized. In vitro, compound 3f exhibited good activities against human colon cancer cells (HCT116) with IC50 values in 9.82 ± 0.27 μM. Further biological evaluations investigated the mechanism of the effective inhibition of cell growth, including apoptosis ratio detection, cell cycle analysis, and migration capacity of HCT116 cells. In apoptosis effect studies, complex 3f increased the percentage of apoptotic HCT116 cells to 26.8% (15 μM).

Silver/Segphos‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition for the Enantioselective Synthesis of Pyrrolidine Spirooxindoles

Enantioselective synthesis of chiral heterocyclic derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, a silver‐catalyzed asymmetric 1,3‐dipolar cycloaddition of glycine iminoesters with 3‐isopropylidene‐2‐oxindoles was developed. The DTBM‐Segphos‐induced spirooxindole cycloaddition reaction was used to synthesize a range of stereodivergent alkyl‐substituted 3‐methylene‐2‐oxindoles, achieving excellent enantioselectivities (up to 99% ee), good diastereoselectivities (up to 20:1 dr), and high yields under mild reaction conditions. Computational insights from DFT calculations indicate that the Michael addition step is crucial in determining the reaction rate and enantioselectivity.

Michael addition of ethyl acetoacetate on dibenzylideneacetone derivatives: Synthesis, spectroscopy, antimicrobial and in silico studies

A series of trisubstituted cyclohexenones incorporating a styryl framework were synthesized by Michael addition reaction of ethyl acetoacetate onto dibenzylideneacetone derivatives. The reaction was carried out in ethanol in the presence of piperidine as a basic catalyst. The cyclocondensation starts with a 1,4-Michael addition of ethyl acetoacetate on only one ethylenic bond of the Michael acceptors, followed by an intramolecular cyclization of the Michael adduct to form the corresponding cyclohexenones. The structures of the synthesized products were established based on the IR, (1H & 13C) NMR, and HRMS spectral data. The in vitro evaluation of the antimicrobial effect of the synthesized compounds was tested against B. subtilis, S. aureus, C. albicans, and P. mirabilis strains. In silico studies, including molecular docking, ADMET predictions, and molecular dynamics simulations, were additionally performed to correlate observed and computed outcomes of the biological screening, providing further insights into the compounds' potential efficacy.

C2-Symmetric Amino Acid Amide-Derived Organocatalysts

N-alkylated C2-symmetric amino acid amide derivatives were shown to catalyse the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 44%. The corresponding trifluoroacetic acid salts also catalysed the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone, leading to the formation of predominantly syn-aldol products in up to 55% ee. Aspects of the solvent dependence of the aldol reaction and the H-bonding of the catalyst were investigated.

Interaction between peptide and solid lignin suggest mechanisms of abiotic covalent bond formation

The mechanisms behind the formation of soil organic matter (SOM) and associated nitrogen immobilization remain partially elusive, while ongoing research continues to shed light on carbon and nitrogen sequestration in the environment. Studies show that quinone-like structures within alkali-soluble humic extracts of SOM can bond covalently with nitrogen-containing molecules derived from proteinaceous organic matter. However, direct molecular evidence for this chemical bonding with lignin in the solid form and non-solvent-extracted SOM is lacking. Using gel-state 1H-15N heteronuclear single quantum coherence (HSQC) high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy, we demonstrate that a 15N-labeled peptide (glycine-glycine-glycine-arginine, GGGR), can covalently bind to solid, untreated, brown rotted wood as well as 1,2-naphthoquinone, a quinone-model molecule typically found in degraded lignin. The new peaks in both reactions represent a change in the environment surrounding the N-functional groups. Interaction of the 15N-labeled peptide with the model quinone produced NMR cross peaks that are similar to those of the solid lignin. This suggests that the quinone-like structures are the most likely functional groups to form covalent bonds with peptides in the degraded lignin. Both Michael addition and Schiff base formation is proposed when the peptide GGGR interacts with white oak lignin and 1,2-naphthoquinone. These processes are of considerable importance to N incorporation into SOM and offer insights into how proteinaceous molecules could potentially be preserved and sequestered through covalent bond formation.

Dipeptidic Proline‐Derived Thiourea Organocatalysts for Asymmetric Michael addition Reactions between Aldehydes and Nitroolefins

AbstractThe enantiodivergent synthesis of syn‐Michael adducts can be easily achieved by switching the terminal proline in dipeptidic proline‐thiourea catalysts. In this study, a dipeptidic proline‐derived thiourea organocatalyst was rationally designed and facilely prepared from dipeptidic proline, a chiral diamine as a linker, and isothiocyanate. This asymmetric bifunctional catalyst for Michael addition between aldehydes and nitroolefins provided chiral 4‐nitro aldehyde adducts with yields of up to 99 %, 92 : 8 syn‐diastereoselectivity, and 97 % enantiomeric excess at room temperature.

Copper-Catalyzed Alkynylation of In Situ-Generated Azoalkenes: An Umpolung Approach to Pyrazoles.

A straightforward umpolung approach to regioselectively N-protected polysubstituted pyrazoles starting from aromatic α-halohydrazones and terminal alkynes has been developed. In this process, azoalkenes generated in situ from α-halohydrazones are involved in the Cu(I)-catalyzed Michael addition with alkynes to give α-alkynyl-substituted hydrazones that cyclize to give the target pyrazoles in 37-85% yield. The method employs readily available starting materials and features good functional group compatibility (nitro, sulfonyl, cyano, trimethylsilyl, and primary bromoalkyl groups, esters, and alcohols are tolerated) and scalability.

Mechanism and Origins of Weak Bonding-Controlled Selectivities in Cinchoninium-Catalyzed Umpolung Michael Addition of Imines

Mechanism and Origins of Weak Bonding-Controlled Selectivities in Cinchoninium-Catalyzed Umpolung Michael Addition of Imines

Development of a new experimental NMR strategy for covalent cysteine protease inhibitors screening: toward enhanced drug discovery.

In the development of antiviral drugs, proteases and polymerases are among the most important targets. Cysteine proteases, also known as thiol proteases, catalyze the degradation of proteins by cleaving peptide bonds using the nucleophilic thiol group of cysteine. As part of our research, we are examining how cysteine, an essential amino acid found in the active site of the main protease (Mpro) enzyme in SARS-CoV-2, interacts with electrophilic groups present in ethacrynic acid (EA) and compounds 4, 6, and 8 to form sulfur-carbon bonds. Nuclear magnetic resonance (NMR) spectroscopy was used to monitor the reaction rate between cysteine and Michael acceptors. We found that the inhibitory activity of these compounds towards Mpro is correlated to their chemical reactivity toward cysteine. This approach may serve as a valuable tool in drug development for detecting potential covalent inhibitors of Mpro and other cysteine proteases.

Exploring 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition: A BTK Story.

Targeted covalent inhibitors (TCIs) directing cysteine have historically relied on a narrow set of electrophilic "warheads". While Michael acceptors remain at the forefront of TCI design strategies, they show variable stability and selectivity under physiological conditions. Here, we show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib, for the inhibition of Bruton's tyrosine kinase. In a few iterations, we discovered new derivatives, which inhibit BTK both in vitro and in cellulo at low nanomolar concentrations, on par with Ibrutinib. Several derivatives also displayed good plasma stability and reduced off-target binding in vitro across 135 tyrosine kinases. This proof-of-concept study on a well-studied kinase/TCI system highlights the 2-sulfonylpyrimidine group as a useful acrylamide replacement. In the future, it will be interesting to investigate its wider potential for developing TCIs with improved pharmacologies and selectivity profiles across structurally related protein families.

Preparation of a chiral hyperbranched polymer based on cinchona alkaloids and investigation of its catalytic activity in asymmetric reactions.

Cinchona alkaloid-derived sulfonamides and ester dimers containing chiral hyperbranched polymers have been successfully synthesized and applied as catalysts in asymmetric reactions. Several hyperbranched polymers derived from cinchona alkaloids, incorporating sulfonamides and esters, were synthesized through Mizoroki-Heck coupling polymerization. These polymers were subsequently applied in enantioselective Michael addition reactions. As the prepared polymers are not soluble in frequently used organic solvents, they act as efficient catalysts in the enantioselective reaction of β-ketoesters to nitroolefins, achieving up to 99% enantioselectivity with good yields. The insoluble property allows them to better satisfy "green chemistry" requirements and be used several times without losing the enantioselectivity.

Three-Component Reaction of Cyclopropanols, DABSO, and N-(Sulfonyl)acrylamides: Preparation of Sulfone-Bridged 1,7-Dicarbonyl Compounds.

A cascade reaction of cyclopropyl alcohols, DABSO (1,4-diazoniabicyclo[2.2.2]octane-1,4-disulfinate), and N-(sulfonyl)acrylamides has been developed. This tandem process went through a cyclopropanol ring opening and Michael addition sequence. The γ-keto sulfinate generated from the reaction between cyclopropanol and DABSO serves as the nucleophilic reagent, and N-(sulfonyl)acrylamide is used as the Michael addition acceptor. By utilizing this strategy, multitudinous sulfone-bridged 1,7-dicarbonyl compounds that contain both a β-sulfonyl amide unit and γ-keto sulfone skeleton were conveniently synthesized.