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The asymmetric [3+2] cycloaddition of azomethine ylides generated from the corresponding imino ester-to-trans-ß-nitrostyrene catalysis by chiral aziridine-containing phosphines and phosphine oxides is described. Of the sixteen stereoisomers that could be formed as a result of the title reaction, three were formed, two of which were obtained in an enantiomerically enriched or pure form, and one in a racemic form. One of the products underwent epimerization under basic reaction conditions.
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ß-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of ß-phenethylamines. Bromide-promoted ring opening generates ß-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of ß-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the ß-functionalized phenethylaminopyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.
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A series of optically pure aziridine phosphines and their corresponding phosphine oxides were synthesized through established chemical methodologies. The compounds were systematically investigated for their biological properties. Notably, all synthesized compounds demonstrated moderate antibacterial activity only against the reference strain of Staphylococcus aureus. However, compounds 5 and 7 exhibited noteworthy cell viability inhibition of human cervical epithelioid carcinoma HeLa cells and endometrial adenocarcinoma Ishikawa cells. Further studies of these compounds revealed additional biological effects, including disruption of the cell membrane in high concentrations, cell cycle arrest in the S phase, and the induction of reactive oxygen species (ROS). Comparative analysis of the two classes of chiral organophosphorus derivatives of aziridines indicated that chiral phosphine oxides displayed significantly higher biological activity. Consequently, these findings suggest that chiral phosphine oxides may be potential candidates for the development of anticancer drugs. In light of the significant interest in preparations whose structure is based on a three-membered aziridine ring in terms of potential anticancer therapy, this research fits into the current research trend and should constitute a valuable addition to the current state of knowledge and the existing library of aziridine derivatives with anticancer properties.
Assuntos
Aziridinas , Fosfinas , Humanos , Células HeLa , Aziridinas/farmacologia , ÓxidosRESUMO
Enantioselective radical N-heterobicyclization of N-allylsulfamoyl azides have been developed via metalloradical catalysis (MRC). The Co(II)-based catalytic system can homolytically activate the organic azides with varied electronic and steric properties for asymmetric radical N-heterobicyclization under mild conditions without the need of oxidants, allowing for stereoselective construction of chiral [3.1.0]-bicyclic sulfamoyl aziridines in excellent yields with high diastereoselectivities and enantioselectivities. The key to achieving the enantioselective radical process relies on catalyst development through ligand design. We demonstrate that the use of new-generation D2-symmetric chiral bridged amidoporphyrin ligand HuPhyrin with judicious variation of the alkyl bridge length can dictate both reactivity and selectivity of Co(II)-based MRC. We present both experimental and computational studies that shed light on the working details of the unprecedented mode of asymmetric induction consisting of enantioface-selective radical addition and stereospecific radical substitution. We showcase the synthetic applications of the resulting enantioenriched bicyclic aziridines through a number of stereospecific transformations.
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Commercially available poly(lactic acid) exhibits poor hydrolytic stability, which makes it impossible for use in durable applications. Therefore, a novel hydrolysis inhibitor based on an aziridine derivative as well as a novel stabilizer composition, containing an aziridine derivative and an acid scavenger, were investigated to improve the hydrolytic stability. To evaluate the stabilizing effect, the melt volume rate (MVR) and molecular weight were monitored during an accelerated hydrolytic aging in water at elevated temperatures. Temperatures were selected according to the glass transition temperature (~60 °C) of PLA. It was shown that the novel hydrolysis inhibitor as well as the novel stabilizer composition exhibited excellent performance during hydrolytic aging, exceeding commercially available alternatives, e.g., polymeric carbodiimides. A molecular weight analysis resulted in a molecular weight decrease of only 10% during approximately 850 h and up to 20% after 1200 h of hydrolytic aging, whereas poly(lactic acid) stabilized with a commercial polycarbodiimide revealed comparable molecular weight reductions after only 300 h. Furthermore, the stabilization mechanism of the aziridine derivative alone, as well as in the synergistic combination with the acid scavenger (calcium hydrotalcite), was investigated using nuclear magnetic resonance (NMR) spectroscopy. In addition to an improved hydrolytic stability, the thermal properties were also enhanced compared to polymeric carbodiimides.
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This manuscript describes the development of alkyne addition to the aziridine moiety of aziridinoquinoxalines using dual Ir(III)/Cu(I) catalytic system under green light-emitting diode (LED) photolysis (λmax =525â nm). This mild method features high levels of chemo- and regioselectivity and was used to generate 30 highly functionalized substituted dihydroquinoxalines in 36-98 % yield. This transformation was also carried asymmetrically using phthalazinamine-based chiral ligand to provide 9â chiral addition products in 96 : 4 to 86 : 14 e.r. The experimental and quantum chemical explorations of this reaction suggest a mechanism that involves Ir(III)-catalyzed triplet energy transfer followed by a ring-opening reaction ultimately leading to the formation of azomethine ylide intermediates. These azomethine intermediates undergo sequential protonation/copper(I) acetylide addition to provide the products.
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Chiral cyclopentadienyl-rhodium(III) Cpx Rh(III) catalysis has been demonstrated to be competent for catalyzing highly enantioselective aziridination of challenging unactivated terminal alkenes and nitrene sources. The chiral Cpx Rh(III) catalysis system exhibited outstanding catalytic performance and wide functional group tolerance, yielding synthetically important and highly valuable chiral aziridines with good to excellent yields and enantioselectivities (up to 99 % yield, 93 % ee). This protocol presents a novel and effective strategy for synthesizing enantioenriched aziridines from simple alkenes. Various transformations were performed on the aziridine products, illustrating the versatility and synthetic potential of this protocol for constructing highly functionalized compounds.
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Azetidines, being four-membered N-heterocycles, possess significant potential in contemporary medicinal chemistry owing to their favorable pharmacokinetic properties. Regrettably, the incorporation of functionalized azetidines into pharmaceutical lead structures has been impeded by the absence of efficient synthetic methods for their synthesis. In this study, a Rh-catalyzed one-carbon ring expansion of aziridines with vinyl-N-triftosylhydrazones is presented, which facilitates the synthesis of high value-added 2-alkenyl azetidine products. This research represents the first example of ring expansion of aziridines enabled by vinyl carbenes. Additionally, a one-pot two-step protocol, initiated from cinnamaldehyde, was successfully achieved, offering a step-economical and facile approach for the synthesis of these compounds. The pivotal aspect of this successful transformation lies in the in situ formation of an alkenyl aziridinium ylide intermediate. Experimental investigations, coupled with computational studies, suggest that a diradical pathway is involved in the reaction mechanism.
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An inâ situ generated photoactive copper(I)-complex-catalyzed aziridination reaction of cyclic N-sulfonyl imines with α-aryl-substituted vinyl azides irradiated by blue-LEDs light is reported for the first time. This novel SET process represents a mild, sustainable, and pragmatic method for accessing synthetically resourceful sulfamidate-fused aziridines in acceptable chemical yields with excellent diastereoselectivities. Delightedly, pharmacologically attractive benzo[f][1,2,3]oxathiazepine dioxides and fused isoxazoline frameworks were achieved through our newly developed metal-free based ring-expansion techniques, highlighting the synthetic value of accessed aziridines. Finally, the possible mechanism for [2+1] aza-cyclization was presented based on the conduction of a series of control experiments.
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N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF3 N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF3 compounds with possible applications in the life sciences.
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Azaheterocycles are three-membered rings, known as aziridines, that occur naturally and have pharmaceutical applications.These compounds are present as several secondary metabolites produced by plants and microorganisms.Recent studies have demonstrated the effectiveness of aziridine derivatives (N-H/N-Me) as anticancer agents.We synthesized 18 compounds containing an N-Me enone aziridine group, the chemistry of which has been previously published. However, these compounds have drug-likeness properties; therefore, we aimed to demonstrate their drug-like properties using in silico and in vitro investigations.The molecular structures of the compounds were optimized using density functional theory (DFT). The ADMET parameters of the derivatives were calculated using SwissADME and PreADMET. Additionally, these derivatives were evaluated for their ability to bind to caspase-3 and caspase-9 and then subjected to molecular docking. The lead chemical AY128 maintained stable complexes with target proteins during molecular dynamics simulations, as evidenced by the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) parameters. In vitro cytotoxicity and ELISA tests showed that the novel aziridine derivatives, especially AY128, had strong anticancer activity against HepG2 hepatocellular carcinoma cells.Our study suggests that AY128 may be a potential drug candidate for hepatocellular carcinoma through the caspase-3 and caspase-9-dependent apoptotic pathways.Communicated by Ramaswamy H. Sarma.
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Azomethine ylides are typically in situ generated synthons for making N-heterocycles through cycloaddition reactions. But an offbeat aspect about them is the isomeric nature of aldiminium-based azomethine ylides and (alkyl/aryl)(amino)carbenes, interconvertible by a formal 1,3-H+ transfer. Herein, two thermally robust azomethine ylides with a N-appended picolyl sidearm are isolated, which cyclize to py aziridines at 80 °C but unprecedentedly result N-pico CAAC-CuCl (CAAC=cyclic(alkyl)(amino)carbene) complexes when heated with CuCl at merely 60 °C. The pendant Npy , as revealed by computational analysis, plays a crucial role in this unusual 1,3-H+ shift using a deprotonation-protonation sequence, as well as in placing the CuCl at the carbenic site in tandem. The softer nature of Cu(I) is also critical. Chelating CAACs are rare and one with a N-tethered additional donor is priorly unknown. Both N-pico CAAC and py aziridine are bidentate chelators giving highly active cationic Rh(I) catalysts for hydrosilylating unactivated olefins by Et3 SiH. Notably, the py aziridine-Rh(I) is superior than the N-pico CAAC-Rh(I) catalyst.
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An unprecedented Pd-catalyzed fluorinative bifunctionalization of aziridines and azetidines was successfully developed via regioselective C-C and C-F bond cleavage of gem-difluorocyclopropanes, leading to various ß,ß'-bisfluorinated amines and ß,γ-bisfluorinated amines. This reaction was achieved by incorporating a 2-fluorinated allyl group and a fluorine atom scissored from gem-difluorocyclopropane in 100 % atom economy for the first time. The mechanistic investigations indicated that the reaction underwent amine attacking 2-fluorinated allyl palladium complex to generate η2 -coordinated N-allyl aziridine followed by fluoride ligand transfer affording the final ß- and γ-fluorinated amines.
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An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.
Assuntos
Azirinas , Azirinas/química , Pirimidinas , Estresse OxidativoRESUMO
Herein, a nickela-electrocatalyzed cross-electrophile coupling of readily available aryl aziridines and aryl bromides under mild and sustainable electrochemical conditions to access synthetic useful ß-arylethylamines is developed. This protocol is characterized by its exquisite chemo- and regioselectivity, broad substrate scope and good functional group compatibility. Mechanistic studies confirmed that the regioselectivity and reactivity observed are a result of electro-induced ring-opening of aziridines under electroreductive conditions to generate a benzyl radical intermediate as the active species. Furthermore, this strategy also enables cross-coupling with CO2 to access ß-amino acids under mild conditions.
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Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans-aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO- ) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron-rich and electron-poor aryl groups were shown to be compatible with this method (33â examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring-opening reactions, with a cyclobutyl-substituted norephedrine derivative obtained through a four-step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans-diastereoselectivity.
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Aziridinas , Aziridinas/química , Ânions/química , Iminas/química , Catálise , EstereoisomerismoRESUMO
The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.
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Antineoplásicos , Neoplasias , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
TFA promoted deprotection of O-Ts activated N-Boc hydroxylamines triggers aminofunctionalization-based polycyclizations of tethered alkenes. The processes involve intramolecular stereospecific aza-Prilezhaev alkene aziridination in advance of stereospecific C-N cleavage by a pendant nucleophile. Using this approach, a wide range of fully intramolecular alkene anti-1,2-difunctionalizations can be achieved, including diaminations, amino-oxygenations and amino-arylations. Trends associated with the regioselectivity of the C-N cleavage step are outlined. The method provides a broad and predictable platform for accessing diverse C(sp3 )-rich polyheterocycles of relevance to medicinal chemistry.
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An enantioselective [3+2] cycloaddition of donor-acceptor aziridines with N-aryl protected imines was developed with a Ni(ClO4 )2 â 6H2 O/N,N'-dioxide catalyst system, providing a broad range of chiral trans-substituted imidazolidine compounds with good yields and excellent enantioselectivities (up to 99 % yield, up to 98 % ee). Control experiments indicated that the products could offer excellent diastereoselectivities with the control of chiral Ni(II)-N,N'-dioxide complex and the interaction of the substrates. The possible catalytic process was proposed to rationalize the stereocontrol.
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The conversion of CO2 as a C1 source into value-added products is an attractive alternative in view of the green synthesis. Among the reported approaches, the cyclization reaction of aziridines with CO2 is of great significance since the generated N-containing cyclic skeletons are extensively found in pharmaceutical chemistry and industrial production. However, a low turnover number (TON) and homogeneous catalysts are often involved in this catalytic system. Herein, one novel copper-organic framework {[Cu2(L4-)(H2O)2]·3DMF·2H2O}n (1) (H4L = 2'-fluoro-[1,1':4',1â³-Terphenyl]-3,3â³,5,5â³-tetracarboxylic acid) assembled by nanosized [Cu12] cages was successfully synthesized and structurally characterized, which exhibits high CO2/N2 selectivity due to the strong interactions between CO2 and open Cu(II) sites and ligands in the framework. Catalytic investigations suggest that 1 as a heterogeneous catalyst can effectively catalyze the cyclization of aziridines with CO2, and the TON can reach a record value of 90.5. Importantly, 1 displays excellent chemical stability, which can be recycled at least five times. The combination explorations of nuclear magnetic resonance (NMR), 13C-isotope labeling experiments, and density functional theory (DFT) clearly uncover the mechanism of this aziridine/CO2 coupling reaction system, in which 1 and tetrabutylammonium bromide (TBAB) can highly activate the substrate molecule, and the synergistic catalytic effect between them can greatly reduce the reaction energy barrier from 51.7 to 36.2 kcal/mol.