RESUMO
The construction of 3,4-dihydroquinolone derivatives has attracted a considerable amount of attention due to their extensive applications in medicinal chemistry. In this study, we present the Pd-catalyzed [4+2] cycloaddition of vinyl benzoxazinanones with α-alkylidene succinimides for the efficient synthesis of 3,4-dihydroquinolones. This approach presents numerous advantages, including the ready availability of starting materials, mild reaction conditions without the use of additional bases, and a wide range of substrates. In particular, all of the desired products can be easily afforded in high yields (≤99%) and excellent diastereoselectivities (>20:1). The practicality and reliability of this strategy were demonstrated by the successful scale-up synthesis and subsequent straightforward synthetic transformations.
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Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.
Assuntos
Compostos Azo , Iminas , Tiossemicarbazonas , Estereoisomerismo , Compostos Azo/farmacologia , CatáliseRESUMO
A silver-catalyzed one-pot cycloisomerization/[2 + 3] cycloaddition of enynamides with in situ generated nitrile imines has been developed. Unlike the well-established cycloisomerization/[4 + n] cycloadditions of enynamides, this strategy provides efficient access to a new type of spiropyrazolines, which exhibit an anti-proliferation effect on multiple tumor cell lines. The compound 3u exhibits obvious anticancer activity by inducing apoptosis in RKO cells. The combination of compound 3u and an autophagy inhibitor could improve its anti-proliferation capacities.
Assuntos
Iminas , Prata , Reação de Cicloadição , Iminas/farmacologiaRESUMO
Herein, a series of chiral δ-lactam frameworks have been synthesized and catalyzed by chiral phosphoric acid (CPA) utilizing two kinds of open-chain aza-dienes and azlactones derived from amino acids. This powerful [4 + 2] annulation produces a broad substrate scope with functional group tolerance in yield up to 97% with up to 98:2 er. Moreover, a facile scale-up and straightforward conversion to diversely substituted products verify the synthetic utility of this method featuring good compatibility and high efficiency.
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Here we report for the first time the regio- and diastereoselective [3+2] annulation of a wide range of aliphatic aldimines with alkenes via the activation of an unactivated ß-C(sp3 )-H bond by half-sandwich scandium catalysts. This protocol offers a straightforward and atom-efficient route for the synthesis of a new family of multi-substituted aminocyclopentane derivatives from easily accessible aliphatic aldimines and alkenes. The annulation of aldimines with styrenes exclusively afforded the 5-aryl-trans-substituted 1-aminocyclopentane derivatives with excellent diastereoselectivity through the 2,1-insertion of a styrene unit. The annulation of aldimines with aliphatic alkenes selectively gave the 4-alkyl-trans-substituted 1-aminocyclopentane products in a 1,2-insertion fashion. A catalytic amount of an appropriate amine such as adamantylamine (AdNH2 ) or dibenzylamine (Bn2 NH) showed significant effects on the catalyst activity and stereoselectivity.
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Though numerous cyanation reactions have been developed for the synthesis of benzonitriles, the construction of valuable fully substituted benzonitriles is still a challenging task. Herein, we reported a tertiary amine-catalyzed [3 + 3]-benzannulation for the green synthesis of CF3-functionalized fully substituted benzonitriles. This strategy features exclusive chemoselectivity, high atom-economy, and good step-economy with environment-friendly reagents and mild conditions. Unique triphenyl-substituted dicyanobenzoate products could be rapidly constructed using this method. The practicality and reliability of this reaction were proved by the successful scale-up synthesis. A mechanistic study indicates that the [3 + 3]-benzannulation was initiated by an intermolecular Rauhut-Currier reaction.
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Newly designed 3-((2,2,2-trifluoroethyl)amino)indolin-2-ones were used for the facile synthesis of chiral fluoroalkyl-containing 3,2'-spirooxindole γ-lactam products. The secondary amine-catalysed Michael/hemiaminalization cascade reaction of 3-((2,2,2-trifluoroethyl)amino)indolin-2-one with α,ß-unsaturated aldehydes followed by oxidation can easily produce the desired products in high yields (up to 86%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to >95 : 5 dr).
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Stereodivergent catalysis is of great importance, as it can allow efficient access to all possible stereoisomers of a given product with multiple stereocenters from the same set of starting materials. We report herein the first diastereodivergent [3 + 2] annulation of aromatic aldimines with alkenes via C-H activation by half-sandwich rare-earth catalysts. This protocol provides an efficient and general route for the selective synthesis of both trans and cis diastereoisomers of multisubstituted 1-aminoindanes from the same set of aldimines and alkenes, featuring 100% atom efficiency, excellent diastereoselectivity, broad substrate scope, and good functional group compatibility. The diastereodivergence is achieved by fine-tuning the sterics or ligand/metal combination of the half-sandwich rare-earth metal complexes.
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The development of switchable chemo-, regio-, or diastereodivergent reactions, in which two or more structurally and stereogenically different types of chiral products could be produced efficiently from an identical set of starting materials under readily tunable catalytic conditions, is one of the ultimate goals in asymmetric catalysis. This tutorial review will focus on the application of a variety of chiral organic catalysts, including Lewis bases, and Brønsted bases and acids, in a diverse range of stereoselective reactions in a switchable manner. Meanwhile, a few examples of divergent reactions through synergistic activation of organocatalysis and metal catalysis will also be discussed.
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The catalytic asymmetric construction of silicon-stereogenic silanes is of great interest and significance, but has met with only limited success to date. We herein report the enantioselective hydrosilylation of alkenes with dihydrosilanes by a chiral half-sandwich scandium catalyst, which constitutes an efficient and general route for the synthesis of a wide range of enantioenriched silicon-stereogenic silanes from easily accessible starting materials. This reaction features a broad substrate scope, high yields, and high enantioselectivity. Some of the chiral tertiary silane products were also converted into valuable derivatives, such as chiral silanol, quaternary silane, and benzosilole compounds.
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Transition metal catalyzed C-H functionalization of organic compounds has proved to be a useful atom-efficient strategy in organic synthesis. In contrast, main-group-element-based catalytic processes for C-H functionalization have remained underexplored to date. Reported herein is the catalytic C(sp)-H silylation of a wide range of terminal alkynes with hydrosilanes by using a combination of B(C6 F5 )3 and an organic base such as triethylenediamine (DABCO). This protocol constitutes the first example of boron-catalyzed C(sp)-H functionalization, offering a convenient route for the synthesis of a variety of alkynylsilanes. Experimental and computational studies have revealed that DABCO plays two crucial roles (Lewis base and Brønsted base) in this catalytic transformation.
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Nitrones commonly act as 1,3-dipoles and electrophiles to furnish valuable isoxazolidine and N-hydroxyl products, respectively. They also can be converted to nitrone ylide species and undergo [3+2] formal cycloadditions to access N-hydroxyl pyrrolidines. Here, asymmetric direct aza-vinylogous-type additions of nitrones from isatins to nitroalkenes are presented, catalyzed by a bifunctional thiourea-tertiary amine, affording highly functionalized nitrones with extended carbon skeletons in excellent stereoselectivity. Notably, the nitrone moiety can be easily removed, thus furnishing the formal asymmetric α-functionalization of alkylamine-type substances. Moreover, the remaining electrophilic nitrone motif enables the subsequent annulations to construct spirocyclic products in high molecular complexity and diversity, which might have potential applications for drug discovery.
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Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst-controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1H-indene-1,3(2H)-diones, in exclusive α-regioselectivity. α-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism.
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7-Azaisatin and 7-azaoxindole skeletons are valuable building blocks in diverse biologically active substances. Here 7-azaisatins turned out to be more efficient electrophiles than the analogous isatins in the enantioselective Morita-Baylis-Hillman (MBH) reactions with maleimides using a bifunctional tertiary amine, ß-isocupreidine (ß-ICD), as the catalyst. This route allows a convenient approach to access multifunctional 3-hydroxy-7-aza-2-oxindoles with high enantiopurity (up to 94% ee). Other types of activated alkenes, such as acrylates and acrolein, could also be efficiently utilized.
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A cooperative gold(I)/DMAP system catalyzes the (2 + 3) cycloadditions of yne-enones with oxindole-derived Morita-Baylis-Hillman (MBH) carbonates, yielding diverse bispiro-cyclopentene oxindole products. The mild, scalable protocol demonstrates broad substrate scope and excellent chemo- and diastereoselectivity. Mechanistic study reveals pivotal roles of both catalysts in the unique (2 + 3) cycloaddition. This strategy showcases superiority in achieving transformation with unique chemoselectivity and excellent diastereoselectivity, unattainable through traditional monocatalytic methodologies.
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Heteroaromatic N-oxides, renowned for their highly polar NâO bond and robust structure, exhibit significant bioactivities and have played a pivotal role in various drug development projects since the discovery of Minoxidil. Moreover, heteroaromatic N-oxides, featuring axially chiral biaryl frameworks, are indispensable as Lewis base catalysts and ligands in organic synthesis. Despite their importance, synthesizing these chiral compounds is challenging, necessitating chiral starting materials or resolution processes. Catalytic strategies rely on the functionalization of heteroaromatic N-oxide compounds, leading to products with a relatively limited skeletal diversity. This study introduces a Cu-catalyzed atroposelective method for synthesizing biaryl N-oxides via de novo heteroaromatic N-oxide ring formation. This mild and efficient approach achieves excellent stereoselectivities (up to 99:1 er), enabling the production of a wide array of N-oxides with novel heteroaromatic scaffolds. The axially chiral N-oxide product 3f demonstrates high stereoselectivity and recyclability as a Lewis base catalyst. Additionally, product 3e exhibits promising therapeutic efficacy against triple-negative breast cancer, with IC50 values of 4.8 and 5.2 µm in MDA-MB-231 and MDA-MB-468 cells, respectively. This research not only advances the synthesis of challenging chiral heteroaromatic N-oxides but also encourages further exploration of N-oxide entities in the discovery of bioactive small molecules.
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Here, we present a versatile, silver-catalyzed multi-auto-tandem reaction involving enamines, alkynals, and nucleophiles, utilizing the highly reactive intermediate azafulvenium. This method allows for flexible and switchable regiodivergent reactions through either intermolecular or intramolecular nucleophilic attacks, which can be controlled by adjusting the catalytic conditions. A range of site-specific functionalized or polycyclic fused pyrrole products were efficiently produced with a high level of chemocontrol.
RESUMO
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
Assuntos
Cardiomegalia , Fibrose , Sirtuína 3 , Animais , Humanos , Masculino , Camundongos , Ratos , Cardiomegalia/genética , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Fibrose/genética , Homeostase/efeitos dos fármacos , Isoproterenol , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/patologia , Mitocôndrias/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Miocárdio/metabolismo , Sirtuína 3/efeitos dos fármacos , Sirtuína 3/metabolismoRESUMO
Significant progress has been made in asymmetric synthesis through the use of transition metal catalysts combined with Lewis bases. However, the use of a dual catalytic system involving 4-aminopyridine and transition metal has received little attention. Here we show a metal/Lewis base relay catalytic system featuring silver acetate and a modified chiral pyrrolidinopyridine (PPY). It was successfully applied in the cycloisomerization/(2 + 3) cycloaddition reaction of enynamides. Bispirocyclopentene pyrazolone products could be efficiently synthesized in a stereoselective and economical manner (up to >19:1 dr, 99.5:0.5 er). Transformations of the product could access stereodivergent diastereoisomers and densely functionalized polycyclic derivatives. Mechanistic studies illustrated the relay catalytic model and the origin of the uncommon chemoselectivity. In subsequent bioassays, the products containing a privileged drug-like scaffold exhibited isoform-selective phosphodiesterase 1 (PDE1) inhibitory activity in vitro. The optimal lead compound displayed a good therapeutic effect for ameliorating pulmonary fibrosis via inhibiting PDE1 in vivo.
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An efficient TsOH-catalyzed consecutive biscyclization cascade reaction of dithioallylic alcohols with 1-styrylnaphthols is demonstrated for the concise construction of pharmaceutically important cyclopenta[b]dihydrobenzofuran scaffolds. This process involved an acid-catalyzed (3+2) cycloaddition followed by an intramolecular nucleophilic addition, providing cyclopenta[b]dihydronaphthofurans bearing a tetra- or fully substituted cyclopentane core in good yields with exclusive diastereoselectivities (>20 : 1 d.r.).