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Quinazolines are an important class of heterocyclic compounds that have proven their significance, especially in the field of organic synthesis and medicinal chemistry because of their wide range of biological and pharmacological properties. Thus, numerous synthetic methods have been developed for the synthesis of quinazolines and their derivatives. This review article briefly outlines the new synthetic methods for compounds containing the quinazoline scaffold employing transition metal-catalyzed reactions.
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Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative πâσ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.
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Domino reactions of chromones with activated carbonyl compounds, such as dimethyl acetone-1,3-dicarboxylate and 1,3-diphenylacetone, and with 1,3-bis(silyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, allow for a convenient synthesis of a great variety of products. The regioselectivity and course of the reaction depends of the substituent located at carbon C3 of the chromone moiety and also on the type of nucleophile employed.
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We describe herein the optimized design and modular synthetic approach towards supramolecularly programmed monomers that can form discrete macrocyclic species of controllable size and shape through amidinium-carboxylate interactions in apolar and polar media.
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We herein report a two-step approach for the enantioselective synthesis of novel chiral δ-lactams. By using a cooperative chiral ITU/achiral Pd-catalyst system, this protocol proceeds via an asymmetric α-allylation of activated aryl esters first, followed by an acid-mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well.
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We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.
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A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.
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Acetona , Lactamas , Lactamas/química , Amino Álcoois , Cetonas/química , Estereoisomerismo , Estrutura MolecularRESUMO
Condensation of 2-vinylanilines and conjugated aldehydes followed by an efficient light-mediated cyclisation selectively yields either substituted tetrahydroquinolines with typically high dr, or in the presence of an iridium photocatalyst the synthesis of quinoline derivatives is demonstrated. These atom economical processes require mild conditions, with the substrate scope demonstrating excellent site selectivity and functional group tolerance, including azaarene-bearing substrates. A thorough experimental mechanistic investigation explores multiple pathways and the key role that imine and iminium intermediates play in the absorption of visible light to generate reactive excited states. The synthetic utility of the reactions is demonstrated on gram scale quantities in both batch and flow, alongside further manipulation of the medicinally relevant products.
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Hidroxiquinolinas , Quinolinas , Ciclização , LuzRESUMO
Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscineâ A.
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Axially chiral biaryls widely exist in natural products and pharmaceuticals and are used as chiral ligands and catalysts in asymmetric synthesis. Compared to the well-established axially chiral 6-membered biaryl skeletons, examples of 5-membered biaryls have been quite scarce, and mono-substituted 3-arylpyrrole atropisomers have not been reported. Here, we disclose a copper-catalyzed atroposelective diyne cyclization for the construction of a range of axially chiral arylpyrrole biaryls in good to excellent yields with generally excellent enantioselectivities via oxidation and X-H insertion of vinyl cations. Importantly, this protocol not only represents the first synthesis of mono-substituted 3-arylpyrrole atropisomers, but also constitutes the first example of atroposelective diyne cyclization and the first atropisomer construction via vinyl cations. Theoretical calculations further support the mechanism of vinyl cation-involved cyclization and elucidate the origin of enantioselectivity.
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Glutaconamide-based [2]rotaxanes are efficiently oxidized to the respective interlocked α-ketoamides, whereas their non-interlocked threads afford hydroxycyclohexene tetraamides under similar reaction conditions. These results showcase the mechanically interlocking of highly reactive substrates as a powerful tool for controlling their chemical behavior. Inside the macrocycle and under irradiation with light, the α-ketoamide threads convert, in a divergent manner, into the corresponding interlocked hydroxy-ß-lactams or oxazolidinones by two modes of Norrish/Yang type-II intramolecular cyclizations, processes that are efficiently chemocontrolled by the mechanical bond.
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The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (-)-daphnezominesâ A and B and (+)-dapholdhamineâ B have been accomplished in 16-20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamineâ B backbone.
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Adamantano , Alcaloides , Estereoisomerismo , CiclizaçãoRESUMO
Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion-π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels-Alder reactions and autocatalytic ether cyclizations. Currently, anion-π catalysis on carbon allotropes gains momentum because the combination with electric-field-assisted catalysis promises transformative impact on organic synthesis.
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Herein, a SnCl4 -catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization to access angular (hetero)aryl-fused polycycles is reported. Subsequent decarboxylation of the readily enolizable products afforded the angular products in up to 71 % yield over two steps, with the trans-diastereomers as the major products. The cyclopropyl homo-Nazarov cyclization precursors were formed using a scalable and modular synthetic route that, ultimately, offers access to 6,6,6-, 6,6,5-, 6,5,6-, 6,6,5,6-, and 6,6,6,5-fused angular polycyclic products. To showcase the rigor and utility of the method, an 8-step total synthesis of (±)-1-oxoferruginol, an antibacterial aromatic abietane diterpenoid, was disclosed.
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Abietanos , Antibacterianos , Catálise , CiclizaçãoRESUMO
Aporphine compounds constitute a class of substances with important pharmacological properties, including anticancer, antiviral, anti-HIV, anti-inflammatory, and leishmanicidal activities. Consequently, several strategies to obtain the aporphine core have been reported. Herein this review, we provide an overview of two relevant approaches used to construct the C-ring in the synthetic routes developed. The first approach, which is based on a one-bond disconnection, allows C-ring formation using a 1-benzyl-1,2,3,4-tetrahydroisoquinoline intermediate (mainly) employing cyclization reactions catalyzed by metals or promoted by light. The second approach, which is derived from a two-bond disconnection, leads to C-ring formation via a sequence of reactions starting with [4+2] cycloadditions. Through these approaches, aporphinoids with a diverse range of substitution patterns and biological activities can be synthesized.
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Aporfinas , Aporfinas/química , Ciclização , Reação de CicloadiçãoRESUMO
Ethyl 2-(2-arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates (1a-k) were synthesized by alkylation on HN- of ethyl 2-(2-arylidenehydrazinyl)thiazole-4-carboxylates. The proposed structures (1a-k) are corroborated by spectro-analytical techniques like UV, FT-IR, 1 H-, 13 C-NMR and HR-MS. All synthesized compounds were screened for their antiglycation and antioxidant assays. The inâ vitro antiglycation results revealed promising activity of compounds 1a, 1b, 1d, 1e, 1f, 1g, 1j and 1k with IC50 values 0.0004±1.097-17.22±0.538â µM when compared to standard, aminoguanidine (IC50 =25.50±0.337â µM). Among all tested compounds 1j and 1k are the best antiglycating agents with IC50 values 1.848±0.646 and 0.0004±1.097â µM, respectively. The in-silico studies also agree with these results where binding energy for 1j and 1k was found to be -9.25 and -8.42â kcal/mol with calculated dissociation constants of 0.16 and 0.67â µM, respectively. The antiglycation results demonstrate the application of these compounds in reducing diabetic complications.
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Antineoplásicos , Tiazóis , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-ß-indolyl-ß-ketoesters. To highlight the method's synthetic utility, a formal total synthesis of murrayafoline A, a bioactive carbazole-containing natural product, was undertaken.
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Acetais , Ácidos de Lewis , Éteres , Ácidos CarboxílicosRESUMO
An operationally simple Ag(I)-catalyzed approach for the synthesis of isoquinoline and quinazoline fused 1,2,3-triazoles was developed by a condensation and amination cyclization cascade of amino-NH-1,2,3-triazoles with 2-alkynylbenzaldehydes involving three new C-N bond formations in one manipulation, in which the group of -NH of the triazole ring serves as a nucleophile to form the quinazoline skeleton. The efficient protocol can be applied to a variety of substrates containing a range of functional groups, delivering novel pentacyclic fused 1,2,3-triazoles in good-to-excellent yields.
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Prata , Triazóis , Ciclização , Triazóis/química , Catálise , Estrutura Molecular , QuinazolinasRESUMO
Simultaneous control over the configuration of multiple stereocenters is accomplished by numerous catalytic methods, providing a reliable basis for the synthesis of stereochemically complex targets in isomerically defined form. In contrast, addressing the configurations of multiple stereogenic axes with diastereodivergent catalyst control is thus far only possible by stepwise approaches. Herein we now describe that all four stereoisomers of atropisomeric two-axis systems are directly tractable by assembling a central aromatic unit of teraryls through an arene-forming aldol condensation. By using cinchona alkaloid-based ion-pairing catalysts, the four feasible reaction pathways are differentiated from identical substrates under defined basic conditions without preactivation, thus enabling complete stereodivergence with enantioselectivities of up to 99 : 1 e.r.
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Aldeídos , Alcaloides de Cinchona , Catálise , EstereoisomerismoRESUMO
The treatment of primary or secondary alkyl iodides with sBu2 Mg in toluene (25-40 °C, 2-4â h) provided dialkylmagnesiums that underwent various reactions with aldehydes, ketones, acid chlorides or allylic bromides. 3-Substituted secondary cyclohexyl iodides led to all-cis-3-cyclohexylmagnesium reagents under these exchange conditions in a highly stereoconvergent manner. Enantiomerically enriched 3-silyloxy-substituted secondary alkyl iodides gave after an exchange reaction with sBu2 Mg stereodefined dialkylmagnesiums that after quenching with various electrophiles furnished various 1,3-stereodefined products including homo-aldol products (99 % dr and 98 % ee). Mechanistic studies confirmed a radical pathway for these new iodine/magnesium-exchange reactions.