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CONTEXT: This study investigates the energetic and polarizability characteristics of three 1,3-dipolar cycloaddition reactions between diazene oxide and substituted ethylenes, focusing on the transition from synchronous to asynchronous mechanisms. Synchronicity analysis, using the reaction force constant, indicates that the bond evolution process becomes increasingly decoupled as the number of cyano groups increases. Polarizability analysis reveals that isotropic polarizability reaches its maximum near the transition state in all cases, while anisotropy of polarizability shifts from the transition state toward the product direction as asynchronicity increases. The larger the shift, the more asynchronous the mechanism, as reflected by the weight of the transition region. A detailed examination of the parallel and perpendicular polarizability components to the newly formed sigma bonds shows that the evolution of the parallel component is closely aligned with the energetic changes along the reaction coordinate, particularly in the synchronous reaction. We have also identified a relationship between the displacement in the maximum state of the parallel component from the transition state and the synchronicity of the mechanism. The larger the displacement, the more asynchronous the mechanism. These findings suggest that asynchronous 1,3-dipolar cycloaddition mechanisms are characterized by a decoupling of isotropic and anisotropic polarizabilities and a shift in the maximum polarizability state of the parallel component toward the product direction. METHODS: Density functional theory calculations were performed at the B3LYP/6-311 + + G(d,p)//B3LYP/6-31G(d,p) level of theory. The polarizability was calculated at each point of the reaction path, obtained using the intrinsic reaction coordinate method, as implemented in Gaussian 16.

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This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

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In this work, the reactions of quadricyclane with dimethyl azodicarboxylate (DMAD) and of quadricyclane with diethyl azodicarboxylate (DEAD) in gas phase and in water environments were studied by a first-principles investigation within the framework of auxiliary density functional theory (ADFT). For these type of organic reactions is known that water is required to accelerate them. Since the reason of why this occur is still unknown, this work aims to gain insight into this reaction mechanism. For this investigation, the generalized gradient approximation as well as a hybrid functional were employed. The obtained optimized structures for the reactants, of the products and of the transition states are reported, together with the corresponding frequency analysis results and the reaction profiles. Along the proposed concerted reaction mechanism, a critical points search of the electron density and a charge analysis were performed. The calculated potential energy barriers of these reactions in gas phase and in water environments are compared. In agreement with experiment, the obtained results indicate that both reactions occur faster in water than in gas phase. This study shows that there is a change in the polarity of the two most important carbon atoms of the formed compounds along the reactions and that the decrease of the activation energy barrier which occurs in liquid phase in these reactions is because the structures of the main transition states are stabilized by the water environment. Therefore, the here obtained results demonstrate the important role played by the water-molecule framework into the activation energy barrier and structures of the molecules that participate in the DMAD and DEAD cycloaddition reactions.

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In the last 50 years, nucleoside analogs have been introduced to drug therapy as antivirals for different types of cancer due to their interference in cellular proliferation. Among the first line of nucleoside treatment drugs, ribavirin (RBV) is a synthetic N-nucleoside with a 1,2,4-triazole moiety that acts as a broad-spectrum antiviral. It is on the World Health Organization (WHO) list of essential medicines. However, this important drug therapy causes several side effects due to its nonspecific mechanism of action. There is thus a need for a continuous study of its scaffold. A particular approach consists of connecting  d-ribose to the nitrogen-containing base with a C-C bond. It provides more stability against enzymatic action and a better pharmacologic profile. The coronavirus disease (COVID) pandemic has increased the need for more solutions for the treatment of viral infections. Among these solutions, remdesivir, the first C-nucleoside, has been approved by the Food and Drug Administration (FDA) for clinical use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It drew attention to the study of the C-nucleoside scaffold. Different C-nucleoside patterns have been synthesized over the years. They show many important activities against viruses and cancer cell lines. 1,2,3-Triazolyl-C-nucleoside derivatives are a prolific and efficient subclass of RBV analogs close to the already-known RBV with a C-C bond modification. These compounds are often prepared by alkynylation of the  d-ribose ring followed by azide-alkyne cycloaddition. They are reported to be active against the Crimean-Congo hemorrhagic fever virus and several tumoral cell lines, showing promising biological potential. In this review, we explore such approaches to 1,2,3-triazolyl-C-nucleosides and their evolution over the years.

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In recent years, N-heterocyclic carbenes (NHC) have gained recognition as versatile molecules capable of acting as organocatalysts in various reactions, particularly through the activation of aldehydes via Breslow-type adducts. This organocatalytic activation has enabled the production of numerous 3,4-dihydropyran-2-ones and related derivatives. In this review, we provide an overview of the production of 3,4-dihydropyran-2-ones and derivatives via organocatalytic processes involving NHCs over the past eight years. These processes involve the use of a diverse range of substrates, catalysts, and reaction conditions, which can be classified into [4+2]-and [3+3]-type cycloadditions, primarily aimed at synthesizing this skeleton due to its biological activity and multiple stereocenters. These processes are scaled up to the gram scale, and the resulting products are often directed towards epimerization and functionalization to produce more complex molecules with potential applications in the biological field. Finally, we provide a perspective and the future directions of this topic in organic synthesis.

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The mechanism of Diels-Alder reactions between cyclopentadiene and several cyanoethylenes was studied by means of Density Functional Theory calculations using QTAIM and IQA (Interacting Quantum Atoms) analyses along complete IRC paths. Each geometry from the IRC had its wavefunction computed and the topology of the electronic density for it was then evaluated. By means of IQA, the global energetic profile was partitioned among the various atoms in the molecule, providing insight into what atoms are the main ones responsible for the magnitude of the energy barriers. The (a)synchronicity of the reaction mechanisms featuring non-symmetrically substituted dienophiles was characterized, from QTAIM, by the electron densities and Laplacians over the LCP's as well as by the different atomic energy barriers obtained from IQA. The magnitude of the atomic barrier nicely explains the (a)synchronicity of the reaction mechanisms, and the degree of (a)synchronicity is nicely revealed by the difference between the earlier and later bond breaking and bond formations. The main conclusion is that important energetic and electronic changes are occurring before and after the position of the transition state structure, mainly for those asynchronous mechanisms, and although these provide essential insight into the reaction mechanism, most studies cannot assess this kind of information because they are focusing solely on reactants, transition states, and products. We advocate that the additional computational effort required for such analyses is more than compensated by the great amount of useful information it provides.

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[3+2] cycloadditions of nitroolefins have emerged as a selective and catalyst-free alternative for the synthesis of 1,2,3-triazoles from azides. We describe mechanistic studies into the cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate-limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5-triazole. Kinetic studies reveal a second-order rate law, and 13 C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and ß-carbons of ß-nitrostyrene. Distortion/interaction-activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less-distorted TS, while intermolecular interaction terms dominate the preference for 1,5- over 1,4-cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronous Ei-type HNO2 elimination mechanism, quasiclassical direct-dynamics calculations reveal the existence of a dynamic intermediate.

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The ketenimines represent an interesting class of organic intermediates which has undergone a regrowth as a consequence of recent extensions of copper catalyzed azide alkyne cycloaddition (CuAAC) to other synthetic fields. This review summarizes the most recent generation methods of ketinimines from CuAAC reaction, highlighting chemical properties focused to the synthesis of cyclic compounds among others, affording a general outlook towards the development of new biologically active compounds.

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According to P.K. Chattaraj. J Phys Chem A 2001, 105, 511-513 "the maximum Fukui function site is the best for the frontier-controlled soft-soft reactions whereas for the charge-controlled hard-hard interactions the preferred site is associated with the maximum net charge and not necessarily the minimum Fukui function". Taking into account these outcomes in this research is explored this reactivity scheme using in first case the reaction between fulminic acid with ethylene (reference reaction), after is varying the dipolarophile in the reaction between fulminic acid with acetylene, and finally is varying the dipole in the reaction between formonitrile imine with ethylene. These results allow study parameter such as charge transfer, polarizability, covalent character on bonding, among other; also shown the preference by the sf- / sf+ interactions in the transition state on the sf- / sf- interactions. On the other hand, these results also were justified using net electrophilicity which is defined as the electrophilic power of a system relative to its own nucleophilic power.

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The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 µM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

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Peperomia pellucida (L.) HBK (Piperaceae) ("jabuti herb") is an herbaceous plant that is widespread in the tropics and has several ethnomedicinal uses. The phytochemical study of leaf extracts resulted in the isolation of 2,4,5-trimethoxycinnamic acid, 5,6,7-trimethoxyflavone, 2,4,5-trimethoxystyrene, 2,4,5-trimethoxybenzaldehyde, dillapiol, and sesamin in addition to pellucidin A. The co-occurrence of styrene and cyclobutane dimers suggested the formation of pellucidin A by a photochemical [2+2] cycloaddition of two molecules of 2,4,5-trimethoxystyrene. To investigate this biogenesis, analysis of plant leaves throughout ontogeny and treatments such as drought, herbivory and, exposure to jasmonic acid and UV365 light were carried out. Significant increases in the content of dillapiol (up to 86.0%) were found when P. pellucida plants were treated with jasmonic acid, whereas treatment under UV365 light increase the pellucidin A content (193.2%). The biosynthetic hypothesis was examined by feeding various 13C-labeled precursors, followed by analysis with GC-MS, which showed incorporation of L-(2-13C)-phenylalanine (0.72%), (8-13C)-cinnamic acid (1.32%), (8-13C)-ferulic acid (0.51%), (8-13C)-2,4,5-trimethoxycinnamic acid (7.5%), and (8-13C)-2,4,5-trimethoxystyrene (12.8%) into pellucidin A. The enzymatic conversion assays indicated decarboxylation of 2,4,5-trimethoxycinnamic acid into 2,4,5-trimethoxystyrene, which was subsequently dimerized into pellucidin A under UV light. Taken together, the biosynthesis of pellucidin A in P. pellucida involves a sequence of reactions starting with L-phenylalanine, cinnamic acid, ferulic acid, 2,4,5-trimethoxycinnamic acid, which then decarboxylates to form 2,4,5-trimethoxystyrene and then is photochemically dimerized to produce pellucidin A.

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The structure of Fischer carbene complexes (FCCs) is electron deficient. If bearing an α,ß-unsaturated system, it can generate a wide variety of compounds by undergoing many different transformations, including higher-order cycloadditions. The latter are described as pericyclic reactions in which more than six electrons participate. These reactions have been employed in various areas of organic synthesis, resulting in highly selective compounds with a broad range of scaffolds. The first studies on higher-order cycloadditions involving FCCs frequently yielded competing byproducts. Many groups have attempted to increase selectivity by exploring distinct reaction conditions, reagents and co-catalysts (e. g., metal-mediated cycloadditions). The present review is the first to focus exclusively on using higher-order cycloadditions involving FCCs to synthesize carbocycles and heterocycles. Based on two decades of reports, an analysis is made of the main aspects of the mechanisms proposed for higher-order cycloadditions and the structural diversity obtained by the substituent effect.

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The triazole heterocycle is a privileged scaffold in medicinal chemistry, since its structure is present in a large number of biologically active molecules, including several drugs currently in the market. Due to their vast applications, a wide variety of methods are described for their preparation, such as the 1,3-dipolar cycloaddition and processes involving diazo compounds and diazo transfer reactions. Considering the significant number of contributions from our research group to this chemistry in recent decades, in this account we discuss both the development of new methods for the synthesis of 1,2,3-triazoles and the preparation of new triazole-functionalized biologically active molecules using classical approaches.

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The 9-azabicyclo[3.3.1]nonane ring system is present in several insect- and plant-derived alkaloids. (-)-Adaline (1) and (+)-euphococcinine (2), found in secretions of Coccinelid beetles, and (+)-N-methyleuphococcinine (3), isolated from the Colorado blue spruce Picea pungens, are members of this alkaloid family. Their unique bicyclic system with a quaternary stereocenter, and the potent biological activity exerted by these homotropane alkaloids, make them attractive synthetic targets. This work aims briefly to review the chemical ecology of Adalia bipunctata and the recent methodologies to obtain adaline (1), euphococcinine (2), and N-methyleuphococcinine (3).

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N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides are converted into natural product inspired scaffolds via iridium photocatalyzed intramolecular [2+2] photocycloaddition. The protocol has a broad substrate scope, whilst operating under mild reaction conditions. Tethering four components forming a trisubstituted cyclobutane core builds rapidly high molecular complexity. Our approach allows the design and synthesis of a variety of tetrahydrocyclobuta[c]quinolin-3(1H)-ones, in yields ranging between 20-99 %, and with excellent regio- and diastereoselectivity. Moreover, it was demonstrated that the intramolecular [2+2]-cycloaddition of 1,7-enynes-after fragmentation of the cyclobutane ring-leads to enyne-metathesis-like products.

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The reaction mechanism of the intramolecular [2 + 2] cycloaddition from a jatrophane precursor to the gaditanane skeleton, an unprecedented 5/6/4/6-fused tetracyclic ring framework recently isolated from Euphorbia spp., was studied using the bond reactivity indices approach. Furthermore, six diterpenoids, including three undescribed jatrophanes isolated from E. gaditana Coss, were described. The structures of these compounds were deduced by a combination of 2D NMR spectroscopy and ECD data analysis.

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The synthesis and characterization of three new dispiro[indoline-3,3'-pyrrolizine-1',5''-thiazolidine] compounds are reported, together with the crystal structures of two of them. (3RS,1'SR,2'SR,7a'SR)-2'-(4-Chlorophenyl)-1-hexyl-2''-sulfanylidene-5',6',7',7a'-tetrahydro-2'H-dispiro[indoline-3,3'-pyrrolizine-1',5''-thiazolidine]-2,4''-dione, C28H30ClN3O2S2, (I), (3RS,1'SR,2'SR,7a'SR)-2'-(4-chlorophenyl)-1-benzyl-5-methyl-2''-sulfanylidene-5',6',7',7a'-tetrahydro-2'H-dispiro[indoline-3,3'-pyrrolizine-1',5''-thiazolidine]-2,4''-dione, C30H26ClN3O2S2, (II), and (3RS,1'SR,2'SR,7a'SR)-2'-(4-chlorophenyl)-5-fluoro-2''-sulfanylidene-5',6',7',7a'-tetrahydro-2'H-dispiro[indoline-3,3'-pyrrolizine-1',5''-thiazolidine]-2,4''-dione, C22H17ClFN3O2S2, (III), were each isolated as a single regioisomer using a one-pot reaction involving L-proline, a substituted isatin and (Z)-5-(4-chlorobenzylidene)-2-sulfanylidenethiazolidin-4-one [5-(4-chlorobenzylidene)rhodanine]. The compositions of (I)-(III) were established by elemental analysis, complemented by high-resolution mass spectrometry in the case of (I); their constitutions, including the definition of the regiochemistry, were established using NMR spectroscopy, and the relative configurations at the four stereogenic centres were established using single-crystal X-ray structure analysis. A possible reaction mechanism for the formation of (I)-(III) is proposed, based on the detailed stereochemistry. The molecules of (I) are linked into simple chains by a single N-H...N hydrogen bond, those of (II) are linked into a chain of rings by a combination of N-H...O and C-H...S=C hydrogen bonds, and those of (III) are linked into sheets by a combination of N-H...N and N-H...S=C hydrogen bonds.

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A series of new organochalcogen derivatives of indolizines was synthesized in moderate to excellent yields from pyridinium salts and chalcogeno-alkynes. The reaction can be carried out under thermal conditions or by sonochemical processes in short reaction times. The stepwise cycloaddition reaction forming chalcogeno-indolizines is regioselective and extends to a broad range of functional groups. Furthermore, novel chalcogeno-alkynes are reported and the first derivatives of teluro-indolizine are described. The influence of selenium functionalization on the photophysical properties of indolizines is also described, in which the compounds showed absorption in the UV-Vis region around 360 nm and emission in the blue-to-green region. Relatively low fluorescence quantum yield (ϕfl) values were calculated, in agreement with the chalcogen effect on other heterocycles.

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Among the many methods available for accessing conformationally diverse cyclic peptides, the derivatization of macrocyclic iminopeptides has remained notably underexplored. Now, a relevant complexity-generating method expands the repertoire of synthetic strategies exploiting the reactivity of an imino bond embedded in the cyclic peptide skeleton. Here we highlight a recent report describing the on-resin construction of a new family of macrocyclic peptide/natural product-inspired hybrids, namely "PepNats", by derivatization of cyclic iminopeptides through 1,3-cycloaddition reactions. A proof-of-concept with PepNats bearing peptide sequences that mimic protein hot loops demonstrated the potential of this strategy to create novel macrocyclic peptide ligands capable of modulating protein-protein interactions.

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Polar-terminated 3,5-diarylisoxazole liquid crystals (ILCs) were synthetized and characterized. ILCs are composed by rigid core 3,5-diarylisoxazol, alkyl chain and polar-terminated flexible spacer. Hydroxyl-, ketal- and 1,2-diol-terminated ILCs rendered smectic C and A mesophase, while bromine-terminated ILCs showed smectic A and B mesophase, for monosubstituted and linear ILCs. For branched alkyl chain monotropic SmA was detected and for disubstituted ILCs no mesophase was detected. Out-of-layer fluctuations (OLFs) are discussed based on X-ray diffraction date and textures. The OLFs are dependent on the bromine atom hardness, hydrogen bonding through collective actions and conformational effects at the interface between layers. Smectic translational order parameter (TOP) Σ was also obtained for orientated bromine- and hydroxyl-terminated ILCs and related it with OLFs. For 1,2-diol-terminated ILCs two SmC sublayers were founded, probably related to the intramolecular hydrogen bond favoring the 5-membered and 6-membered formation.