Ring Fusion Research Articles

Synthesis of a Novel Tetracyclic Isoxazole by Intramolecular Nitrile Oxide Cycloaddition

Intramolecular cycloadditions have the great advantage of forming two rings simultaneously. We report the use of intramolecular [3 + 2] cycloaddition of the nitrile oxide derived from an N-propargylbenzimidazole oxime in the synthesis of a hitherto unreported tetracyclic isoxazole-containing ring system bearing “6-5-5-5”-membered ring fusions. The initial condensation was achieved through reaction of o-phenylenediamine with ethyl diethoxyacetate, followed by alkylation with propargyl bromide, deprotection of the acetal to the aldehyde, formation of an aldoxime, and intramolecular nitrile oxide cycloaddition (INOC). Characterization of the aldoxime and tetracyclic isoxazole is included herein.

Unveiling N-Fused Nitreniums as Potent Catalytic Photooxidants.

The first example of a hitherto-unknown facet of catalytic photooxidant capability of nitrenium cations is reported herein. The fundamental limitation of inability of the traditional and reported nitreniums to achieve the excited-state redox potential beyond +2.0 V (vs Ag/AgCl), the primary requirement for a powerful photooxidant, is addressed in this work by developing a structurally unique class of N-fused nitrenium cations, with the required structural engineering involving extensive π-conjugation through ring fusion at the nitrenium site, which enabled significant lowering of the LUMO energy and easy reduction at the excited state (excited-state redox potential up to +2.5 V vs Ag/AgCl), facilitated by effective delocalization/stabilization of the generated radical. This finding opens a new way to discover novel and useful (photo)catalytic properties of nitrenium cations beyond just Lewis acidity.

6,7-Coumarin-heterocyclic hybrids: A comprehensive review of their natural sources, synthetic approaches, and bioactivity

The hybridization of heterocycles presents a key opportunity to craft innovative multicyclic compounds with enhanced biological activity. Coumarins, being broadly prevalent natural heterocycles, are extensively utilized in the formulation of diverse biologically and pharmacologically active chemicals. The fusion of various hetero rings with the coumarin ring represents a captivating approach to creating novel hybrid molecules endowed with notable biological activities. In the endeavor of developing heterocyclic-fused coumarins, a diverse array of 6,7-heterocycle-coumarin hybrids has been introduced, showcasing remarkable biological efficacy. The impact of heterocyclic annulation at the 6,7-positions of the coumarin ring on the biological activity of the resultant structures has been examined. This review centers on the natural origins, synthetic methodologies, structural activity relationship investigation, and biological potentials of 6,7-heterocycle-coumarin hybrids. We conducted searches across several databases, including Web of Science, Google Scholar, PubMed, and Scopus. After sieving, we ultimately identified and included 161 pertinent studies published between 1995 and the middle of 2023. This will offer valuable insight to medicinal chemists for the future design and synthesis of biologically active lead compounds based on heterocycle-fused coumarin scaffolds with substantial therapeutic effects.

Completely solvent-free synthesis of double heterohelicenes and their further ring fusion using mechanochemical reaction

We succeeded in completely solvent-free synthesis of double heterohelicenes composed of two heteroacenes and their further conversion to semi- and fully planarized molecules using mechanochemical oxidative C–N coupling reactions.

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes.

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

Optimizing stability through conformational locking and ring fusion modulation in organic semiconductors

S,N-Heteroacene-type fused tetrathienophenanthroline monomer was synthesized via intramolecular cyclization, an alternative to the raditional benzodithiophene-4,8-dione units in high-performance photovoltaic materials.

Linear Extension of Carbaporphyrin Chromophores: Synthesis, Protonation, and Metalation of Anthro[2,3-b]carbaporphyrins: Evidence for 30π-Electron Aromatic Circuits in a Palladium(II) Complex.

Acid-catalyzed condensation of a naphtho[2,3-f]indane dialdehyde with a tripyrrane, followed by an oxidation step, afforded an anthro[2,3-b]-21-carbaporphyrin. The presence of a fused anthracene unit induced minor bathochromic shifts and did not significantly affect the aromatic characteristics of the carbaporphyrin core. Protonation led to the formation of a monocation with similar diatropic properties, but the dication generated in the presence of a large excess of trifluoroacetic acid had a weakened Soret band absorption and a broad absorption at 754 nm. Nucleus-independent chemical shift (NICS) calculations indicate that the dication is only weakly aromatic and possesses a 32-atom 30π electron delocalization pathway. Alkylation with methyl iodide and potassium carbonate gave a 22-methyl derivative that reacted with palladium(II) acetate to afford an aromatic palladium(II) complex. Upon heating, the methyl group migrated from the nitrogen to the internal carbon atom and the resulting complex exhibited diminished aromatic character. A comparison with related carbaporphyrin complexes without ring fusion or with benzo- or naphtho-fused units demonstrated that the diatropic character decreased with increasing conjugation. NICS calculations and anisotropy of induced current density (AICD) plots confirmed this trend and showed that the remaining aromatic properties of the anthrocarbaporphyrin complex were due to a 30π electron circuit that extends around the entire anthracene unit.

Expanding Diterpene Complexity and Diversity via Photoinduced Ring Distortions.

Natural products and their semi-synthetic derivatives undoubtedly constitute an important source of therapeutic agents. Their importance lies in their own origin and evolution, since they have great chemical diversity, biochemical specificity, and pharmacological properties. Currently, there is a renewed interest in the development of methodologies capable of efficiently modifying the chemical structure of these bioactive platforms. In this work, the photoderivatization of the diterpene solidagenone was performed using a complexity-to-diversity-oriented approach. By exploring [2+2]-photocycloaddition, photoinduced-hydrogen abstraction, and photoxygenation reactions, a set of solidagenone derivatives was obtained, showing different ring fusions, side chain rearrangements, and modifications of the original furan ring's substitution pattern. The derivatives obtained were characterised by NMR methodologies. To evaluate the structural diversity of the labdane-derived compounds, their physicochemical properties, structural similarity, and chemical space were analysed. These results suggest that photochemical reactions are a useful tool for performing ring distortion transformations, generating derivatives of natural compounds with wide diversity, structural complexity, and with potential biological properties.

Bespoke Tailoring of Graphenoid Sheets: A Rippled Molecular Carbon Comprising Cyclically Fused Nonbenzenoid Rings.

The incorporation of nonbenzenoid rings into the hexagonal networks of graphenoid nanostructures is of immense importance for electronic, magnetic, and mechanical properties, but the underlying mechanisms of nonbenzenoid ring fusion are rather unexplored. Here, we report the synthesis and characterization of a rippled C84 molecular carbon, which contains 10 nonbenzenoid rings (five-, seven-, and eight-membered rings) that are contiguously fused to give a cyclic geometry. The fused nonbenzenoid rings impart high solubility, configurational stability, multiple reversible redox behaviors, unique aromaticity, and a narrow band gap to the system. Moreover, this carbon nanostructure allows for further functionalization via electrophilic substitution and metalation reactions, enabling access to finely tuned derivatives. Interestingly, both the bowl-shaped and planar conformations of the core in molecular carbon are observed in the solid state. Additionally, this molecular carbon displays ambipolar transport characteristics.

In-situ Raman spectroscopy study on coal pyrolysis and subsequent char low temperature oxidation and gasification

Thermal conversion is pivotal for clean and efficient coal utilization. Evolution of solid structure profoundly affects the gasification mechanism. However, in-situ study on coal structure evolution during gasification is limited. In this study, in-situ Raman spectroscopy was used to investigate the carbon structure evolution during thermal conversion. Results revealed two stages in coal pyrolysis: polycondensation and aromatic ring fusion. During polycondensation, numerous side chain groups break, while aromatic compounds condensed and rings fused in the aromatic ring fusion stage, increasing molecular size. In char gasification, larger particles required more time to achieve stable shrinkage, thus delaying coal char graphitization process. Low temperature oxidation led to decreased order due to oxygen-containing structure formation, evolving into a graphite-like structure as disordered carbon diminished. In addition, oxygen-containing groups acted as active oxidation sites. The insights into real-time structure evolution enhance understanding of the particle behavior during thermal conversion of coal.

Luminescent Chiral Furanol-PAHs via Straightforward Ni-Catalysed Csp2 -F Functionalization: Mechanistic Insights into the Scholl Reaction.

Here we report the stepwise synthesis of new nanographenes (NGs) and polycyclic aromatic hydrocarbons (PAHs) obtained via Scholl ring fusion applied at aromatic homologation compounds, which are obtained through one-step Ni-catalysed Csp2 -F functionalization. The latter are rapidly accessed valid precursors for the Scholl reaction, and screening of experimental conditions allowed us to describe for the first time furanol-bearing PAHs. Mechanistic insights are obtained by DFT to rationalize the formation of the furanol PAHs under moderately acidic conditions. All PAHs and NGs synthesized show moderate/weak fluorescent properties, and all PAHs crystallized show some degree of curvature and are obtained as racemic mixtures. Enantiomeric separation by chiral HPLC of one furanol-bearing PAH allowed the study of their chiroptical CD properties.

In silico investigations of high-energy density properties and effect of ring fusion on dinitropyrazole derivatives

In silico investigations of high-energy density properties and effect of ring fusion on dinitropyrazole derivatives

Multifaceted Effects of Ring Fusion in Charged Dialkoxyarene Redoxmers

Redox flow batteries (RFBs) hold promises for long-duration energy storage, with various chemistries demonstrated by academia and industry. However, their practical applications remain limited due to high active material cost, low energy density, narrow voltage window, and limited cyclability. Improving the performance of redox active materials (redoxmers) in RFBs is crucial for addressing these challenges. In this study, to better understand the impact of π-conjugation of aromatic redox cores on the redoxmers’ electrochemical behavior, we systematically investigated a series of dialkoxy benzene based redoxmers, including 1,4-dimethoxy benzene (DMB), 1,4-dimethoxynaphthalene (DMN), 2-ethyl-9,10-dimethoxyanthracene (EDMA). As the conjugation increases from DMB to DMN, we observed a lower redox potential, improved kinetic stability, and longer cycling life. However, further expanding the conjugation as in EDMA resulted in rapid O-dealkylation of the radical cation, possibly due to increased strain in methoxy groups. For DMN, the radical cation is observed to be prone to neutralization (likely via disproportionation) and can be recharged, suggesting a longer cycling life than the calendar life. Our study indicates that extending the π-system alters reactivity in multiple ways, and lowering the oxidation potential through π-conjugation to improve redoxmer stability should be cautiously pursued.

Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library.

The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.

An ECD and NMR/DP4+ Computational Pipeline for Structure Revision and Elucidation of Diphenazine-Based Natural Products.

Discovery and structure elucidation of natural products available in infinitesimally small quantities are recognized challenge. This challenge is epitomized by the diphenazine class of molecules that contain three bridged stereocenters, several conformations, ring fusions, and multiple spatially isolated phenols. Because empirical NMR and spatial analyses using ROESY/NOESY were unsuccessful in tackling these challenges, we developed a computational pipeline to determine the relative and absolute configurations and phenol positions of diphenazines as inhibitors of eukaryotic translation initiation factor 4E (eIF4E) protein-protein interactions. In this pipeline, we incorporated ECD and GIAO NMR calculations coupled with a DP4+ probability measure, enabling the structure revision of phenazinolin D (4), izumiphenazine A (5), and baraphenazine G (7) and the structure characterization of two new diphenazines, baraphenazine H (3) and izumiphenazine E (6). Importantly, through these efforts, we demonstrate the feasibility of NMR/DP4+ analysis for the determination of phenol positions in phenazine-based molecules, further expanding the limits of computational methods for the structure elucidation of complex natural products.

Palladium Catalyzed, Annulative Multiple C-H Bond Activations of BODIPYs to Access π-Extended Polycyclic Heteroaromatic Molecules with Deep Red Emissions and self-aggregation Behaviors.

Aromatic ring fusion on BODIPY core can effectively tune its electronic property, and red-shift the absorption and emission wavelength. In this work, we report that a one-pot Pd(II) catalyzed multiple C-H activation to access acenaphtho[b]-fused BODIPYs though the reaction of α,β-unsubstituted-BODIPYs and 1,8-dibromonaphthalenes. These newly synthesized acenaphtho[b]-fused BODIPYs revealed intensified deep red absorptions (639 - 669 nm) and emissions (643 - 683 nm), with high fluorescence quantum yields (0.53 - 0.84) in dichloromethane. Notably, these acenaphtho[b]-fused BODIPYs exhibited well-defined self-aggregation behavior in water/THF mixture, and for instance, the absorption of 3a was red-shifted by 53 to 693 nm after formingaggregates.

Vertical π-extension of dibenzopentalene: A combined experimental and computational study of a phenanthreno-benzopentalene derivative

The gold-catalyzed synthesis of an unsymmetrical phenanthreno-benzopentalene derivative is reported. The molecule is characterized experimentally by NMR spectroscopy, X-ray crystallography, UV–Vis spectroscopy and cyclic voltammetry. The experimental results are further confirmed by theoretical studies, including the calculation of aromaticity indices (NICS, ACID). The results show that vertical π-extension of dibenzo[a,e]pentalene through formal benzene ring fusions contributes to increased antiaromaticity relative to linear fusion of the same number of benzene rings. This further confirms that antiaromaticity within a polycyclic conjugated system could be efficiently tuned via the nature of the π-system that is fused to the antiaromatic subunit.

A Dualistic Arrangement of a Chiral [1]Rotaxane Based on the Assembly of Two Rings and Two Rods

We demonstrate the synthesis and chiroptical properties of doubled molecules of a chiral [1]rotaxane, based on the assembly of an achiral ring of a phenylacetylene macrocycle (6PAM) and a p-phenylene ethynylene rod. Two molecules of [1]rotaxane constituted the doubled molecule through the ring fusion of 6PAMs to a 10PAM, which assured stationary occupation relative to each optically active unit. The absorption properties of the 10PAM-based doubled molecule and 6PAM-based original unit were consistently characterized by the independent existence of m-phenylene ethynylene ring(s) and p-phenylene ethynylene rod(s). Thus, molar circular dichroism (CD) was directly compared between the doubled molecule (n = 2) and the original unit (n = 1) to show that molar CD was increased more than expected by an increase in the number of units, or by an increase in absorbance. Due to the invariance of the configuration and the relative occupation of two units arranged adjacent to each other in 10PAM, one more comparison was available with an isomeric molecule of two rings and two rods in a threaded-and-unthreaded form. The additional arrangement of an optically inactive unit in an unthreaded form also led to an increase in molar CD, compared to that of the original chiral unit in a threaded form.

Red Emissive Double Aza[7]helicenes with Antiaromaticity / Aromaticity Switching via the Redox‐Induced Radical Cation and Dication Species

AbstractWe herein present the synthetic approach to a new antiaromatic double aza[7]heliceneCthat features NN‐embedded polycyclic aromatic hydrocarbons (PAHs). This heteroatom‐doped helicene showed a rarely obtained long‐wavelength emission and far‐red circularly polarized luminescence (CPL) in the solid state. These optical and chiroptical properties could be ascribed to both the NN‐PAH core structure and the further extension through angular ring fusions. Such a unique electronic structure also culminated in facile chemical oxidations of neutralCto the positively charged chiral radical (C⋅+) and dication species (C2+). Interestingly, DFT computations revealed that the pyridazine central core showed an antiaromaticity‐to‐aromaticity switching, in contrast to the inversed transition for the helical periphery in cationic states. The reported approaches are anticipated to lead to the development of further redox‐active chiral systems for potential applications in chiroptoelectronics, spintronics as well as fluorescent bioimaging.

Somalactams A-D: Anti-inflammatory Macrolide Lactams with Unique Ring Systems from an Arctic Actinomycete Strain.

Four new PKS-NRPS-derived macrolide lactams with three unique ring fusion types were discovered from the Arctic sponge associated actinomycete Streptomyces somaliensis 1107 using a genome mining strategy. Their structures were elucidated by a combination of MS, NMR spectroscopic analysis, and single-crystal X-ray diffraction. Biosynthetically, a novel gene cluster sml consisting of three polyketide synthases and one hybrid polyketide synthase-nonribosomal peptide synthetase together with cytochrome P450s and flavin-containing monooxygenases and oxidoreductases was demonstrated to assemble the unique skeleton. Pharmacological studies revealed that compound 1 displayed a potent anti-inflammatory effect without cytotoxicity. It inhibited IL-6 and TNF-α release in the serum of LPS-stimulated RAW264.7 macrophage cells with IC50 values of 5.76 and 0.18 μM, respectively, and modulated the MAPK pathway. Moreover, compound 1 alleviated LPS-induced systemic inflammation in our transgenic fluorescent zebrafish model.