Ring System Research Articles

Modern Cyclopropanation via Non‐Traditional Building Blocks

AbstractSmall, strained carbocyclic systems have fascinated organic chemists from both a theoretical and synthetic standpoint. These systems often challenge conventional wisdom when it comes to molecular structure and tactics for chemical construction. The cyclopropyl motif is one such ring system that remains at the forefront of method development in the modern era. With the advent of an array of non‐traditional building blocks, a range of new cyclopropanation processes using one‐ and two‐electron strategies have been developed that not only overcome the synthetic shortcomings of classical approaches but also provide entry into a wide range of new classes of cyclopropanes. This review discusses recent advances in this area with an emphasis on their mechanistic underpinnings and potential applications. Additionally, a concise overview of the properties of and traditional approaches to cyclopropanes is provided.

Asymmetric Tandem Michael Addition/Interrupted Nef Reactions of Nitromethane with Oxindole-Derived Alkenes: Enantioselective Synthesis of Spiro-polycyclic Oxindoles.

Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 μM) and HT29 (IC50 = 15.46 μM) cell lines.

Novel Pyridyl Macrocyclic Triarylmethanes: Synthesis by Ring-closing Metathesis and Chemical Analysis

Background:: Nowadays, macrocyclic compounds constitute a privileged source for the development of compounds with interesting biological properties. Ring-closing olefin me-tathesis has received great attention for the synthesis of small, medium, and larger ring systems. Methods:: In the present work, we described the synthesis of eight original pyridyl macrocyclic triarylmethanes using an efficient 3-step synthetic strategy. The bisalkylated 4,4'-(pyridin-X-ylmethylene) diphenols (X=2-4) were prepared by ring-closing metathesis as macrocyclization key step, using Grubbs second generation catalyst. Results:: The pyridyl macrocyclic triarylmethanes were obtained with moderate to good yields. The introduction of a pyridine N-oxide moiety before the macrocyclization proved to be interest-ing to afford a higher yield of the corresponding metathesis product. FT-IR, 1 H NMR, 13C NMR, and X-ray diffraction analysis have been used for the characterization of the synthesized compounds. Conclusion:: The synthetic strategy used here proposes an efficient alternative to prepare macro-cyclic triarylmethanes of different sizes.

Skeletal Transformations of Terpenoid Forskolin Employing an Oxidative Rearrangement Strategy.

The skeletal transformations of diterpenoid forskolin were achieved by employing an oxidative rearrangement strategy. A library of 36 forskolin analogues with structural diversity was effectively generated. Computational analysis shows that 12 CTD compounds with unique scaffolds and ring systems were produced during the course of this work.

Chaetoxylariones A–G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A–G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8–12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7′ and C-10′; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 μM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

Ergosterols with rare peroxide, oxetane ring moiety, and a lactone ring from Aspergillus spectabilis and their immunosuppressive activities

Ten ergostane-type steroids, including seven undescribed ones named spectasteroids A–G, were obtained from Aspergillus spectabilis. Their structures and absolute configurations were determined based on HRESIMS, NMR, ECD calculations, and single-crystal X-ray diffraction analyses. Structurally, spectasteroid A was a unique example of aromatic ergostane-type steroid that featured a rare peroxide ring moiety; spectasteroid B contained a rare oxetane ring system formed between C-9 and C-14; and spectasteroid C was an unusual 3,4-seco-ergostane steroid with an extra lactone ring between C-3 and C-9. Spectasteroids F and G specifically showed inhibitory effects against concanavalin A-induced T lymphocyte proliferation and lipopolysaccharide-induced B lymphocyte proliferation, with IC50 values ranging from 2.33 to 4.22 μM. Spectasteroid F also showed excellent antimultidrug resistance activity, which remarkable enhanced the inhibitory activity of PTX on the colony formation of SW620/Ad300 cells.

Growth and evolution of low-mass planets in pressure bumps

Observations of protoplanetary disks have revealed dust rings that are likely due to the presence of pressure bumps in the disk. Because these structures tend to trap drifting pebbles, it has been proposed that pressure bumps may play an important role in the planet formation process. In this paper, we investigate the orbital evolution of a 0.1 M⊕ protoplanet embedded in a pressure bump using 2D hydrodynamical simulations of protoplanetary disks consisting of gas and pebbles. We examine the role of thermal forces generated by the pebble accretion-induced heat release, taking into account the feedback between the luminosity and the eccentricity. We also study the effect of the pebble-scattered flow on the planet’s orbital evolution. Due to the accumulation of pebbles at the pressure bump, the planet’s accretion luminosity is high enough to induce significant eccentricity growth through thermal forces. Accretion luminosity is also responsible for vortex formation at the planet’s position through baroclinic effects, which cause the planet to escape from the dust ring if dust feedback on the gas is neglected. Including the effect of the dust feedback leads to weaker vortices, which enable the planet to remain close to the pressure maximum on an eccentric orbit. Simulations in which the planet mass is allowed to increase as a consequence of pebble accretion result in the formation of giant planet cores with masses in the range of 5–20 M⊕ over ~2 × 104 yr. This occurs for moderate values of the Stokes number, St ≈ 0.01, such that the pebble drift velocity is not too high and the dust ring mass not too small. Our results suggest that pressure bumps mays be preferred locations for the formation of giant planets, but this requires a moderate level of grain growth within the disk.

Hymoins A–C, three unusual polycyclic polyprenylated acylphloroglucinols with lipid-lowering activity from Hypericum monogynum

Hymoins A–C (1–3), three unusual polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from the flowers of Hypericum monogynum. Hymoin A features the first intriguing 6/5/5/5/7 pentacyclic caged PPAP. Hymoin B is characterized by an unprecedented rearranged 5/6/8 tricyclic ring system, while hymoin C represents the first rearranged PPAP with a fantastic spirocyclic 5/6/7 ring system. Their structures were established by extensive spectroscopic analysis, X-ray crystallography, and computational methods. The plausible biosynthetic routes for the compounds were also proposed. In oleic acid (OA)-induced HepG2 cells, all compounds exhibited significant lipid-lowering activity at the concentrations of 2–8 μmol/L. Further mechanistic study implied that compound 1 exhibited excellent lipid-lowering activity in OA-induced HepG2 cells through inhibiting the proteins of free fatty acids synthesis and improving lipidolysis.

An Unexpected Lewis Acid-Catalyzed Cascade during the Synthesis of the DEF-Benzoxocin Ring System of Nogalamycin and Menogaril: Mechanistic Elucidation by Intermediate Trapping Experiments and Density Functional Theory Studies.

An unexpected Lewis acid-catalyzed carbohydrate rearrangement of a 1,5-bis-glycopyranoside to the product of a formal intramolecular C-aryl glycosylation reaction is reported. Mechanistic studies based mainly on intermediate trapping experiments and density functional theory (DFT) calculations reveal a cascade process involving three transient (a)cyclic oxocarbenium cations, the breaking of three single C(sp3)-O bonds, and the formation of three single bonds (i.e., exo-, endo-, and C-glycosidic bonds), leading to the 2,6-epoxybenzoxocine skeleton of bioactive natural glycoconjugates related to serjanione A and mimocaesalpin E. DFT calculations established that the generation of the pyran moiety embedded in the bridged benzoxocin ring system is likely to proceed through an unusual ring-closure of an ortho-quinone methide intermediate in which the attacking nucleophile is a carbonyl oxygen.

Interaction of natural and architectural landscapes using the example of a city Kharkiv

The article traces the development of the architectural landscape of the city of Kharkov from the moment of the foundation of the Kharkov Fort to the present day. The research shows the main stages: the rise of the fortress of Kharkov (since 1654), the status of a province (since 1787), the development of Kharkov as a cultural and educational center (since 1804), the first World War and revolution (since 1917), second World War and military renewal (from 1941), the creation of Ukraine's Independence (since 1991), a daily war (since 2022). At the skin stage, the infusion of the natural landscape and relief features into the creation and development of the place can be observed. We drew a parallel with the historical concepts and developments of the city, considered the interaction of the architectural landscape with natural transitions, observed connections between compositional dominants and relief differences, so it was search of the spacious accents of the city. According to the research, a spatial model of the city of Kharkov was formulated. The historical center which is the compositional core of the spatial framework is strengthened by dominants. It has a radial ring system of streets perpendicular to the riverbeds. The center of Kharkov is connected with the periphery by compositional and functional axes - the main highways. Active peripheral development enhances the elevations of the relief; buildings in the lowlands is predominantly featureless. Relief features of the landscape, such as embankments and parks, are points of attraction for people what playing an important role in shaping the architectural landscape of the city. So, we formulate opinion about the geological and geographical aspect of the architectural landscape of the Kharkov, determine the look at the further development of the architectural landscape of the apparently natural, and emphasize respect of the importance of using relief features in the city.

Effects of various pyrolysis temperatures on the physicochemical characteristics of crop straw-derived biochars and their application in tar reforming

As a by-product of the rapid pyrolysis of biomass, biochar not only plays an important role in the biomass conversion process but also holds significant potential value in the catalytic conversion field. This study aimed to evaluate the physicochemical properties changes of biochars at different pyrolysis temperatures and their potential application in tar reforming. Biochars derived from three feedstocks of maize straw (MS), rice husk (RH), and cotton straw (CS) were achieved by fast pyrolysis within a broad temperature range of 300–900 °C, respectively. The results showed that the pyrolysis temperature exerted a pronounced influence on the structural characteristics of biochar. With increasing temperature, the H/C and O/C ratios progressively decreased, accompanied by a significant reduction in oxygen-containing structures. In addition, elevated pyrolysis temperatures contributed favorably to the formation of the crystalline structure of biochar. Raman analysis unveiled a correlation between the fused aromatic ring system and H/C ratios, validating the aromatization progress of biochar. In the tar catalytic reforming process, the three representative biochars, under the effect of MS-600 (standing for MS biochar derived at 600 °C), RH-600, and CS-600 catalysts, exhibited outstanding catalytic performance with tar conversion efficiencies of 73.26%, 68.51%, and 71.43%, respectively. This study provided systematic support for the high-value use of biochar from crop straw.

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

Crystal structure and Hirshfeld surface analysis of 6-imino-8-(4-methyl-phen-yl)-1,3,4,6-tetra-hydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbo-nitrile.

In the ten-membered 1,3,4,6-tetra-hydro-2H-pyrido[1,2-a]pyrimidine ring system of the title compound, C17H15N5, the 1,2-di-hydro-pyridine ring is essentially planar (r.m.s. deviation = 0.001 Å), while the 1,3-diazinane ring has a distorted twist-boat conformation. In the crystal, mol-ecules are linked by N-H⋯N and C-H⋯N hydrogen bonds, forming a three-dimensional network. In addition, C-H⋯π inter-actions form layers parallel to the (100) plane. Thus, crystal-structure cohesion is ensured. According to a Hirshfeld surface study, H⋯H (40.4%), N⋯H/H⋯N (28.6%) and C⋯H/H⋯C (24.1%) inter-actions are the most important contributors to the crystal packing.

Some pyrroles as inhibitors of the pentose phosphate pathways enzymes: An in vitro and molecular docking study.

Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) are pentose phosphate pathway enzymes. Compounds with a heterocyclic pyrrole ring system containing this atom can be derivatized with various functional groups into highly effective bioactive agents. In this study, pyrrole derivatives on these enzyme's activity were investigated. The IC50 values of different concentrations of pyrrole derivatives for G6PD were found in the range of 0.022-0.221 mM Ki values 0.021 ± 0.003-0.177 ± 0.021 and for 6PGD IC50 values 0.020-0.147, mM Ki values 0.013 ± 0.002-0.113 ± 0.030 mM. The 2-acetyl-1-methylpyrrole (1g) showed the best inhibition value for G6PD and 6PGD enzymes. In addition, in silico molecular docking experiments were performed to elucidate how these pyrrole derivatives (1a-g) interact with the binding sites of the target enzymes. The study's findings on pyrrole derivatives could be used to create innovative therapeutics that could be a treatment for many diseases, especially cancer manifestations.

Expanding catalytic promiscuity of a bifunctional terpene synthase through a single mutation-induced change in hydrogen-bond network within the catalytic pocket

Fungal bifunctional terpene synthases (BFTSs) catalyze the formation of numerous di-/sester-/tri-terpenes skeletons. However, the mechanism in controlling the cyclization pattern of terpene scaffolds is rarely deciphered for further application of tuning the catalytic promiscuity of terpene synthases for expanding the chemical space. In this study, we expanded the catalytic promiscuity of Fusarium oxysporum fusoxypene synthase (FoFS) by a single mutation at L89, leading to the production of three new sesterterpenes. Further computational analysis revealed that the reconstitution of the hydrogen-bond (H-bond) network of second-shell residues around the active site of FoFS influences the orientation of the aromatic residue W69 within the first-shell catalytic pocket. Thus, the dynamic orientation of W69 alters the carbocation transport, leading to the production of diverse ring system skeletons. These findings enhance our knowledge on understanding the molecular mechanisms, which could be applied on protein engineering terpene synthases on regulating the terpene skeletons.

Construction of Seven-Membered Oxacycles Using a Rh(I)-Catalyzed Cascade C-C Formation/Cleavage of Cyclobutenol Derivatives.

Herein, we describe the synthesis of substituted oxepane derivatives through the skeletal remodeling of 4-hydroxy-2-cyclobutenones, which are readily prepared from commercially available dialkyl squarates upon their reaction with acrylonitrile. Mechanistically, a Rh(I)-catalyzed C-C bond formation and cleavage cascade is proposed. Specifically, a fused [3.2.0] bicycle is proposed to form from dialkyl squarate-derived cyclobutenols via an unusual Rh(I)-catalyzed intermolecular oxa-Michael addition of a tertiary alcohol with acrylonitrile, followed by an intramolecular conjugate addition/migratory insertion. Subsequent C(sp3)-C(sp3) bond cleavage through a Rh-catalyzed β-carbon elimination is then theorized to furnish the oxepane scaffold. Computational studies support the formation of an intermediate [3.2.0] bicycle but also point to an alternative pathway for the formation of the oxepane products involving a Rh(III) intermediate. Additional studies have shown the overall process to be stereoretentive. The functional groups that are introduced in this process can be leveraged to form fused or bridged ring systems.

Lycopodium Alkaloids from Huperzia goebelii.

One new fawcettimine-type Lycopodium alkaloid, hupertimine F (1), together with five known (2-6) Lycopodium alkaloids were isolated from Huperzia goebelii. The structure of 1 was elucidated by 1D and 2D NMR spectra, HRESIMS, and X-ray diffraction. Structurally, 1 represents the fourth example of Lycopodium alkaloids characterized by a 5/5/5/5/6 pentacyclic ring system with a 1-aza-7-oxabicyclo[2.2.1]heptane moiety. These known compounds 2, 3, 5, and 6 were isolated from H. goebelii for the first time. Compounds 1-6 were evaluated for acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B inhibitory activities in vitro.

Couple-close construction of polycyclic rings from diradicals.

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1-3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4-6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7-10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.

10-Bromo-N,N-di-phenyl-anthracen-9-amine.

In the title compound, C26H18BrN, the dihedral angles between the anthracene ring system and the phenyl rings are 89.51 (14) and 74.03 (15)°. In the extended structure, a weak C-H⋯Br inter-action occurs, which generates [100] chains, but no significant π-π or C-H⋯π inter-actions are observed.

A Review of Cyclic Imines in Shellfish: Worldwide Occurrence, Toxicity and Assessment of the Risk to Consumers.

Cyclic imines are a class of lipophilic shellfish toxins comprising gymnodimines, spirolides, pinnatoxins, portimines, pteriatoxins, prorocentrolides, spiro-prorocentrimine, symbiomines and kabirimine. They are structurally diverse, but all share an imine moiety as part of a bicyclic ring system. These compounds are produced by marine microalgal species and are characterized by the rapid death that they induce when injected into mice. Cyclic imines have been detected in a range of shellfish species collected from all over the world, which raises the question as to whether they present a food safety risk. The European Food Safety Authority (EFSA) considers them to be an emerging food safety issue, and in this review, the risk posed by these toxins to shellfish consumers is assessed by collating all available occurrence and toxicity data. Except for pinnatoxins, the risk posed to human health by the cyclic imines appears low, although this is based on only a limited dataset. For pinnatoxins, two different health-based guidance values have been proposed at which the concentration should not be exceeded in shellfish (268 and 23 µg PnTX/kg shellfish flesh), with the discrepancy caused by the application of different uncertainty factors. Pinnatoxins have been recorded globally in multiple shellfish species at concentrations of up to 54 times higher than the lower guidance figure. Despite this observation, pinnatoxins have not been associated with recorded human illness, so it appears that the lower guidance value may be conservative. However, there is insufficient data to generate a more robust guidance value, so additional occurrence data and toxicity information are needed.