Ring System Research Articles

Gold-Catalyzed Oxidative Rearrangement Strategy to Yield 2-Hydroxycyclohepta-1,3-diene-1-carbonyl Compounds.

A gold-catalyzed oxidative rearrangement of propargyl alcohols, derived from commercially available cyclohex-2-en-1-ones and alkynes, was successfully developed for the efficient synthesis of seven-membered rings. Thorough investigations were conducted to optimize the reaction conditions and evaluate its compatibility with various functional groups. Additionally, this methodology was applied to the formal total synthesis of guanacastepene A, demonstrating its practical utility in complex natural product synthesis. This versatile and efficient approach opens up new possibilities for the construction of diverse seven-membered ring systems, providing valuable building blocks for further exploration in drug discovery and the synthesis of intricate molecules.

Dearomative Intramolecular meta-Thermocycloadditions of Benzene Rings via Wheland Intermediates.

Dearomative cycloadditions are powerful synthetic transformations utilizing aromatic compounds for cycloaddition reactions. They have been extensively applied to the synthesis of biologically relevant compounds not only because of the complexity generated from simplicity but also the atom- and step-economy. For the most studied yet challenging benzene ring systems, ortho- and para-cycloadditions have been realized both photochemically and thermally, while the meta-cycloadditions are still limited to the photochemical processes tracing back to the 1960s. Herein, we for the first time realized the thermal cycloadditions of benzene rings with alkenes in a meta fashion via Wheland intermediates. A broad spectrum of readily available C(sp2)-rich aniline-tethered enynes were transformed into C(sp3)-rich 3D complex polycyclic architectures simply by stirring in TFA. Moreover, the reaction could be performed in gram-scales and the products could be diversely elaborated.

One-pot Synthesis of Condensed Azepines

Abstract: Azepine is a privileged nitrogen-containing ring that has been found to display a wide range of biological activities. Azepine is a valuable skeleton in designing novel compounds in medicinal chemistry due to its interesting chemical and biological properties. The study on the synthesis of this ring system engenders a fascinating area of research owing to its potential to form an active pharmacophore for De Novo exploration. In this study, conventional and domino results were compared to access the diverse set of azepines in high yield. The domino approach has revolutionized the way through which the previously impossible yet significant transformations could be conceptualized, allowing the construction of difficult materials in one step. The aim of the present mini-review is to highlight the importance of the one-pot domino reaction for the synthesis of condensed azepines. This review also presents research on this subject from the past two decades.

The crystal structures and Hirshfeld surface analysis of three new bromo-substituted 3-methyl-1-(phenylsulfonyl)-1H-indole derivatives

Three new 1H-indole derivatives, namely, 2-(bromomethyl)-3-methyl-1-(phenylsulfonyl)-1H-indole, C16H14BrNO2S, (I), 2-[(E)-2-(2-bromo-5-methoxyphenyl)ethenyl]-3-methyl-1-(phenylsulfonyl)-1H-indole, C24H20BrNO3S, (II), and 2-[(E)-2-(2-bromophenyl)ethenyl]-3-methyl-1-(phenylsulfonyl)-1H-indole, C23H18BrNO2S, (III), exhibit nearly orthogonal orientations of their indole ring systems and sulfonyl-bound phenyl rings. Such conformations are favourable for intermolecular bonding involving sets of slipped π–π interactions between the indole systems and mutual C—H...π hydrogen bonds, with the generation of two-dimensional monoperiodic patterns. The latter are found in all three structures, in the form of supramolecular columns with every pair of successive molecules related by inversion. The crystal packing of the compounds is additionally stabilized by weaker slipped π–π interactions between the outer phenyl rings (in II and III) and by weak C—H...O, C—H...Br and C—H...π hydrogen bonds. The structural significance of the different kinds of interactions agree with the results of a Hirshfeld surface analysis and the calculated interaction energies. In particular, the largest interaction energies (up to −60.8 kJ mol−1) are associated with pairing of antiparallel indole systems, while the energetics of weak hydrogen bonds and phenyl π–π interactions are comparable and account for 13–34 kJ mol−1.

Toward the Briarane Core via 1,3-Dipolar Cycloaddition.

The complete C20 framework of brianthein W was established, featuring hydroboration/allylation, to provide the C1-C2 quaternary/tertiary stereoarray with excellent stereocontrol. Intramolecular nitrile oxide cycloaddition (INOC) was adopted as the key transformation to establish the trans-fused 6/10-bicyclic ring system. Evolution of the second INOC event revealed the intricacies governing regioselectivity, which ultimately led to construction of the highly strained 10-membered carbocycle.

Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure-Activity Relationships.

Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.

Gravitational disturbance on asteroidal ring systems by close encounter with a small object

To date, rings are found around a Centaur (10199) Chariklo, trans-neptunian objects (TNOs) (136108) Haumea, and (50000) Quaoar. These discoveries suggest that asteroidal ring systems may be common, particularly in the outer solar system. Since collisions are a ubiquitous and fundamental evolutionary process throughout the solar system, we conjecture that asteroidal ring systems must have experienced close encounters with small objects as part of their evolutionary process. Here, we investigate the response of ring systems when they experience gravitational disturbance by a close encounter with another small object, by calculating the change in eccentricity and the fraction of lost ring particles. We find that a perturber needs to be as massive as or more massive than the ringed object, and needs to pass in the immediate vicinity of the ring in order to cause significant disruption. The change in eccentricity expected for Chariklo's inner ring and Quaoar's outer ring agrees with the analytical expression derived from the impulse approximation, while that for Haumea's ring agrees with the analytical expression called “exponential regime”. If we define a lifetime of a ring as the mean time to experience disruptive close encounters that can raise the eccentricity of ring particles >0.1, the lifetime for ring systems around Chariklo, Haumea, and Quaoar are >104 Gyr. We conclude that ring systems around Chariklo, Haumea, and Quaoar are highly unlikely to suffer from close encounters with another small object even if those systems are as old as 4 Gyr. Close encounter with a small object may not be responsible for the finite eccentricity observed for Chariklo's ring system, although eccentricity of ring particles could be increased to ∼10−4 in 4 Gyr. We also find that the lifetime is shorter for smaller ringed objects, and it still exceeds 4 Gyr for km-sized ringed objects in the outer solar system. Therefore, regardless of the size of ringed objects, asteroidal ring systems in the outer solar system are unlikely to suffer severe damage by close encounter with a small object. On the other hand, the lifetime is estimated to be on the order of 100 Myr for km-sized asteroids and 10 Myr for 100 m-sized asteroids in the near-Earth region and the main belt. This finding offers a dynamical explanation why ring systems have not been found in the inner solar system.

A self-consistent model for dust settling and the vertical shear instability in protoplanetary disks

Abstract The spatial distribution of dust particles in protoplanetary disks affects dust evolution and planetesimal formation processes. The vertical shear instability (VSI) is one of the candidate hydrodynamic mechanisms that can generate turbulence in the outer disk region and affect dust diffusion. Turbulence driven by the VSI has a predominant vertical motion that can prevent dust settling. On the other hand, the dust distribution controls the spatial distribution of the gas cooling rate, thereby affecting the strength of VSI-driven turbulence. Here, we present a semi-analytic model that determines the vertical dust distribution and the strength of VSI-driven turbulence in a self-consistent manner. The model uses an empirical formula for the vertical diffusion coefficient in VSI-driven turbulence obtained from our recent hydrodynamical simulations. The formula returns the vertical diffusion coefficient as a function of the vertical profile of the cooling rate, which is determined by the vertical dust distribution. We use this model to search for an equilibrium vertical dust profile where settling balances with turbulent diffusion for a given maximum grain size. We find that if the grains are sufficiently small, there exists a stable equilibrium dust distribution where VSI-driven turbulence is sustained at a level of αz ∼ 10−3, where αz is the dimensionless vertical diffusion coefficient. However, as the maximum grain size increases, the equilibrium solution vanishes because the VSI can no longer stop the settling of the grains. This runaway settling may explain highly settled dust rings found in the outer part of some protoplanetary disks.

Harzianolides B–G: Undescribed Butenolides isolated from the fungus Trichoderma harzianum ZN-4

Five undescribed γ-butyrolactones harzianolides BF (1–5), one precursor harzianolide G (6) along with two known analogues, were isolated and identified from the EtOAc extract of the liquid fermentation of Trichoderma harzianum ZN-4, which was obtained from the sediment of Zhoushan coastal area. Notably, compound 1 featured an unusual carbon skeleton with methylene-bridged furan rings system. Their structures were determined by detailed interpretation of NMR and mass spectroscopic data, and the absolute configurations were unambiguously established based on ECD quantum chemical calculations. In bioassay, 1 and 7 showed inhibitory activity against Pestalotiopsis theae, with MIC values of 25 and 50 μg/mL, respectively.

Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the β-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

Phospholanes via Twofold C‐H‐Addition to Phospholes

AbstractA synthetic route towards phospholanes via twofold C−H‐addition of a DMSO molecule to β‐H substituted phospholes is described. The resulting fused phospholane oxothiolane system in case of symmetric α‐substitution possesses four stereogenic centers or rather six in case of asymmetric α‐substitution. The reaction conditions are shown to be applicable for a variety of phospholes with different P‐ or α‐substituents always leading to stereoselective formation of the fused heterocyclic ring system. All phospholane derivatives with one exception are sufficiently air stable for purification with column chromatography and are fully characterized by NMR and elemental analysis and mass spectrometry. With the help of X‐ray crystallography, the different configurations of the isomers could be demonstrated. For one model system derivatization reactions are presented. When oxidizing or reducing the sulfoxide group only a single diastereomer is observed.

Synthetic study of leptosperol A

Leptosperol A, isolated from the leaves of L. scoparium in 2020 together with leptosperol B, possesses a unique 1-benzyl-2-(2-phenylethyl) cyclodecane framework. A synthetic study of leptosperol A was performed based on a retrosynthetic analysis that indicated that leptosperols A and B could be synthesized efficiently via a common intermediate. Our study showed that unexpected transannular reactions easily occurred to give bicyclo [4.4.0] ring systems instead of the desired cyclodecane ring with a diene moiety. The results communicated here offers useful information to organic chemists involved in medium-sized ring systems.

Patumantanes A-D, seco-Polycyclic Polyprenylated Acylphloroglucinols with Diverse Carbon Skeletons from Hypericum patulum.

Patumantanes A-D (1-4), four new seco-polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from Hypericum patulum. Patumantane A (1) was an unprecedented 1,2-seco-homoadamantane-type PPAP bearing a new 3,7-dioxatetracyclo[7.7.0.01,6.111,15]heptadecane architecture based on a 6/7/5/6 ring system. Patumantane B (2) was a unique 1,9-seco-adamantane-type PPAP with a tricyclo[4.4.4.0.02,12]tridecane core formed by a 6/6/6 carbon skeleton, and the further breakage between C-5 and C-9 decorated patumantane C (3) with the 9-nor-adamantane skeleton. More importantly, compounds 2 and 3 exhibited moderate immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC50 values of 5.6 ± 1.2 and 11.2 ± 1.2 μM, respectively.

Emerindanols A and B: Two Bipolyhydroindenol Sesterterpenes with 5/6-6/5 Coupled Ring System Discovered by Genome Mining.

Genome mining of Emericella sp. XL-029 achieved a new type E sesterterpene synthase, EmES, which affored a novel bipolyhydroindenol sesterterpene, emerindanol A. Heterologous coexpression with the upstream P450 oxidase revealed C-4 hydroxylated product, emerindanol B. Notably, emerindanols A and B represented the first sesterterpenes featuring a unique 5/6-6/5 coupled ring system. EmES was postulated to initiate through C1-IV-V pathway and convert the fused ring intermediate into the final coupled ring product through a spiro skeleton.

Chemistry across dust and gas gaps in protoplanetary disks. Modelling the co-spatial molecular rings in the HD 100546 disk

Nearby extended protoplanetary disks are commonly marked by prominent rings in dust emission, possibly carved by forming planets. High-resolution observations show that both the dust and the gas are structured. These molecular structures may be related to radial and azimuthal density variations in the disk and/or the disk chemistry. The aim of this work is to identify the expected location and intensity of rings seen in molecular line emission in gapped disks while exploring a range of physical conditions across the gap. In particular, we aim to model the molecular rings that are, in contrast with most other gapped disks, co-spatial with the dust rings at sim 20 and sim 200 au in the HD 100546 disk using the thermochemical code DALI. We modelled observations with the Atacama Large Millimeter/submillimeter Array (ALMA) of CO isotopologues C I HCN, CN C2H NO, and HCO+ in the HD 100546 disk. An axisymmetric 3D thermochemical model reproducing the radial profiles of the CO isotopologue observations and the double ring seen in continuum emission was used to make predictions for various emission lines. The effect of the amount of gas in the dust gap, the C/O ratio, an attenuated background UV radiation field, and the flaring index on the radial distribution of different molecules were investigated. The fiducial model of a gapped disk with a gas cavity at $0-15$ au, a dust cavity at $0-20$ au, and a gas and dust gap at $40-175$ au provides a good fit to the continuum and the CO isotopologues in the HD 100546 disk. In particular, the CO isotopologue emission is consistent with a shallow gas gap with no more than a factor of approximately ten drop in gas density at $40-175$ au. Similar to the CO isotopologues, the HCN and HCO+ model predictions reproduce the data within a factor of a few in most disk regions. However, the predictions for the other atom and molecules C I CN C2H and NO, neither match the intensity nor the morphology of the observations. An exploration of the parameter space shows that, in general, the molecular emission rings are only co-spatial with the dust rings if the gas gap between the dust rings is depleted by at least four orders of magnitude in gas or if the C/O ratio of the gas varies as a function of radius. For shallower gaps the decrease in the UV field roughly balances the effect of a higher gas density for UV tracers such as CN C2H and NO. Therefore, the CN C2H and NO radicals are not good tracers of the gas gap depth. In the outer regions of the disk around 300 au, these UV tracers are also sensitive to the background UV field incident on the disk. Reducing the background UV field by a factor of ten removes the extended emission and outer ring seen in CN and C2H respectively, and reduces the ring seen in NO at 300 au. The C/O ratio primarily effects the intensity of the lines without changing the morphology much. The C I HCN, CN, and C2H emission all increase with increasing C/O, whereas the NO emission shows a more complex dependence on the C/O ratio depending on the disk radius. CO isotopologues and HCO+ emission trace gas gaps and gas gap depths in disks. The molecular rings in HCN, CN C2H and NO predicted by thermochemical models do not naturally coincide with those seen in the dust, contrary to what is observed in the HD 100546 disk. This could be indicative of a radially varying C/O ratio in the HD 100546 disk with a C/O above one in a narrow region across the dust rings, together with a shallow gas gap that is depleted by a factor of approximately ten in gas, and a reduced background UV field. The increase in the C/O ratio to approximately greater than one could point to the destruction of some of the CO, the liberation of carbon from ice and grains, or, in the case of the outer ring, it could point to second generation gas originating from the icy dust grains.

Rapid access to divergent fused polycycles via one-pot A3 coupling and intramolecular Diels-Alder reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Primordial dust rings, hidden dust mass, and the first generation of planetesimals in gravitationally unstable protoplanetary disks

We study a new mechanism of dust accumulation and planetesimal formation in a gravitationally unstable disk with suppressed magnetorotational instability and we compare it with the classical dead zone in a layered disk model. We used numerical hydrodynamics simulations in the thin-disk limit ( FEOSAD code) to model the formation and long-term evolution of gravitationally unstable disks, including dust dynamics and growth. We found that in gravitationally unstable disks with a radially varying strength of gravitational instability (GI), an inner region (of several astronomical units) of low mass and angular momentum transport is formed. This region is characterized by a low effective value for the $ GI $ parameter, often used to describe the efficiency of mass transport by GI in young protoplanetary disks. The inner region is also similar in terms of characteristics to the dead zone in the layered disk model. As the disk forms and evolves, the GI-induced dead zone accumulates a massive dust ring, which is susceptible to the development of the streaming instability. The model and observationally inferred dust masses and radii may differ significantly in gravitationally unstable disks with massive inner dust rings. The early occurrence of the GI-induced dust ring, followed by the development of the streaming instability suggest that this mechanism may be behind the formation of the first generation of planetesimals in the inner terrestrial zone of the disk. The proposed mechanism, however, crucially depends on the susceptibility of the disk to gravitational instability and requires the magnetorotational instability to be suppressed.

N-Oxide-to-Carbon Transmutations of Azaarene N-Oxides.

Reactions that change the identity of an atom within a ring system are emerging as valuable tools for the site-selective editing of molecular structures. Herein, we describe the expansion of an underdeveloped transformation that directly converts azaarene-derived N-oxides to all-carbon arenes. This ring transmutation exhibits good functional group tolerance and replaces the N-oxide moiety with either unsubstituted, substituted, or isotopically labeled carbon atoms in a single laboratory operation.

Piston ring and cylinder liner scuffing analysis in dual-fuel low-speed engines considering liner deformation and tribofilm evolution

The piston ring and cylinder liner (PRCL) system in larger-bore low-speed marine engines frequently experiences scuffing failures, which significantly decrease the engine reliability. To understand this failure mechanism, a scuffing failure model subjected to the PRCL system was developed considering multidisciplinary coupling effects that integrate asperity contact, hydrodynamic lubrication, tribochemistry reactions, thermal effects, friction, and surface wear. The impacts of large-scale deformation and gas-combustion mode on the scuffing performances of the PRCL system were examined. The key findings indicate that the larger-scale liner deformation can markedly reduce oil film thickness and exacerbate local asperity contact, influencing the evolution of the tribofilm by increasing the removal process. Under gas-combustion mode, the oil film thickness is even lower, and the asperity contact pressure further increases due to a more starved lubrication state and higher combustion temperature. This leads to tribofilm breakdown and severe wear near the ring opening area, which are aligning with the full-scale experimental results with scuffing failure.

Synthesis and Biological Properties of Fluorescent Strigolactone Mimics Derived from 1,8-Naphthalimide.

Strigolactones (SLs) have potential to be used in sustainable agriculture to mitigate various stresses that plants have to deal with. The natural SLs, as well as the synthetic analogs, are difficult to obtain in sufficient amounts for practical applications. At the same time, fluorescent SLs would be useful for the mechanistic understanding of their effects based on bio-imaging or spectroscopic techniques. In this study, new fluorescent SL mimics containing a substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive furan-2-one moiety were prepared. The structural, spectroscopic, and biological activity of the new SL mimics on phytopathogens were investigated and compared with previously synthetized fluorescent SL mimics. The chemical group at the C-6 position of the naphthalimide ring influences the fluorescence parameters. All SL mimics showed effects similar to GR24 on phytopathogens, indicating their suitability for practical applications. The pattern of the biological activity depended on the fungal species, SL mimic and concentration, and hyphal order. This dependence is probably related to the specificity of each fungal receptor-SL mimic interaction, which will have to be analyzed in-depth. Based on the biological properties and spectroscopic particularities, one SL mimic could be a good candidate for microscopic and spectroscopic investigations.