Cyclic Skeleton Research Articles

Regioselective (diacetoxyiodo)benzene-promoted halocyclization of unfunctionalized olefins.

A metal-free method for intramolecular halocyclization of unfunctionalized olefins was detailed. (Diacetoxyiodo)benzene (PIDA) was very effective for haloamidation, haloetherification, and halolactonization of unfunctionalized olefins. In the presence of 1.1 equiv of PIDA and suitable halogen sources, a variety of unfunctionalized olefins could be converted to the corresponding 1,2-bifunctional cyclic skeletons in good to excellent isolated yields, and key intermediates for biologically interesting compounds could be obtained in high yields under mild conditions via nucleophilic substitution of the thus obtained halocyclization products.

Switchable stereocontrolled divergent synthesis induced by aza-Michael addition of deactivated primary amines under acid catalysis.

Switchable tandem intramolecular aza-Michael/Michael and double aza-Michael reactions allow the oriented synthesis of highly functionalised cyclic skeletons. Conjugate addition of deactivated anilines triggers chemo- and stereo-divergent ring-closure reaction pathways with a striking selectivity depending on reaction conditions.

Exploring the scaffold universe of kinase inhibitors.

The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic criteria into account. Scaffold coverage varied greatly across the kinome, and many scaffolds representing compounds with different activity profiles were identified. The majority of kinase inhibitor scaffolds were involved in well-defined yet distinct structural relationships, which had different consequences on compound activity. Scaffolds exclusively representing highly potent compounds were identified as well as structurally analogous scaffolds with very different degrees of promiscuity. Scaffold relationships presented herein suggest a variety of hypotheses for inhibitor design. Our detailed organization of the kinase inhibitor scaffold universe with respect to different activity and structural criteria, all scaffolds, and the original compound data assembled for our analysis are made freely available.

Palladium-Catalyzed Cyclization Reactions of Allenes in the Presence of Unsaturated Carbon–Carbon Bonds

Modern synthetic chemists have looked for rapid and efficient ways to construct complex molecules while minimizing synthetic manipulation and maximizing atom-economy. Over the last few decades, researchers have made considerable progress toward these goals by taking full advantage of transition metal catalysis and the diverse reactivities of allenes, functional groups which include two cumulative carbon-carbon double bonds. This Account describes our efforts toward the development of Pd-catalyzed cyclization reactions of allenes in the presence of compounds that contain unsaturated carbon-carbon bonds such as alkenyl halides, simple alkenes, allenes, electron-deficient alkynes, or propargylic carbonates. First, we discuss the coupling-cyclization reactions of allenes bearing a nucleophilic functionality in the presence of alkenyl halides, simple alkenes, functionalized and nonfunctionalized allenes, or electron-deficient alkynes. These processes generally involve a Pd(II)-catalyzed sequence: cyclic nucleopalladation, insertion or nucleopalladation, and β-elimination, reductive elimination, cyclic allylation or protonation. We then focus on Pd(0)-catalyzed cyclization reactions of allenes in the presence of propargylic carbonates. In these transformations, oxidative addition of propargylic carbonates with Pd(0) affords allenylpalladium(II) species, which then react with allenes via insertion or nucleopalladation. These transformations provide easy access to a variety of synthetically versatile monocyclic, dumbbell-type bicyclic, and fused multicyclic compounds. We have also prepared a series of highly enantioenriched products using an axial-to-central chirality transfer strategy. A range of allenes are now readily available, including optically active ones with central and/or axial chirality. Expansion of these reactions to include other types of functionalized allenes, such as allenyl thiols, allenyl hydroxyl amines, and other structures with differing steric and electronic character, could allow access to cyclic skeletons that previously were difficult to prepare. We anticipate that other studies will continue to explore this promising area of synthetic organic chemistry.

Synthesis, reaction, and optical properties of cyclic oligomers bearing 9,10-diphenylanthracene based on an aromatic tertiary amide unit

Novel cyclic aromatic amide oligomers containing highly fluorescent 9,10-diphenylanthracene units were prepared by condensation of a monomer with amino and ester functional groups using lithium bis(trimethylsilyl)amide. The cyclic trimer (C3A, 40%) and tetramer (C4A, 8%) were isolated using preparative gel permeation chromatography. Some of the aromatic proton signals derived from anthracene were observed in the upfield region (6.96–6.87 ppm) in the 1H nuclear magnetic resonance spectrum of C3A. X-ray crystallographic analysis indicated that three anthracene moieties are inclined with respect to the cyclic skeleton and partly overlap each other. The fluorescence peak maximum of C3A (438 nm) showed a small red-shift compared with that of an acyclic model compound (425 nm). Reduction of the amide carbonyl group in C3A gave the cyclic trimer HC3A, which has a tertiary amine unit. The fluorescence peak maximum of HC3A (489 nm) was largely red-shifted from that of C3A and exhibited strong solvent dependence. A linear correlation was observed between the Stokes shift (Δν), ranging from 2981 to 6646 cm−1, and the Reichardt's solvent polarity parameter [ET(30)].

Synthesis of a hexacationic cyclophane and formation of EDA-type host–guest complexes

A polycationic cyclophane with six cationic sites (three 4,4′-bipyridinium cation units) supported by a rigid cyclic skeleton was synthesized. It formed electron donor–acceptor complexes with electron-rich compounds, and their inclusion properties with pyrene and calixresorcin[4]arene were studied.

Three-Dimensional Solution Structure of Bottromycin A2: A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

The three-dimensional (3D) structure of bottromycin A(2), a natural anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococci (VRE) agent consisting of seven amino acids, has been investigated through NMR spectroscopy. On the basis of 57 experimental constraints, a total of 34 converged structures were obtained. The average pairwise atomic root mean square difference is 0.74±0.59 Å for all heavy atoms. The resulting structure indicates an interesting feature in that the three C-terminal residues of bottromycin A(2) fold back on the 12-membered cyclic skeleton made by the four N-terminal residues. Thus, MePro(2) and Thia-β-Ala-OMe(7), modification of which significantly affects the antibacterial activities of bottromycin A(2), are located on one side of its 3D structure. These distinct structural features might be important for the binding of bottromycin A(2) with the bacterial ribosome.

Lewis Acid Catalyzed Intramolecular [3+2] Cross‐Cycloaddition of Donor–Acceptor Cyclopropanes with Carbonyls: A General Strategy for the Construction of Acetal[n.2.1] Skeletons

Build a bridge: The first catalytic intramolecular [3+2] cycloaddition of monodonor-monoacceptor cyclopropanes (see scheme) provides a general and efficient strategy for construction of structurally diverse acetal[n.2.1] and 1,4-dioxygen-substituted cyclic skeletons, which are widely distributed in biologically important natural products.

ChemInform Abstract: Challenges to the Synthesis of Structurally Unique Cyclic Skeletons and Application to Biologically Intriguing Natural Product Synthesis

AbstractReview: ca. 100 refs.

Structurally-variable, rigid and optically-active D2 and D3 macrocycles possessing recognition properties towards C60

The reactivity of aromatic dicarboxylic acids, in combination with an axially-chiral, suitable dibenzylic alcohol, derived from BINOL, has been exploited in one-pot esterification reactions for the direct formation of several rigid, homochiral macrocycles. Cyclic adducts possessing, respectively, average molecular D(2) and D(3) symmetries, have been characterized in pure forms, with isolated yields and selectivities which are substantially different from those rising from purely statistical arguments. NMR and CD spectroscopies detect the structural and shape variability in the scaffolds, reflected both in terms of large changes in chemical shifts of selected proton resonances, and in terms of the variation of the CD signature related to the dihedral angle defined by the binaphthyl units embedded in the rigid cyclic skeleton. The crystal structure of two homochiral D(2) macrocycles show the formation of ordered nanostructures in the solid state, with the naphthyl rings of the binaphthyl units packing intermolecularly in an eclipsed-like conformation to yield nonhelical tubular arrangements. The larger D(3) cyclic adducts are able to afford stable complexes with C(60) in toluene solution, with comparable binding strengths, yet whose stoichiometries are dependent on small variations in the spacing units and therefore in the shapes of the internal cavities of the cyclic structures.

One-Pot, Template Syntheses of a New Class of Metallomacrocycles with a Tetraoxime Cyclic Skeleton

Most common macrocycles such as crown ethers, porphyrins, and macrocyclic polyamines show versatile, excellent functions in a variety of research fields such as coordination chemistry, supramolecular chemistry, analytical chemistry, and material sciences. Thus, the rational design of a new class of readily synthesized macrocyclic metal ligands is a key to the development of a new category of functionalized macrocyclic metal complexes. Herein, we report one-pot, template syntheses of a new class of metallomacrocycles with a 16-membered tetraoxime cyclic skeleton from a dioxime in the presence of a template transition-metal ion such as Fe(2+), Ni(2+), Cu(2+), Co(2+), or Ag(+). These metal ions can be easily removed from the mononuclear metallomacrocycles, and, for example, the metal-free tetraoxime ligand was obtained in 90% yield when Fe(2+) was used as the template. It would appear that this one-pot, metal-template cyclization efficiently proceeds through continual metal-mediated oxime exchange reactions. Interestingly, Pd(2+), which does not afford any cyclized products, formed a 1:1 complex with the macrocyclic ligand. The molecular structures of the metal-free ligand, its 1:1 metal complexes with Fe(2+), Ni(2+), Cu(2+), Pd(2+), and Ag(+), and a dinuclear complex with Ag(+) were fully determined by single-crystal X-ray analyses. UV-visible absorption spectra and cyclic voltammetry measurements of these complexes are also reported.

Anti-inflammatory Sesquiterpenoids from a Sponge-Derived Fungus Acremonium sp.

In the course of our search for bioactive metabolites from a sponge-derived fungus Acremonium sp., new sesquiterpenoids (1-4) were isolated along with known derivatives by bioactivity-guided fractionation. The unique cyclic skeleton of compounds 2 and 3 is unprecedented. The absolute configurations were determined by modified Mosher's method and CD spectroscopy, along with comparison of (1)H and (13)C NMR spectroscopic data and specific optical rotation values with those reported. The anti-inflammatory activity of the isolated compounds (1, 5, 7-13) was evaluated by measuring their inhibitory effects on the production of pro-inflammatory mediators (NO, IL-6, and TNF-alpha) in RAW 264.7 murine macrophage cells. Among the compounds tested, compounds 7 and 9 significantly inhibited the production of NO and TNF-alpha at the concentration of 100 microM, while compounds 11 and 12 showed selective inhibition of NO production at the same concentration.

The Molecular Target of Rubimaillin in the Inhibition of Lipid Droplet Accumulation in Macrophages

The naphthohydroquinone rubimaillin, which has an angular-type three cyclic skeleton and was isolated from the Chinese medical plant Rubia cordifola, was found to inhibit lipid droplet accumulation in mouse macrophages and to selectively inhibit cholesteryl ester synthesis (IC(50): 18 microM). The metabolism of cholesterol from lysosomes to lipid droplets was inhibited by the compound with a similar IC(50) (45 microM). Moreover, rubimaillin inhibited acyl-CoA:cholesterol acyltransferase (ACAT1) activity in ACAT1-expressing cells (IC(50): 80 microM). Thus, these data strongly suggest that rubimaillin inhibits macrophage ACAT activity in order to decrease cholesteryl ester (CE) synthesis, leading to a reduction in the number of lipid droplets. Furthermore, rubimaillin was found to inhibit the ACAT2 isozyme in ACAT2-expressing cells (IC(50): 22 microM). We concluded that rubimaillin is a dual inhibitor of ACAT1 and ACAT2, but is more selective for the ACAT2 isozyme.

Second‐harmonic generation from Langmuir–Blodgett film of cyclic peptide carrying two disperse red 1 on fused quartz surface

Cyclic octapeptide carrying one or two nonlinear optical chromophores, disperse red 1 (DR-1), was synthesized and immobilized on a substrate to attain an active surface for second-harmonic generation (SHG). Each cyclic octapeptide was transferred on a fused quartz substrate by the Langmuir-Blodgett (LB) method to afford a uniform monolayer. Infrared reflection-absorption spectroscopy of the LB monolayer revealed that the cyclic skeleton lay roughly flat on the surface. The SHG intensity from the monolayer of the cyclic peptide with two DR-1 units was stronger than that from that with one DR-1 unit. The difference is discussed in terms of molecular orientation and surface density of the active chromophores. The cyclic peptide is shown here to be an effective scaffold to modify a substrate surface with functional groups of a monolayer with taking stability of the monolayer and orientation of the functional group into consideration.

Effect of mono- and bicyclic monoterpenoids upon Dictyostelium minutum and Dictyostelium macrocephalum

We have studied the effect of four monoterpenes on the growth of two cellular slime molds, Dictyostelium minutum Raper and D. macrocephalum Hagiwara, Yeh et Chien. (4S)-(+)-carvone was the monocyclic monoterpene we tested, while (1S)-(-)-verbenone, (1R)-(-)-fenchone, and (1R,5R)-(+)-β-pinene were the bicyclic monoterpenes we employed. One μL of four different concentrations (0.006M, 0.06M, 0.6M and 6M) of each monoterpene were applied to both species, through the use of the Disk Volatilization Technique. (4S)-(+)-carvone possessed a superior inhibitory activity against both D. minutum and D. macrocephalum, at 0.6M concentration (p≤0.001), while growth rate enhancement occurred after application of (4S)-(+)-carvone at concentrations of 0.006M and 0.06M on D. minutum and D. macrocephalum (p<0.05). The inhibitory effects of the monoterpenes on the growth of D. macrocephalum increased proportionally to the applied compound concentrations in most cases. When the bicyclic monoterpenes (1R)-(-)-fenchone and (1S)-(-)-verbenone were administered to D. macrocephalum, however, it was greatly inhibited even at low concentrations (p<0.05 and p<0.001). The bicyclic monoterpene (1R,5R)-(+)-β-pinene inhibited the growth rate of D. minutum and D. macrocephalum at most concentrations, but at 0.006M concentration (1R,5R)-(+)-β-pinene caused slight enhancement. Microscopic examination of changes in the shapes of the fruiting bodies matched the effects observed on the growth rates. These results suggest that the inhibitory or enhancing effects of the selected monoterpenes on both D. minutum and D. macrocephalum depend on the number of cyclic skeletons as well as the concentration of the individual compounds.

Pycnanthuquinone C, an unusual 6,6,5-tricyclic Geranyltoluquinone from the Western Australian brown alga Cystophora harveyi.

Chemical investigation of the Western Australian marine brown alga Cystophora harveyi resulted in the isolation of the new linearly fused 6,6,5-tricyclic compound pycnanthuquinone C (1), in addition to four previously reported geranyltoluquinol derivatives. Structures were elucidated by interpretation of spectrometric data. Compounds with the same cyclic skeleton as 1 have been reported to be useful drug leads for the treatment of type 2 diabetes, while compounds 4 and 7 are known constituents of Chinese medicinal herbs. A biosynthetic scheme encompassing all of the geranyltoluquinol derivatives isolated from C. harveyi is proposed.

Columnar Assembly of Cyclic β-Amino Acid Functionalized with Pyranose Rings

A novel cyclic trimer and tetramer of protected beta-glycamino acids were synthesized and investigated on conformation and assembly formation. A characteristic point of these cyclic beta-glycamino acids is their better solubility than other cyclic beta-amino acids due to the pyranose rings. Thus, the assembling process of the cyclic molecules could be examined by CD or NMR spectroscopy. FT-IR and NMR measurements and geometry optimization revealed a highly symmetric and planar conformation for each cyclic beta-peptide with all-trans amide groups. The amide groups in the cyclic peptides took a vertical orientation against the cyclic skeleton to be suitably arranged for intermolecular hydrogen bonds, which should promote formation of molecular assembly in a columnar structure through molecular stacking. These cyclic beta-peptides were successfully crystallized to yield rod-shaped molecular assemblies in nanometer sizes. Evidence for the columnar structure in the crystals was obtained by electron diffraction analysis, which showed a layer spacing of ca. 4.8 A. Interestingly, the molecular assembly of the cyclic trimer showed a high aspect ratio, width less than 40 nm, and length more than 2 mum, suggesting stable molecular stacking in the column.

Spectroscopic techniques and cyclic voltammetry with synthesis: Manganese(II) coordination stability and its ligand field parameters effect on macrocyclic ligands

Manganese(II) macrocyclic complexes are prepared with different macrocyclic ligands, containing cyclic skeleton bearing organic components which have different chromospheres like N, O and S donor atoms and stereochemistry. Thus, six macrocyclic ligands, were prepared and their capacity to retain the manganese(II) ion in solid as well as in aqueous solution was determined and characterized by elemental analyses, molar conductance measurements, magnetic susceptibility measurements, mass, 1H NMR, IR, electronic spectral and cyclic voltammetric studies. The electronic spectrum of this system showed a dependence that may be consistent with the formation of stable complexes and coordination behaviour of the ions. ESR spectra of all the complexes are recorded in solid as well as solution, which show the oxidation state of the manganese(II). Spin Hamiltonian manganese(II), which can be defined as the magnetic field vector (ℋ): ℋ = g β e H S + D S z 2 − 35 12 + E [ S z 2 − S y 2 ] + A S I + 1 6 a S x 4 + S y 4 + S z 4 − 707 16 + 1 180 F 35 S z 2 − 475 2 S z 2 + 3255 / 10 Significant distortion of the manganese(II) ion in observed geometry is evident from the angle subtended by the different membered chelate rings and the angles spanned by trans donor atoms octahedral geometry. Cyclic voltammetric studies indicate that complexes with all ligands undergoes one electron oxidation from manganese(II) to manganese(III) followed by a further oxidation to manganese(IV) at a significantly more positive potential.

Cyclopropenylidenes: from interstellar space to an isolated derivative in the laboratory.

Like many of the molecular species that have been detected in the interstellar medium, the singlet carbene cyclopropenylidene (C3H2) has been presumed to be too unstable to isolate in the laboratory. However, by appending pi-electron-donating amino groups to the triangular skeleton, we prepared a cyclopropenylidene derivative that is stable at room temperature. In contrast to previously isolated carbenes, this compound does not require a heteroatom adjacent to the electron-deficient carbon to confer stability. Despite the presence of amino groups, the geometric parameters of the cyclic skeleton, revealed by x-ray crystallography, are only slightly perturbed relative to those of the calculated structure of unsubstituted cyclopropenylidene. Stable cyclopropenylidene derivatives might thus serve as models for a better understanding of the formation of carbon-bearing molecules in the interstellar medium.

Catalytic oxidation of 3,5-di- tert-butylcatechol by a manganese(III) 18-azametallacrown-6 compound: Synthesis, crystal structure, fluorescence, magnetic and kinetic investigation

A new macrocyclic hexanuclear manganese(III) 18-azametallacrown-6 compound, [Mn 6(ashz) 6(CH 3OH) 3(H 2O) 3] · 3H 2O · 3DMF ( 1), has been prepared using a trianionic pentadentate ligand N-acetylsalicylhydrazide (ashz 3−) and characterised by various techniques such as elemental analysis, IR, UV-vis and fluorescence spectroscopy, cyclic voltammetry and X-ray diffraction. Six ashz 3− ligands connect six metal ions to form the cyclic skeleton based on the M–N–N–M linkage. Due to the meridional coordination of the ligand to the Mn 3+ ion, the ligand enforces the stereochemistry of the Mn 3+ ions as a propeller configuration with alternating Δ/Λ forms. The kinetic studies on catecholase activity of 1 for the oxidation of 3,5-di- tert-butylcatechol (3,5-DTBC) by O 2 were done using UV–Vis absorption spectra method. Compound 1 has been evaluated as a model system for the catechol oxidase enzyme and it is found that the compound shows high catecholase activity. It exhibits the activity with a turnover number of 270 h −1. A kinetic treatment on the basis of the Michaelis–Menten model has been applied. The magnetic susceptibility (300–5 K) study indicates antiferromagnetic exchange interactions with J = −2.6 cm −1 between the adjacent Mn 3+ ions.