Nine-membered Ring Research Articles

The π-acidity/basicity of cyclic trinuclear units (CTUs): from a theoretical perspective to potential applications.

Cyclic trinuclear units (CTUs) based on Au(i), Ag(i) and Cu(i) cations, featuring near planar nine-membered coordination rings, represent an important class of metal-organic π-acids/bases with highly adjustable π-acidity/basicity. Their superior π-acidity/basicity coupled with Lewis-acidic and metalmetal bonding sites offers excellent attraction for a wide range of acidic/basic species, and usually followed by noticeable changes of luminescence or charge transfer behaviors. A series of representative cases from the past two decades have been selected herein for such cyclic trinuclear units in both oligomeric and polymeric systems. Their fascinating and profound potential applications related to π-acidity/basicity are highlighted, including molecular absorption and separation, luminescence sensing and detection, organic light-emitting diodes (OLEDs), metal-organic field-effect transistors (MOFETs), molecular wires, and catalysis. The challenges in improving the performance for practical application will also be discussed.

Dragocins A-D, Structurally Intriguing Cytotoxic Metabolites from a Panamanian Marine Cyanobacterium.

Dragocins A-D (1-4) were isolated from a dark-red wooly textured marine cyanobacterium collected in Boca del Drago, Panama. Dragocins A-C (1-3) possessed 2,3-dihydroxypyrrolidine, 1-hydroxy-5- O-Me-benzoyl, and 4'-substituted-β-ribofuranose moieties that connected to form a nine-membered macrocyclic ring. Dragocins A-C are members of a unique hybrid structural class with substitution at the C-4' position of a ribofuranose unit. Of the four new compounds, dragocin A was the most potent cytotoxin to human H-460 lung cancer cells.

Crystal structure and Hirshfeld surface analysis of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidine.

The nine-membered ring system of the title compound, C6H6N4, is essentially planar. In the crystal, mol-ecules are linked via C-HTrz⋯NTrz and C-HPyrm⋯NTrz (Trz = triazole and Pyrm = pyrimidine) hydrogen bonds together with weaker C-HPyrm⋯NPyrm hydrogen bonds to form layers parallel to (02). The layers are further connected by π-π-stacking inter-actions between the nine-membered ring system [centroid-centroid = 3.7910 (8) Å], forming oblique stacks along the a-axis direction. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯N/N⋯H (40.1%), H⋯H (35.3%), H⋯C/C⋯H (9.5%), N⋯C/C⋯N (9.0%), N⋯N (3.1%) and C⋯C (3.0%) inter-actions and that hydrogen-bonding and van der Waals inter-actions are the dominant inter-actions in the crystal packing. No significant C-H⋯π inter-actions are observed.

Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A, and (±)-Palhinine D.

The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early-stage direct SN 2 cyclization to construct the nine-membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels-Alder reaction of a masked ortho-benzoquinone using the nine-membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol-mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen-containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.

Total Synthesis of an Atropisomer of the Schisandra Triterpenoid Schiglautone A.

A diastereoselective approach for the total synthesis of an unusual atropisomer of the Schisandra triterpenoid (±)-schiglautone A is described. The efficient synthetic strategy features three key transformations: 1) two sequential titanium(III)-catalyzed radical cyclization/homologation reactions to construct the trans-fused [6,7] bicycle as well as install the quaternary carbons at C10 and C14 with the desired stereochemistry; 2) a Claisen rearrangement followed by a ring-closing metathesis to forge the strained nine-membered ring; and 3) a substrate-controlled Michael addition to enable the introduction of the C17 side-chain with good diastereoselectivity.

The crystal structure of ginorite, Ca2[B14O20(OH)6]·5H2O, and the analysis of dimensional reduction and structural complexity in the CaO–B2O3–H2O system

The crystal structure of ginorite, Ca 2 [B 14 O 20 (OH) 6 ]·5H 2 O, from the Chelkar salt dome, western Kazakhstan, has been refined at 150(2) and 296(2) K. The mineral is monoclinic, P 2 1 / c , unit-cell parameters are (at 150/296 K): a = 12.738(1)/12.728(1), b = 14.240(1)/14.303(1), c = 12.750(1)/12.755(1) A, β = 101.163(2)/101.147(2)°, V = 2268.9(4)/2278.3(4) A 3 , Z = 4. The crystal structure is isotypic to that of strontioginorite and is based upon 2-dimensional anionic layers with the composition [B 14 O 20 (OH) 6 ] 4− . The layers are coplanar to (0 1 0) and are composed of BO 4 tetrahedra and BO 3 triangles. The fundamental building block (FBB) for the crystal structures of ginorite and strontioginorite consists of eight BO 3 triangles and six BO 4 tetrahedra. The adjacent FBBs are linked by sharing O atoms to form layers that possess open nine-membered rings centered by the M 1 and M 2 metal atoms. In the crystal structure of strontioginorite, the M 1 and M 2 sites are occupied by Sr and Ca, respectively, whereas, in ginorite, both sites are occupied by Ca. The Ca ↔ Sr substitution affects the geometry of the M 1O 8 polyhedron significantly, with the difference |Δ| between the Sr–O and Ca–O bond lengths up to 0.157 A. The dimensional reduction, structural and chemical complexity of 45 minerals and inorganic compounds of the CaO–B 2 O 3 –H 2 O system have been analyzed using ternary diagrams. The structures with 0-dimensional structural units (finite clusters) constitute 53.3% (24) of all structures in the system, whereas 1-, 2- and 3-dimensional borate polyanions have been observed in 15.6% (7), 20.0% (9) and 11.1% (5) of all structures in the system, respectively. The average structural complexity for the 42 B-bearing phases in the CaO–B 2 O 3 –H 2 O system is 353 bits/cell agrees well with the average complexity of 340 bits/cell for all boron minerals. Ginorite belongs to the class of very complex structures (1536.000 bits/cell) and is the second in complexity in the system after alfredstelznerite, Ca 4 (H 2 O) 4 [B 4 O 4 (OH) 6 ] 4 ·15H 2 O (4026.707 bits/cell). In general, structural and chemical complexities correlate with each other and indicate the presence of the high-complexity areas in the H 2 O dominant part of the diagram, in a band between ca . 10 and 20 mol% CaO.

Exploitation of Cyclopropane Carbaldehydes to Prins Cyclization: Quick Access to ( E)-Hexahydrooxonine and Octahydrocyclopenta[ b]pyran.

A single-step TiX4-mediated Prins-type cyclization of cyclopropane carbaldehydes with 3-buten-1-ol for the highly stereoselective construction of relatively strained ( E)-hexahydrooxonines is reported. Switching the alcohol to 3-butyn-1-ol prompted a similar route, augmented by another cyclization within a nine-membered ring to afford a bicyclized product (4,4-dihalo-5-aryloctahydrocyclopenta[ b]pyran). Easy transformation of the resulting geminal dihalide to a vinyl halide and a ketone further supplemented the substance of this approach.

Boron Teetotum: Metallic [Ti(B6C xN y)] q and Bimetallic [Ti2(B6C xN y)] q Nine-Membered Heterocycles with x + y = 3 and -1 ≤ q ≤ 3.

We investigated the geometry, stability, and aromaticity of a series of singly and doubly titanium-doped boron clusters. Ti dopants bring in planar cyclic form with a nine-membered boron ring B9- and B93- and C and N isoelectronic derivatives where perfectly planar B6N3, B6CN2, B6C2N, and B6C3 heterorings are coordinated with one and two Ti atoms. The presence of both C and N atoms induces bimetallic heterocycles while Ti2B9q clusters are not stable in cyclic form. Doubly Ti doped clusters have the shape of a teetotum toy. High thermodynamic stability of these bimetallic boron heterocycles, that are global equilibrium structures of corresponding systems, can be understood as the result of a stabilizing overlap between bonding and antibonding MOs of Ti2 with different eigenstates of B6C xN y cycles. Both C and N elements, which are more electronegative than the B atom, also enjoy the formation of planar nine-membered ring via classical 2c-2e bonding, rather than occupancy of high coordination position. A double aromaticity feature which comprises both σ and π aromaticity is supported by magnetic responses of electron density within a planar cycle. Such an aromatic character is also in line with the classical electron count for both sets of delocalized σ and π electron systems.

Synthesis and properties of seven- to nine-membered ring nitrogen heterocycles. Cyclic amidines and cyclic amidinium salts

Synthesis and properties of seven- to nine-membered ring nitrogen heterocycles. Cyclic amidines and cyclic amidinium salts

Polyoxometalate-Based Metal-Organic Frameworks as Visible-Light-Induced Photocatalysts.

Two stable 3D polyoxometalate-based metal-organic frameworks (PMOFs), [CuI12(trz)8(H2O)2][α-SiW12O40]·2H2O (1) and [CuI12(trz)8Cl][α-PW12O40] (2) (Htrz = 1- H-1,2,4-triazole) based on Keggin-type POMs were successfully obtained and fully characterized. The basic building units of the two PMOFs are [CuI12(trz)8], but polyoxoanion (POA) template effect leads to different structures and properties: 1 represents an interesting example that [α-SiW12O40]4- locate in the nine-membered Cu-trz rings through Cu···O weak interactions to form a 3D framework, whereas 2 shows a 3D structure constructed from 2D bilayer cationic network [CuI12(trz)8Cl]3+ and [α-PW12O40]3- lying in the adjacent layers via Cu···O weak interactions. PMOF 1 as unusual visible-light photocatalyst exhibit significantly enhanced photocatalytic activity under visible-light and excellent stability during the photocatalysis process for recovering and recycling, as well as photocatalytic hydrogen evolution activity.

QUANTITATIVE STRUCTURE–PHARMACOKINETICS RELATIONSHIP FOR PLASMA PROTEIN BINDING OF NEUTRAL DRUGS

Objective: Plasma protein binding (PPB) of drugs is important pharmacokinetic (PK) phenomena controlling the free drug concentration in plasma and the overall PK and pharmacodynamic profile. Prediction of PPB at the very early stages of drug development process is of paramount importance for the success of new drug candidates. The study presents a quantitative structure–pharmacokinetics relationship (QSPkR) modelling of PPB for neutral drugs.Methods: The dataset consists of 117 compounds, described by 138 molecular descriptors. Genetic algorithm and stepwise multiple linear regression are used for variable selection and QSPkR models development. The QSPkRs are evaluated by internal and external validation procedures.Results: A robust, significant and predictive QSPkR with explained variance r2 0.768, cross-validated q2LOO-CV 0.731,and geometric mean fold error of prediction (GMFEP) 1.79 is generated, which is able to predict the extent of PPB for 67.6% of the drugs in the dataset within the 2-fold error of experimental values. A simple empiric rule is proposed for distinguishing between drugs with different binding affinity, which allowed correct classification of 78% of the high binders and 87.5% of the low binders.Conclusions: PPB of neutral drugs is favored by lipophilicity, dipole moment, the presence of substituted aromatic and fused rings and a nine-member ring system, and is disfavored by the presence of aromatic N-atoms. Keywords: Plasma protein binding (PPB), Quantitative structure–pharmacokinetics relationship (QSPkR), In silico prediction, Human serum albumin (HSA), Alpha-1-acid glycoprotein (AGP).

Synthesis and characterization of the new tin borate SnB8O11(OH)4

AbstractA new tin(II) borate with the composition SnB8O11(OH)4was synthesized by a simple hydrothermal process. It crystallizes in the centrosymmetric monoclinic space groupP21/n(no. 14) with the lattice parametersa=790.1(1),b=1402.2(2),c=994.8(1) pm, andβ=90.40(5)° (Z=4). The new compound SnB8O11(OH)4is isotypic to PbB8O11(OH)4and isostructural to BaB8O11(OH)4. The borate layers are built up from fundamental building blocks (FBBs) with the composition [B8O11(OH)4]2−. Four of these FBBs form a nine-membered ring wherein the Sn2+cations are located. These boron-oxygen layers are further connected by O–H···O hydrogen bond interactions. The characterization of SnB8O11(OH)4is based on single-crystal X-ray diffraction data, vibrational spectroscopy, DFT calculations, and thermoanalytical investigations including high temperature powder XRD.

QUANTITATIVE STRUCTURE–PHARMACOKINETICS MODELING OF THE UNBOUND CLEARANCE FOR NEUTRAL DRUGS

Objective: Prediction of pharmacokinetic behaviour of new candidate drugs is an important step in drug design. Clearance is a key pharmacokinetic parameter, controlling drug exposure in the body. It depends on numerous factors and is frequently restricted by plasma protein binding. The study is focused on the development of quantitative structure-pharmacokinetic relationship (QSPkR) for the unbound clearance (CLu) of neutral drugs.Methods: The dataset consisted of 117 neutral drugs, divided into training set (n = 94) and external test set (n = 23). Chemical structures were encoded by 113 theoretical descriptors. Genetic algorithm and step-wise multiple linear regression were applied for model development. The model was evaluated by cross-validation in the training set and external test set.Results: Significant, predictive and interpretable QSPkR model was developed with explained variance r2 = 0.617, cross-validated correlation coefficient q2LOO-CV = 0.554, external test set predictive coefficient r2pred = 0.656, and root mean square error in prediction RMSEP = 1.89. The model was able to predict CLu for 56% of the drugs in the external test set within the 2-fold error of experimental values.Conclusion: The model reveals the main molecular features governing CLu of neutral drugs. CLu is favoured by lipophilicity, the presence of fused aromatic rings, ester groups, dihydropyridine moieties and nine-member ring systems, while polarity, molecular size and strong electron withdrawing atoms and groups as substituents in aromatic rings affect negatively CL

Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa-hydro-azonino[5,6-b]indole-2,3-di-carboxyl-ate.

The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa-hydro-azepine to a nine-membered azonine. The nine-membered azonine ring of the mol-ecule adopts a chair-boat conformation. The C=C and C-N bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine CH2-C=C-N-CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3)° as a result of steric effects. The amine N(Et) N atom has a trigonal-pyramidal configuration (sum of the bond angles = 346.3°). The inter-planar angle between the two carboxyl-ate substituents is 60.39 (8)°. In the crystal, mol-ecules form zigzag chains along [010] by inter-molecular N-H⋯O hydrogen-bonding inter-actions, which are further packed in stacks toward [100]. The title azonino-indole might be considered as a candidate for the design of new Alzheimer drugs.

Carbonylative cycloaddition for the synthesis of medium-sized carbo- and heterocycles

Highly functionalized medium-sized carbo- and heterocycles are of great interest for the synthesis of natural molecules and their analogs, yet their synthesis remains challenging. Cycloaddition reactions have proven to be quite efficient methods towards them. This review focuses on the use of carbonylative cycloaddition for the synthesis of the most challenging ring sizes, i.e., seven-, eight-, and nine-membered rings.

Synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products.

The present work deals with the synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products like physalins, with potential as antitumor agents. This synthetic methodology involves several key reactions: (a) synthesis of polyfunctionalized cycloheptenones by [4 + 3] cycloaddition reactions of furan precursors with oxyallyl cations; (b) Nicholas reaction with propargyl cations stabilized as dicobalt hexacarbonyl complexes; (c) demetallation and hydration of the resulting acetylenes; (d) stereoconvergent aldol cyclization to generate a key oxatricyclic intermediate and (e) a β-fragmentation process that affords, under hypoiodite photolysis, the desired product with moderate to good yield. The final compounds are the result of a radicalary β-fragmentation at the level of C2-C6 with respect to the tertiary hydroxyl group on C6, with an unexpected contraction from a ten- to a nine-membered ring system, via a radical addition to the carbonyl group on C4. The synthetic methodology has been scaled up to multigram level with good overall yield. Further biological, biochemical and biophysical studies are being carried out in our laboratory on these 1,7-epoxycyclononane derivatives to determine the potential of this kind of oxabicyclic compound as future hits and/or leads for the development of new anticancer drugs. The preliminary evaluation of the anticancer activity of the representative synthesized compounds, against the leukaemia cancer cell lines K-562 and SR, shows a promising activity with a GI50 = 0.01 μM and a LC50 = 7.4 μM for a conveniently functionalized 10-oxabicyclo[5.2.1]decane.

Поведение катаплеита при нагревании и кристаллическая структура продукта его высокотемпературной трансформации — новой фазы Na6Zr3[Si9027] с девятичленными кольцами кремнекислородных тетраэдров

Поведение катаплеита при нагревании и кристаллическая структура продукта его высокотемпературной трансформации — новой фазы Na6Zr3[Si9027] с девятичленными кольцами кремнекислородных тетраэдров

Synthetic Studies on Presporolide, a Putative Enediyne Precursor of Sporolides.

A synthesis of the core framework of presporolide, which possesses both a strained bicyclo[7.3.0]dodecadiyne moiety and a distinctive macrolactone structure, is reported. This synthesis features: (i) a Cu-mediated O-arylation of a hindered tertiary alcohol using triarylbismuth reagent; (ii) stereoselective construction of the strained nine-membered diyne ring; and (iii) atroposelective formation of the macrolactone.

Gas Separation through Bilayer Silica, the Thinnest Possible Silica Membrane.

Membrane-based gas separation processes can address key challenges in energy and environment, but for many applications the permeance and selectivity of bulk membranes is insufficient for economical use. Theory and experiment indicate that permeance and selectivity can be increased by using two-dimensional materials with subnanometer pores as membranes. Motivated by experiments showing selective permeation of H2/CO mixtures through amorphous silica bilayers, here we perform a theoretical study of gas separation through silica bilayers. Using density functional theory calculations, we obtain geometries of crystalline free-standing silica bilayers (comprised of six-membered rings), as well as the seven-, eight-, and nine-membered rings that are observed in glassy silica bilayers, which arise due to Stone-Wales defects and vacancies. We then compute the potential energy barriers for gas passage through these various pore types for He, Ne, Ar, Kr, H2, N2, CO, and CO2 gases, and use the data to assess their capability for selective gas separation. Our calculations indicate that crystalline bilayer silica, which is less than a nanometer thick, can be a high-selectivity and high-permeance membrane material for 3He/4He, He/natural gas, and H2/CO separations.

Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation.

The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.