18-membered Ring Research Articles

Backbone-Determined Antiarrhythmic Structure-Activity Relationships for a Mirror Image, Oligomeric Depsipeptide Natural Product.

Cyclic oligomeric depsipeptides (COD) are a structural class within naturally occurring compounds with a wide range of biological activity. Verticilide is a COD (24-membered ring) that was identified by its inhibition of insect ryanodine receptor (RyR). We have since found that the enantiomer of verticilide (ent-verticilide, 1) is a potent inhibitor of mammalian RyR2, a cardiac calcium channel, and therefore a potential antiarrhythmic agent. Oddly, nat-verticilide does not inhibit RyR2. To further develop ent-verticilide as an antiarrhythmic, we explored potential SAR through systematic modification of the ester's functionality to both N-H and N-Me amides. The syntheses of these ent-verticilide-inspired analogs are detailed using a monomer-based platform enabled by enantioselective catalysis. Two analogs among 23 exhibited measurable reduction of calcium sparks in a functional assay of RyR2 activity. These findings illustrate the value of natural product-inspired therapeutic development, but the less-studied approach where the non-natural enantiomeric series harbors important SAR.

Stereochemical Assignment of the 36-Membered Macrolide Ring Portion of Poecillastrin C.

Absolute configuration at 12 stereocenters in the 36-membered macrocyclic ring portion of poecillastrin C (1) was disclosed by chemical degradation and NMR analyses of 1, chemical synthesis, and molecular modeling techniques.

Confining carbon dots in extra-large pore zeolite SYSU-3 assembled in a mixed-template system

The 24-membered ring -SYT type extra-large pore zeolite, denoted as DESO-SYSU-3, has been synthesized by employing N,N′-diethylsophoridine and trimethylsulfanium in a mixed-template system, where the N,N′-diethylsophoridine and trimethylsulfanium played different roles in the crystallization process. A single usage of N,N′-diethylsophoridine led to the formation of an unknown phase (donated as SYSU-5). These results reveal that the utilization of alkaloid-derived organic structure-directing agents (OSDAs) is an efficient synthetic strategy to produce specific extra-large pore zeolites and related structures. Compared to the prototype SYSU-3, the addition of TMSF into the system not only improved the silicon content in the framework of DESO-SYSU-3 but also facilitated the generation of carbon dots (CDs) confined in extra-large pore structure. The structure and the proposed formation mechanism of CDs were investigated based on HRTEM, XPS, FI-IR, UV–Vis, Raman and photoluminescence spectrum. The CDs@zeolite composite exhibited intriguing optical properties of both fluorescence and room temperature phosphorescence, respectively. This work extends extra-large pore zeolite as the matrix for the development of CDs@zeolite composites with tunable optical properties.

K2RbB8PO16: A Borophosphate with Moderate Birefringence and Deep-Ultraviolet Transmission.

A new borophosphate, K2RbB8PO16 (KRBPO) was synthesized. It exhibits a bilayer structure consisting of two B-O layers with an 18-membered ring (18-MR) joined by [PO4], which is composed of the π-conjugated group [BO3] and non-π-conjugated groups [BO4] and [PO4]. The UV-vis-NIR diffuse reflectance spectroscopy shows that the cutoff edge is less than 200 nm. The calculation indicates that KRBPO exhibits moderate birefringence of 0.057@1064 nm, and the source of birefringence is mainly from the [BO3] groups.

Crystal structure and luminescence spectrum of a one-dimensional nickel(II) coordination polymer incorporating 1,4-bis-[(2-methyl-imidazol-1-yl)meth-yl]benzene and adamantane-1,3-di-carboxyl-ate co-ligands.

An NiII coordination polymer, namely, poly[(μ2-adamantane-1,3-di-carboxyl-ato-κ4 O 1,O 1':O 3,O 3')[μ2-1,4-bis-(2-methyl-imidazol-1-ylmeth-yl)benzene-κ2 N 3:N 3']nickel(II)], [Ni(C12H14O4)(C16H18N4)]n or [Ni(adc)(bmib)]n, (I) [adc = adamantane-1,3-di-carboxyl-ate, C12H14O4 2- and bmib = 1,4-bis-(2-methyl-imidazol-1-ylmeth-yl)benzene, C16H18N4] was synthesized and characterized. It exhibits a one-dimensional extended structure built up from alternating [Ni2(bmib)2] 26-membered rings and [Ni2(adc)2] 16-membered rings. The nickel atom lies on a crystallographic twofold axis and both ligands are completed by mirror symmetry. The solid-state luminescence spectra of (I) and the bmib ligand show strong emissions at 442 and 410 nm, respectively.

A robust ultra-microporous cationic aluminum-based metal-organic framework with a flexible tetra-carboxylate linker

Al-based cationic metal-organic frameworks (MOFs) are uncommon. Here, we report a cationic Al-MOF, MIP-213(Al) ([Al18(μ2-OH)24(OH2)12(mdip)6]6Cl·6H2O) constructed from flexible tetra-carboxylate ligand (5,5'-Methylenediisophthalic acid; H4mdip). Its crystal structure was determined by the combination of three-dimensional electron diffraction (3DED) and high-resolution powder X-ray diffraction. The structure is built from infinite corner-sharing chains of AlO4(OH)2 and AlO2(OH)3(H2O) octahedra forming an 18-membered rings honeycomb lattice, similar to that of MIL-96(Al), a scarce Al-polycarboxylate defective MOF. Despite sharing these structural similarities, MIP-213(Al), unlike MIL-96(Al), lacks the isolated μ3-oxo-bridged Al-clusters. This leads to an ordered defective cationic framework whose charge is balanced by Cl- sandwiched between two Al-trimers at the corner of the honeycomb, showing strong interaction with terminal H2O coordinated to the Al-trimers. The overall structure is endowed by a narrow quasi-1D channel of dimension ~4.7 Å. The Cl- in the framework restrains the accessibility of the channels, while the MOF selectively adsorbs CO2 over N2 and possesses high hydrolytic stability.

High-pressure synthesis of fully sp2-hybridized polymeric nitrogen layer in potassium supernitride

Searching for fully sp2-hybridized layered structures is of fundamental importance because of their fascinating physical properties and potential to host topologically non-trivial electronic states. However, the synthesis of fully sp2-hybridized layered polymeric nitrogen structures remains a challenging work because of their low stability. Here, we report the synthesis of a fully sp2-hybridized layered polymeric nitrogen structure featuring fused 18-membered rings in potassium supernitride (K2N16) under high-pressure and high-temperature conditions. Bader charge analysis reveals that the potassium atomic layer stabilizes the unique sp2-hybridized polymeric nitrogen layers through the charge transfer effect in K2N16. The calculation of electronic structure indicates that K2N16 is a topological semimetal with multiple Dirac points and hosts higher-order Dirac fermions with cubic dispersion, which are contributed by the sp2-hybridized polymeric nitrogen layers arranged in P6/mcc symmetry. The high-pressure synthesis of the fully sp2-hybridized polymeric nitrogen layered structure provides promising prospects for exploring novel topological materials with effective stabilization routes.

A new 2D Zn(II)-based coordination polymer as photocatalyst for photodegradation of methyl orange in water: Effect of photocatalyst dosage and dye concentration

The metal-organic frameworks (MOFs) a sub-class of well-known coordination polymer are assorted multidimensional materials that could be employed as photocatalysts for dye decomposition present in the wastewater discharge. Herein, a new Zn(II)-based coordination polymer with formula [Zn(bpyp)(5-nip)] (1) (bpyp = 2,5-bis(pyrid-4-yl)pyridine and H2nip= 5-nitroisophthalic acid) has been synthesized and characterized. In 1, the two carboxyl groups of each 5-nip2− ligand adopts μ2-η1:η1 and μ1-η1:η1 coordination fashion to connect ZnII centers into a 1D chain along b direction, which alternately contains 8-membered rings and 16-membered rings. The newly synthesized compounds have been used as the photocatalyst for the photodegradation of methyl blue (MB), methyl orange (MO), rhodamine B (RhB) and methyl violet (MV) dyes under UV light irradiation. The results reveal that amongst all four dyes, 1 decomposes MO dye to maximum extent. The effects of concentration of dyes, and photocatalyst dosages have been monitored on the photocatalytic performance of 1. Under the optimal reaction condition, ∼89.03% photodegradation of MO has been observed at 20 ppm concentration of MO and 20 mg photocatalyst concentration in 50 min time span. The radical trapping experiments suggest that O2·− is the main active species that catalyzes the photodecomposition of dyes. The possible mechanism for the MO degradation of 1 is proposed using density of states (DOS) calculations and Hirshfeld surface analysis.

DFT investigation of Li storage behavior of sceamless α-graphyne and β-graphyne nanotubes

Graphynes have great potential -as anode materials for lithium-ion batteries (LIBs) owing to their advanced structural and electronic properties. Previously, the curvature of γ-graphyne folded into nanotubes (γGyNTs) caused a significant increase in its Li storage capacity and diffusion ability. Here, using density functional theory (DFT) calculations, we report the same curvature effect in α- and β-graphyne nanotubes (αGyNTs and βGyNTs), whose maximum storage capacities are predicted to be -up to 3488 and 3070 mAh/g, respectively, similar to that of pure Li (3861 mAh/g). Such high capacities are attributed to the graphyne nanotubes having larger specific surface areas and pores than those of other carbon materials. Additionally, climbing -image- nudged-elastic- band calculations reveal that Li atoms can diffuse almost freely through acetylenic rings on the concave side of the αGyNTs, indicating an excellent charge -discharge rate ascribed to weaker adsorption on the 18-membered ring than that on the 12-membered rings of the βGyNTs and γGyNTs. Our results suggest that the αGyNTs are promising as the anode material for LIBs with exceptional overall performance. This study also provides a strategy to design anode materials based on their curvature and topological morphology.

Solvothermal synthesis and crystal structures of two new cadmium coordination polymers containing polynitrile ligands

Two new coordination polymers of cadmium-containing polynitrile ligands have been synthesized using sovothermal methods. In both poly[trans,trans,trans-bis(μ-dicyanamido-κ2 N 1:N 3)bis(2-methylbenzimidazole-κN)cadmium(II)], [Cd(C2N3)2(C8H8N2)2] n , (I), and poly[trans,trans,trans-bis(2-methylbenzimidazole-κN)bis(μ-tricyanomethanido-κ2 N:N′)cadmium(II)], [Cd(C4N3)2(C8H8N2)2] n , (II), the Cd atom lies on a centre of inversion, in space groups P21/n and P21/c, respectively. In each polymer, each anionic ligand acts as a bridge between two metal centres, forming sheets of 24-membered rings, and in each structure a single N—H...N hydrogen bond links the polymer sheets to form a three-dimensional framework structure. Comparisons are made with the structures of some related complexes.

Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.

The synthesis of all N-Me and N-H analogues of ent-verticilide is described, enabling a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree of N-methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a single N-Me → N-H modification. The effect in the corresponding 18-membered ring oligomer (ent-verticilide B1) was also investigated. We report here that a high degree of N-methyl amide content is critical for activity in the ent-verticilide series but not entirely so for the ent-verticilide B1 series.

Enantioselective ring-closing aminomethylamination of aminodienes enabled by modified Trost ligands

Optically active N -heterocycles are important building blocks in organic synthesis and medicinal chemistry. However, an enantioselective synthetic protocol with excellent compatibility across the normal-sized, medium-sized, and macro-sized rings remains largely rare. We herein report a Pd-catalyzed highly enantioselective ring-closing aminomethylamination of aminodienes with aminals via C–N bond metathesis, which provides rapid access to enantiomer-enriched 5- to 16-membered β-aminoallylated N -heterocycles (up to 98% ee) under mild conditions with the use of modified Trost ligands. In addition, the enantioselective synthesis of chiral tetrahydroisoquinolines (THIQs) has also been realized by this method. The unity of this method has been demonstrated by the formal synthesis of the natural product (+)-( 8S , 13R )-cyclocelabenzine. Mechanistically, the reaction goes through a challenging and less known stereoselective migratory insertion of alkene into an alkyl-Pd species. We also conducted a detailed analysis of the stereochemical outcome of the reaction, which provided an intriguing view of enantioselection. • Enantioselective migratory insertion of alkene to alkyl-palladium intermediates • Highly efficient synthesis of enantioenriched 5- to 16-membered N -heterocycles • Access to C-4 enantioenriched THIQs with excellent functional-group tolerance • First example of asymmetric C–N bond metathesis reaction Not only are N -heterocycles privileged structural motifs in natural alkaloids, but they are also widely utilized as key intermediates for the synthesis of pharmaceutical molecules and drug candidates. Efficient synthetic approaches toward optically active N -heterocycles, especially ones general for the construction of versatile ring systems, are of paramount importance. The enantioselective domino Heck cyclization/cross-coupling reactions are a powerful approach to functionalized chiral heterocyclic compounds. However, the use of sp 3 C-hybridized alkyl electrophiles in such sequential transformations remains largely elusive. Herein, with modified Trost-type ligands, we report an efficient Pd-catalyzed asymmetric ring-closing reaction that gives access to enantiomer-enriched 5- to 16-membered N -heterocycles. A Pd-catalyzed highly enantioselective ring-closing aminomethylamination of aminodienes with aminals via C–N bond metathesis has been established; it provides rapid and unique access to a wide range of optically active N -heterocycles bearing 5- to 16-membered rings in good to excellent enantioselectivities (up to 98% ee) under mild conditions with the use of modified Trost ligands. Mechanistically, the reaction goes through a challenging and less known stereoselective migratory insertion of alkene into an alkyl-Pd species. This success represents the first time that the Trost ligand has been used to induce asymmetry in Heck reactions.

E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

Ring-Over-Ring Deslipping From Imine-Bridged Heterorotaxanes.

Ring-over-ring slippage and ring-through-ring penetration are important processes in the construction of ring-in-ring multiple interlocked architectures. We have successfully observed “ring-over-ring deslipping” on the rotaxane axle by exploiting the dynamic covalent nature of imine bonds in imine-bridged heterorotaxanes R1 and R2 with two macrocycles of different ring sizes on the axle. When the imine bridges of R1 were cleaved, a hydrolyzed hetero[4]rotaxane [4]R1′ was formed as an intermediate under dynamic equilibrium, and the larger 38-membered macrocycle M was deslipped over the 24-membered ring (24C8 or DB24C8) to dissociate into a [3]rotaxane [3]R3 and a macrocycle M. The time dependent NMR measurement and the determined thermodynamic parameters revealed that the rate-limiting step of the deslipping process was attributed to steric hindrance between two rings and reduced mobility of M due to proximity to the crown ether, which was bound to the anilinium on the axle molecule.

Computational Prediction of Graphdiyne-Supported Three-Atom Single-Cluster Catalysts

Computational Prediction of Graphdiyne-Supported Three-Atom Single-Cluster Catalysts

Synthesis and structures of three benzoannelated macrobicyclic diamides.

We report the synthesis and structures of 9,10,20,21-tetrahydro-5,14-(ethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-6,13-dione [systematic name: 8,11,21,24,29-pentaoxa-1,18-diazatetracyclo[16.8.5.02,7.012,17]hentriaconta-2,4,6,12(17),13,15-hexaene-19,26-dione C24H28N2O8, I], 6,7,9,10,12,13,20,21-octahydro-5,14-(ethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-23,27-dione (8,11,21,24,29-pentaoxa-1,18-diazatetracyclo[16.8.5.02,7.012,17]hentriaconta-2,4,6,12,14,16-hexaene-27,31-dione; C24H28N2O7, II), and 9,10,20,21-tetrahydro-5,14-(ethanooxyethanooxyethano)dibenzo[e,q][1,4,10,13,7,16]tetraoxadiazacyclooctadecine-6,13-dione [8,11,21,24,29,32-hexaoxa-1,18-diazatetracyclo[16.8.8.02,7.012,17]tetratriaconta-2,4,6,12(17),13,15-hexaene-19,26-dione; C26H32N2O7, III]. All three compounds are made up of two tertiary diamides and are composed of two 15-membered rings with N2O3 donor sets and one 18-membered ring with an N2O4 donor set (compounds I and II) or three 18-membered rings with N2O4 donor sets (compound III). The solid-state structures of compounds I and II show little effects from the movement of the amide groups. However, compound III has a larger cavity and a different orientation of donor atoms in comparison to compounds I and II.

A stable aluminosilicate zeolite with intersecting three-dimensional extra-large pores.

Zeolites are crystalline porous materials with important industrial applications, including uses in catalytic and adsorption-separation processes. Access into and out of their inner confined space, where adsorption and reactions occur, is limited by their pore apertures. Stable multidimensional zeolites with larger pores able to process larger molecules are in demand in the fine chemical industry and for the oil processing on which the world still relies for fuels. Currently known extra-large-pore zeolites display poor stability and/or lack pore multidimensionality, limiting their usefulness. We report ZEO-1, a robust, fully connected aluminosilicate zeolite with mutually intersecting three-dimensional extra-large plus three-dimensional large pores. ZEO-1 is stable up to 1000°C, has an extraordinary specific surface area (1000 square meters per gram), and shows potential as a catalytic cracking catalyst.

Investigation of the adsorption behavior of two anticancer drugs on the pristine and BN-doped graphdiyne nanosheet: A DFT-D3 perception

Hydroxyurea (HU) and 5-Fluorouracil (FU) are well-known drugs that are widely used in the treatment of cancers. Interaction of the HU and FU molecules on the pristine graphdiyne (GDY) and BN-doped graphdiyne (BNGDY) nanosheet was evaluated by density functional theory (DFT) method in gas and solution phases. Various adsorption sites of GDY/BNGDY have been examined for different HU/FU drug orientations. The results indicate that the 18-membered ring area and top of the acetylenic linkage are the most suitable sites, unlike the hexagonal ring. The S1, S6, S8, and S10 structures are the most stable configurations for GDY/HU, GDY/FU, BNGDY/HU, and BNGDY/FU with the highest Eads about −0.598, −0.417, −1.289, and −0.603 eV in the gas phase and −0.960, −0.592, −1.599 and −1.485 eV in solution phase, respectively. For GDY + HU/FU, the highest Eads is due to interaction of hydrogen atom of drug with GDY; while, in BNGDY+HU/FU, the oxygen atom of drug interacts effectively with the boron atom of the sheet. Likewise, in GDY complexes, charge transfer occurs from sheet to drug, but it is inverse in BNGDY complexes. The band gap values of the GDY and BNGDY are 0.470 and 0.486 eV, respectively, that drug adsorption decreases them in the range of 2.34 to 22.43%. Adsorption behavior of the structures is further discussed and interpreted using quantum molecular descriptors, band structure, and PDOS diagrams. Recovery time values show that in the field of targeted drug delivery and nanomedicine, GDY and BNGDY are more suitable as carrier for the HU and FU drugs, respectively.

The Formation of Impossible Rings in Macrocyclooligomerizations for Cyclodepsipeptide Synthesis: The 18-from-12 Paradox.

A reinvestigation into the macrocyclooligomerization (MCO) of a tetradepsipeptide is reported, uncovering a paradox in which the MCO of depsipeptide monomers can produce "impossible" ring sizes: a 12-atom chain produced the expected 24-membered ring, alongside unexpected 18- and 30-membered cyclic oligomeric depsipeptides (CODs). We report an alternative preparation of authentic 18- and 36-membered macrocycles for this case using a stepwise synthesis that provides definitive analytical characterization for each ring size. Our investigation yields a recharacterization and reassignment of two macrocycles originally reported in this MCO series, along with updated yields and isothermal titration calorimetry data after implementation of new critical protocols for purification and subsequent analysis. Initial studies to probe this mechanistic conundrum are described.

Photochemical Orifice Expansion of a Cage-Opened C60 Derivative.

Upon light irradiation, a tetraketosulfoxide derivative of C60 was transformed into a diketosulfide carboxylic anhydride via intermolecular nucleophilic addition of the sulfoxide moiety. The thus-formed 18-membered ring enables a spontaneous insertion of an Ar atom. In this encapsulation/release process, the phenyl ring on the orifice works as a dynamic stopper, which potentially adopts three conformations: an open form reduces distortion energy at the transition state while semiopen and closed forms reduce the orifice size.