Cyclic Precursors Research Articles

A quantitative study of white matter hypomyelination and oligodendroglial maturation in focal cortical dysplasia type II

PurposeA diagnostic feature of focal cortical dysplasia (FCD) type II on magnetic resonance imaging (MRI) is increased subcortical white matter (WM) signal on T2 sequences corresponding to hypomyelination, the cause of which is unknown. We aimed to quantify WM pathology in FCD type II and any deficiency in the numbers and differentiation of oligodendroglial (OL) cell types within the dysplasia.MethodsIn 19 cases we defined four regions of interests (ROIs): ROI1 = abnormal WM beneath dysplasia, ROI2 =dysplastic cortex, ROI3 = normal WM, and ROI4 = normal cortex. We quantified axonal and myelin density using immunohistochemistry for neurofilament, myelin basic protein and quantified mature OL with NogoA, cyclic nucleotide 3-phosphodiesterase (CNPase) and OL precursor cell (OPC) densities with platelet derived growth factor receptor (PDGFR)α, β and NG-2 in each region.Key FindingsWe observed a significant reduction in myelin and axons in the WM beneath dysplasia relative to normal WM and there was a correlation between relative reduction of myelin and neurofilament in each case. OL and OPC were present in the WM beneath dysplasia and although present in lower numbers with most markers, were not significantly different from normal WM. Neurofilament and myelin labeling highlighted disorganized orientation of fibers in dysplastic cortex but there were no significant quantitative differences compared to normal cortex. Clinical correlations showed an association between the severity of reduction of myelin and axons in the WM of FCD and duration of epilepsy.SignificanceThese findings indicate a reduction of myelinated axons in the WM of FCD type II rather than dysmyelination as the primary pathologic process underlying WM abnormalities, possibly influenced by duration of seizures. The range of OPC to OL present in FCD type II does not implicate a primary failure of cell recruitment and differentiation of these cell types in this pathology.

ChemInform Abstract: Preparation of NH‐Pyrroles under Superelectrophilic Conditions by an Aza‐Nazarov Reaction Cascade with Indole as Neutral Leaving Group: Experiment and Theory.

AbstractThe synthesis of the pyrroles (III) from the easily available cyclization precursors (I) depends on the acidity.

Radiosynthesis and biological evaluation of alpha-[F-18]fluoromethyl phenylalanine for brain tumor imaging

Radiolabeled amino acids have proven utility for imaging brain tumors in humans, particularly those that target system L amino acid transport. We have prepared the novel phenylalanine analogue, (FMePhe, 9), as part of an effort to develop new system L tracers that can be prepared in high radiochemical yield through nucleophilic [(18)F]fluorination. The tumor imaging properties of both enantiomers of this new tracer were evaluated through cell uptake, biodistribution and microPET studies in the mouse DBT model of high grade glioma. The non-radioactive form of 9 and the cyclic sulfamidate labeling precursor were prepared from commercially available racemic α-benzylserine. Racemic [(18)F]9 was prepared from the labeling precursor in two steps using standard[(18)F]fluoride nucleophilic reaction conditions followed by acidic deprotection. The individual enantiomers [(18)F]9a and [(18)F]9b were isolated using preparative chiral HPLC. In vitro uptake inhibition assays were performed with each enantiomer using DBT cells. Biodistribution and microPET/CT studies were performed with each enantiomer in male BALB/c mice at approximately 2 weeks after implantation of DBT tumor cells. Radiolabeling of the cyclic sulfamidate precursor 5 provides racemic [(18)F]9 in high radiochemical yield (60%-70%, n=4) and high radiochemical purity (>96%, n=4). In vitro uptake assays demonstrate that both [(18)F]9a and [(18)F]9b undergo tumor cell uptake through system L transport. The biodistribution studies using the single enantiomers [(18)F]9a and [(18)F]9b demonstrated good tumor uptake with lower uptake in most normal tissues, and [(18)F]9a had higher tumor uptake than [(18)F]9b. MicroPET imaging demonstrated good tumor visualization within 10 min of injection, rapid uptake of radioactivity, and tumor to brain ratios of approximately 6:1 at 60 min postinjection. The novel PET tracer, [(18)F]FMePhe, is readily synthesized in good yield from a cyclic sulfamidate precursor. Biodistribution and microPET studies in the DBT model demonstrate good tumor to tissue ratios and tumor visualization, with enantiomer [(18)F]9a having higher tumor uptake. However, the brain availability of both enantiomers was lower than expected for system L substrates, suggesting the [(18)F]fluorine group in the β-position affects uptake of these compounds by system L transporters.

Genome Sequence of Lactobacillus pentosus KCA1: Vaginal Isolate from a Healthy Premenopausal Woman

The vaginal microbiota, in particular Lactobacillus species, play an important role in female health through modulation of immunity, countering pathogens and maintaining a pH below 4.7. We report the isolation and genome sequence of Lactobacillus pentosus strain KCA1 (formally known as L. plantarum) from the vagina of a healthy Nigerian woman. The genome was sequenced using Illumina GA II technology. The resulting 16,920,226 paired-end reads were assembled with the Velvet tool. Contigs were annotated using the RAST server, and manually curated. A comparative analysis with the available genomes of L. pentosus IG1 and L. plantarum WCFS1 showed that over 15% of the predicted functional activities are found only in this strain. The strain has a chromosome sequence of 3,418,159 bp with a G+C content of 46.4%, and is devoid of plasmids. Novel gene clusters or variants of known genes relative to the reference genomes were found. In particular, the strain has loci encoding additional putative mannose phosphotransferase systems. Clusters of genes include those for utilization of hydantoin, isopropylmalate, malonate, rhamnosides, and genes for assimilation of polyglycans, suggesting the metabolic versatility of L. pentosus KCA1. Loci encoding putative phage defense systems were also found including clustered regularly interspaced short palindromic repeats (CRISPRs), abortive infection (Abi) systems and toxin-antitoxin systems (TA). A putative cluster of genes for biosynthesis of a cyclic bacteriocin precursor, here designated as pentocin KCA1 (penA) were identified. These findings add crucial information for understanding the genomic and geographic diversity of vaginal lactobacilli.

Formal Total Synthesis of the Algal Toxin (−)‐Polycavernoside A

A concise and largely catalysis-based approach to the potent algal toxin polycavernoside A (1) is described that intercepts a late-stage intermediate of a previous total synthesis; from there on, this challenging target can be reached in a small number of steps. Key to success was a sequence of a molybdenum-catalyzed ring-closing alkyne metathesis (RCAM) reaction to forge the macrocyclic frame, followed by a gold-catalyzed and strictly regioselective transannular hydroalkoxylation of the resulting cycloalkyne that allows the intricate oxygenation pattern of the macrolactone ring of 1 to be properly set. The required cyclization precursor 5 was assembled by the arguably most advanced fragment coupling process based on an Evans-Tishchenko redox esterification known to date, which was optimized to the extent that the precious coupling partners could be used in an almost equimolar ratio (6/7 1:1.3). The preparation of these building blocks features, inter alia, the power of the Sc(OTf)(3)-catalyzed Leighton crotylation as well as the superb selectivities of alkene cross metathesis, asymmetric keto-ester hydrogenation, and the Jacobsen epoxidation/epoxide resolution technologies.

Localization of radiation damages in X-rays irradiated cis-syn-cis-dicyclohexano-18-crown-6 and its inclusion complex with BaCl2

For the first time, structures of radical intermediates generated upon low temperature (77K) X-rays radiolysis of “free” dicyclohexano-18-crown-6 (cis-syn-cis-isomer, DCH18C6) and its inclusion complex with barium chloride (DCH18C6·BaCl2) were identified using EPR spectroscopy. A set of radicals originated from polyether and cyclohexyl rings was detected in DCH18C6·BaCl2 complex and “free” crown ether DCH18C6 irradiated at 77K. Cyclohexyl, macrocyclic OCHCH2 and acyclic CHC(H)O radicals were suggested to be formed at early stages of radiolysis in both investigated compounds, and the fraction of macrocyclic OCHCH2 radicals was predominant immediately after irradiation at 77K. Additionally, an effect of barium cation on post-radiation reactions of the radicals in irradiated DCH18C6·BaCl2 complex upon its subsequent thermal annealing at temperature above 333K was found. In particular, the analysis of EPR spectrum of the irradiated complex annealed at 333–413K implied a presence of signal from acyclic cyclohexanonyl radicals, which may presumably resulted from rearrangement of cyclic α-alkoxycyclohexyl radical precursors. This post-radiation reaction may contribute to accumulation of acyclic radiolytic products in the irradiated complex when comparing with radiolysis of free DCH18C6. The results obtained are essential for understanding the peculiarities of radiation resistance of extraction and sorption systems based on the crown ether under real conditions of radioactive waste reprocessing.

Total synthesis of acerogenins E, G and K, and centrolobol

The first total synthesis of the diarylheptanoid acerogenins E and K, isolated from Acer nikoense MAXIM., is described. Formation of the 13-membered m,m-cyclophane skeleton was successfully achieved on the basis of a domino process involving a Miyaura arylborylation–intramolecular Suzuki reaction. The cyclization precursor was prepared via a Wittig reaction and Claisen–Schmidt condensation, which proceeded in moderate yields. The total synthesis of acerogenin G and centrolobol was also achieved from a common synthetic intermediate.

Synthesis and properties of all-benzene carbon nanocages: a junction unit of branched carbon nanotubes

The first synthesis of an all-benzene carbon nanocage 1, which represents a junction unit of branched carbon nanotubes, has been achieved. A stepwise assembly of six L-shaped units [cis-di(p-bromophenyl)cyclohexane derivative] and two three-way units (1,3,5-triborylbenzene) by cross-coupling and homocoupling provided the unstrained cyclic precursor. Acid-mediated aromatization of cyclohexane moieties in the precursor resulted in the formation of carbon nanocage 1. Photophysical measurements and DFT studies revealed the unique properties of 1, such as D3 symmetry with degenerate HOMO/HOMO − 1 and LUMO/LUMO + 1, high fluorescence quantum yield (ΦF = 0.87), and a relatively large two-photon absorption cross section (500 GM at 590 nm), which are attractive for various applications.

A Unique Synthetic Method to Convert a D‐Sugar into 2‐Deoxy‐L‐ribitol Through Carbonyl Translocation

AbstractA unique and highly efficient radical process was developed to prepare 2‐deoxy‐L‐ribitol. The radical cyclization precursor was prepared over several steps from D‐sugars. Radical cyclization followed by fragmentation gave exclusively the desired product, with carbonyl translocation in an acyclic carbohydrate system. The radical process was optimized to avoid the formation of byproducts. The reaction mechanism was studied by the concentration effect, which indicated that both the radical cyclization and the fragmentation steps are relatively rapid. The stereochemistry of the 2‐deoxy‐L‐ribitol was confirmed by X‐ray crystal structure. By using this synthetic approach, a D‐sugar derivative could be transformed into 2‐deoxy‐L‐ribose in a single radical reaction.

Selective sensing performance of mesoporous carbon nitride with a highly ordered porous structure prepared from 3-amino-1,2,4-triazine

We demonstrate the preparation of highly ordered and graphitic mesoporous carbon nitride with an ordered porous structure and a high nitrogen content (MCN-ATN) by a nano-hard-templating approach through a simple polymerization of 3-amino-1,2,4-triazine (ATN) inside the pore channels of a mesoporous silica template with an Ia3d symmetry and a 3D porous structure. Powder X-ray diffraction and high resolution transmission electron microscopy analysis show that the prepared materials exhibit well-ordered mesopores with a 3D porous network. Nitrogen adsorption measurements also confirm that the samples possess excellent physical parameters including high surface areas (472–635 m2 g−1), large pore volumes (0.71–0.99 cm3 g−1) and tunable pore diameters (5.5–6.0 nm). One of the most important features of this work is that the cyclic aromatic precursor helps to preserve the nitrogen in the carbon matrix of the final product even after the carbonization process. The C/N ratio of the samples is ca. 0.92 which is much lower than that obtained for the samples prepared using ethylene diamine and carbon tetrachloride through a nano-hard templating process. X-ray photoelectron spectroscopy results reveal that MCN-ATN is mainly composed of sp2 hybridized carbon atoms bonded with nitrogen atoms, associated with the triazine moieties from the ATN molecules. Temperature programmed desorption of CO2 over MCN-ATN demonstrates that the sample is basic which originates from the amine groups on the surface of the CN wall structure. Finally, the samples are mounted on the quartz crystal microbalance (QCM) and used for sensing both acidic and basic organic vapors. Among the samples studied, MCN-ATN with the largest pore diameter showed a highly selective sensing performance for acidic molecules, especially the formic acid thanks to the presence of weak basic sites on the CN walls.

Thienannulation: Efficient Synthesis of π‐Extended Thienoacenes Applicable to Organic Semiconductors

AbstractThis microreview focuses on several thiophene‐annulation reactions of less cyclic precursors on aromatic units (“thienannulation reactions”), which have been applied to the synthesis of a range of π‐extended thienoacene‐based organic semiconductors. Those thienannulation reactions can be applicable to the syntheses of two types of fused‐thiophene compounds: those with terminal fused thiophene units, represented by acene(di)thiophenes such as benzo[1,2‐b:4,5‐b′]dithiophene (BDT), and those with internal thiophene units, such as [1]benzothieno[3,2‐b][1]benzothiophene (BTBT). In addition, this microreview discusses the merits, scope, and limitations of the thienannulation reactions and demonstrates their high reproducibility with different substrates. It also shows that the corresponding less cyclic precursor subunits for the thiophene‐fused substructures can be regarded as synthetic equivalents or “synthons” for certain types of thienoacene‐based organic semiconductors.

Dual Hard/Soft Gold Catalysis: Intermolecular Friedel–Crafts‐Type α‐Amidoalkylation/Alkyne Hydroarylation Sequences by N‐Acyliminium Ion Chemistry

Gold catalysts have been applied in cascade-type reactions for the synthesis of different nitrogen-based compounds. The reactions likely proceed by a new gold-catalyzed cascade intermolecular α-amidoalkylation/intramolecular carbocyclization cascade process by unifying both the σ- and π-Lewis acid properties of the gold salts. In the first part of this report we show that the σ-Lewis acidity of gold(I) and gold(III) could be exploited to efficiently catalyze the nucleophilic substitution of various alkoxy- and acetoxylactams. The reaction was found to be applicable to a wide range of cyclic N-acyliminium ion precursors and various nucleophiles, including allyltrimethylsilane, silyl enol ethers, arenes, and active methylene derivatives. As a logical progression of this study, a combined hard/soft binary catalytic gold system was then used to implement an unprecedented tandem intermolecular Friedel-Crafts amidoalkylation/intramolecular hydroarylation sequence allowing an expedient access to new, complex, fused polyheterocyclic structures from trivial materials.

ChemInform Abstract: Synthesis of Polyfluoroalkyl Containing Thiopyran Derivatives and Their Applications in Fluoroorganic Chemistry.

AbstractReview: 55 refs.

Evolutionary Divergence of Sedoheptulose 7-Phosphate Cyclases Leads to Several Distinct Cyclic Products

Sedoheptulose 7-phosphate cyclases are enzymes that utilize the pentose phosphate pathway intermediate, sedoheptulose 7-phosphate, to generate cyclic precursors of many bioactive natural products, such as the antidiabetic drug acarbose, the crop protectant validamycin, and the natural sunscreens mycosporine-like amino acids. These proteins are phylogenetically related to the dehydroquinate (DHQ) synthases from the shikimate pathway and are part of the more recently recognized superfamily of sugar phosphate cyclases, which includes DHQ synthases, aminoDHQ synthases, and 2-deoxy-scyllo-inosose synthases. Through genome mining and biochemical studies, we identified yet another subset of DHQS-like proteins in the actinomycete Actinosynnema mirum and the myxobacterium Stigmatella aurantiaca DW4/3-1. These enzymes catalyze the conversion of sedoheptulose 7-phosphate to 2-epi-valiolone, which is predicted to be an alternative precursor for aminocyclitol biosynthesis. Comparative bioinformatics and biochemical analyses of these proteins with 2-epi-5-epi-valiolone synthases (EEVS) and desmethyl-4-deoxygadusol synthases (DDGS) provided further insights into their genetic diversity, conserved amino acid sequences, and plausible catalytic mechanisms. The results further highlight the uniquely diverse DHQS-like sugar phosphate cyclases, which may provide new tools for chemoenzymatic, stereospecific synthesis of various cyclic molecules.

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure–activity relationship (SAR) studies were also undertaken.

Synthesis of nucleoside phosphosulfates

We describe an efficient and scalable procedure for the chemical synthesis of nucleoside 5′-phosphosulfates (NPS) from nucleoside 5′-phosphorimidazolides and sulfate bis(tributylammonium) salt. Using this method we obtained various NPS with yields ranging from 70–90%, including adenosine 5′-phosphosulfate (APS) and 2′,3′-cyclic precursor of 3′-phosphoadenosine 5′-phosphosulfate (PAPS), which are the key intermediates in the assimilation and metabolism of sulfur in all living organisms.

Reagent-controlled stereoselective synthesis of (±)-gallo- and (±)-epigallo-catechin gallates

Synthesis of (±)-gallocatechin and (±)-epigallocatechin gallates by electrophilic cycloarylation is reported. The precursors for cyclization were prepared by reagent-controlled stereo-selective opening of epoxide with phenol. Activation of the S-oxidized S,O-acetal enabled electrophilic cycloarylation to stereoselectively provide the acylated catechins.

Reductive Heck coupling: an efficient approach toward the iboga alkaloids. Synthesis of ibogamine, epiibogamine and iboga analogs

A mild and efficient synthetic route to the iboga scaffold by employing reductive-Heck type annulation is described. The utility of this process is demonstrated by the direct access to the ibogamine, epiibogamine and iboga-analogs. The cyclization precursors were readily obtained from 2-iodoaniline by heteroannulation reaction with suitable alkynes followed by iodination.

Low-k SiCxNy Films Prepared by Plasma-Enhanced Chemical Vapor Deposition Using 1,3,5-trimethyl-1,3,5-trivinylcyclotrisilazane Precursor

Low-k silicon carbonitride (SiCxNy) films with k of 3.6–4.6 were prepared by radio frequency plasma-enhanced chemical vapor deposition at 25 to 400°C under low power density of 0.15 W/cm3, using a single source precursor, 1, 3, 5-trimethyl-1, 3, 5-trivinylcyclotrisilazane (VSZ), and Ar. At lower deposition temperatures (≤ 200°C), most cyclic VSZ structures were preserved in the SiCxNy films, resulting in a lower density (1.60–1.76 g/cm3), a lower dielectric constant (k∼3.6–3.9) and a fairly good elastic modulus of 22.0–25.0 GPa. When the deposition temperature was raised to 400°C, the cyclic N-Si-N linkages were reformed to a dense Si-N structure, with the desorption of CHx bonds, resulting in higher density (2.0 g/cm3), a dielectric constant of 4.6, and an excellent elastic modulus of 65.2 GPa. The leakage current density of SiCxNy films was reduced from 1.5×10−6 to 4.0×10−8 A/cm2 at 1 MV/cm, upon increasing the deposition temperature from 25°C to 400°C. The conduction mechanism of the SiCxNy films, except the film deposited at 400°C and tested under higher electric field, exhibited Schottky emission due to few charged defects by using a cyclic VSZ precursor and a lower plasma power density of 0.15 W/cm3.

Discovery and application of 6π-azaelectrocyclization to natural product synthesis and synthetic biology

While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural product, we discovered a reaction involving a rapid 6π-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues.The electrocyclic reaction of the 1-azatriene system,a cyclization precursor,exhibited a significant substituent effect.Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural product.Additionally,we developed lysine-based labeling and engineering of biomolecules and living cells based on the rapid 6π-azaelectrocyclization.Both labels and oligosaccharide structures were introduced efficiently and selectively into surface lysines under the mild conditions; notable effects of N -glycans on proteins and living cells were visualized for the first time by PET and noninvasive fluorescence imaging.