Helix-to-Disc Conversion of Thia[6]helicenes into Coronenes Facilitated by Sulfur Oxidation and Fluorination.

Helicenes, with their unique helical structures, have long captured the interest of synthetic chemists, not only as end products, but also as versatile platforms for further chemical transformations. However, transforming [6]helicene into planar coronene typically requires harsh conditions and poses significant challenges. Herein, we demonstrate that replacing the terminal benzene ring of [6]helicene with a thiophene ring enables its photochemical transformation into coronene. Sulfur oxidation of the thiophene ring enables the corresponding thermal transformation, and the terminal tetrafluorination of the opposite benzene ring further accelerates this process, yielding 1,2-difluorocoronene, as confirmed by X-ray crystallography. The transformation begins with an intramolecular Diels-Alder reaction, whose activation energy is significantly lowered by these structural changes. Our findings underscore the utility of strategic modifications such as sulfur oxidation and fluorination in promoting this "helix-to-disc" conversion and opening new avenues for synthesizing functional polycyclic aromatics.

Skeletal Transformation Triggered by C-F Bond Activation after Photochemical Rearrangement of Fluorinated [7]Helicenes.

Tri- and tetra-fluorinated [7]helicenes are photolabile and undergo a double fluorine atom transfer. Herein, we show that the transferred product further undergoes a skeletal transformation on silica gel. The transformation begins with activation of the allylic C-F bond on the silanol surface. Then, the resulting carbocation readily undergoes a regioselective nucleophilic aromatic substitution with water, depending on the position of the fluorine substituents. Hexafluoro-2-propanol also activated the allylic C-F bond and acted as a nucleophile. These findings support the generation of a highly reactive cationic electrophilic intermediate in the successive transformations involving fluorine atoms.

Electrophilic Spirocyclization of a 2-Biphenylacetylene via Conformational Fixing within a Hollow-Cage Host.

A 2-biphenylacetylene was fixed into a specific conformation within the confined cavity of a hollow cage, where it underwent a regioselective spirocyclization in the presence of an electrophile. A 5-endo-dig cyclization proceeded selectively in the cage, which stands in sharp contrast to the 6-endo-dig cyclization that normally occurs in common organic media. The folded conformation adopted by the substrate within the cage was examined by 1 H NMR spectroscopy and X-ray crystallographic analysis.

Cavity-Directed Chromism of Phthalein Dyes.

Phthalein dyes in the quinone dianion form (pseudo-D3, colored) are transformed into the lactone dianion form (pseudo-T(d), colorless) through encapsulation in a T(d)-symmetric host even under basic conditions (pH ∼10). The compatibility in size and symmetry between the lactone and the cavity is essential to the transformation. Upon addition of a guest that strongly binds to the cavity, the encapsulated phenolphthalein is expelled, the color of the basic solution is regained, and the host-guest complexation is thus visualized.

Rectifying Electron-Transport Properties through Stacks of Aromatic Molecules Inserted into a Self-Assembled Cage.

Aromatic stacks formed through self-assembly are promising building blocks for the construction of molecular electronic devices with adjustable electronic functions, in which noncovalently bound π-stacks act as replaceable modular components. Here we describe the electron-transport properties of single-molecule aromatic stacks aligned in a self-assembled cage, using scanning probe microscopic and break junction methods. Same and different modular aromatic pairs are noncovalently bound and stacked within the molecular cage holder, which leads to diverse electronic functions. The insertion of same pairs induces high electronic conductivity (10(-3)-10(-2) G0, G0 = 2e(2)/h), while different pairs develop additional electronic rectification properties. The rectification ratio was, respectively, estimated to be 1.4-2 and >10 in current-voltage characteristics and molecular orientation-dependent conductance measurements at a fixed bias voltage. Theoretical calculations demonstrate that this rectification behavior originates from the distinct stacking order of the internal aromatic components against the electron-transport direction and the corresponding lowest unoccupied molecular orbital conduction channels localized on one side of the molecular junctions.

One-step synthesis of [16]helicene.

A single-strand arylene-vinylene precursor containing four phenylene and three naphthylene units linked together with six vinylene spacers undergoes helical folding via sextuple photocyclization to give a [16]helicene core in a single step. The phenylene and naphthylene units are arranged in the precursor such that unfavorable side reactions (anthracene or benzoperylene formation) are avoided, and this is the key to the success of the one-step synthesis of [16]helicene, which is the longest [n]helicene that has been synthesized to date.

Halogen-Bond-Assisted Guest Inclusion in a Synthetic Cavity.

The confined space inside a self-assembled cage enhanced halogen bonding (XB) between iodoperfluorocarbons (XB donors) and NO3(-) anions or H2O molecules (XB acceptors), as confirmed by NMR spectroscopy in solution and by X-ray crystallography in the solid state. The cavity also bound an XB donor-acceptor pair, C6F3I3 and C6H5NMe2, in a selective pairwise fashion.

Metal-organic proximity in a synthetic pocket.

Proximity between a noninteractive organic substrate and a transition metal (trans-MCl2(PEt3)2; M = Pd or Pt) is achieved by their co-encapsulation within a synthetic cage, as revealed by X-ray crystallographic analysis and NOESY experiments. Through co-encapsulation with a Pd(II) complex, a terminal alkyne was activated within the cage to give a σ-alkynylpalladium complex.

Recognition of polyfluorinated compounds through self-aggregation in a cavity.

Polyfluorinated aliphatic compounds were encapsulated by a self-assembled M6L4 coordination host in aqueous media. NMR titration and X-ray crystallographic analyses clearly revealed that the aggregation of the fluorinated moieties of the guests in the host cavity plays a significant role in the binding. Polyfluorinated aromatics did not show such aggregation in the cavity because of their "nonfluorous" nature.

Adipsia increases risk of death in patients with central diabetes insipidus.

Central diabetes insipidus (CDI) is caused by deficiency of arginine vasopressin, an antidiuretic hormone. Patients with CDI manifest polyuria which is usually compensated for by increases in water intake. However, some patients are not able to sense thirst due to the destruction of osmoreceptors in the hypothalamus. These adipsic CDI patients are easily dehydrated and the consequent dehydration could be life-threatening. The objective of this study was to investigate the prognosis of adipsic CDI patients. We have reviewed 149 patients with CDI in three hospitals using databases of the electronic medical recording systems, and examined whether adipsia could affect the morbidity and mortality in CDI patients with multivariable analyses. Twenty-three patients with CDI were adipsic while the remaining 126 patients were non-adipsic. The multivariate analyses showed that the incidence of serious infections which required hospitalization was significantly higher in the adipsic CDI patients compared to that in non-adipsic CDI patients (p <0.001). A total of 6 patients with CDI died during the follow-up (median duration; 60 months, range 1 to 132 months). Four of them were adipsic, three of whom died of infection. The statistical analyses revealed that the risk of death in adipsic CDI patients was significantly higher than in non-adipsic patients (p =0.007). It is thus suggested that adipsic CDI patients were susceptible to serious infections which could be the causes of death.

Control of silver(I)-dialkyl chalcogenide coordination by a synthetic cavity.

The discrete cavity of a self-assembled palladium-tris(4-pyridyl)triazine cage dictates the ratio of metal, ligand, and a non-coordinative molecule in the formation of silver(I)-dialkyl chalcogenide (Et, nBu; S, Se) complexes and defines their coordination arrangement.

A tray-shaped, Pd(II)-clipped Au3 complex as a scaffold for the modular assembly of [3×n] Au ion clusters.

A tray-shaped Pd(II)3Au(I)3 complex (1) is prepared from 3,5-bis(3-pyridyl)pyrazole by means of tricyclization with Au(I) followed by Pd(II) clipping. Tray 1 is an efficient scaffold for the modular assembly of [3×n] Au(I) clusters. Treatment of 1 with the Au(I)3 tricyclic guest 2 in H2O/CH3CN (7:3) or H2O results in the selective formation of a [3×2] cluster (1⋅2) or a [3×3] cluster (1⋅2⋅1), respectively. Upon subsequent addition of Ag(I) ions, these complexes are converted to an unprecedented Au3-Au3-Ag-Au3-Au3 metal ion cluster.

Noncovalent tailoring of the binding pocket of self-assembled cages by remote bulky ancillary groups.

The binding properties of a self-assembled coordination cage were subtly tuned by ancillary groups on the metal corners of the cage. Since the bulky mesityl groups of the ligand hang over the cage cavity, the effective cavity volume is reduced. Due to the tighter guest packing inside the shrunken cavity, smaller guests were efficiently bound and guest motion was restricted even at high temperatures.

Temporary and permanent trapping of the metastable twisted conformer of an overcrowded chromic alkene via encapsulation.

An overcrowded alkene with an anti-folded conformation was converted to its twisted conformer, accompanied by a dramatic color change from yellow to deep purple, by inclusion in a self-assembled T(d)-symmetric coordination cage. The shape of the caged cavity was suitable and desirable for trapping of the twisted conformer. The twisted conformation was temporarily memorized in the alkene even after guest ejection. Permanent trapping of the twisted conformation was achieved by bromination of the twisted conformer formed in situ in the cage.

Cage-catalyzed Knoevenagel condensation under neutral conditions in water.

A cationic coordination cage dramatically accelerates the Knoevenagel condensation of aromatic aldehydes in water under neutral conditions. The addition of a nucleophile to the aldehyde to generate anionic intermediates seems to be facilitated by the cationic environment of the cavity. The products are ejected from the cage as a result of the host-guest size discrepancy. As a result, the condensation is promoted by a catalytic amount of the cage.

Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome.

Osmotic demyelination syndrome (ODS) is a serious demyelinating disease in the central nervous system usually caused by rapid correction of hyponatremia. In an animal model of ODS, we previously reported microglial accumulation expressing proinflammatory cytokines. Microglia and astrocytes secreting proinflammatory cytokines and neurotrophic factors are reported to be involved in the pathogenesis of demyelinative diseases. Therefore, to clarify the role of microglial and astrocytic function in ODS, we examined the time-dependent changes in distribution, morphology, proliferation, and mRNA/protein expression of proinflammatory cytokines, neurotrophic factors, and matrix metalloproteinase (MMP) in microglia and astrocytes 2 days (early phase) and 5 days (late phase) after the rapid correction of hyponatremia in ODS rats. The number of microglia time dependently increased at demyelinative lesion sites, proliferated, and expressed tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase, and MMP2, 9, and 12 at the early phase. Microglia also expressed leukemia inhibitory factor (a neurotrophic factor) and phagocytosed myelin debris at the late phase. The number of astrocytes time dependently increased around demyelinative lesions, extended processes to lesions, proliferated, and expressed nerve growth factor and glial cell line-derived neurotrophic factor at the late phase. Moreover, treatment with infliximab, a monoclonal antibody against TNF-α, significantly attenuated neurological impairments. Our results suggest that the role of microglia in ODS is time dependently shifted from detrimental to protective and that astrocytes play a protective role at the late phase. Modulation of excessive proinflammatory responses in microglia during the early phase after rapid correction may represent a therapeutic target for ODS.

Noncovalent trapping and stabilization of dinuclear ruthenium complexes within a coordination cage.

A dinuclear ruthenium complex, [(η(5)-indenyl)Ru(CO)(2)](2), was noncovalently enclathrated within a self-assembled coordination cage. In the cavity, rapid cis-trans isomerization and ligand exchange between the terminal and bridging carbonyls were suppressed, and only the carbonyl-bridged cis configuration was observed by X-ray crystallographic analysis.

Synthesis of Terminally Fluorinated [7]Helicenes and Their Application to Photochemical Domino Reactions.

The intramolecular Diels-Alder reactions of helicenes deform their π-conjugated screw-shaped skeletons. In particular, terminally tetrafluorinated [7]helicene (F4 -[7]helicene) undergoes a photoinduced Diels-Alder reaction followed by a photoinduced double fluorine atom transfer. Herein, we thoroughly investigated this photochemical domino process by decreasing the level of fluorine substitution. F3 -[7]Helicenes bearing two fluorine atoms at the dienophile terminal underwent photoinduced Diels-Alder reactions, but the whole domino process became slow. F2 -[7]Helicene, which is difluorinated only at the dienophile terminal, was also photolabile. As a result, two fluorine atoms were sufficient for the photochemical domino reaction to occur. X-ray crystallographic analysis revealed that F2 -[7]helicene was less compressed than F4 -[7]helicene, indicating that terminal polyfluorination enhanced the intramolecular arene-fluoroarene stacking interactions and thus promoted the transformations.

Associations of Dietary Salt and Its Sources with Hemoglobin A1c in Patients with Type 2 Diabetes Not Taking Anti-Diabetic Medications: Analysis Based on 6-Month Intervention with a Moderate Low-Carbohydrate Diet.

OBJECTIVE: Based on biological studies, the hyperglycemic effect mediated by sodium-glucose co-transporter 1 in the intestine is stronger for foods containing more sodium chloride. Observational studies have demonstrated that type 2 diabetes (T2DM) incidence increases as salt intake increases. We aimed to elucidate associations of total salt and its sources with hemoglobin A1c (HbA1c) in patients with T2DM. METHODS: We conducted an observational study using data from a 6-month moderate low-carbohydrate dietary intervention in 245 outpatients with T2DM (138 men) without antidiabetic medication. Intakes of total salt and its sources, carbohydrate and total energy were assessed at baseline and 6 months based on 3-day dietary records. Multiple regression analyses were performed to examine associations of Δtotal salt or its sources with ΔHbA1c. RESULTS: Salt intake significantly decreased in men (change: -0.92 ± 3.53 g/day) but not in women (0.11 ± 2.28). HbA1c (men: -1.5 ± 1.6%; women: -0.9 ± 1.3%), carbohydrate (men: -115 ± 104 g/day; women: -64 ± 71) and total energy (men: -439 ± 660 kcal/day; women: -192 ± 438) significantly decreased in both sexes. Multiple regression analysis revealed that reducing intakes of total salt and salt from salty snacks, meat processed foods, Chinese noodles with soup and table salt by 1.0 g was associated with decreases in HbA1c of 0.11% 1.18% 0.47% 0.38% and 0.26%, respectively, in men, while reducing salt from miso by 1.0 g was associated with a decrease in HbA1c of 0.30% in women. The associations were dependent on Δcarbohydrate or Δtotal energy in men, while the association of Δsalt from miso in women was independent of them. CONCLUSION: Reducing total salt and its sources had differential associations with HbA1c. Individual associations depended on Δcarbohydrate or Δtotal energy in men, while that of salt from miso in women was independent of them.

Reducing Carbohydrate from Individual Sources Has Differential Effects on Glycosylated Hemoglobin in Type 2 Diabetes Mellitus Patients on Moderate Low-Carbohydrate Diets.

Background: We evaluated decreases in glycosylated hemoglobin (HbA1c) achieved by reducing carbohydrate from various sources in type 2 diabetes mellitus patients. Methods: We followed up 138 male and 107 female outpatients on a moderate low-carbohydrate diet without diabetic medication for 6 months. Changes in carbohydrate sources (Δcarbohydrate) were assessed from 3-day dietary records at baseline and 6 months, and associations with changes in HbA1c (ΔHbA1c) were examined with Spearman's correlation coefficients (rs) and multiple regression analysis. Results: ΔHbA1c was -1.5%±1.6% in men and -0.9%±1.3% in women, while Δtotal carbohydrate was -115.3±103.7 g/day in men and -63.6±71.1 g/day in women. Positive associations with ΔHbA1c were found for Δtotal carbohydrate (rs=0.584), Δcarbohydrate from soft drinks (0.368), confectionery (0.361), rice (0.325), bread (0.221), Chinese soup noodles (0.199) in men, and Δtotal carbohydrate (0.547) and Δcarbohydrate from rice (0.376) and confectionery (0.195) in women. Reducing carbohydrate sources by 50 g achieved decreases in HbA1c of 0.43% for total carbohydrate, 1.33% for soft drinks, 0.88% for confectionery, 0.63% for bread, 0.82% for Chinese soup noodles and 0.34% for rice in men and 0.45% for total carbohydrate, 0.67% for confectionery and 0.34% for rice in women, although mean reductions in carbohydrate from these sources were much smaller than that from rice. Conclusion: Decreases in HbA1c achieved by reducing carbohydrate from soft drinks, confectionery, bread and Chinese soup noodles were 2- to 4-fold greater than that for rice. Our results will enable patients to decrease HbA1c efficiently (UMIN000009866).