Total synthesis of isoneoantimycin.

Antimycins are one of the well-known antifungal metabolites produced by Streptomyces bacteria. Neoantimycin and its analogues, the ring-expanded antimycins featuring a 15-membered tetraester ring, have been shown to be effective regulators of the oncogenic proteins GRP78/BiP and K-Ras. Isoneoantimycin was isolated from Streptomyces fradiae IFO12773 (ISP 5063) as a minor metabolite during the fermentation of neoantimycin and is the first reported antibiotic of the antimycin family without the macrolide core. In this study, we explored the total synthesis and stereochemical assignment of isoneoantimycin as an approach to perform structure-activity studies on neoantimycins. Taking the neoantimycin biosynthesis pathway into account, we presumed that the stereochemistry of isoneoantimycin is the same as that of neoantimycin. The synthesis of our target molecule with the (1S,2R,5S,6S,14R,15R,17S) configuration has been achieved by using chiral-pool building blocks. A comparison of the spectroscopic data between the synthetic and natural samples verified our presumption of the stereochemistry of natural isoneoantimycin.

Ligand-Dependant Selective Synthesis of Mono- and Dialkenylcarbazoles through Rhodium(III)-Catalyzed C-H Alkenylation.

The C-H alkenylation of N-acetylcarbazoles proceeds smoothly at the C1-position in the presence of a cationic Cp*Rh(III) catalyst to produce 1-alkenylcarbazoles. The use of a cationic CpE Rh(III) catalyst enables further alkenylation to give 1,8-dialkenylcarbazoles. The direct alkenylation procedure in combination with the ready removal of the acetyl directing group provides a straightforward synthetic pathway to 1- and/or 8-alkenyl-N-H-carbazole derivatives. One of 1-alkenyl-N-H-carbazoles obtained by the present C-H alkenylation/deacetylation exhibits solvatochromism.

Formylation Reaction of Amines Using N-Formylcarbazole.

Formamides are useful starting materials for pharmaceutical syntheses. Although various synthetic methods have been documented in this regard, the use of N-formylcarbazole as a formylation reagent for amines has not yet been reported. We report here the first examples of the use of N-formylcarbazole for the formylation of amines. The characteristic reactivity of N-formylcarbazole enables the selective formylation of sterically less hindered aliphatic primary and secondary amines. In contrast, sterically bulkier amines and weakly nucleophilic amines such as anilines are less reactive under the reaction conditions.

Detection of prostate-specific antigen in semen using DNA aptamers: an application of nucleic acid aptamers in forensic body fluid identification.

In forensics, body fluid identification plays an important role because it aids in reconstructing a crime scene. Therefore, it is essential to develop simple and reliable techniques for body fluid identification. Nucleic acid aptamers are useful tools in analytical chemistry that can be used to improve conventional forensic analytical techniques. They have numerous advantages over antibodies including their low cost, long shelf life, and applicability for chemical modification and PCR amplification. A DNA aptamer against a human prostate-specific antigen (PSA), which is a well-known protein marker for semen identification in forensics, has been reported previously. In this study, as a proof-of-concept for nucleic acid aptamer-based identification of body fluids, we developed a technique of aptamer-based PSA assays for semen identification that employed enzyme-linked oligonucleotide assay (ELONA) and real-time PCR. We evaluated their sensitivity and specificity for semen compared with those for blood, saliva, urine, sweat, and vaginal secretion. The assays have equivalent procedures compared to enzyme-linked immunosorbent assay; their results were consistent with those produced by the conventional immunochromatographic assay. The minimum volume of semen required for detection was 62.5 nL in ELONA and 5 nL in real-time PCR, making this assay applicable for semen detection in actual criminal investigation. Aptamers can be a cost-effective and versatile tool for forensic body fluid identification.

Cerium(IV) Carboxylate Photocatalyst for Catalytic Radical Formation from Carboxylic Acids: Decarboxylative Oxygenation of Aliphatic Carboxylic Acids and Lactonization of Aromatic Carboxylic Acids.

We found that in situ generated cerium(IV) carboxylate generated by mixing the precursor Ce(OtBu)4 with the corresponding carboxylic acids served as efficient photocatalysts for the direct formation of carboxyl radicals from carboxylic acids under blue light-emitting diodes (blue LEDs) irradiation and air, resulting in catalytic decarboxylative oxygenation of aliphatic carboxylic acids to give C-O bond-forming products such as aldehydes and ketones. Control experiments revealed that hexanuclear Ce(IV) carboxylate clusters initially formed in the reaction mixture and the ligand-to-metal charge transfer nature of the Ce(IV) carboxylate clusters was responsible for the high catalytic performance to transform the carboxylate ligands to the carboxyl radical. In addition, the Ce(IV) carboxylate cluster catalyzed direct lactonization of 2-isopropylbenzoic acid to produce the corresponding peroxy lactone and γ-lactone via intramolecular 1,5-hydrogen atom transfer (1,5-HAT).

Rhodium(III)-Catalyzed Redox-Neutral Coupling of α-Trifluoromethylacrylic Acid with Benzamides through Directed C-H Bond Cleavage.

A rhodium(III)-catalyzed redox-neutral coupling of α-trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide-directed C-H bond cleavage to produce ß-[2-(aminocarbonyl)phenyl]-α-trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox-neutral coupling of α-trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen-containing directing group can also be conducted under similar conditions.

Total Syntheses and Configuration Assignments of JBIR-06 and Related Depsipeptides.

The first total syntheses of JBIR-06 and two analogous depsipeptides, 12-membered antimycin-class antibiotics, have been accomplished via Shiina macrolactonization. Comparison of the spectroscopic data of the synthesized compounds with those reported for natural products verified that the absolute configutation of the natural products was (2 S,4 S,6 S,7 R,14 S).

Evaluation of Inhibitory Activities of UK-2A, an Antimycin-Type Antibiotic, and Its Synthetic Analogues against the Production of Anti-inflammatory Cytokine IL-4.

The inhibitory activities of the antimycin-class antibiotics UK-2A, antimycin A, and splenocin B against the production of anti-inflammatory cytokine IL-4, which is related to IgE-mediated allergic responses in rat basophilic leukemia (RBL-2H3) cells, were evaluated. Although antimycin A and splenocin B showed cytotoxicity at concentrations at which IL-4 release from the cells was restricted, UK-2A was found to restrict IL-4 release without cytotoxicity. Three UK-2A analogues (4-6) were then synthesized and assessed. Compound 5 restricted IL-4 release dose-dependently without cytotoxicity, and its effect was more potent than that of UK-2A.

Rhodium(III)-Catalyzed Oxidative Coupling of N-Phenylindole-3-carboxylic Acids with Alkenes and Alkynes via C4-H and C2-H/C2'-H Bond Cleavage.

The rhodium(III)-catalyzed direct alkenylation of N-phenylindole-3-carboxylic acids with alkenes including acrylate ester, acrylamide, and acrylonitrile proceeds smoothly at the C4-position through regioselective C-H bond cleavage directed by the carboxyl group. In marked contrast, the indole substrates react with diarylacetylenes accompanied by cleavage of the C2-H and C2'-H bonds and decarboxylation to produce 5,6-diarylindolo[1,2- a]quinolone derivatives. DFT calculations have suggested that the smooth insertion of an alkene to a C4-rhodated six-membered metallacycle intermediate leads to the C4 alkenylated products, while the latter annulation at the C2- and C2'-positions is attributable to facile reductive elimination in the corresponding seven-membered metallacycles formed by the double C-H bond cleavage and alkyne insertion.

Development of mRNA-based body fluid identification using reverse transcription loop-mediated isothermal amplification.

Identifying body fluids from forensic samples can provide valuable evidence for criminal investigations. Messenger RNA (mRNA)-based body fluid identification was recently developed, and highly sensitive parallel identification using reverse transcription polymerase chain reaction (RT-PCR) has been described. In this study, we developed reverse transcription loop-mediated isothermal amplification (RT-LAMP) as a simple, rapid assay for identifying three common forensic body fluids, namely blood, semen, and saliva, and evaluated its specificity and sensitivity. Hemoglobin beta (HBB), transglutaminase 4 (TGM4), and statherin (STATH) were selected as marker genes for blood, semen, and saliva, respectively. RT-LAMP could be performed in a single step including both reverse transcription and DNA amplification under an isothermal condition within 60 min, and detection could be conveniently performed via visual fluorescence. Marker-specific amplification was performed in each assay, and no cross-reaction was observed among five representative forensically relevant body fluids. The detection limits of the assays were 0.3 nL, 30 nL, and 0.3 µL for blood, semen, and saliva, respectively, and their sensitivities were comparable with those of RT-PCR. Furthermore, RT-LAMP assays were applicable to forensic casework samples. It is considered that RT-LAMP is useful for body fluid identification.

Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with Alkynes: A Remarkable Switch of Oxacyclic Product.

The iridium(III)/copper(II)-catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes proceeds efficiently under atmospheric oxygen through aldehyde C-H bond cleavage and decarbonylation. A variety of benzofuran derivatives can be synthesized by the environmentally benign procedure. DFT calculations suggest that this unique transformation involves the facile deinsertion of CO in the key metallacycle intermediate, which is in marked contrast to the corresponding rhodium(III) catalysis that leads to CO-retentive chromone derivatives.

Total syntheses and configuration assignments of JBIR-04 and unantimycin A.

First total syntheses of JBIR-04 and unantimycin A have been achieved. Comparison of our spectroscopic data with those reported for natural samples verified the structure of the natural products; (2S,4S,6S,7R,9S,28S) configuration was thus assigned via total synthesis.

Rhodium(III)-Catalyzed Ortho-Alkenylation of Anilines Directed by a Removable Boc-Protecting Group.

The rhodium(III)-catalyzed ortho-alkenylation of N-Boc-anilines with alkenes such as acrylate ester and styrene proceeds smoothly through C-H bond cleavage. Obtained o-alkenylanilines can be readily transformed to nitrogen-containing fused heteroaromatic compounds including indoles and quinolines.

Construction of Bisbenzofuro[2,3-b:3',2'-e]pyridines by Palladium-Catalyzed Double Intramolecular Oxidative C-H/C-H Coupling.

The palladium-catalyzed intramolecular oxidative C-H/C-H coupling of 2-aryloxypyridines as challenging substrates is investigated to construct an important class of N,O-mixed heteroacenes, i.e. benzofuropyridines. It is found that 2,6-diaryloxypyridines efficiently undergo double cyclization to provide bisbenzofuro[2,3-b:3',2'-e]pyridines of interest in materials chemistry.

Mano-videoendoscopic assessment in the evaluation of the pharyngeal contraction and upper esophageal sphincter function in dysphagic patients.

OBJECTIVE: Mano-videoendoscopy (MVE) is a manometry technique with endoscopic confirmation of the pressure catheter. This study aimed to investigate the possibility of replacing a videofluorographic swallowing study (VFSS) with MVE for the precise evaluation of the pharyngeal contraction and the upper esophageal sphincter (UES) function. METHODS: The data from 69 patients with dysphagia were retrospectively reviewed. All of the patients underwent both MVE and a VFSS for the evaluation of dysphagia. Manometry was performed with a transnasally inserted catheter (2.6-mm outer diameter and 4 pressure sensors) under endoscopic observation. The sensors were kept at the tongue base, upper pyriform sinus, apex of the pyriform sinus, and UES. We evaluated the pharyngeal contraction and UES function fluorographically and statistically compared the manometric parameters. RESULTS: The fluorographic pharyngeal contraction was diagnosed as good in 28 patients and poor in 41 patients. The UES opening was diagnosed as good in 44 patients and poor in 25 patients. The highest pressure values at the tongue base (sensor 1), upper pyriform sinus (sensor 2), and apex of the pyriform sinus (sensor 3) were significantly larger in the good contraction group than in the poor contraction group. A stepwise logistic regression test revealed that the peak pressure of sensor 2 (upper pyriform sinus) was a robust predictor of fluorographic pharyngeal contraction, and the cut-off level for good fluorographic pharyngeal contraction was >81.5mmHg (specificity, 0.929; sensitivity, 0.870; area under the curve, 0.923). The nadir pressure, pressure drop, and pressure rise in the UES were significantly correlated with the fluorographic UES opening. A stepwise logistic regression test revealed that the pressure drop-the gap between the resting pressure and the nadir of the UES pressure-was a robust predictor of fluorographic UES opening, and the cut-off level to anticipate good fluorographic opening was ≥33.5mmHg (specificity, 0.853; sensitivity, 0.759). CONCLUSION: MVE can supplement the information obtained regarding the pharyngeal contraction and UES function, and overcomes the drawbacks of a videoendoscopic swallowing study (VESS).

Synthesis of Difluorinated Enynes through Sonogashira-Type Coupling.

The Sonogashira-type coupling of 2,2-difluoroethenyl tosylate with a variety of aliphatic and aromatic terminal alkynes proceeds smoothly even at room temperature to produce the corresponding difluorinated enyne derivatives. 2,2-Difluoroethenyl tosylate is a useful difluoroethenyl source because of its ready availability from 2,2,2-trifluoroethanol. Some of the obtained enynes exhibit strong fluorescence in the solid state. Further derivatization of a difluorinated enyne through Rh(III)-catalyzed oxidative coupling has also been examined.

Regioselective Synthesis of Benzo[b]phosphole Derivatives via Direct ortho-Alkenylation and Cyclization of Arylthiophosphinamides.

A new regioselective synthetic methodology for benzo[b]phosphole derivatives has been developed. Thus, a range of functionalized benzo[b]phosphole oxides could be synthesized via Rh(III)-catalyzed C-H alkenylation of arylthiophosphinamides with alkynes followed by formal phospha-Friedel-Crafts cyclization.

Ruthenium-Catalyzed Cross-Coupling of Maleimides with Alkenes.

The cross-coupling of maleimides with electron-deficient alkenes such as acrylates proceeds smoothly under ruthenium catalysis. This unique C-C coupling provides a simple, straightforward synthetic method for preparing alkylidene succinimide derivatives.

Oxidative Annulation of Arenecarboxylic and Acrylic Acids with Alkynes under Ambient Conditions Catalyzed by an Electron-Deficient Rhodium(III) Complex.

It has been established that an electron-deficient Cp(E) rhodium(III) complex catalyzes the oxidative [4+2] annulation of substituted arenecarboxylic and acrylic acids with alkynes under ambient conditions (at RT-40 °C, under air) without using excess amounts of substrates to produce the corresponding substituted isocoumarins and α-pyrones in high yields. Minor modification of reaction conditions depending on the coordination ability of alkynes realized the high efficiency.

Ruthenium-Catalyzed Regioselective C-H Bond Acetoxylation on Carbazole and Indole Frameworks.

The regioselective C-H bond cleavage/C-O bond formation takes place smoothly upon treatment of 9-(pyridin-2-yl)carbazoles with acetic acid in the presence of a silver salt oxidant under ruthenium catalysis to afford the corresponding C1- and C8-diacetoxylated products. Under similar conditions, the acetoxylation of 2-aryl-1-(pyridin-2-yl)indoles as well as 1-aryl-7-azaindoles can also be conducted efficiently.