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.

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.

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).

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.

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.

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.

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.

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.

Synthesis of Benzo[c]thiophenes by Rhodium(III)-Catalyzed Dehydrogenative Annulation.

The dehydrogenative annulation of thiophen-2-carboxamides with 2 equiv of alkynes proceeds efficiently in the presence of a rhodium catalyst and a copper oxidant to furnish multiply substituted benzo[c]thiophenes. Some of the synthesized benzo[c]thiophenes exhibited strong solid-state fluorescence.

Rhodium-catalyzed dehydrogenative coupling of phenylheteroarenes with alkynes or alkenes.

Benzo-fused tri- to heptacyclic heteroarenes were effectively constructed by the rhodium-catalyzed dehydrogenative coupling of phenylheteroarenes with alkynes. Using alkenes as coupling partners, dehydrogenative alkenylation took place selectively on the phenyl moiety of phenylheteroarenes. Several experiments with deuterium-labeled substrates indicated that double C-H bond cleavages take place even in the reaction with alkenes.

Copper-mediated formally dehydrative biaryl coupling of azine N-oxides and oxazoles.

A copper-mediated formally dehydrative biaryl coupling of azine N-oxides and oxazoles has been developed. The C-C bond-forming process proceeds, accompanied by the removal of the oxygen atom from the azine core, to directly afford the azine-oxazole biaryl linkage. Moreover, this system requires no noble transition metals such as palladium and rhodium, which are common promotors in the related dehydrogenative couplings with the azine N-oxide. Thus, the present protocol can provide a unique and less expensive approach to the azine-containing biheteroaryls of substantial interest in pharmaceutical and medicinal chemistry.

Synthesis of indolines by copper-mediated intramolecular aromatic C-h amination.

A Cu(OAc)2-mediated intramolecular aromatic C-H amination proceeds with the aid of a picolinamide-type bidentate coordination group to deliver the corresponding indolines in good yields. The reaction occurs smoothly even under noble-metal-free conditions, and in some cases the use of an MnO2 terminal oxidant renders the process catalytic in Cu. The mild oxidation aptitude of Cu(OAc)2 and/or MnO2 accommodates the formation of electron-rich thiophene- and indole-fused indoline analogues. The Cu-based system can provide an effective approach to various indolines of potent interest in pharmaceutical and medicinal chemistry.

Evaluation of the intrinsic charge carrier transporting properties of linear- and bent-shaped π-extended benzo-fused thieno[3,2-b]thiophenes.

The intrinsic charge carrier transporting properties of two isomeric linear- and bent-shaped 7-ring benzo-fused thieno[3,2-b] thiophenes and their octyl-substituted analogues were newly investigated using flash-photolysis (FP-) and field-induced (FI-) time-resolved microwave conductivity (TRMC) techniques. FP-TRMC study in the solid state revealed that octyl-substitution potentially improved the photoconductivity due to the enhanced crystalline lamellar packing. After this screening process, local-scale hole mobilities at the thienoacene-poly(methylmethacrylate) insulator interfaces were precisely recorded using FI-TRMC, reaching up to 4.5 cm(2) V(-1) s(-1) for the linear-shaped non-alkylated thienoacene. The combination of FP- and FI-TRMC measurements provides a rapid and quantitative evaluation scheme even for a variety of compounds with some issues in the processing conditions, leading to the optimized structure of the compounds used as active (interfacial) layers in practical electronic devices.

Copper-catalyzed stereoselective aminoboration of bicyclic alkenes.

A copper-catalyzed aminoboration of bicyclic alkenes, including oxa- and azabenzonorbornadienes, has been developed. With this method, amine and boron moieties are simultaneously introduced at an olefin with exo selectivity. Subsequent stereospecific transformations of the boryl group can provide oxygen- and nitrogen-rich cyclic molecules with motifs that may be found in natural products or pharmaceutically active compounds. Moreover, a catalytic asymmetric variant of this transformation was realized by using a copper complex with a chiral bisphosphine ligand, namely (R,R)-Ph-BPE.

Unexpected cyclization of tritylamines promoted by copper salt through C-H and C-N bond cleavages to produce acridine derivatives.

Herein, we demonstrate that tritylamines undergo an unprecedented copper-mediated cyclization involving the cleavages of two C-H bonds and one C-N bond to give 9-arylacridine derivatives. This kind of acridines is of interest due to their biological properties and their unique optical and electro- and photochemical properties. Some of obtained acridine derivatives exhibit intense fluorescence in the solid state.

Rhodium-catalyzed annulative coupling of 3-phenylthiophenes with alkynes involving double C-H bond cleavages.

Double CH bond activation took place efficiently upon treatment of 3-phenylthiophenes with alkynes in the presence of a rhodium catalyst and a copper salt oxidant to form the corresponding naphthothiophene derivatives. Dehydrogenative coupling with alkenes was also found to occur on the phenyl moiety rather than the thiophene ring. These reactions provide straightforward synthetic methods for π-conjugated molecules involving a thiophene unit from readily available, simple building blocks.

Iridium-catalyzed annulative coupling of 2-arylbenzoyl chlorides with alkynes: selective formation of phenanthrene derivatives.

2-Arylbenzoyl chlorides undergo annulative coupling with internal alkynes in the presence of a catalyst system of [IrCl(cod)]2/P(t-Bu)3 to selectively afford the corresponding phenanthrene derivatives accompanied by elimination of carbon monoxide and hydrogen chloride. The reaction occurs without addition of any external base. Deuterium-labeling experiments using 2-(d5-phenyl)benzoyl chloride suggest that the rate-determining step does not involve the C2'-H bond cleavage. Formation of a [(t-Bu)3PH][(biphenyl-2,2'-diyl)Ir(CO)Cl2] complex dimer, of which the structure was determined by single-crystal X-ray analysis, from a stoichiometric reaction at 60 °C without addition of alkyne also supports the facile C-H cleavage.

Manganese-mediated C3-selective direct alkylation and arylation of 2-pyridones with diethyl malonates and arylboronic acids.

A manganese-mediated dehydrogenative direct alkylation of 2-pyridones with diethyl malonates has been developed. A similar reaction system is applicable to the direct arylation with arylboronic acids. These manganese-based reactions occur regioselectively at the C3 position of the 2-pyridones. The observed high C3 regioselectivity can complement precedented C-H functionalization protocols of the 2-pyridones in view of the site selectivity.

Synthesis of triarylmethanes by palladium-catalyzed C-H/C-O coupling of oxazoles and diarylmethanol derivatives.

A PdCl2(MeCN)2/PPhCy2 catalyst couples oxazoles with diarylmethyl carbonates or pivalates to form the corresponding triarylmethanes in good yields. The catalysis involves successive secondary benzylic sp(3) C-O and heteroaromatic sp(2) C-H cleavages and provides an effective access to heteroarene-containing triarylmethanes from nonhalogenated and nonmetalated starting materials, which is complementary to precedented cross-coupling technologies with organic halides and organometallic reagents.