Controlled Aerobic Oxidative Dimerization of Hydroxystilbenoids by Chromium Catalysis.

Aerobic oxidative dimerization of hydroxystilbenoids is described. A Cr-salen complex catalyzed the dimerization of hydroxystilbenoids in 1,1,1,3,3,3-hexafluoroisopropanol to form compounds comprising a natural product-like scaffold (quadrangularin) or its precursor depending on the aromatic substituents. The addition of a catalytic amount of scandium triflate [Sc(OTf)3] to the reaction system altered the reaction outcome to give a different natural product-like compound, a pallidol-type dimer.

Electrochemical Characterization of a Novel Organoelectrocatalyst, 7-Azabicyclo[2.2.1]heptan-7-ol (ABHOL), and Its Application to Electrochemical Sensors.

Electrochemical enzyme sensors are suitable for simple monitoring methods, for example, as glucose sensors for diabetic patients; however, they have several disadvantages arising from the properties of the enzyme. Therefore, non-enzymatic electrochemical sensors using functional molecules are being developed. In this paper, we report the electrochemical characterization of a new hydroxylamine compound, 7-azabicyclo[2.2.1]heptan-7-ol (ABHOL), and its application to glucose sensing. Although the cyclic voltammogram for the first cycle was unstable, it was reproducible after the second cycle, enabling electrochemical analysis of ethanol and glucose. In the first cycle, ABHOL caused complex reactions, including electrochemical oxidation and comproportionation with the generated oxoammonium ions. The electrochemical probe performance of ABHOL was more efficient than the typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), and had similar efficiency to 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), which is activated by the bicyclic structure. The results demonstrated the advantages of ABHOL, which can be synthesized from inexpensive materials via simple methods.

Azetidine synthesis by La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines.

Azetidine is a prevalent structural motif found in various biologically active compounds. In this research paper, we report La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines to afford azetidines. This reaction proceeded in high yields even in the presence of acid-sensitive and Lewis basic functional groups.

Determination of antibiotics by amperometry using nortropine N-oxyl, a highly active nitroxyl radical.

Nitroxyl radical compounds oxidize hydroxy groups and some amino groups upon application of an electric potential. The resulting anodic current depends on the concentration of these functional groups in solution. Thus, it is possible to quantify compounds containing these functional groups by electrochemical methods. Cyclic voltammetry has been used to evaluate the catalytic activity of nitroxyl radicals, and the ability of such radicals to sense biological and other compounds. In this study, we evaluated a method for quantifying compounds using constant-potential electrolysis (amperometry) of nitroxyl radicals for application in flow injection analysis and high-performance liquid chromatography as an electrochemical detector. When amperometry was performed using 2,2,6,6-tetramethylpiperidine 1-oxyl, a common nitroxyl radical compound, little change was observed even with 100 mM glucose due to its low reactivity in neutral aqueous solutions. In contrast, 2-azaadamantane N-oxyl and nortropine N-oxyl, which are highly active nitroxyl radicals, showed a concentration-dependent response in neutral aqueous solution. Responses of 33.8 and 125.9 µA, respectively, were observed. By recognition of hydroxy and amino groups, we have succeeded in the electrochemical detection of some drugs by amperometry. Streptomycin, an aminoglycoside antibiotic, was quantifiable in the range of 30-1000 µM.

Asymmetric Total Synthesis of Cytotrienin A: Late-Stage Installation of C11 Side Chain onto the Macrolactam Scaffold.

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

Sequential click modification of a lithium-ion endohedral fullerene connecting small molecules through a dieneazide linker.

A versatile method for the chemical modification of a lithium-ion endohedral fullerene (Li+@C60) to connect various small molecules is described. The designed dieneazide linker enables the facile connection of Li+@C60 with small molecules bearing a terminal alkyne via Huisgen annulation and a subsequent Diels-Alder reaction. This strategy significantly expands the diversity of small molecules to be attached by Li+@C60.

Identification of the Optimal Framework for Nitroxyl Radical/Hydroxylamine in Copper-Cocatalyzed Aerobic Alcohol Oxidation.

8-Azabicyclo[3.2.1]octan-8-ol (ABOOL) and 7-azabicyclo[2.2.1]heptan-7-ol (ABHOL) are the main homologues of hydroxylamine 2-azaadamantan-2-ol (AZADOL) and 9-azabicyclo[3.3.1]nonan-9-ol. Both homologues feature a small bicyclic backbone and are known to be stable; however, to date, they have not been used as catalysts for alcohol oxidation. Herein, we report that these hydroxylamines can efficiently catalyze the oxidation of various secondary alcohols to their corresponding ketones using molecular oxygen in ambient air as the terminal oxidant and copper cocatalysts at room temperature. Furthermore, we show that ABOOL and ABHOL can be easily synthesized from commercially available materials.

Electrochemical reactions of highly active nitroxyl radicals with thiol compounds.

Nitroxyl radicals are known to electrochemically oxidize thiols as well as alcohols and amines. In this study, a preliminary investigation of the electrochemical reaction of thiols with 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), 2-azaadamantane N-oxyl (AZADO), and nortropine N-oxyl (NNO), which are highly active due to their bicyclo structures, for use in electrochemical analysis was performed and the results were compared with those for a typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO). Mercaptopropane sulfonic acid (MPS) was used as a model compound to investigate the electrochemical response in aqueous solution. In addition, electrochemical detection of glutathione, a biological thiol molecule, was performed.

Comprehensive Structural and Electronic Properties of 2-Azaadamantane N-Oxyl Derivatives Correlated with Their Catalytic Ability.

Herein, a comprehensive kinetic study is performed to compare the catalytic efficiency of 2-azaadamantane N-oxyl (AZADO) derivatives with that of 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) used as radical catalysts in the aerobic oxidation of l-menthol. Furthermore, the correlation between the catalytic activity and structural/electronic parameters of AZADOs and TEMPO is elucidated. The reaction rate constants achieved with several AZADO derivatives exhibit moderate relationships with spectroscopic parameters, such as the hyperfine coupling constant of the N atom (AN) and NO stretching vibration frequency (νNO) observed in electron spin resonance and infrared spectra, respectively. The planarity C-(NO)-C angle (φ) at the N atom, determined by density functional theory (DFT) calculations, also strongly correlates with the AN and νNO. Moreover, the bond order of NO, which strongly depends on the structural and electronic properties of NO radicals, correlates with radical activity; thus, the radical activity can be predicted by DFT calculations, thereby accelerating the synthesis of new AZADO derivatives without requiring alcohol oxidation experiments.

A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins.

Although treatments for allergic diseases have improved, side effects and treatment resistance remain as challenges. New therapeutic drugs for allergic diseases are urgently required. Thymic stromal lymphopoietin (TSLP) is a cytokine target for prevention and treatment of allergic diseases. Since TSLP is produced from epithelial cells in allergic diseases, TSLP inhibitors may be new anti-allergic drugs. We previously identified a new inhibitor of TSLP production, named 16D10. However, its target of action remained unclarified. In this study, we found proteins binding to 16D10 from 24,000 human protein arrays by AlphaScreen-based high-throughput screening and identified bromodomain and extra-terminal (BET) family proteins as targets. We also clarified the detailed mode of interaction between 16D10 and a BET family protein using X-ray crystallography. Furthermore, we confirmed that inhibitors of BET family proteins suppressed TSLP induction and IL-33 and IL-36γ expression in both mouse and human keratinocyte cell lines. Taken together, our findings suggest that BET family proteins are involved in the suppression of TSLP production by 16D10. These proteins can contribute to the pathology of atopic dermatitis via TSLP regulation in keratinocytes and have potential as therapeutic targets in allergic diseases.

Toward the Creation of Induced Pluripotent Small (iPS) Molecules: Establishment of a Modular Synthetic Strategy for the Heronamide C-type Polyene Macrolactams and Their Conformational and Reactivity Analysis.

A highly modular synthetic strategy for the heronamide C-type polyene macrolactams was established by synthesizing 8-deoxyheronamide C (2). The developed strategy enabled not only the total synthesis of 8-deoxyheronamide C (2) but also the unified synthesis of four heronamide-like molecules named "heronamidoids" (5-8). Conformational and reactivity analysis of the heronamidoids clarified that (1) the C19 stereochemistry mainly affected the conformation of the amide linkage, resulting in the change of alignment of two polyene units and reactivity toward photochemical [6π + 6π] cycloaddition, and (2) the C8,C9-diol moiety is important for the conversion to the heronamide A-type skeleton from the heronamide C skeleton.

Design, Synthesis, and Antifungal Activity of 16,17-Dihydroheronamide C and ent-Heronamide C.

16,17-Dihydroheronamide C (8) and ent-heronamide C (ent-1) were designed as probes for the mode-of-action analysis of heronamide C (1). These molecules were synthesized by utilizing a highly modular strategy developed in the preceding paper. The evaluation of the antifungal activity of these compounds revealed the exceptional importance of the C16-C17 double bond for the antifungal activity of heronamide C and the existence of chiral recognition between heronamide C (1) and cell membrane components.

Nitroxyl Radical/Copper-Catalyzed Electrooxidation of Alcohols and Amines at Low Potentials.

Nitroxyl radicals, such as 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO), can catalyze the electrochemical oxidation of alcohols and amines. Because the oxidation current obtained in this process depends on the concentration of alcohols and amines, this process can be applied to their sensing. However, the relatively high oxidation potentials required by nitroxyl radicals can induce interfering oxidation currents from various reductive substances in biological samples, which affects the accuracy of analyte measurements. In this study, we examined the electrooxidation of alcohols and amines at a low potential by applying cooperative oxidation catalysis using a nitroxyl radical and a copper salt. Nortropine N-oxyl (NNO), which showed higher catalytic activity than TEMPO was used as the nitroxyl radical. An increase in the oxidation current was observed at the low potential, and this increase depended on the alcohol concentration. In the case of the electrooxidation of amines, a positive correlation between oxidation current and amine concentration was observed at low amine concentrations. Therefore, low-potential cooperative catalysis can be applied to alcohol and amine electrooxidation for the development of accurate sensors suitable for clinical settings.

Expansion of Substrate Scope for Nitroxyl Radical/Copper-Catalyzed Aerobic Oxidation of Primary Alcohols: A Guideline for Catalyst Selection.

Four distinctive sets of optimum nitroxyl radical/copper salt/additive catalyst combinations have been identified for accommodating the aerobic oxidation of various types of primary alcohols to their corresponding aldehydes. Interestingly, less nucleophilic catalysts exhibited higher catalytic activities for the oxidation of particular primary allylic and propargylic alcohols to give α,ß-unsaturated aldehydes that function as competent Michael acceptors. The optimum conditions identified herein were successful in the oxidation of various types of primary alcohols, including unprotected amino alcohols and divalent-sulfur-containing alcohols in good-to-high yields. Moreover, N-protected alaninol, an inefficient substrate in the nitroxyl radical/copper-catalyzed aerobic oxidation, was oxidized in good yield. On the basis of the optimization results, a guideline for catalyst selection has been established.

Chromium-Salen Complex/Nitroxyl Radical Cooperative Catalysis: A Combination for Aerobic Intramolecular Dearomative Coupling of Phenols.

We describe an aerobic intramolecular dearomative coupling reaction of tethered phenols using a catalytic system consisting of a chromium-salen (Cr-salen) complex combined with a nitroxyl radical. This novel catalytic system enables formation of various spirocyclic dienone products including those unable to be accessed by previously reported methods efficiently under mild reaction conditions.

Catalysis of electro-oxidation of antibiotics by nitroxyl radicals and the electrochemical sensing of vancomycin.

Quantifying drug concentrations in vivo quickly and easily is possible using electrochemical methods. The present study describes the electrochemical detection of vancomycin (VCM) and other antibiotics from the current obtained using nitroxyl radicals as electrocatalysts. Nortropine N-oxyl (NNO), which is more active than 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), a typical nitroxyl radical compound, produced greater current values for drugs with intramolecular hydroxy groups and secondary and tertiary amines. However, because the catalytic action of NNO is inactivated by primary amines in the substrate, VCM and teicoplanin with primary amines could not be detected. TEMPO was less active than NNO but not inactivated against primary amines. Therefore, electrochemical sensing of vancomycin was done using 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (A-TEMPO), which has a greater oxidation capacity than TEMPO due to its electron-withdrawing groups. As a result, the current of A-TEMPO increased in the low concentration range of VCM as compared to TEMPO. This method also was able to quantify VCM in the concentration range of 10-100 µM, which is an important concentration range for drug monitoring in blood.

Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3.

Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.

Methyl-Selective α-Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN-AZADO or 1-Me-AZADO).

Methyl-selective α-oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α-oxygenation at the N-methyl positions using molecular oxygen (O2 ) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl-selective α-oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5-dimethyl-9-azanoradamantane N-oxyl (DMN-AZADO) and 1-methyl-2-azaadamanane N-oxyl (1-Me-AZADO), was very important to promote the oxygenation effectively mainly because these N-oxyls have longer life-times than less hindered N-oxyls. Various types of tertiary N-methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine-N-oxyl interactions.

Ln(OTf)3-catalysed highly regioselective alcoholysis of 2,3-epoxy alcohols.

Regioselectivity of Ln(OTf)3-catalysed alcoholysis of 2,3- and 3,4-epoxy alcohols was closely investigated to expand the scope of the transformations. The synthetic use was demonstrated by application to the construction of 4-propoxy-5-hydroxy-2,3-pentanedione (C4-propoxy-HPD), which is a potent synthetic mediator in AI-2 quorum sensing.

2-Azaadamantane N-oxyl (AZADO)/Cu Catalysis Enables Chemoselective Aerobic Oxidation of Alcohols Containing Electron-Rich Divalent Sulfur Functionalities.

The chemoselective oxidation of alcohols containing electron-rich sulfur functionalities (e.g., 1,3-dithianes and sulfides) into their corresponding carbonyl compounds with the sulfur groups can sometimes be a demanding task in modern organic chemistry. A reliable method for this transformation, which features azaadamantane-type nitroxyl radical/copper catalysis using ambient air as the terminal oxidant is reported. The superiority of the developed method was demonstrated by comparing it with various conventional alcohol oxidation methods.