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Palladium-catalyzed ipso -borylation of aryl halides, well-known as Miyaura borylation, is one of the reliable synthetic methods for organoborons. This reaction involves base-mediated nucleophilic activation of diboron that enables transmetalation of an aryl(halo)palladium(II) intermediate with a diboron. As an alternative, herein, we have established Lewis acid-mediated conditions for borylating (pseudo)haloarenes that require no external base. The electrophilic activation of the aryl(halo)palladium(II) intermediate via dehalogenation with Lewis acidic zinc complexes promotes the borylation.

An efficient method for generating 3-triazenylarynes from ortho -iodoaryl triflate-type precursors was developed. The generated arynes reacted with various arynophiles with high regioselectivity because of the triazenyl group. The 3-triazenylaryne precursors functioned as useful intermediates of diverse multisubstituted aromatic compounds through the transformation of the remaining triazenyl group of aryne adducts and triazenyl group-directed ortho -C-H functionalization.

Alkaline nitrobenzene oxidation (AN oxidation) is a significant method for chemical analysis of lignin. Despite its importance in lignin chemistry, the detailed chemical reactions involved in AN oxidation are not yet fully understood. Surprisingly, there is almost no experimentally supported information available regarding the reaction pathways in the AN oxidation of guaiacyl glycerol-β-guaiacyl ether ( GG ), a common model compound in lignin chemistry. This study reports the results of our investigation into the formation pathway of vanillin (4-hydroxy-3-methoxybenzaldehyde) in the AN oxidation of GG . Our series of experiments proposed a vanillin formation pathway involving an enol ether with a C 2 side chain, 2-methoxy-4-[2-(2-methoxyphenoxy)-ethenyl]-phenol C2EE , as an intermediate, in which C2EE is produced by the non-oxidative degradation of GG by alkali. Another enol ether with a C 3 side-chain, Z -4-[3-hydroxy-2-(2-methoxyphenoxy)-1-propen-1-yl]-2-methoxyphenol ( C3EE ), and the condensation products formed under alkaline conditions were found to be insignificant as vanillin sources. On the other hand, the comparison of the vanillin yields from GG and isolated C2EE (80.7 and 86.5 mol %, respectively) in their AN oxidation to the C2EE yield from GG in the absence of nitrobenzene (69.9 mol %) also suggested that the vanillin formation from GG involved unknown pathways in which C2EE is not an intermediate.

A concise route for dibenzoazacyclooctynes (DIBACs) synthesis was developed based on Pictet-Spengler reaction and a novel cobalt decomplexation method established for dibenzo-fused cyclooctyne-cobalt complexes. The method allowed for the facile preparation of functionalized DIBACs, including bisDIBAC, which served as an efficient bisreactive linker for protein modification via the double-click reaction.

Upon treatment of α-azido sulfones with a thiol in the presence of 1,1,3,3-tetramethylguanidine, substitution of the sulfonyl group with a thiolate occurred, resulting in the formation of α-azido sulfides. Based on experimental results and DFT calculations, a reaction mechanism that involves the addition of a thiolate to the azido group and generation of an alkylidene triazene is proposed.

There remains an unmet need for reliable fully synthetic adjuvants that increase lasting protective immune responses from vaccines. We previously reported a high-throughput screening for small molecules that extended nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) activation after a Toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS), stimulation using a human myeloid reporter cell line. We identified compounds with a conserved aminothiazole scaffold including 2D216 [ N -(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide], which increased murine antigen-specific antibody responses when used as a co-adjuvant with LPS. Here, we examined the mechanism of action in human cells. Although 2D216 activated the major mitogen-activated protein kinases, it did not interact with common kinases and phosphatases and did not stimulate many of the pattern recognition receptors (PRRs). Instead, the mechanism of action was linked to intracellular Ca 2+ elevation via Ca 2+ channel(s) at the plasma membrane and nuclear translocation of the nuclear factor of activated T-cells (NFAT) as supported by RNA-seq data, analysis by reporter cells, Ca 2+ flux assays, and immunoblots. Interestingly, 2D216 had minimal, if any, activity on Jurkat T cells but induced cytokine production and surface expression of costimulatory molecules on cells with antigen-presenting functions. A small series of analogs of 2D216 were tested for the ability to enhance a TLR4 ligand-stimulated autologous mixed lymphocyte reaction (MLR). In the MLR, 2E151 , N -(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-((4-propylpiperidin-1-yl)sulfonyl)benzamide, was more potent than 2D216 . These results indicate that a small molecule that is not a direct PRR agonist can act as a co-adjuvant to an approved adjuvant to enhance human immune responses via a complementary mechanism of action.

Bridged indigos were synthesized by bridging the two nitrogen atoms in the indigo structure with a carbon chain, and their properties were carefully examined. These bridged indigos have intrinsic planar chirality, and the enantiomers were separated using chiral high-performance liquid chromatography. When the chiral bridged indigos were subjected to thermo- and photoisomerization, the corresponding ( Z )-indigo was not observed at all, and racemization was observed. This phenomenon is caused by the low activation energy of inversion due to the 1.5 bond order of the double bond of the indigo skeleton and the large energy difference between the ground states of ( E )-indigo and ( Z )-indigo.

We report a Buchwald-Hartwig amination compatible with azido functionality. Treatment of azidoaryl iodides and amines with fourth-generation Buchwald precatalyst coordinated by CPhos and sodium tert -butoxide in 1,4-dioxane at 50 °C afforded the corresponding azidoanilines while leaving the azido groups intact. The method showed a broad substrate scope and was applicable to the synthesis of diazido compounds as photoaffinity probe candidates of pharmaceutical amines and multiazido platform molecules.

To enhance the practicality of photouncaging system using 3-acyl-2-methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed using condensation reagents, generally used for peptide coupling. This method allowed for caging a broad range of carboxylic acids with indolizines. The method enabled a facile synthesis of water-soluble caged bioactive carboxylic acids having an intramolecular photosensitizer. The efficient release of carboxylic acids from the synthesized caged compounds upon red light irradiation was confirmed in neutral buffered solutions.

An efficient, direct sulfinylation of organoborons catalyzed by palladium is disclosed. Treatment of organoborons and sulfinate esters in the presence of a palladium precatalyst provided a broad range of sulfoxides. Various organosulfur compounds having oxidizable functional groups were successfully prepared through the sulfoxide synthesis.

An efficient synthetic method of N -arylphenothiazines from o -sulfanylanilines under transition-metal-free conditions is disclosed. An N - and S -arylation sequence of o -sulfanylanilines enabled us to synthesize a wide variety of N -arylphenothiazines. In particular, one-pot synthesis of N -arylphenothiazines was accomplished from easily available modules through preparation of o -sulfanylanilines by thioamination of aryne intermediates and following N - and S -arylation sequence.

An efficient method to generate aryne intermediates from o -iodoaryl triflates triggered by triethylsilane and cesium fluoride is disclosed. This method realized the acylalkylation of arynes using easily available o -iodoaryl triflate-type precursors, which was difficult when using conventional nucleophilic activators. A wide range of (hetero)arenes including various fused benzothiazoles were successfully synthesized from o -iodoaryl triflates by virtue of their good accessibility and divergent transformations of aryne intermediates.

Fluoroalkenes have shown importance as a metabolically stable isostere of amide compounds. To expedite the synthesis of diverse fluoroalkenes, we have developed a dual-reactive C2-unit, ( Z )-1-boryl-1-fluoro-2-tosyloxyethene, containing nucleophilic and electrophilic moieties. Consecutive palladium-catalyzed cross-coupling reactions of this unit with aryl bromides and aryl boronic acids allow for the convergent synthesis of diverse trans -1,2-diaryl-substituted fluoroethenes in a chemoselective and stereoretentive manner.

A facile method to prepare difluoromethylenes, including α,α-difluorobenzyl chlorides, by single C-F transformations of benzotrifluorides is disclosed. The C-F cleavage followed by chlorination proceeded smoothly using trityl chloride through the generation of trityl cation as an activator and chloride anion as a nucleophile. Diverse difluoromethylenes such as difluorobenzyl ethers were efficiently prepared by virtue of the good versatility of the resulting chloro and fluorosilyl groups.

An efficient synthetic method of benzopyran derivatives involving coumarins is disclosed. Gold-catalyzed benzopyran formation and subsequent aryne reactions enabled us to prepare a wide range of benzopyran derivatives by virtue of their good functional group tolerance and versatile transformability of aryne intermediates. The synthetic utility was showcased by a diarylnaphthopyran synthesis through this method and consecutive cross-coupling reactions.

An efficient transformation of dibenzoxaborins to dibenzofurans by deborylative ring contraction was achieved under mild conditions using a copper catalyst. The method showed a broad substrate scope enabling the preparation of various dibenzofurans, including those bearing a functional group. The ready availability of various dibenzoxaborins enhances the utility of this method, as demonstrated by the regiodivergent synthesis of dibenzofurans.

The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols or carboxylic acids within a few minutes. The method was applicable for photouncaging various functional molecules such as a carboxylic anticancer drug and a phenolic fluorescent dye from the corresponding indolizine conjugates, including an insulin-indolizine-dye conjugate.

The generation of tertiary, secondary, and primary alkyl radicals has been achieved by the direct visible-light excitation of a boracene-based alkylborate. This system is based on the photophysical properties of the organoboron molecule. The protocol is applicable to decyanoalkylation, Giese addition, and nickel-catalyzed carbon-carbon bond formations such as alkyl-aryl cross-coupling or vicinal alkylarylation of alkenes, enabling the introduction of various C(sp 3 ) fragments to organic molecules.

We developed a practical synthetic method for fluorine-18 ( 18 F)-labeled pitavastatin ([ 18 F]PTV) as a positron emission tomography (PET) tracer to assess hepatobiliary transporter activity and conducted a PET scan as a preclinical study for proof-of-concept in rats. This method is a one-pot synthesis involving aromatic 18 F-fluorination of an arylboronic acid ester followed by deprotection under acidic conditions, which can be reproduced in general clinical sites equipped with a standard radiolabeling system due to the simplified procedure. PET imaging confirmed that intravenously administered [ 18 F]PTV was rapidly accumulated in the liver and gradually transferred into the intestinal lumen through the bile duct. Radiometabolite analysis showed that [ 18 F]PTV was metabolically stable, and 80% of the injected dose was detected as the unchanged form in both blood and bile. We applied integration plot analysis to assess tissue uptake clearance (CL uptake, liver and CL uptake, kidney ) and canalicular efflux clearance (CL int, bile ), and examined the effects of inhibitors on membrane transport. Treatment with rifampicin, an organic anion transporting polypeptide inhibitor, significantly reduced CL uptake, liver and CL uptake, kidney to 44% and 64% of control, respectively. In contrast, Ko143, a breast cancer resistance protein inhibitor, did not affect CL uptake, liver but significantly reduced CL int, bile to 39% of control without change in [ 18 F]PTV blood concentration. In addition, we found decreased CL uptake, liver and increased CL int, bile in Eisai hyperbilirubinemic rats in response to altered expression levels of transporters. We expect that [ 18 F]PTV can be translated into clinical application, as our synthetic method does not need special apparatus in the radiolabeling system and PET scan with [ 18 F]PTV can quantitatively evaluate transporter activity in vivo .

An efficient method for the synthesis of diverse 1,3-diarylpyrazoles via consecutive aryne generation has been developed. The bisaryne precursors bearing o -iodo- and o -silylaryl triflate moieties were prepared by sequential Suzuki-Miyaura and Chan-Lam-Evans cross-coupling reactions. The selective generation of the first aryne triggered by a silylmethyl Grignard reagent followed by the second aryne generation mediated by a fluoride ion allowed for the synthesis of diverse multisubstituted 1,3-diarylpyrazoles in a modular synthetic manner with various arynophiles.

A synthetic method for diverse γ-aryl-β-ketoesters through γ-aryl-β-ketoester-type arynes triggered by C-C bond cleavage has been developed. The Mukaiyama aldol reaction of 6-(triflyloxy)benzocyclobutenones with ketene silyl acetals and subsequent treatment of resulting 6-(triflyloxy)benzocyclobutenols with a base triggered the efficient generation of γ-aryl-β-ketoester-type arynes, which reacted with various arynophiles to provide a wide range of γ-aryl-β-ketoesters. The synthetic utility of the method was demonstrated by the synthesis of an analog of ALK inhibitor.

An unexpected gem-diborylation of 2-arylvinyl sulfides with bis(pinacolato)diboron proceeded efficiently with a rhodium catalyst. A wide range of (2,2-diborylvinyl)arenes are easily synthesized by this method using readily available reagents, including the alkenyl sulfides, that are prepared from general materials in one step. Mechanistic studies indicate that the reaction proceeds from either of the stereoisomers in a stepwise manner via borylative C-S bond cleavage and subsequent dehydrogenative borylation.

The synthetic utility of 3-thioaryne intermediates has been demonstrated through an aryne relay approach. The efficient synthesis of o-silylaryl triflate-type 3-thioaryne precursors has been achieved by the regioselective silylthiolation of 3-(triflyloxy)arynes with silyl sulfides. Various 3-thioarynes were successfully generated from these precursors and reacted with various arynophiles to afford diverse multisubstituted aryl sulfides. Further derivatizations of the products enabled easy access to the novel sulfur-containing π-extended heterocycles, which demonstrates the utility of this method.

A mild and odorless copper-catalyzed thiolation of terminal alkynes with thiosulfonates is described. The broad substrate scope provides convenient access to a wide variety of sulfur-containing heterocycles. In particular, divergent benzoheteroles are efficiently prepared in a simple manner by thiolation of ethynylbenzenes bearing ortho-nucleophilic functional groups followed by iodocyclization.

Cu(I), Ag(I), and Au(I) complexes of monophosphine or bisphosphine ligands based on the 3,3,4,4,5,5-hexafluorocyclopentene skeleton were synthesized and structurally characterized by X-ray crystallographic analysis. The electron-withdrawing nature of these polyfluorinated phosphines was experimentally revealed via UV/vis absorption studies and crystal structure analysis. Successful catalytic application of the Au(I) complex for alkyne hydration reactions was investigated.

A method for protecting organic azides from click reactions with alkynes is reported. Treatment of azides with Amphos affords phosphazides, which are stable under click reaction conditions and are easily converted back to azides by treatment with elemental sulfur. Thus, the method allows for facile modification of azide compounds via site-selective click reactions.

5,8-Dihydroxy-[1,4]-naphthoquinone (DHNQ) is one of the key chromophores in cellulosic materials. Its almost ubiquitous presence in cellulosic materials makes it a target molecule of the pulp and paper industry's bleaching efforts. In the presented study, DHNQ was treated with hydrogen peroxide under alkaline conditions at pH 10, resembling the conditions of industrial hydrogen peroxide bleaching (P stage). The reaction mechanism, reaction intermediates, and final degradation products were analyzed by UV/vis, NMR, GC-MS, and EPR. The degradation reaction yielded C 1 -C 4 carboxylic acids as the final products. Highly relevant for pulp bleaching are the findings on intermediates of the reaction, as two of them, 2,5-dihydroxy-[1,4]-benzoquinone (DHBQ) and 1,4,5,8-naphthalenetetrone, are potent chromophores themselves. While DHBQ is one of the three key cellulosic chromophores and its degradation by H 2 O 2 is well-established, the second intermediate, 1,4,5,8-naphthalenetetrone, is reported for the first time in the context of cellulose discoloration.

A diverse range of o-arylthio-substituted diaryl ethers has been synthesized by direct oxythiolation of arynes with diaryl sulfoxides that involves the formation of the C-O and C-S bonds followed by migratory O-arylation.

Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions via copper catalysis. The method has shown an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroethylene (TFE), (trifluorovinyl)arenes, and trifluoromethylated monofluoroalkenes. The choice of boron source was important for the efficient transformation of (difluorovinyl)arenes; (Bpin) 2 was suitable for substrates with an electron-deficient aryl group and (Bnep) 2 for those with an electron-rich aryl group. Derivatization of the (fluoroalkenyl)boronic acid esters to the corresponding potassium trifluoroborate salts has rendered the products easily isolable, which greatly improved the synthetic practicality of the monodefluoroborylation reaction. Stoichiometric experiments indicate that the fate of the regioselectivity depends on the mode of β-fluorine elimination, which depends on the substrate. Further transformation of the boryl group has allowed facile preparation of fluoroalkene derivatives as exemplified by the synthesis of a fluoroalkene mimic of atorvastatin, which potently inhibited the enzyme activity of HMG-CoA reductase.

A facile synthetic method for unsymmetrical tertiary phosphine oxides is reported. Sequential treatment of phosphonodithioic acid S,S-di(p-tolyl) esters with two Grignard reagents enabled the stepwise introduction of different carbon substituents on the phosphorus atom. The chemical stability of dithioesters and monosubstituted thioesters has enhanced the utility of this method, rendering a wide range of organophosphorus compounds easily available.

Among imaging techniques, fluorescence microscopy is a unique method to noninvasively image individual molecules in whole cells. If the three-dimensional spatial precision is improved to the angstrom level, various molecular arrangements in the cell can be visualized on an individual basis. We have developed a cryogenic reflecting microscope with a numerical aperture of 0.99 and an imaging stability of 0.05 nm in standard deviation at a temperature of 1.8 K. The key optics to realize the cryogenic performances is the reflecting objective developed by our laboratory. With this cryogenic microscope, an individual fluorescent molecule (ATTO647N) at 1.8 K was localized with standard errors of 0.53 nm (x), 0.31 nm (y), and 0.90 nm (z) when 10 6 fluorescence photons from the molecule were accumulated in 5 min.

Treatment of benzocyclobutenones bearing a triflyloxy group adjacent to the four-membered ring with organolithium reagents in the presence of arynophiles efficiently affords three-component coupled α-arylketones. Mechanistic studies indicate that the reaction is promoted by generation of the aryne via carbon-carbon bond cleavage of a benzocyclobutenoxide intermediate, which led us to find a fluoride-mediated aryne generation method from triflyloxy-substituted benzocyclobutenone silyl acetal precursors.

A convenient method for the stereoinversion of secondary alcohols, applicable to stereocongested carbocyclic substrates, is reported. A simple three-step procedure, including triflylation of the hydroxy group, nucleophilic oxygenative displacement by the treatment with aqueous N,N-dimethylformamide (DMF), and methanolysis, allowed for efficient stereoinversion of various substrates, including sugar derivatives, in one pot.

A facile synthetic method for preparing 3-amino-2-silylaryl triflates via regioselective silylamination of 3-(triflyloxy)arynes with N-silylamines is described. Fluoride-mediated generation of 3-aminobenzyne from 3-amino-2-silylphenyl triflate, easily prepared by this method, in the presence of various arynophiles efficiently afforded diverse aniline derivatives, including a 5-aminocoumarin derivative, demonstrating the utility of aryne relay approach.

A facile method for preparing diverse aryne-nickel complexes from readily synthesized ortho-borylaryl triflates is described. Exploratory synthetic applications, including the synthesis of 1,2-difunctionalized arenes, based on the nucleophilic character of the aryne-nickel complexes are also demonstrated.

Rhodium-catalyzed transformation of alkyl aryl sulfides into arylboronic acid pinacol esters via C-S bond cleavage is reported. In combination with transition-metal-catalyzed sulfanyl group-guided regioselective C-H borylation reactions of alkylthioarenes, this method allows the synthesis of a diverse range of multisubstituted arenes.

Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method.

A novel method for preparing a diverse range of o-sulfanylanilines is described. Direct thioamination of arynes with sulfilimines gives o-sulfanylanilines, involving C-N and C-S bond formations and migratory N-arylation.

To elucidate the bioavailability of luteolin and its glycosides in Chrysanthemum morifolium flowers, the absorption and metabolism of luteolin from them was investigated in rats and Caco-2 cells using HPLC and LC-MS. After oral administration of C. morifolium extract (1.7 g/kg body weight (bw), equivalent to 22.8 and 58.3 μmol/kg bw of luteolin and luteolin-7-O-glucoside, respectively) to rats, luteolin and its glycosides were quickly absorbed and luteolin, luteolin monoglucoside, and luteolin monoglucuronide were detected in the plasma. Their levels were highest at 1 h after administration (0.76 ± 0.27 μM). These compounds were also detected in media on the basolateral side from Caco-2 cells treated with the C. morifolium extract. These results suggest that luteolin and luteolin monoglucoside are rapidly absorbed after administration of C. morifolium flower extract and that luteolin, luteolin monoglucoside, and luteolin monoglucuronide may circulate in humans.

A novel synthetic method for v-coelenterazine (v-CTZ), which is a vinylene-bridged analog of native CTZ with a large red-shifted luminescence property, is described. The synthesis was achieved in a concise way through the use of three sequential cross-coupling reactions and ring-closing metathesis (RCM). A newly synthesized C2-modified trifluoromethyl analog cf3-v-CTZ showed slightly more red-shifted luminescence than v-CTZ when it was used as a substrate for Renilla luciferases.

Phycocyanobilin, a light-harvesting and photoreceptor pigment in higher plants, algae, and cyanobacteria, is synthesized from biliverdin IXα (BV) by phycocyanobilin:ferredoxin oxidoreductase (PcyA) via two steps of two-proton-coupled two-electron reduction. We determined the neutron structure of PcyA from cyanobacteria complexed with BV, revealing the exact location of the hydrogen atoms involved in catalysis. Notably, approximately half of the BV bound to PcyA was BVH(+), a state in which all four pyrrole nitrogen atoms were protonated. The protonation states of BV complemented the protonation of adjacent Asp105. The "axial" water molecule that interacts with the neutral pyrrole nitrogen of the A-ring was identified. His88 Nδ was protonated to form a hydrogen bond with the lactam O atom of the BV A-ring. His88 and His74 were linked by hydrogen bonds via H3O(+). These results imply that Asp105, His88, and the axial water molecule contribute to proton transfer during PcyA catalysis.

The planar and stereostructures of JBIR-108 isolated from Streptomyces gramineus IR087Pi-4 were determined partly by spectral analysis, and these structural assignments were confirmed and completed by the total synthesis of both 1-epimers. The key stereocenters in JBIR-108 were constructed via a Corey-Bakshi-Shibata (CBS) reduction (C-1), vinylogous Mukaiyama aldol reaction (C-7), and Brown crotylation (C-14 and C-15). Although it was difficult to determine the stereochemistries at the C-1 and C-7 positions in the natural product using the modified Mosher's method, the synthesis of two possible C-1 diastereomers enabled the identification of the configurations at the hitherto unknown stereocenters.

Highly strained cyclic acetylenes 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctenes (Sondheimer-Wong diynes) having various substituents on their benzene rings were synthesized successfully by one-pot treatment of the corresponding formyl sulfones with diethyl chlorophosphate/lithium hexamethyldisilazide (LiHMDS) and then lithium diisopropylamide (LDA). When mixtures of two types of formyl sulfones bearing different substituents were subjected to this protocol, the unsymmetrically substituted Sondheimer-Wong diynes could be synthesized in a stepwise manner by isolation of the heterocoupled vinyl sulfone intermediates followed by their treatment with LDA. The UV-vis absorption spectra and cyclic voltammograms of the substituted Sondheimer-Wong diynes were recorded. The electronic effect of substituents on the diynes was investigated in their click reactions and nucleophilic and electrophilic additions.

An efficient synthetic method for versatile dibenzoxaborins based on boron-selective Suzuki-Miyaura cross-coupling between o-borylphenols and aryl halides or triflates bearing a 1,8-diaminonaphthalene-protected o-boryl group is reported. A short synthesis of defucogilvocarcin M was achieved using the proposed method in combination with several other boron-mediated transformations.

A transient protection method of cyclooctynes from a click reaction with an azide through 1:1 complexation with a cationic copper(I) salt is reported. The application of the method to a cyclooctyne bearing a terminal alkyne enabled the selective copper-catalyzed click conjugation with an azide at the terminal alkyne moiety, which made cyclooctyne derivatives readily accessible.

Glycoside formation in organic synthesis is believed to occur along a reaction path involving an activated glycosyl donor with a covalent bond between the glycosyl moiety and the leaving group, followed by formation of contact ion pairs with the glycosyl moiety loosely bound to the leaving group, and eventually solvent-separated ion pairs with the glycosyl moiety and the leaving group being separated by solvent molecules. However, these ion pairs have never been experimentally observed. This study investigates the formation of the ion pairs from a covalent intermediate, 2,3,4,6-tetra-O-methyl-α-d-glucopyranosyl triflate, by means of computational chemistry. Geometry optimization of the ion pairs without solvent molecules resulted in re-formation of the covalent α- and β-triflates but was successful when four solvent (dichloromethane) molecules were taken into account. The DFT(M06-2X) computations indicated interconversion between the α- and β-covalent intermediates via the α- and β-contact ion pairs and the solvent-separated ion pairs. The calculated activation Gibbs energy of this interconversion was quite small (10.4-13.5 kcal/mol). Conformational analyses of the ion pairs indicated that the oxacarbenium ion adopts (4)H3, (2)H3/E3, (2)H3/(2)S0, E3, (2,5)B, and B2,5 pyranosyl ring conformations, with the stability of the conformers being strongly dependent on the relative location of the counteranion.

The mechanisms underlying the effect of epigallocatechin gallate (EGCG) on the micellar solubility of cholesterol were examined. EGCG eliminated both cholesterol and phosphatidylcholine (PC) from bile salt micelles in a dose-dependent manner in vitro. When the bile salt micelles contained a phospholipid other than PC, neither cholesterol nor the phospholipid was eliminated following the addition of EGCG. When vesicles comprised of various phospholipids were prepared and, EGCG was added to the vesicles, EGCG effectively and exclusively eliminated only PC. An intermolecular nuclear Overhauser effect (NOE) was observed between PC and EGCG in bile salt micelles with EGCG added, but not between cholesterol and EGCG, by using a NOE-correlated spectroscopy nuclear magnetic resonance method. The results of binding analyses using surface plasmon resonance (SPR) showed that EGCG did not bind to cholesterol. These observations strongly suggest that EGCG decreases the micellar solubility of cholesterol via specific interaction with PC.

2,5-Dihydroxy-1,4-benzoquinone (DHBQ) is one of the key chromophores occurring in all types of aged cellulosics. This study investigates the mechanism of H2O2 degradation of DHBQ under conditions relevant to pulp bleaching (3.0% H2O2, NaOH, pH 10), to obtain insights useful for improved pulp processing. DHBQ is degraded quantitatively into malonic acid with an activation energy (E(a)) of 16.1 kcal/mol and activation entropy (Δ(‡)S°) of ~28 cal/mol·K. Higher concentrations of sodium cations increase the reaction rate. Theoretical computations indicate the formation of an intermediate I(O) having an O-O bridge between C-2 and C-5 of the 1,4-cyclohexadione structure. I(O) undergoes O-O homolysis to form a biradical Bt, which is fragmented into malonate anions. The calculated E(a) (17.8 kcal/mol) agrees well with the experimental one. Coordination of Na(+) to I(O) and Bt decreases their energies and enhances the O-O homolysis rate, which is consistent with the acceleration by sodium cation and the negative Δ(‡)S°. The homolysis of I(O) is much favored over that of the neutral counterpart, with the unpaired electrons of Bt being stabilized by the geminal anionic oxygen. This difference in the stability of the intermediates translates into significant variations in the reaction rate and the product distribution between pH 10 and neutral/acidic conditions.

Ammoxidized technical lignins are valuable soil-improving materials that share many similarities with native terrestrial humic substances. In contrast to lignins, the chemical fate of carbohydrates as typical minor constituents of technical lignins during the ammoxidation processes has not been thoroughly investigated. Recently, we reported the formation of N-heterocyclic, ecotoxic compounds (OECD test 201) from both monosaccharides (D-glucose, D-xylose) and polysaccharides (cellulose, xylan) under ammoxidation conditions and showed that monosaccharides are a source more critical than polysaccharides in this respect. GC/MS-derivatization analysis of the crude product mixtures revealed that ammoxidation of carbohydrates which resembles the conditions encountered in nonenzymatical browning of foodstuff affords also a multitude of nonheterocyclic nitrogenous compounds such as aminosugars, glycosylamines, ammonium salts of aldonic, deoxyaldonic, oxalic and carbaminic acids, urea, acetamide, α-hydroxyamides, and even minor amounts of α-amino acids. D-glucose and D-xylose afforded largely similar product patterns which differed from each other only for those products that were formed under preservation of the chain integrity and stereoconfiguration of the respective monosaccharide. The kinetics and reaction pathways involved in the formation of the different classes of nitrogenous compounds under ammoxidation conditions are discussed.

An efficient method of generating aryne has been achieved by treating ortho-(trifluoromethanesulfonyloxy)arylboronic acid pinacol ester with tert- or sec-butyllithium. Monitoring the reaction by (11)B NMR has indicated that a boron-ate complex formed in situ is the eventual precursor that converts into aryne near room temperature. The prior formation of the ate complex at a low temperature has enabled us to use various arynophiles, including those bearing base-sensitive groups. The ready availability of the aryne precursors and mutual orthogonality in aryne generation with widely used ortho-silylaryl triflate have enhanced the utility of the method.