Methyl Ketone Group Research Articles

Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism

Nabumetone, a nonsteroidal anti-inflammatory prodrug, is converted to a pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA); however, it is 11-fold more efficiently converted to 4-(6-methoxy-2-naphthyl)butan-2-ol (MNBO) via a reduction reaction in human hepatocytes. The goal of this study was to identify the enzyme(s) responsible for MNBO formation from nabumetone in the human liver. MNBO formation by human liver microsomes (HLM) was 5.7-fold higher than in the liver cytosol. In a panel of 24 individual HLM samples with quantitative proteomics data, the 17β-hydroxysteroid dehydrogenase 12 (HSD17B12) protein level had the high correlation coefficient (r = 0.80, P < 0.001) among 4457 proteins quantified in microsomal fractions during MNBO formation. Recombinant HSD17B12 expressed in HEK293T cells exhibited prominent nabumetone reductase activity, and the contribution of HSD17B12 to the activity in the HLM was calculated as almost 100%. MNBO formation in HepG2 and Huh7 cells was significantly decreased by the knockdown of HSD17B12. We also examined the role of HSD17B12 in drug metabolism and found that recombinant HSD17B12 catalyzed the reduction reactions of pentoxifylline and S-warfarin, suggesting that HSD17B12 prefers compounds containing a methyl ketone group on the alkyl chain. In conclusion, our study demonstrated that HSD17B12 is responsible for the formation of MNBO from nabumetone. Together with the evidence for pentoxifylline and S-warfarin reduction, this is the first study to report that HSD17B12, which is known to metabolize endogenous compounds, such as estrone and 3-ketoacyl-CoA, plays a role as a drug-metabolizing enzyme.

Crystal structure of zymonic acid and a redetermination of its precursor, pyruvic acid.

The structure of zymonic acid (systematic name: 4-hy-droxy-2-methyl-5-oxo-2,5-di-hydro-furan-2-carb-oxy-lic acid), C6H6O5, which had previously eluded crystallographic determination, is presented here for the first time. It forms by intra-molecular condensation of parapyruvic acid, which is the product of aldol condensation of pyruvic acid. A redetermination of the crystal structure of pyruvic acid (systematic name: 2-oxo-propanoic acid), C3H4O3, at low temperature (90 K) and with increased precision, is also presented [for the previous structure, see: Harata et al. (1977 ▸). Acta Cryst. B33, 210-212]. In zymonic acid, the hy-droxy-lactone ring is close to planar (r.m.s. deviation = 0.0108 Å) and the dihedral angle between the ring and the plane formed by the bonds of the methyl and carb-oxy-lic acid carbon atoms to the ring is 88.68 (7)°. The torsion angle of the carb-oxy-lic acid group relative to the ring is 12.04 (16)°. The pyruvic acid mol-ecule is almost planar, having a dihedral angle between the carb-oxy-lic acid and methyl-ketone groups of 3.95 (6)°. Inter-molecular inter-actions in both crystal structures are dominated by hydrogen bonding. The common R 2 2(8) hydrogen-bonding motif links carb-oxy-lic acid groups on adjacent mol-ecules in both structures. In zymonic acid, this results in dimers about a crystallographic twofold of space group C2/c, which forces the carb-oxy-lic acid group to be disordered exactly 50:50, which scrambles the carbonyl and hydroxyl groups and gives an apparent equalization of the C-O bond lengths [1.2568 (16) and 1.2602 (16) Å]. The other hydrogen bonds in zymonic acid (O-H⋯O and weak C-H⋯O), link mol-ecules across a 21-screw axis, and generate an R 2 2(9) motif. These hydrogen-bonding inter-actions propagate to form extended pleated sheets in the ab plane. Stacking of these zigzag sheets along c involves only van der Waals contacts. In pyruvic acid, inversion-related mol-ecules are linked into R 2 2(8) dimers, with van der Waals inter-actions between dimers as the only other inter-molecular contacts.

Degradation kinetics and pathways of β-cyclocitral and β-ionone during UV photolysis and UV/chlorination reactions

β-cyclocitral and β-ionone are ones of major algal odorants produced by oxidation of the β-carotene that exists in algae cells. These compounds degraded the quality of drinking water therefore it needed to be treated in drinking water treatment by advanced oxidation processes. In this study, UV photolysis and UV-chlorination reactions along with chlorination to remove these odorants in water were compared. Kinetics of three reactions were well fitted at pseudo-first order model. Among three reactions, UV-chlorination was the most effective due to generation of OH and Cl radicals. β-ionone showed faster degradation compared to β-cyclocitral due to the existence of double bond in the alkyl carbon chain. In addition, radical contributions of degradation of odorants were examined. During UV-chlorination, UV photolysis contributed around 50% of removal for two odorants. OH radical took part of 36% removal of β-ionone and 50% removal of β-cyclocitral. Unlike β-ionone, β-cyclocitral was not degraded by reactive chlorine species during UV-chlorination. Acidic pH was favorable for UV-chlorination due to different quantum yield and radical scavenging effect by chlorine species. Formation of trace amount of chloroform was observed during UV-chlorination. The methyl ketone group of β-ionone was the main site for chloroform production. Several byproducts during UV photolysis and UV-chlorination of β-ionone were identified by GC-MS, and these were degraded with further reaction by UV-induced isomerization, OH radical, and bond scission mechanisms. β-cyclocitral was formed as byproducts during UV-chlorination of β-ionone. Based on degradation byproducts, the degradation pathways of β-ionone and β-cyclocitral of UV photolysis and UV-chlorination were suggested based on the identified byproducts. This study showed UV-chlorination process can be applied for degrading odorants like β-cyclocitral and β-ionone.

Revamping a brain cancer drug

Glioblastoma—a type of aggressive, invasive brain tumor—is almost always fatal. Although treatments exist, there is no cure. Now, researchers have taken a fresh look at a drug used to treat glioblastoma, temozolomide (TMZ), and made it a better cancer killer with potential for fewer side effects (ACS Chem. Biol. 2018, DOI:10.1021/acschembio.8b00864). Because only 17% of TMZ gets through the blood-brain barrier, Paul J. Hergenrother of the University of Illinois, Urbana-Champaign, and colleagues wanted to see if they could tweak the molecule’s structure to help it pass into the brain without compromising its anticancer properties. The team swapped out TMZ’s amide group for a series of chemical groups hypothesized to improve brain penetration and then tested the compounds, first in cancer cells and then in mice. The best-performing compound, K-TMZ, contains a methyl ketone group instead of the amide and showed greatly increased brain permeability, with 69% entering the brain compared

Abstract 3804: Structural changes to SN79 result in ligands that stimulate a metabolic function of sigma-2 receptors

Abstract Sigma-2 receptors have been of interest as targets for imaging, diagnosis, and treatment of cancer nearly since their discovery. These membrane-bound proteins are highly upregulated in cancer cells compared to healthy tissue, with further upregulation in rapidly proliferating cancer cells compared to quiescent cells. Activation of sigma-2 receptors by traditional agonists induces programmed cell death. However, this function of sigma-2 receptors is inconsistent with upregulation in cancer cells, which is typically associated with survival benefit. We have recently shown the ability of sigma-2 receptors to induce an independent, non-toxic, metabolically stimulative function that is consistent with survival benefit to both cancer cells and rapidly proliferating normal cells, indicated initially by an increase in MTT reduction. CM764, a novel analog of the sigma-2 antagonist SN79, increased total NADH/NAD+ and ATP levels, decreased basal ROS, and increased VEGF levels via induction of HIF1a expression in SK-N-SH neuroblastoma cells (Nicholson et al., JPET, 2015). We also previously described single-element structural changes to the core structure of SN79 and the effects of these changes on sigma receptor binding affinity and ability to induce cell death (Nicholson et al., Proc. Amer. Assoc. Cancer Res. 75: #2440, 2015). Here, we describe further characterization of the metabolic stimulatory effect induced by binding of members of this series to sigma-2 receptors in SK-N-SH neuroblastoma cells. Substitution of the oxazolone oxygen or methyl ketone moieties of the heterocyclic ring system of the SN79 core structure resulted in ligands that all retained significant binding affinity for sigma-2 receptors. Drastic changes in cell viability effects were observed in response to changes to the methyl ketone position. As previously reported, -NCS substitutions to the methyl ketone position resulted in cytotoxic ligands. By contrast, substitutions of the SN79 methyl ketone moiety with an -NH2, either alone (CM571) or combined with heterocyclic ring oxygen atom substitution for an -NMe group (WA403), resulted in ligands that stimulated reduction of MTT, consistent with the metabolically stimulative phenotype previously described. This phenotype was also observed with -NMe and -S- substitutions to the heterocyclic ring oxygen atom without combined substitution of the methyl ketone group (NF7 and WA504, respectively), and for the nitro-substituted methyl ketone group alone (CM458). All stimulative ligands demonstrated maximal increase in MTT reduction after 24 h incubation at 30 μM, with WA504 exhibiting the greatest stimulation of 161% of the amount of MTT reduced by cells that were not treated. These data further support a dual role for sigma-2 receptor activation, inducing both pro-survival and apoptotic pathways, and highlight the impact of single-element changes to the binding and action of SN79 analogs at sigma-2 receptors. Citation Format: Hilary Elaine Nicholson, Walid Alsharif, Christopher R. McCurdy, Wayne D. Bowen. Structural changes to SN79 result in ligands that stimulate a metabolic function of sigma-2 receptors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3804.

Abstract 2440: Evaluation of structural changes in SN79-derived sigma-2 receptor modulators: effect on apoptotic efficacy in SK-N-SH neuroblastoma

Abstract Sigma receptors are a unique class of membrane bound receptors with key roles in mediating cell survival. The sigma-2 subtype has received attention due to its significant upregulation in rapidly proliferating tumor cells as compared to non-cancerous cells. When activated, the sigma-2 receptor induces apoptosis. Previously, we described the use of -NCS derivatives of SN79, a moderately sigma-2 selective antagonist (Ki = 290 and 30 nM at sigma-1 and sigma-2, respectively), to induce apoptosis in breast, brain, and pancreatic cancer cell lines (Nicholson et al., Proc. Amer. Assoc. Cancer Res. 74: #3237, 2014). CM572, a potent selective partial agonist of the sigma-2 receptor (Ki = &amp;gt;10μM and 15nM at sigma-1 and sigma-2, respectively), was found to irreversibly bind and induce apoptosis in several cancer cell lines. Here we present a series of heterocyclic ring structural variants of CM572 and our evaluation of these ligands for use as potential chemotherapeutics. When the methyl ketone group on the heterocyclic ring of SN79 was substituted with -NO2, the resulting ligand showed low or no selectivity (≤2-fold) for the sigma-2 receptor over the sigma-1 receptor, while -NCS substituted ligands showed higher selectivity (≥10-fold) for the sigma-2 receptor. Substitution of the -O- in the heterocyclic ring of SN79 with -S- resulted in excellent sigma-2 receptor affinity but greatly reduced selectivity, suggesting potential interaction at this position in the binding pocket of the sigma-1 receptor. Substituting this position with -N-Me significantly increased selectivity by reducing sigma-1 receptor affinity, suggesting that steric hindrance rendered this position less amenable to sigma-1 receptor binding. -NCS derivatives of SN79 were cytotoxic to SK-N-SH neuroblastoma, while substitution of -NCS for -NO2 reduced efficacy, potency, and eliminated irreversible binding capability. Substitution of the -NCS group with -NH2 eliminated agonist properties, rendering these ligands unable to induce apoptosis up to 50 μM. Interestingly, while high sigma-2 receptor affinity was retained for -NH2-substituted ligands, they were unable to attenuate agonist activity at the sigma-2 receptor, suggesting poor antagonist activity compared to the parent compound. This data implies that the presence of an electron withdrawing group on the heterocyclic ring imparts agonist activity. We conclude that the greatest potential for a potent, highly efficacious, selective sigma-2 receptor -targeted chemotherapeutic agent will result from an SN79 derivative containing an -NCS at the 4 position of the aromatic moiety and an N-Me group in the heterocyclic ring. Future work will focus on the effects of these compounds in tumor xenograft models across a variety of cancer types, as well as using structural variants to predict characteristics of the binding pockets of sigma-1 and sigma-2 receptors. Citation Format: Hilary Elaine Nicholson, Walid Alsharif, Christopher R. McCurdy, Wayne D. Bowen. Evaluation of structural changes in SN79-derived sigma-2 receptor modulators: effect on apoptotic efficacy in SK-N-SH neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2015-2440

Synthesis of A-Pentacyclic Triterpene α,β-Alkenenitriles

A-seco-triterpenoids with a methylketone group were synthesized from epimeric 3-hydroxy-3-methyl-1-cyano2,3-seco-triterpenoids of the lupane and 19,28-epoxy-18H-oleanane types, which were formed by a Grignard reaction. The resulting methylketones underwent under base-catalysis conditions an intramolecular cyclization to form A-pentacyclic -substituted alkenenitriles. The synthesized compounds included 3-methyl1-cyano-19,28-epoxy-2,3-seco-2-nor-18H-olean-3-one and methyl 3-methyl-1-cyano-2-norlup1(3),20(29)-dien-28-oate, which inhibited in vitro reproduction of human immunodeficiency virus type 1.

Concise Synthesis of 1,4a-Bifunctionalised Decalin Building Blocks by C-H Activation of Decalin

Friedel-Crafts acylation of decalin introduces functionality at C1 and C4a, which may be elaborated to novel building blocks possessing a methyl ketone, methyl carbinol, or vinyl group at the ring junction.

Thermal analysis of two series mono- and di-azocalix[4]arene derivatives

In the present study, thermal decomposition of mono- and di-azocalix[4]arene derivatives (A1–A8 and B1–B8) was investigated by means of thermogravimetry (TG), differential thermal analysis (DTA) and derivative thermogravimetry (DTG). The exclusion of methanol, hydrolysis of benzoyl ester and methyl ketone groups in lower rim, and decomposition of azo groups in upper rim have occurred during thermal analysis, consecutively. The thermal decomposition degrees amount of volatile pyrolysis products were determined in air atmosphere using TG, DTA and DTG curves. In conclusion, the thermal analyses of azocalix[4]arenes demonstrated that its stability depends on the substituted groups and their positions in the calix[4]arene structure.

Comparison of Hydrazone Heterobifunctional Cross-Linking Agents for Reversible Conjugation of Thiol-Containing Chemistry

Reversible covalent conjugation chemistries that allow site- and condition-specific coupling and uncoupling reactions are attractive components in nanotechnologies, bioconjugation methods, imaging, and drug delivery systems. Here, we compare three heterobifunctional cross-linkers, containing both thiol- and amine-reactive chemistries, to form pH-labile hydrazones with hydrazide derivatives of the known and often published water-soluble polymer, poly[N-(2-hydroxypropyl methacrylamide)] (pHPMA), while subsequently coupling thiol-containing molecules to the cross-linker via maleimide addition. Two novel cross-linkers were prepared from the popular heterobifunctional cross-linking agent, succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), modified to contain either terminal aldehyde groups (i.e., 1-(N-3-propanal)-4-(N-maleimidomethyl) cyclohexane carboxamide, PMCA) or methylketone groups (i.e., 1-(N-3-butanone)-4-(N-maleimidomethyl) cyclohexane carboxamide, BMCA). A third cross-linking agent was the commercially available N-4-acetylphenyl maleimide (APM). PMCA and BMCA exhibited excellent reactivity toward hydrazide-derivatized pHPMA with essentially complete hydrazone conjugation to polymer reactive sites, while APM coupled only ∼60% of available reactive sites on the polymer despite a 3-fold molar excess relative to polymer hydrazide groups. All polymer hydrazone conjugates bearing these bifunctional agents were then further reacted with thiol-modified tetramethylrhodamine dye, confirming cross-linker maleimide reactivity after initial hydrazone polymer conjugation. Incubation of dye-labeled polymer conjugates in phosphate buffered saline at 37 °C showed that hydrazone coupling resulting from APM exhibited the greatest difference in stability between pH 7.4 and 5.0, with hydrolysis and dye release increased at pH 5.0 over a 24 h incubation period. Polymer conjugates bearing hydrazones formed from cross-linker BMCA exhibited intermediate stability with hydrolysis much greater at pH 5.0 at early time points, but hydrolysis at pH 7.4 was significant after 5 h. Hydrazones formed with the PMCA cross-linker showed no difference in release rates at pH 7.4 and 5.0.

Disinfection by-products from halogenation of aqueous solutions of terpenoids

We report the formation of trihalomethanes and other disinfection by-products from four polyfunctional terpenoids during simulated chlorination of natural waters. Complex suites of products were identified by closed loop stripping analysis (CLSA)/gas chromatography–mass spectrometry (GC–MS) from halogenation of β-carotene and retinol. β-Ionone appeared to be a key intermediate in the halogenation of β-carotene and retinol, reacting further under the reaction conditions to produce trans-β-ionone-5,6-epoxide and β-cyclocitral. Halogenation of the four terpenoids also produced trihalomethanes (THMs), most likely through haloform reaction on methyl ketone groups within many of the intermediates. Since halogenation of retinol produced a significant quantity of THMs at a slow reaction rate, retinol-based structures may possibly contribute to the slow reacting phase of THM formation in natural waters. Two polyhydroxyphenol model compounds were halogenated for comparison. The only products identified by CLSA/GC–MS from halogenation of 4′,5,7-trihydroxyflavanone and ellagic acid were THMs. 4′,5,7-Trihydroxyflavanone rapidly produced THMs, with an extremely high molar yield (94%) at pH 7. Terpenoids of the β-ionone and retinol type should be considered to be significant THM precursors, while 4′,5,7-trihydroxyflavanone has been shown to be an extremely significant THM precursor, potentially present within natural organic matter in water treatment processes and distribution systems.

Preparation of enantiopure (R)‐hydroxy metabolite of denbufylline using immobilized Lactobacillus kefiri DSM 20587 as a catalyst

Lactobacillus kefiri DSM 20587 cells were immobilized in calcium alginate and carrageenan. The immobilized cells were used as biocatalysts for the enantioselective reduction of the methyl ketone group of denbufylline to synthesize the enantiopure (R)-hydroxy metabolite: (-)-1,3-dibutyl-7-((2'R)-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (1). The experimental conditions for the biotransformation were optimized. As denbufylline is insoluble in aqueous media, the influence of cosolvents (dimethylsulfoxide (DMSO), acetonitrile) and different concentrations of each solvent in the reaction mixture on the yield and enantiomeric excess of the final biotransformation product was studied. The maximum biotransformation yield (96-98%) and highest enantioselectivity (96% ee) for the obtained metabolite were reached using DMSO as a cosolvent at a concentration of 7.5% (v/v) in the presence of L. kefiri immobilized either in calcium alginate or in carrageenan. The absolute configuration of the stereogenic center of 1 was determined by applying Mosher's method.

Rapid Access to Amino-Substituted Quinoline, (Di)Benzofuran, and Carbazole Heterocycles through an Aminobenzannulation Reaction

The use of a powerful aminobenzannulation reaction has been applied for the synthesis of amino-substituted quinolines, dibenzofurans, and carbazoles. The precursors are heterocycles bearing a methyl ketone group ortho to an internal alkyne. They are commercially available or can be obtained in three to four classical and efficient reactions: Vilsmeier-Haack, Sonogashira (diversity point), Grignard, and Ley's oxidation. Upon aminobenzannulation reaction-classical conditions being pyrrolidine neat or in a solvent and 4 A MS-an interesting range of disubstituted quinolines, dibenzofurans, and carbazoles are obtained along with enamine formation in some cases. The reaction is useful since meta-substituted heterocycles are produced and also differs from classical heterocyclic methods which go through closure at the heteroatom-containing ring instead of benzene ring formation.

Characterization and crystal structure of 2R-(−)-6-hydroxytremetone from Xenophyllum poposum (Phil.) V.A. Funk

2R-(−)-6-Hydroxytremetone (C13H14O3) is a bioactive metabolite isolated from Xenophyllum poposum (Phil.) V.A. Funk. (ex. Werneria poposa Phil.), a member of the Asteraceae. Various pharmacological properties attributed by popular medicine to benzofurane derivatives prompted their physical and chemical characterization. The obtained substance was characterized by melting point, optic rotation, ultraviolet spectrum, 1HRMN, 13CRMN, infrared spectroscopy, and thermo-analytical techniques. The molecular structure of 2R-(−)-6-hydroxytremetone was determined by single crystal X-rays diffraction methods. The substance crystallizes in the monoclinic space group P2 1 with a = 8.767(2) Å, b = 5.423(1) Å, c = 24.301(4) Å, β = 90.52(2)°, and two independent but very similar molecules of the same handedness per asymmetric unit (Z = 4). Both molecules have the phenyl ring and its attached oxydryl and methyl ketone groups nearly co-planar to one another and are stabilized by a strong OH ··· Oketone intra-molecular bond (Ohydroxyl ··· Oketone distances of 2.529 and 2.536 Å; O–H ··· Oketone angles of 146.4 and 143.9°, respectively).

Re-examination of the thermal oxidation reactions of polymers3. Various reactions in polyethylene and polypropylene

Many hydroperoxide and peroxide transforming reactions can proceed in polymers. Pseudo-monomolecular and bimolecular hydroperoxide decomposition constitute only part of the overall possibilities. The additional reactions depend heavily on the particular polymer and the conditions of the experiments. The reaction of aldehydes with secondary hydroperoxides in polyethylene (PE) is transforming the aldehydes into acids and the hydroperoxides into ketones. With advancing oxidation acid-catalyzed hydroperoxide decomposition is expected to become increasingly important. It is particularly of interest if it involves special hydroperoxides such as α-keto-hydroperoxides and allylic hydroperoxides because the corresponding reactions give chain scission. The most important special structure formed in PE seems to be the α,γ-keto-hydroperoxides. Their thermal decomposition gives chain scission with simultaneous formation of carboxylic acid and methyl-ketone groups. Thermal decomposition of the ozonides formed on oxidation of PE and polypropylene (PP) also involves chain scission. In PE, contrary to PP, formation of 1,2-dioxetane groups is restricted. In addition, α-hydroxy-hydroperoxides are expected in much smaller amount in PE than in PP. They might be the only source of chemiluminescence in PE.

16α-Hydroxy-20-oxopregn-5-en-3β-yl acetate

In the title compound, C23H34O4, the two saturated six-membered rings have slightly flattened chair conformations and the unsaturated ring assumes a 8β,9α-half chair conformation distorted towards a 8β-sofa. The five-membered ring has an unusual conformation close to a 13β-envelope. The acetoxy and methyl ketone substituents are twisted with respect to the average molecular plane of the steroid nucleus. The mol­ecules are hydrogen-bonded head-to-head via the hydroxy and methyl ketone groups forming dimers, which are stacked in planes perpendicular to the b axis.

Synthesis of Methylketone Containing Nucleoside Triphosphates for RNA Labelling

The three nucleoside triphosphates 1, 2 and 3 bearing a linker with a terminal methylketone group were prepared for incorporation into RNA fragments and post-labelling by the fluorescein derivative 4 containing an aminooxy group.

Oxidation Chemistry of a Pentaerythritol Tetraester Oil

Synthetic oils have come into widespread use due to their inherent stability, consistent physical properties, and reproducible composition. As ever increasing demands are being placed on oil performance in magnetic recording disk drives by increasing rotation rates up to 10,000 rpm, it is important to know the ultimate limitations of these functional fluids due to oxidation; In this study, the authors focus on a pentaerythritol ester oil. Accelerated aging tests were carried out on the oil at elevated temperature. Tests were also done with 50 ppm of dissolved iron in the oil. The progress of oxidation was followed by analytical techniques including UV/visible, infrared, and proton nuclear magnetic resonance spectroscopy, and gel permeation chromatography, thin layer chromatography, viscometry, and differential scanning calorimetry. A new technique of laser desorption mass spectrometry with jet cooling, which provides the parent ion mass spectrum, provided the mass distribution of intermediate oxidation products. These techniques enabled determination of the predominant oxidation products. Oxidation proceeds through interchain and intrachain proton abstraction. Hydroxyl groups form on alkyl chains. Intrachain proton abstraction leads to formation of oxetane and conjugated ketone on the original alkyl chain and to cleavage of the alkyl chain with the formation of methyl ketone and carboxylic acid end groups. Dissolved iron increased the formation rate of hydroxyl and oxetane without changing the hydroperoxide concentration. Oligomers were absent from the mass spectrum of the oxidized oil. The increase in oil viscosity with accelerated aging is due to increasing intermolecular hydrogen bonding between hydroxyl groups formed on alkyl chains.

Efficient Synthesis of Bicyclic Lactones via Tungsten-Mediated Intramolecular Cycloalkenation.

A series of tungsten-eta(1)-alkynols tethered with a dimethylacetal, methyl ketone, or trimethoxymethane group are prepared. Treatment of these functionalized tungsten-alkynols with BF(3).Et(2)O leads to intramolecular cycloalkenation, producing bicyclic tungsten-oxacarbeniums in high yields. Air oxidation of these oxacarbenium salts produces unsaturated bicyclic lactones in good yields. The lactone products include delta- and epsilon-lactones fused with five-, six- and seven-membered carbocyclic rings. The preceding bicyclic tungsten-eta(1)-oxacarbeniums are highly reactive toward organocuprates, Grignard reagents, and diazomethane, leading to demetalation to give various derivatives of bicyclic lactones. A short synthesis of (+/-)-mitsugashiwalactone is developed based on this method.

1-(1,3-Benzothiazol-2-yl)-2-(2-bromo-5-nitrophenyl)ethanone.

The title compound, C15H9BrN2O3S, was isolated as an unexpected product from the reaction of the anion of sodium 2-(1,3-benzothiazolyl)ethanonitrile with alpha,2-dibromo-5-nitrotoluene. Its structure features a benzothiazole fragment and a bromo- and nitro-substituted phenyl ring linked by a methyl ketone group. The dihedral angle between the benzothiazole and phenyl rings is 103.7 (2) degrees. The benzothiazole fragment is planar, with a maximum deviation of 0.021 (2) A. The nitro group is slightly rotated out of the phenyl-ring plane, with a O(2)-N(2)-C(14)-C(15) torsion angle of 16.4(7) degrees.