Giuliano C. Clososki

Direct zincation of functionalized aromatics and heterocycles by using a magnesium base in the presence of ZnCl2.

A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF by using (TMP)(2)Mg2 LiCl (TMP=2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl(2). The possible pathways of this metalation procedure as well as possible reactive intermediates are discussed. This experimental protocol expands the tolerance of functional groups and allows an efficient zincation of sensitive heterocycles such as quinoxaline or pyrazine. The zincated arenes and heteroarenes react with various electrophiles providing the expected products in 60-95 % yield.

Queen signals in a stingless bee: suppression of worker ovary activation and spatial distribution of active compounds

In most species of social insect the queen signals her presence to her workers via pheromones. Worker responses to queen pheromones include retinue formation around the queen, inhibition of queen cell production and suppression of worker ovary activation. Here we show that the queen signal of the Brazilian stingless bee Friesella schrottkyi is a mixture of cuticular hydrocarbons. Stingless bees are therefore similar to ants, wasps and bumble bees, but differ from honey bees in which the queens signal mostly comprises volatile compounds originating from the mandibular glands. This shows that cuticular hydrocarbons have independently evolved as the queens signal across multiple taxa, and that the honey bees are exceptional. We also report the distribution of four active queen-signal compounds by Matrix-assisted laser desorption/ionization (MALDI) imaging. The results indicate a relationship between the behavior of workers towards the queen and the likely site of secretion of the queens pheromones.

Directed metalation of 1-ester-substituted indolizines: base/electrophile-controlled regioselective functionalization.

A variety of C-2 and C-5 difunctionalized indolizines have been prepared through the reaction of 1-ester-substituted indolizines with organometallic bases followed by a reaction with different electrophiles. Metalation takes place under mild conditions allowing the isolation of a number of difunctionalized indolizines in good yields. The regioselectivity of the reaction appears to be governed by the nature of the base and electrophile.

Enzymatic Resolution of 5‐Phenylselanyltetrahydro‐2‐furanone. Enantioselective Preparation of (R) and (S)‐γ‐Valerolactone

Abstract Lipase‐catalyzed lactonization of (2) provides both (R) and (S) enantiomers of 5‐phenylselenyltetrahydro‐2‐furanone (1) in good enantiomeric excess. The kinetic resolution was examined using PPL (Porcine pancreatic lipase), PSL (Amano PS, Pseudomonas sp. lipase), MML (Mucor miehei lipase), CRL (Candida rugosa lipase), CAL‐B (Candida Antarctica lipase, type B) and Novozym 435 (immobilized C. antarctica lipase type B) in different solvents. A tributyltin hydride reduction of enantiomerically enriched 1 gave both (R) and (S) enantiomers of S‐4‐pentanolide (γ‐valerolactone).

Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2-dependent and -independent fever while 4-AA only blocks PGE2-dependent fever

The antipyretic and hypothermic prodrug dipyrone prevents PGE2‐dependent and ‐independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects.

Interspecific chemical communication in raids of the robber bee Lestrimelitta limao

Most social bees collect floral resources to obtain proteins and carbohydrates. However, the obligate cleptoparasite stingless bee Lestrimelitta limao, the so-called robber bee, is a rare exception as it collects resources by raiding other stingless bee nests. The mechanisms these bees use to overcome host colony defenses are poorly understood. Many host species retreat inside the nest during L. limao attacks and the signals triggering this behavior require a better understanding. While some researchers have proposed that robber bees release chemical compounds that are responsible for host retreat, others have hypothesized that the observed behavior results from communication among host workers. In order to investigate the role of interspecific signals in raids, we tested the effects of robber bees’ mandibular and labial gland secretions on the behavior of Frieseomelitta varia workers. We combined behavioral assays with chemical and electrophysiological analyses. We found that citral and 9-nonacosene are major mandibular gland compounds and two esters, hexadecyl acetate and 9-hexadecenyl acetate, are major labial gland compounds. These three major compounds elicited electro-physiological responses on host worker antennae. Robber bee labial gland extracts repelled both foragers and guards, while mandibular gland content increased aggression. Our results suggest that interspecific communication plays a role during natural raids and that esters from L. limao labial glands, rather than citral, are more likely to trigger the host retreat. The results add to our knowledge about L. limao chemical communication and help to elucidate the mechanisms involved in their intriguing foraging strategy.

Zinc, Lithium and Magnesium Carbenoids: Chemical Properties and Relevant Applications in Organic Synthesis

Carbenoids are a class of highly reactive reagents that play an important role in modern organic synthesis. These species are very similar to singlet state carbenes since they have an ambiphilic character and react by a concerted mechanism allowing stereospecific transformations. Herein, we discuss these and other chemical aspects of zinc, lithium and magnesium carbenoids as well as relevant applications of these intermediates in organic synthesis.

Application of the Negishi reaction in the synthesis of thiophene-based lignans analogues with leishmanicidal effects

As lignanas tetraidrofurânicas sao metabolitos secundarios com reconhecida atividade antiprotozoaria. Na literatura, ha varios relatos sobre os efeitos anti-parasitarios de analogos sinteticos de lignanas contendo pontes de enxofre. Neste trabalho, foi realizada a sintese de analogos tiofenicos de lignanas com o uso de uma estrategia sintetica seletiva e de alto desempenho baseada na reacao de acoplamento cruzado de Negishi. Os derivados sinteticos foram obtidos de maneira rapida e apresentaram alto grau de pureza e baixa toxicidade para uma linhagem celular de mamifero e atividade leishmanicida com diferentes potencias. Lignans represent a well-known group of natural products with anti-protozoal activity. In the literature there are many examples of the anti-parasitic activity of synthetic analogues of lignans containing sulphur bridges. In this work, we have obtained thiophene-based analogues by using a selective and high performance synthetic strategy based on the Negishi cross-coupling reaction. The derivatives were quickly obtained and showed great purity, low toxicity toward a mammalian cell line, and leishmanicidal activity with different potencies.

Gas‐phase reactivity of protonated 2‐oxazoline derivatives: mass spectrometry and computational studies

RATIONALE Oxazolines have attracted the attention of researchers worldwide due to their versatility as carboxylic acid protecting groups, chiral auxiliaries, and ligands for asymmetric catalysis. Electrospray ionization tandem mass spectrometric (ESI-MS/MS) analysis of five 2-oxazoline derivatives has been conducted, in order to understand the influence of the side chain on the gas-phase dissociation of these protonated compounds under collision-induced dissociation (CID) conditions. METHODS Mass spectrometric analyses were conducted in a quadrupole time-of-flight (Q-TOF) spectrometer fitted with electrospray ionization source. Protonation sites have been proposed on the basis of the gas-phase basicity, proton affinity, atomic charges, and a molecular electrostatic potential map obtained on the basis of the quantum chemistry calculations at the B3LYP/6-31 + G(d,p) and G2(MP2) levels. RESULTS Analysis of the atomic charges, gas-phase basicity and proton affinities values indicates that the nitrogen atom is a possible proton acceptor site. On the basis of these results, two main fragmentation processes have been suggested: one taking place via neutral elimination of the oxazoline moiety (99 u) and another occurring by sequential elimination of neutral fragments with 72 u and 27 u. These processes should lead to formation of R(+). CONCLUSIONS The ESI-MS/MS experiments have shown that the side chain could affect the dissociation mechanism of protonated 2-oxazoline derivatives. For the compound that exhibits a hydroxyl at the lateral chain, water loss has been suggested to happen through an E2-type elimination, in an exothermic step.

Simultaneous determination of dipyrone metabolites in rat hypothalamus, cerebrospinal fluid and plasma samples by LC-MS/MS

BACKGROUND After oral administration dipyrone is rapidly hydrolyzed to 4-methylaminoantipyrine, which is absorbed and further metabolized to 4-formylaminoantipyrine and to 4-aminoantipyrine, which is acetylated by a polymorphic N-acetyltransferase system to 4-acetylaminoantipyrine. To evaluate the presence of dipyrone metabolites in different rat matrices after intraperitoneal administration, an analytical method was developed and validated. METHODOLOGY The four main dipyrone metabolites were extracted from plasma, cerebrospinal fluid and hypothalamus samples by LLE prior to LC-MS/MS. RESULTS Standard calibration graphs for all metabolites were linear (r > 0.99). The intra- and inter-day precision and accuracy values were both inferior to 15%. CONCLUSION This method is simple and specific for studying dipyrone metabolites after intraperitoneal administration.