Evaluation of synthetic substituted 1,2-dioxanes as novel agents against human leishmaniasis.

The treatment of human leishmaniasis is currently based on few compounds that are highly toxic, expensive and have a high rate of treatment failure. A number of recent studies on new drugs focuses on natural or semi-synthetic compounds. Among them, the endoperoxide artemisinin, extracted from Artemisia annua, and some of its derivatives have shown leishmanicidal activity. In the present work, a series of structurally simple, fully synthetic 1,2-dioxanes were evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani; the cytotoxicity for mammalian cells was also assessed. The six most promising compounds in terms of activity and selectivity were further investigated for their antileishmanial activity on the promastigote forms of L. tropica, L. major and L. infantum and against L. donovani amastigotes. The good performance in terms of potency and selectivity makes these six hits promising candidates for a preliminary lead optimization as antileishmanial agents.

D-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity.

New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 µM).

3-bromozinc propenyl esters: an experimental and theoretical study of the unique stereocrossover observed in their addition to aromatic and aliphatic aldehydes.

We report the results of a combined experimental and theoretical study on the reaction of 3-bromopropenyl acetate in the presence of zinc with three different aldehydes (i.e., benzaldehyde, 2-methylpropanal, and cyclohexanecarboxaldehyde). A 80% de in favor of the anti product has been experimentally observed with both saturated aldehydes, while for benzaldehyde, a 1:1 syn/anti ratio has been found. DFT computations show the existence of three eta1-allylic organozinc complexes [gamma-(Z)-5a, gamma-(E)-5a, and alpha-5a], very close in energy. Only gamma-(Z)-5a and gamma-(E)-5a lead to the observed product. The computational investigation of the reaction of these allylic organozinc complexes with benzaldehyde and 2-methylpropanal demonstrates in both cases the existence of two competitive reaction paths leading to the syn and anti adducts, respectively. An anti preference has been found for 2-methylpropanal with both gamma-(Z)-5a and gamma-(E)-5a species (a diastereoselectivity larger than 80% is predicted), in agreement with the experiment. With benzaldehyde, while the reaction of gamma-(Z)-5a retains an anti-stereopreference (de = 70%), that involving gamma-(E)-5a is characterized by two degenerate transition states. In this case, the agreement between computations and experiments would be satisfactory under the assumption that the initial oxidative addition affords the gamma-(E)-5a zinc complex only. Additional MP2 computations have demonstrated that pi-stacking interactions can play a significant role in determining the relative energy of the transition states leading to the syn and anti products.

A new protocol for the acetoxyallylation of aldehydes mediated by indium in THF.

A new precursor of a formal 1-hydroxy allyl anion is represented by 3-bromo-1-acetoxy-1-propene, which is synthesized by the ZnCl(2)-catalyzed addition of acetyl bromide to propenal. 3-Bromo-1-acetoxy-1-propene reacts with indium powder in THF to give the corresponding 3-acetoxylated ally indium complex, which regioselectively adds to aldehydes, affording monoprotected 1-en-3,4-diols. Diastereoselectivity mainly depends on the nature of the aldehyde; saturated aldehydes afford anti adducts, whereas the alpha,beta-unsaturated aldehydes preferentially lead to the syn isomers. Reaction: see text.

Entropy-controlled selectivity in the vinylation of a cyclic chiral nitrone. An efficient route to enantiopure polyhydroxylated pyrrolidines.

A short synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol (LAB1) (4) and of 1,4-dideoxy-1,4-imino-D-galactitol (5), two azasugars active as enzymatic inhibitors, is reported. The key reaction is the addition of vinylmagnesium chloride to (3S,4S)-3,4-bis(benzyloxy)-3,4-dihydro-2H-pyrrole 1-oxide (3), a nitrone easily available from L-tartaric acid. Unexpectedly, the reaction affords the corresponding (2S,3S,4S)-1-hydroxy-2-ethenyl-3,4-bis(benzyloxy)pyrrolidine (9) in very good yield and in 93/7 diastereomeric ratio (dr) independently of the reaction temperature, thus representing a unique case of entropy-controlled reaction in a 100 K interval (from +20 degrees C to -80 degrees C). The trans intermediate 9 is converted in two steps (reduction, N-protection) into the common intermediate (2S,3S,4S)-1-(benzyloxycarbonyl)-3,4-bis(benzyloxy)-2-ethenylpyrrolidine (11). Double bond oxidation followed by reductive debenzylation opens a route to the target pyrrolidine azasugars 4 and 5.

The first zinc-promoted, environmentally friendly, and highly efficient acetoxyallylation of aldehydes in aqueous ammonium chloride.

An exceptionally mild acetoxyallylation of aldehydes in water promoted by zinc is reported, using 3-bromo-1-acetoxyprop-1-ene as starting material; simple diastereoselectivity mainly depends on the nature of the aldehyde.

Anthropogenically derived mercury in sediments of Pialassa Baiona, Ravenna, Italy.

Pialassa Baiona, a coastal wetland near the city of Ravenna, has been impacted for two decades (1958-1978) by industrial discharges containing mercury and floating agglomerates of residues of polymerization processes. Although the industrial use of mercury completely ceased in the early 90's, surface sediments are still highly contaminated, mercury concentrations decreasing from the southern sub-basin, close to the discharge point, to the farthest northern border. Concentrations of total mercury, synthetic polymers (determined by pyrolysis-GC/MS), total organic carbon, C/N ratio, total sulfur and 210Pb dating, were determined in sediment cores collected in the southern and northern sub-basins. Mercury and polymers exhibited parallel profiles with a peak corresponding to the historic emission record in the southern core, while in northern cores peaks of maximum concentration display a delay reflecting the time required for the pollutants to migrate. A recently developed mercury sequential extraction procedure was applied to the most polluted layers to study inorganic mercury speciation. Results indicate differences between the southern and northern areas, suggesting a more efficient binding of mercury to sediments in the southern sub-basin.

The hydroboration of propargyl bromide. Simple one-Pot three-component routes to (Z)-1-bromoalk-1-en-4-ols and to anti-homoallylic alcohols.

The hydroboration of propargyl bromide with dialkylboranes takes place regioselectively to give 3-bromoprop-1-en-1-yl dialkylboranes 13 which, upon quaternization with bromide ion, undergo a series of transformations into a number of allylic boron species. By a suitable choice of the experimental conditions it is possible to trap the reaction intermediates with aldehydes and to steer the process toward either the synthesis of (Z)-1-bromoalk-1-en-4-ols 6 or anti-homoallylic alcohols 8. Two one-pot three-component processes were developed based on a sequence of four reactions; preparation of dialkylborane and hydroboration of propargyl bromide are the first steps. Then, quaternization with TEBABr may be carried out either in the presence of the aldehyde when (Z)-1-bromoalk-1-en-4-ols 6 are requested, or in the absence of the aldehyde in order to allow the formation of gamma-substituted allyl borane 18 which, successively, adds to the aldehyde affording anti-homoallylic alcohols 8.