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The first example of an aromatic haloform reaction is reported, defining a conceptually new haloform-type approach to the metal-free functionalization of arenes. We demonstrated that heteroarenes bearing a vinylogous nitromethane system, via the stage of a trichloromethane derivative, could undergo aromatic amination to produce N-functionalized arenes in quantitative yields and without the need for transition-metal catalysis. The haloform-type amination was implemented in the development of effective orthogonal N-protection strategies, establishing a new promising N-protecting reagent.

Herein, a high-yielding cycloaddition reaction of β-ketoesters and azides to provide 1,2,3-triazoles is described. The reactions employing 2-unsubstituted β-ketoesters were found to provide 5-methyl-1,2,3-triazoles, whereas 2-alkyl-substituted β-ketoesters provided 5-hydroxy-1,2,3-triazoles (shown to be relatively acidic) in high yields and as single regioisomers. Several novel compounds were reported and characterized including long-chain 5-hydroxy-1,2,3-triazoles potentially bioisosteric to hydroxamic acids.

Herein we report the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the conversion of secondary activated alkyl sulphides to benzylic alkyl bromides, which were obtained in 80–99% yields. The reaction carried out on enantio-pure sulphides provided the corresponding bromides in high yields and enantioselectivity (up to 92% ee; 94% es) at room temperature. The on-water conditions reduced significantly the reaction times compared to similar procedures run in organic media. The condition identified made use of no solvent, required no temperature control and produced a smooth organic phase easily separated for further synthetic use on a multigram-scale without the need for any organic extraction. Therefore, the present constitutes the most operationally simple and environmentally benign approach to a class of much sought organic intermediates.

Herein we report the first organocatalysed enantioselective synthesis of gingesulfonic acids and shogasulfonic acids via a mild and convenient aminothiourea-catalysed conjugate addition of bisulfite to the olefin moiety of α,β-unsaturated carbonyls-a technology previously reported by us. A series of optically active naturally occurring sulfonic acids are prepared in their natural and unnatural configurations, and their absolute configurations are unequivocally confirmed by single crystal X-ray diffractometry.

Chiral phase‐transfer catalysis provides high level of enantiocontrol, however no experimental data showed the interaction of catalysts and substrates. 1H NMR titration was carried out on Cinchona and Maruoka ammonium bromides vs. nitro, carbonyl, heterocycles, and N−F containing compounds. It was found that neutral organic species and quaternary ammonium salts interacted via an ensemble of catalyst +N−C−H and (sp2)C−H, specific for each substrate studied. The correspondent BArF salts interacted with carbonyls via a diverse set of +N−C−H and (sp2)C−H compared to bromides. This data suggests that BArF ammonium salts may display a different enantioselectivity profile. Although not providing quantitative data for the affinity constants, the data reported proofs that chiral ammonium salts coordinate with substrates, prior to transition state, through specific C−H positions in their structures, providing a new rational to rationalize the origin of enantioselectivity in their catalyses., 1H NMR titration experiments were carried out on Cinchona and Maruoka type quaternary ammonium salts, by using neutral ligands. The data clarified the principal interactions involved between catalyst and reactants, showed the binding of halides and non‐coordinating anion BArF to chiral ammonium species, and provided a guide to understanding the enantioselective processes mediated by this class of organocatalysts.

The diastereoselective reduction of γ-keto-sulfonates to afford α,γ-substituted γ-hydroxy sulfonates has been investigated. Herein we report the first example of a diastereoselective carbonyl reduction whereby hydride attack is directed via chelation of a neighbouring sulfonate group to a boron atom, thus affording prevalently trans γ-hydroxy sulfonates.

An enantioselective protocol for the desymmetrization of cis-3,5- O-arylidenecyclohexanones has been developed that proceeded under the catalysis of readily available and inexpensive Cinchona-derived quaternary ammonium salts. The synthetic relevance of the methodology was exemplified by the synthesis of a key intermediate that could be used in the preparation of the active pharmaceutical ingredient, paricalcitol (Zemplar).

Herein, we present the first example of synthesis of 3,4-dihydropyran-2-ones from cinnamic thioesters via a stereoselective phase-transfer-catalyzed domino Michael-cyclization reaction with acetylacetone. The reaction proceeded under the catalysis of Cinchona-derived quaternary ammonium phenoxide that, in combination with inorganic bases, provided 3,4-dihydropyran-2-ones in yields of up to 93% and enantioselectivities of up to 88% enantiomeric excess.

Functionalised medium-sized ether rings were prepared in an efficient manner by [4+3] cycloaddition followed by ring-opening metathesis. This procedure provided medium-sized rings, which were shown to be useful for the assembly of fused bicyclic structures present in complex natural compounds. The potential of the chemistry described in this paper to be used in synthesis has been demonstrated by the preparation of functionalised large cyclic ethers and bicyclic structures.

Herein we describe the preparation of a new class of sterically demanding organocatalysts derived from d -fructose and their use, alongside hitherto unreported doubly quaternarised Cinchona ammonium salts, in the Michael reaction of nitromethane with 4-nitro-5-alkenyl-isoxazoles.

Herein we report a two-step sequence for the preparation of amides starting from azides and enolisable aldehydes. The reaction proceeded via the formation of triazoline intermediates that were converted into amides via Lewis acid catalysis. Preliminary studies on the preparation of triazolines under chiral phase transfer catalysis are also presented, demonstrating that enantioenriched amides could be prepared from achiral aldehydes in moderate to low enantioselectivity.

Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isoprenylcysteine carboxyl methyltransferase (ICMT), a validated target for cancer drug development. There is a high homology between the human and the parasite enzyme isoforms, in addition to being a druggable target. Looking to repurpose its structure as an antimalarial drug, a collection of S-substituted derivatives of thiosalicylic acid were prepared by introducing 1,2,3-triazole as a diversity entry point or by direct alkylation of the thiol. We further investigated the in vitro toxicity of FTS analogues to Plasmodium falciparum in the asexual stages and in Vero cells. An antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (NLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration, including Salirasib. The most potent member of the series has S-farnesyl and the 1,2,3-triazole moiety substituted with phytyl. However, the compound substituted with methyl-naphthyl shows promising physicochemical and activity values. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indices, being starting-point candidates for future antimalarial drug development.

MicroRNAs are a ubiquitous class of non-coding RNAs able to regulate gene expression in diverse biological processes. Widespread miRNAs deregulation was reported in numerous diseases including cancer, with several miRNAs playing oncogenic and/or tumor suppressive role by targeting multiple mRNAs simultaneously. Based on these findings, miRNAs have emerged as promising therapeutic tools for cancer treatment. Herein, for the first time, peptide nucleic acids (PNAs) were studied to develop a new class of molecules able to target 3′UTR on MYCN mRNA without a fully complementary base pairing sequence (as miRNAs). For our proof of concept study we have selected as a model the miRNA-34a, which acts as a tumor suppressor in a number of cancers including neuroblastoma. In particular, miRNA-34a is a direct regulator of MYCN oncogene, whose overexpression is a prominent biomarker for the highly aggressive neuroblastoma phenotype. The design and synthesis of three PNA-based oligomers of different length was described, and their interaction with two binding sites on the target MYCN mRNA was investigated by molecular dynamics simulation, and spectroscopic techniques (CD, UV). Intake assay and confocal microscopy of PNA sequences were also carried out in vitro on neuroblastoma Kelly cells. Despite the presence of multiple mismatches, the PNA/RNA hetero duplexes retain very interesting features in terms of stability, affinity as well as of cellular uptake.

Herein, we report our investigation into the reactivity of 5-enamino-4-nitroisoxazoles. This study revealed that the title compounds, in spite of conjugation to the 4-nitroisoxazole, displayed similar reactivity to enamines, reacting with electrophiles to form new C–C, C–N, and C–Cl bonds.

Heavily substituted cyclopropane esters were prepared in high yields, complete diastereoselection and average (up to 58%) enantioselectivity. The reaction described herein entailed reacting 4-nitro-5-bromostyrylisoxazoles, a class of powerful Michael acceptors with malonate esters under the catalysis of 5 mol% of a chincona derived phase-transfer catalyst.

The chlorination of readily available secondary and tertiary alkyl phenyl sulfides using (dichloroiodo)benzene (PhICl2) is reported. This mild and rapid nucleophilic chlorination is extended to sulfa-Michael derived sulfides, affording elimination-sensitive β-chloro carbonyl and nitro compounds in good yields. The chlorination of enantioenriched benzylic sulfides to the corresponding inverted chlorides proceeds with high stereospecificity, thus providing a formal entry into enantioenriched chloro-Michael adducts. A mechanism implying the formation of a dichloro-λ4-sulfurane intermediate is proposed.

Different methodologies have been applied to forecast oil production curves in many regions or countries. The scientific literature indicates that curve-fitting models, especially the approach of Hubbert, are a simple and suitable tool for first-order projections of future production. This is particularly true when data for ultimately recoverable resources (URR) are uncertain and producers are price-takers. This study estimated Brazil’s oil production curves, according to different URR scenarios (P95, P50 and P5), applying a modified multi-Hubbert model. This model improved the classic methodology by adding productive cycles and allowing the revision of the assumption that production rate is strictly proportional to the first power of both depletion and information effects. Findings show that, without considering the recent discoveries in pre-salt layers, Brazil’s peak oil should hover between 2.37 Mb/d (2015), 3.33 Mb/d (2022) and 6.59 Mb/d (2035), depending on URR scenarios. The accuracy of the fitting related to the observed data from 1954 to 2012 gave a relative standard deviation of less than 2.5%. Considering pre-salt contingent resources, Brazil’s peak oil would be fatter and range from 4.85 Mb/d (2027) to 8.24 Mb/d (2047) depending on the hypotheses made. This last result is, however, highly uncertain.

Cyclopropane esters holding two quaternary centres were prepared in high yields, complete diastereoselection and up to 83% ee. The reaction described herein entailed reacting (Z)-3-substituted-2-(4-pyridyl)-acrylonitrile, a reactive class of Michael acceptor, with 2-bromomalonate esters in the presence of Cinchona derived phase-transfer catalysts. The reaction allowed multi-gram preparation of the desired products.

Curcumin, the main curcuminoid of the popular Indian spice turmeric, is a potent chemopreventive agent and useful in many different diseases. A major limitation of applicability of curcumin as a health promoting and medicinal agent is its extremely low bioavailability due to efficient first pass metabolism, poor gastrointestinal absorption, rapid elimination, and poor aqueous solubility. In the present study, nanotechnology was selected as a choice approach to enhance the bioavailability of the curcuminis. A new polyamidoamine dendrimer (G0.5) was synthesized, characterized, and tested for cytotoxicity in human breast cancer cells (MCF-7). No cytotoxicity of G0.5 was found in the range between 10−3 and 3 × 10−8 M. Consequently, G0.5 was used to prepare spherical nanoparticles of ca. 150 nm, which were loaded with curcumin [molar ratio G0.5/curcumin 1 : 1 (formulation 1) and 1 : 0.5 (formulation 2)]. Remarkably, the occurrence of a single population of nanoparticles having an excellent polydispersity index (

Cyclopropane esters holding two quaternary centres were prepared in high yields, complete diastereoselection and up to 83% ee. The reaction described herein entailed reacting (Z)-3-substituted-2-(4-pyridyl)-acrylonitrile, a reactive class of Michael acceptor, with 2-bromomalonate esters in the presence of Cinchona derived phase-transfer catalysts. The reaction allowed multi-gram preparation of the desired products.

PNAs are emerging as useful synthetic devices targeting natural miRNAs. In particular 3 classes of structurally modified PNAs analogs are herein described, namely α, β and γ, which differ by their backbone modification. Their mode and binding affinity for natural nucleic acids and their use in medicinal chemistry as potential miRNA binders is discussed.

We describe the development of an N-heterocyclic carbene catalysed homoenolate addition to 4-nitro-5-styrylisoxazoles to give substituted cyclopentanones with a unique substitution pattern and as single diastereoisomers. The synthetic utility of the cyclopentanones obtained was briefly explored through their conversion into α-fluorinated diketones and keto acids.

Herein we describe two coupling reactions of aldehydes and activated alkynes to give chalcones or alkenyl esters depending on the base used. Chalcones were obtained by activation of alkynes by Au I and of aldehydes by NHC in presence of triethylamine. Alkenyl esters were obtained via generation of gold nanoparticles, aerial oxidation of aldehydes to carboxylates and their subsequent nucleophilic addition to the alkyne functionality.

We report the first synthetic route to prepare 3-methyl-4-nitro-5-(2-alkylethenyl)isoxazoles in high yields and exclusively as E -diastereoisomers.

This study focuses on the preparation of some 1-alkynyl-2-deoxy- d -riboses and their application to the generation of C-nucleosides analogues. Examples are provided in which the alkyne functionality took part in alkylation or cycloaddition reactions. A discussion of the protecting group used is provided.

A novel synthesis of functionalised monobactams in high isolated yields is described. The procedure involves photochemical cyclisation of commercially available 2-pyridones followed by ring-opening cross-metathesis.

The preparation of E-5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and their reaction with 1,3-dicarbonyl compounds to give cyclopropanes or dihydrofurans is described.

3,5-Diethyl-4-nitroisoxazole reacted with carbonyl compounds in the presence of an amine catalyst. The vinylogous nitroaldol adducts were isolated in good yields.

Herein we describe the preparation of a novel class of isoxazolyl aziridines. The products were obtained exclusively as cis diastereoisomers.

Herein we report a one-pot procedure to prepare a family of homochiral dihydroxy-4-nitroisoxazolines 3. This new methodology affords the title compounds in good yields, excellent enantiopurity, and without the use of chromatography.

The photochemical behaviour of some 5-alkylidene-2,5-dihydroisoxazoles was investigated. This reaction produced cis-4,5-dihydrofuroazetidinones in high yields.

Herein we described the preparation of two novel heterocyclic nuclei isoxazolopyridone and pyrazolopyridone. The syntheses are modular in nature and fast to execute. The title compounds were obtained pure without intervention of chromatography.

Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding γ-nitroacids.

Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding γ-nitroacids.

A synthetic route was devised for a sugar based α-chloroketone, which was subsequently used to generate a family of C-nucleosides via parallel synthetic methodology.

The expected Michael adducts and spiroisoxazolines are obtained from the reaction between 3-methyl-4-nitro-5-styrylisoxazole and bis-enolisable ketones. Contrary to reported data, Michael adducts are obtained in good yields only when a substoichiometric amount of base is used, whereas spiroisoxazolines were obtained as the major product when the base is present in a large excess.

There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS) interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system (UPS) in Plasmodium falciparum, the human malaria parasite, and that P. falciparum protein kinase 7 influences this process. This implies a role of melatonin, an indolamine, in modulating intraerythrocytic development of the parasite. In this report we demonstrate by qPCR analysis, that melatonin induces gene upregulation in nine out of fourteen genes of the UPS, consisting of the same set of genes previously reported, between 4 to 5 h after melatonin treatment. We demonstrate that melatonin causes a temporally controlled gene expression of UPS members.

A method allowing the selective oxygen labelling of aliphatic polyacids, for example, succinic and glutaric acids, is reported. This process is based on the hydrolysis of a 3-alkyl-4-nitroisoxazol-5-yl group by Na 18 OH and affords the products in high yields. The same procedure was applied for the preparation of labelled aliphatic carboxylic acids.

An efficient procedure for the resolution of 2-methylpiperidine is described. The enantiomers were used for a short and effective synthesis of the C2 symmetric piperidine, (+)-lupetidine and (+)-epidihydropinidine.

A multicomponent synthesis of cyclopropanes is described. The title compounds were obtained in high yields from commercially available materials.

A four component one-pot procedure (4-MC) was developed to assemble 3-heteroarylpropionic acids from commercially available materials. This new methodology affords the title compounds in high yields and without the use of chromatography. [reaction: see text]

The cyclopropanation of styryl isoxazoles (I) as cinnamate equivalents with bromomalonate (II) in the presence of a Cinchona alkaloid derived phase-transfer catalyst affords highly substituted cyclopropanes (III) in high yields, complete diastereo- and high enantioselectivity.

Asymmetric addition of sodium bisulfite towards chalcone derivatives (I) is efficiently catalyzed by a cinchona alkaloid-derived bifunctional amine—thiourea catalyst.

Depending on the base used, either chalcon derivatives (III) or alkenyl benzoic esters (IV) are formed by the title reaction of benzaldehydes with alkyne (II).

Michael addition of title compounds (I) with benzyl mercaptan (II) proceeds with good yields in the presence of piperidine.

Dr. F. Fini, M. Scagnetti, Prof. M. F. A. AdamoCentre for Synthesis and Chemical Biology (CSCB)Department of Pharmaceutical and Medicinal ChemistryRoyal College of Surgeons in Ireland123 St. Stephen’s Green, Dublin 2 (Ireland)Fax: ( +353)1-402-2168E-mail: madamo@rcsi.ieHomepage: https://research1.rcsi.ie/pi/madamo/[