Selective Hydrofunctionalization of N-Allenyl Derivatives with Heteronucleophiles Catalyzed by Brønsted Acids.

In this study, we present a novel and environmentally sustainable protocol for the γ-hydrofunctionalization of N-allenyl compounds using various heteronucleophiles catalyzed solely by simple Brønsted acids. The method displays remarkable attributes, highlighting its sustainability, efficiency, regio- and stereoselectivity, as well as its versatile applicability to diverse heteroatom-containing enamides. Notably, our approach eliminates the need for metal catalysts and toxic solvents, representing a significant advancement in greener chemistry practices. We demonstrate the broad scope of our protocol by successfully scaling up reactions to gram-scale syntheses, underscoring its robustness for potential industrial implementation. The resulting γ-heterosubstituted enamides offer new possibilities for further synthetic transformations, yielding highly functionalized compounds with diverse applications. Mechanistic investigations reveal the pivotal role of CSA as a catalyst, enabling alcohol addition via a covalent activation mode.

Stereoselective Synthesis of α-Disubstituted ß-Homoprolines.

An efficient enantioselective synthesis of chiral α-disubstituted ß-homoprolines was developed, starting with the stereodivergent allylation of chiral N-tert-butanesulfinyl imines derived from 4-bromobutanal with indium or zinc and using well-established and reliable synthetic transformations. This methodology allows the easy introduction of different substituents at the α-position of the pyrrolidine scaffold and is characterized by the possibility of switching the absolute configuration of the newly formed stereocenter either by changing the configuration of the tert-butanesufinamide chiral auxiliary or by using a different stereodivergent allylation protocol with the same auxiliary.

Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update.

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

Evaluation of the Pharmacophoric Role of the O-O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans.

Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro, and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania.

A supramolecular bifunctional iridium photoaminocatalyst for the enantioselective alkylation of aldehydes.

The construction of a hybrid metal-organo-photoredox catalyst based on the conjugation of an imidazolidinone organocatalyst and Ir(ppy)2(bipy) (ppy = 2-phenylpyridine, bipy = bipyridine) is described. The introduction of the desired organocatalyst into the bipyridine moiety is quite modular, allowing the preparation of different hybrid photocatalysts, and is realized though a simple click reaction. The hybrid photocatalysts obtained were employed in the benchmark photoredox alkylation of aldehydes. Remarkably, the conjugation of a first-generation MacMillan catalyst produces an active and stereoselective hybrid photoredox catalyst.

Thermochemiluminescent semiconducting polymer dots as sensitive nanoprobes for reagentless immunoassay.

Thermochemiluminescence (TCL) is a potentially simple and sensitive detection principle, as the light emission is simply elicited by thermally-triggered decomposition of a molecule to produce a singlet excited-state product. Here we report about TCL semiconductive polymer dots (TCL-Pdots) obtained by doping fluorescent cyano-polyphenylene vinylene (CN-PPV) Pdots with an acridine 1,2-dioxetane derivative. The TCL-Pdots showed remarkable stability over time and minimum leaching of the thermo-responsive species. Furthermore, detectability of TCL-Pdots was improved by taking advantage of both the high number of 1,2-dioxetanes entrapped in each nanoparticle (about 20 molecules per Pdot) and the 5-fold enhancement of TCL emission due to energy transfer from 1,2-dioxetane to the polymer matrix, which itself acted as an energy acceptor. Indeed, upon heating the TCL-Pdots to 110 °C, 1,2-dioxetane decomposes generating an acridanone product in its electronically excited state. The latter transfers its energy to the surrounding CN-PPV chains via the Förster mechanism (φFRET about 80%), resulting in intense yellow light emission (550 nm wavelength). We next conjugated streptavidin onto the surface of these TCL-Pdots and demonstrated their suitability for use in biological studies. In particular, we used TCL-Pdots as labels in a model non-competitive immunoassay for IgG detection, which showed a LOD of 13 nM IgG and a dynamic range extending up to 230 nM. By combining the biocompatibility, brightness and tunability of Pdot fluorescence emission with the thermally-triggered reagentless light generation from TCL 1,2-dioxetanes, a broad panel of ultrabright TCL nanosystems could be designed for a variety of bioscience applications, even in multiplexed formats.

Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies.

BACKGROUND: The spirocyclic compounds have always aroused a great interest because this motif is present as structural core in a number of natural products and bioactive compounds. In particular, the spirolactone moiety has been recognized in a wide array of natural and non-natural scaffolds showing a variety of useful pharmacological properties. METHODS: Extensive literature search using SciFinder (Databases: CA Plus, CAS Registry, CAS React, Chemlist, Chemcat and Medline) and Web of Science (Database: Web of Science Core Collection) was conducted. RESULTS: Nowadays, many efforts are being devoted to the discovery of new natural products containing the promising spirolactone framework and to the disclosure of the potential bioactivities of these chemical entities. Moreover, the medicinal relevance of many spirolactones makes these scaffolds attractive targets for the design and development of innovative and efficient synthetic strategies, enabling the construction of complex and variably substituted products. CONCLUSION: This review gives an overview on the recent advances in the spirolactones field, in terms of new compounds isolated from natural sources, recently determined bioactivity profiles and innovative synthetic approaches. The collected data demonstrate the key role played by spirolactones in medicinal chemistry and the great attention still devoted by the scientific community to these compounds.

The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism.

In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

Synthesis of 1,2-Dioxetanes as Thermochemiluminescent Labels for Ultrasensitive Bioassays: Rational Prediction of Olefin Photooxygenation Outcome by Using a Chemometric Approach.

Great interest in new thermochemiluminescent (TCL) molecules, for example, in bioanalytical assays, has prompted the design and synthesis of a small library of more than 30 olefins to be subjected to photooxygenation, with the aim of obtaining new 1,2-dioxetane-based TCL labels with optimized properties. Fluorine atoms on the acridan system remarkably stabilize 1,2-dioxetanes when they are located in the 3- and/or 6-position (4 h and 4 i). On the other hand, 2,7-difluorinated acridan dioxetane (4 j) showed a significantly enhanced fluorescence quantum yield with respect to the unsubstituted dioxetane (4 a). Some of the synthesized olefins did not undergo singlet oxygen addition and a rationale was sought to ease the photooxygenation step, leading to the TCL dioxetanes. A chemometric approach has been adopted to exploit principal component analysis and linear discriminant analysis of the structural and electronic molecular descriptors obtained by DFT optimizations of olefins 3. This approach allows the steric and electronic parameters that govern dioxetane formation to be revealed.

The First Enantioselective Organocatalytic Synthesis of 3-Spiro-α-Alkylidene-γ-Butyrolactone Oxindoles.

A new and flexible methodology catalyzed by bifunctional chiral thioureas has been developed to react ß-nitro oxindoles 1 with aldehydes. This approach allowed us to achieve the first enantioselective organocatalytic synthesis of 3-spiro-α-alkylidene-γ-butyrolactone oxindoles 3. We examined the scope of the two starting materials and, varying the structure of the ß-nitro oxindole 1, intriguing new products, derived from unexpected transformations, have been stereoselectively obtained. The aim of this study was to merge two potentially bioactive structural motifs: the spirooxindole substructure and the α-alkylidene-γ-butyrolactone moiety. A preliminary NMR study on the ability to reversibly trap 2-aminoethanethiol gave us promising results.

Highly stereoselective [4+2] and [3+2] spiroannulations of 2-(2-oxoindolin-3-ylidene)acetic esters catalyzed by bifunctional thioureas.

A new Michael-Michael cascade reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2, catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon-carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double-bond configuration of the donor-acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five- and six-membered ß-nitro spirocarbocyclic oxindoles.

Organically modified silica nanoparticles doped with new acridine-1,2-dioxetane analogues as thermochemiluminescence reagentless labels for ultrasensitive immunoassays.

Doped organically modified silica nanoparticles (ORMOSIL NPs) with luminescent molecules represent a potent approach to signal amplification in biomolecule labeling. Herein, we report the synthesis of new ORMOSIL NPs incorporating thermochemiluminescent (TCL) 1,2-dioxetane derivatives to prepare TCL labels for ultrasensitive immunoassay, displaying a detectability comparable to those offered by other conventional luminescence-based systems. Amino-functionalized ORMOSIL NPs were synthesized for inclusion of acridine-containing 1,2-dioxetane derivatives with a fluorescence energy acceptor. The doped ORMOSIL NPs were further functionalized with biotin for binding to streptavidin-labeled species to be used as universal detection reagents for immunoassays. A quantitative non-competitive immunoassay for streptavidin has been developed by immobilizing anti-streptavidin antibody to capture streptavidin, then the antibody-bound streptavidin was detected by the biotinylated TCL ORMOSIL NPs. The analytical performance was similar to that obtained by chemiluminescent (CL) detection using horseradish peroxidase (HRP) as label, being the limits of detection 2.5-3.8 and 0.8 ng mL(-1) for TCL and CL detection, respectively. In addition, since the TCL emission is simply initiated by thermolysis of the label, chemical reagents were not required, thus allowing reagentless detection with a simplification of the analytical protocols. A compact mini dark box device based on the use of a cooled charge-coupled device (CCD) and a miniaturized heater has been developed and used to quantify the light emission after heat decomposition of the label at a temperature of 90-120 °C. These characteristics make TCL-doped ORMOSIL NPs ideal universal nanoprobes for ultrasensitive bioassays such as immuno- and DNA-based assay.

Further optimization of plakortin pharmacophore: structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity.

For the optimization of the plakortin pharmacophore, we recently proposed a straightforward synthesis of 4-carbomethoxy-3-methoxy-1,2-dioxanes as potential antimalarial drug candidates. Herein we report the chemoselective reduction of the 4-carbomethoxy group which has allowed us to prepare in good yields twenty-four new endoperoxides carrying either the hydroxymethyl or the methoxymethyl group on C4 in various stereochemical arrangements with respect to the alkyl groups on C3 and C6 (the endoperoxide carbons). Some of these compounds showed promising in vitro antimalarial activities, both against chloroquine-resistant (CQ-R) and susceptible (CQ-S) strains of Plasmodium falciparum, with IC50 values in the range of 0.5-1.0 µM. Compound 8g showed activity against the CQ-R strain comparable to that of the structurally more demanding plakortin.

Preparation and characterization of thermochemiluminescent acridine-containing 1,2-dioxetanes as promising ultrasensitive labels in bioanalysis.

Thermochemiluminescence is the luminescence process in which a thermodynamically unstable molecule decomposes with light emission when heated above a threshold temperature. We recently reported the thermochemiluminescence properties of an acridine-containing 1,2-dioxetane, which emits at relatively low temperatures (i.e., below 100 °C). Herein, we explored the effect of the introduction of methyl substituents in the acridine system. The methyl group did not determine an excessive destabilization of 1,2-dioxetane ring nor significantly affect the general physical properties of the molecule. Monosubstituted methyl derivatives and a series of derivatives bearing several combinations of two, three, and four methyl groups were prepared. The rate of formation of 1,2-dioxetane derivatives 1b-k strongly depended on the methyl substitution pattern. All members of this library of mono-, di-, tri-, and tetramethyl-substituted derivatives were characterized in terms of photophysical and thermochemiluminescence properties. The introduction of methyl groups into the acridine ring caused a marked decrease in the activation energy of the thermochemiluminescent reaction. Tri- and tetramethyl-substituted acridones had the highest fluorescence quantum yields, in the range 0.48-0.52, and the corresponding 1,2-dioxetanes 1h and 1j showed in thermochemiluminescence imaging experiments limit of detection values more than ten times lower with respect to the unsubstituted derivative.

Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: a stereocontrolled diversity oriented route to oxindole derivatives.

An efficient and highly enantioselective Michael addition of nitroalkanes to 3-ylidene oxindoles is described, mediated by thiourea-based bifunctional organocatalysts. The stereochemistry at C(α) and C(ß) centers is perfectly controlled, and the intermediate C-3 enolate is trapped with a second Michael acceptor. The developed one-pot three-component consecutive reactions generate up to four contiguous stereocenters, including the C-3 all-carbon quaternary center, in a perfectly defined configuration. The conversion of the ß-nitro oxindole into the corresponding ß-amino derivative discloses synthetically useful transformations, exploitable to generate pharmaceutically attractive molecular targets.

Dioxetane-doped silica nanoparticles as ultrasensitive reagentless thermochemiluminescent labels for bioanalytics.

Thermochemiluminescence (TCL; the light emission originating by the thermally triggered decomposition of a molecule) was proposed in the late 1980s as a detection technique for immunoassays. However, after little pioneering work, this technique was abandoned because of the high temperatures required and the poor detectability in comparison to other labels. Here we describe for the first time a thermochemiluminescent acridine-based 1,2-dioxetane with a remarkably low (i.e., below 100 °C) emission-triggering temperature, which made it possible to obtain light emission even in an aqueous environment, as well as amino-functionalized silica nanoparticles loaded with this compound and the fluorescent energy acceptor dipyridamole. Thanks to the signal amplification due to the large number of 1,2-dioxetane molecules in each nanoparticle (about 10(4)) and the increased emission efficiency due to energy transfer to the fluorescent acceptor, the doped nanoparticles could be revealed with a detectability close to that of chemiluminescent enzyme labels (the limit of detection of doped nanoparticles by TCL imaging was 1 × 10(-16) mol mm(-2), thus approaching the value of 5 × 10(-17) mol mm(-2) obtained for the enzyme label horseradish peroxidase with chemiluminescence detection). They could thus be used as highly detectable labels in the development of sensitive TCL-based immunoassays and nucleic acid hybridization assays, in which the detection step does not require any additional chemical reagent. We believe that these doped silica nanoparticles could pave the way for the revival of TCL detection in bioanalytics, taking advantage of the reagentless detection and the high signal/noise ratio in comparison with conventional luminescence detection techniques.

A new class of antimalarial dioxanes obtained through a simple two-step synthetic approach: rational design and structure-activity relationship studies.

A new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold, was designed on the basis of a previously developed pharmacophore. Through a simplified and versatile scheme of synthesis, which utilizes cheap and commercially available starting materials, it was possible to obtain several structurally and stereochemically different compounds that were tested against P. falciparum. Most of compounds showed antimalarial activity in the low micromolar range and no cellular toxicity, all being significantly more active on chloroquine resistant (CQ-R) than on chloroquine sensitive (CQ-S) strains. Resulting structure-activity relationships were analyzed by means of experimental and computational techniques, validating our design rationale and tailoring it for the new scaffold. Our study demonstrated that according to the hypothesized mechanism of action, the antimalarial activity can be improved through rational structural modifications, paving the way for the development of new simplified antimalarial endoperoxides.

Antibacterial agents and cystic fibrosis: synthesis and antimicrobial evaluation of a series of N-thiomethylazetidinones.

The increasing emergence of multidrug-resistant microorganisms is one of the greatest challenges in the clinical management of infectious disease. New antimicrobial agents are therefore urgently required, particularly in the treatment of chronic and recurrent infections often associated with antibiotic-resistant pathogens, as in the case of cystic fibrosis (CF) patients. This study reports the antibacterial activity of a series of monocyclic ß-lactams with an alkylidenecarboxyl chain or electron-withdrawing groups such as 4-OAc, 4-SAc, and 4-SO(2)Ph at the C4 position of the ring. N-Unsubstituted and N-thiomethyl derivatives were compared. A total of 33 azetidinones were tested for their activity against Gram-positive and Gram-negative bacterial clinical isolates. The combination of an N-thiomethyl group and a benzyl ester on the 4-alkylidene side chain were found to increase the potency against Gram-positive bacteria. The N-thiomethyl group clearly elevated the activity of 4-acetoxyazetidinones relative to the corresponding NH derivatives. The most active compounds showed minimum inhibitory concentration (MIC) values of 4 and 8 mg L(-1) against methicillin-resistant Staphylococcus aureus isolated from pediatric patients with CF.

Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases.

We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.

Azetidinones as zinc-binding groups to design selective HDAC8 inhibitors.

2-Azetidinones, commonly known as beta-lactams, are well-known heterocyclic compounds. Herein we described the synthesis and biological evaluation of a series of novel beta-lactams. In vitro inhibition assays against HDAC isoforms showed an interesting isoform-selectivity of these compounds towards HDAC6 and HDAC8. The isoform selectivity changed in response to modification of the azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is a prerequisite for the activity of these compounds in the micromolar range towards HDAC8.