High-Pressure Promoted Nazarov-like Electrocyclization Enables Access to trans-4,5-Diamino-cyclopent-2-enones Bearing Electron-Poor Anilines.

Unlike secondary alkyl amines and electron-rich anilines, secondary electron-poor anilines are challenging amine sources to explore the chemical space of Lewis acid-catalyzed condensation-based transformations with furfural. In this work, we report the efficient synthesis of trans-4,5-diamino cyclopentenones (DCP) using a high-pressure promoted Nazarov-like electrocyclization of Stenhouse salts arising from the Sc(III)-catalyzed condensation of furfural with secondary electron-poor anilines. The reaction enables access to otherwise difficult-to-access DCP and compatibility with a large scope of alkyl and aryl secondary amines. A 2- to 18-fold increase in yields for electron-poor anilines was highlighted using this approach in the synthesis of a pharmacologically active compound.

Diarylethene-Based Ionic Liquids: Synthesis and Photo-Driven Solution Properties.

In this work, the design and synthesis of a series of photochromic gemini diarylethene-based ionic liquids (GDILs) with different cationic motifs is reported. Several synthetic pathways were optimized for the formation of cationic GDILs with chloride as the counterion. The different cationic motifs were achieved through the N-alkylation of the photochromic organic core unit with different tertiary amines, including different aromatic amines such as imidazole derivatives and pyridinium, and other non-aromatic amines. These novel salts present surprising water solubility with unexplored photochromic features that broaden their known applications. The covalent attachment of the different side groups dictates their water solubility and differences upon photocyclization. The physicochemical properties of GDILs in aqueous and in imidazolium-based ionic liquid (IL) solutions were investigated. Upon irradiation with ultraviolet (UV) light, we have observed changes in the physico-chemical properties of distinct solutions containing these GDILs, at very low concentrations. More specifically, in aqueous solution, the overall conductivity increased with the time of UV photoirradiation. In contrast, in IL solution, these photoinducible changes are dependent on the type of ionic liquid used. These compounds can improve non-ionic and ionic liquids' solutions since we can change their properties, such as conductivity, viscosity or ionicity, only by UV photoirradiation. The electronic and conformational changes associated with these innovative stimuli GDILs may open new opportunities for their use as photoswitchable materials.

Preparation of Aminals under Continuous Flow Conditions.

A laboratory experiment was developed for the continuous flow preparation of an aminal derived from the condensation of furfural with morpholine. The experiment introduces the students to concepts of green chemistry, heterogeneous catalysis, and continuous flow. A cheap and easy setup allows the heterogeneous catalyst reactor to be built in class. The use of furfural reinforces the importance of green chemistry by using one of the key synthons obtained from biomass.

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons.

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.

Functionalized Cyclopentenes via the Formal [4+1] Cycloaddition of Photogenerated Siloxycarbenes from Acyl Silanes.

This work describes the first formal cycloaddition reaction of photogenerated nucleophilic carbenes derived from acylsilanes with electrophilic dienes. The resulting transient donor-acceptor cyclopropane rearranges to its stable and highly functionalized cyclopentene isomer in an unprecedented metal-free process. The cyclopropanation-vinyl cyclopropane rearrangement sequence was corroborated by computational calculations. The cyclopropane formation corresponds to a higher energetic barrier, and the vinylcyclopropane-cyclopentene rearrangement proceeds through different mechanisms, although of comparable energies, depending on the stereochemistry of the cyclopropane.

Preparation of Thioaminals in Water.

The presence of sulfur-carbon bonds is transversal to several areas of chemistry, e.g., drug discovery, materials, and chemical biology. However, a lack of efficient and sustainable procedures for the preparation of thioaminals, the N,S-analogues of O,O-acetals, contributes to this functional group often being overlooked by the scientific community. In this work is described the formation of thioaminals in water promoted by copper(II) triflate.

Tuning the 1H NMR Paramagnetic Relaxation Enhancement and Local Order of [Aliquat]+-Based Systems Mixed with DMSO.

Understanding the behavior of a chemical compound at a molecular level is fundamental, not only to explain its macroscopic properties, but also to enable the control and optimization of these properties. The present work aims to characterize a set of systems based on the ionic liquids [Aliquat][Cl] and [Aliquat][FeCl4] and on mixtures of these with different concentrations of DMSO by means of 1H NMR relaxometry, diffusometry and X-ray diffractometry. Without DMSO, the compounds reveal locally ordered domains, which are large enough to induce order fluctuation as a significant relaxation pathway, and present paramagnetic relaxation enhancement for the [Aliquat][Cl] and [Aliquat][FeCl4] mixture. The addition of DMSO provides a way of tuning both the local order of these systems and the relaxation enhancement produced by the tetrachloroferrate anion. Very small DMSO volume concentrations (at least up to 1%) lead to enhanced paramagnetic relaxation without compromising the locally ordered domains. Larger DMSO concentrations gradually destroy these domains and reduce the effect of paramagnetic relaxation, while solvating the ions present in the mixtures. The paramagnetic relaxation was explained as a correlated combination of inner and outer-sphere mechanisms, in line with the size and structure differences between cation and anion. This study presents a robust method of characterizing paramagnetic ionic systems and obtaining a consistent analysis for a large set of samples having different co-solvent concentrations.

Discovery of a Necroptosis Inhibitor Improving Dopaminergic Neuronal Loss after MPTP Exposure in Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent form of regulated cell death mediated by the concerted action of receptor-interacting protein 3 (RIP3) and the pseudokinase mixed lineage domain-like protein (MLKL). It is also usually dependent on RIP1 kinase activity, influenced by further cellular clues. Importantly, necroptosis appears to be strongly linked to several neurodegenerative diseases, including PD. Here, we aimed at identifying novel chemical inhibitors of necroptosis in a PD-mimicking model, by conducting a two-step screening. Firstly, we phenotypically screened a library of 31 small molecules using a cellular model of necroptosis and, thereafter, the hit compound effect was validated in vivo in a sub-acute 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) PD-related mouse model. From the initial compounds, we identified one hit-Oxa12-that strongly inhibited necroptosis induced by the pan-caspase inhibitor zVAD-fmk in the BV2 murine microglia cell line. More importantly, mice exposed to MPTP and further treated with Oxa12 showed protection against MPTP-induced dopaminergic neuronal loss in the SN and striatum. In conclusion, we identified Oxa12 as a hit compound that represents a new chemotype to tackle necroptosis. Oxa12 displays in vivo effects, making this compound a drug candidate for further optimization to attenuate PD pathogenesis.

Resolution of alkaloid racemate: a novel microbial approach for the production of enantiopure lupanine via industrial wastewater valorization.

BACKGROUND: Lupanine is a plant toxin contained in the wastewater of lupine bean processing industries, which could be used for semi-synthesis of various novel high added-value compounds. This paper introduces an environmental friendly process for microbial production of enantiopure lupanine. RESULTS: Previously isolated P. putida LPK411, R. rhodochrous LPK211 and Rhodococcus sp. LPK311, holding the capacity to utilize lupanine as single carbon source, were employed as biocatalysts for resolution of racemic lupanine. All strains achieved high enantiomeric excess (ee) of L-(-)-lupanine (> 95%), while with the use of LPK411 53% of the initial racemate content was not removed. LPK411 fed with lupanine enantiomers as single substrates achieved 92% of D-(+)-lupanine biodegradation, whereas L-(-)-lupanine was not metabolized. Monitoring the transcriptional kinetics of the luh gene in cultures supplemented with the racemate as well as each of the enantiomers supported the enantioselectivity of LPK411 for D-(+)-lupanine biotransformation, while (trans)-6-oxooctahydro-1H-quinolizine-3-carboxylic acid was detected as final biodegradation product from D-(+)-lupanine use. Ecotoxicological assessment demonstrated that lupanine enantiomers were less toxic to A. fischeri compared to the racemate exhibiting synergistic interaction. CONCLUSIONS: The biological chiral separation process of lupanine presented here constitutes an eco-friendly and low-cost alternative to widely used chemical methods for chiral separation.

Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones.

Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6,7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6ß-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectranthus spp. and showed promising biological activities, such as cytotoxicity. The inhibitory effects of the different natural abietanes (1-3) were compared in MFC7, SkBr3, and SUM159 cell lines, as well as SUM159 grown in cancer stem cell-inducing conditions. Based on the royleanones' bioactivity, the derivatives RoyBz (4), RoyBzCl (5), RoyPr2 (6), and DihydroxyRoy (7), previously obtained from 2, were selected for further studies. Protein kinases C (PKCs) are involved in several carcinogenic processes. Thus, PKCs are potential targets for cancer therapy. To date, the portfolio of available PKC modulators remains very limited due to the difficulty of designing isozyme-selective PKC modulators. As such, molecular docking was used to evaluate royleanones 1-6 as predicted isozyme-selective PKC binders. Subtle changes in the binding site of each PKC isoform change the predicted interaction profiles of the ligands. Subtle changes in royleanone substitution patterns, such as a double substitution only with non-substituted phenyls, or hydroxybenzoate at position four that flips the binding mode of ParvD (3), can increase the predicted interactions in certain PKC subtypes.

Synthesis and Applications of Stenhouse Salts and Derivatives.

In recent years, Stenhouse salts have attracted much attention as intermediates for the synthesis of cyclopenten-2-enones. This Minireview aims to present an overview of the methods for preparation, further transformation and applications of Stenhouse and Stenhouse-like salts. In this context, the Piancatelli rearrangement and its variants, and the recently reported donor-acceptor Stenhouse salts (DASA) will be addressed. The photophysical properties of DASA and its applications in colorimetric detection of amines, functionalization of polymers for detection of heat and nerve agents, photolithography and orthogonal photoswitching systems are discussed.

Copper(II) Triflate As a Reusable Catalyst for the Synthesis of trans-4,5-Diamino-cyclopent-2-enones in Water.

trans-4,5-Diamino-cyclopent-2-enones (CP) are usually prepared by Lewis acid-catalyzed condensation of furfural and a secondary amine in an organic solvent. The reaction proceeds through the formation of a Stenhouse salt (SS) intermediate followed by an electrocyclization reaction to afford the desired CP. Herein, we described the use of Cu(OTf)2 as a very efficient catalyst for the synthesis of CP in water at room temperature. Furthermore, the mild reaction conditions, catalyst reusability, and outstanding functional group tolerance suggest that this CP platform can be further used in chemical biology.

Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-dithianes.

The autoxidative condensation of 2-aryl-2-lithio-1,3-dithianes is here reported. Treatment of 2-aryl-1,3-dithianes with n-BuLi in the absence of any electrophile leads to condensation of three molecules of 1,3-dithianes and formation of highly functionalized α-thioether ketones orthothioesters in 51-89% yields upon air exposure. The method was further expanded to benzaldehyde dithioacetals, affording corresponding orthothioesters and α-thioether ketones in 48-97% yields. The experimental results combined with density functional theory studies support a mechanism triggered by the autoxidation of 2-aryl-2-lithio-1,3-dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2-aryl-2-lithio-1,3-dithiane.

Synthesis of Chiral Cyclopentenones.

The cyclopentenone unit is a very powerful synthon for the synthesis of a variety of bioactive target molecules. This is due to the broad diversity of chemical modifications available for the enone structural motif. In particular, chiral cyclopentenones are important precursors in the asymmetric synthesis of target chiral molecules. This Review provides an overview of reported methods for enantioselective and asymmetric syntheses of cyclopentenones, including chemical and enzymatic resolution, asymmetric synthesis via Pauson-Khand reaction, Nazarov cyclization and organocatalyzed reactions, asymmetric functionalization of the existing cyclopentenone unit, and functionalization of chiral building blocks.

Studies on the dynamic resolution of Crizotinib intermediate.

Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e.

Developments in the Reactivity of 2-Methylimidazolium Salts.

Unexpected and unusual reactivity of 2-methylimidazolium salts toward aryl-N-sulfonylimines and aryl aldehydes is here reported. Upon reaction with aryl-N-sulfonylimines, the addition product, arylethyl-2-imidazolium-1-tosylamide (3), is formed with moderate to good yields, while upon reaction with aldehydes, the initial addition product (6) observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights regarding this unexpected reactivity.

Ecotoxicological evaluation of magnetic ionic liquids.

Although magnetic ionic liquids (MILs) are not yet industrially applied, their continued development and eventual commercial use may lead to their appearance into the aquatic ecosystem through accidental spills or effluents, consequently promoting aquatic contaminations. Furthermore, the deficient information and uncertainty surrounding the environmental impact of MILs could be a major barrier to their widespread industrial application and international registration. Thus, in the present work, a range of cholinium salt derivatives with magnetic properties was synthesized and their ecotoxicity was evaluated towards the luminescent bacteria Vibrio fischeri. The results suggest that all MILs structures tested are moderately toxic, or even toxic, to the bacteria. Furthermore, their toxicity is highly dependent on the structural modifications of the cation, namely the alkyl side chain length and the number of hydroxyethyl groups, as well as the atomic number of the metal anion. Finally, from the magnetic anions evaluated, the [MnCl4]2- is the less toxic. In order to improve the knowledge for the prospective design of environmentally safer MILs, it is important to expand this study to other aquatic organisms at different trophic levels.

Oxidation of 5-Chloromethylfurfural (CMF) to 2,5-Diformylfuran (DFF).

2,5-Diformylfuran (DFF) is an important biorenewable building block, namely for the manufacture of new polymers that may replace existing materials derived from limited fossil fuel resources. The current reported methods for the preparation of DFF are mainly derived from the oxidation of 5-hydroxymethylfurfural (HMF) and, to a lesser extent, directly from fructose. 5-Chloromethylfurfural (CMF) has been considered an alternative to HMF as an intermediate building block due to its advantages regarding stability, polarity, and availability from glucose and cellulose. The only reported method for the transformation of CMF to DFF is restricted to the use of DMSO as the solvent and oxidant. We envisioned that the transformation could be performed using more attractive conditions. To that end, we explored the oxidation of CMF to DFF by screening several oxidants such as H2O2, oxone, and pyridine N-oxide (PNO); different heating methods, namely thermal and microwave irradiation (MWI); and also flow conditions. The combination of PNO (4 equiv.) and Cu(OTf)2 (0.5 equiv.) in acetonitrile was identified as the best system, which lead to the formation of DFF in 54% yield under MWI for 5 min at 160 °C. Consequently, a range of different heterogeneous copper catalysts were tested, which allowed for catalyst reuse. Similar results were also observed under flow conditions using copper immobilized on silica under thermal heating at 160 °C for a residence time of 2.7 min. Finally, HMF and 5,5'-oxybis(5-methylene-2-furaldehyde) (OBMF) were the only byproducts identified under the reaction conditions studied.

Diazo- and transition-metal-free C-H insertion: a direct synthesis of ß-lactams.

Carbene intermediates are very useful species for a range of reactions including C-H insertions and cycloadditions. They are most commonly generated by metal-catalyzed release of nitrogen gas from diazo precursors. Herein, we present a novel C-H insertion of simple ß-ketoamide substrates, through reaction with (diacetoxyiodo)benzene (DIB) in the presence of a base. This unprecedented transformation bypasses the use of either diazo precursors or metal catalysts and directly delivers ß-lactam products by an iodonium ylide, in a single step under mild conditions. Mechanistic studies support the intermediacy of a free singlet carbene of unique reactivity and selectivity.

Synthesis of Symmetric Bis(N-alkylaniline)triarylmethanes via Friedel-Crafts-Catalyzed Reaction between Secondary Anilines and Aldehydes.

The first general protocol for the preparation of symmetric triarylmethanes bearing secondary anilines by ytterbium-catalyzed Friedel-Crafts reaction of hetero(aryl) aldehydes and secondary anilines is reported. Mechanistic studies indicated that the iminium ion intermediate is the electrophilic partner. The reaction is greatly accelerated by high pressure (9 kbar) and showed a broad substrate scope on the hetero(aryl) aldehyde. The new triarylmethanes exhibited activity against HT-29 cancer cell lines, with the best result scoring an IC50 of 1.74 µM.