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P2 × 7R is crucial in the pathogenesis of chronic inflammatory diseases, and its activation leads to the release of pro-inflammatory cytokines, exacerbating the inflammatory response. Two new series of scarce cyclic N , O -acetals (ATF 61–74) and corresponding opened N , N -aminals (CS 1–14) have been designed as novel potential P2RX7 antagonists, then synthesized and evaluated for their anti-inflammatory properties through investigating the pro-inflammatory markers and also for their antifungal activity against Candida albicans . Three compounds (ATF 64, CS 8, and CS 9) exhibited dual antifungal and anti-inflammatory properties. ATF 64, CS 8, and CS 9 reduced ROS production and IL-1β expression in macrophages and intestinal cells in a manner correlated with NF-KB expression. These compounds showed excellent antifungal activity against clinical isolates of C. albicans resistant to fluconazole and caspofungin, and reduced C. albicans biofilm formation. Treatment with CS 8 or CS 9 protected the nematode Caenorhabditis elegans against infection with C. albicans and enhanced antimicrobial gene expression. This duality of action offers a promising new pharmacological strategy to counteract inflammatory diseases and propels N , N -aminals as promising candidates for future optimization and investigation.

The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed C sp 3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment in the literature. Ligand development underlies many advances in Pd-catalysed cross coupling but has seen limited application in the growing field of Ni catalysis. Now, a phosphine framework is shown to enable Ni-catalysed Suzuki coupling of acetals. Parameterization studies provide structural insight into ligand success and a quantitative model to facilitate further ligand design.

Complex organic molecules are of great importance to research and industrial chemistry and typically synthesized from smaller building blocks by multistep reactions. The ability to perform multiple (distinct) transformations in a single reactor would greatly reduce the number of manipulations required for chemical manufacturing, and hence the development of multifunctional catalysts for such one-pot reactions is highly desirable. Here we report the synthesis of a hierarchically porous framework, in which the macropores are selectively functionalized with a sulfated zirconia solid acid coating, while the mesopores are selectively functionalized with MgO solid base nanoparticles. Active site compartmentalization and substrate channelling protects base-catalysed triacylglyceride transesterification from poisoning by free fatty acid impurities (even at 50 mol%), and promotes the efficient two-step cascade deacetalization-Knoevenagel condensation of dimethyl acetals to cyanoates. The spatial segregation of distinct catalytic functionalities within the same material holds great promise for cascade or antagonistic reactions, but it remains challenging. Here, the authors report the successful realization of this approach for an efficient hierarchical porous silica catalyst featuring spatially separated sulfated zirconia and magnesium oxide.

Spiroacetals are found in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles; a confined imidodiphosphoric-acid catalyst is now reported that is able to facilitate the stereoselective synthesis of small, unfunctionalized spiroacetals. Non-enzymatic synthesis of spiroacetal The sex pheromone olean, found in the olive fruitfly, has the interesting property that one mirror-image variant attracts males and the other females. Olean contains as its only source of chirality a spiroacetal, a natural product consisting of an acetal (a molecule that contains two oxygen–carbon single bonds at the same carbon atom) joining two rings. Until now chemists have not been able to mimic the enzymatic feat of synthesizing this type of chiral acetal centre, but this paper reports the design and synthesis of new chiral acids that can catalyse selective spiroacetalizations, including one to furnish olean with remarkably high selectivity. A distinctive characteristic of these artificial catalysts is an extremely tight chiral pocket, reminiscent of those found in natural enzymes. Acetals are molecular substructures that contain two oxygen–carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles 1 , 2 . Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals 3 , 4 . Here we report the design and synthesis of confined Brønsted acids based on a C 2 -symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Brønsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates.

Two potential biomass‐derived Cyrene‐based reaction media, i.e., Cyrene dimethyl and diethyl acetals, were synthesized and tested as potential polar aprotic alternatives to fossil‐based common N,N‐dimethylformamide in aminocarbonylation protocols. New solvents were first characterized by their temperature‐dependent physicochemical properties, including vapor pressure, density, viscosity, heat capacity, and surface tension. Based on their characteristics, Cyrene dimethyl acetal (CyDiOMe) was selected and used in the Pd‐catalyzed aminocarbonylation of iodobenzene and morpholine as a model reaction for optimization. Under optimized conditions, a wide substrate scope was demonstrated for the synthesis of various carboxamides with high conversion (up to 95%) and selectivity in a short reaction time. Twenty‐nine products were isolated, proving the applicability of CyDiOMe in Pd‐catalyzed aminocarbonylation. Insert text for Table of Contents here. In this research, the synthesis of new Cyrene derivatives (Cyrene dimethyl acetal and Cyrene diethyl acetal) was accomplished, and the investigation of their physicochemical properties was completed. It was also shown after a detailed optimization study that Cyrene dimethyl acetal could be an appropriate alternative reaction medium for selective amide synthesis via Pd‐catalyzed aminocarbonylation reaction of iodo(hetero)arene compounds.

Vinyl polymers are the focus of intensive research due to their ease of synthesis and the possibility of making well-defined, functional materials. However, their non-degradability leads to environmental problems and limits their use in biomedical applications, allowing aliphatic polyesters to still be considered as the gold standards. Radical ring-opening polymerization of cyclic ketene acetals is considered the most promising approach to impart degradability to vinyl polymers. However, these materials still exhibit poor hydrolytic degradation and thus cannot yet compete with traditional polyesters. Here we show that a simple copolymerization system based on acrylamide and cyclic ketene acetals leads to well-defined and cytocompatible copolymers with faster hydrolytic degradation than that of polylactide and poly(lactide- co -glycolide). Moreover, by changing the nature of the cyclic ketene acetal, the copolymers can be either water-soluble or can exhibit tunable upper critical solution temperatures relevant for mild hyperthermia-triggered drug release. Amphiphilic diblock copolymers deriving from this system can also be formulated into degradable, thermosensitive nanoparticles by an all-water nanoprecipitation process. The non-degradability of vinyl polymers has long limited their use in biomedical applications. In this article, the authors demonstrate a system based on acrylamide and cyclic ketene acetals to obtain copolymers with faster degradation rates for potential drug release and environmental applications.

The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-β-indolyl-β-ketoesters. To highlight the method’s synthetic utility, a formal total synthesis of murrayafoline A, a bioactive carbazole-containing natural product, was undertaken.

E-cigarette aerosol emission studies typically focus on benchmarking toxicant levels versus those of cigarettes. However, such studies do not fully account for the distinct chemical makeup of e-liquids and their unique properties. These approaches often conclude that there are fewer and lower levels of toxins produced by e-cigarettes than by cigarettes. In 2015, we reported the discovery of new hemiacetals derived from the reaction of formaldehyde and the e-liquid solvents. The main finding was that they constituted a significant proportion of potentially undetected formaldehyde. Moreover, unlike gaseous formaldehyde, the hemiacetals reside in the aerosol particulate phase, and thus are capable of delivering formaldehyde more deeply into the lungs. However, the findings were criticized by those claiming that some of the results were obtained under conditions that are averse to vapers. A “reinvestigation” of our study was recently published addressing this latter issue. However, this reinvestigation ignored major details, including no mention of the formaldehyde hemiacetals. Herein, we isolated both gaseous formaldehyde and formaldehyde hemiacetals at an intermediate power level claimed, in the “reinvestigation”, to be relevant to “non-averse,” “normal” usage. The results were that both gaseous formaldehyde and formaldehyde from hemiacetals were produced at levels above OSHA workplace limits.

The development of sustainable plastics from abundant renewable feedstocks has been limited by the complexity and efficiency of their production, as well as their lack of competitive material properties. Here we demonstrate the direct transformation of the hemicellulosic fraction of non-edible biomass into a tricyclic diester plastic precursor at 83% yield (95% from commercial xylose) during integrated plant fractionation with glyoxylic acid. Melt polycondensation of the resulting diester with a range of aliphatic diols led to amorphous polyesters ( M n  = 30–60 kDa) with high glass transition temperatures (72–100 °C), tough mechanical properties (ultimate tensile strengths of 63–77 MPa, tensile moduli of 2,000–2,500 MPa and elongations at break of 50–80%) and strong gas barriers (oxygen transmission rates (100 µm) of 11–24 cc m −2  day −1  bar −1 and water vapour transmission rates (100 µm) of 25–36 g m −2  day −1 ) that could be processed by injection moulding, thermoforming, twin-screw extrusion and three-dimensional printing. Although standardized biodegradation studies still need to be performed, the inherently degradable nature of these materials facilitated their chemical recycling via methanolysis at 64 °C, and eventual depolymerization in room-temperature water. Functionalizing an intact carbohydrate core with acetals allows for the dramatically simplified production of a plastic precursor directly during the initial fractionation of non-edible biomass. When polymerized, the rigid and polar carbohydrate core also leads to bioplastics with competitive material and end-of life properties.

Degradable analogues of polystyrene are synthesized via radical ring-opening (co)polymerization (rROP) between styrene and two cyclic ketene acetals, namely 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO). This approach periodically inserts ester bonds throughout the main chain of polystyrene, imparting a degradation pathway via ester hydrolysis. We discuss the historical record of this approach, with careful attention paid to the conflicting findings previously reported. We have found a common 1H NMR characterization error, repeated throughout the existing body of work. This misinterpretation is responsible for the discrepancies within the cyclic ketene acetal (CKA)-based degradable polystyrene literature. These inconsistencies, for the first time, are now understood and resolved through optimization of the polymerization conditions, and detailed characterization of the degradable copolymers and their corresponding oligomers after hydrolytic degradation.