Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes.

Ketones are ubiquitous in organic synthesis. However, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. Herein, we describe the Ti-catalyzed modular ketone synthesis from carboxylic derivatives and easily accessed gem-dihaloalkanes. Notably, this protocol could achieve the direct catalytic olefination of carboxylic acids. This method features a sequence of olefination and electrophilic transformation and good functional group compatibility and allows rapid access to various functionalized ketones. Preliminary mechanistic studies provide insights into the reaction pathway and support the intermediacy of plausible alkylidene titanocene and gem-bimetallic complexes.

Ex vivo coronary endothelial cell activation associated with indoor coal combustion initiated atherosclerosis.

Plenty of rural populations still chronically exposed to indoor coal burning, which tremendously raises the risk of cardiovascular disease, in China. This study aimed to further investigate the association between indoor coal burning exposure and atherosclerotic cardiovascular diseases to search for relevant markers for disease prevention. Herein, we conducted a cross-sectional study, carried out on 752 local long-term residents with or without bituminous coal for cooking and heating indoor, in Nangong County, Hebei Province, China. We utilized a nearest neighbor propensity score match (PSM) with a caliper distance equal to 0.001 to eliminate bias caused by confounding factors. The expression of genes associated with endothelial activation (CCL2, CCL5, CXCL8, CXCL12, VCAM, ICAM, SELP) in primary human coronary artery endothelial cells (HCAECs) were quantified through ex vivo biosensor assay. Multiple linear regression models with stratification analyses by gender and binary logit regression models were used to evaluate the association between mRNA expression of biosensor genes and indoor coal burning pollution or carotid atherosclerosis, respectively. Protein secretion level was detected by enzyme-linked immunosorbent assay (ELISA). The prevalence of carotid atherosclerosis in exposure group was higher than control (P = 0.023), before PSM. The gene expression of CCL2 in exposure group was significantly higher than control (P = 0.002). Indoor coal burning exposure was correlated with gene expression of CCL2 (ß = 3.45, 95 % CI: 0.04-6.87, P = 0.047) and CXCL8 (ß = 1.25, 95 % CI: 0.02-2.49, P = 0.046) in female. A higher risk of carotid atherosclerosis was observed in the same as the increase expression of CCL2 (OR = 1.07, 95 % CI: 1.01-1.14, P = 0.020). In conclusion, prolonged exposure to indoor coal burning could elevate the gene expression of CCL2 by activating vascular endothelial cells and was relative to the initiation of carotid atherosclerosis.

Nontarget Identification of Novel Per- and Polyfluoroalkyl Substances in Cord Blood Samples.

Per- and polyfluoroalkyl substances (PFASs) can penetrate the placental barrier and reach embryos through cord blood, probably causing adverse birth outcomes. Therefore, novel PFASs identification in cord blood and their relationships with birth outcomes are essential to evaluate prenatal exposure risk of PFASs. Herein, 16 legacy and 12 novel PFASs were identified in 326 cord blood samples collected from pregnant women in Jinan, Shandong, China. The presence of perfluoropolyether carboxylic acids, hydrogen-substituted polyfluoroetherpropane sulfate, and 3:3 chlorinated polyfluoroalkyl ether alcohol in cord blood was reported for the first time. Two extensive OECD (Organization for Economic Co-operation and Development)-defined PFASs named fipronil sulfone and 2-chloro-6-(trifluoromethyl)pyridine-3-ol were also identified. Quantification results showed that the emerging and OECD-defined PFASs separately accounted for 9.4 and 9.7% of the total quantified PFASs, while the legacy PFOA, PFOS, and PFHxS were still the most abundant PFASs with median concentrations of 2.12, 0.58, and 0.37 ng/mL, respectively. Several PFASs (C9-C12 PFCAs, C6-C8 PFSAs, and 6:2 Cl-PFESA) showed significantly higher levels for older maternities than younger ones. PFHxS levels were positively associated with birth weight and ponderal index (p < 0.05). The results provide comprehensive information on the presence and exposure risks of several novel PFASs during the early life stage.

Inhaled tire-wear microplastic particles induced pulmonary fibrotic injury via epithelial cytoskeleton rearrangement.

Tire wear microplastic particles (TWMPs) are emerging microplastic pollutants that have gained increasing attention lately. However, the health effect of inhaled airborne TWMPs has never been explored before and may already be included in particulate matter morbidity and mortality. Here, we endeavored to address the preliminary study of TWMP inhalation-induced pulmonary toxic effects and its epigenetic mechanisms in C57BL/6 mice. As a result, restricted ventilatory dysfunction and fibrotic pathological changes were observed in TWMP-treaded mice. Further research found that attenuation of miR-1a-3p plays an important role in TWMP-induced lung injury. Results from in vitro study confirmed that cytoskeleton regulatory gene twinfilin-1 was one of the target genes of miR-1a-3p, and involved in cytoskeleton rearrangement caused by TWMP exposure. Mechanistically, miR-1a-3p inhibited the F-actin formation by targeting cytoskeletal regulatory proteins twinfilin-1, leading to TWMP-induced pulmonary fibrotic injury. While we are in the very early stages of explaining the role of epigenetics in TWMP-induced lung injury, the potential for the use of epigenetic marks as biomarkers is high and discoveries made in this field will likely bring us closer to better understanding this crucial mechanism.

Ti-Catalyzed Diastereoselective Cyclopropanation of Carboxylic Derivatives with Terminal Olefins.

Cyclopropanols and cyclopropylamines not only serve as important structural motifs in medicinal chemistry but also show diverse reactivities in organic synthesis. Owing to the high ring strain energy, the development of a general protocol from stable and readily available starting materials to afford these cyclopropyl derivatives remains a compelling challenge. Herein, we describe that a Ti-based catalyst can effectively promote the diastereoselective syntheses of cyclopropanols and cyclopropylamines from widely accessible carboxylic derivatives (acids, esters, amides) with terminal olefins. To the best of our knowledge, this method represents the first example of direct converting alkyl carboxylic acids into cyclopropanols. Distinct from conventional studies in Ti-mediated cyclopropanations with reactive alkyl Grignard reagents as nucleophiles or reductants, this protocol utilizes Mg and Me2SiCl2 to turn over the Ti catalyst. Our method exhibits broad substrate scope with good functional group compatibility and is amenable to late-stage synthetic manipulations of natural products and biologically active molecules.

Synthesis of α-amino ketones through aminations of umpoled enolates.

An efficient synthesis of α-amino ketones is developed using the umpolung strategy. Umpoled enolates such as N-alkenoxypyridinium salts react smoothly with diverse amines to give α-amino ketones via an SN2' pathway. This umpolung strategy overcomes the drawbacks of traditional methods such as the need for prefunctionalized ketone derivatives. Our method also offers good chemical yields and high functional group tolerance.