By combining a chiral-at-metal ruthenium catalyst with catalytic amounts of tris(p-fluorophenyl)phosphine (both 1 mol%), the challenging catalytic enantioselective ring-closing C(sp3)-H amination of unactivated aliphatic azides has been achieved with high enantioselectivities.

This study demonstrates that chiral‐at‐iron complexes, in which all coordinated ligands are achiral and the overall chirality the consequence of a stereogenic iron center, are capable of catalyzing asymmetric transformations with very high enantioselectivities. The catalyst is based on a previously reported design (J. Am. Chem. Soc. 2017, 139, 4322), in which iron(II) is surrounded by two configurationally inert achiral bidentate N‐(2‐pyridyl)‐substituted N‐heterocyclic carbenes in a C2‐symmetric fashion and complemented by two labile acetonitriles. By replacing mesityl with more bulky 2,6‐diisopropylphenyl substituents at the NHC ligands, the steric hindrance at the catalytic site was increased, thereby providing a markedly improved asymmetric induction. The new chiral‐at‐iron catalyst was applied to the inverse electron demand hetero‐Diels‐Alder reaction between β,γ‐unsaturated α‐ketoester and enol ethers provide 3,4‐dihydro‐2H‐pyrans in high yields with excellent diastereoselectivities (up to 99 : 1 dr) and excellent enantioselectivities (up to 98 % ee). Other electron rich dienophiles are also suitable as demonstrated for a reaction with a vinyl azide.

Background:The aggressive phenotype of fibroblast-like synoviocytes (FLSs) is essential in the synovitis and bone destruction in rheumatoid arthritis (RA). Punicalagin is a natural polyphenol extracted in pomegranate juice, which possesses antioxidant, anti-inflammatory and anti-tumor properties suggesting it may be a potent drug for RA therapy. However, there is paucity of information on its effect in RA. Objective: To investigate the effects of punicalagin on synovial inflammation and bone destruction in RA. Methods: FLSs were isolated from synovial tissue of RA patients. The mRNA levels were evaluated by quantitative real-time PCR. Western blot was used for protein level measurements. The secretion of pro-inflammatory cytokines and metalloproteinases (MMPs) was detected by ELISA assays. Edu staining assays were carried out to investigate the proliferation of FLSs. Cell migration was assessed by Boyden chambers, wound scratch assays and F-actin staining in vitro. The intracellular translocation of nuclear factor kappa B (NF-κB) was investigated using immunofluorescence. The effects of punicalagin in vivo were measured by using collagen-induced arthritis (CIA) mice. Results: Punicalagin treatments significantly reduced the TNF-α induced expressions of proinflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17A) and MMPs (MMP-1 and MMP-13) of RA FLSs. Punicalagin also suppressed the proliferation and migration of RA FLSs. Moreover, punicalagin (50mg/kg/d) alleviated arthritis severity and bone destruction, and decreased serum IL-6 and TNF-α in CIA mice. Further mechanism studies indicated that punicalagin blocked NF-κB activation via suppressing phosphorylation of IKK and IkBα, and preventing the translocation of 65. Conclusion: Our findings suggested that punicalagin might be one of natural therapeutic compounds for relieving RA progress via suppressing FLSs inflammation and migration through modulating NF-κB pathways.

The origin of enantioselectivity in the asymmetric alkynylation of trihalomethyl ketones catalyzed by octahedral stereogenic-at-ruthenium complexes has been investigated through density functional theory calculations. Computational results support a mechanism involving formation of a ruthenium acetylide, followed by pre-coordination of the trihalomethyl ketone through the carbonyl oxygen and intramolecular attack of the acetylide via a compact four-membered transition state. Differences in computed free energies of activation for the formation of the major and minor propargyl alcohol enantiomers are in good agreement with the experimentally observed levels of asymmetric induction. Analysis of fragment distortion energies shows that disfavored transition states are destabilized due to the more severe distortion and loss of π-conjugation in the coordinated arylketone fragments. Examination of the different substitution patterns in the ketone substrate and the catalyst reveals the key steric factors that control the enantioselectivity. Finally, calculations indicate promising directions for the simplification of the catalyst scaffold while preserving the high levels of enantioselectivity of these alkynylation reactions.

It was previously published that single-nucleotide polymorphism rs2476601 (PTPN22 [protein tyrosine phosphatase non-receptor type 22]-C1858T) might be related to increased sensibility to Mycobacterium tuberculosis and M. leprae infection. However, the results were inconclusive despite a high degree of similarity between both parameters. Herein, we carried out this meta-analysis to systematically summarize and articulate the correlation between PTPN22-C1858T polymorphism and mycobacterial infection. The susceptibility of PTPN22-C1858T carriers with autoimmune conditions receiving immunosuppressive therapy to M. tuberculosis and M. leprae infection was determined. A systematic retrieval of studies on relevance of PTPN22-C1858T polymorphism to susceptibility of M. tuberculosis or M. leprae infection was performed in Chinese National Knowledge Infrastructure, PubMed and Embase databases. We regarded Odds ratios (ORs) and 95% confidence intervals (CIs) as the determined effect size. Finally, four and two case-control studies on tuberculosis and leprosy, respectively, were included. In all genetic models, without indicated association between PTPN22-C1858T polymorphism and tuberculosis’s susceptibility. [C versus T: OR = 0.22 (95% CI: 0.09–0.50, PH = 0.887); CT versus CC: OR = 0.21 (95% CI: 0.09–0.49, PH = 0.889); TT+CT versus CC: OR = 0.21 (95% CI: 0.09–0.49, PH = 0.889)]. A significantly increased risk of leprosy was perceived in patients with the PTPN22-C1858T polymorphism [C versus T: OR = 2.82 (95% CI: 1.02–7.81, PH = 0.108)]. While the PTPN22-C1858T polymorphism is irrelevant to higher susceptibility to the infection of M. tuberculosis in Caucasians and Asians, it is relevant to increased susceptibility to the infection of M. leprae. However, the results of M. leprae are supposed to interpreted with prudence owing to the limited quantity of studies and heterogeneity. Further well-designed studies with sufficient populations are required to verify our conclusions.