Transition-metal-catalyzed[2+2+2] cycloaddition reactions that use two alkynes and a nitrile is the most straightforward and powerful strategy for the construction of multisubstituted pyridines with high atom efficiency. [1,2] The iron-catalyzed [2+2+2] cycloaddition to form pyridines remains a great challenge in this field, [3,4] although significant efforts have been made in various catalytic systems (e.g. Co,[5] Ru, [6] Rh, [7] Ni, [8] Ti, [9] Zr/Ni [10] ) in the last few decades. Guerchais and co-workers described a stoichiometric reaction between an Fe I complex (Scheme 1, structure A) and alkynes with a 73 % yield.[4a] Meanwhile, Zenneck and co-workers developed a cycloaddition reaction catalyzed by an Fe 0 complex (Scheme 1, structure B), [4b,c] however, this approach gave low chemoselectivity and had a complicated procedure for catalyst preparation. A very recent example revealed that no pyridine products were observed from alkynes under iron catalyst even when nitrile was used as the solvent.[11] Therefore, the development of a simple and highly efficient iron catalyst to exclusively generate pyridine compounds would be a useful contribution to this area. Herein, we disclose the [2+2+2] cycloaddition of diynes and unactivated nitriles at room temperature using a simple iron salt as the catalyst precursor, thus resulting in the production of pyridines with up to 98 % yield of isolated product.Two important steps are generally involved in [2+2+2] cycloaddition: 1) formation of a metallacycle intermediate by oxidative cyclization and 2) subsequent reductive elimination to produce pyridines (the "common mechanism").[2] The formation of a metallacycle intermediate [12,13] from a low-valent metal species plays a crucial role in the whole process. Inspired by an investigation by Holland and co-workers revealing that alkynes bind more tightly than phosphines to low-valent iron center, [14] we envisioned that low-valent iron catalysts generated in situ from an inorganic iron salt and phosphine ligands might initiate the reaction through ligand exchange, and thereby promote the oxidative cyclization between an alkyne and an alkyne or a nitrile followed by the formation of metallacycle intermediate (Scheme 1, Step 2). Considering that the formation of benzene rings can be somewhat inhibited in the presence of a certain amount of nitrile compounds [4a] -the nature of the ligand has a dramatic effect on the reaction product-it is possible to generate pyridines with high efficiency when the appropriate iron salt and ligand are used.Initially, diyne 1 a and benzonitrile 2 a were used as model substrates for the optimization of the cycloaddition reaction conditions, and the results are summarized in Table 1. In the first instance, we employed the iron salt FeCl 3 as the catalyst precursor, 1,2-bis(diphenylphosphino)ethane (dppe) as the ligand, and 2 a as the solvent (Table 1, entries 1-4). No desired product was observed in the absence of dppe, as expected, and only trace amounts of 3 a were obtained when FeCl 3 /dp...

The direct C-H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3-disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3-diaryl substituted indoles. Herein, we report the rhodium(III)-catalyzed C-H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3-diaryl-substituted N-unprotected indoles with two different aryl groups. One of the aryl substituents is derived from N=C-aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.

A series of bis(sulfonamide)-diamine (BSDA) ligands were synthesized from commercially available chiral R-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes the enantioselective Henry reaction with excellent enantioselectivity (up to 99%). Moreover, with the assistance of pyridine, a CuBr-3a system promotes the diastereoselective Henry reaction with various aldehyde substrates and gives the corresponding syn-selective adduct with up to a 99% yield and 32.3:1 syn/anti selectivity. The enantiomeric excess of the syn adduct was 97%.

A strategy for achieving diastereodivergent azidations of enynes has been developed, employing azide transfer from the M-N3 complex to alkyl radicals. Following this concept, the diastereoselectivity has been switched by modulating the transition metals and the ligands. The Mn(III)-mediated radical cyclization/azidation cascade of 1,7-enynes afforded trans-fused pyrrolo[3,4-c]quinolinones, whereas the Cu(II)/bipyridine system gave cis-products.

b S Supporting Information I n the past few years, significant efforts have been made on the development of the highly efficient chiral ligands in Rhcatalyzed asymmetric 1,4-addition of organoboron reagents, which has rapidly developed into a powerful tool for the stereoselective formation of carbonÀcarbon bonds. 1À6 Pioneered by the groups of Hayashi and Carreira, chiral olefins as a new class of promising ligands have attracted great attention in recent years, 7À9 and many excellent olefin-based ligands such as diene ligands, 10À23 olefinÀphosphine ligands, 24À30 and olefinÀnitrogen ligands 31,32 have been successfully developed in the HayashiÀMiyaura asymmetric reactions. Meanwhile, except for a chiral auxiliary in numerous asymmetric transformations, the application of sulfoxides 33 as ligands, especially the chiral bis-sulfoxides, 34À38 has most recently been appealing in the HayashiÀMiyaura reaction.In view of ready availability, air and moisture stability, and fine chiral environment of sulfoxides, as well as the relatively good coordination ability of alkenes and sulfoxides to transition metals, we envisioned that the combination of alkenes and sulfoxides would allow the advantages of each class to be united which provided good opportunities to find highly efficient hybrid ligands. However, examples on the combination of alkenes with inherent chiral sulfoxides into chiral olefinÀsulfoxide hybrid ligands were very few; 39À43 the sulfoxides were mainly limited to tert-butylsulfinyl groups, and the incorporation of alkenes with different sulfinyl groups was still absent (Figure 1). Herein, we present our efforts on the development of a class of readily available and easily tunable benzene backbone-based olefinÀsulfoxide ligands for the rhodium-catalyzed asymmetric addition reaction.Inspired by recent success of olefinÀoxazoline 32 and bis-sulfoxide 36 ligands based on benzene backbone in asymmetric catalysis, a benzene ring was chosen as an internal ring skeleton to strengthen the coordination ability of alkenes to transition metals. Olefin and sulfoxide frameworks attached to the benzene ring in a 1,2-fashion would be helpful for the coordination of olefins and sulfoxides to transition metals. We reasoned that the combination of η 2 -binding olefins with η 1 -binding sulfoxide would allow new coordination geometries and possibilities in the class of hybrid ligands. Moreover, to further examine the influence of electronic and steric modulations at the olefinÀsulfoxide hybrid ligands on the reactivity and enantioselectivity of the Rh-catalyzed HayashiÀMiyaura reaction, the ligands bearing different sulfinyl moieties were also examined, and thus the highly modular and easily tunable olefinÀsulfoxide ligands were formed (Scheme 1). Subsequently, a series of electronically and sterically varied benzene backbone-based olefinÀsulfoxide ligands (Figure 2) were prepared in a facile two-step synthesis.As an illustrative example, the synthesis of ligand 6c bearing a (R)-tert-butylsulfinyl group was discussed (Schem...

Background Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Methods Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. Results We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. Conclusion We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

N-aryl-substituted nitrones were employed as five-atom coupling partners in the rhodium-catalyzed cyclization with diynes. In this reaction, the nitrone moiety served as a directing group for the catalytic C-H activation of the N-aryl ring. This formal [2+2+5] approach allows rapid access to bridged eight-membered heterocycles with broad substrate scope. The results of this study may provide new insight into the chemistry of nitrones and find applications in the synthesis of other heterocycles.

Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (μ-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.