Yun-Fei Zhang

Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules

Carbon-nitrogen bond formation from inert C-H bonds is an ideal organic transformation and a highly desirable method for the synthesis of N-containing molecules due to its high efficiency and atom economy. In this report, we develop a general reaction to achieve an unprecedented selective intramolecular amination of unactivated C-H bond in the absence of complex directing groups. Functionalized heterocyclic products are built up from readily available linear amines through simple and reliable silver catalysis, representing a new silver-based C-H functionalization. This method displays preference for primary sp(3) C-H bonds and exhibits distinct chemo- and regioselectivity compared to existing methods of direct amination (Hofmann-Löffler-Freytag reaction and nitrene insertion). The study highlights the manipulation of unfunctionalized groups in organic molecules to furnish complex structural units in the natural and bioactive molecules.

Controllable Mono‐/Dialkenylation of Benzyl Thioethers through Rh‐Catalyzed Aryl CH Activation

Under solvent control: Benzyl thioethers were alkenylated in excellent yields with broad substrate scope and the selectivity (mono- vs. disubstituted product) was controlled by the solvent and ratio of reactants. Sequential alkenylation with two different alkenes was also carried out in a one-pot process. In addition, the thioether directing group was removed in a one-pot process with simultaneous hydrogenation of the double bond to give the toluene derivatives.

Binding capacity and pathophysiological effects of IgA1 from patients with IgA nephropathy on human glomerular mesangial cells

IgA deposition in glomerular mesangium and the interaction with mesangial cells may well be the final common pathway to IgA nephropathy (IgAN). Altered hinge‐region O‐glycosylation of IgA1 from patients with IgAN may predispose to mesangial deposition and activation of the mesangial cell (MC) by IgA1, via a novel IgA1 receptor, and may be a key event in the pathogensis of IgAN. The aim of this study was to investigate the binding capacity and biological effects of IgA1, from both patients with IgAN and healthy controls, on human mesangial cells (HMC). Serum IgA1 was isolated with jacalin affinity chromatography, heated to aggregated form (aIgA1) and labelled with 125I. Binding capacity of aIgA1 in vitro to cultured primary HMC was evaluated by a radioligand binding assay and the specificity of binding was determined by a competitive inhibition assay. Intracellular calcium release was studied by confocal analysis and phosphorylation of extracellular signal‐regulated kinase (ERK) was determined by Western blot analysis. Change of cell cycles was demonstrated by flow cytometry and HMC proliferation was evaluated by direct cell count. Expression of TGF‐β mRNA and production of supernatant fibronectin were tested by RT‐PCR and indirect competitive ELISA, respectively. aIgA1 from both the patients with IgAN and normal controls bound to HMC in a dose‐dependent, saturable manner, and was saturated at approximately 500 pmoles per 0·5 ml of aIgA1. aIgA1 from patients with IgAN, however, bound to HMC at a higher speed and Scatchard analysis revealed a Kd of (8·89 ± 2·1) × 10−8mversus (4·3 ± 1·2) × 10−7m for aIgA1 from healthy controls (P = 0·026).The binding was specific because it was only inhibited by unlabelled Mono‐IgA1 (mIgA1) and not by serum albumin or IgG. aIgA1 from patients with IgAN could induce release of intracellular calcium, phosphorylation of ERK, DNA synthesis, proliferation of HMC, expression of TGF‐βmRNA and secretion of fibronectin in HMC in a similar time‐dependent manner as aIgA1 from healthy controls, but the effects were much stronger and the durations were much longer (P < 0·05, respectively). We conclude that aIgA1 from patients with IgAN has a higher binding capacity to HMC and stronger biological effects than aIgA1 from healthy controls. This suggests that direct interaction between IgA1 and HMC and subsequential pathophysiological responses may play an important role in the pathogenesis for IgAN.

Anti-endothelial cell antibodies (AECA) in patients with propylthiouracil (PTU)-induced ANCA positive vasculitis are associated with disease activity.

Increasing evidence has demonstrated that propylthiouracil (PTU) could induce ANCA positive vasculitis. However, our previous work has suggested that only one‐fifth of the PTU‐induced ANCA positive patients had clinical vasculitis and so the mechanism is not clear. Anti‐endothelial cell antibodies (AECA) have been implicated in the pathogenesis of various vasculitides, including primary ANCA positive systemic vasculitis. The purpose of this study is to investigate the prevalence of AECA and their possible role in the pathogenesis of patients with PTU‐induced ANCA positive vasculitis. Sera from 11 patients with PTU‐induced ANCA positive vasculitis at both active and quiescent phases, and sera from 10 patients with PTU‐induced ANCA but without clinical vasculitis, were studied. Sera from 30 healthy blood donors were collected as normal controls. Soluble proteins from 1% Triton‐100 extracted in vitro cultured human umbilical vein endothelial cells were used as antigens and an immunoblotting technique was performed to determine the presence of AECA, and their specific target antigens were identified. In patients with PTU‐induced ANCA positive vasculitis, 10 of the 11 patients in an active phase of disease were serum IgG‐AECA positive and six protein bands of endothelial antigens could be blotted (61 kD, 69 kD, 77 kD, 85 kD, 91 kD and 97 kD). However, in the quiescent phase, seven of the 10 positive sera turned negative. None of the ANCA positive but vasculitis negative patients or normal controls were AECA positive. In conclusion, AECA could be found in sera from patients with PTU‐induced ANCA positive vasculitis and were associated more closely with vasculitic disease activity.

Synthesis of Dibenzo[c,e]oxepin-5(7H)-ones from Benzyl Thioethers and Carboxylic Acids: Rhodium-Catalyzed Double CH Activation Controlled by Different Directing Groups†

A rhodium(III)-catalyzed cross-coupling of benzyl thioethers and aryl carboxylic acids through the two directing groups is reported. Useful structures with diverse substituents were efficiently synthesized in one step with the cleavage of four bonds (CH, CS, OH) and the formation of two bonds (CC, CO). The formed structure is the privileged core in natural products and bioactive molecules. This work highlights the power of using two different directing groups to enhance the selectivity of a double CH activation, the first of such examples in cross-oxidative coupling.

Ir-Catalyzed C-H Amidation of Aldehydes with Stoichiometric/Catalytic Directing Group.

Ir-catalyzed sp2 C-H amidation of aldehydes with various anilines as stoichiometric or catalytic directing groups was accomplished. A wide range of substrates were selectively amidated in good to excellent yields with broad functional group tolerance. The iridacycle complexes were isolated, characterized, and proved as key intermediates. Kinetic studies and Hammett plots provided detailed understandings of this amidation. According to the mechanism, the electron-rich ArSO2 N3 was proved effective for intermolecular sp3 C-H amidation.

The glycans deficiencies of macromolecular IgA1 is a contributory factor of variable pathological phenotypes of IgA nephropathy

Recent evidence has suggested that IgA1‐containing macromolecules and the glycosylation of IgA1 in sera from patients with IgAN might involve the pathogenesis of IgAN. However, whether the different histological phenotypes can be attributed or not to the aberrant glycosylation of macromolecular IgA1 has not yet been elucidated. The aim of the current study is to investigate the glycosylation of IgA1 molecules in serum IgA1‐containing macromolecules and their association with pathological phenotypes of IgAN. Sera was collected from 40 patients with IgAN and 20 donors. Twenty patients had mild mesangial proliferative IgAN, the remaining 20 had focal proliferative sclerosing IgAN. Polyethylene glycol 6000 was used to precipitate the macromolecules from sera of patients and controls. Biotinylated lectins were used in an enzyme‐linked immunosorbent assay (ELISA) to examine different glycans on IgA1 molecules. The α2,6 sialic acid was detected by elderberry bark lectin (SNA) and the exposure of terminal galactose (Gal) and N‐acetylgalactosamine (GalNAc) were detected by Arachis hypogaea (PNA) and Vilsa villosa lectin (VVL), respectively. The IgA1 glycans levels corrected by IgA1 concentrations were compared between patients and controls. Reduced terminal α2,6 sialic acid of IgA1 (79·89 ± 25·17 versus 62·12 ± 24·50, P = 0·034) was demonstrated only in precipitates from sera of patients with focal proliferative sclerosing IgAN, compared with those from controls. Reduced galactosylation of IgA1 molecules in precipitates was demonstrated in patients with both mild mesangial proliferative IgAN and focal proliferative sclerosing IgAN compared with normal controls (24·52 ± 18·71 versus 76·84 ± 32·59 P = 0·000 and 33·48 ± 25·36 versus 76·84 ± 32·59 P = 0·000). However, no significant difference was found in IgA1 glycosylation in the supernatant between patients and normal controls (P > 0·05). The glycosylation deficiency of IgA1 existed only in serum IgA1‐containing macromolecules of patients with IgAN, and was associated with the renal pathological phenotypes. This suggests that aberrant glycosylation of IgA1 in serum macromolecules might be a contributory factor in the pathogenesis of IgAN.

Development of dental training system with haptic display

This paper discusses the development of a dental training system with haptic display capability. The system architecture is proposed firstly concerning two typical operations, probing and cutting, in dental surgery. Triangle mesh model is used for the tooth to reduce the computation time. Real time collision detection is realized between the tooth and a spherical tool. The operation force is determined from the penetration between the tool and the tooth. Material removal from the tooth is realized using vertex deformation method. Force filtering approach is proposed to eliminate vibration of the haptic device. Experiment results show that the system can provide stable simulation of probing and cutting operation.

Cu-Catalyzed Alkynylation of Unactivated C(sp3)–X Bonds with Terminal Alkynes through Directing Strategy

In this letter, we report an efficient and concise protocol for Cu-catalyzed cross-coupling of unactivated alkyl halides/peusudohalides with terminal alkynes to afford internal alkynes with the assistance of various amides as directing groups. Different alkyl halides/pseudohalides exhibited excellent reactivities, and the inactivated alkyl chlorides and sulfonates showed better reactivity than bromides/iodides. This is the first successful example to apply alkyl chlorides and sulfonates directly in cross-coupling with terminal alkynes in the absence of any additives. A Cu catalyst was found to be more effective than other transition metal catalysts. This reaction also exhibited a broad substrate scope with respect to terminal alkynes.

Direct Oxidation of Aliphatic C–H Bonds in Amino-Containing Molecules under Transition-Metal-Free Conditions

By employing a simple, inexpensive, and transition-metal-free oxidation system, secondary C-H bonds in a series of phthaloyl protected primary amines and amino acid derivatives were oxidized to carbonyls with good regioselectivities. This method could also be applied to oxidize tertiary C-H bonds and modify synthetic dipeptides.