Mono-and 2,2′-di-substituted terminal alkenes can be isomerized into the more stable internal Zand E-alkenes by treating them with catalytic amounts of [(allyl)PdCl] 2 or [(allyl)NiBr] 2 , a triarylphosphine and silver triflate at room temperature. The isomeric ratio (E:Z) depends on the alkenes, the (E)-isomer being the major one. The reaction is tolerant to a wide variety of functional groups including other reactive olefins. Unlike the more reactive Ir catalysts, monosubstituted alkenes give almost exclusively the 2-alkenes. Direct comparison to two of the best-known catalysts for this process, (Ir(PCy 3 ) 3 ] + [BPh 4 ] − , and Grubbs Generation II metathesis catalyst) is also reported.

Sevoflurane is associated with a high incidence of emergence agitation in children. Midazolam and propofol have been examined with the aim of reducing emergence agitation after sevoflurane anaesthesia. However, the effect of both drugs on emergence agitation is still controversial. Therefore we designed this study to measure the effect of midazolam or propofol at the end of surgery on emergence agitation during the recovery period. One hundred and one children, aged one to 13 years, undergoing strabismus surgery were enrolled in this randomised double-blind study. Anaesthesia was induced and maintained with sevoflurane in N2O/O2. Children were randomly assigned to receive midazolam 0.05 mg/kg (group M, n=35), propofol 1 mg/kg (group P, n=31) or saline (group S, n=35). A four-point scale was used to evaluate recovery characteristics upon awakening and during the first hour after emergence from anaesthesia. The incidence of emergence agitation in group M was 42.9% (15/35), in group P 48.4% (15/31) and in group S 74.3% (26/35). The incidence of emergence agitation in groups M and P was significantly less than in group S. The emergence time was prolonged for patients in groups M and P compared to group S. There was no significant difference in the incidence of emergence agitation or in emergence times between the groups P and M. We conclude that propofol or midazolam administration before the end of surgery may be effective in reducing the incidence of emergence agitation in children undergoing strabismus surgery under sevoflurane anaesthesia.

Vinylindoles undergo Ni(II)-catalyzed asymmetric hydrovinylation under very mild conditions (−78 °C, 1 atmosphere ethylene, 4 mol% catalyst) to give the corresponding 2-but-3-enyl derivatives in excellent yields and enantiose-lectivities. Hydroboration of the alkene, oxidation to an acid, followed by Friedel-Crafts annulation gives an indole-annulated cyclopentanone that is a suitable precursor for the syntheses of cis-trikentrins and all known herbindoles. For example, the cyclopentanone from 4-ethyl-7-vinylindole is converted into (+)-cis-trikentin A in four steps (Wittig reaction, alkene isomerization, diastereoselective hydrogenation and nitrogen deprotection). The previous synthesis of this molecule from (S)-(−)-malic acid involved more than 20 steps and a preparative HPLC separation of diastereomeric intermediates.

No abstract

Facile CuI-mediated N-arylation of diketopiperazine using the Fukuyama modification of the Ullmann-Goldberg reaction can be exploited in new approaches to enantio-pure polycyclic diketopiperazines from easily assembled dipeptides or functionalized Schöllkopf reagents.Several molecules containing a 2,5-diketopiperazine (1, DKP) moiety show promising biological activities which are helpful in treating human diseases (e.g., 2, 3). 1 However, there is no general method for the synthesis of enantiopure pyrazino[1,2-a]indole-1,4-diones (2), which have potent immunosuppressive and antimicrobial activities. Reported nonstereoselective methods for this important pharmacophore used a stepwise synthesis starting from indole 2-carboxylic acid derivatives. 2 Our studies in the area had its origin in an approach to lyngbyatoxin A, a potent PKC inhibitor, in which we planned to use a biosynthesisinspired 3 N-arylation to construct the 9-memebered lactam ( Figure 2). While investigating the properties of a dipeptide precursor (4, X = Y = Br) for this intramolecular N-arylation, we have uncovered a number of potentially useful transformations that are relevant to the synthesis of functionalized diketopiperazines, and here we report the details of these investigations.Our studies started with the assembly of the indolyldipeptide 13b (Scheme 1). 4 The starting point for the synthesis is a one-step preparation of 4,7-dibromo-indole 5 via the Bartoli protocol. 5 Reaction of 5 with POCl 3 and DMF gives the carboxaldehyde 6, which after BOCprotection of the nitrogen is converted into the dehydroamino acid derivative 12 via a modified Horner-Emmons reaction using the phosphonate 11. 6 Schmidt's phosphonate 11 was prepared by Rh-catalyzed carbene-insertion into an N-H bond of the amide 9. 7 The Horner-Emmons reaction of the aldehyde 7 with the phosphonate 11 under the prescribed procedure gives 71% of the pure Z-dehydrodipeptide 12 after column chromatography. Installation of the additional chiral center in 12 turned out to be more challenging than we anticipated as even the best Rhcatalysts give only modest diastereoselectivity in the asymmetric hydrogenation reaction. Selected results of Rh-catalyzed hydrogenation of 12 with various catalysts are reported in Table 1 With the appropriately protected substrates 13b and 13c in hand we first examined various intramolecular amination procedures to prepare the 9-membered lactam. Our initial attempts focused on Pd-catalyzed N-arylation reactions [9] of 13c, under conditions remniscent of Buchwald's synthesis of dehydrobufotenine. 10 These experiments (Table 2, Supporting Information) 4 were uniformly unsuccessful and lead to no discernable products. Next we turned our attention to the Fukuyama modification 9f of the Ullmann-Goldberg reaction, which he has used very effectively to prepare highly functionalized nitrogen heterocyles. 11 Studies 4 of various substrates quickily revealed that the the substrate 13b, with both amines deprotected, is compatible with the standard conditions...

Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti‐resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)‐based anabolic drugs present limitations and adverse effects including osteosarcoma during long‐term use. Also, the antibody‐based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/β‐catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl–CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small‐molecule inhibitors of the Dvl–CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/β‐catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo‐cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY‐02061, a representative of the screened compounds. Oral administration of KY‐02327, one of 55 newly synthesized KY‐02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small‐molecule inhibitors of the Dvl–CXXC5 interaction that block negative feedback regulation of Wnt/β‐catenin signaling are potential candidates for the development of bone anabolic anti‐osteoporosis drugs.

Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2 − conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2 + CD161 − T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCRα7.2 − conventional T cells and TCRα7.2 + CD161 − T cells. Genome-wide transcriptomes of MAIT cells, TCRα7.2 − conventional T cells, and TCRα7.2 + CD161 − T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCRα7.2 − conventional T cells and TCRα7.2 + CD161 − T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCRα7.2 − conventional T cells and TCRα7.2 + CD161 − T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.

The efficacy and safety of the routine use of target-controlled infusion of propofol for the sedation of patients undergoing transrectal ultrasound-guided prostate biopsy were assessed. The optimal level of sedation was also evaluated. A total of 250 patients were randomized into five groups according to sedation level determined by the Observer's Assessment of Alertness/Sedation (OAA/S) scale. As the level of sedation was increased, the overall pain and discomfort score decreased and the satisfaction rate tended to increase, although hypoxia meant that intervention occurred more frequently at higher sedation levels. Target-controlled infusion of propofol provided safe and effective sedation during transrectal ultrasound-guided prostate biopsy, particularly if moderate sedation (OAA/S score of 3) was achieved. The effect-site concentration of propofol for this level of sedation was about 1.5 µg/ml.