Mild electrophilic trifluoromethylation of beta-ketoesters and silyl enol ethers with 5-trifluoro methyldibenzothiophenium tetrafluoroborate

Cyclic and acyclic beta-ketoesters were efficiently trifluoromethylated with 5-trifluoromethyldibenzothiophenium tetrafluoroborate in the presence of a phase-transfer catalyst to afford the corresponding alpha-substituted alpha-trifluoromethyl beta-ketoesters in good to excellent yields. In a second approach, 5-trifluoromethyldibenzothiophenium tetrafluoroborate and tetrabutylammonium difluorotriphenylstannate were used for efficient electrophilic trifluoromethylation of various silyl enol ethers leading to the corresponding alpha-trifluoromethyl ketones in good to high yields.     

A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 3',5'-bisphosphate C-nucleotide analogues as the first reported in vivo stable P2Y(1)-receptor antagonists

In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent platelet aggregation inhibitors with enhanced metabolic stability, we developed an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel synthetic approach involved the following: (i) the use of a novel activating group, the N-methyl-N-phenylamino group, which was easily generated in high yield by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under high pressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily available unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8-iodo derivative (16), and (iii) the stereoselective reduction of the ketone group of the furanosyl ring followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine. The beta configuration at the anomeric C-1' position of the glycal moieties was perfectly retained throughout this conversion. This procedure afforded 8-(2'-deoxy-beta-D-ribofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2'-deoxy-beta-D-xylofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (24) with an overall yield of 50% and 39%, respectively. Finally, the conversion of nucleosides 21 and 24 to the pyrazolotriazine C-nucleotides 3',5'-bisphosphate 2 and 3',5'-cyclophosphate 26 is also described herein and represents the first reported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series. Preliminary biological testing has shown that compound 2 strongly inhibits ADP-induced human platelet aggregation and shape change and possesses significant efficacies 30 min after injection in rat, highlighting a strong P2Y(1)-receptor antagonist activity in vitro combined with a prolonged duration of action in vivo.     

Thermal and electrochemical C-X activation (X = Cl,Br, I) by the strong Lewis acid Pd3(dppm)3(CO)2+ cluster and its catalytic applications

The stoichiometric and catalytic activations of alkyl halides and acid chlorides by the unsatured Pd(3)(dppm)(3)(CO)(2+) cluster (Pd(3)(2+)) are investigated in detail. A series of alkyl halides (R-X; R = t-Bu, Et, Pr, Bu, allyl; X = Cl, Br, I) react slowly with Pd(3)(2+) to form the corresponding Pd(3)(X)(+) adduct and "R(+)". This activation can proceed much faster if it is electrochemically induced via the formation of the paramagnetic species Pd(3)(+). The latter is the first confidently identified paramagnetic Pd cluster. The kinetic constants extracted from the evolution of the UV-vis spectra for the thermal activation, as well as the amount of electricity to bring the activation to completion for the electrochemically induced reactions, correlate the relative C-X bond strength and the steric factors. The highly reactive "R(+)" species has been trapped using phenol to afford the corresponding ether. On the other hand, the acid chlorides react rapidly with Pd(3)(2+) where no induction is necessary. The analysis of the cyclic voltammograms (CV) establishes that a dissociative mechanism operates (RCOCl --> RCO(+) + Cl(-); R = t-Bu, Ph) prior to Cl(-) scavenging by the Pd(3)(2+) species. For the other acid chlorides (R = n-C(6)H(13), Me(2)CH, Et, Me, Pr), a second associative process (Pd(3)(2+) + RCOCl --> Pd(3)(2+.....)Cl(CO)(R)) is seen. Addition of Cu(NCMe)(4)(+) or Ag(+) leads to the abstraction of Cl(-) from Pd(3)(Cl)(+) to form Pd(3)(2+) and the insoluble MCl materials (M = Cu, Ag) allowing to regenerate the starting unsaturated cluster, where the precipitation of MX drives the reaction. By using a copper anode, the quasi-quantitative catalytic generation of the acylium ion ("RCO(+)") operates cleanly and rapidly. The trapping of "RCO(+)" with PF(6)(-) or BF(4)(-) leads to the corresponding acid fluorides and, with an alcohol (R'OH), to the corresponding ester catalytically, under mild conditions. Attempts were made to trap the key intermediates "Pd(3)(Cl)(+)...M(+)" (M(+) = Cu(+), Ag(+)), which was successfully performed for Pd(3)(ClAg)(2+), as characterized by (31)P NMR, IR, and FAB mass spectrometry. During the course of this investigation, the rare case of PF(6)(-) hydrolysis has been observed, where the product PF(2)O(2)(-) anion is observed in the complex Pd(3)(PF(2)O(2))(+), where the substrate is well-located inside the cavity formed by the dppm-Ph groups above the unsatured face of the Pd(3)(2+) center. This work shows that Pd(3)(2+) is a stronger Lewis acid in CH(2)Cl(2) and THF than AlCl(3), Ag(+), Cu(+), and Tl(+).     

Covalently Trapped Triarylamine-Based Supramolecular Polymers

C₃-Symmetric triarylamine trisamides (TATAs), decorated with three norbornene end groups, undergo supramolecular polymerization and further gelation by π–π stacking and hydrogen bonding of their TATA cores. By using subsequent ring-opening metathesis polymerization, these physical gels are permanently crosslinked into chemical gels. Detailed comparisons of the supramolecular stacks in solution, in the physical gel, and in the chemical gel states, are performed by optical spectroscopies, electronic spectroscopies, atomic force microscopy, electronic paramagnetic resonance spectroscopy, X-ray scattering, electronic transport measurements, and rheology. The results presented here clearly evidence that the core structure of the functional supramolecular polymers can be precisely retained during the covalent capture whereas the mechanical properties of the gels are concomitantly improved, with an increase of their storage modulus by two orders of magnitude.     

Measurement of long-range cross-correlation rates using a combination of single- and multiple-quantum NMR spectroscopy in one experiment

A method is described to determine long-range cross-correlations between the modulations of an anisotropic chemical shift (e.g., of a C' carbonyl carbon in a protein) and the fluctuations of a weak long-range dipolar interaction (e.g., in cross-correlation between the same C' carbonyl and the H(N) proton of the neighboring amide group). Such long-range correlations are difficult to measure because the corresponding long-range scalar couplings are so small that Redfield's secular approximation is often violated. The method, which combines features of single- and double-quantum NMR spectroscopy, allows one to cancel the effects of dominant short-range dipolar interactions (e.g., between the CSA of the amide nitrogen N and the dipolar coupling to its attached proton H(N)) and is designed so that the secular approximation is rescued even if the scalar coupling between the long-range dipolar coupling partners is very small. The cross-correlation rates thus determined in ubiquitin cover a wide range because of local motions and variations of the CSA tensors.     

Evaluation of automated sample preparation, retention time locked gas chromatography-mass spectrometry and data analysis methods for the metabolomic study of Arabidopsis species

In this paper, automated sample preparation, retention time locked gas chromatography-mass spectrometry (GC-MS) and data analysis methods for the metabolomics study were evaluated. A miniaturized and automated derivatisation method using sequential oximation and silylation was applied to a polar extract of 4 types (2 types×2 ages) of Arabidopsis thaliana, a popular model organism often used in plant sciences and genetics. Automation of the derivatisation process offers excellent repeatability, and the time between sample preparation and analysis was short and constant, reducing artifact formation. Retention time locked (RTL) gas chromatography-mass spectrometry was used, resulting in reproducible retention times and GC-MS profiles. Two approaches were used for data analysis. XCMS followed by principal component analysis (approach 1) and AMDIS deconvolution combined with a commercially available program (Mass Profiler Professional) followed by principal component analysis (approach 2) were compared. Several features that were up- or down-regulated in the different types were detected.     

Dynamic light scattering and cryogenic transmission electron microscopy investigations on metallo-supramolecular aqueous micelles: evidence of secondary aggregation

Metallo-supramolecular diblock copolymers consisting of a polystyrene (PS) block connected to a poly(ethylene oxide) (PEO) block by a bis(terpyridine)ruthenium complex (PS₂₀-[Ru]-PEO _y ) were used to prepare aqueous micelles. The length of the PS block was kept constant, while two PEOs of different molecular weight were used. The resulting hydrated micelles and aggregates were characterized by a combination of cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering measurements. The results were compared to those obtained for a covalent counterpart (PS₂₂-b-PEO₇₀). Cryogenic transmission electron microscopy allowed visualization of the PS core of the micelles. Moreover, the aggregates result from clustering of individual micelles.     

Atomic force microscopy imaging of hair: correlations between surface potential and wetting at the nanometer scale

We report investigations of hair surface potential under wetting at the nanometric scale by atomic force microscopy (AFM). Surface potential imaging was used to characterize the electrostatic properties of the hair samples. We found that the surface potential noticeably increases along the edges of the cuticles. These results are correlated with wetting behavior of different liquids performed using AFM in noncontact mode.     

Structural and electrochemical studies of novel bis(mu-methoxo)diiron complexes: observation of Fe(III)Fe(IV) and Fe(IV)Fe(IV) states resonating with phenoxyl radicals

Novel diiron complexes with an Fe2(mu-OMe)2 core were studied as models of the active site of nonheme iron-containing enzymes. X-ray crystal structures of the complexes showed the existence of two types of ligand folding-parallel and twisted-both of which have four virtually equivalent phenolato groups sticking out from the Fe2O2 rhombic plane. Cyclic voltammetry measurements revealed two or more distinct redox waves in a region of relatively high potential, in addition to known Fe(II)/Fe(III) redox waves in a region of lower potential. These new peaks were assigned to the high-valence state of iron atoms, that is, Fe(III)Fe(IV) and Fe(IV)Fe(IV), resonating with the phenoxyl radical(s). The split width of the redox waves ranged from 0.14 to 0.20 eV, which may be a measure of the electronic interaction of the phenolate groups through the Fe2(mu-OMe)2 core.