Synthesis of the core structure of the lipoteichoic acid of Streptococcus pneumoniae

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2‐acetamino‐4‐amino‐2,4,6‐trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure Glcβ(1‐3)AATDgalβ(1‐3)Glcα(1‐O)DAG in a suitably protected form for further chain extension ( 1 b , 1 c ) and as unprotected glycolipid ( 1 a ) that was employed in biological studies. These studies revealed that 1 a as well as 1 lead to interleukin‐8 release, however not via TLR2 or TLR4 as receptor.     

ADLOC: An Aptamer‐Displacement Assay Based on Luminescent Oxygen Channeling

Functional nucleic acids, such as aptamers and allosteric ribozymes, can sense their ligands specifically, thereby undergoing structural alterations that can be converted into a detectable signal. The direct coupling of molecular recognition to signal generation enables the production of versatile reporters that can be applied as molecular probes for various purposes, including high‐throughput screening. Here we describe an unprecedented type of a nucleic acid‐based sensor system and show that it is amenable to high‐throughput screening (HTS) applications. The approach detects the displacement of an aptamer from its bound protein partner by means of luminescent oxygen channeling. In a proof‐of‐principle study we demonstrate that the format is feasible for efficient identification of small drug‐like molecules that bind to a protein target, in this case to the Sec7 domain of cytohesin. We extended the approach to a new cytohesin‐specific single chain DNA aptamer, C10.41, which exhibits a similar binding behavior to cytohesins but has the advantage of being more stable and easier to synthesize and to modify than the RNA‐aptamer M69. The results obtained with both aptamers indicate the general suitability of the aptamer‐displacement assay based on luminescent oxygen channelling (ADLOC) for HTS. We also analyzed the potential for false positive hits and identified from a library of 18 000 drug‐like small molecules two compounds as strong singlet‐oxygen quenchers. With full automation and the use of commercially available plate readers, we estimate that the ADLOC‐based assay described here could be used to screen at least 100 000 compounds per day.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Experimental and Theoretical Conformational Analysis of 5‐Benzylimidazolidin‐4‐one Derivatives – a ‘Playground’ for Studying Dispersion Interactions and a ‘Windshield‐Wiper’ Effect in Organocatalysis

The PF₆ salts of 5‐benzyl‐1‐isopropylidene‐ and 5‐benzyl‐1‐cinnamylidene‐3‐methylimidazolidin‐4‐ones 1 (Scheme) with various substituents in the 2‐position have been prepared, and single crystals suitable for X‐ray structure determination have been obtained of 14 such compounds, i.e., 2 – 10 and 12 – 16 (Figs. 2–5). In nine of the structures, the Ph ring of the benzyl group resides above the heterocycle, in contact with the cis‐substituent at C(2) (staggered conformation A ; Figs. 1–3); in three structures, the Ph ring lies above the iminium π‐plane (staggered conformation B ; Figs. 1 and 4); in two structures, the benzylic C? C bond has an eclipsing conformation ( C ; Figs. 1 and 5) which places the Ph ring simultaneously at a maximum distance with its neighbors, the CO group, the N?C‐π‐system, and the cis‐substituent at C(2) of the heterocycle. It is suggested by a qualitative conformational analysis (Fig. 6) that the three staggered conformations of the benzylic C? C bond are all subject to unfavorable steric interactions, so that the eclipsing conformation may be a kind of ‘escape’. State‐of‐the‐art quantum‐chemical methods, with large AO basic sets (near the limit) for the single‐point calculations, were used to compute the structures of seven of the 14 iminium ions, i.e., 3, 4 / 12, 5 – 7, 13 , and 16 (Table) in the two staggered conformations, A and B , with the benzylic Ph group above the ring and above the iminium π‐system, respectively. In all cases, the more stable computed conformer (‘isolated‐molecule’ structure) corresponds to the one present in the crystal (overlay in Fig. 7). The energy differences are small (≤2 kcal/mol) which, together with the result of a potential‐curve calculation for the rotation around the benzylic C? C bond of one of the structures, 16 (Fig. 8), suggests that the benzyl group is more or less freely rotating at ambident temperatures. The importance of intramolecular London dispersion (benzene ring in ‘contact’ with the cis‐substituent in conformation A ) for DFT and other quantum‐chemical computations is demonstrated; the benzyl‐imidazolidinones 1 appear to be ideal systems for detecting dispersion contributions between a benzene ring and alkyl or aryl CH groups. Enylidene ions of the type studied herein are the reactive intermediates of enantioselective organocatalytic conjugate additions, Diels–Alder reactions, and many other transformations involving α,β‐unsaturated carbonyl compounds. Our experimental and theoretical results are discussed in view of the performance of 5‐benzyl‐imidazolidinones as enantioselective catalysts.     

Facially coordinating triamine ligands with a cyclic backbone: some structure-stability correlations

Metal complex formation of the two cyclic triamines 6-methyl-1,4-diazepan-6-amine (MeL(a)) and all-cis-2,4,6-trimethylcyclohexane-1,3,5-triamine (Me(3)tach) was studied. The structure of the free ligands (H(x)MeL(a))(x+) and H(x)Me(3)tach(x+) (0 ≤ x ≤ 3) was investigated by pH-dependent NMR spectroscopy and X-ray diffraction experiments. The crystal structure of (H(2)Me(3)tach)(p-O(3)S-C(6)H(4)-CH(3))(2) showed a chair conformation with axial nitrogen atoms for the doubly protonated species. In contrast to a previous report, Me(3)tach was found to be a stronger base than the parent cis-cyclohexane-1,3,5-triamine (tach); pK(a)-values of H(3)Me(3)tach(3+) (25 °C, 0.1 M KCl): 5.2, 7.4, 11.2. The crystal structures of (H(3)MeL(a))(BiCl(6))·2H(2)O and (H(3)MeL(a))(ClO(4))Cl(2) exhibited two distinct twisted chair conformations of the seven membered diazepane ring. [Co(MeL(a))(2)](3+) (cis: 1(3+), trans: 2(3+)), trans-[Fe(MeL(a))(2)](3+) (3(3+)), [(MeL(a))ClCd(μ(2)-Cl)](2) (4), trans-[Cu(MeL(a))(2)](2+) (5(2+)), and [Cu(HMeL(a))Br(3)] (6) were characterized by single crystal X-ray analysis of 1(ClO(4))(3)·H(2)O, 2Br(3)·H(2)O, 3(ClO(4))(3)·0.8MeCN·0.2MeOH, 4, 5Br(2)·0.5MeOH, and 6·H(2)O. Formation constants and redox potentials of MeL(a) complexes were determined by potentiometric, spectrophotometric, and cyclovoltammetric measurements. The stability of [M(II)(MeL(a))](2+)-complexes is low. In comparison to the parent 1,4-diazepan-6-amine (L(a)), it is only slightly enhanced. In analogy to L(a), MeL(a) exhibited a pronounced tendency for forming protonated species such as [M(II)(HMeL(a))](3+) or [M(II)(MeL(a))(HMeL(a))](3+) (see 6 as an example). In contrast to MeL(a), Me(3)tach forms [M(II)L](2+) complexes (M = Cu, Zn) of very high stability, and the coordination behavior corresponds mainly to an "all-or-nothing" process. Molecular mechanics calculations showed that the low stability of L(a) and MeL(a) complexes is mainly due to a large amount of torsional strain within the pure chair conformation of the diazepane ring, required for tridentate coordination. This behavior is quite contrary to Me(3)tach and tacn (tacn =1,4,7-triazacyclononane), where the main portion of strain is already preformed in the free ligand, and the amount, generated upon complex formation, is comparably low.     

Ordered mesoporous MFe(2)O(4) (M = Co, Cu, Mg, Ni, Zn) thin films with nanocrystalline walls, uniform 16 nm diameter pores and high thermal stability: template-directed synthesis and characterization of redox active trevorite

In this paper, we report on ordered mesoporous NiFe(2)O(4) thin films synthesized via co-assembly of hydrated ferric nitrate and nickel chloride with an amphiphilic diblock copolymer, referred to as KLE. We establish that the NiFe(2)O(4) samples are highly crystalline after calcination at 600 °C, and that the conversion of the amorphous inorganic framework comes at little cost to the ordering of the high quality cubic network of pores averaging 16 nm in diameter. We further show that the synthesis method employed in this work can be readily extended to other ferrites, such as CoFe(2)O(4), CuFe(2)O(4), MgFe(2)O(4), and ZnFe(2)O(4), which could pave the way for innovative device design. While this article focuses on the self-assembly and characterization of these materials using various state-of-the-art techniques, including electron microscopy, grazing incidence small-angle X-ray scattering (GISAXS), time-of-flight secondary ion mass spectrometry (TOF-SIMS), X-ray photoelectron spectroscopy (XPS), as well as UV-vis and Raman spectroscopy, we also examine the electrochemical properties and show the benefits of combining a continuous mesoporosity with nanocrystalline films. KLE-templated NiFe(2)O(4) electrodes exhibit reasonable levels of lithium ion storage at short charging times which stem from facile pseudocapacitance.     

Systematic and in situ energy dispersive X-ray diffraction investigations on the formation of lanthanide phosphonatobutanesulfonates: Ln(O(3)P-C(4)H(8)-SO(3))(H(2)O) (Ln = La-Gd)

Using the flexible linker H(2)O(3)P-C(4)H(8)-SO(3)H (H(3)L) and rare earth ions Ln(3+) (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd) we were able to synthesize the new isostructural inorganic organic hybrid compounds Ln(O(3)P-C(4)H(8)-SO(3))(H(2)O). High-throughput experiments were employed to study the influence of the molar ratios Ln:H(3)L and pH on the product formation. The crystal structure of the compounds Sm(O(3)P-C(4)H(8)-SO(3))(H(2)O) (1) and Pr(O(3)P-C(4)H(8)-SO(3))(H(2)O) (2) were determined by single crystal diffraction. The structures are built up from chains of edge-sharing LnO(8)-polyhedra that are connected by the phosphonate and sulfonate groups into layers. These layers are linked by the -(CH(2))(4)- group to form a three-dimensional framework. The synthesis of compound 1 was scaled up in a conventional oven as well as in a microwave reactor system. A modification of a microwave reactor system allowed its integration into the beamline F3 at HASYLAB, DESY, Hamburg. The crystallization was investigated in situ by means of energy dispersive X-ray diffraction using conventional as well as microwave heating methods applying temperatures varying from 110 to 150 °C. The formation of Sm(O(3)P-C(4)H(8)-SO(3))(H(2)O) takes place in two steps. In the first step a crystalline intermediate was observed, which transforms completely into compound 1. The method by Sharp and Hancock was used to determine the rate constants, reaction exponents, and the Arrhenius activation energy for both reaction steps. Comparing both heating methods, microwave heating leads to fully crystallized reaction product after shorter reaction times, but neither the temperature nor the heating method has significant influence on the induction time.     

Electrophilic fluorination: the aminopyridine dilemma

An unusually high yielding fluorination of aminopyralid (3) using F-TEDA (SELECTFLUOR™) in warm water, followed by kinetic resolution (via iterative esterification/saponification) of the crude fluorination product with dry HCl in methanol produced pure ring-fluorinated pyridine 2 in an overall yield of 31% for the two steps.     

Submillimeter-wave and far-infrared spectroscopy of high-J transitions of the ground and ν2 = 1 states of ammonia

Complete and reliable knowledge of the ammonia spectrum is needed to enable the analysis and interpretation of astrophysical and planetary observations. Ammonia has been observed in the interstellar medium up to J=18 and more highly excited transitions are expected to appear in hot exoplanets and brown dwarfs. As a result, there is considerable interest in observing and assigning the high J (rovibrational) spectrum. In this work, numerous spectroscopic techniques were employed to study its high J transitions in the ground and ν(2)=1 states. Measurements were carried out using a frequency multiplied submillimeter spectrometer at Jet Propulsion Laboratory (JPL), a tunable far-infrared spectrometer at University of Toyama, and a high-resolution Bruker IFS 125 Fourier transform spectrometer (FTS) at Synchrotron SOLEIL. Highly excited ammonia was created with a radiofrequency discharge and a dc discharge, which allowed assignments of transitions with J up to 35. One hundred and seventy seven ground state and ν(2)=1 inversion transitions were observed with microwave accuracy in the 0.3-4.7 THz region. Of these, 125 were observed for the first time, including 26 ΔK=3 transitions. Over 2000 far-infrared transitions were assigned to the ground state and ν(2)=1 inversion bands as well as the ν(2) fundamental band. Of these, 1912 were assigned using the FTS data for the first time, including 222 ΔK=3 transitions. The accuracy of these measurements has been estimated to be 0.0003-0.0006?cm(-1). A reduced root mean square error of 0.9 was obtained for a global fit of the ground and ν(2)=1 states, which includes the lines assigned in this work and all previously available microwave, terahertz, far-infrared, and mid-infrared data. The new measurements and predictions reported here will support the analyses of astronomical observations by high-resolution spectroscopy telescopes such as Herschel, SOFIA, and ALMA. The comprehensive experimental rovibrational energy levels reported here will permit further refinement of the potential energy surface to improve ammonia ab initio calculations and facilitate assignment of new high-resolution spectra of hot ammonia.     

Optical response of small closed-shell sodium clusters

Absorption spectra of closed-shell Na(2), Na(3) (+), Na(4), Na(5) (+), Na(6), Na(7) (+), and Na(8) clusters are calculated using a complex Bethe-Salpeter equation derived using a conserving linear response method. In the framework of a quasiparticle approach, we determine electron-hole correlations in the presence of an external field. The calculated results are in excellent agreement with experimental spectra, and some possible cluster geometries that occur in experiments are analyzed. The position and the broadening of the resonances in the spectra arise from a consistent treatment of the scattering and dephasing contributions in the linear response calculation. Comparison between the experimental and the theoretical results yields information about the cluster geometry, which is not accessible experimentally.