Detrimental Ni(0) transfer in Kumada catalyst transfer polycondensation of benzo[2,1‐b:3,4‐b']dithiophene

This article deals with the Kumada Catalyst Transfer Polycondensation (KCTP) of 4,7‐dioctylbenzo[2,1‐b:3,4‐b']dithiophene ( BDP‐Oct ) using Ni(II) catalyst or In/cat combination. A combination of MALDI MS, GPC, and ³¹P NMR spectroscopy is used to reveal the failure of the KCTP of this particular monomer. Intermolecular transfer reactions to monomer appeared to prevent the formation of polymer. This result is remarkable, since isomeric benzo[1,2‐b:4,5‐b']dithiophene polymerizes in a controlled way. The presence of a “non‐aromatic double bond” in annulated monomers is discussed. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1706–1712     

Thermally induced solid-state transformation of cimetidine. A multi-spectroscopic/chemometrics determination of the kinetics of the process and structural elucidation of one of the products as a stable N3-enamino tautomer

Exposure of cimetidine (CIM) to dry heat (160–180 °C) afforded, upon cooling, a glassy solid containing new and hitherto unknown products. The kinetics of this process was studied by a second order chemometrics-assisted multi-spectroscopic approach. Proton and carbon-13 nuclear magnetic resonance (NMR), as well as ultraviolet and infrared spectroscopic data were jointly used, whereas multivariate curve resolution with alternating least squares (MCR-ALS) was employed as the chemometrics method to extract process information. It was established that drug degradation follows a first order kinetics.     

Development of an LC‐MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound

Zhenju antihypertensive compound (ZJAHC) is a combined Chinese–Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography–tandem mass spectrometry (LC‐MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration–time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO‐HCT‐high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO‐HCT‐high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co‐contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine. Copyright © 2014 John Wiley & Sons, Ltd.     

Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

An asymmetric total synthesis of the guaiane sesquiterpene (?)‐englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo‐ and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N‐tetrachlorophthaloyl‐(S)‐tert‐leucinate], [Rh₂(S‐TCPTTL)₄], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo‐face. Another notable feature of the synthesis is ruthenium tetraoxide‐catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.     

Reduced dimensionality (3,2)D NMR experiments and their automated analysis: implications to high‐throughput structural studies on proteins

Protein NMR spectroscopy has expanded dramatically over the last decade into a powerful tool for the study of their structure, dynamics, and interactions. The primary requirement for all such investigations is sequence‐specific resonance assignment. The demand now is to obtain this information as rapidly as possible and in all types of protein systems, stable/unstable, soluble/insoluble, small/big, structured/unstructured, and so on. In this context, we introduce here two reduced dimensionality experiments – (3,2)D‐hNCO canH and (3,2)D‐hN coCA nH – which enhance the previously described 2D NMR‐based assignment methods quite significantly. Both the experiments can be recorded in just about 2–3 h each and hence would be of immense value for high‐throughput structural proteomics and drug discovery research. The applicability of the method has been demonstrated using alpha‐helical bovine apo calbindin‐D9k P43M mutant (75 aa) protein. Automated assignment of this data using AUTOBA has been presented, which enhances the utility of these experiments. The backbone resonance assignments so derived are utilized to estimate secondary structures and the backbone fold using Web‐based algorithms. Taken together, we believe that the method and the protocol proposed here can be used for routine high‐throughput structural studies of proteins. Copyright © 2014 John Wiley & Sons, Ltd.     

Chemistry of Lipid A: At the Heart of Innate Immunity

In many Gram‐negative bacteria, lipopolysaccharide (LPS) and its lipid A moiety are pivotal for bacterial survival. Depending on its structure, lipid A carries the toxic properties of the LPS and acts as a potent elicitor of the host innate immune system via the Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD‐2) receptor complex. It often causes a wide variety of biological effects ranging from a remarkable enhancement of the resistance to the infection to an uncontrolled and massive immune response resulting in sepsis and septic shock. Since the bioactivity of lipid A is strongly influenced by its primary structure, a broad range of chemical syntheses of lipid A derivatives have made an enormous contribution to the characterization of lipid A bioactivity, providing novel pharmacological targets for the development of new biomedical therapies. Here, we describe and discuss the chemical aspects regarding lipid A and its role in innate immunity, from the (bio)synthesis, isolation and characterization to the molecular recognition at the atomic level.     

Minimalistic Ditopic Ligands: An α‐S,N‐Donor‐Substituted Alkyne as Effective Intermetallic Conjugation Linker

The capability of donor‐substituted alkynes to link different metal ions in a side‐on carbon donor‐chelate coordination mode is extended from the donor centers S and P to the second period element N. The complex [Tp′W(CO)₂{η²‐C₂(S)(NHBn)}] (Tp′=hydrido‐tris(3,5‐dimethylpyrazolyl)borate, Bn=benzyl) bearing a terminal sulfur atom and a secondary amine substituent is accessible by a metal‐template synthesis. Subsequent deprotonation allowed the formation of remarkably stable heterobimetallic complexes with the [(η⁵‐C₅H₅)Ru(PPh₃)] and the [Ir(ppy)₂] moiety. Electrochemical and spectroscopic investigations (cyclic voltammetry, IR, UV/Vis, luminescence, EPR), as well as DFT calculations, and X‐ray structure determinations of the W–Ru complex in two oxidation states reveal a strong metal–metal coupling but also a limited delocalization of excited states.     

Reactivity of [M2(μ‐Cl)2(cod)2] (M=Ir,Rh) and [Ru(Cl)2(cod)(CH3CN)2] with Na[H2B(bt)2]: Formation of Agostic versus Borate Complexes

Treatment of [M₂(μ‐Cl)₂(cod)₂] (M=Ir and Rh) with Na[H₂B(bt)₂] (cod=1,5‐cyclooctadiene and bt=2‐mercaptobenzothiazolyl) at low temperature led to the formation of dimetallaheterocycles [(Mcod)₂(bt)₂], 1 and 2 ( 1 : M=Ir and 2 : M=Rh) and a borate complex [Rh(cod){κ²‐S,S′‐H₂B(bt)₂}], 3 . Compounds 1 and 2 are structurally characterized metal analogues of 1,5‐cyclooctadiene. Metal–metal bond distances of 3.6195(9) Å in 1 and 3.6749(9) Å in 2 are too long to consider as bonding. In an attempt to generate the Ru analogue of 1 and 2 , that is [(Rucod)₂(bt)₂], we have carried out the reaction of [Ru(Cl)₂(cod)(CH₃CN)₂] with Na[H₂B(bt)₂]. Interestingly, the reaction yielded agostic complexes [Ru(cod)L{κ³‐H,S,S′‐H₂B(bt)₂}], 4 and 5 ( 4 : L=Cl; 5 : L=C₇H₄NS₂). One of the key differences between 4 and 5 is the presence of different ancillary ligands at the metal center. The natural bond orbital (NBO) analysis of 1 and 2 shows that there is four lone pairs of electrons on each metal center with a significant amount of d character. Furthermore, the electronic structures and the bonding of these complexes have been established on the ground of quantum‐chemical calculations. All of the new compounds were characterized by IR, ¹H, ¹¹B, ¹³C NMR spectroscopy, and X‐ray crystallographic analysis.     

Identification of radical structures on 1‐pentamethylbenzyl‐3‐ethylimidazoliumsilver(I)bromide and 1,3‐bis(pentamethylbenzyl)‐4,5‐dimethylbenzimidazoliumsilver(I)bromide exposed to gamma rays: an EPR study

1‐Pentamethylbenzyl‐3‐ethylimidazoliumsilver(I)bromide and 1,3‐bis(pentamethylbenzyl)‐4,5dimethylbenzimidazoliumsilver(I)bromide and their Ag⁺ complexes were synthesized and their polycrystal forms were produced by recrystallization in dichloromethane/Et₂O solvent system. Structural determinations were carried out by ¹H NMR and ¹³C NMR with a Varian 400 NMR system using tetramethylsilane as internal standard and CDCl₃ as solvent. The disappearance of acidic N‐heterocyclic carbene proton showed the formation of Ag(I) complexes. Also, elemental analyses were carried out. Electron paramagnetic resonance (EPR) measurements were performed to determine the formed radical structure on the samples irradiated at the room temperature for 72 h by using ⁶⁰Co‐source with dose rate of 0.680 kGy. The EPR measurements were carried out in the temperature range of 200 K–450 K. Identical radicals were determined on the irradiated compounds. It was observed that the shapes of the spectra of the samples were independent of the temperature but, the resonance line intensities changed linearly with the temperature. Also, it was detected that the free radical on the 1‐pentamethylbenzyl‐3‐ethylimidazoliumsilver(I)bromide is not stable compared to that on the 1,3‐bis(pentamethylbenzyl)‐4,5dimethylbenzimidazoliumsilver(I)bromide. Copyright © 2016 John Wiley & Sons, Ltd.