Design and synthesis of a diverse morpholine template library

Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.     

The millimeter-wave spectrum of chlorine nitrate (ClONO2): The ν6 vibrational state

The pure rotational spectrum of chlorine nitrate in its v₆ = 1 excited vibrational state has been studied. A total of 2901 lines, with K_a extending to 33 in the ³⁵Cl isotopologue and 30 in the ³⁷Cl isotopologue, respectively, have been recorded and assigned. This analysis, along with our recently reported study of the ν₅/ν₆ν₉ dyad and the improved energy levels of ν₉ reported in this paper, should make possible accurate simulation of the corresponding ν₆ band and its complex hot band structure near 435 cm⁻¹.     

A modified route to unsymmetrically substituted triphenylenes,new functionalised derivatives and twins,and the smallest reported triphenylene mesogen

ABSTRACT

We report the unexpected observation of columnar mesophase formation in a simple 2,7-dibromotetramethoxytriphenylene – by far the most lightly substituted discotic mesogen in this class. This derivative was prepared alongside the 3,6-dibromotriphenylene isomer to demonstrate an alternative, modified synthetic strategy that permits late-stage interchange of alkyl chain substituents. The new method is employed alongside the original route to deliver several new materials, including a conjugated ferrocene–triphenylene–ferrocene triad, a BODIPY–triphenylene–BODIPY triad and a new nematic twin linked through imine bridges.     

Efficient syntheses of 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-dioxide

Expeditious routes to 1,2,3,4,4a,5-hexahydro-pyrazino[2,1-c][1,4]benzothiazine-6,6-dioxide, a methylenesulfone-constrained arylpiperazine, have been developed. The key step forms the tricyclic system in a cascade of reactions via a 1,4-addition, nitrogen alkylation, and aromatic substitution sequence.     

Measuring the intra-individual variability of the plasma proteome in the chicken model of spontaneous ovarian adenocarcinoma

The domestic chicken (Gallus domesticus) has emerged as a powerful experimental model for studying the onset and progression of spontaneous epithelial ovarian cancer (EOC) with a disease prevalence that can exceed 35% between 2 and 7 years of age. An experimental strategy for biomarker discovery is reported herein that combines the chicken model of EOC, longitudinal plasma sample collection with matched tissues, advanced mass spectrometry-based proteomics, and concepts derived from the index of individuality (Harris, Clin Chem 20: 1535–1542, 1974). Blood was drawn from 148 age-matched chickens starting at 2.5 years of age every 3 months for 1 year. At the conclusion of the 1 year sample collection period, the 73 birds that remained alive were euthanized, necropsied, and tissues were collected. Pathological assessment of resected tissues from these 73 birds confirmed that five birds (6.8%) developed EOC. A proteomics workflow including in-gel digestion, nanoLC coupled to high-performance mass spectrometry, and label-free (spectral counting) quantification was used to measure the biological intra-individual variability (CV_W) of the chicken plasma proteome. Longitudinal plasma sample sets from two birds within the 73-bird biorepository were selected for this study; one bird was considered “healthy” and the second bird developed late-stage EOC. A total of 116 proteins from un-depleted plasma were identified with 80 proteins shared among all sample sets. Analytical variability (CV_A) of the label-free proteomics workflow was measured using a single plasma sample analyzed five times and was found to be ≥CV_W in both birds for 16 proteins (20%) and in either bird for 25 proteins (31%). Ovomacroglobulin (ovostatin) was found to increase (p < 0.001) over a 6 month period in the late-stage EOC bird providing an initial candidate protein for further investigation.     

Marine mammal blubber reference and control materials for use in the determination of halogenated organic compounds and fatty acids

The National Institute of Standards and Technology (NIST) has a diverse collection of control materials derived from marine mammal blubber, fat, and serum. Standard Reference Material (SRM) 1945 Organics in Whale Blubber was recertified for polychlorinated biphenyl (PCB) congeners, organochlorine pesticides, and polybrominated diphenyl ether (PBDE) congeners. SRM 1945 has also been assigned mass fraction values for compounds not frequently determined in marine samples including toxaphene congeners, coplanar PCBs, and methoxylated PBDE congeners which are natural products. NIST also has assigned mass fraction values, as a result of interlaboratory comparison exercises, for PCB congeners, organochlorine pesticides, PBDE congeners, and fatty acids in six homogenate materials produced from marine mammal blubber or serum. The materials are available from NIST upon request; however, the supply is very limited for some of the materials. The materials include those obtained from pilot whale blubber (Homogenates III and IV), Blainville’s beaked whale blubber (Homogenate VII), polar bear fat (Homogenate VI), and California sea lion serum (Marine Mammal Control Material-1 Serum) and blubber (Homogenate V).     

Preparation and evaluation of solid-phase microextraction fibres based on functionalized latex nanoparticle coatings for trace analysis of inorganic anions

The use of a functionalized latex nanoparticle coating as a new sorbent phase for solid-phase microextraction (SPME) was examined. By means of electrostatic absorption onto ionized silanol groups, a fused-silica rod was coated with polymeric nanoparticles functionalized with quaternary ammonium groups. Optimum conditions for the preparation of the coated fibre are presented. The fibre was used for the extraction of a mixture of seven anions from water samples which are analysed by coupling the SPME fibre to an ion chromatographic system via a special interface. The results obtained proved the suitability of this novel coating as a new SPME fibre. A linear calibration for the target analytes was achieved over the concentration range from 5 μg L⁻¹ to 5 mg L⁻¹ (r² > 0.988), while limits of detection for these ions were all below 3.7 μg L⁻¹ (S/N = 3). The reproducibility of a single fibre (n = 4) under similar conditions was between 7 and 12%, while the fibre to fibre reproducibility (n = 5) was between 8.9 and 14%.     

Total synthesis of clathculins A and B

Clathculins A and B represent a new class of vic-diamine alkaloids containing a PA2 unit as the basic structure. We report the first total syntheses of 1 and 2, which confirm the assigned structure of each. Dependence of their NMR spectroscopic behavior as a function of protonation state has been observed.     

On the mechanisms involved in the recovery of envelope information from temporal fine structure

Three experiments were designed to provide psychophysical evidence for the existence of envelope information in the temporal fine structure (TFS) of stimuli that were originally amplitude modulated (AM). The original stimuli typically consisted of the sum of a sinusoidally AM tone and two unmodulated tones so that the envelope and TFS could be determined a priori. Experiment 1 showed that normal-hearing listeners not only perceive AM when presented with the Hilbert fine structure alone but AM detection thresholds are lower than those observed when presenting the original stimuli. Based on our analysis, envelope recovery resulted from the failure of the decomposition process to remove the spectral components related to the original envelope from the TFS and the introduction of spectral components related to the original envelope, suggesting that frequency- to amplitude-modulation conversion is not necessary to recover envelope information from TFS. Experiment 2 suggested that these spectral components interact in such a way that envelope fluctuations are minimized in the broadband TFS. Experiment 3 demonstrated that the modulation depth at the original carrier frequency is only slightly reduced compared to the depth of the original modulator. It also indicated that envelope recovery is not specific to the Hilbert decomposition.