MAOS ls for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.     

The photoelectron spectrum and molecular geometry of bicyclo[2.1.1]hexane

The He(I) photoelectron spectrum of bicyclo[2.1.1]hexane shows excellent correlation with a theoretical spectrum based on the eigenvalues obtained in an ab initio calculation at the theoretical molecular geometry. By contrast, a calculation performed at the experimental geometry exhibits an effect of enhanced ring strain in showing a first ionization energy which is considerably lower than the experimental value. This observation offers experimental support for the recent claim that the published structure for bicyclo [2.1.1]hexane based on electron-diffraction measurements is incorrect. It also accounts for inconsistencies observed in the calculated values of some spin—spin coupling constants for substituted bicyclo[2.1.1]hexanes.     

Stability and visible absorption of glutamic acid complexes with uranyl and neodymium ions

Summary The stability constants of the complexes of uranyl and neodymium ions with glutamic acid are determined pH-metrically in 0.1 M NaClO₄ solution at 25° C. In both cases protonated complexes are formed in significant concentrations. A new MA complex is found in the uranyl glutamic acid system. In accordance with this investigation a graphical treatment of the visible spectral data gives the molar absorption coefficients of both MA and MHA species.

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Untersuchung der Stabilität und der Absorption im Sichtbaren von Uranyl- und Neodymkomplexen von Glutaminsäure

Zusammenfassung Die Stabilitätskonstanten der Uranylund Neodymkomplexe von Glutaminsäure wurden pH-metrisch in 0,1 M NaClO₄-Lösung bei 25° C bestimmt. In beiden Fällen werden in beträchtlichen Konzentrationen protonierte Komplexe gebildet. Ein neuer MA-Komplex wurde im Uranyl-Glutaminsäure-System gefunden. Eine graphische Behandlung der spektralen Daten im sichtbaren Bereich ergab die molaren Absorptionskoeffizienten für die MA- und MHA-Komplexe.

     

The effects of substrate orientation on the mechanism of a phosphotriesterase

While the underlying chemistry of enzyme-catalyzed reactions may be almost identical, the actual turnover rates of different substrates can vary significantly. This is seen in the turnover rates for the catalyzed hydrolysis of organophosphates by the bacterial phosphotriesterase OpdA. We investigate the variation in turnover rates by examining the hydrolysis of three classes of substrates: phosphotriesters, phosphothionates, and phosphorothiolates. Theoretical calculations were used to analyze the reactivity of these substrates and the energy barriers to their hydrolysis. This information was then compared to information derived from enzyme kinetics and crystallographic studies, providing new insights into the mechanism of this enzyme. We demonstrate that the enzyme catalyzes the hydrolysis of organophosphates through steric constraint of the reactants, and that the equilibrium between productively and unproductively bound substrates makes a significant contribution to the turnover rate of highly reactive substrates. These results highlight the importance of correct orientation of reactants within the active sites of enzymes to enable efficient catalysis.     

Anionic O --> alpha- and beta-vinyl carbamoyl translocation of 2-(O-carbamoyl) stilbenes

[reaction: see text] New anionic oxygen to alpha- and beta-vinyl carbamoyl migration reactions, 17a and 26a-c --> 18 and 30a-c, proceed under LDA-mediated conditions leading stereoselectively to highly substituted stilbenes bearing electron-donating and -withdrawing substituents. Compounds 17a and 26a-c are prepared by combination of efficient, directed ortho metalation, Sonogashira, and Suzuki-Miyaura cross-coupling procedures.     

Synthesis of proposed oxidation-cyclization-methylation intermediates of the coumarin antibiotic biosynthetic pathway

[structure: see text] A chemoenzymatic synthesis was described to prepare proposed oxidation-cyclization-methylation intermediates of the coumarin antibiotic biosynthetic pathway. The successful synthesis of these fragile molecules relies heavily on mild enzymatic deprotection and efficient enzymatic kinetic resolution to minimize epimerization, decomposition, multiple orthogonal protections, and retro aldol reactions often encountered in their chemical synthesis.     

Morin transition suppression in Polycrystalline 57Hematite (α-Fe2O3) exposed to 56Fe(II)

We used the isotope selectivity of ⁵⁷Fe Mössbauer spectroscopy to investigate changes in the magnetic properties of polycrystalline hematite exposed to ferrous iron (Fe(II)). We found that sorption of ⁵⁶Fe(II), followed by interfacial electron exchange, alters the bulk magnetic properties of ⁵⁷hematite. After reaction with ⁵⁶Fe(II), we observed partial suppression of the Morin transition of ⁵⁷hematite to below 13 K. This is significantly lower than the Morin temperature (T _M) of ～230 K measured for isotopically enriched polycrystalline ⁵⁷hematite, as well as the T _M of 264?±?2 K reported for normal polycrystalline hematite.     

Ligand-free copper-catalyzed arylation of amidines

Copper-catalyzed cross-coupling reactions of amidine salts were utilized to synthesize monoarylated amidines in moderate to high yields with ligand-free conditions. DMF was the superior solvent for the N-arylation of benzamidines, while MeCN was used in the formation of N-aryl amidines in moderate to high yield.     

Should dithiophosphinate esters function as RAFT agents?

[graph: see text] High-level ab initio calculations indicate that *CH3 addition to the sulfur center of S=P(Z)(Z')SCH3 (Z,Z' = CH3, CN, OCH3, Ph) is considerably less exothermic than addition to the corresponding RAFT agents, S=C(Z)SCH3. This suggests that dithiophosphinate esters may have only limited use in controlling free-radical polymerization, but should make excellent radical chain carriers in organic synthesis. The results cast doubt on the notion that phosphoranyl radicals are more "intrinsically" stabilized than carbon-centered radicals.     

An evaluation of the performance of porous polymer monolith assisted electrospray

A novel electrospray interface, which has distinct advantages over conventional pulled silica emitters, has been developed. This novel interface can be easily fabricated by forming a porous polymer monolith (PPM) at the end of a fused-silica capillary that facilitates a stable electrospray over a wide range of flow rates with only a modest increase in back-pressure. A comparison was made between the PPM-assisted electrospray and a commercial nanosprayer in terms of sensitivity, stability and robustness. A PPM-filled electrospray tip produced a day-to-day signal variation of 23% relative standard deviation (RSD) over a 3-day period when spraying a 1.0 microM test peptide solution. Furthermore, three different capillaries fabricated by the same process produced a signal variation of 17% RSD, indicating that the fabrication process shows good reproducibility. The multiple flow paths of the PPM function to split the flow and reduce clogging. Even following the accumulation of debris after prolonged use, a stable spray could still be generated with the PPM-filled capillary while the commercial nanosprayer ceased to function properly. In terms of sensitivity, PPM-assisted electrospray showed an enhancement in sensitivity at infusion flow rates between 100 to 1000 nL/min while commercial nanosprayers performed slightly better at flow rates below 100 nL/min. A sample purification step can be combined with the PPM-assisted sprayer, using the PPM as a stationary phase to desalt and preconcentrate samples prior to mass spectrometric detection.