Synthesis of imidazoles as novel emivirine and S‐DABO analogues

5‐Alkyl‐4‐benzyl‐1,3‐dihydroimidazol‐2‐ones ( 3a‐d ) and 5‐alkyl‐4‐benzyl‐1,3‐dihydroimidazole‐2‐thiones (7a‐d) were prepared via Dakin West reaction on DL‐phenylalanine with the appropriate aliphatic acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate. Compounds 3a‐d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a‐d which were considered analogues of Emivirine with deletion of carbonyl group at the 4‐position. Alkylation of 7a‐d afforded the corresponding S‐alkylated derivatives 8a‐p which in a similar way were considered analogues of S‐DABO. However all the imidazole derivatives were devoid of activity against HIV.     

Thermolysis of N-allylic 1,2,4-triazoles

A number of 4-allylic substituted 3,5-diphenyl-4H-1,2,4-triazoles were thermolyzed at 315–320° in evacuated glass ampoules. The main reaction in the melt was rearrangement to the corresponding 1-substituted triazoles, which appeared to proceed via competing S_N2 and S_N2′ mechanisms. The allylic systems were observed to undergo [2,3]-allyl walk reactions between the 1- and 2-ring positions. Allyl to vinyl isomerization also took place. Substitution of the allylic moiety increased the rate of reaction but decreased the rate of isomerization of allylic to the vinylic substituted triazoles. The 4-vinyl substituted triazoles were inert under the reaction conditions. Some triazoles were converted into substituted pyridines. This was proposed to proceed via nitrogen extrusion and formation of a 1,3-dipolar intermediate (nitrile ylide) which added intramolecularly to the allyl moiety and subsequently aromatized to the pyridine.     

Model studies of the chemisorption of hydrogen and oxygen on nickel surfaces

Atomic chemisorption of hydrogen and oxygen on the Ni(100) surface has been studied using an Effective Core Potential (ECP) approach described in a previous paper. Clusters of up to 50 nickel atoms have been used to model the surface. The computed chemisorption energies are 62 kcal/mol (exp. 63 kcal/mol) for hydrogen and 106 kcal/mol (exp. 115–130 kcal/mol) for oxygen. Correlating the adsorbate and the cluster-adsorbate bonds is extremely important for obtaining accceptable results, particularly for oxygen. Reasonable convergence of chemisorption energies is obtained with 40–50 cluster atoms for both hydrogen and oxygen. For hydrogen the addition of a third cluster layer stabilizes the results considerably. Both hydrogen and oxygen are adsorbed at (or close to) the four-fold hollow site. The calculated barriers for surface migration are also in good agreement with the experimental estimates. The calculated equilibrium heights above the surface are on the other hand too high compared with experiments. This disagreement is believed to be due to core-valence correlation effects, which are not incorporated in the present ECP. The cluster convergence for the height above the surface is much slower than for the chemisorption energy.     

Synthesis of part of a proposed insulin second messenger glycosylinositol phosphate and the inner core of glycosylphosphatidylinositol anchors

Synthesis of 6-O-(2-amino-2-deoxy--D-glucopyranosyl)-D-myo-inositol 1-phosphate, an inner core structure found in various glycosylphosphatidylinositols, and the corresponding 1,2-cyclic phosphate, proposed as part of an insulin second messenger glycosylinositol phosphate, is described. Chirality in the inositol part of the molecule was achieved by the use of a known D-camphor acetal intermediate. The glycosylation used 4-O-allyl-2-azido-3,6-di-O-benzyl-2-deoxy--D-glucopyranosyl fluoride as glycosyl donor. The allyl group can be chemoselectively removed, opening a route to oligosaccharides bound to the 4-position of the glucosamine unit. The phosphorylation was accomplished by the phosphoramidate procedure.     

The bonding in second row transition metal dihydrides,difluorides and dichlorides

Summary The dihydrides, the difluorides and the dichlorides of the second row transition metal atoms from yttrium to palladium have been studied with methods including electron correlation of all valence electrons. Comparisons are made to the previously studied corresponding diatomic systems. It is found that the general trends of the binding energies of the second hydride and halide remain the same as in the diatomic hydrides and halides. The second ligand binding energies for the dihalides thus vary much more than for the dihydrides. This is due to important attractive effects between the halide lone-pairs and empty 4d-orbitals to the left and strong repulsions towards occupied 4d-orbitals to the right. For some systems the second ligand binds much more than the first ligand, as for RuF₂ where the difference is 34.3 kcal/mol, whereas for other systems the reverse is true, as for PdCl₂ where the first ligand binds more than the second with 20.4 kcal/mol. The results can be explained by strong ligand field effects and differences in the atomic spectra.     

Seeding and the Non-Hydrolytic Sol-Gel Synthesis of ZrW2O8 and ZrMo2O8

The unseeded non-hydrolytic sol-gel synthesis of ZrW₂O₈ and ZrMo₂O₈ produces trigonal ZrM₂O₈ (M = W, Mo) at 740 and 300–400°C, respectively. Cubic ZrW₂O₈ can be prepared using non-hydrolytic sol-gel methods by seeding with small amounts of preprepared cubic material, and the formation of the trigonal polymorph can be suppressed completely. Seeds with a small particle size are necessary for the preparation of cubic ZrW₂O₈. In contrast, seeding of ZrMo₂O₈ gels with either cubic ZrMo₂O₈ or cubic ZrW₂O₈ only lowers the temperature at which the trigonal phase crystallizes.     

The rate of homolysis of adducts of peroxynitrite to the C=O double bond.

Nucleophilic addition of the peroxynitrite anion, ONOO(-), to the two prototypical carbonyl compounds, acetaldehyde and acetone, was investigated in the pH interval 7.4-14. The process is initiated by fast equilibration between the reactants and the corresponding tetrahedral adduct anion, the equilibrium being strongly shifted to the reactant side. The adduct anion also undergoes fast protonation by water and added buffers. Consequently, the rate of the bimolecular reaction between ONOO(-) and the carbonyl is strongly dependent on the pH and on the concentration of the buffer. The pK(a) of the carbonyl-ONOO adduct was estimated to be approximately 11.8 and approximately 12.3 for acetone and acetaldehyde, respectively. It is shown that both the anionic and the neutral adducts suffer fast homolysis along the weak O-O bond to yield free alkoxyl and nitrogen dioxide radicals. The yield of free radicals was determined to be about 15% with both carbonyl compounds at low and high pH, while the remainder collapses to molecular products in the solvent cage. The rate constants for the homolysis of the adducts vary from ca. 3 x 10(5) to ca. 5 x 10(6) s(-1), suggesting that they cannot act as oxidants in biological systems. This small variation around a mean value of about 10(6) s(-1) suggests that the O-O bond in the adduct is rather insensitive to its protonation state and to the nature of its carbonyl precursor. An overall reaction scheme was proposed, and all the corresponding rate constants were evaluated. Finally, thermokinetic considerations were employed to argue that the formation of dioxirane as an intermediate in the reaction of ONOO(-) with acetone is an unlikely process.     

ABSORPTION SPECTRAL SHIFTS OF CAROTENOIDS RELATED TO MEDIUM POLARIZABILITY

Abstract–Solvent induced absorption spectral shifts of the electronic transition from ground 1 A_g state to the excited 1B_u state in carotenoids have been studied. It is shown that the shift depends only on dispersion interactions in non-polar solvents. In polar media there is just a small extra contribution to the red-shift, due to other forms of interactions. The spectral shifts are well described by the theory, which expresses the shift relative to the gas phase value, as a function of solvent polarizability. The main conclusion is that the dominating mechanism behind the large red-shifted absorbance of carotenoids in the proteinacous environment, in vivo, is the mutual polarizability interactions between the carotenoids and the surrounding medium. The solution-phase values of the dipole moments of the lA_g to 1B_u transitions and the differences of isotropic polarizability between 1B_u and lA_g states of carotenoids in non-polar solvents are calculated and found to be around 13 D and 360 ų respectively. From the great overlap of absorption spectra between carotenoids in quinoline and carotenoids in vivo in purple bacterial antenna complexes, it can be expected that the carotenoids are surrounded by several aromatic amino acids in vivo. Comparisons have been done between the exicted states in carotenoids and in linear conjugated polyenes.     

Ligand-protein docking using a quantum stochastic tunneling optimization method

A novel hybrid optimization method called quantum stochastic tunneling has been recently introduced. Here, we report its implementation within a new docking program called EasyDock and a validation with the CCDC/Astex data set of ligand-protein complexes using the PLP score to represent the ligand-protein potential energy surface and ScreenScore to score the ligand-protein binding energies. When taking the top energy-ranked ligand binding mode pose, we were able to predict the correct crystallographic ligand binding mode in up to 75% of the cases. By using this novel optimization method run times for typical docking simulations are significantly shortened.     

Regiospecific alkylation of tetronic acids : Formation of 4-alkoxy-5H-furan-2-ones and 2-alkoxy-5H-furan-4-ones

2-Alkoxy-5$\text{H}$-furan-4-ones (7,8) and 4-alkoxy-5$\text{H}$-furan-2-ones (4,5) were prepared regiospecifically and in high yields from tetronic acids (4-hydroxy-5$\text{H}$-furan-2-ones) (2) in the first case by acetylating the 4-OH group and then reacting with trialkyloxonium tetrafluoroborate, and in the second case by alkylating tetrabutylammonium tetronates with dialkyl sulfate, respectively. Direct alkylation of tetronic acids with trialkyloxonium tetrafluoroborate gave in four cases regiospecific 2-O-alkylation, in one case 4-O-alkylation and in two other cases mixtures of 2- and 4-alkoxy derivatives.