Craig S. Wilcox

Ion pair binding by a urea in chloroform solution

Abstract An arylurea has been found to bind very strongly to ion pairs containing sulfonates, phosphates, and carboxylates in chloroform. The data suggest that complexation is due to hydrogen bonding between the urea and the anion. Applications to the design of molecular catalysts are envisioned.

Experimental and theoretical studies of substituent effects in hydrogen bond based molecular recognition of a zwitterion by substituted arylureas

Abstract Electron withdrawing groups have a strong effect on hydrogen bonding to aryl ureas. The effect of para substituents modestly exceeds the effect of meta substituents. Among common substituent parameters, σ − ( ϱ = 1.77, r 2 = 0.988) is found to be the best predictor for the observed effects of para substituents in aryl ureas. Semi-empirical and ab initio methods are used to calculate charge distributions in substituted benzene derivatives and in these ureas. A comparison of experimental and predicted (AM1, STO3G, 321-G ∗ , 631-G ∗∗ ) dipole moments of benzene derivatives is presented. It is shown that calculated surface electric potentials for these thioureas successfully predict the relative hydrogen bonded association energies.

Formation of Enolates

Enolates, or oxyallyl anions, are versatile reagents for the formation of α-substituted carbonyl compounds and are therefore important intermediates for the synthesis of complex molecules. The stereochemical outcome of an enolate reaction often depends on the geometry of the enolate and therefore the selective formation of enolates is a key step in many bond-forming processes.1

Stereoselective preparations of ribofuranosyl chlorides and ribofuranosyl acetates. Solvent effects and stereoselectivity in the reaction of ribofuranosyl acetates with trimethylallylsilane

Abstract The preparation of pure samples of each anomer of 2,3-O-isopropylidene-5-0-t-butyldimethylsilyl-D-ribofuranosyl chloride and the preparation of each corresponding furanosyl acetate is described. The reaction of these acetates with an allylsilane and zinc bromide is not stereospecific, but shows good stereoselectivity in some solvents.

Insight into the unusual reactions of stabilized phosphorus ylides with lactols. A specific intramolecular hydroxyl group effect leads to high z-selectivity.

Abstract In reactions with stabilized ylides, γ-lactols of ribo configuration afford 90% Z-olefins whereas γ-lactols of allo configuration afford predominantly E-olefins. Lactols of arabino configuration give intermediate results. The unusual results in the ribo series completely disappear on protection of the γ-hydroxyl group.

Synthesis of Dibenzazepinones by Palladium-Catalyzed Intramolecular Arylation of o-(2′-Bromophenyl)anilide Enolates

A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. The reactions were completed in 10 min at 100 °C with moderate to excellent yields. Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.

The molecular structure of an O-silyl ketene acetal

Abstract The structure of E-[[1-(1,1-dimethylethoxy)-1-propenyl]oxy](1,1-dimethylethyl)diphenyl silane ( 1 ), as determined by single crystal x-ray diffraction analysis, is described.

A Cdc25A antagonizing K vitamin inhibits hepatocyte DNA synthesis in vitro and in vivo.

Thioalkyl containing K vitamin analogs have been shown to be potent inhibitors of hepatoma cell growth and antagonizers of protein tyrosine phosphatase activity. We now show that they inhibit the activity of specific protein tyrosine phosphatases (PTP) in cell-free conditions in vitro, particularly the dual specificity phosphatase Cdc25A. Using primary cultures of adult rat hepatocytes that are in G0/G1 phase until stimulated into DNA synthesis by epidermal growth factor, we found that 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone or Compound 5 (Cpd 5) inhibited hepatocyte DNA synthesis and PTP activity in cell culture and in vivo after a two-thirds partial hepatectomy. We found a selective inhibition of Cdc25A activity in vitro, using both synthetic substrates and authentic cellular substrate, immunoprecipitated phospho-Cdk4. Intact Cpd 5-treated cells had decreased cellular Cdc25A activity and increased tyrosine phosphorylation of Cdk4, resulting in decreased phosphorylation of retinoblastoma (Rb). Loss of Cdk4 activity was confirmed using Cdk4 immunoprecipitates from either Cpd 5-treated or untreated cells and measuring its kinase activity using GST-Rb as target. We found a similar order of activity for inhibition of growth and Cdc25A activity using several thiol-containing analogs. Cdc25A inhibitors may thus be useful for defining biochemical pathways involving protein tyrosine phosphorylation that mediate cell growth inhibition.

Precipiton strategies applied to the isolation of α-substituted β-ketoesters

Abstract Diaryl alkene 1 Z is a ‘precipiton’, a protecting group that allows reaction products to be isolated by simple filtration. Here we illustrate the use of this protecting group for the preparation and isolation, without distillation or chromatography, of pure α-substituted β-ketoesters. The precipiton 1 Z was prepared in 43% overall yield. It is anticipated that development of precipiton-based syntheses will provide a new alternative for automated reaction product isolation that may be useful for bench-scale and process-scale chemical preparations.

Effect of citreoviridin and isocitreoviridin on beef heart mitochondrial ATPase

Citreoviridin is a toxic metabolite from fungus that has been shown to be an inhibitor of mitochondrial F1-ATPases. Studies of citreoviridin, however, have been compromised by the light-dependent isomerization that it undergoes. The isomerization is a potential source of extensive variability in the studies, if citreoviridin and isocitreoviridin have different kinetic effects and binding properties. Both citreoviridin and isocitreoviridin recently have been purified and have been shown to be stable in the dark. Using the purified isomers, the effects of both citreoviridin and isocitreoviridin on soluble and membrane-bound beef heart mitochondrial F1-ATPase activity were investigated. It was found that citreoviridin was an uncompetitive inhibitor of ATP hydrolysis, and a non-competitive inhibitor of ITP hydrolysis catalyzed by soluble F1-ATPase. Isocitreoviridin had no effect on the hydrolysis of either of the triphosphates catalyzed by soluble F1-ATPase. The inhibition constant, Ki for citreoviridin was determined as 4.5 microM for ATP hydrolysis. The inhibition constants Kii and Kis for ITP hydrolysis were determined as 4.3 and 1.03 microM, respectively. Citreoviridin was an uncompetitive inhibitor of ATP hydrolysis and a noncompetitive inhibitor of ATP synthesis catalyzed by membrane-bound F1-ATPase. The inhibition constant, Ki, for ATP hydrolysis was around 4 microM. For ATP synthesis the inhibition constants were determined as 0.12 and 0.16 microM for Kis and Kii, respectively, when ADP concentration was kept saturating. Isocitreoviridin had no effect on either activity of the membrane-bound enzyme.