Conversion of Allylic Alcohols into Allylic Nitromethyl Compounds via a Palladium-Catalyzed Solvolysis: An Enantioselective Synthesis of an Advanced Carbocyclic Nucleoside Precursor(1)

A two-step reaction sequence to homoallylic nitro compounds from allylic alcohols is presented. Ethoxy carbonylation of the alcohols with ethyl chloroformate provides the corresponding allylic ethyl carbonates in high yields. Exposure of these substrates to catalytic palladium(0) in CH(3)NO(2) initiates a reaction sequence, ionization-decarboxylation-nitromethylation, that culminates with the formation of nitroalkenes. The regio- and stereochemical outcomes of the nitromethyl allylation reaction can be explained by the behavior of the transient pi-allylpalladium complexes. This methodology serves as a centerpiece for the synthesis of an important carbocyclic nucleoside intermediate.     

Infrared-optical properties of vapour-deposited metal films

Spectroscopic infrared ellipsometry was applied to determine the optical constants of thin metal layers deposited on dielectric substrates such as glass or CaF(2). The layers were produced by evaporating gold or silver in a vacuum, and the coverage, that is the deposited mass per area, was chosen in the range 80-1200 mg m(-2) for gold, which refers to thicknesses in the lower nanometer range; in the case of the specifically lighter silver, about half the coverage was applied. At low coverage a metal island structure is obtained, which gives rise to surface-enhanced infrared absorption (SEIRA). Depending on the coverage, the deposited films exhibit either dielectric or metallic optical properties. Atomic force microscopy and conductivity measurements complement the spectroscopic observation.     

Comparisons of NMR spectral quality and success in crystallization demonstrate that NMR and X-ray crystallography are complementary methods for small protein structure determination

X-ray crystallography and NMR spectroscopy provide the only sources of experimental data from which protein structures can be analyzed at high or even atomic resolution. The degree to which these methods complement each other as sources of structural knowledge is a matter of debate; it is often proposed that small proteins yielding high quality, readily analyzed NMR spectra are a subset of those that readily yield strongly diffracting crystals. We have examined the correlation between NMR spectral quality and success in structure determination by X-ray crystallography for 159 prokaryotic and eukaryotic proteins, prescreened to avoid proteins providing polydisperse and/or aggregated samples. This study demonstrates that, across this protein sample set, the quality of a protein's [15N-1H]-heteronuclear correlation (HSQC) spectrum recorded under conditions generally suitable for 3D structure determination by NMR, a key predictor of the ability to determine a structure by NMR, is not correlated with successful crystallization and structure determination by X-ray crystallography. These results, together with similar results of an independent study presented in the accompanying paper (Yee, et al., J. Am. Chem. Soc., accompanying paper), demonstrate that X-ray crystallography and NMR often provide complementary sources of structural data and that both methods are required in order to optimize success for as many targets as possible in large-scale structural proteomics efforts.     

Controlling electron delocalisation in constrained N,N′-dimethyl-4,4′-bipyridinium dications

The synthesis is described of two N,N′-dimethyl-4,4′-bipyridinium salts for which the two pyridinium rings are connected via varying length alkoxy chains attached at the 3,3′-locations.     

Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction

SU11248 is a potent inhibitor of PDGFR, VEGFR, KIT, and Flt3, and is currently under Phase I clinical evaluation as an anticancer drug. A sensitive and specific analytical method for the quantitation of SU11248 and its metabolite in several monkey tissues (liver, kidney, brain and white fat) using LC-MS-MS following semi-automated liquid-liquid extraction (LLE) was developed and validated. Amounts of 50 mg of tissue were homogenized using an ultrasonic processor. After addition of the stable labelled internal standard (IS) and ammonium hydroxide (0.3%), samples were extracted with 2.5 ml of tert-butyl methyl ether. Following centrifugation, aliquots of 1.8 ml of the organic phase were transferred into a 96-well plate. The Packard Multiprobe II robotic liquid handler was used to perform all steps mentioned above. The organic phase was dried and the residue was reconstituted with 800 microl of 15 mM ammonium formate buffer solution (pH 3.25) using a Tomtec Quadra 96 workstation. Aliquots of 10 microl of the resulting solution were injected into the LC-MS-MS system. A Symmetry Shield C8 column (50 mm x 2.1 mm, 3.5 microm) was used to perform the chromatographic analysis. The mobile phase was 15 mM ammonium formate buffer solution (pH 3.25)-acetonitrile (74:26 (v/v)) with a flow-rate of 0.35 ml/min. Retention times of the metabolite and SU11248 were about 2.5 and 3.5 min, respectively. Total cycle time was 5 min. MS detection used the Applied Biosystems-MDS Sciex API 3000 with TurbolonSpray interface and multiple reaction monitoring (MRM) operated in positive ion mode. The method was validated for both compounds over the calibration range of about 2 and 2000 ng/g. The suitability and robustness of the method for in vivo samples were confirmed by analysis of monkey tissues from animals dosed with SU11248.     

Amine catalysis in phosphoryl transfer from 2,4-dinitrophenyl phosphate in aprotic and protic solvents

Reactions of tetra-n-butylammonium 2,4-dinitrophenyl hydrogen phosphate, (ArPH)^?(R₄N)⁺, in aprotic and protic solvents, in the absence and in the presence of alcohols or water, ROH, are compared with analogous reactions of the salt in the presence of hindered and unhindered amines, e.g. diisopropylethyl amine and quinuclidine. Similar studies are performed with the acid, ArPH₂, in the presence of variable amounts of amines. The release of phenol and the fate of the phosphorus compounds are followed by ¹H and ³¹P NMR spectrometry. In the absence of free unhindered amine, reactions of the monoanion are relatively slow, sensitive to steric hindrance in the alcohol, and incapable of producing t-butyl phosphate from t-butanol; reactions of the dianion are relatively fast, insensitive to steric hindrance in the alcohol, and produce t-butyl phosphate. In the presence of free unhindered amine, reactions of the monoanion are relatively fast but still sensitive to steric hindrance in the alcohol, and hence do not produce t-butyl phosphate. The intermediate CH(CH₂CH₂)₃⁺NP(O)(OH)O^? is detected in the presence of quinuclidine. Reactions of the dianion in the presence of unhindered amines are analogous to those observed in the presence of hindered amines. The uncatalyzed and the nucleophilic amine-catalyzed reactions of the monoanion are assumed to proceed via oxyphosphorane, P(5), intermediates. The dianion reactions, which are not susceptible to nucleophilic catalysis, are assumed to proceed via the monomeric metaphosphate ion intermediate, PO₃^?. Significant effects related to solvent properties are observed in these reactions.     

Mass spectra of perfluoroalkyl and perfluoroalkylether nitriles and acyl halides

Electron impact fragmentation patterns were obtained for perfluoroalkylether nitriles, C,F,O[CF(CF₃)CFIO]ICF(CF₃)CN (x = 1 and 2), perfluoroalkylether acyl halides, CSF,OCF(CF,)-CF₂OCF(CF₃)COX (X = F and Cl), n-perfluorooctanonitrile and n-perfiuorooctanoyl chloride. The perfluoroalkyl and perfluoroalkylether nitriles afforded ions characteristic of the nitrile function. The major fragment from the acyl chlorides was the [COClJ]+ ion; the presence of chlorine was evidenced also by rearrangement ions of the general form [R_fCl] t. The perfluoroalkylether compounds appeared to undergo a typical fragmentation governed by the cleavage of the carbon-oxygen bond.     

Enzymatic surface modification of Kevlar fibers

Horseradish peroxidase catalyzed grafting of acrylamide (AM) onto Kevlar fibers has been studied. The modified fiber has been characterized with scanning electron microscopy (SEM), elemental analysis and the grafting yield. From the SEM micrographs, the surface of the grafted Kevlar fiber is rougher than that of the untreated fiber, and the elemental analysis indicated that the nitrogen content of the treated fibers is higher than that of the untreated fiber. All the results suggested that AM must have been grafted onto the Kevlar surface through HRP-mediated radical initiated grafting reaction. The probably mechanism of HRP catalyzed grafting of AM onto Kevlar surface is proposed.     

Total synthesis of (+/-)-perophoramidine

The first total synthesis of racemic perophoramidine is described. The key step features the highly stereoselective introduction of the vicinial quaternary centers via base-promoted carbon-carbon bond formation between a 3-alkylindole and a 3-bromo-3-alkylindolin-2-one. This transformation presumably proceeds through a conjugate addition or Diels-Alder cycloaddition of the 3-alkylindole with a 3-alkylindol-2-one intermediate.     

Host-guest interactions template: the synthesis of a [3]catenane

Formation of a [3]catenane containing dibenzo-24-crown ether wheels and a large dipyridiniumethane ring is templated by formation of a host-guest adduct between the [3]catenane and the external crown ether.