Enzyme-catalyzed synthesis of furanosyl nucleotides

A bacterial alpha-d-glucopyranosyl-1-phosphate thymidylyltransferase was found to couple four hexofuranosyl-1-phosphates, as well as a pentofuranosyl-1-phosphate, with deoxythymidine 5'-triphosphate, providing access to furanosyl nucleotides. The enzymatic reaction mixtures were analyzed by electrospray ionization mass spectrometry and NMR spectroscopy to determine the anomeric stereochemistry of furanosyl nucleotide products. This is the first demonstration of a nucleotidylyltransferase discriminating between diastereomeric mixtures of sugar-1-phosphates to produce stereopure, biologically relevant furanosyl nucleotides.     

Effect of introduced charge in cellulose gels on surface interactions and the adsorption of highly charged cationic polyelectrolytes

The interaction between cellulose surfaces in aqueous solution has been measured using colloidal probe microscopy. Cellulose thin films with varying charge through carboxyl group substitution were used in this study with the surface forces fit to DLVO theory. It was found that the surface potential increased, as expected, with increasing carboxyl substitution. Furthermore, for a given degree of substitution, the surface potential increased as a function of increasing pH. At low pH, the surface forces interaction were attractive and could be fit to the non-retarded Hamaker equation using a constant of 3 x 10(-21) J. At pH greater than 5, the force interactions were monotonically repulsive, regardless of the ionic strength of the solution for all charge densities of the cellulose thin films. The adsorption of polyDADMAC to these charged cellulose films was also investigated using the quartz crystal microbalance. It was found that for the low charge film, a low surface excess of PDADMAC was sensed and that the adsorbed conformation was essentially flat. However for the higher charged cellulose film, a spontaneous de-swelling was observed resulting in no possibility of quantitatively determining the sensed mass using QCM.     

Mechanistic study of asymmetric oxidative biaryl coupling: evidence for self-processing of the copper catalyst to achieve control of oxidase vs oxygenase activity

Copper(I) and copper(II) 1,5-diaza-cis-decalin complexes [(N2)Cu] are effective precatalysts for aerobic oxidative coupling of naphthol substrates. Mechanistic studies, however, reveal that these complexes are not the reactive form of the catalyst under steady-state conditions. Rather, the active catalyst forms in a presteady-state self-processing step that involves oxygenation of the naphthol substrate. The oxygenated substrate, NapHOX, serves as a cofactor that combines with the (N2)Cu complexes to achieve highly selective, steady-state oxidase reactivity (aerobic oxidative biaryl coupling).     

A simple DNase model system comprising a dinuclear Zn(II) complex in methanol accelerates the cleavage of a series of methyl aryl phosphate diesters by 10(11)-10(13)

The di-Zn(II) complex of 1,3-bis[ N1, N1'-(1,5,9-triazacyclododecyl)]propane with an associated methoxide ( 3:Zn(II) 2: (-)OCH 3) was prepared and its catalysis of the methanolysis of a series of fourteen methyl aryl phosphate diesters ( 6) was studied at s (s)pH 9.8 in methanol at 25.0 +/- 0.1 degrees C. Plots of k obs vs [ 3:Zn(II) 2: (-)OCH 3] free for all members of 6 show saturation behavior from which K(M) and kcat (max) were determined. The second order rate constants for the catalyzed reactions (kcat (max)/K(M)) for each substrate are larger than the corresponding methoxide catalyzed reaction (k 2 (-OMe)) by 1.4 x 10(8) to 3 x 10 (9)-fold. The values of k cat (max) for all members of 6 are between 4 x 10(11) and 3 x 10(13) times larger than the solution reaction at s (s)pH 9.8, with the largest accelerations being given for substrates where the departing aryloxy unit contains ortho-NO 2 or C(O)OCH 3 groups. Based on the linear Br?nsted plots of k cat (max) vs s (s)pKa of the phenol, beta lg values of -0.57 and -0.34 are determined respectively for the catalyzed methanolysis of "regular" substrates that do not contain the ortho-NO 2 or C(O)OCH 3 groups, and those substrates that do. The data are consistent with a two step mechanism for the catalyzed reaction with rate limiting formation of a catalyst-coordinated phosphorane intermediate, followed by fast loss of the aryloxy leaving group. A detailed energetics calculation indicates that the catalyst binds the transition state comprising [CH 3O (-): 6], giving a hypothetical [ 3:Zn(II) 2:CH 3O (-): 6] complex, by -21.4 to -24.5 kcal/mol, with the strongest binding being for those substrates having the ortho-NO 2 or C(O)OCH 3 groups.     

Carbon-nitrogen bond formation involving well-defined aryl-copper(III) complexes

Carbon-heteroatom bond formation from copper(III) is commonly invoked as a key step in catalytic reactions, including the century-old Ullmann reactions. Well-defined examples of such reactions have never been observed. Here, we demonstrate that a well-defined Cu(III)-aryl species reacts with a variety nitrogen nucleophiles to undergo facile carbon-nitrogen bond formation.     

Copper-catalyzed aerobic oxidative amidation of terminal alkynes: efficient synthesis of ynamides

A copper-catalyzed method for the preparation of ynamides has been identified that proceeds via aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles, including cyclic carbamates, amides and ureas, and N-alkyl-arylsulfonamides and indoles.     

Emptiness Formation Probability

We consider products of random matrices that are small, independent identically distributed perturbations of a fixed matrix \({\mathcal{T}_0}\). Focusing on the eigenvalues of \({\mathcal{T}_0}\) of a particular size we obtain a limit to a SDE in a critical scaling. Previous results required \({\mathcal{T}_0}\) to be a (conjugated) unitary matrix so it could not have eigenvalues of different modulus. From the result we can also obtain a limit SDE for the Markov process given by the action of the random products on the flag manifold. Applying the result to random Schrödinger operators we can improve some results by Valko and Virag showing GOE statistics for the rescaled eigenvalue process of a sequence of Anderson models on long boxes. In particular, we solve a problem posed in their work.     

Insertion of molecular oxygen into a palladium-hydride bond: computational evidence for two nearly isoenergetic pathways

The reaction of a palladiumII-hydride species with molecular oxygen to form palladiumII-hydroperoxide has been proposed as a key step in Pd-catalyzed aerobic oxidation reactions. We recently reported one of the first experimental precedents for such a step (Angew. Chem., Int. Ed. 2006, 45, 2904-2907). DFT calculations have been used to probe the mechanism for this reaction, which consists of formal insertion of O2 into the palladium-hydride bond of trans-(NHC)2Pd(H)OAc (NHC = N-heterocyclic carbene). Four different pathways were considered: (1) hydrogen atom abstraction (HAA) of the Pd-H bond by molecular oxygen, (2) reductive elimination of HX followed by oxygenation of Pd0 and protonolysis of the (eta2-peroxo)-PdII species, (3) oxygenation of palladiumII-hydride with subsequent reductive elimination of the O-H bond from an eta2-peroxo-PdIV center, and (4) formation of a cis-superoxide adduct of the palladium-hydride species followed by O-H bond formation via hydrogen atom migration. The calculations reveal that pathways 1 and 2 are preferred energetically, and both pathways exhibit very similar kinetic barriers. This result suggests that more than one pathway is possible for catalyst reoxidation in Pd-catalyzed aerobic oxidation reactions.     

The dinuclear Zn(II) complex catalyzed cyclization of a series of 2-hydroxypropyl aryl phosphate RNA models: progressive change in mechanism from rate-limiting P-O bond cleavage to substrate binding

A methoxide-bridged dinuclear Zn(II) complex of 1,3-[N,N'-bis(1,5,9-triazacyclododecane)]propane (1-Zn(II)2:(-OCH3)) was prepared, and its catalysis of the cyclization of a series of 2-hydroxypropyl aryl phosphates (4a-g) was investigated in methanol at pH 9.8, T = 25degreesC by stopped-flow spectrophotometry. An X-ray diffraction structure of the hydroxide analogue of 1-Zn(II)2:(-OCH3), namely 1-Zn(II)2:(-OH), reveals that each of the Zn(II) ions is coordinated by the three N's of the triazacyclododecane units and a bridging hydroxide. The cyclizations of substrates 4a-g reveal a progressive change in the observed kinetics from Michaelis-Menten saturation kinetics for the poorer substrates (4-OCH3 (4g); 4-H (4f); 3-OCH3 (4e); 4-Cl (4d); 3-NO2, (4c)) to second-order kinetics (linear in 1-Zn(II)2:(-OCH3)) for the better substrates (4-NO2,3-CH3 (4b); 4-NO2, (4a)). The data are analyzed in terms of a multistep process whereby a first formed complex rearranges to a reactive complex with a doubly activated phosphate coordinated to both metal ions. The kinetic behavior of the series is analyzed in terms of change in rate-limiting step for the catalyzed reaction whereby the rate-limiting step for the poorer substrates (4g-c) is the chemical step of cyclization of the substrate, while for the better substrates (4b,a) the rate-limiting step is binding. The catalysis of the cyclization of these substrates is extremely efficient. The kcat/KM values for the catalyzed reactions range from 2.75 x 10(5) to 2.3 x 10(4) M-1 s-1, providing an acceleration of 1 x 10(8) to 4 x 10(9) relative to the methoxide reaction (k2OCH3, which ranges from 2.6 x 10(-3) to 5.9 x 10(-6) M-1 s-1 for 4a-g). At a pH of 9.8 where the catalyst is maximally active, the acceleration for the substrates ranges from (1 - 4) x 10(12) relative to the background reaction at the same pH. Detailed energetics calculations show that the transition state for the catalyzed reaction comprising 1-Zn(II)2, methoxide, and 4 is stabilized by about -21 to -23 kcal/mol relative to the transition state for the methoxide reaction. The pronounced catalytic activity is attributed to a synergism between a positively charged catalyst that has high affinity for the substrate and for the transition state for cyclization, and a medium effect involving a reduced polarity/dielectric constant that complements a reaction where an oppositely charged reactant and catalyst experience charge dispersal in the transition state.