Increase In Steric Bulk Research Articles

Triphenylene Analogues with B2N2C2 Cores: Synthesis, Structure, Redox Behavior, and Photophysical Properties

A series of alkyl (1-3), aryl (6), and benzo-annulated (4, 5) heteroaromatic triphenylene analogues with B(2)N(2)C(2) cores have been synthesized via chelation of pyridazine derivatives using difunctional Lewis acidic diborabiphenyl precursors. In contrast to triphenylene, NICS(1) calculations on 1 suggested high aromaticities for the central (-11.3 ppm) and outer borabenzene rings (-7.7 ppm), along with nonaromatic behavior for the pyridazine ring (-0.7 ppm). Crystal structure analyses supported this analysis. When the a- and c-faces of the pyridazine moiety were free of substitution (1, 3), planar structures resulted, but upon substitution, a twisted B(2)N(2)C(2) core was observed due to steric repulsion of neighboring hydrogen atoms (e.g., 5). The increase of steric bulk from H (1) to (i)Pr (3) in the planar species was found to result in a dimeric, head-to-tail herringbone packing motif, held together by close intermolecular B...N interactions of 3.39 Angstrom. One-electron reduction by Cp(2)Co was found to afford the radical anions of 3 and 5, which were characterized by broad, featureless singlets in the EPR spectra; [3](.)(-)[Cp(2)Co](+) was characterized by X-ray crystallography. While the planar structures (1-4) were observed to possess weak fluorescence (Phi(F) = 0.02-0.08) with either yellow-orange (ca. 555 nm) or green emission (521 nm), the twisted structures (5, 6) were found to be nonfluorescent.

Mechanistic Studies with 2-C-Methyl-d-erythritol 4-Phosphate Synthase from Escherichia coli

The mechanism of the reaction catalyzed by 2-C-methyl-d-erythritol 4-phosphate (MEP) synthase from Escherichia coli has been studied by steady-state and single-turnover kinetic experiments for the 1-deoxy-d-xylulose 5-phosphoric acid (DXP) analogues, 1,1,1-trifluoro-1-deoxy-d-xylulose 5-phosphoric acid (CF(3)-DXP), 1,1-difluoro-1-deoxy-d-xylulose 5-phosphoric acid (CF(2)-DXP), 1-fluoro-1-deoxy-d-xylulose 5-phosphoric acid (CF-DXP), and 1,2-dideoxy-d-hexulose 6-phosphate (Et-DXP). CF(3)-DXP, CF(2)-DXP, and Et-DXP were poor inhibitors, most likely because of the increase in steric bulk at C1 of DXP. The three analogues were also poor substrates for the enzyme. In contrast, CF-DXP was a good substrate (k(cat)(CF)(-)(DXP) = 37 +/- 2 s(-)(1), K(m)(CF)(-)(DXP) = 227 +/- 25 microM) for MEP synthase when compared to DXP (k(cat)(DXP) = 29 +/- 1 s(-)(1), K(m)(DXP) = 45 +/- 4 microM). A primary deuterium isotope effect was observed under single-turnover conditions when CF-DXP was incubated with 4S-[(2)H]NADPH ((H)k/(D)k = 1.34 +/-0.01), whereas no isotope effect was observed upon incubation with DXP and 4S-[(2)H]NADPH ((H)k/(D)k = 1.02 +/- 0.02). The reaction did not exhibit burst kinetics for either substrate, indicating that product release is not rate-limiting. These studies suggest that positive charge does not develop at C2 of DXP during catalysis. In addition, the isotope effect with CF-DXP and 4S-[(2)H]NADPH but not DXP indicates that the rearrangement step, which precedes hydride transfer, is rate-limiting for DXP but becomes partially rate-limiting for CF-DXP. Thus, rearrangement appears to be enhanced by substitution of a hydrogen atom in the methyl group of DXP by fluorine. These observations are consistent with a retro-aldol/aldol mechanism for the rearrangement during conversion of DXP to MEP.

Lithium and sodium N, N′-di(2,6-dialkylphenyl)formamidinate complexes

A study has been undertaken of the lithium and sodium metallation of N, N′-di(aryl)formamidines with alkyl groups at the 2- and 6-aryl position. 1H NMR and X-ray diffraction data indicate an increase in steric bulk from 2,6-dimethylphenyl to 2,6-diethylphenyl to 2,6-diisopropylphenyl incites incremental changes in amidinate binding and nuclearity. In selected instances, this invokes the first lithium and sodium amidinate/guanidinate complexes to exhibit metal–arene contacts.

Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase.

As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.

Structural Manipulation of Hydrogen Bond Networks Using Sulfonated Phosphane Ligands and Their Complexes: Competition and Interplay Between Strong and Weak Hydrogen Bonds

AbstractUsing the sulfonated phosphane [PPh2(C6H4‐m‐SO3)]−, L−, we have demonstrated that metal centres can readily be incorporated into guanidinium sulfonate (GS) hydrogen‐bonded networks, and that the increase in steric bulk on going from [C(NH2)3][L] (1) to [C(NH2)3][AuCl(L)] (2) leads to a flattening of the GS sheets. The crystal structures of [C(NH2)3][LS] 3 and [C(NH2)3][LSe] 4 (LS− = [SPPh2(C6H4‐m‐SO3)]−, LSe− = [SePPh2(C6H4‐m‐SO3)]−) reveal disorder in both the sulfonate groups and the guanidinium cations, which is a consequence of pseudo‐sixfold phenyl embraces between the anions. These interactions, identical to those observed in Ph3PS and Ph3PSe, position the sulfonate groups too close together for regular quasihexagonal hydrogen bonding motifs to be formed. The regular GS hydrogen bonding patterns can also be disrupted by using an anion containing two sulfonate groups such as that in [C(NH2)3]2{cis‐[PdCl2(L)2]} (5). In this case the incorporation of two sulfonate groups from each anion into the same hydrogen‐bonded sheet also serves to constrain the distance between the sulfur atoms to a value incommensurate with that enabling a guanidinium cation to hydrogen bond to both groups. In this case irregular GS sheets are formed involving fewer N−H···O hydrogen bonds than in 1 and 2. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Theoretical Study on Bis(imino)pyridyl−Fe(II) Olefin Poly- and Oligomerization Catalysts. Dominance of Different Spin States in Propagation and β-Hydride Transfer Pathways

Mechanisms of chain propagation and β-hydride transfer (BHT) chain termination stages of poly- and oligomerization of ethylene by catalysts of general formula [2,6-(CR1N((2-R2)(4-R4)(6-R3)C6H2)2C5H3N]FeCl2 were studied theoretically. Density functional (B3LYP) and integrated molecular orbitals + molecular mechanics (IMOMM) methods were applied respectively to a model (“low steric bulk”, LSB) system, [2,6-(CHNH)2C5H3N]FeCH3+, and one of the catalytic (“high steric bulk”, HSB) systems studied experimentally, [2,6-(CMeN(2,6-iPr2C6H3))2C5H3N]FeCH3+. We find that two axial ligands are required in order for the dz2 orbital (with the trichelating ligand defining the equatorial xy plane) to be destabilized and for the singlet to be the ground state and that this is realized in BHT chain termination related species. In contrast, in the chain propagation region of potential energy surface (PES) only one axial ligand is present, where, consequently, the dz2 orbital is singly occupied and the singlet becomes a low lying excited state. Our calculations on the LSB system place the lowest (singlet) BHT transition state (TS) 5.7 kcal/mol lower than the lowest (quintet and singlet) chain propagation TSs. Inclusion of both zero point energy and entropy corrections, namely, the Gibbs free energy, notably favors higher spin states, in which metal−ligand antibonding orbitals are occupied. This effect should be of general character for highly coordinated open shell transition metal complexes. On the Gibbs free energy surface of the LSB system, the lowest singlet BHT TS is only 1.0 kcal/mol lower than the lowest quintet chain propagation TS. In the HSB system, the axial positions are sterically destabilized. The main effect of increasing the steric bulk in axial position is the differentiation of the two ways of “saturating” the dz2 orbital, one by destabilizing it, as in singlet species, and the other by populating it with Fe's d electron, in favor of the latter. On the PES of the HSB system, the lowest BHT TS lies 17.6 kcal/mol higher than the lowest chain propagation TS. This is in agreement with the experimentally observed suppression of BHT chain termination upon increase in steric bulk.

An examination of the purported reverse anomeric effect beyond acetylated N-xylosyl- and N-glucosylimidazoles.

Syntheses of six new N-(pentopyranosyl)imidazoles have been achieved, and their conformations were observed with and without protonation. A decisive decrease in J(5',4), consistent with stabilization of the 1C4 conformations, was clearly observed for three N-(pentopyranosyl)imidazoles. As well, no reverse anomeric stabilization was observed for N-(2,3,4-tri-O-acetyl-alpha-D-lyxopyranosyl)imidazole upon protonation. It is suggested that the previous observations of the reverse anomeric effect were due to the slight increase in steric bulk of the imidazole aglycone upon protonation, along with favorable dipolar interactions between ring substituents, and not by a reverse of the anomeric effect.

Thermotropic phase properties of 1,2-di-O-tetradecyl-3-O-(3-O-methyl- beta-D-glucopyranosyl)-sn-glycerol

The hydration properties and the phase structure of 1,2-di-O-tetradecyl-3-O(3-O-methyl-beta-D-glucopyranosyl)-sn-glycerol (3-O-Me-beta-D-GlcDAIG) in water have been studied via differential scanning calorimetry, 1H-NMR and 2H-NMR spectroscopy, and x-ray diffraction. Results indicate that this lipid forms a crystalline (Lc) phase up to temperatures of 60-70 degrees C, where a transition through a metastable reversed hexagonal (Hll) phase to a reversed micellar solution (L2) phase occurs. Experiments were carried out at water concentrations in a range from 0 to 35 wt%, which indicate that all phases are poorly hydrated, taking up < 5 mol water/mol lipid. The absence of a lamellar liquid crystalline (L alpha) phase and the low levels of hydration measured in the discernible phases suggest that the methylation of the saccharide moiety alters the hydrogen bonding properties of the headgroup in such a way that the 3-O-Me-beta-D-GlcDAIG headgroup cannot achieve the same level of hydration as the unmethylated form. Thus, in spite of the small increase in steric bulk resulting from methylation, there is an increase in the tendency of 3-O-Me-beta-D-GlcDAIG to form nonlamellar structures. A similar phase behavior has previously been observed for the Acholeplasma laidlawii A membrane lipid 1,2-diacyl-3-O-(6-O-acyl-alpha-D-glucopyranosyl)-sn-glycerol in water (Lindblom et al. 1993. J. Biol. Chem. 268:16198-16207). The phase behavior of the two lipids suggests that hydrophobic substitution of a hydroxyl group in the sugar ring of the glucopyranosylglycerols has a very strong effect on their physicochemical properties, i.e., headgroup hydration and the formation of different lipid aggregate structures.

Probing the Mechanism of Staphylococcal Nuclease with Unnatural Amino Acids: Kinetic and Structural Studies

Staphylococcal nuclease is an enzyme with enormous catalytic power, accelerating phosphodiester bond hydrolysis by a factor of 10(16) over the spontaneous rate. The mechanistic basis for this rate acceleration was investigated by substitution of the active site residues Glu43, Arg35, and Arg87 with unnatural amino acid analogs. Two Glu43 mutants, one containing the nitro analog of glutamate and the other containing homoglutamate, retained high catalytic activity at pH 9.9, but were less active than the wild-type enzyme at lower pH values. The x-ray crystal structure of the homoglutamate mutant revealed that the carboxylate side chain of this residue occupies a position and orientation similar to that of Glu43 in the wild-type enzyme. The increase in steric bulk is accommodated by a backbone shift and altered torsion angles. The nitro and the homoglutamate mutants display similar pH versus rate profiles, which differ from that of the wild-type enzyme. Taken together, these studies suggest that Glu43 may not act as a general base, as previously thought, but may play a more complex structural role during catalysis.

Unique Stereocontrol in Europium(III)-Catalyzed Cyanosilylation of Chiral α-Alkoxy and α-Amino Aldehydes

Abstract The Eu(III)-catalyzed cyanosilylations of chiral α-alkoxy and α-amino aldehydes are shown to exhibit syn diastereofacial selection, the degree increasing with an increase in steric bulk of the alkyl chain in the aldehydes. The mechanism of this catalytic process is discussed.

Reaction of 1-substituted indenes with diborane or N-bromoacetamide in protic solvents. The effect of the substituent on the stereochemistry of addition

The reaction of 1-substituted Indenes with diborane or N-bromoacetamide (NBA) in protic solvents has been investigated to determine the effect of an increase of steric bulk of the substituent on the stereochemical course of addition. In the hydroboration reaction the proportion of the products via attack by diborane from the less hindered side increases, as the steric bulk of the substituent at C-1 increases. The reaction with NBA in aqueous dioxan, followed by acetylation, gave a mixture of 3-substituted-1-acetoxy-2-bromoindans with trans,trans and trans,cis-configuration: 1-phenylindene gave mainly trans,trans-1-acetoxy-2-bromo-3-phenylindan, while trans,cis-1-acetoxy-2-bromo-3-methylindan was the major product in the case of 1-methylindene.