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At least 397 records · Page 22Linked to original sources
PubMed2006

Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum beta-lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods.

The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.

Aldehydes↗
PubMed2000

Probing furanose ring conformation by gas-phase computational methods: energy profile and structural parameters in methyl beta-D-arabinofuranoside as a function of ring conformation

The potential energy surface of methyl beta-D-arabinofuranoside (3) has been studied by ab initio molecular orbital (HF/6-31G) and density functional theory (B3LYP/6-31G) calculations via minimization of the 10 possible envelope conformers. The partial potential energy surface identified that the global minimum and lowest energy northern conformer was E(2). In the HF calculations, (2)E was the most stable southern conformer, while the density functional theory methods identified (4)E as the local minimum in this hemisphere. Additional calculations at higher levels of theory showed that the B3LYP-derived energies of many of the envelope conformers of 3 are dependent upon the basis set used. It has also been demonstrated that B3LYP/6-31+G//B3LYP/6-31G single point energies are essentially the same as those obtained from full geometry optimizations at the B3LYP/6-31+G level. The northern and southern minima of the B3LYP/6-31+G surface are, respectively, the E(2) and (2)E conformers. The B3LYP/6-31G geometries were used to study the relationship between ring conformation and various structural parameters including bond angles, dihedral angles, bond lengths, and interatomic distances.

Journal Article↗
PubMed2003

Conformational study of 1,2-cycloundecadiene by dynamic NMR spectroscopy and computational methods.

Solutions of 1,2-cycloundecadiene in propane were studied by low-temperature (13)C NMR spectroscopy. A total of 17 peaks were observed at -166.7 degrees C, corresponding to two conformations of similar populations, one of C(1) symmetry (11 peaks) and the other of C(2) symmetry. The line shapes show that the predominant pathway for exchange of the topomers (C(1) and C(1)') of the C(1) conformation does not include the C(2) conformation. From the (13)C spectra, free-energy barriers of 8.38 +/- 0.15, 9.45 +/- 0.15, and 9.35 +/- 0.15 kcal/mol were determined for the C(1) to C(1)', (C(1) + C(1)') to C(2), and C(2) to (C(1) + C(1)') conversions, respectively, at -72.2 degrees C. The NMR results for this compound are discussed in terms of the conformations predicted by molecular mechanics calculations obtained with Allinger's MM3 program. Ab initio calculations of free energies are also reported at the HF/ 6-311G level for 25 conformations.

Carbon Isotopes↗
PubMed2004

A comparison of acetyl- and methoxycarbonylnitrenes by computational methods and a laser flash photolysis study of benzoylnitrene.

Density functional theory (DFT), CCSD(T), and CBS-QB3 calculations were performed to understand the chemical and reactivity differences between acetylnitrene (CH(3)C(=O)N) and methoxycarbonylnitrene (CH(3)OC(=O)N) and related compounds. CBS-QB3 theory alone correctly predicts that acetylnitrene has a singlet ground state. We agree with previous studies that there is a substantial N-O interaction in singlet acetylnitrene and find a corresponding but weaker interaction in methoxycarbonylnitrene. Methoxycarbonylnitrene has a triplet ground state because the oxygen atom stabilizes the triplet state of the carbonyl nitrene more than the corresponding singlet state. The oxygen atom also stabilizes the transition state of the Curtius rearrangement and accelerates the isomerization of methoxycarbonylnitrene relative to acetylnitrene. Acetyl azide is calculated to decompose by concerted migration of the methyl group along with nitrogen extrusion; the free energy of activation for this concerted process is only 27 kcal/mol, and a free nitrene is not produced upon pyrolysis of acetyl azide. Methoxycarbonyl azide, on the other hand, does have a preference for stepwise Curtius rearrangement via the free nitrene. The bimolecular reactions of acetylnitrene and methoxycarbonylnitrene with propane, ethylene, and methanol were calculated and found to have enthalpic barriers that are near zero and free energy barriers that are controlled by entropy. These predictions were tested by laser flash photolysis studies of benzoyl azide. The absolute bimolecular reaction rate constants of benzoylnitrene were measured with the following substrates: acetonitrile (k = 3.4 x 10(5) M(-1) (s-1)), methanol (6.5 x 10(6) M(-1) s(-1)), water (4.0 x 10(6) M(-1) s(-1)), cyclohexane (1.8 x 10(5) M(-1) s(-1)), and several representative alkenes. The activation energy for the reaction of benzoylnitrene with 1-hexene is -0.06 +/- 0.001 kcal/mol. The activation energy for the decay of benzoylnitrene in pentane is -3.20 +/- 0.02 kcal/mol. The latter results indicate that the rates of reactions of benzoylnitrene are controlled by entropic factors in a manner reminiscent of singlet carbene processes.

Journal Article↗
PubMed2005

Conformational study of cis-1,4-di-tert-butylcyclohexane by dynamic NMR spectroscopy and computational methods. Observation of chair and twist-boat conformations.

[reaction: see text] Low-temperature 13C NMR spectra of cis-1,4-di-tert-butylcyclohexane (1) showed signals for the twist-boat (1a) and chair (1b) conformations. 13C NMR signals were assigned to specific carbons based on the different populations, different symmetries (time-averaged C(2v) for 1a and time-averaged C(s) for 1b), and calculated chemical shifts (GIAO, HF/6-311+G*). In addition to slow ring inversion and interconversion of the chair and twist-boat conformations, slow rotation of the tert-butyl groups was found. Most of the expected 13C peaks were observed. Free-energy barriers of 6.83 and 6.35 kcal/mol were found for interconversion of 1a (major) and 1b (minor) at -148.1 degrees C. Conformational space was searched with Allinger's MM3 and MM4 programs, and free energies were obtained for several low-energy conformations 1a-c. Calculations were repeated with ab initio methods up to the HF/6-311+G* level. Molecular symmetries, relative free energies, relative enthalpies and entropies, frequencies, and NMR chemical shifts were obtained. A boat conformation (1d; C(2v) symmetry) was generated and optimized as a transition state by ab initio, MM3, and MM4 calculations.

Journal Article↗
PubMed1999

Conformational Study of Oxacyclooctan-2-one by Dynamic NMR Spectroscopy and Computational Methods.

The slow-exchange (13)C NMR spectrum of the eight-membered lactone, oxacyclooctan-2-one (1), at -154.2 degrees C shows the presence of two conformations with populations of 25.6 and 74.4%. Free-energy barriers of 6.98 and 7.23 kcal/mol were determined at the coalescence temperature for the carbonyl carbon peak (-128.6 degrees C). The (1)H NMR spectrum of the CH(2)O protons splits into two multiplets of equal intensity by -100 degrees C, and the corresponding free-energy barrier of 9.16 kcal/mol at -85.2 degrees C was suggested to be associated with exchange of the geminal protons. Relative free energies and populations at +25 and -160 degrees C were estimated by using Allinger's MM3 program, and free energies and dipole moments were obtained for three conformations using ab initio calculations at the HF/6-311G and MP2/6-311G levels. The spectra were interpreted in terms of two conformations having the E configuration of the lactone group and resembling the boat-chair conformation of cyclooctane.

Journal Article↗
PubMed1999

Conformational Study of trans-Cyclododecene by Dynamic NMR Spectroscopy and Computational Methods.

The (13)C spectrum of trans-cyclododecene (1) dissolved in propane showed seven peaks for the olefinic carbons at -164.5 degrees C, corresponding to three conformations of C(1) symmetry and a fourth conformation, with a population of 20.1%, of C(2) symmetry. The populations of the C(1) conformations were 57.0, 18.6, and 4.3%. Conformational space was searched for 1 using MM2. Free energies and populations were calculated by MM3, and the results of the low-temperature NMR study are discussed in terms of these calculations and the (13)C chemical shifts calculated for eight conformations by the GIAO method at the HF/6-311G level. The conformations of 1 and cyclododecane (2) are compared.

Journal Article↗
PubMed2005

Impact of the computational method on the geometric and electronic properties of oligo(phenylene vinylene) radical cations.

We report on a quantum-chemical study of the electronic and optical properties of unsubstituted oligo(phenylene vinylene) (OPV) radical cations. Our goal is to distinguish the impact of the choice of molecular geometry from the impact of the choice of quantum-chemical method, on the calculated optical transition energies. The geometry modifications upon ionization of the OPV chains are found to depend critically on the theoretical formalism: Hartree-Fock (HF) geometry optimizations lead to self-localization of the charged defects while pure density functional theory (DFT) results in a complete delocalization of the geometric modifications over the whole conjugated backbone. The electronic structure and vertical transition energy associated with the lowest excited state of the radical cations have been calculated at the post-Hartree-Fock level within a configuration interaction (HF-CI) scheme and using the time-dependent DFT (TD-DFT) formalism for different radical cation geometries. Interestingly, the changes in the calculated optical properties obtained when using different geometric structures are less important within a given method than the differences between methods for a given structure. The optical excitation is localized with HF-CI and delocalized with TD-DFT, almost irrespective of the molecular geometry; as a result, HF-CI excitation energies tend to saturate as the chain length increases, in contrast to the results from TD-DFT.

Journal Article↗
PubMed2006

Effects of intermolecular vibrational coupling and liquid dynamics on the polarized Raman and two-dimensional infrared spectral profiles of liquid N,N-dimethylformamide analyzed with a time-domain computational method.

A time-domain method for calculating polarized Raman and two-dimensional infrared (2D-IR) spectra that includes the effects of both the diagonal frequency modulations (of individual molecules in the system) and the off-diagonal (intermolecular) vibrational coupling is presented and applied to the case of the amide I band of liquid N,N-dimethylformamide. It is shown that the effect of the resonant off-diagonal vibrational coupling and the resulting delocalization of vibrational modes is clearly seen as the noncoincidence effect in the polarized Raman spectrum and some spectral features (especially as asymmetric intensity patterns) in the 2D-IR spectra. The type of 2D-IR spectra (concerning the polarization condition) most appropriate for observing this effect is discussed. On the basis of the agreement between the observed and calculated band profiles of the polarized Raman spectrum, the time dependence of the transient IR absorption anisotropy is also calculated. The method of evaluating the extent of delocalization of vibrational modes that is relevant to the features of these optical signals in the time and frequency domains is discussed. The nature of the molecular motions (concerning the liquid dynamics) that are effective on the diagonal frequency modulations is also examined.

Journal Article↗
PubMed2005

Systematic assignment of the configuration of flexible natural products by spectroscopic and computational methods: the bistramide C analysis.

[reaction: see text] The combination of NMR NOE, chemical shift, and J-coupling measurements with molar rotation and circular dichroism (CD) determinations, including RI-DFT BP86/aug-cc-pVDZ calculations, reduced a candidate pool of 1024 possible stereoisomers of (+)-bistramide C to a single absolute configuration assignment for the 10 stereogenic carbons of the marine natural product.

Biological Products↗
PubMed2006

Predicting NMR spectra by computational methods: structure revision of hexacyclinol.

[structure: see text] The structure of the natural product hexacyclinol was reassigned from endoperoxide 1 to the diepoxide 7 on the basis of calculated (13)C chemical shift data using HF/3-21G geometries and mPW1PW91/6-31G(d,p) GIAO NMR predictions. These predictions correlate very well with experimental data for three other highly oxygenated natural products, elisapterosin B, maoecrystal V, and elisabethin A. Hexacyclinol is proposed to arise from acid-catalyzed rearrangement of panepophenanthrin in the presence of methanol.

Biological Products↗
PubMed2004

Foldamer simulations: novel computational methods and applications to poly-phenylacetylene oligomers.

We apply several methods to probe the ensemble kinetic and structural properties of a model system of poly-phenylacetylene (pPA) oligomer folding trajectories. The kinetic methods employed included a brute force accounting of conformations, a Markovian state matrix method, and a nonlinear least squares fit to a minimalist kinetic model used to extract the folding time. Each method gave similar measures for the folding time of the 12-mer chain, calculated to be on the order of 7 ns for the complete folding of the chain from an extended conformation. Utilizing both a linear and a nonlinear scaling relationship between the viscosity and the folding time to correct for a low simulation viscosity, we obtain an upper and a lower bound for the approximate folding time within the range 70 ns<tau<350 ns. This is in agreement with the experimentally measured folding time on the order of 160 ns. The kinetic model used to fit the kinetic behavior of the ensemble of trajectories provides a framework to describe the bulk folding mechanism. We were able to identify two unique clusters of conformations that provide a structural basis to account for the appearance of a kinetic intermediate in the mechanism. We discuss the implications of these findings in the context of helix-coil theory.

Journal Article↗
PubMedDate not supplied

Evaluation of several economical computational methods for geometry optimization of phosphorus acid derivatives.

Several economical methods for geometry optimisation, applicable to larger molecules, have been evaluated for phosphorus acid derivatives. MP2/cc-pVDZ and B3LYP/6-31+G(d) geometry optimizations are used as reference points, results from geometry optimizations for other methods and their subsequent single point energy calculations are compared to these references. The geometries from HF/MIDI! optimizations were close to those of the references and subsequent single point energies with B3LYP/6-31+G(d,p) or EDF1/6-31+G(d) gave a mean average deviation (MAD) of less than 0.5 kcal mol-1 from those obtained with the reference geometries.

Molecular Conformation↗