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Macrolide antibiotics, such as azithromycin and erythromycin, are in widespread use for the treatment of bacterial infections. Macrolides are taken up and excreted mainly by bile. Additionally, they have been implicated in biliary system diseases and to modify the excretion of other drugs through bile. Despite mounting evidence for the interplay between macrolide antibiotics and bile acids, the molecular details of this interaction remain unknown. Herein, we show by NMR measurements that macrolides directly bind to bile acid micelles. The topology of this interaction has been determined by solvent paramagnetic relaxation enhancements (solvent PREs). The macrolides were found to be bound close to the surface of the micelle. Increasing hydrophobicity of both the macrolide and the bile acid strengthen this interaction. Both bile acid and macrolide molecules show similar solvent PREs across their whole structures, indicating that there are no preferred orientations of them in the bile micelle aggregates. The binding to bile aggregates does not impede macrolide antibiotics from targeting bacteria. In fact, the toxicity of azithromycin towards enterotoxic E. coli (ETEC) is even slightly increased in the presence of bile, as was shown by effective concentration (EC50 ) values., (© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Scalar coupling constants and signal splitting patterns in NMR spectra contain a wealth of short-range structural information. The extraction of these parameters from (1)H NMR spectra is often prohibited by simultaneous scalar coupling interactions with several other protons. Here we present a high-resolution NMR experiment where scalar coupling to only one selected signal is visible. All other couplings are removed from the spectrum. This real-time selectively refocused NMR experiment is achieved by spatially selective homonuclear broadband decoupling combined with selective refocusing during acquisition. It allows the unperturbed extraction of scalar coupling constants from the highly resolved acquisition dimension of NMR spectra.

The UV absorption spectra of ten N,N'-bisarylmalonamides have been recorded in the range 200-400 nm in a set of selected solvents. The solute-solvent interactions have been analyzed on the basis of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The effects of substituents on the absorption spectra have been interpreted by correlating absorption frequencies with Hammett substituent constants. Furthermore, the experimental findings have been interpreted using the DFT CAM-B3LYP/6-311+G(d,p) method. Electronic energies have been calculated using the same method in combination with the implicit solvation model (conductor-like polarizable continuum model, CPCM) as well as with the explicit addition of two molecules of solvent.

The vertical excitation energies of 3,4-dicyano-6-methoxy and 3,4-dicyano-6,7-dimethoxy carbostyril have been computed with different approximations for the time-dependent density functional theory (TD-DFT) procedure and with different implementations of the continuum solvation model COSMO. Different DFT functionals were tested in TD-DFT and Tamm-Dancoff approximations (TDA) for the excitation energies in the gas phase. TDA-B3LYP showed the best agreement with the experimental data. Then TDA-B3LYP computations were performed combined with the COSMO model of solvation comparing a linear response (LR) and a post-configuration interaction (CI) implementation of the fast solvent reorganization. The post-CI solvent model overestimates the π→π* transitions and strongly underestimates the n→π* transition. The TDA approximation in combination with the linear response implementation of the COSMO solvation model perfectly computes the experimental results. TDA-LR is the most reliable method for the computation of the vertical excitation energies in a solvent. Comparison with explicit solvent calculations shows there is only a minor effect on the energies of the electronic interaction of the solute with the solvent.

Tautomerization energies of a series of isomeric [(4-R-phenyl)azo]naphthols and the analogous Schiff bases (R = N(CH3)2, OCH3, H, CN, NO2) are calculated by LPNO-CEPA/1-CBS using the def2-TZVPP and def2-QZVPP basis sets for extrapolation. The performance of various density functionals (B3LYP, M06-2X, PW6B95, B2PLYP, mPW2PLYP, PWPB95) as well as MP2 and SCS-MP2 is evaluated against these results. M06-2X and SCS-MP2 yield results close to the LPNO-CEPA/1-CBS values. Solvent effects (CCl4, CHCl3, CH3CN, and CH3OH) are treated by a variety of bulk solvation models (SM8, IEFPCM, COSMO, PBF, and SMD) as well as explicit solvation (Monte Carlo free energy perturbation using the OPLSAA force field).

In this study, we explained the influence of the stepwise protonation of two antihistaminic drugs on their experimental absorption spectra. We demonstrated the capability of the TD-CAM-B3LYP method, combined with a polarizable continuum model, to produce good performance for the calculated spectra. The lowest energy transitions and the molecular orbital plots were analyzed in detail. The calculated UV spectra are proposed as potential alternatives to initialize the well-known MCR-ALS algorithm, especially when the spectra of the pure analytes are not available. Moreover, it can be a useful strategy for planning an experimental methodology oriented to multiway analysis when the drug species exhibit acid-base properties., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The reaction of cyclobutane-1,2-dione with hydroxide was studied by a variety of ab initio (MP2, SCS-MP2, CCSD(T), CEPA/1) and density functional (M06-2X) methods. Three possible reaction paths of the initially formed tetrahedral adduct leading to either 1-hydroxycyclopropane-1-carboxylate (benzilic acid type rearrangement, path A), α-oxobutanoate (path B) or γ-oxobutanoate (path C) were considered. Although the latter two products show similar or even more negative Gibbs free energies of reaction than calculated for the benzilic acid type rearrangement, the Gibbs free energies of activation are substantially higher. According to the calculations, the only feasible reaction appears to be the formation of 1-hydroxycyclopropane-1-carboxylate, which is corroborated by previous experimental observations.

An unexpected, redox-neutral C=C bond isomerization of a γ-butyrolactone bearing an exo-methylene unit to the thermodynamically more favoured endo isomer (k(cat) =0.076 s(-1) ) catalysed by flavoproteins from the Old Yellow Enzyme family was discovered. Theoretical calculations and kinetic data support a mechanism through which the isomerization proceeds through FMN-mediated hydride addition onto exo-Cβ, followed by hydride abstraction from endo-Cβ', which is in line with the well-established C=C bond bioreduction of OYEs. This new isomerase activity enriches the catalytic versatility of ene-reductases., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The degree of C=C bond activation in the asymmetric bioreduction of α,β-unsaturated carboxylic esters by ene-reductases was studied, and general recommendations to render these "borderline-substrates" more reactive towards enzymatic reduction are proposed. The concept of "supported substrate activation" was developed. In general, an additional α-halogenated substituent proved to be beneficial for enzymatic activity, whereas β-alkyl or β-aryl substituents were detrimental for the reactivity of nonhalogenated substrates, and α-cyano groups showed little effect. The alcohol moiety of the ester functionality was found to have a strong influence on the reaction rate. Overall, activities were determined by both steric and electronic effects., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Benzene-methanol cluster structures were investigated with theoretical chemistry methods to describe the microsolvation of benzene and the benzene-methanol azeotrope. Benzene-methanol (MeOH) clusters containing up to six methanol molecules have been calculated by ab initio [MP2/6-311++G(d,p)//MP2/6-31+G(d,p) + BSSE correction] method. The BSSE was found quite large with this basis set, hence, different extrapolation schemes in combination with the aug-cc-pVxZ basis sets have been used to estimate the complete basis set limit of the MP2 interaction energy [ΔE(MP2/CBS)]. For smaller clusters, n ≤ 3, DFT procedures (DFTB+, MPWB1K, M06-2X) have also been applied. Geometries obtained for these clusters by M06-2X and MP2 calculations are quite similar. Based on the MP2/CBS results, the most stable C(6)H(6)(MeOH)(3) cluster is characterized by a hydrogen bonded MeOH trimer chain interacting with benzene via π···H-O and O···H-C(benzene) hydrogen bonds. Larger benzene-MeOH clusters with n ≥ 4 consist of cyclic (MeOH)(n) subclusters interacting with benzene by dispersive forces, to be denoted by C(6)H(6) + (MeOH)(n). Interaction energies and cooperativity effects are discussed in comparison with methanol clusters. Besides MP2/CBS calculations, for selected larger clusters the M06-2X/6-311++G(d,p)//M06-2X/6-31+G(d,p) procedure including the BSSE correction was also used. Interaction energies obtained thereby are usually close to the MP2/CBS limit. To model the benzene-MeOH azeotrope, several structures for (C(6)H(6))(2)(MeOH)(3) clusters have been calculated. The most stable structures contain a tilted T-shaped benzene dimer interacting by π···H-O and O···H-C (benzene) hydrogen bonds with a (MeOH)(3) chain. A slightly less negative interaction energy results for a parallel displaced benzene sandwich dimer with a (MeOH)(3) chain atop of one of the benzene molecules.

The first reaction step of the redox cycle of bovine erythrocyte glutathione peroxidase from class 1 (GPX1) was investigated using hybrid quantum mechanics/molecular mechanics (QM/MM) calculations using the ONIOM methodology. The reduction of hydrogen peroxide by the active-site selenocysteine in selenolate form assisted by the Arg177 residue was modeled based on a proposal from previous molecular dynamics simulations and pKa calculations (J. Chem. TheoryComput. 2010, 6, 1670-1681). The redox reaction is predicted as a concerted SN2 nucleophilic substitution with a concomitant proton transfer from Arg177 onto leaving hydroxide ion upon reduction of hydrogen peroxide. The height of the reaction barrier was predicted in range of 6-11 kcal mol(-1), consistent with an experimental rate constant of ca. 10(7) M(-1) s(-1). The proposed GPX1-Se(-)-Arg177H(+) mechanism for GPX1 is compared with the GPX3-SeH-Gln83 one proposed for human glutathione peroxidase from class 3 (GPX3) and with the solvent-assisted proton exchange mechanism proposed for GPX-like organic selenols. The structural and energetic parameters predicted by various density functional theory methods (B3LYP, MPW1PW91, MPW1K, BB1K, M05-2X, M06-2X, and M06) are also discussed.

A novel reductive biotransformation pathway for β,β-disubstituted nitroalkenes catalyzed by flavoproteins from the Old Yellow Enzyme (OYE) family was elucidated. It was shown to proceed via enzymatic reduction of the nitro-moiety to furnish the corresponding nitroso-alkene, which underwent spontaneous (non-enzymatic) electrocyclization to form highly strained 1,2-oxazete derivatives. At elevated temperatures the latter lost HCN via a retro-[2 + 2]-cycloaddition to form the corresponding ketones. This pathway was particularly dominant using xenobiotic reductase A, while pentaerythritol tetranitrate-reductase predominantly catalyzed the biodegradation via the Nef-pathway.

The Quantum Cluster Equilibrium (QCE) model was applied to the liquid phase for the first few members of the homologous series of unbranched aliphatic primary alcohols, methanol, ethanol, propan-1-ol, and butan-1-ol. Cluster structures and energies were calculated by density functional theory [B3LYP/6-311++G(2d,2p)]. For butan-1-ol the dispersion interaction was also considered with the B3LYP-D method. In agreement with previous findings, cyclic cluster structures are the most probable ones. In addition, weak C-H...O interactions as well as dispersion interactions between the longer alkyl chains were found to be important in the cluster formation. The reliability of the model was assessed by the calculated constant pressure heat capacity (C(p)) values. Larger deviations between theory and experiment were found for higher homologes (propan-1-ol, butan-1-ol) with the B3LYP method. When the B3LYP-D method was applied for butan-1-ol, adequate agreement was found between experimental and calculated C(p) values.

Aqueous acid dissociation constants of substituted areneseleninic, areneselenenic, arenesulfinic, and benzoic acids are calculated by ab initio (MP2) and DFT (B3LYP) methods in combination with bulk solvation models (IEFPCM, CRSrad) from appropriate thermodynamic cycles. Mean absolute deviations (MAD) between experimental and calculated pK(a) values are quite large for basis sets without diffuse functions; however, trends are reasonably well described. Best agreement with experiment as described by MAD as well as correlation coefficient and slope of the correlation equation pK(a) = a*ΔG(calc)/RT ln(10) + b is obtained with the CPCM solvation model using the defaults optimized within COSMO-RS (CRSrad; MAD = 1.54, R(2) = 0.94, a = 0.83). Sulfenic (selenenic) acid tautomers are significantly more stable than the corresponding sulfoxide (selenoxide) forms.

Twelve pyramidatins, i.e., dibenzocyclooctadiene-type lignans, together with Machilin G, were isolated from the dichloromethane extracts of aerial material of Talauma gloriensis, Magnolia fraseri, and Magnolia pyramidata (Magnoliaceae). These lignans contain a highly oxidized 7,9'-epoxy-2,2'-cyclolignane skeleton. Their structures were established using NMR spectroscopy (1D and 2D experiments) and mass spectrometry. The absolute configurations of five pairs of atropisomers (S(a)/R(a)-pyramidatins) and two single atropisomers (S(a)-pyramidatins) were determined by experimental and calculated circular dichroism (CD). In addition, the absolute configuration of (S(a))-3,3',4,4',5,5'-hexamethoxypyramidatin was confirmed using X-ray crystallography. Five pyramidatins, (R(a))-3,3',4,4',5,5'-hexamethoxypyramidatin, (R(a))-3,3'-dimethoxy-4,5:4',5'-bis(methylenedioxy)pyramidatin, (S(a))-3,3',4,5'-tetramethoxy-4,5-methylenedioxypyramidatin, (R(a))-3,3',4,5'-tetramethoxy-4,5-methylenedioxypyramidatin, and (R(a))-3,3',4,5-tetramethoxy-4',5'-methylenedioxypyramidatin are reported herein for the first time. In the current dataset, NMR values are in accordance with the observed and calculated CD values. These values are herein reported with particular reference to previously described data of pyramidatins, which have to be revised., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Three approaches of computational chemistry [quantum mechanics (QM) calculations, docking, and molecular dynamics (MD) simulations] were used to investigate the redox cycle of bovine erythrocyte glutathione peroxidase from class 1 (GPx1, EC 1.11.1.9). The pKa calculations for two redox states of the active-site selenocysteine of GPx1 (selenol, Sec45-SeH, and selenenic acid, Sec45-SeOH) were estimated using a bulk solvent model (B3LYP-IEFPCM and B3LYP-CPCM-COSMO-RS). The calculated pKa values of Sec45-SeH and Sec45-SeOH were corrected via a simple linear fit to a training set of organoselenium compounds, which consisted of aliphatic selenols and aromatic selenenic acids with available experimental pKa values. Based on docking calculations, binding sites for both molecules of the cofactor glutathione (GSH) are described. MD simulations on the dimer of GPx1 have been performed for all chemical states of the redox cycle: without GSH and with one or two molecules of GSH bound at the active site. Conformational analyses of MD trajectories indicate high mobility of the Arg177 and His79 residues. These residues can approach the vicinity of Sec45 and take part in the catalytic mechanism. On the basis of the calculated data, new atomistic details for a generally accepted mechanism of GPx1 are proposed.

Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB(4) production the IC(50) values of aR-6,7-dihydro-6-(1'-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1'-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2+/-0.3microM and 4.5+/-0.2microM, respectively. aR-6,7-Dihydro-6-(1'-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC(50) 32.1+/-2.5microM) and on LTB(4) production (37.3+/-5.5% inhibition at 50microM)., (Copyright 2010. Published by Elsevier Ltd.)

In-depth conformational analyses of 10 known eremophilane (= (1S,4aR,7R,8aR)-decahydro-1,8a-dimethyl-7-(1-methylethyl)napththalene) sesquiterpenes, 1-10, from Petasites hybridus were performed with molecular mechanics as well as density functional theory methods. Electronic transition energies and rotational strengths of these eight eremophilane lactones and two petasins were calculated by time-dependent density functional theory (B3PW91/TZVP). The absolute configurations of the constituents could be assigned by comparison of their simulated and experimental circular dichroism (CD) spectra in methanol as (4S,5R,8S,10R) (1, 2), (2R,4S,5R,8S,10R) (3, 4, 5), (2R,4S,5R,8R,9R,10R) (6), (2R,4S,5R,8R,10R) (7, 8), and (3R,4R,5R) (9, 10). Single-crystal X-ray diffraction data of 8beta-hydroxyeremophilanolide ((8S)-8-hydroxyeremophil-7(11)-en-12,8-olide) (1) served as starting point for the theoretical conformational calculations of the 8beta-epimers of the eremophilane lactones. Experimental CD spectra as well as (1)H NMR spectra of compound 1 in methanol were considerably dependent on sample concentration., (2009 Wiley-Liss, Inc.)

Fast semipreparative HPLC enantioseparation of four axially chiral biscarbostyrils (4,4'-bisquinoline-2-ones) using ULMO as a pi-acidic Pirkle type chiral stationary phase leads to two racemizing pairs (1,2; k(obs) 1.6x10(-4) and 3.0x10(-4)s(-1) at 28 degrees C) and two stable ones (3,4). 3 was stabilized by a crown ether linkage from pos. 6 to 6', and 4 had sterically demanding bromo substituents in pos. 3 and 3'. On-column generated temperature-dependent chromatograms of 1 and 2 were fitted with Auto-DHPLCy2k and DCXplorer. For cpd 2 both programs delivered similar DeltaG values of 90 and 93kJ/mol, well comparable with the 99kJ/mol calculated with the B3LYP/6-31G (d) procedure. At temperatures of high conversion DCXplorer delivered inconsistent series of rate constants for the more tailing and less resolved tetramethoxy derivative 1. We connect this problem with an almost impossible halfwidth calculation of tailing peak pairs which are weakly resolved. However, this problem could be observed only in the case of tetramethoxy derivative 1. Stochastic generated data of Auto-DHPLCy2k could be used at a lower percentage of conversion only while the theoretical plate model did not deliver useful data at temperatures of very low conversion but fitted well high conversion chromatogram series of 1 and 2., (Copyright 2009 Elsevier B.V. All rights reserved.)

Dwindling petroleum feedstocks and increased CO(2)-concentrations in the atmosphere currently open the concept of using CO(2) as raw material for the synthesis of well-defined organic compounds. In parallel to recent advances in the chemical CO(2)-fixation, enzymatic (biocatalytic) carboxylation is currently being investigated at an increased pace. On the one hand, this critical review provides a concise overview on highly specific biosynthetic pathways for CO(2)-fixation and, on the other hand, a summary of biodegradation (detoxification) processes involving enzymes which possess relaxed substrate specificities, which allow their application for the regioselective carboxylation of organic substrates to furnish the corresponding carboxylic acids (145 references).

2-Substituted derivatives of the antihistaminic agents Bamipine, Diphenylpyraline and of their 1-phenyl analogues were tested for their antimycobacterial and H(1)-antagonistic activities. They are strong H1-receptor antagonists and also inhibit the growth of mycobacterials with a maximum MIC of 6.25 microg/mL against Mycobacterium tuberculosis H(37)Rv. H1-receptor antagonistic potency was slightly decreased by substitution in ring position 2 and distinctly diminished by N-aryl substitution. The antimycobacterial potency of Diphenylpyraline was in general increased by substitution in ring position 2, whereas only a few Bamipine derivatives showed markedly improved activity. A correlation between the two activities was not detected for those compounds.

Quasi-irreversible oxidation of sec-alcohols was achieved via biocatalytic hydrogen transfer reactions using alcohol dehydrogenases employing selected ketones as hydrogen acceptors, which can only be reduced but not oxidized. Thus, only 1 equiv of oxidant was required instead of a large excess. For the oxidation of both isomers of methylcarbinols a single nonstereoselective short-chain dehydrogenase/reductase from Sphingobium yanoikuyae was identified and overexpressed in E. coli.

Density functional theory calculations on complexes of 4C1, 1C4 and 2SO ring conformations of methyl beta-D-xylopyranoside 1 with divalent metal cations, M = Mg2+, Ca2+, Zn2+, and Cd2+, are presented. Bridging and pendant cationic, [M(H2O)41]2+ and [M(H2O)(5)1]2+, as well as neutral complexes, [M(OH)2(H2O)(2)1] and [M(OH)2(H2O)(3)1], and neutral complexes involving a doubly deprotonated sugar, [M(H2O)(4)1(2-)], are considered. In aqueous and chloroform solution the stability of cationic and pendant neutral complexes is greatly diminished compared with gas-phase results. In contrast, bridging neutral complexes [M(OH)2(H2O)(2)1] and those of type [M(H2O)(4)1(2-)], are stabilized with increasing solvent polarity. Solvation also profoundly influences the preferred binding position and ring conformation. Compared with complexes of bare metal cations, additional ligands, e.g., H2O or OH-, significantly reduce the stability of 1C4 ring complexes. Irrespective of the cation, the most stable structure of bridging complexes [M(H2O)(4)1]2+ results from coordination of the metal to O3 and O4 of methyl beta-D-xylopyranoside in its 4C1 ring conformation.

The tautomeric enol imine <--> enaminone (phenol <--> quinone) equilibrium of the 1-hydroxy-2-naphthaldehyde Schiff base (2-phenyliminomethyl-naphthalen-1-ol) was investigated by density functional theory (B3LYP) and ab initio (MP2) methods in the IEF-PCM polarizable continuum dielectric solvent approximation and by a combined ab initio + FEP/MC study by considering an explicit solvent model. Special emphasis was put on the effect of solvation on this equilibrium by using an apolar (CCl4), polar aprotic (CH3CN), and polar protic (CH3OH) solvent. Compared with experimental tautomerization Gibbs free energies, the IEF-PCM/B3LYP calculations apparently overestimate the stability of the quinone form both when the 6-31G(d,p) and the 6-311++G(d,p) basis sets are applied. IEF-PCM/MP2 studies with the above basis sets predict the preference of the aromatic phenol tautomer, in contrast to the experiment in methanol and acetonitrile solvent. Calculation of the total relative free energy as DeltaG(tot) = DeltaE(int)(IEF-PCM/QCISD(T)/6-31G(d)) + DeltaG(solv, FEP/MC) + DeltaG(thermal) provided agreement with the experimental values up to 0.6 kcal/mol in the three solvents, and the predominant tautomer was always correctly predicted. In-solution relevant atomic charges, derived by a fit to the molecular electrostatic potential generated by the IEF-PCM/B3LYP/6-31G(d,p) wave function, show strong dependence on the fitting procedure (CHELPG or RESP) and are fairly insensitive to the chemical nature of the actual solvent. Use of the CHELPG charges in FEP/MC simulations revealed to be superior in comparison with the use of the RESP charge set.

Ring and substituent rotamer conformations of methyl 2,4-diacetyl-beta-D-xylopyranoside, for which experimental results are controversial, were studied in the gas phase and in solvents of different polarity (CCl4, CHCl3, DMSO, and H2O) by B3LYP density functional theory. The 1C4 chair is the most stable ring form in the gas phase, followed by 4C1 and 2S0. Solvents of increasing polarity shift the equilibrium toward the 4C1 chair. Homodesmotic reaction energies show that the 1C4 and 2SO forms are stabilized by hydrogen bonding and anomeric effects and that steric repulsion is smallest in the 4C1 chair and largest in skew-boats.

A detailed conformational analysis of hyperolactone C diastereomers and enantiomers ((5R,9R),(5S,9S) and (5S,9R),(5R,9S)) was done with molecular mechanics and density functional theory methods. Time-dependent density functional theory (B3PW91/TZVP) was used to calculate electronic transition energies (UV/vis spectra) and rotational strengths of the respective conformations. The effect of solvation (acetonitrile solution) on excitation energies and electronic circular dichroism was approximated by the polarizable continuum model. By comparison of the simulated CD spectrum with that measured for hyperolactone C isolated from Hypericum lloydii, its absolute configuration can be assigned as (5S,9S)., (Copyright 2005 Wiley-Liss, Inc.)

Asymmetric enzyme-catalyzed hydrolysis of methylene-interrupted bis-epoxides 1 a and 1 b catalyzed by bacterial epoxide hydrolases furnished tetrahydrofuran derivatives 2 a and 2 b through a hydrolysis-rearrangement cascade. Whereas racemic bis-oxiranes 1 b-d underwent kinetic resolution with moderate stereoselectivities to yield products with up to 92 % ee and 66 % de: meso-bis-oxirane cis,cis-1 a was transformed into (6R,7R,9S,10S)-2 a in 94 % ee and 89 % de at high conversion (85 %) by Rhodococcus sp. CBS 717.73 as the major product. The reaction sequence resembles a biomimetic reaction cascade and provides an efficient entry into the structural core of annonaceous acetogenins with simultaneous control of four stereocenters.

The wavenumbers of the IR absorption bands of the C=O, S=O and N-H stretching vibrations for a series of p-substituted N-phenylsulfonylbenzamides were measured in trichloromethane. The bond orders, Mulliken charges, charge densities and heats of formation were calculated using the PM3 method. Fifty significant mutual mono parameter (MP) and six dual parameter (DP) correlations were found for the IR spectral, theoretical structural data, substituent constants and previously reported dissociation constants in five polar organic solvents. The transmission of the substituent effects has been discussed and the solvent effect on the slopes of some linear correlations was evaluated using different solvent parameters. The results showed that the factors describing the electronic structure and controlling the dissociation equilibrium and the IR spectra properties of p-substituted N-phenylsulfonylbenzamides must be the same.

Three novel chiral packing materials for high-performance liquid chromatography were prepared by covalently binding of (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]propan-amide (7), (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-4-methylpentanamide (8), and (2S)-N-(3,5-dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonyl-amino]-2-phenylacetamide (9) to aminopropyl silica. The resulting chiral stationary phases (CSPs 1-3) proved effective for the resolution of racemic 4-aryl-3,4-dihydro-2(1H)-pyrimidone derivatives (TR 1-14). The mechanism of their enantioselection, supported by the elution order of (S)-TR 13 and (R)-TR 13 and molecular modeling of the complex of the slower running (S)-TR 13 with CSP 1 is discussed., (Copyright 2003 Wiley-Liss, Inc.)

The enantioselective ring-opening catalyzed by epoxide hydrolases originating from seven different sources of a series of 2,2-disubstituted oxiranes containing alkyl chains of different lengths, unsaturated (alkenyl, alkinyl) and aromatic groups as well as electronegative heteroatoms at various positions within the side chain was analyzed by quantitative structure-activity relationships. Models for the enantioselectivity were derived with the aid of multiple linear regression analysis (MLR) using several steric and electronic (quantum chemical) descriptors. On the basis of the models derived by MLR nonlinear modeling with artificial neural networks (ANN) was also done. Good predictive performance was observed for both modeling approaches. The models also indicate that different steric and/or electronic features account for the enantioselectivities observed for the individual epoxide hydrolases.

The enantiomers of a series of chiral aryl- and hetaryl-carbinols were separated on a chiral stationary phase (ULMO) based on (S,S)-3,5-dinitrobenzoylated 1,2-diphenylethane-1,2-diamine. In all cases, the homochiral analogs of (S)-1-phenylethanol (mostly also S-enantiomers) were retained more. Log alpha values were modeled with the aid of the 3D-QSAR techniques CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) as well as a descriptor based on normal mode eigenvalues (EVA). Partial least-squares analysis with two (CoMSIA) or three (CoMFA, EVA) latent variables on a set of 22 training analytes gives cross-validated correlation coefficients q(2) = 0.85-0.91 and conventional correlation coefficients r(2) = 0.94-0.99. The quantitative structure-enantioselective retention relationships derived thereby were used to predict the separation factors of the test set, containing also hetaryl-carbinols, e.g., furan and thiophene analogs, with good accuracy., (Copyright 2003 Wiley-Liss, Inc.)

A 3D QSAR analysis (quantitative structure activity relationships) of a set of 2,2-disubstituted epoxides, substrates for epoxide hydrolases originating from four different organisms, was conducted by CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis), with respect to the enantioselective ring opening to the corresponding vicinal diol. Structural variations of the substrates include alkyl chains of different lengths, unsaturated moieties ((E)- and (Z)-alkenyl, alkinyl, aryl) and electronegative groups (ether oxygens, halogen atoms) at different locations within the 2-substituent group. Generally, all four organisms, namely Rhodococcus ruber NCIMB 11216, Rhodococcus ruber DSM 43338, Rhodococcus ruber DSM 44540 and Rhodococcus ruber DSM 44539, preferentially react with the (S)-enantiomer of the epoxide. Enantioselectivities (enantiomeric ratio, In E values) show a rather large variation, ranging from almost no (ln E < 1) to nearly complete selectivity (In E > 5.3). In addition, the response of the epoxide hydrolases stemming from the four organisms towards structural modifications of the substrate is different. Models for the enantioselectivity (enantiomeric ratio, ln E values) obtained by CoMFA and CoMSIA are of different but reasonable predictive power, e.g., q2CV = 0.701 and r2 = 0.937 for the CoMFA model of Rhodococcus ruber DSM 43338. Enantiomeric ratios for the test molecules can be well predicted. Plots of steric and electrostatic CoMFA (CoMSIA) fields allow conclusions to be drawn for the choice of the most suitable organism for a specific type of substrate.

The site of nucleophilic addition to five-membered heterocyclic 2,3-diones (4-iminomethylfuran-2,3-dione A1 and 4-formyl-pyrrole-2,3-dione B1) is studied by density functional theory calculations (B3LYP/6-31G) with water as the nucleophile. Both uncatalyzed and water-assisted 1,2-addition to the lactone (lactam) and the keto carbonyl group, and conjugate addition to C5 of the heterocycle and the heteroatom of the 4-iminomethyl (formyl) moiety are considered. In addition, concerted and stepwise ring fission of the lactone (lactam) ring is also treated. The effect of solvation (aqueous solution) is taken into account by the polarizable continuum model (PCM) and the Poisson-Boltzmann SCRF method (PB-SCRF), as well as explicit water molecules. Only this latter approach yields meaningful activation free energies. Barriers for addition of H2O increase in the order 1,4-addition to C5 < addition to the lactone (lactam) carbonyl < hydration of the 3-keto group. No reaction path for concerted water-assisted ring opening could be found.

Donor-acceptor substituted diazabutadienes and -hexatrienes were prepared by straightforward procedures and their linear optical (UV-vis) and nonlinear optical second harmonic generation (SGH) properties investigated in a combined theoretical and experimental study. Theoretical and experimental results were in reasonable agreement. For the compounds in this study, which contained a p-nitrophenyl group as electron acceptor, the p-dimethylaminophenyl group was the most powerful electron-donating group, leading to the highest maximum absorption wavelengths, as well as to the maximum SHG efficiency.

Hydration of the keto group as well as hydrolysis (ester and amide) of alpha-oxo carboxylic acid derivatives has been studied by density functional theory (B3LYP/6-31G and B3LYP/6-311G). Both uncatalyzed as well as water-assisted processes have been considered. Solvent effects were approximated by the self-consistent isodensity surface polarized continuum (SCIPCM) model. For hydrolysis reactions a concerted as well as a stepwise mechanism was calculated. In the latter one, addition of the nucleophile to a tetrahedral intermediate was found to be rate determining. In uncatalyzed processes both concerted and stepwise mechanisms are calculated to have comparable activation energies and free enthalpies. In catalyzed reactions the stepwise mechanism is predicted to be considerably more favorable. Hydration of the alpha-oxo group should be much more feasible than either ester or amide hydrolysis.

Density functional (B3LYP/6-311+G) and ab initio (MP2/6-311+G and MP4(SDTQ)/6-311+G//MP2/6-311+G) calculations on the ring closure reactions of (E)- and Z-iminodiazomethane ((E)-5, (Z)--5), vinyldiazomethane 7, and formyldiazomethane 9 to 1H-1,2,3-triazole 6, 3H-pyrazole 8, and 1,2,3-oxadiazole 10, respectively, are reported. (E)-5 cyclizes via a low barrier (ca. 10 kcal mol(-)(1)) pseudopericyclic nonrotatory transition state. Ring closure of (Z)-5 and 7 proceeds by a monorotatory movement of the imino or vinyl group with a substantially higher barrier (ca. 25 kcal mol(-)(1)). Despite being endothermic, for the reaction 9 --> 10 also a rather low activation energy (ca. 10 kcal mol(-)(1)) is computed. The NBO analysis is used to interpret the electronic structures of the respective transition states in terms of their pericyclic monorotatory (TS ((Z)-5 --> 6), (TS (7 --> 8)) or pseudopericyclic nonrotatory ((TS ((E)-5 --> 6), (TS (9 --> 10)) nature.

The effect of substituents on the site selectivity (C=C vs C=N) in the [4 + 2] cycloaddition between heterocumulenes (ketene imines) 2a-g with heterodienes (acroleines 9a-n and 4-acylfuran-2,3-diones 1a-d) is treated by semiempirical AM1 molecular orbital and density functional calculations using Becke's three-parameter hybrid method (B3LYP/6-31G). For some reactions calculations were also done at the B3LYP/6-31+G level of theory. For reaction of the oxa 1,3-dienes with ketene imines unsubstituted at the terminal carbon invariably addition across the C=C heterocumulene double bond has a lower activation energy than addition across the C=N double bond. Substitution of methyl or especially phenyl groups at the ketene imine C-terminus leads to a reversal of the respective activation energies. Incorporation of the oxa 1,3-diene system into the heterocyclic dione 1 substantially enhances the reactivity ( approximately 10 kcal mol(-1) lower activation energies) as compared to similarly substituted acroleins. At the DFT level of theory all reactions are found to proceed via a concerted asynchronous mechanism.

Five new atropisomerically chiral 1,8-dihetarylnaphthalenes were prepared by Pd(0)-catalyzed coupling reactions. Variable-temperature proton NMR spectra show those compounds with a 2'-pyridyl or 2'-pyrazinyl ring have a much lower energy barrier for rotation to interconvert conformational isomers than those with a 3'-pyridyl ring. Coalescence temperatures may differ by as much as 100 degrees C. The results of AM1 and PM3 computations indicate the preferred transition state for sigma-bond rotation places the annular nitrogen atom in the 2' or ortho position toward the face of the second hetaryl ring and not toward the naphthalene ring.

Dicationic 1',1'-dimethyl (6a), dipolar 1',1'-dioxide (6b), and 6',6'-dipyridone (7) derivatives of 1,8-di(2'-pyridyl)naphthalene were prepared. Proton NMR failed to reveal the presence of individual anti-syn atropisomers over a wide range of temperatures. By contrast, the 1',1"-dimethyl derivative of 1-(2'-pyridyl)-8-(3"-pyridyl)naphthalene (8), a positional isomer of 6a, existed in DMSO-d(6) as a 2:1 mixture of anti to syn atropisomers at ambient temperatures. Electrostatic repulsion is believed to cause the anti atropisomer to be favored, especially in 6a where the charged regions are closer together than in 8, owing to the splayed-out arrangement of the rings. AM1 and PM3 computations confirm that the anti is highly favored over the synisomer for 6a, 6b, and 7.

The two nitrogen atoms in 1,8-di(3'-pyridyl)naphthalene were quaternized by the addition of either benzyl or methyl groups to give dications; the latter was oxidatively converted to the di(6'-pyridone). N-Oxidation gave the mono- and di-N-oxides. All these compounds in DMSO-d(6) show anti-syn atropisomerism at ambient temperatures by (1)H NMR analysis; similar amounts of both diastereomers are present.