An expeditious route to eight- and nine-membered carbocycles based on a RCM-ring fragmentation strategy

The presence of a temporary one-atom internal tether in 1,9-deca- and 1,10-undecadienes allows their efficient ring-closing metathesis (RCM). Cleavage of the bridging tether of the resulting bicycles provides eight- or nine-membered carbocycles, medium-sized rings that are difficult to assemble using other currently available procedures.     

Calculation of circular dichroism spectra of michellamines A and C, based on a complete conformational analysis

The first quantum chemical calculation of the circular dichroism (CD) spectra of michellamines has been achieved, based on a complete quantum chemical conformational analysis. Michellamines are dimeric naphthylisoquinoline alkaloids and thus naturally occurring quateraryls, with a large molecular size and flexibility and equipped with stereogenic centers and axes.     

A comparison of approaches to estimate the resonance energy

We discuss Ab Initio approaches to calculate the energy lowering (stabilisation) due to aromaticity. We compare the valence bond method and the block-localised wave function approaches to calculate the resonance energy. We conclude that the valence bond approach employs a Pauling–Wheland resonance energy and that the block-localised approach employs a delocalisation criterion. The latter is shown to be more basis set dependent in a series of illustrative calculations.     

The oxygen-bridge templating approach to eight- and nine-membered carbocycles: recent developments based on catalytic reactions

Recent developments concerning metal-catalyzed reactions have led to the implementation of new, rapid, and practical routes to eight- and nine-membered carbocycles based on an oxygen-bridge templated cyclization.     

A DFT conformational analysis and VCD study on methyl tetrahydrofuran-2-carboxylate

DFT calculations were performed on (S)-methyl tetrahydrofuran-2-carboxylate to facilitate the interpretation of IR and VCD spectra. The potential energy surface could not be described unambiguously using the 6-31G* basis set in combination with different density functionals including B1LYP, B3LYP, B3P86, B3PW91, B98, BHandH, BHandHLYP, MPW1PW91 and PBE1PBE. In contrast, a uniform conformational picture could be found using the cc-pVTZ basis set. Using this large basis set and the collection of nine functionals from above, the dipole and rotational strengths were calculated, and compared to experimental values which were extracted from the experimental IR and VCD spectra for (+)-(S)-methyl tetrahydrofuran-2-carboxylate. A detailed analysis on the agreement between experiment and simulated spectra was performed by assigning the experimental bands based on the harmonic fundamentals obtained for all functionals except BHandH, which performs badly over the whole line. Assessing the dipole strengths, all tested functionals perform equally well. For the rotational strengths, differences can be observed: B3LYP, B1LYP and B98 give the highest correlation with experiment, while PBE1PBE gives the lowest correlation. Comparable conclusions are obtained using a neighborhood similarity measure.     

Synthesis and examination of amine-cyanocarboxyboranes, the boron analogues of α-cyanocarboxylic acids: X-ray structural study of the first lactam containing a boron atom in the lactam ring

The first representatives of chiral boron atom-containing amine-cyanomethoxycarbonyl boranes (A · BH(CN)COOMe) have been synthesized either from the corresponding amine-bromocyanomethoxycarbonylborane complexes with [Bu₄N]CN or from Me₃N · BH(CN)COOMe and an amine in a base-exchange reaction. Acid hydrolyses of methyl esters generated the free acids (A · BH(CN)COOH), which are isoelectronic to the α-cyano carboxylic acids. Their pK_a values and hydrolysis half-lives in acidic medium (that is rate of proton reduction) have been determined. Similarly to the alpha cyano carboxylic acids, the cyano group attached to the boron (in alpha position to the COOH group) increased the acid strength of carboxy boranes with 2.0-2.5 orders of magnitude. Independently from the type of the amine, pK_a values of the amine-cyanocarboxyboranes (6.34-5.82) decrease consistently with the increase of pK_b values of the amines. Hydrolytic decomposition rate of the alkylamine complexes increases with increasing pK_b values of the amines while the opposite was found for pyridine base complexes. When considering both types of the amines, hydrolysis half-lives of the complexes range over several orders of magnitude from 0.005 to 400 h. Based on these observations protonation of the amine nitrogen atom appears to be the rate determining step in the hydrolysis process. With loss of methanol, 2-NH₂-py · BH(CN)COOMe transformed into a five membered lactam derivative. X-ray diffraction revealed that the pyridine ring is coplanar with the five membered lactam ring. In the crystal two molecules are connected in a head to tail arrangement by strong intermolecular H-bonds between N(2)-H and the carbonyl oxygen (O1) with a donor and acceptor distance of 2.867(3) Å. Three new cyanomethoxycarbonylborates having the composition of K[BH_n(CN)_3−nCOOMe] (n = 1, 2) and K[B(OH)(CN)₂COOMe] have also been synthesized and their properties examined.     

Pyrene: a probe to study protein conformation and conformational changes

The review focuses on the unique spectral features of pyrene that can be utilized to investigate protein structure and conformation. Pyrene is a fluorescent probe that can be attached covalently to protein side chains, such as sulfhydryl groups. The spectral features of pyrene are exquisitely sensitive to the microenvironment of the probe: it exhibits an ensemble of monomer fluorescence emission peaks that report on the polarity of the probe microenvironment, and an additional band at longer wavelengths, the appearance of which reflects the presence of another pyrene molecule in spatial proximity (~10 ?). Its high extinction coefficient allows us to study labeled proteins in solution at physiologically relevant concentrations. The environmentally- and spatially-sensitive features of pyrene allow monitoring protein conformation, conformational changes, protein folding and unfolding, protein-protein, protein-lipid and protein-membrane interactions.     

Different multidimensional chromatographic approaches applied to the study of wine malolactic fermentation

Different multidimensional chromatographic techniques were used to study wine aroma pattern changes during malolactic fermentation (MLF). Ethyl lactate enantiomeric ratios were determined using on-line multidimensional gas chromatography. The values found agree with a spontaneous MLF. Off-line multidimensional HPLC/GC was used to deconvolute and enrich the sample and ease enantioselective chromatography. Chiral compound enantiomeric ratio changes during MLF were monitored. Evaluation of enantiomeric ratio changes during MLF has never been studied. (R,R), (S,S) and meso-butane-2,3-diol and pentane-2,4-diol (reported in wines for the first time) were submitted to untrained sensory panel tests. All stereoisomers revealed different sensory notes; pentane-2,4-diol showed an aromatic impact.     

Solvent effect on the syn/anti conformational stability: A comparison between conformational bias Monte Carlo and molecular dynamics methods

The solvent effect on the syn/anti population ratio of the mesityl oxide (MOx) was investigated using a new implementation of conformational bias Monte Carlo (CBMC) and molecular dynamics (MD) methods. It was observed by a previous theoretical work (Theor. Chem. Acc. (2012) 131:1214) that in gas-phase the MOx exists dominantly in syn-form and in aqueous solution in anti-form. The syn/anti free energy difference in the gas phase was used in the intramolecular parametrization and a rotational barrier of approximately 10 kcal mol⁻¹ was found. Molecular systems with barriers of this order of magnitude have been studied by experimental techniques. However, they have not been discussed yet comparing CBMC and MD simulations. In this work, we show that the intramolecular geometrical information such as bond lengths, angles and torsional angles sampled with CBMC and MD methods are equivalent. Nonetheless, only the CBMC simulations sample appropriately the syn/anti population ratio. With the CBMC configurations in gas phase, it was obtained 95% in syn-form and 5% in anti-form regardless the initial conformation. An inversion of the population was found in water, 25% in syn-form and 75% in anti-form. Comparing the gas phase and in-water CBMC sampling, it was observed that the MOx spends typically approximately 110 successive MC cycles in anti-form and approximately 2300 in syn-form in gas phase. While it was much larger with explicit water, approximately 400 times more for anti-form and approximately 6 times more for syn-form. We argue that this strong stabilization of the anti-form in aqueous solution, does not come from the MOx-water hydrogen bonds interactions, because they are the same for both conformations. Instead, the stabilization comes from the dipole-dipole interaction caused by a larger dipole moment of the MOx in the anti-form, 7.2 D, than in the syn-form, 5.2 D. With the MD sampled configurations in both conditions, we observe that the syn/anti conformational change is a very rare event due to the rotational barrier, which is approximately 17 times larger than the thermal energy. Therefore, the MD sampling of the MOx is not appropriated because it is strongly dependent on the initial conformation even for large simulations with 150 ns up to 400 ns for the isolated solute and for solute–solvent systems.     

Different approaches to the study of chelating agents for iron and aluminium overload pathologies

Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of “chelation therapy” is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings.

Exchange coupling in transition-metal complexes via density-functional theory: comparison and reliability of different basis set approaches

Theoretical methods based on density-functional theory with Gaussian, plane waves, and numerical basis sets were employed to evaluate the exchange coupling constants in transition-metal complexes. In the case of the numerical basis set, the effect of different computational parameters was tested. We analyzed whether and how the use of pseudopotentials affects the calculation of the exchange coupling constants. For the three different basis sets, a comparison of the exchange coupling constants and spin distributions shows that both the plane-wave and the numerical basis set approaches are accurate and reliable alternatives to the more established Gaussian basis functions.     

Ornithine and lysine based lipotripeptides: synthesis and comparison of transfection efficiency

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Chiral benzisoselenazolones: conformational analysis based on experimental and DFT calculated Se NMR

A series of new enantiomeric N-substituted benzisoselenazol-3(2H)-ones were prepared from 2-(chloroseleno)benzoyl chloride and 9-amino-deoxyquinine (both 9-native and 9-epi) as well as the other chiral primary amines. The ⁷⁷Se NMR parameters for the obtained benzisoselenazolones were measured and theoretically calculated at the DFT level of theory using B97-2 hybrid functional and cc-pVTZ basis set. The DFT ⁷⁷Se chemical shifts for the lowest energy conformers were in agreement with the experimental data, while the conformers of higher energy showed markedly worse fit. Interestingly, the preferred conformation for 2-(1-arylalkyl)-benzisoselenazolones is the gauche type (Se–N–C–H≈±180°), and it is in agreement with those observed in crystals (X-ray). The calculation predicts a much higher sensitivity for the ⁷⁷Se chemical shift of the conformation than for the corresponding ¹³C data. In the ⁷⁷Se NMR spectra of chiral benzisoselenazolones with added racemic or l-N-Boc-phenylglycine, chiral discrimination could not be observed mostly due to signal broadening. In the ¹H NMR spectra, the benzisoselenazole derived from epi-9-amino-deoxyquinine induced splittings of the amino acid signals, thus allowing for discrimination of the enantiomers.     

Experimental and theoretical study of the conformational analysis of hydrochlorothiazide

Hydrochlorothiazide was characterized in order to determine the possible structural modifications at different temperatures due to its importance as a drug to control heart diseases and a diuretic. This compound could present conformers due to the rotation of the NH₂ group, which was studied by using different techniques such as Thermal Analysis, IR spectroscopy, X-Ray Diffraction and complemented by theoretical calculations. The theoretical and experimental results point to the conclusion that no polymorphic forms are present in the compound under study. The calculations confirm the apparent difference in values between theory and experiment for the vibration frequencies explained by the hydrogen bonds between near molecules.     

A comparison of a direct search method and a genetic algorithm for conformational searching

We present results from the application of two conformational searching methods: genetic algorithms (GA) and direct search methods for finding low energy conformations of organic molecules. GAs are in a class of biologically motivated optimization methods that evolve a population of individuals in which individuals who are more “fit” have a higher probability of surviving into subsequent generations. The parallel direct search method (PDS) is a type of pattern search method that uses an adaptive grid to search for minima. Both methods found energies equal to or lower than the energy of the relaxed crystal structure in all cases, at a relatively small cost in CPU time. We suggest that either method would be a good candidate to find 3-D conformations in a large scale screening application. © 1996 by John Wiley & Sons, Inc.     

A new class of non-racemic chiral macrocycles: a conformational and synthetic study

Amino alcohols have been used to introduce non-racemic chirality into macrocycles using a modular approach that relies on a Heck macrocyclisation reaction. A wide variety of macrocycles have been synthesised, and their structures studied using X-ray crystallography and molecular modelling. A fragmentation reaction encountered during the use of (S)-1,1-dimethylvalinol revealed that carboxylic acids generate acylals under reaction conditions often used for Heck reactions.     

A conformational analysis of o,o'- and m,m'-disubstituted diphenyl disulfides and diselenides based on dipole moments and Kerr constants

Conclusions Effective conformations have been established for the o,o'- and m,m'-disubstituted diaryl disulfides and diselenides. Angles of aryl group rotation relative to the C-E-E plane have been determined for these compounds. One of the substituents lies inside, and one outside, the C-E-E-C dihedral angle.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1024–1028, May, 1979.     

Evaluation of docking/scoring approaches: A comparative study based on MMP3 inhibitors

An increasing number of docking/scoring programs are available that use different sampling and scoring algorithms. A reliable scoring function is the crucial element of such approaches. Comparative studies are needed to evaluate their current capabilities. DOCK4 with force field and PMF scoring as well as FlexX were used to evaluate the predictive power of these docking/scoring approaches to identify the correct binding mode of 61 MMP-3 inhibitors in a crystal structure of stromelysin and also to rank them according to their different binding affinities. It was found that DOCK4/PMF scoring performs significantly better than FlexX and DOCK4/FF in both ranking ligands and predicting their binding modes. Most notably, DOCK4/PMF was the only scoring/docking approach that found a significant correlation between binding affinity and predicted score of the docked inhibitors. However, comparing only those cases where the correct binding mode was identified (scoring highest among sampled poses), FlexX showed the best `fine tuning' (lowest rmsd) in predicted binding modes. The results suggest that not so much the sampling procedure but rather the scoring function is the crucial element of a docking program.     

Synthesis and conformational analysis of Substance P antagonist analogues based on a 1,7-naphthyridine scaffold

Two analogues of formerly described piperidine-based Substance P antagonists have been synthesised using an intramolecular Diels-Alder reaction of 1-(4-pentenyl)-3-phenyl-2(1H)-pyrazinones, followed by acidic methanolysis of the strained adducts to form the 8-oxo-6-phenyldecahydro [1,7]-naphthyridine-6-carboxylate esters and further conversion to the corresponding O-benzyl substituted 6-(hydroxymethyl) target compounds. Conformational analyses of intermediates and the final products are presented, based on ¹H NMR and modelling data.