Conformational Study of (8α, 8'β)-Bis (substituted phenyl)-lignano-9, 9'-lactones by Means of Combined Computational, Database Mining, NMR, and Chemometric Approaches (original) (raw)
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Physical Chemistry Chemical Physics, 2011
The conformational landscape of the structural isomers acetovanillone (apocynin, AV) and 6-hydroxy-3-methoxyacetophenone (HMAP) has been investigated in a supersonic jet using Fourier transform microwave spectroscopy. Two conformers have been detected in the jet-cooled expansion for each molecule (s-cis and s-trans in AV; s-trans and a-trans for HMAP), differing in the relative orientation of the acetyl and methoxy groups. Both molecules are stabilized by O-HÁ Á ÁO or O-HÁ Á ÁOQC hydroxyl intramolecular hydrogen bonds, either constraining the local conformations of the methoxy group in AV, or that of the acetyl group in HMAP. Internal rotation splittings have been observed in both conformers of each molecule, originated by the acetyl group, that yield information on the influence of the intramolecular hydrogen bonds on the methyl torsion. The similar internal rotation barriers in both molecules (6.6 and 7.4 kJ mol À1 in AV; 7.3 and 7.0 kJ mol À1 in HMAP) suggest that the acetyl torsion is only slightly affected by intramolecular hydrogen bonding. The absence of torsional tunnellings due to the methoxy group indicates torsional barriers above 10.2 and 8.9 kJ mol À1 for AV conformers, 10.1 and 10.4 kJ mol À1 for HMAP. Conformational ratios and relative free energies have been estimated from relative intensity measurements of the spectral lines. Ab initio (MP2) and density functional calculations using the recent M05-2X empirical functional have been used to aid the experimental work in describing the structures, internal rotation barriers and isomerization potentials.
Detailed 1H and 13C NMR structural assignment of three biologically active lignan lactones
Spectrochimica Acta Part A-molecular and Biomolecular Spectroscopy, 2006
In this paper we present a complete 1 H and 13 C NMR spectral analysis of three lignan lactones (methylpluviatolide, dimethylmatairesinol and hinokinin) by the use of techniques such as COSY, HMQC, HMBC and J-resolved. Complete assignment and all homonuclear hydrogen coupling constant measurements were performed, providing enough data also to the confirmation of the relative stereochemistry.
2008
The knowledge of a bioactive conformation of a known lead or potential lead compounds undoubtedly will offer a save of money and time consuming to pharmaceutical companies aiming towards the development of new drugs. This review article deals with the use of different approaches to explore conformers of biologically active molecules at various environments which may simulate the biological ones. The molecules under study are mostly synthetic organic, with low molecular weight or small peptides. Two of the major structural characteristics of these molecules are: (i) T. Mavromoustakos, S. Golic Grdadolnik, M. Zervou et al. 2 amphiphilicity; and (ii) existence of flexible and rigid pharmacophoric segments. The rigid part of the molecule does not possess much of interest in terms of conformational analysis. However, the flexible segment constitutes a challenging field for conformational analysis exploring of putative bioactive conformations. NMR spectroscopy is a powerful tool to derive putative bioactive conformers of biologically active molecules. Application of 2D NOESY or ROESY spectroscopy could provide enough information for this purpose. Thus, quantitative analysis of the cross peaks reveals interatomic distances between the nuclei interacting through space. When a molecule contains bonds that restraint the molecular motion resulting in different distinct conformations detected by NMR spectroscopy, the use of 2D EXSY spectroscopy can differentiate between conformational exchange processes and spatial interactions. Molecular Modeling (Computational Chemistry) is a supplementary tool for providing the visual means to medicinal chemists, who are interested in the design and synthesis of novel bioactive molecules. Thus, energy minimization algorithms, conformational analysis tools like grid scan, Monte Carlo and molecular dynamics simulations in combination with the experimentally derived distance restraints will determine the putative bioactive conformers. Conformational analysis in a simulated environment is not always sufficient. The derived low energy conformers within a range of energy should be docked in the active site of the receptor. In many cases, drug molecules containing flexible segments can easily adopt conformations with higher energies in the biological matrices or at the active site of the receptor. The increase of energy is then compensated by the many different favorable interactions In some cases, Quantum Mechanics calculations are useful and can be more informative in terms of conformational analysis. For example, chemical shift simulation of NMR spectra may screen low energy conformers derived from the coupling of conformational analysis techniques and NMR spectroscopy. Moreover, 3D QSAR studies provide valuable structural information concerning the optimum bioactive conformation.
Bioorganic Chemistry, 2005
The conformational properties of polygamain and morelensin, two aryltetralin lignan lactones, have been investigated in both the gas-phase and chloroform solution using DFT calculations at the B3LYP/6-311G(d,p) level. Results indicate that the conformation of polygamain is very rigid. Thus, the conformational flexibility of its five-membered rings is considerably restricted as reflects the pseudorotational parameters of the corresponding envelope conformations. On the other hand, morelensin shows a notable conformational flexibility, which is mainly due to its two methoxy groups. Accordingly, 16 minimum energy conformations with relative energies smaller than 2.4 kcal/mol were detected. Furthermore, chemical shifts for 13 C nuclei have been calculated using the GIAO method, results being compared with experimental data. A good agreement was found for both polygamain and morelensin.
The Journal of Organic Chemistry, 1993
The conformational analysis of substituted y-lactones with vicinal hydrogen atoms is carried out by the MM2/3JHH tandem. The agreement between experimentally available and calculated data is globally correct (rms = 1.16 Hz). A general preference for a hydroxyl group to occupy the equatorial position if it is on C-2 or the axial position if it is on C-3 or C-4 is observed as a consequence of the presence of H bond or of the gauche effect, respectively. (1) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J. Org. Chem. 1988,53, 4094. (2) As examplee see: (a) Vekemaus, J. A. M.; Chittenden, €2. G. F. J. Org. Chem. 1987,52,1093 and references cited therein. (b) Ortufio, R. M.; Bigorra, J.; Font, J. Tetrahedron 1988, 44, 5139. (c) Corbera, J.; Font, J.; Modvatje, M.; Ortufio, R. M.; SAnchez-Ferrando, F. J. Org.
Structural Chemistry, 2004
Conformational analysis of 9α-acetoxycumambrine A 1 and 8-O-isobutiryl-9α-acetoxycumambrine B 2 was carried out by low-temperature NMR studies. Results suggested that lactones 1 and 2 are mixtures of two distinctive conformers, I and II. Based on low-temperature 1 H NMR spectra, in four solvents, the thermodynamic parameters of I II exchange process were assessed. Energy of activation of I → II reaction was obtained by dynamic NMR simulations for both compounds. Results revealed that conformational exchange of lactones 1 and 2 occurs due to "chair twisted chair" interconversion of a heptane ring. The same PM3 semiempirical method was applied for geometry optimization of lactones 1 and 2, as well as of 9α-hydroxycumambrine A 3, 9α-acetoxycumambrine B 4, and cumambrine B 5. Table VII. Calculated and Experimental 3 J HH (in Hz) for Conformers of Compounds 1 and 2 J calc. J a exp. Compound Conformer J 7,8 J 8,9 J 7,8 J 8,9 J b exp. Compound Conformer J 7,8 J 8,9 J 7,8 J 8,9
Journal of Molecular Structure, 1992
The conformational behaviour of AsCH(CN)CH(Ar1)CH2COR (R = OCH,; N(CH,),; Ar' = Ph; A13 = Ph or 1-naphthyl) has been investigated by lH and 13C NMR spectroscopy. The vicinal proton-proton coupling constants were used together with those of carbon-proton couplings to provide information on the conformational preference in the compounds studied. The conformational distribution with respect to the C(2kC(3) bond is shifted to the conformation having trans Ph and COR groups. Coupling constants involving the cyano carbon atom and the methine proton are J&H = 2.0 Hz and &,a = 14.1 Hz. The conformation with the cyano group and the methine proton trans to each other, with gauche-oriented protons around the C(3)-C(4) bond is the preferred one for both isomers in the compounds investigated. The results obtained support the assumption that electrostatic (non-bonded attractive) interactions rather than steric demands operate as dominant factors in controlling the conformational equilibrium.