Marcelo A. Muñoz

Stereochemical Analysis of Leubethanol, an Anti-TB-Active Serrulatane, from Leucophyllum frutescens

Bioactivity-guided fractionation of the methanolic root bark extract of Leucophyllum frutescens led to the identification of leubethanol (1), a new serrulatane-type diterpene with activity against both multi-drug-resistant and drug-sensitive strains of virulent Mycobacterium tuberculosis. Leubethanol (1) was identified by 1D/2D NMR data, as a serrulatane closely related to erogorgiane (2), and exhibited anti-TB activity with minimum inhibitory concentrations in the range 6.25-12.50 μg/mL. Stereochemical evidence for 1 was gleaned from 1D and 2D NOE experiments, from 1H NMR full spin analysis, and by comparison of the experimental vibrational circular dichroism (VCD) spectrum to density functional theory calculated VCD spectra of two diastereomers.

Stereostructure reassignment and absolute configuration of isoepitaondiol, a meroditerpenoid from Stypopodium flabelliforme.

Careful examination of the published NMR data for isoepitaondiol, a meroditerpenoid from Stypopodium flabelliforme, suggests that its published structure 1 must be revised. On the basis of extensive 1D and 2D NMR studies, we now propose that structure 2, with a trans-anti-trans-anti-cis arrangement fits isoepitaondiol diacetate. The relative configuration of 2 was confirmed by single-crystal X-ray diffraction, while the absolute configuration was evidenced by vibrational circular dichroism in combination with DFT B3LYP/DGDZVP calculations.

Absolute configuration determination and conformational analysis of (−)‐(3S,6S)‐3α,6β‐diacetoxytropane using vibrational circular dichroism and DFT techniques

The absolute configuration of semisynthetic (-)-3alpha,6beta-acetoxytropane 1, prepared from (-)-6beta-hydroxyhyoscyamine 2, has been determined using vibrational circular dichroism (VCD) spectroscopy. The vibrational spectra (IR and VCD) were calculated using DFT at the B3LYP/DGDZVP level of theory for the eight more stable conformers which account for 99.97% of the total relative abundance in the first 10 kcal/mol range. The calculated VCD spectra of all considered conformations showed two distinctive spectral ranges, one between 1300 and 1200 cm(-1), and the other one in the 1150-950 cm(-1) region. When compared with the experimental VCD spectrum, the first spectral region confirmed the calculated conformational preferences, whereas the second region showed little change with conformation, thus allowing the determination of the absolute configuration of 1 as (3S,6S)-3alpha,6beta-diacetoxytropane. Also, the bands in the second region showed similarities between 1 and 2 in both the experimental and calculated VCD spectra, suggesting that these bands are mainly related to the absolute configuration of the rigid tropane ring system, since they show conformational independency, no variations with the nature of the substituent, and are composed by closely related vibrational modes.

Absolute configuration and 1H NMR characterization of rosmaridiphenol diacetate.

The correction of patented structure 1 of rosmaridiphenol, an antioxidant isolated from rosemary, Rosmarinus officinalis, was made recently. The correct structure is proposed as 11,12-dihydroxy-8,11,13-icetexatrien-1-one (2a) based on 2D NMR data. In order to further support the structure, this work reports the single-crystal X-ray analysis, the complete (1)H NMR assignment by full spin-spin simulation, and the absolute configuration of the diacetate 2b derived via vibrational circular dicroism measurements in comparison with density functional theory calculated data.

DFT-GIAO 1H and 13C NMR prediction of chemical shifts for the configurational assignment of 6β-hydroxyhyoscyamine diastereoisomers

1H and 13C NMR chemical shift calculations using the density functional theory–gauge including/invariant atomic orbitals (DFT–GIAO) approximation at the B3LYP/6‐311G++(d,p) level of theory have been used to assign both natural diastereoisomers of 6β‐hydroxyhyoscyamine. The theoretical chemical shifts of the 1H and 13C atoms in both isomers were calculated using a previously determined conformational distribution, and the theoretical and experimental values were cross‐compared. For protons, the obtained average absolute differences and root mean square (rms) errors for each comparison showed that the experimental chemical shifts of dextrorotatory and levorotatory 6β‐hydroxyhyoscyamines correlated well with the theoretical values calculated for the (3R,6R,2′S) and (3S,6S,2′S) configurations, respectively, whereas for 13C atoms the calculations were unable to differentiate between isomers. The nature of the relatively large chemical shift differences observed in nuclei that share similar chemical environments between isomers was asserted from the same calculations. It is shown that the anisotropic effect of the phenyl group in the tropic ester moiety, positioned under the tropane ring, has a larger shielding effect over one ring side than over the other one. Copyright

Determination of absolute configuration of salvic acid, an ent-labdane from Eupatorium salvia, by vibrational circular dichroism

The relative stereochemistry at C13 and the absolute configuration of salvic acid, a constituent of the leaves of Eupatorium salvia, were established as the 13-(R)-ent-labdane 1. The results follow from vibrational circular dichroism measurements of the derived O-methyl ether methyl ester 3 which were compared to DFT B3LYP/DGDZVP calculated spectra. The relative stereochemistry of salvic acid at C13 was independently verified by single crystal X-ray diffraction measurements of 1, and of its derived diol 4.

Diastereoisomeric assignment in a pacifenol derivative using vibrational circular dichroism

The configuration of a chiral center in semisynthetic (-)-(2R,5R,5aR,8zeta,9aS)- 2,8-dibromo-2,5,9,9a-tetrahydro-5-hydroxy-5,8,10,10-tetramethyl-6H-2,5a-methano-1-benzoxepin-7(8H)-one (3 or 4), prepared in two steps from (-)-(2R,5R,5aR,7S,8S,9aS)-2, 7-dibromo-8-chloro-2,5,7,8,9,9a-hexahydro-5,8,10,10-tetramethyl-6H-2,5a-methano-1-benzoxepin-5-ol, known as pacifenol 1, has been determined using vibrational circular dichroism (VCD) measurements. The vibrational spectra (IR and VCD) of diastereoisomers 3 and 4 were calculated using density functional theory (DFT) at the B3LYP/DGDZVP level of theory for the two conformers that in each case account for the total energetic distribution found in the first 10 kcal/mol range. The DFT conformational optimization of the 8R diastereoisomer 3 indicates the cyclohexanone exists almost exclusively in a boat conformation with a beta-equatorial bromine atom and an alpha-axial methyl group at the chiral center alpha to the carbonyl group, while for the 8S diastereoisomer 4 a 5:1 conformational distribution in favor of a chair conformation with an alpha-axial bromine atom and a beta-equatorial methyl group is calculated, suggesting due to well-known chair versus boat relative stabilities that the plausible diastereoisomer would be the 8S molecule. A comparison of the IR spectrum of the reaction product with the calculated spectra of 3 and 4 provided no means for the diastereoisomeric assignment, while from comparison of the VCD spectra it became immediately evident that the rearranged molecule possesses the 8R absolute configuration as shown in 3, in concordance with a single crystal X-ray diffraction study that could be refined to an R-factor of 2.9%.

Comparative antimicrobial study of the resinous exudates of some Chilean Haplopappus (Asteraceae)

The antimicrobiol properties and preliminary chemical information of the resinous exudates from twigs and leaves of nine Haplopappus species from Chile: H. diplopappus; H. anthylloides; H. schumannii; H. cuneifolius; H. velutinus; H. uncinatus; H. multifolius, H. illinitus and H. foliosus are presented. The results show that those species of genus Haplopappus share similar antimicrobial activities although they differ dramatically in the chemical composition.

Stereospecific 5JHortho,OMe couplings in methoxyindoles, methoxycoumarins, and methoxyflavones

Long‐range coupling constants 5JHortho,OMe were measured in series of methoxyindoles, methoxycoumarins, and methoxyflavones by the modified J doubling in the frequency domain method. The COSY and NOESY spectra revealed the coupling of the –OMe group with a specific proton at the ortho position and its preferred conformation. Homonuclear 1H–1H couplings were confirmed by irradiation of the –OMe signal. Density functional theory calculations of 5JHortho,OMe using the modified aug‐cc‐pVTZ basis set evidenced that the Fermi contact term shows good agreement with the experimental J values. Accurate chemical shift and coupling constant values followed after iterative quantum mechanical spectral analysis using the PERCH software. Copyright

DFT-GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)-scopolamine and (−)-hyoscyamine

The relatively large chemical shift differences observed in the 1H NMR spectra of the anticholinergic drugs (−)‐scopolamine 1 and (−)‐hyoscyamine 2 measured in CDCl3 are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas‐phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published 1H and 13C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent. Copyright