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A computational and spectroscopic study of two epimers of 2-hydroxymutilin was conducted to obtain assignments for the configuration of the carbon at the 2-position. Gas-phase structural models for (R)- and (S)-2-hydroxymutilin were optimized using density functional theory (DFT). These models were validated using internuclear distances measured from 1H nuclear Overhauser effect (NOE) build-up rates in CDCl3 solution. The models were subsequently used to predict NMR parameters using the hybrid B3LYP density functional. After linear scaling, the agreement between predicted gas-phase and observed solution-state chemical shifts was sufficient for relative stereochemical assignments, with an average absolute error of 0.16 and 1.47 ppm for 1H and 13C shifts, respectively. 1H–1H and 1H–13C coupling constants were also predicted using the B3LYP functional with the aug-cc-p-VTZ-J basis set and compared to experimental values (measured by J-resolved and gradient J-HMBC experiments). The predicted coupling constants were within 10% of their experimental values in most cases, and like the chemical shielding, allowed for relative stereochemical assignments of the isomers. DFT prediction of coupling constants gave more useful information than empirical parameterizations. Although just one chiral center changes between the two isomers, with no consequent conformational change and only two affected NOE restraints, predictable effects on 20 different chemical shielding and J-coupling values were observed. Including these values in the stereochemical assignment allows for additional confirmation of the stereochemical results, using data already available in 1D 1H spectra and 2D 1H–13C correlation spectra. Electronic and vibrational circular dichroism (ECD and VCD) spectra of the two isomers are also measured and compared with theoretical predictions. VCD was especially useful for determining the absolute stereochemistry of 2-hydroxymutilin and was found to be superior to ECD in this role. The combination of computational and spectroscopic work is shown to be a useful tool in the analysis of unknown mutilin derivatives or other compounds, such as those present as minor impurities or metabolites in pharmaceutical samples.

GT-2331 [(+)-1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the histamine H3 receptor, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X-ray diffraction studies have provided conflicting data, leaving its three-dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)-enantiomer. Chirality, 2007. © 2007 Wiley-Liss, Inc.

The binding of two isomeric 2-[(chysenylmethyl)amino]-2-methyl- 1 ,3-propanediols (AMAPs) to the biopolymer poly(dG-dC)"poly(dG-dC) was studied using Raman spectroscopy. The Raman spectra of the bound AMAPs were obtained by subtracting the Raman spectrum of the biopolymer in buffered aqueous solution from those recorded for the AMAP-DNA binary complexes. The difference method applied here has been used in other studies to obtain spectra of small molecules bound to macromolecules of biological origin (Yue, K.T. et al., J. Raman Spectrosc., 20, 541-545, 1989, and references therein). Due to the extremely low number of Raman active lines observed in the spectra of these AMAPs, it was also possible to study perturbations in the Raman spectrum of the complexed biopolymer. Spectroscopic data indicated that both AMAPs intercalate with DNA, in agreement with viscometric measurements for these compounds; however, some differences were observed in the Raman spectra of DNA complexed with these drugs, suggesting that the specific AMAP-DNA binding interactions are different.© (1990) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

While incorporating oxazoles into known PPARy agonist an unexpected 6,5,6-tricylic lactam was isolated as the major product.

Reversed-phase high-performance liquid chromatography (HPLC) was used to measure the lipophilicities of a series of biphenyl acids and their non-acid precursors. Values obtained by HPLC for the precursors were as predicted from the calculated lipophilicity values. For biphenyl acids, a systematic deviation in the correlation of calculated log P and log k′ was observed (hydrogen-bond acceptors and non-hydrogen-bonding substituents described two separate lines in the correlaton). An explanation of these results is presented, based on steric effects which control the way the biphenhyl acids interact with the stationary phase.

Capacity ratios (k') for a set of small organic compounds of miscellaneous structure were measured under a variety of reversed-phase liquid chromatoghraphic conditions. The capacity ratios from these experiments were correlated with the binding of these solutes to bovine serum albumin (BSA). Hydrophobic binding of small molecules to BSA is considered to be a nonspecific process (i.e., requiring no special orientation or restriction of movement of the solute molecules) and serves as a model for the hydrophobic binding of small molecules to other macromolecules, such as hemoglobin and ribonuclease. Standard deviations from these correlations were compared using the null hypothesis to determine the set of chromatographic conditions giving the best correlation with the binding constants. The null hypothesis was again applied to compare the correlation of the best chromatographic data with binding to the correlation of the binding data with the octanol-water partition coefficients of these compounds. ...

The development of a method for determining hydrophobicity constants for small, organic molecules by reversed-phase liquid chromatography (RPLC) is presented. The method uses capacity ratios measured at a number of different compositions of methanol to obtain derived values, denoted log k'w, upon which a new scale of hydrophobicity constants can be developed. This scale eliminates potential problems such as peak inversion that hamper RPLC methods using isocratic data to estimate hydrophobicity. The differential hydrogen bond effect observed in most correlations of RPLC data with logarithms of octanol-water partition coefficients (log Po/w) for compounds of opposite net hydrogen bonding capabilities (noncongeners) was minimized by adding trace quantities of n-decylamine and 1-octanol to the eluent and using an octyl-modified silica gel stationary phase. Values of log k'w are shown to be largely column-independent as long as the hydrophobic properties of columns are similar. The correlation of log k'w values with the logarithms of bovine serum albumin binding constants (log 1/C) is shown to be statistically indistinguishable from the correlation of log 1/C with log Po/w, indicating that this data models log 1/C as well as log Po/w for these compounds. Additionally, the chromatographic system is automatable and thus capable of higher sample throughput than measurements of log Po/w by the shake-flask method.

The dynamic range of a polycratic reversed-phase liquid chromatographic (RPLC) method for measuring hydrophobicity constants (log k ′ w ) for non-ionic, organic molecules was examined. Evidence is presented that indicates that the differential hydrogen bonding effect present in most RPLC methods has been minimized by selection of appropriate stationary and mobile phase conditions. Thus, values of log k ′ w determined for compounds of different net hydrogen bonding properties (non-congeners) can be compared directly. Results indicate that noncongeners congeners with hydrophobicities varying between −0.20 ≤ log k ′ w ≤ 5.27 can be measured by this procedure. Additionally, the net hydrogen bonding property of any solute molecule can be predicted from the chromatographic experiment. Finally, the suppression of hydrogen-bonding discrimination effects in this method is shown to be a result of the low levels of octanol and alkylamine added to the mobile phase.