Nuclear magnetic resonance chirality investigation

Nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research has been used primarily in a classical, organic chemistry framework. Typical studies have included (1) the structure elucidation of compounds [1,2], (2) investigating chirality of drug substances [3,4], (3) the determination of cellular metabolism [5,6], and (4) protein studies [7-9], to name but a few. From the development perspective, NMR is traditionally used again for structure elucidation, but also for analytical applications [10]. In each case, solution-phase NMR has been utilized. It seems ironic that although —90% of the pharmaceutical products on the market exist in the solid form, solid state NMR is in its infancy as applied to pharmaceutical problem solving and methods development. 

Methods used to obtain conformational information and establish secondary, tertiary, and quaternary structures involve electron microscopy, x-ray diffraction, refractive index, nuclear magnetic resonance, infrared radiation, optical rotation, and anisotropy, as well as a variety of rheological procedures and molecular weight measurements. Extrapolation of solid state conformations to likely solution conformations has also helped. The general principles of macromolecules in solution has been reviewed by Morawetz (17), and investigative methods are discussed by Bovey (18). Several workers have recently reexamined the conformations of the backbone chain of xylans (19, 20, 21). Evidence seems to favor a left-handed chain chirality with the chains entwined perhaps in a two fold screw axis. Solution conformations are more disordered than those in crystallites (22). However, even with the disorder-... 

The second prerequisite for a stereochemical investigation is that an effective method for assigning configurations at the chiral phosphorus centers in substrates and products must be available. The methods in current use include X-ray diffraction crystallography, mass spectrometry, nuclear magnetic resonance and circular dichroism. The methods by which chiral phosphorothioates can be synthesized and configurationally analyzed are discussed in this section. 

The twisted structure of 4,5-dimethylphenanthrene (1) contributes to the chirality of the molecule. It was recognized early on that the ability to resolve the two enantiomers could provide supporting evidence for the nonplanarity of the aromatic system [1]. Determinations of the rates of racemization and the activation barriers of twisted chiral polyarenes have been actively pursued. Resolutions of the enantiomers to allow these investigations to proceed were achieved in several cases. In other cases, variable-temperature nuclear magnetic resonance (NMR) experiments were employed to provide insights into the configurational stabilities of the molecules. For practical applications, such as using these twisted compounds... 

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