Nuclear magnetic resonance chiral compounds

Online detection using 4H nuclear magnetic resonance (NMR) is a detection mode that has become increasingly practical. In a recent application, cell culture supernatant was monitored on-line with 1-dimensional NMR for trehalose, P-D-pyranose, P-D-furanose, succinate, acetate and uridine.33 In stopped-flow mode, column fractions can also be analyzed by 2-D NMR. Reaction products of the preparation of the neuromuscular blocking compound atracurium besylate were separated on chiral HPLC and detected by 4H NMR.34 Ten isomeric peaks were separated on a cellulose-based phase and identified by online NMR in stopped-flow mode. 

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. 

Enantiomers have identical chemical and physical properties in the absence of an external chiral influence. This means that 2 and 3 have the same melting point, solubility, chromatographic retention time, infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectra. However, there is one property in which chiral compounds differ from achiral compounds and in which enantiomers differ from each other. This property is the direction in which they rotate plane-polarized light, and this is called optical activity or optical rotation. Optical rotation can be interpreted as the outcome of interaction between an enantiomeric compound and polarized light. Thus, enantiomer 3, which rotates plane-polarized light in a clockwise direction, is described as (+)-lactic acid, while enantiomer 2, which has an equal and opposite rotation under the same conditions, is described as (—)-lactic acid. 

Due to the great complexity of this class of molecules, nuclear magnetic resonance (NMR) and mass spectroscopy (MS) are the tools most widely used to identify cucurbitacins. Both one- and two-dimensional NMR techniques have been employed for the structural elucidation of new compounds 2D NMR, 1H-NMR, 13C-NMR, correlated spectroscopy (COSY), heteronuclear chemical shift correlation (HETCOR), attached proton test (APT), distortionless enhancement by polarization transfer (DEPT), and nuclear Overhauser effect spectroscopy (NOESY) are common techniques for determining the proton and carbon chemical shifts, constants, connectivity, stereochemistry, and chirality of these compounds [1,38,45-47]. 

In contrast, high-resolution nuclear magnetic resonance measurements of chiral compounds aim at a detection of parity violating frequency shifts which are caused by parity violating nuclear spin-dependent effects [53, 54,56,67]. These effects are also expected to contribute predominantly to... 

The first four-component calculations on parity violating effects in chiral molecules were performed in 1988 by Barra, Robert and Wiesenfeld [54] within an extended Hiickel framework. Interestingly, this study was on parity violating chemical shift differences in the nuclear magnetic resonance (NMR) spectra of chiral compounds and hence focused as well on the nuclear spin-dependent term of Hpv. Shortly later, however, also the first four-component results on parity violating potentials obtained with an extended Hiickel method were published by Wiesenfeld [150]. 

ECD, VCD, Raman optical activity (ROA), and ORD are at disposal in a spectral range between the IR and the vacuum UV. ACD and AORD, the CD and ORD of chiral anisotropic phases are only available in the UV/vis spectral range. The specific rotation, as a standard, is measmed with the sodium D-line. For special applications other lines, e.g., mercury lines, have been taken. Indirect methods for chiroptical analyses are the nuclear magnetic resonance (NMR) spectroscopy of diastereomeric compounds and the chiral induction of cholesteric phases (helical twisting power (HTP)) combined with ACD/ CD and the corresponding selective reflection. 

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... 

Chiral chromatographic separation techniques such as GC, HPLC, and CE provide the real separation of enantiomers. By real, one means that the two enantiomers of the racemates can actually be separated and obtained in individual containers. Particularly for chiral preparative HPLC, both the optically pure enantiomers can be obtained after the chiral chromatographic separation. However, in spectroscopic techniques, there is no real separation of enantiomers. Nonetheless, chiral spectroscopic techniques are still very important and useful resources for chiral technology in that they can rapidly and accurately determine the enantiopurity of chiral compounds. In addition, they can offer important information regarding the structure-property relationship and differentiation mechanism during chiral interaction and recognition. Recently, CILs have been used as the chiral selectors in spectroscopic techniques such as nuclear magnetic resonance (NMR), fluorescence, and near infrared (NIR). 

Branched fatty acids, known as iso-acids and anteiso-acids, occur normally in small quantities in fats. Their synthesis begins with the amino-acids valine and isoleucine (Figure 3.12). This has been demonstrated with radio-labelled isotopes, by radio-active monitoring and with stable isotopes by C nuclear magnetic resonance spectroscopy or mass spectrometry. Both isobutyric acid and 2-methylbutyric acid are common defensive compounds among insects. Note that a chiral centre is introduced in 2-methylbutyric acid and anteiso acids. 

Chemists have developed an extensive set of specific chemical reactions for which the enantiomeric properties are well known. In many cases, the absolute structure of the target natural product is not known, so chemists make a variety of compounds with different R or S chiral centers and compare various chemical and physical measurements such as optical rotation or nuclear magnetic resonance spectroscopy (NMR) from the synthesized compound and the natural product to see if they are the same. A second common approach is to S)mthe-size racemic mixtures and develop a procedure to separate and... 

Machida Y, Kagawa M, Nishi H. Nuclear magnetic resonance studies for the chiral recognition of (+)-(R)-18-crown-6-tetracarboxylic acid to amino compounds. J. Pharm. Biomed. Anal. 2003 30 1929-1942. 

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