Chiral derivatising agents CDAs

Three types of chiral auxiliary are widely used. Chiral derivatising agents (CDAs)[ l form diastereomers while chiral solvating agents (CSAs)t l and chiral lanthanide shift reagents (CLSRs)t l form diastereomeric complexes in situ with the substrate enantiomers. 

An effective chiral auxiliary should induce significant NMR chemical shift anisochronicity in as large a range of substrates as possible. Further, if the sense of non-equivalence is consistent in a series of compounds, then once a standard of known stereochemistry has been studied the absolute configuration of the major and minor enantiomers present in chemically similar unknown mixtures can be deduced from the NMR spectra. 

The magnitude of the chemical shift non-equivalence is proportional to the size of the applied magnetic field. Lowering the temperature at which the spectrum is recorded can accentuate the anisochronicity between diastereomers. The use of non-polar solvents such as d-chloroform and, in particular, aromatic solvents such as de-benzene or dg-toluene offers considerable advantages. This effectively excludes the application of NMR methods for the assay of the enantiomeric purity of substrates which are only soluble in polar solvents like de-DMSO. It is unfortunate that numerous pharmacologically important compounds fall into this category. In such cases chiral GC or chiral HPLC methods may afford viable alternatives. Proton, i9p and 3ip are the most frequently studied nuclei. It is important to note that measured integrals will only report reliably on the enantiomeric purity in fully relaxed spectra free from any saturation effects. 

Despite these problems and limitations, chiral derivatisation remains the most widely used NMR technique for enantiomer resolution. CDAs are usually simple, multifunctional compounds which are often commercially available and claimed to be pure enantiomers. Derivatisation frequently involves esterification or amidation under non-racemising conditions. The method is reliable, which is not always the case with CSAs or CLSRs. In addition, the sense of nonequivalence is consistent allowing assignment of absolute configuration on the basis of chemical shift to be made with some confidence. Diastereomeric anisochronicity is usually sufficient to permit enantiomeric excess measurement to within 1% even with small applied magnetic fields ( 100 MHz). 

Chiral acids react with chiral alcohols or amines to form diastereoisomeric esters or amides respectively. Mislow andRabanl l first described chemical shift non-equivalence in the proton NMR spectra for diastereoisomeric 1-methylphenylethanoic acid esters of l-(2-fluorophenyl)-ethanol and observed some racemisation during the reaction. A systematic study was made thereafter of a series of substituted phenylethanoic acids as CDAs for the assay of alcohols (Table 3.1). Epimerisation a to the acid carbonyl was the cause of the racemisation observed by Mislow and Raban. In order to avoid this problem Mosher developed a-methoxy-a-trifluoromethyl-phenyl-acetic acid (MTPA), (10), as a CDA.f l It is stable to racemisation because it lacks an a-hydrogen. Induced chemical shift nonequivalence is typically 0.15 ppm (in CDCI3,298 K). A NMR study 

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The dlastereoisomer approach means that enantiomers contain a functional group that can be derivatised using a chemically and optically pure chiral derlvatislng agent (CDA) so that they become a mixture of diastereoisomers. Thus... 

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