Determination of enantiomeric excess

A. Dossena, G. Galaverna, R. Coiradini and R. Marchelli, Two-dimensional liigh performance liquid chromatographic system foi the determination of enantiomeric excess in complex amino acid mixtures. Single amino acids analysis , ]. Chromatogr. 653 229-234 (1993). 

Boyd DR, ND Sharma, R Boyle, RAS McMordie, J Chuna, H Dalton (1992) A h NMR method for the determination of enantiomeric excess and absolute configuration of ciT-dihydrodiol metabolites of polycyclic arenes and heteroarenes. Tetrahedron Lett 33 1241-1244. 

NMR can be a powerful tool for determination of enantiomeric excess or absolute configuration of the optically active compounds, however, these processes require the use of some auxiliaries, for example, chiral lanthanide shift reagents or chiral derivatising agent. In many cases, the starting point for determination of enantiopurity of amines, amino acids or diols is the formation of chiral imines. 

The determination of enantiomeric excess (96% ee) of the Claisen rearrangement products 4a and 4b is accomplished by a Mosher 1H NMR analysis of the (R)-O-acetylmandelate esters that are derived from the primary alcohols. For example, 4a is reduced with UAIH4 (1.0 equiv/THF/0°C) followed by esterification of the resulting primary alcohol with (R)-O-acetylmandelic acid (DCC, 1.5 equiv/cat. DMAP/CH2CI2) to afford the mandelate ester in 91% yield (two steps).3... 

Related to the NMR use of CLSRs is the application of chiral solvating agents (CSAs), so-called because the first report of the determination of enantiomeric excess by NMR was that of a partially racemic sample of 2,2,2-trifluro-l-phenylethanol (98),... 

Determination of Enantiomeric Excess Without Separation of Products. To determine the enantioselectivity in a given enzyme-catalyzed kinetic resolution, the reaction product very often must be isolated before the determination. This is very time-consuming when one... 

The determination of enantiomeric excess by MS detection withont chromatographic or electrophoretic separation prior to detection has also grown in interest. The enantiomeric discrimination in the gas phase by MS can be obtained in different ways, for example, by the formation of diastereomeric complexes and from collision-indnced dissociation in the MS/MS mode. For further information abont this topic, see the review by Schng and Lindner [112],... 

NMR shift differences between groups which are enantiotopic by external comparison (i.e. in enantiomers) may likewise be induced by either chiral solvents 26 27) or chiral shift reagents 52). Integration of the areas of signals of enantiomers so shifted is used for the determination of enantiomeric excess, a topic which cannot be taken up here but has been discussed elsewhere 53). 

Sawada, M. et al., Determination of enantiomeric excess for amino acid ester salts using FAB mass spectrometry. Chem. Commun. 1569-1570 (1998)... 

The rapid development of combinatorial screening methods has been accompanied by the development of ever more efficient high-throughput analysis technologies. These not only enable analysis of catalytic activity but also the determination of enantiomeric excess [2, 21]. Taking these developments together, research in this field can be expected to yield highly active and selective catalysts with structures that could have not been predicted by conventional means. 

The high-throughput screening of asymmetric catalysts requires efficient techniques for the determination of enantiomeric excesses. Siuzdak and Finn recently developed a method for that purpose which makes use of kinetic resolution and mass spectrometry [19]. Various chiral secondary alcohols and amines were esterified on... 

A review appeared on the practice and theory of enantioselective CGC with optically active selectors, e.g. 3-(perfluorobutyryl)-(17 )-camphorate residues forming complexes on a functionalized polysiloxane stationary phase (e.g. Chirasil, 65) SEC operates at temperatures lower than those of CGC, thus allowing better resolution, especially of thermally unstable enantiomers (e.g. those based on restricted free rotation, as is the case of dimethyl l,l -binaphthyl-2,2 -dicarboxylate, 66 ). Various analytical problems were addressed, such as determination of enantiomeric excess, assignment of absolute configuration, the elusive separation of protio- and deuterio-substituted enantiomers and the semipreparative separation of enantiomers. The following chromatographic parameters are related to the chemical and thermodynamic properties enclosed in parentheses of the enantiomeric system (i) peak retention (chemoselectivity, —AG), (ii) peak separation... 

Reagent for Determination of Enantiomeric Excesses and for Chemical Resolution of Alcohols and Amines. 10-... 

Preparative Methods cheap and readily available racemic trans-1,2-diaminocyclohexane can be resolved with d-(—)-tartaric acid, giving (15, 25 )-diaminocyclohexane with >98% enantiomeric excess. Detailed procedures for the resolution have been published. Determination of enantiomeric excess is made by HPLC analysis of the A(Af -bis(m-toluyl) derivative on a Pirkle L-Leucine-DNB column. Direct separation of enantiomers by preparative HPLC on a chiral colunrn has also been described. ... 

In addition, OPEN is an efficient chiral solvating agent for determination of the enantiomeric excess in the H NMR analysis of various chiral mono- and dicarboxylic acids including a-arylpropanoic and a-halo carboxylic acids. The chemical-shift non-equivalence (S A) in certain diastereomeric complexes is greater than 0.05 ppm. A DPEN/Pd(II) complex can be used for determination of enantiomeric excess of the non-protected chiral amino acids by H and C NMR analysis. For example, Pd[(S,S)-dpen](D20)2 and racemic alanine with a base forms the square-planar complex (eq 14). The 5 A of H-NMR resonance in the diastereomeric complexes in D2O is 0.056 ppm, while this complex hardly dissolves in D2O. 

With chiral stationary phases, chromatographic separation of enantiomeric ferrocene derivatives is possible. An apparatus for the resolution of ferrocenyl alcohols and other compounds on triacetylcellulose has been described [60]. Analytical enantiomer separation of ferrocenyl alcohols, ethers, sulfides, and amines for the determination of enantiomeric excesses is best achieved on cyclodextrin bonded phases [61]. 

The protocol for separating a partial racemic mixture calls for the chromatographic conditions to be modified in such a way that the minor component elutes first and is not lost in the trailing edge of the band for the major component. Errors encountered in the determination of enantiomeric excesses when they are in the range of 98-100%, or close to unique protocol is required for every chiral analyte assayed by chiral-HPLC, requiring considerable development time and constant review of the procedure. 

DETERMINATION OF ENANTIOMERIC EXCESS IN PARTIAL RACEMIC MIXTURES... 

Lodevico, R.G. Bobbitt, D.R. Edkins, T.J. Determination of enantiomeric excess using a chiral selective separation mode and polarimetric detection. Talanta 1997, 44, 1353-1363. 

Mangeney, P, Alexakis, A, Normant, J-F, Resolution and determination of enantiomeric excesses of chiral aldehydes via chiral imidazolidines. Tetrahedron Lett., 29, 2677-2680, 1988. 

Hundeck HG, Weifl M, Scheper T, Schubert F (1993) Calorimetric biosensor for the detection and determination of enantiomeric excesses in aqueous and organic phases. Biosens Bioelectron 8 205-208... 

R518 R. Rothchild, NMR Methods for Determination of Enantiomeric Excess , Enantiomer, 2000, 5, 457... 

Wenzel,T.).,Wilcox, J. D. Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy. Chirality, 2003,15, 256-270. 

Something to watch out for is unwanted kinetic resolutions. An example is found in the determination of enantiomeric excess by making derivatives like Mosher s esters using an optically pure reagent. Consider the following. An alcohol 27 has been made in 60% ee - four parts S alcohol to one part R alcohol - but the ee has not yet been determined. Suppose that a reaction to make Mosher s esters is done to 80% completion and that the R alcohol reacts very much faster than the S. 

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