Chiral shift reagents ee determination

The presence of asymmetric C atoms in a molecule may, of course, be indicated by diastereotopic shifts and absolute configurations may, as abeady shown, be determined empirically by comparison of diastereotopic shifts However, enantiomers are not differentiated in the NMR spectrum. The spectrum gives no indication as to whether a chiral compound exists in a racemic form or as a pure enantiomer. 

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The enantiomeric excess (ee) of the hydrogenated products was determined either by polarimetry, GLC equipped with a chiral column or H-NMR with a chiral shift reagent. Methyl lactate and methyl 3-hydroxybutanoate, obtained from 1 and 2, respectively, were analized polarimetry using a Perkin-Elmer 243B instrument. The reference values of [a]o(neat) were +8.4° for (R)-methyl pyruvate and -22.95° for methyl 3-hydroxybutcinoate. Before GLC analysis, i-butyl 5-hydroxyhexanoate, methyl 5-hydroxyhexanoate, and n-butyl 5-hydroxyhexanoate, obtained from 1, 5, and 6, respectively, were converted to the pentanoyl esters, methyl 3-hydroxybutanoate was converted to the acetyl ester, and methyl 4-methyl-3-hydroxybutanoate obtained from 2 was converted the ester of (+)-a-methyl-a-(trifluoromethyl)phenyl acetic acid (MTPA). 

The ee value of the enol acetate is determined indirectly by chemical correlation and is based on H-NMR spectroscopy of a derivative in the presence of a chiral shift reagent. 

Determined by two methods a) reduction with NaBH4 to the corresponding alcohol and acetylation, ee was then determined by 1H NMR using a chiral shift reagent, or b) the ephedrine method 29 using 13C-NMR spectroscopy on the derived oxazolidines. 

When the above-mentioned ring expansion with diazomethane 74) of trimethyl-dioxo[2.2]metacyclophane 65 (methylation was necessary to increase the inversion barrier to > 130 kJ) was performed in the presence of optically active alcohols at —60 °C, asymmetric induction occurred to an extent of ca. 40% ee (enantiomeric excess as determined by nmr-spectroscopy in the presence of chiral shift reagents)85). (+)-DibutyI tartrate favoured the dextrorotatory diketone 66 ([a]D 160° for the optically pure product) — the isomeric 67 was formed only with 3% ee (—)-ethyl lactate on the other hand led to an excess of (+)-67 ([a]D +240°) but gave (+)-66 with only 10% ee85). 

De-values were determined either 1H- or 13C-nmr-speetroscopically or by capillary gas chromatography. Ee-values were determined mainly by 1 H-nmr-spectroscopy using chiral shift reagents. >95% de or ee was assumed, if only one stereoisomer was detectable in the spectrum. 

On hydrolysis of 32 (2 equivalents 0.25 N HC1, r.t.) L-Val-OCH3 and the (R)-amino acid methyl esters 34 are liberated. Their ee can be determined H-nmr-spectroscopically using chiral shift reagents (Table 4)16). 

Enantioface-differentiating conjugate additions have also been performed using modified hydrolytic enzymes14. Thus, the addition of diethylamine to ethyl ( )-4,4,4-trifluoro-2-butenoatc in an organic solvent is catalyzed by a lipase from Candida cylindracea, a-chy-motrypsin or pig liver esterase to afford ethyl (-)-3-diethylamino-4,4,4-trifluorobutanoate in moderate yield (36-47%) and low optical purity (8-37% ee, as determined by l9F NMR using a chiral shift reagent)14. 

Thus, the combination of 2-sulfonylmethyl-2-propenyl carbonate with an unsaturated ester or ketone, catalyzed by chiral ferrocenylphosphane palladium(O) complexes, forms a mixture of cis- and /ra/w-products. The ratio of the products as well as their corresponding ee is dependent on the precise nature of the ferroceny]-based phosphane. The use of the ligand incorporating an additional 1,2-diol functionality leads to the best results with ee values of 75 % and 78 % from the unsaturated ketone, as determined by chiral shift reagent NMR [Eu(hfc),]. For comparison, the use of (S.S)-Chiraphos or (+)-BINAP as phosphane leads to ee values in the range 4 46%. 

The diastereomeric excess (de) of two diastereomers a and b is defined by the formula (de) = [a] — [b] / [a] + [b], where [a] > [b]. Note that the diastereomeric excess tells us nothing about the enantiomeric purity of the diastereomers a and b. It is sometimes seen in the literamre that (ee) and (de) are considered as being equivalent, in particular when the ee) is determined by NMR with the use of a chiral shift reagent. This only makes sense if the ee) of the shift reagent itself is equal to one. 

NMR) Nuclear magnetic resonance of various nuclei. Where used for ee determination, either chiral shift reagent or diastereomeric derivatization is implied. 

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