Chirality/Chiral shift reagents

Chiral liquid crystals Chiral recognition Chiral separation Chiral separations Chiral shift reagents... 

If the amount of the sample is sufficient, then the carbon skeleton is best traced out from the two-dimensional INADEQUATE experiment. If the absolute configuration of particular C atoms is needed, the empirical applications of diastereotopism and chiral shift reagents are useful (Section 2.4). Anisotropic and ring current effects supply information about conformation and aromaticity (Section 2.5), and pH effects can indicate the site of protonation (problem 24). Temperature-dependent NMR spectra and C spin-lattice relaxation times (Section 2.6) provide insight into molecular dynamics (problems 13 and 14). 

Fig. 2.7. NMR spectrum of 1-phenyIethyIamine in the presence of a chiral shift reagent, showing differential chemical shift of methine and methyl signals and indicating ratio of R- to iS-enantio-mers. [Reproduced from J. Am. Chem. Soc. 93 5914 (1971) by permission of the American Chemical Society.]...

The enantiomeric excess was determined by HNMR with ( + )-(/ )-binaphthol as a chiral shift reagent. The absolute configuration of the adducts was not determined. 

A 100 MHz. proton magnetic resonance spectrum (chloroform d) of the amine in the presence of an equal amount of the chiral shift reagent, tris[3-(trifluoromethylhydroxymethylene)-d-camphorato]euro-pium(III)4 (submitters), or in the presence of an equal amount of tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium-(III) (checkers), revealed that the product contained no detectable enantiomeric isomer. 

The submitters report obtaining the product in 99% yield. The enantiomeric excess of the Mosher ester of 3 was measured to be 98% using a Chiralcel OD column (40% 2-propanol/hexane). This optical purity measurement substantiated the optical purity assessment made by 111 NMR studies of 3 and racemic 3 prepared using a different method3. Addition of the chiral shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III) resulted in clear resolution of the respective aromatic proton signals for the two enantiomers, which was demonstrated with the racemate. Under similar conditions, NMR analysis of 3 showed that within the detectable limits of the experiment (ca. <3%), there was none of the disfavored enantiomer. 

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). 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

After removal of the solvent, the residue was eluted through a short silica gel column to remove the catalyst (elution with hexane ethyl acetate = 1 2). The eluent was concentrated in vacuo to give the product 2 (99 % yield) and the diastereoselectivity was determined by HPLC analysis (99 %). The enantios-electivity of the product was determined by lH NMR analysis with chiral shift reagent (+)-Eu(dppm) in CDCI3 and by chiral HPLC analysis (Chir-alcel-OD). 

A 2 1 (- )-90-LAH reagent was employed in the asymmetric synthesis of a cij-diol (91) by reduction of c/j-2-acetoxy-6-phenylcyclohexanone (99,100). Diol 91 is of interest as the tetrahydro derivative of a metabolite obtained from the microbial oxidation of biphenyl. Diol 91 was obtained in 46% e.e. as determined by NMR in the presence of a chiral shift reagent. It was shown to have the absolute stereochemistry (lS,2/ )-dihydroxy-3(S)-phenylcyclohexane by oxidation to ( + )-2-(S)-phenyladipic acid of known absolute stereochemistry. 

Granot and Reuben report an example of an aqueous chiral shift reagent. In water, several proton resonances of norepinephrine exhibit nonequivalence in the presence of cobaltous adenosine-5 -triphosphate (101). 

Finally, one should note that the determination of enantiomeric purity by means of chiral shift reagents appears to be more advantageous than the method of Pirkle because the magnitude of nonequivalence A5 is generally greater, thus leading to a more accurate... 

Recently, new examples of asymmetric induction in the Pummerer reaction of chiral sulfoxides have been described. Oae and Numata (301) reported that the optically active a-cyanomethyl p-tolyl sulfoxide 275 undergoes a typical Pummerer rearrangement upon heating with excess of acetic anhydride at 120°C, to give the optically active a-acetoxy sulfide 276. The optical purity at the chiral a-carbon center in 276, determined by means of H- NMR spectroscopy using a chiral shift reagent, was 29.8%. 

The use of chiral shift reagents, e.g. tris-[3-(trifluoromethyl)- or -(hepta-fluoropropyl)-hydroxymethylene)-d-camphorato)]europium, praseodymium, or ytterbium, in the determination of optical purities of chiral alcohols, ketones, esters, epoxides, amines, or sulphoxides, or in the separation of n.m.r. signals of internally enantiotopic protons e.g. PhCHjOH), has been described. 

---