M. E. Koscho, W. H. Pirkle / Tetrahedron: Asymmetry 16 (2005) 3345–3351
3351
reported. Typically, when usinga CSA, the chemical
shift differences of enantiomeric (or enantiotopic) nuclei
are small (<0.1 ppm),3 as has been observed with CSA 2
(analyte 11 beinga notable exception). Since the extent
of the observed non-equivalence is dependent on the
concentrations of the CSA and the analyte, the temper-
ature, and the solvent, one must be cautious when mak-
ingdirect comparisons between the data herein and the
literature data.
1 (250 · 4.6 mm, Regis Technologies, Morton Grove,
IL), with tri-tert-butylbenzene beingused as a void
volume marker. Semi-preparative chromatography
was carried out usinga commercial (3 R,4S)-CSP 1
(250 · 10 mm). The preparative resolution of CSA 2
was carried out usinga CSP derived from N,N-diallyl-
(S)-Naproxen (900 · 25 mm).11 All 1H NMR spectra
were recorded on a Varian U400 spectrometer operating
at 400 MHz in the deuterium lock mode at ambient tem-
perature (20 2 ꢁC), unless otherwise stated, with resid-
ual solvent signal used as an internal standard.
A few of the analytes used herein have been reported to
afford spectral non-equivalence in the presence of other
CSAs. For example, analyte 3 afforded a chemical shift
difference of 0.011 ppm in the presence of 2,2,2-triflu-
oro-1-(9-anthryl)ethanol, and 0.012 ppm in the presence
of 9,10-bis-(trifluoromethylcarbinol)anthracene (CSA-
analyte ratio of 2:1 in both cases).15 Greater chemical
shift differences were observed for the enantiomers of
analyte 3 in the presence of CSA 2, at a CSA–analyte
ratio of 1:10. A derivative of quinine (DDd = 0.022 ppm,
CSA–analyte ratio of 1:1 in CDCl3),16 and a tris-1-
(1-naphthyl)ethylamino substituted 1,3,5-triazine deriva-
tive (DDd = 0.030 ppm, CSA–analyte ratio of 1:1 in
CDCl3)17 have been used as a CSA for analyte 9 (com-
pare to Fig. 6). O-Acetyl mandelic acid (DDd =
0.075 ppm, CSA–analyte ratio of 1.2:1 in benzene-d6),18
and a-methoxy-a-(trifluoromethyl)phenyl acetic acid
(DDd = 0.035 ppm, CSA–analyte ratio of 1:1 in CDCl3;
DDd = 0.061 ppm, CSA–analyte ratio of 1:1 in pyri-
dine-d5)19 have been used as a CSA for analyte 13
(compare to Fig. 7). A bis-1-(1-naphthyl)ethylamino
substituted 1,3,5-triazine derivative CSA was also used
as a CSA for analyte 14 (DDd = 0.030 ppm, CSA–analyte
ratio of 1.2:1 in CDCl3; compare to DDd = 0.111 ppm,
CSA 2-analyte 14 ratio of 1:2 in CDCl3).17
4.2. Enantioresolution of CSA2
Injection of 1.249 gof CSA 2, onto a CSP derived from
N,N-diallyl-(S)-Naproxen (900 · 25 mm)11 afforded
592 mgof ( S)-CSA 2 (>99% ee) followed by 621 mg
(R)-CSA 2 (94.1% ee) elutingwith 15% THF/hexanes in
a single pass. The assignment of the absolute configura-
tion from the elution order is based on previous work.12
Acknowledgements
This work has been funded by grants from the National
Science Foundation and from Eli Lilly and Company.
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Undoubtedly, there are specific chiral compounds that
are capable of affordinggreater spectral non-equivalence
for each of the analytes reported herein. The utility of
CSA 2 is derived from the scope of analytes that can
successfully be assayed by this CSA (i.e., analytes with
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The solvents used were of HPLC grade or distilled prior
to use. Analytes were either commercially available
from previous studies or prepared by the literature
procedures. The preparation of CSA 2 has been previ-
ously reported.10 Analytical chromatography was
carried out with a commercial version of (3S,4R)-CSP