Chiral amines, including amino acids, have a central
importance in both chemistry and biology. Several CDAs
have been developed to determine the absolute configuration
of the amines,9 but MTPA10 and MPA11 are the two most
frequently used reagents. Because of the complexity of the
conformational distribution, however, the amides derived
from these reagents have small ∆δRS values in general, and
the development of more efficient CDAs is required. To solve
this difficulty, more effective CDAs have been developed
with bigger ∆δRS by taking advantage of intramolecular
hydrogen bonds12 or chelation control via metals.13 Here,
we report that 2′-methoxy-1,1′-binaphthalene-8-carbaldehyde
(MBC, 1),14 which converts the chiral amine substrates to
corresponding imines, is a useful CDA for chiral amines that
produces sufficiently greater ∆δRS values because the pro-
spective conformations of the imines are more simple than
those of the amides.
crystallography data of 2 and the large chemical shift
differences (∆δ 0.35 ppm) between each methyl in the iso-
propyl group of 2 in CDCl3, the iso-propyl group faces the
naphthalene ring, as shown in Scheme 1. In addition, NOE
correlations between the R-proton and the imino proton Ha
suggested that the imine in 2 has an E-geometry and,
predominantly, an eclipsed conformation in solution.
On the basis of this result, configurational correlation
models of the (aR)- and (aS)-imines are depicted in Figure
1A. The intensity of the shielding effects is strongly
dependent on the distance from the naphthalene ring that
faces each proton. Due to the diamagnetic effect of the
1
naphthalene ring, the H NMR signals of the R1 group in
the (aR)-imine derivative should appear at higher field
relative to those of the R1 group in the (aS)-imine derivative,
and vice versa for the R2 group. Therefore, when the
chemical shifts of the amine moiety of the imines are
compared, the ∆δRS () δaR - δaS) values of the left side
of the imino plane, which includes C-8, CdN, and the
R-carbon of the amine moiety, must have negative values
(∆δRS < 0), whereas the ∆δRS values of the right side must
be positive (∆δRS > 0), as shown in Figure 1B. Now,
modified Mosher’s method3 can be applied to our methodol-
ogy. The absolute values of ∆δRS must be proportional to
the distance from the chiral center in the modified Mosher’s
method, however, whereas these values are affected by
distance from the naphthalene ring in our methodology.
Scheme 1
.
NMR Analysis of the Imine Derivative (2) from
Racemic 1 and 2-Propylamine
To obtain preliminary data, imine 2 was prepared from
1
racemic 1 and iso-propylamine and analyzed by H NMR
spectroscopy (Scheme 1) and X-ray crystallography (see
Supporting Information (SI)). The derivatization proceeded
in quantitative yield, and the resultant imine 2 was suf-
ficiently stable for analysis in CDCl3. From the X-ray
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Figure 1. (A) Configurational correlation models of both diaster-
eomers of the imine derivatives. (B) ∆δRS values should be opposite
on both sides of the imino plane.
To verify our methodology, several imines (3-7) were
prepared from each enantiomer of 1 and the corresponding
chiral amines, for which the absolute configurations are
1
known. All H NMR signals of the imines were assigned,
and the chemical shifts were compared for both diastereomers
to obtain ∆δRS values, as shown in Figure 2. The ∆δRS values
show opposite signs on both sides of the imino plane, and
the absolute configurations determined for each amine moiety
corresponded to the known ones.
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Next, this methodology was applied to several amino acid
derivatives, whose absolute configurations are also known.
(14) Synthetic detailes are described in SI.
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