Determination of the absolute configuration and identity of chiral carboxylic acids using a Cu(II) complex of pyridine-benzimidazole-based ligand

Article abstract of DOI:10.1016/j.tetlet.2014.02.032

We report a new achiral Cu host [Cu(bmb-bpy)(H₂O)(OTf) ₂] (bmb-bpy = 6,6′-bis[((1-methylbenzimidazol-2-yl)thio)methyl] -2,2′-bipyridine) for the enantioselective and chemoselective recognition of chiral carboxylic acids. The binding of chiral carboxylic acids to [Cu(bmb-bpy)(H₂O)(OTf)₂] produced an exciton-coupled circular dichroism signal; the linear discriminant analysis allowed the assignment of the absolute configuration, enantiomeric excess, and identity of chiral carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2014.02.032

Tetrahedron Letters 55 (2014) 2097–2100
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Determination of the absolute configuration and identity of chiral
carboxylic acids using a Cu(II) complex of pyridine–benzimidazole-
based ligand
⇑
Shuang Zhao, Shintaro Ito, Yoshihiro Ohba, Hiroshi Katagiri
Graduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
0
Article history:
We report
ylbenzimidazol-2-yl)thio)methyl]-2,2 -bipyridine) for the enantioselective and chemoselective recogni-
2
tion of chiral carboxylic acids. The binding of chiral carboxylic acids to [Cu(bmb–bpy)(H O)(OTf) ]
a
2 2
new achiral Cu host [Cu(bmb–bpy)(H O)(OTf) ] (bmb–bpy = 6,6 -bis[((1-meth-
Received 10 January 2014
Revised 3 February 2014
Accepted 12 February 2014
Available online 20 February 2014
0
2
produced an exciton-coupled circular dichroism signal; the linear discriminant analysis allowed the
assignment of the absolute configuration, enantiomeric excess, and identity of chiral carboxylic acids.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Circular dichroism
Chirality
Molecular recognition
Identity
Carboxylic acid
0
In drug development and natural product synthesis, chiral car-
boxylic acids are important intermediates. The development of a
time-efficient and cost-effective stereoselective assay is essential
for the assignment of enantiomeric purity of chiral carboxylic
acids.1 High-throughput screening (HTS) has been used for the
The synthesis of the ligand, 6,6 -bis[((1-methylbenzimidazol-2-
0
yl)thio)methyl]-2,2 -bipyridine (bmb–bpy), was achieved by the
0
0
coupling of 6,6 -bis(bromomethyl)-2,2 -bipyridine 2 with 2-benz-
imidazolethiol 3 in the presence of potassium hydroxide in toluene
to afford thioether 4, followed by the methylation of 4 with methyl
iodide and anhydrous potassium carbonate in acetonitrile to afford
bmb–bpy (Scheme 1). Starting material 2, which is one of the widely
used materials for the fabrication of bipyridine-based supramolecu-
2
drug discovery in pharmaceutical industry and the discovery of
efficient catalysts for asymmetric reactions.3 Most commonly,
HTS is performed by high-performance liquid chromatography
4
0
(
HPLC) or gas chromatography (GC). However, HPLC or GC is not
lar architecture, was prepared by the bromination of 6,6 -dimethyl-
0
7
an optimal method for HTS because of the low-efficiency and
time-consuming requirements when a large number of samples
are analyzed. The exciton-coupled circular dichroism (ECCD) is a
valuable tool for determining the absolute configurations of chiral
2,2 -bipyridine 1 under heating or irradiation conditions. However,
the reaction yields were moderate and the purification was difficult
because of the uncontrollable formation of brominated by-products.
In this study, we improved this reaction procedure using a dichloro-
5
compounds. Recently, ECCD signals were used along with the lin-
2 2
methane (CH Cl )/water mixture as the solvent and irradiation
ear discriminant analysis (LDA), allowing both enantioselective
and chemoselective recognition, to determine the absolute config-
uration and identity of chiral molecules. In this method, the host
under a 150-W halogen lamp. The use of water/organic solvent
mixtures in photobromination has been reported for different
pyridines.
6
8
molecules should contain two chromophores and a chiral recogni-
tion site for the guest molecules. Herein, we report the Cu(II) com-
plex of a pyridine–benzimidazole-based ligand containing two
benzimidazole units as chromophores and a vacant coordination
site on the Cu(II) and its application for the determination of the
absolute configuration and identity of chiral carboxylic acids.
The Cu(II) complex, Cu(bmb–bpy)(H
the reaction of Cu(II) trifluoromethanesulfonate (Cu(OTf)
2
O)(OTf)
2
, was prepared by
) with
2
bmb–bpy in an equimolar ratio (Scheme 2). The crystal structure
showed that bmb–bpy acted as a tetradentate ligand, coordinating
through the nitrogen atom of the bipyridine group and two benz-
9
imidazoles (Fig. 1). Notably, bmb–bpy ligand was helically
twisted, which is a preferable feature for the ECCD procedure; in
addition, one water molecule existed at the vacant coordination
site on the Cu(II), which is expected to behave as a recognition site
for the target chiral molecules. The UV–visible spectra for the
⇑
Corresponding author. Tel./fax: +81 238 26 3743.
E-mail address: kgri7078@yz.yamagata-u.ac.jp (H. Katagiri).
http://dx.doi.org/10.1016/j.tetlet.2014.02.032
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

2
098
S. Zhao et al. / Tetrahedron Letters 55 (2014) 2097–2100
0
0
Scheme 1. Synthesis of 6,6 -bis[((1-methylbenzimidazol-2-yl)thio)methyl]-2,2 - bipyridine (bmb–bpy).
2 2
Scheme 2. Synthesis of Cu(bmb–bpy)(H O)(OTf) .
2 2
Figure 1. ORTEP drawing of Cu(bmb–bpy)(H O)(OTf) (50% probability). The
triflate and solvent molecules are omitted for clarity.
Figure 2. UV–visible absorption spectra: (A) Titration was carried out by adding
ꢀ
4
ꢀ6
Cu(OTf)
CH Cl ]. (B) Determination of the stoichiometry of the complexation of Cu(II) to
bmb–bpy using the molar ratio method.
2
[1.0 ꢁ 10
M
in CH
2
Cl
2 3
/CH CN = 1/1] to bmb–bpy [1.8 ꢁ 10
M in
2
2
2 2
titration of bmb–bpy with Cu(II) in CH Cl showed that on adding
Cu(II) ion, the absorbance intensity of the band at kmax = 290 nm
decreased, whereas that at kmax = 330 nm increased, and an isos-
bestic point occurred at 310 nm (Fig. 2A). The titration curve for
this system reveals that the stoichiometry is also 1:1 (Fig. 2B).
Four chiral carboxylic acids were used: 2-phenylbutyric acid
3
0.02 wt % CH OH, and all the circular dichroism (CD) spectra were
measured at ꢀ10 °C owing to their low intensity at room temper-
ature (see the Supplementary data, General Procedure, Fig. S15).
The CD analysis results are shown in Figure 4. The achiral host
(
(
PBA), 2-phenylpropionic acid (PPA), 2-bromopropionic acid
BPA), and N-boc-2-piperidinecarboxylic acid (PCA), as reported
2 2
[Cu(bmb–bpy)(H O)(OTf) ] itself displayed no signal in the CD
in the literature for investigating the chiral recognition using the
ECCD spectra and LDA plot (Fig. 3).6a These chiral carboxylic acids
do not absorb above 230 nm. The association study of Cu(bmb–
spectra. The binding of (R)-PBA to the achiral host produced an
ECCD signal that showed the positive first Cotton effect and nega-
tive second Cotton effect at the wavelength range of 300–360 nm
and 260–300 nm, respectively (Fig. 4A). These results may be
bpy)(H
2
O)(OTf)
2
2 2
with PBA was carried out in CH Cl and

S. Zhao et al. / Tetrahedron Letters 55 (2014) 2097–2100
2099
(vide infra). The single crystal X-ray analysis of a (R)-PPA recogni-
tion complex revealed that 1:1 stoichiometric complex was formed
and the water molecule was replaced by the chiral carboxylate an-
9
ion on the metal center (Fig. 5).
The LDA was applied to analyze the CD data and determine the
identity of the chiral carboxylic acids (Fig. 6). LDA is a supervised
pattern recognition protocol that is used for the classification of
data or the assignment of new analytes to their appropriate clas-
1
0
ses. Five replicates were prepared for each enantiomer of each
chiral carboxylic acid, and the data were analyzed at four different
wavelengths (333, 313, 295, and 285 nm) and subjected to the LDA.
These wavelengths were selected because they represent the
amount of variance in the CD data. The LDA plot showed a good
discrimination between the chiral carboxylic acid guests. F1-axis
shows the difference in the absolute configuration between each
enantiomer of the chiral carboxylic acids. The plots of the chiral
carboxylic acids with a positive first Cotton effect appear at a neg-
ative position on F1-axis, whereas the plots of the negative first
Cotton effect appear at a positive position. A stronger CD intensity
shows a larger absolute value of F1, whereas a weaker CD intensity
shows a smaller absolute value. Each enantiomer exists symmetri-
cally with respect to the original point 0 in the LDA plot. F2-axis
shows a small difference in the CD profile for each sample. The
resulting LDA plot was proved to be 100% reliable by the jack-knife
analysis, indicating that this method can be applied for assigning
the identity of the chiral carboxylic acids successfully.
Figure 3. Chiral guest: 2-phenylbutyric acid (PBA), 2-phenylpropionic acid (PPA),
N-boc-2-piperidinecarboxylic acid (PCA), and 2-bromopropionic acid (BPA).
2 2
To apply the ECCD system using Cu(bmb–bpy)(H O)(OTf) for the
determination of the enantiomeric excess (ee) of the chiral carbox-
ylic acids, calibration lines were constructed. Eight unknown sam-
ples were prepared with ee values in the range ꢀ100% (S) to 100%
(R) and measured them by CD spectroscopy. Then, calibration lines
were constructed for each guest from the intensity at 320 nm wave-
length in the CD spectrum; their corresponding actual ee values
were also calculated using this calibration line (Fig. 7). The resulting
2
calibration line fitted a linear regression with R = 0.99, indicating
2 2
that the ECCD system using Cu(bmb–bpy)(H O)(OTf) can be
applied for the determination of the ee of the chiral carboxylic acids.
In this study, we report a new achiral Cu host [Cu(bmb–
2 2
bpy)(H O)(OTf) ] for assigning the absolute configuration, identity,
and ee of chiral carboxylic acids. This system has an advantage over
6
the achiral hosts reported previously owing to the workable prop-
osition at the longer wavelengths. When the host is bound to a chi-
ral guest in the Cu center, the CD signals were observed above
3
20 nm. From the treatment of the CD data by the LDA, the abso-
lute configuration and identity of the chiral carboxylic acids were
Figure 4. (A) CD spectra of Cu(bmb–bpy)(H
each enantiomer of PBA [0.5 mM, in CH Cl
R)- and (S)-PBA [0–2.0 equiv] with Cu(bmb–bpy)(H
2
O)(OTf)
and 0.02 wt % CH
2
O)(OTf) .
2
without and with 2.0 equiv of
2
2
3
OH]. (B) Titration of
(
2
ascribed to the two transition electric dipole moments of each
benzimidazole unit that are oriented in a clockwise direction.
The CD spectrum was completely inverted and resulted in a mirror
image when the opposite enantiomer, (S)-PBA, was used as the chi-
ral carboxylic acid. The theoretical calculation result of the ECCD
spectra was in excellent agreement with that of the experimentally
obtained CD curve (see the Supplementary data, molecular orbital
(
MO) calculations). The CD spectra obtained from the titration of
each enantiomer of PBA with Cu(bmb–bpy)(H O)(OTf) showed
2
2
saturation when 1.0 equiv of PBA was added, and the intensity
did not change with increasing concentration of PBA (Fig. 4B).
Therefore, we decided to use 2.0 equiv PBA in the ECCD–LDA study
Figure 5. Chemical and crystal structure of
Cu(bmb–bpy)(H O)(OTf) and (R)-PPA. The triflate and solvent molecules are
omitted for clarity.
a host–guest complex between
2
2

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S. Zhao et al. / Tetrahedron Letters 55 (2014) 2097–2100
Supplementary data
Supplementary data (details of the synthesis and characteriza-
tion data for all the new compounds, X-ray crystallography, and
MO calculation data for Cu(bmb–bpy)(H O)(OTf) , CD titration
2
2
experiments, and calibration lines for determining ee) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.02.032.
References and notes
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Figure 6. LDA plot of four enantiomeric pair guests with Cu(bmb–bpy)(H
2 2
O)(OTf)
[
0.5 mM, in CH Cl and 0.02 wt % CH OH].
2
2
3
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Figure 7. CD signal at 320 nm with varying ee values for the solution of four chiral
carboxylic acids and Cu(bmb–bpy)(H O)(OTf) [0.5 mM, in CH Cl and 0.02 wt %
CH OH].
2
2
2
2
3
determined. Moreover, in the ee measurements of the eight sam-
ples, a good calibration line for the ee values was obtained. The
ECCD–LDA system requires an obvious change in the profile of
the CD spectra, and the host fulfills this requirement by the in-
duced-fit adjustment to chiral guest binding. We believe that this
system can be applied for the HTS of chiral compounds.
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Acknowledgments
This work was supported by a Grant-in-Aid for Young Scientist
(
B) (19750104 to H.K.) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT).