Rapid regio- and enantioselectivities and kinetic resolution of dl-lysine by an effective supramolecular system in water

Article abstract of DOI:10.1016/j.molliq.2014.06.038

Herein we reported an example of chiral recognition, regioselective and kinetic resolution of dl-lysine by supramolecular interactions in aqueous solution of β-cyclodextrin. High regio- (> 99%) and enantioselectivies (> 99%) are achieved in a short time (< 10 min) under mild conditions.

Full text of DOI:10.1016/j.molliq.2014.06.038

Journal of Molecular Liquids 198 (2014) 1–4
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Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Short Communication
Rapid regio- and enantioselectivities and kinetic resolution of DL-lysine
☆
by an effective supramolecular system in water
1
1
2
Mingfang Ma , Jie Su , Xiang Sheng, Fan Su, Shangyang Li, Pengyao Xing, Aiyou Hao
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2014
Received in revised form 26 June 2014
Accepted 28 June 2014
Available online 10 July 2014
Herein we reported an example of chiral recognition, regioselective and kinetic resolution of DL-lysine by supra-
molecular interactions in aqueous solution of β-cyclodextrin. High regio- (N99%) and enantioselectivies (N99%)
are achieved in a short time (b10 min) under mild conditions.
©
2014 Elsevier B.V. All rights reserved.
Keywords:
β-Cyclodextrin
DL-Lysine
Regioselective
Enantioselective
Kinetic resolution
1
. Introduction
In supramolecular chemistry, the inner hydrogen bonds in the cavity
of cyclodextrins (CDs) make CDs unique materials compared with other
aromatic rings (Fig. 1) [18]. These hydrogen bonds are the critical forces
in the hydrophobic molecules in polar solvents. The weak interactions
can generate significantly different results in chemical reactions [19].
CD is a class of α-1,4-linked cyclic oligosaccharides, can be divided
into α-, β-, γ-CD, according to the repeating glucose unit numbers, six,
seven and eight, respectively [20,21]. β-CD, with a hydrophobic cavity
and hydrophilic outside surface, is widely used as the host molecule in
supramolecular chemistry for its low price, water-solubility and
biocompatibility. CDs and their derivatives had attracted much interest
in the enzyme mimics [22–24].
Very recently, Akashi et al. reported the first example of chiral recog-
nition and kinetic resolution of aromatic amine guests using supramolec-
ular nanocapsules assembled from CD derivatives in nonpolar media [25].
For the limit reports on chiral recognition [26–28] and enantioselective
reactions [29] with supramolecular chiral nanocapsules, this observation
is remarkable and should be applicable as a powerful chiral selector and
a potent reaction tool for various enantioselective reactions.
Selectivity and velocity are the critical issues in the chemical
reaction. In order to observe high selectivity and velocity, many
methods like harsh conditions (relative high or low temperature),
extra reagents, and complicated steps are applied [1–4]. Among all the
methods, catalyst is one of the most common ways to achieve high
selectivity and velocity. But very few catalysts can realize high selectivity
(region and enantio) and velocity at the same time. In human body, high
selectivity (region and enantio) and velocity can be achieved in the pres-
ence of enzyme. No harsh conditions are needed in the process. To mimic
the function of enzyme is still a goal for the chemists. Supramolecular
chemistry, which focuses on van der Waals' force, hydrogen bond, and
other reversible bonds, has attracted more attention [5–9]. A broad
range of organic chemistry subdisciplines has been affected by the
principles of supramolecular chemistry. The interplay of multiple inter-
molecular interactions is the key point of molecular recognition and
self-assembly processes [10]. The concept like hydrogen bond donors
has been used in the organocatalyst design with increasing sophistication
[
11–16]. Furthermore, enzymes are considered as the best-understood
Amino acids, as the basic building concept of peptides, play impor-
tant roles in many fields like drugs and functional materials [30,31]. Chi-
ral is one of the most important properties of amino acid. Only L-amino
acid can form peptides in human body. Meanwhile, most drugs contain
the special fragments of chiral amino acids [32]. In order to obtain the
optical pure amino acids, many methods are invented. The strategy of
isolating the racemization amino acid is still an important way.
L-Lysine is an essential amino acid in human body. It plays an impor-
tant role in drug synthesis, functional material preparation and so on
[33]. It should be noted that the two amino groups of lysine have almost
catalyst system involving hydrogen bonding at this stage [17].
☆
The manuscript entitled “Rapid regio- and enantioselectivities and kinetic resolution
of DL-lysine by an effective supramolecular system in water” is the authors' original
work and has not been published or been submitted simultaneously elsewhere. All au-
thors have checked the manuscript and have agreed to the submission.
E-mail address: haoay@sdu.edu.cn (A. Hao).
1
These authors contributed equally.
Tel.: +86 531 88363306.
2
http://dx.doi.org/10.1016/j.molliq.2014.06.038
0167-7322/© 2014 Elsevier B.V. All rights reserved.

2
M. Ma et al. / Journal of Molecular Liquids 198 (2014) 1–4
Fig. 1. Sketch of the proton positions in a β-CD molecule.
the same chemical activity under normal conditions [34]. As an amino
protecting group, benzyloxycarbonyl (Cbz) is widely used for the high
stability and could be removed easily under hydrogen [35]. Normally,
optical pure lysine is essential to obtain the optical pure mono-Cbz
protected lysine. To the best of our knowledge, pure optical mono-
protected lysine from racemization lysine has not been reported.
In preliminary experiments, we evaluated the regioselectivity of
L-lysine in the presence of β-CD and its derivatives [36,37]. Opposite
regioselectivity can be achieved by modifying the structure of β-CD.
The special inclusion orientation of the amino acid in the cavity of
β-CD is proved by the NMR spectrum and theoretical calculations. In
theory, the inclusion between chiral molecules and CDs is different
implemented in Gaussian 09 program package [46]. To provide realistic
pictures of the interaction between lysine and β-CD, we calculated the
energies of β-CD/D-lysine and β-CD/L-lysine inclusions in solvent
phase using PCM (ε = 80) (see the ESI† for details) [47–49]. It has
been noted by Knowles that 95% ee only involves energy differences of
about 8 kJ/mol, which is approximately the strength of one hydrogen
bond [50]. The calculated energies of α-NH
inclusion is 13.36 kJ/mol higher than those of α-NH
2
secondary face D-lysine
secondary face
2
L-lysine inclusion. Therefore, the β-CD/L-lysine inclusion has a higher
enantioselectivity, which is consistent with our experimental results
(Fig. 3).
[
38]. These properties have been used in the separation of drug stereo-
2
. Conclusions
isomers; chiral selector, etc [39–41]. We proposed that the inclusion of
L- or D-lysine with β-CD is different. This can be used for the chiral
recognition and kinetic resolution.
The result is exciting. We observed high regio- (N99%) and enantio-
meric excess (ee N99%) product in short times (b10 min). No product is
observed in the absence of β-CD in the same time (Table 1 entry 2). This
proved that β-CD plays the key role in the reaction. Long reaction time
and decreased yield are observed when pH decreased (Table 1 entries
In summary, we have demonstrated that high regio- and
1
enantioselectivities of lysine can be achieved in a short time. H NMR
Table 1
Optimization of reaction conditions a.
4
, 5). We propose that base neutralizes hydrogen chloride generated
in the reaction. Through changes in the chemical shifts of guest and
1
host protons, H NMR spectroscopy can be used to prove the existence
of inclusion complexes and provide information about the geometrical
orientation of the guests with their hosts [42]. We therefore undertook
1
a H NMR study to investigate the inclusion complex formed between
β-CD and lysine using different mole ratios between the host and
guest to probe the inclusion effect. From the overlaid spectra provided
in Fig. 2, it can be seen that the chemical shifts (Table 2) of protons α
and β in lysine in D O changed by −0.0380 and −0.0100 ppm respec-
2
tively in the presence of 1 mol equivalent of β-CD, as compared to lysine
alone. By contrast, no chemical shift change was observed for protons γ,
δ, and ε which taken together implies that the α-amino group was po-
sitioned inside the cavity of the cyclodextrin whilst the terminal
amino group was exposed where it is able to react with Cbz-Cl to form
the observed carbamates. 2D NMR ROSEY spectrum, which can provide
more direct evidence for the inclusion complex, was used in our study
Entry Catalyst
pH Temp (°C) Time (min)
Yield (%)b
ee (%)c
[43]. The correlations between H
α
of lysine and H
3
, H
5
of β-CD inner
a
b
c
d
cavity can be observed obviously from 2D NMR ROSEY result (Fig. S1),
meaning that the α-amino group of lysine is recognized and included
by the cavity of β-CD to form supramolecular complex. This result is in
1
2
3
4
5
6
β-CD
None
None
β-CD
β-CD
β-CD
8
8
8
7
7
9
25
25
25
25
25
25
10
10
60
10
30
10
45%
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
N99%
–
–
–
1
–
–
line with the H NMR analysis.
20%
45%
N99%
N99%
Density functional theory (DFT) calculations have been carried out to
study the complexation thermodynamics of CDs [44,45]. The calculated
relative energies using polarizable-continuum model (PCM) can
indicate the stability of the inclusions. All calculations presented here
were performed by using hybrid density functional theory method
a
All reactions were carried out with DL-lysine (1.0 mmol), β-CD (10 mol%), Cbz-Cl
(
0.05 mmol) and H
2
O (10 ml).
b
Isolated yield.
Enantioselectivities were determined by chiral HPLC.
c

M. Ma et al. / Journal of Molecular Liquids 198 (2014) 1–4
3
Fig. 2. 1H NMR (400 MHz) spectra in D
as an internal standard (δ = 4.7000 ppm for H NMR in D
O at 298 K of β-CD (10 mol · L−1) upon addition of DL-lysine. Chemical shifts (δ) are reported in ppm and referenced to the residual solvent peak
−3
2
1
2
O).
Table 2
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δ of DL-lysine protons in β-CD complex (1:1) and alone.
1491–1546.
[
[
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δ (ppm) of DL-lysine protons
DL-Lysine
In complex (1:1)
Δδ
α
β
γ
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3.4552
1.6851
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−0.0380
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[
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ε
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Appendix A. Supplementary data
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M. Ma et al. / Journal of Molecular Liquids 198 (2014) 1–4
Fig. 3. Overview (from primary face) and side view for proposed orientations of β-CD lysine inclusion after being optimized by Gaussian 09 Software. Calculated relative energies are given
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