Chiral sensors for determining the absolute configurations of α-amino acid derivatives

Article abstract of DOI:10.1039/c8ob01933a

A simple strategy for configurational assignments of alpha-amino acids has been developed by comparison of the proton NMR chemical shift values of the alpha hydrogens of N-phthaloyl protected alpha-amino acids in the presence of (R)-CSA 1 and (S)-CSA 1, respectively. Highly resolved NMR spectra can be obtained directly on the mixed solution of the chiral solvating agents with N-phthaloyl protected alpha-amino acids in NMR tubes, giving well distinguishable proton signals without interference which dramatically improve the accuracy of assignment and hasten the assigning procedure. The strategy is widely applicable for varied natural and non-natural amino acids.

Full text of DOI:10.1039/c8ob01933a

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Chiral sensors for determining the absolute configurations of α-
amino acids derivatives †‡
Zhongxiang Chenab, Hongjun Fanc, Shiwei Yangab, Guangling Bian*ab and Ling Song*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A simple strategy for configurational assignments of alpha-amino acids has been developed by comparison of the proton
NMR chemical shift values of alpha hydrogens of N-phthaloyl protected alpha-amino acids in the presence of (R)-CSA 1 and
(S)-CSA 1 respectively. Highly resolved NMR spectra can be obtained directly on mixed solution of the chiral solvating
agents with N-phthaloyl protected alpha-amino acids in NMR tubes, giving well distinguishable proton signals without
interference which dramatically improve the accuracy of assignment and hasten assigning procedure. The strategy is
widely applicable for varied natural and non-natural amino acids.
www.rsc.org/
natural amino acids are usually L, there are exceptions.
Furthermore, with the increasing demand for unnatural amino
Introduction
Chirality is ubiquitous in nature and plays vital roles in biology,
chemistry and materials science.1 Therefore, assignment of the
chirality of molecules is very important and has been
extensively studied by using several methods, such as X-ray
acids for new drug discovery, the assignment of the chirality of
synthetic amino acids of unknown configuration is becoming
increasingly important. To date, widely applicable strategies
for determination of absolute configurations of amino acids
crystallography2, circular dichroism3, NMR spectroscopy4-10
,
are very limited, mainly via CDAs and subsequent NMR, HPLC
12, 13, 36-39
etc. Among them, NMR method only needs a small amount of
sample and can give a stable and credible result by a fast and
easy operation. So, it is one of the most powerful methods for
and electrochemical methods.
There are few reports
on CSAs method. In our previous study, the absolute
configuration of α-OH carboxylic acids was successfully
assigned by CSA 1 (Figure 1)40. In view of the importance of
chirality of amino acids, we demonstrate here the capability of
CSA 1 for accurately assigning the absolute configurations of
various α-amino acids based on a completely different binding
mode from that of α-OH carboxylic acids by 1H NMR.
chirality assignment, mainly using chiral derivatizing agents
11-16
(CDAs)
and chiral solvating agents (CSAs) 17-33. Different
from CDAs method, CSAs method does not require tedious
derivatization steps facilitating NMR measurement by simply
mixing a CSA with a sample. In addition, CSAs method is
particularly useful when recycling a sample is required.
Therefore, CSAs method gradually aroused the interest of
scientists.
Amino acids are not only building blocks in peptides and
proteins but are also key precursors for syntheses of low
molecular weight nitrogenous substances.34-35 Their chirality
plays a central role in the biologically active functionalities of
peptides and proteins, as well as the specific functions of other
chiral substances synthesized from amino acids. So,
assignment of the chirality of amino acids is critical. Although
F3C
S
S
CF3
NH HN
(S)-CSA 1
NH
HN
F3C
F3C
CF3
CF3
(R)-CSA 1
NH HN
a.The Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, P. R. China, E-mail: glb@fjirsm.ac.cn;
songling@fjirsm.ac.cn.
NH
S
HN
S
F3C
CF3
b.University of Chinese Academy of Sciences, 100049, Beijing, P. R. China.
c. The State Key Lab of Molecular Reaction Dynamics, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, Dalian, 116023, P. R. China.
† Dedicated to Prof. Dr Jin-shun Huang on the occasion of his 80th birthday.
‡ Electronic Supplementary Information (ESI) available: See DOI:
10.1039/x0xx00000x.
Figure 1. Structures of bisthiourea CSAs.
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Table 1. Optimization of the discriminating conditions for D, L-alanine derivatives by (S)-CSA 1.a
Entry
D, L-alanine derivative
Base
Spectra b
Result
1
no baseline separation
DABCO
4.0
ppm
interference peak
2
DABCO
4.5
4.0
ppm
no baseline separation
no baseline separation
no baseline separation
3
4
5
DABCO
DABCO
DABCO
5.0
4.8
ppm
4.4
ppm
4.0
ppm
ΔΔδα-H = 0.39 ppm
baseline separation
6
DABCO
Triethylamine
Proton sponge
DMAP
5.0
4.5
ppm
ΔΔδα-H = 0.36 ppm
baseline separation
7
8
5.0
ppm
ΔΔδα-H = 0.18 ppm
baseline separation
5.2
5.0
ppm
ΔΔδα-H = 0.28 ppm
baseline separation
9
5.0
ppm
a(S)-CSA 1, base and D, L-alanine derivatives were mixed in the 50% C6D6/50% CDCl3 (V/V) and 1H NMR data were collected on a Bruker
Avance 400 MHz spectrometer at 25 oC.bSpectra of α-Hs of D, L-alanine derivatives.
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5.0 4.8
ppm
ppm
5.0 4.8
Figure 2. The 1H NMR spectra and proposed structures of complexes.
Structures: (A) (R)-CSA 1/L-Pht-Ala/DABCO, (B) (S)-CSA 1/L-Pht-Ala/DABCO.
The α-H of L-Pht-Ala is shown in green. The intermolecular hydrogen bonds are shown in purple.
1H NMR Spectra of α-Hs of L-Pht-Ala: (a) in complex A, (b) in complex B.
For better understanding the nature of the correlation, the
Results and discussion
new binding mode was further investigated. Assuming the
noncovalent bonded diasteromeric complex was formed with
1:1:1 stoichiometry of CSA 1, L-Pht-Ala and DABCO, 1D NOESY
experiments of the mixture of CSA 1/L-Pht-Ala/DABCO showed
correlation of α-H of L-Pht-Ala with Ar-Hs and N-Hs of CSA 1
(Hb and Hc, see Supporting Information). These results
indicated that the intermolecular noncovalent bonding
interactions presented in the complex structure resulted in the
close of α-H of L-Pht-Ala to Hc and Hb of CSA 1 in space.
However, the mixture of (R)-CSA 1/L-Pht-Ala/DABCO gave
weaker NOESY signals between α-H of L-Pht-Ala and Ar-Hs and
N-Hs of CSA 1 (Hc and Hb, see Supporting Information),
indicating that α-H was farther from Hc and Hb in the complex
of (R)-CSA 1/L-Pht-Ala/DABCO, compared with the α-H in the
complex of (S)-CSA 1/L-Pht-Ala/DABCO.
Since free amino acids have poor solubility in non proton
solvents, protected amino acids are often used as recognition
substrates. Using D, L-alanine (Ala) as a model molecule, we
first investigated the effects of different amine protective
groups on the ability to be identified by (S)-CSA 1 (Table 1,
entries 1-6). It was found the structure of a protective group
has heavy influence on chiral recognition. Protective groups
with strong shielding effects and rigid structures are helpful for
chiral recognition. Phthaloyl group (Pht) was shown as the
most suitable protective group because of its maximum ΔΔδα-H
and no interference peak with α-H (Table 1, entry 6). Selecting
Pht as the optimal protection group, we further examined the
effects of different organic bases on the recognition.
Compared with triethylamine, proton sponge and DMAP,
DABCO was the best base giving the largest chemical shift
nonequivalence for the two enantiomers of Pht-Ala (Table 1,
entries 6-9). Finally, the recognition system with N-phthaloyl
protected α-amino acids as guests and DABCO as bases was
selected.
40,41
According to the above results and our previous study
we proposed that CSA 1/L-Pht-Ala/DABCO formed two kinds of
ternary complexes via multiple intermolecular hydrogen-
bonding interactions as shown in Figure 2. One kind is formed
from (R)-CSA1/L-Pht-Ala/ DABCO (Figure 2, A), and the other is
formed from (S)-CSA 1/L-Pht-Ala/DABCO (Figure 2, B).
Computational modeling studies were performed with
Gaussian09 program 42. Geometries of ternary complexes were
optimized using molecular mechanics method initially and
then DFT method on M06-2x/cc-pVDZ level. All geometry
optimizations were carried out in gas phase. Calculated
chemical shifts for α-Hs of L-Pht-Ala in the two ternary
complexes are reported in Table 2. The calculated δ values are
in good agreement with the experimental values.
Under the optimized conditions, 1H NMR spectra of the
mixture of (R)-CSA 1/L-Pht-Phe /DABCO and that of (S)-CSA
1/L-Pht-Phe /DABCO were recorded separately. By comparison
of the chemical shifts of α-H signals of L-Pht-Phe in the two
R,S
R,S
mixtures, it was found that Δδα-H is 0.43 ppm (Δδα-H = δα-H
of amino acids with (R)-CSA 1 - δα-H of amino acids with (S)-CSA
1). Changing L-Pht-Phe to D-Pht-Phe, the process was repeated
R,S
and Δδα-H was obtained as -0.42 ppm. The results indicate
R,S
that positive Δδα-H correlates to L-Pht-Phe and negative Δδα-
R,S
correlates to D-Pht-Phe. This result is opposite to the
H
The α-H of L-Pht-Ala in left complex is located in the
deshielding range of aromatic system of (R)-CSA 1 (shielding
recognition of a-OH carboxylic acids with CSA 1 40, indicating
that amino acid binds to CSA 1 via a different binding mode.
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Table 2. Calculated and experimentally observed δ values for the Reagents and Apparatus
α-Hs of L-Pht-Ala in ternary complexesa
(R)-CSA 1 and (S)-CSA 1 were prepared from commercial
chiral 1, 2-diphenylethane-1, 2-diamine and isothiocyanate
according to reference40. N-phthaloyl (PHT) protected α-amino
acids were prepared from commercial amino acids and N-
(Ethoxycarbonyl)phthalimide according to reference43. Others
chemicals were purchased from Acros, which were used
without further purification. 1H NMR spectra were recorded on
a Bruker Avance 400 MHz spectrometer (Switzerland) and 1D
NOESY spectra were recorded on a Bruker Avance 500 MHz
spectrometer, using TMS (δH or δC = 0) or CDCl3 (δH = 7.26, δC =
77.16) as internal standards.
experiment
al values
calculated
values
δα-H of L-Pht-Ala (ppm)
(R)-CSA 1/L-Pht-Ala/DABCO
4.80
4.58
4.79
4.41
(S)-CSA 1/L-Pht-Ala/DABCO
50 mM 1:1:1 of CSA 1, DABCO and L-Pht-Ala; 1H NMR data were
collected on a Bruker Avance 400 MHz spectrometer in 50%
a
C6D6/50% CDCl3 (v/v) at 25 oC.
General procedure for the preparation of N-phthaloyl (PHT)
range: above/below the ring plane and inside the ring,
deshielding range: on the periphery of the ring plane), while
the α-H of L-Pht-Ala in right complex is closer to shielding
range of aromatic system of (S)-CSA 1. So, α-H of L-Pht-Ala in
the complex of (R)-CSA 1/L-Pht-Ala/DABCO experiences more
protected α-amino acids.
Amino acid (0.01 mol) and 0.01 mol Na2CO3 were dissolved
in 10 mL water at room temperature. And then, 0.01 mol N-
ethoxycarbonylphthalimide was added to the solution. The
reaction was stirred for 2 hours, then the above solution was
acidified with 2 M aqueous HCl until pH 1-2 at 0 °C and
extracted with ethyl acetate and the organic phase was dried
with anhydrous sodium sulphate and concentrated to obtain
crude product. The crude product is recrystallized by ethyl
acetate : petroleum ether = 1:1 to give the N-phthaloyl (PHT)
protected α-amino acids.
1
deshielding. Its H NMR signal should be more downfield and
the Δδα-HR,S is positive. Mastering the nature of correlation, we
can judge the absolute configurations of N-phthaloyl protected
α-amino acids according to the positive or negative sign of Δδα-
R,S
.
H
Analytical application
In order to confirm the validity of this correlation,
assignments of a series of D and L α-amino acids with known
absolute configurations, containing either alkyl or aromatic
groups, were carried out using the above method. As shown in
Table 3, the assigned configurations were consistent with the
actual configurations for all investigated molecules, whether it
is natural amino acid or non-natural amino acid. However, our
method was not suitable for imino acid because there is no
corresponding N-phthaloyl protected derivative as to imino
acid (such as proline). In addition, our method does not apply
(S)-2-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)acetic acid (Entry 10)
White solid, yield 91%, mp 150-151 oC. 1H NMR (400 MHz, CDCl3
) δ(ppm) 7.82 (d, J = 41.4 Hz, 2H, Ar-H), 7.82 (dt, J = 47.5 Hz, 2H, Ar-
H), 4.69 (d, J = 8.5 Hz, 1H, CH), 2.41-2.50 (m, 1H, CH2), 2.15 (d, J =
12.7 Hz, 1H, CH), 1.61-1.78 (m, 4H, CH2), 0.92-1.38 (m, 5H,1CH and
2CH2); 13C NMR (100 MHz, CDCl3) δ(ppm) 174.4, 167.7, 134.2, 131.6,
123.7, 56.8, 37.3, 31.5, 29.3, 26.0, 25.8, 25.7; HRMS calculated for
[C16H17NO4]+: 287.1158, found: 287.1468.
(R)-2-(1,3-dioxoisoindolin-2-yl)-4,4-dimethylpentanoic acid (Entry
R,S
to acidic amino acids due to the too small Δδα-H (such as,
22)
aspartic acid, Δδα-HR,S = 0.002 ppm, see supporting information
page 25). It should be stressed in particular that the
established method is used to assign α-amino acids to D or L,
not R or S (entry 21, the configuration of L-cysteine is R not S.)
White solid, yield 80%, mp 192-193 oC 1 H NMR (400 MHz, CDCl3 )
δ(ppm) 7.79 (d, J = 43.6 Hz, 2H, Ar-H), 7.79 (dt, J = 54.3 Hz, 2H, Ar-
H), 5.00 (dd, J = 2.9, 9.8 Hz, 1H, CH), 2.17-2.33 (m, 2H, CH2), 0.92 (S,
9H, CH3); 13C NMR (100 MHz, CDCl3) δ(ppm) 176.3, 167.7, 134.2,
131.8, 123.6, 49.4, 41.1, 30.4 ,29.1 HRMS calculated for [C15H17NO4
- H]-: 274.1158, found: 274.1086.
Conclusions
In summary, our chiral sensing method has shown to be
quite applicable for 1H NMR assignments of the absolute
configurations of various N-phthaloyl protected α-amino acids.
The characterization data of other N-phthaloyl (PHT)
protected α-amino acids are consistent with those reported in
the literatures44-53
.
R,S
The positive Δδα-H correlates to L-amino acids and negative
R,S
Δδα-H correlates to D-amino acids. The method is simple to
CSAs for configurational assignments of N-phthaloyl protected α-
amino acids
operate and widely valid for broad substrate scope. In
addition, the obtained spectra are easy to interpret because of
1
large enough H NMR chemical shift nonequivalence (up to
N-phthaloyl protected α-amino acid (15 μmol), DABCO (15
μmol) and (R)-CSA 1 or (S)-CSA 1 (45 μmol) were mixed in a
mixed solvent (0.25 mL CDCl3 + 0.25 mL C6D6) and 1H NMR data
were collected on a Bruker Avance 400 MHz spectrometer at
25 oC. Chemical shifts (ppm) internally referenced to TMS
signal (0 ppm) were obtained.
0.54 ppm) and no interference from bisthiourea CSAs and
DABCO. Therefore, it can be a powerful tool for configuration
assignments of α-amino acids.
Experimental
4 | J. Name., 2012, 00, 1-3
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Table 3. Measurements of Δδα-HR,S of N-phthaloyl protected α-amino acids in the presence of (R)-CSA 1 or (S)-CSA 1.a
R,S
R,S
Contrasting
spectra b
Δδα-H
Contrasting
spectra b
Δδα-H
Entry
Carboxylic acid
Entry
Carboxylic acid
(ppm) c
(ppm) c
0.43
(L)
0.21
(L)
1
12
5.0
5.2
ppm
ppm
ppm
-0.42
(D)
0.35
(L)
2
3
13
14
4.8 4.6
5.0
ppm
ppm
0.39
(L)
0.30
(L)
4.5
ppm
ppm
5.0
0.41
(L)
0.48
(L)
4
15
4.5
ppm
5.1 4.8
0.30
(L)
-0.39
(D)
5
6
7
8
16
17
18
19
4.5
ppm
ppm
5.1
4.8
ppm
ppm
0.39
(L)
-0.41
(D)
4.5
5.4 5.1
0.27
(L)
0.54
(L)
5.0
ppm
ppm
5.1 4.8
ppm
0.33
(L)
0.28
(L)
5.1
4.8
ppm
ppm
ppm
ppm
5.0
5.0
0.45
(L)
0.30
(L)
9
20
21
22
ppm
ppm
ppm
6.0
5.8
0.34
(L)
0.39
(L)
10
4.5
5.0 4.7
0.38
(L)
-0.18
(D)
11
5.0
5.0
a All samples were prepared by mixing 3:1:1 of CSA 1, DABCO and carboxylic acids in NMR tubes; 1H NMR data were collected on a Bruker
Avance 400 MHz spectrometer in 50% C6D6/50% CDCl3 (v/v) at 25 oC (The solvent was CDCl3 in entries 12 and 19). b The black spectra were
obtained with (R)-CSA 1 and the red spectra were obtained with (S)-CSA 1. c The assigned configurations were labeled in parentheses.
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25 G. Bian, S. Yang, H. Huang, H. Zong and L. Song, Sens. Actuat.
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26 G. Bian, S. Yang, H. Huang, H. Zong, L. Song, H. Fan and X.
Conflicts of interest
There are no conflicts to declare.
Sun, Chem. Sci., 2016, 7, 932-938.
27 S. Ito, M. Okuno and M. Asami, Org. Biomol. Chem., 2018, 16
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28 T. Ema, D. Tanida and T. Sakai, J. Am. Chem. Soc., 2007, 129
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The authors gratefully acknowledge the financial supports
from the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000), DICP (Grant: DICP
DMTO201404), the Natural Science Foundation of Fujian
Province, China (No. 2018J01029), The Key Laboratory of Coal
to Ethylene Glycol and Its Related Technology, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of
Sciences.
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