Enantiomeric discrimination of α-hydroxy acids and N-Ts-α-amino acids by1H NMR spectroscopy

Article abstract of DOI:10.1016/j.tetlet.2015.10.060

A new kind of chiral compounds with multiple amino, amido and phenolic hydroxy groups has been synthesized from D-phenylalanine and D-phenylglycine, respectively. The enantiomeric discriminations of α-hydroxy acids and N-Ts-α-amino acids have been finished in the presence of the above chiral compounds as chiral solvating agents by¹H NMR spectroscopy. The results show that the chiral compounds are highly effective and practical chiral solvating agents towards α-hydroxy acids and N-Ts-α-amino acids.

Full text of DOI:10.1016/j.tetlet.2015.10.060

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantiomeric discrimination of
acids by H NMR spectroscopy
a-hydroxy acids and N-Ts-a-amino
1
⇑
⇑
Guangpeng Gao, Caixia Lv, Qiuju Li, Lin Ai , Jiaxin Zhang
College of Chemistry, Beijing Normal University, Beijing 100875, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new kind of chiral compounds with multiple amino, amido and phenolic hydroxy groups has been syn-
thesized from -phenylalanine and -phenylglycine, respectively. The enantiomeric discriminations of
hydroxy acids and N-Ts- -amino acids have been finished in the presence of the above chiral compounds
as chiral solvating agents by 1H NMR spectroscopy. The results show that the chiral compounds are
highly effective and practical chiral solvating agents towards -hydroxy acids and N-Ts- -amino acids.
Received 11 September 2015
Revised 14 October 2015
Accepted 17 October 2015
Available online xxxx
D
D
a-
a
a
a
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Enantiomeric discrimination
a
-Hydroxy acids and N-Ts-
a-amino acids
1H NMR spectroscopy
Determination of enantiomers, assignment of absolute configu-
ration and analysis of enantiomeric excess are significant,
indispensable and basic data to a chiral compound in biology,
pharmaceutical chemistry and asymmetric catalysis.1 Therefore,
many methods and techniques, such as HPLC,2 NMR,3 UV/Vis4
and fluorescence spectroscopy,5 have been developed to meet
these demands. Among them, NMR technology has some distinc-
tive advantages and features, such as less sampling amount, less
environmental pollution, convenient procedure and high accu-
racy.6 Thus, various chiral shift reagents (CSRs) and chiral solvating
agents (CSAs), such as lanthanide complexes,7 cyclodextrins,8
crown ethers,9 porphyrins,10 calixarenes11 and others,12 have been
designed and utilized for this purpose by NMR spectroscopy. In
recent decades, design and synthesis of more effective chiral
auxiliaries with the unique architecture have fascinated many che-
mists for chiral molecular recognition by 1H NMR spectroscopy.13
Herein, we report the highly facile and effective synthesis for chiral
compounds 1a–1h with multiple amino, amide and phenolic
hydroxyl groups as chiral solvating agents to discriminate
H
O
R1
1a: R = Bn, R1 = H, R2 = H
1b: R = Bn, R1 = H, R2 = Cl
1c
1d
1e
O
R
NH HN
NH HN
: R = Bn, R1 = Br, R2 = Br
: R = Bn, R1 = H, R2 = OCH3
: R = Ph, R1 = H, R2 = H
: R = Ph, R1 = H, R2 = Cl
R2
R2
O
H
O
R
1f
1g
1h
R1
: R = Ph, R1 = H, R2 = Br
: R = Ph, R1 = H, R2 = OCH3
1
Figure 1. Chemical structures of chiral compounds 1a–1h.
As shown in Figure 1, molecular structures of 1a–1h contain
some polar functional groups, such as amino, amide and phenolic
hydroxyl groups, which can easily form hydrogen-bonding interac-
tion with some matched guests. These structural features of 1a–1h
will be helpful to improve capability to discriminate enantiomers
of
a
-hydroxy acids and N-Ts-
a
-amino acids by 1H NMR
spectroscopy.
N-Boc-protected
D
-phenylalanine and -phenylglycine were
D
enantiomers of
NMR spectroscopy.
Chiral compounds 1a–1h with multiple binding sites have
been synthesized from (1S,2S)-(+)-1,2-diaminocyclohexane and
a-hydroxy acids and N-Ts-a
-amino acids by 1H
prepared based on the reported literature.14 The coupling reaction
of 3 with (1S,2S)-(+)-1,2-diaminocyclohexane was carried out in
the presence of N,N0-dicyclohexylcarbodiimide (DCC) at ice-salt
bath under nitrogen atmosphere. The crude products were purified
by column chromatography on silica gel to afford pure compounds
4a and 4b (4a: R = Bn, 4b: R = Ph) in 68% and 70% yields, respec-
tively. Chiral diamines 5a and 5b (5a: R = Bn, 5b: R = Ph) were
obtained by deprotection of N-Boc-protected diamide 4 in trifluo-
roacetic acid (TFA).15 The crude product was used in the next step
without further purification (Scheme 1).
D
-phenylalanine or
D
-phenylglycine as chiral sources for enan-
-hydroxy acids and N-Ts-
tiomeric discrimination towards
a
a-
amino acids. Their chemical structures are shown in Figure 1.
⇑
Corresponding authors. Tel.: +86 10 58807843; fax: +86 10 58802075.
E-mail addresses: linaibnu@sina.com (L. Ai), zhangjiaxin@bnu.edu.cn (J. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2015.10.060
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Gao, G.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.060

2
G. Gao et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
R
NHTs
O
R
i
ii
R
COOH
: R = CH3
: R = (CH3)2CH
HO NH2
HO NHBoc
OH
COOH
R1
11
12
2
3
R2
13: R = (CH3)2CHCH2
14: R = HOOCCH2
15: R = CH3SCH2CH2
16: R = Ph
O
R
O
R
: R1 = H, R2 = H
7
8
9
10
NH NH2
NH NH2
NH NHBoc
NH NHBoc
: R1 = Cl, R2 = H
iii
17
: R = PhCH2
: R1 = H, R2 = Cl
: R = H, R2 = OCH3
18
1
COOH
:
N
O
R
O
R
Ts
4
5
Figure 3. Structures of a-hydroxy acids and N-Ts-a-amino acids.
Scheme 1. Synthesis of chiral compounds 4 and 5. Reagents and conditions: (i)
(Boc)2O, NaOH (1 M), isopropanol; (ii) (1S,2S)-(+)-1,2-diamino-cyclohexane, DCC,
EtOAc, ice-salt bath to rt, N2; (iii) TFA, CH2Cl2, N2.
(R)- and (S)-enantiomers of ( )-7 were clearly determined by inte-
gral change of -H signals of (S)-enantiomer when (S)-7 was added
a
to 1:1 mixture of ( )-7 with 1a and 1d, respectively. Their overlaid
R1
1H NMR spectra are shown in Figure 2.
H
O
O
R
Based on the above results, in order to further examine enan-
tiomeric discriminating capability of 1a–1h as CSAs, the following
NH N
NH N
R2
R2
i
ii
5
a
-hydroxy acids and N-Ts-
Their chemical structures are shown in Figure 3.
First, 1H NMR spectra of
-hydroxy acids ( )-7–10 were
a-amino acids were used as guests.
O
H
O
R
R1
a
6
recorded in the presence of 1a–1h as CSAs, respectively. Among
them, enantiomers of most guests can be discriminated by 1a–1h
1a: R = Bn, R1 = H, R2 = H
1b: R = Bn, R1 = H, R2 = Cl
1c
1d
1e
H
O
R1
O
R
as CSAs. The nonequivalent chemical shifts (DDd) of
a-H of ( )-
: R = Bn, R1 = Br, R2 = Br
: R = Bn, R1 = H, R2 = OCH3
: R = Ph, R1 = H, R2 = H
: R = Ph, R1 = H, R2 = Cl
7–10 and protons of OCH3 group of ( )-10 were observed except
( )-7, ( )-9 and ( )-10 in the presence of 1b, ( )-8 and ( )-9 in
the presence of 1c and 1f and ( )-9 in the presence of 1d and 1e,
respectively. After (S)- or (R)-enantiomer of ( )-7–10 was added
to the above 1:1 mixture of the discriminated guest with the cor-
responding CSA, respectively, their 1H NMR spectra were recorded
again at the same condition. The assignment of the (S)- and (R)-
enantiomers was determined by the integral change of the corre-
sponding proton signals. Their chemical shift nonequivalences
NH HN
NH HN
R2
R2
1f
1g
1h
O
H
O
R
R1
: R = Ph, R1 = H, R2 = Br
: R = Ph, R1 = H, R2 = OCH3
1
Scheme 2. Synthesis of chiral compounds 1a–1h. Reagents and conditions: (i)
salicylaldehyde or its derivatives, MeOH, reflux, N2; (ii) NaBH4, MeOH/PhMe.
R
S
(DDd, ppm) are summarized in Table 1.
To further explore enantiomeric discriminating capability of
1a + 7
1a–1h as CSAs, 1H NMR spectra of N-Ts-
a-amino acids ( )-11–18
R
were measured in the presence of 1a–1h, respectively. The
nonequivalent chemical shifts of the two enantiomers of most
guests can be obviously observed by 1H NMR signals by their cor-
responding protons. After adding the (S)- or (R)-enantiomer of ( )-
11–18 to the 1:1 mixture of the discriminated enantiomers with
1a–1h, respectively, their 1H NMR spectra were measured again
under the same condition. The assignment of most (S)- and (R)-
enantiomers was clearly determined by change of integration of
the signals of the corresponding proton. These discriminating
results indicate that 1a–1h are effective chiral solvating agents
towards the above guests. The chemical shift nonequivalences
S
1d + 7
7
1a and 1d
ppm
5.3
5.2
5.1
5.0
4.9
(
DDd, ppm) are shown in Table 2.
A highly effective chiral solvating agent can not only discrimi-
Figure 2. Overlaid 1H NMR spectra of free 1a and 1d, free ( )-7, ( )-7 with 1a and
1d, respectively.
nate a pair of enantiomers, but also have its practicalities in some
ways, for example, determination of enantiomeric excess (ee%) of a
chiral compound. Herein, to examine the practical applicability of
CSAs 1a–1h, all the samples of 7 with 90%, 70%, 50%, 30%, 10%,
0%, ꢀ10%, ꢀ30%, ꢀ50%, ꢀ70% and ꢀ90% ee were prepared in the
presence of 1a for evaluating their enantiomeric excesses by 1H
NMR spectroscopy. 1H NMR spectra of all samples were recorded
and their enantiomeric excesses were calculated based on the inte-
Condensation reactions of 5 with salicylaldehyde and its deriva-
tives were performed to afford chiral diimines 6a–6h, respec-
tively.15 Chiral compounds 1a–1h were obtained by reductive
reaction in the presence of NaBH4.16 They were purified by column
chromatography on silica gel to afford 1a–1h in 55–75% isolated
yields (Scheme 2).
gration of 1H NMR signals of
shown in Figure 4.
a-H of (R)-7 and (S)-7. The results are
To explore enantiomeric discriminating capability of 1a–1h as
CSAs towards
a-hydroxy acids and N-Ts-a
-amino acids by 1H
The above results indicate that the enantiomeric excesses of 7
with different optical compositions were determined in high
accuracy in the presence of 1a by 1H NMR spectroscopy
(y = 0.9996x ꢀ 0.1440, correction coefficient = 0.9999). The linear
correction between the theoretical (x) and observed ee % (y) is
shown in Figure 5.
NMR spectroscopy, ( )-mandelic acid 7 was first used as a guest in
the presence of 1a and 1d, respectively. Their 1H NMR spectra show
that the single peak of
intensity peaks with well-resolved signals. The nonequivalent
chemical shifts DDd) of -H of ( )-7 were given to be
0.0540 and 0.0862 ppm, respectively. Then, the assignments of
a-H of ( )-7 was split into two equal-
(
a
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G. Gao et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 1
Measurements of chemical shift nonequivalences (DDd, ppm) of guests ( )-7–10 (10 ꢁ 10ꢀ3 M) in the presence of 1a–1h (10 ꢁ 10ꢀ3 M) as CSAs by1H NMR spectroscopy
(400 MHz) in CDCl3 at room temperature, respectivelya
Entry
CSA
Guest
Proton
DDdb
Entry
CSA
Guest
Proton
DDdb
1
2
3
4
5
6
7
8
1a
1c
1d
1e
1f
1g
1h
1a
1b
1d
1e
1g
7
7
7
7
7
7
7
8
8
8
8
8
a-H
a-H
a-H
a-H
a-H
a-H
a-H
a-H
a-H
a-H
a-H
a-H
0.0540
0.0056c
0.0862
0.0297
0.0139
0.0132c
0.0488
0.0526
0.0299
0.0796
0.0482
0.0191c
13
14
15
16
17
18
19
20
21
22
23
1h
1a
1g
1h
1a
1c
1d
1e
1f
8
9
9
a
a
a
a
a
OCH3
a
a
-H
-H
-H
-H
-H
0.0670
0.0163
0.0191c
0.0149
0.0476
0.0075
0.0721
0.0242
0.0037
0.0089c
0.0139
0.0459
9
10
10
10
10
10
10
10
-H
-H
9
OCH3
-H
OCH3
-H
10
11
12
1g
1h
a
a
a
b
c
DDd =
D
dR
ꢀ
D
dS;
D
dR = dR ꢀ dfree
;
D
dS = dS ꢀ dfree
.
DDd of the corresponding protons of guests (H:G = 1:1).
Guest (5 ꢁ 10ꢀ3 M), host (5 ꢁ 10ꢀ3 M) CHCl3/CD3OD (5%).
Table 2
Measurements of chemical shift nonequivalences (DDd, ppm) of guests ( )-11–18 (10 ꢁ 10ꢀ3 M) in the presence of 1a–1h (10 ꢁ 10ꢀ3 M) as CSAs by 1H NMR spectroscopy
(400 MHz) in CDCl3 at room temperaturea
Entry
CSA
Guest
Proton
DDdb
Entry
20
CSA
Guest
Proton
DDdb
1
2
3
1a
1e
1f
11
11
11
PhCH3
CH3
CH3
PhCH3
CH3
CH3
PhCH3
PhCH3
PhCH3
CH3
PhCH3
TsNH
CH3
CH3
PhCH3
CH3
CH3
PhCH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
0.0079
0.0456
0.0303
0.0074
0.0117c
0.0357
0.0073
0.0170d
0.0134d
0.0569
0.0076
0.1480
0.0180d
0.0284
0.0052
0.0421
00285
PhCH3
SCH3
PhCH3
SCH3
0.0082d
0.0191
0.0162d
0.0316
0.0271
0.0521
0.0075
0.0067
0.0071
0.0283
0.0195
0.0161
0.0870
0.0248
0.1261
0.0165
0.0497
0.0253
0.1231
0.0071
0.0172
0.0107
0.0150
0.1194
0.0095
0.1164
0.0026
0.0292
0.0216
0.0075
0.0411
1d
15
21
22
23
24
1e
1f
1a
1b
15
15
16
16
4
5
1g
1h
11
11
SCH3
a
-H
PhCH3
-H
PhCH3
6
7
8
1a
1b
1d
12
12
12
a
25
1c
16
a
a
-H
-H
26
27
1d
1e
16
16
PhCH3
-H
PhCH3
-H
PhCH3
-H
PhCH3
-H
9
1f
12
a
28
29
30
1f
16
16
16
10
11
1c
1d
13
13
a
1g
1h
a
0.0102d
0.0167
0.0103
0.0074
0.0172
0.0061
0.0168
0.0157
0.0225c
0.0154
0.0152d
0.0195
0.0052
0.0126
12
13
1e
1f
13
13
a
31
32
33
34
1a
1d
1e
1f
17
17
17
17
PhCH3
PhCH3
PhCH3
PhCH3
14
15
1g
1h
13
13
a
-H
PhCH3
-H
PhCH3
35
36
1g
1a
17
18
16
17
1d
1a
14
15
PhCH3
SCH3
PhCH3
SCH3
PhCH3
SCH3
a
a
a
-H
-H
18
1b
1c
15
15
37
38
39
1b
1d
1f
18
18
18
PhCH3
-H
19
a
a
b
c
DDd =
D
dR
ꢀ
D
dS;
D
dR = dR ꢀ dfree
;
D
dS = dS ꢀ dfree
.
DDd of the corresponding protons of guests (H:G = 1:1).
Guest (5 ꢁ 10ꢀ3 M), host (5 ꢁ 10ꢀ3 M) CHCl3/CD3OD (5%).
d
Nonequivalent chemical shifts were given by adding (S)-enantiomer to the mixture of ( )-guest and host.
To study effect of concentration in the process of enantiomeric
In order to investigate solvent effect on enantiomeric discrimi-
nation, 1H NMR spectra of ( )-7 were measured in the presence of
1a in different deuterated solvents, such as free CDCl3, CDCl3 con-
taining 10% benzene-d6, acetone-d6, methanol-d4 and DMSO-d6,
respectively. The results indicate that deuterated solvents with
strong polar functional group may participate more actively in
the process of enantiomeric discrimination so as to result in weak-
ening or losing of discriminating capability of 1a. Obviously, chlo-
roform-d is more suitable for the enantiomeric discrimination by
1H NMR spectroscopy. The detailed results are shown in Table 3.
Moreover, upon addition of CSA 1a, nonequivalent chemical
discrimination, 1H NMR spectra of ( )-7 at various concentrations
were recorded in the presence of 1a. As the concentration
increases, nonequivalent chemical shifts of
to be increasing until a maximum value (DDd, 25.44 Hz) was
observed at 30 mM. Then, nonequivalent chemical shifts of -H
a-H of ( )-7 were found
a
of ( )-7 were observed to trend downward gradually. Based on
general requirement for concentration in 1H NMR spectroscopy
and slight change of nonequivalent chemical shifts of
a-H of
( )-7 between concentration of 10 and 30 mM, concentration of
10 mM was used for the enantiomeric discrimination. The overlaid
1H NMR spectra of various concentrations of ( )-7 in the presence
of 1a are shown in Figure 6.
shifts (DDd) of
a-H of ( )-7 were found to be increasing gradually
from 12.32 to 21.96 Hz. But, with the continued addition of 1a,
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4
G. Gao et al. / Tetrahedron Letters xxx (2015) xxx–xxx
89.68% (90.00%) ee
69.61% (70.00%) ee
49.86% (50.00%) ee
29.70% (30.00%) ee
Figure 5. Linear correlation between theoretical ee values (X) and observed ee
values (Y) of 7 in the presence of equal amounts of 1a.
11.41% (10.00%) ee
0.48% (0.00%) ee
c
= 2 mM
ΔΔδ
= 14.24 Hz
21.60 Hz
24.28 Hz
c = 5 mM
c = 10 mM
c
= 20 mM
24.88 Hz
25.44 Hz
10.67% (-10.00%) ee
30.59% (-30.00%) ee
c = 30 mM
c = 40 mM
24.64 Hz
23.80 Hz
c = 50 mM
5.15
5.10
5.05
5.00
4.95
4.90
4.85
ppm
49.39% (-50.00%) ee
70.63% (-70.00%) ee
Figure 6. Overlaid 1H NMR spectra of various concentrations of ( )-7 in the
presence of 1a. The mole ratio of 1a and ( )-7 is 1:1, unchangeable.
Table 3
Measurements of chemical shift nonequivalences (DDd, Hz) of
a-H of ( )-7 in the
presence of 1a by 1H NMR spectroscopy in different deuterated solvents at room
temperaturea
Entry
Solvent
DDd (Hz)
1
2
3
4
5
CDCl3
21.60
20.28
6.68
0.00
0.00
CDCl3/C6D6 (10%)
CDCl3/CD3COCD3 (10%)
CDCl3/CD3OD (10%)
CDCl3/DMSO-d6 (10%)
90.08% (-90.00%) ee
a
The concentration of 1a and ( )-7 is 10 mM (1:1) in 0.5 mL of various deuter-
ated solvents in NMR tubes, respectively.
5.2
5.1
5.0
4.9
for enantiomeric discrimination. The overlaid 1H NMR spectra of
( )-7 and 1a with the different molar ratio are shown in Figure 7.
Finally, Job plots of ( )-7 were performed in the presence of 1a
Figure 4. Determination of enantiomeric excesses of 7 (ee% = R% ꢀ S%), the R and S
stand for -H of enantiomers of ( )-7 in the presence of equal amounts of 1a.
a
with a total concentration of 10 mM. A maximum of Xꢂ
Dd of ( )-7
nonequivalent chemical shifts of
change (2.56 Hz) from 1:1 (19.40 Hz) to 3:1 (21.96 Hz) molar ratio
of 1a with ( )-7. The 1:1 molar ratio of host with guest was used
a
-H of ( )-7 were given a small
was observed at X = 0.5 when molar ratio of ( )-7 versus 1a was
1:1. The result indicates that CSA 1a can bind two enantiomers
of ( )-7 to form a complex with 1:1 molar ratio. In theory, three
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G. Gao et al. / Tetrahedron Letters xxx (2015) xxx–xxx
5
Supplementary data
ΔΔδ = 12.32 Hz
16.04 Hz
1a
1a
1a
1a
1a
1a
:
:
:
:
:
:
7
7
7
7
7
7
= 1 : 2
= 1 : 1.5
= 1 : 1
= 1.5 : 1
= 2 : 1
= 3 : 1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
060.
References and notes
19.40 Hz
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Riguera, R. Chem. Rev. 2004, 104, 17–117; (e) Reetz, M. T. Angew. Chem., Int. Ed.
2002, 41, 1335–1338; (f) Machida, Y.; Kagawa, M.; Nishi, H. J. Pharm. Biomed.
Anal. 2003, 30, 1929–1942; (g) Ema, T.; Tanida, D.; Hamada, K.; Sakai, T. J. Org.
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Dissanayake, P.; Allen, M. J. J. Am. Chem. Soc. 2010, 132, 12871–12873; (c)
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2012, 77, 173–187; (d) Sutar, R. L.; Joshi, N. N. Tetrahedron: Asymmetry 2013, 24,
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20.72 Hz
21.36 Hz
21.96 Hz
ppm
4.9
5.2
5.1
5.0
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Figure 7. Overlaid 1H NMR spectra of the various molar ratios of ( )-7 with 1a. The
concentration of ( )-7 is 5 mM in CDCl3, unchangeable.
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X
Figure 8. Job plots for complexation of (R)- and (S)-7 with 1a.
chemical shift change of
D
d standing for
a
-H of (R)- and (S)-7 in the presence of 1a. X standing for
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kinds of complexes (R)/(R)-, (S)/(S)- and (R)/(S)-7 with 1a should be
generated based on the Job plots. However, only two sets of 1H
NMR signals of
a-H of (R)/(R)- and (S)/(S)-7 were obtained in the
presence of 1a. The results may be due to a faster exchange over
NMR timescale among the free guest, host and their complexes.14
The Job plot of (R)- and (S)-7 in the presence of 1a is shown in
Figure 8.
In conclusion, chiral compounds 1a–1h with multiple binding
sites have been efficiently synthesized for enantiomeric discrimi-
nation as chiral solvent agents. Their enantiomeric discriminating
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Mohamod, A. A.; Vinodh, M. Tetrahedron 2015, 71, 1523–1528.
capability was examined towards
a-hydroxy acids and N-Ts-a-
amino acids by 1H NMR spectroscopy. The results show that chiral
compounds 1a–1h are highly effective and practical chiral
solvating agents towards the above guests.
14. Dahiya, R. Pak. J. Pharm. Sci. 2007, 20, 317–323.
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Acknowledgment
16. (a) Equey, O.; Alexakis, A. Tetrahedron: Asymmetry 2004, 15, 1069–1072; (b) Ai,
L.; Xiao, J. C.; Wang, G.; Shen, X. M.; Zhang, C. Synth. Commun. 2006, 36, 2859–
2875.
This work was supported by Beijing Municipal Commission of
Education, China.
Please cite this article in press as: Gao, G.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.060