Synthesis of macrocycles and their application as chiral solvating agents in the enantiomeric recognition of carboxylic acids and α-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2013.03.005

The chiral macrocycles 1 and 2 with multiple binding sites have been synthesized from D-phenylalanine as chiral solvating agents (CSAs) for the enantiomeric discrimination and determination of the enantiomeric excess of carboxylic acids and a-amino acids

Full text of DOI:10.1016/j.tetasy.2013.03.005

Tetrahedron: Asymmetry 24 (2013) 480–491
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Synthesis of macrocycles and their application as chiral solvating agents in
the enantiomeric recognition of carboxylic acids and a-amino acid derivatives
Shengnan Guo a, Guo Wang b, Lin Ai a,
⇑
a College of Chemistry, Beijing Normal University, Beijing 100875, China
b Department of Chemistry, Capital Normal University, Beijing 100048, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 January 2013
Accepted 3 March 2013
The chiral macrocycles 1 and 2 with multiple binding sites have been synthesized from D-phenylalanine
as chiral solvating agents (CSAs) for the enantiomeric discrimination and determination of the enantio-
meric excess of carboxylic acids and a-amino acids derivatives by the 1H NMR spectroscopy. The results
show that chiral macrocycles 1 and 2 are effective CSAs towards the carboxylic acids and a-amino acids
derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral recognition has received considerable attention in recent
years due to the significant importance of chirality in biology,
pharmaceutical chemistry, and asymmetric catalysis.1 In the field
of chirality and related research, the discrimination of the absolute
configuration and the determination of the enantiomeric purity are
indispensable to a chiral compound.2 Therefore, many methods and
techniques, such as HPLC,3 NMR,4 UV–vis,5 and fluorescence
spectroscopy,6 have been developed and used to meet the
increased demands of enantiomeric discrimination and analysis of
enantiomeric excess. Among them, the NMR method has very dis-
tinct advantages, such as only requiring very little of the sample
and deuterated solvent, less environmental pollution, and also
being highly accurate, reliable, and convenient procedures.1d–f,7
Thus, many types of chiral shift reagents (CSRs) and chiral solvating
agents (CSAs), such as lanthanide complexes,8 cyclodextrins,9
crown ethers,10 porphyrins,11 calixarenes,12 and others,13 have
been designed, synthesized, and screened for these purposes. To
the best of our knowledge, these are the only receptors with a struc-
ture capable of differentiating the NMR signals of enantiomers upon
complexation as CSRs or CSAs by NMR spectroscopy.14 Recently,
chiral macrocycles have been recognized as one of the most effec-
tive chiral solvating agents for chiral recognition by NMR spectros-
copy due to their inherent reduced flexibility and complexation
ability.15 Herein we report the synthesis of novel chiral macrocycles
The chiral macrocycles 1 and 2 were designed and synthesized
starting from
Figure 1.
D-phenylalanine. Their structures are shown in
Ph
N
O
O
Bn
HO
HO
O
NH HN
NH HN
NH
HN
N
O
HN
HO
O
Ph
Ph
2
1
Figure 1. Structures of the chiral macrocycles 1 and 2.
The N-Boc-protected
D
-phenylalanine 4 was obtained from
D
-phenylalanine 3 according to the literature.16 The coupling reac-
tion with 4 and o-phenylenediamine was carried out in the pres-
ence of N,N’-dicyclohexylcarbodiimide (DCC) in an ice-salt bath
under a nitrogen atmosphere according to a modified procedure.17
The crude product was purified by column chromatography on
silica gel to afford the pure compound 5 in 83% yield. The chiral
diamine 6 was prepared by deprotection of N-Boc-protected
diamide 5 in trifluoroacetic acid (TFA) in 86% yield17 (Scheme 1).
Chiral diimine 7 was obtained via condensation reaction of chi-
ral diamine 6 with salicylaldehyde in 90% yield.17 The reductive
1 and 2 with multiple bonding sites from
D-phenylalanine and their
application in chiral recognition as chiral solvating agents toward
carboxylic acids and
spectroscopy.
a
-amino acid derivatives by 1H NMR
⇑
Corresponding author. Tel.: +86 1058807843.
E-mail address: linai@bnu.edu.cn (L. Ai).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.005

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
481
Ph
O
Ph
O
Ph
Ph
NH
NHBoc
NHBoc
NH
NH2
NH2
O
O
i
ii
iii
HO
NH2
HO
NHBoc
NH
O
NH
3
4
O
Ph
Ph
5
6
Scheme 1. Synthesis of chiral compounds 5 and 6. Reagents and conditions: (i) NaOH (1 M), isopropanol, (Boc)2O; (ii) EtOAc, o-phenylenediamine, ice-salt bath to rt, N2; (iii)
TFA, CH2Cl2, N2.
Ph
Ph
O
O
HO
HO
NH
NH2
NH2
NH
N
N
iii
i
ii
2
1
NH
O
NH
O
Ph
Ph
6
7
Scheme 2. Synthesis of chiral macrocycles 1 and 2. Reagents and conditions: (i) CH3OH, salicylaldehyde, reflux, N2; (ii) DMF, Zn powder, MsOH, ꢀ35 °C to 0 °C; (iii) K2CO3,
DMF, 2,6-dibromomethylpyridine, N2.
Table 1
Measurements of 1H chemical shift nonequivalence
(DDd) of the guests
(10 ꢁ 10ꢀ3 M) in the presence of CSAs 1–2 (10 ꢁ 10ꢀ3 M) by 1H NMR spectroscopy
(400 MHz) in CDCl3 at 25 °Ca
Entry
Guest
Proton
DDd (Hz) (CSA 1)
DDd (Hz) (CSA 2)
1
2
8
9
a
a
-H
-H
4.76
3.48
15.16
25.36
1.28
24.04
5.88
3.68
2.92
3.96
3.36
2.24
1.76
0.00
8.16
11.32
0.00
36.16
25.44
8.32
10.24
10.68
0.00
24.68
6.20
10.20
2.92
0.00
0.00
0.00
3.24
3.12
0.00
0.00
0.00
0.00
2.24
0.00
1.36
0.00
1.56
14.20
0.00
3.76
16.20
6.28
2.12
19.56
2.76
12.68
0.00
0.00
9.16
0.00
3.08
0.00
OCH3
COCH3
SCH3
a
a
3
10
11
-H
-H
4b
CH3
-H
CH3
-H
5b
6b
7b
8
12
13
14
15
a
a
COCH3
OCH3
PhCH3
SCH3
CH3
PhCH3
CH3
CH3
PhCH3
CH3
CH3
PhCH3
a
9
16
17
18
10
11
12
19
20
13b
-H
Figure 2. X-ray crystal structure of the chiral macrocycle 2.
CH3
CH3
CH3
a
a
14
21
22
23
24
15
coupling reaction was performed for the preparation of chiral mac-
rocycle 1 under the suitably dilute conditions.18 However, despite
our efforts, crystals suitable for X-ray crystal diffraction could not
be obtained. The chiral macrocycle 2 was derived from macrocycle
1 with 2,6-dibromomethylpyridine in the presence of K2CO3 under
a nitrogen atmosphere (Scheme 2).
16b,c
17b
-H
-H
17.44
5.20
a
Typical conditions: concentration of the guest and the CSA 1 or 2 was 10 mM
(1:1) in 0.5 mL of CDCl3, and the spectra were recorded at 25 °C.
b
Using CDCl3/CD3OD (5%) as solvents.
Concentration of the guest was 2.5 mM.
c

482
S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
OH
NHAc
COOR1
NHTs
R COOH
COOH
OR
H
COOH
R
RO
H
16: R = H3CSCH2CH2
17: R = CH3
10:
R
R = H3CSCH2CH2, R1 = H
COOH
11: R = Ph, R1 = H
12: R = CH3, R1 = H
18: R = (CH3)2CHCH2
19: R = (CH3)2CH
20: R = HOOCCH2
21: R = PhCH2
8: R = H
9: R = CH3O
23: R = H
R = (CH3)2CHCH2, R1 = H
13:
24: R = PhCO
14: R = (CH3)2CH, R1 = H
CH2
22:
15: R =
COOH
N
Ts
R
1 = CH3
N
H
Figure 3. Structures of the carboxylic acids and a-amino acid derivatives.
The crystalsofmacrocycle2weregrown by slowevaporationfrom
0.05
0.04
0.03
0.02
0.01
0.00
a mixture of methanol and acetone for X-ray crystal diffraction.19 The
structure of chiral macrocycle 2 was confirmed as having an (R,S,R,R)-
configuration by X-ray crystallography (Fig. 2).
CSA 1 + (S)-21
CSA 2 + (R)-21
CSA 1 + (R)-21
CSA 2 + (S)-21
The structure of chiral macrocycle 1 is shown to have an
(R,S,R,R)-configuration and is a 12-membered ring product based
on the X-ray structure of chiral macrocycle 2. In addition, the struc-
tures of chiral macrocycles 1 and 2 were also characterized by 1H
NMR, 13C NMR, HRMS, and IR.
In order to explore the binding properties of chiral macrocycles
1 and 2 as CSAs for carboxylic acids and a-amino acid derivatives
δ
by NMR spectroscopy, the following carboxylic acids and
a
-amino
acid derivatives were chosen as guests (Fig. 3).
The 1H NMR spectra of the carboxylic acids 8–9 and
a-amino acid
derivatives 10–24 were measured in the presence of the macrocy-
cles 1 and 2 as chiral solvating agents, respectively. Macrocycle 1
exhibited stronger binding properties, a better baseline resolution,
and a fairly wide detection window, for example, the maximum
chemical shift nonequivalence of the CHCH3 signals of 18 was
36.16 Hz (Table 1, entry 11). These results demonstrated that mac-
rocycle 1 was a highly effective chiral solvating agent for carboxylic
0.0
0.2
0.4
0.6
0.8
1.0
X
Figure 5. Job plots for the complexation of (R)- or (S)-21 with CSA 1 and 2.
stands for chemical shift change of the CH3-protons of (R)- or (S)-21 in the presence
of CSA 1 or 2, X stands for the molar fraction of 21, (X = [21]/([21] + [CSA 1 or 2]).
Dd
acids and
a
-aminoacid derivatives. However, macrocycle2 was only
-amino
able to recognize some of the above carboxylic acids and
a
tons of (R)- and (S)-21 exhibited an upfield shift of 0.0604 and
0.0859 ppm in the presence of CSA 1 and 0.0968 and 0.0739 ppm
in the presence of CSA 2, respectively. The chemical shift changes
acid derivatives under the same conditions. Detailed results are
summarized in Table 1.
When mixing 21 and CSA 1 or 2 with a 1:1 molar ratio, the sig-
nals of the CH3– protons of 21 were split into two equal-intensity
(
D
dS) of (S)-21 were larger than those (
ence of CSA 1. In contrast, the chemical shift changes (
(S)-21 were smaller than those ( dR) of (R)-21 in the presence of
D
dR) of (R)-21 in the pres-
D
dS) of
peaks by 1H NMR spectroscopy on
a 400 MHz instrument.
D
Compared to the chemical shift values (2.3982 ppm) of the
CH3– protons of free 21, the chemical shift values of the CH3– pro-
CSA 2. The chemical shift nonequivalence (DDd) of 21 was evalu-
ated in 0.0255 and 0.0229 ppm in the presence of CSA 1 or 2,
S
S
R
1
1
21 S 21
CSA
+
+
+ ( )-
2
2
21 S 21
R
CSA
+
+
+ ( )-
21
CSA
21
CSA
21
21
1
CSA
2
CSA
2.50
2.45
2.40
2.35
2.30
2.45
2.40
2.35
2.30
2.25
(a)
(b)
Figure 4. (a) The overlaid 1H NMR spectra of free CSA 1, free 21, the 1:1 mixture of CSA 1 with 21, the 1:2 mixture of (R)- and (S)-21 in the presence of CSA 1. (b) The overlaid
1H NMR spectra of free CSA 2, free 21, and the 1:1 mixture of CSA 2 with 21, the 1:2 mixture of (R)- and (S)-21 in the presence of CSA 2.

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
483
Figure 6. Proposed 1:2 and 2:3 binding models for the interactions of CSA 1 (a) and CSA 2 (b) with (R)-21, respectively.
S
R
R
S
ΔΔδ = 5.68 Hz
6.00 Hz
ΔΔδ = 9.64 Hz
1 21
= 1:3
CSA
:
2 21
CSA
:
= 1:2
R
S
R
S
S
10.88 Hz
10.68 Hz
CSA 1:21 = 1:2
2 21
:
CSA
CSA
= 2:3
= 1:1
R
S
R
9.16 Hz
8.60 Hz
CSA 1:21 = 2:3
CSA 1:21 = 1:1
2 21
:
R
S
S
R
10.20 Hz
8.72 Hz
2 21
:
CSA
= 2:1
S
R
R
S
8.00 Hz
CSA 1 :21 = 3:2
CSA 2:21 = 3:1
2.41 2.39 2.37 2.35 2.33 2.31 2.29 2.27
2.40
2.38
2.36
2.34
2.32
2.30
2.28
2.26
(a)
(b)
Figure 7. The overlaid 1H NMR spectra of various molar ratio mixtures of CSA 1 with 21 (a) and CSA 2 with 21 (b). The concentration of 21 was 10 mM in CDCl3.
respectively. Meanwhile, the enantiomeric discriminations of race-
mic 21 were determined by integration changes of the CH3– pro-
tons of 21 by adding (S)-21 to a 1:1 mixture of 21 and CSA 1 or
CSA 2 in CDCl3. The following spectra are presented with good
baseline resolution and a fairly wide detection window, which
show the potential of macrocycles 1 and 2 as CSAs for 21 (Fig. 4).

484
S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
ΔΔδ = 0.00Hz
5.04Hz
ΔΔδ = 5.92Hz
C(G) = 2 mM
C(G) = 2 mM
C(G) = 5 mM
8.36 Hz
C(G) = 5 mM
10.88Hz
9.16Hz
9.80Hz
C(G) = 10 mM
C(G) = 10mM
C(G) = 25mM
10.16Hz
C(G) = 25 mM
9.84Hz
C(G) = 50 mM
9.60 Hz
C(G) = 50mM
2.42
2.40
2.38
2.36
2.34
2.32
2.30
2.28
2.26
2.24
2.22
2.40
2.37
2.34
2.31
2.28
(a)
(b)
Figure 8. (a) Concentration variation of DDd for 21 in the presence of CSA 1. (b) Concentration variation of DDd for 21 in the presence of CSA 2. The molar ratio of CSA 1 or 2
versus 21 was 1:2 or 1:1, and was unchanged.
Table 2
2, respectively. Thus, the molar ratios of CSA 1–21 with 1:2 and
CSA 2–21 with 1:1 were the best value for the enantiomeric dis-
crimination of racemic 21 (Fig. 7).
Measurements of the 1H chemical shift nonequivalence (DDd) of CH3-protons of 21 in
the presence of CSA 1 or CSA 2 by 1H NMR spectroscopy (400 MHz) in different
deuterated solventsa
In order to further study the binding properties, the 1H NMR
spectra of the various concentrations of 21 were performed in
the presence of CSA 1 or 2. With variation in concentration, a series
of nonequivalent chemical shifts of 21 were observed from 5.92 to
9.60 Hz in the presence of CSA 1. Among them, the concentration of
10 mM proved to be the best for the enantiomeric discrimination
of 21 based on the maximum nonequivalent chemical shift at
10.88 Hz (Fig. 8a). However, when increasing the concentration, a
slow increase of the nonequivalent chemical shifts of 21 was
observed from 0.00 to 9.84 Hz in the presence of the CSA 2 and a
maximum was not found (Fig. 8b). Based on the experimental
results and the general requirements for concentration in 1H
NMR spectroscopy, a concentration of 10 mM was used for the
Entry
Solvent
DDd (Hz) (CSA 1)b
DDd (Hz) (CSA 2)c
1
2
3
4
5
CDCl3
10.88
9.32
4.60
0.00
0.00
9.16
8.00
0.00
0.00
0.00
CDCl3/C6D6 (10%)
CDCl3/CD3COCD3 (10%)
CDCl3/CD3OD (10%)
CDCl3/DMSO-d6 (10%)
a
All samples were prepared by mixing CSA 1 or CSA 2 with 21 (1:2; 1:1) in NMR
tubes.
The final concentrations of CSA 1 and 21 were 5 and 10 mM in 0.5 mL of various
deuterated solvents.
The final concentrations of CSA 2 and 21 were 10 mM in 0.5 mL of various
deuterated solvents.
b
c
enantiomeric discrimination of the carboxylic acids and
a-amino
acid derivatives in the presence of CSA 2.
The Job plots of racemic 21 with CSA 1 or 2 were obtained with
a total concentration of 10 mM. The maxima were observed at
X = 0.67 and 0.60 until the molar ratios of CSA 1 or 2 versus 21
were 1:2 or 2:3, respectively. These indicate that 1 molecule of
CSA 1 can bind with 2 molecules of 21 to form a complex or that
2 molecules of CSA 2 can bind with 3 molecules of 21 to form a
complex. However, in theory, three kinds of complexes (R)/(R)-,
(R)/(S)-, and (S)/(S)-21 with CSA 1 should be generated based on
the Job plots. Three sets of signals of the tosyl methyl group of
21 should also be observed in the 1H NMR measurements. How-
ever, only two sets of 1H NMR signals of the tosyl methyl group
of (R)/(R)- and (S)/(S)-21 were obtained in the presence of CSA 1.
These results may be due to a faster exchange over the NMR time-
scale among the free guest, host, and their complexes. The Job plots
of (S)- and (R)-21 with CSA 1 or 2 are shown in Figure 5.
Additional 1H NMR experiments of 21 were performed in order
to study solvent effects in the presence of CSA 1 or 2 with a 1:2 or
1:1 molar ratio in CDCl3 containing 10% different deuterated sol-
vents. The experimental results are summarized in Table 2.
As shown in Table 2, upon the addition of the polar solvents, the
binding interactions of 21 with CSA 1 or 2 were weakened and
even removed. For example, the nonequivalent chemical shifts of
21 were changed from 10.88 Hz in CDCl3 to 9.32 Hz in CDCl3/ben-
zene-d6 (10%), 4.60 Hz in CDCl3/acetone-d6 (10%), and 0.00 Hz in
CDCl3/methanol-d4 (10%) and CDCl3/DMSO-d6 (10%) in the pres-
ence of CSA 1, respectively. Thus, solvents with less polarity were
more suitable for studies on the chiral recognition by 1H NMR
spectroscopy, such as chloroform-d and benzene-d6, if the solubil-
ity of guest and host was large enough for NMR testing.
To further explore the practical applications in both the dis-
crimination of enantiomers and the determination of enantiomeric
excess by NMR spectroscopy, the 1H NMR spectra of the carboxylic
Theoretical calculations were performed using an AM1 model
by using a GAUSSIAN 03 program20 in order to investigate the interac-
tions between CSA 1 or 2 with (R)-21. The proposed binding mod-
els for the interactions of CSA 1 and 2 with (R)-21 are shown in
Figure 6.
Upon the addition of CSA 1 or 2, the nonequivalent chemical
shifts of the CH3-protons of (R)- and (S)-21 were found to gradually
increase until the molar ratios of CSA 1 and 2 to racemic 21 were
1:2 and 1:1, respectively. However, with the continued addition
of CSA 1 or 2, the nonequivalent chemical shifts showed a declining
trend. The maximum nonequivalent chemical shifts (DDd) of 21
were obtained at 10.88 and 9.16 Hz in the presence of CSA 1 and
acids and
a-amino acid derivatives were measured by adding
either the (R)- or (S)-enantiomer to a solution containing a racemic
guest and CSA 1 or 2 with a 1:1 molar ratio. However in some
cases, the enantiomeric discriminations of a few of the guests were
determined by comparison to the chemical shift value of the corre-
sponding (R)- or (S)-enantiomer in the presence of CSA 1 or 2 under
the same conditions. A mixture of CDCl3 with 5% CD3OD was used
due to the poor solubility of some carboxylic acids and
a-amino
acid derivatives in CDCl3. The results are summarized in Table 3.

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
485
Table 3
Enantiomeric discrimination of the guests (10 ꢁ 10ꢀ3 M) and different concentrations of the (S)- or (R)-guest in the presence of CSA 1 or 2 (10 ꢁ 10ꢀ3 M) by 1H NMR spectroscopy
in CDCl3 at 25 °Ca
Entry
1
Guest
Proton
Spectrum (CSA 1)
Spectrum (CSA 2)
R
S
( )-8
a
-H
—
2
5.10
5.08
5.
S
(S)-8
(R)-8
( )-9
a
a
-H
-H
—
—
—
5.10
5.05
R
5.10
5.05
S
R
2
OCH3
3.76
3.72
S
R
( )-9+(S)-9
( )-10
OCH3
—
3.75
3.70
R
S
S
R
3
COCH3
COCH3
2.00
S
1.95
1.90
2.06 2.05 2.04 2.03
S
R
R
( )-10+(S)-10
2.00
1.95
2.07 2.06 2.05 2.04 2.03
S
R
4b
( )-11
a
a
-H
-H
—
5.48 5.46 5.44
S
R
( )-11+(S)-11
—
—
—
5.48 5.46 5.44
R
S
( )-11
CH3
CH3
2.03
2.02
2.01
S
R
( )-11+(S)-11
2.04 2.03 2.02 2.01
R
S
S
R
R
R
S
S
5b
( )-12
(S)-12
( )-13
a
a
-H
-H
—
—
4.48
4.44
S
S
S
S
4.48 4.46 4.44 4.42
R
R
S
S
R
R
S
S
6b
CH3
CH3
0.96
0.94
0.96
0.92
S
S
R
R
( )-13+(S)-13
—
0.94 0.92 0.90 0.88
(continued on next page)

486
S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
Table 3 (continued)
Entry
Guest
Proton
CH3
Spectrum (CSA 1)
Spectrum (CSA 2)
S
S
(S)-13
—
0.96
0.94
S
R
R
S
7b
( )-14
a
a
-H
-H
—
—
4.47
4.45
4.43
R
S
S
R
( )-14+(S)-14
4.48 4.46 4.44 4.42
S
R
S
R
8
( )-15
CH3
1.97
1.96
1.97 1.96 1.95 1.94
S
R
S
R
( )-15+(S)-15
CH3
1.97 1.96 1.95 1.94 1.93
1.97 1.96 1.95
S
R
S
R
9
( )-16
SCH3
SCH3
2.35
2.30
2.25
2.34
2.30
S
S
R
R
( )-16+(S)-16
2.36 2.34 2.32 2.30 2.28
2.35 2.30 2.25
S
S
R
R
10
( )-17
(S)-17
( )-17
CH3
—
1.35 1.30 1.25
S S
CH3
—
1.35 1.30 1.25
S
R
PhCH3
—
2.36 2.34 2.32
S
R
( )-17+(S)-17
PhCH3
—
2.35
2.33
R
R
S
S
11
( )-18
(S)-18
CH3
CH3
0.75
0.65
0.80
0.75
S
—
0.7
0.6
S
R
( )-18+(S)-18
( )-18
CH3
CH3
—
0.80
R (S)
0.75
R
R
S
S
0.88 0.86 0.84
0.90 0.85 0.80

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
487
Table 3 (continued)
Entry
Guest
Proton
CH3
Spectrum (CSA 1)
Spectrum (CSA 2)
S
(S)-18
—
0.85
0.80
0.75
R(S)
S
R
( )-18+(S)-18
( )-18
CH3
—
0.88 0.86 0.84
S
S R
R
PhCH3
2.35
2.30
2.2
2.34 2.32 2.30
S
(S)-18
PhCH3
PhCH3
—
2.6
2.4
S
R
( )-18+(S)-18
—
2.34
2.30
S
S
R
S
R
R
12
( )-19
(S)-19
CH3
CH3
0.82
0.78
0.90 0.85 0.80 0.75
S
S
—
0.84 0.82 0.80 0.78 0.76
S
R
( )-19+(S)-19
( )-19
CH3
—
0.85 0.80 0.75
S
R
PhCH3
—
—
2.35
2.30
S
R
( )-19+(S)-19
PhCH3
2.4
2.3
2.2
S
R
13b
( )-20
a
a
-H
-H
—
—
4.00 3.95 3.90 3.85
S
R
( )-20+(S)-20
4.00 3.95 3.90
R
S
R
S
14
( )-21
CH3
2.35
2.30
2.34 2.32 2.30 2.28
S
S
R
R
( )-21+(S)-21
CH3
CH3
2.35
2.30
2.34 2.32 2.30 2.28
S
R
15
( )-22
—
2.46 2.44 2.42 2.40
(continued on next page)

488
S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
Table 3 (continued)
Entry
Guest
Proton
CH3
Spectrum (CSA 1)
Spectrum (CSA 2)
S
R
( )-22+(S)-22
—
2.46 2.44 2.42
(S,S)
(R,R) (S,S)
(R,R)
16b,c
( )-23
a
a
-H
-H
4.55
4.6
4.50
(R,R)
4.45
4.4
4.51 4.50 4.49 4.48
(R,R)
(S,S)
(S,S)
( )-23+(R,R)-23
4.5
4.49
4.47
(S,S)
(R,R)
17
( )-24
a
a
-H
-H
—
—
6.00
5.98
(R,R)
5.96
(S,S)
( )-24+(R,R)-24
5.99
5.97
a
Typical conditions: concentration of the guest and the CSA 1 or 2 is 10 mM (1:1) and various molar ratios of the (S)- or (R)-isomer in 0.5 mL of CDCl3, and the spectra are
recorded at 25 °C. The R and S in the spectra represent the signals of (R)- and (S)-isomers, respectively.
b
Using CDCl3/CD3OD-d4 (5%) as solvents.
Concentration of the guest is 2.5 mM.
c
In order to evaluate the accuracy of the enantiomeric excess
determined by 1H NMR spectroscopy, all samples were prepared
by mixing CSA 1 or 2 and 21 with 60%, 40%, 20%, 0%, ꢀ20%,
ꢀ40%, and ꢀ60% ee according to 1:2 molar ratio of CSA 1 with 21
and a 1:1 molar ratio of CSA 2 with 21 in CDCl3, respectively. The
1H NMR spectra of 21 with different enantiomeric compositions
were recorded in the presence of CSA 1 or CSA 2 by using the 1H
NMR method with a 400 MHz instrument. The enantiomeric excess
of all samples was calculated based on the integration of the sig-
nals of the CH3– protons of (R)- and (S)-21 in the presence of CSA
1 or 2. The results are shown in Figure 9.
The results indicate that the analysis of the enantiomeric excess
has a high accuracy when using 1H NMR spectroscopy in the
presence of macrocycles 1 and 2 as CSAs (y = 1.0087x ꢀ 0.5043,
correlation coefficient = 0.9998; y = 1.0192x ꢀ 0.2184, correlation
coefficient = 0.9996). The linear correlation between the theoreti-
cal (y) and observed ee% values (x) is shown in Figure 10.
structure was determined by a Smart Apex II Single Crystal
Diffractometer.
4.2. Synthesis of chiral macrocycle (R,S,R,R)-1
To a stirred suspension of diimine 7 (3.054 g, 5 mmol) and zinc
powder (5.27 g, 50 mmol) in dry DMF (80 mL), a solution of MsOH
(4.806 g, 50 mmol) in dry DMF (20 mL) was added dropwise over a
period of 30 min at ꢀ35 °C under a nitrogen atmosphere. The mix-
ture was stirred for 10 h at ꢀ35 °C to 0 °C. The reaction mixture
was basified to pH 8–9 with saturated NaHCO3. Next, CHCl3
(50 mL) was added to the above mixture and then stirred for 1 h
at room temperature. The organic phase was separated and the
water phase was extracted with CHC13 (15 mL ꢁ 3). The combined
organic phase was washed with distilled water (30 mL ꢁ 3), dried
over anhydrous Na2SO4 overnight, and concentrated. The residue
was purified by column chromatography on silica gel (petro-
leum/ethyl acetate = 2/1) to afford macrocycle 1 in 21.6% yield as
a white solid. Mp 164–166 °C. Rf = 0.25 (petroleum/EtOAc = 2/1).
½
a 2D0
ꢂ
¼ ꢀ202:9 (c 0.05, CHC13), 1H NMR (400 MHz, CDCl3) d 2.75
3. Conclusion
(d, J = 10.9 Hz, 1H), 2.92–2.95 (m, 2H), 3.00–3.04 (m, 1H), 3.17
(d, J = 10.2 Hz, 1H), 3.59 (s, 2H), 4.27 (d, J = 9.4 Hz, 1H), 4.53
(s, 1H), 5.85 (d, J = 6.7 Hz, 2H), 6.30 (br, 1H), 6.49 (q, J = 7.3 Hz,
1H), 6.57 (d, J = 8.0 Hz, 1H), 6.72–6.81 (m, 5H), 6.92–6.98
(m, 6H), 7.05–7.10 (m, 5H), 7.88 (d, J = 7.7 Hz, 1H), 9.33 (br, 1H),
10.4 (br, 1H). 13C NMR (100 MHz, CDCl3) d 34.5, 38.4, 62.0, 64.7,
66.5, 72.5, 116.1, 116.9, 119.1, 119.4, 120.5, 122.3, 124.3, 124.8,
126.5, 127.0, 127.8, 128.4, 128.6, 129.4, 131.1, 133.0, 136.2,
138.0, 154.5, 158.4, 171.8, 173.1. IR (KBr) 3284, 3051, 3029,
2924, 1665, 1594, 1532, 1455, 1257, 751, 700 cmꢀ1. HRMS(ES+):
calcd for C38H37N4O4 (M+H)+ 613.2815, found 613.2802.
In conclusion, chiral macrocycles 1 and 2 have been synthesized
starting from D-phenylalanine and have been proven to be effective
chiral solvating agents for the enantiomeric discrimination and
determination of the enantiomeric excess of carboxylic acids and
a
-amino acid derivatives by 1H NMR spectroscopy.
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker Advance II spectrometer
at 400 MHz for 1H NMR and 100 MHz for 13C NMR. HRMS spectra
were recorded on a LCT Premier XE spectrometer. IR spectra were
obtained on a Nicolet 360 Avatar IR spectrometer as KBr pellets.
Optical rotations were measured with a Perkin–Elmer Model 343
polarimeter using the sodium D line at 589 nm. X-ray crystal
4.3. Synthesis of chiral macrocycle (R,S,R,R)-2
A mixture of macrocycle 1 (123 mg, 0.2 mmol) and 2,6-dibrom-
ethylpyridine (53 mg, 0.2 mmol) was stirred in the presence of
K2CO3 (276 mg, 2 mmol) in dry DMF (4 mL) at room temperature

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
489
Experimental (expected)
58.0% (60.0%) ee
Experimental (expected)
CSA 2 + 21
CSA 1 + 21
59.1% (60.0%) ee
40.9% (40.0%) ee
20.6% (20.0%) ee
40.5% (40.0%) ee
20.5% (20.0%) ee
0.9% (0.0%) ee
0.0% (0.0%) ee
-19.7% (-20.0%) ee
-39.2% (-40.0%) ee
-20.0% (-20.0%) ee
-38.7% (-40.0%) ee
-58.8% (-60.0%) ee
-59.1% (-60.0%) ee
2.37 2.36 2.35 2.34 2.33 2.32 2.31 2.30 2.29
ppm
2.35 2.34 2.33 2.32 2.31 2.30 2.29 2.28 2.27
ppm
(a)
(b)
Figure 9. Determination of the enantiomeric purity of 21 (ee% = R–S%), the R and S stand for the protons from the CH3 group of the corresponding (R)- and (S)-isomer of 21 in
the presence of 0.5 equiv of CSA 1 (a); in the presence of 1.0 equiv of CSA 2 (b).
y
60
y
60
40
20
40
20
x
-60
-40
-20
20
40
60
x
-60
-40
-20
20
40
60
-20
-40
-60
-20
-40
-60
y = 1.0087x - 0.5043
R2 = 0.9998
y = 1.0192x - 0.2184
R2 = 0.9996
(a)
(b)
Figure 10. The linear correlation between the observed (Y) and theoretical ee% values (X) of 21 in the presence of 0.5 equiv of CSA 1 (a); in the presence of 1.0 equiv of CSA 2
(b).
for 10 h, after which water (20 mL) was added to quench the reac-
tion. The mixture was extracted with CHC13 (5 mL ꢁ 3), and washed
with water (20 mL ꢁ 2) and brine (20 mL). The organic layer was
dried over Na2SO4 overnight and concentrated. The residue was
purified by column chromatography on silica gel (petroleum/acetyl
acetate/dichloromethane = 6/1/1.4) to afford macrocycle 2 as a

490
S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
white solid in 54.3% yield. The crystals suitable for X-ray diffraction
were obtained from methanol–acetone (5:2) as colorless crystals.
References
194–196 °C. Rf = 0.2 (petroleum/EtOAc = 2/1),
½
a 2D0
ꢂ
¼ ꢀ77:85 (c
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3.05–3.14 (m, 3H), 3.56–3.57 (m, 1H), 3.59–3.64 (m, 1H), 4.36 (d,
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At first, CSA 1 or 2, (R)-21 and (S)-21 were separately dissolved
in CDCl3 with a concentration of 10 mM. These solutions were dis-
tributed among nine NMR tubes, with the molar fractions X of the
guest in the resulting solutions increasing from 0.1 to 0.9, with the
total concentration of the host and guest being 10 mM. The 1H
NMR spectra of all samples were recorded on a 400 HMz spectrom-
eter. The recorded Job plots of CSA 1, and (R)-21 and (S)-21 were
found to exhibit a maximum at 0.67. This indicates that the CSA
1 forms a 1:2 complex with 21. However, the recorded Job plots
of CSA 2, and (R)-21 and (S)-21 were found to exhibit a maximum
at 0.6. This indicates that CSA 1 forms a 1:1.5 complex with 21.
4.5. Discrimination ability of CSAs 1 and 2 toward racemic
guests 8–24
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10 mM. For some less soluble guests, such as 11–14, 20, 23, and
24, a CDCl3/CD3OD-5% solution was used as a solvent. In addition,
1 equiv of CSA and 1 equiv of guest 23 were mixed, to which the
mixture of CDCl/CD3OD-5%, was added, and the concentration
was adjusted to 2.5 mM. The 1H NMR spectra of all samples were
recorded on a 400 MHz spectrometer.
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4.6. Determination of the enantiomeric purity of guest 21
In order to demonstrate the accuracy of our method for the
determination of the enantiomeric excess of the guests, we pre-
pared seven samples containing guest (R)-21 with 60%, 40%, 20%,
0%, ꢀ20%, ꢀ40%, and ꢀ60% ee. All samples were prepared by add-
ing 0.5 equiv of CSA 1 or 1 equiv of CSA 2 into the above solutions
with a concentration of 10 mM in CDCl3, and their enantiomeric
compositions were determined by using the 1H NMR method on
a 400 MHz spectrometer. The results, which were calculated based
on the integration of the signals of the CH3– protons of 21, are
shown in Figures 9 and 10.
19. Crystal data for 2ꢃ2ꢃCH3COCH3ꢃ2ꢃCH3OH: C95H96N10O11; M = 1553.82; colorless,
triclinic, space group P1; a = 9.4373(7) Å, b = 12.8563(10) Å, c = 17.2237(13) Å;
V = 2022.8(3) Å3;
l
= 0.084 mmꢀ1; Z = 1; T = 110(2) K; F000 = 824; R1 = 0.0403,
wR2 = 0.0987. The crystallographic data have been deposited at the Cambridge
Crystallographic Data Center (CCDC) under deposition number 890101.
20. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
Acknowledgement
This work was supported by the Beijing Municipal Commission
of Education.

S. Guo et al. / Tetrahedron: Asymmetry 24 (2013) 480–491
491
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
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