Macrocyclic compounds as chiral solvating agents for phosphinic, phosphonic, and phosphoric acids

Article abstract of DOI:10.1016/j.tetasy.2007.12.004

Novel macrocyclic compounds, synthesized and used as chiral solvating agents for phosphinic, phosphonic, and phosphoric acids, are reported in this article. NMR (¹H NMR and/or ³¹P NMR) studies demonstrate that these acids have large nonequivalent chemical shifts in the presence of these macrocyclic compounds. Quantitative analyses of a series of the selected phosphinic acids with different enantiomeric purities show the high accuracy of this method.

Full text of DOI:10.1016/j.tetasy.2007.12.004

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 31–37
Macrocyclic compounds as chiral solvating agents for phosphinic,
phosphonic, and phosphoric acids
Fengnian Ma,a Xiumin Shen,a Jie Ou-Yang,b Zhiwei Dengb and Cong Zhanga,*
aCollege of Chemistry, Beijing Normal University, Beijing 100875, China
bAnalytical and Testing Center, Beijing Normal University, Beijing 100875, China
Received 4 October 2007; accepted 13 December 2007
Abstract—Novel macrocyclic compounds, synthesized and used as chiral solvating agents for phosphinic, phosphonic, and phosphoric
acids, are reported in this article. NMR (1H NMR and/or 31P NMR) studies demonstrate that these acids have large nonequivalent
chemical shifts in the presence of these macrocyclic compounds. Quantitative analyses of a series of the selected phosphinic acids with
different enantiomeric purities show the high accuracy of this method.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
acids are up to 0.80 ppm in the presence of 1a in 1H
NMR (500 MHz) spectra. Herein, we report that the mac-
rocyclic compounds 1a and 1b (see Fig. 1), using (S)-a-
(2-naphthyl)-ethylamine instead of (S)-a-phenylethylamine
as the chiral source to increase the size of the anisotropic
group, can be used as chiral solvating agents for the deter-
mination of ee values of phosphinic, phosphonic, and
The phosphinic and phosphonic acids, such as phosphinic
peptides1,2 and fosfomycin,3–5 are chiral organic molecules
involved in a wide variety of biological processes. In addi-
tion, the chiral phosphoric acids play an important role in
organic synthesis as chiral organocatalysts,6–12 as resolving
agents13–15 and as chiral solvating agents (CSAs).16 Simple
methods for determining the enantiomeric purities of these
chiral compounds are in high demand. NMR spectroscopy,
employed CSA, might even be considered a facile and envi-
ronmentally benign tool.17,18
1
phosphoric acids by H NMR and/or 31P NMR.
N
Some chiral amines, such as a-phenylethylamine,19 a-(1-
naphthyl)-ethylamine,19,20 and ephedrine,19,20 have been
used as CSAs for a-aminophosphonic and a-hydroxyl-
phosphonic acids, but the peaks are not often baseline
separated, because their chemical shift differences are
generally too small. Some better examples21–23 have been
reported by Kafarshi and co-workers, employing cyclodex-
trins as CSAs for a-aminophosphonic and a-aminophos-
phinic acids.
O
O
1a R = Phenyl
1b R = 2-Naphthyl
NH
HN
R
R
Figure 1. The structures of macrocyclic compounds 1a and 1b.
Previously, we demonstrated that24 the macrocyclic
compound 1a is an effective CSA for carboxylic acids.
The nonequivalent chemical shifts (DDd) of enantiomeric
2. Results and discussion
The new macrocyclic compound 1b was synthesized in a
similar manner to 1a.24 First, a Mannich reaction was
undergone, using (S)-a-(2-naphthyl)-ethylamine 2b, b-
naphthol, and m-benzenedialdehyde as starting materials,
to yield aminonaphthol 3b. Then, coupling of 3b with
*
Corresponding author. Tel.: +86 13825661820; fax: +86 10 58210397;
e-mail: czhang@bnu.edu.cn
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.004

32
F. Ma et al. / Tetrahedron: Asymmetry 19 (2008) 31–37
OH
CHO
NH2
THF
+
+
R
80 oC
CHO
OH
R
OH
R
NH
HN
2a
2b
3a
3b
N
O
O
N
Cl
Cl
1a R = Phenyl
1b R = 2-Naphthyl
K2CO3, DMF
NH
HN
R
R
Scheme 1. Synthesis of macrocyclic compounds 1a and 1b.
OH
2,6-bischloromethylpyridine leads to the formation of the
O
target molecule 1b in a high yield (see Scheme 1).
P
Ph OH
a
4
The crystal structure25 of 1b indicates that it is a 16-mem-
bered ring product, and the absolute configuration is
(S,S,S,S) (see Fig. 2), which demonstrates that the newly
formatted stereogenic centers of 3b are also of (S)-
configurations.
b
c
d
e
6.00
5.50
5.00
4.50
4.00
3.50
3.00
2.50
Figure 3. The overlaid 1H NMR spectra of 1a and 4 in various solvents.
The dots indicate the signals of the methine proton of 4. (a) CDCl3; (b)
benzene-d6; (c) DMSO-d6; (d) MeOD-d4; (e) CDCl3/MeOD-d4 (5%).
ing 5% volume of MeOD-d4), the signals were resolved bet-
ter and the DDd increased to 0.35 ppm (500 MHz) for the
a-proton of 4 (10 mM) as 1 equiv of 1a was added, com-
pared to that in MeOD-d4 (0.07 ppm).
The stoichiometry was determined according to Job’s
method of continuous variation.26,27 The Job plots of
DdX versus the mole fraction (X) of (R)- or (S)-4 in the
mixture were obtained, which all showed maxima at
X = 0.6 (see Fig. 4). This indicates that 1a or 1b forms a
‘1:1.5’ complex with (R)-4 or (S)-4. Probably the acid inter-
acts with the two aliphatic nitrogen atoms of 1a or 1b in a
stepwise manner and, a 1:1 complex and a 1:2 complex may
exist at the same time under the experimental condi-
tions. However, we have no direct evidences for these
complexes.
Figure 2. X-ray structure of the new macrocyclic compound 1b.
We previously reported that in less polar solvents, 1a
exhibited better chiral recognition ability (larger DDd) to-
ward carboxylic acids.24 However, for racemic phosphinic
1
acid 4, the H NMR spectra exhibited broad signals in
the presence of 1a in less polar solvents, such as benzene-
d6 and CDCl3. The signals of the two isomers of 4 cannot
be split in DMSO-d6 and a better result was obtained in
MeOD-d4 (see Fig. 3). This can be explained because the
strong intermolecular hydrogen bond between 1a and acid
4 may decrease the rate of exchange between 4 in the free
1
The large nonequivalent H chemical shifts of (R)-4 and
(S)-4 in the presence of 1a inspired us to explore the enan-
tiomeric discriminating ability of 1a and 1b with that of
other acids. A wide variety of racemic acids, including a-
hydroxy phosphinic acids 4–8, N-tosyl-a-amino phosphinic
acids 9 and 10, N-tosyl-a-amino phosphonic acids 11 and
12, cyclic phosphoric acids 13 and 14, were chosen as guests
1
and bound state to the intermediate rate of the H NMR
timescale, which could lead to spectral broadening. Proper
weakening of the hydrogen bond by increasing the polarity
of the solvent will give a better result. Finally, we found
that in the mixed solvent of CDCl3 and MeOD-d4 (contain-

F. Ma et al. / Tetrahedron: Asymmetry 19 (2008) 31–37
33
presence of 1 equiv of 1a. The results (see Fig. 5), which
were calculated based on the integrations of the NMR sig-
nals, are within 2% of the actual enantiopurity of
the samples and demonstrate the high accuracy of this
method.
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1a+(
1b+(
1a+(
1b+(
R
)-4
)-4
R
S
S
)-4
)-4
3. Conclusion
X
In conclusion, we have discovered macrocyclic compounds
1a and 1b, which show excellent ability to discriminate the
enantiomers of a broad variety of phosphinic, phosphonic,
1
and phosphoric acids by H NMR and 31P NMR spectro-
scopy. All the acids chosen, except 8, have a baseline sepa-
ration of NMR signals in 1H NMR and/or 31P NMR
spectra under the experimental conditions.
0.0
0.2
0.4
0.6
0.8
1.0
X
Figure 4. Job plots for the complexation of 1a and 1b with (R)-4 and (S)-4
(X = [1]/([1] + [4]), Dd = variation of the chemical shift of the a-proton of
4).
4. Experimental
4.1. General
to screen the potential of 1a and 1b as CSAs. The results
are summarized in Table 1.
IR spectra were obtained on a Nicolet 360 Avatar IR spec-
trometer as KBr pellets. NMR spectra were recorded on
Avance 500 Bruker spectrometer at 500 MHz for 1H,
125 MHz for 13C and 202 MHz for 31P. Mass spectra were
recorded on Trace MS 2000-Mass Spectrometer using the
EI technique. Elemental analysis was performed on Vario
E1 elemental analyzer. Optical rotations were measured
with a Perkin–Elmer Model 343 polarimeter using the
sodium D line at 589 nm.
As shown in Table 1, in the presence of 1a or 1b, the
methine protons (4–7, 9–11, 14) and the methyl protons
(8, 12) are all split into two peaks due to the different inter-
actions of the two enantiomers of the acids with the CSA.
For most of the examples, the 1H chemical shift nonequiva-
lences are large enough to afford baseline resolution for
accurate integration, especially for a-hydroxy phosphinic
acids and cyclic phosphoric acids; the DDd are up to
173.1 Hz (for 4 in the presence of 1a) and 194.3 Hz (for
14 in the presence of 1b). For phosphonic acids 11 and
12, the DDd are generally equal to or smaller than the cou-
pling constants, which are not suitable for the determina-
tion of the enantiomeric compositions. However, this
problem can be solved as 31P NMR spectroscopy was em-
ployed. In the 31P NMR spectra, the signals of 11 and 12
were split into two peaks at the baseline in the presence
of 1a or 1b. For other acids, the 31P NMR tests were also
done (see Table 1). The results are quite different from that
4.2. Synthesis of aminonaphthol 3b
(S)-a-(2-Naphthyl)-ethylamine (3.80 g, 22 mmol) in 1 mL
THF was added to a solution of m-benzenedialdehyde
(1.34 g, 10 mmol), 2-naphthol (4.00 g, 27 mmol) in 4 mL
of hot THF. The mixture was stirred at 80 °C under a
nitrogen atmosphere for 3d and then purified by flash chro-
matography (acetone–petrol ether = 1:8) affording a crude
product, which was purified by flash chromatography once
again (ethyl acetate–petrol ether = 1:5) affording 3b as a
white solid (1.83 g, 25.1% yield).
1
of the H NMR tests. The two enantiomeric isomers of
20
1
most a-hydroxy phosphinic acids cannot be distinguished
in 31P NMR spectra under the experimental conditions,
while a baseline separation of the 31P NMR signals was
achieved for all the phosphonic and cyclic phosphoric
acids. From a comparison of the chemical shift nonequiva-
Mp 143–144 °C, ½aꢀD ¼ þ280:0 (c 0.51, THF). H NMR
(500 MHz, CDCl3, ppm): d: 1.58 (d, J = 7.9 Hz, 6H),
2.36 (d, J = 12.0 Hz, 2H), 4.02 (dd, J = 11.0, 7.0 Hz, 2H),
5.38 (s, 2H), 6.96 (d, J = 7.6 Hz, 2H), 7.04 (t, J = 7.5 Hz,
2H), 7.05 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 9.0 Hz, 2H),
7.12 (s, 1H), 7.20 (t, J = 7.4 Hz, 2H), 7.27 (d, J = 9.0 Hz,
2H), 7.38 (d, J = 8.5 Hz, 2H), 7.46 (s, 2H), 7.51 (t,
J = 6.9 Hz, 2H), 7.55 (t, J = 6.7 Hz, 2H), 7.70 (d, J =
7.9 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.9 Hz,
2H), 7.90 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H),
13.50 (s, 2H); 13C NMR (125 MHz, CDCl3, ppm): d:
23.03, 56.57, 59.41, 112.88, 120.08, 121.14, 122.42,
123.25, 126.08, 126.34, 126.41, 126.54, 126.79, 127.22,
127.76, 127.92, 128.70, 129.27, 129.85, 132.59, 133.04,
133.30, 139.98, 142.04, 157.35; IR (KBr): 3459, 3304,
3044, 1621, 1600, 1270, 1236 cmꢁ1. Elemental Anal. Calcd
for C52H44N2O2: C, 85.68; H, 6.08; N, 3.84. Found: C,
85.31; H, 6.44; N 3.57.
1
lences in the H and 31P spectra of the chosen acids in the
presence of 1a and 1b, it appears that the change of the
anisotropic group from phenyl to naphthyl does not
improve the chiral discrimination. Perhaps the side chain
is not a key functional group for the discrimination. Unfor-
tunately, we failed to observe intermolecular NOEs in
the 2D NOESY spectra to get even more convincing
evidence.
To explore the quantitative analysis ability of 1a and 1b as
a CSA, six samples containing 4 with 0%, 25%, 45%, 60%,
85% and 90% ee were prepared, and the enantiomeric com-
1
positions were determined by the H NMR method in the

Table 1. Measurements of 1H and 31P chemical shift nonequivalences (DDd) of the acids in the presence of macrocyclic compounds 1a or 1b by 1H NMR (500 MHz) and 31P NMR (202 MHz) in
CDCl3/MeOD-d4 (5%) at 25 °Ca
Acids
1H NMRb
31P NMR
1a
Spectra
1b
Spectra
1a
Spectra
1b
Spectra
DDd (Hz)
DDd (Hz)
DDd (Hz)
DDd (Hz)
OH
O
173.1
129.2
0.0
0.0
P
4
OH
Ph
4.50 4.40 4.30 4.20 4.10
4.50 4.40 4.30 4.20
158.2
126.4
0.0
0.0
OH
O
4.50 4.40 4.30 4.20
4.50 4.40 4.30 4.20
P
5
OH
Ph
MeO
OH
O2N
64.1
17.5d
31.8
39.8
0.0
38.7
0.0
O
P
6
OH
Ph
4.50 4.40 4.30 4.20 4.10
4.050 4.000 3.950 3.900
1.450 1.400 1.350 1.300
4.350 4.300 4.250 4.200
4.4004.3504.3004.2504.200
24.50 24.00 23.50 23.00
24.50 24.00 23.50
OH
O
56.8
Ph
P
7
OH
Ph
4.100 4.050 4.000
OH
Me
11.8c,d
23.5c
44.8
0.0
0.0
O
P
8
9
OH
Ph
1.400
1.350
NHTs
O
44.1
41.7
49.5
P
OH
Ph
4.350 4.300 4.250 4.200
21.50 21.00 20.50 20.00
21.00
20.50
NHTs
O
P
49.2
51.0
45.4
58.0
10
MeO
OH
Ph
4.300 4.250 4.200 4.150 4.100
4.300 4.250 4.200 4.150
21.00
20.50
21.50 21.00 20.50
13.00 12.50 12.00 11.50
13.50 13.00 12.50 12.00
NHTs
31.6e
39.3e
65.6e
83.3e
65.4e
71.8e
O
P
11
OH
HO
4.250 4.200 4.150 4.100
4.300 4.250 4.200 4.150 4.100
12.50 12.00 11.50
NHTs
O
11.8c,e
9.7c,e
P
12
OH
HO
Cl
2.250
2.200
13.5013.0012.5012.0011.50
2.250
2.200

F. Ma et al. / Tetrahedron: Asymmetry 19 (2008) 31–37
35
S
R
Experimental(expected)
0.6%(0.0%)
26.6%(25.0%)
45.2%(45.0%)
60.2%(60.0%)
85.6%(85.0%)
91.3%(90.0%)
4.60
4.50
4.40
4.30
4.20
4.10
4.00
3.90
Figure 5. Determination of the enantiomeric purity of (a-hydroxy-
benzyl)phenylphosphinic acid 4 (ee% = R% ꢁ S%), the (R) and (S) in
the spectra stand for the a-proton of the corresponding isomer of (a-
hydroxybenzyl)phenylphosphinic acid 4.
4.3. Synthesis of macrocyclic compound 1b
A mixture of 1.46 g (2 mmol) aminonaphthol 3b, 0.35 g
(2 mmol) 2,6-dichloromethylpyridine and 2.76 g (20 mmol)
K2CO3 in 40 mL dry DMF was stirred at room tempera-
ture for 36 h. Then it was poured into 100 mL water and
extracted with toluene (20 mL ꢂ 3), washed with water
(20 mL) and brine (20 mL). The organic phase was dried
with Na2SO4, filtrated, and concentrated. The residue
was recrystallized with dichloromethylene and acetone
affording 1b as colorless crystals (1.44 g, 86.7%).
20
Mp 172–174 °C, ½aꢀD ¼ þ19:6 (c 0.23, THF). 1H NMR
(500 MHz, CDCl3, ppm): d: 1.26 (d, J = 5.4 Hz, 6H),
3.76 (q, J = 6.2 Hz, 2H), 4.37 (d, J = 11.4 Hz, 2H), 5.23
(d, J = 8.5 Hz, 2H), 5.30 (d, J = 8.5 Hz, 2H), 5.49 (d,
J = 11.9 Hz, 2H), 6.82 (d, J = 7.0 Hz, 2H), 6.87 (d,
J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 2H), 7.22–7.41 (stack,
14H), 7.52 (d, J = 7.7 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H),
7.60 (d, J = 7.4 Hz, 2H), 7.73–7.64 (m, 1H), 7.77 (d,
J = 7.5 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.98 (d, J =
8.1 Hz, 2H), 8.57 (s, 1H); 13C NMR (125 MHz, CDCl3,
ppm): d: 24.97, 55.65, 57.11, 71.54, 114.56, 121.57,
123.07, 123.52, 125.07, 125.83, 126.57, 127.15, 127.46,
127.69, 127.87, 128.55, 129.04, 129.50, 132.79, 133.38,
134.04, 137.19, 143.13, 144.03, 155.0, 155.68; IR (KBr):
3455, 3051, 1621, 1595, 1260, 1239 cmꢁ1; MS (EI): 831
(M+). Elemental Anal. Calcd for C59H49N3O2: C, 85.17;
H, 5.94; N, 5.05. Found: C, 84.81; H, 5.78; N, 4.86.
4.4. Resolution of (a-hydroxybenzyl)phenylphosphinic acid 4
A mixture of 7.44 g (30 mmol) of (a-hydroxybenzyl)phen-
ylphosphinic acid 4, 5.28 g (18 mmol) of cinchonidine,
45 mL of EtOH and 45 mL of H2O was heated until a clear

36
F. Ma et al. / Tetrahedron: Asymmetry 19 (2008) 31–37
solution took place. The heating mantle is removed, and
the solution is allowed to cool to room temperature. After
method. The results, which were calculated based on the
integrations of the NMR signals, are shown in Figure 5.
24 h the product is collected and washed with 20 mL of
20
EtOH–H2O (1:1) to give 4.65 g of salt with ½aꢀD ¼ ꢁ46:2
Acknowledgment
(c 0.71, CH3OH).
This work was supported by the National Natural Science
Foundation of China (No. 20172008).
Then 4 g of the salt is stirred with 20 mL of EtOH–H2O
(1:1) and 3 mL of concentrated hydrochloric acid, then fil-
tered, washed with water, and dried to give 1.32 g of (S)-4
20
with ½aꢀD ¼ þ56:5 (c 0.75, CH3OH), 92% ee. Recrystalliza-
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20
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20
½aꢀD ¼ ꢁ34:6 (c 0.88, CH3OH), 56% ee. Recrystallization
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20
omerically pure (R)-(ꢁ)-4 ½aꢀD ¼ ꢁ61:5 (c 1.1, CH3OH).
20
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1
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1
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The host 1a or 1b and guest (R)- or (S)-(a-hydroxybenz-
yl)phenylphosphinic acid 4 were separately dissolved in
CDCl3/CD3OD-5% with a concentration of 10 mM. These
solutions were distributed among 9 NMR tubs, with vari-
ous amounts of host 1a or 1b and guest (R)- or (S)-(a-
hydroxybenzyl)phenylphosphinic acid 4, and the total con-
1
centration of host and guest was 10 mM. The H NMR
spectrum of each sample was recorded on a 500 MHz spec-
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maxima at 0.6. This indicates that 1a and 1b forms a
‘1:1.5’ complex with the (a-hydroxybenzyl)phenylphosphi-
nic acid 4.
4.6. Study of the discrimination ability of 1a and 1b toward
guests 4–14
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a CDCl3/CD3OD-5% solution of the guests (10 mM), for
guest 13, 0.5 equiv of 1a or 1b was used, and for guests
11 and 12, CDCl3/CD3OD-10% was used as a solvent.
1
The H NMR and 31P NMR spectra were registered at
room temperature using a 500 MHz instrument.
´
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´
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´
22. Berlicki, Ł.; Rudzinska, E.; Mucha, A.; Kafarski, P. Tetra-
To evaluate the accuracy of our determining method, we
prepared six samples containing (R)-(a-hydroxybenz-
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85% and 90% ee, respectively (all samples were prepared
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CDCl3/CD3OD-5%)), and determined their enantiomeric
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´

F. Ma et al. / Tetrahedron: Asymmetry 19 (2008) 31–37
37
publication numbers CCDC 652314. Copies of the data can
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