Influence of the size and geometry of the anion binding pocket of sugar-urea anion receptors on chiral recognition

Article abstract of DOI:10.1016/j.tetlet.2013.08.019

Three new chiral urea-type anion receptors were synthesized from aromatic diamines and 1-amino-1-deoxyglucose. The anion binding properties of these receptors were studied using chiral carboxylates derived from mandelic acid and three α-amino acids. We found that the size of the anion binding pocket played an important role in chiral recognition processes. The best results were obtained for 1,8-diaminoanthracene and α-amino acid anions.

Full text of DOI:10.1016/j.tetlet.2013.08.019

Tetrahedron Letters 54 (2013) 5608–5611
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Influence of the size and geometry of the anion binding pocket
of sugar–urea anion receptors on chiral recognition
Paulina Hamankiewicz a, Jarosław M. Granda b, Janusz Jurczak a,b,
⇑
a Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new chiral urea-type anion receptors were synthesized from aromatic diamines and 1-amino-1-
deoxyglucose. The anion binding properties of these receptors were studied using chiral carboxylates
Received 14 June 2013
Revised 18 July 2013
Accepted 1 August 2013
Available online 12 August 2013
derived from mandelic acid and three
played an important role in chiral recognition processes. The best results were obtained for 1,8-diamino-
anthracene and -amino acid anions.
a-amino acids. We found that the size of the anion binding pocket
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Anion binding
Chiral recognition
Monosaccharides
Urea
Since most compounds found in Nature are chiral (e.g., amino
acids, peptides, terpenoids, sugars, etc.), it is essential to under-
stand the interactions responsible for chiral differentiation in bio-
logical processes. In principle, chiral recognition is based on
differences in the stability of diastereomeric host/guest com-
plexes.1 As many of these species exist at physiological pH as an-
ions, we decided to investigate their chiral recognition using
neutral synthetic receptors.
the influence of the electronic effect of para substituents located
on the phenyl ring of ligands 2 on the anion binding. Finally, Kim
and Yoon11 described fluorescent sensors for fluoride and pyro-
phosphate anions in which urea moieties were attached to anthra-
cene at positions 1 and 8 (compounds of type 3).
Based on these considerations, we resolved to design and syn-
thesize three new chiral receptors 4–6, using 2,3,4,6-tetra-O-acet-
yl-b-D
-glucopyranosyl isocyanate12 and three different aromatic
Among the common anion binding motifs typical for ligands of-
ten used in supramolecular chemistry (such as amide,2 pyrrole,3
indole,4 and carbazole5), those with incorporated urea functional-
ity6 seemed to be the most promising building blocks for the syn-
thesis of neutral receptors for anions. On the one hand, this is
because a urea moiety can be readily incorporated into a wide
range of anion binding receptors,7 while on the other it is due to
the specific geometry of hydrogen bond donors, which allows
selective binding of carboxylates. For our chiral recognition studies
we considered, as models, the three types of known receptors 1–3
shown in Figure 1.
platforms: commercially available 1,2-diaminobenzene and 1,8-
diaminonaphthalene, as well as 1,8-diaminoanthracene, which is
known from the literature13 (Scheme 1).14 The receptors 4,15 5,16
and 617 (Fig. 2) were obtained in acceptable yields of 80%, 43%,
and 55%, respectively.
The use of different aromatic platforms enabled us to construct
receptors with binding pockets of varying size: the smallest for
naphthalene, medium-size for benzene, and the largest for anthra-
cene. We then investigated the influence of the size and shape of
the anion binding site on the chiral recognition ability of the anion
receptors 4–6 (Fig. 2).
In 2005, Gale and co-workers8 reported the carboxylate binding
properties of bis-urea anion receptor 1 (Fig. 1) with 1,2-diamino-
benzene as an aromatic platform. This work showed that receptor
1 was selective for acetate and benzoate anions in DMSO + 0.5%
H2O. The Nam9 and Tarr10 groups, in turn, have studied a series
of naphthalene urea anion receptors of type 2. They examined
In the first part of our investigation using chiral receptors, we
examined achiral acetate and benzoate anions as guests. Anion
binding studies were conducted applying 1H NMR titration tech-
niques in DMSO-d6 + 0.5% H2O at a constant concentration of
receptor (c = ꢀ1 Â 10À2 M) and each titration was repeated twice.
The results are collected in Table 1. Binding affinities were mea-
sured in terms of the anion complexation-induced resonance shift
change of the urea NH protons. Binding constants were obtained
using nonlinear regression of experimental data using the program
HypNMR.18 In line with previous findings for these anion binding
⇑
Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 6681.
E-mail
addresses:
janusz.jurczak@icho.edu.pl,
jjurczak@chem.uw.edu.pl
(J. Jurczak).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.019

P. Hamankiewicz et al. / Tetrahedron Letters 54 (2013) 5608–5611
5609
O
O
O
NH HN
NH HN
O
O
NH
NH
HN
HN
O
NH HN
NH
HN
R
R
R
R
R = H, F, NO2, OMe, CH3
R = H, NO
2
1
2:
3:
Figure 1. Structures of anion urea-based receptors 1–3.
Ar
AcO
AcO
AcO
AcO
O
O
OAc
OAc
O
Ar
solvent
ΔΤ
O
NH HN
O
NCO
+
NH
HN
H2N
NH2
AcO
OAc
AcO
OAc
AcO
OAc
Scheme 1. The general route to the chiral receptors.
AcO
AcO
O
O
OAc
OAc
OAc
O
NHα HN
NHβ
O
O
NHα
NHβ
HN
O
O
NHα HN
O
NHβ
HN
O
HN
O
O
HN
AcO
O
AcO
AcO
AcO
AcO
OAc
OAc
OAc
OAc
AcO
OAc
AcO
OAc
OAc
AcO
OAc
OAc
OAc
OAc
4
5
6
Figure 2. Structures of urea anion receptors 4–6.
platforms, our experimental data fitted well into a 1:1 host/guest
stoichiometry.
obtained for chiral partners were high enough to be applied for
our studies. Both receptors 4 and 5, possessing smaller binding
pockets, were not satisfactory for chiral recognition of two of our
model chiral guests (mandelic acid and tryptophan), affording
low KD/KL values (entries 1–4 and 5–8, respectively). The relatively
For each receptor we noted higher association constants (Ka) for
the smaller acetate anion (Table 1, entries 1, 3, and 5). The best re-
sults were obtained with compound 6, which had the most spa-
cious anion binding site (entries 5 and 6), while receptor 5, with
the smallest anion binding pocket, was characterized by the lowest
association constants Ka (entries 3 and 4).
We next used receptors 4–6 to explore chiral carboxylic anions.
We selected tetrabutylammonium salts19 of mandelic acid and
Boc-N-amino acids, such as tryptophan (Trp), phenylalanine
(Phe), and valine (Val). The results obtained for both enantiomers
of each chiral guest are presented in Table 2.
Table 2
Association constants (Ka) of hosts 4–6 with chiral guests in DMSO-d6 + 0.5% H2O
Entry Host Guesta
Ka (MÀ1
b
)
KD/KL
dmax
NHad
dmax
NHb
c
d
1
2
3
4
4
4
R-PhCH(OH)COOÀ
40
38
125
1.05
9.36
9.43
9.65
8.29
8.24
8.32
S-PhCH(OH)COOÀ
0.88
D
-TrpCOOÀ
-TrpCOOÀ
The association constants obtained in all complexations of chi-
ral guests by chiral receptors were lower than for pairs of chiral
receptors and achiral guests (cf. Table 1). However, the values
4
4
141
9.67
8.28
L
5
6
7
5
5
5
R-PhCH(OH)COOÀ
16
15
60
1.07
1.12
10.25
10.21
10.31
8.24
8.17
8.46
S-PhCH(OH)COOÀ
D
-TrpCOOÀ
-TrpCOOÀ
8
5
51
10.49
8.36
L
9
10
11
6
6
6
R-PhCH(OH)COOÀ
70
56
343
1.25
1.81
10.10
10.15
10.62
8.38
8.47
8.30
Table 1
S-PhCH(OH)COOÀ
Association constants (Ka) of hosts 4–6 with achiral guests in DMSO-d6 + 0.5% H2O
D
-TrpCOOÀ
-TrpCOOÀ
-PheCOOÀ
-PheCOOÀ
-ValCOOÀ
-ValCOOÀ
NHac
dmax
NHb
c
Entry
Host
Guesta
Ka (MÀ1
b
)
dmax
12
13
14
15
16
6
6
6
6
6
190
483
233
644
266
10.41
10.47
10.33
10.51
10.35
8.45
8.28
8.37
8.29
8.44
L
1
2
3
4
5
6
4
4
5
5
6
6
AcOÀ
1283
444
954
212
7907
780
9.62
8.48
8.53
8.50
8.81
8.69
8.45
2.07
2.42
D
PhCOOÀ
AcOÀ
9.73
10.75
10.95
10.36
10.64
L
PhCOOÀ
AcOÀ
D
L
PhCOOÀ
a
b
c
Added as the tetrabutylammonium salt.
Estimated error less than 10%.
For mandelate anions KR/KS was calculated instead of KD/KL.
a
b
c
Added as the tetrabutylammonium salt.
Estimated error less than 10%.
Asymptotic change in the chemical shift obtained by nonlinear curve fitting.
d
Asymptotic change in the chemical shift obtained by nonlinear curve fitting.

5610
P. Hamankiewicz et al. / Tetrahedron Letters 54 (2013) 5608–5611
urea NHα D-PheCOO-
urea NHα L-PheCOO-
urea NHα D-ValCOO-
urea NHα D-ValCOO-
urea NHα S-mandalate
urea NHα R-mandelate
urea NHα L-TrpCOO-
10.6
10.4
10.2
10.0
9.8
10.6
urea NHα D-TrpCOO-
10.4
10.2
10.0
9.8
9.6
9.6
9.4
9.4
9.2
9.2
0
1
2
3
4
5
0
1
2
3
4
5
number of anion equivalents
number of anion equivalents
Figure 3. Comparison of the chemical shift changes for the urea NH proton of the ligand 6 upon addition of anions, R/S mandelates and
L/D-tryptophan (left) and L/D-
a
phenylalanine and L/D-valine (right). Points show experimental data; the black line is the fitted chemical shift data.
Figure 4. Excerpts of the stacked spectra from the 1H NMR titrations of receptor 6 with tetrabutylammonium salts of Boc-
L-tryptophan (left) and Boc-D-tryptophan (right)
showing chemical shift changes of the acetyl groups.
good results for anthracene receptor 6 with mandelic acid (entries
9 and 10), encouraged us to investigate three representative amino
acids as guests (entries 11–16), for which we obtained satisfactory
results, with the best being for valine (KD/KL = 2.42). Figure 3 illus-
trates the relationship between the chemical shift changes for
receptor 6 during titration with pairs of anions whose chirality
was recognized and without chiral recognition (left), and between
different pairs of anions with good chiral recognition (right).
Moreover, in the case of anions with chirality recognized by
receptor 6, noticeable chemical shift changes of the acetyl groups
were observed. This behavior of the acetyl groups provided evi-
dence that the sugar moieties in receptor 6 interact effectively with
guest molecules. The chemical shift changes of the anion receptor 6
acetyl groups during titration with enantiomeric tryptophan an-
ions are depicted in Figure 4. In each diastereomeric complex,
the acetyl groups behaved differently. Such behavior was not seen
for receptors 4 and 5, which do not possess noticeable chiral recog-
nition ability.
In conclusion, we have shown that the correct geometry of the
anion binding pocket is required to make sugar-urea receptors
effective in chiral recognition. Among three similar anion receptors
4–6, only 6 showed noticeable chiral recognition for mandelic acid
and amino acid anions. It appears that the optimum-sized anion
binding pocket can pre-organize sugar moieties to interact effec-
tively with guest molecules. This modulation of steric hindrance
demonstrates itself in terms of the relative ratio of binding con-
stants for small acetate and more sterically demanding benzoate
(Table 1). This ratio was highest for receptor 6, which possesses
the most pronounced chiral recognition ability.
Acknowledgment
This research was financed by the European Union within the
European Regional Development Fund, Project POIG.01.01.02.-14-
102/09.
References and notes
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A. Chem. Commun. 2008, 4525–4540; (c) Dydio, P.; Zielinski, T.; Jurczak, J. Chem.
Commun. 2009, 4560–4562; (d) Dydio, P.; Lichosyt, D.; Zielinski, T.; Jurczak, J.
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5611
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1.99 (s, 6H, Ac), 1.94 (s, 6H, Ac); 13C NMR (101 MHz, DMSO-d6) d 170.05,
169.49, 169.45, 169.34, 154.66, 130.65, 123.75, 123.45, 78.46, 72.81, 71.71,
70.39, 68.04, 61.85, 20.54, 20.46, 20.41, 20.32; HRMS (ES+) m/z = 877.2581
(M+Na)+, calcd for C36H46N4O20Na = 877.2603; elemental analysis, calcd for
7. Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486–515.
8. (a) Brooks, S. J.; Gale, P. A.; Light, M. A. Chem. Commun. 2005, 4696–4698; (b)
Brooks, S. J.; Edwards, P. R.; Gale, P. A.; Light, M. A. New J. Chem. 2006, 65–70.
9. (a) Cho, E. J.; Moon, J. W.; Ko, S. W.; Lee, J. Y.; Kim, S. K.; Yoon, J.; Nam, K. C. J.
Am. Chem. Soc. 2003, 125, 12376–12377; (b) Lee, J. Y.; Cho, E. J.; Mukamel, S.;
Nam, K. C. J. Org. Chem. 2004, 69, 943–950; (c) Cho, E. J.; Ryu, B. J.; Lee, Y. J.;
Nam, K. C. Org. Lett. 2005, 7, 2607–2609; (d) Joeng, H. A.; Cho, E. J.; Yeo, H. M.;
Ryu, B. J.; Nam, K. C. Bull. Korean Chem. Soc. 2007, 28, 851–854.
10. (a) Xu, G.; Tarr, M. A. Chem. Commun. 2004, 1050–1051; (b) Chakraborty, S.;
Tarr, M. A. Can. J. Chem. 2007, 85, 153–156.
C
36H46N4O20: C 50.6, H 5.4, N 6.5, found: C 50.2, H 5.5, N 6.4.
16. Compound 5: The reaction mixture was refluxed for 1 h in CH2Cl2. White
powder (389 mg, 43%) mp 186–188 °C. [
] = +48.2 (c = 1, CHCl3). 1H NMR
a
(400 MHz, DMSO-d6) d 8.76 (s, 2H, NH), 7.71 (d, J = 7.5 Hz, 2H, ArH), 7.47 (d,
J = 6.8 Hz, 2H, NH), 7.42 (t, J = 7.7 Hz, 2H, ArH), 6.78 (d, J = 9.7 Hz, 2H, ArH),
5.43–5.28 (m, 4H, sugar H), 4.99 (t, J = 9.7 Hz, 2H), 4.91 (t, J = 9.5 Hz, 2H), 4.37
(dd, J = 12.2, 3.6 Hz, 2H), 4.12–4.00 (m, 4H), [14H in the region 5.43–4.00
belong to the sugar moieties], 2.05 (s, 6H, Ac) 1.99 (s, 6H, Ac), 1.98 (s, 6H, Ac),
1.93 (s, 6H, Ac); 13C NMR (101 MHz, DMSO-d6) d 170.20, 169.54, 169.49,
169.30, 155.32, 135.68, 134.05, 125.67, 125.41, 123.52, 122.76, 79.01, 72.95,
72.22, 70.52, 67.73, 61.49, 20.58, 20.52, 20.43, 20.36; HRMS (ES+) m/
z = 927.2759 (M+Na)+, calcd for C40H48N4O20Na = 927.2760; elemental
analysis, calcd for C40H48N4O20ÁH2O: C 52.1, H 5.5, N 6.1, found: C 52.1, H
5.4, N 5.9.
11. Kwon, J. Y.; Jang, Y. J.; Kim, S. K.; Lee, K. H.; Kim, J. S.; Yoon, J. J. Org. Chem. 2004,
69, 5155–5157.
12. Avalos, M.; Babiano, R.; Cinats, P.; Hursthouse, M. B.; Jimenez, J. L.; Light, M. E.;
Palacios, J. C.; Perez, E. M. S. Eur. J. Org. Chem. 2006, 657–671.
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Chem. 2007, 72, 2289–2296.
17. Compound 6: The reaction mixture was refluxed for 2.5 h in CH2Cl2. Brown
solid (525 mg, 55%) mp 235–238 °C. [
a
] = À22.5 (c = 0.2, CHCl3). 1H NMR
(400 MHz, DMSO-d6) d 9.24 (s, 2H, NH), 8.77 (s, 1H, ArH), 8.57 (s, 1H, ArH), 7.90
(d, J = 7.4 Hz, 2H, ArH), 7.77 (d, J = 8.4 Hz, 2H, ArH), 7.54–7.42 (m, 2H, ArH),
7.37 (d, J = 9.9 Hz, 2H, NH), 5.47 (dt, J = 11.3, 9.5 Hz, 4H), 4.99 (dt, J = 15.5,
9.6 Hz, 4H), 4.22 (dd, J = 12.2, 4.8 Hz, 2H), 4.16 (d, J = 9.8 Hz, 2H), 4.01 (d,
J = 12.2 Hz, 2H), [14H in the region 5.47–4.01 belong to the sugar moieties],
2.04 (s, 12H, Ac), 2.01 (s, 6H, Ac), 1.98 (s, 6H, Ac), 13C NMR (101 MHz, DMSO-d6)
14. General procedure for receptor preparation: 2,3,4,6-Tetra-O-acetyl-b-D-
glucopyranosyl isocyanate (2 mmol) was added in one portion to a solution
of the diamino derivative (1 mmol) in dry toluene or CH2Cl2 (10 ml) under an
argon atmosphere. The mixture was stirred for 1–2.5 h at RT or at reflux, and
then the solvent was evaporated and the crude product dissolved in CH2Cl2
(10 ml). The organic layer was washed with 0.1 M HCl (5 ml), saturated
NaHCO3 solution (5 ml), and H2O (5 ml). The organic layer was dried (MgSO4),
concentrated in vacuo and the residue was purified by flash chromatography
(EtOAc/hexane/MeOH, 100:100:1, v/v).
d
170.04, 169.67, 169.54, 169.38, 154.38, 134.28, 131.66, 127.27, 125.73,
124.54, 122.64, 115.83, 113.66, 78.36, 72.78, 71.83, 70.34, 68.13, 61.96, 20.57,
20.51, 20.46, 20.37; HRMS (ES+) m/z = 977.2944 (M+Na)+, calcd for
C44H50N4O20Na = 977.2916;
elemental
analysis,
calcd
for
C44H50N4O20Á0.5H2O: C 54.8, H 5.3, N 5.8, found: C 54.7, H 5.4, N 5.7.
15. Compound 4: The reaction mixture was stirred at RT for 2 h in toluene. White
18. (a) Frassineti, C.; Ghelli, S.; Gans, P.; Sabatini, A.; Moruzzi, M. S.; Vacca, A. Anal.
Biochem. 1995, 231, 374–382; (b) Frassineti, C.; Alderighi, L.; Gans, P.; Sabatini,
A.; Vacca, A.; Ghelli, S. Anal. Bioanal. Chem. 2003, 376, 1041–1052.
19. Tetrabutylammonium salts of anions were prepared by the addition of 1 equiv
of Bu4NOH to 1 equiv of a carboxylic acid or amino acid dissolved in the MeOH.
After evaporating the MeOH in vacuo, the salts were dried under high vacuum
over P2O5.
powder (683 mg, 80%). mp 82–85 °C. [a
] = +18.1 (c = 1, CHCl3). 1H NMR
(400 MHz, DMSO-d6) d 8.04 (s, 2H, NH), 7.50 (dd, J = 6.0, 3.6 Hz, 2H, ArH), 7.30
(d, J = 9.8 Hz, 2H, NH), 7.02 (dd, J = 6.1, 3.6 Hz, 2H, ArH), 5.37 (t, J = 9.5 Hz, 2H),
5.31 (t, J = 9.5 Hz, 2H), 4.91 (t, J = 9.7 Hz, 2H), 4.84 (t, J = 9.5 Hz, 2H), 4.15 (dd,
J = 12.3, 4.8 Hz, 2H), 4.10–4.02 (m, 2H), 3.97 (d, J = 10.3 Hz, 2H), [14H in the
region 5.37–3.97 belong to the sugar moieties], 2.00 (d, J = 1.0 Hz, 12H, Ac),