Exploration of the Chiral Recognition of Sugar-Based Diindolylmethane Receptors: Anion and Receptor Structures

Article abstract of DOI:10.1002/chem.201502932

In this study, we have conducted a systematic investigation of the chiral recognition of carboxylic anions by D-glucuronic acid/diindolylmethane receptors. We investigate the influence of the anion structure on chiral recognition in the diindolylmethane/glucuronic acid-based receptor 1 a. We found that presence of an additional hydrogen-bond donor at the α position to the carboxylic function is essential for effective chiral differentiation in these systems. Furthermore, we present a synthetic procedure that allows for the synthesis of sugar-decorated receptors that possess a modified substituent at the anomeric position. Four new receptors 1 b-e have been synthesized, and their chiral-discrimination ability toward model carboxylates is studied. The obtained results show that the chiral recognition of these receptors can be fine-tuned by incorporation of a proper substituent into the receptor structure.

Full text of DOI:10.1002/chem.201502932

DOI: 10.1002/chem.201502932
Full Paper
&
Carbohydrates
Exploration of the Chiral Recognition of Sugar-Based
Diindolylmethane Receptors: Anion and Receptor Structures
[
a]
Jarosław M. Granda and Janusz Jurczak*
Abstract: In this study, we have conducted a systematic in-
vestigation of the chiral recognition of carboxylic anions by
d-glucuronic acid/diindolylmethane receptors. We investi-
gate the influence of the anion structure on chiral recogni-
tion in the diindolylmethane/glucuronic acid-based receptor
more, we present a synthetic procedure that allows for the
synthesis of sugar-decorated receptors that possess a modi-
fied substituent at the anomeric position. Four new recep-
tors 1b–e have been synthesized, and their chiral-discrimina-
tion ability toward model carboxylates is studied. The ob-
tained results show that the chiral recognition of these re-
ceptors can be fine-tuned by incorporation of a proper sub-
stituent into the receptor structure.
1
a. We found that presence of an additional hydrogen-bond
donor at the a position to the carboxylic function is essential
for effective chiral differentiation in these systems. Further-
Introduction
prompted us to further explore such a hybrid design. This
present study consists of two parts: In the first, we investigate
the influence of anion structure on the chiral-recognition abili-
ty of receptor 1a and present our findings that the presence
of an additional hydrogen-bond donor at the a position to the
carboxylate group is essential for the recognition process. In
the second part, we modified the glucuronic acid part of the
receptor by changing its acyl substituent at the anomeric posi-
tion. It is well known that the substituent present at the
anomeric position plays an important role in carbohydrate
Chiral recognition is one of the most subtle processes found in
nature. This type of recognition requires a capacity to differen-
tiate between enantiomers that differ from one another solely
in terms of the spatial arrangement of the substituents that
[1]
belong to their stereogenic center. For different enantiomers
to be distinguishable, at least three interactions need to exist
[
2]
between a host and guest (the three-point-attachment rule).
By implementing this concept in various ways, many varied
[3]
[4]
[11]
sources of chirality, such as carbohydrates, a-amino acids,
chemistry; therefore, we expected that the chiral recognition
[
5]
[6]
[7]
steroids, chiral amines, and other chiral motifs, have been
used to modify artificial receptors. However, the factors that
underlie the general phenomenon of chiral discrimination and
affect the design of receptors enantioselective for a given
guest still remain poorly understood.
of these receptors may be improved through such a modifica-
tion.
Results and Discussion
[8]
Sugars offer an attractive source of chirality because they
are cheap renewable materials, and the configuration of their
stereogenic centers can easily be modified by using diastereo-
meric sugars derived from the d-series. However, sugars have
to date rarely been used in artificial receptors, especially in
anion-receptor chemistry, owing to their structural complexity.
We previously demonstrated that a hybrid anion receptor
containing diindolomethane and d-glucuronic acid is effective
To gain insight into the role played by anion structure in the
chiral recognition process, we explored the ability of receptor
1a to discriminate various chiral anions that possess different
substituents (Figure 1). Table 1 shows the results obtained
1
from titrations under H NMR spectroscopic control in
[
12]
[D ]DMSO+0.5% H O.
6 2
[9]
in chiral-anion recognition. Another important aspect of this
approach was also enantiomer recognition based on receptor
1
a with different patterns of guest-binding-induced chemical-
[
10]
shift changes. There have been no systematic investigations
of chiral recognition in these systems to date, a fact that
[
a] Dr. J. M. Granda, Prof. J. Jurczak
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw (Poland)
E-mail: janusz.jurczak@icho.edu.pl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502932.
Figure 1. Structure of investigated anion receptor 1a.
16585 ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2015, 21, 16585 – 16592

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1
a, and the binding constants are substantially lower relative
Table 1. Exploring the influence of anion structure on the chiral recogni-
tion ability of receptor 1a.
to mandelates (compare with entries 1 and 2 in Table 1). It
seems that the quaternary center present in these anions
causes many unfavorable steric interactions. This observation
[a]
Entry
Anion
Binding
R S
K /K
À1 [b]
constant [m
]
(
Table 1, entries 1–6) suggests that receptor 1a prefers anions
that possess a hydrogen-bond donor at the a position to be
more effective in chiral recognition. To support this notion, we
carried out titrations of anions derived from 3-hydroxybutyric
acid (Table 1, entries 11 and 12), and the results obtained con-
firmed this requirement. Prompted by this finding, we mea-
sured the binding affinities of anions derived from two other
a-hydroxy acids, namely, 2-hydroxybutyric and 3-phehnyllactic
acid (Table 1, entries 7–10). In both cases, we found that recep-
tor 1a can discriminate these anions with excellent K /K ratios
1
2
119
233
1.95:1
1.02:1
1.31:1
2.55:1
3
4
2236
2284
R
S
of up to 3.68:1. Ratios are given relative to 1.
Armed with this knowledge of the crucial factors important
for receptor 1a to be effective in chiral recognition, we decid-
ed to synthesize four new receptors 1b–e that differ in terms
of the acyl group at the anomeric position. We assumed that
the introduction of aromatic substituents at this position
should allow for improved chiral recognition; for example, the
introduction of the aromatic substituent present in receptors
5
6
35.6
27.0
[
13]
1
c–e might allow for an additional p–p interaction. In con-
trast, chiral recognition can also be tailored by increasing the
steric bulkiness of the receptor; therefore, we also decided to
introduce a tBu substituent at this position to yield receptor
1
b. The synthesis of modified receptors 1b–e started with the
7
8
607
reaction of a protected bromide of d-glucuronic acid 2 with
[
14]
anions of the proper carboxylic acid to give derivatives 3b–
e (Scheme 1). In the next step, the glucuronic esters were de-
[
15]
1542
protected by using [Pd(PPh ) ]
to yield free acids 4b–e,
3
4
which were treated with oxalyl chloride in the last step fol-
lowed by treatment with 1,1-bis-(3-methyl-7-amino-1H-indol-2-
yl)propane in situ to give the desired receptors 1b–e in satis-
factory yields (66–93%).
9
259
952
3.68:1
1
We conducted H NMR spectroscopic titrations of chiral
anions derived from three representative acids to validate how
successful our receptors are. We investigated anions derived
from 3-phenyllactic acid, mandelic acid, and Boc-N-tryphto-
phane. These four new receptors 1b–e allowed for direct com-
parison with the parent receptor 1a (Table 2).
10
11
737
902
1.22:1
In the case of mandelates, receptors 1b–e can discriminate
the enantiomers of mandelic acid on the same level as recep-
tor 1a and showed virtually no dependence of chiral recogni-
tion on the substituent present at the anomeric position. Nev-
ertheless, receptor 1d showed a pronounced increase in the
K /K value to 4.14:1 for anions derived from 3-phenyllactic
12
[
a] Used as tetrabutylammonium salts. [b] Binding constants were record-
ed in [D ]DMSO+0.5% H O and obtained by H NMR spectroscopic anal-
6 2
ysis; the titration errors are less than 10%.
1
R
S
acid, whereas the introduction of a large bulky tBu substituent
in receptor 1b caused a decreased chiral recognition of these
anions of K /K =2.41:1 (compare with entries 9 and 10 in
When comparing the recognition of anions derived from
mandelic acid with its O-methyl derivative (Table 1, entries 1
and 2 versus 3 and 4), one can clearly see that protection of
the hydroxy group causes decreased chiral recognition. More-
over, the binding constants are at least ten times higher than
those for anions derived from mandelic acid itself.
R
S
Table 1). It seems that the methylene spacer in 3-phenyllac-
tates allows additional interactions between the anion and re-
ceptor, that is, favorable interactions for receptor 1d (i.e., p–p
[
13]
interactions between the aromatic rings)
or unfavorable
(steric) interactions for 1b. Figure 2 shows the possible struc-
ture of receptor 1c with d-phenyllactate, thus illustrating the
interactions between the receptor and anion.
Similarly, we found that anions derived from the Mosher
acid (Table 1, entries 5 and 6) are not recognized by receptor
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The third chiral guest investigated was an anion derived
from Boc-N-tryphtophane, which contains a more spatial aro-
matic system and the bulky Boc protecting group, thus allow-
ing for some additional interactions. Modification of the sub-
stituent at the anomeric position led to improved chiral recog-
nition for all receptors 1b–e.
A significant increase in chiral recognition was noted for re-
ceptors 1c–e, which possess aromatic substituents. Receptor
1
b, with a tBu group, exhibited a reduced K /K value of
R S
3
.03:1. The obtained results demonstrate that chiral recogni-
tion by diindolylmethane/glucuronic acid receptors depends
on the structure and can be fine-tuned through modification
of the glucuronic acid unit. On the other hand, the proper
anion geometry is also an important factor, which may allow
for additional interactions with glucopyranose rings that pos-
sess modified anomeric positions. In this regard, anions de-
rived from mandelic acid are geometrically unfit for this pur-
pose. Figure 3 shows a graphical representation of the chiral
recognition of receptors 1a–e with model anions.
Figure 4, in turn, shows representative chemical-shift
changes during the titration of receptors 1d with anions de-
rived from phenyllactic acid. Receptors 1b–e showed similar
binding characteristics relative to 1a, as described in detail in
[
9]
Scheme 1. Synthetic route to receptors 1b–e that possess a modified
anomeric position. i) RCOOH, Cs CO , DMSO 40–67%; ii) [Pd(PPh ], pyrroli-
dine, MeCN, 08C, 71–90%; iii) a) (COCl) , DMF, DCM, 08C; b) 1,1-bis-(3-
methyl-7-amino-1H-indol-2-yl)-propane, pyridine, DCM, 66–93%. DCM=di-
chloromethane.
our previous report. Notably, the enantiomer with the great-
est stability constant out of most of the anions investigated
also exhibited the greatest Ddmax value (see the Supporting In-
formation for binding isotherms of the other anions).
2
3
3 4
)
2
Table 2. Recognition of chiral anions by receptors 1a–e.
[a]
Anion
Receptor
[
b]
[b]
[b]
[b]
[b]
1
a
K /K
R S
1b
K
R
/K
S
1c
K
R
/K
S
1d
K
R
/K
S
1e
R S
K /K
2
9
59
52
3.68:1
328
2.41:1
250
3.44:1
317
4.14:1
304
3.46:1
790
859
1312
1053
1
19
1.95:1
105
206
1.96:1
97
1.92:1
115
245
2.12:1
107
209
1.95:1
233
187
8
2
8
2.57:1
89
3.03:1
77.7
281
3.61:1
104
401
3.85:1
100
353
3.53:1
27
270
1
[
a] Used as tetrabutylammonium salts. [b] Binding constants were recorded in [D
6
]DMSO+0.5% H
2
O and obtained by H NMR spectroscopic analysis; the
titration errors are less than 10%.
Chem. Eur. J. 2015, 21, 16585 – 16592
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Figure 2. Model of the structure that shows possible interactions between
receptor 1c and d-3-phenyllactate. Hydrogen bonds between the carboxyl-
ate anion and binding pocket of the receptor and an additional hydrogen
bond between the hydroxy group of the anion and the anomeric oxygen
atom of the receptor are depicted in blue. The p–p interaction between the
aromatic rings of the host and guest is also visible.
Figure 4. Comparison of binding isotherms for titrations of receptor 1d with
anions derived from 3-phenyllactic acid: A) l-phenyllactate and B) d-3-phe-
nyllacate. Squares represent chemical-shift changes for the indole NH group
and triangles represent the amide groups. Lines show fitted data.
various receptors that may be incorporated into more compli-
cated systems.
Experimental Section
All the solvents were of reagent-grade quality. Dichloromethane
was dried over calcium hydride and THF was dried over sodium
benzophenone ketyl. All the reagents were purchased from Sigma-
Aldrich and used without further purification. N-Boc-protected
amino acids were obtained from Iris Biotech GMBH. Column chro-
matography was carried out by using Merck Kieselgel 60 (230–400
mesh) and TLC analysis was carried out on Merck Kieselgel F254
plates. Melting points were determined on a Botius M HMK hot-
Figure 3. Bar graph that shows chiral recognition of the investigated anions
by receptors 1a–e.
1
13
stage apparatus and were uncorrected. The H and C NMR spec-
tra were recorded on VarianMercury 400 and Varian S600 instru-
ments. Chemical shifts are reported in ppm. The splitting pattern
of multiplets is described by abbreviations (s=singlet, d=doublet,
t=triplet, q=quartet, qn=quintet, dd=doublet of doublets, m=
complex multiplicity, c=covered signal).The J coupling constants
values are reported in Hz. Mass-spectrometric analysis was per-
formed by using ESI-TOF on a Mariner mass spectrometer from
Conclusion
We have investigated the structural factors that are important
for chiral anions to be effectively recognized by receptors of
type 1. We found that the main prerequisite is the presence of
an additional hydrogen-bond donor at the a position. We have
also developed a simple synthetic procedure that allows the
introduction of a variety of substituents into this receptor
class. The modified receptors 1b–e also exhibited improved
chiral recognition relative to receptor 1a, with an enantioselec-
tivity of up to 4.14. These findings pave the way for further ex-
ploration of chiral-anion recognition through the synthesis of
PerSeptive Biosystem. 1,1-Bis-(3-methyl-7-nitro-1H-indol-2-yl)pro-
[16]
pane
and 1,2,3,4-tetra-O-acetyl-b-glucopyranuronic acid allyl
[15]
ester were prepared as described previously. The synthesis of re-
[9]
ceptor 1a is described in our previous report.
Allyl 2,3,4-tri-O-acetyl-a-d-glucopyranosyluronate bromide (2):
1,2,3,4-Tetra-O-acetyl-b-glucopyranuronic acid allyl ester (8.45 g,
21.0 mmol) was dissolved in dichloromethane (21 mL) and cooled
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to 08C in an ice/water bath. A solution of hydrobromic acid in
acetic acid (33%, 31.6 mL) was added to this solution. The reaction
mixture was allowed to reach room temperature over 4 h. After
this time, the reaction mixture was diluted with diethyl ether
Allyl 2,3,4-tri-O-acetyl-1-O-1-naphthoyl-b-d-glucopyranuronate
(3d): This product was obtained by starting from 1-naphtoic acid
(969.5 mg, 4.69 mmol) and cesium carbonate (781 mg, 2.4 mmol).
Compound 3d was purified by column chromatography with di-
chloromethane/AcOEt (20:1, v/v) as the eluent to obtain a white
(
(
(
200 mL), transferred into a separatory funnel, washed with water
3”100 mL) and aqueous saturated sodium hydrogen carbonate
100 mL), and dried over Na SO . The solvent was removed under
20
solid (1.64 g, 67%). M.p. 114–1158C; [a] =À19.5 (c=1.070 in di-
D
1
chloromethane); H NMR (400 MHz, [D ]DMSO): d=8.81–8.76 (m,
2
4
6
reduced pressure and the product was purified by column chroma-
tography with a gradient of dichloromethane!dichloromethane/
AcOEt (9:1, v/v) as the eluent to give colorless crystals (5.51 g,
1H), 8.29 (d, J=8.2 Hz, 1H), 8.15 (dd, J=7.4, 1.3 Hz, 1H), 8.08 (dd,
J=8.3, 1.1 Hz, 1H), 7.73–7.62 (m, 3H), 6.41 (d, J=8.0 Hz, 1H), 5.95–
5.79 (m, 1H), 5.66 (t, J=9.4 Hz, 1H), 5.35–5.21 (m, 3H), 5.16 (t, J=
2
0
6
2%). M.p. 57–588C; [a] = +187.8 (c=1.118 in dichloromethane);
9.5 Hz, 1H), 4.88 (d, J=9.7 Hz, 1H), 4.63–4.48 (m, 2H), 2.02 (s, 3H),
D
1
13
H NMR (400 MHz, [D ]DMSO): d=6.94 (d, J=3.8 Hz, 1H), 5.89 (ddt,
2.02 (s, 3H), 2.01 ppm (s, 3H); C NMR (101 MHz, [D ]DMSO): d=
6
6
J=17.2, 10.4, 5.8 Hz, 1H), 5.46–5.24 (m, 4H), 5.14 (dd, J=9.8,
169.48, 169.29, 169.25, 166.25, 164.29, 134.91, 133.48, 131.60,
131.03, 130.62, 129.02, 128.51, 126.69, 124.97, 124.65, 124.09,
3
.9 Hz, 1H), 4.67–4.52 (m, 2H), 4.51 (dd, J=10.1, 0.5 Hz, 1H), 2.05
1
3
(
[
s, 3H), 2.01 (s, 3H), 1.99 ppm (s, 3H); C NMR (101 MHz,
119.10, 91.33, 71.58, 70.73, 69.84, 68.81, 65.99, 20.35 (s, 2C),
+
D ]DMSO): d=169.54, 169.10, 169.04, 165.45, 131.46, 119.25, 88.04,
20.32 ppm; HRMS: m/z calcd for C H O : 537.1373 [M+Na] ;
6
26 26 11
7
1.98, 69.14, 69.06, 67.58, 66.26, 20.37, 20.32, 20.29 ppm; HRMS:
found: 537.1373.
+
m/z calcd for C H O Br: 445.0110 [M+Na] ; found: 445.0110.
1
5
19
9
Allyl 2,3,4-tri-O-acetyl-1-O-2-naphthoyl-b-d-glucopyranuronate
(3e): This product was obtained by starting from 2-naphtoic acid
(
826.5 mg, 4.8 mmol) and cesium carbonate (781 mg, 2.4 mmol).
General procedure for the synthesis of allyl esters 3b–e
Compound 3e was purified by column chromatography with di-
chloromethane/AcOEt (20:1, v/v) as the eluent to obtain a white
Carboxylic acid (1.0 equiv) and caesium carbonate (1.0 equiv) were
suspended in methanol (50 mL) and stirred for complete dissolu-
tion. Methanol was removed from the reaction mixture under re-
duced pressure. The obtained cesium salt was dissolved in DMSO
20
solid (1.39 g, 67%). M.p. 96–978C; [a] =À23.2 (c=1.080 in di-
D
1
chloromethane); H NMR (400 MHz, [D ]DMSO): d=8.63 (s, 1H),
6
8
1
7
5
3
2
.14 (d, J=7.9 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.2 Hz,
H), 7.93 (dd, J=8.6, 1.7 Hz, 1H), 7.72 (ddd, J=8.2, 6.9, 1.3 Hz, 1H),
.68–7.63 (m, 1H), 6.35 (d, J=7.9 Hz, 1H), 5.86 (ddt, J=17.2, 10.4,
.8 Hz, 1H), 5.64 (t, J=9.4 Hz, 1H), 5.34–5.21 (m, J=9.5, 3.9, 1.4 Hz,
H), 5.16 (t, J=9.5 Hz, 1H), 4.86 (d, J=9.7 Hz, 1H), 4.63–4.46 (m,
(
10 mL) and bromide 2 (0.83 equiv) in DMSO (10 mL) was added to
this solution. The reaction mixture was further stirred in an argon
atmosphere for 3 h, diluted with ethyl acetate (150 mL), and
washed with water (150 mL), aqueous conc. sodium hydrogen car-
bonate (3”100 mL), and brine (100 mL). The solution was dried
over anhydrous Na SO , the solvent was removed under reduced
13
H), 2.03 (s, 3H), 2.00 (s, 3H), 1.98 ppm (s, 3H); C NMR (101 MHz,
[
D ]DMSO): d=169.48, 169.25 (s, 2C), 166.25, 163.91, 135.49,
6
2
4
1
1
31.95, 131.60, 131.56, 129.52, 129.26, 128.81, 127.82, 127.34,
25.23, 124.56, 119.17, 91.52, 71.57, 70.55, 69.82, 68.77, 66.01, 20.37
pressure, and the product was purified by column chromatogra-
phy.
(
s, 2C), 20.30 ppm; HRMS: m/z calcd for C H O : 537.1373 [M+
26 26 11
Allyl
3b): This product was obtained by starting from pivalic acid
491.14 mg, 4.8 mmol) and caesium carbonate (781 mg, 2.4 mmol).
2,3,4-tri-O-acetyl-1-O-(pivaloyl)-b-d-glucopyranuronate
+
Na] ; found: 537.1373.
(
(
Compound 3b was purified by column chromatography with di-
chloromethane/AcOEt (10:1, v/v) as the eluent to obtain a white
General procedure for the deprotection of allyl esters 3b–e
2
0
solid (707 mg, 40%). M.p. 113–1148C; [a] = +10.6 (c=0.956 in di-
D
1
chloromethane); H NMR (400 MHz, [D ]DMSO): d=5.99 (d, J=
Proper allyl ester 3 (1.0 equiv) was dissolved in dry acetonitrile
(15 mL) in an argon atmosphere and cooled to 08C. Complex
[Pd(PPh ) ] (10 mol%) and then pyrrolidine (1.1 equiv) were added
6
8
1
1
1
1
1
6
.2 Hz, 1H), 5.88 (ddt, J=16.1, 10.5, 5.7 Hz, 1H), 5.54 (t, J=9.6 Hz,
H), 5.33 (ddd, J=17.2, 3.0, 1.5 Hz, 1H), 5.26 (dd, J=10.4, 1.5 Hz,
H), 5.11–4.98 (m, 2H), 4.73 (d, J=9.9 Hz, 1H), 4.56 (dddt, J=36.6,
3.3, 5.9, 1.3 Hz, 2H), 1.99 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H),
3
4
to the reaction mixture, which was stirred for 20 min. The mixture
was filtered through a pad of celite, the solvent was removed
under reduced pressure, and the residue was dissolved in AcOEt
(100 mL) and washed with water (100 mL). The organic phase was
removed and the aqueous phase was acidified with aqueous 0.1m
HCl to pH 2. The product was re-extracted with AcOEt (2”50 mL).
The organic phase was separated, dried over anhydrous Na SO ,
1
3
.11 ppm (s, 9H); C NMR (101 MHz, [D ]DMSO): d=175.58, 169.43,
6
69.17, 168.96, 166.17, 131.64, 119.02, 90.84, 71.53, 70.71, 69.66,
8.95, 65.94, 38.23, 26.32 (s, 3C), 20.31 (s, 2C), 20.21 ppm; HRMS:
+
m/z calcd for C H O : 467.1529 [M+Na] ; found: 467.1531.
2
0
28 11
Allyl 2,3,4-tri-O-acetyl-1-O-benzoyl-b-d-glucopyranuronate (3c):
This product was obtained by starting from benzoic acid (586 mg,
2
4
and evaporated to give the corresponding acid.
4
3
.8 mmol) and cesium carbonate (781 mg, 2.4 mmol). Compound
c was purified by column chromatography with dichlorome-
thane/AcOEt (10:1, v/v) as the eluent to obtain a white solid
2,3,4-Tri-O-acetyl-1-O-pivaoyl-b-d-glucopyranuronic acid (4b):
This product was obtained by starting from allyl ester 3b (632 mg,
1.42 mmol) and by using [Pd(PPh ) ] (164 mg, 0.14 mmol) and pyr-
3
4
2
0
(
1.16 g, 63%). M.p. 98–998C; [a] =À11.6 (c=1.117 in dichlorome-
rolidine (1.57 mmol, 0.13 mL, 112 mg). Compound 4b was ob-
D
1
20
thane); H NMR (400 MHz, [D ]DMSO): d=7.97–7.90 (m, 2H), 7.77–
tained as a white solid (401 mg, 71%). M.p. 171–1728C; [a] = +
6
D
1
7
.69 (m, 1H), 7.62–7.54 (m, 2H), 6.27 (d, J=7.9 Hz, 1H), 5.86 (ddt,
8.4 (c=0.967 in dichloromethane); H NMR (400 MHz, [D ]DMSO):
6
J=22.1, 10.4, 5.8 Hz, 1H), 5.62 (t, J=9.4 Hz, 1H), 5.35–5.16 (m, 3H),
d=13.42 (s, 1H), 5.96 (d, J=8.1 Hz, 1H), 5.49 (t, J=9.5 Hz, 1H),
5.07 (t, J=9.6 Hz, 1H), 4.99 (dd, J=9.6, 8.1 Hz, 1H), 4.53 (d, J=
9.9 Hz, 1H), 1.99 (s, 3H), 1.97 (s, 6H), 1.12 ppm (s, 9H); C NMR
5
2
.13 (t, J=9.5 Hz, 1H), 4.82 (d, J=9.7 Hz, 1H), 4.62–4.45 (m, 2H),
.01 (s, 3H), 1.99 (s, 3H), 1.98 ppm (s, 3H); C NMR (101 MHz,
1
3
13
[
D ]DMSO): d=169.45, 169.23, 169.22, 166.22, 163.78, 134.46,
6
(101 MHz, [D ]DMSO): d=175.60, 169.45, 169.05, 169.01, 167.96,
6
1
7
31.59, 129.55 (s, 2C), 129.11 (s, 2C), 127.92, 119.16, 91.41, 71.52,
90.85, 71.73, 70.95, 69.75, 68.87, 38.24, 26.35(s, 3C), 20.35, 20.34,
+
0.53, 69.69, 68.79, 66.00, 20.35 (s, 2C), 20.27 ppm; HRMS: m/z
20.24 ppm; HRMS: m/z calcd for C H O : 427.1216 [M+Na] ;
17
24 11
+
calcd for C H O : 487.1216 [M+Na] ; found: 487.1217.
found: 427.1213.
2
2
24 11
Chem. Eur. J. 2015, 21, 16585 – 16592
www.chemeurj.org
16589
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
,3,4-Tri-O-acetyl-1-O-benzoyl-b-d-glucopyranuronic acid (4c):
This product was obtained by starting from allyl ester 3c (1.088 g,
.34 mmol) and by using [Pd(PPh ) ] (270 mg, 0.234 mmol) and pyr-
was transferred into a separatory funnel and washed with aqueous
HCl (50 mL, 0.1m) and saturated aqueous NaHCO (50 mL). The or-
3
2
ganic layer was dried with Na SO and the solvent was removed by
3
4
2
4
rolidine (2.57 mmol, 0.22 mL, 182 mg). Compound 4c was obtained
evaporation. The crude product was purified by column chroma-
tography.
2
0
as a white solid (772 mg, 77%). M.p. 175–1768C; [a] =À21.9 (c=
D
1
0
.991 in dichloromethane); H NMR (400 MHz, CDCl ) d=8.05–8.01
3
1
,1-Bis-[7-(2,3,4-tri-O-acetyl-1-O-pivaoyl-b-d-glucopyranuronyl)-
amino-3-methyl-1H-indol-2-yl]propane (1b): The acid chloride of
b (829.5 mg, 2.05 mmol) obtained in the presence of oxalyl chlo-
(
m, 2H), 7.63–7.57 (m, 1H), 7.48–7.43 (m, 2H), 7.07 (s, 1H), 6.01 (d,
J=7.3 Hz, 1H), 5.45–5.26 (m, 3H), 4.34 (d, J=9.3 Hz, 1H), 2.06 (s,
4
1
3
3
1
1
2
H), 2.06 (s, 3H), 2.00 ppm (s, 3H); C NMR (101 MHz, CDCl ) d=
3
ride (2.25 mmol, 0.19 mL) and DMF (4.1 mmol, 0.32 mL) was treat-
ed with an amine prepared by the reduction of 1,1-bis-(3-methyl-7-
nitro-1H-indol-2-yl)propane (403 mg, 1.02 mmol) in the presence
of pyridine (5.13 mmol, 0.42 mL). The crude product was purified
by column chromatography with a gradient of CH Cl !CH Cl /
70.11, 169.92, 169.90, 169.48, 164.58, 134.29, 130.37(s, 2C),
28.81(s, 2C), 128.26, 92.01, 72.50, 71.67, 69.90, 68.82, 20.75,
0.69 ppm (s, 2C); HRMS: m/z calcd for C H O : 447.0903 [M+
1
9
20 11
+
Na] ; found: 447.0889.
,3,4-Tri-O-acetyl-1-O-1-naphthoyl-b-d-glucopyranuronic
4d): This product was obtained by starting from allyl ester 3d
1.53 g, 2.97 mmol) and by using [Pd(PPh ) ] (343 mg, 0.297 mmol)
2
2
2
2
2
acid
AcOEt (5:1, v/v) as the eluent, thus giving 1b (752 mg, 66%) as an
20
(
off-white powder. M.p. 224–2258C (decomp.); [a] = +38.0 (c=
D
1
(
3
4
1.002 in dichloromethane); H NMR (600 MHz, [D ]DMSO): d=10.08
6
and pyrrolidine (3.27 mmol, 0.27 mL, 232 mg). Compound 4d was
(
s, 1H), 10.06 (s, 1H), 10.02 (s, 1H), 9.86 (s, 1H), 7.34 (d, J=7.6 Hz,
20
obtained as a white solid (1.106 g, 79%). M.p. 184–1858C; [a] =
D
1H), 7.28 (d, J=7.6 Hz, 1H), 7.24 (dd, J=7.7, 5.2 Hz, 2H), 6.94 (td,
J=7.8, 1.4 Hz, 2H), 6.06 (d, J=8.1 Hz, 1H), 6.03 (d, J=8.1 Hz, 1H),
5.62–5.55 (m, J=14.3, 9.6 Hz, 2H), 5.38–5.32 (m, J=9.6, 5.4 Hz, 2H),
1
À25.3 (c=1.161 in dichloromethane);
H NMR (400 MHz,
[
D ]DMSO): d=13.47 (s, 1H), 8.79 (d, J=8.6 Hz, 1H), 8.29 (d, J=
6
8
7
5
2
1
1
6
.2 Hz, 1H), 8.15 (dd, J=7.3, 1.2 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H),
5
4
2
.17–5.12 (m, 2H), 4.55 (d, J=9.8 Hz, 1H), 4.51 (d, J=9.8 Hz, 1H),
.46 (t, J=8.0 Hz, 1H), 2.28–2.22 (m, 2H), 2.10 (s, 3H), 2.07 (s, 3H),
.02 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.87 (s, 3H), 1.83
.76–7.58 (m, 3H), 6.37 (d, J=7.9 Hz, 1H), 5.61 (t, J=9.4 Hz, 1H),
.28–5.09 (m, 2H), 4.67 (d, J=9.7 Hz, 1H), 2.02 (s, 3H), 2.01 (s, 3H),
13
.01 ppm (s, 3H); C NMR (101 MHz, [D ]DMSO): d=169.50,
6
(s, 3H), 1.14 (s, 9H), 1.13 (s, 9H), 0.92 ppm (t, J=7.2 Hz, 3H);
13
69.34, 169.13, 168.02, 164.34, 134.85, 133.49, 130.99, 130.63,
29.02, 128.49, 126.69, 124.99, 124.69, 124.21, 91.34, 71.77, 70.97,
C NMR (151 MHz, [D ]DMSO): d=175.71, 175.70, 169.48, 169.46,
6
1
1
69.02 (s, 2C), 169.01, 168.97, 164.20, 164.17, 135.49, 135.27,
30.74, 130.67, 127.26, 127.06, 121.61, 121.51, 118.42, 118.40,
9.93, 68.77, 20.40, 20.37, 20.34 ppm; HRMS: m/z calcd for
+
C H O : 497.1060 [M+Na] ; found: 497.1056.
23
22 11
114.98, 114.89, 114.00, 113.78, 106.96, 106.92, 91.11 (s, 2C), 73.85,
73.78, 71.06 (s, 2C), 69.66, 69.63, 69.42 (s, 2C), 38.25, 38.24, 36.91,
26.33 (s, 3C), 26.32 (s, 3C), 25.90, 20.32 (s, 2C), 20.23 (s, 2C), 20.19,
20.16, 12.09, 8.42, 8.41 ppm; HRMS: m/z calcd for C55H N O :
68 4 20
1127.4325 [M+Na] ; found: 1127.4310; elemental analysis (%)
2
(
(
,3,4-Tri-O-acetyl-1-O-2-naphthoyl-b-d-glucopyranuronic
4e): This product was obtained by starting from allyl ester 3e
1.181 g, 2.30 mmol) and by using [Pd(PPh ) ] (265 mg,
acid
3
4
+
0
.230 mmol) and pyrrolidine (2.53 mmol, 0.21 mL, 180 mg). Com-
pound 4e was obtained as a white solid (984 mg, 90%). M.p. 183–
calcd for C55
6.36, N 4.85.
H N O20: C 59.77, H 6.20, N 5.07; found: C 59.76, H
68 4
2
0
1
1
848C; [a] =À38.3 (c=1.203 in dichloromethane); H NMR
D
(
400 MHz, [D ]DMSO): d=13.46 (s, 1H), 8.63 (s, 1H), 8.13 (d, J=
6
1,1-Bis-[7-(2,3,4-tri-O-acetyl-1-O-benzoyl-b-d-glucopyranuronyl)-
amino-3-methyl-1H-indol-2-yl]propane (1c): The acid chloride of
8
(
1
.0 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.94
dd, J=8.5, 1.4 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz,
H), 6.33 (d, J=7.4 Hz, 1H), 5.60 (t, J=9.3 Hz, 1H), 5.26–5.14 (m,
J=19.5, 8.8 Hz, 2H), 4.66 (d, J=9.6 Hz, 1H), 2.02 (s, 3H), 2.01 (s,
4
c (742 mg, 1.75 mmol) obtained in the presence of oxalyl chloride
(
1.92 mmol, 0.16 mL) and DMF (1.92 mmol, 0.26 mL) was treated
with an amine prepared by the reduction 1,1-bis-(3-methyl-7-nitro-
1H-indol-2-yl)propane (343 mg, 0.87 mmol) in the presence of pyri-
dine (2.5 mmol, 0.35 mL). The crude product was purified by
column chromatography with CH Cl /AcOEt (5:1, v/v) as the elue-
1
3
3
1
1
6
H), 1.98 ppm, (s, 3H); C NMR (101 MHz, [D ]DMSO): d=169.50,
6
69.30, 169.14, 168.04, 163.96, 135.48, 131.97, 131.52, 129.53,
29.22, 128.80, 127.82, 127.32, 125.35, 124.58, 91.52, 71.73, 70.80,
2
2
9.91, 68.72, 20.40 (s, 2C), 20.31 ppm; HRMS: m/z calcd for
net, thus giving 1c (932 mg, 93%) as an off-white powder.
+
C H O : 497.1060 [M+Na] ; found: 497.1062.
20
D
23
22 11
M.p. 143–1448C; [a] =À16.7 (c=0.981 in dichloromethane);
1
H NMR (400 MHz, [D ]DMSO): d=10.10 (s, 1H), 10.05 (s, 1H), 9.97
6
(
(
s, 1H), 9.81 (s, 1H), 7.97 (d, J=8.2 Hz, 4H), 7.80–7.65 (m, 2H), 7.57
td, J=7.7, 4.7 Hz, 4H), 7.27 (d, J=7.6 Hz, 1H), 7.23–7.18 (m, 3H),
General procedure for the synthesis of receptors 1b–e
6
2
8
6
.91 (t, J=7.8 Hz, 2H), 6.34 (t, J=7.8 Hz, 2H), 5.69 (q, J=9.8 Hz,
H), 5.48–5.24 (m, 4H), 4.64 (dd, J=15.5, 9.7 Hz, 2H), 4.44 (t, J=
.0 Hz, 1H), 2.28–2.16 (m, 2H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s,
H), 1.98 (s, 3H), 1.97 (s, 3H), 1.90 (s, 3H), 1.86 (s, 3H), 0.90 ppm (t,
Acid 4 (1.0 equiv) was dissolved in dry dichloromethane (100 mL)
and cooled to 08C. Oxalyl chloride (1.10 equiv) and DMF (2.0
equiv) were added to the reaction mixture, which was maintained
at this temperature for 30 min. The mixture was allowed to warm
to room temperature and was stirred for 1 h to yield a solution of
the acid chloride. In a separate flask, 1,1-bis-(3-methyl-7-nitro-1H-
indol-2-yl)propane (1.0 equiv) was dissolved in methanol (50 mL)
and 10% palladium on charcoal (50 mg) was added. The reaction
mixture was stirred in a hydrogen atmosphere. The progress of the
reaction was monitored by TLC analysis. After judging the reaction
to be complete, the catalyst was removed on celite, and solvent
was removed, thus giving 1,1-bis-(7-amino-3-methyl-1H-indol-2-yl)-
propane. A solution of the crude amine and pyridine (2.5 equiv) in
dichloromethane (50 mL) was slowly added to the acid chloride at
13
J=7.2 Hz, 3H); C NMR (151 MHz, [D ]DMSO): d=169.52, 169.50,
6
1
1
1
1
9
3
2
69.29, 169.27, 169.16, 169.09, 164.29, 164.26, 163.93, 163.92,
35.54, 135.29, 134.42, 134.39, 130.71, 130.65, 129.56 (s, 4C),
29.05 (s, 2C), 129.02 (s, 2C), 128.02, 127.98, 127.55, 127.31, 121.49,
21.35, 118.34 (s, 2C), 115.04, 114.93, 114.41, 114.12, 106.84, 106.78,
1.74 (s, 2C), 73.70, 73.65, 70.99, 70.97, 69.78 (s, 2C), 69.46, 69.43,
6.92, 25.97, 20.33 (s, 2C), 20.23 (s, 3C), 20.20, 12.12, 8.42 ppm (s,
+
C); HRMS: m/z calcd for C H N O : 1167.3699 [M+Na] ; found:
59
60
4
20
1167.3665; elemental analysis (%) calcd for C H N O : C 61.88, H
59
60
4
20
5
.25, N 4.89; found: C 61.64, H 5.39, N 4.87.
0
3
8C. The reaction mixture was stirred at this temperature for
0 min and then 2 h at room temperature. The reaction mixture
1,1-Bis-[7-(2,3,4-tri-O-acetyl-1-O-1-naphtoyl-b-d-glucopyranuro-
nyl)amino-3-methyl-1H-indol-2-yl]propane (1d): The acid chlo-
Chem. Eur. J. 2015, 21, 16585 – 16592
www.chemeurj.org
16590
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
ride of 4d (895 mg, 1.89 mmol) obtained in the presence of oxalyl
chloride (2.08 mmol, 0.18 mL) and DMF (3.78 mmol, 0.29 mL) was
treated with an amine prepared by the reduction of 1,1-bis-(3-
methyl-7-nitro-1H-indol-2-yl)propane (372 mg, 0.95 mmol) in the
presence of pyridine (4.72 mmol, 0.35 mL). The crude product was
purified by column chromatography with CH Cl /AcOEt (5:1, v/v)
H NMR spectroscopic titration experiments
Tetrabutylammonium salts were used as a source of anions. Tetra-
butylammonium salts of the investigated acids and amino acids
were prepared by the addition of one equivalent of Bu NOH to
one equivalent of a carboxylic acid or an N-Boc-protected amino
acid dissolved in MeOH, which was removed by evaporation in
vacuo. The salts were dried under high vacuum over P O . Distilled
4
2
2
as the eluent, thus giving 1d (1006 mg, 86%) as an off-white
2
0
2
5
powder. M.p. 160–1618C (decomp.); [a] =À31.8 (c=1.125 in di-
D
water was added to commercially available [D ]DMSO (99.8% iso-
topic purity; Euriso) to obtain the appropriate water concentration.
1
6
chloromethane); H NMR (600 MHz, [D ]DMSO): d=10.11 (s, 1H),
6
1
0.10 (s, 1H), 9.96 (s, 1H), 9.86 (s, 1H), 8.80 (d, J=8.8 Hz, 1H), 8.78
À2
A solution of a receptor in DMSO (ca. 1x10 m) was titrated in an
(
d, J=8.7 Hz, 1H), 8.26 (d, J=8.3 Hz, 2H), 8.17 (ddd, J=7.3, 3.7,
NMR tube with a solution of the respective tetrabutylammonium
salt (ca. 0.1–0.2m). The solution of the salt contained a certain
amount of the receptor to keep a constant concentration during
the titration. A total of 19 data points were recorded. The binding
constants were calculated by taking into account the changes in
the chemical shifts of the ligand NH protons. A nonlinear curve fit-
ting for a 1:1 binding model was carried out by using the HypNMR
1
7
.0 Hz, 2H), 8.08–8.03 (m, 2H), 7.70–7.59 (m, 6H), 7.27 (d, J=
.7 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.1 Hz, 2H), 6.89 (td,
J=7.8, 3.9 Hz, 2H), 6.49 (t, J=8.5 Hz, 2H), 5.75–5.68 (m, J=9.7 Hz,
2
5
J=8.0 Hz, 1H), 2.25–2.18 (m, 2H), 2.03 (s, 6H), 2.03 (s, 12H), 1.90 (s,
3
H), 5.46–5.40 (m, J=9.6, 5.4 Hz, 2H), 5.40–5.34 (m, J=9.6, 8.1,
.4 Hz, 2H), 4.71 (d, J=9.7 Hz, 1H), 4.69 (d, J=9.7 Hz, 1H), 4.41 (t,
1
3
H), 1.87 (s, 3H), 0.87 ppm (t, J=7.2 Hz, 3H); C NMR (151 MHz,
[17]
program to give global-association constants.
[
D ]DMSO): d=169.54, 169.53, 169.37 (s, 2C), 169.20, 169.15,
6
1
1
1
1
64.42 (s, 2C), 164.39, 164.36, 135.47, 135.31, 134.80, 134.78,
33.47, 133.45, 130.98, 130.96, 130.77, 130.68, 130.62, 130.60,
28.96, 128.95, 128.41, 128.38, 127.39, 127.26, 126.64, 126.62,
24.90 (s, 2C), 124.70 (s, 2C), 124.31, 124.26, 121.49, 121.42, 118.32
Acknowledgements
The support from the grant Maestro UMO-2011/02A/ST5/00439
financed by the Polish National Science Centre is acknowl-
edged.
(
s, 2C), 114.97, 114.91, 114.24, 114.10, 106.86, 106.77, 91.62 (s, 2C),
7
2
3.76, 73.73, 71.13 (s, 2C), 69.95, 69.94, 69.44 (s, 2C), 37.11, 25.85,
0.34 (s, 2C), 20.31 (s, 2C), 20.25, 20.23, 12.11, 8.40, 8.37 ppm;
+
HRMS: m/z calcd for C H N O : 1267.3998 [M+Na] ; found:
6
7
64
4
20
1
5
267.4006; elemental analysis (%) calcd for C H N O : C 64.62, H
67 64 4 20
.18, N 4.50; found: C 64.47, H 5.48, N 4.40.
Keywords: anions · carbohydrates · chirality · receptors ·
supramolecular chemistry
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1
,1-Bis-[7-(2,3,4-tri-O-acetyl-1-O-2-naphtoyl-b-d-glucopyranuro-
[2] V. A. Davankov, Chirality 1997, 9, 99–102.
nyl)amino-3-methyl-1H-indol-2-yl]propane (1e): The acid chloride
of 4e (809 mg, 1.70 mmol) obtained in the presence of oxalyl chlo-
ride (1.87 mmol, 0.16 mL) and DMF (3.40 mmol, 0.26 mL) was treat-
ed with an amine prepared by the reduction of 1,1-bis-(3-methyl-7-
nitro-1H-indol-2-yl)propane (333 mg, 0.95 mmol) in the presence
of pyridine(4.25 mmol, 0.34 mL). The crude product was purified by
column chromatography with CH Cl /AcOEt (5:1, v/v) as the eluent,
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4, 5608–5611; c) A. Kormos, I. Moczar, D. Pal, P. Baranyai, J. Kupai, K.
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Tetrahedron: Asymmetry 2007, 18, 1769–1774.
[
2
2
thus giving 1e (846 mg, 80%) as an off-white powder. M.p. 160–
2
D
0
1
618C (decomp.); [a] =À23.2 (c=1.019 in dichloromethane);
1
H NMR (600 MHz, [D ]DMSO): d=10.14 (s, 1H), 10.09 (s, 1H), 10.02
6
(
(
(
s, 1H), 9.84 (s, 1H), 8.65 (s, 2H), 8.08 (dt, J=15.2, 7.5 Hz, 4H), 8.03
dd, J=8.0, 4.7 Hz, 2H), 7.99–7.95 (m, 2H), 7.74–7.69 (m, 2H), 7.64
dd, J=15.9, 8.0 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.6 Hz,
[
5] B. BaragaÇa, A. G. Blackburn, P. Breccia, A. P. Davis, J. de Mendoza, J. M.
Padron-Carrillo, P. Prados, J. Riedner, J. G. de Vries, Chem. Eur. J. 2002, 8,
2931–2936.
1
H), 7.16 (dd, J=7.8, 2.8 Hz, 2H), 6.88 (t, J=7.8 Hz, 2H), 6.45 (dd,
J=10.0, 8.1 Hz, 2H), 5.79–5.70 (m, J=18.9, 9.6 Hz, 2H), 5.48–5.36
m, 4H), 4.71 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.6 Hz, 1H), 4.42 (t, J=
(
[6] a) J. L. Sessler, A. Andrievsky, V. Kral, V. Lynch, J. Am. Chem. Soc. 1997,
19, 9385–9392; b) A. Gonzµlez-lvarez, I. Alfonso, P. Diaz, E. Garcia-
1
8
2
0
1
1
1
1
1
1
2
2
1
.0 Hz, 1H), 2.20 (dt, J=14.9, 7.3 Hz, 2H), 2.07 (s, 3H), 2.05 (s, 6H),
Espana, V. Gotor, Chem. Commun. 2006, 1227–1229.
.04 (s, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.92 (s, 3H), 1.88 (s, 3H),
[
7] a) H. Miyaji, S.-J. Hong, S.-D. Jeong, D.-W. Yoon, H.-K. Na, J. Hong, S.
Ham, J. L. Sessler, C.-H. Lee, Angew. Chem. Int. Ed. 2007, 46, 2508–2511;
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3
.87 ppm (t, J=7.2 Hz, 3H); C NMR (151 MHz, [D ]DMSO): d=
6
70.00, 169.98, 169.76, 169.74, 169.59, 169.54, 164.77, 164.71,
64.50, 164.48, 135.96, 135.91, 135.89, 135.73, 132.35 (s, 2C),
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24.99, 121.95, 121.81, 118.76 (s, 2C), 115.44, 115.33, 114.80, 114.50,
07.24, 107.18, 92.30 (s, 2C), 74.22, 74.13, 71.47 (s, 2C), 70.34 (s,
C), 69.91, 69.87, 37.34, 26.44, 20.80 (s, 2C), 20.69, 20.67, 20.66 (s,
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267.3998 [M+Na] ; found: 1267.4012; elemental analysis (%)
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Received: July 26, 2015
Published online on September 29, 2015
Chem. Eur. J. 2015, 21, 16585 – 16592
www.chemeurj.org
16592
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim