Trimethoxybenzene- and trimethylbenzene-based compounds bearing imidazole, indole and pyrrole groups as recognition units: Synthesis and evaluation of the binding properties towards carbohydrates

Article abstract of DOI:10.1039/c3ob41540f

The aim of the study was to evaluate the potential of trimethoxybenzene- and trimethylbenzene-based compounds bearing imidazole or indole groups as recognition sites in the complexation of carbohydrates. Representatives of these compounds were prepared and their binding properties toward selected carbohydrates evaluated. The results of the binding studies were compared with those obtained for the prepared pyrrole bearing analogues and for the previously described triethylbenzene-based receptors.

Full text of DOI:10.1039/c3ob41540f

Organic &
Biomolecular Chemistry
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PAPER
Trimethoxybenzene- and trimethylbenzene-based
compounds bearing imidazole, indole and pyrrole
groups as recognition units: synthesis and evaluation
of the binding properties towards carbohydrates†
Cite this: Org. Biomol. Chem., 2013, 11,
6569
Jan-Ruven Rosien, Wilhelm Seichter and Monika Mazik*
The aim of the study was to evaluate the potential of trimethoxybenzene- and trimethylbenzene-based
compounds bearing imidazole or indole groups as recognition sites in the complexation of carbo-
hydrates. Representatives of these compounds were prepared and their binding properties toward
selected carbohydrates evaluated. The results of the binding studies were compared with those obtained
for the prepared pyrrole bearing analogues and for the previously described triethylbenzene-based
receptors.
Received 26th July 2013,
Accepted 8th August 2013
DOI: 10.1039/c3ob41540f
www.rsc.org/obc
pyrrole units and 1-substituted imidazole group, respectively.
The 1,3,5-substituted 2,4,6-triethylbenzene scaffold, which was
Introduction
The imidazole ring of His and the indole ring of Trp are often shown to be a valuable building block for carbohydrate recep-
used by carbohydrate-binding proteins to bind the sugar sub- tors4,5 and other artificial receptor molecules,6 was used for the
strate by hydrogen bonding and CH–π interactions,1 as shown construction of both the aminopyridine bearing compounds
in Fig. 1 for galactose binding by human galectin-1 and for a 1–7 and the symmetrical imidazole-based derivatives 8–10. The
complex of Galβ3GalNac with Amaranthus caudatus agglutinin. heterocyclic groups of 1–10 were connected to the central
The participation of these electron-rich heterocycles in biore- benzene ring via –CH2NH-, –CH2NHCH2- or –CONHCH2-
cognition of carbohydrates has inspired us to design artificial linkers. In addition to the analysis of the binding properties of
carbohydrate receptors2 consisting of imidazole- and indole- the indole and imidazole containing compounds, the properties
based recognition units; the first representatives of these of the benzimidazole-based derivative 11 were also reported by
receptor molecules were reported by our group some years our group in a previous work.7
ago.3 Compounds 1–3, 6 and 7, including both 4(5)-substituted
It is well known that hexaethylbenzene and hexasubstituted
imidazole or 3-substituted indole units as the entities used in benzene derivatives possessing substituents nearly isosteric to
nature and 2-aminopyridine group as a heterocyclic analogue ethyl groups adopt a preferred conformation with full up-down
of the asparagine/glutamine primary amide side chain, were alternation of the side-arms, as shown in Fig. 3.8 In this
established to be powerful carbohydrate receptors with interest- arrangement the three CH2X groups of I are oriented toward
ing binding preferences, and were shown to be able to recognize the same face of the central benzene ring, whereas the ethyl
carbohydrates by multiple interactions, including hydrogen groups point in the opposite direction. The 1,3,5 versus 2,4,6
bonding and CH–π interactions. The binding properties of 1–3 facial differentiation of the side-arms of I has been exploited
were compared with those of compounds 4 and 5, containing for the design of artificial receptors with preorganized binding
groups,6 including the acyclic carbohydrate receptors men-
tioned above. The 1,3,5-substituted 2,4,6-triethylbenzene
Institut für Organische Chemie, Technische Universität Bergakademie Freiberg,
scaffold has been found to improve the binding affinities of
Leipziger Strasse 29, 09596 Freiberg, Germany.
artificial receptors compared to analogues, which are based on
E-mail: monika.mazik@chemie.tu-freiberg.de; Fax: +03731393170;
the trimethylbenzene core II.9 By studying experimental data
Tel: +03731392389
†Electronic supplementary information (ESI) available: Representative EQNMR
from the literature and the Cambridge Structural Database,
Hof and Wang concluded that “the steric gearing offered by
the ethyl groups confers some energetic advantage over the
methyl groups, but the size of this advantage can be small and
is dependent on the groups involved”.10
plots (Fig. S1–S11). Representative mole ratio plots (Fig. S12–S18). 1H NMR titra-
tions of compounds 14a, 14b, 16a and 16b with β-glucoside 27a or β-galactoside
29a (Fig. S19–S27). Copies of the 1H and 13C NMR spectra of 12a–16a and 12b–
16b (Fig. S28–S48). CCDC 938511. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ob41540f
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Fig. 1 Examples of noncovalent interactions in the complex of (a) human galectin-1 with galactose1e,f and (b) Amaranthus caudatus agglutinin with
Galβ3GalNAc.1a
Fig. 2 Structures of the previously described imidazole-, indole- and benzimidazole-based receptors 1–11.
Fig. 3 Triethylbenzene- (I), trimethylbenzene- (II) and trimethoxybenzene-based (III) systems (only selected conformations are shown).
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Fig. 4 Structures of the prepared trimethoxybenzene-based compounds 12a–16a and the trimethylbenzene-based analogues 12b–16b.
The trimethoxybenzene-based scaffold III represents a
The aim of the present study was to evaluate the potential
further platform for receptor systems and we were interested to of both trimethoxybenzene- and trimethylbenzene-based com-
see how this scaffold affects binding properties of carbo- pounds bearing imidazole or indole groups (compounds 12a–
hydrate receptors. As mentioned by Biali et al.,11 for derivatives 15a and 12b–15b) in the complexation of carbohydrates and to
of III a lower relative stability of the all-alternated up-down compare their properties with those of the previously
arrangement (III-a) over nonalternated ones, such as III-b, (as described triethylbenzene-based receptors. The properties of
compared to hexaethylbenzene) could be expected since con- the indole and imidazole bearing compounds (in particular
formation III-a should be destabilized by the presence of the the properties of compounds 14a and 14b containing 2-substi-
three OMe dipoles oriented in a nearly parallel fashion. This tuted indole units) were further compared with those of the
effect may influence unfavourably the binding capabilities of pyrrole-based analogues 16a and 16b (Fig. 4).
the trimethoxybenzene-based receptors in comparison to
those of the triethylbenzene-based systems. Compared to I and
II, the methoxy groups of III provide additional hydrogen
bonding sites for substrate complexation; however, the pos-
Results and discussion
sible formation of intramolecular hydrogen bonds in the case
of some derivatives of III, such as III-1 (see Fig. 3), may be
responsible for weaker intermolecular interactions with the
substrate molecule. The central benzene ring is expected to
participate in CH–π interactions with sugar CHs and it should
be noted that the methoxy groups may significantly influence
the contribution of the CH–π interactions to the overall
binding.
The basis for the syntheses of compounds 12a/b–16a/b was
1,3,5-tris(aminomethyl)-2,4,6-trimethoxybenzene (21a) or
1,3,5-tris(aminomethyl)-2,4,6-trimethylbenzene (21b); the syn-
thetic routes for 12a/b–16a/b are shown in Scheme 1. The syn-
thesis of the tris-amines 21a and 21b started from
commercially available 1,3,5-trimethoxybenzene (18) and 1,3,5-
trimethylbenzene (17), respectively, which were converted into
the corresponding tris-bromomethyl derivatives 19a and 19b
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Scheme 1 Reaction conditions: (a) 33% HBr in CH3COOH, (CH2O)n, 100 °C, 24 h (88%); (b) 33% HBr in CH3COOH, (CH2O)n, 70 °C, 3 h (27%); (c) potassium phtha-
limide, dimethyl sulfoxide, 100 °C, 8 h (46% of 20a, 97% of 20b); (d) hydrazine hydrate, ethanol–toluene, reflux, 20 h, KOH (83% of 21a, 58% of 21b); (e) 6 equiv.
of 2-imidazole-carbaldehyde (22), 4(5)-imidazole-carbaldehyde (23), 2-indole-carbaldehyde (24), 3-indole-carbaldehyde (25) or 2-pyrrole-carbaldehyde (26),
CH3OH, r.t., 3–7 days; (f ) 7.5 equiv. of NaBH4, r.t., 24 h (63% of 12a, 89% of 12b, 70% of 13a, 92% of 13b, 83% of 14a, 54% of 14b, 42% of 15a, 29% of 15b,
53% of 16a, 68% of 16b).
by a reaction with paraformaldehyde and hydrobromic acid. chloroform molecule was found to be highly disordered and
Compound 19b could be isolated in a good yield of 88%, could not be satisfactorily modelled. Thus the PLATON
whereas 19a was obtained in a yield of only 27%. By variation SQUEEZE routine was used on the raw data to create a modified
of the reaction conditions no better yield of 19a could be data set that removed the scattering contribution of the dis-
achieved; higher temperatures, longer reaction times or ordered molecule (Fig. 5b). This procedure reveals that the
addition of the catalyst ZnBr2 only led to increased polymer chloroform molecules occupy lattice voids of 181.4 Å3 per unit
formation (see also ref. 12). Conversion of 19a/19b to tris- cell which represents 11.2% of the total cell volume. It should
amines 21a/21b was accomplished via Gabriel synthesis invol- be noted that the conformation adopted in the crystal by 12b
ving the preparation of compounds 20a and 20b in 46% and does not correspond to the concave conformation indicated by
97% yield, respectively. The condensation of the tris-amines molecular modeling for complexes with glycopyranosides; the
21a and 21b with the corresponding carbaldehyde, such as three amino nitrogen atoms (N1, N4 and N7) point to the same
2-imidazole-carbaldehyde (22), 4(5)-imidazole-carbaldehyde face of the receptor (see Fig. 5), but the rest of the arms open
(23), 2-indole-carbaldehyde (24), 3-indole-carbaldehyde (25) or out leaving an open cavity. Noncovalent interactions of 12b with
2-pyrrole-carbaldehyde (26), provided the corresponding chloroform and water molecules as well as packing forces may
imines, which were soluble in the reaction mixture and were be responsible for the nearly open conformation in the crystal.
further reduced with sodium borohydride to give the products
To compare the binding properties of the new compounds
12a/b–16a/b (isolation of the imines was not necessary). All with those of the previously published receptors, three repre-
products were purified by column chromatography on silica sentative monosaccharides, such as octyl β-D-glucoside (27a),
gel using a chloroform–methanol mixture as an eluant and octyl β-D-galactoside (29a), and octyl α-D-galactoside (30a), were
could be isolated in 29%–92% yield (see Scheme 1).
selected as substrates for the binding studies in homogeneous
Crystallization of the tripodal receptor 12b from CHCl3 media (1H NMR spectroscopic titrations). Methyl pyranosides,
yields an inclusion compound with one host molecule, one such as β-glucoside 27b, α-glucoside 28 and β-galactoside 29b
chloroform molecule and six water molecules in the asym- (Fig. 7), were employed for the binding studies in two-phase
metric part of the unit cell, two of the latter being disordered systems.
over two positions. A perspective view of the molecular struc-
Similar to the previously described triethylbenzene-based
ture is displayed in Fig. 5. As is evident from Fig. 5 and 6, the compounds 8–10, incorporating three imidazole groups, the
water molecules primarily contribute to the crystal stabiliz- symmetrical trimethoxybenzene- and trimethylbenzene-based
ation. Although the positions of their hydrogens could not be compounds 12a/b–13a/b, consisting of 2- or 4(5)-substituted
obtained from the difference electron-density map, the O⋯O imidazole groups, were almost insoluble in CDCl3, but could
and O⋯N distances of 2.729(2)–2.836(2) and 2.734(2)–2.884(2) be solubilized in this solvent in the presence of β-glucoside
Å, respectively, indicate the presence of a close network of 27a. Such solubility behavior indicates favorable interactions
O–H⋯O and O–H⋯N hydrogen bonds. The included between the binding partners. The extraction of compounds
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Fig. 5 (a) Molecular structure of 12b in the crystal; CHCl3 and H2O molecules are included in the crystal. (b) ORTEP diagram of the molecular structure of 12b;
thermal ellipsoids are drawn at the 50% probability level; broken lines represent hydrogen bond interactions (the PLATON SQUEEZE routine was used).
Fig. 7 Structures of sugars investigated in this study.
compounds 12a and 13a (the solubilization of 12b was about 6
times more effective than that of 12a). The extractability
decreased in the sequence 12b > 12a > 13a (control experi-
ments were performed in the absence of β-glucoside 27a);
thus, of the two trimethoxybenzene-based compounds, com-
pound 12a, bearing 2-imidazolyl groups, was found to be more
effective than 13a, consisting of 4(5)-substituted imidazole
groups. These results suggest that 2-substituted imidazole
Fig. 6 Packing excerpt of 12b viewed down the crystallographic a-axis. Shaded
groups are particularly suitable building blocks for carbo-
areas represent positions occupied by the disordered chloroform molecules.
hydrate receptors.
Oxygens are displayed as dark grey, and nitrogen atoms as hatched circles.
Compounds 14a/14b, 15a and 16a/16b, incorporating
Hydrogen bond interactions are marked by broken lines.
indole groups substituted in 2- or 3-position or 2-substituted
pyrrole groups, were shown to be soluble in CDCl3 and their
12a/b–13a from the solid state into a 1 mM solution of β-gluco- binding properties could be investigated in this solvent by
side 27a indicated that 12b, consisting of the trimethylbenzene 1H NMR spectroscopic titrations. The 1H NMR titration experi-
core and 2-imidazolyl groups, displays a significantly higher ments with β-glucoside 27a, β-galactoside 29a, and α-galacto-
affinity to β-glucoside than the trimethoxybenzene-based side 30a were carried out by adding increasing amounts of the
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Fig. 8 (a) Partial 1H NMR spectra (400 MHz) of receptor 14a ([14a] = 0.99 mM) after the addition of 0.00–4.00 equiv. of β-galactoside 29a in CDCl3. Chemical
shifts of the indole NH (a), CH2 (b) and CH3 (c) signals of 14a are shown.
sugar to a solution of the corresponding receptor. The com-
The interactions of the trimethylbenzene-based compounds
plexation between 14a/14b, 15a and 16a/16b and mono- 14b and 16b with β-glucoside 27a were shown to be more
saccharides was evidenced by several changes in the NMR effective than those with the trimethoxybenzene-based ana-
spectra; examples are given in Fig. 8 and Fig. S19–S27 in the logues 14a and 16a. The binding affinity of 14a/14b, 15a and
ESI.† The titration data were analyzed using the EQNMR13 16a/16b towards 27a decreased in the sequence 16b > 14b >
program; the binding constants are summarised in Table 1. 16a > 14a > 15a. Among the tested compounds, compound
With only one exception, namely 14a·29a, the movements of 16b, bearing three pyrrole units, was shown to be the most
the receptor signals gave very good fits to a 1 : 1 binding model effective receptor for this monosaccharide (for examples of
(for examples, see Fig. S1–S11 in ESI†). In the case of 14a·29a, effective triethylbenzene-based receptors bearing pyrrole
the curve fitting of the titration data suggested the existence of groups, see ref. 15).
1 : 1 and 2 : 1 receptor–sugar complexes in the CDCl3 solution
In comparison to the tested triethylbenzene-based imid-
(see Fig. S5†); this model was further supported by the mole azole and indole bearing receptors3 and the previously
ratio plot14 (for examples of mole ratio plots, see Fig. S12– described symmetrical aminopyridine-based receptor,4b the tri-
S18†). The binding constant for the 1 : 1 binding was deter- methoxybenzene-based compounds 14a and 16a showed a sig-
mined to be significantly higher than that for the 2 : 1 recep- nificantly decreased binding affinity towards β-glucoside 27a;
tor–sugar complex.
the binding affinity of the three receptor types decreased in
the sequence triethyl→trimethyl→trimethoxy-based com-
pounds (for an analysis of the abilities of 1,3,5-triethylbenzene
and 1,3,5-trimethylbenzene-based scaffolds to preorganize the
binding elements of supramolecular hosts and to improve the
binding of targets, see ref. 10).
Table 1 Association constantsa,b for receptors 14a/14b, 15a and 16a/16b and
carbohydrates 28a, 29a, 30a and 31a,b
K11 [M−1
]
1
Host–guest complex
K21 [M−1]c, β21 = K11K21
The H NMR titration experiments indicated furthermore a
higher binding affinity of 14a and 16a for β-galactoside 29a
than for β-glucoside 27a. The binding affinity of 14a and 16a
towards the tested octyl glycosides decreased in the sequence
β-galactoside 29a > β-glucoside 27a > α-galactoside 30a.
The interactions of β-glucoside 27 with 14a, consisting of
2-substituted indole groups, were shown to be more effective
than those with the analogue 15a, bearing indole groups sub-
stituted in the 3-position (see Tables 1 and 2).
A lower affinity of β-glucoside 27a to compound 14a in com-
parison to the trimethylbenzene-based analogue 14b was also
indicated by liquid–solid extractions (see Table 2). Extraction
of methyl pyranosides from the solid state into a CDCl3
14a·27a
14a·29a
14a·30a
14b·27a
15a·27a
16a·27a
16a·29a
16a·30a
16b·27a
16b·29a
16b·31
1440
5690 (K11), 510 (K21), 2.90 × 106 (β21
)
1210
5950
650
3500
8390
1200
6760
8430
2800 (K11), 82 370 (K21), 2.31 × 108 (β21
)
a Average Ka values from multiple titrations in CDCl3. b Errors in Ka are
less than 5%. K21 corresponds to a 2 : 1 receptor–sugar association
constant.
c
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amine NHs and the methoxy groups, as shown in Fig. 9a/b for
compound 14a (the participation of the indole NH in intra-
molecular NH⋯π interactions was also indicated by molecular
modelling calculations, see Fig. 9b). The participation of the
amine NH in an intramolecular hydrogen bond was further
indicated by NMR spectroscopy (see, for example, Fig. S48†
Table 2 Solubilization of sugars in CDCl3 by receptors 14a, 14b, and 15a
(1 mM solutions)a
Receptor
β-Glucoside 27b
β-Galactoside 29b
α-Glucoside 30b
14a
14b
15a
0.45
0.58
0.24
0.61
0.35
0.24
0.20
0.47
b
1
showing partial H NMR spectra of compound 14a and of the
a Molar ratios sugar–receptor occurring in solution (the 1H NMR
signals of the corresponding sugar were integrated with respect to the
receptor’s signals to provide the sugar–receptor ratio; control
experiments were performed in the absence of the receptor). b Not
determined.
trimethylbenzene-based analogue 14b). Thus, the lower affinity
of the trimethoxybenzene-based compounds towards β-gluco-
side 27 in comparison to the trimethylbenzene-based ana-
logues may be a consequence of the participation of the
important recognition sites of 12a–16a in intramolecular
hydrogen bonds.16
solution of the corresponding receptor (1 mM solution) indi-
cated furthermore a preference of 14a and 14b for β-glucoside
27b versus α-glucoside 28 as well as a preference of 14a for
β-galactoside 29b versus β-glucoside 27b. The β-galactoside
versus β-glucoside preference of 14a was also shown by
1H NMR spectroscopic titrations of 14a with the octyl glyco-
sides 27a and 29a (see above).
In the case of the trimethoxybenzene-based compounds
12a–16a, molecular modeling calculations indicated the for-
mation of intramolecular NH⋯Ο hydrogen bonds between the
According to molecular modeling calculations, the com-
plexes between 12a/b–16a/b and glycosides are stabilized by
both hydrogen bonds and CH⋯π interactions17–19 (for
examples, see Fig. 9c/d). The sugar OH groups are involved in
the formation of cooperative hydrogen bonds, which result
from the simultaneous participation of a sugar OH group as the
donor and acceptor of hydrogen bonds; the central benzene
ring of the corresponding receptor stacks on the sugar ring.
In the case of 16b, the binding properties of this compound
were also tested against a disaccharide, such as dodecyl
Fig. 9 (a) Energy-minimized structure of 14a (MacroModel V.9.8, OPLS_2001 force field, MCMM, 50 000 steps). (b) Examples of intramolecular interactions in 14a.
(c) Energy-minimized structure of the 1 : 1 complex formed between 14a and β-glucopyranoside 27b. (d) Examples of intermolecular interactions in the 14a·27b
complex. Color code: receptor N, blue; receptor C, grey; receptor O, red; the sugar molecule is highlighted in orange.
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β-maltoside 31. In contrast to the relatively weak binding of
monosaccharides, the binding of β-maltoside 31 by compound
16b was shown to be strong (see also ref. 20). Although β-mal-
toside 31 is poorly soluble in CDCl3, it could be solubilized in
this solvent in the presence of 16b and the interactions
between the binding partners could be investigated by
1H NMR titrations (the receptor in CDCl3 was titrated with a
solution of β-maltoside dissolved in the same receptor solution
by following the titration protocol described in ref. 20a). The
addition of only 0.5 equiv. of 31 led to practically complete
complexation of the receptor 31 in CDCl3, indicating the for-
mation of 2 : 1 receptor–disaccharide complexes under the
titration conditions. The binding constants in CDCl3 were
Table 3 Examples of noncovalent interactions indicated by molecular model-
ing calculationsa for the complex formed between receptor 16b and disacchar-
ide 31
Receptor–substrate
complex
Noncovalent interactionsb,c
16b·31
(I) Pyrrole–NH⋯OH-3 (g1)
(II) Amine–NH⋯OH-6 (g1)
2 : 1 receptor–sugar
complexb
(I) Pyrrole–NH⋯OH-2 (g2); (I) amine–
NH⋯OH-2 (g2): (II) pyrrole ring⋯HO-2 (g2)
(I) Pyrrole–NH⋯OH-3 (g2);
(II) amine–N⋯HO-3 (g2)
(II) Amine–NH⋯OH-4 (g2);
(II) pyrrole–N⋯HO-4 (g2)
(I) Amine–NH⋯HO-6 (g2)
determined to be 2800 [M−1] (K11) and 82 370 [M−1] (K21) (β21
=
(I) Amine–NH⋯O-ring (g2)
2.31 × 108 M−2).
(I) Central benzene ring⋯HC-2 (g2);
(I) Pyrrole ring⋯HC-1, HC-3 and HC-5 (g1)
Molecular modeling calculations indicated that in the 2 : 1
receptor–sugar complex the disaccharide 31 is fully encapsu-
lated in the cavity between the two receptor molecules, as
shown in Fig. 10 (it should be noted that the dodecyl-chain
a MacroModel V.9.8, OPLS_2001 force field, MCMM, 50 000 steps.
b I and II: two receptors in the 2 : 1 receptor–sugar complex; c g1 and
g2: the glucose units of 31 (for labeling see Fig. 7).
projects to the exterior). According to the calculations, the
complex is stabilized by several hydrogen bonds, including
cooperative hydrogen bonds, CH–π and OH–π interactions as
well as a number of van der Waals contacts21 (for examples of
noncovalent interactions, see Table 3).
Conclusion
Ten representatives of trimethoxybenzene- (12a–16a) and tri-
methylbenzene-based compounds (12b–16b), bearing imida-
zole, indole and pyrrole groups as recognition units, were
prepared and their binding properties towards selected carbo-
hydrates evaluated. The design of the previously described
receptors consisting of imidazole or indole recognition units
(see Fig. 2) as well as the new tripodal compounds 12a/b–15a/b
was inspired by the crystal structures of protein–carbohydrate
complexes (see Fig. 1). We were furthermore interested to see
how the trimethoxybenzene and trimethylbenzene scaffolds
affect binding properties of carbohydrate receptors. Com-
pounds 16a/b, containing 2-substituted pyrrole groups, were
prepared as analogues of compounds 14a/b, bearing 2-substi-
tuted indole units. 1H NMR titrations as well as binding
studies in two-phase systems, such as dissolution of solid
carbohydrates in apolar media, which were carried out with
14a, 14b, 15a and 16a, revealed β- vs. α-anomer binding prefer-
ences in the recognition of glycosides. The binding studies
showed furthermore a preference of compounds 14a and 16a
for β-galactoside 29 versus β-glucoside 27.
Compounds 12a/b–13a/b, consisting of 2- or 4(5)-substi-
tuted imidazole groups, were almost insoluble in CDCl3, but
could be solubilized in this solvent in the presence of β-gluco-
side 27a, indicating favorable interactions between the binding
partners. The solubilization experiments suggested that 2-sub-
stituted imidazole groups are particularly suitable building
blocks for carbohydrate receptors.
Fig. 10 Energy-minimized structures of (a) compound 16b, (b) the 1 : 1
complex formed between 16b and dodecyl β-maltoside 31 as well as (c–f ) the
2 : 1 receptor–maltoside complex (four different representations). MacroModel
V.9.8, OPLS_2001 force field, MCMM, 50 000 steps. Color code: receptor N, blue;
receptor C, grey; the sugar molecule is highlighted in orange.
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Compared to the previously described triethylbenzene-
1,3,5-Tris[(4-imidazolyl-methyl)aminomethyl]-2,4,6-tri-
based receptors, the tested trimethoxybenzene- and trimethyl- methoxybenzene (13a). Yield: 70%. M.p. 95 °C. 1H-NMR
benzene-based compounds were shown to be less effective in (400 MHz, CDCl3 + MeOD-d4, ∼25 mM): δ = 7.55 (s, 3H), 6.93
the recognition of β-glucoside 27; the binding affinity for (s, 3H), 3.75 (s, 6H), 3.72 (s, 6H), 3.68 (s, 9H) ppm. 13C-NMR
β-glucoside decreased in the sequence triethylbenzene→tri- (100 MHz, CDCl3 + MeOD-d4): δ = 162.38, 139.01, 126.75,
methylbenzene→trimethoxybenzene-based compounds. It 65.95, 45.81, 45.79 ppm. HR-MS (ESI) calcd for C24H34N9O3:
should be however noted that some compounds showed an 496.27846 [M + H]+; found: 496.27839. Rf 0.42 [CHCl3–CH3OH,
interesting preference22 for β-galactoside versus β-glucoside 2 : 1].
(for examples of receptors showing increased binding affinity
1,3,5-Tris[(2-indolyl-methyl)aminomethyl]-2,4,6-trimethoxy-
toward β-galactoside, see ref. 3b). The lower affinity of the tri- benzene (14a). Yield: 83%. M.p. 104 °C. 1H-NMR (400 MHz,
methoxybenzene-based compounds towards β-glucoside 27 in CDCl3, ∼25 mM): δ = 9.18 (br. s, 3H), 7.54 (d, J = 7.7 Hz, 3H),
comparison to the triethylbenzene- and trimethylbenzene- 7.31 (d, J = 8.0 Hz, 3H), 7.13 (ddd, J = 8.1/7.2/1.3 Hz, 3H), 7.06
based analogues may be a consequence of the participation of (ddd, J = 7.9/7.3/1.0 Hz, 3H), 6.37 (s, 3H), 3.96 (s, 6H), 3.73 (s,
the amine NHs of 12a–16a in intramolecular hydrogen bonds 6H), 3.56 (s, 9H), 2.96 (br. S, 3H) ppm. 13C-NMR (100 MHz,
as well as a result of a lower degree of preorganisation of the CDCl3): δ = 158.66, 136.55, 136.23, 128.34, 122.92, 121.53,
trimethoxybenzene scaffold (see above).
120.10, 119.55, 110.86, 100.97, 62.60, 46.34, 42.02 ppm.
The binding properties of compounds 12a/b–16a/b towards HR-MS (ESI) calcd for C39H43N6O3: 643.33966 [M + H]+; found:
various carbohydrates are now analysed in more detail in com- 643.33958. Rf 0.43 [CHCl3–CH3OH, 2 : 1].
petitive and noncompetitive23 media. Efforts to examine the
1,3,5-Tris[(3-indolyl-methyl)aminomethyl]-2,4,6-trimethoxy-
three-dimensional structures of the receptor–sugar complexes benzene (15a). Yield: 42%. M.p. 105 °C. 1H-NMR (400 MHz,
are currently underway.
CDCl3, ∼25 mM): δ = 8.23 (br. s, 3H), 7.60 (d, J = 7.9 Hz, 3H),
7.26 (dt, J = 8.1/0.8 Hz, 3H), 7.12 (ddd, J = 8.1/7.2/1.1 Hz, 3H),
7.03 (ddd, J = 7.9/7.1/1.0 Hz, 3H), 6.97 (d, J = 2.3 Hz, 3H), 3.96
(s, 6H), 3.83 (s, 6H), 3.63 (s, 9H), 1.91 (br. S, 3H) ppm.
13C-NMR (100 MHz, CDCl3): δ = 158.28, 136.37, 127.14, 123.66,
122.69, 121.86, 119.32, 118.92, 115.01, 111.05, 62.26, 44.60,
42.99 ppm. HR-MS (ESI) calcd for C39H43N6O3: 643.33966
Experimental section
Analytical TLC was carried out on silica gel 60 F254 plates
employing chloroform–methanol mixtures as the mobile
phase, and column chromatography was carried out on silica
gel. Melting points are uncorrected. Sugars 27–31, 2-imidazole-
carbaldehyde (22), 4(5)-imidazole-carbaldehyde (23), 2-indole-
carbaldehyde (24), 3-indole-carbaldehyde (25) and 2-pyrrole-
carbaldehyde (26) are commercially available.
+
[M + H] ; found: 643.33957. Rf 0.45 [CHCl3–CH3OH (incl. 1%
7 M NH3 in CH3OH), 2 : 1].
1,3,5-Tris[(2-pyrrolyl-methyl)aminomethyl]-2,4,6-trimethoxy-
benzene (16a). Yield: 53%. M.p. 64 °C. 1H-NMR (600 MHz,
CDCl3, ∼25 mM): δ = 8.78 (br. s, 3H), 6.67–6.65 (m, 3H),
6.12–6.11 (m, 3H), 6.05–6.03 (m, 3H), 3.78 (s, 6H), 3.75 (s, 6H),
3.69 (s, 9H), 2.03 (br. s, 3H) ppm. 13C-NMR (150 MHz, CDCl3):
δ = 158.30, 130.53, 123.58, 116.99, 108.02, 106.24, 62.35, 46.17,
General procedure for the synthesis of compounds 12a–16a
To a solution of the corresponding carbaldehyde (compounds 42.45 ppm. HR-MS (ESI) calcd for C27H37N6O3: 493.29271
22–26) in methanol (12 mL) was added 1,3,5-tris(amino- [M + H]+; found: 493.29261. Rf 0.08 [CHCl3–CH3OH, 5 : 1].
methyl)-2,4,6-trimethoxybenzene (21a) (0.21–0.39 mmol) dis-
General procedure for the synthesis of compounds 12b–16b
solved in methanol (10 mL) and the reaction mixture was
stirred for
6 days at room temperature. Then NaBH4 To a solution of the corresponding carbaldehyde (compounds
(1.56–3.01 mmol) was added in portions and the reaction 22–26) (2.89 mmol) in methanol (10 mL) was added 1,3,5-tris-
mixture was stirred for 24 h at room temperature. The solvent (aminomethyl)-2,4,6-trimethylbenzene (21b)24 (0.48 mmol)
was removed, water was added to the residue and the mixture dissolved in methanol (10 mL). The reaction mixture was
was stirred additionally for 24 h. The suspension was extracted stirred for 7 days at room temperature. Afterwards NaBH4
with chloroform (3 × 20 mL). The combined organic extracts (3.62 mmol) was added in portions and the reaction mixture
were washed with water, dried over MgSO4, and the solvent was stirred for 24 h at room temperature. The solvent was
was removed (or product was present in the water phase). The removed, water was added to the residue and the mixture was
crude product was purified via column chromatography stirred additionally for 24 h. The suspension was extracted
[CHCl3–CH3OH (incl. 1% 7 M NH3 in CH3OH), 7 : 1 to 2 : 1 v/v]. with chloroform (3 × 10 mL). The combined organic extracts
1,3,5-Tris[(2-imidazolyl-methyl)aminomethyl]-2,4,6-tri- were washed with water and dried over MgSO4, and the solvent
methoxybenzene (12a). Yield: 63%. M.p. 124 °C. 1H-NMR was removed (or the product was present in water phase). The
(400 MHz, MeOD-d4, ∼25 mM): δ = 7.07 (s, 6H), 3.91 (s, 6H), crude product was purified via column chromatography
3.83 (s, 6H), 3.68 (s, 9H) ppm. 13C-NMR (100 MHz, MeOD-d4): [CHCl3–CH3OH (incl. 1% 7 M NH3 in CH3OH), 10 : 1 to/or 2 : 1
δ = 160.48, 146.80, 123.13, 122.81, 63.11, 45.95, 42.85 ppm. v/v].
HR-MS (ESI) calcd for C24H34N9O3: 496.27846 [M + H]+; found:
496.27837. Rf 0.06 [CHCl3–CH3OH, 7 : 1].
1,3,5-Tris[(2-imidazolyl-methyl)aminomethyl]-2,4,6-tri-
methylbenzene (12b). Yield: 89%. M.p. 104 °C. 1H-NMR
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(400 MHz, MeOD-d4, ∼30 mM): δ = 7.00 (s, 6H), 3.87 (s, 6H), 13C-NMR (100 MHz, DMSO-d6): δ = 156.91, 125.75, 62.34,
3.66 (s, 6H), 2.19 (s, 9H) ppm. 13C-NMR (100 MHz, MeOD-d4): 35.19 ppm; MS (EI): m/z = 255 [M+], 239, 225, 223, 209, 207,
δ = 148.23, 136.88, 135.34, 122.75, 48.31, 47.07, 15.69 ppm. 195, 165.
HR-MS (ESI) calcd for C24H33N9Na: 470.27566 [M + Na]+;
found: 470.27559. Rf 0.11 [CHCl3–CH3OH (incl. 1% 7 M NH3
in CH3OH), 2 : 1].
1,3,5-Tris[(4-imidazolyl-methyl)aminomethyl]-2,4,6-tri-
Crystallographic data for 12b
ˉ
C24H33N9·CHCl3·6H2O, Mr = 675.06, triclinic, space group P1,
a = 11.5740(3), b = 12.0274(3), c = 13.1839(6) Å, α = 104.872(1),
methylbenzene (13b). Yield: 92%. M.p. (dec.) 160 °C.
β = 101.801(2), γ = 107.204(1)°, T = 100 K, Z = 2, μ =
1H-NMR (400 MHz, MeOD-d4, ∼30 mM): δ = 7.64 (d, J = 1.2 Hz,
0.337 mm−1, RF(RwF) = 0.0657(0.1852) for 6752 observed inde-
3H), 7.03 (d, J = 1.0 Hz, 3H), 3.80 (s, 6H), 3.71 (s, 6H), 2.22 (s,
pendent reflections. The intensity data were collected at 100 K
on a Kappa APEX2 diffractometer (Bruker AXS) with MoKα
radiation (λ = 0.71073 Å) using ω- and ϕ-scans. Reflections
were corrected for background, Lorentz and polarization
9H) ppm. 13C-NMR (100 MHz, MeOD-d4): δ = 136.98, 136.81,
136.41, 135.56, 118.93, 48.02, 46.35, 15.78 ppm. HR-MS (ESI)
calcd for C24H34N9: 448.29372 [M + H]+; found: 448.29365.
Rf 0.03 [CHCl3–CH3OH (incl. 1% 7 M NH3 in CH3OH), 2 : 1].
effects. Preliminary structure models were derived by appli-
1,3,5-Tris[(2-indolyl-methyl)aminomethyl]-2,4,6-trimethyl-
cation of direct methods (SHELXL-97) and were refined by full-
benzene (14b). Yield: 54%. M.p. 99 °C. 1H-NMR (400 MHz,
matrix least-squares calculation based on F2 values for all
CDCl3, ∼25 mM): δ = 8.58 (br. s, 3H), 7.54 (dd, J = 7.3/0.5 Hz,
3H), 7.26 (d, J = 7.3 Hz, 3H), 7.13 (ddd, J = 8.1/7.3/1.4 Hz, 3H),
unique reflections (SHELXS-97). Empirical absorption correc-
tion based on multi-scans was applied by using the SADABS
7.07 (ddd, J = 8.1/7.1/1.1 Hz, 3H), 6.36 (d, J = 1.0 Hz, 3H), 4.00
program. All non-hydrogen atoms were refined anisotropically.
(s, 6H), 3.77 (s, 6H), 2.31 (s, 9H), 1.70 (br. s, 3H) ppm.
With the exception of the amino hydrogens H(1), H(4) and
13C-NMR (100 MHz, CDCl3): δ = 137.38, 135.98, 135.50, 134.75,
H(7) all other hydrogen atoms were included in the models in
128.43, 121.48, 120.12, 119.63, 110.71, 100.42, 48.10, 47.25,
calculated positions and were refined as constrained to
15.62 ppm. HR-MS (ESI) calcd for C39H43N6: 595.35492
bonding atoms. The PLATON SQUEEZE routine was used on
the raw data to create a modified data set that removed the
scattering contribution of the disordered chloroform molecule.
Deposit number: CCDC 938511.
[M + H]+; found: 595.35495. Rf 0.09 [CHCl3–CH3OH, 7 : 1].
1,3,5-Tris[(3-indolyl-methyl)aminomethyl]-2,4,6-trimethyl-
1
benzene (15b). Yield: 29%. M.p. 129 °C. H-NMR (300 MHz,
CDCl3, ∼25 mM): δ = 8.37 (br. s, 3H), 7.60 (d, J = 7.6 Hz, 3H),
7.16 (d, J = 7.9 Hz, 3H), 7.13–7.08 (m, 3H), 7.07–7.02 (m, 3H),
6.86 (s, 3H), 3.99 (s, 6H), 3.76 (s, 6H), 2.23 (s, 9H), 1.33 (br. s,
3H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 136.30, 135.30,
134.96, 127.08, 122.60, 121.85, 119.32, 118.81, 114.76, 111.13,
48.28, 45.14, 15.39 ppm. HR-MS (ESI) calcd for C39H43N6:
595.35492 [M + H]+; found: 595.35492. Rf 0.40 [CHCl3–CH3OH
(incl. 1% 7 M NH3 in CH3OH), 1 : 1].
1,3,5-Tris[(2-pyrrolyl-methyl)aminomethyl]-2,4,6-trimethyl-
benzene (16b). Yield: 68%. M.p. 122 °C. 1H-NMR (400 MHz,
CDCl3, ∼30 mM): δ = 8.63 (br. s, 3H), 6.67–6.65 (m, 3H), 6.12
(dd, J = 5.9/2.7 Hz, 3H), 6.06–6.04 (m, 3H), 3.86 (s, 6H), 3.75 (s,
6H), 2.31 (s, 9H), 1.34 (br. s, 3H) ppm. 13C-NMR (100 MHz,
CDCl3): δ = 135.22, 134.93, 130.56, 117.07, 108.00, 106.09,
48.04, 46.94, 15.43 ppm. HR-MS (ESI) calcd for C27H37N6:
445.30797 [M + H]+; found: 445.30768. Rf 0.03 [CHCl3–CH3OH,
2 : 1].
Notes and references
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Tris(phthalimidomethyl)-2,4,6-trimethoxybenzene
(20a)25
(189 mg, 0.3 mmol) was dissolved in a mixture of dry ethanol–
toluene (15 mL, 2 : 1 v/v) and heated at reflux with hydrazine
hydrate (0.1 mL, 2.1 mmol) for 20 h. Afterwards the mixture
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Drying under vacuum afforded the desired compound 21a as a
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Org. Biomol. Chem., 2013, 11, 6569–6579 | 6579