Synthesis and self-assembly properties of a glycyrrhetinic acid conjugate containing uracil and 2,6-diaminopyridine units

Article abstract of DOI:10.1039/c0sm01392g

A novel glycyrrhetinic acid conjugate containing uracil and 2,6-diaminopyridine units was synthesized and the exclusive supramolecular dimeric structure through six intermolecular hydrogen bonds was characterized by NMR spectroscopy and ESI-MS. The supramolecular dimeric structure could recognize the polar molecule in aprotic polar solvents.

Full text of DOI:10.1039/c0sm01392g

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COMMUNICATION
Synthesis and self-assembly properties of a glycyrrhetinic acid conjugate
containing uracil and 2,6-diaminopyridine units†
a
Jun Hu, Jinrong Lu, Ruofan Li and Yong Ju
a
a
ab
*
Received 30th November 2010, Accepted 21st December 2010
DOI: 10.1039/c0sm01392g
Conjugate 7, in which glycyrrhetinic acid offered the rigid chiral
structure, the complementary 2,6-diaminopyridine and uracil
provided the intermolecular six hydrogen bond pairs, and the
aliphatic chain containing carbonyl groups facilitated the molecular
rotation respectively, was expected to form assembly structures.
Initial evidence for assembly of 7 came from 1H NMR spectroscopy
studies carried out at 298 K in CDCl3 (Fig. 1). Compared to the
A novel glycyrrhetinic acid conjugate containing uracil and 2,6-
diaminopyridine units was synthesized and the exclusive supramo-
lecular dimeric structure through six intermolecular hydrogen bonds
was characterized by NMR spectroscopy and ESI-MS. The
supramolecular dimeric structure could recognize the polar molecule
in aprotic polar solvents.
corresponding signals of compound
4 and the reference
compounds,34 there were significant downfield shifts of Ha (Dd z 3
ppm) and Hg (Dd z 1 ppm) of conjugate 7 (70 mM, CDCl3) in 1H
NMR spectrum, which clearly indicated the formation of an
Glycyrrhetinic acid (1) is a facile pentacyclic triterpenoid presenting in
the form of free acids or aglycones from medicinal plants.1–3 It has
always been noted for the anti-inflammatory, anti-viral and anti-
tumor effects.4–8 However, there are few reports about triterpenoids in
supramolecular chemistry.9–13 Due to their rigid chiral structures,
multiple reaction sites and biocompatibility, they has begun to attract
more and more attention as scaffolds in supramolecular self-assembly
and recognition.
Self-assembly allows access to novel supramolecular architectures
with remarkable structural variety, such as linear, cyclic or three
dimensional arrays, which is difficult for conventional synthesis.14–20
So self-complementary molecular structures, which could assemble to
form well-defined supramolecular systems through hydrogen bonds,
have been designed more and more in recent years.21–26 Meanwhile,
nucleobases have frequently been exploited for the construction of
supramolecular structures because of strong degree of interaction.27–30
In our previous work, a kind of oleanolic acid derivatives with
good gel ability and a glycyrrhetinic acid based receptor for Hg2+
were found.31,32 Here, we report the synthesis of a novel glycyrrhetinic
acid bioconjugate containing uracil and 2,6-diaminopyridine units
and self-assembly property by hydrogen bonds for the first time.
The synthesis of glycyrrhetinic acid conjugate 7 is outlined in
Scheme 1. Glycyrrhetinic acid (1) reacted with acetic anhydride in
pyridine to give 2,33 which was then coupled with 2,6-diaminopyr-
idine to afford 3 in high yield, which subsequently reacted with
lauroyl 4 with potassium carbonate, followed by treatment with
bromoacetyl bromide to give 6. Finally, compound 7 was obtained by
reaction of 6 with uracil in DMF with 86% yield.
aKey Lab. of Bioorganic Phosphorus Chemistry & Chemical Biology,
Ministry of Education, Department of Chemistry, Tsinghua University,
Beijing, 100084, China. E-mail: juyong@tsinghua.edu.cn
bState Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, China
Scheme 1 a) Ac2O, DMAP, pyridine, rt; b) i. SOCl2, Et3N, benzene, 60
ꢀC; ii. 2,6-diaminopyridine, Et3N, THF, rt; c) lauroyl chloride, Et3N,
CHCl3, rt; d) K2CO3, CH3OH–THF, rt; e) BrCH2COBr, K2CO3, CHCl3,
rt; f) uracil, K2CO3, DMF, r.t.
† Electronic supplementary information (ESI) available: Synthesis and
structure data of compounds 2–7. See DOI: 10.1039/c0sm01392g
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Fig. 1 1H NMR (300 MHz) spectrum of conjugate 7 (70 mM) in CDCl3.
Fig. 3 Self-assembly of conjugate7 into dimeric species.
assembled structure involving hydrogen bonding between the 2,6-
diaminopyridine and uracil units.
The appearance of sharp NMR signals further suggested that the
hydrogen bonds have not lead to polymeric aggregates. We studied
the concentration dependence of signals of 7 in 1H NMR spectrum in
the concentration range 0.004–0.095 M (CDCl3, 300MHz) (Fig. 2). It
was observed that the shifts of Ha and Hg at the uracil and 2,6-dia-
minopyridine moieties of 7 moved upfield on dilution and the 1 : 1
dimerization mode was confirmed by plotting the changes in the
chemical shift of Ha upon dilution at the uracil moiety. The dimer-
ization constant (41 Mꢁ1) was calculated35 and the self-association of
7 resulted in head-to-tail structure (Fig. 3).
The additional evidence for the formation of intermolecular
hydrogen bonds between the 2,6-diaminopyridine and uracil moieties
was provided by variable temperature 1H NMR measurements of 7
(70 mM) from 20 ꢀC to 50 ꢀC in CDCl3 (300 MHz) (Fig. 4). As the
temperature increased, upfield shifts of Ha (0.021 ppm/K) and Hg
(0.009 ppm/K) were observed.
Fig. 4 Variable temperature 1H NMR on increasing the temperature
from 20 to 50 ꢀC (CDCl3, 300 MHz) of conjugate 7.
It was further confirmed by ESI-MS to form intermolecular head-
to-tail self-assembly of the conjugate 7. The monomer peaks at m/z
896.6 (M + H)+ and 918.6 (M + Na)+ were assigned to the quasi-
molecular ions in ESI mass spectra. Meanwhile, there were significant
signals for the dimer at m/z 1792.6 (2M + H)+ and 1814.6 (2M + Na)+
in the ESI mass spectra, which were assigned to self-assembly of the
conjugate 7 to form dimer (Fig. 5). No signals for higher aggregates
were observed.
Fig. 5 ESI-MS spectrum of conjugate 7.
In order to confirm the supramolecular dimeric structure could
recognize the polar molecules by both hydrogen bonds and the
specially formed cavitary skeleton, the solubility of cresol red sodium
(CR, a hydrophilic dye) was investigated with 7 in chloroform (an
aprotic polar solvent) based on solid-liquid extraction measurement
(Fig. 6).36 The result showed that the amount of dye extracted
increased linearly with the concentration of 7, while compound 4 and
5 have no effect for the dye encapsulation. It suggested that this cyclic
Fig. 2 Dilution shift for Ha of conjugate 7 in the concentration range
from 0.004–0.095 M in CDCl3 (300 MHz).
892 | Soft Matter, 2011, 7, 891–894
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structure might be used as the potential selective host–guest encap-
sulation in biomaterial.37–40
In conclusion, the glycyrrhetinic acid conjugate 7 containing 2,6-
diaminopyridine and uracil units could assemble a stable cyclic dimer
exclusively through six intermolecular hydrogen bonds. This head-to-
tail self-assembled symmetrical cavity structure showed package
effects for polar molecules in nonpolar solvents, and it might be used
for potential selective encapsulation in biomaterials.
Acknowledgements
The project is supported by NSFC (No.20772071, 20972086) and
SRFDP (No. 20090002110060). We also thank Yang HJ for his kind
suggestion and discussion.
Notes and references
Fig. 6 Solubilization of CR by conjugate 7 (insert: extraction of CR by
increasing concentrations of 7. Left to right: [7] ¼ 0–3.2 mM).
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