Synthesis of a novel uracil-2,6-diaminopyridine-lithocholic acid conjugate that self-assembles into a cyclic dimer

Article abstract of DOI:10.1016/j.tetlet.2008.05.069

Synthesis and self-association studies of a uracil-2,6-diaminopyridine-lithocholic acid conjugate are described. The dimeric supramolecular structure is characterized by NMR spectroscopic, ESI-MS, and size exclusion chromatographic studies.

Full text of DOI:10.1016/j.tetlet.2008.05.069

Tetrahedron Letters 49 (2008) 4640–4643
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Tetrahedron Letters
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Synthesis of a novel uracil-2,6-diaminopyridine-lithocholic acid
conjugate that self-assembles into a cyclic dimer
*
Prosenjit Chattopadhyay, Pramod S. Pandey
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and self-association studies of a uracil-2,6-diaminopyridine-lithocholic acid conjugate are
described. The dimeric supramolecular structure is characterized by NMR spectroscopic, ESI-MS, and size
exclusion chromatographic studies.
Received 5 April 2008
Revised 3 May 2008
Accepted 14 May 2008
Available online 16 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Self-assembly
2,6-Diaminopyridine
Nucleobases
Bile acids
There has been considerable interest in recent years in the
design of self-complementary molecular structures which can
assemble through hydrogen bonding to form well-defined supra-
molecular systems.1 Self-assembly allows access to novel supra-
molecular architectures with remarkable structural variety, such
as linear, cyclic or three dimensional arrays, with interesting appli-
cations that are difficult to obtain through conventional synthe-
sis.1,2 The groups of Meijer3 and Zimmerman4 have developed a
variety of heterocyclic complexes employing a combination of
self-complementary hydrogen bonding arrays.
Nucleobases have also been exploited for the construction of
supramolecular assemblies. Between the two major nucleobase
binding motifs present in nucleic acids, the GC (guanine-cytosine)
couple has received much attention from chemists due to its strong
degree of interaction.5 However, AT/AU (adenine-thymine/ade-
nine-uracil) couples have also been examined for self-assembly.
Sessler and coworkers have reported self-assembling structures
in which AT/GC nucleobases are connected through a very rigid
1,8-diethynylanthracene spacer.6 The studies highlighted the role
of steric influence in hydrogen bond mediated self-assembly as
the AT derived complex was found to form more stable dimers
compared to the corresponding GC derived complex. Gokel et al.
reported self-assembled dimeric structures derived from crown
ethers containing nucleotide bases.7
based macrocycles have received much attention.8a,c The synthesis
of cholaphanes requires a crucial cyclization step that usually gives
low yields. Our group has been able to overcome this problem by
using the Cs-salt methodology for the synthesis of head-to-head
cholaphanes.9
As a part of our interest in bile acid-based systems,10 we report
herein for the first time, the non-covalent synthesis of a head-to-
tail cholaphane which involves self-assembly of a bile acid-based
derivative containing 2,6-diaminopyridine and uracil residues.
2,6-Bis(acylamino)pyridine derivatives are known to bind uracil/
thymine analogues via three hydrogen bonds in non-polar
solvents.11 However, to the best of our knowledge, there is no re-
port on 2,6-diaminopyridine-uracil/thymine-based self-assembled
systems.
The synthesis of lithocholic acid derivative 6 containing uracil
and 2,6-diaminopyridine units is outlined in Scheme 1. 3a-O-
Formyllithocholic acid9d 1 was coupled with 2,6-diaminopyridine
to afford amine 2 in high yield, which was subsequently reacted
with lauroyl chloride to give bile acid derivative 3. This was fol-
lowed by hydrolysis of 3 with LiOH to afford compound 4, which
on treatment with bromoacetyl bromide gave 5. Reaction of 5 with
uracil in DMF afforded compound 6 in 72% yield.
Compound 6 was expected to form self-assembled structures
because of the complementary 2,6-diaminopyridine and uracil
units. However, the nature of assembly (dimer, trimer, etc., or poly-
meric aggregates) could not be envisaged merely on the basis of its
structural features. Initial evidence for self-assembly of 6 came
from 1H NMR spectroscopic studies carried out at 298 K in CDCl3
(Fig. 1). The 1H NMR spectrum of 6 (10 mM, CDCl3) clearly
indicated the formation of a self-assembled structure involving
Bile acids have proved to be promising candidates in the field of
molecular recognition due to their unique molecular architec-
tures.8 In this particular area, cholaphanes which are bile acid-
* Corresponding author. Tel.: +91 11 26591506; fax: +91 11 26582037.
E-mail address: pramod@chemistry.iitd.ac.in (P. S. Pandey).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.069

P. Chattopadhyay, P. S. Pandey / Tetrahedron Letters 49 (2008) 4640–4643
4641
O
N
H
N
i) Ethyl chloroformate
Et3N / THF / rt / 4 h
N
H
O
H
H
O
2
1
ii)DAP / reflux / 12 h
O
H
O
H
(89%)
Lauroyl chloride / Et3N
CHCl3 / rt / 12 h for 3
(85%)
O
O
O
N
O
O
N
LiOH / H2O-THF
N
R1
O
H
H
N
N
rt / 24 h
(84%)
N
R1
H
3 R1=C11H23
H
O
H
4 R1=C11H23
O
OH
BrCH2COBr / K2CO3
CHCl3 / rt / 12 h
(85%)
O
O
O
N
O
N
N
R1
N
H
N
N
H
R1
H
H
Uracil / K2CO3
DMF / rt / 24 h
(72%)
O
O
O
6 R1=C11H23
O
O
5 R1=C11H23
N
Br
O
N
H
Scheme 1. Synthesis of self-assembling bile acid-based conjugate 6 containing uracil and 2,6-diaminopyridine moieties.
lene protons is restricted due to hydrogen bond formation. We
studied the concentration dependence of the 1H NMR spectrum
of 6 in the concentration range 10–0.4 mM in CDCl3. A plot of
observed chemical shifts versus concentration for the imide proton
is shown in Figure 2.
Upfield shifts of the imide and amide protons were observed on
dilution. Plotting the changes in the chemical shift data of the
imide proton upon dilution and subsequent fitting of this data to
a
1:1 dimerization model with the non-linear least square
12
regression program WINEQNMR gave a dimerization constant of
12.5
12.3
12.1
11.9
11.7
11.5
11.3
11.1
10.9
Figure 1. 1H NMR (300 MHz, rt) spectrum of 6 (10 mM) in CDCl3.
hydrogen bonding between the 2,6-diaminopyridine and uracil
units as there was a significant downfield shift of the amide pro-
tons (
D
d ꢀ 2 ppm) and the imide proton ( d ꢀ 4 ppm) as com-
D
pared to the corresponding signals in the reference compounds.11i
The appearance of sharp NMR signals indirectly suggests that
the hydrogen bonding does not lead to polymeric aggregates. Fur-
ther, the appearance of an AB quartet for the methylene protons
(next to the uracil unit) indicates that free rotation of the methy-
0
0.002
0.004
0.006
0.008
0.01
0.012
concentration (M)
Figure 2. Dilution shift for the imide proton in 6 in the concentration range from 10
to 0.4 mM in CDCl3.

4642
P. Chattopadhyay, P. S. Pandey / Tetrahedron Letters 49 (2008) 4640–4643
displayed one peak with a retention time of 23.51 min, which
O
O
corresponds to a mean molecular weight (Mn) of 1623 Da (which
is close to the calculated value for the dimeric species of 1603 Da).
In conclusion, we have shown that bile acid conjugate 6 con-
taining uracil and 2,6-diaminopyridine units forms a stable dimer
exclusively through formation of six intermolecular hydrogen
bonds. Bile acids have a curved profile and the head-to-tail self-
assembly creates a symmetrical cavity. Such self-assembled struc-
tures are potentially useful for selective guest encapsulation. Work
is currently in progress directed towards the synthesis of deoxy-
cholic and cholic acid-based self-assembled structures and their
use for guest encapsulation.
N
H
R1
N
N
H
H
N
O
O
O
O
N
N
O
O
O
O
N
H
6 R1=C11H23
H
H
N
R1
N
N
O
O
Acknowledgements
Figure 3. Self-assembly of 6 into a dimeric species.
P.C. acknowledges the financial support from the Council of
Scientific and Industrial Research, India. We thank Dr. N. D. Kurur,
Indian Institute of Technology, Delhi for helpful discussions, and
Neeraj Jain, Yogesh Sharma and P. Nagraj for ESI-MS
measurements.
(1 0.1) Â 104 MÀ1. Self-association of 6 results in head-to-tail
self-assembly as shown in Figure 3.
The additional evidence for the formation of hydrogen bonds
between the 2,6-diaminopyridine and uracil units was provided
by two-dimensional (2D) NMR (ROESY,13 CDCl3, 300 MHz) studies
(Fig. 4). The ROE contacts between the imide proton and the amide
protons indicated that in solution, the uracil and the 2,6-diamino-
pyridine units are associated by hydrogen bonds.
Supplementary data
1H NMR, 13C NMR and mass spectra of all synthetic compounds,
the dimerization isotherm, the SEC chromatogram and 2-D ROESY
spectrum are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2008.05.069.
Variable temperature 1H NMR measurements at 10 mM of 6 and
from 20 to 56 °C in CDCl3 also revealed intermolecular hydrogen
bonding. As the temperature was increased, upfield shifts of the
imide proton (0.019 ppm/K) and amide protons (0.013 ppm/K)
were observed.
Further direct evidence for the intermolecular head-to-tail self-
assembly of the bile acid conjugate came from ESI-MS studies. In
addition to the monomer peaks at m/z 802.5495 (M+H)+ and
824.5256 (M+Na)+, there were significant signals for the dimer at
m/z 813.5145 (2ÁM+H+Na)2+ and 1626.0827 (2ÁM+Na)+. No signals
for higher aggregates were observed.
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