Synthesis and binding properties of a macrocycle with two binding subcavities

Article abstract of DOI:10.1016/j.tetlet.2006.04.078

A large, covalent macrocycle that can be served as an artificial allosteric model was prepared in a reasonable yield (36%) through the template-directed synthesis. The macrocycle contains two topologically discrete subcavities, each of which consists of f

Full text of DOI:10.1016/j.tetlet.2006.04.078

Tetrahedron Letters 47 (2006) 4141–4144
Synthesis and binding properties of a macrocycle with two binding
subcavities
Kyoung-Jin Chang, Hye-Young Jang and Kyu-Sung Jeong*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
Received 30 March 2006; revised 11 April 2006; accepted 13 April 2006
Available online 9 May 2006
Abstract—A large, covalent macrocycle that can be served as an artificial allosteric model was prepared in a reasonable yield (36%)
through the template-directed synthesis. The macrocycle contains two topologically discrete subcavities, each of which consists of
four amide NHs of pyridine-2,6-dicarboxamide units. The macrocycle strongly binds two molecules of N,N,N0,N0-tetramethyl-
terephthalamide in positive cooperative manner by hydrogen-bonding interactions. The association constants were calculated to
be K1 = 1480 90 and K2 = 5580 150 Mꢀ1 with the Hill coefficient (h) of 1.6 at 25 ꢀC in CDCl3.
ꢁ 2006 Published by Elsevier Ltd.
The design and synthesis of an artificial receptor is at the
heart of supramolecular chemistry to understand funda-
mental principles of molecular recognition. The receptor
needs to have a geometrically well-defined binding cav-
ity of complementary size, shape and functional group
to a guest. In particular, the receptor that contains
multiple binding cavities has attracted much attention
because it provides an opportunity not only to study
allosteric phenomena frequently found in the biological
system, but also to create artificial counterparts capable
of nonlinear amplification of binding affinities, reporting
signals and catalytic activities. A large number of
allosteric models have been developed for the last two
decades,1 but there are a limited number of artificial
receptors that show positive homotropic cooperativity
on the binding event.2
N
NH
O
R
R
R
O
HN
O
L
NH
N
O
R
HN
Ph
Ph
P
OTf
Pd
OTf
N
self-assembly
P
Ph
Ph
O
O
O
O
O
N
N
R
R
NH
HN
NH
HN
R
Ph
P
Ph
Pd
Ph
Ph
P
Ph
R
N
N
L
Pd
L
N
N
P
Ph
R
R
P
Ph
Ph
Utilizing coordination bond-driven self-assembly, we
previously described the preparation of metallocycles 1
from S-shaped bispyridyl ligands and a palladium com-
pound (Scheme 1).3 The metallocycles fold to generate
two binding subcavities, thus binding two molecules of
a diamide guest by hydrogen-bonding interactions in a
positive homotropic cooperative manner.The Hill coeffi-
cients (h), a measure of the cooperativity, depend on the
nature of the linkers (L) in between two cavities, ranging
from 1.4 to 1.8. We extended the self-assembly approach
NH
HN
NH
R
O
HN
R
N
N
O
O
1
Scheme 1. Coordination-driven self-assembly of metallocycles con-
taining two binding subcavities.
to prepare even larger metallocycle containing three
binding subcavities.4
Despite a great advantage in the synthesis, these metal-
locycles are kinetically and thermodynamically labile
owing to the presence of weak covalent bonds, which
*
Corresponding author. Tel.: +82 2 2123 2643; fax: +82 2 364 7050;
e-mail: ksjeong@yonsei.ac.kr
0040-4039/$ - see front matter ꢁ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.04.078

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K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 4141–4144
O
I
N
H
N
O
O
N
I
Cl
Cl
O
NH
2
NH2
b, c
a
NH2
+
H3C
CH3
HN
O
NH
N
NH2
4
I
O
3
5
O
N
H
O
O
O
O
O
O
N
N
N
N
N
NH
NH
HN
HN
NH
NH
HN
HN
O
NH
d
HN
O
NH
O
N
O
O
7
6
Scheme 2. Synthesis of macrocycle 7. Reagents and conditions: (a) i-Pr2NEt, CH2Cl2, 0 ꢀC to room temperature (75%); (b) Pd(PPh3)2Cl2, CuI,
triisopropylsilylethyne, THF, Et3N, 60–65 ꢀC (85%); (c) Bu4NF, THF, 50–60 ꢀC (97%); (d) 5, N,N,N0,N0-tetramethylterephthalamide (10 equiv),
Pd(dba)2, CuI, PPh3, Et3N, toluene/CH3CN, 3 d, room temperature (36%).
leads to many drawbacks in the purification, characteri-
zation, and application. Therefore, we here prepared a
much more stable covalent analogue 7 based on the tem-
plate-directed synthesis. The macrocycle possesses two
topologically discrete subcavities, each of which bears
four hydrogen-bonding donors, amide NHs of pyri-
dine-2,6-dicarboxamide units. The macrocycle strongly
binds two molecules of a guest, N,N,N0,N0-tetra-
methylterephthalamide, in positive cooperative manner
(Hill coefficient h = 1.6) by hydrogen-bonding interac-
tions.
relatively nonpolar medium (1:20, v/v, CH3CN/tolu-
ene),7 the conditions of which possibly optimize the
hydrogen bond-mediated template effect.
The macrocycle 7 was fully characterized by elemental
1
analysis, MALDI-mass, H NMR, and 13C NMR spec-
troscopy.7 As seen in the energy-minimized structure8
(Fig. 1), a monocyclic compound 7 possesses two topo-
logically separated subcavities and its conformation
resembles a figure of eight. Each cavity consists of four
amide NHs, all of which are inward directed as a conse-
quence of intramolecular NHꢁ ꢁ ꢁN (pyridine) hydrogen
bond.9
The synthesis of macrocycle 7 is outlined in Scheme 2.
Compound 5 was prepared in 75% yield by dropwise
addition of diamine 35 and 4-iodo-2,6-dimethylaniline
(4) to a CH2Cl2 solution of pyridine-2,6-dicarbonyl
dichloride (2) under nitrogen. Then, 5 was converted
into compound 6 by palladium/CuI-catalyzed Sono-
gashira coupling6 followed by de-silylation with tetrabut-
ylammonium fluoride. Direct coupling between 5 and 6
was first carried out to synthesize 7 under various Sono-
gashira reaction conditions but yields were very low
(<10%) due to the formation of unidentifiable materials,
possibly polymeric species. The low yield is not so sur-
prising because the reaction requires the formation of
a large, 66-membered macrocycle, via twice Sonogashira
couplings.
The binding property of 7 was investigated at 25 ꢀC with
N,N,N0,N0-tetramethylterephthalamide (G) in the 1H
NMR spectroscopy. When G was gradually added up
to approximately 3 equiv to a CDCl3 solution of 7
(2.00 mM), two NH signals were continuously shifted
Next, we carried out template-directed synthesis using
N,N,N0,N0-tetramethylterephthalamide which was cho-
sen as a template based on our previous studies with
metallocycles 1.3 After several attempts under different
conditions, the desired macrocycle 7 was obtained in a
reasonable yield (36%) when the reaction was performed
with 10 equiv of the template at room temperature in a
Figure 1. A side view of energy-minimized structure (MM3* force
field, MacroModel version 7.1) of macrocycle 7.

K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 4141–4144
4143
Me2N
O
O
The association constants between 7 and G are compa-
rable or higher than those obtained from tetralactam
analogues and diamide guests, the systems of which
were reported to form four hydrogen bonds.3,12 In
addition, when N,N-dimethylbenzamide, was used as a
monoamide guest capable of forming two hydrogen
bonds, the changes in the NH chemical shifts were very
small (<0.2 ppm on the addition of ꢂ4 equiv) compared
to those (1.2–1.4 ppm) induced by G. These observa-
tions are consistent with the formation of four simul-
taneous hydrogen bonds between 7 and G. Finally, the
aromatic signal of G when complexed was considerably
upfield-shifted (Dd = ꢀ0.7 ppm), suggesting that G
inserted into the cavity was surrounded by aryl planes
as shown in Figure 2.
7
+
NMe2
K1
O
O
O
O
N
N
N
NH
HN
NH
NH
HN
HN
O
NMe2
Me2N
NH
O
NH
N
O
O
O
O
O
O
K2
7
O
O
N
O
N
O
In conclusion, a large, 66-membered macrocycle that
can be served as an artificial allosteric model was pre-
pared using the template-directed synthesis. The macro-
cycle possesses two topologically separated binding
cavities and therefore binds two molecules of the guest,
one to each cavity, in positive cooperative manner by
hydrogen-bonding interactions.
NH
HN
NH
HN
NMe2
NMe2
Me2N
NH
Me2N
NH
O
N
O
N
HN
HN
O
O
O
O
Acknowledgments
This work was financially supported by the Ministry of
Commerce, Industry, and Energy, Korea (Project no.
10022947) and the Center for Bioactive Molecular
Hybrids (CBMH).
References and notes
1. For reviews of artificial allosteric systems, see: (a) Rebek,
J., Jr. Acc. Chem. Res. 1984, 17, 258–264; (b) Shinkai, S.;
Ikeda, M.; Sugasaki, A.; Takeuchi, M. Acc. Chem. Res.
2001, 34, 494–503; (c) Takeuchi, M.; Ikeda, M.; Sugasaki,
A.; Shinkai, S. Acc. Chem. Res. 2001, 34, 865–873; (d)
Kovbasyuk, L.; Kra¨mer, R. Chem. Rev. 2004, 104, 3161–
3187; (e) Zhu, L.; Anslyn, E. V.; Zhu, L. Angew. Chem.,
Int. Ed. 2006, 45, 1190–1196.
Figure 2. Proposed structure of the complex (above), experimental (·)
and theoretical (line) titration curves (below), and a Job plot (below,
inset) between 7 and N,N,N0,N0-tetramethylterephthalamide (G).
2. For recent examples, see: (a) Sugasaki, A.; Ikeda, M.;
Takeuchi, M.; Shinkai, S. Angew. Chem., Int. Ed. 2000, 39,
3839–3842; (b) Glass, T. E. J. Am. Chem. Soc. 2000, 122,
4522–4523; (c) Sugasaki, A.; Sugiyasu, K.; Ikeda, M.;
Takeuchi, M.; Shinkai, S. J. Am. Chem. Soc. 2001, 123,
10239–10244; (d) Ayabe, M.; Ikeda, A.; Kubo, Y.;
Takeuchi, M.; Shinkai, S. Angew. Chem., Int. Ed. 2002,
41, 2790–2792; (e) Kawai, H.; Katoono, R.; Nishimura,
K.; Matsuda, S.; Fujiwara, K.; Tsuji, T.; Suzuki, T. J. Am.
Chem. Soc. 2004, 126, 5034–5035.
3. (a) Chang, S.-Y.; Um, M.-C.; Uh, H.; Jang, H.-Y.; Jeong,
K.-S. Chem. Commun. 2003, 2026–2027; (b) Chang, S.-Y.;
Jang, H.-Y.; Jeong, K.-S. Chem. Eur. J. 2004, 10, 4358–
4366.
4. Jang, H.-Y.; Chang, S.-Y.; Chang, K.-J.; Jeong, K.-S.
Tetrahedron Lett. 2005, 46, 2433–2436.
from 8.97 and 9.02 ppm to 10.12 and 10.42 ppm, respec-
tively (Fig. 2). Nonlinear curve fitting analyses of the
titration data using the HOSTEST program10 afforded
the association constants of 1480 90 and 5580
150 Mꢀ1 for K1 (=[7ÆG1]/[7][G]) and K2 (=[7ÆG2]/
[7ÆG1][G]), respectively. The ratio of these constants im-
plies positive homotropic cooperativity, considering the
relationship of K2 = 1/4 K1 for non-cooperative binding.
The titration data were also analyzed by the Hill equa-
tion:11 log(y/(1 ꢀ y)) = hlog[G] + logK, where h and K
are the Hill coefficient and binding constant, respectively,
and y = K/([G]ꢀn + K). The magnitudes of h and log K
were obtained from the slope and the intercept of the lin-
ear plot of log (y/(1 ꢀ y)) versus log [G1]. The Hill coef-
ficient was found to be h = 1.6, which also supports the
positive cooperative binding. In addition, The continu-
ous variation (Job) method11 confirmed 1:2 (7/G) stoichi-
ometry of the complex, showing the maximal complex
formation at 0.33 mol fraction of 7 (Fig. 2).
5. Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5303–5311.
6. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J., Eds.; Wiley: Weinheim
(Germany), 1997; Chapter 5, pp 203–229.
7. To a Schlenk tube were placed 5 (1.68 g, 1.55 mmol), 6
(1.36 g, 1.52 mmol), N,N,N0,N0-tetramethylterephthal-

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K.-J. Chang et al. / Tetrahedron Letters 47 (2006) 4141–4144
76.31; H, 6.13; N, 9.87; MALDI-MS (m/z) [M]+ calcd for
amide (3.49 g, 15.5 mmol), CuI (65.0 mg, 0.078 mmol),
[Pd(dba)2] (76.0 mg, 0.078 mmol), and PPh3 (120 mg,
0.155 mmol). The tube was degassed under vacuum and
refilled with N2, the process of which was repeated three
times. Degassed toluene (200 mL), CH3CN (10 mL),
and triethylamine (10 mL) were added under N2, and
the solution was stirred at room temperature for 3 d. The
reaction mixture was then filtered through Celite, and
the filtrate was concentrated under reduced pressure. The
residue was dissolved in CHCl3 (50 mL) and washed with
saturated NaHCO3 aqueous solution and brine, dried over
anhydrous MgSO4, and concentrated. The residue was
purified by column chromatography (EtOH/acetone/
CHCl3, 1:2:20) to give 7 as a white solid (0.97 g, 36%);
C108H104N12O8: 1696.81. Found: 1096.80.
8. The energy-minimized structure was generated with
MM3* force field implemented in MacroModel 7.1 pro-
gram on a Silicon Graphics Indigo IMPACT workstation
via 1000 separated search steps in Monte Carlo confor-
mational search.
9. (a) Hunter, C. A.; Purvis, D. H. Angew. Chem., Int. Ed.
Engl. 1992, 31, 792–795; (b) Hamuro, Y.; Geib, S. J.;
Hamilton, A. D. J. Am. Chem. Soc. 1997, 119, 10587–
10593; (c) Crisp, G. T.; Jiang, Y.-L. Tetrahedron 1999, 55,
549–560.
10. Wilcox, C. S.; Glagovich, N. M. HOSTEST, v 5.60,
Department of Chemistry, The University of Pittsburgh:
Pittsburgh, PA, 1997. We thank Professor Wilcox for
allowing generously us to use the program.
11. (a) Connors, K. A. Binding Constants; John Wiley & Sons:
New York, 1987; (b) Schneider, H.-J.; Yatsimirsky, A. K.
Principles and Methods in Supramolecular Chemistry; John
Wiley & Sons: New York, 2000.
mp >300 ꢀC; IR (KBr) m 3339 (NH), 1684 (C@O) cmꢀ1
;
1H NMR (500 MHz, CDCl3) d (ppm) 9.02 (s, 4H, NH),
8.97 (s, 4H, NH), 8.55–8.49 (m, 8H, pyridine-H), 8.16 (t,
J = 7.8 Hz, 4H, pyridine-H), 7.36 (s, 8H, Ar-H), 7.06 (s,
8H, Ar-H), 2.26 (s, 48H, CH3), 1.61 (m, 16H, cyclohexyl
CH2), 1.48 (m, 4H, cyclohexyl CH2); 13C NMR (126 MHz,
CDCl3) d (ppm) 161.2, 148.9, 148.5, 148.1, 139.6, 135.4,
134.7, 133.5, 131.5, 130.5, 127.0, 125.8, 125.7, 122.2, 89.2,
45.3, 36.7, 29.7, 26.3, 22.8, 19,0, 18.5. Anal. Calcd for
12. (a) Hunter, C. A.; Sarson, L. D. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2313–2316; (b) Chang, S.-Y.; Kim,
H. S.; Chang, K.-J.; Jeong, K.-S. Org. Lett. 2004, 6,
181–184.
C108H104N12O8: C, 76.39; H, 6.17; N, 9.90. Found: C,