Aromatic oligoureas: Enforced folding and assisted cyclization

Article abstract of DOI:10.1021/ol0526322

Aromatic oligoureas are forced into well-defined conformation by incorporated intramolecular hydrogen bonds. Shape-persistent tetraureas macrocycles were obtained in a one-step [2 + 2] reaction in good yields.

Full text of DOI:10.1021/ol0526322

ORGANIC
LETTERS
2006
Vol. 8, No. 5
803-806
Aromatic Oligoureas: Enforced Folding
and Assisted Cyclization
Aimin Zhang,† Yaohua Han,† Kazuhiro Yamato,† Xiao Cheng Zeng,‡ and
Bing Gong*,†
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260, and Department of Chemistry,
UniVersity of Nebraska-Lincoln, Lincoln, Nebraska 68588
bgong@chem.buffalo.edu
Received October 29, 2005
ABSTRACT
Aromatic oligoureas are forced into well-defined conformation by incorporated intramolecular hydrogen bonds. Shape-persistent tetraureas
macrocycles were obtained in a one-step [2 2] reaction in good yields.
+
In recent years the design of folded unnatural oligomers has
attracted intense interest.1-4 We5 and others4-9 have described
aromatic oligoamides that are forced into folded conforma-
tions by rigidifying the oligoamide backbones using localized
intramolecular hydrogen bonds. Similar to the amide group,
the urea group is also distinguished by its rigidity, planarity,
and hydrogen bonding capability. Indeed, the urea function-
ality has already been adopted in the design of various folded
structures. For example, peptidomimetic oligoureas were
reported to fold into helical conformations,10 and aromatic
oligoureas were designed to adopt switchable conformations11
or to cyclize into rigid macrocycles.12 Backbone-rigidified
aromatic polyureas were found to fold into a helical
conformation according to circular dichroism spectroscopy.13
Herein, we describe the design, enforced folding, and
cyclization of backbone-rigidified aromatic oligoureas con-
sisting of meta-linked benzene rings.14
† The State University of New York.
‡ University of Nebraska-Lincoln.
(1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(2) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893.
Our design is based on diarylurea moiety 1, which is
rigidified by two very strong, intramolecularly H-bonded six-
membered rings involving the urea hydrogens and the
(3) Huc, I. Eur. J. Org. Chem. 2004, 17.
(4) Sanford, A. R.; Yamato, K.; Yuan, L.; Han, Y.; Gong, B. Eur. J.
Biochem. 2004, 271, 1416.
(5) (a) Gong, B.Chem. Eur. J. 2001, 7, 4336. (b) Zhu, J.; Parra, R. D.;
Zeng, H.; Skrzypczak-Jankun, E.; Zeng, X. C.; Gong, B. J. Am. Chem.
Soc. 2000, 122, 4219.
(6) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996,
118, 7529.
(7) Huc, I.; Khoury, R. G.; Krische, M. J.; Lehn, J.-M. Nature 2000,
407, 720.
(8) Jiang, H.; Le´ger, J.-M.; Dolain, C.; Guionneau, P.; Huc, I. Tetrahedron
2003, 59, 8365.
(10) Boeijen, A.; Liskamp, R. M. J. Eur. J. Org. Chem. 1999, 2127.
(11) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk, N.
A.; Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475.
(12) Xing, L. Y.; Ziener, U.; Sutherland,T. C.; Cuccia, L. A. Chem.
Commun. 2005, Advance article. Published on the web 10/20/2005.
(13) van Gorp, J. J.; Vekemans, J. A. J. M.; Meijer, E. W. Chem.
Commun. 2004, 60.
(14) Yuan, L. H.; Zeng, H. Q.; Yamato, K.; Sanford, A. R.; Feng, W.;
Atreya, H. S.; Sukumaran, D. K.; Szyperski, T.; Gong, B. J. Am. Chem.
Soc. 2004, 126, 16528.
(9) Yi, H. P.; Shao, X. B.; Hou, J. L.; Li, C.; Jiang, X. K.; Li, Z. T. New
J. Chem. 2005, 29, 1213.
10.1021/ol0526322 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/07/2006

carbonyl oxygens of the flanking ester groups. Results from
ab initio calculations15 indicate that the trans-trans confor-
mation, as represented by 1a, is energetically favored over
the alternative conformation 1b. Depending on their lengths,
oligomers consisting of 1 with urea linkages being placed
at meta positions should fold into crescent or helical
conformations. In such a design, the ester side groups can
be easily adjusted, leading to folding oligomers with tunable
solubilities and other properties. To probe the folding of such
aromatic oligoureas, we prepared and characterized trimer
9a.
The synthesis of 9a is shown in Scheme 1. Compound 3
was prepared by nitrating the commercially available 4-nitro-
Scheme 1
Figure 1. 2D ROESY spectrum of trimer 9a in CDCl3 (500 MHz,
10 mM, 298 K, mixing time 0.3 s).
m-xylene using 70% nitric acid and concentrated sulfuric
acid, followed by oxidation of 2 into 3 using CrO3 in
concentrated H2SO4. Esterification of diacid 3 via its acid
chloride led to esters 4a and 4b, which were then reduced
into diamino esters 5a and 5b, respectively, by hydrogena-
tion. Treating 5a or 5b with trifluoroacetic anhydride led to
6a or 6b with one protected amino group. Compound 6a or
(15) See Supporting Information for details.
804
Org. Lett., Vol. 8, No. 5, 2006

Scheme 2
6b was converted into the corresponding isocyanate, which
upon reacting with 5a or 5b resulted in dimer 7a or 7b.
Treating 7a with the commercially available methyl 2-cy-
anobenzoate (8), followed by removing the TFA group, led
to the unsymmetrical trimer 9a. The relatively low yields of
7a,b and 9a were probably due to the highly deactivated
nature of the corresponding precursor amines or the presence
of the oxygen atom of the trifluoroacetyl group, which
introduced repulsive interaction during the urea forming
process.
Figure 2. MALDI-TOF spectra of the mixtures of (a) 12a, (b)
12b, and (c) 13a with LiBPh4 (1 equiv), NaBPh4 (1 equiv), and
KBPh4 (1 equiv).
demonstrated a crescent conformation of 9a, which is
expected from backbone rigidification.
Such a curved conformation suggests that, with a sufficient
length, an oligomer should curve into a full turn, leading to
either a “broken ring” or a helix.5 Indeed, molecular
mechanics calculation (MM2)16 indicates that, for this series
of aromatic oligoureas, it takes four residues to complete a
full turn, in which the two ends of the tetramer are placed
into close proximity. It is expected that such a curved
conformation of a tetramer should facilitate its cyclization
into the corresponding macrocycle. To verify this expecta-
tion, dimers 10a and 10b, which were obtained by hydrolyz-
ing 7a and 7b, respectively, were directly heated with
The conformation of trimer 9a was investigated using 2D
NMR (ROESY). The partial ROESY spectra are shown in
Figure 1. Strong ROEs were detected between protons a and
b, and c and d, of the urea groups (Figure 1a) ROEs between
the urea protons and protons e, f, g, and h of the side chains
were also detected (Figure 1b). The existence of these ROEs
is consistent with the persistence of the intramolecularly
H-bonded six-membered rings and the trans-trans conforma-
tion adopted by the urea groups, which implies a crescent
conformation for 9a. Such a crescent conformation of 9a is
convincingly supported by the remote ROEs between protons
i and j, and j and k (Figure 1c). These results clearly
(16) Molecular mechanics (MM2) calculation was performed using the
CAChe (version 3.2) software.
Org. Lett., Vol. 8, No. 5, 2006
805

triphosgene in toluene in the presence of DMAP (Scheme
2a), which should first lead to the formation of the corre-
sponding uncyclized tetramer diamine intermediate 11a or
11b. The preorganized conformation of these intermediates
should facilitate their cyclization, leading to the correspond-
ing macrocyclic oligomers. Indeed, MALDI-TOF indicated
that cyclic tetraureas 12a and 12b were formed as the major
products from the one-pot, four-component synthesis and
were isolated in good yields (65% and 68%, respectively).
The efficient macrocyclization is very likely due to backbone
preorganization of the noncyclic oligomer precursors, which
result from the combination of the rigid benzene rings and
the urea groups, and the intramolecular hydrogen bonds that
limit the overall conformational freedom of the uncyclized
precursors.
Molecular modeling shows that both macrocycles 12a and
12b contain a small cavity ∼5 Å across as measured by the
distance between nonadjacent urea oxygens. Such a cavity,
with its four inward-pointing urea oxygen atoms, may act
as the site for binding metal ions. To probe whether these
cyclic oligoureas can bind metal ions, 12a (or 12b) was
mixed with 1 equiv each of lithium, sodium, and potassium
tetraphenylborate in methanol for 1 h. The mixture was then
examined using MALDI-TOF. As shown in Figure 2a and
b, both 12a and 12b selectively bind the potassium ion in
the presence of the other two metal ions. In each spectrum,
the 1:1 complex of 12a or 12b with the potassium ion appears
as the predominant species. Only a very small peak corre-
sponding to the complex with the sodium ion was observed
in either case. No complex with the lithium ion was observed.
For comparison, the noncyclic tetramer 13a was prepared
by treating 10a with the commercially available 8 (Scheme
2b). MALDI-TOF showed that the noncyclic tetramer 13a
only had a slight preference toward the potassium ion. As
shown in Figure 2c, examining the mixture containing 13a
and one equivalent of each of LiBPh4, NaBPh4, and KBPh4
(mixed in methanol for 1 h) using MALDI-TOF revealed
the existence of the 1:1 complexes of both sodium and
potassium ions with 13a in similar abundance. Similar to
12a and 12b, no complex between 13a and the lithium ion
was detected. The reason for the poor selectivity of 13a
toward sodium and potassium ions may be due to its
insufficient number (three vs four of 12a or 12b) of oxygen
atoms or its noncyclic backbone that is conformationally
more flexible than those of macrocycles 12a and 12b.
Nevertheless, these results clearly demonstrated the high
selectivity of macrocycles 12a and 12b toward the potassium
ion.
In summary, we have demonstrated the feasibility of
limiting the conformational freedom of aromatic oligoureas
by introducing intramolecular H-bonds. The folding of
aromatic oligoureas has been enforced by backbone rigidi-
fication. The intramolecularly hydrogen-bonded groups,
combined with meta-linked benzene rings, lead to crescent-
shaped oligomers. The design principle was confirmed by
characterizing a trimer using ROESY studies, which revealed
ROEs that are fully consistent with the expected conforma-
tion. The preorganization of backbones facilitated the ef-
ficient preparation of macrocyclic tetraureas. These shape-
persistent macrocyclic tetramers contain a well-defined,
hydrophilic cavity. Preliminary MALDI studies demonstrated
the highly selective complexation of potassium ion by these
macrocyclic tetraureas. These macrocyclic oligoureas, with
their large, flat aromatic surfaces, well-defined cavities, and
easily adjustable ester side chains, should find applications
in designing intercalators, hosts for metal ions, and building
blocks for constructing large structures.
Acknowledgment. We thank the NSF (CHE-0314577)
and ONR (N00014-02-1-0519) for financial support.
Supporting Information Available: Experimental pro-
cedures, analytical data, computational method, and molec-
ular models. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0526322
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Org. Lett., Vol. 8, No. 5, 2006