Design, synthesis, and self-assembling properties of novel triazolophanes

Article abstract of DOI:10.1021/ol8003386

A series of novel triazolophanes containing peptidic and nonpeptidic backbones is reported. The crystal structure of one such macrocycle displays self-assembly through nonconventional hydrogen-bonding interactions.

Full text of DOI:10.1021/ol8003386

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1645-1647
Design, Synthesis, and Self-Assembling
Properties of Novel Triazolophanes
V. Haridas,* Kashmiri Lal, Yogesh K. Sharma, and Shailesh Upreti
Department of Chemistry, Indian Institute of Technology, New Delhi, India
haridasV@chemistry.iitd.ac.in
Received February 22, 2008
ABSTRACT
A series of novel triazolophanes containing peptidic and nonpeptidic backbones is reported. The crystal structure of one such macrocycle
displays self-assembly through nonconventional hydrogen-bonding interactions.
The synthesis of macrocyclic compounds has attracted the
interest of the chemical community because of the diverse
utility of these compounds ranging from host-guest chem-
istry,1 supramolecular structures,2 and ionophores3 to medical
applications.4 The design and synthesis of macrocycles with
an appropriate ring size having predictable structure function
coupled with elegant synthesis still remains a challenge.
Pedersen’s classical crown ether synthesis and its ionophoric
applications opened new vistas in supramolecular chemistry;
however, its biological utility was limited because of the
strong binding affinity and slow release rate of crown ethers.5
The design and synthesis of macrocyclic structures and
their assembly are important research topics in contemporary
science.6 Designed macrocyclic peptides can play a signifi-
cant role in biology; as a result of the preorganized structure,
they can interact with large protein surfaces and thus disrupt
protein-protein interactions.7 Many macrocyclic natural
products exhibit biological activities such as immunosup-
pression,8 inhibitions of protein biosynthesis,9 and enzyme
inhibition.10 Macrocyclic heterochiral peptides are known to
self-assemble to form supramolecular transmembrane chan-
nels and thus transport metal ions.11 This class of self-
assembling compounds provides attractive alternatives to
existing antibiotics, as is evident from the action of these
compounds against methicillin-resistant Staphylococcus
aureus infections.12 Macrocyclic peptides with â-hairpin
architecture were shown to mimic the p53 helix region and
were used as p53-MDM2 inhibitors.13 The Chundle approach
to transmembrane channels is based on grafting several
chains onto a polyfunctional macrocycle to improve the ion-
transport profile.14 In this paper, we report the synthesis of
a series of macrocyclic compounds, namely triazolophanes,
utilizing 1,3-dipolar cycloaddition reactions, and also report
(8) Mann, J. Nat. Prod. Rep. 2001, 18, 417.
(9) Beidler, D. R.; Ahuja, D.; Wicha, M. S.; Toogood, P. L. Biochem.
Pharmacol. 1999, 58, 1067.
(10) Rao, F. V.; Houston, D. R.; Boot, R. G.; Aerts, J. M. F. G.;
Hodkinson, M.; Adams, D. J.; Shiomi, K.; Omura, S.; van Aalten, D. M.
F. Chem. Biol. 2005, 12, 65.
(11) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324.
(1) (a) Gatto, V. J.; Gokel, G. W. J. Am. Chem. Soc. 1984, 106, 8240.
(b) Gokel, G. W.; Arnold, K. A.; Delgado, M.; Echeverria, L.; Gatto, V. J.;
Gustowski, D. A.; Hernandez, J.; Kaifer, A.; Miller, S. R; Echegoyen, L.
Pure Appl. Chem. 1988, 60, 461.
(2) (a) Amabilino, D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725. (b)
Yang, W. Y.; Ahn, J. H.; Yoo, Y. S.; Oh, N. K.; Lee, M. Nature Mater.
2005, 4, 399.
(3) (a) Dobler, M. Ionophores and their structures; Wiley: New York,
1981. (b) Gokel, G. W. Chem. Soc. ReV. 1992, 21, 39. (c) Marrone, T. J.;
Merz, Jr., K. M. J. Am. Chem. Soc. 1995, 117, 779.
(12) Fernandez-Lopez, S.; Kim, H. S.; Choi, E. C.; Delgado, M.; Granja,
J. R.; Khasanov, A.; Kraehenbuehl, K.; Long, G.; Weinberger, D. A.;
Wilcoxen, K. M.; Ghadiri, M. R. Nature 2001, 412, 452.
(13) Fasan, R.; Dias, R. L. A.; Moehle, K.; Zerbe, O.; Vrijbloed, J. W.;
Obrecht, D.; Robinson, J. A. Angew. Chem., Int. Ed. 2004, 43, 2109.
(14) (a) Jullien, L.; Lehn, J. M. Tetrahedron Lett. 1988, 29, 3803. (b)
Alpha, B.; Balzani, V.; Lehn, J. M.; Perathoner, S.; Sabbatini, N. Angew.
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10.1021/ol8003386 CCC: $40.75
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Published on Web 03/22/2008

the self-assembly of one such macrocyclic compound devoid
of any conventional hydrogen-bond donor sites. This 1,3-
dipolar cycloaddition reaction, commonly called a click
reaction, involves an azide and an alkyne moiety.15 This
reaction has been successfully employed for the synthesis
of designer cyclopeptides with tubular architecture,16 den-
drimer synthesis,17 and â-turn peptidomimetics.18 The click
reaction has also been employed as a chemical tool to
understand biological processes.19 We envisioned that this
reaction would be an effective synthetic methodology to
generate macrocyclic compounds with peptidic and nonpep-
tidic backbones having the propensity for self-assembly.
Isophthaloyl chloride on reaction with propargyl alcohol
in the presence of 4-dimethylaminopyridine (DMAP) pro-
duced dialkyne 1, which on Cu(I)-mediated reaction with
p-xylyldiazide 2 in the presence of diisopropylethylamine
(DIEA) provided the ester-linked 21-membered triazolophane
3 in ∼30% yield (Scheme 1). The versatility of the synthesis
the 20-membered macrocycle 5 in ∼71% yield. The cystine-
derived diazide 6, synthesized from cystine methyl ester and
azidoacetyl chloride,20 was reacted with dialkyne 1 to produce
the 27-membered macrocycle 7 in ∼69% yield. To demon-
strate the flexibility of the synthesis, we employed various
dialkynes instead of diazides. The chiral amino acids with
side-chain carboxylate functionality are ideal candidates for
generating dialkynes. Asp and Glu with â- and γ-carboxyl-
ates were therefore chosen for this purpose. Boc-aspartic and
Boc-glutamic acids on reaction with propargyl alcohol
furnished dialkynes 8 and 9 in 80% and 84% yield,
respectively (Scheme 2). These on reaction with p-xylyl-
Scheme 2. Synthesis of Triazolophanes 10 and 11
Scheme 1. Synthesis of Triazolophanes 3, 5, and 7
diazide 2 in the presence of Cu(I) afforded the 20- and 21-
membered chiral macrocyclic triazolophanes 10 and 11 in
65 and 68% yields, respectively.
The ester-linked triazolophane 3 is devoid of any con-
ventional H-bonding donor sites and is an ideal candidate
for studying nonconventional noncovalent interactions. There-
fore, we envisaged that the CH close to the electronegative
nitrogen atom can form nonconventional hydrogen-bonding
interactions and can organize in the solid state. Our initial
efforts to crystallize this compound from various solvents
such as chloroform, methanol or ethyl acetate failed to
produce good quality crystals. Crystallization of macrocycle
3 from 1:1 (v/v) chloroform and acetonitrile afforded single
crystals ideal for X-ray crystallographic analysis.
was demonstrated by reacting 1 with various diazides.
Dialkyne 1 was reacted with 1,3-xylyldiazide 4 to produce
(15) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
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2005, 7, 4503. (b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2003, 125, 9372.
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Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2004, 43, 3928.
(18) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595.
(19) Chin, J. W.; Santoro, S. W.; Martin, A. B.; King, D. S.; Wang, L.;
Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 9026. (b) Link, A. J.; Vink,
M. K. S.; Tirrell, D. A. J. Am. Chem. Soc. 2004, 126, 10598. (c) Manetsch,
R.; Krasinski, A.; Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B; Kolb,
H. C. J. Am. Chem. Soc. 2004, 126, 12809. (d) Lewis, W. J.; Green, L. G.;
Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 1053.
The X-ray crystal structure of 3 is consistent with the NMR
and mass spectral analysis. The X-ray crystal structure of 3
demonstrates a unique type of organization as a result of
nonclassical hydrogen-bonding interactions.21 The only hy-
(20) Haridas, V.; Lal, K.; Sharma, Y. K. Tetrahedron Lett. 2007, 48,
4719.
(21) (a) Sutor, D. J. Nature 1962, 195, 68. (b) Taylor, R.; Kennard, O.
J. Am. Chem. Soc. 1982, 104, 5063. (c) Desiraju, G. R. Acc. Chem. Res.
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2000, 24, 463.
1646
Org. Lett., Vol. 10, No. 8, 2008

drogen bond donor available is the CH of the triazole ring.
Interestingly, the crystal structure displayed a unique type
of organization mediated by solvent molecules with CH‚‚‚π
and CH‚‚‚N interactions. The two phenyl groups in 3 are
orthogonal to each other, providing a rigid cavity. The six
nitrogens, three from each triazole unit, point away from the
cavity. The cavity size is 6.792(3) Å from triazole C19 to
triazole C17 and 7.105(4) Å from phenyl C12 to the center
of the phenyl unit (cent(C1-C6)). The macrocycle 3 acts as
a receptor for an acetonitrile molecule (Figure 1), where the
Figure 2. Self-assembly of macrocycle 3 mediated by solvent
molecules.
In conclusion, we have shown that the click reaction can
be employed to synthesize simple triazolophanes having
peptidic and nonpeptidic backbone with propensity for self-
assembly by nonclassical noncovalent interactions. The X-ray
crystal structure of 3 provided evidence for assembly through
complete nonconventional noncovalent interactions. These
self-assembling macrocycles may find use as ionophores or
as receptors for neutral organic molecules. The three nitrogen
atoms on each triazole ring can be exploited for metal-ion
binding and we are presently investigating the ionophoric
applications and the metal-directed self-assembly of these
macrocyclic compounds.
Figure 1. X-ray structure of macrocycle (3) with bound acetonitrile
molecule.
acetonitrile is bound to the macrocycle by two CH‚‚‚N
hydrogen-bonding and one CH‚‚‚π interactions. The nitrogen
atom of the acetonitrile is further linked to the second
macrocyclic molecule (triazole CH) to generate a ribbon
assembly of cyclic triazolophanes. The CH of the second
triazole ring is hydrogen bonded to a second acetonitrile
molecule via a CH‚‚‚N interaction (Figure 2). The macro-
cycles are slightly out of alignment. The molecules of 3 are
arranged in an interdigitated fashion with the methyl group
of the second acetonitrile occupying the hydrophobic region.
This array of molecules is further connected to another array
by a CH‚‚‚π interaction involving the CH2 of the xylyl unit
and the aromatic ring of the xylyl unit.
Acknowledgment. Support for this work by the Depart-
ment of Science and Technology (DST, New Delhi) is
gratefully acknowledged. Support from DST for the single-
crystal X-ray facility at IITD is acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds (1-5 and
7-11), and CIF file. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL8003386
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