Differential and Substrate-Selective Reactivity of Calix[4]arene Derivatives with Cyclenyl-Zn(II) Modifications at the Upper Rim

Article abstract of DOI:10.1021/ol0360694

(Matrix presented) Novel "cone conformation" calix[4]arene derivatives, carrying either one or two cyclen (1,4,7,10-tetra-azacyclododecane) moieties at the upper rim, have been synthesized. The hydrolytic activities of the Zn(II) complexes of these calixa

Full text of DOI:10.1021/ol0360694

ORGANIC
LETTERS
2004
Vol. 6, No. 2
241-243
Differential and Substrate-Selective
Reactivity of Calix[4]arene Derivatives
with Cyclenyl-Zn(II) Modifications at the
Upper Rim
Gulsum Ozturk and Engin U. Akkaya*
Department of Chemistry, Middle East Technical UniVersity, Ankara TR-06531, Turkey
akkayaeu@metu.edu.tr
Received October 23, 2003
ABSTRACT
Novel “cone conformation” calix[4]arene derivatives, carrying either one or two cyclen (1,4,7,10-tetra-azacyclododecane) moieties at the upper
rim, have been synthesized. The hydrolytic activities of the Zn(II) complexes of these calixarenes were studied. A surprising behavior was
observed with p-nitrophenylstearate; whereas the bis-cyclenyl-2Zn(II) complex showed negligible hydrolytic activity over the background, the
mononuclear complex showed a significant 400-fold rate increase at pH 8.5.
Although producing a functional model (mimic) for most of
the enzymes remains extremely challenging, the active site
of a metalloenzyme features a catalytically active metal
center, the activity of which can be replicated in much
simpler abiotic systems. In fact, even simple hydrated metal
ions, if made persistent in aqueous solutions, can be
reasonably active toward many substrates.1 Thus, the reduc-
tionist approach where the enzyme is essentially treated as
a “receptor” with a nearby reactive functional groups is more
likely to succeed with the metalloenzymes. Hydrolytic
metalloenzymes have been mimicked in a number of
supramolecular systems. Most of the earlier work in enzyme
mimics utilized cyclodextrins as the selective binding unit.
Cyclodextrins have moderate affinities for aromatic substrates
in aqueous solutions, and thus appropriate derivatives lead
to satisfactory enzymes models.2 Calixarenes and especially
calix[4]arene have attracted attention, as the regioselective
modification of calixarenes3 is more straightforward and the
conformational flexibility can be adjusted as desired with a
unique potential for allosteric modulation. There are recent
examples4 of calixarene-based metalloenzyme mimics that
hydrolyze activated phosphate substrates in mixed aqueous
solvents.
As active metal center, one is not limited to nature’s
choices. High charge-to-size ratio cations such as Co(III),5
(2) Recent reviews: (a) Breslow, R.; Dong, S. D. Chem. ReV. 1997, 98,
1997-2011. (b) D’Souza, V. T. Supramol. Chem. 2003, 15, 221-229.
(3) (a) Gutsche, C. D. In Calixarenes ReVisited; Stoddart, J. F. Ed.; The
Royal Society of Chemistry: Cambridge, 1998. (b) Calixarenes 2001;
Asfari, Z., Bohmer, V., Harrowfield, J. M., Vicens, J., Eds.; Kluwer
Academic Publishers: Dordrecht, 2001.
(1) (a) Moss, R. A.; Raganuthan, K. G. Chem. Commun. 1998, 1871-
1872. (b) Komiyama, M. Met. Ions Biol. Syst. 2001, 38, 25-41. (c) Moss,
R. A.; Gong, P. K.; Morales-Rojas, H. Org. Lett. 2002, 4, 1835-1838. (d)
Tsang, J. S. W.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc. 2003,
125, 1559-1566.
10.1021/ol0360694 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/18/2003

Scheme 1. Synthesis of Monocyclen Derivative of
Scheme 2. Synthesis of Dicyclen Derivativea
Calix[4]arenea
a Reagents and conditions: (a) CH3OCHCl2, SnCl4, CHCl3, -10
°C, 1 h (50%); (b) NaBH4, EtOH, rt, 3 h (72%); (c) SOCl2, CH2Cl2,
rt, 24 h (78%); (d) tri-t-Boc-cyclen, toluene, DIEA, ∆, 48 h (40%);
(e) TFA/CH2Cl2, rt, 1 h (67%).
a Reagents and conditions: (a) tri-t-Boc-cyclen, toluene, DIEA,
∆, 48 h (22%); (b) TFA/CH2Cl2, rt, 1 h (49%).
Ce(IV),6 and Zr(IV)7 have been demonstrated to have
remarkable hydrolytic efficiencies. However, neutral pH
instability and product inhibition seem to be major problems
in these cases, if true enzymelike catalytic behavior is sought.
Thus, our choice has been substitution-labile Zn(II) cation
as the metal center with its flexible coordination geometry.
The ligand we have focused on is 1,4,7,10-tetra-azacy-
clododecane (cyclen). Earlier work established its utility as
a strong chelator of Zn(II), with the fifth coordination
position almost invariably being water in aqueous solutions.8
Moreover, the Zn(II)-cyclen motif has been utilized suc-
cessfully in a number of model systems.9 Thus, we set out
to synthesize zinc(II) complexes of calixarene derivatives 6
and 9 in order to test cooperative action of two Zn(II) centers.
The synthesis of the target molecules are shown in Schemes
1 and 2.
same procedure. Tris-(t-boc)-protected cyclen11 was then
reacted with the chloromethyl compounds in NMP, and the
products were purified by silica gel column chromatography.
In the final steps of both syntheses, protecting groups were
removed by DCM/TFA treatment at room temperature. Both
compounds were isolated and characterized in analytically
pure forms (see Supporting Information).
The cone conformation of calixarenes was ensured by
ethoxyethyl substitution at the lower rim at an earlier stage
in the synthesis, and that conformation is carried to the final
product. The metal complexes of the ligands were prepared
in situ by mixing with Zn(II) in the form of the perchlorate.
Hydrolysis reactions were carried out in a solvent system
comprising buffer-DMSO mixtures. A series of reactions at
different pH values (buffer component) with different
substrates (Figure 1) were carried out. The pH range of 7.0-
Calix[4]arene 7 was synthesized as described by Arduini10
et al. Compound 4 was also synthesized in analogy to the
(4) (a) Cacciapaglia, R.; Casnati, A.; Mandolini, L.; Ungaro, R. J. Am.
Chem. Soc. 1992, 114, 10956-10958. (b) Molenveld, P.; Engbersen, J. F.
J.; Kooijman, H.; Spek, A. L.; Reinhoudt, D. N. J. Am. Chem. Soc. 1998,
120, 6726-6737. (c) Molenveld, P.; Stikvoort, W. M. G.; Kooijman, H.;
Spek, A. L.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org. Chem. 1999, 64,
3896-3906. (d) Molenveld, P.; Engbersen, J. F. J.; Reinhoudt, D. N. J.
Org. Chem. 1999, 64, 6337-6341. (e) Molenveld, P.; Engbersen, J. F. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. 1999, 38, 3189-3192.
(5) (a) Akkaya, E. U.; Czarnik, A. W. J. Am. Chem. Soc. 1988, 110,
8553-8554. (b) Chung, Y. S.; Akkaya, E. U.; Venkatachalam, T. K.;
Czarnik, A. W. Tetrahedron Lett. 1990, 31, 5413-5416.
(6) Bracken, K.; Moss, R. A.; Ragunathan, K. G. J. Am. Chem. Soc.
1997, 119, 9323-9324.
(7) Moss, R. A.; Zhang, J.; Ragunathan, K. G. Tetrahedron Lett. 1998,
39, 1529-1532.
(8) Aoki, S.; Zulkefeli, M.; Shiro, M.; Kimura, E. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 4894-4899.
Figure 1. Activated ester substrates used this work.
(9) (a) Rosenthal, M. I.; Czarnik, A. W. J. Inclusion Phenom. 1991, 10,
119-126. (b) Kim, D. H.; Lee, S. S. Bioorg. Med. Chem. 2000, 8, 647-
652. (c) Kaminskaia, N. V.; Spingler, B.; Lippard, J. J. Am. Chem. Soc.
2000, 122, 6411-6422.
8.5 studied; at higher pH values some precipitation of zinc-
(II) was apparent. Modest rate accelerations were obtained
242
Org. Lett., Vol. 6, No. 2, 2004

productive binding. It appears that cyclen, especially the
cyclenyl-Zinc(II) complex, is a nonflexible bulky substituent.
It seems to block the entry of the aromatic groups into the
calixarene cavity. This steric blocking is more effective in
the zinc complex of the binucleating ligand 9. This explains
the low rate acceleration factors observed for the two
substrates, 10 and 11. A similar situation takes place with
stearate and 9-2Zn2+. In these reactions, catalysis is likely
to take place without substrate insertion into the calixarene
cavity, at the periphery near the lower rim. However, only
in the mononucleating ligand-Zn2+ complex can the long
alkyl chain of 12 squeeze into the calixarene cavity to form
a productive complex. Michaelis-Menten analysis of the
pseudo-first-order hydrolysis data yields a Km value of 0.028
mM for this substrate. This value is in the expected range
for strong calixarene-binding substrates in similar solvent
systems.4b The difference in binding affinities is reflected
in the pseudo-first-order rate constants. Our results, while
demonstrating the limits of calixarene functionalization for
effective catalysis, also illustrate the versatility of the
calixarene framework for catalyzing the reactions of structur-
ally diverse substrates.
Table 1. Rate Accelerations (kcat/kuncat) Obtained Using
Different Substrates at pH 8.5 under Pseudo-First-Order
Conditionsa
catalyst
p-NPA (10)
bis-p-NPC (11)
p-NPS (12)
6-Zn2+
9-2Zn2+
8.0
2.5
9.1
9.6
400
3.8
a The rates of the reactions were determined spectrophotometrically, by
following the change in absorbance at 400 nm (p-nitrophenolate ion). The
hydrolysis reactions for substrates 10 and 11 were carried out at 25 °C in
a solvent mixture of 50% buffer/50% DMSO. The mixed solvent system
contained 0.48 mM catalyst, 38 mM TRIS buffer, 38 µM substrate, and
0.48 mM Zn2+ for reactions catalyzed by 6 or 0.96 mM Zn2+ for reactions
catalyzed by 9. The rate constants for the uncatalyzed reactions (kuncat) were
determined in buffer/DMSO solutions of the substrates and are as follows:
p-NPA (10), 1.0 × 10-5 s-1; bis-p-NPC (11), 1.2 × 10-3 s-1; p-NPS (12),
8.0 × 10-6 s-1
.
with bis-p-nitrophenyl carbonate and p-nitrophenylacetate as
substrates and with no significant difference among the
binuclear and mononuclear complexes (Table 1). With
p-nitrophenylstearate, the binuclear complex did not show
any better performance, but the mononuclear complex at pH
8.5 resulted in a 400-fold rate increase over that of the
uncatalyzed reaction at the same pH.
Although the results seem to be surprising and counter-
intuitive (negative-cooperativity between the metal centers?)
at first, they can be better interpreted when one focuses on
one of the fundamental requirements for efficient catalysis:
Acknowledgment. We thank METU-BAP and Turkish
Academy of Sciences (TUBA) for grants supporting this
research.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 2-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Arduini, A.; Fanni, S.; Manfredi, G.; Pochini, A.; Ungaro, R.; Sicuri,
A. R.; Ugozzoli, F. J. Org. Chem. 1995, 60, 1448-1453.
(11) Kimura, E.; Aoki, S.; Koike, T.; Shiro, M. J. Am. Chem. Soc. 1997,
119, 3068-3076.
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