C O M M U N I C A T I O N S
macrocycles cyclo(AdcKYAdcKAAdcKTAdcKV) (1c) and cyclo(Ad-
cKYAdcKTAdcKVAdcKA) (1d). These compounds present four dif-
ferent amino acids (Val, Ala, Thr, Tyr), tethered to the aminopro-
poxy side chains of the AdcK units, in different order. These isomers
illustrate the ability of the macrocyclic ι-peptides to achieve
sequence and diversity: If one were to try to prepare a cyclic
tetramer by one-pot cyclooligomerization of four different monomer
units, a mixture of up to 64 different cyclotetramers would form.
Titration experiments show significant differences between the
strength, stoichiometry, and mode of binding of cholate by
macrocycles 1c and 1b (Supporting Information). These differences
illustrate that varying the Adc substituents can modify the binding
properties of the receptor.
We envision that this new class of macrocyclic receptors based
on ι-peptides may prove especially valuable in applications in which
sequence and diversity are important. Current successes in the
application of other macrocycles as ligands for protein surfaces,
for example, have suffered the limitation that it is generally only
practical to prepare most macrocycles with one or two types of
substituents, rather than several in sequence.1b,d,e,f,h,6,7 The unique
combination of size and sequence of the macrocyclic Adc tetramers
illustrates one advantage of these ι-peptides and opens the door to
a variety of other applications.
Figure 1. 1H NMR titration (a) and Job plot (b) experiments illustrating
the binding of cyclo(AdcK)4 to sodium cholate. In these experiments, D2O
solutions of cyclo(AdcK)4 were added to a solution of sodium cholate and
the chemical shift of the cholate C18 methyl group was monitored.
1H NMR mixing studies demonstrate that cyclo(AdcK)4 forms a
1:1 complex with sodium cholate in aqueous (D2O) solution and
that complexation shifts the equilibrium toward the “square”
conformer. Substantial upfield shifting of the C18 and C19 methyl
resonances of sodium cholate occurs upon complexation, indicating
close interaction between these cholate methyl protons and the
aromatic rings of 1b. An 1H NMR titration experiment shows that
sodium cholate binds to cyclo(AdcK)4 with an association constant
of ca. 10 000 M-1 (Figure 1a). Fitting a 1:1 binding isotherm to
the NMR titration data indicates limiting chemical shifts of -0.355
ppm and -0.044 ppm, respectively, for the C18 and C19 methyl
groups of the bound cholate. Consistent with the titration experi-
ment, an 1H NMR Job plot experiment shows 1:1 complexation of
sodium cholate at tenth-millimolar concentrations (Figure 1b).
Titration and Job plot experiments of cyclo(AdcK)4 with the
zwitterionic cholate derivative CHAPS reveal much weaker 1:1
complexation, with an association constant of ca. 500 M-1. The
relative weakness of this complexation likely results from the ab-
sence of charge complementarity between cyclo(AdcK)4 and CHAPS.
Acknowledgment. We thank Professor Samuel H. Gellman for
valuable suggestions and the following for financial support: the
American Chemical Society Petroleum Research Foundation (Grant
38986-AC1), the UCI Institute for Genomics and Bioinformatics,
and the Pakistan Higher Education Commission.
Supporting Information Available: Synthetic procedures, NMR
spectroscopic data, and other experimental details. This material is
References
(1) (a) Breslow, R.; Doherty, J. B.; Guillot, G.; Lipsey, C. J. Am. Chem. Soc.
1978, 100, 3227-3229. (b) Hamuro, Y.; Calama, M. C.; Park, H. S.;
Hamilton, A. D. Angew. Chem., Int. Ed. 1997, 36, 2680-2683. (c) van
Wageningen, A. M. A.; Liskamp, R. M. J. Tetrahedron Lett. 1999, 40,
9347-9351. (d) Jain, R. K.; Hamilton, A. D. Org. Lett. 2000, 2, 1721-
1723. (e) Fazal, M. A.; Roy, B. C.; Sun, S.; Mallik, S.; Rodgers, K. R. J.
Am. Chem. Soc. 2001, 123, 6283-6290. (f) Lin, Q.; Hamilton, A. D. C.
R. Acad Sci., Ser. IIc: Chim. 2002, 5, 441-450. (g) Berghaus, C.; Feigel,
M. Eur. J. Org. Chem. 2003, 16, 3200-3208. (h) Wilson, A. J.; Groves,
K.; Jain, R. K.; Park, H. S.; Hamilton, A. D. J. Am. Chem. Soc. 2003,
125, 4420-4421. (i) Hioki, H.; Ohnishi, Y.; Kubo, M.; Nashimoto, E.;
Kinoshita, Y.; Samejima, M.; Kodama, M. Tetrahedron Lett. 2004, 45,
561-564. (j) Mecca, T.; Consoli, G. M. L.; Geraci, C.; Cunsolo, F. Bioorg.
Med. Chem. 2004, 12, 5057-5062.
(2) (a) Cram, D. J.; Katz, H. E. J. Am. Chem. Soc. 1983, 105, 135-137. (b)
Rasmussen, P. H.; Rebek, J., Jr. Tetrahedron Lett. 1999, 40, 3511-3514.
(c) Chamorro, C.; Hofman, J.-W.; Liskamp, R. M. J. Tetrahedron 2004,
60, 8691-8697. (d) Masu, H.; Okamoto, T.; Kato, T.; Katagiri, K.;
Tominaga, M.; Goda, H.; Takayanagi, H.; Azumaya, I. Tetrahedron Lett.
2006, 47, 803-807.
(3) Rao, P.; Maitra, U. Tetrahedron Lett. 1996, 37, 5791-5794.
(4) The 1H NMR spectra of 1b are sharp at low (<1 mM) concentration in
D2O at 298 K. At higher concentrations, the spectra broaden and the minor
set of resonances grows, suggesting the onset of self-association and a
shift in equilibrium toward “square” conformer A.
(5) (a) Ganis, P.; Avitabile, G.; Benedetti, E.; Pedone, C.; Goodman, M. Proc.
Natl. Acad. Sci. U.S.A. 1970, 67, 426. (b) Itai, A.; Toriumi, Y.; Tomioka,
N.; Kagechika, H.; Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30,
6177-6180. (c) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo,
K. J. Am. Chem. Soc. 1992, 114, 10649-10650.
(6) (a) Peczuh, M. W.; Hamilton, A. D. Chem. ReV. 2000, 100, 2479-2494.
(b) Fletcher, S.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2005, 9, 632-
638.
(7) (a) Park, H. S.; Lin, Q.; Hamilton, A. D. J. Am. Chem. Soc. 1999, 121,
8-13. (b) Fan, E.; Zhang, Z.; Minke, W. E.; Hou, Z.; Verlinde, C. L. M.
J.; Hol, W. G. J. J. Am. Chem. Soc. 2000, 122, 2663-2664. (c) Gradl, S.
N.; Felix, J. P.; Isacoff, E. Y.; Garcia, M. L.; Trauner, D. J. Am. Chem.
Soc. 2003, 125, 12668-12669. (d) Baldini, L.; Wilson, A. J.; Hong, J.;
Hamilton, A. D. J. Am. Chem. Soc. 2004, 126, 5656-5657. (e) Wright,
A. T.; Griffin, M. J.; Zhong, Z.; McCleskey, S. C.; Anslyn, E. V.;
McDevitt, J. T. Angew. Chem., Int. Ed. 2005, 44, 6375-6378. (f) Zhou,
H.; Baldini, L.; Hong, J.; Wilson, A. J.; Hamilton, A. D. J. Am. Chem.
Soc. 2006, 128, 2421-2425.
Molecular modeling studies of cyclo(AdcK)4, using MacroModel,
version 6.5, and the AMBER* force field with GB/SA water
solvation, show that the cavity of the “square” conformer is com-
plementary in size to sodium cholate, the hydrophobic cholate group
can fit into the hydrophobic cavity of the “square” conformer, and the
C18 and C19 methyl groups of the cholate can sit over the faces
of the AdcK aromatic rings in the resulting complex. These modeling
studies also suggest that the ring of the “square” cyclo(AdcK)4
conformer is slightly strained, with an average C-C(O)-N(H)-C
amide torsion angle of 167.5°. This ring strain, in conjunction with
hydrophobic forces and aromatic interactions, may contribute to
the formation of the “rectangular” conformer in D2O solution and
offset the formation of its otherwise unstable cis-amide linkages.
To demonstrate that cyclooligomers with a series of different
substituents in sequence can be prepared, we synthesized isomeric
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