1792
J. Am. Chem. Soc. 2001, 123, 1792-1793
the affinity depends on the area of contact between the interacting
molecular surfaces (Figure 1b).7 Here we show by systematically
varying the size of the host oligomer’s cavity that there is length-
dependent recognition for a rodlike guest based not on specific
interactions, but simply on minimizing the solvent exposed surface
of the complex.
Chain Length-Dependent Affinity of Helical
Foldamers for a Rodlike Guest
Aya Tanatani, Matthew J. Mio, and Jeffrey S. Moore*
Roger Adams Laboratory, Department of Chemistry and
Materials Science & Engineering
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
ReceiVed October 16, 2000
Biology teaches the importance of helical constructs in mac-
romolecular recognition. For example, helical structures play
critical roles in DNA-protein and protein-protein binding, as
well as regulating various biological events such as the expression
of genetic information.1,2 Although directional interactions such
as complementary hydrogen bonds can elicit specificity, shape
recognition arising from the morphological features of interacting
molecular surfaces significantly contributes to binding affinity.3
We imagined that the internal cavity of a helix would be
complementary in shape to rodlike chain molecules of appropriate
diameter. Such a mode of interaction would illustrate an example
of recognition based on a helical scaffold unlike those typical of
biomacromolecules.4 We have previously shown that m-phenylene
ethynylene oligomers 1 exist in a compact helical conformation
in polar solvents.5 The well-ordered conformation of 1 creates a
tubular hydrophobic cavity, and certain monoterpenes (i.e., (-)-
R-pinene) can bind in the cavity of 1 (n ) 12).6 These findings
led us to consider rodlike chiral guest molecules whose shape is
better matched to the cylindrical cavity of oligomer series 1
(Figure 1a). The strength of complex formation is postulated to
depend on the length of the oligomer to its guest. This assumes
Compound 2, cis-(2S,5S)-2,5-dimethyl-N,N′-diphenylpipera-
zine, has a chiral, rodlike structure and its size and shape are
complementary to the cavity of 1, as deduced from molecular
modeling studies (Figure 1c).8 A particularly attractive feature
of this molecule (and higher homologues) is that it can be prepared
in a straightforward manner (eq 1). Enantiomerically pure cis-
(2S,5S)-2,5-dimethylpiperazine, prepared in three steps from
L-alanine derivatives,9 was coupled with 2 equiv of bromobenzene
by Buchwald’s amination method10 using Pd2(dba)3, 2-diphe-
nylphosphino-2′-dimethylaminobiphenyl, and sodium tert-butox-
ide to afford 2 in 91% yield with no epimerization. Interestingly,
amination reactions using other phosphine ligands were unsuc-
cessful. The use of rac-BINAP or 2-diphenylphosphinobiphenyl
resulted in no reaction or a low chemical yield of 2, probably
due to the steric hindrance of methyl groups. Alternatively, 2-di-
(cyclohexyl)phosphino-2′-dimethylaminobiphenyl gave a satisfac-
tory yield, but caused a significant amount of epimerization, as
(1) (a) Saenger, W. Principles of Nucleic Acid Structure; Springer: Hei-
delberg, 1984; pp 220-241. (b) Branden, C.; Tooze, J. Introduction to Protein
Structure; Garland: New York, 1991.
(2) (a) Pabo, C. O. Annu. ReV. Biochem. 1984, 53, 293-321. (b) Travers,
A. A. Annu. ReV. Biochem. 1989, 58, 427-452. (c) Pavletich, N. P.; Pabo, C.
O. Science 1991, 252, 809-817. (d) Cho, Y.; Gorina, S.; Jeffrey, P. D.;
Pavletich, N. P. Science 1994, 265, 346-355. (e) Suzuki, M.; Yagi, N. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 12357-12361. (f) Draper, D. E. Annu. ReV.
Biochem. 1995, 64, 593-620.
(3) (a) Bo¨hm, H.-J.; Klebe, G. Angew. Chem., Int. Ed. Engl. 1996, 35,
2589-2614. (b) Davis, A. M.; Teague, S. J. Angew. Chem. Int. Ed. 1999, 38,
736-749.
1
observed by H NMR.
The binding affinities of 2 for members of oligomer series 1
(n ) 10, 12, 14, 16, 18, 20, 22, 24)11 were determined by circular
dichroism (CD) measurements. Guest molecule 2 itself exhibits
a CD signal at ca. 300 nm. Therefore, induced CD spectra
resulting from the interaction of 2 with oligomer series 1 were
obtained by subtracting the CD spectrum of 2 from that of the
host-guest complex.12 Figure 2 shows a typical series of spectra
resulting from the addition of enantiomerically pure 2 to 22-mer
in 40% aqueous acetonitrile. The piperazine guest induces a strong
Cotton effect at ca. 315 nm corresponding to the oligomer’s
diphenylacetylene chromophore. CD spectra recorded over a range
of guest concentrations showed saturation behavior with an
isodichroic point, which is expected for a single stoichiometry
relationship between 2 and 1 (Figure 2). To verify that binding
takes place within the helical cavity, we studied solutions of
oligomer 3 with guest 2 as a control. Oligomer 3 (n ) 12) posseses
internally situated methyl groups leaving a smaller cavity in the
foldamer. No induced Cotton effect was observed when 2 was
added to 3 (see Supporting Information). These results indicate
that compound 2 binds to the internal cavity of oligomer series
1, rather than associating by intercalation. The stoichiometry of
the complex of 2 and 1 was determined to be 1:1 by the linearity
of Benesi-Hildebrand plots.13 The association constant (K11)
calculated by a nonlinear least-squares fitting method was found
to be 5600 ( 190 M-1 for the 12-mer.14 In addition, a significant
dependence of the binding affinities of 2 on the length of the
oligomers was observed (Figure 3). In each case, the stoichiometry
(4) Selected papers on helical oligomers: (a) Ute, K.; Hirose, K.; Kashimoto,
H.; Hatada, K. J. Am. Chem. Soc. 1991, 113, 6305-6306. (b) Fujiki, M. J.
Am. Chem. Soc. 1994, 116, 11976-11981. (c) Hamuro, Y.; Geib, S. J.;
Hamilton, A. D. J. Am. Chem. Soc. 1997, 119, 10587-10593. (d) Tanatani,
A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo, K.; Kagechika, H. J.
Am. Chem. Soc. 1998, 120, 6433-6442. (e) Seebach, D.; Abele, S.; Sifferlen,
T.; Ha¨nggi, M.; Gruner, S.; Seiler, P. HelV. Chim. Acta 1998, 81, 2218. (f)
Appella, D. H.; Christianson, L. A.; Klein, D. A.; Richards, M. R.; Powell,
D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 7574-7581. (g) Louis
A.; Lehn, J.-M.; Homo, J.-C.; Schmutz, M. Angew. Chem. Int. Ed. 2000, 39,
233-237.
(5) (a) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science
1997, 277, 1793-1796. (b) Prince, R. B.; Saven, J. G.; Wolynes, P. G.; Moore,
J. S. J. Am. Chem. Soc. 1999, 121, 3114-3121. (c) Prince, R. B. Phenylene
Ethynylene Foldamers: Cooperative Conformational Transition, Twist Sense
Bias, Molecular Recognition Properties, and Solid-State Organization. Ph.D.
Thesis, University of Illinois, Urbana Champaign, IL, January 2000.
(6) Prince, R. B.; Barnes, S. A.; Moore, J. S. J. Am. Chem. Soc. 2000,
122, 2758-2762.
(7) (a) Cohen, J. L.; Connors, K. A. J. Pharm. Sci. 1970, 59, 1271-1276.
(b) Matsumura, M.; Becktel, W. J.; Matthews, B. W. Nature 1988, 334, 406-
410.
(8) Molecular modeling was performed with MacroModel 7.0 (OPLS force
field). The Monte Carlo search explored the rotation and translation of 2 with
respect to 1. All atoms of 1 and 2 were free to move during the minimization.
(9) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909-4913.
(10) (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451-8458. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805-818.
(11) The oligomers were synthesized according to our previously reported
methods.5b The purity of each oligomer was determined by 1H NMR, MALDI,
HPLC, and GPC.
(12) No self-aggregation of 2 (in the absence of 1) was observed in the
1
experimental concentration range, as deduced from H NMR studies.
10.1021/ja003678n CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/02/2001