Biased helical folding of chiral oligoindole foldamers

Article abstract of DOI:10.1021/ol8022243

(Chemical Equation Presented) Oligoindole-based chiral foldamers have been synthesized by incorporating (S)- or (R)-1-phenylethylamine to both ends of the tetraindole scaffold. The oligoindoles fold into a helical conformation upon binding an anion by hyd

Full text of DOI:10.1021/ol8022243

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5373-5376
Biased Helical Folding of Chiral
Oligoindole Foldamers
Veluru Ramesh Naidu, Min Cheol Kim, Jae-min Suk, Ho-Joong Kim,
Myongsoo Lee, Eunji Sim,* and Kyu-Sung Jeong*
Department of Chemistry, Yonsei UniVersity, Seoul-120-749 Korea
ksjeong@yonsei.ac.kr
Received September 24, 2008
ABSTRACT
Oligoindole-based chiral foldamers have been synthesized by incorporating (S)- or (R)-1-phenylethylamine to both ends of the tetraindole
scaffold. The oligoindoles fold into a helical conformation upon binding an anion by hydrogen bonds, which gives rise to an induced circular
dichroism (CD) signal of large amplitude, implying the preferential formation of one helical isomer over another. Theoretical calculations
suggest that the (P)-helix of the (S,S)-oligoindole 8a be more energetically stable than the corresponding (M)-helix.
Helical structures are commonly found in proteins and
nucleic acids and are stabilized by the combination of various
noncovalent forces such as hydrophobic interactions, van der
Waals forces, hydrogen bonds, dipole-dipole forces, etc.
Owing to the chiral nature of molecular blocks such as amino
acids and nucleotides, one-handed helices of two possible
helical isomers have been found in proteins and DNA. Much
progress has been made over the past decade for the synthesis
and characterization of foldamers mimicking secondary
structures of biomacromolecules.1,2 These efforts provided
us with the opportunity to gain an insight into understanding
the fundamental principles and factors that determine the
structure and function of biomacromolecules. Moreover, if
the conformation (folding vs unfolding, left- vs right-handed
helix, etc.) can be reversibly controlled by external stimula-
tion, the foldamer would be highly attractive for possible
applications in molecular sensing, data storage, and optical
devices.
A large number of synthetic oligomers capable of adopting
a helical conformation have been reported,1,2 and most of
them fold into a racemic mixture of two helical isomers. For
tuning the relative population of two different helices, many
approaches have been reported, which can be classified
broadly into two categories. One is to bind chiral guests to
achiral foldamers, which results in the biased formation of
two helical complexes.3,4 Another is to introduce chiral
segments to foldamers as a part of the backbones,5 termini,6,7
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10.1021/ol8022243 CCC: $40.75
Published on Web 10/31/2008
2008 American Chemical Society

or side chains,8,9 thus forming unequal ratio of two diaster-
eomeric helices.
Scheme 1. Synthesis of Oligoindole 8a
We have previously described oligoindoles capable of
folding into a helical conformation upon binding a chloride
ion via hydrogen bonding.10 The oligoindoles fold to give a
racemic mixture of two enatiomeric helices, the left- and
right-handed. In order to induce the helical bias, we prepared
chiral oligoindoles 8a and its enantiomer 8b, comprising a
tetraindole backbone with (1S)- or (1R)-phenylethylamido
1
units at both ends. H NMR and circular dichroism (CD)
spectroscopy clearly support the hypothesis that 8a and 8b
adopt a helical structure upon binding an anion such as
chloride by multiple hydrogen bonds. In particular, 8a or
8b alone exhibits almost no CD signal but the addition of
an anion induces a strong Cotton effect, implying the
preferential formation of one particular helix over another.
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The synthesis of chiral oligoindole 8a bearing the (S,S)-
configuration at the benzylic positions of both ends is
outlined in Scheme 1. Coupling of 3-bromobenzoyl chloride
(1) with (1S)-phenylethylamine (2) gave 3 in 92% yield.
Then, Pd(0)/CuI-catalyzed reaction11 of 3 with trimethylsi-
lyl(TMS)-ethyne, followed by removal of the TMS group
under the basic conditions, gave 4 in 81% yield (two steps).
Coupling of 4 with 5 (1.5 equiv) afforded 6 in 60% yield,
part of which was in turn converted into 7. Finally, 6 and 7
were combined to provide a chiral oligoindole 8a in 66%
yield.
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The 1H NMR spectrum of 8a was unambiguously assigned
1
by 2D H-1H COSY, TOCSY, and NOESY experiments
1
(see Suppoting Information). The H NMR spectrum of 8a
shows considerable changes in the chemical shift upon
addition of tetrabutylammonium chloride (TBA+Cl-) (Figure
1).12 First, the indole NH signals are largely downfield shifted
from 10.83 and 10.89 ppm to 12.18 and 13.07 ppm as a
result of hydrogen bonding. Second, signals for the amide
NH and the benzoate CHf are also downfield shifted by ∆δ
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1975, 16, 4467–4470. (b) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107,
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K.; Kohmoto, S. J. Org. Chem. 2005, 70, 1423–1431. (b) Zhao, X.; Schanze,
K. S. Langmuir 2006, 22, 4856–4862.
(12) As a result of fast exchange on the 1H NMR (400 MHz) time scale,
time-averaged signals were observed at room temperature between all the
possible conformational isomers of 8a and complex 8a·Cl-. When the
(10) (a) Chang, K.-J.; Kang, B.-N.; Lee, M.-H.; Jeong, K.-S. J. Am.
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1
temperature was gradually lowered to -40 °C, the H NMR signals were
significantly broadened and not assignable.
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Org. Lett., Vol. 10, No. 23, 2008

1
Figure 1. Partial H NMR spectra (400 MHz, 10 mM acetone-d6,
25 °C) of (a) 8a and (b) 8a + TBACl (3 equiv).
) 0.75 and 1.21 ppm, suggesting that these hydrogens also
participate in hydrogen bonding with the chlordie ion. Third,
the aromatic CH signals exhibit noticeable changes in the
chemical shift (∆δ ) (0.1- 0.5 ppm), indicative of
conformational reorganization. The 2D 1H-1H NOESY
experiment with a mixture of 8a and TBA+Cl- (3 equiv) in
acetone-d6 gave clear evidence for the helical folding,
showing characteristic NOE cross peaks between NH1 and
Hf, Hi and Hj, and Hb and Hn, which could not be observed
in the absence of TBA+Cl- (see Supporting Information).
CD spectroscopy has been widely used to reveal the helical
chirality. In the absence of an anion, 8a shows almost no
CD signal in CH2Cl2 (5 × 10-5 M) at room temperature.
Addition of TBA+Cl- gives rise to strong positive CD signals
centered at 296 nm (θ ) 54 mdeg) and 395 nm (θ ) 120
mdeg), corresponding to the absorption wavelengths of the
benzoate and biindole segments, respectively. The intensity
of the signal gradually increases and becomes saturated upon
addition of approximately 1 equiv of the anion (Figure 3,
top). The enantiomer 8b display identical behaviors of the
CD spectrum but the opposite Cotton effect (Figure 3,
bottom). In addition, other anions such as bromide, iodide,
azide, and nitrate also impart the induced CD signals with
different ellipticities (see Supporting Information). These CD
results suggest that chiral oligoindoles 8a and 8b form one
of two possible helices, at least preferentially.
Figure 3. Changes in CD spectra of 8a (top) and 8b (bottom) (0.05
mM) upon addition of TBACl in CH2Cl2 at 24 ( 1 °C.
The association constants between 8a and anions were
quantitatively measured by UV-vis titration experiments.
Each titration was carried out by increasing the amount of
tetrabutylammonium anion to constant concentration (1.0 ×
10-5 M) of 8a in 99:1 (v/v) CH2Cl2/MeOH at 21 ( 1 °C.
Nonlinear least-squares fitting13 of the titration curve gave
the association constants (Ka ( 15%); 2.9 × 105 M-1 for
Cl-, 6.2 × 104 M-1 for Br-, 2.6 × 102 M-1 for I-, 4.4 ×
104 M-1 for NO3 , and 8.5 × 105 M-1 for N3 . Job plots
suggest that 8a forms 1:1 complexes with all the anions (see
Supporting Information).
-
-
To find out which of the two possible helices of complex
8a·Cl- was more energetically stable, we conducted theoreti-
cal calculations in the gas phase using hybrid ab initio
methods with the Gaussian 03 package.14 First, structure
optimization was performed with the HF/3-21G method for
both cases. Using the optimized structures, we performed
(13) (a) Long, J. R.; Drago, R. S. J. Chem. Educ. 1982, 59, 1037–1039.
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1987.
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M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision C.02; Gaussian, Inc.: Wallingford CT, 2004.
Figure 2
.
Proposed structure of complex 8a·Cl- with the NOE
1
correlation shown in the 2D H-1H NOESY spectrum.
Org. Lett., Vol. 10, No. 23, 2008
5375

primarily responsible for the stabilization of the (P)-helix
over the (M)-helix.16 This kind of interactions has been
known to play an important role in the folding and binding
processes of natural and artificial molecules.17
In conclusion, an oligoindole-based foldamer with chiral
termini folds into a helical conformation upon binding an
anion by hydrogen bonds. The chirality of the terminal group
has been effectively transferred on the folding process, thus
leading to the preferential formation of one helical isomer,
as demonstrated by circular dichroism (CD) spectroscopy.
According to the theoretical calculation, the (P)-helix of
complex 8a·Cl- bearing (S,S)-configuration is more stable
than the corresponding (M)-helix. We are currently attempt-
ing the synthesis of a chiral foldamer possessing a larger
helical cavity able to accommodate chiral species such as
carboxylates and phosphates. This may allow us to reveal
foldamer-based chiral recognition as well as to develop a a
helicity-switching molecular system responsive to a chiral
substrate.
Acknowledgment. This work was financially supported
by the center for Bioactive Molecular Hybrids (CBMH) and
the Korea Science and Engineering Foundation (KOSEF-
R01-2007-000-11831-0, ES). V.R.N., M.C.K., J.-m.S., and
H.-J.K. acknowledge the fellowship of BK 21 program from
the ministry of education and human resources development.
We thank Dr. H. Park for her help with NMR studies.
Figure 4. Energy-minimized structures of the (P)-helix (top) and
the (M)-helix (bottom) of 8a·Cl- (Gaussian 03 package). For clarity,
all the hydrogens are omitted except the indole NHs, bezylic
hydrogen, and methyl group in the dotted circle.
single point calculations with B3LYP/3-21G and MP2/3-
21G methods to compare the energy of the helices. This kind
of structure optimization-single point hybrid calculation is
widely used due to its relatively accurate results yet
inexpensive computation cost.15 For all cases, the (P)-helix
is more stable than the (M)-helix by 24 kJ/mol (HF/3-21G),
19 kJ/mol (HF/3-21G//B3LYP/3-21G), and 16 kJ/mol (HF/
3-21G//MP2/3-21G). In the left-handed (M)-helix, the methyl
substituent at the benzylic position is eclipsed to the adjacent
carbonyl group, while the benzylic hydrogen is oriented
toward the helical strand (Figure 4). On the other hand, the
hydrogen atom and methyl group are oppositely placed in
the right-handed (P)-helix. As a result, the methyl substituent
is directed toward the aromatic strand to exert CH···π
interactions with the indole surface, which appears to be
Supporting Information Available: Synthesis and char-
acterization of oligoindole 8a and 8b. 1D and 2D NMR
spectra, UV-vis, CD spectra, and theoretical caculations.
This material is available free of charge via the Internet at
http//www.pubs.acs.org.
OL8022243
(16) To further examine the significance of the CH···π interaction, we
carried out more simulations. The (P)-helix has been destabilized by ∆E )
102 kJ/mol upon replacing the benzylic methyl group with hydrogen, while
the (M)-helix has been greatly stabilized when the benzylic hydrogen is
changed into the methyl group. For details, see Supporting Information
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