Diastereomeric recognition of chiral foldamer receptors for chiral glucoses

Article abstract of DOI:10.1021/ol070492l

Three chiral aromatic hydrazide foldamers have been designed and synthesized, in which two R- or S-proline units were incorporated at the terminals of their backbones. The ¹H NMR, circular dichroism (CD), and fluorescent experiments and molecul

Full text of DOI:10.1021/ol070492l

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1797-1800
Diastereomeric Recognition of Chiral
Foldamer Receptors for Chiral Glucoses
Chuang Li, Gui-Tao Wang, Hui-Ping Yi, Xi-Kui Jiang, Zhan-Ting Li,* and
Ren-Xiao Wang*
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
ztli@mail.sioc.ac.cn; wangrx@mail.sioc.ac.cn
Received February 27, 2007
ABSTRACT
Three chiral aromatic hydrazide foldamers have been designed and synthesized, in which two R- or S-proline units were incorporated at the
terminals of their backbones. The 1H NMR, circular dichroism (CD), and fluorescent experiments and molecular dynamics simulations revealed
that the foldamers adopted a chiral helical conformation and complexed alkylated glucoses in chloroform with a good diastereomeric selectivity.
The intriguing folded or helical conformation of peptides
and proteins has always fascinated chemists. In the past
decade, there has been considerable interest in developing
foldamers, unnatural oligomers that are capable of folding
into well-defined secondary conformations.1 It has been
expected that progress in this field will eventually lead to
unnatural structures with sizes and functions of biomolecules
such as proteins and DNA.1b One of the interesting functions
of foldamers is their application in molecular recognition.
Depending on the design, binding sites, and cavity size,
foldamers may complex monoterpenes,2 alkylated saccha-
rides,3,4 aliphatic ammoniums,5 water,6 metal ions,7,8 anions,9
and fullerenes.10 However, examples of recognitions of chiral
foldamers for chiral guests are very limited.11 It was revealed
that complexation of achiral foldamers for a chiral guest
could cause significant chiral differentiation for the folded
backbones.2-5 In principle, if one or more chiral units are
incorporated into a folded scaffold to generate an energeti-
(3) Inouye, M.; Waki, M.; Abe, H. J. Am. Chem. Soc. 2004, 126, 2022.
(4) (a) Hou, J.-L.; Shao, X.-B.; Chen, G.-J.; Zhou, Y.-X.; Jiang, X.-K.;
Li, Z.-T. J. Am. Chem. Soc. 2004, 126, 12386. (b) Yi, H.-P.; Shao, X.-B.;
Hou, J.-L.; Li, C.; Jiang, X.-K.; Li, Z.-T. New J. Chem. 2005, 29, 1213.
(5) Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H.-P.; Zhu, S.-Z.; Jiang, X.-K.; Li,
Z.-T. Angew. Chem., Int. Ed. 2005, 44, 5725.
(6) Garric, J.; Le´ger, J.-M.; Huc, I. Angew. Chem., Int. Ed. 2005, 44,
1954.
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Hill, D. J.;
Mio, M. J.; Prince, M. R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001,
101, 3893. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV.
2001, 101, 3219. (d) Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem.
Biol. 2001, 5, 650. (e) Huc, I. Eur. J. Org. Chem. 2004, 17. (f) Cheng, R.
P. Curr. Opin. Struct. Biol. 2004, 14, 512. (g) Sanford, A.; Yamato, K.;
Yang, X. W.; Yuan, L. H.; Han, Y. H.; Gong, B. Eur. J. Biochem. 2004,
271, 1416. (h) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem. Res.
2006, 39, 11. ( i) Li, Z.-T.; Hou, J.-L.; Li, C.; Yi, H.-P. Chem. Asian J.
2006, 1, 766.
(7) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2006, 128, 9988.
(8) Yi, H.-P.; Wu, J.; Ding, K.-L.; Jiang, X.-K.; Li, Z.-T. J. Org. Chem.
2007, 72, 870.
(9) Chang, K.-J.; Kang, B.-N.; Lee, M.-H.; Jeong, K.-S. J. Am. Chem.
Soc. 2005, 127, 12214.
(10) (a) Wu, Z.-Q.; Shao, X.-B.; Li, C.; Hou, J.-L.; Wang, K.; Jiang,
X.-K.; Li, Z.-T. J. Am. Chem. Soc. 2005, 127, 17460. (b) Hou, J.-L.; Yi,
H.-P.; Shao, X.-B.; Li, C.; Wu, Z.-Q.; Jiang, X.-K.; Wu, L.-Z.; Tung, C.-
H.; Li, Z.-T. Angew. Chem., Int. Ed. 2006, 45, 796.
(11) (a) Maurizot, V.; Dolain, C.; Huc, I. Eur. J. Org. Chem. 2005, 1293.
(b) Daniels, D. S.; Petersson, E. J.; Scheparts, A. J. Am. Chem. Soc. 2007,
129, 1532.
(2) Prince, R. B.; Barnes, S. A.; Moore, J. S. J. Am. Chem. Soc. 2000,
122, 2758.
10.1021/ol070492l CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/06/2007

cally favorable chiral conformation, diastereomeric recogni-
tion for chiral guests may be achieved. We previously found
that hydrazide-based foldamers efficiently complexed discrete
saccharides in chloroform.4a By introducing two R- or
S-proline units at the terminals of the backbones, we have
designed three new chiral foldamers. We herein report that
these chiral foldamers complex glucoses with a remarkable
diastereomeric selectivity.12,13
ppm), supporting the existence of intramolecular hydrogen
bonding. As expected, the spectra of 2a and 2b are identical
to each other. To further explore the influence of the chiral
prolines on the conformation of the hydrazide backbone,
compound 6 was also prepared. The X-ray diffraction
analysis revealed that in the solid-state its hydrazide moiety
adopted a rigidified planar conformation, and the methoxyl
oxygen atom was involved in intramolecular hydrogen
bonding (Figure 1). All these results suggested that the
Figure 1. Compound 6 and its solid-state structure.
proline-incorporated hydrazide oligomers possessed a rigidi-
fied helical conformation.
Conformations of methyl-substituted analogues of oligo-
mers 1 and 2a were also explored through molecular
dynamics simulations (see the Supporting Information). Their
conformations of the lowest energy are provided in Figure
2, both of which corresponded to the left-handed (R,R-M)
Three oligomers 1, 2a, and 2b have been synthesized, each
of which bears two R- or S-proline units at the terminals of
the backbone. 2a and 2b are enantiomers. CPK modeling
showed that the backbones of all the molecules were long
enough to form a helical conformation. It was envisaged that
these molecules would produce helical differentiation in
solution due to the introduction of the chiral prolines.
Anomers R-D-glucose (3) and R-L-glucose (4) were chosen
as chiral guest molecules because a previous study revealed
that achiral hydrazide foldamers could complex discrete
sacchrides in chloroform.4a For comparison, achiral triol 5
was also investigated as a guest.4b The syntheses for the
oligomers are provided in the Supporting Information. All
the oligomers are soluble in common organic solvents such
as chloroform and dichloromethane and have been character-
Figure 2. Energy-minimized conformation of 1 (left) and 2a
(right). The octyl chains were replaced with methyl groups for
modeling. An NOE connection is shown for 2a.
1
ized by H NMR, 13C NMR, and HRMS.
helical conformers. Their right-handed (R,R-P) helical di-
astereomers were also analyzed. They were, however,
energetically unfavorable by 12∼15 kcal/mol as compared
to the two conformations shown in Figure 2. These results
also suggest that introduction of two chiral proline units to
the terminals of the hydrazide oligomers leads to important
differentiation of their possible helical conformations. The
1H NMR spectra of both compounds in CDCl3 (see the
Supporting Information) exhibit one set of signals, suggesting
that the M and P helices in solution exchange quickly on
Because the chiral prolines in the oligomers are located
at the ends of the hydrazide backbones, it is reasonable to
assume that, like their proline-free analogues,4a the hydrazide
backbones in these oligomers are also induced by hydrogen
bonding to adopt a folded conformation. Actually, their H
NMR spectra in CDCl3 showed that the NH signals of all
1
the oligomers appeared at the downfield area (10.05-11.54
(12) Chiral aromatic amide or urea foldamers have been reported. See:
(a) Dolain, C.; Jiang, H.; Leger, J.-M.; Guionneau, P.; Huc, I. J. Am. Chem.
Soc. 2005, 127, 12943. (b) Sinkeldam, R. W.; Hoeben, F. J. M.; Pouderoijen,
M. J.; De Cat, I.; Zhang, J.; Furukawa, S.; De Feyter, S.; Vekemans, J. A.
J. M.; Meijer, E. W. J. Am. Chem. Soc. 2006, 128, 16113. (c) Dong, Z.;
Karpowicz, R. J., Jr.; Bai, S.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc.
2006, 128, 14242.
(13) For representative reviews of synthetic receptors for saccharides,
see: (a) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38,
2979. (b) James, T. D.; Shinkai, S. Top. Curr. Chem. 2002, 218, 159. (c)
Striegler, S. Curr. Org. Chem. 2003, 7, 81.
1
the H NMR time scale.
1
2D H NMR NOESY experiments (5 mM, 400 MHz)
revealed an NOE connection between the proton at the chiral
carbon atom and one of the aromatic protons of 2a or 2b, as
shown in Figure 2. Because no similar result was observed
for 1 or 6 of identical concentration, this NOE should be
1798
Org. Lett., Vol. 9, No. 9, 2007

ascribed to cross-ring approach of the two protons. This result
further supported the helical conformation of the oligomer
shown in Figure 2.
The nature of the hydrazide backbones enables circular
dichroism (CD) studies for both the oligomers and their
mixture solution with 3 and 4. As expected, the solutions of
all the oligomers in chloroform are CD active (Figure 3, top).
Figure 4. CD spectra of the mixture solution of 2a and 2b (5.1 ×
10-5 M) with 3 and 4 in chloroform at 25 °C
Mirror symmetry was observed for the spectrum of the two
pairs of complexes of the identical mixture concentration:
2a + 4 vs 2b + 3 and 2a + 3 vs 2b + 4 (Figure 4a vs e and
b vs d). This observation clearly illustrates the “enantiomeric”
feature of the two pairs of complexes and is in accordance
with the quantitative fluorescent binding studies (vide infra).
Because of overlapping with the OCH2 signals of the
oligomers, 1H NMR spectra did not provide useful informa-
tion for the shifting of the hydroxyl signals caused by
intermolecular hydrogen bonding.4a Therefore, the complex-
ation behavior was investigated with fluorescent spectros-
copy. Adding a glucose guest to the solution of the foldamers
in chloroform caused significant emission increase of the
oligomers. On the basis of studies of Job’s plots (Figure 5),15
Figure 3. Top: CD spectra of (a) 2a, (b) 1, and (c) 2b in
chloroform (6.0 × 10-5 M) at 25 °C. Bottom: CD spectra of the
mixture solution of 1 (6.0 × 10-5 M) and 3 and 4 in chloroform at
25 °C.
Because the solution of chiral hydrazide 6 in chloroform is
CD silent, the signals displayed in Figure 3 must be generated
due to the formation of the chiral helical conformation for
their hydrazide skeletons. The spectra of 2a and 2b of
identical concentration are of mirror shape, reflecting the
feature of two symmetric chiral helicates of identical stability.
These observations are consistent with the above results of
1H NMR observations and molecular modeling.14
Adding 3 or 4 to the solution of 1 in chloroform caused
an important change for the CD spectra of 1. The representa-
tive results are shown in Figure 3 (bottom). As expected,
the CD change was increased with the increase of the guest
(Figure 3b-d). The spectra produced upon addition of 3 and
4 of identical concentration are opposite in direction but not
of mirror symmetry (Figure 3a,c).
Figure 5. Job’s plots for the solutions of 2a and 3 (9), 2a and 4
(b), 1 and 3 (2), and 1 and 4 (1) in chloroform at 25 °C (the
emission change at 408 nm as the probe). The total concentration
is 2.0 × 10-5 M for the former two systems and 1.0 × 10-5 M for
the latter two systems.
we could establish a 1:1 stoichiometry for the investigated
complexes. Fluorescent titrations were then carried out by
incremental addition of the glucoses to the solution of the
oligomers of fixed concentration in chloroform.4a Association
CD variations were also observed for the solution of 2a
and 2b in chloroform with the addition of 3 or 4 (Figure 4).
(14) The results do not mean that the favorable helical conformer existed
exclusively but that reasonably it was the major form of the helical
structures.
(15) Job, P. Ann. Chim. Ser. 10 1928, 9, 113.
Org. Lett., Vol. 9, No. 9, 2007
1799

constants were derived from the titration data and are listed
in Table 1.16
2a‚3 vs 2b‚4 and 2a‚4 vs 2b‚3, are very close. This result is
consistent with the above CD observations. By using the
identical method, association constants of the complexes
between the foldamers and achiral triol 5 were also obtained
and listed in Table 1. The values are generally small,
although the value of 1‚5 is notably higher than those of
2a‚5 and 2b‚5.
In conclusion, a new series of hydrogen bonding driven
chiral hydrazide foldamers have been constructed, in which
two R- or S-proline units are introduced at the terminals of
their backbone. The foldamers are induced by the chiral
proline units to display chiral helical differentiation in
solution. The resulting chiral helicates efficiently bind
enantiomeric alklyated glucoses in chloroform. Quantitative
fluorescent investigations revealed a good binding dif-
ferentiation for the diastereomeric complexes. The results
well demonstrate that, by introducing rationally designed
chiral groups, foldamers can be induced to form a chiral
cavity for selective complexation of chiral guests. Future
studies will include the utility of the chiral cavity for
membrane transportation of chiral species and the construc-
tion of foldamer-appended or incorporated polymers for
chirality transfer or amplification.
Table 1. Association Constants of Complexes Among 1, 2a
and 2b, Glucoses 3 and 4, and Triol 5 in CHCl3 at 25 °Ca
Kassoc
(M-1
∆G
Kassoc
(M-1
∆G
(kcal/mol)
complex
)
(kcal/mol) complex
)
1‚3
1‚4
1‚5
2a‚3
2a‚4
1.8 × 103
2.6 × 105
5.0 × 102
3.0 × 102
1.2 × 104
-4.4
-7.4
-3.7
-3.4
-5.6
2a‚5
2b‚3
2b‚4
2b‚5
1.1 × 102
1.3 × 104
3.1 × 102
1.3 × 102
-2.8
-5.6
-3.4
-2.9
a
The results are average values of two titration experiments, and the
error is generally <15%.
Complex 1‚4 gave rise to the largest association constant,
which was about 144 times higher than that of 1‚3. A
previous study revealed that hydrazide foldamers complexed
saccharide guests with their cavity by intermolecular hydro-
gen bonding.4a Considering that the new chiral oligomers
also adopted a folded conformation and formed 1:1 com-
plexes with the glucoses, it should be reasonable to propose
that similar binding patterns exist for the new complexes.
Similar binding differentiation was also observed for 2a
toward 4 over 3 and for 2b toward 3 over 4, with a ratio of
the association constants being approximately 40 and 42,
respectively. These results suggest that the oligomers with
R-proline units were able to complex chiral guest 4 more
efficiently, whereas S-proline-incorporated oligomers pre-
ferred to bind its enantiomer 3. As expected, the association
constants of the complexes of enantiomeric symmetry, i.e.,
Acknowledgment. We thank the NSF (Nos. 20321202,
20332040, 20425208, 20572126, 20672137) and the National
Basic Research Program (2007CB808000) of China for
financial support.
Supporting Information Available: Full experimental
and characterization data for 1, 2a, 2b, and 6; methods and
results of molecular dynamics simulations; 1H NMR spectra
of new compounds and NOESY spectrum of 2a; typical
fluorescent titration spectra; CIF file of 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Conners, K. A. Binding Constants: The Measurement of Molecular
Complex Stability; Wiley: New York, 1987.
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