A new class of folding oligomers: Crescent oligoamides [4]

Full text of DOI:10.1021/ja994433h

J. Am. Chem. Soc. 2000, 122, 4219-4220
4219
was overwhelmingly favored over the alternative conformations
2a,b. The desired conformation, 2, was planar and had two strong
intramolecular hydrogen bonds with O‚‚‚H ) 1.87 Å (S(6)) and
2.14 Å (S(5)), respectively.
A New Class of Folding Oligomers: Crescent
Oligoamides
Jin Zhu,† Rube´n D. Parra,‡ Huaqiang Zeng,†
Ewa Skrzypczak-Jankun,† Xiao Cheng Zeng,‡ and
Bing Gong*,†
Department of Chemistry, The UniVersity of Toledo
Toledo, Ohio 43606
Department of Chemistry, UniVersity of Nebraska-Lincoln
Lincoln, Nebraska 68588
1H NMR studies in CDCl3 indicated a significant downfield
shift of the amide NH signal of 2 (10.60 ppm, independent of
concentration) compared to those of the reference compounds 2d
(at 10 mM, 9.691 ppm) and 2e (at 10 mM, 8.497 ppm), suggesting
formation of the bifurcated hydrogen bonds. The conformation
of 2 in solution was then examined by NOE difference spectros-
copy (600 MHz, 300 K).7 In CDCl3, on saturating the amide-H
signal, NOE enhancements were observed on both methoxy
groups of the benzoate (δ 4.04; 1.14%) and the aniline (δ 3.92;
0.80%) residues. Interestingly, similar NOE enhancements were
also detected in the polar solvent DMSO-d6: on saturating the
amide-H signal, enhancements on the benzoate and aniline
methoxy signals were 1.05% and 0.64%, respectively. These
results suggested the existence of the proposed S(5)- and S(6)-
type hydrogen bonds and thus the proposed conformation of amide
2 in solution. More significantly, the fact that such a rigid
conformation of 2 existed in the very polar solvent DMSO laid
the foundation for the design of oligomers that adopt well-defined
conformations in highly competitive solvents.
ReceiVed December 20, 1999
The assembly of well-defined protein secondary structures,
leads to a bewildering array of tertiary structures.1 As the first
step toward developing artificial oligomers and polymers that fold
like biomacromolecules, there is currently an intense interest in
designing unnatural building blocks that adopt well-defined
secondary structures.2,3 Here we report a new class of oligoamides
with backbones that adopt well-defined, crescent conformations.
Our design is based on diaryl amide oligomers, shown as 1.
The presence of the three-center hydrogen bonding system
consisting of the S(5) and S(6) type4 intramolecularly hydrogen
bonded rings should lead to rigidification of the amide linkage.
Oligoamides containing such amide linkages should have a rigid
backbone. With the two amide linkages on the same benzene ring
being meta to each other, the resulting oligomer should have a
crescent conformation.5
Crystals of amides 3 and 4 were grown from solutions in DMF
by slow cooling. Figure 1 shows their X-ray structures.7
In the solid state, 3 showed the type of conformation as ex-
pected. Two intramolecular hydrogen-bonded rings, S(6) and S(5),
were observed. The planes of the two aromatic rings in 3 were
parallel to each other and to that of the amide group, resulting in
a completely flat molecule with a rigid, curved conformation.
Four hydrogen bonded rings were observed in the structure of
4. As a result, a crescent conformation with the two amide-O
atoms turning inward was formed. These results indicated that
(1) the S(5) and S(6) type intramolecular hydrogen bonds indeed
prevailed in these structures and (2) the two amide O atoms, which
pointed inward and might have repulsive interaction with each
other, did not interrupt the overall curved conformation. This is
significant since it is a critical structural requirement for longer
analogues to adopt curved backbones. Amide 4 was overall flat.
The above results indicate that analogues of amides 2-4 with
longer backbones should adopt a well-defined, curved conforma-
tion. Tetramer 5 in solution was thus investigated by 2D (NOESY)
1H NMR (CDCl3, 800 MHz, 300 K) spectroscopy. At 50 mM,
the amide NH signals of 5 appeared at δ 9.58, 9.90, and 10.13 as
three well-separated peaks. As shown in Figure 2, two cross-
peaks corresponding to each of the three amide protons were
observed: one with a methoxy group and the other with its
neighboring octyloxy R-methylene group. Such contacts suggested
the formation of bifurcated hydrogen bonds between an amide
proton and its neighboring alkoxy-O atoms, which provided the
Ab initio molecular orbital calculations (in vacuo) were
performed on amide 2.6 Conformations 2a-b are constrained to
be planar. The relative energy of each conformation is shown in
parentheses. The computational results indicated significant
differences in the relative energies of the four conformations: 2
* To whom correspondence should be addressed.
† The University of Toledo.
‡ University of Nebraska-Lincoln.
(1) Branden, C.; Tooze, J. Introduction to Protein Structure, 2nd ed.;
Garland Publishing: New York, 1998.
(2) For a recent review, see: Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) For recent examples, see: (a) Appella, D. H.; Christianson, L. A.; Karle.
I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206. (b)
Gong, B.; Yan, Y.; Zeng, H.; Skrzypcak-Jankun, E.; Kim, Y. W.; Zhu, J.;
Ickes, H. J. Am. Chem. Soc. 1999, 121, 5607. (c) Gin, M. S.; Yokozawa, T.;
Prince, R. B.; Moore, J. S. J. Am. Chem. Soc. 1999, 121, 2643. (d) Yang, D.;
Qu, J.; Li, B.; Ng, F.-F.; Wang, X.-C.; Cheung, K.-K.; Wang, D.-P.; Wu,
Y.-D. J. Am. Chem. Soc. 1999, 121, 589. (e) Hanessian, S.; Luo, X.; Schaum,
R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569. (f) Seebach, D.; Abele,
S.; Stifferlen, T.; Ha¨nggi, M.; Gruner, S.; Seiler, P. HelV. Chim. Acta 1998,
81, 2218. (g) Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.;
Barron, A. E.; Truong, K. T.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuck-
ermann, R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A 1998, 95, 4309.
(4) Berstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1555.
(5) Hamilton et al. reported oligomers generated from anthranilic acid,
pyridine-2,6-dicarboxylic acid, and 4,6-dimethoxy-1,3-phenylenediamine units,
in which intramolecular H-bonds enforce a helical (or curved) conformation:
Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1997, 119, 10587.
(6) (a) The Jaguar program6b was used to obtain relative energies of the
optimized structures. Geometry optimizations were carried out at the B3LYP/
6-31G(d) level, whereas the LMP2/6-311G(d) method was used for single
point energy calculations. See Supporting Information for computational
details. (b) Jaguar v3.0, Schordinger, Inc.: Portland, OR, 1997.
(7) The X-ray data of 3 and 4 are given in the Supporting Information.
Additional NMR spectra are also included in the Supporting Information.
10.1021/ja994433h CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/13/2000

4220 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Communications to the Editor
groups, providing additional, unequivocal evidence for the
proposed curved conformation.7
The conformation of hexamer 6, which should make almost a
full circle and thus a nearly closed cavity, was probed by NOESY
(CDCl3, 800 MHz, 280 K) studies.7 At 25 mM, the five amide
NH signals of 6 appeared as three groups of peaks: δ 9.51 and
9.54 (two partially overlapped peaks, 2H), δ 9.69 (single peak,
1H), and δ 9.82 and 9.84 (two partially overlapped peaks, 2H).
On the basis of results from 5, each amide proton should have
two cross-peaks corresponding to the three-center hydrogen bonds.
The NOESY spectrum of 6 revealed exactly 10 cross-peaks
between the amide protons and the protons of the alkoxy
R-methylene and methoxy groups (3.6 to 4.4 ppm). Two of the
four cross-peaks corresponding to the two NH signals at around
δ 9.82 and 9.84 were not completely resolved, but can be clearly
identified. These 10 cross-peaks, corresponding to two contacts
for each amide proton, clearly support the curved conformation
shown here for 6.8
Figure 1. (a) X-ray structure of 3. (b) X-ray structure of 4. The decyl
groups in 4 are replaced with dummy atoms for clarity of view.
In summary, we have described a series of oligoamides with
well-defined, curved backbones. The persistence of the three-
center hydrogen bonds which lead to the rigidification of the
backbones has been established. These compounds can be
prepared from readily available starting materials based on well-
established, highly efficient amide chemistry. These oligoamides
have inherent folding propensities: the conformations of their
backbones depend only on the presence of local intramolecular
hydrogen bonds between amide linkages and their adjacent alkoxy
groups. The curved backbone confirmation should thus be resilient
toward structural variation on the -OR groups. More significantly,
the curved backbone should lead to the formation of a large (∼10
Å in 6 based on computer modeling9), hydrophilic cavity. On
the basis of this new motif, a variety of folding structures with
interior cavities can be envisioned. For example, oligomers such
as 6 can be viewed as acyclic “macrocycles” that may selectively
bind to metal ions and small molecules.10 Oligomers with more
than six rings (or residues) should fold into a new class of helices
with large, interior cavities.
Acknowledgment. This work was supported by grants from the NIH
(CA74402 and GM59235) and NASA (NAG5-8785). Acknwoledgment
is also made to the donors of the Petroleum Research Fund, administered
by the ACS, for partial support of this research (34456-AC4).
Supporting Information Available: Synthetic procedures, NOE
difference spectra of 2, NOESY spectra of 5 and 6, and tables of X-ray
data for 3 and 4 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. NOESY spectrum of 5 in CDCl3 (800 MHz, mixing time:
0.3 s). The contacts between amide Hb and the other protons as determined
by NOESY spectroscopy are indicated in the structure. Amide Ha and
Hc show the same set of contacts. Arrows in the spectrum show contacts
depicted in the text.
JA994433H
(8) Compounds 2, 3, 4, and 6 gave satisfactory results on spectral and
elemental analysis. Data from the characterization of 2-6 are included in the
Supporting Information.
(9) The energy minimization was performed on a Macintosh computer using
the CaChe Program (Oxford Molecular, MM2 force field).
(10) Vo¨gtle, F.; Weber, E. Angew. Chem., Int. Ed. Engl. 1979, 18, 753.
most diagnostic evidence for the curved conformation of 5.
Besides, the NOESY spectrum of 5 also revealed contacts between
the methoxy protons and the â-methylene protons of the octyloxy