Improving foldamer synthesis through protecting group induced unfolding of aromatic oligoamides

Article abstract of DOI:10.1021/ol062103d

(Chemical Equation Presented) The hydrogen bond rigidified backbones of aromatic oligoamides are temporarily interrupted by replacing the amide hydrogens with the acid-labile 2,4-dimethoxybenzyl (DMB) group, which allows the efficient preparation of long

Full text of DOI:10.1021/ol062103d

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5117-5120
Improving Foldamer Synthesis through
Protecting Group Induced Unfolding of
Aromatic Oligoamides
Aimin Zhang,† Joseph S. Ferguson,† Kazuhiro Yamato,† Chong Zheng,‡ and
Bing Gong*,†
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260, and Department of Chemistry and Biochemistry,
Northern Illinois UniVersity, DeKalb, Illinois 60115
bgong@chem.buffalo.edu
Received August 25, 2006
ABSTRACT
The hydrogen bond rigidified backbones of aromatic oligoamides are temporarily interrupted by replacing the amide hydrogens with the
acid-labile 2,4-dimethoxybenzyl (DMB) group, which allows the efficient preparation of long folding oligomers that, upon removal of the DMB
groups, fold into multiturn helices.
Unnatural folding oligomers, or foldamers, have attracted
intense interest lately.1-8 On the basis of backbone rigidifi-
cation, we9-11 and others12-15 reported folding aromatic
oligoamides in recent years. The folding oligomers we
developed are forced into well-defined crescent or helical
conformations by a three-center hydrogen bond.16 The folded
conformations of these molecules are particularly stable in
various solvents and at elevated temperatures. Our oligo-
amide foldamers represent one of the few helical foldamer
systems containing large, well-defined nanocavities with
systematically tunable sizes.17 Depending on its chain length,
† The State University of New York.
‡ Northern Illinois University.
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Z.; Furukawa, M.; Parra, R. D.; Kovalevsky, A. Y.; Mills, J. L.; Skrzypczak-
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(17) Examples of foldamers containing hydrophobic cavities: (a) Nelson,
J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science 1997, 277, 1793.
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10.1021/ol062103d CCC: $33.50
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an oligomer can be regarded as either a broken “macrocycle”
that can act as a receptor for cation and polar molecules or
a folding helical nanotube that may find applications in
designing pores and channels as well as receptors.
5. Acylating 5 with acid chloride 6 led to 7, in which the
DMB group is placed between two monomer units. Dimer
9, with a DMB group at its N-terminus, was prepared by
treating 3 with acid chloride 6, leading to 8 that was
converted into 9 by hydrogenation followed by reductive
amination.
The DMB-modified monomer 5, together with 7 and 9,
allows the efficient preparation of oligomers with DMB
groups placed on the oligoamide backbones. As shown by
Scheme 2, the DMB-modified 7 was converted into acid 10
Efficient synthesis of relatively short oligomers that fold
into crescents or helices of less than two turns has been
developed by us.18 However, the preparation of longer
oligomers was met with increasing difficulty as the chain
length extends. This is likely due to steric hindrance
introduced by the folded (helical) conformation of the
corresponding oligomers. One likely solution is to alter the
folded conformation. This may be realized by replacing the
amide hydrogen atoms with a protecting group that can be
removed later, which interrupts the intramolecular H-bonding
that rigidifies the backbone.
Scheme 2
Thus, as shown by 1a, when an amide hydrogen is re-
placed with the acid-labile 2,4-dimethoxybenzyl (DMB)
group,19 a modified amide group lacking the backbone-rigid-
ifying intramolecular H-bond is obtained. Removing the
DMB group with an acid such as trifluoroacetic acid (TFA)
should restore the three-center H-bond, leading to 1b that
adopts the H-bond-enforced conformation.
Scheme 1 shows the synthesis of DMB-modified 7 and 9.
Hydrogenation of 2 led to amine 3, which was treated with
Scheme 1
by hydrolysis and into amine 11 by hydrogenation. Acid 10
was converted into its acid chloride that was coupled to 11,
leading to tetramer 12. Hydrolysis and hydrogenation of 12
led to the acid 13 and the amine 14, respectively. Coupling
13 and the acid chloride of 14 led to octamer 15 in an isolated
yield of 32%.
(18) Yuan, L. H.; Sanford, A. R.; Feng, W.; Zhang, A. M.; Zhu, J.; Zeng,
H. Q.; Yamato, K.; Li, M. F.; Ferguson, J. S.; Gong, B. J. Org. Chem.
2005, 70, 10660.
(19) N-Substitution of a secondary amide by the 2,4-DMB group was
reported to induce a conformational change that promoted ring-closing
metathesis. See: Creighton, C. J.; Reitz, A. B. Org. Lett. 2001, 3, 893.
the commercially available aldehyde 4, leading to the
intermediate Schiff base that was reduced with NaBH4 into
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Org. Lett., Vol. 8, No. 22, 2006

Surprisingly, hydrogenation of octamer 15 under various
conditions, such as elevated temperatures and increased
pressure, failed to reduce the nitro group into the desired
amino group. Efforts to crystallize 15 have not succeeded.
Instead, single crystals of 7, and those of pentamer 17
(Scheme 3), were obtained. These crystal structures provide
Scheme 3
Figure 1. Crystal structures of DMB-modified (a) dimer 7 and
(b) pentamer 17. The DMB group is shown in green. The H atoms
are removed for clarity.
tamer 23. Compared to the aromatic oligoamides lacking the
DMB group, which often show poor solubility when carrying
short alkyl side chains, oligomers 19 and 21-23 all have
excellent solubility in nonpolar and polar solvents such as
CH2Cl2, CHCl3, and DMSO. As the chain length extends,
the coupling efficiencies showed only small changes. These
results suggest that removing the three-center H-bond from
just one of the amide groups of an otherwise backbone-
insight into the unexpected difficulty encountered in the
seemingly straightforward reduction of 15.
In the crystal structures of 7 and 17, the presence of the
DMB groups leads to crowded conformations. To avoid steric
hindrance due to the presence of the DMB group, the two
benzene rings attached to the amide carbonyl group and the
N atom are almost perpendicular to the plane of the amide
group. In the structure of 7, the ester group sits in between
the aromatic rings of the aniline and the benzyl moieties,
whereas the nitro group is more exposed. For 17, the two
tertiary amide groups, with their DMB groups, lead to an
overall zigzagged conformation. Instead of being in close
proximity as would be expected from the corresponding
folded pentamer with a H-bond-rigidified backbone, the two
ester groups point away from each other. In the solid-state
structures of both 7 and 17, the DMB-modified tertiary amide
groups adopt the cis conformation.
Scheme 4
The structures of 7 and 17 (Figure 1) suggest that a proper
combination of DMB-modified and H-bonded amide groups
is necessary to expose the termini of an oligomer. Too many
DMB groups may result in an overcrowded structure that
prevents the reacting group from being shielded away from
the catalyst and other reagents. It is reasoned that, to expose
the end group(s), one DMB group should be incorporated
for every three to five residues, which should lead to a
modified oligomer with short H-bond-rigidified segments
segregated by DMB-modified amide groups.
Several oligomers bearing one DMB group were prepared
in good yields (Scheme 4). Tetramer 19 was prepared by
coupling the acid chloride and the amine derived from 10
and 18. Starting from 19, acid chlorides 20 and 6 were
sequentially coupled to the corresponding precursor oligo-
mers, which afforded pentamer 21, hexamer 22, and hep-
Org. Lett., Vol. 8, No. 22, 2006
5119

rigidified oligomer can significantly alter its property by
altering the flat oligoamide backbone.
On the basis of the same procedures shown in Scheme
5a, coupling the amino-heptamer derived from 23 to diacid
chloride 24 led to 15mer 26. The DMB groups of 26 were
then removed, giving backbone-rigidified 15mer 26a, which
should fold into a helix of ∼2.5 turns, in a satisfactory overall
yield.20
To probe the efficiency of preparing longer oligomers from
DMB-modified precursors, a convergent route18 involving
the coupling of an amino-terminated oligomer to a diacid
was adopted. As shown in Scheme 5a, hexamer 22, after
Scheme 5
In the 1H NMR spectrum of 22a, the signals of the amide
(9.5-10.5 ppm) and the aromatic (6.2-6.8 and 8.6-9.3
ppm) protons are well-resolved,20 which are the same as those
of the backbone-rigidified folding oligoamides we reported.9-11
Comparing the aromatic and amide proton signals of 25a
and 26a to those of 22a shows that the signals of the longer
oligomers are increasingly overlapped and broadened.18,20
Nevertheless, the corresponding aromatic and amide protons
of 25a and 26a still appear in the same regions as those of
22a,20 suggesting that 25a and 26a are also rigidified and
therefore fold in the same way as shorter oligomers. A two-
1
dimensional (NOESY) H NMR spectrum of 26a shows
extensive NOEs between the amide and alkoxy protons,20
which further support the presence of the three-center
H-bonds and thus the folded conformation.
being reduced into its amino analogue, was treated with 0.5
equiv of diacid chloride 24. Symmetrical 13mer 25 was ob-
tained in 46% yield. The two DMB groups of 25 were then
removed in CH2Cl2 using trifluoroacetic acid (TFA), which
led to backbone-rigidified 13mer 25a that should fold into a
helix with ∼2 turns11 in 72% yield.
Oligomer 26a represents the longest meta-linked oligo-
amide we have prepared. Before adopting the current strat-
egy, the longest meta-linked aromatic oligomer of this series
that we prepared was a symmetrical undecamer.11 Given the
efficiency demonstrated in the preparation of the oligomers
and the good solubility and reactivity of the DMB-modified
precursors and with further optimized reaction conditions,
it is expected that much longer oligomers will be prepared.
This strategy of conformation-alteration should also facili-
tate the preparation of folding aromatic polyamides, which
has been hampered by the exclusive formation of macro-
cycles.21
The efficiency of the strategy involving DMB-modified
oligomers was also demonstrated by preparing 13mer 25a
on the basis of an alternative route (Scheme 5b). In this case,
the DMB group of 22 was removed first, leading to 22a that
should adopt a rigidified, nearly flat and crescent conforma-
tion in which the two termini lie in close proximity. Hexamer
22a was then reduced, followed by coupling to 24, which
led to 23a in a very poor (3.7%) yield. Repeating the same
coupling led to similar low yields. This is in sharp contrast
to the yield of 13mer 25 and the overall yield of 25a shown
in Scheme 5a, which suggest that for a folded oligomer pre-
cursor of a sufficient length (∼1 turn) steric hindrance indeed
played a major role in retarding its reactivity. Obviously, in
this case (Scheme 5b), the H-bond-rigidified conformation
of oligomer 22a is not in rapid equilibrium with an unfolded
state, such as the scenario described by the Curtin-Hammett
principle that would lead to an efficient formation of 25a.
This conclusion is also consistent with our previous observa-
tion11 that this class of backbone-rigidified foldamers adopts
a very stable, folded conformation.
Acknowledgment. Grateful acknowledgment is made to
the NSF (CHE-0314577 to B.G.) and ONR (N000140210519
to B.G.) for support.
Supporting Information Available: Synthetic procedures
and 1D and 2D NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL062103D
(20) See Supporting Information for details.
(21) Yuan, L. H.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu, D. G.;
Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126, 11120.
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