Synthesis of crescent aromatic oligoamides

Article abstract of DOI:10.1021/jo050798a

This article describes the synthetic procedures for the preparation of crescent (and helical) aromatic oligoamides developed in recent years in our laboratory. The large-scale preparation of a variety of monomers derived from various tetrasubstituted benzenes is presented. Three different strategies for constructing various oligomers consisting of meta- and meta/para-linked benzene residues are discussed. Factors affecting coupling efficiency and yields are analyzed. The developed synthetic methods have provided the basis for the preparation of longer oligomers and for the development of solid-phase synthesis.

Full text of DOI:10.1021/jo050798a

Synthesis of Crescent Aromatic Oligoamides
Lihua Yuan, Adam R. Sanford, Wen Feng, Aimin Zhang, Jin Zhu,† Huaqiang Zeng,‡
Kazuhiro Yamato, Minfeng Li, Joseph S. Ferguson, and Bing Gong*
Department of Chemistry, The State University of New York at Buffalo, Buffalo, New York 14260
bgong@chem.buffalo.edu
Received April 19, 2005
This article describes the synthetic procedures for the preparation of crescent (and helical) aromatic
oligoamides developed in recent years in our laboratory. The large-scale preparation of a variety of
monomers derived from various tetrasubstituted benzenes is presented. Three different strategies
for constructing various oligomers consisting of meta- and meta/para-linked benzene residues are
discussed. Factors affecting coupling efficiency and yields are analyzed. The developed synthetic
methods have provided the basis for the preparation of longer oligomers and for the development
of solid-phase synthesis.
Introduction
tunability, and the control of conformational changes
under different environmental conditions that enable the
Intense interest in constructing foldamers, first coined
by Gellman,1 with well-defined secondary structures
triggered the design and synthesis of a large number of
artificial systems1-4 such as aliphatic R-, â-, γ-, and
δ-peptides,4-13 and single-stranded and multistranded
abiotic oligomers.14-16 The challenges for folding synthetic
oligomers include the ease of synthesis, folding stability,
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† Current address: Chengdu Institute of Organic Chemistry, Chi-
nese Academy of Sciences, Chengdu 610041, P. R. China.
‡ Current address: The Scripps Research Institute, Department of
Chemistry, Mail Drop SR202, La Jolla, CA 92037.
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10.1021/jo050798a CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/25/2005
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Synthesis of Crescent Aromatic Oligoamides
FIGURE 1. Design of backbone-rigidified aromatic oligoamides. (a) The three-center hydrogen bond that enforces the folding of
the designed oligamides. (b) Oligoamides consisting of meta- (B1) or meta/para-linked (B2) aminobenzoic acid residues. (c)
Oligoamides consisting of meta-linked diacid and diamine residues (C1), para-linked diamine and meta-linked diacid residues
(C2), and meta-linked diamine and para-linked diacid residues (C3).
molecules to adopt various secondary structures or to
undergo host-guest complexation.17,18 Among the re-
ported foldamer systems, aromatic oligoamides seem to
be one class of promising candidates to satisfy many of
these requirements,19 some of which have already dis-
played interesting activities.20,21
Aromatic oligoamide foldamers were constructed based
on anthranilic acids,22,23 pyridines,24,25 pyridine oxides,22
pyrazines,26 and so on. A few less studied aromatic
oligomers were designed based on ureas27 or hydrazides28
without amide linkages. â-Sheetlike structures29 and
well-defined molecular duplexes4,30-32 were established
based on the combination of both R-peptide backbone and
aromatic rings with alkoxy substituents to form adjacent
hydrogen bonding.29
In recent years we reported a class of oligoamides with
backbones that adopt well-defined, crescent conforma-
tions.4,19,35-38 These oligomers are based on aromatic
oligoamide backbones consisting of benzene rings that
are meta- or meta/para-linked by secondary amide groups.
The presence of a particularly robust three-center hy-
drogen bond4a,36 involving each of the amide groups of
these molecule leads to the rigidification of the amide
linkages and thus the oligoamide backbone. As shown
by general structure A (Figure 1a), the three-center
H-bonds are introduced by placing ether oxygens in the
vicinity of each amide hydrogen, leading to the formation
of a three-center H-bond consisting of five- and a six-
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Yuan et al.
FIGURE 2. Building blocks prepared for constructing backbone-rigidified aromatic oligoamides.
membered H-bonded rings. Such backbone rigidification
results in a crescent or helical conformation depending
on the length of the oligomer. The aromatic oligoamides
can be (1) oligomers consisting of building blocks derived
from (m- or p-)aminobenzoic acids (Figure 1b), (2) co-
oligomers of (m- or p-)benzenedicarboxylic acids and (m-
or p-)phenylenediamines (Figure 1c), or (3) oligomers
with backbones that mix the above two designs and the
corresponding building blocks.
One unique feature of our oligoamide foldamers is the
tuning of their interior and exterior diameters. This has
been achieved by simply varying the ratio of meta- and
para-linked benzene rings in an oligomer (e.g., B2, C2,
and C3 in Figure 1). The higher the ratio of the para-
linked building blocks in an oligomer, the less curved the
corresponding backbone and thus the larger the diam-
eters. These backbone-rigidified foldamers are one of the
few helical foldamer systems with large, well-defined, and
systematically tunable interior cavity sizes (∼10 and 30
Å).35-38
The successful synthesis of these foldamers relies on
two factors: (1) efficient preparation of large quantities
of building blocks (monomers) and (2) feasible strategies
for coupling the building blocks and/or segments into
oligomers of various length. In this paper we present a
detailed account of the synthesis of these backbone-
rigidified aromatic oligoamides.
We have established the efficient preparation of four
different types of building blocks (Figure 2). These are
synthesized based on our own methods, or by modifying
precursors prepared based on previously reported pro-
cedures (2, 3, 4).4,19,31,33,34,39-43 Compounds 1-3 have been
prepared in 100-g quantities and 4 was obtained in
multigram quantities. The nitro group of these monomers
serves as the equivalent of a protected amino group and
is converted into the latter by catalytic hydrogenation
before oligomer synthesis.41 These building blocks have
been incorporated into the corresponding oligomers in a
variety of different combinations, leading to crescent
oligoamides with backbones of various curvatures and
cavity sizes.36-38
FIGURE 3. Coupling strategies for constructing folding
aromatic oligoamides.
(Figure 3a). The second strategy starts chain growth by
coupling monomers to a symmetrical central unit (Figure
3b). This bidirectional chain growth leads to symmetrical
oligomers with two identical termini. The third strategy
includes two possible convergent routes (Figure 3c): (1)
two identical oligomer segments can be coupled with a
symmetrical central residue, leading to symmetrical
oligomers with two identical halves, and (2) two oligomer
segments are coupled into a longer unsymmetrical oli-
gomer.
Results and Discussion
A. Preparation of Building Blocks. Monomeric
building blocks 1-4 (Figure 2) corresponding to meta-
and para-linked residues have been prepared. These
building blocks have been used extensively in construct-
ing various oligomers that are described in this paper.
(1) Building Blocks 1. Two groups of building blocks
1 were prepared starting from the commercially available
2,4-dihydroxybenzoic acid. One group carries identical
side chains (R ) R′), and the other group bears two
different side chains (R * R′ ) CH3).
As shown in Scheme 1, nitration of 2,4-dihydroxy-
benzoic acid followed by esterification in methanol pro-
vided methyl ester 6 in a total yield of ∼60%. Alkylation
was carried out with the corresponding bromides or
tosylate in DMF at 100 °C in the presence of K2CO3.
Hydrolysis of the esters 7a-e with aqueous NaOH or
KOH followed by acidification led to acids 1a-e.
Since ester 7f contained two tert-butyl ester groups
that are labile under strongly basic conditions, LiOH was
employed for its hydrolysis. The hydrolysis in methanol
was carried out for 15-18 h at room temperature, leading
to the desired acid 1f in a yield of 79%. It was noteworthy
that longer reaction time may decrease the yield of 1f
with the removal of one or both tert-butyl groups. These
side products were also observed when bases other than
LiOH were used. For instance, with 4 equiv of NaOH,
after the reaction mixture was stirred for 8 h at room
temperature, the crude product was found to be a mixture
containing two mono-tert-butyl esters, a triacid, and the
desired product 1f that was obtained in a yield of less
than 20%. Among NaOH, LiOH, and Ba(OH)2, only LiOH
Three strategies have been adopted for constructing
oligomers.13,14,19 One involves unidirectional chain growth
by stepwise coupling of monomers derived from amino-
benzoic acid (by reducing 1 and 2), leading to “unsym-
metrical” oligomers with two different (N and C) termini
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Synthesis of Crescent Aromatic Oligoamides
SCHEME 1. Synthesis of Building Blocks 1
SCHEME 2. Synthesis of Building Block 1g
SCHEME 3. Synthesis of Building Blocks 13
gave a major spot on TLC (condition: 3.5-4 equiv of
LiOH; 18 h at room temperature). In this case, controlling
reaction time is crucial for the selective hydrolysis of the
methyl ester while avoiding cleaving the tert-butyl ester
groups. Due to the sensitivity of the tert-butyl ester
groups to acid,44 about 1 equiv of acetic acid (based on
the amount of LiOH) was used to acidify the reaction
mixture after the hydrolysis of 7f.
We have also prepared monomer 1g, which carries two
ethyl ester groups on its side chains (Scheme 2). Due to
the similar reactivity of ethyl and methyl esters, methyl
benzoate such as 6 cannot serve as a precursor for 1g.
The preparation of 1g was realized via tert-butyl ben-
zoates 8 and 9.
The purity of acid 5 was found to be crucial for the
successful preparation of tert-butyl ester 8. The presence
of even a trace amount of nitric acid (from the nitration
step, see Scheme 1) in acid 5 led to a rather low yield
(<15%) of 8. Acid 5 of high purity can be obtained from
its methyl ester 6 (Scheme 1), which was easily collected
by filtration as a white solid. Hydrolysis of ester 6
provided the pure acid 5 as a white powder.
In addition to preparing building blocks of type 1 that
carry two identical side chains, reaction conditions for
preparing acids 13a and 13b, which carry two different
side chains, have also been established. As shown in
Scheme 3, instead of bearing two identical alkoxy groups
on the same residue, 13a,b bear a methoxy and another
alkoxy group on the same benzene ring. The synthesis
began with the alkylation of methyl 2,4-dihydroxy-
benzoate by adding 1.1 equiv of the alkyl bromide (or
tosylate) in the presence of K2CO3, potassium iodide, and
tetrabutylammonium bromide (or chloride). It was found
that, under the above reaction conditions, the alkylation
with alkyl bromide occurred preferentially at the hy-
droxyl group that is para to the methyl ester group,
leading to 10a and 10b. Methylation of the remaining
OH group was realized by using dimethyl sulfate in DMF,
leading to esters 11a and 11b. Hydrolysis of esters 11a
and 11b led to acids 12a and 12b by refluxing in acetone/
NaOH (1 M) followed by acidification. The resulting acids
were then nitrated by dissolving in concentrated H2SO4
and then adding 1.1 equiv of ammonium nitrate over 20
min at 0 °C. The precipitated pure products 13a,b were
collected by filtration in around 95% yield.
(2) Building Block 2. This compound was prepared
by methylating the methyl esters of the known 2,3-
dihydroxy-4-nitrobenzoic acid.44,45 The resulting 2,3-
dimethoxy-4-nitrobenzoate was hydrolyzed into the cor-
responding acid 2.
(3) Building Blocks 3. These building blocks were
synthesized starting from 4,6-dihydroxyisophthalic acid31,33
14 (Scheme 4a). Alkylation of diester 15 led to esters
16a-f, which were converted into acids 3a-f by hydroly-
sis.
(44) Bodanszky, M. Protection of the Carboxyl Group. In Principles
of Peptide Synthesis, 2nd ed.; Springer-Verlag: New York, 1993; pp
84-85.
(45) (a) Kato, S.; Morie, T. J. Heterocycl. Chem. 1996, 33, 1171. (b)
Kato, S.; Morie, T. Org. Prep. Proced. Int. 1999, 31, 106.
J. Org. Chem, Vol. 70, No. 26, 2005 10663

Yuan et al.
SCHEME 4. Synthesis of Building Blocks 3 and 17
SCHEME 5. Synthesis of Building Block 3h
SCHEME 6. Synthesis of Building Blocks 4, 4′, and 4′′
The hydrolysis of ester 16g with similar conditions for
hydrolyzing 7g (see Scheme 1) failed to give diacid 3g as
the major product. Among the separated products the one
with only one methyl ester hydrolyzed was the major
product (72%), together with a small amount of 3g (5%)
and the fully hydrolyzed tetraacid (10%). With shorter
reaction time (15 h) the yield of 3g was raised to about
15% but a significant amount of unreacted 16g (26%) was
recovered.
Partially hydrolyzing dimethyl esters 16 led to mono-
methyl ester acids 17a-c (Scheme 4b). These are very
useful intermediates for coupling steps that need to
distinguish the two carboxyl groups of diacids 3.
As shown in Scheme 5, monomer 3h, with two base-
labile ethyl ester groups on its side chains, was prepared
by first treating the diacid with tert-butyl alcohol, which
led to the di-tert-butyl ester 18 in a moderate yield (55%).
Alkylating 18 with ethyl 3-bromopropionate in aceto-
nitrile in the presence of K2CO3 and KI results in 19
(84%). Removing the tert-butyl groups of 19 with tri-
fluroacetic acid provided the desired diacid 3h in a total
yield of 43.6%. The product was purified by simple
recrystallization from EtAc/n-hexane (1:6).
Dinitro compounds 4a-c were converted into diamines
4′a-c by catalytic hydrogenation. After removing solvent
(methanol or DMF), the air-sensitive 4′a-c were handled
under an inert atmosphere (N2 or Ar) and were usually
used immediately in the subsequent coupling steps.
Selectively reducing one of the two nitro groups of 4a
with use of polysulfide (NaSH‚xH2O + sulfur) led to 2,4-
dimethoxy-5-nitroaniline 4′′a in high (83%) yield.15 The
same procedure was used for the selective reduction of
4c, leading to 4′′b (78%), which is indispensable for the
stepwise construction of oligomers involving diacid and
diamine building blocks.
B. Synethesis of Oligomers. The combination of
meta- and para-disubstituted building blocks leads to
oligomers with different curvatures that are determined
by the ratio of meta- and para-linked residues. Depending
on the orientations of the amide linkages, oligomers with
either unsymmetrical or symmetrical backbones are
obtained.
(1) Unidirectional, Stepwise Coupling. Coupling
of substituted aminobenzoic acids (masked as nitro-
benzoic acids) or their corresponding acid chlorides in a
stepwise fashion leads to oligomers with amide linkages
that orient in the same direction, resulting in oligomers
with unsymmetrical (from the C to the N termini)
backbones.
(4) Building Blocks Based on 4. The ethers (4a-c)
of dinitroresorcinols were prepared by treating the cor-
responding hydroxy compounds and the commercially
available 1,3-difluoro-4,6-dinitrobenzene based on pub-
lished procedures (Scheme 6).46
(46) Lehmann, F. P. A. Tetrahedron 1974, 30, 727.
10664 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of Crescent Aromatic Oligoamides
SCHEME 7. Unidirectional Chain Extension Based on the Coupling of Acid Chlorides and Amines
SCHEME 8. Unidirectional Chain Extension of Oligomers Consisting of the Same Residue 13b
(i) Coupling of Acid Chlorides and Amines. This
coupling strategy involves the incorporation of monomers
1 via their acid chloride35 form (Scheme 7). The monomer
acid chlorides were generated by treating the correspond-
ing acids with thionyl chloride or oxalyl chloride. The
preparation of a number of unsymmetrical oligomers
from dimers 21 to hexamers 25 is shown in Scheme 7 to
illustrate the stepwise coupling reactions. Yields of each
coupling step ranged from 50% to 90%.
Due to the concern of undesirable steric interactions
between bulky side chains flanking an amide group,
residues carrying methyl with other bulkier side chains
were placed on alternating residues along the backbones
of the corresponding oligomers. This requires at least two
different monomer acids or acid chlorides. With mono-
mers such as 13a or 13b that carry a methyl and another
bulkier side chain, homooligomers can be easily con-
structed by the repetitive coupling of the same building
block. For example, starting from the commercially
available 2-methoxy-5-methylaniline, homooligomers
26a-g were constructed by the stepwise coupling of 13b
(via the corresponding acid chloride 13b-Cl) to the amino-
terminated oligomer intermediates (Scheme 8), which
were generated by the hydrogenation of the nitro-
terminated oligomers. Yields for each coupling step
ranged from 60% to 80%. Generally, for each unit added
to the oligomer chain, an additional 5 °C, as well as an
additional 30 min of reaction time, was required for the
completion of the reduction of the terminal nitro group.
This trend plateaued at a reaction time of 4 h and a
reaction temperature of 57 °C for oligomers beyond the
hexamer. The reason behind this could be the increased
bulkiness of the oligomers and thus the inaccessibility
of the nitro groups upon the extension of the oligoaryl-
amide chain. Solubility for all species of this series was
good in chloroform. Of note, however, is octamer 26g,
which exhibited an NMR spectrum of very broad signals.
This was probably due largely in part to the strong
J. Org. Chem, Vol. 70, No. 26, 2005 10665

Yuan et al.
SCHEME 9. Unidirectional Chain Extension with Ph3PCl2 as the Coupling Agent
SCHEME 10. Synthesis of Oligomers Containing Acid-Sensitive Side Chains
intermolecular aggregation of 26g due to the large, well-
defined aromatic surface formed by the helical conforma-
tion of this oligomer.
trimer 28a and tetramer 28b, both of which contain two
tert-butyl ester groups, was achieved by using the cou-
pling reagent EDC in the presence of triethylamine
(Scheme 10). Using the acid chloride of monomer 1d, even
in the presence of an excess amount of triethylamine, led
to significantly reduced coupling yield. The reduction of
28a in CHCl3/ethanol (2:1, v/v) under normal conditions
of hydrogenation (H2, 4 Pa, Pd-C, 50 °C, 3 h) gave a
complicated mixture with a small amount of the desired
product. This was most likely due to the removal of the
tert-butyl groups by the trace amount of acid (e.g., HCl)
from the dehydrochlorination of chloroform or in
Pd-C. Trimer 28a was successfully reduced by hydro-
genation in the same mixed solvent in the presence of
30 equiv of 4-aminopyridine. After hydrogenation, 4-amino-
pyridine was easily removed by filtering through a pad
of silica gel. Coupling of the reduced trimer with mono-
mer 1a using EDC led to tetramer 28b in satisfactory
yield.
(2) Factors Affecting Coupling Efficiency. (i)
Protonation of Amine Intermediates. Although the
reduction of monomers with nitro groups such as 20a,b
can be performed easily by hydrogenation under mild
conditions (room temperature, 1 atm), the hydrogenation
of trimer and longer oligomers became increasingly
sluggish, which usually required elevated temperature
and pressure. Another observation was that during our
early investigation of amide coupling reactions, the yield
of each coupling step fluctuated significantly, ranging
from ∼80% to ∼40%. The amine precursors obtained from
hydrogenation, if washed with aqueous sodium bicarbon-
ate before being coupled to acids or acid chlorides, usually
led to better yields.
The purification of 26a-g typically involved precipitat-
ing the oligomer products from chloroform by adding
methanol, resulting in a >95% pure solid. Purity of the
reacting reagents and intermediates was found critical,
however, for preparing oligomers beyond the tetramer.
Even trace impurities become serious contaminants
beyond the hexamer (26e) stage, which often decreased
the coupling yields from the ideal 70-90% range to 50%
or below.
(ii) Coupling of Acids and Amines. Coupling re-
agents such as EDC, DCC, and HATU have also been
successfully applied for the synthesis of short oligomers.
As chain length increased, the coupling rate was found
to decrease. One coupling reagent, dichlorotriphenylphos-
phorane (Ph3PCl2),47 led to efficiency comparable to that
demonstrated by acid chlorides. Thus, stepwise coupling
of monomer acids with amino-terminated oligomers in
the presence of Ph3PCl2 led to satisfactory yields for the
preparation of homologues 27b-e, which bear ethyl ester
groups on their side chains (Scheme 9).
While the synthesis of oligomers 27b-e could also
employ the coupling of acid chlorides and amines, acid
chlorides become incompatible with monomers and in-
termediates bearing acid-sensitive groups, such as ether,
ester, or carbamate functionality containing the tert-butyl
group. In such cases, acid chlorides usually led to
unsatisfactory results. For example, the synthesis of
(47) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
Tetrahedron 2003, 59, 2325.
10666 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of Crescent Aromatic Oligoamides
SCHEME 11. Bidirectional Chain Extension from a Central Diamine Residue
SCHEME 12. Bidirectional Chain Extension Based on Diacid and Diamine Units
When dimer 21b (Scheme 7) was reduced by hydro-
genation, it was found that the residue (a white solid)
obtained after removing the solvent was only sparsely
soluble in CH2Cl2. This white solid, which was quite
soluble in ethanol, turned out to be the protonated form
of the reduced product (i.e., amino dimer). It gradually
dissolved into CH2Cl2 upon addition of triethylamine.
Obviously, acid (HCl) from the dehydrochlorination of
which, or from the Pd-C catalyst was responsible for the
protonation of the amine. In fact, it is a general phenom-
enon that both the free amine and the corresponding salt
were obtained after the hydrogenation of a nitro com-
pound, with the former accounting for a small fraction
of the hydrogenated product. The free amine form, which
is critical to achieving satisfactory coupling yields, can
be generated by adding an excess of triethylamine or
washing with aqueous NaHCO3 right before the coupling
steps. Another method that avoided the formation of
protonated amines from hydrogenation involved using
DMF as the solvent, in which case no amine salt was
detected. However, using DMF as the solvent for hydro-
genation is not practical since most of the oligomers with
alkyl side chains have very limited solubilities in this
solvent, and completely removing DMF is difficult due
to its high boiling point.
ard coupling reagents such as DCC and EDC. It was
reported47 that dichlorotriphenylphosphorane (Ph3PCl2)
was an effective coupling reagent for forming hindered
tertiary benzanilides from the corresponding substituted
benzoic acids and N-monoalkylated anilines. An advan-
tage of this reagent is that it requires no other additive
for the coupling reaction.47 As already shown in Scheme
9, oligomers 27b-e were prepared in satisfactory yields
with Ph3PCl2. Compared to generating monomer acids
with oxalyl chloride, the coupling method involving
Ph3PCl2 was straightforward and much more convenient.
Oligomers 27b-e were obtained by simply mixing three
reagents (amine, acid, and Ph3PCl2) together and reflux-
ing for 12 to 30 h in methylene chloride or chloroform.
The yield based on free amine is comparable to that with
acid chlorides. Therefore Ph3PCl2 could be a very promis-
ing, inexpensive reagent for constructing aromatic oligo-
amides of the type developed by us. The synthesis of
longer oligomers based on this reagent is currently being
explored.
(3) Bidirectional, Stepwise Coupling. Coupling
acids to a substituted phenylenediamine will lead to
chain growth in two opposite directions, leading to
oligomers with two identical halves. Compared to the
above-discussed unidirectional coupling, this strategy
allows the synthesis of symmetrical oligomers of the same
length with only half of the coupling steps. As shown in
Scheme 11, pentamer 29b was prepared in two coupling
(ii) Coupling Methods. Coupling reactions involving
monomer acid chlorides and oligomer amines generally
led to better coupling yields than reactions using stand-
J. Org. Chem, Vol. 70, No. 26, 2005 10667

Yuan et al.
SCHEME 13. Synthesis of the Symmetrical 35 by Coupling Two Identical Fragments to a Diacid Unit
SCHEME 14. Synthesis of Unsymmetrical Oligomers by Segment Condensation
steps starting from monomer 4b. This strategy is par-
ticularly useful for preparing meta/para-linked oligomers
that require more residues to complete a helical turn than
the all-meta-linked oligomers.
oligomer 35 obtained by this convergent route is sym-
metrical, consisting of two identical halves. In fact, a
meta/para-linked 21mer represents the longest oligomer
we have prepared so far.37 Our previous 2D NMR studies
showed that this 21mer folded into a helical conformation
with a large (>30 Å) interior cavity.37 These oligomers,
with their tri(ethylene glycol) side chains, had good
solubility in polar solvent such as DMSO, DMF, or mixed
solvent of DMSO and methanol.
On the basis of the same strategy, pentamers 31
(Scheme 12a) and 34 (Scheme 12b) were obtained by
coupling the corresponding diacids and diamines. The
adoption of monoacid 17c and nitroaniline 4′′a was the
key for the success of the stepwise coupling shown in
Scheme 12. Continuing the coupling steps should lead
to AB-type oliogmers longer than the pentamers. Pen-
tamers 31 and 34, with their preorganized backbones,
should readily undergo ring-closing when treated with
the corresponding diacid or diamine, leading to shape-
persistent six-residue macrocycles4,19,37 with specifically
incorporated functional groups.
(4) Convergent Synthesis of Oligomers. (i) Cou-
pling Two Identical Amino-Terminated Oligomers
to a Diacid Chloride. Another strategy for constructing
long oligomers with reduced coupling steps involves the
coupling of oligomer fragments. We described previously
the preparation of symmetrical nonamers and undecam-
ers by coupling unsymmetrical oligomers,19,37 which in
turn were prepared by stepwise coupling to a central
diacid (or the corresponding diacid chloride). Longer
oligomers were also prepared based on this strategy in
solution. For example (Scheme 13), 13mer 35 was ob-
tained in reasonable yields by treating hexamer 25 with
the corresponding diacid chloride. Similar to the bidirec-
tional coupling strategy shown in Schemes 11 and 12,
(ii) Segment Condensation of Short Oligomers.
Another convergent approach involves the coupling of two
oligomer precursors, one carrying a terminal carboxyl
group and the other bearing a terminal amino group. Our
earlier attempts to couple nitro-terminated oligomer acids
to amino-terminated oligomers were met with limited
success, which was most likely due to the stacking of the
oligomer precursors. The above-discussed synthetic strat-
egies use the nitro group as the equivalent of a protected
amino group. The need to reduce the nitro group before
each coupling step introduces an extra step that inevi-
tably compromises the overall yield of a multistep oligo-
mer synthesis. It was also discovered that the hydro-
genation of nitro-terminated oligomers became increas-
ingly sluggish as the backbone of the oligomers extended.
In addition to that issue, the hydrogenation step is also
incompatible with the solid-phase synthesis of oligo-
amides currently being developed. To develop efficient
solution and solid phase synthetic strategies, the amino
and carboxyl functionalities of the building blocks and
intermediates need to be protected by using different
10668 J. Org. Chem., Vol. 70, No. 26, 2005

Synthesis of Crescent Aromatic Oligoamides
(2) Preparation of Acid Chloride from the Corre-
sponding Acids. To a solution of acid (1.0 equiv) and oxalyl
chloride (1.2 to 1.5 equiv) in dry CH2Cl2 were added one or
two drops of DMF. The mixture was stirred for 20 min at room
temperature and then refluxed for an additional 30-50 min.
The solvent was evaporated and the resulting acid chloride
was dissolved in dry CH2Cl2, then the solvent was evaporated
to remove any excess oxalic chloride. The residue was used
for the next coupling step.
(3) Hydrolysis of Methyl Esters. A mixture of compounds
7a-f or 16a-f (1 equiv) in MeOH (or THF, water) and sodium
hydroxide (or potassium hydroxide, lithium hydroxide) (2 to
2.5 equiv) dissolved in water was refluxed for 2-12 h. Workup
followed either of the two methods: (A) Water (ca. twice of
the solvent used) was added to cause precipitation while
acidifying with HCl. After removing part of the solvent, the
solid was collected, washed with water, and triturated with
methanol to give the desired acid. (B) The mixture was
acidified followed by removing most of the solvent, and the
residue was extracted twice with ethyl acetate. The organic
layer was washed with water, dried over anhydrous Na2SO4,
and evaporated to afford the desired product.
groups that can be easily removed under orthogonal
conditions.
As shown in Scheme 14, acids 1a and 1d were
converted into amino ester 38 and acid chloride 39,
respectively. Coupling of 38 and 39 in the presence of
triethylamine led to dimer 40. Deprotection of 40 with
trifluoroacetic acid (TFA) and NaOH in methanol gave
acid 41 and amino ester 42, which were coupled via acid
chloride into tetramer 43 in a yield of 76%. Repeating
the deprotection and coupling procedures on tetramer 43
led to octamer 44 as indicated by MALDI-TOF. Condi-
tions for preparing higher oligomers are being pursued.
The coupling strategy as shown in Scheme 14 has
provided a convergent method for the rapid preparation
of long oligomers by doubling the chain length of the
oligomers in each coupling cycle. The orthogonal reac-
tivities of TFA-amido and tert-butyl groups are critical
for the success of this approach. The high efficiency of
the coupling reactions bodes well for applying these
monomer and dimer building blocks to solid-phase syn-
thesis that is being developed.
(4) Hydrogenation of Nitro Compounds. The general
procedure for the preparation of the amines from the corre-
sponding monomer and oligomers (dimers and beyond) bearing
a nitro group by catalytic hydrogenation is as follows:
Conclusions
To a mixture of nitro compounds, 10% Pd/C (10-20 wt % of
nitro compound) and chloroform, was added methanol. (Cau-
tion! Direct addition of methanol to the Pd/C without wetting
the catalyst with solvent may cause fire!) The solution was
purged with hydrogen, and shaken under an atmosphere of
hydrogen gas at the appropriate temperature for a period of
time from one to several hours until only amine appeared on
TLC, which is signaled in most cases by the color change of
spots caused by oxidation under UV lamp or in air. The
mixture was then filtered and the solvent evaporated. The
residue consisting usually of both free amine and amine salt
was treated according to the following two procedures: (A) It
was dissolved in CH2Cl2, and triethylamine was added to the
solution with stirring to convert any amine salt to free amine,
followed by immediate coupling with acid chloride. (B) The
solution of the residue was washed with aqueous NaHCO3 and
water, dried over Na2SO4, and evaporated to dryness to afford
the crude amine (>90%), which was used without further
purification for the next step. For each subsequent higher
nitro-oligomer an additional 5 °C increment of reaction tem-
perature and an additional 20-30 min of reaction time were
required.
The methods developed by us for synthesizing folding
aromatic oligoamides over the past several years are
summarized in this article. The availability of a series
of monomers in large quantities has provided the basis
for the preparation of oligomers with curved backbones
of different curvatures. These tetrasubstituted mono-
mers, along with many of the intermediates developed
during the synthesis, should also be useful for many other
synthetic purposes. The three coupling strategies have
led to the preparation of oligomers of various length.
These oligomers fold into crescent and helical conforma-
tions containing internal hydrophilic cavities from 9 to
30 Å across. The efficient solution synthesis of these
oligomers bodes well for the preparation of longer oligo-
mers and for solid-phase synthesis that is being devel-
oped.
Experimental Section
General Procedures: (1) Preparation of Disubstituted
Methyl Ester with Different Side Chains. A mixture of
2,4-dihydroxy-5-nitrobenzoic acid methyl ester 6 (1 equiv) or
15 (1 equiv) and potassium carbonate (2.5-3.0 equiv) in DMF
was heated at 60 °C with stirring for 1-2 h. Then alkyl
bromide (2.2 equiv) and potassium iodide (1% of alkyl bromide)
were added followed by heating at 90-100 °C for about 2 days.
In the case of 7a CH3I was used, no KI was added, and the
temperature was kept around 38 °C throughout the reaction.
The reaction mixture was filtered while hot and the solid left
was extracted with ethyl acetate. The filtrate and the extract
were combined. After removing the solvent under reduced
pressure, the remaining residue was dissolved in methylene
chloride, washed with brine and water, and dried over
anhydrous Na2SO4. Removal of CH2Cl2 afforded the desired
product.
Synthetic procedures for the preparation of various oligo-
mers, along with analytical and characterization data, can be
found in the Supporting Information.
Acknowledgment. We thank the National Insti-
tutes of Health for support (R01GM63223).
Supporting Information Available: Specific synthetic
procedures for certain compounds; analytical and spectral
characterization data of compounds discussed in the text. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050798A
J. Org. Chem, Vol. 70, No. 26, 2005 10669