Synthesis of linear and cyclic aromatic peptides with fixed conformation owing to intramolecular hydrogen bonding by condensation polymerization method

Article abstract of DOI:10.1016/j.tetlet.2011.10.071

Chain-growth condensation polymerization of 3-(4-octyloxybenzylamino) benzoic acid esters bearing an alkoxy group on the benzene ring was investigated for the synthesis of polyamides having a specific conformation owing to intramolecular hydrogen bonding

Full text of DOI:10.1016/j.tetlet.2011.10.071

Tetrahedron Letters 52 (2011) 7067–7070
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of linear and cyclic aromatic peptides with fixed conformation
owing to intramolecular hydrogen bonding by condensation polymerization
method
Tomoyuki Ohishi a, Toshiya Suzuki a, Tetsurou Niiyama a, Koichiro Mikami a, Akihiro Yokoyama a,
Kosuke Katagiri b, Isao Azumaya b, Tsutomu Yokozawa a,
⇑
a Department of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chain-growth condensation polymerization of 3-(4-octyloxybenzylamino)benzoic acid esters bearing an
alkoxy group on the benzene ring was investigated for the synthesis of polyamides having a specific con-
formation owing to intramolecular hydrogen bonding of CONHꢀ ꢀ ꢀOR. The 4-octyloxybenzyl group on the
nitrogen of the amide linkage was easily removed with trifluoroacetic acid after polymerization to afford
the desired polyamides, which had lower solubility than expected. Furthermore, we found that a cyclic
triamide was selectively obtained by slow addition of the base to a solution of the monomer.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 August 2011
Revised 11 October 2011
Accepted 13 October 2011
Available online 25 October 2011
Keywords:
Chain-growth condensation polymerization
Aromatic peptide
Poly(m-benzamide)
Hydrogen bond
Macrocycles
In recent years, there has been intense interest in developing
unnatural aromatic peptides in which intramolecular hydrogen
bonding leads to macrocycle formation or folding into helical struc-
tures (Scheme 1A).1 These oligomers, however, have been synthe-
sized by time-consuming stepwise condensation reactions. On the
other hand, we have developed chain-growth condensation
polymerization (CGCP) to afford aromatic tertiary polyamides with
controlled molecular weight and low polydispersity.2 Poly(p-benz-
amide)s and poly(naphthalenecarboxamide)s with a chiral side
chain on the amide nitrogen can be easily synthesized by CGCP,3
and they adopt helical conformation on the basis of the high cis con-
formational preference of the tertiary amide linkage4 and the syn
arrangement of the three consecutive aromatic units connected
by two amide linkages. These helical structures are different from
those in Scheme 1A, in that the aromatic rings in the polymer are
almost perpendicular to the amide carbonyl plane. However, polya-
mides with a sheet or curved structure, in which the aromatic rings
and the amide carbonyl are in the same plane, similar to the oligo-
mers in Scheme 1A, could be synthesized by CGCP of alkoxy-substi-
tuted monomers, followed by conversion of the tertiary amide to
secondary amide by removal of the protecting group on the amide
nitrogen (Scheme 1B). Indeed, the structure of N-o-methoxyphe-
nylbenzamide was studied by means of crystallographic analysis,
and this amide has a highly planar structure owing to intramolecu-
lar hydrogen bonding of CONHꢀ ꢀ ꢀOR.5 In this Letter, we synthesized
well-defined aromatic polyamides that exhibit intramolecular
hydrogen bonding between CONH and an alkoxy group by means
of CGCP of 4-alkoxy-3-(4-octyloxybenzylamino)benzoic acid phe-
nyl esters 1 in the presence of base and initiator 2, followed by re-
moval of the 4-octyloxybenzyl (OOB) group. Furthermore, we also
found that cyclic trimers of these monomers were selectively
formed under certain conditions.
The CGCP of monomer 1a was first carried out in the presence of
10 mol % of initiator 2, 1.1 equiv of lithium 1,1,1,3,3,3-hexamethyl-
disilazide (LiHMDS), and 5.5 equiv of LiCl, which is effective for the
stabilization of anions,6,7b in THF ([1a]0 = 0.40 M) at 0 °C. The poly-
merization proceeded homogeneously and was completed within
2 h after slow addition of 1a to the reaction mixture (40–60 min).
The obtained poly1a possessed low polydispersity as well as well-
defined molecular weight based on the feed ratio of monomer 1a
to initiator
2 (Mn (calcd) = 4870, Mn = 4200, Mw/Mn = 1.11)
(Fig. 1a). The 1H NMR spectrum of poly1a showed the methyl signal
of 2 attached to the polymer, and there was no signal of a terminal
amino 1a unit not attached to 2. These results indicate successful
CGCP of 1a from 2 without self-polycondensation of 1a. However,
when the polymerization of 1a was carried out at the feed ratio
[1a]0/[2]0 of 29, the gel-permeation chromatogram (GPC) elution
⇑
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413 9770.
E-mail address: yokozt01@kanagawa-u.ac.jp (T. Yokozawa).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.071

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T. Ohishi et al. / Tetrahedron Letters 52 (2011) 7067–7070
(A)
R
OiBu
R
O
O
H
N
R
O
R
O
O
N
H
C
N
H
N
H
N
O
C
O
C
H
O
H
O
N
N
N
N
H
C
O
N
H
C
O
R
C
H
O
O
R
O
O
N
iBuO
OiBu
R
O
O
R
(B)
R1
O
R1
O
O
C
LiHMDS (1.1 eq)
LiCl (5.5 eq)
CF3COOH
O
C
OPh
OPh
n
THF, 0 oC
OPh
N
OOB
C
O
HN
OOB
C
O
H3C
H3C
2
1a: R1 = CH3
LiHMDS = LiN[Si(CH3)3]2
OOB =
1b: R1 = C8H17
1c: R1 = CH2CH(CH3)2
CH2
OC8H17
R1
R1
O
R1
O
O
R1
H
O
H
N
N
H
O
H
O
O
N
C
C
N
N
C
C
O
or
N
R1
H
H
O
H
O
O
O
N
N
O
O
O
H
R1
R1
R1
Scheme 1. Synthesis of folding oligoamides and polyamides by means of (A) stepwise condensation reactions and (B) chain-growth condensation polymerization.
C8H17
O
C8H17
O
OOB
O
N
C8H17
O
(b)
(a)
(d)
(c)
(f)
N
C
C
LiHMDS
O
OOB
O
OPh
THF
0 ºC, 4 h
N
OOB
C
O
C8H17
HN
OOB
C
O
n
N
OOB
C
O
1b
oligo1b
O
C8H17
cycle1b (70%)
OOB = CH2
OC8H17
(e)
cycle1b
15
20
15
20
15
20
oligo1b
Elution Time (min)
Elution Time (min)
Elution Time (min)
Figure 1. GPC profiles of the crude products of polymerization of 1 with 2 (eluent:
THF). The polymerization was carried out with (a) [1a]0/[2]0 = 10, (b) [1a]0/[2]0 = 29,
(c) [1b]0/[2]0 = 10, (d) [1b]0/[2]0 = 29, (e) [1c]0/[2]0 = 10 and (f) [1c]0/[2]0 = 30.
15
20
Elution Time (min)
Figure 2. GPC profiles of the crude product obtained by the cyclization of 1b in THF
at 0 °C.
curve of the obtained polymer showed a small peak in the lower-
molecular-weight region, as well as the peak corresponding to
poly1a (Mn = 8850, Mw/Mn = 1.12) (Fig. 1b). The 1H NMR spectrum
of this tiny peak product, which was separated by a preparative
HPLC, showed only the signals of the repeat unit of the polymer.
Furthermore, the observed molecular weight determined by
matrix-assisted laser desorption ionization time-of-flight (MALDI-
TOF) mass spectroscopy was consistent with the expected molecu-
lar weight of a cyclic trimer of 1a. Accordingly, it turned out that a
small amount of 1a underwent self-condensation at high feed ratio
to afford the cyclic trimer.
Other monomers 1b and 1c with a bulkier alkoxy group on the
benzene ring were similarly polymerized. A small peak was
observed in the lower-molecular-weight region even in the poly-
merization with 10 mol % of 2 (Fig. 1c and e), and this peak became
larger at the feed ratio [1]0/[2]0 of about 30 (Fig. 1d and f). We con-
firmed that these peak products were the cyclic trimers of 1b and
1c from the 1H NMR spectra and the MALDI-TOF mass spectra. The
accompanying cyclization of monomer 1 is a feature of the CGCP of
1, because the CGCP of meta-substituted monomers without the

T. Ohishi et al. / Tetrahedron Letters 52 (2011) 7067–7070
7069
C8H17
O
C8H17
O
OOB
O
N
H
C
O
N
TFA = CF3COOH
N
C
N
C
O
OOB
O
O
H
O
C
TFA
TIPS
C8H17
C8H17
TIPS =
HSi
reflux, 20 h
N
C
N C
O
O
H
OOB O
O
C8H17
C8H17
cycle1b' (32%)
cycle1b
Scheme 2. Deprotection of cycle1b.
as a model compound of the polyamide, was more stable than a
curved structure (ca. 2.1 kcal/mol). This implies that poly1 would
preferentially adopt a planar zigzag conformation rather than a
curved conformation, and the former conformation is likely to have
stronger intermolecular interaction among polymer chains.
Since the cyclic triamide was obtained as byproduct in the poly-
merization of 1, we next tried to selectively synthesize the cyclic
triamide of 1b. Contrary to the case of cyclic trimerization of N-
alkylated p-aminobenzoic acid esters,9 when LiHMDS was added
to a solution of 1b,10 the GPC profile of the product obtained after
4 h showed a sharp peak due to cyclic triamide (Fig. 2). Purification
on a silica gel column afforded the cyclic triamide of 1b in a 70%
yield.
Deprotection of the cyclic triamide was attempted with TFA, but
the OOB group was not removed. Then, the cyclic triamide was re-
fluxed in neat TFA with triisopropylsilane (TIPS) as a scavenger, as
reported by Wilson et al. (Scheme 2).11 In the 1H NMR spectrum of
the product, the signal of the benzylic protons of the OOB group at
around 4.90 ppm had disappeared, and a new signal due to amide
N–H proton was observed at around 7.27 ppm (Fig. 3). The MALDI-
TOF mass spectrum contained only one peak corresponding to the
Na+ adduct of N–H cyclic triamide (cycle1b0).
h
g
f
h
e
c
O
b
N
C
O
a
H
3
d
e
g
d
a
c
f
b
ppm
7
6
5
4
3
2
1
1
Figure 3. H NMR spectrum (600 MHz, CDCl3) of cycle1b0.
alkoxy group did not afford cyclic triamides.7 The difference may
be accounted for by the lower acidity of the amino group of 1
due to intramolecular hydrogen bonding between the amine pro-
ton and the alkoxy oxygen; slow proton abstraction of the amino
group would induce the reaction of deprotonated 1 with non-
deprotonated 1, leading to self-condensation. Actually, the amino
proton of 1 appears at higher magnetic field (4.64–4.57 ppm), com-
pared to that of meta-substitute monomers without the alkoxy
group (4.09–4.02 ppm).7b
In conclusion, we have demonstrated that well-defined poly(m-
benzamide)s having a specific conformation arising from intramo-
lecular hydrogen bonding between CONH and an alkoxy group can
be obtained by means of CGCP of 1 bearing alkoxy groups on the
benzene ring, followed by removal of the OOB group with TFA. Fur-
thermore, we found that the cyclic trimer of 1 was selectively
obtained by the slow addition of LiHMDS to a solution of 1; the ob-
tained cyclic tertiary triamide was converted to the secondary tria-
mide by the removal of the OOB group with TFA/TIPS.
Removal of the OOB group on the amide nitrogen of the
obtained poly1b and poly1c was conducted with trifluoroacetic
acid (TFA) in CH2Cl2 at ambient temperature for 3 days.7b,8 The
reaction proceeded homogeneously, and the products were puri-
fied by precipitation into a large amount of hexane. In the 1H
NMR spectra of the products, the signal of the benzylic protons
of the OOB group at around 4.90 ppm was absent. The FT-IR spectra
of the products showed N–H stretching bands at 3290 cmꢁ1. There-
fore, the OOB group was quantitatively removed, resulting in the
desired secondary polyamides. However, both the N–H polybenza-
mides were only soluble in TFA and CH2Cl2 and had lower
solubility than poly(N-H-m-benzamide), which is soluble in
dimethylsulfoxide (DMSO) and N,N-dimethylacetamide (DMAc).7b
This result is considered to be due to intramolecular hydrogen
bond formation between amide N–H and the oxygen atom at the
ortho position of the benzene ring in poly1, which favours the for-
mation of a sheet structure, such as a planar zigzag or a curved
Acknowledgment
This study was supported by Scientific Frontier Research Project
Grant from the Ministry of Education, Science, Sport and Culture,
Japan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.071.
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