Improved solid-phase synthesis and study of arylopeptoids with conformation-directing side chains

Article abstract of DOI:10.1016/j.tet.2011.12.049

The development of an improved methodology for iterative solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) using benzoyl chloride building blocks is described. This methodology has enabled the synthesis of arylopeptoids with tert-butyl and phenyl side chains, which allows for complete control over the amide conformation: the tert-butyl results in a 100% cis amide conformation while the phenyl side chain results in a 100% trans amide conformation. The method has furthermore enabled the first synthesis and preliminary conformational studies of arylopeptoids bearing (S)-N-(1-phenylethyl) side chains.

Full text of DOI:10.1016/j.tet.2011.12.049

Tetrahedron 68 (2012) 4444e4454
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved solid-phase synthesis and study of arylopeptoids with
conformation-directing side chains
,
b,
Thomas Hjelmgaard a , Sophie Faure c, Emiliana De Santis d, Dan Staerk a, Bruce D. Alexander e,
*
Alison A. Edwards d, Claude Taillefumier b , John Nielsen
a Department of Basic Sciences and Environment, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark
,
c
,
a
*
b
ꢀ
CNRS, UMR6504, Laboratoire SEESIB, 63177 Aubiere Cedex, France
c
ꢁ
ꢁ
Clermont Universite, Universite Blaise Pascal, BP 10448, 63000 Clermont-Ferrand, France
d Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom
e School of Science, University of Greenwich, Central Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of an improved methodology for iterative solid-phase synthesis of para- and meta-
arylopeptoids (oligomeric N-substituted aminomethyl benzamides) using benzoyl chloride building
blocks is described. This methodology has enabled the synthesis of arylopeptoids with tert-butyl and
phenyl side chains, which allows for complete control over the amide conformation: the tert-butyl re-
sults in a 100% cis amide conformation while the phenyl side chain results in a 100% trans amide con-
formation. The method has furthermore enabled the first synthesis and preliminary conformational
studies of arylopeptoids bearing (S)-N-(1-phenylethyl) side chains.
Received 30 September 2011
Received in revised form 30 November 2011
Accepted 19 December 2011
Available online 23 December 2011
Keywords:
Foldamers
Aromatic oligoamides
Peptoids
Ó 2011 Elsevier Ltd. All rights reserved.
Solid-phase synthesis
Conformational analysis
1. Introduction
O
O
O
R
N
During the last decade, aryl-based foldamers have proven to be
well suited for structural and functional mimicry of biopolymers.1
Among these, aromatic oligoamides built from aromatic amino
acids in a ‘one-way sequence’ have been a main area of interest.2
Most research efforts have been focused on species with free
backbone amide protons for which the folding propensities are
mainly due to intramolecular hydrogen bonds along the artificial
backbone; by contrast, their N-substituted counterparts remain less
developed. Until recently only N-alkylated benzanilides (Fig. 1,
left),3 and N-alkylated naphthanilides (Fig. 1, mid) had been stud-
ied.3b These oligomers have only the amide functionalities in
common with peptide backbones; they contain no aliphatic car-
bons and the amide protons are absent. The hydrogen bonding
capability of the peptide backbone plays a central role in the for-
mation of secondary structures but for these artificial oligomers the
lack of amide proton significantly decreases the capability of intra-
and intermolecular hydrogen bonding.
N
R
N
R
m/p-arylopeptoids
(N-alkylated
m/p-aminomethyl
benzamides)
N-alkylated
N-alkylated
naphthanilide
/ -benzanilides
m p
Fig. 1. N-Alkylated aromatic oligoamides.
Nevertheless, it has been demonstrated that these unnatural ar-
omatic backbones can be driven into stable secondary structures by
solvophobic and/or aromatic interactions. Indeed, N-alkylated ben-
zanilides have been reported to adopt crescent or helical structures,3g
and have been used as a-helix mimetics for inhibition of proteine-
protein p53ehDM2 interactions.3a The arylopeptoids (oligomeric N-
substituted aminomethyl benzamides, Fig. 1, right) may, however,
represent an intriguing addition to N-alkylated aromatic oligoamide
foldamers. Although first reported back in the mid 1990s in connec-
tion with the development of peptoids4,5 (oligomeric N-alkylated
glycines),6 the potential of this type of oligomers remained
* Corresponding authors. Tel.: þ45 35 33 24 27; fax: þ45 35 33 23 98 (T.H.); tel.:
þ33 473 40 54 27; fax: þ33 473 40 77 17 (C.T.); e-mail addresses: thhj@life.ku.dk
(T. Hjelmgaard), claude.taillefumier@univ-bpclermont.fr (C. Taillefumier).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.049

T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4445
unexplored until very recently.7,8 If control of their backbone con-
formations can be achieved, the presence of aliphatic carbons in their
backbones relative to N-alkylated benzanilides and naphthanilides
may allow for sampling of a larger conformational space. The addi-
tional methylene group together with the tertiary amide should also
allow thisartificial polyamide to retain thefavorablecharacteristics of
peptoids, such as large potential for diversity and straightforward
synthesis using submonomer methods. These characteristics are, for
example, crucial for the developmentof large libraries fordiscovering
new inhibitors of proteineprotein interactions.9 Thus, drawing from
our experiences within development of convenient methods for
peptoid synthesis,10 we have reported the first solution-phase syn-
thesis of para- and meta-arylopeptoids.7b The optimized sub-
monomer coupling-substitution cycles were carried out using
bromomethylbenzoyl bromide building blocks in THF at 0 ꢀC fol-
lowed by reactions with primary amines in THF at rt. This method
allowed for gram-scale synthesis of selected arylopeptoids and we
furthermore undertook the first conformational studies of arylo-
peptoids by NMR. Thus, we found that increasing the bulkiness of
simple alkyl side chains greatly favored the cis amide bond confor-
mation. To allow rapid synthesis of large and diversified libraries, we
recentlyadded an efficient solid-phase methodology to the toolboxof
arylopeptoid synthesis.7a While the N-alkylated benzanilides and
naphthanilides have exclusively been synthesized using building
blocks activated as acid chlorides, this method utilizes benzoic acid
building blocks and peptide-type coupling reagents. Thus, having
excluded the use of bromomethyl benzoic acid building blocks due to
their instability under basic conditions, the optimized iterative sub-
monomer method is based on COMU-mediated coupling of chlor-
omethylbenzoic acid building blocks in NMP at rt followed by
reaction with primary amines in DMSO at 50 ꢀC. Although broadly
applicable, this method was found to be inadequatewhen attempting
to install the bulky (S)-N-(1-phenylethyl) (spe) side chains, which
have been used extensively in conformational studies of peptoids.11,12
The method also failed when attempting to install the highly bulky
tert-butyl side chain. The tert-butyl side chain is of interest since we
have shown that it invokes a 100% cis amide conformation.7b The
method was also unsuccessful when attempting to couple the COMU-
activated benzoic acid building blocks to intermediates derived from
use of aniline in the substitution reactions. This hindered insertion of
a sidechain that wasexpectedto give rise to a high proportionof trans
amide conformation.3b,13 Herein we report that the use of chlor-
omethyl benzoyl chlorides rather than COMU-activated benzoic acids
in the acylation steps represents a solution to these limitations. We
also report further conformational studies of these arylopeptoids,
primarily by NMR.
2. Development of synthetic methods
2.1. Method A: direct adaptation from COMU-method
During our preceding solution-phase studies it was demon-
strated that installation of the highly bulky tert-butyl side chains
was possible when using acyl bromides in the coupling steps.7b
We therefore speculated that the solution to the limitations of
our developed solid-phase methodology could be the use of acid
chlorides in place of the corresponding COMU-activated (chlor-
omethyl)benzoic acids in the coupling steps. The required build-
ing blocks, 3- and 4-(chloromethyl)benzoyl chloride are both
commercially available. As in our preceding solid phase studies
we chose to synthesize para-trimers with free acids at the C-
terminus as model targets for testing this hypothesis (Scheme 1
and Table 1). A 2-chlorotrityl chloride polystyrene resin with
a listed loading of 1.50 mmol gꢁ1 was used; employing the same
attachment procedure a loading of 1.23ꢂ0.03 mmol gꢁ1 chlor-
omethylbenzoic acid was obtained.7a Using incorporation of the
bulky spe side chain as a starting point, we replaced the use of
1.0 M COMU-activated 4-(chloromethyl)benzoic acid (3.0 equiv)
in NMP with the use of 0.50 M 4-(chloromethyl)benzoyl chloride
(3.0 equiv) in CH2Cl2 in the coupling steps. Apart from the higher
dilution, which was necessary to facilitate mixing, all other re-
action conditions were left unchanged. The new acid chloride
based method proved very efficient for installing the bulky spe
side chains and the desired model trimer p-1a was isolated in an
excellent 97% crude purity (Table 1, entry 1). No optimization was
needed and we therefore assumed that this directly adapted
method (method A) would also be efficient for installing other
side chains derived from the use of reactive and less bulky
amines. We then found that the method furnished model trimer
p-1b carrying tert-butyl side chains in 80% crude purity (entry 2).
Although obtained in a much less impressive 28% crude purity,
the method was likewise able to provide model trimer p-1c de-
rived from the use of unreactive aniline in the substitution steps
(entry 3). Thus, for installation of side chains derived from highly
bulky tert-butyl amine and unreactive aniline additional optimi-
zation studies were required.
O
R
N
O
n
O
Cl
H
b)
a)
O
Cl
PS
a
Cl
c)
R =
O
O
b
d), e)
R
BzN
N
R
R
N
OH
b)
O
p-1
O
Cl
R
N
O
n
c
O
Scheme 1. Acid chloride based solid-phase synthesis of model arylopeptoid trimers using conditions directly adapted from COMU-mediated synthesis (method A). Key: (a)
ClCH2ArCOOH (1.2 equiv, 0.14 M), DIPEA (6.0 equiv), CH2Cl2, rt, 1 h. (b) R-NH2 (20 equiv, 2.0 M), DMSO, 50 ꢀC, 1 h. (c) ClCH2ArCOCl (3.0 equiv, 0.5 M), DIPEA (6.0 equiv), CH2Cl2, rt,
20 min. (d) BzCl (3.0 equiv, 0.5 M), DIPEA (6.0 equiv), CH2Cl2, rt, 20 min. (e) HFIP/CH2Cl2 1:4, rt, 1 h. See Table 1 for yields.

4446
T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
Table 1
from 1 h to 2 h during the substitution reactions (entry 2). On the
contrary, increased reaction time for the coupling and capping
steps had no effect on the crude purity and crude yield (entry 3)
and we therefore focused the optimizing efforts on the sub-
stitution step.
Results for acid chloride based solid-phase synthesis of model trimer arylopeptoids
using conditions directly adapted from COMU-mediated synthesis (method A)
Entry
Trimer
Crude yield (%)
Crude purity (%)a
1
2
3
p-1a
p-1b
p-1c
78
74
51
97
80
28
Thus, increasing the reaction time to 3 h further improved the
crude purity (75%, entry 4). The use of a more concentrated solution
of aniline in the substitution steps (4.0 M/1 h, entry 5) also resulted
in improved crude purity to 58%. Combination of these two pa-
rameters again furnished the optimal conditions (method C). Thus,
the use of 4.0 M aniline for 3 h (entry 7) provided the best com-
promise between crude purity (87%) and crude yield (75%) since
shortening the reaction time to 2 h gave a lower crude purity (82%,
entry 6) while a reaction time of 4 h resulted in a decreased crude
yield (64%, entry 8) even though the crude purity was improved
slightly (90%). This observed decrease in crude yield is presumably
a result of increased aminolysis of the arylopeptoid chains from the
2-chlorotrityl linker caused by the extended reaction times of the
substitution steps.
a
Determined by analytical HPLC.
2.2. Method B: adaptation for tert-butyl side chains
The reaction conditions for installing tert-butyl side chains were
optimized by synthesizing trimer p-1b as a model target, with 80%
crude purity and 74% crude yield being the starting points (Table 2,
entry 1). We rapidly established that increasing the reaction time
during the substitution steps had no effect on the crude purity and
crude yield (entry 2). Optimization efforts were therefore con-
centrated on the coupling and capping steps. By increasing the
reaction time of these steps from 20 min to 40 min an increase in
crude purity to 90% was obtained (entry 3). A similar improvement
could also be achieved by increasing the concentration and
equivalents of acid chlorides to 1.0 M and 6.0 equiv, respectively,
while keeping the reaction time at 20 min (entry 4). Combination
of these two findings, i.e., use of 6.0 equiv acid chloride at 1.0 M for
40 min provided the optimal conditions (method B) with 94%
crude purity and a crude yield of 89% (entry 5). Increasing the re-
action times further to 1 h did not result in any improvement
(entry 6).
3. Solid-phase synthesis of arylopeptoids
With optimized methods in hand we then synthesized a range of
representative model para- and meta-homohexamers with free acids
(p/m-2) or primary amides (p/m-3) at the C-terminus (Scheme 2 and
Table 4). The syntheses of p/m-2 were performed onthe 2-chlorotrityl
polystyrene resin used in the above optimization studies, while a rink
amide polystyrene resin with a listed loading of 0.74 mmol gꢁ1 was
used for synthesis of p/m-3. For incorporation of the highly bulky tert-
Table 2
Optimization of substitution step (b) and coupling/capping step (c)/(d) for synthesis of p-1b (method B)
Entry
Substitution step (b)
tBuNH2 ([c])
Coupling/capping steps (c)/(d)
Crude yield (%)
Crude purity (%)a
Time (h)
ArCOCl (equiv/[c])
DIPEA (equiv)
Time (min)
1
2
3
4
5
6
2.0
2.0
2.0
2.0
2.0
2.0
1
2
1
1
1
1
3.0/0.5
3.0/0.5
3.0/0.5
6.0/1.0
6.0/1.0
6.0/1.0
6.0
6.0
6.0
12.0
12.0
12.0
20
20
40
20
40
60
74
77
83
87
89
90
80
79
90
91
94
94
a
Determined by analytical HPLC.
2.3. Method C: adaptation for phenyl side chains
butyl side chains we used the optimized conditions from Table 2,
entry 4 (method B) and for installation of phenyl side chains we used
the optimized conditions from Table 3, entry 7 (method C). For in-
stallation of all other side chains we used the initial conditions
(method A). Thus, using method A we first synthesized model hex-
amers p/m-2a, which are decorated with spe side chains (Table 4,
entries 1 and 2). The desired oligomers were isolated in excellent
Next, we turned to optimizing the conditions for installing
phenyl side chains with 28% crude purity and 51% crude yield of
the model trimer p-1c as starting points (Table 3, entry 1). Op-
posite to the tert-butyl optimization, a dramatic improvement to
58% crude purity was observed when increasing the reaction time
Table 3
Optimization of substitution step (b) and coupling/capping step (c)/(d) for synthesis of p-1c (method C)
Entry
Substitution step (b)
PhNH2 ([c])
Coupling/capping steps (c)/(d)
Crude yield (%)
Crude purity (%)a
Time (h)
ArCOCl (equiv/[c])
DIPEA (equiv)
Time (min)
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
4.0
4.0
4.0
4.0
1
2
2
3
1
2
3
4
3.0/0.5
3.0/0.5
3.0/0.5
3.0/0.5
3.0/0.5
3.0/0.5
3.0/0.5
3.0/0.5
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
20
20
40
20
20
20
20
20
51
60
59
66
63
72
75
64
28
58
58
75
58
82
87
90
a
Determined by analytical HPLC.

T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4447
O
X
R
N
O
O
2-chlorotrityl chloride-PS
or
b)
H
a)
X
n
b
a
c
Cl
Rink amide-PS
c)
R =
d
d), e)
R
N
XH
6
e
O
b)
Cl
Bz
O
N
p/m-2
X = O:
X = NH: p/m-3
R
N
X
N
n
f
g
O
Scheme 2. Solid-phase submonomer synthesis of arylopeptoid hexamers with free acids or primary amides at the C-terminus. Key: (a) X¼O: 2-chlorotrityl chloride polystyrene
resin, ClCH2ArCOOH (1.2 equiv, 0.14 M), DIPEA (6.0 equiv), CH2Cl2, rt, 1 h. X¼NH: rink amide polystyrene resin, piperidine/NMP 1:4, rt, 2 and 15 min; then ClCH2ArCOCl (3.0 equiv,
0.5 M), DIPEA (6.0 equiv), CH2Cl2, rt, 20 min (b) method A and B: R-NH2 (20 equiv, 2.0 M), DMSO, 50 ꢀC, 1 h. method C: R-NH2 (20 equiv, 4.0 M), DMSO, 50 ꢀC, 3 h. (c) method A and
C: ClCH2ArCOCl (3.0 equiv, 0.5 M), DIPEA (6.0 equiv), CH2Cl2, rt, 20 min. method B: ClCH2ArCOCl (6.0 equiv, 1.0 M), DIPEA (12.0 equiv), CH2Cl2, rt, 40 min. (d) method A and C: BzCl
(3.0 equiv, 0.5 M), DIPEA (6.0 equiv), CH2Cl2, rt, 20 min. method B: BzCl (6.0 equiv, 1.0 M), DIPEA (12.0 equiv), CH2Cl2, rt, 40 min. (e) X¼O: HFIP/CH2Cl2 1:4, rt, 1 h. X¼NH: TFA/water
95:5, rt, 2 h (2ꢃ10 min for p/m-3a). See Table 4 for yields and purities.
Table 4
speculate that the insolubility is due to at least partial removal of the
tert-butyl side chains caused by the harsh conditions used in the
Results for solid-phase submonomer synthesis of arylopeptoid hexamers
cleavage step thus giving rise to insoluble oligomeric aminomethyl
benzamides with free backbone amide protons. Synthesis of shorter
oligomers and/or shortening the cleavage procedure did not offer
a solution to these insolubility issues.
Hexamers carrying phenyl side chains were synthesized using
method C and the desired model hexamers p/m-2c (entries 9 and
10) and p/m-3c (entries 11 and 12) with free acids and primary
amides at the C-terminus, respectively, were all obtained in good
crude purities (70e78%). The purified yields of p/m-2c (32e36%)
were slightly lower than for p/m-3c (43e54%), which, as mentioned
above, is presumably due to slow aminolysis of the arylopeptoid
chains from the 2-chlorotrityl linker during the extended reaction
times of the substitution steps.
To enable direct comparison with our preceding COMU-based
method,7a the para-hexamers p-2deg and p-3deg, which carry
isopropyl, 4-phenylbutyl, 2-morpholinoethyl, or pyridinylmethyl
side chains were synthesized using the directly adapted method
A (entries 13e20). The corresponding meta-hexamers were not
synthesized since, in general, little or no difference is observed in
the crude purities and purified yields between para-oligomers
and meta-oligomers. Method A provided all the hexamers in
increased crude purities (4e21%) and purified yields (2e14%)
relative to the COMU-based method. The most dramatic increase
was observed for hexamers that carry isopropyl side chains (p-2d
and p-3d: 17e21% increase in crude purity and 7e14% increase in
purified yield) while the smallest overall difference was observed
for the hexamers that carry pyridinylmethyl side chains (p-2g
and p-3g: 7e9% increase in crude purity and 2e4% increase in
purified yield).
The initial methods for synthesizing arylopeptoids using DIC-
activated benzoic acids reported by Zuckermann and co-
workers,6 and by Lokey and Combs,8 were limited to the synthesis
of arylopeptoids with either primary amides or free acids at the
C-terminus, respectively. Our preceding method using COMU-
activated benzoic acids compared favorably with these methods
and was furthermore adaptable to the synthesis of arylopeptoids
with both primary amides and free acids at the C-terminus. The
acid chloride based method we have developed herein represents
a further improvement since the yields are higher than those
obtained in our COMU-based method and it also allows for in-
stallation of side chains that were not previously possible.
Entry
Hexamer
X
Method
Crude
yield (%)
Crude
Purified
purity (%)a
yield (%)b
1
2
3
4
5
6
7
8
p-2a
m-2a
p-3a
m-3a
p-2b
m-2b
p-3b
m-3b
p-2c
m-2c
p-3c
m-3c
p-2d
p-3d
p-2e
p-3e
p-2f
O
O
NH
NH
O
A
A
A
A
B
B
B
B
C
C
C
C
A
A
A
A
A
A
A
A
73
89
128
137
94
87
98
101
56
66
111
113
76
128
68
97
97
119
98
94
95
97
79c
68c
91
97
dd
dd
78
76
70
71
99
97
84
85
94
90
59
60
54
68
67
65
64
65
dd
dd
32
36
43
54
dd
69
46
52
65
62
23
26
O
NH
NH
O
9
10
11
12
13
14
15
16
17
18
19
20
O
NH
NH
O
NH
O
NH
O
NH
O
p-3f
p-2g
p-3g
NH
a
Determined by analytical HPLC.
Yield of product isolated in >99% purity after preparative HPLC.
b
c
Cleavage time reduced to 2ꢃ10 min in order to minimize decomposition.
d
HPLC purification and/or analysis hindered due to poor solubility.
crude purities (95e97%) and good purified yields (54e68%). Their
counterparts p/m-3a with primary amides at the C-terminus were
initially isolated as highly complex mixtures containing less than 20%
of the desired products after cleavage for 2 h with 95% TFA. This
degradation is likely due to the cleavage of spe side chains by for-
mation of benzyl carbocations during the harsh cleavage step and we
found that the problem could be minimized by shortening the
cleavage procedure to only 2ꢃ10 min, which enabled p/m-3a to be
isolated in good crude purities (68e79%, entries 3 and 4) and good
yields (65e67%). Method B successfully provided hexamers p/m-2b
with tert-butyl side chains and a free acid at the C-terminus in ex-
cellent crude purities (91e97%) and good purified yields (64e65%,
entries 5 and 6). The crude products from synthesis of the corre-
sponding hexamers p/m-3b with primary amides at the C-terminus
were unfortunately found to be completely insoluble in any useful
organic solvent, which hindered analysis (entries 7 and 8). We

4448
T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4. NMR studies of model monomers with tert-butyl and
phenyl side chains
than the N-methyl group and to electronic repulsion between the
carbonyl lone-pair electrons and the phenyl
-electrons.14b Over-
p
all, the tert-butyl and phenyl side chains allow for complete control
over the amide conformation in arylopeptoids with the former side
chain resulting in 100% cis while the latter invokes a 100% trans
conformation.
We previously undertook the first conformational studies of
arylopeptoids by means of NMR where we studied para- and meta-
arylopeptoids carrying simple aliphatic side chains of increasing
bulk.7b Arylopeptoids that carried the less bulky methyl, ethyl, and
isopropyl side chains produced NMR spectra with very broad sig-
nals in CDCl3 at rt, indicating that these series underwent con-
formational changes in the intermediate time regime on the NMR
time scale. Partly overlapping sets of signals for carbons and/or
protons in close proximity to the amide nitrogen(s) were observed
due to the presence of cis/trans mixtures. Arylopeptoids decorated
with the highly bulky tert-butyl side chain represented a particu-
larly interesting case since only single, sharp sets of signals were
observed in NMR spectra. NOESY experiments revealed that these
single sets of signals corresponded to a 100% cis conformation.7b
Amongst all the new side chains we have introduced since then,
only the phenyl side chain introduced in this paper likewise gives
rise to very sharp signals in NMR spectra. In order to investigate
this intriguing observation, we synthesized model monomers p/m-
4b with a tert-butyl side chain and p/m-4c, which carry a phenyl
side chain using method B and C, respectively (Fig. 2). Model
monomers p/m-4b were synthesized as a reference and NOESY
spectra confirmed the presence of 100% cis conformation by the
existence of a correlation between the benzylic protons of the
backbone and the aromatic protons of the capping group repre-
senting the next arylopeptoid residue in line. Accordingly, no
correlations between the tert-butyl group and the aromatic pro-
tons of the capping group were observed. On the contrary, for the
model monomers p/m-4c carrying a phenyl side chain, we ob-
served no correlation between the benzylic protons of the back-
bone and the aromatic protons of the N-terminus benzamide.
Instead, correlations between the aromatic protons from the
phenyl side chain and aromatic protons of the N-capping group
were observed, which intriguingly reveal that the sharp sets of
signals in NMR of arylopeptoids with phenyl side chains are due to
a 100% trans conformation. This finding is in full agreement with
the results found in conformational studies of closely resembling
N-alkylated benzanilide monomers.3b The same conformational
preference has also been observed in related N-methyl-N-phenyl-
acetamides.14 Ab initio molecular orbital calculations indicated that
this preference was due to the N-phenyl group being less bulky
5. Conformational studies of arylopeptoids with spe side
chains
The spe side chain has been used extensively in conformational
studies of peptoids,5,10b,11,12 and we were consequently interested
in investigating the influence of the spe side chain upon the con-
formational preference of arylopeptoids. A library of arylopeptoids
bearing the spe side chain was therefore obtained by com-
plementing the synthesis of trimer p-1a and hexamers p/m-2a
described above with the synthesis of monomers p/m-5a, trimer m-
1a, and nonamers p/m-6a (Fig. 3). These were all synthesized in
good purified yields (47e67%) using method A and it is of note that
even the nonamers were isolated in at least 95% crude purity.
O
O
O
Ph
OH
n
N
OH
n
N
Ph
O
p-5a (n = 1): 64% (99% cr. purity) m-5a (n = 1): 67% (99% cr. purity)
p-1a m-1a
(n = 3): 62% (97% cr. purity)
p-2a (n = 6): 54% (95% cr. purity) m-2a (n = 6): 68% (97% cr. purity)
-6a -6a
(n = 3): 71% (99% cr. purity)
p
(n = 9): 47% (95% cr. purity)
m
(n = 9): 50% (97% cr. purity)
Fig. 3. Library of arylopeptoids carrying spe side chains. The yields are of purified
products isolated in >99% purity.
NMR spectra of all the synthesized para- and meta-arylo-
peptoids that carry the spe side chain were recorded at 15e50 mM
in CDCl3 and no distinct length-dependant changes to the spectra
were observed. The spectra were characterized by broad peaks and
seemingly showed only the presence of a single amide conforma-
tion. These features resembled spectra previously obtained from
arylopeptoids with isopropyl chains, which were established to
exist as a w83:17 cis/trans mixture below rt.7b In order to further
investigate these observations, the model monomers p/m-4a
(Fig. 4) mimicking the para- and meta-arylopeptoid backbones
were synthesized in 64e68% purified yield (both obtained in 99%
crude purity) also using method A. The NMR spectra of p/m-4a in
CDCl3 were then recorded in the temperature range 272e308 K
(Fig. 4 and SD). Two distinct signals originating from the presence
of a cis/trans mixture were clearly observed below rt in both cases.
Signal splitting was not observed above rt, indicating a fast ex-
change between the two conformers. At 272 K we measured the
ratios 83:17 and 81:19 between the two conformations of p-4a and
m-4a, respectively, which represents a moderate conformational
heterogeneity (see SD).
O
cis
cis
OH
X
X
X
O
N
O
N
OH
O
p-4b: 57%, >99% purity
m-4b: 63%, >99% purity
(98% cr. purity)
(99% cr. purity)
NOESY, HSQC, and COSY spectra recorded at 278 K did not
provide basis for definite assignment of the conformations due to
overlap in the crowded aromatic region of the spectra. However, we
note that there are some indications that the major conformation
corresponds to a trans amide conformation: (1) in the NOESY of
p-4a at 278 K, the spe side chain methine proton of the major
conformation displays correlations with three distinct sets of aro-
matic protons while the benzylic protons of the backbone only
correlate with a single set of aromatic protons (see SD). Assuming
that the aromatic functionalities in the cis and trans isomers are
able to rotate freely, this set of correlations observed for the major
trans
trans
O
OH
N
OH
N
X
O
O
O
X
X
p-4c: 67%, >99% purity
m-4c: 72%, >99% purity
(98% cr. purity)
(98% cr. purity)
Fig. 2. Model monomer arylopeptoids p/m-4b and p/m-4c and observed NOESY
correlations.

T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4449
6. Conclusions
We have developed an improved solid-phase submonomer
synthetic pathway to para- and meta-arylopeptoids (oligomeric N-
substituted aminomethyl benzamides) using benzoyl chlorides in
the coupling steps rather than the corresponding benzoic acids
activated with peptide-type coupling reagents. Compared to our
previous COMU-based technique, the arylopeptoids were obtained
in higher crude purities and purified yields. Furthermore, the new
methodology has enabled the access to side chains that were pre-
viously not accessible. Thus, we were able to synthesize arylo-
peptoids decorated with tert-butyl and phenyl side chains and
show that they allow for an extraordinary complete control over
the amide conformation with the first side chain resulting in 100%
cis while the latter invokes a 100% trans conformation. We will
continue to explore the potential of these side chains in detail by
synthesis of both heterooligomers and longer homooligomers since
they allow for design of aromatic oligoamides with full control over
the amide conformations. In particular, oligomers with alternating
cis and trans amides would be very exciting architectures to study.
The improved method presented in this paper furthermore enabled
synthesis and preliminary study of arylopeptoids carrying the (S)-
N-(1-phenylethyl) (spe) side chains, which has been used exten-
sively to explore the conformational preference of peptoids. We
will likewise continue to study arylopeptoids with this side chain in
order to increase the understanding of the conformational prefer-
ence of arylopeptoids.
7. Experimental section
7.1. General experimental methods
ꢂ
CH2Cl2 used as solvent in reactions was dried over 4 A molecular
sieves. All other chemicals and solvents obtained from commercial
sources (Alfa Aesar, Fluka, Merck and SigmaeAldrich) were used as
received. 2-Chlorotrityl chloride copoly(styrene-1% DVB) resin
(100e200 mesh) with a listed loading of 1.50 mmol/g and rink
amide copoly(styrene-1% DVB) resin (100e200 mesh) with a listed
loading of 0.74 mmol/g were purchased from Merck. Primary
amines (2.0 or 4.0 M) in DMSO used in the substitution steps were
prepared from the neat, free amines. Melting points were de-
termined on a Mettler Toledo MP70 melting point system and are
referenced to the melting points of benzophenone and benzoic
acid. Routine NMR spectra were recorded on a Bruker Avance
300 MHz spectrometer and temperature studies were recorded on
a Bruker Avance 500 MHz instrument. Chemical shifts are refer-
enced to the residual solvent peak and J values are given in hertz.
The following multiplicity abbreviations are used: (s) singlet, (d)
doublet, (m) multiplet, and (br) broad. Where applicable, assign-
ments were based on COSY, HMBC, HSQC, and J-mod-experiments.
IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer
equipped with a Pike Technologies MIRacleÔ ATR and wave-
Fig. 4. NMR temperature studies of model monomers p-4a (top) and m-4a (bottom) in
CDCl3 at 500 MHz.
isomer may only be observed if the isomer corresponds to a trans
amide conformation. (2) In 1H NMR of peptoids carrying spe side
chains, the spe side chain methine proton corresponding to a trans
amide configuration appears upfield (w5 ppm) relative to that of
a cis amide configuration (w6 ppm).10b,15 In p/m-4a at 272 K (Fig. 4
and SD), a similar displacement of signals is observed with the
major signal (w5.3 ppm) observed upfield relative to the minor
signal (w6.2 ppm). (3) Likewise, in HSQC spectra of peptoids car-
rying spe side chains, the spe side chain methine carbon corre-
sponding to a trans amide configuration appears slightly downfield
(w54 ppm) relative to that of
a cis amide configuration
(w51 ppm).10b,15 In the HSQC spectrum of m-4a at 278 K (see SD),
a similar displacement of signals is again observed with the major
signal (w57 ppm) observed downfield relative to the minor signal
(w53 ppm).
numbers (n
) are expressed in cmꢁ1. HRMS of all arylopeptoids ex-
cept for p/m-3a, p/m-3c, p/m-5a, and p/m-6a were recorded on
a Micromass LCT apparatus equipped with an AP-ESI probe cali-
brated with Leu-Enkephalin. HRMS of p/m-3c, p/m-5a and p/m-6a
were recorded on a Micromass Q-Tof Micro (3000 V) apparatus. The
known arylopeptoids p-2deg and p-3deg were synthesized using
method A and were purified (>99% purity) by preparative HPLC as
previously described.7a See SD for details concerning analytical and
preparative HPLC.
The library of arylopeptoids carrying spe side chains, shown in
Fig. 3, was also used to record the first circular dichroism (CD)
spectra of arylopeptoids (see SD). The spectra were obtained in
CDCl3 to facilitate comparison with CD spectra of N-alkyl poly(m-
benzamide)s16 however, whilst the spectra were not dissimilar, the
limited solvent transparency of CDCl3 was an issue for in-
terpretation. Since these CD spectra are the first reported for ary-
lopeptoids then further CD investigation is required to be able to
relate the spectral features to the conformational preference of
arylopeptoids. A detailed circular dichroism investigation, sup-
ported by other spectroscopic techniques, will be reported in due
course.
7.2. General procedure for attachment to trityl resin
2-Chlorotrityl chloride resin (100 mg, 1.50 mmol gꢁ1; thus
0.150 mmol) was washed with CH2Cl2 (2ꢃ2 mL). The resin was

4450
T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
swelled in CH2Cl2 (2 mL) for 5 min and drained. To a suspension of
3- or 4-(chloromethyl)benzoic acid (30.7 mg, 0.18 mmol) in CH2Cl2
(1.3 mL) at rt was added DIPEA (0.126 mL, 0.72 mmol). The resulting
solution was added to the resin and the resulting mixture was ag-
itated for 1 h at rt after which time a loading of 0.123ꢂ0.003 mmol
was obtained.7a The resin was drained and washed with CH2Cl2
(3ꢃ2 mL) and DMSO (3ꢃ2 mL).
7.9. General procedure for capping step, method B
To a solution of benzoyl chloride, 3-methylbenzoyl chloride or
4-methylbenzoyl chloride (0.76 mmol) in CH2Cl2 (0.76 mL) at rt was
added DIPEA (0.264 mL, 1.52 mmol). The solution was added to the
resin and the resulting mixture was agitated for 40 min at rt. The
resin was drained and washed with CH2Cl2/DIPEA 4:1 (3ꢃ1 mL,
only for arylopeptoids that contain side chains with basic func-
tionalities), CH2Cl2 (3ꢃ2 mL), NMP (3ꢃ2 mL), and CH2Cl2 (3ꢃ2 mL).
7.3. General procedure for attachment to rink amide resin
7.10. General procedure for cleavage from trityl resin
Rink amide resin (162 mg, 0.74 mmol gꢁ1; thus 0.120 mmol) was
washed with CH2Cl2 (2ꢃ2 mL) and NMP (5ꢃ2 mL). Piperidine/NMP
1:4 (1.0 mL) was added and the resin was agitated for 2 min and
drained. Further piperidine/NMP 1:4 (1.0 mL) was added and the
resin was agitated for 15 min, drained and washed with NMP
(3ꢃ2 mL) and CH2Cl2 (3ꢃ2 mL). To a solution of 3- or 4-(chlor-
omethyl)benzoyl chloride (71 mg, 0.38 mmol) in CH2Cl2 (0.76 mL)
at rt was DIPEA (0.132 mL, 0.76 mmol). The mixture was added to
the resin and the resulting mixture was agitated for 20 min at rt.
The resin was drained and washed with CH2Cl2 (3ꢃ2 mL) and
DMSO (3ꢃ2 mL). The resin was drained and washed with CH2Cl2
(3ꢃ2 mL) and DMSO (3ꢃ2 mL).
The resin was cleaved in HFIP/CH2Cl2 1:4 (1 mL) with agitation
for 1 h. The resin was drained and washed with CH2Cl2 (5ꢃ2 mL).
The solvents were evaporated under reduced pressure and the
residue was evaporated with CH2Cl2 (3ꢃ5 mL) yielding the crude
product, which was purified by preparative HPLC (see SD for
details).
7.11. General procedure for cleavage from rink amide resin
The resin was cleaved in TFA/water 95:5 (2 mL) with agitation
for 2 h (2ꢃ10 min for p/m-3a). The resin was drained and washed
with TFA (2 mL) and CH2Cl2 (5ꢃ2 mL). The solvents were evapo-
rated under reduced pressure and the residue was evaporated with
CH2Cl2 (3ꢃ5 mL) yielding the crude product, which was purified by
preparative HPLC (see SD for details).
7.4. General procedure for coupling step, methods A and C
To a solution of 3- or 4-(chloromethyl)benzoyl chloride (71 mg,
0.38 mmol) in CH2Cl2 (0.76 mL) at rt was added DIPEA (0.132 mL,
0.76 mmol). The mixture was added to the resin and the resulting
mixture was agitated for 20 min at rt. The resin was drained and
washed with CH2Cl2 (3ꢃ2 mL) and DMSO (3ꢃ2 mL).
7.12. Spectroscopic and characterization data for
arylopeptoids
7.12.1. Arylopeptoid trimer p-1a. Synthesized using method A (78%
crude yield, 97% crude purity). Data for p-1a: colorless solid (65 mg,
62%, >99% purity). Mp¼123e126 ꢀC. 1H NMR (300 MHz, CDCl3):
7.5. General procedure for coupling step, method B
d
¼8.04e7.84 (m, 2H), 7.64e7.10 (m, 30H), 5.40e5.06 (br m, 3H, 3ꢃ
To a solution of 3- or 4-(chloromethyl)benzoyl chloride (143 mg,
0.76 mmol) in CH2Cl2 (0.76 mL) at rt was added DIPEA (0.264 mL,
1.52 mmol). The mixture was added to the resin and the resulting
mixture was agitated for 40 min at rt. The resin was drained and
washed with CH2Cl2 (3ꢃ2 mL) and DMSO (3ꢃ2 mL).
CONCHCH3), 5.06e4.72 (br m, 3H, 3ꢃ CONCHHAr), 4.24e3.92 (m,
3H, 3ꢃ CONCHHAr), 1.62e1.38 (m, 9H, 3ꢃ CONCHCH3) ppm. 13C
NMR (75 MHz, CDCl3):
d¼173.0, 172.8, 170.5 (4Cq), 140.6, 139.8,
139.7, 136.4, 134.8, 128.2 (10Cq), 130.1, 129.7, 128.7, 128.6, 127.8,
127.7, 127.5, 127.0, 126.9, 126.5, 126.3 (32CH), 57.4 (br, 3ꢃ CH, 3ꢃ
CONCHCH3), 45.3 (br, 3ꢃ CH2, 3ꢃ CONCH2Ar), 18.2 (br, 3CH3, 3ꢃ
CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 2992 (COOH), 2909 (CH), 1713
(C]O acid), 1632, 1611 (C]O amide), 1494, 1445, 1404, 1328 (OH),
1209, 1147, 1027. HRMS (TOF MS ESþ) calcd for C55H52N3O5 [MþH]þ
m/z 834.3901, found 834.3895.
7.6. General procedure for substitution step, methods A and B
A solution of the primary amine (20 equiv, 2 M) in DMSO
(1.3 mL) was added to the resin and the mixture was agitated at
50 ꢀC for 1 h. The resin was drained and washed with DMSO
(3ꢃ2 mL) and CH2Cl2 (3ꢃ2 mL).
7.12.2. Arylopeptoid trimer m-1a. Synthesized using method A
(90% crude yield, 99% crude purity). Data for m-1a: colorless solid
(75 mg, 71%, >99% purity). Mp¼97e100 ꢀC. 1H NMR (300 MHz,
CDCl3):
d
¼7.99e7.77 (m, 2H), 7.68e6.95 (m, 30H), 5.45e5.04 (br m,
7.7. General procedure for substitution step, method C
3H, 3ꢃ CONCHCH3), 5.04e4.70 (br m, 3H, 3ꢃ CONCHHAr),
4.23e3.88 (m, 3H, 3ꢃ CONCHHAr), 1.62e1.34 (m, 9H, 3ꢃ
A solution of the primary amine (20 equiv, 4 M) in DMSO
(0.65 mL) was added to the resin and the mixture was agitated at
50 ꢀC for 3 h. The resin was drained and washed with DMSO
(3ꢃ2 mL) and CH2Cl2 (3ꢃ2 mL).
CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
d¼173.2 (Cq), 173.0
(Cq), 172.9 (Cq), 170.2 (Cq), 139.7, 139.4, 139.1, 136.4, 136.3, 136.2,
129.7 (10Cq), 129.7, 128.7, 128.6, 128.4, 127.8, 127.0, 126.4, 125.2,
124.9 (32CH), 57.4 (br, 3ꢃ CH, 3ꢃ CONCHCH3), 45.3 (br, 3ꢃ CH2, 3ꢃ
CONCH2Ar), 18.1 (br, 3CH3, 3ꢃ CONCHCH3) ppm. nmax/cmꢁ1 (ATR)
2991 (COOH),1717 (C]O acid),1627,1600 (C]O amide),1495,1447,
1406, 1329 (OH), 1306, 1160, 1027. HRMS (TOF MS ESþ) calcd for
C55H52N3O5 [MþH]þ m/z 834.3901, found 834.3910.
7.8. General procedure for capping step, methods A and C
To a solution of benzoyl chloride, 3-methylbenzoyl chloride or
4-methylbenzoyl chloride (0.38 mmol) in CH2Cl2 (0.76 mL) at rt
was added DIPEA (0.132 mL, 0.76 mmol). The solution was added to
the resin and the resulting mixture was agitated for 20 min at rt.
The resin was drained and washed with CH2Cl2/DIPEA 4:1 (3ꢃ1 mL,
only for arylopeptoids that contain side chains with basic func-
tionalities), CH2Cl2 (3ꢃ2 mL), NMP (3ꢃ2 mL), and CH2Cl2 (3ꢃ2 mL).
7.12.3. Arylopeptoid trimer p-1b. Synthesized using method B (89%
crude yield, 94% crude purity). Data for p-1b: colorless solid (61 mg,
70%, >99% purity). Mp¼96e99 ꢀC (dec). 1H NMR (300 MHz, CDCl3):
d
¼9.56e9.34 (br s, 1H, COOH), 8.06e7.98 (m, 2H), 7.36e7.15 (m,
11H), 7.13e7.01 (m, 4H), 4.64 (s, 2H, CONCH2Ar), 4.52 (s, 2H,

T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4451
CONCH2Ar), 4.50 (s, 2H, CONCH2Ar), 1.50 (s, 9H, CONtBu), 1.44 (s,
9H, CONtBu), 1.43 (s, 9H, CONtBu) ppm. 13C NMR (75 MHz, CDCl3):
¼174.4 (Cq), 173.9 (Cq), 173.8 (Cq), 170.3 (Cq), 145.6 (Cq), 141.0 (Cq),
NMR (75 MHz, CDCl3):
d
¼172.8, 172.7, 172.7 (7Cq), 140.6, 139.8,
139.8, 136.5, 134.9, 131.2 (19Cq), 129.6, 128.7, 128.6, 127.8, 127.7,
127.6, 127.4, 126.9, 126.9, 126.4, 126.3 (59CH), 57.3 (br, 6CH, 6ꢃ
CONCHCH3), 45.2 (br, 6CH2, 6ꢃ CONCH2Ar), 18.2 (br, 6CH3, 6ꢃ
CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 3067, 2979 (COOH), 1678, 1630,
1616 (C]O amide), 1495, 1437, 1404, 1328, 1171, 1027. HRMS (TOF
MS ESþ) calcd for C103H99N7O7 [Mþ2H]2þ m/z 772.8803, found
772.8804.
d
140.9 (Cq), 138.3 (Cq), 137.4 (Cq), 137.2 (Cq), 130.5 (2CH), 129.2 (CH),
128.7 (Cq), 128.3 (2CH), 126.4 (4CH), 126.3 (2CH), 126.2 (4CH), 125.9
(2CH), 58.6 (Cq), 58.6 (Cq), 58.5 (Cq), 51.5 (CH2, CONCH2Ar), 51.3
(2CH2, 2ꢃ CONCH2Ar), 28.7 (3CH3, CONtBu), 28.6 (6CH3, 2ꢃ CON-
tBu) ppm. nmax/cmꢁ1 (ATR) 2988 (COOH), 2967 (CH), 1717 (C]O
acid), 1623 (C]O amide), 1394, 1360, 1259, 1197, 1162, 1117, 1018.
HRMS (TOF MS ESþ) calcd for C43H40N3O5 [MþH]þ m/z 690.3901,
found 690.3901.
7.12.8. Arylopeptoid hexamer m-3a. Synthesized using method A
(137% crude yield, 68% crude purity), performing the final cleavage
in 2ꢃ10 min. Data for m-3a: colorless solid (120 mg, 65%, >99%
7.12.4. Arylopeptoid trimer p-1c. Synthesized using method C (75%
crude yield, 87% crude purity). Data for p-1c: colorless solid (48 mg,
51%, >99% purity). Mp¼97e100 ꢀC. 1H NMR (300 MHz, CDCl3):
purity). Mp¼114e117 ꢀC. 1H NMR (300 MHz, CDCl3):
¼7.67e6.80
d
(m, 59H), 6.30e5.98 (br m, 2H, CONH2), 5.38e5.02 (br m, 6H, 6ꢃ
CONCHCH3), 5.02e4.57 (br m, 6H, 6ꢃ CONCHHAr), 4.28e3.82 (m,
6H, 6ꢃ CONCHHAr), 1.72e1.30 (m, 18H, 6ꢃ CONCHCH3) ppm. 13C
d
¼8.08e7.86 (br m, 3H, o-C6H4COO and COOH), 7.43e7.37 (m, 2H),
7.29e7.04 (m, 24H), 6.91e6.85 (m, 2H), 6.78e6.70 (m, 4H), 5.18 (s,
2H, CONCH2Ar), 5.01 (s, 4H, 2ꢃ CONCH2Ar) ppm. 13C NMR (75 MHz,
NMR (75 MHz, CDCl3):
d
¼172.9, 172.7, 170.1 (7Cq), 139.9, 139.8,
139.6, 136.5 (19Cq), 129.7, 128.7, 128.5, 127.8, 127.8, 126.9, 126.3,
CDCl3):
d¼170.8 (Cq), 170.8 (Cq), 170.6 (Cq), 170.5 (Cq), 143.3 (Cq),
125.3, 125.0, 124.8 (59CH), 57.4 (br, 6CH, 6ꢃ CONCHCH3), 45.4 (br,
143.1 (Cq), 142.9 (Cq), 142.8 (Cq), 139.2 (Cq), 139.1 (Cq), 135.4 (Cq),
134.6 (Cq), 134.5 (Cq), 130.4 (2CH), 129.7 (CH), 129.1 (2CH), 129.0,
129.0 (6CH), 128.9 (2CH), 128.6 (2CH), 128.6 (Cq), 128.3 (2CH), 127.9,
127.8 (4CH), 127.7 (2CH), 127.6 (4CH), 127.5 (2CH), 126.9 (CH), 126.8,
126.8 (2CH), 53.7 (CH2, CONCH2Ar), 53.3 (2CH2, 2ꢃ CONCH2Ar)
ppm. nmax/cmꢁ1 (ATR) 3065 (COOH), 2947 (CH), 1715 (C]O acid),
1639, 1612, 1594 (C]O amide), 1493, 1386, 1319 (OH), 1299, 1279,
1214, 1177, 1019. HRMS (TOF MS ESþ) calcd for C49H40N3O5 [MþH]þ
m/z 750.2962, found 750.2969.
6CH2, 6ꢃ CONCH2Ar), 18.2 (br, 6CH3, 6ꢃ CONCHCH3) ppm. nmax
/
cmꢁ1 (ATR) 2984 (CH), 1683, 1630 (C]O amide), 1584, 1494, 1448,
1405, 1329, 1305, 1202, 1170, 1157, 1027. HRMS (TOF MS ESþ) calcd
for C103H99N7O7 [Mþ2H]2þ m/z 772.8803, found 772.8803.
7.12.9. Arylopeptoid hexamer p-2b. Synthesized using method B
(94% crude yield, 91% crude purity). Data for p-2b: colorless solid
(101 mg, 64%, >99% purity). Mp¼125e128 ꢀC (dec). 1H NMR
(300 MHz, CDCl3):
d
¼8.02e7.96 (m, 2H), 7.96e7.81 (br s,1H, COOH),
7.33e7.13 (m, 17H), 7.13e7.00 (m, 10H), 4.63 (s, 2H, CONCH2Ar),
7.12.5. Arylopeptoid hexamer p-2a. Synthesized using method A
(73% crude yield, 95% crude purity). Data for p-2a: colorless solid
(106 mg, 54%, >99% purity). Mp¼143e146 ꢀC. 1H NMR (300 MHz,
4.56e4.44 (m, 10H, 5ꢃ CONCH2Ar), 1.49 (s, 9H, CONtBu), 1.45e1.39
(m, 45H, 5ꢃ CONtBu) ppm. 13C NMR (75 MHz, CDCl3):
¼174.3 (Cq),
d
173.9 (Cq), 173.7 (Cq), 173.7 (2Cq), 173.6 (Cq), 169.3 (Cq), 145.4 (Cq),
141.0, 141.0, 140.9 (5Cq), 138.4 (Cq), 137.5 (2Cq), 137.4 (Cq), 137.4 (Cq),
137.3 (Cq), 130.3 (2CH), 129.1 (CH), 128.9 (Cq), 128.3 (2CH), 126.5,
126.4 (10CH),126.2, 126.2,126.1 (12CH),125.9 (2CH), 58.5 (Cq), 58.5,
58.4, 58.4 (5Cq), 51.5 (CH2, CONCH2Ar), 51.3 (5CH2, 5ꢃ CONCH2Ar),
28.6 (18CH3, 6ꢃ CONtBu) ppm. nmax/cmꢁ1 (ATR) 2982 (COOH), 2934
(CH), 1717 (C]O acid), 1635, 1610 (C]O amide), 1391, 1362, 1256,
1196,1112. HRMS (TOF MS ESþ) calcd for C79H98N6O8 [Mþ2H]2þ m/z
629.3718, found 629.3710.
CDCl3):
d
¼8.12e8.00 (br s,1H, COOH), 8.00e7.84 (m, 2H), 7.64e6.88
(m, 57H), 5.42e5.06 (br m, 6H, 6ꢃ CONCHCH3), 5.06e4.72 (br m,
6H, 6ꢃ CONCHHAr), 4.24e3.92 (m, 6H, 6ꢃ CONCHHAr), 1.62e1.35
(m, 18H, 6ꢃ CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
¼173.1,
d
173.0 (7Cq), 140.5, 136.2, 134.6 (19Cq), 130.1, 129.7, 128.7, 128.6,
127.8, 127.7, 127.5, 127.0, 126.4, 126.3 (59CH), 57.3 (br, 6CH, 6ꢃ
CONCHCH3), 45.2 (br, 6CH2, 6ꢃ CONCH2Ar), 18.1 (br, 6CH3, 6ꢃ
CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 3060 (COOH), 2978 (CH), 1714
(C]O acid), 1635, 1627, 1612 (C]O amide), 1446, 1404, 1329 (OH),
1209, 1172. HRMS (TOF MS ESþ) calcd for C103H98N6O8 [Mþ2H]2þ
m/z 773.3718, found 773.3719.
7.12.10. Arylopeptoid hexamer m-2b. Synthesized using method B
(87% crude yield, 97% crude purity). Data for m-2b: colorless solid
(103 mg, 65%, >99% purity). Mp¼107e110 ꢀC (dec). 1H NMR
7.12.6. Arylopeptoid hexamer m-2a. Synthesized using method A
(89% crude yield, 97% crude purity). Data for m-2a: colorless solid
(132 mg, 68%, >99% purity). Mp¼101e104 ꢀC. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
¼7.92e7.86 (m, 2H), 7.62e7.51 (br s, 1H, COOH),
7.41e7.36 (m, 2H), 7.31e7.09 (m, 25H), 4.59 (s, 2H, CONCH2Ar), 4.50
(s, 2H, CONCH2Ar), 4.47 (s, 4H, 2ꢃ CONCH2Ar), 4.44 (s, 2H, CON-
CH2Ar), 4.43 (s, 2H, CONCH2Ar), 1.48 (s, 9H, CONtBu), 1.39 (s, 9H,
CONtBu), 1.38e1.34 (m, 27H, 3ꢃ CONtBu), 1.34 (s, 9H, CONtBu) ppm.
CDCl3):
d
¼7.98e7.72 (m, 2H), 7.66e6.84 (m, 57H), 5.42e5.02 (br m,
6H, 6ꢃ CONCHCH3), 5.02e4.68 (br m, 6H, 6ꢃ CONCHHAr),
4.20e3.84 (m, 6H, 6ꢃ CONCHHAr), 1.60e1.32 (m, 18H, 6ꢃ
13C NMR (75 MHz, CDCl3):
d¼174.3 (Cq), 173.8 (Cq), 173.7 (Cq), 173.5
CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼172.9, 172.8 (7Cq),
(3Cq), 168.7 (Cq), 140.2 (Cq), 140.0 (2Cq), 140.0 (2Cq), 139.9 (Cq), 139.2
(Cq), 139.0 (Cq), 139.0 (Cq), 139.0 (Cq), 138.8 (Cq), 138.3 (Cq), 130.6
(Cq), 130.6, 129.2, 128.8, 128.7, 128.3, 127.5, 127.0, 126.9, 126.9, 126.8,
126.7, 125.9, 124.7, 124.6, 124.1, 124.1, 124.0, 124.0, 123.9 (29CH),
58.5 (2Cq), 58.4 (Cq), 58.4 (Cq), 58.4 (Cq), 58.4 (Cq), 51.3, 51.2, 51.1
(6CH2, 6ꢃ CONCH2Ar), 28.7, 28.6, 28.6, 28.5 (18CH3, 6ꢃ CONtBu)
ppm. nmax/cmꢁ1 (ATR) 2976, 2915 (CH), 1717 (C]O acid), 1635 (C]
O amide), 1393, 1256, 1093, 1167. HRMS (TOF MS ESþ) calcd for
C79H98N6O8 [Mþ2H]2þ m/z 629.3718, found 629.3724.
139.8, 139.7, 139.5, 136.5, 136.4, 136.4, 129.9 (19Cq), 129.6, 128.6,
128.5, 128.3, 127.7, 127.0, 126.3, 125.3, 125.1, 124.8 (59CH), 57.4 (br,
6CH, 6ꢃ CONCHCH3), 45.3 (br, 6CH2, 6ꢃ CONCH2Ar), 18.2 (br, 6CH3,
6ꢃ CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 3038 (COOH), 2986 (CH),
1715 (C]O acid), 1635 (C]O amide), 1493, 1448, 1405, 1329 (OH),
1305, 1201, 1172, 1027. HRMS (TOF MS ESþ) calcd for C103H98N6O8
[Mþ2H]2þ m/z 773.3718, found 773.3710.
7.12.7. Arylopeptoid hexamer p-3a. Synthesized using method A
(128% crude yield, 79% crude purity), performing the final cleavage
in 2ꢃ10 min. Data for p-3a: colorless solid (125 mg, 67%, >99%
7.12.11. Arylopeptoid hexamer p-2c. Synthesized using method C
(56% crude yield, 78% crude purity). Data for p-2c: colorless solid
(55 mg, 32%, >99% purity). Mp¼130e133 ꢀC. 1H NMR (300 MHz,
purity). Mp¼130e133 ꢀC. 1H NMR (300 MHz, CDCl3):
¼7.78e6.86
d
(m, 59H), 6.32e5.98 (br m, 2H, CONH2), 5.37e5.04 (br m, 6H, 6ꢃ
CONCHCH3), 5.04e4.77 (br m, 6H, 6ꢃ CONCHHAr), 4.24e3.84 (m,
6H, 6ꢃ CONCHHAr), 1.72e1.36 (m, 18H, 6ꢃ CONCHCH3) ppm. 13C
CDCl3):
d
¼8.03e7.98 (m, 2H), 7.42e7.36 (m, 2H), 7.29e7.02 (m,
43H), 6.90e6.85 (m, 2H), 6.78e6.68 (m, 10H), 6.45e6.10 (br s, 1H,
COOH), 5.17 (s, 2H, CONCH2Ar), 5.02e4.94 (m, 10H, 5ꢃ CONCH2Ar)

4452
T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
ppm. 13C NMR (75 MHz, CDCl3):
d
¼170.6 (Cq), 170.5 (Cq), 170.4 (Cq),
p-C6H4CON), 139.8 (Cq, ipso-CHCH3C6H5), 133.2 (Cq, ipso-C6H4CON),
130.2 (2CH, o-C6H4COO), 129.3 (2CH), 128.7 (2CH), 128.0 (Cq, ipso-
C6H4COO), 127.8 (CH), 127.1 (4CH), 126.5 (2CH), 45.2 (br, CH2,
CONCH2Ar [from HSQC correlation]), 21.4 (CH3, CH3Ar), 18.1 (br,
CH3, CONCHCH3) ppm. The peak for CONCHCH3 was presumably
too broad to be detected. nmax/cmꢁ1 (ATR) 3030 (COOH), 2984 (CH),
1714, 1689 (C]O acid), 1634, 1612, 1595 (C]O amide), 1447, 1410,
1331 (OH), 1282, 1209, 1176, 1111, 1018. HRMS (TOF MS ESþ) calcd
for C24H24NO3 [MþH]þ m/z 374.1751, found 374.1744.
170.4 (3Cq), 170.1 (Cq), 143.2, 143.2, 143.0, 142.9, 142.9, 139.3, 139.2,
139.1, 139.1, 135.5, 134.7, 134.6, 134.6, 128.7 (19Cq), 130.3, 129.7,
129.1, 129.0, 128.9, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6, 127.5,
126.9, 126.8 (59CH), 53.6 (CH2, CONCH2Ar), 53.3 (5CH2, 5ꢃ CON-
CH2Ar) ppm. nmax/cmꢁ1 (ATR) 3043 (COOH), 2930, 2853 (CH), 1717
(C]O acid), 1640, 1611, 1594 (C]O amide), 1493, 1383, 1318 (OH),
1299, 1279, 1184, 1152, 1112, 1019. HRMS (TOF MS ESþ) calcd for
C91H74N6O8 [Mþ2H]2þ m/z 689.2779, found 689.2784.
7.12.12. Arylopeptoid hexamer m-2c. Synthesized using method C
(66% crude yield, 76% crude purity). Data for m-2c: colorless solid
(63 mg, 36%, >99% purity). Mp¼97e100 ꢀC. 1H NMR (300 MHz,
7.12.16. Arylopeptoid model monomer m-4a. Synthesized using
method A (85% crude yield, 99% crude purity) at twice the scale
described in the general methods. Data for m-4a: colorless solid
(64 mg, 68%, >99% purity). Mp¼58e61 ꢀC. 1H NMR (300 MHz,
CDCl3):
d¼8.02e7.94 (m, 2H), 7.58e7.52 (m, 1H), 7.29e7.02 (m,
44H), 6.89e6.84 (m, 2H), 6.78e6.68 (m, 10H), 6.62e6.38 (br s, 1H,
COOH), 5.16 (s, 2H, CONCH2Ar), 5.00 (s, 2H, CONCH2Ar), 4.97 (s, 8H,
CDCl3):
d¼8.94e7.73 (br s, 1H, COOH), 8.00e7.75 (m, 2H, o-
C6H4COO and o0-C6H4COO), 7.64e6.98 (m, 11H), 5.45e5.10 (br m,
1H, CONCHCH3), 5.08e4.75 (br m, 1H, CONCHHAr), 4.17 (d,
J¼15.8 Hz,1H, CONCHHAr), 2.38 (s, 3H, CH3Ar),1.54 (d, J¼7.0 Hz, 3H,
4ꢃ CONCH2Ar) ppm. 13C NMR (75 MHz, CDCl3):
¼170.7, 170.6,
d
170.5, 170.4, 170.4 (6Cq), 169.6 (Cq), 143.0, 143.0, 142.9, 142.8, 137.8,
137.1, 137.0, 135.9, 135.9, 135.9, 135.8, 135.8, 135.5, 130.0 (19Cq),
133.2, 129.9, 129.8, 129.8, 129.6, 129.1, 129.0, 128.8, 128.7, 128.6,
128.6, 128.6, 128.0, 127.9, 127.8, 127.6, 127.6, 127.6, 126.8, 126.8
CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
d¼173.5 (Cq, CON),
171.3 (Cq, COO), 139.7, 139.1, 138.7, 136.1, 129.4 (5Cq), 132.6, 130.5,
128.8, 128.7, 128.5, 127.8, 127.0, 123.2 (13CH), 56.8 (br, CH,
CONCHCH3 [from HSQC correlation]), 45.0 (br, CH2, CONCH2Ar
[from HSQC correlation]), 21.4 (CH3, CH3Ar), 18.1 (br, CH3,
CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 3059, 3026 (COOH), 2979, 2923
(CH), 1715, 1692 (C]O acid), 1632, 1593, 1583 (C]O amide), 1494,
1451, 1409, 1331 (OH), 1283, 1198, 1168, 1081, 1027. HRMS (TOF MS
ESþ) calcd for C24H24NO3 [MþH]þ m/z 374.1751, found 374.1755.
(59CH), 53.5, 53.4, 53.4, 53.4, 53.3 (6CH2, 6ꢃ CONCH2Ar) ppm. nmax
/
cmꢁ1 (ATR) 3050 (COOH), 1715 (C]O acid), 1614, 1594, 1583 (C]O
amide), 1494, 1383, 1302, 1280, 1198, 1172. HRMS (TOF MS ESþ)
calcd for C91H74N6O8 [Mþ2H]2þ m/z 689.2779, found 689.2784.
7.12.13. Arylopeptoid hexamer p-3c. Synthesized using method C
(111% crude yield, 70% crude purity). Data for p-3c: colorless solid
(71 mg, 43%, >99% purity). Mp¼114e117 ꢀC. 1H NMR (300 MHz,
7.12.17. Arylopeptoid model monomer p-4b. Synthesized using
method B (77% crude yield, 98% crude purity) at twice the scale
described in the general methods. Data for p-4b: colorless solid
(47 mg, 57%, >99% purity). Mp¼181e184 ꢀC (dec). 1H NMR
CDCl3):
d
¼7.77e7.71 (m, 2H), 7.40e7.34 (m, 2H), 7.28e7.02 (m,
43H), 6.89e6.83 (m, 2H), 6.78e6.67 (m, 10H), 6.50e6.02 (br m, 2H,
CONH2), 5.14 (s, 2H, CONCH2Ar), 5.03e4.94 (m, 10H, 5ꢃ CONCH2Ar)
ppm. 13C NMR (75 MHz, CDCl3):
d¼170.6 (Cq),170.4 (Cq),170.4 (4Cq),
(300 MHz, CDCl3):
d
¼8.09e8.04 (m, 2H, o-C6H4COO), 7.36e7.31 (m,
169.7 (Cq), 143.1, 143.0, 142.9, 141.9, 139.3, 139.2, 139.2, 139.1, 135.6,
134.7, 134.6, 132.0 (19Cq), 129.7, 129.1, 129.0, 128.9, 128.6, 128.5,
127.8, 127.8, 127.7, 127.6, 127.5, 126.9, 126.8 (59CH), 53.6 (CH2,
CONCH2Ar), 53.3 (5CH2, 5ꢃ CONCH2Ar) ppm. nmax/cmꢁ1 (ATR) 3684
(CONH2), 2988, 2972, 2901 (CH), 1642, 1636 (C]O amide), 1493,
1383, 1279, 1075, 1052. HRMS (TOF MS ESþ) calcd for
C91H73N7O7Na2 [Mþ2Na]2þ m/z 710.7683, found 710.7657.
2H, m-C6H4COO), 7.30e7.26 (m, 2H, o-C6H4CON), 7.11e7.06 (m, 2H,
m-C6H4CON), 4.68 (s, 2H, CONCH2Ar), 2.29 (s, 3H, CH3Ar), 1.50 (s,
9H, CONtBu) ppm. 13C NMR (75 MHz, CDCl3):
d
¼174.3 (Cq, CON),
171.0 (Cq, COO), 146.5 (Cq, p-C6H4COO),139.3 (Cq, p-C6H4CON), 135.9
(Cq, ipso-C6H4CON), 130.5 (2CH, o-C6H4COO), 129.0 (2CH, m-
C6H4CON), 128.3 (Cq, ipso-C6H4COO), 126.3 (2CH, m-C6H4COO),
126.1 (2CH, o-C6H4CON), 58.3 (Cq, CONtBu), 51.6 (CH2, CONCH2Ar),
28.8 (3CH3, CONtBu), 21.3 (CH3, CH3Ar) ppm. nmax/cmꢁ1 (ATR) 2979
(COOH), 2895 (CH), 1703 (C]O acid), 1609, 1600 (C]O amide),
1393, 1356, 1254, 1245, 1187, 1114. HRMS (TOF MS ESþ) calcd for
C20H24NO3 [MþH]þ m/z 326.1751, found 326.1752.
7.12.14. Arylopeptoid hexamer m-3c. Synthesized using method C
(113% crude yield, 71% crude purity). Data for m-3c: colorless solid
(89 mg, 54%, >99% purity). Mp¼94e97 ꢀC. 1H NMR (300 MHz,
CDCl3):
d
¼7.79e7.71 (m, 2H), 7.44e7.38 (m,1H), 7.36e7.00 (m, 44H),
6.88e6.83 (m, 2H), 6.76e6.64 (m,10H), 6.50e6.26 (br m, 2H, CONH2),
5.11 (s, 2H, CONCH2Ar), 4.98 (s, 2H, CONCH2Ar), 4.94e4.91 (m, 8H, 4ꢃ
7.12.18. Arylopeptoid model monomer m-4b. Synthesized using
method B (81% crude yield, 99% crude purity) at twice the scale
described in the general methods. Data for m-4b: colorless solid
(52 mg, 63%, >99% purity). Mp¼197e200 ꢀC (dec). 1H NMR
CONCH2Ar) ppm. 13C NMR (75 MHz, CDCl3):
d¼170.8 (Cq), 170.6 (Cq),
170.4 (Cq),170.4 (3Cq),170.1 (Cq),143.0,143.0,142.9,137.8,137.2,137.1,
137.0,135.9,135.9,135.8,135.5,133.1 (19Cq),132.2,129.9,129.8,129.8,
129.2, 129.0,128.8,128.7, 128.6,128.6,128.6,128.0, 127.9,127.8, 127.7,
127.7, 127.6, 127.2, 126.9, 126.9, 126.8 (59CH), 53.7 (CH2, CONCH2Ar),
53.4 (CH2, CONCH2Ar), 53.4 (4CH2, 4ꢃ CONCH2Ar) ppm. nmax/cmꢁ1
(ATR) 3067 (COOH),1641,1594,1583 (C]O amide),1494,1383,1302,
1280, 1204, 1173. HRMS (TOF MS ESþ) calcd for C91H73N7O7Na2
[Mþ2Na]2þ m/z 710.7683, found 710.7676.
(300 MHz, CDCl3/
3
MeOH):
d
¼7.86e7.77 (m, 2H, o-C6H4COO and o0-
C6H4COO), 7.35e7.28 (m, 2H, m-C6H4COO and p-C6H4COO),
7.10e6.98 (m, 4H, o-C6H4CON, o0-C6H4CON, m-C6H4CON, and p-
C6H4CON), 4.54 (s, 2H, CONCH2Ar), 2.16 (s, 3H, CH3Ar), 1.39 (s, 9H,
CONtBu) ppm. 13C NMR (75 MHz, CDCl3/
3 MeOH):
d¼174.5 (Cq, CON),
168.3 (Cq, COO), 139.9 (Cq, m0-C6H4COO), 138.5 (Cq, ipso-C6H4CON),
138.1 (Cq, m0-C6H4CON), 130.7 (Cq, ipso-C6H4COO), 130.4 (CH, p-
C6H4COO), 129.7 (CH), 128.4 (CH), 128.2 (CH), 127.4 (CH, o0-
C6H4CON), 126.3 (CH), 122.5 (CH), 58.2 (Cq, CONtBu), 51.2 (CH2,
7.12.15. Arylopeptoid model monomer p-4a. Synthesized using
method A (80% crude yield, 99% crude purity) at twice the scale
described in the general methods. Data for p-4a: colorless solid
(60 mg, 64%, >99% purity). Mp¼73e76 ꢀC. 1H NMR (300 MHz,
CONCH2Ar), 28.4 (3CH3, CONtBu), 20.9 (CH3, CH3Ar) ppm. nmax
/
cmꢁ1 (ATR) 2971 (COOH), 2781, 2622 (CH), 1708 (C]O acid), 1591,
1569 (C]O amide), 1428, 1404, 1250, 1119. HRMS (TOF MS ESþ)
calcd for C20H24NO3 [MþH]þ m/z 326.1751, found 326.1744.
CDCl3):
d
¼8.04e7.78 (m, 3H, o-C6H4COO and COOH), 7.54e7.15 (m,
11H), 5.52e5.16 (br m, 1H, CONCHCH3), 5.07e4.65 (br m, 1H,
CONCHHAr), 4.11 (d, J¼16.0 Hz,1H, CONCHHAr), 2.38 (s, 3H, CH3Ar),
1.51 (d, J¼7.0 Hz, 3H, CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
7.12.19. Arylopeptoid model monomer p-4c. Synthesized using
method C (82% crude yield, 98% crude purity) at twice the scale
described in the general methods. Data for p-4c: colorless solid
d¼173.4 (Cq, CON), 171.3 (Cq, COO), 145.0 (Cq, p-C6H4COO), 140.0 (Cq,

T. Hjelmgaard et al. / Tetrahedron 68 (2012) 4444e4454
4453
(58 mg, 67%, >99% purity). Mp¼62e65 ꢀC. 1H NMR (300 MHz,
1713, 1691 (C]O acid), 1634, 1606, 1591 (C]O amide), 1495, 1447,
1410, 1329 (OH), 1248, 1193, 1077, 1027. HRMS (TOF MS ESþ) calcd
for C23H21NO3Na [MþNa]þ m/z 382.1419, found 382.1434.
CDCl3):
d¼8.70e8.35 (br s, 1H, COOH), 8.06e8.00 (m, 2H, o-
C6H4COO), 7.45e7.39 (m, 2H, m-C6H4COO), 7.27e7.22 (m, 2H, o-
C6H4CON), 7.20e7.07 (m, 3H, CONC6H5), 7.00e6.94 (m, 2H, m-
C6H4CON), 6.94e6.89 (m, 2H, CONC6H5), 5.20 (s, 2H, CONCH2Ar),
7.12.23. Arylopeptoid nonamer p-6a. Synthesized using method A
(71% crude yield, 95% crude purity). Data for p-6a: colorless solid
(135 mg, 47%, >99% purity). Mp¼148e151 ꢀC. 1H NMR (300 MHz,
2.25 (s, 3H, CH3Ar) ppm. 13C NMR (75 MHz, CDCl3):
d
¼171.4 (Cq,
COO), 170.8 (Cq, CON), 143.6 (Cq, p-C6H4COO), 143.4 (Cq, CONC6H5),
140.2 (Cq, p-C6H4CON), 132.4 (Cq, ipso-C6H4CON), 130.4 (2CH, o-
C6H4COO), 129.1 (2CH, CONC6H5), 129.0 (2CH, o-C6H4CON), 128.5
(Cq, ipso-C6H4COO), 128.4 (2CH, m-C6H4CON), 128.3 (2CH, m-
C6H4COO), 127.5 (2CH, CONC6H5), 126.8 (CH, CONC6H5), 53.8 (CH2,
CONCH2Ar), 21.3 (CH3, CH3Ar) ppm. nmax/cmꢁ1 (ATR) 3023, 1671
(C]O acid), 1643 (C]O amide), 1495, 1428, 1376, 1307, 1281, 1227,
1157. HRMS (TOF MS ESþ) calcd for C22H20NO3 [MþH]þ m/z
346.1438, found 346.1439.
CDCl3):
d
¼8.02e7.80 (m, 2H), 7.62e6.88 (m, 84H), 6.70e6.50 (br s,
1H, COOH), 5.40e5.04 (br m, 9H, 9ꢃ CONCHCH3), 5.04e4.68 (br m,
9H, 9ꢃ CONCHHAr), 4.22e3.88 (m, 9H, 9ꢃ CONCHHAr), 1.62e1.34
(m, 27H, 9ꢃ CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
¼172.9,
d
172.8 (10Cq), 140.6, 139.8, 136.5, 134.8 (28Cq), 130.1, 129.6, 128.7,
128.6, 127.8,127.7,127.5,127.0,126.5,126.3 (86CH), 57.3 (br, 9CH, 9ꢃ
CONCHCH3), 45.2 (br, 9CH2, 9ꢃ CONCH2Ar), 18.2 (br, 9CH3, 9ꢃ
CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 3064 (COOH), 2985 (CH), 1713
(C]O acid), 1632, 1612 (C]O amide), 1494, 1433, 1403, 1329 (OH),
1209, 1168, 1027. HRMS (TOF MS ESþ) calcd for C151H141N9O11Na3
[Mþ3Na]3þ m/z 775.0148, found 775.0109.
7.12.20. Arylopeptoid model monomer m-4c. Synthesized using
method C (85% crude yield, 98% crude purity) at twice the scale
described in the general methods. Data for m-4c: colorless solid
(63 mg, 72%, >99% purity). Mp¼177e180 ꢀC. 1H NMR (300 MHz,
7.12.24. Arylopeptoid nonamer m-6a. Synthesized using method A
(84% crude yield, 97% crude purity). Data for m-6a: colorless solid
(142 mg, 50%, >99% purity). Mp¼129e132 ꢀC. 1H NMR (300 MHz,
CDCl3):
d
¼10.85e10.55 (br s, 1H, COOH), 8.03e7.97 (m, 2H, o-
C6H4COO and o0-C6H4COO), 7.67e7.60 (m, 1H, p-C6H4COO),
7.45e7.37 (m, 1H, m-C6H4COO), 7.25 (s, 1H, o0-C6H4CON), 7.20e6.97
(m, 6H, o-C6H4CON, m-C6H4CON, p-C6H4CON, and CONC6H5),
6.96e6.90 (m, 2H, CONC6H5), 5.20 (s, 2H, CONCH2Ar), 2.22 (s, 3H,
CDCl3):
d
¼7.97e7.70 (m, 2H), 7.70e6.86 (m, 84H), 6.85e6.65 (br s,
1H, COOH), 5.40e5.02 (br m, 9H, 9ꢃ CONCHCH3), 5.02e4.68 (br m,
9H, 9ꢃ CONCHHAr), 4.20e3.84 (m, 9H, 9ꢃ CONCHHAr), 1.62e1.30
CH3Ar) ppm. 13C NMR (75 MHz, CDCl3):
d
¼171.5 (Cq, COO), 171.1 (Cq,
(m, 27H, 9ꢃ CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
¼173.0,
d
CON), 143.1 (Cq, CONC6H5), 137.9 (Cq, m0-C6H4COO), 137.6 (Cq, m0-
C6H4CON), 135.3 (Cq, ipso-C6H4CON), 133.7 (CH, p-C6H4COO), 130.6
(CH), 129.9 (CH, o0-C6H4COO), 129.6 (Cq, ipso-C6H4COO), 129.5 (CH,
o0-C6H4CON), 129.2 (CH, o-C6H4COO), 129.1 (2CH, CONC6H5), 128.7
(2CH, m-C6H4COO), 127.6 (2CH, CONC6H5), 127.5 (CH), 126.8 (CH,
CONC6H5), 125.8 (CH), 53.5 (CH2, CONCH2Ar), 21.1 (CH3, CH3Ar)
ppm. nmax/cmꢁ1 (ATR) 3023, 1671 (C]O acid), 1643 (C]O amide),
1495, 1428, 1376, 1307, 1281, 1227, 1157. HRMS (TOF MS ESþ) calcd
for C22H20NO3 [MþH]þ m/z 346.1438, found 346.1434.
172.9, 172.9 (10Cq), 139.7139.6, 136.5, 136.4, 136.3, 130.0 (28Cq),
129.7, 128.7, 128.5, 128.3, 127.8, 126.9, 126.4, 125.3, 125.2, 124.9
(86CH), 57.4 (br, 9CH, 9ꢃ CONCHCH3), 45.3 (br, 9CH2, 9ꢃ CON-
CH2Ar), 18.2 (br, 9CH3, 9ꢃ CONCHCH3) ppm. nmax/cmꢁ1 (ATR) 2987
(COOH), 2908 (CH), 1716 (C]O acid), 1634, 1601 (C]O amide),
1493, 1447, 1404, 1329 (OH), 1305, 1201, 1156, 1028. HRMS (TOF MS
ESþ) calcd for C151H141N9O11Na3 [Mþ3Na]3þ m/z 775.0148, found
775.0168.
Acknowledgements
7.12.21. Arylopeptoid monomer p-5a. Synthesized using method A
(85% crude yield, 99% crude purity) at twice the scale described in
the general methods. Data for p-5a: colorless solid (58 mg, 64%,
>99% purity). Mp¼66e69 ꢀC. 1H NMR (300 MHz, CDCl3):
We gratefully thank the Villum Kann Rasmussen Foundation for
a grant to T.H., the Carlsberg Foundation (grants 2009_01_0745 and
2010_01_0518) as well as the Lundbeck Foundation. We are like-
d
¼9.55e9.25 (br s, 1H, COOH), 8.08e7.90 (m, 2H), 7.66e7.10 (m,
ꢁ
ꢁ
wise grateful to Bertrand Legeret (Clermont Universite, Laboratoire
SEESIB) for mass spectrometric analysis of p/m-3a, p/m-3c, p/m-5a,
and p/m-6a.
12H), 5.45e5.13 (br m, 1H, CONCHCH3), 5.12e4.78 (br m, 1H,
CONCHHAr), 4.13 (d, J¼16.1 Hz, 1H, CONCHHAr), 1.52 (d, J¼7.0 Hz,
3H, CONCHCH3) ppm. 13C NMR (75 MHz, CDCl3):
(Cq), 144.9 (Cq), 139.7 (Cq), 136.3 (Cq), 130.2 (2CH), 129.7 (CH), 128.7
(4CH), 128.0 (Cq), 127.9 (CH), 127.1 (4CH), 126.4 (2CH), 56.8 (br, CH,
CONCHCH3 [from HSQC correlation]), 45.1 (br, CH2, CONCH2Ar
d
¼173.1 (Cq), 171.3
Supplementary data
Methods used for analytical and preparative HPLC; HPLC profiles
and NMR spectra of all synthesized arylopeptoids; NOESY spectra of
p/m-4b and p/m-4c; temperature NMR studies of p/m-4a; CD
spectra of arylopeptoids with spe side chains in CDCl3. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2011.12.049.
[from HSQC correlation]), 18.1 (br, CH3, CONCHCH3) ppm. nmax
/
cmꢁ1 (ATR) 3066 (COOH), 2984, 2939 (CH), 1714, 1694, 1683 (C]O
acid), 1635, 1612, 1595, 1575 (C]O amide), 1495, 1447, 1410, 1330
(OH), 1280, 1208, 1175, 1108, 1027. HRMS (TOF MS ESþ) calcd for
C23H21NO3Na [MþNa]þ m/z 382.1419, found 382.1425.
7.12.22. Arylopeptoid monomer m-5a. Synthesized using method A
(85% crude yield, 99% crude purity) at twice the scale described in
the general methods. Data for m-5a: colorless solid (61 mg, 67%,
>99% purity). Mp¼56e59 ꢀC. 1H NMR (300 MHz, CDCl3):
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