Efficient and versatile COMU-mediated solid-phase submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides)

Article abstract of DOI:10.1039/c1ob05729d

The development of a highly efficient methodology for solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) with free acids or free amides at the C-terminus is described. The arylopeptoids were synthesised

Full text of DOI:10.1039/c1ob05729d

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PAPER
Efficient and versatile COMU-mediated solid-phase submonomer synthesis of
arylopeptoids (oligomeric N-substituted aminomethyl benzamides)†
Thomas Hjelmgaard,*a Sophie Faure,b,c Dan Staerk,a Claude Taillefumierb,c and John Nielsen*a
Received 9th May 2011, Accepted 6th July 2011
DOI: 10.1039/c1ob05729d
The development of a highly efficient methodology for solid-phase synthesis of para- and
meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) with free acids or free amides
at the C-terminus is described. The arylopeptoids were synthesised by means of a convenient
submonomer protocol in which the arylopeptoid residues were created in an iterative manner on the
growing chain using an acylation–substitution cycle. The uronium salt COMU was found to be the
most efficient reagent for ensuring fast and clean couplings of the benzoic acid building blocks.
Introduction
A group of foldamers which has received ever increasing interest
during the last two decades is “one-way sequence” aromatic
oligoamides comprised of aromatic amino acids.1 While the amide
core structures of these synthetic oligomers are inherently only
distantly related to biopolymers such as peptides, they may still
be brought to mimic the side chain presentation and structure
of such biopolymers and may therefore for example find use
as proteomimetics.2 These aromatic oligoamides may be divided
into two distinct groups: (i) aromatic oligoamides with free
amide protons (Fig. 1a) and (ii) N-alkylated aromatic oligoamides
(Fig. 1b).
In the first group, oligoamides that contain no aliphatic
carbons in the backbone are by far the most widely stud-
ied (Fig. 1a). Examples include benzanilides by the groups
of Hamilton,3 Gong,4 Kilbinger,5 Li,6 Wilson,7 Clayden,8 and
others;9 pyridylamides by the Hamilton group;3a–b,10 and quino-
line and naphthyridine oligoamides by the Huc group.11,12 The
syntheses of these oligomers pass via acylation of comparatively
less reactive aromatic amines and coupling using acid chlorides
is the most commonly used synthetic pathway, primarily in
solution,3,4,5c,6–8,9a–c,e,11,10 but also on solid-phase.5a–b,9d Accordingly,
the only reports of synthesis using free acid building blocks
Fig. 1 Aromatic oligoamides with free amide protons (a) and N-alkylated
aromatic oligoamides (b).
aDepartment of Basic Sciences and Environment, University of
Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
E-mail: thhj@life.ku.dk, jn@life.ku.dk; Fax: +45 3533 2398; Tel: +45 3533
2427
and peptide-type coupling methods include the use of BOP9b
or PyBOP12 in solution-phase. Although less well studied, sev-
eral reports on aromatic oligoamides with free amide protons
and aliphatic carbons in the backbone have been disclosed:
oligoamides of aminomethyl-phenyl acetic acids by the Amblard
group,13 oligoamides of aminophenoxy acetic acids by the Aka-
zome group,14 aminomethyl-pyridylamides by the Huc group,15
and aminomethyl-benzamides by the Hamilton group.16 Since the
syntheses of these oligomers proceed via more reactive aliphatic
intermediates, activation as acid chlorides is not necessary and
they have exclusively been synthesised using peptide-type coupling
bCNRS, UMR6504, Laboratoire SEESIB, 63177 Aubie`re cedex, France
cClermont Universite´, Universite´ Blaise Pascal, BP 10448, 63000 Clermont-
Ferrand, France. E-mail: sophie.faure@univ-bpclermont.fr, claude.
taillefumier@univ-bpclermont.fr
† Electronic supplementary information (ESI) available: Synthesis of
halomethyl-intermediates p-2 and p-3; methods used for analytical and
preparative HPLC; determination of the loading of the 2-chlorotrityl
chloride polystyrene resin; details concerning optimisation of acylation
and substitution steps using HPLC; HPLC profiles and NMR spectra of
all synthesised arylopeptoids. See DOI: 10.1039/c1ob05729d
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reagents such as BOP,13 EDC,14 HBTU,15 in solution-phase and
PyBOP16 on solid-phase. A common trait in this first group of
aromatic oligoamides is that the formation of secondary structures
may be promoted by the presence of intramolecular hydrogen
bonding involving the free amide protons analogous to what is ob-
served in peptides. Accordingly, the presence of spherand or crown
ether-like structures,6 crescent or helical structures,4,11–14 and rod-
like structures,5a,c,7a as well as the use as a-helix mimetics,3a–b,7a,9a–b,10
has been reported.
versatile COMU-based solid-phase methodology that meets these
demands.
Results and discussion
Solution-phase studies
In order to establish the initial conditions for optimisation of solid-
phase submonomer synthesis of arylopeptoids, we first screened a
series of coupling and substitution conditions on a small scale in
solution (see ESI† for details). As a model system for conducting
these studies we used conversion of para-monomer p-1,25 carrying
the moderately bulky isopropyl side chain, into dimer p-425 via
bromomethyl intermediate p-2 or chloromethyl intermediate p-3
(Scheme 1).
Compared to aromatic oligoamides with free amide protons, N-
alkylated aromatic oligoamides remain far less studied (Fig. 1b).
Most of the efforts concerning N-alkylated oligoamides have again
been concentrated around the synthesis and study of oligomers
with no aliphatic carbons in the backbone, including N-alkylated
benzanilides by the groups of Yokozawa,17 Kilbinger,18 Wilson,19
and Clayden;8a and N-alkylated naphthanilides by the Clayden
group.8a These oligomers were exclusively synthesised using ac-
tivation as acid chlorides either in solution-phase8a,17,19b–c or on
solid-phase.18a–b,19a Intriguingly, although they are deprived of free
amide protons, the presence of crescent or helical structures17
as well as the use as a-helix mimetics19a has still been reported.
Furthermore, in connection with their pioneering work on the
development of peptoids (oligomeric N-substituted glycines),20
Zuckermann and co-workers21 briefly mentioned the synthesis of a
few pentamers of para-arylopeptoids22 (oligomeric N-substituted
aminomethyl benzamides) in a series of patents from the mid to late
90’s. The oligomers were synthesised on a Rink amide polystyrene
resin using a submonomer method unique to peptoids and the
benzoic acid building blocks were activated as their corresponding
anhydrides using 0.5 equiv DIC. In 2007, Lokey and Combs then
reported the synthesis of a few tetramers and pentamers of para-
or meta-arylopeptoids using a Wang resin and activation of the
benzoic acid building blocks with 1.0 equiv DIC.23 This method
was, however, not adaptable to synthesis on a Rink amide resin
and provided mediocre yields.
Scheme
1 Model system for solution-phase studies. Key: (a)
XCH2ArCOOH, coupling reagent, DIPEA, solvent, rt, further conditions
in Table 1. (b) iPrNH2, solvent, further conditions in Table 2.
We believe that these arylopeptoids may represent a new
group of oligomers with folding propensities as a result of their
relatively rigid aromatic amide core structure even though their
backbones are deprived of free amide protons. Importantly,
they may be developed to retain the favorable characteristics
of peptoids such as large potential for diversity and straight-
forward synthesis using submonomer methods. Thus, based on
convenient methods we have previously developed for solution-
phase synthesis of peptoid residues,24 we recently published the
first solution-phase synthesis of para- and meta-arylopeptoids.25
Shorter oligomers were synthesised using highly convenient and
efficient submonomer protocols where each arylopeptoid residue
is created in an iterative manner on the growing chain using
an acylation–substitution cycle. Peptide coupling methods were
studied to access longer oligomers and we furthermore undertook
the first conformational studies of arylopeptoids. Thus, the
cis/trans isomerism of arylopeptoid backbones was studied by
means of NMR and we found that increasing the bulkiness of the
side chains would greatly favor the cis amide bond conformation.
Although this solution-phase methodology is highly useful for
gram scale synthesis of lead compounds, the development of
efficient and generally applicable solid-phase methodologies for
synthesis of large and diversified libraries of arylopeptoids is
highly desirable. Thus, herein we describe the development of a
In our preceding paper, we screened a selection of coupling
reagents for peptide-type coupling of arylopeptoid trimers.25 We
found the new uronium salt COMU26 (derived from Oxyma) to be
by far the most efficient coupling reagent and we therefore started
the present study with the use of COMU. Thus, 1 M solutions
of 4-(bromomethyl)benzoic acid or 4-(chloromethyl)benzoic acid
(3 equiv) in DMF were preactivated with COMU (3.5 equiv) and
DIPEA (7 equiv) at room temperature, and were then reacted
with monomer p-1. The reactions were monitored by analytical
HPLC (see ESI† for details) and while the conversion of p-1 into
bromomethyl intermediate p-2 gave rise to a complex reaction
mixture (Table 1, entry 1) the conversion of p-1 into chloromethyl
intermediate p-3 proceeded cleanly in 2.5 min (Table 1, entry 2).
Indeed, we found that while 4-(chloromethyl)benzoic acid remains
reasonably pure in DMF in the presence of DIPEA (99.6% purity
after 5 min; 98.5% purity after 15 min), 4-(bromomethyl)benzoic
acid polymerises quickly under the same conditions (<50% purity
after 5 min). These polymerisation reactions presumably occur
too fast for COMU activation to compete properly and a complex
product mixture is obtained. The use of 4-(bromomethyl)benzoic
acid as a building block for solid-phase submonomer synthesis of
arylopeptoids under basic conditions was therefore abandoned.
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Table 1 Optimisation of coupling step (a)
X, XCH2C6H4COOH
(equiv)
Coupling reagent
(equiv)
DIPEA
(equiv)
Pre-activation
(min)
Reaction timea
(min)
Entry
Solvent
Comments
1
2
3
4
5
6
7
8
Br (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (3.0)
Cl (6.0)
Cl (3.0)
COMU (3.5)
COMU (3.5)
COMU (3.5)
HOTU (3.5)
HATU (3.5)
PyBroP (3.5)
BOP (3.5)
HBTU (3.5)
PyBOP (3.5)
DIC (3.0)
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
0
DMF
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
5
5
5
5
5
5
5
5
5
5
5
<2.5
2.5
5
10
20
Complex mixture
Clean reaction to p-3
Clean reaction to p-3
Clean reaction to p-3
Clean reaction to p-3
Clean reaction to p-3
93% conv. after 30 min
90% conv. after 30 min
85% conv. after 30 min
93% conv. after 30 min
83% conv. after 30 min
30
>30
>30
>30
>30
>30
9
10
11
DIC (3.0)
a Reactions monitored by analytical HPLC.
Next, we found that although the conversion of p-1 into p-3
would proceed slightly slower when using the less toxic NMP
as solvent (5 min, entry 3), the reaction would proceed just as
cleanly as in DMF. A representative selection of other coupling
agents were then screened (entries 4–11). Although most of these
couplings proceeded with the same purity as when COMU was
used, none of the alternative coupling reagents could compete
with COMU with respect to reaction times. Thus, compared
to COMU, HOTU would double the reaction time (10 min,
entry 4), while couplings using HATU and PyBroP would need
20 min and 30 min to reach completion, respectively (entries 5
and 6). Furthermore, couplings using BOP, HBTU and PyBOP
did not reach complete conversion within 30 min (entries 7–9).
Interestingly, both activation of 4-(chloromethyl)benzoic acid as
the corresponding anhydride using 0.5 equiv DIC, as reported in
the patents of Zuckermann and co-workers,21 and coupling using
1.0 equiv DIC as reported by Lokey,23 were found to be much
less efficient than COMU couplings (93% and 83% conversion
after 30 min, respectively, entries 10 and 11). Having established
the combination of 4-(chloromethyl)benzoic acid and COMU as
the optimal set of conditions for peptide type coupling synthesis
of p-3, we then proceeded to investigate the ensuing substitution
reaction with isopropylamine, yielding dimer p-4 (Table 2).
Although we had by now excluded the use of bromomethyl
intermediate p-2, an initial solvent scan was performed using this
more reactive intermediate. Thus, p-2 was reacted with 10 equiv
isopropylamine as 1 M solutions in different solvents at room
temperature (Table 2, entries 1–6) and the evolution of the reac-
tions was followed using analytical HPLC (see ESI† for details).
We found the substitution reaction to occur the fastest in DMSO
(<2 min, entry 6) followed by DMF and NMP (3 min, entries
4–5). When transferring these conditions to the corresponding
chloromethyl intermediate p-3, the reaction times were as expected
drastically increased (entries 7–9) with DMSO still offering the
fastest reaction time (3 h, entry 9). By increasing the concentration
of isopropylamine and the temperature, the reaction time could be
reduced (entries 10–12) and the reaction would be complete within
a reasonable 30 min when using 20 equiv isopropylamine at 2 M
◦
concentration in DMSO at 50 C (entry 12). The reaction could
also be performed in DMSO–water 9 : 1 although the reaction time
increased slightly to 45 min. This result indicated that concentrated
aqueous solutions could be used as a source of small volatile
amines if needed. We also tested the use of microwave irradiation
(95 ◦C) and found that the reaction times could be drastically
reduced to 5 min or less (entries 14–16). Overall, these solution-
phase investigations showed that the optimisation of solid-phase
Table 2 Optimisation of substitution step (b)
Entry
X
iPrNH2 (equiv/[c])
Solvent
Conditions
Reaction timea
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
10.0/1.0
20.0/2.0
20.0/2.0
20.0/2.0
20.0/2.0
10.0/1.0
20.0/2.0
20.0/2.0
MeOH
THF
CH2Cl2
NMP
DMF
DMSO
NMP
DMF
DMSO
DMSO
DMSO
DMSO
DMSO–water 9 : 1
DMSO
DMSO
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4 h
1.5 h
1.5 h
3 min
3 min
<2 min
16 h
12 h
3 h
9
10
11
12
13
14
15
16
2 h
40 ◦
50 ◦
50 ◦
C
C
C
45 min
30 min
45 min
5 min
<2.5 min
<2.5 min
MW, 95 ◦
MW, 95 ◦
MW, 95 ◦
C
C
C
DMSO–water 9 : 1
a Reactions monitored by analytical HPLC.
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Scheme 2 Model system for optimisation of solid-phase synthesis. Key: (a) ClCH2ArCOOH (1.2 equiv, 0.14 M), DIPEA (6.0 equiv), CH2Cl2, rt, 1 h.
(b) iPrNH2 (20 equiv, 2.0 M), DMSO, further conditions in Table 3. (c) ClCH2ArCOOH, COMU, DIPEA, further conditions in Table 3. (d) BzCl (4.0
equiv, 1.0 M), DIPEA (8.0 equiv), CH2Cl2, rt, 15 min. (e) HFIP–CH2Cl2 1 : 4, rt, 1 h.
submonomer synthesis of arylopeptoids should be based on the
use of COMU-mediated coupling of chloromethylbenzoic acid
building blocks and substitution reactions with primary amines in
DMSO either at 50 ◦C or by the use of microwave activation.
of the substitution steps and coupling steps were set to 1 h and
20 min, respectively, and we were satisfied to find that trimer
p-5 could be isolated in 71–74% crude yield and an excellent 96%
crude purity when otherwise adapting the conditions found in the
previous solution-phase studies (Table 3, entry 1). We furthermore
obtained identical crude yields and purities when conducting the
coupling steps at higher dilution (0.5 M) which would prove to be
useful when synthesising longer oligomers (vide infra). Increasing
the amount of COMU-activated 4-(chloromethyl)benzoic acid
added in the coupling steps to 5 equiv did not improve the crude
yield or purity of the synthesis (entry 2). The substitution steps
could also be performed using microwave irradiation at 95 ◦C
which would furnish trimer p-5 in comparable crude yields and
purities (entry 3). However, although the reaction time of the
substitution steps could be reduced to as little as 2.5 min, we
found heating to 50 ◦C using conventional heating blocks to
be more convenient since the entire arylopeptoid synthesis could
be completed without changing the reaction syringe. Otherwise,
specialised equipment would be required. Attempts to change
the initially selected reaction times did not improve the synthesis
either. Thus, reducing the reaction time of the substitution steps
to 15 min (entry 4) or increasing the reaction time of the coupling
steps to 1 h (entry 5) would in both cases decrease the crude purity
slightly to 93%. Furthermore, reducing the reaction time of the
Solid-phase studies
Optimisation of solid-phase submonomer synthesis of arylopep-
toids was performed on a 2-chlorotrityl chloride polystyrene resin
with a listed loading of 1.50 mmol g-1. As a direct continuation
of the solution-phase studies we chose to use para-trimer p-5 with
isopropyl side chains as a model target (Scheme 2). We found
that a constant loading of 1.23 0.03 mmol g-1 was obtained
when the 2-chlorotrityl chloride polystyrene resin was reacted
with 4-(chloromethyl)benzoic acid (1.2 equiv with respect to the
listed loading) in the presence of DIPEA (6.0 equiv) in CH2Cl2
at rt for 1 h (see ESI† for details). A slightly lower loading of
1.10 mmol g-1 was obtained when shortening the reaction time
to 30 min, while longer reaction times were avoided in order to
minimise the risk of polymerisation of 4-(chloromethyl)benzoic
acid. The synthesis of trimer p-5 was then carried out by following
the iterative coupling–substitution cycle illustrated in Scheme 2
followed by capping with benzoyl chloride and cleavage with
HFIP. Based on the solution-phase studies, the reaction times
Table 3 Optimisation of substitution step (b) and coupling step (c)
Substitution step (b)
(temp/time)
Coupling step (c)
ClCH2ArCOOH
(equiv/[c])
COMU
(equiv)
DIPEA
(equiv)
Time
(min)
Crude
yield (%)
Crude
Entry
purity (%)a
1
2
3
4
5
6
50 ◦C/1 h
3.0/0.5–1.0
5.0/1.0
5.0/1.0
3.0/1.0
3.0/1.0
3.0/1.0
3.5
6
6
3.5
3.5
3.5
7
20
20
20
20
60
5
71–74
76
73–75
74
77
69
96
96
95
93
93
82
50 ◦C/1 h
12
12
7
7
7
MW 95 ◦C/2.5–10 min
50 ◦C/15 min
50 ◦C/1 h
50 ◦C/1 h
a Determined by analytical HPLC.
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Scheme 3 Solid-phase submonomer synthesis of model arylopeptoid hexamers with free acids at the C-terminus. 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) ClCH2ArCOOH (3.0 equiv, 1.0 M), COMU (3.5 equiv),
DIPEA (7.0 equiv), rt, 20 min. (d) BzCl (4.0 equiv, 1.0 M), DIPEA (8.0 equiv), CH2Cl2, rt, 15 min. (e) HFIP–CH2Cl2 1 : 4, rt, 1 h. See Table 4 for yields
and purities.
coupling step to 5 min would decrease the crude yield to 69%
and at the same time decrease the crude purity to 82% (entry 6).
Overall, the conditions listed in entry 1 were chosen as the optimal
conditions.
4-phenylbutyl side chains in 12% yield.23 Our method thus provides
longer oligomers in greatly increased yields and is furthermore
more efficient when installing more bulky side chains such as the
isopropyl side chain. We used a concentrated aqueous solution as
the source of ethylamine for the substitution steps in the synthesis
of hexamers p/m-6b which carry ethyl side chains (entries 3 and 4).
Although we had shown in the solution-phase studies that the sub-
stitution step would proceed more slowly in the presence of water,
only a slight decrease in crude purity to 71% was observed. Hexam-
ers p-6b and m-6b were isolated in comparable crude yields which
were slightly lower than the above-mentioned hexamers. Hexamer
p-6b unfortunately also proved too insoluble to allow for pu-
rification, but m-6b was accordingly isolated in a slightly lower
yield than the above-mentioned hexamers after purification (33%,
>99% purity, entry 4). This slight decrease in yield is presumably a
result of slow ester hydrolysis of the arylopeptoid chains from the
2-chlorotrityl linker during the substitution reactions. Hexamer
p-6e with pyridinylmethyl side chains was also synthesised effi-
ciently although the crude purity was reduced to 52% and the
yield of the purified product was only 21% (>99% purity, entry 9).
Synthesis of hexamers carrying highly bulky tert-butyl side chains
was likewise attempted but failed to yield anything but complex
product mixtures.
Solid-phase synthesis of arylopeptoids
With an optimised method for solid-phase submonomer synthesis
of arylopeptoids in hand, we then first synthesised a range
of representative model para-hexamers p-6 and meta-hexamers
m-6 with free acids at the C-terminus (Scheme 3 and Table
4). The syntheses were performed on the 2-chlorotrityl chloride
polystyrene resin used in the above studies using the optimised
conditions. We were satisfied to find that hexamers p/m-6a with
isopropyl side chains, p/m-6c with 4-phenylbutyl side chains and
p/m-6d with 2-morpholinoethyl side chains were all isolated in
good crude purities (78–85%, entries 1–2 and 5–8). Whereas
hexamerp-6aunfortunatelyprovedtooinsolubletobepurified, the
remaining hexamers could easily be obtained in 39–58% yield and
>99% purity after preparative HPLC. For comparison, Lokey and
Combs reported the synthesis of similar N-acetyl capped para- and
meta-arylopeptoid tetramers with 2-morpholinoethyl side chains
in 20% and 37% yield, respectively, and the synthesis of similar
N-acetyl capped para- and meta-arylopeptoid pentamers with
Table 4 Results for solid-phase submonomer synthesis of model arylopeptoid hexamers with free acids at the C-terminus
Entry
Hexamer
Crude yield (%)
Crude purity (%)a
Purified yield (%)b
c
1
2
3
4
5
6
7
8
9
p-6a
m-6a
p-6b
m-6b
p-6c
m-6c
p-6d
m-6d
p-6e
69
91
57
54
66
68
86
87
72
78
80
71
71
80
81
85
81
52
—
55
—
33
39
39
58
41
21
c
a Determined by analytical HPLC. b Yield of product isolated in >99% purity after preparative HPLC. c Preparative HPLC hindered due to very low
solubility.
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Scheme 4 Solid-phase submonomer synthesis of model arylopeptoid hexamers with free amide at the C-terminus. Key: (a) piperidine–NMP 1 : 4, rt, 2
and 15 min; then ClCH2ArCOOH (3.0 equiv, 1.0 M), COMU (3.5 equiv), DIPEA (7.0 equiv), rt, 30 min. (b) R-NH2 (20 equiv, 2.0 M), DMSO, 50 ◦C,
1 h. (c) ClCH2ArCOOH (3.0 equiv, 1.0 M), COMU (3.5 equiv), DIPEA (7.0 equiv), rt, 20 min. (d) BzCl (4.0 equiv, 1.0 M), DIPEA (8.0 equiv), CH2Cl2,
rt, 15 min. (e) TFA–water 95 : 5, rt, 2 h. See Table 5 for yields and purities.
An important point for us was to develop the first efficient
and versatile solid-phase methodology for submonomer synthesis
of arylopeptoids that could generate both oligomers with free
acids at the C-terminus and oligomers with free amides at the C-
terminus. Indeed, Lokey and Combs reported that their method
was not adaptable to the use of Rink amide resins,23 while
synthesis of arylopeptoids with free acids at the C-terminus
was not demonstrated by Zuckermann and coworkers.21 We
were therefore satisfied to find that our methodology was also
adaptable to synthesis of oligomers with free amides at the C-
terminus using a Rink amide polystyrene resin with a listed
loading of 0.74 mmol g-1 (Scheme 4 and Table 5). Compared
to synthesis using the 2-chlorotrityl chloride polystyrene resin,
the only changes to the syntheses were (1) the initial attachment
reactions were carried out for 30 min using 3 equiv of COMU-
activated chloromethylbenzoic acids with respect to the listed resin
loading and (2) the final cleavage was effected using TFA–water
95 : 5 instead of HFIP. Hexamers p/m-7a with isopropyl side
chains, p/m-7c with 4-phenylbutyl side chains and p/m-7d with
2-morpholinoethyl side chains were all isolated in good crude
purities (71–84%, entries 1–2 and 4–7) and good purified yields
after preparative HPLC (46–59%, >99% purity). These results are
comparable to the results obtained above in the synthesis of the
analogous arylopeptoids with free acids at the C-terminus using
the 2-chlorotrityl linker. The two linkers thus perform equally
well with these side chains when applying the standard conditions
we have developed. Furthermore, when using the Rink amide
linker, we did not observe a relative decrease in the yield of
p-7b which carries ethyl side chains even though a concentrated
aqueous solution was again used as the source of ethylamine (54%
yield, >99% purity, entry 3). This supports the assumption that the
relative reduction in yield of p/m-6b is caused by slow hydrolysis
of the arylopeptoid chains from the 2-chlorotrityl linker during
the substitution steps. Our results compare favourably with the
method reported in the patents of Zuckermann and coworkers
where similar, though N-uncapped, para-arylopeptoid pentamers
were obtained in 60–76% crude yield and 80–90% crude purity.21
Installing pyridinylmethyl side chains again resulted in a reduced
crude purity of 51% and we accordingly obtained p-7e in only
22% yield (>99% purity, entry 8). We furthermore synthesised
hexamers p-7f and p-7g which carry 4-aminobutyl side chains and
carboxymethyl side chains, respectively (entries 9–10). These side
chains were installed using tert-butyl (4-aminobutyl)carbamate
and tert-butyl aminoacetate in the substitution steps, respectively,
conveniently unmasking the side chain functionalities during the
cleavage step.
Table 5 Results for solid-phase submonomer synthesis of model arylopeptoid hexamers with free amides at the C-terminus
Entry
Hexamer
Crude yield (%)
Crude purity (%)a
Purified yield (%)b
1
2
3
4
5
6
7
8
9
p-7a
m-7a
p-7b
p-7c
m-7c
p-7d
m-7d
p-7e
p-7f
127
110
120
110
104
93
115
118
77
80
71
82
78
84
79
81
51
77
52
55
58
54
46
53
58
59
22
49
31
10
p-7g
109
a Determined by analytical HPLC. b Yield of product isolated in >99% purity after preparative HPLC.
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In order to firmly underline the utility of the present method
we then easily synthesised the longest arylopeptoid constructs
demonstrated to date: the two hetero-dodecamers p-8 and m-8
shown in Scheme 5, which were obtained in 25% and 27% overall
yield, respectively, after preparative HPLC (>99% purity). The
syntheses were carried out as outlined in Scheme 4 with the only
modifications being that coupling steps beyond the hexamer stage
as well as the final capping step were carried out at higher dilution
(0.5 M) as a result of the expanding of the resin. The dodecamers
were obtained in highly satisfactory 62% and 58% crude purities,
respectively.
synthesis, and we found the new uronium salt COMU to be
the most efficient reagent for ensuring fast and clean couplings.
The present methodology is the first that has been shown to
be adaptable to synthesis of arylopeptoids with both free acids
and free amides at the C-terminus. We found the solubility of
arylopeptoids in different solvents to vary greatly as a function
of the side chain decorations, the substitution patterns of the
backbone and the nature of the C-terminus, lending promise that
arylopeptoids may easily be adapted for a plethora of uses within
for example chemical biology and medicine. The developed solid-
phase methodology will allow for synthesis of highly diversified
libraries of arylopeptoids and we will continue to explore all
aspects of arylopeptoids and will report our findings in due course.
Experimental Section
General experimental methods
CH2Cl2 used as solvent in attachment and capping reactions
˚
was dried over 4 A molecular sieves. All other chemicals and
solvents obtained from commercial sources (Alfa Aesar, Fluka,
Merck and Sigma–Aldrich) were used as received. 2-Chlorotrityl
chloride copoly(styrene-1% DVB) resin (100–200 mesh) with a
listed loading of 1.50 mmol g-1 and Rink amide copoly(styrene-1%
DVB) resin (100–200 mesh) with a listed loading of 0.74 mmol g-1
were purchased from Merck. 2 M solutions of primary amines in
DMSO used in the substitution steps were made from the neat, free
amines except in the case of ethylamine where a saturated aqueous
solution was used as a source of the amine. Melting points were
determined on a Mettler Toledo MP70 melting point system and
are referenced to the melting points of benzophenone and benzoic
acid. NMR spectra were recorded on a Bruker Avance 300 MHz
spectrometer. Chemical shifts are referenced to the residual solvent
peak and J values are given in Hz. The following multiplicity
abbreviations are used: (s) singlet, (q) quartet, (m) multiplet, and
(br) broad. Where applicable, assignments 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 MIRacleTM ATR and wavenumbers (n) are expressed
in cm-1. HRMS of all arylopeptoids except for p-7f and p-7g
were recorded on a Micromass LCT apparatus equipped with an
AP-ESI probe calibrated with Leu-Enkephalin. HRMS of p-7f
and p-7g were recorded on a Micromass Q-Tof Micro (3000V)
apparatus. Model system monomer p-1 and dimer p-4 were
synthesised as previously described.25 See ESI† for details concern-
ing analytical and preparative HPLC as well as for the synthesis
of halomethyl intermediates p-2 and p-3.
Scheme 5 Model hetero-dodecamers p-8 and m-8.
Importantly, we observed that the solubility of the synthesised
arylopeptoid oligomers in different solvents would vary greatly
as a function of the side chain decorations, the substitution
patterns of the backbone and the nature of the C-terminus.
Thus, arylopeptoids that carried hydrophobic side chains such
as ethyl, isopropyl or 4-phenylbutyl were only soluble in organic
solvents such as methanol or CH2Cl2 and the presence of only
small amounts of water would be tolerated before cloudy mixtures
formed. On the contrary, arylopeptoids that carried hydrophilic
side chains such as pyridinylmethyl, 2-morpholinoethyl or 4-
aminobutyl were generally highly water soluble. Furthermore,
we noted that meta-arylopeptoids were generally more readily
soluble than para-arylopeptoids and that arylopeptoids with free
amides at the C-terminus were likewise more readily soluble
than arylopeptoids with free acids at the C-terminus. Overall,
these observations lend promise that arylopeptoids may easily be
adapted for a plethora of uses in chemical biology and medicine.
General procedure for attachment to trityl resin and synthesis of
first arylopeptoid residue
Conclusions
We have developed a highly efficient methodology for solid-
phase synthesis of para- and meta-arylopeptoids (oligomeric
N-substituted aminomethyl benzamides). The oligomers were
synthesised by means of a highly versatile submonomer protocol in
which the arylopeptoid residues are created in an iterative manner
on the growing chain using an acylation–substitution cycle. The
difficult acylation steps of the secondary amines were conveniently
carried out using free acid building blocks reminiscent of peptide
2-Chlorotrityl chloride resin (100 mg, 1.50 mmol g-1; thus
0.150 mmol) was washed with CH2Cl2 (2 ¥ 2 mL). The resin was
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 agitated for 1 h at rt after which time a loading of
1.23 0.03 mmol was obtained (see ESI†). The resin was drained
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and washed with CH2Cl2 (3 ¥ 2 mL) and DMSO (3 ¥ 2 mL). A
solution of the secondary 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 (3 ¥ 2 mL)
and NMP (3 ¥ 2 mL).
General procedure for cleavage from rink amide resin
The resin was cleaved in TFA–water 95 : 5 (2 mL) with agitation
for 2 h. The resin was drained and washed with TFA (2 mL)
and CH2Cl2 (5 ¥ 2 mL). The solvents were evaporated under
reduced pressure and the residue was evaporated with CH2Cl2 (3 ¥
5 mL) yielding the crude product which was purified by preparative
HPLC (see ESI† for details).
General procedure for attachment to rink amide resin and synthesis
of first arylopeptoid residue
Arylopeptoid trimer p-5. Colorless foam (52 mg, 65%, >99%
purity). mp = 87–90 ◦C. 1H NMR (300 MHz, CDCl3): d =
9.85–9.30 (br s, 1H, COOH), 8.12–7.92 (m, 2H), 7.62–6.98 (m,
15H), 4.88–4.44 (br s, 6H, 3¥CONCH2Ar), 4.38–4.03 (br m, 3H,
3¥CONCH(CH3)2), 1.42–0.94 (m, 18H) ppm. 13C NMR (75 MHz,
CDCl3): d = 172.7, 172.6, 170.5 (4Cq), 145.0, 140.6, 136.4, 134.9
(7Cq), 130.3, 129.5, 128.6, 127.0, 126.8, 126.5, 126.1 (17CH), 51.0
(br, 3CH, 3¥CONCH(CH3)2), 43.5 (br, 3CH2, 3¥CONCH2Ar),
21.3 (6CH3) ppm. nmax/cm-1 (ATR) 2980 (CH), 1713 (C O),
1627 (C O), 1464 (CH), 1439, 1409, 1339 (OH), 1174 (CN),
1061. HRMS (TOF MS ES+) calcd for C40H46N3O5 [M + H]+ m/z
648.3432, found 648.3425.
Rink amide resin (162 mg, 0.74 mmol g-1; thus 0.120 mmol) was
washed with CH2Cl2 (2 ¥ 2 mL) and NMP (5 ¥ 2 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 (5 ¥ 2 mL). To a solution of 3- or 4-(chloromethyl)benzoic
acid (64 mg, 0.38 mmol) in NMP (0.38 mL) at rt was added COMU
(187 mg, 0.44 mmol) and then DIPEA (0.157 mL, 0.90 mmol).
After agitating for 5 min, the resulting deep red mixture was added
to the resin and the resulting mixture was agitated for 30 min at
rt. The resin was drained and washed with NMP (5 ¥ 2 mL) and
DMSO (3 ¥ 2 mL). A solution of the secondary 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 (3 ¥ 2 mL) and NMP (3 ¥ 2 mL).
Arylopeptoid hexamer p-6a. Preparative HPLC of the crude
product hindered due to very low solubility. Crude p-6a: Pale rose
◦
1
foam (97 mg, 69%, 78% purity). mp = 223–228 C. H NMR
(300 MHz, CDCl3–MeOD 1 : 1): d = 8.00–7.92 (m, 2H), 7.54–7.10
(m, 27H), 4.78–4.40 (br s, 12H, 6¥CONCH2Ar), 4.24–4.04 (br
m, 6H, 6¥CONCH(CH3)2), 1.32–1.00 (36H, m) ppm. nmax/cm-1
(ATR) 2968, 2929, 1628 (C O), 1437, 1404, 1338 (OH), 1175
(CN), 1054, 842. HRMS (TOF MS ES+) calcd for C73H85N6O8
[M + 2H]2+ m/z 587.3248, found 587.3250.
General procedure for arylopeptoid residue synthesis
To a solution of 3- or 4-(chloromethyl)benzoic acid (64 mg,
0.38 mmol) in NMP (0.38 mL) at rt was added COMU (187
mg, 0.44 mmol) and then DIPEA (0.157 mL, 0.90 mmol). After
agitating for 5 min, the resulting deep red mixture was added to
the resin and the resulting mixture was agitated for 20 min at rt.
The resin was drained and washed with NMP (5 ¥ 2 mL) and
DMSO (3 ¥ 2 mL). A solution of the secondary 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 (3 ¥ 2 mL) and NMP (3 ¥ 2 mL). This general
procedure was repeated until the desired oligomer length was
reached.
Arylopeptoid hexamer m-6a. Colorless foam (82 mg, 55%,
◦
1
>99% purity). mp = 80–83 C. H NMR (300 MHz, CDCl3):
d = 10.06–9.68 (br s, 1H, COOH), 8.10–7.83 (m, 2H), 7.65–7.02
(m, 27H), 4.84–4.40 (br s, 12H, 6¥CONCH2Ar), 4.30–3.88 (br m,
6H, 6¥CONCH(CH3)2), 1.42–0.84 (m, 36H) ppm. 13C NMR
(75 MHz, CDCl3): d = 172.6 (7Cq), 139.6, 139.5, 136.7, 136.6,
130.2 (13Cq), 131.8, 129.5, 128.8, 128.6, 128.5, 128.1, 128.0, 126.1,
124.6 (29CH), 51.0 (br, 6CH, 6¥CONCH(CH3)2), 43.4 (br, 6CH2,
6¥CONCH2Ar), 21.3 (12CH3) ppm. nmax/cm-1 (ATR) 2980, 1713
(C O), 1627 (C O), 1464 (CH), 1447, 1410, 1338 (OH), 1178
(CN), 1062. HRMS (TOF MS ES+) calcd for C73H85N6O8 [M +
2H]2+ m/z 587.3248, found 587.3257.
General procedure for capping with benzoyl chloride
The resin was washed with CH2Cl2 (3 ¥ 2 mL). To a solution
of benzoyl chloride (0.060 mL, 0.52 mmol) in CH2Cl2 (0.52 mL)
at rt was added DIPEA (0.181 mL, 1.04 mmol). The solution
was added to the resin and the resulting mixture was agitated for
15 min at rt. The resin was drained and washed with CH2Cl2–
DIPEA 4 : 1 (3 ¥ 1 mL, only for arylopeptoids that contain side
chains with basic functionalities), CH2Cl2 (3 ¥ 2 mL), NMP (3 ¥
2 mL) and CH2Cl2 (3 ¥ 2 mL).
Arylopeptoid hexamer p-6b. Preparative HPLC of the crude
product hindered due to very low solubility. Crude p-6b: Pale rose
◦
1
foam (77 mg, 57%, 71% purity). mp = 123–128 C. H NMR
(300 MHz, CDCl3/MeOD 1 : 1): d = 8.05–7.96 (m, 2H), 7.52–
7.10 (m, 27H), 4.85–4.48 (br m, 12H, 12¥CONCH2Ar), 3.60–3.18
(br m, 12H, 12¥CONCH2CH3), 1.30–1.01 (m, 18H) ppm.
n
max/cm-1 (ATR) 2973, 2915, 1716 (C O), 1627 (C O), 1464
(CH), 1429, 1312 (OH), 1262, 1175 (CN), 1093, 836. HRMS (TOF
MS ES+) calcd for C67H74N6O8 [M + 2H]2+ m/z 545.2779, found
545.2775.
General procedure for cleavage from trityl resin
The resin was cleaved in HFIP/CH2Cl2 1 : 4 (1 mL) with agitation
for 1 h. The resin was drained and washed with CH2Cl2 (5 ¥
2 mL). The solvents were evaporated under reduced pressure and
the residue was evaporated with CH2Cl2 (3 ¥ 5 mL) yielding the
crude product which was purified by preparative HPLC (see ESI†
for details).
Arylopeptoid hexamer m-6b. Colorless oil (45 mg, 33%, >99%
purity). H NMR (300 MHz, CDCl3): d = 8.11–7.78 (m, 2H),
7.60–7.14 (m, 27H), 4.88–4.63 (br s, 7.20H, 6¥CONCH2Ar, major
rotamer), 4.63–4.36 (br s, 4.80H, 6¥CONCH2Ar, minor rotamer),
3.62–3.33 (m, 4.80H, 6¥CONCH2CH3, minor rotamer), 3.33–
3.04 (m, 7.20H, 6¥CONCH2CH3, major rotamer), 1.32–0.94
1
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(m, 18H) ppm. 13C NMR (75 MHz, CDCl3): d = 172.2 (7Cq),
137.8, 137.5, 136.4, 136.0 (13Cq), 129.7, 129.1, 128.9, 128.6,
126.4, 125.6 (29CH), 51.9 (br, 2.40CH2, 6¥CONCH2Ar, minor
rotamer), 47.1 (br, 3.60CH2, 6¥CONCH2Ar, major rotamer),
43.3 (br, 3.60CH2, 6¥CONCH2CH3, major rotamer), 40.1 (br,
2.40CH2, 6¥CONCH2CH3, minor rotamer), 13.7, 12.2 (6CH3)
ppm. nmax/cm-1 (ATR) 2992, 2933, 1714 (C O), 1627 (C O),
1456 (CH), 1418, 1290 (OH), 1192, 1172 (CN), 1076, 980, 795.
HRMS (TOF MS ES+) calcd for C67H74N6O8 [M + 2H]2+ m/z
545.2779, found 545.2776.
(2CH), 131.2, 129.4, 128.4, 128.0 (27CH), 116.0 (q, J = 290.9 Hz,
6Cq, 6¥CF3COOH), 64.7 (12CH2), 55.8 (6CH2, 6¥CONCH2CH2),
53.7 (6CH2, 6¥CONCH2Ar), 53.1 (12CH2), 41.3 (6CH2) ppm.
n
max/cm-1 (ATR) 3001, 2930, 2858, 1669 (C O), 1635 (C O),
1458 (CH), 1418, 1179 (CN), 1129 (CO), 1088 (CN), 938, 798.
HRMS (TOF MS ES+) calcd for C91H118N12O14 [M + 4H]4+ m/z
400.7217, found 400.7208.
Arylopeptoid hexamer m-6d. Colorless foam isolated as the
cor◦responding TFA-salt (119 mg, 41%, >99% purity). mp = 61–
1
64 C. H NMR (300 MHz, MeCN-d3): d = 7.94–7.75 (m, 2H),
7.54–6.50 (m, 34H, Ar-H, 6¥CF3COOH and COOH), 4.80–4.39
(m, 12H, 6¥CONCH2Ar), 4.12–3.87 (m, 12H), 3.87–3.39 (m,
36H), 3.39–3.16 (m, 12H, 6¥CONCH2CH2), 3.16–2.92 (m, 12H)
ppm. 13C NMR (75 MHz, MeCN-d3): d = 174.6, 174.4, 174.2, 174.2
(6Cq), 168.0 (Cq), 160.8 (q, J = 36.4 Hz, 6Cq, 6¥CF3COOH), 137.7,
137.6, 136.6, 136.5, 136.4, 135.6, 132.2 (13Cq), 132.7, 131.4, 130.4,
130.3, 130.2, 129.9, 129.8, 129.4, 128.6, 127.9, 127.5, 127.2, 125.4,
125.3, 124.8 (27CH), 117.1 (q, J = 290.3 Hz, 6Cq, 6¥CF3COOH),
64.7, 64.3 (12CH2), 56.2, 56.1, 55.9, 55.6 (6CH2, 6¥CONCH2CH2),
53.7 (6CH2, 6¥CONCH2Ar), 53.2 (12CH2), 41.5, 41.0, 40.8 (6CH2)
ppm. nmax/cm-1 (ATR) 3013, 1671 (C O), 1633 (C O), 1463
(CH), 1417, 1269 (OH), 1184 (CN), 1138 (CO), 1088 (CN), 986,
1798. HRMS (TOF MS ES+) calcd for C91H118N12O14 [M + 4H]4+
m/z 400.7217, found 400.7217.
Arylopeptoid hexamer p-6◦c. Colorless foam (82 mg, 39%,
1
>99% purity). mp = 51–54 C. H NMR (300 MHz, CDCl3):
d = 8.58–8.18 (br s, 1H, COOH), 8.11–8.00 (m, 2H), 7.48–
6.95 (m, 57H), 4.86–4.62 (br s, 6.60H, 6¥CONCH2Ar, major
rotamer), 4.62–4.36 (br s, 5.40H, 6¥CONCH2Ar, minor rotamer),
3.57–3.31 (m, 5.40H, 6¥CONCH2CH2, minor rotamer), 3.31–
3.03 (m, 6.60H, 6¥CONCH2CH2, major rotamer), 2.74–2.54
(m, 5.40H), 2.54–2.35 (m, 6.60H), 1.80–1.31 (m, 24H) ppm.
13C NMR (75 MHz, CDCl3): d = 172.5, 172.2, 171.8 (7Cq),
142.0, 141.4, 138.9, 138.4, 135.8, 135.4, 135.1 (19Cq), 130.5
(2CH), 129.7, 128.5, 128.3, 128.0, 127.2, 127.0, 126.8, 126.4,
125.8 (57CH), 52.2 (br, 2.70CH2, 6¥CONCH2Ar, minor rotamer),
48.3 (br, 3.30CH2, 6¥CONCH2CH2, major rotamer), 47.2 (br,
3.30CH2, 6¥CONCH2Ar, major rotamer), 44.6 (br, 2.70CH2,
6¥CONCH2CH2, minor rotamer), 35.4, 35.0 (CH2), 28.6, 27.9,
27.5, 26.3 (12CH2) ppm. nmax/cm-1 (ATR) 3025, 2930, 2859, 1717
(C O), 1632 (C O), 1455 (CH), 1423, 1410, 1308 (OH), 1260,
1174 (CN). HRMS (TOF MS ES+) calcd for C115H121N6O8 [M +
2H]2+ m/z 857.4657, found 857.4657.
Arylopeptoid hexamer p-6e. Pale yellowish foam isolated as
the corresponding TFA-salt (58 mg, 21%, >99% purity). mp =
◦
1
60–63 C. H NMR (300 MHz, MeCN-d3): d = 8.80–8.63 (m,
6H), 8.63–8.54 (m, 6H), 8.51–8.39 (br s, 7H, 6¥CF3COOH and
COOH), 8.36–8.24 (m, 6H), 7.92–7.74 (m, 8H), 7.47–7.07 (m,
27H), 4.84–4.65 and 4.65–4.44 (2¥br s, 2 ¥ 12H, 6¥CONCH2Ar
and 6¥CONCH2Pyr) ppm. 13C NMR (75 MHz, MeCN-d3): d =
173.3, 172.9 (6Cq), 167.7 (Cq), 161.3 (q, J = 36.0 Hz, 6Cq,
6¥CF3COOH), 146.1 (6CH), 142.3 (6CH), 141.6 (6CH), 139.4,
138.9, 136.4, 135.8 (19Cq), 130.9 (2CH), 129.5, 128.6, 128.1,
127.8, 127.6 (27CH), 127.7 (6CH), 117.3 (q, J = 290.9 Hz, 6Cq,
6¥CF3COOH), 53.9 and 47.1 (2 ¥ 6CH2, 6¥CONCH2Ar and
6¥CONCH2Pyr) ppm. nmax/cm-1 (ATR) 3060, 3028, 1675 (C O),
1634 (C O), 1458 (CH), 1410, 1177 (CN), 1135 (CN), 995, 796.
HRMS (TOF MS ES+) calcd for C91H81N12O8 [M + 3H]3+ m/z
489.8761, found 489.8763.
Arylopeptoid hexamer m-6c. Colorless foam (84 mg, 39%,
◦
1
>99% purity). mp = 48–51 C. H NMR (300 MHz, CDCl3):
d = 9.70–9.30 (br s, 1H, COOH), 8.04–7.70 (m, 2H), 7.48–
6.94 (m, 57H), 4.83–4.59 (br s, 6.60H, 6¥CONCH2Ar, major
rotamer), 4.59–4.32 (br s, 5.40H, 6¥CONCH2Ar, minor rotamer),
3.57–3.28 (m, 5.40H, 6¥CONCH2CH2, minor rotamer), 3.28–
3.00 (m, 6.60H, 6¥CONCH2CH2, major rotamer), 2.71–2.51
(m, 5.40H), 2.51–2.33 (m, 6.60H), 1.78–1.22 (m, 24H) ppm.
13C NMR (75 MHz, CDCl3): d = 172.6, 172.2, 171.8 (7Cq),
142.0, 141.4, 137.6, 137.4, 137.3, 136.4, 136.2, 135.7 (19Cq),
129.7, 129.0, 128.5, 128.3, 127.7, 126.4, 126.2, 125.8, 125.6
(59CH), 52.2 (br, 2.70CH2, 6¥CONCH2Ar, minor rotamer),
48.4 (br, 3.30CH2, 6¥CONCH2CH2, major rotamer), 47.4 (br,
3.30CH2, 6¥CONCH2Ar, major rotamer), 44.7 (br, 2.70CH2,
6¥CONCH2CH2, minor rotamer), 35.4, 35.0 (6CH2), 28.5, 27.9,
27.6, 26.4 (12CH2) ppm. nmax/cm-1 (ATR) 3025, 2933, 2860, 1714
(C O), 1630 (C O), 1453 (CH), 1416, 1301 (OH), 1195, 1171
(CN). HRMS (TOF MS ES+) calcd for C115H121N6O8 [M + 2H]2+
m/z 857.4657, found 857.4650.
Arylopeptoid hexamer p-7a. Pale rose foam (77 mg, 55%,
◦
1
>99% purity). mp = 229–232 C. H NMR (300 MHz, CDCl3):
d = 7.82–7.65 (m, 2H), 7.55–6.92 (m, 27H), 6.84–6.16 (m, 2H,
CONH2), 4.82–4.37 (br s, 12H, 6¥CONCH2Ar), 4.34–4.02 (br
m, 6H, 6¥CONCH(CH3)2), 1.42–0.92 (m, 36H) ppm. 13C NMR
(75 MHz, CDCl3): d = 172.6, 172.5, 170.1 (7Cq), 140.8, 136.7,
135.1, 131.3 (13Cq), 129.6, 128.7, 127.9, 127.1, 126.5, 126.2
(29CH), 51.0 (br, 6CH, 6¥CONCH(CH3)2), 43.5 (br, 6CH2,
6¥CONCH2Ar), 21.4 (12CH3) ppm. nmax/cm-1 (ATR) 2969,
2929, 1674 (C O), 1628 (C O), 1437 (CH), 1405, 1338, 1174
(CN), 1054, 842. HRMS (TOF MS ES+) calcd for C73H86N7O7
[M + 2H]2+ m/z 586.8328, found 586.8336.
Arylopeptoid hexamer p-6d. Colorless foam isolated as the
corresponding TFA-salt (164 mg, 58%, >99% purity). mp = 62–
◦
1
65 C. H NMR (300 MHz, MeCN-d3): d = 11.30–9.40 (br s,
7H, 6¥CF3COOH and COOH), 8.00–7.91 (m, 2H), 7.64–7.08 (m,
27H), 4.83–4.44 (m, 12H, 6¥CONCH2Ar), 4.10–3.89 (m, 12H),
3.88–3.66 (m, 24H), 3.66–3.45 (m, 12H), 3.40–3.21 (m, 12H,
6¥CONCH2CH2), 3.20–2.91 (m, 12H) ppm. 13C NMR (75 MHz,
MeCN-d3): d = 174.8, 174.2 (6Cq), 167.9 (Cq), 161.0 (q, J = 36.1 Hz,
6Cq, 6¥CF3COOH), 142.6, 139.5, 136.0, 135.5, 130.9 (13Cq), 131.0
Arylopeptoid hexa◦mer m-7a. Pale rose foam (82 mg, 58%,
>99%). mp = 70–73 C. 1H NMR (300 MHz, CDCl3): d = 7.93–
7.61 (m, 2H), 7.59–6.90 (m, 28H, Ar-H and CONHH), 6.70–6.47
(br s, 1H, CONHH), 4.82–4.34 (br s, 12H, 6¥CONCH2Ar), 4.30–
3.92 (br m, 6H, 6¥CONCH(CH3)2), 1.42–0.92 (m, 36H) ppm. 13
C
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NMR (75 MHz, CDCl3): d = 172.8, 172.7, 170.7 (7Cq), 139.6,
136.4, 132.7 (13Cq), 130.9, 129.5, 128.8, 128.7, 128.6, 128.1, 126.2,
126.1, 124.8, 124.6 (29CH), 51.0 (br, 6CH, 6¥CONCH(CH3)2),
43.5 (br, 6CH2, 6¥CONCH2Ar), 21.3 (12CH3) ppm. nmax/cm-1
(ATR) 2973, 2932, 1678 (C O), 1624 (C O), 1448 (CH), 1410,
1338, 1175 (CN), 1061, 793. HRMS (TOF MS ES+) calcd for
C73H86N7O7 [M + 2H]2+ m/z 586.8328, found 586.8329.
6¥CONCH2CH2, minor rotamer), 35.4, 35.0 (6CH2), 28.6, 28.0,
27.7, 26.4 (12CH2) ppm. nmax/cm-1 (ATR) 3023, 2929, 2858, 1675
(C O), 1631 (C O), 1453 (CH), 1415, 1301, 1200, 793. HRMS
(TOF MS ES+) calcd for C115H123N7O7 [M + 2H]2+ m/z 856.9737,
found 856.9743.
Arylopeptoid hexamer p-7d. Colorless foam isolated as the
corresponding TFA-salt (159 mg, 58%, >99% purity). mp = 69–
◦
1
72 C. H NMR (300 MHz, MeCN-d3): d = 11.50–9.60 (br s,
6H, 6¥CF3COOH), 7.85–7.76 (m, 2H), 7.55–7.14 (m, 27H), 7.09–
6.25 (m, 2H, CONH2), 4.77–4.47 (m, 12H, 6¥CONCH2Ar), 4.08–
3.89 (m, 12H), 3.89–3.65 (m, 24H), 3.65–3.47 (m, 12H), 3.37–3.18
(m, 12H, 6¥CONCH2CH2), 3.18–2.94 (m, 12H) ppm. 13C NMR
(75 MHz, MeCN-d3): d = 174.9, 174.4, 174.2, 169.6 (7Cq), 160.8
(q, J = 36.3 Hz, 6Cq, 6¥CF3COOH), 141.1, 139.5, 135.5, 134.0
(13Cq), 131.2, 129.4, 129.0, 128.4, 128.0, 127.8 (29CH), 117.2 (q,
J = 290.6 Hz, 6Cq, 6¥CF3COOH), 64.7 (12CH2), 55.9 (6CH2,
6¥CONCH2CH2), 53.7 (6CH2, 6¥CONCH2Ar), 53.1 (12CH2),
41.3 (6CH2) ppm. nmax/cm-1 (ATR) 2874, 1675 (C O), 1631
(C O), 1466 (CH), 1181 (CN), 1129 (CO), 1088, 984, 798. HRMS
(TOF MS ES+) calcd for C91H119N13O13 [M + 4H]4+ m/z 400.4757,
found 400.4759.
Arylopeptoid hexamer p-7b. Pale rose foam (70 mg, 54%,
◦
1
>99% purity). mp = 67–70 C. H NMR (300 MHz, CDCl3):
d = 7.86–7.79 (m, 2H), 7.51–7.09 (m, 27H), 6.95–6.32 (m, 2H,
CONH2), 4.90–4.65 (br s, 7.20H, 6¥CONCH2Ar, major rotamer),
4.65–4.41 (br s, 4.80H, 6¥CONCH2Ar, minor rotamer), 3.65–
3.38 (m, 4.80H, 6¥CONCH2CH3, minor rotamer), 3.38–3.11 (m,
7.20H, 6¥CONCH2CH3, major rotamer), 1.33–0.95 (m, 18H)
ppm. 13C NMR (75 MHz, CDCl3): d = 172.4, 171.9, 170.0 (7Cq),
139.0, 138.6, 135.9, 135.2, 131.8 (13Cq), 129.7, 128.5, 128.1,
126.9, 126.3 (29CH), 51.9 (br, 2.40CH2, 6¥CONCH2Ar, minor
rotamer), 47.0 (br, 3.60CH2, 6¥CONCH2Ar, major rotamer),
43.3 (br, 3.60CH2, 6¥CONCH2CH3, major rotamer), 40.2 (br,
2.40CH2, 6¥CONCH2CH3, minor rotamer), 13.7, 12.1 (6CH3)
ppm. nmax/cm-1 (ATR) 2973, 1675 (C O), 1627 (C O), 1430
(CH), 1410, 1286, 1176 (CN), 1095, 1074, 980. HRMS (TOF
MS ES+) calcd for C67H75N7O7 [M + 2H]2+ m/z 544.7859, found
544.7861.
Arylopeptoid hexamer m-7d. Colorless foam isolated as the
corresponding TFA-salt (162 mg, 59%, >99% purity). mp = 57–
60 ◦C. 1H NMR (300 MHz, MeCN-d3): d = 8.60–7.80 (br s,
6H, 6¥CF3COOH), 7.80–7.65 (m, 2H), 7.55–7.13 (m, 28H, Ar-
H and CONHH), 6.60–6.35 (br s, 1H, CONHH), 4.80–4.39 (m,
12H, 6¥CONCH2Ar), 4.10–3.90 (m, 12H), 3.90–3.37 (m, 36H),
3.37–3.15 (m, 12H, 6¥CONCH2CH2), 3.15–2.92 (m, 12H) ppm.
13C NMR (75 MHz, MeCN-d3): d = 175.0, 174.5, 174.1, 169.9
(7Cq), 160.7 (q, J = 36.7 Hz, 6Cq, 6¥CF3COOH), 160.5, 160.0,
137.7, 137.5, 136.7, 136.6, 136.5, 135.7, 135.2 (13Cq), 131.5, 131.4,
129.4, 127.9, 127.5, 127.4, 127.2, 125.5, 125.2, 125.0 (27CH), 117.1
(q, J = 290.1 Hz, 6Cq, 6¥CF3COOH), 64.7 (12CH2), 56.0, 55.9,
55.5 (6CH2, 6¥CONCH2CH2), 53.7 (6CH2, 6¥CONCH2Ar), 53.2
(12CH2), 41.5, 41.1, 41.0 (6CH2) ppm. nmax/cm-1 (ATR) 2973, 1668
(C O), 1634 (C O), 1464 (CH), 1418, 1178 (CO), 1137 (CN),
1088, 983, 798. HRMS (TOF MS ES+) calcd for C91H119N13O13 [M
+ 4H]4+ m/z 400.4757, found 400.4764.
Arylopeptoid hexamer p-7◦c. Colorless foam (95 mg, 46%,
1
>99% purity). mp = 52–55 C. H NMR (300 MHz, CDCl3):
d = 7.82–7.72 (m, 2H), 7.46–6.97 (m, 57H), 6.82–6.20 (m,
2H, CONH2), 4.84–4.60 (br s, 6.60H, 6¥CONCH2Ar, major
rotamer), 4.60–4.36 (br s, 5.40H, 6¥CONCH2Ar, minor rotamer),
3.57–3.31 (m, 5.40H, 6¥CONCH2CH2, minor rotamer), 3.31–
3.05 (m, 6.60H, 6¥CONCH2CH2, major rotamer), 2.74–2.54
(m, 5.40H), 2.54–2.35 (m, 6.60H), 1.80–1.24 (m, 24H) ppm.
13C NMR (75 MHz, CDCl3): d = 172.4, 172.1, 171.7 (7Cq),
142.0, 141.4, 138.9, 138.4, 136.0, 135.4, 135.2 (19Cq), 129.6,
128.5, 128.3, 128.1, 128.0, 127.1, 127.0, 126.8, 126.4, 125.8
(59CH), 52.2 (br, 2.70CH2, 6¥CONCH2Ar, minor rotamer),
48.3 (br, 3.30CH2, 6¥CONCH2CH2, major rotamer), 47.2 (br,
3.30CH2, 6¥CONCH2Ar, major rotamer), 44.6 (br, 2.70CH2,
6¥CONCH2CH2, minor rotamer), 35.4, 35.0 (6CH2), 28.6, 27.9,
27.5, 26.3 (12CH2) ppm. nmax/cm-1 (ATR) 2929, 1675 (C O),
1629 (C O), 1453 (CH), 1410, 1309, 1173 (CN). HRMS (TOF
MS ES+) calcd for C115H123N7O7 [M + 2H]2+ m/z 856.9737, found
856.9747.
Arylopeptoid hexamer p-7e. Pale yellowish foam isolated as
the◦corresponding TFA-salt (58 mg, 22%, >99% purity). mp = 62–
1
65 C. H NMR (300 MHz, MeCN-d3): d = 8.90–8.73 (m, 6H),
8.73–8.62 (m, 6H), 8.50–8.20 (m, 6H), 7.00–7.81 (m, 8H), 7.60–
7.20 (m, 27H), 6.85–6.25 (m, 8H, 6¥CF3COOH and CONH2),
4.95–4.76 and 4.76–4.54 (2¥br s, 2 ¥ 12H, 6¥CONCH2Ar and
6¥CONCH2Pyr) ppm. 13C NMR (75 MHz, MeCN-d3): d = 173.2,
172.9, 169.4 (7Cq), 161.2 (q, J = 36.2 Hz, 6Cq, 6¥CF3COOH),
146.0 (6CH), 142.4 (6CH), 141.6 (6CH), 139.4, 138.9, 136.4,
135.8, 134.3 (19Cq), 130.9, 129.5, 128.9, 128.6, 128.3, 128.2, 127.6
(35CH), 117.3 (q, J = 290.7 Hz, 6Cq, 6¥CF3COOH), 54.0 and 47.0
(2 ¥ 6CH2, 6¥CONCH2Ar and 6¥CONCH2Pyr) ppm. nmax/cm-1
(ATR) 3086, 1673 (C O), 1634 (C O), 1461 (CH), 1410, 1185,
1134, 994, 796. HRMS (TOF MS ES+) calcd for C91H82N13O7
[M + 3H]3+ m/z 489.5481, found 489.5472.
Arylopeptoid hexamer m-7◦c. Colorless foam (109 mg, 53%,
1
>99% purity). mp = 54–57 C. H NMR (300 MHz, CDCl3):
d = 7.84–7.56 (m, 2H), 7.56–6.92 (m, 57H), 6.22–5.54 (m,
2H, CONH2), 4.81–4.56 (br s, 6.90H, 6¥CONCH2Ar, major
rotamer), 4.56–4.32 (br s, 5.10H, 6¥CONCH2Ar, minor rotamer),
3.56–3.29 (m, 5.10H, 6¥CONCH2CH2, minor rotamer), 3.29–
3.03 (m, 6.90H, 6¥CONCH2CH2, major rotamer), 2.71–2.54
(m, 5.10H), 2.54–2.33 (m, 6.90H), 1.75–1.23 (m, 24H) ppm.
13C NMR (75 MHz, CDCl3): d = 172.3, 172.0, 171.6, 169.6
(7Cq), 142.0, 141.4, 137.8, 137.5, 136.8, 136.6, 136.1 (19Cq),
129.6, 129.0, 129.0, 128.5, 128.3, 126.5, 126.2, 125.8, 125.5
(59CH), 52.2 (br, 2.55CH2, 6¥CONCH2Ar, minor rotamer),
48.4 (br, 3.45CH2, 6¥CONCH2CH2, major rotamer), 47.4 (br,
3.45CH2, 6¥CONCH2Ar, major rotamer), 44.6 (br, 2.55CH2,
Arylopeptoid hexamer p-7f. Colorless foam isolated as the
corresponding TFA-salt (119 mg, 49%, >99% purity). mp = 78–
◦
1
81 C. H NMR (300 MHz, MeOD): d = 7.98–7.82 (m, 3H),
7.57–7.12 (m, 26H), 4.90–4.71 (br s, 5.00H, 6¥CONCH2Ar, minor
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rotamer), 4.71–4.48 (br s, 7.00H, 6¥CONCH2Ar, major rotamer),
3.60–3.41 (m, 7.00H, 6¥CONCH2CH2, major rotamer), 3.41–
3.22 (m, 5.00H, 6¥CONCH2CH2, minor rotamer), 3.05–2.85 (m,
7.00H), 2.85–2.65 (m, 5.00H), 1.82–1.30 (m, 24H) ppm. 13C NMR
(75 MHz, MeOD): d = 174.7, 174.4, 174.2, 174.1, 171.9, 171.8
(7Cq), 162.3 (q, J = 35.9 Hz, 6Cq, 6¥CF3COOH), 142.2, 140.8,
140.2, 137.3, 136.7, 136.5, 134.5, 134.2 (13Cq), 131.1, 129.9, 129.3,
129.1, 128.9, 128.4, 128.2, 127.6 (29CH), 117.9 (q, J = 291.4 Hz,
6Cq, 6¥CF3COOH), 53.5 (br, 3.50CH2, 6¥CONCH2Ar, major
rotamer), 50.0 (br, 2.50CH2, 6¥CONCH2CH2, minor rotamer),
48.9 (br, 2.50CH2, 6¥CONCH2Ar, minor rotamer), 46.0, 45.9,
45.7 (br, 3.50CH2, 6¥CONCH2CH2, major rotamer), 40.4, 40.2
(6CH2), 26.4, 25.9, 25.6, 25.1 (12CH2) ppm. nmax/cm-1 (ATR)
3026, 2938, 2874, 1675 (C O), 1609 (C O), 1471 (CH), 1429,
1410, 1200, 1177, 1131, 835, 799. HRMS (TOF MS ES+) calcd for
C79H105N13O7 [M + 2H]2+ m/z 673.9130, found 673.9119.
6.90 (m, 71H), 5.05–4.27 (m, 30H, CONH2, 4¥CF3COOH and
12¥CONCH2Ar), 4.09–3.83 (m, 12H), 3.83–3.37 (m, 24H), 3.37–
3.07 (m, 16H), 3.07–2.87 (m, 8H), 2.65–2.23 (m, 8H), 1.68–1.20
(m, 16H), 1.20–0.90 (m, 24H) ppm. 13C NMR (75 MHz, MeCN-
d3): d = 174.4, 172.7, 172.3, 169.9 (13Cq), 160.5 (q, J = 36.8 Hz,
4Cq, 4¥CF3COOH), 143.0, 141.2, 139.7, 139.0, 137.8, 137.7, 136.4,
135.0 (29Cq), 131.3, 130.2, 129.8, 129.7, 129.6, 129.5, 129.2, 128.8,
127.9, 126.6, 126.4, 125.8 (73 CH), 117.1 (q, J = 288.2 Hz,
4Cq, 4¥CF3COOH), 64.7 (8CH2), 56.2 (4CH2), 54.0 (4CH2,
4¥CON[2-morpholinoethyl]CH2Ar), 53.2 (8CH2), 51.8 (4CH,
4¥CONCH(CH3)2), 49.9, 45.5 (4CH2), 48.6 (4CH2, 4¥CON[4-
phenylbutyl]CH2Ar), 44.0 (4CH2, 4¥CON[isopropyl]CH2Ar),
41.6 (4CH2), 35.9, 35.6 (4CH2), 29.6, 29.4, 28.9, 28.8 (8CH2),
21.4 (8CH3) ppm. nmax/cm-1 (ATR) 2935, 2859, 1669 (C O), 1622
(C O), 1463 (CH), 1414, 1343, 1306, 1269, 1179 (CO), 1136 (CN),
1086, 796. HRMS (TOF MS ES+) calcd for C179H211N17O17 [M +
4H]4+ m/z 717.6537, found 717.6542.
Arylopeptoid hexamer p-7g. Colorless foam (47 mg, 31%,
>99% purity). mp = 181–184 ◦C (decomposition). 1H NMR
(300 MHz, MeOD): d = 7.92–7.82 (m, 2H), 7.52–7.19 (m, 27H),
4.90–4.75 (br s, 5.00H, 6¥CONCH2Ar, minor rotamer), 4.71–
4.55 (br s, 7.00H, 6¥CONCH2Ar, major rotamer), 4.21–4.08
(br s, 7.00H, 6¥CONCH2COOH, major rotamer), 4.01–3.87 (br
s, 5.00H, 6¥CONCH2COOH, minor rotamer) ppm. 13C NMR
(75 MHz, MeOD): d = 175.0, 174.7, 174.5, 172.1, 171.9 (13Cq),
142.0, 141.8, 140.3, 140.2, 136.8, 136.6, 136.2, 136.1, 136.0,
135.9, 135.8, 134.5, 134.3 (13Cq), 131.4, 131.3, 129.9, 129.8,
129.6, 129.5, 129.4, 129.3, 129.2, 128.6, 128.4, 128.3, 128.2, 127.8,
127.6 (29CH), 55.0 (br, 3.50CH2, 6¥CONCH2Ar, major rotamer),
51.6 (br, 2.50CH2, 6¥CONCH2COOH, minor rotamer), 50.6 (br,
2.50CH2, 6¥CONCH2Ar, minor rotamer), 48.3 (br, 3.50CH2,
6¥CONCH2COOH, major rotamer) ppm. nmax/cm-1 (ATR) 1730,
1645, 1634 (C O), 1609 (C O), 1456 (CH), 1423, 1404, 1260,
1199, 1176 (CN), 1006, 952, 838. HRMS (TOF MS ES+) calcd for
C67H61N7O19 [M + 2Na]2+ m/z 656.6909, found 656.6875.
Acknowledgements
We gratefully thank the Villum Kann Rasmussen Foundation
for a grant to T.H, and the Carlsberg Foundation (grants
2009_01_0745 and 2010_01_0518). We are likewise grateful to
Bertrand Le´geret (Clermont Universite´, Laboratoire SEESIB) for
mass spectrometric analysis of p-7f and p-7g.
Notes and references
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Curr. Opin. Chem. Biol., 2005, 9, 632–638.
3 (a) I. Saraogi, J. A. Hebda, J. Becerril, L. A. Estroff, A. D. Miranker
and A. D. Hamilton, Angew. Chem. Int. Ed., 2010, 49, 736–739; (b) I.
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2008, 47, 9691–9694; (c) Y. Hamuro, S. J. Geib and A. D. Hamilton, J.
Am. Chem. Soc., 1996, 118, 7529–7541.
Arylopeptoid hexamer p-8. Colorless foam isolated as the
cor◦responding TFA-salt (99 mg, 25%, >99% purity). mp = 80–
1
84 C. H NMR (300 MHz, MeCN-d3): d = 7.83–7.70 (m, 2H),
7.57–6.90 (m, 71H), 5.15–4.28 (m, 30H, CONH2, 4¥CF3COOH
and 12¥CONCH2Ar), 4.10–3.87 (m, 12H), 3.87–3.63 (m, 16H),
3.63–3.46 (m, 8H), 3.45–3.12 (m, 16H), 3.11–2.89 (m, 8H), 2.67–
2.24 (m, 8H), 1.69–1.23 (m, 16H), 1.22–0.94 (m, 24H) ppm. 13C
NMR (75 MHz, MeCN-d3): d = 174.8, 172.6, 172.3, 169.7 (13Cq),
160.5 (q, J = 37.1 Hz, 4Cq, 4¥CF3COOH), 143.1, 142.1, 138.3,
137.8, 136.1, 134.9, 133.5 (29Cq), 131.3, 129.5, 129.2, 128.8, 128.3,
128.2, 127.8, 127.6, 127.4, 126.6 (73 CH), 117.0 (q, J = 289.7 Hz,
4Cq, 4¥CF3COOH), 64.8 (8CH2), 56.3 (4CH2), 54.1 (4CH2,
4¥CON[2-morpholinoethyl]CH2Ar), 53.2 (8CH2), 51.7 (4CH,
4¥CONCH(CH3)2), 49.9, 46.0 (4CH2), 48.5 (4CH2, 4¥CON[4-
phenylbutyl]CH2Ar), 44.0 (4CH2, 4¥CON[isopropyl]CH2Ar),
41.7 (4CH2), 35.9, 35.6 (4CH2), 30.3, 29.5, 28.9, 28.7 (8CH2),
21.2 (8CH3) ppm. nmax/cm-1 (ATR) 2927, 2864, 1670 (C O), 1625
(C O), 1458 (CH), 1410, 1364, 1311, 1266, 1173 (CO), 1138 (CN),
1088, 928. HRMS (TOF MS ES+) calcd for C179H211N17O17 [M +
4H]4+ m/z 717.6537, found 717.6536.
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Arylopeptoid hexamer m-8. Colorless foam isolated as the cor-
responding TFA-salt (108 mg, 27%, >99% purity). mp = 73–77 ◦C.
1H NMR (300 MHz, MeCN-d3): d = 7.85–7.63 (m, 2H), 7.55–
6842 | Org. Biomol. Chem., 2011, 9, 6832–6843
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This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6832–6843 | 6843
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