Conformational Properties of Aromatic Oligoamides Bearing Pyrrole Rings

Article abstract of DOI:10.1021/acs.joc.8b00349

N-Alkylbenzanilides generally exist in cis conformation both in the crystalline state and in various solvents, and this cis conformational preference can be utilized to construct dynamic helical oligoamides. Here, we synthesized the pyrrole-containing ami

Full text of DOI:10.1021/acs.joc.8b00349

Subscriber access provided by Kent State University Libraries
Conformational Properties of Aromatic Oligoamides Bearing Pyrrole Rings
Yukiko Tojo, Ko Urushibara, Sawori Yamamoto, Hirotoshi Mori, Hyuma Masu,
Mayumi Kudo, Tomoya Hirano, Isao Azumaya, Hiroyuki Kagechika, and Aya Tanatani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00349 • Publication Date (Web): 29 Mar 2018
Downloaded from http://pubs.acs.org on April 5, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 30
The Journal of Organic Chemistry
1
2
3
4
Conformational Properties of Aromatic Oligoamides Bearing Pyrrole Rings
5
6
7
8
Yukiko Tojo,a Ko Urushibara,a Sawori Yamamoto,a Hirotoshi Mori,a Hyuma Masu,b Mayumi
Kudo,a, d Tomoya Hirano,c Isao Azumaya,e Hiroyuki Kagechika,c Aya Tanatani*,a
9
aDepartment of Chemistry, Faculty of Science, Ochanomizu University, 2ꢀ1ꢀ1 Otsuka,
Bunkyoꢀku, Tokyo 112ꢀ8610, Japan, bCenter for Analytical Instrumentation, Chiba University,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
Yayoiꢀcho, Chibaꢀshi, Chiba 263ꢀ8522, Japan, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2ꢀ3ꢀ10 KandaꢀSurugadai, Chiyodaꢀku, Tokyo
101ꢀ0062, Japan, dPresent address: Department of Chemistry and Materials Science, National
e
Institute of Technology, Gunma College, and Faculty of Pharmaceutical Sciences, Toho
University, 2ꢀ2ꢀ1 Miyama, Funabashi, Chiba 274ꢀ8510, Japan.
Corresponding author: A. Tanatani
*TEL/FAX: +81ꢀ3ꢀ5978ꢀ2716. Eꢀmail: tanatani.aya@ocha.ac.jp
Abstract
N-Alkylbenzanilides generally exist in cis conformation both in the crystalline state and in
various solvents, and this cis conformational preference can be utilized to construct dynamic
helical oligoamides. Here, we synthesized the pyrroleꢀcontaining amides 2 – 5 and their
oligomers 6 – 8, and examined their conformations in the crystalline state and in solution. All
the Nꢀmethylated amides showed cis conformational preference in solution, but the ratio of
the cis isomer was decreased when the amide bond was attached at the 4ꢀposition of the
pyrrole ring, probably because the destabilization of the trans conformer due to electronic
repulsion between the pyrrole π electrons and the amide carbonyl loneꢀpair electrons is
reduced due to the small torsion angle between the 5ꢀmembered Nꢀpyrrole and the amide
bond. In the crystalline state, Nꢀmethylated amides showed cis structure, except for compound
5, and cis conformational preference was observed for the pyrrole amides. The CD spectra of
oligoamides 15 – 18 bearing chiral Nꢀsubstituents were consistent with the presence of
dynamic and wellꢀdefined chiral foldamers, which were structurally distinct from Nꢀalkylated
poly(pꢀbenzamide)s 1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
3
4
Introduction
In the past few decades, there has been increasing interest in artificial oligomers with
unique conformational behaviors and chemical functions, known as foldamers,1 inspired by
the wellꢀknown helical structures found in nature, for example in proteins and DNAs.2 In
general, wellꢀdefined structures can be constructed by utilizing a variety of specific
intramolecular noncovalent interactions, such as metal coordination networks, hydrogen
bonding interactions, donorꢀacceptor interactions, and solvophobic interactions.3 The amide
bond is a useful functional group for constructing intramolecular hydrogenꢀbonding
interactions.4 Among aliphatic oligoamides, various αꢀpeptide, βꢀpeptide,5 γꢀpeptide6 and
peptidic analogue foldamers have been developed.7 Aromatic oligoamides are also an
important class of foldamers,8 in which multiple interactions, including amide hydrogen
bonds, aromaticꢀaromatic interactions, and the conformational properties of the bond between
an aromatic ring and an amide bond, contribute to the construction of αꢀhelixꢀ and
βꢀsheetꢀlike foldamers.9 Such foldamers can show interesting functions, such as formation of
double helices,10 conformational switching induced by environmental changes,11 and binding
ability to DNAs or proteins.12
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We have developed aromatic oligobenzamide foldamers, based on the conformational
properties of Nꢀalkylbenzanilides. Thus, secondary aromatic amides such as benzanilide
exist in trans form both in the crystal and in solution, whereas their Nꢀmethylated amides exist
in cis form in the crystal and predominantly in cis form in various solvents (Fig. 1a).13 The
cis conformational preference is general for Nꢀalkylated benzanilides. We found that
oligo(Nꢀalkylꢀpꢀbenzamide)s and poly(Nꢀalkylꢀpꢀbenzamide)s, prepared by the chainꢀgrowth
polycondensation of phenyl pꢀnitrobenzoate as an initiator and phenyl
pꢀ(alkylamino)benzoate as a monomer, adopted helical forms driven by the folded cisꢀamide
structures.14 Poly(Nꢀalkylꢀpꢀbenzamide)s showed dynamic helical properties in solution, and
polyamides 1 bearing a chiral side chain [(S)ꢀ2ꢀ(methoxyethoxyethoxy)propyl group] (Figure
1b) possessed a rightꢀhanded helical conformation (Pꢀhelix), as deduced from exciton model
analysis of the absorption and CD spectra.
(a)
CH3
cis
H
N
N
O
N-Methylation
O
trans
(b)
N
OPh
n
O
O
O
O
cis
O
1
Figure 1. (a) Cis conformational preference of benzanilide caused by Nꢀmethylation. (b) Structures of helical
poly(benzamide)s bearing chiral Nꢀsubstituents. NꢀSubstituents are omitted in the threeꢀdimensional structures
(right).
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The dynamic helical structure of poly(Nꢀalkylꢀpꢀbenzamide)s is unique among helical
oligoamides so far known, in that there are no intramolecular noncovalent interactions, such
as hydrogen bonds, and the structure is driven simply by the cis conformational properties of
the Nꢀalkylbenzanilide moiety. The intrinsic helical properties of poly(Nꢀalkylꢀpꢀbenzamide)s
can be applied to obtain functional helical molecules by means of further structural
derivatization. For example, Nꢀmethylated oligoamides bearing pyridine rings also favor the
cisꢀamide structures, and their conformations can be switched between the folded and
unfolded structures simply by addition of acid.11a Other Nꢀsubstituted amides have also been
reported to undergo conformational switching in response to environmental changes.15
Various foldamers bearing pyridineꢀ or quinolineamide backbones have been
developed,16 whereas the foldamer properties of oligoamides bearing a 5ꢀmembered
heteroaromatic ring are less well known. A number of pyrroleꢀ and imidazoleꢀcontaining
oligoamides have been developed, but most of them were oligomers of secondary amides
developed as artificial DNA minor groove binders targeting specific sequences,17 and there
are only a few reports on the conformational properties of tertiary amides in heterocyclic
rings.11a,16c In this study, we focused on pyrroleꢀcontaining amides and their oligomers, and
investigated their conformations in the crystalline state and in solution, with the aim of
applying them as building blocks for unique foldamers.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
Conformational analysis of pyrrole-containing amides
Many pyrroleꢀcontaining amides have been synthesized,18 but there is little information
about the conformations of tertiary amide derivatives. Therefore, in order to clarify whether
cis conformational preference holds for Nꢀalkylated amide bonds on the pyrrole ring, we
synthesized monoamides 2 – 5 in which one phenyl ring of benzanilide or
Nꢀmethylbenzanilide is replaced with a pyrrole ring (Figure 2). We also synthesized
Nꢀmethylated diamide 6, which has a pyrrole ring as the central aromatic ring, as well as 7,
which has two terminal pyrrole rings, and triamide 8, which has two pyrrole and two phenyl
rings alternately linked by amide bonds.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Structures of pyrroleꢀcontaining amide derivatives
Compound
2
was
prepared
in
49%
yield
by
condensation
of
Nꢀmethylpyrroleꢀ2ꢀcarboxylic acid with aniline in the presence of EDCI/HOBt as coupling
reagents. Ethyl 4ꢀaminoꢀ1ꢀmethylpyrroleꢀ2ꢀcarboxylate was reacted with benzoyl chloride
to afford compound 4 in 62% yield. These secondary amides were Nꢀmethylated to give 3 and
5. The syntheses of diamides 6, 7 and triamide 8 are illustrated in Scheme 1. Monoamide 4
was hydrolyzed under basic conditions to give carboxylic acid 9 (95%), which was condensed
with aniline in the presence of EDCI/DIEA/HOBt to afford diamide 10. Compound 12 was
obtained via the reaction of ethyl 4ꢀaminoꢀNꢀmethylpyrroleꢀ2ꢀcarboxylate with pꢀnitrobenzoyl
chloride, followed by catalytic hydrogenation, and was then allowed to react with
Nꢀmethylpyyroleꢀ2ꢀcarbonyl chloride to give 13. NꢀMethylation of 10 and 13 afforded
diamides 6 and 7, respectively. Triamide 8 was similarly synthesized from diamide 7 by
sequential hydrolysis, acylation and Nꢀmethylation.
Scheme 1. Synthesis of diamides 6, 7 and triamide 8. (a) 2 M NaOH, EtOH, rt; (b) aniline,
EDCI, DIEA, HOBt, CH2Cl2, rt; (c) NaH, DMF; CH3I, rt; (d) Et3N, pꢀnitrobenzoyl chloride,
CH2Cl2, rt; (e) H2, Pd/C; AcOEt, rt; (f) Nꢀmethylpyrroleꢀ2ꢀcarbonyl chloride, pyridine,
CH3CN, rt.
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
The conformations of amide compounds 3 and 5 – 8 in solution were analyzed by H
NMR spectroscopy (Figure 3). The phenyl proton chemical shifts of the secondary amides 2
and 4 were quite similar to those of benzanilide, bearing a transꢀamide bond, in CDCl3 (Table
S1). NꢀMethylamide 3 afforded a simple sharp signal in CD2Cl2 at room temperature and
retained the sharp signal even at 183 K (Figure S1). The chemical shifts of 3 in the aromatic
region were shifted to higher field, compared to those of secondary amide 2. The chemical
shifts of phenyl protons of 3 were similar to those of Nꢀmethylbenzanilide with cis
conformation. These results indicate that 3 exists predominantly in cis form in CD2Cl2.
Compound 5 showed broad signals in CD2Cl2 at room temperature, and two sets of signals
were observed at 218K (Figure S2). Thus, 5 exists in equilibrium between cis and trans forms
in the ratio of 3 : 2 in CD2Cl2 at 218 K.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Conformational equilibrium of Nꢀmethylated amides 3 and 5 ꢀ 8.
N-Methylated diamides 6, 7 and triamide 8 showed broad signals at room temperature,
but these split into two sets of signals at low temperature (Figures S3 – S5). The two sets of
signals of diamide 6 were assigned to (cis, cis) form and (trans, cis) form in a ratio of 4 : 1 in
CD2Cl2 at 208 K, based on a comparison of the chemical shifts with those of monoamides 2 ꢀ
5. 1H NMR signals corresponding to the (cis, trans) and (trans, trans) conformers could be
estimated from the equilibrium of 3 and 5. Similarly diamide 7 existed in equilibrium between
(cis, cis) form and (cis, trans) conformers in a ratio of 7 : 3 in CD2Cl2 at 233 K, and triamide 8
existed in equilibrium between (cis, cis, cis) form and (cis, trans, cis) conformers in a ratio of
17 : 3 in CD2Cl2 at 233 K. Thus, all N-methylated amides on a pyrrole ring showed cis
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
6
7
8
9
conformational preference, like Nꢀmethylbenzanilide. In each case, the Nꢀmethylated amide
bond was attached at the 2ꢀposition of the pyrrole ring, i.e. the 2ꢀpyrrolecarboxamide bond is
predominantly cis, although the ratio of cis conformation was decreased when the
Nꢀmethylated amide bond was attached at the 4ꢀposition of the pyrrole ring. Theoretical
studies on the conformation of Nꢀmethylacetanilide19 showed that the trans conformer, in
which the torsion angle of the bond between Nꢀphenyl and the amide bond is large due to the
steric repulsion, is destabilized by electronic repulsion between π electrons of Nꢀphenyl ring
and amide carbonyl lone pair electrons, as well as steric repulsion between the methyl group
and phenyl group attached to the amide carbonyl. Similar destabilization is likely to occur in
NꢀmethylꢀNꢀphenylꢀpyyroleꢀ2ꢀcarboxamides such as 3. On the other hand, in the case of
NꢀmethylꢀNꢀpyyrolꢀ4ꢀylamides such as 5, the torsion angle between Nꢀpyrrole and the amide
bond would be smaller than that of Nꢀmethylbenzanilide, because of the smaller size of the
5ꢀmembered ring. Indeed, the dihedral angle between the pyrrole ring and amide plane is
small in the crystal structure of 5 (trans form) (see below). Therefore, the electronic repulsion
between pyrrole π electrons and carbonyl lone pair electrons in the trans form of 5 is smaller
than that in trans Nꢀmethylbenzanilide, and consequently the ratio of the cis form is decreased.
Although the cis conformational preference of monoamide 5 is small (60%), it became larger
in the corresponding amide bond in longer chains, such as diamides (80% for 6, and 70% for
7) and triamide (85%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Xꢀray crystal structures of pyrroleꢀcontaining amides 2 – 8 were determined, and
are illustrated in Figure 4 (Table S2). Secondary monoamides 2 and 4 adopted trans form in
the crystal state, as expected from the structures in solution. NꢀMethylated monoamide 3
adopted cis form in the crystal state, whereas Nꢀmethylated monoamide 5 existed in trans
form, presumably due to the small preference for the cis conformer of 5 in solution, or some
intermolecular interactions that would stabilize trans conformer in the crystal (Figure S7). As
discussed above, the torsion angle between the Nꢀpyrrole ring and the amide bond is small,
and the pyrrole ring and the amide plane are nearly parallel.
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Crystal structures of pyrroleꢀcontaining amides 2 ꢀ 8.
The crystal structures of 6 and 7 showed that all amide bonds adopted cis form, as
expected, though the orientations of the amide bonds were different. Thus, the diamide 6
existed in anti conformation, in which two pyrrole rings are located at opposite sides of the
central phenyl ring. On the other hand, the diamide 7 existed in syn conformation, in which
two phenyl rings are located at the side of the central pyrrole ring. Interestingly, the
conformation of triamide 8 in the crystal resembled the connected structure of the
corresponding units of the crystal structures of 6 and 7 (Figure 4). Thus, the three amide
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
8
9
bonds are all cis, and the pyrroleꢀamideꢀphenylꢀamideꢀpyrrole part, corresponding to the
structure of 7, takes cis conformation, while the phenylꢀamideꢀpyrroleꢀamideꢀphenyl part,
corresponding to the structure of 6, takes anti conformation. Although the reason for the
anti/syn conformational preference is unknown, pyrroleꢀcontaining amides appear to have
unique folded structures based on the combination of cisꢀamide bonds with anti/syn
conformational preference,20 in contrast to the helical structures of poly(
ꢀbenzamide)s 1, which have allꢀcisꢀamide bonds with allꢀsyn conformation.
Next, we theoretically examined the conformational properties of pyrroleꢀcontaining
Nꢀalkylated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
p
monoamides 2 – 5. Each structure was optimized by GAMESS21 with LCꢀBLYP/6ꢀ31G**
based on the crystal structure. In order to clarify the conformational preference, energy
analysis was performed for divided fragment structures, two aromatic rings and the amide
moiety. The optimized structures and the results of the conformational analysis are shown in
Figure 5 and Table 1, respectively. Differences in the calculated
trans isomers showed that the trans conformer is predominant for secondary amides 2 and 4,
while the cis conformer is favored for ꢀmethylamides 3 and 5. In the case of ꢀmethylamide
5, the calculated G value is smaller (ꢀ4.8 kJ/mol) than that of 3 (ꢀ9.4 kJ/mol). The theoretical
results agreed well with the cis/trans population calculated from the NMR spectra. Fragment
analysis of the G values suggested that the cis conformational preference of the
ꢀmethylated amide bond reflects the stability of the amide bond itself. Comparison of the
individual values between ꢀmethylamides 3 and 5 revealed a difference in G value in the
fragment Ar2 (aromatic ring on the amide nitrogen atom), probably due to the weak CHꢀ
ꢀG values between cis and
N
N
ꢀ
ꢀ
N
N
ꢀ
π
interaction of the
N
ꢀpyrrole ring, which resulted in a decreased ratio of cis conformer of 5.
(b) Amide 3
(a) Amide 2
(c) Amide 4
(d) Amide 5
Figure 5. Optimized structures of cis and trans conformers of monoamides 2 – 5
Table 1. Theoretical analysis of conformational properties of monoamides 2 – 5
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Compound
Calcd ꢀGa
Calcd population
cis / trans
Calcd ꢀGb (kJ molꢀ1) of fragment structure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(kJ molꢀ1)
Ar1
Am
Ar2
2
3
4
5
20.9
ꢀ9.4
21.0
ꢀ4.8
0.00/1.00
0.98/0.02
0.00/1.00
0.60/0.40
ꢀ6.6
4.3
27.4
ꢀ14.3
25.4
ꢀ14.2
0.1
0.6
0.2
3.9
ꢀ4.6
5.5
aCalcd ꢀG = ꢀG (cis) –ꢀG (trans)
bCalcd by means of divide and conquer method (ref 22).
Theoretical analysis of the conformational properties of diamide 7 and triamide 8 was
also conducted (Table 2). In the case of diamide 7, the most stable conformer was (cis, cis).
The (cis, trans) conformer had a higher
ꢀ
G value than the (cis, cis) conformer by 4.2 kJ/mol,
G values. Similarly,
while the (trans, cis) and (trans, trans) conformers both had much higher
ꢀ
the (cis, cis, cis) and (cis, trans, cis) conformers were the most stable among 8 possible
conformers related to cis/trans amide structures. Thus, the theoretical studies agreed well with
the experimental observations.
Table 2. Theoretical analysis of conformational properties of diamide 7 and triamide 8
Diamide 7
Conformera
Triamide 8
Conformera
Calcd ꢀGb Calcd population
Calcd ꢀGb Calcd population
(kJ molꢀ1)
(kJ molꢀ1)
(cis, cis)
0.0
0.84
0.16
0.00
0.00
(cis, cis, cis)
0.9
0.81
0.01
0.18
0.00
0.00
0.00
0.00
0.00
(cis, trans)
(trans, cis)
(trans, trans)
4.2
(cis, cis, trans)
(cis, trans, cis)
(cis, trans, trans)
(trans, cis, cis)
(trans, cis, trans)
(trans, trans, cis)
10.3
3.7
14.6
23.6
31.2
18.6
22.7
17.7
(trans, trans, trans) 39.8
aCis and trans were assigned to the amide bonds sequentially from the left in the structures shown in Figure 2.
bRelative value to that of the (cis, cis) conformer.
Synthesis of pyrrole-containing oligoamides with chiral side chains.
The results of the conformational analysis of pyrroleꢀcontaining monoꢀ, diꢀ and
triamides led us to synthesize oligoamides in which the phenyl and pyrrole rings were linked
alternately by
Nꢀalkylated amide bonds. Thus, oligoamides 14 – 18, bearing chiral
N
ꢀsubstituents at every second amide bond were designed in order to investigate their folding
structures (Figure 6). As the chiral substituent, a chiral TEG chain was chosen to ensure good
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
solubility in organic solvents and also in water. The chiral TEG chain was introduced onto the
nitrogen atom of the pyrrole ring, not on the phenyl ring, for synthetic convenience.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Structures of oligoamides 14 ꢀ 18 bearing chiral Nꢀsubstituents
Synthesis of the monomeric building block 14 is illustrated in Scheme 2. Ethyl
4ꢀaminoꢀ1ꢀmethylpyrroleꢀ2ꢀcarboxylate was converted to sulfonamide 21 by treatment with
o
ꢀnitrobenzenesulfonyl chloride in pyridine (87% yield). Alkylation of sulfonamide 19 was
carried out under Mitsunobu conditions23 with (
S
)ꢀ20, which was prepared by the reported
procedure,14,24 to give 21 in 87% yield. After removal of the nosyl group of 21 (77%) by
treatment with thiophenol and cesium carbonate, 22 was acylated with p-nitrobenzoyl
1
chloride to give 14 (quantitative). The H NMR spectra of 14 showed that it existed in
equilibrium between cis and trans conformers with a ratio of 10 : 1 in CD2Cl2 at 233 K
(Figure S6a). The ratio of the cis conformer of 14 is much higher than that of 5 (3 : 2) bearing
an
between the pyrrole ring and amide bond, which would destabilize the trans conformer, while
the ꢀnitro group on the benzoyl moiety would also influence the properties of the amide bond.
Actually, introduction of the ꢀnitro group on the benzoyl moiety of 5 increased the ratio of
Nꢀmethyl group. The bulkiness of the chiral Nꢀsubstituent would increase the torsion angle
p
p
cis (4 : 1) in CD2Cl2 at 253 K (Figure S6b). A sequential coupling strategy was used for the
syntheses of the oligoamides 15ꢀ18 (Scheme S1).
N
N
N
COOEt
O
Ns
a
b
c
N
COOEt
COOEt
Ns
H2N
N
H
O
O
19
21
O
N
N
COOEt
O
HN
d
O
HO
O
O2N
O
O
N
(S)-20
O
O
O
O
EtO
22
O
14
Scheme 2. Synthesis of monomer 14. (a)
)ꢀ20, DEAD, PPh3, THF, rt; (c) PhSH, Cs2CO3, CH3CN, rt to 60°C; (d)
chloride, Et3N,CH2Cl2, rt.
o
ꢀnitrobenzenesulfonyl chloride, pyridine, rt; (b)
(S
p
ꢀnitrobenzoyl
The conformations of oligoamides 15ꢀ18 in solution were investigated by means of
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
UV/vis and CD spectroscopy, and the spectra were compared with those of monomeric amide
14 and amine 22 (Figure 7a). Amides 14 – 18 showed similar UV/vis spectra in acetonitrile,
exhibiting two broad bands with absorbance maxima at around 240 nm and 280ꢀ300 nm,
which is different from the monomeric chiral amine 22 (maxima at 250 and 320 nm). The
second band was shifted to longer wavelength in the cases of 16 – 18, compared to the
monomer 14 and dimer 15. In the CD spectra in acetonitrile, the monomeric chiral amine 22
did not show any CD signal, while the chiral monomeric amide 14 showed a signal with a
minusꢀtoꢀplusꢀtoꢀminus pattern in the region of 220ꢀ340 nm. The maximum wavelength was
270 nm. On the other hand, oligomers 15 – 18 showed CD signals with two maxima (around
260 nm and 310 nm) in the region of 250ꢀ330 nm. The CD intensity, especially that of the
second peak (310 nm) increased as the chain length became longer. Compound 18 showed
similar CD spectra in other solvents, such as chloroform and methanol, but not in water
(Figure 7b). The intensity of the CD signals decreased as the temperature was raised (Figure
8). These results indicated that the chirality of the oligomers is not due to the intrinsic
chirality of the chiral side chains, but rather is due to the dynamic chiral folding structures
induced by the chiral side chains. The precise folding structures of oligomers 15 – 18 remain
to be established. In the case of polyamides 1, a strong CD signal was observed in aqueous
methanol, and its intensity did not depend on the ratio of water (0 – 80%). The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
poly(Nꢀalkylated 2,6ꢀnaphthalenecarboxamide)s also showed strong CD signals in aqueous
methanol, and the intensity increased as the ratio of water increased (up to 60%). These
polyamides bearing hydrophobic aromatic moieties showed rigid folding structures in polar
solvents. In contrast, oligoamides 15 – 18 with an electronꢀrich pyrrole ring showed an
intense CD signal in chloroform, a weaker signal in acetonitrile and methanol, and no signal
in water. This indicates that the folding structure and properties of oligoamides bearing
pyrrole rings are different from those of polyamides 1, probably due to the electronic effects
of pyrrole ring itself and the anti/syn conformational properties of the diamide moiety on the
pyrrole ring.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
3
4
5
(a)
(b)
CD
CD
6
7
8
9
1
8
8
-mer
4-mer
17
3-mer
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
2-mer
15
1-mer
14
Amine
UV
22
UV
Figure 7. (a) UV and CD spectra of oligomers 14 ꢀ 18 in CD3CN at 20°C. (b) UV and CD
spectra of oligomer 18 in various solvents.
Figure 8. Temperatureꢀdependency of CD spectra of oligomer 18 in various solvents.
Conclusion
In this study, we systematically investigated the conformational properties of
N
ꢀmethylated pyrroleamides, and established the cis conformational preference of the amide
bonds on the pyrrole ring. We utilized these properties to synthesize a new type of aromatic
oligoamide foldamers; these oligoamides bearing pyrrole and benzene hybridꢀtype structures
folded into wellꢀdefined structures in solution, based on analyses of NMR and UV/CD spectra.
There is no marked intramolecular interaction in these oligomers, and formation of the folded
structures appears to be driven by the unique conformational properties of the aromatic
amides. Oligoamides bearing a pyrrole ring showed different dynamic folding properties, as
compared to known foldamers with cisꢀamide conformation, such as polyamides 1. Further
work is underway on applications of these unique dynamic foldamers based on amide
conformational properties.
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
Experimental
General 1H and 13C NMR spectra were recorded on JEOL NHHꢀAL400, Bruker Advance 500
and JEOL ECAꢀ600 spectrometers. Mass spectral data was obtained on Brucker Daltonics
microTOFꢀ2focus in the positive and negative ion detection modes. UV spectra were
recorded with JASCO Vꢀ650, and CD spectra were recorded with JASCO Jꢀ820
spectropolarimeter using 2 mm quartz cell. The concentration of each solution of CD
experiments was adjusted so that the absorbance of the oligoureas was 1 at the maximum
absorption wavelength in the examined solvents. Crystallographic data were collected on a
Bruker Apex II ultra CCD detector with graphiteꢀmonochromated Mo K radiation and a
Bruker Apex II ultra CCD detector with graphiteꢀmonocromated Cu K radiation. The crystal
structures were solved by direct methods using SHELXSꢀ97 and refined by fullꢀmatrix
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
leastꢀsquares SHELXLꢀ97 (See: A short history of SHELX. G. M. Sheldrick Acta Cryst.
,
2008, A64, 112ꢀ122). All nonꢀhydrogen atoms were refined anisotropically. All hydrogen
atoms were included at their calculated positions.
Synthesis of 2
A mixture of 1ꢀehtylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide (458 mg, 2.40 mmol),
N,Nꢀdiisopropylethylamine (261 mg, 2.00 mmol), and 1ꢀhydroxybenzotriazole (62 mg, 0.400
mmol) was added to a solution of aniline (187 mg, 2.00 mmol) in methylene chrolide. After
30 min, 1ꢀmethylꢀ2ꢀpyrrolecarboxylic acid (254 mg, 2.00 mmol) was added to the mixture,
and the mixture was stirred for 15 h. Solvent was removed in vacuo, and the residue was
extracted with ethyl acetate. The organic layer was wshed with brine, dried over magnesium
sulfate, filetered, and evaporated. The residue was purified by open column chromatography
(silica gel, ethyl acetate/
n
ꢀhexane = 1 : 2) to give 2 (167 mg, 49%). Compound 2: Colorless
1
prisms (ethyl acetate/
n
ꢀhexane); mp 105.9ꢀ107.8°C; H NMR (400 MHz, CDCl3)
δ
7.53 (d,
= 1.6 Hz, 1 H),
= 4.0, 2.8 Hz, 1 H), 3.97 (s, 3 H); 13C NMR (150
160.0, 138.2, 129.2, 129.0, 125.9, 124.2, 120.1, 112.3, 107.6, 37.0; HRMS
J
= 7.2 Hz, 2 H), 7.33 (t,
J
= 7.6 Hz, 2 H), 7.09 (t,
J = 7.6 Hz, 1 H), 7.77 (t, J
6.67 (dd,
J
= 4.4, 2.4 Hz, 1 H), 6.13 (dd,
J
MHz, CDCl3)
δ
(ESI+, TOF) m/z Calcd for C12H13N2O [M+H]+: 201.1022. Found: 201.1024.
Synthesis of 3
Sodium hydride (29 mg, 0.720 mmol) was washed with
0.316 mmol) was added to a suspension of sodium hydride in dimethylformamide (3 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. Iodomethane (60 l) was
nꢀhexane twice. Compound 2 (63 mg,
ꢁ
added at 0°C, and the mixture was stirred for 2 h at room temperature. After removal of the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
5
6
7
8
9
solvent in vacuo, water was added to the residue, and extracted with ethyl acetate. The
organic layer was wshed with brine, dried over magnesium sulfate, filtered and evaporated to
give 3 (58 mg, 0.268 mmol, 85%). Compound 3: Yellow prisms (ethyl acetate); mp
74.1ꢀ77.0°C; 1H NMR (400 MHz, CDCl3)
7.15 (d, 2H, = 7.2 Hz), 6.57 (t, 1H, = 2.0 Hz), 5.77 (dd, 1H,
1H,
= 1.6 Hz, 4.0 Hz), 3.90 (s, 3H), 3.43 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ
7.33 (t, 2H,
J
= 10.0 Hz), 7.24 (t, 1H,
= 3.6 Hz, 3.2 Hz), 5.51 (dd,
163.2,
J = 8.0 Hz),
J
J
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
δ
145.8, 129.4, 127.2, 126.9, 126.8, 125.5, 116.4, 106.8, 38.4, 36.9; HRMS (ESI+, TOF) m/z
Calcd for C13H15N2O [M+H]+: 215.1179, Found: 215.1174.
Synthesis of 4
A solution of ethyl 4ꢀaminoꢀ1ꢀmethylpyrroleꢀ2ꢀcarboxylate (489 mg, 2.91 mmol) in
dichloromethane (40 ml) was added to triethylamine (0.5 ml, 3.59 mmol) and benzoyl
chloride (498 mg, 3.54 mmol) at 0°C, and the mixture was stirred for 13 h at room
temperature. After removal of the solvent in vacuo, the residue was extracted with ethyl
acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and
concentrated. The residue was purified by recrystallization to give 4 (489 mg, 62%).
1
Compound 4: Colorless prisms; mp 128.4ꢀ130.3°C; H NMR (400 MHz, CDCl3)
δ
7.84 (d,
= 7.6 Hz), 6.82 (d, 1H,
= 6.8 Hz, 14.4 Hz), 3.93 (s, 3H), 1.35 (t, 3H,
= 6.8 Hz); 13C NMR
164.9, 161.2, 134.4, 131.7, 128.8, 127.1, 121.9, 121.4, 120.3, 108.5,
2H,
2.0 Hz), 4.29 (dd, 2H,
(150 MHz, CDCl3)
J
= 6.4 Hz), 7.71 (br, 1H), 7.54 – 7.52 (m, 2H), 7.48 (t, 2H,
J
J =
J
J
δ
60.1, 36.9, 14.5; HRMS (ESI+, TOF) m/z Calcd for C15H17N2O3 [M+H]+: 273.1234, Found:
273.1240.
Synthesis of 5
Sodium hydride (32 mg, 8.13 mmol) was washed with nꢀhexane twice. Compound 4 (141 mg,
0.518 mmol) was added to a suspension of sodium hydride in dimethylformamide (5 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. Iodomethane (0.3 ml) was
added at 0°C, and the mixture was stirred for 2 h at room temperature. After removal of the
solvent in vacuo, the residue was extracted with ethyl acetate. The organic layer was wshed
with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified
by open column chromatography to give 5 (140 mg, 94%).Compound 5: Colorless powder;
mp 92.7ꢀ95.3°C; 1H NMR (400 MHz, CDCl3)
H), 3.99 (s, 3 H), 4.26 (q, 2 H, = 7.2 Hz), 1.34 (t, 3 H,
DMSOꢀ 6, 353K) 168.9, 159.7, 136.3, 128.8, 127.4, 127.3, 127.1, 124.3, 119.9, 112.0,
δ
7.25 (br s, 5 H), 6.70 (br s, 1 H), 6.15 (br s, 1
= 6.6 Hz); 13C NMR (150 MHz,
J
J
d
δ
59.1, 37.6, 35.7, 13.7; HRMS (ESI+, TOF) m/z Calcd for C16H19N2O3 [M+H]+: 287.1390,
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
Found: 287.1393.
5
6
7
Synthesis of 9
A solution of 4 (47 mg, 0.171 mmol) in ethanol (2 ml) was added to 2 M sodium hydroxide (2
ml), and the mixture was stirred for 19 h at the room temperature. After removal of the
solvent in vacuo, the residue was extracted with ethyl acetate. Then, the aqueous layer was
acidified with 2 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
dried over magnesium sulfate, filtered and concentrated to afford compound 9 (40 mg, 95%).
1
Compound 9: Colorless powder; mp 193.7ꢀ196.8°C; H NMR (400 MHz, DMSOꢀd6
)
δ
10.3
= 8.0 Hz), 7.50 (d,
= 1.6 Hz), 3.85 (s, 3 H); 13C NMR (150 MHz, CD3OD)
167.4,
(s, 1 H), 7.92 (d, 2 H,
J = 7.2 Hz), 7.54 (t, 1 H, J = 6.4 Hz), 7.51 (t, 2 H, J
1 H, 2.0 Hz), 6.89 (d, 1 H,
J
δ
164.2, 135.7, 132.7, 129.6, 128.4, 123.7, 122.6, 121.6, 110.7, 37.1; HRMS (ESI+, TOF) m/z
Calcd for C13H13N2O3 [M+H]+: 245.0921, Found: 245.0920.
Synthesis of 10
A mixture of 1ꢀehtylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide (330 mg, 1.72 mmol),
N,Nꢀdiisopropylethylamine (175 mg, 1.35 mmol), and 1ꢀhydroxybenzotriazole (153 mg,
0.982 mmol) was added to a solution of aniline (230 mg, 2.47 mmol) in dry methylene
chrolide. After 30 min, compound 9 (306 mg, 1.25 mmol) was added, and the mixture was
stirred for 2 h at the room temperature. After removal of the solvent in vacuo, the residue was
extracted with ethyl acetate. The Organic layer was dried over magnesium sulfate, filetered,
and evaporated. The residue was purified by open column chromatography (silica gel,
methylene chrolide/n-hexane/methanol = 4 : 1 : 0.5) to give 10 (310 mg, 79%). Compound
1
10: Colorless powder; mp 192.4ꢀ195.2°C; H NMR (400 MHz, in CDCl3)
δ
7.85 (d, 2 H,
= 7.2 Hz), 7.55 (t, 1 H, = 7.6 Hz),
= 7.6 Hz), 7.27 (d, 1 H), 7.12 (t, 1 H, 6.8 Hz), 6.83 (d,
165.1, 159.7, 138.0, 134.4,
J =
6.8 Hz), 7.80 (br s, 1 H), 7.60 (br s, 1 H), 7.55(d, 2 H,
J
J
7.48 (t, 2 H,
J
= 6.8 Hz), 7.35 (t, 2 H, J
13
1 H,
J
= 2.0 Hz), 3.96 (s, 3 H); C NMR (150 MHz, CDCl3)
δ
131.9, 129.2, 129.0, 127.0, 124.3, 123.8, 121.7, 120.1, 120.1, 104.2, 37.0; HRMS (ESI+, TOF)
m/z Calcd for C19H18N3O2 [M+H]+: 320.1394, Found: 320.1389.
Synthesis of 6
Sodium hydride (117 mg, 2.93 mmol) was washed with nꢀhexane twice. Compound 10 (308
mg, 0.965 mmol) was added to a suspension of sodium hydride in dimethylformamide (10
ml) at 0°C, and the mixture was stirred for 30 min at room temperature. Iodomethane (0.36
ml) was added at 0°C, and the mixture was stirred for 1 h at room temperature. After removal
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
3
4
5
of the solvent in vacuo, water was added to the residue, and extracted with ethyl acetate. The
organic layer was wshed with water, dried over magnesium sulfate, filtered and evaporated.
6
7
8
The residue was purified by open colmncromatography (silica gel, ethyl acetate/nꢀhexane =
1
1 : 1) to give 6 (292 mg, 87%). Compound 6: Yellow oil: H NMR (400 MHz, in CDCl3)
9
δ
7.25 (m, 10 H), 6.10 (br s, 1 H), 5. 25 (br s, 1 H), 3.67 (br s, 3 H), 3.40 (br s, 3 H), 3.17 (br s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3 H); 13C NMR (150 MHz, DMSOꢀ
127.0, 126.5, 126.0, 125.9, 124.0, 120.6, 109.9, 37.4, 37.0, 34.9; HRMS (ESI+, TOF) m/z
Calcd for C21H22N3O2 [M+H]+: 348.1707, Found: 348.1709.
d
6, 373 K) 168.7, 161.5, 144.5, 136.1, 128.5, 128.4,
δ
Synthesis of 11
Triethylamine (0.6 ml) and pꢀnitrobenzoyl chloride (798 mg, 4.30 mmol) wad added to a
solution of ethyl 4ꢀaminoꢀ1ꢀmethylpyrroleꢀ2ꢀcarboxylate (720 mg, 4.28 mmol) in
dichloromethane (60 ml) at 0°C, and the mixture was stirred for 30 min at room temperature.
After removal of the solvent in vacuo, the residue was extracted with ethyl acetate. The
organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was
purified by open column chromatography (ethyl acetate/nꢀhexane = 1 : 1) to give 11 (1.065 g,
1
79%). Compound 11: Yellow powder; mp 182.2ꢀ184.2°C; H NMR (400MHz, in CDCl3)
δ
8.33 (d, 2 H,
6.84 (d, 1 H,
J
= 6.9 Hz), 7.99 (d, 2 H,
= 1.8 Hz), 4.29 (q, 2 H,
162.8, 161.1, 149.7, 140.0, 128.3, 124.0, 121.4, 121.3, 120.7,
J
= 6.9 Hz), 7.85 (S, 1 H), 7.51 (d, 1 H,
J = 1.8 Hz),
J
J
= 7.2 Hz), 3.94 (s, 3 H), 1.35 (t, 3 H,
J
= 7.1 Hz); 13C
NMR (150 MHz, CDCl3)
δ
108.6, 60.3, 37.1, 14.5; HRMS (ESI+, TOF) m/z Calcd for C15H16N3O5 [M+H]+: 318.1084,
Found 318.1087.
Synthesis of 12
A solution of 11 (112 mg, 0.353 mmol) was hydrogenated with palladium on carbon (12 mg)
in ethyl acetate (5 ml) under hydrogen atmosphere for 1.5 h at room temperature. The reaction
mixture was filtrated on celite, and the filtrate was concentrated in vacuo to give 12 (109 mg,
1
quant). Compound 12: Colorless oil; H NMR (400 MHz, in CDCl3)
δ
7.67 (d, 2 H,
= 2.3 Hz), 6.69 (d, 2 H,
= 7.2 Hz), 4.00 (br s, 2 H), 3.91 (s, 3 H), 1.34 (t, 3 H,
NMR (150 MHz, CDCl3) 164.6, 161.3, 149.9, 128.8, 123.9, 122.2, 121.3, 120.2, 114.4,
J
=
8.7 Hz), 7.59 (br s, 1 H), 7.50 (d, 1 H,
8.7 Hz), 4.28 (q, 2 H,
J
= 1.8 Hz), 6.78 (d, 1 H,
J
J
=
J
J
= 7.2 Hz); 13C
δ
108.3, 60.0, 36.9, 14.6. ; HRMS (ESI+, TOF) m/z Calcd for C15H18N3O3 [M+H]+: 288.1343,
Found: 288.1336.
Synthesis of 13
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.0 M Oxalyl chloride solution in methylene chrolide (4 ml) was added to
1ꢀmethylpyrroleꢀ2ꢀcarboxylic acid (109.9 mg, 0.878 mmol) and a catalytic amount of
dimethylformamide, and the mixture was stirred at room temperature for 1 h. After removal of
the solvent in vacuo to geive crude acid chloride. An iceꢀcooled mixture of 12 (251 mg, 0.874
mmol) and pyridine (81 mg, 1.02 mmol) in dry acetonitrile (7 ml) was added to the acid
chloride. The mixture was stirred at 0°C for 30 min and at room temperature for 2 h. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
precipitate was collected by filtration and dried to give 13 (265 mg, 0.672 mmol, 77%).
1
Compound 13: Colorless powder; mp 224.0ꢀ225.3°C; H NMR (400 MHz, CDCl3)
δ
7.83 (d,
= 8.7 Hz), 6.82 (m, 2 H),
= 3.9, 1.8 Hz), 6.17 (dd, 1 H, = 4.1, 2.7 Hz), 4.28
= 7.3 Hz), 3.99 (s, 3 H), 3.93 (s, 3 H), 1.35 (t, 3 H,
= 7.3 Hz); 13C NMR (150 MHz,
DMSOꢀd6 163.1, 160.4, 159.9, 142.3, 129.4, 128.4, 128.0, 125.1, 122.9, 120.9, 119.0,
2 H,
7.52 (d, 1 H,
(q, 2 H,
J
= 8.7 Hz), 7.72 (br s, 1 H), 7.71 (br s,1 H), 7.69 (d, 2 H,
J
J
= 2.0 Hz), 6.74 (dd, 1 H,
J
J
J
J
)
δ
118.9, 114.3, 108.5, 106.9, 59.4, 36.4, 36.3, 14.3; HRMS (ESI+, TOF) m/z Calcd for
C21H22N4NaO4 [M+Na]+: 417.1533, Found: 417.1521.
Synthesis of 7
Sodium hydride (89 mg, 3.70 mmol) was washed with nꢀhexane twice. Compound 13 (348
mg, 0.881 mmol) was added to a suspension of sodium hydride in dimethylformamide (25
ml) at 0°C, and the mixture was stirred for 30 min at room temperature. Iodomethane (0.2 ml)
was added at 0°C, and the mixture was stirred for 1 h at room temperature. After removal of
the solvent in vacuo, water was added to the residue, and extracted with ethyl acetate. The
organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was
purified by open column chromatography (ethyl acetate/
53%). Compound 7: Colorless plates (chloroform/
(600 MHz, DMSOꢀ 6, at 373 K) 7.30 (d, 2 H, = 8.4 Hz), 7.12 (d, 2 H,
1 H), 6.72 (s,1 H), 6.67 (s, 1 H), 5.74 (dd, 1 H, = 3.6, 2.4 Hz), 5.54 (t, 1 H,
(q, 2 H, = 7.0 Hz), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.32 (s, 3 H), 3.26 (s, 3 H), 1.28 (t, 3 H,
7.2 Hz); 13C NMR(150 MHz, DMSOꢀ
6, 373K) 168.3, 162.0, 159.6, 145.6, 133.9, 127.8,
n
ꢀhexane = 2 :1) to give 7 (199 mg,
1
n
ꢀhexane); mp 136.9ꢀ138.7°C; H NMR
d
δ
J
J
= 7.8 Hz), 6.96 (s,
= 1.8 Hz), 4.22
J
J
J
J =
d
δ
127.2, 125.8, 125.3, 125.2, 124.4, 120.0, 114.1, 112.1, 105.8, 58.9, 37.4, 36.8, 35.6, 34.9;
HRMS (ESI+, TOF) m/z Calcd for C23H27N4O4 [M+H]+: 423.2027, Found: 423.2030.
Synthesis of 8
A mixture of 7 (48.3 mg, 0.114 mmol) in ethanol (2 ml) and 2 M sodium hydroxide (2 ml)
was stirred for 6.5 h at room temperature. The reaction mixture was acidified by 2 M
hydrochloric acid at 0°C, extracted with ethyl acetate. The organic layer was washed with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
3
4
5
brine, dried over magnesium sulfate, filtered and evaporated to give carboxylic acid (46 mg,
1
quant) as colorless powder; H NMR (400 MHz, CDCl3)
δ 7.35 (br, 2 H) , 7.03 (br, 2 H) ,
6
7
8
6.74 (br, 1 H) , 6.57 (s, 1 H) , 6.39 (br, 1 H) , 5.76 (s, 1 H), 5.51 (br, 1 H), 3.87 (s, 3 H), 3.80
(br, 3 H), 3.40 (s, 3 H), 3.37 (s, 3 H); 13C NMR (150 MHz, DMSOꢀ
6, 373 K) 168.3, 162.0,
d
δ
9
160.9, 145.6, 133.9, 127.8, 127.1, 125.8, 125.3, 125.1, 123.9, 120.8, 114.1, 112.2, 105.9, 37.4,
36.8, 35.4, 34.9; HRMS (ESI+, TOF) m/z Calcd for C21H23N4O4 [M+H]+: 395.1714, Found:
395.1725.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Aniline (0.1 ml) and
N,Nꢀdiisopropylethylamine (0.2 ml) were added to a solution of the
carboxylic acid (202 mg, 0.513 mmol), 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide
hydrochloride (126 mg, 0.657 mmol), and 1ꢀhydroxybenzotriazole (6 mg, 0.037 mmol) in dry
methylene chrolide (3 ml), and the reaction mixture was stirred for 2.5 h at room temperature.
After removal of the solvent in vacuo, the residue was extracted with ethyl acetate. The
organic layer was dried over magnesium sulfate, filetered, and evaporated. The residue was
purified by open column chromatography (silica gel, ethyl acetate/n-hexane = 3 : 1) to give
triamide (85 mg, 35%) as colorless powder; 1H NMR (400 MHz, CDCl3)
7.47 (br, 2 H), 7.39 (br, 1 H), 7.35 (t, =7.3 Hz), 7.13 (t, =7.3 Hz), 7.06 (br, 2 H), 6.55 (br, 2
H), 6.39 (br, 1 H), 5.74 (br, 1 H), 5.54 (br, 1 H), 3.86 (br, 6 H), 3.40 (br, 6 H). ; 13C NMR (150
MHz, DMSOꢀ 6, 373 K) 168.3, 161.9, 158.9, 145.6, 138.5, 133.8, 127.9, 127.7, 126.7,
δ 7.53 (d, J=7.8 Hz),
J
J
d
δ
125.7, 125.3, 125.1, 123.6, 123.0, 122.6, 119.8, 114.0, 108.7, 105.9, 37.6, 36.8, 35.4, 34.8;
HRMS (ESI+, TOF) m/z Calcd for C27H28N5O3 [M+H]+: 470.2187, Found: 470.2197.
Sodium hydride (9 mg, 0.225 mmol) was washed with nꢀhexane twice. Triamide (77 mg,
0.163 mmol) was added to a suspension of sodium hydride in dimethylformamide (1.5 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. A solution of iodomethane
(74 mg, 0.524 mmol) in dimethylformamide (0.3 ml) was added at 0°C, and the mixture was
stirred for 2 h at room temperature. After removal of the solvent in vacuo, water was added to
the residue, and extracted with ethyl acetate. The organic layer was dried over magnesium
sulfate, filtered and evaporated to give 8 (79 mg, quant.). Compound 8: Colorless plates
1
(chloroform/
(t, 2 H, = 7.4 Hz), 7.26 (t, 1 H,
Hz), 7.06 (d, 2 H, = 8.5 Hz), 6.75 (t, 1 H,
(dd, 1 H, = 3.8, 2.3 Hz), 5.45 (d, 1 H, = 2.3 Hz), 3.76 (s, 3 H), 3.63 (s, 3 H), 3.33 (s, 3 H),
3.31 (s, 3 H), 3.03 (s, 3 H); 13C NMR (150 MHz, DMSOꢀ
6, 373K) 168.1, 162.0, 161.48,
n
ꢀhexane); mp 190.6ꢀ191.4°C; H NMR (600 MHz, DMSOꢀ
d
6, at 373 K)
= 7.3 Hz), 7.09 (d, 2 H,
= 2.3 Hz), 5.79 (dd, 1 H, = 3.8, 2.3 Hz), 5.57
δ
7.33
J
J
= 7.4 Hz), 7.14 (d, 2 H,
J
J
= 8.5
J
J
J
J
J
d
δ
145.5, 144.6, 133.7, 128.4, 127.9, 126.4, 126.1, 125.9, 125.9, 125.3, 125.0, 124.1, 120.8,
114.1, 109.9, 105.9, 37.3, 37.0, 36.8, 35.0, 34.9. ; HRMS (ESI+, TOF) m/z Calcd for
C28H30N5O3 [M+H]+: 484.2343, Found: 484.2351.
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
Synthesis of 19
6
7
8
9
2ꢀNitrobenzenesulfonyl chloride (1.295 g, 5.84 mmol) was added to a solution of ethyl
4ꢀaminoꢀ1ꢀmethylpyrroleꢀ2ꢀcarboxylate (947 mg, 5.63 mmol) in dry pyridine (4 ml) at 0°C,
and the reaction mixture was stirred for 20 min at room temperature. 2 M hydrochloric acid
was added to the mixture, and extracted with chloroform. The organic layer was washed with
brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
column chromatography (silica gel, ethyl acetate/
n
ꢀhexane = 1 : 1) to give 19 (1.729 g, 87%).
1
Compound 19: Yellow prisms; mp 138.0ꢀ139.4°C; H NMR(600 MHz, CDCl3)
δ
7.88 (dd, 1
H,
H,
J
J
= 3.7, 1.4 Hz), 7.87 (dd, 1 H,
= 7.7, 1.3 Hz), 6.89 (br s, 1 H), 6.76 (d, 1 H,
= 7.1 Hz), 3.84 (s, 3 H), 1.29 (t 3 H,
J
= 3.7, 1.4 Hz), 7.72 (td, 1 H,
J
= 7.7, 1.3 Hz), 7.63 (td, 1
J
= 2.0 Hz), 6.57 (d, 1 H, J = 2.0 Hz), 4.21
13
(q, 2 H,
J
J
= 7.1 Hz,); C NMR (150 MHz, CDCl3)
δ
160.8, 148.3, 133.9, 132.7, 132.6, 132.1, 125.4, 125.0, 121.8, 118.2, 113.3, 60.3, 37.2, 14.5;
HRMS (ESI+, TOF) m/z Calcd for C14H16N3O6S [M+H]+: 354.0754, Found: 354.0750.
Synthesis of 21
Diethyl azodicarboxylate (40% in toluene, 3.2133 g, 7.38 mmol) in dry tetrahydrofuran (7 ml)
was added to a mixture of 19 (1.321 g, 3.74 mmol), (S)-20 (665 mg, 3.73 mmol), and
triphenylphosphine (2.057 g, 7.84 mmol) in dry tetrahydrofuran (23 ml) under argon
atmosphere at 0°C. The reaction mixture was stirred for 1 h at room temperature. After
removal of the solvent in vacuo, the residue was purified by column chromatography (silica
1
gel, ethyl acetate/
NMR (600 MHz, CDCl3)
7.60 (dd, 1 H, = 7.9, 1.3 Hz), 7.55 (td, 1 H,
(d, 1 H, = 2.0 Hz), 4.23 (q, 2 H,
1.31 (t, , 3 H = 7.1 Hz), 1.18 (d, 3H,
n
ꢀhexane = 1 : 1) to give 21 (1.658 g, 87%). Compoud 21: Yellow oil; H
δ
7.74 (dd, 1 H,
J
= 7.9, 1.3 Hz), 7.64 (td, 1 H,
J = 7.9, 1.4 Hz), 6.88 (, 1 H d,
J
J
= 7.3, 1.4 Hz),
= 2.0 Hz), 6.66
J
J
J
= 7.1 Hz), 3.86 (s, 3 H), 3.75ꢀ3.51 (m, 11 H), 3.37 (s, 3 H),
= 5.9 Hz); 13C NMR(150 MHz, CDCl3)
160.9,
J
J
δ
148.3, 133.5, 132.3, 131.9, 131.3, 128.1, 124.0, 121.7, 121.5, 115.0, 74.1, 72.1, 70.8, 70.7,
68.4, 60.3, 59.1, 57.0, 37.3, 17.5, 14.5; HRMS (ESI+, TOF) m/z Calcd for C22H32N3O9S
[M+H]+: 514.1854, Found: 514.1859.
Synthesis of 22
A solution of 21 (90 mg, 0.175 mmol) in dry acetonitrile (1.5 ml) and cesium carbonate (75
mg, 0.230 mmol) were added to a solution of benzenethiol (22 mg, 0.202 mmol) in
acetonitrile (0.5 ml), and the mixture was stirred for 3 h at room temperature. The mixture
was poured into water, and extracted with ethyl acetate. The organic layer was washed with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
5
brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by
column chromatography (silica gel, ethyl acetate/nꢀhexane = 3 : 1) to give 22 (44 mg, 77%).
Compound 22: Brown oil; 1H NMR (600 MHz, CDCl3)
H, = 2.2 Hz), 4.24 (q, 2 H, = 7.1 Hz), 3.82 (s, 3 H), 3.75 (m, 1 H), 3.65 (m, 5 H), 3.55 (m,
3 H), 3.39 (s, 3 H), 2.98 (dd, 1 H, = 12.4, 3.6 Hz), 2.92 (dd, 1 H, = 12.4, 8.0 Hz), 1.32 (t, 3
H, = 7.1 Hz), 1.18 (d, 3 H, 161.3, 120.6, 115.6,
= 6.2 Hz); 13C NMR (150 MHz, CDCl3)
δ 6.44 (d, 1 H, J = 2.2 Hz), 6.29 (d, 1
6
7
8
9
J
J
J
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
δ
106.0, 100.0, 74.4, 72.0, 70.8, 70.5, 68.0, 59.6, 59.0, 53.0, 36.4, 17.7, 14.5); HRMS (ESI+,
TOF) m/z Calcd for C16H28N2NaO5 [M+Na]+: 351.1890, Found: 351.1885.
Synthesis of 14
Triethylamine (0.5 ml) and pꢀnitrobenzoyl chloride (345.9 mg, 1.86 mmol) was added to a
solution of 22 (720 mg, 4.28 mmol) in dry dichloromethane (15 ml) at 0°C, and the mixture
was stirred for 30 min at room temperature. After removal of the solvent in vacuo, the residue
was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered,
and concentrated. The residue was purified by column chromatography (silica gel, ethyl
1
acetate/nꢀhexane = 3 : 1) to give 14 (907 mg, quant). Compound 14: H NMR (400 MHz,
CDCl3)
δ 8.07 (d, 2 H, J = 8.1 Hz), 7.53 (d, 2 H, J = 8.2 Hz), 4.21, (m, 2 H), 3.92 (m, 2 H),
3.77 (m, 4 H), 3.64 (m, 5 H), 3.55 (m, 3 H), 3.35 (s, 3 H), 1.31 (t, 3 H,
J = 7.3 Hz), 1.21 (d, 3
13
H,
J
= 5.5 Hz); C NMR (150 MHz, DMSOꢀ
d
6, 363 K)
δ
167.7, 159.6, 147.1, 143.0, 128.3,
126.7, 122.4, 120.4, 114.2, 72.3, 71.0, 69.8, 69.2, 67.2, 59.1, 57.5, 54.6, 35.7, 17.0, 13.6;
HRMS (ESI+, TOF) m/z Calcd for C23H32N3O8 [M+H]+: 478.2184, Found: 478.2190.
Synthesis of 23
A solution of 14 (417 mg, 0.874 mmol) was hydrogenated with palladium on carbon (42 mg)
in ethyl acetate (16 ml) under hydrogen atmosphere for 4 h at room temperature. The reaction
mixture was filtrated on celite, and the filtrate was concentrated in vacuo to give 23 (386 mg,
1
99%). Compound 23: Colorless oil; H NMR (400 MHz, CDCl3)
δ
7.24 (d, 2 H
= 8.7 Hz), 4.24 (qd, 2 H, = 7.6, 2.3 Hz),
3.93 (br s, 2 H), 3.78 (s, 3 H), 3.73 (m, 1 H), 3.64 (m, 4 H), 3.58 (m, 2 H), 3.53 (m, 2 H), 3.36
(s, 3 H), 1.32 (t, 3 H, = 6.9 Hz), 1.17 (d, 3 H, 6, 373
= 5.9); 13C NMR (150 MHz, DMSOꢀ
K) 169.4, 159.7, 149.3, 129.3, 127.9, 125.6, 119.9, 113.7, 112.0, 72.8, 70.9, 69.7, 69.2,
J = 8.7 Hz),
6.68 (br s, 1 H), 6.60 (br s, 1 H), 6.47 (d, 2 H,
J
J
J
J
d
δ
67.2, 58.9, 57.4, 55.1, 35.5, 17.1, 13.5; HRMS (ESI+, TOF) m/z Calcd for C23H34N3O6
[M+H]+: 448.2442, Found 448.2448.
Synthesis of 24
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A mixture of 14 (422 mg, 0.883 mmol) in ethanol (16 ml) and 2 M sodium hydroxide (16 ml)
was stirred for 18 h at room temperature. The reaction mixture was acidified by 2 M
hydrochloric acid (18 ml), and extracted with ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, filtered and evaporated to give 24 (401 mg, quant).
1
Compound 24: Yellow oil; H NMR (400 MHz, CDCl3)
δ 8.08 (d, 2 H, J = 8.7 Hz), 7.53 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2 H,
3.68 (m, 4 H), 3.56 (m, 4 H), 3.35 (s, 3 H), 1.21 (d, 3 H,
DMSOꢀ 6, 373 K) 167.6, 160.7, 147.1, 142.9, 130.0, 128.2, 126.0, 122.9, 122.2, 121.1, 72.3,
70.9, 69.7, 69.2, 67.1, 57.4, 54.5, 35.4, 16.9; HRMS (ESI+, TOF) m/z Calcd for
C21H27N3NaO8 [M+Na]+: 472.1690, Found: 472.1685.
J = 8.7 Hz), 6.79 (s, 1 H), 6.74 (s, 1 H), 3.97 (m, 2 H) , 3.80 (br s, 1 H), 3.76 (s, 3 H),
13
J
= 5.9 Hz); C NMR (150 MHz,
d
δ
Synthesis of 25
A solution of 23 (381 mg, 0.851 mmol) and 24 (394 mg, 0.876 mmol) in dimethylformamide
(9 ml) was treated with 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl) carbodiimide hydrochloride
(339.1 mg, 1.77 mmol) and N,Nꢀdimethylꢀ4ꢀaminopyridine (270.5 mg, 2.21 mmol) and the
resulting solution was stirred for 19 h at room temperature. The reaction mixture was poured
into ethyl acetate, washed with 2 M hydrochrolide, and saturated sodium hydrogen carbonate.
The organic layer was dried over sodium sulfate, filtered, and evaporated to give 25 (651 mg,
87%). Compound 25: Yellow solid; 1H NMR (400 MHz, CDCl3)
= 8.7 Hz), 7.57 (d, 2 H, = 8.7 Hz), 7.44 (br s, 2 H), 7.39 (br s, 2 H), 7.12 (s, 1 H), 6.67 (br
s, 1 H), 6.58 (br s, 1 H), 6.43 (s, 1 H), 4.24 (m, 2 H), 3.97 (m, 4 H), 3.76 (m, 10 H), 3.65 (m, 6
H), 3.55 (m, 8 H), 3.36 (s, 3 H), 3.19 (s, 3 H), 1.34 (t, 3 H,
= 6.9 Hz), 1.221 (br s, 6 H). ; 13C
NMR (150 MHz, DMSOꢀ 6, 373 K) 168.9, 167.6, 159.6, 158.8, 147.1, 142.8, 139.2, 131.1,
δ 8.32 (br, 1 H), 8.06 (d, 2 H,
J
J
J
d
δ
128.3, 127.8, 126.9, 126.0, 125.5, 124.9, 123.7, 122.2, 120.1, 118.5, 114.0, 110.6, 72.6, 72.2,
70.9, 69.7, 69.2, 67.1, 67.1, 58.9, 57.4, 57.4, 54.8, 54.6, 35.5, 17.0, 13.5; HRMS (ESI+, TOF)
m/z Calcd for C44H59N6O13 [M+H]+: 879.4135, Found: 879.4121.
Synthesis of 15
Sodium hydride (4 mg, 0.098 mmol) was washed with nꢀhexane twice. Compound 25 (30 mg,
0.034 mmol) was added to a suspension of sodium hydride in dimethylformamide (1 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. A solution of iodomethane
(27 mg, 0.192 mmol) in dimethylformamide (0.2 ml) was added t the mixture, and the
mixture was stirred for 1 h at room temperature. After removal of the solvent in vacuo, water
was added to the residue, and extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate, filtered and evaporated. The residue was purified by open column
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
5
6
7
8
9
chromatography (silica gel. ethyl acetate/methanol = 10 :1) to give 15 (29 mg, 94%).
1
Compound 15: Yellow oil; H NMR (600 MHz, DMSOꢀ
d
6, at 353 K)
= 8.3 Hz), 7.04 (d, 2 H, = 8.3 Hz), 6.92 (s, 1 H), 6.64
(br s, 2 H), 6.57 (br s, 1 H), 4.24 (m, 2 H), 3.97 (m, 4 H), 3.876 (m, 10 H), 3.65 (m, 6 H), 3.55
(m, 8 H), 3.36 (s, 3 H), 3.19 (s, 3 H), 1.34 (t, 3 H,
= 6.9 Hz), 1.21 (br s, 6 H); 13C NMR (150
MHz, DMSOꢀ 6, 373 K) 168.4, 167.4, 161.3, 159.6, 147.0, 145.0, 142.8, 134.1, 128.1,
δ 8.07 (d, 2 H, J = 8.4
Hz), 7.36 (br s, 2 H), 7.28 (d, 2 H,
J
J
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
d
δ
128.0, 126.5, 125.8, 124.8, 124.6, 124.3, 122.8, 122.1, 120.2, 113.7, 111.4, 72.5, 72.0, 70.9,
70.9, 69.7, 69.2, 67.1, 67.0, 58.9, 57.4, 54.8, 54.2, 36.9, 35.5, 34.8, 17.0, 16.9, 13.5; HRMS
(ESI+, TOF) m/z Calcd for C45H61N6O13 [M+H]+: 893.4291, Found: 893.4291.
Synthesis of 26
A solution of 25 (263.0 mg, 0.299 mmol) was hydrogenated with palladium on carbon
(26.9 mg) in ethyl acetate (10 ml) under hydrogen atmosphere for 32 h at room temperature.
The reaction mixture was filtrated on celite, and the filtrate was concentrated in vacuo to give
26 (260 mg, quant). Compound 26: Colorless oil; 1H NMR (400 MHz, CDCl3)
H), 7.48 (d, 2 H, = 8.7 Hz), 7.37 (d, 2 H, = 8.7 Hz), 7.28 (d, 2 H, = 8.2 Hz), 7.03 (d, 1 H,
= 1.3 Hz), 6.68 (br s, 1 H), 6.56 (br s, 2 H), 6.45 (d, 2 H, = 8.2 Hz), 4.24 (m, 2 H),
3.47ꢀ4.05 (m, 27 H), 3.82 (s, 3 H), 3.36 (s, 3 H), 3.20 (s, 3 H), 1.32 (t, 3 H, = 6.9 Hz), 1.20
(br s, J= 6 H); 13C NMR (150 MHz, DMSOꢀ
6, 373 K) 169.3, 168.9, 159.6, 159.0, 149.3,
δ 8.31 (br s, 1
J
J
J
J
J
J
d
δ
139.4, 130.9, 129.4, 129.2, 127.8, 127.3, 126.9, 126.0, 124.7, 123.1, 123.1, 120.1, 118.4,
113.9, 111.9, 110.5, 72.8, 72.6, 70.9, 70.9, 69.7, 69.2, 69.1, 67.1, 67.1, 58.9, 57.4, 55.1, 54.8,
35.5, 17.2, 17.0, 13.5; HRMS (ESI+, TOF) m/z Calcd for C44H61N6O11 [M+H]+: 849.4393,
Found: 849.4396.
Synthesis of 27
A solution of 26 (39 mg, 0.0462 mmol) and 24 (23 mg, 0.0512 mmol) in dimethylformamide
(1 mL) was treated with 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl) carbodiimide hydrochloride (19.4
mg, 0.101 mmol) and N,Nꢀdimethylꢀ4ꢀaminopyridine (14.2 mg, 0.116 mmol), and the
resulting solution was stirred for 24 h at room temperature. The reaction mixture was poured
into ethyl acetate, and washed with 2 M hydrochloric acid and saturated aqueous sodium
hydrogen carbobate. The organic layer was dried with sodium sulfate, filtered, and
concentrated. The residue was purified by open column chromatography (silica gel, ethyl
acetate/methanol = 10 :1) to give 27 (38 mg, 66%). Compound 27: Yellow oil; 1H NMR (400
MHz, CDCl3)
δ 8.35 (br, 1 H), 8.32 (br, 1H), 8.05 (d, 2 H, J = 7.8 Hz), 7.57 (d, 2 H, J =
7.8 Hz), 7.42 (m, 8 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 6.68 (br s, 1 H), 6.56 (br s, 1 H), 6.42 (br s,
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
5
2 H), 4.23 (br s, 2 H), 3.54ꢀ4.00 (m, 42 H), 3.36 (s, 3 H), 3.21 (s, 3 H), 3.19 (s, 3 H), 1.32 (t, 3
= 6.9 Hz), 1.20 (br s, 9 H); 13C NMR (150 MHz, DMSOꢀ
H, J d6, 373 K) δ 168.9, 167.6, 159.6,
6
7
8
9
158.9, 158.8, 147.2, 142.8, 139.4, 139.3, 131.0, 131.0, 128.3, 128.0, 127.8, 126.9, 126.3,
126.0, 125.1, 124.9, 123.7, 123.3, 122.2, 120.1, 118.6, 118.5, 114.0, 110.6, 110.6, 72.6, 72.6,
72.2, 70.9, 69.7, 69.2, 69.1, 67.2, 67.1, 67.1, 58.9, 57.4, 57.4, 54.8, 54.6, 35.5, 17.2, 17.0, 17.0,
13.5; HRMS (ESI+, TOF) m/z Calcd for C65H86N9O18 [M+H]+: 1280.6085, Found: 1280.6051.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 16
Sodium hydride (3 mg, 0.075 mmol) was washed with nꢀhexane twice. Compound 27 (22 mg,
0.0174 mmol) was added to a suspension of sodium hydride in dimethylformamide (1 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. A solution of iodomethane
(27.8 mg, 0.196 mmol) in dimethylformamide (0.2 ml) was added, and the mixture was
stirred for 1 h at room temperature. After removal of the solvent in vacuo, the residue was
extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and
evaporated. The residue was purified by open column chromatography (silica gel ethyl
acetate/methanol = 10 :1) to give 16 (18 mg, 80%). Compound 16: Yellow oil; 1H NMR(400
MHz, CDCl3)
6.91 (br s, 2 H), 6.86 (br s, 2 H), 6.64 (br s, 1 H), 6.60 (br s, 1 H), 6.50 (br s, 1 H), 6.45 (br s,
1 H), 5.45 (br s, 1 H), 5.31 (br s, 1 H), 4.24 (q, 2H, = 7.3 Hz), 3.32ꢀ3.88 (m, 57 H), 1.32 (t, 3
H, = 7.3 Hz), 1.19 (br s, 3 H), 1.10 (d, 6 H,
= 6.9 Hz); 13C NMR (150 MHz, DMSOꢀd6
373 K) 168.4, 168.3, 167.5, 161.5, 161.3, 159.6, 147.0, 145.0, 144.8, 142.9, 134.2, 133.9,
δ 8.03 (d, 2 H, J = 8.2 Hz), 7.52 (br s, 2 H), 7.28 (br s, 2 H), 7.15 (br s, 2 H),
J
J
J
,
δ
128.1, 128.0, 126.5, 125.8, 125.6, 124.7, 124.6, 124.3, 124.1, 123.0, 122.1, 120.1, 113.7,
111.4, 111.2, 72.5, 72.3, 72.0, 70.8, 69.7, 69.2, 67.1, 67.1, 58.9, 57.4, 54.8, 54.5, 54.2, 37.0,
37.0, 35.5, 34.8, 34.8, 17.0, 17.0, 16.9, 13.5; HRMS (ESI+, TOF) m/z Calcd for C67H90N9O18
[M+H]+: 1308.6398, Found: 1308.6379.
Synthesis of 28
A mixture of 25 (277 mg, 0.315 mmol) in ethanol (10 ml) and 2 M sodium hydroxide (10 ml)
was stirred for 17 h at room temperature. The reaction mixture was acidified by 2 M
hydrochloric acid (12 ml) at 0°C, extracted with ethyl acetate and THF. The organic layer was
washed with brine, dried over sodium sulfate, filtered and evaporated to give 28 (333 mg,
quant). Compound 28: Yellow solid; 1H NMR (600 MHz, CDCl3)
2 H, = 8.4 Hz), 7.57 (d, 2 H, = 8.4 Hz), 7.46 (br s, 2 H), 7.38 (br s, 2 H), 7.10 (br s, 1 H),
6.76 (br s, 1 H), 6.70 (br s, 1 H), 6.42 (br s, 1 H), 3.54ꢀ4.00 (m, 28 H), 3.36 (s, 3 H), 3.20 (s, 3
δ 8.34 (br s, 1 H), 8.05 (d,
J
J
H), 1.32 (t, 3 H,
J
= 6.9 Hz), 1.19 (br s, 6 H); 13C NMR (150 MHz, DMSOꢀ
d6, 373 K) δ 168.9,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
3
4
5
6
7
8
167.7, 160.9, 158.8, 147.2, 142.8, 139.2, 131.2, 128.3, 127.8, 126.7, 125.5, 124.9, 123.7,
122.2, 120.7, 118.5, 113.9, 110.6, 72.6, 72.2, 70.9, 69.7, 69.2, 69.2, 67.2, 67.1, 57.4, 57.4,
54.8, 54.6, 35.5, 35.4, 17.1, 17.0; HRMS (ESI+, TOF) m/z Calcd for C42H54N6NaO13
[M+Na]+: 873.3641, Found: 873.3660.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 29
A solution of 26 (254 mg, 0.299 mmol) and 28 (326 mg) in dimethylformamide (6 mL) was
treated with 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl) carbodiimide hydrochloride (120 mg, 0.628
mmol) and N,Nꢀdimethylꢀ4ꢀaminopyridine (97 mg, 0.793 mmol), and the resulting solution
was stirred for 22.5 h at room temperature. The reaction mixture was poured into ethyl acetate,
and washed with 2 M hydrochloride and saturated sodium hydrogen carbonate. The organic
layer was dried with sodium sulfate, filtered, and concentrated. The residue was purified by
open column chromatography (silica gel ethyl acetate/methanol = 10 :1) to give 29 (257 mg,
52%). Compound 29: Yellow oil; 1H NMR (400 MHz, CDCl3)
1H), 8.24 (br s, 1H), 8.05 (d, 2 H, = 8.7 Hz), 7.57 (d, 2 H, = 8.7 Hz), 7.40 (m, 12 H), 7.10
δ 8.33 (br s, 1 H), 8.26 (br s,
J
J
(br s, 1 H), 7.07 (br s, 1 H), 7.06 (br s, 1 H), 6.68 (br s, 1 H), 6.56 (br s, 1 H), 6.43 (br s, 3 H),
4.23 (m, 2 H), 3.53ꢀ4.00 (m, 56 H), 3.36 (s, 3 H), 3.21 (s, 3 H), 3.19 (s, 3 H), 3.18 (s, 3 H),
= 7.3 Hz), 1.20 (br s, 12 H); 13C NMR (150 MHz, DMSOꢀ
1.32 (t, 3 H, J d6, 373 K) δ 168.9,
167.6, 159.6, 158.9, 158.8, 147.1, 142.8, 139.4, 139.3, 131.0, 130.9, 130.9, 128.3, 128.0,
127.9, 126.9, 126.3, 126.0, 125.4, 124.1, 124.9, 123.7, 123.3, 122.2, 120.1, 118.6, 118.5,
118.5, 115.0, 113.9, 110.6, 72.6, 72.6, 72.2, 70.9, 69.7, 69.2, 69.1, 67.2, 67.1, 67.1, 58.9, 57.4,
57.4, 54.8, 54.6, 35.5, 17.1, 17.0, 17.0, 13.5; HRMS (ESI+, TOF) m/z Calcd for
C86H113N12O23 [M+H]+: 1681.8036, Found: 1681.8027.
Synthesis of 17
Sodium hydride (6 mg, 0.16 mmol) was washed with nꢀhexane twice. Compound 29 (36 mg,
0.022 mmol) was added to a suspension of sodium hydride in dimethylformamide (0.9 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. A solution of iodomethane
(55 mg, 0.384 mmol) in dimethylformamide (0.1 ml) was added, and the mixture was stirred
for 1.5 h at room temperature. After removal of the solvent in vacuo, the residue was
extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and
evaporated. The residue was purified by open column chromatography (silica gel, ethyl
acetate/methanol = 10 :1) to give 17 (22 mg, 58%). Compound 17: Yellow oil; 1H NMR (600
MHz, DMSOꢀ
d
6, 373K)
δ
8.06(d, 2 H,
J
= 8.6 Hz), 7.38 (d, 2 H,
J
= 8.2 Hz), 7.30 (d, 2 H,
J =
8.4 Hz), 7.15 (d, 2 H,
J
= 8.3 Hz), 7.14 (d, 2 H,
J
= 8.3 Hz), 7.06 (d, 2 H, J
= 8.5 Hz), 7.03 (d,
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2 H,
1 H), 5.61 (d, 1 H,
Hz), 3.37ꢀ3.73 (m, 56 H), 3.29 (s, 3 H), 3.26 (s, 3 H), 3.26 (s, 3 H), 3,26 (s, 3 H), 3.24 (s, 3 H),
3.23 (s, 3 H), 1.26 (t, 3 H, = 7.1 Hz), 1.10 (d, 3 H, = 5.8 Hz), 1.03 (d, 3 H, = 5.8 Hz),
1.01 (d, 3 H, = 5.8 Hz), 1.00 (d, 3 H, 6, 373 K)
= 5.8 Hz); 13C NMR (150 MHz, DMSOꢀ
J
= 8.5 Hz), 7.01 (d, 2 H,
J
= 8.4 Hz), 6.88 (s, 1 H), 6.64 (m, 2 H), 6.60 (s, 1 H) 6.57 (s,
J
= 1.6 Hz), 5.60 (d, 1 H,
J
= 1.6 Hz), 5.58 (s, 1H), 4.19 (q, 2 H, = 7.1
J
J
J
J
J
J
d
δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
168.4, 168.3, 168.3, 167.4, 161.5, 161.5, 161.3, 159.6, 147.0, 145.0, 144.8, 144.7, 142.8,
134.2, 134.0, 133.9, 128.1, 128.0, 128.0, 126.5, 125.7, 125.6, 125.6, 124.7, 124.6, 124.5,
124.3, 124.1, 122.8, 122.8, 122.1, 120.2, 113.8, 113.7, 111.3, 111.1, 111.0, 72.5, 72.3, 72.0,
70.9, 69.7, 69.1, 67.1, 67.1, 67.0, 58.9, 57.4, 54.8, 54.5, 54.5, 54.2, 54.0, 37.0, 37.0, 37.0, 35.5,
34.8, 34.7, 17.0, 17.0, 16.9, 13.5; HRMS (ESI+, TOF) m/z Calcd for C89H119N12O23 [M+H]+:
1723.8506, Found: 1723.8466.
Synthesis of 30
A solution of 29 (72 mg, 0.0426 mmol) was hydrogenated with palladium on carbon (9 mg) in
ethyl acetate (1.5 ml) under hydrogen atmosphere for 29 h at room temperature. The reaction
mixture was filtrated on celite, and the filtrate was concentrated. The residue was purified by
open column chromatography (silica gel, ethyl acetate/methanol = 20 : 3) to give 30 (52 mg,
1
74%). Compound 30: Colorless solid; H NMR (600 MHz, CDCl3, 323K)
δ 8.03 (br, 1 H),
8.02 (br, 1H), 8.00 (br, 1H), 7.40 (m, 14 H), 6.91 (s, 1 H), 6.88 (s, 1 H), 6.67 (s, 1 H), 6.60 (br
s, 1 H), 6.50 (br s, 3 H), 6.45 (d, 2 H, = 8.4 Hz), 4.24 (m, 2 H), 3.49ꢀ4.00 (m, 56 H), 3.36 (s,
3 H), 3.26 (s, 3 H), 3.25 (s, 3 H), 3.24 (s, 3 H), 1.32 (t, 3 H, = 7.2 Hz), 1.20ꢀ1.17 (br s, 12
H); 13C NMR (150 MHz, DMSOꢀ
6, 373 K) 169.3, 168.9, 159.6, 159.0, 158.9, 149.4, 139.4,
J
J
d
δ
139.4, 131.0, 130.9, 130.8, 129.4, 128.0, 127.8, 127.3, 126.9, 126.3, 126.0, 125.1, 124.7,
123.3, 123.1, 123.1, 120.1, 118.5, 118.5, 113.9, 111.9, 110.6, 110.6, 110.5, 72.8, 72.6, 72.6,
70.9, 69.7, 69.2, 69.1, 67.2, 67.1, 58.9, 57.4, 57.4, 55.1, 54.9, 35.5, 17.2, 17.1, 17.0, 13.5;
HRMS (ESI+, TOF) m/z Calcd for C86H115N12O21 [M+H]+: 1651.8294, Found: 1651.8304.
Synthesis of 31
A mixture of 29 (37 mg, 0.222 mmol) in ethanol (0.8 ml) and 2 M sodium hydroxide (0.8 ml)
was stirred for 20 h at room temperature. The reaction mixture was acidified by 2 M
hydrochloric acid at 0°C, extracted with ethyl acetate and THF. The organic layer was washed
with brine, dried over sodium sulfate, filtered and evaporated to give 31 (40 mg, quant).
Compound 31: Yellow solid; 1H NMR (600 MHz, CDCl3, 323K)
δ 8.20 (br s, 1 H), 8.05 (br s,
2 H), 8.03 (br s, 1H), 7.94 (br s, 1H), 7.57 (br s, 2 H), 7.39 (m, 12 H), 6.96 (br s, 1 H), 6.88
(br s, 1 H), 6.75 (br s, 1 H), 6.71 (br s, 1 H), 6.65 (br s, 1 H), 6.57 (br s, 1 H), 6.51 (br s, 1 H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
3
4
5
3.50ꢀ4.00 (m, 56 H), 3.36 (s, 3 H), 3.26 (s, 3 H), 3.23(br s, 6 H), 3.18 (s, 3 H), 1.32 (t, 3 H,
= 7.3 Hz), 1.20 (br s, 12 H); 13C NMR (150 MHz, DMSOꢀ
d6, 373 K) δ 168.9, 167.6, 160.9,
J
6
7
8
9
158.9, 158.8, 147.1, 142.8, 139.4, 139.3, 139.2, 131.0, 130.9, 128.3, 128.0, 127.8, 126.7,
126.3, 125.5, 125.1, 124.9, 124.9, 123.6, 123.3, 123.3, 122.2, 120.7, 118.6, 118.5, 118.5,
113.9, 110.6, 110.6, 72.6, 72.6, 72.2, 70.9, 69.7, 69.2, 69.1, 67.1, 67.1, 57.4, 57.4, 54.8, 54.8,
54.6, 35.5, 35.4, 17.1, 17.1, 17.0; HRMS (ESI+, TOF) m/z Calcd for C84H109N12O23 [M+H]+:
1653.7723, Found: 1653.7733.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 32
A solution of 30 (49 mg, 0.0297 mmol) and 31 (49 mg, 0.0297 mmol) in dimethylformamide
(2.1 ml) was treated with 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl) carbodiimide hydrochloride (12
mg, 0.0636 mmol) and N,Nꢀdimethylꢀ4ꢀaminopyridine (9 mg, 0.074 mmol), and the resulting
solution was stirred for 44 h at room temperature. The reaction mixture was poured into ethyl
acetate, and washed with 2 M hydrochloric acid and saturated sodium hydrogen carbonate.
The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was
purified by open column chromatography (silica gel, ethyl acetate/methanol = 5 :1) and
preparative TLC (silica gel, ethyl acetate/methanol = 5 :1) to give 32 (43 mg, 44%).
Compound 32: Yellow solid; 1H NMR (600 MHz, DMSOꢀ
2 H, = 8.7 Hz), 7.56 (m, 16 H), 7.34 (m, 12 H), 7.28 (d, 2 H,
6.82 (br s, 6 H), 6.63 (d, 1 H,
3.26 (s, 3 H), 3.24 (m, 18 H), 1.25 (t, 3 H,
DMSOꢀ 6, 373 K)
d
6, 373K)
δ 9.40 (m, 7 H), 8.09 (d,
J
J
= 8.6 Hz), 6.88 (m, 9 H),
J
= 2.0 Hz), 4.19 (q, 2 H,
J
= 7.1 Hz), 3.42ꢀ3.79 (m, 112 H),
13
J
= 7.1 H), 1.13 (m, 24 H); C NMR (150 MHz,
d
δ
168.9, 158.9, 158.8, 147.1, 142.8, 139.4, 139.2, 131.0, 130.9, 128.3,
128.0, 127.8, 126.3, 126.0, 125.1, 125.0, 123.3, 122.2, 120.1, 118.6, 118.5, 118.5, 113.9,
110.6, 110.5, 72.6, 72.2, 70.9, 69.7, 69.1, 67.2, 67.1, 58.9, 57.4, 54.9, 54.6, 35.5, 17.1, 17.0,
17.0, 13.5; HRMS (ESI+, TOF) m/z Calcd for C170H221N24O43 [M+H]+: 3286.5839, Found:
3286.5902.
Synthesis of 18
Sodium hydride (6 mg, 0.138 mmol) was washed with nꢀhexane twice. Compound 32 (25 mg,
0.0076 mmol) was added to a suspension of sodium hydride in dimethylformamide (1.5 ml) at
0°C, and the mixture was stirred for 30 min at room temperature. Iodomethane (56 mg, 0.392
mmol) was added, and the mixture was stirred for 1 h at room temperature. After removal of
the solvent in vacuo, the residue was extracted with ethyl acetate. The organic layer was dried
over magnesium sulfate, filtered and evaporated. The residue was purified by preparative
TLC (methylene chrolide/methanol = 20 : 1) to give 18 (15 mg, 58%). Compound 18: Yellow
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
3
1
oil; H NMR (600 MHz, DMSOꢀ
Hz), 7.29 (d, 2 H, = 8.5 Hz), 7.15 (m, 12 H), 7.03 (m, 14 H), 6.88 (br s, 1 H), 6.58 (m, 2 H),
6.57 (m, 6 H), 5.60 (m, 7 H), 4.20 (q, 2 H, = 7.0 Hz), 3.35ꢀ3.74 (m, 112 H), 3.25 (m, 45 H),
1.26 (t, 3 H, = 7.0 Hz), 1.10 (d, 3 H,
= 5.9 Hz), 1.01 (m, 21 H); 13C NMR (150 MHz,
DMSOꢀ 6, 373 K) 168.4, 168.3, 168.3, 167.5, 161.6, 161.5, 161.4, 159.6, 147.0, 145.0,
d6, 373K) δ 8.06 (d, 2 H, J = 8.7 Hz), 7.37 (d, 2 H, J = 8.6
4
5
6
7
8
9
J
J
J
J
d
δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
144.8, 142.9, 134.2, 134.0, 128.2, 128.1, 128.0, 128.0, 125.8, 125.6, 124.7, 124.7, 124.6,
124.1, 122.2, 122.1, 120.1, 111.1, 72.5, 72.3, 72.0, 70.9, 69.7, 69.2, 67.2, 67.1, 67.1, 58.9,
57.4, 54.8, 54.5, 54.3, 40.1, 37.1, 37.0, 37.0, 35.5, 34.8, 34.8, 28.4, 28.0, 17.0, 16.9, 13.5;
HRMS (MALDIꢀTOF) m/z Calcd for C177H234N24O43 [M+Na]+: 3406.6754, Found:
3406.6536.
Acknowledgements
This work was partly supported by JSPS KAKENHI Grant No 16K08318 (to AT) and JSPS
CoreꢀtoꢀCore Program, A. Advanced Research Networks. AT gratefully acknowledge funding
from The Sumitomo Foundation and The Naito Foundation. KU is grateful for financial
support from JSPS Research Fellow for Young Scientists.
Supporting Information Available: 1H and 13C NMR spectra, synthetic scheme of oligomers,
crystal data and structures and cartesian coordinates of the calculation. This material is
available free of charge via the Internet at http://pubs.acs.org.
Referencers
1) (a) Tomasini, C.; Huc, I.; Aitken, D. J.; Fülöp, F. Foldamers. Eur. J. Org. Chem. 2013,
3408ꢀ3409. (b) Foldamers: Structures, Properties, and Applications; Hecht, S., Huc, I., Eds.;
WileyꢀVCH: Weinheim, 2007. (c) Guichard, G.; Huc, I. Synthetic foldamers. Chem. Commun.
2011, 47, 5933ꢀ5941.
2) (a) Gellman, S. H. Foldamers:ꢁ A manifesto. Acc. Chem. Res. 1998, 31, 173ꢀ180. (b) Hill, D.
J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. A field guide to foldamers. Chem. Rev. 2001, 101
,
3893ꢀ4011.
3) (a) Juwarker, H.; Jeong, K.ꢀS. Anionꢀcontrolled foldamers. Chem. Soc. Rev. 2010, 39
,
3664ꢀ3674. (b) Horeau, M.; Lautrette, G.; Wicher, B.; Blot, V.; Lebreton, J.; Pipelier, M.;
Dubreuil, D.; Ferrand, Y.; Huc, I. Metalꢀcoordinationꢀassisted folding and guest binding in
helical aromatic oligoamide molecular capsules. Angew. Chem. Int. Ed. 2017, 56, 6823ꢀ6827.
(c) Ikkanda, B. A.; Iverson, B. L. Exploiting the interactions of aromatic units for folding and
assembly in aqueous environments. Chem. Commun. 2016, 52, 7752ꢀ7759. (d) Saraogi, I.;
Hamilton, A. D. Recent advances in the development of arylꢀbased foldamers. Chem. Soc. Rev.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
5
6
7
8
9
2009, 38, 1726ꢀ1743. (e) Ohishi, Y.; Abe, H.; Inouye, M. Native mannoseꢀdominant
extraction by pyridineꢀphenol alternating oligomers having an extremely efficient repeating
motif of hydrogenꢀbonding acceptors and donors. Chem. Eur. J. 2015, 21, 16504ꢀ16511.
4) Zhang, D.ꢀW.; Zhao, X.; Hou, J.ꢀL.; Li, Z.ꢀT. Aromatic amide foldamers: Structures,
properties, and functions. Chem. Rev. 2012, 112, 5271ꢀ5316.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. βꢀPeptide
foldamers: Robust helix formation in a new family of betaꢀamino acid oligomers. J. Am.
Chem. Soc. 1996, 118, 13071ꢀ13072.
6) Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B. γ2ꢀ, γ3ꢀ, and γ2,3,4ꢀAmino acids, coupling
to
γꢀhexapeptides: CD spectra, NMR solution and Xꢀray crystal structures of
γꢀpeptides.
Chem. Eur. J. 2002,
8
, 573ꢀ584.
7) Martinek, T. A.; Fülöp, F. Peptidic foldamers: ramping up diversity. Chem. Soc. Rev. 2012,
41, 687ꢀ702.
8) (a) Huc, I. Aromatic oligoamide foldamers. Eur. J. Org. Chem. 2004, 17ꢀ29. (b) Gong, B.
Crescent oligoamides: From acyclic “macrocycles” to folding nanotubes. Chem. Eur. J. 2001,
7
, 4336ꢀ4342.
9) (a) Sebaoun, L.; Maurizot, V.; Granier, T.; Kauffmann, B.; Huc, I. Aromatic oligoamide
βꢀsheet foldamers. J. Am. Chem. Soc. 2014, 136, 2168ꢀ2174. (b) Lamouroux, A.; Sebaoun, L.;
Wicher, B.; Kauffmann, B.; Ferrand, Y.; Maurizot, V.; Huc, I. Controlling dipole orientation
through curvature: Aromatic foldamer bent βꢀsheets and helix–sheet–helix architectures. J.
Am. Chem. Soc. 2017, 139, 14668ꢀ14675.
10) Gan, Q.; Li, F.; Li, G.; Kauffmann, B.; Xiang, J.; Huc, I.; Jiang, H. Heteromeric double
helix formation by crossꢀhybridization of chloroꢀand fluoroꢀsubstituted quinoline oligoamides.
Chem. Commun. 2010, 46, 297ꢀ299.
11) (a) Okamoto, I.; Nabeta, M.; Hayakawa, Y.; Morita, N.; Takeya, T.; Masu, H.; Azumaya,
I.; Tamura, O. Acidꢀinduced molecular folding and unfolding of
Nꢀmethyl aromatic amide
bearing 2,6ꢀdisubstituted pyridines. J. Am. Chem. Soc. 2007, 129, 1892ꢀ1893. (b) Dolain,
C.; Maurizot, V.; Huc, I. Protonationꢀinduced transition between two distinct helical
conformations of a synthetic oligomer via a linear intermediate. Angew. Chem. Int. Ed. 2003,
42, 2738ꢀ2740. (c) Shang, J.; Gan, Q.; Dawson, S. J.; Rosu, F.; Jiang, H.; Ferrand, Y.; Huc, I.
Selfꢀassociation of aromatic oligoamide foldamers into double helices in water. Org. Lett.
2014, 16, 4992ꢀ4995.
12) (a) Peczuh, M. W.; Hamilton, A. D. Peptide and protein recognition by designed
molecules. Chem. Rev. 2000, 100, 2479ꢀ2494. (b) Campbell, F.; Plante, J. P.; Edwards, T. A.;
Warriner, S. L.; Wilson, A. J.
NꢀAlkylated oligoamide αꢀhelical proteomimetics. Org. Biomol.
Chem. 2010, , 2344ꢀ2351. (c) Gopapakrishnan, R.; Frolov, A.; Knerr, L.; Drury, W. J. III;
8
Valeur, E. Therapeutic potential of foldamers; From chemical biology tools to drug
candidates? J. Med. Chem. 2016, 59, 9599ꢀ9621. (d) Jewginski, M.; Granier, T.; Langlois
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
d'Estaintot, B.; Fischer, L.; Mackereth, C. D.; Huc, I. Selfꢀassembled protein–aromatic
foldamer complexes with 2:3 and 2:2:1 stoichiometries. J. Am. Chem. Soc. 2017, 139
,
2928ꢀ2931.
7
8
9
13) (a) Kagechika, H.; Himi, T.; Kawachi, E.; Hashimoto, Y.; Shudo, K. Retinobenzoic acids.
4. Conformation of aromatic amides with retinoidal activity. Importance of transꢀamide
structure for the activity. J. Med. Chem. 1989, 32, 2292ꢀ2296. (b) Itai, A.; Toriumi, Y.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K. Stereochemistry of Nꢀmethylbenzanilide
and benzanilide. Tetrahedron Lett. 1989, 30, 6177ꢀ6180. (c) Yamaguchi, K.; Matsumura, G.;
Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.; Shudo, K. Aromatic architecture. Use of the
N
ꢀmethylamide structure as a molecular splint. J. Am. Chem. Soc. 1991, 113, 5474ꢀ5475.
14) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui, C.; Shiro, M.; Uchiyama,
M.; Muranaka, A.; Kobayashi, N.; Yokozawa, T. Helical structure of ꢀalkylated
poly( ꢀbenzamide)s. J. Am. Chem. Soc. 2005, 127, 8553ꢀ8561.
N
p
15) (a) Kolomiets, E.; Berl, V.; Odriozola, I.; Stadler, A.ꢀM.; Kyritsakas, N.; Lehn, J.ꢀM.
Contraction/extension molecular motion by protonation/deprotonation induced structural
switching of pyridine derived oligoamides. Chem. Commun. 2003, 2868ꢀ2869. (b) Yamasaki,
R.; Tanatani, A.; Azumaya, I.; Saito, S.; Yamaguchi, K.; Kagechika, H. Amide conformational
switching induced by protonation of aromatic substituent. Org. Lett. 2003,
Yamasaki, R.; Tanatani, A.; Azumaya, I.; Masu, H.; Yamaguchi, K.; Kagechika, H.
Solventꢀdependent conformational switching of ꢀphenylhydroxamic acid and its application
in crystal engineering. Crystal Growth & Design 2006, , 2007ꢀ2010 (d) Okamoto, I.;
5, 1265ꢀ1267. (c)
N
6
.
Yamasaki, R.; Sawamura, M.; Kato, T.; Nagayama, N.; Takeya, T.; Tamura, O.; Masu, H.;
Azumaya, I.; Yamaguchi, K.; Kagechika, H.; Tanatani, A. Redoxꢀinduced conformational
alteration of N,Nꢀdiarylamides. Org. Lett. 2007, 9, 5545ꢀ5547. (e) Ito, A; Sato, M.; Yamasaki,
R.; Okamoto, I. Acidꢀ and baseꢀinduced conformational alterations of N-arylꢀ
Nꢀtroponyl
amides. Tetrahedron Lett. 2016, 57, 438ꢀ441.
16) (a) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J.ꢀM. Helical molecular programming: folding
of oligopyridineꢀdicarboxamides into molecular single helices. Chem. Eur. J. 2001,
7,
2798ꢀ2809. (b) Jiang, H.; Léger, J.ꢀM.; Dlain, C.; Guionneau, P.; Huc, I. Aromatic δꢀpeptides:
design, synthesis and structural studies of helical, quinolineꢀderived oligoamide foldamers.
Tetrahedron 2003, 59, 8365ꢀ8374. (c) Yamasaki, R.; Fujikake, S.; Ito, A.; Migita, K.; Morita,
N.; Tamura, O.; Okamoto, I. Acidꢀinduced molecularꢀstructural transformation of Nꢀmethyl
aromatic oligoamides bearing pyridineꢀ2ꢀcarboxamide. Tetrahedron Lett. 2016, 57, 56ꢀ59.
17) Dervan, P. B. Molecular recognition of DNA by small molecules. Bioorg. Med. Chem.
2001, 9, 2215ꢀ2235.
18) Recent selected papers: (a) Sessler, J. L.; Barkey, N. M.; Pantos, G. D.; Lynch, V. M.
Acyclic pyrroleꢀbased anion receptors: design, synthesis, and anionꢀbinding properties. New J.
Chem. 2007, 31, 646ꢀ656. (b) Dydio, P.; Lichosyt, D.; Jurczak, J. Amideꢀ and
ACS Paragon Plus Environment