Synthesis and chiral discrimination of cyclic aromatic amides and the determination of their absolute configuration by TD-DFT calculations

Article abstract of DOI:10.1016/j.tetasy.2009.10.032

Novel chiral cyclic molecules composed of aromatic triamides were constructed in modest yield from 4-N-(4′-methoxybenzyl)amino-3-decyloxybenzoic acid using dichlorotriphenylphosphorane, because of the preorganized component of the tertiary benzanilide moi

Full text of DOI:10.1016/j.tetasy.2009.10.032

Tetrahedron: Asymmetry 20 (2009) 2646–2650
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and chiral discrimination of cyclic aromatic amides and the
determination of their absolute configuration by TD-DFT calculations
Kosuke Katagiri a, Takashi Ikeda a, Atsuya Muranaka b, Masanobu Uchiyama b, Masahide Tominaga a,
Isao Azumaya a,
*
a Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
b Advanced Elements Chemistry Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel chiral cyclic molecules composed of aromatic triamides were constructed in modest yield from 4-
N-(40-methoxybenzyl)amino-3-decyloxybenzoic acid using dichlorotriphenylphosphorane, because of
the preorganized component of the tertiary benzanilide moieties. A racemic mixture of two diastereo-
mers, syn and anti conformers of cyclic aromatic triamides, was resolved into enantiomers by HPLC using
a preparative chiral column. The absolute configuration of each enantiomer in both diastereomers was
determined by comparison of the time-dependent density functional theory (TD-DFT) calculated circular
dichroic (CD) spectra with the experimentally derived CD spectra recorded on each sample.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 September 2009
Accepted 20 October 2009
Available online 24 November 2009
1. Introduction
A variety of structurally well-defined macrocyclic compounds
have been designed and extensively studied for more than three
decades.1 This is because compounds such as cyclophanes,2 calixa-
renes,3 crownethers,4 and cyclodextrins5 have attracted strong
interest as potential molecular receptors for various organic mole-
cules and metal ions. Such compounds have unique properties such
as specific recognition, selective binding and complexation. Along
with the rapid development of macrocyclic compounds, chiral mac-
rocycles represent a valuable research topic in the fields of supramo-
lecular chemistry and materials science because of their potential
ability for chiral recognition6,1l and asymmetric ligand systems.7
Planar chiral-substituted [2.2]paracyclophanes have been widely
investigated as a versatile backbone structure.8 However, there are
limited numbers of enantiomerically pure cyclic trimers composed
of aromatic rings that can act as model compounds of [3.3]paracy-
clophane.9 We have previously demonstrated that a family of
macrocycles consisting of aromatic amides could easily be synthe-
sized using conformational alternation by N-alkylation of aromatic
amides from trans to cis.10 Using this structural property, a cyclized
trimer of 4-(methylamino)benzoic acid was obtained, which indi-
cated a stable and rigid cyclic framework and a small cavity sur-
rounded by three arene rings. In this crystal structure, all the
amide bonds are nearly planar and the three aromatic rings are tilted
from the orthogonal planes to the amide plane (Chart 1). We have
therefore applied this framework as a building block to construct
Chart 1. The structural formula and stereoview of a crystal structure10b in a space-
filling model of a cyclized trimer of 4-(methylamino)benzoic acid.
chiral macrocyclic molecules. Recently, the absolute configurations
of chiral cyclophane systems and biaryl compounds with axial chi-
rality systems were determined by a comparison of experimental
chiroptical properties and density functional theory (DFT) calcula-
tions.9e,11 Herein, we report the synthesis and resolutions of two chi-
ral cyclic triamides by a condensation reaction of 3-substituted-4-
alkylaminobenzoic acid (Chart 2), and the determination of the
absolute configuration by a comparison of circular dichroism (CD)
spectra and time-dependent DFT (TD-DFT) calculations.
2. Results and discussion
The synthesis of the cyclic aromatic triamides is shown in
Scheme 1. After esterification of commercially available 3-hydro-
* Corresponding author. Tel.: +81 87 894 5111x6308; fax: +81 87 894 0181.
E-mail address: azumayai@kph.bunri-u.ac.jp (I. Azumaya).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.032

K. Katagiri et al. / Tetrahedron: Asymmetry 20 (2009) 2646–2650
2647
R
O
C10H21
O
C
O
10H21O
R
C10H21
O
C10H21O
O
OC10H21
OC10H21
N
R
R
O
N
N
N
R
N
O
O
R
N
O
R
N
O
R
N
O
N
N
N
R
N
R
R
R
O
C10H21
O
O
O
C10H21O OC10H21
OC10H21
O
C10H21
O
C10H21
(R,R,S)-anti-5
(R,R,R)-syn-5
(S,S,S)-syn-5
(R,S,S)-anti-5
R = p-methoxybenzyl
Chart 2. Configuration of four types of cyclic aromatic triamides 5.
C10H21
I
NO2
NO2
NO2
NH2
conc. H2SO4
K2CO3
OH
OH
OC10H21
OC10H21
Pd/C, H2
DMF
EtOH
EtOH
rt
COOH
COOEt
COOEt
1. 83%
COOEt
reflux, 6 h
60 °C, 5.5 h
84%
2. 91%
MeO
CHO
NH
cat. PhSO3H•H2O
BH3•Pyridine
4 M NaOHaq.
OC10H21
MeO
MeO
EtOH
MeOH
EtOH
reflux, 7 h
reflux, 8 h
60 °C, 3 h
COOEt
62% (for two steps)
3
OC10H21
O
N
NH
O
OMe
Ph3PCl2
OC10H21
MeO
N
C10H21
O
(CHCl2)2
N
120 °C, 4 h
OC10H21
COOH
O
4. 93%
5. 30%
syn : anti = 1 : 2
OMe
Scheme 1. The synthesis of the cyclic aromatic triamides 5 with a syn/anti mixture.
xy-4-nitrobenzoic acid, ethyl 3-hydroxy-4-nitrobenzoate was
converted into ethyl 3-decyloxy-4-nitrobenzoate 1 by the etherifi-
cation reaction of the hydroxyl group. Ethyl 3-decyloxy-4-amino-
benzoate 2 was obtained by hydrogenation over Pd/C of 1 in 91%
yield. The reaction of 2 with p-methoxybenzaldehyde afforded an
imine derivative, followed by reduction using a borane–pyridine
complex in methanol to give ethyl 3-decyloxy-4-(N-40-methoxy-
benzyl)aminobenzoate 3 in 62% yield for the two steps. Hydrolysis
of 3 followed by the cyclization reaction using dichlorotriphenyl-
phosphorane afforded the cyclic triamide with decyloxy groups
at the ortho position to the amide nitrogen 5 with a syn/anti
mixture (1:2) in 30% yield, which was separated into each of the
diastereomers by silica gel column chromatography. The diastereo-
meric structure of 5 was determined by 1H NMR analysis.
Two diastereomers 5 have two enantiomeric conformations
based on the direction of the amide bond, and are therefore ob-
tained as a racemic mixture of each enantiomer. Chiral separation
of racemic syn-5 and anti-5 was achieved by high performance li-
quid chromatography using CHIRALPAK OJ-H and CHIRALPAK IA
from Daicel Chemical Industries, Ltd eluting with 2-propanol/
hexane = 1:9 using a flow rate of 1.0 mL/min (Fig. 1). The enantio-
merically pure (>99% ee) syn-5 and anti-5 were obtained, respec-
tively. Furthermore, no racemization was observed after the
chloroform solution of 5 was refluxed for 3 h. The CD spectrum
of the first-eluted sample (retention time: 12.3 min for syn-5 and
retention time: 14.8 min for anti-5) was a mirror image of the CD
spectrum of the second-eluted sample (retention time: 25.6 min
for syn-5 and retention time: 18.2 min for anti-5). As shown in

2648
K. Katagiri et al. / Tetrahedron: Asymmetry 20 (2009) 2646–2650
Figure 1a, the first-eluted sample of syn-5 has an intense negative
CD signal, and the second-eluted sample of syn-5 has a positive CD
signal at ꢀ230 nm. Conversely, the first-eluted sample of anti-5
indicates a negative CD signal and the second-eluted sample of
anti-5 shows a positive CD signal at ꢀ230 nm (Fig. 1b).
Time-dependent (TD) DFT calculations at the B3LYP/6-31G(d)
level of (R,R,R)-syn-6 and (R,R,S)-anti-6 as model compounds of
the corresponding cyclic triamides 5 were performed to predict
the CD spectra. As shown in Figure 2a, (R,R,R)-syn-6 has an intense
positive CD signal at ꢀ254 nm and a negative CD signal at ꢀ320 nm.
Figure 1. Resolution of the enantiomeric mixtures of syn-5 (a) and anti-5 (b) by HPLC using CHIRALPAK OJ-H and CHIRALPAK IA columns and their respective CD spectra.
a
b
MeO
R
OMe
MeO
MeO
OMe
R
O
O
N
N
R
N
O
O
R
N
O
O
N
R
N
R
MeO
R = p-methoxybenzyl
(R,R,R)-syn-6
R = p-methoxybenzyl
(R,R,S)-anti-6
Figure 2. Predicted UV and CD spectra of (R,R,R)-syn-6 (a) and (R,R,S)-anti-6 (b) calculated using the TD-DFT method (B3LYP/6-31G(d)). Gaussian bands with a half-band
width of 2500 cmꢁ1 were used to produce the spectra. Rotational strengths are given in cgs (10ꢁ40 erg esu cm/G).

K. Katagiri et al. / Tetrahedron: Asymmetry 20 (2009) 2646–2650
2649
The predicted spectrum of (R,R,R)-syn-6 was similar to that of the
second-eluted sample for syn-5 (Fig. 1a, blue line). On the other
hand, the calculations for (R,R,S)-anti-6 also showed an intense po-
sitive CD signal at ꢀ254 nm and a negative CD signal at ꢀ320 nm
(Fig. 2b). The predicted spectrum of (R,R,S)-anti-6 corresponds to
that of the second-eluted sample for anti-5 (Fig. 1b, green line).
column chromatography (eluent: ethyl acetate/hexane = 1:5) to
give pure 2 as a white powder (3.68 g, 91%): mp 54–55 °C; 1H
NMR (400 MHz, CDCl3): d 7.54 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (d,
J = 1.6 Hz), 6.65 (d, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.20 (s,
2H), 4.05 (t, J = 6.4 Hz, 2H), 1.82 (q, J = 7.0 Hz, 2H), 1.80–1.40 (m,
2H), 1.37 (t, J = 6.8 Hz, 3H), 1.35–0.90 (m, 12H) and 0.88 (t,
J = 6.8 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): d 166.90, 145.58,
141.11, 123.78, 119.91, 113.06, 112.10, 68.43, 60.37, 31.89, 29.58,
29.56, 29.40, 29.31, 29.26, 26.12, 22.67, 14.46 and 14.10 ppm;
FAB-MS m/z 321.45; Calcd for C19H31NO3: C, 70.99; H, 9.72; N,
4.36. Found: C, 70.72; H, 9.51; N, 4.44.
3. Conclusion
In conclusion, we have designed and synthesized the chiral cyc-
lic aromatic triamides by utilizing the stereochemistry of the aro-
matic amide. The optical resolution was achieved by HPLC using
a preparative chiral column. The absolute configurations of the
synthesized products were determined by a comparison of the
experimental CD spectra of the cyclic triamides and the theoreti-
cally calculated CD spectra of cyclic triamide analogues. We believe
that the chiral cyclic aromatic triamides will be useful as chiral li-
gands in chemical transformations and as chiral building blocks in
supramolecular architectures.
4.4. Ethyl 4-(N-40-methoxybenzylamino)-3-decyloxybenzoate 3
4-Methoxybenzaldehyde and benzene sulfonic acid monohy-
drate were added to a solution of ethyl 4-amino-3-decyloxybenzo-
ate 2 in dry EtOH by stirring. After filtering through a funnel filled
with molecular sieves (4 Å) which was equipped to remove water,
the reaction mixture was heated at reflux for 7 h. The solvent was
evaporated and to the residual material dry MeOH and pyridine
borane were added by stirring. The reaction mixture was heated
at reflux for 8 h. The solvent was evaporated and the residue was
purified by silica gel column chromatography (eluent: ethyl ace-
tate/hexane = 1:40) to give pure 3 as a colorless oil: 1H NMR
4. Experimental section
4.1. General
Melting points were determined by using ATM-01 (AS ONE). 1H
(400 MHz, CDCl3):
d 7.58 (dd, J = 8.0, 2.0 Hz, 1H), 7.41 (d,
and 13C NMR spectra were performed on
a Bruker AV400
J = 2.0 Hz), 7.27 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.52 (d,
J = 8.4 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 5.2 Hz, 2H), 4.31
(q, J = 7.2 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.80 (s, 3H), 1.80 (q,
J = 7.0 Hz, 2H), 1.80–1.40 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.35–
0.90 (m, 12H) and 0.88 (t, J = 6.8 Hz, 3H) ppm; 13C NMR
spectrometer (1H operating frequency of 400 MHz) at 298 K in
chloroform-d. Low mass spectra were obtained on a JEOL MStation
JMS-700 spectrometer and high mass spectra were obtained on a
JEOL AccuTOF JMS-T100LC spectrometer. Column chromatography
was performed using a Wakogel C200 and thin-layer chromatogra-
phy was carried out on 0.25 mm Merckprecoated silica gel glass
plates. Gel Permeation Chromatography (GPC) was performed
using recycling preparative HPLC (LC-9204, Japan Analytical Indus-
try Co., Ltd) and a JAIGEL H series column (Japan Analytical Indus-
try Co., Ltd). Elemental analyses were within 0.3% of their
theoretical values.
(125 MHz, CDCl3):
d 167.09, 158.93, 145.12, 142.30, 130.70,
128.51, 124.29, 117.89, 114.10, 110.87, 108.22, 68.55, 60.24,
55.28, 46.79, 31.89, 29.58, 29.54, 29.37, 29.32, 29.20, 26.13,
22.68, 14.49 and 14.10 ppm; FAB-MS m/z 411.3; Calcd for
C26H37NO3: C, 75.87; H, 9.06; N, 3.40. Found: C, 75.74; H, 9.11;
N, 3.50.
4.5. 4-(N-40-Methoxybenzylamino)-3-decyloxybenzoic acid 4
4.2. Ethyl 3-decyloxy-4-nitrobenzoate 1
4 M NaOH was added to a solution of ethyl 4-(N-40-methoxy-
benzylamino)-3-decycloxybenzoate 3 in EtOH by stirring and the
reaction mixture was heated at reflux for 3 h. The reaction mixture
was cooled in an ice-water bath and neutralized by 2 M HCl with
cooling and subsequently extracted with AcOEt. The organic layer
was washed with brine and dried over Na2SO4. The solvent was
evaporated to give the residual material 4 as a white powder:
mp 113–114 °C; 1H NMR (400 MHz, CDCl3): d 7.67 (dd, J = 8.0,
1.8 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.89
(d, J = 7.2 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 4.06 (t,
J = 6.6 Hz, 2H), 3.83 (s, 3H), 1.80 (q, J = 7.0 Hz, 2H), 1.80–1.40 (m,
2H), 1.35–0.90 (m, 12H) and 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3): d 172.22, 158.97, 145.02, 143.10, 130.49,
128.51, 116.35, 114.14, 111.14, 108.17, 68.56, 55.28, 46.70, 31.88,
29.57, 29.53, 29.36, 29.15, 26.10, 22.67 and 14.09 ppm; FAB-MS
m/z 383.3; Calcd for C24H33NO3: C, 75.16; H, 8.67; N, 3.65. Found:
C, 75.01; H, 8.81; N, 3.44.
To
a solution of ethyl 3-hydroxy-4-nitrobenzoate (3.16 g,
15 mmol) in DMF (150 mL), K2CO3 (4.09 g, 15 mmol) and decyl io-
dide (3.2 mL, 15 mmol) were added. The solution was continuously
stirred and the reaction mixture was heated at reflux for 7 h. The
solvent was evaporated and the residual material was purified by
silica gel column chromatography (eluent: toluene) to give pure
1 as a colorless oil (4.39 g, 83%): 1H NMR (400 MHz, CDCl3): d
7.80 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 8.4,
1.6 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.16 (t, J = 6.4 Hz, 2H), 1.84
(q, J = 7.0 Hz, 2H), 1.80–1.45 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H),
1.40–0.90 (m, 12H) and 0.89 (t, J = 6.8 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3):
d 164.83, 151.99, 142.56, 135.08, 125.10,
121.02, 115.45, 69.97, 61.90, 31.87, 29.50, 29.48, 29.28, 29.20,
28.83, 25.78, 22.66, 14.24 and 14.08 ppm; FAB-MS m/z 351.4; Calcd
for C19H29NO5: C, 64.93; H, 8.32; N, 3.99. Found: C, 65.03; H, 8.20;
N, 3.88.
4.6. 1,7,13-Tris(40-methoxybenzyl)-1,7,13-triaza- 5,11,17-tride
cyloxy-[2,2,2]paracyclophane-2,8,14-trione (5)
4.3. Ethyl 3-amino-4-decyloxybenzoate 2
To a solution of 1 (4.39 g, 12.5 mmol) in dry EtOH (200 mL) was
added 10% palladium on active carbon. The reaction mixture was
vigorously stirred under a hydrogen atmosphere at room temper-
ature for 30 h. The catalyst was filtered off and the filtrate was
evaporated. Toluene was added to the residue and the mixture
was evaporated. The crude material was purified by silica gel
Dichlorotriphenylphosphorane was added to a solution of 4-(N-
40-methoxybenzylamino)-3-decycloxybenzoic acid (4) in 1,1,2,2-
tetrachloroethane under argon by stirring for 4 h at 120 °C. The
solvent was evaporated and the residue was purified by silica gel
column chromatography (eluent: ethyl acetate/hexane = 1:3) to
give the mixture of trimer and hexamer. The material was purified

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by preparative gel permeation chromatography using JAIGEL-2H
and -2.5H columns with chloroform as the mobile phase to give
5 as a white powder.
4.6.1. syn-Conformation
Mp >300 °C; 1H NMR (400 MHz, CDCl3): d 7.10 (dd, J = 6.0,
2.0 Hz, 6H), 6.74 (dd, J = 6.8, 2.0 Hz, 6H), 6.57 (d, J = 1.2 Hz, 3H),
6.36 (dd, J = 8.0, 1.6 Hz, 3H), 6.28 (d, J = 8.0 Hz, 3H), 5.28 (d,
J = 14.0 Hz, 3H), 4.19 (d, J = 14.0 Hz, 3H), 3.81–3.72 (m, 12H),
3.60–3.54 (m, 3H), 1.78–1.69 (m, 6H), 1.39–1.30 (m, 42H) and
0.90 (t, J = 6.8 Hz, 9H) ppm; 13C NMR (125 MHz, CDCl3): d 171.41,
158.98, 153.62, 137.84, 130.78, 130.67, 129.05, 119.11, 113.61,
109.36, 68.16, 55.17, 50.52, 31.91, 29.72, 29.54, 29.43, 29.37,
26.31, 22.69, and 14.10 ppm; FAB-MS m/z 1186.40.
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4.6.2. anti-Conformation
Mp >300 °C; 1H NMR (400 MHz, CDCl3): d 7.10 (dd, J = 8.0,
2.0 Hz, 6H), 6.75 (dd, J = 7.2, 2.0 Hz, 6H), 6.56 (d, J = 1.2 Hz, 1H),
6.49 (dd, J = 9.4, 1.4 Hz, 2H), 6.47 (m, 3H), 6.24 (d, J = 7.6 Hz, 1H),
6.17 (d, J = 7.6 Hz, 1H), 5.36 (dd, J = 14.8, 3.6 Hz, 2H), 5.28 (d,
J = 13.6 Hz, 1H), 4.21 (d, J = 14.0 Hz, 1H), 4.15 (d, J = 8.4 Hz, 1H),
4.12 (d, J = 8.4 Hz, 1H), 3.79–3.74 (m, 15H), 1.73–1.71 (m, 6H),
1.41–1.24 (m, 36H) and 0.89 (t, J = 1.6 Hz, 9H) ppm; 13C NMR
(125 MHz, CDCl3):
d 171.29, 171.25, 158.96, 153.85, 153.81,
153.67, 137.88, 137.73, 131.30, 131.30, 130.82, 130.80, 130.77,
130.64, 130.57, 129.14, 129.12, 129.06, 129.01, 117.06, 116.91,
113.60, 113.57, 110.74, 109.37, 68.33, 68.14, 67.92, 55.14, 50.45,
50.33, 50.21, 29.63, 29.59, 29.55, 29.52, 29.46, 29.37, 29.32,
29.29, 29.27, 29.14, 29.11, 26.23, 26.07, 26.02, 22.66, and
14.08 ppm; FAB-MS m/z 1186.40.
5. Computational details
8. (a) Nugent, M. J.; Weigang, O. E., Jr. J. Am. Chem. Soc. 1969, 91, 4556–4558; (b)
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2008, 73, 9125–9128.
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37, 5003–5006; (b) Azumaya, I.; Okamoto, T.; Takayanagi, H. Anal. Sci. 2001, 17,
1363–1364; (c) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
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F.; Takayanagi, H. Tetrahedron 2003, 59, 2325–2331; (e) Imabeppu, F.; Katagiri,
K.; Masu, H.; Kato, T.; Tominaga, M.; Therrien, B.; Takayanagi, H.; Kaji, E.;
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All computations were performed using the GAUSSIAN 03 package
of programs.12 Geometry optimizations of cyclic benzamides were
executed with the DFT method employing the B3LYP hybrid func-
tional and 6-31G(d) basis sets. The C10H21O group was omitted and
replaced with a methoxyl group for these calculations. The TD-DFT
method was used to calculate the excitation energies, oscillator
strengths, and rotatory strengths at the B3LYP/6-31G(d) level. CD
spectra were generated using the rotatory strengths computed
with the dipole velocity form to which a Gaussian band-shape
was applied with 2500 cmꢁ1 as a half-height width.
Acknowledgments
Calculations were performed using the RIKEN Super Combined
Cluster (RSCC). The authors thank those administering these com-
putational facilities for the generous allocation of computer time.
11. (a) Bringmann, G.; Maksimenka, K.; Mutanyatta-Comar, J.; Knauer, M.; Bruhn,
T. Tetrahedron 2007, 63, 9810–9824; (b) Stephaens, P. J.; Devlin, F. J.; Schürch,
S.; Hulliger, J. Theor. Chem. Acc. 2008, 119, 19–28.
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