Identification of absolute helical structures of aromatic multilayered oligo(m-phenylurea)s in solution

Article abstract of DOI:10.1021/jo901934r

(Chemical Equation Presented) The oligomeric aromatic ureas bearing N,N′-dimethylated urea bonds such as 3 have aromatic multi-layered structure, based on the (cis,cis)-urea structure, and also have dynamic helical structure (all-R or all-S axis chirality) when the benzene rings are connected at the meta positions. The absolute helical structure of oligo(m-phenylurea)s were identified by the empirical and theoretical studies on the CD and vibrational CD (VCD) spectra. Thus, each enantiomer of the oligo(m-phenylurea)s 4 bearing a chiral N-2-(methoxyethoxyethoxy)propyl group were synthesized. Intense dispersion-type CD spectra of 4 were observed, which indicated the induction of handedness in the helical structure. In the VCD spectra of 4 in the film state, the signals due to the carbonyl and aromatic ring vibrations were seen with negative and positive values for compounds 4a and 4b, respectively. The calculations of both CD and VCD spectra of oligo(m-phenylurea)s 3 without any chiral N-substituent gave the same assignment about the axis chirality of 4. Thus, the absolute configurations of 4a and 4b are all-R and all-S structures, respectively. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901934r

pubs.acs.org/joc
Identification of Absolute Helical Structures of Aromatic Multilayered
Oligo(m-phenylurea)s in Solution
,^,#
Mayumi Kudo,† Takayuki Hanashima,‡ Atsuya Muranaka,*,§ Hisako Sato,
Masanobu Uchiyama,§ Isao Azumaya,z Tomoya Hirano,‡ Hiroyuki Kagechika,‡ and
Aya Tanatani*,†,^
†Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo
112-8610, Japan, ‡School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo
Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan, §Advanced
Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Faculty of
Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, ^PRESTO, Japan Science
and Technology Agency (JST), Japan, and zFaculty of Pharmaceutical Sciences at Kagawa Campus,
Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan. #Present address: Graduate
School of Science and Engineering, Ehime University.
atsuya-muranaka@riken.jp; tanatani.aya@ocha.ac.jp
Received September 22, 2009
The oligomeric aromatic ureas bearing N,N0-dimethylated urea bonds such as 3 have aromatic multi-
layered structure, based on the (cis,cis)-urea structure, and also have dynamic helical structure (all-R or
all-S axis chirality) when the benzene rings are connected at the meta positions. The absolute helical
structure of oligo(m-phenylurea)s were identified by the empirical and theoretical studies on the CD and
vibrational CD (VCD) spectra. Thus, each enantiomer of the oligo(m-phenylurea)s 4 bearing a chiral
N-2-(methoxyethoxyethoxy)propyl group were synthesized. Intense dispersion-type CD spectra of 4were
observed, which indicated the induction of handedness in the helical structure. In the VCD spectra of 4 in
the film state, the signals due to the carbonyl and aromatic ring vibrations were seen with negative and
positive values for compounds 4a and 4b, respectively. The calculations of both CD and VCD spectra of
oligo(m-phenylurea)s 3 without any chiral N-substituent gave the same assignment about the axis
chirality of 4. Thus, the absolute configurations of 4a and 4b are all-R and all-S structures, respectively.
Introduction
key roles in living systems.1 Therefore, many functional
polymers utilizing such structures have been synthesized,
not only to mimic biological compounds but also to develop
so-called intelligent materials.2 In addition to stable helical
The helix is a unique structural motif; for example, the
double helix of DNA and R-helical structure of proteins play
(1) (a) Watson, J. D.; Crick, F. H. C. Nature 1953, 171, 737–738.
(b) Branden, C.; Tooze, J. Introduction to Protein Structure; Garland:
New York, 1991.
(2) (a) Petka, W. A.; Hardin, J. L.; McGrath, K. P.; Wirtz, D.; Tirrell,
D. A. Science (Washington, D. C.) 1998, 281, 389–392. (b) Osada, Y.; Gong,
J.-P. Adv. Mater. 1998, 10, 827–837.
8154 J. Org. Chem. 2009, 74, 8154–8163
Published on Web 10/08/2009
DOI: 10.1021/jo901934r
r
2009 American Chemical Society

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FIGURE 1. Preference for cis conformation of aromatic N-methylated amides and ureas and their application to helix construction.
polymers with a rigid backbone, there is great interest in
polymers such as polyisocyanates,3 polysilanes,4 and poly-
acetylenes,5 which show rapid helical reversal and are classi-
fied as dynamic helical polymers.6 Induction of handedness
in such helical polymers has attracted widespread interest
because of its possible applications in optical devices or for
data storage7 and also because of its relevance to chiral
amplification, which may have occurred at the early stages
in the evolution of living things.8 Several methodologies have
been developed, including the introduction of optically
active side chains or the addition of chiral components
that interact with the polymers,9-11 though it remains still
difficult to identify strictly right- or left-handed helical
conformation, especially for the artificial polymers. We
previously reported that N-alkylated poly(p-benzamide)s
such as 1 (Figure 1) take a helical structure in solution.12
The proposed helical structure of N-alkylated aromatic
polyamides is clearly supported by the results of exciton
analysis of the electronic absorption and CD spectra of
polyamides bearing a chiral side chain on the nitrogen atom.
Recently, the assignment of absolute handedness of several
helical polymers were achieved.11,13-15
Monomeric or oligomeric folded components are neces-
sary to construct helical structure, and the helical oligomers
with dynamic behaviors are classified as foldamers.16 In the
case of polyamides 1, the helical conformation results from
the cis conformational properties of N-alkylated benzani-
lides (Figure 1). Benzanilide exists in trans form both in the
crystal and in solution, whereas N-methylbenzanilide exists
(3) (a) Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.;
Lifson, S. Science 1995, 268, 1860–1866. (b) Okamoto, Y.; Matsuda, M.;
Nakano, T.; Yashima, E. J. Polym. Sci., Part A: Polym. Chem. 1994, 32, 309–
315. (c) Mruk, R.; Zentel, R. Macromolecules 2002, 35, 185–192.
(4) Fujiki, M. J. Am. Chem. Soc. 2000, 122, 3336–3343.
(5) (a) Ciardelli, F.; Lanzillo, S.; Pieroni, O. Macromolecules 1974, 7, 174–
179. (b) Moore, J. S.; Gorman, C. B.; Grubbs, R. H. J. Am. Chem. Soc. 1991,
113, 1704–1712. (c) Yashima, E.; Huang, S.; Matsushima, T.; Okamoto, Y.
Macromolecules 1995, 28, 4184–4193. (d) Nomura, R.; Furushima, Y.;
Nakako, H.; Masuda, T. J. Am. Chem. Soc. 2000, 122, 8830–8836.
(6) (a) Maeda, K.; Yashima, E. Top. Curr. Chem. 2006, 265, 47–88. (b)
Yashima, E.; Maeda, K.; Furusho, Y. Acc. Chem. Res. 2008, 41, 1166-1180 and
references therein.
(12) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui,
C.; Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N.; Yokozawa, T.
J. Am. Chem. Soc. 2005, 127, 8553–8561.
(13) (a) van Beijnen, A. J. M.; Notle, R. J. M.; Drenth, W.; Hezemans, A.
M. F. Tetrahedron 1976, 32, 2017–2019. (b) Ito, Y.; Ihara, E.; Murakami, M.
Macromolecules 1992, 25, 6810–6813. (c) Takei, F.; Hayashi, H.; Onitsuka,
K.; Kobayashi, N.; Takahashi, S. Angew. Chem., Int. Ed. 2001, 40, 4092–
4094.
(7) Onouchi, H.; Miyagawa, T.; Furuko, A.; Maeda, K.; Yashima, E.
J. Am. Chem. Soc. 2005, 127, 2960–2965.
(8) (a) Wald, G. Ann. N.Y. Acad. Sci. 1957, 69, 352–368. (b) Avalos, M.;
(14) (a) Dong, Z.; Karpowicz, R. J. Jr.; Bai, S.; Yap, G. P. A.; Fox, J. M.
J. Am. Chem. Soc. 2006, 128, 14242–14243. (b) Dong, Z.; Yap, G. P. A.; Fox,
J. M. J. Am. Chem. Soc. 2007, 129, 11850–11853.
ꢀ
Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Chem. Commun. 2000,
887–892. (c) Buschmann, H.; Thede, R.; Heller, D. Angew. Chem. 2000, 112,
4197–4200. Angew. Chem., Int. Ed. 2000, 39, 4033-4035.
ꢀ
(15) (a) Dolain, C.; Jiang, H.; Leger, J.-M.; Guionneau, P.; Huc, I. J. Am.
(9) Yashima, E.; Maeda, K.; Furusho, Y. Acc. Chem. Res. 2008, 41, 1166–
1180.
Chem. Soc. 2005, 127, 12943–12951. (b) Buffeteau, T.; Ducasse, L.; Poniman,
L.; Delsuc, N.; Huc, I. Chem. Commun. 2006, 2714–2716.
(10) Yashima, E.; Maeda, K.; Okamoto, Y. Nature 1999, 399, 449–451.
(11) (a) Kawauchi, T.; Kitaura, A.; Kumaki, J.; Kusanagi, H.; Yashima,
E. J. Am. Chem. Soc. 2008, 130, 11889–11891. (b) Kawauchi, T.; Kumaki, J.;
Kitaura, A.; Okoshi, K.; Kusanagi, H.; Kobayashi, K.; Sugai, T.; Shinohara,
H.; Yashima, E. Angew. Chem., Int. Ed. 2008, 47, 515–519.
(16) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (b) Hill, D. J.;
Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101,
3893–4011. (c) Huc, I. Eur. J. Org. Chem. 2004, 17–29. (d) Foldamers:
Structure, Properties and Applications: Hecht, S. M., Huc, I., Eds.; Wiley-VCH:
Weinheim, Germany, 2007.
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SCHEME 1. Synthesis of Chiral 2-(Methoxyethoxyethoxy)propanols 5
in cis form in the crystal and predominantly in cis form in
solution.17 Thus, various well-known polyamides, such as
poly(p-phenylene terephthalamide) and poly(p-benzamide),
contain secondary amide bonds with trans conformation and
form hydrogen bonds between polymer chains to generate a
sheet structure (rod-like).18 On the other hand, the helical
structure of N-alkylated poly(p-benzamide)s 1 arises from
the inherent structural propensity of N-alkylated amide
bonds for folded cis conformation.12
the oligoureas could detect the chirality of the backbone.21
The NMR technique using such diastereotopicity is very
useful to evaluate the well-defined three-dimensional struc-
tures of foldamers. On the other hand, the detailed helical
structure of the oligo(m-phenylurea)s 3, especially the dis-
tinction of the enantiomeric isomers, remains an issue. Here
we report the helical structure of aromatic multilayered
oligoureas in solution and the identification of their absolute
structure based on empirical and theoretical studies of CD
and vibrational CD (VCD) spectra.
The cis conformational character induced by N-methyla-
tion is also observed in aromatic ureas (Figure 1).19,20 Thus,
N,N0-dimethyl-N,N0-diphenylurea exists in (cis,cis) confor-
mation, in which two phenyl rings lie in a face-to-face
position with a dihedral angle (∼30ꢀ) smaller than that of
N-methylbenzanilide (∼60ꢀ). As a result of the difference of
the two folded conformations in the dihedral angles between
aromatic rings, N-methylated oligo- and polyamides form
helical structures, whereas N,N0-dimethylated oligoureas 2
and 3 form aromatic multilayered structures. Further, when
the phenyl rings are connected by N,N0-dimethylurea bonds
at the meta position, the oligomers 3 shows well-ordered
helical structure based on the all-R or all-S axial chirality of
(cis,cis)-urea bonds in the crystal, in which both enantiomers
exist in a 1:1 ratio.20 In solution, the equilibrium between the
enantiomers is rather fast. Recently, Clayden et al. reported
that chiral or prochiral probes introduced at the terminal of
Results
1. Synthesis of Oligo(m-phenylurea)s with Chiral N-Sub-
stituents. To distinguish right- and left-handed helical struc-
tures of aromatic multilayered oligoureas, chiral side chains
were introduced into the urea bonds of 3. Since N-methy-
lated oligo(m-phenylurea)s have rather poor solubility,
we designed tetraureas 4a and 4b with two chiral
N-2-(methoxyethoxyethoxy)propyl groups on the two nitro-
gen atoms attached to the central benzene ring and N-n-
propyl groups on the other nitrogen atoms of the urea bonds.
The enantiomers of 2-(methoxyethoxyethoxy)propanol 5
were prepared via different synthetic routes (Scheme 1).
(S)-5 was synthesized from ethyl (S)-lactate as the starting
material by modification of the reported synthetic proce-
dures.22 After protection of the hydroxyl group, reduction of
the ester group of 6 afforded alcohol 7. Compound 7 was
benzylated, followed by deprotection of the THP group, and
then reacted with methoxyethoxyethyl tosylate to give 9,
which in turn was hydrogenated over Pd-C to afford (S)-5.
(R)-5 was prepared by a more convenient procedure from
(R)-1,2-propanediol. Protection of the primary hydroxyl
(17) (a) Kagechika, H.; Himi, T.; Kawachi, E.; Hashimoto, Y.; Shudo, K.
J. Med. Chem. 1989, 32, 2292–2296. (b) Itai, A.; Toriumi, Y.; Tomioka, N.;
Kagechika, H.; Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30, 6177–
6180. (c) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433–6442.
(18) (a) Northolt, M. G.; van Aartsen, J. J. J. Polym. Sci., Polym. Lett. Ed.
1973, 11, 333–337. (b) Northolt, M. G. Eur. Polym. J. 1974, 10, 799–804.
(c) Tashiro, K.; Kobayashi, M.; Tadokoro, H. Macromolecules 1977, 10,
413–420.
(19) Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito,
Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 5474–5475.
(20) Tanatani, A.; Kagechika, H.; Azumaya, I.; Fukutomi, R.; Ito, Y.;
Yamaguchi, K.; Shudo, K. Tetrahedron Lett. 1997, 38, 4425–4428.
ꢁ
(21) (a) Clayden, J.; Lemiegre, L.; Helliwell, M. J. Org. Chem. 2007, 72,
2302–2308. (b) Clayden, J.; Lemiegre, L.; Morris, G. A.; Pickworth, M.;
Snape, T. J.; Jones, L. H. J. Am. Chem. Soc. 2008, 130, 15193–15202.
(22) Prince, R. B.; Brunsveld, L.; Meijer, E. W.; Moore, J. S. Angew.
Chem., Int. Ed. 2000, 39, 228–230.
ꢁ
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SCHEME 2. Synthesis of Tetraureas 4 Bearing Chiral Substituents
TABLE 1. 1H NMR Chemical Shifts of Aromatic Protons of the Oligoureas in CDCl3
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
3 at rt
3 at 223 K
3 (calcd)a
6.89
6.89
6.94
6.99
6.98
6.94
7.15
6.94
6.92
6.95 t
6.91
6.70
6.66
6.48
7.09
6.60
6.55
6.62
6.57
6.04
5.88
5.66
6.42b
6.43b
6.76
6.72
6.72
6.94
6.33b
6.33b
6.68
6.04
5.86
5.67
6.33
6.33
6.65
6.72
6.72
6.88
4 at rt
6.85
6.83
6.85
6.83
5.92
5.73
5.99
5.82
6.40b
6.36b
6.33b
6.32b
6.63
6.61
6.60 t
6.59
6.29b
6.29b
6.20b
6.19b
6.27
6.29
6.52
6.44
6.52
6.45
4 at 243 K
17 at rt
17 at 243 K
6.21 br
6.08
5.93
6.21 br
6.15
6.10
aValues were calculated by the B3LYP/6-31G** method. bProton signals for H5 and H7 could not be distinguished from each other and are tentatively
assigned.
group of (R)-1,2-propanediol with monomethoxytrityl
Thus, m-phenylenediamine was converted to sulfonamide
12 by treatment with o-nitrobenzenesulfonyl chloride (NsCl).
Alkylation of 12 was carried out under Mitsunobu condi-
tions with each chiral 5. Removal of the o-nitrobenzenesul-
fonyl group of 13 was performed by treatment with PhSH
and Cs2CO3 to give 14. N-(Aminophenyl)-N0-phenyl-N,N0-
di(n-propyl)urea 15, prepared from m-nitroaniline in three
steps, was converted to the isocyanate by treatment with
triphosgene, followed by addition of 14 to give tetraurea 16.
The alkylation of two secondary nitrogen atoms by using
sodium hydride as a base afforded compounds 4.
chloride (MMTrCl) in the presence of tetrabutylammonium
iodide (TBAI) and N,N-diisopropylethylamine (DIEA) gave
monoalcohol 10. Compound 10 was reacted with methox-
yethoxyethyl tosylate, followed by deprotection to give (R)-
5. The optical purity of each enantiomer was confirmed by
the values of the angle of rotation.
Construction of aromatic tetraureas is shown in
Scheme 2. Introduction of each chiral substituent was per-
formed by means of Fukuyama’s nosyl methodology.23
The conformations of 4 in solution were examined by
(23) (a) Fukuyama, T.; Jow, C. -K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373–6374. (b) Fukuyama, T.; Cheung, M.; Jow, C. -K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831–5834.
1
means of H NMR spectroscopy (Table 1). Both 3 and 4
showed the signals of the aromatic protons at higher fields
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FIGURE 2. (a) X-ray and (b) optimized structures of N-methylated
oligo(phenylurea) 3 with all-R axis chirality.
(6.0-7.0 ppm) compared with the unfolded ureas (bearing
N-H atoms), as well as N,N0-dimethyl-N,N0-diphenylurea.
Comparison of the chemical shifts between these ureas
indicated that compounds 4 also exist predominantly in
aromatic multilayered structure with all-cis forms of the four
urea bonds, as observed in the crystal structure of 3.20,21 The
existence of minor conformers could not be observed at
lower temperature, possibly due to the lower rotational
barrier of the C-N bond, compared with aromatic amides
(Figure S2, Supporting Information).
FIGURE 3. (a) CD and (b) UV spectra of 4a in CH3CN.
2. Geometry Optimizations. To rationalize the relationship
between the spectral features and helical structure of the
oligo(phenylurea)s in solution, we performed geometry op-
timization calculation on N-methylated oligo(m-phenylurea)
(3) at the B3LYP/6-31G** level. The optimized conforma-
tion of the oligourea exhibits a helical structure with multi-
layered aromatic rings, as observed in the X-ray structure of
3.20 As shown in Figure 2, we found a close similarity
between the optimized and X-ray structures, but these
structures, especially their terminal geometries, do not
strictly match. This may arise from crystal packing forces,
which sometimes have considerable influence on the con-
FIGURE 4. Mirror-image CD spectra of 4a and 4b in (a) CH3CN
and (b) CHCl3 at 25 ꢀC.
intense dispersion-type CD spectra are not due to the
intrinsic chirality of the side chain of 4a but to an excess of
a single-handed helical structure of 4a.24
Compound 4b showed mirror-image CD spectrum
(Figure 4a). Similar mirror-image CD spectra were obtained
for 4a and 4b in CHCl3 (Figure 4b). To examine the effect of a
chiral N-substituent, the tetraurea with N-(R)-3,7-dimethy-
loctyl groups 17 (Figure 1) was synthesized. Compound 17
exhibited only very weak CD signals in acetonitrile (see
Figure S3, Supporting Information). Thus, the distance
between the chiral center of the N-substituent and the
aromatic multilayered structure is significant for the obser-
vation of CD signals.25 Further, the CD signals of oligoureas
4a and 4b were highly temperature-dependent,26 decreasing
with increasing temperature. This observation suggested that
1
formations of flexible molecules. When H NMR chemical
shifts were calculated for the optimized structure of 3 using
the B3LYP method, there was good agreement between
calculated and experimental shifts (Table 1). Therefore, it
can be concluded that the present oligoureas predominantly
adopt a helically stacked structure in solution.
3. UV and CD Spectra of Chiral Oligo(m-phenylurea)s. The
oligoureas 4 showed broad electronic absorption in the
190-310 nm region, which consisted apparently of a strong
absorption at 190-220 nm and absorption at 230-310 nm in
acetonitrile (Figure 3b). In the CD spectra of 4a, a
plus-minus pattern was detected in the region of 200-290
nm, viewing from longer wavelength. A very weak positive
signal was detected at 270-290 nm, with a strong negative
signal at 200-270 nm, and an intense positive signal at
190-200 nm (Figure 3a). Monomeric chromophore 13a
showed much weaker integral type CD signals, so that the
(24) Berova, N.; Nakanishi, K.; Woody, R. W. Circular Dichroism:
Principles and Applications, 2nd ed.; Wiley-VCH: New York, 2000.
(25) Nakako, H.; Mayahara, Y.; Nomura, R.; Tabata, M.; Masuda, T.
Macromolecules 2000, 33, 3978–3982.
(26) (a) Shinohara, K.; Yasuda, S.; Kato, G.; Fujita, M.; Shigekawa, H.
J. Am. Chem. Soc. 2001, 123, 3619–3620. (b) Morino, K.; Maeda, K.;
Okamoto, Y.; Yashima, E.; Sato, T. Chem.-Eur. J 2002, 8, 5112–5120.
(c) Tabei, J.; Nomura, R.; Masuda, T. Macromolecules 2003, 36, 573–577.
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Kudo et al.
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system are not chromophoric, the effect of the chiral chains
on the spectroscopic properties in the 200-350 nm range
should be negligible. From these results, induction of the
handedness of 4a and 4b resulted from the preferable all-R
and all-S conformations, respectively.
5. Vibrational CD Analysis. Comparison of empirically
and theoretically obtained CD spectra is a powerful tool to
identify the absolute structures of well-defined molecules.
Recently, infrared and vibrational CD (VCD) spectra have
proven to be useful for such purposes. There are many
reports on the VCD analysis of molecular chirality, though
most of them are studies on natural polymers such as
peptides and nucleic acid derivatives or small organic mole-
cules or inorganic compounds.29-31 Recently, the usefulness
of VCD analysis for some synthetic helical polymers was
reported.11,15b We then applied VCD analysis to our oligour-
ea system. The region (1500-1800 cm-1) corresponding to
the carbonyl C-O (ca. 1650 cm-1) and aromatic ring
(ca. 1600 cm-1) vibrations was examined, since the other
signals, especially in the fingerprint region, would overlap
with those derived from the chiral substituent. First, the
VCD spectra of compounds 4 in CDCl3 were examined.
However, the VCD intensity was very small, even after
10,000 accumulations, while the signals corresponding to
the aromatic ring vibrations reproducibly showed negative
and positive values for compounds 4a and 4b, respectively
(Figure S5, Supporting Information). Then, we examined
the VCD spectra of compounds 4 in the film state. To elimi-
nate minor absorption artifacts and increase the signal-to-
noise ratio, the sample was examined 10,000 times, and
the average VCD spectrum of the enantiomers was used as the
baseline (Figure 6a). In this case, clear signals due to the carbonyl
and aromatic ring vibrations were seen with negative and
positive values for compounds 4a and 4b, respectively. The
intensity of the VCD signal was different between 4a and 4b.
One possible reason was that the thickness of the films was
not uniform over the incident area, since they were prepared
by the cast method. The sign of each signal was the same as
that observed for the weak signal in CDCl3 solution.
FIGURE 5. Calculated spectra for the optimized structure of N-
methylated oligo(phenylurea) (3) with all-R axis chirality (a) and
1,3-diaminobenzene (b) obtained using the ZINDO/S method.
Gaussian bands with a half-bandwidth of 3000 cm-1 were used.
the predominant dynamic helicity of oligoureas 4 was in-
duced by the chiral side chains. The CD magnitude of 4
showed almost linear correlation with temperature in the
examined range of temperature. The conversion between two
helices would exist at the temperature. Further study at lower
temperature will be needed to clarify the dynamic behaviors
of 4 in solution.
4. Calculated UV and CD Spectra. We employed the
semiempirical ZINDO/S method to calculate the UV and
CD spectra of the oligo(phenylurea)s. The ZINDO method
was chosen to obtain results in a reasonable computational
time.27 Lewis et al. have applied this method to interpret the
electronic excited states of tertiary naphthyl oligoarylur-
eas.28 Figure 5a shows the simulated spectra of the optimized
structure of 3 with all-R axial chirality. The UV spectrum of
1,3-diaminobenzene was also calculated for comparison
(Figure 5b). As can be seen from the figures, the appearance
of the calculated UV spectra of both the monomeric unit and
the oligo(phenylurea) is in close agreement with the spectral
features observed for 13a and 4. As for the simulated CD
spectrum, 3 with all-R axial chirality was calculated to have
intensely negative CD signals corresponding to a less intense
absorption band in the 230-260 nm region, reproducing well
the observed spectral features of 4a. Negative CD signals
were also predicted on the basis of the X-ray structure of 3
with all-R axial chirality (Figure S4, Supporting
Information). Because the chiral side chains in the present
To assign the configuration, the VCD for compound 3
with all-R axis chirality was calculated at the B3LYP/6-
31G** level (Figure 6c). Comparison of the bands corre-
sponding to the carbonyl or aromatic region in the empirical
and calculated results showed that the calculated VCD
spectrum of 3 with all-R chirality has negative bands similar
to those of compound 4a with the (S)-substituent. To
(29) (a) Nafie, L. A.; Cheng, J. C.; Stephene, P. J. J. Am. Chem. Soc. 1975,
97, 3842–3843. (b) Nafie, L. A.; Keoderling, T. A.; Stephens, P. J. J. Am.
Chem. Soc. 1976, 98, 2715–2723.
(30) Recent selected papers for VCD. (a) Shanmugam, G.; Polavarapu,
P. L. J. Am. Chem. Soc. 2004, 126, 10292–10295. (b) Bour, P.; Keiderling, T.
ꢀ
A. J. Phys. Chem. B 2005, 109, 23687–23687. (c) Buffeteau, T.; Lagugne-
Labarthet, F.; Sourisseau, C. Appl. Spectrosc. 2005, 59, 732–745. (d) Shan-
mugam, G.; Polavarapu, P. L. Appl. Spectrosc. 2005, 59, 673–681. (e)
Petrovic, A. G.; Polavarapu, P. L. J. Phys. Chem. B 2006, 110, 22826–
22833. (f) Monde, K.; Miura, N.; Hashimoto, M.; Taniguchi, T.; Inabe, T. J.
€
Am. Chem. Soc. 2006, 128, 6000–6001. (g) Gartier, C.; Burgi, T. J. Am. Chem.
Soc. 2006, 128, 11079–11087. (h) Losada, M.; Xu, Y. Phys. Chem. Chem.
ꢀ
ꢂ €
Phys. 2007, 9, 3127–3135. (i) Setnicka, V.; Novy, J.; Bohm, S.; Sreeniva-
(27) (a) Anderson, W. P.; Edwards, W. D.; Zerner, M. C. Inorg. Chem.
1986, 25, 2728–2732. (b) Telfer, S. G.; Tajima, N.; Kuroda, R. J. Am. Chem.
Soc. 2004, 126, 1408–1418. (c) Petrovic, A. G.; Polavarapu, P. L. J. Phys.
ꢀ
Chem. B 2005, 109, 23698–23705. (d) Maheut, G.; Castaings, A.; Pecaut, J.;
Lawson Daku, M. L.; Pescitelli, G.; Di Bari, L.; Marchon, J.-C. J. Am. Chem.
Soc. 2006, 128, 6347–6356.
(28) Santos, G. B. D.; Lewis, F. D. J. Phys. Chem. A 2005, 109, 8106–
8112.
ꢀ
sachary, N.; Urbanova, M.; Volka, K. Langmuir 2008, 24, 7520–7527.
(j) Debie, E.; Butinck, P.; Herrebout, W.; van der Veken, B. Phys. Chem.
Chem. Phys. 2008, 10, 3498–3508. (k) Sato, H.; Hori, K.; Sakurai, T.;
Yamagishi, A. Chem. Phys. Lett. 2008, 467, 140–143. (l) Nicu, V. P.;
Neugebauer, J.; Baerends, E. J. J. Phys. Chem. A 2008, 112, 6978–6991.
(31) Sato, H.; Taniguchi, K.; Nakahashi, A.; Monde, K.; Yamagishi, A.
Inorg. Chem. 2007, 46, 6755–6766. and references therein.
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FIGURE 6. VCD (a) and IR (b) spectra of 4a (blue line) and 4b (red line). Calculated VCD (c) and IR (d) spectra of 3 with all-R axis chirality.
No correction of introducing a scale factor was made in the calculated spectra.
examine the effect of a chiral N-substituent on the vibration
of the carbonyl groups or aromatic rings, we calculated the
IR and VCD spectra of compound 18, an analogue of 3
bearing two N-(S)-2-methoxy-1-propyl substituents (Figure
S6, Supporting Information) and obtained similar results.
Thus, the assignment of the absolute structure by VCD
analysis was identical to that by CD analysis.
of 4a and 4b are all-R and all-S conformations, respectively.
The results indicate that VCD analysis is useful to analyze
the conformation and configuration of macromolecules of
this type.11,15
The CD spectra of 4 were strongly temperature-depen-
dent, as is the case for polyamides 1. Introduction of only two
chiral N-substituents is enough for the induction of handed-
ness, while the distance of the chiral center of the substituent
from the oligo(m-phenylurea) backbone seemed important,
deduced from the comparison of CD spectra of 4 and 17.
Clayden et al. reported that a diastereotopic probe at the
terminal benzene ring of N-methylated oligo(m-phenylurea)s
could distinguish the prochirality even when separated by 24
bond lengths (corresponding to the tetraureas), though long-
er distances diminished the effect.21 Overall, the results
indicate that N-alkylated oligo(m-phenylurea)s have dy-
namic helical properties in solution.
In conclusion, the N-alkylated oligo(m-phenylurea)s have
helical conformations in solution, and handedness could be
induced by the introduction of chiral N-substituents. The
absolute structures of the helices in 4 were determined from
the CD and VCD spectra. Since N-alkylated oligo(m-
phenylurea)s have both dynamic helical and aromatic multi-
layered properties, these systems should be applicable to
construct aromatic functional molecules with unique phys-
icochemical properties.
Discussion
The cis conformational preference of aromatic N-methy-
lated amide, urea, and related compounds affords folded
aromatic structures that are useful as monomer units to
construct helical foldamers.16 In contrast to the polyamides
1, in which the phenyl ring is oriented parallel to the helical
axis with three monomer units per turn,12 N-alkylated oligo-
(m-phenylurea)s such as 3 are expected to adopt a helical
conformation in which the phenyl ring is arranged vertical to
the helical axis. As observed in the crystal of 3, configura-
tions of the axis chirality were consistent (all-R or all-S),
probably due to steric hindrance. In solution, the origoureas
such as 3 exist mainly in the folded structures as observed in
the crystal, which was deduced from 1H NMR chemical
shifts (Table 1) and NOE study (data not shown), as dis-
cussed by us20 and Clayden et al.21 1H NMR spectra of 3, 4,
and 17 even at 223 K did not show any signals corresponding
to the possible minor conformers. Further, the addition of
some chiral reagents could not distinguish the two folded
Experimental Section
1
conformers (all-R and all-S) of 3 at 223 K in H NMR.20
Synthesis of 6. Pyridinium toluene-p-sulfonate (0.245 g,
0.98 mmol) was added to a solution of ethyl (S)-(-)-lactate
(30.21 g, 256 mmol) and 3,4-dihydro-2H-pyran (27.72 g,
330 mmol) in dry CH2Cl2 (340 mL), and the mixture was stirred
overnight at room temperature. The reaction mixture was
washed with saturated NaHCO3 and dried over sodium sulfate.
After evaporation, the residue was distilled (64 ꢀC at 1 Torr) to
yield 6 (47.07 g, 91%) as a mixture of two diastereomers (ratio is
1:1): 1H NMR (600 MHz, CDCl3) δ 4.72 (t, 1 H, J = 3.6 Hz),
4.70 (t, 1 H, J = 3.6 Hz), 4.42 (q, 1 H, J = 7.0 Hz), 4.16-4.23
(m, 5 H), 3.91-3.95 (m, 1 H), 3.83-3.87 (m, 1 H), 3.50-3.54
(m, 1 H), 3.44-3.48 (m, 1 H), 1.84-1.89 (m, 2 H), 1.67-1.79
(m, 4H), 1.52-1.61 (m, 6 H), 1.46 (d, 3 H, J= 6.9 Hz), 1.40 (d, 3 H,
J = 6.9 Hz), 1.28 (t, 3 H, J = 7.3 Hz), 1.27 (t, 3 H, J = 7.3 Hz).
Therefore, the conversion between the enantiomeric helices
of 3 seems to be quite fast in solution, although it would
require the inversion of all axis chirality.
In the present study, chiral substituents were introduced at
the two nitrogen atoms of the central benzene rings of the N-
alkylated oligo(m-phenylurea) structure. The presence of
aromatic layered structures of 4 was indicated by 1H NMR
analysis, and the induction of handedness could be observed
clearly in the CD spectra and also in the VCD spectra. The
calculations about both CD and VCD spectra on N-alky-
lated oligo(m-phenylurea)s gave the same results for the
absolute configuration of 4, that is, the preferable structure
8160 J. Org. Chem. Vol. 74, No. 21, 2009

Kudo et al.
JOCArticle
Synthesis of 7. A solution of 6 (30.44 g, 151 mmol) in ether
(150 mL) was added dropwise to an ice cooled solution of
LiAlH4 (12.65 g, 333 mmol) in dry ether (300 mL) under Ar
atmosphere over 1 h. The reaction mixture was stirred for 1.5 h,
and saturated aqueous ammonium chloride (80 mL) was added.
Precipitated salts were filtered off and washed well with ether.
The combined organic layers were dried over magnesium sulfate
and filtered. Evaporation afforded crude 7 (23.28 g, 96%) as a
mixture of two diastereomers (ratio is 1:0.6): 1H NMR (600
MHz, CDCl3) δ 4.74 (dd, 0.6 H, J = 5.2, 2.7 Hz), 4.55 (m, 1 H),
3.98-4.01 (m, 1 H), 3.93-3.96 (m, 0.6 H), 3.86-3.91 (m, 0.6 H),
3.80-3.85 (m, 1 H), 3.67 (dd, 1 H, J = 9.4, 2.9 Hz), 3.59 (m, 0.6
H), 3.45-3.57 (m, 3.2 H), 2.22 (dd, 0.6 H, J = 7.6, 5.2 Hz),
1.72-1.87 (m, 3.6 H), 1.52-1.62 (m, 7 H), 1.22 (d, 1.8 H, J = 6.5
Hz), 1.14 (d, 3 H, J = 6.5 Hz).
Synthesis of 8. A solution of t-BuOK (49.24 g, 439 mmol) in
t-BuOH (450 mL) was added dropwise to 7 (23.28 g, 146 mmol).
The solution was stirred for 2 h, concentrated in vacuo, and
subsequently diluted with dioxane (150 mL). A catalytic amount
of tetrabutylammonium chloride (1.28 g, 4.61 mmol) was added
after which benzyl chloride (55 mL, 434 mmol) was added
dropwise at room temperature. The mixture was heated at 80 ꢀC
for 1 h. Upon reaction completion, water was added, and the
mixture was extracted with ether twice. The organic layers were
combined, washed with water and brine, dried over magnesium
sulfate, and concentrated in vacuo leaving a yellow oil. Distilla-
tion (104-114 ꢀC at 1 Torr) afforded (S)-1-benzyloxy-2-pro-
pane tetrahydropyran-2-yl ether (34.34 g, 94%).
and N,N-diisopropylethylamine (23.5 mL, 137 mmol) in dry
dichloromethane (155 mL) at 0 ꢀC, and the mixture was stirred
for 2.5 h at room temperature. The reaction mixture was poured
into water, and extracted with dichloromethane. The organic
layer was washed with brine, dried over magnesium sulfate, and
filtered. After evaporation, residue was purified by silica gel
column chromatography (ethyl acetate/hexane 1:3) to give 10
(16.1 g, 46.1 mmol, 88%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 7.2 Hz, 4 H), 7.31 (d, J = 8.8 Hz, 2 H),
7.30 (t, J = 7.2 Hz, 4 H), 7.23 (tt, J = 2.4, 7.2 Hz, 2 H), 6.24
(dt, J = 2.4, 7.2 Hz, 2 H), 3.98 (m, 1 H), 3.80 (s, 3 H), 3.13 (dd,
J = 3.6, 9.2 Hz, 1 H), 2.98 (dd, J = 8.0, 9.2 Hz, 1 H), 2.37 (br d,
J = 2.4 Hz, 1 H), 1.10 (d, J = 6.4 Hz, 3 H). 13C NMR (150 MHz,
CDCl3) δ 158.7, 144.5, 144.5, 135.7, 130.5, 128.5, 128.0, 127.1,
113.3, 86.5, 69.0, 67.2, 55.4, 19.1. HRMS (ESIþ) calcd for
C23H24NaO3 (Mþ þ Na) 371.1618, found 371.1609.
Synthesis of 11. A solution of 10 (16.1 g, 46.1 mmol) in dry
DMF (50 mL) was added to a suspension of sodium hydride
(60%, 2.76 g, 6.90 mmol, washed with hexane twice) in dry
DMF (50 mL) at 0 ꢀC. After stirring for 1 h at room tempera-
ture, a solution of 2-(methoxyethoxy)ethyl tosylate (22.8 g, 83.0
mmol) in dry DMF was added to the mixture at 0 ꢀC, and the
mixture was heated at 60 ꢀC for 2 h. The solvent was removed in
vacuo, poured into water, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium
sulfate, and filtered. After evaporation, residue was purified by
silica gel column chromatography (ethyl acetate/hexane 3:1) to
give 11 (11.9 g, 26.5 mmol, 57%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.46 (dd, J = 1.6, 8.0 Hz, 4 H), 7.33 (dt, J = 2.0,
8.8 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 4 H), 7.21 (tt, J = 2.4, 7.2 Hz, 2
H), 6.82 (dt, J = 2.4, 8.8 Hz, 2 H), 3.79 (s, 3 H), 3.70 (m, 2 H),
3.65 (m, 5 H), 3.53 (m, J = 2 H), 3.36 (s, 3 H), 3.19 (dd, J = 6.0,
10.0 Hz), 2.96 (dd, J = 5.2, 9.2 Hz, 1 H), 1.15 (d, J = 6.4 Hz, 3
H). 13C NMR (150 MHz, CDCl3) δ 158.6, 144.9, 144.8, 136.0,
130.5, 128.6, 127.9, 126.9, 113.1, 86.3, 75.7, 72.1, 71.1, 70.1, 69.0,
67.5, 59.2, 55.3, 17.9. HRMS (ESIþ) calcd for C28H34NaO5
(Mþ þ Na) 473.2298, found 473.2308.
p-TsOH H2O (1.18 g, 137 mmol) was added to an ice cooled
3
solution of (S)-1-benzyloxy-2-propane tetrahydropyran-2-yl
ether (34.34 g, 137 mmol) in methanol (150 mL). The solution
was subsequently stirred at room temperature overnight. After
addition of NaHCO3, dihydropyran were evaporated. The resi-
due was extracted with ether, dried over magnesium sulfate, and
filtered. After evaporation, the crude yellow product was distilled
1
(77-81 ꢀC at 1 Torr) to give 8 (15.01 g, 66%): H NMR (500
MHz, CDCl3) δ 7.28-7.38 (m, 5 H), 4.56 (t, 2 H, J = 12 Hz),
3.97-4.04 (m, 1 H), 3.48 (dd, 1 H, J = 9.3, 3.0 Hz), 3.29 (dd, 1 H,
J= 9.3, 8.2 Hz), 2.40 (d, 1 H, J=3.2Hz), 1.15(d, 3H, J= 6.3Hz).
Synthesis of 9. A mixture of 8 (16.45 g, 0.099 mol),
2-(methoxyethoxy)ethyl tosylate (38.20 g, 0.139 mol), and po-
tassium hydroxide (18.43 g, 0.328 mol) in THF (200 mL) was
heated under reflux for 24 h under Ar atmosphere. Subsequently
water (40 mL) was added to hydrolyze excess tosylate. The
reaction mixture was extracted with dichloromethane, dried
over magnesium sulfate, and filtered. Evaporation of the solvent
gave the crude yellow product, which was distilled (117-132 ꢀC
at 1 Torr) to give 9 as a colorless oil (13.35 g). The distillation
residue was chromatographed on silica gel (ethyl acetate/hexane
Synthesis of (R)-5. (()-10-Camphorsulfonic acid (677 mg,
2.91 mmol) was added to a solution of 11 (11.9 g, 26.5 mmol) in
dry methanol (60 mL) at 0 ꢀC, and the mixture was stirred for
2.5 h at room temperature. After addition of triethylamine
(10 mL) at 0 ꢀC, the solvent was removed in vacuo. The residue
was purified by silica gel column chromatography (ethyl acet-
ate/hexane 2:1) to give (R)-5 (3.56 g, 20.0 mmol, 75%) as a
colorless oil. (R)-5: 1H NMR (400 MHz, CDCl3) δ 3.79 (m, 1 H),
3.60 (m, 9 H), 3.44 (dd, J = 8.0, 11.6 Hz, 1 H), 3.38 (s, 3 H), 2.32
(br s, 1 H), 1.11 (d, J = 6.4 Hz, 3 H). [R]D -25.8ꢀ (CHCl3).
Synthesis of 12. 2-Nitrobenzenesulfonyl chloride (12.0 g, 54.0
mmol) was added to a solution of m-phenylenediamine (2.53 g,
23.4 mmol) in dry pyridine (15 mL) at 0 ꢀC, and the mixture was
stirred for 3 h at room temperature. The raction mixture was
poured into 1 M hydrochloric acid and extracted with dichlor-
omethane. The organic layer was washed with brine, dried over
magnesium sulfate, and filtered. The solvent was removed in
vacuo to afford 12 (8.16 g, 17.1 mmol, 74%) as an orange
powder: 1H NMR (400 MHz, DMS0-d6) δ 10.78 (s, 2 H), 7.98
(d, J = 7.3 Hz, 2 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.84 (t, J = 7.8
Hz, 2 H), 7.75 (t, J = 7.8 Hz, 2 H), 7.15 (t, J = 8.3 Hz, 1 H), 7.03
(br t, 1 H), 6.82 (dd, J = 2.0, 8.3 Hz, 2 H). 13C NMR (150 MHz,
DMS0-d6) δ 147.8, 137.6, 134.8, 132.5, 131.1, 130.2, 129.9,
124.8, 116.2, 111.7. HRMS (ESIþ) calcd for C18H13N4O8S2
(Mþ - H) 477.0169, found 477.0171.
1
1:2) to afford 8.17 g of 9 (totally 65%): H NMR (600 MHz,
CDCl3) δ 7.34 (d, 4 H, J = 4.5 Hz), 7.26-7.30 (m, 1 H), 4.57 (d, 1
H, J = 12 Hz), 4.54 (d, 1 H, J = 12 Hz), 3.67-3.71 (m, 3 H),
3.63-3.66 (m, 4 H), 3.53-3.54 (m, 2 H), 3.51 (dd, 1 H, J = 10,
5.8 Hz), 3.42 (dd, 1 H, J = 10, 4.6 Hz), 3.37 (s, 3 H), 1.18 (d, 3 H,
J = 6.2 Hz).
Synthesis of (S)-5. Compound 9 (2.027 g, 7.6 mmol) was
dissolved in ethanol (20 mL) and acidified with concentrated
hydrochloride (2 drops). A catalytic amount of 10% Pd-C
(0.216 g) was added to the solution, and hydrogenation was carried
out at 40 ꢀC. After filtration and evaporation of the solvents, the
crude was distilled to give pure (S)-5 as a colorless oil (1.289 g,
95%): 1H NMR (400 MHz, CDCl3) δ 3.79 (m, 1 H), 3.60 (m, 9 H),
3.44 (dd, J = 8.0, 11.6 Hz, 1 H), 3.38 (s, 3 H), 2.32 (br s, 1 H), 1.11
(d, J = 6.4 Hz, 3 H). HRMS (ESIþ) calcd for C8H18NaO4 (Mþ þ
Na) 201.1097, found 201.1093. [R]D þ22.1ꢀ (CHCl3).
Synthesis of 13a. Diethyl azodicarboxylate (40% in toluene,
3.45 g, 7.93 mmol) was added to a solution of 12 (1.79 g, 3.74
mmol), (S)-5 (1.29 g, 7.24 mmol), and triphenylphosphine
(2.03 g, 7.74 mmol) in dry THF (30 mL) under Ar atmosphere
at 0 ꢀC. After stirring for 3 h at room temperature, the solvent
was removed in vacuo. The residue was used for the next
Synthesis of 10. 4-Methoxytrityl chloride (17.9 g, 57.9 mmol)
was added to a solution of (R)-1,2-propanediol (3.85 mmol,
52.6 mmol), tetrabutylammonium iodide (1.94 g, 5.26 mmol),
J. Org. Chem. Vol. 74, No. 21, 2009 8161

Kudo et al.
JOCArticle
reaction without further purification. 13a: 1H NMR (400 MHz,
CDCl3) δ 7.61 (m, 8 H), 7.27 (m, 3 H), 7.04 (s, 1 H), 3.54 (m, 22
H), 3.35 (s, 6 H), 1.12 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz,
CDCl3) δ 148.1, 140.0, 133.9, 131.9, 131.6, 131.5, 129.8, 129.7,
129.5, 123.9, 74.4, 72.1, 70.7, 70.7, 68.2, 59.2, 56.9, 17.7. HRMS
1,2-dichloroethane (3.5 mL) at 0 ꢀC. After 1 h, triethylamine
(0.1 mL, 1.5 equiv) and then 13a (106 mg, 0.25 mmol) were
added to the reaction mixture at 0 ꢀC, and the whole was stirred
for 12 h at room temperature. After evaporation, the residue was
diluted with ethyl acetate and filtered to remove triethylamine
hydrochloride. The filtrate was purified by silica gel column
chromatography (ethyl acetate/hexane 3:1) to give 16a (139 mg,
0.13 mmol, 25%) as a colorless foam: 1H NMR (400 MHz,
CDCl3) δ 7.46 (t, J = 8.0 Hz, 1 H), 7.34-7.26 (m, 3 H), 7.00
(t, J = 7.6 Hz, 4 H), 6.89 (t, J = 7.6 Hz, 2 H), 6.86 (d, J = 6.4 Hz,
4 H), 6.82 (s, 2H), 6.74 (d, J = 7.6 Hz, 4 H), 6.36 (d, J = 6.4 Hz, 2
H), 3.84-3.44 (m, 32 H), 3.29 (s, 6 H), 1.58-1.52 (m, 6 H), 1.18
(d, J = 6.4 Hz, 6 H), 0.85 (t, J = 7.2 Hz, 6 H), 0.83 (t, J = 7.2 Hz,
6 H). 13C NMR (100 MHz, CDCl3) δ 160.4, 154.7, 144.7, 144.3,
144.2, 139.4, 130.4, 128.3, 128.3, 127.0, 126.4, 125.7, 124.5,
121.3, 117.9, 115.7, 77.2, 75.4, 71.9, 70.6, 70.4, 68.3, 59.0, 56.0,
53.4, 53.3, 21.6, 21.5, 17.3, 11.5, 11.5. HRMS (ESIþ) calcd for
C62H86N8NaO10 (Mþ þ Na) 1125.6359, found 1125.6327.
Synthesis of 4a. A solution of 16a (134 mg, 0.12 mmol) in
DMF (2.5 mL) was added to a suspension of sodium hydride
(22.4 mg, 4.7 equiv, washed with hexane twice) in DMF (1.5 mL)
at 0 ꢀC, and the mixture was stirred at room temperature for 20
min. 1-Bromopropane (0.1 mL, 9.3 equiv) was added to the
mixture at room temperature, and the whole was stirred for 12 h.
After removal of the solvent in vacuo, the residue was poured
into water and extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate, and
filtered. After evaporation, the residue was purified by prepara-
tive thin-layer chromatography to give 4a (16 mg, 0.013 mmol,
11%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 6.94
(t, J = 7.6 Hz, 4 H), 6.85 (t, J = 7.6 Hz, 2 H), 6.65 (t, J = 7.6 Hz,
2 H), 6.60 (d, J = 8.0 Hz, 4 H), 6.51 (t, J = 7.6 Hz, 1 H), 6.39 (br
d, J = 7.6 Hz, 2 H), 6.28 (br s, 1 H), 6.27 (d, J = 7.6 Hz, 4 H),
5.90 (s, 2 H), 3.7-3.54 (m, 20 H), 3.47-3.30 (m, 6 H), 3.39 (s, 6
H), 3.20-3.10 (m, 8 H), 1.52-1.35 (m, 12 H), 1.10 (t, J = 6.0 Hz,
6 H), 0.87 (t, J = 7.6 Hz, 6 H), 0.84 (t, J = 7.6 Hz, 6 H), 0.82
(t, J = 7.6 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 160.1,
159.2, 145.8, 144.9, 144.3, 144.2, 128.3, 127.8, 126.5, 124.8,
123.6, 123.3, 123.3, 123.2, 122.2, 73.8, 72.0, 70.8, 70.6, 67.7,
59.0, 57.5, 53.4, 21.59, 21.56, 21.51, 17.8, 11.4, 11.4, 11.3. HRMS
(ESIþ) calcd for C68H98N8NaO10 (Mþ þ Na) 1209.7298, found
1209.7252.
(ESIþ) calcd for C34H46N4NaO14S (Mþ þ Na) 821.2344,
2
found 821.2366.
Synthesis of 14a. A solution of crude 13a (1.06 g, 1.33 mmol)
in acetonitrile (5 mL) was added to a solution of benzenethiol
(0.3 mL, 2.4 equiv) and cesium carbonate (1.33 g, 3.1 equiv) in
acetonitrile (5 mL), and the mixture was refluxed for 12 h. The
reaction mixture was allowed to cool to room temperature,
diluted with water, and extracted with ethyl acetate twice. The
organic layer was washed with brine, dried over magnesium
sulfate, and filtered. After the solvent was removed in vacuo, the
residue was purified by silica gel column chromatography
(hexane/ethyl acetate 1:2, then ethyl acetate) to give 14a (322
mg, 69% from 12) as an orange oil: 1H NMR (400 MHz, CDCl3)
δ 6.96 (t, J = 8.0 Hz, 1 H), 6.02 (dd, J = 2.0, 8.4 Hz, 2 H), 5.92
(s, 1 H), 3.77-3.64 (m, 18 H), 3.39 (s, 6 H), 3.19 (dd, J = 3.6, 12.4
Hz, 2 H), 3.03 (dd, J = 7.6, 12.4 Hz, 2 H), 1.21 (d, J = 6.4 Hz, 6
H). 13C NMR (150 MHz, CDCl3) δ 149.6, 130.0, 103.5, 98.2,
74.5, 72.1, 70.9, 70.7, 68.1, 59.2, 49.4, 18.0. HRMS (ESIþ) calcd
for C22H41N2O6 (Mþ þ H) 429.2959, found 429.2968.
Synthesis of 15. Phenyl isocyanate (7.4 mL, 68.3 mmol) was
added to a solution of m-nitroaniline (9.33 g, 67.6 mmol) in THF
at room temperature. After 1 h, the solvent was removed in
vacuo. The residue was washed with ethyl acetate to afford
N-phenyl-N0-(3-nitrophenyl)urea (16.2 g, 63.0 mmol, 93%): 1H
NMR (400 MHz, CDCl3) δ 9.19 (s, 1 H), 8.82 (s, 1 H), 8.55
(t, J = 2.2 Hz, 1 H), 7.81 (dd, J = 7.8, 2.4 Hz, 1 H), 7.70 (d, J =
6.8 Hz, 1 H), 7.56 (t, J = 8.2 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 2 H),
7.29 (t, J = 8.0 Hz), 6.99 (t, J = 6.8 Hz, 1 H).
A solution of N-phenyl-N0-(3-nitrophenyl)urea (264 mg,
1.02 mmol) in THF (5 mL) was added to a suspension of sodium
hydride (60%, 230 mg, 5.75 mmol, washed with hexane twice) in
THF (3 mL) at 0 ꢀC. After 30 min of stirring for at room
temperature, 1-bromopropane (0.90 mL, 9.99 mmol) was added
to the mixture at 0 ꢀC, and the mixture was refluxed for 12 h. The
solvent was removed in vacuo, poured into water, and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over magnesium sulfate, and filtered. After evaporation,
residue was purified by silica gel column chromatography (ethyl
acetate/hexane 1:5) to give N,N0-di-n-propyl-N-phenyl-N0-(3-
nitrophenyl)urea (66 mg, 0.194 mmol, 19%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 2.0, 8.4 Hz, 1 H), 7.52
(t, J = 2.0 Hz, 1 H), 7.17 (t, J = 8.4 Hz, 1 H), 7.06 (dd, J = 0.8,
7.2 Hz, 1 H), 7.00 (t, J = 8.0 Hz, 2 H), 6.89 (t, J = 7.2 Hz, 1 H),
6.89 (d, J = 7.2 Hz, 2 H), 3.56 (t, J = 8.0 Hz, 4 H), 1.61 (sextet,
J = 8.0 Hz, 4 H), 0.90 (t, J = 7.6 Hz, 6 H).
Compound 4b was prepared similarly by the synthetic meth-
ods of 4a from 12 using (R)-5.
Computational Details. All computations were performed
using Gaussian 03 package of programs.32 Geometry optimiza-
tions of N-methylated oligo(phenylurea) (3) and 1,3-diamino-
benzene were carried out with constrained C2 and C2v symmetry.
B3LYP hybrid functional was used with the 6-31G** basis sets.
NMR properties were calculated using the GIAO-B3LYP/
6-31G** method. The calculated chemical shifts were analyzed
by subtracting the isotropic shift for each hydrogen atom from the
corresponding shift for TMS calculated using the same method
(31.7551 ppm). The semiempirical ZINDO/S calculations were
performed to obtain the excitation energies, oscillator strengths,
and rotatory strengths. The transition velocity form was used to
calculate rotatory strengths. Calculated absorption and CD
curves were generated by superimposing Gaussian bands with
a half-bandwidth of 3000 cm-1 for each transition. The IR and
VCD spectra were calculated according to the magnetic field
perturbation (MFP) theory.
A solution of N,N0-di-n-propyl-N-phenyl-N0-(3-nitrophenyl)-
urea (7.87 g, 23.1 mmol) in methanol (50 mL) was hydrogenated
with Pd-C (10%, 1.52 g) for 1.5 h at room temperature. The
reaction mixture was filtered on Celite, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (ethyl acetate/hexane 1:2) to give 15 (6.65 g, 21.4
1
mmol, 93%): H NMR (400 MHz, CDCl3) δ 7.03 (t, J = 7.2
Hz, 2 H), 6.94 (t, J = 7.2 Hz, 1 H), 6.76 (t, J = 8.0 Hz, 1 H), 6.75
(d, J = 7.2 Hz, 2 H), 6.25 (dd, J = 2.0, 8.0 Hz, 1 H), 6.12 (dd, J =
2.0, 8.0 Hz, 1 H), 5.98 (t, J = 2.0 Hz, 1 H), 3.50 (t, J = 7.6 Hz, 2
H), 3.45 (t, J = 7.6 Hz, 2 H), 1.57 (sextet, J = 7.6 Hz, 2 H), 1.56
(sextet, J = 7.2 Hz, 2 H), 0.87 (t, J = 7.6 Hz, 3 H), 0.86 (t, J =
7.6 Hz, 3 H). 13C NMR (150 MHz, CDCl3) δ 160.8, 146.7, 145.5,
144.5, 129.1, 128.4, 127.2, 124.8, 117.5, 113.9, 111.8, 53.5, 53.4,
21.7, 21.7, 11.6. HRMS (ESIþ) calcd for C19H25N3NaO (Mþ þ
Na) 334.1890, found 334.1898.
VCD Spectra. The VCD spectra were recorded with a spectro-
meter PRESTO-S-2007 (JASCO, Japan). The absorption sig-
nals were detected using a liquid nitrogen cooled MCT infrared
detector equipped with ZnSe windows. Spectra were recorded at
Synthesis of 16a. Compound 15 (157 mg, 0.50 mmol) was
added to a solution of triphosgene (49.9 mg, 0.33 equiv) in
(32) Frisch, M. J. et al. Gaussian 03, revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004.
8162 J. Org. Chem. Vol. 74, No. 21, 2009

Kudo et al.
JOCArticle
4 cm-1 resolution. Signals were accumulated for 104 scans
in about 2 h. The FT-IR absorbance was adjusted below 1.0
in order to attain the optimal signal-to-noise ratio in the
VCD measurements. A film sample for VCD measurements
was prepared in the following way: first the weighed amount
(ca. 5 mg) of the enantiomeric sample was dissolved in CDCl3
(ca. 200 μL) . Thereafter about 40 μL of the solution was cast on
a CaF2 plate to prepare a transparent thin film with an area of
ca. 2 cm2.
and Culture, Japan. A.T. thanks The Asahi Glass Founda-
tion for financial support. We gratefully acknowledge the
computational resources of the RIKEN Super Combined
Cluster (RSCC).
Supporting Information Available: 1H and 13C NMR spec-
tra of compounds 4 and 10-17, temperature-dependent 1H
NMR of 4 and 17, UV and CD spectra of compound 17,
calculated structure of 3, calculated UV/CD spectra for the X-
ray structure of 3, IR/VCD spectra of 4 in solution, and
calculated IR/VCD spectra of a derivative of 3 with chiral
substituents. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The work described in this paper
was partially supported by Grants-in-Aid for Scientific
Research from The Ministry of Education, Science, Sports
J. Org. Chem. Vol. 74, No. 21, 2009 8163