Resolution of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole via diastereomeric salt formation with N-Tosyl-(R)-phenylglycine

Article abstract of DOI:10.1246/cl.2010.968

Enantiopure l,2,3,3a,4,8b-hexahydrocyclopenta[b]indole, the starting material of indoline dyes, could be obtained from the diastereomeric salt with N-tosyl-(R)-phenylglycine in ethanol.

Full text of DOI:10.1246/cl.2010.968

doi:10.1246/cl.2010.968
968
Published on the web August 5, 2010
Resolution of 1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole via Diastereomeric
Salt Formation with N-Tosyl-(R)-phenylglycine
Shinji Higashijima,*1,2 Yukiko Inoue,1 Takaya Maehashi,1 Hidetoshi Miura,1
Yasuhiro Kubota,2 Kazumasa Funabiki,2 and Masaki Matsui2
1Chemicrea Inc., Tsukuba Center Inc. D-14, 2-1-6 Sengen, Tsukuba, Ibaraki 305-0047
2Department of Material Science and Technology, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193
(Received June 7, 2010; CL-100532; E-mail: higashis@chemicrea.co.jp)
Enantiopure 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole,
the starting material of indoline dyes, could be obtained from
the diastereomeric salt with N-tosyl-(R)-phenylglycine in ethanol.
salt or (3aS,8bS)-1/(R)-2 salt as shown in Figure 2.7 A typical
experimental procedure is as follows: To a 50 mL flask were
added racemic 1 (0.8 g, 5.0 mmol), (R)-2 (1.5 g, 5.0 mmol), and
solvent (5 mL), and the mixture was heated to 50 °C to give a
clear solution. Then the solution was cooled, seeded (0.5 mg) at
40 °C, and gradually cooled to 20 °C. After aging this solution at
20 °C for 24 h, the resulting crystals were filtered off to afford 1/
(R)-2 diastereomeric salt. When crystallization was not observed,
the solution was cooled to ¹20 °C, aged at ¹20 °C for 24 h and
filtered to afford the salt. The results are summarized in Table 1.
We serendipitously found that the absolute configuration of 1
in the diastereomeric salt was controlled by the kind of seed.
In most solvents, when (3aS,8bS)-1/(R)-2 salt was seeded,
(3aS,8bS)-1/(R)-2 salt was obtained, and when (3aR,8bR)-1/(R)-
2 salt was seeded, (3aR,8bR)-1/(R)-2 salt was obtained. The
solubility of two types of diastereomeric salts in ethanol is
similar {(3aR,8bR)-1/(R)-2 salt: 11 g/100 g, (3aS,8bS)-1/(R)-2
salt: 8 g/100 g at 18 °C}. Therefore both the diastereomers could
be obtained from the same solution by seeding different kinds of
diastereomeric crystals. Furthermore, the diastereomeric excess
(de) of the salt depended on the dielectric constant of the solvent.
When the dielectric constant was in the range of 21 to 24, the
diastereomeric salt of (3aS,8bS)-1 was obtained with good de
(Entries 7 and 9). And the diastereomeric salt of (3aR,8bR)-1 was
obtained with good de when the dielectric constant was in the
range of 24 to 29 (Entries 6 and 8). In the solvents of higher
(>30) and lower (<20) dielectric constants, the diastereomeric
salts with lower de were obtained (Entries 1, 2, 11, and 12). When
the dielectric constant was larger than 28.5, the resolution
efficiency of (3aS,8bS)-1 salt was higher than that of (3aR,8bR)-1
salt (Entries 1-4). When the dielectric constant was smaller than
28.5, the resolution efficiency of (3aS,8bS)-1 was lower than that
of (3aR,8bR)-1 salt (Entries 7-12). Sakai et al. have reported that
the dielectric constant of the solvent employed in the resolution
Dye-sensitized solar cells (DSCs) have been extensively
investigated as potential candidates for renewable-energy sys-
tems.1 A number of organic dyes such as coumarin,2a oligothio-
phene,2b porphyrin,2c ethyldioxythiophenethienothiophene,2d
oligo(phenylenevinylene),2e phenoxazine,2f and indoline dyes
have been proposed as highly efficient sensitizers. In particular,
indoline dyes D149 and D205 shown in Figure 1 have attracted
much attention as highly efficient sensitizers.3a,3b
Indoline dyes have been synthesized from 1,2,3,3a,4,8b-
hexahydrocyclopenta[b]indole 1. Since compound 1 is prepared
as racemates, all the reported indoline dyes are racemates.
Racemic dyes can easily aggregate to decrease conversion
efficiency.4 We believe that optically active indoline dyes can
show improved performance compared to racemates. This
strategy might enable us to investigate the inherent performance
of these dyes, excluding the effects of additives such as
chenodeoxycholic acid.3b However, no method for preparing
enantiopure 1 has been reported so far.
We tried to accomplish the resolution via diastereomeric salt
formation, because this is simple and useful for obtaining
enantiopure compounds in large scale.
First, to find the most suitable resolving agent for racemic 1,
several acidic resolving agents such as L-tartaric acid, L-malic
acid, (R)-mandelic acid, dibenzoyl-L-tartaric acid, N-tosyl-(S)-
phenylalanine, and N-tosyl-(R)-phenylglycine ((R)-2) were
examined using ethanol as a solvent.5 The resolving agents
except for (R)-2 did not afford any crystals. Compound (R)-2
gave the best results (38.7% yield, 56.4% de (diastereomeric
excess), 43.7% resolution efficiency).6
Next, the resolution conditions of racemic 1 with (R)-2 were
optimized in various solvents by seeding pure (3aR,8bR)-1/(R)-2
Ts
HN
H
O
H
R
COOH
/ (R)-2
N
S
H
N
H
H
(R)-2
S
S
N
H
N
(3aR,8bR)-1 / (R)-2 salt
*
O
(1.0 equiv)
*
HOOC
Solvent
Seed
H
N
H
H
Codename
D149
R
/ (R)-2
rac-1
C2H5
H
N
H
Ph
D205
C8H17
Ph
(3aS,8bS)-1 / (R)-2 salt
Figure 1. The structure of indoline dye.
Figure 2. Resolution of racemic 1 with (R)-2.
Chem. Lett. 2010, 39, 968-969
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

969
Table 1. Resolution of racemic 1 with (R)-2 in various solvents with seeding
Filtration
Resolution
efficiency
/%f
Dielectric
Seed
typeb
Yield
de
Absolute
configurationg
Entry
Solvent
temperature
constanta
/%d
/%e
/°Cc
1
2
3
4
5
6
7
8
9
MeOH
MeOH
33.1
33.1
31.9
31.9
28.5
28.5
23.8
23.8
20.7
20.7
18.0
18.0
S
R
S
R
S
R
S
R
S
¹20
¹20
¹20
¹20
¹20
20
20
20
¹20
¹20
20
43.0
53.4
40.5
42.6
33.5
18.5
20.6
34.8
14.6
22.3
47.7
52.5
36.6
9.0
31.5
9.6
(3aS,8bS)
(3aR,8bR)
(3aS,8bS)
(3aR,8bR)
(3aS,8bS)
(3aR,8bR)
(3aS,8bS)
(3aR,8bR)
(3aS,8bS)
(3aR,8bR)
(3aR,8bR)
(3aR,8bR)
MeOH/acetone = 9/1
MeOH/acetone = 9/1
MeOH/EtOH = 1/1
MeOH/EtOH = 1/1
EtOH
EtOH
Acetone
Acetone
i-PrOH
53.2
26.3
50.3
95.1
85.5
74.6
84.4
59.7
13.4
14.3
43.1
22.4
33.7
35.2
35.2
51.9
24.6
26.6
12.8
15.0
10
11
12
R
S
R
i-PrOH
20
aDielectric constant for a mixed solvent is the weighted average value calculated from those of pure solvents. bSeed types are as follows:
S = (3aS,8bS)-1/(R)-2 salt, R = (3aR,8bR)-1/(R)-2 salt. cThese temperatures were almost corresponded to the crystallization temperature.
e
dYield was calculated based on racemic 1. Diastereomeric excess was determined by chiral HPLC using a CHIRALPAK AD-H column.
g
fResolution efficiency = yield (%) © de (%) © 0.02. Absolute configuration of the major enantiomer of 1 in a diastereomeric salt.
Grätzel, Chem. Commun. 2008, 2635.
2
a) Z.-S. Wang, Y. Cui, Y. Dan-oh, C. Kasada, A. Shinpo, K. Hara,
J. Phys. Chem. C 2007, 111, 7224. b) N. Koumura, Z.-S. Wang, S.
Mori, M. Miyashita, E. Suzuki, K. Hara, J. Am. Chem. Soc. 2006,
128, 14256; Z.-S. Wang, N. Koumura, Y. Cui, M. Takahashi, H.
Sekiguchi, A. Mori, T. Kubo, A. Furube, K. Hara, Chem. Mater.
2008, 20, 3993. c) W. M. Campbell, K. W. Jolley, P. Wagner, K.
Wagner, P. J. Walsh, K. C. Gordon, L. Schmidt-Mende, M. K.
Nazeeruddin, Q. Wang, M. Grätzel, D. L. Officer, J. Phys. Chem.
C 2007, 111, 11760; H.-P. Lu, C.-L. Mai, C.-Y. Tsia, S.-J. Hsu,
C.-P. Hsieh, C.-L. Chiu, C.-Y. Yeh, E. W. Diau, Phys. Chem.
Chem. Phys. 2009, 11, 10270. d) G. Zhang, H. Bala, Y. Cheng, D.
Shi, X. Lv, Q. Yu, P. Wang, Chem. Commun. 2009, 2198. e) H. Im,
S. Kim, C. Park, S.-H. Jang, C.-J. Kim, K. Kim, N.-G. Park, C.
Kim, Chem. Commun. 2010, 46, 1335. f) H. Tian, X. Yang, J.
Cong, R. Chen, J. Liu, Y. Hao, A. Hagfeldt, L. Sun, Chem.
Commun. 2009, 6288.
H(5)
O(1)
N(1)
Figure 3. Structure of (3aR,8bR)-1/(R)-2 salt (All hydrogen atoms
except that attached to nitrogen are omitted for clarity). Selected bond
distances and angles: O(1)£N(1) 2.705 ¡.
significantly affects the molecular discrimination process by
controlling the molecular interactions involving the solvent
molecules such as water.8 However, in our case, (3aR,8bR)-1 and
(3aS,8bS)-1 salts do not include any solvent molecules judging
from elemental analysis.6 It is suspected that the added seed could
determine the kind of produced diastereomeric salt.
The crystal structure of (3aR,8bR)-1/(R)-2 salt is shown in
Figure 3. The protonated amino moiety of (3aR,8bR)-1 forms
the salt with the carboxylate anion of (R)-2.9
Pure diastereomeric salts were easily obtained by recrystall-
izing the salts from ethanol. Then, the target enantiopure 1 was
obtained by neutralizing the pure diastereomeric salts in 80-90%
yield.
In conclusion, we have established a convenient and
efficient preparation of enantiopure 1,2,3,3a,4,8b-hexahydro-
cyclopenta[b]indole, the starting material of optically active
indoline dyes. The diastereomeric salts with N-tosyl-(R)-phenyl-
glycine were resolved in ethanol. The absolute configuration of
the diastereomeric salts were controlled by changing the
chirality of seed.
3
a) S. Ito, S. M. Zakeeruddin, R. Humphry-Baker, P. Liska, R.
Charvet, P. Comte, M. K. Nazeeruddin, P. Péchy, M. Takata, H.
Miura, S. Uchida, M. Grätzel, Adv. Mater. 2006, 18, 1202. b) S.
Ito, H. Miura, S. Uchida, M. Takata, K. Sumioka, P. Liska, P.
Comte, P. Péchy, M. Grätzel, Chem. Commun. 2008, 5194.
M. Matsui, T. Fujita, Y. Kubota, K. Funabiki, H. Miura, M. Shiro,
Bull. Chem. Soc. Jpn. 2010, 83, 709.
Synthesis of racemic 1: a) J. Shimizu, S. Murakami, T. Oishi, Y.
Ban, Chem. Pharm. Bull. 1971, 19, 2561. Synthesis of (R)-2: b) H.
Murakami, S. Satoh, T. Tobiyama, K. Sakai, H. Nihira, Eur. Pat.
Appl. EP 710,652, 1996.
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
The absolute configuration of resolved 1 was assigned by
comparing the retention time of (3aR,8bR)-1/(R)-2 salt whose
absolute configuration was determined by X-ray analysis.
K. Sakai, R. Sakurai, N. Hirayama, Tetrahedron: Asymmetry 2004,
15, 1073; K. Sakai, R. Sakurai, A. Yuzawa, N. Hirayama,
Tetrahedron: Asymmetry 2003, 14, 3713.
A single crystal of (3aR,8bR)-1/(R)-2 salt was recrystallized from
EtOH. Crystal data. C26H28N2O4S, Mr = 464.56, orthorhombic,
a = 5.413(3), b = 13.686(6), c = 31.066(16) ¡, U = 2301(2) ¡3,
T = 123 K, space group P212121 (no. 19), Z = 4, 5222 reflections
measured, 4640 unique (Rint = 0.063) which were used in all
calculation. The final wR2 was 0.132 (all data). Crytstallographic
data reported in this manuscript have been deposited with
Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-776684.
4
5
6
7
8
9
References and Notes
1
B. O’Regan, M. Grätzel, Nature 1991, 353, 737; M. Grätzel,
Nature 2001, 414, 338; F. Gao, Y. Wang, J. Zhang, D. Shi, M.
Wang, R. Humphry-Baker, P. Wang, S. M. Zakeeruddin, M.
Chem. Lett. 2010, 39, 968-969
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/