Synthesis of chiral polymers containing thioetherified cinchonidinium repeating units and their application to asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2014.08.013

A thiol-ene reaction of dithiol and two equivalents of cinchonidine afforded a thioetherified cinchonidine dimer. The dimer was treated with benzyl bromide to give a quaternary ammonium dimer. An ion exchange reaction of the cinchonidinium dimer and disod

Full text of DOI:10.1016/j.tetasy.2014.08.013

Tetrahedron: Asymmetry 25 (2014) 1309–1315
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral polymers containing thioetherified
cinchonidinium repeating units and their application
to asymmetric catalysis
⇑
Md. Robiul Islam, Parbhej Ahamed, Naoki Haraguchi, Shinichi Itsuno
Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2014
Accepted 13 August 2014
A thiol-ene reaction of dithiol and two equivalents of cinchonidine afforded a thioetherified cinchonidine
dimer. The dimer was treated with benzyl bromide to give a quaternary ammonium dimer. An ion
exchange reaction of the cinchonidinium dimer and disodium disulfonate gave polymers containing chi-
ral quaternary ammonium repeating units in their main-chain structures. Another type of chiral polymer
was synthesized by quaternization polymerization. Repeated quaternization reactions between the
thioetherified cinchonidine dimer and dihalides yielded chiral polymers containing cinchonidinium
structures in their main chains. Both of these chiral polymers were successfully used as catalysts for
the asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester. The chiral cinchonidinium
polymers explored in this study showed excellent catalytic activity in asymmetric alkylation reactions
and were reused several times without loss of activity.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
One of the more efficient methodologies to avoid such problems
is to use polymer-immobilized organocatalysts.7 Several
Cinchona alkaloid-based quaternary ammonium salts are some
of the most widely investigated and most effective chiral organo-
catalysts for asymmetric transformations.1 Cinchona alkaloids pos-
sess various functionalities in spite of their relatively low
molecular weights of less than 300. For example, cinchonidine
has functional groups such as a vinyl group, a hydroxyl group,
quinuclidine nitrogen, and quinoline ring. Suitable chiral catalyst
designs for asymmetric organocatalysts can be realized by utilizing
approaches to immobilize chiral organocatalysts onto polymers
have been reported.8 Cross-linked polystyrene is the most fre-
quently used polymer support for the immobilization of a catalyst.9
Unfortunately, most of them lead to lowering of the catalytic activ-
ity and enantioselectivity, mainly because of their insolubility
caused by the crosslinkage and randomly attached chiral catalyst
molecules onto random polymer chains. Several approaches to
immobilize cinchona-derived organocatalysts onto polymers have
also been reported. In most cases, the immobilization strategy
employed involves the attachment of cinchona-derived catalysts
onto the side chains of the polymers, resulting in chiral polymers
containing randomly attached cinchona moieties on the cross-
linked polymer supports.10
We have recently concentrated on the synthesis of chiral poly-
mers containing repeating units of an organocatalyst in their main-
chain structures.11 In this study, we have developed novel types of
chiral polymers containing cinchonidinium salt structures in their
main-chain repeating units. These chiral polymers were prepared
by two methods, ion exchange polymerization12 and quaternized
polymerization.13 For these polymerizations, cinchonidinium
dimers were required as the repeating units. The vinyl groups of
the cinchonidine were utilized for thiol-ene reactions.14 The reac-
tion of dithiol and cinchonidine was useful for the synthesis
of cinchonidine dimers, which were successfully used for the
these functionalities.2 Indeed,
a large number of quaternary
ammonium salts based on cinchona alkaloids have been developed
for chiral organocatalysis applications.3 Recently, highly active cat-
alysts have been also reported.4 However, compared to transition
metal catalyzed reactions, organocatalyst-mediated reactions
require a relatively large amount of the catalyst.5 The quaternary
ammonium salts are amphiphilic, which is an essential property
of these types of catalysts regarding their performance as phase
transfer catalysts.6 The amphiphilicity of such catalysts usually
hinders their separation from the reaction mixture. If a reaction
requires a large amount of such an amphiphilic catalyst, a decrease
in the product yield may occur during the product isolation
process.
⇑
Corresponding author. +81 (0)532 44 6813.
E-mail address: itsuno@ens.tut.ac.jp (S. Itsuno).
http://dx.doi.org/10.1016/j.tetasy.2014.08.013
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1310
M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315
synthesis of polymers having main-chain chirality. We found that
these chiral thioetherified cinchonidinium polymers are excellent
organocatalysts for asymmetric alkylation reactions. Details of
the cinchonidine dimer synthesis followed by polymerization and
asymmetric benzylation of N-diphenylmethylene glycine tert-butyl
ester by using the chiral polymers are discussed in this article.
to prepare the polymers 12. During the polymerization, polymers
12 were precipitated in the solution. The isolated yields, molecular
weights, molecular weight distributions, and the specific rotation
values of chiral polymers 12 are summarized in Table 1. Chiral
ionic polymers having molecular weights of 4600–14,000 were
synthesized by this method.
Another group of polymers containing chiral quaternary ammo-
nium structures in their main chains was synthesized by using
quaternization polymerization (Scheme 4).17 Thioetherified dimer
6 was allowed to react with dihalides 13 to give chiral quaternized
polymers 14 in high yields (Table 2). The isolated yields, molecular
weights, molecular weight distributions, and the specific rotation
values of the chiral polymers 14 are summarized in Table 2. Chiral
quaternized polymers 14 having molecular weights of 3400–
17,300 were synthesized by this method.
We then used the chiral quaternary ammonium dimers and
polymers as catalysts for the asymmetric benzylation of N-diphe-
nylmethylene glycine tert-butyl ester 1518 (Scheme 5). Results
with dimeric catalysts 7 are summarized in Table 3. Compared
with unmodified cinchonidinium salt 8 (entry 1), thioetherified
cinchonidinium salt 4 showed somewhat higher enantioselectivity
(entry 2). The same reaction also smoothly occurred with the
dimeric catalysts 7 to give 16 (entries 3 and 4). The dimeric cata-
lysts 7 showed even higher enantioselectivities in the same reac-
tion. The linker structure of dimer 7 affected the enantioselectivity.
Chiral ionic polymers 12 were easily synthesized from quatern-
ized dimers 7 and disodium disulfonate 11 (Scheme 3). By using 7a
and 7b, chiral ionic polymers 12 were synthesized and used as cat-
alysts for the asymmetric benzylation reaction. Table 4 summa-
rizes the results of asymmetric reactions with 12. In the presence
of the chiral ionic polymer 12, the reactions took place smoothly
to give chiral products with high levels of enantioselectivity. Using
12a, slightly higher enantioselectivities (82–85% ee, entries 1–4)
were obtained than using the corresponding dimeric catalyst 7a
(81% ee (Table 3, entry 3)). When the reaction temperature was
decreased to À20 °C, 90% ee was obtained with 12ad (entry 5).
2. Results and discussion
Of the various kinds of vinyl group reactions, thiol-ene reactions
have recently attracted the attention of researchers owing to the
recognition of their click characteristics.14b The thiol-ene reactions
are generally rapid and tolerant of the presence of oxygen and
moisture.15 The reactions proceed with quantitative conversion
to give the corresponding thioether in a regioselective manner.
As a model reaction, tert-butylthiol 2 was allowed to react with
cinchonidine 1 (Scheme 1). In the presence of AIBN, the thioetheri-
fication reaction occurred smoothly to give 3. Quaternization of 3
with benzyl bromide gave N-benzyl derivative 4 in high yield.
Chiral polymer synthesis requires the preparation of a dimer of
a cinchona alkaloid. We have prepared thioether-linked dimers 6
of cinchonidine (Scheme 2). Two equivalents of cinchonidine were
allowed to react with dithiol 5 to give thioether linked dimeric
compounds 6. A subsequent quaternization reaction of the dimers
6 was carried out with benzyl bromide at 80 °C in a mixed solvent
of ethanol, DMF, and chloroform (5:6:2).16 The quaternized dimers
7 were obtained in quantitative conversion (Scheme 2).
We used the quaternary ammonium dimers 7 for the synthesis
of chiral ionic polymers 12 as shown in Scheme 3. An ion exchange
reaction between quaternary ammonium bromide 8 and sodium
sulfonate 9 occurred smoothly to give the quaternary ammonium
sulfonate 10 in a quantitative conversion. The model reaction of
8 and 9 prompted us to apply the ion exchange reaction for the
synthesis of chiral polymers. Repeated ion exchange reactions
between dimers 7 and disodium disulfonate 11 gave chiral ionic
polymers 12. Various kinds of disodium disulfonates 11 were used
S
S
SH
2
PhCH2Br
(1.1 equiv.)
N
N
Br
Ph
N
AIBN
CHCl3
OH
EtOH:DMF:CHCl3
= 5 : 6 : 2
OH
OH
60 oC, 24 h
N
N
80 oC, 6 h
N
3
4
1
Scheme 1. Synthesis of thioetherified cinchonidinium salt 4.
N
HS
R
5
SH
N
Ph
N
HO
OH
PhCH2Br
N
(2.1 equiv.)
AIBN
HO
OH
1
S
R
N
CHCl3
Br
EtOH:DMF:CHCl3
= 5 : 6 : 2
Ph
70 oC, 12h
R
Br
S
S
N
N
80 oC, 6h
S
N
7
6
SH
HS
5a
:
SH
5b
:
HS
Scheme 2. Synthesis of thioether linked dimeric catalysts 7.

M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315
1311
Me
O3S
Br
N
NaO3S
N
+
OH
Me
OH
N
9
N
8
10
N
Ph
Br
O3S
OH
R
SO3
NaO3S
R
SO3Na
HO
N
Na
11
7
MeOH / H2O
N
R
Ph
S
Br
S
N
n
12
NaO3S
12aa: 7a + 11a
12ab: 7a + 11b
NaO3S
12ac 7a 11c
:
+
12ad 7a 11d
:
+
SO3Na
SO3Na
12ae 7a 11e
:
+
12ba 7b 11a
:
+
11c
11a
11b
12bb 7b 11b
:
+
12bd 7b 11d
:
+
NaO3S
SO3Na
12be 7b 11e
:
+
NaO3S
SO3Na
11d
11e
SO3Na
NaO3S
Scheme 3. Synthesis of chiral ionic polymers 12.
Table 1
Synthesis of chiral ionic polymer 12 from quaternized dimer 7 and disulfonate 11
a
a
25b
Entry
Dimer
Disulfonate
Polymer
Yield (%)
Mn
Mw/Mn
[a]
D
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7b
7b
7b
7b
11a
11b
11c
11d
11e
11a
11b
11d
11e
12aa
12ab
12ac
12ad
12ae
12ba
12bb
12bd
12be
92
94
95
92
87
87
87
85
72
14,000
7400
7000
7200
5900
5400
9000
6500
4600
1.13
1.42
1.22
1.94
2.57
1.50
2.05
1.87
1.58
À106.1
À101.3
À99.1
À94.7
À100.1
À75.9
À78.5
À75.6
À80.1
a
Determined by SEC measurement using DMF as a solvent at a flow rate of 1.0 mL/min at 40 °C.
Specific rotation values were measured for the DMSO solution at concentration of c 1.0.
b
Reusability of polymeric catalysts is always an important issue
from a green chemical point of view. Polymeric catalysts 12 were
insoluble in both the organic and aqueous phases. After the reac-
tion was complete, the polymeric catalyst could be easily separated
from the reaction mixture. The recovered polymers can be reused
for the same reactions. We demonstrated the use of the recycled
polymeric catalyst 12bd. For entries 9 to 12, the same polymer
12bd was reused. These experiments revealed that the polymeric
catalyst can be reused at least several times without any significant
loss of catalytic activity.
Next, we examined the catalytic activity of another type of poly-
mer 14 having chiral quaternary ammonium structures in their
main-chain structures. From thioetherified dimers 6 and various
kinds of dihalides 13, chiral polymers 14 were prepared as shown
in Scheme 4. We found that these polymers also showed high cat-
alytic activity in the asymmetric benzylation reaction. The results
obtained by using polymeric catalysts 14 are summarized in Table 5.
In most cases, these polymeric catalysts 14 showed somewhat
higher enantioselectivities compared with those obtained from
the corresponding dimeric ones 7. For example, the use of 14aa
resulted in 85% ee (entry 1), which was higher than that obtained
with 7a (81% ee). All other polymers 14a showed higher enantiose-
lectivities except for 14ae (entry 5). Polymers 14b also showed sim-
ilar tendencies. In particular, the use of 14bc afforded the chiral
product 16 in 92% ee (entry 9). Lowering the reaction temperature
resulted in increases of the enantioselectivities (entries 11–13), as
expected. Although a longer reaction time was required at À40 °C,
the reaction still occurred to give the product in high yield with
95% ee (entry 12). Almost no reaction occurred at À60 °C after
24 h (entry 12). The aqueous phase was completely frozen at
À60 °C and the solid polymeric catalyst could not interact with
the reagents at this temperature. This type of polymeric catalyst

1312
M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315
N
X
R
HO
X
R
X
N
13
OH
6
N
R
DMSO, 80 oC, 10h
S
X
13d
13e
S
N
n
14
Br
Br
Br
14aa 6a 13a
:
+
Br
14ab 6a 13b
:
+
14ac 6a 13c
:
+
13a
13b
14ad: 6a + 13d
14ae: 6a + 13e
14ba: 6b + 13a
14bb: 6b + 13b
14bc: 6b + 13c
14bd: 6b + 13d
14be: 6b + 13e
Cl
Cl
Cl
Br
Cl
Br
13c
Scheme 4. Quaternization polymerization of thioetherified dimer 6 and dihalide 13.
Table 2
Table 4
Synthesis of chiral quaternized polymer 14 from thioetherified dimer 6 and dihalide
13
Asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester by using
chiral ionic polymer 12 at 0 °C
Yielda (%)
% eeb
Config.
a
a
25b
Entry
Dimer
Dihalide
Polymer Yield
Mn
Mw/Mn
[a
]
Entry
Catalyst
Time (h)
D
1
2
3
4
5
6
7
8
9
10
6a
6a
6a
6a
6a
6b
6b
6b
6b
6D
13a
13b
13c
13d
13e
13a
13b
13c
13d
13e
14aa
14ab
14ac
14ad
14ae
14ba
14bb
14bc
14bd
14be
94
99
93
99
80
90
92
92
90
92
7100
3900
3400
4200
4100
4700
17,300
3900
5200
3500
1.30
1.30
1.35
1.75
1.62
1.21
1.66
1.19
1.66
1.56
À102.7
À125.8
À41.9
1
2
3
12aa
12ab
12ac
12ad
12ad
12ae
12ba
12bb
12bd
12bd
12bd
12bd
12be
4
2
7
1
7
2
1
3
2
2
4
5
2
83
85
89
89
93
85
82
87
89
89
80
80
83
84
83
82
85
90
84
81
81
82
81
82
80
81
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
À100.9
À152.4
À90.7
4
5c
6
À94.7
7
8
9
À160.2
À125.6
À55.9
10d
11e
12f
13
a
Determined by SEC measurement using DMF as a solvent at a flow rate of
1.0 mL/min at 40 °C.
b
Specific rotation values were measured for the DMSO solution at concentration
a
b
c
d
e
f
of c 1.0.
Isolated yield.
The ee values were determined by HPLC using a CHIRALCEL OD-H column.
Reaction was carried out at À20 °C.
Catalyst 12bd used in entry 9 was reused.
catalyst (10 mol%)
O
Ph
Ph
O
Ph
Ph
Catalyst 12bd used in entry 10 was reused.
Catalyst 12bd used in entry 11 was reused.
benzyl bromide (1.2 eq.)
N
N
OtBu
Ph
OtBu
toluene : chloroform = 7:3,
50wt % KOH, 0 o
C
15
16
3. Conclusions
Scheme 5. Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester
15.
Dimers of cinchonidine were successfully prepared by means of
thiol-ene reactions of dithiols and cinchonidine. From these
dimers, we synthesized polymers 12 and 14 containing chiral qua-
ternary ammonium repeating units in their main-chain structures
by using two different approaches. The first approach involved chi-
ral ionic polymer synthesis by ion exchange reactions between
quaternized dimers of thioetherified cinchonidinium salts 7 and
disodium disulfonates 11. The second approach was quaternization
polymerization of thioetherified dimers of cinchonidine 6 and
dihalides 13. Both polymerizations occurred smoothly to give the
chiral polymers 12 and 14 containing cinchonidinium structures
in their main-chain repeating units.
The chiral polymers 12 and 14 were successfully applied to
catalysis for the asymmetric benzylation of N-diphenylmethylene
glycine tert-butyl ester 15 to give a phenylalanine derivative 16
in high yields with high levels of enantioselectivity. In most cases,
using polymeric catalysts 12 and 14 resulted in higher enantiose-
Table 3
Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester 15 with
dimeric catalyst
Entry
Catalyst
Time (h) Yielda (%)
% eeb
Config.
1
2
3
4
8c
4
7a
7b
5
3
3
5
91
86
89
91
71
77
81
85
(S)
(S)
(S)
(S)
a
b
c
Isolated yield.
The ee values were determined by HPLC using a CHIRALCEL OD-H column.
11b
See Ref.
.
was also recovered easily and reused as exemplified by 14bb
(entries 7 and 8) and 14bc (entries 9, 10, and 13).

M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315
1313
Table 5
were used. Calibration curves were plotted to determine num-
ber-average molecular weight (Mn) and molecular weight distribu-
tion (Mw/Mn) values with polystyrene standards. HPLC analyses
were performed with a JASCO HPLC system composed of a 3-line
degasser DG-980, HPLC pump PV-980, column oven CO-965,
equipped with a chiral column (CHIRALCEL OD-H, Daicel) using
hexane/2-propanol as eluent. A UV detector (JASCO UV-975 for
the JASCO HPLC system) was used for peak detection. Optical rota-
tions were recorded with a JASCO DIP-149 digital polarimeter
using a 10 cm thermostated microcell.
Asymmetric alkylation of N-diphenylmethylene glycine tert-butyl ester by using
polymeric catalysts 14
Entry
Catalyst
Time (h)
Temp. (°C)
Yielda (%)
eeb (%)
Config.
1
2
3
4
5
6
14aa
14ab
14ac
14ad
14ae
14ba
14bb
14bb
14bc
14bcd
14bc
14bc
14bce
14bc
14bd
14be
3
3
3
2
3
2
2
2
12
10
10
24
24
24
8
0
0
0
0
0
0
0
0
0
95
90
87
78
71
77
91
90
93
91
94
83
87
N.D
85
72
85
87
84
82
79
84
89
88
92
92
94
95
95
N.D
84
81
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
—
7
8c
9
4.2. Procedure for the synthesis of thioetherified cinchonidine 3
10
11
12
13
14
15
16
0
À20
À40
À40
À60
0
A mixture of cinchonidine (1, 0.88 g, 3.00 mmol), tert-butyl
mercaptan (2, 0.54 g, 6.00 mmol), and AIBN (0.02 g, 0.12 mmol)
was stirred at 70 °C for 24 h. After removal of the solvent under
vacuum, the residue was washed several times with hexane. The
(S)
(S)
3
0
white product 3 (0.89 g, 77% yield) was used for the next reaction
a
b
c
25
Isolated yield.
without further purification. Mp 158–159 °C. [
a]
= À63.9 (c 1.0,
D
The ee values were determined by HPLC using a CHIRALCEL OD-H column.
Compound 14bb used in entry 7 was reused.
Compound 14bc used in entry 9 was reused.
Compound 14bc used in entry 10 was reused at À40 °C.
DMSO); 1H NMR (400 MHz, CDCl3): d 1.26 (s, 6H), 1.39–1.55 (m,
4H), 1.70–1.80 (m, 4H), 2.3–2.43 (t, J = 6 Hz, 2H), 2.55–2.68 (m,
1H), 3.01–3.13 (m, 2H), 3.41–3.50 (m, 1H), 3.94 (s, 1H), 5.64 (d,
J = 3 Hz, 1H), 7.38–7.42 (m, 1H), 7.57 (t, J = 3 Hz, 1H), 7.63–7.67
(m, 1H), 7.95–7.97 (m, 1H), 8.08 (d, J = 6 Hz, 1H), 8.82 (d,
J = 3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.26, 25.86, 26.26,
28.12, 31.04, 34.79, 35.01, 42.03, 43.35, 58.37, 60.29, 71.77, 118.38,
123.08, 125.72, 126.71, 129.13, 130.28, 148.18, 149.65, 150.14; IR
d
e
lectivities than using their corresponding dimeric catalysts. Achiral
repeating units in the chiral polymers such as thioetherified linkers
in 12 and 14, disulfonate in 12, and dihalide in 14 influenced the
catalytic activity and enantioselectivity of the polymeric catalysts.
From the various combinations of linker structures and cinchonid-
inium salts, 12ad and 14bc gave the best results for each polymer
structure. The polymeric chiral catalysts were active enough even
at lower temperatures such as À40 °C to give chiral products in
high yields with high enantioselectivities of up to 95% ee using
14bc. Since the cinchonidinium polymers are insoluble in both
the organic and aqueous phases, polymeric catalysts 12 and 14
were easily recovered from the reaction mixtures and reused sev-
eral times without any significant loss of catalytic activity. Applica-
bility of these chiral polymer catalysts for other asymmetric
reactions is now under investigation.
(KBr):
m 1507 (C@N), 1098 (C–O), 756 (C–S); Anal. Calcd for C23H32-
N2OS: C 71.83, H 8.39, N 7.28. Found: C 71.74, H 8.54, N 7.98.
4.3. Procedure for the synthesis of thioetherified chiral quater-
nary ammonium salt 4
A mixture of 3 (0.52 g, 1.34 mmol) and benzyl bromide (0.25 g,
1.48 mmol) in EtOH/DMF/CHCl3 = 5/6/2 mixed solvent (5 mL) was
stirred at 80 °C for 6 h. After cooling the reaction mixture to room
temperature, the solvent was removed under vacuum and the
crude product was dissolved in MeOH (2.5 mL) and poured into
Et2O (100 mL). The mixture was stirred at room temperature for
1 h and filtered. The resulting solid was washed with Et2O several
times to give product 4 (0.67 g, 90% yield) as a white solid. Mp
161–163 °C; [
a]
25 = À125.3 (c 1.0, DMSO); 1H NMR (400 MHz,
4. Experimental
4.1. General
D
DMSO-d6): d 1.15 (s, 9H), 1.49–1.56 (m, 2H), 1.84–2.07 (m, 4H),
2.34–2.38 (m, 2H), 3.03–3.19 (m, 2H), 3.48–3.51 (d, J = 9 Hz, 1H),
4.06–4.11 (t, J = 6 Hz, 1H), 4.61 (s, 1H), 5.56–5.59 (d, J = 9 Hz, 1H),
5.70–5.73 (d, J = 9 Hz, 1H), 6.52 (s, 2H), 7.10–7.19 (m, 5H), 7.61–
7.63 (m, 3H), 7.80 (d, 1H), 8.13 (t, 1H), 8.80 (d, 1H); 13C NMR
(100 MHz, DMSO-d6): d 20.69, 23.86, 24.93, 30.62, 32.68, 41.72,
50.59, 61.20, 62.78, 63.95, 67.61, 120.11, 123.71, 124.36, 127.18,
127.93, 128.87, 129.34, 129.81, 133.63, 145.28, 147.62, 150.11; IR
All solvents and reagents were purchased from Sigma–Aldrich,
Wako Pure Chemical Industries, Ltd, or Tokyo Chemical Industry
Co., Ltd at the highest available purity and used as was, unless
noted otherwise. Reactions were monitored by thin-layer chroma-
tography (TLC) using Merck precoated silica gel plates (Merck
5554, 60F254). Column chromatography was performed using a
silica gel column (Wakogel C-200, 100–200 mesh). Melting points
were recorded using a Yanaco micro melting apparatus and were
uncorrected. 1H and 13C NMR (300 MHz or 400 MHz) spectra were
measured in CDCl3 or DMSO-d6 on a JEOL JNM-ECS300 or JNM-
ECX400 spectrometer. Peaks were referenced to the (CH3)4Si
(TMS) peak at d = 0 (1H) or the solvent peaks [i.e., the CDCl3 peak
(KBr):
m 1508 (C@N), 764 (C–S); Anal. Calcd for C30H39N2OS: C
64.85, H 7.08, N 5.04. Found: C 64.31, H 7.05, N 5.41.
4.4. General procedure for the synthesis of thioether linked
dimer 6
A mixture of cinchonidine 1 (2.35 g, 8.00 mmol), dithiol 5
(4.00 mmol), and AIBN (12.8 mg, 0.08 mmol) in CHCl3 (12 mL)
was stirred at 80 °C for 12 h. During the reaction AIBN (0.02 mmol)
was added three times. The residue, after the removal of solvent
under high vacuum was purified by column chromatography to
give the products 6.
at d = 7.26 (1H)/77.1
(
13C) or the DMSO-d6 peak at d = 2.5
(1H)/39.5 (13C)]. The J values were reported in Hertz. IR spectra
were recorded with a JEOL JIR-7000 FT-IR spectrometer and are
reported in reciprocal centimeters (cmÀ1). Elemental analyses
were performed at the Microanalytical Center of Kyoto University.
Size exclusion chromatography (SEC) was performed with a Tosoh
instrument with HLC 8020 UV (254 nm) or refractive index detec-
tion. DMF was used as a carrier solvent at a flow rate of 1.0 mL/min
4.4.1. Thioether linked dimer 6a
Off-white solid, yield 57%; mp 101–102 °C; [
a]
25 = À57.6 (c 1.0,
D
DMSO); 1H NMR (400 MHz, CDCl3): d 1.31 (m, 3H), 1.41–1.52 (m,
at 40 °C. Two polystyrene gel columns with bead sizes of 10 lm

1314
M.R. Islam et al. / Tetrahedron: Asymmetry 25 (2014) 1309–1315
8H), 1.62 (s, 2H), 1.73–1.76 (m, 6H), 2.33–2.42 (m, 10H), 2.50 (m,
2H), 3.01–3.07 (m, 4H), 3.40–3.47 (m, 2H), 4.38 (s, 2H), 5.61–5.62
(d, J = 3 Hz, 2H), 7.40–7.43 (m, 2H), 7.53 (d, J = 3 Hz, 2H), 7.63–
7.67 (m, 2H), 7.99 (d, J = 3 Hz, 2H), 8.10 (d, J = 3 Hz, 2H), 8.77 (d,
J = 3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 20.92, 25.72, 28.05,
28.41, 29.43, 30.09, 32.15, 34.62, 43.25, 58.27, 60.22, 71.45,
118.38, 123.05, 125.63, 126.67, 129.09, 129.97, 147.94, 149.91,
4.6. General procedure for the synthesis of main-chain chiral
ionic polymer 12
A solution of disodium disulfonate salt 11 (0.5 mmol) in water
(5 mL) was added dropwise to a solution of dimeric quaternary
ammonium salt 7 (0.5 mmol) in MeOH (5 mL). This mixture was
stirred vigorously at room temperature for 24 h. After removing
the MeOH under high vacuum, the suspension was filtered and
washed with water and hexane to obtain the resulting ionic poly-
mer 12. Yield, molecular weight, molecular weight distribution,
and the specific rotation value are described in Table 1.
150.25; IR (KBr):
m 1507 (C@N), 1,098 (C–O), 760 (C–S); Anal. Calcd
for C44H58N4O2S2: C 71.50, H 7.91, N 7.58. Found: C 71.11, H 8.02, N
7.54.
4.4.2. Thioether linked dimer 6b
25
Off-white solid, yield 24%; mp 108–110 °C; [
a
]
= À35.4 (c 1.0,
4.7. General procedure for the synthesis of main-chain chiral
quaternary ammonium polymer 14
D
DMSO); 1H NMR (400 MHz, CDCl3): d 1.37–1.41 (m, 6H), 1.68–1.71
(m, 8H), 2.22–2.26 (m, 6H), 2.49–2.53 (m, 2H), 2.98–3.01 (m, 4H),
3.40 (m, 2H), 3.49–3.59 (m, 6H), 4.26 (s, 2H), 5.60 (d, J = 3 Hz, 2H),
7.08 (m, 4H), 7.51–7.52 (m, 4H), 7.64–7.67 (m, 2H), 8.04–8.09 (m,
4H), 8.78 (d, J = 3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.29,
25.76, 28.11, 29.27, 34.28, 34.82, 36.02, 43.26, 58.26, 60.29, 71.71,
118.40, 123.17, 125.80, 126.81, 128.95, 129.19, 130.30, 137.20,
A mixture of cinchonidine dimer 7 (0.500 mmol) and dihalide
13 (0.500 mmol) in DMSO (2 mL) was stirred at 80 °C for 10 h.
The residue, after the removal of the solvent under high vacuum,
was dissolved in MeOH (5 mL) and poured into Et2O (200 mL).
After filtration of the mixture, the solid was washed with hexane
and ethyl acetate, and was dried under high vacuum to give the
polymer 14. Yield, molecular weight, molecular weight distribu-
tion, and the specific rotation value are described in Table 2.
148.23, 149.76, 150.12; IR (KBr):
m 1507 (C@N), 759 (C–S); Anal.
Calcd for C46H54N4O2S2: C 72.78, H 7.17, N 7.38. Found: C 72.98, H
7.26, N 7.21.
4.8. General procedure for enantioselective alkylation of N-
diphenylmethylene glycine tert-butyl ester 15 using chiral
polymeric catalyst 14aa
4.5. General procedure for the synthesis of thioether linked di-
meric catalyst 7
A
mixture of 6 (1.00 mmol) and benzyl bromide (0.36 g,
Chiral polymeric catalyst 14aa (0.017 mmol) and N-diphenylm-
ethylene glycine tert-butyl ester (12: 0.050 g, 0.170 mmol) were
added into a mixed solvent of toluene (0.7 mL) and chloroform
(0.3 mL). 50 wt% aqueous KOH solution (0.25 mL) was added to
the above mixture. Benzyl bromide (0.035 g, 0.203 mmol) was then
added dropwise at 0 °C to the mixture. The reaction mixture was
stirred vigorously at 0 °C for several hours. Saturated sodium chlo-
ride solution (2 mL) and ethyl acetate (2 mL) were then added, and
the mixture was subsequently filtered to recover 14aa, which was
washed several times with water and ethyl acetate. The organic
phase was separated, and the aqueous phase was extracted with
ethyl acetate. The organic extracts were washed with brine and
dried over MgSO4. Evaporation of the solvents and purification of
the residual oil by column chromatography on silica-gel (ether/hex-
ane = 1:10 as eluent) gave (S)-tert-butyl N-(diphenylmethyl-
ene)phenylalaninate 16. The enantiomeric excess was determined
by HPLC analysis [Daicel CHIRALCEL OD-H, hexane/2-propanol =
100:1, flow rate = 0.3 mL/min, retention times: (R)-enantiomer =
27.6 min, (S)-enantiomer = 47.9 min]. The absolute configuration
was determined by comparison of the HPLC retention time with
the authentic sample independently synthesized by the reported
procedure.
2.1 mmol) in EtOH/DMF/CHCl3 = 5/6/2 mixed solvent (10 mL) was
stirred at 80 °C for 6 h. After cooling the reaction mixture to room
temperature, the solvent was removed under vacuum and dis-
solved in MeOH (3 mL) and poured into Et2O (250 mL). The mix-
ture was stirred at room temperature for 1 h and filtered. The
resulting solid was washed with Et2O several times and then with
hexane to give the products 7.
4.5.1. Thioether linked dimeric catalyst 7a
Off white solid, yield 99%; mp 163–165 °C; [
a
]
D
25 = À105.9 (c 1.0,
DMSO); 1H NMR (400 MHz, DMSO-d6): d 1.13–1.15 (m, 3H), 1.29–
1.43 (m, 10H), 1.72–1.75 (m, 2H), 1.94–2.02 (m, 8H), 2.28–2.32 (m,
8H), 3.17–3.18 (m, 2H), 2.46–2.49 (d, J = 6 Hz, 2H), 3.93–3.96 (t,
J = 4 Hz, 2H), 4.23–4.28 (t, J = 6 Hz, 2H), 4.87–4.90 (d, J = 9 Hz,
2H), 5.12–5.15 (d, J = 9 Hz, 2H), 6.55 (d, 2H), 6.73–6.74 (d,
J = 3 Hz, 2H), 7.56–7.57 (m, 6H), 7.69–7.76 (m, 6H), 7.80–7.84 (m,
4H), 8.09–8.10 (d, J = 6 Hz, 2H), 8.27–8.30 (d, J = 9 Hz, 2H), 8.98–
8.99 (d, J = 3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 20.67,
23.86, 24.66, 27.62, 28.32, 28.80, 30.77, 32.62, 50.57, 61.26,
62.77, 63.99, 67.55, 119.04, 120.09, 123.71, 124.36, 127.17,
127.93, 128.87, 129.33, 129.81, 133.68, 145.29, 147.62, 150.10; IR
(KBr):
m 1508 (C@N), 762 (C–S); Anal. Calcd for C58H72Br2N4O2S2:
C 64.43, H 6.71, N 5.18. Found: C 64.78, H 6.81, N 5.16.
Acknowledgements
4.5.2. Thioether linked dimeric catalyst 7b
25 = À85.8 (c 1.0,
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas ‘‘New Polymeric Materials
Based on Element-Blocks’’ (No. 25102515) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
Off white solid, yield 95%; mp 164–166 °C; [
a]
D
DMSO); 1H NMR (400 MHz, DMSO-d6): d 1.26 (s, 6H), 1.39–1.55 (m,
4H), 1.70–1.80 (m, 4H), 2.3–2.43 (t, J = 6 Hz, 2H), 2.55–2.68 (m,
1H), 3.01–3.13 (m, 2H), 3.41–3.50 (m, 1H), 3.94 (s, 1H), 5.64 (d,
J = 3 Hz, 1H), 7.38–7.42 (m, 1H), 7.57 (t, J = 3 Hz, 1H), 7.63–7.67
(m, 1H), 7.95–7.97 (m, 1H), 8.08 (d, J = 6 Hz, 1H), 8.82 (d,
J = 3.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 20.59, 23.82,
24.54, 31.98, 32.61, 41.16, 50.61, 61.28, 63.02, 64.21, 67.49,
120.30, 122.50, 124.05, 126.35, 127.76, 128.75, 130.08, 133.71,
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