Synthesis of chiral quaternary ammonium polymers for asymmetric organocatalysis application

Article abstract of DOI:10.1016/j.tet.2013.03.018

Main-chain chiral quaternary ammonium polymers have been synthesized using cinchonidine or 10,11-dihydrocinchonidine as a chiral source. Since the quinuclidine moiety of cinchonidine is easily quaternized with halide to form cinchonidinium salt, the quate

Full text of DOI:10.1016/j.tet.2013.03.018

Tetrahedron 69 (2013) 3978e3983
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral quaternary ammonium polymers for asymmetric
organocatalysis application
Parbhej Ahamed, Md. Aminul Haque, Mikiya Ishimoto, Md. Masud Parvez,
*
Naoki Haraguchi, Shinichi Itsuno
Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8480, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Main-chain chiral quaternary ammonium polymers have been synthesized using cinchonidine or 10,11-
dihydrocinchonidine as a chiral source. Since the quinuclidine moiety of cinchonidine is easily quater-
nized with halide to form cinchonidinium salt, the quaternized reaction (Menshutkin reaction)
was applied to the dimeric compound of cinchonidine and dihalide. The quaternization polymerization
between cinchonidine dimer and dihalide smoothly occurred to afford the chiral polymers containing
cinchonidinium salt structure in its main-chain. This atom economical addition polymerization was also
applied to dimer of 10,11-dihydrocinchonidine. The corresponding chiral quaternary ammonium poly-
mers were found to perform as polymeric organocatalysts for enantioselective benzylation of N-diphe-
nylmethylene glycine tert-butyl ester to afford the desired (S)-phenylalanine derivative in high yields and
high enantioselectivities (up to 95% ee).
Received 7 February 2013
Received in revised form 27 February 2013
Accepted 5 March 2013
Available online 13 March 2013
Keywords:
Quaternary ammonium salt
Organocatalyst
Polymeric catalyst
Asymmetric alkylation
Cinchonidinium salt
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
catalyst for asymmetric reaction.11 In this article, we have developed
atom economical synthesis of chiral polymers by using repetitive
Chiral quaternary ammonium salts of cinchona alkaloid de-
quaternization reaction (Menshutkin reaction) between cinchona
alkaloid dimer and dihalide. We have examined the catalytic activity
of the chiral polymeric catalyst in asymmetric alkylation reaction.
Various kinds of achiral quaternary ammonium polymers called
ionene have been synthesized since Gibbs and co-workers found
rivatives are oneof themostefficientorganocatalystfor various types
1e3
of asymmetric transformations.
A typical asymmetric reaction
using cinchonidinium salts is asymmetric alkylation of glycinate
imines under phase transfer condition, which was successfully in-
4
12
troduced by O’Donnel et al. Further improvements have been done
the polymerization of tertiary diamine and dihalide in 1933. The
by Lygo,5 Corey,6 Jew, and Park. Polymer-immobilized cinchona
7
7
ionene polymers have many potential uses in biomedical applica-
1
3
14
alkaloid based organocatalysts have also been developed mainly due
tion including DNA transfer agents, multifunctional gelators,
and antimicrobial applications. Recently pyridinium ionene poly-
mer has been developed to prepare self-assembled supramolecular
8
to their easy separation and recyclability. The advantages of
polymer-immobilized chiral catalysts are now widely recognized
and the progress in the polymeric chiral catalysts has been reviewed
15
complex, which was used as a catalyst for organic reactions.
9
in the literature. Some of cinchona alkaloid based chiral quaternary
However, optically active ionene polymers have not been pre-
pared. We applied this simple polyaddition reaction to the syn-
thesis of optically active quaternary ammonium polymers. By using
this polymerization, chiral quaternary ammonium salt structure is
regularly incorporated into the polymer main-chain. The catalytic
activity of these chiral polymers for enantioselective alkylation of
N-diphenylmethylene glycine tert-butyl ester was discussed.
ammonium salts were attached onto the side-chain of polymer-
support. For example, cinchonidinium salts were attached onto the
side-chain of cross-linked polystyrenes, which were used as poly-
meric organocatalyst in the same reaction.1 These classical type of
polymeric catalysts worked in the asymmetric alkylation with low-
ering the catalytic activities. The development of chiral polymer
catalysts with rigid and sterically regular structure may have a better
defined microenvironment at the catalytic sites and have allowed
systematic modification of their catalytic properties. For that pur-
pose, we have demonstrated some chiral main-chain polymers as
0
2
2
. Results and discussion
.1. Synthesis of chiral quaternary ammonium polymers
The ether-linked cinchonidine dimer 3 was prepared from cin-
chonidine 1 and dihalide 2. The cinchona alkaloids react selectively
*
Corresponding author. Tel./fax: þ81 532 44 6813; e-mail address: itsuno@en-
s.tut.ac.jp (S. Itsuno).
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.018

P. Ahamed et al. / Tetrahedron 69 (2013) 3978e3983
3979
at the quinuclidine ring with halide, such as benzyl bromide.16 The
quaternary ammonium salt is quantitatively formed. This quater-
nization reaction can be applied to the chiral dimeric compounds 3
and dihalide, such as 4, the chiral polymer should be formed. We
found that the copolymerization of 3 and 4 via the intermolecular
quaternization reaction smoothly occurred to give the corre-
sponding chiral quaternary ammonium polymer 5, which we term
‘quaternization polymerization’. We first surveyed the reaction
condition of the quaternization polymerization. Quaternization
reaction is sometimes sensitive to the solvent used. Table 1
Table 1
Quaternization polymerization of cinchonidine dimer 3a and dihalide 4b
ꢀ
Entry Solvent
Temperature
C
Reaction time h Yield %
1
2
3
4
5
6
DMF
DMSO
MeOH
Toluene
DMF/DMSO (1:1)
100
90
70
110
100
21
20
24
24
24
28
84
96
0
0
55
94
3
EtOH/DMF/CHCl (5:6:2) 100
summarizes the result of quaternization polymerization of cin-
chonidine dimer 3a and p-xylene dibromide 4b. The polymeriza-
tion in DMSO gave the chiral polymer 5b in high yield, while the use
of methanol and toluene resulted in no polymer formation. We
used DMSO as solvent for the polymerization of other monomer
combinations. The chiral polymers 5 were easily isolated by pre-
cipitation in ether followed by filtration. This is a highly atom
economical addition polymerization to give the chiral polymer
(Scheme 1).
In order to evaluate the catalytic activity of the resulting chiral
quaternary ammonium polymers, enantioselective alkylation of
N-diphenylmethylene glycine tert-butyl ester 6 was conducted in
the presence of the polymer 5 (Fig. 1).
As shown in Table 2, although the polymeric catalyst 5 was not
soluble both in the organic solvent and aqueous phase used in this
reaction, the enantioselective benzylation of 6 occurred with the
polymeric catalyst to give the corresponding chiral product 7 in
good yield (Scheme 2). The catalytic activity and enantioselectivity
were influenced by the chiral polymer structure. Polymeric cata-
Scheme 1. Quaternization polymerization of chiral diamine and dihalide.
2
lysts 5c, 5g and 5h having naphthalene derived linkers (R derived
from 4c, 4d) gave higher enantioselectivities in the asymmetric
reaction (entries 3, 9, 10). Organic solvent used in the reaction also
influenced on the catalytic activity. In some solvents tested in the
reaction, toluene/chloroform mixed solvent system developed by
The quaternary ammonium polymers 9 can be prepared by an-
other method, that is, etherification polymerization.1 The quater-
nized dimer 10 was treated with dihalide in the presence of NaH to
form ether linkages between chiral diol 10 (Scheme 3). The obtained
8
7
Park and Jew showed higher enantioselectivity (entries 4e6).
Next, we have prepared 10,11-hydrocinchonidine17 derived
quaternized ammonium polymers 9 by quaternization polymeri-
zation method (Scheme 3). 10,11-Hydrocinchonidine dimers 8 were
prepared from 10,11-hydrocinchonidine and dihalide 2. The dimers
8
were then allowed to react with dihalide 4 to give 9. These chiral
quaternized polymers efficiently catalyzed the same asymmetric
benzylation reaction of 6. The results are summarized in Table 3. In
most cases, the polymeric catalysts
9 derived from 10,11-
hydrocinchonidine gave higher enantioselectivities compared to
those obtained using 5. Naphthalene linked polymer catalyst 9d
gave the highest enantioselectivity (95% ee) in the reaction (Table 3,
entry 4). The chiral polymer 9 containing relatively bulky ethyl
group instead of vinyl group of 5 in their repeating unit would have
a different conformation compared with that of 5, which might
influence on the catalytic activity (Scheme 4).
Since these polymeric catalysts are insoluble in the solvent used,
the catalysts were readily removed from the reaction mixture. The
recovered polymeric catalyst 9d was reused for the same reaction.
The polymer 9d was reused twice without any loss of the catalytic
activity.
Fig. 1. Structure of Cinchonidium based polymeric catalysts.

3980
P. Ahamed et al. / Tetrahedron 69 (2013) 3978e3983
Table 2
Table 3
Asymmetric alkylation reaction of N-diphenylmethylene glycine tert-butyl ester by
Asymmetric alkylation reaction of N-diphenylmethylene glycine tert-butyl ester by
using polymeric catalyst
using polymeric catalyst
Entry
Catalyst
Time (h)
Yielda (%)
eeb,c (%)
Entry
Catalyst
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
4
5
6
7
8
9
1
1
5a
5b
5c
5d
5d
5d
5e
5f
4
4
4
4
4
4
4
4
4
4
4
87
76
84
81
44
92
66
72
95
93
66
53
80
84
80
51
74
58
77
88
86
66
1
2
3
4
5
6
7
8
9
10
11
1
1
1
1
1
1
9a
9b
9c
9d
9d
9d
9e
9f
9g
9h
9h(EP)
9i
9i(EP)
4
4
4
4
4
4
4
4
4
4
12
4
16
4
12
4
91
92
92
95
92
93
86
90
92
92
80
92
88
91
68
86
93
73
87
90
95
95
95
89
67
87
90
82
93
90
90
81
82
86
d
d
e
e
5g
5h
5i
0
1
f
2
3
4
5
6
7
a
The reaction was carried out with 1.2 equiv of benzyl bromide and 50 wt %
f
aqueous KOH in the presence of 10 mol % of the polymeric catalyst in toluene/
9j
9j(EP)
9k
9l
ꢀ
chloroform (7:3) at 0 C.
f
b
The yields were determined by 1H NMR spectroscopy.
The ee values were determined by HPLC on a chiral stationary phase using
c
4
a Chiralcel OD-H column.
d
a
Isolated yield was determined by 1H NMR spectrum.
Enantiopurity of the alkylated product was determined by HPLC analysis using
Toluene was used as solvent.
CPME was used as solvent.
e
b
Chiral column (Chiralcel (OD-H) with Hexane: IPA (200:1) as solvent).
c
(S) configuration was determined by the relative retention times of the
(
R/S)-isomers reported in the literature.
d
Catalyst recovered from entry 4 was reused.
Catalyst recovered from entry 5 was reused.
e
f
EP means etherification polymerization.
Scheme 2. Asymmetric benzylation of N-diphenylmethylene glycine tert-butyl ester.
Scheme 4. Etherification polymerization of 10,11-hydrocinchonidinium dimer 10 and
dihalide.
3. Conclusions
In conclusion, we have successfully synthesized chiral quater-
nary ammonium polymers by means of quaternization polymeri-
zation of cinchonidine dimer 3 or hydrocinchonidine dimer 8 with
dihalide 4. This is an important example of the highly atom eco-
nomical polymerization method to prepare chiral polymers. In
most cases, hydrocinchonidinium polymers 9 gave higher enan-
tioselectivities compared with those obtained from cinchonidinium
polymers 5 in the asymmetric benzylation reaction. The structure
1
2
of spacers (R , R ) between quinuclidine nitrogens in the polymeric
catalysts influenced on the enantioselectivity of the polymeric
catalyst. The polymeric catalyst was easily recovered from the re-
action mixture and reused several times without any loss of the
catalytic activity.
Scheme 3. Quaternization polymerization of hydrocinchonidine dimer 8 and dihalide.
4
4
. Experimental section
.1. General methods
polymer structure is the same as those obtained by quaternized
polymerization. However, both the yields and enantioselectivities
obtained in the asymmetric benzylation reaction with these poly-
mers 9(EP) were somewhat lower compared with those obtained
by using the polymeric catalysts synthesized by quaternization
polymerization (entries 10, 12, 14 vs 11, 13, 15).
All reagents were purchased from SigmaeAldrich, Wako Pure
Chemical Industries, Ltd., or Tokyo Chemical Industry Co., Ltd. at the
highest available purity and used as is unless noted otherwise.
Reactions were monitored by thin-layer chromatography (TLC)
using Merck precoated silica-gel plates (Merck 5554, 60F254).

P. Ahamed et al. / Tetrahedron 69 (2013) 3978e3983
3981
Column chromatography was performed with a silica-gel column
Wakogel C-200, 100e200 mesh). Melting points were recorded
10, 11-dihydrocinchonodine (6.78 mmol, 2.0 g) under N
sphere, and the mixture was stirred at room temperature for 1 h.
The mixture was cooled in an ice-water bath and a solution of
dichloro-p-xylene (3.39 mmol, 0.593 g) in DMF (5 mL) was added.
After 1 h, the ice-water bath was removed and the reaction mixture
was stirred at room temperature for 20 h, and then poured into ice-
2
atmo-
(
1
0
using a Yanaco micro-melting apparatus and are uncorrected. H
NMR (300 MHz) spectra were measured on a Varian Mercury 300
spectrometer. Elemental analyses were performed at the Micro-
analytical Center of Kyoto University. GC analyses were performed
with a Shimadzu Capillary Gas Chromatograph 14B equipped with
a,
a
-
water (50 mL). The mixture was extracted with CH
the combined organic extracts were washed with brine (30 mL) and
dried over anhydrous MgSO . The solvents were evaporated under
2
Cl
2
(30 mLꢁ2),
a capillary column (SPERCO
b-DEX 325, 30 mꢁ0.25 mm). HPLC
analyses were performed with a JASCO HPLC system comprising
a three-line degasser DG-980-50, an HPLC pump PV-980, and
a CO-965 column oven equipped with a chiral column (CHIRALCEL
OD or AD, Daicel); hexane/2-propanol was used as an eluent. A UV
detector (JASCO UV-975 for JASCO HPLC system) was used for peak
detection. Optical rotations were recorded with a JASCO DIP-149
digital polarimeter, using a 10-cm thermostated microcell. Size
exclusion chromatography (SEC) was obtained with Tosoh in-
strument with HLC 8020 UV (254 nm) or refractive index detection.
4
reduced pressure to give a pale yellow solid. The crude solid was
washed with hexane (30 mL) on a glass filter to give 8a as a white
ꢀ
25
solid (1.77 g, 75% yield). Mp 234 C [
a]
D
þ34.77 (c 1.0 g/dL in
1
DMSO). H NMR (300 MHz, CDCl
3
): 0.75e0.80 (m, 3H), 1.18e1.22
(m, 2H), 1.39e1.42 (m, 4H), 1.68e1.75 (m, 4H), 1.98 (s, 1H),
2.31e2.36 (m, 1H), 2.54e2.60 (m, 1H), 2.96e3.04 (m, 2H), 3.44
(br, 1H), 4.19 (s, 1H), 5.63 (d, J¼3.9 Hz, 1H), 7.26e7.40 (m, 1H), 7.57
(d, J¼4.8 Hz, 1H), 7.61e7.66 (m, 1H), 7.95 (d, J¼8.70 Hz, 1H),
13
DMF was used as a carrier solvent at a flow rate of 1.0 mL/min at
8.06e8.09 (m,1H), 8.81 (d, J¼4.2,1H). C NMR (75 MHz, CDCl
3
,
d¼0
ꢀ
4
0 C. Two polystyrene gel columns of bead size 10
mm were used.
((CH
3
)
4
Si)):
d
¼12.23, 21.48, 25.70, 27.80, 28.44, 37.68, 43.47, 58.77,
A calibration curve was made to determine number-average mo-
lecular weight (M ) and molecular weight distribution (M /M
values with polystyrene standards.
60.33, 72.16, 118.42, 123.24, 125.88, 126.79, 129.18, 130.43, 149.61,
150.33. IR (KBr):
(CeO). Anal. Calcd for C46
ꢂ1
ꢂ1
ꢂ1
n
w
n
)
n
¼1590 cm (C]N), 1206 cm (CeN), 1108 cm
54 4 2
H N O
: C 79.44, H 7.77, N 8.05; found C
79.56, H 7.82, N 8.09.
4
.2. Preparation of cinchonidine dimers 3
4.3.2. Preparation of 8b. The same procedure was followed as de-
4
2
.2.1. Preparation of 3a. To a suspension of sodium hydride (0.49 g,
0.4 mmol) in DMF (20 mL) was added (ꢂ)-cinchonidine (3.00 g,
scribed for 8a using 10,11-dihydrocinchonidine (6.78 mmol, 2.0 g)
and trans-1,4-dibromo-2-butene (3.39 mmol, 0.725 g). 1.62 g of 8b
ꢀ
25
1
10.2 mmol) under an atmosphere of dry nitrogen, and the mixture
(74%) was obtained. Mp 236 C [
a
]
D
ꢂ47.00 (c 1.0 g/dL in DMSO). H
was stirred at room temperature for 1 h. The mixture was cooled in
an ice-water bath and a solution of
NMR (300 MHz, CDCl
3
): 0.76e0.81 (m, 3H), 1.18e1.27 (m, 2H),
0
a
,a
-dichloro-p-xylene 2a
1.41e1.50 (m, 4H), 1.67e1.79 (m, 7H), 2.34e2.38 (m, 1H), 2.56e2.65
(m, 1H), 2.99e3.09 (m, 2H), 3.42e3.51 (br, 2H), 5.63 (d, J¼3.9 Hz,
1H), 7.26e7.47 (m, 1H), 7.58 (d, J¼4.8 Hz, 1H), 7.64e7.70 (m, 1H),
(
0.89 g, 5.1 mmol) in DMF (15 mL) was added. After 1 h, the ice-
water bath was removed and the reaction mixture was stirred at
room temperature for 20 h, and then poured into ice-water (70 mL).
The mixture was extracted with CH
organic extracts were washed with brine (30 mL) and dried over
anhydrous MgSO . The solvents were evaporated under reduced
1
3
7.99 (d, J¼7.8 Hz, 1H), 8.10 (d, J¼8.1, 1H), 8.85 (d, J¼4.5 Hz, 1H).
C
2
Cl
2
(30 mLꢁ2), the combined
NMR (75 MHz, CDCl
3
,
d
¼0 ((CH
3
)
4
Si)):
d
¼12.24, 21.62, 25.70, 27.80,
28.46, 37.70, 43.48, 58.786, 60.36, 72.25, 118.38, 123.24, 125.91,
126.81, 129.20, 130.50, 148.43, 149.43, 150.37. IR (KBr):
4
ꢂ1
ꢂ1
ꢂ1
(CeN),
pressure to give a pale yellow solid. The crude solid was washed
with hexane (30 mL) on a glass filter to give 3a as a white solid
n
¼1682 cm
(C]C), 1590 cm
(C]N), 1206 cm
: C 78.40, H 8.96, N
ꢂ1
1083 cm (CeO). Anal. Calcd for C42
H
52
N
4
O
2
ꢀ
25
1
(
2.63 g, 75% yield). Mp 132 C [
NMR (300 MHz, CDCl 1.56 (br, 4H), 1.81 (br, 2H), 2.05 (br, 4H),
.28 (br, 2H), 2.65 (br, 4H), 3.14 (br, 4H), 3.42 (br, 2H), 4.43 (br, 4H),
.92 (br, 4H), 5.73 (br, 2H), 7.27 (br, 4H), 7.59 (br, 4H), 7.75 (br, 2H),
a
]
D
ꢂ1.43 (c 1.0 g/dL in CHCl
3
). H
8.71; found C 78.49, H 8.90, N 8.71.
3
) d
2
4
8
4
4.4. Preparation of cinchonidinium polymers 5
13
.16 (br, 4H), 8.91 (br, 2H). C NMR (75 MHz, CDCl
0.07, 43.44, 57.15, 60.96, 71.28, 114.59, 118.77, 123.39, 126.75,
27.07, 127.99, 129.43, 130.75, 137.62, 141.92, 146.53, 148.79, 150.33.
3
)
d
27.84, 28.11,
4.4.1. Preparation of 5a. A solution of cinchonidine dimer 3a
0
(0.345 g, 0.50 mmol) and
a
,a
-dibromo-m-xylene 4a (0.132 g,
ꢀ
1
0.50 mmol) in 4 mL DMSO was heated at 90 C for 24 h. The whole
mixture was concentrated under reduced pressure and the residue
was dissolved in methanol (8 mL). The methanol solution of the
chiral polymer was poured into ether (200 mL) to precipitate the
product. The precipitate was collected on a glass filter and washed
with ethyl acetate and hexane. The polymer solid was dried under
vacuum to give light brown powder 5a (0.458 g, 96%). [
(c 1.0 g/dL in DMF), Anal. Calcd for C54 : C 67.92, H 6.12,
N 5.87; found C 67.55, H 6.10, N 5.58. M
(SEC)¼21.0 kg/mol,
/M
¼1.43.
ꢂ1
IR (KBr)
50 4 2
n 1584, 1229, 1080 cm . Anal. Calcd for C46H N O :
C 79.97, H 7.29, N 8.11; found: C 79.30, H 7.20, N 8.09.
4
.2.2. Preparation of 3b. The same procedure was followed as de-
scribed for 3a using (ꢂ)-cinchonidine (2.00 g, 6.8 mmol) and trans-
,4-dibromo-2-butene 2b (0.73 g, 3.4 mmol).1.84 g (84% yield) of 3b
2
5
1
a]
D
ꢂ100.3
ꢀ
25
1
was obtained. Mp 205 C [
a
]
D
ꢂ2.57 (c 1.0 g/dL in CHCl
¼1.50 (br, 4H), 1.79 (br, 7H), 2.24 (br, 3H), 2.61
br, 4H), 3.08 (br, 4H), 3.47 (br, 2H), 4.40 (br, 2H), 4.90 (t, J¼6.0 Hz,
H), 5.60e5.78 (m, 4H), 7.36 (t, J¼2.6 Hz, 2H), 7.56e7.68 (m, 4H), 8.01
3
). H NMR
2 4 2
H58Br N O
(
(
4
300 MHz, CDCl
3
)
d
n
M
w
n
13
(
dd, J¼3.0 Hz, 2.8 Hz, 4H), 8.82 (d, J¼4.8 Hz, 2H). C NMR (75 MHz,
4.4.2. Preparation of 5b. The same procedure was followed as de-
scribed for 5a using 3a (0.345 g, 0.50 mmol) and 4b (0.132 g,
CDCl
3
) d¼21.85, 27.79, 28.10, 40.10, 43.40, 57.17, 60.56, 72.07, 114.58,
2
5
118.40, 123.18, 125.86, 126.78, 129.27, 130.47, 141.97, 148.47, 149.47,
0.50 mmol). 5b was obtained in 92% yield (0.437 g). [
(c 1.0 g/dL in DMF), Anal. Calcd for C54 : C 67.92, H 6.12,
N 5.87; found C 67.58, H 5.95, N 5.65. M
(SEC)¼8.5 kg/mol,
/M
¼1.84.
a]
D
ꢂ111.45
ꢂ1
ꢂ1
ꢂ1
150.34. IR (KBr):
n
ꢂ1
¼1633 cm (C]C), 1585 cm (C]N), 1213 cm
2 4 2
H58Br N O
(
CeN), 1098 cm (CO). Anal. Calcd for C42
H
48
N
4
O
2
: C 78.71, H 7.55,
n
N 8.74; found: C 78.60, H 7.43, N 8.81.
M
w
n
4
.3. Preparation of dihydrocinchonidine dimers 8
4.4.3. Preparation of 5c. The same procedure was followed as de-
scribed for 5a using 3a (0.345 g, 0.50 mmol) and 4c (0.157 g,
2
5
4.3.1. Preparation of 8a. To a suspension of sodium hydride
0.50 mmol). 5c was obtained in 90% yield (0.452 g). [
a
]
D
ꢂ67.27
(
13.6 mmol, 0.326 g, washed by hexane) in DMF (15 mL) was added
(c 1.0 g/dL in DMF), Anal. Calcd for C58 : C 69.32, H 6.02,
2 4 2
H60Br N O

3982
P. Ahamed et al. / Tetrahedron 69 (2013) 3978e3983
2
5
N 5.58; found C 69.10, H 5.88, N 5.47. M
¼1.86.
n
(SEC)¼9.3 kg/mol, M
w
/
0.50 mmol). 9c was obtained in 87% yield (0.439 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C58 : C 68.99, H 6.34,
N 5.55; found C 68.19, H 6.47, N 5.43. M
(SEC)¼5.1 kg/mol,
/M
¼1.45.
a
]
D
ꢂ123.4
M
n
2 4 2
H64Br N O
n
4.4.4. Preparation of 5d. The same procedure was followed as de-
M
w
n
scribed for 5a using 3a (0.345 g, 0.50 mmol) and 4e (0.138 g,
2
5
0
.50 mmol). 5d was obtained in 71% yield (0.344 g). [
a
]
D
ꢂ8.83
: C 77.08, H 6.47, N
(SEC)¼7.6 kg/mol,
4.5.4. Preparation of 9d. The same procedure was followed as de-
scribed for 9a using 8a (0.347 g, 0.5 mmol) and 4d (0.157 g,
(c 1.0 g/dL in DMF), Anal. Calcd for C62
H62Cl
2
N
4
O
2
2
5
5
M
.80; found C 76.98, H 6.32, N 5.76. M
/M
¼2.26.
n
0.50 mmol). 9d was obtained in 88% yield (0.444 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C58 : C 68.99, H 6.34,
N 5.55; found C 68.74, H 6.49, N 5.42. M
(SEC)¼6.3 kg/mol,
/M
¼1.48.
a
]
D
ꢂ93.8
w
n
2 4 2
H64Br N O
n
4.4.5. Preparation of 5e. The same procedure was followed as de-
M
w
n
scribed for 5a using 3b (0.320 g, 0.50 mmol) and 4a (0.132 g,
2
5
0
.50 mmol). 5e was obtained in 87% yield (0.392 g). [
a
]
D
ꢂ83.33 (c
: C 66.37, H 6.24, N
(SEC)¼9.3 kg/mol,
4.5.5. Preparation of 9e. The same procedure was followed as de-
scribed for 9a using 8a (0.347 g, 0.5 mmol) and 4e (0.138 g,
1
.0 g/dL in DMF), Anal. Calcd for C50
H56Br
2
N
4
O
2
2
5
6
M
.19; found C 65.98, H 6.14, N 6.02. M
/M
¼2.07.
n
0.50 mmol). 9e was obtained in 58% yield (0.282 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C62 : C 76.70, H 6.80,
N 5.77; found C 76.51, H 6.60, N 5.73. M
(SEC)¼5.3 kg/mol,
/M
¼1.68.
a
]
D
þ250.0
w
n
2 4 2
H66Cl N O
n
4.4.6. Preparation of 5f. The same procedure was followed as de-
M
w
n
scribed for 5a using 3b (0.320 g, 0.50 mmol) and 4b (0.132 g,
2
5
0
(
.50 mmol), 5f was obtained in 93% yield (0.422 g). [
c 1.0 g/dL in DMF), Anal. Calcd for C50 : C 66.37, H 6.24, N
(SEC)¼7.1 kg/mol, M /M ¼1.84.
a]
D
ꢂ104.9
4.5.6. Preparation of 9f. The same procedure was followed as de-
scribed for 9a using 8b (0.321 g, 0.5 mmol) and 4a (0.132 g,
2 4 2
H56Br N O
2
5
6.19; found C 66.15, H 6.14, N 5.95. M
n
w
n
0.50 mmol). 9f was obtained in 95% yield (0.431 g). [
c 1.0 g/dL in DMSO), Anal. Calcd for C50 : C 66.02, H 6.60, N
6.16; found C 67.08, H 7.20, N 7.40. M /M ¼1.63.
(SEC)¼6.0 kg/mol, M
a
]
D
ꢂ141.2
(
2 4 2
H60Br N O
4.4.7. Preparation of 5g. The same procedure was followed as de-
n
w
n
scribed for 5a using 3b (0.238 g, 0.372 mmol) and 4c (0.117 g,
2
5
0
.372 mmol). 5g was obtained in 82% yield (0.292 g). [
a
]
D
ꢂ139.30
: C 67.92, H 6.12, N
(SEC)¼4.2 kg/mol,
4.5.7. Preparation of 9g. The same procedure was followed as de-
scribed for 9a using 8b (0.321 g, 0.5 mmol) and 4b (0.132 g,
(
c 1.0 g/dL in DMF), Anal. Calcd for C54
H58Br
2
N
4
O
2
2
5
5
M
.87; found C 67.58, H 5.97, N 5.66. M
/M
¼2.97.
n
0.50 mmol). 9g was obtained in 95% yield (0.431 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C50 : C 66.02, H 6.60,
N 6.16; found C 65.84, H 6.50, N 5.90. M
(SEC)¼8.0 kg/mol,
/M
¼1.68.
a
]
D
ꢂ87.44
w
n
2 4 2
H60Br N O
n
4.4.8. Preparation of 5h. The same procedure was followed as de-
M
w
n
scribed for 5a using 3b (0.320 g, 0.5 mmol) and 4d (0.157 g,
2
5
0
.50 mmol). 5h was obtained in 84% yield (0.403 g). [
a
]
D
ꢂ139.0
: C 67.92, H 6.12, N
(SEC)¼8.5 kg/mol,
4.5.8. Preparation of 9h. The same procedure was followed as de-
scribed for 9a using 8b (0.321 g, 0.5 mmol) and 4c (0.157 g,
(
c 1.0 g/dL in DMF), Anal. Calcd for C54
H58Br
2
N
4
O
2
2
5
5
M
.87; found C 67.58, H 5.89, N 5.80. M
/M
¼1.87.
n
0.50 mmol). 9h was obtained in 77% yield (0.368 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C54 : C 67.54, H 6.52,
N 5.84; found C 66.72, H 6.32, N 5.57. M
(SEC)¼6.5 kg/mol,
/M
¼1.47.
a
]
D
ꢂ164.9
w
n
2 4 2
H62Br N O
n
4.4.9. Preparation of 5i. The same procedure was followed as de-
M
w
n
scribed for 5a using 3b (0.320 g, 0.5 mmol) and 4e (0.138 g,
2
5
0
.50 mmol). 5i was obtained in 58% yield (0.266 g). [
:C76.05,H 6.60, N6.12;
(SEC)¼3.7 kg/mol, M /M ¼2.49.
a]
D
ꢂ278.4 (c
4.5.9. Preparation of 9i. The same procedure was followed as de-
scribed for 9a using 8b (0.321 g, 0.5 mmol) and 4d (0.157 g,
1.0g/dLinDMF), Anal.CalcdforC58
H60Cl N
2 4
O
2
2
5
found C 75.78, H 6.48, N 6.05. M
n
w
n
0.50 mmol). 9i was obtained in 85% yield (0.406 g). [
c 1.0 g/dL in DMSO), Anal. Calcd for C54 : C 67.54, H 6.52,
N 5.84; found C 66.78, H 6.49, N 5.76. M
(SEC)¼5.7 kg/mol,
/M
¼1.65.
a
]
D
ꢂ119.02
(
2 4 2
H62Br N O
4
.5. Preparation of dihydrocinchonidinium polymers 9
n
M
w
n
4.5.1. Preparation of 9a. A solution of 10,11-hydrocinchonidine di-
mer 8a (0.347 g, 0.5 mmol) and 4a (0.132 g, 0.50 mmol) in 4 mL
DMSO was heated at 90 C for 24 h. The whole mixture was con-
4.5.10. Preparation of 9j. The same procedure was followed as de-
scribed for 9a using 8b (0.321 g, 0.5 mmol) and 4e (0.138 g,
ꢀ
2
5
centrated under reduced pressure and the residue was dissolved in
methanol (8 mL). The methanol solution of the chiral polymer was
poured into ether (200 mL) to precipitate the product. The pre-
cipitate was collected on a glass filter and was washed with ethyl
acetate and hexane. The polymer solid was dried under vacuum to
0.50 mmol). 9j was obtained in 58% yield (0.266 g). [
(c 1.0 g/dL in DMSO), Anal. Calcd for C58 : C 75.65, H 6.95,
N 6.08; found C 75.46, H 6.35, N 6.35. M
(SEC)¼3.5 kg/mol,
/M
¼1.20.
a
]
D
ꢂ114.02
2 4 2
H64Cl N O
n
M
w
n
2
5
give light brown powder 9a (0.422 g, 88%). [
in DMSO), Anal. Calcd for C54 : C 67.58, H 6.67, N 5.84;
found C 67.45, H 6.46, N 5.81. M /M ¼1.90.
(SEC)¼5.1 kg/mol, M
a
]
D
ꢂ102.3 (c 1.0 g/dL
4.5.11. Preparation of 9k. The same procedure was followed as
described for 9a using 8c (0.373 g, 0.5 mmol) and 4a (0.132 g,
H
2 4 2
62Br N O
2
5
n
w
n
0.50 mmol). 9k was obtained in 85% yield (0.429 g). [
c 1.0 g/dL in DMSO), Anal. Calcd for C57 : C 67.79, H 5.94,
N 5.55; found C 67.66, H 6.03, N 5.25. M
(SEC)¼5.1 kg/mol,
/M
¼1.48.
a
]
D
þ13.56
(
2 4 2
H60Br N O
4.5.2. Preparation of 9b. The same procedure was followed as de-
n
scribed for 9a using 8a (0.347 g, 0.5 mmol) and 4b (0.132 g,
M
w
n
2
5
0
.50 mmol). 9b was obtained in 97% yield (0.465 g). [
a
]
D
ꢂ124.9
: C 67.58, H 6.67,
(SEC)¼5.4 kg/mol,
(
c 1.0 g/dL in DMSO), Anal. Calcd for C54
N 5.84; found C 67.35, H 6.74, N 5.78. M
/M
¼1.51.
H62Br
2
N
4
O
2
4.5.12. Preparation of 9l. The same procedure was followed as de-
scribed for 9a using 8c (0.373 g, 0.5 mmol) and 4b (0.132 g,
n
2
5
M
w
n
0.50 mmol). 9l was obtained in 91% yield (0.460 g). [
c 1.0 g/dL in DMSO), Anal. Calcd for C57 : C 67.79, H 5.94,
N 5.55; found C 67.61, H 6.18, N 5.05. M
(SEC)¼4.7 kg/mol,
/M
¼1.52.
a
]
D
ꢂ25.46
(
2 4 2
H60Br N O
4.5.3. Preparation of 9c. The same procedure was followed as
n
described for 9a using 8a (0.347 g, 0.5 mmol) and 4c (0.157 g,
M
w
n

P. Ahamed et al. / Tetrahedron 69 (2013) 3978e3983
3983
4
.6. General procedure for enantioselective benzylation of N-
References and notes
diphenylmethylidene glycine tert-butyl ester (6) using chiral
polymeric catalyst 9d
1
. Enantioselective Organocatalyzed Reactions; Mahrwald, R., Ed.; Springer:
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2
3
. Cinchona Alkaloids in Synthesis and Catalysis; Song, C. E., Ed.; Wiley-VCH
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thylidene glycine tert-butyl ester (6: 0.050 g, 0.170 mmol) were added
into a mixed solvent of toluene (0.7 mL) and chloroform (0.3 mL).
5
0 wt % aqueous KOH solution (0.25 mL) was added to the above
4. O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353e2355.
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5
mixture. Benzyl bromide (0.035 g, 0.203 mmol) was then added
ꢀ
ꢀ
dropwise at 0 C to the mixture. The reaction mixture was stirred
7
vigorously at 0 C. Saturated sodiumchloride solution (2 mL) wasthen
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was washed with water and dichloromethane several times. The or-
ganic phasewas separated, and the aqueous phasewas extracted with
dichloromethane. The organic extracts were washed with brine and
8
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nocatalysis 2; Maruoka, K., Ed.; Thieme: Stuttgart, Germany, 2012; pp 673e695.
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4
dried over MgSO . Evaporation of solvents and purification of the
residual oil by column chromatography on silica-gel (ether/
hexane¼1:10 as eluent) gave (S)-tert-butyl N-(diphenylmethylidene)
phenylalaninate (7) (0.062 g, 0.161 mmol, 95% yield). The enantio-
meric excess (95% ee) was determined by HPLC analysis (Daicel
Chiralcel OD-H, hexane/2-propanol¼100:1, flow rate¼0.3 mL/min,
retention time: R enantiomer¼27.6 min, S enantiomer¼47.9 min).
9
1
0. Chinchilla, R.; Maz oꢀ n, P.; N aꢀ jera, C. Tetrahedron: Asymmetry 2000, 11,
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4
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (No. 23350053) and by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Molecular Activation Directed to-
ward Straightforward Synthesis’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
1
1
635e4641.
1
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2
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1
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.018.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
1
1
1