Design and synthesis of chiral hyperbranched polymers containing cinchona squaramide moieties and their catalytic activity in the asymmetric Michael addition reaction

Article abstract of DOI:10.1016/j.jcat.2019.07.060

Chiral hyperbranched polymers (HBP) containing cinchona alkaloids were synthesized using a Mizoroki–Heck (MH) coupling polymerization reaction between a cinchona squaramide dimer and tri- or tetra-substituted aromatic iodides. This is a new type of polyme

Full text of DOI:10.1016/j.jcat.2019.07.060

Journal of Catalysis 377 (2019) 543–549
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Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Design and synthesis of chiral hyperbranched polymers containing
cinchona squaramide moieties and their catalytic activity in the
asymmetric Michael addition reaction
⇑
Sadia Afrin Chhanda, Shinichi Itsuno
Department of Applied Chemistry & Life Science, 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:
Chiral hyperbranched polymers (HBP) containing cinchona alkaloids were synthesized using a Mizoroki–
Heck (MH) coupling polymerization reaction between a cinchona squaramide dimer and tri- or tetra-
substituted aromatic iodides. This is a new type of polymeric chiral organocatalyst. We found that the
as-obtained chiral HBPs show excellent catalytic activity in the asymmetric Michael reaction. Almost per-
fect enantioselectivity (>99% ee) was achieved in the reaction of b-ketoester and trans-b-nitrostyrene. The
three-dimensional network structure of the chiral HBPs is structurally robust and can be reused for fur-
ther reaction without any loss in their catalytic activity.
Received 11 June 2019
Revised 26 July 2019
Accepted 31 July 2019
Keywords:
Chiral hyperbranched polymer
Cinchona squaramide
Ó 2019 Elsevier Inc. All rights reserved.
Mizoroki–Heck polymerization
Asymmetric Michael reaction
1
. Introduction
Macromolecular catalysts sometimes display advantages in
their synthesis is usually complicated and contain several tedious
processes [15,16]. HBPs are relatively easily to synthesis using a
one-step polymerization reaction.
asymmetric catalysis [1]. In the transition state of an asymmetric
reaction, macromolecular catalysts may provide a distinct differ-
ence between the preferable diastereomeric transition state and
unfavorable one. The catalyst conformation in the polymer chain
may be resistant to change. On the other hand, due to the relative
conformational flexibility of low molecular weight catalysts, such a
difference may be reduced by stabilization of the unfavorable con-
formation. Suitably designed macromolecular chiral catalysts have
potential to be highly stereoselective catalysts in asymmetric
catalysis. Most macromolecular catalysts involve crosslinked
polymer-supported catalysts. In some cases, linear chiral polymers
containing catalytic sites in their main chain repeating units have
been synthesized. Hyperbranched polymers (HBPs), highly
branched tree-like macromolecules bearing unique three-
dimensional structures, have attracted a lot of attention in various
applications [2–13]. Chiral HBPs containing chiral catalytic moi-
eties are potential polymer catalysts in asymmetric catalysis. Their
interesting chemical and physical properties, and potential appli-
cations have attracted considerable attention. However, only a lim-
ited number of chiral HBPs have been synthesized to date [14].
Although chiral dendrimers have precisely controlled structures,
In the various kinds of chiral organocatalysts available for
asymmetric catalysis, cinchona alkaloid derivatives [17,18] have
shown very successful applications in asymmetric synthesis [19–
23]. As a privileged class of chiral catalysts, cinchona alkaloid-
derived catalysts exhibit outstanding catalytic activity in various
enantioselective reactions [24]. Cinchona-based chiral HBPs have
not been reported to date. In our previous reports, we have devel-
oped a Mizoroki–Heck polymerization reaction to synthesize chiral
linear polymers from cinchona alkaloid derivatives [25–27]. We
have confirmed that the Mizoroki–Heck coupling reaction was a
reliable CAC bond forming reaction to form chiral polymers from
cinchona alkaloid derivatives [25–27]. We noticed that this
methodology is applicable toward the synthesis of chiral HBPs
from cinchona alkaloid derivatives. HBPs are usually easily pre-
pared when compared to dendrimers, which requires a multi-
step synthesis [28]. One of the simple HBPs can be prepared via
the combination of bifunctionalized (A2) and trifunctionalized
(B3) compounds, as shown in Scheme 1. A quantitative reaction
between functionalities A and B is necessary to prepare HBPs.
We have used the Mizoroki–Heck reaction as an efficient CAC bond
forming reaction between an olefinic double bond (A) and aromatic
iodide (B). Cinchona alkaloid possesses an olefinic double bond at
the C3 position, therefore the reaction between cinchona alkaloid
⇑
Corresponding author.
E-mail address: itsuno@chem.tut.ac.jp (S. Itsuno).
https://doi.org/10.1016/j.jcat.2019.07.060
021-9517/Ó 2019 Elsevier Inc. All rights reserved.
0

5
44
S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
rotations were determined on a JASCO DIP-149 digital polarimeter
using a 10 cm thermostatted microcell.
2.2. Synthesis of tris (4((4-iodobenzyl) oxy)phenyl)methane 2a [31]
Tris (4-hydroxy phenyl)methane 3 (292 mg, 1.0 mmol) and 4-
iodo benzyl bromide 4 (979 mg, 3.3 mmol) were dissolved in
5.0 mL of CH CN in a 30 mL flask. After adding cesium carbonate
Cs CO (1.08 g, 3.3 mmol) to the resulting solution, the mixture
was stirred at 60 °C for 10 h under an Ar atmosphere. The reaction
mixture was poured into CH Cl (60 mL) and the organic solution
1
3
+
2
3
A2
B3
2
2
was washed with water (2 ꢁ 30 mL) and brine (2 ꢁ 30 mL), and
then dried over anhydrous magnesium sulfate. The solution was
filtered and evaporated under reduced pressure to give the crude
product, which was purified by column chromatography on silica
Chiral
hyperbranched
polymer (HBP)
gel (hexane:CH
solid. R : 0.42 (CH
NMR (400 MHz, CDCl
J = 8.4 Hz, 6H), 6.98 (d, J = 8.4 Hz, 6H), 7.16 (d, J = 8.0 Hz, 6H),
2 2
Cl ; 55:45) to give 2a (647 mg, 69%) as a white
1
f
2
Cl
2
/hexane = 5.0/5.0); mp: 119–123 °C;
H
3
): d 4.96 (s, 6H), 5.38 (s, 1H), 6.86 (d,
1
3
7
.70 (d, J = 8.0 Hz, 6H); C NMR (100 MHz, CDCl
3
): d 54.5, 69.4,
Scheme 1. Synthesis of chiral hyperbranched polymers (HBPs).
9
3.5, 114.6, 129.3, 130.3, 136.9, 137.2, 137.7, 157.0; Elemental
analysis: calcd C = 51.09% and H = 3.32%, found C = 51.01% and
H = 3.30%.
dimer (A2) and trisubstituted aromatic iodide (B3) may give rise to
chiral hyperbranched polymers.
2.3. Synthesis of demethylated quinine squaramide 1c [27]
Cinchona squaramides [29,30] and their dimers [25], such as 1,
show high stereoselectivity in asymmetric reactions. Therefore, we
used dimer 1 for the synthesis of three chiral HBPs. This is the first
synthesis of cinchona-based chiral HBPs. In this paper we applied
these chiral HBPs in asymmetric catalysis and evaluated their cat-
alytic performance in the asymmetric Michael addition reaction.
Quinine squaramide 1b (500 mg, 0.690 mmol) was dissolved in
dry CH
2
Cl
2
and cooled to ꢀ78 °C under an Ar atmosphere. 30 mL of
1
M BBr
3
in CH Cl
2
2
was added to the resulting solution at ꢀ78 °C
and stirred for 2 h. The reaction mixture was allowed to warm to
room temperature and stirred for 48 h. Water was added to the
3
reaction mixture to decompose the unreacted BBr , 10 wt% NaOH
2
. Experimental
solution added to adjust the mixture to pH 12–13, and the organic
phase was discarded. To the aqueous phase was added 2 N HCl to
adjust the solution to pH 7–8. The resulting precipitate was fil-
2.1. Materials and methods
tered, washed with CH
(471 mg, 98%) as a yellow solid. R
2
Cl
2
and water and dried to give 1c
: 0.74 (CH Cl /MeOH = 5.0/5.0;
decomposition point: 262–277 °C. H NMR (500 MHz, DMSO d ):
All reagents and solvents used during the investigation were
f
2
2
1
procured from Sigma Aldrich, Wako Pure Chemical Industries,
Ltd., or Tokyo Chemical Industry (TCI) Co., Ltd. Thin layer chro-
matography (TLC) was carried out using pre-coated silica gel plates
6
d 0.82 (s, 1H), 1.45–1.65 (m, 4H), 1.83 (br s, 1H), 2.06 (m, 2H),
2.36 (m, 2H), 2.71 (s,1H), 3.71 (br s, 1H), 5.0–5.2 (m, 2H), 5.88–
6.2 (m, 1H), 7.44 (d, J = 8.5, 1H), 7.55 (s, 1H), 7.79 (br s, 1H), 7.95
(
Merck TLC silica gel, 60F254) to monitor the progress of the reac-
tions. Column chromatography was performed to purify the as-
synthesized compounds using a silica gel column (Wakogel C-
(d, J = 8.5 1H), 8.75 (s, 1H), 9.53 (s, 1H, NH) 10.36 (s, 1H, OH); 13
C
NMR (100 MHz, DMSO d
52.0,53.6,60.6, 104.7, 117.7, 123.4, 128.2, 132.6, 139.1, 144.4,
147.8, 147.9, 157.7, 157.8, 168, 183.1. IR (KBr): = 3931, 3801,
6
): d 24.4, 24.5, 39.9, 40.9, 41.5,
2
00, 100–200 mesh). NMR spectroscopy was recorded on JEOL
JNM-ECS400 and JEOL JNM-ECX500 spectrometers in CDCl or
3
m
1
DMSO d
00 MHz ( H), and 100 MHz ( C{ H}). Chemical shifts were
reported in parts per million (ppm) using tetramethyl silane
6
at room temperature operated at 400 MHz ( H),
3417, 3230, 2938, 2824, 2626, 2032, 1798, 1681, 1618, 1587,
1
13
1
ꢀ1
5
1526, 1467, 1277, 1219, 1093, 992, 851, 691 cm ; HRMS (ESI)
+
+
m/z for C42
[a]
D
H
44
N
6
O
4
[M H ] calcd. 697.3502, found 697.3467;
2
5.8
(
(
TMS) as a reference and the J values were reported in Hertz
Hz). IR spectroscopy was recorded using KBR pellets on a JEOL
= –139 (c 0.22, DMF).
JIR-7000 FTIR spectrometer and the wavenumbers were reported
2.4. Synthesis of cinchona-based chiral squaramide hyperbranched
polymers using a Mizoroki–Heck polymerization reaction
ꢀ1
in cm . HRMS (ESI) was recorded on a Bruker micro OTOF II HRMS
instrument. High-performance liquid chromatography (HPLC) was
carried out on a Jasco HPLC system composed of a DG-980-50
three-line degasser, a HPLC pump (PU-980), and a column oven
CO-2065 equipped with a chiral column (Chiralpak OD-H, Daicel)
using hexane/2-propanol as the eluent at a flow rate of 1.0 mL/
min at room temperature. For peak detection, a Jasco UV-975 UV
detector was used. Size exclusion chromatography (SEC) was per-
formed using a Tosoh instrument with HLC 8020 UV (254 nm) or
refractive index detector. Two polystyrene gel columns with a bead
Squaramide 1a (150 mg, 0.225 mmol) and tris(4((4-iodobenzyl)
oxy)phenyl) methane 2a (212 mg, 0.225 mmol) were added to a
20 mL flask and triethyl amine (66 mL, 0.450 mmol) was added to
the mixture. After adding palladium acetate (10 mol%) and DMF
(4 mL), the reaction mixture was stirred for 48 h at 100 °C. The sol-
vent was evaporated and the crude residue was precipitated using
diethyl ether. The compound was dried in a vacuum oven to afford
1
P1aa (355 mg, 62%) as a dark brown solid. H NMR (400 MHz,
size of 10
l
m were used and dimethylformamide (DMF) was used
DMSO d
5.02 (6H,–CH
(vinylic H), 6.8–8.4 (aromatic H), 9.03 (NH); IR (KBr):
6
): d 0.85, 1.12, 1.45–1.87, 2.06, 2.30 (quinuclidine H),
from monomer), 5.39 (–CH from monomer), 6.38
= 3931,
ꢀ1
as the carrier solvent at a flow rate of 1.0 mL min at 40 °C. A cal-
ibration curve was established to determine the number average
2
m
molecular weight (M
n
) and molecular weight distribution (M
w
/
3852, 3710, 3688, 3420, 2930, 2870, 2360, 2041, 1793, 1682,
M
n
) values by comparison with polystyrene standards. Optical
1602, 1586, 1506, 1454, 1419, 1361, 1299, 1221, 1110, 1013,

S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
545
70, 824, 766, 697 cmꢀ1; [
34000; M /M = 2.10.
The other chiral HBPs used in this study were synthesized using
a]
26.1
= +295 (c 0.085, DMF); M
(SEC)
2a containing three iodophenyl groups was easily prepared from
trisphenol 3 and iodobenzylbromide 4 (Scheme 2) [31]. Another
trifunctional compound, 2b, was prepared from trihydroxybenzene
5 and iodobenzoylchloride 6 (Scheme 2) [33]. Tetrafunctional
9
=
n
w
n
this procedure from cinchona squaramides 1a-c and the tri- and
tetraiodo aromatic derivatives.
compound 2c was prepared via
a
two-step synthesis from
literature procedure
1
-bromoadamantane according to a
7
2
.5. Enantioselective Michael addition reaction of b-ketoesters to
(Scheme 3) [34]. Using these components, the novel chiral HBPs
containing cinchona-based squaramides were designed and
synthesized.
trans-b-nitrostyrene.
Trans-b-nitrostyrene 9 (82.1 mg, 0.55 mmol) and the HBP
(
5 mol%) were added to a reaction vessel with 2.5 mL of solvent.
3.1. Preparation of cinchona-based squaramide chiral HBPs
Methyl 2-oxocyclopentanecarboxylate 8 (63 L, 0.50 mmol) was
l
added via a syringe into the resulting solution. The reaction was
stirred at room temperature and was monitored using TLC. The
reaction mixture was then filtered, and the filtrate concentrated
in vacuo. The crude compound was purified by column chromatog-
raphy on silica gel (100–200 mesh) using hexane/EtOAc = 6.0/1.0
as the eluent to afford the addition product 10 as a colorless oil.
The enantioselectivity (ee) and diastereomeric ratio (dr) were
determined using HPLC on a CHIRALCEL OD-H column.
In our previous paper, we prepared linear polymers of 1b by
using Mizoroki-Heck polymerization technique [25]. We applied
this methodology to the synthesis of chiral HBP.
As illustrated in Scheme 1, the repetitive reaction between com-
ponents A2 and B3 may give chiral HBPs. In the presence of Pd
2
OAc) , repetitive Mizoroki–Heck reactions take place between cin-
chona squaramide dimers 1 and various aromatic iodides 2 to give
the corresponding chiral HBPs (P1) in good yield. In most cases, the
as-obtained chiral HBPs were soluble in DMF and DMSO, and partly
(
The other asymmetric Michael addition reactions were con-
ducted using this procedure and the results summarized in Tables
soluble in other commonly used organic solvents, such as CH
2 2
Cl ,
2
and 3 (Scheme 4)
CHCl , MeOH, EtOAc, and THF. Fig. 2 shows the typical structure
3
of chiral HBP P1. Table 1 summarizes the yield and molecular
weight of the as-obtained HBPs.
2
.6. Enantioselective Michael addition reaction of anthrone to trans-b-
nitrostyrene.
3
.2. Asymmetric Michael addition reaction of b-ketoesters to trans
Trans-b-nitrostyrene 9 (29.83 mg, 0.20 mmol) and the HBP
catalyst (10 mol%) were added to reaction vessel with 2.5 mL of
CH Cl . Anthrone 21 (46.62 mg, 0.24 mmol) was added to the
resulting solution. The reaction was stirred at room temperature
and was monitored using TLC. The reaction mixture was then fil-
tered, and filtrate concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (100–200 mesh)
using hexane/EtOAc = 5.0/1.0 as the eluent to afford 22 as a white
solid. The enantioselectivity (ee) and diastereomeric ratio (dr)
were determined using HPLC on a CHIRALCEL AS-H column.
b-nitrostyrene
2
2
Dimeric cinchona squaramide 1a was first examined as an
organocatalyst in the asymmetric Michael addition reaction of
methyl 2-oxocyclopentanecarboxylate 8 and trans-b-nitrostyrene
9
(Scheme 4). In the presence of 1a, the asymmetric reaction
smoothly occurred to give chiral product 10 in 95% yield and 98%
ee (Table 2, entry 1). High diastereoselectivity (>100:1) was also
obtained with 1a. In our previous report, we synthesized chiral lin-
ear polymer PLb from quinine [25]. We also prepared cinchonidine
3
. Results and discussion
Novel chiral HBPs containing cinchona-based squaramides
were designed and synthesized using a combination of bifunc-
tional compound A2 and trifunctional compound B3, as shown in
Scheme 1. As bifunctional compounds, cinchona squaramide
dimers 1a and 1b were synthesized from C9-aminated cinchona
alkaloid and dimethyl squarate according to a literature procedure
(Fig. 1) [25,27,32]. C’6-OH compound 1c was obtained via
demethylation of 1b with BBr (Fig. 1). Trifunctional compound
3
Scheme 2. Synthesis of iodides 2: (i) Cs
2 3 3
CO , CH CN, Ar gas, 60 °C, 10 h; (ii) 4-
3 2
Fig. 1. (i) 1 M BBr , dry CH Cl
2
, Ar gas, –78 °C to rt, 48 h.
dimethylaminopyridine, Et N, CH Cl , rt, 4 h.
3
2
2

5
46
S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
microenvironment for the asymmetric reaction was created in
the chiral polymer network. The polymer effect on the stereoselec-
tivities (dr and ee) may be caused by the conformational rigidity of
HBP catalysts (See Supporting Information). The other chiral HBPs
showed excellent enantioselectivity (>99% ee) except for the result
0
obtained using P1ca bearing a C6 -OH group (Table 2, entry 7),
which may take a different interaction between catalytic moiety
and substrate molecules in the transition state. The corresponding
dimeric catalyst 1c also gave lower stereoselectivity (entry 2). The
structural difference between iodides 2a, 2b, and 2c had almost no
effect on the catalytic activity of their corresponding chiral HBPs
(
entries 5, 8, 9).
Next, the solvent effect on the asymmetric reaction was exam-
ined using P1aa (Table 3). Except for hexane as a solvent (entry 9),
high levels of enantioselectivity (>99% ee) were found for the major
diastereomer. The diastereoselectivity varied with the solvent
used. The reaction of P1aa in dichloromethane gave the desired
product with the highest diastereoselectivity (entry 1).
Scheme 3. Synthesis of 1,3,5,7-tetrakis(4-iodophenyl) adamantane 2c: (i) AlCl
, t-BuBr; (ii) PIFA, I , CHCl
3
,
C
H
6 6
2
3
.
derived linear polymer PLa. These polymers showed the similar
enantioselectivities compared with the results obtained with
dimeric catalyst 1a (entries 3, 4). We then applied the correspond-
ing chiral HBPs (P1–P3) as organocatalysts in the same reaction.
These chiral HBP catalysts showed excellent performance in the
3.3. Recyclability of chiral HBPs
Chiral HBP catalysts P1–P3 were insoluble in dichloromethane
and formed a suspension. The asymmetric reaction occurred in this
heterogeneous system. After completion of the reaction, the chiral
HBPs can be easily separated and recovered via simple filtration.
Recovered polymeric catalysts P1aa and P3ac were reused in the
same reaction to examine their recyclability. P1aa was recycled
six times and P3ac four times, and the results of the recycling
experiments summarized in Tables 4 and 5, respectively. Both
2 2
asymmetric reaction. When P1aa was used as a catalyst in CH Cl ,
chiral product 10 was obtained in 90% yield even under heteroge-
neous conditions (entry 5). Although the diastereoselectivity
decreased to some extent, the enantioselectivity of the major
diastereomer was almost perfect with P1aa (entry 5). The enan-
tioselectivity obtained by the chiral HBP was even higher than that
obtained with the corresponding dimeric catalyst. A suitable
Fig. 2. Typical structure of chiral HBP P1.

S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
547
Table 1
Synthesis of chiral HBPs P1–P3 from cinchona squaramide dimers 1a–c and aromatic iodides 2a–c.
a
a
a
Entry
Dimer
Iodides
Chiral HBP
Yield [%]
M
n
M
w
w n
M /M
A2
B3
1
2
3
5
4
1a
1b
1c
1a
1a
2a
2a
2a
2b
2c
P1aa
P1ba
P1ca
P2ab
P3ac
62
60
60
61
41
34,000
37,000
14,000
16,000
27,000
72,000
46,000
27,000
28,000
46,000
2.10
1.66
1.92
1.69
1.72
a
ꢀ1
Determined by SEC using DMF as solvent at a flow rate of 1.0 mL min at 40 °C (polystyrene standard).
Table 3
Solvent effect for the asymmetric Michael addition reaction of b-ketoester 8 to trans-
a
b-nitrostyrene in the presence of chiral HBP P1aa.
Entry
Solvent
CH Cl
Ethyl acetate
Acetone
Methanol
Acetonitrile
THF
Diethyl ether
Toluene
Reaction time [h]
Yieldb [%]
drc [%]
eec [%]
1
2
3
4
5
6
7
8
9
2
2
24
48
28
18
32
35
38
39
48
90
74
79
78
72
83
80
89
64
27:1
12:1
21:1
12:1
20:1
16:1
7:1
>99
99
>99
>99
99
99
>99
99
9:1
15:1
Hexane
97
a
The asymmetric reactions were carried out at rt with 8 (0.50 mmol),
0.55 mmol), and the monomeric or polymeric catalyst (5 mol%) in 2.5 mL of
solvent.
9
(
b
Isolated yield of the product after column chromatography.
The enantioselectivity (ee) was determined using HPLC (CHIRALCEL OD-H col-
c
umn at a flow rate of 1.0 mL/min).
Table 4
Recyclability examination of chiral HBP P1aa in the asymmetric Michael addition
a
reaction of b-ketoester 8 and trans-b-nitrostyrene.
Entry
Reaction time [h]
Yieldb [%]
drc [%]
eec [%]
Scheme 4. Synthesis of linear polymer PL by MH polymeization.
Fresh polymer
Cycle 1
Cycle 2
Cycle 3
Cycle 4
24
31
32
32
32
32
32
90
85
80
81
86
85
84
27:1
31:1
13:1
28:1
32:1
30:1
29:1
>99
>99
99
>99
99
Table 2
Asymmetric Michael addition reaction of b-ketoester 8 to trans-b-nitrostyrene using
Cycle 5
Cycle 6
>99
>99
a.
dimeric and HBP catalysts.
Yieldb [%]
drc [%]
eec [%]
a
Entry
Catalyst
Reaction time [h]
The asymmetric reactions were carried out at rt with 8 (0.50 mmol), 9
(
0.55 mmol), and the polymeric catalyst (5 mol%) in 2.5 mL of CH
2
Cl
2
.
1
2
3
1a
1c
PLa
PLb
P1aa
P1ba
P1ca
P2ab
P3ac
4
95
89
88
71
90
88
83
84
88
>100:1
2:1
98
71
98
97
>99
99
40
>99
99
b
Isolated yield of the product after column chromatography.
The enantioselectivity (ee) was determined using HPLC (CHIRALCEL OD-H col-
18
24
30
24
24
21
24
24
c
32:1
28:1
27:1
18:1
2:1
d
umn at a flow rate of 1.0 mL/min).
4
5
6
7
8
9
Table 5
20:1
26:1
Recyclability examination for chiral HBP P3ac in enantioselective Michael addition
reaction of b-ketoester 8 and trans-b-nitrostyrene.
a
a
The asymmetric reactions were carried out at rt with 8 (0.50 mmol),
9
Entry
Reaction time [h]
Yieldb [%]
drc [%]
eec [%]
(
0.55 mmol), and the polymeric catalyst (5 mol%) in 2.5 mL of CH
2
Cl
2
.
b
Isolated yield of the product after column chromatography.
The enantioselectivity (ee) was determined using HPLC (CHIRALCEL OD-H col-
Fresh polymer
Cycle 1
Cycle 2
Cycle 3
Cycle 4
24
33
33
33
33
88
84
82
82
80
26:1
17:1
41:1
46:1
40:1
99
99
99
>99
99
c
umn at a flow rate of 1.0 mL/min).
d
See Ref. [25].
a
these chiral HBP catalysts maintained a high level of catalytic
activity without any decrease in the diastereoselectivity and
enantioselectivity.
The asymmetric reactions were carried out at rt with 8 (0.50 mmol), 9
(
0.55 mmol), and the polymeric catalyst (5 mol%) in 2.5 mL of CH
2
Cl
2
.
b
Isolated yield of the product after column chromatography.
The enantioselectivity (ee) was determined using HPLC (CHIRALCEL OD-H col-
c
umn at a flow rate of 1.0 mL/min).
3.4. Michael addition reaction of other substrate combinations
oxocyclopentanecarboxylate 8 and 11, a high level of enantioselec-
tivity was obtained (Table 6 entries 1–4). However, catalyst P1aa
could not catalyze the reaction of malononitrile 19 and chalcone
Chiral HBP P1aa was applied to other Michael addition reac-
tions as shown in Scheme 5. In the reaction with 2-

5
48
S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
Scheme 5. Enantioselective Michael addition reaction of methyl 2-oxocyclopentanecarboxylate 8 to trans-b-nitrostyrene 9.
Table 6
The asymmetric Michael addition reaction using chiral HBP catalyst P1aa.a
Entry
Michael donor
Michael acceptor
Product
Reaction time [h]
Yieldb [%]
drc [%]
eec [%]
1
2
3
4
11
8
8
8
21
21
9
15
16
17
18
22
22
24
24
24
24
17
24
89
91
92
94
85
82
39:1
49:1
21:1
27:1
–
93
94
>99
96
9
12
13
14
9
e
5
d,e
6
9
–
18
a
b
c
The asymmetric reactions were carried out at rt in CH
Isolated yield of the product after column chromatography.
The enantioselectivity (ee) was determined using HPLC (CHIRALCEL OD-H column at a flow rate of 1.0 mL/min for entries 1–4; CHIRALCEL AS-H column at a flow rate of
2
Cl
2
using the chiral HBP catalyst.
0
.7 mL/min for entry 5 and 6; HPLC pump PU 2080, UV/Vis detector UV-2075).
d
P1ca was used as the HBP catalyst.
e
2
2 2
1 (0.24 mmol), 9 (0.20 mmol), and polymeric catalyst (10 mol%) were used in 2.5 mL of CH Cl .
Scheme 6. Asymmetric Michael addition reaction using chiral HBP catalyst P1aa.
2
0. Anthrone 21 was allowed to react with trans-b-nitrostyrene 9
polycondensation reaction. Chiral HBPs P1–P3 were applied in
the asymmetric Michael addition reaction and showed excellent
enantioselectivity (>99% ee) in the Michael addition reaction of
b-ketoesters to trans-b-nitrostyrene. Very high enantioselectivi-
ties were constantly obtained with P1aa in all solvents used in
the asymmetric reaction. The HBPs can be easily separated and
reused up to six times without losing their catalytic activity and
enantioselectivity. This is the first example of a chiral HBP
organocatalyst successfully applied to the asymmetric Michael
addition reaction.
in the presence of P1aa to give the Michael adduct 22 in good yield.
However, only low enantioselectivities were obtained with the chi-
ral HBP catalyst (see Scheme 6).
4
. Conclusions
Chiral HBPs containing the cinchona squaramide moiety were
successfully synthesized from cinchona squaramide dimer 1 and
tri- or tetrasubstituted aromatic iodide 2 via a Mizoroki–Heck

S.A. Chhanda, S. Itsuno / Journal of Catalysis 377 (2019) 543–549
549
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