Design and synthesis of cinchona-based chiral hyperbranched polymers and their application in asymmetric reactions

Article abstract of DOI:10.1016/j.tet.2020.131247

Cinchona-based chiral hyperbranched polymers (HBPs) were designed and successfully synthesized via the Mizoroki-Heck (MH) coupling reaction. AB₂ and A₂B-type chiral monomers were prepared from cinchona squaramide derivatives, where A (vinyl) reacted only with B (iodophenyl) under MH reaction conditions. The chiral HBPs obtained by the MH polymerization contained cinchona squaramide moieties and demonstrated excellent diastereoselectivity and enantioselectivity in asymmetric Michael addition reactions of methyl 2-oxocyclopentanecarboxylate and trans-β-nitrostyrene. These newly designed HBPs were structurally robust and could be reused for further reaction without losing their catalytic activity.

Full text of DOI:10.1016/j.tet.2020.131247

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Design and synthesis of cinchona-based chiral hyperbranched polymers and their
application in asymmetric reactions
Sadia Afrin Chhanda, Shinichi Itsuno
PII:
S0040-4020(20)30389-6
https://doi.org/10.1016/j.tet.2020.131247
TET 131247
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 March 2020
Revised Date: 22 April 2020
Accepted Date: 25 April 2020
Please cite this article as: Chhanda SA, Itsuno S, Design and synthesis of cinchona-based chiral
hyperbranched polymers and their application in asymmetric reactions, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2020.131247.
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Design and synthesis of cinchona-based
chiral hyperbranched polymers and their
application in asymmetric reactions
Sadia Afrin Chhanda and Shinichi Itsuno
Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, 441-8580, Japan.

1
Tetrahedron
journal homepage: www.elsevier.com
Design and synthesis of cinchona-based chiral hyperbranched polymers and their
application in asymmetric reactions
Sadia Afrin Chhandaa and Shinichi Itsunoa
a Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, 441-8580, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Cinchona-based chiral hyperbranched polymers (HBPs) were designed and successfully
synthesized via the Mizoroki-Heck (MH) coupling reaction. AB2 and A2B-type chiral monomers
were prepared from cinchona squaramide derivatives, where A (vinyl) reacted only with B
(iodophenyl) under MH reaction conditions. The chiral HBPs obtained by the MH
polymerization contained cinchona squaramide moieties and demonstrated excellent
diastereoselectivity and enantioselectivity in asymmetric Michael addition reactions of methyl 2-
oxocyclopentanecarboxylate and trans-β-nitrostyrene. These newly designed HBPs were
structurally robust and could be reused for further reaction without losing their catalytic activity.
Available online
Keywords:
Hyperbranched Polymer
Mizoroki Heck
Chiral squaramide
Catalytic activity
Michael addition
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +81-532-44-6813; fax: +81-532-48-5833; e-mail: itsuno@chem.tut.ac.jp

2
Tetrahedron
1. Introduction
of the cinchona-derived iodide and olefinic double bond in the
presence of a Pd catalyst to produce a substituted olefin.23 The
reaction afforded high yields and showed high functional group
selectivity.23
Hyperbranched polymers (HBPs), which are highly
branched three-dimensional macromolecules, have attracted
significant attention for various applications.1,
Compared to
2
Cinchona alkaloid derived organocatalysts possess a C3-vinyl
group that can be used as a MH reactive site. Several types of
cinchona-based chiral organocatalysts have been developed for
asymmetric catalysis.27 For example, cinchona squaramide
derivatives have shown excellent catalytic activities in
asymmetric transformations. In this study, we chose the cinchona
squaramide structure as the chiral catalyst site of the chiral HBPs.
Chiral HBP catalysts are different from the classical polymer-
supported cinchona catalysts.28-32 In this study, we designed the
chiral AB2 monomer using cinchona alkaloid squaramide. We
applied MH polymerization technique to prepare chiral HBPs.
Two iodophenyl groups were introduced into the cinchona
squaramide derivative to obtain the AB2 monomer. One
component self-polycondensation of AB2 monomer gives an
HBP having focal site A and surface (terminal) functional groups
B. The A2B monomer can also be polymerized to give another
type of chiral HBP, which possess focal site B and surface
(terminal) functional groups A.
In both chiral HBPs derived from AB2 and A2B
polymerization, each branching point involves a catalytic active
site. The catalyst conformation in the interior branches may be
uniform or different from that of the corresponding low
molecular weight catalysts in homogeneous solution and the
linear polymer catalysts. The interior cavities of HBP can provide
a suitable microenvironment for asymmetric transformations.
Based on this rationale, we synthesized novel chiral cinchona-
based AB2 and A2B monomers and conducted their MH
polymerization. We subsequently applied these chiral HBPs in
asymmetric catalysis and evaluated their catalytic performance.
linear polymers, HBPs possess properties analogous to those of
dendrimers, such as fragile molecular entanglement, higher
viscosity, higher solubility, and large numbers of functional
groups, because they have diverse branching points and terminal
groups.3-8 As dendrimers have precise molecular weights and
exact numbers of repeating units, they require multistep synthesis
with isolation and purification at each step.3,9-11 Further, this
process is time consuming and difficult to scale up. In contrast,
the preparation of HBPs is suitable for large-scale production,
even though the resulting HBPs constitute a mixture of chains
with different molecular weights.12 The highly branched tree-like
structure is an important and unique characteristic of HBPs,
which differentiates them from linear and cross-linked polymers.1
Various kinds of achiral HBPs have been prepared.1,2,13-21
Although these have promising potential in asymmetric reactions,
the number of synthesized chiral HPBs is limited. We have
previously prepared chiral branched polymers from A2 and B3
monomers.22 In the A2 + B3 approach, network polymers may
form by crosslinking and there is often very little control over the
molar mass and topology.
In this study, we have focused on the AB2 approach to
prepare a novel type of chiral HBPs. The AB2 monomer yields an
HBP with A as the focal unit. The Mizoroki-Heck (MH) coupling
is one of the most efficient C-C bond forming reactions.23 It
proceeds smoothly between olefinic compounds and an aromatic
iodide. We have reported several types of cinchona-based linear
polymers using MH polymerization.24-26 The MH reaction was
performed between an aryl or alkenyl halide and a terminal olefin
Figure 1. Chiral hyperbranched polymer (HBP) catalysts.
2. Results and Disscussions
Novel chiral HBPs containing cinchona squaramide moieties
were designed and synthesized via the MH coupling
polymerization. The monomer for the chiral HBPs was a
cinchona squaramide derivative having an iodophenyl group.
Cinchona squaramide 4 having two iodophenyl groups was
equivalent to an AB2-type monomer for MH polymerization.
Similarly, monomer 7 with two cinchona squaramide units and
one iodophenyl group was an A2B-type monomer.
Polymerization of these monomers to HBPs is illustrated in
Figure 1. One component and one step self-polycondensation is
one of the easiest methods to obtain novel chiral HBPs.
For the synthesis of AB2 monomer 4, a bis-iodophenyl
component is required. Bis(4-iodobenzyl)amine
1
was
synthesized from 4-iodobenzylamine via the Fukuyama
secondary amine synthesis method.33 Then, squaramide squarate
2 was synthesized by reacting 1 with an equimolar amount of
diethyl squarate. AB2 monomer 4 was finally obtained by the
reaction of 2 with 9-amino substituted cinchonidine 3 (Scheme
1).
The A2B type squaramide 7 was synthesized by the reaction of
(5-iodo-1,3-phenylene)dimethanamine
5
with cinchonidine
squaramide 6 (Scheme 2). For comparison of the catalytic

3
performances of the Chiral HBPs and a linear polymer, we also
synthesized monoiodobenzyl squaramide 10 from 4-iodobenzyl
amine 8 and 3 (Scheme 3).
polycondensation system.24 We applied these polymerization
conditions to the synthesis of chiral HBPs. Similarly, monomer 7
was polymerized under these MH conditions to give P2. Linear
polymer PL was also prepared by the MH polymerization. The
obtained chiral HBPs were soluble in DMF and DMSO, and
insoluble in other commonly used organic solvents such as
CH2Cl2, CHCl3, MeOH, EtOAc, and THF. Figure 2 shows the
structure of chiral HBP P1 and P2 and linear polymer PL. The
yield and molecular weight of the HBPs and linear polymer are
summarized in Table 1.
2.1 Preparation of chiral cinchona-based squaramide HBPs
The synthesized chiral monomers contain both an iodophenyl
group and an olefinic double bond. These functional groups are
suitable for the MH reaction. In the presence of Pd(OAc)2,
monomer 4 underwent the MH reaction to give the corresponding
chiral HBP P1 in quantitative yield, as shown in Table 1. The
MH polymerization conditions were established for the synthesis
of chiral cinchona squaramide polymers using a two component
Table 1. Synthesis of chiral HBPs P1, P2 and linear polymer PL from cinchona squaramide 4, 7, 10 and their GPC data.
d
d
Ne
35
Mw
Mw/Mn
1.14
d
Entry
1a
2b
Squaramide
Chiral HBP
Yield [%]
Mn
20000
88000
10000
23000
125000
15000
4
7
P1
P2
PL
99
99
99
183
21
1.43
3c
10
1.48
a Polymerization was carried out with squaramide 4 (0.31 mmol), triethylamine (0.61 mmol) in DMF (3.5 mL) in the presence of 10 mol% Pd(OAC)2.
b Polymerization was carried out with squaramide 7 (0.14 mmol), triethylamine (0.28 mmol) in DMF (3.0 mL) in the presence of 10 mol% Pd(OAC)2.
c Polymerization was carried out with squaramide 10 (0.41 mmol), triethylamine (0.82 mmol) in DMF (4.0 mL) in the presence of 10 mol% Pd(OAC)2.
d Determined by SEC using DMF as a solvent at a flow rate of 1.0 mL min−1 at 40 °C (polystyrene standard).
e Average number of catalyst unit per chain calculated from Mn.

4
Tetrahedron
Figure 2. Structures of chiral HBPs, P1 and P2, and chiral linear polymer PL.
2.2
Asymmetric
Michael
addition
of
methyl
2-
(diastereomer ratio (dr) >100:1). Enantioselectivity (in terms of
enantiomeric excess, ee) of the major diastereomer was 98%
(Table 2 entry 2). The results of the asymmetric reaction are
summarized in Table 2. The catalytic activity of another HBP P2
was almost equivalent to that of P1 (entry 3). We also used a
linear polymer catalyst PL for the same reaction. A similar result
of high stereoselectivity was obtained with PL (entry 4). Further,
all synthesized polymeric catalysts P1, P2, and PL showed
excellent catalytic activity with higher stereoselectivity compared
to the corresponding low molecular weight catalyst 4 (entry 1).
oxocyclopentanecarboxylate to trans-β-nitrostyrene
We tested the catalytic activity of the chiral HBP catalyst P1 (5
mol %, calculated from the unit molecular weight of the polymer
catalyst)) in the asymmetric Michael addition reaction of methyl
2-oxocyclopentanecarboxylate 11 and trans-β-nitrostyrene 12
(Scheme 4). Although P1 was insoluble in solvent used for the
asymmetric reaction, the reaction under the heterogeneous
condition proceeded smoothly to give the corresponding Michael
adduct 13 in 93% yield with excellent diastereoselectivity

5
Scheme 1. Synthesis of squaramide 4.
Scheme 2. Synthesis of squaramide 7.
Scheme 3. Synthesis of squaramide 10.
The effect of solvents on the catalytic performance was
surveyed using P1. In hexane, both the yield and
diastereoselectivity were low (entry 5). In contrast, both THF and
methanol as solvents led to high yields with low
2.3 Recyclability of chiral HBPs
Chiral HBP catalysts were mostly insoluble in commonly used
organic solvents, except for DMF and DMSO. In spite of the
diastereoselectivity
(entries
6
and
7).
Interestingly,
enantioselectivities higher than 99% ee were attained for the heterogeneous system, the asymmetric reaction with chiral HBP
major diastereomer in these solvents (entries 5–7). Lowering the catalysts proceeded smoothly to give the product. The insoluble
catalyst could be easily separated and recovered after completion
of the reaction via simple filtration. Recovered polymeric catalyst
P1 was reused in the same reaction in methanol to examine its
recyclability. P1 could be recycled four times and the results of
the recycling experiments are summarized in Table 3. Even after
recycling for four catalytic runs, the catalytic activity and
reaction temperature to 0 °C in methanol afforded somewhat
higher diastereoselectivity compared to that obtained at room
temperature (entry 8). Two other nitroolefins, 14 and 16, were
tested for the asymmetric reaction with P1 in CH2Cl2 and
methanol. Similar trends in the catalytic activity and
stereoselectivity was observed in these cases (entries 9–12).
stereoselectivity
were
still
maintained.

6
Tetrahedron
Scheme 4. Enantioselective Michael addition of methyl 2-oxocyclopentanecarboxylate 11 to trans-β-nitrostyrene 12.
Table 2. Asymmetric Michael addition reaction of 11 with nitroolefins using HBP catalysts.a
Reaction time
Entry
Catalyst
Solvent
Michael acceptor
Product
Yieldb [%]
drc [%]
eec [%]
[h]
48
24
24
24
48
24
19
24
24
24
24
24
1
2
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
THF
12
12
12
12
12
12
12
12
14
14
16
16
13
13
13
13
13
13
13
13
15
15
17
17
85
93
90
92
64
91
91
70
93
90
92
89
56:1
>100:1
>100:1
>100:1
34:1
98
98
P1
P2
PL
P1
P1
P1
P1
P1
P1
P1
P1
3
98
4
98
5
99
6
51:1
>99
>99
>99
98
7
8d
MeOH
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
42:1
97:1
9
>100:1
54:1
10
11
12
91
>100:1
36:1
98
94
aAsymmetric reaction was carried out with 11 (0.5 mmol), nitroolifin (0.55 mmol) and 5 mol% catalyst in solvent (2.0 mL) at room temperature.
bIsolated yield of the product after column chromatography.
c Enantioselectivity (ee) and dr value were determined using HPLC (Chiralcel OD-H column).
d Reaction was performed at 0 °C.
Table 3. Recyclability of chiral HBP P1 in enantioselective Michael addition reaction of 11 and trans-β-nitrostyrene in
methanol.a
Entry
Fresh polymer
Cycle 1
Reaction time [h]
Yieldb [%]
drc [%]
42:1
eec [%]
>99
92
19
24
24
24
24
91
85
86
88
86
47:1
Cycle 2
39:1
94
Cycle 3
36:1
99
Cycle 4
30:1
99
aAsymmetric reaction was carried out with 11 (0.5 mmol), 12 (0.55 mmol) and 5 mol% catalyst in methanol (2.0 mL) at room temperature.
bIsolated yield of the product after column chromatography.
cEnantioselectivity (ee) and dr values were determined using HPLC (Chiralcel OD-H column).
2.4 Asymmetric Michael addition reaction of other active
methylene compounds to trans-β-nitrostyrene
after 24 h even under heterogeneous conditions and gave high
enantioselectivity (81%, entry 4). Enantioselectivity improved to
85% when this reaction was performed at 0 °C, although the
reaction time was prolonged to 48 h (entry 7). At 50 °C, ee was
Other active methylene compounds (18 and 20) were
examined as Michael donors in the asymmetric addition reaction. reduced to 77% (entry 8). Using HBP P2, the reaction resulted in
In the presence of the low molecular weight cinchona squaramide
catalysts 4, 7, and 10, the reaction of acetylacetone 18 and 12
proceeded smoothly to give the chiral adduct 19 (Table 4, entries
88% yield with 58% ee (entry 5). The corresponding linear
polymer catalyst PL gave the product 19 with almost similar
catalytic activity and enantioselectivity (entry 6). A suitable
1–3). Cinchona squaramide 10 gave the best enantioselectivity microenvironment was created for the asymmetric reaction in the
among these catalysts (entry 3). The corresponding chiral
polymeric catalysts P1, P2, and PL were then applied in the same
reaction. These chiral HBP catalysts showed excellent
chiral polymer network in the case of catalyst P1. The Michael
addition of anthrone 20 to β-nitrostyrene 12 was also examined
using the polymeric catalysts. The HBP P1 catalyst showed
performance in the asymmetric reaction. When P1 was used as a higher enantioselectivity compared to other polymeric catalysts
catalyst in CH2Cl2, chiral product 19 was obtained in 83% yield (entries 9–11).

7
O
O
O
O
NO2
5 mol % cat
Me
Me
+
NO2
Me
Me
CH2Cl2, temp
18
12
19
Scheme 5. Asymmetric Michael addition reaction using chiral HBP catalysts.
Table 4. Asymmetric Michael addition reaction using chiral low molecular weight catalysts and HBP catalysts.a
Entry
Catalyst
4
Michael donor
Product
19
Temperature [°C]
Reaction time [h]
Yieldb [%]
eec[%]
36
1
2
18
18
18
18
18
18
18
18
20
20
20
rt
rt
rt
rt
rt
rt
0
24
24
24
24
24
24
48
24
20
16
16
92
91
90
89
88
85
77
86
82
80
79
7
19
76
3
10
19
95
4
P1
P2
PL
P1
P1
P1
P2
PL
19
81
5
19
58
6
19
58
7
19
85
8
19
50
rt
rt
rt
77
9d
10d
11d
21
61
21
16
21
47
aAsymmetric reaction was carried out with 18 (0.275 mmol), 12 (0.25 mmol) and 5 mol% catalyst in CH2Cl2 (2.0 mL).
bIsolated yield of the product after column chromatography.
c Enantioselectivity (ee) was determined using HPLC (Chiralpak AD-H and Chiralpak AS-H columns for entries 9–11).
dAsymmetric reaction was carried out with 20 (0.24 mmol), 12 (0.20 mmol) and 5 mol% catalyst in CH2Cl2 (2.0 mL).
3. Conclusion
4. Experimental Section
We synthesized novel chiral HBPs from cinchona squaramide
4.1 material and methods
monomers 4 and 7 possessing both vinyl (A) and iodophenyl (B)
groups in their structure. These AB2 and A2B monomers were
successfully polymerized by the MH coupling reaction between
the A and B functionalities to give chiral HBPs P1 and P2,
respectively. The chiral HBPs (P1, P2) prepared by one step MH
polymerization were used as catalysts in asymmetric Michael
reactions. The reactions occurred smoothly to give the
corresponding chiral product. In case of the reaction between
methyl 2-oxocyclopentanecarboxylate 11 and trans-β-nitrostyrene
12, the HBP catalysts showed high catalytic activity with
excellent diastereoselectivity and enantioselectivity. Reactions
between some other substrate combinations also occurred
smoothly with the HBP catalysts. P1 exhibited superior
selectivity in these reactions. Interestingly, the HBP catalysts
gave higher diastereoselectivity compared to that obtained with
the low-molecular-weight catalyst 4. Somewhat higher catalytic
activity was also observed with HBP catalyst. Precise control of
the catalyst conformation may be possible in case of polymer
catalyst. These results show that the design of chiral HBP catalyst
may lead the development of high performance polymeric
catalyst.The HBP catalysts were easily recovered from the
reaction mixture and reused several times without any decrease in
catalytic activity and stereoselectivity.
All reagents and solvents were purchased from Sigma Aldrich,
Wako Pure Chemical Industries, Ltd., or Tokyo Chemical
Industry (TCI) Co., Ltd. To monitor the progress of the reactions,
thin layer chromatography (TLC) was performed using pre-coated
silica gel plates (Merck TLC silica gel, 60F254). To purify the
synthesized compounds, column chromatography was performed
using a silica gel column (Wakogel C-200, 100–200 mesh). NMR
spectra were recorded on JEOL JNM-ECS400 and JEOL JNM-
ECX500 spectrometers in CDCl3 or DMSO-d6 at room
temperature operated at 400 MHz (1H) and 500 MHz (1H), and
400 MHz (13C{1H}) and 500 MHz (13C{1H}), respectively.
Chemical shifts are reported in parts per million (ppm) using
tetramethylsilane (TMS) as a reference and the J values are
reported in Hertz (Hz). IR spectra were recorded using KBr
pellets on
a
JASCO FT/IR-230 spectrometer and the
wavenumbers are reported in cm−1. HRMS (ESI and APCI) data
was obtained using a Bruker micro OTOF II HRMS instrument.
High-performance liquid chromatography (HPLC) was performed
on a Jasco HPLC system composed of a DG-980-50 three-line
degasser, an HPLC pump (PU-980), and CO-2065 column oven
equipped with a chiral column (Chiralcel OD-H, Chiralpak AD-
H, and Chiralpak AS-H, Daicel) using hexane/2-propanol as the
eluent at a flow rate of 1.0 mL/min and 0.7 mL/min at room
temperature. For peak detection, a Jasco UV-975 UV detector

8
Tetrahedron
was used. Size exclusion chromatography (SEC) was performed
using a Tosoh instrument with HLC 8020 UV (254 nm) or a
refractive index detector. Two polystyrene gel columns with a
bead size of 10 μm were used and dimethylformamide (DMF)
6.38, 6.80–8.20, 8.92; IR (KBr): ν = 3586, 3470, 2933, 2862,
2385, 2114, 1790, 1673, 1582, 1431, 1319, 1257, 1143, 1059,
969, 844, 767, 620 cm−1; [α]23.9D = −22.1(c 0.05, DMF); Mn
(SEC) = 20000; Mw/Mn = 1.14.
was used as the carrier solvent at a flow rate of 1.0 mL min−1 at The other two chiral HBPs used in this study were synthesized by
40 °C. A calibration curve was established to determine the
number average molecular weight (Mn) and molecular weight
distribution (Mw/Mn) values by comparison with polystyrene
standards. Optical rotations were determined on a JASCO DIP-
149 digital polarimeter using a 10 cm thermostatted microcell.
following this procedure.
4.5 Synthesis of P2
Squaramide 7 (140 mg, 0.139 mmol) and double amount of
triethyl amine (38 µL, 0.279 mmol) were taken in 20 mL flask.
After adding palladium acetate (10 mol %) and DMF (3 mL)
reaction mixture was stirred for 48 hours at 100 oC. Subsequently,
the solution was concentrated by evaporation and poured into
diethyl ether. The precipitated polymer was collected by filtration
and washed with diethyl ether (3×60 mL) and water (40 mL).
After that the compounds were dried over in vacuum oven to
afford the P2 as a light brown Solid. Yield: 138 mg; 1H NMR
(500 MHz, DMSO-d6); δ 0.72-2.0, 2.95, 4.65, 5.01, 5.86, 6.39,
7.0-8.58, 8.98; IR (KBr); ν = 3470, 3223, 2936, 2866, 2128,
1797, 1671, 1619, 1530, 1428, 1240, 1084, 979, 814, 767,
4.2 Synthesis of squaramide 2
In a 30 mL flask, 5.0 mmol (734 µL) of diethylsquarate and 15
mL of ethanol were mixed. Next, 2.0 mmol of triethyl amine was
added and to the stirred solution, 1.0 mmol (449 mg) of bis(4-
iodobenzyl)amine 1 was added slowly. The mixture was stirred at
reflux for ~18 h under Ar. Subsequently, the solution was cooled
to room temperature. Eventually, off-white crystals were formed,
which were filtered and dried. Yield: 430 mg (75%). Rf: 0.43
1
(hexane/EtOAc = 2.0/1.0); mp: 145–149 ºC; H NMR (400 MHz,
619 cm−1.
[α]24.1D = –104
(c
0.02,
DMF).
Mn
CDCl3): δ 1.44 (t, J = 7.2 Hz, 3H), 4.37 (s, 2H), 4.67 (s, 2H), 4.81
(q, J = 6.8 Hz, 2H), 6.95 (dd, J = 7.6 Hz and 14.4 Hz, 4H), 7.71
(dd, J = 8.4 Hz and 12.4 Hz, 4H); 13C NMR (400 MHz, CDCl3): δ
15.99, 50.58, 51.20, 70.32, 94.39, 130.05, 130.69, 134.25, 134.37,
138.27, 138.39, 171.95,176.79, 182.80, 188.68; IR (KBr): ν =
3076, 2979, 2880, 2081, 1908, 1800, 1702, 1562, 1460, 1383,
1282, 1183, 1069, 984, 889, 795, 719, 628, 532 cm−1; HRMS
(APCI) m/z for C20H18I2NO3 [M+H+] calcd. 573.9376, found
573.9371.
(SEC) = 88000; Mw/Mn = 1.43.
4.6 Synthesis of PL
Squaramide 10 (250 mg, 0.414 mmol) and triethyl amine
(115.8 µL, 0.828 mmol) were taken in a 20 mL flask and
palladium acetate (10 mol %) and DMF (4 mL) were added in the
reaction mixture and it was stirred for 48 hours at 100 oC.
Subsequently, the solution was concentrated by evaporation and
poured into diethyl ether. The precipitated polymer was collected
by filtration and washed with diethyl ether (3×60 mL) and water
(40 mL). After that the compounds were dried over in vacuum
4.3 Synthesis of squaramide 4
Compound 2 (410 mg, 0.714 mmol) was mixed with 10 mL of
ethanol in a 30 mL volumetric flask. To the stirred solution, 0.862
mmol (253 mg) of 3 in 10 mL ethanol was added slowly. The
mixture was stirring at reflux for ~24 h under Ar. A white
precipitate was formed, and it was filtered, washed with ethanol,
and dried to obtain 4 (460 mg, 78%) as a white solid. Rf: 0.48
1
oven to afford the PL as a light brown Solid. Yield: 248 mg; H
NMR (400 MHz, DMSO-d6): δ 0.93-1.93, 2.95, 4.65, 6.41, 7.0–
8.60, 8.44; IR (KBr): ν = 3469, 3222, 2935, 1797, 1673 1590,
1459, 1348, 1242, 973, 846, 768, 617, 529 cm−1; [α]24.3D = –101 (c
0.035, DMF); Mn (SEC) = 10000; Mw/Mn = 1.48
1
(CH2Cl2/MeOH = 9.0/1.0; mp: 229–232 ºC. H NMR (400 MHz,
CDCl3): δ 0.90 (m, 1H), 1.29 (m, 2H), 1.57 (m, 4H), 2.27 (br,1H),
2.57–3.14 (m, 4H), 4.59 (br, 4H), 4.93 (m, 2H), 5.63 (m, 1H),
6.95 (d, J = 8.0 Hz, 4H), 7.72 (m, 8H), 8.14 (d, J = 8.0 Hz, 1H),
8.86 (d, J = 4.4 Hz, 1H); 13C NMR (500 MHz, CDCl3): δ 25.9,
27.31, 27.69, 39.54, 40.77, 56.0, 94.20, 114.90, 123.57, 127.16,
129.56, 135.32, 138.41, 141.20, 149.99, 167.46, 168.0, 182.87,
183.50. IR (KBr): ν = 3324, 3065, 2933, 2862, 1788, 1667, 1561,
1484, 1343, 1285, 1182, 1088, 981, 839, 771, 649, 564 cm−1;
HRMS (APCI) m/z for C37H35I2N4O2 [M+H+] calcd. 821.0849,
found 821.0844; [α]23.7D = –166 (c 0.22, DMF).
4.7 Enantioselective Michael addition reaction of Methyl 2-
oxocyclopentanecarboxylate to trans-β-nitrostyrene
trans-β-Nitrostyrene 12 (82.1 mg, 0.55 mmol) and the HBP (5
mol%, calculated from the unit molecular weight of the polymer
catalyst) were added to a reaction vessel with 2.0 mL of solvent.
Methyl 2-oxocyclopentanecarboxylate 11 (63 μL, 0.50 mmol)
was added via a syringe into the resulting solution. The reaction
was stirred at room temperature and its progress was monitored
by TLC. The reaction mixture was then filtered, and the filtrate
was concentrated in vacuo. The crude compound was purified by
column chromatography on silica gel (100–200 mesh) using
hexane/EtOAc = 6.0/1.0 as the eluent to afford the addition
product 13 as a colorless oil. The enantioselectivity (ee) and
diastereomeric ratio (dr) were determined using HPLC on a
Chiralcel OD-H column using solvent mixture hexane:2-
propanol=4:1. Experiments to understand the effect of the solvent,
substrate scope, and recyclability were conducted according to
this procedure.
4.4 Synthesis of chiral cinchona-based squaramide
hyperbranched polymers via the MH polymerization
In a 30 mL flask, squaramide 4 (250 mg, 0.305 mmol) and two
equivalents of triethylamine (85.0 µL, 0.610 mmol) were mixed
together. Next, palladium acetate (10 mol%) and DMF solvent
(3.5 mL) were added and the reaction mixture was stirred for 48 h
at 100 °C. Subsequently, the solution was concentrated by
evaporation and poured into diethyl ether. The precipitated
polymer was collected by filtration and washed with diethyl ether
(3×60 mL) and water (40 mL). Next, the compounds were dried
in a vacuum oven to afford the P1 as a light brown solid. Yield:
245 mg; 1H NMR (400 MHz, DMSO-d6): δ 0.83, 1.20–2.00, 4.62,
4.8 Enantioselective Michael addition reaction between
acetylacetone and trans-β-nitrostyrene

9
5. Tomalia D. A.; Durst H. D. Top. Curr. Chem. 1993, 165, 193-313.
trans-β-Nitrostyrene 12 (37.3 mg, 0.25 mmol) and the HBP (5
mol%) were added to a reaction vessel with 1.0 mL of CH2Cl2.
Next, acetylacetone 18 (30.6 μL, 0.275 mmol) was added using a
syringe into the resulting solution. The reaction was stirred at
room temperature and monitored using TLC. The reaction
mixture was then filtered, and the filtrate was concentrated in
vacuo. The crude compound was purified by column
chromatography using hexane/EtOAc/CH2Cl2 = 6.0/1.0/1.0 as the
eluent on silica gel (100-200 mesh) to afford the addition product
19 as a white solid. The ee values were determined using HPLC
on a Chiralpak AD-H column using solvent mixture hexane:2-
propanol=9:1.
6. Newkome G. R.; Moorefield C. N.; Baker G. R.; Johnson A. L.; Behera R.
K. Angew. Chem., Int. Ed. Engl. 1991, 30, 1176-1178.
7. Voit B. I. Acta Polym. 1995, 46, 87-99.
8. Morikawa A.; Kakimoto M.; Imai Y. Macromolecules 1991, 24, 3469-
3474.
9. (a) Tomalia D. A.; Baker H.; Dewald J.; Hall M.; Kallos G.; Martin S.;
Roeck J.; Ryder J.; Smith P. Polym. J. 1985, 17, 117-132. (b) Tomalia D. A.;
Baker H.; Dewald J.; Hall M.; Kallos G.; Martin S.; Roeck J.; Ryder J.; Smith
P. Macromolecules 1986, 19, 2466-2468.
10. Newkome G. R.; Yao Z.; Baker G. R.; Gupta V. K. J. Org. Chem. 1985,
50, 2003-2004.
11. Morikawa A.; Kakimoto M.; Imai Y,.Macromolecules 1993, 26, 6324-
6329.
12. Yan D.; Gao C.; Frey H. Hyperbranched Polymers. Synthesis, Properties,
and Applications. John Wiley & Sons, 2011.
13. Gao C.; Yan D. Prog. Polym. Sci. 2004, 29, 183-275.
14. Zimmerman S. C.; Lawless L. Top. Curr. Chem. 2001, 217, 95-120.
15. Vogtle F.; Gestermann S.; Hesse R; Schwierz H.; Windisch B. Prog.
Polym. Sci. 2000, 25, 987-1041.
16. Gong L. -Z.; Hu Q. -S.; Pu L. J. Org. Chem. 2001, 66, 2358-2367.
17. Wyatt S. R.; Hu Q. -S.; Yan X. -L.; Bare W. D.; Pu L. Macromolecules
2001, 34, 7983-7988.
18. Ma L.; Lee S. J.; Lin W. Macromolecules 2002, 35, 6178-6184.
19. Satoh N.; Nakashima T.; Yamamoto K. J. Am. Chem. Soc. 2005, 127,
13030-13038.
20. Imaoka T.; Tanaka R.; Arimoto S.; Sakai M.; Fujii M.; Yamamoto K. J.
Am. Chem. Soc. 2005, 127, 13896-13905.
21. Yamanaka K.; Jikei M.; Kakimoto M. Macromolecules 2000, 33, 6937-
6944.
22. Chhanda S. A.; Itsuno S. J. Catal. 2019, 377, 543-549.
23. (a) Mizoroki T.; Mori K.; Ozaki A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
(b) Heck R. F.; Nolley J. P. J. Org. Chem. 1972, 37, 2320-2322. (c) Heck R.
F. Org. React. 1982, 27, 345-390.
4.9 Enantioselective Michael addition reaction between anthrone
and trans-β-nitrostyrene
trans-β-Nitrostyrene 12 (29.8 mg, 0.20 mmol) and the HBP
catalyst (5.0 mol%) were added to a reaction vessel with 2.0 mL
of CH2Cl2. Anthrone 20 (46.6 mg, 0.24 mmol) was added to the
resulting solution. The reaction was stirred at room temperature
and monitored using TLC. The reaction mixture was then filtered,
and the filtrate was 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 21 as a
white solid. The ee was determined using HPLC on a Chiralpak
AS-H column using solvent mixture hexane:2-propanol=5:1.
Acknowledgement
24. Ullah M. S.; Itsuno S. Mol. Catal. 2017, 438, 239-244.
25. Ullah M. S.; Itsuno S. ACS Omega 2018, 3, 4573-4582.
26. Kumpuga B. T.; Itsuno S. J. Catal. 2018, 361, 398-406.
27. Tian S.-K.; Chen Y.; Hang J.; Tang L.; Daid P. M. C.; Deng L. Acc.
Chem. Res. 2004, 37, 621-631.
The authors would like to thank Dr. Naoki Haraguchi at the
Toyohashi University of Technology for useful discussions.
28. Kacprzak K.; Gawronski J. Synthesis, 2001, 7, 961-998.
29. Sykora D.; Vozka J.; Tesarova E.; Kalikova K.; Havlik M.; Matejka P.;
Kral V., Electrophoresis, 2017, 38, 1956–1963.
Reference
30. Fernandes S. D.; Porta R.; Barrulas P. C.; Pugliusi A; Burke A. J.;
Benaglia M. Molecules, 2016, 21, 1-9.
31. Itsuno S. J. Syn. Org. Chem. Jpn. 2016, 74, 710-719.
32. Jumde R.P.; Di Pietro A.; Manariti A.; Mandoli A. Chem. Asian J. 2015,
10, 397–404.
1. Zheng Y.; Li S.; Weng Z.; Gao C. Chem. Soc. Rev. 2015, 44, 4091-4130.
2. Yates C. R.; Hayes W. Eur. Polym. J. 2004, 40, 1257-1281.
3. Shi Y.; Nabae Y.; Hayakawa T.; Kobayashi H.; Yabushita M.; Fukuoka A.;
Kakimoto M. Polym. J. 2014, 46, 722-727.
4. Tomalia D. A.; Naylor A. M.; Goddard W. A. Angew. Chem., Int. Ed. Engl.
1990, 29, 138-175.
33. KanT.; Fukuyama T. Chem. Commun. 2004, 353-359.

Design and synthesis of cinchona-based chiral hyperbranched polymers and their
application in asymmetric reactions
Sadia Afrin Chhanda and Shinichi Itsuno*
Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, 441-8580, Japan.
Highlights
• Chiral hyperbranched polymers (HBPs) having cinchona squaramide.
• Highly stereoselective chiral HBPs by one step self-polycondensation.
• Robust and reusable HBP catalyst for asymmetric Michael reaction.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: