Polymer-Supported Chiral Cis-Disubstituted Pyrrolidine Catalysts and Their Application to Batch and Continuous-Flow Systems

Article abstract of DOI:10.1021/acs.oprd.0c00268

Polymer-supported cis-pyrrolidine catalysts were developed that allowed for high enantioselectivity and diastereoselectivity compared with those obtained from common trans-pyrrolidine catalysts. Not only configurational but also polymeric effects contribute to the high diastereoselectivity and enantioselectivity. Polymer catalysts were also successfully applied in a continuous-flow process. Acceleration of the reaction rate, an increase in diastereoselectivity, and an improvement in durability were observed in continuous-flow operation compared with the batch system.

Full text of DOI:10.1021/acs.oprd.0c00268

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Polymer-Supported Chiral Cis-Disubstituted Pyrrolidine Catalysts
and Their Application to Batch and Continuous-Flow Systems
Hidenori Ochiai,* Akira Nishiyama,* Naoki Haraguchi, and Shinichi Itsuno
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ABSTRACT: Polymer-supported cis-pyrrolidine catalysts were developed that allowed for high enantioselectivity and
diastereoselectivity compared with those obtained from common trans-pyrrolidine catalysts. Not only configurational but also
polymeric effects contribute to the high diastereoselectivity and enantioselectivity. Polymer catalysts were also successfully applied in
a continuous-flow process. Acceleration of the reaction rate, an increase in diastereoselectivity, and an improvement in durability
were observed in continuous-flow operation compared with the batch system.
KEYWORDS: chiral organocatalyst, diphenylmethylpyrrolidine, polymer-supported catalyst, continuous-flow process,
asymmetric Michael reaction, trans-β-nitrostyrene, butyraldehyde
INTRODUCTION
■
Chiral pyrrolidine derivatives, readily derived from inexpensive
prolines, are among the most important asymmetric organo-
catalysts and are frequently used for asymmetric syntheses of
complex molecules, including active pharmaceutical ingre-
dients (APIs), agrochemicals, and natural products.1 They are
generally stable, readily available, and environmentally friendly,
and therefore, they have attracted the interest of many
synthetic chemists in industrial and academic fields. One of the
most distinguished catalysts is diphenylprolinol silyl ether, also
known as the Jørgensen−Hayashi catalyst.2,3
Figure 1. Our concept: cis-2,4-disubstituted pyrrolidines.
Meanwhile, the immobilization of chiral catalysts on
polymer supports has also been attracting considerable
interest.4 These polymer-supported chiral catalysts are largely
selectivity caused by arranging the substituents on the same
insoluble in most reaction solvents, which allows for easy
recovery and recycling of the catalysts. To date, much effort
has been devoted to the design and development of polymer-
face of the pyrrolidine ring (Figure 1, right).2a,7 In the case of
nonpolymeric 2,4-disubstituted pyrrolidine catalysts, it is
reported that a cis-2,4-disubstituted catalyst was superior to
the corresponding trans-2,4-disubstituted catalyst in terms of
immobilized chiral pyrrolidine catalysts, aiming for high
enantioselectivity and diastereoselectivity.8 As polymer-sup-
catalytic performance as well as high reusability.5 In line with
ported catalysts, we expected that in addition to the reaction
recent developments, some of these catalysts were extended to
site, the polymer chain would further improve the steric bias by
continuous-flow processes, making them further attractive
acting as a bulky substituent. This hypothesis (i.e., polymeric
tools from the viewpoints of operational simplicity, environ-
effect) is partly supported by recent reports on the asymmetric
mental compatibility, and cost efficiency.6
addition of a hydroxylamine derivative9 and malonate10 to
As described above, a wide variety of polymer-supported
enals catalyzed by polystyrene-supported cis-2,4-disubstituted
chiral pyrrolidine catalysts have been investigated, but the
diphenylprolinol silyl ether.
configuration of substituents on the pyrrolidine ring of the
On the basis of this background, we embarked on the
diphenylmethylpyrrolidine moiety has not been well-inves-
synthesis of polymer-supported cis-pyrrolidine derivatives as
tigated to date. In most cases, trans-2,4-disubstituted
efficient catalysts for asymmetric reactions with the intention
pyrrolidine catalysts have been used for polymer-supported
asymmetric catalysts, initially because of their easy availability
and cost efficiency.
However, at this point we envisioned that the polymer-
Special Issue: Flow Chemistry Enabling Efficient
Synthesis
supported cis-2,4-disubstituted pyrrolidine catalysts derived
from cis-4-hydroxyproline would provide higher enantioselec-
tivity and diastereoselectivity than their polymer-supported
trans analogues (Figure 1, left) because of the enhanced facial
Received: June 4, 2020
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© XXXX American Chemical Society
A

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of expanding the application of these catalysts to continuous-
flow synthesis.
mmol, 1 equiv), butyraldehyde (4) (5.0 mmol, 5.0 equiv),
benzoic acid (0.10 mmol, 10 mol %), and 1-cis-OTMS (0.05
mmol, 5.0 mol %) in CH2Cl2 at 25 °C for 24 h afforded the
desired product (2S,3R)-2-ethyl-4-nitro-3-phenylbutanal (5) in
good yield with excellent diastereoselectivity and enantiose-
lectivity (Table 1, entry 1). The reactivity of the polymer
catalyst was strongly influenced by the solvent, which was
partly attributed to swelling of the polymer gel. Since 1-cis-
OTMS is a hydrophobic gel-type polymer, it easily swells in
low-polarity solvents (CH2Cl2, hexane, etc.), which would
maximize the potential of the catalyst (entries 1 and 2 and
Table S1). High conversion was not achieved when high-
polarity solvents were used, partly because the substrate and
reagents cannot approach the active site inside of a nonswollen
polymer catalyst (entries 3−5 and Table S1, entries 5−8).
Decreasing the reaction temperature had little effect on the
diastereoselectivity and enantioselectivity and only decreased
the reaction rate (entry 6 and Table S2, entry 2). The addition
of acid was critical to the catalyst activity, which was attributed
to accelerated generation of the imine as the reactive
intermediate (entry 7 and Table S3).2e Reducing the amount
of catalyst resulted in incomplete conversion even with a
prolonged reaction time, suggesting deactivation of the
polymer catalyst (entry 8 and Table S4).
RESULTS AND DISCUSSION
■
Following the aforementioned concept, we have designed three
types of cis-2,4-disubstituted polymer catalysts with a range of
substituents (1-cis-OTMS, 1-cis-OMe, and 1-cis-H) and their
corresponding trans polymers (2-trans-OTMS, 2-trans-OMe,
and 2-trans-H) for comparison. Cross-linked polystyrene was
chosen as a polymer support because of its mechanical stability
and easily tunable properties. These six polymer catalysts were
synthesized by radical polymerization of monomers bearing a
styrene derivative, styrene, and divinylbenzene (Figure 2; for
the synthesis of the polymer catalysts, see the Supporting
Information).
Configurational Effect and Polymeric Effect. With the
optimal conditions in hand, we next focused on evaluating the
effect of the configuration on the pyrrolidine ring by
comparison of cis and trans polymers in the same reaction
(Tables 2 and S5−S7). As we anticipated, cis polymers
Table 2. Investigation of the Steric Effect of the Substituent
Figure 2. Polymer-supported chiral pyrrolidine catalysts.
Optimization of the Reaction Conditions in the Batch
System Utilizing 1-cis-OTMS. After screening of the
reaction conditions using 1-cis-OTMS, it was found that our
polymer efficiently catalyzed the asymmetric Michael addition
of an aldehyde to nitrostyrene in a heterogeneous batch system
(Table 1). Stirring a mixture of trans-β-nitrostyrene (3) (1.0
a
b
c
Table 1. Screening of the Reaction Conditions
entry
catalyst
yield (%)
dr
% ee
config.
1
2
2-trans-OTMS
1-cis-OTMS
6
28
93
90
97
95
96
51
99
6:1
>20:1
13:1
7:1
5:1
5:1
90.3
99.0
98.0
97.3
78.7
87.0
95.2
95.5
(2R,3S)
(2S,3R)
(2S,3R)
(2S,3R)
(2R,3S)
(2S,3R)
(2R,3S)
(2S,3R)
d
3
4
e
7
5
6
7
8
2-trans-H
1-cis-H
2-trans-OMe
a
b
c
4:1
16:1
entry
solvent
yield (%)
dr
% ee
1-cis-OMe
1
2
3
4
5
CH2Cl2
hexane
THF
EtOAc
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
93
51
3
10
0
79
32
30
>20:1
19:1
7:1
9:1
−
>20:1
8:1
>20:1
99.0
97.8
95.7
95.4
−
98.9
98.2
98.9
a
b
Isolated yields. The dr (syn:anti) values were determined by NMR
c
spectroscopy. The ee values of the syn isomer were determined by
chiral HPLC. The reaction time was 2 h. The reaction time was 1 h.
d
e
d
6
exhibited higher reactivity,11 diastereoselectivity, and enantio-
selectivity compared with the corresponding trans polymers
(entries 1, 2, and 5−8), showing the configurational effect. To
evaluate the polymeric effect, 1-cis-OTMS and monomeric
catalysts 6 and 7 were also tested (entries 2−4). The results
suggest that the diastereoselectivity and enantioselectivity were
enhanced by having the substituent on the same face of the
pyrrolidine ring at C-4 (entries 3 and 4) and that polymer
e
7
f
8
a
b
Isolated yields. The dr (syn:anti) values were determined by NMR
spectroscopy. The ee values of the syn isomer were determined by
chiral HPLC. The reaction was performed at 0 °C. The reaction
was performed in the absence of PhCO2H. A 1 mol % loading of the
c
d
e
f
catalyst was used. The reaction time was 96 h.
B
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chain works as a bulky substituent and further enhances the
facial selectivity (entries 2 and 3), as we hypothesized in Figure
1.
Application to Continuous-Flow Process. Encouraged
by the batch-mode results with our polymeric cis catalysts,
including the clear polymeric and configurational effects, we
turned our attention to the application of these polymer
catalysts to a continuous-flow process as illustrated in Figure 3.
reaction rate compared with the batch system (entry 2). This
can be explained by the relatively high local concentration of
the catalyst. Reducing the residence time further while
increasing the dr value could not achieve high conversion
(entry 3). Increasing the concentration of the reactant showed
improvement in the productivity (entry 4). Increasing the flow
rate resulted in decreased conversion and an increased dr value
(entry 5), while decreasing the flow rate resulted in high
conversion but also a decreased yield, which shows a non-
negligible diffusion effect against the flow direction (entry 6).
Decreasing the reaction temperature resulted in increased
diastereoselectivity as well as enantioselectivity (entry 7).
Durability Study. The durability of the polymer catalyst 1-
cis-H was investigated in both batch and continuous-flow
operations. The result of the recycling test under batch
conditions can be seen in Table S8. In the batch system, all of
the catalysts have low reusability, suggesting fast deactivation
of the catalyst, and it was found that the presence of
butyraldehyde is the main contributor to the deactivation.
This is presumably explained by the generation of an inactive
species such as β,β-disubstituted enamine S23 and hemiaminal
ether S25 (see Table S9 and Scheme S5). This hypothesis is
also supported by the recent report by Schnitzer and
Wennemers.13
Figure 3. Illustration of the continuous-flow process for asymmetric
Michael addition.
A packed-bed reactor was filled with a preground mixture of
1-cis-H (0.100 mmol, 10 mol %) and sea sand. The sea sand
was used as a spacer in order to control the residence time and
to restrict clogging. The temperature of the packed-bed
column was controlled by an HPLC column oven.
On the other hand, improved durability of the catalyst was
observed in continuous-flow operation (Figure 4). As can be
A solution12 of 3 (1.0 mmol, 1 equiv), benzoic acid (0.10
mmol, 10 mol %), and 4 (5.0 mmol, 5.0 equiv) in CH2Cl2 (5
mL) was passed through the packed-bed column at the
indicated flow rate and temperature. After the injection of the
substrate solution was completed, CH2Cl2 (5 mL) was passed
through the column for washout at the same flow rate and
temperature. After evaporation and purification, the resulting 5
was analyzed by NMR spectroscopy, HPLC, and chiral HPLC.
These results are shown in Table 3.
For comparison between the batch and continuous-flow
systems, the results of experiments performed in the batch
system using 10 mol % 1-cis-H can be seen in entry 0. In the
batch system, the conversion was only 69% at 50 min (Table 3,
entry 0, top), and reaction completion required almost 180
min to afford 5 in good yield (entry 0, bottom). Following
these results, it was found that a higher catalyst loading gave a
higher diastereoselectivity and enantioselectivity, suggesting
that the higher loading provided suppression of an undesired
background reaction (Table 2, entry 6). In the continuous-flow
process using 1-cis-H as the catalyst, the asymmetric Michael
addition proceeded smoothly to afford 5 (entry 1). Reduction
of the residence time from 100 to 50 min increased the
Figure 4. Durability study of 1-cis-H in continuous-flow operation.
seen in Figure 4, the continuous-flow reaction showed a
decrease in reaction conversion (red line) and a slight decrease
in diastereomeric ratio (blue line) as time passed, but
interestingly, the turnover number was obviously superior to
that of the batch system without any processing of the catalyst.
Table 3. Asymmetric Michael Addition Using the Continuous-Flow System
a
b
c
d
e
entry
0
T (°C) flow rate (mL/min) column volume (mL) residence time (min) conc. (M) yield (%)
conv. (%)
dr (syn:anti)
% ee
f
25
batch
−
50
180
100
50
0.2
−
69.3
100
−
11:1
9:1
10:1
11:1
12:1
16:1
13:1
17:1
−
f
91.7
86.2
86.5
68.4
89.4
62.0
77.1
48.3
91.1
95.6
91.8
92.3
91.3
92.4
91.1
93.6
1
2
3
4
5
6
7
25
25
25
25
25
25
5
0.05
0.05
0.05
0.05
0.10
0.025
0.05
5.0
2.5
1.0
2.5
5.0
5.0
5.0
0.2
0.2
0.2
0.4
0.2
0.2
0.2
98.6
94.9
82.2
96.1
73.6
99.4
72.9
20
50
50
200
100
a
b
c
d
1
1-cis-H (0.100 mmol) was used. Isolated yields. Determined by HPLC [area/(area + areaSM)]. Determined by H NMR spectroscopy
e
f
(integration of peak area). The ee values of the syn isomer were determined by chiral HPLC. The reaction time is indicated.
C
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It should be mentioned that the enantiomeric excess (green
line) did not change even after extended reaction times.
Although the durability test using 1-cis-OTMS showed a
similar trend, the reaction conversion was relatively low
compared with that of 1-cis-H, suggesting that steric hindrance
at the reaction site influences the reactivity (Figures S3 and
S4).14 It should be noted that increasing the catalyst loading
resulted in increased conversion in the case of 1-cis-OTMS
(Figures S3 and S4), suggesting that further increases in
reaction conversion would be possible.
Investigation of Epimerization. Continuous-flow oper-
ation (as described in Table 3) shows an increase in
diastereoselectivity in line with a decrease in the residence
time as well as an increase in the flow rate. This suggests that
reducing the contact time of the reaction mixture with the
catalyst is important for high dr values. This can be partly
attributed to limiting the undesired epimerization of the
product by minimizing the exposure to the catalyst. In order to
investigate this epimerization effect, the dr value was evaluated
upon treatment with 1-cis-H in the batch system, as shown in
Figure 5 (see Table S14). In the presence of 1-cis-H and
to efficient synthesis of APIs, agrochemicals, etc. using these
catalysts in continuous-flow mode, and further investigation of
the substrate scope and scale-up application to specific APIs is
underway.
EXPERIMENTAL SECTION
■
General Procedure for Asymmetric Michael Addition
of Butyraldehyde to Nitrostyrene. To a solution of trans-β-
nitrostyrene (3) (149 mg, 1.00 mmol, 1 equiv) in a solvent (5
mL) were added an acid (0.100 mmol, 0.10 equiv),
butyraldehyde (4) (361 mg, 5.00 mmol, 5.0 equiv), and a
polymer catalyst (0.0500 mmol, 5.0 mol %) at 25 °C. After 24
h of stirring at the same temperature, the reaction mixture was
filtered to remove the polymer catalyst. The eluent was
concentrated under reduced pressure to obtain the crude
mixture, which was purified by silica gel column chromatog-
raphy (5:1 n-Hex/EtOAc) to afford a diastereomixture of 2-
ethyl-4-nitro-3-phenylbutanal (5) as a colorless oil. The dr
value of 5 (syn-5:anti-5) was determined by 1H NMR
spectroscopyy (integration of peak area). The ee value of
syn-5 was determined by chiral HPLC.
General Procedure for Continuous-Flow Synthesis.
Preliminary Preparation. A mixture of 1-cis-H (0.100 mmol,
10 mol %) and sea sand was ground in a mortar and charged
into a glass column. CH2Cl2 (ca. 10 mL) was passed through
the packed-bed column for swelling of 1-cis-H in advance. The
temperature of the packed-bed column was controlled by a
column oven for HPLC.
Continuous-Flow Experiment. A solution of 3 (149 mg,
1.00 mmol, 1 equiv), benzoic acid (12.2 mg, 0.100 mmol, 10
mol %), and 4 (361 mg, 5.00 mmol, 5.0 equiv) in CH2Cl2 (5
mL) was passed through the packed-bed column at the
indicated flow rate and temperature. After the injection of the
substrate solution was complete, CH2Cl2 (5 mL) was passed
through the column at the same flow rate and temperature for
washout. The eluent was concentrated under reduced pressure
to obtain a crude mixture, which was purified by silica gel
column chromatography (5:1 n-Hex/EtOAc) to afford a
diastereomixture of 5 as a colorless oil. The dr value of 5
(syn-5:anti-5) was determined by 1H NMR spectroscopy
(integration of peak area). The ee value of syn-5 was
determined by chiral HPLC.
HPLC Method. High-performance liquid chromatography
(HPLC) was performed on an LC-2030 Plus chromatograph
with a YMC-triart C18 column (250 mm × 4.6 mm i.d.). The
column oven was set at 40 °C, and the UV detector was set at
210 nm. Mobile phases A (0.1% aqueous phosphoric acid) and
B (acetonitrile) were utilized at a flow rate of 1.5 mL/min.
Mobile phase B was increased linearly from 15% to 80% over
22.5 min and maintained at 80% for 5 min. Retention times: 3
(15.5 min), syn-5 (16.0 min), anti-5 (16.6 min).
Figure 5. Investigation of epimerization.
benzoic acid, the dr value of 5 decreased over time (red line).
On the other hand, in the absence of 1-cis-H, the dr value did
not decrease as expected (green line), suggesting that the
interaction of product 5 with the catalyst caused undesired
epimerization. The addition of butyraldehyde resulted in
partial restriction of undesired epimerization (blue line),
suggesting competitive enamine formation from butyraldehyde
and 1-cis-H.
CONCLUSION
Chiral HPLC Method. The optical purity (enantiomeric
excess) of 5 (syn isomer) was analyzed on an LC-2030 Plus
chromatograph with a Chiralpak OD-H column (250 mm ×
4.6 mm i.d.). The column oven was set at 25 °C, and the UV
detector was set at 215 nm. Isocratic flow (80:20 n-Hex/IPA)
at a flow rate of 0.8 mL/min was used. Retention times:
(2S,3R)-5 (17.7 min), (2R,3S)-5 (22.6 min).
■
An array of polymer-supported cis-2,4-diphenylmethylpyrroli-
dine derivatives were designed and synthesized, with the cis
polymers showing higher diastereoselectivity and enantiose-
lectivity than the trans polymers using the asymmetric Michael
addition of butyraldehyde to trans-β-nitrostyrene as a model
reaction. It was also found that the polymer chain plays an
important role in the high selectivity. Moreover, expanded
investigation of these catalysts to a continuous-flow process
was explored and showed an improvement in durability and
increases in reaction rate diastereoselectivity compared with
the batch system results. These findings lend themselves well
1
syn-5. H NMR (CDCl3) δ 9.72 (dd, J = 2.6, 1.4 Hz, 1H),
7.36−7.27 (m, 3H), 7.19−7.17 (m, 2H), 4.72 (dd, J = 12.6, 4.9
Hz, 1H), 4.63 (dd, J = 12.6, 9.8 Hz, 1H), 3.80 (td, J = 9.8, 4.9
Hz, 1H), 2.71−2.66 (m, 1H), 1.55−1.46 (m, 2H), 0.83 (td, J =
7.5, 1.2 Hz, 3H). 13C NMR (CDCl3) δ 203.2 (1CH), 136.7
D
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Article
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6.1, 0.6 Hz, 1H), 4.76 (dd, J = 13.0, 9.2 Hz, 1H), 3.84−3.77
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00268.
■
sı
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AUTHOR INFORMATION
Corresponding Authors
■
Hidenori Ochiai − Pharma & Supplemental Nutrition
Solutions Vehicle, Pharma Business Division, Kaneka
Cooperation, Takasago, Hyogo 676-8688, Japan; orcid.org/
0000-0003-1544-9663; Email: Hidenori.Ochiai@
kaneka.co.jp
Akira Nishiyama − Pharma & Supplemental Nutrition
Solutions Vehicle, Pharma Business Division, Kaneka
Cooperation, Takasago, Hyogo 676-8688, Japan;
Email: Akira.Nishiyama@kaneka.co.jp
Authors
Naoki Haraguchi − Department of Applied Chemistry and Life
Science, Graduate School of Engineering, Toyohashi University
of Technology, Toyohashi, Aichi 441-8580, Japan
Shinichi Itsuno − Department of Applied Chemistry and Life
Science, Graduate School of Engineering, Toyohashi University
of Technology, Toyohashi, Aichi 441-8580, Japan;
orcid.org/0000-0003-0915-3559
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00268
Author Contributions
̀
2018, 47, 2722−2771. (l) Rodríguez-Escrich, C.; Pericas, M. A.
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Catalytic Enantioselective Flow Processes with Solid-Supported
Chiral Catalysts. Chem. Rec. 2019, 19, 1872−1890. (m) Itsuno, S.;
Haraguchi, N. Catalysts Immobilized onto Polymers. In Catalyst
Immobilization: Methods and Applications; Benaglia, M., Puglisi, A.,
Eds.; Wiley-VCH: Weinheim, Germany, 2020; Chapter 2, pp 23−75.
(5) For polymer-immobilized diphenylprolinol silyl ethers, see:
(a) Varela, M. C.; Dixon, S. M.; Lam, K. S.; Schore, N. E. Asymmetric
Epoxidation, Michael Addition, and Triple Cascade Reaction Using
Polymer-Supported Prolinol-Based Auxiliaries. Tetrahedron 2008, 64,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Prof. Dr. Yujiro Hayashi (Tohoku
University) for the helpful discussions.
■
10087−10090. (b) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe,
̈
G. Control of Four Stereocentres in a Triple Cascade Organocatalytic
Reaction. Nature 2006, 441, 861−863. (c) Kristensen, T. E.; Vestli,
K.; Jakobsen, M. G.; Hansen, F. K.; Hansen, T. A General Approach
for Preparation of Polymer-Supported Chiral Organocatalysts via
Acrylic Copolymerization. J. Org. Chem. 2010, 75, 1620−1629.
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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̈
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1
(12) The stability test of the starting material was performed by H
NMR spectroscopy before the continuous-flow experiment was
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX