Continuous-Flow Dynamic Kinetic Resolution of Racemic Alcohols by Lipase–Oxovanadium Cocatalysis

Article abstract of DOI:10.1002/ejoc.202000186

A continuous-flow dynamic kinetic resolution of racemic secondary alcohols was carried out using a single column reactor packed with a mixture of immobilized lipase and an immobilized oxovanadium species, VMPS4. As a result, optically pure esters were produced in 88–92 % yields. Problems encountered in this study were overcome by using fillers that efficiently maintained the initial distribution of the catalysts in the reactor and by using a packing method in which the mixing ratio of the two catalysts was varied in a stepwise fashion. The flow process led to an increased turnover number of each catalyst compared to those of batch reactions.

Full text of DOI:10.1002/ejoc.202000186

A Journal of
Accepted Article
Title: Continuous-Flow Dynamic Kinetic Resolution of Racemic
Alcohols by Lipase–Oxovanadium Cocatalysis
Authors: Koichi Higashio, Satoko Katsuragi, Dhiman Kundu, Niklas
Adebar, Carmen Plass, Franziska Kühn, Harald Gröger, and
Shuji Akai
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000186
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000186
Supported by

10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
Continuous-Flow Dynamic Kinetic Resolution of Racemic
Alcohols by Lipase–Oxovanadium Cocatalysis
Koichi Higashio,[a] Satoko Katsuragi,[a] Dhiman Kundu,[a] Niklas Adebar,[b] Carmen Plass,[b] Franziska
a]
Kühn,[b] Harald Gröger,*[b] and Shuji Akai*[
Abstract: A continuous-flow dynamic kinetic resolution of racemic
secondary alcohols was carried out using a single column reactor
packed with a mixture of immobilized lipase and an immobilized
oxovanadium species, VMPS4. As a result, optically pure esters were
produced in 88–92% yields. Problems encountered in this study were
overcome by using fillers that efficiently maintained the initial
distribution of the catalysts in the reactor and by using a packing
method in which the mixing ratio of the two catalysts was varied in a
stepwise fashion. The flow process led to an increased turnover
number of each catalyst compared to those of batch reactions.
catalyzed KR with the in situ racemization of the less reactive
enantiomers in a single flask, thus allowing the conversion of
racemic alcohols into optically pure esters in up to 100% yield.[4]
For rapid racemization, an additional catalyst is employed, which
consists of, for example, Ru(II), Ir(III), and Fe(II) complexes or
Pd(0) supported on matrices,[4,5] aluminum compounds,[6]
oxovanadium compounds,[7] strong acids supported on solid
materials,[8] and inorganic solid acids such as zeolites.[9] Some
reagents, such as Ru(II) complexes and the aluminum
compounds, have been proved to be relatively tolerant to lipases,
whereas other catalysts require separation from lipases to
prevent mutual inactivation.
We also invented oxovanadium compounds for the
racemization of benzylic, allylic, and propargylic alcohols and
applied them to the DKR of these racemic alcohols in a batch
system.[10] Among our DKR methods, the use of our original
catalyst, VMPS4, in which oxovanadium species were covalently
bound to the inner surface of mesoporous silica, dramatically
enhanced the catalyst compatibility with immobilized lipases
(Scheme 1).
A pioneering work on the lipase–oxovanadium cocatalyzed
continuous-flow DKR of racemic sec-alcohols was reported by
Poppe et al. using a reactor alternately connected with catalyst
cartridges containing Candida antarctica lipase B and V2O4.[7c]
Another continuous-flow DKR system reported by Souza et al.
used a single column reactor in which four layers of Candida
antarctica lipase B and three layers of VOSO4•nH2O were
alternately arranged and physically separated by a thin cotton
layer.[7a,b] In both cases, the separation of the oxovanadium
compounds with lipase was needed because of their
incompatibility with each other. In contrast, taking the advantages
of excellent compatibility between VMPS4 and lipases,[10] we
applied our DKR process to a continuous-flow system using a
single column reactor packed with a complete mixture of these
two catalysts. However, we realized that our flow system, in which
two different reactions, viz., racemizatio and kinetic resolution,
proceeded simultaneously had critical problems that had not been
observed in our previous batch reactions.[10] We speculate that
Introduction
Flow chemistry has drawn increasing attention in the last few
decades.[1] In particular, the application of flow reactors for
continuously running processes in the presence of
heterogeneous catalysts has emerged with great potential.[1,2] The
use of packed-bed reactors, for example, improves the turnover
numbers and lifetimes of the catalysts by avoiding their tedious
recovery for reuse as in case of batch reactions that requires
additional handling to set up the next reaction. Additionally, the
continuous-flow processes generally present advantages over
batch procedures, such as better mass and heat transfer,
improved safety profiles, easier work-up and as well as the
accurate control of temperature, pressure and reaction time. Thus,
continuous-flow processes have higher productivity and
reproducibility than the batch reactions, and are also favorable for
automation and scale-up.[1-3]
Lipases, a class of hydrolases, exhibit high catalytic activity
and enantioselectivity even in organic solvents and have been
widely used for kinetic resolution (KR) of racemic alcohols.
However, KR has an inherent limitation: the maximum yield of
each product is 50%. To overcome this problem, dynamic kinetic
resolution (DKR) has been developed by combining lipase-
[a]
K. Higashio, S. Katsuragi, Dr. D. Kundu and Prof. Dr. S. Akai
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamadaoka, Suita, Osaka 565-0871, Japan
racemization
lipase
OCOR3
Tel/Fax: 81-6-6879-8210, E-mail: akai@phs.osaka-u.ac.jp
Homepage URL: http://handai-seizo.jp/
OH
R2
O=VX3
(VMPS4)
vinyl ester
X2
V
VMPS4
lipase
vinyl ester
R1
(R)-1
R1
R2
OH
R2
O
O
kinetic
resolution
(R)-2
[b]
N. Adebar, C. Plass, F. Kühn, and Prof. Dr. H. Gröger
Chair of Industrial Organic Chemistry and Biotechnology
Faculty of Chemistry, Bielefeld University
Universitätsstraße 25,33615 Bielefeld, Germany
Tel: 49-521-106-2057, Fax: 49-521-106-6146
E-mail: harald.groeger@uni-bielefeld.de
R1
(±)-1
OH
R2
R1
R2
R1
R2
R1
(S)-1
A
O
1
+
R1
R2
Homepage URL: https://www.uni-
side product 3
bielefeld.de/chemie/arbeitsbereiche/oc1/HG/
Scheme 1. Lipase–Oxovanadium Cocatalyzed Dynamic Kinetic Resolution of
Racemic Alcohols 1.
Supporting information for this article is given via a link at the end
of the document.
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
similar problems could arise in other continuous-flow reactions
using column reactors homogeneously packed with multiple solid
catalysts. In this paper, we report our strategy to overcome these
problems. Furthermore we report the substrate scope of our flow
DKR and the results of continuous-flow operation over 3 days.
particles were mixed well, and the mixture was poured into the
column reactor. Then, a solution of either (±)-1a (0.1 M) or (±)-1b
(0.1 M) with vinyl acetate (0.4 M) in MeCN was pumped into the
reactor at 35 °C at a flow rate of 0.03 mL/min. Note that the
amount of each filler was selected to adjust the residence time to
30 min (for details of the effects of residence time, see Table S1
in Supporting Information). Of the tested fillers, Celite (particle
size 0.020–0.10 mm) and silica gel (particle size 0.040–0.050
mm) were found to be relatively efficient, yielding (R)-2a (ca. 80%
yield, 99% ee) (Table 2, entries 1 and 2) and (R)-2b (ca. 70% yield,
96–98% ee) (entries 4 and 5); however, the slow downstream
movement of VMPS4 was still observed in these cases. After
further investigation, a more advantageous filler, DualPoreTM
silica beads (particle size 0.020–0.063 mm),[15] was discovered.
Thus, a reactor was packed with a homogeneous mixture of CALB,
VMPS4, and DualPoreTM silica beads, which were found to
maintain their initial distribution for more than 3 days when
running the process in a continuous-flow mode (vide infra).
Fortuitously, this experimental setup also resulted in better
consumption of 1 (Table 2, entries 3 and 6) than that using either
Celite or silica gel as the filler. In addition, the use of DualPoreTM
silica beads efficiently enhanced the racemization, giving the best
yield of (R)-2b (Table 2, entries 4–6).
Results and Discussion
First, we carried out preliminary studies on the application of our
batch reactions[10] to continuous-flow KR[11] using a column
reactor[12] which was packed with 0.30 g of Candida antarctica
lipase B (CALB) immobilized on an acrylic resin (commercial
name: Novozym 435 or Chirazyme L-2 C4). During the reaction,
a solution of (±)-1a (0.1 M) and vinyl acetate (0.4 M) in MeCN was
pumped into the reactor at 35 °C. The flow rate of the substrate
solution was changed in a stepwise manner (Table 1), and it was
found that the conversion rate of the reaction reached 50% when
the flow rate was 0.05 mL/min or lower, which secured a
residence time[13] of 15 min or more. In all cases, ester (R)-2a was
obtained with 96–99% ee, and the corresponding E values[14]
were greater than 200.
Table 1. Effects of Flow Rate on the Continuous-Flow KR of (±)-1a Using a
Column Reactor Packed with CALB.
Another issue observed in our continuous-flow DKR was the
formation of significant amounts of dimeric ethers 3a and 3b,
which were generated by the reaction of a racemization
intermediate, allyl cation A, with another molecule of 1 (Scheme
1).[16] Similar problems were also reported in the flow DKR using
other oxovanadium catalysts; however, no solution has been
found yet.[7] After extensive screening of the reaction conditions,
we found that the use of a reactor packed in a stepwise manner
with increasing ratio of VMPS4 to CALB in three layers, had a
significant suppressing effect on the formation of 3b (Table 3,
compare entries 1 and 4, 2 and 5, and 3 and 7). In addition,
reducing the total ratio of VMPS4 to CALB suppressed the
formation of 3b, although the recovery of 1b was gradually
increased (Table 3, entries 4–7). On the other hand, the use of a
reactor packed in a stepwise decreasing ratio of VMPS4 to CALB
produced (R)-2b, (S)-1b, and 3b (Table 3, entry 8), whose molar
ratio was similar to that obtained using the single layer reactor
(Table 3, entries 2 and 3), and the optical purity of recovered (S)-
1b was higher, that is, the racemization of (S)-1b was less
efficient, than that listed in Table 3, entry 6. A similar flow DKR of
(±)-1a using a column reactor with a ratio gradient of CALB and
VMPS4 significantly decreased the molar ratio of 3a and thereby
improved the yield of (R)-2a compared to that using a single layer
reactor (entries 9 and 10). The flow DKR using a similar reactor
with four times amount of each material, CALB (1.20 g), VMPS4
(0.40 g), and DualPoreTM silica (0.39 g), was conducted at the flow
rate of 0.12 mL/min (residence time: 30 min) to produce similar
CALB (0.30 g)
35 °C
OAc
OH
OH
+
1a
(±)- (0.1 M)
vinyl acetate (0.4 M)
in MeCN
(R)-2a
(S)-1a
Flow rate
Residence
time [min]
Conv.[a]
[%]
(R)-2a,
ee[b] [%]
Entry
E value[c]
[mL/min]
1
2
3
4
0.10
7.5
15
20
30
46
50
51
51
99
98
97
96
>200
>200
>200
>200
0.05
0.03
0.02
[a] Conversion was determined by 1H NMR analysis of the crude product
obtained from 2 mL of the eluent collected after the system had reached a
steady state. [b] Optical purity was determined by HPLC using a chiral column,
Daicel CHIRALPAK AD-3 (4.6 mm × 250 mm). [c] See Ref. [14]
We then investigated the DKR of (±)-1a and its para-
methoxy derivative (±)-1b using a column reactor containing a
mixture of CALB and VMPS4 (vanadium content: 0.2 mmol/g);
however, we noticed that the initial homogeneous distribution of
the two catalysts in the column reactor was gradually lost during
operation, resulting in a decrease in the efficiency of our
collaborative catalysis process. This change in the catalyst
distribution was caused by the significantly different particle sizes
of CALB (0.35–0.70 mm) and VMPS4 (0.030–0.050 mm) so that
the smaller VMPS4 particles moved downstream along the flow.
To solve this problem, filler particles were examined to maintain
the initial distribution of the catalysts in the reactor. Thus, CALB
(0.30 g), VMPS4 [100 mg (0.02 mmol of vanadium amount) for 1a
and 20 mg (0.004 mmol of vanadium amount) for 1b], and filler
1
results, 91% H NMR molar ratio of (R)-2a (98% ee) (entry 11)
(for the detail of the flow DKR of 1a, see Supporting Information).
These studies demonstrate an increased efficiency of the column
reactor, when containing two different catalysts, with a suitable
catalyst-ratio gradient for the continuous-flow DKR.
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
Table 2. Effects of Fillers on the Continuous-Flow DKR of (±)-1a, b Using a Reactor Containing CALB and VMPS4.
Entry
1
VMPS4
Filler[a]
(R)-2
(S)-1
3
Ratio[b]
[%]
ee[c]
[%]
Ratio[b]
[%]
ee[c]
[%]
Ratio[b,d]
[%]
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
100 mg
100 mg
100 mg
20 mg
Celite[e] (0.30 g)
(R)-2a
(R)-2a
(R)-2a
(R)-2b
(R)-2b
(R)-2b
84
82
84
71
74
87
99
99
99
97
96
98
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1b
(S)-1b
2
5
nd
nd
nd
91
88
28
3a 14
3a 13
3a 16
silica gel[f] (0.20 g)
DualPore silica[g] (100 mg)
Celite[e] (0.50 g)
<1
28
22
4
3b
3b
3b
1
4
9
20 mg
silica gel[f] (0.28 g)
20 mg
DualPore silica[g] (140 mg)
[a] The amount of the filler was selected to adjust the residence time to 30 min. [b] Molar ratio [%] was determined by 1H NMR analysis of the crude product
obtained from 2 mL of the eluent collected after the system had reached a steady state. [c] Optical purity was determined by HPLC using a chiral column, Daicel
CHIRALPAK AD-3 (4.6 mm × 250 mm). Nd: not determined. [d] The ratio was calculated on the basis of the alcohol moiety and corresponded to half this quantity
based on the molar amount. [e] Kishida Chemical Co., Ltd., particle size: 0.020–0.10 mm. [f] Kanto Chemical Co., Inc., particle size: 0.040–0.050 mm, density:
0.49 g/mL. [g] DPS Inc., particle size: 0.020–0.063 mm, density: 0.16 g/mL.
Table 3. Continuous-Flow DKR of (±)-1a, b Using a Reactor with a Ratio Gradient of CALB and VMPS4.
Entry (±)-1
VMPS4 DualPore
silica[a]
(R)-2
(S)-1
Ratio (w/w) of VMPS4/CALB
Ratio in each layer
3
Total
ratio
Ratio[b] ee[c]
[%] [%]
Ratio[b] ee[c]
[%] [%]
Ratio[b,d]
[%]
1
2
(±)-1b 61 mg 118 mg
(±)-1b 30 mg 135 mg
(±)-1b 15 mg 143 mg
(±)-1b 61 mg 118 mg
(±)-1b 30 mg 135 mg
(±)-1b 22 mg 139 mg
(±)-1b 15 mg 143 mg
(±)-1b 22 mg 139 mg
(±)-1a 100 mg 98 mg
(±)-1a 100 mg 98 mg
0.20:1
0.10:1
0.05:1
0.20:1
0.10:1
0.07:1
0.05:1
0.07:1
0.33:1
0.33:1
0.33:1
one layer
(R)-2b 78
98
98
98
97
98
98
98
98
98
98
98
(S)-1b <1
nd
nd
30
nd
nd
0
3b 22
one layer
(R)-2b 81
(R)-2b 70
(R)-2b 88
(R)-2b 91
(R)-2b 88
(R)-2b 89
(R)-2b 77
(R)-2a 84
(R)-2a 93
(R)-2a 91
(S)-1b <1
(S)-1b 15
(S)-1b <1
(S)-1b <1
3b 19
3b 15
3b 12
3
one layer
4
0.11:1 (1st), 0.17:1 (2nd), 0.33:1 (3rd)
0.06:1 (1st), 0.10:1 (2nd), 0.14:1 (3rd)
0.05:1 (1st), 0.07:1 (2nd), 0.10:1 (3rd)
0.03:1 (1st), 0.05:1 (2nd), 0.07:1 (3rd)
0.10:1 (1st), 0.07:1 (2nd), 0.05:1 (3rd)
one layer
5
3b
3b
3b
9
8
5
6
(S)-1b
(S)-1b
(S)-1b
4
6
4
7
22
74
nd
nd
nd
8
3b 19
3a 16
9
(S)-1a <1
(S)-1a <1
10
11[e]
0.17:1 (1st), 0.33:1 (2nd), 0.50:1 (3rd)
0.17:1 (1st), 0.33:1 (2nd), 0.50:1 (3rd)
3a
3a
7
6
(±)-1a 0.40 g
0.39 g
(S)-1a
3
[a]–[d] Same as footnotes in Table 2. [e] Similarly to the typical procedure for the preparation of (R)-2a shown in the experimental section, a reactor was prepared
using the following materials: 1st column; CALB (400 mg), VMPS4 (68 mg), and DualPore silica (160 mg); 2nd column; CALB (400 mg), VMPS4 (132 mg), and
DualPore silica (132 mg); 3rd column; CALB (400 mg), VMPS4 (200 mg), and DualPore silica (100 mg), which were connected in series. A solution of (±)-1a (89
mg, 0.60 mmol), vinyl acetate (0.22 mL, 2.4 mmol) in dry MeCN (6.0 mL) was pumped through the reactor at a flow rate of 0.12 mL/min (residence time: 30 min)
using a syringe pump. A whole eluent was collected and subjected to 1H NMR and chiral HPLC analyses.
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
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Table 4. Continuous-Flow DKR of Secondary Alcohols (±)-1a–1f.
Figure 1. Continuous-Flow DKR of (±)-1a over 3 Days Using a Five-Layered
Packed Column.
Conclusions
(R)-2a
88%, 99% ee
2:91:7
(R)-2b
92%. 98% ee
<1:91:9
(R)-2c
91%, 99% ee
<1:92:8
We achieved the continuous-flow DKR of various secondary
alcohols to give optically pure esters in 88–92% isolated yields.
Our DKR method features the use of a column reactor packed
with a mixture of two solid catalysts, that is, CALB (commercial
Candida antarctica lipase B immobilized on an acrylic resin) and
VMPS4 (oxovanadium species immobilized on inner surface of
mesoporous silica). Their high compatibility is one of the major
advantages because the catalysts can be mixed without any
special care and their catalytic activity is maintained for days.
However, the large difference in the particle size of these two
catalysts resulted in the loss of the initial homogeneous
distribution in the column reactor. This is due to a move of small
particles when pumping the solution through the reactor and
resulted in a decreased efficacy of the collaborative DKR process.
Another critical issue affecting our continuous flow DKR process
was the formation of side products, in detail dimeric ethers, which
hardly occurred in the batch method. The formation of these side
products was probably caused by increased catalyst
concentration compared to batch. The former problem was
overcome by using DualPoreTM silica beads as a filler, resulting in
the maintenance of the initial distribution of the individual catalysts.
The latter problem was solved by a packing method in which the
mixing ratio of the two catalysts was changed in a stepwise
fashion. The use of DualPoreTM silica beads also enabled the
latter packing method. Thanks to these improvements, the flow
DKR could be conducted for continuous 3 days to produce
optically pure esters by using smaller amounts of CALB and
VMPS4 compared to the corresponding batch reactions.
Considering the increasing need and importance of continuous-
flow reactions,[1–3,7,9b,11,17] these studies should provide useful
information for continuous-flow systems using a column reactor
packed with multiple catalysts where several different reactions
proceed simultaneously.
(R)-2d
92%, 96% ee
<1:92:8
(R)-2e[c]
88%, 99% ee
2:91:7
(R)-2f[d]
92%, 99% ee
5:94:1
[a]The w/w ratios of VMPS4/CALB were 0.33:1 for 2a, 0.10:1 for 2b, 0.14:1 for
2c–2e, and 0.50:1 for 2f. The amount of DualPore silica was selected to obtain
a residence time of 30 min. The ratios of VMPS4/CALB in each layer are listed
in the Supporting Information. [b]The values below each compound number
present the isolated yield and optical purity of (R)-2 and the 1H NMR molar ratio
of 1, 2, and 3 of the crude product. [c]Flow rate: 0.015 mL/min and residence
time: 60 min. [d]Using vinyl butyrate instead of vinyl acetate.
Based on the above results, a range of secondary alcohols
(±)-1a–1f (0.60 mmol) were applied for continuous-flow DKR
using the three-layered column reactor packed with a gradient
ratio of VMPS4 and CALB. The alcohols include aromatic allylic
alcohols 1a–1c, aliphatic dienol 1d, benzylic alcohol 1e, and
propargylic alcohol 1f. After optimization of the ratio of VMPS4 to
CALB for each substrate (±)-1a–1f (for details, see Supporting
Information), the corresponding esters (R)-2a–2f were obtained
in 88–92% isolated yield with 96–99% ee (Table 4). In most cases,
the alcohols were consumed within a residence time of 30 min.
The flow DKR of was continuously conducted for 3 days
(Figure 1). In this case, the addition of two layers comprising
CALB alone before and after the three-layered gradient catalysts
containing VMPS4 and CALB resulted in a slight improvement in
the conversion (a comparison with the DKR using a three-layered
column as well as the time course of these two reactions are
shown in Supporting Information). Thus, the use of 0.50 g of
CALB and 0.10 g (20 mol, 0.16 mmol %) of VMPS4 was enough
to convert (±)-1a (1.82 g, 12.3 mmol) into optically pure (R)-2a
(2.13 g, 11.2 mmol, 91% isolated yield). In our previous batch
system, 100 mg of CALB and 17 mg (0.50 mol %) of VMPS4 were
used to convert 100 mg of (±)-1a to optically pure (R)-2a (98%
isolated yield).[10d] Therefore, the amount of CALB per 1 gram of
1a used in the abovementioned 3-day continuous flow DKR was
reduced to less than 1/10 of the batch reaction and that of VMPS4
was about 1/3 (for detailed comparison, see Supporting
Information). These facts exhibit the higher turnover numbers of
each catalyst in the continuous-flow DKR reactions compared to
those of the batch reactions.
One of the well-known advantages of the flow reactions is
easy scale up while mainlining their efficiency. In this study, an
increased production per hour was proven by a preliminary study
using a reactor with four time amount of each catalyst and filler at
four time flow rate (Table 3, entries 10 and 11). Therefore, we
believe that our method will be applied to further scale-up
production by enlargement of the reactor as well as its numbering-
up.
Further studies on the improvement of our continuous-flow
DKR process using a column reactor with a combination of
immobilized enzymes and immobilized racemization catalysts
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
brine, dried over MgSO4, and evaporated in vacuo. The residue was
purified by column chromatography (CH2Cl2/EtOAc = 9:1) to afford
(±)-1c (1.58 g, 96% yield) as a slight yellow oil. 1H NMR data of the
obtained (±)-1c was in good agreement with those reported in the
literature.[19]
and its application to a wider range of substrates are currently
ongoing in our laboratories.
Experimental Section
A typical procedure for continuous-flow DKR of (±)-1 using a column
reactor with a ratio gradient of CALB and VMPS4 in three layers
(Table 4)
General considerations
Infrared (IR) absorption spectra were recorded on a SHIMADZU
FTIR-8400S spectrophotometer. 1H and 13C NMR spectra were
measured on JEOL JNM-ECA500 (1H: 500 MHz, 13C: 125 MHz) and
JEOL JNM-ECS400 (1H: 400 MHz, 13C: 100 MHz) instruments.
Chemical shifts of 1H and 13C NMR spectra are reported in δ (ppm)
relative to the residual nondeuterated solvent signal for 1H (CHCl3: δ
= 7.26 ppm) and relative to the solvent signal for 13C (CDCl3: δ = 77.0
ppm). The mass spectra (MS) were measured on JEOL JMS-S3000
(MALDI). HPLC analyses were carried out using a JASCO LC-
2000Plus system (HPLC pump: PU-2080, UV detector: MD-2018)
equipped with Daicel CHIRALPAK AD-3 with a size of 4.6 mm x 250
mm. Optical rotations were measured on a JASCO P-1020
polarimeter.
(R,E)-4-Phenyl-3-buten-2-yl acetate [(R)-2a] (The results of the reaction
condition optimization of the flow DKR of (±)-1a are shown in Table S2 in
Supporting Information, and its entry 5 was selected as the best
conditions)
An Omnifit® EZ SolventPlusTM column, its adjustable endpiece, a PTFE
tube, two 12-mL syringes, and three 12-mL screw cap tubes were vacuum-
dried and filled with argon. The first-layer materials for the column reactor
[CALB (100 mg), VMPS4 (17 mg), and DualPore silica (40 mg)] were well
mixed in a screw cap tube and filled with argon. The second-layer
materials [CALB (100 mg), VMPS4 (33 mg), and DualPore silica (33 mg)]
and the third-layer ones [CALB (100 mg), VMPS4 (50 mg), DualPore silica
(25 mg)] were placed in separate tubes, mixed well, and filled with argon.
The first-layer materials were poured into the reactor (Cautions: This
operation was conducted in front of a static eliminator to prevent from
sticking particles to the tube or reactor wall. Tapping of the reactor is not
recommended because the homogeneity of the materials gets lost). In a
similar way, the second-layer materials and the third-layer materials were
placed in the reactor sequentially, and the adjustable endpiece was
fastened to fix the packed layers. PTFE tubes were connected to the
reactor, which was placed in an incubator at 35 °C and washed with dry
MeCN (10 mL) at a flow rate of 0.10 mL/min using a syringe pump. A
solution of (±)-1a (89 mg, 0.60 mmol), vinyl acetate (0.22 mL, 2.4 mmol) in
dry MeCN (6.0 mL) was pumped through the reactor at a flow rate of 0.03
mL/min using a syringe pump. After pumping the whole solution, another
solution of vinyl acetate (0.073 mL, 0.80 mmol) in dry MeCN (2 mL) was
immediately pumped at a flow rate of 0.03 mL/min to wash out the
compounds remaining in the reactor. The whole eluent was concentrated
Candida antarctica lipase B (CALB) immobilized on an acrylic resin
(commercial name: Novozym 435 or Chirazyme L-2 C4) was
purchased from Roche Diagnostics K. K., Japan and was used as
received without further purification. VMPS4 (vanadium content: 0.2
mmol/g) was prepared according to the reported method[10e] (it is now
commercially available from FUJIFILM Wako Pure Chemical Corp.,
Japan). DualPoreTM silica beads (particle size: 0.020–0.063 mm,
density: 0.16 g/mL) consist of microsized through-pores (pore size
0.5–1 µm) and nanosized pores (pore size 20 nm), available from
DPS Inc., was used as received without further purification. Silica gel
60N purchased from Kanto Chemical Co., Inc., Japan was used for
column chromatography. All reagents were of reagent grade. In
general, the reactions were carried out in commercial anhydrous
solvents.
Equipment for Continuous-Flow DKR
1
in vacuo. H NMR analysis of the residue showed that the molar ratio of
An Omnifit® EZ SolventPlus™ column complete AF set (inner
diameter 6.6 mm, total length 100 mm) with an adjustable endpiece
and a fixed endpiece, purchased from Diba Industries Inc., USA, was
used as a reactor for the flow DKR. A polytetrafluoroethylene (PTFE)
tube (outer diameter 1/16", inner diameter 1/32"), dual syringe pumps
(Catamaran HII-10), purchased from Techno Applications Co., Ltd.,
Japan, and an incubator CN-25A, purchased from Mitsubishi Electric
Engineering Co., Ltd., Japan, were used.
1a, 2a, and 3a was 2:91:7. The residue was purified by SiO2 column
chromatography (hexanes/EtOAc = 20:1) to give (R)-2a (100 mg, 88%
yield, 99% ee) as a colorless oil. The spectroscopic data of the obtained
product (R)-2a was in good agreement with those reported in our previous
paper.[10f] Its optical purity was determined by HPLC analysis at 20 °C
using a CHIRALPAK AD-3 column (hexanes/2-propanol = 99:1, 1.0
mL/min, UV detection: 248 nm, retention times: 6.3 (R), 7.5 min (S)). [훼]ꢀꢁꢂ
= +149.5 (c 1.0, CHCl3) (lit.[10f] [훼]ꢀꢁꢃ = +144.5 (c 1.00, CHCl3) for 98% ee,
lit.[20] [훼]ꢀꢁꢂ = +120.2 (c 1.14, CHCl3) for 94% ee).
Preparation of Racemic Alcohols 1
The known alcohols [(±)-1a[10f], (±)-1b[10f], (±)-1d[10f], (±)-1e[10e], and
(±)-1f[10a]] were prepared according to the reported methods, and (±)-
1c were prepared as follows.
(R,E)-4-(4-Methoxyphenyl)-3-buten-2-yl acetate [(R)-2b]
Similarly to the preparation of (R)-2a, (R)-2b (122 mg, 92% yield, 98% ee)
was obtained from (±)-1b (107 mg, 0.60 mmol) using the reactor made of
the following materials: 1st layer; CALB (100 mg), VMPS4 (6 mg), and
DualPore silica (47 mg); 2nd layer; CALB (100 mg), VMPS4 (10 mg), and
DualPore silica (45 mg); 3rd layer; CALB (100 mg), VMPS4 (14 mg), and
DualPore silica (43 mg). A colorless oil. [훼]ꢁꢀꢂ = +139.4 (c 1.0, CHCl3)
(lit.[10f] [훼]ꢀꢁꢃ = +125.9 (c 1.10, CHCl3) for >99% ee, lit.[21] [훼]ꢁꢀꢃ = +137.8 (c
1.1, CHCl3) for 98.9% ee). The spectroscopic data of the obtained product
(R)-2b were in good agreement with those reported in our previous
paper.[10f] Its optical purity was determined by HPLC analysis at 20 °C
(E)-4-(3,4,5-Trimethoxyphenyl)but-3-en-2-ol [(±)-1c]: Under an
argon atmosphere, MeLi (a 1.16 M solution in Et2O, 6.6 mL, 7.6
mmol)
was
added
to
a
solution
of
(E)-3-(3,4,5-
trimethoxyphenyl)prop-2-enal[18] (1.53 g, 6.9 mmol) in THF (30 mL)
at -78 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 10 h. After the reaction was quenched
with sat. aq. NH4Cl at 0 °C, the organic materials were extracted with
EtOAc three times. The combined organic extract was washed with
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
using a Daicel CHIRALPAK AD-3 column (hexanes/2-propanol = 99:1, 1.0
2.4 mmol) using the reactor made of the following materials: 1st layer;
CALB (100 mg), VMPS4 (33 mg), and DualPore silica (33 mg); 2nd layer;
CALB (100 mg), VMPS4 (50 mg), and DualPore silica (25 mg); 3rd layer;
CALB (100 mg), VMPS4 (67 mg) and DualPore silica (17 mg). A yellow oil.
[훼]ꢁꢀꢅ = +30.7 (c 1.0, CHCl3) (lit.[10a] [훼]ꢀꢁꢁ = +28.0 (c 0.82, CHCl3) for 98%
ee). The spectroscopic data of the obtained product (R)-2f was in good
agreement with those reported in our previous paper.[10a] Its optical purity
was determined by HPLC analysis at 20 °C using a Daicel CHIRALPAK
AD-3 column (hexanes/2-propanol = 99:1, 1.0 mL/min, UV detection: 235
nm, retention times: 6.8 (R), 7.4 min (S)).
mL/min, UV detection: 263 nm, retention times: 9.4 (R), 11.3 min (S)).
(R,E)-4-(3,4,5-Trimethoxyphenyl)-3-buten-2-yl acetate [(R)-2c] (The
results of the reaction condition optimization of flow DKR of (±)-1c are
shown in Table S3, and its entry 3 was selected as the best conditions)
Similarly to the preparation of (R)-2a, (R)-2c (153 mg, 91% yield, 99% ee)
was obtained from (±)-1c (143 mg, 0.60 mmol) using the reactor made of
the following materials: 1st layer; CALB (100 mg), VMPS4 (7 mg), and
DualPore silica (47 mg); 2nd layer; CALB (100 mg), VMPS4 (14 mg), and
DualPore silica (43 mg); 3rd layer; CALB (100 mg), VMPS4 (22 mg), and
DualPore silica (39 mg). A slight yellow oil. [훼]ꢁꢀꢁ = +110.1 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3) δ 1.41 (d, J = 6.5 Hz, 3H), 2.08 (s, 3H), 3.84
(s, 3H), 3.87 (s, 6H), 5.51 (m, 1H), 6.10 (dd, J = 16.0, 6.5 Hz, 1H), 6.53 (d,
J = 16.0 Hz, 1H), 6.60 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 20.31, 21.35,
55.98, 60.85, 70.88, 103.47, 128.18, 131.56, 131.94, 137.91, 153.20,
170.30. IR (neat) ν: 1736 cm–1. HRMS (ESI) m/z calcd for C15H20O5 [M]+:
280.1311, found: 280.1305. Its optical purity was determined by HPLC
analysis at 20 °C using a Daicel CHIRALPAK AD-3 column (hexanes/2-
propanol = 90:10, 1.0 mL/min, UV detection: 223 nm, retention times: 8.9
(R), 10.0 min (S)).
Continuous-Flow DKR of (±)-1a over 3 Days Using a Five-Layered
Packed Column.
Similarly to the preparation of (R)-2a, a reactor was prepared using the
following materials: 1st layer; CALB (100 mg) and DualPore silica (40 mg);
2nd layer; CALB (100 mg), VMPS4 (17 mg), and DualPore silica (40 mg);
3rd layer CALB (100 mg), VMPS4 (33 mg), and DualPore silica (33 mg);
4th layer CALB (100 mg), VMPS4 (50 mg), and DualPore silica (25 mg);
and 5th layer CALB (100 mg) and DualPore silica (40 mg). A solution of
(±)-1a (1.82 g, 12.3 mmol), vinyl acetate (4.6 mL, 49 mmol) in MeCN (123
mL) was continuously pumped through the reaction column at a flow rate
of 0.03 mL/min at 35 °C. The whole solution was pumped into the reactor
over 3 days, and then another solution of vinyl acetate (0.073 mL, 0.80
mmol) in dry MeCN (2 mL) was immediately pumped at a flow rate of 0.03
mL/min to wash out the compounds remaining in the reactor. The eluent
was collected in a flask every 12 hours, and the 6th fraction and the
washout solution were collected in the 6th flask. Each fraction was
concentrated in vacuo, and the residue was subjected to 1H NMR and
chiral HPLC analyses to determine the molar ratio of (S)-1a, (R)-2a, and
3a and the optical purity of (S)-1a and (R)-2a (see Figure S2 in Supporting
Information). All fractions were combined and purified by column
chromatography (EtOAc/hexane = 1:10) to afford (R)-2a (2.13 g, 91% yield,
99% ee).
(R,E)-4-(1-Cyclohexen-1-yl)-3-buten-2-yl acetate [(R)-2d] (The results
of the reaction condition optimization of flow DKR of (±)-1d are shown in
Table S4, and its entry 4 was selected as the best conditions)
Similarly to the preparation of (R)-2a, (R)-2d (106 mg, 92% yield, 96% ee)
was obtained from (±)-1d (91 mg, 0.60 mmol) using the reactor made of
the following materials: 1st layer; CALB (100 mg), VMPS4 (7 mg), and
DualPore silica (47 mg); 2nd layer; CALB (100 mg), VMPS4 (14 mg), and
DualPore silica (43 mg); 3rd layer; CAL-B (100 mg), VMPS4 (22 mg), and
DualPore silica (39 mg). A colorless oil. [훼]ꢁꢀꢁ = +87.5 (c 1.0, CHCl3) (lit.[10f]
[훼]ꢁꢀꢄ = +72.7 (c 1.18, CHCl3) for 92% ee). The spectroscopic data of the
obtained product (R)-2d were in good agreement with those reported in
our previous paper.[10f] Its optical purity was determined by HPLC analysis
at 20 °C using a Daicel CHIRALPAK AD-3 column (hexanes/2-propanol =
99.5:0.5, 1.0 mL/min, UV detection: 233 nm, retention times: 5.7 (R), 6.8
min (S)).
Acknowledgements
This work was financially supported by the JSPS KAKENHI
[18HO4411 (Middle Molecular Strategy) and 18H02556] and
Platform Project for Supporting Drug Discovery and Life Science
Research from AMED under Grant Number JP19am0101084. We
acknowledge DPS Inc. for the kind gift of the DualPoreTM silica
beads. In addition, the authors gratefully acknowledge generous
support from the German Academic Exchange Service (DAAD)
and Japan Society for the Promotion of Science (JSPS),
respectively, within the joint DAAD-JSPS funding program “DAAD
PPP Japan 2017/2018” (DAAD grant no. 57345562) and the
DAAD funding program PAJAKO (DAAD grant no. 57449901).
(R)-1-(4-Methoxyphenyl)ethyl acetate [(R)-2e] (The results of the
reaction condition optimization of flow DKR of (±)-1e are shown in Table
S5, and its entry 6 was selected as the best conditions)
Similarly to the preparation of (R)-2a, (R)-2e (103 mg, 88% yield, 99% ee)
was obtained from (±)-1e (91 mg, 0.60 mmol) using the reactor made of
the following materials: 1st layer; CALB (100 mg), VMPS4 (7 mg),
DualPore silica (47 mg); 2nd layer; CALB (100 mg), VMPS4 (14 mg), and
DualPore silica (43 mg); 3rd layer; CALB (100 mg), VMPS4 (22 mg), and
DualPore silica (39 mg). Flow rate was changed into 0.015 mL/min. A
colorless oil. [훼]ꢀꢁꢅ = +127.6 (c 1.0, CHCl3) (lit.[10e] [훼]ꢁꢀꢆ.ꢃ = +121.7 (c 1.00,
CHCl3) for 99% ee). The spectroscopic data of the obtained product (R)-
2e was in good agreement with those reported in our previous paper.[10e]
Its optical purity was determined by HPLC analysis at 20 °C using a Daicel
CHIRALPAK AD-3 column (hexanes/2-propanol = 99:1, 1.0 mL/min, UV
detection: 225 nm, retention times: 7.4 (R), 14.1 min (S)).
Keywords: Lipase; Oxovanadium; Dynamic kinetic resolution;
Flow reaction; Alcohol
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was obtained from (±)-1f (83 mg, 0.60 mmol) and vinyl butyrate (0.31 mL,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202000186
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
A continuous-flow
dynamic kinetic
Koichi Higashio, Satoko
Katsuragi, Dhiman Kundu,
Niklas Adebar, Carmen Plass,
Franziska Kühn, Harald
OH
O
resolution of racemic
R1 R2
secondary alcohols was
O
R3
R2
racemate
+
carried out using a
column reactor packed
with a mixture of
R1
Gröger,* and Shuji Akai*
vinyl ester
in MeCN
35 °C
88-92% isolated yield
96-99% ee
residence time: 30-60 min
immobilized lipase and
an immobilized
Page No. – Page No.
immoblized lipase
immobilized oxovanadium, VMPS4
oxovanadium species,
VMPS4 to produce
optically pure esters in
88–92% yields. The use
of a filler and a packing
method of the two
catalysts were critical to
a successful 3-day
operation.
Continuous-Flow Dynamic
Kinetic Resolution of
Racemic Alcohols by
Lipase–Oxovanadium
Cocatalysis
Key Topic:
Flow reaction
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