High-efficiency and minimum-waste continuous kinetic resolution of racemic alcohols by using lipase in supercritical carbon dioxide

Article abstract of DOI:10.1039/b406882c

A novel continuous-flow scCO₂ process for kinetic resolution of racemic alcohols can be performed with an immobilized lipase to lead to a quantitative mixture of the corresponding optically active acetates with up to 99% ee and unreacted alcohols with up to 99% ee, in which the productivity of the optically active compounds was improved by over 400 times compared to the corresponding batch reaction using scCO₂.

Full text of DOI:10.1039/b406882c

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High-efficiency and minimum-waste continuous kinetic resolution of
racemic alcohols by using lipase in supercritical carbon dioxide{
a
Tomoko Matsuda,* Kazunori Watanabe, Tadao Harada, Kaoru Nakamura, Yoshitaka Arita,
a
a
b
c
c
c
Yukihiro Misumi, Shinichiro Ichikawa and Takao Ikariya*
d
a
Department of Materials Chemistry, Ryukoku University, Otsu, Shiga 520-2194, Japan
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
b
c
Joint Research Center for Supercritical Fluids, Japan Chemical Innovation Institute (JCII), Tokyo
Institute of Technology 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
d
Graduate School of Science and Engineering and Frontier Collaborative Research Center, Tokyo Institute
of Technology 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received (in Cambridge, UK) 10th May 2004, Accepted 6th July 2004
First published as an Advance Article on the web 26th August 2004
2
A novel continuous-flow scCO process for kinetic resolution
of racemic alcohols can be performed with an immobilized
lipase to lead to a quantitative mixture of the corresponding
optically active acetates with up to 99% ee and unreacted
alcohols with up to 99% ee, in which the productivity of the
optically active compounds was improved by over 400 times
compared to the corresponding batch reaction using scCO
2
.
Great efforts have been extended to homogeneous catalysis in
1
scCO
supercritical homogeneous phase has gained significant attention
because of the intrinsic properties of scCO including high
miscibility of the gaseous reactants, favorable mass transfer, and
tunable solvent power. scCO is now realized to be a promising
2
since the early 1990’s, and the area of catalysis in the
Scheme 1
2
2
reacted faster than (S)-enantiomer (S)-1 and that the reaction
stopped after about 7 h when the (R)-enantiomer was consumed.
The ratio of the specificity constants of the enantiomers, E-value,
was more than 100 when the conversion was 48%.
The utilization of a continuous flow reactor (Fig. 1) for the
kinetic resolution of (R/S)-1 over the Novozym catalyst caused a
significant improvement in the efficiency of the reaction. The
reaction of (R/S)-1 and vinyl acetate 2, with the molar ratio of
reaction medium for environmentally benign chemical processes.
However, difficulties in separation of the homogeneous catalysts
and products have remained unresolved except for recent advances
in reaction and extraction techniques or multiphase catalysis
7
8
2
systems including a SCF phase.
Biocatalysis for organic synthesis has advantages in green
chemistry because enzymes are reproducible and reusable catalysts
with excellent chemo-, regio-, and enantioselectivities. A combina-
3
21
1
: 2 ~ 1 : 0.5 at a flow rate of 0.70 mL min , over the catalyst
under 13 MPa of scCO (1.5 mL min ) gave the desired acetate 3
2
1
tion of the concept of the heterogeneous biocatalysis with scCO2
2
9
having unique properties has attracted considerable attention to
achieve highly stereoselective molecular transformations. In fact,
there have been many reports on asymmetric synthesis with
with 99.7% ee in 47% yield. { The E value exceeds 1800. The use of
a slight excess of 2 resulted in an increase in the chemical yield of
optically active (R)-3 from 47% to 50%, in which the unreacted
alcohol (S)-1 with 98.8% ee was recovered quantitatively (Table 1).
The NMR spectrum of the reaction mixture shows that no side
reaction occurred. Noticeably, even when a large amount of 2 was
used, the over-reaction of (S)-enantiomer hardly proceeded under
the same conditions, providing a quantitative mixture of acetate 3
4
,5
enzymes in scCO
continuous flow scCO
2
using batch type reactors since 1985. However,
phase reactions over enzymatic catalysts as
a practical procedure for synthesis of optically active compounds
2
6
remain largely unexplored except for recent reports. Here we
2
report a novel continuous scCO flow system for enzymatic
asymmetric synthesis of optically active alcohols, in which racemic
alcohols were efficiently converted to the corresponding optically
pure acetates via kinetic resolution. The use of a continuous flow
reaction system for the kinetic resolution resulted in a significant
improvement in the productivity for long period of the reaction
2
and unreacted 1 with over 99% ee. Changing the CO pressure
ranging from 8.9 to 20 MPa did not significantly change the
outcome of the reaction.
Similarly, the aliphatic alcohols 2-undecanol 4a and 1-tetralol 4b
were kinetically resolved with the Novozym catalyst under
conditions similar to those described above (4 : 2 ~ 1 : 0.6) to
give a mixture of optically active R-ester of 4a or 4b and unreacted
1
time, leading to virtually solventless reaction.
First, kinetic resolution of racemic 1-phenylethanol (R/S)-1 with
vinyl acetate 2 catalyzed by an immobilized lipase from Candida
antarctica, Novozym 435, in scCO was examined using a batch
2
system. The reaction of (R/S)-1 (0.83 mmol) with vinyl acetate 2
(5.4 mmol) in the presence of the enzyme (5.0 mg) under 9 MPa of
CO at 40 uC proceeded to give a 1 : 1 mixture of optically active
2
(R)-acetate (R)-3 with 99.8% ee and unreacted (S)-alcohol (S)-1
with 90.6% ee in 48% conversion (Scheme 1). The time courses of
the reactions at 9 and 13 MPa revealed that (R)-enantiomer (R)-1
{
Electronic supplementary information (ESI) available: NMR spectrum
of the product, (S)-1-phenylethanol and the corresponding (R)-acetate,
without any purification procedure, figure and table showing kinetic
resolution of (R/S)-1 by Novozym and experimental details. See http://
www.rsc.org/suppdata/cc/b4/b406882c/
8
Fig. 1 Simplified illustration of experimental apparatus.
2
2 8 6
C h e m . C o m m u n . , 2 0 0 4 , 2 2 8 6 – 2 2 8 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
a
2
Table 1 The effect of reaction conditions on kinetic resolution of (R/S)-1 by Novozym using scCO flow reactor
e
1
: 2 (mol/mol)
Pressure/MPa
(S)-1 (% ee)
(R)-3 (% ee)
Conv. (%)
E
b
1
1
1
1
1
a
:0.50
13.0
13.0
12.9
8.9
89.6
98.8
w99.5
w99.5
w99.5
99.7
99.2
99.0
99.0
99.0
47
50
50
50
50
1850
1240
w1000
w1000
w1000
c
:0.60
: 1.30
d
d
:1.30
:1.30
d
20.0
21
21 b
.
Conditions: 42–43 uC, Novozym: 5.0 mL, scCO
0.070 mL min
to 3 based on the starting amount of 1.
2
flow: 1.5 mL min , flow rate of 1: 0.050 mL min
Flow rate of the mixture of 1 and 2: 0.074 mL min . Flow rate of the mixture of 1 and 2: 0.100 mL min . Conversion
Flow rate of the mixture of 1 and 2:
2
1 c
21
d
21 e
2
1
sent to the reactor at the flow rate of 0.070 mL min . The sample was
collected after 1.2 h without using any organic solvent at room temperature
and was analyzed by GC (Chirasil-DEX CB), LC (Daisel Chiralcel OJ-H),
1
and H NMR (400 MHz) without any purification. Visual inspection of the
reaction mixture in an autoclave equipped with sapphire windows showed
2
that the reactants and products were all soluble in scCO under the reaction
conditions.
1
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Fig. 2 The reaction profile of kinetic resolution of (R/S)-1 with Novozym in
continuous-scCO -flow reactor. (Conditions: Novozym: 5.0 mL (1.73 g),
2
21
: 2 ~ 1 : 0.6, flow rate of the mixture of 1 and 2: 0.074 mL min , scCO
flow: 1.5 mL min , 12.9–13.0 MPa, 42 uC.)
1
2
21
2
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in 48–50% yield and with an excellent ee (E ~ 112–137 for 4a and
over 1500 for 4b).
The present continuous asymmetric synthesis of optically active
alcohols and their derivatives with the Novozym catalyst is
characterized by a rapid and highly stereoselective transformation.
Although the batch reaction using 10 mL of the reactor, produced
0.83 mmol of optically active compounds during 7 h reaction, the
continuous-flow reactor (5 mL) gave the products at the rate of
2
2
1
21
5 mmol h (3 mL h ). Furthermore, the reaction even with a
3 A. Schmid, J. S. Dordick, B. Hauer, A. Kiener, M. Wubbolts and
B. Witholt, Nature, 2001, 409, 258; A. M. Klibanov, Nature, 2001, 409,
small excess of vinyl acetate 2 proceeded smoothly to provide the
desired product with an excellent ee, minimizing the use of
unnecessary liquid materials and the production of waste during
the reaction. This synthetic process is particularly useful for the
large-scale production of optically active alcohols. As shown in
Fig. 2, the present biocatalyst maintained its performance in terms
of the reactivity and selectivity during 3 days’ operation under a
supercritical condition (12.9–13 MPa at 42 uC) and resulted in a
quantitative transformation of (R/S)-1 (221 g) to (S)-1 with 99% ee
2
41; Enzyme catalysis in organic synthesis a comprehensive handbook, eds.
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9
and (R)-3 with 99% ee using 1.73 g of the immobilized enzyme.
Notes and references
7
{ Safety warning: operators of high-pressure equipment should take proper
precautions to minimize the risk of personal injury.
Experimental procedure: in a typical reaction, an immobilized lipase
s p
determined by using ee values of the substrate (ee ) and product (ee ).
8 T. Oku and T. Ikariya, Angew. Chem., Int. Ed., 2002, 41, 3476; T. Oku,
Y. Arita, H. Tsuneki and T. Ikariya, J. Am. Chem. Soc., 2004, 126,
7368.
2
1
(Novozym, 5 mL, 1.89 g, approx. 10.000 U g for propyl laurate
synthesis) was introduced to the reactor and placed in the oven. The
¯
9 Encouraged by this promising result, dynamic kinetic resolution (DKR)
is in progress in our
2
reaction temperature was increased to 42 oˆ C and the CO pressure was
21
increased to 13.0 MPa, and the flow rate was set to 1.500 mL min . Then
using both the lipase and the Ru catalyst in scCO
laboratory.
2
a mixture of 1-phenylethanol (R/S)-1 and vinyl acetate 2 (1 : 2 = 1 : 0.5) was
C h e m . C o m m u n . , 2 0 0 4 , 2 2 8 6 – 2 2 8 7
2 2 8 7