Optimised dynamic kinetic resolution of benzoin by a chemoenzymatic approach in 2-MeTHF

Article abstract of DOI:10.1016/j.molcatb.2011.04.018

Different influential parameters in the Dynamic Kinetic Resolution of racemic benzoin via lipase-ruthenium catalyst enantioselective transesterification have been improved in order to develop a more productive process. In this sense, 2-Methyltetrahydrofur

Full text of DOI:10.1016/j.molcatb.2011.04.018

Journal of Molecular Catalysis B: Enzymatic 72 (2011) 20–24
Contents lists available at ScienceDirect
Journal of Molecular Catalysis B: Enzymatic
journal homepage: www.elsevier.com/locate/molcatb
Optimised Dynamic Kinetic Resolution of benzoin by a chemoenzymatic
approach in 2-MeTHF
Pilar Hoyos , M. Alberto Quezada , José Vicente Sinisterraa,c, Andrés R. Alcántaraa,∗
a
b
a
Biotransformations Group, Organic and Pharmaceutical Chemistry Department, Pharmacy Faculty, Complutense University of Madrid/Ciudad Universitaria s/n, 28040 Madrid, Spain
Biotransformations and Natural Products Group, Chemical Engineering Faculty, National University of Trujillo-Perú/Av. Juan Pablo II s/n, Trujillo, Peru
Industrial Biotransformations Unit, Scientific Park of Madrid/Tres Cantos, 28760, Madrid, Spain
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Different influential parameters in the Dynamic Kinetic Resolution of racemic benzoin via
lipase–ruthenium catalyst enantioselective transesterification have been improved in order to develop a
more productive process. In this sense, 2-Methyltetrahydrofuran (2-MeTHF) is proposed as an excellent
and greener substitute of THF for this biotransformation; on the other hand, by scaling up the reaction,
much better results were obtained by using a much simpler one-pot methodology (compared to the pre-
viously described three-steps protocol), resulting not only in higher amounts of enantiopure product (85%
conversion, >99% ee of the product), but also in an enhanced sustainability of the process, because lower
acyl donor concentrations and lower ruthenium catalyst amounts (protected from oxygen deactivation)
are required.
Received 22 December 2010
Received in revised form 18 March 2011
Accepted 21 April 2011
Available online 29 April 2011
Keywords:
Benzoin
Dynamic Kinetic Resolution
2
-MeTHF
©
2011 Elsevier B.V. All rights reserved.
1
. Introduction
drawback of KR can limit its applicability, as just a maximum
theoretical yield of 50% could be reached. This limitation can
be overcome by the racemisation in situ of the remaining sub-
strate in a Dynamic Kinetic Resolution (DKR) process, which allows
the achievement of a theoretical 100% yield. A large number of
protocols depict the synthesis of optically active alcohols by the
combination of a lipase-catalysed enantioselective transesterifi-
cation and an in situ racemisation of the unreacted enantiomer
mediated by a transition metal catalyst [19–21]. Although the use
of this last strategy is nowadays widespread, just few examples can
be found describing a large-scale process for an ulterior industrial
implementation [22,23].
As a part of our ongoing research about the enantioselective
preparation of benzoins (1,2-diaryl-2-hydroxyethanone struc-
tures), we have previously reported an efficient DKR process of
this type of ␣-hydroxyketones [13] by the combined action of
lipase from Pseudomonas stutzeri and a ruthenium catalyst (Shvo ˇı s
catalyst) in THF; later on, the productivity of the process was
enhanced by lipase immobilization [24]. Although high conver-
sions and excellent enantiomeric purity had been reached, reaction
parameters should be modified and optimised in order to prepare a
further scaling up of the process. Several factors may be considered
in order to develop, not only a greener procedure by a biocatalytic
strategy, but also a more economic process by the enlargement of
the productivity, which also contributes to the sustainability of the
system [19,25].
Optically pure ␣-hydroxyketones are considered valuable build-
ing blocks for the fine chemical industry as well as pharmaceuticals.
This acyloin intermediate is included in the synthesis of differ-
ent natural products and biologically active compounds [1]. In
virtue of the increasing interest towards these molecules, different
strategies have been developed for obtaining ␣-hydroxyketones
in an enantioselective manner. Although several attempts have
been carried out by using asymmetric synthesis [1], biocataly-
sis is a real alternative, because more sustainable processes can
be implemented [2,3]: in fact, the employment of enzymes and
microorganisms as catalysts generally means a decrease in the
number of reaction steps and in the waste production, as well
as milder reaction conditions, resulting in more environmentally
and economically attractive processes [4,5]. In this sense, chiral
␣
-hydroxyketones can be efficiently prepared by different bio-
catalytic approaches, such as aldehydes carboligation catalysed
by thiamine-diphosphate dependent lyases [6–8], stereoselective
reduction of ␣-dicarbonyl compounds [9–11] or the Dynamic
Kinetic Resolution (DKR) of racemic mixtures [12,13].
Kinetic Resolution (KR) of racemic mixtures has been shown
to be the methodology of choice for the synthesis of many chiral
secondary alcohols (including ␣-hydroxyketones [14–16]), partic-
ularly by using lipases as catalysts [17,18]. However, an important
In this work we present the optimisation of the different param-
eters involved in the DKR process of benzoin obtaining promising
results for further scale-up. Furthermore, it is proposed the
∗ Corresponding author. Tel.: +34 91 394 1820; fax: +34 91 394 1822.
E-mail address: andresr@farm.ucm.es (A.R. Alcántara).
1
381-1177/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcatb.2011.04.018

P. Hoyos et al. / Journal of Molecular Catalysis B: Enzymatic 72 (2011) 20–24
21
Scheme 1. DKR process of benzoins (1,2-diaryl-2-hydroxyethanones) catalysed by lipase from Pseudomonas stutzeri and Shvo ˇı s catalyst.
substitution of THF by 2-Methyltetrahydrofuran (2-MeTHF), con-
sidered a more environmentally friendly solvent [26,27].
flask. Anhydrous 2-MeTHF was incorporated and the reaction
was started by the addition of trifluoroethyl butyrate (1.132 ␮L,
◦
7
.5 mmol). The mixture was stirred at 55 C under Argon atmo-
sphere. After 24 h, 50 mg of fresh lipase were added. Conversion
and enantiomeric excess were determined by HPLC analysis, fol-
lowing a similar protocol to that described in the previous section.
Product ((S)-2) was purified by silica column chromatography (n-
hexane/ethyl acetate, 5/1) yielding a colorless oil (80% isolated
yield). [␣]20 : + 154.2 (c 4 CHCl ). Spectroscopic data of (S)-2 are
2
. Experimental
2.1. Materials and methods
Lipase (Triacylglycerol lipase EC 3.1.1.3) from P. stutzeri
®
(
Lipase TL , Lot TH3401, 52% of protein content, Bradford
D
3
in accordance with those previously reported [13].
methodology as previously reported [24]) was pur-
chased from Meito Sangyo Co. Ltd., Nagoya, Japan (see
&
http://www5.mediagalaxy.co.jp/meito/kaseihin/index e.html for
details); Shvo ˇı s catalyst (1-hydroxytetraphenylcyclopentadienyl
3. Results and discussion
(
tetraphenyl-2,4-cyclopentadien-1-one)-␮-
As it has been commented above, in our research group we have
previously described the lipase from P. stutzeri (Lipase TL ) and
the Shvo ˇı s catalyst as the most convenient catalysts for the DKR of
benzoins (Scheme 1) [13].
®
hydrotetracarbonyldiruthenium (II) was obtained from Strem
Chemicals Inc.; 2-MeTHF and other common reagents were
obtained from Sigma–Aldrich.
HPLC analyses were performed with a chiral column Chiralcel®
OD-H at room temperature; mobile phase n-hexane/2-propanol
The main requirement for a successful scalable DKR is the previ-
ous optimisation of the KR process and its successful combination
with the in situ racemisation of the substrate.
9
0/10, at a flow rate of 1 mL/min.
NMR spectra were recorded on a Bruker AC-250. Chemical shifts
Based on the work of Aoyagi and co-workers [16], Lipase TL® was
identified as the best biocatalyst for benzoin resolution, and reac-
tion conditions were improved, reaching maximum conversions
1
(
7
␦) are reported in parts per million (ppm) relative to CHCl ( H: ␦
3
13
.27 ppm) and CDCl3 ( C: ␦ 77.0 ppm).
◦
and enantiomeric excess after 1 h in THF at 50 C. This tempera-
2
.2. General procedure for the Kinetic Resolution of benzoin
ture was necessary for a posterior DKR reaction, in which Shvo ˇı s
catalyst, which is completely compatible with the lipase, was able
to racemise the unreacted substrate. With all these data, a further
improvement is required as a previous step for a potential scal-
ing up of the process: substrate concentration should be increased
and the loading of acyl donor, enzyme and Shvo ˇı s catalyst should
be reduced, for obvious productivity reasons. In this sense, the
previously described protocol was employed as starting point for
optimising the process, and KR of benzoin was chosen as standard
reaction in order to find optimum conditions before the coupling
with the ruthenium catalyst (Scheme 2). At this level, all test assays
were performed in 1 mL volume at room temperature (typically,
Different amounts of (R,S)-1 (20 mg, 94 ␮mol in the standard
protocol) were dissolved in 1 mL of freshly distilled 2-MeTHF (or
THF): subsequently, Lipase TL (20 mg of the commercial prepara-
tion) and a certain amount of VB (vinyl butyrate, 71.6 ␮L, 564 ␮mol,
in the standard conditions, molar excess 6:1) were added. The mix-
ture was stirred at room temperature (20–25 C). At fixed reaction
times, samples (20 ␮L) were taken from the reaction medium, re-
dissolved in 1 mL of n-hexane, and filtered through Millex -GV
®
◦
®
(
PVDF, 0.22 ␮m pore size) to stop the enzymatic reaction. As THF or
MeTHF (polar solvents) may damage the chiral column (Chiralcel
OD-H ), each sample was evaporated under vacuum and the solid
®
◦
20–25 C), varying the different reaction parameters.
collected was re-solved in 1 mL of n-hexane/2-propanol (50:50, v/v)
before analyzing by HPLC to measure conversion and enantiomeric
excess values.
3.1. Effect of the solvent
2
-MeTHF is a commercial solvent obtained from renewable
2
.3. General procedure for the 10 mL-Dynamic Kinetic Resolution
sources and it has emerged as a greener substitute of traditional
THF, suitable in different synthetic procedures [26,28,29] and grad-
ually being introduced in the biocatalysis field [27,30]. Although
lipases commonly present high activity in low polarity organic
solvents, lipase from P. stutzeri has showed an excellent behav-
of benzoin
Shvo ˇı s catalyst (13.5 mg, 0.0125 mmol; 0.5 mol %), Lipase TL®
150 mg) and (R,S)-1 (530 mg, 2.5 mmol) were added to a 25 mL
(
Scheme 2. Benzoin Kinetic Resolution catalysed by lipase from Pseudomonas stutzeri.

2
2
P. Hoyos et al. / Journal of Molecular Catalysis B: Enzymatic 72 (2011) 20–24
Table 1
®
Kinetic Resolution (KR) of benzoin catalysed by Lipase TL in 2-MeTHF and THF.
a
Eb
−1
Vo (␮mol min )
Run
Solvent (1 mL)
Lipase (mg)
(R,S)-1 (mg)
VB (equiv.)
Conv . (3 h) (%)
eep (%)
1
2
THF
2-MeTHF
20
20
20
20
6
6
39
49
>99
>99
>200
>200
0.52
0.76
a
Calculated based on the percentage of product appearance.
Enantiomeric ratio.
b
ior in THF [13,24]. Physical properties of 2-MeTHF prompted us
to carry out the benzoin resolution reaction in this solvent. Results
are compared with those obtained by the use of THF in Table 1. As
recently stated by Gardossi et al. [31], when describing a biocatal-
ysed synthesis, reporting a value of conversion, yield or product
concentration at a single timepoint is useful (reaction time must
always be stated), although the progress curve has to be taken into
account for monitoring the overall the process. Thus, in Fig. 1 the
progression of both reactions at room temperature (20–25 C) is
represented.
It is worth mentioning that not only the sustainability of the
biocatalytic reaction was increased but also the lipase activity was
enhanced by the use of 2-MeTHF. Under the same reaction con-
ditions, the initial rate (of the process in 2-MeTHF was almost
always in molar excess, due to the fact that an excess of acyl donor
is needed for shifting the equilibrium towards the desired prod-
uct [32,33]. Following the units recommended by Gardossi et al.
[31], the values of initial rate V0 (expressed as ␮mol of product
obtained per minute), the maximum conversion (monitoring prod-
uct appearance) and the productivity (␮moles of (S)-2 obtained by
mg of commercial lipase per minute) were determined on each case
and summarised in Table 2.
As can be seen in Table 2, it was necessary to add at least 3 equiv-
alents of VB to obtain good conversions, although a great excess of
this reagent was not required, as can be seen from the fact that bet-
ter results were not obtained by adding more than 6 equivalents
of VB. Although it is assumed that an excess of the acyl donor is
needed for shifting the equilibrium towards the desired products
[32,33], in fact this excess has to be controlled in order just to reduce
waste and simplify product purification. In any case, the enantiose-
lectivity of the lipase biocatalyst remained exquisite regardless the
excess of acyl donor used, as shown in Table 2, always leading to E
values higher than 200.
◦
1
.5-fold increased, and maximum conversion of a kinetic resolu-
tion (50%) was achieved just in 3 h, while it was needed al least
h to reach same conversion in THF. On the other hand, excellent
4
enantioselectivity was maintained, without detecting any trace of
the acylation of the R enantiomer of the substrate. Taking these
results into account, 2-MeTHF was the solvent of choice to develop
lipase-catalysed benzoin resolution.
3.2. Effect of acyl donor concentration
3.3. Effect of substrate concentration
In previous studies vinyl butyrate was selected as the best acyl
With the aim of developing a more economically attractive pro-
donor for benzoin ((R,S)-1) KR [13]. Thus, starting from the standard
conditions (entry 3, Table 2, molar ratio acyl donor/substrate = 6/1)
the effect of the acyl donor concentration was studied; while sub-
strate concentration and lipase amount were held constant in
cedure, the effect of substrate concentration over lipase activity was
investigated. Acyl donor concentration was maintained constant
and increasing substrate concentrations were employed. Thus, dif-
ferent relations substrate-acyl donor were studied, which would
allow us to determine best reaction parameters. Results obtained
working in 2-MeTHF are shown in Fig. 2, while the data derived
from those curves are shown in Table 3 (entry 3 corresponds again
to the initial conditions). Parallel experiments were performed in
THF to confirm the suitability of its substitution in this biocatalytic
process.
1
mL of 2-MeTHF, different amounts of vinyl butyrate were added,
The comparison of the initial rates and productivity values mea-
sured in both solvents confirms the choice of 2-MeTHF as a better
medium for developing the resolution of this ␣-hydroxyketone
®
catalysed by Lipase TL . In fact, when using 2-MeTHF not only the
initial rate was higher than the rate measured in THF, but also the
reaction time needed to obtain the optimal KR was reduced, which
is directly related to a productivity increase.
As shown in Fig. 2, substrate concentration can be raised without
a great increase of the reaction time needed to reach conversion val-
ues close to 50%. Taking into account the results shown in Table 3,
in the case of benzoin concentrations higher than 280 mM, longer
times were needed to render maximum conversion, but excellent
enantioselectivity was maintained in all cases.
As can be observed, the productivity of this biotransformation
is definitively enhanced, as the biocatalyst is able to carry out
the acylation of amounts of substrate considerably higher than
those previously described [13]. Not only 2-MeTHF was contribut-
ing to perform a greener process, but also the decrease on acyl
donor loading and the substrate concentration raise collaborate in
a reduction of the waste of the biotransformation, then decreasing
the E(nvironmental) factor (kg waste per kg product) of the process
Fig. 1. Comparison of the benzoin KR progress catalysed by Lipase TL® in 2-MeTHF
and THF at room temperature.
[
4,34,35].

P. Hoyos et al. / Journal of Molecular Catalysis B: Enzymatic 72 (2011) 20–24
23
Table 2
KR of benzoin employing different amounts of acyl donor and 2-MeTHF as solvent.
V0a (␮mol min−1
)
Conv. (%)
eep (%)
Eb
Productivity × 10
−1 −1
3
Entry
(R,S)-1 (mg)
Lipase (mg)
VB (equiv.)
(
␮mol min mg lipase)c
1
2
3
4
5
20
20
20
20
20
20
20
20
20
20
1.5
3
6
9
12
0.73
0.75
0.76
0.86
0.86
23
49
>49
>49
>49
>99
>99
>99
>99
>99
>200
>200
>200
>200
>200
4.8
5.7
6.4
6.8
6.7
a
Experimental error 5%.
Enantiomeric ratio.
Calculated at reaction times for maximum conversion in each case.
b
c
Table 3
Kinetic Resolution of different concentrations of benzoin in 1 mL of 2-MeTHF, catalysed by lipase from Pseudomonas stutzeri.
V0a (␮mol min−1
)
Conv. (%)
eep (%)
Eb
Productivity × 10
−1
3
Entry
(R,S)-1 mg (mM)
Lipase (mg)
VB (equiv.)
−
1
(
␮mol min mg lipase)c
d
d
1
2
3
4
5
6
7
8
9
5(24)
10(47)
20(94)
30(141)
40(188.5)
60(283)
90(424)
110(518)
130(612)
20
20
20
20
20
20
20
20
20
24
12
6
4
3
0.27 (0.17)
>49
>99
>99
>99
>99
>99
>99
>99
>99
>99
>200
>200
>200
>200
>200
>200
>200
>200
>200
2.4 (1.6)
d
d
0.43 (0.32)
>49
>49
>49
>49
>49
47
3.5 (2.6)
d
d
0.76 (0.52)
5.1 (3.8)
d
0.80 (0.61)
1.00 (0.80)
1.34
2.26
3.32
4.08
5.5 (4.2)
6.6 (5.4)
d
d
2
8.4
1.3
1.1
0.9
13.6
19.7
23.8
44
42
a
Experimental error 5%.
Enantiomeric ratio.
b
c
Calculated at the reaction time required for the maximum conversion quantified (ranging from 3 to 14 h).
Calculated values in THF.
d
◦
3
.4. Dynamic Kinetic Resolution
MeTHF at 55 C under argon atmosphere was tested. The higher
boiling point of 2-MeTHF than THF allowed the increase of the
◦
As it was described above, lipase-catalysed KR can be coupled
temperature from 50 to 55 C, which would be more convenient
with a racemisation system, which allows the achievement of a
theoretical conversion of 100%, in order to obtain a commercially
viable process.
for the catalyst activation. In fact, starting from pure (R)-1, racemic
(R,S)-1 was obtained in 1 h; a small amount of the dicarbonyl com-
pound (benzyl, intermediate of the redox-racemisation) was also
identified.
Before studying the scaling up to higher volume processes, the
DKR of (R,S)-1 in 1 mL of 2-MeTHF was tested, coupling the action
of Lipase TL® and Shvo ˇı s catalyst. As it is well known, the use
of vinyl esters as acyl donors for the transesterification reaction
can interfere with the activity of the racemisation catalyst [36].
Therefore, as the suitability of trifluoroethyl butyrate was already
proved [13], it was chosen as acyl donor. In a first attempt, a low
In this context, with the idea of optimising the synthesis of
enantiomerically pure benzoin through a biocatalytic process, we
investigated the combination of the optimised KR procedure with
the racemisation of the unreacted enantiomer mediated by the
Shvo ˇı s catalyst. 2-MeTHF had been chosen as a better solvent for
the transesterification reaction, but it must be also compatible with
the ruthenium catalyst. To check the viability of this method, the
racemisation of (R)-1 in the presence of the Shvo ˇı s catalyst in 2-
Fig. 2. Kinetic Resolution progress of different 1 mL assays starting from increasing substrate concentrations.

2
4
P. Hoyos et al. / Journal of Molecular Catalysis B: Enzymatic 72 (2011) 20–24
substrate concentration was employed (94 mM) in 1 mL of 2-
MeTHF, and lipase (20 mg), ruthenium catalyst (5% mol) and
trifluoroethyl butyrate (3 equiv.) were added and stirred at 55 C
from an UCM Project, inside the “VI CONVOCATORIA UCM DE
COOPERACIÓN AL DESARROLLO 2009, Modalidad 1A: Cooperación
Universitaria con países de menor nivel de desarrollo: Formación
de un Grupo de Investigación Interuniversitario para el Desarrollo
Sostenible del Altiplano y la Amazonía peruana”.
◦
under argon atmosphere. After 24 h 70% conversion was reached.
Although all substrate had been converted, a great amount of
the residual dicarbonyl compound had been accumulated in the
medium. We had already described how this lipase shows a grad-
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[
edged. Authors would also like to acknowledge the supporting