Spatial effects of oxovanadium-immobilized mesoporous silica on racemization of alcohols and application in lipase-catalyzed dynamic kinetic resolution

Article abstract of DOI:10.1039/c6cy00257a

We recently reported a new dynamic kinetic resolution (DKR) method based on the combination of lipase-catalyzed kinetic resolution of racemic alcohols and the V-MPS3-catalyzed in situ racemization of less reactive alcohol enantiomers. In V-MPS3, oxovanadium moieties were covalently bound to the inner surface of mesoporous silica (MPS) with a pore size of about 3 nm. The catalytic activity of V-MPS3 was much higher than that of related vanadium compounds; however, we could neither explain its unusually high activity nor confirm that the racemization predominantly occurred inside the V-MPS pores. Therefore, in this study, we prepared V-MPS2 and V-MPS4 from the corresponding MPS with pore diameters of approximately 2 nm and 4 nm, respectively and compared their racemization activities with that of V-MPS3 using some optically active alcohols with different molecular sizes and polarities. We discovered a positive correlation between the pore size of V-MPS and substrate racemization rate as well as the high polarity of the MPS pores. The results suggested that the racemization predominantly occurs in the pores of V-MPS and that a small pore size (2-4 nm) is essential to generate the polar environment of V-MPS, which probably accelerates the racemization by facilitating the C-O bond cleavage of the vanadate intermediates. Using V-MPS with a pore size suitable for each substrate, lipase/oxovanadium combo-catalyzed DKR could be applied to a wider range of alcohols including allyl alcohols, benzylic alcohols, and propargyl alcohols to give the corresponding esters in excellent isolated yields and enantioselectivities.

Full text of DOI:10.1039/c6cy00257a

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Catalysis Science & Technology
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Spatial effects of oxovanadium-immobilized mesoporous silica on
racemization of alcohols and application in lipase-catalyzed
dynamic kinetic resolution
Received 00th January 20xx,
Accepted 00th January 20xx
Koji Sugiyama,a Yasuhiro Oki,a Shinji Kawanishi,a Katsuya Kato,b Takashi Ikawa,a Masahiro Egi,c and
Shuji Akai*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
We recently reported a new dynamic kinetic resolution (DKR) method based on the combination of lipase-catalyzed kinetic
resolution of racemic alcohols and the V-MPS3-catalyzed in situ racemization of less reactive alcohol enantiomers. In V-
MPS3, oxovanadium moieties were covalently bound to the inner surface of mesoporous silica (MPS) with a pore size of
about 3 nm. The catalytic activity of V-MPS3 was much higher than that of related vanadium compounds; however, we
could neither explain its unusually high activity nor confirm that the racemization predominantly occurred inside the V-
MPS pores. Therefore, in this study, we prepared V-MPS2 and V-MPS4 from the corresponding MPS with pore diameters
of approximately 2 nm and 4 nm, respectively and compared their racemization activities with that of V-MPS3 using some
optically active alcohols with different molecular sizes and polarities. We discovered a positive correlation between the
pore size of V-MPS and substrate racemization rate as well as the high polarity of the MPS pores. The results suggested
that the racemization predominantly occurs in the pores of V-MPS and that a small pore size (2–4 nm) is essential to
generate the polar environment of V-MPS, which probably accelerates the racemization by facilitating the C–O bond
cleavage of the vanadate intermediates. Using V-MPS with a pore size suitable for each substrate, lipase/oxovanadium
combo-catalyzed DKR could be applied to a wider range of alcohols including allyl alcohols, benzylic alcohols, and
propargyl alcohols to give the corresponding esters in excellent isolated yields and enantioselectivities.
substrates (Scheme 1),4 which are very different from the rutheniumꢀ
catalyzed DKR. Accordingly, we developed a new racemization
catalyst, VꢀMPS3, in which oxovanadium moieties are covalently
bound to the inner surface of mesoporous silica (MPS) with a pore
size of about 3 nm (Figures 1A and 1B).4c,5 MPS is a rigid, wellꢀ
ordered hexagonal material with uniform pore size, large surface
area (averaging 1000 m2/g or more), and mild acidity. Various kinds
of MPS with different pore sizes (ranging from 2 nm to 50 nm) are
Introduction
The enzymatic dynamic kinetic resolution (DKR) of racemic
secondary alcohols has gained much attention because it is a simple
method to obtain optically pure esters in quantitative yields.1 DKR is
typically performed using a combination of hydrolaseꢀcatalyzed
kinetic resolution and rutheniumꢀcatalyzed in situ continuous
racemization of less reactive alcohol enantiomers via a redox
process. The efficiency of the strategy is demonstrated by its
applicability to a wide range of alcohols.2,3 However, some issues
ensue when the strategy is applied to allyl alcohols, including the
formation of significant amounts of sideꢀproducts.1c
Recently, we have developed a new DKR method, which is
particularly useful for allyl alcohols, based on the combined use of
lipases and oxovanadium catalysts. In this method, racemization
occurs along with the 1,3ꢀmigration of hydroxyl groups and enables
the use of regioisomeric allyl alcohols (1 and 2) as equivalent
VꢀMPS3
R2 OCOR4
R2 OH
OH
lipase
R2
acyl donor
R3
R3
R1
(R)ꢀ3
R1
R3
R1
or
up to 100%
(±)ꢀ1
(±)ꢀ2
up to >99% ee
lipase
acyl donor
Reaction mechanism:
R2 OH
OH
R2
R3
R1
R1
R3
Xnꢀ1
V
O
Xnꢀ1
(R)ꢀ1
V
(R)ꢀ2
O
O
O
R2
O=VXn
(VꢀMPS3)
R2
R1
R3
R1
R3
A
B
R2 OH
R3
OH
R2
R3
R1
R1
(S)ꢀ1
(S)ꢀ2
Scheme 1 Dynamic kinetic resolution of racemic alcohols (1 and 2) by V-
MPS3/lipase combo catalysis.
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and/or polarities and on lipaseꢀcatalyzed DKR. We also obtained
strong evidences for our hypotheses that the racemization
predominantly occurred inside the pores of VꢀMPS and that the
polarity of the VꢀMPS pores accelerated the racemization. Notably,
by choosing VꢀMPS with a suitable pore size for each substrate, the
scope of viable substrates for DKR was expanded.
Figure 1 Structure of MPS3 (A) and estimated structure of V-MPS3 (B).4c
Results and discussion
Preparation of V-MPS with different pore sizes and their
application in the racemization of various alcohols.
readily available.6 The combined use of lipases and VꢀMPS3
significantly increased the chemical and optical yields of the
products, (R)ꢀ3, as compared to our previous DKR methods, in
We prepared VꢀMPS2 and VꢀMPS4 by the silanolꢀexchange reaction
of the corresponding MPS2 and MPS4 with O=V(OSiPh3)3, in a
manner similar to that described for VꢀMPS3.4c The structures of Vꢀ
MPS2 and VꢀMPS4 were determined by Brunauer–Emmett–Teller
(BET), Barrett–Joyner–Halenda (BJH), inductively coupled plasma
(ICP), and elemental analyses (Table 1). The average pore sizes of
VꢀMPS2 and VꢀMPS4, as measured by BET, were 1.7 nm and 3.3
nm, respectively (for reference, the average pore size of VꢀMPS3 is
2.6 nm). The loading of the vanadium component of VꢀMPS4, as
measured by ICP, was 0.20 mmol/g and was almost the same as that
of VꢀMPS3 (0.20–0.22 mmol/g). On the other hand, the loading of
the vanadium component of VꢀMPS2 was 0.02 mmol/g, and such a
low vanadium loading is probably due to the narrow pore of MPS2,
which might hamper the incorporation of O=V(OSiPh3)3 into MPS2.
The similarity of the solidꢀstate 13C NMR data (δ 135.0, 130.3,
128.0) of VꢀMPS4 to those of O=V(OSiPh3)3 and the elemental
analysis indicated that the immobilized vanadium of VꢀMPS4 had a
single OSiPh3 group, similar to VꢀMPS3 (Figure 1B) [for more
information about the synthesis of VꢀMPS2 and VꢀMPS4 and the
solidꢀstate 13C NMR spectra, see Electronic Supplementary
Information (ESI)].
4a
which a homogenous catalyst O=V(OSiPh3)3 and a polymerꢀ
supported oxovanadium compound4b were used. One of the most
outstanding improvements of VꢀMPS3 was the excellent
compatibility with lipases, because the combined use of lipases and
4a
our previous catalysts, such as O=V(OSiPh3)3 and a polymerꢀ
supported oxovanadium compound,4b resulted in a loss of their
catalytic activities owing to mutual interaction. The compatibility of
VꢀMPS3 and lipases was supposed to be due to the narrow pores of
MPS3, which effectively separated the vanadium moiety and lipases
and completely suppressed the mutual inactivation. However, we
had no evidence to confirm that the racemization predominantly
occurred inside the pores of MPS. In addition, VꢀMPS3 exhibited
the highest racemization activity among several oxovanadium
compounds, including O=V(OSiPh3)3,4a
a
polymerꢀsupported
oxovanadium compound,4b and oxovanadium moieties covalently
immobilized on the pore surface of macroporous silica with a pore
size of either 100 nm or 400 nm.4c These results were especially
surprising because polymer supported catalysts are often less
reactive than homogeneous catalysts and also because the relatively
narrow pore size of VꢀMPS3 was thought to prevent alcohols from
rapidly coming in and out of the pores. The abovementioned
unexpectedly high racemization activities of VꢀMPS3 suggested that
the nanosized pores of MPS3 exhibited unknown chemical as well as
physical effects on the racemization. We speculated that the small
pores of MPS3, whose surface was covered with silanols, created a
polar environment7 that accelerated the racemization by facilitating
the C–O bond cleavage of the vanadate A and stabilizing ionic
intermediate B, although we had no evidence to support this
hypothesis.
Insert Table 1
The catalytic activities of VꢀMPS2, VꢀMPS3, and VꢀMPS4 (1.0
mol% of the amount of vanadium in each case) were evaluated in the
racemization of (S)ꢀ1a (>99% ee) in CH3CN at 35 °C as a model
case (Scheme 2); the time course for each reaction is shown in
Figure 2A. Both VꢀMPS3 and VꢀMPS4 showed similar activities
and the racemization was complete within 2 h; however, VꢀMPS2
showed much lower activity. At the same time, a mixture of two
diastereomers of dimeric ethers 4a, generated by the reaction of
cationic intermediate B and 1a, was formed,19 and the formation rate
was dependent on the pore size of VꢀMPS (Figure 2B).
We next investigated the efficiency of VꢀMPS2, VꢀMPS3, and
VꢀMPS4 with larger substrates. For example, alcohol (S)ꢀ1b (>99%
ee) with a length of about 1.4 nm was evaluated (Figure 3).20
Racemization proceeded when VꢀMPS3 and VꢀMPS4 were used,
although 5.0 mol% of VꢀMPS was required at slightly higher
Since its discovery in the early 1990s,6 MPS has found
widespread application in catalysis,8 carriers,9 adsorption,7,10
sensing,11 and chromatography12 among other areas.13 On the
contrary, there are limited reports on the use of MPS pores in
transformations of organic molecules, which include acetalization
reactions,14 porphyrin synthesis,15 Friedel–Crafts reactions,16
metathesis,17 DKR,2f,2k and polymerization.18 Among the available
reports, the active use of pore size effects of MPS were studied in
very few cases,14,15 and most studies used MPS with a single pore
size.
In this study, we prepared VꢀMPS2 and VꢀMPS4, with pore
sizes of approximately 2 and 4 nm, respectively, and compared their
racemization activities with that of VꢀMPS3. We observed some
characteristic effects of VꢀMPS on the racemization of several
optically active secondary alcohols with different molecular sizes
2 | J. Name., 2012, 00, 1-3
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Xnꢀ1
V
VꢀMPS
(1.0 mol%)
OH
OH
OH
100
80
60
40
20
0
O
O
+
O
a
p
p
CH3CN (0.08 M)
35 °C
r
o
x
>99% ee
Ph
VꢀMPS
(5.0 mol%)
i
m
4a
1a
(±)ꢀ
B
a
1a
(S)ꢀ
t
a mixture of two
diastereomers
racemiꢀ
zation
e
l
VꢀMPS: VꢀMPS2, VꢀMPS3 and VꢀMPS4
y
acetone
(0.08 M)
50 °C
1
.
4
n
m
Scheme 2 Racemization of optically pure (S)-1a with V-MPS with
different pore sizes.
1b
(S)ꢀ
(>99% ee)
0
2
4
6
8
10 12
time (h)
100
(A)
100
80
60
40
20
0
Figure 3 Racemization of optically pure (
S
)-1b catalyzed by V-MPS2
(B)
(–■
–), V-MPS3 (–
▲
–), and V-MPS4 (–●–) (5.0 mol% of the amount of
80
60
40
20
0
vanadium).
OH
oxovanadium catalyst
racemization
0
2
4
6
8
10 12
0
2
4
6
8
10 12
CH3CN (0.08 M)
35 °C
R
>99% ee
time (h)
time (h)
1c
(S)ꢀ : R = OnC11H23
Figure 2 Racemization of optically pure (S)-1a catalyzed by V-MPS2
(S)ꢀ1d: R = O(CH2CH2O)3CH3
(– –), V-MPS3 (– –), and V-MPS4 (–●–) (1.0 mol% of the amount of
vanadium). (A) Change in optical purity (ee %) of (S)-1a over time. (B)
■
▲
100
(B)
(A)
80
60
40
20
0
Formation of 4a over time.
temperature such as 50 °C because of the decreased catalytic activity
with such a bulky alcohol. Racemization by VꢀMPS4 was much
faster than that by VꢀMPS3, probably due to the better mobility of
1b into and out of VꢀMPS4. On the other hand, racemization by Vꢀ
MPS2 was very slow. These results give good evidence for our
hypothesis that the racemization predominantly occurred inside the
pores of VꢀMPS.
Next the effect of substrate polarity on the racemization was
examined to prove the polarity of the MPS pores. Thus, the
racemization of a 1:1 mol mixture of optically pure (S)ꢀ1c and (S)ꢀ1d,
0
2
4
6
8
0
2
4
6
8
time (h)
time (h)
100
80
60
40
20
0
(D)
(C)
each of which has a side chain of almost the same length but with
different polarity, was examined in the presence of VꢀMPS2, Vꢀ
MPS3, and VꢀMPS4 (1.0 mol% vanadium each for the total amount
of 1c and 1d) under identical reaction conditions. Notably, the
0
2
4
6
8
0
2
4
6
8
time (h)
time (h)
Figure 4 Racemization of optically pure (S)-1c (–•–) and (S)-1d (–○–)
catalyzed by V-MPS. (A) V-MPS2 (1.0 mol% for total amount of 1c and
1d); (B) V-MPS3 (1.0 mol% for total amount of 1c and 1d); (C) V-MPS4
(1.0 mol% for total amount of 1c and 1d); (D) by O=V(OSiPh3)3 (10 mol%
for total amount of 1c and 1d).21
racemization of (
(Figures 4A–C). On the other hand, the racemization rate of (
and (
vanadium) was almost the same, although 10 times the amount of
O=V(OSiPh3)3 was needed to obtain similar activity (Figure 4D). In
addition, the racemization activity of VꢀMPS was dependent on the
S
)ꢀ1d was faster than that of (
S
)ꢀ1c in all cases
)ꢀ1c
S)ꢀ1d using a homogenous catalyst O=V(OSiPh3)3 (10 mol%
S
21
OH
100
pore size, viz., VꢀMPS2 (Figure 4A) < VꢀMPS3 (Figure 4B)
≅ Vꢀ
R
MPS4 (Figure 4C). The difference between the racemization by Vꢀ
MPS and that of O=V(OSiPh3)3 unambiguously demonstrates that
the majority of racemization by VꢀMPS occurs in the narrow pores
of the MPS and that there is a positive correlation between the
polarity of the substrate and the racemization rate by VꢀMPS.
80
>99% ee
60
40
20
0
R
1e
(S)ꢀ : R = OnC11H23
(S)ꢀ1f: R = O(CH2CH2O)3CH3
VꢀMPS
(5.0 mol%)
The racemization of bulky alcohols (S)ꢀ1e (>99% ee) and (S)ꢀ1f
racemization
0
2
4
6
8
10
12
CH3CN (0.08 M)
50 °C
(>99% ee), each of which has two side chains of almost the same
length but different polarities, was also compared using either Vꢀ
MPS3 or VꢀMPS4 (each 5.0 mol% vanadium) under identical
conditions. The racemization of (S)ꢀ1f was faster than that of (S)ꢀ1e
when using either VꢀMPS3 or VꢀMPS4. In addition, the
racemization using VꢀMPS4 was faster than that using VꢀMPS3 for
time (h)
Figure 5 Racemization of optically pure (
MPS (5.0 mol% vanadium for each alcohol). (
)-1e with V-MPS4 (- -●- -), ( )-1f with V-MPS3 (–
S
)-1e and (
)-1e with V-MPS3 (–
–), and ( )-1f with V-
S
)-1f catalyzed by V-
S
▲
–),
(S
S
△
S
MPS4 (- -○- -).
both (S)ꢀ1e and (S)ꢀ1f (Figure 5).
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We also observed the positive correlation between the sizes of
the MPS pores and those of the substrates which strongly affects the
racemization rate. Among some reports on the use of MPS pores in
selective transformations of organic molecules,2f,2k,14ꢀ18 the pore size
effects of MPS were studied in only acetalization reactions14 and
porphyrin synthesis,15 and most studies used MPS with a single pore
size. In the present work, we found that the pore size of VꢀMPS can
differentiate the molecular size of substrates.
R
20%
15%
10%
5%
>99% ee
R
1e
(S)ꢀ : R = OnC11H23
(S)ꢀ1f: R = O(CH2CH2O)3CH3
1e
1f
)
(a 1:1 mixture of
and
MPS4 (2.0 w/w for
total amount of 1e
HPLC analysis to
determing the amount
of each alcohol inside
the MPS pore
1f)
and
0%
0
30
60
90
120
CH3CN (0.08 M)
r.t.
time (min)
V-MPS/lipase combo-catalyzed DKR
Figure 6 Incorporation of (
S
)-1e and (
S
)-1f into MPS4 (twice the amount
)-1f (- -○- -).
VꢀMPS2, VꢀMPS3, and VꢀMPS4 were combined with
commercially available immobilized lipases, such as Candida
antarctica lipase B (CALꢀB) and Burkholderia cepacia lipase (PSꢀ
IM), and used for the DKR of alcohols (±)ꢀ1 and (±)ꢀ2.
by weight of 1e + 1f). ( )-1e (- -●- -) and (
S
S
To obtain further information about the polarity of the MPS
pores, we investigated the incorporation rate of 1e and 1f into MPS4
First, (±)ꢀ2a was treated with CALꢀB in the presence of VꢀMPS4
(not VꢀMPS4). Thus, a 1:1 mol mixture of (S)ꢀ1e and (S)ꢀ1f (100 mg
(1.0 mol%) in CH3CN at 35 °C for 24 h to give (R)ꢀ3a (98% ee) in
total) was mixed with MPS4 (200 mg; twice the amount by weight
of 1e + 1f) in CH3CN, and the mixture was stirred at room
temperature. The amount of alcohol inside the MPS pores was
determined via HPLC analysis of the alcohols in the supernatant.
The timeꢀcourse of the experiment shown in Figure 6 reveals that
both 1e and 1f were incorporated in the pores, and that the
incorporation ratio of 1f was about 1.5 times that of 1e.
95% isolated yield (Table 2, entry 3), which was very similar to the
result obtained with VꢀMPS3 (entry 2).4c On the other hand, with Vꢀ
MPS2, (
and optically pure (
to the lower racemization activity of VꢀMPS2 (see Figure 2A).
Despite the yields, the formation of ( )ꢀ3a with excellent optical
R)ꢀ3a (98% ee) was obtained in a lower yield (74% yield),
S)ꢀ2a was recovered in 24% yield. This was due
R
purity (98–99% ee) in all cases demonstrated the outstanding
compatibility of VꢀMPS with lipase. Although the use of VꢀMPS4
(1.0 mol%) alone afforded dimer 4a in 28% yield after 12 h (see
Figure 2B), the combined use of VꢀMPS4 and lipase dramatically
suppressed the formation of 4a to 5% even after 24 h (entry 3). A
50% reduction in the amount of VꢀMPS4 (0.5 mol%) sufficiently
The aforementioned results (Figures 2–6) generated the
following discussion about the characteristic effects of VꢀMPS as
well as MPS on the racemization: (1) The racemization
predominantly proceeds inside the pores of VꢀMPS, which is quite
reasonable because the majority of vanadium moieties should be
immobilized on the inner surface of the MPS (870–1200 m2/g); (2)
more polar substrates (1d and 1f) tend to go into the MPS pores
more and racemize faster than less polar substrates such as 1c and
1e; and (3) a polar environment is generated inside pores of VꢀMPS
as well as MPS. In our previous studies, we observed that the use of
highly polar solvents significantly accelerated the racemization of
optically active alcohols using either the polymer supported
oxovanadium compound4b or VꢀMPS3.4c,22 These solvent effects on
the racemization are accountable by the acceleration of the C–O
bond cleavage of vanadate A and by the stabilization of ion pair
intermediate B (see Scheme 1) in highly polar media. It is also
reported that the inner surface of MPS pores is locally polar due to
the silanols (Figure 1A).7 Therefore, we assume that the small pore
size of VꢀMPS generates the polar environment in the whole pore
space, which should be the most plausible reason why the
racemization by VꢀMPS is much faster than that by homogeneous
diminished the yield of 4a to 1% and improved the yield of (
R)ꢀ3a to
98% with an optical purity of 98% ee (entry 4). Notably, a similar
reation using 0.10 mol% of VꢀMPS4 also produced (
in 94% yield, although it took 5 days (entry 5).
R)ꢀ3a (98% ee)
Insert Table 2
The DKR of various (±)ꢀ1 and (±)ꢀ2 is summarized in Table 3.
The effects of the pore size of VꢀMPS can be summarized as
follows: (1) with bulky alcohols (±)ꢀ2b, (±)ꢀ2e, and (±)ꢀ2f, VꢀMPS4
gave optically pure esters (R)ꢀ3b, (R)ꢀ3e, and (R)ꢀ3f in better yields
than those with VꢀMPS3 (entries 1–6). These results reflect the
faster racemization by VꢀMPS4. (2) DKR of (±)ꢀ2c, (±)ꢀ2d, (±)ꢀ2g,
(±)ꢀ1h–j, and (±)ꢀ1m, which have moderate molecular sizes, by Vꢀ
MPS4 and VꢀMPS3 afforded the corresponding esters (R)ꢀ3 in
nearly identical chemical and optical yields (entries 7–20, and 26).
(3) When VꢀMPS2 was used at a slightly elevated temperature
catalyst O=V(OSiPh3)3,4a
a polymer supported oxovanadium
compound,4b and related oxovanadium species covalently
immobilized on the pore surface of macroporous silica with a pore
size of either 100 nm or 400 nm.4c In addition, for the racemization
to occur in unsymmetrically substituted substrates (see Scheme 1),
the allyl cation has to leave the oxovanadium anion to change face,
for which the pore size as well as the polar environment should also
have some significant effects.
From another mechanistic view point, it is worth noting that the
incorporation of both 1e and 1f into MPS4 reached a steady state
within 15 min (Figure 6). Thus, the mobility of alcohols into and out
of the pores is sufficiently high compared with the racemization rate.
(50 °C), the chemical and optical yields of (R)ꢀ3 were similar to
those obtained with VꢀMPS3 and VꢀMPS4 (entries 9–14). (4) On the
other hand, the efficient DKR of compact and unstable alcohols such
as (±)ꢀ2l23 could only be achieved with VꢀMPS2 (entries 23–25).24 In
this case, the racemization by VꢀMPS3 or VꢀMPS4 caused gradual
decomposition of 2l, whereas that with VꢀMPS2 did not.
Furthermore, VꢀMPS4 could be used in the DKR of alcohols
having a cyano (±)ꢀ1m or terminal alkynyl group (±)ꢀ1n to give
optically pure (R)ꢀ3m and (R)ꢀ3n in excellent chemical yields
(entries 26 and 27). The successful DKR of 1n is notable, because
while the reaction of 1n and VꢀMPS4 gave an E/Z mixture of 3ꢀ(4ꢀ
methoxyphenyl)propenal via MeyerꢀSchuster rearrangement, such
4 | J. Name., 2012, 00, 1-3
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products were not observed in the presence of the lipase and vinyl stimulate new avenues of research into enantioselective
acetate (entry 27).
transformations.
Insert Table 3
Acknowledgements
To summarize the VꢀMPS/lipase comboꢀcatalyzed DKR of
alcohols 1 and 2, the viable substrate scope was expanded by
choosing suitable pore size of VꢀMPS. Both VꢀMPS3 and VꢀMPS4
showed similar activity for mediumꢀsized substrates (e.g., MW < ca.
400 and/or the shorter lengh < ca. 0.7 nm), while VꢀMPS4 was
particularly beneficial for larger substrates such as 2b, 2e, and 2f.
When dimeric ethers such as 4a were formed as byproducts, a
reduction in the amount of VꢀMPS4 suppressed the formation of the
dimeric ethers and improved the yields of 3 while maintaining their
optical purities (e.g., Table 1, entry 4). The excellet availability of
the alchols, such as 1j, 1m and 1n, possessing a functional group at
the terminal position will extend the practical utility of this DKR for
further modification of the products.
This research was supported by a GrantꢀinꢀAid for Scientific
Research on Innovative Areas “Organic Synthesis Based on
Reaction Integration,” a GrantꢀinꢀAid for Exploratory Research
and for Scientific Research (B), and the Platform Project for
Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics, and Structural Life
Science) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), and Japan Agency for
Medical Research and Development (AMED). The Japan
Society for the Promotion of Science is gratefully
acknowledged for the preꢀdoctoral fellowship to K.S. We
acknowledge Amano Enzyme, Inc. for supplying the lipases
and Taiyo Kagaku Co. Ltd., Chemical Ltd. for providing MPS.
We are grateful to Prof. Hironao Sajiki of Gifu Pharmaceutical
University (Japan) for his useful advice in clarifying the
Conclusions
We previously reported a new DKR method based on the structure of VꢀMPS and to N.E. Chemcat Corporation and
combination of lipaseꢀcatalyzed kinetic resolution of racemic Wako Pure Chemical Industries, Ltd. for measuring ICP and
alcohols and the VꢀMPS3ꢀcatalyzed in situ racemization of less conducting elemental analysis.
reactive enantiomers.4c In VꢀMPS3, oxovanadium moieties were
covalently bound to the inner surface of MPS with a pore size of
Notes and references
about 3 nm. Although the catalytic activity of VꢀMPS3 was much
higher than that of related vanadium compounds, we had no
evidence to confirm that the racemization occurred inside the pores
of MPS or to explain its unusually high activity. In this study, we
prepared VꢀMPS2 and VꢀMPS4 from the corresponding MPS with
pore diameters of approximately 2 and 4 nm, respectively, and
compared their racemization activities using some optically active
alcohols with different molecular sizes and polarities with the
activity of VꢀMPS3. We discovered unique features of VꢀMPS, such
as a positive correlation between the pore size of VꢀMPS and
substrate racemization rate. The high polarity of the MPS pores
possibly accelerates the racemization by facilitating the C–O bond
cleavage of the vanadate A and stabilizing ion pair intermediate B; a
small pore size (2–4 nm) efficiently functions to generate this polar
environment in the entire pores, while macroporous silica with a
pore size of 100–400 nm does not exhibit similar effects. These
results demonstrated that the racemization predominantly occured in
the pores of VꢀMPS. We expect that the unique polarity of MPS and
their ability to distinguish substrate sizes will be useful in the
development of new MPSꢀimmobilized catalysts.
1
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racemization of variousꢀsized alcohols, and the combination of Vꢀ
MPS4 and lipases enabled highly effective DKR to afford optically
active esters in excellent chemical and optical yields. In some cases,
VꢀMPS2 was more suitable. Therefore, appropriate selection of Vꢀ
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(a) S. Akai, K. Tanimoto, Y. Kanao, M. Egi, T. Yamamoto, 19 Similar formation of dimeric ethers from allyl alcohols was
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c
) M. Egi, K. Sugiyama, M. Saneto, R. 20 Due to the poor solubility of
(
S
)ꢀ1b in CH3CN, the
Hanada, K. Kato, S. Akai, Angew. Chem. Int. Ed. 2013, 52,
3654–3658.
In our previous paper, we used MPS with a pore size of
approximately 2.7 nm to synthesize VꢀMPS.4c In this paper,
we called it VꢀMPS3 in order to differentiate it with other Vꢀ
MPS with different pore sizes.
racemization of (S)ꢀ1b was examined in acetone.
21 The data of Figure 4D were obtained using a 300:1 mol ratio
of water and amount of O=V(OSiPh3)3. After the publication
on the use of VꢀMPS34c we found that the addition of a range
of water [ca. 10–300:1 mol ratio of water and amount of
O=V(OSiPh3)3] to the reaction mixture was very important to
exhibit catalytic activity of the racemization and also to
obtain good reproducibility. Investigation to clarify the role
of water in these reactions is in progress in our laboratory.
5
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(
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) S. Inagaki, Y. Fukushima, J. Chem. Soc., 22 The racemization in CH3CN was faster than that in acetone4b
and heptane.4c
(d
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23 Alcohol 2l was reported to be very sensitive to acid and
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For related studies on the hydrophilicity of mesoporous
24 The use of VꢀMPS2 under the standard reaction conditions
7
generated (R)ꢀ3l in poor chemical and optical yields. After
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b
) S.
3), 0.20 w/w of CALꢀB, iPr2O produced (R)ꢀ3l in the better
8
9
M. M. Heravi, K. Bakhtiari, H. Alinejhad, M. Saeedi, R.
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chemical and optical yields. In particular, the portionꢀwise
addition of the acyl donor was the key for the high optical
purity as shown in Table 2, entry 23, and the use of a slightly
less amount of the acyl donor made the purification of the
product easier.
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Chem. Commun. 2011, 47, 9972–9985. ( ) S. Jana, S. Haldar,
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13 AlꢀMPS, in which silicon was partly replaced with aluminum,
have also been used for various reactions. See (
H.ꢀC. Lin, S.ꢀH. Cheng, T.ꢀS. Lin, C.ꢀY. Mou, J. Phys. Chem.
2009, 113, 16058–16069. ( ) M. Onaka, N. Hashimoto, Y.
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Table 1. Analytical data of MPSs and VꢀMPSs
vanadium
average surface area pore
elemental
analysis
content
pore
size
(nm)
1.7
(m2/g)
volumn
(cm3/g)
0.41
0.40
0.01
1.04
0.90
0.14
1.17
1.02
0.15
carbon hydrogen
(%)
6.7
(%)
1.2
MPS2
0.87 x 103
0.86 x 103
0.01 x 103
1.02 x 103
0.94 x 103
0.08 x 103
0.92 x 103
0.86 x 103
0.06 x 103
VꢀMPS2
0.1 w/w%
(0.02 mmol/g)
1.7
0.0
2.8
2.6
0.2
3.7
3.3
0.4
8.3
–1.6
2.5
1.2
0.0
MPS2 –
(VꢀMPS2)
MPS3a
0.7
VꢀMPS3a
1.0 w/w%
(0.20 mmol/g)
7.3
1.0
MPS3 –
(VꢀMPS3)
MPS4
–4.8
1.6
–0.3
0.5
VꢀMPS4
1.0 w/w%
(0.20 mmol/g)
6.8
0.9
MPS4 –
–5.2
–0.4
(VꢀMPS4)
a) Cited from ref. 4c.
Table 2 Comparison of three different VꢀMPS on lipaseꢀcatalyzed DKR
of (±)ꢀ2a.
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Table 3 DKR of alcohols (±)ꢀ1 and (±)ꢀ2 by lipases and VꢀMPS with different pore sizes.a
a) Unless otherwise noted, reactions were carried out using 0.1–0.3 mmol of substrates. b) A: Candida antarctica lipase B (CALꢀB) in CH3CN, B:
Burkholderia cepacia lipase (PSꢀIM) in heptane. c) A 1:1 mixture of (E)ꢀ and (Z)ꢀ2 was used. d) Acetone was used instead of CH3CN. e)
Performed using 5.0 mol% of VꢀMPS at 50 °C for 72 h (entries 1–4) or at 35 °C for 24 h (entries 5 and 6). f) Cited from ref. 4c. g) Conducted at
50 °C. h) Vinyl decanoate was used instead of vinyl acetate. i) 2,2,2ꢀTrifluoroethyl docosanate (0.30 equiv), 0.20 w/w of CALꢀB, iPr2O were used
instead of vinyl acetate, 3.0 w/w of CALꢀB, and CH3CN, respectively. Additional 2,2,2ꢀtrifluoroethyl docosanate (0.30 equiv) was added after 12
and 24 h, and the reaction mixture was stirred tor total 36 h. The isolated yield of (R)ꢀ3l was based on (±)ꢀ2l. j) Vinyl butyrate and toluene were
used instead of vinyl acetate and heptane, respectively. k) Vinyl butyrate was used instead of vinyl acetate at 50 °C.
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A table of contents entry
The nano-scale pores of mesoporous silica and their polar
environment accelerate the racemization to make the
lipase/oxovanadium combo-catalysed DKR applicable to
a wider range of alcohols.