Highly efficient dynamic kinetic resolution of secondary aromatic alcohols at low temperature using a low-cost sulfonated sepiolite as racemization catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.07.102

A highly efficient dynamic kinetic resolution system for secondary aromatic alcohol using low-cost sulfonated sepiolite as a racemization catalyst has been developed. The system operates at 25 °C, achieves good ee_p (>99%) and substrate conversi

Full text of DOI:10.1016/j.tetlet.2014.07.102

Tetrahedron Letters 55 (2014) 5129–5132
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Tetrahedron Letters
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Highly efficient dynamic kinetic resolution of secondary aromatic
alcohols at low temperature using a low-cost sulfonated sepiolite as
racemization catalyst
⇑
Jian-Ping Wu, Xiao Meng, Liang Wang, Gang Xu , Li-Rong Yang
Institute of Biological Engineering, Department of Chemical and Biological Engineering, Zhejiang University, 310027 Hangzhou, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient dynamic kinetic resolution system for secondary aromatic alcohol using low-cost sul-
fonated sepiolite as a racemization catalyst has been developed. The system operates at 25 °C, achieves
good eep (>99%) and substrate conversion ratio (>99%), is applicable to a variety of substrates and can
be reused more than 10 times.
Received 20 March 2014
Revised 23 July 2014
Accepted 24 July 2014
Available online 30 July 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dynamic kinetic resolution
Aromatic secondary alcohol
Sepiolite
Racemization catalyst
Low temperature
Introduction
3 in Table 1)5 performed well in organic media as racemization cat-
alysts of optically pure enantiomer of aromatic secondary alcohols.
Dynamic kinetic resolution (DKR) is
a
widely researched
Their catalytic activity is derived from their sulfuric acid groups
(–SO3H). DKR systems of aromatic sec-alcohols have been well
established by coupling these racemization catalysts with Nov-
ozym 435 (immobilized Candida antarctica lipase B), and when
the acylation reaction was carried out at 40 °C using p-chloro-
phenyl valerate as acyl donor, both eep and substrate conversion
were greater than 99%.5,6
method for the preparation of optically pure chiral secondary alco-
hols. By combining enzyme-catalyzed kinetic resolution (KR) with
an in situ racemization, normally catalyzed by chemical catalyst,
DKR increases the maximum yield of enantiopure product of a
KR process from 50% to 100%.1 The key aspect of a successful and
practical DKR system is a highly efficient and low cost racemiza-
tion catalyst capable for mild reaction conditions that an enzyme
requires.2 However, currently available racemization catalysts are
either difficult to synthesize homogeneous metal complexes or
supported transition metals, which typically require either high
temperature or the presence of high-pressure hydrogen.3
Here, we report a highly efficient DKR system for chiral aro-
matic alcohols that works at a quite mild temperature (25 °C) using
low-cost sulfonated sepiolite as the racemization catalyst. The
system was applied to a variety of substrates, all achieving both
high eep (>99%) and substrate conversion (>99%).
However, 40 °C, which the acidic resin and solid super acid
require to racemize chiral aromatic sec-alcohols, is still not low
enough for most commercially available lipases other than Nov-
ozym 435 (which is known to be pretty thermally stable). There-
fore, the racemization catalyst needed further improvements for
even higher efficiency, so as to build truly enzyme-compatible
for use in a practical DKR system. Because solid super acid dis-
played higher stability than the acidic resins in the very reaction
condition of aromatic alcohol resolution in organic media, this cat-
alyst was targeted for enhancement. Nano-scaling is a widely
accepted approach for the activation of catalysts, so large specific
surface area nanosized materials with different microstructures
with large specific surface areas, such as SBA-15, nanosized SiO2,
and SBA-3 were prepared according to the literature,7 and then sul-
fonated to make the corresponding nanosized super acids (entries
4, 5, and 6 in Table 1). These catalysts did have higher catalytic
activity than the previously synthesized catalysts (entries 1, 2,
and 3 in Table 1), but unfortunately, they also produced significant
Results and discussion
In our previous research, acidic resins (CD550 and CD8604,
entries 1 and 2 in Table 1)4 and solid super acids (TiO2/SO24À, entry
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2014.07.102
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5130
J.-P. Wu et al. / Tetrahedron Letters 55 (2014) 5129–5132
Table 1
Racemization performance of nanosized super acids and sulfonated natural minerals as compared with other acidic catalysts
Entry
Catalyst
Microscopic structure
Average pore size (nm)
Specific surface area (m2 gÀ1
)
Reaction Ia
Reaction IIb
ee (%)
Styrene (mmol LÀ1
)
Conversion (%)
1
2
3
4
5
6
7
8
CD550
Porous
Porous
35.7
39.4
—
4.0
—
—
16.2
12.0
31
31
92
534
1015
1266
87
16.3
12.5
6.4
9.5
7.7
3.9
5.5
0.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
13.3
32.6
33.3
0.0
CD8604
TiO2/SO24Àc
Spherical
Porous
Spherical
Spherical
Porous
SBA-15/SO24Àc
Nanosized-SiO2/SO42Àc
SBA-3/SO24Àc
Halloysite/SO42Àc,d
Sepiolite/SO42Àc,e
Porous
154
0.0
a
Reaction conditions for racemization (Reaction I): toluene (1 mL), (S)-1-phenylethanol (100 mmol LÀ1), and catalyst (10 mg) were mixed in a 2 mL tube, reacted for 6 h at
40 °C, and agitated at 200 rpm.
b
Non-enzymatic acylation (Reaction II) is a side reaction in which acidic catalyst might catalyze during DKR process. This side reaction lowers the overall eep of DKR and
should be avoided. In the table, higher conversion ratio of Reaction II indicates a poorer specificity of the catalyst. Reaction conditions for the non-enzymatic acylation
(Reaction II): toluene (1 mL), rac-1-phenylethanol (100 mmol LÀ1), p-chlorophenyl valerate (300 mmol LÀ1), and catalyst (10 mg) were mixed in a 2 mL tube, reacted for 6 h at
40 °C, and agitated at 200 rpm.
c
Sulfonation conditions for entries 3, 4, 5, 6, 7, and 8: the solid was impregnated in H2SO4 (0.5 mol LÀ1) for 4 h and then heated at 400 °C for another 4 h.
d
The standard crystallochemical formula of halloysite is Al2O3Á2SiO2Á4H2O.
e
The standard crystallochemical formula of sepiolite is Mg8(H2O)4[Si6O16]2(OH)4Á8H2O.
amounts of side-products in the non-enzymatic acylation of aro-
matic sec-alcohol (reaction II in Table 1). Of these three spherical
Table 2
nanosized catalysts, the porous SBA-15/SO24À had the lowest side
Racemization performance of the sulfonated sepiolite at different temperatures
reactions.
Entry
Temperature (°C)
Time (h)
ee (%)
Styrene (mmolÁLÀ1
)
From this, it can be inferred that the large specific surface area
of nanosized material tend to over-activate the catalyst, lowering
their specificity. The porous microstructure, however, was able to
inhibit the non-enzymatic acylation side reaction. Working from
this, and the complexity of the preparation and higher cost of the
1
2
3
4
40
35
30
25
4
6
12
24
0
0
0
0
0
0
0
0
Table 3
DKR of various sec-alcohols with p-chlorophenyl valerate as the acyl donor
a
b
Entry
1
Substrate
Product
eep (%)
>99
Conversion (Yield c) (%)
>99 (95)
2
3
>99
>99
>99 (95)
>99 (95)
4
5
>99
>99
>99 (95)
>99 (94)

J.-P. Wu et al. / Tetrahedron Letters 55 (2014) 5129–5132
5131
Table 3 (continued)
b
Entry
Substrate
Product
eep (%)
Conversion (Yield c) (%)
6
>99
>99
>99
>99
>99
>99
>99
>99 (92)
7
>99 (90)
>99 (88)
>99 (90)
>99 (92)
>99 (89)
>99 (92)
8
9
10
11
12
13
>99
>99
>99 (88)
>99 (90)
14
15
>99
>99
>99 (92)
>99 (90)
16
Reaction conditions: toluene (1 mL), racemic aromatic sec-alcohol (100 mmol LÀ1), p-chlorophenyl valerate (300 mmol LÀ1), Novozym 435 (10 mg), and sepiolite/SO24À
(10 mg) were mixed in a 2 mL tube, reacted at 25 °C for 24 h, and agitated at 200 rpm.
a
b
Conversion ratio (%) = [converted substrate (mol)]/[total initial substrate (mol)] Â 100%.
c
Isolated yield (%) = [isolated product (mol)]/[total initial substrate (mol)] Â 100%. The enantiomerically pure DKR products were isolated from the reactant by column
chromatography using n-hexane/ethyl acetate = 10:1 (v/v) as a developing agent.
nanosized catalysts, we decided to synthesize a super acid based
on low cost natural minerals with a porous microstructure and a
specific surface area between those of common catalysts (CD550,
CD8604, and TiO2/SO42À) and nanosized catalysts (SBA-3/SO24À
,
nanosized SiO2/SO24À, and SBA-15/SO24À). Sepiolite and halloysite
are among those cheapest minerals with the largest specific sur-
face areas.8 After sulfonation, they displayed higher catalytic activ-
ity in the racemization of (S)-1-phenylethanol than CD-550, CD-
8604, and the TiO2/SO24À, and better specificity than SBA-15/SO24À
,
nanosized SiO2/SO24À, and SBA-3/SO24À. The racemization tempera-
ture of sepiolite/SO24À was investigated further (Table 2), indicating
that this newly developed catalyst performed well at temperatures
as low as 25 °C. At 25 °C, sulfonated sepiolite was then employed
as the racemization catalyst in the DKR of several chiral aromatic
sec-alcohols, coupled with Novozym 435 as the resolution catalyst
and all achieved eep >99% and conversions >99% (Table 3). This
DKR system could be reused more than 10 times without any
decrease in eep and conversion (Fig. 1).
Conclusions
In summary, a low-cost racemization catalyst based on sulfo-
nated sepiolite was developed and employed in the DKR of second-
ary aromatic alcohols, achieving good eep and substrate conversion
ratios at 25 °C, which was the lowest reported DKR temperature.
Acknowledgments
Figure 1. Operational stability of the DKR system in a series of batch reactions.
After a batch of reaction, the catalysts (sepiolite/SO24À and Novozym 435) were
separated by centrifugation (12,000 rpm for 5 min using a Sigma 3-18K centrifuge).
The recycled catalysts were then washed by toluene 3 times and stored at 25 °C for
the next batch of use.
This work was supported financially by the National Basic
Research Program of China (973 Program, No. 2011CB710800),
Hi-Tech Research and Development Program of China (863 Pro-

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J.-P. Wu et al. / Tetrahedron Letters 55 (2014) 5129–5132
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