Highly efficient dynamic kinetic resolution of secondary aromatic alcohols using a low-cost solid super acid as a racemization catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.07.016

A new, efficient dynamic kinetic resolution (DKR) of secondary aromatic alcohols using self-made solid super acid TiO₂/SO42- as a racemization catalyst was developed. Low-cost and easily produced TiO ₂/SO42- showed excellent racemiza

Full text of DOI:10.1016/j.tetlet.2013.07.016

Tetrahedron Letters 54 (2013) 5026–5030
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Tetrahedron Letters
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Highly efficient dynamic kinetic resolution of secondary aromatic
alcohols using a low-cost solid super acid as a racemization catalyst
⇑
Gang Xu, Liang Wang, Yongjun Chen, Yongmei Cheng, Jianping Wu , Lirong Yang
Institute of Bioengineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, Zhejiang, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, efficient dynamic kinetic resolution (DKR) of secondary aromatic alcohols using self-made solid
super acid TiO2=SO2À as
a racemization catalyst was developed. Low-cost and easily produced
Received 16 April 2013
Revised 8 June 2013
Accepted 3 July 2013
Available online 10 July 2013
4
TiO2=SO2À showed excellent racemization activity. When coupled with the lipase, Novozym 435, good
4
biocompatibility was observed, and optically pure aromatic acetate (>99%) was obtained with a high
yield. It is noteworthy that the system could be reused more than 10 times with little loss of yield or
reduction in the enantiomeric excess (ee) value of product.
Keywords:
DKR
Ó 2013 Elsevier Ltd. All rights reserved.
Racemization catalyst
Solid super acid
TiO2=SO24À
Introduction
racemization temperature, 60 °C, produced poor biocompatibility
with lipase, and byproducts of styrene and ether were produced
Dynamic kinetic resolution (DKR) is a kinetic resolution (KR)
coupled with in situ racemization of the slow-reacting enantiomer.
The DKR approach could overcome the limitation of KR and increase
the theoretical maximum yield from 50% to 100%, thus avoiding
separation of the unwanted enantiomer from the reaction system.1
According to previous studies, for successful chemo-enzymatic
DKR, a highly selective KR catalyst, an efficient racemization cata-
lyst, and the compatibility between them are essential.2 To date,
many reported lipases meet the necessary selectivity of KR,
whereas only two main types of racemization catalysts have been
shown to be effective for DKR of sec-alcohols.3 Transition metal
catalysts are one type of racemization catalyst reported to be
involved in the hydrogen-transfer mechanism and are called
pentaphenylcyclopentadienyl ruthenium complexes.4 An excellent
enantiomeric excess (ee) value and a high yield have been obtained
by coupling this catalyst type with lipase; however, the high cost of
the ruthenium complexes, the complexity of the preparation
process, the difficulty of the ruthenium complexes to be recycled,
and in some cases, the requirement of rigorous reaction conditions
may prevent the use of ruthenium complexes in further applica-
tions.5 Acid racemization catalysts are another type of racemization
catalyst that is involved in the transfer of hydrogen protons and the
formation of carbenium ions. Acid zeolite, a common acid racemi-
zation catalyst, was first used in DKR of sec-alcohols.6 Because of
in the DKR process.7 In our previous study, CD 8604 and CD 550,
which are two types of cation exchange resins with large pore poly-
ethylene-divinylbenzene copolymer as vector and –SO3H as the
catalytic functional group, were found to be very efficient and more
compatible with lipase in the DKR of secondary alcohols.8 A high
yield (>99%) and excellent ee (>99%) were obtained.9 However,
one limitation of the latter study was that the catalysts gradually
dissolved in the solvent, and the solved acid group –SO3H reduced
the lipase activity. Furthermore, it also makes the separation
process more difficult.
Herein, we develop a new type of acid racemization catalyst, a
nano solid super acid, which showed high efficient racemization
capability. When coupling this new racemization catalyst with
the lipase, Novozym 435, good biocompatibility was demonstrated,
and optically pure aromatic acetate was obtained.
Results and discussion
Several solid super acid catalysts were synthesized smoothly
and screened for their racemization activity to (S)-1-phenylethanol
(Table 1).10 Additionally, the racemization activity of other catalysts
is also summarized in Table 1.
We were intrigued to find that all the new racemic catalysts,
TiO2=SO2À, Al2O3=SO2À, and Fe2O3=SO2À, showed efficient racemiza-
4
4
4
a
non-selective transesterification reaction, a high yield and
tion, and (S)-1-phenylethanol was almost completely racemized after
6 h (Table 1, entries 1–3). The acid resin CD 8604 and CD 550 were
two types of efficient racemization catalysts according to our previ-
ous report (entries 4 and 5).8 The racemization of three solid super
acid catalysts with H0s of À12 to À1410c was slightly more efficient
excellent ee value could not be obtained simultaneously. A high
⇑
Corresponding author. Tel./fax: +86 0571 87952363.
E-mail address: wjp@zju.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.016

G. Xu et al. / Tetrahedron Letters 54 (2013) 5026–5030
5027
Table 1
Table 2
The racemization of (S)-1-phenylethanol with different racemic catalysts
Physical properties of racemization catalysts
OH
Entry
1
Catalyst
d (nm)
S (m2 gÀ1
)
OH
Acid racemic catalyst
TiO2=SO24À
CD 8604
CD 550
8.5
92
+
2
3
39.4
35.7
31.46
31.15
Toluene, 40 °C
d Stands for the pore size calculate from the adsorption branch
by the BJH method, S is the BET surface area.
(S)-1-phenylethanol
Styrene
Acid group Reaction time (h) eeS (%) Styrene (%)
Rac-1-phenylethanol
Entry Catalyst
TiO2=SO24À
1
–SO3H
–SO3H
–SO3H
6
6
6
6.4
9.5
0
0
0
cessfully synthesized. Based on the mechanism of acid racemiza-
tion, (S)-1-phenylethanol could be racemized under acid
conditions, and the reaction to styrene was reversible. Addition-
ally, this reversible reaction had difficulty producing byproducts
under strong acid conditions. Thus, the byproduct was effectively
Al2O3=SO24À
2
Fe2O3=SO24À
3
10.8
4
5
6
7
8
CD 8604
CD 550
HY-zeolite
D 113
–SO3H
–SO3H
Al3+
–COOH
–COOH
6.5
6.5
6
6
6
12.5
16.3
28
>99
>99
0
0
15
0
0
inhibited when TiO2=SO2À was used as the racemization catalyst
4
(Table 1, entry 1).
116
The physicochemical parameters of TiO2=SO2À are summarized
4
Reactions: 2 mL toluene, 100 mmol/L (S)-1-phenylethanol, 80 mg racemic catalyst,
at 40 °C and 200 rpm.
ees is the enantiomeric excess value of substrate, D 113 and 116 are two types of
cation exchange resins with large pore acrylic acid copolymer as vector and –COOH
as catalytic functional group.
in Table 2. The BET surface area of TiO2=SO2À was much larger than
4
that of CD 8604 and CD 550, providing much more loading sites for
ÀSO3H. Thus, (S)-1-phenylethanol could be racemized more rap-
idly with TiO2=SO2À
.
4
The N2 adsorption–desorption isotherm of TiO2=SO2À exhibited a
4
typical IUPAC type IV pattern with the presence of a H2 hysteresis
loop and is presented in Figure 2. The hysteresis loop is a typical
than racemization with CD 8604 and CD 550, and the byproduct sty-
rene was not detected in the reaction system. Although (S)-1-phenyl-
ethanol was racemized under Al3+, which is a medium strong acid
with an H0 of approximately À9,11 the side reaction was not success-
fully inhibited, and 15% byproduct was obtained (Table 1, entry 6).
Carboxylic acid is a weak acid; thus, (S)-1-phenylethanol was barely
racemized (Table 1, entries 7 and 8). Taken together, racemization
capacity was enhanced and byproduct was reduced with the increas-
ing of acid strength, these results proved that these three solid super
acids with –SO3H were effective racemic catalysts. With the best
racemization activity, TiO2=SO2À was chosen as our racemization cat-
4
alyst in the present study.
The as-prepared solid super acid TiO2=SO2À was characterized
4
by FT-IR, BET, and SEM.
Figure 1 illustrates the FT-IR spectra of TiO2=SO2À in the region
4
of 400–4000 cmÀ1. Two bands at 1125 and 1138 cmÀ1 were char-
acteristic of asymmetric and symmetric stretching of S@O vibra-
tions, respectively.10d,e The band at 1383 cmÀ1 was related to the
S@O stretching vibration from the sulfate ion on the surface of
the solid. The bending and stretching vibrations of OH produced
the band at 1633 cmÀ1, and the band at 3404 cmÀ1 represented
the surface hydroxyl group of TiO2. Thus, the racemization catalyst
TiO2=SO2À with a strong acid group and a polarity vector was suc-
4
Figure 2. N2 adsorption–desorption isotherm and pore size distribution of
TiO2=SO2À
.
4
Figure 1. FTIR spectrometer of TiO2=SO2À
.
Figure 3. SEM of TiO2=SO2À
.
4
4

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G. Xu et al. / Tetrahedron Letters 54 (2013) 5026–5030
Table 3
The DKR of various sec-alcohols with 4-chlorophenyl valerate as acyl donor
O
(CH2)3CH3
O
O
OH
Cl
O
(CH2)3CH3
R
R
Toluene,40 °C
2-
Novozym 435, TiO2/SO4
Entry
1
Substrate
OH
Product
Yield (%)
eep (%)
Time (h)
10
O
O
>99
>99
>99
>99
OH
O
O
2
3
>99
>99
10
10
OH
O
O
OH
O
O
4
5
6
>99
>99
>99
>99
>99
>99
10
10
10
OH
OH
O
O
O
O
OH
O
O
7
>99
>99
10
OH
O
O
8
9
>99
>99
98
14
14
Cl
Cl
Cl
OH
O
O
>99
Cl

G. Xu et al. / Tetrahedron Letters 54 (2013) 5026–5030
5029
Table 3 (continued)
Entry
Substrate
Product
Yield (%)
>99
eep (%)
Time (h)
OH
OH
O
O
Cl
O
O
10
11
>99
14
14
Cl
>99
>99
>99
>99
Br
O
O
Br
O
O
OH
O
O
O
O
12
13
12
14
OH
>99
>99
>99
>99
O
O
OH
O
O
14
14
O
O
Reactions: 2 ml toluene, 100 mmol/L sec-alcohols, 300 mmol/L 4-chlorophenyl valerate, 50 mg/mL TiO2=SO24À, 10 mmg/mL Novozym 435, at 40 °Cand 200 rpm.
eep is the enantiomeric excesses value of product.
characteristic of mesoporous materials. A sharp increase in P/P0 was
rac-1-phenylethanol, with 4-chlorophenyl valerate as the acyl
observed in the range of 0.6–0.9, indicating good homogeneity and a
donor, were used in repeated experiments. The DKR reaction was
fairly small pore size of TiO2=SO2À
.
As presented in Figure 2, the
carried out 10 times with the recycling of both TiO2=SO2À and
12
4
4
pore size distribution obtained from the Barrett–Joyner–Halenda
Novozym 435. We found that the eep was almost unchanged after
10 cycles, and the yield of (R)-1-phenylethyl pentanoate remained
method is quite narrow. In conclusion, the synthesized TiO2=SO2À
4
was a nano-size catalyst with uniform pore distribution. A nano-
aperture could provide additional loading sites to ÀSO3H and
stronger steric hindrance to suppress the side reaction to the ester.
constant (>99%). Thus, the combination of lipase and TiO2=SO2À dis-
4
played good operation stability, high efficiency, and great practical
value in the production of chiral chemicals.
Typical SEM images (Fig. 3) of TiO2=SO2À calcined at 400 °C for
4
4 h indicated that the as-prepared TiO2=SO2À had many worm-like
4
Conclusions
channels, providing a large BET surface area, additional loading
sites for ÀSO3H, and improved efficiency of racemization.
In our previous study, nonpolar toluene and 4-chlorophenyl
valerate were the best solvent and acyl donor, respectively, for
In summary, a highly efficient DKR of secondary aromatic alco-
hols using TiO2=SO2À as the racemization catalyst coupled with
4
the DKR process. Therefore, TiO2=SO2À was employed in the DKR
enzymatic KR was developed. During the reaction, the solid super
4
acid TiO2=SO2À was found to be competent and sufficiently stable
of rac-1-phenylethanol coupled with Novozym 435 at 40 °C using
4-chlorophenyl valerate as the acyl donor and toluene as the sol-
vent. As expected, both a good eep (>99%) and a high yield (>99%)
were obtained (Table 3, entry 1). Encouraged by this excellent
result, we used this system with other sec-alcohols, and the results
are summarized in Table 3.
4
to be a racemization catalyst. The system of solid super acid
coupled with lipase has also been used in the application of
sec-alcohol resolution. Furthermore, this catalysis system could
be recycled for more than 10 runs without loss of yield or
reduction of eep.
The DKRs of other sec-alcohols were found to proceed quickly
and produced high yields and high eep values when 4-chlorophenyl
valerate was used as the acyl donor. Most of the DKR reactions
achieved almost 100% optical purity at 100% yield (Table 3, entries
2–14). The reaction required less time when electro-donating
groups were substituted on the benzene ring than when electro-
withdrawing groups were used.
Acknowledgments
This work was financially supported by the National Basic Re-
search Program of China (973 programs, No. 2011CB710800), Hi-
Tech Research and Development Program of China (863 Program,
No. 2011AA02A209), National Natural Science Foundation of China
(No. 20936002), and Science and Technology Planning Project of
Zhejiang Province (No. 2010C31127).
To investigate the reusability of the solid super acid-lipase cou-
pled catalysis system, TiO2=SO2À and Novozym 435 in the DKR of
4

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Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 4240; (c) Kim, M. J.; Kim, H.
References and notes
M.; Kim, D.; Ahn, Y.; Park, J. Green Chem. 2004, 6, 471.
6. (a) Wuyts, S.; Temmerman, K. D.; Vos, D. D.; Jacobs, P. Chem. Commun. 2003,
1928; (b) Zhu, Y. Z.; Fow, K. L.; Chuah, G. K.; Jaenicke, S. Chem. Eur. J. 2007, 13,
541.
7. (a) Lozano, P.; Diego, T. D.; Mira, C.; Montague, K.; Vaultierb, M. V.; Iborra, J. L.
Green Chem. 2009, 11, 538; (b) Costa, L.; Coelho, A.; Lemos, F.; Ribeiro, F. R. Appl.
Catal., A 2009, 33, 354; (c) Xiang, L.; Shi, Y.; Wang, Z. J.; Zhang, Y. H.; Tang, Y. J.
Catal. 2012, 288, 24.
1. (a) Lee, J. H.; Han, K.; Kim, M. J.; Park, J. Eur. J. Org. Chem. 2010, 999; (b) Kim, N.;
Ko, S. B.; Kwon, M. S.; Kim, M. J.; Park, J. Org. Lett. 2005, 7, 4523; (c) Martn-
Matute, B.; Edin, M.; Bogár, K.; Bäckvall, J. E. Angew. Chem., Int. Ed. 2004, 43,
6535; (d) Odman, P.; Wessjohann, L. A.; Bornscheuer, U. T. J. Org. Chem. 2005,
70, 9551; (e) Riermeier, T. H.; Gross, P.; Monsees, A.; Hoff, M.; Trauthwein, H.
Tetrahedron Lett. 2005, 46, 3403.
2. (a) Langvik, O.; Saloranta, T.; Kirilin, A. ChemCatChem 2010, 2, 1615; (b) Stirling,
M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48, 1247; (c) Pàmies, O.;
Bäckvall, J. E. Trends Biotechnol. 2004, 22, 130.
3. (a) Martín-Matute, B.; Edin, M.; Bogár, K.; Kaynak, F. B.; Bäckvall, J. E. J. Am.
Chem. Soc. 2005, 127, 8817; (b) Pellissier, H. Tetrahedron 2008, 64, 1563; (c)
Kamaruddin, A. H.; Uzir, M. H.; Aboul-Enein, H. Y. Chirality 2009, 21, 449; (d)
Ödman, P.; Wessjohann, L. A.; Bornscheuer, U. T. J. Org. Chem. 2005, 70,
9551.
4. (a) Koh, J. H.; Jeong, H. M.; Park, J. Tetrahedron Lett. 1998, 39, 5545; (b) Do, Y. S.;
Hwang, I.-C.; Him, M.-J.; Park, J. J. Org. Chem. 2010, 75, 5470; (c) Ohkuma, T.;
Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C.; Noyori, R. J. Am. Chem. Soc.
2006, 128, 8724.
5. (a) Mavrynsky, D.; Päiviö, M.; Lundell, K.; Sillanpää, R.; Kanerva, L. T.; Leino, R.
Eur. J. Org. Chem. 2009, 1317; (b) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi, A.;
8. Cheng, Y. M.; Xu, G.; Wu, J. P.; Zhang, C. S.; Yang, L. R. Tetrahedron Lett. 2010, 51,
2366.
9. Xu, G.; Chen, Y. J.; Wu, J. P.; Cheng, Y. M.; Yang, L. R. Tetrahedron: Asymmetry
2011, 22, 1373.
10. (a) Krishnakumar, B.; Swaminathan, M. Catal. Commun. 2011, 16, 50; (b) Jiang,
F.; Zheng, Z.; Xu, Z. Y.; Zheng, S. R.; Guo, Z. B.; Chen, L. Q. J. Hazard. Mater., B
2006, 134, 94; (c) Yin, H. L.; Tan, Z. Y.; Liao, Y. T.; Feng, Y. J. J. Environ. Radioact.
2006, 87, 227; (d) Xu, Y. H.; Wang, L. Y.; Zhang, Q.; Zheng, S. J.; Li, X. J.; Huang,
C. Mater. Chem. Phys. 2005, 92, 470; (e) Ropero-Vega, J. L.; Aldana-Pérez, A.;
Gómez, R.; Niño-Gómez, M. G. Appl. Catal., A 2010, 379, 24.
11. Fraenkel, D.; Jentzsch, N. R.; Starr, C. A.; Nikrad, P. V. J. Catal. 2010, 274, 29.
12. (a) Sreethawong, T.; Suzuki, Y.; Yoshikawa, S. J. Solid State Chem. 2005, 178,
329; (b) Blanco, M. N.; Pizzio, L. R. Appl. Surf. Sci. 2010, 256, 3546; (c) Fuchs, V.;
Méndez, L.; Blanco, M.; Pizzio, L. Appl. Catal., A 2009, 358, 73.