Dynamic kinetic resolution of secondary aromatic alcohols with new efficient acyl donors

Article abstract of DOI:10.1016/j.tetasy.2011.06.034

A new and efficient dynamic kinetic resolution (DKR) process of secondary aromatic alcohols by using long carbon-chain esters as acyl donors has been developed. During the process, the transesterification catalyzed by CD8604 was found to be the main reason for the decrease in enantiomeric excess (ee). Using complex acyl donors, such as 4-chlorophenyl valerate, we could effectively inhibit the resin-catalyzed transesterification, and an excellent ee value (>99%) at high yield (>99%) was achieved. The mechanism for the inhibition of resin-catalyzed transesterification is believed to be the formation of micro-micelles in the pores of CD8604. It is noteworthy that the system can be reused more than 20 times without a loss of yield or ee value.

Full text of DOI:10.1016/j.tetasy.2011.06.034

Tetrahedron: Asymmetry 22 (2011) 1373–1378
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Tetrahedron: Asymmetry
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Dynamic kinetic resolution of secondary aromatic alcohols with new
efficient acyl donors
⇑
⇑
Gang Xu , Yongjun Chen, Jianping Wu, Yongmei Cheng, Lirong Yang
Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient dynamic kinetic resolution (DKR) process of secondary aromatic alcohols by using
long carbon-chain esters as acyl donors has been developed. During the process, the transesterification
catalyzed by CD8604 was found to be the main reason for the decrease in enantiomeric excess (ee). Using
complex acyl donors, such as 4-chlorophenyl valerate, we could effectively inhibit the resin-catalyzed
transesterification, and an excellent ee value (>99%) at high yield (>99%) was achieved. The mechanism
for the inhibition of resin-catalyzed transesterification is believed to be the formation of micro-micelles
in the pores of CD8604. It is noteworthy that the system can be reused more than 20 times without a loss
of yield or ee value.
Received 20 April 2011
Accepted 27 June 2011
Available online 1 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
a better DKR process was achieved and aromatic valerates of vari-
ous secondary alcohols with excellent yield (>99) and high ee val-
Dynamic kinetic resolution (DKR) provides an efficient method
for preparing enantiomerically pure compounds. Dynamic kinetic
resolution is a kinetic resolution coupled with an in situ racemiza-
tion of slow-reacting substrate,1,2 that could potentially surpass
the main drawback of kinetic resolution,3,4 increase the theoretical
maximum yield from 50% to 100% and avoid separation of the un-
wanted enantiomer from the reaction system. According to previ-
ous studies, for an efficient chemo-enzymatic DKR of secondary
alcohols, resolution and racemization catalysts are two indispens-
able requirements. Until now, there are several lipases that meet
the requirements for the dynamic kinetic resolution (DKR) of sec-
ondary alcohols,5–10 and only a few species of racemization cata-
lysts have been reported to be applicable.11 However, in these
commonly used racemization catalysts, while the transition metal
catalysts were commercially available and effective enough, they
were expensive while acid zeolites were relatively ineffective. In
our previous research, an acid resin, known as CD8604, was found
to be very efficient in the DKR of secondary alcohols.12 As a racemi-
zation catalyst, CD8604 was less expensive, less toxic, and more
compatible with the enzymes,13–19 although there were still some
disadvantages in using it. During the DKR process of secondary
alcohols, non-selective transesterification of the substrates cata-
lyzed by CD8604 usually occurred as well, and thus the ee values
of many products were not satisfactory enough. Herein, a further
study about inhibiting the non-selective transesterification cata-
lyzed by CD8604 is reported and the mechanism is studied. Also,
ues (>99) were obtained. The same excellent results can be
achieved when the system is used more than 20 times.
2. Result and discussion
In our previous study, CD8604 catalyzed non-selective transe-
sterification of substrates was presumed to be the reason for the
low ee value of the DKR of 1-phenylethanol. Similar to previous lit-
erature,8,20,21 using complex acyl donors instead of common ones
such as vinyl acetate and isopropyl acetate was an effective meth-
od to increase the selectivity of the DKR. However, this method
helped us obtain an efficient DKR of some limited secondary alco-
hols. Firstly, the non-selective transesterification of 1-phenyletha-
nol catalyzed by CD8604 with
a different acyl donor was
investigated and the results are shown in Table 1. It was found that
Table 1
Transesterification catalyzed by acid resin
Entry
Acyl donor
Yield (%)
Time (h)
1
2
3
4
5
6
7
8
Vinyl acetate
Isopropenyl acetate
Phenyl acetate
2-Chlorophenyl acetate
3-Chlorophenyl acetate
4-Chlorophenyl acetate
4-Methylphenyl acetate
4-Methoxybenzyl acetate
100
100
10
10
12
12
12
12
12
12
20.6
16.5
17.6
15.8
14.0
11.6
Reaction conditions: 1-phenylethanol, 100 mmol/L; toluene, 2 mL; donors,
300 mmol/L; temperature, 40 °C; rotation speed, 200r/min; CD8604, 20 mg/ml.
⇑
Corresponding authors.
E-mail address: xugang_1030@zju.edu.cn (G. Xu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.034

1374
G. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 1373–1378
all acyl donors used in previous studies could catalyze the non-
selective transesterification of substrates, which coincided with
our previous assumptions.12 For example, if vinyl acetate, which
had the fastest transesterification rate catalyzed by a resin (Table 1,
entry 1), was chosen as the acyl donor, the ee value of the DKR was
only 24.2%. However, when we used 4-chlorophenyl acetate with
the lower rate of non-selective transesterification (Table 1, entry
6), the ee value of the DKR could reach 71.0%.
Since changing the alcohol moiety of the acyl donors would
suppress the rate of non-selective transesterification, the same re-
sults could also be achieved if the acyl moiety of the acyl donors
were changed. In the reaction of DKR, 4-chlorophenyl acetate per-
formed better than other acyl donors.12 Therefore, a series of acyl
donors were synthesized with 4-chlorophenyl as the alcohol moi-
ety and different long carbon-chain acids as the acyl moiety for fur-
ther study; the data are shown in Table 2.
Figure 1. The micro-micelles in the pore of acid resin.
Table 2
Table 3
The kinetic resolution of 1-phenylethanol with different acyl donors
Transesterification catalyzed by acid resin
Entry
Acyl donor
Yield (%)
Time (h)
Entry
Acyl donor
eep (%)
Yield (%)
Time (min)
1
2
3
4
5
6
7
8⁄
4-Chlorophenyl acetate
4-Chlorophenyl propionate
4-Chlorophenyl butyrate
4-Chlorophenyl valerate
4-Chlorophenyl caproate
4-Chlorophenyl enanthate
4-Chlorophenyl caprylate
4-Chlorophenyl valerate
15.8
12.9
5.12
0
0
0
12
12
12
18
18
18
18
20
1
2
3
4
5
6
7
4-Chlorophenyl acetate
4-Chlorophenyl propionate
4-Chlorophenyl butyrate
4-Chlorophenyl valerate
4-Chlorophenyl caproate
4-Chlorophenyl enanthate
4-Chlorophenyl caprylate
>99
>99
>99
>99
>99
>99
>99
50
50
50
50
50
50
50
30
30
30
30
30
30
30
0
8.24
Reaction conditions: 1-Phenylethanol, 100 mmol/L; toluene, 2 mL; donors,
Reaction conditions: 1-Phenylethanol, 100 mmol/L; donors, 300 mmol/L; temper-
ature, 40 °C; rotation speed, 200 r/min; toluene, 2 mL.
300 mmol/L; temperature, 40 °C; rotation speed, 200 r/min; Novozyme 435, 10 mg/
ml.
Entries 1–7—CD8604 (moisture: 40%), 20 mg/ml.
Entry 8⁄—CD8604 (moisture: ꢀ5%) was dried for 7 days at 7 Pa and 80 °C.
This was encouraging since the yield and ee of DKRs were nearly
100% when we used long carbon-chain acyl donors, such as 4-chlo-
rophenyl valerate and so on (Table 4, entries 5–8).
As expected, when the carbon chain of the acyl donor became
longer, the rate of transesterification catalyzed by the resin became
lower. Non-selective transesterification was almost completely
inhibited when the number of acyl carbon atoms was over five
(Table 2, entries 4–7).
Table 4
The DKR of 1-phenylethanol with different acyl donors
Entry
Acyl donor
eep (%)
Yield (%)
Time (h)
There may be two main reasons for the inhibition of the long
carbon-chain esters in the transesterification reaction catalyzed
by the resin. One is the steric effect of the substrates, since the
complex structures would make the active site more difficult to
reach. The second reason is the moisture of the resin catalytic envi-
ronment. The resin has the ability to retain water inside its pores,
thus creating a microenvironment with a high water content (40%).
This is a good environment that favors the formation of micro-
micelles, when the long-chain donors are placed into the aperture
(Fig. 1). Due to the formation of micro-micelles, long-chain acyl do-
nors are locally enriched. Consequently, without enough reactive
sites of the acyl donor, secondary alcohols can be subjected to a
racemization reaction rather than the transesterification. This pro-
posal might be explained by a designed experiment (Table 2, entry
8⁄). If CD8604 was dried as shown, the micro-micelles were unable
to form due to the loss of most of its moisture. Therefore, second-
ary alcohols were able to react with the acyl donor and non-selec-
tive transesterification took place.
Complex acyl donors could inhibit the transesterification reac-
tion effectively, and the enzymatic reaction was almost unaffected
when these esters were used as acyl donors in the kinetic resolu-
tion (Table 3). The results of the experiment are shown in Table 3.
It can be seen that all of the kinetic resolutions achieved 50% yield
in 0.5 h with high ee values of the products.
Encouraged by these results, we used these esters as acyl do-
nors in the dynamic kinetic resolution of 1-phenylethanol. As ex-
pected, the results of the DKRs were greatly improved while the
non-selective transesterification reaction was suppressed (Table 4).
1
2
3
4
5
6
7
8
4-Methylphenyl acetate
4-Chlorophenyl acetate
4-Chlorophenyl propionate
4-Chlorophenyl butyrate
4-Chlorophenyl valerate
4-Chlorophenyl caproate
4-Chlorophenyl enanthate
4-Chlorophenyl caprylate
96.1
70.9
86.2
92.1
57.8
92.4
>99
>99
>99
>99
>99
>99
24
6
6
6
6
6
6
6
>99
>99
>99
>99
Reaction conditions: 1-phenylethanol, 100 mmol/L; donors, 300 mmol/L; temper-
ature, 40 °C; rotation speed, 200 r/min; Novozyme 435, 10 mg/ml; CD8604,
20 mg/ml, toluene, 2 mL.
Since 4-chlorophenyl valerate performed very well as an acyl
donor in the DKR of 1-phenylethanol, it was thus employed in
the DKR of other secondary alcohols. The results are summarized
in Table 5.
It is noteworthy that 4-chlorophenyl valerate gave good results
an acyl donor in the DKRs of secondary alcohols. Most of the reac-
tions achieved nearly 100% ee at 100% yield. The reaction also pro-
ceeded quicker when electro-donating groups were substituted on
the benzene ring. However, when the substituents were electron-
withdrawing groups, the rate of reaction decreased.
In order to investigate the reusability of the resin-lipase coupled
catalysis system, the repeated use of CD8604 and Novozym435 in
the DKR of rac-1-phenylethanol with 4-chlorophenyl valerate as an
acyl donor was studied.
As shown in Figure 2, after 20 cycles, the ee was almost un-
changed, while the yields remained nearly the same (>99%). Thus,

G. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 1373–1378
Table 5 (continued)
1375
Table 5
The DKR of secondary alcohols with 4-chlorophenyl valerate as the acyl donor
Entry
Substrate
Product
ee (%) Yield (%)
Entry
Substrate
Product
ee (%) Yield (%)
OH
OH
O
OH
O
O
O
O
Cl
O
O
O
O
O
1 (5a)
>99
>99
>99
>99
>99
>99
10 (5j)
>99
>99
Cl
OH
O
O
O
O
O
O
2 (5b)
11 (5k)
>99
>99
>99
>99
Br
O
O
Br
O
O
OH
OH
OH
3 (5c)
12 (5l)
OH
13 (5m)
>99
>99
4 (5d)
5 (5e)
6 (5f)
>99
>99
>99
>99
>99
>99
O
O
OH
O
OH
OH
O
O
O
O
O
14 (5n)
>99
>99
O
O
O
O
Reaction conditions: alcohols, 100 mmol/L; donors, 300 mmol/L; CD8604, 20 mg/
ml, temperature, 40 °C; rotation speed, 200 r/min; Novozyme 435, 10 mg/ml; tol-
uene, 2 mL.
100
80
OH
O
O
O
7 (5g)
>99
>99
Yield of product
e.e of product
60
40
20
0
OH
O
O
8 (5h)
>99
95.6
Cl
Cl
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Cl
OH
The cycle of catalysts reuse
O
Figure 2. The catalyst reuse with 4-chloropheny valerate as the acyl donor.
9 (5i)
>99
>99
4-chlorophenyl valerate is an excellent donor in the DKR of second-
ary alcohols.
Cl

1376
G. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 1373–1378
J = 6.4 Hz, H; CH), 7.31 (t, H; Ph-H), 7.37 (d, J = 3.6 Hz, 4H; Ph-H).
3. Conclusion
13C NMR (400 MHz, CDCl3) d (ppm) 13.62, 22.14 (CH3), 22.18,
26.94, 34.24 (CH2), 71.92 (CH), 125.96, 127.69, 128.37, 141.78
(Ph), 172.98 (CO). EI-MS (70 eV): m/z (%) 206 (35), 122 (100), 104
(100), 77 (60), 57 (31), 41 (15), 29 (12). IR absorption bands
(cmꢁ1): 3303 (w), 2960 (s), 2932 (s), 2870 (m), 1736 (vs), 1495
(w), 1454 (n), 1374 (n), 1250 (s), 1174 (s), 1063 (s), 1029 (m),
In conclusion, a highly efficient DKR of secondary aromatic alco-
hols using long carbon-chain esters as acyl donors has been devel-
oped. During the process, the transesterification catalyzed by
CD8604 was found as the main reason for the decrease in ee. Using
complex acyl donors inhibited the resin-catalyzed transesterifica-
tion, and excellent ee values (>99%) and high yields (>99%) were
achieved. The mechanism for the inhibition of resin-catalyzed
transesterification might be the formation of micro-micelles in
the pores of CD8604. It is noteworthy that this reaction system
has been proven to be applicable for many substrates and also
showed good stability. It can also be reused for more than 20 times
without a loss of yield or ee.
940 (w), 758 (m), 698 (m), 539 (w). ½a D25
¼ þ69:1 (c 1.00, CH2Cl2).
ꢂ
4.6.2. 1-(2-Methylphenyl)ethanol valerate 5b
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.95 (t, J = 7.2 Hz, 3H;
CH3), 1.39 (m, J = 7.2 Hz, 2H; CH2), 1.54 (d, J = 6.8 Hz, 3H; CH3), 1.66
(m, J = 7.2 Hz, 2H; CH2), 2.38 (t, J = 5.6 Hz, 2H; CH2), 2.4 (s, 3H;
CH3), 6.14 (m, J = 6.4 Hz, H; CH), 7.24 (m, J = 8.0 Hz, 3H; Ph-H),
7.43 (d, J = 6.8 Hz, H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm)
13.64, 18.94, 21.31 (CH3), 22.16, 26.95, 34.21 (CH2), 68.84 (CH),
125.15, 126.15, 127.47, 130.31, 134.62, 140.16 (Ph), 172.98 (CO).
EI-MS (70 eV): m/z (%) 118 (100), 91 (30), 77 (10), 57 (12), 41
(10), 29 (10). IR absorption bands (cmꢁ1): 2960(s), 2931 (s), 2870
(m), 1735 (s), 1491 (w), 1459 (m), 1374 (m), 1252 (m), 1175 (s),
1090 (m), 1064 (s), 1001 (w), 941 (w), 758(m), 726(w), 459(w).
4. Experimental
4.1. General
All substrates and acyl donors were synthesized, except for 1-
phenylethanol, which is a product from Aladdin. Lipase Novozyme
435 was obtained from Novozymes and CD8604 was obtained
from Hangzhou Zhengguang resin Co., Ltd.
½
a 2D5
ꢂ
¼ þ62:4 (c 1.00, CH2Cl2).
4.6.3. 1-(4-Methylphenyl)ethanol valerate 5c
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.94 (t, J = 8.0 Hz, 3H;
CH3), 1.36 (m, J = 7.2 Hz, 2H; CH2), 1.56 (d, J = 6.4 Hz, 3H; CH3), 1.65
(m, J = 8.0 Hz, 2H; CH2), 2.34 (t, J = 1.2 Hz, 2H; CH2), 2.36 (s, 3H;
CH3), 5.90 (m, J = 6.8 Hz, H; CH), 7.19 (d, J = 8.0 Hz, 2H; Ph-H),
7.28 (d, J = 8.0 Hz, 2H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm)
13.63, 21.03, 22.16 (CH3), 22.10, 26.97, 34.28 (CH2), 71.85 (CH),
126.00, 129.06, 137.41, 138.83 (Ph), 173.00 (CO). EI-MS (70 eV):
m/z (%) 220 (75), 136 (100), 117 (100), 103 (27), 91 (87), 77 (25),
57 (38), 41 (25), 29 (15). IR absorption bands (cmꢁ1): 2960 (s),
2931 (s), 2870 (s), 1735 (vs), 1614 (w), 1517 (m), 1455 (m), 1374
(m), 1250 (s), 1173 (vs), 1094 (m), 1062 (s), 1021 (m), 1012 (m),
The results of the reactions were detected by GC (Fuli 9790) on
a CP-CYCLODEXTRIN b-2,3,6-M-19, FS 50X.25(.25) chiral column
with FID detection. 1H and 13C NMR spectra were recorded on a
Varian MercuryVx 400 spectrometer (400 MHz) using CDCl3 as
the solvent.
4.2. General procedure for the non-selective transesterification
reaction
At first, rac-1-phenylethanol (24.4 mg, 200 mmol) and CD8604
(40 mg) were dissolved in toluene (2 mL). The acyl donors
(600 mmol) were then added into the mixture system, and the sys-
tem stirred at 40 °C.
941 (m), 860 (w), 815 (s), 727 (w), 541 (m). ½a D25
¼ þ71:3 (c 1.00,
ꢂ
CH2Cl2).
4.6.4. 1-(3,5-Dimethylphenyl)ethanol valerate 5d
4.3. Kinetic resolution of 1-phenylethanol
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.95 (t, J = 7.2 Hz, 3H;
CH3), 1.39 (m, J = 8.0 Hz, 2H; CH2), 1.52 (d, J = 6.0 Hz, 3H; CH3), 1.66
(m, J = 7.6 Hz, 2H; CH2), 2.27 (t, J = 5.2 Hz, 2H; CH2), 2.35 (s, 6H;
CH3), 6.10 (m, J = 6.0 Hz, H; CH), 7.04 (m, J = 8.8 Hz, 2H; Ph-H),
7.22 (s, H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.66,
18.48, 21.30, 22.16 (CH3), 21.03, 26.99, 34.23 (CH2), 68.99 (CH),
125.86, 128.21, 130.26, 131.26, 135.53, 139.85 (Ph), 172.99 (CO).
EI-MS (70 eV): m/z (%) 150 (12), 133 (100), 117 (100), 105 (30),
91 (30), 77 (15), 57 (15), 41 (12), 29 (10). IR absorption bands
(cmꢁ1): 2960 (s), 2926 (s), 2869 (m), 1735 (vs), 1503 (m), 1457
(m), 1373 (m), 1249 (s), 1176 (s), 1089 (m), 1063(s), 1026(m),
In a typical kinetic resolution, the acyl donor (600 mmol) was
added to a stirred solution of rac-1-phenylethanol (24.4 mg,
200 mmol) and lipase Novozyme 435 (20 mg) in toluene (2 ml) at
40 °C.
4.4. Dynamic kinetic resolution of 1-phenylethanol
The reaction consisted of rac-1-phenylethanol (24.4 mg,
200 mmol), lipase Novozyme 435 (20 mg), acid resin CD8604
(40 mg) and acyl donor (600 mmol). After all the materials were
dissolved in toluene (2 mL), the solvent was stirred at 40 °C.
941 (w), 889 (w), 811 (m), 468 (m). ½a D25
¼ þ47:8 (c 1.00, CH2Cl2).
ꢂ
4.5. General procedure for the dynamic kinetic resolution of
secondary alcohols
4.6.5. 1-(2,4-Dimethylphenyl)ethanol valerate 5e
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.94 (t, J = 7.2 Hz, 3H;
CH3), 1.36 (m, J = 7.6 Hz, 2H; CH2), 1.52 (d, J = 6.8 Hz, 3H; CH3), 1.65
(m, J = 8.0 Hz, 2H; CH2), 2.25 (t, J = 4.8 Hz, 2H; CH2), 2.32 (s, H;
CH3), 2.36 (s, H; CH3), 6.10 (m, J = 6.0 Hz, H; CH), 6.99 (s, H; Ph-
H), 7.05 (d, J = 8.0 Hz, H; Ph-H), 7.31 (d, J = 8.0 Hz, H; Ph-H). 13C
NMR (400 MHz, CDCl3) d (ppm) 13.63, 18.87, 22.11, 22.16 (CH3),
20.89, 26.95, 34.23 (CH2), 68.87 (CH), 125.23, 126.82, 126.90,
131.09, 134.59, 137.13 (Ph), 173.04 (CO). EI-MS (70 eV): m/z (%)
150 (5), 132 (100), 117 (50), 105 (18), 91 (20), 77 (10), 57 (10),
41 (10), 29 (8). IR absorption bands (cmꢁ1): 3426 (w), 2957 (s),
2921 (vs), 2852 (s), 1735 (s), 1607 (w), 1508 (w), 1460 (m), 1375
(m), 1254 (m), 1175 (s), 1091 (w), 1060 (s), 942 (w), 819 (w),
The rac-alcohol (200 mmol) and acid resin CD8604 (40 mg)
were dissolved in toluene (2 mL). The mixture was stirred at
40 °C after which lipase Novozyme 435 (20 mg) and acyl donor
4-chlorophenyl valerate (600 mmol) were added.
4.6. Spectroscopic data for all the compounds
4.6.1. 1-Phenylethanol valerate 5a
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.94 (t, J = 7.6 Hz, 3H;
CH3), 1.38 (m, J = 7.6 Hz, 2H; CH2), 1.56 (d, J = 6.4 Hz, 3H; CH3), 1.65
(m, J = 7.6 Hz, 2H; CH2), 2.3 (t, J = 7.6 Hz, 2H; CH2), 5.92 (m,
737 (m). ½a 2D5
¼ þ43:2 (c 1.00, CH2Cl2).
ꢂ

G. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 1373–1378
1377
4.6.6. 1-(3,4-Dimethylphenyl)ethanol valerate 5f
156 (100), 139 (95), 103 (82), 77 (35), 57 (25), 41 (10), 29 (10).
IR absorption bands (cmꢁ1): 3448 (w), 2960 (s), 2931 (s), 2870
(m), 1737 (vs), 1598 (w), 1575 (m), 1460 (m), 1374 (m), 1250
(m), 1171 (s), 1064 (s), 1013 (m), 941 (w), 882 (w), 826 (w), 786
1H NMR (400 MHz, CDCl3) d (ppm) 0.92 (t, J = 7.2 Hz, 3H, CH3),
1.34 (m, J = 7.2 Hz, 2H, CH2), 1.54 (d, J = 6.4 Hz, 3H, CH3), 1.63 (t,
J = 7.6 Hz, 2H, CH2), 2.28 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.33 (t,
J = 8.0 Hz, 2H, CH2), 5.87 (m, J = 6.4 Hz, 1H, CH), 7.13 (d,
J = 7.2 Hz, 2H, Ph-H), 7.16 (s, H, Ph-H). 13C NMR (400 MHz, CDCl3)
d (ppm) 13.66, 19.39, 19.75 (CH3), 22.14, 26.98, 34.31 (CH2),
71.92 (CH), 123.42, 127.39, 129.65, 136.10, 136.54, 139.27 (Ph),
173.05 (CO). EI-MS (70 eV): m/z (%) 234 (80), 150 (100), 135
(100), 117 (100), 105 (50), 91 (55), 77 (25), 57 (38), 41 (25), 29
(16). IR absorption bands (cmꢁ1): 2960 (s), 2931 (s), 2869 (m),
1735 (vs), 1505 (w), 1453 (m), 1374 (m), 1248 (m), 1175 (s),
(m), 694 (m). ½a 2D5
¼ þ63:3 (c 1.00, CH2Cl2).
ꢂ
4.6.11. 1-(4-Bromophenyl)ethanol valerate 5k
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.92 (t, J = 7.2 Hz, 3H;
CH3), 1.36 (m, J = 8.0 Hz, 2H; CH2), 1.51 (d, J = 6.8 Hz, 3H; CH3), 1.62
(m, J = 7.6 Hz, 2H; CH2), 2.35 (t, J = 5.6 Hz, 2H; CH2), 5.86 (m,
J = 6.8 Hz, H; CH), 7.24 (d, J = 8.4 Hz, 2H; Ph-H), 7.48 (d, J = 8.8 Hz,
2H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.59, 22.07
(CH3), 22.11, 26.89, 34.15 (CH2), 71.23 (CH), 121.55, 127.71,
131.51, 140.83 (Ph), 172.85 (CO). EI-MS (70 eV): m/z (%) 284 (40),
202 (100), 182 (100), 157 (10), 104 (100), 85 (75), 77 (62), 57
(50), 41 (20), 29 (15). IR absorption bands (cmꢁ1): 3500 (w),
2959 (s), 2932 (s), 2869 (m), 1737 (vs), 1594 (w), 1490 (s), 1458
(m), 1410 (m), 1374 (m), 1248 (s), 1171 (s), 1068 (s), 1009 (s),
1065 (m), 1020 (m), 943 (w), 819 (m), 721 (w). ½a D25
¼ þ50:2 (c
ꢂ
1.00, CH2Cl2).
4.6.7. 1-(2,3-Dimethylphenyl)ethanol valerate 5g
1H NMR (400 MHz, CDCl3) d (ppm) 0.94 (t, J = 7.2 Hz, 3H, CH3),
1.36 (m, J = 7.2 Hz, 2H, CH2), 1.56 (d, J = 6.4 Hz, 3H, CH3), 1.65 (t,
J = 7.6 Hz, 2H, CH2), 2.30 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.37 (t,
J = 8.0 Hz, 2H, CH2), 5.89 (m, J = 6.4 Hz, 1H, CH), 1.16 (m, 3H, Ph-
H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.66, 19.39, 19.75 (CH3),
22,14, 26.98, 34.31 (CH2), 71.92 (CH), 123.42, 127.39, 129.65,
136.10, 136.54, 139.27 (Ph), 173.05 (CO). EI-MS (70 eV): m/z (%)
234 (80), 150 (100), 135 (100), 117 (100), 105 (50), 91 (55), 77
(25), 57 (38), 4 1 (25), 29 (16). IR absorption bands (cmꢁ1): 2960
(s), 2931 (s), 2869 (m), 1735 (vs), 1505 (w), 1453 (m), 1374 (m),
1248 (m), 1175 (s), 1065 (m), 1020 (m), 943 (w), 819 (m), 721
941 (m), 823 (s), 784 (w), 535(m). ½a D25
¼ þ63:5 (c 1.00, CH2Cl2).
ꢂ
4.6.12. 1-(4-Methoxyphenyl)ethanol valerate 5l
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.91 (t, J = 7.2 Hz, 3H;
CH3), 1.33 (m, J = 7.6 Hz, 2H; CH2), 1.52 (d, J = 6.8 Hz, 3H; CH3), 1.60
(m, J = 7.6 Hz, 2H; CH2), 2.32 (t, J = 6.0 Hz, 2H; CH2), 3.81 (s, 3H;
CH3), 5.88 (m, J = 6.8 Hz, H; CH), 6.90 (d, J = 8.8 Hz, 2H; Ph-H),
7.30 (d, J = 8.4 Hz, 2H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm)
13.61, 21.92 (CH3), 22.12, 26.93, 34.28 (CH2), 55.17 (OCH3), 71.61
(CH), 113.70, 127.44, 133.84, 159.10 (Ph), 173.07 (CO). EI-MS
(70 eV): m/z (%) 236 (45), 152 (12), 135 (100), 119 (43), 91(45),
77(12), 65(12), 57(10), 41 (10), 29 (8). IR absorption bands
(cmꢁ1): 3450 (w), 2959 (vs), 2933 (vs), 2870 (s), 2838 (m), 1732
(vs), 1613 (s), 1586 (m), 1515 (vs), 1460 (s), 1374 (m), 1298 (s),
1248 (vs), 1174 (vs), 1093 (m), 1061 (s), 1035 (s), 1006 (m), 940
(w). ½a 2D5
¼ þ44:3 (c 1.00, CH2Cl2).
ꢂ
4.6.8. 1-(4-Chlorophenyl)ethanol valerate 5h
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.93 (t, J = 7.6 Hz, 3H;
CH3), 1.36 (m, J = 7.6 Hz, 2H; CH2), 1.52 (d, J = 6.4 Hz, 3H; CH3), 1.65
(m, J = 7.6 Hz, 2H; CH2), 2.35 (t, J = 6.4 Hz, 2H; CH2), 5.88 (m,
J = 6.4 Hz, H; CH), 7.30 (d, J = 8.0 Hz, 2H; Ph-H), 7.34 (d, J = 9.2 Hz,
2H; Ph-H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.59, 22.11
(CH3), 22.11, 26.87, 34.16 (CH2), 71.19 (CH), 127.38, 128.55,
133.43, 140.32 (Ph), 172.86 (CO). EI-MS (70 eV): m/z (%) 240 (38),
156 (100), 138 (100), 103 (100), 85 (62), 57 (40), 41 (20), 29
(15). IR absorption bands (cmꢁ1): 3450 (w), 2960 (s), 2932 (s),
2870 (m), 1737 (vs), 1598 (w), 1494 (s), 1457 (m), 1413 (m), 374
(m), 1249 (s), 1172 (s), 1092 (s), 1063 (s), 1014 (s), 941 (m), 827
(m), 831 (s), 733 (w), 550 (m), 448 (w). ½a D25
¼ þ95:7 (c 1.00,
ꢂ
CH2Cl2).
4.6.13. 1-(3,4-Dimethoxyphenyl)ethanol valerate 5m
1H NMR (400 MHz, CDCl3) d (ppm) 0.85 (t, J = 7.6 Hz, 3H, CH3),
1.29 (m, J = 7.2 Hz, 2H, CH2), 1.49 (d, J = 6.4 Hz, 3H, CH3), 1.56 (m,
J = 8.0 Hz, 2H, CH2), 2.27 (t, J = 7.6 Hz, 2H, CH2), 3.84 (s, 3H, CH3),
3.87 (s, 3H, CH3), 5.82 (m, J = 6.4 Hz, 1H, CH), 6.80 (m, 3H, Ph-H).
13C NMR (400 MHz, CDCl3) d (ppm) 13.60, 21.97 (CH3), 22,11,
26.94, 34.24 (CH2), 55.73, 55.76 (OCH3), 71.79 (CH), 109.37,
110.83, 118.43, 134.26, 148.52, 148.77 (Ph), 173.02 (CO). EI-MS
(70 eV): m/z (%) 266 (100), 182 (100), 164 (100), 149 (80), 134
(20), 121 (40), 103 (30), 91 (40), 77 (37), 57 (25), 41 (20), 29
(15). IR absorption bands (cmꢁ1): 3445 (s), 2957 (vs), 2930 (vs),
2869 (s), 2837 (s), 1731 (vs), 1595 (s), 1515 (vs), 1460 (s), 1419
(s), 1370 (s), 1315 (s), 1259 (vs), 1164 (vs), 1103 (s), 1063 (s),
1028 (vs), 942 (m), 909 (m), 853 (m), 808 (s), 763 (m), 642 (m),
(s), 789 (w), 539 (m). ½a D25
¼ þ69:1 (c 1.00, CH2Cl2).
ꢂ
4.6.9. 1-(2-Chlorophenyl)ethanol valerate 5i
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.94 (t, J = 7.2 Hz, 3H;
CH3), 1.39 (m, J = 7.6 Hz, 2H; CH2), 1.54 (d, J = 6.4 Hz, 3H; CH3), 1.66
(m, J = 7.2 Hz, 2H; CH2), 2.39 (t, J = 7.2 Hz, 2H; CH2), 6.26 (m,
J = 6.4 Hz, H; CH), 7.24 (t, J = 7.6 Hz, H; Ph-H), 7.30 (t, J = 6.8 Hz,
H; Ph-H), 7.36 (d, J = 8.0 Hz, H; Ph-H), 7.47 (d, J = 7.6 Hz, H; Ph-
H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.62, 20.97 (CH3), 22.14,
26.91, 34.09 (CH2), 68.85 (CH), 126.42, 126.98, 128.61, 129.48,
131.87, 139.68 (Ph), 172.57 (CO). EI-MS (70 eV): m/z (%) 203 (90),
139 (100), 121 (62), 103 (75), 77 (38), 57 (18), 41 (10), 29 (10).
IR absorption bands (cmꢁ1): 3068 (w), 2960 (s), 2932 (s), 2870
(m), 1740 (vs), 1472 (m), 1443 (m), 1373 (m), 1247 (s), 1173 (s),
1134 (m), 1075 (s), 1043 (s), 1006 (m), 943 (m), 755 (s), 693 (m),
576 (w). ½a 2D5
¼ þ86:5 (c 1.00, CH2Cl2).
ꢂ
4.6.14. 1-(3,4-Methylenedioxy)ethanol valerate 5n
1H NMR (400 MHz, CDCl3) d (ppm) 0.87 (t, J = 7.6 Hz, 3H, CH3),
1.29 (m, J = 7.2 Hz, 2H, CH2), 1.48 (d, J = 6.8 Hz, 3H, CH3), 1.57 (m,
J = 7.6 Hz, 2H, CH2), 2.28 (t, J = 7.6 Hz, 2H, CH2), 5.79 (m,
J = 6.8 Hz, 1H, CH), 5.93 (s, 2H, CH2), 6.74 (m, 3H, Ph-H). 13C NMR
(400 MHz, CDCl3) d (ppm) 13.61, 22.12 (CH3), 22,14, 26.90, 34.24
(CH2), 71.83 (CH), 100.96 (CH2), 106.59, 108.02, 119.63, 135.68,
147.03, 147.62 (Ph), 173.04 (CO). EI-MS (70 eV): m/z (%) 166 (40),
166 (55), 149 (100), 119 (25), 91 (40), 77 (5), 66 (12), 57 (10), 41
(10), 29 (10). IR absorption bands (cmꢁ1): 3441 (m), 2960 (s),
2931 (s), 2873 (s), 2779 (w), 1733 (vs), 1609 (m), 1493 (s), 1445
(s), 1374 (s), 1322 (m), 1242 (vs), 1174 (s), 1135 (w), 1097 (m),
1040 (s), 937 (m), 911 (w), 859 (m), 811 (m), 761 (w), 726 (w),
462 (m). ½a 2D5
¼ þ41:3 (c 1.00, CH2Cl2).
ꢂ
4.6.10. 1-(3-Chlorophenyl)ethanol valerate 5j
1H NMR (400 MHz, CDCl3, 25 °C): d (ppm) 0.93 (t, J = 7.6 Hz, 3H;
CH3), 1.37 (m, J = 7.2 Hz, 2H; CH2), 1.52 (d, J = 6.4 Hz, 3H; CH3), 1.66
(m, J = 7.6 Hz, 2H; CH2), 2.36 (t, J = 7.6 Hz, 2H; CH2), 5.87 (m,
J = 6.4 Hz, H; CH), 7.23 (m, J = 3.2 Hz, 4H; Ph-H), 7.34 (s, H; Ph-
H). 13C NMR (400 MHz, CDCl3) d (ppm) 13.59, 22.11 (CH3), 22.16,
26.89, 34.13 (CH2), 71.16 (CH), 124.13, 126.06, 127.81, 129.69,
134.27, 143.86 (Ph), 172.84 (CO). EI-MS (70 eV): m/z (%) 240 (20),
636 (m), 558 (w). ½a D25
¼ þ64:6 (c 1.00, CH2Cl2).
ꢂ

1378
G. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 1373–1378
4. Huerta, F. F.; Bäckvall, J.-E. Chem. Soc. Rev. 2001, 30, 321–331.
Acknowledgments
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9. Kim, M.-J.; Park, J. Org. Lett. 2008, 10, 1295–1298.
This work was financially supported by the National Natural
Science Foundation of China (Nos. 20606030, 20936002 and
21076187), Supported by Science and Technology Planning Project
of Zhejiang Province (No. 2010C31127), National Basic Research
Program of China (973 Program) (Nos. 2011CB710800 and
2009CB724706), and Hi-Tech Research and Development Program
of China (No. 2006AA020103).
10. Haak, R. M.; de Vries, J. G. J. Am. Chem. Soc. 2008, 130, 13508–13509.
11. Lee, J. H.; Park, J. Eur. J. Org. Chem. 2010, 999–1015.
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