Y. Cheng et al. / Tetrahedron Letters 51 (2010) 2366–2369
2367
Table 1
Catalytic activity of resins in racemization of (S)-1-phenylethanol and (R)-1-phenylethanol acetate
Entrya
Resinc
Acid group
BET surface area (m2/g)
BJH desorption average pore diameter (nm)
Reaction time (h)
eealcohol (%)
1
2
3
4
5
6
D113
116
–COOH
–COOH
–SO3H
–SO3H
–SO3H
–SO3H
–SO3H
–SO3H
–SO3H
1.40
2.18
31.15
31.46
ꢀ0
41.0
3.07
35.7
39.4
<0.35
<0.35
<0.35
35.7
39.4
48
48
6.5
6.5
48
48
48
6.5
6.5
>99
>99
CD550
CD8604
001*7
001*8
001*10
CD550
CD8604
16.3
12.5
60.4
58.3
81.8
>99d
>99d
1.71
0.26
31.15
31.46
7
8b
9b
a
b
c
Reaction conditions: 2 mL toluene, 80 mg resin, 118 mmol/L (S)-1-phenylethanol at 40 °C under stirring.
Reaction conditions: 2 mL toluene, 80 mg resin, 100 mmol/L (R)-1-phenylethanol acetate at 40 °C under stirring.
Acid resins were commercially available from Zhejiang Zhengguang Industrial Co., Ltd.
d
eeester
.
OAc
OAc
OH
electron-donating groups on the benzene ring gave higher ee val-
ues than those with electron-attracting groups, but longer reaction
time was needed. Resin-catalyzed transesterifications with differ-
ent acyl donors were also investigated and the experiment results
indicated that complex acyl donors could slow down the transeste-
rification rate. For instance, the conversion of resin-catalyzed
transesterification of 1-phenylethanol with 1,3-diacetoxybenzene
as acyl donor decreased to below 5% while the eep was zero after
24 h’s reaction. The results were in good agreement with those of
DKR with different acyl donors. Therefore, the selectivity of the
DKR could be successfully enhanced by using more complex acyl
donors to inhibit the acid resin-catalyzed transesterification.
To expand the application area of the results, several substrates
with different substitution groups on its benzene ring were tested
with vinyl acetate. To our disappointment, none of the eeP values
could exceed 50%. Considering the good performance in DKR of
1-phenylethanol, 1,3-diacetoxybenzene was selected as the acyl
donor for expectation of better results and the results are summa-
rized in Table 3. It was shown that the reactions could proceed
smoothly and give excellent yields and high eep values when elec-
tron-withdrawing group was substituted on its para position of the
benzene ring (Table 3, entries 1 and 2). Moderate results were ob-
tained when electron-donating group was substituted on its para
position (Table 3, entry 3). But when groups were substituted on
other position of the benzene ring, especially with electron-with-
drawing group on its ortho and meta position (Table 3, entries 6
and 7), longer time was usually needed and unsatisfied results
were obtained. A plausible explanation was that the acyl donor
may inhibit the lipase-catalyzed transesterification more than the
resin-catalyzed transesterification. And then we found that if
1,3-diacetoxybenzene was used as acyl donor, the lipase-catalyzed
resolution of 1-(2-chlorophenyl)ethanol and 1-(3-chlorophenyl)
ethanol at 40 °C should be performed at least 72 h to obtain
46.9% and 47.7% conversion, respectively. So it could be considered
that 1,3-diacetoxybenzene was not the appropriate acyl donor for
all of these substrates.
Novozym 435
CD8604
ROAc
ROH
+
+
+
rac-1-phenylethanol
R-1-phenylethanol acetate S-1-phenylethanol acetate
1
2
Scheme 1. The dynamic kinetic resolution of 1-phenylethanol by acid resin and
lipase coupling catalysis.
Table 2
The DKR of 1-phenylethanol catalyzed by CD8604 and Novozym435 with different
acyl donorsa
Entry
Acyl donor
Time (h)
Yield (%)
eeP (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Vinyl acetate
Isopropenyl acetate
3
3
3
3
3
3
24
3
3
24
3
3
24
3
24
>99
>99
94.3
92.6
>99
>99
>99
92.0
98.2
77.2
95.4
96.2
>99
>99
>99
24.2
31.1
82.1
71.0
70.9
66.0
28.3
91.7
68.4
88.8
52.9
93.2
95.8
80.5
54.4
3-Chlorophenyl acetate
4-Chlorophenyl acetate
2,3-Dichlorophenyl acetate
2,4-Dichlorophenyl acetate
2,6-Dichlorophenyl acetate
2,4,5-Trichlorophenyl acetate
2,4,6-Trichlorophenyl acetate
4-Methoxybenzyl acetate
4-Nitrophenyl acetate
1,2-Diacetoxybenzene
1,3-Diacetoxybenzene
1,4-Diacetoxybenzene
3,5-Dimethyl phenyl acetate
a
Reaction conditions: 2 mL toluene, 20 mg/mL resin, 10 mg/mL Novozym435,
100 mmol/L 1-phenylethanol, 3 equiv acyl donor at 40 °C under stirring.
process, the eep would be increased.15 Moreover, using 4-chloro-
phenyl acetate instead of common acyl donors could help to stop
the side-reaction in ruthenium–enzyme catalyzed the DKR of
1-phenylethanol, and increased the yield and the eep.16 So it was
reasonable that complex acyl donor might help to inhibit or de-
crease the acid resin-catalyzed transesterification. The strategy is
to change the alcohol part of the acyl donor. Then a series of phenyl
acetate derivatives were synthesized and investigated for increas-
ing the eep. Before the DKR of 1-phenylethanol with different acyl
donors, the KR with these acyl donors were studied first. Despite
the different reaction rate, it was pleased that complex acyl donors
did not affect the enantioselectivity of Novozym435 (E >200) at all.
Later on, the DKR of 1-phenylethanol with different acyl donors
was studied and the results are summarized in Table 2. It was
shown that the eep was greatly improved by using complex acyl
donors. When 1,3-diacetoxybenzene was used as the acyl donor,
good yield (>99%) and high ee value of product (95.8%) were ob-
tained (Table 2, entry 13). Generally speaking, the acyl donors with
When substrate changed, the rate of lipase-catalyzed transeste-
rification, resin-catalyzed transesterification, and racemization
also changed, so did the appropriate acyl donor. Considering the
slow reaction of these substrates, what we need should be an acyl
donor that could accelerate the lipase-catalyzed transesterification
reaction. Then, 4-chlorophenyl acetate was selected as a new acyl
donor. It was exciting that all of the reactions were improved and
the results are listed in Table 4. It was shown that the reaction
could proceed more quickly and give excellent yields and high
eep values when electron-donating groups were substituted on
the benzene ring. But when electron-withdrawing groups were
on its ortho or meta position, steric effect and electronic effect of
the substituent would make combined effects on the lipase-cata-