Lipase-catalyzed dynamic kinetic resolution giving optically active cyanohydrins: use of silica-supported ammonium hydroxide and porous ceramic-immobilized lipase

Article abstract of DOI:10.1016/j.tet.2007.12.030

Synthetically useful cyanohydrin acetates, ArCH(OAc)CN (Ar=C₆H₅, 3,4-methylenedioxyphenyl, 4-Me-C₆H₄, 4-Cl-C₆H₄, 4-F-C₆H₄, 4-CF₃-C₆H₄), were successfully synthesized in high enantiomeric purities (79-93% ee) via the lipase-catalyzed dynamic kinetic resolution (DKR) of cyanohydrins synthesized in situ from the corresponding aldehydes and acetone cyanohydrin. The combined use of silica-supported BTAH (benzyltrimethylammonium hydroxide) and porous ceramic-immobilized lipase under the optimized reaction conditions enabled the remarkable acceleration of the enantioselective DKR reactions.

Full text of DOI:10.1016/j.tet.2007.12.030

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2178e2183
www.elsevier.com/locate/tet
Lipase-catalyzed dynamic kinetic resolution giving optically active
cyanohydrins: use of silica-supported ammonium hydroxide
and porous ceramic-immobilized lipase
*
Takashi Sakai , Kefei Wang, Tadashi Ema
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University,
Tshushima-naka, Okayama 700-8530, Japan
Received 28 November 2007; received in revised form 11 December 2007; accepted 11 December 2007
Available online 15 December 2007
Abstract
Synthetically useful cyanohydrin acetates, ArCH(OAc)CN (Ar¼C
-CF eC ), were successfully synthesized in high enantiomeric purities (79e93% ee) via the lipase-catalyzed dynamic kinetic resolution
DKR) of cyanohydrins synthesized in situ from the corresponding aldehydes and acetone cyanohydrin. The combined use of silica-supported
6 5 6 4 6 4 6 4
H , 3,4-methylenedioxyphenyl, 4-MeeC H , 4-CleC H , 4-FeC H ,
4
(
3
6 4
H
BTAH (benzyltrimethylammonium hydroxide) and porous ceramic-immobilized lipase under the optimized reaction conditions enabled the
remarkable acceleration of the enantioselective DKR reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Lipase; Dynamic kinetic resolution; Cyanohydrin
1
. Introduction
DKR system for the cyanohydrin synthesis using silica-
supported ammonium hydroxide (or acetate) as a base for race-
mization and a porous ceramic-immobilized lipase as a
biocatalyst.
Enzymatic DKR systems have attracted much attention as
an interdisciplinary technology for green sustainable chemis-
6
try. Among them, the lipase-catalyzed DKR using aromatic
Optically active cyanohydrins are versatile intermediates for
the synthesis of a wide variety of useful compounds including
1b
amino acids, hydroxy acids, and others;
chemical and enzymatic synthetic methods for optically
active cyanohydrins have been developed extensively. The
enzymatic methods are especially attractive because high enan-
tioselectivity can be attained easily with commercially avail-
able enzymes. The enzymatic methods reported so far can be
classified into three categories: (a) the hydrocyanation of alde-
hydes with HCN using oxynitrilases; (b) the lipase-catalyzed
4
kinetic resolution of racemic cyanohydrins; and (c) the dy-
namic kinetic resolution (DKR) of cyanohydrins. The last
method is attractive for the preparative-scale synthesis because
a single enantiomer can be obtained via a simple and safe ex-
perimental procedure. Here we developed a more practical
1
a
1c,d
and therefore
2
3
aldehydes and acetone cyanohydrin was pioneered by Oda
5
a
and co-workers in 1992, where the less reactive enantiomer
of cyanohydrin was racemized by a basic anion-exchange
ꢀ
resin (Amberlite IRA-904, OH form). A variety of aromatic
3
cyanohydrin acetates with a functional group can be obtained
in high yields with high enantiomeric purities (70e91% ee)
in a simple one-pot reaction. However, there are still problems
to be solved: (a) the instability of the basic anion-exchange
resin, which gradually decomposes, giving off an unpleasant
smell, and which causes a problem of disposal; (b) the pro-
longed reaction time (2e8 days), which can result in the race-
mization of cyanohydrin acetates produced; and (c) optically
unstable aromatic cyanohydrin acetates substituted with an
electron-withdrawing group have not yet been prepared by
4
,5
*
Corresponding author. Tel.: þ81 86 251 8090; fax: þ81 86 251 8092.
E-mail address: tsakai@cc.okayama-u.ac.jp (T. Sakai).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.030

T. Sakai et al. / Tetrahedron 64 (2008) 2178e2183
2179
5
a
5b
4
this method. Although Hanefeld and Kanerva et al. have
recently reported the DKR method, the difficult-to-handle
resin was still used.
enantiomeric purity (86% ee) although considerable amounts
of 1a (4%) and 2a (53%) were also obtained (entry 2). These
results indicate that just a simple kinetic resolution took place
and that, unfortunately, BTAH (5a) was not effective for the in
situ racemization of 2a. The reaction with 6a at 50 C gave 3a
in a moderate yield but with little or no enantiomeric excess
Here, we report that the combined use of silica-supported
benzyltrimethylammonium hydroxide (BTAH, 5a) (or its
acetate 5b) and a Burkholderia cepacia lipase immobilized
on a porous ceramic support called Toyonite (lipase PS-C
b,8
II ) led to the highly accelerated DKR reaction, making
the reaction applicable even to optically unstable cyanohydrins
bearing a fluorinated (4-F or 4-CF ) phenyl group, which have
ꢁ
7
(entry 3), while no acceleration was observed with 6b even
ꢁ
7
at 50 C (entry 4). As a result of the screening of enzymes,
lipase PS-C II was found to be the best biocatalyst showing
high catalytic activity in the presence of the base, BTAH
(5a). A few examples are listed in Table 1. Lipase AK and
LIP-300, both of which showed comparable activity and enan-
tioselectivity (entries 5 and 6), are inferior to lipase PS-C II
(entry 2). Novozym 435 exhibited a much lower activity
with a large amount of 2a accumulated (entry 7), partly be-
cause the resin support was dissolved by BTAH (5a). The sol-
vent effect was briefly investigated for the lipase PS-C II
mediated reactions at room temperature (entries 8e11). The
use of acetone resulted in the base-catalyzed aldol reaction,
giving a trace amount of product (entry 8). The DKR in
THF gave only 17% conversion, while the reactions in
t-BuOMe and cyclopentyl methyl ether (CPME) afforded
moderate conversions (entries 9e11). These results indicated
3
5
never been obtained by the DKR reaction or by the oxynitri-
3
lase-catalyzed hydrocyanation of aldehydes.
2
. Results and discussion
2
.1. Optimization of the DKR reaction conditions
ꢀ
We initially employed Amberlyst A-27 (OH form) as
a base for the racemization of cyanohydrin in the lipase-
catalyzed DKR reaction; however, the reactions were accom-
panied with many impurities, and the resin was decomposed
in a few weeks. Another attempt to covalently immobilize
ammonium hydroxide to a porous ceramic support, Toyonite,
was unsuccessful. We therefore examined the possibility
of readily available BTAH (5a) (0.13 equiv with respect to
that i-Pr
In the above reactions, BTAH (5a) is insoluble in i-Pr
O is the best solvent for this system.
2
O,
2
1
a). The reaction was conducted with the porous ceramic-
which might hamper its racemizing power. In order to solve
this problem, we examined silica-supported BTAH and, to our
delight, found that it is a quite effective racemizing agent as
shown in Table 2. To prepare an active agent, silica-supported
BTAH, silica was added to a methanolic solution of 5a, and
MeOH was then evaporated thoroughly to dryness under vac-
uum. Silica-supported BTAH thus prepared is considered to
be dispersed on the silica surface, allowing 5a on silica to
immobilized lipase called lipase PS-C II, 1a, acetone cyano-
hydrin (4), BTAH (5a), and vinyl acetate (6a) or isopropenyl
acetate (6b) in i-Pr O. The results are summarized in
Table 1.
As shown in Table 1, the reaction with 6a at room
temperature (entry 1) gave cyanohydrin acetate 3a with only
2
6
2% ee, while the use of 6b gave 3a with a much improved
Table 1
Lipase-catalyzed DKR of cyanohydrin 2a using BTAH (5a) as a racemizing agent in the absence of silica
a
O
HO CN
OH
CN
OAc
CN
4
lipase
6: AcOCR=CH2
a: R = H; b: R = Me
H
+
–
BnN Me OH
3
BTAH (5a)
1a
2a
3a
ꢁ
b
Ratio (%)
Entry
Lipase
6
Solvent
T ( C)
Time (h)
3a
c
% Yield (% ee)
d
1
a
2a
3a
1
2
3
4
5
6
7
8
9
PS-C II
PS-C II
PS-C II
PS-C II
AK
6a
6b
6a
6b
6b
6b
6b
6b
6b
6b
6b
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
2
2
2
2
2
2
2
O
O
O
O
O
O
O
rt
24
15
24
24
39
39
39
5
15
4
60
53
16
26
60
62
83
25
43
66
36
30
33
5
23 (62)
32 (86)
60 (2)
rt
50
50
rt
18
38
10
5
34 (1)
26 (74)
31 (80)
LIP-300
Novozym 435
PS-C II
PS-C II
PS-C II
PS-C II
rt
e
rt
12
Trace
5
d
e
d
Acetone
THF
rt
Trace
78
65
Trace
17
26
30
rt
24
24
24
16 (85)
24 (81)
27 (90)
1
1
0
1
a
t-BuOMe
CPME
rt
9
rt
9
61
˚
Conditions: 1a (1.0 mmol), 4 (5.0 mmol), 5a (0.13 mmol), 6 (10 mmol), lipase (125 mg), molecular sieves 3 A (several pieces), dry solvent (10 mL).
1
Determined by H NMR.
b
c
Isolated yield.
Determined by capillary GC with a CP-cyclodextrin-b-2,3,6-M-19 column (Chrompack, f 0.25 mmꢂ25 m).
d
e
Not isolated.

2180
T. Sakai et al. / Tetrahedron 64 (2008) 2178e2183
Table 2
Optimization of the lipase-catalyzed DKR of cyanohydrin 2a using silica-supported BTAH as a racemizing agent
a
Entry
Lipase (mg)
Silica (mg)
5a (equiv)
6b (equiv)
Time (h)
Ratio (%)
% Yield (% ee)
1
a
2a
3a
1
2
3
4
5
a
125
125
125
237
300
50
80
80
80
80
0.13
0.20
0.20
0.20
0.20
10
3
19
22
41
44
26
0
36
30
18
13
3
64
70
82
87
92
52 (83)
60 (85)
75 (82)
80 (75)
80 (79)
Trace
Trace
0
3
3
3
5
˚
Conditions: 1a (1.0 mmol), 4 (5.0 mmol), 5a (indicated above), 6 (indicated above), lipase PS-C II (indicated above), molecular sieves 3 A (several pieces), dry
2
O (10 mL for entries 1 and 2 and 8 mL for entries 3e5), rt.
i-Pr
effectively exert its ability as a base. Table 2 shows that the use of
silica (entry 1) greatly accelerated the reaction, giving a higher
yield in a shorter reaction time. Obviously, the DKR process pro-
ceeded. When larger amounts of silica and 5a were used, the
amount of acylating agent 6b could be decreased (entry 2).
The DKR in a longer reaction time afforded the product 3a in
a higher yield (entry 3). These results show that silica-supported
BTAH is a readily available, stable, and effective racemizing
agent useful for the DKR reaction. Finally, the amount of lipase
PS-C II was optimized (entries 4 and 5). An increased amount of
lipase (300 mg) gave the best result with 92% conversion and
The results are shown in Table 3. Cyanohydrin acetates with
a methylenedioxy or methyl group, 3b and 3c, were obtained
in good yields with high enantiomeric purities in shorter reac-
tion times (entries 2 and 3). The longer reaction time gave an
improvement in the conversion, with high enantioselectivity
retained (entry 4). The advantage of the present method
5
a
over the previously reported method is that the former could
be applied successfully even to cyanohydrins with an electron-
withdrawing group (Cl or F) on the phenyl group; for exam-
ple, 3d and 3e were obtained in 82% ee within 25 h (entries
5 and 6). The shortened reaction time as compared with that
5
a
7
9% ee in a short reaction time of 26 h (entry 5). Thus, the com-
in the literature may have led to the high enantiomeric
purities. However, the application of the optimized reaction
conditions to 4-(trifluoromethyl)benzaldehyde (1f) furnished
3f with only 10% ee at 75% conversion, which is probably
due to its optical instability (entry 7). Although furyl-
substituted cyanohydrin acetate 3g was obtained in 53% ee
(entry 8), which is close to the previous value (47% ee), the
reaction was faster than that reported previously (73% conver-
bined use of lipase PS-C II and silica-supported BTAH resulted
in the considerable acceleration of the reaction. The DKR under
the optimized reaction conditions is now a convenient and read-
ily accessible method for the laboratory-scale preparation of 3a.
2
.2. Synthesis of a variety of cyanohydrin acetates
5
a
The optimized conditions (Table 2, entry 5) were next ap-
plied to the synthesis of a variety of cyanohydrin derivatives.
sion in 6 days). Except for 3e and 3f, for which no lipase-
mediated DKR has been reported, all the cyanohydrin acetates
Table 3
Lipase-catalyzed DKR of cyanohydrins 2aef using silica-supported BTAH as a racemizing agent
a
HO CN
O
4
OH
CN AcOCMe=CH
6b
OAc
CN
3a–g
lipase PS-C II
Ar
1
H
Ar
2a–g
Ar
BTAH on silica
2
a–g
a: Ar =
e: Ar =
b: Ar =
f: Ar =
c: Ar =
Me d: Ar =
Cl
O
O
F
CF3 g: Ar =
O
Entry
Ar
Time (h)
Ratio (%)
3
b
% Yield (% ee)
c
1
2
3
R/S
1
2
3
4
5
6
7
8
a
a
b
c
c
d
e
f
26
15
25
45
25
24
28
71
5
10
5
3
0
92
90
73
89
88
87
75
96
80 (79)
84 (87)
63 (93)
79 (91)
71 (82)
74 (82)
55 (10)
90 (53)
S
S
S
S
S
S
S
R
22
11
11
13
25
4
0
1
0
0
g
0
˚
Conditions: 1 (1.0 mmol), 4 (5.0 mmol), silica-supported BTAH (0.2 mmol, silica 80e90 mg), 6 (3.0 mmol), lipase PS-C II (300 mg), molecular sieves 3 A
(
several pieces), dry i-Pr
2
O (8 mL), rt.
b
Isolated yield.
Determined by capillary GC with a CP-cyclodextrin-b-2,3,6-M-19 column (Chrompack, f 0.25 mmꢂ25 m).
c

T. Sakai et al. / Tetrahedron 64 (2008) 2178e2183
2181
Table 4
Lipase-catalyzed DKR of cyanohydrin 2f using benzyltrimethylammonium
a crystalline compound, we decided to purify 2f, derived
from 3f with 81% ee, by recrystallization. Recrystallization
of 2f from hexane/Et O gave white needles, and the enantio-
a
acetate (5b) or benzoate (5c) on alumina or silica as a racemizing agent
2
Entry 5 (mmol)
Support (mg) Time (h) Ratio (%)
2f 3f
3f
meric purity of 2f was determined to be >99% ee by converting
2f to 3f by the treatment with Ac O and Sc(OTf) in MeCN.
The Lewis acid, Sc(OTf) , was found to be essential because
1
f
% Yield
(
2
3
% ee)
3
1
2
3
4
5
6
7
None (d) A (90)
69
21
38
23
29
42
42
26 36
38 19 (91)
100 81 (21)
58 53 (87)
78 62 (65)
69 48 (90)
85 75 (81)
80 65 (72)
cyanohydrin 2f and acetate 3f were readily racemized under ba-
sic conditions, for example, with Ac O and pyridine, which
were used in the synthesis of 4-fluoro derivative 3e.
5b (0.057) A (100)
5b (0.012) A (100)
5b (0.030) A (100)
5b (0.072) S (70)
5b (0.072) S (60)
5c (0.072) S (60)
0
0
5
0
0
0
0
42
17
31
15
20
2
OAc
CN
OH
CN
a
p-TsOH
Conditions: 1f (1.0 mmol), 4 (5.0 mmol), 5b on alumina (A) or silica (S)
indicated above), 6 (3.0 mmol), lipase PS-C II (400 mg), molecular sieves
EtOH
(
R
R
˚
A (several pieces), dry i-Pr O (8 mL), rt.
3e: R = F
f: R = CF3
2e: R = F
2f: R = CF3
3
2
3
Ac O
2
in Table 3 had the same enantiopreferences as those reported
5
2
2
e
f
3e
a
pyridine, Et2O
previously.
To improve the % ee value of compound 3f, the basicity
of the ammonium salt 5 was tuned by anion exchange from
Ac O
2
3f
Sc(OTf) , MeCN
3
ꢀ
ꢀ
OH to OAc or benzoate and by choosing either silica or alu-
mina as an inorganic support (Table 4). When basic alumina
was used in the absence of the organic base, only kinetic reso-
lution of 2f took place (entry 1), which indicates that the basi-
city of basic alumina used in this study is too weak to bring
about the racemization of 2f. We therefore employed benzyl-
trimethylammonium acetate (5b), which is a weaker base as
compared with 5a. The use of 0.057 equiv of 5b resulted in
Scheme 1. Conversion of 3eef to 2eef to determine the absolute configura-
tions and conversion of 2eef back to 3eef to determine the enantiomeric
purities.
3. Conclusion
Silica-supported BTAH (benzyltrimethylammonium hy-
droxide), prepared very easily, is a quite effective racemizing
agent. Moreover, it does not give off a bad smell as ion-exchange
resins do, and it is easy to handle. Using silica-supported BTAH
(or its acetate) together with porous ceramic-immobilized lipase
(lipase PS-C II), efficient lipase-catalyzed DKR of cyano-
hydrins, prepared from aldehydes and acetone cyanohydrin in
one pot, have been carried out. The DKR under the optimized
conditions gave cyanohydrin acetates, ArCH(OAc)CN (Ar¼
C H , 3,4-methylenedioxyphenyl, 4-MeeC H , 4-CleC H ,
1
00% conversion but with only 21% ee (entry 2). Obviously,
product 3f was racemized by 5b. The use of 0.012 equiv of
b made the reaction too slow (entry 3), while the addition
of 0.03 equiv of 5b hampered the enantioselectivity (entry
). On the other hand, the combination of 5b and silica gel
5
4
produced better results. For example, 3f with 90% ee was
obtained at 69% conversion (entry 5). A slight decrease in
the amount of silica yielded the best result, giving 3f in 81%
ee at 85% conversion (entry 6). The replacement of the
counter anion to benzoate resulted in a lower conversion
with a reduced % ee value (entry 6). Thus, we could optimize
the reaction conditions for the DKR of the optically unstable
cyanohydrin 2f.
6
5
6
4
6 4
4-FeC H , 4-CF eC H , 2-furyl), with high enantiomeric
6
4
3
6 4
purities in short reaction times. Because the present DKR
system is efficient, practical, and user-friendly, we expect that
this system will be used widely for the synthesis of a variety
of chiral cyanohydrin derivatives.
2
.3. Determination of the absolute configurations
4. Experimental
The absolute configurations of compounds 3ae3d and 3g
4.1. General
were determined by comparing the signs of their specific rota-
tions with those of the reported values, and those of the fluori-
nated compounds 3e and 3f were determined in the same way
after conversion to the corresponding cyanohydrins 2e and 2f,
respectively. As shown in Scheme 1, 3e and 3f were converted,
respectively, to 2e and 2f by the treatment with p-TsOH in
EtOH. The retention of the enantiomeric purity of 3e during
the transesterification was confirmed by the conversion of 2e
back to 3e by the treatment with Ac O and pyridine in Et O
Silica gel (BW-127ZH, 100e270 mesh) was purchased
from Fuji Silysia Chemical, Ltd, and used for column chroma-
tography and for supporting the ammonium salts. Aluminum
oxide 90 active basic was purchased from Merck and used
as a support. Thin layer chromatography (TLC) was per-
formed on Merck silica gel 60 F254. Lipase PS-C ‘Amano’ II
(Amano Enzyme Inc.) and LIP-300 were purchased from
Wako Pure Chemical Industries, Ltd and Toyobo Co., Ltd, re-
spectively. Lipase AK and Novozym 435 were provided by
Amano Enzyme Inc. and Novozymes Japan Ltd, respectively.
2
2
and the subsequent determination of the % ee value of 3e. On
the other hand, because cyanohydrin 2f with a high enantio-
meric purity had never been reported and because 2f is
1
13
H and C NMR spectra were measured in CDCl at 200 and
3

2182
T. Sakai et al. / Tetrahedron 64 (2008) 2178e2183
5
0 MHz, respectively. Capillary GC was performed with a CP-
4.2.4. (S)-(ꢀ)-1-Cyano-1-(4-fluorophenyl)methyl
acetate (3e)
Enantiomeric excess: 82%; [a]D ꢀ1.98 (c 1.01, CHCl );
cyclodextrin-b-2,3,6-M-19 (Chrompack, f 0.25 mmꢂ25 m)
ꢁ
ꢁ
26
column (Inj. 250 C, Det. 220 C).
3
ꢁ
1
chiral GC: Col. 130 C, (R) 26 min, (S) 31 min; H NMR
200 MHz, CDCl ) d 2.17 (s, 3H), 6.39 (s, 1H), 7.15 (t,
(
3
4
.2. Typical procedure for the one-pot synthesis of optically
13
J¼8.7 Hz, 2H), 7.52 (dd, J¼5.2, 8.6 Hz, 2H); C NMR
active cyanohydrin acetates 3 from aldehydes 1
(
1
50 MHz, CDCl ) d 20.3, 62.1, 115.9, 116.2 (d, J ¼21.9 Hz),
3
CF
27.7 (d, J ¼2.7 Hz), 129.9 (d, J ¼8.2 Hz), 163.5 (d,
CF
CF
Silica (80 mg) and benzyltrimethylammonium hydroxide
BTAH, 5a) (40% in MeOH, 90 mL, 0.2 mmol) were placed in
J ¼249.5 Hz), 168.7. For determination of the absolute con-
CF
(
figuration of 3e, it was transformed into 2e. To a solution of
acetate (S)-3e (238 mg, 1.23 mmol, 80% ee) in EtOH
a 25 mL round-bottomed flask, and concentrated in vacuo to re-
move MeOH. Then, lipase PS-C II (300 mg), molecular sieves
3
acetone cyanohydrin (4) (426 mg, 5.0 mmol), isopropenyl ace-
tate (6b) (300 mg, 3.0 mmol), and i-Pr O (8 mL) were added
successively. The mixture was stirred at room temperature for
2
with brine (3 mL), and then dried over Na SO . The solvent was
removed under reduced pressure, and the residual oil was ana-
1
lyzed by H NMR. Purification by silica gel column chromatog-
(
6 mL), p-TsOH$H O (234 mg, 1.23 mmol) was added, and
2
˚
A (several pieces), benzaldehyde (1a) (106 mg, 1.0 mmol),
the mixture was stirred at room temperature for 2 days. The
mixture was concentrated under reduced pressure and ex-
tracted with EtOAc, and the organic layer was dried over
Na SO , filtered, and concentrated under reduced pressure to
2
2
4
6 h under N . The mixture was filtered through Celite, washed
2
give a viscous oil. The product was purified by silica gel col-
umn chromatography (hexane/EtOAc (14:1)) to give (S)-2e as
2
4
2
6
a colorless oil (178 mg, 96% yield); [a] ꢀ31.4 (c 0.69,
D
2
b
22
CHCl ), lit. [a]D ꢀ36.4 (c 0.8, CHCl ) for (S)-2e with
3
3
raphy (hexane/EtOAc (12:1)) gave acetate (S)-3a as a colorless
2
96% ee. Then, 2e (16.0 mg, 0.104 mmol) was added into a so-
lution of pyridine (25 mL), DMAP (1.3 mg, 0.01 mmol) and
5
D
oil (141 mg, 80% yield, 79% ee); [a] ꢀ4.97 (c 0.905, CHCl ),
3
1
0
21
lit. [a]D ꢀ6.92 (c 2.20, CHCl ) for (S)-3a with 95% ee; chiral
3
Ac O (19.6 mL, 0.208 mmol), and the mixture was stirred at
2
ꢁ
1
GC: Col. 130 C, (R) 27 min, (S) 30 min; H NMR (200 MHz,
room temperature for 1 h. The mixture was concentrated under
reduced pressure and extracted with EtOAc, and the organic
layer was dried over Na SO , filtered, and concentrated under
1
3
CDCl ) d 2.17 (s, 3H), 6.41 (s, 1H), 7.44e7.52 (m, 5H); C
NMR (50 MHz, CDCl ) d 20.4, 62.8, 116.0, 127.7, 129.1,
1
3
3
2
4
30.3, 131.6, 168.8.
reduced pressure. The product was purified by silica gel col-
umn chromatography (hexane/EtOAc (12:1)) to give acetate
(S)-3e as a colorless oil with a slightly reduced % ee value
(17.4 mg, 87% yield, 79% ee).
4
phenyl]methyl acetate (3b)
.2.1. (S)-(þ)-1-Cyano-1-[3,4-(methylenedioxy)-
2
4
Enantiomeric excess: 87%; [a] þ12.4 (c 0.70, CHCl ),
D
3
5
a
25
lit. [a]D þ42.7 (c 1.53, C H ) for (S)-3b with 91% ee; chiral
4.2.5. (S)-(ꢀ)-1-Cyano-1-[4-(trifluoromethyl)phenyl]methyl
acetate (3f)
6
6
ꢁ
1
GC: Col. 160 C, (R) 50 min, (S) 54 min; H NMR (200 MHz,
CDCl ) d 2.15 (s, 3H), 6.03 (s, 2H), 6.31 (s, 1H), 6.84 (dd,
2
6
Enantiomeric excess: 81%; [a] ꢀ3.41 (c 0.53, CHCl );
3
D
3
ꢁ
1
J¼0.7, 7.7 Hz, 1H), 6.98 (s, 1H), 7.0 (dd, J¼0.7, 7.7 Hz, 1H);
chiral GC: Col. 130 C, (R) 23 min, (S) 27 min; H NMR
(200 MHz, CDCl ) d 2.20 (s, 3H), 6.47 (s, 1H), 7.66 (d,
1
3
C NMR (50 MHz, CDCl ) d 20.5, 62.6, 101.7, 108.2, 108.6,
3
16.1, 122.4, 125.2, 148.3, 149.3, 168.8.
3
1
3
1
J¼8.7 Hz, 2H), 7.74 (d, J¼8.7 Hz, 2H); C NMR (50 MHz,
CDCl ) d 20.2, 62.1, 115.5, 120.7, 126.1 (q, J ¼3.7 Hz),
3
CF
1
28.1, 132.3 (q, J ¼32.8 Hz), 135.4, 168.6. A solution of ac-
CF
4
acetate (3c)
.2.2. (S)-(þ)-1-Cyano-1-(4-methylphenyl)methyl
etate (S)-3f (319 mg, 1.32 mmol, 81% ee) and p-TsOH$H O
2
(250 mg, 1.32 mmol) in EtOH (8 mL) was stirred at room tem-
2
6
Enantiomeric excess: 93%; [a] þ6.31 (c 0.60, CHCl ),
D
3
perature for 2 days. The resulting solution was concentrated in
vacuo, and the residual solid was purified by silica gel column
chromatography (hexane/EtOAc (4:1)) to give (S)-2f as a white
5
a
25
lit. [a]D þ30.4 (c 1.41, C H ) for (S)-3c with 91% ee; chiral
6
6
ꢁ
1
GC: Col. 130 C, (R) 39 min, (S) 45 min; H NMR (200 MHz,
CDCl ) d 2.15 (s, 3H), 2.38 (s, 3H), 6.37 (s, 1H), 7.25 (d,
3
29
solid (264 mg, 98% yield); [a]D ꢀ19.3 (c 0.64, CHCl ). The
1
3
3
J¼8.2 Hz, 2H), 7.41 (d, J¼8.2 Hz, 2H); C NMR (50 MHz,
product was further purified by recrystallization from hex-
CDCl ) d 20.4, 21.2, 62.7, 116.1, 127.7, 128.7, 129.7, 140.5,
3
25
D
ane/Et O to give enantiomerically pure (S)-2f; [a] ꢀ25.8
2
1
68.8.
9
(
c 0.70, CHCl ), lit. [a] þ19.0 (c 1.759, CHCl ) for (R)-2f
3
D
3
ꢁ
ꢁ
3d
with 80% ee; mp 78 C (67e69 C for rac-2f ). Cyanohydrin
2f (40 mg, 0.2 mmol) in MeCN (2 mL) was added to a mixture
of Sc(OTf)3 (0.98 mg, 0.002 mmol) and Ac O (38 mL,
4
acetate (3d)
.2.3. (S)-(þ)-1-Cyano-1-(4-chlorophenyl)methyl
2
2
6
Enantiomeric excess: 82%; [a] þ9.03 (c 0.78, CHCl ),
0.4 mmol). The mixture was stirred at room temperature for
1 h, and then concentrated under reduced pressure to give cya-
nohydrin acetate 3f. Purification by silica gel column chro-
matography (hexane/EtOAc (21:1)) gave the desired product
(S)-3f as a colorless oil (46 mg, 94% yield, with >99% ee);
D
3
1
1
20
lit. [a]D ꢀ14.1 (c 1, CHCl ) for (R)-3d with 97% ee; chiral
3
ꢁ
1
GC: Col. 130 C, (R) 65 min, (S) 77 min; H NMR (200 MHz,
1
3
CDCl ) d 2.17 (s, 3H), 6.38 (s, 1H), 7.40e7.50 (m, 4H); C
NMR (50 MHz, CDCl ) d 20.4, 62.1, 115.7, 129.2, 129.4,
1
3
3
2
5
30.1, 136.5, 168.6.
[a] ꢀ4.26 (c 0.94, CHCl3).
D

T. Sakai et al. / Tetrahedron 64 (2008) 2178e2183
2183
4
.2.6. (R)-(þ)-1-Cyano-1-(2-furyl)methyl acetate (3g)
Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M. Tetrahedron
2004, 60, 10433e10447; (f) Liu, X.; Qin, B.; Zhou, X.; He, B.; Feng,
X. J. Am. Chem. Soc. 2005, 127, 12224e12225; (g) Lundgren, S.;
Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005, 127,
2
0
Enantiomeric excess: 53%; [a] þ7.8 (c 1.09, CHCl ),
D
3
1
1
22
lit. [a]D ꢀ18.8 (c 1, CHCl ) for (S)-3g with 98% ee; chiral
3
ꢁ
1
GC: Col. 130 C, (S) 9.6 min, (R) 10.2 min; H NMR
200 MHz, CDCl ) d 2.17 (s, 3H), 6.45 (dd, J¼1.9, 3.8 Hz,
1
1592e11593.
(
1
3. (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555e1564; (b)
Duffield, J. J.; Regan, A. C. Tetrahedron: Asymmetry 1996, 7, 663e666;
(c) Kiljunen, E.; Kanerva, L. T. Tetrahedron: Asymmetry 1996, 7,
3
H), 6.47 (s, 1H), 6.69 (dd, J¼0.8, 3.8 Hz, 1H), 7.51 (dd,
3
1
3
J¼0.8, 1.9 Hz, 1H); C NMR (50 MHz, CDCl ) d 20.2,
1
105e1116; (d) Han, S.; Chen, P.; Lin, G.; Huang, H.; Li, Z. Tetrahedron:
5
5.6, 111.0, 112.5, 114.0, 143.9, 144.9, 168.6.
Asymmetry 2001, 12, 843e846; (e) Chen, P.; Han, S.; Lin, G.; Li, Z.
J. Org. Chem. 2002, 67, 8251e8253; (f) Kobler, C.; Effenberger, F.
Tetrahedron: Asymmetry 2004, 15, 3731e3742.
. Paizs, C.; T a¨ htinen, P.; Tosa, M.; Majdik, C.; Irimie, F.-D.; Kanerva, L. T.
Tetrahedron 2004, 60, 10533e10540.
Acknowledgements
4
We are grateful to the SC-NMR Laboratory of Okayama
University for the measurement of NMR spectra.
5
. (a) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Org. Chem. 1992, 57,
5643e5649; (b) Veum, L.; Hanefeld, U. Tetrahedron: Asymmetry 2004,
1
5, 3707e3709.
6
. (a) Mart ´ı n-Matute, B.; Edin, M.; Bog a´ r, K.; Kaynak, F. B.; B a¨ ckvall, J.-E.
J. Am. Chem. Soc. 2005, 127, 8817e8825; (b) Akai, S.; Tanimoto, K.;
Kanao, Y.; Egi, M.; Yamamoto, T.; Kita, Y. Angew. Chem., Int. Ed.
2006, 45, 2592e2595; (c) Ko, S.-B.; Baburaj, B.; Kim, M.-J.; Park, J.
J. Org. Chem. 2007, 72, 6860e6864.
References and notes
1
. (a) Warmerdam, E. G. J. C.; van Rijn, R. D.; Brussee, J.; Kruse, C. G.; van
der Gen, A. Tetrahedron: Asymmetry 1996, 7, 1723e1732; (b) DeSantis,
G.; Zhu, Z.; Greenberg, W. A.; Wong, K.; Chaplin, J.; Hanson, S. R.;
Farwell, B.; Nicholson, L. W.; Rand, C. L.; Weiner, D. P.; Robertson,
D. E.; Burk, M. J. J. Am. Chem. Soc. 2002, 124, 9024e9025; (c) Fechter,
M. H.; Griengl, H. Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 2; (d) Effen-
berger, F.; Bohrer, A.; F o¨ rster, S. Future Directions in Biocatalysis;
Matsuda, T., Ed.; Elsevier: Amsterdam, 2007.
7. (a) Sakai, T.; Matsuda, A.; Korenaga, T.; Ema, T. Bull. Chem. Soc. Jpn.
2003, 76, 1819e1821; (b) Sakai, T.; Hayashi, K.; Yano, F.; Takami, M.;
Ino, M.; Korenaga, T.; Ema, T. Bull. Chem. Soc. Jpn. 2003, 76,
1441e1446.
8. Sakai, T.; Matsuda, A.; Tanaka, Y.; Korenaga, T.; Ema, T. Tetrahedron:
Asymmetry 2004, 15, 1929e1932.
9. Matthews, B. R.; Jackson, W. R.; Jayatilake, G. S.; Wilshire, C.; Jacobs,
H. A. Aust. J. Chem. 1988, 41, 1697e1709.
2. (a) Kirsten, C. N.; Herm, M.; Schrader, T. H. J. Org. Chem. 1997, 62,
6
2
882e6887; (b) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67,
702e2704; (c) Casas, J.; N a´ jera, C.; Sansano, J. M.; Sa a´ , J. M. Tetra-
10. Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am. Chem. Soc. 2005,
127, 10776e10777.
hedron 2004, 60, 10487e10496; (d) Li, Y.; He, B.; Qin, B.; Feng, X.;
Zhang, G. J. Org. Chem. 2004, 69, 7910e7913; (e) Belokon’, Y. N.;
11. Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; Hogg, D.; North, M.;
Reeve, C. Eur. J. Org. Chem. 2006, 4609e4617.