Enzymatic kinetic resolution of racemic cyanohydrins via enantioselective acylation

Article abstract of DOI:10.1016/j.tet.2009.11.074

Enzymatic kinetic resolution of a series of aromatic and aliphatic cyanohydrins in organic media has been investigated. The behavior of potential lipases, molecular sieves, acyl reagent, reaction temperature, and organic solvents on the kinetic resolution was studied. The influence of substrate structure, steric, and electronic nature and position of the aryl substituent on the enantioselectivity was discussed. Under the optimized reaction conditions, good enantioselectivity could be achieved for most of the investigated compounds. Specifically, substrates 1a, 1c, 1d, 1f, 1u could be resolved with the kinetic enantiomer ratio (E) higher than 200.

Full text of DOI:10.1016/j.tet.2009.11.074

Tetrahedron 66 (2010) 624–630
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enzymatic kinetic resolution of racemic cyanohydrins via enantioselective
acylation
,b,
Qing Xu a, Yongli Xie a, Xiaohong Geng a, Peiran Chen a
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 Renmin Road North, Songjiang District, Shanghai 201620, China
b State Key Laboratory of Bioorganic Chemistry and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, CAS, 345 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Enzymatic kinetic resolution of a series of aromatic and aliphatic cyanohydrins in organic media has been
investigated. The behavior of potential lipases, molecular sieves, acyl reagent, reaction temperature, and
organic solvents on the kinetic resolution was studied. The influence of substrate structure, steric, and
electronic nature and position of the aryl substituent on the enantioselectivity was discussed. Under the
optimized reaction conditions, good enantioselectivity could be achieved for most of the investigated
compounds. Specifically, substrates 1a, 1c, 1d, 1f, 1u could be resolved with the kinetic enantiomer ratio
(E) higher than 200.
Received 24 September 2009
Received in revised form
15 November 2009
Accepted 17 November 2009
Available online 7 December 2009
Keywords:
Enzymatic kinetic resolution
Cyanohydrin
Ó 2009 Elsevier Ltd. All rights reserved.
Enantioselective acylation
Lipase
1. Introduction
enantiopurity with a yield close to 50%, which is usually not good
for final product but might be good in the case where both of the
Cyanohydrins have considerable synthetic potential as chiral
building blocks since they bear a hydroxyl group and a cyano group
on one chiral carbon. They therefore provide a wide space for
transformation into a large number of chiral molecules, especially
in a wide range of pharmaceuticals and agrochemicals. Stereo-
selective synthesis of cyanohydrins has been extensively in-
vestigated topics and there have appeared quite a number of
excellent reviews.1 The methodology of such formation can roughly
be divided into three major categories: (1) hydrocyanation of
aldehydes or ketones catalyzed by chemical catalyst, (2) hydro-
cyanation of aldehydes or ketones catalyzed by biological catalyst,
and (3) enantioselective acylation or hydrolytic deacylation of
racemic cyanohydrins or racemic cyanohydrin esters catalyzed by
esterase or lipase, namely, simple kinetic resolution (KR) and
dynamic kinetic resolution (DKR).
In the KR, a cyanohydrin racemate is treated by an acylating
reagent in the presence of a lipase or an esterase to stereoselectively
obtain an acylated enantiomer and an unreacted enantiomer, or
alternatively, an acylated cyanohydrin racemate is stereoselectively
hydrolyzed in the presence of a lipase or an esterase to give a hy-
drolyzed enantiomer and an unreacted enantiomer.2 In ideal case,
both of the enantiomers can be obtained simultaneously in high
resolved enantiomers are useful as starting material in synthesis.
In this article, we wish to report the results3 obtained in our
continuous effort for the preparation of enantiopure cyanohydrins.4
2. Results and discussion
2.1. Optimization of reaction conditions5
2.1.1. Variation of catalyst. A number of lipases and esterases have
been reported in the literatures for the kinetic resolution of sec-
ondary alcohols. Among them we chose Apf-12, P-30, P-30(LPMO),
and PS-30 due to their high efficiency and good accessibility.
Screening using racemic mandelonitrile as a model compound
showed that lipase PS-30 was the best one of the four, which could
give a value of kinetic enantiomeric ratio (E) up to 102.6 at 37%
conversion. Table 1 summarized the results. Lipase PS-30 was
consequently used throughout this study.
2.1.2. Effect of molecular sieves. Results shown in Table 2 demon-
strated that addition of 4A molecular sieves (MS) to the reaction did
have a benefit effect in shortening the reaction time and enhancing
the E values although the reaction per se did not yield any water.
2.1.3. Variation of acyl reagent. Vinyl acetate and isopropenyl ace-
tate were tested as the acyl reagent and vinyl acetate gave higher E
* Corresponding author. Tel.: þ86 21 67792594; fax: þ86 21 67782608.
E-mail address: prchen@dhu.edu.cn (P. Chen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.074

Q. Xu et al. / Tetrahedron 66 (2010) 624–630
625
that up to 87.1 at 43% conversion after 48 h, whereas isopropenyl
acetate gave an E value of 51.1 after 24 h (Table 3). Therefore, we
used vinyl acetate as the acylating reagent in the following study.
and racemation of the products might be caused by those solvents
with high hydrophilic character, such as THF, acetone, or acetoni-
trile (entries 9–11), leading to low E values.
Table 1
Variation of lipase
Table 5
Variation of solvent
Entry
Lipase
Reaction time (h)
% eeE
% eeA
% CHPLC
E
Entry
Solvent
Reaction time (h)
% eeE
% eeA
% CHPLC
E
1
2
3
4
Apf-12
P-30
P-30(LPMO)
PS-30
25
27
27
27
93.1
94.0
96.6
96.6
24.1
16.0
14.0
55.7
21
15
13
37
35.3
38.1
65.9
1
2
3
4
n-hexane
Toluene
CCl4
CHCl3
CHCl3
Et2O
Et2O
i-Pr2O
THF
24
48
25
24
25
48
24
24
49
49
29
27
71.9
95.1
64.8
64.1
87.4
98.2
98.3
91.0
59.7
63.0
85.5
96.6
72.6
72.2
35.7
26.6
45.9
74.5
71.1
85.3
19.0
80.3
13.8
55.7
50
43
36
29
34
43
42
48
24
56
14
37
13.1
87.1
6.6
5.9
23.4
247.7
249.3
57.6
4.8
10.5
14.6
102.6
102.6
5
Reaction conditions: 1 mmol substrate/0.05 g lipase/4 grains of 4A molecular sieves/
5 ml vinyl acetate, 15 ꢀC. eeE and eeA were established by CSP-HPLC. Enantio-
selectivity factor (E) is defined in Ref.
ln[(1ꢁCHPLC)(1þeeA)], where CHPLC¼100ꢂeeA/(eeEþeeA).
6a
7
6
as E¼ln[(1ꢁCHPLC)(1ꢁeeA)]/
8
9
10
11
12
Acetone
Acetonitrile
Vinyl acetate
Table 2
Effect of molecular sieves
Reaction conditions: 1 mmol substrate/0.05 g PS-30/4 grains of MS/5 ml solvent,
2 equiv % vinyl acetate at 15 ꢀC.
Entry Lipase
MS Reaction time (h) % eeE % eeA % CHPLC
E
a
10 ꢀC.
1
2
3
4
P-30(LPMO)
ꢁ
þ
ꢁ
þ
47
27
47
27
91.9
96.6
94.9
96.6
4.8
14.0
42.2
55.7
5
13
31
37
24.9
65.9
57.9
PS-30
102.6
In summary, by the above-mentioned optimization, we could
establish our reaction conditions: in the presence of 4A molecular
sieves, lipase PS-30 as the catalyst, diethyl ether as the solvent, vinyl
acetate as the acylating reagent, 15 ꢀC as the reaction temperature.
Reaction conditions: 1 mmol substrate/0.05 g lipase/5 ml vinyl acetate, 15 ꢀC.
Table 3
Variation of acyl reagent
2.2. Kinetic resolution of cyanohydrins
Entry
Acetate
Reaction time (h)
% eeE
% eeA
% CHPLC
E
1
2
Vinyl
Isopropenyl
48
24
95.1
93.9
72.2
47.8
43
34
87.1
51.1
Under the above optimized reaction conditions, twenty-three
racemic substrates were subjected to the kinetic resolution. Results
were summarized in Table 6–8.
Reaction Conditions: 1 mmol substrate/0.05 g PS-30/4 grains MS/5 ml toluene,
2 equiv% acyl reagent, 15 ꢀC.
2.2.1. Aromatic cyanohydrins. The enantioselectivity of acylation
depends on how strong the interaction between the aromatic ring
of the substrate and the lipase. The interaction is a sum of electronic
and steric ones in nature. Electron-donating substituent (entries 2–
4) favored the interaction electronically, while such favorable effect
might, to some extent, be compromised by their bulky volume. In
the case of electron-withdrawing substituent (entries 5–13), the
interaction was diminished both electronically and sterically. Sim-
ilarly, the substrates with naphthyl group only got moderate E
values (entry 14 and 15) since they could not fit well with the
combining pocket of lipase owing to the larger space demand of the
naphthyl group compared to the phenyl group.
2.1.4. Variation of temperature. As shown in Table 4 (entry 3), 15 ꢀC
appeared to be the most proper reaction temperature to give a high
E value with a reasonable conversion in shorter reaction time. At
lower temperature (0 ꢀC), PS-30 showed low activity, which led to
low E and conversion after a prolonged reaction time. E value was
also low when the reaction temperature was raised to 40 ꢀC, which
might cause decomposition of the substrate and racemation of the
product.
Table 4
Variation of temperature
Specifically, by comparison of the data shown in Table 6, it could
be seen that mandelonitrile, the one with unsubstituted aryl group
(entry 1) gave the highest E value. In the case of the electron-do-
nating substitution, 4-Me group (entry 2) led to the decreasing of E
value because its favorable electronic effect was weaker than its
unfavorable steric effect. 4-MeO- (entry 3) and 4-MeS- (entry 4)
substitution resulted in E values higher than that given by 4-Me
substitution due probably to their stronger electron-donating and
conjugate effects to the aromatic system. However, the larger steric
hindrance of MeS- than that of MeO- made the E value of entry 4
lower than that of entry 3.
Entry
T(ꢀC)
Reaction
time (h)
% eeE
% eeA
% CHPLC
E
1
2
3
4
5
6
0
71
71
48
48
36
36
82.1
96.7
95.1
90.1
90.9
85.9
12.0
44.6
72.2
76.5
55.5
61.7
13
32
43
46
38
42
11.4
94.3
87.1
44.1
36.6
24.8
10
15
20
30
40
Reaction Conditions: 1 mmol substrate/0.05 g PS-30/4 grains MS/5 ml toluene,
2 equiv % vinyl acetate.
Meanwhile, all substrates with electron-withdrawing sub-
stituent gave low E values (entries 5–13). In the case of halogen
substituents, with the increasing electronegativity of the sub-
stituent (Br, 2.8; Cl, 3.0; and F, 4.0),7 the E values dropped down
gradually (135, 123, and 94, entries 8, 11 and 7). However, when
fluoro substitution was on the meta position of the aryl group, the
inductive effect of the substituent appears to be of no much
influence on the E value (228, entry 6). In the case of bromo
substitution, when the substituents were closer to the cyanohydrin
2.1.5. Variation of solvent. As shown in Table 5, both of the highest
enantioselectivity (E¼249) and good conversion (c¼42%) were
obtained with Et2O as solvent at 15 ꢀC in a relative short reaction
time (24 h). Reaction at 10 ꢀC also gave high enantioselectivity
(E¼247) with satisfied conversion (c¼43%), but a longer reaction
time (48 h) was needed (entry 6). When vinyl acetate was used as
both of the acyl donor and solvent (entry 12), moderate enantio-
selectivity (E¼103) was obtained. Decomposition of the substrates

626
Q. Xu et al. / Tetrahedron 66 (2010) 624–630
Table 6
Table 6 (continued)
Enantioselective acetylation of cyanohydrins (1a–o) with vinyl acetate in diethyl
Reaction
time (h)
ether at 15 ꢀC catalyzed by lipase PS-30
Entry
R
eeE (2) (%)
eeA (3) (%)
E
C (%)
16
12
89.3
17.6
21
23
46
F3C
1l
Entry
1
R
eeE (2) (%)
eeA (3) (%)
E
C (%)
42
Reaction
time (h)
13
14
91.4
87.2
1.5
2
48.5
O2N
98.3
71.1
249
24
1a
1m
2
98.3
98.7
97.8
48.6
47.1
74.2
191
244
203
33
32
43
23.5
36.5
21
17
30
25
24
H3C
1b
1c
1d
1n
3
4
29
15
72.8
82.3
54
H3CO
H3CS
1o
45.5
Table 7
Enantioselective acetylation of heteroaromatic cyanohydrins (1p–r) with vinyl
acetate in diethyl ether at 15 ꢀC catalyzed by lipase PS-30
5
6
7
94.3
98.6
92.8
31.3
47.8
93. 6
46
25
33
50
25
27
50
F
1e
Entry
1
R
eeE (2) (%)
eeA (3) (%)
E
C (%)
11
Reaction time (h)
45
228
F
N
54.6
6.5
4
1f
1p
2
3
93.0
93.4
41.5
79.9
41
31
46
21
30
94
O
F
1q
1g
1h
1i
8
96.3
37.4
92.1
95.5
81.3
8.6
135
46
19
38
47
45
S
71.7
Cl
1r
9
2.4
48
group (para- vs meta- vs ortho-), their unfavorable steric effect
showed higher negative influence on the E values (123, 43.3, and
2.4, entry 12, 11 and 10). By comparing the results of entry 5 and
entry 9, it could be seen that the –Br group on ortho position de-
creased the E value much effectively than the –F group because of
the larger steric hindrance of –Br relative to that of –F, even though
–F possesses much higher electronegativity (4.0 vs 2.0 of –Br). This
meant that the steric hindrance of the substituents might affect
more strongly on the E values of products than the inductive effect.
The same conclusion could be made by comparing the results of
entry 8 and entry 11.
Br
10
11
57.3
86.3
43.3
45.5
39.5
Br
Br
1j
123
2.2.2. Heteroaromatic cyanohydrins. The relative low E values given
1k
by the substrates with heterocyclic group (entry 1, 2, and 3 in Table 7)

Q. Xu et al. / Tetrahedron 66 (2010) 624–630
627
Table 8
Enantioselective acetylation of aliphatic cyanohydrins (1s–w) with vinyl acetate in
diethyl ether at 15 ꢀC catalyzed by lipase PS-30
Figure 1.
Entry
1
R
eeE (2) (%) eeA (3) (%)
E
C (%) Reaction time (h)
system as the unacylated alcohol. Configuration of some of the
acylated products and the unreacted alcohols, which were
obtained after the cyanohydrins were converted into the corre-
sponding acetate (2a–2c,3 2e–2g,3 2h,3 2i–2k,2a 2l,9a 2m,9d 2n,3
2o,3 2p,2l 2s,9b 2t,3 2u,3 2v,2i 2w9c) were further proved by
comparison of the observed optical rotations of the obtained
products with those reported in the literatures. Configuration of
compound 2d was proposed to have the same assignment as the
known ones based on the Kazlauskas’ rule. However, in the case
of furyl and thienyl compounds (2q and 2r, entry 18 and 19), the
slow reacting enantiomer was assigned to (S)-configuration by
comparison of the observed optical rotation with the reported
lit.9b, while the fast reacting one to (R)-configuration due to the
Cahn–Ingold–Prolog rule.
97.2
78.8
172 45
35
1s
2
3
94.1
82.6
85 47
20
1t
98.4
40.8
80.7
88.7
314 45
24
20
1u
4
5
6
68
3. Conclusion
8
In this work, we have performed the kinetic resolution of a se-
ries of cyanohydrins with lipase PS-30 as the catalyst. The results
showed that, in the case of aromatic cyanohydrins, where the aryl
group was a phenyl group (or a phenyl group substituted by an
electron-donating group) and in the case of aliphatic cyanohydrins
including cyclohexyl cyanohydrin and those with a short carbon
chain connected with a phenyl group, the system could give high E
values. The influence of the inductive and the steric effects of the
substituents on the phenyl group in the reaction results has also
been examined. The obtained E values showed that a considerable
number of examined cyanohydrins could be resolved to produce
enantiopure forms from preparative purposes.
1v
88.2
84.2
42 49
20
1w
could be owing to the hetero atoms in the aryl ring, which might
weaken the interaction between the substrates and the enzyme. The
particularly low E value given by 2-pyridyl cyanohydrin (entry 1)
reminded us the fact that 2-pyridylcarboxaldehyde gave poor out-
come (40% yield, 0 ee) in the almond hydroxynitrile lyase catalyzed
hydrocyanation.4b
4. Experimental section
4.1. Method and materials
2.2.3. Aliphatic cyanohydrins. Five aliphatic cyanohydrins (acyclic
and cyclic) were tested as the substrates of lipase PS-30 and good
results were observed. Cyclohexyl cyanohydrin (entry 1) gave good
selectivity (E¼172). Those aliphatic cyanohydrins with short carbon
1H NMR spectra were recorded on a Bruker AV-400 (400 MHz)
spectrometer with Me4Si as an internal standard. 19F NMR spectra
were obtained on a Bruker AM-300(282 MHz) spectrometer using
CFCl3 as an external standard; downfield shifts being designated
chain connected to a phenyl group at
b or g position (entries 2 and
3) gave high E values (85 and 314); comparing with the moderate E
value (42, entry 5) of the substrate with short carbon chain con-
as positive, all chemical shifts (d) were expressed in ppm and
coupling constants (J) are in Hertz. Mass spectra were recorded on
a Finnigan-MAT-8430 instrument using EI ionization at 70 eV. IR
spectra were recorded on a Nicolet 380 spectrometer. High-Res-
olution mass spectral analyses were performed on a Finnigan-
MAT-8430 spectrometer. Optical rotations were measured by
WZZ-2 polarimeter. Melting points were measured on a WRS-2A
melting point apparatus. Enantiomeric excess values were
performed by a Breeze LC system (Waters Corporation) on
a Chiralcel OJ-H, OD-H or AD-H column using isopropanol–hex-
anes as mobile phase. All the lipases were purchased from Sigma–
AldrichÔ. All the solvents used in the reaction were purified by
re-distillation. Vinyl acetate and isopropyl acetate were purified
by re-distillation. Other reagents were used as purchased from
commercial suppliers without further purification.
nected to a methyl group at
b position, it could be seen that the
phenyl group on the short carbon chain might exert good influence
to the combination between the substrates and the enzyme. The
poor E value (6) in entry 4 showed the poor interaction of
the substrate with long linear carbon chain and the enzyme.
2.3. Configuration assignment of the fast reacting
enantiomer and the slow reacting enantiomer
According to the rule proposed by Kazlauskas8 (Fig. 1), the –CN
would act as medium-sized group located in the medium-sized
pocket, thus the (S)-enantiomer was favorable to interact with the
lipase leading to the acylated product. Therefore, the (S)-enan-
tiomer was the fast reacting enantiomer, which was isolated from
the reaction mixture as the acylated product, while the (R)-en-
antiomer was the slow reacting one, remaining in the reaction
Racemic cyanohydrins were prepared from various aldehydes
and NaHSO3 and NaCN and the acylated derivatives were prepared
according to known method.5

628
Q. Xu et al. / Tetrahedron 66 (2010) 624–630
4.2. General kinetic resolution experiment
1618, 1538, 1495, 1455, 1365, 1216, 1101, 956, 762; Chiralcel OJ-H,
Hexane/i-PrOH¼98:02, 1.0 ml/min, 254 nm, tR¼22.52 min, tR¼
A 5 ml bake-dried vial charged with lipase PS-30 (0.025 g,
corresponding to 0.5 mmol of the racemic cyanohydrins) and
two grains of 4A molecular sieves was flushed with nitrogen for
several times, the racemic cyanohydrins dissolved in dry Et2O
(1 ml) and vinyl acetate (86 mg, 1 mmol) dissolved in dry Et2O
(1.5 ml) were added. The mixture was stirred at 15 ꢀC and ana-
lyzed by TLC [petroleum ether/ethyl acetate (20:1–3:1)] until
consumption of the starting material was about 50%. The mix-
ture was then filtered and the solid washed with dry acetone
(2 ml). The solvent was evaporated in vacuo and the residue was
purified on silica gel using petroleum ether/ethyl acetate as the
eluent. The unreacted cyanohydrin was acylated for de-
termination of ee value by adding 0.3 ml of an acylating solution
[anhydrous pyridine (5 ml), acetic or propionic anhydride
(1 mmol), and DMAP (1% wt/volume)] to 1 mg of the unreacted
cyanohydrin. Enantiomeric excess was determined for the
obtained acylated products on Chiralcel OJ-H, OD-H or AD-H
column monitored at 220 nm or 254 nm using hexanes/i-propyl
alcohol as the mobile phase. The absolute configuration of the
resolution compounds was obtained by comparison of the ob-
served optical rotations with the literature data.
25.51 min.
4.2.6. (S)-(ꢁ)-Acetoxy-(3-fluoro-phenyl)-acetonitrile (2f)3. Clear oil.
26
[
a
]
ꢁ6.9 (c 0.49, CHCl3), 98.6% ee; 1H NMR (400 Hz, CDCl3)
d 7.47–
D
7.14 (m, 4H), 6.40 (s, 1H), 2.19 (s, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ110.54–ꢁ110.60 (q, J¼7.52 Hz, 1F); MS (EI 70 eV) m/z: 193 (Mþ,
14), 194 (Mþ1, 4), 151 (71), 134 (46), 133 (41), 123 (23), 124 (14), 107
(22), 95 (11), 75 (8), 57 (8), 43 (100); IR (film, cmꢁ1): 2929, 2851,
1755, 1617, 1596, 1490, 1453, 1372, 1270, 1212, 1143, 1026, 894, 868,
792, 690; Chiralcel OJ-H, Hexane/i-PrOH¼95:05, 1.0 ml/min,
220 nm, tR¼29.46 min, tR¼34.85 min.
4.2.7. (S)-(ꢁ)-Acetoxy-(4-fluoro-phenyl)-acetonitrile
(2g)3. Clear
26
oil. [
a]
ꢁ3.5 (c 1.99, CHCl3), 89.8% ee; 1H NMR (400 Hz, CDCl3)
D
d
7.47–7.05 (m, 4H), 6.32 (s, 1H), 2.09 (s, 3H); 19F NMR (376 MHz,
CDCl3)
d
ꢁ109.53–ꢁ109.59 (q, J¼7.52 Hz, 1F); MS (EI 70 eV) m/z:
194 (Mþ1, 4), 193(Mþ, 12), 151(60), 134(85), 133(100), 123(38),
107(29), 95(18), 75(12), 57(19), 43(84); IR(film, cmꢁ1): 2969, 1754,
1607,1512,1423,1372,1216,1161,1024, 963, 834, 789, 567; Chiralcel
OJ-H, Hexane/i-PrOH¼95:05, 0.4 mL/min, 220 nm, tR¼63.46 min,
tR¼66.66 min.
4.2.1. (S)-(ꢁ)-Acetoxy-phenyl-acetonitrile (2a)3. Clear oil. [
a
]
ꢁ5.6
4.2.8. (S)-(þ)-Acetoxy-(4-chloro-phenyl)-acetonitrile
(2h)3. Clear
8.26 (c 0.58, CHCl3), 96.32% ee; 1H NMR (400 Hz, CDCl3)
26
D
20
(c 0.58, CHCl3), 98.3% ee; 1H NMR (400 Hz, CDCl3)
d
7.53–7.51(m,
oil. [a]
D
2H,), 7.49–7.44(m, 3H), 6.41(s, 1H), 2.17(s, 3H); Ms (EI 70 eV) m/z:
176(Mþ1, 31), 175(31), 159(6), 149(32), 133(73), 116(100), 115(61),
105(39), 89(26), 43(69); IR (film, cmꢁ1): 3008, 2925, 1745, 1449,
1370, 1210, 898, 755, 520; HPLC: Chiralcel OD-H, Hexane/i-
PrOH¼99:01, 1.0 ml/min, 254 nm, tR¼12.61 min, tR¼14.15 min.
d 7.49–7.41 (m, 4H), 6.38 (s, 1H), 2.17 (s, 3H); MS (EI 70 eV) m/z: 209
(Mþ, 21), 210 (Mþþ1, 3), 211 (Mþþ2, 7), 167 (81), 168 (8), 169 (27),
149 (88), 150 (81), 151(36), 152 (27), 139 (28), 133 (22), 123 (22), 114
(50), 111 (16), 75 (23), 43 (100); IR(film, cmꢁ1): 2916, 2848, 1749,
1573, 1537, 1464, 1209, 1091, 1019, 803, 720; HPLC: Chiralcel OD-H,
Hexane/i-PrOH¼90:10,
0.7 ml/min,
220 nm,
tR¼11.25 min,
26
4.2.2. (S)-(ꢁ)-Acetoxy-p-tolyl-acetonitrile (2b)3. Clear oil.
[a]
D
tR¼12.51 min.
ꢁ14.6 (c 0.51, CHCl3), 98.3% ee; 1H NMR (400 Hz, CDCl3)
d 7.53–7.03
(m, 4H), 6.44 (s,1H), 3.92 (s, 3H), 2.22(s, 3H); MS (EI 70 eV) m/z: 163
(31), 145 (100), 146 (98), 135(24), 116 (15), 91 (12), 77 (15), 76(13),
43 (23); IR(film, cmꢁ1): 2969, 2917, 2849, 1738, 1652, 1540, 1455,
1365, 1216, 1123, 1032, 798, 527; Chiralcel OD-H, Hexane/i-
PrOH¼95:05, 0.4 ml/min, 220 nm, tR¼28.12 min, tR¼32.36 min.
4.2.9. (S)-(ꢁ)-Acetoxy-(2-bromo-phenyl)-acetonitrile (2i)2a. Clear
24.2
oil. [
d
a
]
ꢁ10.3(c 0.66, CH2Cl2), 37.4%ee; 1H NMR (400 Hz, CDCl3)
D
7.75–7.73 (d, J¼7.68 Hz, 1H), 7.66–7.64 (d, J¼8.0 Hz, 1H), 7.47–7.43
(t, J¼7.6 Hz, 1H), 7.38–7.33 (m, 1H), 6.67 (s, 1H), 2.20(s, 3H); MS (EI
70 eV) m/z: 255 (Mþ1, 2), 253 (Mꢁ1, 2), 213 (16), 211 (17), 196 (19),
194 (19), 174 (60), 132 (91), 115 (28), 114 (56), 43 (100), 44 (23); IR
(film, cmꢁ1): 3068, 2937, 1757, 1580, 1466, 1437, 1372, 1207, 1026,
967, 910, 757, 571; HPLC: Chiralcel OD-H, Hexane/i-PrOH¼90:10,
0.7 ml/min, 220 nm, tR¼10.42 min, tR¼12.58 min.
4.2.3. (S)-(þ)-Acetoxy-(4-methoxy-phenyl)-acetonitrile (2c)3. Clear
26
oil. [
d
a
]
þ6.77 (c 0.69, CHCl3), 98.7% ee; 1H NMR (400 Hz, CDCl3)
D
7.49–7.33 (m, 4H), 6.45 (s, 1H), 2.47 (s, 3H), 2.24 (s, 3H); MS (EI
70 eV) m/z: 205 (Mþ, 1), 189(31), 147 (79), 129 (100), 119 (31), 103
(31), 91 (28), 77 (21), 65(13), 51 (11), 43 (44), 39 (9), 28 (18); IR (film,
cmꢁ1): 2969, 2918, 2849, 1737, 1653, 1540, 1456, 1365, 1216, 1127,
1034, 901, 798, 527; Chiralcel OJ-H, Hexane/i-PrOH¼95:05, 1.0 ml/
min, 220 nm, tR¼20.71 min, tR¼23.04 min.
4.2.10. (S)-(ꢁ)-Acetoxy-(3-bromo-phenyl)-acetonitrile (2j)2a. Clear
22.6
oil. [
d
a]
ꢁ11.3 (c 0.5, CH2Cl2), 92.1% ee; 1H NMR (400 Hz, CDCl3)
D
7.67 (br s, 1H), 7.58 (d, J¼8.0 Hz, 1H), 7.46 (d, J¼8.0 Hz, 1H), 7.33 (t,
J¼7.8 Hz,1H), 7.31(s,1H), 6.37(s,1H), 2.19 (s, 3H); MS (EI 70 eV) m/z:
255(Mþ1, 13), 253(Mꢁ1, 13), 213(29), 211(30), 196(14), 194(15),
132(17), 116(24), 114(48), 88(11), 50(11), 43(100); IR(film, cmꢁ1):
3072, 2937, 1758, 1580, 1474, 1425, 1374, 1207, 1029, 882, 785, 693,
600; HPLC: Chiralcel OD-H, Hexane/i-PrOH¼95:05, 0.8 ml/min,
220 nm, tR¼12.56 min, tR¼14.09 min.
4.2.4. (S)-(þ)-Acetoxy-(4-methylsulfanyl-phenyl)-acetonitrile
26.2
(2d). White solid, mp 67.2–68.2 ꢀC; [
a]
þ35.0 (c 0.88, CHCl3),
D
(97.82% ee); 1H NMR (400 Hz, CDCl3)
d
7.36 (d, J¼8.8 Hz, 2H), 7.22
(d, J¼8.8 Hz, 2H), 6.29(s, 1H), 2.43(s, 3H), 2.08(s, 3H); MS (EI 70 eV)
m/z: 221 (Mþ,72), 222 (Mþ1,12), 223 (Mþ2, 3), 179 (39), 162 (100),
161(95), 160(38), 151(18), 146 (31), 147(24), 132(8), 43(32); HR-EI:
Calcd for: C11H11NO2S, Found: 221.0516; IR(film, cmꢁ1): 2921, 2850,
1753, 1599, 1494, 1437, 1408, 1370, 1212, 1093, 1015, 960, 904, 812,
568; HPLC: Chiralcel OJ-H, Hexane/i-PrOH¼70:30, 0.7 ml/min,
254 nm, tR¼29.21 min, tR¼32.83 min.
4.2.11. (S)-(ꢁ)-Acetoxy-(4-bromo-phenyl)-acetonitrile (2k)2a. Clear
22.8
oil. [
d
a]
ꢁ17.3 (c 0.52, CH2Cl2), 95.5% ee; 1H NMR (400 Hz, CDCl3)
D
7.61–7.58 (d, J¼8.52 Hz, 2H), 7.41–7.38 (d, J¼8.48 Hz, 2H), 6.369 (s,
1H), 2.171 (s, 3H); MS (EI 70 eV) m/z: 255 (Mþ1, 23), 253 (Mꢁ1, 23),
213 (53), 211 (55), 196 (35), 195 (34), 194 (36), 193 (32), 132 (17), 115
(38), 114 (87), 88 (19), 75 (11), 43 (100); IR (film, cmꢁ1): 2925, 2847,
1756, 1589, 1491, 1409, 1368, 1213, 1070, 962, 815; HPLC: Chiralcel
OD-H, Hexane/i-PrOH¼90:10, 0.7 ml/min, 220 nm, tR¼13.77 min,
tR¼16.46 min.
4.2.5. (S)-(ꢁ)-Acetoxy-(2-fluoro-phenyl)-acetonitrile (2e)3. Clear oil.
26
[
d
a
]
ꢁ19.9 (c 0.79, CHCl3), 94.3% ee; 1H NMR (400 Hz, CDCl3)
D
7.58–7.08 (m, 4H), 6.56 (s, 1H), 2.11(s, 3H); 19F NMR (376 MHz,
CDCl3)
167 (10), 166(39), 165(54), 151 (20), 134(68), 133 (28), 123(100),
107(23), 95(18), 75(160), 57(10), 43(45); IR (film, cmꢁ1): 2920,1736,
d
ꢁ116.29–ꢁ116.35(m, 1F); MS (EI 70 eV) m/z: 193 (Mþ, 2),
4.2.12. (S)-(ꢁ)-Acetoxy-(4-trifluoromethyl-phenyl)-acetonitrile
20
(2l)9a. Clear oil. [
a]
D ꢁ4.21 (c 1.91, CHCl3), 89.3% ee; 1H NMR (400 Hz,

Q. Xu et al. / Tetrahedron 66 (2010) 624–630
629
CDCl3)
d
7.722–7.652 (dd, J¼8.4, 27.6 Hz, 4H), 6.470(s,1H), 2.196(s, 3H);
70 eV) m/z: 139 (19), 99 (100), 83 (96), 67 (10), 57 (19), 55 (87), 43
(77), 41 (35); IR (film, cmꢁ1): 2933, 2858, 1755, 1449, 1373, 1221,
1033; Chiralcel OJ-H, Hexane/i-PrOH¼100:0, 0.7 ml/min, 220 nm,
tR¼17.42 min, tR¼20.13 min.
19F NMR (376 MHz, CDCl3)
d
ꢁ62.97 (s, 3F); MS (EI 70 eV) m/z:243(Mþ,
6), 201 (83), 184 (49), 183 (46), 173 (35), 145 (12), 134 (23), 43 (100); IR
(KBr, cmꢁ1): 2945, 1758, 1622, 1420, 1374, 1327, 1215, 1170, 1130, 1068,
1020, 963, 912, 828, 744, 602; HPLC: Chiralcel OD-H, Hexane/i-
PrOH¼90:10, 1.0 ml/min, 220 nm, tR¼8.06 min, tR¼9.48 min.
4.2.20. (S)-(ꢁ)-Acetoxy-3-phenyl-propanenitrile (2t)3. Clear oil.
26
[
d
a
]
ꢁ53.2 (c 0.67, CHCl3), 94.1% ee; 1H NMR (400 Hz, CDCl3)
D
20
4.2.13. (S)-(ꢁ)-Acetoxy-(3-nitro-phenyl)-acetonitrile (2m)9d. [
a
]
7.31–7.19 (m, 5H), 5.41 (t, J¼7.2 Hz, 1H), 3.11 (d, J¼6.8, 2H), 2.04 (s,
D
ꢁ5.6 (c 0.43, CHCl3), 91.4% ee; 1H NMR (400 Hz, CDCl3)
d
8.405–
3H); MS (EI, 70 eV) m/z: 189 (Mþ, 1), 130 (13), 129 (97), 103 (8), 91
(100), 77 (9), 73 (17), 71 (14), 69 (13), 65 (13), 60 (14), 57 (24), 55
(20), 51 (8), 43 (69), 41 (19), 39 (8), 29 (7), 28 (6); IR(film, cmꢁ1):
2969, 2925, 1750, 1650, 1537, 1497, 1455, 1372, 1217, 1091, 1036, 752,
701; Chiralcel OJ-H, Hexane/i-PrOH¼95:05, 0.4 ml/min, 220 nm,
tR¼102.43 min, tR¼122.04 min.
8.330 (m, 2H), 7.890 (d, J¼8.0 Hz, 1H), 7.692 (t, J¼8.0 Hz, 1H), 6.508
(s, 1H), 2.227 (s, 3H); MS (EI 70 eV) m/z: 193 (9), 178 (31), 161 (31),
160 (24), 134 (34), 114 (39), 88 (9), 43 (100); IR (KBr, cmꢁ1): 2917,
2848, 1757, 1576, 1535, 1467, 1430, 1352, 1207, 1091, 1029, 807, 734,
594; HPLC: Chiralcel OJ-H, Hexane/i-PrOH¼70:30, 1.0 ml/min,
254 nm, tR¼46.30 min, tR¼59.09 min.
26
4.2.21. (S)-(ꢁ)-Acetoxv-4-phenyl-butanenitrile (2u)3. Clear oil. [
a]
D
4.2.14. (S)-(ꢁ)-Acetoxy-(1-naphthyl)-acetonitrile (2n)3. Clear oil.
ꢁ27.2 (c 0.7, CHCl3), 98.8% ee; 1H NMR (400 Hz, CDCl3)
d 7.26–7.14
26
[
a]
ꢁ42.6 (c 0.53, CHCl3), 87.2% ee; 1H NMR (400 Hz, CDCl3)
d
8.02
(m, 3H), 7.11(d, J¼7.6, 2H), 5.19(t, J¼6.8,1H), 2.76 (t, J¼7.2, 2H), 2.19–
2.14(q, J¼7.2, 2H), 2.05 (s, 3H); MS (EI, 70 eV) 203 (Mþ, 2),143 (100),
116 (39), 105 (25), 91 (46), 77 (12), 73 (34), 71 (27), 65 (14), 60 (28),
57 (49), 55 (38), 51 (6), 43 (93), 41 (33); IR (film, cmꢁ1): 3015, 2969,
1738, 1434, 1365, 1216, 1092, 896; Chiralcel OD-H, Hexane/i-
PrOH¼95:05, 0.4 ml/min, 220 nm, tR¼44.39 min, tR¼52.58 min.
D
(d, J¼8.4 Hz, 1H), 7.99–7.93 (m, 2H), 7.82 (d, J¼7.2 Hz, 1H), 7.64–7.51
(m, 3H), 7.03 (s, 1H), 2.23 (s, 3H); MS (EI, 70 eV) m/z: 225 (Mþ, 26),
183 (24), 166 (64), 165 (100), 164 (17), 155 (20), 140 (17), 139 (20),
127 (18), 43 (30); IR (film, cmꢁ1): 2926, 2854, 1742, 1441, 1369, 1211,
1091, 1022, 901, 799, 773, 520; Chiralcel OJ-H, Hexane/i-
PrOH¼95:05, 0.4 ml/min, 220 nm, tR¼84.92 min, tR¼94.06 min.
4.2.22. (S)-(ꢁ)-2-Acetyloxy-undecanenitrile (2v)2i. Clear oil. [
a]
D
22.6
4.2.15. (S)-(þ)-Acetoxy-(2-naphthyl)-acetonitrile (2o)3. White sold,
ꢁ15.4 (c 0.51, CHCl3), 40.8% ee; 1H NMR (400 Hz, CDCl3)
d 5.31(t,
þ18.6 (c 0.6, CHCl3), 72.9% ee; 1H NMR
J¼6.8 Hz,1H), 2.13(s, 3H),1.92–1.86 (m, 2H),1.51–1.45 (m, 2H),1.36–
1.27 (m, 12H), 0.88(t, J¼6.8 Hz, 3H); MS (EI, 70 eV) m/z: 226 (Mþþ1,
1), 183 (9), 182 (12), 154 (7), 140 (6), 136 (11), 122 (13), 109 (12), 97
(12), 95 (26), 86 (10), 83 (13), 81 (21), 57 (12), 55 (17), 43 (100), 41
(28); IR (film, cmꢁ1): 2927, 2858, 1756, 1637, 1459, 1375, 1221, 1036;
Chiralcel OJ-H, Hexane/i-PrOH¼100:0, 0.5 ml/min, 220 nm,
tR¼20.08 min, tR¼21.64 min.
26
mp 33.8–34.5 ꢀC; [
a]
D
(400 Hz, CDCl3)
d 7.95(s, 1H), 7.94–7.79 (m, 3H), 750–7.47 (m, 3H),
6.51 (s, 1H), 2.11 (s, 3H); MS (EI, 70 eV) m/z: 225 (Mþ, 42), 183 (95),
166 (70),165 (100),164 (22),155 (19),140 (19),139 (21),127 (22), 43
(27); IR (film, cmꢁ1): 3058, 2925, 2852,1754,1602, 1509,1432,1370,
1214, 1022, 943, 894, 817, 749; Chiralcel OJ-H, Hexane/i-
PrOH¼99:01,1.0 ml/min, 220 nm, tR¼50.76 min, tR¼57.83 min.
4.2.16. (S)-(ꢁ)-Acetoxy-(2-pyridyl)-acetonitrile (2p)2l. Clear oil.
4.2.23. (S)-(ꢁ)-2-Acetoxy-(4-methyl)-pentanenitrile (2w)9c. Clear
22.9
24.2
[
a]
ꢁ10 (c 0.30, CHCl3), 54.6% ee; 1H NMR (400 Hz, CDCl3)
d
8.67
oil. [
a
]
ꢁ64.18 (c 1.7, CHCl3), 88.2% ee; 1H NMR (400 Hz, CDCl3)
D
D
(d, J¼4.8 Hz, 1H), 7.85–7.80(td, J¼1.6, 7.6 Hz, 1H), 7.55 (d, J¼7.6 Hz,
1H), 7.40–7.37 (m, 1H), 6.50(s, 1H), 2.23 (s, 3H); MS (EI, 70 eV) m/z:
176 (Mþ, 3), 134 (100), 117 (14), 106 (15), 90 (14), 79 (72), 78 (28), 51
(14), 43 (70); IR (film, cmꢁ1): 3061, 2925, 2854, 1758, 1590, 1468,
1438, 1372, 1215, 1101, 1049, 996, 967, 907, 776, 618, 571; Chiralcel
AD-H, Hexane/i-PrOH¼95:05, 1.0 ml/min, 254 nm, tR¼14.34 min,
tR¼16.61 min.
d
5.35 (t, J¼7.62, 1H), 2.14 (s, 3H), 1.88–1.76 (m, 3H), 0.98(dd, J¼4.80,
6.40, 6H); MS (EI, 70 eV) m/z: 129 (MþꢁCN,5), 113 (8), 112 (9), 99
(15), 95 (10), 94 (8), 80 (14), 71 (15), 57 (44), 43 (100), 41 (33); IR
(film, cmꢁ1): 2963, 2876, 1756, 1468, 1373, 1221, 1131, 1063, 1029,
931; Chiralcel OJ-H, Hexane/i-PrOH¼100:0, 0.5 ml/min, 220 nm,
tR¼24.85 min, tR¼27.00 min.
Acknowledgements
4.2.17. (R)-(þ)-Acetoxy-(2-furyl)-acetonitrile (2q)9b. Pale yellow oil.
[a] d 7.51
24.2 20.9(c 1.05, CHCl3), 93.0% ee; 1H NMR (400 Hz, CDCl3)
D
We are grateful to The National Natural Science Foundation of
China for financial support (Grant No. 20602007) for financial
support.
(dd, J¼0.68, 1.80 Hz, 1H), 7.69 (d, J¼3.32 Hz, 1H), 6.48 (s, 1H), 6.45
(dd, J¼1.88, 3.36 Hz, 1H), 2.17 (s, 3H); MS (EI, 70 eV) m/z: 165 (Mþ,
38), 123 (57), 106 (100), 105 (36), 95 (14), 78 (18), 77 (52), 68 (5), 51
(24), 43 (77), 28 (25); IR (film, cmꢁ1): 2917, 2849, 1732, 1575, 1539,
1466, 1090, 799; HPLC: Chiralcel AD-H, Hexane/i-PrOH¼95:05,
1.0 ml/min, 220 nm, tR¼7.37 min, tR¼8.32 min.
Supplementary data
Supplementary data includes synthetic procedures of the race-
mic substrates, 1H MNR, 19F NMR spectra, and chiral HPLC chro-
matograms. Supplementary data associated with this article can be
found in online version, at doi:10.1016/j.tet.2009.11.074.
4.2.18. (R)-(þ)-Acetoxy-(2-thienyl)-acetonitrile (2r)9b. Clear oil.
23.2
[
d
a
]
þ11.05 (c 0.51, CHCl3), 93.38% ee; 1H NMR (400 Hz, CDCl3)
D
7.46 (dd, J¼1.02, 5.12 Hz, 1H), 7.36 (dd, J¼0.6, 3.64 Hz, 1H), 7.05
(dd, J¼3.64, 5.12 Hz,1H), 6.64 (s,1H), 2.17 (s, 3H); MS (EI, 70 eV) m/z:
181 (Mþ, 15), 139 (16), 139 (15), 122 (100), 121 (46), 111 (64), 95 (10),
83 (8), 69 (8), 58 (11), 51 (4), 45 (15), 43 (16), 39 (18), 32 (6), 28 (20);
IR(film, cmꢁ1): 3111, 2931, 2853, 1755, 1431, 1371, 1212, 1019, 941,
848, 715; HPLC: Chiralcel OJ-H, Hexane/i-PrOH¼90:10, 1.0 ml/min,
220 nm, tR¼18.38 min, tR¼19.61 min.
References and notes
1. For examples. (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649–3682; (b) Brussee, J.;
Van der Gen, A. In Stereoselective Biocatalysis; Ramesh, N. P., Ed.; Marcel Dekker:
New York, NY, 2000; pp 289–320; (c) Effenberg, F. In Stereoselective Biocatalysis;
Ramesh, N. P., Ed.; Marcel Dekker: New York, NY, 2000; pp 321–342; (d) North,
M. Tetrahedron: Asymmetry 2003, 14, 147–176; (e) Brunel, J.-M.; Holems, I. P.
Angew Chem., Int. Ed. 2004, 43, 2752–2778; (f) Chen, F.-X.; Feng, X. Curr. Org.
Synth. 2006, 3, 77–97; (g) Roberge, C.; Fleitz, F.; Pollard, D.; Devine, P. Tetrahe-
dron: Asymmetry 2007, 18, 208–214; (h) Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.;
Agrawal, S.; Jasra, R. Coord. Chem. Rev. 2008, 252, 593–623; (i) North, M.; Usanov,
4.2.19. (S)-(ꢁ)-Acetoxy-(2-cyclohexyl)-acetonitrile (2s)9b. Clear oil.
22.5
[
d
a
]
ꢁ54.5 (c 0.52, CH2Cl2), 97.2% ee; 1H NMR (400 Hz, CDCl3)
D
5.18 (d, J¼6.0 Hz,1H), 2.15(s, 3H), 1.82(m, 6H),1.24 (m, 5H); MS (EI,

630
Q. Xu et al. / Tetrahedron 66 (2010) 624–630
D. L.; Young, C. Chem. Rev. 2008, 108, 5146–5226; (j) Holt, J.; Hanefeld, U. Curr.
Org. Synth. 2009, 6, 15–37.
4. (a) Han, S.; Chen, P.; Lin, G.; Huang, H.; Li, Z. Tetrahedron: Asymmetry 2001, 12,
843–846; (b) Chen, P.; Han, S.; Lin, G.; Huang, H.; Li, Z. Tetrahedron: Asymmetry
2001, 12, 3273–3279; (c) Chen, P.; Han, S.; Lin, G.; Li, Z. J. Org. Chem. 2002, 67,
8251–8253; (d) Lu, W.; Chen, P.; Lin, G. Tetrahedron 2008, 64, 7822–7827.
5. (a) Ghanem, A.; Schurig, V. Chirality 2001, 13, 118–123; (b) Ghanem, A.; Schurig,
V. Tetrahedron: Asymmetry 2003, 14, 2547–2555.
6. (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299; (b) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L.,
Wilen, S. H., Eds.; John Wiley and Sons: New York, NY, 1988; Vol. 18,
pp 249–330.
2. For examples, (a) van Almsick, A.; Buddrus, J.; Honicke-Schmidt, P.; Laumen, K.;
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1989, 1391–1393; (b) Effenberger,
F.; Gutterer, B.; Ziegler, T.; Eckhardt, E.; Aichholz, R. Liebigs Ann. Chem. 1991,
47–54; (c) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Org. Chem. 1992, 57,
5643–5649; (d) Va¨nttinen, e.; Kanerva, L. T. Tetrahedron: Asymmetry 1995, 6,
1779–1786; (e) Hanefeld, U.; Li, Y.; Sheldon, R. A.; Maschmeyer, T. Synlett 2000,
1775–1776; (f) Veum, L.; Kuster, M.; Telalovic, S.; Hanefeld, U.; Maschmeyer, T.
Eur. J. Org. Chem. 2002, 1516–1522; (g) Paizs, C.; Tahtinen, P.; Lundell, K.; Poppe,
L.; Irimie, F. D.; Kanerva, L. T. Tetrahedron: Asymmetry 2003, 14, 1895–1904; (h)
Levy, L. M.; Gotor, V. J. Org. Chem. 2004, 69, 2601–2602; (i) Veum, L.; Hanefelt,
U. Synlett 2005, 2382–2384; (j) Veum, L.; Kanerva, L. T.; Halling, P. J.; Masch-
meyer, T.; Hanefeld, U. Adv. Synth. Catal. 2005, 347, 1015–1021; (k) Holt, J.;
Arends, I. W. C. E.; Minnaard, A. J.; Hanefeld, U. Adv. Synth. Catal. 2007, 349,
1341–1344; (l) Hamber, A.; Lundgren, S.; Wingstrand, E.; Moberg, C.; Hult, K.
Chem.dEur. J. 2007, 13, 4334–4341; (m) Shen, Z.; Zhou, W.; Liu, Y.; Ji, S.; Loh, T.
Green Chem. 2008, 10, 283–286.
7. Data Taken from Advanced Organic Chemistry; March, J., Ed.; John Wiley & Sons:
New York, NY, 1992; p 15.
8. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
1991, 56, 2656–2665.
9. (a) Sakai, T.; Wang, K.; Ema, T. Tetrahedron 2008, 64, 2178–2183; (b) Schmidt,
´
M.; Herve, S.; Klempier, N.; Griengl, H. Tetrahedron 1996, 52, 7833–7840; (c)
Ohta, H.; Hiraga, S.; Miyamoto, K.; Tsuchihashi, G. Agric. Biol. Chem. 1988, 52,
3023–3027; (d) Yoneda, R.; Santo, K.; Harusawa, S.; Kurihara, T. Synthesis 1986,
1054–1055.
3. Xu, Q.; Geng, X.; Chen, P. Tetrahedron Lett. 2008, 49, 6440–6441.