Enantioselective hydrolysis of various racemic α-substituted arylacetonitriles using Rhodococcus sp. CGMCC 0497

Article abstract of DOI:10.1016/S0957-4166(02)00017-4

The enantioselective hydrolysis of 17 racemic α-substituted arylacetonitriles by Rhodococcus sp. CGMCC 0497 is described. The corresponding (R)-amides and (S)-acids were obtained with excellent enantiomeric excess in most cases. The effect of steric and electronic factors on the outcome of the reactions are discussed here. The results prove that nitrile-converting enzymes are efficient tools for the synthesis of sterically unencumbered chiral α-arylpropionic acids and amides.

Full text of DOI:10.1016/S0957-4166(02)00017-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3305–3312
Enantioselective hydrolysis of various racemic a-substituted
arylacetonitriles using Rhodococcus sp. CGMCC 0497
Zhong-Liu Wu and Zu-Yi Li*
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 12 December 2001; accepted 27 December 2001
Abstract—The enantioselective hydrolysis of 17 racemic a-substituted arylacetonitriles by Rhodococcus sp. CGMCC 0497 is
described. The corresponding (R)-amides and (S)-acids were obtained with excellent enantiomeric excess in most cases. The effect
of steric and electronic factors on the outcome of the reactions are discussed here. The results prove that nitrile-converting
enzymes are efficient tools for the synthesis of sterically unencumbered chiral a-arylpropionic acids and amides. © 2002 Published
by Elsevier Science Ltd.
1. Introduction
We have screened and optimized the culture conditions
for the strain Rhodococcus sp. CGMCC 0497, which
was isolated by our group and proved to have high
nitrile-converting activity and enantioselectivity.5 As an
extension of these findings, we now report the results
obtained in a detailed investigation on the synthetic
usefulness and limitation of this biocatalysts. Herein,
we report a study in which 17 cyano compounds were
hydrolyzed to the corresponding amides and acids
using Rhodococcus sp. CGMCC 0497 as the catalyst.
Excellent enantiomeric excesses were achieved in most
cases.
a-Arylpropionic acids are related to the non steroidal
anti-inflammatory profen drugs. All profens other than
naproxen have been sold as racemic mixtures. However,
the claim that the (S)-(+)-isomer may have advantages
over the racemate has prompted frantic efforts to exam-
ine all profens for racemic switch potential.1
Among enzymatic methods, nitrile-converting enzymes
as well as esterases or lipases can achieve this goal.
However, compared with esterases or lipases, the stud-
ies on nitrile-converting enzymes are relatively few.2
Although studied by a number of groups, the tested
substrates for this class of enzyme are very limited.3
Until now, there has been no detailed report on the
substrate adaptability, which gives an impression that
nitrile-converting enzymes are not a generally accepted
and efficient means for the synthesis of chiral a-arylpro-
pionic acids. In fact, nitrile hydratase has been success-
fully applied in the production of arylamides for many
years,4 which proves that nitrile-converting enzymes
can be powerful tools in organic syntheses. In order to
exploit this potential, we were interested in the study of
nitrile-converting enzymes in detail with regard to their
ability to convert racemic a-substituted arylacetonitriles
to the corresponding chiral amides and acids.
2. Results and discussion
In order to gain meaningful results, we used the fresh
microorganism cultivated under the optimal conditions.
The enantiomeric excesses of amides b and acids c were
determined by means of chiral HPLC or chiral GC
analysis after conversion to the corresponding methyl,
ethyl or isopropyl esters. The configurations of the
products were obtained by comparing the sign of spe-
cific rotations with those reported in the literature. The
recovered nitrile 15a was converted to the correspond-
ing methyl ester by chemical reaction and its configura-
tion was thus assigned by comparing the retention time
of this ester with the samples derived from the corre-
sponding (R)-amide or (S)-acid using chiral HPLC.
The enantiomeric excess of the recovered 15a was deter-
mined directly by chiral HPLC.
* Corresponding author. Tel.: +86-021-64163300-1406; fax: +86-021-
64166128; e-mail: lizy@pub.sioc.ac.cn
0957-4166/01/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00017-4

3306
Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
We first tested 14 nitriles with phenylacetonitrile as the
basic structure bearing variety of substituents at the
benzene ring and the a-position (Scheme 1). As shown
in Table 1, the hydrolysis of all of the nitrile com-
pounds proceeded smoothly and completely. In all
cases, (R)-amides and (S)-acids were obtained and the
total isolated yields of both products reached at least
90%.
Most probably for a similar reason, the position of the
substituent on the benzene ring also plays an important
role on the rate and selectivity of the reaction. As
shown in Table 1, hydrolysis of ortho-substituted 5a
proceeded not only much more slowly than the corre-
sponding meta- and para-substituted substrates, 6a and
7a, but also with a significant reduction in the enan-
tioselectivity. This is also shown in the reaction of 8a
versus 9a and 10a. The Cl atom is relatively small,
hence the yield of acid 8c could reach 46%, while the
methoxy group is much larger and the hydrolysis of
amide 5b to acid 5c was too slow to reach the termina-
tion of resolution.
The influence of the substituent at the a-position (Table
1, entries 1–3) has been reported by Wang et al.6 They
reported incomplete conversion when a bulky and con-
formationally flexible group was introduced. Under our
reaction conditions, the same substrate 3a was
hydrolyzed effectively to the amide as well as 1a and 2a,
but the conversion of amide to acid was rather slow
and prolonged reaction time hardly had any effect. It is
obvious that the significant effect of steric factors still
exists. At the a-position, the larger the substituent is,
the more time was needed to achieve the same yield of
acid. Moreover, a decrease in enantioselectivity was
observed when the substituent was too large, as demon-
strated by the fact that the e.e. of acid 3c was 96%
when the yield was only 14%, while the e.e. values of 1c
and 2c were 96 and 99% and the yields reached 48 and
38%, respectively. The enantiomeric ratio (E) calculated
according to the enantiomeric excess of the acids frac-
tion for entry 1 was 146, for entry 2 was 371, and for
entry 3 was only 57. It can be inferred that substituents
larger than n-Pr will give worse results.
The steric effects of meta-substitution only resulted in a
decrease in the reaction rate but not in enantioselectiv-
ity (Table 1, entries 6 and 9). The e.e. value of the
products were all above 97%, the same level as the
para-substituted ones, while the reaction time was pro-
longed compared with the para-substituted ones.
Except the nitro-substituted cyano compounds, all
para-substituted substrates gave two products with
excellent enantioselectivity of 96% up to 100%, whether
the substituents were electron-donating, such as
methoxy and methyl groups (Table 1, entries 7 and 14)
or electron-withdrawing halogen groups (Table 1,
entries 10–13). The reaction time ranged from 3.5 to 7
h.
Scheme 1.
Table 1. Enantioselective hydrolysis of nitriles with phenylacetonitrile as the basic structure by Rhodococcus sp. CGMCC
0497
Entry
Substrate A
X
R
Time (h)
(R)-Amide b
E.e. (%)
(S)-Acid c
E.e. (%)
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
H
H
H
CH3
Et
3
34
50
5.5
34
10
5
30
12
7
42
50
80
47
65
42
43
45
43
46
45
45
42
47
97a
97a
48
38
14
44
28
49
50
46
48
48
47
46
50
46
96
99
96
90
91
\98
98
55
n-Pr
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
13b
4%-NO2
2%-OMe
3%-OMe
4%-OMe
2%-Cl
3%-Cl
4%-Cl
4%-F
86a
34c
\99c
100d
50a
9
9
\99c
\98a
\99c
\98c
\99c
99c
97
10
11
12
13
14
10
11
12
13
14
\98
\98
96
97
100
4
5
3.5
7
4%-Br
4%-I
4%-CH3
a E.e. values of the corresponding ethyl esters determined by chiral HPLC.
b E.e. values of the corresponding methyl esters determined by chiral GC.
c E.e. values of the corresponding methyl esters determined by chiral HPLC.
d E.e. values of the corresponding isopropyl esters determined by chiral HPLC.

Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
3307
The nitro group is a distinct substituent exerting a
strong electron-withdrawing effect. Treatment of the
supernatant reaction mixture with 2N aq. NaOH
before extraction could cause partial racemization of
the products 4b and 4c, so satd aq. NaHCO3 solution
was used instead, or direct acidification followed by
extraction of both products was carried out. The
result indicated that a strong electron-withdrawing
group may have some unfavorable effect on the enan-
tioselectivity of the enzyme, but not on the activity.
This result is reasonable and can be explained by the
combination of nitrile hydratase and amidase, both of
which are S-selective toward their substrates, 15a and
15b, respectively. When racemic amide 15b was used
as the substrate directly in order to test the amidase
independently, low activity and enantioselectivity was
found (Table 2, entry 3). The yield of acid only
reached 28% within 168 h, but the configuration of
recovered amide was R, in accordance with the reso-
lution rule.
In general, steric effects exerted more influence on the
activity and enantioselectivity of the nitrile-converting
enzymes in Rhodococcus sp. CGMCC 0497 than elec-
tronic effects did. To shed more light on the effects
of steric factors on the course of this reaction, nitriles
15a, 16a and 17a with a naphthene ring as the basic
structure were prepared and subjected to the hydroly-
sis catalyzed by Rhodococcus sp. CGMCC 0497
(Scheme 2). The results listed in Table 2 show that
b-naphthyl substituted cyano compounds 16a and
17a, structurally similar to para- and meta-disubsti-
tuted substrate in Table 1, were hydrolyzed to the
corresponding (R)-amide and (S)-acid completely
though with a little decrease of enantioselectivity
(Table 2, entries 4 and 5). While the a-naphthyl sub-
stituted compound, 15a, which is structurally similar
to the ortho- and meta-disubstituted substrate, could
not be hydrolyzed completely even after 168 h. More-
over, to our surprise, the amide 15b was of the same
configuration as that of the acid 15c. (S)-Amide,
instead of (R)-amide, was generated. Consequently,
the recovered nitrile 15a was confirmed to be of R-
configuration (Table 2, entries 1 and 2).
Thus, with these 17 cyano compounds of different
electronic and steric characteristics studied, we could
infer that our nitrile-converting enzymes from Rhodo-
coccus sp. CGMCC 0497 are effective tools for the
conversion of most a-substituted arylacetonitriles with
relatively low steric hindrance to the correspond-
ing amides and acids with excellent enantiomeric
excess.
Esterification of (S)-(+)-2-(4%-bromophenyl)propanoic
acid 12c and the hydrolyzed product of (R)-(−)-2-(4%-
bromophenyl)propionamide
12b
using
tropine
afforded enantiopure (+)-PG9 and (−)-PG9 with reten-
tion of configuration (Scheme 3), which have been
shown to be potent analgesic and cognition-enhancing
drugs by Gualtier et al.7 The racemic mixture and the
enantiopure compounds have different effects. The
study is far from thorough, partly due to problems in
obtaining sufficient quantities of both enantiomers of
PG9 with satisfactory enantiomeric purity. However,
our study afforded an efficient method to both enan-
tiomers with enantiomeric excess higher than 96%.
Scheme 2.
Table 2. Enantioselective hydrolysis of nitriles and (9)-2-(1%-naphthyl)propionamide 15b with a naphthene ring as the basic
structure by Rhodococcus sp. CGMCC 0497
Entry
Substrate
X
Time (h)
Amide b
E.e. (%)
Acid c
Yield (%)
Yield (%)
E.e. (%)
1a
2b
3
15a
15a
15b
16a
17a
H
H
H
H
96
168
168
24
41
45
65
52
52
90 Sd
63 S
12
16
28
40
43
93 S
48 S
78 S
98 S
99 S
21 R
4
69 Re
75 Re
5c
OMe
32
a (R)-Substrate recovered with a yield of 38% and e.e. of 80%.
b (R)-Substrate recovered with a yield of 25% and e.e. of 98%.
c The product 17c is the famous anti-inflammatory drug (S)-naproxen.
d E.e. values of the corresponding methyl esters determined by chiral HPLC.
e E.e. values of the corresponding ethyl esters determined by chiral HPLC.

3308
Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
Scheme 3. Reagents and conditions: (a) CH2Cl2, HCl; (b) SOCl2, 80°C, 2 h; (c) CHCl3, tropine, 80°C, 8 h.
3. Experimental
3.1. Materials and methods
3.3. General procedure with whole cells
A suspension of washed wet cells (10 g) and aq. potas-
sium phosphate buffer (pH 7.0, 0.1 mM, 40 mL) was
incubated at 30°C for 30 min with continuous magnetic
stirring before the addition of the substrate, a solution
of 2-phenylpropionitrile or 2-phenylpropionamide (100
mg) in tetrahydrofuran (200 mL). The reaction, moni-
tored by thin layer chromatography, was quenched
after a period of time by centrifugation using an
HIMAC centrifuge CR20B2 (Hitachi, Japan) with a
RPR20-4-154 rotor (7800g, 30 min, 20°C), the resulting
supernatant was basified with 2N aq. NaOH to pH 12
(for substrate 4a, satd NaHCO3 solution was used
instead), and extracted with diethyl ether. The organic
solutions, after drying (MgSO4) and concentration,
gave the amide and unreacted nitrile. The separation of
amide and nitrile was effected by column chromatogra-
phy. The aqueous solution was then acidified using 3N
HCl to pH 2 and extracted with diethyl ether. Acid was
obtained after removal of the solvent under reduced
pressure.
The commercially available reagents were used without
further purification. Melting points were determined on
a Mettler FP62 and are uncorrected. H NMR spectra
1
were recorded on a Varian EM 390 (90 MHz), Bruker
AMX-300 (300 MHz), or Bruker AMX-400 (400 MHz)
spectrometer at room temperature with TMS as inter-
nal standard. Chemical shifts in ppm were positive for
upfield shifts. IR spectra were recorded neat or in KBr
and measured in cm−1, using a Shimadzu IR-440 IR
spectrophotometer. EI-MS spectra were recorded on an
HP 5989A. High resolution mass spectra were obtained
on a Finnigan MAT8430. Microanalyses were carried
out on an Italian Carlo-Erba 1106. Polarimetry was
carried out using an optical activity Perkin Elmer
241ML polarimeter and the measurements were made
at the sodium D-line with a 10 cm pathlength cell.
Concentrations (c) are given in g/100 ml. Enantiomeric
excesses: chiral HPLC was conducted with a PE NEL-
SON NCI900 using Chiralcel OJ, OD or Chiralpak AS
columns at a flow rate of 0.7 ml/min with 2-propanol/
hexane as the mobile phase. Chiral GC separations
were conducted with an Rt-bDex column using nitrogen
as the carrier gas.
3.3.1. (R)-(−)-2-Phenylpropionamide 1b. White crystal,
mp 90–91°C lit.:6 90–92°C; [h]D25=−54.7 (c 2.0, CHCl3)
lit.:6 >99% e.e., [h]D25=−53.4 (c 4.13, CHCl3), R, e.e.
97%; 1H NMR (90 MHz, CDCl3): l 7.49 (s, 5H, Ar-H),
5.5 (br s, 2H, NH2), 3.63 (q, 1H, J=8 Hz, CH), 1.55 (d,
3H, J=8 Hz, CH3); IR (KBr): 3056, 3199 (NH2), 1656
(CꢀO) cm−1; EIMS m/z: 150 (M+1+, 3%), 149 (M+, 8),
Racemic nitriles 1a, 8a, 9a, 10a, 14a8 were prepared
following the literature methods but were carried out in
THF at −75°C using t-BuOK as a base. 2a, 3a, 5a, 6a,
7a, 15a, 16a, 17a9 and 4a, 11a, 12a, 13a10 were prepared
following the literature methods.
+
105 (M−CONH2 , 100).
3.3.2. (S)-(+)-2-Phenylpropanoic acid 1c. Colorless oil,
[h]D25=+66.1 (c 1.8, CHCl3) lit.:6 90% e.e., [h]2D5=+61.8
1
Racemic amide 15b was obtained from chemical
hydrolysis of 15a.11
(c 4.27, CHCl3), S, e.e. 96%; H NMR (90 MHz, CCl4):
l 11.4 (s, 1H, COOH), 7.17 (s, 5H, Ar-H), 3.56 (q, 1H,
J=8 Hz, CH), 1.39 (d, 3H, J=8 Hz, CH3); IR (neat):
2870–3110 (br, COOH), 1706 (CꢀO) cm−1; EIMS m/z:
150 (M+, 27%), 105 (M−COOH+, 100).
3.2. Analytical procedure for the determination of enan-
tiomeric excess: general procedure
Amides b in methanol, ethanol or isopropanol were
treated with catalytic conc. sulfuric acid under gentle
reflux for 3 h to yield the corresponding esters. Acids c
in dichloromethane was treated with 1 equiv. of dicy-
clohexylcarbodiimide, 3 equiv. of methanol, ethanol or
isopropanol and catalytic 4-dimethylaminopyridine at
rt for 1 h to achieve the esters and the esters were
subjected to chiral HPLC or GC.
3.3.3. (R)-(−)-2-Phenylbutyramide 2b. White crystal, mp
77–79°C lit.:6 74–76°C; hD26=−55.8 (c 1.8, CHCl3) lit.:6
1
96% e.e., [h]2D5=−56.5 (c 6.99, CHCl3), R, e.e. 97%; H
NMR (90 MHz, CDCl3): l 7.36 (s, 5H, Ar-H), 5.95 (br
s, 2H, NH2), 3.33 (t, 1H, J=8 Hz, CH), 2.46–1.49 (m,
2H, CH2), 0.92 (t, 3H, J=8 Hz, CH3); IR (KBr): 3391,
3175 (NH2), 1653 (CꢀO) cm−1; EIMS m/z: 164 (M+1+,
5%), 163 (M+, 10), 91 (100).

Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
3309
3.3.4. (S)-(+)-2-Phenylbutyric acid 2c. Colorless oil,
[h]D26=+59.9 (c 1.7, CHCl3) lit.:6 >99% e.e., [h]2D5=+61.3
ArH), 3.8 (s, 3H, OCH3), 4.01 (q, 1H, J=7 Hz, CH),
2.43 (d, 3H, J=7 Hz, CH3); IR (KBr): 3050–2750 (br,
OH), 1702 (CꢀO) cm−1; EIMS m/z: 180 (M+, 29%), 135
(M−COOH+, 100).
1
(c 4.97, CHCl3), S, e.e. 99%; H NMR (90 MHz, CCl4):
l 10.62 (s, 1H, COOH), 7.26 (s, 5H, Ar-H), 3.39 (t, 1H,
J=8 Hz, CH), 2.41–1.43 (m, 2H, CH2), 0.93 (t, 3H,
J=8 Hz, CH3); IR (neat): 2865–3110 (OH), 1708 (CꢀO)
cm−1; EIMS m/z: 164 (M+, 27%), 91 (100).
3.3.11. (R)-(−)-2-(3%-Methoxyphenyl)propionamide 6b.
White crystal, mp 97–98°C; [h]1D6=−46.4 (c 1.7, CHCl3),
1
e.e. 99.6%; H NMR (400 MHz, CDCl3): l 7.29–7.25
3.3.5. (R)-(−)-2-Phenylvaleramide 3b. White crystal, mp
78–80°C lit.:6 78–79°C; [h]D23=−11.8 (c 4.0, CHCl3) lit.:6
(m, 1H, Ar-H), 6.91–6.81 (m, 3H, ArH), 5.53 (s, 1H,
NH), 5.35 (s, 1H, NH), 3.81 (s, 3H, OCH3), 3.58 (q,
1H, J=7.2 Hz, CH), 1.52 (d, 3H, J=7.2 Hz, CH3); IR
(KBr): 3265, 3206 (NH2), 1689 (CꢀO) cm−1; EIMS m/z:
1
41% e.e., [h]2D5=+39.9 (c 5.80, CHCl3), S, e.e. 13%; H
NMR (300 MHz, CDCl3): l 7.36–7.24 (m, 5H, Ar-H),
5.67 (br s, 1H, NH), 5.41 (br s, 1H, NH), 3.39 (t, 1H,
J=7.2 Hz, CH), 2.18–2.06 (m, 1H, CH), 1.82–1.70 (m,
1H, CH), 1.34–1.19 (m, 1H, CH2), 0.91 (t, 3H, J=7.3
Hz, CH3); IR (KBr): 3409, 3188 (NH2), 1651 (CꢀO)
cm−1; EIMS m/z: 178 (M+1+, 1%), 177 (M+, 0.3), 91
(100).
180 (M+1+, 18%), 179 (M+, 79), 135 (M−CONH2 ,
+
100). Anal. calcd for C10H13NO2 C, 67.02; H, 7.31; N,
7.81; Found: C, 66.99; H, 7.27; N, 7.74%.
3.3.12. (S)-(+)-2-(3%-Methoxyphenyl)propanoic acid 6c.
Colorless oil, [h]1D6=+60.5 (c 1.9, CHCl3) lit.:13,14 62%
e.e., [h]D=−34 (c, CHCl3), R, 97.5% e.e., [h]D=+62.3 (c
1
3.3.6. (S)-(+)-2-Phenylvaleric acid 3c. Colorless oil,
[h]D23=+54.5 (c 1.0, CHCl3) lit.:6 >99% e.e., [h]2D5=+55.0
1, CHCl3), S, e.e. 98.2%; H NMR (400 MHz, CDCl3):
l 10.39 (br s, 1H, OH), 7.27–7.21 (m, 1H, Ar-H),
691–6.85 (m, 2H, Ar-H), 6.80–6.78 (m, 1H, Ar-H), 3.81
(s, 3H, OCH3), 3.70 (q, 1H, J=7.1 Hz, CH), 1.52 (d,
3H, J=7.1 Hz, CH3); IR (neat): 3050–2850 (br, OH),
1708 (CꢀO) cm−1; EIMS m/z: 180 (M+, 29%), 135
(M−COOH+, 100).
1
(c 1.09, CHCl3), S, e.e. 96.4%; H NMR (300 MHz,
CDCl3): l 7.40–7.22 (m, 5H, Ar-H), 3.54 (t, 1H, J=7.7
Hz, CH), 2.06–2.01 (m, 1H, CH), 1.80–1.72 (m, 1H,
CH), 1.34–1.23 (m, 2H, CH2), 0.91 (t, 3H, J=7.3 Hz,
CH3); IR (neat): 3100–2650 (br, OH), 1706 (CꢀO) cm−1;
EIMS m/z: 178 (M+, 27%), 91 (100).
3.3.13. (R)-(−)-2-(4%-Methoxyphenyl)propionamide 7b.
White crystal, mp 126–127°C; [h]2D5=−83.2 (c 1,
CHCl3), e.e. 100%; 1H NMR (300 MHz, CDCl3): l
7.20–6.85 (AB, 4H, J=8.5 Hz, Ar-H), 6.15 (s, 1H,
NH2), 5.44 (s, 1H, NH2), 3.79 (s, 3H, OCH3), 3.52 (q,
1H, J=7.1 Hz, CH), 1.48 (d, 3H, J=7.1 Hz, CH3); IR
(KBr): 3347, 3170 (NH2), 1662 (CꢀO) cm−1; EIMS m/z:
3.3.7. (R)-(−)-2-(4%-Nitrophenyl)propionamide 4b. Pale
yellow crystal, mp 118–119°C; [h]2D5=−41.0 (c 1.74,
1
CHCl3), e.e. 86%; H NMR (90 MHz, CDCl3): l 7.52,
8.32 (AB, 4H, J=8 Hz, Ar-H), 5.83 (br s, 2H, NH2),
3.72 (q, 1H, J=8 Hz, CH), 1.56 (d, 3H, J=8 Hz, CH3);
IR (KBr): 3455, 3283 (NH2), 3202, 1675 (CꢀO), 1515,
1350 (NO2) cm−1; EIMS m/z: 195 (M+1+, 46%), 151
180 (M+1+, 4%), 179 (M+, 9), 135 (M−CONH2 , 100).
+
+
(M+1−CONH2 , 86), 91 (100).
3.3.14. (S)-(+)-2-(4%-Methoxyphenyl)propanoic acid 7c.
White solid, mp 71–72°C lit.:15 74–77°C; [h]D25=+69.1 (c
2, EtOH) lit.:15 87.3% e.e., [h]2D2=−61.5 (c 1.15, EtOH),
3.3.8. (S)-(+)-2-(4%-Nitrophenyl)propanoic acid 4c. Pale
yellow crystal, mp 96–97°C; [h]2D5=+62.3 (c 1.07,
CHCl3), e.e. 90%; 1H NMR (90 MHz, CCl4): l 10.59 (s,
1H, COOH), 7.47–8.27 (AB, 4H, J=9 Hz, Ar-H), 3.83
(q, 1H, J=8 Hz, CH), 1.59 (d, 3H, J=8 Hz, CH3); IR
(KBr): 2730–3150 (br, OH), 1675 (CꢀO), 1515, 1350
(NO2) cm−1; EIMS m/z: 195 (M+, 24%), 150 (M−
COOH+, 100).
1
R, e.e. 98%; H NMR (300 MHz, CDCl3): l 7.23–6.84
(AB, 4H, J=8.7 Hz, Ar-H), 3.78 (s, 3H, OCH3), 3.68
(q, 1H, J=7.2 Hz, CH), 1.48 (d, 3H, J=7.1 Hz, CH3);
IR (KBr): 3500–2800 (br, OH), 1723 (CꢀO) cm−1;
EIMS m/z: 180 (M+1+, 4%), 179 (M+, 9), 135 (M−
+
CONH2 , 100).
3.3.9. (R)-(−)-2-(2%-Methoxyphenyl)propionamide 5b.
White crystal, mp 134–135°C; [h]2D2=−41.5 (c 1.23,
3.3.15. (R)-(−)-2-(2%-Chlorophenyl)propionamide 8b.
White crystal, mp 121–122°C; [h]1D3=−48.2 (c 1.6,
CHCl3), e.e. 50%; 1H NMR (90 MHz, CDCl3): l
7.71–6.9 (m, 4H, Ar-H), 5.65 (br, s, 2H, NH2), 4.14 (q,
1H, J=7 Hz, CH), 1.52 (d, 3H, J=7 Hz, CH3); IR
(KBr): 3400, 3203 (NH2), 1658 (CꢀO) cm−1; EIMS m/z:
186 (M+3+, 5%), 184 (M+1+, 14), 148 (M−Cl+, 100), 141
(M+2−CONH2 , 13), 139 (M−CONH2 , 34). Anal.
calcd for C9H10ClNO: C, 58.87; H, 5.49; Cl, 19.31; N,
7.63. Found: C, 58.82; H, 5.74; Cl, 19.22; N, 7.53%.
1
CHCl3), e.e. 34.2%; H NMR (300 MHz, CDCl3): l
7.32–7.23 (m, 2H, Ar-H), 6.98 (dd, 1H, J1=J2=7.5 Hz,
ArH), 6.90 (d, 1H, J=8.2 Hz, ArH), 5.66 (s, 2H, NH2),
3.88 (s, 3H, OCH3), 4.04 (q, 1H, J=7.1 Hz, CH), 1.48
(d, 3H, J=7.1 Hz, CH3); IR (KBr): 3393, 3196 (NH2),
1648 (CꢀO) cm−1; EIMS m/z: 179 (M+, 22%), 135
+
+
+
(M−CONH2 , 100). Anal. calcd for C10H13NO2: C,
67.02; H, 7.31; N, 7.81. Found: C, 67.15; H, 7.28; N,
7.81%.
3.3.16. (S)-(+)-2-(2%-Chlorophenyl)propanoic acid 8c.
White solid, mp 85–86°C; [h]1D3=+32.8 (c 1.31, CHCl3),
3.3.10. (S)-(+)-2-(2%-Methoxyphenyl)propanoic acid 5c.
White solid, mp 95–96°C lit.:12 94–95°C; [h]D22=+60.3 (c
0.9, CHCl3) lit.:12 67% e.e., [h]D=−46 (c, CHCl3), R,
1
e.e. 55%; H NMR (90 MHz, CCl4): l 11.33 (s, 1H,
COOH), 7.5–6.9 (m, 4H, Ar-H), 4.25 (q, 1H, J=7 Hz,
CH), 1.53 (d, 3H, J=7 Hz, CH3); IR (KBr): 3050–2650
(br, OH), 1704 (CꢀO) cm−1; EIMS m/z: 186 (M+2+,
1
e.e. 91.4%; H NMR (90 MHz, CCl4): l 10.73 (s, 1H,
COOH), 7.35–7.0 (m, 2H, Ar-H), 7.0–6.65 (m, 2H,

3310
Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
6%), 184 (M+, 16), 149 (M−Cl+, 57), 141 (M+2−
COOH+, 33), 139 (M−COOH+, 100); HRMS (EI) calcd
for C9H9O2Cl: 184.02911, Found 184.02735.
Hz, CH3); IR (KBr): 3150–2780 (br, OH), 1710 (CꢀO)
cm−1; EIMS m/z: 168 (M+, 28%), 123 (M−COOH+,
100).
3.3.17. (R)-(−)-2-(3%-Chlorophenyl)propionamide 9b.
White crystal, mp 98–99°C; [h]1D8.5=−73.3 (c 1.22,
3.3.23. (R)-(−)-2-(4%-Bromophenyl)propionamide 12b.
White crystal, mp 107–108°C; [h]2D2=−53.6 (c 2.0,
CHCl3), e.e. 98.3%; 1H NMR (90 MHz, CDCl3): l 7.16,
7.48 (AB, 4H, J=9 Hz, Ar-H), 5.63 (br s, 2H, NH2),
3.55 (q, 1H, J=7 Hz, CH), 1.47 (d, 3H, J=7 Hz, CH3);
IR (KBr): 3395, 3200 (NH2), 1657 (CꢀO) cm−1; EIMS
m/z: 229 (M+2+, 20%), 227 (M+, 20), 185 (M+2−
CONH2 , 96), 183 (M−CONH2 , 96), 104 (100). Anal.
calcd for C9H10BrNO: C, 47.32; H, 4.42; N, 6.12 Br,
35.03; C10H13NO2. Found: C, 47.50; H, 4.42; Br, 35.20;
N, 6.00%.
1
CHCl3), e.e. 99.2%; H NMR (400 MHz, CDCl3): l
7.33 (s, 1H, Ar-H), 7.29–7.25 (m, 2H, Ar-H), 7.22–7.20
(m, 1H, Ar-H), 5.46 (br, s, 1H, NH), 5.24 (br s, 1H,
NH), 3.57 (q, 1H, J=7.2 Hz, CH), 1.52 (d, 3H, J=7.2
Hz, CH3); IR (KBr): 3351, 3199 (NH2), 1643 (CꢀO)
cm−1; EIMS m/z: 185 (M+2+, 8%), 183 (M+, 22), 142
+
+
+
(32), 141 (37), 140 (97), 139 (M−CONH2 , 86), 105
(100). Anal. calcd for C9H10ClNO: C, 58.87; H, 5.49;
Cl, 19.31; N, 7.63. Found: C, 58.56; H, 5.43; Cl, 19.70;
N, 7.62%.
3.3.24. (S)-(+)-2-(4%-Bromophenyl)propanoic acid 12c.
White solid, mp 88–90°C lit.:17 88–92°C; [h]D22=+46.9 (c
1.5, MeOH) lit.:7a 93.9% e.e. [h]D=+46 (MeOH), S, e.e.
3.3.18. (S)-(+)-2-(3%-Chlorophenyl)propanoic acid 9c.
Colorless oil, [h]D12=+53.9 (c 1.2, CHCl3) lit.:16 81% e.e.,
1
1
[h]2D5=+41.0 (c 1.0, CHCl3), S, e.e. 97.4%; H NMR
96%; H NMR (400 MHz, CDCl3): l 10.75 (br, s, 1H,
(300 MHz, CDCl3): l 11.32 (br s, 1H, OH), 7.24 (s, 1H,
Ar-H), 7.19–7.10 (m, 3H, Ar-H), 3.62 (q, 1H, J=7.2
Hz, CH), 1.46 (d, 3H, J=7.2 Hz, CH3); IR (neat):
3100–2850 (br, OH), 1710 (CꢀO) cm−1; EIMS m/z: 186
(M+2+, 10%), 184 (M+, 30), 149 (M−Cl+, 12.1), 141
(M+2−COOH+, 38), 139 (M+−COOH, 100).
COOH), 7.43, 7.18 (AB, 4H, J=8.5 Hz, Ar-H), 3.66 (q,
1H, J=7.1 Hz, CH), 1.49 (d, 3H, J=7.1 Hz, CH3); IR
(KBr): 3050–2870 (br, OH), 1702 (CꢀO) cm−1; EIMS
m/z: 230 (M+2+, 35%), 228 (M+, 34), 185 (M+2−
COOH+, 98), 183 (M−COOH+, 100), 149 (M−Br+, 4).
3.3.25.
(R)-(−)-2-(4%-Iodophenyl)propionamide
13b.
3.3.19. (R)-(−)-2-(4%-Chlorophenyl)propionamide 10b.
White crystal, mp 101–102°C; [h]1D8=−47.9 (c 1.1,
White crystal, mp 144–145°C; [h]1D6.5=−39.8 (c 0.25,
1
CHCl3), e.e. 99.2%; H NMR (400 MHz, CDCl3): l
1
CHCl3), e.e. 98.5%; H NMR (300 MHz, CDCl3): l
7.68, 7.08 (AB, 4H, J=8.3 Hz, Ar-H), 5.40 (br s, 1H,
NH), 5.30 (br s, 1H, NH), 3.54 (q, 1H, J=7.2 Hz, CH),
1.50 (d, 3H, J=7.2 Hz, CH3); IR (KBr): 3393, 3202
(NH2), 1638 (CꢀO) cm−1; EIMS m/z: 276 (M+1+, 28%),
7.30, 7.25 (AB, 4H, J=8.4 Hz, Ar-H), 5.94 (br, s, 1H,
NH), 5.43 (br, s, 1H, NH), 3.56 (q, 1H, J=7.2 Hz,
CH), 1.47 (d, 3H, J=7.2 Hz, CH3); IR (KBr): 3393,
3220 (NH2), 1654 (CꢀO) cm−1; EIMS m/z: 185 (M+2+,
275 (M+, 44), 231 (M−CONH2 , 100), 148 (M−I+, 6).
+
6%), 184 (M+1+, 6), 183 (M+, 17), 141 (M+2−CONH2 ,
Anal. calcd for C9H10INO: C, 39.30; H, 3.66; I, 46.13;
N, 5.09. Found: C, 39.19; H, 3.60; I, 46.04; N, 4.97%.
+
+
38), 140 (45), 139 (M−CONH2 , 100).
3.3.20. (S)-(+)-2-(4%-Chlorophenyl)propanoic acid 10c.
White solid, mp 77–78°C; [h]1D8=+66.3 (c 0.9, CHCl3),
3.3.26. (S)-(+)-2-(4%-Iodophenyl)propanoic acid 13c.
White crystal, mp 137–138°C lit.:18 139–140°C; [h]1D6.5
=
1
e.e. 98.5%; H NMR (300 MHz, CDCl3): l 7.29, 7.24
+40.8 (c 1.5, CHCl3) lit.:18 96% e.e. [h]D=+39.0 (c 2.45,
1
(AB, 4H, J=8.5, Ar-H), 3.69 (q, 1H, J=7.2 Hz, CH),
1.50 (d, 3H, J=7.2 Hz, CH3); IR (KBr): 3100–2750 (br,
OH), 1704 (CꢀO) cm−1; EIMS m/z: 186 (M+2+, 12%),
184 (M+, 32), 141 (M+2−COOH+, 36), 139 (M−COOH+,
100).
CHCl3), S, e.e. 96.7%; H NMR (400 MHz, CDCl3): l
10.86 (br, s, 1H, COOH), 7.62, 7.05 (AB, 4H, J=8.3
Hz, Ar-H), 3.64 (q, 1H, J=7.1 Hz, CH), 1.48 (d, 3H,
J=7.2 Hz, CH3); IR (KBr): 3084 (br, OH), 1713 (CꢀO)
cm−1; EIMS m/z: 277 (M+1+, 10%), 276 (M+, 75), 232
(12), 231 (M−COOH+, 100).
3.3.21. (R)-(−)-2-(4%-Fluorophenyl)propionamide 11b.
White crystal, mp 103–104°C; [h]1D6=−56.6 (c 1.0,
3.3.27. (R)-(−)-2-(4%-Methylphenyl)propionamide 14b.
White crystal, mp 94–95°C lit.:19 105–106°C; [h]D14=
−46.3 (c 1.6, CHCl3) lit.:19 >95% e.e. [h]D=−49.7 (c
1.14, CHCl3), R, e.e. 98.9%; 1H NMR (400 MHz,
CDCl3): l 7.19, 7.15 (AB, 4H, J=8.1 Hz, Ar-H), 5.69
(br, s, 1H, NH), 5.30 (br, s, 1H, NH), 3.55 (q, 1H,
J=7.2 Hz, CH), 2.33 (s, 3H, CH3), 1.49 (d, 3H, J=7.2
Hz, CH3). IR (KBr): 3355, 3179 (NH2), 1659 (CꢀO)
cm−1; EIMS m/z: 164 (M+1+, 5%), 163 (M+, 12), 120
1
CHCl3), e.e. 99.1%; H NMR (400 MHz, CDCl3): l
7.29–7.25 (m, 2H, Ar-H), 7.04–7.00 (m, 2H, Ar-H), 5.94
(br, s, 1H, NH), 5.42 (br s, 1H, NH), 3.57 (q, 1H,
J=7.2 Hz, CH), 1.49 (d, 3H, J=7.2 Hz, CH3); IR
(KBr): 3353, 3197 (NH2), 1650 (CꢀO) cm−1; EIMS m/z:
168 (M+1+, 36%), 167 (M+, 18), 124 (41), 123 (M−
+
CONH2 , 100). Anal. calcd for C9H10FNO: C, 64.66;
H, 6.03; N, 8.38; F, 11.36. Found: C, 64.68; H, 5.98; N,
8.14; F, 11.46%.
+
(28), 119 (M−CONH2 , 100).
3.3.22. (S)-(+)-2-(4%-Fluorophenyl)propanoic acid 11c.
White solid, mp 51–52°C; [h]1D8=+53.5 (c 0.62, CHCl3),
3.3.28. (S)-(+)-2-(4%-Methylphenyl)propanoic acid 14c.
White solid, mp 67–68°C lit.:19 48–49°C; [h]D14=+66.4 (c
0.71, CHCl3) lit.:19 >95% e.e. [h]D=+66.0 (c 0.7,
1
e.e. 98.4%; H NMR (300 MHz, CDCl3): l 11.20 (br s,
1
1H, OH), 7.24–7.19 (m, 2H, Ar-H), 6.96–6.90 (m, 2H,
Ar-H), 3.61 (q, 1H, J=7.2 Hz, CH), 1.43 (d, 3H, J=7.2
CHCl3), S, e.e. 100%; H NMR (400 MHz, CDCl3): l
11.35 (br s, 1H, OH), 7.16, 7.08 (AB, 4H, J=7.9 Hz,

Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
3311
Ar-H), 3.64 (q, 1H, J=7 Hz, CH), 2.23 (s, 3H, CH3),
1.48 (d, 3H, J=7.1 Hz, CH3); IR (KBr): 3100–2750 (br,
OH), 1703 (CꢀO) cm−1; EIMS m/z: 164 (M+, 25%), 119
(M−COOH+, 100).
3.3.35. (R)–(−)-2-(6%-Methoxy-2%-naphthyl)propionamide
17b. White crystal, mp 174–176°C lit.:21 173–176°C;
[h]2D5=−16.3 (c 1.2, CHCl3) lit.:21 [h]2D5=+20 (c 1,
1
CHCl3, S, e.e. 75%; H NMR (300 MHz, CDCl3): l
7.75–7.68 (m, 4H, Ar-H), 7.41–7.38 (m, 1H, Ar-H),
7.18–7.12 (m, 2H, Ar-H), 5.45 (br s, 1H, NH), 5.34 (br
s, 1H, NH), 3.92 (s, 3H, OMe), 3.74 (q, 1H, J=7.2 Hz,
CH), 1.60 (d, 3H, J=7.2 Hz, CH3); IR (KBr): 3350,
3170 (NH2), 1661 (CꢀO) cm−1; EIMS m/z: 230 (M+1+,
3.3.29. (R)-(+)-2-(1%-Naphthyl)propionitrile (R)-(+)-15a.
Colorless viscous oil, [h]1D5=+48.8 (c 1.25, CHCl3), e.e.
80.3%; 168 h (25%) [h]1D5=+59.6 (c 0.8, CHCl3), e.e.
1
98%; H NMR (300 MHz, CDCl3): l 7.89–7.84 (4H,
8%), 229 (M+, 36), 186 (22), 185 (M−CONH2 , 100).
+
Ar-H), 7.80–7.78 (1H, Ar-H), 7.68–7.66 (1H, Ar-H),
7.56–7.43 (m, 3H, Ar-H), 4.56 (q, 1H, J=7.2 Hz, CH),
1.75 (d, 3H, J=7.2 Hz, CH3); IR (film): 2242 (CN);
EIMS m/z: 182 (M+1+, 10), 181 (M+, 47), 166 (M−CH+3,
100).
3.3.36. (S)-(+)-2-(6%-Methoxy-2%-naphthyl)propanoic acid
17c. White solid, mp 150–152°C lit.:22 155–157°C;
[h]D26=+64.9 (c 1.8, CHCl3) lit.:22 [h]2D5=−67.2 (c 1.096,
1
CHCl3, R, e.e. 99%; H NMR (300 MHz, CDCl3): l
3.3.30. (S)-(+)-2-(1%-Naphthyl)propionamide (S)-(+)-15b.
White crystal, mp 136–138°C lit.:20 133–138°C; [h]D18=
+66.3 (c 1.2, Me2CO/phH 1/1, v/v) e.e. 90.3%; [h]1D8=
+46.9 (c 1.2, Me2CO/phH 1/1, v/v) lit.:20 [h]D25=−74.0 (c
7.72 (d, 3H, J=8.7 Hz, Ar-H), 7.41 (d, 1H, J=8.8 Hz,
Ar-H), 7.14–7.10 (m, 2H, Ar-H), 4.02 (s, 3H, OMe),
3.87 (q, 1H, J=7.1 Hz, CH), 1.6 (d, 3H, J=7.1 Hz,
CH3); IR (KBr): 3196 (br, OH), 1729 (CꢀO) cm−1;
EIMS m/z: 230 (M+, 48%), 185 (M+−COOH, 100).
1
2.073, Me2CO/phH 1/1, v/v), R, e.e. 63.2%; H NMR
(400 MHz, CDCl3): l 8.05 (d, 1H, J=8.2 Hz, Ar-H),
7.88–7.86 (m, 1H, Ar-H), 7.80 (d, 1H, J=8 Hz, Ar-H),
7.56–7.44 (m, 4H, Ar-H), 5.40 (br s, 1H, NH), 5.22 (br
s, 1H, NH), 4.32 (q, 1H, J=7.2 Hz, CH), 1.70 (d, 3H,
J=7.2 Hz, CH3); IR (KBr): 3384, 3197 (NH2), 1656
(CꢀO) cm−1; EIMS m/z: 200 (M+1+, 13%), 199 (M+,
3.4. Esterification of 12c and the hydrolyzed product of
12b using tropine
+
37), 156 (33), 155 (M−CONH2 , 100).
3.4.1. (R)-(−)-Tropanyl 2-(4%-bromophenyl)propionate
(R)-18. The amide 12b (0.2 mmol) was dissolved in
CH2Cl2 (1 mL) and 8N aq. HCl (2 mL) was added. The
mixture was stirred for 8 h at 90°C. The reaction
mixture was poured into water (10 mL) and extracted
with ethyl acetate. The organic solutions, after washing
(satd brine), drying (MgSO4) and concentration, gave
the acid (42 mg, 92%). The reaction of the (R)-acid
sequentially with SOCl2 and tropine7a gave (R)-18. Pale
yellow oil, [h]1D7=−16.5 (c 1.3, EtOH) lit.:7a 90% e.e.,
3.3.31. (R)-(−)-2-(1%-Naphthyl)propionamide (R)-(−)-
15b. [h]1D8=−16.7 (c 1.0, Me2CO/phH 1/1, v/v) e.e.
63.2%,
3.3.32. (S)-(+)-2-(1%-Naphthyl)propanoic acid 15c. White
solid, mp 64–66°C lit.:20 60°C; h1D8=+133.6 (c 0.5,
CHCl3), e.e. 93.2%; 168 h (16%) h1D8=+(c 0.5, CHCl3)
lit.:15 87% e.e., hD25=+125.7 (c 0.35, CHCl3), S, e.e.
1
47.7%; H NMR (400 MHz, CDCl3): l 8.07 (d, 1H,
1
[h]2D0=−14.6 (abs. EtOH), R, e.e. 98.3%; H NMR (300
J=8.5 Hz, Ar-H), 7.83 (d, 1H, J=7.9 Hz, Ar-H), 7.74
(d, 1H, J=8.1 Hz, Ar-H), 7.53–7.41 (m, 4H, Ar-H),
4.51 (q, 1H, J=7.2 Hz, CH), 1.67 (d, 3H, J=7.2 Hz,
CH3); IR (KBr): 2550–3070 (br, COOH), 1702 (CꢀO)
cm−1; EIMS m/z: 200 (M+, 2%), 155 (M−COOH+, 2),
123 (100), 105 (96).
MHz, CDCl3): l 7.45, 7.17 (AB, 4H, J=8.4 Hz, Ar-H),
4.96 (t, 1H, J=5.3 Hz, CHO), 3.61 (q, 1H, J=7.2 Hz,
CH), 3.10 (t, 1H, J=3.3 Hz, CHN), 3.03 (t, 1H, J=3.1
Hz, CHN), 2.26 (s, 3H, NMe), 2.26–2.09 (m, 2H, CH2),
1.86–1.62 (m, 4H, 2CH2), 1.48 (d, 3H, J=7.2 Hz, CH3),
1.36–1.53 (m, 2H, CH2). IR (film): 1729 (CꢀO) cm−1;
EIMS m/z: 353 (M++2, 8%), 351 (M+, 8), 185 (4), 183
(4), 124 (100).
3.3.33. (R)-(−)-2-(2%-Naphthyl)propionamide 16b. White
crystal, mp 141–143°C lit.:20 135–142°C; [h]D25=−22.1 (c
1.6, Me2CO) lit.:20 [h]D25=−31.10 (c 1.045, Me2CO), R,
e.e. 69.3%; 1H NMR (90 MHz, CDCl3): l 7.60–7.98 (m,
4H, Ar-H), 7.30–7.60 (m, 3H, Ar-H), 5.60 (br s, 2H,
NH2), 3.80 (q, 1H, J=8 Hz, CH), 1.60 (d, 3H, J=8 Hz,
CH3); IR (KBr): 3349, 3192 (NH2), 1652 (CꢀO) cm−1;
3.4.2. (S)-(+)-Tropanyl 2-(4%-bromophenyl)propionate
(S)-18. The reaction of (S)-2-(4%-bromophenyl)-
propionate acid sequentially with SOCl2 and tropine7a
gave (S)-18. [h]1D7=+15.3 (c 1.1, EtOH) lit.:7a 94% e.e.,
[h]2D0=+16.0 (abs. EtOH), S, e.e. 96%,
EIMS m/z: 199 (M+, 28%), 156 (25), 155 (M−CONH2 ,
+
100).
3.3.34. (S)-(+)-2-(2%-Naphthyl)propanoic acid 16c. White
solid, mp 140–142°C lit.:20 135–143°C; [h]D26=+65.0 (c
0.65, EtOH) lit.:20 [h]D25=+65.35 (c 0.812, EtOH), S, e.e.
98%; 1H NMR (90 MHz, CDCl3): l 11.09 (s, 1H,
COOH), 7.54–7.91 (m, 4H, Ar-H), 7.07–7.54 (m, 3H,
Ar-H), 3.85 (q, 1H, J=8 Hz, CH), 1.59 (d, 3H, J=8
Hz, CH3); IR (KBr): 2800–3080 (br, COOH), 1698
(CꢀO) cm−1; EIMS m/z: 200 (M+, 44%), 155 (M−
COOH+, 100).
Acknowledgements
We are grateful to the National Science Foundation of
China (Grant No. 20032020) for financial support. We
thank Professor Lijun Xia, Miss ZuoDing Ding and
Miss Xiaowei Dong for performing the chiral HPLC
and chiral GC analysis.

3312
Z.-L. Wu, Z.-Y. Li / Tetrahedron: Asymmetry 12 (2001) 3305–3312
10. Oldenziel, O.; van Leusen, D.; van Leusen, A. M. J. Org.
References
1. Stahly, G. P.; Starrett, R. M. In Chirality in Industry:
Chem. 1977, 42, 3114–3118.
11. Sandler, S. R.; Karo, W. Organic Functional Group
Preparations, 2nd ed.; Academic Press: New York, 1983;
pp. 349–350.
12. Matsumoto, T.; Imai, S.; Minichi, S.; Sugibayashi, H.
Bull. Chem. Soc. Jpn. 1985, 58, 340–345.
Production Methods for Chiral Non-Steroidal Anti-
Inflammatory Profen Drugs; Collins, A. N.; Sheldrake, G.
N.; Crosby, J., Eds.; John Wiley & Sons: New York,
1997; pp. 19–40.
13. Ahmar, M.; Girard, C.; Bloch, R. Tetrahedron Lett. 1989,
30, 7053–7056.
2. Faber, K. Biotransformations in Organic Chemistry: A
Textbook, 4th ed.; Springer: Berlin, 2000.
14. Fadel, A. Synlett 1992, 48–50.
15. Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc.,
Perkin Trans. 1 1983, 1009–1027.
16. Page, P. C. B.; Mckenzie, M. J.; Allin, S. M.; Klair, S. S.
Tetrahedron 1997, 53, 13149–13164.
17. Gualtier, F.; Gualtieri, F.; Conti, G.; Dei, S.; Giovan-
noni, M. P.; Nannucci, F.; Romanelli, M. N.; Scapecchi,
S.; Teodori, E.; Fanfani, L.; Ghelardini, C.; Giotti, A.;
Bartolini, A. J. Med. Chem. 1994, 37, 1704–1711.
18. Hamon, D. P. G.; Massy-Westropp, R. A.; Newton, J. C.
Tetrahedron 1995, 51, 126450–126460.
3. Wieser, M.; Nagasawa, T. In Stereoselective Biocatalysis:
Stereoselective Nitrile-Converting Enzymes; Patel, R. N.,
Ed.; Dekker: New York, 2000; pp. 461–486.
4. (a) Kobayashi, M.; Shimizu, S. Curr. Opin. Chem. Biol.
2000, 4, 95–102; (b) Kobayashi, M.; Nagasawa, T.;
Yamada, H. TIBTECH 1992, 10, 402–408.
5. Wu, Z.-L.; Li, Z.-Y. Biotechnol. Appl. Biochem., accepted
for publication.
6. Wang, M.-X.; Lu, G.; Ji, G.-J.; Huang, Z.-T.; Meth-
Cohn, O.; Colby, J. Tetrahedron: Asymmetry 2000, 11,
1123–1135.
19. Beard, T.; Cohen, M. A.; Parratt, J. S.; Turner, N. J.;
Crosby, J.; Moilliet, J. Tetrahedron: Asymmetry 1993, 4,
1085–1104.
20. Menicagli, R.; Piccolo, O.; Lardicci, L.; Wis, M. L.
Tetrahedron 1979, 35, 1301–1306.
21. Fisher, L. E.; Caroon, J. M.; Stabler, S. R.; Lundberg, S.;
Zaidi, S.; Sorensen, C. M.; Sparacino, M. L.;
Muchowski, J. M. Can. J. Chem. 1994, 72, 142–145.
22. Tsuchihashi, G.; Mitamura, S.; Kitajima, K.; Kobayashi,
K. Tetrahedron Lett. 1982, 23, 5427–5430.
7. (a) Romanelli, M. N.; Bartolini, A.; Bertucci, C.; Dei, S.;
Ghelardini, C.; Giovannini, M. G.; Gualtieri, F.; Pepeu,
G.; Scapecchi, S.; Teodori, E. Chirality 1996, 8, 225–233;
(b) Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Marchese,
V.; Bellucci, C.; Bartolini, A. J. Pharmacol. Exp. Ther.
1998, 284, 806–816.
8. Bailey, W. F.; Jiang, X.-L.; McLeod, C. E. J. Org. Chem.
1995, 60, 7791–7795.
9. Hiyama, T.; Inoue, M.; Saito, K. Synthesis 1986, 645–
647.