Kinetic resolution of tropic acid ethyl ester and its derivatives by lipase PS

Article abstract of DOI:10.1016/j.tetasy.2004.08.013

The first kinetic resolution of tropic acid ethyl ester (TAEE) with lipase PS and vinyl acetate as an acylating agent is reported. The resulting (S)-(-)-3-acetoxy tropic acid ethyl ester and (R)-(+)-tropic acid ethyl ester are produced in high yields and in excellent ee (87-94%). The method has been extended to resolve a variety of tropic acid ester derivatives. In addition, an improved method for the preparation of racemic mixtures of tropic acid ethyl ester and its derivatives from 3-hydroxy-2-phenylacrylic acid ethyl ester using NaBH₄ in methanol is reported. This procedure is better than the previous ones because it is cleaner, safer and can be worked up easily. An improved method of deacylating the chiral 3-acetoxy tropic acid ethyl ester without any loss of stereochemical integrity using HCl/CH₃OH is also reported.

Full text of DOI:10.1016/j.tetasy.2004.08.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3091–3101
Kinetic resolution of tropic acid ethyl ester and its derivatives by
lipase PS
Mary Rose Atuu, Syed J. Mahmood, Frank Laib and M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin–Milwaukee, Milwaukee, WI 53201, USA
Received 21 June 2004; accepted 30 July 2004
Abstract—The first kinetic resolution of tropic acid ethyl ester (TAEE) with lipase PS and vinyl acetate as an acylating agent is
reported. The resulting (S)-(ꢀ)-3-acetoxy tropic acid ethyl ester and (R)-(+)-tropic acid ethyl ester are produced in high yields
and in excellent ee (87–94%). The method has been extended to resolve a variety of tropic acid ester derivatives. In addition, an
improved method for the preparation of racemic mixtures of tropic acid ethyl ester and its derivatives from 3-hydroxy-2-phenyl-
acrylic acid ethyl ester using NaBH4 in methanol is reported. This procedure is better than the previous ones because it is cleaner,
safer and can be worked up easily. An improved method of deacylating the chiral 3-acetoxy tropic acid ethyl ester without any loss
of stereochemical integrity using HCl/CH3OH is also reported.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
resolution of tropic acid using quinine as the resolving
reagent was reported,12 and later, Watson determined
the configuration of natural tropic acid.15 More re-
cently, two methods of synthesizing the (R)-(+)-tropic
acid ester in excellent ee with low yield were pub-
lished.16,17 Until now, the biosynthesis of tropic acid
has been the only means of obtaining the enantiomeri-
cally pure (S)-enantiomer.1,3 Herein, we report the first
lipase-catalyzed kinetic enzymatic resolution of tropic
acid ethyl ester and its derivatives ( )-2a–i in high yields
and with excellent ee (Schemes 1 and 6). As primary
alcohols ( )-2a–i acylation takes place without much
hindrance, making the kinetic resolution procedure is
simple and efficient. We also report a method of synthe-
sizing racemic tropic acid ethyl esters ( )-2a–i that im-
proves on one previously patented by Sletzinger and
Paulsen.13
(S)-(ꢀ)-Tropic acid is an important building block for
biologically active tropane alkaloids, such as hyoscyam-
ine and scopolamine1–3 (Fig. 1). The use of these alka-
loids has its roots in ancient times and they continue
to be valuable drugs in the pharmaceutical field. Scopol-
amine is used as an anesthetic during surgery, for treat-
ment of mental illnesses and as a vomiting inhibitor.4
Hyoscyamine is used to treat cardiacarythmia and is
also as an anesthetic.5–7 Motofen,8 which contains difen-
oxin hydrochloride and atropine sulfate, is used as
adjunctive therapy in the management of acute diarrhea.
Atrovent,9 another commercial drug, is used to treat
chronic bronchitis and emphysema. Furthermore, the
presence of the two functional groups (hydroxyl and
acid) in the tropic acid greatly aids in the further modi-
fication of the molecule, thus permitting several impor-
tant derivatives to be made from this single chiral
building block. As there are many important uses for
chiral tropic acid, an efficient method for synthesizing
this compound is greatly desired.
Enzymatic resolution is a well-investigated area of re-
search in resolving a-hydroxy compounds.16,18–27 How-
ever, not many examples of resolution of b-hydroxy
compounds like tropic acid esters are known. The pres-
ence of the two functional groups (hydroxyl and ester) in
the tropic acid ester greatly aids in the further modifica-
tion of the molecule, thus permitting several important
derivatives to be made from this single building block.
Unlike its a-hydroxy counterpart, protonation of the
hydroxyl group on this b-hydroxy compound does not
destroy the stereogenic center. Furthermore, the acylation
of primary alcohols 2a–i, can easily take place without
Since 1881, several methods have been developed to syn-
thesize the racemic tropic acid, some of which have been
patented.1–3,10–15 In 1919, the first method of chemical
*
Corresponding author. Tel.: +1 414 229 6698; fax: +1 414 229
5530; e-mail: mahmun@uwm.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.013

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M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
CH3
N
H3C
N
O
H
O
H
O
O
HO
O
O
H
H
H
CH2OH
CH2OH
CH2OH
(S)-Tropic acid
Scopolamine
Hyoscyamine
CH(CH3)2
H3C
+
N
H
Br-H2O
O
O
H
CH2OH
®
Atrovent
H3C
N
HO
CN
O
.HCl
H
O
N
H2SO4.H2O
O
H
®
CH2OH
Difenoxin Hydrochloride
®
Atropine Sulfate
Figure 1. Biologically active compounds and drugs derived from (S)-(ꢀ)-tropic acid.
COOEt
CH2OAc
COOEt
CH2OH
COOEt
CH2OH
Lipase PS
+
OCOCH3
(R)-(+)-2a
46% yield, 94% ee
( )-2a
(S)-(-)-3a
molecular sieves
39% yield, 87% ee
5% HCl in MeOH
COOEt
CH2OH
(S)-(-)-2a
87% ee
Scheme 1. Enzymatic kinetic resolution of tropic acid ethyl ester with lipase PS.
much hindrance, thereby making the kinetic resolution
procedure simple and efficient.
2-phenylacrylic acid ethyl ester30 1a–i with sodium boro-
hydride in methanol (Scheme 2; Table 1). The reduction
was performed for 8h at 0–25ꢁC, and the resulting alco-
hol isolated by column chromatography in high yield.
Better yields were obtained with the introduction of elec-
tron-donating substituents (Table 1, entries 1–6). The
yields of the products decrease with electron-withdraw-
ing substituents (Table 1, entries 8 and 9). These results
support the notion that electronic effects rather than
steric effects play the major role in lower product yields.
2. Results and discussion
2.1. Synthesis of the racemic mixtures of tropic acid ethyl
ester and its derivatives ( )-2b–i
The tropic acid ethyl ester, 2a28,29 and its derivatives ( )-
2b–i were easily prepared by the reduction of 3-hydroxy-

M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
3093
Table 2. Summary of the results from the screening of enzymes
Entry Enzyme Percent conversion at
1h 4h 8h 24h
40
COOEt
H
COOEt
CH2OH
1. NaBH4, MeOH
0 oC, 8h
2. H2O, H+
OH
R
R
1
Porcine liver esterase
10
30
30
38
2
Pseudomonas cepacia lipase
Porcine Pancreatic lipase
Candida rugosa lipase
37 ꢁ50 100
R= H, OCH3, CH3, Br, F and Cl
3
25
35 80
25 100
4
Scheme 2. Reduction of 3-hydroxy-2-arylacrylic acid ethyl esters 1a–i
with sodium borohydride.
5
Candida rugosa esterase
Pseudomonas species lipase
ChiroCLEC-CR (dry)
Aspergillus oryzae protease
Candida antarctica ‘B’ lipase
Candida antarctica ‘A’ lipase
Candida lipolytica lipase
Subtilisin carlsberg
20
10
25
25
15
35
30
30
0
90
60
35
34
24
6
7
8
Table 1. Isolated yields of racemic tropic acid ethyl esters from NaBH4
reduction
9
0
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Entry
Substrate
R group
T (ꢁC)
t (h)
%Yield
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
0
0
0
0
0
0
0
0
0
8
8
8
8
8
8
8
8
8
90
95
92
84
80
83
79
74
62
Humicola lanuginosa lipase
Bacillus species protease
alpha-Chymotrypsin
3,5-(OCH3)2
4-OCH3
2,5-(CH3)2
4-CH3
ChiroCLEC-BL (dry)
ChiroCLEC-PC (dry)
Rhiiopus delmar lipase
Rhizopus niveus lipase
Rhizo2us oryzae lipase
5-Br-2-OCH3
4-Br
1g
1h
1i
6-Cl-2-F
4-F
Chromobacterium viscosum lipase NR
Alcaligenes species lipase
Geotricurn candidum lipase
Mucoijavanicus lipase
Mucormeihei lipase
Penicillin acyldse
NR
NR
NR
NR
NR
NR
NR
NR
NR
2.2. Enzymatic acetylation and screening of enzymes.
Lipase-catalyzed acylation of tropic acid ethyl ester
( )-2a
Papain
Aspergillus species protease
PeptiCEC-TR (dry)
Aspergillus niger lipase
2.2.1. Screening of enzymes. Initially, 30 enzymes were
screened to resolve the racemic tropic acid ester. Each of
the reaction mixtures was subjected to similar experi-
mental conditions (solvent, temperature, and time) and
vinyl acetate used as the acylating agent. Each mixture
was monitored at 1, 4, 8, and 24h by TLC and GC.
Of these 30 enzymes, five (porcine liver esterase, Pseudo-
monas cepacia lipase, porcine pancreatic lipase, chiro
CLEC-CR and Candida rugosa esterase) (entries 1–3
and 5–6) were able to resolve the tropic acid ester with
35–50% conversion in a reasonable time of 4–8h
(Table 2).
in the acetic anhydride could have been due to the for-
mation of acetic acid, which may have racemized the
product, as observed in a previous study.31
2.2.3. Determination of the enantiomeric excess of (R)-
(+)-tropic acid ethyl ester (R)-(+)-2a. The ee of (R)-(+)-
tropic acid ethyl ester (R)-(+)-2a was determined by
analysis of the 1H NMR spectrum of its (R)-(ꢀ)-a-meth-
oxyphenyl acetic acid derivative.33 First, racemic tropic
acid ethyl ester ( )-2a was reacted with enantiomerically
pure (R)-(ꢀ)-a-methoxyphenyl carboxylic acid in the
presence of dicyclohexylcarbodiimide (DCC) and 4-
dimethylaminopyridine (DMAP). The reaction was
run in CH2Cl2 at ꢀ20ꢁC for 3h. After work-up, the
1:1 diastereomeric mixture of esters (R,R)-5a and
(S,R)-5a was determined by the 1H NMR spectrum
(Scheme 3). A 1:1 peak area ratio of the methoxyphenyl
ester methine proton peaks of the two diastereoisomers
was observed at 3.720 and 3.385ppm in CDC13 (Fig.
2a).
2.2.2. Enzymatic kinetic resolution with lipase PS. Of
these five enzymes, Pseudomonas cepacia lipase (entry
2), commercially known as lipase PS, was found to be
the best at resolving the tropic acid ethyl ester ( )-2a
(ꢁ50% conversion) at a reasonable rate (4–8h), in high
yields and with excellent % ee. As shown in Scheme 1,
the racemic tropic acid ethyl ester was resolved to pro-
vide (S)-(ꢀ)-3-acetoxy tropic acid ethyl ester 3a in 39%
yield with 87% ee and (R)-(+)-tropic acid ethyl ester 2a
in 42% yield with 94% ee.
For an easier work-up, the enzyme-catalyzed reactions
were performed with a Celite-supported enzyme. The
Celite support aids the ease of separation by filtration
of the enzyme once the reaction is complete. Molecular
sieves were used to enhance the rate and yields of the
product.31,32
Under identical conditions, the chiral (2R)-(+)-tropic
acid ethyl ester 2a isolated from the enzymatic reaction
was treated with (R)-(ꢀ)-a-methoxyphenyl carboxylic
acid 4 (Scheme 3, reaction B). The same two proton
NMR peaks were observed (Fig. 2b) and a 94% ee for
the chiral acid ester (2S,2R)-5a calculated, based on
peak areas.
Lipase PS was found to resolve the tropic acid ester bet-
ter with vinyl acetate (94% ee) than acetic anhydride
(51% ee) as the acylating reagent. The decrease in % ee

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M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
OCH3
H
COOEt
O
OCH3
COOH
O
O
O
COOEt
CH2OH
4
(R,R)-5a
H
a
DCC, DMAP
CH2Cl2, -20 oC, 3h
OCH3
H
COOEt
O
(
)-2a
(S,R)-5a
OCH3
COOEt
COOH
H
4
OCH3
H
COOEt
O
CH2OH
b
DCC, DMAP
(R)-(+)-2a
CH2Cl2, -20 oC, 3h
(R,R)-5a
OCH3
OCH3
H
COOEt
O
COOH
H
COOEt
CH2OH
4
O
c
DCC, DMAP
CH2Cl2, -20 oC, 3h
(S)-(-)-2a
(S,R)-5a
Scheme 3. Synthesis of (R,R)-5a and (S,R)-5a (2-methoxy-2-phenyl-propionic acid 2-phenyl-2-ethoxy carbonyl ethyl ester), that is, diastereoisomers
from racemic and non-racemic tropic acid ethyl esters using chiral derivatizing agent33–37 (Scheme 3 and Fig. 2 have parallel information).
COOEt
CH2OH
S
R
COOEt
CH2OAc
anhydrous HCl
MeOH
(a)
87 % ee
(S)-(-)-2a
(S)-(-)-3a
Scheme 4. Deacylation of (S)-(ꢀ)-3-acetoxy tropic acid ethyl ester
(S)-(ꢀ)-3a.
(b)
(c)
(S)-(ꢀ)-3a, the compound was hydrolyzed to the tropic
acid ethyl ester (S)-(ꢀ)-2a in the presence of anhydrous
HCl in methanol (Scheme 4). The ee of the converted
(S)-(ꢀ)-2a was determined by the derivatization, as pre-
viously described for the (R)-(+)-2a enantiomer, and
was found to be 87% ee (Fig. 2c). Resolution followed
by the deacylation provided the tropic acid ethyl ester
(S)-(ꢀ)-2a in high % ee, which is the building block of
several naturally occurring biologically active com-
pounds (Fig. 1).
3.37
3.38
Figure 2. 1H NMR spectra of diastereomeric mixture of the phenyl-
methoxy ester; (a) reference spectrum of 1:1 diastereomeric mixture of
5a; (b) spectra of the diastereomers obtained from the kinetically
resolved (R)-(+)-2a; (c) diastereomers from (S)-(ꢀ)-2a (which was
obtained from (S)-(ꢀ)-3 after deacylation).
2.3.2. Confirmation of the effectiveness of the acid
hydrolysis. It is reasonable to assume that during the
hydrolysis under acidic conditions, some of the (S)-
(ꢀ)-3-acetoxy tropic acid ethyl ester may have been
2.3. Deacylation of (S)-(ꢀ)-3-acetoxy tropic acid ethyl
ester (S)-(ꢀ)-3a and determination of (S)-(ꢀ)-tropic acid
ethyl ester (S)-(ꢀ)-2a % ee
The use of shift reagents such as Europium tris[3-(trifluoro-
methylhydroxymethylene)-(+)-camphoratel], Praseodymium tris[3-
(heptafluoropropylhydroxymethylene)-(+)-camphorate] and Euro-
pium tris[(heptafluoropropylhydroxymethylene)-(+)-camphorate] to
resolve this ester was unsuccessful.
2.3.1. Determination of ee of (S)-(ꢀ)-3-acetoxy tropic
acid ethyl ester (S)-(ꢀ)-3a. For the determination of
the ee of the (S)-(ꢀ)-3-acetoxy tropic acid ethyl ester

M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
3095
COOEt
CH2OH
COOEt
CH2OAc
HCl/MeOH
COOEt
CH2OH
Acetic Anhydride
DCC, DMAP
(R)-(+)-2a
87% ee
(R)-(+)-3a
(R)-(+)-2a
87% ee
OCH3
COOH
OCH3
COOH
(R)-4
DCC, DMAP
(R)--4
DCC, DMAP
CH2Cl2
CH2Cl2
-10o, 3h
OCH3
-10o, 3h
COOEt
OCH3
COOEt
O
O
H
O
H
O
(R,R)-5a
(R,R)-5a
Scheme 5. Acylation and deacylation reactions.
COOET
CH2OH
arylpropanoic acid ester without any racemization at
the stereogenic center has been found.
COOEt
CH2OH
COOEt
CH2OH
Lipase PS
on celite
+
Selective hydrolysis of (S)-(ꢀ)-3-acetoxy tropic acid
ester 3a to (S)-(ꢀ)-tropic acid ester 2a without any loss
of enantiomeric excess proved to be a real challenge. In
one case, the use of a known method of selective hydrol-
ysis with methanolic potassium carbonate38 (a mild
base) was found to be unsuccessful, yielding only 2-phen-
yl-propenoic acid ester. In another case, there was no
reaction when scandium trifluoromethanesulfonate39
was used for the hydrolysis of the 3-acetoxy tropic acid
ester 3a.
OAc
R
R
R
( )-2b-i
(S)-(-)-3b-i
(R)-(+)-2b-i
molecular sieves,
toluene, rt, 4-6 h
R = OCH3, CH3
Br, F, Cl
Scheme 6. Kinetic resolution of the derivatives of tropic acid ethyl
ester 2b–i.
racemized. In order to determine if any racemization
occurred during the acid hydrolysis (deacylation), the
following control reaction was performed. First, the
optically active (R)-(+)-tropic acid ester 2a with known
% ee was converted to the (R)-(+)-3-acetoxy tropic acid
ethyl ester 3a by reacting (R)-(+)-2a with acetic anhy-
dride in the presence of DCC and DMAP (Scheme
3b). This (R)-(+)-3-acetoxy tropic acid ethyl ester was
then hydrolyzed back to the (R)-(+)-2a in the presence
of 5% HCl in methanol and derivatized to form diaste-
reomer 5a (Scheme 5). The resulting ee of (R)-(+)-tropic
acid ester 2a indicated that no loss of ee occurred during
the hydrolysis reaction (Fig. 3). Consequently, an im-
proved and easy procedure of hydrolyzing the chiral
3-acetoxy-2-arylpropanoic acid ester to 3-hydroxy-2-
2.4. Kinetic resolution of tropic acid ethyl ester derivatives
2b–i
After accomplishing the enzymatic kinetic resolution of
2a, we proceeded to resolve the racemic mixture of the
derivatives 2b–i. Indeed, we obtained (R)-(ꢀ)-2b–i and
(S)-(ꢀ)-3b–i using lipase PS with vinyl acetate as the
acylating agent (Scheme 6). The results of the enzymatic
resolution of the eight compounds, 2b–i are listed in
Table 3.
The substituted compounds bearing electron-donating
substituents gave excellent yields and % ee (entries 1–
5), except for the methyl substituent (entry 6), which
gave good yields but low % ee. The compounds bearing
electron-withdrawing substituent gave high yields of
both products, but only gave moderate enantiomeric
excesses (entries 7–9).
3. Conclusion
3.38
3.38
3.37
3.37
In summary, we have successfully resolved racemic trop-
ic acid ethyl ester and a number of its derivatives by
lipase PS in high yield and excellent % ee. We have also
prepared the derivatives of racemic tropic acid ethyl
Figure 3. 1H NMR spectrum of (a) diastereomeric mixture 5a of
(R)-(+)-2a before acylation; (b) diastereomeric mixture 5a of (R)-
(+)-2a after acylation and deacylation.

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M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
Table 3. Kinetic resolution of the derivatives of tropic acid ethyl ester
Entry
Starting material
R group
(S)-(ꢀ)-3b–i
% Yield
(R)-(+)-2b–i
Product
% Ee
Product
% Yield
% Ee
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
3,5-(OCH3)2
4-OCH3
2,5-(CH3)2
4-CH3
3b
3c
3d
3e
3f
49
ꢁ40
ꢁ30
39
94
98
83
65
81
64
65
50
2b
2c
2d
2e
2f
43
48
94
>99
87
44.5
40.5
41.5
47
50
81
5-Br-2-OCH3
4-Br
42
46
2g
2h
2i
3g
3h
3i
2g
2h
2i
67
67
6-CI-2-F
4-F
31
ꢁ40
38
44
55
ester by using an improved method over the previous
patented one. During our studies, we have developed a
more efficient procedure for deacylating the chiral 3-
acetoxy tropic acid ethyl esters (S)-(ꢀ)-3a–i to the corre-
sponding ethyl esters (S)-(ꢀ)-2a–i with no detectable
loss of ee.
was dissolved in methanol (25mL) and the solution
cooled to 0ꢁC. Sodium borohydride (59.3mg,
1.56mmol) was added slowly over a period of 15min
and the reaction continued to stir at 0ꢁC for 6–8h. After
the solvent was removed under reduced pressure, ether
(20mL) and water (10mL) were added to the viscous,
crude semi-solid. This semi-solid was extracted with
ether (4 · 20mL) and the combined ether extracts
washed with water (20mL), brine (20mL), and then
dried over Na2SO4. After removal of the solvent under
reduced pressure, the oil was purified via column chro-
matography (silica gel, 5–20% ether in pentane) to pro-
vide ( )-2a as a colorless oil (177mg, 0.911mmol, 70%):
1H NMR (CDCl3, 300MHz): d 7.26–7.10 (m, 5H), 4.23
(t, 1H), 4.18, (dd, 1H), 4.14 (q, 2H), 3.85 (m, 1H), 2.71
(s b, 1H), 1.21 (t, 3H, J = 7.14Hz); 13C NMR ketyl.
HPLC grade methanol (EM Science) was distilled under
nitrogen from magnesium iodide. Reagent grade ben-
zene (EM Science) was distilled from (CDC13,
300MHz): d 173.15, 135.55, 128.47, 128.10, 126.57,
64.58, 61.09, 50.65, 14.02.
4. Experimental
4.1. General methods
All the glassware was oven dried and purged with nitro-
gen before use. 1H and 13C NMR spectra were obtained
in CDCl3 on a Bruker 300 or 250MHz NMR spectro-
meter. Chemical shifts are expressed in ppm relative to
tetramethylsilane and CDCl3 was used as the lock
solvent. Optical rotations were recorded on a Jasco
DIP-370 digital polarimeter at 25ꢁC. Mass spectra were
obtained on a Hewlett–Packard 5985B (H/P). GC(FID)
were obtained on a Shimadzu Gas Chromatograph-
2GC-14A. GC/MS system, operated in DIP (direct
insertion probe) CI IE-70eV.
4.2.2. 3-Hydroxy-2-(3,5-dimethoxyphenyl) propionic acid
ethyl ester ( )-2b. Prepared according to the general
procedure described above in Section 4.2.1 for ( )-2a
from 3-hydroxy-2-(3,5-dimethoxyphenyl)-acrylic acid
ethyl ester (250.2mg, 0.991mmol) and sodium borohy-
dride (59.3mg 1.56mmol). The products were separated
by column chromatography on silica gel (5–20% ether/
pentane). Compound ( )-2b was isolated as a tan color
Column chromatography was performed using EM Sci-
ence silica gel 60 (70–230mesh). Thin layer chromatog-
raphy was performed using EM Science F254 silica
gel 60. Celite 521 was obtained from Across Chemicals.
˚
Molecular sieves, 3A, 1–2mm beads was obtained from
Lancaster Synthesis. HPLC grade CH2Cl2 and tetra-
hydrofuran (EM Science) were freshly distilled under a
nitrogen atmosphere from sodium benzophenone so-
dium under nitrogen prior to use. Vinyl acetate and ace-
tic anhydride were obtained from Aldrich Chemical Co.
(R)-(ꢀ)-methoxyphenyl acetic acid, 4-dimethylaminopy-
ridine, (DMAP), and 1,3-dicyclohexylcarbodimime
(DCC) were purchased from Acro Chemicals. Phos-
phate buffer (pH7) was obtained from Fisher Scientific.
Lipase Amano PS was a gift from Amano Chemicals.
Lipase VII was purchased from Aldrich Chemicals.
Chiro-Screen TE kit was purchased from Altus Biolo-
gies Inc. The 3-hydroxy-2-phenylacrylic acid ethyl esters
1a–i were prepared by the method described in the
literature.30
1
oil (240mg, 0.941mmol, 95% yield). H NMR (CDCl3,
300MHz): d 7.30 (s, H), 7.16 (dd, 2H, J = 4.2 and
2.93Hz), 4.54 (t, 1H, J = 9.65Hz), 4.27, (q, 2H,
J = 5.62Hz), 4.14 (dd, 2H, J = 5.0 and 2.2Hz), 3.85 (s,
6H), 2.24 (br s, 1H), 1.25 (t, 3H J = 7.14Hz); 13C
NMR (CDCl3, 300MHz): d 171.62, 162.83, 148.30,
126.65, 126.15, 121.48, 112.99, 110.74, 110.53, 108.16,
60.86, 55.77,14.61; MS (EI, m/z%): 254(M+, 43),
224(100), 195(72), 181(67), 167(30), 151(70), 137(38),
121(64), 139(5), 109(10), 103(6); HRMS (EI, m/z%):
calcd for C13H18O5 [M]+ 254.1154. Observed:
254.1174. Anal. Calcd for C13H18O5: C, 61.41, H, 7.14.
Observed: C, 61.08, H, 6.84.
4.2.3. 3-Hydroxy-2-(4-methoxyphenyl)-propionic acid
ethyl ester ( )-2c.40–42 Prepared according to the gen-
eral procedure described above in Section 4.2.1 for ( )-
2a from 3-hydroxy-2-(4-methoxyphenyl)-acrylic acid
ethyl ester 1c (250.2mg, 1.124mmol) and sodium
borohydride (59.3mg, 1.56mmol). The products were
4.2. Reduction of 3-hydroxy-2-phenylacrylic acid ethyl
ester 1a–i to 2a–i
4.2.1. Tropic acid ethyl ester ( )-2a.28,29 3-Hydroxy-2-
phenylacrylic acid ethyl ester 1a (250mg, 1.30mmol)

M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
3097
separated by column chromatography on silica gel (5–
20% ether/pentane). Compound ( )-2c was isolated as
(dd, 1H, J = 9.6 and 5.3Hz), 4.14 (q, 2H, J = 5.3Hz),
3.85 (dd, 1H, J = 9.9 and 11.5Hz), 2.24 (br s, 1H),
1.24 (t, 3H, J = 7.1Hz); 13CNMR (CDCl3, 300MHz):
d 175, 160, 157, 130, 117, 116, 104, 99, 63, 61, 55,
51, 48, 47, 29, 14: MS (EI, m/z%): 304/302(M+, 31),
274/272(100), 258(6), 245(11), 228/226(60), 213(31),
199(30), 187(23), 185(27), 164(11), 150(60), 134(13),
121(64), 118(340), 1079(17). Anal. Calcd for
C12H15BrO4, 47.54, H, 4.99. Observed: C, 46.88, H,
4.41.
1
a light orange oil (240mg, 1.070mmol, 95% yield). H
NMR (CDCl3, 300MHz): d 7.20 (d, 2H, J = 8.9Hz),
6.89 (d, 2H, J = 8.8Hz), 4.20 (m, 3H), 3.85 (dd, 2H,
J = 5.52 and 10.65Hz), 3.80 (s, 3H, OCH3), 2.18 (br s,
1H), 1.21 (t, 3H, J = 7.14Hz CH3); 13C NMR (CDCl3,
300MHz): d 173.15, 135.55, 128.47, 128.10, 117.21,
126.57, 64.58, 61.09, 50.48, 14.02. HRMS: (EI, m/z%)
224(M+, 24), 194(98), 180(8), 165(99), 151(64),
137(44), 134(16), 121(100), 109(30), 105(14); HRMS:
(EI, m/z%): calcd for C13H18O5 [M]+ 224.1049. Ob-
served: 224.1044.
4.2.7. 3-Hydroxy-2-(4-bromophenyl)-propionic acid ethyl
ester ( )-2g. Prepared according to the general proce-
dure described above in Section 4.2.1 for ( )-2a from
3-hydroxy-2-(4-bromophenyl)-acrylic acid ethyl ester
1g (250.2mg, 1.30mmol) and sodium borohydride
(59.3mg 1.56mmol). The products were separated by
column chromatography on silica gel (5–20% ether/pen-
tane). Compound ( )-2g was isolated as a light yellow
4.2.4. 3-Hydroxy-2-(2,5-dimethylphenyl)-propionic acid
ethyl ester ( )-2d. Prepared according to the general
procedure described above in Section 4.2.1 for ( )-2a
from 3-hydroxy-2-(2,5-dimethylphenyl)-acrylic acid
ethyl ester 1d (250.2mg, 1.30mmol) and sodium borohy-
dride (59.3mg 1.56mmol). The products were separated
by column chromatography on silica gel (5–20% ether/
pentane). Compound ( )-2d was isolated as a colorless
1
oil (199mg, 0.728mmol, 79% yield): H NMR (CDCl3,
300MHz): d 7.26 (d, 2H, J = 5.36Hz), 7.10 (dd, 2H,
J = 8.65Hz), 4.23 (t, 1H), 4.18 (dd, 1H), 4.14 (m, 1H),
3.85 (s, 3H, OCH3), 2.7 (br s, 1H, OH), 1.25 (t, 3H,
J = 7.14Hz); 13C NMR (CDCl3, 300MHz): d 173.10,
137.31, 132.81, 130.34, 129.68, 65.76, 61.02, 53.54,
14.97; MS (EI, m/z%) 272/270(M+, 20), 256/258(5),
242/244(3), 224/226(68.4), 196/198(19), 183/185(100),
170/172(15), 155/153(37), 155/153(37), 89(90), 75/(36),
63(24).
1
oil (190mg, 0.855mmol, 84% yield). H NMR (CDCl3,
300MHz): d 7.26 (dd, 2H, J = 5.4Hz), 7.10 (dd, 2H,
J = 8.7Hz), 4.23 (t, 1H, J = 6.2Hz), 4.18 (dd, 1H),
4.14 (q, 2H, J = 5.3Hz), 3.85 (dd, 1H, J = 5.7Hz), 2.71
(br s, 1H), 1.21 (t, 3H, J = 7.14Hz); 13C NMR (CDCl3,
300MHz): d 173.74, 138.93, 135.89, 129.81, 123.49,
66.47, 65.20, 61.47, 54.33, 52.62, 21.68, 14.51; MS (EI,
m/z%) 222(M+, 21) 222(21), 208(4), 192(80), 178(3),
163(22), 149(28), 146(100), 135(3), 131(20), 119(44),
107(55), 105(27), 137(21), 103(12). Anal. Calcd for
C13H18O3: C, 70.24, H, 8.16. Observed: C, 69.58, H,
8.04.
4.2.8. 3-Hydroxy-2-(2-chloro-6-fluorophenyl)-propionic
acid ethyl ester ( )-2h. Prepared according to the gen-
eral procedure described above in Section 4.2.1 for ( )-
2a from 3-hydroxy-2-(2-chloro-6-fluorophenyl)-acrylic
acid ethyl ester 1h (250.2mg, 1.30mmol) and sodium
borohydride (59.3mg, 1.56mmol). The products were
separated by column chromatography on silica gel (5–
20% ether/pentane). Compound ( )-2h was isolated as
a colorless oil (185mg, 0.756mmol, 74% yield). 1H
NMR (CDCl3, 300MHz): d 7.26 (m, 2H and 1F), 7.10
(m, 1H and 1F), 4.25 (dd, 1H, 1F, J = 4.38 and
8.43Hz), 4.23 (m, 3H), 3.74 (dd, 1H and 1F J = 4.38
and 11.31Hz), 2.71 (br s, 1H), 1.21 (t, 3H,
J = 7.14Hz); 13C NMR (CDCl3, 300MHz): d 172.62,
162.89, 159.59, 135.07, 129.29, 123.10, 114.43, 63.32,
61.71, 46.27, 13.89; MS (EI, m/z%): 246(M+, 1),
228(3), 218(30), 216(100), 188(60), 173/170/(65), 154/
156(50), 143(70), 142(15), 125(50), 109(65), 107(68),
95(5), 83(10), 75(50, 57(5). Anal. Calcd for C11H12-
ClFO3: C, 53.56, H, 4.90. Observed: C, 53.53, H, 4.76.
4.2.5. 3-Hydroxy-2-(4-tolylphenyl)-propionic acid ethyl
ester ( )-2e.41 Prepared according to the general pro-
cedure described above in Section 4.2.1 for ( )-2a from
3-hydroxy-2-(4-methylphenyl)-acrylic acid ethyl ester 1e
(250.2mg, 1.30mmol) and sodium borohydride (59.3mg
1.56mmol). The products were separated by column
chromatography on silica gel (5–20% ether/pentane).
Compound ( )-2e was isolated as a colorless oil
(202mg, 0.970mmol, 80% yield). 1H NMR (CDCl3,
300MHz): d 7.15 (d, 2H, J = 5.4Hz), 7.10 (d, 2H,
J = 8.7Hz), 4.23 (t, 1H, J = 6.2Hz), 4.18 (dd, 1H),
4.14 (q, 2H, J = 5.3Hz), 3.85 (dd, 1H, J = 5.7Hz), 2.71
(br s, 1H), 1.21 (t, 3H, J = 7.14Hz); 13C NMR (CDCl3,
300MHz): d 173.19, 135.89, 129.93, 116.78, 104.22,
65.20, 61.46, 50.29, 48.47, 14.02.
4.2.6.
3-Hydroxy-2-(5-bromo-2-methoxyphenyl)-prop-
4.2.9. 3-Hydroxy-2-(4-fluorophenyl) propionic acid ethyl
ester ( )-2i.43,44 Prepared according to the general
procedure described above in Section 4.2.1 for ( )-2a
from 3-hydroxy-2-(4-fluorophenyl)-acrylic acid ethyl
ester 1i (250.2mg, 1.30mmol) and sodium borohydride
(59.3mg 1.56mmol). The products were separated by
column chromatography on silica gel (5–20% ether/pent-
ane). Compound ( )-2i was isolated as a colorless oil
(156mg, 0.737mmol, 62% yield). 1H NMR (CDCl3,
300MHz): d 7.30 (d, 2H and 1F, J = 5.94 and
10.17Hz), 7.26 (dd, 2H and 1F, J = 8.72 and 5.7Hz),
4.18 (m, 2H), 4.14 (q, 2H, J = 7.12Hz), 3.82 (dd, 1H
ionic acid ethyl ester ( )-2f. Prepared according to
the general procedure described above in Section 4.2.1
for 2a from 3-hydroxy-2-(5-bromo-2-methoxyphenyl)-
acrylic acid ethyl ester 1f (250.2mg, 1.30mmol) and
sodium borohydride (59.3mg, 1.56mmol). The products
were separated by column chromatography on silica gel
(5–20% ether/pentane). Compound ( )-2f was isolated
as a golden oil (199mg, 0.728mmol, 83% yield).
1H NMR (CDCl3, 300MHz): d 7.4 (d, 2H, J = 3.12
and 13Hz), 6.77 (d, 2H, J = 8.7Hz), 4.45 (dd, 1H,
10.78 and J = 12.4Hz), 4.23 (t, 1H, J = 6.2Hz), 4.18

3098
M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
and 1F, J = 3.70Hz), 2.45 (br s, 1H, -OH), 1.23 (t, 3H,
J = 7.14Hz CH3); 13C NMR (CDCl3, 300MHz): d
172.92, 163.80, 160.53, 135.48, 129.61, 115.46, 64.67,
61.11, 52.18, 13.93; MS (EI, m/z%): 212(M+, 8),
198(5), 182(92), 168(21), 165(2), 154(60), 136(48),
121(44), 109(100), 97(38), 91(30), 83(18), 75(12),
57(10), 51(6).
rt and monitored by TLC. At 50% completion, as deter-
mined by TLC, the Celite-supported lipase PS and
molecular sieves were filtered and the remaining solvent
was removed under reduced pressure. The resulting res-
idue was purified via column chromatography (silica gel,
5–10% ether/pentane) to furnish 2a (42mg, 0.216mmol,
42%) and 3a (46mg, 0.195mmol, 37.81%) as colorless
25
D
oils. Compound 2a: ½aꢂ ¼ þ24 (c 2.17, CHCl3),
25
51.3% ee; 3a: ½aꢂ ¼ ꢀ28 (c 1.65, CHCl3), 83% ee.
4.3. Kinetic resolution of racemic tropic acid ethyl
esters 2a
D
4.3.5. Preparation of (R)-(+)-3-acetoxytropic acid ethyl
ester 3a. The (R)-(+)-tropic acid ethyl ester (120mg,
0.62mmol) was dissolved in dichloromethane (15mL),
DCC (130mg, 0.62mmol), DMAP (76mg, 0.62mmol)
and acetic anhydride (0.10mL, 0.93mmol) added to
the reaction mixture. The solution was then stirred for
2–3h at rt, and the solvent removed under reduced pres-
sure. Water (15mL) was then added to the resulting res-
idue and the mixture extracted with diethyl ether
(3 · 15mL). The combined organic phases were washed
with saturated sodium bicarbonate solution, brine and
dried over Na2SO4. The solvent was removed under re-
duced pressure to provide (R)-3a (139mg, 0.589mmol,
96%) as a colorless oil.
4.3.1. Screening of enzymes. Racemic tropic acid ethyl
ester ( )-2a (50mg, 0.258mmol) was dissolved in tolu-
ene (50mL). An aliquot (1mL) of this solution was
added to each of the 30 vials containing different en-
zymes and an aliquot (1mL) of 2a was also added to a
vial without any enzyme to act as the control. Vinyl ace-
tate (two drops) was then added to each vial. All solu-
tion transfers were accomplished using disposable
pipettes and vial caps were immediately replaced after
each addition in order to avoid cross-contamination.
The reaction mixtures were stirred at rt and monitored
for the presence of tropic acid ester and 3-acetoxy tropic
acid ester by TLC and GC at 1, 4, 8, and 24h.
4.3.2. Preparation of lipase PS on Celite support. Celite
521 (0.5g) was washed with distilled water (10mL), fol-
lowed by 0.1M phosphate buffer (10mL, pH7). Lipase
PS (0.17g, activity 3000u/g) was mixed with the Celite
and suspended in 0.1M phosphate buffer (2mL, pH7).
This suspension was allowed to air dry completely at rt.
4.4. Deacylation of (R)-(+)-3-acetoxy tropic acid ester 3a
A sample of (R)-(+)-3-acetoxy tropic acid ester 3a
(52mg, 0.24mmol, 92% ee) was dissolved in dry metha-
nol (5mL) and anhydrous HCl (23mg, 0.631mmol) in
methanol (2.5mL) then added to the solution. The reac-
tion was monitored by TLC and stirred until the starting
material had completely hydrolyzed to tropic acid ethyl
ester (2h at rt). After the solvent was removed under re-
duced pressure, the pale yellow oil was extracted with
diethyl ether (4 · 10mL) and the combined organic
phases washed with water and dried over Na2SO4. The
ether was then removed under reduced pressure to pro-
vide (R)-(+)-2a (45mg, 96% yield, and 92% ee).
4.3.3. Kinetic resolution of racemic tropic acid ethyl ester
using vinyl acetate as the acylating agent. In a 100mL
side-arm round-bottom flask, racemic tropic acid ethyl
ester 2a (100mg, 0.515mmol) was dissolved in freshly
distilled benzene or toluene (15mL). After lipase PS sup-
ported on Celite (1.2g) and the molecular sieves (2g)
were added to the solution, vinyl acetate (0.05mL,
0.62mmol, 1.2equiv) was added. The reaction mixture
was stirred at rt and monitored by TLC or GC. After
about 20min, a second spot appeared and the reaction
was stopped when the intensity of the two spots were al-
most equal (approx. 3–4h at rt). The Celite-supported
enzyme and molecular sieves were then filtered from
the mixture and the solvent was removed under reduced
pressure. The resulting residue was purified via column
chromatography (silica gel, 5–20% ether/pentane) to af-
ford (+)-2a (43mg, 0.222mmol, 43% yield, 94% ee) and
4.5. Determination of enantiomeric excess of chiral
3-hydroxy-2-phenyl-propionic acid ethyl esters 2a–i
and corresponding acetoxy ethyl esters 3a–i
4.5.1. (R)-(+)-Tropic acid ethyl ester (R)-(+)-2a.
A
sample (0.390g, 0.20mmol) of (R)-(+)-2a and di-
cyclohexylcarbodiimide (46mg, 0.20mmol) were added
to a solution of (R)-(ꢀ)-a-methoxyphenyl acetic acid 4
(33mg, 0.20mmol) and 4-dimethylaminopyridine
(0.847mg, 0.04mmol) in methylene chloride (5mL) at
ꢀ10ꢁC. After the mixture was stirred at ꢀ10ꢁC for
3h, the precipitated urea was removed by filtration
and the solvent removed under reduced pressure. The
sample was further dried under vacuum pump and the
1H NMR spectrum of the crude product, which was ob-
tained in CDCl3, indicated a split peak (d 3.43) corre-
sponding to the methine proton of (S)-(ꢀ)-tropic acid
ethyl ester. The integration ratio of these methine
peaks was used to calculate the % ee. The corresponding
1:1 diastereomeric mixture of (R)-(ꢀ)-a-methoxyphe-
nyl ester derivative was prepared from the ( )-2a analo-
gous to the procedure described for the individual
enantiomers.
(ꢀ)-3a (48mg, 203mmol, 39.45% yield, 87% ee) as color-
25
less oils. Compound 2a: ½aꢂ ¼ þ42 (c 0.5, CHCl3); 3a:39
D
25
D
½aꢂ ¼ ꢀ32:5 (c 1.31, CHCl3); 1H NMR (CDCl3,
300MHz): d 7.26–7.20 (m, 5H), 4.71 (t, 1H), 4.52 (dd,
1H), 4.32 (q, 2H), 3.92 (dd, 1H), 2.01 (s, 3H), 1.21 (t,
3H).
4.3.4. Kinetic resolution of racemic tropic acid ethyl ester
using acetic anhydride as the acylating agent. Resolu-
tion was performed using the same procedure previously
described for vinyl acetate. Racemic ( )-2a (100mg,
0.52mmol), lipase PS supported on Celite (0.75g),
molecular sieves (2g) and acetic anhydride (0.04mL.
0.75equiv) were combined. The reaction was stirred at

M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
3099
4.5.2. Enantiomeric excesses of 2b–i. The same proce-
dure as described for compound (R)-(+)-2a was used to
determine the enantiomeric excess of compounds 2b–i.
according to the general procedure as described in Sec-
tion 4.3.3. Compound (R)-(+)-2d was isolated as a color-
less oil (44.5mg, 0.204mmol, 44.5%), 87% ee;
25
½aꢂ ¼ þ45:7 (c 0.25, CHCl3); same spectroscopic char-
D
acteristics as of the racemic one (Section 4.1.4). Com-
4.5.3. Enantiomeric excesses of (S)-(ꢀ)-3a–i. All
acetoxy propanoic acid esters were converted to corre-
sponding hydroxy phenyl propanoic acid ethyl esters
(S)-(ꢀ)-2a–i and the % ee determined by derivatization
with (R)-(ꢀ)-a-methoxyphenyl acetic acid using the
same procedure as described above in Section 4.5.1 for
(R)-(+)-2a.
pound (S)-(ꢀ)-3d was isolated as light yellow oil
25
(71mg, 0.269mmol, 30%); 83% ee, ½aꢂ ¼ ꢀ30:5 (c
D
1.35, CHCl3); 1H NMR (CDCl3, 300MHz): d 7.26–
7.20 (m, 3H), 4.61 (t, 1H, J = 9.42 and 10.89Hz), 4.34
(dd, 1H, J = 5.7 and 10.81Hz), 4.21 (m, 2H), 3.92 (dd,
1H, J = 5.6 and 9.41Hz), 2.32 (s, 6H), 2.01 (s, 3H,
COCH3), 1.21 (t, 3H, J = 7.1Hz); 13C NMR (CDCl3)
300MHz): d 173.19, 160.45, 138.91, 135.89, 129.93,
123.49, 116.78, 104.22, 65.20, 61.46, 54.34, 50.29,
48.47, 29.68, 14.02.
4.6. Enzymatic kinetic resolution reactions 2b–i and 3b–i
4.6.1. (R)-(+)-3-Hydroxy-2-(3,5-dimethoxyphenyl)-propi-
onic acid ethyl ester (R)-(+)-2b and (S)-(ꢀ)-3-acetoxy-2-
(3,5-dimethoxyphenyl)-propionic acid ethyl ester (S)-(ꢀ)-
3b. Racemic ( )-2b (100mg, 0.393mmol) was resolved
according to the general procedure as described in Sec-
tion 4.3.3. Compound (R)-(+)-2b was isolated as a light
4.6.4. (R)-(+)-3-Hydroxy-2-(4-methylphenyl)-propionic
acid ethyl ester (R)-(+)-2e and (S)-(ꢀ)-3-acetoxy-2-(4-
methylphenyl)-propionic acid ethyl ester (S)-(ꢀ)-
3e. Racemic ( )-3e (l00mg, 0.48mmol) was resolved
accordingly to the general procedure as described in Sec-
tion 4.3.3. Compound (R)-(+)-2e41 was isolated as a col-
yellow-brown oil (49mg, 0.204mmol, 49.0%), 94%;
25
D
teristics as of the racemic one (Section 4.1.2).
½aꢂ ¼ þ38:7 (c 1.5, CHCl3); same spectroscopic charac-
orless oil (40.5mg, 0.194mmol, 40.5%) 50% ee;
25
D
acteristics as that of the racemic one (Section 4.1.5).
Compound (S)-(ꢀ)-3b was isolated as a light yellow
½aꢂ ¼ þ27:8 (c 2.11, CHCl3) same spectroscopic char-
oil (50.05mg, 0.169mmol, 43.3%); 94% ee,
25
D
½aꢂ ¼ ꢀ32:5 (c 1.01, CHCl3); 1H NMR (CDCl3,
The (S)-(ꢀ)-3e was isolated as a colorless oil (47mg,
25
D
300MHz): d 7.26–7.20 (m, 3H), 4.59 (t, 1H, J = 10.9
and 9.5Hz), 4.35, (dd, 1H, J = 10.89 and 5.7Hz), 4.22,
(dd, 1H, J = 7.14Hz), 3.92 (dd, 1H, J = 9.5 and
5.7Hz), 3.85 (s, 6H), 2.01 (s, 3H, COCH3), 1.21 (t, 3H,
J = 7.14Hz); 13C NMR (CDCl3, 300MHz): d 171.65,
170.60, 149.02, 148.66, 127.24, 120.29, 111.19, 110.90,
65.18, 61.03, 55.80, 55.82, 50.16, 20.75, 14.02. (EI, m/
z%): 296(M+, 8), 237(21), 236(100), 223(16), 195(10),
181(9), 163(17), 151(13), 139(5), 119(5), 107(3), 91(5),
77(7), 51(1).
0.188mmol, 39.1%); 65% ee, ½aꢂ ¼ ꢀ31:8 (c 1.31,
1
CHCl3); H NMR (CDCl3, 300MHz): d 7.26–7.20 (m,
5H, J = 6.24Hz), 4.71 (t, 1H, J = 6.23Hz), 4.52, (dd,
1H, J = 6.24Hz), 4.32 (q, 2H, J = 5.72Hz), 3.92 (dd,
1H, J = 5.60Hz), 2.01 (s, 3H), 1.21 (t, 3H,
J = 7.12Hz); 13C NMR (CDCl3, 300MHz): d 173.19,
160.45, 135.89, 129.93, 116.78, 104.22, 65.20, 61.46,
50.29, 48.47, 29.68, 14.02. MS (EI, m/z %): 250(M+,
3), 205(4), 190(100), 176(83), 164(11), 150(17), 146(66),
132(40), 117(98), 105(49), 91(54), 77(41), 65(17), 51(12).
4.6.2. (R)-(+)-3-Hydroxy-2-(4-methoxyphenyl)-propionic
acid ethyl ester (R)-(+)-2c and (S)-(ꢀ)-3-acetoxy-2-(4-
methoxphenyl)-propionic acid ethyl ester (S)-(ꢀ)-
3c. Racemic ( )-2c (100mg, 0.45mmol) was resolved
according to the general procedure as described in Sec-
tion 4.3.3. Compound (R)-(+)-2c42 was isolated as a
4.6.5. (R)-(+)-3-Hydroxy-2-(5-bromo-2-methoxyphenyl)-
propionic acid ethyl ester (R)-(+)-2f and (S)-(ꢀ)-3-acet-
oxy-2-(5-bromo-2-methoxyphenyl)-propionic acid ethyl
ester (S)-(ꢀ)-3f. Racemic ( )-2f (100mg, 0.33mmol)
was resolved according to the general procedure as de-
scribed in Section 4.3.3. Compound (R)-(+)-2f was iso-
light brown oil (48mg, 0.214mmol, 48%), >99% ee;
½aꢂ ¼ þ44:2 (c 2.44, CHCl3); same spectroscopic char-
lated as a light brown oil (41.5mg, 0.137mmol,
41.5%), 81% ee; ½aꢂ ¼ þ38:7 (c 1.5, CHCl3); same
25
D
acteristics as of the racemic one (Section 4.1.3.). The (S)-
25
D
spectroscopic characteristics as of the racemic one (Sec-
(ꢀ)-3c42 was isolated as colorless oil (47.4mg,
tion 4.1.6). (S)-(ꢀ)-3f was isolated an a light brown oil
25
D
25
D
0.178mmol, 39.9%); 98% ee, ½aꢂ ¼ ꢀ38:2 (c 1.20,
(48mg, 0.139mmol, 42.2%); 81% ee, ½aꢂ ¼ ꢀ28:5
1
1
CHCl3); H NMR (CDCl3, 300MHz): d 7.26–7.20 (m,
4H,), 4.71 (t, 1H, J = 9.45 and 10.86Hz), 4.52, (dd,
1H, J = 5.76 and 10.89Hz), 4.32 (m, 2H), 3.92 (dd,
1H, J = 5.64 and 9.40Hz), 3.80 (s, 3H, OCH3), 2.01 (s,
3H, COCH3), 1.21 (t, 3H, J = 7.14Hz CH3). 13C
NMR (CDCl3, 300MHz): d 173.41, 168.08, 159.09,
129.68, 128.99, 114.12, 113.18, 66.11, 55.08, 47.54,
29.28, 14.30. MS (EI, m/z%): 266(M+, 6) 221(1),
205(17), 206(100), 193(23), 165(33), 162(27), 151(29),
137(19), 133(66), 121(37), 109(7), 105(4).
(c 1.62, CHCl3); H NMR (CDCl3, 300MHz): d 7.26–
7.20 (m, 3H), 4.45 (dd 1H, 10.78 and J = 12.44) 4.23
(t, 1H, J = 6.21Hz), 4.18 (dd, 1H J = 9.63 and
5.34Hz), 4.14 (m, 2H), 3.85 (dd, 1H, J = 9.91 and
11.53Hz), 2.24 (br s, 1H), 1.24 (t, 3H, J = 7.141Hz);
13C NMR (CDCl3, 300MHz):
d 175.23, 160.17,
157.35, 130.43, 117.27, 116.35, 104.45, 99.19, 63.38,
61.04, 55.70, 51.04, 48.23, 47.47, 29.23, 14.31. HRMS
(EI, m/z%): calcd for C14H7BrO5 [M]+ 346.0238/
344.0259. Observed: 346.0243/344.0259.
4.6.3. (R)-(+)-3-Hydroxy-2-(2,5-dimethylphenyl)-tropic
acid ethyl ester (R)-(+)-2d and (S)-(ꢀ)-3-acetoxy-2-(2,5-
dimethylphenyl)-propionic acid ethyl ester (S)-(ꢀ)-
3d. Racemic ( )-2d (100mg, 0.38mmol) was resolved
4.6.6. (R)-(+)-3-Hydroxy-2-(4-bromophenyl)-propionic
acid ethyl ester (R)-(+)-2g and (S)-(ꢀ)-3-acetoxy-2-(4-
bromophenyl)-propionic acid ethyl ester (S)-(ꢀ)-
3d. Racemic ( )-2g (l00mg, 0.41mmol) was resolved

3100
M. R. Atuu et al. / Tetrahedron: Asymmetry 15 (2004) 3091–3101
according to the general procedure as in Section 4.3.3.
Compound (R)-(+)-2g was obtained as a light yellow
Fo¨rsterling for his technical assistance in NMR. We
are very grateful indeed to Dr. Kent Molter, Dr. Ron
Theys, Ms. Laura Hall and Mrs. Jessica Chen for their
helpful suggestions and corrections.
25
D
oil (47mg, 0.172mmol, 47%), 67% ee, ½aꢂ ¼ þ30:5 (c
2.31, CHCl3). The (S)-(ꢀ)-3g was isolated as a light
brown oil (51.1mg, 0.162mmol, 45.9%); 64% ee,
25
D
½aꢂ ¼ ꢀ27:5 (c 2.31, CHCl3); 1H NMR (CDCl3,
300MHz): d 7.26–7.20 (m, 4H, J = 6.2Hz), 4.59 (t, H,
J = 9.45 and 10.89Hz), 4.52, (dd, 1H, 5.7 and
10.89Hz), 4.32 (m, 2H), 3.92 (dd, 1H, J = 5.6 and
9.35Hz), 2.32 (s, 3H, COCH3), 1.21 (t, 3H,
J = 7.14Hz). 13C NMR (CDCl3, 300MHz): d 171.10,
165.32, 137.31, 132.81, 130.34, 129.68, 65.76, 61.02,
53.54, 27.97, 14.97.
References
1. Leete, E. J. Am. Chem. Soc. 1960, 82, 612.
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4. Glasby, J. S. In Encyclopaedia of the Alkaloids; Plenum:
New York, 1975; Vol. 1, p 731.
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4.6.7.
(R)-(+)-3-Hydroxy-2-(6-fluoro-2-chlorophenyl)-
propionic acid ethyl ester (R)-(+)-2h and (S)-(ꢀ)-3-
acetoxy-2-(6-fluoro-2-chlorophenyl)-propionic acid ethyl
ester (S)-(ꢀ)-3h. Racemic ( )-2h (100mg, 0.41mmol)
was resolved according to the general procedure as in
Section 4.3.3. Compound (R)-(+)-2h was isolated as a
colorless oil (48mg, 0.204mmol, 48%) 67% ee;
25
D
teristics as of the racemic one (Section 4.1.7). Com-
½aꢂ ¼ þ37 (c 0.5, CHCl3); same spectroscopic charac-
8. PhysicianÕs Desk Reference, 56 ed.; 2002; p 1993.
9. PhysicianÕs Desk Reference, 56 ed.; 2002; p 1030.
10. Landernburg, A. Justus LiebigÕs Annal. Der. Chem. 1881,
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16. Kawai, Y.; Tsujimoto, M.; Kondo, S.; Takanobe, K.;
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pound (S)-(ꢀ)-3h was isolated as a colorless oil (73mg,
25
D
0.296mmol, 31%); 65% ee, ½aꢂ ¼ ꢀ29:7 (c 2.35,
1
CHCl3); H NMR (CDCl3, 300MHz): d 7.30 (dd, 2H
and 1F, J = 5.5 and 8.8Hz), 7.05 (t, HF J = 8.8Hz),
4.44 (dd, 1H, J = 9.30 and 10.89Hz), 4.34 (q, 1H,
J = 5.78 and 10.89Hz), 4.19 (m, 2H), 3.92 (dd, 1H,
J = 5.8 and 9.2Hz), 2.84 (s, 3H, COCH3), 2.71 (br s,
1H), 1.21 (t, 3H, J = 7.14Hz); 13C NMR (CDCl3,
300MHz): d 172.62, 170.33, 162.89, 159.59, 135.07,
129.29, 123.10, 114.43, 63.32, 61.71, 46.27, 29.36,
13.89. MS (EI, m/z%): 288(M+, 1), 253(7), 245(8),
228(13), 218(15), 216(37), 193(100), 170(16), 156(58),
143(34), 142(33), 121(18), 107(28), 101(10), 81(3),
75(7), 57(4).
18. Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asym-
metry 1999, 10, 107.
4.6.8. (R)-(+)-3-Hydroxy-2-(4-fluorophenyl)-propionic acid
ethyl ester (R)-(+)-2i and (S)-(ꢀ)-3-acetoxy-2-(4-fluoro-
phenyl)-propionic acid ethyl ester (S)-(ꢀ)-3i. Racemic
( )-2i (100mg, 0.47mmol) was resolved according to
the general procedure as in Section 4.3.3. The (R)-(+)-
´
19. Kiełbasinski, P.; Omelanczuk, J.; Mikolaczyk, M. Tetra-
hedron: Asymmetry 1998, 9, 3283.
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1985, 3, 33–45.
2i was isolated as a light yellow oil (44mg, 0.207mmol,
25
D
scopic characteristics as of the racemic one (Section
44%), 67% ee; ½aꢂ ¼ þ39 (c 0.5, CHCl3); same spectro-
4.1.8). (S)-(ꢀ)-3-acetoxy-2-(4-fIuorophenyl)-propionic
25
acid ethyl ester 3i was isolated as colorless oil
(48.5mg, 0.191mmol, 40.5%), 50% ee; ½aꢂ ¼ ꢀ32:5 (c
D
1.31, CHCl3); 1H NMR (CDCl3, 300MHz): d 7.30
(dd, 2H and 1F, J = 5.5 and 8.8Hz), 7.05 (t, 2HF
J = 8.8Hz), 4.44 (dd, 1H, J = 9.30 and 10.89Hz), 4.34
(q, 1H, J = 5.78 and 10.89Hz), 4.19 (m, 2H), 3.92, (dd
1H, J = 5.81 and 9.24Hz), 2.04 (s, 3H), 1.24 (t, 3H,
J = 7.14Hz); 13C NMR (CDCl3, 300MHz): d 175.23,
163.97, 160.70, 130.57, 129.70, 115.82, 64.94, 61.29,
49.8, 20.68, 13.97.
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1983, 95, 1024.
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Acknowledgements
We thank the Altus and the Amano companies for pro-
viding us with the enzymes. We also thank Dr. Holger
31. Bianchi, D.; Cesti, P.; Battistel, E. Org. Chem. 1988, 53,
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