Kinetic resolution of 1-chloro-3-(1-naphthyloxy)-2-propanol, an intermediate in the synthesis of β-adrenergic receptor blockers

Article abstract of DOI:10.1016/S0045-2068(03)00050-6

(R)- and (S)-1-chloro-3-(1-naphthyloxy)-2-propanol are intermediates in the synthesis of β-adrenergic blocking agents and antihypertensive drugs such as propranolol and nadoxolol. Herein, improvement in the preparation of racemic 1-chloro-3-(1-naphthyloxy)-2-propanol generated from 1-naphthol and epichlorohydrin are reported. In addition, kinetic resolution studies have been conducted to obtain both (R) and (S)-1-chloro-3-(1-naphthyloxy)-2-propanol. These compounds were obtained in highly optically pure form by the stereoselective hydrolysis of its acyl derivatives using whole cell preparations containing enzymes from native sources. The results were compared with those obtained using commercial lipases.

Full text of DOI:10.1016/S0045-2068(03)00050-6

BIOORGANIC
CHEMISTRY
Bioorganic Chemistry 31 (2003) 259–269
www.elsevier.com/locate/bioorg
Kinetic resolution of
1-chloro-3-(1-naphthyloxy)-2-propanol,
an intermediate in the synthesis of b-adrenergic
receptor blockersq
M. Kapoor,a N. Anand,a S. Koul,a S.S. Chimni,b K.S. Manhas,a
C. Raina,a R. Parshad,a S.C. Taneja,a,* and G.N. Qazia
a
Biotechnology Division, Regional Research Laboratory, Jammu 180001, India
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b
Received 15 December 2002
Abstract
(R)- and (S)-1-chloro-3-(1-naphthyloxy)-2-propanol are intermediates in the synthesis of
b-adrenergic blocking agents and antihypertensive drugs such as propranolol and nadoxolol.
Herein, improvement in the preparation of racemic 1-chloro-3-(1-naphthyloxy)-2-propanol
generated from 1-naphthol and epichlorohydrin are reported. In addition, kinetic resolution
studies have been conducted to obtain both (R) and (S)-1-chloro-3-(1-naphthyloxy)-2-propa-
nol. These compounds were obtained in highly optically pure form by the stereoselective
hydrolysis of its acyl derivatives using whole cell preparations containing enzymes from native
sources. The results were compared with those obtained using commercial lipases.
Ó 2003 Elsevier Science (USA). All rights reserved.
Keywords: Racemic 1-chloro-3-(1-naphthyloxy)-2-propanol; Kinetic resolution; Stereoselective hydrolysis
q RRL Contribution No. 2387. Part of the data presented in ‘‘National Conference on Utilization of
Bioresources, 2002’’ at Bhubaneshwar, India.
* Corresponding author. Fax: +91-191-2548607/2543829.
E-mail address: sc_taneja@yahoo.co.in (S.C. Taneja).
0045-2068/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S0045-2068(03)00050-6

260
M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
1. Introduction
It is now well established that the biological activities of molecules have close re-
lationships with their chemical structures and that the chirality of the molecule plays
an important role in its biological activity. Consequently, in most bioactive sub-
stances consisting of one or more optical centers such as drugs, insecticides, flavors,
and fragrances, only one of the enantiomers may contribute to the biological
activity. In b-adrenergic blocking agents (so called b-blockers) related to aryloxypro-
pylamines (e.g., propranolol and atenolol), the therapeutic effect resides mainly in
(S)-enantiomer [1–4]. It is reported that the (S)-enantiomer of propranolol is 130
times more active than the (R)-enantiomer (ER ¼ 130) [5]. Therefore, resolution of
the racemic precursors for the preparation of optically enriched (S)-enantiomer is
important [4].
The synthetic approaches for the preparation of (S)-propranolol or their precur-
sors are generally based on asymmetric syntheses [6–14] or chemoenzymatic methods
[15–41]. Racemic 1-chloro-3-(1-naphthyloxy)-2-propanol (1, Scheme 1) is an impor-
tant and easily preparable precursor of propranolol/nadoxolol, which may be syn-
thesised by the condensation of 1-naphthol (2) with epichlorohydrin (3). The
present studies are directed at the improved preparation of racemic 1 from 2 (Scheme
1). In addition, kinetic resolution studies of racemic 1 were carried out by the stereo-
selective hydrolysis of its acyl derivatives with crude lipases procured from commer-
cial sources as well as whole cell preparations from native strains of the InstituteÕs
repository (Scheme 2). This methodology represents an improvement in the prepara-
tion of the enantiomers of 1.
Scheme 1.

M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
261
Scheme 2.
2. Materials and methods
2.1. General methods and materials
1H NMR spectra were recorded in CDCl3 on a Bruker (200 MHz) spectrometer
using TMS as an internal standard. The enantiomeric excess (ee%) was measured by
chiral HPLC (Shimadzu using R, R -Whelk-O 1 chiral column, mobile phase
3:97:0.1 iso-propanol:n-hexane:acetic acid glacial, flow rate 0.55 ml/min.). Lipase PS
‘‘Amano’’ (PSL) (810 U/mg) LPSAZ0951148 was a gift from Amano Pharmaceutical,
Japan. Candida antarctica lipase (CAL A + B) (3.0 U/g), immobilized on Sol–Gel AK,
and Mucor javanicus lipase (MJL) (696 U/mg) were purchased from Fluka Biochemi-
cal (Switerzland) and Sigma Chemical (Germany), respectively. All the above lipases
were used without further purification. Two native strains from the InstituteÕs repos-
itory RRLY-15 (52 U/mg), RRL-1789 (650 U/mg), and PLAP (pig liver acetone pow-
der, 1170 U/mg) prepared from fresh pig liver [42], were used in the form of whole cells.
2.2. Cultivation of Trichosporon sp. RRLY-15
The yeast RRLY-15 used in this process has been isolated from locally fer-
mented cottage cheese as per the procedure described by Beech and Davenport
[43]. A culture medium comprising of 1.5% glucose, 0.05% potassium dihydrogen
phosphate (KH2PO4) 1.0% corn steep liquor, and 0.3% urea (pH 6.8 before steriliza-
tion and pH 6.5 after sterilization) was prepared and dispensed into shake flasks
(200 ml each) and into a 10 L stainless steel (SS 304s) fermenter (working volume
7.5 L) and autoclaved. The preculture of strain Trichosporon sp. RRLY-15 was pre-
pared by inoculating a loop full of the culture prepared from solid agar medium and
incubating on a shaker at 28Æ1 °C. The 24 h old preculture thus produced was
inoculated into the culture medium and fermentation carried out at 500 rpm,
1.0 vvm aeration rate and at a temperature of 28Æ1 °C for 15–18 h. After fermen-
tation the wet cell biomass (120 g/L) was centrifuged at 8000g. The wet cell
biomass (60 g) was lyophilized to a dry powder (15 g) and used directly for the ki-
netic resolution studies. The yeast strain RRLY-15 has been deposited at Deutsche

262
M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
Sammlung von Mikroorganismen und Zellekulturen GmbH (DSMZ) Braunchweig,
Germany under Accession No. DSM 11829.
2.3. Cultivation of Bacillus sp. RRL-1789
Bacillus sp. RRL-1789 has been isolated from fresh water sources in the hilly areas
of Jammu region as per the procedure described by Breed et al. [44]. A culture me-
dium comprising of yeast (1.0 g/L), peptone (10 g/L), glucose (10 g/L), and sodium
chloride (5 g/L), (pH 7.0 before sterilization and 6.8 after sterilization) was prepared
and dispensed into shake flasks (200 ml each) and into a 10 L stainless steel (SS 304s)
fermenter (working volume 10.0 L) and autoclaved. The preculture of strain Bacillus
sp. RRL-1789 was prepared in the shake flask by inoculating a loop full of the cul-
ture prepared from solid agar medium and incubating at 200 rpm at 28Æ1 °C . The
24 h old preculture thus produced was inoculated into the culture medium and fer-
mentation carried out at 400 rpm, 0.7 vvm aeration rate and at a temperature of
28Æ1 °C for 15–18 h. After fermentation the wet cell biomass (10 g/L) was centri-
fuged at 10,000g. The wet cell biomass (10 g) was lyophilized to a dry powder (2 g)
and used directly for kinetic resolution studies.
2.4. Synthesis of 1-chloro-3-(1-naphthyloxy)-2-propanol (1)
A solution of 1-naphthol 2 (14.4 g, 0.1 mol), epichlorohydrin 3 (39 ml, 0.5 mol)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 200 ll) was refluxed on a water bath
for 20 min until the TLC showed the completion of the reaction. The excess epichlo-
rohydrin was removed under reduced pressure. The resulting reaction mixture was
extracted with dichloromethane (3 Â 100 ml). The combined organic layers were
washed with water (2 Â 30 ml), dried over anhydrous sodium sulphate and the sol-
vent removed under vacuum to give a crude mixture of 1 and 1a in the ratio of
80:20 (as estimated by GC).
Subsequently, the mixture was dissolved in dichloromethane (60 ml) and conc. hy-
drochloric acid was added dropwise. The mixture stirred for two hours at 5 °C . Af-
ter completion of the reaction (monitored by TLC), water (50 ml) was added and the
organic layer separated. The aqueous layer was extracted with dichloromethane
(50 ml) followed by washing of the combined organic layers with water (2 Â 30 ml),
and drying and removal of solvent under vacuum. The resulting oil (22.5 g) was
purified by column chromatography over silica gel using EtOAc:n-hexane (1:49) as
eluent to yield 22 g of 1 (92.5%).
1H NMR (CDCl3): d 2.8 (1H, bs, OH), 3.9 (2H, d, J ¼ 4:7 Hz; CH2Cl), 4.1–4.4
(3H, m, OCH2 CHOH), 6.8–8.3 (7H, m, Ar–H).
2.5. General procedure for the preparation of acyl derivatives of 1-chloro-3-
(1-naphthyloxy)-2-propanol (4a–c)
A solution of 1 (4.73 g, 20 mmol), alkyl acid anhydride (22mmol) and 4-dimeth-
ylaminopyridine (DMAP, in catalytic amount) was stirred at room temperature

M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
263
for 12 h. Addition of cold water followed by dichloromethane extraction, washing
with water, drying, removal of solvent followed by purification on silica gel gave
the acyl derivatives 4a–c in 90–95% yield.
1-Chloro-2-acetoxy-3-(1-naphthyloxy) propane
1H NMR (CDCl3); d 2.15 (3H, s, CH3), 3.95 (2H, d, J ¼ 5:0 Hz, CH2Cl), 4.36
(2H, d, J ¼ 5:0 Hz, OCH2), 5.52 (1H, m, CH), 6.8-8.3 (7H, m, Ar–H).
1-Chloro-2-propanoyloxy-3-(1-naphthyloxy) propane
1H NMR (CDCl3); d 1.26 (3H, t, J ¼ 7:5 Hz, CH3), 2.45 (2H, q, J ¼ 7:5 Hz,
COCH2), 3.9 (2H, d, J ¼ 4:5 Hz, CH2Cl), 4.36 (2H, d, J ¼ 5:0 Hz, OCH2), 5.54
(1H, m, CH), 6.8–8.3 (7H, m, Ar–H).
1-Chloro-2-butanoyloxy-3-(1-naphthyloxy) propane
1H NMR (CDCl3); d 0.97 (3H, t, J ¼ 7:45 Hz, CH3), 1.68 (2H, m, CH2), 2.34 (2H,
t, J ¼ 7:4 Hz, COCH2), 3.92 (2H, d, J ¼ 5 Hz, CH2Cl), 4.36 (2H, d, J ¼ 5 Hz,
OCH2), 5.52 (1H, m, CH), 6.8–8.3 (7H, m, Ar–H).
2.6. General procedure for lipase catalysed kinetic resolution of acyl derivatives of
1-chloro-3-(1-naphthyloxy)-2-propanol
A mixture of substrate 4 (200 mg), crude enzyme preparations in the ratio given
in Tables 2 and 3, and sodium phosphate buffer (0.1 M, pH 7, 4 ml) was stirred at
27Æ1 °C, maintaining pH 7 by the addition of 0.1 NNaOH solution. The course
of the reaction was monitored by chiral HPLC. After a certain degree of conver-
sion, the reaction was terminated by centrifugation of the reaction mixture at
10,000g to remove cell mass and the suspended particles. The clear solution and
the centrifuged cell mass was extracted separately with ethyl acetate (3 Â 10 ml).
The organic layers were combined and washed with water, dried and the or-
ganic layers concentrated under reduced pressure. The resulting mixture consisted
of the alcohol and ester, which were separated by column chromatography over
silica gel using EtOAc:n-hexane (1:49) as eluent to furnish the optically enriched
1 and 4.
2.7. Procedure for lipase catalysed kinetic resolution of 1-chloro-2-acetoxy-3-
(1-naphthyloxy) propane (4a) by RRLY-15
A mixture of substrate 4a (200 mg, 0.72 mmol), RRLY-15 (100 mg), and sodium
phosphate buffer (0.1 M, pH 7, 4 ml) was stirred at 27Æ1 °C , maintaining pH 7
by the addition of 0.1 NNaOH solution. The course of the reaction was monitored
by chiral HPLC. The reaction was terminated after 47% hydrolysis, by centrifuga-
tion of reaction mixture at 10,000g to remove cell mass and the suspended particles.
The clear solution and the centrifuged cell mass were extracted separately with ethyl
acetate (3 Â 10 ml). The organic layers were combined and washed with water, dried
and concentrated under reduced pressure. The resulting mixture consisted of the al-
cohol and ester, which were separated by column chromatography over silica gel us-
ing EtOAc:n-hexane (1:49) as eluent to furnish optically enriched 1 (70 mg, 0.3 mmol,
35%) (ee > 99%)and 4a (96 mg, 0.34 mmol, 48%) (ee 88%).

264
M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
2.8. Procedure for lipase catalysed kinetic resolution of 1-chloro-2-butanoyloxy-3-
(1-naphthyloxy) propane (4c) by M. javanicus lipase (MJL)
A mixture of substrate 4c (200 mg, 0.65 mmol), MJL powder (200 mg), and so-
dium phosphate buffer (0.1 M, pH 7, 4 ml) was stirred at 27Æ1 °C , maintaining
pH 7 by the addition of 0.1 NNaOH solution. The course of the reaction was mon-
itored by chiral HPLC. After 52% hydrolysis, the reaction was worked up as de-
scribed above and the components were separated by column chromatography
over silica gel using EtOAc:n-hexane (1:49) as eluent to furnish optically enriched
1 (64 mg, 0.27 mmol, 32%) (ee 91%)and 4c (88 mg, 0.28 mmol, 44%) (ee > 99%).
3. Results and discussion
1-Chloro-3-(1-naphthyloxy)-2-propanol, 1, was synthesised by a modification of
StephensonÕs method [45], consists of a condensation reaction between 1-naphthol
2 and epichlorohydrin 3 in presence of a base (Scheme 1). The results of the conden-
sation reaction in the presence of various bases are presented in Table 1.
Reaction of 1-naphthol 2 with epichlorohydrin 3 in a molar ratio of 1:5, where
epichlorohydrin was used as a solvent, in the presence of potassium carbonate [45]
in acetone, yielded a mixture of glycidyl-1-naphthyl ether 1a and chlorohydrin 1
in approximately 40:60 ratio. Optimization of the experimental conditions improved
the product ratio to 23:77 in 24 h [15]. However, when the organic base 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) was used in a catalytic amount the ratio improved to
10:90 in 72 h. By further optimization of the reaction conditions it was possible to
obtain a ratio of 20:80 within just 20 min. No further attempts were made to improve
the product ratio. However, the 20:80 product mixture could be smoothly converted
to a major product 1, by treatment with conc. hydrochloric acid at 5 °C followed by
purification by column chromatography. The racemic chlorohydrin 1 was obtained
in an over all yield of 92%. The pure product was then converted to its racemic o-acyl
Table 1
Effect of different bases on the product distribution ratio (1a:1) in the condensation of 1-naphthol (2) with
epichlorohydrin (3)a
Base
Ratiob
Temp./exp.
conditions
Time
Product ratiod
(1a:1)
NaOH
1:1
1:1
Reflux
28 h
24 h
35:65
40:60
50:50
10:90
20:80
K2CO3/acetone
Piperidine
DBU
Reflux
1:0.05
1:0.01
1:0.01
RTc/stirring
RTc/stirring
Reflux
48 h
72 h
DBU
20 min
a 1-Naphthol:epichlorohydrin (mole ratio) ¼ 1:5 [Epichlorohydrin used as solvent].
b 1-Naphthol:base (mole ratio).
c Room temperature (27Æ1 °C).
d Estimated by GC.

M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
265
derivatives (4a–c), which were used as substrates for detailed kinetic resolution
studies.
The lipase-catalyzed stereoselective hydrolysis of 4a–c was studied using three
crude lipases procured from commercial sources and whole cell preparations ob-
tained from two native strains of the InstituteÕs repository and one prepared from
fresh pig liver. All preparations were used without modification or purification.
The hydrolytic reactions were generally carried out in 0.1 M sodium phosphate buf-
fer at pH 7, at concentration of 50 g/L and at a temperature of 27Æ1 °C (Scheme 2).
The results of the experiments using commercial lipases are summarized in Table 2.
From the data in Table 2, it is evident that M. javanicus lipase (MJL) showed the
greatest selectivity for the S-ester ðE > 300Þ while PSL showed faster hydrolase ac-
tivity with moderate enantioselectivity (E ¼ 18, ee ¼ 85%, reported ee > 95% [15]).
CAL, on the other hand, proved to be the most sluggish and showed moderate se-
lectivity (E ¼ 22, ee ¼ 87%). As expected, all the three commercial lipases exhibited
a preference for the S-enantiomer in the hydrolysis reaction, thus following Kazlaus-
kasÕs rule of selectivity [47]. Among the acylated derivatives (4a–c), MJL showed the
greatest selectivity for the butyrate 4c (ee > 99%). A graph depicting the comparative
enantiopurity vs. time course of the reaction using the commercial MJL is presented
in Fig. 1.
After screening a large number of microorganisms from the InstituteÕs microbial
repository two native strains were selected. Pig liver acetone powder (PLAP) was
prepared by a known method from freshly procured pig liver [42]. Table 3 depicts
the results of kinetic resolution studies under optimized conditions of the selected
Table 2
Lipase-catalysed kinetic resolution of acyl derivatives of 1-chloro-3-(1-naphthyloxy)-2-propanol using
commercial lipases
Ee
Enzyme Subs.a S:Eb Time Conv. Ester
Alcohol
(h)
(%)c
Isolated Conf. ee (%)
yieldd (%)
Isolated
yieldd (%)
Conf. ee (%)
MJL
PSL
4a
4b
4c
1:1
1:1
1:1
403
174
118
32
34
52
58
53
44
(R)
(R)
(R)
42
47
25
23
32
(S)
(S)
(S)
80.0
86.5
91.0
13
21
>99
>300
4a
4b
4c
1:0.3 13
1:0.3 20
1:0.3 20
35
40
32
55
53
61
(R)
(R)
(R)
75
68
44
23
21
20
(S)
(S)
(S)
85.4
82.8
85.1
18
18
18
CAL
4a
4b
4c
1:1
1:1
1:1
435
33
31
31
60
57
58
(R)
(R)
(R)
48
49
40
24
22
40
(S)
(S)
(S)
84.1
84.0
87.5
17
17
22
387
196
a Subs., Substrate.
b S:E, substrate:enzyme ratio (w/w).
c Conversions based on HPLC.
d Isolated yield in mmol (after column chromatography) based on conversions.
e Calculated according to Chen et al. [46]; MJL, Mucor javanicus lipase; PSL, Lipase PS ‘‘Amano’’
(Pseudomonas cepacia); CAL, Candida Antarctica (A + B mixture) lipase.

266
M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
Fig. 1. Study of hydrolase activity of MJL for the acylates of 1-chloro-3-(1-naphthyloxy)-2-propanol
4a–c.
Table 3
Kinetic resolution of acyl derivatives of 1-chloro-3-(1-naphthyloxy)-2-propanol using whole cell prepara-
tions from native strains
Ee
Enzyme
Subs.a S:Eb Time Conv.c Ester
(h)
Alcohol
Isolated Conf. ee (%) Isolated Conf. ee (%)
yieldd (%)
yieldd (%)
RRLY-15 4a
1:0.5 25
1:0.5 18
1:0.5 35
47
33
21
48
60
71
(S)
(S)
(R)
88
29
4
35
25
22
(R)
(R)
(S)
>99
30
>550
14
4b
4c
30
2
RRL-1789 4a
1:0.1 40
1:0.1 20
1:0.1 25
36
36
38
53
54
51
(R)
(R)
(R)
39
44
43
26
24
24
(S)
(S)
(S)
64
62
47
6
6
4
4b
4c
PLAP
4a
4b
4c
1:0.08 19
1:0.08 19
1:0.08 19
49
55
49
34
32
35
(S)
(S)
(S)
49
48
30
24
26
22
(R)
(R)
(R)
35
24
23
3
2
2
a Subs., Substrate.
b S:E, substrate:enzyme ratio (w/w).
c Conversions based on HPLC.
d Isolated yield in mmol (after column chromatography) based on conversions.
e Calculated according to Chen et al. [46]; RRLY-15 ¼ Trichosporon sp.; RRL-1789 ¼ Bacillus sp.;
PLAP, pig liver acetone powder.
hydrolases preparations obtained from native strains. In these studies Trichosporon
sp. (RRLY-15) was found to be the best one, displaying the highest selectivity
(E > 550). In fact, among all the enzymes studied for the stereoselective hydrolysis,
RRLY-15 established its superiority with respect to high enantioselectively and
moderate rate of hydrolysis. Furthermore RRLY-15 produced the desired alcohol
(R-enantiomer) with the highest enantiopurity (ee > 99%). The hydrolases from
the other strains [i.e., Bacillus sp. (RRL-1789) and PLAP] displayed low to moderate
selectivity.
From Table 3 it is evident that both RRLY-15 and PLAP behave like esterases
showing reverse selectivity (preference for the R enantiomer) compared to results

M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
267
Fig. 2. Effect of the substrate concentration of 1-chloro-2-acetoxy-3-(1-naphthyloxy)propane on the
hydrolase activity of RRLY-15.
obtained from commercial lipases (Table 2). Another important characteristic of
RRLY-15 is the reversal of selectivity with the increase in the size of the alkyl
group from acetyl to butyryl, which is not observed with any other enzyme strain.
In order to improve the yield of the product (R-alcohol) using RRLY-15, the ef-
fect of the increase in concentration (g/L) of substrate (4a) was studied keeping
the substrate to enzyme ratio constant. The results of these studies are depicted
in Fig. 2. It is evident that the substrate concentration of 50 g/L is the optimum
one which is easily tolerated by enzyme. Above 50 g/L, conversion is significantly
reduced.
RRL-1789 showed moderate selectivity for the substrate. The rate of hydrolysis
with PLAP was comparatively high. Using a lower substrate to enzyme ratio resulted
in a significant improvement in the enantioselectivity. However, to further improve
the enantioselectivity, the effect of lowering the reaction temperature for both RRL-
1789 and PLAP was studied. RRL-1789 showed marked improvement in enantiose-
lectivity for 4a only. The ee of the product was improved to 90%, displaying much
lower rates of hydrolysis (conversion 27% after 110 h at 10 °C). On the contrary,
PLAP displayed significant reduction in selectivity (ee ¼ 11%) as well as the rate
of hydrolysis (conversion 26% after 24 h at 10 °C).
4. Conclusions
The preparation of racemic 1-chloro-3-(1-naphthyloxy)-2-propanol, 1, the precur-
sor to antihypertensive drug propranolol/nadoxolol (b-blockers) has been success-
fully modified. The acylates of the above precursor were subjected to kinetic
resolution studies using three commercial lipases and hydrolases from two native
strains and PLAP. M. javanicus lipase (MJL) showed high selectivity for the butyrate
furnishing the S-alcohol of ee 91% and R-ester of ee > 99%. Trichosporon sp. RRLY-
15, the native yeast strain, proved to be the most suitable one for kinetic resolution
of 1 and furnished the desired R-alcohol in ee > 99% along with the S-ester (ee 88%)
demonstrating higher rates of hydrolysis as well as selectivity.

268
M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
Acknowledgments
We thank Amano Pharmaceutical Co., Japan for a gift of enzyme PS ‘‘Amano.’’
One of the authors (M.K.) is thankful to DST, New Delhi for a research fellowship.
References
[1] R.R. Rufflo, Tetrahedron 47 (1991) 9953.
[2] W.L. Nelson, T.R. Burke, J. Org. Chem. 43 (1978) 3641.
[3] R. Howe, B.S. Rao, J. Med. Chem. 11 (1968) 1118.
[4] S. Borman, Chem. Eng. News 68 (28) (1990) 9 (and references cited therein).
[5] R.A. Sheldon, Chirotechnology, Industrial Synthesis of Optically Active compounds, Marcel Dekker,
New York, 1993, p. 51.
[6] J.M. Klunder, S.Y. Ko, K.B. Sharpless, J. Org. Chem. 51 (1986) 3710.
[7] R.A. Veloo, G.J. Koomen, Tetrahedron: Asymmetry 4 (1993) 2401.
[8] M. Shibazaki, H. Sasai, Jpn. Kokai Tokkyo Koho Japanese Patent 06,256,270 [94,256,270].
[9] T. Kumamoto, N. Aoyama, S. Nakano, T. Ishikawa, S. Narimatsu, Tetrahedron: Asymmetry 12
(2001) 791 (and references cited therein).
[10] T. Hayashi, A. Katsumura, M. Konishi, M. Kumada, Tetrahedron Lett. 20 (1979) 425.
[11] H. Sasai, T. Suzuki, N. Itoh, K. Tanaka, D. Tadamasa, K. Okamura, M. Shibasaki, J. Am. Chem.
Soc. 115 (1993) 10372.
[12] H. Sasai, Y.M.A. Yamada, T. Suzuki, M. Shibasaki, Tetrahedron 50 (1994) 12313.
[13] K.B. Sharpless, W. Amberg, Y.L. Bennani, G.A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K.
Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 57 (1992) 2768.
[14] H. Chang, K.B. Sharpless, Tetrahedron Lett. 37 (1996) 3219.
[15] H.S. Bevinakatti, A.A. Banerji, J. Org. Chem. 56 (1991) 5372 (and references cited therein).
[16] D. Bianchi, P. Cesti, E. Battistel, J. Org. Chem. 53 (1988) 5531.
[17] S.V. Damle, P.N. Patil, M.M. Salunkhe, Bioorg. & Med. Chem. 8 (2000) 2067.
[18] S.V. Damle, P.N. Patil, M.M. Salunkhe, Synth. Commun. 29 (1999) 3855.
[19] T.-W. Chiou, C.-C. Chang, C.-T. Lai, D.-F. Tai, Bioorg. Med. Chem. Lett. 7 (1997) 433–436.
[20] M. Yamamoto, S. Senda, T. Komata, Y. Tsuda, Jpn. Kokai Tokkyo Koho Japanese Patent
62,151,196 [87,151,196].
[21] Y.F. Wang, H.S. Kou, B. Lee, L. Hwang, J. Chin. Chem. Soc. (Taipei) 32 (1986) 189.
[22] N. Matsuo, M. Mitsuta, Jpn. Kokai Tokkyo Koho Japenese Patent 61,162,192 [86,162,192].
[23] C. Fuganti, P. Grasselli, P.F. Seneci, S. Servi, Tetrahedron Lett. 27 (1986) 2061.
[24] N. Matsuo, N. Ohno, Tetrahedron Lett. 26 (1986) 5533.
[25] S. Iriuchijima, N. Kojima, Agri. Biol. Chem. 46 (1982) 1153.
[26] Y. Terao, M. Murata, K. Achiwa, T. Nishio, M. Akamatsu, M. Kamimura, Tetrahedron Lett. 29
(1988) 5173.
[27] B.K. Pchelka, A. Loupy, J. Plenkiewicz, L. Blanco, Tetrahedron: Asymmetry 11 (2000) 2719 (and
references cited therein).
[28] M.-J. Kim, Y.K. Choi, J. Org. Chem. 57 (1992) 1605.
[29] D. Bianchi, A. Bosetti, P. Cesti, P. Golini, Tetrahedron Lett. 33 (1992) 3231.
[30] Y.F. Wang, H.S. Kou, B. Lee, L. Hwang, J. Chin. Chem. Soc. (Taipei) 33 (1986) 189.
[31] S.H. Hsu, S. Shihn, Y.F. Wang, C.H. Wong, Tetrahedron Lett. 31 (1990) 6403.
[32] T.N.B. Kaimal, R.B.N. Prasad, T.C. Rao, Biotechnol. Lett. 14 (1992) 21.
[33] U. Ader, M.P. Schneider, Tetrahedron: Asymmetry 3 (1992) 521.
[34] M.J. Kim, H. Cho, J. Chem. Soc. Chem. Commun. 19 (1992) 1411.
[35] R.S. Bhaskar, T.-W. Chiou, D.-F. Tai, Tetrahedron: Asymmetry 6 (1995) 1519.
[36] J.L. Bermudez, C.D. Compo, L. Salazar, E.F. Llama, J.V. Sinisterra, Tetrahedron: Asymmetry 7
(1996) 2485.

M. Kapoor et al. / Bioorganic Chemistry 31 (2003) 259–269
269
[37] Y.-P. Zhaung, J.-H. Xu, S.-L. Zhang, Ann. N. Y. Acad. Sci. (1998) 864 (Ch.).
[38] Y.-P. Zhaung, J.-H. Xu, S.-L. Zhang, Huadong Ligong Daxue Xuebao 25 (1999) 43 (Ch.).
[39] Y.-P. Zhaung, J.-H. Xu, S.-L. Zhang, L. Zhou, Yaowu Shengwu Jishu 4 (1997) 216.
[40] S.C. Mohapatra, J.T. Hsu, Biotechnol. Bioeng. 64 (1999) 213.
[41] L. Salazar, J.L. Bermudez, C. Ramirez, E.F. Llama, J.V. Sinisterra, Tetrahedron: Asymmetry 10
(1999) 3507.
[42] K. Adachi, S. Kobayashi, M. Ohno, Chimia 40 (1986) 311.
[43] F.W. Beech, R.R. Davenport, Methods in Microbiology, vol. 4, Academic Press, New York, 1971,
p. 153.
[44] R.S. Breed, E.G.D. Murray, N.R. Smith, BergeyÕs Manual of Determinative Bacteriology, vol. 7,
William & William Co., Baltimore, MD, 1957, p. 987.
[45] O. Stephenson, J. Chem. Soc. (1954) 1571.
[46] C.S. Chen, Y. Fujimoto, G. Girdaukas, C.J. Sih, J. Am. Chem. Soc. 104 (1982) 7294.
[47] Z.S. Kazlauskas, A.N.E. Weissfloch, A.T. Rappaport, L.A. Cuccia, J. Org. Chem. 56 (1991) 2656.