Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates

Article abstract of DOI:10.1016/j.tetasy.2005.07.009

A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ～ 316), 1-(3,4-methylenedioxyphenyl) ethanol and pentanol (E ～ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ～ 340), 2-(benzylthio)propanoic acid (E ～ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2- naphthyl)propan-1-ol and carboxylic acids such as 2-(5-bromo-6-methoxy-2- naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it displayed moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates for comparative studies.

Full text of DOI:10.1016/j.tetasy.2005.07.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2575–2591
Trichosporon beigelli esterase (TBE): a versatile esterase for
the resolution of economically important racemates
Surrinder Koul, Jawahir Lal Koul, Budh Singh, Munish Kapoor, Rajinder Parshad,
Kuldeep S. Manhas, Subhash C. Taneja* and Ghulam N. Qazi
Biotechnology Division, Regional Research Laboratory (CSIR), Jammu Tawi 180001, India
Received 18 May 2005; accepted 4 July 2005
Abstract—A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has
displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include
racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ꢀ 316), 1-(3,4-methylenedioxyphenyl)ethanol and penta-
nol (E ꢀ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ꢀ 340), 2-(benzylthio)propanoic acid
(E ꢀ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2-naphthyl)propan-1-ol and carboxylic acids such as
2-(5-bromo-6-methoxy-2-naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it dis-
played moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates
for comparative studies.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
specificity and hydrolytic activity, which is not only a
function of the structure of the substrate but may also
be influenced by the reaction conditions. These hydro-
lytic enzymes have been extensively used in the genera-
tion of a large number of enantiomerically enriched
molecules such as alcohols, esters, amides, acids, etc.,
which are valuable as fine chemicals, building blocks,
or synthetic intermediates.11–20 Their applications in
the protecting group chemistry of highly functionalized
molecules such as peptides, saccharides, and their conju-
gates have been a steadily growing area.21
Amongst the large variety of hydrolases currently being
used for industrial applications, the availability of true
esterases is limited to a few only. These applications have
generally been performed by a handful of esterases avail-
able from animal sources such as pig and horse liver
esterases,1 acetylcholine esterase,2 plant/animal choles-
terol esterase,3 etc. Microbial carboxyl-esterase NP4 or
proteases, such as a-Chymotrypsin5 Bacillus subtilisin,6
and papain7 are also being used for hydrolysis. Despite
the progress made in the area of genetic engineering,
the supply of synthetically useful esterases still remains
inadequate. Therefore, the search for and development
of new esterases preferably from microbial sources capa-
ble of accepting a wide variety of non-natural substrates
is always desirable. Biocatalytic properties especially
those of esterases and lipases have been well documented
and so have been their uses in organic synthesis.8–10
These hydrolases are of general interest since they can
be used without the requirement of expensive cofactors
and are available at affordable prices. Most of the known
hydrolases display a wide and varying range of substrate
The effectiveness of some of the most commonly known
commercial enzyme preparations such as Pseudomonas
sp., Candida rugosa, Candida cylindracea, and Candida
antarctica A and B, Pig liver esterase, Mucor miehei,
etc., lies in their broad substrate acceptability and high
enantioselectivity. Several new biocatalysts, including
lipases and esterases,22 have been isolated from various
sources through the screening of thousands of strains
and added to the armory of organic chemists. Besides
being advantageous in terms of activity and selectivity,
a biocatalyst needs to fulfill the requirements of robust-
ness,23 such as that shown by the above mentioned com-
mercial enzymes. We have been continuously engaged in
the search for new sources of hydrolases and dehydro-
genases and our efforts in this direction have been
*
Corresponding author. Tel.: +91 191 2572002; fax: +91 191 2548607/
2543829; e-mail: sc_taneja@yahoo.co.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.009

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S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
successful, as many of these new enzymes have found
applications in the preparation of chiral auxiliaries, drug
intermediates, and useful chemical entities.24–28
chiral auxiliaries used in the synthesis of optically active
compounds33 and also in the fine chemical industry,34
was efficiently carried out using TBE (Scheme 1). The
hydrolase displayed a high enantioselectivity for the ace-
tyl derivative (E ꢀ 316, 99% ee), showing a preference
for the (S)-enantiomer, thus exhibiting an opposite
selectivity to all the commercial lipases viz. CCL, PPL,
and PSL, which afforded the (R)-alcohol. With an
increase in the size of alkyl ester group from acetate to
butyrate, there was a considerable decrease in reactiv-
ity/selectivity profiles of TBE, whereas commercial lip-
ases displayed significant improvements with the
exception of PSL, which did not show any noteworthy
changes in the rates of hydrolysis. PSL also displayed
the best selectivity for the acetyl derivative (E ꢀ 492,
99% ee) while CCL and PPL showed a preference for
butyrate derivative (E ꢀ 53, 93.2% ee and E ꢀ 159,
99% ee, respectively). XAD resin immobilized Pseudo-
monas sp., PPL, and rabbit gastric juice have previously
been reported for the preparation of (R)-1.35a–c Table 1
summarizes the results obtained from these studies.
2. Results and discussion
Recently, we reported the activity of an enantioselective
hydrolase Trichosporon sp. (DSMZ no. 11829, a yeast
strain isolated from local cottage cheese) now identified
as Trichosporon beigelli.27,28 There, we successfully dem-
onstrated the high enantioselectivity displayed by the
strain in the resolution of the racemic chlorohydrin inter-
mediate27 of (S)-propranolol (E >550) as well as in the
preparation of (S)-naproxen by the kinetic resolution of
its racemic methyl ester (E ꢀ 500).28a Lipases from other
yeasts, especially from the genera Candida and Saccharo-
myces are well known including their applications in
biotransformation reactions.29–31 Herein, we report the
general applicability of T. beigelli in the resolution of
some economically important molecules, especially in
the resolution of aryl alkyl carbinols (primary as well as
secondary alcohols), arylpropanoic acids, aryloxypropa-
noic acid, and substituted 2-thiopropanoic acids. The
present results together with data previously published
by us28b show T. beigelli to be one of the more versatile
hydrolases (as a whole cell preparation, cell free extract,
or purified form), which is capable of accepting a wide
range of non-natural substrates.32 These studies also
finally establish the identity of T. beigelli as a true esterase
(now designated as TBE) and not a lipase as mentioned
earlier.27,28 These conclusions are based on the data
obtained from N-terminal amino acids sequencing32
together with the reactivity/selectivity profiles of TBE,
taking into account the opposite selectivity observed dur-
ing the hydrolysis of various racemic esters in compari-
son to the results obtained from some commercial lipases.
3.2. Kinetic resolution of racemic 1-(3,4-methylene-
dioxyphenyl)ethanol 2 and 1-(3,4-methylenedioxy-
phenyl)pentanol 3
1-(3,4-Methylenedioxyphenyl)ethanol 2 and 1-(3,4-meth-
ylenedioxyphenyl)pentanol 3 are important members of
a class of molecules that are used as chiral auxiliaries in
organic synthesis. Alkyl acylates of racemic 2a–c and
3a–c (R = CH3, C2H5, C3H7) were subjected to kinetic
resolution using TBE and commercial lipases (Scheme
2). As expected, TBE exhibited preference for S-enantio-
mer of acetyl derivative (E = 179.6, 98% ee) and lower
activity and selectivity for the higher homologues. Con-
versely, the commercial enzymes, which furnished R-
alcohols, did not discriminate among the alkyl acylates
appreciably in terms of activity and selectivity. Table 2
summarizes the results obtained from the above studies.
3. Hydrolysis of alkyl acylates of secondary and primary
alcohols
3.3. Kinetic resolution of racemic 2-(6-methoxy-2-
naphthyl)propanol 4
3.1. Kinetic resolution of racemic 1-(6-methoxy-2-
naphthyl)ethanol 1
After demonstrating an excellent resolution of second-
ary alcohols, we next decided to study the resolution
potential of TBE with respect to a primary alcohol,
which are generally hard to resolve with high enantio-
The kinetic resolution of alkyl acylates of racemic 1-(6-
methoxy-2-naphthyl)ethanols 1a–c, which are valuable
OCOR
CH3
OH
CH3
+
CH3O
CH3O
OCOR
TBE
Enriched (R)-(+)-1a-c
OCOR
(S)-(-)-1
CH3
OH
CCL
PPL
PSL
CH3O
CH3
CH3
(RS)-1a-c
+
CH3O
CH3O
1a, R= CH3
1b, R= CH2CH3
Enriched (S)-(-)-1 a-c
1c, R= CH2CH2CH3
(R)-(+)-1
Scheme 1.

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2577
Table 1. Hydrolysis of racemic alkyl acylates of 1-(6-methoxy-2-naphthyl)ethanols 1a–c using TBE and commercial lipases CCL, PPL, and PSL
Entry
TBE
CCL
Conf. E Factor Conv. ee
PPL
PSL
Conv. ee
Conf. E Factor Conv. ee
Conf. E Factor Conv. ee
Conf. E Factor
(%)
(%) prod.
(%)
(%) prod.
(%)
(%) prod.
(%)
(%) prod.
1a
1b
1c
32.0
10.0
08.0
99.0
69.6
62.0
S
S
S
316
2.2
4.5
24.0
32.0
40.0
12.6
14.8
93.2
R
R
R
1.34
1.44
52.9
10.0
32.0
40.0
13.0
54.0
99.0
R
R
R
1.31
4.26
158.9
46.0
43.0
36.0
99.0
64.0
70.0
R
R
R
492
7.3
8.29
Substrate concn 40 g/L, incubation time 16 h, temp 20 ꢁC, pH 7.0 (0.1 M sodium phosphate buffer) ratio of substrate/enzyme 1:0.3 (dry powder of
commercial enzyme) and 1:0.75 (lyophilized TBE). Ee% determined by HPLC using Chiralcel-OD-H with hexane/2-propanol (95:5) as the mobile
25
phase. The specific rotation of the resolved (S)-alcohol 1 (99% ee) was ½aꢁD ¼ ꢂ39.6 (c 0.8, CHCl3). The absolute configuration was determined by
comparison of the sign of the specific rotation with those reported.36 Specific optical rotation of the resolved alcohol was determined after separation
of the acyl ester and alcohol on silica gel column and elution with dichloromethane and methanol (19:1). The resolved bio-products were obtained in
overall yields of 75–80%.
OH
OCOR
CH3
O
O
O
O
CH3
+
TBE
OCOR
CH3
(S)-(-)-2
Enriched (R)-(+)-2a-c
O
O
OH
OCOR
CCL
PPL
PSL
O
O
(RS)-2a-c
CH3
CH3
+
2a, R= CH3
O
O
2b, R= CH2CH3
2c, R= CH2CH2CH3
(R)-(+)-2
OH
Enriched (S)-(-)-2a-c
OCOR
O
O
O
CH2CH2CH2CH3
CH2CH2CH2CH3
+
O
TBE
OCOR
(S)-(-)-3
Enriched (R)-(+)-3a-c
O
O
CH2CH2CH2CH3
OCOR
CH2CH2CH2CH3
OH
CCL
PPL
PSL
O
O
(RS)-3a-c
CH2CH2CH2CH3
+
O
O
3a, R= CH3
3b, R= CH2CH3
(R)-(+)-3
3c, R= CH2CH2CH3
Enriched (S)-(-)-3a-c
Scheme 2.
selectivity due to the presence of a carbon atom between
hydroxyl group and the stereogenic center. Naproxol,
that is, 2-(6-methoxy-2-naphthyl)propanol 4, which
was selected for these studies, is a commercially impor-
tant molecule that is reported to possess more potent
anti-inflammatory activity than (S)-naproxen.37 (S)-
Naproxol has reportedly been prepared by the use of lip-
ases and dehydrogenases with low to moderate ees.38,39
Its enantiomeric excess was further improved by a sec-
ond kinetic resolution reaction, for example, PPL cata-
lyzed double kinetic resolution.39 Microbial oxidation
of racemic naproxol using Glomerella cingulata has also
been used for the preparation of (R)-(+)-naproxol.40
Herein, racemic acylates of naproxols 4a–d were sub-
jected to kinetic resolution using TBE, CCL, PPL, and
PSL (Scheme 3). Except for PPL, which showed some-
what better selectivity (ee ꢀ 77%), the other three
enzymes including TBE proved to be ineffective in the
high resolution of the substrates 4a–c. Though long
chain alkyl esters of primary alcohols are reported to af-
ford products with higher ees,41 an increase in the size of
alkyl group such as in the acylate 4d, further decreased
the selectivity as well as the reactivity with the exception
of PPL where octanoyl ester displayed a significant
improvement in selectivity (ee ꢀ 91.4%). Here, both
TBE and PSL showed preference for the (R)-enantio-
mer, while CCL and PPL hydrolyzed the (S)-enantio-
mer. Table 3 summarizes the results obtained from
these studies. In these studies, standard (S)- and (R)-
naproxol were prepared by lithium aluminum hydride
(LAH) reduction of methyl esters of enantiomerically
pure (R)- and (S)-naproxen, respectively.
4. Hydrolysis of alkyl esters of carboxylic acids
4.1. Kinetic resolution of racemic 2-(5-bromo-6-methoxy-
2-naphthyl)propanoic acid 5
Racemic 2-(5-bromo-6-methoxy-2-naphthyl)propanoic
acid 5 is a key intermediate in the synthesis of
the anti-inflammatory drug naproxen.42a,b Generally,

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S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
Table 2. Hydrolysis of racemic acyl esters of 1-(3,4-methylenedioxyphenyl)ethanols 2a–c and 1-(3,4-methylenedioxyphenyl)pentanols 3a–c using
TBE and commercial enzymes CCL, PPL, and PSL
Entry
TBE
CCL
PPL
PSL
Conf.
Conv. ee
(%)
Conf. E Factor Conv. ee
(%) prod.
Conf. E Factor Conv. ee
(%) prod.
Conf. E Factor Conv. ee
(%) prod.
E
(%)
(%)
(%)
(%) prod. Factor
2a
2b
2c
37.4
33.6
27.4
98
28
08
S
S
S
179.7
2.0
1.2
42.6
43.2
43.6
98
98
98
R
R
R
216.7
222.8
227.2
41.4
38.5
30.7
98
98
97
R
R
R
206.7
185.9
100.3
45.3
43.2
39.4
98
98
99
R
R
R
249.7
222.8
388.3
3a
3b
3c
31.8
27.6
21.7
98
59
33
S
S
S
155.7
4.8
2.2
31.8
35.7
39.6
98
98
98
R
R
R
155.7
171.3
192.8
31.8
35.2
39.8
96
91
84
R
R
R
76.3
34.7
20.0
39.3
33.6
32.7
98
96
95
R
R
R
190.8
79.4
61.5
Substrate concn 40 g/L, incubation time 16 h, temp 20 ꢁC, pH 7.0 (0.1 M sodium phosphate buffer); ratio of substrate/enzyme 1:0.25 (dry powder of
commercial enzyme) and 1:0.75 (lyophilized TBE). Ee% determined by HPLC using Chiralcel-OD-H chiral column with hexane/2-propanol (95:5) as
25
25
the mobile phase. The specific rotation of the resolved (R)-alcohol 2 99% ee ½aꢁD ¼ þ55.4 (c 1, CHCl3), (S)-alcohol 3 (98% ee) ½aꢁD ¼ ꢂ61.9 (c 0.54,
CHCl3). Absolute configuration was determined by comparison of the sign of the specific rotation with those reported in the literature.26 The
combined yields of the resolved bio-products were in the range of 75–85%.
CH3
CH3
CH3OH
CH2OCOR
+
CH3OH
CH3O
TBE
PSL
CH3
CH2OCOR
Enriched (S)-(-)-4a-d
(R)-(+)-4
CH3
CH3
CH3O
CCL
PPL
CH2OCOR
(RS)-4a-d
CH3OH
+
CH3O
4a, R= CH3
CH3O
4b, R= CH2CH3
4c, R= CH2CH2CH3
4d, R= n-C7H15
Enriched (R)-(+)-4a-d
(S)-(-)-4
Scheme 3.
Table 3. Hydrolysis of racemic acyl esters of 2-(6-methoxy-2-naphthyl)propan-1-ol 4a–d using TBE and commercial enzymes CCL, PPL, and PSL
TBE CCL PPL PSL
Conf. E Factor Conv. ee Conf. E Factor Conv. ee Conf. E Factor Conv. ee Conf. E Factor
(%) prod.
R
Conv. ee
(%) (%) prod.
(%)
(%) prod.
(%)
(%) prod.
(%)
4a 39.0
4b 38.0
42.8
59.6
24.1
13.0
9.4
R
R
R
R
R
3.2
5.0
1.9
1.3
1.2
41.0
41.0
45.0
9.6
13.0
40.0
5.0
3.0
3.8
S
S
S
S
S
1.3
1.1
1.1
1.1
1.1
43.0
26.0
23.0
23.0
26.0
77.0
53.7
75.0
72.4
91.4
S
S
S
S
S
14.3
3.9
10.1
7.7
43.0
35.0
27.0
8.6
14.0
17.7
20.0
8.9
R
R
R
R
R
1.5
1.6
1.7
1.2
1.0
4c
4d 12.3
4d*
8.4
33.7
7.0
30.4
8.4
2.0
Authentic samples of (R)- and (S)-alcohols were prepared by LAH reduction of methyl esters of (R)-(ꢂ)- and (S)-(+)-6-methoxy-a-methyl-2-
naphthaleneacetic acid and purified by CC over SiO2 with dichloromethane/ethyl acetate (9:1) as the eluent to give (R)-alcohol (99%ee) with
25
25
½aꢁD ¼ þ17.5 (c 1, CHCl3) and (S)-alcohol (ee 99%) ½aꢁD ¼ ꢂ17.5 (c 1, CHCl3).
* Cosolvent 2-propanol 20% v/v with buffer (0.1 M phosphate), substrate concentration 35 g/L, incubation time 30 h, temp 26 ꢁC, pH 7.0, ratio of
substrate/enzyme 1:0.3 (dry powder of commercial enzyme) and 1:0.75 (lyophilized TBE). Ee% determined by HPLC using Whelk (R,R) O 1 chiral
column with mobile phase hexane/2-propanol/acetic acid (90:10:0.1). The combined yields of the resolved bio-products were in the range of 75–80%.
(S)-(+)-naproxen is obtained through a final step resolu-
tion of its esters by enzymatic hydrolysis whereas the
resolution at the penultimate stage, that is, the resolu-
tion of 5, may provide an alternative route to the asym-
metric synthesis thus making the process more simple
and economically advantageous.42c Earlier, we have also
successfully demonstrated the superiority of TBE in
the resolution of racemic naproxen.28 We, therefore,
envisaged to undertake the resolution of racemic 5a–c
(Scheme 4) and study the effect of a bulkier group such
as bromine on overall reactivity and selectivity. Most of
the alkyl esters of 5 proved to be poor substrates for the
two biocatalysts used in these transformations. TBE
hydrolyzed the methyl ester of racemic 5 to the corre-
sponding (S)-bromoacid with 43% enantiomeric excess.
Ethyl and butyl esters also proved to be equally poor
substrates for TBE both in terms of reactivity and selec-
tivity. However, in our hands the commercial enzyme

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2579
system.44 The high selectivity of TBE for (S)-naproxen
prompted us to explore the possibility of kinetic resolu-
tion of racemic ibuprofen, that is, 4-(2-methylpropyl)-a-
methyl phenylacetic acid 6. Therefore, racemic methyl,
ethyl, and butyl esters 6a–c were prepared and subjected
to hydrolysis using TBE (Scheme 5) as well as CCL. As
expected, TBE displayed high enantioselectivity for the
methyl and ethyl ester giving an (S)-acid of high enan-
tiomeric excess (E ꢀ 117 and 340, ee 98.5% and 99%,
respectively) but showed poor selectivity for higher
esters. Commercial lipase CCL, on the other hand was
also selective for methyl ester (E ꢀ 238, 98% ee), which
is in agreement with the results published earlier by
McConville et al.45 Table 5 summarizes the results of
these experiments.
Table 4. Hydrolysis of racemic esters of 2-(5-bromo-6-methoxy-2-
naphthyl)propanoic acid 5a–c using TBE and commercial enzyme
CCL
Entry
Enzyme
Time
(h)
Conv.
(%)
ee
(%)
Conf.
prod.
E Factor
5a
5b
5c
TBE
CCL
TBE
CCL
TBE
CCL
150
90
150
105
150
105
31
39
12
40
8.0
26.6
42.8
99
28.6
61.9
17.8
28.7
S
S
S
S
S
S
2.9
383
2.4
6.3
1.5
2.0
Substrate concentration 16 g/L, temp 30 ꢁC, pH 8.0 (0.1 M phosphate
buffer) ratio of substrate/enzyme 1:1 (dry powder of commercial
enzyme, lyophilized TBE). Ee% determined by HPLC using Whelk
(S,S)-O 1 chiral column (hexane/2-propanol/acetic acid, 90:10:0.1).
The specific rotation of the resolved (S)-acid ee >99% was
25
½aꢁD ¼ þ42.5 (c 1, CHCl3). The combined yields of the resolved bio-
Resolution studies of racemic substrates 1–6 clearly
showed the efficacy of TBE as an important esterase.
In general, during the kinetic resolution studies of alkyl
acylates of primary and secondary alcohols, it was
observed that TBE and commercial lipases exhibited
preferences for opposite enantiomers. However, in the
hydrolysis of alkyl esters of carboxylic acids, both
TBE and CCL displayed preference for the (S)-
enantiomers.
products were in the range of 60–70%.
CCL exhibited the highest enantioselectivity for the
methyl ester 5a affording (S)-5 in an enantiomerically
pure form (E ꢀ 383, >99% ee), while other esters 5b
and 5c displayed moderate selectivity. This is an impor-
tant outcome of these studies indicating that CCL can
be advantageously used for the resolution of the precur-
sor 5 for the preparation of (S)-naproxen. To the best of
our knowledge this is the first report of the use of CCL
for the preparation of (S)-5 with high enantiopurity. The
results of these studies are summarized in Table 4.
4.3. Kinetic resolution of racemic 2-(2-naphthyloxy)-
propanoic acid 7
In addition to naproxen and ibuprofen, we also studied
the resolution of naphthyloxypropanoic acid as sub-
strate for TBE (Scheme 6). Aryloxypropanoic acids are
reportedly associated with several biological activities,
such as herbicidal, hypocholesterolemic, microsomal,
stearoyl-Coa-desaturase activity46,47 thereby making
them valuable substrates for kinetic resolution. In these
experiments, TBE catalyzed hydrolysis of the alkyl es-
ters of racemic 2-(2-naphthyloxy)propanoic acid 7a–c
4.2. Kinetic resolution of racemic ibuprofen 6
Ibuprofen is one of the blockbuster drugs used in the
treatment of inflammation, pain, and fever.43 As in the
case of (S)-naproxen, it is the (S)-ibuprofen, which is
clinically active though it is reported that the (R)-enan-
tiomer isomerizes to the bioactive form in the biological
CH3
COOH
CH3
COOR
CH3
TBE
COOR
+
CCL
CH3O
CH3O
CH3O
Br
Br
Br
(RS)-5a-c
Enriched (R)-(-)-5a-c
(S)-(+)-5
5a, R= CH3
5b, R= CH2CH3
5c, R= CH2CH2CH2CH3
Scheme 4.
CH3
CH3
COOH
CH3
TBE
CCL
COOR
COOR
+
(RS)-6a-c
(S)-(+)-6
Enriched (R)-(-)-6a-c
6a, R= CH3
6b, R= CH2CH3
6c, R= CH2CH2CH2CH3
Scheme 5.

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S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
Table 5. Hydrolysis of racemic alkyl esters of 4-(2-methylpropyl)-a-methylphenylacetic acid 6a–c using TBE and commercial enzymes CCL
Entry
Enzyme
Time (h)
Conv. (%)
ee (%) product
Conf. (product)
E Factor
6a
TBE
CCL
TBE
CCL
TBE
CCL
96
36
96
48
96
48
34.8
43.0
32.2
34.0
7.2
98.5
98.0
99.0
63.0
17.4
22.3
S
S
S
S
S
S
117
2.4
340
6
0.9
1.4
6b
6c
27.0
Substrate concentration 50 g/L, temp 29 ꢁC, buffer pH 8.0 (0.1 M sodium phosphate) ratio of substrate/enzyme 1:0.7 (dry powder of commercial
enzyme, lyophilized TBE). Ee% determined by HPLC using Chiradex column with mobile phase (MeOH/H2O/TEA, 50:50:0.1). The combined yields
of the resolved bio-products were in the range of 70–80%.
Table 6. Hydrolysis of racemic alkyl esters of 2-(2-naphthyloxy)propanoic acid 7a–c using TBE and commercial CCL
Entry
TBE
Conf. prod.
CCL
Conf. prod.
Conv. (%)
ee (%)
E Factor
Conv. (%)
ee (%)
E Factor
7a
7b
7c
38.0
23.0
07.3
79.0
23.0
34.0
R
R
R
14.1
1.7
2.0
44.0
43.0
44.0
33.9
30.0
43.0
R
R
R
2.6
2.3
1.3
Substrate concentration 35 g/L, incubation time 64 h, temp 25 ꢁC, pH 7.5 (0.1 M sodium phosphate buffer), ratio of substrate/enzyme 1:0.6 (dry
powder of commercial enzyme) and 1:1 (lyophilized TBE powder). Ee% determined by HPLC using Whelk (S,S)-O 1 chiral column with mobile
25
phase (hexane/2-propanol/acetic acid, 90:10:0.1). The specific rotation of the resolved (R)-acid (ee 79%) was ½aꢁD ¼ þ49.2 (c 1, CHCl3,); ee 97%
25
½aꢁD ¼ þ60.1 (c 1, CHCl3) after crystallization. The combined yields of the resolved bio-products were in the range of 65–80%.
O
CH3
O
CH3
O
CH3
TBE
CCL
+
COOR
COOH
COOR
Enriched (S)-(-)-7a-c
(RS)-7a-c
(R)-(+)-7
7a, R= CH3
7b, R= CH2CH3
7c, R= CH2CH2CH2CH3
Scheme 6.
to afford the (R)-acid with 79% ee, which was highest for
the methyl ester (after one crystallization enantiopurity
improved to 97% and total yield 28%) but exhibited
low activity as well as selectivity for the higher homo-
logues. CCL also displayed poor selectivity for all the es-
ters to give the (R)-(+)-acid. Resolution of racemic 7 has
also been reported using microbial strains like G. cingu-
lata and Glocosporium olivarum.40 Table 6 summarizes
the results of the above experiments.
thio)propanoic acid 8a–c, 2-(n-butylthio)propanoic acid
9a–c, 2-(phenylthio)propanoic acid 10a–c, and 2-(benz-
ylthio)propanoic acid 11a–c were synthesized and sub-
jected to kinetic resolution using both TBE and CCL
(Scheme 7). The two enzymes exhibited opposite selec-
tivities for the esters of 2-(allylthio)propanoic acids
8a–c, however, CCL gave products with higher enantio-
purity (8c, E ꢀ 19.38, 86% ee) as compared to TBE. In
all other substrates 9–11a–c, both the enzymes displayed
a preference for the same enantiomer producing (R)-
acids. For the substrates 2-(n-butylthio)propanoic acid
esters 9a–c and 2-(phenylthio)propanoic acid esters
10a–c, TBE showed low to moderate selectivities and
CCL in comparison was even less effective. Tan et al.
have reported the resolution of substrate 10a using Pseu-
domonas cepacia with poor reactivity and high enanti-
oselectivity.51 Surprisingly, in the resolution of one of
the substrates 11a, that is, methyl ester of 2-(benzyl-
thio)propanoic acid, TBE displayed exceptionally high
enantioselectivity (E >1000, >99% ee) that steadily
decreased with increase in size of alkyl ester group
11b,c. Table 7 summarizes the results of the above
experiments.
5. Resolution of racemic 2-(allylthio)propanoic acid 8a–c,
2-(n-butylthio)propanoic acid 9a–c, 2-(phenylthio)propa-
noic acid 10a–c, and 2-(benzylthio)propanoic acid 11a–c
Herein, we also included the alkyl esters of 2-(allyl-
thio)propanoic acid 8a–c, 2-(n-butylthio)propanoic acid
9a–c, 2-(phenylthio)propanoic acid 10a–c, and 2-(ben-
zylthio)propanoic acid 11a–c, in order to explore the
potential of TBE in accepting a diverse range of sub-
strates. Enantiomerically enriched thio analogues, such
as 2-methyl-3-mercaptopropanoic acid or related com-
pounds, have found applications as chiral synthons
including components of enzyme inhibitors48,49 and also
as precursors of ACE inhibitors like captopril, analpril,
cizalapril, etc.50 Herein, racemic alkyl esters of 2-(allyl-
For the data obtained from the resolution studies of
alkyl esters of 8–11a–c and taking into consideration

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2581
CH3
CH3
S
COOH
S
COOR
+
CH3
TBE
CCL
(S)-(-)-8
Enriched (R)-(+)-8a-c
COOR
S
CH3
CH3
(RS)-8a-c
S
COOH
S
COOR
+
(R)-(+)-8
Enriched (S)-(-)-8a-c
CH3
CH3
CH3
TBE
S
S
COOR
COOH
S
COOR
Enriched (S)-(-)-9a-c
CH3
+
CCL
(RS)-9a-c
(R)-(+)-9
CH3
CH3
TBE
CCL
PhS
PhS
COOH
COOR
COOR
+
PhS
(RS)-10a-c
(R)-(+)-10
Enriched (S)-(-)-10a-c
CH3
CH3
CH3
TBE
CCL
PhCH2S
PhCH2S
COOR
PhCH
+
2S
COOR
COOH
(RS)-11a-c
(R)-(+)-11
Enriched (S)-(-)-11a-c
a, R= CH3
b, R= CH2CH3
c, R= CH2CH2CH2CH3
Scheme 7.
Table 7. Hydrolysis of racemic alkyl esters of 2-(allylthio) propanoic acid 8a–c, 2-(n-butylthio) propanoic acids 9a–c, 2-(phenylthio) propanoic acids
10a–c, and 2-(benzylthio) propanoic acids 11a–c using TBE and CCL
CCL
Conv.
TBE
Substrate
(entry)
Time
(h)
ee
(%)
Conf.
prod.
E Factor
Substrate
(entry)
Time
(h)
Conv.
(%)
ee
(%)
Conf.
prod.
E Factor
(%)
8a
8b
4
6
12
4
12
12
4
12
12
8
42.2
38.0
31.0
41.8
40.0
12.2
33.0
17.5
15.5
25.2
18.6
20.8
2.0
23.0
86.0
33.6
57.7
64.0
11.7
37.8
2.0
R
R
R
R
R
R
R
R
R
R
R
R
1.05
1.81
19.8
2.51
5.37
4.97
2.81
2.39
1.03
1.35
1.05
1.02
8a
8b
12
12
12
12
12
12
12
12
12
12
12
12
34.6
40.0
42.0
15.4
27.0
33.5
23.4
35.9
8.3
41.2
8.0
6.5
63.9
1.5
11.5
33.5
20.7
3.3
S
2.94
1.12
1.18
5.08
1.0
S
8c
9a
8c
9a
S
R
R
R
R
R
R
R
R
R
9b
9c
9b
9c
1.33
2.21
1.68
1.07
>1000
2.74
1.1
10a
10b
10c
11a
11b
11c
10a
10b
10c
11a
11b
11c
26.0
2.6
2.0
36.5
35.5
9.9
>99.5
38.4
5.8
12
12
Substrate concentration 50 g/L, pH 8.0 (0.1 M sodium phosphate buffer), temp 25 ꢁC, ratio of substrate/enzyme 1:0.45 (dry powder of commercial
enzyme, lyophilized TBE). Ee% determined by HPLC using Diacel OD-H chiral column (hexane/2-propanol, 95:5) with flow rate 0.5 mL/min. The
25
25
25
optical rotation of the resolved (S)-acid 8 ½aꢁD ¼ ꢂ30.7 {authentic sample ½aꢁD ¼ þ84.8, (c 1, CHCl3)}, (R)-acid 9 ½aꢁD ¼ þ18.3 {authentic sam-
25
25
25
ple ½aꢁD ¼ þ28.6, (c 1, CHCl3)}, (R)-acid 10 ½aꢁD ¼ þ24.0 {authentic sample +71.5, (c 1 CHCl3)} and (R)-acid 11, ½aꢁD ¼ þ129.1 {authentic
25
sample ½aꢁD ¼ þ130, (c 0.9, CHCl3)}. The absolute configuration was determined by a comparison of the sign of the specific rotation reported in
the literature51 as well as by the comparison of the sign of specific rotation with (R)-(+)-thio acid synthesized by condensation of enantiomerically
pure (S)-(ꢂ)-2-bromopropanoic acid with respective mercaptol in dry acetone/potassium carbonate to furnish, after usual workup, substituted (R)-
(+)-2-thiopropanoic acid. The combined yields of the resolved bio-products were in the range of 60–70%.
the selectivity factor E (which generally falls in the range
1–5) it can be concluded that most of them are poor sub-
strates for both TBE and CCL with the exception of 8c
and 11a. The determination of ee% and the absolute

2582
S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
configurations of the products was also established,
which is based on the data obtained from their mandel-
ate esters using a method described below.
fate solution for detection of the spots. All the com-
pounds were characterized by spectral methods, which
include FT-IR (Brucker 270-30), 1H NMR (Brucker
Avance DPX-200) at 200 MHz, and 13C NMR at
50 MHz with CDCl3 as solvent and TMS as internal
standard, MS on JEOL MSD-300 and GCMS-QP 2000.
The enantiopurity of resolved acid from the ester of 2-
(benzylthio)propanoic acid was determined by HPLC
(on a chiral column Whelk (S,S) O-1 using mobile phase
of hexane/2-propanol/acetic acid, 90:10:0.2). The ee% of
other kinetically resolved acids could not be determined
directly by chiral HPLC due to the failure to achieve res-
olution on chiral columns available with us. Therefore,
authentic (R)-mercaptoacids were synthesized by con-
densing (S)-(ꢂ)-2-bromopropanoic acid with alkyl mer-
captols, with the resulting enantiomerically enriched
(R)-mecaptoacids esterified with methyl (R)-mandelate.
For 1-(6-methoxy-2-naphthyl)ethanol, 1-(3,4-methylene-
dioxyphenyl)ethanol, and 1-(3,4-methylenedioxyphen-
yl)pentanol, the resolution was effected on Chiralcel
OD-H HPLC column (5 lm) using n-hexane/2-propanol
(95:5) with a flow rate of 0.5 mL/min. The enantiopurity
and progress of this reaction for aryloxypropanoic acid
was monitored by analyzing on Lichro Cart-250-4,
Whelk (S,S)- or (R,R)-O 1 (5 lm) chiral column (mobile
phase hexane/2-propanol/acetic acid, 90:10:0.1) flow
rate 0.8 mL/min and double array detector. For nap-
roxol the resolution was effected on Whelk (R,R)-O 1
chiral column using hexane/2-propanol/acetic acid
(90:10:0.1) with a flow rate of 0.5 mL/min. For 5-bro-
monaproxen the resolution was carried out on Whelk
(S,S)–O 1 chiral column (hexane/2-propanol/acetic acid,
90:10:0.1) with a flow rate of 0.8 mL/min. For ibuprofen
the resolution was effected on a Chiradex column (5 lm)
using methanol/water/triethylamine (50:50:0.1) with a
flow rate of 0.8 mL/min. Commercial lipases like por-
cine pancreatic lipase (PPL 2.33 U/mg solid) C. cylindr-
aceae lipase (CCL 1.5 U/mg solid) was procured from
Sigma Chemical, USA. Pseudomonas sp. (PSL, 13 U/
mg solid) was obtained as a gift from Amano, Japan.
The procured lipases were used as such without further
purification. Metrohm pH stat-718 was used for main-
taining pH during biotransformations.
1
The synthetic mandelates were analyzed by H NMR
to rule out the possibility of racemization, which might
have had occurred during the preparation of these (R)-
acids. However, in all the synthetic samples enantiome-
rically >98% was recorded by 1H NMR, which dis-
played
a single methine proton signal for the
diastereoisomer (R)-mecaptoacid mendalates whereas a
clear splitting of methine protons signals at d 5.9–6.0
for the (R)- and (S)-diastereoisomers was observed in
a racemic sample. A comparison of the specific rotation
values of synthesized (R)-acids and resolved acids
enabled us to determine their ee% to a fair degree of accu-
racy besides establishing their absolute configurations
by comparison of the signs of the specific rotations.
Table 7 summarizes the results of these experiments.
6. Conclusion
The efficacy and high enantioselectivity of hydrolase
producing strain TBE in its crude native form has been
effectively demonstrated on a broad spectrum of mole-
cules, which include the alkyl esters of alcohols and car-
boxylic acids, for example, 1-aryl alkanols, NSAIDS
(such as Ibuprofen), and a variety of thiocarboxylic
acids. Earlier, we have already demonstrated the high
efficacy of TBE in the resolution of anti-inflammatory
drug naproxen as well as chlorohydrin precursor of a
b-blocker drug propranalol. There are currently very
few esterases commercially available possessing such a
broad and diverse range of substrate acceptability.
TBE, which is fairly stable and robust, is another addi-
tion to such a small list of esterases.
The crude cell pellet of T. beigelli esterase (45 U/g dry
cell mass) was prepared by the method as reported ear-
lier.28 The cell biomass (TBE) was centrifuged, washed
twice with distilled water, and stored at ꢂ40 ꢁC in small
aliquots for future use. The wet cell biomass (150 g) was
lyophilized to a dry powder (38 g) and used directly for
kinetic resolution studies. Protein estimation was made
according LowryÕs method using BSA as the reference
protein.52
7.1. Preparation of 1-(6-methoxy-2-naphthyl)ethanol 1
Sodium borohydride (0.6 g, 15.8 mmol) in four install-
ments was added at ꢂ5 to 0 ꢁC in 30 min to a stirring
methanolic solution (100 mL) of 2-acetyl-6-methoxy-
naphthalene (10 g, 50 mmol) and the reaction monitored
by TLC. After the completion of the reaction, the con-
tents were concentrated in vacuo and the residue poured
in ice-water (100 mL), extracted with dichloromethane
(4 · 30 mL), organic layer washed with brine
(2 · 15 mL), dried over anhydrous sodium sulfate, and
concentrated. The crude reaction product was purified
by chromatography over silica gel using toluene/ethyl
acetate (7:3) as the eluant to afford the carbinol 1 as a
crystalline white solid, mp 113–114 ꢁC (9.54 g,
47.2 mmol, 94.4%); IR (KBr): 3333, 3007, 1632, 1606,
1504, 1487, 1463, 1390, 1348, 1260, 1235, 1217, 1195,
7. Experimental
All the reagents used in the study were of analytical
grade. The authenticity of racemic esters prepared dur-
ing the study was confirmed by spectroscopic analysis
including NMR, LC/MS, and that of the resolved enan-
tiomers by specific rotation and chiral chromatographic
methods. Melting points recorded by capillary method
are uncorrected. The optical rotations were measured
on a Perkin–Elmer 241 polarimeter with chloroform as
the solvent. Chiral HPLC analysis carried out on Shima-
dzu LC10 AT model. TLCs were run on 0.25 mm silica
gel 60 F254 plates (E. Merck) using UV light, or ceric sul-
1163, 1119, 1073, 1028, 961, 930, 892, 853, 815 cmꢂ1
1H NMR (200 MHz): d 1.57 (3H, d, J = 6.4 Hz, CH3),
;

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2583
3.92 (3H, s, –OCH3), 5.03 (1H, q, J = 6.3 Hz, CHOH),
7.13 (2H, m, Ar–H), 7.50 (1H, dd, J = 8.0 and 1.2 Hz,
Ar–H), 7.70 (3H, m, Ar–H); 13C NMR (50 MHz): d
24.9, 55.2, 70.0, 105.7, 118.9, 123.7, 124.4, 127.0,
128.7, 129.4, 133.9, 141.0, 157.5; MS (m/z) (%): 202
(70), 188 (13), 187 (100), 159 (73), 144 (84), 141 (10),
127 (22), 115 (44), 93 (9), 89 (6), 64 (11); Anal. Calcd
for C13H14O2: C, 83.83; H, 7.57. Found: C, 83.99; H,
7.58.
reaction (monitored by TLC), the mixture was poured
in ice-water and extracted with dichloromethane
(3 · 50 mL). The organic layer separated and washed
with water (2 · 20 mL), dried over sodium sulfate, con-
centrated in vacuo, and purified by chromatography
over silica gel using toluene/ethyl acetate in increasing
proportion as eluant to give the following acyl esters;
1a (2.24 g, 9.2 mmol, 91.8%): 1b (2.35 g, 9.1 mmol,
90.18%); 1c (2.46 g, 9.04 mmol, 90.0%). 2a (2.95 g,
14.2 mmol, 94.8%); 2b (3.04 g, 13.7 mmol, 91.2%); 2c
(3.23 g, 13.7 mmol, 92.1%). 3a (3.60 g, 14.4 mmol,
96.2%); 3b (3.8 g, 14.4 mmol, 96.4%), and 3c (3.94 g,
14.2 mmol, 94.4%).
7.2. Preparation of 1-(3,4-methylenedioxyphenyl)ethanol
2 and 1-(3,4-methylenedioxyphenyl)pentanol 3
Dry diethyl ether solution (100 mL) of piperonal (7.5 g
each, 50 mmol each) under nitrogen current was added
to Grignard reagent prepared by reacting methyl
iodide/n-butyl bromide (65 mmol) and magnesium
metal (70 mmol) in dry ether (120 mL) at 0–5 ꢁC. After
the completion of the reaction and usual workup, it
was purified by column chromatography over silica gel
using pet. ether/ethyl acetate (17:3) as eluant to give
corresponding carbinols 2 (a colorless liquid, 8.1 g,
48.8 mmol, 96.4%) and 3 (a colorless liquid, 9.8 g,
47.1 mmol, 94.2%).
7.3.1. 1-Acetoxy-1-(6-methoxy-2-naphthyl)ethane 1a.
A
white solid; mp 66 ꢁC; IR (KBr): 2972, 2939, 1732, 1631,
1606, 1506, 1486, 1461, 1420, 1391, 1309, 1238, 1179,
1120, 1107, 1083, 1025, 994, 962, 930, 900, 855,
808 cmꢂ1
;
1H NMR (200 MHz): d 1.64 (3H, d,
J = 7.2 Hz, CH3), 2.08 (3H, s, OCOCH3), 3.92 (3H, s,
OCH3), 6.0 (1H, q, J = 7.2 Hz, CH–O), 7.08 (1H, s,
Ar–H), 7.15 (1H, d, J = 8.1 Hz, Ar–H), 7.40 (1H, d,
J = 8.5 Hz, Ar–H), 7.48–7.72 (3H, m, Ar–H); 13C
NMR (50 MHz): d 21.4, 22.1, 55.3, 72.5, 105.7, 119.1,
124.8, 125.1, 127.2, 128.7, 129.5, 134.3, 136.7, 157.9,
170.4; MS (m/z) (%): 244 (58), 201 (13), 187 (49), 185
(9), 171 (10), 169 (100), 153 (32), 141 (38), 128 (15),
127 (19), 114 (12); Anal. Calcd for C15H16O3: C,
78.91; H, 7.06. Found: C, 79.02; H, 7.11.
7.2.1. 1-(3,4-Methylenedioxyphenyl)ethanol 2. A color-
less liquid; IR (KBr): 3374, 2973, 1609, 1503, 1488, 1442,
1371, 1320, 1244, 1189, 1130, 1101, 1074, 1039, 1008,
1
926, 877, 813 cmꢂ1; H NMR (200 MHz): d 1.41 (3H,
d, J = 6.3 Hz, CH3), 4.76 (1H, q, J = 6.3 Hz, CHOH),
5.9 (2H, s, CH2O), 6.73 (1H, d, J = 8.0 Hz, Ar–H),
6.83 (1H, d, J = 8.6 Hz, Ar–H), 6.85 (1H, s, Ar–H);
13C NMR (50 MHz): d 25.1, 70.0, 100.9, 106.0, 108.1,
118.6, 140.1, 141.7, 147.6; MS (m/z) (%): 166 (38), 151
(53), 123 (24), 121 (8), 93 (100), 75 (15), 66 (56), 65
(58); Anal. Calcd for C9H10O3: C, 65.05; H, 6.065.
Found: C, 65.43; H, 6.071.
7.3.2. 1-Propanoyloxy-1-(6-methoxy-2-naphthyl)ethane
1b. A white solid; mp 58–59 ꢁC; IR (KBr): 2974,
2941, 1733, 1632, 1607, 1505, 1486, 1460, 1419, 1391,
1363, 1328, 1309, 1269, 1237, 1179, 1122, 1105, 1084,
1056, 1025, 994, 962, 925, 856, 821, 807 cmꢂ1 1H
;
NMR (200 MHz): d 1.16 (3H, t, J = 7.5 Hz, CH3),
1.62 (3H, d, J = 6.5 Hz, CH3), 2.38 (2H, q, J = 7.4 Hz,
COCH2), 3.92 (3H, s, OCH3), 6.05 (1H, q, J = 6.5 Hz,
CHCH3), 7.14–7.26 (2H, m, Ar–H), 7.46 (1H, dd,
J = 1.4 and 8.3 Hz, Ar–H), 7.72–7.76 (3H, m, Ar–H);
13C NMR (50 MHz): d 9.15, 22.2, 27.9, 55.3, 72.3,
106.7, 119.1, 124.7, 124.9, 127.2, 128.6, 129.5, 134.2,
136.9, 157.8, 173.8; MS (m/z) (%): 258 (39), 202 (38),
187 (15), 185 (100), 170 (18), 153 (10), 141 (27), 115
(19), 58 (23); Anal. Calcd for C16H18O3: C, 79.91; H,
7.06. Found: C, 79.98; H, 7.08.
7.2.2. 1-(3,4-Methylenedioxyphenyl)pentanol 3. A col-
orless liquid; IR (neat): 3381, 2931, 1630, 1609, 1503,
1487, 1442, 1379, 1326, 1245, 1187, 1109, 1091, 1041,
1
935, 866, 811, 777, 640 cmꢂ1; H NMR (200 MHz): d
0.87 (3H, t, J = 6.7 Hz, CH3), 1.16–1.33 (4H, m,
2 · CH2), 1.60–1.77 (2H, m, CH2), 4.51 (1H, t, J = 6.4,
CHOH), 5.92 (2H, s, CH2O), 6.74 (2H, s, Ar–H), 6.77
(1H, s, Ar–H); 13C NMR (50 MHz): d 14.0, 22.6, 28.0,
38.7, 74.5, 100.9, 106.4, 108.0, 119.3, 139.1, 146.8,
147.7; MS (m/z) (%): 208 (100), 190 (7), 152 (98), 149
(37), 148 (10), 135 (19), 123 (95), 121 (31), 93 (98), 89
(12), 77 (42), 66 (26), 65 (97); Anal. Calcd for
C12H16O3: C, 69.20; H, 7.74. Found: C, 69.69; H, 7.72.
7.3.3.
1-Butanoyloxy-1-(6-methoxy-2-naphthyl)ethane
1c. A white solid; mp 35 ꢁC; IR 2964, 2934, 1731,
1633, 1608, 1547, 1506, 1485, 1461, 1418, 1391, 1308,
1265, 1238, 1220, 1173, 1063, 1032, 951, 924, 892, 851,
810 cmꢂ1
; d 0.95 (3H, t,
1H NMR (200 MHz):
7.3. General method for the preparation of acyl deriva-
tives of compounds 1-(6-methoxy-2-naphthyl)ethanol 1, 1-
(3,4-methylenedioxyphenyl)ethanol 2, and 1-(3,4-methyl-
enedioxyphenyl)pentanol 3: preparation of 1a–c, 2a–c,
and 3a–c
J = 7.3 Hz, CH3), 1.57 (3H, d, J = 6.2 Hz, CHCH3),
1.60–1.72 (2H, m, CH2), 2.32 (2H, t, J = 7.2 Hz,
CH2CO), 3.87 (3H, s, OCH3), 6.05 (1H, q, J = 6.2 Hz,
O–CH), 7.11 (1H, s, Ar–H), 7.15 (1H, d, J = 8.5 Hz,
Ar–H), 7.46 (1H, dd, J = 8.5 and 1.42 Hz, Ar–H),
7.69–7.73 (3H, m, Ar–H); 13C NMR (50 MHz): d 13.6,
18.2, 22.1, 36.1, 55.2, 72.3, 105.6, 119.0, 124.7, 124.9,
127.2, 128.6, 129.5, 134.2, 136.8, 157.8, 173.3; MS (m/z)
(%): 272 (32), 202 (40), 185 (100), 170 (16), 154 (8),
141 (26), 115 (17), 45 (39); Anal. Calcd for C17H20O3:
C, 79.65; H, 7.86. Found: C, 79.88; H, 7.83.
Acyl derivatives of 1–3 were prepared by subjecting
secondary alcohols (10 mmol) to react with respective
alkanoic anhydrides (15 mmol) in the presence of
dimethylaminopyridine (DMAP, 5 mg) and the contents
heated for 5 min at 50 ꢁC. After the completion of the

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S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
7.3.4.
1-Acetoxy-1-(3,4-methylenedioxyphenyl)ethane
1610, 1504, 1490, 1445, 1380, 1359, 1335, 1248, 1185,
1108, 1080, 1040, 935, 891, 862, 728, 639 cmꢂ1 1H
2a. A colorless liquid; IR (KBr): 2982, 1739, 1609,
;
1489, 1444, 1360, 1244, 1173, 1124, 1097, 1080, 1039,
NMR (200 MHz): 0.84 (3H, t, J = 7.0 Hz, CH3), 1.05–
1.31 (7H, m, 2 · CH2 and CH3), 1.63–1.93 (2H, m,
CH2), 2.30 (2H, q, J = 7.0 Hz, COCH2), 5.67 (1H, t,
J = 7.0 Hz, OCH), 5.89 (2H, s, OCH2), 6.69–6.80 (3H,
m, Ar–H); 13C NMR (50 MHz): d 9.0, 13.9, 22.4, 27.7,
27.8, 36.0, 75.8, 101.0, 126.9, 108.0, 120.3, 135.0,
147.1, 147.7, 173.8; MS (m/z) (%): 264 (26), 208 (21),
191 (12), 161 (13), 151 (100), 135 (51), 131 (17), 103
(8), 93 (10), 77 (12), 65 (16), 58 (89); Anal. Calcd for
C15H20O4: C, 68.16; H, 7.626. Found: C, 68.63; H,
7.666.
1
1015, 933, 867, 842, 808, 745, 727, 717, 699 cmꢂ1; H
NMR (200 MHz): d 1.49 (3H, d, J = 6.5 Hz, CH3),
2.06 (3H, s, CH3), 5.79 (1H, q, J = 6.5 Hz, CH), 5.93
(2H, s, OCH2O), 6.75 (1H, d, J = 8.5 Hz, Ar–H), 6.78
(1H, d, J = 8.5 Hz, Ar–H), 6.85 (1H, s, Ar–H); 13C
NMR (50 MHz): d 21.3, 22.1, 72.1, 101.0, 106.7, 108.1,
119.8, 135.6, 147.2, 147.8, 170.2; MS (m/z) (%): 208
(23), 152 (12), 148 (100), 135 (27), 133 (42), 105 (14),
93 (28), 77 (49), 65 (12); Anal. Calcd for C11H12O4: C,
63.45; H, 5.580. Found: C, 63.91; H, 5.813.
7.3.5. 1-Propanoyloxy-1-(3,4-methylenedioxyphenyl)eth-
ane 2b. A colorless liquid; IR (KBr): 2981, 1734,
1610, 1505, 1490, 1445, 1361, 1324, 1249, 1186, 1137,
1104, 1081, 10389, 1009, 937, 921, 894, 861, 809,
7.3.9. 1-Butanoyloxy-1-(3,4-methylenedioxyphenyl)pen-
tane 3c. A colorless liquid; IR (KBr): 2960, 1734,
1610, 1504, 1490, 1381, 1303, 1247, 1178, 1095, 1040,
967, 936, 909, 861, 728, 638 cmꢂ1
;
1H NMR
728 cmꢂ1
;
1H NMR (200 MHz):
d
1.09 (3H, t,
(200 MHz): d 0.90 (3H, t, J = 7.1 Hz, CH3), 1.0 (3H, t,
J = 7.4 Hz, CH3), 1.09–1.34 (4H, m, 2 · CH2), 1.55–
1.73 (4H, m, 2 · CH2), 2.30 (2H, q, J = 7.7 Hz,
COCH2), 5.68 (1H, t, J = 7.0 Hz, CH–O), 5.96 (2H, s,
OCH2O), 6.78 (1H, d, J = 7.7 Hz, Ar–H), 6.83 (1H,
dd, J = 1.1 and 7.9 Hz, Ar–H), 6.84 (1H, s, Ar–H);
13C NMR (50 MHz): d 13.56, 13.62, 18.16, 22.40,
27.69, 35.90, 36.50, 75.79, 101.0, 106.9, 108.0, 120.3,
134.9, 147.1, 147.7, 173.0; MS (m/z) (%): 278 (4), 221
(12), 208 (35), 191 (16), 161 (17), 152 (9), 151 (100),
149 (21), 135 (71), 131 (20), 103 (10), 77 (14), 71 (94),
65 (17); Anal. Calcd for C16H22O4: C, 69.04; H, 7.966.
Found: C, 69.22; H, 7.972.
J = 7.5 Hz, CH3), 1.51 (3H, d, J = 6.3 Hz, CH3), 2.31
(2H, q, J = 7.5 Hz, COCH2), 5.8 (1H, q, J = 6.5 Hz,
CHCH3), 5.89 (2H, s, OCH2O), 6.73 (1H, d,
J = 8.0 Hz, Ar–H), 6.77 (1H, d, J = 8.0 Hz, Ar–H),
6.81 (1H, s, Ar–H); 13C NMR (50 MHz): d 8.96, 22.1,
27.7, 71.9, 101.0, 106.6, 108.0, 119.6, 135.7, 147.1,
147.7, 173.6; MS (m/z) (%): 222 (83), 166 (82), 151
(46), 149 (100), 148 (98), 121 (10), 119 (45), 93 (12), 89
(21), 77 (11), 65 (64); Anal. Calcd for C12H14O4: C,
64.85; H, 6.349. Found: C, 65.01; H, 6.352.
7.3.6. 1-Butanoyloxy-1-(3,4-methylenedioxyphenyl)eth-
ane 2c. A colorless liquid; IR (KBr): 2968, 1733,
1610, 1505, 1490, 1445, 1373, 1325, 1248, 1180, 1137,
7.4. Preparation of 2-(6-methoxy-2-naphthyl)propan-1-ol
4
1
1103, 1039, 1005, 937, 810 cmꢂ1; H NMR (200 MHz):
d
0.91 (3H, t, J = 7.4 Hz, CH3), 1.48 (3H, d,
J = 6.6 Hz, CH3), 1.77 (2H, h, J = 7.3 Hz, CH2), 2.25
(2H, t, J = 7.2 Hz, COCH2), 5.81 (1H, q, J = 6.5 Hz,
CH), 5.90 (2H, s, OCH2O), 6.75 (1H, d, J = 8.0 Hz,
Ar–H), 6.77 (1H, d, J = 8.0 Hz, Ar–H), 6.84 (1H, s,
Ar–H); 13C NMR (50 MHz): d 13.5, 18.5, 22.2, 36.4,
71.8, 101.0, 106.6, 108.2, 119.7, 135.7, 147.1, 147.7,
172.8; MS (m/z) (%): 236 (84), 166 (100), 151 (40), 149
(100), 148 (98), 121 (11), 119 (50), 91 (94), 89 (22), 77
(12), 71 (54), 65 (68); Anal. Calcd for C13H16O4: C,
66.08; H, 6.825. Found: C, 66.77; H, 6.849.
Lithium aluminum hydride (LAH) (1.2 g) was added
slowly to a solution of racemic methyl 2-(6-methoxy-2-
naphthyl)propanoic acid (9.4 g, 41 mmol) in dry diethyl
ether (100 mL) and after the completion of the reaction
(monitored by TLC), the reaction was worked up by
quenching the excess of LAH by the addition of ethyl
acetate. The contents were diluted with water, the
organic layer separated and aqueous layer extracted
with solvent ether (2 · 50 mL). The combined organic
layer was washed with water (2 · 15 mL) dried over
sodium sulfate and concentrated to give crude product,
which on column chromatography over silica gel using
dichloromethane/ethyl acetate (9:1) gave 4 (8.02 g,
37.12 mmol, 92.3%); A white solid; mp 88 ꢁC; IR
(KBr): 3346, 2961, 2936, 1734, 1633, 1605, 1502, 1484,
1461, 1414, 1392, 1323, 1264, 1212, 1164, 1121, 1102,
7.3.7. 1-Acetoxy-1-(3,4-methylenedioxyphenyl)pentane
3a. A colorless liquid; IR (KBr): 3074, 2957, 1731,
1631, 1610, 1504, 1445, 1370, 1335, 1237, 1109, 1096,
1040, 935, 907, 861, 811, 621 cmꢂ1
;
1H NMR
(200 MHz): d 0.86 (3H, t, J = 7.0 Hz, CH3), 1.15–1.32
(4H, m, 2 · CH2), 1.71–2.0 (2H, m, CH2), 2.04 (3H, s,
COCH3), 5.64 (1H, t, J = 7.0 Hz, CHOH), 5.90 (2H, s,
CH2O), 6.70–6.82 (3H, m, Ar–H); 13C NMR
(50 MHz): d 13.9, 21.2, 22.4, 27.7, 35.9, 76.0, 101.0,
106.9, 108.0, 120.4, 134.7, 147.2, 147.7, 170.3; MS
(m/z) (%): 250 (100), 208 (56), 193 (52), 161 (47), 152
(98), 148 (58), 135 (99), 131 (77), 103 (35), 93 (96), 77
(47), 65 (90); Anal. Calcd for C14H18O4: C, 67.18; H,
7.248. Found: C, 67.31; H, 7.255.
1029, 959, 927, 882, 854, 813 cmꢂ1
;
1H NMR
(200 MHz): d 1.38 (3H, d, J = 7.0 Hz, CH3), 3.0–3.11
(1H, m, CH), 3.74 (2H, d, J = 6.8 Hz, CH2OH), 3.90
(3H, s, OCH3), 7.13 (1H, d, J = 2.4 Hz, Ar–H), 7.16
(1H, d, J = 8.39 Hz, Ar–H), 7.36 (1H, dd, J = 8.4 and
1.6 Hz, Ar–H), 7.6 (1H, s, Ar–H), 7.77 (2H, dd, J =
2.4 and 8.5 Hz, Ar–H); 13C NMR (50 MHz): d 17.7,
42.4, 51.2, 55.3, 68.6, 105.6, 118.9, 125.9, 126.3, 127.2,
129.1, 133.6, 138.7, 157.5; MS (m/z) (%): 216 (12), 198
(8), 189 (19), 177 (21), 161 (100), 140 (13), 134 (37),
118 (20), 82 (10), 80 (12), 63 (21); Anal. Calcd for
C14H16O2: C, 77.74; H, 7.45. Found: C, 77.99; H, 7.44.
7.3.8. 1-Propanoyloxy-1-(3,4-methylenedioxyphenyl)pen-
tane 3b. A colorless liquid; IR (KBr): 2957, 1737, 1631,

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2585
7.5. General method for the preparation of alkyl acyl
derivatives of compounds 2-(6-methoxy-2-naphthyl)-
propan-1-ol 4: preparation of 4a–d
(63), 171 (100), 144 (92), 127 (44), 115 (39), 89 (4), 77
(8), 58 (8); Anal. Calcd for C17H20O3: C, 74.97; H,
7.40. Found: C, 75.11; H, 7.43.
The esters of racemic 4 were prepared by taking
10 mmol each of racemic 4 and adding alkanoic anhy-
drides (acetic anhydride, propanoic anhydride, butyric
anhydride, 15 mmol each) in the presence of catalytic
amounts of DMAP and the contents heated to 50 ꢁC
for half an hour and thereafter stirred at room temper-
ature for a further 24 h. The reaction mixture was
poured into ice-water and the crude solids washed
several times with cold water and then dissolved in
dichloromethane (50 mL), dried over sodium sulfate,
concentrated, and crystallized from pet. ether/ethylace-
tate (17:3) to give 4a (2.50 g, 9.7 mmol, 97.2%), 4b
(2.61 g, 9.6 mmol, 96.6%), and 4c (2.74 g, 9.6 mmol,
95.8%).
7.5.3. 1-Butanoyloxy-2-(6-methoxy-2-naphthyl)propane
4c. A white solid; mp 37 ꢁC; IR (KBr): 2976, 1734,
1506, 1486, 1458, 1392, 1368, 1267, 1233, 1182, 1163,
1140, 1083, 1030, 872, 817, 670 cmꢂ1
;
1H NMR
(200 MHz): d 1.07 (3H, t, J = 7.5 Hz, CH3), 1.35 (3H,
d, J = 7.0 Hz, CH3CH), 1.42–1.46 (2H, m, CH2), 2.26
(2H, t, J = 7.5 Hz, COCH2), 3.24 (1H, q, J = 7.0 Hz,
CH3CH), 3.88 (3H, s, OCH3), 4.23 (2H, ddd, J = 18.2,
10.8, and 7.2 Hz, OCH2), 7.1 (1H, s, Ar–H), 7.12 (1H,
d, J = 8.0 Hz, Ar–H), 7.32 (1H, dd, J = 1.4 and
8.4 Hz, Ar–H), 7.57 (1H, s, Ar–H), 7.68 (2H, d,
J = 8.3 Hz, Ar–H); 13C NMR (50 MHz): d 13.2, 18.2,
27.6, 38.9, 55.3, 69.3, 105.6, 118.9, 125.6, 126.3, 127.0,
129.0, 129.2, 133.5, 138.4, 157.5, 174.5; MS (m/z) (%):
286 (4), 198 (100), 185 (33), 170 (10), 153 (7), 141 (10),
115 (7), 45 (26); Anal. Calcd for C18H22O3: C, 75.49;
H, 7.743. Found: C, 75.92; H, 7.77.
The octanoate derivative 4d was prepared by stirring a
dichloromethane solution (50 mL) of racemic 4 (2.2 g,
>10 mmol), DCC (2.5 g, 12 mmol), and octanoic acid
(1.8 g, 13 mmol) in the presence of a catalytic amount
of DMAP (10 mg) for 12 h. The contents diluted with
n-hexane (20 mL), the precipitate filtered, and washed
with n-hexane/dichloromethane (9:1, 30 mL). The com-
bined filtrate was concentrated and dissolved in ethyl
acetate (60 mL), washed with water (2 · 10 mL), the
organic layer dried, concentrated, and the product chro-
matographed over silica gel and eluted with pet. ether/
ethyl acetate mixture (19:1) to give 4d (3.29 g, 9.6 mmol,
96.2%).
7.5.4. 1-Octanoyloxy-2-(6-methoxy 2-naphthyl)propane
4d. A white solid; mp 24 ꢁC; IR (KBr): 2967, 1731,
1634, 1607, 1506, 1485, 1463, 1418, 1319, 1266, 1106,
1033, 961, 886, 851, 811, 674 cmꢂ1
;
1H NMR
(200 MHz): d 0.85 (3H, t, J = 6.8 Hz, CH3), 1.20–1.27
(8H, m, 4 · CH2), 1.36 (3H, d, J = 7.0 Hz, CH3CH),
1.50–1.56 (2H, m, CH2), 2.24 (2H, t, J = 7.4 Hz,
COCH2), 3.17–3.27 (1H, m, CHCH3), 3.89 (3H, s,
OCH3), 4.24 (2H, ddd, J = 20.2, 10.8, and 7.2 Hz,
CH2CH), 7.10 (1H, s, Ar–H), 7.13 (1H, dd, J = 2.3
and 8.5 Hz, Ar–H), 7.33 (1H, dd, J = 1.5 and 8.5 Hz,
Ar–H), 7.58 (1H, s, Ar–H), 7.68 (2H, d, J = 8.4 Hz,
Ar–H); 13C NMR (50 MHz): d 14.1, 18.2, 22.6, 25.0,
28.9, 29.1, 31.7, 34.4, 38.9, 55.3, 69.2, 105.6, 118.9,
125.6, 126.3, 127.0, 129.1, 129.2, 133.6, 138.41, 157.5,
173.9; MS (m/z) (%): 342 (2), 199 (100), 186 (19), 155
(3), 141 (4), 116 (3), 58 (7); Anal. Calcd for C22H30O3:
C, 77.15; H, 8.828. Found: C, 77.86; H, 8.833.
7.5.1.
1-Acetoxy-2-(6-methoxy-2-naphthyl)propane
4a. A white solid; mp 64–65 ꢁC; IR 2969, 1739, 1630,
1606, 1505, 1486, 1463, 1390, 1367, 1233, 1182, 1162,
1
1032, 980, 855, 816, 675 cmꢂ1; H NMR (200 MHz): d
1.37 (3H, d, J = 7.0 Hz, CH3), 2.06 (3H, s, COCH3),
3.17–3.27 (1H, m, CH), 3.91 (3H, s, OCH3), 4.24 (2H,
ddd, J = 17.8, 10.8, and 7.3 Hz, CH2O), 7.11 (1H, s,
Ar–H), 7.13 (1H, d, J = 8.2 Hz, Ar–H), 7.33 (1H, d,
J = 8.5 Hz, Ar–H), 7.59 (1H, s, Ar–H), 7.70 (2H, d,
J = 8.5 Hz, Ar–H); 13C NMR (50 MHz): d 18.2, 20.9,
38.8, 55.3, 69.5, 105.6, 118.9, 125.5, 126.3, 127.0,
129.0, 129.2, 133.5, 138.4, 157.5, 171.1; MS (m/z) (%):
258 (12), 198 (100), 185 (50), 170 (15), 153 (10), 141
(13), 128 (40), 115 (10), 45 (43); Anal. Calcd for
C16H18O3: C, 74.39; H, 7.02. Found: C, 74.88; H, 7.08.
7.6. Preparation of compounds 2-(5-bromo-6-methoxy-2-
naphthyl)propanoic acid 5, 4-(2-methylpropyl)-a-methyl-
phenylacetic acid 6, and 2-(2-naphthyloxy)propanoic acid
7
Compound 5 was received as a gift sample from an
Indian Pharma company while commercially available
compound 6 was used directly for the preparation of
its alkyl esters. Compound 7 was prepared by refluxing
an acetone solution of b-naphthol (15 g, 104 mmol,
160 mL) and 2-bromopropanoic acid (18 mL,
120 mmol) for 46 h. After completion of reaction it
was concentrated in vacuo followed by dilution with di-
lute HCl to pH 2. The contents were extracted with ethyl
acetate (4 · 100 mL), the organic layer washed with
water (2 · 50 mL) dried over sodium sulfate, and con-
centrated to give crude product, which on purification
by cc over silica gel and elution with pet. ether/ethyl ace-
tate (4:1) afforded 7 (20.4 g, 94.5 mmol, 90%).
7.5.2. 1-Propanoyloxy-2-(6-methoxy-2-naphthyl)propane
4b. A white solid; mp 60–62 ꢁC; IR (KBr): 2977, 1733,
1631, 1606, 1506, 1460, 1418, 1392, 1379, 1369, 1267,
1
1233, 1181, 1164, 1030, 897, 817, 671 cmꢂ1; H NMR
(200 MHz): d 1.07 (3H, t, J = 7.5 Hz, CH3), 1.40 (3H,
d, J = 7.0 Hz, CH3), 2.27 (2H, q, J = 7.5 Hz, COCH2),
3.17–3.27 (1H, m, CHCH3), 3.89 (3H, s, OCH3), 4.24
(2H, ddd, J = 18.3, 10.5, and 7.2 Hz, OCH2), 7.10
(1H, s, Ar–H), 7.13 (1H, dd, J = 2.4 and 8.2 Hz, Ar–
H), 7.32 (1H, dd, J = 8.45 and 1.67 Hz, Ar–H), 7.58
(1H, d, J = 8.4 Hz, Ar–H), 7.73 (2H, d, J = 8.2 Hz,
Ar–H); 13C NMR (50 MHz): d 9.18, 18.2, 27.6, 38.9,
55.3, 69.3, 105.6, 118.9, 125.6, 126.3, 126.9, 129.1,
129.2, 133.5, 138.4, 157.5, 174.5; MS (m/z) (%): 272
7.6.1. 2-(5-Bromo-6-methoxy-2-naphthyl)propanoic acid
5. A white solid; mp 177–179 ꢁC; IR (KBr): 3320,

2586
S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2973, 2942, 1701, 1627, 1598, 1555, 1495, 1480, 1457,
1440, 1414, 1378, 1352, 1335, 1273, 1252, 1229, 1200,
9.4 mmol, 93.8%); 6a (2.18 g, 9.9 mmol, 94.7%), 6b
(2.26 g, 9.7 mmol, 93.4%), 6c (2.51 g, 9.6 mmol,
92.3%); 7a (2.10 g, 9.1 mmol, 95.4%), 7b (2.2 g,
9.0 mmol, 94.9%), and 7c (2.50 g, 9.2 mmol, 95.8%).
1181, 1158, 1061, 973, 820, 800 cmꢂ1
;
1H NMR
(200 MHz): d 1.56 (3H, d, J = 6.6 Hz, CH3), 3.9 (1H,
q, J = 7.2 Hz, CH), 3.99 (3H, s, OCH3), 7.22 (1H, d,
J = 8.8 Hz, Ar–H), 7.50 (1H, d, J = 8.4 Hz, Ar–H),
7.66 (1H, s, Ar–H), 7.72 (1H, d, J = 8.8 Hz, Ar–H),
8.16 (1H, d, J = 8.3 Hz, Ar–H); 13C NMR (50 MHz):
d 18.4, 45.3, 57.1, 108.5, 114.0, 126.4, 126.6, 127.2,
127.8, 129.0, 132.4, 136.8, 153.8, 177.3; MS (m/z) (%):
308 (Mꢂ1) (30), 278 (6), 264 (100), 227 (3), 197 (9),
183 (35), 169 (29), 153 (40); Anal. Calcd for
C14H13BrO3: C, 54.57; H, 4.238. Found: C, 54.940; H,
4.246.
7.7.1. Methyl 2-(5-bromo-6-methoxy-2-naphthyl)propa-
noic acid 5a. A white solid; mp 72–73 ꢁC; IR (KBr):
3068, 1731, 1647, 1629, 1597, 1557, 1494, 1458, 1440,
1376, 1356, 1340, 1275, 1252, 1213, 1180, 1140, 1090,
68, 944, 912, 881, 872, 851, 823, 801, 762, 750 cmꢂ1
;
1H NMR (200 MHz): d 1.55 (3H, d, J = 7.1 Hz, CH3),
3.63 (3H, s, OCH3), 3.84 (1H, q, J = 7.0 Hz, CH), 3.97
(3H, s, OCH3), 7.17 (1H, d, J = 9.0 Hz, Ar–H), 7.47
(1H, dd, J = 1.5 and 8.8 Hz, Ar–H), 7.61 (1H, s, Ar–
H), 7.70 (1H, d, J = 9.0 Hz, Ar–H), 8.15 (H, d,
J = 8.8 Hz, Ar–H); 13C NMR (50 MHz): d 18.5, 45.1,
52.1, 57.0, 108.5, 113.9, 126.3, 126.7, 127.7, 128.9,
129.8, 132.3, 136.5, 153.8, 174.8; MS (m/z) (%): 324
(M+1) (13), 322 (37), 266 (13), 265 (95), 264 (9), 263
(100), 184 (65), 169 (19), 153 (18), 141 (40), 139 (17),
115 (20), 64 (12); Anal. Calcd for C15H15BrO3: C,
55.74; H, 4.677. Found: C, 56.04; H, 4.683.
7.6.2. 4-(2-Methylpropyl)-a-methylphenylacetic acid
6. A white solid; mp 75 ꢁC; IR (KBr): 3210, 2956,
1721, 1508, 1461, 1420, 1380, 1365, 1321, 1268, 1230,
1183, 1123, 1092, 1067, 1008, 969, 935, 900, 866, 834,
1
820, 779, 690 cmꢂ1; H NMR (200 MHz): d 0.89 (6H,
d, J = 6.5 Hz, 2 · CH3), 1.49 (3H, d, J = 7.8 Hz, CH3),
1.77–1.90 (1H, m, CH), 2.44 (2H, d, J = 7.0 Hz,
CHCH2), 3.70 (1H, q, J = 7.0 Hz, CH3CH), 7.1 (2H,
d, J = 8.0 Hz, Ar–H), 7.22 (2H, d, J = 8.0 Hz, Ar–H);
13C NMR (50 MHz): d 18.1, 22.4, 30.2, 45.0, 45.0,
127.3, 129.4, 137.0, 140.9, 181.2; MS (m/z) (%): 206
(47), 163 (100), 119 (55), 107 (51), 91 (82), 77 (13); Anal.
Calcd for C13H18O2: C, 75.69; H, 8.794. Found: C,
75.81; H, 8.801.
7.7.2. Ethyl 2-(5-bromo-6-methoxy-2-naphthyl)propanoic
acid 5b. A white solid; mp 69–70 ꢁC; IR (KBr): 2976,
1727, 1628, 1599, 1497, 1479, 1451, 1405, 1375, 1354,
1336, 1325, 1273, 1253, 1226, 1178, 1157, 1070, 975,
1
897, 856, 800, 762, 753, 690, 662, 627 cmꢂ1; H NMR
(200 MHz): d 1.40 (3H, t, J = 7.1 Hz, CH3), 1.55 (3H,
d, J = 7.1 Hz, CH3CH), 3.83 (1H, q, J = 7.2 Hz, CH),
3.94 (3H, s, OCH3), 4.10 (2H, q, J = 7.1 Hz, OCH2),
7.18 (1H, d, J = 9.0 Hz, Ar–H), 7.54 (1H, d,
J = 8.9 Hz, Ar–H), 7.65 (1H, s, Ar–H), 7.72 (1H, d,
J = 9.0 Hz, Ar–H), 8.15 (1H, d, J = 8.8 Hz, Ar–H); 13C
NMR (50 MHz): d 14.2, 18.5, 45.3, 57.0, 60.9, 108.5,
113.9, 126.2, 126.6, 127.7, 128.9, 129.8, 132.3, 136.6,
153.7, 174.4; MS (m/z) (%) 338 (M+1) (37), 336 (38),
265 (100), 263 (100), 184 (48), 169 (16), 153 (16), 141
(33), 139 (15), 115 (15); Anal. Calcd for C16H17BrO3:
C, 56.98; H, 5.081. Found: C, 56.83; H, 5.079.
7.6.3. 2-(2-Naphthyloxy)propanoic acid 7. A white
solid; mp114 ꢁC; IR (KBr): 3651, 3060, 2988, 1705,
1629, 1599, 1510, 1467, 1421, 1391, 1370, 1359, 1335,
1312, 1257, 1244, 1217, 1184, 1139, 1121, 1099, 1048,
;
1020, 971, 837, 813, 745, 681 cmꢂ1 1H NMR
(200 MHz): d 1.70 (3H, d, J = 6.8 Hz, CH3), 4.92 (1H,
q, J = 6.8 Hz, CH), 7.07 (1H, d, J = 1.6 Hz, Ar–H),
7.13 (1H, dd, J = 8.9 and 2.4 Hz, Ar–H), 7.30–7.46
(2H, m, Ar–H), 7.73 (1H, d, J = 8.1 Hz, Ar–H), 7.70
(2H, d, J = 8.5 Hz, Ar–H); 13C NMR (50 MHz): d
18.5, 72.1 107.9, 118.8, 124.2, 126.6, 126.9, 127.7, 129.5,
129.9, 134.3, 155.2, 177.9; MS (m/z) (%): 216 (100), 202
(10), 194 (5), 173 (5), 159 (16), 148 (3), 121 (3); Found:
M+, 216.2333 C13H12O3 requires M 216.2348.
7.7.3. Butyl 2-(5-bromo-6-methoxy-2-naphthyl)propanoic
acid 5c. A white solid; mp 55–56 ꢁC; IR (KBr): 2960,
1731, 1629, 1601, 1558, 1496, 1481, 1461, 1377, 1355,
1327, 1273, 1252, 1211, 1179, 1117, 1067, 1024, 975,
7.7. General method for the preparation of alkyl esters
of 2-(5-bromo-6-methoxy-2-naphthyl)propanoic acid 5,
4-(2-methylpropyl)-a-methylphenyl acetic acid 6, and
2-(2-naphthyloxy)propanoic acid 7: preparation of
5a–c, 6a–c, and 7a–c
942, 920, 888, 862, 824, 800 cmꢂ1
;
1H NMR
(200 MHz): d 0.82 (3H, t, J = 7.3 Hz, CH3), 1.16–1.31
(2H, m, CH2), 1.45–1.57 (2H, m, CH2CH2), 1.55 (3H,
d, J = 7.2 Hz, CH3CH), 3.84 (1H, q, J = 7.1 Hz,
CH3CH), 3.98 (3H, s, OCH3), 4.05 (2H, t, J = 6.5 Hz,
OCH2), 7.20 (1H, d, J = 9.0 Hz, Ar–H), 7.45 (1H, dd,
J = 1.5 and 8.4 Hz, Ar–H), 7.65 (1H, s, Ar–H), 7.72
(1H, d, J = 9.0 Hz, Ar–H), and 8.16 (1H, d,
J = 8.8 Hz, Ar–H); 13C NMR (50 MHz): d 13.7, 18.5,
19.1, 30.6, 45.3, 57.1, 64.8, 108.5, 113.9, 126.2, 126.6,
127.8, 128.8, 129.8, 132.3, 136.7, 153.7, 174.5; MS (m/
z) (%): 366 (M+1) (30), 364 (3), 265 (100), 263 (100),
184 (38), 169 (12), 153 (12), 141 (23), 115 (9), 58 (7);
Anal. Calcd for C18H21BrO3: C, 58.13; H, 5.452. Found:
C, 58.77; H, 5.449.
The alkyl ester derivatives of 5–7 were prepared by
refluxing a benzene solution of a mixture of the respec-
tive carboxylic acid (30 mmol), thionylchloride
(35 mmol) in the presence of catalytic amounts of pyri-
dine (0.5 mL) for 2–3 h. The contents were concentrated
and the resulting acid chloride allowed to react with dry
alcohols (methanol/ethanol/n-butanol) in dichlorometh-
ane. After the usual workup, the alkyl esters were puri-
fied by chromatography over silica gel using n-hexane/
ethyl acetate in increasing proportion as eluent to give
following esters, respectively, 5a (3.1 g, 9.6 mmol,
95.6%), 5b (3.18 g, 9.4 mmol, 90%), 5c (3.44 g,
7.7.4. Methyl 4-(2-methylpropyl)-a-methylphenylacetic
acid 6a. A colorless liquid; IR (neat): 2954, 2869,

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2587
1740, 1613, 1512, 1459, 1434, 1376, 1366, 1334, 1249,
1206, 1165, 1122, 1095, 1070, 1022, 1010, 969, 921,
7.7.8. Ethyl 2-(2-naphthyloxy)propanoic acid 7b.
A
creamish solid; mp 52–53 ꢁC; IR (KBr): 2985, 1753,
859, 800 cmꢂ1
;
1H NMR (200 MHz): d 0.94 (6H, d,
1630, 1600, 1510, 1468, 1445, 1390, 1257, 1216, 1182,
1
J = 6.6 Hz, 2 · CH3), 1.52 (3H, d, J = 7.2 Hz, CH3),
1.32–1.45 (1H, m, CHCH2), 2.49 (2H, d, J = 7.2 Hz,
CH2), 3.66 (3H, s, COOCH3), 3.73 (1H, q, J = 7.0 Hz,
CH3CH), 7.1 (2H, d, J = 8.0 Hz, Ar–H), 7.22 (2H, d,
J = 8.0 Hz, Ar–H); 13C NMR (50 MHz): d 18.6, 22.4,
30.2, 45.0, 45.1, 51.8, 127.1, 129.3, 137.8, 140.5, 175.1;
MS (m/z) (%): 220 (37), 161 (100), 121 (29), 117 (64),
105 (24), 91 (58), 77 (18), 60 (20); Anal. Calcd for
C14H20O2: C, 76.32; H, 9.149. Found: C, 76.74; H,
9.143.
1130, 1095, 1017, 971, 839, 812, 749 cmꢂ1; H NMR
(200 MHz): d 1.23 (3H, t, J = 7.1 Hz, CH3), 1.67 (3H,
d, J = 6.8 Hz, CH3CH), 4.25 (2H, q, J = 7.2 Hz,
CH2O), 4.88 (1H, q, J = 6.8 Hz, CH3CH), 7.05 (1H, d,
J = 2.4 Hz, Ar–H), 7.22 (1H, dd, J = 2.5 and 8.9 Hz,
Ar–H), 7.29–7.46 (2H, m, Ar–H), 7.63 (1H, d,
J = 8.0 Hz, Ar–H), 7.75 (2H, d, J = 8.8 Hz, Ar–H);
13C NMR (50 MHz): d 14.2, 18.6, 61.3, 72.7, 107.8,
118.9, 124.0, 126.5, 126.9, 127.7, 129.7, 129.9, 134.3,
155.6, 172.3; MS (m/z) (%): 244 (61), 171 (88), 144
(100), 127 (40), 115 (39), 77 (7); Anal. Calcd for
C15H16O3: C, 73.75; H, 6.601. Found: C, 74.00; H,
6.609.
7.7.5. Ethyl 4-(2-methylpropyl)-a-methylphenylacetic acid
6b. A colorless liquid; IR (neat): 2956, 2933, 1735,
1512, 1464, 1421, 1367, 1330, 1245, 1166, 1095, 1072,
1
1024, 848, 799, 728 cmꢂ1; H NMR (200 MHz): d 0.92
7.7.9. Butyl 2-(2-naphthyloxy)propanoic acid 7c. A vis-
cous liquid; IR (neat): 2960, 1755, 1630, 1600, 1511,
1408, 390, 1356, 1257, 1216, 1182, 1095, 1048, 1019,
(6H, d, J = 6.6 Hz, 2 · CH3), 1.22 (3H, t, J = 7.1 Hz,
CH3CH2), 1.50 (3H, d, J = 7.16 Hz, CH3CH), 1.30–
1.44 (1H, m, CHCH2), 2.49 (2H, d, J = 7.1 Hz,
CHCH2), 3.70 (1H, q, J = 7.0 Hz, CH3CH), 4.13 (2H,
q, J = 7.1 Hz, CH2O), 7.11 (2H, d, J = 8.1 Hz, Ar–H),
7.23 (2H, d, J = 8.1 Hz, Ar–H); 13C NMR (50 MHz):
d 14.1, 18.6, 22.4, 30.2, 45.1, 45.2, 60.6, 127.1, 129.3,
137.9, 140.4, 174.7; MS (m/z) (%): 234 (52), 162 (100),
119 (93), 115 (34), 105 (46), 91 (85), 77 (25), 58 (32);
Anal. Calcd for C15H22O2: C, 76.88; H, 9.462. Found:
C, 77.11; H, 9.471.
1
972, 944, 839, 811, 748 cmꢂ1; H NMR (200 MHz): d
0.83 (3H, t, J = 7.0 Hz, CH3), 1.18–1.31 (2H, m,
CH2CH3), 1.46–1.66 (2H, m, CH2), 1.68 (3H, d,
J = 6.9 Hz, CH3CH), 4.19 (2H, t, J = 6.5 Hz,
OCH2CH2), 4.92 (1H, q, J = 6.8 Hz, CH3–CHO), 7.05
(1H, br s, Ar–H), 7.20 (1H, dd, J = 2.3 and 8.9 Hz,
Ar–H), 7.29–7.45 (2H, m, Ar–H), 7.68 (1H, d,
J = 8.1 Hz, Ar–H), 7.74 (2H, d, J = 8.7 Hz, Ar–H);
13C NMR (50 MHz): d 13.6, 18.6, 19.0, 30.6, 65.2,
72.7, 107.7, 118.9, 124.0, 126.5, 126.9, 127.7, 129.4,
134.4, 155.6, 172.4; MS (m/z) (%): 272 (62), 171 (100),
144 (97), 127 (43), 115 (36), 77 (7), 43 (16); Anal. Calcd
for C17H20O3: C, 74.97; H, 7.401. Found: C, 75.21; H,
7.394.
7.7.6. Butyl 4-(2-methylpropyl)-a-methylphenylacetic acid
6c. A colorless liquid; IR (neat): 2958, 2933, 1737,
1512, 1464, 1421, 1383, 1331, 1243, 1201, 1167, 1120,
1
1093, 1071, 1022, 941, 817, 798, 726 cmꢂ1; H NMR
(200 MHz): d 0.88 (3H, t, J = 7.0 Hz, CH3), 0.92 (6H,
d, J = 6.6 Hz, 2 · CH3), 1.24–1.35 (2H, m, CH2), 1.42–
1.62 (3H, m, CH2 and CH), 1.50 (3H, d, J = 7.2 Hz,
CH3CH), 2.42 (2H, d, J = 7.2 Hz, CH2CH), 3.71 (1H,
q, J = 7.2 Hz, CH3CH), 4.09 (2H, t, J = 6.5 Hz,
CH2O), 7.21 (2H, d, J = 8.1 Hz, Ar–H), 7.24 (2H, d,
J = 8.1 Hz, Ar–H); 13C NMR (50 MHz): d 13.6, 18.4,
19.3, 20.3, 30.6, 45.1, 45.2, 64.4, 127.1, 129.2, 137.9,
140.4, 174.7; MS (m/z) (%): 262 (27), 219 (13), 162
(39), 161 (100), 145 (5), 119 (52), 105 (17), 91 (42), 77
(11), 58 (72), 45 (44), 43 (90); Anal. Calcd for
C17H26O2: C, 77.81; H, 9.987. Found: C, 77.98; H,
9.982.
7.8. General method for the preparation of alkyl esters of
2-(allylthio) propanoic acid 8; preparation of 8a–c
A mixture of thiolactic acid (15 mL, 168 mmol), allyl
bromide (15.6 mL, 180 mmol) in acetone (200 mL),
and anhydrous potassium carbonate (15 g) was refluxed
for 4 h. After the completion of reaction, the contents
were concentrated and then diluted with ice-water
(200 mL). The reaction mixture was extracted with
dichloromethane (3 · 100 mL). The aqueous portion
after acidification with dil. HCl was extracted with ethyl
acetate (4 · 100 mL). The organic layer was washed with
water, dried over anhydrous sodium sulfate, and con-
centrated in vacuo to give crude 2-allylthiolactic acid
as a liquid (16.2 g). The crude acid was dissolved in
dichloromethane (150 mL), and thionyl chloride
(11 mL, >150 mmol) and pyridine (1.6 mL, 20 mmol)
were added and the contents refluxed for 50 min,
concentrated, and reconstituted in dichloromethane
(90 mL) to divide into three equal parts. Dry methanol,
ethanol, and n-butanol (5 mL each) were separately
added to each part. Each of the reaction mixtures were
heated at 60–70 ꢁC for 10 min, concentrated and after
usual workup, purification by cc over silica gel using
n-hexane/ethyl acetate (99:1) as eluant to give the respec-
tive esters 8a (6.8 g, 42.5 mmol, 78.6%), 8b (7.3 g,
41.9 mmol, 74.9%), and 8c (8.2 g, 40.6 mmol, 72.5%).
7.7.7. Methyl 2-(2-naphthyloxy)propanoic acid 7a.
A
creamish solid; mp 55–56 ꢁC; IR (KBr): 2954, 1759,
1630, 1599, 1510, 1468, 1446, 1390, 1375, 1257, 1133,
1096, 1052, 981, 839, 812, 749 cmꢂ1
;
1H NMR
(200 MHz): d 1.67 (3H, d, J = 6.8 Hz, CH3), 3.74 (3H,
s, COOCH3), 4.92 (1H, q, J = 6.8 Hz, CH), 7.04 (1H,
s, Ar–H), 7.17 (1H, dd, J = 2.2 and 8.88 Hz, Ar–H),
7.32–7.42 (2H, m, Ar–H), 7.69 (1H, d, J = 8.0 Hz, Ar–
H), 7.83 (2H, d, J = 8.8 Hz, Ar–H); 13C NMR
(50 MHz): d 18.7, 52.4, 72.6, 107.7, 118.9, 124.1, 126.5,
126.9, 127.7, 129.4, 129.8, 134.4, 155.5, 172.7; MS (m/
z) (%): 230 (67), 171 (65), 144 (100), 127 (39), 115 (60),
60 (12); Anal. Calcd for C14H14O3: C, 73.07; H, 6.117.
Found: C, 73.66; H, 6.123.

2588
S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
7.8.1. Methyl 2-(allylthio)propanoic acid 8a. A light
(12), 117 (16), 109 (14), 89 (59), 75 (100), 74 (19.4), 57
(43); Found: M+, 176.2791 C8H16O2S requires M
176.2784.
yellowish liquid; IR (neat): 2925, 1736, 1632, 1402,
1
1255, 1156, 1021, 923, 794 cmꢂ1; H NMR (200 MHz):
d 1.39 (3H, d, J = 7.3 Hz, CH3), 3.1–3.28 (2H, m,
CH2S), 3.29 (1H, q, J = 7.2 Hz, CHCH3), 3.70 (3H, s,
COOCH3), 5.06–5.7 (2H, m, CH2@CH), 5.66–5.86
(1H, m, @CH); 13C NMR (50 MHz): d 17.0, 34.6,
39.7, 52.1, 117.8, 133.5, 173.6; MS (m/z) (%): 161
(M+1) (33), 137 (20), 128 (12), 117 (10), 115 (10), 101
(29), 99 (11), 88 (100), 78 (11), 75 (45), 74 (34), 68
(22); Found: M+, 160.2366 C7H12O2S requires M
160.2358.
7.9.2. Ethyl 2-(n-butylthio)propanoic acid 9b. A yellow-
ish liquid; IR (neat): 2961, 2933, 1733, 1450, 1373, 1321,
1255, 1221, 1160, 1095, 1063, 1021, 897 cmꢂ1; 1H NMR
(200 MHz): d 0.90 (3H, t, J = 7.1 Hz, CH3), 1.28 (3H, t,
J = 7.0 Hz, CH3CH2O), 1.42 (3H, d, J = 7.2 Hz,
CH3CH), 1.34–1.63 (4H, m, 2 · CH2), 2.62 (2H, m,
SCH2), 3.38 (1H, q, J = 7.2 Hz, CH3CH), 4.14 (2H, q,
J = 7.1 Hz, OCH2); 13C NMR (50 MHz): d 13.7, 14.2,
17.2, 22.0, 31.0, 31.4, 41.7, 61.0, 173.3; MS (m/z) (%):
190 (23), 134 (2), 117 (33), 102 (100), 91 (4), 89 (6), 77
(5), 75 (88), 74 (43), 61 (55), 57 (16); Found: M+,
190.3055 C9H18O2S requires M 190.3052.
7.8.2. Ethyl 2-(allylthio)propanoic acid 8b. A yellowish
liquid; IR (neat): 2980, 2934, 1734, 1635, 1448, 1428,
1375, 1324, 1257, 1233, 1160, 1096, 1062, 1022, 990,
1
921, 859, 741 cmꢂ1; H NMR (200 MHz): d 1.25 (3H,
t, J = 7.1 Hz, CH3), 1.38 (3H, d, J = 7.2 Hz, CHCH3),
3.12–3.38 (3H, m, CH2 and CH), 4.15 (2H, q,
J = 7.0 Hz, OCH2), 5.05–5.16 (2H, m, CH2@CH),
5.70–5.78 (1H, m, @CH); 13C NMR (50 MHz): d 14.2,
17.0, 34.6, 39.8, 61.0, 117.8, 133.5, 173.2; MS (m/z)
(%): 174 (30), 102 (100), 101 (40), 85 (5), 75 (8), 74
(63), 67 (28), 61 (15), 60 (94), 57 (12), 47 (46), 43 (96);
Found: M+, 174.2632 C8H14O2S requires M 174.2626.
7.9.3. Butyl 2-(n-butylthio)propanoic acid 9c. A yellow-
ish liquid; IR (neat): 2960, 2933, 1733, 1453, 1376, 1321,
1253, 1219, 1163, 1070, 1018 cmꢂ1
;
1H NMR
(200 MHz): d 0.84 (3H, t, J = 7.2 Hz, CH3), 1.21 (3H,
t, J = 7.1 Hz, CH2CH3), 1.35 (3H, d, J = 7.1 Hz,
CHCH3), 1.27–1.63 (8H, m, 4 · CH2), 2.55 (2H, m,
CH2S), 3.29 (1H, q, J = 7.1 Hz, CH3CH), 4.11 (2H, t,
J = 7.2 Hz, OCH2); 13C NMR (50 MHz): d 13.5, 13.6,
17.1, 18.8, 19.0, 21.9, 34.7, 41.1, 62.3, 64.9, 173.5; MS
(m/z) (%): 218 (14), 130 (20), 117 (32), 89 (9), 74 (100),
62 (35), 59 (37), 56 (24), 47 (11), 43 (57); Found: M+,
218.3597 C11H22O2S requires M 218.3588.
7.8.3. n-Butyl 2-(allylthio)propanoic acid 8c. A light
brownish liquid; IR (neat): 2960, 2934, 1733, 1455,
1
1377, 1322, 1256, 1164, 1066, 1018, 996, 938 cmꢂ1; H
NMR (200 MHz): d 0.94 (3H, t, J = 7.2 Hz, CH3),
1.42 (3H, d, J = 7.2 Hz, CH3CH), 1.35–1.46 (2H, m,
CH2CH3), 1.56–1.68 (2H, m, CH2CH2), 3.21–3.42 (3H,
m, CH2S and CH), 4.14 (2H, t, J = 6.5 Hz, OCH2),
5.10–5.22 (2H, m, CH2@CH), 5.70–5.86 (1H, m,
CH2@CH); 13C NMR (50 MHz): d 13.7, 17.1, 19.2,
30.7, 34.6, 39.9, 64.9, 117.8, 133.6, 173.3; MS (m/z)
(%): 204 (M+2) (16), 130 (18), 101 (33), 85 (4), 75
(16), 74 (100), 67 (17), 61 (10), 60 (55), 58 (21), 47
(22), 43 (89); Found: M+, 202.3171 C10H18O2 requires
M 202.3162.
7.10. General method for the preparation of alkyl esters of
2-(phenylthio)propanoic acid 10; preparation of 10a–c
The title compound was obtained by stirring an acetone
solution (200 mL) of thiolactic acid (15 mL, 168 mmol),
bromobenzene (19 mL, 180 mmol), and potassium car-
bonate (15 g) at room temp till the completion of reac-
tion. The crude acid obtained was directly esterified by
the method as described in Section 7.8 above to give
ester 10a (16.3 g, 42 mmol, 80%), 10b (8.3 g, 39.5 mmol,
70.4%), and 10c (9.7, 40.7 mmol, 72.4%).
7.9. General method for the preparation of alkyl esters of
2-(n-butylthio)propanoic acid 9; preparation of 9a–c
7.10.1. Methyl 2-(phenylthio)propanoic acid 10a. A yel-
lowish liquid; IR (neat): 2989, 1736, 1583, 1475, 1438,
1375, 1329, 1260, 1228, 1192, 1161, 1067, 1025, 965,
The title compound was prepared by refluxing an ace-
tone solution (200 mL) of thiolactic acid (15 mL,
168 mmol) and n-butyl bromide (19.5, 180 mmol) in
the presence of potassium carbonate (15 g) for 50 h
and the resulting crude acid that was obtained after
the usual workup was subjected to esterification by the
procedure as described in Section 7.8 to give 9a (7.2 g,
40.9 mmol, 73%), 9b (7.5 g, 39.5 mmol, 70%), and 9c
(8.92 g, 40.9 mmol, 73.1%).
1
854, 749, 691 cmꢂ1; H NMR (200 MHz): d 1.47 (3H,
d, J = 7.1 Hz, CH3), 3.66 (3H, s, COOCH3), 3.79 (1H,
q, J = 7.1 Hz, CH3CH), 7.40–7.47 (5H, m, Ar–H); 13C
NMR (50 MHz): d 17.5, 45.2, 52.3, 128.1, 128.9, 133.1,
173.0; MS (m/z) (%): 196 (46), 137 (100), 135 (17), 109
(45), 103 (7), 77 (11), 69 (11); Found: M+, 196.2693
C10H12O2S requires M 196.2688.
7.10.2. Ethyl 2-(phenylthio)propanoic acid 10b. A yel-
lowish liquid; IR (neat): 2981, 2934, 1733, 1584, 1476,
1440, 1374, 1323, 1256, 1225, 1095, 1067, 1024, 748,
7.9.1. Methyl 2-(n-butylthio)propanoic acid 9a. A yel-
lowish liquid; IR (neat): 2956, 1738, 1454, 1374, 1333,
1
1260, 1062, 1009, 995, 854, 776, 695 cmꢂ1. H NMR
692 cmꢂ1 1H NMR (200 MHz):
; d 1.17 (3H, t,
(200 MHz): d 0.92 (3H, t, J = 7.2 Hz, CH3), 1.34–1.61
(4H, m, 2 · CH2), 1.40 (3H, d, J = 7.2 Hz, CH3CH),
2.58–2.66 (2H, m, CH2S), 3.41 (1H, q, J = 7.1 Hz,
CH3CH), 3.76 (3H, s, COOCH3); 13C NMR
(50 MHz): d 13.5, 17.1, 21.4, 30.9, 31.3, 40.8, 52.0,
173.5; MS (m/z) (%): 176 (27), 147 (1), 137 (25), 130
J = 7.1 Hz, CH3), 1.48 (3H, d, J = 7.1 Hz, CHCH3),
3.29 (1H, q, J = 7.1 Hz, CH), 4.13 (2H, q, J = 7.1 Hz,
OCH2), 7.18–7.26 and 7.40–7.49 (5H, m, Ar–H); 13C
NMR (50 MHz): d 14.0, 17.4, 45.3, 61.2, 126.9, 128.9,
132.9, 133.9, 172.7; MS (m/z) (%): 210 (51), 137 (100),
135 (19), 109 (43), 103 (8), 77 (12), 65 (17), 60 (23), 52

S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
2589
(13), 47 (12); Found: M+, 210.2962 C11H14O2S requires
M 210.2956.
65.0, 127.1, 128.5, 129.0, 137.6, 173.2; MS (m/z) (%):
252 (11), 151 (10), 130 (25), 124 (13), 123 (100), 117
(6), 92 (16), 91 (98), 77 (8), 75 (15), 74 (98), 61 (11), 58
(19), 57 (22), 43 (28); Found: M+, 252.3766 C14H20O2S
requires M 252.3760.
7.10.3. Butyl 2-(phenylthio)propanoic acid 10c. A yel-
lowish liquid; IR (neat): 2982, 2933, 1733, 1584, 1475,
1440, 1374, 1322, 1256, 1225, 1160, 1095, 1066, 1024,
1
776, 748, 692 cmꢂ1; H NMR (200 MHz): d 0.86 (3H,
7.12. Preparation of (R)-2-(benzylthio)propanoic acid 11
t, J = 7.1 Hz, CH3), 1.29 (3H, d, J = 7.2 Hz, CHCH3),
1.34–1.60 (4H, m, 2 · CH2), 3.20 (1H, q, J = 7.2 Hz,
CHCH3), 4.0 (2H, t, J = 6.5 Hz, OCH2), 7.26–7.33 and
7.43–7.49 (5H, m, Ar–H); 13C NMR (50 MHz): d 13.7,
16.9, 30.1, 35.9, 40.5, 65.0, 127.1, 128.5, 129.0, 137.6,
173.2; MS (m/z) (%): 238 (32), 137 (100), 135 (13), 110
(9), 109 (29), 103 (5), 65 (11), 60 (15), 58 (7), 43 (17),
41 (11); Found: M+, 238.2499 C13H18O2S requires M
238.2492.
A mixture of acetone solution of (S)-(ꢂ)-2-bromopropa-
noic acid (0.46 g, 3.0 mmol), benzylmercaptol (0.4 g,
3.2 mmol), and fused potassium carbonate (0.5 g) was
stirred at 20 ꢁC for 15 h. After completion of the reaction,
the contents were filtered, the solid material washed with
acetone (2 · 15 mL). The combined organic layer concen-
trated in vacuo, reconstituted in chloroform (30 mL) and
the contents diluted with water and pH adjusted to 4, the
organic layer separated, washed with water (2 · 10 mL),
dried, concentrated, and cc over SiO2 using n-hexane/
EtOAc (9:1) as eluant gave R-2-(benzylthio)propanoic
7.11. General method for the preparation of alkyl esters of
2-(benzylthio)propanoic acid 11; preparation of 11a–c
acid as a white solid (mp 66 ꢁC) (0.51 g, 2.6 mmol,
25
The title compound was obtained by reacting an acetone
solution (200 mL) of thiolactic acid (15 mL, 168 mmol),
benzylbromide (21.5 mL, 180 mmol), and potassium
carbonate (15 g) for 24 h. The crude acid obtained thus
was directly esterified by the method described in Sec-
tion 7.8 above to give the products 11a (9.4 g,
44.7 mmol, 80%), 11b (10.6 g, 47.3 mmol, 84.4%), and
11c (11.7 g, 46.4 mmol, 81.25%).
86.7% yield) ½aꢁD ¼ þ130.1 (c 1, CHCl3).
7.13. General procedure for the hydrolysis of racemic
acylates of primary and secondary alcohols
Racemic acylate of primary/secondary alcohol
(ꢀ1 mmol) in sodium phosphate buffer (0.1 M) at
pH 7 and specified temperature was stirred after the
addition of crude enzyme in a specified ratio (as given
in Tables 1–4). The pH of the reaction maintained by
pH-stat using 0.05 M NaOH solution. The samples were
analyzed on chiral HPLC after the extraction of the ali-
quots (25–50 lL) with HPLC grade ethyl acetate
(100 lL), centrifugation at 8000g and filtration of the
organic layer through 0.45 lm pore size filter. After
the termination of the reaction, the contents were
extracted with organic solvents, concentrated in vacuo,
and separated on a silica gel column to get optically
enriched ester and the alcohol.
7.11.1. Methyl 2-(benzylthio)propanoic acid 11a.
colorless liquid; IR (neat): 3029, 1736, 1602, 1495,
1453 cmꢂ1 1H NMR (200 MHz): d 1.38 (3H, d,
A
;
J = 7.2 Hz, CH3), 3.31 (1H, q, J = 7.1 Hz, CH), 3.70
(3H, s, COOCH3), 3.82 (2H, d, J = 18.48 Hz, CH2Ph),
7.21–7.36 (5H, m, Ar–H); 13C NMR (50 MHz): d 16.9,
36.0, 40.3, 52.2, 127.2, 128.5, 129.1, 137.6, 173.5; MS
(m/z) (%): 210 (3), 194 (39), 164 (5), 151 (4), 123 (35),
121 (3), 107 (9), 91 (100), 88 (6), 77 (5), 65 (12); Found:
M+, 210.2359 C11H14O2 S requires M 210.2356.
7.11.2. Ethyl 2-(benzylthio)propanoic acid 11b. A yel-
lowish liquid; IR (neat): 2980, 2934, 1733, 1602, 1495,
1453, 1375, 1323, 1258, 1222, 1159, 1093, 1065, 1023,
7.14. Typical example of kinetic resolution of 1-acetoxy-
(6-methoxynaphthyl)ethane 1a
1
858, 768, 702 cmꢂ1; H NMR (200 MHz): d 1.25 (3H,
In a typical experiment, a mixture of 1a (250 mg,
P1 mmol) and TBE (190 mg) in sodium phosphate buf-
fer (0.1 M, pH 7.0, 6 mL) was stirred at 20 ꢁC and after
completion of the reaction (16 h) and usual workup, the
bio-products were separated on a silica gel column after
t, J = 7.1 Hz, CH3), 1.37 (3H, d, J = 7.2 Hz, CHCH3),
3.27 (1H, q, J = 7.2 Hz, CH), 3.82 (2H, d,
J = 20.42 Hz, PhCH2), 4.16 (2H, q, J = 7.2 Hz,
OCH2), 7.20–7.36 (5H, m, Ar–H); 13C NMR
(50 MHz): d 14.2, 16.9, 35.9, 40.4, 61.1, 127.1, 128.5,
129.0, 137.6, 173.0; MS (m/z) (%): 224 (14), 151 (13),
124 (14), 123 (100), 102 (52), 92 (19), 91 (94), 77 (11),
74 (44), 65 (37), 61 (12), 52 (11), 47 (55), 41 (18); Found:
M+, 224.3231 C12H16O2S requires M 224.3224.
elution with dichloromethane/methanol (19:1) to give 1a
25
(119 mg, 0.49 mmol), ½aꢁD ¼ þ41.6 (c 0.56, CHCl3)
25
and 1 (52 mg, 0.27 mmol), ½aꢁD ¼ ꢂ39.6 (c 0.8, CHCl3).
7.15. Typical example of kinetic resolution of 1-buta-
noyloxy-1-(3,4-methylenedioxyphenyl)ethane 2c
7.11.3. Butyl 2-(benzylthio)propanoic acid 11c. A yel-
lowish liquid: IR (KBr): 2960, 1733, 1602, 1494, 1454,
In a typical experiment, a mixture of 2c (236 mg, 1 mmol)
and PSL (60 mg) in sodium phosphate buffer (0.1 M,
pH 7.0, 5 mL) was stirred at 20 ꢁC and after completion
of the reaction (16 h) and usual workup, the bio-prod-
ucts were separated on a silica gel column after elution
1
1377, 1323, 1257, 1164, 1069, 1028, 767, 701 cmꢂ1; H
NMR (200 MHz): d 0.93 (3H, t, J = 7.1 Hz, CH3),
1.38 (3H, d, J = 7.2 Hz, CHCH3), 1.32–1.43 (2H, m,
CH2CH3), 1.52–1.61 (2H, m, OCH2CH2), 3.27 (1H, q,
J = 7.2 Hz, CH), 3.82 (2H, d, J = 19.4 Hz, PhCH2),
4.12 (2H, t, J = 6.5 Hz, OCH2), 7.21–7.36 (5H, m, Ar–
H); 13C NMR (50 MHz): d 13.7, 16.9, 30.1, 35.9, 40.5,
with pet. ether/ethyl acetate (19:1) to give 2c (110
25
mg, 0.46 mmol), ½aꢁD ¼ ꢂ96.6 (c 0.8, CHCl3) and 2
25
(55 mg, 0.33 mmol), ½aꢁD ¼ þ55.4 (c 1.0, CHCl3).

2590
S. Koul et al. / Tetrahedron: Asymmetry 16 (2005) 2575–2591
7.16. Typical example of kinetic resolution of 1-acetoxy-
1-(3,4-methylenedioxyphenyl)pentane 3a
India for a free sample of 2-(5-bromo-6-methoxy-2-
naphthyl)propanoic acid.
In a typical experiment, a mixture of 3a (250 mg,
1 mmol) and TBE (188 mg) in sodium phosphate buffer
(0.1 M, pH 7.0, 6.5 mL) was stirred at 20 ꢁC and after
completion of the reaction (16 h) and usual workup,
the bio-products separated on a silica gel column after
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7.17. General procedure for the hydrolysis of racemic
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ified ratio (as given in Tables 5–7) and the pH main-
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7.18. Typical example of kinetic resolution of methyl 2-
(5-bromo-6-methoxy-2-naphthyl)propanoic acid 5a
In a typical experiment, a mixture of 5a (140 mg,
0.5 mmol) and CCL (140 mg) in sodium phosphate buf-
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pletion of the reaction (90 h) and usual workup, the
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25
enriched 5a (62 mg, 0.19 mmol), ½aꢁD ¼ ꢂ27.2 (c 0.8,
25
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7.19. Typical example of kinetic resolution of methyl
2-(benzylthio)propanoic acid 11a
In a typical experiment, a mixture of 11a (210 mg,
1 mmol) and TBE (100 mg) in sodium phosphate buffer
(pH 8.0, 4 mL) was stirred at 25 ꢁC and after completion
of the reaction (24 h) and usual workup, the bio-prod-
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25
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25
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sample of PSL and to Natco Pharma Lab. Hyderabad,

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