CaL-B a highly selective biocatalyst for the kinetic resolution of furylbenzthiazole-2-yl-ethanols and acetates

Article abstract of DOI:10.1016/j.tetasy.2010.06.010

A highly stereoselective enzymatic kinetic resolution of novel various substituted racemic furylbenzthiazole-2-yl-ethanols and their acetates has been developed. Both processes, the enzymatic acylation of the racemic alcohols and the enzymatic methanolysis of racemic acetates yielded highly enantiomerically enriched (ee >98%) resolution product, when CaL-B was used as a biocatalyst in acetonitrile. The absolute configuration of the obtained (R)-(+)-1-(5-(4- chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol was determined by a detailed ¹H NMR study of rac- and (+)-1-(5-(4-chlorobenzo[d]thiazol-2-yl) furan-2-yl)ethanol Mosher derivatives.

Full text of DOI:10.1016/j.tetasy.2010.06.010

Tetrahedron: Asymmetry 21 (2010) 1999–2004
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
CaL-B a highly selective biocatalyst for the kinetic resolution
of furylbenzthiazole-2-yl-ethanols and acetates
*
László Csaba Bencze, Csaba Paizs, Monica Ioana To ßs a, Maria Trif, Florin Dan Irimie
Department of Biochemistry and Biochemical Engineering, Babe ßs -Bolyai University of Cluj-Napoca, RO-400028 Cluj-Napoca, Arany János 11, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective enzymatic kinetic resolution of novel various substituted racemic furylbenzthiaz-
ole-2-yl-ethanols and their acetates has been developed. Both processes, the enzymatic acylation of the
racemic alcohols and the enzymatic methanolysis of racemic acetates yielded highly enantiomerically
enriched (ee >98%) resolution product, when CaL-B was used as a biocatalyst in acetonitrile. The absolute
configuration of the obtained (R)-(+)-1-(5-(4-chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol was deter-
mined by a detailed 1H NMR study of rac- and (+)-1-(5-(4-chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol
Mosher derivatives.
Received 6 May 2010
Accepted 3 June 2010
Available online 3 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
mediated kinetic resolution of 1-(5-(benzo[d]thiazol-2-yl)furan-
2
-yl)ethanols. Lipases (triacylglycerol hydrolases) are one of the
Over the last decades, due to the high demand for fine mate-
most suitable enzymes for kinetic resolution processes. The major
advantages of using lipases are that they are available in free and
immobilized forms, can be produced in large quantities, do not re-
quire any cofactors and also that they can accept a wide range of
unnatural substrates. The lipase-catalyzed kinetic resolution of
racemic alcohols proved to be an efficient method for the synthesis
of various enantiomerically pure secondary alcohols.7 Besides its
major drawback (maximal theoretic yield of 50%) it is still one of
the most important methods for the preparation of enantiopure
compounds. Exploiting the attribute of lipases that usually retain
their enantiomeric preference in hydrolysis or alcoholysis correlat-
ing to the acylation, the development of the enzymatic acylation
and alcoholysis or hydrolysis should result in opposite enantio-
meric forms of the 1-heteroarylethanols and 1-heteroarylethyl
acetates. This advantage has been successfully applied in various
lipase-mediated kinetic resolution procedures, thus obtaining both
1
rials and chemicals (agrochemicals and pharmaceuticals), the
synthesis of enantiomerically enriched compounds has become
a research area of increasing interest. Synthetic routes to produce
these compounds have emerged as one of the most important
fields of organic chemistry. Due to their chiral nature, biocatalysts
are predominantly suited for the production of enantiopure com-
1
pounds. Moreover, biocatalytic processes have proved to be
greener, less hazardous and less polluting. Accordingly, biocataly-
sis has developed from a research technology to a widely used
manufacturing method in the pharmaceutical and fine chemical
2
industries.
Benzthiazole and furan-based structures show a large spectrum
of biological activities.3 However, furylbenzthiazole derivatives
have not been intensively studied, their fluorescence being the
most known and employed property.4 Recently, the biological
activity of some furylbenzthiazoles was studied, and it was found
that they exhibit strong antimicrobial effects.5
As part of our interest in the development of stereoselective
methods for the preparation of optically active heteroaromatic
compounds, with potential biological activity or with potential
application as chiral intermediates, the enantioselective synthesis
of furylbenzthiazole-based optically active secondary alcohols at-
tracted our interest.
8
enantiomers of the products.
Herein, we describe the synthesis of both enantiomeric forms of
various 1-(5-(benzo[d]thiazol-2-yl)furan-2-yl)ethanols and of their
esters by enzymatic acylation of the racemic ethanols and by enzy-
matic alcoholysis of the corresponding racemic acetates.
2
. Results and discussion
Based on the high activity and selectivity of lipases shown in the
previously developed enantioselective synthesis of furylbenzthiaz-
ole-based cyanohydrin-acetates by dynamic kinetic resolution, and
First the synthesis of racemic 1-(5-(benzo[d]thiazol-2-yl)furan-
-yl)ethanols rac-2a–d from the corresponding heteroaryl
aldehydes 1a–d by a Grignard reaction was performed. The corre-
sponding acetates rac-3a–d were obtained by the chemical acyla-
tion of the heteroarylethanols rac-2a–d.
2
6
a
kinetic resolution, we opted for the development of a lipase-
To investigate the stereoselectivity of the enzymatic kinetic res-
olution and the activity of the enzymes, the chromatographic
*
Corresponding author. Tel.: +40 264 593833; fax: +40 264 590818.
E-mail address: irimie@chem.ubbcluj.ro (F.D. Irimie).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.010

2
000
L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 1999–2004
enantiomeric separation of the racemates rac-2,3a–d was first
established.
Table 1
The influence of the nature of the enzyme on the enzymatic acylation of rac-2a with
vinyl acetate (8 equiv) in acetonitrile
In order to obtain highly enantiomerically enriched resolution
products, using racemic 1-(5-(benzo[d]thiazol-2-yl)furan-2-yl)eth-
anol rac-2a as a model compound, potentially useful lipases were
screened in various organic solvents for enantiomer selective acyl-
ation of racemic alcohol rac-2a with vinyl acetate (5 equiv), and for
alcoholysis with methanol, ethanol, propanol and butanol (8 equiv)
of racemic acetate rac-3a (Scheme 1).
Due to the poor solubility of rac-2a in neat vinyl acetate screen-
ing with several lipases for the enzymatic acylation of the hetero-
aylethanol was performed in acetonitrile, in which the solubility of
the substrates was highest. It was found that Novozyme 435 (li-
pase B from Candida antarctica, CaL-B) was the most active and
selective enzyme for this purpose (Table 1, entry 5). Interestingly,
lipase A from C. antarctica, (CaL-A) previously found to be the most
efficient for the kinetic resolution and dynamic kinetic resolution
of furylbenzthiazole-based cyanohydrins,6a showed lower activity
Entry
Enzyme
Time (h)
c (%)
ee
P
(%)
ee
S
(%)
E
1
2
3
4
5
6
7
8
CaL-A
LPS
LF
LAK
CaL-B
CCL
CRL
PPL
14
14
14
3
34
15
0
26
50
9
>99.5
>99.5
—
52.3
18
—
34.4
98
10
9
ꢀ200
>200
—
138
ꢀ200
>200
108
—
98
3
>99.5
>99.5
98
14
14
14
8
0
—
—
Table 2
The influence of the nature of the solvent on the CaL-B-mediated aceylation of rac-2a
with vinyl acetate (8 equiv) in different solvents after 3 h
Entry
Solvent
c (%)
ee
P
(%)
ee
S
(%)
E
1
2
3
4
5
Acetonitrile
MTBE
Toluene
1,4-Dioxane
Chloroform
50
49
47
16
38
>99.5
>99.5
>99.5
>99.5
>99.5
98
95
90
19.6
62.3
ꢀ200
ꢀ200
ꢀ200
>200
(Table 1, entry 1) than lipase B from C. antarctica for the enzymatic
acylation of rac-2a.
Further, using the most efficient enzyme, solvent effects on the
enzymatic acylation was tested. Due to the low solubility of the
substrate, only a small number of organic solvents proved to be
useful for the CaL-B-mediated acylation. A strong solvent influence
upon the reaction rate was observed, while the selectivities were
high in most cases. In accordance with the values shown in Table 2,
acetonitrile (Table 2, entry 1) proved to be the most appropriate
solvent (high ee and highest reaction rate value) for the enzymatic
acylation of rac-2a.
Performing the same screening procedure for the rest of the
substrates rac-2b–d, the optimal method was the same as found
for rac-2a.
To prepare the opposite enantiomers of the resolution products,
the (R)-1-heteroarylethanols (R)-2a–d and the (S)-1-heteroaryleth-
yl acetates (S)-3a–d, the analytical scale enzymatic alcoholysis of
racemic 1-(5-(benzo[d]thiazol-2-yl)furan-2-yl)ethyl acetates rac-
ꢀ200
Table 3
The influence of the nature of solvent upon the selectivity and velocity of CaL-B
catalyzed methanolysis (8 equiv) after 2 h
Entry
Solvent
c (%)
eeP (%)
eeS (%)
E
1
2
3
4
5
Acetonitrile
MTBE
Toluene
1,4-Dioxane
Chloroform
50
40
15
14
18
>99.5
>99.5
>99.5
>99.5
>99.5
99
66
17
16.6
22
ꢀ200
ꢀ200
>200
>200
>200
screening procedure for the enzymatic methanolysis of rac-3a are
shown.
3
a–d was investigated further. The screening process involved
enzymatic alcoholysis with various amounts (2, 4, 6, 8, 10 equiv)
of methanol, ethanol, propanol and butanol, in the same solvents
used for the enzymatic acylation. Interestingly, only CaL-B was cat-
alytically active. With all the other lipases showing activity for the
enzymatic acylation (CaL-A, LPS, LAK, CCL and CRL), the alcoholysis
failed. The nature and the concentration of the nucleophile
strongly influenced the selectivity of the CaL-B-catalyzed alcoholy-
sis. The best results were obtained when 8 equiv of methanol was
used in acetonitrile. In Table 3 some selected results from the
To verify the general validity of the optimal conditions for the
enzymatic methanolysis of rac-3a, the same screening procedure
was further extended to the other racemic acetates rac-3b-d. As
was expected, the CaL-B-catalyzed methanolysis (8 equiv) in ace-
tonitrile was found to be the most selective procedure.
The reaction times, conversions and ee values for both analyti-
cal scale enzymatic acylation of rac-2a–d and methanolysis of
rac-3a–d are presented in Table 4. In all cases at 50% conversion,
high ee values were obtained, for both product and unreacted
OH
OAc
OH
I.
III.
+
R
O
R
R
R
1
a-d
rac-2a-d
(R)-3a-d
(S)-2a-d
R:
R1
II.
N
S
O
R2
OH
OAc
R
OAc
IV.
+
R
R1
R2
R
rac-3a-d
(S)-3a-d
(R)-2a-d
a
H
Cl
H
H
H
Cl
b
c
d
H
CH3
Scheme 1. Preparation and enzymatic kinetic resolution of racemic 1-(5-(benzo[d]thiazol-2-yl)furan-2-yl)ethanols rac-2a–d and their acetates rac-3a–d. Reagents and
0
3
conditions: I (a) CH MgI/THF; (b) NH
4
Cl/H
2
O. II AcCl, DMAP/Py/CH
Cl
2 2
. III Lipase, vinyl-acetate/org.solv. IV Lipase, R OH/org. solv.

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 1999–2004
2001
Table 4
Cl
Cl
The optimal conditions for the analytical scale enzymatic kinetic resolution of
racemic alcohols rac-2a–d and acetates rac-3a–d with CaL-B in acetonitrile
N
N
Entry
Substrate
Time (h)
c (%)
ee
p
(%)
s
ee (%)
S
S
O
(R )C H3
H
3
C(S)
O
1
2
3
4
5
6
7
8
rac-2a
rac-2b
rac-2c
rac-2d
rac-3a
rac-3b
rac-3c
rac-3d
4
8
14
12
2
12
8
8
50
50
50
50
50
50
50
50
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
98
>99.5
98
>99.5
>99.5
>99.5
98
H
O
H
O
Ph
Ph
OCH3
OCH3
(
S)
(S)
O
O
CF
3
CF
3
98
>99.5
a
b
>99.5
(S)-MTPA-(R)-2b
(S)-MTPA-(S)-2b
enantiomer of the substrate, showing high enantioselectivity and
activity of CaL-B in acetonitrile towards all the investigated 1-(5-
Figure 1. (S)-MTPA derivatives of (R)-2b (a) and (S)-2b (b).
(
benzo[d]thiazol-2-yl)furan-2-yl)-based derivatives.
Based on the analytical scale optimal procedure, the preparative
mal. Hence, based on the observed selectivity of the esterification,
the H NMR signals of the two diastereomers, (S)-MTPA-(R)-2b and
1
scale enzymatic resolutions were performed for both rac-1-hetero-
arylethanols rac-2a–d and the corresponding ethyl acetates
rac-3a–d. All dilutions, substrate–biocatalyst ratio and reaction
conditions were the same as in the case of the analytical scale reac-
tions. The reactions were monitored by HPLC and TLC and were
stopped at an approx. 50% conversion, removing the enzyme by fil-
tration. Data on yield, enantiomeric excess and specific rotatory va-
lue of the obtained enantiomers are presented in Table 5.
(
S)-MTPA-(S)-2b, could be assigned unambiguously as follows: the
signals with major intensity (d = 1.70 ppm and d = 3.54 ppm)
belonged to the –CH and –OCH groups, respectively, in the (S)-
MTPA-(S)-2b environment, while the minor signals at d =
.78 ppm and d = 3.58 ppm belonged to the (S)-MTPA-(R)-2b dia-
3
3
1
stereomer (Fig. 2a). Supporting evidence is also provided by the
phenyl group’s diamagnetic effect on the proximal groups. Thus
in the case of (S)-MTPA-(S)-2b the strong diamagnetic effect of
the phenyl ring caused the proximal CH
3
protons to resonate up-
protons are found to be more
shielded, dCH3 = 1.70 ppm, in comparison with the CH protons of
S)-MTPA-(R)-2b (dCH3 = 1.78 ppm) where the distance between
2
.1. The absolute configuration of the resolution products
14a
field
(Fig. 1a). Indeed, CH
3
3
According to Kazlauskas’ empirical rule9 for predicting which
(
enantiomer reacts faster during the resolution of secondary chiral
alcohols, the absolute configurations of the products obtained by
the lipase-mediated kinetic resolution can be assigned. However,
a few exceptions to this rule have been reported so far.11 Therefore,
the absolute configurations of the novel enantiopure alcohols was
the phenyl and the methyl groups is higher (Fig. 2b). The methoxy
protons of the (S)-MTPA-(S)-2b were also found to be more
shielded, dOCH3 = 3.54 ppm, when compared with their analogues
in (S)-MTPA-(R)-2b, dOCH3 = 3.58 ppm. This is due to the diamag-
netic effect of the proximal heteroaryl ring (Fig. 2b). However, in
this case the diamagnetic effect of the heteroaryl moiety is lower,
10
1
determined by a detailed H NMR study in the case of the Mosher’s
1
2
derivative of 2b. Thus, the racemic and enantiomerically pure 2b
was esterified with (R)-MTPA-Cl and the resulting diastereomers
were differentiated by their 1H NMR spectra. The esterification of
racemic rac-2b with the (R)-MTPA-Cl occured selectively affording
the expected mixture of the corresponding Mosher esters, but in a
as shown by the difference between the d values as
.08 ppm and OCH3 = 0.04 ppm, due to the larger distance be-
tween the OCH group and the heteroaryl moiety.
CH3
Dd =
0
Dd
3
The esterification of the enantiomerically pure alcohol re-
mained untransformed during the CaL-B-mediated acylation
reaction with (R)-MTPA chloride, producing the down fielded (S)-
MTPA-(S)-2b diastereomer (Fig. 2b), thus confirming the (S) abso-
lute configuration predicted by the Kazlauskas empirical rule.
The absolute configuration for the rest of the compounds was
established by comparing their signs of the specific rotation with
1
.7:1 ratio (Fig. 2a) in agreement with the previous observation of
1
3
Heathcock. We noted that, depending on the sterical hindrance
involving the OH group, the above unequal distribution is not al-
1
4
15
ways observed. Next, previous structural data suggested that
the most plausible conformation of the (S)-MTPA fragment is that
presented in Figure 1. If so, in the case of (S)-MTPA-(R)-2b, there is
a steric repulsion between the heteroaryl moiety of 2b and the
phenyl group of the MTPA counterpart. In contrast, in the case of
(
+)-(S)-2b.
3
. Conclusions
(S)-MTPA-(S)-2b, the heteroaryl and phenyl groups are not proxi-
An efficient enzymatic kinetic resolution of various furylbenz-
Table 5
thiazole-based ethanols rac-2a–d and their acetates rac-3a–d has
been achieved. Both processes, the enzymatic acylation and the
enzymatic alcoholysis were efficient in acetonitrile using CaL-B
as a catalyst, affording the highly enantiomerically enriched enan-
tiomers of the target compounds.
Yield, ee and specific rotatory value for the products of CaL-B-mediated kinetic
resolutions
2
5
c
25
D
d
Entry Product Yield ee
%) (%)
Product Yield ee
(%)
½a
ꢁ
½aꢁ
D
(
1a
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(R)-2a
(R)-2b
(R)-2c
(R)-2d
49
48
49
49
49
47
48
50
>99.5 ꢂ28.3 (R)-3a
49
49
49
47
48
49
48
37
>99.5
99
99
+97
+92.9
+109.5
+87.5
The absolute configuration of the obtained products was deter-
a
2
98
99
ꢂ40.3 (R)-3b
ꢂ18.7 (R)-3c
1
a
mined by a detailed H NMR study of the Mosher’s derivative of
3
a
4
>99.5 ꢂ12.8 (R)-3d
>99.5
rac-2b and (S)-2b.
b
5
>99.5
98
98
+31.1 (S)-3a
+42.7 (S)-3b
+19.8 (S)-3c
+10.3 (S)-3d
>99.5 ꢂ107
b
6
99
98
99
ꢂ97
b
4. Experimental
7
ꢂ103.4
ꢂ94.3
b
8
>99.5
a
b
c
4.1. Analytical methods
Products obtained by enzymatic acylation.
Products obtained by enzymatic alcoholysis.
c 0.5 mg/mL.
The 1H and 13C NMR spectra were recorded on a Bruker spec-
trometer operating at 300 MHz and 75 MHz, respectively. Spectra
d
c 0.25 mg/mL.

2
002
L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 1999–2004
3 3
Figure 2. Signals of the CH protons and OCH
protons from the 1H NMR spectra of the (S)-MTPA-(R) and (S)-2b and of the (S)-MTPA-(S)-2b.
were recorded at 25 °C in CDCl
3
. 1H and 13C NMR spectra were ref-
4.2. Reagents and solvents
erenced internally to the solvent signal. Electron impact mass spec-
tra (EI-MS) were taken on a VG 7070E mass spectrometer
operating at 70 eV. High performance liquid chromatography
2 5
Anilines, 2-furoyl chloride, vinyl acetate, iodomethane, P S ,
POCl and all other inorganic and organic reagents and solvents
3
(
HPLC) analyses were conducted with an Agilent 1200 instrument
were products of Aldrich or Fluka. All solvents were dried and puri-
fied by standard methods as required. Novozyme 435 (lipase B
from C. antarctica), CaL-A (lipase A from C. antarctica reticulated
with glutaraldehyde), LPS (lipase from Pseudomonas cepacia), LAK
(lipase from Pseudomonas fluorescens), CRL (lipase from Candida
rugosa), LF (lipase from Rhizopus oryzae), CCL (lipase from Candida
cylindracea) and PPL (lipase from porcine pancreas) were pur-
chased from Novozymes, Fluka and Sigma, respectively. Baker’s
yeast produced as wet cakes by Budafok Ltd, Hungary was from
a local store.
using a Chiralcel OJ-H column (4.6 ꢃ 250 mm) and a mixture of n-
hexane and 2-propanol 80:20 (v/v) as eluent for the enantiomeric
separation of rac-2,3a–c and Chiralpak IA-IB tandem columns and a
mixture of n-hexane and 2-propanol 90:10 (v/v) as eluent for the
enantiomeric separation of rac-2,3d. Retention times for (R)- and
(S)-2,3a–d are presented in Table 6. Thin layer chromatography
(
TLC) was carried out using Merck Kieselgel 60 F254 sheets. Spots
were visualized by treatment with 5% ethanolic phosphomolybdic
acid solution and heating. Preparative chromatographic separa-
tions were performed using column chromatography on Merck
Kieselgel 60 (63–200
l
m). Melting points were determined by
4.3. Synthesis of racemic alcohols and their acetates
the hot plate method and are uncorrected. Optical rotations were
2
D
5
determined on a Perkin–Elmer 201 polarimeter and ½
aꢁ
values
The synthesis of racemic secondary alcohols rac-1a–d and their
corresponding acetates rac-2a–d was performed as shown in
Scheme 2. 2-Furan-2-ylbenzothiazole carbaldehydes 1a–d were
prepared as previously described starting from 2-furoyl chloride.6
ꢂ1
2
ꢂ1
are given in units of 10 deg cm g
.
Further, using CH
3
MgI as Grignard reagent the racemic alcohols
Table 6
2
a–d were prepared. The synthesis of racemic acetates 3a–d was
Retention times of the enantiomers of rac-2,3a–d
achieved by chemical acylation with AcCl.
Compound
t
R
(min)
(S)-2a
(S)-2b
(S)-2c
(R)-2d
(S)-3a
(S)-3b
(S)-2c
(R)-3d
(R)-2a
(R)-2b
(R)-2c
(S)-2d
(R)-3a
(R)-2b
(R)-2c
(S)-3d
21.3
15.7
16.8
22.9
16.8
13.1
13.7
15.1
30.5
20.1
22.3
23.7
23.8
18.3
19.1
16.1
4.3.1. Synthesis of racemic alcohols rac-2a–d
Into a stirred solution of methylmagnesium iodide, prepared
from magnesium (7.4 mmol, 0.177 g) and iodomethane (7.4 mmol,
1
.05 g, 0.46 mL) in THF (10 mL), a solution of a heteroaryl-carbal-
dehyde 1a–d (6.2 mmol) dissolved in THF was slowly added at
room temperature under argon. The resulting mixture was stirred
at room temperature for 6 h. After quenching the reaction by slow
addition of saturated ammonium chloride solution (10 mL), the or-
ganic layer was isolated and the aqueous layer was extracted with
Et
2
O (2 ꢃ 10 mL). The combined organic layer was dried over anhy-
drous Na
2
SO . The solvent was removed by distillation in vacuo.
4
The crude product was purified by column chromatography using
hexane/ethylacetate (1:1, v/v) as eluent.

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 1999–2004
2003
a
b
c
d
COCl
R1
O
R1
R2
H
H
Cl
H
H
H
NH2
Cl
CH3
R2
R1
O
R1
R1
O
H
N
H
baker's yeast
O
N
S
P2S5
N
O
R2
S
R2
R2
POCl3
O
AcO
HO
R1
R1
R1
CHO
N
O
N
S
O
N
CH3MgI
R2
S
R2
R2
S
rac-3a-d
rac-2a-d
Scheme 2. The synthesis of 1-(5-(benzo[d]thiazol-2-yl)furan-2-yl) derivatives.
1a-d
4
.3.1.1. 1-(5-Benzo[d]thiazol-2-yl)furan-2-yl)ethanol rac-2a
14 2
C H13NO S: 259.0667): 259.0671; MS: m/z (%) = 260 (M+1, 1),
259 (M+, 3), 244 (2), 149 (1), 58 (39), 44 (2), 43 (100), 42 (6), 41
(2), 39 (4).
1
Yellow solid; yield: 87%; mp 106–107 °C; H NMR: 1.62 (1H, d,
J = 6.7 Hz), 2.1–2.4 (1H, s, br), 4.99 (1H, q, J = 6.7 Hz), 6.01 (1H, q,
J = 6.7 Hz), 6.43 (1H, d, J = 3.5 Hz), 7.12 (1H, d, J = 3.5 Hz), 7.37
(
1H, dd, J = 7.8 Hz, J = 6.8 Hz), 7.48 (1H, dd, J = 6.8 Hz, J = 8.2 Hz),
4.3.2. Chemical acylation of rac-2a–d
Into the solution of one of the heteroarylethanols rac-2a–d
(1 mmol) in dichloromethane (10 mL) were added acetyl chloride
7
6
1
2
1
9
.87 (1H, d, J = 8.2 Hz), 8.04 (1H, d, J = 7.8 Hz); 13C NMR: 22.1,
4.3, 108.7, 113.2, 122.2, 123.7, 125.9, 127.2, 134.8, 148.4, 154.2,
+
+
58.2, 161.2; HRMS:
M
found (M calcd for
C
13
2
H11NO S:
(1.5 mmol, 108
lL) and a catalytic amount of 4-N,N-dimethyl-
45.0511): 245.0509; MS: m/z (%) = 246 (M+1, 15), 245 (M+,
00), 231 (16), 202 (41), 149 (49), 125 (30), 111 (43), 109 (35),
7 (59), 83 (51), 71 (45), 69 (48), 57 (70), 43 (41).
amino-pyridine in pyridine (100
l
L, 1% solution). After stirring
for 30 min at room temperature, the solvent was evaporated in va-
cuo and the crude product was purified by column chromatogra-
phy using hexane/ethylacetate (1:1, v/v) as eluent.
4
.3.1.2. 1-(5-(4-Chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol
1
rac-2b. Yellow solid; yield: 87%; mp 90.5–91; H NMR: 1.62 (3H,
d, J = 6.5 Hz), 2.3–2.5 (1H, s, br), 4.99 (1H, q, J = 6.5 Hz), 6.42 (1H,
d, J = 3.5 Hz), 7.22 (1H, d, J = 3.5 Hz), 7.25–7.29 (1H, m), 7.49 (1H,
4.3.2.1. 1-(5-Benzo[d]thiazol-2-yl)furan-2-yl)ethyl acetate rac-
1
3a. Yellow solid; yield: 93%; mp 113–113.5 °C; H NMR: 1.66 (1H,
d, J = 6.7 Hz), 2.1 (3H, s), 6.01 (1H, q, J = 6.7 Hz), 6.51 (1H, d,
J = 3.2 Hz), 7.13 (1H, d, J = 3.2 Hz), 7.37 (1H, dd, J = 8.2 Hz,
1
3
dd, J = 1 Hz, J = 7.8 Hz), 7.75 (1H, dd, J = 1.2 Hz, J = 8 Hz);
C
NMR: 21.9, 64.3, 108.8, 113.8, 120.7, 126.2, 127.4, 128.4, 136.3,
J = 7.2 Hz), 7.48 (1H, dd,
J = 8.2 Hz), 8.04 (1H, d, J = 8.4 Hz); C NMR: 19.1, 21.7, 65.7,
111.2, 112.7, 122.2, 123.8, 123.9, 125.9, 126.1, 127.2, 134.9, 149,
J =7.2 Hz, J = 8.2 Hz), 7.87 (1H, d,
+
+
13
1
48.2, 151.5, 158.9, 161.5; HRMS: M found (M calcd for
3
7
C
13
H
10ClNO
.2), 278 (M+1, Cl, 0.1), 321 (M+, Cl, 0.6), 59 (2), 58 (38), 57
2), 44 (2), 43 (100), 42 (7), 39 (4).
2
S: 279.0121): 279.0121; MS: m/z (%) = 279 (M+, Cl,
3
5
35
+
+
0
154.4, 156.7, 158, 170.8; HRMS:
M
found (M calcd for
S: 287.0616): 287.0611; MS: m/z (%) = 288 (M+1, 2),
87 (M+, 8), 244 (15), 228 (12), 167 (18), 139 (10), 111 (6), 58
(
C
2
15 3
H13NO
4
.3.1.3. 1-(5-(6-Chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol
(25), 57 (11), 43 (100).
1
rac-2c. Yellow solid; yield: 83%; mp 134–135 °C; H NMR: 1.56
(
3H, d, J = 6.4 Hz), 2.9–3.1 (1H, s, br), 4.97 (1H, q, J = 6.4 Hz), 6.56
4.3.2.2. 1-(5-(4-Chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethyl ace
tate rac-3b. White solid; yield: 95%; mp 84.5–85 °C; H NMR: 1.65
(3H, d, J = 6.5 Hz), 2.1 (3H, s), 6.01 (1H, q, J = 6.5 Hz), 6.52 (1H, d,
1
(
1H, d, J = 3.4 Hz), 7.23 (1H, d, J = 3.4 Hz), 7.53 (1H, dd, J = 8.7 Hz,
1
3
J = 1.9 Hz), 7.96 (1H, d, J = 8.7 Hz), 8.13 (1H, d, J = 1.9 Hz);
C
NMR: 21.4, 62.8, 107.8, 121.6, 123.7, 127.1, 130.2, 135.7, 147.2,
J = 3.2 Hz), 7.25–7.30 (2H, m), 7.49 (1H, dd, J = 1.2 Hz, J = 7.6 Hz),
+
+
13
1
2
57.9, 162.6; HRMS: M found (M calcd for C13
H
10ClNO
2
S:
7.75 (1H, dd, J = 0.8 Hz, J = 8 Hz);
C NMR: 18.9, 21.8, 65.6,
37
79.0121): 279.0119; MS: m/z (%) = 281 (M+, Cl, 7), 280 (M+1,
111.3, 113.4, 120.8, 126.3, 127.4, 128.5, 136.4, 148.8, 151.5, 157,
3
5
Cl, 4), 279 (M+, 35Cl, 25), 266 ( Cl, 8), 264 ( Cl, 25), 107 (5),
37
35
+
+
158.8, 170.8; HRMS: M found (M calcd for C15
3
H12ClNO S:
3
7
7
7 (5), 58 (26), 43 (100).
321.0226): 321.0225; MS: m/z (%) = 323 (M+, Cl, 10), 322 (M+1,
Cl, 5), 321 (M+, Cl, 28), 280 ( Cl, 28), 278 ( Cl, 65), 171 (25),
3
5
35
37
35
4
.3.1.4. 1-(5-(6-Methylbenzo[d]thiazol-2-yl)furan-2-yl)ethanol
169 (37), 135 (26), 58 (30), 57 (21), 43 (100).
1
rac-2d. Brown solid; yield: 89%; mp 90–91 °C; H NMR: 1.61 (3H,
d, J = 6.7 Hz), 2.47 (3H, s), 2.6–2.8 (1H, s, br), 4.98 (1H, q,
J = 6.7 Hz), 6.39 (1H, d, J = 3.5 Hz), 7.05 (1H, d, J = 3.5 Hz), 7.28
4.3.2.3. 1-(5-(6-Chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethyl ace
tate rac-3c. Yellow solid; 93%; mp 125–126 °C; H NMR: 1.65 (3H,
d, J = 6.7 Hz), 2.09 (3H, s), 6.05 (1H, q, J = 6.7 Hz), 6.72 (1H, d,
1
1
3
(
1H, d, J = 8.2 Hz), 7.64 (1H, s), 7.89 (1H, d, J = 8.2 Hz); C NMR:
2
1
2.1, 22.2, 64.2, 108.6, 112.8, 121.9, 123.1, 128.8, 134.9, 136.1,
48.4, 152.3, 157.3, 161.1; HRMS: M found (M calcd for
J = 3.4 Hz), 7.27 (1H, d, J = 3.4 Hz), 7.55 (1H, dd, J = 8.8 Hz,
+
+
13
J = 2.2 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.16 (1H, d, J = 2.2 Hz);
C

2
004
L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 1999–2004
NMR: 17.7, 20.1, 64.5, 110.6, 112.5, 121.6, 123.9, 130.5, 135.7,
MS, NMR and IR spectra of the optically active products were
indistinguishable from those of their racemates. Data on yield,
enantiomeric composition and specific rotation of the products
are shown in Table 5.
+
+
1
C
47.9, 152.7, 156.8, 157.6, 169.3; HRMS: M found (M calcd for
3
7
15 3
H12ClNO S: 321.0226): 321.0229; MS: m/z (%) = 323 (M+, Cl,
3
5
37
35
0
.4), 321 (M+, Cl, 1), 171 ( Cl, 3), 169 ( Cl, 9), 142 (1), 87 (2),
8 (34), 43 (100), 42 (6), 39 (3).
5
4
.6. Preparation of the Mosher’s esters
4
.3.2.4. 1-(5-(6-Methylbenzo[d]thiazol-2-yl)furan-2-yl)ethyl ace
1
tate rac-3d. Brown solid; yield: 91%; mp 82–83 °C; H NMR: 1.66
Into the solution of racemic 1-heteroarylethanol rac-2b or enan-
(
6
3H, d, J = 6.7 Hz), 2.1 (3H, s), 2.47 (3H, s), 6.01 (1H, q, J = 6.7 Hz),
tiomerically pure 1-heterorarylethanol (S)-2b (20 mg, 0.071 mmol)
in CH Cl (2 mL), 4-N,N-dimethylamino-pyridine in pyridine
(100 L, 1% solution) was added, followed by the addition of (R)-
.49 (1H, d, J = 3.5 Hz), 7.1 (1H, d, J = 3.5 Hz), 7.28 (1H, d,
2
2
13
J = 8.2 Hz), 7.65 (1H, s), 7.9 (1H, d, J = 8.2 Hz); C NMR: 19.1,
l
2
1
C
3
1
1.9, 22.2, 65.7, 111.1, 112.3, 121.9, 123.3, 128.8, 135.1, 136.2,
MTPA-Cl (35 mg, 0.14 mmol). The reaction mixture was stirred for
24 h at room temperature. The solvent was further removed in va-
cuo, and the product was purified by column chromatography using
n-hexane-ethylacetate (1:1, v/v) as eluent.
+
+
49.1, 152.5, 156.4, 157.1, 170.8; HRMS: M found (M calcd for
S: 301.0773): 301.0772; MS: m/z (%) = 302 (M+1, 12),
16 3
H15NO
01 (M+, 65), 259 (23), 258 (100), 242 (83), 226 (14), 216 (6),
50 (6) 93 (3), 43 (2).
Acknowledgements
4
4
.4. Analytical scale procedure
L.C.B. is grateful for grants from the Romanian National Council
of Scientific Research of Higher Education (BD, Cod CNCSIS: 384)
and the Hungarian Academy of Science (Hungarian Science Abroad
Scholarship Programe, MTA HTMTÖP). We thank also Professor
Mircea D a˘ r a˘ ban ßt u for useful discussions on the stereochemistry
topics of the manuscript.
.4.1. Analytical scale enzymatic acylation of racemic 1-
heteroarylethanols rac-2a–d
In a typical small scale experiment, one of the 1-heteroaryleth-
anols rac-2a–d (0.05 mmol) and vinyl acetate (0.1, 0.2, 0.25,
0
.4 mmol) were dissolved in a dry organic solvent (1 mL). After
adding lipase (10 mg), the mixture was shaken at 300 rpm at room
temperature. Samples (10 L) were taken at different intervals of
time, diluted with the same solvent (100 L) as the mobile phase
for HPLC (see Section 4.1) and analyzed by HPLC.
l
References
l
1
.
.
(a) Caner, S.; Groner, E.; Levy, L. DDT 2004, 9, 105–110; (b) Francotte, E.;
Lindner, W. Chirality in Drug Research; Wiley-VCH: Weinheim, 2006. pp 13–18.
(a) Andreas, S.; Bommarius, B.; Riebel, R. Biocatalysis; Wiley-VCH, 2004. pp 2–
14; (b) Liese, A.; Seelback, K.; Wandrey, C. Industrial Biotransformations; Wiley-
WCH, 2006. pp 10–43.
2
4
.4.2. Analytical scale enzymatic alcoholysis of racemic 1-
heteroarylethyl acetates rac-3a–d
3.
(a) Magdolen, P.; Zahradník, P.; Foltínová, P. Pharmazie 2000, 55, 8; (b) Su, X.;
Vicker, N.; Trusselle, M.; Halem, H.; Culler, M. D.; Potter, B. L. V. Mol. Cell.
Endocrinol. 2009, 301, 169–173; (c) Su, X.; Vicker, N.; Ganeshapillai, D.; Smith,
A.; Purohit, A.; Reed, J. M.; Potter, B. L. V. Mol. Cell. Endocrinol. 2006, 248, 169–
In a typical small scale experiment, one of the 1-heteroarylethyl
acetates rac-3a–d (0.05 mmol) was dissolved in dry organic sol-
vent and lipase (10 mg) and methanol (0.1, 0.2, 0.3, 0.4 mmol)
were added into the solution. The mixture was shaken at
173; (d) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209; (e) Onitsuka, S.; Nishino, H.;
Kurosawa, K. Tetrahedron Lett. 2000, 41, 3149; (f) Alagoz, O.; Yilmaz, M.; Pekel,
A. T. Synth. Commun. 2006, 36, 1005; (g) Lipshut, B. H. Chem. Rev. 1986, 86, 795;
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Karminski-Zamola, G. Bioorg. Med. Chem. 2010, 18, 1038–1044.
3
00 rpm at room temperature. Samples were taken at different
intervals of time, diluted with the same solvent (100 L) as the mo-
bile phase for HPLC (see Section 4.1) and analyzed with HPLC.
l
4.
Tralic-Kulenovic, V.; Racane, L.; Kaminski-Zamola, G. Spectrosc. Lett. 2003, 36,
4
3–50.
5. Zajac, M.; Hrobarik, P.; Magdolen, P.; Foltinova, P.; Zahradnik, P. Tetrahedron
008, 64, 10605–10618.
4
.5. Preparative scale procedure
2
6
.
(a) Paizs, C.; Tosa, M.; Majdik, C.; Tähtinen, P.; Irimie, F. D.; Kanerva, L. T.
Tetrahedron: Asymmetry 2003, 14, 619–627; (b) Paizs, C.; To sß a, M. I.; Majdik, C.;
Mi ßs ca, R.; Irimie, F. D. Roum. Biotechnol. Lett. 2001, 6, 325–331.
4
.5.1. Preparative scale enzymatic acylation of racemic 1-
heteroarylethanols rac-2a–d
7
8
.
.
Kamal, A.; Azhar, A. M.; Krishajni, T.; Malik, M. S.; Azeeza, S. Coordin. Chem. Rev.
A mixture of rac-3a–d (100 mg), vinyl acetate (300 lL) and CaL-
2008, 252, 569–592.
B (100 mg) in acetonitrile was shaken at 300 rpm at room temper-
ature. Samples from the reaction mixture (5 L) were diluted with
n-hexane/2-propanol (8:2, 100 L) and analyzed by HPLC. The
reactions were stopped by filtering the enzyme at approximately
0% conversions. The solvent was removed in vacuo, and the crude
(a) Ghanem, A.; Aboul-Enein, H. Y. Tetrahedron: Asymmetry 2004, 15, 3331–
3351; (b) To sß a, M. I.; Pilbák, S.; Moldovan, P.; Paizs, C.; Szatzker, G.; Szakács, G.;
Novak, L.; Irimie, F. D.; Poppe, L. Tetrahedron: Asymmetry 2008, 19, 1844–1852;
l
l
(
c) Bencze, L. C.; Paizs, C.; To sß a, M. I.; Vass, E.; Irimie, F. D. Tetrahedron:
Asymmetry 2010, 21, 443–450; (d) Chojnacka, A.; Obara, R.; Wawrzenczyk, C.
Tetrahedron: Asymmetry 2007, 18, 101–107.
5
9
.
Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
product was purified by column chromatography using n-hexane/
ethyl acetate (1:1, v/v) as eluent, resulting in the optically active 1-
heteroarylethanols (S)-2a–d and 1-heteroarylethyl acetates (R)-
1991, 56, 2656–2665.
10. Jing, Q.; Kazlauskas, R. J. Chirality 2008, 20, 724–735.
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Szakács, G.; Poppe, L. J. Mol. Catal. B: Enzym. 2006, 39, 141–148; (b) Bosch, B.;
Meissner, R.; Berendes, F.; Rainhard, K. US2005/0153404A1.
3
a–d.
1
2. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
092–4096.
13. Dutcher, J. S.; Macmillan, J. G.; Heathcock, C. H. J. Org. Chem. 1976, 41, 2663–
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4. (a) Baskar, B.; Pandian, N. G.; Priya, K.; Chadha, A. Tetrahedron: Asymmetry
004, 15, 3961–3966; (b) Chen, H.; Nagabandi, S.; Smith, S.; Goodman, J. M.;
4
.5.2. Preparative scale enzymatic alcoholysis of racemic 1-
4
heteroarylethyl acetates rac-3a–d
2
A mixture of rac-3a–d (100 mg), vinyl acetate (300 lL) and CaL-
1
1
B (100 mg) in acetonitrile was shaken at 300 rpm at room temper-
ature. Samples from the reaction mixture (5 L) were diluted with
n-hexane/2-propanol (8:2, 100 L) and analyzed with HPLC. The
reactions were stopped by filtering the enzyme at approximately
0% conversions. The solvent was removed in vacuo, and the crude
2
l
Plettner, E. Tetrahedron: Asymmetry 2009, 20, 449–456.
5. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Sullivan, G.
R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143; (c) Merckx, E. M.;
Vanhoeck, L.; Lepoivre, J. A.; Alderweireld, F. C.; Van Der Veken, B. J.;
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Doesburg, H. M.; Petit, G. H.; Merckx, E. M. Acta Crystallogr., Sect. B 1982, 38,
l
5
product was purified by column chromatography using n-hexane/
ethyl acetate (1:1, v/v) as eluent, resulting in the optically active 1-
heteroarylethanols (S)-2a–d and 1-heteroarylethyl acetates (R)-
1181; (e) Oh, S. S.; Butler, W. H.; Koreeda, M. J. Org. Chem. 1989, 54, 4499.
3
a–d.