Kinetic resolution of 1-(benzofuran-2-yl)ethanols by lipase-catalyzed enantiomer selective reactions

Article abstract of DOI:10.1016/S0957-4166(03)00358-6

Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a-d was performed by lipase-catalyzed enantiomer selective acylation (E?100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a-d and (1S)-1-(benzofuran-2-yl)ethanols (S)-1a-d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO₂ medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a-d yielded almost quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a-d.

Full text of DOI:10.1016/S0957-4166(03)00358-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1943–1949
Kinetic resolution of 1-(benzofuran-2-yl)ethanols by
lipase-catalyzed enantiomer selective reactions
Csaba Paizs,a Monica Tos¸a,a Vikto´ria Bo´dai,b,c Gyo¨rgy Szaka´cs,c Ildiko´ Kmecz,d Be´la Sima´ndi,d
Cornelia Majdik,a Lajos Nova´k,b Florin-Dan Irimiea,* and La´szlo´ Poppeb,*
aDepartment of Biochemistry and Biochemical Engineering, Babes¸-Bolyai University, Arany Ja´nos 11,
RO-3400 Cluj-Napoca, Romania
bInstitute for Organic Chemistry and Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences,
Budapest University of Technology and Economics, H-1111 Budapest, Gelle´rt te´r 4, Hungary
cDepartment of Agricultural Chemical Technology, Budapest University of Technology and Economics, Gelle´rt te´r 4,
H-1111 Budapest, Hungary
dDepartment of Chemical Engineering, Budapest University of Technology and Economics, Muegyetem Rkp 3,
H-1521 Budapest, Hungary
Received 26 March 2003; accepted 11 April 2003
Abstract—Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d was performed by lipase-catalyzed enantiomer
selective acylation (Eꢀ100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d and (1S)-1-(benzofuran-2-yl)ethanols
(S)-1a–d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting
from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO2
medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d yielded almost
quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a–d. © 2003 Elsevier Science Ltd. All rights reserved.
becoming increasingly attractive tools for synthetic
1. Introduction
chemistry.9,10
Benzofuran-based structures are important units for the
Recently, we have investigated the baker’s yeast reduc-
synthesis of various kinds of biologically active
tion of 1-(benzofuran-2-yl)ethanones, -2-hydroxy-
molecules. (Benzofuran-2-yl)carbinols exhibit various
ethanones and -2-acetoxyethanones for the preparation
biological activities. Such derivatives were investigated
of optically active (benzofuran-2-yl)carbinols.13 By this
as antibacterial1 or antifungal agents.1,2 Moreover, opti-
method, both enantiomeric forms of 1-(benzofuran-2-
cally
active
2-(2-tert-butylamino-1-hydroxyethyl)-
yl)ethane-1,2-diols were obtained in acceptable enan-
tiomeric purities (84–93% ee).13 Baker’s yeast reduction
of the 1-(benzofuran-2-yl)ethanones, however, resulted
in the formation of only the (S)-enantiomers of 1-(benzo-
furan-2-yl)ethanols in moderate enantiomeric purities
(55–88% ee).13
benzofurans were investigated as b-blockers.3 There are
2-substituted benzofuran drugs such as Amiodarone
(cardiac anti-arrythmic)4,5 and Benziodarone (coronary
vasodilator).6 2-Substituted benzofuranes can also
inhibit the HIV-1 reverse transcriptase7 or act as anti-
aging compounds.8
Since for the baker’s yeast reduction study methods for
preparation of the racemic 1-(benzofuran-2-yl)ethanols
rac-1a–d from the 1-(benzofuran-2-yl)ethanones 3a–d
were also developed13 (Fig. 1) and we have recently
isolated a range of novel hydrolases from thermophilic
filamentous fungi exhibiting high enantiomer selectivity
towards aryl methyl carbinols,14 it seemed worthwhile
to investigate the enzyme-catalyzed kinetic resolution of
the racemic 1-(benzofuran-2-yl)ethanols rac-1a–d by
lipase-catalyzed acylation (Fig. 1).
Since for discovery of novel biological activities chiral
compounds as single enantiomers are required, appro-
priate methods providing enantiopure compounds are
essential. Thus, biocatalysts where the homochirality of
an enzyme is the source of the stereoselectivity, are
* Corresponding author. Tel.: +36-1 463 2229; fax: +36-1 463 3297;
e-mail: poppe@mail.bme.hu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00358-6

1944
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
Figure 1. Preparation and lipase-mediated enantiomer separation of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d.
tiomeric preference towards the (R)-enantiomer of the
racemic alcohol, thus yielding a mixture of (R)-acetate
(R)-2a and unreacted (S)-alcohol (S)-1a.
2. Results and discussion
With the racemic 1-(benzofuran-2-yl)ethanols rac-1a–
d13 and with a wide selection of commercial and pre-
pared enzymes14 in hand, firstly enantiomer selectivity
of the enzyme-catalyzed acylations of the unsubstituted
racemic 1-(benzofuran-2-yl)ethanol rac-1a was screened
with different lipases (Fig. 1, Table 1).
This stereochemical preference of lipase PS following
the so called Kazlauskas rule15—which is derived from
an empirical active site model consisting of two pockets
of different sizes which distinguish between the two
enantiomers of the secondary alcohols due to the size
and steric arrangement of their substituents—seems to
be more general for secondary alcohols.
As a result of the screen performed with about three
dozen different enzymes, a number of highly enan-
tiomer selective lipases for the acylation of 1-(benzo-
furan-2-yl)ethanol rac-1a were found. As expected from
the earlier results,9–12 lipases from Pseudomonas strains
(lipase PS, lipase AK) were quite enantiomer selective
(Eꢀ100). In addition, several fungal lipases (Lipozyme
TL IM, and a number of our novel preparations from
thermophilic fungi14) also exhibited excellent selectivi-
ties (Eꢀ100). Almost all of these lipases had an enan-
Interestingly, lipases from Rhizomucor species (lipase
from Rhizomucor javanicus and lipase F) exhibited
opposite enantiomer preference and resulted in the
formation of the (S)-acetate (S)-2a.
The two enzymes from the screen of the racemic 1-(ben-
zofuran-2-yl)ethanol rac-1a which exhibited the highest
Table 1. Enantiomer selective enzymatic acylation of racemic 1-(benzofuran-2-yl)ethanol rac-1aa
Lipase
Time (h)
cb (%)
Ee (%)
(S)-1ac
Ec
(R)-2ac
Lipase TUB 3b
Lipase AK
Lipozyme TL IM
Lipase PS
24
14
14
14
48
14
48
48
48
48
48
48
72
48
48
72
72
50
50
35
45
16
52
10
3
7
3
3
12
12
22
8
11
3
>99
99
99
98
99
96
98
98
97
94
89
86
83
80
79
88d
47d
>99
99
52
82
18
>98
11
2
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
>100
90
PPL
Novozyme 435
Lipase TUB 16b
Lipase TUB 7b
Lipase TUB 4a
Lipase TUB 19b
Lipase TUB 18a
Lipase TUB 20b
CrL
CcL
Lipase AY
Lipase F
Lipase Rh. javanicus
83
77
31
18
15
12
11
9
7
3
3
11
11
22
7
11e
1e
18
3
a Reactions with c >3% within 72 h. For details, see Section 4.2.
b Determined from GC on HP Chiral column.
c Calculated from c and ee2a
d (S)-2a was produced.
e (R)-1a was produced.
.

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
1945
Table 2. Enantiomer selective acylation of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d mediated by Lipase TUB 3b and
Lipase F
Products 1,2
Lipase
Time (h)
ca (%)
2
1
Ec
Config.b
Ee (%)a
Config.b
Ee (%)c
a
b
c
d
a
b
c
TUB 3b
TUB 3b
TUB 3b
TUB 3b
F
F
F
F
24
168
24
168
72
168
168
168
50
49
50
51
11
13
12
5
R
R
R
R
S
S
S
S
>99
97
>99
98
88
95
S
S
S
S
R
R
R
R
>99
99
>99
>99
11
15
12
6
ꢀ100
ꢀ100
ꢀ100
ꢀ100
18
44
20
>100
89
99
d
a Determined from GC on HP Chiral column.
b Determined by comparison with samples of known configuration.
c Calculated from c and ee2.
Table 3. Preparative scale enantiomer selective acylation of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d mediated by Lipase
AK
Products 1,2
Time (h)
(S)-1a
Eeb (%)
(R)-2a
Eec (%)
E
Yield (%)
Yield (%)
a
b
c
14
18
72
72
49
48
51
51
98.6
97.5
81.0
81.0
48
47
44
43
99.1
98.6
>99.8
99.1
ꢀ100
ꢀ100
ꢀ100
ꢀ100
d
a Configurations were determined by comparison with literature data.13
b Determined by GC on HP Chiral column.
c Determined after chemical acylation by GC on HP Chiral column.
enantiomer selectivities towards the (R)- and (S)-enan-
tiomers of the racemic alcohol, were further tested for
the acylation of substituted racemic 1-(benzofuran-2-
yl)ethanols rac-1b–d (Table 2). As expected, the
enzymes which performed the acylation of the unsubsti-
tuted racemic alcohol rac-1a with the highest selectivi-
ties were also quite selective towards the substituted
ones rac-1b–d.
ity but lowered the rate of reaction, whereas sub-
stituents with +M effects at positions 5 and 7 (entries 6
and 8, 1b, R=5-Br and 1d, 7-MeO, respectively)
enhanced the degree of enantiomer selectivity. The cost
of this enhancement in selectivity towards the (S)-enan-
tiomer of the 7-methoxy-substituted alcohol (S)-1d,
however, was a drop in the rate of the reaction.
Next, for full characterization of the products kinetic
resolutions were performed on the racemic 1-(benzo-
furan-2-yl)ethanols (rac-1a–d, 200 mg, each) with the
most selective commercial enzyme, lipase AK (Table 3).
In the reactions with the best performing enzyme
exhibiting (R)-enantiomeric preference, lipase TUB 3b
(isolated during our screen for lipases from ther-
mophilic filamentous fungi14), the high degree of selec-
tivity remained unaltered and the quality and/or
position of the substituents effected only the rate of the
reaction (entries 1–4 in Table 2). Compared to the
unsubstituted derivative (entry 1, 1a), electron with-
drawing substituent at position 5 (entry 3, 1c, R=5-
NO2) had no strong influence on the rate of acylation,
whereas substituents with +M effects at positions 5 and
7 (entries 2 and 4, 1b, R=5-Br and 1d, 7-MeO, respec-
tively) significantly lowered the rate of the reaction.
In the reactions with lipase AK—as with lipase TUB
3b—the degree of the selectivity remained high and
unaltered regardless of the quality and/or position of
the substituents which affected only the rate of the
reaction. Interestingly, in acylations performed with
lipase AK—in contrast to lipase TUB 3b acylations—
the 5-bromo substitution (entry 2, 1b) did not have any
influence but the 5-nitro substitution (entry 3, 1c) low-
ered the rate of the reaction.
On the contrary, with lipase F which showed the
highest degree of (S)-enantiomeric preference not only
the rate but the selectivity of the acylation reaction was
dependent on the substitution pattern. In this case, the
electron withdrawing substituent at position 5 (entry 7,
1c, R=5-NO2) had no significant effect on the selectiv-
Finally, the degree of enantioselectivity was tested in
alcoholysis/hydrolysis reactions of the racemic 1-acet-
oxy-1-(benzofuran-2-yl)ethane rac-2a with the most
selective immobilized lipase (Lipozyme TL IM) (Table
4).

1946
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
Table 4. Alcoholysis/hydrolysis of 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2a mediated by Lipozyme TL IMa
Methoda
Nucleophile
Time (h)
cb (%)
Ee (%)
(R)-2ab
Ec
(S)-1ac
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
H2O
H2O
H2O
24
24
4
24
24
4
24
24
4
24
24
4
40
20
9
3
5
34
4
7
50.0
17.5
6.7
0.7
3.7
1.3
2.1
9.4
1.6
7.7
24.2
3.2
14.3
58.2
1.0
11.4
7.2
5.2
1.5
8.8
2.1
12.8
8.5
1.3
54.9
8.2
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
PrOH
PrOH
PrOH
BuOH
BuOH
BuOH
<1
<1
<1
<1
1
<1
<1
8
<1
6
41
<1
4
3
11
11
7
25
6
30
41
6
3.3
2.3
19.6
1.4
24
24
4
a Method A: neat nucleophile, Method B: hexane containing nucleophile (10%), Method C: supercritical CO2 containing nucleophile (1%). The
reactions with Methods A and B were performed at room temperature, reactions with Method C were made at 38°C.
b Determined from GC on HP Chiral column.
c Calculated from c and ee2.
For alcoholysis/hydrolysis of the racemic 1-acetoxy-1-
(benzofuran-2-yl)ethane rac-2a three conditions were
compared. The reactions were first performed in alco-
hol/water as solvent at room temperature (Method A).
Then the alcoholysis/hydrolysis reactions were carried
out at room temperature in hexane containing 10% of
the different nucleophiles (Method B) and in supercriti-
cal CO2 containing 1% of the nucleophile at 38°C
(Method C).
Table 5. Lipase-catalyzed ethanolysis of (1R)-1-acetoxy-1-
(benzofuran-2-yl)ethanes (R)-2a–d
Product 1
Yield (%)
Eea (%)
[h]2D0 (c 1.0, CHCl3)
a
b
c
96
95
97
96
>99
99
>99
>99
+16.6
+14.5
+18.9
+14.8
d
a Determined by GC on HP Chiral column as acetate derivative.
The results indicated that any of the tested alcoholysis/
hydrolysis reaction condition was significantly less
enantiomer selective (Table 4: Eꢁ1.3–54.9) than the
corresponding acylation (entry 3, Table 1: Eꢀ100).
Interestingly, different nucleophiles exhibited the
highest selectivities for the three different conditions. In
reactions performed in the nucleophile as solvent
(Method A) the highest selectivity was achieved with
propanol (entry 10, Table 4: E=54.9). In the reactions
conducted in hexane as solvent (Method B) butanol
provided the highest selectivity (entry 14, Table 4:
E=19.6), whereas among the reactions carried out in
supercritical CO2 water as nucleophile gave the highest
selectivity (entry 3, Table 4: E=5.2).
(Poppe, L., unpublished). The enzymatic method, how-
ever, gave from the highly enantiopure (R)-acetates
(R)-2a–d non-racemized alcohols (R)-1a–d almost
quantitatively.
3. Conclusion
For kinetic resolution of racemic 1-(benzofuran-2-
yl)ethanols rac-1a–d by enantiomer selective acylation
several highly selective (Eꢀ100) bacterial and fungal
lipases were positively tested. Most enzymes exhibited
(R)-enantiomeric preference yielding (1R)-1-acetoxy-1-
(benzo-furan-2-yl)-ethanes (R)-2a–d and (1S)-1-(benzo-
furan-2-yl)ethanols (S)-1a–d but a few lipases (e.g.
lipase F) had opposite enantiopreference. The prepara-
tive scale reactions with lipase AK resulted in the
acetates (R)-2a–d and alcohols (S)-1a–d in highly enan-
tiopure form. The degree of enantiomer selectivity for
enzymatic alcoholysis/hydrolysis processes starting
from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2
was also tested under various conditions including
supercritical CO2 medium and found it significantly
lower than that of the acylation process. Preparative
scale lipase-catalyzed ethanolysis was used for racem-
ization-free production of enantiopure (1R)-1-(benzo-
furan-2-yl)ethanols (R)-1a–d in almost quantitative
yields.
Although the low selectivities made alcoholysis/hydrol-
ysis reactions unattractive as alternative for kinetic
resolution purposes, this approach seemed to be ideal
for racemization-free desacetylation of the produced
highly enantiopure (R)-acetates (R)-2a–d (Table 5).
Although it seems to be simple, the racemization-free
desacetylation of esters of aryl methyl carbinols is not a
trivial task. It was observed by the hydrolysis of the
enantiopure (1R)-1-phenylethyl acetate that desacetyla-
tion either with 5% aqueous NaOH or catalytical
NaOMe/MeOH at room temperature resulted in about
5% racemization and thus ꢁ90% ee for the product

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
1947
4. Experimental
4.1. Materials and methods
4.3. Preparative scale acylation of racemic 1-(benzo-
furan-2-yl)ethanols catalyzed by lipase AK
To a solution of racemic 1-(benzofuran-2-yl)ethanol
(rac-1a–d, 200 mg, each) in vinyl acetate (6 ml) lipase
AK (200 mg) was added and the mixture was stirred at
rt for the time indicated in Table 2. Then the enzyme
was filtered off and washed with acetone (2×5 ml).
Solvents were distilled off from the combined filtrates
and the residue was purified by column chromatogra-
phy (silica gel, CH2Cl2) yielding the optically active
alcohol (S)-1a–d and acetate (R)-2a–d.
1
4.1.1. Analytical methods. The H and 13C NMR spec-
tra were recorded in CDCl3 solution on a Brucker
DRX-500 spectrometer operating at 500 and 125 MHz,
respectively. Chemical shifts are expressed in ppm val-
ues from TMS as internal standard. IR spectra were
recorded in KBr on a Specord 2000 spectrometer and
the wavenumbers are reported in cm−1. GC analyses
were made by an Agilent 4890D gas chromatograph
(carrier gas H2; head pressure: 12 psi, injector: 250°C;
FID detector: 250°C) on a HP-Chiral column (30 m×
0.32 mm, 0. 25 mm 20% permethylated b-cyclodextrin,
No. 19091G-B312). Optical rotations were determined
on a Perkin–Elmer 241 polarimeter. Preparative vac-
uum-chromatography16 was performed on Merck
Kieselgel 60 (0.063–0.200 mm).
4.3.1. (1S)-1-(Benzofuran-2-yl)ethanol, (S)-1a. Yield:
49%; ee: 98.6% (by GC after conversion to acetate);
1
[h]2D0 −16.6 (c 1.0, CHCl3); H NMR: 1.66 (3H, d), 2.41
(1H, broad s), 5.04 (1H, q), 6.63 (1H, s), 7.23–7.26 (1H,
m), 7.28–7.32 (1H, m), 7.49 (1H, d), 7.57 (1H, d); 13C
NMR: 21.47, 64.14, 101.36, 112.69, 115.84, 123.75,
127.11, 130.20, 153.58, 161.60; IR: 3384, 2984, 1456,
1376, 1304, 1256, 1152, 1076, 1008, 944, 808, 748. Anal
calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 74.16;
H, 6.25%.
4.1.2. Reagents and solvents. Vinyl acetate and the other
commercial chemicals and solvents were products of
Aldrich or Fluka. All solvents were purified and dried
by standard methods. Racemic 1-(benzofuran-2-
yl)ethanols rac-1a–d and 1-acetoxy-1-(benzofuran-2-
4.3.2. (1S)-1-(5-Bromobenzofuran-2-yl)ethanol, (S)-1b.
Yield: 48%; ee: 97.5% (by GC after conversion to
acetate); [h]2D0 −14.5 (c 1.0, CHCl3); 1H NMR: 1.63 (3H,
d), 2.26 (1H, broad s), 5.00 (1H, q), 6.55 (1H, s),
7.27–7.37 (2H, m), 7.66 (1H, s); 13C NMR: 21.47, 64.14,
101.36, 112.69, 115.84, 123.75, 127.11, 130.20, 153.58,
161.69; IR: 3408, 2984, 1448, 1372, 1300, 1264, 1152,
1088, 1024, 936, 808. Anal calcd for C10H9BrO2: C,
49.82; H, 3.76; Br, 33.14. Found: C, 49.76; H, 3.65; Br,
33.05%.
yl)ethanes
rac-2a–d
were
prepared
from
2-acetylbenzofuranes 3a–d according to the published
procedures.13
4.1.3. Biocatalysts. Lipase A, lipase AK, lipase AY,
lipase M, lipase PS and lipase R were obtained from
Amano Europe. Lipozyme IM, Lipozyme IM 20,
Lipozyme TL IM, Novozyme 435 and Candida antarc-
tica lipase A were products of Novozymes, Denmark.
Lipases from Candida rugosa and Pseudomonas fluores-
cens were purchased from Fluka. PPL and lipase from
Candida cylindracae were obtained from Sigma. A
selection of extracellular hydrolases from various ther-
mophilic fungi (lipases TUB 1-52a,b) were isolated as
4.3.3. (1S)-1-(5-Nitrobenzofuran-2-yl)ethanol, (S)-1c.
Yield: 51%; ee: 81.0% (by GC after conversion to
acetate); [h]2D0 −15.5 (c 1.0, CHCl3); 1H NMR: 1.66 (3H,
d), 2.42 (1H, broad s), 5.06 (1H, q), 6.75 (1H, s), 7.51
(1H, d), 8.18 (1H, d), 8.43 (1H, s); 13C NMR: 21.50,
64.06, 102.58, 111.54, 117.57, 120.94, 128.64, 144.16,
157.64, 163.91; IR: 3320, 1528, 1348, 1296, 1264, 1160,
1080, 1024, 884, 816, 736. Anal calcd for C10H9NO4: C,
57.97; H, 4.38; N, 6.76. Found: C, 57.92; H, 4.27; N,
6.77%.
acetone
dried
supernatants
of
shake
flask
fermentations.14
4.1.4. Reactor for SCF alcoholysis/hydrolysis tests.
Reactions in supercritical CO2 were performed in a
thermostated (38°C) tube-reactor (reactor volume 5
ml). Supercritical CO2 was filled in the system (total
volume 20 ml) by an SFC 300 pump (Carlo Erba) and
recycled through the reactor by a pump system. The
CO2 used in this study was 99.5% (w/w) pure and
supplied by Messer Griesheim Hungaria Ltd.
(Budapest).
4.3.4. (1S)-1-(7-Methoxybenzofuran-2-yl)ethanol, (S)-
1d. Yield: 51%; ee: 81.0% (by GC after conversion to
acetate); [h]2D0 −12.1 (c 1.0, CHCl3); 1H NMR: 1.64 (3H,
d), 2.46 (1H, broad s), 4.00 (3H, s), 5.03 (1H, q), 6.60
(1H, s), 6.76–6.80 (1H, m), 7.14 (2H, d); 13C NMR:
21.41, 55.98, 64.08, 102.02, 106.29, 113.46, 123.46,
129.86, 143.96, 145.26, 160.64; IR: 3296, 2984, 1624,
1600, 1496, 1440, 1376, 1312, 1272, 1200, 1184, 1096,
1032, 936, 892, 836, 728. Anal calcd for C11H12O3: C,
68.74; H, 6.29. Found: C, 68.66; H, 6.25%.
4.2. Lipase-catalyzed acylations of racemic 1-(benzo-
furan-2-yl)ethanol rac-1a
To a solution of racemic 1-(benzofuran-2-yl)ethanol
(rac-1a, 20 mg) in vinyl acetate (0.5 ml) lipase (20 mg)
was added and the mixture was shaken at room temper-
ature and 1000 rpm for the time indicated in Table 1.
Samples from the supernatant were analyzed by GC [Rt
(HP Chiral; oven: 165°C)/min: 3.50 1a, 3.75 (S)-2a,
3.84 (R)-2a] according to the published procedure.13
Conversion and enantiomeric composition data are pre-
sented in Table 1.
4.3.5. GC determination of the enantiomeric purity of
1-(benzofuran-2-yl)ethanols 1a–d. Alcohols 1a–d were
transformed to acetates 2a–d according to the published
procedure13 [alcohol (1a–d, 0.3 mmol), triethylamine
(33.5 mg, 46 ml, 0.33 mmol), CH2Cl2 (2 ml), acetyl
chloride (26 mg, 24 ml, 0.33 mmol), stirring at room

1948
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
temperature for 2 h] and analysed by GC on HP Chiral
column [2a, GC (165°C) RT(R): 3.75 min, RT(S): 3.84
min; 2b: GC (120–170°C, 1°C/min) RT(R): 37.34 min,
Method C: Racemic 1-acetoxy-1-(benzofuran-2-
yl)ethane (rac-2a, 50 mg) was evaporated from CH2Cl2
(20 ml) onto Perfil 100™ (500 mg, expanded and milled
perlite, Baumit Co., Budapest) and the resulted dry
material was filled into the SCF reactor. Over this
layer, immobilized enzyme (Lipozyme TL IM, 200 mg)
and nucleophile (1 ml) were also added. After filling the
reactor CO2 was pumped in and the supercritical CO2
was recycled through the so-prepared reactor at 38°C
and 120 bar for 4 h. Work up of the reaction was
performed by releasing the CO2 into a dry-ice cooled
trap. The trap, the adsorbent and the enzyme were
washed with acetone (2×20 ml). The unified acetone
solutions were evaporated and the residue was analysed
by GC as described in Section 4.2.
RT(S): 38.06 min; 2c: GC (130–180°C, 1°C/min) RT(R)
:
46.94 min, RT(S): 47.56 min; 2d: GC (120–170°C, 1°C/
min) RT(R): 33.39 min, RT(S): 34.07 min].
4.3.6. (1R)-1-Acetoxy-1-(benzofuran-2-yl)ethane, (R)-2a.
Yield: 48%; ee: 99.1% (by GC); [h]2D0 +198.2 (c 1.0,
1
CHCl3); H NMR: 1.71 (3H, d), 2.13 (3H, s), 6.13 (1H,
q), 6.72 (1H, s), 7.24–7.29 (1H, m), 7.31–7.34 (1H, m),
7.51 (1H, d), 7.58 (1H, d); 13C NMR: 18.43, 21.16,
65.51, 104.24, 111.37, 121.24, 122.87, 124.56, 127.86,
154.86, 155.99, 170.12; IR: 1744, 1456, 1372, 1236,
1060, 1028, 752. Anal calcd for C12H12O3: C, 70.57; H,
5.92. Found: C, 70.62; H, 5.95%.
Details for and results of the reactions with the three
methods (kind of nucleophile, reaction time, c, ee and E
values) are reported in Table 4.
4.3.7.
(1R)-1-Acetoxy-1-(5-bromobenzofuran-2-yl)-
ethane, (R)-2b. Yield: 47%; ee: 98.6% (by GC); [h]D20
1
+144.1 (c 1.0, CHCl3); H NMR: 1.66 (3H, d), 2.11
4.5. Preparative scale ethanolysis of (1R)-1-acetoxy-1-
(benzofuran-2-yl)ethanes (R)-2a–d
(3H, s), 6.07 (1H, q), 6.63 (1H, s), 7.33–7.39 (2H, m),
7.67 (1H, s); 13C NMR: 18.80, 21.52, 65.68, 104.05,
113.24, 116.30, 124.27, 127.87, 130.26, 153.99, 157.84,
170.44; IR: 1740, 1448, 1372, 1264, 1024, 800. Anal
calcd for C12H11BrO3: C, 50.91; H, 3.92; Br, 28.22.
Found: C, 50.82; H, 3.88; Br, 28.34%.
Lipozyme TL IM (100 mg) was added to an ethanolic
solution of (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes
(100 mg in 5 ml) obtained from the preparative
acylations (Section 4.2). The reaction mixture was
shaken at 1000 rpm and rt overnight until complete
conversion (by TLC). Then the enzyme was filtered off
and washed with ethanol (2×5 ml). The solvent was
evaporated in vacuum and the crude product was
purified by vacuum chromatography on silica gel with
CH2Cl2 yielding the alcohols (R)-1a–d (for isolated
yield, optical rotation and enantiomeric composition
data, see Table 5).
4.3.8. (1R)-1-Acetoxy-1-(5-nitrobenzofuran-2-yl)ethane,
(R)-2c. Yield: 44%; ee: >99.8% (by GC); [h]2D0 +139.2 (c
1
1.0, CHCl3); H NMR: 1.70 (3H, d), 2.13 (3H, s), 6.10
(1H, q), 6.83 (1H, s), 7.55 (1H, d), 8.23 (1H, d), 8.48,
(1H, s); 13C NMR: 18.42, 21.08, 65.10, 104.85, 111.78,
117.8, 120.48, 128.34, 144.31, 157.61, 159.66, 169.70;
IR: 1748, 1524, 1348, 1232, 1064, 1032, 952. Anal calcd
for C12H11NO5: C, 57.83; H, 4.45; N, 5.62. Found: C,
57.75; H, 4.52; N, 5.68%.
Acknowledgements
4.3.9.
(1R)-1-Acetoxy-1-(7-methoxybenzofuran-2-yl)-
ethane, (R)-2c. Yield: 43%; ee: 99.1% (by GC); [h]D20
1
+156.0 (c 1.0, CHCl3); H NMR: 1.69 (3H, d), 2.09
Financial support for the Hungarian OTKA Founda-
tion (T-033112 and T-025235), for the Hungarian Min-
istry of Education, National R&D Project
(NKFP3-35-2002) and Romanian Ministry of Educa-
tion and Research (AT-18/600) is gratefully acknowl-
edged. C.P. and C.M. thank Domus Hungarica and
Agora Foundation.
(3H, s), 4.01 (3H, s), 6.08 (1H, q), 6.79–6.82 (1H, m),
6.69 (1H, s), 7.14–7.16 (2H, m); 13C NMR: 18.93, 21.58,
56.41, 66.41, 105.01, 107.09, 113.93, 123.97, 129.95,
144.56, 145.78, 156.57, 170.50; IR: 1740, 1496, 1372,
1272, 1096, 1056, 1028, 852, 928, 732. Anal calcd for
C13H14O4: C, 66.66; H, 6.02. Found: C, 66.62; H,
6.11%.
4.4. Alcoholysis/hydrolysis of racemic 1-acetoxy-1-(ben-
zofuran-2-yl)ethane rac-2a
References
1. Bevinakatti, H. S.; Badiger, V. V. Arch. Pharm. (Wein-
heim) 1981, 314, 162–167.
2. Wahbi, Y.; Caujolle, R.; Tournaire, C.; Payard, M.;
Linas, M. D.; Seguela, J. P. Eur. J. Med. Chem. Chim.
Ther. 1995, 30, 955–962.
Method A: To a solution of racemic 1-acetoxy-(benzo-
furan-2-yl)ethane (rac-2a, 20 mg) in the nucleophile
(500 ml, see Table 4) Lipozyme TL IM (20 mg) was
added and the mixture was shaken at 1000 rpm and rt
for the time indicated in Table 4.
3. Machin, P. J.; Hurst, D. N.; Osbond, J. M. J. Med.
Chem. 1985, 28, 1648–1651.
Method B: To a solution of racemic 1-acetoxy-(benzo-
furan-2-yl)ethane (rac-2a, 20 mg) in hexane (450 ml)
containing nucleophile (50 ml, see Table 4) Lipozyme
TL IM (20 mg) was added and the mixture was shaken
at 1000 rpm and rt for the time indicated in Table 4.
4. Charlier, R.; Deltour, G.; Baudine, A.; Chaillet, F.
Arzneimittel-Forschung 1968, 18, 1408–1417.
5. Tomaselli, G. HeartDrug 2001, 1, 183–185.
6. Bekaert, J.; Deltour, G.; Broekhuysen, J. Arch. Intern.
Pharmacodyn. 1961, 132, 339–348.

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1943–1949
1949
7. Hoffman, J. M.; Smith, A. M.; Rooney, C. S.; Fisher, T.
E.; Wai, J. S.; Thomas, C. M.; Bamberger, D. L.; Barnes,
J. L.; Williams, T. M. J. Med. Chem. 1993, 36, 953–966.
8. Knoll, J. CNS Drug Rev. 2001, 7, 317–345.
9. Poppe, L.; Nova´k, L. Selective Biocatalysis: A Synthetic
Approach; VCH: Weinheim, 1992.
10. Faber, K. Biotransformations in Organic Chemistry, 4th
ed.; Springer: Berlin, 2000.
11. Liese, A.; Seelbach, K.; Wandrey, C. Industrial Bio-trans-
formations; Wiley-VCH: Weinheim, 2000.
12. Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic
Synthesis; Wiley-VCH: Weinheim, 2002.
13. Paizs, C.; Tos¸a, M.; Majdik, C.; Moldovan, P.; Nova´k, L.;
Kolonits, P.; Marcovici, A.; Irimie, F.-D.; Poppe, L.
Tetrahedron: Asymmetry 2003, 14, 1494–1501.
14. Bo´dai, V.; Peredi, R.; Ba´lint, J.; Egri, G.; Nova´k, L.;
Szaka´cs, G.; Poppe, L. Adv. Synth. Catal. 2003, in press.
15. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.
16. Poppe, L.; Nova´k, L. Magy. Ke´m. Lapja 1985, 40, 366–369.