Sequential use of regio- and stereoselective lipases for the efficient kinetic resolution of racemic 1-(5-phenylfuran-2-yl)ethane-1,2-diols

Article abstract of DOI:10.1016/j.tetasy.2011.03.006

Possible routes for the enzymatic transformation of various substituted 1-(5-phenylfuran-2-yl)ethane-1,2-diols and their mono- and diacetylated counterparts were studied. Combining the regioselectivity of LPS mediated acylation of the starting racemic dio

Full text of DOI:10.1016/j.tetasy.2011.03.006

Tetrahedron: Asymmetry 22 (2011) 675–683
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Sequential use of regio- and stereoselective lipases for the efficient kinetic
resolution of racemic 1-(5-phenylfuran-2-yl)ethane-1,2-diols
⇑
László Csaba Bencze, Csaba Paizs, Monica Ioana Toßsa, Florin Dan Irimie
Department of Biochemistry and Biochemical Engineering, Babeßs-Bolyai University, Arany János str. 11, 400028 -Cluj Napoca, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Possible routes for the enzymatic transformation of various substituted 1-(5-phenylfuran-2-yl)ethane-
1,2-diols and their mono- and diacetylated counterparts were studied. Combining the regioselectivity
of LPS mediated acylation of the starting racemic diols, the stereoselectivity of LAK shown in the enan-
tiomer selective transformation of the previously formed racemic primary acetates and the LPS mediated
mild hydrolysis–alcoholysis of the resolution products, an efficient preparative scale procedure for the
synthesis of various highly enantiomerically enriched (R)- and (S)-phenylfuran-2-yl-ethane-1,2-diols
has been developed.
Received 23 February 2011
Accepted 18 March 2011
Available online 7 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Lipase mediated biotransformations of arylethane-1,2-diols
have been studied extensively.5–12 Enzymatic acylation of racemic
Phenylfuran based structures are important structural subunits
in various biologically active compounds. Recently some phenyl-
furanyl derivatives have exhibited cytoprotective effects against
neurotoxin- and LPS-induced cell death,1 while others have proven
to be efficient inhibitors of the methionine aminopeptidase (Me-
tAP), which is a promising target for the development of novel anti-
bacterial, antifungal, and anticancer agents.2 Accordingly there is
an increasing interest for the synthesis of novel phenylfuran based
compounds with potential application in the pharmaceutical
industry.
1,2-Ethanediols are important chiral intermediates in asymmet-
ric synthesis, frequently used for the synthesis of pharmaceuti-
cals.3 Our previous work4 devoted to the chemo-enzymatic
synthesis of both enantiomeric forms of phenylfuran-2-yl-
ethane-1,2-diols via Baker’s yeast mediated biotransformation
1,2-diols,5–9,11,12 of primary9–11 and secondary9,11 acetates of 1,2-
diols, as well as the hydrolysis5,9,11 or alcoholysis5,11 of primary
and secondary monoacetates or 1,2-diol diacetates have all been
investigated. Significant differences were found between the enzy-
matic transformations of 1,2-diols and their acylated derivatives.
Lipases showed the highest activity and enantioselectivity for the
kinetic resolution of various primary esters of the 1,2-diols.5–12
LPS (formerly the lipase from Pseudomonas cepacia, now lipase
from Burkholderia cepacia) was found to be a proper regio- and
enantioselective catalyst. Thus, in the transformation of racemic
1,2-diols in the first acylation step, the racemic primary monoace-
tates of the 1,2-diols were formed, followed by a second highly
enantioselective acylation step yielding both enantiomerically
enriched diacetylated 1,2-diols and primary monoacetates. An effi-
cient LAK (lipase AK from Pseudomonas fluorescens) mediated acyl-
ation of the secondary monoacetate of 1-phenylethane-1,2-diol
was also reported.9
With the exception of the CaLB (lipase B from Candida antarc-
tica) mediated one-pot methanolysis of the diacetate of 1-phe-
nyl-ethane-1,2-diol,11 which allows the preparation of the (S)-1-
phenylethane-1,2-diol and the (R)-1-acetoxy-1-phenylethanol
with high ee, enzymatic alcoholysis or hydrolysis generally shows
lower regioselectivity and enantioselectivity.
In contrast to the numerous lipase mediated kinetic resolutions
of arylethane-1,2-diols, except for the LPS mediated enzymatic res-
olution of racemic 2-(2-furyl)-2-hydroxyethyl acetate,10 enzymatic
resolution of heteroarylethane-1,2-diols has not been reported.
The significant differences observed in the regio- and stereose-
lectivity of various enzymatic transformations, prompted us to
of
a-acetoxymethyl-5-phenylfurane-2-yl-ethanones and of a-
hydroxymethyl-5-phenylfuran-2-yl-ethanones did not give the ex-
pected results. Due to the observed strong substituent effect, in
some cases no biotransformation occurred, or products with low
enantiomeric excess were formed; the method proved to be unsat-
isfactory as a general synthetic procedure for the synthesis of both
enantiomers of phenylfuran-2-yl-ethane-1,2-diols.
Therefore, we turned our interest to lipase mediated kinetic res-
olution, as an alternative procedure for the synthesis of highly
enantiomerically enriched forms of phenylfuran-2-yl-ethane-1,2-
diols.
⇑
Corresponding author. Tel.: +40 264 593 833; fax: +40 264 593 818.
E-mail address: irimie@chem.ubbcluj.ro (F.D. Irimie).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.006

676
L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
investigate all the possible enzymatic reactions of phenylfuran-2-
yl-ethane-1,2-diols and their primary or secondary monoacylated
or diacylated counterparts in order to develop an efficient enzy-
matic procedure for the synthesis of both enantiomers of various
phenylfuran-2-yl-ethane-1,2-diols.
reaction media and vinyl acetate as the acyl donor, most of the li-
pases tested showed little to no activity. Only the highly active
LPS and PPL (porcine pancreatic lipase) with moderate activity cat-
alyzed regioselectively the acylation of the rac-5a–d, yielding the
racemic 2-hydroxy-2-(5-phenylfuran-2-yl)ethyl acetates rac-6a–
d. CaLA (lipase A from C. antarctica) catalyzed in the first step with
poor regioselectivity; the acylation of rac-5a–d yielding both rac-
6a–d and rac-8a–d with an approximate 4:1 ratio. In the second
step, the monoacylated compounds formed were further acylated
by CaLA. As described in the next paragraph, while the acetylation
of rac-6a–d proceeded stereoselectively, rac-8a–d was transformed
rapidly with low stereoselectivity, lowering the ee of (R)-7a–d pro-
duced in the reaction mixture (Scheme 2). Thus the use of the race-
mic heteroaryl-ethane-1,2-diols rac-5a–d as substrates for an
efficient enzymatic enantiomer selective resolution was ruled out.
2. Results and discussion
2.1. Preparation of the racemic substrates by chemo-enzymatic
methods
Racemic 1-(5-phenylfuran-2-yl)ethane-1,2-diols rac-5a–d were
prepared by the chemoenzymatic method described earlier by us.4
These were transformed by chemical acylation into racemic diace-
tates rac-7a–d (Scheme 1).
In order to avoid the usual drawbacks of the protecting groups
employed for the regioselective acylation of rac-5a–d and because
the chemical synthesis of racemic 2-hydroxy-1-(5-phenylfuran-2-
yl)ethyl acetates rac-6a–d and 2-hydroxy-2-(5-phenylfuran-2-
yl)ethyl acetates rac-8a–d by the previously described methods11
were unsuccessful, we turned our attention toward highly regiose-
lective, but non-stereoselective enzymatic methods.
In the enzymatic acylation of racemic 1,2-ethanediols rac-5a–d
it was observed that LPS acts in a highly regioselective manner,
yielding only rac-6a–d (Scheme 1). LPS was also found to be an
appropriate biocatalyst for the synthesis of racemic 2-hydroxy-2-
(5-phenylfuran-2-yl)ethyl acetates rac-8a–d. Thus, by the LPS
mediated hydrolysis of the racemic diacetates rac-7a–d in THF–
water mixture (1:1, v/v) rac-8a–d were quantitatively obtained.
The gram-scale procedures were carried out in a similar way;
the isolation and the purification of the target compounds was easy
and simple to carry out thus providing an accessible synthetic
route to both monoacetylated phenylfuran-2-yl-ethane-1,2-diols
rac-6,8a–d. In this manner the use of difficult chemical meth-
ods,9,11,13 requiring special reagents or experimental conditions,
was avoided.
2.3. The enzymatic kinetic resolution of rac-6,8a–d
It is known that lipases catalyze in their biological function the
1,3-regioselective hydrolysis of triacylglycerols at water–lipid
interfaces. Consequently, we decided to investigate the enzymatic
kinetic resolution of racemic 2-hydroxy-2-(5-phenylfuran-2-
yl)ethyl acetates rac-8a–d, since the enzymatic acylation of the pri-
mary hydroxyl group should be favoured.
Using racemic 1-(5-(4-bromophenyl)furan-2-yl)2-hydroxy-
ethyl acetate rac-8b as a model compound, potentially useful li-
pases were screened for enantiomeric selective acylation with vi-
nyl acetate (8 equiv) in various organic solvents. Most of the
lipases showed high activity and low enantioselectivity in all
tested solvents. The best results were obtained in diisopropyl ether
(DIPE), however, the obtained results were unsatisfactory (E <7,
Scheme 3a), as shown in Table 1. These results can be explained
by the fact that the reacting hydroxyl group is near to the asym-
metric center, thus the steric recognition between the catalytic
center of the enzyme and the enantiomers of the substrate is poor.
The enzymatic alcoholysis or hydrolysis of the racemic second-
ary monoacetate rac-8b also gave unsatisfactory results. Most of
the lipases and other hydrolases like PLE, Acylase I and esterase
from Rhizopus oryzae were catalytically inactive in neat alcohols
such as methanol, ethanol, propanol, and butanol as well as in var-
ious organic solvents with a content of 8 equiv of the previously
mentioned nucleophiles. The enzymatic hydrolysis performed in
water or in THF–water (1:1, v/v) mixture also unsuccessful. A
mixed enzymatic alcoholysis–hydrolysis process, with moderate
In order to synthesize enantiomerically pure 1-(5-phenylfuran-
2-yl)ethane-1,2-diols, the enzymatic kinetic resolution of authen-
tic racemic compounds rac-5–8a–d was further investigated.
2.2. The enzymatic acylation of racemic diols rac-5a–d
In our first approach we focused on the enzymatic acylation of
the racemic 1,2-ethanediols rac-5a–d. Using various solvents as
O
O
O
O
I.
II.
III.
Br
OAc
OH
R
R
R
R
1a-d
2a-d
3a-d
4a-d
R:
IV.
O
X
OH
OH
VI.
OH
OAc
R
R
rac-5a-d
rac-6a-d
X
1-5
a
V.
2-Cl
4-Br
2-NO2
4-NO2
b
c
d
OAc
OAc
VII.
OH
OAc
R
R
rac-8a-d
rac-7a-d
Scheme 1. Chemo-enzymatic synthesis of racemic rac-5–8a–d. Reagents and conditions: (I) pyridinium tribromide/CH3COOH, 90 °C; (II) NaOAc, 18C6/1,4-dioxane, reflux ;
(III) Novozyme 435/MeOH; (IV) NaBH4 /MeOH; (V) AcCl, DMAP/Py. in CH2Cl2; (VI) LPS, vinyl acetate; (VII) LPS/H2O–THF (1:1, v/v)

L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
677
OAc
OH
OAc
OH
first acylation
O
step
O
O
OH
OH
+
X
X
X
rac-6a-d
rac-8a-d
rac-5a-d
second acylation
step
second acylation
step
OAc
OAc
OAc
OAc
O
O
OH
O
+
X
OAc
X
X
(S)-6a-d
(R)-7a-d
rac-7a-d
Scheme 2. CaLA mediated acylation of racemic phenylfuran-2-yl-ethane-1,2-diols rac-5a–d.
OAc
OAc
OAc
a
lipase
OH
OH
OH
OAc
OH
+
E < 7
R
R
R
vinyl-acetate
(S)-8a-d
rac-8a-d
(R)-7a-d
OAc
OAc
OH
lipase
b
OH
E < 10
+
R
R
R
DIPE:MeOH:H2O
(R)-5a-d
rac-8a-d
(S)-8a-d
OH
OH
OAc
c
lipase
OAc
OAc
OAc
+
E > 81
E < 1
R
R
R
vinyl-acetate
(R)-7a-d
(S)-6a-d
rac-6a-d
OH
OH
OH
lipase
d
OAc
OAc
OH
+
R
R
R
MeOH or H2O
(S)-6a-d
(R)-5a-d
rac-6a-d
Scheme 3. Enzymatic kinetic resolution of the racemic monoacylated diols.
Table 1
Enzymatic acylation with vinyl acetate of rac-8b in DIPE
Table 2
Lipase catalyzed acylation of the primary monoacetate rac-6c
Entry
Enzyme
Time
c (%)
eeP (%)
eeS (%)
E
Entry
Enzyme
Time (h)
c (%)
eeP (%)
eeS (%)
E
1
2
3
4
CaLA
LPS
2 h
2 h
2 h
16 h
29.5
61
61
31
52
46
49
13
81
72
58
2
7
6
5
1
2
3
4
5
6
CaLA
CLEA
IMMCaLA T2–150
LAK
CaLB
CrL
6
4
4
24
16
16
47
40
34
43
4
91
85
73
94
50
53
76
56
37
71
2
49
22
9
69
3
CaLB*
CrL
54
*
Anti-Kazlauskas type.
21
14
4
enantioselectivity (E <10), yielding the (R)-5b (ee: 65%) and the (S)-
8b (ee: 35%), occurred when the reaction was performed in a DIPE–
MeOH–water (1:1:2, v/v) mixture in the presence of LPS
(Scheme 3b). Similar results were found also for the LPS mediated
mixed alcoholysis–hydrolysis for the rest of the substrates rac-
8a,c,d.
The enzymatic acylation of primary monoacetate derivatives
rac-6a–d was also performed (Scheme 3c). 2-Hydroxy-2-(5-(2-
nitrophenyl)furan-2-yl)ethyl acetate rac-6c was used as the model
compound for the screening of potentially useful lipases. All
screening procedures were performed in DIPE in the presence of vi-
nyl acetate (8 equiv) as reactant. Among the lipases tested, only
CaLA (Table 2, entries 1–3), and LAK (Table 2, entry 4) proved to
be efficient catalysts. CaLA showed higher activity than LAK, but
the latest enzyme displayed a higher selectivity. In addition to
CaLA, which is a Celite supported enzyme (Table 2, entry 1), other
immobilized lipases A from C. antarctica such as CLEA (enzyme
reticulated with glutaraldehyde, Table 2, entry 2) or IMMCALA
T2–150 (covalently immobilized enzyme, Table 2, entry 3) were
tested and it was found that with regard to stereoselectivity they
are inefficient biocatalysts.
This behavior of CaLA is in accordance with the SN2 preference
showed by the enzyme toward triacylglycerols, however, CaLA was
rarely used in enantioselective reactions14, in many cases being re-
ported to be highly active in a nonselective manner, as in the case
of the kinetic resolution of phenylfuran based cyanohydrins15 or b-
hydroxynitriles.16

678
L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
More surprising is the contrary behavior of the LAK compared to
d. The reactions were performed in various solvents containing
8 equiv of nucleophile, as well as in neat methanol. While most
of the lipases were catalytically inactive, CaLB was able to trans-
form rac-7a–d into the (R)-diacetate and the (S)-secondary mono-
acetate as expected,11 but surprisingly, in an anti-Kazlauskas
manner.17 However, the ee of the reaction products were only
moderate [e.g., ee 82% for (R)-7d and ee 51% for (S)-8d] and at high-
er conversions the presence of a slight amount of the diol (5–10%)
was also observed.
When the reactions were performed in a mixture of THF–H2O
(1:1, v/v), CaLB and LPS were able to regioselectively hydrolyze
rac-7a–d into rac-8a–d. Using a mixture of DIPE–MeOH–H2O as
the reaction media LPS rapidly catalyzed the transformation of
rac-7a–d into rac-8a–d, followed by the stereoselective lysis of
the latest racemates, yielding (R)-5a–d and (S)-8a–d with moder-
ate enantioselectivity (ee 65–71% for (R)-5a–d and 59–67% for
(S)-8a–d). The possible routes are depicted in Scheme 4.
previously reported observations, when it was found as a highly
selective biocatalyst for the acylation of the secondary monoace-
tate of several 1,2-ethanediols, while in the case of acylation of
the primary monoacetate it showed significantly lower activity
and selectivity.9
Using the most efficient enzymes (CaLA, LAK) solvents effects
on the selectivity of the enzymatic acylation was next tested.
A strong solvent influence upon the reaction rate and selectivity
was observed. In addition to various organic solvents, ionic liquids,
previously found as appropriate media for the LPS-catalyzed enzy-
matic acylation of different substituted 1-phenylethane-1,2-
diols,12 were also used (Table 3, entries 7 and 14) with unsatisfac-
tory results in the present case (Table 3, entries 7 and 14). The best
results for the LAK mediated reaction were obtained in DIPE (Ta-
ble 3, entry 8).
The same screening procedure was performed for the rest of the
substrates and in all cases the optimal transformation was identi-
cal to that found in case of rac-6c (Table 4, entries 2, 4, 6, and 8). It
is important to note that the CaLA mediated transformation of rac-
6a–d in neat vinyl acetate was also satisfactory in most cases (Ta-
ble 4, entries 1, 3, and 5), excepting the enzymatic transformation
of rac-6d (Table 4, entry 7).
The enzymatic hydrolysis or alcoholysis of rac-6a–d was also
tested (Scheme 3d). Using the methodology previously described
for rac-8a–d it was found that most of the tested hydrolases (CaLA,
LAK, LPS, PLE, CrL, lipase from Mucor javanicus, PLE, Acylase I) were
useless. Only LPS and CaLB transformed in a totally nonselective
manner, all the substrates into the corresponding racemic diols
rac-5a–d, when the reactions were performed in a mixture of diiso-
propyl ether–methanol–water (1:1:2, v/v).
2.5. Preparative scale synthesis of enantiomerically pure (R)-
and (S)-5a–d
Using racemic 1,2-diols rac-5a–d as starting materials, their
regioselective LPS mediated enzymatic acylations were carried
out to quantitatively yield rac-6a–d (Scheme 5). Further, the LAK
mediated enantioselective enzymatic acylation of rac-6a–d was
also performed, obtaining (S)-6a–d and (R)-7a–d in highly enanti-
omerically enriched forms by stopping the reactions at an approx.
50% conversion (monitored with HPLC) by removing the enzyme
by filtration (Scheme 5). All dilutions, substrate-biocatalyst ratios
and reaction conditions were the same as in the analytical scale
reactions. Data on yields, enantiomeric excesses, and specific rota-
tions of the enantiomers obtained are presented in Table 5. The iso-
lated (S)-6a–d and (R)-7a–d were quantitatively transformed into
the corresponding diols (S)- and (R)-5a–b without any loss of enan-
tiopurity, by the LPS catalyzed mixed alcoholysis–hydrolysis pro-
cedure (Scheme 5). The chemical hydrolysis18 and alcoholysis11,12
2.4. Kinetic resolution of the racemic diacetylated derivatives
rac-7a–d
Finally the same hydrolases were tested as potential catalysts
for methanolysis of the racemic diacetylated derivatives rac-7a–
Table 3
OAc
OAc
The influence of the nature of solvent upon the CaLA and LAK mediated acylation of
OH
E < 8
rac-6c
lipase
OAc
+
R
R
MeOH
Entry Enzyme Solvent
Time (h) c (%) eeP (%) eeS (%)
E
(S)-8a-d
(R)-7a-d
1
2
3
4
5
6
7
8
CaLA
CaLA
CaLA
CaLA
CaLA
CaLA
CaLA
LAK
LAK
LAK
LAK
LAK
DIPE
tBME
CH2Cl2
Acetonitrile
Toluene
Vinyl acetate
[bmim]PF6
DIPE
tBME
Toluene
Vinyl acetate 24
CH2Cl2
Acetonitrile
[bmim]PF6
6
6
4
4
4
6
6
24
24
24
50
41
6
89
81
85
70
88
89
88
95
90
93
89
93
91
91
91
56
5
54
16
13
6
OAc
OAc
R
lipase
16
34
50
30
43
35
34
16
17
12
20
13
45
92
37
71
48
47
17
19
13
23
OAc
OH
OH
R
24
56
22
83
31
44
20
33
24
27
THF:H2O 1:1
rac-7a-d
rac-8a-d
9
OAc
lipase
OH
R
10
11
12
13
14
E < 11
OH
+
R
DIPE:MeOH:H2O
24
24
24
(S)-8a-d
(R)-5a-d
LAK
LAK
Scheme 4. Lipase catalyzed reactions of the racemic diacylated diols.
Table 4
Comparison of the CaLA and LAK mediated acylation of rac-6a–d
Entry
Substrate
Enzyme
Solvent
Time (h)
c (%)
eep (%)
ees (%)
E
1
2
3
4
5
6
7
8
rac-6a
rac-6a
rac-6b
rac-6b
rac-6c
rac-6c
rac-6d
rac-6d
CaLA
LAK
CaLA
LAK
CaLA
LAK
CaLA
LAK
Vinyl acetate
DIPE
Vinyl acetate
DIPE
Vinyl acetate
DIPE
Vinyl acetate
DIPE
6
13
9
9
6
30
12
22
48
50
50
50
50
50
55
50
95
97
92
97
89
93
46
92
83
97
91
96
92
95
56
93
133
>200
76
>200
56
102
5
81

L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
679
OH
OH
OH
OAc
I.
II.
OAc
OH
OAc
OAc
+
R
R
R
R
rac-6a-d
(R)-7a-d
(S)-6a-d
rac-5a-d
III.
III.
R:
X
1-5
a
b
c
2-Cl
4-Br
2-NO2
4-NO2
O
X
OH
OH
OH
OH
d
R
R
(S)-5a-d
(R)-5a-d
Scheme 5. Enzyme catalyzed preparative scale synthesis of (R)- and (S)-5a–d. Reagents and conditions: (I) LPS/vinyl acetate; (II) LAK, vinyl acetate/DIPE; III. LPS/MeOH–
DIPE–H2O (1:1:2, v/v).
Table 5
Yields, ee and specific rotations for products of the preparative scale procedure
Yielda (%)
ee (%)
½aꢂ
D25b
Product
Yielda (%)
ee (%)
½ ꢂ
a 2D5
b
Entry
Product
1
2
3
4
5
6
7
8
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-5a
(S)-5b
(S)-5c
(S)-5d
49
48
49
48
47
46
48
46
97
96
95
93
97
96
95
93
ꢁ6.7
(R)-7a
(R)-7b
(R)-7c
(R)-7d
(R)-5a
(R)-5b
(R)-5c
(R)-5d
49
49
47
47
47
48
46
46
97
97
93
92
97
96
93
92
+33.1
+42.7
+82.3
+65.5
+24.3
+21.9
+31.4
+25.1
ꢁ10.4
ꢁ23.8
ꢁ18.7
ꢁ24.5
ꢁ21.2
ꢁ33.9
ꢁ25.8
a
Calculated for rac-5a–d.
c 0.5, CHCl3.
b
of (S)-6a–d and (R)-7a–d were also tested, but due to the structural
instability of the diols in acidic or basic media, in most of the cases,
the appearance of several by-products and partial racemization of
the produced diols was observed.
The absolute configurations of the produced enantiomerically
enriched 1,2-diols were established by comparing the chromato-
graphic retention times of the enantiomers and the signs of the
specific rotations for the produced enantiomerically enriched diols
with previously reported data.4
4. Experimental
4.1. Analytical methods
The 1H- and 13C- NMR spectra were recorded on a Bruker spec-
trometer operating at 300 MHz and 75 MHz, respectively. Spectra
were recorded at 25 °C in CDCl3 or acetone-d6. 1H- and 13C- NMR
spectra were referenced internally to the solvent signal. Electron
impact mass spectra (EI-MS) were taken on a VG 7070E mass spec-
trometer operating at 70 eV. High performance liquid chromatog-
raphy (HPLC) analyses were conducted with an Agilent 1200
instrument using a Chiralpak AS-H column (4.6 ꢀ 250 mm) and a
mixture of n-hexane and 2-propanol 90:10, 85:15, and 78.5:21.5
(v/v) as eluent for the enantiomeric separation of rac-5–8a,5c,
rac-5–8b, and rac-5–8c, respectively, and Chiralpak IB column
and a mixture of n-hexane and 2-propanol 80:20 and 87:13 (v/v)
as eluent for the enantiomeric separation of rac-5d and rac-6–8d,
respectively (Table 6). Thin layer chromatography (TLC) was car-
ried out using Merck Kieselgel 60F254 sheets. Spots were visual-
ized by treatment with 5% ethanolic phosphomolybdic acid
solution and heating. Preparative chromatographic separations
were performed using column chromatography on Merck Kieselgel
3. Conclusion
All possible routes of enzymatic transformations of phenyl-fur-
ane-ethane-1,2-diols rac-5a–d and their mono- and diacetylated
counterparts rac-6,7,8a–d have been studied. Except for CaLB,
which displayed anti-Kazlauskas selectivity in the acylation of
the secondary monoacetate rac-8a–d, and during alcoholysis of
diacetate derivatives rac-7a–d, all other enzymes involved in the
stereoselective reactions acted in accordance with the Kazlauskas
rule.17 For the investigated structures, the behavior of the lipases
significantly differed from those previously reported in the field
of kinetic resolutions of the arylethane-1,2-diols and their acylated
analogues.
60 (63–200 lm). Melting points were determined by the hot plate
method and are uncorrected. Optical rotations were determined on
Out of all of the possible kinetic resolutions the most efficient,
in terms of stereoselectivity and activity, proved to be LAK medi-
ated acylation of racemic primary monoacetates rac-6a–d. Com-
bining the regioselectivity of LPS mediated acylation of the
starting racemic diols, the stereoselectivity of LAK showed in the
enantiomer selective transformation of the previously formed
racemic primary acetates and the LPS mediated mild hydrolysis–
alcoholysis of the resolution products, an efficient preparative scale
procedure was developed for the synthesis of various highly enan-
tiomerically enriched (R)- and (S)-phenylfuran-2-yl-ethane-1,2-
diols.
a Perkin–Elmer 201 polarimeter and a2D5 values are given in units of
10ꢁ1 deg cm2 gꢁ1
.
4.2. Reagents and solvents
Pyridinium tribromide, sodium acetate, phase transfer catalyst
18C6 and all inorganic and organic reagents and solvents were
products of Aldrich or Fluka. All solvents were dried and purified
by standard methods as required. The racemic 1,2-ethanediols
5a–d were prepared as previously reported by us.4 LAK from P. flu-

680
L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
J = 7.5 Hz), 7.79 (1H, d, J = 7.5 Hz); 13C NMR (acetone-d6): 66.6,
70.1, 110.2, 111.7, 124.9, 125.2, 129.9, 130.1, 133.5, 148.8, 159.1.
Table 6
Chromatographic retention times of the enantiomers of rac-5–8a–d
Compound
tR (min)
Compound
tR (min)
4.3.4. 1-(5-(4-Nitrophenyl)furan-2-yl)ethane-1,2-diol rac-5d
Yellow solid, mp: 98–99 °C; 1H NMR (acetone-d6): 3.8–3.95 (2H,
ddd J = 6.8 Hz, J = 5.3 Hz, J = 11.5 Hz), 4.02–4.15 (1H, s, broad),
4.65–4.75 (1H, s, broad), 4.82 (1H, dd, J = 5.3 Hz, J = 6.8 Hz), 6.55
(1H, d, J = 3.8 Hz), 7.14 (1H, d, J = 3.8 Hz), 7.94 (2H, d, J = 9.1 Hz),
8.28 (2H, d, J = 9.1 Hz); 13C NMR (acetone-d6): 66.8, 70.4, 111.2,
112.2, 125.6, 126.1, 138.4, 148.1, 152.5, 160.1.
(R)-5a
(R)-5b
(R)-5c
(R)-5c
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(R)-7a
(R)-7b
(R)-7c
(R)-7d
(R)-8a
(R)-8b
(R)-8c
(R)-8d
16.2
13.9
24.1
15.8
15.3
10.7
15.9
15.2
7.7
(S)-5a
(S)-5b
(S)-5c
(S)-5c
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-8a
(S)-8b
(S)-8c
(S)-8d
14.9
12.9
25.5
17.2
17.5
12.1
20.3
15.9
9.1
8.6
17.7
9.9
18.3
9.9
16.1
17
9.1
4.4. Synthesis of the primary monoacylated derivatives rac-6a–
d
14.5
11.4
15.9
12.2
18.1
16.3
A mixture of the racemic 1,2-ethanediol rac-5a–d (100 mg), vi-
nyl acetate (4 mL) and LPS (100 mg) was shaken at 300 rpm at
room temperature. When the reaction was completed (checked
by TLC, approx. 16 h) the enzyme was filtered off, and the solvent
was removed in vacuo, to obtain the pure product rac-6a–d with-
out further purification.
orescens, LPS from B. cepacia (previously P. cepacia) were from
Amano Europe, England. Lipase B from C. antarctica (CaLB, Novo-
zyme 435) was purchased from Novozymes, Denmark. Lipase A
from C. antarctica immobilized on celite (CaLA) was a generous gift
from the research group of Dr. Liisa Kanerva. Lipase A from C. ant-
arctica reticulated with glutaraldehyde (CLEA) or covalently immo-
bilized (IMMCaLA T2-150) were purchased from Fluka and
Chiralvision, respectively. CrL, PPL, PLE, Acylase I, lipase from M.
javanicus, esterase from R. oryzae were purchased from Sigma–Al-
drich and Fluka.
4.4.1. 2-(5-(2-Chlorophenyl)furan-2-yl)-2-hydroxyethyl acetate
rac-6a
Yield: 97%; white oil; 1H NMR (CDCl3): 2.12 (3H, s), 4.45 (2H,
m), 5.04 (1H, dd, J = 5.6 Hz, J = 5.3 Hz), 6.48 (1H, d, J = 3.8 Hz),
7.08 (1H, d, J = 3.8 Hz), 7.2 (1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.31
(1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.83 (1H, d,
J = 7.5 Hz); 13C NMR (CDCl3): 20.8, 65.9, 66.3, 111.5, 111.6, 126.7,
128.1, 128.6, 130.2, 130.7, 148.9, 150.6, 170.3; HRMS: M+ found
(M+ calculated for C14H13ClO4: 280.0502): 280.0511; MS: m/z
(%) = 282 (M+, 37Cl, 3), 280 (M+, 35Cl, 9), 223 (37Cl, 5), 222 (37Cl,
31), 221 (35Cl, 15), 220 (35Cl, 100), 209 (37Cl, 22), 207 (35Cl, 91),
205 (32), 192 (7), 151 (8), 149 (26), 147 (8), 115 (13), 43 (16).
4.3. Synthesis of rac-1-(heteroaryl)-ethane-1,2-diols rac-5a–d
The racemic 1,2-ethanediols 5a–d were prepared by known
methods, using as starting material the corresponding phenylfu-
ran-2yl-ethanones 1a–d as depicted in Scheme 1. By an a-bromin-
4.4.2. 2-(5-(4-Bromophenyl)furan-2-yl)-2-hydroxyethyl acetate
rac-6b
ation we obtained the corresponding bromo-derivatives 2a–d,
which were further transformed by NaOAc and 18C6 as catalyst
into the acetoxymethyl ketones 3a–d; these were then subjected
Yield: 95%; white oil; 1H NMR (CDCl3): 2.12 (3H, s), 2.47–2.55
(1H, s, broad) 4.43 (2H, m), 5.02 (1H, dd, J = 5.3 Hz, J = 9.1 Hz),
6.42 (1H, d, J = 3.8 Hz), 6.62 (1H, d, J = 3.8 Hz),7.48–7.52 (4H, m);
13C NMR (CDCl3): 20.9, 66.4, 66.5, 106.2, 109.6, 121.4, 125.3,
131.8, 152.5, 152.9, 171.1; HRMS: M+ found (M+ calculated for
to the CaLB mediated alcoholysis to obtain the a-hydromethyl ke-
tone derivatives 4a–d, followed by their chemical reduction with
NaBH4, yielding the racemic 1,2-ethanediols rac-5a–d. The yield
values, 1H-, 13C- NMR data were in accordance with the data re-
ported earlier.4
C
14H13BrO4: 323.9997): 323.9884; MS: m/z (%) = 308 (81Br, 11),
306 (79Br, 11), 266 (81Br, 19), 264 (79Br, 19), 258 (81Br, 17), 256
(
79Br, 18), 222 (20), 220 (59), 200 (20), 185 (28), 151 (16), 149
4.3.1. 1-(5-(2-Chlorophenyl)furan-2-yl)ethane-1,2-diol rac-5a
White semisolid; 1H NMR (acetone-d6): 3.72–3.88 (2H, m)
3.88–4.05 (1H, s, broad), 4.49–4.65 (1H, s, broad), 4.79 (1H, dd,
J = 4.5 Hz, J = 5.4 Hz), 6.49 (1H, d, J = 3 Hz), 7.1 (1H, d, J = 3 Hz),
7.29 (1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.41 (1H, dd, J = 7.5 Hz,
J = 7.5 Hz), 7.5 (1H, d, J = 7.5 Hz), 7.89 (1H, d, J = 7.5 Hz); 13C NMR
(acetone-d6): 66.8, 70.4, 110.3, 113.5, 129.1, 129.5, 130.9, 131.1,
132,5, 150.6, 157.9.
(50), 125 (11), 111 (12), 97 (12), 83 (20), 71 (33), 69 (25), 57
(45), 43 (100).
4.4.3. 2-Hydroxy-2-(5-(2-nitrophenyl)furan-2-yl)ethyl acetate
rac-6c
Yield: 97%; yellow semisolid; 1H NMR (CDCl3): 2.1 (3H, s), 2.73–
2.84 (1H, s, broad), 4.34–4.41 (2H, m), 4.97 (1H, dd, J = 5.3 Hz,
J = 10.9 Hz), 6.45 (1H, d, J = 3 Hz), 6.62 (1H, d, J = 3 Hz), 7.42 (1H,
dd, J = 7.5 Hz, J = 7.5 Hz), 7.57 (1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.69
(2H, d, J = 7.5 Hz); 13C NMR (CDCl3) : 20.8, 66.3, 66.4, 109.4,
110.4, 123.8, 123.9, 128.4, 128.8, 131.9, 147.4, 148.2, 154.2,
171.2; HRMS: M+ found (M+ calculated for C14H13NO6:
291.0743): 291.0746; MS: m/z (%) = 291 (M+, 9), 231 (20), 218
(84), 188 (100), 172 (25), 144 (16), 117 (27), 116 (58), 115 (29),
97 (93), 77 (14), 43 (60).
4.3.2. 1-(5-(4-Bromophenyl)furan-2-yl)ethane-1,2-diol rac-5b
White semisolid; 1H NMR (acetone-d6): 3.74–3.85 (2H, m), 3.9–
4.01 (1H, s, broad), 4.5–4.6 (1H, s, broad), 4.71 (1H, dd, J = 4.5 Hz,
J = 6.8 Hz), 6.39 (1H, d, J = 3.8 Hz), 6.8 (1H, d, J = 3.8 Hz), 7.5–7.65
(4H, m); 13C NMR (acetone-d6): 66.5, 70.1, 108.3, 110.2, 121.8,
126.7, 131.7, 133.3, 153.1, 153.8.
4.3.3. 1-(5-(2-Nitrophenyl)furan-2-yl)ethane-1,2-diol rac-5c
Yellow, semisolid; 1H NMR (acetone-d6): 3.65–3.85 (2H, ddd,
J = 6.8 Hz, J = 4.5 Hz, J = 10.9 Hz), 3.89–4.11 (1H, s, broad), 4.53–
4.71 (1H, s, broad), 4.7 (1H, dd, J = 4.5 Hz, J = 6.8 Hz), 6.44 (1H, d,
J = 3.8 Hz), 6.71 (1H, d, J = 3.8 Hz), 7.5 (1H, dd, J = 7.5 Hz,
J = 7.5 Hz), 7.64 (1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.74 (1H, d,
4.4.4. 2-Hydroxy-2-(5-(4-nitrophenyl)furan-2-yl)ethyl acetate
rac-6d
Yield: 96%; yellow semisolid; 1H NMR (CDCl3): 2.12 (3H, s),
2.73–2.95 (1H, s, broad), 4.43–4.45 (2H, m), 5.05 (1H, dd,
J = 5.3 Hz, J = 5.7 Hz), 6.45(1H, d, J = 3 Hz), 6.83 (1H, d, J = 3 Hz),
7.76(2H, d, J = 9.1 Hz), 8.22 (2H, d, J = 9.1 Hz); 13C NMR (CDCl3):

L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
681
20.8, 66.4, 66.5, 109.7, 110.1, 123.9, 124.3, 136, 146.5, 151.5, 154.6,
171.1; HRMS: M+ found (M+ calculated for C14H13NO6: 291.0743):
291.0733; MS: m/z (%) = 291 (M+, 1) 285 (7), 229 (20), 160 (7), 159
(100), 158 (9), 140 (7), 71 (8), 57 (10), 43 (10).
m/z (%) = 333.1 (M+, 1), 231 (20), 222 (10), 220 (25), 218 (10),
207 (18), 205 (15), 204 (16), 167 (12), 161 (13), 159 (14), 149
(29), 147 (12), 115 (11), 57 (13), 45 (34), 43 (100).
4.6. Synthesis of secondary monoacetate derivatives rac-8a–d
4.5. Synthesis of 1,2-diacetoxy-derivatives rac-7a–d
Into a solution of the racemic diacetate derivative rac-7a–d
(100 mg) in THF (4 mL), LPS (100 mg), and phosphate buffer
(10 mM, pH 7.5, 4 mL) were added, and the resulting mixture
was shaken at 300 rpm, until the reaction was complete (checked
by TLC, approx. 16 h). The enzyme was filtered off, and the solvent
was removed in vacuo, to obtain the pure product rac-6a–d. In
some cases, supplementary column chromatography purification,
using dichloromethane–methanol 95:5 (v/v) as eluent, was
necessary.
To a solution of one of the racemic 1,2-ethanediols rac-5a–d
(1 mmol) in dichloromethane (10 mL), acetyl chloride (4 mmol,
290
lL), and a catalytic amount of 4-N,N-dimethylamino-pyridine
in pyridine (290
lL, 1% solution) were added. After stirring for
30 min at room temperature, the solvent was evaporated in vacuo
and the crude product was purified by column chromatography
using dichloromethane as eluent.
4.5.1. 1-(5-(2-Chlorophenyl)furan-2-yl)ethane-1,2-diyl
diacetate rac-7a
4.6.1. 1-(5-(2-Chlorophenyl)furan-2-yl)-2-hydroxyethyl acetate
rac-8a
Yield: 93%; white oil; 1H NMR (CDCl3): 2.07 (3H, s), 2.11 (3H, s),
4.48 (1H, dd, J = 7.5 Hz, J = 12.1 Hz), 4.56 (1H, dd, J = 4.5 Hz,
J = 12.1 Hz), 6.2 (1H, dd, J = 7.5 Hz, J = 4.3 Hz), 6.53 (1H, d,
J = 3 Hz), 7.08 (1H, d, J = 3 Hz), 7.2 (1H, dd, J = 7.5 Hz, J = 6.1 Hz),
7.31 (1H, dd, J = 7.5 Hz, J = 6.1 Hz), 7.42 (1H, d, J = 7.5 Hz), 7.83
(1H, d, J = 7.5 Hz); 13C NMR (CDCl3): 20.8, 21, 63.3, 66.3, 111.5,
111.6, 126.9, 128, 128.5, 128.6, 130.2, 130.7, 148.6, 150.5, 169.9,
170.5; HRMS: M+ found (M+ calculated for C16H15ClO5:
322.0608): 322.0787; MS: m/z (%) = 324 (M+, 37Cl, 4), 323 (M+1,
35Cl, 2), 322 (M+, 35Cl, 13), 264 (37Cl, 14), 262 (35Cl, 35), 223 (37Cl,
6), 222 (37Cl, 33), 221 (35Cl, 21), 220 (35Cl, 100), 209 (37Cl, 15),
207 (35Cl, 49), 123 (24), 107 (8), 43 (10).
Yield: 87%; white oil 1H NMR (CDCl3): 2.13 (3H, s), 4.03 (1H, dd,
J = 4.5 Hz, J = 11.5 Hz), 4.11 (1H, dd, J = 7.5 Hz, J = 11.5 Hz), 5.99
(1H, dd, J = 4.5 Hz, J = 7.5 Hz), 6.54 (1H, d, J = 3.8 Hz), 7.07 (1H, d,
J = 3.8 Hz), 7.21 (1H, ddd, J = 1.5 Hz, J = 7.5 Hz, J = 7.5 Hz), 7.32
(1H, ddd, J = 1.5 Hz, J = 8.3 Hz, J = 7.5 Hz), 7.43 (dd, J = 7.5 Hz,
J = 1.5 Hz), 7.81 (1H, dd, J = 8.3 Hz, J = 1.5 Hz); 13C NMR (CDCl3):
21.1, 63, 66.6, 111.5, 111.6, 126.8, 128, 128.4, 128.7, 130.2, 130.7,
149.4, 150.5, 170.5; HRMS: M+ found (M+ calculated for
C
14H13ClO4: 280.0502): 280.0491; MS: m/z (%) = 282 (M+, 37Cl, 6),
280 (M+, 35Cl, 13), 264 (37Cl, 4), 262 (35Cl, 12), 223 (37Cl, 5), 222
(
37Cl, 22), 221 (35Cl, 15), 220 (35Cl, 68), 209 (37Cl, 30), 207 (35Cl,
100), 205 (6), 151 (37Cl, 5), 149 (35Cl, 13), 144 (6), 115 (19), 77
(4), 43 (4).
4.5.2. 1-(5-(4-Bromophenyl)furan-2-yl)ethane-1,2-diyl
diacetate rac-7b
Yield: 93%, white oil; 1H NMR (CDCl3): 2.08 (3H, s), 2.11 (3H, s),
4.51 (2H, ddd, J = 4.5 Hz, J = 7.5 Hz, J = 12.1 Hz), 6.13 (1H, dd, J = 4.5,
J = 7.5 Hz), 6.48 (1H, dd, J = 3.8 Hz), 6.61 (1H, J = 3.8 Hz), 7.48–7.54
(4H, m); 13C NMR(CDCl3): 20.8, 21, 63.2, 66.3, 106.2, 111.8, 121.6,
125.4, 131.8, 149, 152.8, 153.3, 170, 170.6; HRMS: M+ found (M+
calculated for C16H15BrO5: 366.0103): 366.0095; MS: m/z
(%) = 268 (M+, 81Br, 8), 266 (M+, 79Br, 8), 308 (81Br, 27), 306 (79Br,
27), 267 (81Br, 21), 266 (81Br, 51), 265 (79Br, 22), 264 (79Br, 50),
253 (81Br, 29), 252 (81Br, 10), 251 (79Br, 36), 250 (79Br, 12), 242
4.6.2. 1-(5-(4-Bromophenyl)furan-2-yl)2-hydroxyethyl acetate
rac-8b
Yield: 89%; white oil; 1H NMR (CDCl3): 2.13 (3H, s), 4.03 (1H, dd,
J = 4.5 Hz, J = 12.1 Hz), 4.09 (1H, dd, J = 7.5 Hz, J = 12.1 Hz), 5.97
(1H, dd, J = 4.5 Hz, J = 7.5 Hz), 6.49 (1H, d, J = 3.8 Hz), 6.61 (1H, d,
J = 3.8 Hz),7.48–7.52 (4H, m); 13C NMR (CDCl3): 21.1, 62.9, 69.6,
106.2, 111.8, 121.5, 125.3, 129.2, 131.8, 149.7, 153.1, 170.5; HRMS:
M+ found (M+ calculated for C14H13BrO4: 323.9997): 323.9913; MS:
m/z (%) = 326 (M+, 81Br, 11), 324 (M+, 79Br, 11), 308 (81Br, 31), 306
(
81Br,10), 240 (79Br,11), 220 (25), 187 (17), 186 (11), 185 (49),
(
79Br, 29), 282 (81Br, 16), 280 (79Br, 17), 267 (81Br, 60), 266 (81Br,
183 (29), 149 (16), 115 (11), 87 (13), 43 (100).
61), 265 (79Br, 64), 264 (79Br, 56), 253 (81Br, 85), 251 (79Br, 100),
222 (15), 220 (31), 205 (27), 193 (20), 187 (24), 185 (61), 183
(31), 149 (32), 115 (30), 114 (18), 77 (12), 57 (12), 43 (83).
4.5.3. 1-(5-(2-Nitrophenyl)furan-2-yl)ethane-1,2-diyl diacetate
rac-7c
Yield: 91%; yellow semisolid; 1H NMR (CDCl3): 2.1 (3H, s), 2.13
(3H, s), 4.43 (1H, dd, J = 7.5 Hz, J = 12.1 Hz), 4.53 (1H, dd, J = 4.5 Hz,
J = 12.1 Hz), 6.11 (1H, dd, J = 7.5 Hz, J = 4.5 Hz), 6.52 (1H, d,
J = 3.8 Hz), 6.64 (1H, d, J = 3.8 Hz), 7.43 (1H, dd, J = 7.5 Hz,
J = 6.8 Hz), 7.61 (1H, dd, J = 7.5 Hz, J = 7.1 Hz) 7.68–7.71 (2H, m);
13C NMR (CDCl3): 20.8, 20.9, 63.1, 66.2, 109.6, 110.3, 111.7,
123.7, 124, 128.7, 129, 132, 147.6, 148.7, 150.6, 170, 170.6; HRMS:
M+ found (M+ calculated for C16H15NO7: 333.0849): 333.0931; MS:
m/z (%) = 333.1 (M+, 5), 273 (11), 218 (52), 189 (10), 188 (80), 172
(19), 149 (11), 144 (11), 117 (13), 116 (32), 115 (12), 97 (100), 57
(10), 43 (78).
4.6.3. 2-Hydroxy-1-(5-(2-nitrophenyl)furan-2-yl)ethyl acetate
rac-8c
Yield: 87%; yellow semisolid; 1H NMR (CDCl3): 2.12 (3H, s),
3.95–4.07 (2H, ddd, J = 5.3 Hz, J = 5.7 Hz, J = 12 Hz), 5.91 (1H, dd,
J = 5.3 Hz, J = 5.7 Hz), 6.53 (1H, d, J = 3 Hz), 6.64 (1H, d, J = 3 Hz),
7.44 (1H, dd, J = 7.5 Hz, J = 7.5 Hz), 7.59 (1H, dd, J = 7.5 Hz,
J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.71 (1H, d, J = 7.5 Hz); 13C
NMR (CDCl3): 21, 62.7, 69.3, 110.2, 111.8, 123.8, 124, 128.6,
128.9, 132, 151.3, 170.3; HRMS: M+ found (M+ calculated for
C14H13NO6: 291.0743): 291.0737; MS: m/z (%) = 291 (M+, 22),
219 (20), 218 (100), 188 (91), 172 (44), 171 (14), 149 (20), 145
(17), 144 (20), 128 (13), 117 (26), 116 (63), 115 (33), 97 (72), 77
(14), 43 (71).
4.5.4. 1-(5-(4-Nitrophenyl)furan-2-yl)ethane-1,2-diyl diacetate
rac-7d
Yield: 91%; yellow semisolid; 1H NMR (CDCl3): 2.09 (3H, s), 2.14
(3H, s), 4.47–4.62 (2H, m), 6.17 (1H, dd, J = 4.5 Hz, J = 6.8 Hz), 6.57
(1H, d, J = 3.3 Hz), 6.86 (1H, d, J = 3.3 Hz), 7.79 (2H, d, J = 9.1 Hz)
8.26 (2H, d, J = 9.1 Hz); 13C NMR (CDCl3): 20.8, 21, 63.1, 66.2,
109.6, 112.3, 124.2, 124.4, 135.8, 151, 152, 170, 170.5; HRMS: M+
found (M+ calculated for C16H15NO7: 333.0849): 333.0911; MS:
4.6.4. 2-Hydroxy-1-(5-(4-nitrophenyl)furan-2-yl)ethyl acetate
rac-8d
Yield: 90%; yellow semisolid; 1H NMR (CDCl3): 2.15 (3H, s), 4.04
(1H, dd, J = 4.5 Hz, J = 12.1 Hz), 4.11 (1H, dd, J = 6.8 Hz, J = 12.1 Hz),
5.98 (1H, dd, J = 4.53 Hz, J = 6.8 Hz), 6.57 (1H, d, J = 3.8 Hz), 6.84
(1H, d, J = 3.8 Hz), 7.78 (2H, d, J = 9.1 Hz), 8.24 (2H, d, J = 9.1 Hz);

682
L. C. Bencze et al. / Tetrahedron: Asymmetry 22 (2011) 675–683
13C NMR (CDCl3): 21, 62.9, 69.5, 109.5, 112.1, 124.1, 124.3, 135.9,
146.6, 151.8, 170.3; HRMS: M+ found (M+ calculated for
C
(8), 231 (10), 229 (21), 218 (13), 160 (11), 159 (100), 149 (37),
115 (11), 71 (14), 57 (19), 43 (29).
tion (10 mg), diisopropyl ether (250
lL), methanol (250 lL) and
phosphate buffer (500 L, 10 mM, pH 7.5), was shaken at
l
14H13NO6: 291.0743): 291.07804; MS: m/z (%) = 291 (M+, 2), 285
300 rpm at room temperature. Samples were taken at different
intervals of time and extracted with ethyl-acetate. The organic
phase was dried over Na2SO4, the solvent was removed in vacuo,
and the sample obtained was diluted with the same solvent
4.7. Analytical scale procedure
(100 lL) as the mobile phase for HPLC (see Section 4.1.) and ana-
lyzed with HPLC.
4.7.1. Analytical scale enzymatic acylation of racemic
heteroaryl-1,2-ethadiols rac-5a–d
In a typical small scale experiment, one of the heteroaryl-1,2-
ethanediols rac-5a–d (0.05 mmol) and vinyl acetate (0.1, 0.2,
0.25, and 0.4 mmol) were dissolved in a dry organic solvent
(1 mL). Lipase preparation (10 mg) was added. The mixture was
4.8. Preparative scale procedure
4.8.1. Preparative scale enzymatic acylation of racemic 1,2-
ethanediols rac-5a–d
The procedure described in Section 4.4. was used.
shaken at 300 rpm at room temperature. Samples (10
ken after different intervals of time, diluted with the same solvent
(100 L) as the mobile phase for HPLC and analyzed with HPLC.
lL) were ta-
4.8.2. Preparative scale enzymatic acylation of racemic primary
monoacetates rac-6a–d
l
A mixture of rac-6a–d (100 mg), vinyl acetate (2 mL) and LAK
(50 mg) was shaken at 300 rpm at room temperature. Samples
4.7.2. Analytical scale enzymatic acylation of racemic
heteroaryl-2-acetoxy-1-ethanol rac-6a–d
In a typical small scale experiment, one of the heteroaryl-2-
acetoxy-1-ethanol rac-6a–d (0.05 mmol) and vinyl acetate
(0.4 mmol) were dissolved in a dry organic solvent (1 mL). Lipase
preparation (10 mg) was added. The mixture was shaken at
from the reaction mixture (20
lL) were diluted with n-hexane–2-
propanol (8:2, 200 L) and analyzed with HPLC. The reactions were
l
stopped by filtering the enzyme at approximately 50% conversions.
The solvent was removed in vacuo, and the crude product was
purified by column chromatography using dichloromethane–
methanol (95:5 v/v), resulting in the optically active primary
monoacetates (S)-6a–d and the corresponding diacetylated prod-
ucts (R)-7a–d.
300 rpm at room temperature. Samples (10
different intervals of time, diluted with the same solvent
(100 L) as the mobile phase for HPLC and analyzed with HPLC.
lL) were taken after
l
4.7.3. Analytical scale enzymatic acylation of racemic
heteroaryl-1-acetoxy-1-ethanol rac-8a–d
In a typical small scale experiment, one of the heteroaryl-1-
acetoxy-1-ethanol rac-8a–d (0.05 mmol) and vinyl acetate
(0.4 mmol) were dissolved in a dry organic solvent (1 mL). Lipase
preparation (10 mg) was added. The mixture was shaken at
4.8.3. Preparative scale mixed enzymatic alcoholysis–hydrolysis
of enantiomerically enriched primary monoacetates and
diacetates (S)-6a–d and (R)-7a–d
The mixture of the enantiomerically enriched derivative rac-
6,7a–d (100 mg), LPS (50 mg), diisopropyl ether (1 mL), MeOH
(1 mL) and phosphate buffer (10 mM, pH 7.5, 2 mL) added was sha-
ken at 300 rpm, until the reaction was complete (checked by TLC,
approx. 12 h). The enzyme was filtered off, and the solvent was re-
moved in vacuo, to give the pure enantiomerically enriched prod-
uct (S)-5a–d and (R)-5a–d.
300 rpm at room temperature. Samples (10
different intervals of time, diluted with the same solvent
(100 L) as the mobile phase for HPLC and analyzed with HPLC.
lL) were taken after
l
4.7.4. Analytical scale enzymatic alcoholysis of racemic primary
monoacetates, secondary monoacetates, and the diacetylated
derivatives rac-6–8a–d
In a typical small scale experiment, the mixture of one of the 1-
heteroarylethyl acetates rac-6–8a–d (0.05 mmol), lipase prepara-
The MS, NMR 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.
tion (10 mg), and methanol (500
room temperature. Samples were taken at different intervals of
time, diluted with the same solvent (100 L) as the mobile phase
lL), was shaken at 300 rpm at
Acknowledgment
l
The financial support to C.P. from the Romanian Ministry of
Education and Research (CNCSIS No. 527/2461) is gratefully
acknowledged.
for HPLC (see Section 4.1.) and analyzed with HPLC.
4.7.5. Analytical scale enzymatic hydrolysis of racemic primary
monoacetates, secondary monoacetates, and the diacetylated
derivatives rac-6–8a–d
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