Lipase mediated sequential resolution of aromatic β-hydroxy esters using fatty acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.09.005

The lipase-catalyzed kinetic resolution of a series of aromatic β-hydroxy esters in organic media has been investigated. Decanoic acid and its esters were successfully used as acyl donors for selective O-acylation. The regio- and enantioselective enzymatic hydrolysis of the decanoate moiety of the diesters was also investigated. The effects of water, reaction temperature, and solvent type, and also the influence of substrates structure on the catalytic behavior of potential commercially available lipases were studied. A novel procedure was developed for the efficient and highly stereoselective synthesis of both enantiomers of both novel and known target compounds. Copyright

Full text of DOI:10.1016/j.tetasy.2011.09.005

Tetrahedron: Asymmetry 22 (2011) 1672–1679
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Lipase mediated sequential resolution of aromatic b-hydroxy esters using
fatty acid derivatives
Jürgen Brem a, Mara Naghi a, Monica-Ioana Toßsa a, Zoltán Boros b, László Poppe b, Florin-Dan Irimie a,
Csaba Paizs a,
⇑
a Department of Biochemistry and Biochemical Engineering, Babeßs-Bolyai University of Cluj-Napoca, Ro-400028 Cluj-Napoca, Arany János 11, Romania
b Department of Organic Chemistry and Technology and Research Group for Alkaloid Chemistry HAS, Budapest University of Technology and Economics, H-1111 Budapest,
Müegyetem rkp. 3, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The lipase-catalyzed kinetic resolution of a series of aromatic b-hydroxy esters in organic media has been
investigated. Decanoic acid and its esters were successfully used as acyl donors for selective O-acylation.
The regio- and enantioselective enzymatic hydrolysis of the decanoate moiety of the diesters was also
investigated. The effects of water, reaction temperature, and solvent type, and also the influence of sub-
strates structure on the catalytic behavior of potential commercially available lipases were studied. A
novel procedure was developed for the efficient and highly stereoselective synthesis of both enantiomers
of both novel and known target compounds.
Received 8 August 2011
Accepted 7 September 2011
Available online 5 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
the hydrolysis of the corresponding diesters proceeded with high
regio- and enantioselectivity, yielding deprotection only at the
Due to their dual functionality, b-hydroxycarboxylic acids, and
their esters are versatile chiral synthons in organic synthesis. Opti-
cally active b-hydroxycarboxylic acids and their derivatives bear-
ing various aromatic moieties have been used as starting
materials for the preparation of enantiopure bioactive compounds,
such as vitamins, antibiotics, pheromones, and flavor compounds.1
For their synthesis, several chiral organometallic or enzymatic pro-
cedures are available: (1) enantioselective reduction of the corre-
sponding b-ketoesters; (2) kinetic or dynamic kinetic resolution
(KR or DKR) of the racemic b-hydroxycarboxylic acids and their
derivatives; (3) deracemization of b-hydroxy esters,2 and so on.
The enzymatic kinetic resolution of various chiral substrates
with fatty acids or their derivatives as acyl donors or the stereose-
lective enzymatic hydrolysis of long chain fatty acid esters have al-
ready been investigated,3 but to the best of our knowledge, long
chain fatty acid derivatives have not been used so far for the kinetic
resolution of the herein presented aromatic b-hydroxy esters. The
general, eco-friendly biocatalytic procedure presented herein could
be a valuable method for the synthesis of enantiomerically pure b-
hydroxy esters.
b-position.
2. Results and discussion
The aim of this work was to study the enantioselective
lipase-catalyzed O-acylation versus the lipase mediated selective
hydrolysis to produce both enantiomeric forms of various
b-hydroxy esters and their O-acylated diesters with high enantio-
meric purity (Scheme 1).
2.1. Optimization of the enzymatic kinetic resolution of
aromatic b-hydroxy esters
Since the enzymatic hydrolysis of b-hydroxy esters generally
proceeds with only moderate stereoselectivity,4 the kinetic resolu-
tion via enantioselective lipase-catalyzed O-acylation was first
investigated.
2.2. Lipase-catalyzed kinetic resolution by O-acylation
Herein we report a novel, enantioselective O-acylation of vari-
ous aromatic b-hydroxy esters using fatty acid esters as acyl do-
nors. Importantly, the long acyl chain from the forming diesters
proved to be a good leaving group in the reverse reaction. Thus,
2.2.1. Biocatalyst and solvent screening and the effect of water
To develop a general procedure for the enzymatic kinetic reso-
lution of various aromatic b-hydroxy esters rac-1a–m, first the
stereoselective lipase-catalyzed O-acylation of ethyl 3-hydroxy-3-
phenylpropanoate rac-1a was used as the model substrate and
tested under various conditions. Commercial lipases (25 mg/mL,
each) were screened for the lipase mediated O-acylation of
⇑
Corresponding author. Tel.: +40 264 593 833; fax: +40 264 590 818.
E-mail address: paizs@chem.ubbcluj.ro (C. Paizs).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.005

J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
1673
O
OH
O
C9H19
O
O
OH
O
Lipase, C9H19COOR2
+
R1
OEt
R1
OEt
R1
OEt
organic solvent,
molecular sieves
1a-m
2a-m
1a-m
(S)-
rac-
(R)-
C9H19COCl
Py, DMAP,
DCM, r.t.
O
O
C9H19
O
O
OH
O
C9H19
O
O
Lipase, water
+
R1
OEt
R1
OEt
O
R1
OEt
organic solvent
2a-m
1a-m
rac-
(S)-
2a-m
(R)-
S
MeO
Cl
S
O
S
R1
=
a
b
c
d
e
f
g
h
O
O
Cl
O
S
O
i
k
l
m
j
R2
=
H, Et, i-Pr, n-Bu, vinyl
Scheme 1. Kinetic resolution of racemic b-hydroxy esters rac-1a–m and their diesters rac-2a–m.
Table 1
Lipase (25 mg/mL) and solvent (1 mL) screening for the selective O-acylation of rac-1a (0.025 M) with decanoic acid (0.1 M) at room temperature after 15 h
Entry
Lipase
Solvent
c (%)
ee(R)-2a (%)
ee(S)-1a (%)
E
1
2
3
4
5
6
7
8
CaL-A on Celite
CaL-A on Celite
CaL-A on Celite
CrLa-VII
DIPE
27.7
21.3
19.7
4.3
8.6
12.6
12.6
82.7
85.5
97.9
98.5
97.8
3.3
3.4
3.1
3.7
6.3
18.4
20.2
6.2
1.2
1.3
1.3
11
13
113
161
95
Toluene
n-Octane
DIPE
Toluene
n-Octane
n-Octane
n-Octane
CrLa-VII
6.9
CrLa-VII
15.8
17.0
6.0
CrLa (free, AYS Amano)
CrLa (immob., T2-150)
a
Candida rugosa is abbreviated as CrL.
rac-1a (0.025 M) with decanoic acid as the acyl donor (0.1 M) in
various organic solvents at room temperature. Free and immobi-
lized forms of lipases A and B from Candida antarctica (CaL-A and
CaL-B), lipase from Burkholderia cepacia (formerly Pseudomonas
cepacia; LPS), lipase from Pseudomonas fluorescens (LAK), and lipase
from Candida rugosa (CrL), were tested as suitable biocatalysts in
dry organic solvents. Since even small traces of water could pro-
mote hydrolytic reactions, thus yielding undesired by-products,
all of the acylation tests were performed in the presence of molec-
ular sieves in the reaction mixture.
Lipases LAK, LPS, and CaL-B were unsatisfactory as biocatalysts
for the acylation of rac-1a in all of the solvents tested; 3-hydroxy-
3-phenylpropanoic acid, formed by enzymatic hydrolysis of the
carboxyethyl moiety, was detected as the major product. In the
control reaction (performed without adding the acyl donor), a
quantitative hydrolysis of rac-1a was observed with all three li-
pases. Consequently, the high residual water content prohibits
the use of these biocatalysts for our main purpose.
tential biocatalysts in the stereoselective acylation of rac-1a; hence
further tests were performed only with CaL-A and CrL (Table 1).
Among the variations of solvents and enzymes investigated, the
best results were achieved in n-octane with CrL (free, AYS Amano)
(entry 7). Therefore, further tests were performed with this en-
zyme (CrL, from now on) and solvent.
2.2.2. The effect of the acyl donor
The fast regio- and enantioselective lipase-catalyzed deprotec-
tion of various O-acylated b-hydroxy esters could provide a practi-
cal and useful method to perform kinetic resolutions. To achieve
this goal, an O-acyl moiety with a longer carbon chain is required.
For this purpose various fatty acids (decanoic acid, lauric acid, and
stearic acid) were tested as acyl donors. The preliminary tests indi-
cated that CrL showed catalytic activity only when decanoic acid
was used.
Since the nature of the acyl donor could significantly influence
the selectivity and activity of CrL in n-octane, further the reactions
were carried out in the presence of various decanoic acid deriva-
tives (Table 2). With ethyl, isopropyl, and butyl ester as acyl
A similar control reaction indicated no significant hydrolytic
activity with CaL-A and CrL, which renders these enzymes as po-

1674
J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
Table 2
be the low solubility of certain substrates, which was pronounced
for benzo[b]tiophen-3-yl-hydroxy-propanoate rac-1j.
The influence of decanoic acyl donors (0.1 M) upon the selectivity of CrL (25 mg/mL)
for the O-acylation of rac-1a (0.1 M) in n-octane at room temperature after 15 h
Entry
Acyl donor
c (%)
ee(R)-2a (%)
ee(S)-1a (%)
E
Table 4
Selective O-acylation of different aromatic b-hydroxy esters rac-1b–m (0.025 M) with
CrL (25 mg/mL) in n-octane with vinyl decanoate (0.1 M) at room temperature after
15 h
1
2
3
4
5
Decanoic acid
17.0
4.0
6.1
2.0
44.8
98.5
98.6
>99
>99
97.2
20.2
4.1
6.4
2.1
78.9
161
148
>200
>200
170
Ethyl decanoate
Isopropyl decanoate
Butyl decanoate
Vinyl decanoate
Entry
Substrate
c (%)
ee(R)-2a (%)
ee(S)-1a (%)
E
1
2
3
4
5
6
7
8
rac-1b
rac-1c
rac-1d
rac-1e
rac-1f
rac-1g
rac-1h
rac-1i
rac-1j
rac-1k
rac-1l
rac-1m
49.7
22.0
52.0
50.7
51.6
35.2
47.8
41.9
20.3
21.9
40.7
51.7
98.3
98.5
92.1
87.3
91.1
94.7
97.2
>99
87.7
97.5
96.6
93.3
97.2
27.8
>99
>200
174
182
45
91
61
>200
ꢁ200
19
103
115
»200
donors, CrL showed high stereoselectivity but moderate activity
(entries 2–4). When vinyl decanoate was used as the acyl donor,
the enantioselectivity decreased slightly, the enzyme activity was
considerably enhanced (entry 5). Accordingly, further studies were
performed with vinyl decanoate as the acyl donor.
89.9
97.1
51.5
89.1
72.1
22.3
27.4
66.2
>99
9
10
11
12
2.2.3. The temperature effect
As the performance of CrL in the acylation of rac-1a with vinyl
decanoate in n-octane could strongly depend on the reaction
temperature, the temperature effect was also studied (Table 3).
While the selectivity increased at higher temperatures, a strong
irreversible decrease of the CrL activity was also observed due to
its thermal inactivation. Retesting the already used (at 45 °C) CrL
catalyst in the same reaction resulted in an acylation with low con-
version (c <5%). Since the heat treated CrL and the untreated
enzyme presented similar enantioselectivity (E ꢀ165 and E = 170
respectively), we supposed that the enhancement of selectivity at
the increased temperature (E ꢁ 200) was determined not by the
selective denaturation of a less selective component from the
crude enzyme, but by an intrinsic feature of the enzyme. Taking
both the selectivity and activity into account, the optimal reaction
temperature for the acylation of rac-1a appeared to be 25 °C.
2.3. Lipase-catalyzed regio- and enantioselective hydrolysis
It is already known that lipases usually retain their enantiopre-
ference in hydrolysis or alcoholysis.5 Consequently, using the in-
verse reactions, the opposite enantiomeric forms of the alcohol
and ester fractions should result. It was previously reported that
CrL is a highly enantioselective catalyst for the hydrolysis of vari-
ous types of racemic aromatic b-hydroxy-b-arylpropanoates or of
their O-acylated derivatives.6 Therefore, the catalytic performance
of CrL in the selective hydrolysis of the decanoate esters rac-2a–m
was also investigated.
2.3.1. Solvent screening for lipase-catalyzed regio- and
enantiomer selective hydrolysis
Table 3
In order to determine the optimal reaction conditions, various
organic solvents were used as reaction media for the CrL mediated
selective hydrolysis of racemic diester rac-2a (0.025 M). In the case
of water miscible solvents (acetonitrile, THF) and of polar solvents
The influence of temperature on the selectivity and activity of the CrL (25 mg/mL)
mediated selective O-acylation of rac-1a (0.025 M) with vinyl decanoate (0.1 M) in n-
octane after 15 h
Entry
t (°C)
c (%)
ee(R)-2a (%)
ee(S)-1a (%)
E
with high water solubility (DCM) the presence of water (10
was not beneficial (data not shown).
lL/mL)
1
2
3
4
15
25
35
45
36.7
44.8
32.9
10.9
95.8
97.2
>99
55.6
78.9
48.5
12.2
82
170
>200
ꢁ200
The best results in terms of enzyme activity and selectivity were
obtained in water-saturated nonpolar solvents (Table 5). In n-oc-
tane or toluene (Table 5, entries 3 and 4) higher selectivity and
lower activity were detected in comparison with those obtained
in ethers (Table 5, entries 1 and 2). Due to the better solubility of
the substrates and the higher activity of the enzyme in DIPE, this
solvent was used as the reaction medium in further experiments.
>99
2.2.4. The regio- and enantioselective O-acylation of racemic
aromatic b-hydroxy esters rac-1a–m
In order to investigate the biocatalytic behavior of CrL in kinetic
resolutions, the O-acylation of other racemic aromatic b-hydroxy
esters rac-1b–m were tested under the optimal conditions previ-
ously found for rac-1a (Table 4). In almost all cases, the reaction
proceeded with good selectivity and activity; however, the results
were influenced considerably by the nature of the aromatic ring in
the substrates rac-1b–m.
Table 5
Solvent screening for the hydrolysis of the racemic diacetate, rac-2a (0.025 M) in
presence of CrL (25 mg/mL) at room temperature after 15 h
Entry
Solvent
c (%)
ee(R)-1a (%)
ee(S)-2a (%)
E
The outcome of the acylation was obviously dependent on sev-
eral factors, such as the size and charge distribution of the aromatic
moiety, or the linear or bent nature of the substrate. In general, the
polar and smaller substituents were less beneficial in terms of both
activity and selectivity (entries 2 and 6). Whereas the extension of
the bulkiness in a linear direction was tolerated and beneficial
(entries 1, 7, and 8), the bulky but bent substrates were less tolerated
and acylated with lower rates and selectivity (entries 9 and 10). The
slightly bent and polarized phenylfuran compound resulted in an
acylation with moderate rate and selectivity (entry 11). By further
extension of the substituent (the 5-(4-chlorophenyl)furan-2-yl moi-
ety) an excellent substrate, rac-1m, emerged (entry 12). An addi-
tional effect that influenced the overall rate of the acylation might
1
2
3
4
DIPE
MTBE
Toluene
n-Octane
17.2
16.4
4.3
98.8
98.6
>99
20.5
19.4
4.5
>200
171
ꢁ200
>200
12.8
99.1
14.6
2.3.2. Selective hydrolysis of aromatic diesters rac-2a–m
The CrL-catalyzed hydrolysis of the following substrates rac-
2b–m (Table 6) was investigated under the optimal conditions
found for the selective hydrolysis of rac-2a (Table 5, entry 1).
Importantly, no traces of byproducts due to the hydrolysis of the
ethoxycarbonylic group were detected in any case. Only the highly
hydrophobic phenyl-furan substituted diester rac-2l was hydro-
lyzed with higher selectivity (Table 6, entry 11) than that found

J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
1675
for the O-acylation of its parent alcohol rac-1l (Table 4, entry 11).
In all other cases, lower selectivities were detected compared to
those found for the enzymatic selective O-acylation. The substitu-
ent effects in the selective CrL-catalyzed hydrolysis were almost
opposite to those obtained for the enzymatic O-acylation. Lower
selectivity was obtained for the methoxylated rac-2b (Table 6,
entry 1) compared to the substrates bearing the stronger elec-
tron-withdrawing chlorine (Table 6, entries 2 and 12). The results
obtained for the kinetic resolution of the O- and S-containing het-
eroaryl diesters rac-2b–k, indicated that the aromatic character
had the highest impact upon the enantioselectivity of the enzy-
matic hydrolysis (Table 6, entries 3–10).
2.4. Preparative scale CrL-catalyzed reactions for the synthesis
of both enantiomers of 1a–m
While a relatively high 25 mg/mL enzyme concentration was
used on an analytical scale, lower enzyme concentrations (5–
25 mg/mL) were first tested for synthetic purposes. The convenient
enzyme concentration was found to be 10 mg/mL, offering similar
reaction times and selectivity of the enzymatic acylation as those
found on an analytical scale. A sequential kinetic resolution pro-
cess catalyzed by CrL (Scheme 2) resulted in both enantiomers of
aromatic b-hydroxy esters (R)- and (S)-1a–m with good enantio-
meric excesses and yields (Table 7).
First, the selective O-acylation was performed until the conver-
sion slightly exceeded 50%. This first kinetic resolution resulted in
the residual substrate fraction (S)-1a–m with good yield and high
enantiomeric excess. Next, the enantiomerically enriched O-acyl-
ated esters (R)-2a–m were subjected to the CrL mediated hydroly-
sis to yield the (R)-enantiomer of the aromatic b-hydroxy esters
(R)-1a–m in high enantiopurity. The absolute configurations of
the (R)- and (S)-1a–k were determined by comparing the sign of
their specific rotations with those existing in the literature. The
absolute configurations of the novel compounds (R)-and (S)-1l–m
were assigned in accordance with Kazlauskas’ rule.
Table 6
CrL (25 mg/mL) mediated regio- and enantioselective hydrolysis of various diesters,
rac-2b-m (0,025 M) in DIPE at room temperature after 15 h
Entry
Substrate
c (%)
ee(R)-1 (%)
ee(S)-2 (%)
E
1
2
3
4
5
6
7
8
rac-2b
rac-2c
rac-2d
rac-2e
rac-2f
rac-2g
rac-2h
rac-2i
rac-2j
rac-2k
rac-2l
rac-2m
42.8
44.9
51.7
53.1
50.3
57.0
51.6
51.0
23.3
26.7
51.1
44.9
90.6
97.3
91.5
86.9
86.1
59.0
91.8
92.5
96
67.8
79.3
97.8
98.5
87.1
78.2
97.8
96.2
29.2
35.6
99.6
77.9
41
178
101
69
38
9
105
102
65
3. Conclusion
9
Herein, a new general method for the lipase mediated kinetic
resolution of a series of aromatic b-hydroxy esters has been re-
ported. Using a lipase from C. rugosa and a long chain fatty acid
10
11
12
97.5
95.3
95.7
112
>200
108
O
C9H19
O
O
OH
O
OH
O
CrL, C9H19COOCH=CH2
+
R1
OEt
R1
OEt
OEt
R1
OEt
n-octane, molecular sieves, r.t.
2a-m
1a-m
(S)-
1a-m
(R)-
rac-
CrL, water,
DIPE, r.t.
OH
O
R1
(R)-1a-m
Scheme 2. Preparative scale sequential kinetic resolution of aromatic b-hydroxy esters rac-1a–m.
Table 7
Preparative scale synthesis of both enantiomeric forms of aromatic b-hydroxy esters (R)- and (S)-1a-m
Substrate
Products after acylation
Product after hydrolysis
(S)-1a–m
Yielda (%)
(R)-2a–m
Yielda (%)
49
(R)-1a–m
ee (%)
ee (%)
Yielda (%)
ee (%)
rac-1a
rac-1b
rac-1c
rac-1d
rac-1e
rac-1f
rac-1g
rac-1h
rac-1i
rac-1j
rac-1k
rac-1l
rac-1m
46
47
45
46
41
44
43
49
48
38
44
43
48
>99
>99
>99
>99
>99
>99
>99
>99
>99
65.9
>99
>99
>99
90.0
98.1
90.6
90.3
71.9
83.2
77.5
89.5
>99
76.6
85.4
81.7
>99
45
46
44
44
37
42
35
43
47
35
42
41
47
>99
>99
>99
>99
>99
>99
81.2
>99
>99
>99
>99
>99
>99
49
48
49
45
48
47
48
49
42
46
45
48
a
Isolated yields based on the racemic starting material rac-1a–m.

1676
J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
moiety for the selective acylation and hydrolysis, good yields, and
stereoselectivities were obtained in organic media under mild con-
ditions. The enantiomeric excess of the products formed were en-
riched using a sequential kinetic resolution procedure, first by
lipase mediated O-acylation with vinyl decanoate and second by
the enzymatic hydrolysis of the enantiomerically enriched diesters.
In this way, both enantiomers of the aromatic b-hydroxy esters
were produced with high enantiopurity.
semisolid. The yield and enantiomeric excess of the products are
listed in Table 7.
4.2.2. Selective hydrolysis of the enantiomerically enriched
diesters (R)-2a–m
At first, CrL (AYS Amano, 100 mg) was added into a solution of
the enantiomerically enriched diester (R)-2a–m (0.25 mmol) in
water saturated DIPE (10 mL). The reaction mixture was shaken
(1350 rpm) at room temperature until the conversion reached
ꢀ85% [based on the amount of added (R)-2a–m]. The enzyme
was removed by filtration and the reaction mixture was concen-
trated in vacuo. The crude product was separated by column chro-
matography on silica gel using n-hexane/EtOAc (different ratio,
depending on the substrate) as eluent to give the enantiomerically
enriched (R)-alcohol (R)-1a–m as a semisolid. The yield and enan-
tiomeric excess data for the products are listed in Table 7.
4. Experimental
4.1. Methods and materials
The 1H and 13C NMR spectra were recorded on a Bruker spec-
trometer operating at 300 MHz and 75 MHz, respectively, at
25 °C using tetramethylsilane (TMS) as internal standard and CDCl3
as the solvent. Mass spectra were recorded on GC–MS Shimadzu
QP 2010 Plus spectrometer using direct injection and EI+ ionization
at 30–70 eV. The spectroscopic data for 1a and 1d–k are in accor-
dance with the literature data.4
4.2.2.1.
1a.
(S)-Ethyl
3-hydroxy-3-phenylpropanoate
(S)-
Yield: 46%; clear oil; ½a D25
ꢄ
¼ ꢃ43:8 (c 1, CHCl3), ee >99%;
lit.8a
½
a 2D5
ꢄ
¼ ꢃ43:6 (c 1, CHCl3), ee 93%; tandem Chiralpak IA-IB,
n-hexane/i-PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 22.4/
Optical rotations were determined on a Bellingham-Stanley
ADP 220 polarimeter using solution with 10 mg/mL concentration
and chloroform as solvent, at 25 °C. IR spectra were recorded on a
FTIR BRUKER VECTOR 22 spectrometer using a GOLDEN GATE™
system (Singel Reflection Diamond ATR Series MKII). Thin Layer
Chromatography (TLC) was carried out using Merck Kieselgel
60F254 sheets. Spots were visualized by treatment with 5% etha-
nolic phosphomolybdic acid solution and heating. Preparative
chromatographic separations were performed using column chro-
23.1 min.
4.2.2.2. (R)-3-Ethoxy-3-oxo-1-phenylpropyl decanoate (R)-
2a.
Yield: 49%; clear oil; ½a D25
¼ þ22:1 (c 1, CHCl3), ee 90.0%,
ꢄ
tandem Chiralpak IA-IB, n-hexane/i-PrOH = 95:5, 1.0 mL/min,
218 nm, tR[(S)/(R)] = 11.5/10.4 min; 1H NMR: (300 MHz, CDCl3)
d = 0.87 (t, J = 6.4 Hz, 3H), 1.19–1.30 (m, 15H), 1.53–1.63 (m, 2H),
2.29 (t, J = 7.5 Hz, 2H), 2.83 (ddd, J = 5.2 Hz, J = 9.0 Hz, J = 15.8 Hz,
2H), 4.12 (q, J = 7.0 Hz, 2H), 6.17 (dd, J = 5.2 Hz, J = 9.0 Hz, 1H),
7.28–7.37 (m, 5H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 22.6,
24.8, 28.9, 29.1, 29.3, 31.8, 34.3, 41.5, 60.6, 71.8, 126.4, 128.2,
matography on Merck Kieselgel 60 Å (63–200 lm).
The enantiomeric separations of 1a–m and 2a–m were per-
formed by high performance liquid chromatography (HPLC) with
an Agilent 1200 instrument equipped with the appropriate chiral
columns (4.6 ꢂ 250 mm) at 25 °C using 1 mL/min flow rate. The
enantioselectivity (E) values were calculated with the equation:
E = ln[(1 ꢃ c)(1 ꢃ eeS)]/ln[(1 ꢃ c)(1 + eeS)].7
128.5; 139.3, 169.7, 172.5; IR:
m = 3001, 2925, 2860, 2642, 1735,
1464, 1267, 1165, 1111, 755; MS (EI 30 eV) m/z: 348(M, 3),
209(51), 208(48), 206(100), 193(20), 148(20), 119(32), 96(32),
73(33), 43(32).
All reagents were purchased from Merck or Sigma-Aldrich and
used as received. Solvents and acyl donors for the enzymatic reac-
tions were stored over molecular sieves unless otherwise stated.
Lipases from P. fluorescens (L-AK), B. cepacia (BCL), and C. rugosa
(CrL, free AYS Amano) were products of Amano. Immobilized CrL
(immob. T2-150) was purchased from Chiral Vision. Lipase from
C. rugosa type VII. (CrL-VII) was purchased from Sigma-Aldrich. Li-
pase A from C. antarctica (CAL-A) was the product from Roche
(Chirazyme L-5, lyo), and it (5 g) was adsorbed on celite (17 g) in
the presence of sucrose (3 g). Lipase B from C. antarctica (CAL-B,
Novozym 435) was purchased from Novozymes, Denmark.
Racemic b-hydroxy esters were prepared from the correspond-
ing aldehydes using the Reformatsky reaction and the racemic
diesters were prepared by chemical acylation.4
4.2.2.3. (R)-Ethyl 3-hydroxy-3-phenylpropanoate (R)-1a.
Yield:
¼ þ44 (c
45%; clear oil; ½a D25
ꢄ
¼ þ44:1 (c 1, CHCl3), ee >99%; lit.8b
½
a 2D0
ꢄ
1.015, CHCl3), ee 92%; tandem Chiralpak IA-IB, n-hexane/i-
PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 22.4/23.1 min.
4.2.2.4. (S)-Ethyl 3-hydroxy-3-(4-methoxyphenyl)propanoate
(S)-1b.
Yield: 47%; orange solid; mp: 35–37 °C; ½a D25
¼ ꢃ29:2
ꢄ
(c 1, CHCl3), ee >99%; lit.8a
½
a 2D6
ꢄ
¼ ꢃ28:6 (c 1, CHCl3) ee 94%; tan-
dem Chiralpak IA-AS-H, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
218 nm, tR[(S)/(R)] = 42.9/32.3 min; 1H NMR: (300 MHz, CDCl3):
d = 1.28 (t, J = 6.7 Hz, 3H), 2.73 (ddd, J = 3.9 Hz, J = 8.4 Hz,
J = 15.9 Hz, 2H), 3.81 (s, 3H), 4.19 (q, J = 7.4 Hz, 2H), 5.10 (dd,
J = 3.9 Hz, J = 8.4 Hz, 1H), 6.90 (d, J = 9 Hz, 2H), 7.31 (d, J = 8.7 Hz,
2H); 13C NMR: (75 MHz, CDCl3): d = 14.1, 43.3, 52.2, 60.8, 69.9,
113.9, 126.9, 134.7, 159.1, 172.4; IR:
m = 2990, 2839, 2796, 1722,
4.2. Preparative scale lipase mediated kinetic resolution
1617, 1510, 1313, 1243, 1186, 1168, 1029, 838; MS (EI 70 eV) m/
z: 225(M+1, 16), 224(M, 55), 207(48), 179(30), 150(19), 137(100),
134(68), 94(61), 77(53), 60(15).
4.2.1. Selective acylation of rac-1a–m
At first, CrL (AYS Amano, 1 g) and 4 Å molecular sieves (100 mg)
were added into a solution of the substrate (rac-1a–m, 2.5 mmol)
in n-octane (100 mL) and the reaction was started by the addition
of vinyl decanoate (10 mmol, 1.98 g, 2.23 mL). The reaction
mixture was shaken (1350 rpm) at room temperature until the
conversion slightly exceeded 50%. The enzyme was removed by
filtration and the reaction mixture was concentrated by vacuum
distillation. The crude products were separated by column chroma-
tography on silica gel using n-hexane/EtOAc (different ratio,
depending on the substrate) as eluent to give the enantiomerically
enriched product (R)-2a–m and the residual alcohol (S)-1a–m as a
4.2.2.5. (R)-3-Ethoxy-1-(4-methoxyphenyl)-3-oxopropyl decan-
oate (R)-2b.
Yield: 49%; clear oil; ½a D25
¼ þ36:9 (c 1, CHCl3),
ꢄ
98.1% ee, tandem Chiralpak IA-AS-H, n-hexane/i-PrOH = 90:10,
1.0 mL/min, 218 nm, tR[(S)/(R)] = 13.4/11.3 min; 1H NMR:
(300 MHz, CDCl3): d = 0.86 (t, J = 6.7 Hz, 3H), 1.19–1.30 (m, 15H),
1.51–1.61 (m, 2H), 2.26 (t, J = 7.5 Hz, 2H), 2.83 (ddd, J = 5.2 Hz,
J = 9.0 Hz, J = 15.8 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 6.12
(dd, J = 5.2 Hz, J = 9.0 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.29 (d,
J = 8.3 Hz, 2H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 22.6, 24.8,
28.9, 29.1, 29.3, 31.8, 34.3, 41.3, 55.1, 60.7, 71.5, 113.7, 113.8,

J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
1677
127.9, 131.4, 159.4, 169.8; IR:
m
= 3047, 2926, 2850, 2033, 1732,
4.2.2.13. (S)-Ethyl 3-(furan-2-yl)-3-hydroxypropanoate (S)-
1616, 1519, 1282, 1168, 1112, 1032, 837, 786, 730; MS (EI 40 eV)
m/z: 378(M, 2), 224(14), 223(100), 207(27), 165(21), 150(10),
137(18), 135(66), 71(12), 43(26).
1e.
Yield: 41%; clear oil; ½a D25
¼ ꢃ15:9 (c 1, CHCl3), ee >99%;
ꢄ
lit.4c
½
a 2D5
ꢄ
¼ ꢃ16 (c 1, CHCl3), ee 99%; Chiralpak IA, n-hexane/i-
PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 16.0/16.7 min.
4.2.2.6. (R)-Ethyl 3-hydroxy-3-(4-methoxyphenyl)propanoate
4.2.2.14. (R)-3-Ethoxy-1-(furan-2-yl)-3-oxopropyl decanoate
(R)-1b.
Yield: 46%; orange solid; mp: 35–37 °C; ½a D25
ꢄ
¼ þ28:8
(R)-2e.
Yield: 45%; clear yellow oil; ½a D25
¼ þ53:6 (c 1, CHCl3),
ꢄ
(c 1, CHCl3), ee >99%; lit.8c
½
a 2D5
ꢄ
¼ þ25:7 (c 1.4, CHCl3), ee 81%; tan-
71.9% ee, Chiralpak IA, n-hexane/i-PrOH = 95:5, 1.0 mL/min,
218 nm, tR[(S)/(R)] = 5.9/6.2 min; 1H NMR: (300 MHz, CDCl3):
d = 0.86 (t, J = 6.7 Hz, 3H), 1.19–1.31 (m, 15H), 1.51–1.62 (m, 2H),
2.26 (t, J = 7.5 Hz, 2H), 2.96 (ddd, J = 6.0 Hz, J = 9.0 Hz, J = 15.8 Hz,
2H), 4.11 (q, J = 7.3 Hz, 2H), 6.24–6.36 (m, 3H), 7.36 (s, 1H); 13C
NMR: (75 MHz, CDCl3): d = 14.0, 22.6, 24.8, 28.9, 29.1, 29.3, 31.7,
34.1, 37.6, 60.7, 64.5, 108.8, 110.3, 142.6, 151.2, 169.3, 172.5; IR:
dem Chiralpak IA-AS-H, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
218 nm, tR[(S)/(R)] = 42.9/32.3 min.
4.2.2.7. (S)-Ethyl 3-(4-chlorophenyl)-3-hydroxypropanoate (S)-
1c.
Yield: 45%; clear yellow oil; ½a D25
¼ ꢃ28:3 (c 1, CHCl3), ee
ꢄ
>99%; lit.8d
½
a 2D5
ꢄ
¼ ꢃ43:7 (c 1.38, CHCl3), ee 99%; Chiralpak IA, n-
hexane/i-PrOH = 96:4, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 18.2/
19.3 min; 1H NMR: (300 MHz, CDCl3): d = 1.27 (t, J = 7 Hz, 3H),
2.71 (ddd, J = 4.1 Hz, J = 8.6 Hz, J = 16.4 Hz, 2H), 4.19 (q, J = 7.3 Hz,
2H), 5.11 (dd, J = 4.1 Hz, J = 8.6 Hz, 1H), 7.28–7.36 (m, 4H); 13C
NMR: (75 MHz, CDCl3): d = 14.1, 43.2, 61.0, 69.6, 127.0, 128.6,
m = 3082, 2927, 2860, 2367, 1738, 1457, 1371, 1243, 1161, 709;
MS (EI 70 eV) m/z: 338(M, 0.1), 184(11), 183(100), 167(8),
137(25), 115(18), 110(8), 95(23), 57(10), 43(7).
4.2.2.15. (R)-Ethyl 3-(furan-2-yl)-3-hydroxypropanoate (R)-
133.4, 141.0, 172.2; IR:
m
= 3343, 3298, 3180, 2982, 1725, 1495,
1e.
Yield: 37%; clear oil; ½a D25
¼ þ16:0 (c 1, CHCl3), ee >99%;
ꢄ
1270, 1196, 1021, 830, 756; MS (EI 70 eV) m/z: 230(M, 37Cl, 4),
228(M, 35Cl, 14), 156(37Cl, 3), 154(35Cl, 10), 143(37Cl, 27),
141(35Cl, 100), 115(37Cl, 5), 113(35Cl, 17), 88(38), 77(32), 60(20).
lit.4c
½
a 2D5
ꢄ
¼ þ10 (c 1, CHCl3), ee 63%; Chiralpak IA, n-hexane/i-
PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 16.0/16.7 min.
4.2.2.16. (S)-Ethyl 3-hydroxy-3-(thiophen-3-yl)propanoate (S)-
4.2.2.8. (R)-1-(4-Chlorophenyl)-3-ethoxy-3-oxopropyl decano-
1f.
Yield: 44%; clear orange oil; ½a D25
¼ ꢃ44:7 (c 1, CHCl3), ee
ꢄ
ate (R)-2c.
Yield: 48%; clear yellow oil; ½a D25
ꢄ
¼ þ30:4 (c 1,
>99%; lit.4c
½
a 2D5
ꢄ
¼ ꢃ44 (c 1, CHCl3), ee 99%; Chiralpak IB, n-hex-
CHCl3), ee 90.6%, Chiralpak IA, n-hexane/i-PrOH = 96:4, 1.0 mL/
min, 218 nm, tR[(S)/(R)] = 10.4/8.0 min; 1H NMR: (300 MHz,
CDCl3): d = 0.86 (t, J = 6.4 Hz, 3H), 1.19–1.30 (m, 15H), 1.51–1.62
(m, 2H), 2.28 (t, J = 7.5 Hz, 2H), 2.83 (ddd, J = 5.2 Hz, J = 9.0 Hz,
J = 15.4 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 6.12 (dd, J = 5.2 Hz,
J = 9.0 Hz, 1H), 7.30 (s, 4H); 13C NMR: (75 MHz, CDCl3): d = 14.0,
22.6, 24.8, 28.9, 29.1, 29.3, 31.8, 34.2, 41.3, 60.8, 71.2, 127.9,
ane/i-PrOH = 90:10, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 7.4/16.3 min.
4.2.2.17. (R)-3-Ethoxy-3-oxo-1-(thiophen-3-yl)propyl decanoate
(R)-2f.
Yield: 48%; clear yellow oil; ½a D25
¼ þ38:9 (c 1, CHCl3), ee
ꢄ
83.2%, Chiralpak IB, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 218 nm,
tR[(S)/(R)] = 4.9/6.0 min; 1H NMR: (300 MHz, CDCl3): d = 0.89 (t,
J = 6.4 Hz, 3H), 1.22–1.33 (m, 15H), 1.51–1.65 (m, 2H), 2.30 (t,
J = 7.5 Hz, 2H), 2.90 (ddd, J = 5.2 Hz, J = 8.3 Hz, J = 15.8 Hz, 2H),
4.14 (q, J = 7.3 Hz, 2H), 6.33 (dd, J = 5.2 Hz, J = 8.3 Hz, 1H), 7.08–
7.11 (m, 2H), 7.28–7.32 (m, 1H); 13C NMR: (75 MHz, CDCl3):
d = 14.0, 22.6, 24.8, 28.9, 29.1, 29.3, 31.8, 34.3, 40.7, 60.7, 67.5,
128.7, 134.0, 137.9, 169.4, 172.4; IR:
m = 3031, 2667, 2498, 2393,
1910, 1734, 1268, 1018, 752, 708; MS (EI) m/z: 382 (M, 0.1),
212(37Cl, 14), 210(35Cl, 44), 172(11), 171(100).
4.2.2.9. (R)-Ethyl 3-(4-chlorophenyl)-3-hydroxypropanoate (R)-
122.8, 125.8, 126.1, 140.1, 169.6, 172.5; IR: m = 2929, 2863, 2749,
1c.
Yield: 45%; clear yellow oil; ½a D25
ꢄ
¼ þ28:5 (c 1, CHCl3), ee
1735, 1462, 1380, 1286, 1242, 1165, 1107, 787, 775; MS (EI
70 eV) m/z: 355(M+1, 15), 354(M, 0.6), 200(50), 199(38), 111(43),
97(36), 85(34), 71(48), 69(36), 57(100), 55(56), 43(78).
>99%; lit.8e
½
a 2D5
ꢄ
¼ þ41:3 (c 1.5, CHCl3), ee 96%; Chiralpak IA, n-hex-
ane/i-PrOH = 96:4, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 18.2/19.3 min.
4.2.2.10. (S)-Ethyl 3-hydroxy-3-(thiophen-2-yl)propanoate (S)-
4.2.2.18. (R)-Ethyl 3-hydroxy-3-(thiophen-3-yl)propanoate (R)-
1d.
Yield: 46%; clear yellow oil; ½a D25
ꢄ
¼ ꢃ17:2 (c 1, CHCl3), ee
1f.
Yield: 42%; clear orange oil; ½a D25
¼ þ44:4 (c 1, CHCl3), ee
ꢄ
>99%; lit.4c
½
a 2D5
ꢄ
¼ ꢃ17 (c 1, CHCl3), ee 99%; Chiralpak IB, n-hex-
>99%; lit.4c
½
a 2D5
ꢄ
¼ þ21 (c 1, CHCl3), ee 51%; Chiralpak IB, n-hex-
ane/i-PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 7.3/13.6 min.
ane/i-PrOH = 90:10, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 7.4/16.3 min.
4.2.2.11. (R)-3-Ethoxy-3-oxo-1-(thiophen-2-yl)propyl decanoate
4.2.2.19. (S)-Ethyl 3-(furan-3-yl)-3-hydroxypropanoate (S)-
(R)-2d.
Yield: 49%; clear oil; ½a D25
ꢄ
¼ þ45:8 (c 1, CHCl3), ee 90.3%,
1g.
Yield: 43%; clear red oil; ½a D25
¼ ꢃ29:8 (c 1, CHCl3), ee
ꢄ
Chiralpak IB, n-hexane/i-PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/
(R)] = 4.7/5.5 min; 1H NMR: (300 MHz, CDCl3): d = 0.89 (t,
J = 6.4 Hz, 3H), 1.20–1.30 (m, 15H), 1.53–1.63 (m, 2H), 2.28 (t,
J = 7.5 Hz, 2H), 2.97 (ddd, J = 5.2 Hz, J = 9.0 Hz, J = 15.8 Hz, 2H),
4.13 (q, J = 7.0 Hz, 2H), 6.48 (dd, J = 5.2 Hz, J = 9.0 Hz, 1H), 6.95–
6.98 (m, 1H), 7.10 (d, J = 3.7 Hz, 1H), 7.28 (d, J = 3.7 Hz, 1H); 13C
NMR: (75 MHz, CDCl3): d = 14.0, 22.6, 24.8, 28.9, 29.1, 29.3, 31.8,
34.2, 41.3, 60.8, 67.0, 125.5, 126.0, 126.6, 141.9, 169.2, 172.4; IR:
>99%; lit.4c
½
a 2D5
ꢄ
¼ ꢃ29 (c 1, CHCl3), ee 97%; Chiralpak IB, n-hex-
ane/i-PrOH = 90:10, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 6.6/12.1 min.
4.2.2.20. (R)-3-Ethoxy-1-(furan-3-yl)-3-oxopropyl decanoate
(R)-2g.
Yield: 47%; clear yellow oil; ½a D25
¼ þ31:1 (c 1, CHCl3),
ꢄ
77.5% ee, Chiralpak IB, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
218 nm, tR[(S)/(R)] = 4.3/5.1 min; 1H NMR: (300 MHz, CDCl3):
d = 0.86 (t, J = 6.7 Hz, 3H), 1.20–1.31 (m, 15H), 1.52–1.64 (m, 2H),
2.26 (t, J = 7.5 Hz, 2H), 2.83 (ddd, J = 5.2 Hz, J = 9.0 Hz, J = 15.8 Hz,
2H), 4.12 (q, J = 7.0 Hz, 2H), 6.19 (dd, J = 5.2 Hz, J = 9.0 Hz, 1H),
6.38 (s, 1H), 7.36 (s, 1H), 7.44(s, 1H); 13C NMR: (75 MHz, CDCl3):
d = 14.0, 22.6, 24.8, 28.9, 29.2, 29.3, 31.8, 34.3, 40.0, 60.7, 64.4,
m
= 3070, 2990, 2929, 2864, 2695, 1737, 1460, 1287, 1180, 1153,
754, 710; MS (EI 70 eV) m/z: 201(6), 200(21), 199(100), 153(21),
141(7), 115(21), 111(32), 110(10), 71(8), 57(9), 43(9).
4.2.2.12. (R)-Ethyl 3-hydroxy-3-(thiophen-2-yl)propanoate (R)-
108.7, 123.8, 140.4, 143.3, 169.6, 172.6; IR: m = 3113, 2971, 2928,
1d.
Yield: 44%; clear yellow oil; ½a D25
ꢄ
¼ þ17:4 (c 1, CHCl3), ee
2851, 1734, 1460, 1287, 1167, 1023, 755, 681; MS (EI 70 eV) m/z:
339(M+1, 1), 338(M, 3), 184(59), 183(72), 167(14), 155(100),
125(26), 95(69), 71(64), 57(76), 43(35).
>99%; lit.4c
½
a 2D5
ꢄ
¼ þ11 (c 1, CHCl3), ee 68%; Chiralpak IB, n-hex-
ane/i-PrOH = 95:5, 1.0 mL/min, 218 nm, tR[(S)/(R)] = 7.3/13.6 min.

1678
J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
4.2.2.21. (R)-Ethyl 3-(furan-3-yl)-3-hydroxypropanoate (R)-
4.2.2.29. (R)-1-(Benzo[b]thiophen-3-yl)-3-ethoxy-3-oxopropyl
1g.
Yield: 35%; clear red oil; ½a D25
ꢄ
¼ þ23:7 (c 1, CHCl3), ee
decano-ate (R)-2j.
Yield: 42%; clear yellow oil; ½a D25
¼ þ22:1
ꢄ
81.2%; lit.4c
½
a 2D5
ꢄ
¼ þ16 (c 1, CHCl3), ee 60%; Chiralpak IB,
(c 1, CHCl3), ee 76.6%; Chiralpak IA, n-hexane/i-PrOH = 96:4,
1.0 mL/min, 254 nm, tR[(S)/(R)] = 9.3/9.7 min; 1H NMR: (300 MHz,
CDCl3): d = 0.87 (t, J = 6.7 Hz, 3H), 1.19–1.31 (m, 15H), 1.54–1.64
(m, 2H), 2.32 (t, J = 7.5 Hz, 2H), 3.02 (ddd, J = 5.2 Hz, J = 9.0 Hz,
J = 15.8 Hz, 2H), 4.13 (q, J = 7.3 Hz, 2H), 6.62 (dd, J = 5.2 Hz,
J = 9.0 Hz, 1H), 7.32–7.44 (m, 3H), 7.85 (d, J = 6.7 Hz, 1H), 7.94
(d, J = 6.7 Hz, 1H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 22.6, 24.8,
29.0, 29.1, 29.3, 31.8, 34.2, 40.1, 60.8, 67.1, 122.2, 122.8, 124.2,
n-hexane/i-PrOH = 90:10,
1.0 mL/min,
218 nm,
tR[(S)/(R)] =
6.6/12.1 min.
4.2.2.22. (S)-Ethyl 3-(benzo[b]thiophen-2-yl)-3-hydroxypropan-
oate (S)-1h.
Yield: 49%; yellow solid; mp: 30–32 °C;
½
a 2D5
ꢄ
¼ ꢃ13:3 (c 1, CHCl3), ee >99%; lit.4a
½
a 2D5
ꢄ
¼ ꢃ13:5 (c 1, CHCl3),
ee 99%; Chiralpak IA, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
254 nm, tR[(S)/(R)] = 14.2/12.7 min.
124.3, 124.5, 134.1, 136.7, 140.6, 169.6, 172.5; IR:
m = 3077, 3012,
2928, 2862, 2338, 1744, 1634, 1528, 1275, 1155, 1058, 753; MS
(EI 70 eV) m/z: 405(M+1, 1), 404(M, 3), 251(16), 250(100),
249(32), 191(29), 163(23), 162(23), 161(80), 160(35), 135(33),
115(33), 57(38), 43(36).
4.2.2.23. (R)-1-(Benzo[b]thiophen-2-yl)-3-ethoxy-3-oxopropyl
decano-ate (R)-2h.
Yield: 48%; clear yellow oil; ½a D25
¼ þ50:2
ꢄ
(c 1, CHCl3), ee 89.5%, Chiralpak IA, n-hexane/i-PrOH = 90:10,
1.0 mL/min, 254 nm, tR[(S)/(R)] = 8.1/7.3 min; 1H NMR: (300 MHz,
CDCl3): d = 0.87 (t, J = 6.4 Hz, 3H), 1.20–1.38 (m, 15H), 1.58–1.70
(m, 2H), 2.32 (t, J = 7.5 Hz, 2H), 3.02 (ddd, J = 5.2 Hz, J = 8.3 Hz,
J = 15.8 Hz, 2H), 4.16 (q, J = 7.0 Hz, 2H), 6.56 (dd, J = 5.2 Hz,
J = 8.3 Hz, 1H), 7.31–7.39 (m, 3H), 7.71–7.81 (m, 2H); 13C NMR:
(75 MHz, CDCl3): d = 14.0, 22.5, 24.8, 28.9, 29.1, 29.3, 31.7, 34.2,
41.1, 60.9, 67.7, 122.3, 122.6, 123.8, 124.3, 124.6, 138.9, 139.4,
4.2.2.30. (R)-Ethyl 3-(benzo[b]thiophen-3-yl)-3-hydroxypropan-
oate (R)-1j.
Yield: 35%; clear yellow oil; ½a D25
¼ þ46:2 (c 1,
ꢄ
CHCl3), ee >99%; lit.4a
½
a 2D5
ꢄ
¼ þ42:3 (c 1, CHCl3), ee 94%; Chiralpak
IA, n-hexane/i-PrOH = 96:4, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 24.0/
25.3 min.
142.5, 169.1 172.4; IR:
m = 3136, 2959, 2848, 1941, 1739, 1467,
4.2.2.31. (S)-Ethyl 3-(benzofuran-3-yl)-3-hydroxypropanoate
1285, 1146, 1005, 950, 743; MS (EI 70 eV) m/z: 404(M, 1),
251(14), 250(77), 249(80), 203(18), 162(27), 161(100), 160(35),
115(34), 57(20), 43(22).
(S)-1k.
Yield: 44%; clear orange oil; ½a D25
¼ ꢃ26:2 (c 1, CHCl3),
ꢄ
ee >99%; lit.4a
½
a 2D5
ꢄ
¼ ꢃ24:5 (c 1, CHCl3), ee 95%; Chiralpak IA, n-
hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 13.7/
11.8 min.
4.2.2.24. (R)-Ethyl 3-(benzo[b]thiophen-2-yl)-3-hydroxypropan-
oate (R)-1h.
Yield: 43%; yellow solid; mp: 30–32 °C;
a 2D5
ꢄ
¼ þ13:3 (c 1, CHCl3), ee;>99% lit.4a
½
a 2D5
ꢄ
¼ þ13:5 (c 1, CHCl3),
4.2.2.32. (R)-1-(Benzofuran-3-yl)-3-ethoxy-3-oxopropyl decan-
½
oate (R)-2k.
Yield: 46%; clear yellow oil; ½a D25
¼ þ22:9 (c 1,
ꢄ
ee 99%; Chiralpak IA, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
CHCl3), ee 85.4%, Chiralpak IC, n-hexane/i-PrOH = 90:10, 1.0 mL/
min, 254 nm, tR[(S)/(R)] = 7.8/7.5 min; 1H NMR: (300 MHz, CDCl3):
d = 0.89 (t, J = 6.7 Hz, 3H), 1.22–1.33 (m, 15H), 1.56–1.66 (m, 2H),
2.32 (t, J = 7.5 Hz, 2H), 3.06 (ddd, J = 5.2 Hz, J = 8.3 Hz, J = 15.8 Hz,
2H), 4.16 (q, J = 7.3 Hz, 2H), 6.52 (dd, J = 5.2 Hz, J = 8.3 Hz, 1H),
7.26–7.36 (m, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.68 (s, 1H), 7.73 (d,
J = 6.7 Hz, 1H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 22.5, 24.8,
28.9, 29.1, 29.3, 31.7, 34.2, 39.6, 60.8, 64.5, 111.7, 119.0, 120.3,
254 nm, tR[(S)/(R)] = 14.2/12.7 min.
4.2.2.25. (S)-Ethyl 3-(benzofuran-2-yl)-3-hydroxypropanoate
(S)-1i.
Yield: 48%; clear orange oil; ½a D25
¼ ꢃ24:9 (c 1, CHCl3),
ꢄ
ee >99%; lit.4a
½
a 2D5
ꢄ
¼ ꢃ24:3 (c 1, CHCl3), ee 98%; Chiralpak IA, n-
hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 13.7/
11.8 min.
122.8, 124.6, 125.4, 142.7, 155.4, 169.5, 172.6; IR:
m = 2929, 2660,
4.2.2.26. (R)-1-(Benzofuran-2-yl)-3-ethoxy-3-oxopropyl decan-
2568, 1742, 1644, 1514, 1463, 1268, 1158, 1108, 756; MS (EI
70 eV) m/z: 388(M, 1), 234(32), 233(28), 188(16), 175(10),
145(27), 97(52), 57(100), 43(38).
oate (R)-2i.
Yield: 49%; clear yellow oil; ½a D25
¼ þ37:6 (c 1,
ꢄ
CHCl3), ee >99%, Chiralpak IC, n-hexane/i-PrOH = 90:10, 1.0 mL/
min, 254 nm, tR[(S)/(R)] = 7.8/7.5 min; 1H NMR: (300 MHz, CDCl3):
d = 0.89 (t, J = 6.7 Hz, 3H), 1.23–1.34 (m, 15H), 1.56–1.70 (m, 2H),
2.34 (t, J = 7.5 Hz, 2H), 3.09 (ddd, J = 6.0 Hz, J = 9.0 Hz, J = 15.8 Hz,
2H), 4.17 (q, J = 7.3 Hz, 2H), 6.44 (dd, J = 6.0 Hz, J = 9.0 Hz, 1H),
6.76 (s, 1H), 7.21–7.33 (m, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.56 (d,
J = 6.7 Hz, 1H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 22.5, 24.7,
28.9, 29.1, 29.3, 31.7, 34.1, 37.7, 60.8, 65.0, 105.3, 111.3, 121.3,
4.2.2.33. (R)-Ethyl 3-(benzofuran-3-yl)-3-hydroxypropanoate
(R)-1k.
Yield: 42%; clear orange oil; ½a D25
¼ þ25:8 (c 1, CHCl3),
ꢄ
ee >99%; lit.4a
½
a 2D5
ꢄ
¼ þ24:7 (c 1, CHCl3), ee 95%; Chiralpak IA, n-
hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 13.7/
11.8 min.
122.8, 124.6, 127.6, 153.6, 154.7, 169.2, 172.4; IR:
m = 2926, 2848,
4.2.2.34. (S)-Ethyl 3-hydroxy-3-(5-phenylfuran-2-yl)propanoate
1745, 1684, 1504, 1461, 1267, 1148, 1035, 752; MS (EI 70 eV) m/
z: 388(M, 1), 234(26), 233(100), 187(24), 160(20), 145(93),
144(56), 115(55), 71(22), 57(47), 43(46), 29(53).
(S)-1l.
Yield: 43%; clear red oil; ½a D25
¼ ꢃ40:7 (c 1, CHCl3), ee
ꢄ
>99%, Chiralpak IA, n-hexane/i-PrOH = 96:4, 1.0 mL/min, 286 nm,
tR[(S)/(R)] = 26.0/30.3 min; 1H NMR: (300 MHz, CDCl3): d = 1.29 (t,
J = 7.1 Hz, 3H), 2.88–3.04 (m, 2H), 3.40 (br s, 1H), 4.22 (q,
J = 7.3 Hz, 2H), 5.20–5.24 (m, 1H), 6.39 (d, J = 3.7 Hz, 1H), 6.61
(d, J = 3.0 Hz, 1H), 7.25–7.30 (m, 1H), 7.36–7.43 (m, 2H), 7.65–
7.69(m, 2H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 39.8, 60.9, 64.2,
105.5, 108.4, 123.6, 127.3, 128.5, 130.5, 153.5, 154.2, 171.9; IR:
4.2.2.27. (R)-Ethyl 3-(benzofuran-2-yl)-3-hydroxypropanoate
(R)-1i.
Yield: 47%; clear orange oil; ½a D25
¼ þ24:8 (c 1, CHCl3),
ꢄ
ee >99%; lit.4a
½
a 2D5
ꢄ
¼ þ24:3 (c 1, CHCl3), ee 98%; Chiralpak IA, n-
hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 13.7/
11.8 min.
m
= 3131, 2987, 2394, 1727, 1557, 1405, 1285, 1201, 1025, 796;
MS (EI 70 eV) m/z: 261(M+1, 4), 260(M, 12), 243(25), 242(24),
4.2.2.28. (S)-Ethyl 3-(benzo[b]thiophen-3-yl)-3-hydroxypropan-
214(11), 196(16), 173(56), 170(43), 105(100), 57(8), 43(9).
oate (S)-1j.
Yield: 38%; clear yellow oil; ½a D25
¼ ꢃ30:7 (c 1,
ꢄ
CHCl3), ee 65.9%; lit.4a
½
a 2D5
ꢄ
¼ ꢃ42:5 (c 1, CHCl3), ee 94%; Chiralpak
4.2.2.35.
(R)-3-Ethoxy-3-oxo-1-(5-phenylfuran-2-yl)propyl
decanoate (R)-2l.
(c 1, CHCl3), ee 81.7%, Chiralpak IA, n-hexane/i-PrOH = 96:4,
Yield: 45%; clear orange oil; ½a D25
¼ þ21:1
ꢄ
IA, n-hexane/i-PrOH = 96:4, 1.0 mL/min, 254 nm, tR[(S)/(R)] = 24.0/
25.3 min.

J. Brem et al. / Tetrahedron: Asymmetry 22 (2011) 1672–1679
1679
1.0 mL/min, 286 nm, tR[(S)/(R)] = 8.9/8.4 min; 1H NMR: (300 MHz,
CDCl3): d = 0.88 (t, J = 6.7 Hz, 3H), 1.23–1.35 (m, 15H), 1.54–1.64
(m, 2H), 2.32 (t, J = 7.1 Hz, 2H), 3.07 (ddd, J = 6.0 Hz, J = 9.0 Hz,
J = 15.8 Hz, 2H), 4.17 (q, J = 7.3 Hz, 2H), 6.34 (dd, J = 6.0 Hz,
J = 9.0 Hz, 1H), 6.47 (d, J = 3.7 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H),
7.26–7.31 (m, 1H), 7.37–7.42 (m, 2H), 7.66–7.75 (m, 2H); 13C
NMR: (75 MHz, CDCl3): d = 14.0, 22.6, 24.8, 28.9, 29.2, 29.3, 31.8,
34.2, 37.7, 60.8, 64.7, 105.5, 111.0, 123.8, 124.2, 127.5, 128.6,
4.2.2.39. (R)-Ethyl 3-(5-(4-chlorophenyl)furan-2-yl)-3-hydroxy-
propanoate (R)-1m.
1, CHCl3), ee >99%, Chiralpak IC, n-hexane/i-PrOH = 90:10, 1.0 mL/
min, 286 nm, tR[(S)/(R)] = 24.1/16.8 min.
Yield: 47%; clear red oil; ½a D25
¼ þ35:1 (c
ꢄ
Acknowledgments
J.B. thanks the financial support provided from programs co-fi-
nanced by The Sectoral Operational Program Human Resources
Development, Contract POSDRU 6/1.5/S/3–‘‘Doctoral studies:
through science towards society’’. This work is also related to
the scientific program of ‘‘Development of quality-oriented and
harmonized R+D+I strategy and functional model at BME’’ Project
(TÁMOP-4.2.1/B-09/1/KMR-2010-0002), supported by the New
Hungary Plan.
128.7, 130.3, 150.6, 153.9, 169.4, 172.6; IR:
m = 2927, 2860, 1750,
1737, 1650, 1560, 1539, 1509, 1154, 742; MS (EI 70 eV) m/z:
415(M+1, 1), 414(M, 10), 260(20), 259(100), 244(10), 243(50),
242(15), 171(70), 170(81), 115(45), 57(40), 43(42).
4.2.2.36. (R)-Ethyl 3-hydroxy-3-(5-phenylfuran-2-yl)propanoate
(R)-1l.
Yield: 41%; clear red oil; ½a D25
¼ þ40:5 (c 1, CHCl3), ee
ꢄ
>99%, Chiralpak IA, n-hexane/i-PrOH = 96:4, 1.0 mL/min, 286 nm,
tR[(S)/(R)] = 26.0/30.3 min;
References
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propa-noate (S)-1m.
Yield: 48%; clear red oil; ½a D25
¼ ꢃ35:2 (c
ꢄ
1, CHCl3), ee >99%, Chiralpak IC, n-hexane/i-PrOH = 90:10, 1.0 mL/
min, 286 nm, tR[(S)/(R)] = 24.1/16.8 min; 1H NMR: (300 MHz,
CDCl3): d = 1.26 (t, J = 7.1 Hz, 3H), 2.83–2.99 (m, 2H), 3.40(br s,
1H), 4.18 (q, J = 7.0 Hz, 2H), 5.15–5.19 (m, 1H), 6.35 (d, J = 3.7 Hz,
1H), 6.55 (d, J = 3.7 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.54 (d,
J = 9.0 Hz, 2H); 13C NMR: (75 MHz, CDCl3): d = 14.0, 39.7, 60.9,
64.1, 106.0, 108.5, 124.8, 128.7, 128.9, 132.9, 152.4, 154.5, 171.8;
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IR:
m = 3034, 2798, 2026, 1763, 1718, 1474, 1405, 1197, 1090,
1025, 752; MS (EI 70 eV) m/z: 297(M+1, 37Cl, 1), 296(M, 37Cl, 6),
295(M+1, 35Cl, 3), 294(M, 35Cl, 18), 209(37Cl, 31), 207(35Cl, 100),
151(37Cl, 3), 149(35Cl, 10).
4.2.2.38. (R)-1-(5-(4-Chlorophenyl)furan-2-yl)-3-ethoxy-3-oxo-
propyl decanoate (R)-2m.
Yield: 48%; clear orange oil;
¼ þ12:0 (c 1, CHCl3), ee 99%, Chiralpak IC, n-hexane/i-
½
a 2D5
ꢄ
PrOH = 90:10, 1.0 mL/min, 286 nm, tR[(S)/(R)] = 8.8/10.4 min; 1H
NMR: (300 MHz, CDCl3): d = 0.84 (t, J = 6.7 Hz, 3H), 1.19–1.31 (m,
15H), 1.51–1.61 (m, 2H), 2.28 (t, J = 6.7 Hz, 2H), 3.03 (ddd,
J = 6.0 Hz, J = 9.0 Hz, J = 15.8 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 6.30
(dd, J = 6.0 Hz, J = 9.0 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 6.55
(d, J = 3.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H);
13C NMR: (75 MHz, CDCl3): d = 13.9, 22.5, 24.8, 28.9, 29.1, 29.2,
31.7, 34.1, 37.6, 60.7, 64.5, 106.0, 111.0, 124.9, 128.7, 128.8,
7. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.
8. (a) Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.; Nishiyama, H. Chem. Commun.
2009, 40, 5987–5989; (b) Boaz, N. W. J. Org. Chem. 1992, 57, 4289–4292; (c) Cozzi,
P. G.; Benfatti, F.; Capdevila, M. G.; Mignogna, A. Chem. Commun. 2008, 28, 3317–
3318; (d) Padhi, S. K.; Chadha, A. Tetrahedron: Asymmetry 2005, 16, 2790–2798;
(e) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry 2003, 14, 581–
586.
128.9, 133.1, 150.9, 152.7, 169.2, 172.4; IR:
m = 2917, 2866, 1741,
1475, 1284, 1241, 1159, 1102, 1016, 838, 787; MS (EI 70 eV) m/z:
450(M, 37Cl, 3), 448(M, 35Cl, 9), 295(37Cl, 29), 293(35Cl, 85),
206(37Cl, 40), 204(35Cl, 100), 151(37Cl, 12), 149(35Cl, 39), 57(60),
43(50).