Green methodology for enzymatic hydrolysis of acetates in non-aqueous media via carbonate salts

Article abstract of DOI:10.1016/j.tetasy.2012.06.001

Herein we report a new approach to enantiomerically enriched acetates using a lipase-catalyzed hydrolysis in non-aqueous media by alkaline carbonate salts. The use of sodium carbonate in the enzymatic hydrolysis with Candida antarctica lipase B (CAL-B) of racemic acetates shows a large enhancement of the reactivity and selectivity of this lipase. The role of the carbonate salts, the amount and the nature of the alkaline earth metal on the efficiency of this new pathway are investigated. The enzymatic kinetic resolution of acetates 1a-9a, by enzymatic-carbonate hydrolysis under mild conditions is described. In all cases, the resulting alcohols and remaining acetates were obtained in high ee values (up to >99%) while the selectivities reached E >500.

Full text of DOI:10.1016/j.tetasy.2012.06.001

Tetrahedron: Asymmetry 23 (2012) 828–833
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Green methodology for enzymatic hydrolysis of acetates in non-aqueous
media via carbonate salts
Mounia Merabet-Khelassi , Zahia Houiene , Louisa Aribi-Zouioueche , Olivier Riant b,
a
a
a,
⇑
⇑
a
Equipe de Synthèse Asymétrique et Biocatalyse LCAE, Université Badji Mokhtar-Annaba, B.P12, 23000 Annaba, Algeria
Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université Catholique de Louvain, Bâtiment Lavoisier, Pl. Louis Pasteur, 1, bte 3, 1348
Louvain La Neuve, Belgium
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 March 2012
Accepted 7 June 2012
Herein we report a new approach to enantiomerically enriched acetates using a lipase-catalyzed hydro-
lysis in non-aqueous media by alkaline carbonate salts. The use of sodium carbonate in the enzymatic
hydrolysis with Candida antarctica lipase B (CAL-B) of racemic acetates shows a large enhancement of
the reactivity and selectivity of this lipase. The role of the carbonate salts, the amount and the nature
of the alkaline earth metal on the efficiency of this new pathway are investigated. The enzymatic kinetic
resolution of acetates 1a–9a, by enzymatic-carbonate hydrolysis under mild conditions is described. In all
cases, the resulting alcohols and remaining acetates were obtained in high ee values (up to >99%) while
the selectivities reached E >500.
Ó 2012 Elsevier Ltd. All rights reserved.
9
1
. Introduction
formed in aqueous media, or in a biphasic system: aqueous/
1
0
11
organic solvent. The catalytic mechanism of the hydrolysis is
held on the interface of the two phases (Scheme 1).
Hydrolytic enzymes are very attractive and are one of the most
useful synthetic tools, which integrate numerous organic transfor-
mations in a large variety of catalytic reactions. Their use contrib-
utes to the development of the basic principles of green
1
2
1
2
1
(RS)-R COOR + H O
(S)-R COOR + (R)-R -OH + R COOH
2
2
1
chemistry. Serine hydrolases (EC.3.1.1.3) are the most widely used
for their ease of manipulation and for their remarkable chemo-,
regio-, and enantioselectivity,2 especially in kinetic resolutions.
They offer access to a wide range of biotransformations, such as
the manufacture of pharmaceuticals, cosmetics, agricultural chem-
icals, and fine chemicals.4
Scheme 1.
3
However, enzymatic hydrolysis in biphasic media (water, buffer
or water saturated) is still limited because of two major disadvan-
tages; the first is the decrease of the lipase’s enantioselectivity due
to the co-solvent nature; the second is the difficulty of controlling
the pH value of the aqueous solution during the hydrolysis proce-
dure. These limitations explain its moderate applications for the
resolution of secondary
compared to the enzymatic transesterifications.
Herein we have developed a green and easy pathway for enzy-
matic hydrolysis in non-aqueous organic media, in the presence of
sodium carbonates. We have also applied this procedure to a large
range of aromatic acetates.
Furthermore, their utility has also been reinforced by the possi-
bility of combining enzymatic and homogeneous catalysis. More-
over, efficient methods for deracemizations via biocatalyzed
kinetic resolutions have been developed over the last decade, and
offer new pathways for the production of enantioenriched mole-
cules with high yields and selectivities.5
12
9b,13
14
and/or the primary benzylic acetates
15
Lipases are highly active and stable, both in water and organic
solvents. They are powerful tools for biotransformations involving
either (trans)esterification of carboxylic acids and alcohols in or-
6
ganic media, or hydrolysis in aqueous media. Recently, an efficient
approach for deacylation of secondary acetates using free ammonia
in non-aqueous media has been described.7
2. Results and discussion
The most conventional methods for the enzymatic kinetic reso-
lution through hydrolysis, as reported in the literature, were per-
8
The enzymatic hydrolysis was carried out on an equimolecular
mixture of racemic acetates and sodium carbonate in the presence
of catalytic amounts of lipase, in toluene, without the addition of
any more water (Scheme 2). We examined various parameters of
the reaction and then studied the effect of the sodium carbonate
⇑
Corresponding authors.
E-mail address: olivier.riant@uclouvain.be (O. Riant).
0
957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.001

M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 23 (2012) 828–833
829
according to these parameters, such as the lipase’s nature, its cat-
alytic loading and the temperature.
The data from Table 1 show that no hydrolysis took place in the
absence of both lipase and sodium carbonate (entry 1). Further-
more, none of the corresponding alcohol was obtained when
1
equiv of sodium carbonate but no biocatalyst was used (entry 2).
A slight improvement in the hydrolysis of 1a occurred, only in
Lipase / Na CO
2
3
(
RS)-RCOOR'
(S)-RCOOR' + (R)-R'-OH
toluene
Scheme 2.
the presence of CAL-B, and the conversion reached C = 9% after
days (entry 3). The (R)-phenylethanol was obtained with an
excellent enantioselectivity (ee >99.5%). With the introduction of
both Na CO and CAL-B, the conversion achieved C = 40% while
3
2
3
2
.1. Effect of the amount and the nature of the lipase
maintaining high enantioselectivity (entry 4). In contrast, the use
of free lipases: CCL, CRL, and PCL, gave very low reactivity, with
only C <10% conversion of starting material being obtained after
6 days (entries 9, 10 and 11), although PCL gave high enantioselec-
tivity (entry 11). With the immobilized lipase CAL-B, our results
showed a significant improvement, giving high selectivities
E >500 and good conversion 33% < C < 40% (entries 4 and 6).
When the amount of immobilized lipase was doubled, 40% con-
version of the starting acetate was reached after stirring for 72 h
(entry 7). While heating at 40 °C, we achieved the optimum con-
version, C = 50%, and both the remaining acetate and the resulting
alcohol were obtained with ee values of up to 99% (entry 8).
In our preliminary kinetic resolution investigation, the racemic
phenylethyl acetate 1a was chosen as a model substrate in order to
evaluate the suitable reaction conditions.
Various commercially available lipases were screened: the Can-
dida cylindracea lipase (CCL; LA = 3.85 U/mg), Candida rugosa lipase
(CRL; LA = 1170 U/mg), Pseudomonas cepacia lipase (PCL;
LA >30,000 U/mg) and an immobilized lipase: the Candida antarc-
tica lipase fraction B immobilized on acrylic resin (CAL-B;
LA >10,000 U/g). The catalytic amount of the biocatalysts, reaction
times and temperature were also examined (Scheme 3) in order to
OAc
OH
OAc
Lipase / Na CO3
2
+
organic solvent
(
±)-1a
(+)-(R)-1
(-)-(S)-1a
Scheme 3.
determine the appropriate conditions. Hydrophobic solvents, sub-
jected beforehand to molecular sieves, were employed, in order to
determine the water source in the hydrolysis reaction media. The
course and selectivity of the kinetic resolution were checked by
sampling the reaction mixture by chiral GC. The results are sum-
marized in Table 1.
2
The use of another hydrophobic solvent Et O, gave an analogous
selectivity E >500 and reactivity (entry 5), than those obtained
when toluene was employed as the organic media.
From all of these data, we are able to conclude that since the
solvents used were hydrophobic (aromatics and ether), the water
implicated in the hydrolysis processes probably originates from
the lipase.
Fülöp et al. reported similar phenomena and noted that
hydrolysis of an acetate took place without the addition of any
Table 1
Effect of the amount and the nature of lipase
Entrya Lipase (mg)
Time
h)
ee
(S)
(%)i-
ee
(R)
(%)i-
Cj(%) Ej
S
P
2
H O. This fact was attributed to the residual water present in
k
k
(
the Burkholderia cepacia lipase preparation or in the solvent
b
17
1
2
3
4
5
6
7
8
9
1
1
—
—
72
72
72
72
48
72
72
72
—
—
9.5
67
86
49
70
99
—
—
—
—
—
—
used.
c
The CAL-B and PCL lipases displayed good enantioselectivi-
ties, but only the CAL-B exhibited high reactivity. In contrast,
CRL and CCL were inactive for the hydrolysis processes in these
cases.
In order to validate this novel approach, we decided to apply the
optimized conditions of the enzymatic kinetic resolution via
hydrolysis to a series of primary and secondary aromatic acetates
2a–9a.
d,e
CALB (40)
99.5
99.5
99.5
99.5
99.5
99.5
7
9
40
46
33
41
50
5
>200
>500
>500
>500
>500
>500
1
CAL-Be (40)
e,g
CAL-B (40)
CAL-B (50)
CAL-B (100)
CAL-B (100)
CCL (100)
CRL (100)
PCL (100)
f
f
f,h
6 days
6 days
6 days
0.4
0.4
6.4
0
1
12.4
99.5
3
6
1
>500
a
Reaction conditions: 1 mmol of racemic acetate, 1 mmol of Na
toluene in the presence of lipase at room temperature.
2
CO
3
in 3 mL of
2
.2. Enzymatic-alkaline hydrolysis of racemic acetates 2a–9a
b
2 3
Reaction was performed without lipase or Na CO .
c
d
e
f
Reaction was performed without lipase and in the presence of Na
Reaction was performed in the presence of lipase and without Na
CALB purchased from Aldrich. Specific activity >10,000 U/g.
CALB purchased from Sigma. Specific activity >10,000 U/g.
Et O as the organic solvent.
2
At 40 °C.
2
CO
CO
3
.
.
The enzymatic-alkaline hydrolysis reactions of racemic acetates
2
3
2
a–9a (Scheme 4), under the new reaction conditions, were per-
formed. All experiments were carried out with 1 mmol of sub-
strate, with 1 equiv of sodium carbonate in the presence of a
catalytic amount of CAL-B, in 3 mL of toluene for 72 h at 40 °C.
The results are summarized in Table 2.
All of the substrates showed good to high selectivities (Table 2),
albeit with slight differences in the reactivity of the lipase toward
some substrates, in the presence of sodium carbonate in organic
media.
g
h
i
Measured by GC.
Conversion:
j
16
selectivity16
C = ee
S
/ee
P
+ ee
s
;
E = Ln[(1 ꢀ C)(1 ꢀ ee(S))]/
Ln[(1 ꢀ C)(1 + ee(S))].
k
The absolute configuration was determined by the sign of the specific rotation
of the isolated product with the literature (see Section 4).

8
30
M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 23 (2012) 828–833
OAc
OAc
OAc
OAc
OAc
SPh
Fe
R
R
n
(
±)-3a: R = OMe
±)-4a: R = OEt
(±)-5a: R = H
(±)-7a: n = 1
(±)-8a: n = 2
(±)-9a
rac-2a
(
(±)-6a: R = OMe
Scheme 4.
Table 2
Enzymatic-alkaline hydrolysis of aromatic acetates
Entrya
Substrate
CAL-B (mg)
Solvent
Hexane
ee
b
(%) -(S)g
Yieldc (%)
ee
b
(%) -(R) g
Yieldc (%)
Cd (%)
Ed (%)
S
P
e
e
e
e
e
e
e
e
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
5a
5a
6a
6a
8a
8a
3a
3a
4a
4a
7a
7a
9a
40
40
40
40
40
19.5
5
11
20.5
—
34
69
65
95
98
99
93
78
99.5
95
96
92
95
95
ND
ND
ND
ND
99.5
99.5
99.5
99.5
—
99.5
99.5
99.5
99.5
98.6
99.5
96.3
99.5
99.5
97
ND
ND
ND
ND
16
4
>500
>500
>500
>500
—
>500
>500
>500
>500
>500
>500
>150
>500
>500
>300
>200
150
Et
iPr
TBME
CH Cl
2
O
2
O
10
17
f
2
2
—
NDe
42
40
47
48
32
29
46
48
47
48
45
42
35
36
35
—
NDe
30
35
45
48
34
30
35
48
46
48
40
35
30
32
27
NR
40
80
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
41
40
49
50
50
49
44
50
49
49.6
49
49.3
49
50
100
100
50
100
50
100
50
100
50
100
50
100
50
10
11
12
13
14
15
16
17
18
19
20
21
97
95.6
97.6
99.5
99
>300
>500
>500
>300
98.2
90.3
50
98.2
47.9
a
Reactions were carried out with 1 mmol of racemic acetate, 1 mmol of Na
2 h.
Measured by GC or HPLC.
2 3
CO in 3 mL of solvent at 40 °C, in the presence of a catalytic amount of CAL-B (>10,000 U/g), for
7
b
c
d
e
f
Isolated yields.
Conversion: C = ee /ee + ee
S P s
Not determined.
No reaction.
16
; selectivity16 E = Ln[(1 ꢀ C)(1 ꢀ ee(S))]/Ln[(1 ꢀ C)(1 + ee(S))].
g
Absolute configuration was determined by comparison of the sign of the specific rotation of the isolated product with the literature (see Section 4).
The amount of CAL-B was then reduced to 50 mg (entries 10, 12,
4, 16, 18, 20, and 21); the lipase’s reactivity and selectivity re-
2.3. Effect of the sodium carbonate
1
mained unaffected, for most of the substrates tested.
We next studied the influence of carbonate salts on the out-
come of the enzymatic hydrolysis in non-aqueous organic media.
The nature of the counter-ion of the carbonate was first investi-
gated. For this, we chose Na , K and Ca . We also studied the
influence of the amount of sodium carbonate on the hydrolysis
reaction, which was performed with 1 mmol of phenylethyl ace-
tate 1a with 50 mg of CAL-B in 3 mL of toluene, for 72 h at 40 °C.
The amount of sodium carbonate was varied from 0.1 to 3 mmol.
The results are shown in Table 3.
In general, lipases showed high enantioselectivity toward sec-
ondary alcohols or ester derivatives, but exhibited low enantiose-
lectivity toward primary substrates. The best selectivity E >500
was reached using 80 mg of lipase, at 40 °C, with a high conversion,
C = 41% (entry 7).
We were pleased to note that we could obtain the (RFC)-2-
hydroxymethy-1-phenylthioferrocene 2, via hydrolysis of the pri-
mary acetate 2a, with excellent enantiomeric excess ee = 99.5%.
Furthermore, the other enantiomer, (SFC)-2-hydroxymethy-1-phe-
nylthioferrocene was obtained with high enantioselectivity via
enzymatic acylation in our previous investigations.18 Both enanti-
omers of this primary substrate were thus obtained in high enanti-
oselectivity with the same lipase.
This methodology for enzymatic-alkaline hydrolysis is simple,
easy to use, and effective and can be used under environmentally
friendly conditions. We have improved upon these novel reaction
conditions for a range of various potentially useful substrates with
CAL-B. The enantiomerically enriched alcohols and acetates have
been obtained in good isolated chemical yields.
+
+
2+
2.4. Attempt to interpret the reaction mechanism
The reaction was performed in toluene, a hydrophobic solvent.
Without any added carbonate, it was thought that the hydrolysis
was probably triggered by the structural water molecules from
the enzyme. Using these conditions, moderate conversion (9%)
was obtained (Table 3; entry 1). In the presence of sodium or
potassium carbonate, a high increase in the lipase reactivity was
noted and a conversion of C = 50% was reached (Table 3; entry 6)
without any noticeable change in the selectivity.

M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 23 (2012) 828–833
831
Table 3
Effect of the carbonate salts
Entrya
Carbonate (mmol)
ee
d
(%)
Yielde (%)
ee
P
d
(%)
Yielde (%)
Cf (%)
Ef
S
b
1
2
3
4
5
6
7
8
9
Without
9.5
—
59
—
99.5
—
98
99.5
99.5
98.7
>99
98.2
>99
97
99.5
99
>99
>99
7
—
9
—
>200
—
c
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
(1)
(3)
(2)
(1)
(0.5)
(0.4)
(0.3)
(0.2)
(0.1)
(1)
(0.5)
(1)
99.5
99.5
83
97.5
99.2
75.2
36.2
31
95
99
15
15
15
18
43
23
28
24
70
26
28
24
—
48
24
30
22
15
19
15
10
15
19
—
50.5
50
46
49.7
48
43
27
24
49
50
13
13
>500
>500
>500
>500
>500
>300
>250
97
>500
>500
>250
>250
10
11
12
13
14
K
K
2
CO
CO
3
2
3
CaCO
CaCO
3
3
(0.5)
—
—
a
b
c
d
e
f
Reaction conditions: 1 mmol of racemic acetate, appropriate amount of carbonate in 3 mL of solvent at 40 °C, in the presence of 50 mg of CAL-B (>10,000 U/g) for 72 h.
Reaction in the presence of lipase and without a carbonate.
Reaction without lipase and in the presence of a carbonate.
Measured by GC or HPLC.
Isolated yields.
Conversion: C = ee /ee +ee
S P s
16
; selectivity16 E = Ln[(1 ꢀ C)(1 ꢀ ee(S))]/Ln[(1 ꢀ C)(1 + ee(S))].
Recently, the use of CaCO
3
as a stabilizing agent of fungal lipase
presence of divalent carbonates, a marked decrease of the reaction
rate to C = 13% was observed. It should be noted that the selectivity
was still high with all of the substrates studied E >250.
has been reported. The authors assumed that this stabilization
2
+
brought about by Ca and by safeguarding the medium at pH 6
1
9
during the hydrolysis of 2-ethylhexyl acetate in aqueous media.
In our case, maintaining the lipase’s excellent enantioselectivity
could be attributed to the capture of the leaving group (AcO ) by
3
. Conclusion
ꢀ
the metal ion during the course of the reaction; a minimum of
Herein we have reported a novel methodology for kinetic reso-
0
.5 equiv was crucial in activating the hydrolysis process. The pres-
lution via enzymatic hydrolysis in non-conventional media via car-
bonate salts. The performance of this reaction was improved with
various types of primary and secondary aromatic acetates.
Enzymatic hydrolysis was carried out under hydrophobic or-
ganic media, in the presence of both sodium carbonate and CAL-
B lipase. The effect of the carbonate salts was investigated, and pro-
ven to have a significant influence on the enzymatic reactivity,
without any perturbation on its selectivity. An equimolar amount
+
+
2+
ence of cations Na , K , or Ca , afforded a salt residue, which was
easy to remove by simple filtration with the lipase. The salts
formed may shift some equilibrium toward the desired direction.
When the reaction is carried out in aqueous media; the by-product
formed is an acid. In addition, the literature reports that the addi-
2
tion of metal salts, such as, LiCl or MgCl enhanced the enantiose-
lectivity of Candida rugosa lipase (CRL) during the course of
enzymatic hydrolysis in biphasic media.20 This enhancement in
enantioselectivity was attributed to a change of conformation
and the lipase’s flexibility. Similar observations have been reported
by Salgin et al., who demonstrated that the treatment of CRL with
metal ions, or their use as additives, increased the hydrolysis rate
of racemic naproxen methyl ester in biphasic media. These addi-
tives may ensure electrostatic interactions between metal ions/en-
zyme, thus inducing conformational changes. The increase in the
interaction energy allows better accessibility to the enzyme by
2 3
of Na CO must be present in order to achieve the optimal conver-
sion. Finally, we have developed a novel methodology for the enzy-
matic hydrolysis, in the presence of sodium carbonate, using
simple and green chemistry.
4
4
. Experimental
.1. General
2
1
the substrate.
NMR spectra were recorded on Brucker spectrometers
In our case, it is noteworthy that in the absence of a carbonate
salt, moderate reactivity with an optimum conversion of 9% is
1
13
(
300 MHz for H, 75 MHz for C). Chemical shifts are reported in
d ppm from tetramethylsilane with the solvent resonance as the
reached. The introduction of an increasing amount of Na
an important effect on the reaction rate and an optimum C = 50%
was finally reached; this was also observed with K CO . When, a
2
CO
3
has
1
internal standard for H NMR and chloroform-d (d 77.0 ppm) for
13
C NMR. Coupling constants (J) are given in Hertz. The following
2
3
abbreviations classify the multiplicity: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad signal. The mass
spectra were obtained from the mass-service at the Catholic Uni-
versity of Louvain (FINNIGAN-MAT TSQ 7000 and FINNIGAN-MAT
LQC spectrometers). IR spectra were recorded on Shimadzu FTIR-
2
+
divalent cation Ca was introduced, we observed a dramatic de-
crease of the reaction rate, and the conversion does not exceed
1
3%, showing almost no improvement compared to the reaction
carried out without a carbonate (Table 3, entries 13 and 14); attest-
ing more difficulties that reduced the substrate penetration to the
active site. However, the approach of substrates to the active site
seemed to be easier in the presence of monovalent cations in the
8
400S spectrometer. Optical rotations were determined using a
Perkin–Elmer 241 Polarimeter at room temperature using a cell
of 1 dm length and k = 589 nm. The enantiomeric excesses were
2
2
reaction medium.
Ò
measured by a chiral stationary phase HPLC on Chiralpak AD col-
The resolution of acetates with CAL-B, an immobilized lipase,
via hydrolysis in the presence of carbonate salts is applicable on
equimolar scale in organic media; optimal conversion was
achieved with C >45% with monovalent carbonates. When, in the
Ò
umn and Chiralcel ODH or by gas chromatography (ThermoFinni-
gan Trace GC) equipped with an automatic autosampler and using
a CHIRALSIL-DEX CB column (25 m; 0.25 mm; 0.25
times are reported in minutes.
lm). Retention

8
32
M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 23 (2012) 828–833
4
.2. Synthesis of 2-hydroxymethyl-1-phenylthioferrocene
4.5. Chiral GC analysis and/or chiral HPLC analysis
The starting racemic 2-hydroxy-methyl-1-phenylthio-ferrocene
was prepared as previously described starting from commercially
available N,N-dimethylamino-ferrocene. Ortholithiation by tert-
butyllithium in diethyl ether followed by electrophilic trapping
with diphenyl disulfide afforded the N,N-dimethylaminomethyl-
The chemical analysis was performed by gas chromatography
(ThermoFinnigan Trace GC) equipped with an automatic autosam-
pler and using a CHIRALSIL-DEX CB column (25 m; 0.25 mm;
18
0.25 lm), or by a chiral stationary phase HPLC on Chiralpak-AD
column or Chiralcel-ODH column. Retention times are reported
in minutes. The absolute configurations of all chiral compounds
were determined by polarimetry in comparison with the literature
data. The conditions for the analysis of alcohols (R)-1–9 and ace-
tates (S)-1a–9a are reported below.
1
-phenylthio-ferrocene. The alcohol was then generated by the
reaction of the amine in acetic anhydride followed by methanolysis
the resulting the 2-acetoxymethyl-1-phenylthioferrocene.
1
8
4
.2.1. N,N-Dimethylaminomethyl-1-phenylthio-ferrocene
ꢀ1
Mp: 70 °C, IR (film, cm ) :
103.2; 1176.5; 1261.3; 1477.3; 1581.5; 2765.7; 2812; 2939.3. H
): d = 2.02 (s, 6H, N(CH ); 3.37 & 3.42; 3.43
3.47 AB (dd, J = 13.3 Hz for each one, 2H , CH N(CH ); 4.6 (s, 5H,
); 4.32 (s, 1H, C ), 4.46 & 4.50 (d, 2H, J = 13.6 Hz, C ); 7.01–7.11
, 5H, Ar). C NMR (75 MHz, CDCl ): d = 45.1; 57.0; 69.1; 70.3;
1.3; 75.6; 76.0; 88.0; 124.8; 126.2; 128.5; 140.0. MS (D-APCI;
m = 690.4; 736.7; 817.7; 1026; 1080;
4
.5.1. (R)-(+)-1-Phenylethanol 1
GC (Chiralsil-Dex CB,): = 3.9 min,
) for 99% ee.
1
1
t
R
t
S
= 4.1 min (Tcolumn
=
=
=
=
NMR (300 MHz, CDCl
&
C
3
3
)
2
20
D
15b
1
40 °C), ½
aꢁ
¼ þ53 (c 0.2, CHCl
3
2
3 2
)
P
P
P
1
3
4.5.2. (R)-(+)-1-(4-Methoxyphenyl) ethanol 3
(
m
a
3
GC (Chiralsil-Dex CB): t
R
= 12.7 min. t
3
) for 97% ee.
S
= 13.5 min (Tcolumn
7
2
0
23
+
+
135 °C), ½
a
ꢁ
D
¼ þ40 (c 0.2, CHCl
m/z): 242.18 ([FcCH
2
NMe
2
] , 100%); 307 ([FcSPhCH
2
] , 49%);
+
+
+
3
4
1
50.08([MꢀH] , 35%); 351 ([M] , 24%); 352.04 ([M+H] , 6%).
4
.5.3. (R)-(+)-1-(4-Ethoxyphenyl) ethanol 4
GC (Chiralsil-Dex CB): t = 13.1 min., t
¼ þ41 (c 0.5, CHCl
18
R
S
= 13.9 min (Tcolumn
3
) for 97.6% ee.
.2.2. 2-Acetoxymethyl-1-phenylthioferrocene 2a
2
D
0
24
ꢀ1
1
55 °C). ½
aꢁ
Mp: 128 °C. IR (film, cm ):
022.2; 1238.2; 1369.3; 1577.6; 1728.1
): 1.75(s, 3H, O@C–CH ); 4.27 (s, 5H, C
), 4.52 et 4.55 (d, 2H, J = 10.17Hz, C ); 4.90 et 4.94 (d,
OH; 7.04–
): d = 20.61; 61.00;
9.62; 70.21; 71.83; 76.17; 85; 124.95; 126.17; 128.48; 141.5;
m
= 690.4; 744.4; 817.7; 952.7; 999;
1
(
m
C@O).
H
NMR
(
300 MHz, CDCl
3
3
P
); 4.41(s,
4.5.4. (R)-(+)-1-(2-Naphthyl) ethanol 5
GC (Chiralsil-Dex CB): t = 10.2 min, t = 10.5 min. T
column
1
H, C
P
P
R
S
2
D
0
15b
J = 11.38 Hz, 1H) et 5.07–5.11 (d, J = 12.39Hz, 1H) CH
2
170 °C, ½
a
ꢁ
¼ þ38:3 (c 0.25, CHCl ) for 99% ee.
3
1
3
7
6
1
a 3
.2 (m , 5H, Ar). C NMR (75 MHz, CDCl
4.5.5. (R)-(+)-1-(6-Methoxynaphthalen-2-yl) ethanol 6
+
+
72. MS (EI; m/z): 43.9 ([Ac] , 86%); 148.8 ([Fc-H] , 71%); 185.8
GC (Chiralsil-Dex CB): tR = 17.2 min. t = 17.7 min. Tcol-
S
+
+
+
20
D
15b
(
[Fc] , 53%); 366 ([M] , 100%); 367.1 ([M+H] , 24%).
= 180 °C). ½
aꢁ
¼ þ39:8 (c 0.15, CHCl ) for 99% ee.
umn
3
1
8
4
.2.3. 2-Hydroxymethyl-1-phenylthioferrocene 2
4.5.6. (R)-(ꢀ)-1-Indanol 7
ꢀ1
MP: 127 °C. IR (film, cm ):
m
= 690.4; 740.6; 817.7; 987.4;
GC (Chiralsil-Dex CB), t = 51.2 min. t = 51.9 min. T
column
=
R
S
1
20
1
006.7; 1076.2; 1107; 1249.7; 1481.2; 1581.5; 3244 (
): 1.51 (br s, OH); 4.27 (s, 5H, C
); 4.37(m, 2H, C ), 4.53 (m, 1H, CP + 2H, CH OH); 7.06 (m,
H, Ph); 7.17 (m, 2H, Ph). C NMR (75 MHz, CDCl ): d = 59.0;
0.1; 70.0; 75.6; 91.0; 96.2;125.2; 125.8; 128.9; 140.0. MS (EI;
m
P
OH).
H
80 °C for 7 min, after 135 °C for 5 min. ½
aꢁ
¼ ꢀ16 (c 0.1, CHCl3)
D
1
5b
NMR (300 MHz, CDCl
3
); 4.41(s,
for 99% ee.
1
3
7
H, C
P
P
2
13
3
4.5.7. (R)-(ꢀ)-1,2,3,4-Tetrahydronaphthalen-1-ol 8
GC (Chiralsil-Dex CB), t = 63.7 min. t = 65.0 min. T
S
R
column
=
+
+
20
m/z): 185.8 ([Fc] , 100%); 323.9 ([M] , 100%).
80 °C for 7 min, after 135 °C for 5 min. ½
aꢁ
¼ ꢀ28 (c 0.5, CHCl3)
D
1
5b
for 99% ee).
4
9
.3. General procedure for the synthesis of racemic acetates 1a–
a
4.5.8. (R)-(ꢀ)-Acenaphthenol 9
R S
Chiral HPLC: Chiracel OD-H column, t = 38.2 min; t = 41.5 min.
2
0
The acetates were synthesized by classical chemical acetyla-
Eluant (v,v): hexane/i-PrOH: 97/3; debit 0.5 mL/min; ½
aꢁ
¼ ꢀ1:4
D
1
3d
tions via the corresponding racemic alcohol (1 equiv), using
.5 equiv of anhydride acetic, 1.2 equiv of Et N, and a catalytic
3
(c 0.5, CHCl ) for 98.2% ee.
1
3
amount of 4-dimethylaminopyridine (0.1 equiv) in 4 ml of ether.
The acetates were obtained pure after standard work-up. The H
NMR spectra of these products were in good agreement with the
literature.
4.5.9. (RFc)-(+)-2-Hydroxymethyl-1-phenylthioferrocene 2
Chiral HPLC: Chiralpak AD column, t = 30.6 min, t = 34.1 min.
1
R
S
20
Eluant (v,v): hexane/EtOH: 97/3; debit: 1 mL/min. ½
a
ꢁ
¼ þ56 (c
D
1
8a
1, CH Cl ) for 99% ee).
2
2
4
1
.4. General procedure for the hydrolysis of racemic acetates
a–9a with Candida Antarctic- B lipase
4.5.10. (S)-(ꢀ)-1-(Phenylethyl) acetate 1a
GC (Chiralsil-Dex CB), t = 2.9 min. t = 3.2 min, T
S
R
column
= 140 °C.
2
0
15b
½
aꢁ
¼ ꢀ136 (c 0.1, CHCl
3
) for 99% ee.
D
A dry Schlenk tube was charged with 1 mmol of the racemic
acetate 1a–9a is dissolved in 3 mL of solvent before the addition
of 1 mmol of sodium carbonate and 50 mg of CAL-B. The suspen-
sion was stirred at 40 °C for the indicated time. The reaction mix-
ture was filtered on Celite and concentrated in vacuo. The acetate
formed and the remaining alcohol were separated by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate: 80/20) and
analyzed by chiral HPLC or GC.
4.5.11. (S)-(ꢀ)-1-(4-Methoxyphenyl)ethyl acetate 3a
GC (Chiralsil-Dex CB), t = 10.9 min. t = 12.1 min, T
S
R
23
column
=
=
2
0
135 °C. ½
a
ꢁ
¼ ꢀ13 (c 0.3, CHCl ) for 96% ee.
3
D
4.5.12. (S)-(ꢀ)-1-(4-Ethoxyphenyl)ethyl acetate 4a
GC (Chiralsil-Dex CB), t = 12.2 min. t = 13.4 min. T
S
R
column
2
0
24
155 °C. ½
a
ꢁ
¼ ꢀ110 (c 0.5, CHCl ) for 95% ee.
3
D

M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 23 (2012) 828–833
833
4
.5.13. (S)-(ꢀ)-1-(Naphthalen-2-yl) ethyl acetate 5a
Chlenov, M.; Di, L.; Fan, K.; Goljer, I.; He, Y.; Herold, D.; Kagan, M.; Kerns, E.;
Koehn, F.; Kraml, C.; Marathias, V.; Marquez, B.; Mcdonald, L.; Nogle, L.;
Petucci, C.; Schlingmann, G.; Tawa, G.; Tischler, M.; Williamson, R. T.;
Sutherland, A.; Watts, W.; Young, M. D.; Zhang, M. Y.; Zhang, Y.; Zhou, D.;
Ho, D. Chirality 2007, 19, 658–682.
GC (Chiralsil-Dex CB), t
S
= 8.6 min. t
R
= 8.9 min. Tcolumn = 170 °C.
20
15b
½
a
ꢁ
¼ ꢀ110:7 (c 0.12, CHCl
3
) for 98% ee.
D
5
.
.
(a) Stercher, H.; Faber, K. Synthesis 1997, 1–16; (b) Strauss, U. T.; Felfer, U. F.;
Faber, K. Tetrahedron: Asymmetry 1999, 10, 107–117; (c) Faber, K. Chem. Eur. J.
4
1
4
.5.14. (S)-(ꢀ)-1-(6-methoxynaphthalen-2-yl) ethyl acetate 6a
GC (Chiralsil-Dex CB), t
S
= 16.2 min. t
R
= 16.6 min. Tcolumn
=
=
2001, 7, 5005–5010; (d) Turner, N. J. Curr. Opin. Biotechnol. 2003, 14, 401–406;
2
D
0
15b
80 °C. ½
a
ꢁ
¼ ꢀ110 (c 0.1, CHCl
3
) for 99% ee.
(e) Kamal, A.; Azhar, M. A.; Krishnaji, T.; Malik, M. H.; Azeeza, S. Coord. Chem.
Rev. 2008, 569–592; (f) Merabet-Khelassi, M.; Vriamont, N.; Riant, O.; Aribi-
Zouioueche, L. Tetrahedron: Asymmetry 2011, 22, 1790–1796.
.5.15. (S)-(ꢀ)-2,3-dihydro-1H-inden-yl acetate 7a
GC (Chiralsil-Dex CB): t = 46.1 min. t = 46.9 min. Tcolumn
6
Boland, W.; Frossl, C.; Lorenz, M. Synthesis 1991, 1049–1072.
S
R
7. Wang, B.; Jiang, L.; Wang, J.; Ma, J.; Liu, M.; Yu, H. Tetrahedron: Asymmetry 2011,
2, 980–985.
8. (a) Moreno, J. C. M.; Samoza, A.; de Campo, C.; Llama, E. F.; Sinisterra, J. C. V. J.
Mol. Catal. A: Chem. 1995, 95, 179–192; (b) Steenkamp, L.; Brady, D. Enzyme
Microb. Technol. 2003, 32, 472–477.
2
D
0
2
8
0 °C for 7 min, after 135 °C for 5 min. ½
a
ꢁ
¼ ꢀ101 (c 0.8, CHCl
3
)
2
3
for 97% ee.
9
.
(a) Szatzker, G.; Moczar, I.; Kolonists, P.; Novak, L.; Huszthy, P.; Poppe, L.
Tetrahedron: Asymmetry 2004, 15, 2483–2490; (b) Shimizu, N.; Akita, H.;
Kawamata, T. Tetrahedron: Asymmetry 2002, 13, 2123–2131; (c) Bellezza, F.;
Cipiciani, A.; Riccib, G.; Ruzziconib, R. Tetrahedron 2005, 61, 8005–8012.
4
.5.16. (S)-(ꢀ)-1,2,3,4-Tetrahydronaphthalen-1-yl acetate 8a
GC (Chiralsil-Dex CB): t = 57.4 min. t = 58.6 min. Tcolumn
R
S
=
20
8
0 °C for 7 min, after 135 °C for 5 min. ½
a
ꢁ
¼ ꢀ107 (c 0.7, CHCl
3
)
D
2
3
for 99% ee.
10. (a) Shen, L.-L.; Jeong, J.-H. Tetrahedron: Asymmetry 2008, 19, 1647–1653; (b)
Petucci, C.; Di, L.; Mcconnell, O. Chirality 2007, 19, 701–705; (c) Kirschner, A.;
Lenger, P.; Bornscheuer, U. T. Tetrahedron: Asymmetry 2004, 15, 2871–2874.
4
.5.17. (S)-(ꢀ)-1-Acenaphthyl acetate 9a
R
Chiral HPLC: Chiracel OD-H column. t = 11.5 min; t = 12.8 min.
1
1. (a) Ghanem, A. Tetrahedron 2007, 63, 1721–1754; (b) Kazlauskas, R. J.; Weber,
H. K. Curr. Opin. Chem. Biol. 1998, 2, 121–126; (c) Carrea, G.; Riva, S. Angew.
Chem., Int. Ed. 2000, 39, 2226–2254; (d) Janes, L. E.; Kazlauskas, R. J.
Tetrahedron: Asymmetry 1997, 8, 3719–3733.
S
2
D
0
Eluant (v,v): hexane/i-PrOH: 99.3/0.7; debit 1 mL/min; ½
aꢁ
¼ ꢀ78
c 0.15, CHCl
3
) for 90% ee.1
3d
(
1
1
2. Rakels, J. L. L.; Straathof, A. J. J.; Heijneii, J. J. Tetrahedron: Asymmetry 1994, 5,
93–100.
3. (a) Kang, S. K.; Jeon, J.-H.; Yamaguchi, T.; Kim, J.-S.; Ko, B.-S. Tetrahedron:
Asymmetry 1995, 6, 2139–2142; (b) Igarashi, Y.; Otsutomo, S.; Harada, M.;
Nakano, S. Tetrahedron: Asymmetry 1997, 8, 2833–2837; (c) Doussot, J.; Guy, A.;
Garreau, R.; Falguières, A.; Ferroud, C. Tetrahedron: Asymmetry 2000, 11, 2259–
4
.5.18. (SFc)-(ꢀ)-2-Acetoxymethyl-1-phenylthioferrocene 2a
Chiral HPLC: Chiralpak AD column. t = 9.5 min, t = 12.8 min.
S
R
18a
Eluant (v,v): hexane/EtOH: 99/1; debit 1 mL/min.
2
4
262; (d) Aribi-Zouioueche, L.; Fiaud, J.-C. Tetrahedron: Lett. 2000, 41, 4085–
088; (e) Joly, S.; Nair, M. S. Tetrahedron: Asymmetry 2001, 12, 2283–2287; (f)
Acknowledgments
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1
(
2
b) Goto, M.; Kawasaki, M.; Kometani, T. J. mol. catal. B: Enzym. 2000, 9, 245–
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D. M. G. J. mol. catal. B: Enzym. 2011, 69, 42–46.
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Algerian ministry of education and scientific research (FNR
000 and PNR), Catholic University of Louvain, and FNRS are grate-
2
fully acknowledged for financial support of this work.
2
Tetrahedron Asymmetry 2006, 17, 797–800; (c) Merabet, M.; Melaïs, N.;
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