A green route to enantioenriched (S)-arylalkyl carbinols by deracemization via combined lipase alkaline-hydrolysis/Mitsunobu esterification

Article abstract of DOI:10.1016/j.tetasy.2013.01.020

Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates 1a-9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with esterification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic resolution (KR). The KR of racemic acetates 1a-9a via an enzymatic hydrolysis, with CAL-B lipase and Na₂CO₃, in non-aqueous media was optimized and gave high selectivities (E ? 200) at good conversions (C >49%) for all of the substrates studied. This method competes well with the traditional one performed in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in moderate to excellent enantiomeric excess 75% < ee < 99%, in acceptable isolated yields 70% < yield < 89%, and with some variations according to the acetate structure.

Full text of DOI:10.1016/j.tetasy.2013.01.020

Tetrahedron: Asymmetry 24 (2013) 290–296
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A green route to enantioenriched (S)-arylalkyl carbinols by deracemization
via combined lipase alkaline-hydrolysis/Mitsunobu esterification
Zahia Houiene a, Mounia Merabet-Khelassi a, Nassima Bouzemi a, Olivier Riant b,
,
⇑
Louisa Aribi-Zouioueche a,
⇑
a Ecocompatible Asymmetric Catalysis Laboratory (LCAE), Badji Mokhtar Annaba-University, B.P. 12, 23000 Annaba, Algeria
b Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université Catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur, 1, bte
3, 1348 Louvain La Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 December 2012
Accepted 28 January 2013
Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates
1a–9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with ester-
ification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic res-
olution (KR). The KR of racemic acetates 1a–9a via an enzymatic hydrolysis, with CAL-B lipase and
Na2CO3, in non-aqueous media was optimized and gave high selectivities (E ꢀ 200) at good conversions
(C >49%) for all of the substrates studied. This method competes well with the traditional one performed
in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in
moderate to excellent enantiomeric excess 75% < ee < 99%, in acceptable isolated yields 70% < yield < 89%,
and with some variations according to the acetate structure.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Over the last decade, efficient methods for deracemization5
have been developed and have led to access to single enantiomers
Biocatalysts, such as lipases are powerful catalytic tools for
modern synthetic chemistry and are recognized as important tools
for the enantioselective synthesis of functionalized substrates via
an enzymatic kinetic resolution1 under mild and eco-friendly con-
ditions.2 Kinetic resolution is one of the most useful methodologies
and can be carried out by transesterification in organic solvents3 or
hydrolysis in water,4 albeit with the main inconvenience of a lim-
itation in the theoretical yield of 50%.
with high enantiomeric purity and good chemical yields. The un-
wanted enantiomer recovered after the classical enzymatic kinetic
resolution can be recycled, via spontaneous racemization,6 direct
stereoinversion7 or by an oxido-reduction driven racemization of
the substrates.8
Among the deracemization methods, stereoinversion combined
with enzymatic kinetic resolution (Scheme 1) is one of the most
Retention
Fast
PR
SR
SS
PR
PS
SR
SS
P: Product
S: Substrate
Inversion
Symmetry plane
Slow
Theorical yield: 50% P + 50% S
Classical kinetic resolution
Theorical yield: 100% P
Deracemization
Scheme 1. Principle of deracemization via stereoinversion.
⇑
Corresponding authors. Fax: +32 (0)10474168 (O.R.); fax: +213 (0)38871712 (L.A.-Z.).
E-mail addresses: olivier.riant@uclouvain.be (O. Riant), louisa.zouioueche@univ-annaba.org (L. Aribi-Zouioueche).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.020

Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
291
important methods for the production of enantioenriched
alcohols.7
One equivalent of the racemic acetate, diluted in 1 mL of ether,
was hydrolysed in the presence of 150 mg of CAL-B (specific activ-
ity UA = 4500 U/g), in 6 mL of phosphate solution pH 7, at room
temperature for two days (Scheme 3, path A).
Both enantiomers of the residual acetates and alcohols formed
were recovered after filtration of the lipase and liquid–liquid
extraction. The course and selectivity of the enzymatic hydrolysis
were quantified by chiral chromatography, and the results are
summarized in Table 1.
The results from Table 1, demonstrate the important influence
of CAL-B on both selectivity and reactivity depending directly on
the structure of the acetates studied during the course of the enzy-
matic hydrolysis. The CAL-B displays (R)-enantiopreference since
the (R)-acetate was selectively hydrolysed in all cases.
This method uses an in situ transformation of the remaining
alcohol to the corresponding carboxylic ester with inversion of
configuration at the stereogenic centre. One of the most powerful
methods used so far is the Mitsunobu protocol9 since it uses an
activation of the alcohol and SN2 mechanism with a carboxylate
to yield the desired ester with clean stereoinversion.
Hydrolysis via an enzymatic kinetic resolution is modestly em-
ployed10 due to the difficulty of solubility of organic substrates in
aqueous media, which results in moderate yields and selectivi-
ties.11 Recently we have reported a novel approach for the enzy-
matic hydrolysis12 of various ester derivatives triggered by
simple carbonate salts that allowed the use of non-aqueous media
under mild conditions. This methodology of alkali-mediated enzy-
matic hydrolysis can be easily incorporated into a deracemization
process via stereoinversion with the Mitsunobu esterification. In a
previous investigation,7e deracemization through sequential enzy-
matic acylation/Mitsunobu inversion gave access to the (R)-ace-
tates of arylalkylcarbinols in good yields and with high
enantiomeric excesses.
Table 1
Enzymatic hydrolysis of acetates 1a–9a
Entry
Substratea
eeP (%)b (R)d
eeS (%)b (S)d
Cc (%)
Ec
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
>99
89
94
>99
>99
>99
75
89
98
6
44
83
50
53
51
46
49
49
6
ꢀ200
91
>150
37
ꢀ200
ꢀ200
200
In continuation of our investigations, we herein report an enan-
tiocomplementary pathway by integrating the alkali-mediated
enzymatic hydrolysis in non-aqueous media coupled to the Mitsun-
obu esterification, to give access to the corresponding (S)-acetates of
arylalkylcarbinols in a straightforward and practical manner.
87
>99
>99
>99
96
32
46
68
ꢀ200
98
a
2. Results and discussion
Reaction conditions: 1 mmol of racemic acetate, 12 mL of buffer phosphate pH
7, 2 mL Et2O, 150 mg of CAL-B, at room temperature for 2 days.
b
Measured by chiral chromatography, GC or HPLC (see Section 5).
The enzymatic hydrolysis of the secondary aromatic acetates
1a–9a (Scheme 2) was carried out with the Candida antarctica li-
pase fraction B immobilized on acrylic resin (CAL-B), following
two methods for comparison (Scheme 3).
c
Conversion and selectivity:14 C = eeS/eeP + ees; E = Ln[(1 ꢂ C)(1 ꢂ ee(S))]/
Ln[(1 ꢂ C)(1 + ee(S))].
d
Absolute configuration was determined by the sign of the specific rotation of
the isolated product with the literature (see Section 5).
Path A
CAL-B
The enzymatic hydrolysis was performed according to the con-
ventional protocol (phosphate buffer pH 7) and showed a great
diversity of results, with reactivities in the range of 6% < C < 53%
and selectivities ranging 37 < E ꢁ 200, for various acetate struc-
tures. The best results were obtained with the acetates 1a, 2a,
3a, 5a, 6a and 9a (entries 1, 2, 3, 5, 6 and 9), with high selectivities
91 < E ꢁ 200 and conversions 46% < C < 52%. The comparison be-
tween the results obtained with 2a and 3a and 1a, shows that
the substitution of the para-position on the aromatic ring with
methoxy- and ethoxy-groups, respectively, led to a decrease in
the selectivity factor E ꢀ 200 to E = 91 (entry 1 vs 2) with a slight
improvement of the conversion. However, the presence of a polar
moiety on the naphthyl ring of structure 6a compared to 5a, did
not have any influence on the reactivity or on the selectivity (entry
5 vs 6).
R1
R1
H
H
R1
buffer phosphate,
pH=7 / Et2O, tr, 2 days
+
Ar
OAc
Ar
OH
Ar
OAc
(R)
(S)
(RS)
CAL-B/Na2CO3
toluene; 40°C,
Path B
3 days
Scheme 3. Enzymatic hydrolysis.
The first method uses the conventional hydrolysis in a biphasic
medium and the second uses our protocol involving sodium car-
bonate in organic solvent. We have examined the selectivity and
the reactivity obtained by each hydrolysis method.
2.1. Enzymatic hydrolysis in biphasic media
When a monocyclic aryl ring was replaced with an a-naphthyl
4a, the reactivity of the lipase was preserved, albeit with a strong
decrease in the selectivity (C = 46%; E = 37; entry 4). However, in
the case of isomer 5a, the lipase gave excellent selectivity while
The enzymatic hydrolysis of racemic acetates 1a–9a was per-
formed in a biphasic system: phosphate buffer solution/Et2O (v/
v) (6/1) pH 7, according to the classical protocols.13
OAc
OAc
OAc
OAc
OAc
R
(n)
R
1a
( )- : R=H
5a
7a
( )-
( )-8a: n=1
( )-9a: n=2
( )- : R=H
( )-4a
2a
( )- : R=OMe
( )-6a: R=OMe
( )-3a: R=OEt
Scheme 2. Substrate models.

292
Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
keeping excellent conversion C = 49% and E ꢀ 200 (entry 5). Low to
moderate reactivity was observed with cyclic substrates 7a and 8a,
albeit with a high selectivity for 7a (entries 7 and 8). Finally, an
excellent selectivity was observed for the flat cyclic substrate 9a,
with only a slight decrease in the overall reactivity (entry 8).
This large diversity of results and the lack of obvious structure–
activity relationship could be attributed to the structure of the sub-
strates, and also to their moderate solubility in the aqueous media.
3. Deracemization through a selective alkaline-enzymatic
hydrolysis/Mitsunobu esterification sequence
The reaction mixture containing the (S)-remaining acetate and
the (R)-recovered alcohol from hydrolysis reaction underwent
the Mitsunobu reaction to yield the (S)-acetate (Scheme 4).
Acetates 1a–9a were hydrolysed according to the conditions
established below. After three days at 40 °C, the enzyme was fil-
tered. The enantiomeric excesses of the remaining acetate and
the recovered alcohol were evaluated by chiral chromatography
(GC or HPLC). Next, 1.2 equiv of triphenyl phosphine, and 1.2 equiv
of acetic acid were added directly to the filtrate. The diisopropyl-
azodicarboxylate (DIAD) (1.2 equiv) was added slowly at 0 °C, to
convert the (R)-alcohol into the (S)-acetate. The desired acetate
was then isolated after standard work-up and purification by sil-
ica-gel column chromatography. The enantiomeric purity was
determined by chiral chromatography (GC or HPLC), and the abso-
lute configuration was determined by the sign of the specific rota-
tion compared to the literature data. The results are shown in
Table 3.
2.2. Enzymatic-alkaline hydrolysis in non-aqueous media
We carried out the enzymatic-alkaline hydrolysis of acetates
1a–9a in toluene, according to the literature.12 The hydrolysis reac-
tion was carried out in 1 mmol of substrate (Scheme 3, path B),
3 mL of toluene, in the presence of 50 mg of CAL-B, for three days
at 40 °C. We checked the influence of the amount of sodium car-
bonate (0.5 and 1 equiv) in order to assess the generality, flexibility
and reproducibility of our method on various substrates (Table 2).
The carbonate promoted hydrolysis presented in Table
2
showed good to high reactivities and selectivities
(42.5% < C < 50%, E >150) within the range of the acetates studied.
We also saw that a stoichiometric equivalent of sodium carbon-
ate gave the best conversions, while keeping the best selectivities E
>200 at optimal conversions in all cases.
Recapitulative histograms of the two sets of experiments
(Fig. 1) allow a comparative illustration (conversion C and selectiv-
ity E) between both methods of enzymatic acetate hydrolysis. It is
obvious from both figures that our new method performs better
than the conventional hydrolytic method in aqueous media, within
the range of substrates studied.
The alkaline-enzymatic hydrolysis using Na2CO3 is thus a very
attractive method due to the high reactivities and selectivities re-
corded. It also facilitates the work-up procedure and avoids the
use of liquid–liquid extraction, thus providing an economy of sol-
vent and optimization of the isolated chemical yields. These advan-
tages of our non-conventional methodology make it an ideal
candidate to be combined with the Mitsunobu esterification proto-
col (Fig. 2), in order to establish deracemization via stereoinver-
sion. The two steps can be combined through a simple filtration
of the enzyme, and addition of the Mitsunobu reagents immedi-
ately to the reaction mixture without any prior work-up.
The results detailed in Table 3 show that the (S)-acetates 1a–9a
were obtained quantitatively in moderate to high enantiomeric ex-
cesses 57% < ee < 99%. We have noted in some cases some notable
loss in the enantiomeric purity of the acetates, whereas the starting
materials present excellent enantiomeric excesses 96% < eeP < 99%.
This decrease was recorded after the Mitsunobu esterification. The
(S)-acetates 1a, 4a and 7a were recovered with clean stereoinver-
sion of the (R)-alcohol obtained after hydrolysis with ee >99% (en-
tries 1, 4 and 7); in these cases the enantiomeric purities of the
initial alcohols were conserved through the (S)-acetates, which
were recovered in excellent enantiomeric purity ee >99% and good
isolated chemical yields (70–89%). However, for alcohols 5, 8 and 9
(98% < ee < 99% after hydrolysis), partial racemization occurred
during the Mitsunobu reaction to yield the corresponding (S)-ace-
tates with an overall decrease of the enantiomeric excesses of
approximately 10% (entries 5, 8 and 9). This effect was even more
important with substrates 2a, 3a and 6a since the enantiomeric ex-
cesses of the remaining acetates after Mitsunobu esterification de-
creased to 57% < ee < 65% (entries 2, 3 and 6). This shows that these
alcohols underwent the Mitsunobu reaction with almost full
racemization.
Table 2
Optimization of the enzymatic alkaline-hydrolysis in non aqueous media
Entry
Substratea
Amount of Na2CO3 (mmol)
ees (%)b (S)e
eep (%)b (R)e
Cc (%)
Ec
1
2
3
4
5
6
7
8
1a
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
0.5
1
>99
83
>99
95
>99
96
73
>99
99.5
93
98
>99
97
50
45.5
52
49
50
50
42.5
50
ꢀ200
ꢀ200
144
2a
3a
4a
5a
6a
7a
8a
9a
ꢀ200
ꢀ200
ꢀ200
ꢀ200
ꢀ200
ꢀ200
ꢀ200
NDd
>99
>99
>99
98
>99
84
9
46
10
11
12
13
14
15
16
17
18
98
50
NDd
93
NDd
96
NDd
49
>150
NDd
>99
NDd
98
NDd
>99
NDd
>99
>99
>99
NDd
50
NDd
ꢀ200
NDd
ꢀ200
ꢀ200
ꢀ200
NDd
50
0.5
1
89
>99
47.5
50
a
b
c
Reaction conditions: 2 mmol of racemic acetate, appropriate amount of Na2CO3, 6 mL of toluene, 50 mg of CAL-B, 40 °C for 3 days.
Measured by chiral chromatography, GC or HPLC (see Section 5).
Conversion and selectivity:14 C = eeS/eeP + ees; E = Ln[(1 ꢂ C)(1 ꢂ ee(S))]/Ln[(1 ꢂ C)(1 + ee(S))].
d
e
Not determined.
Absolute configuration was determined by the comparison of sign of the specific rotation of the isolated product with the literature (see Section 5).

Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
293
Figure 1. Comparison between the efficiency of the alkaline hydrolysis and the conventional one.
Conventional
Drying the organic layers
Moderate isolated Yield
Filtration
Filtration
Conventional
Concentration in vacuo
Liquid-Liquid Extraction
1a-9a
(S)-
+
(S)-1a-9a
Mitsunobu
(RS)-
(R)-1-9
1a-9a
Only filtration
Hydrolysis
75%<ee<99%
Non Conventional
Good isolated Yield
70%<yield<89%
Non Conventional
Figure 2. Comparison between the two processes.
Misunobu esterification, under the same conditions, where a race-
mization phenomenon occurred during the enantioselective syn-
thesis of (R)-acetates.7e
R1
R1
Ar
CAL-B/Na2CO3
toluene; 40°C
H
R1
H
+
Ar
OH
Ar
OAc
OAc
In our case, we observed a strong decrease in the enantiose-
(R)
(S)
lectivity for the substrates bearing
a strong electrodonating
(RS)
group on the aryl ring. Recently, a similar observation was re-
ported regarding a racemization occurring over the course of
an enantioselective synthesis via Mitsunobu substitution.15 This
loss of enantiomeric purity may arise from a competitive substi-
tution process that proceeds via an attack of the carbocation
intermediate, via a non-stereoselective (SN1) process to generate
the racemic product,16 which in our case will give rise to an
overall decrease in the enantiomeric excess of recovered (S)-
acetates.
PPh3; DIAD
AcOH
Scheme 4. Deracemization via a combined enzymatic-alkaline hydrolysis/Mitsun-
obu inversion.
Similar observations were also noted in our previous investiga-
tions regarding deracemization through enzymatic acetylation/

294
Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
Table 3
Deracemization via a combination of the alkaline enzymatic hydrolysis with Mitsunobu inversion
Entry
Substratea
Enzymatic alkaline hydrolysisc
ees (%)b (S)-remaining acetate eep (%)b (R)-recovered alcohol
Mitsunobu inversion
Ec
ee (%)b (S)-acetate
Yieldd (%)
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
>99
95
96
>99
98
93
>99
98
>99
>99
98
97
>99
98
96
>99
>99
>99
>500
>300
>200
>500
>500
>150
>500
>500
>500
>99
57
60
>99
92
65
>99
90
90
70
72
89
82
87
77
89
81
74
a
b
c
Reaction conditions: 2 mmol of racemic acetate.
Measured by chiral chromatography, GC or HPLC (see Section 5).
Conversion and selectivity:14 C = eeS/eeP + ees; E = Ln[(1 ꢂ C)(1 ꢂ ee(S))]/Ln[(1 ꢂ C)(1 + ee(S))].
d
Isolated yield.
5.3. General procedure for the conventional hydrolysis of
4. Conclusion
racemic acetates 1a–9a with Candida antarctica-B lipase
We have prepared (S)-arylalkylcarbinol acetates 1a–9a through
deracemization via alkaline-hydrolysis catalysed by CAL-B lipase
combined with Mitsunobu esterification. The hydrolysis using
CAL-B in the presence of Na2CO3 gave high selectivities and reactiv-
ities C >49% for all of the studied substrates, and we have shown that
this method is more advantageous than the traditional one in an
aqueous media buffer. This process reduces the number of steps
and gives a more practical experimental protocol. After optimization
of the amount of the sodium carbonate used, this hydrolysis path-
way was combined with Mitsunobu esterification after simple filtra-
tion. The recovered (S)-acetates after the stereoinversion protocol
were isolated in excellent enantiomeric purity ee >99% for 1a, 4a
and 7a, to good ee >99% for 5a, 8a and 9a and moderate ee >57%
for 2a, 3a and 6a. For these three cases, we observed almost full race-
mization during the nucleophilic substitution reaction due to the
presence of an electron donating substituent on the aromatic ring.
At first, 2 mmol of racemic acetates 1a–9a was dissolved in 2–
3 mL of ether and added to 12 mL of phosphate buffer pH 7. Next,
300 mg of CAL-B (UA = 4500 U) was added. The suspension was
stirred at room temperature for two days. The reaction mixture
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
analysed by chiral HPLC or GC.
5.4. General procedure for the alkaline-hydrolysis of racemic
acetates 1a–9a with Candida antarctica-B lipase
A dry Schlenk tube was charged with 1 mmol of racemic ace-
tates 1a–9a, which was dissolved in 3 mL of solvent before the
addition of 1 mmol of sodium carbonate and 50 mg of CAL-B. The
suspension was stirred at 40 °C for the indicated time. The reaction
mixture was filtered on Celite and concentrated in vacuo. The ace-
tate formed and the remaining alcohol were separated by flash
chromatography on silica gel (petroleum ether/ethyl acetate: 80/
20) and analysed by chiral HPLC or GC.
5. Experimental
5.1. General
NMR spectra were performed with Bruker spectrometers
(300 MHz for 1H, 75 MHz for 13C). Chemical shifts were reported
in d ppm from tetramethylsilane with the solvent resonance as
internal standard for 1H NMR and chloroform-d (d 77.0 ppm) for
13C NMR. The enantiomeric excesses were measured by gas chro-
matography (ThermoFinnigan Trace GC) equipped with an auto-
matic autosampler and using a CHIRALSIL-DEX CB column (25 m;
5.5. General procedure for the esterification under Mitsunobu
conditions
To the filtrate recovered after the enzymatic-alkaline hydroly-
sis, 1.2 equiv of AcOH and 1.2 equiv of PPh3 were added; followed
by the slow addition of 1.2 equiv of DIAD, at 0 °C. The reaction mix-
ture was stirred vigorously at room temperature for 24 h. The sol-
vent was removed under reduced pressure and the crude product
was purified by silica-gel column chromatography using petro-
leum ether/ethyl acetate (80/20).
0.25 mm; 0.25 lm), or by a chiral stationary phase HPLC on Chiral-
cel-ODH column. Retention times are reported in minutes. Optical
rotations were determined using a Perkin–Elmer 241 Polarimeter
at room temperature using a cell of 1 dm length at 589 nm.
5.6. Chiral GC analysis and/or chiral HPLC analysis
5.2. General procedure for the synthesis of racemic acetates 1a–
9a
The absolute configurations of all chiral compounds (isolated
after chromatography) were determined by polarimetry by com-
parison with the literature. The conditions for the analysis of alco-
hols (R)-1–9 and acetates (S)-1a–9a are reported below.
The acetates were synthesized by chemical acetylation from the
corresponding racemic alcohol (1 equiv), using 1.5 equiv of acetic
anhydride, 1.2 equiv of Et3N and a catalytic amount of 4-dimithyla-
minopyridine (0.1 equiv) diluted in ether. The acetates were ob-
tained with enough purity after standard work up. The 1H NMR
spectra of these products were in good agreement with the
literature.
5.6.1. (R)-(+)-1-Phenylethanol 1
GC (Chiralsil-Dex CB,): tR = 3.9 min, tS = 4.1 min (Tcol-
umn = 140 °C, flow 1.2 mL/min).

Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
295
5.6.2. (R)-(+)-1-(4-Methoxyphenyl) ethanol 2
GC (Chiralsil-Dex CB): tR = 12.7 min, tS = 13.5 min (Tcolumn
135 °C, flow 1.2 mL/min).
min; ½a 2D0
ꢃ
¼ ꢂ79:4 (c 0.2, CHCl3) for 90% ee, {Lit. [
a
]
D = ꢂ85.2 (c
=
=
2.4, CHCl3); 99% ee (S)}.13a
5.6.17. (S)-(ꢂ)-2,3-Dihydro-1H-inden-yl acetate 8a
5.6.3. (R)-(+)-1-(4-Ethoxyphenyl) ethanol 3
GC (Chiralsil-Dex CB): tR = 13.1 min, tS = 13.9 min (Tcolumn
155 °C, flow 1.2 mL/min).
GC (Chiralsil-Dex CB): tS = 46.1 min, tR = 46.9 min (Tcolumn =
80 °C for 7 min, after 135 °C for 5 min, flow 1.2 mL/min). ½a D20
ꢃ
ꢂ100 (c 0.5, CHCl3) for 90% ee, {Lit. [
a]D = +85 (c 1, CHCl3) for
80% ee (R)}.17
5.6.4. (R)-(+)-1-(Naphthalene-1-yl) ethanol 4
Chiral HPLC: Chiracel OD-H column, tR = 20.05 min,
tS = 28.90 min. Eluant (v,v): hexane/i-PrOH: 90/10; flow 0.5 mL/min.
5.6.18. (S)-(ꢂ)-1,2,3,4-Tetrahydronaphthalen-1-yl acetate 9a
GC (Chiralsil-Dex CB): tR = 57.4 min, tS = 58.6 min (Tcolumn
80 °C for 7 min, after 135 °C for 5 min, flow 1.2 mL/min).
=
5.6.5. (R)-(+)-1-(2-Naphthyl) ethanol 5
½
a 2D0
ꢃ
¼ ꢂ97:5 (c 0.5, CHCl3) for 90% ee, {Lit. [
a]D = +105 (c 1, CHCl3)
GC (Chiralsil-Dex CB): tR = 10.2 min, tS = 10.5 min (Tcolumn
170 °C, flow 1.2 mL/min).
=
=
for 92% ee (R)}.17
Acknowledgments
5.6.6. (R)-(+)-1-(6-Methoxynaphthalen-2-yl) ethanol 6
GC (Chiralsil-Dex CB): tR = 17.2 min, tS = 17.7 min (Tcolumn
180 °C, flow 1.2 mL/min).
Algerian Ministry of education and scientific research (FNR
2000 and PNR), Université catholique de Louvain and FNRS are
gratefully acknowledged for their financial support of this work.
5.6.7. (R)-(ꢂ)-Acenaphthenol 7
Chiral HPLC: Chiracel OD-H column, tR = 28.80 min,
tS = 34.67 min. Eluant (v,v): hexane/i-PrOH: 95/5; flow 0.5 mL/min.
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5.6.8. (R)-(ꢂ)-1-Indanol 8
GC (Chiralsil-Dex CB), tR = 51.2 min, tS = 51.9 min (Tcolumn
80 °C for 7 min, after 135 °C for 5 min, flow 1.2 mL/min).
=
=
5.6.9. (R)-(ꢂ)-1,2,3,4-Tetrahydronaphthalen-1-ol 9
GC (Chiralsil-Dex CB), tS = 63.7 min, tR = 65.0 min (Tcolumn
80 °C for 7 min, then 135 °C for 5 min, flow 1.2 mL/min).
5.6.10. (S)-(ꢂ)-1-(Phenylethyl) acetate 1a
GC (Chiralsil-Dex CB), tS = 2.9 min, tR = 3.2 min (Tcolumn = 140 °C,
flow 1.2 mL/min). ½a D20
¼ ꢂ136 (c 0.1, CHCl3) for 99% ee, {Lit.
ꢃ
[a]
D = +135.9 (c 1, CHCl3) for 99% ee (R)].17
5.6.11. (S)-(ꢂ)-1-(4-Methoxyphenyl)ethyl acetate 2a
GC (Chiralsil-Dex CB), tS = 10.9 min, tR = 12.1 min (Tcolumn
=
135 °C, flow 1.2 mL/min). ½a D20
ꢃ
¼ ꢂ8 (c 0.2, CHCl3) for 57% ee, {Lit.
[a]
D = +11.4 (c 1.2, CHCl3) for 84% ee (R)].17
5.6.12. (S)-(ꢂ)-1-(4-Ethoxyphenyl)ethyl acetate 3a
GC (Chiralsil-Dex CB), tS = 12.2 min, tR = 13.4 min (Tcolumn
=
155 °C, flow 1.2 mL/min). ½a D20
ꢃ
¼ ꢂ70:8 (c 0.5, CHCl3) for 60% ee,
{Lit. [
a]
D = ꢂ113.1 (c 0.9, CHCl3) for >85% ee (S)}.18
5.6.13. (S)-(ꢂ)-1-(Naphthalen-1-yl) ethyl acetate 4a
Chiral HPLC: Chiracel OD-H column, tR = 9.87 min,
tS = 13.50 min. Eluant (v,v): hexane/i-PrOH: 90/10; flow 0.5 mL/
min. ½a 2D0
ꢃ
¼ ꢂ46:5 (c 0.2, CHCl3) for 99% ee, {Lit. [
a]D = +49.5 (c 1,
CHCl3) for 99% ee (R)}.17
5.6.14. (S)-(ꢂ)-1-(Naphthalen-2-yl) ethyl acetate 5a
GC (Chiralsil-Dex CB), tS = 8.6 min, tR = 8.9 min (Tcolumn = 170 °C,
flow 1.2 mL/min). ½a D20
¼ ꢂ104 (c 0.2, CHCl3) for 92% ee, {Lit.
ꢃ
[a]
D = +110.2 (c 1, CHCl3) for 99% ee (R)}.17
5.6.15. (S)-(ꢂ)-1-(6-Methoxynaphthalen-2-yl) ethyl acetate 6a
GC (Chiralsil-Dex CB), tS = 16.2 min, tR = 16.6 min (Tcolumn
=
180 °C, flow 1.2 mL/min). ½a D20
¼ ꢂ64:5 (c 0.3, CHCl3) for 65% ee,
ꢃ
{Lit. [a]
D = +110 (c 1, EtOH) for 99% ee (R)}.17
5.6.16. (S)-(ꢂ)-1-Acenaphthyl acetate 7a
12. Merabet-Khelassi, M.; Houiene, Z.; Aribi-Zouioueche, L.; Riant, O. Tetrahedron:
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Chiral HPLC: Chiracel OD-H column. tS = 11.88 min,
tR = 12.52 min. Eluant (v,v): hexane/i-PrOH: 95/5; flow 0.5 mL/

296
Z. Houiene et al. / Tetrahedron: Asymmetry 24 (2013) 290–296
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