Easy kinetic resolution of some β-amino alcohols by Candida antarctica lipase B catalyzed hydrolysis in organic media

Article abstract of DOI:10.1016/j.tetasy.2016.10.003

Herein, we present an easy and eco-friendly pathway to obtain some enantiomerically enriched β-amino alcohols using essentially as β-blockers. The enzymatic hydrolysis is conducted in hydrophobic organic media, assisted by sodium carbonate and CAL-B. We describe a new and effective procedure in terms of the chemo- and enantioselectivity, which allows for the formation of both enantiomers: the 2-acetamido-1-arylacetates and 2-acetamido-1-arylethanols were obtained with high ee values (up to >99%), while the selectivities reached E >200. The obtained results show a high CAL-B affinity toward the deacylation of the 2-acetamido-1-arylacetates compared to the acylation one. The structure of the 2-acetamido-1-arylacetates had a significant influence on both reactivity and selectivity of the CAL-B catalyzed deacylation. A multigram scale O-deacylation of racemic 2-acetamido-1-phenylacetate has been carried out, giving access both enantiomers with high enantiomeric purity and good isolated chemical yields.

Full text of DOI:10.1016/j.tetasy.2016.10.003

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Easy kinetic resolution of some b-amino alcohols by Candida
antarctica lipase B catalyzed hydrolysis in organic media
Affef Alalla a, Mounia Merabet-Khelassi 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, Pl. 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:
Herein, we present an easy and eco-friendly pathway to obtain some enantiomerically enriched b-amino
alcohols using essentially as b-blockers. The enzymatic hydrolysis is conducted in hydrophobic organic
media, assisted by sodium carbonate and CAL-B. We describe a new and effective procedure in terms
of the chemo- and enantioselectivity, which allows for the formation of both enantiomers: the 2-aceta-
mido-1-arylacetates and 2-acetamido-1-arylethanols were obtained with high ee values (up to >99%),
while the selectivities reached E >200. The obtained results show a high CAL-B affinity toward the dea-
cylation of the 2-acetamido-1-arylacetates compared to the acylation one. The structure of the 2-aceta-
mido-1-arylacetates had a significant influence on both reactivity and selectivity of the CAL-B catalyzed
deacylation. A multigram scale O-deacylation of racemic 2-acetamido-1-phenylacetate has been carried
out, giving access both enantiomers with high enantiomeric purity and good isolated chemical yields.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 27 September 2016
Revised 3 October 2016
Accepted 5 October 2016
Available online xxxx
1. Introduction
OH
OH
O
N
H
NH2
X
Y
NH2
Enantiomerically pure amino alcohols are an important class of
compounds widely used in medicinal chemistry1 and asymmetric
synthesis;2 they are key building blocks for the synthesis of biolog-
ically and pharmacologically active compounds. It is widely
reported that the 2-amino-1-aryl alcohol is a common structural
motif in biologically active compounds: adrenaline, b-adrenergic
blockers, anti-asthma drugs, amphenicol antibiotics, and several
bioactive natural products. The structure–activity relationship for
ligands interacting with adrenergic receptors showed that the
essential structural features for direct activity on the receptors
were the 2-amino-1-phenylethanol skeleton, the substituent on
the phenyl ring and the substituent on the amino group (Fig. 1).3
Thus, the design of new eco-compatible access protocols for
enantiomerically pure vicinal amino alcohols continues to
grow,4–6 while obeying some greener criteria such as the ease of
use, atom economy and energy. One of the most effective target
protocols is biocatalysis, which is a sustainable and clean way to
get them properly by protection/deprotection of bi- and/or poly-
functional molecules and thus with high chemo-, regio- and stere-
oselectivity at high TON (turnover number).7 The strict constraints
in pharmaceutical and synthetic applications, require that the
OH
MeO
adrenanline derivatives
Figure 1. Some b-amino alcohols within biological activity.
tembamide derivative
propanolol
chiral amino alcohols have high enantiomeric purity, which in turn
requires highly selective asymmetric syntheses or more easily sup-
ported by biocatalytic modes.
One of these modes is the enzymatic kinetic resolution of race-
mic compounds, a widely used technique that presents a green
way for the preparation of single-isomer chiral drugs.8 Hydrolytic
enzymes are more frequently used in different industries,9 espe-
cially lipases for the hydrolysis or transesterification reactions.10
Lipases in particular have proven to be excellent biocatalysts for
the resolution of alcohols and amines.11 Lipases (triacylglycerol
acyl hydrolases, EC.3.1.1.3) are one of the most efficient biotools
to hydrolyze selectively acylated amino alcohols.12
An analysis of the literature data showed that the lipase-
catalyzed acylation reactions are the most recently studied;13
generally it is reported that lipases catalyze, chemoselectively,
the N- or O-acylation of amino alcohols, depending on the amino
⇑
Corresponding author. Tel.: +213 (0)774037059; fax: +213 (0)38871712.
E-mail address: louisa.zouioueche@univ-annaba.dz (L. Aribi-Zouioueche).
http://dx.doi.org/10.1016/j.tetasy.2016.10.003
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alalla, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.003

2
A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
alcohol structure, the solvent, the acyl donor and the nature of
lipase used as biocatalyst.14 For instance, Kanerva et al. have
reported an effective acylation and deacylation via alcoholysis of
2-amino-1-phenylethanol derivatives using lipase PS and CCL.15
On the other hand, the enzymatic deacylation via hydrolysis
methodology has scarcely been reported for the preparation of
optically active 2-amino cycloalkanols and 1,2-aminoindanols.16
Honig et al. have reported the hydrolysis of 20-substituted cyclo-
hexylbutanoates by different commercially available lipases17
and Takada et al. described enzymatic hydrolysis for the resolution
of ( )-trans-2-substituted aminocyclohexanol by Pseudomonas
cepacia lipase.18 More recently, CAL-A has been successfully
employed for the N-acylation of some b-aminoesters and the
N-deacylation of their corresponding b-amidoesters.19
From the literature data, it can be seen that the conventional
enzymatic hydrolysis protocols in biphasic media (water, buffer
or water saturated) are limited by disadvantages including the
decrease of the lipase’s enantioselectivity due to the difficulty of
controlling the pH value following the release of acetic acid of
the aqueous solution, during the hydrolysis procedure.20 Major
constraints of aqueous media also include a slow solubility of the
substrate and the liquid–liquid extraction step. Recently, we devel-
oped a highly enantioselective method for the deacylation of a set
of benzylic acetates in a non-aqueous media catalyzed by CAL-B in
the presence of sodium carbonate.21 To extend the scope of this
methodology, we have employed this procedure for the selective
deprotection of N,O-protected amino alcohols.
chemoselective enzyme that preferentially catalyzes O-acylation
over N-acylation.22
2.1. Enzymatic acylation of (R,S)-2-acetamide-1-phenylethanol
2a versus alkaline-enzymatic deacylation of 3a and 4a
We examined the kinetic resolution catalyzed by CAL-B, the
acylation and the hydrolysis, to compare the lipase performance
using two complementary approaches (Scheme 1), and using 2-
amino-1-phenyl ethanol as a model substrate. The mono-acyl
derivative was prepared according to
a recently described
method23 (Scheme 1i) and the bi-protected derivative by conven-
tional organic methods (Scheme 1ii–iii).
We first carried out the enzymatic acylation reactions of the N-
monoacylated substrate 2a. Reactions were performed on 1 mmol
of (RS)-2a with 3 mmol of acyl donor in the presence of a catalytic
amount of lipase (CAL-B) in 3 mL of toluene (logP = 2.5) or diethyl
ether (logP = 0.85) (Scheme 1iv). All reaction media were subjected
to magnetic stirring at 40 °C for 24 h and the results are presented
in Table 1.
The hydrolysis reactions were performed with an equimolecu-
lar ratio (1:1) of the protected amino alcohol (RS)-2a and Na2CO3,
diluted in 3 mL of toluene, in the presence of 50 mg of CAL-B.
The progress of the reactions is monitored by TLC. After 3 days of
magnetic stirring at 40 °C, no progress was recorded. This indicated
that CAL-B did not have the power to cleave the amide function
under these conditions (Scheme 1vi).
We thus turned our attention to the O-deacylation of racemic
N-protected-2-amino-1-phenylethyl acetates (Scheme 1v). The
same experimental protocol was followed, and we studied the
influence of the steric effect of the N-protecting group on the reac-
tivity and selectivity of the enzymatic alkaline-hydrolysis of race-
mic 3a and 4a. The outcome of the reactions was monitored by
chiral HPLC (Table 1).
Herein, the hydrolysis by alkaline-enzymatic kinetic resolu-
tion21a of N,O-protected amino alcohols in organic media is
carried out. The efficiency of this process in terms of chemo- and
enantioselectivity for the preparation of enantiomerically
enriched 2-amino-1-arylethanols is described. Some aspects of
the process are taken into consideration for developing a green
and easy pathway via enzymatic hydrolysis in non-aqueous
organic media in the presence of sodium carbonate.
The results detailed in Table 1, show the low reactivity of CAL-B
during the acylation of 2-acetamide-1-phenylethanol 2a, with both
acylating agents (entries 1–5). A very low selectivity was achieved
for the kinetic resolutions carried out in Et2O (E = 13, entry 1).
Increasing the amount of enzyme slightly improved the conversion
of the substrate, with both tested solvents (entry 1 vs 3 and entry 2
vs 4). Significant results in term of reactivity and selectivity were
recorded with the hydrolysis of N,O-protected derivatives 3a–4a
catalyzed by CAL-B (50 mg) with sodium carbonate (1 mmol) in
3 mL toluene. Under these conditions, high chemo- and enantiose-
lectivity were successfully achieved.
2. Results and discussion
The amino alcohols selected herein are commercially available
or easily synthesized from readily available starting material. The
selected enzyme was the lipase from Candida antarctica fraction
B (CAL-B), immobilized on an acrylic resin, with a specific activity
>10,000 U/g; this choice was based on our previously investiga-
tions which show that only this lipase, present high reactivity
and high enantioselectivities for this technique.21a Furthermore, a
recent study shows that Candida antarctica lipase
B
is
a
OH
OH
OAc
NH2
NHAc
2a
NHGP
CAL-B deacylation
N,O-protection
N-acylation
X
(RS)-
(ii) or (iii) a)-, b)-
(i)
(RS)-1a
(vi)
3a
(RS)-
GP=Ac
(iv)
(v)
(RS)-4a
GP=Cbz
CAL-B deacylation
CAL-B acylation
OH
H
OAc
H
OH
OAc
N
N
NHAc
NHAc
GP
GP
+
+
3a
(R)- or (R)-
4a
3a
(S)-
2a
5a
(S)-
(S)-
GP=Ac
GP=Cbz
2a
(R)-
(i) Isopropenyl acetate, free solvent. (ii) Acetic anhydride, CH2Cl2. (iii)-a) NaOH 1M, CH2Cl2, CbzCl in toluene. (iii)-b) CH2Cl2, Et3N, Ac2O,
DMAP. (iv) CAL-B, acyl donor, solvent, 24h, 40°C. (v) CAL-B, Na2CO3, toluene, 72h, 40°C.
Scheme 1. Complementary approaches for enzymatic kinetic resolution.
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A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Lipase acylation of 2a versus deacylation of 3a–4a
d
d
Entry
Substrate
Nucleophile
CAL-B (mg)
Solvent
ees (%) (Conf.)h
eep (%) (Conf.)h
ce (%)
Ef
1a
2a
20
20
50
50
50
Et2O
Toluene
Et2O
Toluene
Et2O
3 (R)
2 (R)
8 (R)
9 (R)
1 (R)
86 (S)
99 (S)
90 (S)
97 (S)
30 (S)
3
2
8
8
3
13
OH
NHAc
200
21
72
2
Isopropenyl acetate
Vinyl acetate
3a
4a
5a
2a
6b
7c
50
50
Toluene
Toluene
57 (R)
89 (S)
39
50
>200
>200
OAc
99 (47)g (R)
98 (43)g (S)
NHAc
3a
OAc
Na2CO3
NHCbz
8c
50
Toluene
90 (45)g (R)
99 (48)g (S)
48
>200
4a
a
b
c
1 mmol of (RS)-2a, 3 mmol of acyl donor in 3 mL of solvent in the presence of CAL-B for 24 h.
1 mmol of (RS)-3a, 1 mmol of Na2CO3 in 3 mL of toluene, 50 mg of CAL-B, for 24 h.
1 mmol of (RS)-3a, 1 mmol of Na2CO3 in 3 mL of toluene, 50 mg of CAL-B, for 72 h.
Measured by chiral HPLC.
d
e
f
Conversion:24 c = ees/eep + ees.
Selectivity:24 E = ln[(1 ꢀ C)(1 ꢀ ees)]/ln[(1 ꢀ C)(1 + ees)].
g
h
Isolated yields.
Absolute configuration measured and confirmed by literature data.
OH
OAc
OAc
NHAc
NHAc
+
NHAc
CAL-B, Na2CO3
toluene, 72h, 40°C.
3a
(R)-
(S)-2a
(RS)-3a
Reaction scale
ee(S) (yield%)
ee(P) (yield%)
c %
E
1 mmol
5 mmol
21 mmol
98% (47%)
92% (42%)
90% (40%)
99% (43%)
99% (39%)
99% (38%)
50
52
52
> 200
> 170
> 140
Scheme 2. Application of the kinetic resolution of (RS)-3a with CAL-B on a multigram scale.
This method allowed us to isolate both enantiomers of the start-
using our optimized conditions to other substrates 4b–4f. It should
be noted that to the best of our knowledge the enzymatic hydrol-
ysis has never been reported previously, in either conventional or
non-conventional media. The racemic 2-acetamido-1-arylacetates
4b–4e were synthesized, in good overall chemical yields in three
steps from the corresponding aldehydes following a modified syn-
thesis protocol (Scheme 3) that incorporates easy and soft
pathways.25
b-Nitro-alcohols 2b–2e were obtained by coupling the corre-
sponding aldehydes 1b–1e with nitromethane in the presence of
a catalytic amount of metformin (5 mol %), without a solvent, at
room temperature according to the modified Henry reaction.26
They are obtained with chemical yields between 70% and 88%.
Racemic b-amino alcohols 3b–3e were obtained by the reduction
of the corresponding b-nitro-alcohols using Pd/C under an atmo-
sphere of H2,27 and were recovered with isolated chemical yields
between 86% and 95% yield.
Finally, 2-acetamido-1-aryl acetates 4b–4e were quantitatively
obtained by chemical acylation of the b-amino alcohols 3b–3e
using acetic anhydride (>96% yield). Following the same acylation
procedure, the N-acetylamino-acetate 4f was recovered with yield
of 54% directly from the commercially propranolol 3f. The kinetic
resolution via enzymatic hydrolysis in non-conventional media
using sodium carbonate was applied to the synthesized (RS)-4b–
4f compounds. The reactions were carried out using optimized
conditions described in Table 1. The reaction mixture was stirred
magnetically at 40 °C for 72 h (Scheme 4).
ing materials and the deacylated products with excellent conver-
sions 48% < C < 50% and high enantioselectivities (E >200) (entries
7–8). Furthermore, the steric hindrance of the N-protecting group
does not affect the enantioselectivity and has very little effect on
the conversion (entry 7 vs 8). The CAL-B enantiopreference for
the (S)-enantiomer was confirmed and checked by a derivation of
the commercially available (R)-2-amino-1-phenyl ethanol. The
obtained (R)-2-acetamido-1-phenyl ethanol and (R)-2-acetamido-
1-phenyl acetate was analyzed by chiral HPLC.
Considering the promising results obtained during the deacyla-
tion of 2-acetamide-1-phenylethyl acetate 3a, we completed this
investigation with a multigram scale reaction. Thus, a scaling up
of the kinetic resolution was carried out starting from 1 g (5 mmol)
to 4.7 g (21 mmol) of amido acetate 3a in toluene, 1 equiv of Na2-
CO3 and an appropriate amount of CAL-B (Scheme 2).
The quantitative yields were obtained regardless of the scale,
with a conversion of c = 52% and a selectivity of E >140. The
remaining enantiomer (R)-3a was isolated in 40% yield and with
high enantiomeric excess (ee >99%) and the provided enantiomer
(S)-2a in 38% yield and with 92% ee.
2.2. Alkaline enzymatic deacylation of some 2-acetamido-1-
arylacetates
To study the scope of the CAL-B catalyzed hydrolysis in non-
aqueous media by carbonate salts, we extended the methodology
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A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
OH
O
OH
OAc
(ii)
(iii)
up to 96% yield
(i)
NO2
NH2
NHAc
Ar
1b-1e
H
Ar
Ar
Ar
up to 70% yield
up to 77% yield
2b-2e
3b-3f
4b-4f
(i) Nitromethane, metformin, rt, 1h ; (ii) Pd-C/H2, EtOH, rt, 24h ; (iii) CH2Cl2, Et3N, Ac2O, DMAP, rt, 4h
OAc OAc
OAc
O
N
NHAc
N
NHAc
NHAc
OAc Ac
R
4d
4e
4f
4b: R = -Ph
4c
: R = -OMe
Scheme 3. General synthetic route to 2-acetamido-1-aryl acetates.
OAc
OH
OAc
ness of the stereogenic center that impacts negatively on
selectivity.
CAL-B , Na2CO3
+
NHAc
(RS)-4b-4e
NHAc
(S)-5b-5e
NHAc
(R)-4b-4e
Ar
toluene, 40°C, 72h
Ar
Ar
3. Conclusion
Scheme 4. Kinetic resolution via enzymatic hydrolysis of 4b–4e with Na2CO3.
We have developed a new and efficient route to access enan-
tiomerically pure b-amino alcohols via alkaline hydrolysis under
hydrophobic organic media using CAL-B as biocatalysts. This
allows direct access to a number of interesting building blocks with
high enantiomeric excesses. The enantioenriched b-amino alcohols
derivatives were obtained by chemo- and enantioselective path-
ways promoted by CAL-B catalyzed hydrolysis and assisted by
sodium carbonate in toluene. CAL-B shows a very interesting selec-
tive activity with the enantioselective cleavage of O-acetyl group.
The synthesis of racemic b-amino alcohols was carried out via a
modified Henry reaction, catalyzed by a super organic base: met-
formin, and the products were obtained with good chemical yields
(yield >80%) using a simpler and greener synthesis. A novel hydrol-
ysis process in toluene with sodium carbonate catalyzed by CAL-B
has been successfully extended to a set of 2-amino-1-arylethanol
derivatives 3a, 4a, 4c, and 4d. The substitution of the aromatic ring
by electron withdrawing groups and the remoteness of the stere-
ogenic center cause a drop in reactivity and selectivity, while the
aromaticity (phenyl or pyridyl group) is in favor of the enantiomer
(S)-mono acylated by CAL-B (ee up to 99%). We have also devised a
straightforward and high yield preparation of both enantiomers of
1,2-amino phenylethanol, which be easily prepared on a large scale
and is useful for further transformations.
The progress of the reaction and the enantiomeric excess of the
residual substrate and the N-monoacylated were determined by
high performance liquid chromatography. The results are summa-
rized in Table 2.
The results of Table 2 show the significant influence of the
structure of 2-acetamido-1-aryl acetates on the reactivity and
selectivity of the CAL-B during their hydrolysis in the presence of
sodium carbonate. The highest enantiomeric excess was recorded
for the resolution of (RS)-4d, the kinetic resolution is highly selec-
tive with a conversion of c = 50% and a selectivity of E >200.
The enantiomers (product and substrate) were obtained with
high enantiomeric purity >99% ee, the presence of the pyridine
moiety intervenes favorably to the enantioselection by CAL-B
under those conditions (entry 3). CAL-B showed a very good affin-
ity during the hydrolysis of this substrate. Selectivity was also very
high for 4c (E >200) with a small decrease of the conversion
c = 33%. This phenomenon can be attributed to the presence of
methoxy substituent at the para-position of the aromatic ring.
The oxygen or azote atom, with its high electronegativity, can
inductively withdraw electrons through sigma –bonds and so
should be taken into account.28
For the other hydrolyzed substrates, CAL-B retained its reactiv-
ity; the conversions obtained for 4b and 4e were c = 34% and
c = 57%, respectively (entries 1 and 4), with drastic loss of enantios-
electivity (E <8). Finally, with propranolol, the rate of progress of
the hydrolysis did not exceed the 20% without an enantioprefer-
ence (entry 5). These outcomes can be attributed to the inductive
effects negatively distressing the enantioselection for compound
4b, but in the case of 4e and 4f, it is more because of the remote-
4. Experimental
4.1. General
All reagents purchased from either Aldrich, Acros, TCI or Alfa
Aesar and were used as received. The Candida antarctica lipase
Table 2
CAL-B-catalyzed hydrolysis of 4a–4f with Na2CO3
Entrya
Substrate
ees (%) (Conf.)f
b
Yieldc (%)
eep (%) (Conf.)f
b
Yieldc (%)
cd (%)
Ee
1
2
3
4
5
4b
4c
4d
4e
4f
36 (R)
49 (R)
>99 (R)
48 (R)
3
64
50
44
60
83
69 (S)
97 (S)
>99 (S)
35 (S)
12
35
30
40
30
12
34
33
50
57
20
8
>200
>200
3
1
a
b
c
d
e
f
1 mmol of racemic N-acetyl-aminoacetate, 1 mmol of Na2CO3 in 3 mL of toluene in the presence of 50 mg of CAL-B for 72 h.
Measured by chiral HPLC.
Isolated yields.
Conversion:24 c = ees/eep + ees.
Selectivity:24 E = ln[(1 ꢀ C)(1 ꢀ ees)]/ln[(1 ꢀ C)(1 + ees)].
20
Sign of [a] .
D
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A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
immobilized on acrylic resin CAL-B was purchased from Aldrich.
Specific activity >10,000 U/g used without any pre-treatment.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on Silica gel 60F254 plates type MERCK 5179, 250 mesh,
using UV light (254 nm) as the visualizing agent and ninhydrin
solution and heat as developing agents.
NMR spectra were recorded on Bruker spectrometers (300 MHz
for 1H, 75 MHz for 13C) instrument and calibrated using residual
deuterated solvent as an internal reference (peak at 7.26 ppm in
1H NMR and 3 peaks at 77 ppm in 13C NMR in the case of
CDCl3; peak at 4.87 ppm in 1H NMR and 7 peaks at 49 ppm in
13C NMR in the case of CD3OD). The following abbreviations
were used to designate multiplicities: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad, dd = double-
4.2.2.1.4. 2-Nitro-1-(pyridin-2-yl)ethanol 2d. Yield: 70%; 1H
NMR (300 MHz, CDCl3) d 4.3 (br s, 1H), 4.6 (dd, J = 13.0, 8.5 Hz,
1H), 4.7 (dd, J = 13.0, 3.6 Hz, 1H), 5.4 (dd, J = 8.5, 3.6 Hz, 1H), 7.3
(ddd, J = 7.6, 4.9, 0.8 Hz, 1H), 7.4 (dd, J = 7.9, 0.5 Hz, 1H), 7.7 (td,
J = 7.7, 1.7 Hz, 1H), 8.5 (ddd, J = 4.8, 1.4, 0.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 156.6, 149, 137.6, 123.7, 121, 80.8, 70.4.
4.2.2.1.5. 1-Nitro-4-phenylbutan-2-ol 2e. Yield: 88%; 1H NMR
(300 MHz, CDCl3) d 1.7–1.9 (m, 2H), 2.6–2.7 (m, 1H), 2.7–2.9 (m,
2H), 4.2–4.3 (m, 1H), 4.3–4.4 (m, 2H), 7.2–7.25 (m, 3H), 7.29–
7.35 (m, 2H).
4.2.3. General procedure for the reduction of b-nitroalcohols
3b–3e
In a round bottom flask, the b-nitroalcohol (1 mmol) was dis-
solved in 5 mL of ethanol and charged with a catalytic amount of
palladium on activated carbon (10 mol %). The reaction vessel
was evacuated and aerated with hydrogen gas. The reaction mix-
ture was stirred at room temperature for 24 h. The solution was
then filtered through a pad of Celite and evaporated to dryness.
The 1H and 13C NMR spectra of the b-amino alcohols were in good
agreement with the literature.
doublet,
ddd = double-double-doublet,
td = triple-doublet,
qd = quartet-doublets. Chemical shifts are expressed in ppm and
coupling constant (J) in Hz. The enantiomeric excesses were mea-
sured by a chiral stationary phase HPLC on ChiralpakÒAD-H
(4.6 ꢁ 250 mm), ChiralpakÒIC (4.6 ꢁ 250 mm) and ChiralpakÒIA
(4.6 ꢁ 250 mm) 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 and
k = 589 nm.
4.2.3.1. 1-([1,10-Biphenyl]-4-yl)-2-aminoethanol 3b.
Yield:
95%; Rf = 0.09 (CH2Cl2/Acetone: 50/50). 1H NMR (300 MHz, CDCl3)
d 1.9 (br s, 2H), 2.8 (dd, J = 12.6, 7.8 Hz, 1H), 3 (dd, J = 12.5,
4.0 Hz, 1H), 4.6 (q, J = 4.0 Hz, 1H), 7.32–7.37 (m, 1H), 7.42–7.46
(m, 4H), 7.58 (d, J = 8.1 Hz, 4H); 13C NMR (75 MHz, CDCl3) d
141.6, 141, 140.6, 128.9, 127.4, 127.3, 127.2, 126.4, 74.2, 49.3.
4.2. Synthesis procedures of all racemic compounds and their
NMR data
4.2.1. Preparation of (RS)-2-acetamide-1-phenylethanol 2a
A mixture of 2-amino-1-phenylethanol 1a (1 mmol, 0.137 g)
and isopropenyl acetate (3 mmol, 0.300 g) were stirred at room
temperature for 24 h until complete consumption of the amino
alcohol. The excess isopropenyl acetate was then eliminated under
reduced pressure. Acetamide 2a was obtained quantitatively with-
out purification, as a white powder (0.179 g, >99%). Rf = 0.57 (CH2-
Cl2/Acetone: 50/50). 1H NMR (300 MHz, CD3OD) d 1.9 (s, 3H), 3.3
(dd, J = 7.6 and 5.9 Hz, 1H), 3.4 (dd, J = 13.6, 4.6 Hz, 1H), 4.7 (dd,
J = 8.0, 4.6 Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR (75 MHz, CD3OD) d
172.5, 142.8, 128.2, 127.5, 126.0, 72.4, 21.4.
4.2.3.2. 2-Amino-1-(4-methoxyphenyl)ethanol 3c.
Yield:
92%; Rf = 0.08 (CH2Cl2/Acetone: 50/50). 1H NMR (300 MHz, CDCl3)
d 2.5 (br s, 2H), 2.8 (dd, J = 12.7, 7.9 Hz, 1H), 2.9 (dd, J = 12.4,
4.1 Hz, 1H), 3.8 (s, 3H), 4.6 (dd, J = 7.9, 4.0 Hz, 1H), 6.89–6.91 (m,
2H), 7.27–7.3 (m, 2H); 13C NMR (75 MHz, CDCl3) d 159.1, 134.7,
127.2, 113.8, 73.9, 55.3, 49.3.
4.2.3.3. 2-Amino-1-(pyridin-2-yl)ethanol 3d.
Yield: 92%;
Rf = 0.06 (CH2Cl2/Acetone: 30/70). 1H NMR (300 MHz, CDCl3) d
2.8 (d, J = 6.6 Hz, 2H), 2.8 (d, J = 6.6 Hz, 1H), 3 (dd, J = 13.1, 3.8 Hz,
1H), 4.6 (dd, J = 6.6, 3.8 Hz, 1H), 7.1 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H),
7.3 (d, J = 7.9 Hz, 1H), 7.6 (td, J = 7.7, 1.8 Hz, 1H), 8.4 (ddd, J = 4.8,
1.5, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 160.7, 148.4, 136.8,
122.4, 120.5, 73.9, 48.5.
4.2.2. General procedures for the synthesis of racemic amino
alcohols 3b–3e
4.2.2.1. General synthesis of nitroalcohols 2b–2e. 4.2.2.1.1.
Preparation of free metformin. To a solution of NaOH (40 mg,
1 mmol) and ethanol (5 mL) was added metformin hydrochloride
(165.5 mg, 1 mmol) and the resulting suspension was stirred for
1 h at room temperature. The recovered suspension was filtered,
and ethanol was removed from the filtrate with rotary evaporation
leading to free metformin in 99% yield. The obtained free met-
formin was freshly used in the next experiments. A mixture of
the aldehyde (1 mmol), nitromethane (2 mmol) and metformin
(5 mol %) was stirred at room temperature for 1 h. The reaction
was monitored by NMR. After total consumption of the aldehyde,
the reaction mixture was well-washed using distilled water and
evaporated to give the appropriate b-nitroalcohol. The 1H and 13C
NMR spectra of the b-nitroalcohols were in good agreement with
the literature.
4.2.3.4. 1-Amino-4-phenylbutan-2-ol 3e.
Yield: 86%;
Rf = 0.14 (CH2Cl2/Acetone: 60/40). 1H NMR (300 MHz, CDCl3) d
1.7–1.8 (m, 2H), 2.50 (s, 2H), 2.6 (dd, J = 12.6, 8.4 Hz, 1H), 2.7–2.8
(m, 1H), 2.9 (ddd, J = 12.8, 8.5, 4.9 Hz, 2H), 3.5–3.6 (m, 1H), 7.3
(dd, J = 7.6, 3.0 Hz, 3H), 7.3–7.4 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 142.1, 128.5, 128.4, 125.8, 71.1, 47.5, 36.5, 32.
4.2.4. Synthesis of (RS)-2-(((benzyloxy)carbonyl)amino)-1-phen-
ylethyl acetate 4a
To a solution of 1a (2 mmol, 0.274 g) in 2 mL of CH2Cl2 was
added a solution of NaOH 1 M (2 mL) and the mixture was cooled
to 0 °C. To the mixture, 50% of benzyl chloroformate in toluene
(2 mmol) was added and the reaction was stirred at room temper-
ature for 16 h. The reaction crude was washed with H2O and the
organic phases were combined, dried over MgSO4 and evaporated
under reduced pressure to give 0.5 g of a white solid (92% isolated
yield). To a solution of this product in 2 mL of CH2Cl2 were added,
successively, 2 equiv of anhydride acetic, 2 equiv of Et3N, and a cat-
alytic amount of 4-dimethylaminopyridine (0.2 equiv). The final
product 4a was obtained pure after standard work-up in yield
>99%. Rf = 0.5. (Petroleum ether/AcOEt: 70/30). 1H NMR
(300 MHz, CDCl3) d 2 (s, 3H), 2.2 (s, 2H), 3.4–3.6 (m, 2H), 5.1 (br
4.2.2.1.2. 1-([1,10-Biphenyl]-4-yl)-2-nitroethanol 2b. Yield: 88%;
1H NMR (300 MHz, CDCl3) d 2.9 (br s, 1H), 4.6 (qd, J = 13.3, 6.3 Hz,
2H), 5.52 (dd, J = 9.3, 2.7 Hz, 1H), 7.3–7.4 (m, 5H), 7.5–7.6 (m, 4H);
13C NMR (75 MHz, CDCl3) d 142, 140.3, 137, 129, 127.8, 127.8,
127.2, 126.5, 81.2, 70.9.
4.2.2.1.3. 1-(4-Methoxyphenyl)-2-nitroethanol 2c. Yield: 70%;
1H NMR (300 MHz, CDCl3) d 2.79 (br s, 1H), 3.8 (s, 3H), 4.4 (dd,
J = 13.2, 3.2 Hz, 1H), 4.5 (dd, J = 13.2, 9.6 Hz, 1H), 5.3 (dd, J = 9.5,
3.2 Hz, 1H), 6.9–6.9 (m, 2H), 7.3–7.3 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 55.4, 70.7, 81.3, 114.5, 127.4, 130.3, 160.1.
Please cite this article in press as: Alalla, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.003

6
A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
s, 1H), 5.8 (dd, J = 7.8, 4.4 Hz, 1H), 7.2–7.3 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 170.1, 166.4, 137.6, 136.4, 128.6, 128.5, 128.4,
128.1, 126.4, 66.8, 45.8, 22.1, 21.
was shaken at 40 °C for 24 h. After removal of the enzyme by filtra-
tion and evaporation of the solvent, the reaction mixture was ana-
lyzed by chiral HPLC.
4.2.5. General procedure for the synthesis of racemic b-N-acetyl-
aminoacetate 3a, 4b–4f
4.3.2. General procedure for the enzymatic hydrolysis of
racemic b-N-protected-aminoacetate 3a, 4a–4f
The N-acetyl-aminoacetates were synthesized by classical
chemical acylation via the corresponding racemic b-amino alcohol
(1 equiv), using 2 equiv of anhydride acetic, 2 equiv of Et3N, and a
catalytic amount of 4-dimethylaminopyridine (0.2 equiv) in 1 mL
of CH2Cl2. The final products were obtained pure after standard
work-up in excellent yields. The 1H and 13C NMR spectra of these
products were in good agreement with the literature.
In a typical procedure, 1 mmol of racemic b-N-protected-
aminoacetates 3a, 4a–4f is dissolved in 3 mL of toluene before
the addition of 1 mmol of sodium carbonate and 50 mg of CAL-B.
The mixture was stirred at 40 °C for 72 h. After removal of the
enzyme by filtration and evaporation of the solvent, the reaction
mixture was purified by flash chromatography (CH2Cl2/EtOAc:
with different fraction) to separate the residual (R)-N-protected-
aminoacetate and the furnished (S)-N-protected-amino alcohol.
The two optically active compounds were analysed by chiral HPLC.
4.2.5.1. 2-Acetamido-1-phenylethyl acetate 3a.
Yield: >99%;
Rf = 0.79 (CH2Cl2/Acetone: 50/50). 1H NMR (300 MHz, CDCl3) d 1.9
(s, 3H), 2 (s, 3H), 3.5 (ddd, J = 14.0, 8.2, 5.6 Hz, 1H), 3.6 (ddd,
J = 14.0, 6.2, 4.4 Hz, 1H), 5.8 (dd, J = 8.2, 4.4 Hz, 1H), 7.2–7.3 (m,
5H); 13C NMR (75 MHz, CDCl3) d 170.4, 170.2, 137.7, 128.5,
128.3, 126.3, 74.4, 44.3, 22.9, 21.
Acknowledgments
Algerian Ministry of education and Scientific Research (FNR
2000 and PNR), Catholic University of Louvain, and FNRS are grate-
fully acknowledged for their financial support of this work. Wal-
lonie-Bruxelles International (WBI) is acknowledged for a grant
to Affef ALALLA.
4.2.5.2. 1-([1,10-Viphenyl]-4-yl)-2-acetamidoethyl acetate 4b.
Yield: >99%; Rf = 0.84. (CH2Cl2/Acetone: 60/40). 1H NMR
(300 MHz, CDCl3) d 1.9 (s, 3H), 2.1 (s, 3H), 3.5–3.7 (m, 2H), 5.8 (q,
J = 4.4 Hz, 1H), 7.35–7.38 (m, 1H), 7.40–7.47 (m, 4H), 7.55–7.6
(m, 4H); 13C NMR (75 MHz, CDCl3) d 170.4, 170.2, 141.4, 140.4,
136.6, 128.8, 127.5, 127.4, 127.1, 126.9, 74.4, 44.3, 23.2, 21.2.
A. Supplementary data
Supplementary data (all experimental procedures; characteri-
zation spectra (NMR and chiral chromatography) of all synthesized
products) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetasy.2016.10.003.
4.2.5.3. 2-Acetamido-1-(4-methoxyphenyl)ethyl acetate 4c.
Yield: >99%; Rf = 0.63. (CH2Cl2/Acetone: 60/40). 1H NMR
(300 MHz, CDCl3) d 1.9 (s, 3H), 2 (s, 3H), 3.4–3.6 (m, 3H), 3.7 (s,
3H), 5.7 (dd, J = 8.0, 4.8 Hz, 1H), 6 (br s, 1H), 6.82–6.87 (m, 2H),
7.21–7.25 (m, 2H); 13C NMR (75 MHz, CDCl3) d 170.5, 170.2,
159.7, 129.8, 128, 114.1, 74.3, 55.3, 44.3, 23.3, 21.3.
References
1. (a) Ager, D.; Prakash, J. I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (b) Fujita,
T.; Yoneta, M.; Hirose, R.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Adachi, K.;
Arita, M.; Chiba, K. Bioorg. Med. Chem. Lett. 1995, 5, 847–852.
4.2.5.4.
2-Acetamido-1-(pyridin-2-yl)ethyl
acetate
4d.
Yield: 96%; Rf = 0.57. (CH2Cl2/Acetone: 30/70). 1H NMR (300 MHz,
CDCl3) d 1.9 (s, 3H), 2.1 (s, 3H), 3.6–3.7 (m, 1H), 3.8–3.9 (m, 1H),
5.8 (dd, J = 6.4, 4.9 Hz, 1H), 6.2 (br s, 1H), 7.2 (ddd, J = 7.6, 4.9,
1.1 Hz, 1H), 7.3 (d, J = 7.9 Hz, 1H), 7.6 (td, J = 7.7, 1.8 Hz, 1H), 8.5
(ddd, J = 4.9, 1.6, 0.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 170.3,
170.3, 156.9, 149.2, 136.9, 134.6, 123.2, 122, 74.3, 42.6, 23.2, 21.
2. (a) Fürstner, A. Synthesis 1989, 8, 571–590; (b) Soaï, K.; Kawase, Y. Tetrahedron:
Asymmetry 1991, 2, 781–784; (b) Krake, S. H.; Bergmeier, S. C. Tetrahedron
2010, 66, 7337–7360; (c) Zeror, S.; Collin, J.; Fiaud, J.-C.; Aribi-Zouioueche, L.
Adv. Synth. Catal. 2008, 350, 197–204; For reviews, see: (d) Vicario, J. L.;
Badía, D.; Carrillo, L.; Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219–235;
(e) Everaere, K.; Mortreux, A.; Carpentier, J. F. Adv. Synth. Catal. 2003, 345, 67–
77.
3. (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576; (b) Lee, T. J. F.; Stitzel, R.
E. Adrenomimetic Drugs. In Modern Pharmacology with Clinical Applications;
Craig, C. R., Stitzel, R. E., Eds.; Lippincott Williams & Wilkins: Philadelphia,
2004; pp 109–121.
4. (a) Chang, H. T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219–3222; (b)
Marino, S. T.; Stachurska-Buczek, D.; Huggins, D. A.; Krywult, B. M.; Sheehan, C.
S.; Nguyen, T.; Choi, N.; Parsons, J. G.; Griffiths, P. G.; James, I. W.; Bray, A. M.;
White, T. M.; Boyce, R. S. Molecules 2004, 9, 405–426.
5. (a) Quiros, M.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry 1999, 10, 473–
486; (b) Sehl, T.; Hailes, H. C.; Ward, J. M.; Wardenga, R.; von Lieres, E.;
Offermann, H.; Westphal, R.; Pohl, M.; Rother, D. Angew. Chem., Int. Ed. 2013, 52,
6772–6775.
4.2.5.5. 1-Acetamido-4-phenylbutan-2-yl acetate 4e.
Yield:
>99%; Rf = 0.41. (CH2Cl2/Acetone: 60/40). 1H NMR (300 MHz,
CDCl3) d 1.80–1.9 (m, 2H), 1.9 (s, 3H), 2 (s, 3H), 2.5–2.7 (m, 2H),
3.3–3.4 (m, 2H), 4.90–4.95 (m, 1H), 5.9 (br s, 1H), 7.14–7.19 (m,
3H), 7.28 (m, 2H).
4.2.5.6. 1-(N-Isopropylacetamido)-3-(naphthalen-1-yloxy)pro-
pan-2-yl acetate 4f.
Yield: 54%; Rf = 0.88 (CH2Cl2/Acetone:
6. Schrittwieser, J. H.; Coccia, F.; Kara, S.; Grischek, B.; Kroutil, W.; d’Alessandro,
N.; Hollmann, F. Green Chem. 2013, 15, 3318–3331.
7. (a) Reetz, T. Biocatal. Biotransform. 2002, 6, 145–150; (b) Grogan, G. Ann. Rep.
Prog. Chem., Sect. B. 2011, 107, 199–225; (c) Bornscheuer, U. T.; Kazlauskas, R. J.
Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations;
90/10). 1H NMR (300 MHz, CDCl3) d 1.2–1.36 (m, 6H), 2–2.24 (m,
6H), 3.4 (dd, J = 14.3, 6.9 Hz, 1H), 3.8–3.89 (m, 1H), 4 (dt, J = 13.4,
6.7 Hz, 1H), 4.3 (ddd, J = 16.9, 10.7, 3.9 Hz, 2H), 5.4–5.7 (m, 1H),
6.8 (dd, J = 16.2, 7.2 Hz, 1H), 7.3–7.5 (m, 4H), 7.7–7.8 (m, 1H), 8.2
(dd, J = 8.3, 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 171.3, 170.6,
154.3, 134.5, 127.7, 127.5, 126.4, 125.9, 125.3, 121.9, 120.6,
104.9, 71.7, 68.4, 49.6, 41.4, 22.2, 21.8, 21.2, 21.
Wiley-VCH: Weinheim, 2005;
p 61; (d) Barbayianni, E.; Kokots, G.
ChemCatChem 2012, 4, 592–608.
8. Gotor-Fernández, V.; Brieva, R.; Gotor, V. J. Mol. Catal. B: Enzym. 2006, 40, 111–
120.
9. Meyer, H.-P.; Eichhorn, E.; Hanlon, S.; Lutz, S.; Schurmann, M.; Wohlgemuth,
R.; Coppolecchia, R. Catal. Sci. Technol. 2013, 3, 29–40.
10. Gotor, V. Org. Process Res. Dev. 2002, 6, 420–426.
4.3. Enzymatic kinetic resolutions procedures
11. (a) Alfonso, I.; Gotor, V. Chem. Soc. Rev. 2004, 33, 201–209; (b) Carrea, G.; Riva,
S. Angew. Chem., Int. Ed. 2000, 39, 2226–2254; (c) Quijada, F. J.; Gotor, V.;
Rebolledo, F. Org. Lett. 2010, 12, 3605; (d) Lihammar, R.; Millet, R.; J-E. Bäckvall,
R. Adv. Synth. Catal. 2011, 353, 2321–2327; (e) Merabet-Khelassi, M.; Vriamont,
N.; Riant, O.; Aribi-Zouioueche, L. Tetrahedron: Asymmetry 2011, 22, 1790–
1796; (f) Manoel, E. A.; Ribeiro, M. F.; dos Santos, J. C.; Coelho, M. A. Z.; Simas,
A. B.; Fernandez-Lafuente, R.; Freire, D. M. Process Biochem. 2015, 50, 1557–
1564.
4.3.1. Enzymatic acylation of 2a
All enzymatic acylation reactions were performed using 1 equiv
of (RS)-2-acetamide-1-phenylethanol 2a (1 mmol, 0.179 g) and
3 equiv of the appropriate acetyl donor dissolved in 3 mL of sol-
vent. A catalytic amount of CAL-B was added and the mixture
Please cite this article in press as: Alalla, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.003

A. Alalla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
12. (a) Busto, E.; Gotor-Fernandez, V.; Gotor, V. Chem. Rev. 2011, 111, 3998–4035;
(b) Jaeger, K. E.; Eggert, T. Curr. Opin. Biotechnol. 2002, 13, 390–397; (c) Sharma,
R.; Chisti, Y.; Banerjee, U. C. Biotechnol. Adv. 2001, 19, 627–662; (d) Sheldon, R.
A.; van Pelt, S. Chem. Soc. Rev. 2013, 42, 6223–6235.
13. (a) Rodríguez-Rodríguez, J. A.; Quijada, F. J.; Brieva, R.; Rebolledo, F.; Gotor, V.
Tetrahedron 2013, 69, 5407–5412; (b) Le Joubioux, F.; Henda, Y. B.; Bridiau, N.;
Achour, O.; Graber, M.; Maugard, T. J. Mol. Catal. B: Enzym. 2013, 85, 193–199;
(c) Schönstein, L.; Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2013, 24, 202–
206; (d) Husson, E.; Garcia-Matilla, V.; Humeau, C.; Chevalot, I.; Fournier, F.;
Marc, I. Enzyme Microb. Technol. 2010, 46, 338–346; (e) Husson, E.; Humeau, C.;
Blanchard, F.; Framboisier, X.; Marc, I.; Chevalot, I. J. Mol. Catal. B: Enzym. 2008,
55, 110–117.
14. (a) Le Joubioux, F.; Bridiau, N.; Ben Henda, Y.; Achour, O.; Graber, M.; Maugard,
T. J. Mol. Catal. B: Enzym. 2013, 95, 99–110; (b) Quan, J.; Wang, N.; Cai, X.-Q.;
Wu, Q.; Lin, X.-F. J. Mol. Catal. B: Enzym. 2007, 44, 1–7; (c) Kanerva, L. T.;
Vänttinen, E.; Huuhtanen, T. T.; Dahlqvist, M. Acta Chem. Scand. 1992, 46, 1101–
1105; (d) Yildirim, D.; Seyhan Tukel, S. Process Biochem. 2013, 48, 819–830.
15. (a) Kanerva, L. T.; Rahiala, K.; Vänttinen, E. J. Chem. Soc., Perkin Trans. 1 1992, 14,
1759–1762; (b) Lundell, K.; Katainen, E.; Kiviniemi, A.; Kanerva, L. T.
Tetrahedron: Asymmetry 2004, 15, 3723–3729.
19. Maenpaa, H.; Kanerva, L. T.; Liljeblad, A. ChemCatChem 2016, 8, 1–8.
20. (a) Rakels, J. L. L.; Straathof, A. J. J.; Heijneii, J. J. Tetrahedron: Asymmetry 1994, 5,
93–100; (b) Manoel, E. A.; dos Santos, J. C. S.; Freire, D. M. G.; Rueda, N.;
Fernandez-Lafuente, R. Enzyme Microb. Technol. 2015, 71, 53–57; (c) Cambillau,
C.; Longhi, S.; Nicolas, A.; Martinez, C. Curr. Opin. Struct. Biol. 1996, 6, 449–455.
21. (a) Merabet-Khelassi, M.; Houiene, Z.; Aribi-Zouioueche, L.; Riant, O.
Tetrahedron: Asymmetry 2012, 23, 828–833; (b) Houiene, Z.; Merabet-
Khelassi, M.; Bouzemi, N.; Riant, O.; Aribi-Zouioueche, L. Tetrahedron:
Asymmetry 2013, 24, 290–296.
22. Le Joubioux, F.; Achour, O.; Bridiau, N.; Graber, M.; Maugard, T. J. Mol. Catal. B:
Enzym. 2011, 70, 108–113.
23. (a) Alalla, A.; Merabet-Khelassi, M.; Aribi-Zouioueche, L.; Riant, O. Synth.
Commun. 2014, 44, 2364–2376; (b) Pelagalli, R.; Chiarotto, I.; Feroci, M.;
Vecchio, S. Green Chem. 2012, 14, 2251–2255.
24. (a) Chen, C. S.; Fujimoto, Y.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299; (b)
Kagan, H. B.; Fiaud, J.-C. Kinetic Resolution In Topics in Stereochemistry; Eliel, E.
L., Wilen, S. H., Eds.; J. Wiley & Sons: New York, 1988; Vol. 18, pp 249–330.
25. Alizadeh, A.; Khodaei, M. M.; Abdi, G.; Kordestani, D. Bull. Korean Chem. Soc.
2012, 33, 3640–3644.
26. Luzzio, A. Tetrahedron 2001, 57, 915–945.
16. Rouf, A.; Gupta, P.; Aga, M. A.; Kumar, B.; Parshad, R.; Taneja, S. C. Tetrahedron:
Asymmetry 2011, 22, 2134–2143.
17. Honig, H.; Seufer-Wasserthal, P. Synthesis 1990, 1137–1140.
27. Bhabak, K. P.; Arenz, C. Bioorg. Med. Chem. 2012, 20, 6162–6170.
28. Melais, N.; Boukachabia, M.; Aribi-Zouioueche, L.; Riant, O. Bioprocess Biosyst.
Eng. 2015, 38, 1579–1588.
18. Takada, H.; Takagi, S.; Kawakubo, H. Bull. Chem. Soc. Jpn. 1994, 67, 1196–1197.
Please cite this article in press as: Alalla, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.003