Diastereoselective and enantioselective alkaline-hydrolysis of 2-aryl-1-cyclohexyl acetate: a CAL-B catalyzed deacylation/acylation tandem process

Article abstract of DOI:10.1016/j.tetasy.2017.09.010

Candida antarctica lipase proved to be a particularly efficient lipase for the resolution of racemic 2-arylcyclohexyl acetate in hydrolysis reaction with Na₂CO₃ in an organic medium. The (1R,2S)-trans-2-arylcyclohexanols 2a–2d were obtained with high ee values (up to >99%) and the selectivity reached E > 200. The influence of the enol ester and the solvent on (±)-trans-2-arylcyclohexanol in the CAL-B catalyzed acylation was also studied and compared with the deacylation. The CAL-B exhibits a better affinity for the alkaline hydrolysis reaction compared with acylation with the enol esters in the same organic solvents. The best conditions were applied to resolve a stereoisomeric mixture cis/trans-2-phenyl-1-cyclohexanol and its corresponding acetate by acylation and deacylation. The obtained results show a highly enantio- and diastereoselectivity of the CAL-B during the acylation and the deacylation in favor of the trans-(R)-enantiomer product. The resolution of a mixture of cis/trans-2-arylcyclohexanols was an easy, convenient approach to provide only one stereoisomer of a mixture of four with high enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2017.09.010

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective and enantioselective alkaline-hydrolysis
of 2-aryl-1-cyclohexyl acetate: a CAL-B catalyzed
deacylation/acylation tandem process
b
Fatma Zahra Belkacemi a, Mounia Merabet-Khelassi a, Louisa Aribi-Zouioueche a, , Olivier Riant
⇑
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:
Candida antarctica lipase proved to be a particularly efficient lipase for the resolution of racemic 2-aryl-
cyclohexyl acetate in hydrolysis reaction with Na2CO3 in an organic medium. The (1R,2S)-trans-2-arylcy-
clohexanols 2a–2d were obtained with high ee values (up to >99%) and the selectivity reached E > 200.
The influence of the enol ester and the solvent on ( )-trans-2-arylcyclohexanol in the CAL-B catalyzed
acylation was also studied and compared with the deacylation. The CAL-B exhibits a better affinity for
the alkaline hydrolysis reaction compared with acylation with the enol esters in the same organic sol-
vents. The best conditions were applied to resolve a stereoisomeric mixture cis/trans-2-phenyl-1-cyclo-
hexanol and its corresponding acetate by acylation and deacylation. The obtained results show a
highly enantio- and diastereoselectivity of the CAL-B during the acylation and the deacylation in favor
of the trans-(R)-enantiomer product. The resolution of a mixture of cis/trans-2-arylcyclohexanols was
an easy, convenient approach to provide only one stereoisomer of a mixture of four with high enan-
tiomeric excess.
Received 13 August 2017
Accepted 12 September 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
rac-trans-2-arylcyclohexanols has been used as an easy route with
various lipases: Pseudomonas amano sp.,10 PS30 lipase,11 Candida
The importance of enantiopure secondary alcohols derivatives
as versatile building blocks for the synthesis of biologically active
compounds is well established.1 The trans-2-arylcyclohexanol
derivatives, developed by Whitesell et al.,2 are important as chiral
sources for asymmetric transformations or chiral materials for the
asymmetric manufacture of physiologically active substances such
as diltiazem.3 Their high asymmetric inductions are attributed to
the high stereoselective control due to both steric and electronic
effects of the aryl moiety. The routes reported in the literature to
access enantioenriched trans-2-phenylcyclohexanol use asymmet-
ric transformations such as hydroboration,4 epoxidation5 or dihy-
droxylation6 of 1-phenylcyclohexene, or also by enantioselective
protonation/reduction starting from the corresponding prochiral
enol acetate.7 Other routes have also used kinetic resolutions8
such as the diastereo- and enantioselective silylation of
rugosa lipase (CRL)12 and Pseudomonas fluorescens lipase (AK).13
The standard protocol reported for these reactions engages vinyl
acetate as acyl donor and tert-butylmethylether (TBME) as solvent.
The enzymatic hydrolysis of trans-2-arylcyclohexyl derivatives is
less reported, to the best of our knowledge, with only the Crude
Chicken Liver Esterase (CCLE) being used in biphasic media.14 The
lipase from Candida antarctica fraction B is a very robust biocatalyst
in an organic medium, with high catalytic efficiency in kinetic res-
olutions.15 In our previous work, CAL-B was successfully used for
the resolution of arylakylcarbinols16 and primary 1,2-disbstituted
ferrocene derivatives.17 Furthermore, we have developed a green
and easy pathway for the enzymatic hydrolysis in non-aqueous
organic media, in the presence of sodium carbonates.18 We have
also effectively applied this procedure to the deracemization of a
large range of aromatic acetates19 and the chemoselective
deacylation of N,O-protected amino alcohols.20
2-arylcyclohexanols.9
The
enzymatic
acylation
of
the
In order to extend the field of application of the CAL-B catalyzed
alkaline hydrolysis approach, we applied it to some trans-2-arylcy-
clohexyl derivatives. Herein we describe the kinetic resolution
via alkaline hydrolysis mediated by CAL-B of four compounds:
⇑
Corresponding author.
E-mail addresses: louisa.zouioueche@univ-annaba.dz, louisa.zouioueche@gmail.
com (L. Aribi-Zouioueche).
https://doi.org/10.1016/j.tetasy.2017.09.010
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Belkacemi, F. Z.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.010

2
F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
OAc
OR
OH
Ar
OH
Ar
OAc
Ar
CAL-B
CAL-B
+
+
enol ester
Na2CO3
Ar
Ar
( )-trans
R = H , OAc
(1S,2R)
(1R,2S)
acylation
(1R,2S)
deacylation
(1S,2R)
Scheme 1. Acylation/deacylation tandem approaches.
trans-2-phenyl-cyclohexyl acetate 3a, trans-2(2-methoxyphenyl)-
cyclohexyl acetate 3b, trans-([1,10-biphenyl]-4-yl)-cyclohexyl acet-
ate 3c, trans-2-(naphthalen-2-yl)-cyclohexyl acetate 3d. The
efficiency of CAL-B as a biocatalyst used in the alkaline hydrolysis
approach is comparable to the acylation reaction using two differ-
ent enol esters in various solvents (Scheme 1). We also studied the
isomeric mixture of cis–trans-2-phenyl-1-cyclohexanol. The
optimized conditions of both approaches are applied to the direct
diastereo- and enantioselective resolution of racemic cis–trans-2-
phenyl-1-cyclohexanol.
OAc
Aryl
OH
OR
CAL-B, nucleophile
+
organic solvant
Aryl
Aryl
acylation: R=H: ( )-trans-2a-2d
3a-3d
(1R,2S)-3a-3d
(1S,2R)-2a-2d
2a-2d
3a-3d
deacylation: R= Ac:( )-trans-
(1S,2R)-
(1R,2S)-
Scheme 3. Enzymatic deacylation/acylation approaches of trans-2-arylcyclohexyl
derivatives.
(Scheme 3). The stereochemical preference of the CAL-B was deter-
mined by establishing the absolute configuration of the remaining
alcohols and acetates after comparison of the specific rotations
with those reported in the literature. In both cases CAL-B preferen-
tially catalyzed the (1R)-enantiomer following Kazlauskas rule.21
The results of both enzymatic resolution approaches of rac-trans-
2-arylcyclohexyl derivatives are summarized in Table 1.
All the experiments show a high enantioselectivity of the CAL-B
during the alkaline hydrolysis of acetates 3a–3d (Table 1). The con-
versions essentially depend on both the bulkiness of the aryl sub-
stituent and the solvent hydrophobicity. The best results are
recorded using TBME as the solvent in deacylation where the
CAL-B hydrolyze efficiently the acetates 3a and 3c in favor of the
(1R,2S)-enantiomer (entries 2 and 5). Moderate conversions are
noted in toluene for 3a and 3b 17% ꢀ c ꢀ 30% (entries 1 and 3).
In TBME as solvent, a conversion of 46.5% was reached for 3a, while
the conversion strongly decreases in the case of more hindered and
less soluble substrate 3b (entry 2 and 4); the same effect being
noted in toluene (entry 3 vs. 1). Based on those results, the hydrol-
ysis reactions of 3c and 3d are performed only in TBME. The
recorded results are in the same lines, the acetates 3c and 3d are
hydrolyzed selectively (E > 200) with conversion rates of
c = 49.5% for 3c and c = 31% for 3d (entries 5 and 6).
2. Results and discussion
Herein we focused on four substrates: ( )-trans-2-arylcyclo-
hexyl derivatives 2a–2d and 3a–3 including aryl groups with
different steric and electronic environments. The first one
( )-trans-2-phenyl-1-cyclohexanol 2a is commercially available,
while the last three 2b, 2c, 2d are obtained via copper(I) catalyzed
ring opening of cyclohexane oxide 1 by means of the appropriate
arylmagnesium bromide with satisfactory yields (Scheme 2A).
The ( )-trans-2-arylcyclohexyl acetates 3a–3d were obtained via
standard chemical acylation (Scheme 2B).
A
B
OH
OAc
Aryl-MgBr
Ac2O, Et3N
O
CuCl (Cat.)
THF/-78°C
4-DMAP
Aryl
Aryl
1
3a-3d
( )-trans-
( )-trans-2a-2d
2b
aryl = 2-methoxyphenyl , Yield=60%
2c
aryl = biphenyl , Yield=69%
aryl = naphthyl 2d, Yield=77%
Scheme 2. Synthesis of trans-2-arylcyclohexyl derivatives.
Using the same guidelines, the resolution of ( )-trans-2-arylcy-
clohexanol 2a–2d was carried through CAL-B catalyzed acylation
using both enol esters and the two solvents used in alkaline
hydrolysis. In all cases, high selectivity for the acylation was
observed with vinyl and isopropenyl acetates (E > 97) in both sol-
vents always with a (R)-enantiopreference. However, the CAL-B
reactivity was modulated according to the reaction partners: the
steric effects of the aryl-substituent’s, the enol ester used as well
as the solvent. Thus, the presence of either a phenyl or naphthyl
substituent contributes in favor of the CAL-B acylation reactivity,
and the best results were obtained (c = 47%) using isopropenyl
acetate as acyl donor in toluene for 2a or in TBME with 2d (entries
7–10 and 19–22). Moreover, isopropenyl acetate shows a signifi-
cant effect of the solvent for the resolution of 2b, as the conversion
jump from c = 6% in TBME to c = 30% in toluene (entry 11 vs. 12).
This solvent effect is not observed in the case of the substrates
2a and 2d under the same conditions (entries 7–8, and 19–20)
while for 2c, the activity of CAL-B is low c < 11% (entries 15–16).
Furthermore, the presence of a methoxy-substituent at the ortho-
position of the aromatic ring causes a significant decrease in the
conversion using isopropenyl acetate in TBME (entry 11 vs 7); this
fact is less pronounced in toluene (entry 12 vs 8). The same mod-
erate activity of CAL-B lipase occurs during the alkaline hydrolysis
of the acetate 3b.
The Candida antarctica lipase fraction B, immobilized on acrylic
resin, was used as the catalyst for the kinetic resolution of acetates
3a–3d via alkaline hydrolysis. The same lipase was used for the
acylation of alcohols 2a–2d by two enol esters in organic solvents
with different hydrophobicities, the tert-butylmethylether (TBME,
logP = 1.35) and toluene (PhMe, logP = 2.5).
2.1. CAL-B catalyzed deacylation/ acylation of ( )-trans-2-
Arylcyclohexyl derivatives
The alkaline hydrolysis experiments are established on an
equimolecular mixture of racemic acetates 3a–3d and sodium car-
bonate (1 mmol/1 mmol), diluted in 2 mL of organic solvent, in the
presence 200 mg of CAL-B (>10,000 U/g). The acylation experi-
ments were performed on 1 mmol of racemic alcohols 2a–2d with
3 equiv of enol esters:vinyl acetate (VA) and isopropenyl acetate in
2 mL of organic solvent with the same loading amount of CAL-B.
The reaction mixture of the alkaline hydrolysis was stirred at
40 °C for three days and that of the acylation was stirred for one
day at room temperature. The isolated yields of the products and
the residual substrates were quantified after removing the lipase
by simple filtration and their separation by flash chromatography.
Their enantiomeric excesses were determined by chiral HPLC or GC
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F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
CAL-B catalyzed deacylation of 3a–3d versus acylation of 2a–2d
c
c
Entry
Substrate
Nucleophile
Solvent
eeS (%) Yieldd (%)
eeP % Yieldd (%)
Cc (%)
Ec
OAc
1
2
Toluene
TBME
43 (65)
86 (51)
>99 (24)
>99 (38)
30
46.5
>200
>200
3a
OAc
3
4
Toluene
TBME
20 (ND)
38 (68)
99 (ND)
>96 (20)
17
28.4
>200
71
MeO
3b
OAc
a
Na2CO3
5
6
TBME
TBME
96.5 (45)
>99 (44)
>99 (25)
49.5
>200
>200
3c
OAc
44 (55)
31
3d
OH
7
8
9
TBME
Toluene
TBME
Toluene
60 (50)
89 (43)
53.5 (60)
36.5 (70)
>99 (30)
>99 (40)
>99 (33)
>99 (20)
38
47
35
27
>200
>200
>200
>200
Isopropenyl acetateb
Vinyl acetateb
10
2a
OH
11
12
13
14
TBME
Toluene
TBME
Toluene
6 (ND)
42 (55)
32 (ND)
6 (ND)
>99 (ND)
>99 (20)
>99 (ND)
>99 (ND)
6
30
25
6
>200
>200
>200
>200
Isopropenyl acetateb
Vinyl acetateb
MeO
2b
OH
15
16
17
18
TBME
Toluene
TBME
Toluene
12 (ND)
6 (ND)
24 (69)
5 (ND)
98 (ND)
98 (ND)
>99 (15)
>99 (ND)
11
6
19.5
5
97
>200
>200
>200
Isopropenyl acetateb
Vinyl acetateb
2c
OH
19
20
21
22
TBME
Toluene
TBME
Toluene
87 (40)
73 (37)
67 (40)
38 (65)
>99 (41)
>99 (40)
>99 (32)
>99 (15)
47
42
40
28
>200
>200
>200
>200
Isopropenyl acetateb
Vinyl acetateb
2d
ND: No determined.
a
Reaction conditions: 1 mmol of racemic acetate, 1 mmol of Na2CO3, 200 mg of CAL-B, in 2 mL of organic solvent at 40 °C for 72 h.
b
c
Reaction conditions: 1 mmol of racemic alcohol, 3 mmol of enol ester, 200 mg of CAL-B, in 2 mL of organic solvent at room temperature for 24 h.
Conversion: C = eeS/eeP + eeS; Selectivity: E = Ln[(1 ꢁ C)(1 ꢁ ee(S))]/Ln[(1 ꢁ C)(1 + ee(S))].22
Isolated yield after separation by flash chromatography.
d
When the vinyl acetate was employed as the acyl donor, these
vinyl acetate in TBME (entry 17). The effect of the structure of
the aryl-substituent appeared more clearly in the acylation of 2d.
The lipase CAL-B was still active and selective with a naphthyl
group (entries 19–22); the high E value indicates that the spatial
structure of substrate 2d fits nicely in the active site of the enzyme
for acylation. This is not the case for substrate 2c, where the pres-
ence of a biphenyl moiety strongly reduces the reactivity of the
lipase (entries 15–18). The biphenyl group would undergo steric
interactions related to the substituted phenyl, which probably
results were inverted. In TBME, the conversion was slightly dimin-
ished from c = 35% to c = 25% (entries 9 and 13), while it was
strongly reduced in toluene from c = 27% to c = 6% (entries 10 and
14). The use of vinyl acetate as the acyl donor in TBME gave the
best CAL-B activity in the acylation of the four substituted-cyclic
alcohols 19.5% ꢀ C ꢀ 40% (entries 9, 13, 17 and 21). A drastic
decrease of the lipase activity was observed during the acylation
of 2c, and the best conversion c = 19.5% was obtained using the
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4
F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
interferes with the active conformation of the lipase. Similar obser-
vations were previously described by the Pseudomonas fluorescens
lipase with arylalkycarbinols.23 The impact of the steric effect com-
pletely declined during the alkaline hydrolysis, where the recorded
conversions for 3c and 3d are c = 49.5% and c = 31%, respectively
(entries 5–6). Such results highlight the steric and the spatial
requirements for both the reactivity and selectivity of the CAL-B
catalyzed acylation of substituted cyclohexanol.
Herein, we have compared two kinetic resolution approaches for
rac-2-arylcyclohexanols of different structures in an organic med-
ium with CAL-B: the alkaline hydrolysis by Na2CO3 and the acylation
using two enol esters. The structure and the electronic effects of the
aryl-substituent strongly impact both the reactivity and selectivity
of the CAL-B and they mutually with the nucleophile used according
to the solvent hydrophobicity. The alkaline hydrolysis by means of
CAL-B as a biocatalyst constitutes a practical route for the separation
of both antipodes of those chiral auxiliaries. Both enzymatic studied
approaches are enantiocomplementary with (R)-enantioselection of
the substrate. Based on the obtained results from the CAL-B cat-
alyzed kinetic resolution of the trans-substituted cyclohexanols
via alkaline hydrolysis and acylation, the best results were applied
to the direct resolution of the racemic isomeric mixture cis/trans-
2-phenyl-1-cyclohexanol.
mixture ( )-cis/trans-2-pheny-1-cyclohexanol 2a was obtained
via reduction of the corresponding ketone using NaBH4 in THF/
water, with a diastereoisomeric ratio of cis/trans: 20/80 (Sche-
me 4A). The corresponding acetate mixture was prepared via stan-
dard chemical acylation (Scheme 4B). The separation of all eight
isomers of both cis/trans-alcohol et cis/trans-acetate was per-
formed by chiral CG analysis (Fig. 1).
The enzymatic acylation was performed using isopropenyl acet-
ate as the acyl donor in toluene at room temperature, and moni-
tored by chiral GC. Aliquots from the reaction mixture at 24 h,
48 h and 72 h were analyzed. The enzymatic alkaline hydrolysis
was carried out in TBME and stirred for 72 hours at 40 °C. The
obtained results are given in Table 2.
The CAL-B catalyzed acylation and deacylation was performed
and showed that only the trans-stereoisomer was transformed,
with (R)-enantioselection and high E-values achieved (E > 200,
Table 2). The cis-stereoisomer remained untransformed due to its
spatial structure, which disadvantages the approach to the active
site of CAL-B. Similar observations have been reported during
the acylation of cis-b-hydroxy-cyclohexanol catalyzed by the
CAL-B24a and during the acylation of cis-4-tert-butyl-c-2-ethynyl-
r-1-cyclohexanol catalyzed by PSL. The study explains that the
cis-isomer reacts more slowly than the trans-analogue by
conformational effects on the lipase, which affect both the
reactivity and enantioselectivity of this lipase depending on the
equatorial or axial position of OH and the bulkiness of the
substituent at the 2-position.25
2.2. CAL-B catalyzed Acylation/Deacylation of ( )-cis/trans-2-
phenyl-1-cyclohexanol
To the best of our knowledge, the direct kinetic resolution of the
isomeric cis/trans mixture of 2-phenyl-1-cyclohexanol and deriva-
tives is very modestly reported.24 At this stage of our investigation,
we applied the optimized conditions for the kinetic resolution of
the racemic cis/trans-2-phenyl-1-cyclohexanol in order to examine
the CAL-B enantio- and diastereoselectivity during the approaches,
alkaline hydrolysis and acylation with enols esters. The isomeric
In our case, the acylation of cis/trans-2a using CAL-B showed a
high selectivity (E > 200), and a conversion of C = 48% after 72 h
of stirring was achieved (entry 3); and the trans-(1R,2S)-3a was
obtained with ee >99%. The reaction time was prolonged compared
to the acylation of the stereoisomer trans-2a where the same con-
version was achieved after 24 h under identical conditions (Table 1:
entry 8). Otherwise, the CAL-B maintains a high selectivity during
A
B
OAc
Ph
OH
Ph
OH
Ph
OAc
OR
Ph
OH
Ph
OAc
CAL-B
CAL-B
+
+
+
+
AI
Na2CO3
Ph
Ph
(
)-cis-2a
(1R,2S)-3a
2a
(1S,2R)-
(1R,2S)-2a
3a
(1S,2R)-
3a
)-cis-
2a
A- R=H:( )-(trans/cis)- (80/20)
(
3a
B- R= Ac:( )-(trans/cis)- (80/20)
Scheme 4. Enzymatic deacylation versus acylation of isomeric mixture of cis/trans ( )-2-phenyl-1-cyclohexyl derivatives.
trans-3a
cis-3a
trans-2a
cis-2a
Figure 1. Chromatogram of the isomeric mixtures cis/trans 2a and 3a.
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F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 2
CAL-B catalyzed acylation/deacylation of isomeric mixture ( )-cis/trans-2-phenyl-1-cyclohexyl derivatives
e
e
Entry
Approach
Acylation
Solvent
Toluene
eeS (%)
eeP
%
Cf (%)
Ef
1a
2b
3c
58
71
93
99
99
99
37
42
48
>200
>200
>200
4d
Deacylation
TBME
57
99
36
>200
a
b
c
d
e
f
Reaction conditions: 1 mmol of racemic alcohol, 3 mmol of isopropenyl acetate, 200 mg of CAL-B, in 2 mL of toluene at room temperature for 24 h.
Reaction conditions: for 48 h.
Reaction conditions: for 72 h.
Reaction conditions: 1 mmol of racemic acetate, 1 mmol of Na2CO3, 200 mg of CAL-B, in 2 mL of organic solvent at 40 °C for 72 h.
Enantiomeric excess are measured by chiral GC or chiral HPLC.
Conversion: C = eeS/eeP + ees; Selectivity: E =Ln[(1 ꢁ C)(1 ꢁ ee(S))]/Ln[(1 ꢁ C)(1 + ee(S))].22
the alkaline hydrolysis of the cis/trans-3a (E > 200) and the conver-
sion achieves the threshold of C = 36% after 72 h, in favor of trans-
(1R,2S)-2a with ee >99% (entry 4). For the same reaction time, a
conversion of c = 46% was recorded during the hydrolysis of
trans-2a-isomer (Table 1: entry 2). The CAL-B catalyzed kinetic
resolutions of the isomeric mixtures of either cis/trans-2a or
cis/trans-3a are also slowed down. Finally, the kinetic resolution
of the isomeric mixture of ( )-cis/trans-2a and ( )-cis/trans-3a by
means of CAL-B was enantio- and diastereoselective using the both
tandem process: alkaline hydrolysis/acylation.
on Bruker spectrometers (300 MHz for 1H, 75 MHz for 13C) instru-
ment and calibrated using residual deuterated solvent as an inter-
nal reference (peak at 7.26 ppm in 1H NMR and 3 peaks at 77 ppm
in 13C NMR in the case of CDCl3). The following abbreviations were
used to designate multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad, dd = doublet–doublet.
Chemical shifts were expressed in ppm and coupling constant (J)
in Hz. Melting points were measured using BÜCHI MELTING POINT
B-545. The mass spectra were obtained using FINNIGAN-MAT TSQ
7000 and FINNIGAN-MAT LQC spectrometers. The enantiomeric
excesses were measured by a chiral stationary phase HPLC: Chiral-
pakÒAD (4.6 ꢂ 250 mm) and ChiralpakÒIA (4.6 ꢂ 250 mm) col-
umn; or by gas chromatography (ThermoFinnigan Trace GC)
equipped with an automatic autosampler and using a CHIRALSIL-
DEX CB column (25 m; 0.25 mm; 0.25 mm). Retention times are
reported in minutes. Optical rotations were determined using a
Perkin-Elmer 341 Polarimeter at room temperature using a cell
of 1 dm length and k = 589 nm.
3. Conclusion
A novel hydrolysis process in TBME with sodium carbonate cat-
alyzed by CAL-B has been successfully extended to a set of trans-2-
arylcyclohexanols derivatives. The performance of this reaction
was improved with various types of trans-2-phenylcyclohexanol
and this allows direct access to a number of interesting chiral aux-
iliary with high ee values (up to >99%) and high selectivities
E > 200, allowing us to isolate enantiomerically pure alcohols and
acetates.
4.2. Synthesis procedures of all racemic compounds and their
NMR data
The effectiveness of CAL-B in alkaline hydrolysis was compared
to acylation with two enol esters in the same solvents. The CAL-B
exhibited a better affinity for the alkaline hydrolysis reaction com-
pared with acylation with the enol esters in the same organic sol-
vents. The structure of the aryl group had a significant influence on
both the reactivity of the CAL-B lipase. The substitution of the aro-
matic ring with a methoxy moiety at the ortho-position and the
hydrophobicity of the organic solvent caused a decrease in the
reactivity and selectivity.
The best conditions were applied to resolve a stereoisomeric
mixture cis/trans-2-phenyl-1-cyclohexanol and its corresponding
acetate in acylation and deacylation. The obtained results showed
the highly enantio- and diastereoselectivity of the CAL-B during
the acylation and the deacylation in favor of the trans-(R)-enan-
tiomer product to the detriment of the cis-isomer which does not
react. The CAL-B catalyzed resolution of mixture cis–trans-2-arylcy-
clohexanols is an easy and convenient approach to provides only one
stereoisomer of a mixture of four with high enantiomeric excess.
The trans-2-phenylcyclohexanol 2a is commercially available,
whereas the rest of the alcohols were prepared by opening of
cyclohexene oxide in the presence of Grignard reagent and a cat-
alytic amount of copper salts (I).
4.2.1. Synthesis procedure of racemic trans-2-arylcyclohexanols
2b–2d
To a stirred refluxing suspension of 0,26 g of Magnesium turn-
ing (10.7 mmol, 1 equiv) in 1.5 mL of dry THF, under an argon
atmosphere, was added dropwise a solution of 10 mmol (1 equiv)
of the appropriate bromoaryl diluted in 15 mL of THF. A drop of
dibromoethane was also added to initiate the reaction. After 1 h
of stirring, the solution was cooled to ꢁ78 °C and a suspension of
copper chloride(I) (48 mg, 0.045 equiv) was added. Ten minutes
later, a mixture of cyclohexene oxide (0.75 ml, 0.7 equiv) in 3 mL
of THF was added dropwise and stirred for ten minutes at the same
temperature. The temperature was then gradually raised to ambi-
ent temperature with stirring overnight. For the treatment, the
reaction mixture was quenched with 15 mL of saturated NH4Cl
and 10 mL of diethyl ether were added. The organic layer was
washed with brine and dried over magnesium sulphate, filtered
and concentrated in vacuo. The crude reaction mixture was puri-
fied by flash chromatography on silica gel (50/50 diethyl ether/pet-
roleum ether).
4. Experimental
4.1. General
All reagents purchased from either: Aldrich, Acros, TCI or Alfa
Aesar were used as received. The Candida antarctica lipase immobi-
lized 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. NMR spectra were recorded
4.2.1.1. trans-2-(2-Methoxyphenyl)-cyclohexanol 2b. Molecular
formula:
C13H18O2 206.28 g/mol; white crystals; yield = 60%
Melting point: 56.7 °C; Rf = 0.67. (Cyclohexane/Ethyl acetate:
80/20). 1H NMR (300 MHz, CDCl3) d (ppm) = 1.33–1.54 (ma, 4H,
Please cite this article in press as: Belkacemi, F. Z.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.010

6
F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
cycle), 1.97–1.85 (ma, 4H, cycle), 2.14–2.17 (ma, 1H, cycle), 2.98–
3.07 (ma, 1H, cycle), 3.72–3.8 (ma, 1H, cycle), 3.85 (s, 3H, O-CH3),
6.9–7.01 (ma, 2H aromatics), 7.2–7.3 (ma, 2H aromatics); 13C
NMR (75 MHz, CDCl3) d (ppm) = 157.8, 131.6, 127.5, 127.4, 121.1,
110.9, 74.1, 55.6, 45.1, 35.3, 32.4, 26.3, 25.2; MS (D-ESI; m/z):
229.68 ([M+Na]+, 100%).
cycle), 2.6–2.75 (m, 1H, HCAOAc), 4.9–5.1 (m, 1H, HCAPh), 7.1–
7.3 (m, 5H aromatics); 13C NMR (62.9 MHz, CDCl3): d (ppm)
= 170.4, 143.1, 128.2, 127.5, 126.4, 119.9, 75.9, 49.7, 33.8, 32.3,
25.8, 24.8, 21.
4.2.3.2. trans-2-Phenyl-cyclohexyl acetate 3a. Molecular for-
mula: C14H18O2 218.29 g/mol; crude oil, yield = 77%; Rf = 0.79
(Cyclohexane/Ethyl acetate 80/20). 1H NMR (300 MHz, CDCl3): d
(ppm) = 1.3–1.66 (ma, 4H cycle), 1.99 (s, 3H, OACACH3), 1.82–
1.98 (ma, 1H, cycle), 2.11–2.23 (ma, 1H cycle), 2.63–2.93 (m, 1H
cycle), 4.95–5.03 (ma, 1H cycle), 7.19–7.31 (ma, 5H aromatic);
13C NMR (75 MHz, CDCl3) d (ppm) = 170.4, 143.2, 128.3, 127.5,
126.4, 75.9, 49.8, 33.8, 32.4, 25.9, 24.8, 21.
4.2.1.2. trans-2-Biphenyl-4-yl-cyclohexanol 2c. Molecular for-
mula: C18H20O 252.15 g/mol; white crystal, yield = 69%; Melting
point: 131.2 °C; Rf = 0.69 (Petroleum ether/Ethyl acetate: 80/20).
1H NMR (300 MHz, CDCl3): d (ppm) = 1.38–1.67 (m, 4H, cycle),
1.85 (s, 2H, cycle), 1.93–1.98 (m, 2H, cycle), 2.17–2.21 (m, 1H,
OH), 2.50–2.58 (ma, 1H cycle), 3.70–3.78 (ma, 1H, cycle), 7.37–
7.44 (m, 3H aromatics), 7.48–7.05 (m, 2H aromatics), 7.61–7.68
(m, 4H aromatics); 13C NMR (75 MHz, CDCl3): d (ppm) = 144.6,
140.9, 139.7, 128.8, 128.4, 127.4, 127.2, 127, 74.4, 52.8, 34.6,
33.4, 26.1, 25.1; HRMS (D-ESI; m/z): 275.14 ([M+Na]+, 100%).
4.2.3.3.
trans-2-(2-Methoxy-phenyl)-cyclohexyl
acetate
3b. Molecular formula: C15H20O3 248,32 g/mol; white crystals,
yield = 78%; Melting point: 71.2 °C; Rf = 0.71, cyclohexane/Ethyl
acetate: (80/20); 1H NMR (300 MHz, CDCl3): d (ppm) = 1.28–1.55
(ma, 5H cycle), 1.77 (s, 3H, OACACH3), 1.83–1.93 (ma, 2H cycle),
2.10–2.26 (ma, 1H cycle), 3.15–3.22 (ma, 1H cycle) 3.82 (s, 3H,
OACH3), 5.12–5.20 (ma, 1H cycle), 6.73–6.82 (q, J = 8.7 Hz, 2H aro-
matics), 7.03–7.09 (ma, 2H aromatics); 13C NMR (75 MHz, CDCl3) d
(ppm) = 170.4, 157.3, 131.3, 127.1, 127, 120.6, 110.6, 74.8, 55.4,
32.8, 32.4, 25.9, 24.8, 20.9.
4.2.1.3. trans-2-(Naphthalen-2-yl)-cyclohexanol 2d. Molecular
formula: C16H18O 226.14 g/mol; yellow solid, yield = 77%; Melting
point: 93.8 °C; Rf = 0.53 (Dichloromethane); 1H NMR (300 MHz,
CDCl3): d (ppm) = 1.34–1.54 (m, 3H cycle), 1.58–1.73 (m, 1H cycle),
1.83–187 (m, 2H cycle), 1.92–1.99 (m, 2H cycle), 2.15–2.20 (m, 1H
cycle), 2.59–2.68 (m, 1H-OH), 3.73–3.81 (m, 1Hcycle), 7.41–7.45
(dd, J = 8.5 & 1.6 Hz, 1Haromatics), 7.48–7.57 (m, 2H aromatics),
7.76–7.88 (m, 4H aromatics). 13C NMR (75 MHz, CDCl3): d (ppm)
= 140.8, 133.6, 132.6, 128.4, 127.7, 126.6, 126.1, 126, 125.5, 74.2,
53.3, 34.5, 33.4, 26.1, 25.1; HRMS (D-ESI; m/z): 249.12 ([M+Na]+,
100%).
4.2.3.4.
trans-([1,10-Biphenyl]-4-yl)-cyclohexyl
acetate
3c. Molecular Formula: C20H22O2 294.16 g/mol; yellow crystal,
yield = 90%; Melting point: 98.5 °C; Rf = 0.92, (Petroleum ether/
Ethyl acetate: 80/20). 1H NMR (300 MHz, CDCl3): d (ppm) = 1.36–
1.48 (m, 2H cycle), 1.49–1.62 (m, 2H cycle), 1.84 (s, COACH3,
3H), 1.86 (m, 3H, cycle), 2.17 (m, 1H, cycle), 2.68–2.76 (m, 1H
cycle), 4.98–5.05 (m, 1H, cycle), 7.26–7.61 (m, 9H aromatics); 13C
NMR (75 MHz, CDCl3) d 170.5, 142.4, 141, 139.2, 128.8, 128,
127.1, 127, 75.9, 49.4, 34, 32.4, 25.9, 24.8, 21.1. HRMS (D-ESI;
m/z): 317.151 ([M+Na]+, 100%).
4.2.2. Synthesis of isomeric mixture cis/trans-2-phenyl-1-cyclo-
hexanol 2a
The racemic alcohol mixture was obtained after reduction of
1 equiv of the corresponding ketone (1 g, 5.7 mmol diluted in
35 mL of THF), using 6 equiv of NaBH4 (1.3 g, 34.4 mmol) in
(THF/H2O, 4/1 v/v, 52 mL/13 mL). The reaction mixture was stirred
under at 0 °C. The evolution of the reactions was monitored by TLC.
After the total consumption of the ketone, the reaction mixture
was neutralized by HCl (1 M), and the THF was evaporated. Then,
the alcohol was extracted from water by ethyl acetate and the
organic layers was dried with MgSO4 and evaporated in vacuo.
The resulting isomeric mixture of the alcohol was obtained pure
as white solid in 75% yield.
4.2.3.5. trans-2-(Naphthalen-2-yl)-cyclohexyl acetate 3d. Molec-
ular formula: C18H20O2 268.15 g/mol; yellow solid, yield = 92%;
Rf = 0.86 (Dichloromethane). 1H NMR (300 MHz, CDCl3): d (ppm)
= 0.99–1.08 (ma, 2H cycle), 1.11–1.27 (ma, 2H cycle); 1.29 (s, 3H,
OACH3), 1.36–1.48 (ma, 2H cycle), 1.54–1.60 (ma, 1H cycle),
1.77–1.82 (ma, 1H cycle), 2.7–2.79 (m, 1H cycle), 4.71–4.79 (m,
1H cycle), 6.96–7.06 (ma, 3H, aromatic), 7.35–7.40 (ma, 4H aro-
matic); 13C NMR (75 MHz, CDCl3): d (ppm) = 170, 140.5, 132.3,
132.2, 127.7, 127.5, 127.4, 125.8, 125.7, 125.1, 75.5, 49.6, 33.8,
32.2, 25.7, 24.6, 20.7; HRMS (D-ESI; m/z): 291.13 ([M+Na]+, 100%).
4.2.2.1. cis/trans-2-Phenyl-1-cyclohexanol 2a. Molecular for-
mula:
C12H16O 176.12 g/mol. Melting point: 53.3 °C. Rf = 0.5
(Cyclohexane/Ethyl acetate 80/20). 1H NMR (250 MHz, CDCl3): d
(ppm) = 1.33–1.87 (m, 11H, cycle + OH), 1.91–2.13 (m, 1H, cycle),
2.46–2.75 (m, 1H, HC-OH), 3.64–4.04 (m, 1H, HC-Ph), 7.02–7.61
(ma, 5H aromatics); 13C NMR (62.9 MHz, CDCl3): d (ppm) = 143.3,
128.8, 128.6, 128, 127.8, 126.9, 74.5, 53.2, 34.5, 33.4, 26.1, 25.1
4.3. Enzymatic kinetic resolutions procedures
4.3.1. Enzymatic acylation
All enzymatic acylation reactions were performed using 1 equiv
of racemic alcohol and 3 equiv of the appropriate acetyl donor dis-
solved in 2 mL of solvent. Next, 200 mg of CAL-B were added and
the mixture was shaken at room temperature for 24 h. After
removal of the enzyme by filtration and evaporation of the solvent,
the reaction mixture was purified by flash chromatography (petro-
leum ether/EtOAc: 8/2) to separate the obtained arylcyclohexylac-
etate and the furnished trans-aryl cyclohexyl acetate. The two
optically active compounds were analyzed by chiral HPLC or CG.
4.2.3. Procedure for the synthesis of racemic 2-arylcyclohexyl
acetates 3a–3d
The arylcyclohexyl acetates were synthesized by classical
chemical acylation via the corresponding racemic trans-arylcyclo-
hexanol alcohol (1 equiv), using 2 equiv of anhydride acetic,
2 equiv of Et3N, and a catalytic amount of 4-dimethylaminopy-
ridine (0.2 equiv) in 1 mL of diethyl ether. The final products were
obtained pure after standard work-up in excellent yields. All struc-
ture was confirmed by the 1H and 13C NMR spectra.
4.3.2. Enzymatic hydrolysis using carbonate salts
In a typical procedure, 1 mmol of racemic aryl cyclohexyacetate
was dissolved in 2 mL of solvent before the addition of 1 mmol of
sodium carbonate and 200 mg of CAL-B. The mixture was shaken at
40 °C for 72 h. After removal of the enzyme by filtration and evap-
oration of the solvent, the reaction mixture was purified by flash
4.2.3.1. cis/trans-2-Phenyl-cyclohexyl acetate 3a. Molecular for-
mula: C14H18O2 218.29 g/mol; crude oil, yield = 77%; Rf = 0.79
(Cyclohexane/Ethyl acetate 80/20). 1H NMR (250 MHz, CDCl3): d
(ppm) = 1.2–1.9 (ma, 10H cycle + 3HAOCACH3), 2.1–2.2 (m, 1H,
Please cite this article in press as: Belkacemi, F. Z.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.010

F. Z. Belkacemi et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
chromatography (Petroleum ether/EtOAc: 8/2) to separate the
residual arylcyclohexylacetate and the furnished trans-arylcyclo-
hexanol alcohol. The two optically active compounds were ana-
lyzed by chiral HPLC or CG.
and FNRS are gratefully acknowledged for financial support of this
work. Wallonie-Bruxelles International (WBI) is acknowledged for
a grant to Fatma-Zahra BELKACEMI.
A. Supplementary data
4.4. Chiral GC analysis and/or chiral HPLC analysis
Supplementary data (all experimental details, characterization
spectra (NMR and chiral chromatography) of all synthesized pro-
duct) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetasy.2017.09.010.
The absolute configurations of all chiral compounds (isolated
after chromatography) were determined by polarimetry by com-
parison with literature’s data. The conditions for the analysis of
alcohols and acetates are reported below:
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t1 = 9.04 min,
t2 = 9.61 min
(Tcolumn = 155 °C, flow 1.2 mL/min). [a]
89% ee, [Lit. [
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20 = ꢁ7 (c 0.1, CH2Cl2) for
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20 = +20 (c 0.1, CHCl3) for 42% ee, [Lit. [
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4.4.4. (1R,2S)-(ꢁ)-2-(2-Methoxyphenyl)-cyclohexyl acetate 3b
GC
(Chiralsil-Dex
CB,):
t1 = 7.86 min,
t2 = 7.99 min
(Tcolumn = 170 °C, flow 1.2 mL/min). [
99% ee.
a]
20 = ꢁ2.4 (c 0.1, CHCl3) for
D
4.4.5. (1R,2S)-(ꢁ)-2-([1,10-Biphenyl]-4-yl)-cyclohexanol 2c
Chiral HPLC: Chiralpak IA column, tRD10.11 min; tSD18.43 min.
Eluant (v,v): iso-hexane/EtOH: 90/10; flow 1 mL/min. [
(c 0.03, CH2Cl2) for 99% ee.
a]
20 = ꢁ41
D
4.4.6. (1R,2S)-(ꢁ)-2-([1,10-Biphenyl]-4-yl)-cyclohexyl acetate 3c
Chiral HPLC: Chiralpak IA column, tR = 4.44 min; tS = 5.06 min.
Eluant (v,v): iso-hexane/EtOH: 90/10; flow 1 mL/min. [
(c 0.05, CH2Cl2) for 99% ee.
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20 = ꢁ5
D
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a
]
20 = ꢁ24
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Chiral HPLC: Chiralpak IA column, tR = 7.59 min; tS = 7.99 min.
20
Eluant (v,v): iso-hexane/-PrOH: 98/2; flow 0.7 mL/min. [
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=
D
+32.8 (c 0.1, CH2Cl2) for 99% ee, [Lit. [
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99% ee (1R,2S)].10
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Acknowledgments
The Algerian Ministry of Higher Education and Scientific
Research (FNR 2000 and PNR), the Catholic University of Louvain,
Please cite this article in press as: Belkacemi, F. Z.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.010