Efficient access to both enantiomers of 3-(1-hydroxyethyl)phenol by regioselective and enantioselective CAL-B–catalyzed hydrolysis of diacetate in organic media by sodium carbonate

Article abstract of DOI:10.1002/chir.23025

In the present paper, we describe several pathways employing immobilized lipase from Candida antarctica B (CAL-B) as biocatalyst to prepare easily both enantiomers of 3-(1-hydroxyethyl)phenol. We have applied hydrolysis with Na₂CO₃ i

Full text of DOI:10.1002/chir.23025

Received: 14 May 2018
DOI: 10.1002/chir.23025
Revised: 3 August 2018
Accepted: 30 August 2018
R E G U L A R A R T I C L E
Efficient access to both enantiomers of 3‐(1‐hydroxyethyl)
phenol by regioselective and enantioselective CAL‐B–
catalyzed hydrolysis of diacetate in organic media by
sodium carbonate
Nabila Braia | Mounia Merabet‐Khelassi
| Louisa Aribi‐Zouioueche
Ecocompatible Asymmetric Catalysis
Abstract
Laboratory (LCAE), Department of
In the present paper, we describe several pathways employing immobilized lipase
from Candida antarctica B (CAL‐B) as biocatalyst to prepare easily both enantio-
mers of 3‐(1‐hydroxyethyl)phenol. We have applied hydrolysis with Na2CO3 in
organic media under mild conditions. The reaction parameters solvent effect,
amount of lipase, and Na2CO3 were examined with 3‐(1‐acetoxyethyl)phenyl ace-
tate as substrate. In alkaline hydrolysis, (R)‐3‐(1‐hydroxyethyl)phenol was
obtained with ee = 99% and (S)‐(−)‐3‐(1‐acetoxyethyl)phenol with ee = 98% at
optimal conversion (c = 50%) and high selectivity (E > 200). Two other
deacylation reactions were compared: alcoholysis with MeOH and with NEt3.
The acylation of 3‐(1‐hydroxyethyl)phenol with vinyl acetate was also examined.
Alkaline hydrolysis gave the best results, while good regioselectivity and
enantioselectivity were observed in alcoholysis and acylation reactions. Finally,
(S)‐ and (R)‐3‐(1‐hydroxyethyl)phenol (ee > 98%), key intermediates for the
synthesis of important drugs, were prepared from the corresponding racemic
diacetate through alkaline hydrolysis.
Chemistry, Badji Mokhtar University—
Annaba, Annaba, Algeria
Correspondence
Louisa Aribi‐Zouioueche, Ecocompatible
Asymmetric Catalysis Laboratory (LCAE),
Department of Chemistry, Badji Mokhtar
University—Annaba, BP 12, 23000
Annaba, Algeria.
Email: louisa.zouioueche@gmail.com;
louisa.zouioueche@univ‐annaba.dz
Funding information
Algerian Ministry of Higher Education
and Scientific Research (MESRS, FNR
2000)
KEYWORDS
alkaline hydrolysis, Candida antarctica Lipase B, carbonate salts, diol, enzymatic resolution,
nonaqueous media
1 | INTRODUCTION
for the synthesis of enantiomerically pure compounds
especially by transesterification in organic solvents or by
The use of lipases in organic synthesis makes it possible
to obtain enantiopure building blocks under mild, ecolog-
ical, and environmentally friendly conditions.1,2 Enzy-
matic kinetic resolution is one of the most potent and
important method to access enantiopure compounds3,4
and is widely used for the synthesis of chiral intermedi-
ates for pharmaceutical chemistry5,6 where approxi-
mately 80% of the drugs currently under development
are chiral.7,8 Lipases (EC 3.1.1.3) are the most widely
employed biocatalysts and have high industrial potential
hydrolysis in aqueous or biphasic media.9,10 Enantiopure
(hydroxyalkyl)phenols and their derivatives are impor-
tant synthetic intermediates to develop drugs,11,12 thus
highlighting the industrial interest.13-16 Enantiomers of
3‐(1‐hydroxy‐ethyl)phenol and its derivatives are impor-
tant synthetic intermediates for preparing drugs such as
(S)‐(−)‐Rivastigmine, an acetylcholinesterase inhibitor
that is prescribed for the treatment of mild to moderate
dementia in patients with Alzheimer's disease and
Parkinson's disease,17,18 and (R)‐(−)‐Phenylephrine, a
Chirality. 2018;1–9.
wileyonlinelibrary.com/journal/chir
© 2018 Wiley Periodicals, Inc.
1

2
BRAIA ET AL.
potent adrenergic agent and β‐receptor sympathomimetic
drug, exclusively commercialized in the optically active
form (Figure 1).
path B, MeOH was used as the nucleophile of alcoholysis,
and for path C, the deacylation was carried out in the
presence of NEt3 as additive. The acylation of the (R,S)‐
3‐(1‐hydroxy‐ethyl)phenol is also examined (path D)
(Figure 2). Up to now, there are no examples of the reso-
lution of the racemic diacetate 1 by classic enzymatic
hydrolysis.
Chemoenzymatic synthesis of enantiopure (S)‐(−)‐
Rivastigmine19-23 or (R)‐(−)‐Phenylephrine24-27 has been
performed with multipathway processes involving asym-
metric transformations of 3‐hydroxyacetophenone to
optically active corresponding esters. Lipase‐catalyzed
kinetic resolution for the production of enantiomerically
pure alcohols precursors is a less described path.28,29
The development of procedures to obtain
chemoselectively monoacetylated compounds from mole-
cules containing phenolic and aliphatic hydroxyl groups
is a challenge.30,31 Candida antarctica Lipase B as a
robust and environmentally benign biocatalyst with high
stereoselectivity is attractive for a wide range of applica-
tions.32-35 It catalyzes specifically regioselective and
enantioselective acylations of polyfunctional compounds
in mild conditions.36,37 This lipase was described as the
best catalyst for the regioselective monoacetylation of var-
ious diols that are important structural subunits in bio-
logically active compounds38,39 and was applied to
chemoselective acylation of 4‐(2‐hydroxyethyl)phenol.40
We previously developed a simple and practical enzy-
matic hydrolysis method with sodium carbonate in
organic medium catalyzed by CAL‐B.41 This alkaline
2 | MATERIALS AND METHODS
2.1 | General information
All reagents purchased from Aldrich were used as
received. The C antarctica Lipase B immobilized on
acrylic resin (CAL‐B) was purchased from Aldrich. Spe-
cific activity >10 000 U/g used without any pre‐treat-
ment. 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. Nuclear magnetic reso-
nance (NMR) spectra were recorded on Bruker spectrom-
1
eters (300 MHz for H and 75 MHz for 13C) instrument
and calibrated using residual deuterated solvent as an
1
internal reference (peak at 7.26 ppm in H NMR and
three peaks at 77 ppm in 13C NMR in the case of CDCl3
and DMSO). The following abbreviations were used to
designate multiplicities: s = singlet, d = doublet, t = trip-
let, q = quartet, m = multiplet, br = broad, and dd = dou-
ble doublet. Chemical shifts were expressed in parts per
million and coupling constant (J) in hertz. The enantio-
meric excesses were measured by a chiral stationary
phase High‐Performance Liquid Chromatography
(HPLC): Chiralpak OD‐H column (4.6 × 250 mm) and
Chiralpak IA column (4.6 × 250 mm); retention times
hydrolysis
has
been
successfully
applied
to
arylalkylcarbinol acetates,42 N,O‐protected amino alco-
hols,43 and 2‐aryl‐1‐cyclohexyl acetates.44 In all cases,
CAL‐B showed high enantioselectivity and broad sub-
strate specificity simultaneously after adjusting reactions
parameters. In this context, and in the continuity of our
investigations, we studied the regioselectivity and
enantioselectivity of the lipase CAL‐B in kinetic resolu-
tion of (R,S)‐3‐(1‐hydroxy‐ethyl)phenol and its diacetates
by deacylation/acylation paths in organic medium. The
goal can be achieved by two routes, one by the selective
removal of a single acyl group from the diacetylated
compounds and the other by the selective monoacylation
of the dihydroxy compounds. The first method of
deacylation (path A) was CAL‐B–catalyzed alkaline
hydrolysis in organic media via sodium carbonate. In
FIGURE 2 Different routes for enzymatic kinetic resolution
FIGURE 1 Biological interest of both
enantiomers of diol

BRAIA ET AL.
3
are reported in minutes. Optical rotations were deter-
mined using a Perkin‐Elmer 341 Polarimeter at room
amount of sodium carbonate and CAL‐B lipase. The sus-
pension was stirred at 40°C for the indicated time. The
reaction mixture was filtered on celite and
concentrated in vacuo. The obtained product and the
remaining substrate were separated by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate: 80/20)
and analyzed by chiral HPLC. (S)‐(−)‐3‐(1‐acetoxyethyl)
phenol 2: yield = 44%. Chiral HPLC: Chiralpak IA col-
umn, tR = 26.05 minutes, tS = 28.50 minutes. Eluant
(v,v): hexane/iPrOH: 97/03; flow rate: 1 mL/min.
temperature using
a
cell of 1‐dm length and
λ = 589 nm. The absolute configurations of all chiral
compounds were determined by polarimetry by compari-
son with literature data.
2.2 | General procedure of preparation of
racemic substrates
2.2.1 | Preparation of rac‐3‐(1‐hydroxyethyl)
phenol 3
ee = 98%. (S)‐2 [α]20 = −109.3 (c 0.1, MeOH).
D
[Lit. [α]20 = +108.2 (c 1, MeOH), 98% ee (R)].23 (R)‐
D
(+)‐3‐(1‐hydroxyethyl)phenol 3: yield = 40%. Chiral
HPLC: Chiralpak OD‐H column, tR = 14.52 minutes,
tS = 16.48 minutes. Eluant (v,v): heptane/iPrOH: 92/08;
flow rate: 1 mL/min. ee > 99%. (R)‐3 [α]D = +33.83
The racemic diol 3 was prepared by the reduction of 3‐
hydroxyacetophenone (0.136 g, 1 mmol) with sodium
borohydride (0.228 g, 6 mmol) in tetrahydrofuran
(THF)/H2O (80/20) mL. The reaction mixture was stirred
under at 0°C. The evolution of the reactions was moni-
tored by TLC. After 2 hours, the crude reaction mixture
was quenched by adding a 10% (v/v) hydrochloric acid
solution, after which the solvent was evaporated in vac-
uum and the mixture extracted with ethyl acetate. The
organic layer was concentrated in vacuum followed by
purification with silica gel chromatography using ethyl
acetate as the mobile phase to produce rac‐3. Yield = 80%.
1H NMR (300 MHz, DMSO) δ = 1.28 (d, J = 6.5 Hz, 3H),
4.62 (q, J = 6.5 Hz, 1H) 5.08 (d, 1H, OH), 6.57‐6.61 (dd,
1H), 6.71‐6.76 (m, 2H), 7.08 (t, J = 7.5 Hz, 1H), 9.26
(s, 1H, OH). 13C NMR (75 MHz, DMSO) δ = 26, 68.1,
112.2, 113.4, 116, 128.9, 149, 157.1.
(c 0.1, MeOH). [Lit. (R)‐3a: [α]20 = +32 (c 1, MeOH),
D
99% ee].45
2.3.2 | Alcoholysis of racemic diacetate 1
with CAL‐B
To 1 mmol (m = 0.222 g) of the racemic diacetate 1 dis-
solved in 3 mL of THF are added 4 mmol of MeOH,
40 mg of CAL‐B, and 60 mg of molecular sieves 4 Å.
The suspension was stirred at 40°C for 72 hours. The
reaction mixture was filtered on celite and concentrated
in vacuo. The obtained product and the remaining
substrate were separated by flash chromatography on
silica gel (petroleum ether/ethyl acetate: 80/20)
and analyzed by chiral HPLC. (S)‐(−)‐3‐(1‐acetoxyethyl)
2.2.2 | Synthesis of rac‐3‐(1‐acetoxyethyl)
phenyl acetate 1
phenol 2: yield = 40%. [α]20 = −56.2 (c 0.1, MeOH).
D
(R)‐(+)‐3‐(1‐hydroxyethyl)phenol 3: yield
=
30%.
The diacetate 1 was synthesized by classical chemical
acetylation of the rac‐1‐(3‐hydroxyphenyl)‐ethanol 3
(1 equiv), using 3 equiv of acetic anhydride, 2.4 equiv of
Et3N, and catalytic amount of 4‐dimethylaminopyridine
(0.2 equiv) in 4 mL of CH2Cl2. The acetates are obtained
pure after standard workup. Yield = 80%. 1H NMR
(300 MHz, CDCl3) δ = 1.52 (d, J = 6.6 Hz, 3H), 2
(s, 3H), 2.29 (s, 3H), 5.86 (q, J = 6.5 Hz, 1H), 7 (dd, 2H),
7.08 (s, 1H), 7.19 (t, 1H). 13C NMR (75 MHz, CDCl3)
δ = 21.2, 22.2, 71.7, 119.3, 121.1, 123.6, 129.5, 143.4,
150.8, 169.4, 170.2.
[α]20 = +33.8 (c 0.1, MeOH).
D
2.3.3 | Deacylation of rac‐diacetate 1 with
CAL‐B in the presence of Et3N
To 1 mmol (m = 0.222 g) of racemic diacetate 1 dissolved
in 3 mL of THF, 4 mmol (m = 0.404 g) of the
triethylamine, 40 mg of CAL‐B, and 60 mg of molecular
sieves 4 Å were added. The suspension was stirred at
40°C for 72 hours. The outcome of the reaction was mon-
itored by TLC. Only the monoacetate 2 was formed. The
reaction mixture was filtered on celite and concentrated
in vacuo. Rac‐3‐(1‐acetoxyethyl)phenol 2: Yield = 67%.
1H NMR (300 MHz, CDCl3) δ = 1.52 (d, J = 6.6 Hz,
3H), 2 (s, 3H), 5.84 (q, J = 6.5 Hz, 1H), 6.02 (br, 1H,
OH), 6 (dd, J1 = 7.9 Hz, J2 = 2.5 Hz, 1H), 6.82 (s, 1H),
6.89 (d, J = 7.7 Hz, 1H), 7.2 (t, J = 7.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ = 21.2, 22.2, 72.6, 113.2, 115,
118.1, 129.9, 143.4, 150, 171.2.
2.3 | General procedure for the enzymatic
kinetic resolution pathways
2.3.1 | Alkaline hydrolysis of rac‐diacetate
1 with CAL‐B
To 1 mmol (m = 0.222 g) of the racemic diacetate 1 dis-
solved in organic solvent are added an appropriate

4
BRAIA ET AL.
sodium carbonates. Several organic solvents having
diverse hydrophobicities were used: THF, toluene, ace-
tone, heptane, and dichloromethane. The alkaline hydro-
lysis experiments were carried out using diacetate 1
(1 mmol), Na2CO3 (0.5 mmol), and 40 mg of CAL‐B dis-
solved in 2 mL of the organic solvent.41 The reaction
was stirred for 72 hours at 40°C, and the evolution of
the reaction was monitored by TLC (Scheme 1). Conver-
sions and enantiomeric excesses were determined by chi-
ral HPLC after separations by flash chromatography. The
results are summarized in Table 1.
Results in Table 1 show an important influence of the
solvent on the regioselectivity of CAL‐B in alkaline hydro-
lysis of diacetate 1. Moreover, selective hydrolysis of phe-
nolic hydroxyl groups in the presence of aliphatic
hydroxyl group was achieved. The fast regioselective
cleavage of the acetyl moiety depends on the solvent
hydrophobicity. The diol 3 and the monoacetate 2 were
recovered only in THF and acetone as solvents (Table 1,
entries 1‐2). In both cases, enantiomer ratio is high
(E > 200) and the diol 3 was recovered enantiopure
(ee > 99%). More importantly, conversion was recorded
in THF as solvent compared with acetone in which dena-
turation of enzyme could occur.47 In toluene or in dichlo-
romethane, monoacetate 2 and residual diacetate 1 are
obtained both in racemic form (Table 1, entries 3‐4).
Surprisingly in heptane, hydrophobic solvent, only the
cleavage of the aromatic acetyl was observed with total
conversion in favor of the monoacetate 2 (Table 1,
entry 5). The above results show that the THF is the
2.3.4 | Enzymatic acylation of 3‐(1‐
hydroxyethyl)phenol 3
The enzymatic acetylation was performed using 1 equiv
of 3‐(1‐hydroxyethyl)phenol (0.138 g, 1 mmol) and
(0.258 g, 3 mmol) of the vinyl acetate dissolved in 3 mL of
THF. Then, 40 mg of CAL‐B was added and the resulting
mixture was stirred at room temperature for 72 hours. After
removal of the enzyme by filtration and evaporation of the
solvent, the obtained product and the remaining sub-
strate were separated by flash chromatography on silica
gel (petroleum ether/ethyl acetate: 80/20) and analyzed
by chiral HPLC. (S)‐(−)‐3‐(1‐hydroxyethyl)phenol 3:
yield = 37%. Chiral HPLC: Chiralpak OD‐H column,
tR = 14.52 minutes, tS = 16.48 minutes. Eluant (v,v): hep-
tane/PrOH: 92/08; flow rate: 1 mL/min. ee = 87%. (S)‐3
[α]20 = −28 (c 0.1, MeOH). (R)‐(+)‐3‐(1‐acetoxyethyl)
D
phenol 2: Yield = 35%. Chiral HPLC: Chiralpak IA col-
umn; tR = 26.05 minutes, tS = 28.50 minutes. Eluant (v,
v): hexane/iPrOH: 97/03; flow rate: 1 mL/min. ee = 94.2%.
(R)‐2 [α]D = +103.8 (c 0.11, MeOH).
3 | RESULTS AND DISCUSSION
3.1 | CAL‐B–catalyzed alkaline hydrolysis
of racemic diacetate 1 (path A)
The studies of the solvent effect have been firstly con-
ducted on the alkaline hydrolysis of 3‐(1‐acetoxyethyl)
phenyl acetate 1 catalyzed by CAL‐B in the presence of
SCHEME 1 Lipase CAL‐B–catalyzed
hydrolysis of diacetate 1 in the presence of
Na2CO3
TABLE 1 Solvent effect in CAL‐B–catalyzed alkaline hydrolysis of diacetate 1
1
2
3
Entrya
Solvent (LogP)
ee, %b Yield, %c
ee, %b Yield, %c
ee, %b Yield, %c
c, %d
Ee
1
2
3
4
5
THF (0.48)
Acetone (−0.23)
CH2Cl2 (1.01)
Toluene (2.5)
Heptane (4)
‐
31 (40)
4 (15)
>99% (21)
24
4
>200
‐
>99 (trace)
>200
6 (8)
5 (10)
‐
1.5 (40)
4 (50)
‐
‐
‐
80
1
1
‐
55.6
100
4 (65)
Bold entries indicate the best result.
aReaction conditions: 1 mmol of racemic diacetate, 0.5 mmol of Na2CO3, 40 mg of CAL‐B, in 2 mL of organic solvent at 40°C for 72 hours.
bEnantiomeric excess of recovered products are measured by chiral high‐performance liquid chromatography.
cIsolated yields.
dConversion: c = eeS/eeP + ees.46
eEnantiomeric ratio: E = ln [(1 −c) (1 − ee(S))]/ln [(1 − c) (1 + ee(S)).

BRAIA ET AL.
5
suitable organic media for the alkaline‐enzymatic hydro-
lysis of diacetate 1. In order to optimize the alkaline
hydrolysis conditions, various parameters were examined
such as the amount of lipase, the amount of Na2CO3, and
the reaction time. Conversions and enantiomeric excesses
were determined by chiral HPLC after separations by
flash chromatography. The results are summarized in
Table 2.
Results in Table 2 show a high regioselectivity and
enantioselectiviy of CAL‐B in alkaline hydrolysis of
diacetate 1 in the optimized experimental conditions.
(R)‐diol 3 was obtained enantiopure with a high selectiv-
ity (E > 200), but conversion depends on the other
parameters of the reaction: catalytic charge, amount of
Na2CO3, and reaction time. The use of 0.2 equiv of
Na2CO3 in the presence of 40 mg of enzyme during
72 hours yielded the racemic monoacetate 2 (72% yield)
(Table 2, entry 2). No reaction was occurred without
Na2CO3 (Table 2, entry 1). Progressive increase of the
amount of Na2CO3 from 0.3 to 1 equiv enhances signifi-
cantly the conversion ratio of the alkaline hydrolysis
(Table 2, entries 3‐6). Prolongation of the reaction time
to 96 hours improves the conversion rate up to c = 35%
(Table 2, entry 8). Increasing the amount of Na2CO3
(2 equiv) with dilution of the reaction medium for a bet-
ter solubility achieves 40% conversion, which does not
change after a longer reaction time up to 96 hours
(Table 2, entries 10‐12). However, the increase of the
lipase loading to 120 mg allows reaching the optimal res-
olution (c = 50% and E > 200). The enantiomers (S)‐
monoacetate 2 and (R)‐diol 3 are recovered enantiopure
(ee > 98%) (Table 1, entry 13). This result supports our
hypothesis that the alkaline hydrolysis efficiency is due
probably to the water provided by the enzyme itself.41
3.2 | CAL‐B–catalyzed deacylation of
racemic diacetate 1 and acylation of
racemic diol 3 (paths B, C, and D):
comparison of regioselectivity and
enantioselectivity
Then, we intended to examine the regioselectivity and the
enantioselectivity of the CAL‐B in other kinetic resolution
approaches of deacylation of diacetate 1 and in the
TABLE 2 CAL‐B–catalyzed alkaline hydrolysis of diacetate 1: study of several parameters
(S)‐2
ees, %e Yield, %f
(R)‐3
eep, %e Yield, %f
Na2CO3,
Eq.
CAL‐
B, mg
Entry
Time, h
c, %g
Eh
1a
‐
40
40
40
40
40
40
‐
72
72
72
72
72
72
72
96
96
72
96
96
96
‐
‐
‐
‐
‐
‐
NR
‐
‐
‐
2a
0.2
0.3
0.4
0.5
1
0.1
12
72
55
50
40
44
‐
3a
4a
>99
>99
>99
>99
‐
8
10
14
23
25
NR
35
36
40
40
40
50
>200
>200
>200
>200
‐
17
31
33
‐
10
21
20
‐
5a
6a
7b
1
8a
9c
1
40
40
40
40
80
120
53
55
67
67
67
98
34
36
44
37
30
44
>99
>99
>99
>99
>99
>99
30
30
36
38
28
40
>200
>200
>200
>200
>200
>200
1.5
2
10c
11c
12c
13d
2
2
2
Bold entries indicate the best result.
Abbreviation: NR, no reaction.
a1 mmol racemic diacetate an appropriate amount of Na2CO3, 40 mg of CAL‐B in 2 mL of tetrahydrofuran (THF) at 40°C.
bWithout lipase in presence of 0.02 mL of water.
c4 mL of THF.
d6 mL of THF.
eEnantiomeric excess of recovered alcohols and remaining acetates are measured by chiral high‐performance liquid chromatography.
fIsolated yields.
gConversion: c = eeS/eeP + ees.46
hEnantiomeric ratio: E = ln [(1 − c) (1 − ee(S))]/ln [(1 − c) (1 + ee(S))].46

6
BRAIA ET AL.
TABLE 3 Comparison CAL‐B–catalyzed acylation/deacylation approaches
[(S)‐substrate]
[(R)‐product]
Entry
Approach
Nucleophile
ees, %e Yield, %f
eep, %e Yield, %f
c, %g
Eh
1a
2b
3c
Deacylation
Na2CO3
MeOH
Et3N
[2] 98 (44)
[2] 51 (40)
[2] 1.5 (67)
[3] 99 (40)
[3] 99 (30)
‐
50
34
100
>200
>200
‐
4d
Acylation
[3] 87 (37)
[2] 94.2 (35)
48
70
Bold entries indicate the best result.
a1 mmol racemic diacetate, 2 mmol Na2CO3, and 120 mg CAL‐B in 6 mL of tetrahydrofuran (THF) at 40°C for 96 hours.
b1 mmol racemic diacetate, 4 mmol of MeOH, and 40 mg CAL‐B in 3 mL of THF at 40°C for 72 hours.
c1 mmol racemic diacetate, 4 mmol of Et3N, and 40 mg CAL‐B in 3 mL of THF at 40°C for 72 hours.
d1 mmol racemic diol, 3 mmol vinyl acetate, and 40 mg CAL‐B in 3 mL of THF at room temperature for 72 hours.
eEnantiomeric excess of recovered alcohols and remaining acetates are measured by chiral high‐performance liquid chromatography.
fIsolated yields.
gConversion: c = eeS/eeP + ees.46
hEnantiomeric ratio: E = ln [(1 − C) (1 − ee(S))]/ln [(1 − C) (1 + ee(S))].46
acylation of diol 3 using enol ester as an acylating agent
(path D). Two deacylation routes were studied:
alcoholysis using methanol as acetyl acceptor48 (path B)
and with the Et3N as basic additive49 (path C) according
to previous works (Figure 2). The alcoholysis was carried
out on 1 mmol of diacetate 1 and 4 equiv of MeOH in the
presence of 40 mg of CAL‐B and 60 mg of molecular
sieves 4 Å in 3 ml THF. The deacylation using
triethylamine was performed under the same conditions
using 4 equiv of tertiary amine. The acylation of diol 3
was performed using 3 equiv of vinyl acetate in the same
solvent. All kinetic resolution reactions were stirred at
40°C during 72 hours. The evolution of the reaction was
monitored by TLC. The conversions and the enantio-
meric excesses of products were quantified by chiral
HPLC after separations by flash chromatography. Results
of comparison CAL‐B–catalyzed acylation/deacylation
approaches are summarized in Table 3.
The kinetic resolution of racemic diacetate 1 via CAL‐
B–catalyzed alcoholysis (path B) shows
a
high
enantioselectivity and furnishes the enantiopure (R)‐3
diol (ee > 99%) at conversion rate of c = 34%. The
deacylation using triethylamine leads only to racemic
monoacetate 2 (path C). The acylation of racemic diol 3
gives (R)‐monoacetate 2 with ee = 94.2% and the (S)‐diol
3 with ee = 87% and selectivity E = 70 at 48% conversion
rate (path D). The results of the different pathways
(Table 3) show clearly that the best results in terms of
reactivity and enantioselectivity were afforded by CAL‐
B–catalyzed alkaline hydrolysis reaction (path A)
(Figure 3).
Lipase was highly regioselective and enantioselective;
the (S)‐monoacetate 2 and (R)‐diol 3 enantiomers
FIGURE 3 Chromatograms of enantiomers (path A)

BRAIA ET AL.
7
were obtained enantiomerically pure in high yields. CAL‐
ORCID
B
lipase leads to selective hydrolysis of the
Mounia Merabet‐Khelassi
7149-5878
Louisa Aribi‐Zouioueche
7206
http://orcid.org/0000-0002-
phenolic hydroxyl group and (R)‐enantioselection of the
chiral hydroxyl. Furthermore, alkaline hydrolysis of
diacetate 1 and acylation of diol 3 are selective
and enantiocomplementary reactions. Alkali‐mediated
enzymatic hydrolysis in organic media gives access to
(S)‐monoacetate 2 and (R)‐diol 3 enantiomers in a
straightforward and practical manner. This approach that
makes it possible to valorize both enantiomers of racemic
3‐(1‐hydroxyethyl)phenol is described for the first time.
http://orcid.org/0000-0002-2619-
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4 | CONCLUSION
We developed a novel and efficient process to access
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How to cite this article: Braia N, Merabet‐
Khelassi M, Aribi‐Zouioueche L. Efficient access to
both enantiomers of 3‐(1‐hydroxyethyl)phenol by
regioselective and enantioselective CAL‐B–
catalyzed hydrolysis of diacetate in organic media
by sodium carbonate. Chirality. 2018;1–9. https://
doi.org/10.1002/chir.23025
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