Kinetic and chemical resolution of different 1-phenyl-2-propanol derivatives

Article abstract of DOI:10.1016/j.tetasy.2006.07.019

Seven chiral target molecules containing a hydroxy group have been resolved by both biocatalytic and chemical means. The lipase-catalyzed acylation mainly yielded the acylated derivative of the (R)-alcohols with moderate enantiomeric excess and the enantiopure (S)-alcohols. In the course of the chemical resolution, first the dicarboxylic acid monoesters of the target molecules were synthesized and the resolution of these monoesters was attempted by different homochiral bases. By re-resolution and/or optimization of the reaction time and/or recrystallization, respectively, each molecule was produced in very high enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2006.07.019

Tetrahedron: Asymmetry 17 (2006) 2220–2234
Kinetic and chemical resolution of different
1-phenyl-2-propanol derivatives
a
b
Violetta Kiss,a Gabriella Egri,a, Jozsef Balint, Istvan Ling,
*
´
´
´
b
a
´
´
´
Jozsef Barkoczi and Elemer Fogassy
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics,
PO Box 91, H-1521 Budapest, Hungary
bEGIS Pharmaceuticals Ltd, PO Box 100, H-1475 Budapest 10, Hungary
Received 20 June 2006; accepted 17 July 2006
Abstract—Seven chiral target molecules containing a hydroxy group have been resolved by both biocatalytic and chemical means. The
lipase-catalyzed acylation mainly yielded the acylated derivative of the (R)-alcohols with moderate enantiomeric excess and the enantio-
pure (S)-alcohols. In the course of the chemical resolution, first the dicarboxylic acid monoesters of the target molecules were synthesized
and the resolution of these monoesters was attempted by different homochiral bases. By re-resolution and/or optimization of the reaction
time and/or recrystallization, respectively, each molecule was produced in very high enantiomeric purity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
benzodiazepines, which are chiral structures, thus their
enantiomers are of interest.
Benzodiazepines explain their therapeutically effect (anxio-
litic, sedatohipnotic, anticonvulsive and muscle relaxant)
on the benzodiazepine binding site of the GABAA receptor:
they enhance the GABA-erg neurotransmission in the cen-
tral nervous system. Herein we report the kinetic and
chemical resolution of seven compounds (Scheme 1: 1-phen-
yl-2-propanol 1, 1-benzo[1,3]dioxol-5-yl-2-propanol 2, 1-
(3-chloro-phenyl)-2-propanol 3, 1-(4-chloro-phenyl)-2-pro-
panol 4, 1-(3,4-dichloro-phenyl)-2-propanol 5, 1-(4-fluoro-
phenyl)-2-propanol 6, 1-(3-bromo-4-methoxy-phenyl)-2-
propanol 7) as starting materials for new derivatives of
Enantiomerically pure compounds can be obtained by clas-
sical resolution techniques via diastereoisomers,1 enantio-
selective reduction of the corresponding ketones by chiral
hydride donors,2 micro-organisms3 or oxidoreductases,4
or by enantioselective hydrolases of the corresponding
esters using hydrolases or micro-organisms.5 The tremen-
dous potential of enzymes as practical catalysts is well
recognized.6,7 In particular, they are being increasingly
exploited for asymmetric synthetic transformation,8 fuelled
by the growing demand for enantiopure pharmaceuticals.9
Today, kinetic resolution of racemic substrates by enzyme
catalysis has become a standard reaction in organic synthe-
sis.7,10 Enzymes, especially lipases,11,12 have some advanta-
ges for use in stereoselective transformations since they are
highly selective, environmentally friendly and easy to work
with.
racemic alkohol
R1
H
R2
R1
R2
rac-1
rac-2
rac-3
rac-4
rac-5
rac-6
rac-7
H
benzo[1.3]dioxole
Cl
H
Cl
H
Br
H
Cl
Cl
F
OH
rac-alcohol
Resolution via diastereoisomeric salt formation is usually
based on the separation of diastereoisomers by fractional
crystallization.2 When a racemate contains a basic or an
acidic group, its resolution can generally be accomplished
by diastereoisomeric salt formation as among the large
number of basic or acidic resolution agents at least one
effective resolution agent can be found.1,13 Resolution of
CH3O
Scheme 1. The target molecules.
*
Corresponding author. Fax: +36 1 463 3648; e-mail addresses: vikiss@
mail.bme.hu; egrig@ella.hu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.019

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2221
alcohols is more complicated. One can attempt to prepare
2. Results and discussion
an acidic or basic derivative and seek a salt forming resolv-
ing agent. The separated and purified enantiomers can be
then converted back to the starting molecule.
In the course of the investigation of the resolution by
biocatalytic method first, for 1, several enzymes were tested
in vinyl acetate. The results are shown in Table 1.
There are several reports on the lipase-catalyzed resolu-
tion of the racemic 1-phenyl-2-propanol rac-1 and success-
ful resolution procedures of this alcohol by kinetic
reaction have been described.14–18 We found only some re-
ports available for the preparation of the enantiomers of
1-phenyl-2-propanol derivatives,19–27 but no paper on
the chemical resolution has been found in the literature.
Racemic 1 is commercially available, and compounds 2,
3, 4, 5, 6 and 7 are available by the reduction of the
corresponding propanones (1-benzo[1,3]dioxol-5-yl-2-
propanone, 1-(3-chloro-phenyl)-2-propanone, 1-(4-chloro-
phenyl)-2-propanone, 1-(3,4-chloro-phenyl)-2-propanone,
1-(4-fluoro-phenyl)-2-propanone and 1-(3-bromo-4-meth-
oxy-phenyl)-2-propanone, respectively). Except for com-
pounds 1 and 2, no biocatalytic resolution has been
reported, although it can be a highly selective, easily man-
ageable, economical and environmentally friendly method.
In addition, they have not been found to be resolved by
chemical means, which can be very useful in the pharma-
ceutical practice. Herein we report on their lipase-cata-
lyzed acylation and resolution via diastereoisomeric salt
formation.
In all cases the (R)-enantiomer was preferentially acylated,
and a mixture of the unreacted (S)-alcohol and the (R)-ace-
tate was obtained. As it can be seen in Table 1, high enan-
tiomer separation was obtained by Amano AK, Amano
PS-C, PfL and Novozym 435. Further investigations were
elaborated with Amano PS-C enzyme: the effect of different
solvents and acylating agent on the separation of the enan-
tiomers was examined. The solvents were hexane and tetra-
hydrofuran, the acylating agents were vinyl propionate and
vinyl butyrate. The results are summarized in Table 2.
As it can be seen in Table 2, enantiomer separation was not
improved when other solvents and acylating agent were
employed.
Amano PS-C enzyme preparation has been found to be
appropriate for the other compounds, therefore, further
investigations were elaborated in vinyl acetate with this
enzyme. The results are shown in Table 3. As it can be seen
in Table 3, moderate enantiomer separation was obtained
with compounds 2–7 by Amano PS-C.
Table 1. Enzymatic acetylation of 1: screening with six commercially available enzyme preparations
(R)
(S)
enzyme
+
in vinyl acetate
rt
O
OH
OH
rac-1
O
(R)-(-)-1-acetate
(S)-(+)-1
NaOH/H2O
CH3OH
(R)
OH
(R)-(-)-1
Enzyme name (mg)
Time (h)
Hydrolyzed alcohol
Remaining alcohol
(R)-(ꢀ)-1
(S)-(+)-1
Y [%]
eeb (%)
Y (%)
eeb (%)
Ec
Amano AKa (20)
Amano PSa (20)
Amano PS-Ca (20)
PfLa (20)
Novozym 435a (100)
CrLa (100)
68
191
48
68
3
85
92
97
81
79
46
97
82
93
>99
>99
64
104
97
92
108
110
142
81
77
>99
41
85
19
>100
23
>100
>100
>100
5
191
a Amano AK: lipase AK from Pseudomonas fluorescens; Amano PS: lipase from Burkholderia cepacia; Amano PS-C: lipase from Burkholderia cepacia
immobilized on ceramic particles (>1000 U/g);1 PfL: lipase from Pseudomonas fluorescens; Novozym 435: lipase B from Candida antarctica immobilized
on acrylic resin; CrL: lipase from Candida rugosa (cylindracea).
b The enantiomeric excess of the alcohol was determined by GC.
c
ln½ð1 ꢀ cÞð1 ꢀ eeSÞꢁ
ln½ð1 ꢀ cÞð1 þ eeSÞꢁ
eeS
E ¼
;
c ¼
:
eeS þ eeP
eeS = enantiomeric excess of substrate, eeP = enantiomeric excess of product.

2222
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
Table 2. Enzymatic acylation of 1 with various solvents and acylating agent
(R)
(S)
enzyme
+
O
acylating agent
OH
R
OH
solvent
rt
O
(S)-(+)-1
rac-1
1
(R)-(-)- -ester
R= CH3: acetate
CH2-CH3: propionate
CH2-CH2-CH3: butyrate
NaOH/H2O
CH3OH
(R)
OH
1
(R)-(-)-
Compound
Time (h)
Acylating agent/solvent
Hydrolyzed alcohol
Remaining alcohol
(R)-(ꢀ)-1
(S)-(+)-1
Y (%)
ee (%)
Y (%)
ee (%)
E
1
48
48
48
48
Vinyl acetate/hexane
Vinyl acetate/THF
Vinyl propionate/hexane
Vinyl butyrate/hexane
89
91
98
97
96
97
97
98
97
101
91
>99
96
>99
>99
>100
>100
>100
>100
93
Table 3. Enzymatic acetylation of 2–7
(R)
(S)
R1
R2
R1
R1
R2
Amano PS-C
+
O
in vinyl acetate
OH
rt
OH
R2
O
(S)-(+)-2-7
rac-2-7
(R)-(-)-2-7-acetate
NaOH/H2O
CH3OH
(R)
R1
OH
R2
(R)-(-)-2-7
Compound
Time (h)
Hydrolyzed alcohol
Remaining alcohol
(R)-(ꢀ)-2–7
(S)-(+)-2–7
Y (%)
eea (%)
Y (%)
eea (%)
E
2
3
4
5
6
7
18
32
48
48
13
48
81
90
99
105
95
74
86
85
84
62
53
93
106
89
94
80
70
15
89
92
85
89
99
40
40
31
12
15
65
111
a The enantiomeric excess of the 2–6 alcohols was determined by GC. The enantiomeric excess of 7 alcohol was determined by polarimeter, the specific
25
rotation of the pure enantiomer: ½aꢁD ¼ þ32:2 (c 2, chloroform).
2.1. Enantiopure substances
Compounds (S)-(+)-2–7 were obtained with 100% enantio-
meric excess by preparing the maleic acid monoester of the
residual alcohol from the enzymatic reaction. Hydrolysis of
the acetate gave (R)-(ꢀ)-2–7 with high overall yield but its
enantiomeric purity is not so high. The results are shown in
Table 4.
The enantiomers of compounds 2–7 could be obtained by
Amano PS-C enzyme preparation in vinyl acetate with
optimization of the reaction time. The work-up method
was also changed, as described below (Scheme 2).

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2223
(R)
(S)
R1
R1
R2
R1
Amano PS-C
in vinyl acetate
rt
+
O
OH
OH
R2
R2
O
rac-2-7
(S)-(+)-2-7
2 7
(R)-(-)- - -acetate
R1
R2
NaOH/H2O
CH3OH
maleic acid anhydride
CH2Cl2, Et3N
2
rac-
benzo[1.3]dioxol
rac-3
rac-4
rac-5
rac-6
H
Cl
H
Cl
Cl
Cl
H
(S)
R1
R2
(R)
R1
R2
F
7
O
rac-
Br
CH3O
OH
O
(R)-(-)-2-7
O
OH
(S)-(+)-2-7 maleic monoester
NaOH/H2O
(S)
R1
OH
(S)-(+)-2-7
R2
Scheme 2. Resolution of (S)- and (R)-2–7.
Table 4. Enzymatic acetylation of racemic 2–7 by Amano PS-C with optimization
Compound
Time (h)
(R)-(ꢀ)-Enantiomer
Alcohol
(S)-(+)-Enantiomer
(S)-(+)-Alcohol
Acetate
Maleic acid monoester
Y (%)
Y (%)
ee (%)
Y (%)
Y (%)
ee (%)
E
2
3
4
5
6
7
6
36
48
30
15
30
97
120
155
110
119
115
92
116
147
107
96
82
58
28
65
64
64
90
75
43
78
79
79
81
67
39
69
59
68
100
100
100
100
100
100
52
18
7
23
22
22
113
Compounds (R)-(ꢀ)-2–7 were obtained by the Amano
PS-C catalyzed acetylation from the acetate fraction with
moderate enantiomeric excess and high overall yield.
The remaining alcohols were converted into maleic acid
monoesters and their hydrolysis yielded pure (S)-(+)-2–7.
the reaction time, but very high enantiomeric excess could
also be obtained by lipase-catalyzed re-resolution.
Compound (R)-(ꢀ)-4 was obtained by Amano PS-C cata-
lyzed acetylation from the acetate fraction. It was subjected
to acetylation by Amano PS-C again, yielding (R)-(ꢀ)-4
with moderate yield and 92% enantiomeric excess (Scheme
3).
The enantiopure (S)-(+)-alcohols were obtained by the
Amano PS-C catalyzed acetylation with optimization of
Table 5. Lipase-catalyzed re-resolution of (R)-(ꢀ)-alcohol
Initial alcohol [ee (%)]
Enzyme/acylating agent
Time (h)
(S)-(+)-Alcohol
(R)-(ꢀ)-Enantiomer
Acetate Alcohol
Y (%)
ee (%)
Y (%)
Y (%)
ee (%)
(R)-(ꢀ)-5 [28]
(R)-(ꢀ)-5 [88]
(R)-(ꢀ)-7 [57]
(R)-(ꢀ)-7 [96.5]
(R)-(ꢀ)-7 [97.2]
0.4 · Amano PS-C/4 · vinyl acetate
0.2 · Amano PS-C/4 · vinyl acetate
0.05 · Novozym 435/3 · vinyl acetate
0.02 · Novozym 435/3 · vinyl acetate
0.1 · Novozym 435/3 · vinyl acetate
7
1.5
11
6
30
28
20
31
30
95
72
86
92
86
68
67
78
66
68
65
66
76
61
63
88
92
96.5
97.2
99
1.5

2224
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
(S)
OH
Cl
(S)-(+)-4
Y: 30%
ee: 95%
Amano PS-C
(R)
in vinyl acetate
(R)
rt, 7h
OH
NaOH/H2O
CH3OH
Cl
O
OH
Cl
4
(R)-(-)-
ee: 28%
Cl
(R)-(-)-4
Y: 65%
ee: 88%
O
(R)-(-)-4-acetate
Amano PS-C
in vinyl acetate
rt, 5h
(S)
(R)
(R)
NaOH/H2O
CH3OH
+
O
OH
OH
Cl
Cl
Cl
4
(R)-(-)-
(S)-(+)-4
Y: 29%
ee: 72%
O
Y: 66%
ee: 92%
4
(R)-(-)- -acetate
Scheme 3. Re-resolution of (R)-(ꢀ)-4.
Racemic 7 was acetylated by Amano PS-C, affording (S)-
(+)-7- and (R)-(ꢀ)-7-acetates, both of moderate enantio-
meric purity. (R)-(ꢀ)-7-Acetate was then hydrolyzed, yield-
ing (R)-(ꢀ)-7. Afterwards it was purified by repeated
lipase-catalyzed re-resolution with Novozym 435, yielding
(R)-(ꢀ)-7 with 99.2% enantiomeric excess (Scheme 4).
amine 28, and quinine 29. The results are summarized in
Table 8.
Compounds (S)-4, (R)-5 and (S)-7 were obtained after salt
splitting followed by hydrolysis with quite moderate enan-
tiomeric excesses.
In the course of the investigation of the resolution by chem-
ical means, some dicarboxylic acid monoesters of the target
molecules were synthesized (Scheme 5). The maleic acid
monoesters, succinic acid monoesters and phthalic acid
monoesters were prepared at 83–99% yield.
The phthalic acid monoesters were successfully resolved by
(S)-(ꢀ)-phenylethylamine 26, (R,R)-(ꢀ)-1-(4-nitro-phenyl)-
2-amino-1,3-propanediol 30 and (S)-(+)-benzyl-amino-
butanol 31. The results are summarized in Table 9.
Compounds (S)-4, (S)-5 and (R)-7 were obtained after salt
splitting followed by hydrolysis also with low enantiomeric
excess. Nevertheless, during the resolution of rac-25 by (S)-
(+)-benzyl-aminobutanol 31, (S)-7 was obtained from the
mother liquor with 70% enantiomeric excess and moderate
overall yield.
Resolution of these monoesters was attempted by different
homochiral bases (Table 6). Successful separation was ob-
tained with the maleic acid, succinic acid and phthalic acid
monoesters resolved by (S)-(ꢀ)- and (R)-(+)-phenylethyl-
amine 26 and 27, (+)-dehydroabiethylamine 28, quinine
29, (R,R)-(ꢀ)-1-(4-nitro-phenyl)-2-amino-1,3-propanediol
30 and (S)-(+)-benzyl-aminobutanol 31 in different
solvents and solvent mixtures.
Enantiomeric enrichment can be accomplished by re-reso-
lution of the enantiomers or recrystallization of the dia-
steroisomeric salts. We evaluated the re-resolution of the
alcohol enantiomers. First, the required (S)- and (R)-
monoesters were prepared from the (S)- and (R)-alcohols,
and these monoesters were resolved by the same resolving
agent as described above. The results are summarized in
Table 10.
The maleic acid monoesters were successfully resolved by
(S)-(ꢀ)-phenylethylamine 26, (R)-(+)-phenylethylamine
27 and (+)-dehydroabiethylamine 28 too. The results are
summarized in Table 7. As it can be seen in Table 7, during
the resolution of rac-8 by (S)-(ꢀ)-phenylethylamine 26, the
more stable diastereoisomeric salt was formed with the (S)-
enantiomer. It was recrystallized twice from ethyl acetate,
and after salt splitting followed by hydrolysis, (S)-2 was
obtained at moderate overall yield but with very high enan-
tiomeric excess. Good results were obtained by (+)-de-
hydroabiethylamine 28 without recrystallization.
As it can be seen in Table 10, for re-resolving (ꢀ)-8 by (R)-
(+)-phenylethylamine 27, the diastereoisomeric salt was
recrystallized twice from ethyl acetate and after salt split-
ting followed by hydrolysis, (ꢀ)-2 was obtained with very
good enantiomeric excess but quite moderate overall yield.
Good re-resolution results were achieved for (ꢀ)-11 with
both (R)-(+)-phenylethylamine 27 and (+)-dehydroabieth-
ylamine 28 as resolving agents. The diastereoisomeric salt
The succinic acid monoesters were successfully resolved
by (R)-(+)-phenylethylamine 27 (+)-dehydroabiethyl-

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2225
(S)
Br
OH
O
(S)-(+)-7
Y: 20%
ee: 86%
Br
Novozym 435
in vinyl acetate
rt, 11h
OH
O
Br
(R)
(R)-(-)-7
ee: 57%
O
O
O
7
(R)-(-)- -acetate
Br
(R)
NaOH/H2O
CH3OH
OH
O
7
(R)-(-)-
Y: 77%
ee: 95%
Novozym 435
in vinyl acetate
rt, 6h
(R)
OH
Br
(S)
Br
Br
(R)
NaOH/H2O
CH3OH
+
O
O
OH
(R)-(-)-7
O
O
Y: 61%
(S)-(+)-7
Y: 31%
ee: 92%
ee: 97.2%
O
(R)-(-)-7-acetate
Novozym 435
in vinyl acetate
rt, 1.5h
(S)
OH
(R)
Br
Br
+
O
O
O
(S)-(+)-7
Y: 30%
ee: 86%
O
(R)-(-)-7-acetate
NaOH/H2O, CH3OH
(R)
OH
Br
O
(R)-(-)-7
Y: 63%
ee: 99.2%
Scheme 4. Re-resolution of (R)-(ꢀ)-7.
was recrystallized from methanol in case of (R)-(+)-phenyl-
ethylamine 27 as a resolving agent, and after salt splitting
and hydrolysis, (ꢀ)-3 was obtained with moderate enantio-
meric excess. In case of dehydroabiethylamine 28 as a
resolving agent, the diastereoisomeric salt was recrystal-
lized twice from acetone. After salt splitting followed by
hydrolysis, (ꢀ)-3 was obtained with very good enantio-
meric excess. In both cases, the overall yield was rather
low. Compound (ꢀ)-15 with moderate enantiomeric excess
was re-resolved with (S)-(ꢀ)-phenylethylamine 26. The dia-
stereoisomeric salt was recrystallized twice from acetone
and after salt splitting followed by hydrolysis, (ꢀ)-4 was
obtained with 100% enantiomeric excess and moderate
overall yield. In case of re-resolution of (+)-4, (ꢀ)-5 and
(ꢀ)-7, we found the alcohol enantiomers were obtained
with 88% enantiomeric excesses.
Enantiomeric enrichment can also be accomplished by
recrystallization of the monoester or alcohol enantiomers.
This can only be considered when the alcohol or the mono-
ester is solid. We examined the recrystallization of the
monoester and alcohol enantiomers, and the results are
summarized in Table 11.
During the recrystallization of (ꢀ)-8 from toluene, the
(ꢀ)-alcohol was prepared from the mother liquor. Com-
pound (ꢀ)-5 was recrystallized three times, once from hex-
ane and twice from a mixture of hexane and toluene, and
the (ꢀ)-alcohol was obtained with 100% enantiomeric
excess from the crystalline phase. Compounds (ꢀ)-7 and
(+)-7 were also recrystallized from a mixture of hexane
and toluene. In case of (ꢀ)-7, the enantiopure alcohol
was prepared from the mother liquid. Furthermore, (+)-7

2226
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
R1
R2
R1
dicarboxylic acid
anhydride
CH2Cl2
Et3N
OH
racemic alcohol
O
X
OH
R2
O
O
racemic monoester
racemic
R1
R2
X = CH=CH X = CH2-CH2
X = C6H4
alcohol
rac-2
rac-3
rac-4
rac-5
rac-6
rac-7
benzo[1.3]dioxole
Cl
H
Cl
F
Br
rac-8
rac-11
rac-14
rac-17
rac-20
rac-23
rac-9
rac-12
rac-15
rac-18
rac-21
rac-24
rac-10
rac-13
rac-16
rac-19
rac-22
rac-25
H
Cl
Cl
H
CH3O
Scheme 5. Monoesters of the 1-phenyl-2-propanol derivatives.
Table 6. Chiral bases as resolving agents
NH2
NH2
28
26
(R)
(S)
27
NH2
H
OH OH
H
N
(R)
(R)
HO
30
29
H
31
NH
(S)
NH2
O
O2N
OH
Table 7. Resolution of maleic acid monoesters
Racemate
Resolving agent
Solvent
Diastereoisomeric salt
Mother liquor
Config.
Y (%)
ee (%)
S
Config.
Y (%)
ee (%)
rac-8
rac-8
rac-11
0.60 · 26
0.65 · 28
0.75 · 28
1.4 · Ethyl acetate
3 · Ethyl acetate
5 · Ethyl acetate
(S)
(R)
(R)
48
55
47
98
72
80
0.47
0.40
0.38
(R)
(S)
(S)
117
73
66
48
67
59
0.25 · Ethyl acetate
0.25 · Acetone
rac-11
0.65 · 27
(R)
35
31
0.11
(S)
135
9
4.5 · Diisopropyl-ether
3 · Ethyl acetate
2 · Acetone
rac-17
rac-17
rac-23
0.75 · 28
0.75 · 27
0.65 · 28
(R)
(R)
(R)
33
71
45
65
4
64
0.21
0.3
0.29
(S)
(S)
(S)
58
65
78
35
4
45
2 · Ethyl acetate
was obtained with good enantiomeric excess from the
crystal.
high enantiomeric purity. Although the use of the lipases
is limited by their relatively high price, the excellent enan-
tiomeric purity can compensate for the price of the biocat-
alyst. Furthermore, lipase-catalyzed kinetic resolution is an
easily manageable, economical and environmentally
friendly method. The monoester resolution by homochiral
bases has also proved itself by being appropriate for each
of the racemic alcohols. It was possible to find a working
3. Conclusion
We can conclude that lipase-catalyzed kinetic resolution is
suitable for preparing the homochiral substances at very

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
Table 8. Resolution of succinic acid monoesters
2227
Racemic
Resolving agent
Solvent
Diastereoisomeric salt
Mother liquor
Config.
Y (%)
ee (%)
S
Config.
Y (%)
ee (%)
rac-15
rac-15
rac-18
rac-24
1.00 · 27
0.75 · 29
0.75 · 28
1.00 · 27
2 · Ethyl acetate
6 · Ethyl acetate
2 · Ethyl acetate
1 · Ethyl acetate
(S)
(S)
(R)
(S)
48
76
42
11
35
12
17
6
0.17
0.9
0.7
0.1
(R)
(R)
(S)
(R)
114
64
101
51
14
12
11
4
Table 9. Resolution of phthalic acid monoesters
Racemic
Resolving agent
Solvent
Diastereoisomeric salt
Mother liquor
Config.
Y (%)
ee (%)
S
Config.
Y (%)
ee (%)
rac-16
rac-19
rac-25
rac-25
0.60 · 30
0.75 · 27
0.65 · 27
0.65 · 31
1 · Ethyl acetate
4 · Diisopropyl-ether
2 · Ethyl acetate
3 · Ethyl acetate
(S)
(S)
(R)
(R)
87
24
87
74
17
29
5
0.15
0.7
0.4
0.23
(R)
(R)
(S)
(S)
97
72
45
39
15
25
9
31
70
Table 10. Enantiomeric enrichment by re-resolution of the enantiomers
Initial compound [ee0 (%)]
Resolving agent
Solvent
Diastereoisomeric salt
Mother liquor
Config.
Y (%)
ee (%)
S
Config.
Y (%)
ee (%)
(ꢀ)-8 [48]
0.60 · 27
1.00 · 27
1.00 · 28
1.50 · 26
1.00 · 27
1.00 · 26
1.00 · 28
1 · Ethyl acetate
5 · Diethyl ether
5 · Ethyl acetate
1 · Acetone
5 · Ethyl acetate
4 · Diisopropyl-ether
1 · Ethyl acetate
(R)
(R)
(R)
(R)
(S)
(R)
(R)
24
11
18
21
62
26
25
97
74
97
100
99
88
0.23
0.8
(R)
(R)
(R)
(R)
(S)
(R)
(R)
50
61
60
59
23
46
18
14
45
34
33
79
34
10
(ꢀ)-11 [58]
(ꢀ)-11 [58]
(ꢀ)-15 [52]
(+)-15 [96]
(ꢀ)-19 [65]
(ꢀ)-23 [64]
0.17
0.21
0.61
0.23
0.24
97
Table 11. Purification by recrystallization of the enantiomers
Initial compound [ee0 (%)]
Solvent
Crystal phase
Mother liquid
Config
Y (%)
ee (%)
S
Config.
Y (%)
ee (%)
(ꢀ)-8 [48]
(ꢀ)-5 [61]
(ꢀ)-5 [80]
(ꢀ)-5 [98.6]
(ꢀ)-7 [57]
(+)-7 [86]
2 · Toluene
1 · Hexane
1 · Hexane/1 · toluene
3 · Hexane/1 · toluene
2.2 · Hexane/0.8 · toluene
2 · Hexane/1 · toluene
(R)
(R)
(R)
(R)
(R)
(S)
23
66
55
84
85
73
14
80
98,6
100
76
0.3
(R)
(R)
(R)
(R)
(R)
(S)
66
34
44
7
13
26
59
27
58
90
100
82
0.53
0.54
0.84
0.65
0.65
89
monoester/chiral base combination for five racemic
alcohols.
heating of the dried plates. Preparative vacuum-chroma-
tography was performed using Merck Kieselgel 60 F254
.
CrL enzyme was obtained from Sigma. Amano enzymes
were courtesy of Amano. Novozym was courtesy of Novo
Nordisk. Vinyl acetate, vinyl propionate and vinyl butyrate
were products of Fluka. All solvents used were freshly
distilled.
4. Experimental
The gas chromatographic measurements were completed
on an Agilent 4890D instrument using FID. Separations
were achieved on a 30 m · 0.250 mm HP Chiral (20% per-
methylated b-cyclodextrin) and ALPHA DEXTM 120 chiral
stationery phases. The carrier gas was H2 and injections
were made in split mode. Optical rotation values were
determined on a Perkin–Elmer 241 polarimeter. Thin-layer
chromatography (TLC) was made using Merck Kieselgel
60 F254 alumina sheets. Spots were visualized by treatment
with 5% ethanolic phosphomolybdic acid solution and
4.1. Lipase-catalyzed acylation of racemic 1-phenyl-2-
propanol rac-1 by various enzymes: general procedure
To a solution of racemic 1-phenyl-2-propanol rac-1
(200 mg) in vinyl acetate (2 mL), enzyme (for amount,
see Table 1) was added and the resulting suspension
was stirred at room temperature (for reaction time, see
Table 1). The reaction was monitored by TLC and was

2228
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
stopped by filtering out the enzyme. Vinyl acetate was
evaporated in vacuum and the residue was separated by
preparative vacuum column chromatography (hexane–
ethyl acetate = 10:2) to obtain (+)-1 and (ꢀ)-1-acetate.
The acetate fraction was hydrolyzed with NaOH in water
and methanol. For yields and enantiomeric excesses, see
Table 1.
(R)-(ꢀ)-Acetate and NaOH (0.3·) were dissolved in water
(0.65–1.5·) and methanol (0.7–1·). The mixture was boiled
for 5 min and after cooling to room temperature, methanol
was evaporated in vacuo. It was extracted by diethyl ether.
The combined organic phase was dried over Na2SO4 and
the solvent was evaporated to yield (R)-(ꢀ)-alcohol.
The aqueous phase containing the sodium salt of the (S)-
(+)-alcohol maleic acid monoester was added to 37%
HCl and it was extracted by dichloromethane. The com-
bined dichloromethane phase was dried over Na2SO4 and
the solvent was evaporated to yield (S)-(+)-alcohol maleic
acid monoester.
4.2. Lipase-catalyzed acylation of racemic 1-phenyl-2-
propanol rac-1 by Amano PS-C enzyme preparation
with various acylating agents in various solvents: general
procedure
To a solution of racemic 1-phenyl-2-propanol rac-1
(200 mg) in the chosen solvent (1 mL, for solvents, see
Table 2), the chosen enzyme (0.1 · Amano PS-C) and the
acylating agent (1 mL, for acylating agents see Table 2)
were added, and the resulting suspension was stirred at
room temperature. Work-up of the products was carried
out as described in the previous section.
(S)-(+)-Alcohol maleic acid monoester and NaOH (0.5·)
were dissolved in water (1.5–3·). The mixture was boiled
for 1 min and after cooling to room temperature it was
extracted by diethyl ether. The combined organic phase
was dried over Na2SO4 and the solvent was evaporated
to yield (S)-(+)-alcohol. For reaction times, yields and
enantiomeric compositions, see Table 4.
For reaction times, yields and enantiomeric composition,
see Table 2.
4.5. Lipase-catalyzed re-resolution of (R)-(ꢀ)-alcohol:
general procedure
4.3. Lipase-catalyzed acylation of racemic 1-phenyl-2-
propanol derivatives rac-2–7 by Amano PS-C enzyme
preparation: general procedure
(R)-(ꢀ)-Alcohol (for enantiomer excess, see Table 5) and
Amano PS-C (for amount, see Table 5) were dissolved in
vinyl acetate (for amount, see Table 5), and the resulting
suspension was stirred at room temperature (for reaction
time, see Table 5). The reaction was stopped by filtering
out the enzyme, then it was washed by vinyl acetate, and
vinyl acetate was evaporated in vacuo to obtain a mixture
of (S)-(+)-alcohol and (R)-(ꢀ)-acetate.
To a solution of racemic 1-phenyl-2-propanol derivatives
(rac-2–7) (200–250 mg) in vinyl acetate (5·), enzyme
(0.1 · for 2 and 0.3· for 3–7) was added and the resulting
suspension was stirred at room temperature. Work-up of
the products was carried out as described in the previous
section.
The mixture of (S)-(+)-alcohol and (R)-(ꢀ)-acetate was
separated by preparative vacuum column chromatography
(hexane–ethyl acetate = 10:1) to obtain (S)-(+)-alcohol
and (R)-(ꢀ)- acetate.
For reaction times, yields and enantiomeric composition,
see Table 3.
4.4. Preparation of enantiopure substances: general
procedure
(R)-(ꢀ)-Acetate and NaOH (0.35) were dissolved in water
(0.5–2·) and methanol (1–2·). The mixture was boiled up
and it was stirred for half an hour. The methanol was evap-
orated in vacuo and the residue was extracted by diethyl
ether. The combined organic phase was dried over Na2SO4
and the solvent was evaporated to yield (R)-(ꢀ)-alcohol.
For yields and enantiomeric compositions, see Table 5.
Racemic alcohol and Amano PS-C (0.3· for 2, 4, 6 and
0.085· for 3, 5, 7) were dissolved in vinyl acetate (5· for
2, 4, 6 and 3· for 3, 5, 7) and the resulting suspension
was stirred at room temperature. The reaction was stopped
by filtering out the enzyme, then it was washed by vinyl
acetate, and vinyl acetate was evaporated in vacuo to
obtain a mixture of (S)-(+)-alcohol and (R)-(ꢀ)-acetate.
4.6. Preparation of the monoesters of racemic 1-phenyl-2-
propanol derivatives: general procedure
The mixture of (S)-(+)-alcohol and (R)-(ꢀ)-acetate was
dissolved in dichloromethane (2.5–3·), and triethylamine
(1.3·) and maleic acid anhydride (1.0–1.2·) were added.
The solution was heated and its colour turned into dark
brown. It was stirred for 5 min. After cooling to room tem-
perature, it was extracted by 1.5 M HCl solution and
water. Then the organic phase was extracted by 1 M
Na2CO3 solution. The combined aqueous phase was
extracted again by dichloromethane. (The aqueous phase
contains the sodium salt of the (S)-(+)-alcohol maleic acid
monoester.) The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
a yellow oil of (R)-(ꢀ)-acetate.
To a solution of racemic 1-benzo[1,3]dioxol-5-yl-2-propa-
nol rac-1 (60.00 g, 332.96 mmol) in dichloromethane
(240 mL), triethylamine (50 mL, 359.2 mmol, d = 0727)
was added and the mixture was stirred at room tempera-
ture. Then maleic acid anhydride (33.00 g, 336.53 mmol)
was added to the solution and the mixture was heated up
while the colour of the solution turned into dark brown.
It was stirred and refluxed for 10 min. After cooling to
room temperature, it was extracted with 1 · 300 mL and
1 · 60 mL 1.5 M HCl solution and 1 · 60 mL water. The
organic phase was dried over Na2SO4 and the solvent
was removed in vacuo yielding a dense brown oil of race-

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2229
mic 1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid mono-
ester rac-8 (90.50 g, 325.23 mmol, Y: 98%). Later the oil
was solidified (bp: 93–96 ꢁC).
The resolution mother liquid was washed with 1.5 M HCl
solution (1 · 65 mL and 2 · 10 mL). The organic phase
was dried over Na2SO4 and the solvent was removed in
vacuo to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
4.7. Resolution of racemic monoesters with chiral bases:
resolution of racemic 1-benzo[1,3]dioxol-5-yl-2-propanol
maleic acid monoester rac-8 with (S)-(ꢀ)-phenylethyl-
amine 26
maleic acid monoester (ꢀ)-8 (59.04 g, 213.47 mmol, Y:
25
131.6%) {½aꢁD ¼ ꢀ11:0 (c 2, CHCl3)}.
The monoester was removed: (ꢀ)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (59.04 g) was
heated with a mixture of water (100 mL) and NaOH
(25 g) for 1 min and it was allowed to cool to room temper-
ature. The aqueous phase was washed with diethyl ether
(4 · 100 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
Racemic 1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid
monoester rac-8 (90.30 g, 324.51 mmol) was dissolved in
ethyl acetate (125 mL), and (S)-(ꢀ)-phenylethylamine 26
(23.60 g, 194.75 mmol) was added to the solution. The
solution was stirred for 20 min, diethyl ether (271 mL)
was added to the clear solution and it was inoculated with
some diastereoisomeric salt. The crystals were placed at
1 ꢁC overnight and then were filtered, washed with diethyl
ether (3 · 45 mL) and dried to afford the solid diastereoiso-
meric salt: (+)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic
acid monoester (+)-8 (S)-(ꢀ)-phenylethylamine salt
(47.40 g, 118.7 mmol, Y: 73.1%), brownish crystal.
(ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
(ꢀ)-2
(34.1 g,
25
116.7 mmol, Y: 116.7%) {½aꢁD ¼ ꢀ15:3 (c 2, CHCl3)}, ee:
48%.
4.8. Resolution of racemic 1-benzo[1,3]dioxol-5-yl-2-prop-
anol maleic acid monoester rac-8 with (+)-dehydroabiethyl-
amine 28: general procedure
The diastereoisomeric salt (47.0 g) was dissolved in hot
ethyl acetate (94 mL) and cooled to room temperature
slowly. It was allowed to crystallize for 1 h and the crystals
were filtered, washed with diethyl ether (3 · 25 mL) and
dried to afford the solid recrystallized diastereoisomeric
salt: (+)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid
monoester (+)-8 (S)-(ꢀ)-phenylethylamine salt (42.10 g,
105.40 mmol, Y: 65.0%), brownish crystal.
Racemic 1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid
monoester rac-8 (4.65 g, 16.72 mmol) and (+)-dehydroabi-
ethylamine 28 (3.10 g, 10.86 mmol) were dissolved in ethyl
acetate (14 mL) during heating. The solution was placed at
15 ꢁC overnight and the crystals were filtered, washed with
ethyl acetate (4 · 3 mL) and dried to afford the solid diaste-
reoisomeric salt: (+)-1-benzo[1,3]dioxol-5-yl-2-propanol
maleic acid monoester (+)-8 (+)-dehydroabiethylamine salt
25
(4.14 g, 7.34 mmol, Y: 87.9%), {½aꢁD ¼ þ9:9 (c 2, glacial
The recrystallized diastereoisomeric salt (41.7 g) was dis-
solved in hot ethyl acetate (83 mL) and cooled to room
temperature slowly once again. It was allowed to crystallize
for 1 h and the crystals were filtered, washed with diethyl
ether (3 · 25 mL) and dried to afford the solid twice recrys-
tallized diastereoisomeric salt: (+)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (+)-8 (S)-(ꢀ)-phenyleth-
acetic acid)}, mp: 139–141 ꢁC.
The crystals (4.14 g) were suspended in ethyl acetate
(10 mL), and 1 M Na2CO3 solution (1 · 10, 1 · 5 mL)
was added. The phases were separated and the combined
aqueous phase was washed with ethyl acetate (2 · 5 mL),
it was acidified with 37% HCl (2 mL) and then it was
extracted with ethyl acetate (3 · 10 mL). The combined
organic phase was dried over Na2SO4 and the solvent was
removed in vacuo to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-
ylamine salt (36.80 g, 92.13 mmol, Y: 56.8%), brownish
25
crystal, {½aꢁD ¼ þ6:9 (c 2, glacial acetic acid)}; mp: 155–
160 ꢁC, it frizzled up from 95 ꢁC.
propanol maleic acid monoester (ꢀ)-8 (1.63 g, 5.85 mmol,
25
The crystals (36.4 g) were suspended in ethyl acetate
(300 mL), and 20% HCl (25 mL) was added and the solu-
tion was stirred for 30 min (clear two-phase solution).
The phases were separated and the organic phase was
washed with 1.5 M HCl solution (2 · 20 mL), then it was
dried over Na2SO4 and the solvent was removed in vacuo
to afford an oil of (+)-1-benzo[1,3]dioxol-5-yl-2-propanol
Y: 70.1%) {½aꢁD ¼ ꢀ10:7 (c 10, CH3OH)}.
The monoester was removed: (+)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (1.63 g) was
heated with mixture of methanol (1 mL), water (3 mL)
and NaOH (1 g) for 1 min and it was allowed to cool to
room temperature. Water (10 mL) was added and the
methanol was removed in vacuo. The residue was extracted
with ethyl acetate (4 · 10 mL). The combined organic
phase was dried over Na2SO4 and the solvent was removed
maleic acid monoester (+)-8 (23.92 g, 86.00 mmol, Y:
25
53.0%) {½aꢁD ¼ þ11:9 (c 2, CHCl3)}.
The monoester was removed: (+)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (+)-8 (23.47 g) was
heated with a mixture of water (45 mL) and NaOH (15 g)
for 1 min and it was allowed to cool to room temperature.
The aqueous phase was washed with diethyl ether
(4 · 45 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
in vacuo to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
25
(ꢀ)-2 (0.83 g, 4.61 mmol, Y: 55.1%) {½aꢁD ¼ ꢀ23:1 (c 2,
CHCl3)}, ee: 72%.
The resolution mother liquid was extracted with 1 M
Na2CO3 solution (1 · 15 mL and 1 · 5 mL). The combined
aqueous phase was washed with ethyl acetate (2 · 5 mL), it
was acidified with 37% HCl (2 mL) and then it was
extracted with ethyl acetate (3 · 10 mL). The combined
organic phase was dried over Na2SO4 and the solvent
(+)-1-benzo[1,3]dioxol-5-yl-2-propanol (+)-2 (14.04 g,
25
77.91 mmol, Y: 48.0%) {½aꢁD ¼ þ31:5 (c 2, CHCl3)}, ee:
98%.

2230
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
was removed in vacuo to afford (+)-1-benzo[1,3]dioxol-
and it was allowed to cool to room temperature. The aque-
ous solution was extracted with ethyl acetate (4 · 10 mL).
The combined organic phase was dried over Na2SO4 and
the solvent was removed in vacuo to afford (+)-1-(3-
5-yl-2-propanol maleic acid monoester (+)-8 (2.32 g,
25
8.33 mmol, Y: 99.8%) {ð½aꢁD ¼ þ11:1 (c 10, CH3OH)}.
The monoester was removed: (+)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (+)-8 (2.32 g) was
heated with a mixture of methanol (1 mL), water (3 mL)
and NaOH (1 g) for 1 min and it was allowed to cool to
room temperature. Water (10 mL) was added and the
methanol was removed in vacuo. The residue was extracted
with ethyl acetate (4 · 10 mL). The combined organic
phase was dried over Na2SO4 and the solvent was removed
chloro-phenyl)-2-propanol (+)-3 (0.43 g, 2.52 mmol, Y:
135.4%) {½aꢁD ¼ þ3:2 (c 2, CHCl3)}, ee: 9%.
25
4.10. Resolution of racemic 1-(4-chloro-phenyl)-2-propanol
succinic acid monoester rac-15 with quinine 29
Racemic 1-(4-chloro-phenyl)-2-propanol succinic acid
monoester rac-15 (1.00 g, 3.69 mmol) was dissolved in ethyl
acetate (6 mL) and quinine 29 (0.90 g, 2.77 mmol) was
added to the solution. The solution was inoculated with
some diastereoisomeric salt and the crystals were placed
for 24 h. The crystals were filtered, washed with ethyl
acetate (2 · 1 mL) and dried to afford the solid diastereo-
isomeric salt: (+)-1-(4-chloro-phenyl)-2-propanol succinic
acid monoester (+)-15 quinine salt (1.07 g, 1.80 mmol, Y:
97.3%).
in vacuo to afford (+)-1-benzo[1,3]dioxol-5-yl-2-propanol
25
(+)-2 (1.32 g, 6.10 mmol, Y: 73.1%) ½aꢁD ¼ þ21:5 (c 2,
CHCl3), ee: 67%.
4.9. Resolution of racemic 1-(3-chloro-phenyl)-2-propanol
maleic acid monoester rac-11 with (R)-(+)-phenylethyl-
amine 27: general procedure
Racemic 1-(3-chloro-phenyl)-2-propanol maleic acid
monoester rac-11 (1.00 g, 3.72 mmol) was dissolved in the
mixture of ethyl acetate (0.25 mL), acetone (0.25 mL) and
diisopropyl ether (4.5 mL), and (R)-(+)-phenylethylamine
27 (0.30 g, 2.48 mmol) was added to the solution. The
solution was inoculated with some diastereoisomeric salt
and the crystals were placed for 24 h. The crystals were
filtered, washed with diisopropyl ether (2 · 1 mL) and dried
to afford the solid diastereoisomeric salt: (ꢀ)-1-(3-
chloro-phenyl)-2-propanol maleic acid monoester (ꢀ)-11
(R)-(+)-phenylethylamine salt (0.28 g, 0.72 mmol, Y:
38.7%).
The crystals (1.07 g) were suspended in ethyl acetate
(10 mL), and 1 M Na2CO3 solution (1 · 10 mL) was added,
and the solution was stirred for 5 min. The phases were
separated and the aqueous phase was washed with ethyl
acetate (2 · 10 mL), it was acidified with 1.5 M HCl
(20 mL) and then it was extracted with diethyl ether
(3 · 10 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
(+)-1-(4-chloro-phenyl)-2-propanol succinic acid mono-
ester (+)-15 (0.39 g, 1.44 mmol, Y: 78.0%).
The monoester was removed: (+)-1-(4-chloro-phenyl)-2-
propanol succinic acid monoester (+)-15 (0.39 g) was
heated with a mixture of water (5 mL) and NaOH (0.8 g)
for 1 min and it was allowed to cool to room temperature.
The aqueous solution was extracted with diethyl ether
(4 · 5 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
The crystals (0.28 g) were suspended in ethyl acetate
(10 mL), and 1.5 M HCl (5 mL) was added and the solu-
tion was stirred for 5 min. The phases were separated and
the organic phase was washed with 1.5 M HCl solution
(2 · 5 mL), then it was dried over Na2SO4 and the solvent
was removed in vacuo to afford an oil of (ꢀ)-1-(3-chloro-
phenyl)-2-propanol maleic acid monoester (ꢀ)-11 (0.18 g,
(+)-1-(4-chloro-phenyl)-2-propanol (+)-4 (0.24 g, 1.41
25
25
0.67 mmol, Y: 36.0%) {½aꢁD ¼ ꢀ10:8 (c 2, CHCl3)}.
mmol, Y: 76.1%) {½aꢁD ¼ þ3:8 (c 2, CHCl3)}, ee: 12%.
The monoester was removed: (ꢀ)-1-(3-chloro-phenyl)-2-
propanol maleic acid monoester (ꢀ)-11 (0.18 g) was heated
with a mixture of water (5 mL) and NaOH (0.8 g) for 1 min
and it was allowed to cool to room temperature. The aque-
ous solution was extracted with diethyl ether (4 · 5 mL).
The combined organic phase was dried over Na2SO4 and
the solvent was removed in vacuo to afford (ꢀ)-1-(3-
Ethyl acetate (10 mL) and 1 M Na2CO3 solution (10 mL)
was added to the resolution mother liquid and the solution
was stirred for 5 min. The phases were separated, the aque-
ous phase was extracted with 1 M Na2CO3 solution
(2 · 5 mL), it was acidified with 1.5 M HCl (20 mL) and
then it was extracted with diethyl ether (3 · 10 mL). The
combined organic phase was dried over Na2SO4 and the
solvent was removed in vacuo to afford (ꢀ)-1-(4-chloro-
phenyl)-2-propanol succinic acid monoester (ꢀ)-15
(0.35 g, 1.29 mmol, Y: 70.0%).
chloro-phenyl)-2-propanol (ꢀ)-3 (0.11 g, 0.64 mmol, Y:
25
34.6%) {½aꢁD ¼ ꢀ10:8 (c 2, CHCl3)}, ee: 31%.
Ethyl acetate (10 mL) was added to the resolution mother
liquid and it was washed with 1.5 M HCl solution
(3 · 5 mL). The organic phase was dried over Na2SO4
and the solvent was removed in vacuo to afford (+)-1-(3-
The monoester was removed: (ꢀ)-1-(4-chloro-phenyl)-2-
propanol succinic acid monoester (ꢀ)-15 (0.35 g) was
heated with a mixture of water (5 mL) and NaOH (0.8 g)
for 1 min and it was allowed to cool to room temperature.
The aqueous solution was extracted with diethyl ether
(4 · 5 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
chloro-phenyl)-2-propanol maleic acid monoester (+)-11
25
(0.79 g, 2.94 mmol, Y: 158.0%) {½aꢁD ¼ þ2:6 (c 2, CHCl3)}.
The monoester was removed: (+)-1-(3-chloro-phenyl)-2-
propanol maleic acid monoester (+)-11 (2.32 g) was heated
with a mixture of water (5 mL) and NaOH (0.8 g) for 1 min
(ꢀ)-1-(4-chloro-phenyl)-2-propanol (ꢀ)-4 (0.20 g, 1.17
25
mmol, Y: 63.5%) {½aꢁD ¼ ꢀ3:9 (c 2, CHCl3)}, ee: 12%.

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2231
4.11. Resolution of racemic 1-(4-chloro-phenyl)-2-propanol
phthalic acid monoester rac-16 with (R,R)-(ꢀ)-1-(4-nitro-
phenyl)-2-amino-1,3-propanediol 30
The solution was inoculated with some diastereoisomeric
salt and the crystals were placed for 24 h. The crystals were
filtered, washed with diethyl ether (3 · 1 mL) and dried to
afford the solid diastereoisomeric salt: (ꢀ)-1-(3-bromo-4-
methoxy-phenyl)-2-propanol phthalic acid monoester rac-
25 (S)-(+)-benzyl-aminobutanol salt (0.89 g, 1.55 mmol,
Y: 122.3%).
Racemic 1-(4-chloro-phenyl)-2-propanol phthalic acid
monoester rac-16 (3.40 g, 10.67 mmol) was dissolved in
ethyl acetate (3.4 mL), and (R,R)-(ꢀ)-1-(4-nitro-phenyl)-
2-amino-1,3-propanediol 30 (1.36 g, 6.41 mmol) was added
to the solution and it was heated. After cooling to room
temperature, diethyl ether (13.6 mL) was added to the solu-
tion and the solution was placed for 48 h. The crystals were
filtered, washed with diethyl ether and dried to afford the
solid diastereoisomeric salt: (+)-1-(4-chloro-phenyl)-2-pro-
panol phthalic acid monoester (+)-16 quinine salt (2.65 g,
4.99 mmol, Y: 93.6%).
The crystals (0.89 g) were suspended in ethyl acetate
(10 mL), and 1.5 M HCl (5 mL) was added and the
solution was stirred for 5 min. The phases were separated
and the organic phase was washed with 1.5 M HCl solution
(2 · 5 mL), then it was dried over Na2SO4 and the solvent
was removed in vacuo to afford (ꢀ)-1-(3-bromo-
4-methoxy-phenyl)-2-propanol phthalic acid monoester
25
(ꢀ)-25 (0.56 g, 1.42 mmol, Y: 112.0%), ½aꢁD ¼ ꢀ7:4 (c 2,
The crystals (2.65 g) were suspended in ethyl acetate
(35 mL), and 1.5 M HCl (20 mL) was added and the solu-
tion was stirred for 5 min. The phases were separated and
the organic phase was washed with 1.5 M HCl solution
(2 · 20 mL), then it was dried over Na2SO4 and the solvent
was removed in vacuo to afford an oil of (+)-1-(4-chloro-
phenyl)-2-propanol phthalic acid monoester (+)-16
(1.58 g, 4.96 mmol, Y: 92.9%).
CHCl3).
The monoester was removed: (ꢀ)-1-(3-bromo-4-methoxy-
phenyl)-2-propanol phthalic acid monoester (ꢀ)-25
(0.56 g) was heated with a mixture of water (5 mL) and
NaOH (0.8 g) for 1 min and it was allowed to cool to room
temperature. The aqueous solution was extracted with
diethyl ether (4 · 5 mL). The combined organic phase
was dried over Na2SO4 and the solvent was removed in
The monoester was removed: (+)-1-(4-chloro-phenyl)-2-
propanol phthalic acid monoester (+)-16 (1.58 g) was
heated with a mixture of water (20 mL) and NaOH (3 g)
for 1 min and it was allowed to cool to room temperature.
The aqueous solution was extracted with diethyl
ether (4 · 25 mL). The combined organic phase was dried
over Na2SO4 and the solvent was removed in vacuo to
vacuo to afford (ꢀ)-1-(3-bromo-4-methoxy-phenyl)-2-pro-
25
panol (ꢀ)-7 (0.23 g, 0.94 mmol, Y: 73.8%), {½aꢁD ¼ ꢀ7:8
(c 2, CHCl3)}, ee: 31%.
Ethyl acetate (10 mL) was added to the resolution mother
liquid and it was washed with 1.5 M HCl solution
(3 · 5 mL). The organic phase was dried over Na2SO4
and the solvent was removed in vacuo to afford (+)-1-(3-
afford (+)-1-(4-chloro-phenyl)-2-propanol (+)-4 (0.79 g,
25
4.63 mmol, Y: 86.8%), {½aꢁD ¼ þ5:2 (c 2, CHCl3)}, ee:
bromo-4-methoxy-phenyl)-2-propanol phthalic acid mono-
25
17%.
ester (+)-25 (0.35 g, 0.89 mmol, Y: 70.0%), {½aꢁD ¼ þ13:1
(c 2, CHCl3)}.
Ethyl acetate (35 mL) was added to the resolution mother
liquid and it was washed with 1.5 M HCl solution
(3 · 20 mL). The organic phase was dried over Na2SO4
and the solvent was removed in vacuo to afford (ꢀ)-1-(4-
chloro-phenyl)-2-propanol phthalic acid monoester (ꢀ)-
16 (1.75 g, 5.49 mmol, Y: 102.9%).
The monoester was removed: (+)-1-(3-bromo-4-methoxy-
phenyl)-2-propanol phthalic acid monoester (+)-25
(0.35 g) was heated with a mixture of water (5 mL) and
NaOH (0.8 g) for 1 min and it was allowed to cool to room
temperature. The aqueous solution was extracted with
diethyl ether (4 · 10 mL). The combined organic phase
was dried over Na2SO4 and the solvent was removed in
The monoester was removed: (ꢀ)-1-(4-chloro-phenyl)-2-
propanol phthalic acid monoester (ꢀ)-16 (1.75 g) was
heated with a mixture of water (20 mL) and NaOH
(3 g) for 1 min and it was allowed to cool to room temper-
ature. The aqueous solution was extracted with diethyl
ether (4 · 35 mL). The combined organic phase was
dried over Na2SO4 and the solvent was removed in
vacuo to afford (+)-1-(3-bromo-4-methoxy-phenyl)-2-pro-
25
panol (+)-7 (0.12 g, 0.89 mmol, Y: 38.5%) ½aꢁD ¼ ꢀ17:5
(c 2, CHCl3), ee: 70%.
4.13. Re-resolution of the enantiomers with chiral bases:
resolution of racemic (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
maleic acid monoester (ꢀ)-8 with (R)-(+)-phenylethylamine
27: general procedure
vacuo to afford (ꢀ)-1-(4-chloro-phenyl)-2-propanol (ꢀ)-4
25
(0.88 g, 5.16 mmol, Y: 96.7%) {½aꢁD ¼ ꢀ4:6 (c 2, CHCl3)},
ee: 15%.
(ꢀ)-1-Benzo[1,3]dioxol-5-yl-2-propanol maleic acid mono-
ester (ꢀ)-8 (10.00 g, 35.94 mmol, ee: 48%) was dissolved
in ethyl acetate (10 mL) with heating, and (R)-(+)-phenyl-
ethylamine 27 (2.5 g, 20.63 mmol) and diethyl ether
(30 mL) were added to the solution. The solution was
inoculated with some diastereoisomeric salt and the crys-
tals were placed for 2 h at room temperature. The crys-
tals were filtered, washed with diethyl ether (4 · 4 mL)
and dried to afford the solid diastereoisomeric salt:
4.12. Resolution of racemic 1-(3-bromo-4-methoxy-phenyl)-
2-propanol phthalic acid monoester rac-25 with (S)-(+)-
benzyl-aminobutanol 31
Racemic 1-(3-bromo-4-methoxy-phenyl)-2-propanol phth-
alic acid monoester rac-25 (1.00 g, 2.54 mmol) was dis-
solved in ethyl acetate (3 mL), and (S)-(+)-benzyl-amino-
butanol 31 (0.30 g, 1.67 mmol) was added to the solution.

2232
V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
(ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid mono-
ester (ꢀ)-8 (R)-(+)-phenylethylamine salt (6.78 g, 16.97
mmol, Y: 47.2%), off-white crystals.
4.14. Re-resolution of (ꢀ)-1-(3-chloro-phenyl)-2-propanol
maleic acid monoester (ꢀ)-11 with (+)-dehydroabiethylamine
28: general procedure
The diastereoisomeric salt (6.78 g) was dissolved in hot
ethyl acetate (20 mL) and cooled to room temperature
slowly. It was allowed to crystallize for 1 h and the crystals
were filtered, washed with ethyl acetate (3 · 2.5 mL) and
dried to afford the solid recrystallized diastereoisomeric
salt: (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic acid
monoester (ꢀ)-8 (R)-(+)-phenylethylamine salt (6.08 g,
15.22 mmol, Y: 42.3%), off-white crystals.
(ꢀ)-1-(3-Chloro-phenyl)-2-propanol maleic acid monoester
(ꢀ)-11 (16.00 g, 59.54 mmol, ee: 58%) was dissolved in
ethyl acetate (80 mL) and (+)-dehydroabiethylamine 28
(28.0 g, 59.0 mmol). The solution was inoculated with some
diastereoisomeric salt and the crystals were placed for 10 h.
The crystals were filtered, washed with ethyl acetate
(5 · 5 mL) and dried to afford the solid diastereoisomeric
salt: (ꢀ)-1-(3-chloro-phenyl)-2-propanol maleic acid mono-
ester (ꢀ)-11 (+)-dehydroabiethylamine salt (13.13 g,
23.69 mmol, Y: 39.8%).
The recrystallized diastereoisomeric salt (6.08 g) was dis-
solved in hot ethyl acetate (18 mL) and cooled to room
temperature slowly once again. It was allowed to crystal-
lize for 1 h and the crystals were filtered, washed with
ethyl acetate (3 · 2.5 mL) and dried to afford the solid
twice recrystallized diastereoisomeric salt: (ꢀ)-1-benzo-
[1,3]dioxol-5-yl-2-propanol maleic acid monoester (ꢀ)-8
The diastereoisomeric salt (13.13 g) was dissolved in hot
acetate (350 mL), then it was evaporated to 86 g, cooled
to room temperature slowly and was allowed to crystallize
for 1 h. The crystals were filtered, washed with ethyl acetate
(5 · 5 mL) and dried to afford the solid recrystallized dia-
stereoisomeric salt: (ꢀ)-1-(3-chloro-phenyl)-2-propanol
maleic acid monoester (ꢀ)-11 (+)-dehydroabiethylamine
salt (10.20 g, 18.40 mmol, Y: 30.9%).
(R)-(+)-phenylethylamine salt (5.27 g, 13.19 mmol, Y:
25
36.7%), off-white crystal, {½aꢁD ¼ ꢀ6:1 (c 2, glacial acetic
acid)}.
The crystals (4.87 g, 12.19 mmol) were suspended in ethyl
acetate (40 mL), and 20% HCl (5 mL) was added and the
solution was stirred for 15 min (clear two-phase solution).
The phases were separated and the organic phase was
washed with 1.5 M HCl solution (3 · 5 mL), then it was
dried over Na2SO4 and the solvent was removed in vacuo
to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic
The recrystallized diastereoisomeric salt (10.20 g) was dis-
solved in hot acetone (300 mL), then it was evaporated to
63 g, cooled to room temperature slowly and was allowed
to crystallize for 1 h. The crystals were filtered, washed with
diethyl ether (5 · 5 mL) and dried to afford the solid twice
recrystallized diastereoisomeric salt: (ꢀ)-1-(3-chloro-phe-
nyl)-2-propanol maleic acid monoester (ꢀ)-11 (+)-dehy-
acid monoester (ꢀ)-8 (3.38 g, 12.14 mmol, Y: 33.8%)
droabiethylamine salt (7.97 g, 14.38 mmol, Y: 24.2%),
25
25
{½aꢁD ¼ ꢀ15:3 (c 2, CHCl3)}.
{½aꢁD ¼ ꢀ10:9 (c 2, CH3OH)}, mp: 140–143 ꢁC.
The monoester was removed: (ꢀ)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (2.98 g,
10.70 mmol) was heated with a mixture of water (4.5 mL)
and NaOH (1.5 g) for 1 min and it was allowed to cool
to room temperature. The aqueous phase was washed with
diethyl ether (4 · 40 mL). The combined organic phase was
dried over Na2SO4 and the solvent was removed in vacuo
to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol (ꢀ)-2
The crystals (7.97 g) were suspended in methanol (25 mL),
and a mixture of water (5 mL) and NaOH (0.8 g), then
water (100 mL) were added to the solution. It was extracted
with dichloromethane (3 · 30 mL), then it was acidified
with 37% HCl solution (3 mL) and extracted with dichloro-
methane (3 · 30 mL) again. The combined organic phase
was dried over Na2SO4 and the solvent was removed in
vacuo to afford (ꢀ)-1-(3-chloro-phenyl)-2-propanol maleic
acid monoester (ꢀ)-11 (3.34 g, 12.43 mmol, Y: 20.9%).
(1.52 g (after vacuo distillation), 8.43 mmol, Y: 23.5%)
25
{½aꢁD ¼ ꢀ31:3 (c 2, CHCl3)}, ee: 97%.
The monoester was removed: (ꢀ)-1-(3-chloro-phenyl)-2-
propanol maleic acid monoester (ꢀ)-11 (3.34 g) was heated
with a mixture of water (6 mL) and NaOH (2.5 g) for 1 min
and it was allowed to cool to room temperature. The
solution was extracted with diethyl ether (4 · 20 mL). The
combined organic phase was dried over Na2SO4 and the
solvent was removed in vacuo to afford (ꢀ)-1-(3-chloro-
The resolution mother liquid was washed with 1.5 M HCl
solution (1 · 15 mL and 2 · 5 mL). The organic phase
was dried over Na2SO4 and the solvent was removed in
vacuo to afford (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
maleic acid monoester (ꢀ)-8 (6.19 g, 22.24 mmol, Y:
25
61.9%) {½aꢁD ¼ ꢀ3:8 (c 2, CHCl3)}.
phenyl)-2-propanol (ꢀ)-3 (1.82 g, 10.67 mmol, Y: 17.9%),
25
The monoester was removed: (ꢀ)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (6.19 g) was
heated with a mixture of water (9 mL) and NaOH (3 g)
for 1 min and it was allowed to cool to room temperature.
The aqueous phase was washed with diethyl ether
(4 · 100 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
{½aꢁD ¼ ꢀ33:8 (c 2, CHCl3)}, ee: 97%.
The solvent was removed in vacuo from the resolution
mother liquid, and methanol (35 mL), a mixture of water
(10 mL) and NaOH (1 g) and then water (100 mL) were
added to the residue. The solution was extracted with
dichloromethane (3 · 50 mL), it was acidified with 37%
HCl (5 mL) and then it was extracted with dichlorometh-
ane (4 · 25 mL). The combined organic phase was dried
over Na2SO4 and the solvent was removed in vacuo to
(ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
(ꢀ)-2
(3.23 g,
25
17.92 mmol, Y: 49.9%) {½aꢁD ¼ ꢀ4:4 (c 2, CHCl3)}, ee:
14%.

V. Kiss et al. / Tetrahedron: Asymmetry 17 (2006) 2220–2234
2233
afford (ꢀ)-1-(3-chloro-phenyl)-2-propanol maleic acid
monoester (ꢀ)-11 (10.22 g, 38.04 mmol, Y: 63.9%).
filtered, washed with hexane (3 · 2 mL) and dried to afford:
(ꢀ)-1-(3,4-dichloro-phenyl)-2-propanol
(ꢀ)-5
(4.43 g,
25
21.60 mmol, Y: 65.6%), white crystals, {½aꢁD ¼ ꢀ23:1 (c
The monoester was removed: (ꢀ)-1-(3-chloro-phenyl)-2-
propanol maleic acid monoester (ꢀ)-11 (10.22 g) was
heated with a mixture of water (20 mL) and NaOH (5 g)
for 1 min and it was allowed to cool to room temperature.
The solution was extracted with diethyl ether (4 · 20 mL).
The combined organic phase was dried over Na2SO4 and
the solvent was removed in vacuo to afford (ꢀ)-1-(3-
2, CHCl3)}, ee: 80%.
The mother liquid was evaporated: (ꢀ)-1-(3,4-dichloro-
phenyl)-2-propanol (ꢀ)-5 (2.27 g, 11.07 mmol, Y: 33.6%),
25
{½aꢁD ¼ ꢀ7:8 (c 2, CHCl3)}, ee: 27%.
chloro-phenyl)-2-propanol (ꢀ)-3 (6.08 g, 35.63 mmol, Y:
Acknowledgements
25
59.8%) {½aꢁD ¼ ꢀ11:7 (c 2, CHCl3)}, ee: 34%.
The Hungarian OTKA Foundation (Project No. T042725
E.F.) is gratefully acknowledge for financial support.
V.K. thanks Gedeon Richter Ltd, for doctoral fellowship.
4.15. Purification by recrystallization of the enantiomers
4.15.1. Purification of (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propa-
nol maleic acid monoester (ꢀ)-8 enantiomer with recrystal-
lization. (ꢀ)-1-Benzo[1,3]dioxol-5-yl-2-propanol maleic
acid monoester (ꢀ)-8 (10.00 g, 35.94 mmol, ee: 48%) was
dissolved in toluene (20.0 mL) with heating. The solution
was inoculated with pure (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-
propanol maleic acid monoester (ꢀ)-8 and stirred for 3 h
at room temperature. The crystals were filtered, washed
with toluene (3 · 2 mL) and hexane (3 · 2 mL), and dried
to afford: (ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol maleic
References
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25
crystals, {½aꢁD ¼ ꢀ2:7 (c 2, CHCl3)}.
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The monoester was removed: (ꢀ)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (2.50 g) was
heated with a mixture of water (4 mL) and NaOH (1.2 g)
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Na2SO4 and the solvent was removed in vacuo to afford
(ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol (ꢀ)-2 (1.46 g, 8.10
25
mmol, Y: 22.5%), oil, {½aꢁD ¼ ꢀ4:5 (c 2, CHCl3)}, ee: 14%.
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5-yl-2-propanol maleic acid monoester (ꢀ)-8 (7.45 g,
25
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The monoester was removed: (ꢀ)-1-benzo[1,3]dioxol-5-yl-
2-propanol maleic acid monoester (ꢀ)-8 (7.45 g) was
heated with a mixture of water (11 mL) and NaOH
(3.8 g) for 1 min and it was allowed to cool to room tem-
perature. The aqueous phase was washed with diethyl ether
(4 · 10 mL). The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo to afford
(ꢀ)-1-benzo[1,3]dioxol-5-yl-2-propanol
(ꢀ)-2
(4.24 g,
25
23.53 mmol, Y: 65.5%), oil, ½aꢁD ¼ ꢀ19:1 (c 2, CHCl3),
ee: 59%.
4.15.2. Purification of (ꢀ)-1-(3,4-dichloro-phenyl)-2-propa-
nol (ꢀ)-5 enantiomer with recrystallization: general proce-
dure. (ꢀ)-1-(3,4-Dichloro-phenyl)-2-propanol
(ꢀ)-5
(6.75 g, 32.91 mmol, ee: 61%) was dissolved in hot hexane
(6.8 mL). The solution was divided into two phases during
the cooling to 20 ꢁC. The two-phase solution was inocu-
lated with pure (ꢀ)-1-(3,4-dichloro-phenyl)-2-propanol
(ꢀ)-5 and it was stirred for 20 min. The crystals were
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