Kinetic resolution of (E)-4-(2′,5′-dimethylphenyl)-but-3-en-2-ol and (E)-4-(benzo[d][1′,3′]dioxol-5′-yl)-but-3-en-2-ol through lipase-catalyzed transesterification

Article abstract of DOI:10.1016/j.tetasy.2015.05.006

Abstract A short and efficient chemoenzymatic pathway was developed to produce both enantiomeric forms of allyl alcohols possessing a bulky aromatic substituent at the stereogenic center, namely (E)-4-(2′,5′-dimethylphenyl)-but-3-en-2-ol and (E)-4-(benzo[

Full text of DOI:10.1016/j.tetasy.2015.05.006

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
0
0
Kinetic resolution of (E)-4-(2 ,5 -dimethylphenyl)-but-3-en-2-ol
0
0
0
and (E)-4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol through
lipase-catalyzed transesterification
a,
⇑
a
a
a
b
Witold Gładkowski , Anna Gliszczy n´ ska , Monika Siepka , Marta Czarnecka , Gabriela Maciejewska
a
Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
Central Laboratory of the Instrumental Analysis, Wrocław University of Technology, Wybrze z_ e Wyspia n´ skiego 27, 50-370 Wrocław, Poland
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient chemoenzymatic pathway was developed to produce both enantiomeric forms of
Received 1 April 2015
Accepted 7 May 2015
Available online xxxx
0
0
allyl alcohols possessing a bulky aromatic substituent at the stereogenic center, namely (E)-4-(2 ,5 -
0
0
0
dimethylphenyl)-but-3-en-2-ol and (E)-4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol. Alcohols were sub-
jected to the lipase-catalyzed transesterification and the lipase from Candida antarctica (CAL-B) proved to
be the most effective biocatalyst in the screening experiments showing a high enantiopreference toward
(
R)-enantiomers. Replacing vinyl propionate with isopropenyl acetate decreased the conversion degree of
0
0
0
all lipase-catalyzed transesterifications of (E)-4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol, but in the
case of CAL-B and two preparations of Amano Lipase PS, the enantioselectivity was significantly enhanced
0
0
(
E >100). In a preparative-scale reaction of (E)-4-(2 ,5 -dimethylphenyl)-but-3-en-2-ol with vinyl propi-
onate catalyzed by CAL-B, unreacted (ꢀ)-(S)-alcohol (ee = 98%) and (+)-(R)-propionate (ee = 98%) were
0
0
obtained after 2 h in yields of 43% and 45%, respectively. The kinetic resolution of (E)-4-(benzo[d][1 ,3 ]-
0
dioxol-5 -yl)-but-3-en-2-ol using isopropenyl acetate and CAL-B after 1 h gave (ꢀ)-(S)-alcohol (ee = 99%)
and (+)-(R)-acetate (ee = 91%) in yields of 44% and 46%, respectively. (+)-(R)-Alcohols were obtained by
0
0
0
the hydrolysis of the corresponding esters. Except for (+)-(R,E)-4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-
-ol, all enantiomerically enriched compounds were not previously reported. The absolute configurations
2
of their stereogenic centers were assigned by comparison with literature data or based on the Kazlauskas
rule. The presented methodology provides straightforward access to valuable building blocks, which can
be widely employed in organic synthesis for the production of non-racemic chiral molecules with differ-
ent biological activities.
Ó 2015 Elsevier Ltd. All rights reserved.
1
. Introduction
agents, that is, (R)- and (S)-3-methyl-2-phenylbutylamine,18 and
a
naturally occurring sesquiterpene, cis-(1S,4S)-7-methoxy-
1
9
Chiral allyl alcohols have found wide applications in many
calamenene.
branches of industry. Some of them possess valuable odoriferous
properties useful in the food or cosmetic industry.1 They are also
important building blocks in the synthesis of optically active odor-
Recently, starting from racemic 4-arylbut-3-en-2-ols with
unsubstituted, p-methyl substituted and p-isopropyl substituted
–3
phenyl ring, we synthesized some d-halo-c-lactones with anti-
4
–6
7–9
12
20
ants,
molecules with various pharmacological activity
or
cancer activity. Taking into account the influence of the configu-
rations of the stereogenic centers on the biological properties of
compounds, we have also developed a convenient chemoenzy-
matic pathway leading to iodolactones in both enantiomerically
10
11
compounds with antifungal, antibacterial,
insecticidal, or
antifeedant properties.13 An interesting group of allyl alcohols used
as chiral synthons in the synthesis of biologically active molecules
are compounds with a 4-arylbut-3-en-2-ol system. They are used
2
1
enriched forms. Our strategy was based on the kinetic resolution
of racemic 4-arylbut-3-en-2-ols by lipase-catalyzed transesterifi-
cation. Previous investigations concerned the resolution of alcohols
with unsubstituted or p-substituted phenyl ring. Due to interest in
the synthesis of another series of biologically active chiral lactones,
we decided to apply the enzymatic kinetic resolution to the pro-
duction of another two useful chiral building blocks belonging to
14
as starting materials in the production of (R)-baclofen, (R)- and
1
5
(S)-verapamil, (+)-L-733,060—neurokinin substance P receptor
1
6
17
antagonist, b-branched phenylalanine derivatives, resolving
⇑
Corresponding author. Tel.: +48 713205197; fax: +48 713283576.
E-mail address: glado@poczta.fm (W. Gładkowski).
http://dx.doi.org/10.1016/j.tetasy.2015.05.006
957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Gładkowski, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.006

2
W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
0
0
this group, namely (E)-4-(2 ,5 -dimethylphenyl)-but-3-en-2-ol and
(
which were necessary as the standards for chiral gas
chromatography.
0
0
0
E)-4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol. The latter com-
pound in its racemic form has found many applications in organic
synthesis including the allylation of 1,3-dicarbonyl compounds,
Racemic alcohols 5,6 were subjected to kinetic resolution by
enzymatic transesterification. The goal of these studies was to
select a biocatalyst which could be applied to the production of
both enantiomers of starting alcohols with very high enantiomeric
purity in the shortest possible time. For this purpose, we decided to
apply lipases whose properties and applications as biocatalysts in
organic synthesis and industry are widely described in the litera-
22–24
sulfonamides, and carbamates,
and the synthesis of allylic
2
5
26
azides and unsaturated phosphonates. Moreover, the 1,3-ben-
zodioxole system is present in various natural and synthetic bio-
logically active compounds, which show antiproliferative, anti-
inflammatory or anticonvulsant properties.2
7–30
3
2–34
ture.
In the first step of our studies, we tested four lipase
preparations. Three of them were immobilized in different carriers;
macroporous acrylic resin (lipase B from Candida antarctica—CAL-
B), macroporous ion-exchange resin (lipase from Mucor miehei—
Lipozyme ), and granulate (Lipozyme TL IM). Only lipase from
Candida cylindracea (CCL) was in free form. CAL-B and CCL were
2
. Results and discussion
Both racemic allyl alcohols 5 and 6 were synthesized in a two-
Ò
step synthesis from 2,5-dimethylbenzaldehyde 1 and piperonal 2,
respectively, by Claisen–Schmidt condensation with acetone and
subsequent reduction of the carbonyl group using sodium borohy-
dride (Scheme 1). (E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-ol 5
has not been obtained before in either racemic or enantiomerically
pure form. Its structure was confirmed on the basis of spectro-
scopic data. The presence of a hydroxy group at the secondary car-
earlier successfully applied in our research group in the resolution
3
5,36
Ò
0
0
of secondary aliphatic and cyclic allyl alcohols.
Lipozyme and
Lipozyme TL IM were reported as highly enantioselective biocata-
lysts in the resolution of many racemic mixtures of acids and
3
7,38
alcohols.
ꢀ1
0
0
Transesterification of racemic (E)-4-(2 ,5 -dimethylphenyl)-but-
-en-2-ol (5) was carried out with vinyl propionate in diisopropyl
bon atom was indicated by the characteristic bands at 3297 cm
ꢀ
1
3
(
O–H stretching vibrations) and 1057 cm (C–O stretching vibra-
1
ether (Scheme 2) and the results are presented in Table 1.
tions) in the IR spectrum and the multiplet from H-2 in the H NMR
spectrum, which was shifted to 4.51 ppm due to the neighboring
electronegative oxygen atom. The retention of the E-configuration
of the double bond was clearly proved by the value of the coupling
constant (J = 15.9 Hz) found in the two multiplets from the olefinic
protons: doublet of doublets at 6.15 ppm (from H-3) and doublet at
Ò
CAL-B, Lipozyme , and Lipozyme TL IM exhibited high enan-
tioselectivity in this process (E >100). The most effective biocata-
lyst was CAL-B and after 1 h of the reaction catalyzed by this
enzyme, 53% conversion of alcohol 5 was achieved. The enan-
tiomeric excesses of unreacted (ꢀ)-alcohol 5 and (+)-propionate
7
b were 93% and 98%, respectively. After 2 h and 4 h of the process,
6
.76 ppm (from H-4). The same two-step procedure was applied to
0
0
0
98% ee of (ꢀ)-alcohol 5 was determined whereas the ee of (+)-pro-
the synthesis of racemic 4-(benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-
-ol 6. This alcohol was obtained earlier by Skrobiszewski et al.
Ò
pionate 7b remained unchanged. Lipozyme TL IM and Lipozyme
2
were also useful biocatalysts in the resolution of enantiomers of
alcohol 5 although the reaction rate was lower. In the case
of Lipozyme TL IM after 4 h of reaction at 55% conversion, the ee
of (ꢀ)-alcohol 5 and (+)-propionate 7b were 97% and 98%,
as a starting material in the synthesis of racemic hydroxylactones
with antifeedant activity.31 Alcohols 5 and 6 were also treated with
acetyl chloride and propionyl chloride to afford racemic acetates
7
a,8a and propionates 7b,8b (Scheme 1), not reported previously,
O
O
O
OH
2
O
R
6
'
5
'
1'
1
H
i
ii
4
iii
3
2
'
4
'
3
'
1
3
rac-7a,b
rac-5
a: R = Me
b: R = Et
O
O
OH
O
2
R
O
3
O
'
4'
3
a'
5'
O
O
O
O
1
H
O
O
4
i
ii
iii
2
'
3
6
'
1' O 1a'
7
'
rac-8a,b
2
4
rac-6
(
i) acetone, NaOH, rt, 24 h; (ii) NaBH4, MeOH, 0 oC to rt, 8 h; (iii) acyl chloride, Et2O, pyridine, 0 oC to rt, 24 h
Scheme 1. Synthesis of racemic 4-arylbut-3-en-2-ols 5,6, their acetates 7a,8a and propionates 7b,8b.
O
OH
OH
O
O
H
lipase
+
+
O
diisopropyl
ether
rac-5
(-)-(3E,2S)-5
(+)-(3E,2R)-7b
Scheme 2. Lipase-catalyzed kinetic resolution of rac-5.
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W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 1
Results of the transesterification of rac-5 with vinyl propionate catalyzed by different lipases
Enzyme
CAL-B
Time (h)
Conversiona (mol %)
ee of (ꢀ)-(S)-alcohol 5 (%)
ee of (+)-(R)-propionate 7b (%)
Eb
1
2
4
1
2
4
6
8
53
58
58
7
93
98
98
6
7
9
11
14
20
36
63
88
95
98
37
78
97
98
98
98
98
98
90
90
88
86
81
78
96
98
99
99
99
98
96
98
98
98
>100
>100
>100
20
CCL
10
13
15
18
23
31
43
53
55
56
36
48
55
56
56
20
17
14
10
9
69
2
4
1
2
4
6
8
1
2
4
6
8
LipozymeÒ
>100
55
>100
>100
>100
>100
>100
>100
>100
Lipozyme TL IM
a
According to chiral GC analysis.
b
The enantiomeric ratio calculated according to the equation: E = ln[(1 ꢀ ee
s
)/(1 + (ee
s
/ee
p
)]/ln[(1 + ee
s
)/(1 + (ee
s
/ee
p
)]; ee
s
-enantiomeric excess of unreacted (ꢀ)-alcohol 5,
ee
p
-enantiomeric excess of (+)-propionate 7b.
respectively. Using LipozymeÒ, satisfactory resolution was
achieved after 8 h when at 56% conversion ee of (ꢀ)-alcohol 5
and (+)-propionate 7b reached 98% and 99%, respectively.
Reaction with lipase from C. cylindracea (CCL) proceeded very
slowly and with poor enantioselectivity. In this case the enan-
tiomeric ratio (E) did not exceed 20. The conversion and enan-
tiomeric excess of (ꢀ)-alcohol 5 gradually increased but even
after 24 h they were very low, 23% and 20%, respectively, whereas
the ee of (+)-propionate 7b decreased from 90% after 1 h to 78%
after 24 h.
studies conducted by Brenna et al. who successfully employed
Amano Lipase PS in the enantioselective resolution of allyl alcohols
1
8,19
with 4-arylbut-3-en-2-ol system.
In our screening procedure,
we tested two enzymes called Amano Lipase PS: one in free form
(Amano Lipase PS from Burkholderia cepacia) and one in immobi-
lized form (Amano Lipase PS immobilized on diatomite). For the
free enzyme, poor enantioselectivity was observed (E = 8–16).
After 8 h the conversion reached 52% but low ee of (ꢀ)-alcohol 6
and (+)-propionate 8b were determined (58% and 66%, respec-
tively). Prolonging the reaction time to 24 h did not significantly
changed the enantiopurity of (ꢀ)-alcohol 6, whereas ee of (+)-pro-
pionate 8b decreased to 57%. The reaction catalyzed by Amano PS
immobilized on diatomite was characterized by a much more
higher rate; the conversion reached 60% after 1 h of process and
increased to almost 80% after 6 h although the enantioselectivity
of the lipase was still low (E = 5–8). After 1 h of reaction, 33% ee
of unreacted (ꢀ)-alcohol 6 was determined and it increased pro-
gressively to reach 63% after 6 h by a simultaneous decrease of
ee of (+)-propionate 8b was observed from 71% to 48%.
The application of the same four biocatalysts and reaction con-
ditions (solvent diisopropyl ether, vinyl propionate as the acyl
0
0
0
donor) to the resolution of racemic 4-(benzo[d][1 ,3 ]dioxol-5 -
yl)-but-3-en-2-ol 6 (Scheme 3) gave significantly worse results
(Table 2). The most effective and enantioselective biocatalyst in
this process was also CAL-B and after 1 h 60% conversion was
achieved. Compared to the results of the transesterification of alco-
hol 5 catalyzed by this enzyme, significantly lower enantioselectiv-
ity was observed (E = 25). Enantiomeric excesses of unreacted
(
ꢀ)-(S)-alcohol 6 and (+)-(R)-propionate 8b (76% and 83%, respec-
Bearing in mind the influence of an acyl donor on the enantios-
electivity of lipases, we decided to change the reagent. We chose
isopropenyl acetate, which was successfully used by Ghanem and
Schurig in the lipase-catalyzed acylation of 4-phenylbut-3-en-2-
ol. In all transesterification processes, replacing vinyl propionate
with isopropenyl acetate led to decreased reaction rates and lower
conversions of alcohol 6. The effect of an acyl donor on the enan-
tioselectivity of the process was dependent on the lipase used. In
the case of CCL, LipozymeÒ and Lipozyme TL IM the enantioselec-
tivity did not change significantly. In the reactions catalyzed by
these three lipases, the conversion did not exceed 20%. In the case
of CCL, after 4 h no ester formation was observed. After 24 h at 20%
tively) were also distinctly lower and hardly changed for the next
3
6
Ò
h of the process. In the case of Lipozyme TL IM and Lipozyme ,
0% conversion was achieved after 6 h but in both cases the ee of
3
9
the products were moderate and ranged from 71% to 76% for
(
ꢀ)-alcohol 6 and from 74% to 79% for (+)-propionate 8b. Similar
to the transesterification of alcohol 5, the least effective enzyme
was CCL. In this case, the reaction proceeded at a slower rate and
after 24 h, the conversion was 47% and ee of (ꢀ)-alcohol 6 and
(
+)-propionate 8b were only 18% and 31%, respectively.
Searching for a more enantioselective biocatalyst to catalyze the
resolution of alcohol 6, we took into consideration the earlier
O
OH
O
R
OH
O
R1
O
O
O
O
O
lipase
+
+
O
R
O
diisopropyl
ether
rac-6
(-)-(3 E,2S)-6
(+)-(3 E,2R)-8a,b
a: R, R1 = Me
b: R = Et, R1 = H
Scheme 3. Lipase-catalyzed kinetic resolution of rac-6.
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4
W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 2
Results of the transesterification of rac-6 by different lipases using two acyl donors
Enzyme
Time
h)
Acyl donor
(
Vinyl propionate
Isopropenyl acetate
Conversiona
mol %)
ee of (ꢀ)-(S)-
ee of (+)-(R)-
propionate 8b (%)
Eb Conversiona
ee of (ꢀ)-(S)-
ee of (+)-(R)-
acetate 8a (%)
Eb
(
alcohol 6 (%)
(mol %)
alcohol 6 (%)
CAL B
CCL
1
2
4
1
2
4
6
8
4
1
2
4
6
8
1
2
4
6
8
1
2
4
6
8
4
1
2
4
6
60
61
61
20
23
30
32
36
47
23
57
58
60
60
53
58
59
60
60
12
20
38
48
52
55
60
70
75
78
76
78
78
3
83
83
83
41
41
38
37
32
31
77
74
74
74
74
82
80
79
78
77
87
80
74
71
66
57
71
71
54
48
24
25
25
2
2
2
2
2
2
9
47
47
47
0
0
0
11
13
20
<1
2
>99
>99
>99
—
—
—
10
11
16
5
7
9
91
91
91
0
0
0
40
48
51
>99
>99
90
87
85
>99
>99
97
85
83
>99
>99
>99
>99
>99
>99
71
91
91
91
>100
>100
>100
—
—
—
12
13
15
17
18
19
36
66
74
76
36
59
71
71
75
7
13
52
54
58
60
33
43
53
63
2
3
3
2
LipozymeÒ
>100
>100
20
16
14
>100
>100
77
15
13
>100
>100
>100
>100
>100
>100
10
72
83
83
9
13
14
15
14
16
18
17
17
15
16
11
10
8
5
6
8
4
11
12
7
Lipozyme TL IM
9
14
17
22
25
11
23
40
53
59
94
55
93
96
96
12
16
18
3
Amano Lipase PS from
B. cepacia
7
13
17
12
31
34
45
47
47
2
6
8
8
5
Immobilized Amano
Lipase PS
5
a
According to chiral GC analysis.
b
The enantiomeric ratio calculated according to the equation: E = ln[(1 ꢀ ee
s
)/(1 + (ee
s
/ee
p
)]/ln[(1 + ee
s
)/(1 + (ee
s
/ee
p
)]; ee
s
-enantiomeric excess of unreacted (ꢀ)-alcohol 6,
ee
p
-enantiomeric excess of (+)-propionate 8b or (+)-acetate 8a.
conversion (+)-acetate 8a was obtained with 51% ee whereas the ee
of unreacted enantiomer of alcohol (ꢀ)-6 was only 16%. A very
slow transesterification rate with isopropenyl acetate was
[47% conversion, 91% ee of (+)-ester 8a and slightly lower ee of
(ꢀ)-alcohol 6—96%] were obtained after 4 h. In this case, the enan-
tioselectivity of resolution was also considerably improved com-
pared to the reaction with vinyl propionate (E = 83 vs E = 5).
Good resolution of alcohol 6 (E >100) was also achieved during
the transesterification with isopropenyl acetate catalyzed by
Amano Lipase PS from B. cepacia, although the reaction rate was
slower than that observed for the immobilized form of this
enzyme. After 24 h, 31% conversion and high enantiomeric
excesses of (ꢀ)-alcohol 6 and (+)-acetate 8a (94% and >99%, respec-
tively) were achieved.
Based on the screening experiments we carried out the prepar-
ative-scale resolution of alcohols 5 and 6. In both processes we
used CAL-B as the biocatalyst. In the case of alcohol 5, vinyl propi-
onate was used as the acyl donor and the reaction was carried out
for 2 h whereas for the resolution of alcohol 6 isopropenyl acetate
was applied and the reaction was stopped after 1 h. The enan-
tiomerically enriched products of the reaction were separated
and purified by column chromatography to yield unreacted (S)-al-
cohols and esters of their (R)-enantiomers. The resolution of rac-5
gave its (ꢀ)-(S)-enantiomer (43% yield, 98% ee after recrystalliza-
tion) and (+)-(R)-propionate 7b (45% yield, 98% ee) and the resolu-
tion of rac-6 afforded its (ꢀ)-(S)-enantiomer (44% yield, 99% ee
after recrystallization) and (+)-(R)-acetate 8a (46% yield, 91% ee).
In order to obtain the (R)-enantiomers of alcohols 5 and 6, (+)-
(R)-propionate 7b and (+)-(R)-acetate 8a were hydrolyzed in
ethanolic NaOH solution (Scheme 4) to afford (+)-(R)-alcohol 5
(99% yield, 98% ee after recrystallization) and (+)-(R)-alcohol 6
(95% yield, 93% ee after recrystallization), respectively.
Ò
observed in the case of Lipozyme , which after 8 h the conversion
was only 8% (compared to 60% with vinyl propionate), the ee of (+)-
acetate 8a was relatively high (85%) but a very low ee for (ꢀ)-alco-
hol 6 was achieved (12%). Transesterification with isopropenyl
acetate catalyzed by Lipozyme TL IM proceeded with 18% conver-
sion after 8 h; the ee of (ꢀ)-alcohol 6 reached 25% whereas (+)-ac-
etate 8a, which in the first 2 h, was observed as a single
enantiomer, after 8 h was obtained with only 83% ee. For both
Ò
Lipozyme and Lipozyme TL IM after 8 h the enantiomeric ratio
values were similar (E = 13–14) making them unacceptable for
practical purposes. The different effect of isopropenyl acetate was
observed in the experiments carried out with CAL-B and two
Amano Lipase PS preparations. Although the conversions were
lower than those achieved in the reaction with vinyl propionate,
the ee of both the alcohol and ester as well as the enantioselectiv-
ities were considerably higher. The best results of the resolution
were obtained for CAL-B where after 1 h the conversion reached
4
7% and (ꢀ)-alcohol 6 was obtained with excellent enantiopurity
(
ee >99%) while the ee of (+)-acetate 8a was also very high (91%).
The enantiomeric ratio value exceeded 100 and no changes in con-
version or the ee of products in the next 3 h were observed. These
results were significantly better compared to the reaction of alco-
hol 6 with vinyl propionate catalyzed by CAL-B when E was only 25
and the ee of (ꢀ)-alcohol 6 and (+)-propionate 8b reached only 78%
and 83%, respectively. In the case of the immobilized Amano Lipase
PS, comparable results of the reaction with isopropenyl acetate
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W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
O
Previous investigations on the kinetic resolution of this type of
allyl alcohols mostly concerned 4-phenyl-but-3-en-2-ol or its
derivatives with a p-methoxy or p-chlorophenyl ring. The most
effective enzyme catalyzing transesterification of these alcohols
were CAL-B, Amano PS or PSL-D (Pseudomonas cepacia lipase) and
excellent ee for the products were obtained except in the reaction
O
OH
NaOH
EtOH
(+)-(3E,2R)-7b
(+)-(3E,2R)-5
3
9
O
reported by Ghanem and Schurig. Usually long reaction times
1
4,17–19
(
15 h or 24 h) were required.
Studies on the usefulness of
O
OH
enzymatic transesterification in the resolution of enantiomers of
alcohols of that type with sterically hindered aromatic substituents
are limited. Brenna et al. carried out the transesterification of (Z)-3-
O
O
NaOH
EtOH
O
O
(
3,4-dimethoxyphenyl)-1,4-dimethylpent-2-enol using Amano
(+)-(3E,2R)-8a
(+)-(3E,2R)-6
from B. cepacia and the reaction was very slow: after 108 h reaction
time, the conversion was only 34% and the ee of remaining alcohol
Scheme 4. Hydrolysis of (+)-(R)-esters 7b,8a.
1
5
was only 47%. The reaction conditions applied in our studies led
to the successful resolution of alcohols with 2,5-dimethylsubsti-
tuted phenyl ring or benzodioxolane ring within only 1 h or 2 h.
We have reported previously similar short reaction times and
excellent enantiopurity of the products during transesterification
Among the enantiomerically enriched products, only the
R)-enantiomer of alcohol 6 was obtained previously with 90%
(
ee by asymmetric reduction of ketone 4 with potassium borohy-
0
40
dride catalyzed by chiral N,N -dioxide–scandium(III) complexes.
Comparison of the specific rotation sign of the faster reacting
0
of (E)-4-phenyl- and 4-(4 -methylphenyl)but-3-en-2-ol by CAL-B
2
1
under the same conditions.
(
+)-enantiomer of alcohol 6 with that reported for the enantiomer
40
synthesized by He et al.
proved the R-configuration of
stereogenic center for both alcohol (+)-6 and its (+)-acetate 8a.
As consequence, the configuration of slower reacting
ꢀ)-enantiomer of alcohol 6 obtained directly as a product of
3. Conclusion
a
(
In conclusion, the optimal conditions of a fast and efficient pro-
duction of valuable chiral synthons 5 and 6 in both enantiomeric
forms through enzymatic resolution were established. The CAL-B
was selected as the most effective biocatalyst yielding the unre-
acted (ꢀ)-(S)-alcohols and corresponding (+)-(R)-esters with high
to excellent enantiomeric excesses. The enantioselectivity of CAL-
B- and Amano PS-catalyzed transesterifications of alcohol 6 was
considerably improved upon by using isopropenyl acetate instead
of vinyl propionate as the acyl donor. Compared to the most recent
kinetic resolutions of other allyl alcohols with a 4-arylbut-3-en-2-
ol system significantly shorter reaction times are required to
achieve satisfactory conversion of alcohols 5,6 with high enantiop-
urity of the products.
enzymatic resolution was assigned as (S). These findings are in
accordance with our earlier results of the resolution of structurally
related 4-arylbut-3-en-2-ols21 and confirm the enantiopreference
of CAL-B toward the (R)-enantiomers in the transesterification of
this type of allyl alcohols. This enantiopreference is consistent with
the known Kazlauskas’ rule41 which suggests that in the case of
most lipases, the enantiorecognition between enantiomeric
secondary alcohols is due to the sizes of the two substituents at
the stereogenic center (Scheme 5). According to this rule and
assuming the sequence rule order of substituents OH > large sub-
stituent > medium substituent, most lipases preferentially catalyze
the transesterification of the (R)-enantiomers. Taking into
consideration the enantiopreference of CAL-B, the positive specific
rotation signs for all the lipase-favoured enantiomers presented in
Scheme 5 and the structural similarity of these alcohols, we pro-
posed that the absolute configuration of the previously unknown,
faster esterified (+)-enantiomer of alcohol 5 was (R). The same con-
figuration was ascribed to its (+)-propionate 7b and consequently
an (S)-configuration was assigned to the slower reacting
4
4
. Experimental
.1. General
Purification of compounds was performed by column chro-
matography on silica gel (Kieselgel 60, 230–400 mesh, Merck) with
mixtures of hexane and acetone in various ratios as the eluents.
(ꢀ)-enantiomer of alcohol 5.
OH
enantiomer preferred by CAL-B
in acylation reactions
M
L
OH
OH
OH
O
O
M
M
M
L
L
L
(+)-(R)
(+)-(R)
OH
(+)-(R)-6
M
L
(+)-(R)-5
Scheme 5. Enantiomers of 4-arylbut-3-en-2-ols favoured by lipase from C. antarctica (CAL-B) in transesterification processes according to the empirical Kazlauskas’ rule; M-
medium substituent, L-large substituent.
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6
W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Analytical thin layer chromatography (TLC) was conducted on sil-
ica gel coated aluminum plates (DC-Alufolien Kieselgel 60 F254
Merck) using mixtures of hexane and acetone in different ratios
as developing systems. A solution of 1% Ce(SO and 2%
[P(Mo ] in 10% H SO was used as a visualizing agent.
Gas chromatography analysis was performed on Agilent
Technologies 6890 N instrument equipped with autosampler, split
injection (50:1) and FID detector. The progress of reactions was
monitored using DB-17 column ((50%-phenyl)-methylpolysilox-
of stirring at room temperature the mixture was acidified with
1 M HCl to pH = 2. The product was extracted with methylene chlo-
ride (3 ꢁ 40 mL). The organic extract was washed with brine, dried
,
4
)
2
4
over anhydrous MgSO , and filtered. The solvent was evaporated in
H
3
3
O
10
)
4
2
4
vacuo and pure ketone was obtained.
0
0
4.3.1. (E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-one 3
Obtained from aldehyde 1. Yield 98% (11.9 g); yellow liquid;
2
0
ꢀ1
n
D
= 1.5662; IR (film, cm ): 1670 (s), 1601 (s), 1497 (s), 976 (s),
1
ane, 30 m ꢁ 0.25 mm ꢁ 0.25
l
m) with hydrogen as a carrier gas.
812 (s); H NMR (300 MHz) d 2.33 and 2.41 (two s, 6H, 2 ꢁ
Temperature program was as follows: injector 280 °C, detector
Ph-CH
3
), 2.39 (s, 3H, CH
3
-1), 6.65 (d, J = 16.1 Hz, 1H, H-3),
0
0
0
(
(
FID) 280 °C, column temperature: 80 °C (1 min), 80–200 °C
20 °C min ), 200–300 °C (30 °C min ), 300 °C (2 min); The enan-
7.10ꢀ7.11 (m, 2H, H-3 and H-4 ), 7.39 (s, 1H, H-6 ), 7.80 (d,
ꢀ1
ꢀ1
13
J = 16.1 Hz, 1H, H-4), C NMR (75 MHz) d 19.2, 20.9 (2 ꢁ Ph-CH
3
),
0
0
0
tiomeric excesses were determined by chiral gas chromatography
CGC) using Varian CP Chirasil-DEX CB column (25 m ꢁ
.25 mm ꢁ 0.25 m) with the following temperature programs:
for products of transesterification of alcohol 5: 80 °C, 80–130 °C
27.7 (C-1), 126.9 (C-6 ), 127.7 (C-3), 130.7, 131.1 (C-3 , C-4 ), 133.0
0
0
0
(
(C-1 ), 134.8, 135.8 (C-2 , C-5 ), 141.0 (C-4), 198.4 (C-2). HRMS: calcd
+
0
l
14 2
for C12H O [M+H] : 191.1072, found 191.1076.
ꢀ
1
ꢀ1
0
0
0
(
0.5 °C min ), 130–200 °C (30 °C min ), 200 °C (2 min), for
4.3.2. (E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-one 4
Obtained from aldehyde 2. Yield 99% (13.1 g); white crystals;
products of transesterification of alcohol 6: 80 °C, 80–150 °C
ꢀ
1
ꢀ1
42
(
2 °C min ), 150–200 °C (10 °C min ), 200 °C (2 min). Under
mp 105ꢀ110 °C (lit. 109ꢀ111 °C); spectroscopic data consistent
4
2
these conditions, the enantiomers of alcohol 5,6 were inseparable
and were analyzed as the corresponding ester derivatives after
treatment with acetyl or propionyl chloride. Racemic acetates 7a
with those reported in the literature.
4.4. General procedure for the reduction of ketones 3,4
1
and 8a and propionates 7b and 8b were used as the standards. H
1
3
NMR, C NMR (including DEPT 135 experiment) and HMQC spec-
tra were recorded for CDCl solutions on a Brüker Avance AMX 300
spectrometer. Residual solvent signals (d = 7.26, d = 77.0) were
A solution of ketone (30 mmol) in methanol (150 mL) was
placed in an ice bath and 1.66 g (43 mmol) of NaBH dissolved in
4
3
H
C
10 mL of water was added dropwise to the stirring solution. The
reaction mixture was stirred for 1 h in the ice bath and then at
room temperature. When the ketone was reacted completely
(TLC, GC, 8 h), the mixture was diluted with hot water and the
alcohol was extracted with methylene chloride (3 ꢁ 40 mL). The
organic layer was washed with brine, dried over anhydrous
used as references for chemical shifts. IR spectra were determined
using Mattson IR 300 Thermo Nicolet spectrophotometer using KBr
pellets or in liquid films. High resolution mass spectra (HRMS)
were recorded using electron spray ionization (ESI) technique on
spectrometer Waters ESI-Q-TOF Premier XE. The melting points
were determined on Boetius apparatus. The indexes of refraction
were measured on Carl Zeiss Jena refractometer. Optical rota-
tions were measured for samples dissolved in methylene chloride
or chloroform on a Jasco P-2000-Na digital polarimeter with
intelligent Remote Module (iRM) controller.
4
MgSO , and filtered. The solvent was removed by evaporation in
vacuo and pure racemic alcohol was obtained.
0
0
4.4.1. (E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-ol rac-5
Obtained from ketone 3. Yield 91% (4.8 g); white solid; mp
ꢀ
1
5
9ꢀ63 °C; IR (KBr, cm ): 3297 (s), 1610 (w), 1453 (m), 1057 (s),
1
4
.2. Chemicals and enzymes
,5-Dimethylbenzaldehyde (purity 99%), piperonal (purity 99%),
968 (s), 804 (s); H NMR (CDCl
3
) d 1.39 (d, J = 6.6 Hz, 3H, CH
3
-1),
1
.67 (s, 1H, OH), 2.31 and 2.32 (two s, 6H, 2 ꢁ Ph-CH
3
), 4.51 (m,
2
1H, H-2), 6.15 (dd, J = 15.9, 6.6 Hz, 1H, H-3), 6.76 (d, J = 15.9 Hz,
1H, H-4), 6.98 (dd, J = 7.8, 1.5 Hz, 1H, H-4 ), 7.04 (d, J = 7.8 Hz, 1H,
H-3 ), 7.27 (s, 1H, H-6 ), C NMR (CDCl
23.5 (C-1), 69.2 (C-2), 126.3 (C-6 ), 127.3 (C-4), 128.3 (C-4 ), 130.2
(C-3 ), 132.4 (C-1 ), 134.6 (C-3), 135.42 (C2 , C5 ). HRMS: calcd for
12 16 2
C H O [M+Na] : 215.1048, found 215.1065.
0
vinyl propionate (purity 98%), isopropenyl acetate (purity 99%).
diisopropyl ether (purity P 98.5%), acetyl chloride (purity P 99%),
propionyl chloride (purity 98%) and diatomaceous earth (Celite
0
0
13
3
) d 19.3, 21.0 (2 ꢁ Ph-CH
3
),
0
0
0
0
0
0
5
60) were purchased from Sigma–Aldrich (USA). Sodium borohy-
dride (98%) was purchased from ABCR GmbH Co. KG
Germany). Analytical grade chemicals: sodium hydrogen carbon-
+
&
(
0
0
0
ate, sodium hydroxide, anhydrous magnesium sulfate, all organic
solvents, sodium chloride and hydrochloric acid (35–37%) were
purchased from P.P.H. Stanlab (Poland), Chempur (Poland) or
POCH (Poland). Lipase from Candida antarctica immobilized in
4.4.2. (E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol rac-6
Obtained from ketone 4. Yield 99% (5.7 g), yellow solid; mp
3
1
32ꢀ34 °C (lit. 36ꢀ38 °C); spectroscopic data consistent with
3
1
those reported in the literature.
Ò
acrylic resin (>5000 U/g), lipase from Mucor miehei (Lipozyme )
immobilized in macroporous ion-exchange resin (30 U/g), Amano
Lipase PS from Burkholderia cepacia (P30,000 U/g), Amano Lipase
PS (immobilized on diatomite) (P500 U/g), lipase from Candida
cylindracea (5.18 U/mg) were purchased from Sigma–Aldrich
4.5. General procedure for the synthesis of racemic acetates
7a,8a and propionates 7b,8b
The alcohol (3 mmol) was dissolved in 50 mL of dry diethyl
ether and 2 mL of dry pyridine. The mixture was stirred with a
magnetic stirrer in an ice bath and 1 mL of the appropriate acyl
chloride (acetyl chloride or propionyl chloride) was added drop-
wise. The reaction was continued at room temperature and moni-
tored by TLC (hexane/acetone 3:1) and GC. When the substrate was
reacted completely (24 h), the mixture was acidified by 5 mL of
(
USA). Immobilized granulate Thermomyces lanuginosus lipase
preparation (Lipozyme TL IM, 250 U/g) was purchased from
Novozymes (Denmark).
4
.3. General procedure for the Claisen–Schmidt condensation of
aldehydes 1,2 with acetone
0
.1 M HCl and the products were extracted with diethyl ether
(3 ꢁ 50 mL). The combined organic layers were washed with satu-
rated NaHCO , brine (until neutral), and dried over anhydrous
MgSO . After filtration and evaporation of the solvent in vacuo,
The aldehyde (70 mmol) was dissolved in acetone (20 mL) and
water (1 mL). The reaction mixture was stirred in a water bath
and 10% solution of NaOH (2 mL) was added dropwise. After 24 h
3
4
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W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
the crude ester was purified by column chromatography (hex-
ane/acetone, 10:1).
4.6. General procedure for the enzymatic transesterification of
racemic alcohols 5,6-analytical scale
0
0
Racemic alcohol (50 mg), lipase (25 mg), enol ester (vinyl propi-
onate or isopropenyl acetate, 3 mL) and 0.5 mL of diisopropyl ether
were placed in the 10 mL vial. The mixture was stirred on a mag-
netic stirrer at room temperature. After several time intervals sam-
ples of the reaction mixtures (0.3 mL) were withdrawn, filtered
through Celite, and derivatized prior to chiral GC analysis. The
derivatization procedure was as follows: 0.5 mL of dried pyridine,
0.3 mL of propionyl chloride or acetyl chloride, and 1 mL od dry
diethyl ether were added to the filtered samples. The mixtures
were stirred for 0.5 h at room temperature and diluted with 1 mL
of 1 M HCl and 1 mL of diethyl ether. The ether layers were sepa-
4
.5.1. (E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-yl acetate rac-7a
Obtained in the reaction of rac-5 with acetyl chloride. Yield 75%
20
(
(
1
(
(
(
(
1
1
1
490 mg); colorless liquid;
R) = 15.5 min; IR (film, cm ): 1738 (s), 1611 (w), 1497 (m),
240 (s), 1041 (s), 967 (m), 808 (m); H NMR (300 MHz): d 1.42
d, J = 6.3 Hz, 3H, CH
n
D
= 1.5180;
R R
t (S) = 15.3 min, t
ꢀ1
1
3
-1), 2.08 (s, 3H, CH
3
C(O)O–), 2.30 and 2.31
two s, 6H, 2 ꢁ Ph-CH
3
), 6.07 (dd, J = 15.9, 6.9 Hz, 1H, H-3), 6.80
0
d, J = 15.9 Hz, 1H, H-4), 6.98 (dd, J = 7.8, 1.5 Hz, 1H, H-4 ), 7.03
0
0
13
d, J = 7.8 Hz, 1H, H-3 ), 7.25 (s, 1H, H-6 ), C NMR (75 MHz): d
9.2, 20.9 (2 ꢁ Ph-CH
3
), 20.5 (C-1), 21.4 (CH
3
C(O)O–), 71.3 (C-2),
0
0
0
26.2 (C-6 ), 128.5 (C-4 ), 129.6 (C-4), 129.8 (C-3), 130.2 (C-3 ),
0
0
0
3
rated, washed with saturated NaHCO , brine, and dried over anhy-
32.6 (C-1 ), 135.1, 135.4 (C-2 , C-5 ), 170.3 (CH
3
C(O)O–). HRMS:
+
drous MgSO . After filtration and evaporation of the solvent in
4
calcd for C14
H
18
O
2
[M+Na] : 241.1204, found 241.1208.
vacuo, the residues were dissolved in 1 mL of hexane, transferred
0
0
0
to the vials and analyzed by GC.
4
.5.2. (E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-yl acetate
rac-8a
Obtained in the reaction of rac-6 with acetyl chloride. Yield 85%
4
.7. General procedure for the enzymatic transesterification of
20
racemic alcohols 5,6-preparative scale
(
(
(
D R R
596 mg); colorless liquid; n = 1.5440; t (S) = 41.9 min, t
ꢀ1
R) = 42.3 min; IR (film, cm ): 1734 (s), 1607 (w), 1490 (s), 1243
s), 1039 (s), 966 (m), 801 (m); 1H NMR (300 MHz): d 1.38 (d,
Lipase from C. antarctica (50% w/w of alcohol) was placed in a
2
50 mL round-bottomed flask containing a mixture of racemic
J = 6.6 Hz, 3H, CH
3
-1), 2.06 (s, 3H, CH
-2 ), 6.01 (dd, J = 15.9, 6.9 Hz, 1H, H-3), 6.51 (d,
J = 15.9 Hz, 1H, H-4), 6.74 (d, J = 7.8 Hz, 1H, H-7 ), 6.81 (dd,
J = 7.8, 1.8 Hz, 1H, H-6 ), 6.92 (d, J = 1.8 Hz, 1H, H-4 ), C NMR
300 MHz): d 20.4 (C-1), 21.4 (CH
), 105.7 (C-4 ), 108.2 (C-7 ), 121.4 (C-6 ), 127.0 (C-3), 130.7 (C-
), 131.3 (C-4), 147.4 (C-3 a), 148.0 (C-7 a), 170.3 (CH
3
C(O)O–), 5.48 (m, 1H, H-2),
0
alcohol (33 mmol) and vinyl propionate or isopropenyl acetate
(46 mmol) in 50 mL of diisopropyl ether. The reaction was con-
ducted on a magnetic stirrer at room temperature. After 1 h (in
the case of alcohol 6) or 2 h (in the case of alcohol 5) the enzyme
was filtered off and the organic solvent was removed by rotary
evaporation in vacuo. Enantiomerically enriched products were
separated by column chromatography (hexane/acetone, 15:1).
After transesterification of rac-5 (0.6 g) with vinyl propionate the
following products were obtained:
5
.95 (s, 2H, CH
2
0
0
0
13
(
2
5
3
C(O)O–), 71.1 (C-2), 101.1 (C-
0
0
0
0
0
0
0
3
C(O)O–).
+
HRMS: calcd for C13
H
14
O
4
[M+Na] : 257.0790, found 257.0801.
0
0
4
.5.3. (E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-yl propionate
rac-7b
Obtained in the reaction of rac-5 with propionyl chloride. Yield
8% (612 mg); colorless liquid; t (S) = 16.9 min, t (R) = 17.0 min;
= 1.5144; IR (film, cm ): 1736 (s), 1610 (w), 1497 (m), 1187
s), 1040 (m), 967 (m), 807 (m); H NMR (300 MHz): d 1.17 (t,
J = 7.5 Hz, 3H, CH CH C(O)O–), 1.42 (d, J = 6.6 Hz, 3H, CH -1), 2.30
and 2.31 (two s, 6H, 2 ꢁ Ph-CH ), 2.36 (q, J = 7.5 Hz, 2H,
CH CH C(O)O–), 5.56 (m, 1H, H-2), 6.07 (dd, J = 15.6, 6.6 Hz, 1H,
H-3), 6.79 (d, J = 15.6 Hz, 1H, H-4), 6.98 (dd, J = 7.8, 1.5 Hz, 1H, H-
0
0
4
.7.1. (ꢀ)-(2S,3E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-ol (ꢀ)-5
Yield 43% (0.26 g); colorless crystals (crystallization from mix-
8
R
R
ture hexane/acetone, 15:1); mp 46ꢀ52 °C; ee = 98%, t
R
= 15.3 min.
= 16.1 (c 1.9,
); spectroscopic data were identical to those reported herein
for rac-5.
2
0
ꢀ1
n
D
20
(
determined after derivatization into acetate); [
a]
D
1
(
CH Cl
2
2
3
2
3
3
3
2
0
0
4
.7.2. (+)-(2R,3E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-yl
propionate (+)-7b
0
0
0
13
4
), 7.03 (d, J = 7.8 Hz, 1H, H-3 ), 7.25 (m, 1H, H-6 ), C NMR
20
R D
Yield 45% (0.35 g); ee = 98%; t = 17.0 min.; [a] = +116.8 (c 1.6,
(
(
75 MHz): d 9.1 (CH
C-1), 27.9 (CH CH
3
CH
2
C(O)O–), 19.2, 20.9 (2 ꢁ Ph-CH
3
), 20.5
2 2
CH Cl ); other physical and spectroscopic data were identical to
0
0
3
2
C(O)O–), 71.0 (C-2), 126.2 (C-6 ), 128.5 (C-4 ),
29.3 (C-4), 129.9 (C-3), 130.2 (C-3 ), 132.6 (C-1 ), 135.2, 135.4
those reported herein for rac-7b.
After transesterification of rac-6 (0.5 g, 2.6 mmol) with iso-
propenyl acetate the following products were obtained:
0
0
1
0
0
(
C-2 , C-5 ), 173.7 (CH
3
CH
2 20 2
C(O)O–). HRMS: calcd for C15H O
+
[
M+Na] : 255.1361, found 255.1365.
0
0
0
4
(
.7.3. (ꢀ)-(2S,3E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol
ꢀ)-6
Yield 44% (0.22 g); colorless crystals (crystallization from mixture
hexane/acetone, 15:1); mp 38ꢀ40 °C; ee = 99% (determined after
0
0
0
4
.5.4. (E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-yl
propionate rac-8b
Obtained in the reaction of rac-6 with propionyl chloride. Yield
9% (587 mg); colorless liquid; t (S) = 45.3 min, t (R) = 45.5 min;
= 1.5371; IR (film, cm ): 1732 (s), 1607 (w), 1504 (s), 1252
2
0
7
R
R
derivatization into acetate); t
R
= 41.9 min.; [
a]
D
= ꢀ23.6 (c 3.8, CHCl
3
);
2
0
ꢀ1
31
n
D
spectroscopic data were identical to those reported for rac-6.
1
(
1
s), 1190 (s), 1039 (s) 966 (m), 803 (m); H NMR (300 MHz): d
.14 (t, J = 7.5 Hz, 3H, CH CH C(O)O–), 1.38 (d, J = 6.6 Hz, 3H,
CH -1), 2.33 (q, J = 7.5 Hz, 2H, CH CH C(O)O–), 5.50 (m, 1H, H-2),
.94 (s, 2H, CH
0
0
0
3
2
4
.7.4. (+)-(2R,3E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-yl
3
3
2
acetate (+)-8a
0
20
5
2
-2 ), 6.01 (dd, J = 15.9, 6.9 Hz, 1H, H-3), 6.51 (d,
R D
Yield 46% (0.24 g); ee = 91%; t = 42.3 min; [a] = +137.5 (c
Cl ); other physical and spectroscopic data were identical
2 2
to those reported herein for rac-8a.
0
J = 15.9 Hz, 1H, H-4), 6.74 (d, J = 8.1 Hz, 1H, H-7 ), 6.81 (dd,
J = 8.1, 1.8 Hz, 1H, H-6 ), 6.91 (d, J = 1.8 Hz, 1H, H-4 ), C NMR
1
.35, CH
0
0
13
(
75 MHz): d 9.1 (CH
3
CH
2
0
C(O)O–), 20.4 (C-1), 27.9 (CH
3
CH
2
C(O)O–
0
0
0
)
, 70.8 (C-2), 101.1 (C-2 ), 105.7 (C-4 ), 108.2 (C-7 ), 121.4 (C-6 ),
4
.8. Hydrolysis of optically active esters (+)-7b and (+)-8a
0
0
0
1
1
2
27.1 (C-3), 130.7 (C-5 ), 131.2 (C-4), 147.4 (C-3 a), 148.0 (C-7 a),
CH C(O)O–). HRMS: calcd for C14H O [M+Na] :
3 2 16 4
71.0946, found 271.0941.
+
73.7 (CH
The ester (12 mmol) was heated at reflux in 100 mL of 5% solu-
tion of NaOH in EtOH and 20 mL of water. When the substrate was
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8
W. Gładkowski et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
reacted completely (3 h, TLC), the solvent was evaporated in vacuo
and the residue was diluted with water. The product was extracted
with methylene chloride (3 ꢁ 40 mL). The combined organic frac-
tions were washed with brine until neutral and dried over anhy-
11. Yoshida, M.; Shoji, Y.; Shishido, K. Org. Lett. 2009, 11, 1441–1443.
1
1
1
2. Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N. Org. Lett. 2010, 12,
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Asymmetry 1997, 8, 3801–3805.
5
drous MgSO
4
. After evaporation of the solvent in vacuo, pure
alcohol was obtained.
1
1
5. Brenna, E.; Fuganti, C.; Grasselli, P.; Serra, S. Eur. J. Org. Chem. 2001, 1349–1357.
6. Emmanuvel, L.; Sudalai, A. Tetrahedron Lett. 2008, 49, 5736–5738.
0
0
17. Quirin, C.; Kazmaier, U. Synthesis 2009, 10, 1725–1731.
8. Brenna, E.; Fuganti, C.; Gatti, F. G.; Passoni, M.; Serra, S. Tetrahedron: Asymmetry
003, 14, 2401–2406.
19. Brenna, E.; Dei Negri, C.; Fuganti, C.; Gatti, F. G.; Serra, S. Tetrahedron:
Asymmetry 2004, 15, 335–340.
20. Gładkowski, W.; Skrobiszewski, A.; Mazur, M.; Siepka, M.; Pawlak, A.;
Obmi n´ ska-Mrukowicz, B.; Biało n´ ska, A.; Poradowski, D.; Drynda, A.;
Urbaniak, M. Tetrahedron 2013, 69, 10414–10423.
4
.8.1. (+)-(2R,3E)-4-(2 ,5 -Dimethylphenyl)-but-3-en-2-ol (+)-5
Obtained from propionate (+)-7b (0.22 g). Yield 99% (0.16 g);
colorless crystals (crystallization from mixture hexane/acetone,
5:1); mp 63ꢀ68 °C; ee = 98% (determined as acetate derivative);
1
2
1
2
0
t
R
= 15.5 min.; [
D 2 2
a] = +16.2 (c 1.7, CH Cl ); spectroscopic data were
identical to those reported herein for rac-5.
2
1. Gładkowski, W.; Skrobiszewski, A.; Mazur, M.; Siepka, M.; Biało n´ ska, A. Eur. J.
0
0
0
Org. Chem. 2015, 605–615.
2. Rao, W.; Tay, A. H. L.; Goh, P. J.; Choy, J. M. L.; Ke, J. K.; Chan, P. W. H.
Tetrahedron Lett. 2008, 49, 122–126.
4
(
.8.2. (+)-(2R,3E)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-but-3-en-2-ol
+)-6
Obtained from acetate (+)-8a (0.2 g). Yield 95% (0.76 g); color-
less crystals (crystallization from mixture hexane/acetone, 15:1);
2
23. Wu, W.; Rao, W.; Er, Y. Q.; Loh, J. K.; Poh, C. Y.; Chan, P. W. H. Tetrahedron Lett.
008, 49, 2620–2624.
4. Kothandaraman, P.; Rao, W.; Zhang, X.; Chan, P. W. H. Tetrahedron 2009, 65,
833–1838.
2
2
4
0
mp 38ꢀ40 °C; (lit. 57–59 °C); ee = 93% (determined as acetate
1
2
0
40
derivative);
t
R
= 42.3 min; = +20.7 (c 3.8, CHCl
[a
]
D
3
)
{lit.
25. Rueping, M.; Vila, C.; Uria, U. Org. Lett. 2012, 14, 768–771.
26. Shi, D. Q.; Chen, R. Y. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 164, 229–237.
7. Da Silva, R.; de Souza, G. H. B.; da Silva, A. A.; de Souza, V.; Pereira, A. C.; de A.
Royo, V.; de Silva, M. L. A.; Donate, P. M.; de Matos Araújo, A. L. S.; Carvalho, J. C.
T.; Bastos, J. K. Bioorg. Med. Chem. Lett. 2005, 15, 1033–1037.
2
3
[a
]
D
= +29.7 (c 3.8, CHCl ), ee = 90%}; spectroscopic data were
identical to those reported for rac-6.
3
2
31
2
2
8. Alizadeh, B. H.; Foroumadi, A.; Emami, S.; Khoobi, M.; Panah, F.; Ardestani, S.
K.; Shafiee, A. Eur. J. Med. Chem. 2010, 45, 5979–5984.
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Acknowledgements
This work was financially supported by the Ministry of Science
and Higher Education, Poland (Grant number NOZ/270/2014/S).
30. Quereshi, Z.; Weinstabl, H.; Suhartono, M.; Liu, H.; Thesmar, P.; Lautens, M. Eur.
_
J. Org. Chem. 2014, 4053–4069.
3
3
1. Skrobiszewski, A.; Gładkowski, W.; Lis, M.; Gliszczy n´ ska, A.; Maciejewska, G.;
Klejdysz, T.; Obmi n´ ska-Mrukowicz, B.; Nawrot, J.; Wawrze n´ czyk, C. Przem.
Chem. 2014, 93, 1637–1643.
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