Mild chemo-enzymatic synthesis of polymer-supported cinchona alkaloids and their application in asymmetric Michael addition

Article abstract of DOI:10.1016/S0040-4039(01)00731-6

Cinchona alkaloid (CA) monomers were synthesised enzymatically in high yield (90%) by selectively acrylating the primary -OH group of the CA, and the co-polymers obtained with acrylonitrile were tested for their efficiency for asymmetric induction in Mich

Full text of DOI:10.1016/S0040-4039(01)00731-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4541–4543
Mild chemo-enzymatic synthesis of polymer-supported cinchona
alkaloids and their application in asymmetric Michael addition
Vilas Athawale* and Narendra Manjrekar
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai 400 098, India
Received 25 July 2000; revised 15 January 2001; accepted 2 May 2001
Abstract—Cinchona alkaloid (CA) monomers were synthesised enzymatically in high yield (90%) by selectively acrylating the
primary -OH group of the CA, and the co-polymers obtained with acrylonitrile were tested for their efficiency for asymmetric
induction in Michael addition reactions. © 2001 Elsevier Science Ltd. All rights reserved.
Asymmetric synthesis of optically active compounds
from prochiral substrates using chiral catalysts is a very
attractive methodology in organic chemistry. However,
removal of the expensive chiral catalyst from the crude
reaction product after the completion of reaction is a
tedious job. Polymer-supported catalysts are advanta-
geous, as they can be recovered from the reaction
product by simple filtration and can be reused, thus,
making the process economically viable.
In the present study, porcine pancreatic lipase (PPL)
was used for acrylating selectively the primary -OH
group of the CA, in the presence of the secondary -OH
group, to obtain the acrylate derivative of CA (Scheme
1).
In the cinchona alkaloid catalysed Michael addition of
thiols, the -OH group at C(9) in the cinchona alkaloid
should be free to form a hydrogen bond with thiophen-
oxide ion, thereby enhancing the rate of reaction and
enantiomeric excess. It has been reported that in trans-
esterification reactions catalysed by PPL, the primary
A systematic study of the addition of thiols to a,b-
unsaturated ketones in the presence of cinchona alka-
1
loids as chiral catalyst has been reported.
-
OH group of a diol was selectively acylated in the
Polymer-supported cinchona alkaloids have been syn-
7
presence of a secondary -OH group.
2
–4
thesised chemically, however, no reports are available
on a biocatalytic approach for the synthesis of deriva-
tives of the alkaloids.
A primary -OH group was introduced into the CAs
quinine 1 and quinidine 2 by reacting them with 2-mer-
captoethanol using AIBN to obtain the corresponding
Enzyme mediated processes are becoming standard syn-
thetic technologies for selective transformations in
organic synthesis. Among biocatalysts of synthetic
interest, lipases (triglycerol hydrolases, EC 3.1.1.3) have
been used most frequently because they are cheap,
available from many sources, easy to handle, and com-
diols, 11-[2-thioethanol]-10,11-dihydroquinine 3 and 11-
3
[
2-thioethanol]-10,11-dihydroquinidine 4. The transes-
terification of 3 or 4 with 2,3-butanedione mono-oxime
acrylate 7 in the presence of PPL selectively leads to the
formation of 11-[2-(acryloyloxy)ethylthio]-10,11-dihy-
droquinine 5 and 11-[2-(acryloyloxy)ethylthio]-10,11-
5
,6
patible with a broad range of substrates.
Lipase
8
dihydroquinidine 6, respectively (Scheme 1), in which
catalysed reactions show high chemo-, regio- and enan-
tioselectivities and, unlike chemical reactions, no unde-
sirable side-products are formed.
the -OH group at C(9) is free, which was confirmed by
9
NMR data. The reactivity of the enzyme towards 3
and 4 is similar as expected since the primary hydroxyl
groups in both substrates are away from the bulkier
part of the molecule, making it easily available for
attack by the enzyme–acylating agent complex. The
type of organic solvent used has a profound effect on
the reaction kinetics and stability of enzymes. Reactions
Keywords: chemo-enzymatic synthesis; lipase; cinchona alkaloid;
polymer-supported catalyst.
*
Corresponding author. Tel.: 91:22:652 7957-61, ext. 567; fax:
1:22:652 85 47; e-mail: polymer2000@rediffmail.com
were carried out in chloroform (CHCl ), dichloro-
3
9
methane (CH Cl ) and tetrahydrofuran (THF) with
2
2
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00731-6

4
542
V. Athawale, N. Manjrekar / Tetrahedron Letters 42 (2001) 4541–4543
Scheme 1.
stirring at 30°C for 6 h. Among the solvents tried,
initiator under an argon atmosphere (Table 1). Molecu-
CHCl proved to be a better solvent (92% yield) com-
lar weights (M ) of the polymer catalysts 8 and 9 were
3
w
pared to CH Cl (84% yield). The lowest conversion in
determined using GPC and their values were 15,682
and 16,894, respectively. Incorporation of the alkaloid
derivatives 5 and 6 was confirmed by hydrolysing the
polymers 8 and 9 followed by Soxhlet extraction. The
alkaloid contents in polymers 8 and 9 were 9.12 and
8.94%, respectively. The polymers 8 and 9 obtained
were tested for their efficiency in catalysing the Michael
addition of thiophenol (Scheme 2) to 2-cyclohexen-1-
2
2
the case of THF (56% yield) as solvent can be
attributed to the fact that THF must absorb water from
the enzyme, which is essential for its catalytic activity.
The effect of variation in temperature on the rate of
transesterification was studied at 10, 20, 30 and 40°C in
CHCl for 6 h. It was found that at lower temperatures
3
(
10 and 20°C) the yields were very low (36 and 75%,
1
respectively), indicating a slow rate of reaction. When
the reaction was carried out at 30°C there was a
gradual increase in the yield (92%). With further
increase in the temperature (at 40°C) there was no
change in the yield (90%). The copolymers of
monomers 5 and 6 were obtained by reacting 1 mol of
one (reaction 1, Table 2) and dimethyl maleate (reac-
10
tion 2, Table 3). In the case of reaction 1, the Michael
adducts showed higher ee’s (50%) as compared to the
products obtained by using non-polymeric catalyst
11
(41%), whereas the Michael adducts in reaction 2
showed lower optical rotations compared to those
12
5
or 6 with 9 mol of acrylonitrile, using AIBN as an
obtained by using non-polymeric catalysts.
Table 1. Preparation of alkaloid–acrylonitrile copolymers
2
5
Copolymer
Yield (%)
[h] in DMF
Elemental analysis (%)
D
C
H
N
Polymer 8
Polymer 9
65
66.2
−31 (c 1.003)
+33 (c 1.01)
66.21
66.83
6.19
6.22
18.12
18.47

V. Athawale, N. Manjrekar / Tetrahedron Letters 42 (2001) 4541–4543
4543
Scheme 2.
Table 2. Asymmetric addition of the thiophenol catalysed
on 2-cyclohexen-1-one
4. Hodge, P.; Khoshdel, E.; Waterhouse, J. J. Chem. Soc.,
Perkin Trans. 1 1983, 2205.
5
6
7
. Klibanov, A. M. CHEMTECH 1986, 354.
. Zaks, A.; Klibanov, A. M. J. Biol. Chem. 1988, 3194.
. Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1986,
Catalyst
Yield (%)
%ee
Polymer 8
Polymer 9
86
85
51
50
5
638.
. Preparation of 11-[2-(acryloyloxy)ethylthio]-10,11-dihy-
droquinine and 11-[2-(acryloyloxy)ethylthio]-10,11-
dihydroquinidine 6: A mixture of the alkaloid 3 or 4 (3 g,
.45 mmol), 2,3-butanedione mono-oxime acrylate 7
0.577 g, 3.73 mmol) and enzyme (500 mg) was dissolved
in CHCl and the reaction mixture was stirred at 35°C for
8
5
Table 3. Asymmetric addition of the thiophenol catalysed
on dimethyl maleate
7
(
2
5
Catalyst
Yield (%)
[h] in CH Cl
D 2 2
3
6
h. The reaction mixture was filtered to separate the
Polymer 8
Polymer 9
87
85
+17.6 (c 5.00)
−17.1 (c 5.02)
enzyme and the filtrate was concentrated. The residue
was treated with 2 M HCl and extracted with ether (2×25
mL). The aqueous layer was made alkaline with Na CO3
2
and extracted with dichloromethane. The extracts were
washed with brine and dried over anhydrous Na SO and
concentrated. The residue was purified on silica gel
In conclusion, the above-mentioned chemo-enzymatic
method is a mild and selective route. This method may
be of importance in the synthesis of the compounds,
where selectivity as well as mild reaction conditions are
required by simultaneously replacing conventional cata-
lysts with environment-friendly ‘green catalysts’.
2
4
column {eluent CHCl (50): MeOH (2): Et N (1)} to give
3
3
2
5
monomer 5, yield=3.14 g (92%) [h] =−108 (c 1.032 in
EtOH) and monomer 6, yield=3.04 g (89%) [h] =+110
D
2
5
D
(
c 1.04 in EtOH), respectively.
9. Inagaki, M.; Hiratake, J.; Yamamoto, Y.; Oda, J. Bull.
Chem. Soc. Jpn. 1987, 60, 4121.
0. Yamashaita, H.; Mukaiyama, T. Chem. Lett. 1985, 363.
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11. The ee for the Michael adduct from reaction 1 using
non-polymeric catalyst was 41% (Reference 1).
4
12. The optical rotations for the Michael adduct from reac-
2
3
7
tion 2 using non-polymeric catalysts were [h] =+18.1 (c
D
2
3
5.00, CH Cl ) and [h] =−29.2 (c 5.00, CH Cl ), respec-
2
2
D
2
2
1
tively, (Reference 7).
.