Effective method of lipase-catalyzed enantioresolution of 6-alkylsulfanyl-1,4-dihydropyridines

Article abstract of DOI:10.3987/COM-13-12839

A series of 6-alkylsulfanyl-1,4-dihydropyridines (±)-2 bearing a methoxycarbonylethyl group as a mild easily removable protecting group at S atom have been prepared by alkylation of 6-thioxo-1,4-dihydropyridines 1 with methyl bromopropionate. Candida antarctica lipase B (Novozyme 435, CAL-B) - and Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been investigated in water-saturated diisopropyl ether (IPE) at 25 and 45 °C. After acrylic acid methyl ester as leaving group cleavage and alkylation of formed enantioenriched 1,4-dihydropyridine-6-thiolates (-)-4 and (+)-4, optically active 1,4-dihydropyridines (-)-2, (+)-2, (-)-5 and (+)-5 were obtained in 85-99% enantiomeric excess. The experiments present the 6-(methoxycarbonylethyl)- sulfanyl group as an essentially new enzymatically labile (activating) group. The ester group being 6 bonds remote from the chiral center undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of racemic 1,4-DHPs. This developed method offers access to mild optically active nucleophilic tiolates, which could be easily derivatized with electrophilic reagents.

Full text of DOI:10.3987/COM-13-12839

HETEROCYCLES, Vol. 89, No. 1, 2014
43
HETEROCYCLES, Vol. 89, No. 1, 2014, pp. 43 - 58. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 12th September, 2013, Accepted, 11th November, 2013, Published online, 27th November, 2013
DOI: 10.3987/COM-13-12839
EFFECTIVE
METHOD
OF
LIPASE-CATALYZED
ENANTIORESOLUTION
DIHYDROPYRIDINES
OF
6-ALKYLSULFANYL-1,4-
Zigmars Andzans,1,2* Ilze Adlere,1 Aleksandrs Versilovskis,1 Laura
Krasnova,1 Signe Grinberga,1 Gunars Duburs,1 and Aivars Krauze1
1Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia;
E-mail: andzans@osi.lv
2University of Latvia, 19 Raina Blvd., Riga LV 1586, Latvia
Abstract – A series of 6-alkylsulfanyl-1,4-dihydropyridines (±)-2 bearing a
methoxycarbonylethyl group as a mild easily removable protecting group at S atom
have been prepared by alkylation of 6-thioxo-1,4-dihydropyridines 1 with methyl
bromopropionate. Candida antarctica lipase B (Novozyme 435®, CAL-B) - and
Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been
investigated in water-saturated diisopropyl ether (IPE) at 25 and 45 C. After
acrylic acid methyl ester as leaving group cleavage and alkylation of formed
enantioenriched 1,4-dihydropyridine-6-thiolates (-)-4 and (+)-4, optically active
1,4-dihydropyridines (-)-2, (+)-2, (-)-5 and (+)-5 were obtained in 85-99%
enantiomeric excess. The experiments present the 6-(methoxycarbonylethyl)-
sulfanyl group as an essentially new enzymatically labile (activating) group. The
ester group being 6 bonds remote from the chiral center undergoes easy enzymatic
hydrolysis and could be used for kinetic resolution of racemic 1,4-DHPs. This
developed method offers access to mild optically active nucleophilic tiolates, which
could be easily derivatized with electrophilic reagents.
INTRODUCTION
1,4-Dihydropyridine (DHP) scaffold represents a heterocyclic unit of remarkable pharmacological
efficiency.1-4 DHP derivatives depending on their structure may bind to the L-, T- and N-types calcium,
* Corresponding author. Tel.: +371 26309236; fax: +371 67550338; e-mail adress: zigmars.andzans@inbox.lv.

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HETEROCYCLES, Vol. 89, No. 1, 2014
sodium, potassium or chloride channels and act as selective or multifunctional molecules for the various
pharmacobiological activities such as bioprotective,5 neurotropic,6 membrane protecting,7-9
radioprotecting,10 antidiabetic,11 gene-transfection,12 and antibacterial.13
6-Alkylsulfanyl-1,4-DHPs display cardiovascular,14-15 hepatoprotective,16 antioxidant,17 and antiradical18
activities (in addition to the above mentioned activities), however, these compounds are still insufficiently
studied.
Chirality plays an important role in the activity of 1,4-DHPs and both quantitative and qualitative
differences between different stereoisomers (enantiomers) have been reported.19,20 Pharmaceutical
evaluations of chiral 1,4-DHPs revealed that their strereoisomers usually have different biological
activities. Sometimes the undesired enantiomer caused serious side effects, while in other cases
enantiomers were reported to have even the opposite action profile (calcium antagonist - calcium agonist;
hypotensive activity - hypertensive activity).21
Chemoenzymatic methods for preparation of chiral drugs have a number of distinct advantages: they are
simple, direct, efficient, mild, and cheap in case of multiple (repeated) use of the enzyme. The standard
resolution technique, such as incorporation of an enzymatically labile group for the resolution of
monocyclic 1,4-DHPs has been in use for the last decade. This approach has been pioneered by groups of
Sih22 and Achiwa,23 applied to 6-derivatised 1,4-DHPs24-26 and also used by our research group.27-32
It is worth mentioning that many activating groups applicable to enantioselective lipase-catalyzed kinetic
resolution of 1,4-dihydropyridine-3-carboxylates have been screened. An asymmetric 1,4-DHPs
alkoxycarbonylmethoxycarbonyl (double esters),27,28 alkylcarboxymethyloxycarbonyl (reverse esters) in
position 525,30-33 and acetoxymethyl group in position 624,26,34,35 were the best characterised.
Esters are good substrates for the lipases and nowadays a lot of enzymes are commercially available.
Lipases such as CAL-B and Amano acylase were evaluated for the resolution of esters and often possitive
results are achieved.33-37
RESULTS AND DISCUSSION
The aim of our research was the synthesis of new 1,4-DHPs containing lipophilic
methoxycarbonylethylsulfanyl group at position 6, which could act as mild and easily removable
protecting group at S atom. Though the ester group is 6 bonds remote from the chiral center (stereogenic
carbon at the 4 position), we expected that the enzymatic hydrolysis of this group could promote kinetic
resolution of the target 1,4-DHPs. It is worth mentioning that our efforts to prepare optically active
6-alkylsulfanyl-1,4-DHPs by carrying out enzyme catalyzed hydrolysis of so called activated double
esters - ethoxycarbonylmethyl 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylates were unsuccessful,40

HETEROCYCLES, Vol. 89, No. 1, 2014
45
at the same time enantioresolution of 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridines gave
target products with up to 70% enantiomeric excess.32
The starting substrates 3-alkoxycarbonyl-5-cyano-2-methyl-4-aryl-1,4-dihydropyridine-6-thiones 1 were
prepared by a one-pot three-component condensation of alkyl acetoacetate, aromatic aldehyde and
2-cyanothioacetamide according to the synthesis protocol mentioned previously.41
Ar
O
R
O
CN
O
O
Ar
piperidine,
MeOH
Br
O
O
S
O
O
Ar
N
H
O
CN
S
R
R
CN
S
O
+
piperidine
HCl/EtOH
2a-d
(±)-
O
H2N
O
O
N
H
O
Ar
R
Br
OH
piperidine,
CN
S
1a-d
O
O
a: Ar = Ph, R = Me
b: Ar = 2-ClC6H4, R = Me
c: Ar = 3,4,5-(OMe)3C6H2, R = Et
d: Ar = 2-F2CHOC6H4, R = Me
DMSO
N
H
(±)-
OH
3a-d
Scheme 1
Alkylation of thiones 1 bearing several nucleophilic reaction centres (5-C, S, N) in basic (alkaline)
medium under mild reaction conditions with methyl bromopropionate proceeds preferably at the sulfur
atom giving rise to methyl 4-aryl-6-methoxycarbonylethylsulfanyl-1,4-dihydropyridine-3-carboxylates
(±)-2 in 71-87% yields.
Carboxylic acids (±)-3, as authentic samples for investigation of enzyme catalyzed hydrolysis, were
prepared by alkylation of thiones 1 with bromopropionic, acid in the presence of piperidine, in 64-85%
yields.
Enzymatic screening of the substrates (±)-2 was performed in water-saturated (maximal water
concentration was approximately 4 g/L) diisopropyl ether (IPE) (was found to be the best solvent) by
using an Amano Acylase (Aspergillus mellus) and Candida antarctica lipase B (CAL-B, Novozyme
435®). The reaction was monitored by HPLC and when ~50% of acid (+)-3 was formed the reaction was
stopped, enzyme was filtered off, washed with IPE and the filtrate was evaporated. The mixture of acid
(+)-3 and the remaining ester (-)-2 was separated by column chromatography. The enantiomeric excess
(ee) of the remaining esters (-)-2 were determined by HPLC using chiral column (Table 1).
Due to usage of water-saturated IPE as a solvent, the concentration of substrate needs to be less than
0.01 mol/L,
otherwise
precipitation
takes
place.
To
increase
the
solubility
of

46
HETEROCYCLES, Vol. 89, No. 1, 2014
6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines (±)-2, 0.5-10% of dichloromethane (DCM) was
added to the reaction mixture and provided that remains substrate concentration 0.0025 mol/L. It
increased the reaction rate, but enantioselectivity of the reaction decreased. When the ratio between DCM
and water-saturated IPE was 1:10, ee of ester (-)-2a was 83%, but when the content of DCM was
decreased from 9% (entry 5) to 5%, ee of (-)-2a was increased to 95% (entries 6).
To hydrolyze 6-methoxycarbonylethylsulfanyl-1,4-DHPs (±)-2 an Amano Acylase was used. To our
surprise, hydrolysis of DHPs (±)-2a and (±)-2b in water-saturated IPE did not take place at 45 C (entries
14 and 15). In case of substrate (±)-2d hydrolysis yielding racemic acid (±)-3d and ester (±)-2d (entry 17)
was observed, but in case of DHP (±)-2c just 20% ee of unreacted ester (-)-2c was reached. By carrying
out hydrolysis of the ester (±)-2b with Amano Acylase at 25 C 89% ee of (-)-2b was reached. In case of
DHPs (-)-2a, (-)-2c and (-)-2d (entries 10, 12, 13) 38-52% ee was reached.
Table 1 shows that CAL-B gave better results and in case of 4-(3,4,5-trimethoxyphenyl)substituted
6-(2-methoxycarbonylethylsulfanyl)-1,4-DHP (±)-2c enzyme catalyzed hydrolysis carried out at 45 C
over 26 h provided 99% ee of (-)-2c.
O
Ar
O
Ar
Ar
O
R
R
CN
R
CN
CN
enzyme
O
O
+
O
O
O
O
O
DCM/DIPE
N
H
S
O
N
H
S
O
N
H
S
OH
(-)-2a-d
(±)-2a-d
(+)-3a-d
CH2N2
O
Ar
a: Ar = Ph, R = Me
b: Ar = 2-ClC6H4, R = Me
R
CN
O
c: Ar = 3,4,5-(OMe)3C6H2, R = Et
d: Ar = 2-F2CHOC6H4, R = Me
O
N
H
S
(+)-2a-c
Scheme 2
Table 1 shows that in contrast to Amano Acylase, better results for CAL-B were reached by raising the
temperature from 25 C (65-82% ee) to 45 C (86-99% ee).

HETEROCYCLES, Vol. 89, No. 1, 2014
47
Table 1 Yields of enzymatic hydrolysis (reaction conditions)
Ratio
Enantio-
meric
excess of
(-)-2, %
82
Yield of
product
(-)-2
Yield of
product
(+)-3
Temp.,
between
DCM and
IPE/H2O, v/v
1:20
Time,
h
Entry
Substrate
Enzyme
C
1
2
(±)-2a
(±)-2b
(±)-2c
(±)-2d
(±)-2a
(±)-2a
(±)-2b
(±)-2c
(±)-2d
(±)-2a
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
Amano
Acylase
Amano
Acylase
Amano
Acylase
Amano
Acylase
Amano
Acylase
Amano
Acylase
Amano
Acylase
Amano
Acylase
25
25
25
25
45
45
45
45
45
25
48
165
51
49
46
46
46
48
49
46
46
46
47
47
48
47
46
47
47
48
46
46
48
1:20
1:200
1:60
1:10
1:20
1:20
1:200
1:60
1:20
80
77
65
83
95
92
99
86
52
3
4
264
40
5
6
18
7
48
8
26
9
168
96
10
11
12
13
14
15
16
17
(±)-2b
(±)-2c
(±)-2d
(±)-2a
(±)-2b
(±)-2c
(±)-2d
1:20
1:200
1:60
25
25
25
45
45
45
45
310
100
336
*
45
48
45
-
89
48
47
48
-
38
48
1:20
-
1:20
*
-
-
-
1:200
1:60
90
46
47
20
47
48
336
racemate
* Reaction doesn`t take place within 6 weeks
We did not succeed to find out an appropriate HPLC conditions for enantioseparation of carboxylic acids
(+)-3 nor on Whelk O1, nor Lux Cellulose-2 chiral HPLC columns. To characterize the opposite
enantiomer optically active acids (+)-3b and (+)-3c were methylated with diazomethane and enantiomeric
excess of the corresponding methyl 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridine-3-carboxylates
(+)-2b and (+)-2c were determined (Table 2).

48
HETEROCYCLES, Vol. 89, No. 1, 2014
O
Ar
O
Ar
O
Ar
CN
S
CN
S-
CN
S
O
O
MeI
O
O
3M NaOH/H2O
MeOH
N
H
N
H
N
H
O
Na+
(-)-5a,b and (+)-5a,b
(-)-4a,b and (+)-4a,b
(-)-2a,b and (+)-2a,b
a) Ar = Ph; b) Ar = 2-ClC6H4
Scheme 3
Enantioenriched thiolates (-)-4 and (+)-4 were prepared by deacrylation of mercaptopropionates (-)-2 and
(+)-2 with 3N NaOH water solution. Even after alkylation of (-)-4 and (+)-4 with methyl iodide
enantioenriched methyl 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylates (-)-5 and (+)-5 were still
obtained (Table 2).
Table 2. Enantiomeric excess and optical yields of compounds (-)-2, (+)-2, (+)-3, (-)-5 and (+)-5
[]20, deg, (c 1, MeOH)
Entry
Compound
ee, %
1
2
(+)-3a
(+)-3b
(+)-3c
(-)-2a
(-)-2b
(-)-2c
(+)-2a
(+)-2b
(+)-2c
(-)-5a
(+)-5a
(-)-5b
(+)-5b
-
+168.6
+171.9
+182.1
-127.8
-134.9
-152.9
+120.3
+133.9
+134.9
-104.8
+92.6
-
3
-
4
95
92
99
93
92
94
93
85
92
92
5
6
7
8
9
10
11
12
13
-110.4
+80.5
Candida antarctica lipase B and Amano Acylase catalyzed kinetic resolution has been investigated in
water-saturated diisopropylether at 25 and 45 C. Further deacrylation and alkylation of enantioenriched
1,4-dihydropyridine-6-thiolates gave rise to optically active 1,4-dihydropyridines with 85-99%
enantiomeric excess.

HETEROCYCLES, Vol. 89, No. 1, 2014
49
Experiments performed by our group allow characterisation of the 6-(methoxycarbonylethyl)sulfanyl
group as an essentially new enzymatically labile (activating) group. The ester group being 6 bonds remote
from chiral center undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of
racemic 1,4-DHPs. Since methoxycarbonylethylsulfanyl group at position 6 of 1,4-DHP ring acts as a
mild, easily removable protecting group at sulfur atom, the method developed by our group becomes
effective because it offers an access to mild synthesis of optically active nucleophilic thiolates, which
could be easily derivatized with electrophilic reagents.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 580 B spectrometer in Nujol, or in thin layer. NMR spectra
were recorded with a Varian 400-MR (400 MHz). Chemical shifts are reported in ppm relative to
hexamethyldisiloxane ( 0.055). Mass spectral data and chromatographic separation were obtained by
using an Q-TOF mass spectrometer (Micromass) operating in the ESI positive or negative ion mode
connected to an Acquity UPLC system (Waters) with Acquity UPLC BEH C18 column (1.7 m, 2.1  50
mm). A gradient elution with MeCN–HCO2H (0.1%) in water was used to separate analytes. The
enantiomeric excesses were determinated by HPLC on a Lux Cellulose-2 column (4 m, 4.6  150 mm),
as a mobile phase a 0.1% acetic acid in 2-PrOH:hexane (50:50, v/v) was used, flow rate was 1 mL/min,
UV detector was operated at 254 nm. Melting points were determined using OptiMelt (SRS Stanford
Research Systems). Elemental analyses were performed by using an EA 1106 (Carlo Erba Instruments).
Optical rotation values were measured with a Rudolph Research Analytical autopol VI automatic
polarimeter. TLC was performed on 20  20 cm Silica gel TLC-PET F254 foils (Fluka) by using different
elution solvent systems. All reagents were purchased from Aldrich, Acros, Fluka or Merck and used
without further purification.
Preparation of compounds 1a, (±)-2a and (±)-3a was described in,41 1b in,40 and 1d in.32
1.1. Methyl
5-cyano-2-methyl-6-thioxo-4-(3,4,5-trimethoxyphenyl)-1,4,5,6-tetrahydropyridine-
3-carboxylate (1c)
A mixture of 3,4,5-trimethoxybenzaldehyde (0.20 g, 1.0 mmol), ethyl acetoacetate (0.13 g, 1.0 mmol) and
piperidine (0.03 mL, 0.3 mmol) in EtOH (20 mL) was stirred for 5 min at room temperature. Then
2-cyanothioacetamide (0.1 g, 1.0 mmol) and piperidine (0.1 mL, 1.0 mmol) were added and reaction
mixture was stirred for 30 min at room temperature. The resulting reaction mixture was acidified with
0.6 mL of 3M hydrochloric acid in EtOH. The precipitate was separated by filtration, washed with cold
(-10 C) MeOH (5 mL) and water (20 mL) to give 0.28 g (58%) of thione 1c as yellow powder, mp

50
HETEROCYCLES, Vol. 89, No. 1, 2014
174-176 C. 1H NMR (400 MHz, CDCl3):  1,06 (t, cis-, J = 7.0 Hz, 3H), 1,08 (t, trans-, J = 7.0 Hz, 3H);
2.32 (s, cis-, 3H), 2.39 (s, trans-, 3H), 3.73-3.76 (m, 9H), 3.93 (q, cis-, J = 7.0 Hz, 3H), 4.03 (q, trans-, J
= 7.0 Hz, 3H); 4.16 (d, cis-, J = 6.3 Hz, 1H); 4.27 (d, cis-, J = 6.3 Hz, 1H), 4.53 (d, trans-, J = 2.7 Hz,
1H), 5.03 (d, trans-, J = 2.7 Hz, 1H), 6.39-6.46 (m, 2H), 12.10 (br s, cis-, 1H), 12.26 (br s, trans-, 1H). IR
(Nujol) 1706 (C=O), 2260 (C≡N), 3220 (br s, NH, OH) cm-1. Anal. Calcd for C19H22N2O5S: C 58.45, H
5.68, N 7.17. Found: C 58.59; H 5.54; N 7.11.
1.2. Methyl
5-cyano-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylate ((±)-2a)
A mixture of thione 1a (0.29 g, 1.0 mmol) and piperidine (0.1 mL, 1.0 mmol) in MeOH (20 mL) was
stirred for 10 min at room temperature. Then methyl bromopropionate (0.14 mL, 1.3 mmol) was added
and the reaction mixture was stirred at 80 C for 1 h. The precipitate was separated by filtration, washed
with cold (-10 C) MeOH (5 mL) and water (20 mL) to give 0.30 g (80%) of ester (±)-2a as white powder,
mp 109-110 C. 1H NMR (400 MHz, CDCl3):  2.43 (s, 3H), 2.60-2.76 (m, 2H), 2.97-3.20 (m, 2H), 3.58
(s, 3H), 3.76 (s, 3H), 4.64 (s, 1H), 7.17–7.29 (m, 4H), 7.99 (s, 1H). IR (Nujol) 171 (C=O), 2198 (C≡N),
3309 (NH) cm-1. MS m/z 373 (M+), 342, 296, 287. Anal. Calcd for C19H20N2O4S: C 61.27; H 5.41; N 7.52.
Found: C 61.20; H 5.44; N 7.49.
1.3. Methyl
4-(2-chlorophenyl)-5-cyano-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-1,4-
dihydropyridine-3-carboxylate ((±)-2b)
Compound (±)-2b was prepared in the same manner as (±)-2a using thione 1b instead of 1a. Yield 0.29 g
1
(71%) of ester (±)-2b as white powder, mp 109-110 C. H NMR (400 MHz, CDCl3):  2.45 (s, 3H);
2.67-2.75 (m, 2H), 2.96-3.25 (m, 2H), 3.56 (s, 3H), 3.79 (s, 3H), 5.29 (s, 1H), 7.10–7.35 (m, 4H), 8.15 (s,
1H). IR (Nujol) 1714 (C=O), 2198 (C≡N), 3309 (NH) cm-1. MS m/z 407 (M+), 377, 343, 295, 289, 209.
Anal. Calcd for C19H19ClN2O4S: C 56.09; H 4.70; N 6.88. Found: C 55.95; H 4.58; N 6.78.
1.4. Ethyl 5-cyano-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-4-(3,4,5-trimethoxyphenyl)-1,4-
dihydropyridine-3-carboxylate ((±)-2c)
Compound (±)-2c was prepared in the same manner as (±)-2a using thione 1c instead of 1a. Yield 0.38 g
(79%) of ester (±)-2c as white powder, mp 138-139 C. 1H NMR (400 MHz, CDCl3):  1.11 (t, J = 7.0 Hz,
3H), 2.39 (s, 3H), 2.58-2.68 (m, 2H), 2.94-3.10 (m, 2H), 3.71 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.77 (s,
3H), 3.99 (q, J = 7.0 Hz, 3H), 4.58 (s, 1H), 6.39 (s, 2H), 7.88 (s, 1H). IR (Nujol) 1684, 1712 (C=O), 2198
(C≡N); 3240 (NH) cm-1. MS m/z (rel. int.) 499 (M+Na+), 447, 432, 309, 277, 223. Anal. Calcd for
C23H28N2O7S: C 57.97, H 5.92, N 5.88. Found: C 57.89, H 5.91, N 5.81.

HETEROCYCLES, Vol. 89, No. 1, 2014
51
1.5. Methyl 5-cyano-4-(2-difluoromethoxyphenyl)-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-
1,4-dihydropyridine-3-carboxylate ((±)-2d)
Compound (±)-2d was prepared in the same manner as (±)-2a using thione 1d instead of 1a. Yield 0.38 g
1
(87%) of ester (±)-2d as white powder, mp 134-135 C. H NMR (400 MHz, CDCl3):  2.42 (s, 3H),
2.67-2.74 (m, 2H), 2.96-3.24 (m, 2H), 3.55 (s, 3H), 3.78 (s, 3H), 5.06 (s, 1H), 6.54 (q, J = 73.2 Hz, 1H),
6.96–7.27 (m, 4H), 8.03 (s, 1H). IR (Nujol) 1710 (C=O), 2201 (C≡N), 3183 (NH) cm-1. MS m/z 439 (M+),
420, 399, 333, 296. Anal. Calcd for C20H20F2N2O5S: C 54.79; H 4.60; N 6.39. Found: C 54.79; H 4.47; N
6.26.
1.6. Methyl
6-carboxyethylsulfanyl-5-cyano-2-methyl-4-phenyl-1,4-dihydropyridine-3-
carboxylate ((±)-3a)
A mixture of thione 1a (0.29 g, 1.0 mmol) and piperidine (0.1 mL, 1.0 mmol) in DMSO (20 mL) was
stirred for 10 min at room temperature. Then bromopropionic acid (0.15 g, 1.0 mmol) was added and the
reaction mixture was stirred at 70 C for 30 min. Resulting mixture was diluted with water (30 mL) and
extracted with EtOAc (3 x 30 mL). The combined organic extracts were evaporated and crystallized from
CH2Cl2. The precipitate was separated by filtration, washed with cold (-10 C) MeOH (5 mL) and water
1
(20 mL) to give 0.31 g (85%) of acid (±)-3a as white powder, mp 165-167 C. H NMR (400 MHz,
DMSO):  2.30 (s, 3H), 2.40-2.50 (m, 2H), 2.97-3.17 (m, 2H), 3.48 (s, 3H), 4.46 (s, 1H), 7.10-7.30 (m,
3H), 10.33 (s, 1H), 12.42 (s, 1H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175 and 3225 (NH and OH) cm-1.
MS m/z 359 (M+), 327, 281, 209. Anal. Calcd for C18H18N2O4S: C 60.32 H, 5.06; N 7.82. Found: C 60.25,
H 5.17, N 7.88.
1.7. Methyl 6-carboxyethylsulfanyl-4-(2-chlorophenyl)-5-cyano-2-methyl-1,4-dihydro-pyridine-3-
carboxylate ((±)-3b)
Compound (±)-3b was prepared in the same manner as (±)-3a using thione 1b instead of 1a. Yield 0.29 g
1
(69%) of acid (±)-3b as white powder, mp 177-180 C. H NMR (400 MHz, DMSO):  2.30 (s, 3H),
2.51-2.44 (m, 2H), 2.98-3.18 (m, 2H), 3.42 (s, 3H), 5.07 (s, 1H), 7.21-7.37 (m, 4H), 9.54 (s, 1H), 12.42 (s,
1H), IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175, 3225 (NH and OH) cm-1. MS m/z 393 (M+), 375, 281,
209. Anal. Calcd for C18H17ClN2O4S: C 55.03; H 4.36; N 7.13. Found: C 54.48; H 4.32; N 6.90.
1.8. Ethyl
6-carboxyethylsulfanyl-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl-1,4-dihydro-
pyridine-3-carboxylate ((±)-3c)
Compound (±)-3c was prepared in the same manner as (±)-3a using thione 1c instead of 1a. Yield 0.31 g

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HETEROCYCLES, Vol. 89, No. 1, 2014
(85%) of acid (±)-3c as white powder, mp 105-107 C. 1H NMR (400 MHz, CDCl3):  1.11 (t, J = 7.0 Hz,
3H), 2.27 (s, 3H), 2.46-2.52 (m, 2H), 3.01-3.22 (m, 2H), 3.60 (s, 3H), 3.69 (s, 3H), 3.77 (s, 3H), 3.99 (q, J
= 7.0 Hz, 3H), 4.44 (s, 1H), 6.39 (s, 2H), 9.51 (s, 1H), 12.40 (s, 1H). IR (Nujol) 1685 (C=O), 2216 (C≡N),
3175, 3225 (NH and OH) cm-1. MS m/z 462 (M+), 447, 432, 309, 277, 223. Anal. Calcd for C22H26N2O7S:
C 57.13, H 5.67, N 6.06. Found: C 57.25, H 5.49, N 6.32.
1.9. Methyl
6-carboxyethylsulfanyl-5-cyano-4-(2-difluoromethoxyphenyl-2-methyl-1,4-dihydro-
pyridine-3-carboxylate ((±)-3d)
Compound (±)-3d was prepared in the same manner as (±)-3a using thione 1d instead of 1a. Yield 0.27 g
1
(64%) of acid (±)-3d as white powder, mp 157-158 C. H NMR (400 MHz, DMSO):  2.26 (s, 3H),
2.43-2.48 (m, 2H), 2.95-3.17 (m, 2H), 3.40 (s, 3H), 4.87 (s, 1H), 7.17-7.39 (m, 3H), 9.49 (s, 1H), 12.37 (s,
1H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175 and 3225 (NH and OH) cm-1. MS m/z 425 (M+), 405, 385,
333, 281. Anal. Calcd for C19H18F2N2O5S: C 53.77, H 4.27, N 6.60. Found: C 53.84, H 4.20, N 6.51.
1.10. General procedure of preparative Candida antarctica lipase B, Novozyme 435 (CAL-B)
catalyzed hydrolysis of esters (±)-2.
1 mmol of ester (±)-2 was dissolved in 2 mL of CH2Cl2 and appropriate amount of water-saturated
diisopropyl ether was added as mentioned in Table 1 to give substrate concentration (0.0025 mol/L) and
ratio between d CH2Cl2 and water-saturated diisopropyl ether. Then 0.4 g of Novozyme 435®
(≥10,000 U/g) was added and the reaction mixture was placed in an incubator – shaker (45 C) and stirred
at 300 rpm. Every 10-20 min a 10-20 L samples were taken with a syringe from the reaction mixture,
transferred into the 1 mL vial containing 75% of MeCN - water solution. Obtained solution was stirred
for 15 sec and analysed by HPLC. Reaction was stopped when ~ 50% of acid 4 was formed. Blank
reactions without enzyme showed no conversion of substrate. The enzyme was separated from the
reaction mixture by filtration. Filtrate was evaporated to dryness under reduced pressure at 50 C and the
residue was purified by flash chromatography. Purified acids (+)-3 and esters (-)-2 were analyzed by
HPLC.
1.11. (+)-Methyl
6-carboxyethylsulfanyl-5-cyano-2-methyl-4-phenyl-1,4-dihydropyridine-3-
carboxylate ((+)-3a)
1
0.17 g (47%) of acid (+)-3a as white powder, mp 165-167 C. H NMR (400 MHz, DMSO):  2.30 (s,
3H), 2.40-2.50 (m, 2H), 2.97-3.17 (m, 2H), 3.48 (s, 3H), 4.46 (s, 1H), 7.10-7.30 (m, 3H), 10.33 (s, 1H),
12.42 (s, 1H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175, 3225 (NH and OH) cm-1. MS m/z 359 (M+),

HETEROCYCLES, Vol. 89, No. 1, 2014
53
327, 281, 209. Anal. Calcd for C18H18N2O4S: C 60.32 H, 5.06; N 7.82. Found: C 60.22, H 5.19, N 7.88.
[]20D +168.6 (c 1.0, MeOH).
1.12. (+)-Methyl 6-carboxyethylsulfanyl-4-(2-chlorophenyl)-5-cyano-2-methyl-1,4-dihydropyridine-
3-carboxylate ((+)-3b)
1
0.19 g (48%) of acid (+)-3b as white powder, mp 177-180 C. H NMR (400 MHz, DMSO):  2.30 (s,
3H), 2.51-2.44 (m, 2H), 2.98-3.18 (m, 2H), 3.42 (s, 3H), 5.07 (s, 1H), 7.21–7.37 (m, 4H), 9.54 (s, 1H),
12.42 (s, 1H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175, 3225 (NH and OH) cm-1. MS m/z 393 (M+),
375, 281, 209. Anal. Calcd for C18H17ClN2O4S: C 55.03; H 4.36; N 7.13. Found: C 54.86; H 4.25; N 6.88.
[]20D +171.9 (c 1.0, MeOH).
1.13. (+)-Ethyl
6-carboxyethylsulfanyl-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl-1,4-dihydro-
pyridine-3-carboxylate ((+)-3c)
0.21 g (46%) of acid (+)-3c as white powder, mp 105-107 C. 1H NMR (400 MHz, DMSO):  1.11 (t, J =
7.0 Hz, 3H), 2.27 (s, 3H), 2.46-2.52 (m, 2H), 3.01-3.22 (m, 2H), 3.60 (s, 3H), 3.69 (s, 3H), 3.77 (s, 3H),
3.99 (q, J = 7.0 Hz, 3H), 4.44 (s, 1H), 6.39 (s, 2H), 9.51 (s, 1H), 12.40 (s, 1H). IR (Nujol) 1684, 1712
(C=O), 2198 (C≡N), 3240 (NH) cm-1. MS m/z 462 (M+), 447, 432, 309, 277, 223. Anal. Calcd for
C22H26N2O7S: C 57.13, H 5.67, N 6.06. Found: C 57.29, H 5.51, N 6.38. []20D +182.1 (c 1.0, MeOH).
1.14. (-)-Methyl
5-cyano-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylate ((-)-2a)
1
0.30 g (49%) of ester (-)-2a as white powder, mp 109-110 C. H NMR (400 MHz, CDCl3):  2.43 (s,
3H), 2.60-2.76 (m, 2H), 2.97-3.20 (m, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 4.64 (s, 1H), 7.17–7.29 (m, 4H),
7.99 (s, 1H). IR (Nujol) 1714 (C=O), 2198 (C≡N), 3309 (NH) cm-1. MS m/z 373 (M+), 342, 296, 287.
Anal. Calcd for C19H20N2O4S: C 61.27; H 5.41; N 7.52. Found: C 61.20; H 5.44; N 7.49. []20D -127.8 (c
1.0, MeOH), 95% ee.
1.15. (-)-Methyl
4-(2-chlorophenyl)-5-cyano-6-(2-methoxycarbonyl-ethylsulfanyl)-2-methyl-1,4-
dihydropyridine-3-carboxylate ((-)-2b)
1
0.29 g (46%) of ester (-)-2b as white powder, mp 109-110 C. H NMR (400 MHz, CDCl3):  2.45 (s,
3H), 2.67-2.75 (m, 2H), 2.96-3.25 (m, 2H), 3.56 (s, 3H), 3.79 (s, 3H), 5.29 (s, 1H), 7.10-7.35 (m, 4H),
8.15 (s, 1H). IR (Nujol) 1714 (C=O), 2198 (C≡N), 3309 (NH) cm-1. MS m/z 407 (M+), 377, 343, 295, 289,
209. Anal. Calcd for C19H19ClN2O4S: C 56.09; H 4.70; N 6.88. Found: C 55.95; H 4.58; N 6.78. []20
D

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HETEROCYCLES, Vol. 89, No. 1, 2014
-134.9 (c 1.0, MeOH), 92% ee.
1.16. (-)-Ethyl 5-cyano-6-(2-methoxycarbonylethylsulfanyl)-2-methyl-4-(3,4,5-trimethoxyphenyl)-
1,4-dihydropyridine-3-carboxylate ((-)-2c)
0.38 g (46%) of ester (-)-2c as white powder, mp 138-139 C. 1H NMR (400 MHz, CDCl3):  1.11 (t, J =
7.0 Hz, 3H), 2.39 (s, 3H), 2.58-2.68 (m, 2H), 2.94-3.10 (m, 2H), 3.71 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H),
3.77 (s, 3H), 3.99 (q, J = 7.0 Hz, 3H), 4.58 (s, 1H), 6.39 (s, 2H), 7.88 (s, 1H). IR (Nujol) 1684, 1712
(C=O); 2198 (C≡N); 3240 (NH) cm-1. MS m/z 499 (M+Na+), 447, 432, 309, 277, 223. Anal. Calcd for
C23H28N2O7S: C 57.97, H 5.92, N 5.88. Found: C 57.89, H 5.91, N 5.81. []20 -152.9 (c 1.0, MeOH),
D
92% ee.
1.17. (+)-Methyl 5-cyano-6-methoxycarbonylethylsulfanyl-2-methyl-4-phenyl-1,4-dihydropyridine-
3-carboxylate ((+)-2a)
A mixture of acid (+)-3a (0.11 g, 0.3 mmol) and 0.5M diazomethane ether solution (1.0 mL) in CH2Cl2 (7
mL) was stirred for a 10 min at room temperature. After 10 min reaction mixture was evaporated to
dryness under reduced pressure at 50 C to give 0.10 g (97%) of ester (+)-2a as oil. 1H NMR (400 MHz,
CDCl3):  2.43 (s, 3H), 2.60-2.76 (m, 2H), 2.97-3.20 (m, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 4.64 (s, 1H),
7.17-7.29 (m, 4H), 7.99 (s, 1H). IR (Nujol) 1714 (C=O), 2198 (C≡N), 3309 (NH) cm-1. MS m/z 373 (M+),
342, 296, 287. Anal. Calcd for C19H20N2O4S: C 61.27; H 5.41; N 7.52. Found: C 61.18; H 5.47; N 7.43.
[]20D +120.3 (c 1.0, MeOH), 93% ee.
1.18. (+)-Methyl
4-(2-chlorophenyl)-5-cyano-6-methoxycarbonylethylsulfanyl-2-methyl-1,4-
dihydropyridine-3-carboxylate (+)-2b
Compound (+)-2b was prepared in the same manner as (+)-2a. Yield 0.10 g (97%) of ester (+)-2b as oil.
1H NMR (400 MHz, CDCl3):  2.45 (s, 3H); 2.67-2.75 (m, 2H); 2.96-3.25 (m, 2H); 3.56 (s, 3H); 3.79 (s,
3H); 5.29 (s, 1H); 7.10–7.35 (m, 4H); 8.15 (s, 1H). IR (Nujol) 1714 (C=O); 2198 (C≡N); 3309 (NH) cm-1.
MS m/z 407 (M+), 377, 343, 295, 289, 209. []20D +133.9 (c 1.0, MeOH), ee 92%.
1.19. (+)-Ethyl 5-cyano-6-methoxycarbonylethylsulfanyl-2-methyl-4-(3,4,5-trimethoxyphenyl)-1,4-
dihydropyridine-3-carboxylate (+)-2c
Compound (+)-2c was prepared in the same manner as (+)-2a. Yield 0.10 g (95%) of ester (+)-2c as oil.
1H NMR (400 MHz, CDCl3):  1.11 (t, J = 7.0 Hz, 3H); 2.39 (s, 3H); 2.58-2.68 (m, 2H); 2.94-3.10 (m,
2H); 3.71 (s, 3H); 3.75 (s, 3H); 3.76 (s, 3H); 3.77 (s, 3H); 3.99 (q, J = 7.0 Hz, 3H); 4.58 (s, 1H); 6.39 (s,

HETEROCYCLES, Vol. 89, No. 1, 2014
55
2H); 7.88 (s, 1H); IR (Nujol) 1684, 1712 (C=O); 2198 (C≡N); 3240 (NH) cm-1. MS m/z 499 (M+Na+),
447, 432, 309, 277, 223. []20D +134.9 (c 1.0, MeOH), 94% ee.
1.20. (-)-Methyl
((-)-5a)
5-cyano-2-methyl-6-methylsulfanyl-4-phenyl-1,4-dihydropyridine-3-carboxylate
A mixture of ester (-)-2a (0.37g, 1.0 mmol) and 3N NaOH/H2O (0.34 mL, 1.0 mmol) in MeOH (20 mL)
was stirred for 30 min at room temperature. Then iodomethane (0.08 mL, 1.3 mmol) was added and the
reaction mixture was stirred at 40 C for 1 h. The precipitate was separated by filtration, washed with cold
(-10 C) MeOH (5 mL) and water (20 mL) to give 0.29 g (95%) of ester (-)-5a as white powder, mp
120-121 C. 1H NMR (400 MHz, CDCl3):  2.37 (s, 3H), 2.45 (s, 3H), 3.55 (s, 3H), 5.27 (s, 1H), 5.98 (s,
1H), 7.12-7.34 (m, 5H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175 (NH) cm-1. MS m/z 301 (M+), 269,
223. Anal. Calcd for C16H16N2O2S: C 63.98, H 5.37, N 9.33. Found: C 64.12, H 5.31, N 9.24. []20
D
-104.8 (c 1.0, MeOH), 93% ee.
1.21. (-)-Methyl
4-(2-chlorophenyl)-5-cyano-2-methyl-6-methylsulfanyl-1,4-dihydropyridine-3-
carboxylate (-)-5b
Compound (-)-5b was prepared in the same manner as (-)-5a. Yield 0.32 g (94%) of ester (-)-5b as white
powder, mp 120-121 C. 1H NMR (400 MHz, CDCl3):  2.37 (s, 3H); 2.45 (s, 3H), 3.55 (s, 3H), 5.27 (s,
1H), 5.98 (s, 1H), 7.12-7.34 (m, 4H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3225 (NH) cm-1. MS m/z 335
(M+), 303, 223. Anal. Calcd for C16H15ClN2O2S: C 57.40, H 4.52, N 8.37. Found: C 57.29, H 4.63, N
8.38. []20D -110.4 (c 1.0, MeOH), 92% ee.
1.22. (+)-Methyl 5-cyano-2-methyl-6-methylsulfanyl-4-phenyl-1,4-dihydropyridine-3-carboxylate
((+)-5a)
Compound (+)-5a was prepared in the same manner as (-)-5a. Yield 0.29 g (96%) of ester (+)-5a as white
powder, mp 120-121 C. 1H NMR (400 MHz, CDCl3):  2.37 (s, 3H), 2.45 (s, 3H), 3.55 (s, 3H), 5.27 (s,
1H), 5.98 (s, 1H), 7.12-7.34 (m, 5H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3175 (NH) cm-1. MS m/z 301
(M+), 269, 223. Anal. Calcd for C16H16N2O2S: C 63.98, H 5.37, N 9.33. Found: C 64.20, H 5.30, N 9.19.
[]20D +92.6 (c 1.0, MeOH), 85% ee.
1.23. (+)-Methyl
4-(2-chlorophenyl)-5-cyano-2-methyl-6-methylsulfanyl-1,4-dihydropyridine-3-
carboxylate ((+5)-b)
Compound (+)-5b was prepared in the same manner as (-)-5a. Yield 0.32 g (95%) of ester (+)-5b as white

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HETEROCYCLES, Vol. 89, No. 1, 2014
powder, mp 120-121 C. 1H NMR (400 MHz, CDCl3):  2.37 (s, 3H), 2.45 (s, 3H), 3.55 (s, 3H), 5.27 (s,
1H), 5.98 (s, 1H), 7.12-7.34 (m, 4H). IR (Nujol) 1685 (C=O), 2216 (C≡N), 3225 (NH) cm-1. MS m/z 335
(M+), 303, 223. Anal. Calcd for C16H15ClN2O2S: C 57.40, H 4.52, N 8.37. Found: C 57.29, H 4.63, N
8.38. []20D +80.5 (c 1.0, MeOH), 92% ee.
ACKNOWLEDGEMENTS
This work was supported by European Regional Development Fund (ERDF) project no.
2010/2DP/2.1.1.1.0/10/APIA/VIAA/072 and by the European Social Fund within the project ”Support for
Doctoral Studies at University of Latvia – 2”.
The authors would like to thank Dr.chem. Arkady Sobolev and Dr.chem. Maurice Franssen for valuable
advice.
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