Candida rugosa lipase-catalyzed kinetic resolution of 3-(isobutyryloxy) methyl 4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4- dihydrobenzothieno[3,2-b]pyridine-3-carboxylate

Article abstract of DOI:10.1023/B:COHC.0000044578.17992.95

The lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b] pyridine-3-carboxylate has been performed. The most enantioselective reaction (E = 28) was transesterificatio

Full text of DOI:10.1023/B:COHC.0000044578.17992.95

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
Candida rugosa LIPASE-CATALYZED KINETIC
RESOLUTION OF 3-(ISOBUTYRYLOXY)METHYL
4-[2-(DIFLUOROMETHOXY)PHENYL]-2-METHYL-
5,5-DIOXO-1,4-DIHYDROBENZOTHIENO-
[3,2-b]PYRIDINE-3-CARBOXYLATE
A. Sobolev1, R. Zhalubovskis1, M. C. R. Franssen2, B. Vigante1, B. Chekavichus1,
G. Duburs1, and Ae. de Groot2
The lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl 4-[2-(difluoromethoxy)phenyl]-2-
methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate has been performed. The most
enantioselective reaction (E = 28) was transesterification with n-butanol in water-saturated toluene at
45°C.
Keywords: enantiopure 1,4-dihydropyridines, enzyme-catalyzed reaction, kinetic resolution,
transesterification.
The pharmacological activities of drugs depend on their interaction with biological matrices (so-called
drug targets). These drug targets, such as proteins (receptors, enzymes), nucleic acids, and biomembranes
(phospholipids and glycolipids), have complex three-dimensional structures, which are capable of recognizing
and binding specifically the ligand (drug) molecule in only one of the many possible arrangements in three-
dimensional space [1, 2]. As a result of this direct correlation between drug stereochemistry and biological
activity, the governing bodies that regulate the approval of new medicines in the USA [3, 4] and Europe [5] have
issued specific rules pertaining to the development of stereoisomeric drugs [2, 6, 7].
Chirality plays an important role in the activity of 1,4-dihydropyridines (1,4-DHPs) and both
quantitative and qualitative differences have been reported [8, 9]. The preferred method for the resolution of
monocyclic 1,4-DHPs is enzymatic kinetic resolution, often assisted by the incorporation of an enzymatically
labile group. This approach has been pioneered by the group of Sih [10] and Achiwa [11] and has been
successfully used also by our research group [12-14]. Polycyclic 1,4-DHPs in enantiopure form are desired for
extended pharmacological studies, since racemic 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 1 [15] and
5-oxo-4,5-dihydro-1,4-indeno[1,2-b]pyridines 2 [16] have exhibited various biological activities. Many
representatives of both classes of compounds (e.g., 1 [R = phenyl, 4-bromophenyl, 4-nitrophenyl] and 2b) show
coronary dilating activities [17-19]. 1,4-DHPs 2a and 2c have exhibited anticancer activities [20].
Herein, we report the Candida rugosa lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl
4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate as a
model compound for the resolution of these polycyclic 1,4-DHP derivatives.
__________________________________________________________________________________________
1
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: Arkady@osi.lv. 2 Laboratory of
Organic Chemistry, Wageningen University, 6703 HB Wageningen, The Netherlands; e-mail:
Maurice.Franssen@wur.nl. Published in Khimii Geterotsiklicheskikh Soedinenii, No. 7, 1076-1080, July, 2004.
Original article submitted February 24, 2003.
0009-3122/04/4007-0931©2004 Springer Science+Business Media, Inc.
931

R
O
R1
O
S
N
H
Me
R = H, Me, Ph, C6H4Cl-4, C6H4OMe-4, C6H4OH-4,
C6H4Br-4, C6H3(OMe)2-2,3, C6H4NO2-4,
PhCH=CH
1
R1 = COOAlk, COMe, CN, C(O)SEt, C(S)OEt, C(S)SEt
R
O
R1
N
H
Me
N
H
Ph
N
2a R =
, R1 = COOMe
2
2b R = Ph, C6H4OH-2, C6H4NO2-2 and -4;
R1 = C(O)SEt, C(O)SCH2Ph
COO
, R1 =
2c R =
N
The synthesis of enantiopure polycyclic 1,4-DHPs has been performed via lipase-catalyzed kinetic
resolution of the corresponding acyloxymethyl derivative 8. The racemic acyloxymethyl ester 8 has been
prepared in a four-step sequence as depicted in scheme 1. Thus, condensation of benzo[b]thiophen-3(2H)-one
1,1-dioxide (3) [21] with 2-(difluoromethoxy)benzaldehyde, followed by Hantzsch cyclization of the
intermediate 4 with 2-cyanoethyl 3-aminocrotonate (5), furnished the polycyclic 1,4-DHP 6 framework
according to the earlier reported method [15]. The hydrolysis of cyanoethyl ester 6 with KOH gave carboxylic
acid 7. The last step consists of the esterification of 7 with isobutyryloxymethyl chloride [13].
The choice of enzymes for primary screening was based on the previous work of our group [12-14, 22]
and literature data [11, 23]. The primary screening was carried out in water-saturated diisopropyl ether (IPE) at
45°C. Of these tested hydrolases (Lipase PS and AH, Candida antarctica lipase B [Novozym 435® and
Chirazyme L-2, c.-f., C3, lyo. (CAL-B)], Rhizomucor miehei lipase, Burkholderia cepacia lipase, and Candida
rugosa lipase [CRL]), only CRL showed significant hydrolytic activity towards substrate 8. CRL-Mediated
hydrolysis of 8 in water-saturated IPE at 45°C (Table 1, entry 1) occurred with moderate enantioselectivity
(E = 12 [24]). The very low solubility of the substrate in IPE and the moderate enantioselectivity of CRL led us
to investigate other reaction conditions. The influence of the solvent on the enantioselectivity of CRL was
studied in more detail and some examples are given in Table 1. It was found that the use of toluene as the solvent
increased the solubility of substrate 8. CRL-Catalyzed hydrolysis in toluene that was saturated with water at the
reaction temperature occurred with moderate selectivity (Table 1, entry 2). CRL was found to be not active when
toluene was used with n-butanol as nucleophile in the absence of water (Table 1, entry 3). Better results were
obtained when 5-50 mmol/l n-butanol in water-saturated toluene was used as the reaction
932

Scheme 1
O
O
OCHF2
O
O
S
a
O
S
+
OCH2CH2CN
42%
O
O
H2N
Me
5
4
3
b
49%
OCHF2
OCHF2
O
O
H
O
H
COOCH2CH2CN
O
O
S
S
OH
c, d
66%
N
Me
N
Me
H
H
7
6
e
46%
OCHF2
O
O
O
H
O
S
O
O
N
H
8
Me
Reagents and conditions: a – 2-(difluoromethoxy)benzaldehyde, AcOH, piperidine, ∆, 3 h;
b – EtOH : AcOH (20 : 1), ∆, 3 h; c – EtOH, KOH, room temperature, 3 h; d – H2O, HCl;
e – ClCH2OC(O)Pr-i, K2CO3, DMF, room temperature, 3 h
medium (Table 1, entries 4-7). Using less n-butanol at higher temperatures appeared to give the most
enantioselective reaction (E = 28) (Table 1, entry 6). The amount of water in the reaction mixture seems to be
important for the enantioselectivity of CRL, as E = 22 for the reaction where the toluene was water-saturated at
room temperature, whereas an E = 28 was obtained in the case where the toluene was water-saturated at 45°C
(Table 1, entry 6). The experimentally determined water content in toluene was around 0.045 and 0.10% at 25
and 45°C, respectively.
The monoacid 7 and the remaining ester 8 were isolated after 2 h of reaction with CRL when the
conversion reached ~30%, in order to have a good enantiomeric excess of the reaction product (eep). The
enantiomerically pure monoacid 7 appeared to have an optical rotation of -61.4° (c 0.5, acetone) whereas the
enantiomerically enriched remaining ester had an optical rotation of +29.1° (c 1.0, acetone). The remaining
substrate (+)-8 preferentially crystallises as a single enantiomer. After purification of (+)-8 via crystallization
from diluted methanol, the eep of the product was much higher than expected (94%).
933

TABLE 1. CRL-Catalyzed Kinetic Resolution of 8
Conversion
%
Entry
T, °C
Reaction medium
Ea
Time, h
eep, %
1
2
3
4
5
45
25
45
45
25
IPE/H2Ob
6
49
25
—
42
41
69
82
—
77
83
12.0±1.0
14.0±0.8
—
Toluene/H2Oc
20
4
50 mmol/l n-butanol in toluened
50 mmol/l n-butanol in toluene/H2Oe
5 mmol/l n-butanol in toluene/H2Oe
5 mmol/l n-butanol in toluene/H2Oe
5 mmol/l n-butanol in toluene/H2Of
5.5
6.0
16.0±1.4
23.0±1.6
6
7
45
45
2.0
4.5
31
25
90
89
28.0±2.8
22.0±2.7
_______
a
The enantiomeric ratio (E) was calculated using the computer program
EIVFIT [25].
b
A solution of 5 mg of 8 in 20 ml IPE that was water-saturated at room
temperature with 5 mg of CRL was shaken at 250 revolutions per minute
(rpm).
c
A solution of 5 mg of 8 in 5 ml of toluene that was water-saturated at the
reaction temperature with 5 mg of CRL was shaken at 250 rpm.
d
A solution of 5 mg of 8 in 5 ml of 50 mmol/l n-butanol in toluene with
5 mg of CRL was shaken at 250 rpm.
e A solution of 5 mg of 8 in 5 ml of 5-50 mmol/l n-butanol in toluene that
was water-saturated at the reaction temperature with 5 mg of CRL was
shaken at 250 rpm.
f A solution of 5 mg of 8 in 5 ml of 5 mmol/l n-butanol in toluene that was
water-saturated at room temperature with 5 mg of CRL was shaken at
250 rpm.
Scheme 2
OCHF2
OCHF2
O
OCHF2
O
O
O
O
O
a
O
H
H
H
O
O
O
S
+
S
O
S
O
O
*
O
O
OH
*
N
Me
N
H
Me
N
H
Me
H
rac-8
(+)-8
(-)-7
34%
94% ee
31%
91% ee
Reagents and conditions: a – Candida rugosa lipase, 5 mmol/l n-butanol solution in toluene
that was water-saturated at the reaction temperature, 2 h at 45°C
In conclusion, the Candida rugosa lipase-catalyzed kinetic resolution of 3-(isobutyryloxy)methyl
4-[2-(difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-carboxylate has
been developed. The enantioselectivity of Candida rugosa lipase can be improved by changing the reaction
medium and the temperature. The change of the reaction medium from water-saturated diisopropyl ether to
934

5 mmol/l solution of n-butanol in toluene resulted in a higher enantiomeric ratio (E = 28). This method shows
that these tricyclic compounds are accepted by CRL and that enantiomeric recognition is feasible. This opens
new avenues for the preparation of enantiopure fused 1,4-DHPs.
EXPERIMENTAL
All reagents were purchased from Aldrich, Acros or Merck and used without further purification. HPLC
grade solvents were from Labscan (Dublin, Ireland). Candida rugosa lipase, (lipase (EC 3.1.1.3) Type VII from
Candida rugosa, 875 U/mg) was purchased from Sigma. Lipase AH, and Lipase PS were gifts from Amano
Pharmaceutical Co., Ltd. (Japan). Immobilized Candida antarctica lipase B (Novozym 435®) was a gift from
Novo Nordisk A/S (Bagsvaerd, Denmark). Rhizomucor miehei lipase (Chirazyme L-9, c.-f, lyo.), Candida
antarctica lipase B (Boehringer Mannheim, Chirazyme L-2, c.-f., C3, lyo.), and Burkholderia cepacia lipase
(Chirazyme L-1, c.-f., lyo.) were gifts from Boehringer-Mannheim (Mannheim, Germany). Enzymatic reactions
were carried out in a New Brunswick Scientific Innova 4080 incubatory orbital shaker at 250 rpm. Flash column
chromatography was performed on Merck silica gel 60 (230-400 mesh or 70-230 mesh). TLC was performed on
1
20 × 20 cm Silica gel TLC-PET F254 foils (Fluka). H NMR spectra were recorded on a Bruker WH 90/DC (90
13
MHz) or a Bruker AC-E 200 (200 MHz) spectrometer. C NMR spectra were recorded on a Bruker AC-E 200
(50 MHz). Mass spectral data were determined on a AEI MS-905 mass spectrometer. Melting points were
determined on a Boetius apparatus and are uncorrected. Optical rotation values were measured with a Perkin–
Elmer 241 digital polarimeter. Elemental analyses were determined on a Carlo-Erba elemental analyzer. The
conversions and enantiomeric excesses of all enzymatic reactions were analyzed by HPLC on an
enantioselective column Chirex 3011, 4.6 × 250 mm, 5 µm (Phenomenex) using a Ginkotek 580A pump
(Germering, Germany) and an Applied Biosystems 759A absorbance detector at 254 nm or a LC-1110 pump and
a LC-1200 UV/Vis detector at 254 nm, GBC (Dandenong, Australia). The eluent was 0.05 M ammonium acetate
in MeOH at a flow rate of 1 ml/min. Peak areas were determined electronically with the Chromeleon
chromatography data system, Dionex Softron GmbH (Germering, Germany) or DP-800, GBC (Dandenong,
Australia). Water content in toluene was determined by gas chromatography, using a Hewlett Packard 5890 gas
chromatograph equipped with a thermal conductivity detector (TCD) and a Porapak QS column.
2-[2-(Difluoromethoxy)benzylidene]benzo[b]thiophen-3(2H)-one
1,1-Dioxide
(4).
Benzo-
[b]thiophen-3(2H)-one 1,1-dioxide 3 (1.64 g, 9 mmol), 2-(difluoromethoxy)benzaldehyde (1.55 g, 9 mmol), and
piperidine (0.06 ml) in acetic acid (20 ml) were stirred under reflux for 3 h. After storing in the refrigerator the
precipitated product was filtered to give 1.38 g of crude 4. The precipitate was crystallized from methanol to give
white crystals of 4 (1.27 g, 42%); mp 195-198°C. 1H NMR spectrum (DMSO-d6, 90 MHz), δ, ppm (J, Hz): 7.10-
8.40 (m, 9H, Ar–H and =CH); 7.40 (t, 1H, JH–F = 74.0, OCHF2). MS: 336 [M]+. Found, %: C 56.20; H 2.94.
C16H10F2O4S. Calculated, %: C 57.14; H 3.00.
3-(2-Cyanoethyl)
4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno-
[3,2-b]pyridine-3-carboxylate (6). To a solution of 4 (1.34 g, 4 mmol) in a mixture of ethanol (20 ml) and
acetic acid (4 ml), 2-cyanoethyl 3-aminocrotonate 5 (0.62 g, 4 mmol) was added. The reaction mixture was
stirred under reflux for 3 h. After refrigeration of the mixture, the orange precipitate was filtered off. The crude
product was crystallized from methanol–acetic acid to give a yellow powder of 6 (0.92 g, 49%); mp 230-234°C.
1H NMR spectrum (DMSO-d6, 90 MHz), δ, ppm (J, Hz): 2.40 (s, 3H, CH3, overlap with DMSO-d6); 2.70 (t, 2H,
J = 6.5, CH2CH2CN); 4.05 (t, 2H, J = 6.5, CH2CH2CN); 5.30 (s, 1H, CH); 6.90-8.10 (m, 8H, Ar-H); 6.97 (t, 1H,
JH-F = 76.0, OCHF2); 9.80 (s, 1H, NH). MS: 472 [M]+. Found, %: C 57.79; H 3.74; N 5.59; S 6.57.
C23H18F2N2O5S. Calculated, %: C 58.47; H 3.84; N 5.93; S 6.79.
4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-
carboxylic Acid (7). Compound 6 (1.89 g, 4 mmol) in ethanol (20 ml) was heated under reflux until dissolution
was complete, after which it was cooled down. Crushed KOH (0.28 g, 5 mmol) was added to the reaction
935

mixture at room temperature and this mixture was then stirred for 3 h at the same temperature before being
evaporated. The residue was diluted with water. The ice-cooled solution was acidified with diluted aqueous HCl
to pH 4.0-5.0. The precipitated product was filtered off, washed with water, and crystallized from methanol to
1
give a yellow powder of 7 (1.11 g, 66%); mp 223-225°C. H NMR spectrum (DMSO-d6, 90 MHz), δ, ppm
(J, Hz): 2.40 (s, 3H, CH3, overlap with DMSO-d6); 5.30 (s, 1H, CH); 6.98 (1H, t, JH–F = 76.0, OCHF2); 7.04-8.10
(m, 8H, Ar–H); 9.55 (br. s, 1H, NH); 10.90 (br. s, 1H, COOH). Found, %: C 56.95; H 3.52; N 3.39; S 7.71.
C20H15F2NO5S. Calculated, %: C 57.28; H 3.60; N 3.34; S 7.65.
3-(Isobutyryloxy)methyl 4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzo-
thieno[3,2-b]pyridine-3-carboxylate (8). To a solution of 7 (0.53 g, 1.3 mmol) in dry DMF (7 ml), K2CO3
(0.21 g, 1.5 mmol) was added at room temperature and the reaction mixture was stirred for 2 h, after which
isobutyryloxymethyl chloride (0.22 g, 1.6 mmol) was added. The mixture was stirred for 3 h, poured into ice
cold water, and extracted with CHCl3. The organic layer was washed with water (three times) and brine, dried
over MgSO4, and evaporated. The remaining residue was crystallized from methanol to give 0.30 g (46%) of 8 as
1
a yellow powder; mp 185-187°C. H NMR spectrum (CDCl3, 200 MHz), δ, ppm (J, Hz): 1.05 (d, 3H, J = 6.9,
CHCH3); 1.07 (d, 3H, J = 6.9, CHCH3); 2.40 (septet, 1H, J = 6.9, CH(CH3)2); 2.44 (s, 3H, CH3); 5.43 (s, 1H,
CH); 5.69 (ABq, 2H, OCH2O); 6.54 (t, 1H, JH–F = 74.4, OCHF2); 6.59 (br. s, 1H, NH); 7.00-7.64 (m, 8H, Ar–H).
MS: 519 [M]+. Found, %: C 57.64; H 4.35; N 2.64; S 6.26. C25H23F2NO7S. Calculated, %: C 57.80; H 4.46;
N 2.70; S 6.17.
Candida Rugosa Lipase-catalyzed Kinetic Resolution of Racemic 8. To a solution of 8 (85 mg,
0.16 mmol) in 5 mmol/l n-butanol in toluene (85 ml) that was water-saturated at 45°C was added Candida
rugosa lipase (85 mg) and the resulting mixture was shaken for 2 h at 45°C. The reaction mixture was diluted
with acetonitrile (200 ml), evaporated and directly flash chromatographed on silica gel with chloroform–
petroleum ether (bp 40-60°C)–acetone–ethanol (9:7:2:2) to give (–)-7 and (+)-8. The ee’s of both compounds
were determined after crystallisation.
(–)-4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydrobenzothieno[3,2-b]pyridine-3-
carboxylic Acid ((–)-7). Yield 21 mg (31%) as a yellow powder from methanol–water; mp 166-167°C; 91% ee;
1
[α]D20 -61.4 (c 0.5, acetone). H NMR spectrum (DMSO-d6, 200 MHz), δ, ppm (J, Hz): 2.46 (s, 3H, CH3); 5.36
(s, 1H, CH); 6.98 (t, 1H, JH–F = 74.3, OCHF2); 7.03-7.34 (m, 4H, Ar–H); 7.58-8.08 (m, 4H, Ar–H); 9.71 (br. s,
1H, NH). 13C NMR spectrum (DMSO-d6, 50 MHz), δ, ppm (J, Hz): 18.35 (CH3); 30.12 (CH); 102.07 (C);
110.16 (C); 116.82 (CH, t, JC–F = 250.0, OCHF2); 116.83 (CH); 120.27 (CH); 121.20 (CH); 125.19 (CH); 126.04
(C); 128.07 (CH); 130.00 (CH); 130.65 (CH); 132.93 (CH); 135.36 (C); 135.75 (C); 137.86 (C); 146.22 (C);
148.31 (C); 167.75 (C). Found, %: C 56.72; H 3.40; N 3.37; S 7.75. C20H15F2NO5S. Calculated, %: C 57.28;
H 3.60; N 3.34; S 7.65.
(+)-3-(Isobutyryloxy)methyl
4-[2-(Difluoromethoxy)phenyl]-2-methyl-5,5-dioxo-1,4-dihydro-
benzothieno[3,2-b]pyridine-3-carboxylate ((+)-8). Yield 29 mg (34%) as a yellow powder from methanol–
water; mp 85-86°C; 94% ee; [α]D20 +29.1 (c 1.0, acetone). 1H NMR (DMSO-d6, 200 MHz), δ, ppm (J, Hz): 0.92
(d, 3H, J = 6.9, CHCH3); 0.97 (d, 3H, J = 6.9, CHCH3); 2.39 (septet, 1H, J = 6.9, CH(CH3)2); 2.48 (s, 3H, CH3);
5.34 (s, 1H, CH); 5.62 (ABq, 2H, J = 5.8, OCH2O); 7.02 (t, 1H, JH–F = 74.2, OCHF2); 7.07-7.32 (m, 4H, Ar–H);
7.60-8.09 (m, 4H, Ar–H); 9.99 (br. s, 1H, NH). 13C NMR spectrum (DMSO-d6, 50 MHz), δ, ppm (J, Hz): 18.00
(CH3); 18.04 (CH3); 18.69 (CH3); 29.90 (CH); 32.61(CH); 78.26 (CH2); 99.63 (C); 110.94 (C); 116.56 (CH);
116.75 (CH, t, JC–F = 255.1 Hz, OCHF2); 120.38 (CH); 121.27 (CH); 125.02 (CH); 125.76 (C); 128.25 (CH);
129.87 (CH); 130.77 (CH); 133.03 (CH); 134.88 (C); 135.02 (C); 137.71 (C); 148.47 (C); 149.61(C); 164.50
(C); 174.58 (C). MS: 519 [M]+. Found, %: C 57.50; H 4.31; N 2.62; S 6.29. C25H23F2NO7S. Calculated, %:
C 57.80; H 4.46; N 2.70; S 6.17.
Financial support by NATO (Linkage grant LST.CLG 974948) and Programme 04.12 of the Latvian
Council of Science is gratefully acknowledged.
936

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