Catalytic asymmetric oxidation of sulfide with titanium-mandelic acid complex: Practical synthesis of (S)-3-[1-(2-methylphenyl)imidazol-2-ylsulfinyl]propan-1-ol, the key intermediate of OPC-29030

Article abstract of DOI:10.1016/S0040-4020(01)00152-1

An effective catalytic asymmetric oxidation of prochiral sulfide 1a to (S)-2a has been achieved by the use of chiral titanium-mandelic acid complex. The enantioselectivity was found to be not influenced by moisture, and moderate to high selectivity (76% e

Full text of DOI:10.1016/S0040-4020(01)00152-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2739±2744
Catalytic asymmetric oxidation of sul®de with titanium±mandelic
acid complex: practical synthesis of
(S)-3-[1-(2-methylphenyl)imidazol-2-ylsul®nyl]propan-1-ol, the
key intermediate of OPC-29030
Masato Matsugi,p Norio Fukuda, Yasuaki Muguruma, Taizo Yamaguchi, Jun-ichi Minamikawa
and Sei Otsuka
Process Research Department, Second Tokushima Factory, Otsuka Pharmaceutical Co. Ltd., 224-18, Ebisuno, Hiraishi, Kawauchi-Cho,
Tokushima 771-0182, Japan
Received 26 December 2000; accepted 5 February 2001
AbstractÐAn effective catalytic asymmetric oxidation of prochiral sul®de 1a to (S)-2a has been achieved by the use of chiral titanium±
mandelic acid complex. The enantioselectivity was found to be not in¯uenced by moisture, and moderate to high selectivity (76% ee) was
obtained at room temperature (258C). Thus a practical synthetic method for the platelet adhesion inhibitor, OPC-29030, was established
utilising asymmetric oxidation of 1a. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ee by one recrystallization from methanol. As a result, we
could obtain optically pure 2a in 42% overall yield from
prochiral 1a1 (Scheme 1). Due to the unsatisfactory low
optical yield, we tried to ®nd out a better stereoselective
mono-oxidation method for the sul®de.
(S)-(1)-3,4-Dihydro-6-[3-(1-o-tolyl-2-imidazolyl)sul®nyl-
propoxy]-2(1H)-quinolinone (OPC-29030, Fig. 1) is known
as a sul®nyl derivative which exhibits potent inhibition of
the platelet adhesion by interfering with the release of 12(S)-
hydroxyeicosatetraenoic acid (12-HETE) from platelets.1,2
In this article, we wish to report the details of the study
regarding the practical asymmetric oxidation of 1a to give
(S)-2a, which is a key intermediate for the synthesis of
OPC-29030.
The present synthetic method to obtain the optically pure
OPC-29030 involves Sharpless±Kagan oxidation3,4 of 3-[1-
(2-methylphenyl)imidazol-2-ylthio]propan-1-ol 1a5 as a
key step to introduce chirality to the molecule. However,
the reaction proceeded with only 54% ee and the corre-
sponding sulfoxide 2a was isolated in 78% yield, although
the optical purity of 2a was easily raised to more than 99.5%
2. Results and discussion
First of all, we examined some well-known asymmetric
oxidation methods6±9 on 1a, which resulted in lower optical
yields (Scheme 2). Then, we focussed on the Sharpless±
Kagan method, since titanium(IV) was already claimed to
be a good metal for the mono-oxidation of sul®de 1a.4 We
examined various kinds of mono-, bi- and tridentate ligands
instead of the usual tartaric ester (Table 1).10
O
(S)
N
H
N
+
N
S
O
-
O
As is clear from Table 1, chiral mandelic acid gave the best
result.11 The enantiomeric excess (76% ee)12 obtained by
this ligand is superior to that from the Sharpless±Kagan
oxidation. As a next step, we examined the reaction with
some mandelic acid derivatives and found that the presence
of a free a-hydroxy carboxylic acid moiety is essential to
exhibit high selectivity (Table 1).
Figure 1. Inhibitor of the platelet adhesion OPC-29030.
Keywords: asymmetric induction; catalysts; oxidation; sulfoxides; titanium
and compounds.
Corresponding author. Present address: Department of Materials Chem-
istry, Graduate School of Engineering, Osaka University, Suita Osaka
565-0871, Japan. Fax: 181-6-6879-7930;
e-mail: matsugi@ap.chem.eng.osaka-u.ac.jp
p
The reaction was con®rmed to proceed in catalytic way. The
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00152-1

2740
M. Matsugi et al. / Tetrahedron 57 (2001) 2739±2744
(+)-DET(2 equiv.)
N
N
+
S
CHP(1 equiv.)
OH
NCS
OH
NH2
1)
2)
S
N
Ti(OiPr)4(0.5 equiv.)
MS4A in CH2Cl2, -20 ˚C
54% ee
EtO
Br
N
-
O
OH
Y = 87.6% (2 steps)
(S)-2a
1a
O
N
H
(S)
Recrystallization
1) MsCl
2)NaO
N
+
S
N
O
42% (from 1a)
-
N
H
O
> 99.5% ee
O
Y = 63.9% (2 steps)
OPC-29030
Scheme 1. Present synthetic route of OPC-29030.
a) 4% ee (S) 6
b) 36% ee (S)7
c) 12% ee (R) 8
d) 14% ee (S) 9
N
N
OH
+
OH
S
N
S
N
*
-
O
Asymmetric Oxidation
2a
1a
Scheme 2. Asymmetric oxidation of sul®de 1a using known procedures. (a) (1)-DET (1 equiv.), CHP (1 equiv.), Ti(OiPr)4 (0.5 equiv.), H2O (0.5 equiv.),
MS4A in C2H4Cl2, 2308C. (b) (1)-Binaphthol (1 equiv.), CHP (1 equiv.), Ti(OiPr)4 (0.5 equiv.), MS4A in CH2Cl2, 258C. (c) (1)-(10-Camphorsulfonyl)ox-
aziridine (Davis reagent) in CH2Cl2, 258C. (d) (2)-N,N0-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese chloride (Jacobsen's catalyst),
H2O2 tBuOH soln. in MeCN, 258C.
Table 1. Asymmetric oxidation of 1a using various titanium complexes10
Chiral Ligand (2 equiv.)
Ti(OiPr)4 (1 equiv.)
N
N
+
S
OH
OH
CHP (1 equiv.)*
MS4
S
N
N
*
-
O
CH2Cl2 rt
2a
1a
ee (%)**(config.) [yield (%)]
*CHP: Cumene hydroperoxide; the commercial product was used without further puri®cation. **Enantiomeric excess was determined by HPLC
(CHIRALCELw OJ)
O
O
OMe
OH
HO
HO
O
O
OH
HO
O
Ph
OH
O
O
O
O
HO
N
O
Ph
O
O
O
OH
O
O
3 (S) [74]
2 (R) [97]
12 (S) [52]
2 (S) [76]
10 (S) [78]
1 (S) [75]
Ph
Ph
Ph
Ph
O
O
Ph
Ph
OH OH
OH
OH
OH
OH
OH
OH
Ph
HO
OH
OH OH
Ph
66 (S) [17]
4 (R) [40]
22 (R) [35]
3 (R) [71]
10 (S) [36]
2 (R) [70]
Ph
HN
CO2H
O
Me
O
O
N
NH2
Ph
Ph
Ph
NO2
OH
Ph
OH
N
H
Ph
NH2
H2N
NH2
OH
OH
O2N
NO2
NO2
15 (S) [29]
5 (S) [8]
3 (S) [81]
0 [8]
31 (S) [16]
13 (R) [62]
Me
CO2H
OMe
Me
OH
CO2H
NH2
CO2H
OH
CO2Me
OH
CO2H
HO
76 (S) [74]
39 (S) [39]
5 (R) [43]
2 (R) [34]
- [6]
48 (S) [63]

M. Matsugi et al. / Tetrahedron 57 (2001) 2739±2744
2741
correlation between the amount of the titanium complex and
ee of the product is shown in Fig. 2. The optimised molar
ratio, that is, sul®de/Ti(OiPr)4/mandelic acid is 1:0.4:0.6.
The presence of water in the reaction medium has no signi®-
cant in¯uence on the stereoselectivity, however, the reaction
rate is slightly reduced (Table 2, entry 2). This result is
surprising, because in the usual Sharpless oxidation, even
the presence of a small amount of water greatly in¯uences
the stereoselectivity by changing the aggregation state of
the chiral titanium complex13 The remarkable feature that
the presence of water does not affect the stereoselectivity of
the product in the present study is particularly useful for
large-scale synthesis.
In our reaction, the substituent group (R) attached to the
a-hydroxy carboxylic acid moiety plays an important role
to exhibit the high enantioselectivity. It is also found that the
electron-donating ability of the aryl function is a more
important factor than the steric effect (Table 2, entries
3±6). These trends suggest that p-stacking effect is
probable14 in the enantioselectivity determining step.
Figure 2. The correlation between the amount of titanium complex and ee
of the product.
Terminal hydroxyl function of 1a is observed to be essential
Table 2. Catalytic oxidation using various titanium±a-hydroxycarboxylic acid complexes
CO2H
R
(0.6 equiv.)
OH
Ti(OiPr)4 (0.4 equiv.)
CHP (1 equiv.)
MS4A
N
N
+
OH
OH
S
S
N
N
O -
(S)-2a
CH2Cl2
25 °C, 7 hr
1a
Entry
R
Yield of 2 (%)
Ee of 2 (%)a
1
Ph
Ph
89
56
63
70
89
69
76
75
77
51
48
31
2b
3
p-Methoxyphenyl
p-Chlorophenyl
Cyclohexyl
4
5
6
Isopropyl
a
Enantiomeric excess was determined by HPLC (CHIRALCELw OJ).
In the presence of H2O (1 equiv.) instead of MS4A.
b
Table 3. Effect of hydroxyl function and chain length (**the absolute con®guration was estimated by the retention time observed in chiral HPLC)
Ph
CO2H
(0.6 equiv.)
OH
Ti(OiPr)4 (0.4 equiv.)
N
N
R
R
CHP (1 equiv.)
MS4A
S
S
N
N
O-
(S*)-2a-d**
Ee of 2 (%)a
CH2Cl2
1
25 °C, 7 hr
Entry
R
Yield of 2 (%)
1
2
3
Me:
1b
1c
91
91
89
48
6
49
76
27
:
OH
:
1a
OH
OH
4
: 1d
a
Enantiomeric excess was determined by HPLC (CHIRALCELw OJ).

2742
M. Matsugi et al. / Tetrahedron 57 (2001) 2739±2744
JASCO DIP-360 polarimeter. E. Merck silica gel 60 (70±
230 mesh ASTM) was used for column chromatography.
H
O L O
Ti
L = iPrO
Ph
O
CHP
N
Sulfoxide
3.1.1. 1-o-Tolyl-1H-imidazole-2-thiol.1 This compound
was essentially prepared by the published method.1 To a
solution of 1100 g of 2-methylphenyl isothiocyanate
(7.37 mol) in 556 ml of methanol was added 780 g of 2,2-
N
Ar =
O L S
Ar
Scheme 3. Speculated structure of titanium complex.
(R)-Mandelic acid (0.6 equiv.)
CHP(1 equiv.)
Ti(OiPr)4(0.4 equiv.)
N
N
+
S
OH
OH
S
N
N
-
O
Zeolite in CH2Cl2, 25 °C
O
(S)-2a
(S)
1a
26.7 kg
N
H
2 steps15
N
Recrystallization
+
S
N
(S)-2a
O
54.9 % (from 1a)
16.8 kg
99.7% ee
-
O
OPC-29030
Scheme 4. Large-scale synthesis of OPC-29030 via practical asymmetric oxidation.15
to obtain the high enantioselectivity (Table 3, entry 1) and
the length of carbon chain attached to the hydroxyl also
in¯uences the stereoselectivity (Table 3, entries 2±4).
dimethoxyethylamine (7.42 mol) at 68C under stirring. Stir-
ring was continued for 1 h at 6±388C and then conc. HCl
(780 g) was added to the mixture. Stirring was continued for
1 h at 37±508C. After the addition of 12.0 kg of water, the
mixture was heated at 908C for 4 h and allowed to reach
room temperature and resulted precipitate was collected by
®ltration. After washing with 3.30 kg of water followed by
drying at 608C gave 1292 g (92.1%) of 1-o-tolyl-1H-imida-
zole-2-thiol. This was employed in the next step without
From the following two facts, (1) the necessity of a free
a-hydroxyl carboxylic acid function in the ligand, and (2)
no signi®cant in¯uence of water regarding the selectivity, it
is suggested that the reaction may proceed via rigid chelate
complex as shown in Scheme 3.
1
further puri®cation. H NMR (CDCl3, 200 MHz) d 2.14
Finally, the present method was scaled-up in pilot plant and
satisfactory results were obtained (Scheme 4).15 Several
bene®cial aspects of the present oxidation method in
large-scale production are obvious from the following
observations. (1) The reaction proceeds at ambient tempera-
ture (258C) affording products with moderate to high
enantioselectivity. (2) The chiral ligand, i.e. mandelic
acid, is cheap enough and could be recovered readily by
extracting with a weak base. (3) No care is necessary for
atmospheric moisture.
(s, 3H), 6.72 (d, Jˆ1.6 Hz, 1H), 6.83 (d, Jˆ1.6 Hz, 1H),
7.29±7.40 (m, 4H), 12.31 (bs, 1H). Anal. calcd for
C10H10N2S: C, 63.13; H, 5.30; N, 14.72; found: C, 62.97;
H, 5.24; N, 14.42.
4. Sul®des (1a±d)
4.1. General procedure, preparation of 1a2
To a solution of 10.01 g of 1-o-tolyl-1H-imidazole-2-thiol
(52.61 mmol) in 80 ml of isopropylalcohol was added
5.31 g of 3-chloro-1-propanol (56.12 mmol), 2.30 g of
sodium hydroxide and 20 ml of deionized water at 258C
under stirring. Stirring was continued for 2.5 h under re¯ux.
The mixture was allowed to reach room temperature and
then 70 ml of water and 50 ml of toluene were added to
the mixture. The organic layer was separated, dried
(MgSO4) and concentrated in vacuo. The residue was
puri®ed by short silica-gel column chromatography [eluent:
n-hexane±AcOEt (3:1, v/v)] to give 3-(1-o-tolyl-1H-
imidazol-2-ylsulfanyl)-propan-1-ol (13.04 g) in 99.8%
yield.
Attempts to extend the reaction to other substrates are the
next theme that will be studied in the near future.
3. Experimental
3.1. General
Melting points were determined on a Yamato Melting Point
Apparatus MP-21 and uncorrected. H NMR spectra were
1
recorded on a Varian XL-200 (200 MHz) and JEOL JMN-
A500 (500 MHz) using CDCl3 or DMSO-d6 as the solvent
with TMS as internal standard. Mass spectra were obtained
on a Shimadzu GCMS QP1000 or JEOL JMS SX-102A
spectrometer. The ee values were determined by HPLC on
a CHIRALCELw OJ (DAICEL) column (eluent: EtOH/
hexaneˆ1/4). Optical rotations were measured on a
4.1.1. 3-(1-o-Tolyl-1H-imidazol-2-ylthio)propan-1-ol
(1a). Colorless crystals from Et2O±n-hexane); mp 47±
1
488C. H NMR (CDCl3, 200 MHz) d 1.84±1.91 (m, 2H),
2.09 (s, 3H), 3.32 (t, Jˆ5.5 Hz, 2H), 3.73 (t, Jˆ5.3 Hz, 2H),
5.86 (bs, 1H), 6.96 (d, Jˆ1.4 Hz, 1H), 7.12 (d, Jˆ1.4 Hz,

M. Matsugi et al. / Tetrahedron 57 (2001) 2739±2744
2743
1H), 7.19±7.42 (m, 4H). Anal. calcd for C18H14N4O3S: C,
59.00; H, 3.85; N, 15.29; found: C, 58.74; H, 3.55; N, 14.99.
NMR (CDCl3, 200 MHz) d 1.65±1.95 (m, 4H), 2.10 (bs,
3H), 2.36 (bs, 1H), 3.43±3.47 (m, 2H), 3.69 (m, 2H), 7.15
(d, Jˆ1.1 Hz, 1H), 7.29 (d, Jˆ1.1 Hz, 1H), 7.36±7.47 (m,
4H); HRMS calcd for C14H19N2O2S: 279.1167; found:
279.1152.
4.1.2. 2-Methylthio-1-o-tolyl-1H-imidazole (1b). 98%
yield, colorless oil. H NMR (CDCl3, 200 MHz) d 2.09 (s,
1
3H), 2.57 (s, 3H), 6.98 (d, Jˆ1.4 Hz, 1H), 7.19 (d,
Jˆ1.4 Hz, 1H), 7.21±7.43 (m, 4H). Anal. calcd for
C11H12N2S: C, 64.67; H, 5.92; N, 13.71; found: C, 64.45;
H, 5.93; N, 13.77.
4.2.5. Large-scale synthesis of 2a. To a suspension of
zeolite 3A (28.65 kg) in dichloromethane (286.5 L) was
added 3-(1-o-tolyl-1H-imidazol-2-ylsulfanyl)-propan-1-ol
(28.65 kg, 115.36 mol), titanium tetraisopropoxide (13.13
kg, 46.19 mol) and (R)-(2)-mandelic acid (10.53 kg,
69.21 mol) at room temperature and stirred for 0.5 h.
Then, cumenehydroperoxide (21.4 kg, 140.6 mol) was
added to the above mixture below 258C and stirred for 2 h
at 22±278C. After the ®ltration of zeolite, 10% (1)-tartaric
acid solution16 (286.5 L) was added and stirred for 1 h.
Then, 20% NaOH solution (85.95 L) and 8.3% sodium thio-
sulfate solution (85.95 L) were added in succession to the
reaction mixture and further stirred for 0.5 h at room
temperature. The organic layer was separated, dried
(MgSO4) and concentrated in vacuo. The residue was
recrystallized from ethyl acetate (57.3 L) to give 16.77 kg
of almost enantiomerically pure 2a (54.9%, 99.7% ee) as
colorless crystals.
4.1.3. 2-(1-o-Tolyl-1H-imidazol-2-ylthio)ethanol (1c).
94.5% yield, colorless crystals from AcOEt; mp 84±858C.
1H NMR (CDCl3, 270 MHz) d 2.10 (s, 3H), 3.17 (t,
Jˆ4.6 Hz, 2H), 4.02 (t, Jˆ4.6 Hz, 2H), 5.99 (s, 1H),
6.98±7.40 (m, 6H). Anal. calcd for C12H14N2OS: C,
61.51; H, 6.02; N, 11.96; found: C, 61.47; H, 5.94; N, 11.96.
4.1.4. 4-(1-o-Tolyl-1H-imidazol-2-ylthio)butan-1-ol (1d).
59% yield, pale yellow viscous oil. 1H NMR (CDCl3,
200 MHz) d 1.65 (dt, Jˆ6.4, 12.8 Hz, 2H), 1.84 (dt,
Jˆ7.3, 12.8 Hz, 2H), 2.08 (s, 3H), 3.09 (t, Jˆ7.3 Hz, 2H),
3.84 (s, 1H), 3.72 (t, Jˆ6.4 Hz, 2H), 6.98 (d, Jˆ1.4 Hz, 1H),
7.17 (d, Jˆ1.4 Hz, 1H), 7.20 (d, Jˆ8.5 Hz, 1H), 7.27±7.39
(m, 3H).
4.2.6. (S)-(1)-3,4-Dihydro-6-[3-(1-o-tolyl-2-imidazolyl)-
sul®nylpropoxy]-2(1H)-quinolinone (OPC-29030). Mp
265±2688C (dec.). 1H NMR (DMSO-d6, 500 MHz) d
1.93±2.06 (m, 2H), 2.02 (s, 3H), 2.39 (t, Jˆ7.3 Hz, 2H),
2.82 (t, Jˆ7.3 Hz, 2H), 3.38 (ddd, Jˆ13.8, 8.4, 6.5 Hz, 1H),
3.47 (ddd, Jˆ13.8, 8.4, 6.5 Hz, 1H), 4.00 (t, Jˆ6.1 Hz, 2H),
6.67 (dd, Jˆ8.6, 2.7 Hz, 1H), 6.72 (d, Jˆ2.7 Hz, 1H), 6.75
(d, Jˆ8.6 Hz, 1H), 7.34±7.38 (m, 2H), 7.36 (d, Jˆ1.2 Hz,
1H), 7.47 (ddd, Jˆ7.4, 5.9, 2.4 Hz, 1H), 7.43 (bd, Jˆ7.4 Hz,
4.2. General procedure for the asymmetric oxidation
To a suspension of molecular sieves 4A in dry dichloro-
methane was added titanium tetraisopropoxide and (R)-
(2)-mandelic acid at room temperature and stirred for
0.5 h. To the mixture was added 3-(1-o-tolyl-1H-imidazol-
2-ylthio)propan-1-ol, stirred for 1 h, and then added cumene
hydroperoxide. The mixture was stirred for 2±6 h. After
concentration of the reaction mixture in vacuo, the residue
was puri®ed by column chromatography on silica gel
(CH2Cl2±MeOH as eluent) to give chiral sulfoxide.
20
1H), 7.58 (bd, Jˆ1.2 Hz, 1H), 9.73 (s, 1H); [a]D ˆ21748
(c 0.5, DMF). Anal. calcd for C22H23N3O3S: C, 64.53; H,
5.66; N, 10.26; found: C, 64.45; H, 5.65; N, 10.03.
4.2.1. (S)-3-(1-o-Tolyl-1H-imidazol-2-ylsul®nyl)propan-
1-ol (2a). 89% yield, colorless powder from AcOEt; mp
110±1118C. H NMR (CDCl3, 200 MHz) d 2.03 (m, 2H),
1
References
2.04 (s, 3H), 3.03 (bs, 1H), 3.41±3.53 (m, 2H), 3.72 (m, 2H),
7.15 (d, Jˆ1.2 Hz, 1H), 7.37 (d, Jˆ1.2 Hz, 1H), 7.27±7.46
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Bull. 1995, 43, 1724±1733.
24
(m, 4H); [a]D ˆ167.58 (c 1.0, MeOH). Anal. calcd for
C13H16N2O2S: C, 59.07; H, 6.10; N, 10.60; found: C,
58.86; H, 5.92; N, 10.30.
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4.2.2. (Sp)-2-Methylsul®nyl-1-o-tolyl-1H-imidazole (2b).
91% yield, 6% ee, colorless viscous oil. H NMR (CDCl3,
1
200 MHz) d 2.10 (bs, 3H), 3.09 (s, 3H), 7.15 (d, Jˆ1.2 Hz,
1H), 7.37 (d, Jˆ1.2 Hz, 1H), 7.31±7.41 (m, 4H); Anal.
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C, 60.11; H, 5.59; N, 12.63.
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4.2.3. (Sp)-2-(1-o-Tolyl-1H-imidazol-2-ylsul®nyl)ethanol
(2c). 91% yield, 49% ee, colorless powder from AcOEt;
mp 103±1058C. H NMR (CDCl3, 200 MHz) d 2.11 (bs,
3H), 3.40±3.64 (m, 2H), 4.06±4.14 (m, 1H), 4.33±4.40
(m, 1H), 7.15 (d, Jˆ1.1 Hz, 1H), 7.29 (d, Jˆ1.1 Hz, 1H),
7.36±7.47 (m, 4H). Anal. calcd for C12H14N2O2S: C, 57.58;
H, 5.64; N, 11.19; found: C, 57.41; H, 5.70; N, 11.08.
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1-ol (2d). 48% yield, 27% ee, pale yellow viscous oil. H
1

2744
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enantioselectivity was not at all affected.
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